N-Heterocyclic carbene-catalyzed direct cross-aza-benzoin reaction: Efficient synthesis of α-amino-β-keto esters

Article abstract of DOI:10.3762/bjoc.8.169

An efficient catalytic synthesis of α-amino-β-keto esters has been newly developed. Cross-coupling of various aldehydes with α-imino ester, catalyzed by N-heterocyclic carbene, leads chemoselectively to α-amino-β-keto esters in moderate to good yields with high atom efficiency. The reaction mechanism is discussed, and it is proposed that the α-amino-β-keto esters are formed under thermodynamic control.

Full text of DOI:10.3762/bjoc.8.169

N-Heterocyclic carbene-catalyzed direct
cross-aza-benzoin reaction:
Efficient synthesis of α-amino-β-keto esters
Takuya Uno, Yusuke Kobayashi and Yoshiji Takemoto*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1499–1504.
Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
doi:10.3762/bjoc.8.169
Received: 31 May 2012
Email:
Accepted: 06 August 2012
Published: 10 September 2012
Yoshiji Takemoto* - takemoto@pharm.kyoto-u.ac.jp
* Corresponding author
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
Keywords:
α-amino-β-keto esters; cross-aza-benzoin; α-imino ester;
N-heterocyclic carbenes; organocatalysis; umpolung reactions
© 2012 Uno et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
An efficient catalytic synthesis of α-amino-β-keto esters has been newly developed. Cross-coupling of various aldehydes with
α-imino ester, catalyzed by N-heterocyclic carbene, leads chemoselectively to α-amino-β-keto esters in moderate to good yields
with high atom efficiency. The reaction mechanism is discussed, and it is proposed that the α-amino-β-keto esters are formed under
thermodynamic control.
Introduction
α-Amino-β-keto ester derivatives are one of the fundamental tion of the N-acyl glycine derivatives [18]. The other consists of
structural subunits in natural products such as miuraenamides C–N bond-forming reactions, such as (c) a rhodium-catalyzed
[1], and important building blocks for the synthesis of a variety N–H insertion reaction with α-diazo-β-keto esters [19-21], and
of heterocyclic compounds [2] and pharmaceutically active (d) α-oxidation of β-keto esters to the corresponding oximes and
products [3-5]. In addition, they are valuable intermediates for the subsequent hydrogenation [22]. However, the former
chiral α-amino acids [6,7], including β-hydroxy-α-amino acids methods require a stoichiometric amount of strong bases, and
[8-14]. Consequently, significant efforts have been devoted to the latter employ inaccessible substrates or multistep protocols.
synthesizing the privileged structure (Figure 1), and two main Recently, Zhang and co-workers reported Zn(ClO4)2·6H2O-
distinct approaches based on the bond-forming position have catalyzed, mild and direct α-amination of β-keto esters with
been developed. One approach utilizes Cα–Cβ bond formations, TsNH2, but in this case, a stoichiometric amount of PhI=O is
such as (a) acylation of Schiff bases or α-isocyano esters with needed as the oxidant (Figure 1, (e)) [23]. Therefore, mild, effi-
acyl halides [4,15-17], and (b) intramolecular N–C acyl migra- cient and environmentally friendly strategies for the synthesis of
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Beilstein J. Org. Chem. 2012, 8, 1499–1504.
Figure 1: Synthetic methods for α-amino-β-keto esters.
these esters are still needed. We envisioned that highly atom- and atom-economical synthesis of the α-amino-β-keto esters by
efficient synthesis of α-amino-β-keto esters could be achieved NHC-catalyzed cross-aza-benzoin reaction of aldehydes with
by a novel umpolung approach including C–C bond construc- α-imino esters under mild basic conditions.
tion, that is, formal addition of acyl anion equivalents gener-
ated from aldehydes 1 with NHCs, to α-imino esters 2 Results and Discussion
(Figure 1, (f)).
