Copper(I)-catalyzed cascade synthesis of 2-arylsulfanyl-arylcyanamides

Article abstract of DOI:10.1002/adsc.201000383

We have developed a ligand-assisted copper(I)-catalyzed two sequential heteroarylation sequence. An intramolecular S-arylation is followed by an intermolecular N-arylation leading to the direct synthesis of N-aryl-2-aminobenzothiazoles. In most cases however, the 2-arylsulfanyl- arylcyanamide was the major product obtained via an intramolecular C-S bond formation, associated with C-S bond breakage, followed by an intermolecular S-arylation. The selectivity of this ligand-assisted reaction is quite different as compared to that of ligand-free reactions and the rates are much faster giving good yields of products. Various cyanamides can be prepared in excellent yields from their corresponding 1-substituted thioureas with or without the assistance of a ligand with a catalytic quantity of copper(I).

Full text of DOI:10.1002/adsc.201000383

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DOI: 10.1002/adsc.201000383
Copper(I)-Catalyzed Cascade Synthesis of 2-Arylsulfanyl-
arylcyanamides
Santosh K. Sahoo,a Latonglila Jamir,a Srimanta Guin,a and Bhisma K. Patela,*
a
Department of Chemistry, Indian Institute of Technology Guwahati, 781 039 Assam, India
Fax : (+91)-36-1269-0762; e-mail: patel@iitg.ernet.in
Received: May 16, 2010; Revised: August 19, 2010; Published online: October 12, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000383.
Abstract: We have developed a ligand-assisted cop- different as compared to that of ligand-free reactions
per(I)-catalyzed two sequential heteroarylation se- and the rates are much faster giving good yields of
quence. An intramolecular S-arylation is followed by products. Various cyanamides can be prepared in ex-
an intermolecular N-arylation leading to the direct cellent yields from their corresponding 1-substituted
synthesis of N-aryl-2-aminobenzothiazoles. In most thioureas with or without the assistance of a ligand
cases however, the 2-arylsulfanyl-arylcyanamide was with a catalytic quantity of copper(I).
the major product obtained via an intramolecular
À
À
C S bond formation, associated with C S bond Keywords: 2-arylsulfanyl-arylcyanamides; cascade
breakage, followed by an intermolecular S-arylation. reactions; copper catalysis; ligand role; one-pot reac-
The selectivity of this ligand-assisted reaction is quite tion
Introduction
Results and Discussion
The interest in metal-catalyzed multistep processes We have been developing methods for the synthesis
such as cascade, tandem and domino reactions in of various heterocycles.[6] Recently, we have reported
which one or more catalysts are employed for two or several ligand-assisted Cu(I)-catalyzed syntheses of 2-
more transformations in one-pot has experienced an mercaptobenzimidazoles,[7a] 2-substituted 1,3-benzo-
explosive development in recent years.[1] Of all the thiazoles,[7b] and arylthiobenzothiazoles.[1h] The later
metal catalysts, the Cu-catalyzed inter- and intramo- synthesis involves sequential intra- and intermolecular
lecular domino reactions involving carbon-heteroatom S-arylations leading to the direct synthesis of arylthio-
bond formations for the synthesis of a wide variety of benzothiazoles.[1h] As a part of our ongoing research
heterocycles have advantages over the others in terms in developing alternative methods for the synthesis of
of efficacy, selectivity and low cost.[2] Even though the heterocycles,[6,7] and taking cues from our recent
À
À
À
chemistry of Cu-catalyzed C C, C N and C O bond double S-arylation strategy involving intra- and inter-
[1h]
formations is well explored,[3] methods available for molecular C S coupling,
we envisaged a one-pot
À
À
C S bond formation are relatively fewer in the litera- synthesis of N-aryl-2-aminobenzothiazoles. The retro-
ture, which of course is growing in number.[4] Several synthetic strategy is shown in Scheme 1. In this strat-
reports revealed that the ligand-assisted Ullmann- egy, an initial intramolecular S-arylation of 2-halo-1-
type coupling not only lowers the reaction tempera- arylthioamide yields the intermediate 2-aminobenzo-
tures but also accelerates the reaction rates.[2e,5] Fur- thiazole (K), (Scheme 1), which is then followed by
thermore, an orthogonal selectivity has been observed an intermolecular N-arylation, directly giving N-aryl-
in Cu-catalyzed reactions when assisted by a ligand.[5e] 2-aminobenzothiazole (1a’) using a single catalytic
Thus, a proper selection of ligand would not only pre- system as shown in Scheme 1.
