Deoxycyanamidation of Alcohols with N-Cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS)

Article abstract of DOI:10.1021/acs.orglett.7b01710

The first one-pot deoxycyanamidation of alcohols has been developed using N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) as both a sulfonyl transfer reagent and a cyanamide source, accessing a diverse range of tertiary cyanamides in excellent isolated yields. This approach exploits the underdeveloped desulfonylative (N-S bond cleavage) reactivity pathway of NCTS, which is more commonly employed for electrophilic C- and N-cyanation processes.

Full text of DOI:10.1021/acs.orglett.7b01710

Letter
pubs.acs.org/OrgLett
Deoxycyanamidation of Alcohols with N‑Cyano‑N‑phenyl-p-
methylbenzenesulfonamide (NCTS)
James N. Ayres,† Matthew W. Ashford,† Yannick Stockl,† Vassili Prudhomme,† Kenneth B. Ling,‡
̈
James A. Platts,† 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: The first one-pot deoxycyanamidation of
alcohols has been developed using N-cyano-N-phenyl-p-
methylbenzenesulfonamide (NCTS) as both a sulfonyl transfer
reagent and a cyanamide source, accessing a diverse range of tertiary cyanamides in excellent isolated yields. This approach
exploits the underdeveloped desulfonylative (N−S bond cleavage) reactivity pathway of NCTS, which is more commonly
employed for electrophilic C- and N-cyanation processes.
Scheme 1. Previous Work and Outline of the
Deoxycyanamidation Strategy
he nitrile functional group holds a privileged position
Twithin synthetic chemistry and is a common motif within
natural products, agrochemicals, and pharmaceuticals.1 As such,
a diverse array of synthetic methodologies have been developed
to access nitrile-containing compounds. Electrophilic cyanation
describes the reaction of C-, N-, O-, and S-based nucleophiles
with electrophilic nitrile sources “+CN”.2 Traditionally,
cyanogen halides have been employed for this purpose,3 but
their high associated toxicity has driven the development of
alternative electrophilic cyanating reagents including cyanates
(O−CN),4 thiocyanates (S−CN),5 cyanamides (N−CN),6
nitriles (C−CN),7 and hypervalent iodine reagents (I−CN).8
In 2011, Beller employed N-cyano-N-phenyl-p-methyl-
benzenesulfonamide (NCTS),9 as an electrophilic cyanating
reagent for the C-cyanation of aryl Grignards (Scheme 1, eq
1).10 Easily accessible in one step from inexpensive phenylurea,
NCTS has subsequently attracted widespread interest from the
synthetic community and has been applied to a diverse range of
C-cyanation processes.11 In 2015, Raghunadh reported the use
of NCTS in N-cyanation, accessing quinazolinones upon
intramolecular cyclization of a cyanamide intermediate
(Scheme 1, eq 2).12 In comparison to the use of NCTS as
an electrophilic C- and N-cyanating reagent, the alternative
desulfonylative pathway, via N−S bond cleavage, has been
largely overlooked.13 In 2016, Moses and Sharma reported the
desulfonylative formation of cyanamide anions from NCTS via
treatment with tetrabutylammonium fluoride.14 An intermo-
lecular cyclizative capture of the released cyanamide anion with
nitrile oxides enabled the synthesis of various oxadiazol-5-
imines (Scheme 1, eq 3). Taking inspiration from these reports,
we envisaged a deoxycyanamidation of alcohols, proceeding via
an initial N- to O-sulfonyl transfer, followed by a recombination
of the resulting cyanamide anion and alkyl sulfonate to access
biologically relevant and synthetically useful cyanamide
products (Scheme 1, eq 4).15 The approach would expand
the reactivity profile of NCTS to include O-nucleophiles,
permitting access to a diverse range of bespoke cyanamide
products through variation of the alcohol and sulfonamide
starting materials. Herein, we report the successful implemen-
tation of this strategy and describe the first one-pot
deoxycyanamidation protocol of primary and secondary
alcohols.
In order to test our hypothesis, we selected 2-fluorobenzyl
alcohol 1 and NCTS 2 (1.1 equiv) in bench-grade THF as a
model system, cognizant of the opportunity to monitor reaction
progress using in situ 19F NMR (Table 1).16 We were
Received: June 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01710
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Organic Letters
Letter
a
a
Table 1. Optimization of Deoxycyanamidation Protocol
Scheme 2. Alcohol Scope
b
entry
base (equiv)
t (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
NaH (3)
50
rt
rt
rt
rt
rt
rt
rt
rt
0.5
6
84
NaH (2)
80
DBN (2)
6
0
DBU (2)
6
60
TBD (2)
6
32
KOt-Bu (2)
NaOt-Am (2)
NaOt-Am (2)
NaOt-Am (1.1)
6
85
6
85
c
8
3
100 (80)
c
9
23
80
a
Reactions performed using 1 mmol of alcohol 1 and bench-grade
b
THF. [1] = 0.2 M. Yield as determined by 19F NMR analysis of crude
reaction mixture with 1,3,5-trifluorobenzene as the internal standard.
