Design of Novel Hydrogen-Bonding Donor Organocatalysts and Their Application to Asymmetric Direct Aldol Reaction

Abstract

Asymmetric catalytic activities of various organocatalysts bearing double hydrogen-bonding donor units showing different pK _a values were examined for direct aldol reactions of cyclohexanone with aromatic aldehydes. Organocatalyst with motif exhibiting the highest acidity resulted in the corresponding aldol products with the highest enantioselectivity. A good correlation has been observed between the asymmetric catalytic activity for direct aldol reactions and acidities of double hydrogen-bonding donating units.

In general, organocatalysts exhibit desirable properties such as low toxicity, convenient handling, and stability compared to metal catalysts and can efficiently synthesize a valuable chiral molecule under mild reaction conditions. A number of organocatalysts have been successfully developed over the past few decades due to their benefits.[1] An organocatalyst bearing thiourea group that can function as a double hydrogen-bonding donor such as the Takemoto catalyst is one of the most effective catalyst and finds application in a wide range of asymmetric reactions.[2] Based on the concept of a double hydrogen-bonding donor, the modified Takemoto catalyst, exhibiting enhanced acidity by the introduction of an electron-withdrawing group, has been developed by some research groups.[3] In addition, the squaramide motif also served as a double hydrogen-bonding donor, and the molecules containing squaramide skeleton are excellent organocatalysts for various stereoselective reactions.[4] Recently, we reported that organocatalysts bearing diaminomethylenemalononitrile (DMM) motif, illustrated as (NC)₂C=C(NHR)₂, make it possible to promote some asymmetric carbon–carbon or carbon–phosphine bond-forming reactions.[5] We demonstrated that DMM motif served as a hydrogen-bonding donor to provide an excellent catalytic activity. Aldol reactions of cyclic ketones with aromatic aldehydes in the presence of organocatalyst 6 and 2,4-dinitrobenzoic acid easily afforded aldol products with high enantioselectivities. However, in the conditions without 2,4-dinitrobenzoic acid, we obtained aldol products with low stereoselectivities.[5d] Therefore, we envisaged that the development of a double hydrogen-bonding donor that can efficiently activate a substrate without the addition of a protic acid is vital. The remarkable feature on the push–pull ethylene structure of DMM is that the structure can control the acidity of N–H moieties by introducing other electron-withdrawing groups instead of two cyano groups in the DMM motif. Moreover, we reported that the diaminomethyleneindendione derivative is a good organocatalyst for the asymmetric additions of ketones to maleimides.[6] We infer that the acidity of a double hydrogen-bonding donating group plays a significant role for the asymmetric catalytic activity of organocatalysts. However, to the best of our knowledge, a good correlation between asymmetric catalytic activity and the acidity of a double hydrogen-bonding donating group has not been reported. We hypothesized that by increasing the acidity of the N–H moieties in the DMM motif, the activity of coordination to electrophiles could be enhanced and higher activities and stereoselectivities of organocatalysts would be obtained. Here we describe the good correlation between acidity of a double hydrogen-bonding donating group and the asymmetric organocatalytic activity for direct aldol reactions.

First, we examined the acidities of N–H moieties on various push–pull ethylene motifs. To measure the exact pK _a values of push–pull ethylene motifs, each organocatalysts 2–5 bearing simple isopropylated structure without chiral amine groups were prepared. By means of a voltammetric method based on the appearance of the reduction prepeak of vitamin K3,[7] the pK _a values of organocatalysts 1–5 in DMSO solution were determined (Figure [1]). Weak acidities of thiourea 1 and urea 2 were observed (pK _a >15).[8] The DMM motif 3 showed a lower pK _a value than 1 and 2. Organocatalyst 4 [9] with two triflyl groups as more powerful electron-withdrawing group exhibited higher acidity than 3. Although the number of fluorine atoms of organocatalysts 4 and 5 [10] is equal, the strongest acidity was observed by organocatalyst 5 bearing cyclic perfluorohexanedisulfonyl group.