vent aggregation of the metal and improve the solu-
Initially, the coupling of 1-(2-bromophenyl)thiourea
bility of the catalyst/co-catalyst but also increase the (1) and iodobenzene (a) was chosen to optimize the
reaction rate.
reaction conditions. The reaction was performed by
taking CuI (5 mol%) as the precatalyst, 1,10-phenan-
throline (L1) (10 mol%) as the ligand and NaOH
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Copper(I)-Catalyzed Cascade Synthesis of 2-Arylsulfanyl-arylcyanamides
Scheme 1. The design of a one-pot synthesis of N-aryl-2-ami-
nobenzothiazoles.
Figure 1. ORTEP view of (1a).
(3 equiv.) as the base at 908C in DMSO (Scheme 2,
path 1). Complete disappearance of the starting mate- obtained exclusively, further proving the intermediacy
rials, 1-(2-bromophenyl)thiourea (1) and iodobenzene of 2-aminobenzothiazole (K) (Scheme 2 and
(a) was observed within 45 min. On isolation and Scheme 3).
characterization, the product was found to be 2-(phe-
When the above reaction was carried out in the ab-
nylthio)phenylcyanamide (1a) (Scheme 2, path 1) and sence of 1,10-phenanthroline ligand (L1), the exclu-
not the expected N-aryl-2-aminobenzothiazole (1a’). sive product obtained was 2-bromophenylcyanamide
The structure of the product (1a) has been further (1a’’’), irrespective of the presence or absence of
confirmed by X-ray crystallography as shown in phenyl iodide (a) in the reaction medium as shown in
Figure 1.
Scheme 2 (path 3 and path 4). This observation is sim-
The failure to achieve the target synthesis of N- ilar to the recently reported ligand-free CuSO4-cata-
aryl-2-aminobenzothiazole (1a’) was rather surprising lyzed reaction where 2-bromophenylcyanamide (1a’’’)
because following a similar strategy we have recently was obtained from 1-(2-bromophenyl)thiourea (1) but
accomplished the synthesis of several 2-arylthiobenzo- at a much longer reaction time (3–6 h).[1p] A ligand-
thiazoles[1h] where we have observed a facile intramo- free reaction of 1-(2-halophenyl)thiourea gives as
lecular S-arylation. Thus, in the present reaction, 2- product 2-(phenylthio)phenylcyanamide (1a) only
aminobenzothiazole (K) (Scheme 1) must have been when the halogen substituent in the 2-position is an
an intermediate in this overall transformation. To as- iodo group (1’) (Scheme 3) and not a bromo (1).[1p]
certain this, when 1-(2-bromophenyl)thiourea (1) was Thus, the present work is a further demonstration of
treated with Cu(I), 1,10-phenanthroline (L1) and base the increasing reactivity and differential selectivity in
(NaOH), in the absence of iodobenzene (a), 2-amino- the Ullmann reaction when assisted by a ligand. Thus,
benzothiazole (K) (Scheme 2 and Scheme 3) was ob- this ligand-assisted reaction not only accelerates the
À
tained exclusively supporting our assumption of the first step, i.e., intramolecular C S bond formation
facile intramolecular S-arylation (Scheme 2, path 2). giving the intermediate 2-aminobenzothiazole (K) but
À
Furthermore, when the isolated intermediate, 2-ami- also accelerates the C S bond cleavage leading to S-
nobenzothiazole (K) was treated with iodobenzene arylated cyanamide (1a). However, when the 2-halo
(a) in the presence Cu(I), 1,10-phenanthroline (L1) group in 1-(2-halophenyl)thiourea (1’’) is Cl, the intra-
and NaOH, 2-(phenylthio)phenylcyanamide (1a) was molecular S-arylation could not take place
Scheme 2. Ligand dependency of the coupling reaction.
