N-Cyanation of Secondary Amines Using Trichloroacetonitrile

Article abstract of DOI:10.1021/acs.orglett.6b02775

A one-pot N-cyanation of secondary amines has been developed using trichloroacetonitrile as an inexpensive cyano source. A diverse range of cyclic and acyclic secondary amines can be readily transformed into the corresponding cyanamides in good isolated yields, with the method successfully utilized in the final synthetic step of a biologically active rolipram-derived cyanamide. This approach exhibits distinct selectivity when compared to the use of highly toxic cyanogen bromide.

Full text of DOI:10.1021/acs.orglett.6b02775

Letter
pubs.acs.org/OrgLett
N‑Cyanation of Secondary Amines Using Trichloroacetonitrile
James N. Ayres,† Kenneth B. Ling,*,‡ and Louis C. Morrill*,†
†School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, U.K.
‡Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, U.K.
S
* Supporting Information
ABSTRACT: A one-pot N-cyanation of secondary amines has been
developed using trichloroacetonitrile as an inexpensive cyano source. A
diverse range of cyclic and acyclic secondary amines can be readily
transformed into the corresponding cyanamides in good isolated yields,
with the method successfully utilized in the final synthetic step of a biologically active rolipram-derived cyanamide. This approach
exhibits distinct selectivity when compared to the use of highly toxic cyanogen bromide.
Scheme 1. Outline of the N-Cyanation Strategy
he cyanamide functionality is present in a variety of
Tbiologically active compounds including natural products,
agrochemicals, and pharmaceuticals (Figure 1). For example, 11-
N-cyano-11-N-methylmoloka’iamine is a naturally occurring
compound with antibacterial properties,1 and sulfoxaflor has
been marketed as an insecticide with nicotinic acetylcholine
receptor (nAChR) activity.2 Furthermore, medicinal chemistry
programs have unearthed pyrrolidine-derived cyanamides that
demonstrate cathepsin C3 and type IV phosphodiesterase4
(PDE4) inhibition.
In additiontotheir utilityas ligands incoordination chemistry,5
cyanamides have diverse synthetic applications, serving as
building blocks in the production of guanidines and various
heterocyclic scaffolds.6 The most commonly employed method
forcyanamidesynthesis istheelectrophilic N-cyanationofamines
usinghighlytoxiccyanogenbromide(Scheme1,eq1).7,8 Inrecent
years, several alternative N-cyanation procedures have been
reported that aim to address the safety implications associated
with using such reagents. In 2014, Chen and co-workers reported
the in situ generation of cyanogen chloride for the electrophilic N-
cyanation of secondary amines using bleach and trimethylsi-
lylcyanide.9 Cheng and co-workers subsequently disclosed a
copper-mediated oxidative N-cyanation of secondary amines that
requires superstoichiometric copper(I) cyanide and an oxygen
atmosphere.10 In 2015, the same group reported an alternative
protocol, usingazobis(isobutyronitrile) (AIBN)asasafercyanide
source.11 Alcarazo and co-workers have demonstrated the utility
of bespoke imidazolium thiocyanates as group-transfer reagents
for electrophilic cyanation of various substrates including
amines.12 Despite these notable advances, a general and
operationally simple N-cyanation procedure that offers an
alternative to cyanogen bromide remains largely elusive.
Furthermore, methods for selective cyanamide formation within
substrates containing multiple nucleophilic sites are desirable.
In 1930, Houben and Fischer reported a two-step C-cyanation
of electron-rich arenes (Scheme 1, eq 2).13 In the first step,
aluminum(III) chloride catalyzed a Friedel−Crafts reaction with
trichloroacetonitrile,14 forming a ketimine. Subsequent elimi-
nation of chloroform using potassium hydroxide afforded the aryl
nitrileproduct.Takinginspirationfromthisreport, wequestioned
whether a one-pot N-cyanation of amines could be developed
usinginexpensivetrichloroacetonitrile (Scheme1,eq3).15,16 This
approach would obviate the need for highly toxic reagents and
hazardous reaction conditions. Furthermore, the decreased
reactivity of trichloroacetonitrile when compared to cyanogen
bromide offers opportunities for distinct selectivity patterns.
Received: September 14, 2016
Figure 1. Biologically active molecules with N−CN group.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02775
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Organic Letters
Letter
a
a
Table 1. Optimization of Amidine Formation
Scheme 2. N-Cyanation of Cyclic Amines
b
c
entry
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
MeOH
CHCl3
DME
23
23
23
23
23
23
5
22
61
84
THF
87
DCM
96
toluene
DMF
96
95
DMSO
MeCN
MeCN
5
94
5
97
d
10
23
97 (88)
a
b
Reactions performed using 0.6 mmol of amine 1. Bench-grade
c
solvents were used. [1] = 1 M. Yield after 5 or 23 h as determined by
19F NMR analysis of crude reaction mixture with 1,3,5-trifluor-
obenzene as the internal standard. Isolated yield given in brackets.
d
With 1.1 equiv of trichloroacetonitrile.
a
Table 2. Optimization of Cyanamide Formation
b
c
a
entry
base
DBN
solvent
time (h)
yield (%)
Reactions performed using 1 mmol of amine starting material.
