Comprehensive Strategies for the Synthesis of 1,3-Enyne Derivatives

Abstract

The synthesis of 1,3-enyne has widespread appeal in organic synthesis due to their proven adaptability as intermediates in routes to compounds of significant biological and material interest. A variety of methods have been designed to formulate 1,3-enynes from diverse substrates, such as alkynes, 1,3-diynes, alkynyl-substituted cyclopropanes, and propargyl alcohols. This review covers the synthesis of 1,3-enynes utilizing the homo- and cross-coupling of alkynes, nucleophilic metal/acid-induced cyclopropane ring opening, and rearrangement/dehydration of propargyl alcohols. A key concern in procedures starting from alkynes and 1,3-diynes is the management of regio-, stereo-, and, where fitting, chemoselectivity. In contrast, in cyclopropyl ring opening nucleophile orientation determines the 1,3-enynes formed. Efficient methods for the broad and selective synthesis of 1,3-enynes are highlighted and specific examples are given to demonstrate the efficacy of these processes.

1 Introduction and Scope

2 Synthesis

2.1 Synthesis of 1,3-Enynes from Alkynes

2.1.1 Metal-Catalyzed Cross-Coupling/Additions of Alkynes with Alkenes or Vinyl or Aryl Halides

2.1.1.1 Palladium Catalysis

2.1.1.2 Rhodium Catalysis

2.1.1.3 Copper Catalysis

2.1.1.4 I ron Catalysis

2.1.1.5 Nickel Catalysis

2.1.1.6 Miscellaneous

2.2 Synthesis of Enynes from Propargyl Alcohols

2.3 Metal/Acid-Catalyzed Ring Opening of Cyclopropanes

3 Conclusion

Biographical Sketches

(from left to right) Mr. Kamal Kant completed his B.Sc. degree in 2018 from ARSD College, Delhi University and M.Sc. in 2020 from Kirorimal College North Campus, Delhi University. In February 2021, he joined as Ph.D. scholar under the supervision of Dr. Chandi C. Malakar at the Department of Chemistry, National Institute of Technology Manipur, India. His research interests involve novel method development using electrocatalysis and photocatalysis for the synthesis of N-heterocycles.

Chandresh Kumar Patel earned his B.Sc. (2015) from Veer Bahadur Singh Purvanchal University and M.Sc. Chemistry in 2018 from the National Institute of Technology(NIT) Manipur, India. In June 2019, he joined as Ph.D. scholar under the supervision of Dr. Chandi C. Malakar at the Department of Chemistry, National Institute of Technology Manipur, India. His research interests involve novel method development of novel transition-metal-catalyzed synthetic methodology towards heterocyclic compounds.

Ms. Reetu was born in Haryana, India. She completed her B.Sc. degree in 2016 and M.Sc. in 2018 from D.A.V. College sec. 10, Punjab University, Chandigarh. In Jan 2021, she joined Ph.D. under the supervision of Dr. Chandi C. Malakar in the Department of Chemistry, National Institute of Technology Manipur, India. Her research interests involves novel method development towards C–H activation, transition-metal-free catalysis, N-heterocycle synthesis.

Yaqoob A. Teli received his Master’s degree in Chemistry from RTM. Nagpur University, India in 2018. He obtained his M.Phil. degree in organic chemistry from Central University of Tamil Nadu in 2020 following studies in the area of glycolysis under the supervision of Prof. T. Mohan Das. In July 2021, he joined Ph.D. under the supervision of Dr. Chandi C. Malakar in the Department of Chemistry, National Institute of Technology Manipur, India. His research interest involves novel method development towards C–H activation and nanocatalysis.

Priyadarshini Naik received her B.Sc. degree from Shailabala Women’s Autonomous College, Ramadevi Women’s University Bhubaneswar in 2021. She obtained her M.Sc. degree in Chemistry from the National Institute of Technology (NIT) Manipur, India. She completed her Master’s project under Dr. Chandi C. Malakar. Currently she is pursuing internship at IIT-Delhi under the supervision of Dr. Chinmoy K. Hazra. Her research interest focuses on the development of novel transition-metal-free, transition-metal-catalyzed organic transformations and photocatalyzed synthetic methodology towards N-heterocyclic compounds.

Sanjukta Some was born in 1990 in Kolkata, West Bengal, India. She obtained her M.Sc. in Chemistry in 2015 from the Indian Institute of Technology (ISM) Dhanbad, India. Subsequently she worked as research associate at TCG Lifesciences Private Ltd., Kolkata & Syngene International Ltd., a Biocon company, Bangalore. Then she joined as senior research associate at Aragen Life Science in Bangalore. Currently she is working as Scientist at Aurigene Pharmaceutical Services Ltd., Bangalore.

Dr. Chinmoy Kumar Hazra is an associate professor at the Indian Institute of Technology Delhi (India). Before this, he worked as a postdoctoral scientist under the supervision of Prof. Magnus Rueping at the King Abdullah University of Science and Technology (Saudi Arabia). He also completed his 2nd postdoctoral assignment with Prof. Sukbok Chang at the Korea Advanced Institute of Science & Technology (South Korea) 2018. Moreover, He stayed at the University of Strasbourg (France) for a postdoctoral experience with Prof. Françoise Colobert. He obtained his Ph.D. from the Westfälische Wilhelms-Universität Münster (Germany) in 2013 (Ph.D. supervisor: Prof. Martin Oestreich) and his M.Sc. degree in chemistry from the Indian Institute of Technology Bombay (India) in 2010. His research interests include the development of metal-free catalysis with mechanistic understanding and synthetic applications.

Dr. Nayyef Al-Jaar received his B.Sc. (1995) from Yarmouk (Jordan), M.Sc. (2004) from Al al-Bayt University (Jordan), and Ph.D. (2013) in Organic Chemistry from the University of Hohenheim, Germany under the supervision of Professor Uwe Beifuss. He started his career as an assistant professor of organic chemistry at the department of pharmacy in Al-Ahiyya Amman University (2013–2018) and then in 2018, he moved to the department of chemistry in Hashemite University. His current research interest focuses on the development of novel transition-metal-catalyzed synthetic methodology towards heterocyclic compounds.

Dr. Ananta Kumar Atta completed M.Sc. in organic chemistry in 2003 from Vidyasagar University, West Bengal. He received Ph.D. from the Indian Institute of Technology, Kharagpur in 2010 with the thesis entitles ‘Acyclic Vinyl Sulfone-modified Carbohydrates: Synthesis and Intermediates for Carbocycles and Heterocycles’. Dr. Atta pursued his postdoctoral studies in supramolecular chemistry with Prof. Dong Gyu Cho from April 2010 to August 2013 at Inha University, Incheon, South Korea. After post-doctoral studies, he started his career at the National Institute of Technology Arunachal Pradesh as an Assistant Professor in September 2013. Currently, he is the Associate Professor of Chemistry at the National Institute of Technology Jharkhand, India. His current research mainly focuses on the design and synthesis of fluorescent and colorimetric probes for detecting metal ions and anions, and nitroaromatics. He also started to work on carbon nanotubes with their applications. He has published many reputable papers in the fields mentioned above.

Dr. Chandi C. Malakar obtained his M.Sc. degree in Chemistry from the Indian Institute of Technology Kanpur in 2006. Then, he completed Ph.D. in 2011 from the University of Hohenheim Stuttgart, Germany under the supervision of Professor Uwe Beifuss. After postdoctoral research with Prof. K. A. Tehrani at the University of Antwerp (2011–2012), Prof. Günter Helmchen at Ruprecht-Karls-Universität Heidelberg (2012–2014), Prof. P. S. Mukherjee at the Indian Institute of Science, Bangalore (2015) and industrial experience (2014–2015) as Senior Principal Scientist at SignalChem LifeSciences Pvt. Ltd., he started his career at the National Institute of Technology Jalandhar as an Assistant Professor in July 2015. Then, Dr. Malakar moved to the National Institute of Technology Manipur in October 2015 and currently, he is working as Associate Professor, and Dean Research & Consultancy. His current research interests are C–H activation, asymmetric synthesis, transition metal catalysis, organocatalysis, and electrocatalysis.

Introduction and Scope

1,3-Enynes, or conjugate enynes, are present in a multitude of biologically active natural products.[1] They also serve as critical components within organic synthesis as significant intermediates in the synthesis of highly substituted aromatic rings, 1,3-enynes can undergo double and triple bond functionalization,[2] which is of interest in materials research,[3] and they can be used in the creation of complex molecules.[4] C–C Bond formation is a remarkable phenomenon that is an essential process for the construction of diverse organic compounds.[5] In the realm of synthesis, the creation of linear molecules is a testament to the ingenuity and artistry of chemical craftsmanship. The assembly of these elongated structures confers specific functionalities, mechanical integrity, and desirable reactivity profiles, thus enabling the realization of compounds that drive fundamental biological processes, technological advancements, and material innovation.[6] Recent methodological advancements in the production of 1,3-enynes have commanded significant attention and heralded revolutionary changes within the synthetic field.[7] Since the pioneering work the Trost group in 1985, 1,3-enynes have become invaluable structures within organic chemistry.[8] There are existing protocols for the preparation of various organic moieties of 1,3-enynes[9] and various strategies for their synthesis, such as the catalytic coupling of alkynes, nucleophilic metal- or acid-catalyzed ring opening of cyclopropane, the rearrangement or dehydration cascade of propargyl alcohols, and the reduction of 1,3-diynes; these procedures are particularly appealing due to their efficiency. Significant advances have been made in this area in the past few decades. As a result, some efficient and highly atom economic methods for the preparation of 1,3-enynes and other products have been developed.[10] These methods have been applied to the synthesis of natural products and this underscores their importance in modern organic chemistry. Furthermore, the synthesis of carbocyclic and heterocyclic moieties represents a captivating saga of molecular diversity and intricacy, essential to the fabric of organic chemistry. The formation of carbocyclic frameworks, characterized by the seamless union of carbon atoms, imparts molecules with remarkable stability, geometric precision, and structural elegance.[6d] [11] Meanwhile, the synthesis of heterocyclic compounds, integrating diverse atoms such as nitrogen, oxygen, or sulfur within the carbon-based rings, yields diverse compounds, endowing molecules with a breathtaking array of bioactivities, electronic properties, and structural versatility.[6a,12] This review will discuss salient methods for the synthesis of 1,3-enynes, and particular attention will be paid to coupling reactions employing various metals due to the versatility and utility associated with these processes.

This review is organized to first introduce the systematic synthesis of 1,3-enynes via alkynes, propargyl alcohols, and cyclopropane in the scientific community.

Conjugated 1,3-enyne structures are important motifs in organic chemistry, and they are found in many compounds, such as natural products and functionalized materials.[13] In organic synthesis, the 1,3-enyne motif plays a pivotal role as a versatile building block for constructing numerous compounds such as substituted naphthalenes[14] and heterocycles.[15] Additionally, the synthesis of 1,3-enynes is of particular interest in different fields such as biology, electronics, and photonics. 1,3-enynes have found increasing application in the construction of electronic and optical materials[16] and conjugated oligo- and polymers[17] and they are present in a wide range of bioactive compounds with promising biological properties, such as caryoynenins with antimicrobial activity,[18] terbinafine with antifungal activity,[19] and NNC 61-46559, which is a peroxisome proliferator-activated receptor agonist and is used to reduce blood lipids.[20] Linear trans-1,3-enynes are an important motif found in several biologically active compounds and natural products, including oxamflatin[21] [22] a bioactive constituent isolated from Asparagus cochinchinensis (Figure [1]).[22]

Synthesis

Synthesis of 1,3-Enynes from Alkynes

There are various strategies for the successfully homo- and cross-coupling of alkynes to 1,3-enynes, primarily using transition metal catalysts. During such reactions, maintaining control over regio-, stereo-, and, when relevant, chemoselectivity, typically presents a significant challenge. In this context, notable methodologies for the selective synthesis of 1,3-enynes have been highlighted. Trost and Masters­ and Wang and co-workers published comprehensive reviews of this area in 2016.[24]

Metal-Catalyzed Cross-Coupling/Additions of Alkynes with Alkenes or Vinyl or Aryl Halides

Metal-catalyzed alkyne coupling has significant relevance for the synthesis of enyne derivatives. This section discusses the metal-catalyzed cross-coupling of alkynes with a variety of alkenes, vinyl or aryl halides, and other activated terminal alkynes with a focus on key methodologies for the selective synthesis of 1,3-enynes using advanced metal catalytic systems.

