Copper-catalyzed carbonylation of anilines by diisopropyl azodicarboxylate for the synthesis of carbamates

Article abstract of DOI:10.1039/C6RA22108D

A Cu-catalyzed efficient methodology for the direct carbonylation of anilines has been developed. The N-H bond cleavage and N-C bond formation were notably achieved under solvent-free conditions and a variety of carbamates were synthesized from readily available anilines using diisopropyl azodicarboxylate (DIAD) as the carbonylating source.

Full text of DOI:10.1039/C6RA22108D

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Copper-catalyzed carbonylation of anilines by diisopropyl
azodicarboxylate for the synthesis of carbamates
Received 00th January 20xx,
Accepted 00th January 20xx
Muhammad Usman, Zhi-Hui Ren, Yao-Yu Wang and Zheng-Hui Guan*
DOI: 10.1039/x0xx00000x
www.rsc.org/advances
Cu-catalyzed an efficient methodology of direct carbonylation of carbonyl sources is also desirable (Scheme 1b). As part of our
anilines has been developed. The N-H bond cleavage and N-C bond
formation was notably achieved under solvent-free conditions and
variety of carbamates were synthesized from readily available
anilines using diisopropyl azodicarboxylate (DIAD) as
carbonylating source.
a
Dialkyl azodicarboxylates, as potential reagents, are very
useful in organic synthesis such as Mitsunobu reaction.1 Due to
its unique structural and electronic features, azodicarboxylates
are used in zwitterions intermediate reactions,2 as oxidants,3
aldehydic C-H bond functionalization by hydroacylation,4
amination of C-H bonds,5 α-amination of carbonyl and
cyanoacetate compounds.6 However, the investigation of
dialkyl azodicarboxylates as carbonylating reagent is very Scheme 1 Different carbonyl sources used for the synthesis of carbamates from
amines.
limited.7
Organic carbamates are important intermediates for the
previous work related to carbamate synthesis,10d we
synthesis of pesticides, herbicides and pharmaceutical drugs.8
speculated that carbamates could be formed with the aid of
Several methods for carbamates synthesis have been reported
dialkyl azodicarboxylate under mild reaction conditions. We
using N,N’-carbonyldiimidazole, carbamoylimidazolium salts
selected copper as a possible catalyst because, it has robust
and toxic phosgene or its derivatives.8c,9 The other available
catalytic activities.15 Cu-catalyzed direct C-N bond formation is
carbonyl sources for the synthesis of carbamates are urea,
more desirable atom-economic synthetic approach.15a In this
dialkyl carbonate, CO2 and CO (Scheme 1a).10 Transition metals
regard, Cu-catalyzed reactions of diazo compounds have
catalyzed poisonous CO oxidative11 and reductive12
gained significant achievement.15c However, to the best of our
carbonylation of amines and nitro compounds have been
knowledge copper-catalyst had never been studied in the
reported respectively. Industrially important methods are
carbonylation reaction of dialkyl azodicarboxylates. Herein, we
through carbonylation of amines with organic carbonates.13
wish to report
carbamates via
a
a
simple method for the synthesis of
novel reaction by using diisopropyl
The synthesis of carbamates have also been accomplished via
Lossen, Curtius and Hofmann rearrangements.14 The
limitations of these methods are due to multi step procedures,
harsh reaction conditions and lack of easily available
substrates. Despite these advances, the development of more
convenient and alternative methods based upon other
azodicarboxylate (DIAD) as the carbonyl source over copper-
catalyst notably under solvent-free conditions.
We initially tried to optimize the reaction conditions of
aniline 1b with DIAD 2a by using different solvents.
Gratifyingly, we observed that 1b could be transformed into
the desired carbamate 3b in 23% yield (Table 1, entry 1) using
CuI as the catalyst in THF. In addition, the effects of various
organic solvents and catalysts were investigated, and we found
that solvents do not play an important role in this reaction.
When toluene, DMSO or DMF was used as a solvent, major
change in carbonylation did not occur, but a very low yield of
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry
of Education, Department of Chemistry & Materials Science Northwest University,
Xi’an 710127, P.R. China. E-mail: guanzhh@nwu.edu.cn
Homepage: http://chem.nwu.edu.cn/teacher.php?id=189.
†Electronic Supplementary Information (ESI) available: Experimental section,
characterization of all compounds and copies of 1H and 13C NMR spectra for all
selected compounds. See DOI: 10.1039/x0xx00000x
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Journal Name
13d
Cu(OAc)2
-
-
-
RT
RT
68
0
corresponding product was obtained (15-20%) (Table 1, entries
2-4). The change of different catalysts in THF further reduced
the product yield (Table 1, entries 5-7). When Pd(OAc)2 was
used as a catalyst, no reaction was observed (Table 1, entry 8).
We speculated that the employment of solvent-free conditions
would improve the reaction yield. Delightedly, the yield of 3a
increased to 27% in the absence of solvent when the reaction
was carried out in the presence of CuI at room temperature for
