Guiding the nitrogen nucleophile to the middle: Palladium-catalyzed decarboxylative cyclopropanation of 2-alkylidenetrimethylene carbonates with isocyanates

Article abstract of DOI:10.1039/c0cc05308b

A palladium-catalyzed decarboxylative cyclopropanation of 2-alkylidenetrimethylene carbonates with isocyanates is described to form oxazolidinones of (1-aminocyclopropyl)methanols with high selectivity. The site of nucleophilic attack is directed by conne

Full text of DOI:10.1039/c0cc05308b

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COMMUNICATION
Guiding the nitrogen nucleophile to the middle: palladium-catalyzed
decarboxylative cyclopropanation of 2-alkylidenetrimethylene carbonates
with isocyanatesw
Ryo Shintani,* Kohei Moriya and Tamio Hayashi*
Received 1st December 2010, Accepted 19th January 2011
DOI: 10.1039/c0cc05308b
A palladium-catalyzed decarboxylative cyclopropanation of
2-alkylidenetrimethylene carbonates with isocyanates is
described to form oxazolidinones of (1-aminocyclopropyl)-
methanols with high selectivity. The site of nucleophilic attack
is directed by connecting the two reaction components and by
employing an electron-deficient triarylphosphine ligand.
intermediate B, thereby guiding the direction of successive
nucleophilic attack to the central carbon to form a cyclo-
propane (C) rather than allylic amination products.8 In this
communication, we specifically demonstrate this strategy by
employing isocyanates as the pre-nucleophile to form
oxazolidinones derived from (1-aminocyclopropyl)methanols
with high selectivity. The products obtained here belong to a
family of 1-aminocyclopropanecarboxylic acids, which are
widely found as structural motifs in various biologically active
compounds.9
Cyclopropanation through a nucleophilic attack at the central
carbon of a p-allylpalladium complex was first described by
Hegedus and coworkers in 1980 in the context of stoichiometric
reactions with ester enolates.1 Since then, several examples
have been reported including catalytic reactions,2,3 but most
of them utilize enolate-based carbon nucleophiles and the
selectivity toward cyclopropanation over allylic substitution
is not always high enough.4 In addition, the use of nitrogen-
based nucleophiles has been much less explored and is so far
limited to the lactam-forming cyclization processes.5
In an initial investigation, we prepared 2-benzylidenetri-
methylene carbonate (1a) as a model reagent in three steps
from commercially available 1,3-diacetoxyacetone (eqn (1)).
Thus, a Wittig reaction with benzylidene(triphenyl)phosphorane,
followed by hydrolysis of the acetates, gave 2-benzylidene-1,3-
propanediol in 80% yield over two steps,10 and treatment of
this diol with triphosgene cleanly provided 1a in 79% yield.11
Having established a concise synthesis of 1a, we conducted
reactions of 1a with benzyl isocyanate (2a) in the presence of
several Pd/2PAr3 catalysts (5 mol%) in CH2Cl2 at 40 1C to
realize the strategy outlined above (Scheme 1), and found that
the reactivity and selectivity of cyclopropanation vs. allylic
amination are both highly dependent on the electronic nature
of the phosphine ligand (Table 1). Although the use of
electron-rich tris(4-methoxyphenyl)phosphine as the ligand
gave neither cyclopropanation product 3aa nor allylic amination
product 4aa (entry 1), both yield and selectivity of 3aa
Considering the difficulty of developing a general catalytic
method to form cyclopropanes by the attack of nitrogen
nucleophiles at the central carbon of p-allylpalladium inter-
mediates while suppressing the well-known allylic amination
pathway,6 here we describe the use of 2-alkylidenetrimethylene
carbonates 17 (Scheme 1) toward this goal. This reagent is
designed to generate a p-allylpalladium species having an
alkoxide tether (A) via oxidative addition to a palladium(0)
catalyst followed by decarboxylation.7 This then would react
with a nitrogen-based pre-nucleophile (pre-NNu) to form
Table 1 Palladium-catalyzed decarboxylative cyclopropanation of
2-benzylidenetrimethylene carbonate (1a) with benzyl isocyanate
(2a): effect of phosphine ligand
Scheme 1 Schematic representation for the palladium-catalyzed
decarboxylative cyclopropanation of 2-alkylidenetrimethylene
carbonates 1 with nitrogen-based pre-nucleophiles (pre-NNu).
