Application of the Pictet-Spengler reaction to aryl amine substrates linked to deactivated aromatic heterosystems

Article abstract of DOI:10.1016/j.tet.2008.07.003

Three new substrates with an aryl amine moiety attached to quinoxalines, triazoles and tetrazoles either via C or N have been used for the Pictet-Spengler reaction. The substrates have been designed by applying the concept of 'aryl amine attached to a dea

Full text of DOI:10.1016/j.tet.2008.07.003

Tetrahedron 64 (2008) 8676–8684
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Application of the Pictet–Spengler reaction to aryl amine substrates linked
to deactivated aromatic heterosystemsq
*
B. Saha, S. Sharma, D. Sawant, B. Kundu
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2008
Received in revised form 30 June 2008
Accepted 1 July 2008
Available online 3 July 2008
Three new substrates with an aryl amine moiety attached to quinoxalines, triazoles and tetrazoles either
via C or N have been used for the Pictet–Spengler reaction. The substrates have been designed by ap-
plying the concept of ‘aryl amine attached to a deactivated heteroaromatic ring’ in a manner to facilitate
endo cyclization. This is in contrast to the substrates used traditionally and reported earlier by us that are
based on either aliphatic or aryl amine, respectively, attached to an activated heterocyclic ring. The
Pictet–Spengler condensation of the three substrates with aldehydes led to the synthesis of novel N-rich
polyheterocyclic system hitherto not reported. Our modified strategy opens up possibilities to design
novel substrates with aryl amines linked via C or N to either deactivated or activated heterocyclic
privileged structure, which in turn can be used for the synthesis of novel fused polyheterocyclic
skeletons.
Keywords:
Pictet-Spengler reaction
Deactivated ring
Quinoxaline
Triazole
Ó 2008 Elsevier Ltd. All rights reserved.
Tetrazole
1. Introduction
shown that by enhancing the electrophilic nature of the iminium
intermediate, 6-endo cyclization can be affected.5 The electrophi-
The Pictet–Spengler reaction1 is one reaction in organic chem-
istry that has been extensively used for the construction of a variety
of natural products and novel heterocycles of biological interest.2
licity of the imine has been generally enhanced by two main
methods to affect the -cyclization. In one of the methods stronger
p
acids are used to protonate the imine with the view to produce the
iminium ion intermediate with enhanced electrophilicity. But de-
spite its wide application, the strategy is not suitable for acid labile
functional groups. The second strategy involves endo cyclization
via more electrophilic N-substituted iminium reactive species
such as N-acyliminium6,20/N-alkyliminium7/N-sulfonyliminium8
derivatives. Though this elegant strategy has a major impact in the
field of Pictet–Spengler reaction, it has a major limitation that the
acylating species remains hanged on to the molecule and has to be
removed.
Recently, we enhanced the electrophilic nature of the iminium
intermediate by replacing aliphatic amine with aryl amine, which
was linked to the electron-rich aromatic heterocycles either
through C or N.9 Our observation was based on the fact that imines
derived from the aromatic amines are more electrophilic than the
aliphatic amines. Using our modified strategy, we extended its
application to five new substrates derived from imidazoles (4 and
5), thiazoles (6), pyrazoles (7), benzohistamine (8) and bicyclic
heterocycles (9 and 10). Following our report several groups
reported new substrates (Fig. 1) based on our concept derived from
dimethoxy arene (11), indole (12), thiophene (13) and benzoqui-
none (14).10 These aromatic amine-derived substrates represent
second-generation substrates9c in the line of traditional aliphatic
amine-derived first-generation substrates (1–3; Fig. 1) and led to
The method generally involves condensation of an
u-aromatic
amine and an aldehyde leading to polycyclic structure of biological
significance.3 The aliphatic amine is generally linked to the elec-
tron-rich aromatic/heteroaromatic rings that is involved in
clizations with an electrophilic imine derived from the amine.
Traditionally, the systems employed in these cyclizations are
derived from any of the three electron-rich aromatic rings (Fig.1) as
indoles (1), activated phenethylamines (2) and imidazoles (3). Thus,
despite being a powerful reaction, it is the activated ring systems
(1–3) that dominated the conventional Pictet–Spengler reaction
substrates for the last hundred years and were exclusively used to
p-cy-
p
generate
b-carboline, tetrahydroisoquinoline and tetrahy-
droimidazopyridine ring systems.4
The Pictet–Spengler reaction of these substrates with various
carbonyl compounds suggests that the use of an aldehyde with
electron donating group such as salicylaldehyde generally fails to
furnish the desired product due to the poor electrophilic nature of
the resulting iminium intermediate. Cook et al. and others have
q
CDRI communication no. 7556.
* Corresponding author. Tel.: þ91 522 2262411–18x4383; fax: þ91 522 2623405.
E-mail address: bijoy_kundu@yahoo.com (B. Kundu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.003

B. Saha et al. / Tetrahedron 64 (2008) 8676–8684
8677
Conventional Pictet-Spengler Method
based on aliphatic amine substrates
Modified Pictet-Spengler Method
based on aryl amine substrates
Y
N
X
Y
R-CHO
Y = 0
X
Ar
Ar
Ar
NH
Ar
NH2
R1
H2N
R-CHO
Conventional
substrates
R
Modified substrates
X = Lone pair
of electrons
X = C, N
Y = 0, CH2, NH, S
Ar
N
Poor electrophilicity of
imines limits scope
X
R1 = EDG
no reaction
R1
Y
X
X
R
Ar
N
Ar
NH
Methods to improve electrophilicity
R
6-membered
7-membered
Diversity in Aromatic heterocycles
Improved electrophilicity
Construction of 6- and 7-membered
heterocyclic ring
By protonation of imine
X = H
N- or C-originated aryl amines
Modified Substrates (Second generation)
Ar
[Ref. 6]
[Ref. 7]
[Ref. 8]
NH
N-Acyliminium
X = COR2
R1
1. Reported by our group
N
Ar
NH2
N
COR2
N
N
NH2
R1
N
H2N
N
NH2
N
H
N-Alkyliminium
S
X = Bn
4 [Ref. 9a]
5 [Ref. 9b]
6 [Ref. 9c]
7 [Ref. 9c]
Ar
S
N
Bn
R1
N
N
N
N
N-Sulfonyliminium
N
H2N
X = SO2Ph
H2N
H2N
N
H
8 [Ref. 9d]
9 [Ref. 9d]
10 [Ref. 9d]
Ar
N
SO2Ph
R1
2. Reported by others (following diclosure of our concept)
Conventional Substrates (First generation)
O
O
X
N
N
N
N
N
Cl
O
H2N
NH2
NH2
Cl
NH2
O
11 [Ref. 10a]
N
12 [Ref. 10b]
H
2
1
O
H
H2N
N
N
NH2
S
13 [Ref. 10c]
N
N
H
H
O
3
14 [Ref. 10d]
Figure 1. Comparison between the traditional and our modified Pictet–Spengler reaction.