Palladium Catalysis

Unlike other metals, palladium plays a crucial role in the field of 1,3-enynes synthesis. Palladium complexes can enhance the coupling of alkynes with either alkenes or other alkynes to produce 1,3-enynes with precise regio-, stereo-, and chemoselectivity. This section will examine palladium-catalyzed cross-coupling and additions of terminal alkynes with alkynes and alkenes bearing various substitutions, as a significant tool for the synthesis of 1,3-enyne derivatives. In 1998, the Trost group reported the synthesis of 1,3-enynes with controlled stereoselectivity using palladium acetate.[23a] Using the combination of internal alkyne 2 and terminal alkyne 1 using Pd(OAc)₂ and TDMPP as the catalytic system generally regioselectively gave the product of β-addition, (E)-1,3-enynes 3. The radical-catalyzed E/Z isomerization was then exploited using catalytic diphenyl diselenide to give the (Z)-1,3-enynes 4. This strategy has shown to be a resource-efficient pathway for the synthesis of (Z)-1,3-enynes 6 (Scheme [1]).

The Trost group also found that methyl undec-10-ynoate (1a) underwent addition with 4-substituted ethyl non-2-ynoates 5b to give mixtures of β- and α-substituted products A and B, respectively (Table [1]).[23a] Using the PMB or silyl ether (TBDMS) of 5b gave greater amounts of α-substituted product B than the anticipated β-substituted product A (¹H NMR analysis). Conversely, when 5b contained a hydroxy group then β-substituted product A was obtained through β-C–C bond formation, hence this appears to be a steric issue.

In 2001, the Trost group reported a reversal in the regiochemistry of the alkyne coupling occurred using silyl-substituted alkynoates. The Pd/TDMPP-catalyzed cross-coupling of cyclopropylacetylene with ethyl 3-(dimethylphenylsilyl)propynoate gave exclusively the α-alkynylated product in 93% yield, with similar results using alkylalkynes or phenylacetylene. Thus the carbopalladation mechanism is sensitive to both steric and electronic parameters.[23b]

Trost’s methodology promotes the combined addition of the two alkynes, offering a straightforward, atom-efficient, and highly productive route. This approach strategically avoids the dimerization of the terminal alkyne because of the activation of the disubstituted alkyne acceptors by ester groups. This significant shift from homocoupling to cross-coupling using a 1:1 ratio suggests that the reaction follows a conjugate addition-type mechanism.[23]

The mechanistic aspects have been covered in detail in an excellent review by Trost in 2016, and this will not be covered in full detail here.[24a]

Table 1 Unusual Regioselectivity at α-Position of Alkynoate

R	Yield (%)
	A	B
TBDMS	66	34
PMB	77	23
H	exclusively A	–

There are potentially multiple reasons for the regioselectivity shown in Table 1[23] which can be explained by the hypothesis currently being used. The crucial step that determines the regioselectivity is the migratory insertion step involving the alkynoate and Pd-activated alkyne, as illustrated in step 5 (Scheme [2]). In the absence of any unusual effects or steric hindrance, the bond polarizes towards the α-carbon in the transition state D, resulting in carbopalladation to give F and the formation of product 6a. However, if R³ is highly bulky β-addition is disfavored on steric grounds leading to the formation of product 6b. The intermediates formed in the reaction can be clearly observed in Scheme [3].

Hara and co-workers reported the successful synthesis of 1,3-enynes through a Pd-catalyzed cross-coupling reaction between terminal alkynes and β-fluoroalkenyl iodides derived from (β-fluoroalkenyl)iodonium salts (Scheme [4]).[25] The cross-coupling of (β-fluoroalkenyl)iodonium salt 7 with hex-1-yne (1b) catalyzed by Pd(OAc)/PPh₃/CuI gave 1-fluoro-1,3-enyne 9 together with a significant amount of p-tolylhexyne (10). The formation of p-tolylhexyne (10) was suppressed by reacting (β-fluoroalkenyl)iodonium salt 7 with CuI/KI to give 1-iodo-2-fluoroalk-1-ene 8, which was then reacted in the Pd-catalyzed cross-coupling.

Optimizing the reaction conditions for the Pd-catalyzed cross-coupling, it was initially found that the use of 8 mol% of CuI resulted in the formation of a large amount of the dimer of hex-1-yne (1b). The use of 2.0 equiv. of hex-1-yne was required to obtain the product 9. Using 16 mol% of CuI was used successfully suppressed the formation of the dimer of hex-1-yne (1b) to give 9 in good yields with only 1.2 equiv. of hex-1-yne. The catalyst system for the coupling of 1-iodo-2-fluoroalk-1-ene 8 with hex-1-yne thus comprised of Pd(OAc)₂ and PPh₃, with Et₂NH as the reaction medium to give 1-fluoro-1,3-enyne 9 in 85% yield; various 1-fluoro-1,3-enynes were synthesized under these conditions with stereoselectivity >98% (Scheme [5]).

Thadani and Rawal reported the one-pot stereocontrolled synthesis of 1,3-enynes where the Pd(II) catalyst from the initial bromo- or chloroallylation step can be utilized for in situ Sonogashira cross-coupling (Scheme [6]).[26]

First the reaction of oct-4-yne and an equimolar amount of allyl bromide (11, X = Br) with PdBr₂(PhCN)₂ as the catalyst (3.0 mol%) and DME as the solvent gave alkenyl bromide 12 (R¹ = R² = Pr, X = Br). Then, CuI (1.0 equiv.), HN ⁱ Pr₂, and P ^t Bu₃ and then 2-methylbut-3-ynol were added, in that order, to the mixture containing alkenyl bromide 12 (R¹ = R² = Pr, X = Br) and the palladium catalyst and the mixture was stirred for 12 h resulting in a highly substituted functionalized 1,3-enyne 13 (R¹ = R² = Pr, R³ = CMe₂OH) in 87% yield. This process demonstrated the effectiveness of utilizing the palladium(II) catalyst from the initial bromo/chloroallylation step. Various alkynes were subjected to Sonogashira cross-coupling (Table [2]), including both terminal (entries 1–3) and internal alkynes (entries 4 and 5), which were successfully transformed into functionalized 1,3-enyne derivatives 13 in good yields.

Table 2 Scope of the Pd-Catalyzed Synthesis of Tetrasubstituted 1,3-Enynes

Entry	R1	R2	R3	Yield (%)
1	Bu	H	CMe2OH	85
2	CMe2OH	H	CMe2OH	73
3	Ph	H	CMe2OH	79
4	Pr	Pr	Ph	84
5	Pr	Pr	CMe2OH	87

Phenylacetylene underwent a tandem process to form a diketone in very good yield (Scheme [7]).[26] In this case, the initial reaction of phenylacetylene with allyl bromide using a Pd catalyst was followed by addition of CuI as the cocatalyst and H₂O under an oxygen atmosphere for a Wacker–Tsuji oxidation.

The formation of diketones via Saegusa-type oxidation proceeds through a two-step process (Scheme [8]), haloenone A is hydrolyzed with Pd(II) to form organopalladium halohydrin B followed by the removal of HX and reductive elimination to yield product 14.

In 2004, Chen and Li reported the cross-coupling of terminal alkynes with electron-deficient alkynes 15 using a combination of a palladium–phosphine complex as the catalyst and copper co-catalyst using water as the solvent to give 1,3-enynes 16 (Scheme [9]).[27] An important aspect of their approach was the prevention of the homocoupling of the terminal alkyne; the use of a Cu/Pd catalyst system, along with triphenylphosphine as a ligand source, allowed the straightforward and efficient generation of 1,3-enynes. This reaction was carried out in water, which proved to be a more convenient solvent compared to toluene.

A proposed tentative mechanism involves the activation of terminal alkyne 1 through C–H activation by Cu(I). This forms a copper acetylide compound A that undergoes transmetalation with palladium to produce palladium acetylide B. The final product 16 is generated through an addition reaction with activated alkynes 15 (Scheme [10]).

Gómez, López, and co-workers reported the synthesis of 1,3-enynes containing a carbohydrate group (Scheme [11]).[28] Using carbohydrate motifs, such as bromo or iodo-exo-glycals, that can be easily obtained from furanoses and pyranoses with a 1-exomethylene group, Sonogashira coupling with terminal alkynes using Et₂NH, Pd(PPh₃)₄, CuI, gave 1,3-enynes 18. This enyne structure was successfully in extended to enediyne compounds by employing standard Sonogashira coupling conditions. Thus, a silyl-substituted 1,3-enyne, such as 19a, was converted into the terminal 1,3-enyne 19b and then this underwent a second Sonogashira coupling with an alkynyl iodide to give a enediyne product (Scheme [12]). Additionally, the enediynes were also obtained directly from halo-exo-glycals by the Sonogashira coupling of iodo-exo-glycals with diyne compounds (Scheme [12]).

In 2005, Stefani and co-workers reported a general method for the Suzuki-type coupling of potassium alkynyltrifluoroborates 26 and vinyl tellurides 25 to give (Z)-1,3-enynes 27 in varying yields (Scheme [13]). The reaction conditions were optimized using phenyl vinyl telluride with potassium phenyltrifluoroborate and various palladium catalysts (Table [3]); palladium(II) bis(acetylacetonate) gave the best yield of 77% yield. Optimization of the base using found that Cs₂CO₃, K ^t OBu, NaOH, and KF gave the product in 34–39% yield while, K₂CO₃ improved the yield to 49%, but an amine base in dry MeOH gave the best yield. Using the optimized conditions (15.0 mol% Pd(acac)₂, 3.0 equiv. of Et₃N, dry MeOH), yields were found to be favorable compared to the traditional Suzuki reaction using organic halides (Table [3]). By utilizing commercially available Pd(acac)₂, (Z)-vinylic tellurides, and potassium organotrifluoroborate salts, this procedure is a convenient and effective method for the synthesis of 1,3-enynes (Scheme [13]).

Table 3 Optimization of the Catalyst in the Suzuki-Type Coupling of Phenyl Vinyl Telluride with Potassium Phenyltrifluoroborate

Entry	Catalyst	Yield (%)
1	PdCl2	53
2	Pd(PPh3)4	16
3	Pd(OAc)2	55
4	Pd(acac)2	77
5	Pd(dba)3	40
6	[Pd(allyl)Cl]2	68
7	PdCl2(PhCN)2	66

In 2006, Santelli, Doucet, and co-workers introduced an effective method for the Sonogashira cross-coupling reaction of vinyl bromides with terminal alkynes using palladium catalyst with a tetrakis(phosphine) to give 1,3-enynes in good yields 1,3-enynes (Scheme [14]).[30] The reaction was compatible with various alkynes, such as 2-methylbut-1-en-3-yne, 3,3-diethoxyprop-1-yne, propargylamine, dec-1-yne, a variety of alk-1-ynols, and phenylacetylene. The palladium catalyst, [PdCl(C₃H₅)]₂/cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane (Tedicyp) could be used at lower loadings for reactions involving sterically hindered vinyl bromides like 1-bromo-1,2,2-triphenylethene or 2-bromo-3-methylbut-2-ene.

