1,2,3-Triazole as a safer and practical substitute for cyanide in the Bruylants reaction for the synthesis of tertiary amines containing tertiary alkyl or aryl groups

Article abstract of DOI:10.1016/j.tetlet.2005.06.066

Tertiary amines containing tertiary alkyl or aryl groups were synthesized by the reaction of a ketone with an amine and 1,2,3-triazole followed by substitution of the triazole adduct with a Grignard reagent. Thus, 1,2,3-triazole serves as a safer and practical alternative to cyanide in the Bruylants reaction.

Full text of DOI:10.1016/j.tetlet.2005.06.066

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5455–5458
1,2,3-Triazole as a safer and practical substitute for cyanide in
the Bruylants reaction for the synthesis of tertiary amines
containing tertiary alkyl or aryl groups
*
Mahavir Prashad, Yugang Liu, Denis Har, Oljan Repic and Thomas J. Blacklock
ˇ
Process Research and Development, Chemical and Analytical Development, Novartis Pharmaceuticals Corporation,
One Health Plaza, East Hanover, NJ 07936, USA
Received 2 June 2005; accepted 14 June 2005
Available online 1 July 2005
Abstract—Tertiary amines containing tertiary alkyl or aryl groups were synthesized by the reaction of a ketone with an amine and
1,2,3-triazole followed by substitution of the triazole adduct with a Grignard reagent. Thus, 1,2,3-triazole serves as a safer and prac-
tical alternative to cyanide in the Bruylants reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
Tertiary amines containing tertiary alkyl group, such as
4-methyl-4-(4-alkyl-piperazin-1-yl)-piperidine-1-carboxy-
lic acid tert-butyl ester, are intermediates in the synthesis
of biologically important molecules.1 Their synthesis uti-
lized two steps, a Strecker reaction of a ketone with an
amine and potassium cyanide (or diethyl aluminum cya-
nide) and a Bruylants reaction of resulting aminonitrile
with a Grignard reagent.2 Use of toxic cyanide reagents
as well as the use of cyanide as a leaving group makes
this synthesis undesirable for large-scale preparations.
Benzotriazole was reported by Katritzky et al.3 as a sub-
stitute for cyanide. However, benzotriazole is known to
be an explosive reagent,4 and in some cases, the yield of
the product was poor. We were recently faced with the
challenge of developing a safer and practical alternative
to cyanide that is amenable for large scale. In this paper,
we report 1,2,3-triazole as a safer and practical alterna-
tive to cyanide in the Bruylants reaction for the synthesis
of tertiary amines containing tertiary alkyl and aryl
groups that is also superior to benzotriazole. 1,2,3-Tria-
zole is also more atom efficient than benzotriazole, and
its cost in large scale is well acceptable.
Bruylants reaction since neither of these compounds
were reported to be explosive. In addition, our own
safety tests of these materials showed no hazard. Thus,
the reaction of cyclohexanone with piperidine in the pres-
ence of 1,2,3-triazole in toluene at 108–114 °C with azeo-
tropic removal of water afforded a solution of the
corresponding triazolyl intermediate (I, Scheme 1),
which was not isolated and was added to a solution of
phenylmagnesium bromide at 24 °C to afford the desired
product 1-(1-phenylcyclohexyl)piperidine (1) in 80% iso-
lated yield (entry 1, Table 1). Similarly, methylmagne-
sium chloride afforded the corresponding methyl
compound (2) in 73% yield (entry 4, Table 1). The same
reaction in the presence of 1,2,4-triazole and benzotriaz-
ole gave lower yields of 1 (54% and 55%, respectively, en-
tries 2 and 3) with phenylmagnesium bromide and of 2
(60% and 50%, respectively, entries 5 and 6) with methyl-
magnesium chloride. These results suggested that 1,2,3-
triazole was superior to 1,2,4-triazole and benzotriazole.
Similar results were obtained during the reaction of
cyclohexanone with morpholine and N-methylpiperazine
followed by the reaction of the corresponding triazolyl
intermediate with phenylmagnesium bromide. The reac-
tion of cyclohexanone with pyrrolidine in the presence of
benzotriazole followed by phenylmagnesium bromide
was reported3 to afford only 13% of 5. In our hands,
we obtained a 12% yield of 5 with benzotriazole (entry
14). However, use of 1,2,3-triazole afforded 5 in 52%
yield (entry 13). The yield of 6 from cyclohexanone,
N-benzylmethylamine, and phenylmagnesium bromide
was only 31% in the presence of 1,2,3-triazole (entry
We reasoned that 1,2,3-triazole and 1,2,4-triazole would
be safer and practical alternatives to the cyanide in the
Keywords: 1,2,3-Triazole; Tertiary amines; Bruylants reaction.
*
Corresponding author. Tel.: +1 862 778 3467; fax: +1 973 781
2188; e-mail: mahavir.prashad@novartis.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.066

