O-silylative passerini reaction: A new one-pot synthesis of α-siloxyamides

Article abstract of DOI:10.1021/ol101763w

Figure Presented. A new method for the highly effective synthesis of α-siloxyamides is described. The addition of isocyanide to aldehyde proceeded smoothly in the presence of silanol to give the corresponding α-siloxyamides in high yields. A wide range of aldehydes and isocyanides are applicable in this reaction.

Full text of DOI:10.1021/ol101763w

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4341-4343
O-Silylative Passerini Reaction: A New
One-Pot Synthesis of r-Siloxyamides
Takahiro Soeta,* Yuuki Kojima, Yutaka Ukaji, and Katsuhiko Inomata*
DiVision of Material Sciences, Graduate School of Natural Science and Technology,
Kanazawa UniVersity, Kakuma, Kanazawa 920-1192, Japan
soeta@se.kanazawa-u.ac.jp; inomata@se.kanazawa-u.ac.jp
Received July 29, 2010
ABSTRACT
A new method for the highly effective synthesis of r-siloxyamides is described. The addition of isocyanide to aldehyde proceeded smoothly
in the presence of silanol to give the corresponding r-siloxyamides in high yields. A wide range of aldehydes and isocyanides are applicable
in this reaction.
Multicomponent reactions of isocyanides are powerful
synthetic tools for the preparation of diverse complex
molecules in practical, time-saving one-pot operations through
combinatorial strategies or parallel synthesis. Classically, the
reaction of isocyanide with aldehyde and carboxylic acid,
named the Passerini reaction, is one of the most important
multicomponent reactions to synthesize R-acyloxy amides.1
After being discovered in 1921, various modifications have
been developed;2 however, the use of other components
instead of carboxylic acid has not been realized until recently.
by the carboxylate affords the final product by migration of
the acyl group onto the oxygen atom originated from
aldehyde.
Therefore, a carboxylic acid is generally necessary in the
reaction of isocyanide with aldehyde or imine in the Ugi
reaction. In other words, the use of a carboxylic acid limits
application of this reaction to the construction of a broad
range of molecules. Only two examples using other com-
ponents instead of carboxylic acid have been reported so far.
An O-aryrative Passerini reaction using nitrophenol deriva-
tives has been developed by El Kaim, Grimaud, and
co-workers in 2006.3 Taguchi reported the direct alkylative
Passerini reaction of aldehyde, isocyanide, and a free
aliphatic alcohol catalyzed by In(III).4 Acetals and ketals are
also useful for the reaction of isocyanide catalyzed by Lewis
or Brønsted acid, affording R-alkoxyimidates.5
One of the reasons carboxylic acid is crucial in this
reaction depends on the reaction mechanism. The mechanism
of the Passerini reaction has been widely examined; activa-
tion of aldehyde by carboxylic acid followed by addition of
isocyanide and trapping of the resulting nitrilium intermediate
As described above, the acyl group in a carboxylic acid
consequently acts as an electrophile and the OH group works
as a nucleophile to the nitrilium intermediate in the Passerini
(1) Passerini, M. Gazz. Chem. Ital. 1921, 51, 126–181.
(2) For recent enantioselective Passerini-type reactions, see: (a) Mihara,
H.; Xu, Y.; Shepherd, N. E.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2009, 131, 8384–8385. (b) Yue, T.; Wang, M.-X.; Wang, D.-X.; Zhu,
J. Angew. Chem., Int. Ed. 2008, 47, 9454–9457. (c) Wang, S.-X.; Wang,
M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 388–391.
(d) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667–9676. (e)
Andreana, P. R.; Liu, C. C.; Schreiber, S. L. Org. Lett. 2004, 6, 4231–
4233. (f) Kusebauch, U.; Beck, B.; Messer, K.; Herdtweck, E.; Do¨mling,
A. Org. Lett. 2003, 5, 4021–4024. (g) Denmark, S. E.; Fan, Y. J. Am. Chem.
Soc. 2003, 125, 7825–7827.
(3) (a) El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem.
2007, 72, 4169–4180. (b) El Kaim, L.; Gizolme, M.; Grimaud, L. Org.
Lett. 2006, 8, 5021–5023.
(4) Yanai, H.; Oguchi, T.; Taguchi, T. J. Org. Chem. 2009, 74, 3927–
3929.
(5) (a) Tobisu, M.; Kitajima, A.; Yoshioka, S.; Hyodo, I.; Oshita, M.;
Chatani, N. J. Am. Chem. Soc. 2007, 129, 11431–11437. (b) Yoshioka, S.;
Oshita, M.; Tobisu, M.; Chatani, N. Org. Lett. 2005, 7, 3697–3699.
10.1021/ol101763w  2010 American Chemical Society
Published on Web 09/07/2010