the construction of polycyclic frameworks analogous to naturally
occurring frameworks. Interestingly, during the course of endo cy-
clization with our aryl amine substrates (4–10),9 we observed that
generation) having aliphatic amine. The faster rate of reaction for
aryl amine substrates can be attributed to the enhanced electro-
philicity of the resulting imines than the imines derived from
aliphatic amine substrates (1–3). Since enhancement of the
electrophilic nature of the iminium intermediate has been docu-
mented by several groups5 as driving force for endo cyclization, we
(1) unlike traditional substrates, the
p-cyclizations occurred with
a wide variety of aldehydes having both electron donating and
withdrawing substituents and (2) the rate of Pictet–Spengler re-
action in substrates (second-generation) with aryl amine was faster
than the conventional Pictet–Spengler reaction substrates (first-
envisaged that the
p-cyclization could be affected even when aryl
amine is linked to a deactivated (poorly nucleophilic) heterocyclic

8678
B. Saha et al. / Tetrahedron 64 (2008) 8676–8684
ring. Accordingly, we decided to explore the application of our aryl
amine strategy to deactivated heterocyclic nucleus,11 with the view
to move beyond the age old general concept involving exclusive use
Relative decrease in the propensity for
electrophilic substitution
of the activated p-nucleophile as substrates for the Pictet–Spengler
reaction. Literature search for the Pictet–Spengler reaction in-
volving use of substrate with an amine attached to a hetero-
N
N
H
aromatic ring with poor p-nucleophilic character led to two papers
by Stokker12 and Zhang et al.13 In the first paper, it was reported
that phenethylamine with or without electron-withdrawing sub-
stitution on the phenyl ring, underwent Pictet–Spengler reaction
only via N-acyliminium strategy and required strong acidic condi-
tions (H2SO4). However, major drawback with the strategy was that
the reaction could not be extended to other aldehydes except
paraformaldehyde. Similarly, the second paper described synthesis
of a single compound pyridoindolobenzodiazepine (an antipsy-
chotic agent) by allowing N-1-linked aryl amine in the indole to
undergo cyclization at the C-7 of the aromatic ring, again only in the
presence of paraformaldehyde, and under strong acidic conditions
such as neat TFA. In contrast, the traditional and our modified
Pictet–Spengler cyclization are generally affected under mild acidic
conditions (2% TFA–DCM at 0 ꢀC or pTSOH) with a wide variety of
aldehydes.
N
N
N
=
N
N
H
N
H
N
N
N
N
N
H
N
N
N
N
H
Figure 2. Comparative trends of electrophilic substitutions among five- and six-
membered N-heterocycles.
results in the relative decrease in the overall
p-nucleophilic char-
2. Result and discussion
acter in such systems. This phenomenon is also evident in the
quinoxaline ring system (a benzoannulated derivative of pyrazine),
which has been reported to undergo electrophilic substitution
exclusively on its benzene ring, thereby suggesting that the het-
erocyclic counterpart is highly deactivated. Hence, among six-
membered deactivated heterocyclic rings we selected quinoxaline
as a model to prove our proposed concept. In this communication,
we report Pictet–Spengler cyclization on aryl amine substrates 17,
22 and 27 derived from deactivated heterosystems: quinoxaline,
tetrazole and triazole, respectively. In the substrate 17, an aryl
In order to test the viability and generality of our proposed
concept, initially we searched for an entirely new generation of
substrates having aryl amine linked to either carbon or nitrogen of
a deactivated heterocyclic system. In the first instance, we directed
our efforts towards five- and six-membered heterocyclic skeletons
that behaved as deactivated
p-nucleophiles towards the electro-
philic substitution. Among five-membered N-containing hetero-
cyclic frameworks pyrroles demonstrate superior reactivity
towards electrophilic substitution than the six-membered coun-
terpart pyridine.9 This observation can be attributed to the fact that
the electron-sink effect exerted by the multiply bonded nitrogen
makes six-membered N-containing heterocycles considerably less
reactive than the five-membered N-containing heterocycles, where
nitrogen acts as electron donor thereby activating the ring carbons
towards electrophilic substitution. But if a second multiply bonded
nitrogen is introduced in the pyrrole (as in azoles), it makes the
activated five-membered ring system less reactive towards elec-
trophile and introduces differentiation in the reactivity of hetero-
cyclic carbons towards electrophilic substitution. The carbons at
amine has been allowed to originate from one of the
with the view to facilitate ring closure via 6-endo cyclization on the
second -carbon (Fig. 2). In contrast in the substrates 22 and 27, an
a-carbons
a
aryl amine has been allowed to originate from N-1 with the view to
allow ring closure via C–C bond formation at the C-5 (Fig. 2) in both
the heterocyclic rings. As depicted in Figure 2, based on electro-
philic distribution pattern for triazoles, we had an additional option
of allowing the aryl amine to originate from the C-4 followed by
ring closure at C-5. However, in view of higher chemical diversity,
we restricted our self to the substrate 27 since synthesis of the
second substrate with aryl amine originating from C-4 of the tri-
azole involved use of 1-ethynyl-2-nitrobenzene, for which no
commercial diversity is available. The Pictet–Spengler reaction on
these substrates in the presence of aldehydes led to the formation
of new polycyclic skeletons (18, 19 and 26) hitherto not reported in
the literature. Polycyclic systems derived from privileged structures
(quinoxalines, triazole and tetrazoles) constitute an interesting
class of compounds for any drug discovery program.15
The synthesis of substrate 17 has been depicted in Scheme 1. It
can be readily obtained by first treating o-nitrophenacyl bromide
with o-phenylenediamine (15) to give nitro derivative of quinoxa-
line 16, which was further reduced in the presence of SnCl2$2H2O to
give 2-quinoxalin-2-yl-phenylamine 17.
For the Pictet–Spengler cyclization, substrate 17 was treated
with p-tolylbenzaldehyde under a variety of traditional Pictet–
Spengler protocols involving pTsOH in toluene at reflux, 5% TFA in
DCM at rt, and neat toluene at 80 ꢀC. The 6-endo cyclization
resulting in triaza-benzo[a]anthracene 18 (Scheme 2) occurred
only when pTsOH was used as a proton source, other two protocols
furnished imines as the only product. The crude product obtained
after workup was purified by silica gel column chromatography
using EtOAc/hexane as an eluent and characterized by MS and
a
- and
whereas the
such multiply bonded nitrogen are introduced in the ring system,
the -nucleophilic character is further diminished (Fig. 2). Thus,
g
-positions to the multiply bonded nitrogen are deactivated,
b-carbon is the least deactivated. However, if more
p
triazoles and tetrazoles with 3 and 4 nitrogens, respectively, in their
rings are the most deactivated heterocycles towards electrophilic
substitution. Literature survey also revealed few reports14 dealing
with the electrophilic substitution at the carbon(s) present in tri-
azoles and tetrazoles. Hence, for our studies triazole and tetrazole
appeared to be good substrates under five-membered deactivated
ring systems to prove our concept.