In 2007, Tsukada and co-workers reported an unprecedented single step synthesis of 1,3-enynes by employing binuclear palladium complex 32 with N,N′-bis[2-(diphenylphosphino)phenyl]amidinate (DPFAM) as a ligand (Scheme [15]); a mononuclear complex with DPFAM was also used but it is thought to form a binuclear complex under the reaction conditions.[31] Using catalyst 32, the cross-addition of unactivated internal alkynes and (triisopropylsilyl)acetylene (TIPSA) gave 1,3-enynes in moderate to high yields. Investigation showed that terminal alkynes and dinuclear palladium complexes give homodimeric products of the terminal alkynes. To prevent homodimerization, the presence of a bulky group on the silylacetylene is required. The reaction of (triisopropylsilyl)acetylene and hex-3-yne at 110 °C afforded the 1,3-enyne product in 82% yield with 3% of the dimeric product.

Examples of the cross addition of (triisopropylsilyl)acetylene to various terminal and internal alkynes are summarized in Table [4].[31] The addition of diphenylacetylene and dialkylacetylenes gave 1,3-enynes (entries 1–3) in low to moderate yields. The high regioselectivity was observed upon the cross-addition of 1-phenylprop-1-yne and (triisopropylsilyl)acetylene (entry 5). The presence of a hydroxy group at the propargylic carbon did not control the regioselectivity and cross addition (triisopropylsilyl)acetylene to methyl tetrolate gave a mixture of isomers (entry 7). The reactions of terminal alkynes and (triisopropylsilyl)acetylene gave branched cross adducts (entries 8–13) in low yields.

Table 4 Palladium-Catalyzed Cross-Addition of (Triisopropylsilyl)acetylene to Various Alkynes

Entry	Alkyne		Time (h)	Yield (%)
	R1	R2
1	Et	Et	20	20
2	Pr	Pr	67	67
3	Ph	Ph	24	24
4	CH2Ome	CH2OMe	–	63
5	Ph	Me	43	43
6	Me	CH2OH	27	27
7	Me	CH2OMe	17	17
8	n-hexyl	H	18	18
9	n-hexyl	H	37	37
10	n-pentyl	H	17	17
11	n-heptyl	H	30	30
12	t Bu	H	19	19
13	(CH2)4OH	H	19	19

(Triisopropylsilyl)acetylene has advantages over other terminal alkynes because of the presence of the bulky silyl group. The selective cross addition was observed (Scheme [16]) using the Hiyama coupling[32] reaction in which 3-ethylhex-3-en-1-ynyltriisopropylsilane (31a, R¹ = R² = Et) was transformed into 3-ethyl-1-phenylhex-3-en-1-ye 34 using a Pd catalyst (Scheme [16]). The treatment of 3,4-diphenylbut-3-en-1-ynyltriisopropylsilane (31c, R¹ = R² = Ph) with TBAF and THF gave 3,4-diphenylbut-3-en-1-yne (34) that can undergo further modification (Scheme [16]).

Enyne synthesis has been discussed vide supra using terminal alkynes, internal alkynes, vinyl halides, and tellurides etc. In 2010, Sakai and co-workers reported a three-component synthesis of 1,1,2-trisubstituted 1,3-enynes from alkynylsilanes, aryl iodides, and internal alkynes using a palladium catalyst (Scheme [17]).[33] Optimization using 2.0 mol% of Pd(OAc)₂, 3.0 equiv. of K₂CO₃, and DMA gave 42% of 1,3-enyne along with 16% of Sonogashira product. To enhance the selectivity in favor of the 1,3-enyne product, several additives were added; ^t Bu₃P and the addition of co-solvent were found to improve the product yield. Further optimization of the molar ratio of substrates found that the ratio aryl iodide/internal alkyne/alkynylsilane 2:4:1 enhanced the selectivity and increased the yield of 1,3-enyne up to 80%. The use of 2.0 mol% of phenylacetylene also gave the coupling product as the major product in 80% yield.

Tetrasubstituted alkynes were obtained by the reaction of aryl iodide, symmetrical internal alkyne and alkynylsilanes under the optimized conditions (Table [5]).[33] The reactions of alkynylsilanes obtained from 1-(4-substituted-phenyl)-2-(trimethylsilyl)acetylenes gave tetrasubstituted alkynes in excellent yields. Using thienyl or pyridyl-substituted ethynylsilanes gave heterocyclic 1,3-enynes in 62% and 60% yield a (Table [5], entries 5 and 6).

The regioselectivity of this coupling reaction was evaluated by using iodobenzene, trimethyl(phenylethynyl)silane (40), and unsymmetrical 1-phenylprop-1-yne (41) and gave E-isomer 43 and Z-isomer 42 in 17% and 44% yield, respectively (Scheme [18]).[33] The phenylethynyl group of the trimethyl(phenylethynyl)silane (40) occupies the more hindered side (Ph side) of the internal 1-phenylpropyne (41) while the phenyl group of aryl halide favors the less hindered side of the internal alkyne.

Performing the same reaction using an unsymmetrical internal alkyne 44 containing a strong electron-withdrawing group with trimethyl(phenylethynyl)silane (40) and 4-tolyl iodide (45) gave stereoselectively the coupling product 46 in 58% yield (Scheme [19]).[33] The p-tolyl moiety was favored on the electron-deficient side of internal alkyne 44 and the alkynyl group added to the electron-rich side. In this case,[34] [35] the product was solely E-isomer 46, whereas in Scheme [18] the products were obtained as a mixture of E- and Z-isomers because of the isomerization of alkenylpalladium intermediate.

Table 5 Pd-Catalyzed Synthesis of Tetraaryl-Substituted Enynes

Entry	Ar1	Ar2	Ar3	Yield (%)
1	Ph	Ph	Ph	75
2	Ph	Ph	4-MeC6H4	60
3	Ph	Ph	4-MeOC6H4	70
4	Ph	Ph	4-FC6H4	62
5	Ph	Ph	3-pyridyl	60
6	Ph	Ph	2-thienyl	62
7	4-FC6H4	4-FC6H4	4-FC6H4	80
8	4-FC6H4	4-FC6H4	Ph	80
9	4-MeC6H4	4-MeC6H4	Ph	40

Using bis(trimethylsilyl)acetylene (48) was used as the coupling partner with iodobenzene (32) and diphenylacetylene (47) under similar reaction conditions gave a 1,3-enyne product 49 containing a trimethylsilyl-substituted C≡C bond (Scheme [20]).[33] The addition of a further equivalent of iodobenzene (32) to the reaction mixture at 100 °C for an addition 2 h gave 1,1,2,4-tetraphenylbut-1-en-3-yne (50) in 62% yield.

By using vinylsilanes instead of alkynylsilanes, a 1,3-diene product is obtained. Thus, reaction of trimethyl(vinyl)silane (52), 1-iodo-4-methoxybenzene (52), and diphenylacetylene (47) gave 1-(4-methoxyphenyl)-1,2-diphenylbuta-1,3-diene (53) as a mixture of E- and Z-isomers in 65% yield (Scheme [21]).[33]

Experiments were performed in order to understand the mechanism.[33] A two-component reaction using iodobenzene (32) and trimethyl(phenylethynyl)silane (40) using 2.0 mol% of Pd(OAc)₂, 8.0 mol% t-Bu₃P, and 3.0 equiv. of TBAF in DMA resulted in Sonogashira coupling to give diphenylacetylene in 74% yield, whereas under the standard conditions diphenylacetylene was obtained in only 18% yield (Scheme [22]). This observation suggests that TBAF facilitates the cleavage of the C–Si bond, favoring transmetalation of the acetylide ion over the insertion of an internal alkyne with Pd, thus resulting in a sila-Sonogashira-type or Hiyama-type coupling reaction.

In 2011, Yorimitsu, Oshima, and co-workers reported the alkynylthiolation of terminal alkynes using a palladium catalyst.[36] The reaction of phenyl (triisopropylsilyl)ethynyl sulfide and phenylacetylene (56) using Pd₂(dba)₃ as a catalyst and PPh₃ as a ligand in toluene at 110 °C gave regio- and stereoselectively (Z)-1-(phenylthio)-1,3-enyne 58 in 63% yield (Table [6], entry 1). The reaction was optimized by varying the silyl group (Table [6]). The triisopropylsilyl group gave a satisfactory 63% yield (Table [6], entry 1), but a lower yield was obtained for the corresponding triethylsilyl- and tert-butyldimethylsilyl-substituted substrates (Table [6], entries 2 and 3). Mesitylethynyl phenyl sulfide gave the corresponding product 58 in 57% yield (Table [6], entry 4), but other alkyl- and phenyl-substituted ethynyl groups gave low yields (Table [6], entries 5–7). The resultant alkenyl sulfides 58 can be utilized in the synthesis of complex organosulfur skeletons, such as thiophenes and multisubstituted alkenes.

Table 6 Pd-Catalyzed Addition of Alkynyl Sulfides to Phenylacetylene

Entry	R	Yield (%)
1	SiPr3	63
2	SiEt3	27
3	Si t BuMe2	22
4	Mes	57
5	t Bu	27
6	Ph	<10
7	n-hexyl	<10

Examining the terminal alkyne used in this reaction under the same conditions (Table [7]),[36] found that the electron-deficient alkyne 4-(trifluoromethyl)phenylacetylene gave a moderate 56% yield (entry 1). The reaction of phenylacetylene or 4-(trifluoromethyl)phenylacetylene under the same conditions but replacing triphenylphosphine with tricyclohexylphosphine as the ligand gave the corresponding products in 88–89% yield (Table [7], entries 2 and 3). Interestingly, the use of tert-butylacetylene gave a low 41% yield (Table [7], entry 8). The lower reactivity of tert-butylacetylene is probably due to its steric bulkiness. Replacing the terminal alkyne with a less reactive internal alkyne under solvent-free conditions gave much lower yields because the steric repulsion of the C≡C bond would hamper the insertion step.

Table 7 Pd-Catalyzed Addition of Phenyl (Triisopropylsilyl)ethynyl Sulfide to Terminal Alkynes

Entry	R	Yield (%)
1	4-CF3C6H4	56
2	Ph	88a
3	4-CF3C6H4	89a
4	4-ClC6H4	62
5	2-naphthyl	81
6	CMe=CH2	69
7	n-hexyl	88
8	t Bu	41
9	(CH2)9OH	84

^a Using PCy₃ instead of PPh₃ as the ligand.

The proposed mechanistic pathway of this reaction[36] is by oxidative addition of 59 to Pd(0) to give alkynylpalladium phenylthiolate A. The cleavage of the C–S bond aids in the coordination of the internal alkyne to give the palladium(II) complex B. Finally, the reductive elimination of B regenerates Pd(0) with the formation of 60 with regio- and stereoselective control (Scheme [23]).

Jiang and co-workers developed a strategy for the synthesis of 1,3-enynes 63 by the palladium-catalyzed cross-coupling of bromoacetylenes 62 and unactivated alkenes 61.[37] Optimization found the best reaction conditions to be Pd(OAc)₂ as catalyst, with K₂CO₃ as the best base in DMF at 80 °C. This reaction was highly efficient for a broad range of styrene derivatives 61 and 1-aryl-2-bromoacetylenes 62 that gave 1,3-enynes 63 in excellent yields (Scheme [24]).

