A new multicomponent reaction catalyzed by a [Lewis acid] +[Co(CO)4]- catalyst: Stereospecific synthesis of 1,3-oxazinane-2,4-diones from epoxides, isocyanates, and CO

Article abstract of DOI:10.1021/ja069065d

The use of mechanistic information to develop a new, catalytic multicomponent reaction is described. The complex [(salph)AI(THF) ₂]⁺[Co(CO)₄]^- (1, salph = N,N′-o-phenylenebis(3,5-di-tert-butyl-salicylideneimine), THF = tetrahydrofuran), which is known to carbonylate epoxides, aziridines, and β-lactones, was used to catalyze the synthesis of 1,3-oxazinane-2,4-diones from epoxides, isocyanates, and CO. Under optimized conditions, the reaction was both selective and high-yielding. 1,3-Oxazinane-2,4-diones were synthesized from a variety of epoxides and isocyanates, including some epoxides that do not undergo simple ring-expansion carbonylation. The best results were obtained using highly electrophilic isocyanates. The mechanism of the multicomponent reaction was investigated using labeling and stereochemistry, and the data obtained were consistent with the 1-catalyzed formation of β-lactone and 1,3-oxazinane-2,4-dione from a common intermediate.

Full text of DOI:10.1021/ja069065d

Published on Web 06/12/2007
A New Multicomponent Reaction Catalyzed by a [Lewis
Acid]+[Co(CO)4]- Catalyst: Stereospecific Synthesis of
1,3-Oxazinane-2,4-diones from Epoxides, Isocyanates, and CO
Tamara L. Church, Christopher M. Byrne, Emil B. Lobkovsky, and
Geoffrey W. Coates*
Contribution from the Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell UniVersity, Ithaca, New York 14853-1301
Received December 18, 2006; E-mail: gc39@cornell.edu
Abstract: The use of mechanistic information to develop a new, catalytic multicomponent reaction is
described. The complex [(salph)Al(THF)2]+[Co(CO)4]- (1, salph ) N,N′-o-phenylenebis(3,5-di-tert-butyl-
salicylideneimine), THF ) tetrahydrofuran), which is known to carbonylate epoxides, aziridines, and
â-lactones, was used to catalyze the synthesis of 1,3-oxazinane-2,4-diones from epoxides, isocyanates,
and CO. Under optimized conditions, the reaction was both selective and high-yielding. 1,3-Oxazinane-
2,4-diones were synthesized from a variety of epoxides and isocyanates, including some epoxides that do
not undergo simple ring-expansion carbonylation. The best results were obtained using highly electrophilic
isocyanates. The mechanism of the multicomponent reaction was investigated using labeling and
stereochemistry, and the data obtained were consistent with the 1-catalyzed formation of â-lactone and
1,3-oxazinane-2,4-dione from a common intermediate.
Scheme 1. Proposed Mechanism of 1,3-Oxazinane-2,4-dione
Formation from Epoxides, Isocyanates, and CO. L ) Lewis base
(solvent, epoxide, etc.)
Introduction
Results obtained in mechanistic studies can lead to improve-
ments upon a catalytic system through the directed variation of
reaction conditions or catalyst architecture. Well-known reac-
tions such as enantioselective amination,1a olefin copolymeri-
zation,1b hydrolytic kinetic resolution,1c ring-opening metathesis
polymerization,1d asymmetric transfer hydrogenation,1e and
asymmetric dihydroxylation1f have benefited from such studies.
Over the past 5 years, our group has developed several catalysts
that carbonylate epoxides to â-lactones.2 These complexes, all
of the form [Lewis acid]+[Co(CO)4]-, vary considerably in
activity and substrate scope. With the goal of understanding
the differences between these catalysts, we have recently
examined the mechanism by which [(salph)Al(THF)2]+[Co-
(CO)4]- (1, Scheme 1, salph ) N,N′-o-phenylenebis(3,5-di-tert-
butylsalicylideneimine), THF ) tetrahydrofuran) carbonylates
epoxides (2) to â-lactones.3 During this study, we found an
(1) For some leading references, see: (a) Leitner, A.; Shekhar, S.; Pouy, M.
J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15506-15514. (b) Williams,
B. S.; Leatherman, M. D.; White, P. S.; Brookhart, M. J. Am. Chem. Soc.
2005, 127, 5132-5146. (c) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond,
D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360-1362. (d) Choi,
T.-L.; Grubbs, R. H. Angew. Chem., Int. Ed. 2003, 42, 1743-1746. (e)
Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102. (f) Wai, J.
S. M.; Marko´, I.; Svendson, J. S.; Finn, M. G.; Jacobsen, E. N.; Sharpless,
K. B. J. Am. Chem. Soc. 1989, 111, 1123-1125.
(2) (a) Getzler, Y. D. Y. L.; Mahadevan, V.; Lobkovsky, E. B.; Coates, G. W.
J. Am. Chem. Soc. 2002, 124, 1174-1175. (b) Mahadevan, V.; Getzler, Y.
D. Y. L.; Coates, G. W. Angew. Chem., Int. Ed. 2002, 41, 2781-2784. (c)
Getzler, Y. D. Y. L.; Mahadevan, V.; Lobkovsky, E. B.; Coates, G. W.
Pure Appl. Chem. 2004, 76, 557-564. (d) Schmidt, J. A. R.; Mahadevan,
V.; Getzler, Y. D. Y. L.; Coates, G. W. Org. Lett. 2004, 6, 373-376. (e)
Schmidt, J. A. R.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc.
2005, 127, 11426-11435. (f) Kramer, J. W.; Lobkovsky, E. B.; Coates,
G. W. Org. Lett. 2006, 8, 3709-3712.
opportunity to extend the capabilities of 1 to catalyze the
coupling of epoxides, isocyanates (3), and CO to form 1,3-
oxazinane-2,4-diones (ODs, 4). Our study of epoxide carbony-
lation by 1 indicated that the catalyst resting state is a
(â-aluminoxy)acylcobalt species (A, Scheme 1).3 In the rate-
determining step, A undergoes intramolecular cyclization to
â-lactone (Scheme 1, path I) via a Lewis base assisted
(3) Church, T. L.; Getzler, Y. D. Y. L.; Coates, G. W. J. Am. Chem. Soc.
