Synthesis of Cyanamides via a One-Pot Oxidation-Cyanation of Primary and Secondary Amines

Article abstract of DOI:10.1021/acs.orglett.8b04007

An operationally simple oxidation-cyanation method for the synthesis of cyanamides is described. The procedure utilizes inexpensive and commercially available N-chlorosuccinimide and Zn(CN)₂ as reagents to avoid direct handling of toxic cyanogen halides. It is demonstrated to be amenable for the cyanation of a variety of primary and secondary amines and aniline derivatives as well as a complex synthetic intermediate en route to verubecestat (MK-8931). Additionally, kinetic measurements and other control experiments are reported to shed light onto the mechanism of this cyanation reaction.

Full text of DOI:10.1021/acs.orglett.8b04007

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Cyanamides via a One-Pot Oxidation−Cyanation of
Primary and Secondary Amines
Nadine Kuhl,* Saurin Raval, and Ryan D. Cohen
Department of Process Research & Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: An operationally simple oxidation−cyanation method for the synthesis of cyanamides is described. The
procedure utilizes inexpensive and commercially available N-chlorosuccinimide and Zn(CN)2 as reagents to avoid direct
handling of toxic cyanogen halides. It is demonstrated to be amenable for the cyanation of a variety of primary and secondary
amines and aniline derivatives as well as a complex synthetic intermediate en route to verubecestat (MK-8931). Additionally,
kinetic measurements and other control experiments are reported to shed light onto the mechanism of this cyanation reaction.
yanogen halides, such as cyanogen bromide (BrCN), are
1
Chighly versatile reagents in organic synthesis
with
additional applications such as peptide mapping2 and
nucleotide ligation.3 Due to the high electrophilicity of their
CN-moiety, cyanogen halides are most commonly used for the
cyanation of N, S, O, and C nucleophiles,4 with the formation
of cyanamides from primary, secondary, or tertiary amines
(von Braun reaction5) being most prominent.6 The cyanamide
moiety is found in selected pharmaceuticals and agro-
chemicals.7 But it is more commonly used as an intermediate
toward the synthesis of amidine8- and guanidine9-containing
heterocycles, ultimately rendering cyanogen halides key
reagents for the synthesis of biologically active compounds.
This is further exemplified in the development of a second
generation synthesis of verubecestat (3, MK-8931),10 a BACE1
Figure 1.
inhibitor evaluated for the treatment of Alzheimer’s disease.11
BrCN was identified as the crucial reagent for the cyanation of
advanced primary amine intermediate 1.12 The reaction
conditions allowed for the clean formation of cyanamide 2,
which was further telescoped into the final guanidinylation step
to furnish the key iminothiadiazine dioxide core of 3 (Figure
1A).
However, the efficiency of BrCN as a reagent is over-
shadowed by its acute toxicity, unfavorable physical properties
(in particular, its low melting and boiling points of 52 and 61.5
°C, respectively), and sensitivity to moisture (causing release
of toxic HCN and corrosive HBr)13 which render any handling
extremely hazardous and shipping on manufacturing scale very
costly. The development of alternative reagents or conditions
for the direct cyanation of amines is therefore highly desirable.
To be applicable in the final stages of an active pharmaceutical
ingredient synthesis, alternatives to using BrCN would ideally
proceed in one step and utilize benign and inexpensive
reagents. We proposed that an in situ oxidation of amine 1 to
an electrophilic amine intermediate followed by nucleophilic
cyanation with a simple commercially available cyanide salt,
thus reversing the polarity of the amine and cyanation reagent,
could fulfill these requirements. Strategies to circumvent the
handling of cyanogen halides in the synthesis of cyanamides
have been reported including examples of the in situ generation
of cyanogen halides,14 the application of alternative electro-
philic cyanation reagents,15 elimination16 or rearrangement17
of imines, and transition metal catalyzed cyanation reactions.18
Reactions between electrophilic N-haloamines and simple
cyanide nucleophiles to furnish cyanamides, however, are
surprisingly rare.19 The use of N-haloamines in electrophilic
amination reactions with organolithium, -magnesium, -zinc,
and -boron nucleophiles to form N−C bonds has been
extensively studied for multiple decades.20 With cyanide being
considered a strong nucleophile,21 we decided to investigate if
a related electrophilic amination of cyanide nucleophiles could
Received: December 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04007
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
in fact generate cyanamides in a cyanogen halide free fashion
(Figure 1B).
indicating that a very polar and water-miscible solvent such as
acetonitrile is beneficial.
