Carboxylation and Mitsunobu reaction of amines to give carbamates: Retention vs inversion of configuration is substituent-dependent

Article abstract of DOI:10.1021/ol0491080

(Equation Presented) A mild method for the synthesis of carbamates from amino alcohols involves sequential carboxylation with carbon dioxide, followed by a Mitsunobu reaction. Unexpectedly, the stereochemical course of the Mitsunobu reaction is dependent on whether the carbamic acid intermediate is N-substituted with hydrogen (retention) or carbon (inversion).

Full text of DOI:10.1021/ol0491080

ORGANIC
LETTERS
2004
Vol. 6, No. 17
2885-2888
Carboxylation and Mitsunobu Reaction
of Amines to Give Carbamates:
Retention vs Inversion of Configuration
Is Substituent-Dependent
Christopher J. Dinsmore* and Swati P. Mercer
Department of Medicinal Chemistry, Merck Research Laboratories,
West Point, PennsylVania 19486
christopher_dinsmore@merck.com
Received May 14, 2004
ABSTRACT
A mild method for the synthesis of carbamates from amino alcohols involves sequential carboxylation with carbon dioxide, followed by a
Mitsunobu reaction. Unexpectedly, the stereochemical course of the Mitsunobu reaction is dependent on whether the carbamic acid intermediate
is N-substituted with hydrogen (retention) or carbon (inversion).
Cyclic carbamates are frequently employed as fragments in
biologically active materials for pharmaceutical and agri-
cultural use1 and as auxiliaries in useful synthetic transfor-
mations.2 These materials are most commonly prepared from
amino alcohols by carbonylation using phosgene or its
functional equivalent or by oxidative carbonylation using CO
and a catalyst. Using these methods, stereochemistry at the
oxygen-bearing center is retained in the product. Alterna-
tively, methods involving the cyclization of N-(hydroxy-
alkyl)carbamates, following activation of the hydroxyl group
for displacement, affect inversion of configuration at the
oxygen-bearing center. In a synthesis of 2-oxazolidinones
from ethanolamines by in situ N-carboxylation and Mit-
sunobu cyclodehydration reported by Kodaka et al.,3a reten-
tion of configuration was observed. Here, we have optimized
and expanded the scope of this reaction3b and have discovered
that either inversion or retention of stereochemistry unex-
pectedly occurs in a manner dictated by the amino alcohol
substituents. Mechanistic studies support an N-substituent-
dependent dual reaction manifold.
In the course of a recent drug discovery program, an
unintended result provided the stimulus for this study (eq
1). In an attempt to cyclize the hydroxy amide 1 under
Mitsunobu conditions4 to produce piperazinone 2 in ac-
cordance with close literature precedent,5 we were surprised
(3) (a) Kodaka, M.; Tomohiro, T.; Okuno, H. J. Chem. Soc., Chem.
Commun. 1993, 81. (b) Although the utility of this reaction was established,
the substrate scope in this study was limited to a small set of 2-amino
alcohols and the reported yields were based on HPLC analysis rather than
product isolation.
(4) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org. Prep.
Proced. Int. 1996, 28, 127.
(1) (a) Dyen, M. E.; Swern, D. Chem. ReV. 1967, 67, 197. (b) Brickner,
S. J.; Hutchinson, D. K.; Barbachyn, M. R.; Manninen, P. R.; Ulanowicz,
D. A.; Garmon, S. A.; Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford,
C. W.; Zurenko, G. E. J. Med. Chem. 1996, 39, 673.
(2) (a) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (b) Alger, D. J.;
Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835.
(5) Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R. P.; Reider, P. J.
Tetrahedron Lett. 1998, 39, 7459.
10.1021/ol0491080 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/24/2004

