Efficient synthesis of methyl carbamate via Hofmann rearrangement in the presence of TsNBr2

Article abstract of DOI:10.1016/j.tetlet.2012.04.011

An efficient method has been developed for the synthesis of carbamates from the corresponding amides via the Hofmann rearrangement using N,N-dibromo-p-toluenesulfonamide (TsNBr₂) in the presence of DBU in methanol. The reaction goes into completion in 10-20 min at 65 °C to produce the corresponding carbamate in excellent yield.

Full text of DOI:10.1016/j.tetlet.2012.04.011

Tetrahedron Letters 53 (2012) 3035–3037
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Tetrahedron Letters
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Efficient synthesis of methyl carbamate via Hofmann rearrangement in the
presence of TsNBr2
⇑
Arun Jyoti Borah, Prodeep Phukan
Department of Chemistry, Guwahati University, Guwahati 781014, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method has been developed for the synthesis of carbamates from the corresponding amides
via the Hofmann rearrangement using N,N-dibromo-p-toluenesulfonamide (TsNBr2) in the presence of
DBU in methanol. The reaction goes into completion in 10–20 min at 65 °C to produce the corresponding
carbamate in excellent yield.
Received 10 January 2012
Revised 3 April 2012
Accepted 4 April 2012
Available online 12 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
TsNBr2
Hofmann rearrangement
Amides
Carbamate
O
H
Hofmann reaction is a well known useful method for the syn-
thesis of amines or carbamates from primary carboxamides.1 Clas-
sical Hofmann rearrangement was carried out by using aqueous
NaOH and bromine.1 However this method is not always effec-
tively applicable to all kinds of substrates. Therefore, several mod-
ifications have been initiated to improve the reaction conditions
which include important examples such as hypervalent iodine spe-
cies,2 lead tetra acetate,3 benzyltrimethylammonium tribromide,4
NBS-(HgOAc)2,5 NBS-NaOMe,6 NBS-DBU,7 MeOBr,8 TBA-Br3,9 and
NaBrO2-NaBr.10 Many of the reported methods suffer from draw-
backs such as requirement of a large excess of oxidizing agent, over
oxidation of the carbamate products, and substrate scope limita-
tion. However, by introducing modified protocols, these drawbacks
have been minimized to different extents. Recently Miranda et al.
reported a microwave assisted Hofmann rearrangement mediated
by tribromoisocyanuric acid (TBCA).11 As a part of our ongoing
work on the development of synthetic methods using N,N-dibro-
mo-p-toluenesulfonamide (TsNBr2),12 we report herein a fast and
efficient method for Hofmann rearrangement of carboxamides
using TsNBr2 in the presence of DBU in MeOH for the synthesis
of carbamates (Scheme 1).
N
OMe
TsNBr2, DBU
MeOH, reflux
NH2
O
2
1
Scheme 1. Hofmann rearrangement using TsNBr2.
To begin with, a study was carried out to check the feasibility of
the method using benzamide as the model substrate. The results
are summarized in Table 1. The reaction was carried out by adding
TsNBr2 (1 mmol) to a solution of benzamide (1 mmol) and DBU
(3 mmol) in methanol (10 mL). Initial experiment at room temper-
ature afforded 88% yield of the corresponding carbamate after 12 h
of reaction. To improve the rate of the reaction, we have investi-
gated the reaction at reflux temperature (65 °C). Interestingly, we
found that the reaction works excellently and completes in
10 min with an improved yield of 95%. Further investigation by
lowering the amount of TsNBr2 to 0.5 mmol produced 76% of the
corresponding carbamate after 30 min of reaction at reflux temper-
ature. Finally, 1 equiv of TsNBr2 was considered to be the optimum
amount at reflux temperature of methanol.
After finding the optimum condition, we have extended the reac-
tion to a variety of amides. The results are summarized in Table 2.
The reaction was carried out by refluxing a mixture of amide (1 mmol),
TsNBr2 (1 mmol), and DBU (3 mmol) in methanol (10 mL).16 Initially,
we have screened several aromatic carboxamides to examine the
scope of the reaction which produced the corresponding methyl carba-
mate in excellent yield (Table 2, entries 1–6). Thereafter, a few amides
N,N-Dibromo-p-toluenesulfonamide is known for a long time in
organic synthesis. Since the discovery of the reagent by Kharasch,13
it has been utilized for a variety of organic transformations.14
TsNBr2 employed for this purpose was prepared from Chlora-
mine-T by following literature procedure.15
⇑
Corresponding author.
E-mail address: pphukan@yahoo.com (P. Phukan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.011

