A Mild and Efficient Modified Hofmann Rearrangement

Full text of DOI:10.1021/jo9708553

J . Org. Chem. 1997, 62, 7495-7496
7495
A Mild a n d Efficien t Mod ified Hofm a n n
Sch em e 1
Rea r r a n gem en t
Xicai Huang, Mehran Seid, and J effrey W. Keillor*
D e´ partement de chimie, Universit e´ de Montr e´ al, C.P. 6128,
Succursale centre-ville, Montr e´ al, PQ, H3C 3J 7 Canada
Ta ble 1. Con ver sion of P r im a r y Am id es 1 to Meth yl
Ca r ba m a tes 2 w ith NBS/DBU
Received May 13, 1997
RCONH2a
yield of
obs.
lit.
mp (°C)
The classical Hofmann rearrangement is the conver-
R )
2 (%)b
mp (°C)c
method ref
sion of a primary carboxamide to a primary amine using
1
p-MeOC6H4
,4-(MeO)2C6H3
p-MeC6H4
C6H5
95
89
84
95
94
70
95
90
73
68
43
87-89
80-81
98-99
45-46
113-115 115-117
177-178 177.5-178
88-89
81
99-101
47-48.5
A
A
A
A
A
A
A
A
A
B
B
8
9
aqueous NaOH and Br
2
.
In order to improve the
3
reaction conditions and yield, many modifications have
been made by using oxidative reagents including iodi-
10
10
10
11
12
13
1
2
3
ne(III) species, lead tetraacetate, benzyltrimethylam-
p-ClC H4
6
monium tribromide,4 NBS-Hg(OAc) OBr.6
, and CH
2 3
5
d
p-NO2C6H4
C6H5CH2
CH3(CH2)8
CH3(CH2)14
,4-(MeO)2C6H3
64-65
<rt
61-62
55-56
65
When methanol is used as a solvent, the corresponding
methyl carbamate is produced. However, clean conver-
sion of p-methoxybenzamide to its corresponding methyl
carbamate is impossible through the use of the oxidants
mentioned above because they cause further oxidation
e
e
61-62
2
14
15
p-(CH3)2NC6H4
98-100 100-102
a
Prepared from the corresponding carboxylic acid or acid
7
of the product. Recently, we reported an alternative
b
chloride.
Refers to pure isolated and characterized product.
c
d
method for the preparation of p-anisidine through the
use of NBS in the presence of NaOMe in methanol. This
method was shown to be broadly useful for the conversion
of carboxamides to their corresponding methyl carbam-
ates. Its principal disadvantage is its use of a strong base
Determined in capillary tubes and uncorrected.
Overnight
e
reflux. 50 mL of MeOH for 0.5 mmol of amide.
of NBS. Two equivalents of NBS were generally used to
ensure complete conversion. Even p-nitrobenzamide
undergoes rearrangement, although not quite as rapidly.
For the long chain aliphatic amides, a large volume of
methanol was used in order to avoid the formation of
N,N′-dialkylurea. For example, for the reaction of
(
NaOMe); in addition, this method is not capable of
effecting the rearrangement of either p-(dimethylami-
no)benzamide or p-nitrobenzamide. However, following
further modification of the reaction conditions, we are
now able to prepare a wide series of methyl carbamates
that includes these two compounds. Herein we report a
mild and efficient modified Hofmann rearrangement
through the use of NBS and DBU in methanol (Scheme
).
As shown in Table 1, this modification is widely useful
for the conversion of alkyl and aryl carboxamides to their
corresponding methyl carbamates in excellent yields
under extremely mild conditions. The reaction is usually
complete in 25 min in boiling methanol, in the presence
CH
3 2 2
(CH )14CONH in the presence of 5 mL of methanol
on a 0.5 mmol scale, the major product was the urea;
however, in the presence of 50 mL of methanol the yield
of the desired methyl carbamate was increased to 70%.
