Carbonyldiimidazole-mediated lossen rearrangement

Article abstract of DOI:10.1021/ol9023387

[Chemical Equation Presented] Carbonyldiimidazole (CDI) was found to mediate the Lossen rearrangement of various hydroxamic acids to isocyanates. This process is experimentally simple and mild, with imidazole and CO ₂ being the sole stoichiometric byproduct. Significant for large-scale application, the method avoids the use of hazardous reagents and thus represents a green alternative to standard processing conditions for the Curtius and Hofmann rearrangements.

Full text of DOI:10.1021/ol9023387

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5622-5625
Carbonyldiimidazole-Mediated Lossen
Rearrangement
Pascal Dube´,* Noah F. Fine Nathel, Michael Vetelino, Michel Couturier, Claude
Larrive´e Aboussafy, Simon Pichette, Matthew L. Jorgensen, and Mark Hardink
Chemical Research and DeVelopment, Pfizer Global Research and DeVelopment,
Eastern Point Road, P.O. Box 8013, Groton, Connecticut 06340-8013
pascal.dube@pfizer.com
Received October 9, 2009
ABSTRACT
Carbonyldiimidazole (CDI) was found to mediate the Lossen rearrangement of various hydroxamic acids to isocyanates. This process is
experimentally simple and mild, with imidazole and CO2 being the sole stoichiometric byproduct. Significant for large-scale application, the
method avoids the use of hazardous reagents and thus represents a green alternative to standard processing conditions for the Curtius and
Hofmann rearrangements.
The oxidative degradation of carboxylic functions is now
viewed as a standard chemical transformation.1 Both the
Hofmann2 and Curtius3 rearrangements have been developed
to a point where reaction understanding and process engi-
neering have enabled their utilization on a kilogram scale.4
Examples of large-scale applications of the Hofmann rear-
rangement feature controlled addition of the oxidant along
with flow processes.5 Moreover, procedures involving reverse
addition of sensitive reagents and flow engineering have
rendered the Curtius reaction accessible to the process groups
of the pharmaceutical industry.6 However, these methods are
inherently limited by the safety hazards associated with the
handling of azides and transient high-energy intermediates
along with impractical dilution requirements.7 The develop-
ment of an alternative method avoiding such limitations is
thus still of interest.
The Lossen rearrangement, which describes the transfor-
mation of an activated hydroxamic acid into the correspond-
ing isocyanate, has received comparatively little attention
since its original publication.8 Although many studies have
focused on the development of activation methods to promote
the Lossen rearrangement,9 the inherent problems associated
with competitive dimerization have been partially addressed
by creative solutions.10 Nonetheless, the complexity of
existing procedures and the presence of many stoichiometric
byproduct have limited the application of the Lossen rear-
rangement on a kilogram scale.11
(1) Shioiri, T. ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6, p 800.
(2) Wolff, M. E. Chem. ReV. 1963, 63, 55.
(3) (a) Scriven, E. F.; Turnbull, K. Chem. ReV. 1988, 88, 297. (b) Smith,
P. A. S. Org. React. 1946, 3, 337.
(6) (a) Am Ende, D. J.; DeVries, K. M.; Cliford, P. J.; Brenek, S. J.
Org. Process Res. DeV. 1998, 2, 382. (b) Nettekoven, M.; Jenny, C. Org.
Proc. Res. DeV. 2003, 7, 38. (c) Govindan, C. K. Org. Process Res. DeV.
2002, 6, 74. (d) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.;
Smith, C. D. Org. Biomol. Chem. 2008, 6, 1587.
(4) For a review, see: Caron, S.; Dugger, R. W.; Gut Ruggeri, S.; Ragan,
J. A.; Brown Ripin, D. H. Chem. ReV. 2006, 106, 2943.
(5) For selected examples, see: (a) Amato, J. S.; Bagner, C.; Cvetovich,
R. J.; Gomolka, S.; Hartner, F. W., Jr.; Reamer, R. J. Org. Chem. 1998,
63, 9533. (b) Zhang, L.-H.; Chung, J. C.; Costello, T. D.; Valvis, I.; Ma,
P.; Kauffman, S.; Ward, R. J. Org. Chem. 1997, 62, 2466. (c) Kaufhold,
M.; Kleemiss, W.; Feld, M. European Patent EP970943, 2000. (d) Jones,
S. A.; Jersak, U. German Patent DE3909142 , 1990.
(7) (a) Landgrebe, J. A. Chem. Eng. News 1981, 59, 47. (b) Middleton,
W. J. J. Org. Chem. 1984, 49, 4541.
(8) (a) Yale, H. L. Chem. ReV. 1943, 33, 209. (b) Bauer, L.; Exner, O.
Angew. Chem., Int. Ed. Engl. 1974, 13, 376.
10.1021/ol9023387  2009 American Chemical Society
Published on Web 11/12/2009

