Palladium-catalyzed insertion of CO2 into vinylaziridines: New route to 5-vinyloxazolidinones

Article abstract of DOI:10.1021/ol201193d

2-Vinylaziridines undergo a mild Pd-catalyzed ring-opening cyclization reaction with an ambient atmosphere of carbon dioxide to give 5-vinyloxazolidinones. The process is high yielding as well as regio- and stereoselective.

Full text of DOI:10.1021/ol201193d

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3454–3457
Palladium-Catalyzed Insertion of CO2
into Vinylaziridines: New Route
to 5-Vinyloxazolidinones
Francesco Fontana, C. Chun Chen, and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, U.K.
V.Aggarwal@bristol.ac.uk
Received May 5, 2011
ABSTRACT
2-Vinylaziridines undergo a mild Pd-catalyzed ring-opening cyclization reaction with an ambient atmosphere of carbon dioxide to give
5-vinyloxazolidinones. The process is high yielding as well as regio- and stereoselective.
Vinylaziridines are valuable synthetic intermediates1
which, as an illustration, undergo a host of very useful
palladium-catalyzed transformations (Scheme 1). For
example, we2 and others3 showed that they could be
converted into unsaturated β-lactams with a high level
of stereocontrol. In the presence of doubly activated
Michael acceptors they can also be converted into
pyrrolidines.4a,b We recently extended this methodology
to singly activated acceptors and demonstrated its utility in
a stereocontrolled synthesis of (þ)-kainic acid.4c The Pd-
catalyzed reaction of vinylaziridines with heterocumulenes
(e.g., isocyanates, carbodiimides, and isothiocyanates) is
also well established,5 but insertion into the archetypal
heterocumulene, CO2, has not been reported.6 Such a reac-
tion would give vinyloxazolidinones, important motifs
in both synthesis7ꢀ9 and pharmacology.10 However, this
reaction did not seem promising since Ibuka had reported
that 3-tosyl-5-vinyloxazolidin-2-ones underwent Pd-cata-
lyzed decarboxylation to give cis-N-tosyl-2-vinylaziridines
(Scheme 1).11 Furthermore, Knight4b,12 had shown that
vinyloxazolidinones bearing electron-withdrawing groups
(1) For reviews, see: (a) Ohno, H. In Aziridines and Epoxides in
Asymmetric Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, Germany,
2006; Chapter 2. (b) Sweeney, J. B. In Science of Synthesis; Enders, D., Ed.;
Scheme 1. Pd-Catalyzed Applications of Vinylaziridines
€
Georg Thieme Verlag: 2009; Vol. 40a, pp 643ꢀ772. (c) Muller, P.; Fruit, C.
Chem. Rev. 2003, 103, 2905–2920. (d) Sweeney, J. B. Aziridines and
Epoxides in Asymmetric Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim,
Germany, 2006; Chapter 4.
(2) Fontana, F.; Tron, G. C.; Barbero, N.; Ferrini, S.; Thomas, S. P.;
Aggarwal, V. K. Chem. Commun. 2010, 46, 267–269.
(3) (a) Tanner, D.; Somfai, P. Bioorg. Med. Chem. Lett. 1993, 3,
2415–2418. (b) Spears, G. W.; Nakanishi, K; Ohfune, Y. Synlett 1991,
91–92.
(4) (a) Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem.
2002, 67, 5977–5980. (b) For an analogous reaction on vinyloxazolidi-
nones, see: Knight, J. G.; Stoker, P. A.; Tchabanenko, K.; Harwood,
S. J.; Lawrie, K. W. M. Tetrahedron 2008, 64, 3744–3750. (c) Lowe,
M. A.; Ostovar, M.; Ferrini, S.; Chen, C. C.; Lawrence, P. G.; Fontana,
F.; Calabrese, A. A.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2011, DOI:
10.1002/anie.201101389.
(5) For selected examples, see: (a) Butler, D. C. D.; Inman, G. A.;
Alper, H. J. Org. Chem. 2000, 65, 5887–5890. (b) Fandrick, D. R.; Trost,
B. M. J. Am. Chem. Soc. 2003, 125, 11836–11837. (c) Dong, C.; Alper, H.
Tetrahedron: Asymmetry 2004, 15, 1537–1540.
r
10.1021/ol201193d
Published on Web 06/06/2011
2011 American Chemical Society

on nitrogen readily lost CO2 upon treatment with Pd(0)
and that the resulting π-allyl Pd intermediate could be
trapped with CO or dipolarophiles.
