Reductive aldol-type reaction of α,β-unsaturated esters with aldehydes or ketones in the presence...
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Reductive aldol-type reaction of a,b-unsaturated esters with aldehydes or ketones in the presence of Rh catalyst and Et 2 Zn Kazuyuki Sato, Motoyuki Isoda, Yoriko Tokura, Keiko Omura, Atsushi Tarui, Masaaki Omote, Itsumaro Kumadaki, Akira Ando ⇑ Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan article info Article history: Received 17 July 2013 Revised 20 August 2013 Accepted 26 August 2013 Available online 3 September 2013 Keywords: Reductive aldol reaction Reformatsky–Honda reaction RhCl(PPh 3 ) 3 Diethyl zinc Rh–H complex abstract The reaction of RhCl(PPh 3 ) 3 with Et 2 Zn easily generated a rhodium–hydride complex (Rh H) that added to a,b-unsaturated esters to form rhodium enolate complexes by formal 1,4-reduction. These rhodium enolates gave the corresponding Reformatsky-type reagents through transmetalation, and they reacted with various aldehydes and ketones to give reductive aldol-type products in good to excellent yields. Ó 2013 Elsevier Ltd. All rights reserved. Various intermolecular reductive aldol-type reactions with aldehydes using metals such as copper, 1 cobalt, 2 and rhodium cat- alysts 3 have been reported, and synthetic versatility was shown with high stereoselectivity in many cases. However reductive al- dol-type reaction with ketones has still been rare owing to the poor nucleophilicity, and this might be the reason why hydrosilanes (R 3 Si–H) or hydrogen was used as the reductant in most of the reports. 4 Recently we reported the reductive Reformatsky–Honda reaction with various electrophiles to give the corresponding prod- ucts in good to excellent yields, even if ketones were used as the electrophile. 5 In the current study we examine the reductive al- dol-type reaction of a,b-unsaturated esters with various aldehydes and ketones under the Reformatsky–Honda reaction condition (the combination of RhCl(PPh 3 ) 3 and Et 2 Zn), 6 with a focus on the scope and limitations of this reaction (Scheme 1). Firstly, the best reaction condition was sought by using methyl acrylate (1a) and benzaldehyde (2a) as shown in Table 1. Under the previous condition, 5b the desired product (3a) was obtained in an excellent yield (entries 1 and 2). On the other hand, the product was not 3a but methyl 2-(1-hydroxy-1-phenylmethyl)pentanoate (4a) in the absence of Rh catalyst as shown in entry 3. This shows the importance of Rh catalyst. Most of the solvents gave 3a in good to excellent yields, although insolubility of the Rh catalyst in hex- ane or Et 2 O led to the low yield (entries 8–13). Among various examinations, entry 14 was the best condition. Next, we investigated various other substrates and the results are summarized in Table 2. 7 Both of electron withdrawing and electron donating groups on benzaldehyde did not affect the yields and the reaction gave the desired products (3a–f) in excellent yields. Naphthyl aldehydes and aliphatic aldehydes also reacted smoothly and they gave the products (3g–j) in good yields, respec- tively. It is interesting that benzophenone and cyclohexanone gave the products (3k and 3l) in good yields, since there are only a few examples of the intermolecular reductive aldol reaction with ketones. 4 However all products did not give the satisfiable diaste- reoselectivity. So we then changed the alkyl part of ester from methyl to tert-butyl or phenyl. These gave the corresponding prod- uct (3m and 3n) in excellent yields but the selectivity was not much improved. Furthermore methyl crotonate and 2(5H)-fura- none gave the corresponding products (3o and 3p) in moderate to good yields, but methyl cinnamate only gave a complex mixture. Rh H complex must have played an important role on the basis of previous result, 8 since the reaction did not give the desired 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.08.109 ⇑ Corresponding author. E-mail address: [email protected] (A. Ando). R 1 O O R 2 + RhCl(PPh 3 ) 3 2 1 3 Et 2 Zn R 3 R 4 O R 2 OH R 3 R 4 O OR 1 Scheme 1. Reductive aldol-type reaction under Reformatsky–Honda reaction condition. Tetrahedron Letters 54 (2013) 5913–5915 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Transcript of Reductive aldol-type reaction of α,β-unsaturated esters with aldehydes or ketones in the presence...
Tetrahedron Letters 54 (2013) 5913–5915
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier .com/ locate/ tet le t
Reductive aldol-type reaction of a,b-unsaturated esterswith aldehydes or ketones in the presence of Rh catalyst and Et2Zn
0040-4039/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetlet.2013.08.109
⇑ Corresponding author.E-mail address: [email protected] (A. Ando).
