Synthesis of vinylogous carbamates by rhodium(II)-catalyzed olefination of tertiary formamides with a silylated diazoester

Article abstract of DOI:10.1021/ol0510872

(Chemical Equation Presented) Treatment of tertiary formamides with a silylated diazoester in the presence of a rhodium(II) catalyst leads to the formation of 3-amino-2-silyloxyacrylates in good yield. No olefination is observed if a nonsilylated diazo co

Full text of DOI:10.1021/ol0510872

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3453-3455
Synthesis of Vinylogous Carbamates by
Rhodium(II)-Catalyzed Olefination of
Tertiary Formamides with a Silylated
Diazoester
Gurdeep S. Nandra,† Pui Shan Pang,† Michael J. Porter,*,† and Jason M. Elliott‡
Department of Chemistry, UniVersity College London, Christopher Ingold Building,
20 Gordon Street, London, WC1H 0AJ, UK, and The Neuroscience Research Centre,
Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road,
Harlow, Essex, CM20 2QR, UK
m.j.porter@ucl.ac.uk
Received May 11, 2005
ABSTRACT
Treatment of tertiary formamides with a silylated diazoester in the presence of a rhodium(II) catalyst leads to the formation of 3-amino-2-
silyloxyacrylates in good yield. No olefination is observed if a nonsilylated diazo compound is employed.
The reaction of metal carbenes derived from R-diazocarbonyl
compounds with heteroatom lone pairs is a well-established
method for the preparation of ylids.1 Recently, the use of
R-silylated R-diazoesters compounds has been found to be
beneficial in a range of ylid-forming2 and other metal carbene
reactions;3 better selectivity and fewer side-reactions than
with the parent diazoesters are frequently observed. In this
communication, we describe the use of such a silylated
diazoester in an unusual and unexpected formamide olefi-
nation reaction.
As part of a program directed toward the synthesis of the
sarain alkaloids, we recently synthesized bicyclic aminal 1.4
It was anticipated that treatment of 1 with silylated diaz-
oacetate 25 in the presence of an appropriate metal catalyst
would lead to formation of an ammonium ylid 3 from the
more nucleophilic of the nitrogen atoms, followed by
rearrangement to a ring-expanded product 4. Contrary to
these expectations, when 1 and 2 were heated in benzene in
the presence of 10 mol % rhodium(II) acetate, the major
product obtained was the vinylogous carbamate 6. This
product arises from reaction of the intermediate metal carbene
with the formamide oxygen to give 5 and subsequent
rearrangement (Scheme 1).
† University College London.
‡ Merck Sharp & Dohme Research Laboratories.
(1) (a) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263. (b) Clark,
J. S. In Nitrogen, Oxygen and Sulfur Ylide Chemistry; Clark, J. S., Ed.;
Oxford University Press: Oxford, 2002; pp 1-113.
(2) (a) Ioannou, M.; Porter, M. J.; Saez, F. Chem. Commun. 2002, 346.
(b) Ioannou, M.; Porter, M. J.; Saez, F. Tetrahedron 2005, 61, 43. (c) Alt,
M.; Maas, G. Chem. Ber. 1994, 127, 1537. (d) Alt, M.; Maas, G.
Tetrahedron 1994, 50, 7435. (e) Bolm, C.; Saladin, S.; Kasyan, A. Org.
Lett. 2002, 4, 4631. (f) Ducept, P. C.; Marsden, S. P. Synlett 2000, 692. (g)
Bolm, C.; Kasyan, A.; Drauz, K.; Gu¨nther, K.; Raabe, G. Angew. Chem.,
Int. Ed. 2000, 39, 2288. (h) Bolm, C.; Kasyan, A.; Heider, P.; Saladin, S.;
Drauz, K.; Gu¨nther, K.; Wagner, C. Org. Lett. 2002, 4, 2265.
(3) (a) Maas, G.; Werle, T.; Alt, M.; Mayer, D. Tetrahedron 1993, 49,
881. (b) Maas, G.; Alt, M.; Mayer, D.; Bergstra¨sser, U.; Sklenak, S.; Xavier,
P.; Apeloig, Y. Organometallics 2001, 20, 4607. (c) Braddock, D. C.;
Badine, D. M.; Gottschalk, T.; Matsuno, A. Synlett 2003, 345. (d) Maier,
G.; Volz, D.; Neudert, J. Synthesis 1992, 561. (e) Arrowood, T. L.; Kass,
S. R. Tetrahedron 1999, 55, 6739. (f) Kablean, S. N.; Marsden, S. P.; Craig,
A. M. Tetrahedron Lett. 1998, 39, 5109. (g) Marsden, S. P.; Pang, W.-K.
Tetrahedron Lett. 1998, 39, 6077. (h) Clark, J. S.; Middleton, M. D. Org.
Lett. 2002, 4, 765. (i) Mu¨ller, P.; Lacrampe, F.; Bernardinelli, G.
Tetrahedron: Asymmetry 2003, 14, 1503.
The scope and limitations of this reaction were next
explored. Using 1-formylpyrrolidine (7a, Figure 1) as a test
substrate,6 it was established that 0.4 mol % rhodium(II)
(4) Nandra, G. S.; Porter, M. J.; Elliott, J. M. Synthesis 2005, 475.
(5) Allspach, T.; Gu¨mbel, H.; Regitz, M. J. Organomet. Chem.1985, 290,
33.
10.1021/ol0510872 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/08/2005