5456
M. Prashad et al. / Tetrahedron Letters 46 (2005) 5455–5458
Y
N
Y
N
N
O
X
HN
N
H
N
RMgX
THF
N
N
N
R
+
toluene
Y
X
X
R=Me, Ph
X=CH2, N-BOC
Y=CH2, N-Me, O
(I)
Scheme 1.
Table 1. Comparison of triazoles with cyclohexanone
Entry
Ketone
Amine
Triazole
Grignard reagent
Product
Isolated yield (%)
O
1
2
3
1,2,3-Triazole
1,2,4-Triazole
Benzotriazole
PhMgBr
PhMgBr
PhMgBr
80
54
55
H
N
Ph
N
N
(1)
O
H
N
4
5
6
1,2,3-Triazole
1,2,4-Triazole
Benzotriazole
MeMgCl
MeMgCl
MeMgCl
73
60
50
Me
(2)
O
H
N
O
O
7
8
9
1,2,3-Triazole
1, 2,4-Triazole
Benzotriazole
PhMgBr
PhMgBr
PhMgBr
84
68
67
Ph
N
(3)
N
O
H
N
Me
10
11
12
1,2,3-Triazole
1,2,4-Triazole
Benzotriazole
PhMgBr
PhMgBr
PhMgBr
74
57
53
Ph
Ph
Ph
N
N
N
Me
(4)
O
O
H
N
13
14
1,2,3-Triazole
Benzotriazole
PhMgBr
PhMgBr
52
12
(5)
Me
N
15
16
17
PhCH2NHMe
1,2,3-Triazole
1,2,4-Triazole
Benzotriazole
PhMgBr
PhMgBr
PhMgBr
31
25
20
Ph
(6)
15), nevertheless it was better than those obtained with
1,2,4-triazole and benzotriazole, which were 25% and
20%, respectively (entries 16 and 17).
presence of benzotriazole and subsequent reaction of
the resulting adduct with methylmagnesium bromide
was reported3 to afford only the enamine as the major
product. This reaction in the presence of 1,2,3-triazole
afforded the desired product in 38% yield (entry 7).
These results once again suggested that 1,2,3-triazole is
superior to benzotriazole.
The synthetic utility of 1,2,3-triazole was further studied
with several ketones and amines, and the results are
listed in Table 2. Six-membered ketones gave excellent
yield with various amines (entries 1–3, Table 2). The
reaction of cycloheptanone with morpholine and benzo-
triazole, followed by the treatment of the adduct with
phenylmagnesium bromide was reported3 to afford only
13% yield of 10. However, the yield of 10 with 1,2,3-tri-
azole was 45% (entry 4). These results further confirmed
the superiority of 1,2,3-triazole over benzotriazole. The
yields of 11 and 12 from cycloheptanone in the presence
of 1,2,3-triazole were also modest (entries 5 and 6, Table
2). Reaction of cyclopentanone with morpholine in the
In summary, 1,2,3-triazole is a safer and practical alter-
native to cyanide in the Bruylants reaction for the syn-
thesis of tertiary amines containing tertiary alkyl or
aryl groups. The scope of this reaction will be further
studied with other ketones and Grignard reagents.
Typical experimental procedure: A three-necked flask,
equipped with a mechanical stirrer, a Dean–Stark trap,
a condenser with nitrogen inlet–outlet was charged with

M. Prashad et al. / Tetrahedron Letters 46 (2005) 5455–5458
5457
Table 2. Reaction with 1,2,3-triazole
Entry
Ketone
Amine
Triazole
Grignard reagent
MeMgCl
Product
Isolated yield (%)
Me
O
N
H
N
Me
Me
Me
N
1
1, 2,3-Triazole
79
N
Me
(7)
N
BOC
N
BOC
O
O
H
N
N
2
1,2,3-Triazole
MeMgCl
90
(8)
N
BOC
O
N
BOC
O
N
H
N
3
1,2,3-Triazole
MeMgCl
85
N
BOC
(9)
N
BOC
O
O
H
N
Ph
N
4
5
1, 2,3-Triazole
1, 2,3-Triazole
PhMgBr
MeMgCl
45 (13)a
(10)
O
Me
H
N
O
N
Me
Me
N
N
40
N
Me
(11)
O
H
N
6
7
1,2,3-Triazole
MeMgCl
MeMgCl
40
38
(12)
H
N
O
O
N
1, 2,3-Triazole
Me
(13)
O
a Yield reported in Ref. 4.
an amine (55 mmol), ketone (50 mmol), 1,2,3-triazole,
or 1,2,4-triazole, or benzotriazole (60 mmol) and
50 mL of toluene. The reaction mixture was heated to
108–114 °C to achieve reflux and stirred for 6–8 h while
collecting water via a Dean–Stark trap. The reaction
mixture was cooled to room temperature and added to
phenylmagnesium bromide (200 mmol, 1 M in THF)
or methylmagnesium chloride (200 mmol, 3 M in
THF) over a period of 30 min with efficient stirring
while maintaining the internal temperature at <24 °C.
The reaction mixture was stirred at room temperature
for an additional 1 h. It was then added to a 20% ammo-
nium chloride solution (120 g) over a period of 30 min
while maintaining the internal temperature at <30 °C.
The organic layer was separated. The aqueous layer
was extracted with ethyl acetate (200 mL). The com-
bined organic layers were washed with 2 N sodium
hydroxide (100 mL), water (100 mL), and concentrated.
The crude material was purified by silica gel chromato-
graphy to afford compounds 1–13. All the com-
pounds gave satisfactory spectral and analytical data.
Compounds 1, 3, 5, and 10 are cataloged chemicals.
Compounds 2, 4, and 12 are known in the literature.5
References and notes
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