The first catalytic, asymmetric α-additions of isocyanides. Lewis-base-catalyzed, enantioselective Passerini-type reactions

Article abstract of DOI:10.1021/ja035410c

The first, catalytic, enantioselective α-additions of isocyanides to aldehydes have been demonstrated (Passerini-type reactions). The catalytic system of silicon tetrachloride and a chiral bisphosphoramide 5a provided high yields and good to excellent enantioselectivities for the addition of tert-butyl isocyanide to a wide range of aldehydes (aromatic, olefinic, acetylenic, aliphatic). Aqueous workup afforded the α-hydroxy tert-butyl amides, whereas methanolic quench followed by basic workup afforded the ∞-hydroxy methyl esters. Copyright

Full text of DOI:10.1021/ja035410c

Published on Web 06/07/2003
The First Catalytic, Asymmetric r-Additions of Isocyanides.
Lewis-Base-Catalyzed, Enantioselective Passerini-Type Reactions
Scott E. Denmark* and Yu Fan
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, 600 South Mathews AVenue, Urbana,
Illinois 61801
Received April 1, 2003; E-mail: denmark@scs.uiuc.edu
Bearing a formally divalent carbon, isocyanides are capable of
engaging in a unique class of carbon-carbon bond forming
reactions known as R-additions. Since the early studies by
Passerini,1 and by Ugi and co-workers,2 the power of the R-addition
reaction in constructing polyfunctional molecules has been well
appreciated. In the classical Passerini reaction, an R-acyloxy
carboxamide is formed in one step from three components, an
isocyanide, a ketone or an aldehyde, and a carboxylic acid (Scheme
1). In the Ugi reaction, four components, an isocyanide, an amine,
a carbonyl compound, and a carboxylic acid, react to form an
R-acylamino amide. Although both reactions have been widely
applied, generating molecular diversity for drug discovery and
natural product synthesis,3 the challenge of stereocontrol, wherever
a new stereocenter is generated, has not been satisfactorily
addressed. Diastereoselective approaches developed by Ugi and
others achieved varying degrees of success in controlling the
stereochemical outcome of the R-additions of isocyanides.4-7
However, all of these methods suffer from low efficiency in that
chiral auxiliaries have to be removed from the product destructively.
A method for the catalytic, asymmetric R-addition of isocyanides
is still lacking.
phosphoramide through displacement of a chloride ion which results
in the formation of a cationic silicon species.12 The trichlorosilyl
adduct is capable of activating aldehydes toward nucleophilic attack.
An important advantage of this system is that the weak Lewis acid
can be used in stoichiometric quantities without the fear of
competing achiral pathways because kinetically competent species
are formed only upon binding the chiral ligand. Unlike with
conventional chiral Lewis acids, catalyst turnover is the transfer of
the chiral ligand from the intermediate product to the Lewis acid,
not the cleavage of the bond between the MXn unit and the product.
Furthermore, the nitrilium ion intermediate could capture the
chloride ion and be converted into an imidoyl chloride (M ) Si, X
) Cl, iii, Scheme 2), which would preclude further addition of an
isocyanide. Finally, the attenuated Lewis acidity of the silicon center
in the imidoyl chloride would result in facile transfer of the Lewis
base catalyst to SiCl4. Herein, we report the successful combination
of these features in a chiral-Lewis-base-catalyzed, enantioselective
Passerini-type reaction.13
Scheme 2
Scheme 1
The absence of a catalytic, enantioselective variant of this class
of reactions is striking, particularly in light of the recent develop-
ment of chiral Lewis acid catalysts for stereoselective carbon-
carbon bond formation with both carbonyl and imine substrates.8
The problems facing the development of Lewis-acid-catalyzed,