Among six-membered heterocyclic ring systems, the presence
of a doubly bonded nitrogen atom not only deactivates the ring
towards electrophilic substitution than benzene (Fig. 2), but also
imparts a differentiating effect on the carbons towards electrophilic
substitution.9 The carbons at
bonded nitrogen are more deactivated than
in accordance with the literature reports demonstrating electro-
philic substitutions at the
-carbon.9 However, introduction of one
a
- and
g-positions to the multiply
b-position, and this is
b
more multiply bonded atom in the ring at C-4, introduces sym-
metry in the molecule and all the four carbons now behave as
a
-carbon to either of the nitrogen (pyrazine; Fig. 2). This in turn

B. Saha et al. / Tetrahedron 64 (2008) 8676–8684
8679
O
Br
NO2
R1
R2
R1
R2
R1
R2
N
N
NH2
NH2
N
N
.
NH2
NO2
SnCl2 2H2O
EtOH,reflux,
1.5h
EtOH,reflux,2h
16a-b
17a-b
15a-b
15,16,17a R1 = R2 = H
15,16,17b R1 = R2 = CH3
Scheme 1. Synthesis of the Pictet–Spengler substrate 17 involving deactivated heteroarene quinoxaline.
NMR. The scope and limitation of our strategy were established by
synthesizing five compounds based on 18 by using three aldehydes
and two phenylenediamines. Purities of the crude products were
typically in excess of 85% based on HPLC analysis and substitutions
on aldehydes or phenylenediamine had no effect on the isolated
yields (62–70%) of the cyclized products. It is interesting to note
that aromatic aldehydes with both electron donating (except sali-
cylaldehyde and N,N-dimethyl benzaldehyde) and withdrawing
cyclization, which was found to be complete after 16 h. The pro-
longed duration required for the endo cyclization of the substrate
22 in comparison to the substrate 17 can be explained by com-
paring the electrophilicities of the corresponding imines formed as
precursors during endo cyclization. Cook et al. earlier demonstrated
that amines with lower pKa value furnished imines with higher
electrophilicity thereby facilitating the ease of endo cyclization. In
our substrate 17, aryl amine is linked to an already deactivated
carbon of the quinoxaline ring, which causes relative decrease in
the pKa value than the aryl amine in the substrate 22 originating
from the N-1, which behaves as an electron donor. Similar obser-
vation was made earlier by us during our studies with second-
generation substrates comprising C- and N-linked aryl amines.9 The
crude product obtained after workup was purified by silica gel
column chromatography using EtOAc/hexane as an eluant and
characterized by MS and NMR. The scope and limitation of our
strategy were established by synthesizing four compounds based
on 23 by treating the substrate 22 with five different aldehydes.
Purities of the crude products were typically in excess of 80% based
on HPLC analysis with moderate to good isolated yields (47–68%)
for the cyclized products 23. Aliphatic aldehydes and ketones again
failed to undergo endo cyclization with 22.
groups successfully underwent
p-cyclizations. No reaction was
detected with aliphatic aldehydes and ketones and this may be
attributed to the relatively poor electrophilicity of the imines de-
rived from aliphatic aldehydes and ketones coupled with the
deactivated p-nucleophile. On the contrary, aromatic aldehydes in
general, furnished imine with sufficient electrophilicity that trig-
gered endo cyclization even in the presence of a deactivated
p-nucleophile.
R3
R1
R2
N
N
R1
R2
N
N
O
NH2
N
R3
R4
pTsOH, Toluene
7 h
18a-g
17a-b
We next examined the efficacy of our strategy on yet another
deactivated five-membered ring triazoles. The desired substrate 27
based on triazole was synthesized using a modified Huisgen cy-
cloaddition method as depicted in Scheme 5.17 Initially the reaction
was carried out by subjecting alkyne, o-nitroaryl halide and azide to
redox coupling in Cu(0)/CuSO4 to get intermediate 26 using the
literature procedure.18 However, the reaction produced the desired
intermediate in diminished yield. We then applied our modified
strategy reported earlier for the synthesis of N-aryltriazoles 26 by
replacing CuSO4 by FeCl3 using water as the sole reaction me-
dium.19 Subsequently, the nitro derivative 26 was reduced in the
presence of SnCl2 to furnish 27 in good yield and purity (Scheme 5).
The final endo cyclization was performed by reacting 27 with
various aryl aldehydes to give triazolo[1,5-a]quinoxalines 28
(Scheme 6). The duration required for endo cyclization was in par
with that observed for substrate 22 as in both the substrates the
aryl amine originates from the nitrogen of the deactivated het-
erocyclic rings.
18a. R1= R2= H, R3 = 4-CH3-C6H4, R4= H; Yield = 67%
18b. R1= R2= H, R3 = 4-Br-C6H4, R4= H; Yield =68%
18c. R1= R2= CH3, R3 = 4-CH3-C6H4, R4= H; Yield =72%
18d. R1= R2= CH3, R3 = 2-OCH3-C6H4, R4= H; Yield =62%
18e. R1= R2= CH3, R3 = 4-Br-C6H4, R4= H; Yield =70%
18f R1= R2= H, R3= 4-(CH3)2N-C6H4, R4= H; no reaction
18g R1= R2= H, R3 = CH3CH2, R4= H; no reaction
18h R1= R2= H, R3 = C6H5, R4= CH3; no reaction
Scheme 2. The Pictet–Spengler reaction on substrate 17.
The synthesis of the second substrate based on tetrazole 22 has
been depicted in Scheme 3. It commenced with the condensation of
sodium azide with o-nitro phenylisothiocyanate (19) to give in-
termediate 20 followed by oxidative desulfurization to obtain 21 by
the literature procedure.16 The resulting tetrazole derived nitro
derivative 21 was subjected to SnCl2 reduction to give substrate 22.
For the Pictet–Spengler cyclization, substrate 22 was treated
with p-tolylbenzaldehyde in toluene at reflux in the presence of
pTsOH (Scheme 4) to give pentaaza-cyclopenta[a]naphthalene 23.
The reaction was monitored on TLC and within 2 h we first ob-
served a spot due to the formation of imine, which slowly dis-
appeared with the appearance of a new spot arising from endo
Thus, using substrates 17, 22 and 27, we have successfully
demonstrated that the Pictet–Spengler cyclization could be carried
out even with deactivated p-nucleophile systems by introducing an
aryl amine. The incorporation of aryl amine instead of aliphatic
amine compensates for the loss in the availability of activated
HS
N
N
NCS
N
N
N
N
N
CHCl3/H2O
Reaflux,2 h
SnCl2
NO2
+
H2O2
NH4OH
0-100 °C
N
N
N
N
N
NaN3
EtOH,
Reflux,1.5h
NH2
NO2
NO2
19
20
21
22
Scheme 3. Synthesis of the Pictet–Spengler substrate 22 involving deactivated heteroarene tetrazole.