First we initiated the cross-aza-benzoin reaction of benzalde-
hyde (1a) by employing 20 mol % of commercially available
Although a large number of NHC-catalyzed umpolung reac- precatalyst 3a (Figure 2) and K2CO3. Gratifyingly, when ethyl
tions, such as the benzoin reaction and Stetter reaction, have N-PMP-2-iminoacetate (4) was used as acyl anion acceptor
been developed [24-34], the related reactions of aldehydes with [44], the reaction proceeded smoothly in THF at room tempera-
imines, i.e., the cross-aza-benzoin reactions, have been much ture to generate the desired product 5a in 58% yield (Table 1,
less studied, in spite of the pharmaceutical and biological entry 1). Surprisingly, no benzoin 6 arising from homo-coupling
importance of providing α-amino ketones [35-43]. In particular, of 1a was obtained. Encouraged by this result, we then
a reaction employing the imines directly has rarely been devel- attempted the other precatalysts 3b–e depicted in Figure 2.
oped [40,42], due to the unproductive reaction of NHCs with Imidazolium salt 3b and simple triazolium salt 3c gave no
the imines. Therefore, in situ generation of imines or iminium coupled product 5a (Table 1, entries 2 and 3). Further screening
ions from their precursors is generally required to control their revealed that bicyclic triazolium salt 3d could catalyze the reac-
reactivity. We anticipated that the introduction of appropriate tion to give 5a in 42% yield (Table 1, entry 4). We reasoned
protecting groups of the nitrogen atom of α-imino esters 2, that the acidity of the NHC precursor was important to promote
which have been known to be excellent electrophiles, would the reaction under mild basic conditions (Table 1, entry 3 versus
suppress an unexpected reaction of 2 with NHCs, enabling the entry 4), and therefore we next investigated the substituent on
direct use of 2 as acyl anion acceptors in the cross-aza-benzoin the nitrogen atom of NHC. As envisaged, N-pentafluorophenyl-
reaction. In this communication, we describe a new, efficient, substituted precatalyst 3e [45-49], whose C-2 proton is more
Figure 2: Structures of several NHC precatalysts.
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Beilstein J. Org. Chem. 2012, 8, 1499–1504.
acidic than 3d, furnished the coupled product 5a in good yield hydes, which are often known to be less reactive in NHC-
(Table 1, entry 5). Subsequently, we attempted several bases to catalyzed reactions, could be coupled with 4 to provide 5h and
find that cesium carbonate gave slightly lower yield (Table 1, 5i in 66% and 68% yields, respectively (Table 2, entries 7 and
entry 6), whereas an amine base and a stronger base were not 8). Notably, heteroaromatic aldehydes, such as 3-thiophenecar-
effective, due to the competitive decomposition of 4 under these boxaldehyde and furfural, were also successful in yielding
conditions (Table 1, entries 7 and 8). Different solvents, such as the expected products 5j and 5k in 72% and 49% yield, respec-
CH2Cl2, toluene, and MeCN, have been tested in this reaction, tively (Table 2, entries 9 and 10).
and THF was found to be optimal in terms of chemical yield
(Table 1, entries 9–11).
Table 2: Substrate scope.a
Table 1: Reaction optimization.a
Entry
Ar
5
Yield (%)b
1
2
3
4
5
6
7
8
9
10
4-ClC6H4
5b
5c
5d
5e
5f
69
59
61
45
39
73
66
68
72
49
3-ClC6H4
2-ClC6H4
4-NO2C6H4
4-CNC6H4
4-MeOCOC6H4
4-MeC6H4
4-MeOC6H4
thiophen-3-yl
furan-2-yl
Entry
Cat. 3
Base
Solvent
Yield (%)b
5g
5h
5i
1
3a
3b
3c
3d
3e
3e
3e
3e
3e
3e
3e
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
NEt3
THF
58
<5
<5
42
70
66
56
37
61
56
40
2
THF
5j
3
THF
5k
4
THF
aReactions performed with 1 (0.3 mmol) and 4 (1.3 equiv) in THF
(0.5 M). bIsolated yields.
