The direct carbamoylation of organometallic reagents with 1,2,3- benzotriazole-1-carboxamides

Article abstract of DOI:10.1039/a809181a

Various (hetero)aromatic amides are synthesized efficiently by the carbamoylation of organometallic reagents.

Full text of DOI:10.1039/a809181a

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230 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 230^231y
The Direct Carbamoylation of Organometallic
Reagents with 1,2,3-Benzotriazole
-1-carboxamidesy
Alan R. Katritzky,* Daphne A. Monteux, Dmytro O.Tymoshenko
and Sergei A. Belyakovz
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville,
FL 32611-7200, USA
Various (hetero)aromatic amides are synthesized efficiently by the carbamoylation of organometallic reagents.
R1
Bt
Tertiary aromatic and heterocyclic carboxamides are import-
ant bioactive agents showing activity as antifungal agents,1
squalene epoxidase inhibitors,2 melatonin analogs,3 potential
anti-HIV drugs, and antitumor agents.4
+
HN
Bt
R2
2a–e
O
1
THF
Reflux
R1
Many tertiary carboxamides are prepared by the
electrophilic acylation of amines.5 However, instead of the
formation of the CO^N bond, it is sometimes convenient
to construct tertiary amides by C^CON bond formation.
Three main variants of this strategy have been reported:
(i) the coupling of organometallics with carbamoyl
N
N
R3
Bt
Bt =
N
R1
R3M
N
N
O
O
R2
3a–e
R2
4a–o
8
chlorides,6 (ii) an alternative homolytic amidation of aro-
matic compounds which is limited to protonated
heteroaromatics,9 and (iii) metal-catalyzed carbonylation
reactions of organic halides,10;11 often under tuned con-
ditions.12;13
Scheme 1 (R1, R2=alkyl, aryl; R3 ˆ aryl, heteroaryl; M ˆ Mg, Li).
Carbamoylation of aryl Grignard reagents with
intermediates 3a^e led to tertiary carboxamides 4a^i (Table
2). Diaryl-(4a) and N-aryl-N-alkylamides (4b^i) were
obtained in high yields. Aryl Grignards substituted with
an electron withdrawing group (4-Cl) (4f,g) a¡orded good
yields in THF while aryl Grignards substituted with an
electron-donating group (Me) required toluene to achieve
good yields (4h,i). Heterocyclic lithio-derivatives (generated
The leaving group properties of benzotriazole14 suggested
a
possible utility of 1,10-carbonylbisbenzotriazole for
N-carbamoylation. The utility of this reagent in enabling
the successive substitution of two benzotriazole moieties with
N-nucleophiles was recently demonstrated by general
syntheses of unsymmetrical tetrasubstituted ureas15 and
oxamides.16
We now report the carbamoylation reaction of carbanions
with N,N-disubstituted-1,2,3-benzotriazole-1-carboxamides as
a new synthetic pathway to (hetero)aryl amides as shown
in Scheme 1. Intermediates 3a^e were prepared by the
reaction of 1.1 equiv. of the corresponding secondary amines
2a^e with 1.0 equiv. of 1,10- carbonylbisbenzotriazole 1
which yielded the corresponding N,N-disubstituted-1,2,3-
benzotriazole-1-carboxamides 3a^e (Table 1). Increasing
the reported reaction time15 improved the yield of intermedi-
ate 3b and enabled synthesis of compound 3c, a precursor of
reportedly bioactive tetrahydroisoquinoline amides.17
from the corresponding heterocycle and BunLi by lithiation
20
procedures18
were reacted with intermediates 3 to yield
heterocyclic amides 4j^o in moderate to good yields, as
shown in Table 2. Attempts with alkyl Grignard reagents
at room temperature provided only starting materials after
a
few hours; when heated to re£ux temperature,
decomposition occurred. Alkyl zinc reagents also failed.
In summary, the benzotriazole moiety of compounds 3a^e
was readily displaced by organometallic reagents (Grignard
or lithio derivatives) to yield the desired benzamides or
heterocyclic amides in moderate to good yields.
Table 1 Preparation of N,N-disubstituted-1,2,3-benzotriazole-1-carboxamides 3a^e
Found (Calc.) (%)
Mp
R1
R2
Yield (%)
(lit. mp)/8C
C
H
N
3a
3b
3c
3d
3e
Ph
Ph
Me
öa
Me
22
68
72
80
74
100^102
(103^105)
75^77
(76^78)
109^111
Ph
öa
69.03
(69.04)
67.55
5.19
(5.08)
5.12
20.30
(20.14)
21.16
4-MeC6H4
57^59
(67.55)
(5.31)
(21.04)
(CH2)2O(CH2)2
101^102
(102^103)
a
ˆ 1,2,3,4-Tetrahydroisoquinoline-2-yl.
* To receive any correspondence.
Experimental
y This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).
z Current address: Guilford Pharmaceuticals, 6611 Trubutary St.,
Baltimore, MD 21224, USA.
Compounds 3a^e were prepared by the procedure reported in ref.15.
General Procedure for the Preparation of Amides 4a^i.öTo a sol-
ution of 3a^e (1mmol) under nitrogen in 10 ml of dry THF (or
toluene) was added the corresponding Grignard reagent (2 mmol).