The proposed mechanism (Scheme [25])[37] begins with the oxidative addition of the bromoacetylene 61 to Pd(0) to give alkynylpalladium(II) intermediate A. Then, Heck-type of cross-coupling of styrene 62 with A via cis-insertion produces intermediate B and finally β-H elimination gives 1,3-enyne 63 and regenerates the Pd(0) catalyst.

In 2012, Huang and co-workers reported a method for the synthesis of 1,3-enynes using a new palladium(II) complex based on N,N-dimethylethanolamine [(SP-4-1′)-bis[N,N-dimethylaminoethoxy-κN,O]palladium(II) complex, Cat. A.] in Sonogashira cross-coupling reactions without the use of a ligand and CuX cocatalyst.[38] The optimized conditions were found to be 1.0 mol% of Pd catalyst and 2 equiv. of Cs₂CO₃ in DMF under a N₂ atmosphere at room temperature.

Using arylacetylenes 65 with (E)-β-bromostyrene (64) gave 1,3-enynes 66 in moderate to high yields (Table [8]).[38] The use of phenylacetylene or 4-methylphenylacetylene, containing an electron-donating group, gave the corresponding 1,3-enynes in high yields (Table [8], entries 1 and 2), slightly lower yields were obtained with arylacetylenes with an electron-withdrawing group in the 4-position (Table [8], entries 3 and 4), while the use of 2-(trifluoromethyl)phenylacetylenes considerably reduce the yield (Table [8], entry 5). This is perhaps due to steric repulsion by the trifluoromethyl group. The use of an alkyl-substituted acetylene instead of arylacetylenes gave a comparable yield of product, but the use of alk-1-enyl bromides was unsuccessful. (Z)-β-Bromostyrene gave predominantly the corresponding Z-product.

Table 8 Sonogashira Cross-Coupling of (E)-β-Bromostyrene with Arylacetylenes

Entry	R	Yield (%)
1	H	97 (E/Z 93:7)
2	4-CH3	93 (E/Z 93:7)
3	4-F	92 (E/Z 93:7)
4	4-Br	77 (E/Z 93:7)
5	2-CF3	12 (E/Z 93:7)
6	4- t Bu	40 (E/Z 93:7)

In 2015, Ando and co-workers reported the Sonogashira cross-coupling of (E)-trimethyl(3,3,3-trifluoroprop-1-enyl)silane (67) and terminal alkyne 65 catalyzed by Pd(OAc)₂ with Ag as a co-catalyst and fluoride ion source to give 5-aryl-1,1,1-trifluoropent-2-en-4-ynes 68 (Scheme [26]).[39] The use of AgF co-catalyst is essential and the reaction was unsuccessful with CuF₂, CsF, or ZnF₂.

A number of substituted phenylacetylenes 65 containing electron-withdrawing or electron-donating groups were used in this reaction (Table [9]).[39] Phenylacetylenes bearing electron-donating groups in the 4- and 2-position were well tolerated and gave the 1,3-enynes 69 in high yields (91–99%) (Table [9], entries 1–3 and 7). In contrast, phenylacetylenes bearing electron-withdrawing groups gave moderate yields (55–67%) (Table [9], entries 4–6). The mechanism of this palladium-catalyzed mechanism is shown in Scheme [27] and involves steps such as oxidative addition and reductive elimination.

Table 9 Scope of the Reaction of Phenylacetylenes with (E)-Trimethyl(3,3,3-trifluoroprop-1-enyl)silane

Entry	R	Yield (%)
1	4- t Bu	99
2	4-Et	95
3	4-OMe	91
4	4-F	67
5	4-COMe	65
6	4-CO2Et	55
7	2-OMe	99

In 2017, Trolez and co-workers reported a three-component synthesis using arylacetylenes, 3-bromoprop-2-ynenitrile (70) and a secondary amine with PdCl₂(PPh₃)₂ (10.0 mol%) as the catalyst and CuI (10 mol%) co-catalyst in THF at r.t. to give stereoselectively 1,3-enynenitriles 71.[40] The use of various amines was examined (Table [10]), of which isopropylamine gave the highest yield of 71 (82%).

Table 10 Reaction of Phenylacetylene, 3-Bromoprop-2-ynenitrile, and a Secondary Amine

Entry	NHR2	Yield (%)
1		42
2		82
3		34

Examining the scope of the acetylenes 1 in the reaction with 3-bromoprop-2-ynenitrile (70) and diisopropylamine found that trimethylsilyl-, triethylsilyl-, and (triisopropylsilyl)acetylene gave lower yields compared to phenylacetylene (Table [11], entry 1 vs entries 2–4).[40] The reduction of the yield is due to steric hindrance; the use of mesitylacetylene completely inhibited the reaction (Table [11], entry 9).

Table 11 Formation of Enynes by Using Different Terminal Alkynes

Entry	R	Yield (%)
1	Ph	82
2	TMS	60
3	TES	25
4	TIPS	23
5	C≡CTIPS	75
6	n-hexyl	55
7	CMe2OH	trace
8	4-MeC6H4	57
9	Mes	0
10	4-(CN)C6H4	0
11	4-(CO2Me)C6H4	55
12	4-CF3C6H4	82

In 2017, Smith and Tunge reported a new strategy for the decarboxylative coupling of propargyl prop-2-ynoates 73 catalyzed by Pd(PPh₃)₄ (5 mol%) in THF at 50 °C to give conjugated allenynes 74 (Scheme [28]).[41] The reaction tolerated substitution by alkyl and aryl groups in the propynoate (R²) and gave 74 in moderate to high yields. Electron-withdrawing groups in the 4-position of 3-phenylpropynoates 73 gave slightly lower yields, while electron-donating substituents increased the yield and reduce the rection time. The reason for the reduction of the yield may be due to the high volatility of the allene. In addition, the scope of this reaction was further expanded by utilizing secondary propargyl esters 73 (R³ = Me, (CH₂)₂Ph, ⁱ Pr, Ph) to obtain trisubstituted allenynes 74. In the case of hex-3-yn-2-yl 3-phenylpropynoate (73, R¹ = Et, R² = Ph, R³ = Me) the product 74m was obtained in 27% yield due to its high volatility. Replacing the propargyl substituents by bulky groups or using 4-methoxyphenylpropynoates enhanced the yield up to 88%.

In 2006, Ogilvie and co-workers reported a mild and convenient two-step protocol for the regioselective synthesis of tetrasubstituted 1,3-enynes 76 (Scheme [29]).[42] In the first step, alk-2-ynoates 5 were converted into (E)-β-chloro-α-iodo-α,β-unsaturated esters 75 in the presence of tetrabutylammonium iodide; the (E)-β-chloro-α-iodo-α,β-unsaturated esters 75 underwent Pd-catalyzed cross-coupling with terminal acetylenes and then the resulting 1-chloroenynes underwent Sonogashira coupling or Suzuki–Miyaura­ coupling reactions to generate regio- and stereoselectively tetrasubstituted 1,3-enynes 76 in high yields.

The reactions tolerated a variety of functionalities on the terminal alkyne, including aryl (Table [12], entries 1 and 2) and silyl, alkyl, and tethered silyl ethers (Table [12], entries 3–6), while the (E)-β-chloro-α-iodo-α,β-unsaturated esters 77 gave trisubstituted 1-chloro-1,3-enynes 78 substituted with cyclohexyl and alkyl chains (Table [12], entries 7 and 8).[42]

The trisubstituted 1-chloro-1,3-enynes 79 (Table [12]) underwent coupling with terminal alkynes by the Sonogashira coupling and aryl- and alkylboronic acids by Suzuki–Miyaura coupling reaction to give tetrasubstituted 1,3-enynes in high yields (Table [13]).[42]

Table 12 Pd-Catalyzed Coupling of (E)-β-Chloro-α-iodo-α,β-unsaturated Esters with Terminal Acetylenes To Give Trisubstituted 1-Chloro-1,3-enynes

Entry	R1	R2	Yield (%)
1	Me	Ph	78
2	Me	4-FC6H4	77
3	Me	TMS	68
4	Me	n-hexyl	74
5	Me	CH2OTBS	76
6	Me	(CH2)2OTBS	72
7	Cy	Ph	68
8	(CH2)2OTBS	TMS	79

Table 13 Tetrasubstituted Enynes by Sonogashira and Suzuki–Miyaura Coupling of Trisubstituted 1-Chloro-1,3-enynes

Entry	R3	R4	Yield (%)
1a	C≡CPh	H	42
2b	Ph	B(OH)2	77
3b	4-CH3C6H4	B(OH)2	75
4b	4-FC6H4	B(OH)2	71
5b		B(OH)2	67
6b		B(OH)2	64

^a Reaction conditions: acetylene (6.0 equiv.), Pd(PPh₃)₂Cl₂ (10.0 mol%) CuI (15.0 mol%), DIPEA (3.0 equiv.), dioxane (0.1 M), rt, 18 h.

^b Reaction conditions: R³B(OH)₂ (2.0 equiv.) Pd(dba)₃, (5.0 mol%) P ^t Bu₃·HBF₄ (20.0 mol%), Cs₂CO₃ (2.0 equiv.), dioxane (0.1 M), rt, 2 h.

The regio- and stereoselectivity were confirmed by NMR methods (Scheme [30]).[42] Z-Isomer 81 was isomerized to the E-isomer 82 upon brief photolysis and then they were reduced to the corresponding alcohols 83 and 84 using DIBAL-H. The nuclear Overhauser effect (NOE) was found for the methyl and methylene groups of compounds 83, indicating a cis-interaction between them which is not observed in 84. Other tetrasubstituted 1,3-enyne products given in Table [13] also gave the same result confirming their regioselectivity.

Perumal and co-workers reported gold-catalyzed cycloisomerization of 2-alkynylcycloalkyl-2-enols to give fused furans.[43] The 2-alkynylcycloalk-2-enols were obtained by Sonogashira coupling between 2-iodocycloalk-2-enols 85 and terminal alkynes using Pd(PPh₃)₂Cl₂ catalyst, CuI co-catalyst, and triethylamine as base (Scheme [31]). This reaction has a broad substrate scope with a variety of alkyl-, aryl-, and heteroaryl-acetylenes giving the 2-alkynylcycloalkyl-2-enols 86 in moderate to high yields.

In 2006, Lyapkalo and Vogel designed a two-step coupling protocol for the synthesis of 1,3-enynes (Scheme [32]).[44] The first step involved the o-sulfonation of carbonyl compounds to give alkenyl nonaflates that underwent C–C cross-coupling with terminal acetylenes, generated from aldehydes and methyl ketones, to give 1,3-enynes. The low nucleophilic phosphazene bases, which were used for the generation of the alkenyl nonaflates and the terminal alkynes, were compatible with NfF and did not impede the subsequent Sonogashira reaction.

The reaction has a broad substrate scope using different cyclic and heterocyclic ketones with cyclic and acyclic ketones and aldehydes in an aprotic solvent leading to complete conversion in high yields (Scheme [33]).[44] The P₁ base gives a high regioselective control of deprotonation but in some cases, the P₁ base did not give high regioselectivity and the much stronger base P₂ was used to obtain a higher regioselective control. As aldehydes are more acidic and react faster than ketones, they enable highly selective reactions for the synthesis of 1,3-enynes in the presence of a ketone group.