To elucidate the relationship between asymmetric catalytic activity of organocatalysts and acidities of double hydrogen-bonding donating units, organocatalysts 6–9 [11] with the corresponding motifs were prepared and were examined for the catalytic activities for direct aldol reactions (Figure [2]). We selected direct aldol reactions of cyclohexanone (11) with 4-nitrobenzaldehyde (10a) as one of the most popular and valuable asymmetric reactions using organocatalysts.[1] [12] [13] Among the examined organocatalysts 6–9, catalyst 9 bearing hydrogen-bonding donating group, which showed the most lowest pK _a value, exhibited the highest stereoselectivity (Table [1]).

Table 1 Catalyst Screening

Entry	Catalyst	Yield (%)b	anti/syn b	ee (%)c
1d	6	98	77:23	–11
2	7	63	68:32	–31
3	8	86	93:7	95
4	9	91	93:7	97

^a Isolated yield.

^b Determined by ¹H NMR analysis.

^c Determined by chiral HPLC analysis.

^d Ref. 5d.

Table 2 Study of Reaction Conditions

Entry	Cat. 9 (mol%)	Temp (°C)	Time (h)	Yield (%)a,b	anti/syn b	ee (%)c
1	10	r.t.	72	91	97:3	97
2	10	40	48	97	94:6	94
3	10	60	24	83	88:12	88
4	5	40	24	42	95:5	97
5	1	40	48	28	93:7	96

^a Isolated yield.

^b Determined by ¹H NMR analysis.

^c Determined by chiral HPLC analysis.

We optimized the reaction conditions for the enantioselective direct aldol reactions as shown in Table [2]. Aldol reactions were performed with aldehyde 10a and cyclohexanone (11, 10 equiv) in the presence of a catalytic amount of 9 (10 mol%) under neat conditions. To improve the reaction time, the reactions were performed at higher temperatures (40 °C or 60 °C), and the reaction times were reduced, which caused decrease in enantioselectivities (Table [2], entries 1–3). High enantioselectivities were retained, although yields were decreased when lowering the catalyst loading to 5 mol% and 1 mol% at 40 °C (Table [2], entries 4 and 5). Therefore, the optimized reaction conditions were determined to be those used for entry 1 (Table [2]).

By determining the optimal conditions, the scope and limitations of the direct aldol reactions of cyclohexanone with various aromatic aldehydes (10b–l) were examined (Table [3]).[14] We selected the substrates bearing nitro, trifluo­romethyl, cyano, and halogen substituents as representatives of electron-withdrawing group at benzene ring. The reaction of aldehydes substituted by a nitro group at meta or ortho positions (10b and 10c) with cyclohexanone (11) produced the corresponding anti-aldol products 12b and 12c in high yields with excellent stereoselectivities (Table [3], entries 1 and 2). The benzaldehydes substituted by cyano, trifluoromethyl, bromo, and chloro groups at para position (10d–g) were also converted into the corresponding anti-aldol products (12d–g) in good yields with high enantioselectivities (Table [3], entries 3–6). Aldehydes with a chloro group at meta or ortho positions (10h and 10i) reacted with 11 to provide the adducts 12h and 12i with good enantio­selectivities (Table [3], entries 7 and 8). The aldol reactions of substrates 10j and 10k bearing multihalogen substituents afforded excellent diastereoselectivities and enantioselectivities (Table [3], entries 9 and 10). Simple and low reactive benzaldehyde (10l) also reacted with 11 in the presence of catalyst 9, affording the corresponding aldol products 12l with moderate yield and high enantioselectivity (Table [3], entry 11). The reaction of 10a with ketone bearing acetal group proceeded, affording the corresponding product 12m with excellent stereoselectivity (Table [3], entry 12). Note that, in this reaction, the catalyst 9 did not affect acid-sensitive acetal functionality under the present conditions. Acetone as other type ketone reacted with aldehyde 10a to give the aldol product 12n with moderate enantioselectivity (Table [3], entry 13). The reaction of cycloheptanone with 10a did not provide the corresponding aldol product.

Table 3 Study of Substrate Scope

Entry	Aldehyde 10	Product 12	Time (h)	Yield (%)a,b	anti/syn b	ee (%)c
1	10b	12b	120	80	96:4	97
2	10c	12c	120	89	93:7	98
3	10d	12d	72	71	95:5	92
4	10e	12e	120	65	94:6	93
5d	10f	12f	120	74	93:7	94
6 d	10g	12g	120	73	92:8	90
7	10h	12h	120	66	94:6	92
8d	10i	12i	120	87	88:12	89
9	10j	12j	120	88	>99:1	94
10	10k	12k	96	79	>99:1	96
11	10l	12l	120	42	89:11	82
12e	10a	12m	72	68	93:7	95
13f	10a	12n	120	57		68

^a Isolated yield.

