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DOI: 10.1055/s-0034-1380444
Rhodium-Azavinylcarbene: A Versatile Synthon-Enabling Divergent Synthesis of Nitrogen Heterocycles
Publication History
Received: 29 April 2015
Accepted after revision: 21 May 2015
Publication Date:
07 July 2015 (online)
Abstract
Over the past several years, rhodium-azavinylcarbene (Rh-AVC) has grown into an enabling synthon for the synthesis of diverse nitrogen heterocycles. Herein we present an overview of our recent achievements in this field, including the Rh-AVC-promoted formal [4+3], [3+3], and [3+2] cycloadditions. These reactions allow for the efficient synthesis of several classes of important nitrogen heterocycles, such as azepines, pyrroles, and pyrazines. Some relevant works from other groups are also briefly discussed.
1 Introduction
2 Formal [4+3] and [3+2] Cycloadditions of 1,2,3-Triazoles with 1,3-Dienes
3 Formal [3+2] Cycloadditions of 1,2,3-Triazoles with Silyl or Alkyl Enol Ethers
4 Formal [3+3] and [3+2] Cycloadditions of 1,2,3-Triazoles with 2H-Azirines
5 Conclusion and Perspective
# 1
Introduction
1,2,3-Triazoles are an important class of heterocycles which find widespread applications in organic chemistry, medicinal chemistry, and material science.[1] Historically, the development of new methods for the synthesis of 1,2,3-triazoles attracted considerable interests from the synthetic community.[2] In contrast, their potential as the precursors for accessing other heterocycles has rarely been explored. In 2007, Gevorgyan reported a novel rhodium(II)-catalyzed formal [3+2] cycloaddition of pyridotriazoles with terminal alkynes,[3] which opened a new avenue to utilize 1,2,3-triazoles as convenient precursors for generating rhodium-azavinylcarbene (Rh-AVC), a versatile synthon that enables the synthesis of diverse nitrogen-containing heterocycles.[4] Since then, explosive developments have been witnessed in this research area, mainly attributed to the contributions from the Fokin, Gevorgyan, Murakami, and Davies group.[5]
Xiaoqiang Lei was born in Gansu Province, P. R. of China in 1990. He received his BSc degree from Changzhou University in 2013, then joined Prof. Yupeng He’s research group in Liaoning Shihua University to pursue his MSc degree. He is currently working as a visiting student in Prof. Yefeng Tang’s group at Tsinghua University. His current research mainly focuses on the development of novel synthetic methodology for heterocycle synthesis.
Yefeng Tang was born in Xinjiang Province, P. R. of China in 1976. He received his BSc degree from Lanzhou University, and then his MSc degree from the Institute of Materia Medica, Chinese Academy of Medical Science. During the period of 2003–2006, he pursued his PhD degree under the supervision of Prof. Zhen Yang at Peking University. He then joined Prof. K. C. Nicolaou’s group at The Scripps Research Institute as a postdoctoral associate (2006–2009). He started the independent career as a tenure-track assistant professor in the Department of Pharmacology and Pharmaceutical Sciences, Tsinghua University in 2010, and then was promoted to associate professor in 2013. His major research interests include the total synthesis of bioactive natural products, synthetic methodology development, and antiviral drug discovery.
Readily generated from 1-sulfonyl 1,2,3-triazoles upon treatment with rhodium(II) catalyst (Scheme [1]), Rh-AVC displays versatile reactivities beyond the classical diazo-compound-derived metallocarbenes. As shown, it could serve as the [1C]-synthon in cyclopropanation,[6] X–H (X = C, O and N) insertion,[7] and ylide formation followed by rearrangement.[8] Alternatively, due to its dipolar nature it could also function as the aza-[3C]-synthon in a wide range of cycloadditions, such as formal [3+2],[9] [3+3],[10] and [4+3][11] reactions. More recently, the application of Rh-AVC as the [2C]-synthon was also demonstrated (Scheme [1]).[12]
Our interests on this emerging research area arise from a collaborative program between our group and Bayer Health Care Company Ltd. The primary goal of this program is to get some valuable heterocycles that could be applied to fragment-based drug discovery (FBDD). The Rh-AVC chemistry attracted our attention mainly for two reasons. First, the versatile reactivities of Rh-AVC perfectly match our objective to build up the different heterocycle libraries. Second, we anticipated that the synthetic potential of Rh-AVC chemistry is far from fully explored, thus leaving room for the invention of some novel chemistries. During the past two years, we successfully developed several interesting Rh-AVC-promoted cycloaddition reactions,[11a] [d] [12a] [13] which enabled the efficient synthesis of various valuable heterocycles, including azepines, pyrroles, 3-pyrrolin-2-ones, and pyrazines (Scheme [2]). Herein we present an overview of our recent achievements on this subject. Meanwhile, some other relevant works are also briefly discussed.
