Curtius rearrangement of aromatic carboxylic acids to access protected anilines and aromatic ureas

Article abstract of DOI:10.1021/ol0622920

(Diagram presented) The reaction of a chloroformate or di-tert-butyl dicarbonate and sodium azide with an aromatic carboxylic acid produces the corresponding acyl azide, presumably through the formation of an azidoformate. The acyl azide undergoes a Curtius rearrangement to form an isocyanate derivative which is trapped either by an alkoxide or by an amine to form the aromatic carbamate or urea. The reaction conditions are compatible with a variety of functional groups and allow the synthesis of a number of aniline derivatives containing alkyl, halide, nitro, ketone, ether, and thioether substituents.

Full text of DOI:10.1021/ol0622920

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5717-5720
Curtius Rearrangement of Aromatic
Carboxylic Acids to Access Protected
Anilines and Aromatic Ureas
He´le`ne Lebel* and Olivier Leogane
De´partement de chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada, H3C 3J7
helene.lebel@umontreal.ca
Received September 18, 2006
ABSTRACT
The reaction of a chloroformate or di-tert-butyl dicarbonate and sodium azide with an aromatic carboxylic acid produces the corresponding
acyl azide, presumably through the formation of an azidoformate. The acyl azide undergoes a Curtius rearrangement to form an isocyanate
derivative which is trapped either by an alkoxide or by an amine to form the aromatic carbamate or urea. The reaction conditions are compatible
with a variety of functional groups and allow the synthesis of a number of aniline derivatives containing alkyl, halide, nitro, ketone, ether, and
thioether substituents.
Polysubstituted aromatic anilines are an important class of
compounds that display a variety of interesting properties.
These are found as the active agent in a variety of areas,
including pharmaceutical1 and agrochemical2 industries, as
well as in materials science.3 Although free anilines them-
selves are typically mutagenic and carcinogenic,4 they serve
as intermediates in the preparation of numerous aromatic
carbon-nitrogen bond containing molecules. A number of
methods to access anilines have been developed, including
hydrogenation of nitro derivatives,5 electrophilic nitration,6
nucleophilic aromatic amination,7 as well as palladium and
copper-catalyzed amination.8,9 Besides all these modern
methods, Curtius rearrangement of acyl azides remains very
popular, especially in the preparation of pharmacologically
active compounds.10 Diphenylphosphorazidate is the most
widely used reagent, as it allows the direct transformation
of carboxylic acids into carbamates.11 However, the difficulty
in purifying the desired product from the phosphorus residues
remains a serious drawback associated with the use of this
reagent.12 Herein, we wish to disclose the use of di-tert-butyl
dicarbonate or chloroformates and sodium azide as reagents
for the preparation of aromatic carbamates directly from
(1) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337-2347.
(2) (a) Harrison, W. J. Biomol. Screen. 1999, 4, 61-65. (b) Walter, M.
W. Nat. Prod. Rep. 2002, 19, 278-291. (c) Lopez, O.; Fernandez-Bolanos,
J. G.; Gil, M. V. Green Chem. 2005, 7, 431-442.
(3) (a) Kanbara, T.; Honma, A.; Hasegawa, K. Chem. Lett. 1996, 1135-
1136. (b) Honma, A.; Kanbara, T.; Hasegawa, K. Mol. Cryst. Liq. Cryst.
2000, 345, 449-454. (c) Thomas, K. R. J.; Lin, J. T.; Tao, Y. T.; Ko, C.
W. AdV. Mater. 2000, 12, 1949-1951. (d) Thomas, K. R. J.; Lin, J. T.;
Tsai, C. M.; Lin, H. C. Tetrahedron 2006, 62, 3517-3522.
(4) Benigni, R.; Giuliani, A.; Franke, R.; Gruska, A. Chem. ReV. 2000,
100, 3697-3714.
(5) (a) Rains, R. K.; Lambers, E. A.; Genetti, R. A. Chem. Ind. 1996,
68, 43-52. (b) Blaser, H. U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner,
H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103-151. (c) Prasad, K.; Jiang,
X. L.; Slade, J. S.; Clemens, J.; Repic, O.; Blacklock, T. J. AdV. Synth.
Catal. 2005, 347, 1769-1773.
(6) (a) Waller, F. J.; Ramprasad, D.; Barrett, A. G. M.; Braddock, D. C.
Chem. Ind. 1998, 75, 289-305. (b) Laali, K. K.; Gettwert, V. J. J. Org.
Chem. 2001, 66, 35-40. (c) Smith, K.; El-Hiti, G. A. Curr. Org. Synth.
2004, 1, 253-274.
(7) (a) Ibata, T.; Isogami, Y.; Toyoda, J. Chem. Lett. 1987, 1187-1190.
(b) Warawdekar, M. G.; Rajadhyaksha, R. A. Zeolites 1987, 7, 574-578.
(c) Stern, M. K.; Cheng, B. K. J. Org. Chem. 1993, 58, 6883-6888. (d)
Pagoria, P. F.; Mitchell, A. R.; Schmidt, R. D. J. Org. Chem. 1996, 61,
2934-2935.
(8) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. AdV. Synth.
Catal. 2006, 348, 23-39 and references therein.
(9) Review: (a) Downing, R. S.; Kunkeler, P. J.; vanBekkum, H. Catal.
Today 1997, 37, 121-136. Alternative method: (b) Neumann, H.; von
Wangelin, A. J.; Klaus, S. N.; Strubing, D.; Gordes, D.; Beller, M. Angew.
Chem., Int. Ed. 2003, 42, 4503-4507.
10.1021/ol0622920 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/16/2006