This modified method is most useful for the conversion
of benzamides with strongly electron-donating substitu-
ents. With 2,4-dimethoxybenzamide and 4-(dimethy-
lamino)benzamide, 1 equiv of NBS was added at -78 °C
to avoid bromination of the benzene ring, and then the
mixture was kept at room temperature for 4 h. Good to
moderate yields result under these conditions, and the
unreacted starting material can easily be recovered and
recycled. When 2 equiv of NBS was used, no rearrange-
ment occurred; rather, electrophilic aromatic mono-
bromination of the benzamides was found to be the major
reaction. An attempt was made to effect the rearrange-
ment of p-hydroxybenzamide, but even at -78 °C in the
presence of 1 equiv of NBS, mono-bromination of the
benzene ring still occurred more rapidly than the rear-
rangement, which was not observed.
1
(
1) Wallis, E .S.; Lane, J . F. Org. React. 1946, 3, 267-306.
(2) Moriarty, R. M.; Chany, C. J ., II; Vaid, R. K.; Prakash, O.;
Tuladhar, S. M. J . Org. Chem. 1993, 58, 2478-2482.
3) Baumgarten, H. E.; Smith, H. L.; Staklis, A. J . Org. Chem. 1975,
0, 3554-3561.
4) Kajigaeshi, S.; Asano, K.; Fujisaki, S.; Kakinami, T.; Okamoto,
T. Chem. Lett. 1989, 463-464.
5) J ew, S.-S.; Park, H. G.; Park, H.-J .; Park, M.-S.; Cho, Y.-S.
(
4
(
(
Tetrahedron Lett. 1990, 31, 1559-1562.
(
(
(
6) Radlick, P.; Brown, L. R. Synthesis 1974, 290-292.
7) Huang, X; Keillor, J . W. Tetrahedron Lett. 1997, 38, 313-316.
8) Esch, P. M.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1992,
1
6
4
8, 3445-3462.
9) Experimental data: 1H NMR (300 MHz, CDCl
) 3.75 (s, 3H), 3.85
3
Recently, Sananyake and co-workers reported that
in aqueous potassium hydroxide the active brominating
species derived from NBS is KO CCH CH CONKBr,
2 2 2
which was found to decompose at 20 °C. In our previ-
ously reported use of NBS in boiling methanol in the
presence of NaOMe, we suggested that the brominating
(
(
1
6
s, 3H), 3.89 (s, 3H), 6.64 (bs, 1H), 6.74-6.78 (m, 2H), 7.10-7.22 (b,
H). Literature melting point: Brunner, O.; W o¨ hrl, R. Monatsh. 1933,
3, 374-384.
(10) Fujisaki, S.; Tomiyasu, K.; Nishida, A.; Kajigaeshi, S. Bull.
Chem. Soc. J pn. 1988, 61, 1401-1403.
7
(11) Hegarty, A. F.; Frost, L. N. J . Chem. Soc., Perkin Trans. 2 1973,
1
3
719-1728.
2 2 2
species is the analogous MeO CCH CH CONNaBr, which
(
(
(
12) de la Saulni e` re, P. C. Ann. Chim. 1942, 17, 353-370.
is able to effect the desired rearrangement prior to its
decomposition. In order to determine the brominating
species in the present study, the byproducts of the
reaction of benzamide with 2 equiv of NBS were isolated
+
13) Experimental data: HRMS (M + 1) ) 202.17990
14) Experimental data: H NMR (300 MHz, CDCl
1
3
) δ 3.76 (s, 3H),
.80 (s, 3H), 3.85 (s, 3H), 6.45-6.52 (m, 2H), 6.98 (bs, 1H), 7.82-7.89
) δ 155.831, 148.993, 143.520,
21.005, 119.120, 103.768, 98.656, 55.604, 55.496, 52.131. Anal. Calcd
: C, 56.86; H, 6.22; N, 6.63. Found: C, 56.89; H, 6.36;
(
b, 1H); 13C NMR (75 MHz, CDCl
3
1
for C10
N, 6.60.
15) Laidlaw, R. K.; Miura, Y.; Panetta, C. A. Acta. Crystallogr. 1988,
C44, 2009-2013.
H13NO
4
(16) 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.