Scheme 1. Unanticipated Generation of a Vinylogous
Table 1. Conversion of Formamides to Vinylogous
Carbamatesa
Carbamate
entry
amide
time
product
yield %
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
90 min
90 min
45 min
90 min
240 hd
165 min
45 min
90 min
90 min
90 min
90 min
180 min
8a
8b
8c
8d
8e
8f
8g
8h
8i
80b
83c
90
87
63
82
64
90
97
85
69
50e
10
11
12
7j
7k
7l
8j
8k
8l
a Conditions: 7a-l (1 mmol), 2 (1.25 mmol), Rh2(OAc)4 (4 µmol),
benzene (6 mL), reflux. b Yield of 89% was obtained after 16 h. c Yield of
92% was obtained after 16 h. d Further 2 (1.25 mmol) and Rh2(OAc)4 (4
µmol) were added after 144 h. e Ratio of Z:E isomers was 3:2.
acetate was sufficient to catalyze the reaction, and the
corresponding alkene 8a could be obtained in g80% yield
as a single geometric isomer, by chromatography on alumina
(entry 1, Table 1). The (Z)-geometry of the double bond was
established by observation of a nuclear Overhauser enhance-
ment between the CH2N protons of the pyrrolidine ring and
the methylene protons of the triethylsilyl moiety. Control
experiments established that no reaction took place in the
absence of the rhodium catalyst and that if ethyl diazoacetate
was used in place of the silylated analogue 2, the starting
amide was recovered unchanged.7
Similarly efficient reactions were observed with piperidine-
and morpholine-derived formamides (entries 2-4), but when
1-formyl-4-methylpiperazine (7e) was employed as the
substrate, the reaction proceeded very slowly (entry 5). This
reduced reactivity was ascribed to competitive complexation
of the rhodium catalyst by the tertiary amine of the substrate.8
Nevertheless, a moderate yield of alkene 7e could be obtained
after an extended reaction time. 1-Formylpiperazines in
which the coordinative ability of the second nitrogen was
lowered by substitution with a bulky benzhydryl group (7f,
entry 6) or by derivatization with a 3-chlorophenyl substituent
(7g, entry 7) underwent reaction at a similar rate to
compounds 7a-d.
Formamides derived from acyclic secondary amines were
also converted to the corresponding vinylogous carbamates
in moderate to high yields under these reaction conditions
(entries 8-12). In the case of formanilide 7l, the alkene
product 8l was obtained as a mixture of geometric isomers
(entry 12). For all other substrates, solely the (Z)-alkenes
were obtained.
It is noteworthy that in all cases, the only product isolated
from the reaction was the vinylogous carbamate: for the
piperazine-derived formamides 7e-g, no products arising
from ammonium ylid formation were observed, and in the
case of alkene-containing substrates 7i and 7j, no cyclopro-
pane products were obtained.
The reaction described in this letter is analogous to an
intramolecular reaction of some amido diazoketones that has
been reported by Padwa et al.9 Related intramolecular
reactions between diazoketones and thiolactams were utilized
(6) Formamides were used as received from commercial sources or
prepared by reaction of the corresponding secondary amines with ethyl
formate; see: Moffat, J.; Newton, M. V.; Papenmeier, G. J. J. Org. Chem.
1962, 27, 4058.
(7) In this case, peaks corresponding to diethyl maleate and diethyl
fumarate could be observed in the 1H NMR spectrum of the crude reaction
mixture.
(8) Doyle, M. P.; Tamblyn, W. H.; Bagheri, V. J. Org. Chem. 1981, 46,
5094.
(9) Padwa, A.; Hasegawa, T.; Liu, B.; Zhang, Z. J. Org. Chem. 2000,
65, 7124.
Figure 1. Tertiary formamides subjected to the olefination
conditions.
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Org. Lett., Vol. 7, No. 16, 2005