8680
B. Saha et al. / Tetrahedron 64 (2008) 8676–8684
N
O
R1
23a R1 = 4-CH3-C6H4, R2 = H; Yield = 62%
23b R1 = 4-Br-C6H4, R2 = H; , Yield = 68%
23c R1 = 4-Cl-C6H4, R2 = H; , Yield = 62%
23d R1 = 2-OH-C6H4, R2 = H; , Yield = 47%
23e R1 = 4-(CH3)2N-C6H4, R2 = H; no reaction
23f R1 = CH3CH2, R2 = H; no reaction
N
N
R1 R2
N
N
N
N
pTsOH, Toluene,
16 h, reflux
N
NH2
N
22
23a-d
23g R1 = C6H5, R2 = CH3; no reaction
Scheme 4. The Pictet–Spengler reaction on substrate 22.
R1
R1
SnCl2
EtOH,reflux,
1.5h
F
N
N
N
NO2
N
N
N
NO2
Cu/FeCl3
NaHCO3,
H2O
NaN
+
+
3
NH2
Reflux, 7 h
24
25a-b
26a-b
27a-b
25,26,27a R1 = H
25,26,27b R1 = 4-CH3
Scheme 5. Synthesis of the Pictet–Spengler substrate 27 involving deactivated heteroarene triazole.
p
-nucleophile by furnishing imines with enhanced electrophilic
a deactivated heterocyclic ring’. Our modified strategy opens up
possibilities to design novel substrates with aryl amines linked via
C or N to heterocyclic privileged structures, which in turn can be
used for the synthesis of novel fused polyheterocyclic skeletons. N-
Substituted fused polyheterocyclic systems due to their strong
structural analogy to natural products are widely known to be as-
sociated with a wide range of biological activities.22 Currently work
is in progress in our lab with several second- and third-generation
substrates designed on the basis of our new concept for the Pictet–
Spengler reaction and will be reported soon.
character than imines derived from aliphatic amines. However, we
did observe few exceptions with respect to the generality of our
strategy. Aldehydes with strong electron donating groups such as
N,N-dimethylbenzaldehyde failed to undergo
substrates 17, 22 and 27. This may be attributed to the deactivated
-nucleophile systems that in turn failed to facilitate C–C bond
p-cyclizations with
p
formation. This is in contrast to our observation on the second-
generation substrates (4–12; Fig. 2) where N,N-dimethylbenzalde-
hyde successfully underwent
presence of electron-rich -systems. However, studies with the
first-generation substrates 1, 2 and 3 have shown that despite
the presence of electron-rich -systems, they failed to undergo
p-cyclizations, probably due to the
p
4. Experimental
p
endo cyclization with N,N-dimethylbenzaldehyde due to the com-
paratively poor electrophilic character of imines derived from ali-
phatic amines than aryl amines. Indeed, increasing the electrophilic
character of imines derived from 1, 2 and 3 either via N-acylimi-
nium20 or via Na-benzylation strategy6e,g–k,21 eventually furnished
the endo cyclized product. It is thus evident that substrates with an
aryl amine furnished imine with relative increase in its electrophilic
character to the extent that even when linked to the deactivated
4.1. General consideration
All solvents were commercially available and used without
purification. All products were characterized by 1H NMR, 13C NMR,
ESMS, IR and HPLC. Analytical TLC was performed using 2.5ꢁ5 cm
plated coated with a 0.25 mm thickness of silica gel 60F254 Merck
and visualization was accomplished with UV light and iodine.
Column chromatography was performed using silica gel 60 Thomas
Baker (100–200 mesh). 1H NMR spectra (200–300 MHz) are
reported as follows: chemical shifts in parts per million downfield
p-systems, 6-endo cyclization is favoured albeit with limitations for
aldehydes with strong electron donating group. Since our present
substrates with deactivated heterosystems differ from the second-
generation substrates having activated heterosystems reported
earlier by us, substrates 17, 22 and 27 could be grouped under
‘third-generation’ substrates for the Pictet–Spengler cyclization.
from TMS as internal standard (
d
scale), multiplicity [br¼broad,
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
o¼overlapped, integration and coupling constant (Hz)]. All 13C
NMR spectra (50–75 MHz) were recorded at 25 ꢀC with complete
proton decoupling and reported in parts per million except for
compounds 18b, 23b, 23c and 23d, which were insoluble at higher
concentration. Elemental analyses were performed on a Carlo Erba
1108 microanalyzer or Elementar’s Vario EL III microanalyzer. An-
alytical HPLC was performed on C-18 reverse-phase column
3. Conclusion
In summary, we have identified new substrates for the Pictet–
Spengler reaction, based on the concept of ‘aryl amine attached to
CHO
R1
R1
N
28a R1 = H, R2=4-CH3, Yield = 67%
28b R1 = H, R2 = 4-Br, Yield = 70%
28c R1 = 4-CH3, R2 = 4 CH3, Yield = 62%
28d R1 = 4-CH3, R2 = Br, Yield = 62%
28e R1 = H, R2 = Cl, Yield = 61%
N
N
R2
N
N
N
N
NH2
pTsOH, Toluene,
12 h, reflux
R2
28f R1 = H, R2 = 4-(CH3)2NC6H4, no reaction
27a-b
28a-d
Scheme 6. The Pictet–Spengler reaction on substrate 27.

B. Saha et al. / Tetrahedron 64 (2008) 8676–8684
8681
(250ꢁ4.6 mm). The micro-analyses were performed at Sophisti-
4.4. General procedure for the Pictet–Spengler reaction on
substrate 17
cated Analytical Instrument Facility Division, of our institute. Mass
spectra were recorded on a Merck MS-8000 spectrometer. Melting
points reported were uncorrected.
A
mixture of 2-quinoxalin-2-yl-phenylamine (17a) (0.10 g,
0.45 mmol), p-tolylbenzaldehyde (54 L, 0.49 mmol) and p-tolyl-
m
4.2. General procedure for the synthesis of 2-(2-nitro-
phenyl)-quinoxaline (16)
sulphonic acid (6.08 mg, 0.032 mmol) was refluxed in toluene
(5 mL) for 7 h. Toluene was evaporated in vacuo and residue so
obtained was dissolved in ethyl acetate (50 mL). The organic layer
was washed with 5% aqueous sodium bicarbonate, water
(2ꢁ10 mL) and brine solution (1ꢁ10 mL). The organic layers were
combined and dried over anhydrous Na2SO4 and evaporated to
obtain a residue. The residue so obtained was purified on column
chromatography on silica gel with hexane/ethyl acetate (80:20, v/v)
as eluent to afford 18a as a yellow solid.
A mixture of phenylenediamine 15a (1.06 g, 8.3 mmol), and 2-
bromo-20-nitro acetophenone (2.00 g, 8.19 mmol) was refluxed in
ethanol (20 mL) for 2 h. Ethanol was evaporated in vacuo and EtOAC
(2ꢁ50 mL) was added to the reaction mixture. The organic layer was
washed with saturated NaHCO3 solution (30 mL), water and brine
(30 mL) and dried over Na2SO4 and evaporated to obtain a residue.