to find that no reaction had taken place. However, adding
the base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to the
reaction mixture triggered the accumulation of oxazolidinone
3 as the only observed product. We assumed that the source
of carbon in this reaction was CO2, likely present in the
nondegassed commercial anhydrous THF used as solvent.
The fixation of CO2 in a zwitterionic DBU-CO2 complex
is a known process, as is the subsequent transcarboxylation
of this complex and amines.6 Thus, in the errant reaction it
appeared that DBU promoted the carboxylation of amine 1
to produce a carbamic acid intermediate that underwent
Mitsunobu cyclization to provide 3.
Following from this and Kodaka’s earlier observations,3
we became interested in further expanding the scope of a
tandem amino alcohol carboxylation and Mitsunobu reaction
strategy for preparing carbamates. Given the mildness with
which an amino alcohol could be carboxylated to give a
carbamic acid intermediate (e.g., 4 f 5, Scheme 1), the
DBU, tributylphosphine, and di-tert-butyl azodicarboxylate
under a balloon of CO2 gas resulted in 55% conversion to
an equal mixture of the desired oxazolidinone 6a and the
hydrazine adduct 7 (entry 1). Using substoichiometric DBU
gave the same result (entry 2). These results implied the
incomplete formation of carbamic acid intermediate (e.g., 4
f 5), allowing Mitsunobu alkylation of di-tert-butyl hydra-
zine-1,2-dicarboxylate to compete (4a f 7). Gratifyingly,
pretreating 4a with DBU-CO2 for 45 min prior to adding
the n-Bu3P and DBAD completely suppressed the formation
of byproduct 7 (entry 3).8 Finally, increasing the number of
equivalents of Mitsunobu reagents (entries 4 and 5) led to
complete and clean conversion of 4a to 6a, isolated in 92%
yield after purification.
These reaction conditions were applied to a variety of
substrates (Table 2). After the successful cyclization of the
simple N-substituted ethanolamine 4a (entry 1), we were
gratified to find that a variety of substitution patterns are
accommodated in high-yielding reactions. The aniline 4b
gave N-phenyloxazolidinone 6b in almost quantitative yield
(entry 2). Primary amines gave N-unsubstituted oxazolidi-
nones with substituents at either the 4-position (6c, 6d), the
5-position (6e), or both (6e, 6f) in good yields. Consistent
with earlier work,3 primary amine substrates 4e-g produced
6e-g with retention of configuration at the oxygen-bearing
center (entries 5-7). However, this was not the case for
analogous substrates containing secondary amines, which
unexpectedly gave oxazolidinones with inVersion of config-
uration at the oxygen-bearing center.9 This stereochemical
divergence was most evident in comparisons of 4g with 4h
(entry 7 vs 8) and 4i with 4j (entry 9 vs 10). Further exploring
the scope of the reaction, we found that 4k produced the
bicyclic oxazolidinone 6k efficiently and that the 1,3-amino
alcohol 8 cyclized readily to provide the six-membered
oxazinone 9 in high yield.
Scheme 1
stereoselectivity of the Mitsunobu transformation (e.g., 5 f
6), and the potential for adapting the reaction to other
substrate types, this method was anticipated to compliment
existing carbamate synthesis strategies.
The conversion of aminoethanol 4a to oxazolidinone 6a
was chosen to optimize reaction conditions (Table 1).
Intrigued by the N-substitution-dependent stereochemical
divergence observed in these reactions, we undertook isotope
labeling experiments designed to differentiate pathways
involving either retention or inversion of configuration in
the Mitsunobu cyclization.10 In the reaction of a carbamic
acid 5 to produce 6 (Scheme 1), the use of 18O-labeled carbon
Table 1. Optimization of Reaction Conditions
(6) (a) Mizuno, T.; Okamoto, N.; Ito, T.; Miyata, T. Tetrahedron Lett.
2000, 41, 1051. (b) Perez, E. R.; da Silva, M. O.; Costa, V. C.; Rodrigues-
Filho, U. P.; Franco, D. W. Tetrahedron Lett. 2002, 43, 4091.
(7) Alternatively, the use of Cs2CO3, either in the presence or absence
of added CO2, met with limited success, affording only partial conversion
of 4a to 6a. For reports of amine carboxylation using carbonate salts, see:
(a) Butcher, J. K. Synlett 1994, 825. (b) Inesi, A.; Mucciante, V.; Rossi, L.
J. Org. Chem. 1998, 63, 1337. (c) Salvatore, R. N.; Chu, F.; Nagle, A. S.;
Kapxhiu, E. A.; Cross, R. M.; Jung, K. W. Tetrahedron 2002, 58, 3329.
(8) In this and related reactions a precipitate often appears during the
CO2 pretreatment period, implying that an alkylammonium N-alkylcarbamate
salt (RNH3+‚-O2CNHR) is formed. The extent to which complete conver-
sion to carbamic acid 5 occurs before n-Bu3P and DBAD are added is
unknown. See: Hampe, E. M.; Rudkevich, D. M. Tetrahedron 2003, 59,
9619.
load timea
CO2
equiv of
conversionb ratiob
entry
DBU/n-Bu3P/DBAD
(%)
6a :7
1
2
3
4
5
0 min
0 min
45 min
45 min
45 min
1.1/1.1/1.1
0.1/1.1/1.1
0.1/1.1/1.1
0.1/1.5/1.5
0.1/2.1/2.1
55
57
74
95
100
52:48
50:50
100:0
100:0
100:0
a Time for which solution of 4a and DBU are pretreated with CO2 via
balloon, before n-Bu3P/DBAD were added. b Determined by LC-MS (UV,
λ ) 215 nm).
(9) Kodaka et al.3a had found that although 4c and 4i were converted to
6c and 6i with retention of configuration, using Ph3P instead of n-Bu3P
promoted inversion in the case of 4c f 6c. No secondary amine substrates
were evaluated for stereochemical outcome.
(10) Retention of configuration in the Mitsunobu reaction: (a) Ahn, C.;
DeShong, P. J. Org. Chem. 2002, 67, 1754. (b) Smith, A. B.; Safonov, I.
G.; Corbett, R. M. J. Am. Chem. Soc. 2002, 124, 11102. (c) Liao, X.; Wu,
Y.; De Brabander, J. K. Angew. Chem., Int. Ed. 2003, 42, 1648.
Consistent with literature examples of amine carboxylation,
we selected acetonitrile as solvent and DBU-CO2 as the
carboxylation promoter.6,7 Subjecting 4a to 1 equiv each of
2886
Org. Lett., Vol. 6, No. 17, 2004