1h (Table 1, entry 9). The best result was obtained when the
reaction was performed in the presence of Cu(OAc)2 (Table 1,
entry 11). Further changing the catalyst loading showed less
efficiency in term of yields (Table 1, entries 12-13).
Furthermore, no reaction occurred in the absence of copper-
catalyst (Table 1, entry 14).
14
a Reaction conditions: 1b (0.3 mmol), 2a (0.6 mmol) and catalyst (5 mol%)
in solvent (1 ml) under Ar for 1 h. b Isolated yields. c Cu(OAc)2 (1 mol%). d
Cu(OAc)2 (20 mol%).
Table 2 Cu-catalyzed carbonylation of anilinesa
Entry
Substrate
Product
Yieldb (%)
1
81
After optimizing the reaction conditions, the substrate
scope of the reaction was investigated (Table 2). This solvent
free carbonylation was found to be a good methodology for
the synthesis of carbamates. Carbonylation of aniline 1a with
DIAD 2a gives carbamate 3a in 81% yield (Table 2, entry 1).
While, diethyl azodicarboxylate (DEAD) 2b led to
comparatively the same yield (Table 2, entry 2). Anilines
substituted at the aryl ring with Me, MeO, F, Cl Br, and I were
converted into the corresponding products efficiently, (Table
2, entries 3-9). However, the reaction of 1h and 1i was sluggish
and was achieved with long reaction time at elevated
temperature (Table 2, entries 10-11). When meta-substituted
anilines 1j and 1k were employed, the corresponding products
3j and 3k were obtained up to 71% and 81% yields,
respectively (Table 2, entries 12-13). In addition, ortho-
substituted anilines 1l and 1m were transformed into the
corresponding carbamates 3l and 3m in moderate yields (Table
2, entries 14-15). Moreover, the 3,4-dimethylaniline and 2,4-
di-methylaniline smoothly furnished the desired products in
good yields (Table 2, entries 16-17). Intresteingly, when the
heterocyclic analogues 1p was subjected to the standard
reaction conditions, the desired product 3p was obtained in
30% yield (Table 2, entry 18). However, the scope of this
reaction was limited to primary anilines.
2
3
79
75
4
5
6
7
8
9
74
74
78
83
82
66
Table 1 Optimization of reaction conditionsa
10
11
48c
52c
Entry
1
Catalyst
CuI
Solvent
THF
toluene
DMSO
DMF
THF
THF
THF
THF
-
Temp (oC)
120
120
120
120
120
120
120
120
RT
Yieldb (%)
23
2
CuI
15
3
CuI
20
4
CuI
18
5
CuBr2
19
6
CuCl2
Trace
Trace
0
12
13
71
81
7
Cu(NO3)2
Pd(OAc)2
CuI
8
9
27
10
11
12c
Cu(TFA)2
Cu(OAc)2
Cu(OAc)2
-
RT
21
-
RT
75
-
RT
66
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Further, the decomposition of aliphatic azo compounds
accomplished the free radicals that could be used for further
transformations.7a,7b,17 We found that, when 1a reacted with
2a under standard reaction conditions, 3a and diisopropyl
14
53
45
O
4
were formed (Scheme 3).7a We believed that
H
N
carbonate
decomposition of 2a would generate the oxyacyl radicals A 18
O
15
,
O
some of which undergo carbonylation to form carbamates,
while some of them would undergo decarbonylation to
generate diisopropyl carbonate.
3m
16
17
18
79
73
On the basis of these studies, a possible mechanism for
this C-N bond formation utilizing DIAD and aniline is proposed
(Scheme 4). The N-H bond carbonylation using DIAD, the
proposed mechanism is triggered by copper catalyst, first the
DIAD 2a decomposes to give the oxyacyl radicals
supposed to abstract hydrogen from aniline to generate the
aminyl radical B 19
DIAD 2a serves as an aniline radical initiator
as well as radical trapping reagent in the reaction.20 The
resulting radicals and combine together to give
corresponding carbamate
A, which is
1
.
30d
A
B
a Reaction conditions: anilines 1 (0.3 mmol), 2 (0.6 mmol) and Cu(OAc)2 (5
mol%) under Ar at room temperature for 1 h. b Isolated yields. c 80 oC instead of
room temperature for 4 h. d 80 oC for 1 h. R = iPr, Et.
3
.
In conclusion, we have uncovered a novel method for the
synthesis of carbamates by Cu-catalyzed reaction of simple
anilines with commercially available diethyl or diisopropyl
azodicarboxylate. The N-H bond cleavage and N-C bond
formation was notably achieved under solvent-free conditions.
Various electron-donating and electron-withdrawing groups on
anilines are compatible with this method. The use of readily
available dialkyl azodicarboxylate and an inexpensive copper-
catalyst make this method mild, general and efficient, thus
providing an extremely preferable protocol for the synthesis of
variety of carbamates. Further studies on extending the scope
of the reaction and detailed investigation into the reaction
mechanism are under progress in our laboratory.
Scheme 2 . Synthetic transformation of 1q. Reaction conditions: 1q (0.3 mmol),
DEAD 2b (0.6 mmol) and Cu(OAc)2 (5 mol%) under Ar at 80 oC for 1 h.
Scheme 3 Investigation of the reaction mechanism.
Acknowledgements
This work was supported by generous grants from the National
Natural Science Foundation of China (21272183 and
21472147) and Fund of the Shanxi Province (2016JM2007).
Notes and references
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Graphical Abstract:
Herein a simple Cu-catalyzed system for the synthesis of carbamates has been
developed using anilines with diisopropyl azodicarboxylate as a carbonyl source
under solvent-free conditions.