Acyl-isothiocyanates as efficient thiocyanate transfer reagents

Article abstract of DOI:10.1021/ol901561j

An unprecedented transfer of a thiocyanate (-SCN) group from aroyl/acyl isothiocyanate to alkyl or benzylic bromide is observed in the presence of a tertiary amine. This process is most effective when the bromomethyl proton is less acidic, while the prese

Full text of DOI:10.1021/ol901561j

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3382-3385
Acyl-isothiocyanates as Efficient
Thiocyanate Transfer Reagents
Charuta C. Palsuledesai, Siva Murru, Santosh K. Sahoo, and Bhisma K. Patel*
Department of Chemistry, Indian Institution of Technology Guwahati,
Guwahati 781 039, India
patel@iitg.ernet.in
Received June 2, 2009
ABSTRACT
An unprecedented transfer of a thiocyanate (-SCN) group from aroyl/acyl isothiocyanate to alkyl or benzylic bromide is observed in the
presence of a tertiary amine. This process is most effective when the bromomethyl proton is less acidic, while the presence of a more acidic
proton gives 1,3-oxathiol-2-ylidine and other related products.
In biological systems, coenzymes catalyze a variety of
reactions including transfer of various functional groups, for
example, thiamine pyrophosphate (TPP), coenzyme (CoASH),
biotin, and tetrahydrofolate (THF) transfer, two-carbon
fragments, acyl groups, carboxyl groups, and one-carbon
groups, respectively.1 Similarly, transfer of various functional
groups or a fragment of a molecule from one system to
another is well-known in the literature.2 However, transfer
of a thiocyanate group from one molecule to another has
not been observed so far. As a continuation of our efforts
and interest in developing methods for the synthesis of
heterocyclic compounds from thioureas and their analogues,3
we were prompted to study the reactivity of benzoyl
isothiocyanates toward R-bromoketones in the presence of
a tertiary amine, where thiocyanation of R-bromoketones was
observed. This observation is surprising since a nucleophilic
substitution product is formed in the absence of any
nucleophilic thiocyanate ion (Scheme 1).
Scheme 1. Formation of R-Thiocyanatoacetophenone 1a
When benzoyl isothiocyanate (1 equiv) was treated with
R-bromoacetophenone (1) (1 equiv) in the presence of
N-methylimidazole (1 equiv) in acetonitrile, both the reac-
tants got consumed giving a new product. Spectroscopic
analysis of the product revealed the structure to be R-thio-
cyanatoacetophenone (1a). However, no reaction was ob-
served in the absence of N-methylimidazole, suggesting the
definite involvement of a tertiary amine in this reaction
process.
(1) (a) David, L. N.; Cox, M. M. Lehninger Principle of Biochemistry,
3rd ed.; Macmillon, 1982. (b) Bruce, P. Y. Organic Chemistry, 3rd ed.;
Printice-Hall, Inc.; Pearson Education, 1995.
(2) (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809. (b)
Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus, P. J.; Millar,
S. J. J. Am. Chem. Soc. 1999, 121, 11638. (c) Arai, S.; Bellemin-Laponnaz,
S.; Fu, G. C. Angew. Chem., Int. Ed. 2001, 40, 234. (d) Denmark, S. E.;
Fu, J. J. Am. Chem. Soc. 2001, 123, 9488. (e) Shaw, S. A.; Aleman, P.;
Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368. (f) Vedejs, E.; Daugulis,
O.; Harper, L. A.; MacKay, J. A.; Powell, D. R. J. Org. Chem. 2003, 68,
5020. (g) Spivey, A. C.; Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest,
L. R. J. Org. Chem. 2003, 68, 7379. (h) Birman, V. B.; Uffman, E, W.;
Jiang, H.; Li, X.; Kilbane, C. J. J. Am. Chem. Soc. 2004, 126, 12226. (i)
Fu, G. C. Acc. Chem. Res. 2004, 37, 542. (j) Enders, D.; Balensiefer, B.
Acc. Chem. Res. 2004, 37, 534. (k) Birman, V. B.; Li, X.; Han, Z. Org.
Lett. 2007, 9, 37. (l) Sanchez-Rosello, M.; Puchlopek, A. L. A.; Morgan,
A. J.; Millar, S. J. J. Org. Chem. 2008, 73, 1774. (m) Wiberg, K. B.; Wang,
Y.-g.; Millar, S. J.; Puchlopek, A. L. A. J. Org. Chem. 2009, 74, 3659.
(3) (a) Singh, C. B.; Murru, S.; Kavala, V.; Patel, B. K. Org. Lett. 2006,
8, 5397. (b) Singh, C. B.; Murru, S.; Kavala, V.; Patel, B. K. J. Chem. Res.
2007, 136. (c) Murru, S.; Singh, C. B.; Kavala, V.; Patel, B. K. Tetrahedron
2008, 64, 1931. (d) Yella, R.; Ghosh, H.; Patel, B. K. Green Chem. 2008,
10, 1307. (e) Ghosh, H.; Yella, R.; Nath, J.; Patel, B. K. Eur. J. Org. Chem.
2008, 6189. (f) Ghosh, H.; Singh, C. B.; Murru, S.; Kavala, V.; Patel, B. K.
Tetrahedron Lett. 2008, 49, 2601.
10.1021/ol901561j CCC: $40.75
Published on Web 07/16/2009
 2009 American Chemical Society