2006, 128, 10125-10133.
9
8156
J. AM. CHEM. SOC. 2007, 129, 8156-8162
10.1021/ja069065d CCC: $37.00 © 2007 American Chemical Society

Stereospecific Synthesis of 1,3-Oxazinane-2,4-diones
A R T I C L E S
Scheme 2. Synthetic Uses of 1,3-Oxazinane-2,4-diones
Scheme 3. Precursors for the Synthesis of
1,3-Oxazinane-2,4-diones
ring closure, and regenerates the catalytic species. Leveraging
insight gained from our mechanistic studies, we reasoned that
prolonging the lifetime of intermediate A would enable its
intermolecular reaction with electrophiles such as isocyanates
(3).4 Reaction of the aluminum alkoxide of A with an isocyanate
(Scheme 1, path II), followed by ring closing, would yield a
1,3-oxazinane-2,4-dione (OD, 4). The net result would therefore
be a new, catalytic, multicomponent reaction (MCR) that forms
an OD.
ODs have found use as versatile synthetic intermediates
because they can be transformed, in stereospecific fashion, to a
variety of functional groups (Scheme 2). They have been used
in the synthesis of trisubstituted (E)-R,â-unsaturated amides
(Scheme 2, path a),5 which have in turn been elaborated to (E)-
R,â-unsaturated acids5a and to C-nucleoside precursors.5c Ka-
mino et al. have formed â-ketoesters from ODs (Scheme 2, path
b).6 In their total synthesis of the antibiotic neooxazolomycin,
Kende et al. used an OD to form a key â-hydroxy-acid
intermediate (Scheme 2, path c) that was difficult to produce
in enantiopure form by other methods.7 Finally, a functionalized
OD has been used in the enantioselective synthesis of a linear
polyol (Scheme 2, path d, R1 ) -CHdCHCH3, R2 ) -OBn).6
A number of synthetic methods for producing ODs have been
described, and these are summarized in Scheme 3. Several routes
are available for the conversion of â-hydroxy acids to ODs
(Scheme 3, path a). In general, these involve either (i) reaction
with an isocyanate or cyanate, and subsequent condensation,5c,8
or (ii) derivatization to a â-hydroxy amide, followed by reaction
with a carbonyl equivalent such as carbonyl diimidazole or
diphosgene.9 Though high-yielding in some cases, these syn-
theses require at least two steps and necessarily generate
byproducts. The latter is also true of OD syntheses in which a
â-hydroxy10 or â-metalloxy11 ester is condensed with an
isocyanate (Scheme 3, path b).12 Recently, OD synthesis has
been reported via the base-mediated (and, in some cases, metal-
catalyzed) rearrangement of â-hydroxy N-acyloxazolidin-2-ones,
which are the aldol products of N-acyloxazolidin-2-ones (Scheme
3, path c),5a,b,6,7,13 and by similar rearrangements.14 These
reactions, first reported in 1989,7b are stereoselective and with
careful choice of catalyst can produce highly stereopure ODs.
Barton and Liu have also reported an unrelated rearrangement
route to OD (Scheme 3, path d).15
In the particular case of benzo-fused ODs (Scheme 3,
-CHR1CHR2- ) -o-C6H4-), an excellent route from iodophenols
is available (Scheme 3, path e).16,17 Larksarp and Alper used a
palladium-coupling strategy to construct a series of benzox-
azinediones from 2-iodophenols, isocyanates, and CO.16 Though
this synthesis is restricted to benzoxazinedione formation, and
does produce a coupling byproduct, it proceeds in good yields
(9) (a) Kurz, T. Tetrahedron 2005, 61, 3091-3096. (b) Kolasa, T.; Miller, M.
J. Tetrahedron 1989, 45, 3071-3080. (c) Pintye, J.; Fu¨lo¨p, F.; Berna´th,
G.; Soha´r, P. Monatsch. Chem. 1985, 116, 857-868. (d) Shapiro, S. L.;
Rose, I. M.; Freedman, L. J. Am. Chem. Soc. 1957, 79, 2811-2814.
(10) (a) Boontheung, P.; Perlmutter, P. Tetrahedron Lett. 1998, 39, 2629-2630.
(b) Ohshiro, Y.; Ando, N.; Komatsu, M.; Agawa, T. Synthesis 1985, 276-
279.
(11) (a) Lapkin, I. I.; Semenov, V. I.; Saitkulova, G. F. Russ. J. Org. Chem.
1982, 18, 2189. (b) Saitkulova, F. G.; Semenov, V. I.; Lapkin, I. I. Khim.
Elementoorg. Soedin. 1982, 22-26.
(4) In related chemistry, the reaction of CO2, which is isoelectronic with
isocyanates, into Al-O bonds has been studied; see, for example: (a)
Chisholm, M. H.; Zhou, Z. J. Am. Chem. Soc. 2004, 126, 11030-11039.
(b) Aida, T.; Inoue, S. J. Am. Chem. Soc. 1983, 105, 1304-1309.
(5) (a) Feuillet, F. J. P.; Cheeseman, M.; Mahon, M. F.; Bull, S. D. Org. Biomol.
Chem. 2005, 3, 2976-2989. (b) Feuillet, F. J. P.; Robinson, D. E. J. E.;
Bull, S. D. Chem. Commun. 2003, 2184-2185. (c) Katagiri, N.; Hirose,
M.; Sato, M.; Kaneko, C. Chem. Pharm. Bull. 1989, 37, 933-938.
(6) Kamino, T.; Murata, Y.; Kawai, N.; Hosokawa, S.; Kobayashi, S.
Tetrahedron Lett. 2001, 42, 5249-5252.
(12) The electrochemically initiated condensation of a â-bromo amide with CO2
has been reported to form OD; however, a large amount of R,â-unsaturated
amide was also generated, possibly from decomposition of OD under the
reaction conditions; see: Casadei, M. A.; Cesa, S.; Moracci, F. M.; Inesi,
A.; Feroci, M. J. Org. Chem. 1996, 61, 380-383.
