Trapping Reactive Intermediates by Mechanochemistry: Elusive Aryl N-Thiocarbamoylbenzotriazoles as Bench-Stable Reagents

Article abstract of DOI:10.1002/anie.201502026

Monitoring of mechanochemical thiocarbamoylation by in situ Raman spectroscopy revealed the formation of aryl N-thiocarbamoylbenzotriazoles, reactive intermediates deemed unisolable in solution. The first-time isolation and structural characterization of these elusive molecules demonstrates the ability of mechanochemistry to access otherwise unobtainable intermediates and offers a new range of masked isothiocyanate reagents.

Full text of DOI:10.1002/anie.201502026

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201502026
German Edition: DOI: 10.1002/ange.201502026
Mechanochemistry
Trapping Reactive Intermediates by Mechanochemistry: Elusive Aryl
N-Thiocarbamoylbenzotriazoles as Bench-Stable Reagents**
ˇ
Vjekoslav Strukil,* Davor Gracin, Oxana V. Magdysyuk, Robert E. Dinnebier, and
Tomislav Fri sˇ cˇ i c´ *
Abstract: Monitoring of mechanochemical thiocarbamoyla-
tion by in situ Raman spectroscopy revealed the formation of
aryl N-thiocarbamoylbenzotriazoles, reactive intermediates
deemed unisolable in solution. The first-time isolation and
structural characterization of these elusive molecules demon-
strates the ability of mechanochemistry to access otherwise
unobtainable intermediates and offers a new range of masked
isothiocyanate reagents.
M
echanochemistry has emerged as an efficient means for
[1]
rapid, solvent-free, and energy-efficient synthesis.
In
neat and liquid-assisted grinding
LAG) has provided rapid and clean access to a number
of transformations, excellent control of reaction stoichiom-
[
2]
organic synthesis,
(
[
3]
[
4–6]
etry, and previously unknown reactivity.
We now demon-
strate the ability of mechanochemistry to access reactive
intermediates considered unisolable in solution. We describe
the first synthesis and isolation of aryl N-thiocarbamoylben-
zotriazoles (2a–g, Scheme 1) as bench-stable solids by milling
[
7]
bis(benzotriazolyl)methanethione
(
(1)
with
anilines
[14–16]
Scheme 1. a,b) In contrast to solution chemistry,
cal reactions of 1 and anilines give N-thiocarbamoylbenzotriazoles
2a–g) as stable solids which, upon milling with anilines and a base,
mechanochemi-
Table 1). Mechanochemical isolation of 2a–g allows their
(
afford thioureas (3a–g).
ˇ
[
*] Dr. V. Strukil, Prof. T. Fri sˇ cˇ i c´
Department of Chemistry, McGill University
Table 1: LAG synthesis of aryl N-thiocarbamoylbenzotriazoles 2a–g and
thioureas 3a–g.
[a]
8
01 Sherbrooke Street West, Montreal, H3A 0B8 (Canada)
E-mail: tomislav.friscic@mcgill.ca
1
2
Compound
R
R
Yield of isolated product [%]
ˇ
Dr. V. Strukil, Dr. D. Gracin
2
2
2
2
2
2
2
3
3
3
a
b
c
d
e
f
g
a
b
c
4-Br
4-Cl
–
–
–
–
–
–
–
99
98
98
99
98
99
99
Ru d¯ er Bo sˇ kovi c´ Institute
Bijeni cˇ ka cesta 54, 100002 Zagreb (Croatia)
E-mail: vstrukil@irb.hr
4-CH3
4-OCH3
Dr. O. V. Magdysyuk, Prof. Dr. R. E. Dinnebier
Max Planck Institute for Solid State Research
Heisenbergstrasse 1, 70569 Stuttgart (Germany)
2-NH2
4-NH2
4-NH2
4-Br
[b]
Dr. O. V. Magdysyuk
Diamond Light Source Ltd.
Harwell Science and Innovation Campus, OX11 0DE Didcot (UK)
[c]
4-Br
4-Cl
4-CH3
4-OCH3
4-Cl
97
4-Cl
97
98
98
97
99
98
4-CH3
4-OCH3
4-OCH3
4-Cl
[
**] We thank Dr. E. Stavitski and Dr. J. Reid for synchrotron PXRD data
collected at the CLS (supported by the Canadian Foundation for
Innovation (CFI), NSERC, NRC Canada, Canadian Institutes of
Health Research, Government of Saskatchewan, Western Economic
Diversification Canada, and University of Saskatchewan). We
acknowledge support from an NSERC Discovery Grant, FRQNT
Nouveaux Chercheurs grant, CFI, and McGill University. Prof. D. S.
Bohle and C. Mottillo are acknowledged for single-crystal X-ray
diffraction data, and Dr. F. Morin for help in acquiring solid-state
NMR data. The LS2 laser source used for Raman measurements in
this study was kindly donated by PD-LD Inc., Pennington, New
Jersey (USA).
3d
3e
3 f
3g
[
[
[
d]
c,d]
d,e]
4-Br
2-NH2
4-Br
À1
[
a] 10 min LAG with CH CN (h=0.25 mLmg ), 10 mm ball. [b] 2 equiv
3
of 1. [c] 45 min LAG. [d] Two-step synthesis. [e] 30 min LAG.
use as reagents for the controlled solvent-free synthesis of
thioureas (3a–g) without using corrosive isothiocyanates.
As part of our interest in the mechanosynthesis of ureas
[
8,9]
and thioureas,
we applied the recently introduced tech-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502026.
nique of in situ Raman spectroscopy monitoring of mecha-
8
440
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Angew. Chem. Int. Ed. 2015, 54, 8440 –8443

