Direct alkylative Passerini reaction of aldehydes, isocyanides, and free aliphatic alcohols catalyzed by indium(III) triflate

Article abstract of DOI:10.1021/jo900354e

(Chemical Equation Presented) In(OTf)₃ was found to be a useful Lewis acid catalyst for direct alkylative Passerini reaction of aldehydes, isocyanides, and free aliphatic alcohols. In the present reaction, aromatic and α,β-unsaturated aldehydes

Full text of DOI:10.1021/jo900354e

nide, and silyl-protected aliphatic alcohol can be catalyzed by
triflic acid to give R-alkoxy amide in moderate yield.5 However,
direct P3C-type reaction of aldehydes, isocyanides, and free
aliphatic alcohols has not been achieved.
Direct Alkylative Passerini Reaction of
Aldehydes, Isocyanides, and Free Aliphatic
Alcohols Catalyzed by Indium(III) Triflate
As one of our ongoing research projects, we have been
exploring synthetic reactions catalyzed by indium(III) complexes
such as indium halides and indium(III) triflate [In(OTf)3].6 Since
In(III) complexes are known as mild, soft, and chemically stable
Lewis acids,7 we were interested in the application of In(III)
Lewis acids to the Passerini-type reaction in protic media.8,9
That is, In(III)-catalyzed formation of an oxocarbenium inter-
mediate from carbonyl substrates in alcohol solvents followed
by nucleophilic addition of isocyanides to the resultant oxo-
carbenium species should provide the direct procedure for
O-alkylative P3C reaction using free alcohols.10 In this paper,
we disclose the first example for alkylative Passerini reaction
of aldehydes, isocyanides, and free aliphatic alcohols.
Hikaru Yanai, Tomoko Oguchi, and Takeo Taguchi*
School of Pharmacy, Tokyo UniVersity of Pharmacy and Life
Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392,
Japan
taguchi@ps.toyaku.ac.jp
ReceiVed February 17, 2009
To explore the effective Lewis acids for direct O-alkylative
P3C reaction, we examined the reaction of benzaldehyde and
tert-butyl isocyanide in 2-propanol in the presence of various
Lewis acids. Selected results are summarized in Table 1. In the
presence of 20 mol % of In(OTf)3, the reaction of benzaldehyde
1a with 1.0 molar equiv of tert-butyl isocyanide in 2-propanol
at 80 °C for 24 h gave alkylative Passerini product 2a in 38%
yield along with the formation of a trace amount of nonalkylated
adduct 3a (entry 1). The increase in tert-butyl isocyanide to
2.0 molar equiv improved the product yield to 50% (entry 2).
Moreover, we found that stepwise addition of In(OTf)3 and tert-
butyl isocyanide dramatically increases the product yield. For
example, in the presence of 10 mol % of In(OTf)3, benzaldehyde
1a was reacted with 1.0 molar equiv of tert-butyl isocyanide at
80 °C for 12 h, then further treatment by additional both 10
mol % of In(OTf)3 and 1.0 molar equiv of tert-butylisocyanide
at the same temperature for 12 h gave 2a and 3a in 76 and 7%
yield, respectively (entry 3). Employing this stepwise addition
procedure, we examined the efficiency of other Lewis acids.
The catalytic activity of other In(III) complexes, such as InCl3,
InF3, and InBr3, was significantly lower than that of In(OTf)3
(entry 5). FeCl3 and Sc(OTf)3 were ineffective for the present
reaction. Bi(OTf)3 and certain lanthanoid(III) triflates, such as
In(OTf)3 was found to be a useful Lewis acid catalyst for
direct alkylative Passerini reaction of aldehydes, isocyanides,
and free aliphatic alcohols. In the present reaction, aromatic
and R,ꢀ-unsaturated aldehydes performed as nice substrates
to give the corresponding R-alkoxy amide products in good
yield.
The Passerini three-component (P3C) reaction, which was
discovered in 1921, is one of the most important multicompo-
nent reactions.1 This reaction is three-component condensation
of aldehydes, isocyanides, and carboxylic acids to give R-acy-
loxy amides in one step. Various modifications of this reaction
have already been developed,2,3 while the use of phenol or
aliphatic alcohol derivatives instead of a carboxylic acid
component has not been realized until recently. In 2006, El Kaim
and Grimaud reported the O-arylative Passerini-type reaction
using nitrophenol derivatives,4 which have a more acidic proton
compared to aliphatic alcohols. On the other hand, Chatani and
co-workers reported that the reaction of benzaldehyde, isocya-
(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.
(1) (a) Passerini, M. Gazz. Chem. Ital. 1921, 51, 126–181. (b) Ugi, I.;
Lohberger, S.; Karl, R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 1083. (c) Do¨mling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210. (d) Banfi, L.; Riva, R.
