N-methylimidazole-catalyzed synthesis of carbamates from hydroxamic acids via the lossen rearrangement

Article abstract of DOI:10.1021/ol303424b

An efficient, one-pot, N-methylimidazole (NMI) accelerated synthesis of aromatic and aliphatic carbamates via the Lossen rearrangement is reported. NMI is a catalyst for the conversion of isocyanate intermediates to the carbamates. Moreover, the utility of arylsulfonyl chloride in combination with NMI minimizes the formation of often-observed hydroxamate-isocyanate dimers during the sequence. Under the present conditions, lowering of temperatures is also possible, enabling a mild protocol.

Full text of DOI:10.1021/ol303424b

ORGANIC
LETTERS
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Vol. XX, No. XX
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N‑Methylimidazole-catalyzed Synthesis
of Carbamates from Hydroxamic Acids
via the Lossen Rearrangement
Sabesan Yoganathan and Scott J. Miller*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut
06520, United States
scott.miller@yale.edu
Received December 14, 2012
ABSTRACT
An efficient, one-pot, N-methylimidazole (NMI) accelerated synthesis of aromatic and aliphatic carbamates via the Lossen rearrangement is
reported. NMI is a catalyst for the conversion of isocyanate intermediates to the carbamates. Moreover, the utility of arylsulfonyl chloride in
combination with NMI minimizes the formation of often-observed hydroxamate-isocyanate dimers during the sequence. Under the present
conditions, lowering of temperatures is also possible, enabling a mild protocol.
Conversion of carboxylic acid derivatives to the corre-
sponding isocyanates is often achieved through oxidative
rearrangements, such as the Hofmann or Curtius re-
arrangements.1 These approaches have been successfully
employed to incorporate amine functionality into many
substrates, including drug molecules.2 In addition, isocya-
nates;the direct product of the Lossen rearrangement;
are useful precursors for the synthesis of carbamate and
urea derivatives with pharmaceutical3 and agrochemical
relevance.4 Despite the widespread use of these oxidative
rearrangement methods, the use of strong hypervalent
iodine reagents (Hofmann rearrangement) and potentially
explosive azides (Curtius rearrangement) limit the appli-
cation of these methods in large scale synthesis as well
as for the derivatization of complex natural products with
sensitive functional groups. As an alternative, the Lossen
rearrangement5,6 provides access to isocyanates under
somewhat more mild conditions. However, the application
of the Lossen rearrangement is limited due to a competing
side reaction, where the isocyanate 3 reacts with the
hydroxamate 1, often yielding undesired pseudodimers
like 4 (Scheme 1).5,6
(1) (a) Shiori, Y. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, p 795. (b) Franklin, E. C.
Chem. Rev. 1934, 14, 219.
(2) (a) Ishikawa, H.; Bondzic, B. P.; Hayashi, Y. Eur. J. Org. Chem.
2011, 6020. (b) Maung, K. M.; Wustmann, D. J.; Herzon, S. B. Chem.
Sci. 2011, 2, 2251.
(3) (a) Kasnanen, H.; Myllymaki, M. J.; Minkkila, A.; Kataja, A. O.;
Saario, S. M.; Nevalainen, T.; Koskinen, A. M. P.; Poso, A. ChemMed-
Chem 2010, 5, 213. (b) Otrubova, K.; Ezzili, C.; Boger, D. L. Bioorg.
Med. Chem. Lett. 2011, 21, 4674. (c) Li, H. Q.; Lv, P. C.; Yan, T.; Zhu,
(5) (a) Yale, H. L. Chem. Rev. 1943, 33, 209. (b) Hurd, C. D.; Bauer,
L. J. Am. Chem. Soc. 1954, 76, 2791. (c) Bauer, L.; Exner, O. Angew.
Chem., Int. Ed. Engl. 1974, 13, 376. (d) Stolberg, M. A.; Tweit, R. C.;
Steinberg, G. M.; Wagner-Jauregg, T. J. Am. Chem. Soc. 1955, 77, 765.
(e) Pihuleac, J.; Bauer, L. Synthesis 1989, 61.
(6) For selected examples, see: (a) Wallace, R. G.; Barker, J. M.;
Wood, M. L. Synthesis 1990, 1143. (b) Hoare, D. G.; Olson, A.;
Koshland, D. E., Jr. J. Am. Chem. Soc. 1968, 90, 1638.
€
H. L. Anti-Cancer Agents Med. Chem. 2009, 9, 471. (d) Boije af Gennas,
G.; Mologni, L.; Ahmed, S.; Rajaratnam, M.; Marin, O.; Lindholm, N.;
Viltadi, M.; Gambacorti-Passerini, C.; Scapozza, L.; Yli-Kauhaluoma,
J. ChemMedChem 2011, 6, 1680.
(4) Ma, H. J.; Xie, R. L.; Zhao, Q. F.; Mei, X. D.; Ning, J. J. Agric.
Food Chem. 2010, 58, 12817.
r
10.1021/ol303424b
XXXX American Chemical Society

