Synthesis of Cyanamides from Cyanogen Bromide under Mild Conditions through N-Cyanation of Allylic Tertiary Amines

Article abstract of DOI:10.1055/s-0036-1588533

Cyanamides were selectively formed through a one-step nucleophilic substitution reaction of allylic tertiary amines with cyanogen bromide. Because of the mild reaction conditions and good yields of the reaction, as well as the commercial availability of the starting materials, this new method represents a valuable tool for the synthesis of cyan-amides through an N-deallylation reaction and an N-cyanation reaction in one pot.

Full text of DOI:10.1055/s-0036-1588533

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
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A
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H. Liang et al.
Letter
Synlett
Synthesis of Cyanamides from Cyanogen Bromide under Mild
Conditions through N-Cyanation of Allylic Tertiary Amines
R1
Honggang Liang
Lingxiang Bao
Yao Du
R1
R1
CN
N
R2
one pot
N
R2
N
R2
Br–
CN
CHCl3, r.t.
BrCN
Yiying Zhang
Siping Pang
Chenghui Sun*
25 examples, up to yield 86%
· Broad substrate scope · Selectivity
· High yield
· Simple operation and mild conditions
School of Materials Science and Engineering, Beijing
Institute of Technology, South Street of No. 5,
Zhongguancun, Haidian District, Beijing, 100081,
P. R. of China
sunch@bit.edu.cn
Received: 05.06.2017
Accepted after revision: 09.07.2017
Published online: 17.08.2017
NC
N
O
S
O
EtO
P N
DOI: 10.1055/s-0036-1588533; Art ID: st-2017-w0431-l
N
n-PrS
Et
N
N
Abstract Cyanamides were selectively formed through a one-step nu-
cleophilic substitution reaction of allylic tertiary amines with cyanogen
bromide. Because of the mild reaction conditions and good yields of the
reaction, as well as the commercial availability of the starting materials,
this new method represents a valuable tool for the synthesis of cyan-
amides through an N-deallylation reaction and an N-cyanation reaction
in one pot.
S
CN
R
Cl
N
N-cyano 2-(substituted amino)ethyl
methyl sulfoximine
imicyafos
CN
O
N
Key words cyanamides, cyanogen bromide, cyanation, deallylation,
allylic amines
N
CN
O
N
N
F
F
MeO
F
The cyanamide moiety has been used in building blocks
for heterocyclic compounds in the field of organic chemis-
try1 and for ligands for various metals in inorganic chemis-
try and material science.2 Furthermore, some cyanamides
are known to have biological activities. For example, N-cya-
no 2-(substituted amino)ethyl methyl sulfoximines3 and
imicyafos4 (Figure 1) have been tested for their insecticidal
activity against peach aphids and nematodes, respectively.
In addition, some cyanamides that inhibit Rhizoctonia sola-
ni5 and type IV phosphodiesterase (PDE4)6 have been iden-
tified in medicinal chemistry.
Several approaches have been used to synthesize an in-
creasing number of cyanamide derivatives. The most com-
mon method involves the use of cyanogen chloride or bro-
mide, copper cyanide, trichloroacetonitrile, or azodiisobu-
tyronitrile (AIBN) as a cyanide source in combination with
an amine,7 amide,8 or ketimine.9 Therefore, to use tertiary
amines as starting materials for the synthesis of cyan-
amides by one of these methods, it is necessary to convert
them into non-tertiary amines, amides, or ketimines.
R. solani inhibitor
PDE4 inhibitor
Figure 1 Biologically active molecules containing an N–CN group
Owing to its stability under basic and acidic conditions,
the allyl moiety can serve as a protecting group for allyl
carboxylates, carbonates, carbamates, ethers, alcohols, or
amines.10 The allyl group can also be used in combination
with a wide range of protecting groups in orthogonal pro-
tection strategies that permit its use in syntheses of com-
plex natural products.11 The most widely used reagents for
the deprotection of allylic tertiary amines are transition-
metal catalysts12 (Scheme 1, eq. 1). However, selectivity and
byproduct formation can be a problem. In recent years, sev-
eral alternative methods have been reported for N-deal-
lylation of allylic tertiary amines that aim to address the se-
lectivity problem by using other catalysts.13,14 For example,
in 2009, Jackson and co-workers reported a method for
N-deallylation of allylic tertiary amines by using alkali
metals in silica gel (Na2K-SG) as a catalyst13 (Scheme 1, eq.
2). Kumar and co-workers reported a chemoselective
deprotection procedure using DDQ (Scheme 1, eq. 3).14 Be-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
H. Liang et al.
Letter
Synlett
cause their oxygenated moieties form good leaving groups,
chloroformates such as trichloroethyl15 or propargyl chloro-
formate (HC≡CCH2OCOCl)16 are among the most effective
reagents for N-deallylation (Scheme 1, eqs. 4 and 5). How-
ever, all these reported procedures are expensive or com-
plex as they involve use of catalysts or two-step reactions.