Org. React. 2005, 65, 1–140. (e) Do¨mling, A. Chem. ReV. 2006, 106, 17–89.
(2) For recent examples for enantioselective Passerini-type reaction, see: (a)
Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem., Int. Ed. 2008,
47, 388–391. (b) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7824–
7825. (c) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667–9676. (d)
Kusebauch, U.; Beck, B.; Messer, K.; Herdtweck, E.; Do¨mling, A. Org. Lett.
2003, 5, 4021–4024. (e) Andreana, P. R.; Liu, C. C.; Schreiber, S. L. Org. Lett.
2004, 6, 4231–4233.
(3) For recent examples of isocyanide-based reactions, see: (a) Tobisu, M.;
Yamaguchi, S.; Chatani, N. Org. Lett. 2007, 9, 3351–3353. (b) Li, X.; Yuan,
Y.; Berkowitz, W. F.; Todaro, L. J.; Danishefsky, S. J. J. Am. Chem. Soc. 2008,
130, 13222–13224. (c) Li, X.; Yuan, Y.; Kan, C.; Danishefsky, S. J. J. Am.
Chem. Soc. 2008, 130, 13225–13227.
(6) (a) Yanai, H.; Obara, S.; Taguchi, T. Org. Biomol. Chem. 2008, 6, 2679–
2685. (b) Yanai, H.; Saito, A.; Taguchi, T. Tetrahedron 2005, 61, 7087–7093.
(c) Yanai, H.; Taguchi, T. Tetrahedron Lett. 2005, 46, 8639–8643.
(7) (a) Chua, G.-L.; Loh, T.-P. In(III) Lewis Acids. In Acid Catalysis in
Modern Organic Synthesis; Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH:
Weinheim, Germany, 2008; Vol. 1, pp 377-467. (b) Auge, J.; Lubin-Germain,
N.; Uziel, J. Synthesis 2007, 1739–1764.
(8) For metal-triflate-catalyzed Passerini-type reactions, see: (a) Xia, Q.;
Ganem, B. Org. Lett. 2002, 4, 1631–1634. (b) Wang, S.; Wang, M.-X.; Wang,
D.-X.; Zhu, J. Eur. J. Org. Chem. 2007, 4076–4080.
(9) For metal-triflate-catalyzed Ugi reaction, see: (a) Ireland, S. M.; Tye,
H.; Whittaker, M. Tetrahedron Lett. 2003, 44, 4369–4371. (b) Keung, W.; Bakir,
F.; Patron, A. P.; Rogers, D.; Priest, C. D.; Darmohusodo, V. Tetrahedron Lett.
2004, 45, 733–737. (c) Okandeji, B. O.; Gordon, J. R.; Sello, J. K. J. Org. Chem.
2008, 73, 5595–5597.
(10) It is known that reaction of acetals and isocyanides in the presence of
acid catalysts gives R-alkoxy amides. See: (a) Mukaiyama, T.; Watanabe, K.;
Shiono, M. Chem. Lett. 1974, 1457–1458. (b) Barrett, A. G. M.; Barton, D. H. R.;
Falck, J. R.; Papaioannou, D.; Widdowson, D. A. J. Chem. Soc., Perkin Trans.
1 1979, 652–661.
(4) (a) El Kaim, L.; Gizolme, M.; Grimaud, L. Org. Lett. 2006, 8, 5021–
5023. (b) El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem. 2007,
72, 4169–4180.
10.1021/jo900354e CCC: $40.75
Published on Web 04/17/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3927–3929 3927

TABLE 1. Alkylative P3C Reaction of 1a, t-BuNC, and i-PrOH
formation of the 1,4-adduct was not observed and short reaction
time (within 5 h) was also realized (method B). Under the same
conditions, furfural and crotonaldehyde gave the corresponding
R-isopropoxy amides 2g and 2i in 76 and 75% yield, respec-
tively (entries 6 and 8).11
Unfortunately, with aliphatic aldehydes, the yield of O-
alkylated products was not so good. For example, according to
method A, we conducted the reaction of cyclohexanecarbalde-
hyde 1j with tert-butyl isocyanide in 2-propanol, and the desired
product 2j was obtained only in 47% yield due to the
competitive formation of nonalkylated R-hydroxy amide 3j in
14% yield (Scheme 1). To solve this problem, we planned an
alkylative P3C reaction of R,ꢀ-unsaturated carbonyls followed
by hydrogenation. In the presence of 5 mol % of In(OTf)3, the
reaction of 1k, tert-butyl isocyanide (2.0 molar equiv), and
trimethyl orthoformate (1.5 molar equiv) in 2-propanol gave
the corresponding R-isopropoxy amide 2k in 72% yield without
formation of R-hydroxy side product. Following hydrogenation
of this alkylative Passerini product using H2 and palladium on
carbon in MeOH gave 2j in 98% yield.