5
THF
6
THF
7
THF
8
KOt-Bu
K2CO3
K2CO3
K2CO3
THF
We next investigated the reaction with several aliphatic alde-
hydes (Scheme 1). Generally, unactivated aliphatic aldehydes
are unsuccessful for the NHC-catalyzed reactions, because of
their low electrophilicity relative to aromatic aldehydes
[40,46,47,50]. To our delight, this methodology was found to be
also suitable for the enolizable aliphatic aldehydes. Under the
optimal reaction conditions (Table 1, entry 5), acetaldehyde and
other primary alkyl aldehydes bearing functional groups such as
ether, carbamate, and phenyl groups, were converted into the
corresponding products 5l–o in good yields. The α-branched
aldehyde, however, failed to give the desired product 5p,
presumably due to the increased steric hindrance along with the
inherently low electrophilicity.
9
CH2Cl2
toluene
MeCN
10
11
aReactions conducted with 1a (0.3 mmol) and 4 (1.3 equiv) in THF
(0.5 M). bIsolated yields.
With the efficient catalytic system in hand (20 mol % of 3e and
K2CO3 in THF at room temperature), we next evaluated the
substrate generality with a variety of aromatic aldehydes 1
bearing a diverse range of functionality (Table 2). Chloro-,
nitro-, cyano-, and methoxycarbonyl-substituted aromatic alde-
hydes were compatible with the reaction conditions (Table 2,
entries 1–6). In all cases, the reaction led to the desired prod-
ucts in moderate to good yields. In addition, ortho-substituted In order to elucidate the reaction mechanism, a 0.5 equiv of
aldehyde, which is considered to be a poor acyl donor in benzoin (6) was used instead of aldehyde 1a under standard
benzoin reactions [46], was also smoothly converted to the conditions, affording the cross-coupled product 5a in 40% yield
expected product 5d in 61% yield (Table 2, entry 3). It is note- (Scheme 2). In addition, when the reaction was conducted with
worthy that chloro-substituted aldehydes were tolerated, α-amino-β-keto ester 5b in place of α-imino ester 4, the cross-
because the corresponding products 5b–d could in principle over product 5a was not detected. These findings indicate that
undergo further functionalization by palladium-catalyzed cross- the formation of benzoin is reversible via the Breslow inter-
coupling reactions. Additionally, electron-rich aromatic alde- mediate, whereas the retro-benzoin reaction of cross-coupled
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Beilstein J. Org. Chem. 2012, 8, 1499–1504.
Scheme 2: Cross-over experiments.
lated that the desired product 5 is thermodynamically more
stable than 6 and the formation of 5 is the irreversible step, from
the finding that cross-coupled product 5 is predominantly
obtained under the reaction conditions.
Scheme 1: Scope of aliphatic aldehydes.
product 5 does not occur under the present reaction conditions, Conclusion
and that the product 5 is formed under thermodynamic control. In conclusion, we have developed a direct, atom-efficient syn-
thesis of α-amino-β-keto esters by an umpolung reaction. We
A plausible mechanism for the cross-aza-benzoin reaction is found that the NHC-catalyzed cross-aza-benzoin reaction of
shown in Scheme 3. Carbene I is generated by deprotonation of aldehydes with N-PMP-imino ester proceeds chemoselectively
triazolium salt 3e in the presence of K2CO3. The carbene I under very mild conditions. Therefore, the reaction is tolerant of
reacts with aldehyde 1 to afford Breslow intermediate II, which a range of functional groups and substituents, including ali-
could lead to benzoin (6), or tetrahedral intermediate III when phatic aldehydes, and thus this method would be an attractive
treated with α-imino ester 4. Intermolecular proton transfer approach for deriving various α-amino-β-keto ester derivatives,
from III gives intermediate IV, which could release the product which are useful synthetic blocks and valuable pharmaceutical
5 and the carbene I to complete the catalytic system. We specu- intermediates.
Scheme 3: Proposed reaction mechanism.
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18.Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998, 39, 5537–5540.
doi:10.1016/S0040-4039(98)01093-4
Supporting Information
19.Bertelsen, S.; Nielsen, M.; Bachmann, S.; Jørgensen, K. A. Synthesis
2005, 13, 2234–2238. doi:10.1055/s-2005-869952
20.Bourdon, L. H.; Fairfax, D. J.; Martin, G. S.; Mathison, C. J.;
Zhichkin, P. Tetrahedron: Asymmetry 2004, 15, 3485–3487.
doi:10.1016/j.tetasy.2004.10.005
Supporting Information File 1
Experimental details and characterization of the synthesized
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-169-S1.pdf]
21.Moody, C. J.; Swann, E. Synlett 1998, 135–136.
doi:10.1055/s-1998-1610
22.Mordant, C.; Dünkelmann, P.; Ratovelomanana-Vidal, V.; Genet, J.-P.