Thus, the potential for incorporating CO2 into
vinylaziridines,13 perhaps because of its high thermodynamic
and kinetic stability, seemed remote. Nevertheless, our
interest in the synthesis14 and utility2 of vinylaziridines
together with the contemporary environmental need to
find further uses of CO2 as a raw material15,16 prompted us
to investigate this area further.
The formation of the cis-aziridine 2a is in keeping with
Ibuka’s observations as he had previously found that
trans-N-tosyl aziridines readily isomerized to cis-aziridines
(98:2) in the presence of Pd(0).11
The isolation of the isomerized starting material 2a
implicated a slow reaction between the amide anion and
CO2. We reasoned that ion pairing of the amide anion with
the cationic Pd complex might compromise its reactivity and
that increased nucleophilicity of the aza-anion could be
achieved by rendering the Pd center neutral. Such a change
had been pivotal in the successful reactions of vinyl azir-
idines with singly activated Michael acceptors.4c We there-
fore decided to add tetrabutylammonium chloride (TBAC).18
While reaction at RT was lower yielding, at 0 °C the product
vinyloxazolidinone 3a was obtained in 86% yield (entries 2
and 3). We were able to achieve similar results at a lower
phosphine loading (entry 4). Replacing the highly hygro-
scopic TBAC with the more easily manageable fluoride
source tetrabutyl-ammonium difluorotriphenylsilicate
(TBAT) led to a further increase in yield (92%) with no
detectable traces of starting material 1a or cis-aziridine 2a.
Furthermore the reaction was now completed over a shorter
reaction time (entry 5). A control experiment in the absence
of TBAT or Pd (entries 6, 7) confirmed the beneficial effects
of both species in promoting the carboxylation.
Scheme 2. Synthesis of Vinylaziridines
We initially synthesized a series of N-tosyl-2-vinylazir-
idines 1 using our sulfur ylide methodology as shown in
Scheme 2 (see Supporting Information (SI)).2 Treatment
Having developed an optimized protocol we then
screened the scope of the reaction (Table 2). Carboxylation
occurred uneventfully for a series of diaryl-substituted
trans-aziridines 1bꢀ1g bearing either electron-donating
or -withdrawing para substituents (entries 2, 3, 6, 7, 9).
However, when R1 possessed greater electron-donating
character the addition of TBAT became detrimental and
of the vinylaziridine 1a with Pd2(dba)3 CHCl3 in the
3
presence of Ph3P and just an ambient atmosphere of CO2
gave the trans-vinyloxazolidinone 3a in a promising 61%
yield. In addition, cis-aziridine 2a was also obtained
together with traces of the starting material, trans-aziridine
1a (Table 1, entry 1).17
(11) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.;
Miwa, Y.; Taga, T.; Nakai, K; Tamamura, H.; Fujii, N. J. Org. Chem.
1997, 62, 999–1015.
(6) Trost has reported the insertion of CO2 into vinylepoxides at
elevated pressure. See: (a) Trost, B. M.; Angle, S. R. J. Am. Chem. Soc.
1985, 107, 6123–6124. Yoshida reported the conversion of amino-
alkenyl carbamates into vinyloxazolidinones. See: (b) Yoshida, M.;
Ohsawa, Y.; Sugimoto, K.; Hidetoshi, T; Ihara, M. Tetrahedron Lett.
2007, 48, 8678–8682.
(7) (a) For a recent review, see: Zappia, G.; Cancelliere, G.; Gacs-
Baitz, E.; Delle Monache, G.; Misiti, D.; Nevola, L.; Botta, B. Curr. Org.
Synth. 2007, 4, 238–307.
(8) For representative examples on the use of 5-vinyloxazolidinones
in synthesis, see: (a) Reference 4b. (b) Cook, G. R.; Shanker, P. S.;
Peterson, S. L. Org. Lett. 1999, 1, 615–617. (c) Yamamoto, T.; Hasegawa,
H.; Ishii, S.; Kaji, S.; Masuyama, T.; Harada, S.; Katsumura, S. Tetrahedron
2008, 64, 11647–11660. (d) Robertson, J.; Abdulmalek, E. Tetrahedron Lett.