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Santosh K. Sahoo et al.
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Scheme 3. Ligand dependency of the reaction.
(Scheme 3) even when the reaction was assisted by a the coupling of the substrate (1) was carried out with
ligand and the product obtained was 2-chlorophenyl- phenyl iodide (a) with less than 5 mol% of the cata-
cyanamide (1a’’, Table 3).
lyst and 10 mol% of the ligand, the outcome was com-
One can envisage the formation of S-arylated cyan- pletely different, i.e., similar to the ligand-free condi-
amide (1a) by the in situ formation of 2-phenylthio- tions.[1p] For example, with 1 mol% of the catalyst and
cyanamide (Y) followed by an intermolecular S-aryla- 2 mol% of the ligand, the only product observed after
tion. When the isolated 2-aminobenzothiazole (K) 4 h was 2-bromophenylcyanamide (1a’’’, 85%). The
was treated with Cu(I), ligand (L1) and base, it did observation was the same even when 2.5 mol% of the
not undergo any change but the same reaction when catalyst was used giving product (1a’’’, 92%) in 2 h.
carried out in the presence of iodobenzene (a) gave Thus, the catalyst quantity was maintained at 5 mol%
2-(phenylthio)phenylcyanamide (1a) in quantitative for all the substrates having a 2-bromo substituent.
yield. We have also observed that once the intermedi- The reactivity changes with changes in the ligand
À
ate 2-aminobenzothiazole (K) is formed, C S bond (Figure 2) but the selectivity remains the same. Con-
cleavage giving 2-(phenylthio)phenylcyanamide (1a) sistent with our previous report on intramolecular
[7a]
À
is quite facile indicating that the intramolecular S-ary- C N bond formation, 1,10-phenanthroline (L1) was
lation is the rate-determining step in this reaction. found to be an efficient ligand giving 93% isolated
This led us to postulate the following mechanism as yield of the product. Interestingly, the less expensive
shown in Scheme 4 (path I).
dimethylethylenediamine (DMEDA) (L7) was found
This transformation was found to be effective to be even better giving quantitative conversion (by
giving complete conversion to product with 5 mol% GC) and 97% isolated yield.
of the precatalyst Cu(I) in less than 0.75 h when as-
Various solvents were tested during the optimiza-
sisted by 1,10-phenanthroline as ligand (L1), thus tion reaction such as DMF, 1,4-dioxane, DMSO,
there was no necessity for further optimization. When DMA, toluene, acetonitrile, amongst which DMSO
Scheme 4. Proposed mechanism for the formation of 2-(arylthio)arylcyanamides (path I) and N-aryl-2-aminobenzothiazoles
(path II).
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Copper(I)-Catalyzed Cascade Synthesis of 2-Arylsulfanyl-arylcyanamides
Table 1. Synthesis of arylsulfanyl-arylcyanamides and N-aryl-2-aminobenzothia-
zoles.[a]
AHCTUNGTRENNUNG
[a]
[b]
[c]
Reactions were performed at 908C for 0.75 h.
1
Confirmed by IR, H NMR, and 13C NMR spectroscopy.
Isolated yields.
was found to be the best giving quantitative conver- Et3N, DBU, DABCO, DBN only gave the intramolec-
sion in a shorter reaction time (0.75 h). In all other ular product 2-aminobenzothiazole (K) which neither
solvent systems, reactions either took a longer time or underwent N-arylation to give our targeted N-aryl-2-
À
gave a mixture of products. Organic bases such as aminobenzothiazole (1a’) nor cleavage of the C N
bond to afford 2-(phenylthio)phenylcyanamide (1a).
