Catalytic, enantioselective α-additions of isocyanides: Lewis base catalyzed Passerini-type reactions

Article abstract of DOI:10.1021/jo050549m

The generality of catalytic, enantioselective α-additions of isocyanides to aldehydes has been demonstrated (Passerini-type reactions). The catalytic system of silicon tetrachloride and a chiral bisphosphoramide (R,R)-1b provided high yields and good to excellent enantioselectivities for the addition of tert-butyl isocyanide to a wide range of aldehydes (aromatic, heteroaromatic, olefinic, acetylenic, aliphatic). Aqueous workup afforded the α-hydroxy tert-butyl amides whereas a low-temperature methanol quench followed by basic workup afforded the α-hydroxy methyl esters. The reaction is also successful for other isocyanides, albeit with reduced enantioselectivity. Reaction conditions, particularly the rate of addition of the isocyanide was found to be crucial for good yields and high selectivities.

Full text of DOI:10.1021/jo050549m

VOLUME 70, NUMBER 24
NOVEMBER 25, 2005
© Copyright 2005 by the American Chemical Society
Catalytic, Enantioselective r-Additions of Isocyanides: Lewis Base
Catalyzed Passerini-Type Reactions
Scott E. Denmark* and Yu Fan
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received March 17, 2005
The generality of catalytic, enantioselective R-additions of isocyanides to aldehydes has been
demonstrated (Passerini-type reactions). The catalytic system of silicon tetrachloride and a chiral
bisphosphoramide (R,R)-1b provided high yields and good to excellent enantioselectivities for the
addition of tert-butyl isocyanide to a wide range of aldehydes (aromatic, heteroaromatic, olefinic,
acetylenic, aliphatic). Aqueous workup afforded the R-hydroxy tert-butyl amides whereas a low-
temperature methanol quench followed by basic workup afforded the R-hydroxy methyl esters. The
reaction is also successful for other isocyanides, albeit with reduced enantioselectivity. Reaction
conditions, particularly the rate of addition of the isocyanide was found to be crucial for good yields
and high selectivities.
Introduction
molecular diversity for drug discovery and in heterocycle
synthesis4,5
As a rare class of stable divalent carbon nucleophiles,
isocyanides have the interesting ability of forming mul-
tiple bonds on the terminal carbon atom in a single
reaction. Passerini, Ugi, and others have long recognized
the unique synthetic utility of isocyanides when combined
with various reagents and serving as a latent amide
function.1 In the classical Passerini reaction, the combi-
nation of an isocyanide with a ketone or an aldehyde and
a carboxylic acid produces an R-acyloxy carboxamide. The
reaction is believed to proceed via a nitrilium ion adduct
which is intercepted by the carboxylate to form an acyl
imidate. Subsequent Mumm rearrangement affords the
R-acyloxy carboxamide product.2 In the Ugi reaction, an
R-amido carboxamide is formed from the reaction of an
isocyanide with an imine (usually generated in situ) and
a carboxylic acid.3 Both of these reactions have been
featured in numerous applications such as generating
Because these synthetically useful reactions generate
stereogenic centers, they have been the subject of many
studies on methods of stereocontrol. Apart from the
diastereoselectivity that attends the use of chiral alde-
hydes,6 the use of chiral auxiliaries have been most
(3) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbru¨ckner, C. Angew. Chem.
1959, 71, 386. (b) Ugi, I.; Steinbru¨ckner, C. Angew. Chem. 1960, 72,
267-268.
(4) For recent reviews, see: (a) Banfi, L.; Riva, R. Org. React. 2005,
65, 1-140. (b) Zhu, J. Eur. J. Org. Chem. 2003, 1133-1144. (c) Hulme,
C. Gore, V. Curr. Med. Chem. 2003, 10, 51-80. (d) Do¨mling, A. Curr.
Opin. Chem. Bio. 2002, 6, 306-313. (e) Bienayme, H.; Hulme, C.;
Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321-3329. (f) Do¨mling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169-3210. (g) Armstrong,
R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 29, 123-131.
(5) For recent applications of Passerini reactions, see: (a) Owens,
T. D.; Araldi, G.-L.; Nutt, R. F.; Semple, J. E. Tetrahedron Lett. 2001,
42, 6271-6274. (b) Banfi, L.; Guanti, G.; Riva, R. Chem. Commun.
2000, 985-986. (c) Beck, B.; Magnin-Lachaux, M.; Herdtweck, E.;
Do¨mling, A. Org. Lett. 2001, 3, 2875-2878. (d) Ovens, T. D.; Semple,
J. E. Org. Lett. 2001, 3, 3301-3304. (e) Semple, J. D.; Owens, T. D.;
Nguyen, K.; Levy, O. E. Org. Lett. 2000, 2, 2769-2772. (f) Banfi, L.;
Guanti, G.; Riva, R.; Basso, A.; Calcagno, E. Tetrahedron Lett. 2002,
43, 4067-4069.
* To whom correspondence should be addressed.
(1) Ugi, I. Isonitrile Chemistry; Academic Press: New York, 1971.
(2) (a) Passerini, M.; Simone, L. Gazz. Chim. Ital. 1921, 51, 126-
129. (b) Passerini, M.; Ragni, G. Gazz. Chim. Ital. 1931, 61, 964-969.
10.1021/jo050549m CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/25/2005
J. Org. Chem. 2005, 70, 9667-9676
9667

Denmark and Fan
extensively developed.7-9 In the early studies by Ugi and
co-workers, excellent diastereoselectivities have been
accomplished in the addition of isocyanides to chiral
imines with ferrocenyl auxiliaries. More recently, Kunz
and co-workers have demonstrated that chiral scaffolds
derived from carbohydrates induce high selectivities in
the Lewis acid mediated Ugi reaction.8 On the other
hand, the use of R-methylbenzylamine auxiliary proved
to be ineffective for asymmetric induction.9 With regard
to the use of chiral isocyanide, only one successful
example has been reported by Ugi and co-workers for the
addition reaction with aldehydes.10 Despite the fact that
high diastereoselectivities can be achieved by the use of
certain chiral auxiliaries, all of these methods suffer from
the fact that chiral auxiliaries have to be stoichiomet-
rically incorporated and then removed from the product.
In view of the similarity of these reactions to cyanohydrin
additions and Strecker reactions11 it is surprising that
prior to our initial communication, there were no ex-
amples of catalytic enantioselective process. Subse-
quently, two reports have appeared; one that employs
chiral Bronsted catalysis with modest enantioselectivity
and a second that employs a copper bisoxazoline complex
and gives generally higher selectivities with a broader
range of substrates.12
SCHEME 1
addition of isocyanide and often generates multiple
addition product ii.13c,14c Furthermore, even if the adduct
iii could be generated, the dissociation of the MXn1 unit
from this intermediate would be required for the turnover
of Lewis acid catalyst, which has rarely seen success.14
We recognized that these problems could be addressed
by application of the newly introduced concept of Lewis
base activation of Lewis acids.15 This concept has been
successfully demonstrated in the context of various
enantioselective carbon-carbon bond-forming reactions.16
Chiral binaphthyldiamine-derived bisphosphoramide
(R,R)-1b effectively activates a weak Lewis acid, SiCl4,
and generates a highly reactive and selective silyl cation
for the asymmetric additions of allylstannanes, trialkyl-
silyl ketene acetals and silyl enol ethers to aldehydes
(Scheme 2).15 An important feature of these reactions is
Background
The formal divalency of the isocyanide nucleophile
provides a challenge to the successful development of
chiral Lewis acid catalysis in the R-addition reactions.