(
S0022-3263(97)00855-4 CCC: $14.00 © 1997 American Chemical Society

7
496 J . Org. Chem., Vol. 62, No. 21, 1997
Notes
by flash column chromatography and identified by proton
NMR. The major byproducts were found to be succin-
Gen er a l Rep r esen ta tive Exp er im en ta l
P r oced u r es
2 2 2 2
imide (1.3 equiv) and MeO CCH CH CONH (0.4 equiv),
suggesting that in the absence of methoxide the active
brominating species may be simply NBS. This species
is probably also unstable in boiling methanol, but when
excess NBS is added in two portions, the active bromi-
nating species is apparently sufficiently long-lived to
promote rearrangement.
Kajigaeshi and co-workers have reported17 the use of
DBU as a base for the Hofmann rearrangement (in their
case, with tetrabutylammonium tribromide), and it ap-
pears as though DBU is particularly well suited to effect
the rearrangement. For example, in the absence of DBU,
we have found that 4-(dimethylamino)benzamide reacts
with NBS to undergo only mono-bromination at room
temperature, and no rearrangement occurs. Further-
Meth od A. p-Methoxybenzamide (76 mg, 0.5 mmol), NBS
90 mg, 0.5 mmol), and DBU (230 µL) in methanol (5 mL) were
(
heated at reflux for 15 min, at which point more NBS (90 mg,
.5 mmol) was added. The reaction was allowed to continue for
0
another 10 min. Methanol was then removed by rotary evapo-
ration, and the residue was dissolved in 50 mL of EtOAc. The
EtOAc solution was washed with 5% HCl and saturated NaH-
CO
methoxyphenyl)carbamate, was purified by flash column chro-
matography (silica gel, eluant 5% EtOAc in CH Cl ) to give a
3 4
and was then dried over MgSO . The product, methyl (p-
2
2
white solid (86 mg, 95%), which was further purified by
8
recrystallization from hexane, mp 87-89 °C (lit. mp 88-89 °C).
Meth od B. 2,4-Dimethoxybenzamide (91 mg, 0.5 mmol) and
DBU (230 µL) in methanol (5 mL) and CH Cl (5 mL) were cooled
2 2
to -78 °C, followed by the addition of NBS (90 mg, 0.5 mmol).
The resulting mixture was stirred at -78 °C for 30 min until
all of the NBS was dissolved and then allowed to warm up slowly
to room temperature. Stirring was continued at room temper-
ature for another 4 h. Methanol was removed by rotary
evaporation, and the residue was purified directly by flash
more, when an attempt was made to use NEt
of DBU, no rearrangement was observed for benzamide
even at higher temperatures. Apparently NEt , while
3
in place
3
only slightly less basic than DBU, is not a strong enough
base to promote the rearrangement.
column chromatography (silica gel, eluant 5% EtOAc in CH
to give the product, methyl (2,4-dimethoxyphenyl)carbamate,
2 2
Cl )
Our conditions for the modified Hofmann rearrange-
ment are among the mildest available. Surprisingly, our
conditions are also widely useful, and the series of amides
that we have easily and efficiently transformed into
methyl carbamates is one of the broadest reported to
date.18 This reaction should therefore be very useful for
the practical transformation of primary amides to their
corresponding primary amines for an extremely wide
range of both aromatic and aliphatic compounds.
14
isolated as an oil (69 mg, 68%) which was further purified
through recrystallization from hexane, mp 55-56 °C.
Although the results reported in Table 1 are based on the
mmol-scale procedures described above, we have found that
gram-scale reactions also afforded the methyl carbamates in
similar yields.
Ack n ow led gm en t. The authors gratefully acknowl-
edge the financial support of the University of Montr e´ al,
the Natural Sciences and Engineering Research Council
(
17) Fujisaki, S.; Tomiyasu, K.; Nishida, A.; Kajigaeshi, S. Bull.
Chem. Soc. J pn. 1988, 61, 1401-1403.
18) Furthermore, when the reaction of benzamide with NBS in the
(NSERC) of Canada, and the Fonds pour la formation
(
presence of DBU is carried out in benzyl alcohol, the corresponding
benzyl carbamate is isolated in 76% yield. When the reaction is carried
out in water, aniline is obtained directly in 50% yield.
de chercheurs et l’aide a` la recherche (FCAR) of Qu e´ bec.
J O9708553