Inorganic bases such as Na2CO3, K2CO3, Cs2CO3
were found to be better than organic bases but took
longer reaction times (3–6 h). Alkali hydroxides
NaOH, KOH were superior to carbonates and were
equally good when used in DMSO. Thus NaOH was
used for the coupling reactions but, if desired, particu-
larly for substrates possessing sensitive functional
groups, carbonates (Na2CO3, K2CO3, Cs2CO3) can be
used. The precatalyst CuI was found to be the best
among the series of Cu salts tested such as CuBr,
Figure 2. Effect of ligands on the Cu(I)-catalyzed reaction.
Cu2O, CuBr2, CuCl2·2H2O, CuACTHNGUTREN(NUG OAc)2·2H2O and
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Table 2. Synthesis of arylsulfanyl-arylcyanamides and N-aryl-2-aminobenzothia-
zoles.[a]
AHCTUNGTRENNUNG
[a]
[b]
[c]
Reactions were performed at 908C for 0.75 h.
1
Confirmed by IR, HNMR, and 13CNMR spectroscopy.
Isolated yields.
CuSO4·5H2O. With other Cu salts, the reaction time served in addition to the S-arylated cyanamides (1d,
was longer even when assisted by ligand (L7), for ex- 31%) or (1e, 60%) as the case may be. The formation
ample CuSO4·5H2O took 1.5 h even when carried out of N-aryl-2-aminobenzothiazole (1d’) and (1e’) can be
in the presence of DMEDA ligand (L7) as opposed to explained by the initial intramolecular S-arylation of
0.5 h when Cu(I) was used. Bromobenzene and 1-(2-bromophenyl)thiourea (1) to 2-aminobenzothia-
chloroACHTUNGTRENNUNGbenzene were found to be ineffective giving a zole (K). This is then followed by an intermolecular
number of side products, thus coupling was done N-arylation with nitroaryl iodides (d or e) leading to
mostly with the iodoarenes, a trend (I>Br@Cl) fol- the direct synthesis of N-aryl-2-aminobenzothiazole
lowed for most coupling reactions.[2e–f,3e,8] Thus, from a (1d’) and (1e’) as we anticipated at the beginning. It
series of experiments, the optimum ratio of the 1-(2- may be mentioned here that a non-ligand-assisted re-
bromophenyl)thiourea (1), iodobenzene (a), CuI, action of analogous substrates is reported to give ex-
ligand (L7), base (NaOH) was found to be clusively S-arylated cyanamides and no traces of N-
1:1:0.05:0.10:3.
aryl-2-aminobenzothiazole.[1p] Thus, this is yet another
We next investigated the influence of various aryl manifestation of the differential reactivity/selectivity
iodides on the coupling reactions. As can be seen of a non-ligand-assisted over a ligand-assisted reac-
from Table 1, the present catalytic system has substan- tion. It is known that for heteroarylations, iodoarenes
tial substrate scope. Electron-donating aryl iodides having a strong electron-donating group react more
such as p-methyl iodobenzene (b) and p-amino iodo- slowly as compared to substrates possessing an elec-
benzene (c) gave exclusively S-arylated cyanamides tron-withdrawing group.[9] Perhaps a highly active spe-
(1b) and (1c) respectively, in excellent yields by a cas- cies is formed by the oxidative addition of iodoni-
cade coupling process. However, an interesting troarenes (d) and (e) as shown in Scheme 4. This
change in the reactivity profile was observed when an active species could undergo nucleophilic substitution
À
electron-withdrawing group ( NO2) is present in the either with the soft sulfur nucleophile (path I) or with
aryl iodide either in a para (d) or in ortho (e) posi- the hard amine nucleophile (path II) giving S-arylated
tion. For the first time the formation of N-aryl-2-ami- cyanamides and N-aryl-2-aminobenzothiazole, respec-
nobenzothiazole (1d’, 62%) or (1e’, 30%) was ob- tively. When the nitro group is present in the ortho
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Copper(I)-Catalyzed Cascade Synthesis of 2-Arylsulfanyl-arylcyanamides
Table 3. Synthesis of cyanamides from thioureas.[a]
[a]
Reactions were performed at 908C and monitored by TLC.