Herein, we report the development of a general and
operationally simple oxidation−cyanation procedure of
primary and secondary amines as well as its application for
the cyanation of complex amine intermediate 1. Furthermore,
key mechanistic experiments to verify our initial proposal
(Figure 1B) are also presented.
We commenced our reaction optimization using 1-phenyl-
ethylamine (4) as our model substrate. An initial control
experiment confirmed that 4 is oxidized instantaneously to the
corresponding N-chloroamine at 0 °C in acetonitrile upon
addition of N-chlorosuccinimide (NCS).22 Having confirmed
the feasibility of the oxidation step, we then evaluated different
cyanide salts for the subsequent substitution step. The addition
of copper(I) cyanide or an aqueous solution containing 1 equiv
of either potassium cyanide or sodium cyanide to the in situ
prepared N-chloroamine intermediate of 4 (4-Cl) furnished
the desired cyanamide 5 in 47−57% yield (Table 1, entries 2−
A control experiment showed that preformation of 4-Cl
prior to the addition of Zn(CN)2 is not required for the
reaction to proceed smoothly (Table 1, entry 10). The use of
water as cosolvent was shown to be critical to affect the
cyanation reaction (Table 1, entry 11) suggesting that it is
necessary for the dissolution of Zn(CN)2. Notably, the
cyanation of 4 reached completion within 2 h when NBS
was used instead of NCS (Table 1, entry 12). Nonetheless,
NCS was selected as the optimal oxidant for further studies, as
it is less prone to promote undesired halogenation reactions
such as electrophilic aromatic halogenations.24
With optimized conditions in hand, we examined the scope
of this one-pot oxidation−cyanation procedure. Derivatives of
model substrate 4, containing electron-donating, -withdrawing,
or -neutral groups at different positions of the benzene ring,
yielded the corresponding cyanamides in moderate to good
yields (Scheme 1, compounds 6−8). Notably, when 4-
phenylbutylamine was subjected to the reaction conditions,
N-alkylcyanamide 9 was also obtained in acceptable yield.
Dialkylamines, such as N-methylbenzylamine, N-methyl-2-
phenylethylamine, and 1,2,3,4-tetrahydroisoquinoline were
also readily converted to cyanamides 10, 11, and 12 in 85%,
84%, and 80% yield, respectively. These results prompted us to
subject other saturated nitrogen-containing heterocycles to our
cyanation conditions. Various piperidines easily underwent
cyanation (Scheme 1, compounds 13−16) leading to syntheti-
cally important building blocks such as 14 and 15 further
showcasing the tolerability of acetal and alcohol functional
groups under the reaction conditions. 2-Phenylpyrrolidine
could also be cyanated using our oxidation−cyanation protocol
albeit in only 51% yield (Scheme 1, compound 17),25 whereas
a highly functionalized 3-aminopyrrolidine was readily
converted to its corresponding N-cyanopyrrolidine 18 in
78% yield. While we were initially concerned about potential
electrophilic chlorination side reactions of anilines, we found
that derivatives with electron-withdrawing groups were indeed
amenable to the one-pot oxidation−cyanation protocol
(Scheme 1, 19, 57%; 20, 59%).26,27 The substrate scope of
anilines could be further expanded through the introduction of
a deactivating benzyl group onto the aniline nitrogen thus
allowing the cyanation of electron-poor and even electron-rich
N-benzyl anilines in good yields (Scheme 1, compounds 21−
25).28 Notably, when commercial (1R,2S)-cis-1-amino-2-
indanol was employed under the reaction conditions,
cyanation was immediately followed by nucleophilic attack of
the proximal alcohol leading to the formation of 2-amino-
oxazoline 26 in 69% yield. This tandem cyanation−cyclization
process could also be applied to 2-amino-5-chlorophenol and
4-nitro-1,2-diaminobenzene which yielded the desired hetero-
cycles 27 and 28 in 68% and 48% yield, respectively.29
Having demonstrated the application of our oxidation−
cyanation protocol to a variety of amine substrate classes, we
returned to our initial goal, the BrCN-free generation of
cyanamide 2. While the oxidation of 1 occurred easily using
NCS as an oxidant, a productive cyanation required the use of
NBS instead.22 Further optimization of the reaction solvent
and temperature allowed the formation of N-cyano inter-
mediate 2 in 80% assay30 and 67% isolated yield,31 leaving the
unprotected sulfonamide moiety untouched (Scheme 2).