^b Determined by ¹H NMR analysis.

^c Determined by chiral HPLC analysis.

^d Catalyst 9 (20 mol%) was used.

^e Ketone (2 equiv) and THF (0.2 mL) were used.

^f The reaction was carried out at 40 °C.

Based on the stereochemistry of the aldol products 12, we inferred that the aldol reactions of aldehydes with cyclohexanone using organocatalyst 9 would proceed through a plausible transition-state model as shown in Figure [3].

In conclusion, the novel organocatalyst 9 exhibited more powerful acidity among the examined organocatalysts 6–9 and can efficiently work for the direct aldol reaction of various aldehydes with ketones under neat conditions without additive such as a protic acid to provide the corresponding aldol products with excellent enantioselectivities. The good correlation between the asymmetric catalytic activity of organocatalysts and acidities of double hydrogen-bonding donating units were observed. In addition, the application of the push–pull ethylene structure-type of organocatalysts to other types of asymmetric reactions and the development of additional novel organocatalysts are currently being investigated in our laboratory.

No conflict of interest has been declared by the author(s).

Acknowledgment

This work was supported by JSPS KAKENHI Grant Number 16K08178. We thank Dr. Tsunetoshi Honda (Mitsubishi Materials Electronic Chemicals Co., Ltd.) for the kind donation of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride.

• References and Notes


For selected reviews, see:
• 1a Dalko PI, Moisan L. Angew. Chem. Int. Ed. 2004; 43: 5138-5138
  CrossrefSearch in Google Scholar
• 1b Modern Aldol Reactions . Vol. 1 and 2. Mahrwald R. Wiley-VCH; Weinheim: 2004
  Search in Google Scholar
• 1c Mukherjee S, Yang JW, Hoffmann S, List B. Chem. Rev. 2007; 107: 5471-5471
  CrossrefSearch in Google Scholar
• 1d Pellisier H. Tetrahedron 2007; 63: 9267-9267
  CrossrefSearch in Google Scholar
• 1e Dondoni A, Massi A. Angew. Chem. Int. Ed. 2008; 47: 4638-4638
  CrossrefSearch in Google Scholar
• 1f Gruttadauria M, Giacalone F, Noto R. Adv. Synth. Catal. 2009; 351: 33-33
  CrossrefSearch in Google Scholar
• 1g Lattanzi A. Chem. Commun. 2009; 1452-1452
• 1h Liu X, Lin L, Feng X. Chem. Commun. 2009; 6145-6145
• 1i Raj M, Singh VK. Chem. Commun. 2009; 6687-6687
• 1j Bhowmick S, Bhowmick KC. Tetrahedron: Asymmetry 2011; 22: 1945-1945
  CrossrefSearch in Google Scholar
• 1k Bhanushali M, Zhao C.-G. Synthesis 2011; 1815-1815
  Thieme Connect
• 1l Heravi MM, Asadi S. Tetrahedron: Asymmetry 2012; 23: 1431-1431
  CrossrefSearch in Google Scholar
• 1m Bisai V, Bisai A, Singh VK. Tetrahedron 2012; 68: 4541-4541
  CrossrefSearch in Google Scholar
• 1n Scheffler U, Mahrwald R. Chem. Eur. J. 2013; 19: 14346-14346
  CrossrefSearch in Google Scholar
• 1o Mlynarski J, Baś S. Chem. Soc. Rev. 2014; 43: 577-577
  CrossrefSearch in Google Scholar
• 2a Okino T, Hoashi Y, Takemoto Y. J. Am. Chem. Soc. 2003; 125: 12672-12672
  CrossrefSearch in Google Scholar