Angewandte
Chemie
bamoylbenzotriazole 2a (Scheme 1, Table 1). Intrigued by the
possibility of mechanochemically accessing such elusive
molecules, we conducted LAG of 1 with a series of substituted
anilines (Table 1, Scheme 1a,b). In all cases, LAG followed by
simple aqueous washing gave crystalline solids, which were
identified as N-thiocarbamoylbenzotriazoles 2a–g by cross-
13
15
polarization magic angle spinning (CP-MAS) C and
N
solid-state NMR spectroscopy (SSNMR, Figure 2a), ther-
Figure 1. a) Mechanochemical base-assisted reaction of 1 and p-bro-
moaniline to form the thiourea 3a and b) in situ collected Raman
spectra for this reaction.
[10–13]
nochemical reactions
to the mechanosynthesis of 3a by
milling 1 with two equivalents of 4-bromoaniline in the
presence of Na CO (Figure 1a). While 1 is a known reagent
2
3
for base-catalyzed thioacylations and thiocarbamoylations in
[
7,14]
solution,
thereby giving benzotriazole (HBt) as a by-
product, its mechanochemical reactivity is still unexplored.
Monitoring the reaction in situ reveals that characteristic
bands of 1 are completely replaced with those of 3a (e.g. 407,
À1
7
12, 1170, 1302 cm , Figure 1b) within 40 min. A character-
15
Figure 2. a) N NMR CP-MAS SSNMR spectrum of 2d; b) a centro-
istic band of the by-product HBt sodium salt also appears at
380 cm . However, the spectra also revealed an unknown
intermediate with bands at 544, 1041, 1159, 1248, and
511 cm , appearing about 2 min into milling and disappear-
symmetric pair of 2d molecules in the crystal structure, based on
PXRD data; and c) final Rietveld fit for the crystal-structure determi-
nation of 2d by PXRD.
À1
1
À1
1
ing concomitantly with the appearance of 3a.
Katritzky et al. proposed that 1 reacts with anilines in
solution via reactive aryl N-thiocarbamoylbenzotriazole
intermediates that are not isolable due to their rapid
mogravimetric analysis (TGA), differential scanning calorim-
etry (DSC), and, where possible, structure determination
from synchrotron powder X-ray diffraction (PXRD) data
(Figure 2b,c and Figure 3a–d). Solid-state characterization
was mandated by the instability of 2a–g in solution: the
[14–16]
fragmentation into isothiocyanates (Scheme 1).
Speculating that the herein observed intermediate might
be the elusive N-thiocarbamoylbenzotriazole, we repeated
the milling without a base, and with only one equivalent of
aniline. Under these conditions the intermediate was
obtained as the only product (see the Supporting Informa-
1
H NMR spectra in CDCl , [D ]DMSO, or CD CN reveals
3
6
3
degradation to isothiocyanates in minutes (see the Supporting
Information). The 2-amino derivative 2e decomposed in
solution into 2-mercaptobenzimidazole (4) and HBt. In
contrast, the compounds were stable in the solid state:
FTIR-ATR spectra of mechanochemically prepared 2a–d did
1
tion). Solution H NMR spectroscopy and thin-layer chroma-
tography revealed this product deteriorates quickly in organic
solvents into HBt and 4-bromophenylisothiocyanate. How-
[
17]
not change after storage for more than 1 year.
1
13
ever, a H NMR spectrum recorded immediately after
The CP-MAS C SSNMR spectra of 2a–g reveal the
dissolution was consistent with the generation of N-thiocar-
signal of the thiocarbonyl group shifted downfield by about 2–
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8441