[b]
[c]
[d]
1
Confirmed by IR, H NMR, and 13C NMR spectroscopy.
Isolated yields.
Reaction was performed at room temperature.
position (e), only 30% of the 2-arylaminobenzothia- (d) and (e) gave a mixture of products consisting of
zoles (1e’) was obtained as compared to the 62% of N-aryl-2-aminobenzothiazole [(1d’), (1e’), (2d’), (2e’),
the product (1d’) when the nitro group is in the para (3e’)] and S-arylated cyanamides [(1d), (1e), (2d),
position (d). This can be accounted due to the higher (2e), (3e)] as the case may be as shown in Table 1. As
steric hindrance for a substrate having an o-NO2 was observed for (d) when an electron-withdrawing
À
group (e) in path II compared to its para (d) ana- ( NO2) group is present in the para position in an
logue.
aryl iodide, a higher percentage of 2-N-aryl-2-amino-
Various 1-(2-bromophenyl)thioureas having sub- benzothiazoles 1d’ (62%), 2d’ (54%) was obtained
stituents such as p-Me (2), p-OMe (3), p-Br (4) and compared to S-arylated cyanamides 1d (31%), 2d
p-(1,3-dithiolane) (5) underwent the cascade reaction (38%). However, the trend was nearly reversed when
À
with a range of aryl iodides bearing p-Me (b), p-NH2 the NO2 group is present in the ortho position, as
(c) when coupled in the presence of Cu(I) and assist- shown in Table 1, i.e., a higher percentage of S-arylat-
ed by the ligand (L7) giving the corresponding S-ary- ed cyanamides 1e (60%), 2e (53%), 3e (46%) was ob-
lated cyanamides as shown in Table 1. While aryl io- tained compared to 2-arylaminobenzothiazoles 1e’
À
dides bearing an electron-withdrawing group ( NO2) (30%), 2e’ (42%), 3e’ (36%).
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The scope of this strategy was then extended to useful intermediates for the synthesis of various bio-
other thioureas containing a 2-iodo substituent in- logically active compounds. Due to their unique struc-
stead of a 2-bromo substituent. As discussed above, ture and reactivity, cyanamides have attracted consid-
and as was observed by others, the intramolecular S- erable attention in organic synthesis.[10] Cyanamides
arylation is very facile when the halo substituent is an are key precursors to N-alkyl- or N-arylimides[11] and
iodo group and proceeds without a ligand with also serve as a useful protecting group in the synthesis
2.5 mol% of the catalyst (CuSO4).[1p] However, when of heterocycles containing secondary and tertiary
assisted by the ligand (L7), the same reaction can be amines.[12] They are important precursors in the syn-
carried out with just 1 mol% of the catalyst, when the thesis of herbicides[13] and pharmaceutically active
catalyst used is CuI instead of CuSO4. Further, the su- heterocycles such as tumor inhibitors,[14] and a vasodi-
periority of Cu(I) catalyst over CuSO4 can be judged lator medication called minoxidil,[13] known for its
by the fact that with 2.5 mol%, each of these in the ability to reduce hair loss and promote hair regrowth.