2009, 50, 3516–3518.
(9) For examples of hydrolysis of vinyloxazolidinones to unsaturated
β-aminoalcohols, see: (a) Olofsson, B.; Khamrai, U.; Somfai, P. Org.
Lett. 2000, 2, 4087–4089. (b) Disadee, W.; Ishikawa, T. J. Org. Chem.
2005, 70, 9399–9406.
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L. M.; Gadwood, R. C.; Lund, E. T.; Cavey, G. S.; Mathews, W. R.;
Adams, L. D.; Cecil, E. T.; Pearson, J. D.; Bock, J. H.; Mott, J. E.;
Shinabarger, D. L.; Xiong, L.; Mankin, A. S. J. Biol. Chem. 2003, 278,
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Jacobs, M. R.; Appelbaum, P. C. Antimicrob. Agents Chemother. 2003,
47, 1148–1150. (c) Jacqueline, C.; Caillon, J.; Le Mabecque, V.; Miegeville,
A.-F.; Donnio, P.-Y.; Bugnon, D.; Potel, G. J. Antimicrob. Chemother.
2003, 51, 857–864. (d) Moellering, R. C., Jr. Ann. Intern. Med. 2003, 138,
135–142. (e) Rubinstein, E.; Isturiz, R.; Standiford, H. C.; Smith, L. G.;
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F.; Fallah, M. S.; Shafaghi, A. Med. Sci. Monit. 2002, 8, I27–PI30. (g)
Kaatz, G. W.; Rybak, M. J. Emerging Drugs 2001, 6, 43–55. (h) Fluit, A. C.;
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50, 271–276.
(12) (a) Knight, J. G.; Ainge, S. W.; Harm, A. M.; Harwood, S. J.;
Maughan, H. I.; Armour, D. R.; Hollinshead, D. M.; Jaxa-Chamiec,
A. A. J. Am. Chem. Soc. 2000, 122, 2944–2945. (b) Knight, J. G.;
Tchabanenko, K. Tetrahedron 2002, 58, 6659–664. (c) Knight, J. G.;
Lawson, I. M.; Johnson, C. N. Synthesis 2006, 227–230.
(13) For examples of the conversion of alkyl aziridines into oxazo-
lidinones catalyzed by LiI, see: (a) Miller, A. W.; Nguyen, S. T. Org. Lett.
2004, 6, 2301–2304. (b) Hancok, M. T.; Pinhas, A. R. Synthesis 2004, 14,
2347–2355. (c) Mu, W.-H.; Chasse, G. A.; Fang, D.-C. J. Phys. Chem. A
2008, 112, 6708–6714.
(14) (a) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd,
G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433–1436. (b) Illa,
O.; Arshad, M.; Ros, A.; McGarrigle, E. M.; Aggarwal, V. K. J. Am.
Chem. Soc. 2010, 132, 1828–1830. For a recent review, see: (c) Li, A.-H.;
Dai, L.-X.; Hou, X.-L.; Chen, M.-B. J. Org. Chem. 1996, 61, 4641–4648.
(d) Zhu, B.-H.; Zheng, J.-C.; Yu, C.-B.; Sun, X.-L.; Zhou, Y.-G.; Shen,
Q.; Tang, Y. Org. Lett. 2010, 3, 504–507. (e) McGarrigle, E. M.; Myers,
E. L.; Illa, O.; Shaw, M. A.; Riches, S. L.; Aggarwal, V. K. Chem. Rev.
2007, 107, 5841–5883. For routes from aziridine aldehydes, see: (f)
Baktharaman, S.; Afagh, N.; Vandersteen, A.; Yudin, A. K. Org. Lett.
2010, 12, 240–243.
(15) For a recent review on the use of CO2 in synthesis, see: Sakakura,
T.; Choi, J.-C.; Yasuda, H. Chem. Rev. 2007, 107, 2365–2387.
(16) For an example of waste CO2 being converted into useful
molecules, see: North, M.; Villuendas, P.; Young, C. Chem.;Eur. J.
2009, 15, 11454–11457.
(17) To avoid any further reaction of the desired oxazolidinone, the
reaction mixture was promptly filtered through a pad of silica to remove
the catalyst (see Supporting Information).