yielda (%)
entry
acid cat
additive
none
none
none
HC(OMe)3
none
none
none
none
none
none
none
none
2a
3a
1b
2
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
InCl3
38
50
76
80
28
59
15
6
61
64
59
3
trace
trace
7
0
2
7
trace
0
6
3c
4c
5c
6c
Bi(OTf)3
FeCl3
7c
8c
Sc(OTf)3
Y(OTf)3
Gd(OTf)3
Yb(OTf)3
TFA
9c
10c
11c
12c
11
8
8
a Isolated yield. b One molar equiv of t-BuNC was used. c Acid
catalyst, t-BuNC, and additive were added twice. See text.
As shown in Scheme 2, this reaction also proceeded in
secondary or primary alcohol in place of 2-propanol. For
example, according to method B, the reaction of cinnamaldehyde
1h in cyclopentanol gave R-cyclopentyloxy-ꢀ,γ-enamide 2m
in 72% yield. Under the same conditions, the reaction in
cyclohexanol gave 2n in 68% yield. While, in general, the
reactivity of primary alcohol such as 2-methylpropan-1-ol was
lower than that of several secondary alcohols, 2o was obtained
in moderate yield without the formation of R-hydroxy product
when the reaction was carried out under method A conditions.
Concerning these results, we conducted some controlled
studies to reveal the reaction pathway of the present reaction.
In the absence of tert-butyl isocyanide, the reaction of benzal-
dehyde 1a in 2-propanol in the presence of 20 mol % of In(OTf)3
gave benzyl alcohol in 95% yield, which was possibly generated
by In(OTf)3-catalyzed Meerwein-Ponndorf-Verley (MPV)
reduction through the simultaneous coordination of both car-
bonyl oxygen of benzaldehyde and hydroxy oxygen of 2-pro-
panol to the In(III) center (eq 1).12 This finding indicated that
further addition of isocyanide completely retards the MPV
reduction, possibly via coordination of isocyanide to In com-
plex.13 Furthermore, the reaction of benzaldehyde dimethyl
acetal 1a′ with tert-butyl isocyanide in the presence of In(OTf)3
in 2-propanol provided the clean formation of R-isopropoxy
amide 2a in 69% yield (eq 2).
TABLE 2. Alkylative P3C Reaction of 1, t-BuNC, and i-PrOH
entry
1
R
methoda
time (h)
2
yieldb (%)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
4-BrC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
2-naphthyl
2-furyl
A
A
A
A
A
B
B
B
24
24
24
24
24
5
2b
2c
2d
2e
2f
2g
2h
2i
82
83
73
71
77
76
82
75
PhCHdCH
MeCHdCH
5
5
a Method A: 20 mol % of In(OTf)3, 3.0 molar equiv of HC(OMe)3,
and 4.0 molar equiv of t-BuNC were added twice. Method B: 5 mol %
of In(OTf)3, 1.5 molar equiv of HC(OMe)3, and 2.0 molar equiv of
t-BuNC were added twice. b Isolated yield.
Y(OTf)3, Gd(OTf)3, and Yb(OTf)3, were less effective due to
slow formation of 2a (entries 6-11). In addition, the use of
trifluoroacetic acid (TFA) as a Brønsted acid was not effective
to obtain 2a in good yield (entry 12). We also found that the
use of trimethyl orthoformate as an additive is effective to avoid
the formation of R-hydroxy side product 3a (entry 4).
Next, we examined the reaction with various aldehydes (Table
2). In the reaction of 4-substituted benzaldehyde derivatives
under the optimized conditions (method A), electronic effect
of the substituent on the product yield was found to be small to
give the corresponding R-isopropoxy amides 2b-2e in good
yield (entries 1-4). Although, in the absence of trimethyl
orthoformate, 2-naphtharenecarbaldehyde 1f gave the product
2f in low yield (36%) due to the rapid generation of 2-naph-
thylmethanol (33%), the addition of orthoester inhibited this
reduction as a side reaction to result in clean formation of 2f
(entry 5, 77% yield). Interestingly, the reactivity of furfural 1g
and R,ꢀ-unsaturated aldehydes 1h-1i was higher than that of
benzaldehyde derivatives. For examples, the reaction of cinna-
maldehyde, tert-butyl isocyanide, and 2-propanol in the presence
of 1.5 molar equiv of trimethyl orthoformate was nicely
catalyzed by only 5 mol % of In(OTf)3 to give alkylative
Passerini product 2h in 82% yield (entry 7). In this case, the
On the basis of these results, we propose the reaction pathway
of the alkylative Passerini reaction as shown in Scheme 3.14
That is, in the presence of In(OTf)3, formation of oxocarbenium
(11) When the reaction of furfural 1g was carried out under method A
conditions, 2g was obtained in 83% yield,
(12) To the best of our knowledge, this is the first example of MPV reduction
catalyzed by In(III) Lewis acid.