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo, Kyoto 606-8502, Japan.
E-mail: shintani@kuchem.kyoto-u.ac.jp,
thayashi@kuchem.kyoto-u.ac.jp; Fax: +81 75-753-3988;
Tel: +81 75-753-3983
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. CCDC 802126. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c0cc05308b
Entry
Ar
Yielda (%)
3aa/4aab
dr of 3aab
1
2
3
4
4-MeOC6H4
Ph
4-FC6H4
4-CF3C6H4
0
27
41
84
—
—
—
499/1
96/4
o1/99
34/66
92/8
a
b
Combined isolated yield of 3aa and 4aa. Determined by 1H NMR.
c
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gradually became higher by changing the ligand to more
electron-deficient triarylphosphines (entries 2–4), and 3aa
was obtained in high yield with 92% selectivity in the presence
of tris(4-trifluoromethylphenyl)phosphine (entry 4). The selective
formation of 3aa with an electron-deficient phosphine ligand is in
accordance with our previous observation in the context of
lactam-forming reactions using g-methylidene-d-valerolactones.5c
Fig. 1 X-Ray crystal structure of major diastereomer of 3ca (hydro-
ð1Þ
gen atoms except at the stereocenter are omitted for clarity).
499/1; entries 7–10). The use of phenyl isocyanate, however,
completely reverses the selectivity to give only the allylic
amination product (entry 11).5b,c The relative configuration of
the major diastereomer of 3ca obtained in entry 3 was established
by X-ray crystallographic analysis as shown in Fig. 1.12
Under the conditions using tris(4-trifluoromethylphenyl)-
phosphine as the ligand, several 2-arylmethylidenetrimethylene
carbonates
1 efficiently undergo decarboxylative cyclo-
propanation with isocyanate 2a with high selectivity (3/4 = 88/12
to 98/2, dr = 93/7 to 98/2; Table 2, entries 1–5). The reaction
can be easily scaled up to a gram quantity under reduced
catalyst loading (2.5 mol%) with a similar efficiency to give
3aa/4aa = 91/9 and dr of 3aa = 97/3, and the major
diastereomer of 3aa was isolated in 68% yield (eqn (2)).
Unsubstituted 2-methylidenetrimethylene carbonate (1f) is
also applicable to give the cyclopropanation product with
perfect selectivity in high yield (entry 6). In addition to these
cyclic carbonates, analogous N-tosyl carbamate 5 also undergoes
the same mode of transformation with isocyanate 2a to give
cyclopropanation product 6, a spirocyclic imidazolidinone, in
63% yield with no formation of the corresponding allylic
amination product (eqn (3)). With regard to the nitrogen
substituent of isocyanates, both primary and secondary alkyl
groups are tolerated in the reaction with 1a to give cyclo-
propanes 3 selectively (3/4 = 84/16 to 499/1, dr = 84/16 to
ð2Þ
ð3Þ
A proposed catalytic cycle of this process is illustrated in
Scheme 2. Oxidative addition of the allyl carbonate of 1 to
palladium(0) gives p-allylpalladium carbonate I. Successive
decarboxylation forms p-allylpalladium alkoxide II, which
then attacks the electrophilic carbon of isocyanate 2 to give
intermediate III. Ring-closing nucleophilic attack of the
nitrogen atom to the central carbon of the p-allylpalladium
moiety of III leads to palladacyclobutane IV.2d Reductive
elimination releases cyclopropane product 3 along with
Table 2 Palladium-catalyzed decarboxylative cyclopropanation of
2-alkylidenetrimethylene carbonates 1 with isocyanates 2: scope
Yielda
Entry 1 (R)
2 (R0)
(%) 3/4b
dr of 3b
1
2
1a (Ph)
1b (4-MeC6H4) 2a
1c (4-ClC6H4) 2a
1d (2-MeC6H4) 2a
1e (2-naphthyl) 2a
2a (PhCH2)
84
89
91
63
77
93
92/8
91/9
93/7
96/4
98/2
98/2
93/7
98/2
—
3
4c
5
98/2
88/12
499/1
93/7
84/16 499/1
499/1
93/7
6
1f (H)
1a
1a
1a
1a
2a
7d
8
2b (4-MeOC6H4CH2) 95
97/3
2c (4-ClC6H4CH2)
2d (Et)
2e (Cy)
67
73
70e
82
9
10
11
88/12
84/16
—
1a
2f (Ph)
o1/99
a
b
Combined isolated yield of 3 and 4 unless otherwise noted. Deter-
mined by 1H NMR. 1.5 equiv. of 1d and 1.0 equiv. of 2a were
c
d
e
used. 1.5 equiv. of 2b was used. Isolated yield of the major
diastereomer of 3.