The primary adduct of the R-addition is a zwitterionic
nitrilium ion i, Scheme 1. In the classical Passerini and
Ugi reactions, a carboxylate combines with i and leads
to productive reaction pathways. However, for the Lewis-
acid-mediated R-addition, without a facile transfer of the
counterion X, this intermediate is subject to further
SCHEME 2
(6) Cuny, G.; Ga´mez-Montan˜o, R.; Zhu, J. Tetrahedron 2004, 60,
4879-4885.
(7) For additions to chiral imines with ferrocenyl auxiliaries, see:
(a) Ugi, I.; Offermann, K. Angew. Chem. 1963, 75, 917; Angew. Chem.,
Int. Ed. Engl. 1963, 2, 624. (b) Ugi, I.; Offermann, K.; Herlinger, H.
Angew. Chem. 1964, 76, 613; Angew. Chem., Int. Ed. Engl. 1964, 3,
656-657. (c) Urban, R.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1975, 14,
61-62. (d) Eberle, G.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1976, 15,
492-493. (e) Ugi, I.; Offermann, K.; Herlginer, H.; Marquarding, D.
Justus Liebigs Ann. Chem. 1967, 709, 1-10. (f) Demharter, A.; Ugi, I.
J. Prakt. Chem. 1993, 335, 244-245.
(8) For additions to chiral imines with carbohydrate auxiliaries,
see: (a) Oertel, K.; Zech, G.; Kunz, H. Angew. Chem. 2000, 112, 1489-
1491; Angew. Chem., Int. Ed. 2000, 39, 1431. (b) Kunz, H.; Pfrengle,
W. J. Am. Chem. Soc. 1988, 110, 651-652. (c) Kunz, H.; Pfrengle, W.
Tetrahedron 1988, 44, 5487-5494. (d) Kunz, H.; Pfrengle, W.; Sager,
W. Tetrahedron Lett. 1989, 30, 4109-4110. (e) Kunz, H.; Pfrengle, W.;
Ruck, K.; Sager, W. Synthesis 1991, 1039-1042. (f) Kunz, H.; Ruck,
K. Angew. Chem. 1993, 105, 355-377. (g) Goebel, M.; Ugi, I. Synthesis
1991, 1095-1098. (h) Lehnhoff, S.; Goebel, M.; Karl, R. M.; Klosel, R.;
Ugi, I. Angew. Chem. 1995, 107, 1208-1211; Angew. Chem., Int. Ed.
Engl. 1995, 34, 1104-1107. (i) Ross, G. F.; Herdtweck, E.; Ugi, I.
Tetrahedron 2002, 58, 6172-6133.
(13) For early examples of Lewis acid promoted R-addition reaction
of isocyanides, see: (a) Muller, E.; Zeeh, B. Liebigs Ann. Chem. 1966,
696, 72-80. (b) Muller, E.; Zeeh, B. Liebigs Ann. Chem. 1968, 715,
47-51. (c) Saegusa, T.; Taka-Ishi, N.; Fujii, H. Tetrahedron 1968, 24,
3795-3798. (d) Seebach, D.; Schiess, M. Helv. Chim. Acta 1983, 66,
1618-1623. (e) Seebach, D.; Adam, G.; Gees, T.; Schiess, M.; Weigand,
W. Chem. Ber. 1988, 121, 507-517. (f) Carofiglio, T.; Cozzi, P. G.;
Floriani, C.; Chiesa-Villa, A.; Rizzoli, C. Organometallics 1993, 12,
2726-2736.
(14) For recent examples of Lewis acid promoted R-addition reac-
tions of isocyanides, see the following. (a) Zn(OTf)2/TMSCl-promoted
Passerini-type reaction: Xia, Q.; Ganem, B. Org. Lett. 2002, 4, 1631-
1634. (b) LiOTf-promoted addition of isocyanides to epoxides and
aziridines: Kern, O. T.; Motherwell, W. B. Chem. Commun. 2003,
2988-2989. (c) GaCl3-mediated addition of isocyanides to epoxides:
Bez, G.; Zhao, C.-C. Org. Lett. 2003, 5, 4991-4993. (d) GaCl3-catalyzed
addition of isocyanides to enones: Chatani, N.; Oshita, M.; Tobisu,
M.; Ishii, Y.; Murai, Y. J. Am. Chem. Soc. 2003, 125, 7812-7813. (e)
Ti-TADDOL complex promoted Passerini reaction: Kusebauch, U.;
Beck, B.; Messer, K.; Herdtweck, E.; Do¨mling, A. Org. Lett. 2003, 5,
4021-4024.
(9) For additions to chiral imines with R-methylbenzylamine aux-
iliary, see: (a) Divanfard, H. R.; Lysenko, Z.; Wang, P. C.; Joullie, M.
M. Synth. Commun. 1978, 8, 269-273. (b) Semple, J. E.; Wang, P. C.;
Lysenko, Z.; Joullie, M. M. J. Am. Chem. Soc. 1980, 102, 7505-7510.
(10) For addition of a chiral isocyanide to aldehydes and imines,
see: Bock, H.; Ugi, I. J. Prakt. Chem. 1997, 339, 385-389.
(11) (a) Mori, A.; Inoue, S. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag:
Heidelberg, 1999; Vol. II; Chapter 28. (b) Groger, H. Chem. Rev. 2003,
103, 2795-2827.
(15) (a) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123,
6199-6200. (b) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem.
Soc. 2002, 124, 13405-13407. (c) Denmark, S. E.; Beutner, G. L. J.
Am. Chem. Soc. 2003, 125, 7800-7801. (d) Denmark, S. E.; Heemstra,
J. R., Jr. Org. Lett. 2003, 5, 2303-2306.
(12) (a) Frey, R.; Galbraith, S. G.; Guelfi, S.; Lamberth, C.; Zeller,
M. Synlett 2003, 1536-1538. (b) Andreana, P.; Liu, C. C.; Schreiber,
S. L. Org. Lett. 2004, 5, 4231-4233.
9668 J. Org. Chem., Vol. 70, No. 24, 2005

Lewis Base Catalyzed Passerini-Type Reactions
that the weak Lewis acid, SiCl4, can be used in stoichio-
metric quantities without the fear of achiral pathways
promoted by SiCl4 because the kinetically competent
species are formed only upon binding of SiCl4 to the chiral
catalyst. Furthermore, in these reactions, catalyst turn-
over is the transfer of the phosphoramide from a trichlo-
rosilyl species to the bulk of the achiral Lewis acid SiCl4
instead of the cleavage of the bond between the SiCl3 unit
and the product of the addition reaction.
The use of a stoichiometric amount of a weak Lewis
acid and the fundamental change in the catalyst turnover
step are ideally suited for the development of catalytic,
asymmetric R-addition reactions. This report details our
full investigation on the scope and limitation of the Lewis
base catalyzed, SiCl4-mediated, Passerini-type reac-
tions.17
amount of SiCl4 was most effective in promoting the
addition. In the presence of 10 mol % of HMPA or
pyridine N-oxide, the SiCl4-mediated addition proceeded
to completion within 4 h at -78 °C (Table 1, entries 3
and 4). Furthermore, the use of 5 mol % chiral bisphos-
phoramide (R,R)-1b delivered the product 5a (from a mild
quench with aqueous base) in good enantioselectivity
which provided conclusive evidence that the SiCl4-medi-
ated addition was highly responsive to Lewis base
catalysis (Table 1, entry 5).