Scheme 1. Formation of the Undesired Dimeric Side Product
during the Lossen Rearrangement under Thermal Conditions
Scheme 2. Hypothesized NMI-catalyzed Carbamate Synthesis
Efforts to prevent the dimerization reaction have in-
cluded (a) attempted preformation of an activated hydro-
xamate and (b) performing the rearrangement at high
temperature (65À85 °C).7 These conditions are typically
unfavorable for incorporation of carbamate functionality
into complex natural products or substrates that tend to
undergo additional reactions under basic conditions (e.g.,
conjugated alcohols and beta-hydroxy-ketones). Despite
the development of several BrØnsted base,8 BrØnsted acid,9
Lewis base10 and Lewis acid promoters11 for the synthesis of
carbamates in this context, such methods still have limited
application. To the best of our knowledge, an effective and
mild Lewis base-catalyzed protocol for the synthesis of
carbamates had been underexplored. Therefore, develop-
ment of a Lewis base-dependent method would be a useful
addition if advantages were apparent.
Thus, in an effort to develop a simple, low temperature
method to promote the Lossen rearrangement, we hypothe-
sized that a suitable nucleophilic catalyst might accelerate
the sulfonyl-group transfer during the initial O-activation
step. Such a catalyst would prevent the undesired consump-
tion of 3, and hence the formation of dimeric side product 4
(Scheme 2). The same Lewis base, in principle, might also
accelerate the reaction of the isocyanate intermediate in the
presence of a suitable nucleophile, en route to carbamate
products. Previously, our research group had shown that
peptide-based catalysts containing the NMI moiety (e.g.,
π-methylhistidine) are quite effective for catalysis of sulfonyl
group transfer reactions.12
Our initial investigation began with examination of
several arylsulfonyl reagents for the Lossen rearrangement
of hydroxamic acid 6 in the presence and absence of NMI
(Scheme 3). We found that under optimized conditions,
sulfonyl chlorides, in particular 4-nitrobenzenesulfonyl
chloride (4-NsCl) promoted the Lossen rearrangement of
6 very effectively at 0 °C within 2 h, yielding the isocyanate
7a with essentially complete conversion. Two aspects of
this observation were surprising. First, it was unexpected
that Lossen rearrangement to 7a would occur so efficiently
and spontaneously at 0 °C. In contrast, when tosyl chloride
is used as the sulfonylating agent, the reaction also results
in isocyanate formation, but the reaction is not as effcient.13
Second, control experiments revealed that NMI was in fact
not required for the formation of the isocyanate. Indeed,
this may be due to the heightened reactivity of hydroxamic
acids toward sulfonly chlorides, relative to the lower reac-
tivity of aliphatic alcohols in this context.12 On the other
hand, NMI proved essential for the conversion of 7a to
carbamate 7b at ambient temperature (vide infra).
Scheme 3. Conversion of Hydroxamate 6 to either the Isocya-
nate or the Carbamate
(7) (a) Miller, M. J.; Loudon, G. M. J. Am. Chem. Soc. 1975, 97, 5295.
(b) Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E. M.; Feldman,
P. L. J. Org. Chem. 1998, 63, 10040. (c) Anilkumar, R.; Chandrasekhar,
To gain more insight into NMI-catalyzed conversion of
isocyanates to carbamates, we evaluated several possible
Lewis bases (Table 1). We observed quite rapid and high
conversion of isocyanate 8 to carbamate 9 in the presence
of either NMI (entry 2; 10 mol %) or N,N-dimethylami-
nopyridine (entry 3; 10 mol %). At 23 °C, complete con-
version of 8 was observed within 60 min with either catalyst.
When the catalyst is omitted from the reaction, the product
is observed in only 3% yield. It is also notable that neither
imidazole (entry 4) nor pyridine (entry 5) are catalysts for
the process. The NMI-catalyzed reaction also proceeds
effectively at 0 °C, with a modest extension of the reaction
time (∼3 h), or with higher loading of NMI (20À30 mol %).
ꢀ
S.; Sridhar, M. Tetrahedron Lett. 2000, 41, 5291. (d) Dube, P.; Nathel,
N. F. F.; Vetelino, M.; Couturier, M.; Aboussafy, C. L.; Pichette, S.;
Jorgensen, M. L.; Hardink, M. Org. Lett. 2009, 11, 5622.
(8) Dillard, R. D.; Poore, G. A.; Easton, N. R.; Sweeney, M. J.;
Gibson, W. R. J. Med. Chem. 1968, 11, 1155.
(9) (a) Benalil, A.; Roby, P.; Carboni, B.; Vaultier, M. Synthesis 1991,
787. (b) Lammiman, S. A.; Satchell, R. S. J. Chem. Soc., Perkin Trans. 2
1974, 877.
€
€
(10) (a) Hofle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int.
Ed. 1978, 17, 569. (b) Keyes, R. F.; Carter, J. J.; Zhang, X.; Ma, Z. Org.
Lett. 2005, 7, 847.
(11) (a) Duggan, M. E.; Imagire, J. S. Synthesis 1989, 131. (b)
Nishikawa, T.; Urabe, D.; Tomita, M.; Tsujimoto, T.; Iwabuchi, T.;
Isobe, M. Org. Lett. 2006, 8, 3263. (c) Stock, C.; Bruckner, R. Synlett
2010, 2429. (d) Stock, C.; Bruckner, R. Adv. Synth. Catal. 2012, 354,
2309. (e) Spino, C.; Joly, M. A.; Godbout, C.; Arbour, M. J. Org.
Chem. 2005, 70, 6118. (f) Francis, T.; Thorne, M. P. Can. J. Chem.
1976, 54, 24.
(12) Fiori, K. W.; Puchlopek, A. L. A.; Miller, S. J. Nat. Chem 2009, 1,
630.
(13) TsCl, 3-NsCl and 4-NsCl gave complete conversion of 6 to 7a.
TsF and 4-NsF gave no conversion to the desired isocyanate 7a.
B
Org. Lett., Vol. XX, No. XX, XXXX