Conditions as in Table 1, entry 10 (1st step) and Table 2, entry 7 (2nd
step) unless noted otherwise. All yields are isolated yields after
1
2
3
4
5
6
7
THF
THF
THF
THF
THF
THF
DME
23
23
23
23
0.5
0.5
0.5
0
DBU
0
b
chromatographic purification. HCl salt of amine used with biphasic
TBD
5
c
solvent system in the first step (1:1, MeCN/NaHCO3(aq)). NMR
NaH
100
1
yield was 75% as determined by H NMR analysis of crude reaction
KOt-Bu
NaOt-Am
NaOt-Am
89
mixture with mesitylene as the internal standard.
95
100 (82)
a
b
tert-pentoxide were also excellent bases for this transformation,
with NaOt-Am giving clean conversion to 3 after only 30 min at rt
in DME,18 in 82% isolated yield.17
Reactions performed using 0.1 mmol of amidine 2. Bench-grade
c
solvents were used. [2] = 0.2 M. Yield after 0.5 or 23 h as determined
by 19F NMR analysis of crude reaction mixture with 1,3,5-
trifluorobenzene as the internal standard. Isolated yield given in
parentheses.
Conveniently, the two steps can be readily telescoped into a
one-pot protocol by simply removing the solvent and excess
trichloroacetonitrile after complete conversion to amidine 2,19
then diluting with DME, and adding NaOt-Am, which gave
cyanamide3in71%isolatedyield(Scheme2). Withrespecttothe
scopeofthesecondaryaminesubstratesthatmaybeemployed,we
have found that a range of 5-, 6-, and 7-membered heterocyclic
amines function as suitable substrates. For example, a variety of
1,2,3,4-tetrahydroisoquinolines and 4-substituted piperidines are
readily converted to the corresponding cyanamides in high yields
(products 3−9, 61−76% yield). The reaction performs well upon
scale-up, with the formation of cyanamide 5 successfully carried
out on a 20 mmol scale in 76% yield to provide 2.42 g of product.
Pyrrolidines can also be employed, including those substituted at
the 2-position (products 10−12, 64−75% yield). Formation of
nicotineanalogue11in64%yielddemonstratesthatthemethodis
tolerant of additional basic nitrogen atoms within the substrate.
Various other heterocyclic compounds including piperazine,
morpholine, thiomorpholine, and azepane are also well tolerated
(products 13−16, 46−80% yield). It is noteworthy that 6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline, which provides cyan-
amide 4 in 61% yield, can be used directly as its commercially
available hydrochloride salt by employing a biphasic system in the
first step (1:1, MeCN/NaHCO3(aq)). The lower isolated yield in
Herein, we report the successful implementation of this strategy
and describe an operationally simple N-cyanation protocol for a
diverse range of cyclic and acyclic secondary amines.
In order to test our hypothesis, we selected 6-fluoro-1,2,3,4-
tetrahydroisoquinoline 1 as a model substrate, cognizant of the
opportunitytomonitorreactionprogressusinginsitu19FNMR. A
variety of bench-grade solvents were assessed for the reaction of 1
with trichloroacetonitrile (2 equiv) at room temperature to form
amidine2(Table1).Althoughtolueneanddichloromethanewere
identified as suitable solvents for amidine formation,17 it was
found that polar aprotic solvents (MeCN, DMF, and DMSO)
increased the rate of reaction and that 1.1 equiv of
trichloroacetonitile was sufficient in MeCN, giving 2 in 88%
isolated yield after 23 h.
With amidine 2 in hand, suitable reaction conditions were
sought for conversion to cyanamide 3 (Table 2). Treatment of 2
with 2 equiv of amidine bases DBN and DBU in THF at room
temperature for 23 h returned only starting material whereas
guanidinebaseTBDshowedtraceconversiontocyanamide3.On
the other hand, sodium hydride gave complete conversion to 3
after23hatrt.Toourdelight,potassiumtert-butoxideandsodium
B
DOI: 10.1021/acs.orglett.6b02775
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Organic Letters
Letter
a
Scheme 3. N-Cyanation of Acyclic Amines
Scheme 4. Role of Imidazole Catalyst
Scheme 5. Distinct Selectivity Profiles of Trichloroacetonitrile
and Cyanogen Bromide
a
Reactions performed using 1 mmol of amine starting material.