For reviews, see:
• 2b Miyabe H, Takemoto Y. Bull. Chem. Soc. Jpn. 2008; 81: 785-785
  CrossrefSearch in Google Scholar
• 2c Connon SJ. Chem. Commun. 2008; 2499-2499
• 2d Connon SJ. Synlett 2009; 354-354
  Thieme Connect
• 2e Takemoto Y. Chem. Pharm. Bull. 2010; 58: 593-593
  CrossrefSearch in Google Scholar
• 2f Bhadury PS, Li H. Synlett 2012; 23: 1108-1108
  Thieme ConnectSearch in Google Scholar
• 3a Robak MT, Trincado M, Ellman JA. J. Am. Chem. Soc. 2007; 129: 15110-15110
  CrossrefSearch in Google Scholar
• 3b Kimmel KL, Robak MT, Ellman JA. J. Am. Chem. Soc. 2009; 131: 8754-8754
  CrossrefSearch in Google Scholar
• 3c Inokuma T, Furukawa M, Uno T, Suzuki Y, Yoshida K, Yano Y, Matsuzaki K, Takemoto Y. Chem. Eur. J. 2011; 17: 10470-10470
  CrossrefSearch in Google Scholar
• 3d Kimmel KL, Weaver JD, Lee M, Ellman JA. J. Am. Chem. Soc. 2012; 134: 9058-9058
  CrossrefSearch in Google Scholar
• 3e Kobayashi Y, Taniguchi Y, Hayama N, Inokuma T, Takemoto Y. Angew. Chem. Int. Ed. 2013; 52: 11114-11114
  CrossrefSearch in Google Scholar
• 4a Malerich JP, Hagihara K, Rawal VH. J. Am. Chem. Soc. 2008; 130: 14416-14416
  CrossrefSearch in Google Scholar