Isolated yield given in brackets. With tetrabutylammonium iodide (10
c
mol %).
encouraged to observe 84% conversion to cyanamide 3 using
sodium hydride (3 equiv) as a base at 50 °C (Table 1, entry 1).
The reaction could be performed at 25 °C, and the quantity of
base reduced to 2 equiv without any significant drop in
conversion (Table 1, entry 2). Considering the inherent safety
concerns associated with using NaH, particularly on a large
scale,17 we searched for alternative bases. Treatment of 1 and 2
(1.1 equiv) with 2 equiv of amidine (DBN and DBU) and
guanidine (TBD) bases all gave reduced conversion to
cyanamide 3 (Table 1, entries 3−5). To our delight, potassium
tert-butoxide and sodium tert-pentoxide are effective substitutes
for NaH, giving comparable conversions to 3 (Table 1, entries
6 and 7).18 These reactions are typically heterogeneous, and it
was found that using TBAI (10 mol %) as an additive with
sodium tert-pentoxide (2 equiv) gave complete conversion to
cyanamide 3 after 1 h at 25 °C with an 80% isolated yield
(Table 1, entry 8).
For the purposes of assessing the scope of this protocol, the
reaction time was extended to 16 h to ensure full conversion
across a range of substrates (Scheme 2). Under these
conditions, a variety of aryl substituted primary alcohols were
readily converted to the corresponding aryl/alkyl cyanamides in
excellent yields (products 3−12, 70−90% yield). The reaction
performs well upon scale-up, with the formation of cyanamide
4 successfully carried out on a 20 mmol scale in 78% yield to
provide 3.23 g of product. Within the aryl unit, 4-Me, 3-Me,
and 2-Me substitution was tolerated in addition to electron-
donating (4-OMe) and electron-withdrawing (4-F and 4-CF3)
substituents. Heteroaryls (2-furyl, 2-thiophenyl, and 4-pyridyl)
can be present within the alcohol, although the reaction using
4-pyridinemethanol required heating at 100 °C in 1,4-dioxane
with 2 equiv of NCTS to achieve a full conversion, giving
cyanamide 12 in 75% yield. Allyl alcohol performed well,
accessing aryl/allyl substituted cyanamide 13 in 79% yield.
Simple alkyl substituted primary alcohols (e.g., 1-decanol)
required extended reaction times and more forcing reaction
conditions and gave cyanamide 14 in 55% yield.19 Secondary
alcohols were also readily tolerated, giving cyanamides 15 and
16 in 72% and 80% yield, respectively. The stereospecificity of
the process was investigated using (R)-1-phenylethanol. Under
standard reaction conditions, cyanamide (S)-16 was formed in
a
Reactions performed using 1 mmol of alcohol starting material. All
b
yields are isolated yields after chromatographic purification. NCTS (2
equiv) in 1,4-dioxane at 100 °C for 16 h NCTS (2 equiv) in 1,4-
dioxane at 100 °C for 48 h.
c
74% e.e. (80% e.e. in the absence of TBAI) indicative of
competing SN1 and SN2 pathways.20 A substrate limitation was
identified upon testing tertiary alcohols 2-phenyl-2-propanol
and triphenylmethanol. These hindered alcohols did not react
with NCTS to give cyanamides 17 and 18 even after heating for
prolonged reaction times, with starting materials returned.21
Having successfully demonstrated deoxycyanamidation with
a variety of primary and secondary alcohols, we next
investigated the reaction scope with respect to the sulfonamide
(Scheme 3). Under the standard reaction conditions with
benzyl alcohol it was found that a range of N-aryl substituents
within the sulfonamide could be incorporated, giving aryl/alkyl
cyanamides in excellent yields (products 4 and 19−25, 72−
89% yield). Aryl substitution at the 4-, 3-, and 2-position was
tolerated in addition to electron-donating (4-OMe) and
electron-withdrawing (4-F, 4-Cl, and 4-CF3) substituents. An
N-butyl sulfonamide was used to afford alkyl/alkyl cyanamide
26 in 52% yield. The effect of electronics within the S-
substituent of the sulfonamide was also probed. Both 4-
OMeC6H4 and 4-NO2C6H4 S-substituents resulted in lower
isolated yields of cyanamide 4 (62% and 63% respectively).