Acyclic nonaflates are almost unreactive towards cross-coupling reactions, so some modification were made to obtain a coupling product by using acyclic carbonyl precursors. The highly reactive soluble fluoride source phosphazenium fluoride [P base]H⁺F^– generated during the course of the reaction of methyl ketone 87a and aldehyde 88a successfully generated in situ nonaflate by the addition of trimethylsilyl enol ethers 91 (Scheme [34]).[44] The nonaflate was utilized in the Sonogashira coupling with alkynes to selectively generate 1,3-enynes 92.

Ranu and Chattopadhyay, in 2007, reported the formation of C–C bonds by the stereoselective reaction of (E)-1,2-diiodoalk-1-enes 93 with acrylates 94 (R² = CO₂Me, CO₂Bu) or acrylonitrile 94 (R² = CN) catalyzed by in situ formed recyclable Pd(0) nanoparticles in aqueous solution to give (E)- and (Z)-alk-2-en-4-ynoates and -nitriles 95 (Scheme [35]).[45]

A range of catalytic systems, including Pd(OAc)₂, TBAB, Na₂CO₃ or PdCl₂, TBAB, Na₂CO₃ in water; Pd₂(dba)₃, P(o-Tol)₃, Et₃N in CH₃CN, were used to optimize the reaction. The optimized conditions used PdCl₂, TBAB, and Na₂CO₃ in water at 80 °C.

Examining the scope of the reaction, acrylonitrile (94, R² = CN) gave products 95 as a mixture of E- and Z-isomers favoring the Z-isomer (Table [14], entries 3, 5, and 9) while acrylates (94, R² = CO₂R) gave stereoselectively 95 as the E-isomer (Table [14]).[45] Using (E)-α,β-diiodostyrenes (93, R¹ = aryl) the reaction was complete in 6–7 h, but (E)-1,2-diiodoalk-1-enes (93, R¹ = alkyl) generally required much longer reaction times (Table [14], entry 10).

Mechanistically,[45] the reaction is proposed to involve two distinct sequential routes (route X and route Y; Scheme [36]). Route X begins with HI elimination from the (E)-1,2-diiodoalk-1-ene 93a to give an iodoalkyne that subsequently undergoes the Heck reaction with an acrylate to give 1,3-enyne 95a. In route B Y, the iodo-palladium complex A is formed from (E)-1,2-diiodoalk-1-ene 93a and an acrylate through oxidative addition. This complex then undergoes β-elimination to give hydridopalladium halide π-complex B. The removal of hydridopalladium halide results in the creation of two isomers, C and F. Isomer C then forms 1,3-enyne 95a through syn-elimination, while isomer F forms 1,3-enyne 95a through an E-type elimination mechanism. Theoretical calculations show that isomer C is 0.3 kcal/mol more favorable than isomer F.

In 2008, Ranu and co-workers extended this work to an easy-to-use and efficient process using (E)-1,2-diiodoalk-1-enes 93 and acrylates 96 catalyzed by a palladium complex supported on hydroxyapatite (PdHAP) to give stereoselectivity (E)-alk-2-en-4-ynoates 97 in good to high yields (Scheme [37]).[46] The PdHAP catalyst has a high turnover number (>16000) and it is recyclable catalyst making this method is highly attractive. Among these (E)-alk-2-en-4-ynoates, one showed extraordinary fluorescence with a high quantum yield, suggesting potential applications as a biomarker.

The scope of the reaction is shown in Table [15]. Both (E)-α,β-diiodostyrenes (93, R¹ = aryl) and (E)-1,2-diiodoalk-1-enes (93, R¹ = alkyl) were utilized successfully and stereoselectively gave (E)-alk-2-en-4-ynoates 97. The (E)-α,β-diiodostyrenes 93 containing halogen (Br, Cl, and F) substitution in the phenyl ring were used successfully (Table [15]). (E)-1,2-Dibromoalk-1-enes were also used as substrates in this reaction but required a longer reaction time and gave lower yields.

Table 15 Scope of the Stereoselective Formation of (E)-Alk-2-en-4-ynoates from (E)-1,2-Diiodoalk-1-enes and Acrylates Using PdHAP

Entry	R1	R2	Time (h)	Yield (%)
1	Ph	CO2Bu	6	75
2	n-hexyl	CO2Me	6	75
3	4-MeC6H4	CO2Bu	6.5	78
4	2-BrC6H4	CO2Bu	4.5	62
5	4-FC6H4	CO2Bu	6	68
6	3-MeOC6H4	CO2Bu	6	85
7	4-MeC6H4	CO2Me	6.5	78
8	4-ClC6H4	CO2Me	5	85
9	2-BrC6H4	CO2 t Bu	5	78
10	Bu	CO2Bu	5.5	72
11	Ph	CO2Bu	7	72
12	4-ClC6H4	CO2Bu	5.5	90
13	3-MeOC6H4	CO2Me	7.0	75

Mechanistically, it is probable that this PdHAP-catalyzed coupling does not proceed via the traditional Pd(0)/Pd(II) cycle and it is more likely to move through the Pd(II)/Pd(IV) states, as observed in other PdHAP-catalyzed Heck reactions, since no Pd(0) was identified in the fresh or employed catalyst. Two possible mechanistic approaches are given in Scheme [38]. In route A, (E)-1,2-diiodoalk-1-ene 93a is treated with PdHAP under the reaction conditions to give 1-iodo-2-phenylacetylene that combines with the acrylate 96a to form the 1,3-enyne 97a. A control experiment mixing butyl acrylate with 1-iodo-2-phenylacetylene in the presence of PdHAP gave the 1,3-enyne, hence route A is the more likely one. In route B, initial Heck coupling of (E)-1,2-diiodoalk-1-ene 93a and acrylate 96a gives a 1-iodoalka-1,3-diene that undergoes HI elimination to give 1,3-enyne 97a. The preference here for further HI elimination over Heck coupling in the second step was validated by a model experiment employing iododiphenylethene. The selective Heck coupling with the terminal iodide group in the first step may be explained by steric considerations. Thus, the operation of route B is also not totally excluded.

Rhodium Catalysis

Rhodium catalysis has been used for the homocoupling of terminal alkynes and also the coupling between two different terminal alkynes and an internal alkyne and a terminal alkyne.[24] Nishiyama and co-workers reported the synthesis of a range of substituted 1,3-enynes by the Phebox-Rh acetate complex catalyzed addition of a terminal alkyne to an internal alkyne typically with good Z-selectivity.[47] The cross-coupling process between terminal alkynes 1 and dimethyl acetylenedicarboxylate (98) catalyzed by Phebox-Rh acetate was accelerated by the presence of hydrogen gas to give 1,3-enynes 99 in high yields using arylacetylenes 1 (R = aryl), but reactions with alkyl- or silyl-substituted acetylenes were less efficient with moderate to good yields (Table [16]).

Mechanistically (Scheme [39]),[47] it is proposed the acetylide complex A is created by C–H bond activation via deprotonation using the acetate ligand as a base. The vinyl complex B is obtained by subsequently inserting internal alkyne 98 into the Rh–acetylide bond. Further reaction of B (path X) with terminal alkyne 1 results in the acetylide-1,3-enyne intermediate C, which undergoes elimination of 99 to regenerate A. This route has frequently been suggested for the homo- and cross-coupling of alkynes. A different route would be for B to react with H₂ to produce the hydride intermediate D and 99 (path Y). It is assumed that a crucial step in the activation of the catalytic precursor (route Z) is the reversible synthesis of the hydride intermediate D, which is produced by the direct interaction of E with H₂. In this instance, the σ-bond metathesis of an alkyne with the Rh–H bond is mediated by intermediate D, which also re-forms A.

Table 16 Phebox-Rh Acetate Catalyzed Coupling of Terminal Alkynes with Dimethyl Acetylenedicarboxylate

Entry	R	Isolated yield (%)	Ratio Z/E
1	4-CF3C6H4	79	98:2
2	4-BrC6H4	87	97:3
3	4-MeOC6H4	49	99:1
4	4-MeC6H4	66	99:1
5	2-MeC6H4	85	97:3
6	1-naphthyl	74	96:4
7	Cy	9	100:0
8	n-hexyl	14	100:0
9	n-hexyl	40	98:2
10	SiMe3	26	99:1
11	CO2Et	3	100:0

Ozerov and co-workers reported a regiospecific, moisture- and somewhat air-tolerant alkyne dimerization reaction between terminal acetylenes 100 catalyzed by a rhodium complex that contains a PNP pincher ligand to give 1,3-enynes 101 and 102 (Scheme [40]).[48] The ‘tied’ ^TPNP ligand A exerts a greater degree of steric pressure than the ‘untied’ ligands ^MePNP B and ^FPNP C. The terminal alkyne dimerization diarylamino-based PNP pincer ligands A–C in Rh complexes showed remarkable selectivity for the (E)-1,3-enyne product 101 (Scheme [40]).

Mechanistically (Scheme [41]) hydrogenation of the C≡C bond in alkyne 100 depletes the Rh center of two hydrogens, producing an alkene byproduct 105 (detected by NMR in the reaction mixtures). The Rh(III) hydrido-alkynyl complex C is produced by C–H oxidative addition to give Rh(I)–alkyne complex B. The second alkyne equivalent is then inserted into the Rh–H bond to give C that undergoes reductive coupling to give 1,3-enyne complex D. The catalytic loop closes when the alkyne displaces the 1,3-enyne.

In 2008, Miura and co-workers reported a highly regio- and stereoselective rhodium-catalyzed process for the reaction of (triisopropylsilyl)acetylene (106) or 1-(trimethylmethylsiloxy)-1,1-diphenylprop-2-yne and bulky terminal alkynes to give 1,3-enyne 107 as the E-isomer (Table [17]).[49] The optimized conditions were found to be alkyne 100 and silylacetylene 106 (1.0 equiv.) with [RhCl(cod)]₂ (3.0 mol% Rh) as the catalyst and Xantphos as the ligand (ratio Rh/Xantphos 1:2) in refluxing toluene.

Table 17 Rh-Catalyzed reaction of (Triisopropylsilyl)acetylene with Various Terminal Alkynes

Entry	R	Time (h)	Isolated yield (%)
1	CH2Ph	6	76
2	Cy	6	63
3	(CH2)3CN	3	58
4	(CH2)3OH	3	60
5	(CH2)3CO2Me	3	85
6	CH(OH)(CH2)4Me	6	57
7	CMe2OH	3	70
8	1-hydroxycyclohexyl	3	61
9	1-aminocyclohexyl	6	68
10	4-MeOC6H4	3	56

Conjugated 1,3-enynes are a special class of building blocks with several uses in material science and organic chemistry. They are often made by dehydrating propargylic alcohols, Wittig olefination of conjugated alkynals, or cross-coupling of a terminal alkyne and a preactivated alkyne under transition metal catalysis. The cross-coupling of two terminal alkynes is problematic in terms of problems of chemo-, regio-, and stereoselectivity. Utilizing the steric and/or electronic differences between the two alkynes to create chemo- and regioselectivity is one method of to overcome these challenges. Xu and co-workers described a head-to-tail cross-dimerization reaction that produced 1,3-enynes with high efficiency and selectivity (Scheme [42]).[50]

The cross-coupling reaction between propargyl alcohol 109 or propargylamine 110 and terminal alkynes 1c using [Rh(COD)Cl]₂ and Ph₃P as the catalyst system in dichloromethane at 40 °C gave 1,3-enynes 111 as the major product with good selectivity; the reaction scope is shown in Table [18].