We came across a report by Sauer and Mayer where the
thermolysis of 3-phenyl-1,4,2-dioxazol-5-one 1 produced
sulfoximine 2 along with symmetrical urea 3 (Scheme 1).12
The fact that rearrangement occurred under such mild
conditions sharply contrasted with the reported high temperature
required for the thermolysis (Scheme 1). Our screen of various
solvents revealed that conversion and purity was optimal in
acetonitrile15 and that 1 could be secured by performing the
CDI reaction in toluene at 0 °C. Moreover, control experiments
established that imidazole was essential for the conversion of
dioxazolone 1 into phenylisocyanate 5.
Scheme 1.
Thermolysis of 3-Phenyl-1,4,2-dioxazol-5-one 112
As this CDI-mediated Lossen rearrangement compared
favorably with established conditions, we evaluated the
electronic requirements of the reaction. The conversion of
various para-substituted phenyl hydroxamic acids into the
corresponding Cbz carbamates was thus investigated (Table
1). Accordingly, treatment of hydroxamic acid 4a with CDI
The latter was proposed to form through the addition of
aniline, from the partial decomposition of phenylisocyanate
with residual water, onto isocyanate 5. Inspired by their
results, we hoped to optimize the oxidative rearrangement
pathway via the screening of various additives.
Although dioxazolone 1 can be prepared by treatment of
benzohydroxamic acid 4a with phosgene,13 we sought a less
hazardous phosgene equivalent. Initial experiments using
carbonyldiimidazole (CDI) in acetonitrile led to the formation
of dioxazolone 1 within 10 min at ambient temperature.
Surprisingly, partial conversion to N-phenyl-1H-imidazole-
1-carboxamide 6 by way of addition of imidazole to
phenylisocyanate 5 was also observed under these conditions
(Scheme 2).14 Complete conversion of dioxazolone 1 to urea
Table 1. Lossen Rearrangement of para-Substituted Phenyl
Hydroxamic Acidsa
entry
X
cmpd
time of rearrangement
yield (%)b
1
2
3
4
5
6
7
H
a
b
c
d
e
f
15 min
<5 min
<5 min
10 min
40 min
40 min
24 h
93
99
93
82
85
81
5c
NMe2
OMe
Me
CI
F
NO2
g
Scheme 2
.
CDI-Mediated Formation of 1 and Subsequent
a Conditions: hydroxamic acid (1.0 equiv), CDI (1.2 equiv), BnOH (3
Rearrangement
equiv). b Isolated yield. c Conversion by HPLC.
and heating the reaction mixture to 60 °C led to the smooth
formation of the desired isocyanate over the course of a few
minutes, with the Cbz-protected aniline 7a being isolated in
high yield after a simple aqueous workup.16 Whereas the
rearrangement of electron-rich arenes was complete upon
reaching 60 °C (entries 1-4), the conversion was signifi-
cantly affected by the presence of electron-withdrawing
substituents (entries 5-7). As expected, the rate of rear-
rangement proved to be proportional to the electron density
of the migrating group.17,18
6 could be achieved within 15 min by heating the reaction
mixture to 60 °C.
Having confirmed the electronic nature of the rearrange-
ment, a broader study of the scope revealed the generality
of the method (Table 2). The capture of isocyanates with
morpholine typically provides ureas in quantitative yield.19
We thus opted for a consistent use of this nucleophile to
evaluate the efficiency of the oxidative rearrangement itself.
(9) For selected examples, see: (a) Wallace, R. G.; Barker, J. M.; Wood,
M. L. Synthesis 1990, 1143. (b) Bachman, G. B.; Goldmacher, J. E. J. Org.
Chem. 1964, 29, 2576. (c) Hoare, D. G.; Olson, A.; Koshland, D. E., Jr.
J. Am. Chem. Soc. 1968, 90, 1638. (d) Bittner, S.; Grinberg, S.; Kartoon,
I. Tetrahedron Lett. 1974, 23, 1965. (e) King, F. D.; Pike, S.; Walton,
D. R. M. J. Chem. Soc., Chem. Commun. 1978, 3521. (f) Salomon, C. J.;
Breuer, E. J. Org. Chem. 1997, 62, 3858. (g) Pihuleac, J.; Bauer, L. Synthesis
1989, 61. (h) Burungule, A. S.; Bondge, S. P.; Munde, S. B.; Bhingolikar,
V. E.; Mane, R. A. Synth. Commun. 2003, 33, 1923.
(10) (a) Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E. M.;
Feldman, P. L. J. Org. Chem. 1998, 63, 10040. (b) Anilkumar, R.;
Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett. 2000, 41, 5291. (c) Miller,
M. J.; Loudon, G. M. J. Am. Chem. Soc. 1975, 97, 5295.
(15) Other solvents led to lower conversion of 4a after 2 h: toluene
(50%), THF (90%), EtOAc (60%), dichloroethane (55%).
(16) See Supporting Information.
(17) For a comparative rate study of Hofmann rearrangements, see:
(11) Marzoni, G.; Varney, M. D. Org. Process Res. DeV. 1997, 1, 81.
(12) Sauer, J.; Mayer, K. K. Tetrahedron Lett. 1968, 3, 319.
(13) Beck, G. Chem Ber. 1951, 84, 688.
Hauser, C. R.; Renfrow, W. B., Jr. J. Am. Chem. Soc. 1937, 59, 121.
(18) For rate studies of the Lossen rearrangement, see: (a) Swenson,
J. S.; Davis, A. M.; Deyo, R. A.; Graham, B. W.; Jahn, E. P.; Mattice,
J. D. J. Org. Chem. 1973, 38, 3956. (b) Bright, R. D.; Hauser, C. R. J. Am.
Chem. Soc. 1939, 61, 618. (c) Renfrow, W. B., Jr.; Hauser, C. R. J. Am.
(14) Such a rearrangement was proposed to explain the decomposition
of R-hydroxy hydroxamic acids. Geffken, D. Liebigs Ann. Chem. 1982,
211.
Chem. Soc. 1937, 59, 2308
.
Org. Lett., Vol. 11, No. 24, 2009
5623