asymmetric R-addition of isocyanides are intrinsically associated
with the formal divalency of the nucleophile. The primary adduct
of the R-addition is the zwitterionic intermediate i, Scheme 2. In
the classical Passerini and Ugi reactions, a carboxylate combines
with this adduct, and the subsequent Mumm rearrangement leads
to the observed products. However, for the Lewis-acid-mediated
R-addition, in the absence of the carboxylate, this adduct is subject
to further addition of isocyanide and often leads to undesired
pathways (ii, Scheme 2).9 Moreover, catalyst turnover for conven-
tional Lewis acid catalysis requires the cleavage of the bond
between the MXn unit and the product, which has seen only limited
success for R-additions.10,11 Furthermore, asymmetric modification
of the Lewis acid leads to diminished reactivity.11b
Initial studies employed the addition of tert-butyl isocyanide 1a
to benzaldehyde 2a. Low-temperature 1H NMR analysis indicated
that SiCl4 alone effectively promoted this reaction. The addition
proceeded to 83% conversion within 4 h at -78 °C, and the hydroxy
amide product 3a was obtained in 79% yield after aqueous workup
under basic conditions (Table 1, entry 1). This result was in sharp
contrast to the allylation and the Mukaiyama aldol reaction wherein
no background was observed in the absence of the Lewis base
promoter.12 The susceptibility of the reaction to nucleophilic
catalysis was next examined. In the presence of 10 mol % of HMPA
(4a) or pyridine-N-oxide (4b), quantitative conversion was observed
under the same reaction conditions. Conclusive evidence of Lewis
base catalysis was forthcoming from the use of 5 mol % of the
chiral bisphosphoramide 5a,12,17 which gave promising enantiose-
lectivity (entry 4).14 To further improve the selectivity, we focused
on improving the rate ratio between the catalyzed asymmetric and
the achiral pathways. Consideration of the mechanistic differences
between the two pathways led to the conclusion that decreasing
We recognized that the newly introduced concept of Lewis base
activation of Lewis acid is ideally suited to address these problems.
Recent publications from these laboratories have demonstrated that
the weak Lewis acid, SiCl4, can be activated by a Lewis basic
9
10.1021/ja035410c CCC: $25.00 © 2003 American Chemical Society
J. AM. CHEM. SOC. 2003, 125, 7825-7827
7825

C O M M U N I C A T I O N S
Table 1. Addition of Isocyanides to Benzaldehyde
Table 2. Addition of tert-Butyl Isocyanide to Aldehydes
a
entry
isocyanide
product
catalyst
yield, %
erb
catalyst
1c
2d
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
3a
3a
3a
3a
3a
3a
3a
3n
3n
3o
3o
3p
3p
79
90
94
83
94
89
96
76
82
72
83
69
80
4b
5a
yield, %
4a
4b
5a
5a
5a
5a
4b
5a
4b
5a
4b
5a
a,b
a,c
entry
R
product yield, %
erd
3e
4f,g
90.2/9.8
94.3/5.7
98.1/1.9
>99/1k
1
2
3
4
5
6
7
8
9
4-CH3C6H5 (2b)
4-CH3OC6H4 (2c)
4-CF3C6H4 (2d)
2-naphthyl (2e)
1-naphthyl (2f)
3b
3c
3d
3e
3f
3g
3h
3i
87
92
87
90
87
76
73
86
85
89
72
84
91
89
89
93
92
83
81
86
76
92
53
87
99.9/0.1
98.3/1.7
96.5/3.5
99.7/0.3
92.2/7.8e
95.9/4.1f
97.8/2.2
67.4/32.6
77.0/23.0
81.9/18.1
87.1/12.9f
70.0/30.0
5f,h
6f,i
7f,j
8e,l
9f,j
73.2/26.8
83.3/16.7
88.5/11.5
2-furyl (2g)
10e,m
11f,m
12e,m
13f,m
(E)-PhCHdCH (2h)
(E)-PhCHdCH(CH3) (2i)
phenylpropargyl (2j)
3j
3k
3l
10 PhCH2CH2 (2k)
11 cyclohexyl (2l)
12g PhCH2CH2 (2k)
a Yields of chromatographically homogeneous material. b Determined by
CSP-SFC. c Without promoter. d With 10 mol % of 4a. e With 10 mol %
of 4b. f With 5 mol % of 5a. g 1a added in one portion. h 1a added over 2
h. i 1a added over 3 h and with 30 mol % of i-Pr2NEt. j Isocyanide added
over 4 h with 10 mol % of i-Pr2NEt. k Absolute configuration established
as S, others assigned by analogy. l Isocyanide added over 30 min. m Iso-
cyanide added in one portion.