Table 18 Scope of the Rh-Catalyzed Cross-Coupling between Propargyl Alcohols or Propargylamines and Terminal Alkynes

Entry	Donor 1c	Acceptor		Yield (%) of 111
	Ar		OR or NHR′
1	4-MeOC6H4	109	OH	55
2	4-O2NC6H4	109	OH	52
3	2-BrC6H4	109	OH	88
4	4-MeOC6H4	110	NHTs	92
5	4-O2NC6H4	110	NHTs	77
6	2-BrC6H4	110	NHTs	95

In 2015, Nachtsheim and co-workers reported the Rh(III)-induced, fully stereo- and chemoselective direct CH-alkynylation of 2-vinylphenols using hypervalent iodine reagent TIPS-EBX* in combination with [(Cp*RhCl₂)₂] to give highly substituted 1,3-enynes in good yields (Scheme [43], Table [19]).[52] This is a very uncommon instance of an OH-directed alkynylation under CH-activating conditions.

Table 19 Scope of the Rh-Catalyzed OH-Directed Alkynylation of 2-Vinylphenols with Ethynylbenziodoxolones

Entry	R1	R2	Yield (%)
1	H	H	40
2	H	Me	91
3	H	Et	78
4	H	Ph	83
5	4-Fa	Me	86
6	4-NO2 a	Me	92
7	4-OMea	Me	87

^a Position relative to phenol OH group.

The mechanism is shown in Scheme [44]. A process of base-assisted ligand exchange with 113, trailed by CH bond activation through an addition/elimination cascade, culminates in the formation of rhodacycle A. Subsequently, the insertion of the C≡C bond neighboring the hypervalent iodine of TIPS-EBX* generates rhodacycle B, which, in turn, undergoes an elimination process resulting in 2-iodo-6-methylbenzoate, leading to the formation of the rhodium vinylidene complex C. A subsequent 1,2-migration of the vinyl group followed by ligand exchange ultimately liberates 114 and regenerates the rhodium(III) catalyst.

Copper Catalysis

In the last 20 years, many methods have been developed for the copper-catalyzed coupling of alkynes and vinyl iodides.[53] [54] [55] [56] [57] [58] [59] [60] In 2001, Marshall and co-workers reported the CuCl-promoted coupling of (trimethylsilyl)alkynes with vinyl iodides to give 1,3-enynes in high yields.[61]

In 2004, Venkataraman and co-workers reported the coupling of terminal alkynes and vinyl iodides in a Cu(I)-catalyzed procedure to give 1,3-enynes.[62] Optimization of the copper catalyst found that either the use of [Cu(bipy)PPh₃Br] with K₂CO₃ as the base (Table [20] and Scheme [45]) or [Cu(phen)(PPh₃)₂]NO₃ with Cs₂CO₃ as the base (Table [21]) in toluene at 110 °C were optimal

Table 20 Cross-Coupling of Phenylacetylene with Various Vinyl Iodides Using [Cu(bipy)PPh₃Br] with K₂CO₃

Entry	Vinyl iodide	Yield (%)
1		81
2		90
3		97
4		97
5		99

Table 21 Cross-Coupling of Phenylacetylene with Various Vinyl Iodides Using [Cu(phen)(PPh₃)₂]NO₃ with Cs₂CO₃

Entry	Vinyl iodide	Yield (%)
1		99
2		98
3		98
4		78
5		98

In 1993, Miura and co-workers reported the Cu-catalyzed coupling of aryl iodides with terminal alkynes to give aryl- and vinylacetylenes thus avoiding the use of expensive metals.[63] In 2004, Venkataraman and co-workers used a Cu(I) complex for the coupling of vinyl iodides and terminal alkynes to give 1,3-enynes.[62] In 2009, Bao and co-workers reported the coupling of (E)-β-bromostyrenes with terminal alkynes using Cu(I) catalyst to give 1,3-enynes.[64] The optimum catalytic system was CuI as the catalyst with 1,10-phenanthroline as the ligand and Cs₂CO₃ as the base. (E)-β-Bromostyrenes substituted with electron-deficient groups gave better yields of 1,3-enynes 66 (Table [22]). It is noteworthy that the double bond geometry of the (E)-β-bromostyrenes 64 was retained in the 1,3-enynes 66.

Table 22 Cu-Catalyzed Coupling of (E)-β-Bromostyrenes with Terminal Alkynes

Entry	R1	R2	Yield (%)
1	H	H	88
2	4-Me	H	69
3	4-OMe	H	52
4	3,4-(OMe)2	H	46
5	4-Br	H	90
6	4-Cl	H	91
7	2-Cl	H	73
8	H	4-OMe	89
9	H	4-Et	90
10	H	4-Br	63
11	4-Br	4-Me	92
12	4-Me	4-OMe	78
13	4-Cl	4-OMe	92
14	2-Cl	4-OMe	79

In 2011, Mao and co-workers reported the synthesis of 1,3-enynes without the use of a ligand.[53] The domino coupling of β-bromostyrenes using 10 mol% of CuI and K₃PO₄ as the base at 135 °C temperature gave 1,3-enynes 66 together with a small amount of the homocoupling product 118 (Table [23]). The use of β-chlorostyrenes was unsuccessful and β-iodostyrenes gave low yields with high yields of 1,3-diynes 118 (Table [23], entries 6 and 7). The geometry of the β-bromostyrene was retained in the 1,3-enyne product (Table [23], entries 1 and 8). The coupling of (E)-β-halostyrenes and arylacetylenes under the same conditions also gave unsymmetrical 1,3-enynes in good yields (Table [24]).

Table 23 CuI-Catalyzed Domino Coupling of (E)-β-Halostyrenes

Entry	X	R	Yield (%)
1	Br	H	82
2	Br	4-F	55
3	Br	4-Me	69
4	Br	4-Cl	70
5	Br	3-Me	55
6	I	H	45
7	I	4-Me	52
8	Bra	H	25

^a (Z)-β-Bromostyrene was used.

Table 24 CuI-Catalyzed Coupling of (E)-β-Halostyrenes and Alkynes

Entry	X	R1	R2	Yield (%)
1	Br	H	H	>99
2	Br	4-F	H	81
3	Br	4-Me	H	68
4	Br	4-Cl	H	41
5	Br	3-Me	H	67
6	Br	H	4-Me	99
7	Br	H	4-F	76
8	Br	4-F	4-Me	76
9	Br	4-F	4-F	62
10	Bra	H	H	27
11	I	H	H	20
12	Cl	H	H	trace
13	Br	–b	H	42

^a (Z)-β-Bromostyrene was used.

^b (E,E)-1-Bromo-4-phenylbuta-1,3-diene was used.

In 2006, Hoshi and co-workers used a copper catalyst to produce both E- and Z-configured 1,3-enynes (Table [25]). Using 1-bromo-2-(trimethylsilyl)acetylene (120) and vinylboranes using Cu(acac)₂ and LiOH·H₂O base at –15 °C to room temperature gave the TMS-1,3-enynes, while NaOMe gave 1,3-enynes in both cases the products were formed in good yields (62–74%).[54] Examples are shown for the formation of (E)-1,3-enynes 121 and 122 from (E)-vinylboranes in Table [25]. (Z)-Enynes were similarly obtained started from (Z)-vinylboranes in comparable yields.

Table 25 (E)-Enynes by Coupling of (Trimethylsilyl)ethynyl Bromide and Vinylboranes Using Cu(acac)₂ and LiOH·H₂O or NaOMe Base

Entry	Base	R	R1	R2	Product	Yield (%)
1	LiOH·H2O	CHMe i Pr	n-hexyl	H	122a	70
2	LiOH·H2O	CHMe i Pr	Ph	H	122b	70
3	LiOH·H2O	CHMe i Pr	cyclohex-1-enyl	H	122c	63
4	LiOH·H2O	CHMe i Pr	(CH2)3Cl	H	122d	67
5	LiOH·H2O	CHMe i Pr	CH2OBn	H	122e	74
6	LiOH·H2O	CHMe i Pr	Pr	Pr	122f	70
7	NaOMe	Cy	n-hexyl	H	122a	72
8	NaOMe	Cy	Ph	H	122b	73
9	NaOMe	Cy	cyclohex-1-enyl	H	122c	62
10	NaOMe	Cy	(CH2)3Cl	H	122d	72
11	NaOMe	Cy	CH2OBn	H	122e	63
12	NaOMe	Cy	Pr	Pr	122f	65

In 2007, Liu and Ma coupled vinyl iodides 123 and terminal alkynes 1 using CuI and N,N-dimethylglycine as the catalyst system and Cs₂CO₃ as the base in 1,4-dioxane as solvent at 80 °C to prepare 1,3-enynes 124 in good to excellent yields (61–91%) (Table [26]).[55]

In 2012, Ranu and co-workers coupled (E)-β-bromostyrenes and terminal alkynes using Cu(I)-HAP (hydroxyapatite-supported copper(I)) as the catalyst with NaOH as the base in DMF at 120 °C to produce 1,3-enynes in 76–86% yield (Table [27]).[56] (E)-β-Bromostyrenes gave enynes in good yields, but (Z)-β-bromostyrenes underwent base-catalyzed formation of arylacetylenes and these cross-coupled with the terminal alkyne to give unsymmetrical 1,3-diynes. The catalyst could be recycled and was actively for up to three consecutive reactions.

In 2014, Ranu and co-workers reported copper ferrite assisted by Cs₂CO₃ base as a green catalytic system for the coupling of bromoacetylenes with alkynylboronates or vinylboronic acids to give 1,3-diynes and 1,3-enynes, respectively. Bromoacetylenes 62 and alkynylboronates 125 underwent copper ferrite catalyzed reaction using Cs₂CO₃ as the base in refluxing DMC (dimethyl carbonate) to give 1,3-diynes 126 (Scheme [46a]). The bromoacetylenes 62 also underwent coupling with vinylboronic acids 127 under the same conditions (Scheme [46b]) to give 1,3-enynes 128 in 54–92% yield (Scheme [47]).[57]

Table 26 Coupling of Vinyl Iodides and Terminal Alkynes Using CuI/N,N-Dimethylglycine Catalyst

Entry	Vinyl iodide	Arylacetylene	Yield (%)
1			75
2			75
3			84
4			60
5			91
6			67
7			78
8			71
9			79
10			61

1,3-Enynes, or conjugated alkynes, are important in organic chemistry and synthesis.[58] The most common method for accessing 1,3-enynes is the Pd-catalyzed Sonogashira reaction.[59] Its foundation is an electrophilic vinyl moiety bonded to an alkyne that is nucleophilic. In 2014, Riant and co-workers reported a mild and efficient Hiyama-type cross-coupling of vinyl(triethoxy)silanes 130 and bromoalkynes 62 using a copper catalyst with TBAT to give 1,3-enynes 131 (Scheme [48]).[60] (Z)-, (E)-, and 1,1′-disubstituted vinyl(triethoxy)silanes 130 were utilized with full retention of stereochemistry. Vinyl(triethoxy)silanes 130 and bromoalkynes 62 containing sensitive groups, such as aldehydes, ketones, and bromides, were successfully used under these mild conditions. Using disubstituted vinyl(triethoxy)silanes gave trisubstituted 1,3-enynes. Two nitrogen-containing 1,3-enynes, tosylamine and phthalimide, were successfully synthesized in large amounts.

