Boc-protected 1-(3-oxocycloalkyl)ureas via a one-step Curtius rearrangement: Mechanism and scope

Article abstract of DOI:10.1016/j.tetlet.2013.12.021

1-(3-Oxocyclobutyl) carboxylic acid (4a) was converted into N-Boc-protected 1-(3-oxocyclobutyl) urea (5a), a key intermediate for the preparation of agonists of metabotropic glutamate receptor 5, in one-step when treated with diphenyl phosphoryl azide and triethylamine in tert-butanol. The mechanism of the reaction involves a nucleophilic addition of the in situ generated tert-butyl carbamate to the isocyanate intermediate. This reaction is applicable to other 1-(3-oxocycloalkyl) carboxylic acids but not to linear γ-keto carboxylic acids.

Full text of DOI:10.1016/j.tetlet.2013.12.021

Accepted Manuscript
Boc-protected 1-(3-oxocycloalkyl)ureas via a one-step Curtius rearrangement:
mechanism and scope
Xianyu Sun, Rachita Rai, Jeffrey R. Deschamps, Alexander D. MacKerell Jr.,
Alan I. Faden, Fengtian Xue
PII:
S0040-4039(13)02096-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.12.021
TETL 43935
Reference:
Tetrahedron Letters
To appear in:
Please cite this article as: Sun, X., Rai, R., Deschamps, J.R., MacKerell, A.D. Jr., Faden, A.I., Xue, F., Boc-protected
1-(3-oxocycloalkyl)ureas via a one-step Curtius rearrangement: mechanism and scope, Tetrahedron Letters (2013),
doi: http://dx.doi.org/10.1016/j.tetlet.2013.12.021
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Boc-protected 1-(3-oxocycloalkyl)ureas via a one-step Curtius rearrangement: mechanism and
scope
Xianyu Suna,d, Rachita Raia, Jeffrey R. Deschampsc, Alexander D. MacKerell, Jr.a, Alan I. Fadenb, and
Fengtian Xuea,*
aDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street,
Baltimore, Maryland 21201
bDepartment of Anesthesiology, University of Maryland School of Medicine, 20 Penn Street, Baltimore,
Maryland 21201
cNaval Research Laboratory, Code 6930, 4555 Overlook Ave., Washington, DC 20375
dCollege of Animal Science and Technique, Heilongjiang Bayi Agriculture University, Daqing 163319,
Heilongjiang, PR China
*Correspondence to Professor Fengtian Xue at the Department of Pharmaceutical Sciences, University of
Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201
Phone: 410-706-8521
Email: fxue@rx.umaryland.edu
Keywords:
1-(3-Oxo)ureas
Curtius rearrangement
Carbamoylcarbamate
γ-Keto carboxylic acid
1-(3-Oxocyclobutyl) carboxylic acid
1

Abstract
1-(3-Oxocyclobutyl) carboxylic acid (4a) was converted into N-Boc-protected 1-(3-oxocyclobutyl) urea
(5a), a key intermediates for the preparation of agonists of metabotropic glutamate receptor 5, in one-step
when treated with diphenyl phosphoryl azide and triethylamine in tert-butanol. The mechanism of the
reaction involves a nucleophilic addition of the in situ generated tert-butyl carbamate to the isocyanate
intermediate. This reaction is applicable to other 1-(3-oxocycloalkyl) carboxylic acids but not to linear γ-
keto carboxylic acids.
Graphic Abstract
2