Table 1 Optimization of N-Deallylation/N-Cyanation of an Allylic Ter-
tiary Aminea
CN
cyanamide source
N
N
r.t., solvent
R1
N
transition-metal
catalyst
H
N
Entry
Solvent
Reagent
Additive
Yield (%)
R2
(1)
R1
R2
N-deallylation
b
1
2
THF
Cl3CCN
Cl3CCN
Cl3CCN
Cl3CCN
AIBN
K2CO3
NaHCO3
t-BuOK
NaH
K2CO3
K2CO3
K2CO3
K2CO3
_
–
THF
–
–
R1
N
i) Na2K-SG
ii) H2O
3
THF
H
N
(2)
R2
R1
R2
4
THF
–
N-deallylation
5
MeOH
CHCl3
THF
–
6
AIBN
–
R1
N
H
N
DDQ
7
AIBN
–
(3)
(4)
R2
R1
R2
8
MeCN
CHCl2
CHCl3
THF
AIBN
–
N-deallylation
9
BrCN
55c
75
63
50
i) ClCO2CH2CCl3
ii) MeOH
10
11
12
BrCN
_
R1
H
BrCN
_
N
N
R1
N-deallylation
1,4-dioxane
BrCN
_
a Reagents and conditions: 4 mmol scale; cyanide source (1.1 equiv), addi-
tive (1.1 equiv), solvent (5 mL), r.t., under N2.
i) HC≡CCH2OCOCl
ii) (BnNEt3)2MoS4
H
b Yield after the recovery of the starting materials.
c Yield after column chromatography on silica gel.
N
N
(5)
N-deallylation
Scheme 1 Outline of N-deallylation strategies
yields (75–82%). N-Allylpiperazines were also employed, in-
cluding those substituted at the 4-position, giving products
10–14 in 52–65% yield.17 The synthesis of products 13 and
14 demonstrated that the reaction proceeded successfully
in the presence of a tert-butoxycarbonyl (Boc) protecting
group.
As discussed above, allylic tertiary amines can be trans-
formed into cyanamides by N-deallylation followed by N-
cyanation. Our work combines these two reaction steps
into one reaction under mild conditions.
Initially, we selected N-allylpiperidine as a model sub-
strate to optimize the reaction conditions (Table 1). First,
we chose Cl3CCN and AIBN as cyanide sources, but N-al-
lylpiperidine did not react with either of these under a
range of conditions (Table 1, entries 1–8). We then exam-
ined the reaction of N-allylpiperidine with cyanogen bro-
mide (BrCN) in various solvents (Table 1, entries 9–12), and
we obtained piperidine-1-carbonitrile in 50–75% yield.16
We therefore chose BrCN as a reagent under a N2 atmo-
sphere in CHCl3 at room temperature as the optimal condi-
tions (Table 1, entry 10).
Encouraged by these results, we subjected various sub-
strates to the N-cyanation reaction (Scheme 2). The hetero-
cyclic compounds N-allylpyrrolidine, N-allylmorpholine,
and N-allylthiomorpholine were converted into the corre-
sponding cyanamides 2–4 in 70, 73, and 68% yield, respec-
tively. The reactions of 2-, 3-, and 4-substituted and 3,5-
disubstituted N-allylpiperidines and of 2-allyl-1-methyl-
1,2,3,4-tetrahydroisoquinoline proceeded well to form the
corresponding cyanamides 5–9 and 15, respectively, in high
The substrate scope was not limited to cyclic allylic ter-
tiary amines; acyclic allylic tertiary amines could also be
used under the same reaction conditions, leading to the
acyclic cyanamides 17–21.18 However, 1-allyl-1,2,3,4-tetra-
hydroquinoline, N-allyl-N-methylaniline, N-allyl-N-phe-
nylaniline, and N-allyl-N-benzylaniline did not afford the
corresponding target compounds 16 and 22–24 when BrCN
was used under the same reaction conditions, and the
starting materials were recovered. This demonstrated that
when the nitrogen atom is linked directly to an aromatic
ring, the reaction does not proceed because the p–π conju-
gative effect reduces the nucleophilicity of the central ni-
trogen atom, impeding its ability to attack the CN group.