Table 27 Coupling of (E)-β-Bromostyrenes and Terminal Alkynes Using Cu(I)-HAP Catalyst

Entry	R	R1	Yield (%)
1	H	Ph	84
2	4-Cl	Ph	86
3	4-F	Ph	84
4	4-Me	Ph	82
5	4-Et	Ph	80
6	4-F	4-MeOC6H4	76
7	H	n-hexyl	84
8	4-Me	n-hexyl	80

Iron Catalysis

There are many well-known examples of the synthesis of unsaturated compounds using Pd-catalyzed Csp–Csp² couplings, such as the Heck reactions, Negishi couplings, and Sonogashira couplings.[65] [66] [67] Koch, in 1971,[69] and Cahiez, in 1998,[68] reported the iron-catalyzed coupling of organomagnesium reagents and alkenyl halides, but these reactions were limited to aryl- and alkylmagnesium reagents.[68] [69] In 2008, Nakamura and co-workers formed an alk-1-ynylmagnesium bromide from the alk-1-yne and then reacted this with an alkenyl bromide to give a 1,3-enyne.[70] This is shown in Scheme [49] for the reaction of oct-1-yne (101) with methylmagnesium bromide to give oct-1-ynylmagnesium bromide (132a) that underwent FeCl₃-catalyzed coupling in the presence of LiCl or LiBr with (E)-β-bromostyrene (64a) to give 1-phenyldec-1-en-3-yne (133). The scope of the reaction is shown in Scheme [50] and Table [28]. The reaction is stereoselective; reaction of (E)-1-bromoprop-1-ene ((E)-64e) with 132c gave the (E)-1,3-enyne in 92% yield (E/Z 95:5) and (Z)-1-bromoprop-1-ene ((Z)-64e) in the same reaction gave the (Z)-1,3-enyne in 94% yield (E/Z 35:65) (Table [28]).

Mechanistically, the Fe(III) catalyst is first reduced to a low valent state, such as Fe(0), A. In the absence of a lithium salt, the initial reduction is largely dependent on the structure of the alkynyl moiety. When the Fe complex A is oxidatively coupled with an alkenyl bromide in the subsequent phase, the higher-valent Fe(II) complex B is produced that reductively eliminates the Fe(0) C and 1,3-enyne 133. The loss of stereochemical purity in the reaction of vinyl bromides (Table [28], entries 13 and 14) points to an electron-transfer reaction based oxidative addition (Scheme [51]).

C–C Bond formation by coupling between sp²- and sp-hybridized carbon centers is a commonly utilized cross-coupling process.[71] In 2008, Nakamura and co-workers reported the coupling of terminal alkynes and vinyl halides by using in situ generated alkynyl-Grignard reagents and Fe catalyst.[70] Bolm and co-workers used ligand-assisted Fe catalysis for the C–C cross-coupling of terminal alkynes and aryl iodides to produce arylalkynes.[72] In 2009, Li and co-workers cross-coupled terminal alkynes 1 and (E)-vinyl iodides 115 using FeCl₃ as the catalyst, 1,10-phenanthroline as the ligand, and Cs₂CO₃ as the base in toluene at reflux to obtain 1,3-enynes 128 in 45–90% yield (Scheme [52]).[73] Arylacetylenes and substituted alk-1-ynes were utilized as the terminal alkyne, while the vinyl iodides used included (E)-β-iodostyrenes and (E)-1-iodoalk-1-enes.

Nickel Catalysis

In the past 20 years, new techniques for producing 1,3-enynes from vinyl organometallic reagents or vinyl halides have been developed. Enediyne and 1,3-enyne systems have been prepared from vinylic chalcogenides such as vinyl tellurides and vinyl selenides.[74] [75] In 2003, Silveira, Zeni, and co-workers reported the cross-coupling of alkynes with (E,E)- and (Z,Z)-divinylic chalcogenides 134 catalyzed by nickel catalysis to give (E)- and (Z)-1,3-enynes 135 (Table [29]).[76] The optimized conditions for the reaction were CuI (5 mol%), Ni(dppe)Cl₂ (5 mol%), divinyl chalcogenide (1 mmol), pyrrolidine (10 mL), and terminal alkyne (4 mmol) at room temperature. Under these conditions (E,E)- and (Z,Z)-divinylic chalcogenides 134 gave the corresponding (E)- and (Z)-1,3-enynes 135 with complete retention of configuration. This reaction has wide scope of the reaction including the use of a hydroxy-substituted divinyl telluride (Table [29]).

Table 29 Nickel-Catalyzed Cross-Coupling Reaction of Divinyl Chalcogenides and Terminal Acetylenes

Entry	Divinyl chalcogenide			Alkyne R1	Time (h)	Yield (%)
	Isomer	Y	R	R1
1	Z,Z	Te	Ph	n-pentyl	20	78
2	Z,Z	Te	Ph	Ph	16	61
3	Z,Z	Te	Ph	CH2OH	20	73
4	Z,Z	Te	Ph	(CH2)3OH	20	72
5	E,E	Te	Ph	n-pentyl	20	57
6	E,E	Te	Ph	Ph	16	72
7	E,E	Te	Ph	CH2OH	15	81
8	E,E	Te	Ph	(CH2)3OH	20	68
9	Z,Z	Se	Ph	n-pentyl	20	61
10	Z,Z	Se	Ph	Ph	20	54
11	Z,Z	Se	Ph	CH2OH	16	56
12	Z,Z	Se	Ph	(CH2)3OH	22	76
13	E,E	Se	Ph	n-pentyl	22	71
14	E,E	Se	Ph	Ph	20	63
15	E,E	Se	Ph	CH2OH	20	75
16	E,E	Se	Ph	(CH2)3OH	20	83
17	Z,Z	Te	CH2OH	n-pentyl	20	71
18	Z,Z	Te	CH2OH	CMe2OH	24	61

Boron-based organic synthesis has been made possible by the comprehensive study of novel organoboron compound reactions with transition metal catalysts, such as Ru-catalyzed CH/organoborane cross-coupling systems, Suzuki–Miyaura coupling, and Rh-catalyzed conjugative additions.[77] [78] [79] In contrast to conventional synthesis techniques, such as uncatalyzed hydroboration, catalytic procedures frequently provide highly efficient and focused means of producing functionalized organoboron molecules.[80]

In 2006 Suginome and co-workers reported the coupling of alkynyl(pinacol)boranes and internal alkynes catalyzed by Ni(cod)₂ with PCy₃ or PCy₂Ph as the ligand to give cis-1-borylbut-1-en-3-ynes such as 137 (Table [30]).[81] Important to this reaction was the slow (over 1–3 h using a syringe pump) addition of the internal alkyne to the mixture of alkynylborane and Ni(cod)₂ with PCy₃ or PCy₂Ph. Using 1-arylalk-1-ynes resulted in regioselective alkynylboration, with the selective introduction of the alkynyl groups at the 1-position, where the aryl group was attached (Table [30], entries 4–9). The alkynyl(pinacol)boranes utilized included arylethynyl(pincol)boranes and silylethynyl(pincol)boranes; the reactions of silylethynyl(pincol)boranes 136 with various internal alkynes gave cis-1-boryl-4-silylbut-1-en-3-ynes 137 in good yields (Table [30]). The 1-boryl-4-silylbut-1-en-3-ynes 137 could undergo further reactions such as protodesilylation or cross-coupling.

Table 30 Ni-Catalyzed Cross-Coupling of Silylethynyl(pincol)boranes and Internal Alkynes

Entry	R1	R2	Yielda (%)	Regioselectivity	Ratio cis/trans
1	Pr	Pr	92 (99)	–	92:8
2	CH2Ph	CH2Ph	67 (76)	–	96:4
3	Ph	Me	57 (62)	81:19	90:10
4	Ph	Et	65 (79)	92:8	87:13
5	Ph	Bu	68 (80)	93:7	89:11
6	4-MeOC6H4	Bu	71 (99)	93:7	73:27
7	1-naphthyl	Me	51 (79)	88:12	99:1
8	4-EtO2CC6H4	Bu	51 (79)	92:8	93:7
9	Ph	(CH2)2CH=CH2	60 (72)	94:6	89:11

^a NMR yields in parentheses.

Organotelluriums have been the subject of thorough and extensive research and are useful synthetic intermediates.[82] Vinylic tellurides are frequently used in chemical synthesis and can be obtained by the hydrotelluration of alkynes.[83] There is evidence for organic tellurium-centered radical formation that suggest hydrotelluration reactions of alkynes occur by a free radical mechanism to give the Z-configured product.[84] Comasseto and co-workers reported on the reaction of organometallic reagents with sp, sp² and sp³ hybridization (Li, MgX, and Zn species) and vinyl tellurides using catalysts such as Ni(PPh₃)₂Cl₂ or Ni(dppe)Cl₂.[85] Thus vinyl tellurides 138 reacted with lithium acetylide 139 utilizing 4–5 mol% of Ni(dppe)Cl₂ to give (Z)-1,3-enynes 140 in high yields (Table [31]).

Table 31 Ni-Catalyzed Coupling Reaction of Vinyl Tellurides and Lithium Acetylides

Entry	R	R1	Time (h)	Yield (%)
1	Ph	n-pentyl	3	100
2	Ph	Ph	12	93
3		n-pentyl	7	100
4		SiMe3	4	64
5		n-pentyl	5	97
6			5	75
7		n-pentyl	12	100

Miscellaneous

In 2020, Malakar and co-workers developed a metal-free efficient protocol for the synthesis of 1,3-enynes 141 using easily available phenylacetylenes 1 and catalytic amount of TEMPO and potassium tert-butoxide at room temperature (Scheme [53]).[86] Mechanistically, this reaction proceeds via a radical pathway (Scheme [54]). KO ^t Bu initially reacts with phenylacetylene 1 to give an intermediate potassium acetylide A that undergoes single electron transfer to give radical B. Radical B combines with another molecule of phenylacetylene via anti-approach resulting in vinyl radical C that undergoes protonation to give the 1,3-enyne product. Various functional groups were tolerated under the optimized conditions to give 1,3-enynes 141 in excellent yields and with E-selectivity (Scheme [54]).[86]

Katayama, Ozawa, and co-workers reported cross-coupling of arylacetylenes 1 and silylacetylenes 142 catalyzed by a vinylideneruthenium(II) complex to selectively give (Z)-1,3-enynes (Scheme [55]).[87] The homodimerization of arylacetylenes using catalytic Ru(II) complex I and N-methylpyrrolidine in dichloromethane at room temperature gave 1,4-diarylbut-1-en-3-ynes with high Z-selectivity, for example 4-tolylacetylene gave 1,4-di-4-tolylbut-1-en-3-yne in >99% yield and ratio Z/E/gem 92:0:8; arylacetylenes with electron-rich substituents gave high yields and high Z-selectivity while those with electron-withdrawing substituents or alk-1-ynes were unsuccessful (Table [32]). The cross-dimerization of arylacetylenes and silylacetylenes gave 1-aryl-4-silylbut-1-en-3-ynes in good yields with high Z-selectivity using ruthenium(II) complex I.

Table 32 Homocoupling of Terminals Alkynes

Entry	Ar	Time (h)	Yield (%) of 143	Ratio Z/E/gem
1	Ph	3	>99	96:1:3
2	4-MeC6H4	9	>99	92:0:8
3	4-MeOC6H4	5	96	91:1:8
4	2-fluorenyl	2	99	90:0:10
5	2-thienyl	6	82	97:0:3
6	2-MeC6H4	5	>99	93:0:7

In 2020, Gómez-Bengoa, Fernández, Lassaletta, and co-workers developed a Au(I)-catalyzed reaction between terminal alkynes and 1-aryl-2-haloacetylenes that proceeds through divergent pathways depending on the nature of the catalyst counteranion.[88] The reaction of 1-aryl-2-bromoacetylene with an arylacetylene using a AuI catalyst with a BArF₄ counteranion that has a noncoordinating nature resulted in cis-bromoalkylation to give to give 1,4-diaryl-1-bromobut-1-en-3-ynes 147a. On the other hand, under the same conditions the reaction of 1-aryl-2-haloacetylene with an arylacetylene but with a triflate counteranion that is weakly basic gave 2,4-diaryl-1-halobut-1-en-3-ynes 147b by trans-hydroalkynylation (Scheme [56]). Mechanistically, C2 from the activated haloalkyne is targeted by terminal alkyne for nucleophilic attack (Scheme [57]). The proton abstraction by the triflate anion and protodeauration are limiting steps (shown experimentally by the primary kinetic isotope effect). The gold catalyst SIPrAuCl was the most suitable catalyst giving the products 147 in up to 87% yield.