In the course of our research in developing novel agonists for metabotropic glutamate receptor
subtype 5 (mGluR5), we were interested in the synthesis of 1-(3-oxocyclobutyl)urea (1a), a key
intermediate to various small molecule agonists of mGluR5. To synthesize 1a, we planned to form the
urea beginning with 3-aminocyclobutanone (2a, Scheme 1).1 Although several synthetic routes are
known for the generation of 2a, they usually require multiple steps and/or often give poor overall yields.2
To obtain amine 2a rapidly and efficiently, we attempted to use the Curtius rearrangement to directly
convert carboxylic acid 4a into carbamate 3a,3 which in turn, can easily lead to 2a after removing the N-
protecting group.
Scheme 1. Synthetic plan to 1a.
Our initial effort was to synthesize tert-butyl 3-oxocyclobutylcarbamate (3a). To generate 3a, a
solution of 4a in tert-butanol (t-BuOH) was treated with diphenyl phosphoryl azide (DPPA)4 and
triethylamine (Et3N). After heating the reaction mixture at 50 ºC for 16 h, a major product was isolated in
1
38% yield. To our surprise, mass spectrum and H NMR data of the product did not match those of the
anticipated product (3a). This major product only has an (M+H+) peak at 229, which was 43 daltons
more than the calculated molecular weight of 3a (M+H+ = 186), implying a possible insertion of a –
CONH– fragment into the desired product. This speculation was confirmed by the fact that there was an
1
extra singlet at 8.10 ppm (integrating to one proton) in the H NMR spectrum of the product in CDCl3.
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Further C NMR data showed a peak at 204.7 ppm, indicating the retaining of the ketone functionality.
More interestingly, after treating this compound with trifluoroacetic acid (TFA), urea 1a was isolated and
characterized. On the basis of these results, we assigned the product of the original reaction as tert-butyl
N-((3-oxocyclobutyl) carbamoyl)carbamate (5a, Scheme 2). The chemical structure of 5a was confirmed
3

by single crystal X-ray analysis (Figure 1 and Table 1). The crystallographic analysis showed that the N4
participated in intramolecular hydrogen bonding with the carbonyl group, the N4–H···O7 hydrogen bond
length was 2.08 Å (Table S7), which explained the downfield shift of the corresponding signal (8.10 ppm)
1
in the H NMR. In addition to 5a, the desired product (3a) was isolated as a relatively non-polar
compound with only 5% yields. It is also noted that upon heating at 85 °C for 2 h, the cyclobutanone ring
of 3a broke to form a significant amount of the α,β-unsaturated methylketone. The thermal instability of
3a might also account for the low yield of previously reported methods to this compound.2c
Scheme 2. The Curtius rearrangement of 4a in t-BuOH.
Figure 1. Single crystal structure of compound 5a.
Table 1
Selected crystallographic data of 5a
Empirical formula
Formula weight
Temperature
C10H16N2O4
228.25
150(2) K
Wavelength
0.71073 Å
Crystal system
Space group
Orthorhombic
P n m a
Unit cell dimensions
a = 24.798(2) Å, = 90°
4

b = 9.0377(7) Å, = 90°
c = 5.2093(4) Å, = 90°
Volume
3
1167.49(16) Å
Z
4
Density (calculated)
3
1.299 Mg/m
Absorption coefficient
-1
0.101 mm
488
F(000)
Crystal size
3
0.617 × 0.431 × 0.157 mm
To elucidate the origin of 5a, the reaction was repeated in which carboxylic acid 4a was treated
with DPPA and Et3N in t-BuOH and monitored closely by thin layer chromatography (TLC). Time
course studies clearly showed the disappearance of the starting material (4a) and the emergence of
carbamate 3a within the first hour of the reaction. However, the amount of 3a generated did not change
significantly during the course of reaction. After stirring the reaction for 2 h, compound 5a, with
significantly higher polarity to that of 3a, was formed and built up. Accordingly, we speculated that 3a
might be an intermediate, which was transformed into 5a by the insertion of the –CONH– fragment.
Specifically, we proposed that at the beginning of the reaction, Curtius rearrangement of 4a formed
isocyanate 6a, which was then attacked by t-BuOH to generate carbamate 3a (Scheme 3). Since
compound 3a was not stable under basic environment, it lost a molecule of tert-butyl carbamate via
elimination to form cyclobut-2-enone.5 The resulting tert-butyl carbamate attacked the isocyanate group
of 6a in the reaction mixture to generate compound 5a. It is noted that the theoretical yield of the reaction
is 50%, which explains the relatively modest yields of compound 5a.
5