(13) (a) Feuillet, F. J. P.; Niyadurupola, D. G.; Green, R.; Cheeseman, M.; Bull,
S. D. Synlett 2005, 1090-1094. (b) Ito, Y.; Terashima, S. Tetrahedron
1991, 47, 2821-2834.
(14) (a) Yang, K.-S.; Chen, K. Org. Lett. 2002, 4, 1107-1109. (b) Abbas, T.
R.; Cadogan, J. I. G.; Doyle, A. A.; Gosney, I.; Hodgson, P. K. G.; Howells,
G. E.; Hulme, A. N.; Parsons, S.; Sadler, I. H. Tetrahedron Lett. 1997, 38,
4917-4920. (c) Narasaka, K.; Yamamoto, I. Tetrahedron 1992, 48, 5743-
5754.
(7) (a) Kende, A. S.; Kawamura, K.; DeVita, R. J. J. Am. Chem. Soc. 1990,
112, 4070-4072. (b) Kende, A. S.; Kawamura, K.; Orwat, M. J.
Tetrahedron Lett. 1989, 30, 5821-5824.
(8) (a) Shibuya, I.; Goto, M.; Shimizu, M.; Yanagisawa, M.; Gama, Y.
Heterocycles 1999, 51, 2667-2673. (b) Paik, S.; Carmeli, S.; Cullingham,
J.; Moore, R. E.; Patterson, G. M. L.; Tius, M. A. J. Am. Chem. Soc. 1994,
116, 8116-8125. (c) Vorbru¨ggen, H. Tetrahedron Lett. 1968, 9, 1631-
1634. (d) Testa, E.; Fontanella, L.; Cristiani, G.; Gallo, G. J. Org. Chem.
1959, 24, 1928-1936.
(15) Barton, D. H. R.; Liu, W. Chem. Commun. 1997, 571-572.
(16) Larksarp, C.; Alper, H. J. Org. Chem. 1999, 64, 9194-9200.
(17) The reaction of phenols with N-(chlorocarbonyl)isocyanate, followed by
intramolecular Friedel-Crafts reaction, has also been shown to form
benzoxazinediones; see: Hagemann, H. Angew. Chem., Int. Ed. Engl. 1977,
16, 743-750.
9
J. AM. CHEM. SOC. VOL. 129, NO. 26, 2007 8157

A R T I C L E S
Church et al.
Table 1. OD Formation in Various Solventsa
and was demonstrated for several phenols and isocyanates. This
reaction is formally a transition-metal-catalyzed MCR and is
among a number of transition-metal-catalyzed MCRs that have
been reported,18-20 though one of only a few to use CO as a
reactant.16,19a,20a,c,g The versatility of MCRs makes them attrac-
tive synthetic tools in organic and combinatorial chemistry.21
A modular, atom-economic, multicomponent synthesis of other
(i.e., non-benzo-fused) ODs from readily obtained starting
materials, such as the one illustrated in Scheme 1 (path II),
would be a versatile and convenient route to a useful synthetic
building block, and we therefore pursued its development.
Herein we describe a new, transition-metal-catalyzed MCR for
the synthesis of OD that stemmed from the mechanistic study
of epoxide carbonylation by 1.
lactoneb
ODb
[%]
selectivityc
[%]
entry
solvent
[%]
1
2
3
hexanes
pentane
toluene
8
5
20
40
24
10
17
14
13
4
83
82
33
32
28
28
5
4
diethyl ether
36
5
6
7
1,2-difluorobenzene
tert-butyl methyl ether
tetrahydropyran
36
34
74
8
acetonitrile
77
3
4
Results and Discussion
9
1,4-dioxane
>97
>97
91
91
83
ndd
ndd
ndd
ndd
ndd
0
0
0
0
10
11
12
13
2,5-dimethyltetrahydrofuran
1,2-dimethoxyethane
2-methyltetrahydrofuran
tetrahydrofuran
1. Reaction Development. As part of our study of â-lactone
formation by 1, we attempted the MCR under typical epoxide-
carbonylation conditions;3,22 little or no OD was detected.
However, if â-lactone and OD are formed from a common
intermediate A, then isocyanate incorporation will require
conditions that slow â-lactone ring closing relative to reaction
with isocyanate. Using the coupling of 1,2-epoxybutane (2a),
phenyl isocyanate (3a′), and CO as a representative reaction,
we screened conditions until we achieved >97% conversion to
the OD 4aa′ (eq 1), with no observed â-valerolactone (â-VL)
formation. Previously, we have found that Lewis basic solvents
0
a Reaction conditions: 0.010 mmol 1, 0.50 mmol each of 2a and 3a′,
300 psi CO, in 1.0 mL of dry solvent at 25 °C for 24 h. b Conversion with
respect to epoxide, determined by 1H NMR spectroscopy of crude reaction
mixture (see experimental section for details). â-VL and OD were the only
epoxide-derived products. c Value is equal to 100 × [OD]/([lactone] +
[OD]). d nd ) none detected.
epoxide-to-isocyanate ratio, and catalyst loading on the MCR.
Higher temperature, less catalyst, and extra equivalents of
isocyanate each produced more â-lactone, and in some cases
suppressed OD formation. Performing the reaction under lower
pressures of carbon monoxide caused significant isomerization
of epoxide to ketone, a side reaction also observed in carbo-
nylation chemistry.2,24 On the basis of the results of these
optimization reactions, a standard set of conditions was imple-
mented for test-scale OD syntheses: hexanes solution (1 mL,
[2] ) 0.25 M), 1/2/3 ) 1:25:25, 800 psi CO, 25 °C, 48 h.
2. Substrate Scope. Having optimized the yield of 4aa′ from
the MCR (see eq 1), we sought to establish this reaction as a
general route for the coupling of epoxides, isocyanates, and CO
to build a family of structurally and functionally diverse ODs.
