Rearrangements of N-acyl isothioureas. alternate access to acylguanidines from cyanamides

Article abstract of DOI:10.1021/ol3026439

We report a tin-free one-pot radical approach to the synthesis of N-acyl isothioureas and acylguanidines from N-acyl cyanamides. Photoactivated reduction of aromatic disulfides in the presence of Huenig's base results in hydrothiolation of the cyanamide moiety, followed by spontaneous 1,3-migration of the acyl group. Onward reaction of the isothioureas obtained with amines led to the corresponding N-acylguanidines, where the acyl group is attached to the nitrogen atom formerly at the cyano-end of the starting material.

Full text of DOI:10.1021/ol3026439

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5538–5541
Rearrangements of N‑Acyl Isothioureas.
Alternate Access to Acylguanidines from
Cyanamides
†
†
†
†
ꢀ ꢁ
Giovanni Maestri, Marie-Helene Larraufie, Cyril Ollivier, Max Malacria,
†
Louis Fensterbank, and Emmanuel Lacote*
,†,‡
^
ꢀ
UPMC Universite Paris 06, IPCM (UMR 7201), 4 Pl. Jussieu, C. 229, 75005 Paris,
France, and ICSN CNRS, Bat. 27, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France
^
emmanuel.lacote@univ-lyon1.fr
Received September 25, 2012
ABSTRACT
We report a tin-free one-pot radical approach to the synthesis of N-acyl isothioureas and acylguanidines from N-acyl cyanamides. Photoactivated
€
reduction of aromatic disulfides in the presence of Hunig’s base results in hydrothiolation of the cyanamide moiety, followed by spontaneous 1,3-
migration of the acyl group. Onward reaction of the isothioureas obtained with amines led to the corresponding N-acylguanidines, where the acyl
group is attached to the nitrogen atom formerly at the cyano-end of the starting material.
Cyanamides are attractive 1CÀ2N building blocks for
nitrogen-rich molecules, whose reactivity can be further tuned
by installing an acyl group next to the sp2 nitrogen.1 We have
studied the reactivity of N-acylcyanamides as partners for
radical cascade reactions. This allowed us to selectively
prepare quinazolinones2 as well as cyclic N-acyl guanidines.3
In the latter case, the acyl group in the acylguanidine
formed was attached to the nitrogen that was bearing the
cyanide moiety (Scheme 1a, highlighted in yellow). In the
present communication we now report on the preparation of
isomeric acylguanidines in which the acyl group is positioned
on the nitrogen of the cyanide moiety (Scheme 1b,
highlighted in red).
Our initial goal was to extend the scope of the radical
cascades involving N-acyl cyanamides to thiyl radicals
with the aim of accessing polycyclic isothioureas such as A
(Table 1), for which no radical synthesis has been reported
to date. Isothioureas are great ligands for transition metals,4
precursors of guanidines,5 and organocatalysts for asym-
metric reactions.6
Reaction of substrate 1a with diphenyldisulfide was
attempted under various conditions designed to generate
the corresponding thiyl radical (Table 1). No conversion
was observed when using AIBN, even in large excess
†
ꢀ
UPMC Universite Paris 06.
‡ ICSN CNRS.
(1) Larraufie, M.-H.; Maestri, G.; Malacria, M.; Ollivier, C.;
^
Fensterbank, L.; Lacote, E. Synthesis 2012, 44, 1279–1292.
(2) (a) Servais, A.; Azzouz, M.; Lopes, D.; Courillon, C.; Malacria,
(4) Srinivas, K.; Srinivas, P.; Prathima, P. S.; Balaswamy, K.;
Sridhar, B.; Rao, M. M. Catal. Sci. Technol. 2012, 2, 1180–1187.
(5) (a) Berlinck, R. G. S.; Kossuga, M. H.; Nascimento, A. M. Sci.
Synth. 2005, 18, 1077–1116. (b) Manimala, J. C.; Anslyn, E. V. Eur. J.
Org. Chem. 2002, 3909–3922.
(6) (a) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.;
Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714–2720. (b) Bumbu, V. D.;
Birman, V. B. J. Am. Chem. Soc. 2011, 133, 13902–13905. (c) Taylor, J. E.;
Bull, S. D.; Williams, J. M. W. Chem. Soc. Rev. 2012, 41, 2109–2121.
M. Angew. Chem., Int. Ed. 2007, 46, 576–579. (b) Larraufie, M.-H.;
Courillon, C.; Ollivier, C.; Lacote, E.; Malacria, M.; Fensterbank, L. J.
Am. Chem. Soc. 2010, 132, 4381–4387. For an SmI2-mediated radical
cascade involving cyanamides, see also (c) Hu, Z.; Li, S.-d.; Hong, P.-z.
Arkivoc 2010, 171–177.
^
(3) Larraufie, M.-H.; Ollivier, C.; Fensterbank, L.; Malacria, M.;
^
Lacote, E. Angew. Chem., Int. Ed. 2010, 49, 2178–2181.
r
10.1021/ol3026439
Published on Web 10/23/2012
2012 American Chemical Society