Table 2. Rearrangement of Aryl and Hetero Aryl Hydroxamic Acidsa
Table 3. Rearrangement of Aliphatic Hydroxamic Acidsa
a Conditions: hydroxamic acid (1.0 equiv), CDI (1.2 equiv), R2NH (3
equiv). b Isolated yield. c Determined by chiral SFC analysis. See Supporting
Information for details.
a Conditions: hydroxamic acid (1.0 equiv), CDI (1.2 equiv), R2NH (3
equiv). b Isolated yield.
Accordingly, a variety of ureas could be obtained in good
yields without a need for purification on silica gel. The
mildness of these conditions was highlighted by the isolation
of thioanisole urea 12 in 95% yield and aminothiophene 13
in 81%. Moreover, aminopyridone 14 was obtained in 68%
yield via the CDI-promoted Lossen rearrangement. It is worth
mentioning that conversion of these substrates into the
corresponding isocyanates would have been a challenging
task under Hofmann-like conditions.
Having established the generality of the CDI-mediated Lossen
rearrangement, we sought to gain mechanistic insights into the
reaction. Treatment of dioxazolone 1 with morpholine at
ambient temperature led to the smooth formation of O-
hydroxamic carbamate 23 in quantitative yield (Scheme 3).
Further exploration of the scope showed that a wide range
of aliphatic hydroxamic acids undergo the rearrangement in
high yield (Table 3). Aryl- and alkyl-substituted tertiary
hydroxamic acids were effectively converted to the corre-
sponding amines in high yields by treatment with CDI
(entries 1-3). As secondary substrates performed equally
well, enantio-enriched R-methylphenyl carboxamide 19 was
obtained with complete retention of stereochemistry through
our mild conditions.20 Finally, the rearrangement of unsub-
stituted alkyl hydroxamic acid cleanly provided primary
amines in high yields (entries 7 and 8).
Scheme 3. Isolation and Lossen Rearrangement of Carbamate 23
(19) The reaction of isocyanates with various nucleophiles has been
extensively reported in the literature. For selected examples, see: (a)
Braunstein, P.; Nobel, D. Chem. ReV. 1989, 89, 1927. (b) Ozaki, S. Chem.
ReV. 1972, 72, 457. (c) Spino, C.; Joly, M.-A.; Godbout, C.; Arbour, M. J.
Org. Chem. 2005, 70, 6118, and reference therein. (d) Han, C.; Porco, J. A.
Org. Lett. 2007, 9, 1517.
When 23 was heated to 80 °C for 30 min, only traces of the
corresponding urea could be observed. However, complete
conversion was obtained when 0.5 equiv of morpholine was
5624
Org. Lett., Vol. 11, No. 24, 2009