For a review, see:
• 4b Alemán J, Parra A, Jiang H, Jørgensen KA. Chem. Eur. J. 2011; 17: 6890-6890
  CrossrefSearch in Google Scholar
• 5a Kanada Y, Yuasa H, Nakashima K, Murahashi M, Tada N, Itoh A, Koseki Y, Miura T. Tetrahedron Lett. 2013; 54: 4896-4896
  CrossrefSearch in Google Scholar
• 5b Hirashima S, Sakai T, Nakashima K, Watanabe N, Koseki Y, Mukai K, Kanada Y, Tada N, Itoh A, Miura T. Tetrahedron Lett. 2014; 55: 4334-4334
  CrossrefSearch in Google Scholar
• 5c Nakashima K, Hirashima S, Kawada M, Koseki Y, Tada N, Itoh A, Miura T. Tetrahedron Lett. 2014; 55: 2703-2703
  CrossrefSearch in Google Scholar
• 5d Nakashima K, Hirashima S, Akutsu H, Koseki Y, Tada N, Itoh A, Miura T. Tetrahedron Lett. 2015; 56: 558-558
  CrossrefSearch in Google Scholar
• 5e Hirashima S, Nakashima K, Fujino Y, Arai R, Sakai T, Kawada M, Koseki Y, Murahashi M, Tada N, Itoh A, Miura T. Tetrahedron Lett. 2014; 55: 4619-4619
  CrossrefSearch in Google Scholar
• 5f Hirashima S, Arai R, Nakashima K, Kawai N, Kondo J, Koseki Y, Miura T. Adv. Synth. Catal. 2015; 357: 3863-3863
  CrossrefSearch in Google Scholar
• 6a Nakashima K, Kawada M, Hirashima S, Kato M, Koseki Y, Miura T. Synlett 2015; 26: 1248-1248
  Thieme ConnectSearch in Google Scholar
• 6b Nakashima K, Kawada M, Hirashima S, Kosugi A, Kato M, Yoshida A, Koseki Y, Miura T. Tetrahedron: Asymmetry 2016; 27: 888-888
  CrossrefSearch in Google Scholar
• 7a Takamura K, Fuse T, Arai K, Kusu F. J. Electroanal. Chem. 1999; 468: 53-53
  CrossrefSearch in Google Scholar
• 7b Kim H.-S, Chung TD, Kim H. J. Electroanal. Chem. 2001; 498: 209-209
  CrossrefSearch in Google Scholar
• 8 pK _a values of thiourea derivatives in DMSO solutions were reported as follows: O=C(NH₂)₂ (26.9), S=C(NH₂)₂ (18.7), S=C(NHPh)₂ (13.4). See: Jakab G, Tancon C, Zhang Z, Lippert KM, Schreiner PR. Org. Lett. 2014; 14: 1724-1724
  Search in Google Scholar
• 9 Hanack M, Hackenberg J, Menke O, Subramanian LR, Schlichenmaier R. Synthesis 1994; 249-249
  Thieme Connect
• 10 Organocatalyst 5 Colorless powder; mp 147–148 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.35 (12 H, d, J = 6.4 Hz), 3.86–4.03 (2 H, m), 6.02 (2 H, br, NH), ¹³C NMR (100 MHz, CD₃CN): δ = 19.9, 21.0, 46.0, 50.3, 66.7, 153.4. HRMS (ESI-TOF): m/z calcd for C₁₁H₁₆F₆N₂NaO₄S₂ [M + Na]⁺: 441.0353; found: 441.0357.