While CO is structurally invariable, there are many readily
available epoxides and isocyanates to which this system is
applicable, and we varied each component in turn.
such as THF and DME accelerate â-lactone formation (Scheme
1, path I);3 accordingly, MCRs attempted in these solvents
yielded â-lactone but no OD (Table 1, entries 9-13). The use
of nonpolar, non-coordinating solvents (in which â-lactone
formation is slow) enabled OD formation, and hexanes gave
the best selectivity for OD among the solvents screened (Table
1, entry 1).23 We also examined the effects of temperature,
We found that the nature of the isocyanate had a strong
influence on the reaction (Table 2). Reactions performed with
aryl isocyanates having varying para substituents revealed a
direct correlation between the electrophilicity of the isocyanate
and the selectivity of OD formation. Similarly to the unsubsti-
tuted PhNCO (entry 1), aryl isocyanates with electron-
withdrawing groups in the para position (entries 2-4) gave
complete conversion of epoxide to OD, with no â-lactone
formation. In fact, the very electrophilic isocyanate 3b′ reacted
completely with 2a and CO in only 12 h under the standard
reaction conditions. Conversely, the presence of electron-
donating groups (entries 5 and 6) reduced catalytic efficiency,
lowering both selectivity and overall conversion of epoxide.
These observations are consistent with the pathway shown in
Scheme 1, as more electrophilic isocyanates react quickly with
A and therefore allow path II to dominate. Despite this, we
examined the MCR with alkyl isocyanates (entries 7 and 8) to
(18) A recent issue of Tetrahedron was devoted to multicomponent reactions:
Tetrahedron 2005, 61, 11299-11519.
(19) For reviews of transition-metal-mediated cycloaddition and heterocycle
formation, including multicomponent examples: (a) Nakamura, I.; Yama-
moto, Y. Chem. ReV. 2004, 104, 2127-2198. (b) Fru¨hauf, H.-W. Chem.
ReV. 1997, 97, 523-596. (c) Lautens, M.; Klute, W.; Tam, W. Chem. ReV.
1996, 96, 49-92.
(20) For some representative examples, see references 16, 18, and: (a) Kondo,
T.; Nomura, M.; Ura, Y.; Wada, K.; Mitsudo, T.-A. J. Am. Chem. Soc.
2006, 128, 14816-14817. (b) Siamaki, A. R.; Arndtsen, B. A. J. Am. Chem.
Soc. 2006, 128, 6050-6051. (c) Wegner, H. A.; de Meijere, A.; Wender,
P. A. J. Am. Chem. Soc. 2005, 127, 6530-6531. (d) Kamijo, S.; Jin, T.;
Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 7786-7787. (e)
Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880-2881.
(f) Goodman, S. N.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41,
4703-4705. (g) Muraoka, T.; Kamiya, S.; Matsuda, I.; Itoh, K. Chem.
Commun. 2002, 1284-1285. (h) Dghaym, R. D.; Dhawan, R.; Arndtsen,
B. A. Angew. Chem., Int. Ed. 2001, 40, 3228-3230. (i) Montgomery, J.
Acc. Chem. Res. 2000, 33, 467-473.
(21) For several useful reviews, see: (a) Orru, R. V. A.; de Greef, M. Synthesis
2003, 10, 1471-1499. (b) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed.
2000, 39, 3168-3210. (c) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt,
P. Chem.sEur. J. 2000, 6, 3321-3329. (d) Armstrong, R. W.; Combs, A.
P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996,
29, 123-131. (e) Posner, G. H. Chem. ReV. 1986, 86, 831-844.
(22) Typical epoxide carbonylation conditions: 1,2-epoxybutane, 1.25 M in THF,
[epoxide]/[1] ) 100:1, PCO ) 300 psi, T ) 25 °C.
(23) As 1 is only sparingly soluble in hexanes, stirring was essential to the
success of the reaction.
(24) Molnar, F.; Luinstra, G. A.; Allmendinger, M.; Rieger, B. Chem.sEur. J.
2003, 9, 1273-1280.
9
8158 J. AM. CHEM. SOC. VOL. 129, NO. 26, 2007

Stereospecific Synthesis of 1,3-Oxazinane-2,4-diones
A R T I C L E S
Table 2. Formation of 1,3-Oxazinane-2,4-diones Using Various
Table 3. Formation of 1,3-Oxazinane-2,4-diones Using Various
Isocyanatesa
Monosubstituted Epoxidesa
â
[%]
-VLb
ODb
[%]
selectivityc
[%]
entry
R3
OD
lactoneb
[%]
ODb
[%]
selectivityc
[%]
ndd
ndd
ndd
ndd
20
14
19
15
>97
>97
>97
>97
60
42
39
13
>97
>97
>97
>97
75
75
67
46
entry
R1
OD
1
2
3
4
Ph
4aa′
4ab′
4ac′
4ad′
4ae′
4af′
4ag′
4ah′
4-O2N-C6H4
4-F-C6H4
4-Br-C6H4
4-MeO-C6H4
4-Me-C6H4
PhCH2
1
2
3
4
5
6
7
8
9
10
11e
12
13
14
Et
Me
4ab′
4bb′
4cb′
4db′
4eb′
4fb′
4gb′
4hb′
4ib′
4jb′
4kb′
4lb′
4mb′
4nb′
ndd
ndd
ndd
3
>97
>97
>97
94
10
>97
94
>97
80
97
>97
>97
>97
97
53
>97
94
>97
88
97
>97
>97
>97
naf
nBu
c-C6H11
tBu
5
6
9
7e
8e
(CH2)2CHdCH2
CH2OCH2CHdCH2
CH2OnBu
ndd
6
Et
2
8
3
a Reaction conditions: 0.010 mmol 1, 0.25 mmol each of 2a and 3, 800
psi CO, in 1.0 mL of dry hexanes at 25 °C for 48 h. b Conversion with
respect to epoxide, determined by 1H NMR spectroscopy of crude reaction
mixture (see experimental section for details). â-VL and OD were the only
epoxide-derived products. c Value is equal to 100 × [OD]/([lactone] +
[OD]). d nd ) none detected. e Some isocyanate was converted to the
corresponding trialkyl isocyanurate.