Synthesis of Enynes from Propargyl Alcohols

There are difficulties in the direct conversion of propargyl alcohols into 1,3-enynes and there few results were available in the period 1968–2018. The most efficient was found to be the self-dimerization of propargyl alcohols, metal-based dehydration cascades, and alkynylation of alkenes through C–C bond cleavage.

In 1968, Wilkinson and Singer treated propargyl alcohols with Rh catalysts to obtain 1,3-enynes.[89] Specifically, the reaction of 2-methylbut-3-yn-2-ol (148) with RhCl(PPh₃)₃ in refluxing benzene gave (E)-head-to-head product 149 in 73% yield (Scheme [58]). Under the same conditions, propargyl alcohol was not dimerized, while but-1-yn-3-ol gave a mixture of linear polymers, but 3-methylpent-1-yn-3-ol and 1-ethynylcyclohexan-1-ol gave high yields of the 1,3-enyne as the trans isomer.

The dehydration cascade process has been employed to carry out this difficult transformation using metal catalysts such as Pd, Ru, and Fe; some zeolite catalysts have also been utilized.

In 1996, Sartori and co-workers reported the dehydration of propargyl alcohols using a less acidic zeolite (HSZ-360) to give 1,3-enynes (Table [33]).[90] Thus, heating propargyl alcohols 150a–f with HSZ-360 at 65 °C for 2 h in chlorobenzene gave 1,3-enynes 151a–f in excellent yields (85–100%). The fact that the 1,3-enynes 151a (E) and 151c (Z) were obtained as the sole product is remarkable. This is most likely because the linear C≡C bond presents less steric interference than the aromatic ring.

Table 33 Zeolite (HSZ 360) Catalyzed Dehydration of Propargyl Alcohols

Entry	Substrate	R1	R2	R3	Product	Yield (%)	Isomers
1	150a	Me	Ph	H	151a	100	E
2	150b	H	Ph	Me	151b	100	E + Z
3	150c	Me	Ph	Ph	151c	100	Z
4	150d	H	Ph	H	151d	85	E + Z
5	150e	H	3-NO2C6H4	Me	151e	95	E + Z
6	150f	Et	H	Ph	151f	100	E + Z a

^a 1:1 Ratio of the two isomers was detected.

In 2003, Uemura and co-workers reported the palladium-catalyzed oxidative alkynylation of alkenes under an oxygen atmosphere by employing tert-propargylic alcohols as the alkynylation substrate to give enynes through C–C bond cleavage (Scheme [59]).[91] The reaction of tert-propargyl alcohol 148a and alkene 61 using Pd(acac)₂ as the catalyst and pyridine (2 equiv) as the base under an oxygen atmosphere gave enynes 152 in moderate yields. Pyridine was the preferred base, and at least 2 equiv. of pyridine were required for the reaction to proceed effectively without producing metallic palladium. The mechanism is for the β-carbon elimination reaction from the palladium alcoholate of tert-propargylic alcohols is shown in Scheme [60].

In 2003, Nishibayashi and co-workers examined the ruthenium-catalyzed propargylic reduction of propargylic alcohols with silanes. The reaction of 2-methyl-4-phenylbut-3-yn-2-ol (148c) and 2,4-diphenylbut-3-yn-2-ol (148d) with triethylsilane under ruthenium catalysis unexpectedly gave 2-methyl-4-phenylbut-1-en-3-yne (153) and 2,4-diphenylbut-1-en-3-yne (154), respectively (Scheme [61]).[92]

In 2012, Shi and co-workers developed a novel ligand 1,2,3-benzotriazole-1-ethanol (L8) and used it in the iron-catalyzed dehydration of propargyl alcohols 150 to give 1,3-enynes with a broad substrate range, outstanding stereoselectivity (Z-isomers only), and good to exceptional yields (up to 95%) (Scheme [62]).[93] Various triazoles were examined as ligands, of these 1,2,3-triazole L was the most effective. Even though they have similar binding patterns, N-2-hydroxyethyl-substituted tetrazole, pyridine, and 1,2,4-triazole gave poor results (5%), indicating the significant character of 1,2,3-triazole ligand L in iron catalysis.

In 2018, Li, Bao, and co-workers reported the construction of substituted 1,3-enynes by an Fe-catalyzed dehydrative decarboxylative cascade coupling process using peresters 156 and propargyl alcohols 155 (Scheme [63]).[94] The tert-butyl perester was used for the introduction of generally primary, secondary, or tertiary alkyl groups into 1,3-enynes (formed from the propargyl alcohol by Fe-catalyzed dehydration) to give 1,3-enynes 157 in moderate to good yields in an overall Fe-based dehydrative alkylation. Mechanistic findings points to the involvement of a radical-polar crossover pathway.

This route was also used for the synthesis of tetrasubstituted 1,3-enynes. Using a diacyl peroxides gave a dialkylated product, for example the reaction of excess di(dodecanoyl) peroxide (158) and propargyl alcohol 159 under the same Fe-catalyzed conditions gave diundecyl-substituted 1,3-enyne 160 in 47% yield. The reaction of 1-undecyl-substituted 1,3-enyne 161 with bis(2-(methoxycarbonyl)ethyl) peroxide (162) gave 1-undecyl-1-(2-(methoxycarbonyl)ethyl)-substituted 1,3-enyne 163 in 38% yield (Scheme [64]).

Mechanistically (Scheme [65]), based on control experiments, initially Fe(III) activates propargyl alcohol 155m to produce water and intermediate B via intermediate A. The alkyl radical is formed through a single electron transfer process between the alkyl perester 156m and Fe(II), which then attacks intermediate B to give benzylic radical intermediate C. Benzylic radical C is oxidized by Fe(III) to produce benzylic carbocation intermediate D and Fe(II). Finally, the benzylic carbocation D is deprotonated to provide the targeted 1,3-enyne 157m.

Metal/Acid-Catalyzed Ring Opening of Cyclopropanes

New protocols for the synthesis of 1,3-enynes are highly desirable because of their reliability in constructing many compounds of biological and material interest. One area of interest is the ring opening of cyclopropanes through nucleophilic attack.[95] In 2007, Liang and co-workers reported Au(III)-catalyzed ring-opening reaction of 1-cyclopropyl-2-yn-1-ols 164 with nucleophiles, shown in Scheme [66] for methanol as the nucleophile, to give substituted 1,3-enynes 165 in excellent yields and high regio- and stereoselectivity.[96] A range of alcohols were used as the nucleophile giving the corresponding 1,3-enynes in 78–90% yields. In a metal-free approach, the ring opening of 164a with TsOH gave 1,3-enyne 165a in a lower 58% yield (Scheme [67]).[96] Mechanistically, it is proposed that the cyclopropane with a hydroxy group at the α-position undergoes a ring-opening reaction after being activated by the gold catalyst in the presence of the nucleophile.

In 2005, Nishibayashi and co-workers reported the Ru-catalyzed reactions of 1-cyclopropylprop-2-yn-1-ols with nitrogen- and oxygen-centered nucleophiles in the presence of a catalytic amount of a sulfur-bridged diruthenium complex in an efficient preparation of 1,3-enynes in 45–87% yields (Scheme [68]).[97] The nucleophiles were predominantly anilines with 2 examples of the use of water. For example, the reaction of 1-cyclopropyl-1-phenylprop-2-yn-1-ol (166) and aniline (167) using diruthenium complex X gave N,4-diphenylhex-3-en-5-ynylamine (168) in 89% yield. This route was utilized for the stereoselective synthesis tri- and trisubstituted 1,3-enynes.

In 2008, Chan and Rao reported the gold- and silver-catalyzed tandem amination/ring expansion of cyclopropyl methanols with sulfonamides as an expedient route to pyrrolidines.[98] The AuCl/AgOTf-catalyzed tandem cyclopropane ring opening strategy was utilized for the reaction of 1-cyclopropyl-3-(4-tolyl)prop-2-yn-1-ol (169) with tosylamine (170) to give AuCl/AgOTf-catalyzed tandem ring expansion of the cyclopropane ring resulting in the formation of 6-(4-tolyl)-N-tosylhex-3-en-5-ynamine (171) in 69% yield with E/Z 1:1 (Scheme [69]).

In 2009, Chan and co-workers utilized the catalyst ytterbium(III) triflate for the ring opening of 1-cyclopropylprop-2-yn-1-ols 164 in a straightforward and efficient synthetic route for the preparation of 1,3-enynes 172 in moderate to good yields with high regioselectivity (Scheme [70]).[95]

Also in 2009, Chan and Mothe reported a highly efficient metal-free approach for the ring opening of a various 1-cyclopropylprop-2-yn-1-ols 173 using alcohols as the nucleophile to obtain 1,3-enynes 174 (Scheme [71]).[99] The catalyst (TfOH) loading was as low as 0.01 mol% with complete regioselectivity and excellent yields (up to 100%).

Mechanistically (Scheme [72]), the reaction is initiated by the catalyst TfOH reacting with propargyl alcohol 173 to give protonated A, followed loss of water to give carbocation B and ring opening of the cyclopropane moiety and finally nucleophilic attack by the alcohol forming the 1,3-enyne product 174.

Conclusion

The synthesis of 1,3-enynes has garnered considerable interest due to its diverse applications in organic synthesis. Palladium complexes have been employed to facilitate the synthesis of 1,3-enyne through Sonogashira cross-coupling reactions and other established methods. These alkynylation reactions have emerged as a prominent area in organometallic chemistry, with Pd complexes, particularly neutral and cationic complexes, serving as the most potent catalysts for sp–sp and sp–sp² carbon coupling reactions. The process of arylalkynylation involves the utilization of aryl or vinyl iodides, internal or terminal alkynes, alkynylsilanes, and TIPSA, all under Pd catalysis and mild conditions. Notably, the significant progress in the efficient and cost-effective synthesis of 1,3-enynes has been facilitated by the development of newly formed palladacycles, as well as the exploration of alternative metals such as copper, iron, and nickel, thus reducing reliance on expensive metals like Pd, Rh, and Ru. The introduction of these economical metals has revolutionized the perspective of carbon coupling, with their potential being further enhanced in the presence of suitable ligands and bases. However, the absence of these auxiliaries poses a challenge to achieve comparable results. Hence, the conjunction of these cost-effective metals with environmentally friendly ligands and bases has the potential to replace precious metals and advance the synthesis of various organic compounds. This wealth of knowledge contributes to the potential substitution of expensive metals in catalyzing diverse coupling reactions, thereby enhancing the quality and mitigating the limitations of organic compound synthesis. This review also examines cascade dehydration processes of propargyl alcohols using different metal catalysts, as well as metal- or acid-catalyzed ring opening of cyclopropane moieties for the synthesis of 1,3-enynes. These examples underscore the efficacy and sophistication involved, emphasizing the critical role of metal and acid catalysts in organic synthesis, thereby inspiring the development of novel protocols for the synthesis of essential building blocks such as 1,3-enynes.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We sincerely thank all the chemists who contributed towards the wellbeing of the scientific community. The authors are grateful to all the co-workers whose names appeared in the references.

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