3m
a Yields of chromatographically homogeneous material. b With 10 mol
% of pyridine-N-oxide. c With 5 mol % of 5a. d Determined by CSP-SFC.
e Determined by CSP-HPLC. f Determined by CSP-GC. g 1,1,3,3-Tetra-
methylbutyl isocyanide (1e) served as the nucleophile.
phoramides derived from 1,2-cyclohexanediamine, stilbene-1,2-di-
amine, and 2,2′-bispyrrolidine did not provide useful selectivities.16
A survey of substrate scope with aromatic, conjugated, and
aliphatic aldehydes was next conducted in the addition of 1a, under
the slow-addition protocol. We were delighted to find that all of
the aldehydes reacted and provided the desired products in high
yield, Table 2. Aromatic and conjugated aldehydes were found to
react faster than aliphatic aldehydes in the presence of both pyridine-
N-oxide (4b) and the chiral catalyst 5a (compare entries 1-9 and
entries 10-12). Whereas the reaction with most aromatic and
conjugated aldehydes proceeded to completion within 8 h, aliphatic
aldehydes required longer reaction times.
the concentration of isocyanide would favor the catalyzed pathway
versus the uncatalyzed pathway and thus increase the enantiose-
lectivity.15 Indeed, the enantioselectivity was found to depend on
the rate of addition of 1a (entries 5-7) and reached a maximum
when a 4 h addition protocol was used (entry 7). Furthermore, the
addition of 10 mol % of Hu¨nig base to sequester adventitious HCl
had no deleterious effects. Under these optimized reaction condi-
tions, 3a was obtained in >99/1 er in nearly quantitative yield (entry
7). The absolute configuration of (S)-3a indicated a Re face attack
on the aldehyde by the isocyanide, which is in agreement with the
sense of asymmetric induction observed in the allylation and the
Mukaiyama aldol reactions.12
The enantioselectivities were also highly dependent on the
aldehyde structure. Aromatic aldehydes gave excellent enantiose-
lectivities. Subtle electronic and steric influence on enantioselec-
tivity was observed. Whereas 4-tolualdehyde gave the same results
as benzaldehyde, a detectable but minimal erosion in enantiose-
lectivities was observed with both strongly electron-rich and
electron-poor aldehydes (entries 1-3). Slight erosion was also
observed when the aldehyde moiety became sterically encumbered.
Although 2-naphthaldehyde provided essentially the same result
as benzaldehyde, the enantioselectivity for 1-naphthaldehyde
decreased (entries 4 and 5). Electron-rich heteroaromatic aldehydes,
such as furfural, were compatible with the catalyst system and
provided the product in high enantioselectivity (entry 6). Nonaro-
matic conjugated aldehydes reacted cleanly and in good yield, but
with variable enantioselectivity. (E)-Cinnamaldehyde gave the best
results, but with either greater or lesser steric encumbrance near
the aldehyde, the enantioselectivities eroded (entries 7-9). On the
other hand, for aliphatic aldehydes, the enantioselectivities increased
with increasing steric bulk (entries 10 and 11). The influence of
increasing the size of isocyanide on the enantioselectivity of the
addition to hydrocinnamaldehyde was briefly examined. Although
bulkier than 1a, 1,1,3,3-tetramethylbutyl isocyanide 1e was found
to react with 2k smoothly and provided good yields in the presence
of both pyridine-N-oxide and 5a (entry 12). However, the increased
size of the isocyanide decreased the enantioselectivity, suggesting
that the dependence of the enantioselectivity on the size of
isocyanides is different for aromatic aldehydes and aliphatic
aldehydes. The absolute configurations of 3a, 3h, and 3k were
The scope of isocyanide structures that could be used in the
reaction was surveyed next. Results of the addition of three
representative isocyanides to 2a are summarized in Table 1 (entries
8-13). Phenyl isocyanide 1b provided a similarly high yield of
the product in the presence of both pyridine-N-oxide and 5a (entries
8 and 9), albeit with reduced enantioselectivity in the latter. Ethyl
isocyanoacetate 1c and tosylmethyl isocyanide 1d, both of which
possess two protons of significant acidity, were tested for functional
group compatibility. In these cases, the hydroxy amide products
3o and 3p were obtained in good yields when the isocyanide was
added in one portion, albeit after prolonged reaction time. Under
these conditions, attenuated but respectable enantioselectivities were
obtained for both 1c and 1d (entries 11 and 13).