CH2OBn
t
CH2OSiMe2 Bu
CH2Cl
ndd
ndd
ndd
ndd
70
n
(CH2)2CO2 Pr
>97
>97
ndd
(CH2)3OC(O)nPr
Ph
a Reaction conditions: 0.010 mmol 1, 0.25 mmol each of 2 and 3b′,
800 psi CO, in 1.0 mL of dry hexanes at 25 °C for 12 h. b Conversion with
respect to epoxide, determined by 1H NMR spectroscopy of crude reaction
mixture (see experimental section for details). Lactone and OD were the
only epoxide-derived products. c Value is equal to 100 × [OD]/([lactone]
+ [OD]). d nd ) none detected. e Reaction time was 24 h. f na ) not
applicable.
expand the functional diversity of this component. As expected,
OD formation and selectivity dropped precipitously because of
the reduced electrophilicity of the isocyanate reaction compo-
nent. In addition, these reactions generated tribenzyl and triethyl
isocyanurate, respectively. The production of these cyclic trimers
suggests that electron-rich isocyanates may interact with 1
independently of epoxide. Fortunately, in most cases where side
reactions accompanied the MCR, the product OD could be
readily separated from the reaction mixture.25,26
Scheme 4. MCR of 2o, 3b′, and CO to Yield 4ob′, and a Possible
Mechanism for Its Decay to Form the Crotonamide 5 (LA+
Lewis Acid)
)
We also incorporated an array of monosubstituted epoxides
into ODs (Table 3). Variation of the epoxide component not
only demonstrates the versatility of this MCR, it also diversifies
the library of ODs synthesized by this method. As 2a, 3b′, and
CO were converted to 4ab′ after only 12 h, we used isocyanate
3b′, and a reaction time of 12 h, for test reactions with epoxides.
OD formation was much less sensitive to the identity of the
epoxide than of the isocyanate; high yield and selectivity were
obtained in almost all cases. For example, ODs were synthesized
from epoxides having shorter (entry 2) and longer (entry 3) alkyl
chains than 2a, and selectivity was only slightly reduced when
a secondary alkyl substituent was present (entry 4). However,
yield and selectivity suffered when the epoxide bore a tertiary
alkyl substituent (entry 5). A pendant alkene (entry 6) was also
successfully incorporated into a 1,3-oxazinane-2,4-dione. ODs
with ether side chains were also produced in high yield (entries
7-10), though they were accompanied by small amounts of
â-lactone. The MCR with epichlorohydrin (entry 11) was
selective, but slower than that with other epoxides; it was only
49% complete after 12 h and only 70% complete after 24 h.
Ester functionalities were also incorporated effectively into ODs
(entries 12 and 13). Unfortunately, styrene oxide (entry 14)
proved a problematic substrate, yielding neither â-lactone nor
OD under these conditions.27
1
reaction of 2o with 3b′ and CO, the H NMR spectrum of the
crude reaction mixture showed a trace of â-lactone, along with
a major product whose spectrum was similar to those of related
ODs (multiplets at 3.01, 3.04, and 4.94 ppm; pseudodoublets
at 7.42 and 8.34 ppm). However, efforts to isolate this compound
uniformly returned (E)-4-(4-nitrophenylamino)-4-oxobut-2-enyl
The attempted formation of OD from glycidyl butanoate (2o,
Scheme 4) gave an unusual result. Following the test-scale
1
butanoate, 5 (Scheme 4). As OD 4ob′ appeared by H NMR
spectroscopy to be the initial product of the reaction, we
conclude that 5 was produced by its decomposition. Though
other ODs can be induced to form crotonamides in the presence
(25) See Supporting Information for details.
(26) We were unable to separate OD 4ah′ from triethylisocyanurate.
(27) Though most of the epoxide was unchanged following the reaction, small
amounts of styrene and unidentified compounds were produced.
9
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A R T I C L E S
Church et al.
Table 4. Formation of 1,3-Oxazinane-2,4-diones Using
As a complement to the test-scale syntheses, we performed
the MCR with two substrates on a larger scale and isolated the
OD products. The reaction of 4-bromophenyl isocyanate (3d′,
1.25 mmol), propylene oxide (2b, 1.25 mmol), catalyst 1 (0.050
mmol), and CO (800 psi) in 5.0 mL of dry hexanes yielded
0.250 g of pure 4bd′ after crystallization, representing 70%
yield. Similarly, the MCR of 2a, 3a′, and CO on the 2.5-mmol
scale gave pure 4aa′ in 71% yield.
Disubstituted Epoxidesa
lactoneb
[%]
ODb
[%]
selectivityc
[%]
3. Mechanism. Having found the 1-catalyzed MCR of
epoxides, isocyanates, and CO to be a useful and general
reaction, we carried out several experiments to probe its
mechanism. First, to rule out OD formation via a â-lactone
intermediate rather than directly from the starting materials, we
attempted the synthesis of OD from a â-lactone. When â-VL
was combined with isocyanate 3b′, catalyst 1, and CO, no
reaction occurred, even after 48 h at 60 °C. This is in accord
with the prior observations that 1 reacts with â-lactone more
slowly than with epoxide and that 1 reacts with â-lactone at
the â carbon (rather than at the carbonyl group, which would
be required for OD formation).33 As OD is not generated from
â-lactone under the reaction conditions, â-lactone cannot be an
intermediate in OD formation.
entry
R1, R2
OD
1
cis-Me2
trans-4pb′
cis-4pb′
trans-4qb′
trans-4rb′
trans-4sb′
11
89
19
>97
>97
nde
89
>97
>97
>97
naf
2d
3
trans-Me2
cis-(CH2)3-
cis-(CH2)4-
cis-(CH2)6-
nde
nde
nde
nde
4
5
a Reaction conditions: 0.010 mmol 1, 0.25 mmol each of 2 and 3b′,
800 psi CO, in 1.0 mL of dry hexanes at 25 °C for 12 h. b Conversion with
respect to epoxide, determined by 1H NMR spectroscopy of crude reaction
mixture (see experimental section for details). Lactone and OD were the
only epoxide-derived products. c Value is equal to 100 × [OD]/([lactone]
+ [OD]). d Reaction was run for 24 h. e nd ) none detected. f na ) not
applicable.