# 2
Formal [4+3] or [3+2] Cycloadditions of 1,2,3-Triazoles with 1,3-Dienes
Initiated in early 2013, our first project[11a] was directed toward the synthesis of azepines, a class of seven-membered nitrogen heterocycles that are widely distributed in natural products and pharmaceuticals. While many approaches have been developed for their synthesis,[14] most suffer from several inherent issues including the difficult availability of precursors, limited substrate scope, and moderate efficiency. Given that Rh-AVC has proved to be an enabling aza-[3C]-synthon in a variety of [3+2] cycloadditions,[9] we conceived that it was feasible to achieve the [4+3] cycloadditions with 1,3-dienes used as [4C] component.
Initially, 4-phenyl-1-tosyl 1,2,3-triazole (1a) and (E)-1-phenyl-1,3-butadiene (2a) were treated with 1 mol% Rh2(oct)4 in 1,2-DCE at 120 °C for 12 hours. As a result, the expected [4+3] adduct 3a was isolated in 37% yield, together with another product, the formal [3+2] adduct 4a in 55% yield (Scheme [3], eq. 1). We further found that extending the reaction time led to the formation of 4a as the sole product, indicating that 3a could gradually convert into 4a in the reaction.
Encouraged by initial outcomes, we optimized the reaction conditons to improve the [4+3]/[3+2] selectivity of the cycloadditions. After evaluating several reaction parameters including rhodium(II) catalysts, temperature, solvent, and geometry of the 1,3-diene partner, we finally found that the geometry of the 1,3-dienes played a crucial role in determining the product distribution. When the reaction was performed with (E)-1-phenyl-1,3-butadiene (2a) at high temperature for long reaction time, the [3+2] product 4a was obtained as the sole product in excellent yield (Scheme [3], eq. 2). In contrast, when (Z)-1-phenyl-1,3-butadiene (5a) was employed with low temperature and short reaction time, the [4+3] product 3a could be isolated predominantly (Scheme [3], eq. 3). These findings were notable, since they enabled the diverted synthesis of two types of different heterocycles from the common 1,2,3-triazoles with the judicious selection of the substrates and reaction conditions.
The generality of the above transformations was evaluated with a range of 1-aryl-1,3-dienes and 4-aryl-1,2,3-triazoles. Generally, when (E)-1-aryl-1,3-dienes and conditions A were employed, the reactions led to the [3+2] adducts 4 in good to excellent yields. In contrast, for the reactions using (Z)-1-aryl-1,3-dienes and conditions B, the 2,5-dihydroazepines 3 were obtained with good efficiency. Both of the two types of cycloadditions showed little electronic and steric effects with regard to the Ar1 and Ar2 substituents (Scheme [4]). Furthermore, it was proved that 2-aryl-1,3-dienes could also be applied to the cycloadditions. Different from 1-aryl-1,3-dienes, this type of substrates mainly afforded the [4+3] adducts 7, although small amounts of the corresponding [3+2] adducts could also be identified in some cases.
Comparably, when 1-alkyl-substituted 1,3-dienes (e.g., 8a,b) were submitted to the reactions, a mixture of the corresponding [4+3] and [3+2] adducts were obtained, generally favoring the latter products (Scheme [5]). Importantly, some cyclopropylaldimine intermediates such as 9a and 9b could be observed at the early stage of these reactions, which, after isolation, could further convert into the corresponding [3+2] and [4+3] adducts under the thermal conditions (140 °C, 12 h).
The plausible mechanism of the cycloadditions of 1,2,3-triazoles with 1,3-dienes is depicted in Scheme [6]. As shown, Rh-AVC A first reacts with 1,3-diene B via [2+1] cycloaddition to form cyclopropylaldimine C, which then further converts into 2,5-dihydroazepine D and 2,3-dihydropyrrole E, respectively, via aza-Cope-rearrangement[15] (path a) and cyclopropylimine rearrangement (path b).[16] It appears that both the substitution pattern and geometry of the 1,3-diene partners have profound impact on the reaction pathways. For examples, when (Z)-1-aryl- and 2-aryl-1,3-dienes were employed, the path a would take place predominantly to afford D. In contrast, for (E)-1-aryl-1,3-dienes and 1-alkyl-1,3-dienes, both path a and b might proceed concurrently, yielding a mixture of D and E. For the 1-aryl-1,3-dienes, the resulting product D (R = 2-Ar, Scheme [6]) could readily undergo allylic amine 1,3-migration to advance to thermodynamically more stable E.