1.2. Optimization of Reaction Conditions for
Enantioselective Addition. To improve the enantiose-
lectivity, the ratio between the catalyzed, asymmetric
pathway and the achiral pathway has to be increased.
The presence of an achiral background reaction has not
been seen in other reactions with SiCl4, but in this case
it is not surprising because the isocyanide nucleophile is
itself a Lewis base. Because the bisphosphoramide is used
in trace amounts, a simple solution to suppressing the
background reaction is to decrease the instantaneous con-
centration of the isocyanide by slow addition to a mixture
of all the other reaction components.18 Another source of
background reaction could be Bronsted acid catalysis2
from traces of HCl in the SiCl4.15d Experiments to exam-
ine the effect of addition rate were performed by adding
a solution of t-BuNC in CH2Cl2 (1.0 M) to a solution of
the mixture of SiCl4, benzaldehyde, phosphoramide cata-
lyst (R,R)-1b, and Hu¨nig’s base in CH2Cl2 (1.0 M) over
the period of time as indicated in Table 2.
Results
1. R-Additions of tert-Butyl Isocyanide to Benzal-
dehyde. 1.1. Survey of Lewis Base Catalyst. In the
orienting experiments, the ability of various Lewis bases
to accelerate the SiCl4-mediated R-additions of isocya-
nides to aldehydes was examined. Because of their proven
promoting ability in the SiCl4-mediated addition reac-
tions, HMPA, pyridine N-oxide, and the chiral bisphos-
phoramide (R,R)-1b were tested in this reaction between
tert-butyl isocyanide 2a to benzaldehyde (3a). The initial
survey was conducted in a series of VT 1H NMR experi-
ments, and the results are summarized in Table 1.
TABLE 1. SiCl4-Mediated Addition of t-BuNC to
TABLE 2. Optimization for (R,R)-1b-Catalyzed Addition
of t-BuNC to Benzaldehyde
Benzaldehyde
loading, conv, yield,a
entry addition time, h i-Pr2NEt, mol % yield,a %
S/Rb,c
entry
catalyst
mol %
%
%
erb
1d
21e
31e
41e
83
94
89
96
90.2/9.8
94.3/5.7
1
none
83
0
100
100
100
79
2
3
4
2c
3
(R,R)-1b
100
10
10
5
30
10
98.1/1.9
HMPA
90
94
83
> 99.0/1.0
4
5
pyridine N-oxide
(R,R)-1b
a Yields of chromatographically homogeneous material. b De-
termined by CSP-SFC. c Absolute configuration is S by correla-
tion.19 d Isocyanide was added in one portion. e Reaction mixture
was kept at -74 °C for 4 h after the addition of the isocyanide.
90.2/9.8
a Yields of chromatographically homogeneous material. b De-
termined by CSP-SFC. c No SiCl4 was used, and the reaction
temperature was 25 °C for 24 h.
Low-temperature 1H NMR analysis indicated that
SiCl4 alone could effectively promote the addition of
t-BuNC to benzaldehyde. In the presence of a stoichio-
metric amount of SiCl4, the addition proceeded to 83%
conversion within 4 h at -78 °C, and the imidoyl chloride
intermediate 4 was formed cleanly. After aqueous work-
up, the hydroxy amide product 5a was obtained in 79%
yield (Table 1, entry 1). On the other hand, bisphos-
phoramide (R,R)-1b alone did not promote the addition
(Table 1, entry 2). Gratifyingly, the combination of a
small amount of a Lewis base and a stoichiometric
The results show clearly that the enantioselectivity
was dependent on the rate of the addition of t-BuNC.
When a 2 h addition period was used rather than one
portion addition, the enantiomeric ratio increased from
90.2/9.8 to 94.3/5.7 (Table 2, entries 1 and 2). Further
increases in the enantioselectivity were observed when
the isocyanide was added over 3 h in the presence of 30
mol % of Hu¨nig’s base (Table 2, entry 3). The enantiose-
lectivity reached the maximum when a 4 h addition
protocol was used in the presence of 10 mol % of Hu¨nig’s
base (Table 2, entry 4). Thus, the key factors for sup-
(16) For full accounts of the development of this concept, see: (a)
Denmark, S. E.; Fujimori, S. In Modern Aldol Reactions; Mahrwald,
R., Ed.; Wiley-VCH: Weinheim, 2004; Vol. 2, Chapter 7. (b) Denmark,
S. E.; Beutner, G. L.; Wynn, T. Eastgate, M. D. J. Am. Chem. Soc.
2005, 127, 3774-3789.
(17) Part of this work has been communicated: Denmark, S. E.; Fan,
Y. J. Am. Chem. Soc. 2003, 125, 7824-7827.
(18) Lowering the concentration of the isocyanide may also disfavor
the background reaction if the order in isocyanide is higher in this
process than in the catalyzed addition. By analogy to other reactions,
we expect that the isocyanide is first order in the catalyzed process:
(a) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2000, 122, 12021-12022.
(b) Denmark, S. E.; Pham, S. Helv. Chem. Acta 2000, 83, 1846-1853.
(c) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488-9489.
J. Org. Chem, Vol. 70, No. 24, 2005 9669

Denmark and Fan
TABLE 3. Catalyst Survey for the Addition of t-BuNC
pressing achiral background reaction were identified:
minimizing the concentration of the isocyanide nucleo-
phile and the suppression of Brønsted acid catalysis.
Under the optimized conditions, the single enantiomer
of the hydroxy amide 5a was obtained in near quantita-
tive yield. From the sign of optical rotation ([R] 2D4 +28.8,
MeOH), the absolute configuration of the product ob-
tained with catalyst (R,R)-1b was determined to be S by
correlation to the literature value.19 This configuration
indicated a Re-face attack on the aldehyde by the
isocyanide, which is in agreement with the sense of
asymmetric induction observed in the addition of allyl-
tributylstannane and trialkylsilyl ketene acetals to ben-
zaldehyde.15
1.3. Catalyst Survey. Clearly, chiral binaphthyl-
diamine-derived catalyst (R,R)-1b is highly effective in
discriminating the enantiotopic faces of benzaldehyde in
the R-addition reaction. To identify other potentially
useful catalysts for a broader range of aldehyde classes,
a survey of catalyst structures was deemed profitable. A
wide variety of dimeric Lewis bases have been synthe-
sized in this laboratory, and hence several were inves-
tigated in the addition of t-BuNC to benzaldehyde (Chart
1).20 Bisphosphoramides (R,R)-1a and (R,R)-1c, prepared
to Benzaldehyde
entry
catalyst
loading, mol %
yield,a %
S/Rb
1
2
3
4
5
6
(R,R)-1a
(R,R)-1c
1d
5
5
10
10
10
10
93
86
82
92
87
87
96.4/3.6
95.6/4.4
34.7/65.3
51.4/48.6
66.3/33.7
51.5/48.5
1e
1f
P-(R,R)-1g
a Yields of chromatographically homogeneous material. b De-
termined by CSP-SFC.
Not surprisingly, the selectivity was highly sensitive
to the structure of the diamine backbone, linker length
and identity of the Lewis-base catalyst. Within the class
of dimeric phosphoramides, chiral 1,1′-binaphthyl-2,2′-
diamine-derived bisphosphoramides 1a-c proved to be
the most selective (Table 3, entries 1 and 2). Although
all three linker lengths provided excellent enantioselec-
tivity, the optimal linker length between two binaphth-
diamine was found to be five methylene units (Table 3,
entry 4).21 On the other hand, none of the bisphosphora-
mides 1d-f, derived from cyclohexane-1,2-diamine, stil-
bene-1,2-diamine, and 2,2′-bispyrrolidine, delivered use-
ful selectivity (Table 3, entries 3-5). Bis-N-oxide (P)-
(R,R)-1g was not selective at all; nearly racemic product
was obtained (Table 3, entry 6).
