Synthesis and Reactivity of N-Allenyl Cyanamides

Article abstract of DOI:10.1021/acs.orglett.8b02225

N-Allenyl cyanamides have been accessed via a one-pot deoxycyanamidation-isomerization approach using propargyl alcohol and N-cyano-N-phenyl-p-methylbenzenesulfonamide. The utility of this novel class of allenamide was explored through derivatization, with hydroarylation, hydroamination, and cycloaddition protocols employed to access an array of cyanamide products that would be challenging to access using existing methods.

Full text of DOI:10.1021/acs.orglett.8b02225

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis and Reactivity of N‑Allenyl Cyanamides
James N. Ayres,† Matthew T. J. Williams,† Graham J. Tizzard,‡ Simon J. Coles,‡ Kenneth B. Ling,§
and Louis C. Morrill*,†
†School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, U.K.
‡UK National Crystallographic Service, Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, U.K.
§Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, U.K.
S
* Supporting Information
ABSTRACT: N-Allenyl cyanamides have been accessed via a
one-pot deoxycyanamidation−isomerization approach using
propargyl alcohol and N-cyano-N-phenyl-p-methylbenzene-
sulfonamide. The utility of this novel class of allenamide was
explored through derivatization, with hydroarylation, hydro-
amination, and cycloaddition protocols employed to access an
array of cyanamide products that would be challenging to
access using existing methods.
llenamides, also referred to as N-allenyl amides,1 are
cyanamides, where the cyano group serves as the stabilizing
2
Aversatile synthetic building blocks in organic chemistry. electron-withdrawing N-substituent. A variety of biologically
In comparison to allenamines,3 which require careful
active compounds, including agrochemicals and pharmaceut-
icals, contain the cyanamide (N−CN) functional group,9
preparation and handling due to their susceptibility toward
which is most commonly introduced via electrophilic N-
cyanation of amines using highly toxic cyanogen bromide.10
Employing our recently developed deoxycyanamidation
method,8b we anticipated that the reaction of propargyl
alcohol with N-cyano-N-phenyl-p-methylbenzenesulfonamide
(NCTS)11 would afford an N-propargyl cyanamide, which
could undergo a base-catalyzed isomerization in situ to access
an N-allenyl cyanamide (Scheme 1B). Herein, we report the
successful implementation of this strategy and describe a one-
pot deoxycyanamidation−isomerization protocol for the syn-
thesis of N-allenyl cyanamides. Furthermore, the derivatization
of the allenyl functional group within this novel class of
allenamide has been explored through cycloaddition, hydro-
arylation, and hydroamination protocols, accessing cyanamide
products that would be difficult to access using traditional
approaches.
hydrolysis and polymerization, allenamides exhibit enhanced
stability due to delocalization of the nitrogen lone pair of
electrons into the electron-withdrawing carbonyl. In addition
to N-acyl allenamides,4 alternative classes have been
introduced through variation of the electron-withdrawing N-
substituents, including N-phosphoryl,5 N-sulfonyl,6 and N-
heteroaryl7 allenamides (Scheme 1A).
Taking inspiration from these reports, and as a part of our
ongoing investigations into the development of new synthetic
routes toward cyanamides,8 we envisaged accessing N-allenyl
Scheme 1. Proposed Synthesis and Derivatization of N-
Allenyl Cyanamides
To test our hypothesis, we selected propargyl alcohol 1 and
NCTS 2 (1.1 equiv) in THF as a model system (Table 1).12
Tetrabutylammonium iodide (TBAI) (10 mol %) was
employed as an additive from the start of our investigation
due to the previous observation that it improved the efficiency
of deoxycyanamidation via both cation exchange and in situ
conversion of the alkyl tosylate to a more reactive alkyl
iodide.8b Initially, the base was added to a mixture of propargyl
alcohol 1 and TBAI in THF to preform the sodium alkoxide
prior to addition of NCTS 2. We were encouraged to observe
76% conversion to N-allenyl cyanamide 3 using sodium
hydride (2 equiv) as a base at rt after 6 h (Table 1, entry 1).