aromatic acids via a Curtius rearrangement, presumably
through the formation of the corresponding azidoformate (eq
1). The use of a chloroformate containing a less nucleophilic
Table 1. Curtius Rearrangement of Benzoic Acid:
Optimization of the Reaction Conditions (Equation 3)a
entry
reaction conditions
conversion (%)b
1
2
3
4
5
6
7
8
Bu4NBr, Zn(OTf)2/THF c
Bu4NBr, Zn(OTf)2/THF
<5
15
10
20
15
15e
20e
>95e
alkoxy moiety allowed the use of external nucleophiles, such
as amines, thus leading to the formation of aromatic ureas.
We have recently reported a mild and efficient one-pot
Curtius rearrangement for the synthesis of aliphatic Boc-
protected amines.13 Aliphatic carboxylic acids were reacted
with a mixture of di-tert-butyl dicarbonate and sodium azide
to form an acyl azide intermediate, which underwent a
Curtius rearrangement at 40-50 °C (eq 2).
Bu4NBr, pyridine,d Zn(OTf)2/THF
Bu4NBr, HOBT,d Zn(OTf)2/THF
no additive or catalyst/THF
no additive or catalyst/toluene
no additive or catalyst/MeCN
no additive or catalyst/DME
a Conditions: Boc2O (1.1 equiv), NaN3 (3.5 equiv), additive (15 mol
%), catalyst (3.3 mol %), solvent, 16 h. b Conversion by GC-MS. c 40 °C.
d Pyridine or HOBT (1.1 equiv). e NaN3 (1.5 equiv).
stable than their aliphatic counterparts. The reaction was thus
heated at 75 °C to promote the rearrangement. Although
carbamate 1 was produced under these reaction conditions,
only 15% conversion was observed (entry 2). Neither the
addition of pyridine nor the addition of 1-hydroxybenzo-
triazole (HOBT) increased the yield of carbamate 1 (entries
3 and 4). Indeed, the reaction proceeded to the same extent
in the absence of catalyst (entry 5). Finally, solvent optimiza-
tion led to high conversion when the reaction was run in
1,2-dimethoxyethane (DME) (entry 8). This observation
suggested that the solubility of the various species and
intermediates is crucial for the reaction to occur.14
The trapping of the isocyanate derivative in the presence
of tetrabutylammonium bromide and zinc(II) triflate led to
the desired tert-butyl carbamate in high yields. In sharp
contrast, using similar reaction conditions, aromatic car-
boxylic acids led mainly to the formation of the correspond-
ing tert-butyl ester, presumably via the displacement of an
azide leaving group with tert-butoxide (Table 1, entry 1).
We postulated that the Curtius rearrangement did not take
place at 40 °C, as aromatic acyl azides are known to be more
The Boc-aniline 1 was isolated in 79% yield after 20 h of
reaction (Table 2, entry 1). Other unfunctionalized anilines
(10) Selected examples: (a) Romine, J. L.; Martin, S. W.; Meanwell,
N. A.; Epperson, J. R. Synthesis 1994, 846-850. (b) Proctor, G. R.; Harvey,
A. L. Curr. Med. Chem. 2000, 7, 295-302. (c) Alonso-Alija, C.; Michels,
M.; Peilstocker, K.; Schirok, H. Tetrahedron Lett. 2004, 45, 95-98. (d)
Dombroski, M. A.; Letavic, M. A.; McClure, K. F.; Barberia, J. T.; Carty,
T. J.; Cortina, S. R.; Csiki, C.; Dipesa, A. J.; Elliott, N. C.; Gabel, C. A.;
Jordan, C. K.; Labasi, J. M.; Martin, W. H.; Peese, K. M.; Stock, I. A.;
Svensson, L.; Sweeney, F. J.; Yu, C. H. Bioorg. Med. Chem. Lett. 2004,
14, 919-923. (e) Gopalsamy, A.; Lim, K.; Ellingboe, J. W.; Mitsner, B.;
Nikitenko, A.; Upeslacis, J.; Mansour, T. S.; Olson, M. W.; Bebernitz, G.
A.; Grinberg, D.; Feld, B.; Moy, F. J.; O’Connell, J. J. Med. Chem. 2004,
47, 1893-1899. (f) Ple, P. A.; Green, T. P.; Hennequin, L. F.; Curwen, J.;
Fennell, M.; Allen, J.; Lambert-van der Brempt, C.; Costello, G. J. Med.
Chem. 2004, 47, 871-887. (g) Sit, S. Y.; Xie, K.; Jacutin-Porte, S.; Boy,
K. M.; Seanz, J.; Taber, M. T.; Gulwadi, A. G.; Korpinen, C. D.; Burris,
K. D.; Molski, T. F.; Ryan, E.; Xu, C.; Verdoorn, T.; Johnson, G.; Nichols,
D. E.; Mailman, R. B. Bioorg. Med. Chem. 2004, 12, 715-734. (h)
Takigawa, Y.; Ito, H.; Omodera, K.; Ito, M.; Taguchi, T. Tetrahedron 2004,
60, 1385-1392. (i) Dominguez, J. N.; Leon, C.; Rodrigues, J.; de
Dominguez, N. G.; Gut, J.; Rosenthal, P. J. J. Med. Chem. 2005, 48, 3654-
3658. (j) Opacic, N.; Barbaric, M.; Zorc, B.; Cetina, M.; Nagy, A.; Frkovic,
D.; Kralj, M.; Pavelic, K.; Balzarini, J.; Andrei, G.; Snoeck, R.; De Clercq,
E.; Raic-Malic, S.; Mintas, M. J. Med. Chem. 2005, 48, 475-482. (k)
Suzuki, T.; Nagano, Y.; Kouketsu, A.; Matsuura, A.; Maruyama, S.;
Kurotaki, M.; Nakagawa, H.; Miyata, N. J. Med. Chem. 2005, 48, 1019-
1032. (l) Varaprasad, C.; Johnson, F. Tetrahedron Lett. 2005, 46, 2163-
2165.
Table 2. tert-Butylazidoformate in the Curtius Rearrangement
of Benzoic Acids (Equation 4)a
(11) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972,
94, 6203-6205. (b) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron
1974, 30, 2151-2157. (c) Murato, K.; Shioiri, T.; Yamada, S. Chem. Pharm.
Bull. 1975, 23, 1738-1740. (d) Capson, T. L.; Poulter, C. D. Tetrahedron
Lett. 1984, 25, 3515-3518. (e) Wolff, O.; Waldvogel, S. R. Synthesis 2004,
1303-1305. (f) Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S.
Tetrahedron Lett. 2006, 47, 7219-7223.
a Conditions: Boc2O (1.1 equiv), NaN3 (1.5 equiv), 20 h. b Isolated yield.
were isolated with similar yields (entries 2 and 3). However,
functional groups such as methyl ether, thiomethyl ether,
5718
Org. Lett., Vol. 8, No. 25, 2006