Interestingly, we observed selective N-cyanation of an
N-allyl group over an N-methyl group in product 10. N-Eth-
yl, N-benzyl, N-isopropyl, and N-Boc groups were also
found to be compatible under the standard reaction condi-
tion (products 11–14 and 17–21). Therefore, this method
might be useful for selective N-cyanation of an N-allyl
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
H. Liang et al.
Letter
Synlett
Table 2 N-Cyanation of Substituted Allylic Tertiary Aminesa
CN
N
BrCN (1.1 equiv)
CHCl3, r.t., 24 h
Entry
1
Substrate
Product
Yieldb (%)
59
N
X
n
X
n
Boc
N
CN
N
CN
N
CN
N
CN
CN
N
CN
N
N
Ph
N
Boc
13
N
25
O
S
2
3
78
58
Boc
N
CN
N
1.75% yield
2.70% yield
3.73% yield
4.68% yield
5. 82% yield
CN
N
CN
N
CN
N
CN
N
CN
N
N
N
Boc
N
26
13
O
O
Bn
N
CN
N
6.76% yield
7.78% yield
8.75% yield
9.68% yield
10.52% yield
CN
N
CN
N
CN
N
CN
N
N
Ph
N
CN
Bn
12
N
27
N
N
N
Boc N
4
5
65
75
Bn
Boc
CN
N
S
11.60% yield 12.65% yield
13.56% yield 14.58% yield
15.86% yield
N
Ph
CN
S
CN
CN
Bn
CN
CN
N
N
4
N
N
N
28
Bn
N
CN
Bn
N
16.0% yield
17.72% yield
18.78 yield
19.55% yield
20.60% yield
Bn
21
Bn
Bn
N
CN
Ph
CN
Ph
CN
29
Ph
CN
N
N
N
a Reagents and conditions: 4 mmol scale; BrCN (1.1 equiv), anhyd CHCl3 (5
mL), r.t., N2.
Bn
Bn
Ph
b Yield after column chromatography (silica gel).
21.63% yield
22.0% yield
23.0% yield
24.0% yield
Scheme 2 N-Cyanation of allylic tertiary amines. Reagents and condi-
tions: 4 mmol scale; substrate (1.1 equiv), BrCN (1.1 equiv), anhyd
CHCl3 (5 mL), r.t., N2. Reported yields are those of isolated products af-
ter column chromatography (silica gel).
On the basis of the above experiments and previous re-
ports in the literature,19,20 we propose the mechanism out-
lined in Scheme 3. Initially, BrCN is attacked by the allylic
tertiary amine in anhydrous chloroform at room tempera-
ture under a N2 atmosphere to generate an intermediate
quaternary ammonium salt. The allyl group then leaves and
a cyanamide is formed. We successfully detected allyl bro-
mide by LC/MS (See Supporting Information; N-allylpiperi-
dine was selected as the model substrate for the detection
of allyl bromide in the reaction mixture).
group in the presence of several other functionalities, and
might be useful in the design and synthesis of complex
products.
Encouraged by these initial results, we then investigated
the compatibility of other allylic tertiary amines in this re-
action. We found that a range of compounds substituted at
the terminal end of the double bond of allylic tertiary
amines were also suitable substrates (Table 2). For example,
tert-butyl 4-cinnamylpiperazine-1-carboxylate, tert-butyl
Br
Br–
CN
R1
CN
N
R2
N
R2
C
N
N
R2
+
Br
R1
R1
4-(3-methylbut-2-en-1-yl)piperazine-1-carboxylate,
1-
benzyl-4-cinnamylpiperazine, 4-cinnamylthiomorpholine,
and N,N-dibenzyl-3-methylbut-2-en-1- amine were readily
converted into the corresponding cyanamides in good to
high yields (Table 2, entries 1–5).
Scheme 3 Proposed mechanism
The substituted allylic groups in compounds 25–29
were also good leaving groups, and the corresponding cyan-
amides were obtained in good yields. However, when R1 or
R2 was an aromatic ring, as in compounds 22–24, no cyana-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
H. Liang et al.
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Synlett
mide products were obtained under the standard reaction
conditions. The weak nucleophilicity of the central nitrogen
atom is the main reason for the failure of the attack on the
CN group.
(2) (a) Miyasaka, H.; Clérac, R.; Campos-Fernádez, C. S.; Dubner, K.
R. Inorg. Chem. 2001, 40, 1663. (b) Pombeiro, A. J. L. Inorg. Chim.
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ARKIVOC 2008, (xvi), : 99.
The selectivity of this approach was demonstrated by
the syntheses of compound 10–14 and 17–21. This was at-
tributed to the higher stability of the allyl cation compared
with that of methyl, ethyl, benzyl, isopropyl, or Boc cations.
In conclusion, the nucleophilic substitution reaction of
allylic tertiary amines with BrCN under mild conditions can
be effectively used to simplify the laborious procedures in-
volved in transforming allylic tertiary amines into cyan-
amides by N-deallylation and subsequent N-cyanation. In
addition, this new method represents a general, selective,
and synthetically simple method that integrates N-deallyla-
tion and direct N-cyanation in a one-step reaction for the
first time. The only disadvantage is that this method is un-
suitable for substrates containing an aromatic group adja-
cent to allylic tertiary amine group.