Table 1. Discovery and Optimization of the Migration of
Hydrothiolated N-Acylcyanamides
Scheme 1. Access to N-Acylguanidines from
N-Acyl-Cyanamides
temp
yield
(%)
entry
conditionsa
solvent
(°C)
1
AIBN (1.5 equiv)
AIBN (4 equiv)
Bu3SnH, AIBN
(2 equiv)
toluene
toluene
toluene
80
Δ
Δ
À
À
À
2
3b
4b
5b
Bu3SnH, AIBN
(2 equiv)
t-BuOH
Δ
À
À
(entries 1À2). Introduction of tributyltin hydride was also
unsuccessful, and pushing the conditions resulted only in
some degradation of 1a (entries 3À5). Neither triethylbor-
ane/O2 initiation nor irradiation (Xenon lamp) led to
observable conversion (entries 6À8).
Bu3SnH, AIBN
(2 equiv)
MeCN
90
6
Et3B/O2 (2 equiv)
Et3B/O2 (2 equiv)
xenon lamp
toluene
toluene
toluene
Et3N
rt
80
rt
rt
Δ
90
rt
rt
À
7
À
8
À
9
Et3N (solvent)
Et3N (2 equiv)
DIPEA (2 equiv)
DIPEA (6 equiv)
DIPEA (6 equiv),
light bulb (14 W)
29c
21c
36c
38c
78c
10
11
12
13
t-BuOH
MeCN
MeCN
MeCN
a Reactions conditions: 1a (0.1 mmol, 0.1 M solution), PhSSPh
(2 equiv), and reagents indicated in the table. Yield given for product
2. b Slow addition (0.05 mmol/h). c 1H NMR yield using MeNO2 as an
internal standard.
Compound2turnedout tobeanacyclicN-acyl isothiourea
in which the acyl moiety substituted the imino nitrogen
atom, instead of the expected amino group, as would
have been the case in the simple hydrothiolation of the
starting cyanamides. This reactivity has not previously been
reported.
Figure 1. X-ray structure of 2.
We then turned to conditions introduced by Ishibashi
for the formation of thiyl radicals via single electron
transfer to the corresponding disulfides from an excess
amine.7 Irradiation with a 14 W lightbulb of a triethyl-
amine solution of 1a in the presence diphenyldisulfide
delivered 2 in 29% yield (entry 9). When 1a was heated at
reflux in tert-butanol in the presence of only 2 equiv of NEt3,
almost complete conversion was observed, but only 21% of
product was measured by NMR spectroscopy (entry 10).
We found that N,N-diisopropylethylamine (DIPEA) in
MeCN at reflux was a better combination to generate 2
(36%, entry 11). Further optimization showed that an
excess of DIPEA and irradiation with a 14 W light bulb
at rt yielded 78% of 2 (entries 12À13). In particular, the
mode of irradiation proved to be a key factor to obtain a
synthetically useful yield (see below).
The carbonÀnitrogen bond lengths of the imino and the
˚
amino groups of 2 are very similar (1.31 and 1.33 A
respectively). These distances are both slightly higher than
usual carbonÀnitrogen double bonds, as well as signifi-
cantly shorter than a usual single bond (for example the
˚
NÀC (methyl) bond length is 1.47 A), suggesting a tauto-
meric equilibrium. Thisisfurthersupportedbytwo distinct
1H signals (δ 11 and 5.5 ppm in CDCl3) for the labile
proton, partially present on both nitrogens. Finally, the
isothiourea is trans.
With the optimized reaction conditions in hand, we
examined the scope of the reaction (Table 2). Different
substituents can be installed on the cyanamide (on the
nitrogen and/or the acyl group), as well as on the disulfide.
The reaction did not work with alkyldisulfides, so we
concentrated on diversely substituted aryldisulfides. Electron-
rich aryl disulfides (p-MeC6H4, p-MeOC6H4) led to good
yields of rearranged adducts (entries 4À6, 8À9, 14). In
contrast, the electron-deficient aryldisulfide (p-Cl-C6H4S)2
did not add well to cyanamide 1a (25%, entry 2).
The NMR signals of the major product obtained (2)
were too broad for unambiguous assignment. However,
HRMS analysis indicated that the product had two hydro-
gen atoms more than was expected for A. We eventually
obtained crystals of 2 suitable for X-ray diffraction, and
this allowed us to elucidate its structure (Figure 1).
At the acyl site, electron-rich arenes and heteroarenes
delivered good yields of the expected adducts in a fast
(7) Taniguchi, T.; Fujii, T.; Idota, A.; Ishibashi, H. Org. Lett. 2009,
11, 3298–3301.
Org. Lett., Vol. 14, No. 21, 2012
5539