(18) For a review on the effects of halide additives in palladium
chemistry, see: Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002,
41, 26–47.
Org. Lett., Vol. 13, No. 13, 2011
3455

Table 1. Optimization of the Carboxylation Reactiona
entry
[Pd] mol %
PPh3/Pd
additive (equiv)
t (°C)
time (h)
conversion (%)b
yield 2a (%)b
yield 3a (%)b
1
10
10
10
10
10
10
ꢀ
6
6
6
2
2
2
ꢀ
ꢀ
rt
rt
0
8
18
18
4
98
99
29
11
traces
ꢀ
61
42
86
86
92c
71
ꢀ
2
TBAC (0.2)
TBAC (0.2)
TBAC (0.2)
TBAT (0.2)
ꢀ
3
100
100
100
98
4
0
5
6
7d
0
2
ꢀ
0
2
ꢀ
TBAT (0.2)
0
2
0e
ꢀ
a dba = dibenzylideneacetone. TBAC = tetrabutylammonium chloride. TBAT = tetrabutylammonium difluorotriphenylsilicate. Aziridine
concentration = 6 ꢁ 10ꢀ2 M. b Determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. c Isolated yield. d Carried out in the
presence of PPh3 (0.2 equiv). e Only starting material was recovered.
Table 2. Scope of Pd-Catalyzed Carboxylation Reactiona
entry
aziridine
R1
R2
dr (1:2)
time (h)
yield (%)b
92
dr (3:4)c
1
1a
1b
1c
1c/2c
2c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
>98:2
>98:2
97:3
2
2
>98:2
>98:2
97:3
2
p-Me-C6H4
86
3
p-OMe-C6H4
4
87
62d
4
p-OMe-C6H4
52:48
2:>98
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
85:15
-
4
79:21
8:92
5
p-OMe-C6H4
4
40
6
p-Cl-C6H4
Ph
4
86
>98:2
>98:2
>98:2
>98:2
96:4
7
p-Me-C6H4
4
89
8e
9
p-OMe-C6H4
Ph
4
91
1g
1h
1i
p-Cl-C6H4
Ph
2
84
10
11
12e
13
14e
15
Ph
Ph
Cy
Ph
H
Me
3
78
TMS
Ph
24
4
40
>98:2
>98:2
85:15
ꢀ
1j
83
71f
1k/2k
H
0.5
0.5
2
1l
H
68
(2R,3R)-1a (98:2 er)
Ph
Ph
>98:2
89 (>99:1 er)g
>98:2
a dba = dibenzylideneacetone. TBAT = tetrabutylammonium difluorotriphenylsilicate. Aziridine concentration = 6 ꢁ 10ꢀ2 M. b Isolated yield.
c Determined by 1H NMR of the crude. d Determined by 1H NMR with 1,1,2,2-tetrachloroethane as internal standard. e Conducted in the absence of
TBAT. f 1H NMR of the crude showed the desired oxazolidinones together with cis-aziridine 2j in a ratio of 85:15. g Determined by chiral HPLC (see SI).
higher yields were achieved without it (entry 8). Alkyl
residues were well tolerated on both the vinyl moiety, 1h
(R2 = Me), 1i (R2 = SiMe3), and the aziridine core, 1i
(R1 = Cy) (entries 10, 11, 12). The unsubstituted aziridine
1l underwent carboxylation, but as before, higher yields
were observed in the absence of TBAT (entry 13). Inter-
estingly, the ratio of trans- and cis-vinyloxazolidinones
reflected the ratio of trans- and cis-aziridines that we
started with. Using enantioenriched aziridine (2R,3R)-1a,
the trans-vinyloxazolidinone (þ)-3a was obtained with
very high er, indicating that no erosion in enantiopurity
took place (entry 14). We were also able to test the
cis-aziridine 2c and a ∼1:1 mixture of cis/trans isomers
1c/2c (entries 4, 5). Unexpectedly, the cis-aziridine mainly
gave the cis-oxazolidinone 4c and the ∼1:1 mixture led to a
79:21 mixture of trans/cis oxazolidinones.