Scheme
2 Proposed catalytic cycle for the palladium-catalyzed
decarboxylative cyclopropanation of 1 with 2.
c
3058 Chem. Commun., 2011, 47, 3057–3059
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regeneration of a palladium(0) species.1–3 The step from III to
IV creates two contiguous stereocenters and the observed
diastereoselectivity can be explained by an outer-sphere attack
of the nitrogen atom to a syn-p-allylpalladium species.13,14
The guiding effect of the alkoxide tether in the step of
nucleophilic attack to the p-allylpalladium in the present
catalysis is highlighted in the following intermolecular control
experiment. A reaction of allyl acetate with sodium benzoyl-
(benzyl)amide under the catalysis of Pd/2P(4-CF3C6H4)3 gave
exclusively allylation product 7 with no formation of a cyclo-
propanation product (eqn (4)). This result indicates that
connecting two reaction components together in the reaction
of 1 and 2 can significantly alter the direction of the nucleo-
philic attack.
Sports, Science and Technology, Japan (the Global COE
Program ‘‘Integrated Materials Science’’ of Kyoto
University).
Notes and references
1 L. S. Hegedus, W. H. Darlington and C. E. Russell, J. Org. Chem.,
1980, 45, 5193.
2 (a) H. M. R. Hoffmann, A. R. Otte and A. Wilde, Angew. Chem.,
Int. Ed. Engl., 1992, 31, 234; (b) A. Wilde, A. R. Otte and H. M.
R. Hoffmann, J. Chem. Soc., Chem. Commun., 1993, 615;
(c) A. R. Otte, A. Wilde and H. M. R. Hoffmann, Angew. Chem.,
Int. Ed. Engl., 1994, 33, 1280; (d) H. M. R. Hoffmann, A. R. Otte,
A. Wilde, S. Menzer and D. J. Williams, Angew. Chem., Int. Ed.
Engl., 1995, 34, 100.
3 (a) M. Formica, A. Musco, R. Pontellini, K. Linn and C. Mealli,
J. Organomet. Chem., 1993, 448, C6; (b) A. Satake and T. Nakata,
J. Am. Chem. Soc., 1998, 120, 10391; (c) A. Satake, H. Koshino
and T. Nakata, Chem. Lett., 1999, 49; (d) A. Satake,
H. Kadohama, H. Koshino and T. Nakata, Tetrahedron Lett.,
1999, 40, 3597; (e) R. Shintani, S. Park and T. Hayashi, J. Am.
Chem. Soc., 2007, 129, 14866; (f) W. Liu, D. Chen, X.-Z. Zhu,
X.-L. Wan and X.-L. Hou, J. Am. Chem. Soc., 2009, 131, 8734.
4 For examples of obtaining cyclopropanes as a minor product in the
palladium-catalyzed allylic alkylation, see: (a) C. Carfagna,
L. Mariani, A. Musco, G. Sallese and R. Santi, J. Org. Chem.,
1991, 56, 3924; (b) C. Carfagna, R. Galarini, A. Musco and
R. Santi, J. Mol. Catal., 1992, 72, 19; (c) H. Rudler, P. Harris,
A. Parlier, F. Cantagrel, B. Denise, M. Bellassoued and
J. Vaissermann, J. Organomet. Chem., 2001, 624, 186.
5 (a) R. Grigg and M. Kordes, Eur. J. Org. Chem., 2001, 707;
(b) R. Shintani, S. Park, F. Shirozu, M. Murakami and
T. Hayashi, J. Am. Chem. Soc., 2008, 130, 16174;
(c) R. Shintani, T. Tsuji, S. Park and T. Hayashi, J. Am. Chem.