nitro, and halides were not tolerated, and the corresponding
anilines were isolated in less than 25% yield.
Table 4. Curtius Rearrangement of Aromatic Carboxylic Acids
Using Azidoformates (Equation 6)a
We hypothesized that the full equivalent of base generated
from the reaction between di-tert-butyl dicarbonate and
sodium azide could be the source of the problem, leading to
undesired side reactions with these functional groups.
We turned our attention to the use of chloroformates,
another class of reagent that could also lead to azidoformate
upon reaction with sodium azide. In this case, the byproduct
of the reaction is sodium chloride. When benzoic acid was
reacted with a mixture of allylchloroformate and sodium
azide in DME at 75 °C, 25% of carbamate 6 was obtained
(Table 3, entry 1).15
Table 3. Curtius Rearrangement of Benzoic Acid:
Optimization of the Reaction Conditions with
Allylchloroformate (Equation 5)a
entry
base
none
pyridine
DMAP
K2CO3
NaOAc
NaH
conversion (%)b
1
2
3
4
5
6
7
8
25
<5
<5
<5
90
90
95
43
t-BuONa
t-BuONac
a Conditions: AllocCl (1.1 equiv), NaN3 (1.5 equiv), base (15 mol %),
16 h. b Conversion by GC-MS. c The solvent was dioxane.
The use of pyridine bases or potassium carbonate did not
lead to any product (entries 2-4). Conversely, 15 mol % of
sodium acetate or sodium hydride promoted the reaction and
led to 90% conversion of carbamate 6 (entries 5 and 6). The
optimal base was found to be potassium tert-butoxide (entry
7). The reaction was also performed in dioxane but led to
carbamate 6 in a lower yield. Clearly, a small amount of
base is required to promote the reaction.16 Whereas the
generation of a full equivalent of base was found to be
deleterious for the functional group compatibility, the use
of a catalytic amount was well tolerated, and a variety of
carbamates were prepared in high yields (Table 4). Both allyl
a Conditions: ROCOCl (1.1 equiv), NaN3 (1.7 equiv), t-BuONa (15 mol
%), 16 h. b Isolated yield. c 85 °C.
and benzyl chloroformate were sucessfully used to generate
Alloc- and CBz-protected anilines. Electron-rich benzoic
acids led to the formation of the corresponding carbamates
in 45-77% yields (entries 1-4). The reaction is faster with
substrates containing an electron-withdrawing group, sug-
gesting that the addition of the nucleophile to the isocyanate
intermediate to form the carbamate is the slowest step of
the process. Indeed p-nitro and p-acetyl benzoic acid
substrates provided the desired carbamate in 66-84% yields
(entry 5). Halides are also well tolerated, and o-iodo benzoic
(12) Alternative procedures using solid-phase synthesis: (a) Richter, L.
S.; Andersen, S. Tetrahedron Lett. 1998, 39, 8747-8750. (b) Sunami, S.;
Sagara, T.; Ohkubo, M.; Morishima, H. Tetrahedron Lett. 1999, 40, 1721-
1724. (c) Lu, Y.; Taylor, R. T. Tetrahedron Lett. 2003, 44, 9267-9269.
(13) Lebel, H.; Leogane, O. Org. Lett. 2005, 7, 4107-4110.
(14) Furthermore, the reaction mixture is completely insoluble when
dioxane is used as solvent.
(15) The rest of the material was the isocyanate.
(16) A control experiment was run with chloroformate, sodium azide,
and carboxylic acid at room temperature and showed the formation of acyl
azide, suggesting that the base is not essential for the formation of this
intermediate. The base is probably involved in the formation of the
carbamate from the isocyanate, by trapping the proton of the nucleophile.
Org. Lett., Vol. 8, No. 25, 2006
5719