On the basis of these observations together with pre-
vious studies,2 we propose the mechanism shown in
Scheme 3. The trans-E-vinylaziridine can react with Pd(0)
to give the π-allyl palladium intermediate 5. PdꢀPd
3456
Org. Lett., Vol. 13, No. 13, 2011

R2 = SiMe3.2,21 Surprisingly, we observed that carbonylation
of vinyloxazolidinones 3a (R1, R2 = Ph) and 3d (R1 = Ph,
R2 = p-Cl-C6H4) afforded the β-lactams 9, albeit in lower
yields and diastereoselectivity as compared to the correspond-
ing aziridines (see SI for details).2 This indicates that the
intermediates involved prior to insertion of CO are subtly
different. It is likely that decarboxylation is not instantaneous
and that the product distribution is influenced by the rates of
isomerization of the π-allyl Pd species and by the rates of
carbonylation and decarboxylation, all of which will be
substrate-dependent.
Scheme 3. Proposed Mechanism
Scheme 4. Regioselectivity of Carbonylation
mediated isomerization19 would give the isomeric complex
6 which can ring close to the cis-E-vinylaziridine 2. This is
the accepted mechanism for isomerization of trans- and
cis-vinylaziridines. Capture of the π-allyl palladium inter-
mediates 5 and 6 by CO2 then give the vinyloxazolidinones
3 and 4 respectively. The fact that cis-aziridine 2c gives
mostly the cis-oxazolidinone 4c implies that isomerization
of the π-allyl palladium intermediates 5 and 6 has been
significantly suppressed under the reaction conditions.
Factors that reduce the extent of such isomerization
include (i) a lower temperature and (ii) use of a halide
additive.20,4c Indeed, at RT and in the absence of halide
salts the cis-aziridine 2c gave considerably more of trans-
oxazolidinone (68 cis/32 trans) indicating that a greater
degree of isomerization had taken place. Moreover, sub-
jecting the cis-oxazolidinone 4c (91 cis/9 trans) to the
reaction conditions resulted in the same ratio of isomers
indicating that no isomerization occurred. Again, at RT
but in the absence of halide salts the isomerization of 4c
was much more rapid giving increased amounts of trans-
oxazolidinone (76 cis/24 trans). These experiments show that
cisꢀtrans isomerization of both the aziridines and oxazoli-
dinones is largely arrested under the reaction conditions
(kinetic control) but can occur in the absence of halide ions
and higher temperatures (thermodynamic control).
In conclusion, we have discovered that readily available
trans-vinylaziridines can be converted into trans-vinylox-
azolidinones through a Pd-catalyzed carboxylation pro-
cess. The use of CO2 in such processes is rare because CO2
is widely regarded as thermodynamically stable and kine-
tically unreactive. The results presented herein show that it
is far from kinetically unreactive, as should be expected for
an electron-deficient carbon atom bearing two strongly
activated electron sinks.
Knight has shown that 5-vinyloxazolidinones can serve
as substrates for Pd(0)-catalyzed reactions, e.g. carbonyla-
tion, in a manner analogous to vinylaziridines.12 However,
subtle differences in product distributions are observed
(Scheme 4). For example, N-tosyl-2-vinylaziridines where
R2 = H or Ar are known to afford β-lactams 9.2,3a
However, Knight reported that submission of the corre-
sponding N-tosyl-vinyloxazolidinones (R2 = H) to carbony-
lation gave the δ-lactam derivative 10 instead.12c The
same regioisomers were obtained from vinylaziridines when
Acknowledgment. V.K.A. thanks the EPSRC for a
ꢀ
Studi di Milano” for funding. The authors thank Dr. Mairi
Haddow (University of Bristol) for X-ray structure deter-
mination of compound 1i.
Senior Research Fellowship. F.F. thanks “Universita degli
Supporting Information Available. Synthesis and char-
acterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
€
(19) Gangberg, K. L.; Backvall, J.-E. J. Am. Chem. Soc. 1992, 114,
6858–6863.
(20) Cantat, T.; Agenet, N.; Jutand, A.; Pleixats, R.; Moreno-Manas,
(21) We ascribed this result to an inherent preference for carbonyla-
tion to occur adjacent to Si due to the shorter CꢀPd bond length. See:
Branchadell, V.; Moreno-Manas, M.; Pleixats, R. Organometallics 2002,
21, 2407–2412.
M. Eur. J. Org. Chem. 2005, 4277–4286.
Org. Lett., Vol. 13, No. 13, 2011
3457