reaction. We tried to survey such molecules that have the
same function as the carboxylic acid. If the molecule
potentially possesses an electrophilic and a nucleophilic
groups (Z-OH), it could act like a carboxylic acid in the
Passerini reaction (Scheme 1).
Table 1. Reaction Conditions for the O-Silylative Passerini
Reaction
Scheme 1. A Working Hypothesis
entry 2a (equiv) 3a (equiv) solv
(R3)3-Si
4 yield (%)
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
1.0
1.5
1.5
1.5
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
2.0
1.5
1.5
1.5
1.5
benzene Ph3 (3a)
toluene Ph3 (3a)
xylene Ph3 (3a)
37 (4aaa)
48 (4aaa)
45 (4aaa)
40 (4aaa)
33 (4aaa)
32 (4aaa)
25 (4aaa)
trace (4aaa)
90 (4aaa)
76 (4aaa)
76 (4aaa)
87 (4aaa)
nr
DCE
EtCN
Ph3 (3a)
Ph3 (3a)
dioxane Ph3 (3a)
THF Ph3 (3a)
MeOH Ph3 (3a)
toluene Ph3 (3a)
toluene Ph3 (3a)
toluene Ph3 (3a)
toluene Ph3 (3a)
toluene i-Pr3 (3b)
toluene Et3 (3c)
9
10
11
12
13
14
15
At first, we examined whether silanol can induce the three-
component coupling reaction with aldehyde and isocyanide
to afford the corresponding R-siloxyamides.
20 (4aac)
toluene t-BuPh2 (3d) 42 (4aad)
R-Siloxyamide or R-hydroxyamide derivatives6 are ver-
satile synthetic intermediates of biologically active peptide
mimics.7 Only one example for the preparation of R-siloxya-
mides in a one-pot reaction was reported by Nemoto, where
the reaction of aldehyde, amine, and “masked acyl cyanide
(MAC)” gave the R-siloxyamides in high yields.8 Herein,
we wish to describe the first example for O-silylative
Passerini reaction consisting of aldehyde, isocyanide, and
silanol to give the corresponding R-siloxyamides in high
yields.
Our initial studies began using aldehyde, isocyanide, and
silanol in benzene or toluene (entries 1 and 2 in Table 1).
To our delight, triphenylsilanol (3a) (1.0 equiv) cleanly
reacted with phenylpropionaldehyde (1a) and tert-octyl
isocyanide (2a) in toluene at 110 °C to afford the expected
R-siloxyamides 4aaa in 48% yield after 48 h. This reaction
proceeded smoothly in aromatic solvents and dichloroethane
(DCE) to afford 4aaa in moderate yields (entries 1-4);
however, polar solvents and cyclic ethers were less effective
(entries 5-7). In the case of methanol, which has been used
in the Ugi reaction as a protic solvent, the reaction was very
sluggish and only trace amount of the product was obtained
(entry 8). Although the yield of the product was low to
moderate, little or no side products were obtained under these
conditions.
A significant increase in yield was observed when 2.0
equiv of isocyanide and silanol were used, and the product
4aaa was isolated in 90% yield (entry 9). By decreasing the
amount of isocyanide or silanol to 1.0 equiv, the yields were
lowered to 76%, respectively (entries 10 and 11). Finally,
the desired product was obtained in 87% yield when 1.5
equiv of isocyanide and silanol were used in this reaction
(entry 12).
As an efficient method for an O-silylative Passerini
reaction was established, we set out to evaluate silanols
bearing other substituents (entries 13-15). Using trialkyl-
silanol 3b and 3c, yields of the product were poor (0% and
20%), respectively. In the case of tert-butyldiphenylsilanol
3c, the product was obtained in moderate yield. These results
indicated that the Lewis acidity of the Si atom is crucial for
the reaction to proceed efficiently.
It was attempted to expand the scope of isocyanides and
aldehydes applicable to the present O-silylative Passerini
reaction utilizing triphenylsilanol (3a) as shown in Table 2.
In these reactions, the optimal amounts of aldehydes 1a-g
(1.0 equiv) and isocyanides 2a-h (1.5 equiv) were used in
the presence of 1.5 equiv of triphenylsilanol (3a). From these
results, we found that the conditions were applicable to a
wide variety of aldehydes and isocyanides, and most reac-
tions were completed within 48 h. The reaction of aliphatic
isocyanides (R2 ) t-Oct, Bn, and c-Hex) with 1a and 3a
gave the product in high yields (entries 1-3). Aldehyde 1a
was consumed in 17 h when cyclohexylisocyanide (2c) was
used, giving the product in 89% yield (entry 3). In the case
of tert-butylisocyanide (2d), although the reaction gave the
desired product in 53% yield, Passerini product 5 was also
obtained in 20% yield, probably due to partial oxidation of
1a even though the reaction was carried out after degassing
(6) (a) Greco, M. N.; Zhong, H. M.; Maryanoff, B. E. Tetrahedron Lett.
1998, 39, 4959–4962. (b) Maryanoff, B. E.; Greco, M. N.; Zhang, H.-C.;
Adrade-Gordon, P.; Kauffman, J. A.; Nicolaou, K. C.; Liu, A.; Brungs,
P. H. J. Am. Chem. Soc. 1995, 117, 1225–1239.
(7) (a) Babine, R. E.; Bender, S. L. Chem. ReV. 1997, 97, 1359–1472.
(b) Nagai, M.; Kojima, F.; Naganawa, H.; Hamada, M.; Aoyagi, T.;
Takeuchi, T. J. Antibiot. 1997, 50, 82–84. (c) Sakurai, M.; Higashida, S.;
Sugano, M.; Komai, T.; Yagi, R.; Ozawa, Y.; Handa, H.; Nishigaki, T.;
Yabe, Y. Bioorg. Med. Chem. 1994, 2, 807–825.
(8) Nemoto, H.; Ma, R.; Suzuki, I.; Shibuya, M. Org. Lett. 2000, 2,
4245–4247.
4342
Org. Lett., Vol. 12, No. 19, 2010