Of note, shortly after we disclosed our results, a similar transformation was achieved independently by Lee and co-workers.[11b] As shown, the cycloadditions of various 4-aryl-1-(methylsulfonyl)-1,2,3-triazoles and 1-aryl-1,3-dienes were investigated, which led to either the [3+2] or [4+3] adducts (Scheme [7]). Impressively, in this work the product distribution could be controlled by using different reaction conditions, which enhanced the synthetic utility of these transformations.
Almost at the same time, Sarpong and co-workers reported an intramolecular [4+3] cycloaddition of dienyltriazoles, which resulted in the formations of a variety of bicyclic fused azepine derivatives.[11c] Mechanistically, the intramolecular reaction was also believed to proceed through tandem cyclopropanation–aza-Cope rearrangement via the intermediate 14. Notably, in parallel with Sarpong’s work, we also achieved the same transformations independently, albeit with slightly different reaction conditions and substrate scope documented (Scheme [8]).[11d]
# 3
Formal [3+2] Cycloadditions of 1,2,3-Triazoles with Silyl or Alkyl Enol Ethers
As extension of the first part of work, we recently reported another synthetically useful transformation, the formal [3+2] cycloadditions of 1,2,3-triazoles with silyl or alkyl enol ethers.[13] The original idea was inspired by an occasional observation in our previous work. When we investigated the cycloaddition of 1a with 2-TIPSO-1,3-diene (15), substantial amounts of the [3+2] adduct 16 was obtained besides the [4+3] adduct (Scheme [9, a]). Interestingly, it was found that 16 was unstable and gradually converted into the pyrrole derivative 17 upon chromatographic purification. This discovery inspired us to develop a general strategy for the synthesis of pyrroles via a formal [3+2] cycloaddition with silyl enol ethers used as [2C] component (Scheme [9, b]). While the formal [3+2] cycloaddition of 1,2,3-triazoles with alkynes and allenes were well documented,[9a] [b] [c] [d] their synthetic utilities for pyrrole synthesis often suffer from limited substrate scope and poor regioselectivity. We assumed that the electron-rich nature of silyl enol ether combined with its dipolar character would render the proposed [3+2] cycloadditions with ideal reactivity and selectivity.
The designed chemistry was quickly validated. As shown, the treatment of 1a and TIPS-protected 1,1-disubstituted enol ether 18a with 1% Rh2(oct)4 in 1,2-DCE at 100 °C for one hour afforded the corresponding [3+2] adduct, which, not isolated, was further treated with TsOH (2.0 equiv) for another three hours, providing the desired product 19a in 79% yield. Furthermore, we found that the less hindered TBS-enol ether 18b displayed superior reactivity than 18a by giving a higher yield of product (Scheme [10], eq. 1).
In contrast, when 1,2-disubstituted substrate TBS-enol ether 20a was submitted to the reaction, only a moderate yield of the desired product 21a was obtained. It appeared that the increasing steric hindrance of 1,2-disubstituted silyl enol ether might decrease its reactivity. Thus, we turned to examine the less sterically hindered alkyl enol ethers in the reaction. To our delight, while the methyl enol ether 20b failed to give the desired product in satisfying yield, the ethyl enol ether 20c displayed superior reactivity by affording 21a in 90% yield (Scheme [10], eq. 2).
The generality of the above transformations was then examined by employing various 1,1- or 1,2-substituted silyl/alkyl enol ethers. To our delight, most of the reactions with aryl-substituted enol ethers could undergo the desired transformations, affording the corresponding pyrrole products in good to excellent yields. Comparably, although the alkyl-substituted enol ethers also proved to be amenable to the transformations, they generally displayed slightly inferior reactivity, with only moderate yields of products obtained (Scheme [11]).
Finally, we proved that the silyl ketene acetals could also be used as [2C] component in the cycloadditions. As shown, as the proof-of-concept cases, three representative silyl ketene acetals 22a–c (R = H, Me, or Ph) were evaluated. All of them underwent the desired cycloadditions smoothly. However, the resulting products were unstable and readily underwent sequential elimination–deprotection–isomerization to afford the 3-pyrrolin-2-ones 23a–c as final products (Scheme [12]). Notably, 3-pyrrolin-2-one represents a key structural element in various natural products and bioactive molecules. Thus, the above reaction provides a new method to access related heterocycles.