The residue so obtained was purified on a silica gel column using
hexane/ethyl acetate (80:20, v/v) as eluent to afford 16a as a solid.
4.4.1. 6-p-Tolyl-5,7,12-triaza-benzo[a]anthracene (18a)
Yield 67%; yellow solid; mp 230–232 ꢀC; Rf¼0.56 (1:19 EtOAc/
4.2.1. 2-(2-Nitrophenyl)-quinoxaline (16a)
hexane); –IR nmax (KBr) 3023, 2973, 2843 cmꢂ1; 1H NMR (200 MHz,
Yield 78%; yellow solid; mp 116–118 ꢀC; Rf¼0.52 (1:9 EtOAc/
CDCl3):
7.87 (m, 3H, ArH), 7.89 (t, J¼7.2 Hz, 1H, ArH), 7.42 (d, J¼7.5 Hz, 2H,
ArH), 2.51 (s, 3H, CH3). 13C (50.2 MHz, CDCl3):
d¼9.27 (d, J¼8.1 Hz, 1H, ArH), 8.39–8.22 (m, 5H, ArH), 7.99–
hexane); IR nmax (KBr) 1610, 1533, 1350 cmꢂ1 1H NMR (300 MHz,
;
CDCl3):
d
¼8.96 (s, 1H, ArH), 8.20–8.09 (m, 3H, ArH), 7.85–7.68 (m,
d¼161.17, 145.49,
5H, ArH). Mass (FAB) m/z 252 (Mþþ1). Anal. Calcd for C14H9N3O2: C,
143.94, 140.10, 136.89, 135.52, 132.49, 131.76, 131.04, 130.65, 130.32,
129.75, 129.20, 128.07, 127.61, 124.78, 21.95. Mass (FAB) m/z 322
(Mþþ1). Anal. Calcd for C22H15N3: C, 82.22; H, 4.70; N,13.08. Found:
C, 82.34; H, 4.82; N, 13.30.
66.93; H, 3.61; N, 16.73. Found: C, 66.73; H, 3.53; N, 16.80.
4.2.2. 6,7-Dimethyl-2-(2-nitro-phenyl)-quinoxaline (16b)
Yield 72%; brown solid; mp 154–157 ꢀC; Rf¼0.61 (1:9 EtOAc/
hexane); IR nmax (KBr) 2939, 2849, 1604, 1522, 1338 cmꢂ1; 1H NMR
4.4.2. 6-(4-Bromo-phenyl)-5,7,12-triaza-benzo[a]anthracene (18b)
Yield 68%; brown solid; mp 214–216 ꢀC; Rf¼0.62 (1:19 EtOAc/
(200 MHz, CDCl3):
7.93–7.61 (overlapped, 5H, ArH), 2.53 (s, 3H, CH3), 2.51 (s, 3H, CH3).
13C (50 MHz, CDCl3):
d¼8.87 (s, 1H, ArH), 8.07 (d, J¼8.0 Hz, 1H, ArH),
hexane); IR nmax (KBr) 3033 cmꢂ1 1H NMR (200 MHz, CDCl3):
;
d
¼150.28, 149.36, 143.56, 141.68, 141.60,
d
¼9.28 (d, J¼7.8 Hz, 1H, ArH), 8.37–8.22 (m, 5H, ArH), 7.97–7.91 (m,
141.19, 140.95, 133.42, 132.14, 131.31, 130.42, 128.96, 128.63, 125.25,
20.77. Mass (FAB) m/z 280 (Mþþ1). Anal. Calcd for C16H13N3O2: C,
68.81; H, 4.69; N, 15.05. Found: C, 68.69; H, 4.83; N, 15.25.
4H, ArH), 7.74 (d, J¼8.5 Hz, 2H, ArH). Mass (ESþ) m/z 386.1 (Mþþ1).
DART-HRMS Calcd for C21H13BrN3: 386.02928, found 386.02671.
Anal. Calcd for C21H12BrN3: C, 65.30; H, 3.13; N, 10.88. Found: C,
65.13; H, 3.32; N, 103.67.
4.3. General procedure of reduction of 2-(2-nitro-phenyl)-
quinoxaline (16a) to 2-quinoxalin-2-yl-phenylamine (17a)
4.4.3. 9,10-Dimethyl-6-p-tolyl-5,7,12-triaza-benzo[a]-
262#anthracene (18c)
To the solution of compound 16a (2.0 g, 7.93 mmol) in ethanol
(20 mL) was added SnCl2$2H2O (5.34 g, 23.8 mmol) and the re-
action mixture was heated at reflux with stirring for 1.5 h under
nitrogen atmosphere. After this ethanol was evaporated and the
residue was made alkaline with saturated NaHCO3 (30 mL) and
then EtOAc (100 mL) was added. The organic layer was separated,
dried (Na2SO4) and concentrated to afford a residue, which was
purified by silica gel chromatography using hexane/EtOAc (20:80,
v/v) as eluent to afford 17a.
Yield 72%; yellow solid; mp 210–212 ꢀC; Rf¼0.65 (1:19 EtOAc/
hexane); IR nmax (KBr) 3061, 2981, 2830 cmꢂ1 1H NMR (200 MHz,
;
CDCl3):
d
¼9.23 (d, J¼8.6 Hz, 1H, ArH), 8.27–8.19 (m, 3H, ArH), 8.05
(d, J¼7.8 Hz, 2H, ArH), 7.90–7.76 (m, 3H, ArH), 7.41 (d, J¼8.2 Hz, 1H,
ArH), 2.57 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.45 (s, 3H, CH3). 13C
(50.2 MHz, CDCl3):
d
¼161.13, 143.99, 142.16, 139.68, 135.76, 131.77,
130.76, 130.21, 129.80, 129.41, 128.82, 128.25, 127.78, 125.12, 124.52,
122.74, 121.19, 112.42, 110.38, 21.95, 21.10, 20.8. Mass (FAB) m/z 350
(Mþþ1). Anal. Calcd for C24H19N3: C, 82.49; H, 5.48; N,12.03. Found:
C, 82.72; H, 5.32; N, 12.34.