R1O
O
R2+
RhCl(PPh3)321 3
Et2Zn
R3 R4O
R2
OHR3R4
O
OR1
Scheme 1. Reductive aldol-type reaction under Reformatsky–Hondacondition.
Kazuyuki Sato, Motoyuki Isoda, Yoriko Tokura, Keiko Omura, Atsushi Tarui, Masaaki Omote,Itsumaro Kumadaki, Akira Ando ⇑Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
a r t i c l e i n f o
Article history:Received 17 July 2013Revised 20 August 2013Accepted 26 August 2013Available online 3 September 2013
Keywords:Reductive aldol reactionReformatsky–Honda reactionRhCl(PPh3)3
Diethyl zincRh–H complex
a b s t r a c t
The reaction of RhCl(PPh3)3 with Et2Zn easily generated a rhodium–hydride complex (Rh�H) that addedto a,b-unsaturated esters to form rhodium enolate complexes by formal 1,4-reduction. These rhodiumenolates gave the corresponding Reformatsky-type reagents through transmetalation, and they reactedwith various aldehydes and ketones to give reductive aldol-type products in good to excellent yields.
� 2013 Elsevier Ltd. All rights reserved.
reaction
Various intermolecular reductive aldol-type reactions withaldehydes using metals such as copper,1 cobalt,2 and rhodium cat-alysts3 have been reported, and synthetic versatility was shownwith high stereoselectivity in many cases. However reductive al-dol-type reaction with ketones has still been rare owing to the poornucleophilicity, and this might be the reason why hydrosilanes(R3Si–H) or hydrogen was used as the reductant in most of thereports.4 Recently we reported the reductive Reformatsky–Hondareaction with various electrophiles to give the corresponding prod-ucts in good to excellent yields, even if ketones were used as theelectrophile.5 In the current study we examine the reductive al-dol-type reaction of a,b-unsaturated esters with various aldehydesand ketones under the Reformatsky–Honda reaction condition (thecombination of RhCl(PPh3)3 and Et2Zn),6 with a focus on the scopeand limitations of this reaction (Scheme 1).
Firstly, the best reaction condition was sought by using methylacrylate (1a) and benzaldehyde (2a) as shown in Table 1. Under theprevious condition,5b the desired product (3a) was obtained in anexcellent yield (entries 1 and 2). On the other hand, the productwas not 3a but methyl 2-(1-hydroxy-1-phenylmethyl)pentanoate(4a) in the absence of Rh catalyst as shown in entry 3. This showsthe importance of Rh catalyst. Most of the solvents gave 3a in goodto excellent yields, although insolubility of the Rh catalyst in hex-ane or Et2O led to the low yield (entries 8–13). Among variousexaminations, entry 14 was the best condition.
Next, we investigated various other substrates and the resultsare summarized in Table 2.7 Both of electron withdrawing andelectron donating groups on benzaldehyde did not affect the yieldsand the reaction gave the desired products (3a–f) in excellentyields. Naphthyl aldehydes and aliphatic aldehydes also reactedsmoothly and they gave the products (3g–j) in good yields, respec-tively. It is interesting that benzophenone and cyclohexanone gavethe products (3k and 3l) in good yields, since there are only a fewexamples of the intermolecular reductive aldol reaction withketones.4 However all products did not give the satisfiable diaste-reoselectivity. So we then changed the alkyl part of ester frommethyl to tert-butyl or phenyl. These gave the corresponding prod-uct (3m and 3n) in excellent yields but the selectivity was notmuch improved. Furthermore methyl crotonate and 2(5H)-fura-none gave the corresponding products (3o and 3p) in moderateto good yields, but methyl cinnamate only gave a complex mixture.
Rh�H complex must have played an important role on the basisof previous result,8 since the reaction did not give the desired
Table 1Optimization of the reaction condition
OMe
O+
RhCl(PPh3)32a1a 3a
Et2Zn
Ph H
O OH
Ph
O
OMe
OH
Ph
O
OMe
4a
Entry 2a (equiv) Solv. RhCl(PPh3)3 Et2Zn (equiv) Temp (�C) Time (h) Yielda (%) (anti:syn)b
1 2 THF 2 mol % 1.5 0 3 95 (53:47)2 1 THF 2 mol % 1.5 0 1 95 (49:51)3 1 THF None 1.5 0 3 0c
4 1 THF 1 mol % 1.5 0 3 64 (50:50)5 1 THF 2 mol % 0.5 0 3 48 (50:50)6 1 THF 2 mol % 1.5 �78 24 07 1 THF 2 mol % 1.5 �45 10 93 (51:49)8 1 THF 2 mol % 1.5 rt 0.5 94 (51:49)9 1 Hexane 2 mol % 1.5 rt 1 34 (50:50)
10 1 Et2O 2 mol % 1.5 rt 5 48 (50:50)11 1 DME 2 mol % 1.5 rt 1 93 (54:46)12 1 CH3CN 2 mol % 1.5 rt 0.5 92 (47:53)13 1 CH2Cl2 2 mol % 1.5 rt 0.5 94 (52:48)14 1 THF 2 mol % 1.2 rt 0.5 95 (52:48)
a Isolated yield.b Diastereomeric ratio after purification.c Compound 4a was obtained in 99%.