Coincidentally, when this part of work was undertaken in our lab, some relevant studies were independently conducted by several other groups. For examples, the [3+2] cycloadditions of 1,2,3-triazoles with the alkyl enol ethers were subsequently disclosed by Lee[17] and Anbarasan.[18] The cycloadditions of 1,2,3-triazoles with silyl ketene acetals was also achieved by Li and co-workers.[19] While these elegant works largely enrich the current toolbox of methods for the synthesis of pyrroles and related derivatives, we will not discuss the details on this occasion for the limited space.
# 4
Formal [3+3] or [3+2] Cycloadditions of 1,2,3-Triazoles with 2H-Azirines
As mentioned in the introduction, the synthetic utility of Rh-AVC as [1C] or aza-[3C] synthon has been fully explored during the past several years. However, its potential as [2C] synthon has not been discovered until very recently. In early of 2015, we disclosed an unprecedented formal [3+3] and [3+2] cycloaddition of 1,2,3-triazoles with 2H-azirines.[12a] Of note, the reported [3+2] cycloaddition represents the first application of 1,2,3-triazoles as [2C] component in related cycloaddition reactions.
Our initial plan was to achieve a formal [3+3] cycloaddition with 1,2,3-triazoles and 2H-azirines, wherein both reactants were supposed to serve as aza-[3C] component. However, to our surprise, when the substrates 1a and 24a were treated with the standard conditions employed in our previous studies [Rh2(OAc)4, 1,2-DCE, 140 °C], a 3-amino-pyrrole derivative 25a was obtained in 48% yield, with no trace amount of the [3+3] adduct 26a observed (Scheme [13]). This discovery, albeit unexpected, deserved further investigation, since it represented a formal [3+2] cycloaddition, in which the triazole partner served as an unusual [2C] component.
After a simple optimization of reaction conditions, we found that using the bidentate catalyst Rh2(esp)2 could notably increase the yield to 81%. More pleasingly, the generality of the transformation turned out to be pretty good. As shown, a diverse range of 3-aryl- or 2-alkyl-2H-azirines and 4-aryl-1,2,3-triazoles could tolerate the optimal conditions very well, affording the corresponding 3-amino-pyrrole products in satisfying yields (Scheme [14]).
However, when 2,3-diphenyl-2H-azirine 27a was submitted to the optimal conditions, a mixture of 3-amino-pyrrole 28a and 1,2-dihydropyrazine 29a were obtained. To improve the synthetic utility of the reaction, we conducted a systematic screening of conditions. Finally, we found that changing the solvent from 1,2-DCE to toluene resulted in the formation of 29a as major product; in comparison, the use of substoichiometric amounts of ClCH2COOH as additive could invert the selectivity by furnishing 28a with high yield (Table [1]).
The above discovery was encouraging, since it enabled the divergent synthesis of two different heterocycles from the common precursor simply by tuning reaction conditions. Gratifyingly, the dual reaction systems could be extended to an array of 2,3-diaryl-2H-azirines and 2-alkyl-3-phenyl-2H-azirines, all of which afforded the expected [3+3] adducts, under conditions B and [3+2] adducts under conditions C in good yields and selectivity.
Furthermore, we found that the 2-aryl-3-alkyl-2H-azirines displayed different reactivity from the above-mentioned 2,3-disubstituted 2H-azirines. This type of substrates only yielded the [3+3] adducts 31, regardless of whether conditions B or C were employed. In sharp contrast, when the 2-carboxylate-3-aryl/alkyl-2H-azirines were used in the reaction, they showed propensity similar to the monosubstituted 2H-azirines, affording [3+2] adducts 30 in excellent yields (Scheme [15]).
The plausible mechanism of the formal [3+3] and [3+2] cycloadditions of 1,2,3-triazoles with 2H-azirines was postulated as shown in Scheme [16]. Thus, nucleophilic attack of 2H-azirine to the Rh-AVC intermediate A leads to azirinium ylide B. At this point, there are several possibilities for B to evolve into the final products, which are highly dependent on the structural feature of the 2H-azirines. On one hand, a ring-opening reaction followed by nucleophilic attack of N-1 to C-2 with the release of rhodium(II) catalyst could afford the dihydropyrazine (path a-1) directly. Alternatively, B could convert into 1,4-azatriene C at first, which then advanced to the dihydropyrazine via 6π electrocyclization (path a-2). While both of the two pathways may account for the formation of the [3+3] adduct, the usage of nonpolar solvent (e.g., toluene, conditions B) might favor the latter process. On the other hand, B could also evolve to carbocation D via a resonant equilibrium, which then undergoes ring expansion to give the zwitterionic intermediate E. After proton transfer followed by tautomerization, E could advance to the 3-amino-pyrrole (path b). This pathway proceeds dominantly in the reactions with monosubstituted 2H-azirine or 2-carboxylate-3-aryl/alkyl-2H-azirine (R2 = H or CO2Et).