4.3.1. 2-Quinoxalin-2-yl-phenylamine (17a)
Yield 68%; yellow solid; mp 146–148 ꢀC; Rf¼0.45 (1:4 EtOAc/
4.4.4. 6-(2-Methoxy-phenyl)-9,10-dimethyl-5,7,12-triaza-benzo[a]-
anthracene (18d)
hexane); IR nmax (KBr) 3426, 1595 cmꢂ1; 1H NMR (200 MHz, CDCl3):
d
¼9.32 (s, 1H, ArH), 8.12–8.02 (m, 2H, ArH), 7.85–7.65 (m, 3H, ArH),
7.32–7.23 (overlapped, 1H, ArH), 6.86–6.81 (m, 2H, ArH). 13C
(50 MHz, CDCl3):
Yield 62%; brown solid; mp >250 ꢀC; Rf¼0.53 (1:19 EtOAc/
hexane); IR nmax (KBr) 1341, 2923, 2844 cmꢂ1 1H NMR (200 MHz,
;
d
¼150.28, 149.36, 143.56, 141.68, 141.60, 140.95,
CDCl3):
d
¼8.46 (d, J¼8.4 Hz, 1H, ArH), 8.06 (s, 1H, ArH), 7.88 (s, 1H,
133.42, 132.14, 131.31, 130.42, 128.96, 128.63, 125.25, 20.77. Mass
(FAB) m/z 222 (Mþþ1). Anal. Calcd for C14H11N3: C, 76.00; H, 5.01;
N, 18.99. Found: C, 76.30; H, 5.21; N, 18.75.
ArH), 7.57 (t, J¼7.6 Hz,1H, ArH), 7.34 (t, J¼7.6 Hz, 2H, ArH), 7.30–7.17
(overlapped, 1H, ArH), 6.92 (d, J¼8.2 Hz, 2H, ArH), 6.75 (t, J¼8.4 Hz,
1H, ArH), 3.94 (s, 3H, OCH3), 2.52 (s, 6H, 2ꢁCH3). 13C (50.2 MHz,
CDCl3):
d
¼157.41, 146.25, 144.59, 139.88, 139.51, 138.76, 136.38,
4.3.2. 2-(6,7-Dimethyl-quinoxalin-2-yl)-phenylamine (17b)
Yield 63%; yellow solid; mp 160–164 ꢀC; Rf¼0.51 (1:4 EtOAc/
hexane); IR nmax (KBr) 3373, 2921, 2859, 1603, 1349 cmꢂ1; 1H NMR
130.77, 128.94, 128.84, 128.42, 127.57, 125.14, 122.63, 121.11, 121.03,
120.17, 110.63, 55.79, 20.76, 20.51. Mass (FAB) m/z 366 (Mþþ1).
Anal. Calcd for C24H19N3O: C, 78.88; H, 5.24; N, 11.50. Found: C,
78.78; H, 5.36; N, 11.34.
(200 MHz, CDCl3):
d
¼9.19 (s, 1H, ArH), 7.82–7.78 (m, 3H, ArH), 7.26–
7.24 (m,1H, ArH), 6.84 (t, J¼8.2 Hz, 2H, ArH), 7.10 (br s, 2H, NH2), 2.45
(s, 6H, 2ꢁCH3). 13C (50.2 MHz, CDCl3):
d
¼153.04, 148.32, 144.07,
4.4.5. 6-(4-Bromo-phenyl)-9,10-dimethyl-5,7,12-triaza-benzo[a]-
anthracene (18e)
140.96, 139.92, 139.71, 139.48, 131.30, 129.55, 128.55, 128.16, 119.01,
117.90, 117.80, 20.65. Mass (FAB) m/z 250 (Mþþ1). Anal. Calcd for
Yield 70%; yellow solid; mp 198–200 ꢀC; Rf¼0.59 (1:19 EtOAc/
C
16H15N3: C, 77.08; H, 6.06; N,16.85. Found:C, 77.24; H, 6.20; N,16.51.
hexane); IR nmax (KBr) 3021, 2931, 2853 cmꢂ1 1H NMR (200 MHz,
;

8682
B. Saha et al. / Tetrahedron 64 (2008) 8676–8684
CDCl3):
d
¼9.23 (dd, J¼7.8, 1.4 Hz, 1H, ArH), 8.27–8.20 (m, 3H, ArH),
a separating funnel. The organic layer was separated, dried
(Na2SO4) and concentrated to afford a residue, which was purified
by silica gel chromatography using hexane/EtOAc (60:40, v/v) as
eluent to afford 22 as off white solid.
8.10 (s, 1H, ArH), 8.02 (s, 1H, ArH), 7.92–7.71 (m, 4H, ArH), 2.59 (s,
3H, CH3), 2.55 (s, 3H, CH3). 13C (75 MHz, CDCl3):
d¼158.2, 157.9,
144.2, 142.1, 133.2, 132.1, 131.3, 130.7, 130.1, 129.1, 128.1, 124.3, 121.3,
117.5, 21.0, 20.7. Mass (ESþ) m/z 414.1 (Mþþ1). DART-HRMS Calcd
for C23H17BrN3: 414.06058, found 414.05659. Anal. Calcd for
4.7.1. 2-Tetrazol-1-yl-phenylamine (22)
C
23H16BrN3: C, 66.68; H, 3.89; N, 10.14. Found: C, 66.60; H, 3.66; N,
Yield 84%; off white solid; mp 98–99 ꢀC; Rf¼0.64 (2:3 EtOAc/
10.24.
hexane); IR nmax (KBr) 3440, 3355, 1602 cmꢂ1 1H NMR (300 MHz,
;
CDCl3):
d
¼8.98 (s, 1H, ArH), 7.37–7.19 (overlapped, 2H, ArH), 6.98–
6.85 (m, 2H, ArH), 4.45 (s, 2H, NH2). 13C (50.2 MHz, CDCl3):
4.5. Preparation of 1-(o-nitrophenyl)-5-mercapto-
tetrazole (20)
d
¼143.39, 141.86, 131.57, 125.33, 119.55, 118.32, 118.10. Mass (FAB)
m/z 162 (Mþþ1). Anal. Calcd for C7H7N5: C, 52.17; H, 4.38; N, 43.45.
Found: C, 52.27; H, 4.67; N, 43.67.
A
solution of o-nitro phenylisothiocyanate 19 (2.00 g,
11.11 mmol) in 5 mL of chloroform was placed in a round-bottom
flask equipped with a magnetic stirrer and reflux condenser. So-
dium azide (1.08 g, 16.55 mmol) dissolved in 10 mL of water was
added dropwise at rt to the reaction mixture. After the initial
exothermic reaction subsided, the stirred solution was heated to
reflux for 3 h. Then the solution was cooled and filtered. The
aqueous layer was separated and acidified with 10 mL of 37%
hydrochloric acid. The precipitate of crude yellow thiol containing
some o-nitrophenylcyanamide was separated by suction filtration,
washed with distilled water and air dried. The crude solid was
slurried with 20 mL of benzene and allowed to stand for 1–3
days. The mixture was filtered and the pure 1-(o-nitrophenyl)-5-
mercaptotetrazole 20 was washed with benzene and was air
dried.
4.8. General procedure for the Pictet–Spengler reaction on
substrate 22
A
mixture of 2-tetrazol-1-yl-phenylamine 22 (0.10 g,
0.62 mmol), p-tolylbenzaldehyde (74 L, 0.62 mmol) and p-tolyl-
m
sulphonic acid (12 mg, 0.064 mmol) was refluxed in toluene (5 mL)
for 12 h. Toluene was evaporated in vacuo and residue so obtained
was dissolved in ethyl acetate (50 mL). The organic layer was
washed with 5% aqueous sodium bicarbonate, water (2ꢁ10 mL) and
brine solution (1ꢁ10 mL). The organic layers were combined and
dried over anhydrous Na2SO4 and evaporated to obtain a residue.