Received: July 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02225
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of N-Allenyl Cyanamide Synthesis
Scheme 2. Substrate Scope
b
entry
base (equiv)
TBAI (mol %)
yield (6 h, 23 h) (%)
1
2
3
4
5
6
7
NaH (2)
DBN (2)
DBU (2)
LHMDS (2)
KOt-Bu (2)
NaOt-Am (2)
NaH (2)
NaH (2)
NaH (1.5)
10
10
10
10
10
10
0
76, 56
0, 0
0, 5
0, 0
18, 19
61, 58
36, 40
73, 76 (57)
52, 56
c
8
9
10
10
c
a
Reactions performed using 1 mmol of alcohol 1. [1] = 0.2 M. Bases
b
(2 equiv) added to 1 in THF prior to the addition of 2. Determined
by 1H NMR analysis of crude reaction mixture with 1,3,5-
trimethylbenzene as the internal standard. Isolated yield given in
c
parenteses. NaH (2 equiv) added last to the reaction mixture.
However, the NMR yield decreased to 56% after 23 h,
indicating that the N-allenyl cyanamide was decomposing
slowly under the reaction conditions. A selection of alternative
bases were examined, but lower conversion to 3 was observed
in each case (Table 1, entries 2−6). As anticipated, removing
TBAI also resulted in diminished NMR yield (Table 1, entry
7). It was found that simply adding NaH last to the reaction
mixture suppressed decomposition of the N-allenyl cyanamide
product after 23 h (Table 1, entry 8), allowing 3 to be obtained
in a synthetically useful 57% isolated yield.13 Reducing the
quantity of NaH to 1.5 equiv resulted in only 56% conversion
to 3 after 23 h (Table 1, entry 9), confirming the requirement
for 2 equiv of base to be used.
a
Reactions performed using 1 mmol of alcohol starting material. All
yields are isolated yields after chromatographic purification.
b
1
Determined by H NMR analysis of crude reaction mixture with
1,3,5-trimethylbenzene as the internal standard.
propargyl tosylate (Scheme 3A). Subsequent SN2-type
alkylation of the cyanamide anion with propargyl tosylate
affords N-propargyl cyanamide, which undergoes base-
For the purpose of assessing the scope of this protocol, the
reaction time was set to 16 h to ensure full conversion across a
range of substrates (Scheme 2). Under the optimized reaction
conditions (Table 1, entry 8) with propargyl alcohol 1, it was
found that a range of N-aryl substituents within the
sulfonamide could be incorporated, giving aryl/allenyl
cyanamides in good yields (products 3−11, 51−73% yields).
Aryl substitution at the 4-, 3-, and 2-position was tolerated in
addition to electron-donating (4-OMe) and electron-with-
drawing (4-CF3) substituents. Unambiguous structural con-
firmation was obtained via X-ray crystal structure analysis of N-
allenyl cyanamide 4. The reaction performs well upon scale-up,
with the formation of 4 successfully carried out on a 14 mmol
scale in 73% yield to provide 1.69 g of product. The use of N-
4-chlorophenyl- and N-4-bromophenyl-substituted sulfona-
mides was successful, incorporating an additional functional
handle into the products for subsequent elaboration via cross-
coupling methods.14 N-Isopropyl and N-butyl sulfonamides
were used to afford alkyl/allenyl cyanamides 12 and 13 in 38%
and 15% isolated yields, respectively. The low isolated yields
observed for 12 and 13 were attributed to volatility (higher
NMR yields) and poor product stability, both under the
reaction conditions and when subjected to silica gel chromato-
graphic purification.
a
Scheme 3. Mechanistic Studies
With respect to the mechanism of this process, in
accordance with our previous studies,8b we proposed an initial
N- to O-sulfonyl transfer between NCTS and sodium alkoxide
(generated in situ from propargyl alcohol and NaH), to give
a
1
Determined by H NMR analysis of crude reaction mixture with
1,3,5-trimethylbenzene as the internal standard.