(10 mol %) were added to the reaction mixture to afford
16a in 73% yield.
Table 2. Scope of the Rearranged N-Acyl Isothiourea Synthesis
The reaction was generally efficient, except when an
electron-poor disulfide was used (Table 3, entry 2) and in
the case of cyclopropylamine cyanamide 1d (entry 8). The
low yield likely reflects the inefficiency of the initial thiol
addition.
Table 3. One-Pot Synthesis of Acylguanidine from
N-Acylcyanamides
yield
entry SM
Ar1
R
Ar2
prod.
(%)
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Bn
Bn
Et
Ph
2
3
4
5
6
7
78
25
81
83
82
79
4-Cl-C6H4
Ph
4-Me-C6H4
4-Me-C6H4
4-MeO-
C6H4
Et
7
8
9
1d
1e
1f
Ph
Ph
c-Pr Ph
8
38
68
92
entry
substratea
Ar2
product
yield (%)
Ph
Et
4-Me-C6H4
9
2-furyl
4-MeO-
C6H4
Ph
10
1
1a
1a
1b
1b
1c
1c
1c
1d
1f
Ph
16a
16a
16b
16b
16c
16c
16c
16d
16f
73
19
69
70
65
65
61
29
67
65
37
73
52
66
2
4-Cl-C6H4
10
11
12
13
14
1f
2-furyl
Et
Et
Et
Et
11
12
13
14
15
93
86
84
60
86
3
Ph
1g
1h
1i
2-thienyl
4-pyridyl
3-pyridyl
Ph
4
4-Me-C6H4
Ph
5
Ph
Ph
6
4-Me-C6H4
1j
4-MeO-C6H4 Et
4-MeO-
C6H4
7
4-MeO-C6H4
8
Ph
9
Ph
10
11
12
13
14
1f
4-MeO-C6H4
16f
1g
1h
1i
Ph
Ph
Ph
Ph
16g
16h
16i
reaction (for example, see entries 9 and 14). With electron-
poor arenes (4-nitrophenyl and 2,6-difluorophenyl), the
reactions were sluggish, although pyridyl reagents worked
satisfactorily (entries 12À13).
1j
16j
a See Table 1 for structures.
Also, various alkyl R substituents on the nitrogen of the
reacting N-acylcyanamides are tolerated by the reaction.
The reaction worked with aniline derivative 1e (entry 8),
but the yield dropped sharply with cyclopropylamine
substrate 1d (entry 7). We attributed the stereochemistry
by analogy to that of 2. However, the NMR spectra of
isothioureas are messy, certainly reflecting rotameric as
well as tautomeric equilibria.
Employing diamines, it was possible to obtain the bis-
acylguanidines 17À19 (Scheme 2). Because the latter have
the same rigid N,O scaffold as many ligands of the
bimetallic and/or bischelated complexes used for catalytic
epoxidation or insertion polymerization,9 our method
could provide an entry to such complexes.
One can also take advantage of the nucleophilicity of the
acylguanidine to obtain cyclic adducts (Scheme 3). Em-
ploying bromopropylamine positions a leaving group on
the adduct, which can cyclize to 20 in 70% overall yield
(Scheme 3a). Similarly, aza-imidazolones such as 21 can be
obtained from C-protected amino acids after formation of a
lactam (57% for the phenylalanine derivative, Scheme 3b).
Interestingly, C-protected lysine is a diamine which led
to 22, where the two amino groups reacted differently.
The side-chain amino led to a regular acylguanidine, and the
amino acid led to an aza-imidazolone. An X-ray structure
was obtained for 21 (see Supporting Information). The
Isothioureas are the precursors of choice to guanidines.8
We thus wondered whether N-acylguanidines could be
prepared from 2À15. In support of this possibility was
˚
the fact that the CÀS bond is slightly elongated (1.79 A,
Figure 1).
The reaction of 2 with 1 equiv of benzylamine in the
presence of triethylamine (1 equiv) and catalytic DMAP
(30 mol %) at rt readily afforded guanidine 16a in 77%
yield (together with 18% of benzylbenzamide, likely com-
ing from transamidation at the carbonyl group of 2).
Gratifyingly, an optimized one-pot procedure for the
direct synthesis of the N-acylguanidines from the starting
cyanamides was devised. In a typical experiment, after
completion of the sulfenylation, benzylamine and DMAP
(9) For reviews: (a) Trifonov, A. A. Coord. Chem. Rev. 2010, 254,
1327–1347. (b) Gupta, K. C.; Sutar, A. K. Coord. Chem. Rev. 2008,
252, 1420–1450. Recent examples with bis-chelating ketoiminates:
(c) Kirillov, E.; Roisnel, T.; Carpentier, J.-F. Organometallics 2012,
31, 3228–3240. (d) Song, D.-P.; Shi, X.-C.; Wang, Y.-X.; Yang, J.-X.; Li,
Y.-S. Organometallics 2012, 31, 966–975.
(8) For a recent review on biological properties of guanidines:
(a) Castagnolo, D.; Schenone, S.; Botta, M. Chem. Rev. 2011, 111,
5247–5300. (b) Ishikawa, T. Chem. Pharm. Bull. 2010, 58, 1565–1568.
5540
Org. Lett., Vol. 14, No. 21, 2012