The residue so obtained was purified by column chromatography
on silica gel with hexane/ethyl acetate (70:30, v/v) as eluent to
afford 23a as off white solid.
4.5.1. 1-(2-Nitro-phenyl)-1H-tetrazole-5-thiol (20)
Yield 75%; yellow solid; mp 118–120 ꢀC; IR nmax (KBr) 1607,1529,
4.8.1. 4-p-Tolyl-tetrazolo[1,5-a]quinoxaline (23a)
1348, 1292 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼8.25 (d, J¼8.0 Hz,
Yield 62%; off white solid; mp 170–172 ꢀC; Rf¼0.46 (3:7 EtOAc/
1H, ArH), 7.93–7.71 (m, 3H, ArH). 13C (50.2 MHz, CDCl3): 164.78,
144.75, 135.72, 132.94, 130.64, 126.56, 126.40. Mass (ESþ) m/z 224
(Mþþ1). Anal. Calcd for C7H5N5O2S: C, 37.67; H, 2.26; N, 31.38.
Found: C, 37.71; H, 2.31; N, 31.10.
hexane); IR nmax (KBr) 3042, 2928, 2849, 1620 cmꢂ1 1H NMR
;
(300 MHz, CDCl3):
d
¼8.85 (d, J¼8.1 Hz, 2H, ArH), 8.63 (dd, J¼8.1,
3.0 Hz, 1H, ArH), 8.31 (dd, J¼8.1, 1.8 Hz, 1H, ArH), 7.87–7.82 (m, 2H,
ArH), 7.44 (d, J¼8.1 Hz, 2H, ArH), 2.49 (s, 3H, CH3). 13C (50.2 MHz,
CDCl3):
d
¼148.15, 143.17, 142.41, 137.15, 131.70, 130.75, 130.61,
4.6. Oxidation of 1-(2-nitro-phenyl)-1H-tetrazole-5-thiol (20)
to 1-(2-nitro-phenyl)-1H-tetrazole (21)
130.15, 129.97, 129.81, 129.36, 123.98, 116.46, 22.02. Mass (FAB) m/z
262 (Mþþ1). Anal. Calcd for C15H11N5: C, 68.95; H, 4.24; N, 26.80.
Found: C, 68.88; H, 4.39; N, 26.98.
To a stirred solution of 1-(2-nitro-phenyl)-1H-tetrazole-5-thiol
20 (1.8 g, 8.07 mmol) in NH4OH (1 N, 10 mL) at 0 ꢀC was added
dropwise 30% H2O2 (7 mL) and stirring was continued for 4 h at
0 ꢀC. The solution was boiled for 10 min and cooled. The solid
product was collected by suction filtration, washed and dried to
give white crystals 21.
4.8.2. 4-(4-Bromo-phenyl)-tetrazolo[1,5-a]quinoxaline (23b)
Yield 68%; white solid; mp 181–182 ꢀC; Rf¼0.54 (3:7 EtOAc/
hexane); IR nmax (KBr) 3028, 1611 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
¼8.85 (d, J¼8.6 Hz, 2H, ArH), 8.64–8.61 (m,1H, ArH), 8.33–8.29 (m,
1H, ArH), 7.88–7.86 (m, 2H, ArH), 7.75 (d, J¼8.6 Hz, 2H, ArH). Mass
(FAB) m/z 326 (Mþþ1). Anal. Calcd for C14H8BrN5: C, 51.56; H, 2.47;
N, 21.47. Found: C, 51.45; H, 2.86; N, 21.68.
4.6.1. 1-(2-Nitro-phenyl)-1H-tetrazole (21)
Yield 82%; yellow solid; mp 65–66 ꢀC; Rf¼0.55 (1:9 EtOAc/hex-
ane); IR nmax (KBr) 1606, 1533, 1353 cmꢂ1 1H NMR (300 MHz,
;
4.8.3. 4-(4-Chloro-phenyl)-tetrazolo[1,5-a]quinoxaline (23c)
Yield 62%; white solid; mp 165–167 ꢀC; Rf¼0.62 (3:7 EtOAc/
CDCl3):
d
¼9.04 (s, 1H, ArH), 8.25 (dd, J¼8.0, 1.8 Hz, 1H, ArH), 7.96–
7.81 (m, 2H, ArH), 7.65 (dd, J¼7.6, 1.8 Hz, 1H, ArH). 13C (50.2 MHz,
hexane); IR nmax (KBr) 3031, 1608, 1593 cmꢂ1 1H NMR (300 MHz,
;
CDCl3):
d
¼144.38, 143.97, 135.16, 132.70, 129.15, 127.31, 126.64.
CDCl3):
d
¼8.95 (d, J¼8.4 Hz, 2H, ArH), 8.67–8.64 (m, 1H, ArH),
Mass (ESþ) m/z 192.3 (Mþþ1). Anal. Calcd for C7H5N5O2: C, 43.98;
8.36–8.32 (m, 2H, ArH), 7.91–7.87 (m, 2H, ArH), 7.44 (d, J¼8.4 Hz,
1H, ArH). Mass (ESþ) m/z 298.2 (Mþþ1). Anal. Calcd for
H, 2.64; N, 36.64. Found: C, 43.76; H, 2.73; N, 36.79.
C14H8ClN5: C, 59.69; H, 2.86; N, 24.86. Found: C, 59.78; H, 2.76; N,
4.7. Reduction of 1-(2-nitro-phenyl)-1H-tetrazole (21) to 2-
24.76.
tetrazol-1-yl-phenylamine (22)
4.8.4. 4-(2-Hydroxyphenyl)-tetrazolo[1,5-a]quinoxaline (23d)
Yield 47%; yellow solid; mp 230–231 ꢀC; Rf¼0.41 (3:7 EtOAc/
To the solution of compound 21 (1.4 g, 7.32 mmol) in ethanol
(20 mL) was added SnCl2$2H2O (4.95 g, 21.98 mmol) and the re-
action mixture was heated at reflux with stirring for 1.5 h under
nitrogen atmosphere. After this ethanol was evaporated and the
residue was made alkaline with saturated NaHCO3 (30 mL) and
then EtOAc (100 mL) was added. The suspension was passed
through a bed of Celite and the filtrate was partitioned in
hexane); IR nmax (KBr) 3404, 1605, 1595 cmꢂ1 1H NMR (300 MHz,
;
CDCl3):
d
¼9.68 (d, J¼7.6 Hz, 1H, ArH), 8.68–8.63 (m, 1H, ArH), 8.23–
8.18 (m, 1H, ArH), 7.90–7.85 (m, 2H, ArH), 7.53 (t, J¼7.2 Hz, 1H, ArH),
7.18–7.11 (overlapped, 3H, ArH). Mass (FAB) m/z 264 (Mþþ1). Anal.