absence of any ligand and Cs2CO3 as the base in Tetrazoles are an important class of heterocycle pre-
DMSO the former gave product 2-(phenylthio)phe- pared from cyanamide and are present in several drug
nylcyanamide (1a, 95%) within 3 h, whereas the latter molecules.[15]
gave 40% of intermediate 2-aminobenzothiazole (K)
Organic cyanamides are prepared by the reaction
and only 60% of (1a) at a similar reaction time. It is of cyanogen chloride/bromide with amines or with
therefore not surprising that substrates 1-(2-iodophe- imide salts.[16] However, the preparation of cyanogen
nyl)thiourea (1’) and 2-iodophenylthioureas having halide involves the use of extremely toxic potassium/
substituents such as p-Me (2’), and p-Br (4’) under- sodium cyanide and bromine make the protocol envi-
went similar cross-coupling reactions with various aryl ronmentally unacceptable. Other available synthetic
iodides bearing p-Me (b), p-NH2 (c), when coupled in strategies are cyanation of amines using CN+ equiva-
the presence of Cu(I) and assisted by the ligand (L7), lents as synthons,[17] Tiemann rearrangement of ami-
to give S-arylated cyanamides as shown in Table 2. doximes,[18] coupling reactions involving Pd isocya-
Here again, aryl iodides bearing an electron-with- nides, allyl carbonates and trimethylsilyl azide,[19] and
À
drawing group ( NO2) in its ortho (d) or para (e) po- sodium bis(trimethylsilyl)amide as deoxygenating or
sition gave a mixture of products consisting of N-aryl- desulfurizing agents.[20] Yet another method for the
2-aminobenzothiazole [(1d’), (2d’)] and S-arylated cy- preparation of cyanamides involves the reaction of
anamides [(1d), (2d)], as the case may be, as shown in hypervalent iodine(V) species with N.N’-disubstituted
Table 2. Perhaps the most interesting aspect is that glycylamide.[21] All the literature methods reported so
the ratio of the product N-aryl-2-aminobenzothiazole far involve the direct or indirect use of toxic and cor-
1d’ and S-arylated cyanamide (1d) formed was nearly rosive reagents, strong alkaline conditions, expensive
identical irrespective of the starting materials 1-(2- reagents and catalysts, high reaction temperatures and
bromophenyl)thiourea (1) or 1-(2-iodophenyl)thiour- tedious purification procedures and are therefore en-
ea (1’) used. This regioselectivity in the product for- vironmentally unattractive. We have recently devel-
mation in these reactions further confirms the inter- oped two environmentally benign methods for the
mediacy of 2-aminobenzothiazole (K) via an intramo- synthesis of organic cyanamides, one involving hyper-
lecular S-arylation. Irrespective of its origin either valent iodine, diacetoxyiodobenzene (DIB)[22] and the
from (1) or (1’), once the intermediate 2-aminobenzo- other using molecular iodine.[23] Thus, the present cat-
thiazole (K) is formed in the media, it undergoes a alytic synthesis of alkyl and aryl cyanamides from
cascade reaction with 1-iodo-4-nitrobenzene (d), monosubstituted alkyl- and arylthioureas would be a
either via path I or by path II as shown in Scheme 4 better practical alternative for the synthesis of cyana-
to yield product (1d) and (1d’) in the same ratio of mides over the existing methods.
2:1.
The optimized reaction conditions were basically
As can be seen from Scheme 2, during the cross- the same as were employed for the above reactions
coupling of 1-(2-bromophenyl)thiourea (1) with except the reactions were performed in the absence
phenyl iodide in the absence of any ligand, only 2- of any ligand. Thus, in a typical reaction, 2-bromophe-
bromophenylcyanamide (1a’’’) was obtained. Further, nylthiourea (1) (1 equiv.), Cu(I) (2.5 mol%), NaOH
we have noticed that 1-(2-chlorophenyl)thiourea in (3 equiv.) in DMF (1 mL) was heated at 908C. Com-
the presence of Cu(I) and ligand did not undergo in- plete conversion to 2-bromophenylcyanamide was ob-
tramolecular S-arylation to give 2-aminobenzothia- served within 2 h and the product was isolated in 92%
zole (K), rather, 2-chlorophenylcyanamide (1a’’) was after usual work-up and purification. The proposed
obtained exclusively. This prompted us to develop a mechanism for the formation of cyanamide is shown
catalytic strategy for the synthesis of aryl and alkyl cy- in Scheme 5.
anamides from their corresponding thioureas.