Due to the poor solubility of Zn(CN)2 under the cyanation
conditions described above, we initially expected the rate of
a
Table 1. Reaction Optimization
b
entry
MCN
BrCN
MCN (equiv)
solvent
MeCN
yield (%)
c
1
1
79
2
3
4
5
6
7
8
9
CuCN
KCN
NaCN
NaCN
Zn(CN)2
Zn(CN)2
Zn(CN)2
Zn(CN)2
Zn(CN)2
Zn(CN)2
Zn(CN)2
1
1
1
2
1
0.5
1
1
1
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
EtOAc
THF
MeCN/H2O
MeCN
47
57
57
55
81
79
41
55
d
10
11
12 ,
78 (77)
e
1
1
0
f g
MeCN/H2O
77
a
Reaction conditions: Reaction run on 0.2 mmol scale. NCS (1.05
equiv) and 1-phenylethylamine (1.0 equiv) were mixed at 0 °C in
CD3CN (1.8 mL) for 5 min, followed by the addition of MCN and
b
1
water (0.18 mL). Yield determined by H NMR in CD3CN using
c
CH2Br2 as internal standard. Isolated yield in brackets. No NCS
added. No prestirring of NCS and 1-phenylethylamine. No reaction
of 4-Cl. 2 h instead of 16 h. NBS instead of NCS.
d
e
f
g
4) but did not lead to full conversion of the 4-Cl intermediate.
Even increasing the amount of sodium cyanide to 2 equiv did
not result in further improvement in yield or conversion
(Table 1, entry 5). Instead, complete conversion of 4-Cl, along
with a cleaner reaction profile, was obtained when 4-Cl was
subjected to Zn(CN)2 in a 9:1 v/v acetonitrile/water mixture.
Despite the low solubility of Zn(CN)2 in water and other
organic solvents,23 the heterogeneous conditions yielded 5 in
81% yield (Table 1, entry 6), comparable to the result obtained
with cyanogen bromide (Table 1, entry 1). The Zn(CN)2
charge could be even further reduced to 0.5 equiv without
negatively impacting the yield of 5 which suggests that both
CN-moieties of the zinc salt are transferred to form product
(Table 1, entry 7). Reactions in other organic solvents, such as
THF and EtOAc, did not reach completion within the
standard reaction time of 16 h (Table 1, entries 8−9)
B
DOI: 10.1021/acs.orglett.8b04007
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 1. Substrate Scope of Primary and Secondary Amines
a
All reaction were run on 1−3 mmol scale unless otherwise indicated. Isolated yields are given. Yields in parentheses correspond to yields
b
c
d
e
determined by 1H NMR using an internal standard. Run on 8.3 mmol scale. Run on 0.9 mmol scale for 25 h. Run on 0.5 mmol scale. Run on
0.7 mmol scale for 24 h. Run for 68 h. Run for 96 h at 40 °C, unreacted starting material recovered. Run for 72 h.
f
g
h
Scheme 2. Cyanation of Amine 1 en Route to Verubecestat
cyanamide formation to be mass transfer limited. To verify this
hypothesis, we monitored the formation of our standard
cyanamide 5 using different initial charges of Zn(CN)2 (Figure
2).32 Indeed, the cyanation reaction proved to be zero-order in
Figure 3. Hammett plot. kX and kH are rates of product formation. R
⧫
■
▲
= Me ( red), R = H ( blue), R = Br ( green).
Based on the observed zero-order dependence on electro-
phile and nucleophile concentration, it is plausible to assume a
mass transfer limited scenario in which precoordination
between Zn(CN)2 and the reactive N-chloroamine alters the
effective cyanide nucleophile concentration in solution and
therefore dictates the reaction rate. However, an intra-
molecular SN-type mechanism which proceeds via a stable
Zn(CN)2−N-chloroamine complex prior to the rate-determin-
ing substitution step could also fit the kinetic data collected.
In order to rule out the latter scenario and to shed more
light on the nature of the actual cyanamide formation step, we
turned to investigate the possibility of the in situ generation of
cyanogen chloride from 4-Cl and Zn(CN)2.33 Reacting NCS
with Zn(CN)2 in a control experiment led to the formation of
succinimide as well as cyanogen chloride (Scheme 3, eq 1). To
answer the question whether or not 4-Cl could be equally able
to oxidize Zn(CN)2 to cyanogen chloride, we performed a
crossover experiment between the in situ generated 4-Cl and
N-benzylaniline (31) (Scheme 3, eq 3). While N-benzylaniline
(31) is successfully cyanated under our standard conditions
(Scheme 1, compound 21), it is not readily oxidized to its N-
chloroamine intermediate as amine 4 (Scheme 3, eq 2). If
cyanation of amines proceeds via an SN-type mechanism from a
Zn(CN)2−N-chloroamine complex, a crossover experiment
should only produce cyanamide 5. Instead, a 1.8/1 mixture of
Figure 2. Reaction profile for the formation of 5 (40% conversion): 1
⧫
■
equiv of Zn(CN)2 ( blue), 0.75 equiv of Zn(CN)2 ( red), and 0.5
▲
equiv of Zn(CN)2 ( green).