B
DOI: 10.1021/acs.orglett.8b02225
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catalyzed isomerization4 to give N-allenyl cyanamide. The
validity of N-propargyl cyanamide as an intermediate was
probed via treatment with NaH (2 equiv) at 25 °C in THF,
giving >95% conversion to the expected N-allenyl cyanamide
after 23 h (Scheme 3B). An SN2-type alkylation was favored
over an alternative SN2′-type alkylation due to studies
involving the reaction of propargyl tosylate with phenyl
cyanamide (Scheme 3C). Under the standard reaction
conditions, employing NaH (0.5 equiv) as base, 49%
conversion to N-propargyl cyanamide was observed, with no
N-allenyl cyanamide formed. Upon increasing the quantity of
NaH employed to 1, 1.5, and 2 equiv, increasing conversion to
N-allenyl cyanamide was observed, providing evidence for an
initial SN2-type alkylation followed by isomerization. In light of
the three-step reaction process (N- to O-sulfonyl transfer,
cyanamide alkylation, isomerization), we believe that this one-
pot access to N-allenyl cyanamide is synthetically attractive.
With an understanding of the reaction mechanism in place
and having successfully demonstrated the formation of N-
allenyl cyanamide from propargyl alcohol, we next investigated
the use of substituted propargyl alcohols (Scheme 4). Using
a
Scheme 5. Derivatization of N-Allenyl Cyanamides
a
Scheme 4. Use of Substituted Propargyl Alcohols
Aniline (1.05 equiv) employed as nucleophile.
pot deoxycyanamidation−isomerization protocol developed
proceeds via an initial N- to O-sulfonyl transfer, followed by
cyanamide N-alkylation and isomerization, giving a selection of
N-allenyl cyanamides in good yields. The utility of these
products was explored through derivatization, with hydro-
arylation, hydroamination, and cycloaddition protocols em-
ployed to access an array of cyanamide products.
the optimized reaction conditions (Table 1, entry 8), reaction
of 2-butyn-1-ol 14 with NCTS 2 gave exclusively N-propargyl
cyanamide 15 in 72% isolated yield. Treatment of purified 15
with NaH (2 equiv) at 25 °C in THF gave no observable
conversion to the corresponding N-allenyl cyanamide after 23
h, indicating that the isomerization is not favored in 15.
Alternatively, employing 3-butyn-2-ol 16 as the alcohol
resulted in the formation of a complex mixture of inseparable
products. From analysis of the reaction mixture before and
after silica gel chromatographic purification, it appeared that
multiple allene- and alkyne-containing products are formed,
which may be attributed toward competing β-elimination, SN2
and SN2′-type cyanamide N-alkylation processes involving a
secondary alkyl tosylate intermediate (cf. Scheme 3).
Considering that N-allenyl cyanamides are a novel structural
motif, we next explored their derivatization with a view toward
generating a variety of cyanamides that would be challenging
to access using existing methods. To this end, employing the
method developed by Kimber and co-workers,15 a variety of N-
alkenyl cyanamides16 17−20 were accessed from N-allenyl
cyanamide 4 in high yields (68−93%) via intermolecular
Au(I)-catalyzed hydroarylation and hydroamination protocols
(Scheme 5A). Furthermore, 4 participates in stereoselective [2
+ 2] and [4 + 2] cycloadditions with phenylacetylene17 and
cyclopentadiene,18 giving cycloadducts 21 and 22 in 75% and
64% yield, respectively (Scheme 5B). In both cases, the
structure of the major stereoisomer formed was determined
using NOESY experiments.12
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02225.
■
S
Optimization data, experimental procedures, character-
ization of new compounds, and spectral data (PDF)
Accession Codes
CCDC 1844708 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK; fax: + 44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: morrilllc@cardiff.ac.uk.
ORCID
Simon J. Coles: 0000-0001-8414-9272
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.2018.0055747356 (accessed Aug 14, 2018).
In conclusion, we have introduced a new class of allenamide,
namely N-allenyl cyanamides. The operationally simple one-
C
DOI: 10.1021/acs.orglett.8b02225
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(13) A similar NMR yield (75% after 23 h) was observed using
NaO-t-Am (2 equiv) as base in 1,2-dimethoxyethane as solvent.
However, this procedure exhibited poor reproducibility when
compared to the optimized reaction conditions (Table 1, entry 8).
(14) (a) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T.
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(c) Haas, D.; Hammann, J. M.; Greiner, R.; Knochel, P. ACS Catal.
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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/M5063X/1) and the EPSRC UK National Mass
Spectrometry Facility at Swansea University.
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DOI: 10.1021/acs.orglett.8b02225
Org. Lett. XXXX, XXX, XXX−XXX