5914 K. Sato et al. / Tetrahedron Letters 54 (2013) 5913–5915
product (3a) but 4a in the absence of Rh catalyst. Furthermore,methyl vinyl ketone (5) did not give the corresponding reductivealdol product (6) in the reaction with benzaldehyde, but methylacrylate (1a) gave the product (3a) in an excellent yield (Scheme 2).
Table 2Scope and limitation of the reaction with various aldehydes and ketones
R1O
O
R2+
Rh21
R3 R4O
Entry 3
1 OH
OMe
O
Y
Y@H2 CF3
3 Cl4 COOMe5 Me6 OMe7
Y
OH
OMe
O Y=1-naphthyl8 2-naphthyl9 Ph–C2H4-
10 cyclohexyl
11OH
OMe
O
12
OH
OMe
O
13e
OH
OtBu
O
14e
OH
O
O
These results suggest that a Reformatsky-type reagent could gen-erate from 1 with Et2Zn because of the formation of 4a. The stron-ger nucleophilicity of a metal enolate delivered from a,b-unsaturated ester (1) would be concerned in the reaction.
Cl(PPh3)33
Et2Zn
R2
OHR3R4
O
OR1
Time (h) Yielda (%) dr
3a 0.5 95 (52:48)b
3b 0.5 96 (48:52)b
3c 0.5 94 (50:50)b
3d 2 95 (43:57)b
3e 3 93 (49:51)b
3f 2 95 (48:52)b
3g 3 82 (53:47)b
3h 9 70 (41:59)b
3i 5 76 (45:55)c
3j 1 81 (42:58)d
3k 7 77
3l 5 75
3m 5 91 (40:60)d
3n 3 90 (63:37)d
Table 2 (continued)
Entry 3 Time (h) Yielda (%) dr
15
OH
OMe
O3o 24 56 (52:48)b
16
OH
O
O3p 1 80 (61:39)b
a Isolated yield.b Diastereomeric ratio (syn:anti) after purification.c Diastereomeric ratio (syn:anti) by GLC.d Diastereomeric ratio (syn:anti) by 1H NMR.e The reaction was carried out at 0 �C.
O+ Ph
O
RhCl(PPh3)3
Et2ZnPh H
O OH
MeO
O+ Ph OMe
O
Ph H
O OH
0°C, THF 6 (24h, n.d.)
3a (3h, 95%)RhCl(PPh3)3
Et2Zn
0°C, THF
MeO
O+ Ph OMe
O
Ph H
OOH
4a (3h, 99%)
Et2Zn
0°C, THFEt1a2a
52a
1a2a
Scheme 2. Mechanistic studies on Rh-catalyzed reductive aldol reaction.
Rh X Et2Zn
Rh HO
R1O
O
R1ORh(I)
HR2
EtZnO
R1O
XZn Et8
Int A
7
9
10
1
Rh Et
H
R2
R2ethylene
Figure 1. Proposed reaction mechanism of the reductive aldol-type reaction byusing Reformatsky–Honda reaction condition.
K. Sato et al. / Tetrahedron Letters 54 (2013) 5913–5915 5915
Thus we proposed the following mechanism (Fig. 1).RhCl(PPh3)3 reacted with Et2Zn to give the rhodium hydride com-plex (9) through ethyl rhodium complex (7) along with the elimi-nation of ethylene. The 1,4-reduction of a,b-unsaturated ester by 9to form rhodium enolate (10) is followed by transmetalation by azinc species to give Reformatsky-type reagent (Int A). The highernucleophile of Reformatsky-type reagent promptly reacted withelectrophiles to give the corresponding b-hydroxyesters (3) evenif ketones were used as the electrophile.
In conclusion, we synthesized various b-hydroxyesters from thea,b-unsaturated esters with aldehydes and ketones in good toexcellent yields. It is especially interesting to note that this reduc-tive aldol reaction gave the product from ketones in good yields. Infuture research we will investigate the enantioselective reductivealdol reaction.