• 11 Organocatalyst 8 Colorless powder; mp 225–227 °C; [α]_D ²⁰ +79.2 (c 1.00, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 1.97 (m, 2 H), 2.13–2.15 (m, 2 H), 3.25–3.33 (m, 2 H), 3.5 (dd, J = 5.7, 14.8 Hz, 1 H), 3.78 (m, 1 H), 3.93 (m, 1 H), 7.55 (s, 1 H), 7.60 (s, 2 H). ¹³C NMR (100 MHz, CD₃OD): δ = 25.6, 28.0, 45.0, 46.5, 62.4, 68.9, 116.7, 120.4, 125.0 (q, ¹ J _C–F = 271.7 Hz), 125.2, 132.5 (q, ² J _C–F = 32.7 Hz), 151.7, 154.2. Anal. Calcd for C₁₇H₁₅F₁₂N₃O₄S₂: C, 33.07; H, 2.45; N, 6.81. Found: C, 32.98; H, 2.59; N, 6.68. Organocatalyst 9 Colorless powder; mp 243–245 °C; [α]_D ²⁰ +85.7 (c 1.00, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 1.90–2.03 (m, 2 H), 2.11–2.19 (m, 2 H), 3.30–3.33 (m, 2 H), 3.55 (dd, J = 6.2, 15.0 Hz, 1 H), 3.84 (dd, J = 2.8, 15.0 Hz, 1 H), 3.87–3.97 (m, 1 H), 7.34 (S, 2 H), 7.51 (s, 1 H); ¹³C NMR (100 MHz, CD₃OD): δ = 25.6, 28.1, 45.0, 46.6, 62.6, 68.8, 116.8, 125.0 (q, ¹ J _C-F = 272.0 Hz), 125.6, 132.7 (q, ² J _C–F = 33.0 Hz), 152.8, 154.4. Anal. Calcd for C₁₈H₁₅F₁₂N₃O₄S₂: C, 34.35; H, 2.40; N, 6.68. Found: C, 34.51; H, 2.68; N, 6.65.
• 12 For pioneer work, see: List B, Lerner RA, Barbas III. CF. J. Am. Chem. Soc. 2000; 122: 2395-2395
  CrossrefSearch in Google Scholar

For selected recent work, see:
• 13a Li Z.-Y, Chen Y, Zheng C.-Q, Yin Y, Wang L, Sun X.-Q. Tetrahedron 2017; 73: 78-78
  CrossrefSearch in Google Scholar
• 13b Mridha M, Ma G, Palo-Nieto C, Afewerki S, Cordova A. Synthesis 2017; 49: 383-383
  Thieme ConnectSearch in Google Scholar
• 13c Yadav GD, Singh S. RSC Adv. 2016; 6: 100459-100459
  CrossrefSearch in Google Scholar
• 13d Ashokkumar V, Chithiraikumar C, Siva A. Org. Biomol. Chem. 2016; 14: 9021-9021
  CrossrefSearch in Google Scholar
• 13e Fanjul-Mosterín N, Concellón C, Amo V. Org. Lett. 2016; 18: 4266-4266
  CrossrefSearch in Google Scholar
• 13f Guo G, Wu Y, Zhao X, Wang J, Zhang L, Cui Y. Tetrahedron: Asymmetry 2016; 27: 740-740
  CrossrefSearch in Google Scholar
• 13g Lan L, Xie G, Wu T, Feng D, Ma X. RSC Adv. 2016; 6: 55894-55894
  CrossrefSearch in Google Scholar
• 13h Sóti PL, Yamashita H, Sato K, Narumi T, Toda M, Watanabe N, Marosi G, Mase N. Tetrahedron 2016; 72: 1984-1984
  CrossrefSearch in Google Scholar
• 14 Typical Procedure of the Aldol Reaction Using Organocatalyst 9 To a mixture of p-nitrobenzaldehyde (10a, 30.2 mg, 0.200 mmol) and cyclohexanone (209 μL, 2.00 mmol) was added organocatalyst 9 (12.6 mg, 0.0200 mmol) at r.t. After stirring at r.t. for 72 h, the reaction mixture was directly purified by flash column chromatography on silica gel with a 2:1 mixture of hexane and EtOAc to afford 12a (44.9 mg, 90%) as a white powder.