(13) Bertani, R.; Crociani, L.; D’Arcangelo, G.; Rossetto, G.; Traldi, P.;
Zanella, P. J. Organomet. Chem. 2001, 626, 11–15.
3928 J. Org. Chem. Vol. 74, No. 10, 2009

SCHEME 1. Direct and Stepwise Syntheses of 2j
SCHEME 2. Alkylative P3C Reaction in Various Alcohols
gave isopropylated Passerini product 2a. Furthermore, in all
examples shown here, the absence of some side products, such
as enamines,15 diimides,5a or R-alkoxy esters,5b which are
potentially expected products by the addition of the second
isocyanide to B or by alcoholysis of B, indicated that hydrolysis
of nitrilium intermediate B is faster than the addition of sterically
hindered isocyanide or alcohols.
In summary, we developed the direct alkylative P3C reaction
of aldehydes, isocyanides, and free aliphatic alcohols. This is
the first example of the Passerini-type reaction using free
aliphatic alcohols instead of a carboxylic acid component. The
present reaction is a highly useful method to construct the
chemical library of R-alkoxy amide derivatives. Further studies
on this reaction are in progress in our laboratory.
SCHEME 3. Proposed Reaction Pathway of the Present
Reaction
Experimental Section
General Procedure for Method A. To a solution of In(OTf)3
(0.05 mmol, 10 mol %) in 2-propanol (2.0 mL) were added aromatic
aldehyde (0.50 mmol), t-BuNC (1.0 mmol, 2.0 equiv), and
HC(OMe)3 (0.75 mmol, 1.5 equiv). After being stirred at 80 °C
for 12 h, the reaction mixture was treated by additional In(OTf)3
(0.05 mmol, 10 mol %), t-BuNC (1.0 mmol, 2.0 equiv), and
HC(OMe)3 (0.75 mmol, 1.5 equiv) at 80 °C for 12 h. The resultant
mixture was concentrated under reduced pressure and purified by
column chromatography on silica gel.
General Procedure for Method B. To a solution of In(OTf)3
(12.5 µmol, 2.5 mol %) in 2-propanol (2.0 mL) were added R,ꢀ-
unsaturated aldehyde (0.50 mmol), t-BuNC (0.5 mmol, 1.0 equiv),
and HC(OMe)3 (0.325 mmol, 0.75 equiv). After being stirred at
80 °C for 2.5 h, the reaction mixture was treated by additional
In(OTf)3 (2.5 µmol, 2.5 mol %), t-BuNC (0.5 mmol, 1.0 equiv),
and HC(OMe)3 (0.325 mmol, 0.75 equiv) at 80 °C for 2.5 h. After
extractive workup and evaporation, the resultant residue was purified
by column chromatography.
species A by the reaction of aldehydes with alcohols initially
occurs. The addition of orthoester possibly accelerates the
formation of A. The nucleophilic attack of tert-butyl isocyanide
to oxocarbenium species A and the following hydrolysis of the
resultant nitrilium intermediate B by H2O, which is generated
in the oxocarbenium formation step, provide the alkylative
Passerini products 2. This mechanism would also be supported
by the fact that benzaldehyde dimethyl acetal 1a′ in 2-propanol
(14) The treatment of R-hydroxy amide 3a by a catalytic amount of In(OTf)3
in 2-propanol resulted in no reaction. This finding supports that the formation
of 2a does not proceed via In(OTf)3-catalyzed nucleophilic substitution of
hydroxy group of 3a by 2-propanol. (a) Yasuda, M.; Saito, T.; Ueba, M.; Baba,
A. Angew. Chem., Int. Ed. 2004, 43, 1414–1416. (b) Yasuda, M.; Somyo, T.;
Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793–796.
(15) (a) Pellissier, H.; Meou, A.; Gil, G. Tetrahedron Lett. 1986, 27, 2979–
2980. (b) Pellissier, H.; Meou, A.; Gil, G. Tetrahedron Lett. 1986, 27, 3505–
3506.
Supporting Information Available: Detailed experimental
1
procedure, compound characterization data, H and 13C NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO900354E
J. Org. Chem. Vol. 74, No. 10, 2009 3929