The catalyst CuI, after the first cycle, presumably
The wide applications of organic cyanamides in or- gets converted to CuS or forms an array of polynuc-
ganic synthesis are now well documented which are lear anions containing sulfur rings or a chain which is
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Copper(I)-Catalyzed Cascade Synthesis of 2-Arylsulfanyl-arylcyanamides
form CuO which can serve the same purpose in the
second cycle. The existence of CuO and CuS can be
judged from the EDS analysis of the sample obtained
from the reaction. Some of the regions in the SEM
picture (Figure 3, A) are rich in CuO, known to be an
efficient catalyst,[3d,25] while the other regions are com-
posed of fine fibrous PbS particles (Figure 3).
Irrespective of the mechanism of the reaction, this
is one of the most efficient methods for the synthesis
of cyanamides from thioureas. Gratifyingly, various
mono- (1, 1’’, 7, 8, 9, 11, 12, 13, 14, 15) and di- (2, 3,
10) substituted thioureas having electron-donating
and electron-withdrawing substituents all gave their
corresponding cyanamides in good to excellent yields.
Electron-withdrawing substituents took a slightly
longer time giving lower yields compared to sub-
strates having electron-donating substituents as shown
in Table 3. Aliphatic thioamide (16) gave a poor yield
of corresponding cyanamide (16a), an observation
consistent with our previous report,[22,23] which is due
to the higher pKa of its parent amine thereby explain-
Scheme 5. Proposed mechanism for the formation of cyan-
ACHTUNGTRENNUNGamides.
well known in the text books.[24] Alternatively, at this ing the difficulty in deprotonation during the cyan-
temperature, some of the CuS would decompose to
ACHTUNGTRENaNUNG mide formation. Both benzylic (17) as well as ben-
Figure 3. SEM and EDS analysis of the Cu salt.
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Santosh K. Sahoo et al.
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(7 mL) were stirred in a preheated oil bath at 908C. The
progress of the reaction was monitored by TLC using ethyl
acetate and hexane (2:8). After 2 h, the reaction mixture
was cooled to room temperature and diluted with ethyl ace-
tate (20 mL). Then reaction mixture was filtered over Celite
and washed with ethyl acetate (3ꢁ10 mL). The filtrate was
washed successively with 1N HCl (2ꢁ5 mL) and with water
(2ꢁ10 mL). The ethyl acetate layer was dried over anhy-
drous Na2SO4 and the solvent was removed under reduced
pressure. The crude product was purified over a column of
silica gel with EtOAc:hexane (2:8) as the eluents to give the
product 1a’’’; yield: 0.906 g (92%).
zoylic (18) thioamides gave their cyanamides (17a)
and (18a) in excellent yields (Table 3).
Conclusions
We have developed an efficient, ligand-assisted,
Cu(I)-catalyzed cascade reaction. Two different reac-
tion paths are followed depending on the nature of
the aryl halide. In one path, 2-bromo-/iodothioamide
undergoes an intramolecular S-arylation followed by
an N-arylation, particularly for aryl halides having a
nitro group, directly giving N-aryl-2-aminobenzothia-
zole. Aryl bromides are resistant to intramolecular S-
arylation when performed in the absence of a ligand
but are very facile when assisted by ligands. Further,
selectivity is completely different particularly for aryl
iodides having a nitro group. The reactivity changes
with the change in the ligand but the overall selectivi-
ty remains the same. The ligand-assisted reactions are
much faster compared to the non-ligand-assisted reac-
tions and proceeds with less catalyst loading. Finally,
an efficient catalytic method for the synthesis of cyan-
amide from monosubstituted thiourea has been devel-
oped under ligand-free conditiona. The low catalyst
loading, inexpensive metal catalyst and ligands, lower
reaction temperature, and shorter reaction time make
these methods a better alternative to some of the ex-
isting methods of their preparation.
Acknowledgements
B. K. P acknowledges support of this research from DST
New Delhi (SR/S1/OC-79/2009) and CSIR 01ACTHNURGTNE(NUG 2270)/08/
EMR-II. S.K.S. thanks the institute and L.J. amd S.G. thank
the CSIR for fellowships. Thanks are due to CIF IIT Guwa-
hati for NMR and mass spectra and DST FIST for the XRD
facility.
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Experimental Section
General Procedure for the Synthesis of 2-(Phenyl-
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