Scheme 2. Access to Bis N-Acylguanidines
Scheme 4. Mechanistic Proposal
dialkyldisulfides,10 which did not add to the cyanamides
under the reported conditions. No conversion was ob-
served in the presence of stoichiometric soluble Ag(I) salts,
which are more easily reduced than diphenyldisulfide,11 or
TEMPO. Both additives would capture the electron in-
stead of the diaryldisulfides.
Scheme 3. Access to Functionalized N-Acylguanidines
through Tandem Reactions Involving Subtitution (a) or
Transamidation (b)
In contrast to our previous free-radical cascades,1À3 this
appears to trigger hydrothiolation of the acylcyanamide to
C, without radical dearomatization. The exact mechanism
for that step is still not clear, but after that, C undergoes
spontaneous migration, likely by nucleophilic attack of the
imine on the carbonyl, followed by fragmentation to 2a.
The absence of cyclopropyl ring-opened products (see 2d)
makes it unlikely that the rearrangement proceeds via a
radical pathway.
In conclusion we have developed a new method for the
synthesis of N-acyl isothioureas and N-acyl cyanamides
from N-acylcyanamides with geometries different from
those accessible through our previous free radical cycliza-
tions. This opens access to a large family of compounds
with structures potentially of interest as organocatalysts or
ligands for transition metals.
configurations of the other guanidines were attributed by
analogy with 21.
A tentative mechanism for the rearrangement of acyl-
cyanamides is presented in Scheme 4.
We believe the reaction starts with single electron
transfer from DIPEA to the disulfide, as suggested by
Ishibashi.7 This would generate a radical anion that would
collapse to both a thiyl radical and a thiolate. This electron
transfer would not be possible for the less readily reduced
Acknowledgment. We thank CNRS, UPMC, IUF (M.M.,
ꢀ
(Grant Credox) for funding of this work. Analytical
equipment was generously offered through FR 2769. We
thank Geoffroy Gontard (UPMC) for the X-ray diffrac-
tion analysis.
L.F.), the region Ile-de-France (M.-H.L.), and ANR
Supporting Information Available. Experimental pro-
cedure, characterization data, and NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) Christensen, T. B.; Daasbjerg, K. Acta Chim. Scand. 1997, 51,
307–317.
(11) Analogous electron transfer with even less readily reduced
copper: Sreenath, K.; Suneesh, S. C.; Ratheesh Kumar, V. K.; Gopidas,
K. R. J. Org. Chem. 2008, 73, 3245–3251.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
5541