References and notes
1. For Cu-catalyzed reductive aldol reactions: (a) Ooi, T.; Doda, K.; Sakai, D.;Maruoka, K. Tetrahedron Lett. 1999, 40, 2133–2136; (b) Lam, H. W.; Joensuu, P.M. A. Org. Lett. 2005, 7, 4225–4228; (c) Welle, A.; Díez-González, S.; Tinant, B.;Nolan, S. P.; Riant, O. Org. Lett. 2006, 8, 6059–6062.
2. For Co-catalyzed reductive aldol reactions: (a) Isayama, S.; Mukaiyama, T. Chem.Lett. 1989, 2005–2008; (b) Baik, T. G.; Luis, A. L.; Wang, L. C.; Krische, M. J. J. Am.Chem. Soc. 2001, 123, 5112–5113; (c) Wang, L. C.; Jang, H.-Y.; Roh, Y.; Lynch, V.;Schultz, A. J.; Wang, X.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448–9453; (d)Lam, H. W.; Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.; Prieto, O.; Luebbers, T.Org. Lett. 2006, 8, 3729–3732; (e) Lumby, R. J. R.; Joensuu, P. M.; Lam, H. W. Org.Lett. 2007, 9, 4367–4370.
3. For Rh-catalyzed reductive aldol reactions: (a) Revis, A.; Hilty, T. K. TetrahedronLett. 1987, 28, 4809–4812; (b) Nishiyama, H.; Shiomi, T.; Tsuchiya, Y.; Matsuda,I. J. Am. Chem. Soc. 2005, 127, 6972–6973; (c) Willis, M. C.; Woodward, R. L. J. Am.Chem. Soc. 2005, 127, 18012–18013; (d) Bee, C.; Han, S. B.; Hassan, A.; Iida, H.;Krische, M. J. J. Am. Chem. Soc. 2008, 130, 2746–2747; (e) Hashimoto, T.; Ito, J.;Nishiyama, H. Tetrahedron 2008, 64, 9408–9412; (f) Shiomi, T.; Adachi, T.; Ito, J.;Nishiyama, H. Org. Lett. 2009, 11, 1011–1014.
4. For intermolecular reductive aldol reactions with ketones: (a) Zhao, D.; Oisaki,K.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 1403–1407; (b)Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem., Int. Ed.2006, 45, 1292–1297; (c) Shiomi, T.; Nishiyama, H. Org. Lett. 2007, 9, 1651–1654; (d) Lumby, R. J. R.; Joensuu, P. M.; Lam, H. W. Tetrahedron 2008, 64, 7729–7740; (e) Kato, M.; Oki, H.; Ogata, K.; Fukuzawa, S. Synlett 2009, 1299–1302.
5. (a) Sato, K.; Yamazoe, S.; Yamamoto, R.; Ohata, S.; Traui, A.; Omote, M.; Ando, A.;Kumadaki, I. Org. Lett. 2008, 10, 2405–2408; (b) Sato, K.; Isoda, M.; Ohata, S.;Morita, S.; Tarui, A.; Omote, M.; Kumadaki, I.; Ando, A. Adv. Synth. Catal. 2012,354, 510–514.
6. (a) Kanai, K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2, 2549–2551; (b)Kanai, K.; Wakabayashi, H.; Honda, T. Heterocycles 2002, 58, 47–51; (c) Honda,T.; Wakabayashi, H.; Kanai, K. Chem. Pharm. Bull. 2002, 50, 307–308.
7. General procedure for the reductive aldol-type reaction of a,b-unsaturated ester is asfollows: a,b-unsaturated ester (1; 1 mmol) and aldehyde (2; 1 mmol) wereadded to a solution of RhCl(PPh3)3 (2 mol %) in THF (2.5 mL) at ambienttemperature. Then, 1.0 M Et2Zn in hexane (1.2 mmol) was gradually added tothe mixture, and the mixture was stirred at same temperature. After the time inTable 2, the mixture was quenched with 10% HCl and extracted with AcOEt. TheAcOEt layer was washed with satd NaCl and dried over MgSO4. The solvent wasremoved in vacuo, and the residue was purified by column chromatography(AcOEt:hexane = 1:4) to give each diastereomer of b-hydroxyester (3) as a solecompound.
8. Sato, K.; Ishida, Y.; Murata, E.; Oida, Y.; Mori, Y.; Okawa, M.; Iwase, K.; Tarui, A.;Omote, M.; Kumadaki, I.; Ando, A. Tetrahedron 2007, 63, 12735–12739.