acids were not reactive under these reaction conditions, the
use of other sp2-substituted carboxylic acids is possible, as
cinnamic acid provided the Alloc and Cbz carbamates 31
and 32 in 52% and 51% yields, respectively.
Table 5. Synthesis of Ureas from Aromatic Carboxylic Acids
via Curtius Rearrangement (Equation 7)a
If one could use nucleophiles other than the alkoxide
generated from the chloroformate, this would certainly
increase the versatility of this method. The use of phenyl
chloroformate that contained a less nucleophilic alcohol was
envisioned to achieve this task. Indeed, a mixture of phenyl
chloroformate, sodium azide, and carboxylic acid led to the
formation of the acyl azide. The reaction was then heated at
75 °C to promote the formation of the isocyanate while
adding an amine to trap this intermediate and form the
corresponding urea (Table 5). Good yields were obtained
for the formation of aromatic ureas via the addition of another
aniline (entries 1-5). Furthermore, the addition of hydroxy-
lamine allowed the formation of hydroxyurea 38 in 54% yield
(entry 6). Finally, aliphatic amines can also be added with
good yields, such as in the case of the formation of urea 39
(entry 7).
In conclusion, we have developed a very efficient process
for the Curtius rearrangement that allows the direct conver-
sion of aromatic carboxylic acids into carbamates and ureas.
This process is based on the use of various commercially
available chloroformates and sodium azide, which presum-
ably generate the corresponding azidoformate. The formate
serves to activate the carboxylic acids and as a source of
nucleophilic alkoxide. Finally, the synthesis of aromatic ureas
is also possible as amines can be used as nucleophiles, when
using phenyl chloroformate and sodium azide as reagents.
Acknowledgment. This research was supported by
NSERC (Canada), the Canada Foundation for Innovation,
AstraZeneca Canada Inc., Boehringer Ingelheim (Canada)
Ltd., Merck Frosst Canada Ltd., and the Universite´ de
Montre´al. O.L. thanks the “Conseil ge´ne´ral de la Guade-
loupe” for a graduate fellowship.
a Conditions: PhOCOCl (1.1 equiv), NaN3 (1.5 equiv), t-BuONa (15
d
mol %), RNH2 (1.5 equiv). b Isolated yield. c NH2OH‚HCl (2 equiv). The
reaction mixture was heated to 75 °C prior to the addition of the amine
(see Supporting Information for details).
acid is one of the most reactive substrates (entries 6 and 7).
In this case, the use of the less nucleophilic alcohol,
trichloroethanol, as the nucleophile is possible leading to the
Troc carbamate 26 in 71% yield. Furthermore, the reaction
conditions are compatible with thiomethyl ether and benzo-
furan (entries 8 and 9). Finally, although aliphatic carboxylic
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and 1H spectra of
all the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0622920
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Org. Lett., Vol. 8, No. 25, 2006