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Angewandte
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1
(Scheme 1b). Attempted analogous synthesis of the bis-N-
thiocarbamoylbenzotriazole 5 from o-pda and two equiva-
lents of 1 yielded the bisthione 6, probably as a result of an
intramolecular cyclization of the expected product (Fig-
ure 4a,b, see also the Supporting Information). The alter-
Figure 3. Centrosymmetric arrangement of molecules (top) and the
final Rietveld fits (bottom) for the crystal structures of a) 2b and
b) 2e, determined from PXRD data.
5
ppm relative to that of 1. The spectrum of 2 f reveals signal
[18]
twinning, thus suggesting Z’ = 2. With the exception of 2 f,
the C SSNMR spectra for all the compounds are consistent
1
3
with one molecule per asymmetric unit (Z’ = 1).
1
5
The N CP-MAS SSNMR spectra of 2d and 2g (Fig-
ure 2a, see also the Supporting Information) showed four
signals, consistent with four non-equivalent nitrogen atoms
per molecule. TGA shows 2a–d to be stable to approximately
1
208C, with the first decomposition event corresponding to
elimination of aryl isothiocyanate, followed by loss of HBt.
DSC of 2a–d reveals a melting signal at 90–1058C. Compound
2
e also undergoes an exothermic event at 928C, as a result of
Figure 4. a) Mechanochemical reaction of o-pda with 1 in a 1:1 stoi-
chiometric ratio yields 2e (which slowly degrades into 4) and milling
in 1:2 ratio affords 6, most likely by intramolecular cyclization of the
expected 5. b) Molecular structure of 6 from single-crystal X-ray
diffraction. c) The use of mechanochemically prepared aryl N-thiocar-
bamoylbenzotriazoles as masked isothiocyanates.
cyclization to 4 with loss of HBt, as confirmed by TGA and
PXRD (see the Supporting Information). Crystal structures
of 2b, 2d, and 2e were determined from synchrotron PXRD
data collected at the Canadian Light Source (CLS) beamline
0
8B1-1 (l = 0.6897 Š). Indexing gave monoclinic unit cells
with Z = 4. Determination of the structure using TOPAS
revealed Z’ = 1, in agreement with SSNMR spectroscopic
analysis. 2d, 2b, and 2e are nonplanar, with the angle between
the phenyl and benzotriazolyl substituents being 838, 658, and
native path, cyclization of 2e into 4 followed by reaction with
1, was dismissed because 1 and 4 do not react on milling.
Compounds 2a–d represent masked aryl isothiocyanates
that are useful in thiourea mechanosynthesis. Milling 2a–d
with anilines and Na CO gave 3a–g in near quantitative
8
68, respectively. The thione and benzotriazole groups are
nearly coplanar in all cases. The molecules form centrosym-
2
3
metric pairs with long NÀH···N interactions between the
yields (Table 1). Symmetrical 3a–d were also obtained by
milling 1 with two equivalents of an aniline and Na CO , while
thiocarbamoyl group and benzotriazole (2b, 2d) or 2-amino-
phenyl (2e) groups of neighboring molecules (Figures 2 and
2
3
nonsymmetrical 3e–g were obtained by a two-step one-pot
procedure from 1, thus confirming the structures of 2a–d.
Similarly, 2g allows the synthesis of bisthioureas: milling 2g
with p-anisidine and Na CO gave 7 quantitatively after 3 h.
3
).
Amino-substituted N-thiocarbamoylbenzotriazoles, such
as 2e and 2 f, are attractive as precursors for catalytically
2
3
[19]
interesting aminothioureas and amino-substituted isothio-
The same product was obtained in 98% yield by milling 2d
and p-pda with Na CO for 45 min (Figure 4c).
cyanates. Both 2e and 2 f were readily obtained by milling
2
3
1
with one equivalent of either ortho- (o-pda) or para-
In summary, real-time monitoring revealed the utility of
mechanochemistry to trap and quantitatively synthesize
molecules too reactive to access in solution. Solid-state
analysis enabled the first structural, physical, and chemical
identification of aryl thiocarbamoylated benzotriazoles and,
in combination with structure determination from PXRD
data, full structural characterization of members of this
compound family. In addition to providing a new family of
bench-stable thiocarbamoylation reagents, this also estab-
1
phenylenediamine (p-pda). The H NMR spectrum of 2 f in
D ]DMSO reveals rapid decomposition to the tentatively
[
6
identified p-aminophenyl isothiocyanate (see the Supporting
Information). Although stable for weeks, solid 2 f slowly
degrades on prolonged standing, as shown by H NMR and
FTIR-ATR spectroscopy.
The bis-N-thiocarbamoylbenzotriazole 2g was quantita-
tively obtained by LAG of p-pda with two equivalents of
[
20]
1
8
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Angew. Chem. Int. Ed. 2015, 54, 8440 –8443

Angewandte
Chemie
lishes mechanochemistry as a means to circumvent solvent-
induced limitations of traditional synthesis.
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1
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´
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wR = 0.0814 (1795 data, I ꢀ 2s ); 6: triclinic, P1, a = 7.1962(11), b =
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I
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.8855(12), c = 12.7962(19) Š, a = 98.710(2), b = 104.144(2), g =
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1
2
(
1
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I
1
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3
4.7693(9), c = 3.9624(1) Š, b = 97.125(3)8, V= 1265.5(1) Š , Z = 4,
ˇ
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p
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1
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1
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3
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p
wp
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3
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[
Keywords: mechanochemistry · reactive intermediates ·
thiocarbamoylation · thiourea
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Angew. Chem. Int. Ed. 2015, 54, 8440 –8443
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8443