Conditions as in Table 1, entry 10 (1st step) and Table 2, entry 7 (2nd
step) unless noted otherweise. All yields are isolated yields after
b
chromatographic purification. 4-Methylstyrene (1 equiv) was added
c
in second step. 1st step was performed at 80 °C with imidazole (10
mol %).
certain cases, e.g., a 46% yield for morpholine-derived cyanamide
14, is indicative of product volatility rather than poor conversion
(NMR yield of 75%). A substrate limitation was identified upon
testingindoline17and1,2,3,4-tetrahydroquinoline 18.Theseless
nucleophilic secondary amines do not react with trichloro-
acetonitrile even after prolonged reaction times, heating to 80 °C,
or in the presence of various Lewis acid additives.20,21
amidine formation over the competing reverse pathway (Scheme
4, eq 5).27
Due to the decreased reactivity of trichloroacetonitrile when
compared to cyanogen bromide, we predicted distinct selectivity
profiles. To test this hypothesis, the reactivity of diamine 27 was
investigated (Scheme 5). Treatment of 27 with 2 equiv of
cyanogen bromide afforded dicyanamide 28 as the sole product,
isolated in 48% yield (Scheme 5, eq 6). Using our optimized
reaction conditions, 2 equiv of trichloroacetonitrile formed
exclusively monocyanamide 29 (60% isolated yield), with the
more hindered α-branched acyclic secondary amine unreactive
(Scheme 5, eq 7). Employing 1 equiv of cyanogen bromide does
not result in clean monocyanation, but rather produces mixtures
containing28and29.Weanticipatethatthisabilitytodifferentiate
between multiple reactive sites within a molecule will prove
beneficial in more complex systems.
Finally, the utility of this approach for the synthesis of
medicinally relevant cyanamides was demonstrated (Scheme 6).
Rolipram-derived pyrrolidine 30 was synthesized in 50% yield
over 5 steps from 3-hydroxy-4-methoxybenzaldehyde according
to literature procedures.28 Subsequent N-cyanation proceeded
smoothly, forming known PDE4 inhibitor 31 in 71% yield. This is
a significant improvement over the reported N-cyanation
procedure, which employed highly toxic cyanogen bromide and
gave the product in only 38% yield.4
HavingsuccessfullydemonstratedN-cyanationwithavarietyof
cyclic secondary amines, we next investigated whether acyclic
amines also participate in this new protocol. It was found that a
range of symmetrical and orthogonally substituted acyclic
secondary amines also function as suitable substrates (Scheme
3). For example, dibutylamine, N-benzylmethylamine, and N-
methylphenethylamine can be readily converted to the corre-
sponding cyanamides in good to high yields (products 19−21,
56−71% yield). Under the standard reaction conditions diallyl-
amine afforded cyanamide 22 in only 33% isolated yield. In this
case, we suspected that dichlorocarbene formation (via chloro-
form deprotonation) might result in undesired side reactions.22
Indeed, it was found that adding 4-methylstyrene (1 equiv) as a
dichlorocarbene scavenger increased the isolated yield of 22 to
64%.23,24 More sterically encumbered acyclic secondary amines,
including dibenzylamine and N-isopropylbenzylamine, gave no
conversion to the corresponding amidines after stirring with
trichloroacetonitrile for23 hatroomtemperature. After extensive
screening of reaction conditions and additives, we were pleased to
discover that increasing the reaction temperature to 80 °C and
adding a catalytic quantity of imidazole (10 mol %) enabled these
reactionstoproceed, givingcyanamides23and24insynthetically
usefulyields.25 However,suitablereactionconditionscouldnotbe
identified to convert less nucleophilic diphenylamine and N-
cyclohexylanilinetotheircorrespondingcyanamides(25and26),
representing a current limitation of this methodology.26
Scheme 6. Synthesis of a Biologically Active Cyanamide
WeinitiallysuspectedthatimidazolemightserveasaLewisbase
catalyst for this transformation by reacting with trichloroacetoni-
trile to form a more reactive amidine (Scheme 4, eq 4). However,
when imidazole and trichloroacetonitrile are stirred at 80 °C in
MeCN,onlystartingmaterialsarereturned.Inlightofthisresult,it
seems more plausible that imidazole acts as a shuttle base to favor
C
DOI: 10.1021/acs.orglett.6b02775
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
National Institutes of Health: https://toxnet.nlm.nih.gov/cgi-bin/sis/
search2/r?dbs+hsdb:@term+@DOCNO+708 (accessed Oct 7, 2016).
(9) Zhu, C.; Xia, J.-B.; Chen, C. Org. Lett. 2014, 16, 247.
(10) Teng, F.; Yu, J.-T.; Jiang, Y.; Yang, H.; Cheng, J. Chem. Commun.
2014, 50, 8412.