Chem. Commun. 2004, 1296–1297. doi:10.1039/b401631a
23.Yu, J.; Liu, S.-S.; Cui, J.; Hou, X.-S.; Zhang, C. Org. Lett. 2012, 14,
832–835. doi:10.1021/ol203358f
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scien-
tific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysis” and “Targeted Proteins
Research Program” from The Ministry of Education, Culture,
Sports, Science and Technology of Japan.
24.Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606–5655. doi:10.1021/cr068372z
25.Marion, N.; Díez-González, S.; Nolan, S. P. Angew. Chem., Int. Ed.
2007, 46, 2988–3000. doi:10.1002/anie.200603380
26.Phillips, E. M.; Chan, A.; Scheidt, K. A. Aldrichimica Acta 2009, 42,
55–66.
27.Moore, J. L.; Rovis, T. Top. Curr. Chem. 2010, 291, 77–144.
doi:10.1007/128_2008_18
References
1. Ojika, M.; Inukai, Y.; Kito, Y.; Hirata, M.; Iizuka, T.; Fudou, R.
Chem.–Asian J. 2008, 3, 126–133. doi:10.1002/asia.200700233
2. Sanz-Cervera, J. F.; Blasco, R.; Piera, J.; Cynamon, M.; Ibáñez, I.;
28.Chiang, P.-C.; Bode, J. W. TCI Mail 2011, 149, 2–17.
29.Vora, H. U.; Rovis, T. Aldrichimica Acta 2011, 1, 3–11.
30.Hirano, K.; Piel, I.; Glorius, F. Chem. Lett. 2011, 40, 786–791.
doi:10.1246/cl.2011.786
Murguía, M.; Fustero, S. J. Org. Chem. 2009, 74, 8988–8996.
doi:10.1021/jo9016265
31.Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182–1195.
doi:10.1021/ar2000716
3. Phansavath, P.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.;
Genêt, J.-P. Eur. J. Org. Chem. 2000, 3903–3907.
doi:10.1002/1099-0690(200012)2000:23<3903::AID-EJOC3903>3.0.C
O;2-Q
32.Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.;
Sreekumar, V. Chem. Soc. Rev. 2011, 40, 5336–5346.
doi:10.1039/c1cs15139h
4. Miyake, F.; Hashimoto, M.; Tonseingsom, S.; Yakushijin, K.;
Horne, D. A. Tetrahedron 2010, 66, 4888–4893.
33.Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012, 3, 53–57.
doi:10.1039/C1SC00621E
doi:10.1016/j.tet.2010.03.109
34.Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511–3522.
doi:10.1039/c2cs15333e
5. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604–3606.
doi:10.1021/jo00066a004
35.Castells, J.; López-Calahorra, F.; Bassedas, M.; Urrios, P. Synthesis
1988, 314–315. doi:10.1055/s-1988-27552
6. Nemoto, T.; Harada, T.; Matsumoto, T.; Hamada, Y. Tetrahedron Lett.
2007, 48, 6304–6307. doi:10.1016/j.tetlet.2007.07.020
7. Singh, J.; Gordon, T. D.; Earley, W. G.; Morgan, B. A. Tetrahedron Lett.
1993, 34, 211–214. doi:10.1016/S0040-4039(00)60549-X
8. Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995,
68, 36–55. doi:10.1246/bcsj.68.36
36.Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.;
Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696–9697.
doi:10.1021/ja0165943
37.Frantz, D. E.; Morency, L.; Soheili, A.; Murry, J. A.; Grabowski, E. J. J.;
Tillyer, R. D. Org. Lett. 2004, 6, 843–846. doi:10.1021/ol0498803
38.Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6, 4363–4366.
doi:10.1021/ol0481129
9. Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Tetrahedron: Asymmetry
2008, 19, 2816–2828. doi:10.1016/j.tetasy.2008.12.024
10.Hamada, Y.; Makino, K. J. Synth. Org. Chem., Jpn. 2008, 66,
1057–1065. doi:10.5059/yukigoseikyokaishi.66.1057
11.Liu, Z.; Shultz, C. S.; Sherwood, C. A.; Krska, S.; Dormer, P. G.;
Desmond, R.; Lee, C.; Sherer, E. C.; Shpungin, J.; Cuff, J.; Xu, F.