added to the reaction mixture. This result suggests that the
conversion of 1 into phenylisocyanate 5 proceeds through an
acyclic precursor with the assistance of a second amine in the
rate-limiting step, in agreement with mechanistic studies on the
Lossen rearrangement supporting an initial N-H deprotonation
of the activated hydroxamic acid followed by migration.18,21
A current limitation to the method is the availability of
hydroxamic acids. A more practical method would promote
the direct conversion of a carboxylic acid moiety into the
desired amine functionality. Preliminary results indicate the
feasibility of such a transformation using CDI as activating
agent twice (eq 1). Following a stepwise addition procedure,
isoquinoline-1-carboxylic acid 25 was converted into car-
boxamide 26 in 63% yield through a one-pot operation.
byproducts enables the direct oxidative rearrangement of
carboxylic acids, thus providing a rapid access to in situ
generated isocyanates. The simplicity and mildness of this
method should make it a versatile and useful transformation
with potential for large scale application. Preliminary data
supports a second order in amine and detailed kinetic studies
will be reported in due course.
Acknowledgment. The authors would like to thank
Professor Justin Du Bois of Stanford University for discus-
sions.
Supporting Information Available: Experimental pro-
cedures and compound characterization data with corre-
1
sponding H and 13C NMR. This material is available free
of charge via the Internet at http://pubs.acs.org
OL9023387
(20) (a) Hirrlinger, B.; Stolz, A. App. EnViron. Microbiol. 1997, 63,
3390. (b) Bauer, L.; Miarka, S. V. J. Org. Chem. 1959, 24, 1293. (c)
Chandrasekhar, S.; Sridhar, M. Tetrahedron: Asymmetry 2000, 11, 3467.
(21) Bauer, L.; Exner, O. Angew. Chem., Int. Ed. 1974, 13, 376.
Our studies support the generality and versatility of the
CDI-mediated Lossen rearrangement. The nature of the
Org. Lett., Vol. 11, No. 24, 2009
5625