In conclusion, we have developed a new one-pot protocol for
the N-cyanation of secondary amines that employs inexpensive
trichloroacetonitrile as the cyano source and is applicable to a
diverse array of cyclic and acyclic substrates. Ongoing studies are
focused on further applications of trichloroacetonitrile in
synthesis, and these results will be reported in due course.
(11) Teng, F.; Yu, J.-T.; Zhou, Z.; Chu, H.; Cheng, J. J. Org. Chem. 2015,
80, 2822.
(12) Talavera, G.; Pena, J.; Alcarazo, M. J. Am. Chem. Soc. 2015, 137,
8704.
̃
ASSOCIATED CONTENT
■
S
(13) Houben, J.; Fischer, W. Ber. Dtsch. Chem. Ges. B 1930, 63, 2464.
(14) Sherif, S. M.; Erian, A. W. Heterocycles 1996, 43, 1083.
(15) To the best of our knowledge, this is the first report that utilizes
trichloroacetonitrile in a N-cyanation process. For reports that describe
the reactivity of secondary amines with trichloroacetonitrile, see:
(a) Backer, H. J.; Wanmaker, W. L. Recl. Trav. Chim. Pays-Bas 1951, 70,
638.(b)Grivas, J.C.;Taurins,A.Can.J.Chem.1958,36,771.(c)Grivas, J.
C.; Taurins, A. Can. J. Chem. 1959, 37, 795. (d) Grivas, J. C.; Taurins, A.
Can.J.Chem.1959,37,1260.(e)Saari,W.S.;Freedman, M.B.;Huff,J.R.;
King, S. W.; Raab, A. W.;Bergstrand, S. J.; Engelhardt, E. L.; Scriabine, A.;
Morgan, G.;Morris, A.;Stavorski, J. M.;Noll, R. M.;Duggan, D. E. J. Med.
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b02775.
Optimization data, experimental procedures, character-
ization of new compounds and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: Kenneth.ling@syngenta.com.
*E-mail: MorrillLC@cardiff.ac.uk.
Notes
́
Chem. 1978, 21, 1283. (f) L’Abbe, G.; Albrecht, E. J. Heterocycl. Chem.
1992, 29, 451. (g) Bock, M. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.;
Veber, D. F.; Freidinger, R. M.; Chang, R. S. L.; Lotti, V. J. J. Med. Chem.
1988, 31, 176. (h) Dunsford, J. J.; Camp, J. E. Tetrahedron Lett. 2013, 54,
4522.
The authors declare no competing financial interest.
Informationaboutthedatathatunderpinstheresultspresentedin
this article, including how to access them, can be found in the
Cardiff University data catalogue at http://doi.org/10.17035/d.
2016.0011295237 (accessed Oct 13, 2016).
(16) For safety information, see the Hazardous Substances Data Bank
on the Toxicology Data Network of the U.S. National Library of
Medicine, National Institutes of Health: https://toxnet.nlm.nih.gov/cgi-
bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+7618 (accessed Oct
13, 2016).
(17) See Supporting Information for full details of optimization studies.
(18) 1,2-Dimethoxyethane (DME) was the preferred solvent, as
products arising from solvent decomposition were occasionally observed
in THF.
(19) Control experiments showed that the removal of trichloro-
acetonitrile prior to the elimination step was essential for reproducible
high yields in this process.
(20) Kanzian, T.; Nigst, T. A.; Maier, A.; Pichl, S.; Mayr, H. Eur. J. Org.
Chem. 2009, 2009, 6379.
(21) Cu-, Au-, Ag-, and Pt-based additives (10 mol %) were tested
including PtCl2, which was shown by Camp and co-workers to catalyze
thereactionofprimaryandsecondaryamineswithtrichloroacetonitrilein
nonpolar solvents. See ref 15h.
(22) Vogel, E.; Klug, W.; Breuer, A. Org. Synth. 1974, 54, 11.
(23) Vivekanand, P. A.; Wang, M.-L. Catal. Commun. 2012, 22, 6.
(24) For all other amine substrates tested, the addition of 4-
methylstyrene had no effect on isolated product yield. 2,3-Dimethyl-2-
butene can also be employed as a dichlorocarbene scavenger.
(25) Heating the reaction mixture to 80 °C for 24 h without imidazole
gave 40% and <5% conversion to the corresponding amidines,
respectively.
(26) At this time, primary amines are also out with the scope of the
described methodology. The reactions of anilines (Lester, R. P.; Camp, J.
E. ACSSustainableChem. Eng. 2013, 1, 545)andbenzylamines(Yavari, I.;
Malekafzali, A.; Skoulika, S. Tetrahedron Lett. 2014, 55, 3154) with
trichloroacetonitrile to form the corresponding amidines are known.
However, we have not yet been able to determine suitable reaction
conditions to affect conversion of these amidines to the corresponding
cyanamides.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the School of Chemistry, Cardiff
University for generous support and the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
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Org. Lett. XXXX, XXX, XXX−XXX