Chiral bronsted acid catalyzed enantioselective addition of α-isocyanoacetamides to aldehydes

Article abstract of DOI:10.1021/ol1007789

A clean and highly efficient enantioselective addition of α-isocyanoacetamides to aliphatic aldehydes catalyzed by chiral phosphoric acid in the presence of MS 5 A in toluene at -40 °C was developed. Excellent yields (85-98%) and good to excellent enantio

Full text of DOI:10.1021/ol1007789

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2414-2417
Chiral Brønsted Acid Catalyzed
Enantioselective Addition of
r-Isocyanoacetamides to Aldehydes
Xiaofei Zeng, Kehan Ye, Min Lu, Pei Juan Chua, Bin Tan, and Guofu Zhong*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, 21 Nanyang Link, Singapore 637371, Singapore
guofu@ntu.edu.sg
Received April 4, 2010
ABSTRACT
A clean and highly efficient enantioselective addition of r-isocyanoacetamides to aliphatic aldehydes catalyzed by chiral phosphoric acid in
the presence of MS 5 Å in toluene at -40 °C was developed. Excellent yields (85-98%) and good to excellent enantioselectivities (up to >99%
ee) were achieved.
The classic Passerini (P-3CR)1 and Ugi2 (U-4CR) reactions
based on the isocyanide multicomponent reactions (IMCRs)
have been well developed and widely used to generate
molecular complexity and molecular diversity for natural
product synthesis and drug discovery.3 All of the above-
mentioned multicomponent reactions involve the R-addition
of isocyanide to both electrophiles and nucleophiles to form
polyfunctionalized molecules. Although some chiral sub-
strate4 or chiral auxiliary5 controlled diastereoselective
R-additions of isocyanides to aldehydes have been reported
in the past decades,6 the development of the enantioselective
R-addition of isocyanide to aldehydes still remains a
significant challenge. Despite some efforts toward the
asymmetric version of the reactions, only limited examples
succeeded in achieving high enantioselectivities.7 Zhu, Wang,
and co-workers reported two examples of enantioselective
R-additions of R-isocyanoacetamides to aldehydes catalyzed
by chiral salen-Al8 and phosphoric acid-Al complexes.9 The
desired 2-(1-hydroxyalkyl)-5-aminooxazoles were obtained
in good to excellent yields, but only moderate to good
enantioselectivites (50-87% ee) were given. Shibasaki,
Matsunaga, and co-workers revealed that by using their
heterobimetallic Ga(OiPr)3/Yb(OTf)3/Schiff base complex as
(1) For an excellent review, see: Banfi, L.; Riva, R. Org. React. 2005,
65, 1–140.
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Linderman, R. J.; Binet, S.; Petrich, S. R. J. Org. Chem. 1999, 64, 336. (c)
Ross, G. F.; Herdtweck, E.; Ugi, I. Tetrahedron 2002, 58, 6127. (d) Basso,
A.; Banfi, L.; Riva, R.; Guanti, G. J. Org. Chem. 2005, 70, 576. (e) Banfi,
L.; Basso, A.; Guanti, G.; Merlo, S.; Repetto, C.; Riva, R. Tetrahedron
2008, 64, 1114. (f) Bonger, K. M.; Wennekes, T.; Filippov, D. V.; Lodder,
G.; van de Marel, G. A.; Overkleeft, H. S. Eur. J. Org. Chem. 2008, 3678.
(6) Banfi, L.; Basso, A.; Guanti, G.; Banfi, L. Asymmetric Isocyanide-
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Wiley-VCH: Weinheim, 2005; pp 1-32.
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Denmark, S.; Fan, Y. J. Org. Chem. 2005, 70, 9667. (c) Kusebauch, U.;
Beck, B.; Messer, K.; Herdtweck, E.; Domling, A. Org. Lett. 2003, 5, 4021.
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R. V. A.; De Greef, M. Synthesis 2003, 1471. (c) Nair, V.; Rajesh, C.;
Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L.
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J. 2008, 14, 8444. (h) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65,
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2009, 109, 796.
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10.1021/ol1007789  2010 American Chemical Society
Published on Web 04/29/2010