To optimize the enantioselectivity, several bisphosphoramides
were briefly surveyed in the addition of 1a to 2a. Bisphosphora-
mides 5a-c,12a prepared by linking two chiral binaphthyldiamine
units, provided excellent enantioselection with all three tether
lengths (5a (n ) 5), 96% yield, er >99/1; 5b (n ) 4), 93% yield,
er 96.4/3/6; 5c (n ) 6), 86% yield, er 95.6/4/4). Other bisphos-
9
7826 J. AM. CHEM. SOC. VOL. 125, NO. 26, 2003

C O M M U N I C A T I O N S
for the addition reactions (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
assigned as S by comparison of optical rotations of the derived
methyl esters (vide infra). All others were assumed to be S by
analogy.
References
To circumvent the reactivity and selectivity dependence on the
isocyanide, we next explored the possibility of employing the most
selective isocyanide 1a and directly converting the imidoyl chloride
intermediate into a carboxylic ester (Table 3). Gratifyingly, the
corresponding methyl ester could be obtained by a simple two-
step workup procedure. After complete consumption of the alde-
hyde, the intermediate imidoyl chloride was first converted to a
methyl imino ether upon addition of methanol. Subsequent hy-
drolysis of the imino ether under basic conditions provided car-
boxylic ester in high yield. This procedure was successfully applied
to all three classes of aldehydes. In each case, the stereochemical
integrity was preserved; the enantiomeric composition of the ester
product matched that of the corresponding hydroxy amide. The
absolute configuration of all ester products was determined to be
S, which revealed the same sense of asymmetric induction for all
classes of aldehydes.
(1) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b) Passerini, M.; Ragni,
G. Gazz. Chim. Ital. 1931, 61, 964.
(2) (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.
(3) Recent reviews: (a) Do¨mling, A. Curr. Opin. Chem. Biol. 2002, 6, 306.
(b) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169. (c)
Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating,
T. A. Acc. Chem. Res. 1996, 29, 123.
(4) Addition to chiral imines using carbohydrate auxiliaries: (a) Kunz, H.;
Pfrengle, W. J. Am. Chem. Soc. 1988, 110, 651. (b) Kunz, H.; Ru¨ck, K.
Angew. Chem. 1993, 105, 355. (c) Oertel, K.; Zech, G.; Kunz, H. Angew.
Chem. 2000, 112, 1489; Angew. Chem., Int. Ed. 2000, 39, 1431. (d)
Goebel, M.; Ugi, I. Synthesis 1991, 1095. (e) Lehnhoff, S.; Goebel, M.;
Karl, R. M.; Klosel, R.; Ugi, I. Angew. Chem. 1995, 107, 1208; Angew.
Chem., Int. Ed. Engl. 1995, 34, 1104. (f) Ross, G. F.; Herdtweck, E.;
Ugi, I. Tetrahedron 2002, 58, 6127. (g) Ziegler, T.; Kaisers, H.-J.;
Schlo¨mer, R.; Koch, C. Tetrahedron 1999, 55, 8397. (h) Linderman, R.
J.; Binet, S.; Petrich, S. R. J. Org. Chem. 1999, 64, 336.
(5) Addition to chiral imines with ferrocenyl auxiliaries: (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. (c) Ugi, I.;
Offermann, K.; Herlginer, H.; Marquarding, D. Justus Liebigs Ann. Chem.
1967, 709, 1. (d) Demharter, A.; Ugi, I. J. Prakt. Chem. 1993, 335, 244.
(6) Addition to chiral imines with R-methylbenzylamine auxiliary: (a)
Divanfard, H. R.; Lysenko, Z.; Wang, P. C.; Joullie, M. M. Synth.
Commun. 1978, 8, 269. (b) Semple, J. E.; Wang, P. C.; Lysenko, Z.;
Joullie´, M. M. J. Am. Chem. Soc. 1980, 102, 7505.