CHART 1
2. Aldehyde Substrate Survey. A broad survey of
the structure of the aldehyde acceptor was conducted to
explore the scope of the enantioselective addition reaction
with t-BuNC. Aldehydes from all basic structural classes,
including aromatic (3b-f), olefinic (3g,h), acetylenic (3i),
linear (3j), and branched aliphatic (3k) (Chart 2), were
investigated in the addition of t-BuNC. Also, aldehydes
containing common heterocycles are also included in this
survey (3l-o).
CHART 2
by linking two axially chiral 1,1′-binaphthyl-2,2′-diamine
molecules with aliphatic diamine chains, were chosen to
examine the effect of the linker length on enantioselec-
tivity. The influence of varying the structure of the chiral
backbones on the enantioselectivity was investigated
using bisphosphoramides 1d, 1e, and 1f. To access the
reactivity and selectivity of the class of bis-N-oxides,
catalyst (P)-(R,R)-1g, possessing both central and axial
chiral elements, was employed.20 The optimized reaction
protocol was used for this catalyst survey: a solution of
t-BuNC in CH2Cl2 (1.0 M) was added over 4 h to a
solution of the mixture of SiCl4, benzaldehyde, catalyst,
and 10 mol % of Hu¨nig’s base in CH2Cl2 (1.0 M). The
results are summarized in Table 3.
2.1. Additions Catalyzed by Pyridine N-Oxide. To
test the scope of the aldehyde substrate and generate
racemic sample to aid enantiomeric analysis, these
aldehydes were first studied in the pyridine N-oxide
catalyzed reaction. Reactions were performed by adding
(19) S-5a, [R] 2D4 +28.3 (MeOH), mp 82.5-84 °C: Kelly, S. E.;
LaCour, T. Synth. Commun. 1992, 22, 859-869.
(20) For the preparation bisphosphoramides 1a-c, see ref 15a; 1d,
see ref 18a; 1f, see 18c. For the preparation of bis-N-oxide (P)-(R,R)-
1g, see: Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233-
4235.
(21) For a discussion of the origin of the tether length effect, see:
Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2003, 125, 2208-2216.
9670 J. Org. Chem., Vol. 70, No. 24, 2005

Lewis Base Catalyzed Passerini-Type Reactions
TABLE 4. Additions of t-BuNC to Aldehydes Catalyzed
by Pyridine N-Oxide
TABLE 5. Additions of tert-Butyl Isocyanide to
Aldehydes Catalyzed by (R,R)-1b
yield,a %
erb
entry
aldehyde
product
yield,a %
entry
aldehyde
product
1
2
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3j
3j
3j
(()-5b
(()-5c
(()-5d
(()-5e
(()-5f
(()-5g
(()-5h
(()-5i
(()-5j
(()-5k
(()-5l
(()-5m
(()-5n
(()-5o
(()-5j
(()-5j
(()-5j
(()-5k
(()-5k
(()-5k
87
92
89
90
87
73
86
85
44
37
76
89
95
99
35
59
89
37
62
72
1
2
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
13o
91
89
89
93
92
81
86
76
92
53
83
86
89
81
99.9/0.1
98.3/1.7
96.5/3.5
99.7/0.3
92.2/7.8c
97.8/2.2
67.4/32.6
77.0/23.0
81.9/18.1
87.1/12.9d
95.9/4.1d
96.2/3.8
94.2/5.8
94.3/5.7
3
3
4
4
5
5
6
6
7
7
8
8
9b
9e,g
10f,g
11
12
13
14
10b
11
12
13
14
15b,c
16bd
17e
18b,d
19e
20f
a Yields of chromatographically homogeneous material. b De-
termined by CSP-SFC. c Determined by CSP-HPLC. d Determined
by CSP-GC. e Isocyanide was added over 8 h. f Isocyanide was
added over 12 h. g No Hu¨nig’s base was used.
3k
3k
3k
cinnamaldehyde (3j) (Table 4, entry 16). The yield was
further enhanced when the isocyanide was added over a
longer period of time (Table 4, entry 17). The slow
addition protocol was also effective with the R-branched
aldehyde (3k) (Table 4, compare entries 19-20 with entry
10). A respectable yield of the product was obtained albeit
a long addition time was necessary (Table 4, entry 20).
2.2. Additions Catalyzed by (R,R)-1b. The enantio-
selectivity in the addition of t-BuNC to the same set of
aldehydes catalyzed by the chiral bisphosphoramide
(R,R)-1b was investigated. The optimized conditions
established for the addition to benzaldehyde were em-
ployed: t-BuNC in CH2Cl2 (1.0 M) was added over 4 h to
a solution of the mixture of an aldehyde, SiCl4, 5 mol %
of (R,R)-1b, and 10 mol % of Hu¨nig’s base in CH2Cl2 (1.0
M).
The enantioselectivities, compiled in Table 5, were
found to be highly dependent on the structure of the
aldehyde. Aromatic and heteroaromatic aldehydes were
among the best performers and generally gave excellent
enantioselectivities. In contrast, results with olefinic and
aliphatic aldehydes were highly variable. Subtle elec-
tronic influences on the enantioselectivity were observed
in the class of 4-substituted benzaldehydes. 4-Tolualde-
hyde, a moderately electron-rich substrate, gave the same
results as benzaldehyde (Table 5, entry 1). On the other
hand, noticeable decreases in the enantioselectivity were
observed with strongly electron-rich and electron-poor
aldehydes (Table 5, entries 2 and 3). Variations of the
steric encumbrance of the aldehyde acceptor had signifi-
cant influence on the enantioselectivity. Whereas 2-naph-
thaldehyde provided essentially the same result as
benzaldehyde, the enantioselectivity with sterically en-
cumbered 1-naphthaldehyde decreased significantly (Table
5, entries 4 and 5). Excellent yields were obtained in the
addition to nonaromatic conjugated aldehydes. However,
enantioselectivities with this class of aldehydes were
highly variable. (E)-Cinnamaldehyde provided the best
result, but with sterically more congested 2-methylcin-
namaldehyde or less encumbered phenylpropargyl alde-
a Yields of chromatographically homogeneous material. b Un-
reacted aldehyde was recovered. c The reaction temperature was
-24 °C. d The isocyanide was added over 4 h. e The isocyanide was
added over 8 h. f The isocyanide was added over 12 h.
a solution of t-BuNC in CH2Cl2 (1.0 M) to a solution of
the mixture of SiCl4, aldehyde, and 10 mol % of pyridine
N-oxide in CH2Cl2 (1.0 M) at -74 °C over 30 min.