Tetrahedron Lett. 2011, 52, 1685–1688.
39.Mennen, S. M.; Gipson, J. D.; Kim, Y. R.; Miller, S. J.
J. Am. Chem. Soc. 2005, 127, 1654–1655. doi:10.1021/ja042650z
40.Li, G.-Q.; Dai, L.-X.; You, S.-L. Chem. Commun. 2007, 852–854.
doi:10.1039/b611646a
41.Enders, D.; Henseler, A.; Lowins, S. Synthesis 2009, 24, 4125–4128.
doi:10.1055/s-0029-1217070
doi:10.1016/j.tetlet.2011.01.146
12.Maeda, T.; Makino, K.; Iwasaki, M.; Hamada, Y. Chem.–Eur. J. 2010,
16, 11954–11962. doi:10.1002/chem.201001298
42.DiRocco, D. A.; Rovis, T. Angew. Chem., Int. Ed. 2012, 51,
5904–5906. doi:10.1002/anie.201202442
13.Seashore-Ludlow, B.; Villo, P.; Häcker, C.; Somfai, P. Org. Lett. 2010,
12, 5274–5277. doi:10.1021/ol102323k
43.DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 8094–8097.
doi:10.1021/ja3030164
14.Hamada, Y.; Koseki, Y.; Fujii, T.; Maeda, T.; Hibino, T.; Makino, K.
Chem. Commun. 2008, 6206–6208. doi:10.1039/b816524f
15.Suzuki, M.; Iwasaki, T.; Miyoshi, M.; Okumura, K.; Matsumoto, K.
J. Org. Chem. 1973, 38, 3571–3575. doi:10.1021/jo00960a028
16.Krysan, D. J. Tetrahedron Lett. 1996, 37, 3303–3306.
doi:10.1016/0040-4039(96)00581-3
44.We employed several imines bearing a variety of substituents on the
nitrogen atom (N-Bn, N-t-Bu, N-OBn); however, no desired products
were detected.
45.Baragwanath, L.; Rose, C. A.; Zeitler, K.; Connon, S. J. J. Org. Chem.
2009, 74, 9214–9217. doi:10.1021/jo902018j
46.O'Toole, S. E.; Rose, C. A.; Gundala, S.; Zeitler, K.; Connon, S. J.
J. Org. Chem. 2011, 7, 347–357. doi:10.1021/jo101791w
17.Schultz, K.; Stief, L.; Kazmaier, U. Synthesis 2012, 600–604.
doi:10.1055/s-0031-1289674
1503

Beilstein J. Org. Chem. 2012, 8, 1499–1504.
47.Jin, M. Y.; Kim, S. M.; Han, H.; Ryu, D. H.; Yang, J. W. Org. Lett. 2011,
13, 880–883. doi:10.1021/ol102937w
48.Mao, H.; An, S. L.; Kim, S. M.; Yang, J. W. Bull. Korean Chem. Soc.
2011, 32, 4408–4410. doi:10.5012/bkcs.2011.32.12.4408
49.Kim, S. M.; Jin, M. Y.; Kim, M. J.; Cui, Y.; Kim, Y. S.; Zhang, L.;
Song, C. E.; Ryu, D. H.; Yang, J. W. Org. Biomol. Chem. 2011, 9,
2069–2071. doi:10.1039/c0ob01178a
50.Rose, C. A.; Gundala, S.; Fagan, C.-L.; Franz, J. F.; Connon, S. J.;
Zeitler, K. Chem. Sci. 2012, 3, 735–740. doi:10.1039/C2SC00622G
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