• References and Notes


For selected reviews, see:
• 1a Dalko PI, Moisan L. Angew. Chem. Int. Ed. 2004; 43: 5138-5138
  CrossrefSearch in Google Scholar
• 1b Modern Aldol Reactions . Vol. 1 and 2. Mahrwald R. Wiley-VCH; Weinheim: 2004
  Search in Google Scholar
• 1c Mukherjee S, Yang JW, Hoffmann S, List B. Chem. Rev. 2007; 107: 5471-5471
  CrossrefSearch in Google Scholar
• 1d Pellisier H. Tetrahedron 2007; 63: 9267-9267
  CrossrefSearch in Google Scholar
• 1e Dondoni A, Massi A. Angew. Chem. Int. Ed. 2008; 47: 4638-4638
  CrossrefSearch in Google Scholar
• 1f Gruttadauria M, Giacalone F, Noto R. Adv. Synth. Catal. 2009; 351: 33-33
  CrossrefSearch in Google Scholar
• 1g Lattanzi A. Chem. Commun. 2009; 1452-1452
• 1h Liu X, Lin L, Feng X. Chem. Commun. 2009; 6145-6145
• 1i Raj M, Singh VK. Chem. Commun. 2009; 6687-6687
• 1j Bhowmick S, Bhowmick KC. Tetrahedron: Asymmetry 2011; 22: 1945-1945
  CrossrefSearch in Google Scholar
• 1k Bhanushali M, Zhao C.-G. Synthesis 2011; 1815-1815
  Thieme Connect
• 1l Heravi MM, Asadi S. Tetrahedron: Asymmetry 2012; 23: 1431-1431
  CrossrefSearch in Google Scholar
• 1m Bisai V, Bisai A, Singh VK. Tetrahedron 2012; 68: 4541-4541
  CrossrefSearch in Google Scholar
• 1n Scheffler U, Mahrwald R. Chem. Eur. J. 2013; 19: 14346-14346
  CrossrefSearch in Google Scholar
• 1o Mlynarski J, Baś S. Chem. Soc. Rev. 2014; 43: 577-577
  CrossrefSearch in Google Scholar
• 2a Okino T, Hoashi Y, Takemoto Y. J. Am. Chem. Soc. 2003; 125: 12672-12672
  CrossrefSearch in Google Scholar

For reviews, see:
• 2b Miyabe H, Takemoto Y. Bull. Chem. Soc. Jpn. 2008; 81: 785-785
  CrossrefSearch in Google Scholar
• 2c Connon SJ. Chem. Commun. 2008; 2499-2499
• 2d Connon SJ. Synlett 2009; 354-354
  Thieme Connect
• 2e Takemoto Y. Chem. Pharm. Bull. 2010; 58: 593-593
  CrossrefSearch in Google Scholar
• 2f Bhadury PS, Li H. Synlett 2012; 23: 1108-1108
  Thieme ConnectSearch in Google Scholar
• 3a Robak MT, Trincado M, Ellman JA. J. Am. Chem. Soc. 2007; 129: 15110-15110
  CrossrefSearch in Google Scholar
• 3b Kimmel KL, Robak MT, Ellman JA. J. Am. Chem. Soc. 2009; 131: 8754-8754
  CrossrefSearch in Google Scholar
• 3c Inokuma T, Furukawa M, Uno T, Suzuki Y, Yoshida K, Yano Y, Matsuzaki K, Takemoto Y. Chem. Eur. J. 2011; 17: 10470-10470
  CrossrefSearch in Google Scholar
• 3d Kimmel KL, Weaver JD, Lee M, Ellman JA. J. Am. Chem. Soc. 2012; 134: 9058-9058
  CrossrefSearch in Google Scholar
• 3e Kobayashi Y, Taniguchi Y, Hayama N, Inokuma T, Takemoto Y. Angew. Chem. Int. Ed. 2013; 52: 11114-11114
  CrossrefSearch in Google Scholar
• 4a Malerich JP, Hagihara K, Rawal VH. J. Am. Chem. Soc. 2008; 130: 14416-14416
  CrossrefSearch in Google Scholar