Table 2. Scope of Aldehydes and Isocyanides
The addition reaction of isocyanide 2a to aldehyde 1a in
the absence of triphenylsilanol (3a) did not proceed in
refluxing toluene for 48 h (eq 1). When the reaction of
R-hydroxyamide 6 with silanol 3a was carried out in
refluxing toluene, no R-siloxyamide was obtained and 6 was
recovered (eq 2). These results indicate that the R-siloxya-
mide can not be formed by dehydration between R-hy-
droxyamide 6 and silanol.
On the basis of these results, we propose the reaction
mechanism of the present O-silylative Passerini reaction as
shown in Scheme 2. Aldehyde was activated by silanol
Scheme 2. Proposed Mechanism
a The reaction was completed in 17 h. b 20% Passerini product 5 was
also obtained. c An almost 1:1 ratio of diastereomers was obtained.
(entry 4). Chiral isocyanides 2e and 2f, which were prepared
from the corresponding amino acids, gave the products in
high yields; however, no chiral induction was observed
(entries 5 and 6).
through coordination of carbonyl oxygen to the silicon atom.
Subsequently, nucleophilic attack of isocyanide to carbonyl
group provides a nitrilium intermediate A. The hydroxy
group on the silanol rearranges to the nitrilium intermediate,
which tautomerizes to afford the corresponding R-siloxya-
mide (Scheme 2)
In summary, we developed a direct O-silylative Passerini
reaction consisting of aldehydes, isocyanides, and silanols.
This reaction is the first example of the isocyanide-based
multicomponent reaction using a silanol instead of a car-
boxylic acid component, giving the corresponding R-siloxya-
mides in high yields. A wide range of aldehydes and
isocyanides are applicable to this reaction. Further studies
on this reaction are in progress in our laboratory.
Aromatic isocyanides bearing an electron-withdrawing or
-donating group at the para position also afforded the
corresponding R-siloxyamides in high yields (entries 7 and
8).
Reactivity toward various aldehydes using cyclohexyliso-
cyanide (2c) was next examined. Aliphatic aldehydes 1b and
1c gave the product in 83% and 61% yields, respectively
(entries 9 and 10). Cinnamaldehyde (1d) was less reactive
and afforded the product in only 15% yield (entry 11).
Aromatic aldehydes also showed low reactivities (en-
tries12-14). Desired product was not obtained at all when
4-(N,N-dimehyl)benzaldehyde (1e) possessing an electron-
donating group was employed, and the starting materials were
recovered. However, benzaldehyde (1f) and 4-nitrobenzal-
dehyde (1g), which is activated by an electron-withdrawing
group, reacted with 2c and 3a, giving the products in
moderate yields (entries 13 and 14).
Acknowledgment. This work was supported by Grant-
in-Aid for Young Scientist (Start-up) (20850017).
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
To reveal the reaction mechanism, we conducted some
control experiments.
OL101763W
Org. Lett., Vol. 12, No. 19, 2010
4343