catalyst, the R-additions of R-isocyanoacetamides to alde-
hydes afforded excellent enantioselectivities (88-98% ee).10
Very recently, a chiral phosphoric acid catalyzed R-addition
of R-isocyanoacetamides to imines providing 2-(1-ami-
noalkyl)-5-aminoxazoles in moderate to good enantioselec-
tivities11 was reported by Zhu, Wang, and co-workers.
However, the authors failed to obtain high ee in the
R-additions of R-isocyanoacetamides to aldehydes in the
presence of these catalysts. Herein, we report the chiral
phosphoric acid catalyzed R-addition of R-isocyanoaceta-
mides to aldehydes, leading to products in excellent yields
(85-98%) with up to >99% ee.
afford racemic oxazole in 90% yield. This encouraged us to
further investigate various chiral phosphoric acids in the
reaction, and the results are summarized in Table 1. All the
Table 1. R-Addition of R-Isocyanoacetamides to Pivalaldehyde
Catalyzed by Different Chiral Phosphoric Acids at Room
Temperaturea
Chiral phosphoric acids have been extensively studied
and are well-established as versatile chiral Brønsted acid12
catalysts, especially in the catalytic asymmetric nucleo-
philic addition to imines, 1,4-addition and transfer hy-
drogenation reactions.13,14 However, the chiral phosphoric
acid catalyzed nucleophilic addition to aldehydes was rarely
reported. We hypothesized that chiral phosphoric acids
should catalyze the R-addition reaction and control the
enatioselectivity through the hydrogen bonding between the
catalyst and aldehydes.
entry
catalyst (5 mol %)
time (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
(R)-4a
(R)-4b
(R)-4c
(R)-4d
(R)-4e
(R)-4f
(R)-4g
(R)-4h
(R)-4i
(R)-4j
(R)-4k
(R)-5
2
2
2
12
5
5
2
2
2
2
90
94
91
48
95
90
98
89
85
93
90
97
15
45
18
29
48
39
37
45
48
53
9
To validate this, we began our investigation with a reaction
by using pivalaldehyde (1a) and 2-isocyano-1-morpholino-
3-phenyl propan-1-one (2a) as reactants and racemic 1,1′-
binaphthyl-2,2′-diyl hydrogenphosphate (rac-4) as catalyst
in toluene at room temperature. To our delight, the addition
reaction proceeded smoothly in the presence of rac-4 to
9
10
11
12
2
1.5
56
a The reactions were performed with pivalaldehyde (0.2 mmol, 2.0 equiv)
and 2-isocyano-1-morpholino-3-phenylpropan-1-one (0.1 mmol, 1.0 equiv)
in the presence of 5 mol % (R)-5 (0.005 mmol) in 1 mL of toluene at rt (23
°C). b Isolated yield. c Determined by chiral HPLC analysis.
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chiral catalysts could afford the products in excellent yields
except (R)-4d (Table 1, entry 4), which gave only 48% yield,
and this may be mainly due to the formation of an unknown
side product. Unfortunately, the enantioselectivities varied
significantly from 9% to 56% ee. Catalysts (R)-4j and (R)-5
were found to be the best considering the enantioselectivities
(53% and 56% ee in Table 1, entries 10 and 12), most
probably because of bearing more sterically hindered groups
on the 3,3′-positions of these catalysts.
Further investigation of the solvent effect of this reaction
was carried out by using (R)-5 as catalyst at room temper-
ature. Common solvents such as DCM, CHCl3, toluene,
benzene, and TBME (Table 2, entries 1, 2, and 4-6) are all
good reaction mediates for this reaction, and all gave
excellent yields (>90%). Notably, even hexane, which
afforded the product in 89% yield and 56% ee (Table 2, entry
3), but in a relatively longer time (6 h) mainly due to the
low solubility of the reactant. Among these solvents, toluene
was found to be the best (Table 2, entry 5). Next, we
examined the effect of reaction temperature in toluene using
(R)-5. The most appropriate temperature we found was -40
°C as the product was obtained in 98% yield and 77% ee in
24 h. With the decreasing of the temperature from -40 °C
to -60 °C, the reaction became much slower and the
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Org. Lett., Vol. 12, No. 10, 2010
2415