of heat or base,28 only 4ob′ undergoes this reaction during
purification attempts. Notably, the ester-substituted ODs 4lb′
and 4mb′ do not form crotonamide under these conditions, as
both were easily isolated. On the basis of the critical role played
by the position of the ester substituent in the elimination, we
propose that it participates in the reaction, possibly through
anchimeric assistance.29,30 A plausible mechanism for this
process is shown in Scheme 4; we have previously observed a
related rearrangement in â-lactones produced from glycidyl
esters.2e
OD was also formed from 1,2-disubstituted epoxides (Table
4). Both cis- and trans-2,3-epoxybutane were converted to OD
(entries 1 and 2) with good selectivity. The former, cis-2p, was
completely converted to product in 12 h, whereas trans-2p
reacted very slowly, producing only a trace of OD over the same
period. Even after 24 h, only 19% of the epoxide was converted
to OD. The alicyclic epoxides of cyclopentene (entry 3) and
cyclohexene (entry 4) were converted cleanly to OD after 12
h. Cyclooctene oxide (entry 5), however, was unchanged
following the reaction. The success of the MCR with cyclo-
pentene oxide and cyclohexene oxide is significant because the
â-lactones from cyclohexene oxide and the trans-ring-fused
â-lactone from cyclopentene oxide have not been prepared by
epoxide carbonylation. The trans-ring-fused â-lactones of these
epoxides, in particular, are inaccessible under most circum-
stances.31,32 As ODs can be converted to many of the same
moieties as â-lactones (for example, â-hydroxyacids, Scheme
2c), this MCR offers a route to structures inaccessible via
â-lactone chemistry.
The CO-derived carbonyl group in the product heterocycle
was located using the MCR of 2a, 3b′, and 13CO to form 4ab′-
13C. The 1H NMR spectrum of this compound showed additional
splitting of both methylene signals compared to that of unlabeled
4ab′. The coupling constants for these splittings were 6.4 and
2
7.4 Hz, consistent with a JC-H value.34,35 Further, in the 13C
NMR spectrum of 4ab′-13C, the resonance at 167.8 ppm was
very large, indicating the presence of the isotope label. This
chemical shift is consistent with an amide carbonyl but
downfield of the range for a carbamate carbonyl.34 Both of these
results suggest that CO is incorporated adjacent to the less
substituted C atom of the OD, consistent with the reaction
pathway shown in Scheme 1.
Crucial to the utility of ODs as synthetic intermediates is the
ability to form them with a high degree of stereocontrol. Thus
the stereochemical outcome of the new MCR informs on its
utility as well as its mechanism. The relative stereochemistry
of the ODs formed from disubstituted epoxides was assigned
on the basis of 1H NMR spectroscopic coupling constants. The
pair of methine protons in compounds formed from the reaction
of CO and 3b′ with cis-disubstituted epoxides cis-2p, 2q, and
2r split one another with 3J ) 12 ( 1 Hz, consistent with trans
ring fusion, and with coupling constants for previously char-
acterized trans-5,6-disubstituted 1,3-oxazinane-2,4-diones.13b,15
3
Conversely, those in the OD produced from trans-4pb′ had J
) 4.1 Hz, consistent with a cis-5,6-disubstituted 1,3-oxazinane-
2,4-dione.13b Therefore in all cases, cis/trans stereochemistry
was interconverted during OD formation. For the case of (rac)-
4qb′, which was produced from the coupling of isocyanate 3b′,
cyclopentene oxide, and CO, this result was confirmed by X-ray
analysis (Figure 1).25 The trans ring fusion evident in this
structure suggests that only one stereocenter of the starting
(28) For example, when 4ab′ was heated to 90 °C in CDCl3 for 4 days, 50%
conversion to the elimination product was observed. The OD 4bb′ was
completely converted to N-(4-nitrophenyl)-(E)-crotonamide after 3 hours
at 0 °C in the presence of NaOsBu.
(29) Winstein, S.; Buckles, R. E. J. Am. Chem. Soc. 1942, 64, 2780-2786.
(30) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry, 5th ed.;
John Wiley & Sons, Inc.: New York, 2001.
(31) Using semiempirical methods, we have calculated the trans-ring-fused
â-lactone from cyclopentene oxide to be approximately 45 kcal/mol higher
in energy than the cis-ring-fused form (see ref 2e).
(32) Sander, Maguire, and co-workers have reported observing trans-ring-fused
7-oxabicyclo[4.2.0]octan-8-one in an argon matrix using IR spectroscopy;
see: Sander, W.; Strehl, A.; Maguire, A. R.; Collins, S.; Kelleher, P. G.
Eur. J. Org. Chem. 2000, 3329-3335.
(33) Getzler, Y. D. Y. L.; Kundnani, V.; Lobkovsky, E. B.; Coates, G. W. J.
Am. Chem. Soc. 2004, 126, 6842-6843.
(34) Silverstein, R. M.; Webster, F. X. Spectrometric Identification of Organic
Compounds, 6 ed.; John Wiley & Sons, Inc.: New York, 1998.
2
3
(35) Though JC-H and JC-H values are generally comparable in magnitude,34
the methylene unit of the 1,3-oxazinane-2,4-dione ring is directly adjacent
to one carbonyl group and three carbons from the other. Thus the JC-H at
2
4
this position is expected to be a JC-H or a JC-H value.
9
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Stereospecific Synthesis of 1,3-Oxazinane-2,4-diones
A R T I C L E S
by 1 and have attributed this to their ability to stabilize the
aluminum cation formed upon ring closure.3 Isocyanates may
also be able to fulfill this role, increasing â-lactone production.