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Funding Information
The authors are grateful to the National Natural Science Foundation of
China (Grant NO.21576026) and the Joint Fund of the National Natu-
ral Science Foundation of China and the China Academy of Engineer-
ing Physics (Grant NO.11176004) for financial support.
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(8) (a) For a review on the preparation of cyanamides from amides,
see: Zhang, M.; Sheng, W.; Ji, P.; Liu, Y.; Guo, C. RSC Adv. 2015, 5,
56438; see also ref. 1.
Acknowledgment
(9) For reviews on the preparation of cyanamides from ketimines,
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4522. (b) Ayres, J. N.; Ling, K. B.; Morrill, L. C. Org. Lett. 2016, 18,
5528.
The authors gratefully acknowledge the kind advice of Professor Zhi-
gang Xu on the preparation of this paper.
(10) Krompiec, S.; Krompiec, M.; Penczek, R.; Ignasiak, H. Coord.
Chem. Rev. 2008, 252, 1819.
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S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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MeOH–CH2Cl2) to give a colorless liquid; yield: 0.26 g (52%).
IR (film): 2943, 2798, 2211 (C≡N), 1452, 1375, 1002, 787 cm–1
.
1H NMR (600MHz, CDCl3): δ = 2.19 (s, 3 H), 2.36 (t, J = 5.4, 4.8
Hz, 4 H), 3.14 (t, J = 5.4 Hz, 4 H). 13C NMR (CDCl3, 150 MHz):
δ = 117.6, 53.3, 48.9, 46.1. HRMS (ESI+): m/z [M + H]+ calcd for
C6H12N3: 126.102620, found 126.102574.
(13) Nandi, P.; Dye, J. L.; Jackson, J. E. Tetrahedron Lett. 2009, 50,
3864.
(14) Kumar, P.; Cherian, S. K.; Jain, R.; Show, K. Tetrahedron Lett.
2014, 55, 7172.
(18) Dimethylcyanamide (17)
Prepared from N,N-dimethylprop-2-en-1-amine (4 mmol) as
for compound 1, and purified by column chromatography (silica
gel, 10% EtOAc–PE) to give a colorless liquid; yield: 0.20 g, (72%).
(15) Kapnang, H.; Charles, G. Tetrahedron Lett. 1983, 24, 3233.
(16) Piperidine-1-carbonitrile (1); Typical Procedure
BrCN (4.4 mmol) was slowly added to a solution of N-allylpiper-
idine (4 mmol) in anhyd CHCl3 (5 mL) at r.t. under N2, and the
mixture was then stirred for 24 h at r.t. until the reaction was
complete (TLC). The mixture was then purified by column chro-
matography (silica gel, 10% EtOAc–PE) to give a colorless liquid;
yield: 0.33 g (75%).
IR (film): 2971, 2823, 2217 (C≡N), 1455, 1339, 1058, 762 cm–1
.
1H NMR (600MHz, CDCl3): δ = 2.75 (s, 6 H). 13C NMR (150 MHz,
CDCl3): δ = 119.3, 40.4. HRMS (ESI+): m/z [M + Na]+ calcd for
C3H6N2Na: 93.042365; found: 93.042319.
(19) Bhat, R. G.; Ghosh, Y.; Chandrasekaran, S. Tetrahedron Lett. 2004,
45, 7983.
IR (film): 2945, 2857, 2210 (C≡N), 1451 cm–1
.
1H NMR (600
(20) (a) Katritzky, A. R.; Brycki, B. E. Chem. Soc. Rev. 1990, 19, 83.
(b) Helmick, J. S.; Martin, K. A.; Heinrich, J. L.; Novak, M. J. Am.
Chem. Soc. 1991, 113, 3459. (c) Rossi, R. A.; Pierini, A. B.;
Peñéñory, A. B. Chem. Rev. 2003, 103, 71. (d) Médoc, M.; Sobrio,
F. RSC Adv. 2014, 4, 35371.
MHz, CDCl3): δ = 1.47 (m, 2 H), 1.53–1.54 (m, 4 H), 3.06–3.07
(m, 4 H). 13C NMR (150 MHz, CDCl3): δ = 118.6, 50.1, 24.5, 23.0.
HRMS (ESI+): m/z [M + Na]+ calcd for C6H10N2Na: 133.073677;
found: 133.073619.
(17) 4-Methylpiperazine-1-carbonitrile (10); Typical Procedure
Prepared from 1-allyl-4-methylpiperazine (4 mmol) as for com-
pound 1, and purified by column chromatography (silica gel, 2%
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