Under this set of reaction conditions, all the aldehydes
reacted and the corresponding hydroxy amides products
were obtained after workup (Table 4, entries 1-14). A
trend in the reactivity is readily apparent: the addition
of t-BuNC to all conjugated aldehydes proceeded to
completion within 4 h at -74 °C, and the hydroxy amide
products were obtained in excellent yields (Table 4,
entries 1-8 and 11-14); on the other hand, only low
yields of the products were obtained with both aliphatic
aldehydes (Table 4, entries 9 and 10). In these low-
yielding reactions, the aldehyde starting material was
recovered after aqueous workup. To improve the yield
with aliphatic aldehydes the effect of increasing the
reaction temperature was investigated. However, for both
linear and R-branched structures the increase in the
temperature did not improve the conversions, and both
aldehyde starting materials were recovered (Table 4,
entries 15 and 18). In many other addition reactions
studied in these laboratories, aliphatic aldehydes have
been notoriously slow substrates. Their sluggish reaction
rates have been rationalized by in situ formation of
unreactive R-chloro trichlorosilyl ethers in the presence
of SiCl4 and a phosphoramide catalyst.16b In the case at
hand, there is a competing reaction between SiCl4 and
the isocyanide that has analogy in the reactions with
TiCl4.13 Consideration of this unproductive pathway led
to the hypothesis that decreasing the concentration of the
isocyanide would increase the yield of the R-addition
product and thus, the effect of slow addition of the
isocyanide was studied. Indeed, a significant improve-
ment in the yield was observed when a 4 h addition
protocol was used for the addition of t-BuNC to hydro-
J. Org. Chem, Vol. 70, No. 24, 2005 9671

Denmark and Fan
TABLE 6. Addition of Isocyanides to Aldehydes
Catalyzed by Pyridine N-Oxide
hyde the enantioselectivity decreased dramatically (Table
5, entries 6-8). With aliphatic aldehydes, the presence
of Hu¨nig’s base proved to be deleterious to the yields of
the products. It was necessary to perform the reaction
without the use of Hu¨nig’s base. Thus, under the condi-
tions employed for the pyridine N-oxide catalyzed addi-
tion, aliphatic aldehydes (3j and 3k) gave similar yields
of the hydroxy amide products in the enantioselective
additions (Table 5, entries 9 and 10). Unfortunately, both
the linear and R-branched aliphatic aldehydes gave lower
enantioselectivities than aromatic aldehydes. It is notice-
able that the R-branched aldehyde (3k) delivered a
slightly higher enantioselectivity than the linear alde-
hyde (3j) (Table 5, compare entries 9 and10). Electron-
rich heteroaromatic aldehydes, such as furfural and
2-thiophenecarboxaldehyde, reacted cleanly and provided
the product in good yields (Table 5, entries 11 and 12).
Nitrogen-containing heteroaromatic aldehydes with strong
electron-withdrawing protecting group were also highly
reactive and delivered high yields of the products as well
(Table 5, entries 13 and 14). Despite the structural
difference, very good enantioselectivities were obtained
with all these heteroaromatic aldehydes (Table 5, entries
11-14).
3. Survey of Isocyanide Structure. The isocyanide
provides a useful dimension of structural diversity in
these reactions. Because isocyanides can be easily pre-
pared from primary amines,22 this is an easily modifiable
component. In addition, the structure of the isocyanide
may influence the rate and selectivity of the addition.
Accordingly, the commercially available isocyanides shown
in Chart 3 were investigated. 1,1,3,3-Tetramethylbutyl
isocyanide (2b) was chosen to study the effect of increas-
ing the size of the isocyanide on the enantioselectivity.
Because hydrocinnamaldehyde (3j) gave poor enantiose-
lectivity in the addition of t-BuNC (2a), it was chosen as
the acceptor partner for the addition of 2b. Phenyl
isocyanide (2c) was chosen as the representative of
electronically deactivated isocyanides. Ethyl isocyano-
acetate (2d) and tosylmethyl isocyanide (2e), both of
which possess two protons of significant acidity, were
employed to investigate the functional group tolerance
of the SiCl4-Lewis base system.
entry
isocyanide
product
yield,a %
1b,c
2d,e
3d,e
4d,e
2b
2c
2d
2e
(()-6
(()-7
(()-8
(()-9
84
76
72
69
a Yields of chromatographically homogeneous material. b Hy-
drocinnamaldehyde (3j) was used. c Isocyanide (2b) was added over
8 h. d Benzaldehyde (3a) was used. e Isocyanide 2c was added over
30 min.
deactivated isocyanide (2c) and enolizable isocyanides
(2d and 2e) delivered respectable yields of the hydroxy
amide products within 4 h at -74 °C.23
3.2. Additions Catalyzed by (R,R)-1b. The depen-
dence of enantioselectivity on the structure of the iso-
cyanide in reactions catalyzed by (R,R)-1b was next
examined, Table 7. To provide a direct comparison in the
enantioselectivity, the same reaction protocol was em-
ployed for the additions of t-BuNC (2a) and 2b to
hydrocinnamaldehyde (3j). Under this set of conditions,
the bulkier nucleophile 2 provided a good yield of the
hydroxy amide product 6 but with diminished enatio-
selectivity (compare Table 7, entry 1, and Table 5, entry
9). For the additions of 2c-e to benzaldehyde, the yields
of the products were high, but the selectivities of the
reactions were dependent on the structure of the isocya-
nide. Whereas the aromatic isocyanide 2c gave a modest
selectivity (Table 7, entry 2), both functionalized aliphatic
aldehydes delivered respectable enantioselectivities when
the reactions were carried out in the absence of Hu¨nig’s
base and the isocyanide is added in one portion (Table
7, entries 3 and 4). Additions of 2c-e to other aldehydes
or with other catalysts were not attempted.24
TABLE 7. Addition of Isocyanides to Aldehydes
Catalyzed by (R,R)-1b
CHART 3
entry isocyanide aldehyde product yield,a %
erb
1c
2b
2c
2d
2e
3j
(-)-6
(+)-7
(+)-8
(-)-9
87
82
83
80
70.0/30.0
73.2/26.9
83.3/16.7
88.5/11.5
2d,e
3d
4d
3a
3a
3a
3.1. Additions Catalyzed by Pyridine N-Oxide. To
provide a direct comparison for the reactions with t-BuNC
(2a), the slow addition protocol (8 h) employed for the
addition of to hydrocinnamaldehyde (3j) was applied in
the reaction with 2b. Under these conditions, despite the
increase in the steric bulk of the isocyanide (2b), the
hydroxy amide product 6 was produced in good yield
(Table 6, entry 1). On the other hand, with benzaldehyde,
isocyanides (2c-e) were added over 30 min (Table 6,
entries 2-4). Under this set of conditions, electronically
a Yields of chromatographically homogeneous material. b De-
termined by CSP-SFC. c 2b was added over 8 h. d Isocyanides were
added in one portion. e 10 mol % of i-Pr2NEt was used.
4. Conversion of Imidoyl Chlorides to Carboxylic
Esters. The immediate products of the addition reaction
are likely R-trichlorosilyloxy imidoyl chlorides (see the
(23) In the presence of Hu¨nig’s base, reaction of 2d with benzalde-
hyde afforded 8 in 43% yield along with a double addition product 13
in 10% yield. Under these conditions, 2e afforded 9 in 64% yield along
with two byproducts, benzoin (14a) in 9% yield and tosylmethyl-
formamide (14b) in 7% yield; see the Discussion and Supporting
Information.
(22) (a) Ugi, I.; Meyr, R.; Lipinski, M.; Bodesheim, F.; Rosendahl,
F. Org. Synth. 1961, 41, 13-15. (b) Gokel, G. W.; Widera, R. P.; Weber,
W. P. Organic Syntheses; Wiley: New York, 1988; Collect. Vol. VI, pp
232-235.