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J. CHEM. RESEARCH (S), 1999 231
Table 2 Preparation of alkyl, aryl and heterocyclic amides 4
Found (Calc.) (%)
Mp
R1
R2
R3
Yield(%)
81
(lit. mp)/8C
C
H
N
4a
4b
4c
4d
4e
4f
Ph
Ph
Me
öa
Me
Ph
163
5.32
(5.13)
6.93
(6.63)
5.87
(5.90)
6.64
(6.22)
6.94
(7.33)
5.49
(5.70)
5.10
(5.16)
6.15
(177)21
Oil7
(83.48)
79.24
(79.59)
(5.54)
6.39
(6.21)
Ph
Ph
75
öa
Ph
78
Oil22
Oil23
Oil24
Oil25
Oil
(80.98)
79.88
(79.96)
(6.38)
6.88
(6.72)
4-MeC6H4
Ph
83
ꢀCH2†2OꢀCH2†
Ph
81
2
(69.08)
68.23
(68.43)
(6.87)
4.98
(4.93)
Ph
öa
Ph
öa
Ph
öa
Me
öa
Me
öa
Me
öa
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
öb
93
4g
4h
4i
93
(70.71)
(79.96)
(5.20)
(6.72)
90
Oil7
Oil
(6.22)
5.55
(5.57)
5.39
(5.24)
4.55
89
(81.24)
71.65
(71.88)
(6.83)
4.97
(4.91)
4j
58
11526
öe
Oil
4k
4l
öb
60
(73.68)
(69.13)
(5.16)
(5.31)
(4.78)
5.33
(5.66)
10.42
(10.60)
9.58
(9.65)
17.03
(17.42)
(CH2)2O(CH2)2
öb
71
94
öf
4m
4n
4o
Ph
öa
öa
Me
öa
öa
öc
31
Oil27
(74.24)
78.22
(78.59)
(6.11)
6.24
(6.26)
öc
26
123
ög
Oil
öd
60
(69.68)
(6.28)
a 1,2,3,4-tetrahydroisoquinoline-2-yl. b Benzo[b]thiophene-2-yl. c 1-Methylindole-2-yl. d 1-Methylimidazole-2-yl. e Not reported, f Patent
(Chem. Abstr., 1995, 122, 239533a]. g New compound.
After completion of the reaction (TLC), the reaction mixture was
hydrolyzed by NH4Cl (50%) and extracted with ethyl acetate
ꢀ3 Â 10 ml). The organic layers were dried with MgSO4, ¢ltered
and the solvent was removed in vacuo. The resulting oil was subjected
to column chromatography (silica gel; eluent: hexanes^ethyl acetate)
to give the pure products 4a^i. The compounds were characterized
by NMR (1H, 13C) and elemental analysis (Table 2).
General Procedure for the Preparation of Amides 4j^o.öTo the cor-
responding heterocycle (1mmol) in 10 ml of dry THF under nitrogen
was added dropwise BunLi (1mmol) at 78 8C. The resulting solution
was stirred for 15 min, and compound 3a^e (1mmol) in dry THF
(10 ml) was added dropwise. The mixture was stirred at 78 8C
for 16 h and then allowed to warm to 20 8C. After quenching with
H2O (5 ml) and extraction with Et2O (3 Â 10ml), the combined
organic layers were dried over MgSO4, ¢ltered and the solvent
was removed in vacuo. The resulting oil was puri¢ed by column
chromatography (silica gel; eluent: hexanes^ethyl acetate) to give
the pure products 4j^o. The compounds were characterized by
NMR (1H, 13C) and elemental analysis (Table 2).
7
8
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Received, 24th November 1998; Accepted 15th December 1998
Paper E/8/09181A
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