The low temperature, together with the mild nature of the
catalyst (e.g., pKa of NMI ∼ 7.4), provide a very mild and
practical method for the synthesis of carbamates.
reaction of conjugated carbamate 14. Since many of the
previously reported methods employ more harsh condi-
tions, which could cause elimination of such carbamates,11d
the present protocol provides a superior alternative. On the
other hand, the reactivity of tertiary alcohol (entry 5) is
Table 1. Conversion of Isocyanate 8 to the Carbamate 9 using
Various Nucleophilic Catalysts
Scheme 4. Synthesis of Aromatic and Aliphatic Carbamates
entry
catalysta
yieldb (%)
1
2
3
4
5
No catalyst
NMI
3
93
95
3
DMAP
Imidazole
Pyridine
4
a 10 mol % catalyst was used. b Isolated yield.
We then evaluated the versatility of this approach by
exposure of isocyanate 8 to various alcohols under the
optimized conditions (Table 2). Both primary (entries 1
and 2) and secondary alcohols (entries 3 and 4) work well,
leading to the carbamates in high yield. Additionally,
conversion of trans,trans-2,4-hexadien-1-ol to the corre-
sponding carbamate (entry 6) in excellent yield indicates
that the reported method does not cause an elimination
Table 3. NMI-catalyzed Synthesis of Aryl and Aliphatic Car-
bamates
Table 2. NMI-catalyzed Carbamate Synthesis using Various
Alcohols
a 2 equiv was used. b Isolated yield. c 3 equiv alcohol was used.
a Isolated yield. b Yield calculated over 3 steps.
Org. Lett., Vol. XX, No. XX, XXXX
C