bamic acid group (configurational retention). As expected,
we found that the reaction of primary amine 4g in the
presence of C(18O)2 gave mono-18O-labeled oxazolidinone
10, along with 18O-tributylphosphine oxide (eq 2).11a In
contrast, the analogous secondary amine 4h produced doubly
labeled 11 with no isotope label in the tributylphosphine
oxide (eq 3).11b
Table 2. Examples of Carboxylation/Mitsunobu Cyclization
Reactiona
A proposed reaction mechanism (Scheme 2) accounts for
the N-substitution-dependent stereochemical divergence char-
acteristic of this carboxylation-Mitsunobu cyclization method.
After carboxylation of an amino alcohol with CO2 to produce
carbamic acid 12 the addition of n-Bu3P and DBAD to the
reaction mixture provides the ylide 13.12a,b,d Consistent with
literature evidence for the formation of acyloxyphosphoniun
ion intermediates during the traditional Mitsunobu reaction,12c,f,g
the carbamoyloxyphosphonium ion 14 is produced along with
hydrazide anion 15. If the nitrogen atom of 14 bears a carbon
substituent (R * H), then hydroxyl group deprotonation gives
the carbamoyloxyphosphonium alkoxide 16, which isomer-
izes to the oxyphosphonium carbamate intermediate 17.10a,12f
Cyclization of 17 with loss of n-Bu3PO gives the final
product 18 with inversion of configuration. The defining
characteristic responsible for retention vs inversion of
stereochemistry in this reaction is the availability of a car-
bamoyl N-H group. If the nitrogen atom of 14 bears a proton
(R ) H), then N-H deprotonation gives the zwitterion 19,
which collapses with loss of n-Bu3PO to give the isocyanate
20. The cyclization of a 2-(hydroxyethyl)isocyanate (e.g.,
20) to give an oxazolidinone (21) with retention of config-
uration is a known transformation,13 and would account for
(11) Reactions were conducted as per the standard conditions reported
in Supporting Information, substituting CO2 for C(18O)2. (a) The 1H NMR
(500 MHz) spectrum of the crude reaction mixture containing 10 was
identical to that for crude 6g. The position of the 18O atom in 10 is not
proven. HRMS (APCI): exact mass calcd for 10, C10H12NO18O (M + H+)
180.0905; found 180.0906. Calcd for n-Bu3P18O, C12H28P18O (M + H+)
a Reactions were run on a 0.5-2 mmol scale according to the conditions
described in Supporting Information. b Yield of isolated carbamate product
after purification. 1H NMR and mass spectra are in accordance with assigned
structures. Diastereomeric purities of relevant products were >95:5 by 1H
NMR spectroscopy. Unless otherwise indicated, relative and absolute
stereochemistry were confirmed by comparison to commercially available
materials or based on literature data. c Hydrolysis of 6f (20% KOH, EtOH,
60 °C) gave amino alcohol 4f, confirming structure. d Hydrolysis of 6j and
6k (20% KOH, EtOH, 60 °C) gave diastereomers of 4j and 4k, respectively.
1
221.1915; found 221.1915. (b) The H NMR (500 MHz) spectrum of the
crude reaction mixture containing 11 was identical to that for crude 6h.
HRMS (APCI): exact mass calcd for 11, C11H14N18O2 (M + H+) 196.1104;
found 196.1106. Calcd for n-Bu3PO, C12H28PO (M + H+) 219.1872; found
219.1875.
(12) Mechanistic studies of the Mitsunobu reaction: (a) Hughes, D. L.;
Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. J. J. Am. Chem. Soc. 1988,
110, 6487. (b) Camp, D.; Jenkins, I. D. J. Org. Chem. 1989, 54, 3045. (c)
Camp, D.; Jenkins, I. D. J. Org. Chem. 1989, 54, 3049. (d) Wilson, S. R.;
Perez, J.; Pasternak, A. J. Am. Chem. Soc. 1993, 115, 1994. (e) Hughes, D.
L.; Reamer, R. A. J. Org. Chem. 1996, 61, 2967. (f) Ahn, C.; Correia, R.;
DeShong, P. J. Org. Chem. 2002, 67, 1751. (g) McNulty, J.; Capretta, A.;
Laritchev, V.; Dyck, J.; Robertson, A. J. Angew. Chem., Int. Ed. 2003, 42,
4051.
dioxide should afford an 18O-labeled carbonyl group oxygen,
but the origin of the ring oxygen would depend on whether
cyclodehydration of 5 occurs with loss of an OH group from
the hydroxyl group (configurational inversion) or the car-
Org. Lett., Vol. 6, No. 17, 2004
2887