It should be pointed out that, in a very short period of time after we disclosed our results, several relevant works were successively published elsewhere. Shi, Tang, and co-workers reported a formal [3+2] cycloaddition of 1,2,3-triazoles with various 2-carboxylate-3-aryl/alkyl-2H-azirines (Scheme [17], eq. 1).[12b] Similar to our results, the 3-amino-pyrrole derivatives 32 were obtained in most of the documented cases. In sharp contrast, while similar substrates were employed by Lee and co-workers, they achieved a formal [3+3] cycloaddition by using different reaction conditions (Scheme [17], eq. 2).[10b] Moreover, in the latter transformations, the resulting dihydropyrazines could convert into the corresponding pyrazine derivatives in situ via elimination of the arylsulfinic acid. Thus, these works together with ours provide another showcase of diverted synthesis of different heterocycles with the same precursors but different reaction conditions.
# 5
Conclusion and Perspective
In conclusion, as an emerging research area, Rh-AVC chemistry is now undergoing its golden age of development. A vast amount of intriguing transformations have been developed over the past several years, which largely extends its synthetic utility in organic synthesis, especially for the rapid construction of various heterocycles. Looking ahead, there remain some considerable challenges to be addressed in this area, which include but are not limited to: 1) discovering new mode of reaction with Rh-AVC, such as its underdeveloped synthetic potential as [2C] synthon; 2) searching for new variants of Rh-AVC derived from other metal catalysts or precursors; 3) developing new Rh-AVC-promoted multicomponent reactions to get some valuable structural motifs which could not be readily accessed by the currently known methods; 4) applying Rh-AVC-based methodologies to the total synthesis of complex molecules, such as natural products and drug molecules. There is no doubt that many more conceptually novel and synthetically useful transformations based on Rh-AVC chemistry will appear in the near future.
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Acknowledgment
We gratefully acknowledge the financial supports from the NSFC (21272133), Beijing Natural Science Foundation (2132037) and Tsinghua-Bayer Collaborative Project.
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For selected reviews, see:
For selected examples, see:
For leading reviews, see:
For selected examples, see:
For selected examples, see:
For selected examples of the synthesis of azepines, see:
For examples of aza-Cope rearrangement leading to azepines and related derivative, see:
For reviews on cyclopropylimine rearrangement, see:
For selected examples, see:
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References
- 1a Fan WQ, Katritzky AR In Comprehensive Heterocyclic Chemistry II . Vol. 4. Katritzky AR. Pergamon Press; Oxford: 1996: 1
- 1b Muller T, Bräse S. Angew. Chem. Int. Ed. 2011; 50: 11844
- 1c Thirumurugan P, Matosiuk D, Jozwiak K. Chem. Rev. 2013; 113: 4905
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For selected reviews, see:
For selected examples, see:
For leading reviews, see:
For selected examples, see:
For selected examples, see:
For selected examples of the synthesis of azepines, see:
For examples of aza-Cope rearrangement leading to azepines and related derivative, see:
For reviews on cyclopropylimine rearrangement, see:
For selected examples, see:
Xiaoqiang Lei was born in Gansu Province, P. R. of China in 1990. He received his BSc degree from Changzhou University in 2013, then joined Prof. Yupeng He’s research group in Liaoning Shihua University to pursue his MSc degree. He is currently working as a visiting student in Prof. Yefeng Tang’s group at Tsinghua University. His current research mainly focuses on the development of novel synthetic methodology for heterocycle synthesis.
Yefeng Tang was born in Xinjiang Province, P. R. of China in 1976. He received his BSc degree from Lanzhou University, and then his MSc degree from the Institute of Materia Medica, Chinese Academy of Medical Science. During the period of 2003–2006, he pursued his PhD degree under the supervision of Prof. Zhen Yang at Peking University. He then joined Prof. K. C. Nicolaou’s group at The Scripps Research Institute as a postdoctoral associate (2006–2009). He started the independent career as a tenure-track assistant professor in the Department of Pharmacology and Pharmaceutical Sciences, Tsinghua University in 2010, and then was promoted to associate professor in 2013. His major research interests include the total synthesis of bioactive natural products, synthetic methodology development, and antiviral drug discovery.