9672 J. Org. Chem., Vol. 70, No. 24, 2005

Lewis Base Catalyzed Passerini-Type Reactions
Discussion). Imidoyl chlorides and ethers are versatile
intermediates in organic synthesis and can be converted
into a variety of useful products.25 Up to now, the simple
hydrolysis of this intermediate has provided R -hydroxy
carboxamides in good yield. Direct transformation of the
imidoyl chloride into carboxylic esters would have obvious
synthetic utility. However, because the alcoholysis of the
intermediate also produces four equivalents of HCl,
racemization under such acidic conditions was of concern.
Initial studies therefore focused on the effects of bases
and buffers on the efficiency of methanolysis. These
studies were performed by quenching a solution of 4
(generated from the addition of t-BuNC to benzaldehyde)
under the indicated conditions with 60 equiv of methanol.
The reaction mixture from the methanol quench was
poured into a saturated aqueous NaHCO3 solution. From
the ratio of the ester product 10 to the amide product
5a, the efficiency of methanolysis was evaluated, Table
8.
S-enantiomer of imidoyl chloride 4 was generated in situ
and was independently subjected to both conditions.
Quenching of 4 with methanol alone at low temperature
(followed by workup with saturated aqueous NaHCO3
solution) afforded 10 in excellent yield and with no
detectable racemization (Table 8, entry 5). On the other
hand, the use of sodium methoxide led to significant
racemization (Table 8, entry 6).
This protocol was then applied as a quench/workup
procedure for the reactions of an olefinic (3g) and an
aliphatic aldehyde (3j). In both cases, the corresponding
esters, 11 and 12 were obtained in good yields (71% and
88%, respectively) and enantioselectivities comparable to
those for the carboxamides (97.9/2.1 and 81.8/18.2,
respectively). Finally, the absolute configurations of the
ester products was determined to be S (see the Experi-
mental Section), confirming the same sense of asym-
metric induction for aromatic, conjugated, and aliphatic
aldehydes in the isocyanide additions.
TABLE 8. Conversion of Imidoyl Chloride to Methyl
Ester
Discussion
1. SiCl4-Mediated Additions of Isocyanides to
Aldehydes. As a Lewis acid promoter, SiCl4 is unique
for the R-additions of isocyanides to aldehydes. In the
presence of SiCl4 alone, the addition of t-BuNC to
benzaldehyde proceeds to 83% conversion within 4 h at
-78 °C and produces the imidoyl chloride 4 cleanly (Table
1, entry 1). This reaction is remarkable for a number of
reasons including: (1) the mild conditions, (2) the absence
of byproducts from multiple addition of the isocyanide
and (3) the scarcity of high yielding Lewis acid promoted
R-addition reactions. Moreover, isocyanides behave dif-
ferently compared to other nucleophiles employed in the
SiCl4-mediated additions to aldehydes. π-Nucleophiles
such as trialkylsilyl ketene acetals, silyl enol ethers and
allyltrialkylstannanes do not add to aldehydes in the
presence of SiCl4 alone.15 However, the addition of all
these nucleophiles is dramatically accelerated in the
presence of both a strong Lewis base promoter and SiCl4.
Considering the Lewis basicity of the isocyanide and the
highly responsive nature of SiCl4 toward Lewis base
activation, it must be concluded that the unique reactivity
of isocyanide in the SiCl4-mediated addition reactions
stems from activation of SiCl4 by the isocyanide.
yield of yield of
entry
base
none
i-Pr2NEt 20.0
i-Pr2NEt 20.0
NaOMe
none
NaOMe
equiv T, °C time, min 10,a %
5a,a %
1
-74
-74
25
40
120
120
120
40
83
0
0
86
66
0
2
3
17
89
95
89
4
4.8
25
5b,c
6b,d
-74
25
0
0
4.8
120
a Yields of chromatographically homogeneous material. b The
imidoyl chloride was prepared by the asymmetric addition protocol
using bisphosphoramide catalyst (R,R)-1b. c S/R ratio of the ester
product was determined by SFC and was greater than 99/1. d S/R
ratio was 90.9/9.1.
In the absence of base, methanolysis of 4 proceeded to
completion within 40 min at -74 °C to afford (after
workup with saturated aqueous NaHCO3 solution) a high
yield of the ester 10 (Table 8, entry 1). In contrast, under
basic conditions, imidoyl chloride 4 was resistant to
methanolysis. When the reaction mixture was buffered
with Hu¨nig’s base, the imidoyl chloride group was intact
after 2 h -74 °C as evidenced by the high yield of the
hydroxy amide product 5a (Table 8, entry 2). Increasing
the temperature afforded a small amount of methyl ester
10 but with low efficiency (Table 8, entry 3). Further
increase in the temperature (to 40 °C) led to the decom-
position of 4 and did not improve the yield of 10. The
stronger base, sodium methoxide, proved to be reactive
toward 4 and provided a high yield of 10 after 2 h at 25
°C (Table 8, entry 4). The two methods for the conversion
of imidoyl chloride 4 to ester 10 were then tested for the
intervention of racemization. Thus, from the addition of
t-BuNC to benzaldehyde catalyzed by (R,R)-1b, the
Although the mechanism by which isocyanide activates
SiCl4 has not been studied, it is reasonable to propose
that isocyanide behaves like other activating Lewis bases
as well as the nucleophile in this reaction (Scheme 3).
SCHEME 3
(24) A number of experiments were performed with (S)-1-phenyl-
ethyl isocyanide to determine the influence of a chiral isocyanide alone
and in double diastereoselection with catalyst (R,R)-1b. In the addition
to benzaldehyde, high yields were obtained, but in no case was the
influence of the stereogenic center on the isocyanide manifested.
(25) The Chemistry of Amidines and Imidates; Patai, S., Rapoport,
Z., Eds.; John Wiley: New York, 1991.
Thus, ionization of SiCl4 takes place upon binding one
or two molecules of sterically unencumbered isocyanide
J. Org. Chem, Vol. 70, No. 24, 2005 9673

Denmark and Fan
and results in the formation of a zwitterionic species iv.
The addition of t-BuNC to the complexed aldehyde in
activated complex v leads to the formation of a nitrilium
species vi. Subsequent capture of vi by the nucleophilic
fragment results in the formation of imidoyl chloride vii,
which precludes further attack by the isocyanide. Upon
aqueous workup, the hydroxy amide product viii is
obtained.
enolizable protons would be enhanced by the coordination
of these isocyanides to SiCl4 or to a highly electrophilic
trichlorosilyl cation. Thus, even a sterically encumbered
base can deprotonate the isocyanides and form the
trichlorosilyl enolate ix. The addition of ix to benzalde-
hyde leads to the formation of intermediate x which then
can function as an isocyanide in the normal capacity with
a second molecule of benzaldehyde to form xi which, after
hydrolysis affords byproduct 13. Although we cannot rule
out the possibility that 13 is a secondary product of 8,
we believe the acidity of the methylene hydrogens in xii
is considerably reduced.
When tosylmethyl isocyanide (TOSMIC) was employed
as the nucleophile in the presence of Hu¨nig’s base, two
byproducts were obtained along with the desired product
9 (Scheme 5). Whereas the formation of the formamide
14b arises from simple hydrolysis of TOSMIC, the
mechanism of formation of benzoin 14a under these
conditions is obscure.