by Danishefsky et al. in syntheses of A58365A10 and
indolizomycin,11 and one example of an intermolecular
reaction between a thiolactam and ethyl diazoacetate was
also reported.10 In addition, Corey has reported the conver-
sion of some cyclic secondary amides to imidates using ethyl
diazoacetate and a rhodium catalyst.12
pressed, relative to reaction with the formamide substrate,
upon silylation of the diazo compound.14 This may be
attributable to the increased steric hindrance that pertains to
the silylated compound, and/or to the π-acceptor character
of the silyl substituent, which renders the diazo compound
less nucleophilic. The unusual chemoselectivity observed
with formamides 1, 7e, and 7f, in which the metal carbene
reacts with a formamide oxygen rather than the ostensibly
more nucleophilic tertiary amine, may also be steric in nature.
The stereoselectivity of the olefination is likely to be
thermodynamically controlled; while the reaction may ini-
tially give a mixture of isomers, rapid conversion to the
thermodynamically more stable (Z)-isomer is expected to
occur15 under the reaction conditions, due to the partial
single-bond character of the olefin. Only with the anilide-
derived product 8l, in which the degree of electron-release
from the nitrogen is lower, is this equilibration suppressed,
resulting in the observed mixture of (E)- and (Z)-isomers.
In conclusion, we have discovered a new and general
method for the conversion of tertiary formamides to R-si-
lyloxy-â-dialkylaminoacrylates. We are currently investigat-
ing further transformations of these intriguing products.16
The mechanism we propose for this conversion is es-
sentially the same as that put forward by Padwa for
intramolecular reactions (Scheme 2).9 Reaction of the diazo
Scheme 2. Proposed Course of the Olefination Reaction
Acknowledgment. We thank Dr. Abil Aliev for as-
sistance with NOE experiments, the Engineering and Physical
Sciences Research Council and Merck Sharp & Dohme for
a “CASE for New Academics Award”, and University
College London for the award of a Graduate School Research
Scholarship (to P.S.P.).
compound with the metal catalyst leads to a rhodium carbene
species (9), which serves to transfer the carbene moiety to
the carbonyl group of the amide, giving carbonyl ylid 10.
Cyclization of this intermediate to an epoxide 11 is followed
by ring-opening to zwitterion 12. Finally, silyl group
migration from carbon to oxygen13 gives the observed
product 5.
Supporting Information Available: Experimental pro-
cedures; full spectroscopic details for all new compounds,
1
and copies of H and 13C NMR spectra for compounds 6
The importance of the triethylsilyl group to this process
can be judged by the fact that attempts to carry out reactions
between ethyl diazoacetate and tertiary formamides do not
lead to any olefination of the amide; instead, the diazo
compound is consumed unproductively in the formation of
diethyl maleate and diethyl fumarate, and the amide is
recovered unchanged. This “carbene dimerization” is sup-
and 8a-l. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0510872
(14) It should be noted that in the absence of a nucleophilic substrate,
“carbene dimerization” of silylated diazoesters is observed; see: Maas, G.;
Gimmy, M.; Alt, M. Organometallics 1992, 11, 3813.
(15) (a) Dudek, G. O.; Volpp, G. P. J. Am. Chem. Soc. 1963, 85, 2697.
(b) Go´mez Sa´nchez, A.; Bellanato, J. J. Chem. Soc., Perkin Trans. 2 1975,
1561.
(16) For previously reported applications of R-alkoxy-â-aminoacrylates,
see: (a) Schmidt, R. R.; Betz, R. Synthesis 1982, 748. (b) Schmidt, R. R.;
Talbiersky, J.; Betz, R. Chem. Ber. 1982, 115, 2674. (c) Pe´rez, D.; Bure´s,
G.; Guitia´n, E.; Castedo, L. J. Org. Chem. 1996, 61, 1650. (d) Escudero,
S.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Org. Chem. 1997, 62, 3028. (e)
Smodi, J.; Stanovnik, B. Tetrahedron 1998, 54, 9799.
(10) Fang, F. G.; Prato, M.; Kim, G.; Danishefsky, S. J. Tetrahedron
Lett. 1989, 30, 3625.
(11) (a) Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem.
Soc. 1990, 112, 2003. (b) Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.;
Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
(12) Busch-Petersen, J.; Corey, E. J. Org. Lett. 2000, 2, 1641.
(13) Moser, W. H. Tetrahedron 2001, 57, 2065.
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