Zn(CN)2. Moreover, the reaction profile for the reaction of 4
to 5 exhibited overall zero-order kinetics suggesting a zero-
order dependence in the concentration of amine 4.22
To further gain insight into the role of amine 4 and its
corresponding N-chloroamine 4-Cl, we performed a Hammett
study using different para-substituted 1-arylethylamines
(Figure 3, R = Me, H, Br). Overall, electron-rich N-
chloroamines were found to react faster under the standard
cyanation conditions than electron-deficient substrates. A good
correlation between the logarithm of the relative rates of
product formation and the σpara parameters with a negative ρ-
value further suggests positive charge buildup in the rate-
determining step.
C
DOI: 10.1021/acs.orglett.8b04007
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Letter
a
Kenilworth, NJ, USA, W. Pinto and L. Yang for supporting
compound characterization and Y. H. Lam, A. Klapars, J.
Mccabe Dunn, W. Morris, C. C. Nawrat, M. Pirnot, and D.
Thaisrivongs for helpful discussions.
Scheme 3. Control and Crossover Experiments
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In summary, we have developed an operationally simple
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as such provided an alternative procedure for cyanamide 2 en
route to MK-8931 (3). Our mechanistic studies demonstrated
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̈
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04007.
Experimental procedures, compound characterization
data, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nadine.kuhl@merck.com.
ORCID
Nadine Kuhl: 0000-0003-1183-5620
Saurin Raval: 0000-0001-8504-7331
Notes
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The authors declare no competing financial interest.
̈
(9) Suhs, T.; Konig, B. Synthesis of Guanidines in Solution. Mini-
ACKNOWLEDGMENTS
■
Rev. Org. Chem. 2006, 3, 315.
We gratefully acknowledge the following colleagues of Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.,
(10) Scott, J. D.; Stamford, A. W.; Gilbert, E. J.; Cumming, J. N.;
Iserloh, U.; Misiaszek, J. A.; Li, G. Iminothiadiazine Dioxide
D
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were not observed in reaction mixtures forming products 19 and 20.
(28) N-Benzyl-4-trifluoroaniline remained unreacted using NCS/
Zn(CN)2. The use of NBS/Zn(CN)2 resulted in bromination of the
aniline ring instead of N-cyanation.
(29) The formation of 2-aminooxazolines and 2-aminooxazoles from
amino alcohols is also reported using BrCN. However, other recently
reported cyanation procedures do not promote this cyclization; see
for example ref 14b.
(30) The assay yield of 2 was determined by 1H NMR of the crude
reaction mixture using CH2Br2 as the internal standard.
(31) The use of EtOAc instead of acetonitrile for the cyanation of 1
potentially leads to increased stability of the 1-Br intermediate. For
further details of the solvent and temperature optimization, see Table
S1 in the Supporting Information.
(32) The oxidation of amine 4 with NCS is instantaneous.
Therefore, the reaction profile represents the rate for the cyanation
of the corresponding N-chloroamine 4-Cl.
(33) Calvo, P.; Crugeiras, J.; Ríos, A.; Ríos, M. A. Nucleophilic
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(34) Chlorine transfer between amines was not observed, but has
been reported for benzylamine; see: Calvo, P.; Crugeiras, J.; Ríos, A.
Kinetic and Thermodynamic Barriers to Chlorine Transfer between
Amines in Aqueous Solution. J. Org. Chem. 2009, 74, 5381.
(35) Zn(CN)2 is a toxic chemical. For more information, see: Zinc
cyanide, MSDS No. 256498 [Online]; Sigma-Aldrich: Saint Louis,
MO, Nov 10, 2018. https://www.sigmaaldrich.com/catalog/product/
aldrich/256498?lang=en&region=US (accessed Jan 21, 2019). See
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E
DOI: 10.1021/acs.orglett.8b04007
Org. Lett. XXXX, XXX, XXX−XXX