Soc., 2010, 132, 7508.
ð4Þ
Cleavage of the tether, namely a ring-opening of the
oxazolidinone moiety of 3aa, can be accomplished in various
ways depending on the reaction conditions (eqn (5)). Thus,
decarbonylation using ethylenediamine cleanly produces N-H
aminoalcohol 8 in 83% yield. In contrast, reduction of 3aa
with LiAlH4 gives N-methyl aminoalcohol 9 in 80% yield.
Furthermore,
a nucleophilic ring-opening with phenyl-
magnesium bromide leads to N-benzoyl-protected aminoalcohol
10 in 85% yield.
6 For recent reviews, see: (a) B. M. Trost and D. R. Fandrick,
Aldrichimica Acta, 2007, 40, 59; (b) B. M. Trost and
M. L. Crawley, Chem. Rev., 2003, 103, 2921; (c) Handbook of
Organopalladium Chemistry for Organic Synthesis, ed. E. Negishi,
John Wiley & Sons, Hoboken, NJ, 2002, vol. 2.
7 This type of cyclic carbonate has been employed under palladium
catalysis to produce mono-functionalized 2-methylene-1,3-
propanediol derivatives: (a) I. Shimizu, Y. Ohashi and J. Tsuji,
Tetrahedron Lett., 1984, 25, 5183; See also: (b) P. Breuilles and
D. Uguen, Tetrahedron Lett., 1987, 28, 6053; (c) S.-K. Kang,
D.-C. Park, C.-H. Park and S.-B. Jang, Synth. Commun., 1995,
25, 1359.
8 For examples of palladium-catalyzed regio-directed allylic
substitution reactions, see: (a) M. E. Krafft, A. M. Wilson,
Z. Fu, M. J. Procter and O. A. Dasse, J. Org. Chem., 1998, 63,
1748; (b) B. M. Trost, R. C. Bunt, R. C. Lemoine and
T. L. Calkins, J. Am. Chem. Soc., 2000, 122, 5968;
(c) G. R. Cook, H. Yu, S. Sankaranarayanan and P. S. Shanker,
J. Am. Chem. Soc., 2003, 125, 5115 and the references cited therein.
9 For a review, see: F. Brackmann and A. de Meijere, Chem. Rev.,
2007, 107, 4493.
10 This diol can also be obtained in one step from commercially
available diethyl benzylidenemalonate by reducing it with
(i-Bu)2AlH in ca. 60% yield.
11 Use of ethyl chloroformate in place of triphosgene gives 1a in ca.
40% yield.
12 CCDC 802126 contains the supplementary crystallographic data
ð5Þ
In summary, we have described a palladium-catalyzed
decarboxylative cyclopropanation of 2-alkylidenetrimethylene
carbonates with isocyanates to form oxazolidinones of
(1-aminocyclopropyl)methanols with high selectivity. The site
of nucleophilic attack has been efficiently directed by connecting
the two reaction components and by employing an electron-
deficient triarylphosphine ligand. The reaction is also easily
scaled up and the products thus obtained can be derivatized to
variously substituted (1-aminocyclopropyl)methanols. Future
studies will explore further usage of the present strategy
including the development of an asymmetric variant of this
process.
for this communication. See also ESIw.
13 The observed stereochemical outcome is consistent with the literature
results in the stoichiometric cyclopropanation of syn-p-allylpalladium
complexes with enolate nucleophiles: ref. 2c.
14 For NMR studies of related 1,2-disubstituted p-allylpalladium
complexes, see: G. Maglio, A. Musco and R. Palumbo,
Inorg. Chim. Acta, 1970, 4, 153.
Support has been provided in part by a Grant-in-Aid for
Scientific Research, the Ministry of Education, Culture,
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3057–3059 3059