(7) Addition of a chiral isocyanide to aldehydes and imines: Bock, H.; Ugi,
I. J. Prakt. Chem. 1997, 339, 385.
(8) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH:
Weinheim, 2001.
(9) (a) BF3‚Et2O or AlCl3 catalysis: Muller, E.; Zeeh, B. Liebigs Ann. Chem.
1966, 696, 72. (b) BF3‚Et2O catalysis: Muller, E.; Zeeh, B. Liebigs Ann.
Chem. 1968, 715, 47. (c) Saegusa, T.; Taka-Ishi, N.; Fujii, H. Tetrahedron
1968, 24, 3795.
(10) Zn(OTf)2/TMSCl promoted Passerini reaction: Xia, Q.; Ganem, B. Org.
Lett. 2002, 4, 1631.
(11) TiCl4 promoted Passerini reaction: (a) Schiess, M.; Seebach, D. HelV.
Chim. Acta 1983, 66, 1618. (b) Seebach, D.; Adam, G.; Gees, T.; Schiess,
M.; Weigand, W. Chem. Ber. 1988, 121, 507. (c) Carofiglio, T.; Cozzi,
P. G.; Floriani, C.; Chiesi-Villa, A.; Rizzoli, C. Organometallics 1993,
12, 2726.
(12) (a) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199. (b)
Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc. 2002, 124,
13405. (c) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125,
7800.
(13) Recent examples of Passerini reactions: (a) Owens, T. D.; Araldi, G.-L.;
Nutt, R. F.; Semple, J. E. Tetrahedron Lett. 2001, 42, 6271-4. (b) Banfi,
L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985. (c) Beck, B.; Magnin-
Lachaux, M.; Herdtweck, E.; Domling, A. Org. Lett. 2001, 3, 2875. (d)
Owens, T. D.; Semple, J. E. Org. Lett. 2001, 3, 3301. (e) Semple, J. E.;
Owens, T. D.; Nguyen, K.; Levy, O. E. Org. Lett. 2000, 2, 2769. (f) Banfi,
L.; Guanti, G.; Riva, R.; Basso, A.; Calcagno, E. Tetrahedron Lett. 2002,
43, 4067.
(14) A control experiment with 1a, benzaldehdye, and 5a (10 mol %) in CDCl3
showed no reaction after 4 h at room temperature.
(15) We speculate that the catalyzed reaction is first order in isocyanide by
analogy to the allylation and aldol processes (ref 16), whereas the
“uncatalyzed reaction” is promoted by the isocyanide and is likely higher
order.
(16) (a) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2000, 122, 12021. (b)
Denmark, S. E.; Pham, S. M. HelV. Chim. Acta 2000, 83, 1846. (c)
Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488.
(17) Catalyst 5a is commercially available from Obiter Research, LLC. Contact
waboulanger@obiterresearch.com.
Table 3. Conversion of Imidoyl Chlorides to Methyl Esters
catalyst
4b
yield, %
5a
yield, %
a,b
a,c
aldehyde
product
config
erd
2a
2h
2k
6
7
8
83
74
83
97
71
88
S
S
S
>99/1
97.9/2.1e
81.8/18.2
a Yields of chromatographically homogeneous material. b With 10 mol
% of pyridine-N-oxide. c With 5 mol % of 5a. d Determined by CSP-SFC.
e Determined by CSP-GC.
In summary, the first catalytic, enantioselective, R-additions of
isocyanides have been documented. The chiral bisphosphoramide‚
SiCl4 system catalyzes a Passerini-type reaction for a wide range
of aldehydes and isocyanides in high yields with good to excellent
enantioselectivities. Application of this catalyst system to the Ugi
reaction and development of new Lewis base activated Lewis acid
systems for catalytic, asymmetric R-addition reactions are in
progress.
Acknowledgment. We are grateful to the National Science
Foundation for generous financial support (NSF CHE 0105205).
Y.F. thanks the Boehringer Ingelheim Pharmaceutical Co. for a
graduate fellowship.
Supporting Information Available: Full characterization of all
products along with optimization experiments and detailed procedures
JA035410C
9
J. AM. CHEM. SOC. VOL. 125, NO. 26, 2003 7827