For a review, see:
• 4b Alemán J, Parra A, Jiang H, Jørgensen KA. Chem. Eur. J. 2011; 17: 6890-6890
  CrossrefSearch in Google Scholar
• 5a Kanada Y, Yuasa H, Nakashima K, Murahashi M, Tada N, Itoh A, Koseki Y, Miura T. Tetrahedron Lett. 2013; 54: 4896-4896
  CrossrefSearch in Google Scholar
• 5b Hirashima S, Sakai T, Nakashima K, Watanabe N, Koseki Y, Mukai K, Kanada Y, Tada N, Itoh A, Miura T. Tetrahedron Lett. 2014; 55: 4334-4334
  CrossrefSearch in Google Scholar
• 5c Nakashima K, Hirashima S, Kawada M, Koseki Y, Tada N, Itoh A, Miura T. Tetrahedron Lett. 2014; 55: 2703-2703
  CrossrefSearch in Google Scholar
• 5d Nakashima K, Hirashima S, Akutsu H, Koseki Y, Tada N, Itoh A, Miura T. Tetrahedron Lett. 2015; 56: 558-558
  CrossrefSearch in Google Scholar
• 5e Hirashima S, Nakashima K, Fujino Y, Arai R, Sakai T, Kawada M, Koseki Y, Murahashi M, Tada N, Itoh A, Miura T. Tetrahedron Lett. 2014; 55: 4619-4619
  CrossrefSearch in Google Scholar
• 5f Hirashima S, Arai R, Nakashima K, Kawai N, Kondo J, Koseki Y, Miura T. Adv. Synth. Catal. 2015; 357: 3863-3863
  CrossrefSearch in Google Scholar
• 6a Nakashima K, Kawada M, Hirashima S, Kato M, Koseki Y, Miura T. Synlett 2015; 26: 1248-1248
  Thieme ConnectSearch in Google Scholar
• 6b Nakashima K, Kawada M, Hirashima S, Kosugi A, Kato M, Yoshida A, Koseki Y, Miura T. Tetrahedron: Asymmetry 2016; 27: 888-888
  CrossrefSearch in Google Scholar
• 7a Takamura K, Fuse T, Arai K, Kusu F. J. Electroanal. Chem. 1999; 468: 53-53
  CrossrefSearch in Google Scholar
• 7b Kim H.-S, Chung TD, Kim H. J. Electroanal. Chem. 2001; 498: 209-209
  CrossrefSearch in Google Scholar
• 8 pK _a values of thiourea derivatives in DMSO solutions were reported as follows: O=C(NH₂)₂ (26.9), S=C(NH₂)₂ (18.7), S=C(NHPh)₂ (13.4). See: Jakab G, Tancon C, Zhang Z, Lippert KM, Schreiner PR. Org. Lett. 2014; 14: 1724-1724
  Search in Google Scholar
• 9 Hanack M, Hackenberg J, Menke O, Subramanian LR, Schlichenmaier R. Synthesis 1994; 249-249
  Thieme Connect
• 10 Organocatalyst 5 Colorless powder; mp 147–148 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.35 (12 H, d, J = 6.4 Hz), 3.86–4.03 (2 H, m), 6.02 (2 H, br, NH), ¹³C NMR (100 MHz, CD₃CN): δ = 19.9, 21.0, 46.0, 50.3, 66.7, 153.4. HRMS (ESI-TOF): m/z calcd for C₁₁H₁₆F₆N₂NaO₄S₂ [M + Na]⁺: 441.0353; found: 441.0357.
• 11 Organocatalyst 8 Colorless powder; mp 225–227 °C; [α]_D ²⁰ +79.2 (c 1.00, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 1.97 (m, 2 H), 2.13–2.15 (m, 2 H), 3.25–3.33 (m, 2 H), 3.5 (dd, J = 5.7, 14.8 Hz, 1 H), 3.78 (m, 1 H), 3.93 (m, 1 H), 7.55 (s, 1 H), 7.60 (s, 2 H). ¹³C NMR (100 MHz, CD₃OD): δ = 25.6, 28.0, 45.0, 46.5, 62.4, 68.9, 116.7, 120.4, 125.0 (q, ¹ J _C–F = 271.7 Hz), 125.2, 132.5 (q, ² J _C–F = 32.7 Hz), 151.7, 154.2. Anal. Calcd for C₁₇H₁₅F₁₂N₃O₄S₂: C, 33.07; H, 2.45; N, 6.81. Found: C, 32.98; H, 2.59; N, 6.68. Organocatalyst 9 Colorless powder; mp 243–245 °C; [α]_D ²⁰ +85.7 (c 1.00, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 1.90–2.03 (m, 2 H), 2.11–2.19 (m, 2 H), 3.30–3.33 (m, 2 H), 3.55 (dd, J = 6.2, 15.0 Hz, 1 H), 3.84 (dd, J = 2.8, 15.0 Hz, 1 H), 3.87–3.97 (m, 1 H), 7.34 (S, 2 H), 7.51 (s, 1 H); ¹³C NMR (100 MHz, CD₃OD): δ = 25.6, 28.1, 45.0, 46.6, 62.6, 68.8, 116.8, 125.0 (q, ¹ J _C-F = 272.0 Hz), 125.6, 132.7 (q, ² J _C–F = 33.0 Hz), 152.8, 154.4. Anal. Calcd for C₁₈H₁₅F₁₂N₃O₄S₂: C, 34.35; H, 2.40; N, 6.68. Found: C, 34.51; H, 2.68; N, 6.65.
• 12 For pioneer work, see: List B, Lerner RA, Barbas III. CF. J. Am. Chem. Soc. 2000; 122: 2395-2395
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For selected recent work, see:
• 13a Li Z.-Y, Chen Y, Zheng C.-Q, Yin Y, Wang L, Sun X.-Q. Tetrahedron 2017; 73: 78-78
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• 13b Mridha M, Ma G, Palo-Nieto C, Afewerki S, Cordova A. Synthesis 2017; 49: 383-383
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• 13c Yadav GD, Singh S. RSC Adv. 2016; 6: 100459-100459
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• 13d Ashokkumar V, Chithiraikumar C, Siva A. Org. Biomol. Chem. 2016; 14: 9021-9021
  CrossrefSearch in Google Scholar
• 13e Fanjul-Mosterín N, Concellón C, Amo V. Org. Lett. 2016; 18: 4266-4266
  CrossrefSearch in Google Scholar
• 13f Guo G, Wu Y, Zhao X, Wang J, Zhang L, Cui Y. Tetrahedron: Asymmetry 2016; 27: 740-740
  CrossrefSearch in Google Scholar
• 13g Lan L, Xie G, Wu T, Feng D, Ma X. RSC Adv. 2016; 6: 55894-55894
  CrossrefSearch in Google Scholar
• 13h Sóti PL, Yamashita H, Sato K, Narumi T, Toda M, Watanabe N, Marosi G, Mase N. Tetrahedron 2016; 72: 1984-1984
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• 14 Typical Procedure of the Aldol Reaction Using Organocatalyst 9 To a mixture of p-nitrobenzaldehyde (10a, 30.2 mg, 0.200 mmol) and cyclohexanone (209 μL, 2.00 mmol) was added organocatalyst 9 (12.6 mg, 0.0200 mmol) at r.t. After stirring at r.t. for 72 h, the reaction mixture was directly purified by flash column chromatography on silica gel with a 2:1 mixture of hexane and EtOAc to afford 12a (44.9 mg, 90%) as a white powder.

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