Because isocyanate concentration impacts both competing
pathways in this reaction, a careful balance is necessary for
selectivity. Additionally, more electron-rich isocyanates are
doubly disadvantaged for OD formationsthey react more slowly
with intermediate A and more effectively accelerate â-lactone
formation.
Figure 1. ORTEP structure of OD (rac)-4qb′ showing the trans stereo-
chemistry of ring fusion. Thermal ellipsoids drawn at the 30% probability
level.
Conclusion
A mechanistic study of epoxide carbonylation to â-lactones
by [(salph)Al(THF)2]+[Co(CO)4]- led us to the development
of a new three-component reaction that combines epoxides,
isocyanates, and carbon monoxide to form 1,3-oxazinane-2,4-
diones. The reaction is atom-economic, as all of the atoms in
the starting materials are present in the product. With careful
choice of reaction conditions, ODs can be selectively produced
in high yield using this method. The reaction tolerates a variety
of substitutions on the epoxide component, and is fastest and
most selective when electron-poor isocyanates are employed.
Further, the coupling is stereospecific, with configuration being
retained R to the ring oxygen, and inverted â to the ring oxygen.
Thus enantiopure ODs can be formed using the appropriate
chiral epoxide. Stereochemical and labeling evidence support
the formation of both â-lactone and OD from a common
intermediate. Larksarp and Alper have previously demonstrated
a catalytic, carbonylative MCR route to benzoxazines,16 and the
present method provides an ideal complement to this reaction.
We are currently working toward including new substrate classes
in the scope of this reaction.
Figure 2. ORTEP structure of (R)-4bd′ showing the absolute stereochem-
istry at the stereogenic center. Thermal ellipsoids are drawn at the 40%
probability level.
epoxide was inverted, as has been shown to be the case in
â-lactone formation catalyzed by 1.2a-c,36
The absolute stereochemistry of a monosubstituted OD was
investigated using the reaction of (R)-propylene oxide ((R)-2b),
4-bromophenyl isocyanate (3d′), and CO. Following the MCR
of these compounds, the product OD, 4bd′, was crystallized
from EtOAc and examined by X-ray diffraction (Figure 2). The
OD had (R) stereochemistry, indicating that the MCR occurs
with retention of stereochemistry at the stereogenic carbon. As
the X-ray structure of 4qb′ showed that OD is formed with
inversion at a single C atom of the epoxide, the inverted center
in the product OD must be the one â to the oxygen atom,
adjacent to the inserted carbon monoxide (eq 2). These results
Experimental Procedures
General Considerations. All air- and/or water-sensitive reactions
were carried out under dry nitrogen using an MBraun UniLab drybox
or standard Schlenk line techniques. All syringes were gastight and
were dried overnight in a glassware oven prior to use. NMR spectra
were recorded on Varian Mercury 300 (1H, 300 MHz; 13C, 75 MHz),
Bruker ASX 300 (1H, 300 MHz; 13C, 75 MHz), or Varian INOVA-
400 (1H, 400 MHz; 13C, 100 MHz) spectrometers and referenced versus
residual nondeuterated solvent shifts. HRMS analyses were performed
on a JEOL GCMate II, using EI+ ionization. X-ray crystallographic
data were collected using a Bruker X8 APEX II (Mo KR, λ ) 0.71073
Å) at 173(2) K, and frames were integrated with the Bruker SAINT+
program. The absolute configuration of (R)-3-(4-bromophenyl)-6-
methyl-1,3-oxazinane-2,4-dione (R)-4bd′ was determined by refining
an enantiomorph-sensitive Flack parameter x ) 0.007(8) using 1341
measured Friedel pairs.37
are consistent with the stereochemical outcome of epoxide
carbonylation to â-lactone by 1,2a-c and support the formation
of â-lactone and OD from a common intermediate, A.
Though a kinetic analysis of the MCR was not carried out,
the trend of more electrophilic isocyanates returning higher
selectivity for OD suggests that the reaction of intermediate A
with isocyanate is rate-determining. However, in the screening
reactions described above, the selectivity for OD 4aa′ was not
improved by extra equivalents of isocyanate; rather, the yields
of both â-lactone and OD increased. Though an increase in OD
formation at higher isocyanate concentration is consistent with
a rate-determining isocyanate incorporation, the increased
â-lactone production is surprising. We have previously noted
that Lewis bases such as THF accelerate â-lactone formation
Materials. Hexanes, pentane, toluene, and diethyl ether were dried
and degassed over columns of alumina and copper.38 Tetrahydrofuran
was dried over columns of alumina and degassed by freeze-pump-
thaw cycles. 1,2-Dimethoxyethane, 1,4-dioxane, 2-methyltetrahydro-
furan, 2,5-dimethyltetrahydrofuran, and tetrahydropyran were refluxed
with and distilled from Na/benzophenone under atmospheric pressure
of N2, and degassed by freeze-pump-thaw cycles. tert-Butyl methyl
ether was stirred with Na/benzophenone, degassed by freeze-pump-
thaw cycles, and vacuum transferred. Acetonitrile was stirred with CaH2,
degassed by freeze-pump-thaw cycles, and vacuum transferred. 1,2-
Difluorobenzene was stirred with P2O5, degassed by freeze-
pump-thaw cycles, and vacuum transferred. The catalyst
(36) An exception to this trend is observed in â-lactone formation from
cyclopentene oxide. Whereas carbonylation of this cis epoxide to the trans
â-lactone has not been observed, it has been carbonylated to the cis
â-lactone.2e This reaction was proposed to occur via a cationic intermediate.
(37) Flack, H. D. Acta Cryst. 1983, A39, 876-881.
(38) Glass Contour Systems, Laguna Beach, CA, 92652.
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J. AM. CHEM. SOC. VOL. 129, NO. 26, 2007 8161

A R T I C L E S
Church et al.