Furthermore, employing a sulfonamide bearing a thiomethyl
substituent resulted in a complex reaction mixture, giving 4 in
only 19% yield. The commonly reported tosyl sulfonamides
(e.g., NCTS) gave the highest yields for this protocol.
With respect to the mechanism of this process, we propose
an initial N- to O-sulfonyl transfer between NCTS and sodium
alkoxide (generated in situ from 2-fluorobenzyl alcohol and
NaOt-Am), to give 2-fluorobenzyl tosylate, which has been
directly observed using in situ 19F NMR during optimization
studies (Scheme 4, eq 5).22 Subsequent alkylation of the
B
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a
conversion to 90% was also observed when NaI (10 mol %)
was used as an additive, indicative of in situ conversion of the
alkyl tosylate to a more reactive alkyl iodide.24 These effects are
combined when using n-Bu4NI (10 mol %) as an additive,
giving 99% conversion to cyanamide 3 after just 30 min at 25
°C. We envisaged two possible mechanistic pathways for the
observed N- to O-sulfonyl transfer (Scheme 4, eq 7): (1)
alkoxide attack at C followed by intramolecular N- to O-sulfonyl
transfer; (2) intermolecular N- to O-sulfonyl transfer via direct
attack of alkoxide at S. Computational experiments revealed
that nucleophilic attack at C (pathway 1), forming a
carbamimidate intermediate, was approximately 15 kJ mol−1
lower in energy than attack at S (pathway 2).25 However, the
large energy barrier associated with intramolecular N- to O-
sulfonyl transfer to phenyl cyanamide and methyl tosylate (Ga =
161.7 kJ mol−1) is unlikely to be overcome at 25 °C.
Furthermore, the lack of any observable products resulting
from O-cyanation (the lowest energy pathway from the
carbamimidate intermediate) suggests that the observed
sulfonyl transfer proceeds via direct attack at S (pathway 2).26
In conclusion, we have developed a new operationally simple
one-pot protocol for the deoxycyanamidation of primary and
secondary alcohols using N-cyano-N-phenyl-p-methylbenzene-
sulfonamide (NCTS), accessing a diverse array of tertiary
cyanamide products in excellent yields. This process exploits
the underdeveloped desulfonylative (N−S bond cleavage)
reactivity pathway of NCTS, which is more commonly
employed for C- and N-cyanation processes. Ongoing studies
are focused on further applications of NCTS in synthesis, and
these results will be reported in due course.
Scheme 3. Sulfonamide Scope
a
Reactions performed using 1 mmol of alcohol starting material. All
yields are isolated yields after chromatographic purification.
a
Scheme 4. Mechanistic Considerations
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01710.
Optimization data, experimental procedures, character-
ization of new compounds, and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: MorrillLC@cardiff.ac.uk.
ORCID
James A. Platts: 0000-0002-1008-6595
Louis C. Morrill: 0000-0002-6453-7531
Notes
The authors declare no competing financial interest.
Information about the data that underpins the results presented
in this article, including how to access them, can be found in
the Cardiff University data catalogue at http://doi.org/10.
17035/d.2017.0038300689 (accessed Jun 28, 2017).
a
As determined by 19F NMR analysis of crude reaction mixture with
1,3,5-trifluorobenzene as the internal standard.
cyanamide anion with alkyl tosylate affords the tertiary
cyanamide product. The role of the additive in this reaction
was also investigated (Scheme 4, eq 6). In the absence of any
additives, 42% conversion to cyanamide 3 was observed after 30
min using the standard reaction conditions. The conversion
increased to 90% and 92% upon addition of n-Bu4NPF6 (10
mol %) and n-Bu4NBF4 (10 mol %), respectively, indicating
rate enhancement via cation exchange.23 An increase in
ACKNOWLEDGMENTS
■
We gratefully acknowledge the School of Chemistry, Cardiff
University for generous support, the EPSRC Doctoral Training
Grant for a part-funded Ph.D. studentship (J.N.A., EP/
M50631X/1), the German Academic Exchange Service
(DAAD) for a RISE Worldwide Research Scholarship (Y.S.),
the Royal Society for a Research Grant (RG150466), and the
C
DOI: 10.1021/acs.orglett.7b01710
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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reflux. See ref 9.
EPSRC UK National Mass Spectrometry Facility at Swansea
University.
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