Scheme 3. Proposed reaction mechanism for the formation of 5a in t-BuOH.
To test this hypothesis, we carried out reactions under the same conditions starting with
cyclobutanecarboxylic acid (7) and 4-oxocyclohexanecarboxylic acid (8). For both reactions, no
carbamoylcarbamates were detected (Scheme 4). When 7 was used, the normal Curtius product tert-butyl
cyclobutylcarbamate was isolated in good yields. This result indicated that without the presence of the γ-
carbonyl group, the Curtius product was stable and no elimination of tert-butyl carbamate happened. On
the other hand, treatment of 8 with the same conditions generated bicyclic 6-azabicyclo[3.2.1]octane-2,7-
dione.6 These results confirmed that the presence of the γ-keto acid group to the carboxylic acid
functionality was essential for the generation of carbamoylcarbamates, which accelerated the elimination
of tert-butyl carbamate from carbamate 3a.
Scheme 4. Reactions starting with compounds 7 and 8.
We also repeated the reaction of 4a with DPPA and Et3N in other alcohols (Scheme 5). When
sterically less hindered primary alcohols (e.g., MeOH, EtOH, and p-methoxybenzyl) were used, the
corresponding esters were isolated as the only products (9a-c) in good yields. On the other hand, the
reaction performed in i-PrOH gave carbamate 3b as the major product. Although the iso-propyl N-((3-
oxocyclobutyl)carbamoyl)carbamate (5b) was also isolated, the yield was significantly less than that of 5a
from the previous reaction in t-BuOH. These results indicated that the outcome of the reaction was
largely controlled by the nucleophilicity of the alcohols involved in the reactions.
6

Scheme 5. The Curtius rearrangement of 4a in other alcohols.
To study the scope of the reaction, similar reactions were conducted under similar conditions
using other γ-keto acids (Scheme 6). When 3-oxocyclopentanecarboxylic acid (4c) and 3-oxocyclo-
hexanecarboxylic acid (4d) were used, the corresponding Boc-protected 1-(3-oxo)ureas (5c and 5d) were
obtained as the major products. However, the reactions starting with non-cyclic γ–keto acids 4e and 4f
generated compounds 5e and 5f in minimum yields, instead, 3,4-dihydro-2H-1,3-oxazin-2-ones 10e and
10f were isolated as the major products. The chemical structure of compound 10e was confirmed by
single crystal X-ray analysis (Figure 2). These results showed that the formation of carbamoyl
carbamates was only applicable to 1-(3-oxocycloalkyl)carboxylic acids, as for the starting materials
employing a non-cyclic γ–keto carboxylic acid functionality, the reaction will favor the formation of 3,4-
dihydro-2H-1,3-oxazin-2-ones via an intramolecular cyclization mechanism.
Scheme 6. Reaction results using γ–keto acids 4c-f.
7

Figure 2. Single crystal structure of compound 10e.
In summary, we report an unexpected one-step formation of Boc-protected 1-(3-oxo)ureas
starting with 1-(3-oxo)acids. In the reaction mechanism, the initially generated carbamate product from
the Curtius rearrangement was not stable. It eliminated the tert-butyl carbamate that attacks the
isocyanate intermediate in the reaction mixture to generate the final product. The application of this
method has been highlighted by a rapid preparation of urea 1a, a key fragment for the development of
agonists for mGluR5. The conditions described herein is applicable to the preparation of other 1-(3-
oxocycloalkyl)ureas.
Acknowledgements
We gratefully acknowledge funding from the Department of Pharmaceutical Sciences, University of
Maryland School of Pharmacy. The X-ray crystallographic work was supported by NIDA through
Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL).
Supplementary data
Supplementary data associated with this article can be found, in the online.
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Graphic Abstract
1