[(salph)Al(THF)2]+[Co(CO)4]- (1, salph ) N,N′-o-phenylenebis(3,5-
di-tert-butylsalicylideneimine), THF ) tetrahydrofuran) was prepared
according to the literature procedure.2a Labeled 13CO was purchased
from Cambridge Isotope Labs, Inc., with the aid of a research grant,
and used as received. Cyclohexylethylene oxide (2d),39 tert-butyl
ethylene oxide (2e),40 n-propyl 4,5-epoxypentanoate (2l),2e and 4,5-
epoxypentyl butyrate (2m)2e were prepared according to published
procedures. (R)-PO ((R)-2b) was isolated from rac-PO (rac-2b) using
the method of Jacobsen.41 Liquid epoxides were stirred with CaH2 and
vacuum distilled prior to use, and solid epoxides were used as received.
Liquid isocyanates were dried over P2O5 and vacuum transferred,
whereas solids were used as received. â-VL42 was prepared from 1,2-
epoxybutane and CO using catalyst 1, washed through Celite with
diethyl ether, and distilled. It was then stirred for 1 week with 4-Å
molecular sieves, vacuum transferred onto CaH2, stirred for 1 week,
and vacuum transferred.
of the epoxide 2 and the isocyanate 3, and 1.0 mL dry hexanes. Once
all chambers were loaded, the reactor was sealed, removed from the
glovebox, and pressured to 800 psi with CO. After stirring at 25 °C
for the indicated time, the reactor was placed on dry ice and vented
slowly. Crude reaction mixtures were analyzed by H NMR spectros-
copy using the same method as for the solvent screening reactions.
1
Representative Procedure for the Synthesis of 4bd′. A 60-mL,
stainless steel, high-pressure Parr reactor was dried at 120 °C under
vacuum for 16 h, refilled with N2, and brought into a nitrogen glovebox.
Catalyst 1 (43.7 mg, 0.050 mmol) was weighed into an oven-dried
glass insert, and a stir bar was added. Dry hexanes (5.0 mL), 2b (88.0
µL, 1.26 mmol), and 3d′ (248 mg, 1.25 mmol) were added. The reactor
was sealed, removed from the glovebox, and pressured with 800 psi
CO. After stirring at 25 °C for 48 h, the reactor was vented slowly.
The reaction mixture was poured into a round-bottom flask, rinsed with
CH2Cl2, and the solvents were removed by rotary evaporation. The
resulting solid was washed through silica with ethyl acetate to remove
catalyst residue, and the filtrate was concentrated under reduced
pressure. It was then dissolved in CH2Cl2, and layered with hexanes to
afford 0.250 g of crystalline 3-(4-bromophenyl)-6-methyl-1,3-oxazi-
Procedure for the Screening of Solvents for OD Formation. A
custom-fabricated, six-chamber, high-pressure reactor, which has been
described,2d,33 was used for all test-scale syntheses. The reactor was
dried at 120 °C under vacuum for 16 h, refilled with N2, and brought
into a glove box. Each chamber was charged with 0.010 mmol of
catalyst 1, 0.50 mmol each of epoxide and phenyl isocyanate, and 1.0
mL dry solvent. Once all chambers were loaded, the reactor was sealed,
removed from the glovebox, and pressured to 300 psi with CO. After
stirring at 25 °C for 24 h, the reactor was placed on dry ice and vented
1
nane-2,4-dione, 4bd′ (isolated yield ) 70%). H NMR (CDCl3, 300
3
2
2
MHz): δ 1.56 (2 H, d, J ) 6.3 Hz), 2.81 (1 H, dd, J ) 17.1 Hz, J
) 11.1 Hz), 2.94 (1 H, dd, 2J ) 17.1 Hz, 2J ) 3.6 Hz), 4.81 (1 H, m),
7.07 (2 H, pseudo-d), 7.59 (2 H, pseudo-d). 13C NMR (CDCl3, 75
MHz): δ 20.4, 38.6, 71.3, 123.3, 130.2, 132.8, 133.7, 151.2, 167.9.
HRMS (EI): m/z calcd (C11H10NO379Br), 282.9831; found, 282.9834;
calcd (C11H10NO381Br), 284.9824; found, 284.9825.
1
slowly. Crude reaction mixtures were analyzed by H NMR spectros-
copy as follows: to each reaction mixture, 1-2 mL of CDCl3 were
added to dissolve all of the products, as most ODs were insoluble in
hexanes. An aliquot of the resulting solution was filtered through Celite
545 to remove catalyst residue, and the sample was diluted with CDCl3.
Acknowledgment. This work was generously supported by
the National Science Foundation (Grant CHE-0243605) and the
Department of Energy (DE-FG02-05ER15687). T.L.C. thanks
the Natural Sciences and Engineering Research Council (NSERC)
Canada for a Postgraduate Fellowship. We are grateful to
Cambridge Isotope Laboratories, Inc. for a research grant to
aid in the purchase of 13CO. We are indebted to Dr. J. Schmidt
and Mr. D. Treitler for epoxide synthesis and to Dr. I. Keresztes
for performing the HRMS analyses.
1
The H NMR spectrum of this solution was recorded, and the signals
for OD, â-lactone, and epoxide were integrated. Conversion to OD
was calculated by determining the ratio of [OD] versus the sum of
[OD], [lactone], and [epoxide].
Procedure for the Test-Scale Formation of ODs. Test-scale
synthesis of ODs was performed in a manner similar to the solvent-
screening reactions. The reactor was dried at 120 °C under vacuum
for 16 h, refilled with N2, and brought into a nitrogen glovebox. Each
chamber was charged with 0.010 mmol of catalyst 1, 0.25 mmol each
Supporting Information Available: Isolation and character-
ization details and 1H NMR spectra of new compounds; crystal
structure data for compounds (rac)-4qb′ and (R)-4bd′. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(39) Vyvyan, J. R.; Meyer, J. A.; Meyer, K. D. J. Org. Chem. 2003, 68, 9144-
9147.
(40) Mischitz, M.; Kroutil, W.; Wandel, U.; Faber, K. Tetrahedron: Asymmetry
1995, 6, 1261-1272.
(41) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997,
277, 936-938.
(42) Noels, A. F.; Herman, J. J.; Teyssie, P. J. Org. Chem. 1976, 41, 2527-
2531.
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8162 J. AM. CHEM. SOC. VOL. 129, NO. 26, 2007