3036
A. J. Borah, P. Phukan / Tetrahedron Letters 53 (2012) 3035–3037
Table 1
reaction time for the rearrangement could be significantly shortened
(10–20 min) by increasing the reaction temperature. After being suc-
cessful in producing methyl carbamate, the reaction was further ex-
tended to other alcohols as solvents. The reaction also works well for
primary alcohols such as ethanol (Table 2, entry 10), n-propanol (Table
2, entry 11), and n-butanol (Table 2, entry 12). However secondary
alcohols such as isopropanol, cyclohexanol, and tert-butanol failed to
produce the desired product. Our effort to extend the procedure for
2-(trimethylsilyl)ethanol was found to be negative. This may be due
to the strong oxidizing nature of the reagent.12c We have also exam-
ined the scope of the reaction for a heteroaromatic substrate, nicotin-
amide which produced the desired product in excellent yield (Table 2,
entry 13).
Hofmann rearrangement of benzamide under different conditionsa
Entry
TsNBr2 (mmol)
Temp (°C)
Time
Yieldb (%)
1
2
3
1
rt
12 h
88
95
76
1
0.5
65
65
10 min
30 min
a
Reaction condition: Benzamide (1 mmol), DBU (3 mmol), methanol (10 mL).
Isolated yield.
b
bearing aliphatic chain were screened. Excellent yields were obtained
in these cases also (Table 2, entries 7–9). In general, this procedure
works well for a variety of aromatic as well as aliphatic amides to
produce the corresponding carbamate in excellent yield.16 The
Table 2
Synthesis of methyl carbamates via Hofmann rearrangement in the presence of TsNBr2
Entry
Substrate (a)
Alcohol
Product (b)
Time (min)
Yielda (%)
Mp (°C)
Obsd
Lit.
O
H
N
OMe
1
2
MeOH
MeOH
10
20
95
97
46–47
47–497
NH2
1b
O
O
H
N
OMe
115–1177
NH2
113–115
Oil
O
2b
Cl
Cl
O
H
N
OMe
NH2
NH2
3
4
5
MeOH
MeOH
MeOH
20
20
20
90
97
94
—
—
O
3b
Cl
Cl
O
H
N
OMe
Oil
O
4b
Br
Br
O
H
N
OMe
88–897
NH2
88–90
O
5b
MeO
MeO
O
H
N
OMe
6
7
8
MeOH
MeOH
MeOH
20
20
20
97
92
92
97–99
Semi solid
38–40
99–1017
NH2
O
6b
O
H
N
OMe
7b
—
—
NH2
O
O
H
N
OMe
NH2
O
O
8b
H
N
OMe
NH2
9
MeOH
20
92
58–60
—
O
9b
MeO
MeO
O
O
O
O
H
N
OEt
10
11
12
EtOH
10
10
10
85
86
82
47–49
52–54
60–62
49–509
54–559
629
NH2
NH2
NH2
NH2
10b
O
H
N
OnPr
n-PrOH
n-BuOH
O
11b
H
N
OnBu
12b
O
H
N
OEt
13
EtOH
20
78
81–83
841e
O
N
13b
N
Isolated yield after chromatographic purification.
a