2. Scope of the Aldehyde Acceptor. All basic
structural types of aldehydes are reactive in the SiCl4-
mediated additions of isocyanides, including aromatic,
heteroaromatic, olefinic, acetylenic, and aliphatic alde-
hydes, albeit with variable rates and selectivities. In
general, conjugated aldehydes were much more reactive
than aliphatic aldehydes in both the pyridine N-oxide and
the chiral bisphosphoramide catalyzed additions. The
same trend was also observed in other Lewis base
catalyzed, SiCl4-mediated additions, but the range of
reactivity was not as pronounced in the additions of
t-BuNC. In addition, for aliphatic aldehydes, slow addi-
tion of the isocyanide was necessary to achieve good
yields of the hydroxy amide products. Although the origin
of this improvement is not certain, it clearly relates to
the well-known production of R-chloro trichlorosilyl ethers
from aliphatic aldehydes. Ordinarily, the formation of
these unreactive intermediates leads only to attenuated
addition rates, but with t-BuNC an unproductive con-
sumption of the nucleophile intervenes, such that ex-
tended times or elevated temperatures afford no improve-
ment. Apparently, when the isocyanide is added slowly,
reaction with the small amount of activated aldehyde
present at equilibrium can compete with decomposition
of the nucleophile.
3. Scope of the Isocyanide. Both aromatic and
aliphatic isocyanides participate in the SiCl4-mediated
additions to aldehydes. However, with aliphatic isocya-
nides containing acidic protons (2d and 2e), the outcome
of the reactions were highly dependent on the protocol.
To obtain good yields, it was necessary to perform these
reactions in the absence of a Brønsted base and the
isocyanides must be added in one portion. The lower
yields obtained in the presence of Hu¨nig’s base are due
to unproductive pathways initiated by enolization of the
isocyanides (Scheme 4). It is likely that the acidity of the
SCHEME 5
4. Mechanism of Chiral Bisphosphoramide Cata-
lyzed Addition. A hypothetical catalytic cycle for the
Lewis base catalyzed, SiCl4-mediated, Passerini-type
reaction is shown in Scheme 6. The details of this cycle
SCHEME 6
SCHEME 4
nicely illustrate the unique features of Lewis base
catalysis and also serve to distinguish the roles of each
component. Binding of a neutral Lewis base (catalyst) to
SiCl4 causes ionization to generate an chirally modified-
siliconium ion xiii. This complex (which exists as a
hexachlorosilicate ion pair)16b is the catalytically active
species, but as it is consumed in each cycle is more
accurately described as a “pseudocatalyst”.26 Thus, the
addition of the isocyanide to the activated aldehyde in
complex xiv would produce nitrilium ion intermediate
(26) For the IUPAC definitions of catalyst and pseudocatalyst see
http://www.chem.qmul.ac.uk/iupac/gtpoc/.
9674 J. Org. Chem., Vol. 70, No. 24, 2005

Lewis Base Catalyzed Passerini-Type Reactions
FIGURE 1. Stereochemical model for the R-addition of isocyanides.
xv. Subsequent capture of xv by the chloride anion would
result in the formation of an imidoyl chloride xvi. The
newly generated nonbonding pair on the nitrogen has two
important consequences: (1) by coordinating the SiCl3
fragment, the bulk product of the reaction xvii can be
removed from the catalytic cycle and (2) the attenuated
Lewis acidity of the silicon center in xvii would assist
the dissociation of the Lewis base catalyst to repeat the
catalytic cycle.
Because the isocyanide itself is a strong Lewis base,
several types of silyl cations can be generated in a
mixture of isocyanide and phosphoramide: a complex
with two isocyanide molecules, a complex with one
isocyanide and one Lewis base molecule, and a complex
with two Lewis base molecules. Each of these species
could activate aldehyde toward nucleophilic attack and
the relative contribution from each of these species would
depend on their ability to activate the aldehyde as well
as the concentration of these species under the reaction
conditions.
mediated addition reactions.16 It is believed that an in
situ generated cationic silicon complex [(R,R)-1b•SiCl3]
+ Cl- is responsible for enantioselection. A stereochem-
ical model has been proposed to account for the origin of
the enantioselection by the cationic silicon complex (R,R)-
1b•SiCl3 (Figure 1).27 In the active complex, the carbonyl
oxygen is coordinated trans to the phosphoramide donor
in a canonical sp hybridized orbital. The alternative
binding sites are both sterically and electronically less
favorable (hypervalent orbitals). In this position, the
conformation of benzaldehyde may be stabilized by the
π-π interaction between the benzene ring and one of the
naphthyl units in an edge-on fashion. The Re-face of the
aldehyde thus is exposed to nucleophilic attack while the
Si-face is shielded by one of the N-methyl groups on the
chiral scaffold. This topicity has been seen for the
addition of many classes of nucleophiles to bound alde-
hydes.
Conclusion
Without kinetic measurements it is impossible to
quantitatively evaluate the contribution from each of
these pathways. However, the results from reaction
optimization can provide a qualitative ordering of the
importance of these pathways in the R-additions. In the
presence of 5 mol % of (R,R)-1b, the SiCl4-mediated
additions of t-BuNC to a wide range of conjugated
aldehydes proceed with excellent enantioselection. Such
a high level of asymmetric induction supports the notion
that this reaction is controlled by chiral catalyst and the
influence from the isocyanide promoted pathways are less
significant, as long as the concentration of the isocyanide
is minimized. However, because a lower enantioselectiv-
ity is obtained when the isocyanide is added in one
portion (Scheme 7), it must be concluded that the
isocyanide-promoted achiral addition can be competitive
to the phosphoramide-promoted addition.
In summary, the first catalytic, enantioselective R-ad-
dition reaction of isocyanides has been demonstrated with
an SiCl4•bisbinaphthyldiamine phosphoramide catalyst.
Good yields have been obtained with aromatic, het-
eroaromatic, conjugated nonaromatic and nonbranched
aliphatic aldehydes. Aromatic, aliphatic and functional-
ized isocyanides provided high yields of R-addition prod-
ucts. Enantiomeric ratios ranging from 92/8 to 99/1 have
been achieved in the addition of tert-butyl isocyanide to
aromatic aldehydes. The imidoyl chloride intermediates
has been directly converted into chiral R-hydroxy amides
and carboxylic esters without loss in enantiomeric purity.
Studies to improve catalyst design for aliphatic aldehydes
and development of new methods for the transformation
of the chloro imidate intermediates are ongoing.
Experimental Section
SCHEME 7
General Experimental Procedures. See the Supporting
Information.
N-tert-Butyl-2-hydroxy-2-(2-naphthyl)acetamide ((()-
5e). A solution of tert-butyl isocyanide (125 µL, d ) 0.735, 1.2
mmol, 1.2 equiv) in CH2Cl2 (2.0 mL) was added via a syringe
pump over 30 min to a cold (-74 °C, internal temperature)
solution of 2-naphthaldehyde 3e (156 mg, 1.0 mmol), pyridine
N-oxide (9.5 mg, 0.1 mmol, 0.1 equiv), and SiCl4 (125 µL, d )
5. Origin of Enantioselection with Catalyst (R,R)-
1b. Chiral binaphthyldiamine-derived catalyst (R,R)-1b
has demonstrated extraordinary ability in discriminating
the enantiotopic faces of aromatic aldehydes in the SiCl4-
(27) The calculations on a complex of benzaldehyde and the dimeric
phosphoramide (R,R)-1b bound trichlorosilyl cation were performed
using the PC version of GAMESS(US) QC Package employing the PM3
basis set.