The reactivity, i.e., the hard-soft nucleophilic character
of thiourea and its analogues toward various R-haloketones,
is probably not well understood, thus leading to the proposal
of several erroneous mechanisms and structures by various
research groups.4 One common mistake made in these
proposed mechanisms is the attack of the thionamidic
nitrogen (hard nucleophile) instead of sulfur (soft nucleo-
phile) on a halomethylene carbon of R-haloketone (soft
electrophile). Thioureas are S-based nucleophiles particularly
toward soft electrophiles.3a-d,4,5 Similar to the acyl transfer
reaction mechanism involving alkylimidazole analogues,2b,l
a mechanism as shown in Scheme 2 can be proposed for
interaction). The benzoyl carbonyl carbon is susceptible to
nucleophilic (N-methylimidazole or water from acetonitrile)
attack due to the enhanced electrophilicity of the benzoyl
carbonyl group, possibly because of the presence of conju-
gated imidazolium system (Y). This nucleophilic substitution
gives rise to a tetrahedral intermediate which then collapses
with concomitant departure of N-methylimidazole giving the
expected thiocyanato product (Scheme 3).
The success of this strategy was subsequently applied to
several other R-bromoketones (1-5) as shown in Table 1.
Table 1. Thiocyanation Using Benzoylisothiocyanatea
Scheme 2. Proposed Mechanism for Isothiocyanate Transfer
this novel thiocyanate transfer. In this mechanism, the
imidazole nitrogen attacks on the carbonyl group forming a
tetrahedral negatively charged intermediate (K). The activated
intermediate then intramolecularly transfers the NCS group
to the R-bromoketone 2 giving the expected product (Scheme
2).
On the basis of the reactivity of thioureas toward R-ha-
loketones and in terms of hard-soft nucleophilic character,
the following alternative mechanism can also be envisaged
(Scheme 3), which involves the attack of N-methylimidazole
Scheme 3. Alternative Mechanism for Isothiocyanate Transfer
a Reactions were monitored by TLC. b Yields of pure isolated product.
These R-bromoketones on treatment with benzoyl isothio-
cyante in the presence of N-methylimidazole gave good
yields of thiocyanato products (1a-5a). The structure of the
product (2a) has been confirmed by X-ray crystallography
(see Supporting Information). Thus, in these reactions,
benzoylisothiocyante is acting as an efficient thiocyanate
donor reagent and organic bromides as acceptors.
The reaction of benzyl bromide 6 and p-nitrobenzyl
bromide 7 gave corresponding thiocyanato products 6a and
7a, respectively, proving the fact that benzoylisothiocyanate
has the ability to transfer a thiocyanato group to other systems
other than R-bromoketones. This methodology is also com-
patiable in the presence of amides and esters functionality
as was tested in substrates 8 and 9 giving the corresponding
thiocyanato product 8a and 9a, respectively.
at the cumulated sp-hybridized C-atom of benzoyl isothio-
cyanate forming an activated thiourea species (X) which
reacts with haloketone giving S-alkylated product (Y)
(soft-soft interaction) and not N-alkylated product (hard-soft
(4) (a) Zeng, R.-S.; Zou, J.-P.; Zhi, S.-J.; Chen, J.; Shen, Q. Org. Lett.
2003, 5, 1657. (b) Wang, X.-C.; Wang, F.; Quan, Z.-J.; Wang, M.-G.; Li,
Z. J. Chem. Res. 2005, 689. (c) Kidwai, M.; Vankatraman, R.; Dave, B.
Green. Chem. 2001, 3, 278.
However, when 2-bromoethylacetoacetate (10) was reacted
with benzoylisothiocyanate and N-methylimidazole under an
(5) (a) Manaka, A.; Ishii, T.; Takahashi, K.; Sato, M. Tetrahedron Lett.
2005, 46, 419. (b) Schmeyers, J.; Kappu, G. Tetrahedron 2002, 58, 7241.
Org. Lett., Vol. 11, No. 15, 2009
3383