Table 2. R-Addition of R-Isocyanoacetamides to Aldehyde
Catalyzed by (R)-5 at -40 °C in Different Solvents and
Additivesa
entry
R1
solvent t (°C) time (h) yieldb (%) eec (%)
1
2
3
4
5
6
7
8
t-Bu DCM
rt
rt
rt
rt
rt
2
2
6
2
2
95
94
89
97
95
90
95
95
85
98
96
95
31
37
56
57
57
56
68
73
72
76
77
92
t-Bu CHCl3
t-Bu hexane
t-Bu toluene
t-Bu benzene
t-Bu TBME
t-Bu toluene
t-Bu toluene
t-Bu toluene
t-Bu toluene
t-Bu toluene
i-Pr toluene
rt
4
-20
-40
-60
-40
-40
-40
10
24
48
24
24
24
9
10d
11e
12e
a The reactions were performed with pivalaldehyde (0.2 mmol, 2.0 equiv)
and 2-isocyano-1-morpholino-3-phenylpropan-1-one (0.1 mmol, 1.0 equiv)
in the presence of 5 mol % (R)-5 (0.005 mmol) in 1 mL of toluene at room
temperature. b Isolated yield. c Determined by chiral HPLC analysis. d 100
mg of MS 4 Å was added. e 100 mg of MS 5 Å was added.
Figure 1. Substrate scope of the R-addition of R-isocyanoaceta-
enantioselectivity was not improved at all; only 85% yield
was obtained (Table 2, entry 9). Furthermore, the molecular
sieves (MS) were revealed to be useful in improving the
asymmetric induction, the best ee (77%) was then achieved
when MS 5 Å was added into the reaction (Table 2, entry
11). Overall, the optimum reaction condition was estab-
lished with 5 mol % of (R)-5 in the presence of MS 5 Å
in toluene at -40 °C. To our surprise, the ee value could
be dramatically increased to 92% when isobutyraldehyde,
instead of pivalaldehyde, was utilized under the identical
conditions (Table 2, entry 12).
The scope of the R-addition reaction was evaluated.
Oxazoles synthesized are listed in Figure 1. The reaction is
applicable to a wide range of aliphatic aldehydes including
acetyldehyde, isobutyaldehyde, pivalaldehyde, and octanal.
The excellent yields and good to excellent enantioselecivities
were attainable within 24 h. Notably, the ee value was
increased with the longer chain aldehydes; for example, lower
ee were obtained when acetylaldehyde (3e, ee ) 69%) and
propionaldehyde (3f, ee ) 73%) were used, and with the
increased steric hindrance of the aldehydes, the ee values
were improved from 77% to 89% (from 3g to 3l). Unfor-
tunately, when aromatic benzaldehyde was employed in the
R-addition reaction, the reaction could not happen. In
addition, different DL-phenylalanine derived R-isocyanoac-
etamides varied from morpholine 3a to pyridine 3b and
dibenzyl 3c were also investigated in the reaction, and
excellent yields and enantioselectivities were achieved.
Surprisingly, 99% ee was obtained with the substrate
2-isocyano-3-phenyl-1-(piperidin-1-yl)propan-1-one (3b). Less
satisfactory result was found in the reaction of R-isocy-
anoacetamide 3d (derived from DL-2-phenylglycine) with
mides to aldehyde catalyzed by (R)-5. The reactions were performed
with aldehyde (0.2 mmol, 2.0 equiv) and R-isocyanoacetamide (0.1
mmol, 1.0 equiv) in the presence of 5 mol % (R)-5 (0.005 mmol)
and 0.1 g of MS 5 Å in 1 mL of toluene at -40 °C. For 3e, 5.0
equiv of acetaldehyde was used.
isobutyraldehyde; the ee value was just moderate (ee ) 68%).
The similar substrate that was also derived from DL-2-
phenylglycine gave the desired product 3m in excellent yield
(95%) and good enantioselectivity (ee ) 85%). The absolute
configuration of these compounds was determined to be (S)
by comparing the optical rotation value and chiral HPLC
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2416
Org. Lett., Vol. 12, No. 10, 2010

spectra with those of the known compounds.9e The X-ray
crystal structure of oxazole 3d is shown in Figure 2.
Scheme 1. Proposed Mechanism of the R-Addition of
R-Isocyanoacetamides to Aldehyde
Figure 2. X-ray crystal structure of 3d.
Based on the previous study on phosphoric acid catalysts,16
we hereby propose the mechanism of the reaction (Scheme
1). First, the aldehyde is activated by the chiral phosphoric
acid catalyst through the hydrogen bonding, which is then
attacked by the isocyano group to form the intermediate II.
The following cyclization leads to the formation of oxazole
ring intermediate III. The subsequent cleavage of III releases
product 3 and the catalyst. The recovery of the catalyst
completes the catalytic cycle.11
In conclusion, a clean and highly efficient enantioselective
R-addition of R-isocyanoacetamides to aliphatic aldehydes
catalyzed by the chiral phosphoric acid in the presence of
MS 5 Å in toluene has been developed. For all cases,
excellent yields and good to excellent enantioselectivities
were achieved. Further investigation to understand the
reaction mechanism, exploration of other types of reactions,
and application to synthesize other important chiral com-
pounds are underway.
Acknowledgment. Research support from the MOE in
Singapore (ARC12/07, no. T206B3225) and NTU (URC,
RG53/07) is gratefully acknowledged. We thank Dr. Yongxin
Li in Nanyang Technological University for the X-ray
crystallographic analysis.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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2009, 11, 3036. (b) Lu, M.; Zhu, D.; Lu, Y.-P.; Zeng, X.; Tan, B.; Xu,
Z.-J.; Zhong, G. J. Am. Chem. Soc. 2009, 131, 4562.
OL1007789
Org. Lett., Vol. 12, No. 10, 2010
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