J. Org. Chem, Vol. 70, No. 24, 2005 9675

Denmark and Fan
1.483, 1.1 mmol, 1.1 equiv) in a two-necked, round-bottomed
flask fitted with an argon inlet adapter and thermocouple. The
reaction solution was stirred for 4 h at -74 °C, warmed to rt,
and was transferred dropwise to a vigorously stirred, ice-cold,
saturated aqueous solution of NaHCO3 (20 mL). The mixture
was further stirred for 2 h at rt. The white precipitate was
filtered off through Celite, and the filtrate was extracted with
CH2Cl2 (4 × 20 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The crude
product was purified by silica gel chromatography (20 mm
column, 60 g SiO2, Rf 0.17, hexane/EtOAc, 3/1) to afford 230
mg (90%) of (()-5e as a white solid. White crystals of (()-5e
(204 mg, 80%) were obtained after recrystallization from a 3/1
mixture of heptane and benzene: mp 118-119°C (heptane/
benzene, 3/1); 1H NMR (400 MHz, CDCl3) 7.45-7.87 (m, 7 H,
aryl), 5.72 (bs, 1 H, NH), 5.06 (d, J ) 3.7, 1 H, HC(2)), 3.88 (d,
J ) 3.4, 1 H, OH), 1.31 (s, 9 H, 3 × H3C(2′′)); 13C NMR (100
MHz, CDCl3) 171.2 (C(1)), 137.2 (C(2′)), 133.4 (C(9′) or C(10′)),
133.2 (C(9′) or C(10′)), 129.0 (C(8′)), 128.0 (C(3′)), 127.8 (C(4′)),
126.5 (C(5′)), 126.4 ((C(1′) or C(6′)), 126.3 (C(6′) or C(1′)), 124.0
(C(7′)), 74.2 (C(2)), 51.6 (C(1′′)), 28.6 (C(2′′)); IR (CHCl3) 3612
(m), 3413 (m), 3010 (m), 2973 (m), 1677 (s), 1602 (s), 1523 (s),
1425 (w), 1394 (w), 1367 (m), 1278 (w), 1267 (m), 1234 (w),
1170 (w), 1124 (w), 1079 (m), 877 (w); TLC Rf 0.17 (hexane/
EtOAc, 3/1); SFC (R)-5e, tR 3.71 min (50.3%); (S)-5e, tR 4.58
min (49.7%) (Chiracel AD, 10.0% MeOH in CO2, 125 bar, 40
°C, 3.0 mL min-1); MS (FI, 70 eV) 258 (19), 257 (100). Anal.
Calcd for C16H19NO2 (257.33): C, 74.68; H, 7.44; N, 5.44.
Found: C, 74.65; H, 7.70; N, 5.61.
N-tert-Butyl-2-hydroxy-2-(2-naphthyl)acetamide ((+)-
5e). A solution of tert-butyl isocyanide (125 µL, d ) 0.735, 1.2
mmol, 1.2 equiv) in CH2Cl2 (1.0 mL) was added via a syringe
pump over 4 h to a cold (-74 °C, internal temperature) solution
of 2-naphthaldehyde 3e (156 mg, 1.0 mmol), catalyst (R,R)-
1b (43 mg, 0.05 mmol, 0.05 equiv), SiCl4 (125 µL, d ) 1.483,
1.1 mmol, 1.1 equiv), and diisopropylethylamine (18 µL, d )
0.742, 0.1 mmol, 0.1 equiv) in CH2Cl2 (1.0 mL) in a two-necked,
round-bottomed flask fitted with an argon inlet adapter and
thermocouple. The mixture was stirred further for 4 h at -74
°C. The reaction mixture was then transferred dropwise to a
vigorously stirred, ice-cold, saturated aqueous solution of
NaHCO3 (20 mL). The mixture was stirred for 2 h at rt. The
white precipitate was filtered off through Celite, and the
filtrate was extracted with CH2Cl2 (4 × 20 mL). The combined
organic layers were dried (MgSO4) and concentrated under
reduced pressure. The crude product was purified by silica gel
chromatography (20 mm column, 60 g SiO2, Rf 0.17, hexane/
EtOAc, 3/1) to afford 242 mg (93%) of (+)-5e as a white solid.
An analytically pure sample was obtained after sublimation
(90 °C/0.5 mmHg): mp 94-96 °C (sublimed); SFC (R)-5e, tR
3.73 min (0.3%); (S)-5e, tR 4.58 min (99.7%) (Chiracel AD, 10%
MeOH in CO2, 125 bar, 40 °C, 3.0 mL min-1); [R] D24 +44.9 (c )
0.96, MeOH). Anal. Calcd for C16H19NO2 (257.33): C, 74.68;
H, 7.44; N, 5.44. Found: C, 74.60; H, 7.54; N, 5.66.
(S)-(+)-Methyl-2-hydroxy-2-phenylacetate ((S)-10). A
solution of tert-butyl isocyanide (125 µL, d ) 0.735, 1.2 mmol,
1.2 equiv) in CH2Cl2 (1.0 mL) was added via a syringe pump
over 4 h to a cold (-74 °C, internal temperature) solution of
benzaldehyde (104 µL, d ) 1.044, 1.0 mmol), catalyst (R,R)-
1b (43 mg, 0.05 mmol, 0.05 equiv), SiCl4 (125 µL, d ) 1.483,
1.1 mmol, 1.1 equiv), and diisopropylethylamine (18 µL, d )
0.742, 0.1 mmol, 0.1 equiv) in CH2Cl2 (1.0 mL) in a two-necked,
round-bottomed flask fitted with an argon inlet adapter and
thermocouple. The mixture was stirred for 4 h at -74 °C
whereupon dry MeOH (2.5 mL) was added dropwise to the
reaction mixture at -74 °C. After being stirred for 40 min at
-74 °C, the mixture was transferred dropwise to a vigorously
stirred, ice-cold, saturated aqueous solution of NaHCO3
(20
mL) and stirred for 2 h further at rt. The white precipitate
was filtered off through Celite, and the filtrate was extracted
with CH
2Cl2 (4 × 20 mL). The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure to
provide the crude product. Purification afforded 160 mg (97%)
of (S)-10 after silica gel column chromatography (20 mm
column, 60 g SiO2, Rf 0.31, hexane/EtOAc, 3/1). Bulb-to-bulb
distillation provided 158 mg (95%) of (S)-10 as colorless oil,
which solidified upon standing. From the sign of optical
rotation of the product ([R] 2D4 +143.2, MeOH), the absolute
configuration was deduced to be S (lit.6 (S) enantiomer, [R]24
D
+144.0, MeOH): mp 56-58 °C; bp 120 °C (0.5 mmHg); 1H
NMR (400 MHz, CDCl3) 7.33-7.44 (m, 5 H, aryl); 5.18 (d, J )
5.3, 1 H, HC(2)); 3.77 (s, 3 H, OCH3); 3.42 (d, J ) 4.7, 1 H,
OH)); TLC Rf 0.31 (hexane/EtOAc, 3/1); SFC (S)-10, tR 3.97
min (99.9%); (R)-10, tR 4.31 min (0.1%) (Chiracel AS, 1.4%
MeOH in CO2, 125 bar, 40 °C, 2.5 mL min-1); [R] D24 +143.2 (c
) 0.57, MeOH).
Acknowledgment. We are grateful for the National
Science Foundation generous financial support
(NSF CHE0105205 and CHE0414440). Y.F. thanks the
Boehringer Ingelheim Pharmaceutical Company for a
graduate fellowship.
Supporting Information Available: Full characteriza-
tion of all products along with optimization experiments and
detailed procedures for the addition reactions. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO050549M
9676 J. Org. Chem., Vol. 70, No. 24, 2005