A. J. Borah, P. Phukan / Tetrahedron Letters 53 (2012) 3035–3037
3037
O
Supplementary data
O
O
H
H
..
_
N
..
H
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.04.011.
R
N
..
Br
H
..
R
O
S
O
R
N
14
Br
Br
:
15
DBU
N
+
References and notes
H
DBU
+ TsNHBr + DBU
1. (a) Wallis, E. F.; Lane, J. F. Org. React. John Wiley & Sons, New York 1946, 3, 267–
306; (b) Hofmann, A. W. Ber. Dtsch. Chem. 1881, 14, 2725–2736; (c) Hofmann,
A. W. Ber. Dtsch. Chem. 1885, 18, 2734–2741; (d) Senanayake, C. H.;
Fredenburgh, L. E.; Reamer, R. A.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.
J. Am. Chem. Soc. 1994, 116, 7947–7948; (e) Saulniere, L.; Chabrier, P. Ann. Chim.
Appl. 1942, 17, 353–370; (f) Shioiri, T. Comp. Org. Syn. 1991, 6, 800–806.
2. (a) Almond, M. R.; Stimmel, J. B.; Thompson, E. A.; Loudon, G. M. Org. Synth. Coll.
1993, 8, 132; (b) Moriarty, R. M.; Chany, C. J., II; Vaid, R. K.; Prakash, O.;
Tuladhar, S. M. J. Org. Chem. 1993, 58, 2478–2482; (c) Zagulyaeva, A. A.; Banek,
C. T.; Yusubov, M. S.; Zhdankin, V. V. Org. Lett. 2010, 12, 4644–4647.
3. Baumgarten, H. E.; Smith, H. L.; Staklis, A. J. Org. Chem. 1975, 40, 3554–3561.
4. Jajigaeshi, S.; Asano, K.; Fujasaki, S.; Kakinami, T.; Okamoto, T. Chem. Lett. 1989,
463–464.
Me
H
O
O
..
_
Br
:
O
C
17
N
DBU
..
R
N
..
R
16
+
+ HBr + DBU
H
_
DBU
R
H
N
N
:
OMe
R
H
+
O
O
O
5. Jew, S.-S.; Park, H. G.; Park, H.-J.; Park, M.-S.; Cho, Y.-S. Tetrahedron Lett. 1990,
31, 1559–1562.
6. Huang, X.; Keillor, J. W. Tetrahedron Lett. 1997, 38, 313–316.
7. (a) Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997, 62, 7495–7496; (b)
Keillor, J. W.; Huang, X. Org. Synth. Coll. 2004, 10, 549.
18
Me
Scheme 2. Probable mechanistic pathway.
8. Radlick, P.; Brown, L. R. Synthesis 1974, 290–292.
9. Fujisaki, S.; Tomiyasu, K.; Nishida, A.; Kajigaeshi, S. Bull. Chem. Soc. Jpn. 1988,
61, 1401–1403.
10. Kajigaeshi, S.; Nakagawa, T.; Fujisaki, S.; Nishida, A.; Noguchi, M. Chem. Lett.
1984, 713–714.
A probable mechanistic pathway to explain the rearrange-
ment process is depicted in Scheme 2.17 Initial step of the
reaction is the deprotonation of the NH2 group by the non-
nucleophilic base DBU. The resulting N-based anion (14)
subsequently picks up Br+ ion from TsNBr2. Since, TsNBr2 is an
excellent source of Br+ species,12e formation of an intermediate
N-bromoamide (15) is very facile in this case. In the next step,
the bromoamide anion (16) formed in a DBU-promoted proton
loss, undergoes an intramolecular Hofmann rearrangement via
a nitrene intermediate, to form the corresponding isocyanate
(17). Finally, the electrophilic cyanate group is trapped by meth-
anol to form the carbamate.
11. Miranda, L. S. M.; Silva, T. R.; Crespo, L. T.; Esteves, P. M.; Matos, L. F.;
Diederichs, C. C.; Souza, R. O. M. A. Tetrahedron Lett. 2011, 52, 1639–1640.
12. (a) Phukan, P.; Chakraborty, P.; Kataki, D. J. Org. Chem. 2006, 71, 7533–7537; (b)
Saikia, I.; Phukan, P. Tetrahedron Lett. 2009, 50, 5083–5087; (c) Saikia, I.;
Chakraborty, P.; Phukan, P. ARKIVOC 2009, xiii, 281–286; (d) Saikia, I.; Kashyap,
B.; Phukan, P. Synth. Commun. 2010, 40, 2647–2652; (e) Saikia, I.; Kashyap, B.;
Phukan, P. Chem. Commun. 2011, 47, 2967–2969; (f) Saikia, I.; Rajbongshi, K. K.;
Phukan, P. Tetrahedron Lett. 2012, 53, 761–768.
13. Kharasch, M. S.; Priestley, H. N. J. Am. Chem. Soc. 1939, 61, 3425–3432.
14. (a) Terauchi, H.; Kowata, K.; Minematsu, T.; Takemura, S. Chem. Pharm. Bull.
1977, 25, 556–562; (b) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982,
104, 2444–2451; (c) Revesz, L.; Blum, E.; Wicki, R. Tetrahedron Lett. 2005, 46,
5577–5580; (d) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118,
9526–9538; (e) Shen, R.; Huang, X. J. Org. Chem. 2007, 72, 3961–3964; (f) Han,
J.; Li, T.; Pan, Y.; Kattuboina, A.; Li, G. Chem. Biol. Drug. Des. 2008, 71, 71–77; (g)
Shen, R.; Huang, X. Org. Lett. 2009, 11, 5698–5701; (h) Zhi, S.; An, G.; Sun, H.;
Han, J.; Li, G.; Pan, Y. Tetrahedron Lett. 2010, 51, 2745–2747.
In conclusion, an efficient protocol for Hofmann rearrangement
reaction of various amides has been established by using N,N-di-
bromo-p-toluenesulfonamide in the presence of DBU. Although
the reaction works well at room temperature, use of a higher tem-
perature could push the reaction forward at a much faster rate. The
procedure is very fast, easy to perform, and applicable to various
aromatic, aliphatic, and heteroaromatic amides to produce the
corresponding carbamates in excellent yields.
15. Nair, C. G. R.; Indrasen, P. Talanta 1976, 23, 239.
16. Experimental procedure for the synthesis of carbamate: To a solution of amide
(1 mmol) in methanol (10 mL) was added DBU (0.5 mL). To this solution
TsNBr2 (1 mmol) was added. The reaction mixture was heated under reflux
condition for a period of 10–20 min (TLC). After completion of the reaction
(TLC) methanol was evaporated under reduced pressure. The crude mixture
was then dissolved in EtOAc. This solution was washed with 5% HCl and then
with saturated Na2CO3 solution. The organic extracts were separated and dried
over anhydrous Na2SO4. The crude product was purified by flash column
chromatography using petroleum ether and ethyl acetate (4:1) as eluent to get
the pure carbamate product.
Acknowledgments
Financial Support from DST (Grant No. SR/S1/OC-43/2011) is grate-
fully acknowledged. A.J.B. thanks the UGC for research fellowship.
17. Morrison, R. T.; Boyd, R. N.; Bhattacharjee, S. K. Organic Chemistry, 7th ed.;
Pearson Education-Dorling Kindersley: India, 2011. pp. 711–712.