noticeably low, with carbamate 13 formed in only 17% yield
under the analogous reaction conditions, presumably due to
the steric hindrance.
(entries 8À13) also undergo rearrangement at 0 °C; how-
ever, the formation of aliphatic carbamates (23À28) were
carried out at slightly elevated temperature (35 °C) to
afford the desired carbamates in a convenient time frame.
The basis of the NMI-accelerated alcoholysis of isocya-
nates is not immediately clear. On the other hand, the role of
nucleophilic catalysts such as DMAP for accelerating reac-
tions of this nature seems an appropriate analogy.10a At this
time, we do not have a clear understanding of the reaction
mechanism to provide a definitive proposal for this aspect.
In conclusion, we have developed a quite mild and
efficient catalytic approach for the conversion of hydro-
xamic acids to the corresponding carbamate in a one-pot
operation. As the Lossen rearrangement provides a prac-
tical alternative approach for the modification of a car-
boxylic acid, the reported method can be used for oxidative
rearrangement of carboxylic acids found in complex mo-
leculesaswellasinsensitivesubstrates. Ourgrouphas been
interested in developing chemical methods to modify
complex natural products.15 Efforts will be taken to in-
vestigate the application of the reported method to intro-
duce amine and carbamate functionalities into complex
natural products in the near future.
To demonstrate that NMI accelerates the reaction of
both aromatic and aliphatic isocyanates, 4-methoxyphenyl
isocyanate and cyclohexyl isocyanate were examined
(Scheme 4). In each case, we observed efficient reactions,
with the corresponding Cbz-carbamates 10 and 16 formed
in 99% and 55% yield, respectively. We observed that
cyclohexyl isocyanate 15 was less reactive and required
slightly elevated temperature (35 °C) and a somewhat
extended reaction time (6 h) to afford the observed result.
We achieved an improved conversion of 15 with even
longer reaction time (14 h; see Table 3, entry 12).
Since our initial goal was to develop an improved Lossen
rearrangement protocol, we investigated the generality of
the Lossen rearrangement protocol presented herein for a
one-pot synthesis of carbamates. We synthesized various hy-
droxamic acid substrates from the corresponding carboxylic
acid in one simple step (see Supporting Information).7d,14
Each hydroxamic acid was exposed to 4-NsCl (1.1 equiv), in
the presence of iPr2EtN (2.5 equiv) at 0 °C for 2 h. This time
frame appears adequate for complete conversion of the
hydroxamate to the corresponding isocyanate. Subsequently,
NMI and allyl alcohol were added to the reaction mixture to
afford the desired carbamates (Table 3). This general
procedure proved quite effective for a wide range of
compounds, which are discussed in Table 3.
Acknowledgment. We thank colleagues at Cubist Phar-
maceuticals, Inc. (Drs. Y. Gu, N. Yin and Y. He) for
support and insightful discussions. We are also grateful to
the National Institutes of Health (R37 GM068649) and
Yale University for partial support of this effort.
As shown in entries 1À7, aryl hydroxamic acids prove to
begood substrates, undergoing the completeone-pot (two-
step) transformation, giving the desired carbamate in good
to excellent yields (59À97% yields). Our observations that
the electron withdrawing substituents on the aromatic
rings may lead to slower rearrangement, perhaps due to
reduced electron density of the migrating group, is con-
sistent with prior studies.7d The aliphatic hydroxamates
Supporting Information Available. Procedures and
characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) (a) Fowler, B. S.; Laemmerhold, K. M.; Miller, S. J. J. Am.
Chem. Soc. 2012, 134, 9755. (b) Pathak, T. P.; Miller, S. J. J. Am. Chem.
Soc. 2012, 134, 6120. (c) Lewis, C. A.; Miller, S. J. Angew. Chem., Int. Ed.
2006, 45, 5616.
(14) Usachova, N.; Leitis, G.; Jirgensons, A.; Kalvinsh, I. Synth.
Commun. 2010, 40, 927.
The authors declare no competing financial interest.
D
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