Scheme 2
the observed results. Consistent with the proposed interme-
carbon (inversion) or hydrogen (retention), owing to a
possible mechanistic divergence as evidenced by isotope
labeling studies.
diacy of isocyanate 20, benzylamine was subjected to the
carboxylation-Mitsunobu reaction conditions in acetonitrile-
1
d3 and was found by H NMR spectroscopy to produce
Acknowledgment. We thank Dr. David L. Hughes for
helpful comments, Joan Murphy for mass spectral data, and
Sandor Varga for NMR structure determinations.
benzyl isocyanate. An alternative mechanism for retention
of configuration involving the direct cyclization of a car-
bamoyloxyphosphonium alkoxide 16 (with R ) H) to give
21, although mechanistically feasible, is less satisfactory
since a role for the R-group in dictating the relative
cyclization rates of 16 (retention) vs 17 (inversion) is not
compelling.14
To further expand the scope of the tandem amine car-
boxylation and Mitsunobu reaction, we evaluated an inter-
molecular variant (eq 4). The conversion of the amine 22 to
the benzyl carbamate 23 in good yield and under mild
conditions indicates that the reaction is not restricted to
intramolecular cyclizations.
Supporting Information Available: Experimental pro-
1
cedures; characterization data for compounds; copies of H
NMR spectra for 6a-k, 9, and 23; and LCMS and HRMS
spectra for 10 and 11. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0491080
(13) (a) Matsushita, M.; Maeda, H.; Kodama, M. Tetrahedron Lett. 1998,
39, 3749. (b) Ariza, X.; Pineda, O.; Urpi, F.; Vilarassa, J. Tetrahedron Lett.
2001, 42, 4995.
(14) (a) Additionally, a mechanism for net retention of configuration
involving aziridine formation (A f B f C) and regioselective rearrange-
ment (C f D)14b is unsatisfactory, since the analogous pathway from E
would afford the same aziridine intermediate (E f F f C) and therefore
the same product distribution (C f D but not G). Since 4d and 4e provide
different products (6d and 6e respectively), an aziridine pathway is unlikely.
In summary, we have expanded the scope of a mild and
efficient carbamate synthesis method, involving in situ
carboxylation with carbon dioxide followed by Mitsunobu
cyclodehydration. Unexpectedly, the stereochemical course
of the Mitsunobu cyclization is dependent on whether the
carbamic acid intermediate is N-substituted with either a
(b) Banks, M. R.; Cadogan, J. I. G.; Gosney, I.; Hodgson, P. K. G.;
Thomson, D. E. J. Chem. Soc., Perkin Trans. 1 1991, 961.
2888
Org. Lett., Vol. 6, No. 17, 2004