identical reaction condition, the major product (10b) (55%
yield) obtained was not the expected thiocyanato product
but was found to have a completely different structure (Figure
1). X-ray crystallographic analysis of the product unequivo-
To support the fact that the acidity of the bromomethyl
proton dictates whether the product formed will be 1,3-
oxathiol-2-ylidene (10b) or thiocyanoto product, reaction of
2-bromoacetoacetate (10) with benzoyl isothiocyanate in the
presence of N-methylimidazole (1 equiv) was carried out,
and two new products (10a and 10c) were isolated along
with the expected product 10b as shown in Scheme 5.
Scheme 5. Formation of Three Distinct Products
Figure 1. ORTEP view of 10b.
cally revealed the presence of the 1,3-oxathiol-2-ylidine
skeleton as shown in Figure 1.
The only difference between 2-bromoethylacetoacetate
(10) and the bromo compounds (1-9) listed in Table 1 is
probably the acidity of the bromomethyl proton. The
bromomethyl proton in the former (10) is more acidic (active
methylene) compared to the substrates (1-9) listed in Table
1. After the initial S-alkylation as proposed in Scheme 3,
the active methylene proton of 2-bromoethylacetoacetate,
flanked by a sulfur and two carbonyl groups, is more
susceptible to enolization (Scheme 4). The intramolecular
Formation of product (10b) has been explained above. The
product (10a) is obtained by a thiocyanate transfer process
from the isomerized 2-bromoethylacetoacetate (10) to 4-bro-
moethylacetoacetate (10′). This process of isomerization of
10 to 10′ (Scheme 5) is well-known in the literature.7 The
most surprising result, however, is the formation of product
10c where an additional NH-CdS moiety is flanked
between the benzoyl group and the 1,3-oxathiol-2-ylidine
unit (Scheme 5). The formation of product (10c) can be
explained by the possible attack of nucleophile (such as water
or tert-amine) on initially formed product 10b leading to a
tetrahedral intermediate, which undergoes debenzoylation and
concomitant attack of nucleophilic imine on a second
molecule of benzoyl isothiocyanate giving product 10c, as
shown in Scheme 6. When isolated product 10b was treated
Scheme 4
.
Proposed Mechanism for the Formation of
1,3-Oxathiol-2-ylidine
enol attack on the imine carbon displaces 2-methylimidazole
giving a product containing a 1,3-oxathiol-2-ylidine skeleton
(10b) as shown in Scheme 4. Any one of the mechanisms
proposed in Scheme 2 and Scheme 3 can account for the
formation of isothiocyanate transfer products. However, the
formation of the 1,3-oxathiol-2-ylidine can be better ex-
plained by the latter mechanism (Schemes 3 and 4), the
possibility of multiple mechanisms thus depending on the
nature of the substrate.
Scheme 6
.
Proposed Mechanism for the Insertion of the
NH-CdS Group
In recent literature, the reaction of the in situ generated
benzoylisothiocyanate and 2-chloroethylacetatoacetate is
reported to give 1,3-oxazolin-2-thione.6 The reported data
with benzoyl isothiocyanate in the presence of N-methylimi-
dazole, 10c was formed thus supporting the proposed
mechanism in Scheme 6.
During the course of further investigation, it was observed
that the reaction of benzoyl isothiocyanate with 2-bromoet-
hylbenzoacetate (11) gave an unclean reaction, from which
1
(mp, H and 13CNMR) are in agreement with our proposed
structure (10b) confirming the fact that they are infact
identical compounds. The interpretation of an incorrect
isomeric structure is due to the proposal of an incorrect
reaction mechanism.6
(6) Yavari, I.; Hossaini, Z.; Souri, S.; Sabbaghan, M. Synlett 2008, 1287.
(7) Choi, H. Y.; Chi, D. Y. Org. Lett. 2003, 5, 411.
Org. Lett., Vol. 11, No. 15, 2009
3384

product 11c could be isolated in 10% yield. The structure
of the product (11c) has been confirmed by crystal X-ray
crystallography as shown in Figure 2. Formation of product
11c reconfirms the NH-CdS insertion in this system.
and benzoyl amides.8 In neutral reaction medium, acetamides
undergo hydrolysis faster than benzamides.
In conclusion we have demonstrated that three distinct
products are obtained from the reactions of aroyl/acyl
isothiocyanate with different R-bromoketones in the presence
of N-methylimidazole. Benzoyl isothiocyanate acts as an
efficient thiocyanate (-SCN) transfer reagent, and R-bro-
moketones or benzylic bromide act as efficient acceptors
when the bromomethyl proton is less acidic. When acidity
increases, usually a 1,3-oxathiol-2-ylidine skeleton or
NH-CdS is inserted, and the 1,3-oxathiol-2-ylidine product
is obtained. Further scope and limitation of the process is
currently ongoing in our laboratory.
Acknowledgment. We are grateful to the Department of
Science and Technology (SR/S1/OC-15/2006) and CSIR
[01(2270)/08/EMR-II] for funding. S.M. thanks the CSIR
for fellowships. Thanks are also due to CIF, IIT Guwahati
for Mass and NMR spectra, and DST-FIST for X-RD facility.
Figure 2. ORTEP view of 11c.
The significance of the acidity of the bromomethyl proton
can be further judged when 3-bromoacetylacetone (12) gave
the product 12b, having a 1,3-oxathiol-2-ylidine skeleton
(46%). The low isolated yield in most cases is due to the
formation of side products which could not be isolated.
In addition to N-methylimidazole, other tertiary amines
such as triethylamine and DBU were also found to be
effective. Acetyl isothiocyanate was found to be an even
better thiocyanate transfer agent than benzoyl isothiocyanate.
This can be explained in terms of rate of hydrolysis of acetyl
Supporting Information Available: General information,
1
experimental procedures, spectral data, and copies of H
NMR and 13C NMR spectra for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901561J
(8) Smith, C. R.; Yates, K. Can. J. Org. Chem. 1972, 50, 771.
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