Calcd for C14H9N5O: C, 63.87; H, 3.45; N, 26.60. Found: C, 63.58; H,
3.53; N, 26.87.

B. Saha et al. / Tetrahedron 64 (2008) 8676–8684
8683
4.9. General procedure for the preparation of 1-(2-nitro-
phenyl)-4-phenyl-1H-[1,2,3]triazole (26a)
(Mþþ1). Anal. Calcd for C15H14N4: C, 71.98; H, 5.64; N, 22.38. Found:
C, 71.88; H, 5.72; N, 22.61.
1-Fluoro-2-nitrobenzene 25a (2.0 mmol), phenylacetylene
(2.2 mmol), sodium azide (2.2 mmol) and NaHCO3 (2.2 mmol) were
suspended in water (10 mL) in a 50 mL round-bottom flask equip-
ped with a small magnetic stirring bar. To this was added copper
powder (100 mg) and ferric chloride (100 mg). The mixture was
then heated to reflux for 7 h. After cooling the reaction mixture,
EtOAc (50 mL) was added. The suspension was passed through
a bed of Celite and the filtrate was partitioned in a separating
funnel. The organic layer was separated, dried (Na2SO4) and con-
centrated to afford a residue, which was purified by silica gel
chromatography using hexane/EtOAc (70:30, v/v) as eluent to af-
ford 26a as yellow solid.
4.11. General procedure for the Pictet–Spengler reaction on
substrate 27
A mixture of 2-(4-phenyl-[1,2,3]triazol-1-yl)-phenylamine (27a)
(0.10 g, 0.42 mmol), p-tolylbenzaldehyde (46 mL, 0.42 mmol) and p-
tolylsulphonic acid (8 mg, 0.042 mmol) was refluxed in toluene for
12 h. Toluene was evaporated in vacuo and residue so obtained was
dissolved in ethyl acetate (50 mL). The organic layer was washed
with 5% aqueous sodium bicarbonate (30 mL), water (2ꢁ10 mL) and
brine solution (1ꢁ10 mL). The organic layers were combined and
dried over anhydrous Na2SO4 and evaporated to obtain a residue.
The residue so obtained was purified by column chromatography
on silica gel with hexane/ethyl acetate (70:30, v/v) as eluent to
afford 28a as a white solid.
4.9.1. 1-(2-Nitro-phenyl)-4-phenyl-1H-[1,2,3]triazole (26a)
Yield 65%; yellow solid; mp 144–145 ꢀC; Rf¼0.63 (3:7 EtOAc/
hexane); IR nmax (KBr) 1604, 1534, 1351 cmꢂ1 1H NMR (300 MHz,
;
CDCl3):
d
¼8.12 (dd, J¼7.9, 1.3 Hz, 1H, ArH), 8.09 (s, 1H, ArH), 7.94–
4.11.1. 3-Phenyl-4-p-tolyl-[1,2,3]triazolo[1,5-a]quinoxaline (28a)
Yield 67%; off white solid; mp 160–171 ꢀC; Rf¼0.39 (3:7 EtOAc/
hexane); IR nmax (KBr) 3038, 2938, 2852 cmꢂ1; 1H NMR (300 MHz,
7.91 (m, 2H, ArH), 7.84–7.81 (m, 1H, ArH), 7.76–7.70 (m, 2H, ArH),
7.51–7.46 (m, 2H, ArH), 7.43–7.40 (m,1H, ArH). Mass (ESþ) m/z 267.1
(Mþþ1). Anal. Calcd for C14H10N4O2: C, 63.15; H, 3.79; N, 21.04.
Found: C, 63.26; H, 3.57; N, 21.25.
CDCl3):
d
¼8.81 (d, J¼7.2 Hz, 1H, ArH), 8.24 (dd, J¼8.1, 1.8 Hz, 1H,
ArH), 7.81–7.77 (m, 2H, ArH), 7.37 (d, J¼8.1 Hz, 2H, ArH), 7.32–7.25
(overlapped, 3H, ArH), 7.25–7.17 (m, 2H, ArH), 7.03 (d, J¼7.90 Hz,
4.9.2. 1-(4-Methyl-2-nitrophenyl)-4-phenyl-1H-1,2,3-
triazole (26b)
2H, ArH), 2.36 (s, 3H, CH3). 13C (75 MHz, CDCl3):
d
¼152.76, 142.02,
139.05, 135.42, 132.13, 129.26, 128.76, 128.64, 126.96, 126.47, 123.97,
Yield 71%; yellow solid; mp 162–165 ꢀC; Rf¼0.77 (3:7 EtOAc/
121.41, 114.34, 20.06. Mass (FAB) m/z 337 (Mþþ1). Anal. Calcd for
hexane); IR nmax (KBr) 1604, 1529, 1356 cmꢂ1
;
1H NMR (300 MHz,
C22H16N4: C, 78.55; H, 4.79; N, 16.66. Found: C, 78.44; H, 4.53; N,
CDCl3):
d
¼8.036–8.03 (overlapped, 2H, ArH), 7.93–7.89 (m, 2H,
16.73.
ArH), 7.51–7.45 (m, 4H, ArH), 7.42–7.37 (m, 1H, ArH), 2.57 (s, 3H,
CH3). Mass (ESþ) m/z 281.1 (Mþþ1). Anal. Calcd for C15H12N4O2: C,
64.28; H, 4.32; N, 19.99. Found: C, 64.39; H, 4.53; N, 19.76.
4.11.2. 4-(4-Bromo-phenyl)-3-phenyl-[1,2,3]triazolo[1,5-a]-
quinoxaline (28b)
Yield 70%; off white solid; mp 184–186 ꢀC; Rf¼0.46 (3:7 EtOAc/
4.10. Reduction of 1-(2-nitro-phenyl)-4-phenyl-1H-
[1,2,3]triazole (26a) to 2-(4-phenyl-[1,2,3]triazol-1-yl)-
phenylamine (27a)
hexane); IR nmax (KBr) 3032, 1601 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
¼8.82 (dd, J¼7.6, 1.4 Hz, 1H, ArH), 8.25 (dd, J¼8.2, 1.8 Hz, 1H, ArH),
8.06 (d, J¼8.2 Hz, 1H, ArH), 7.94–7.91 (m, 2H, ArH), 7.85–7.79 (m,
2H, ArH), 7.36–7.23 (overlapped, 6H, ArH). 13C (75 MHz, CDCl3):
To the solution of compound 26a (1.2 g, 4.51 mmol) in ethanol
(10 mL) was added SnCl2$2H2O (3.05 g, 13.53 mmol) and the re-
action mixture was heated at reflux with stirring for 1.5 h under
nitrogen atmosphere. After this ethanol was evaporated and the
residue was made alkaline with saturated NaHCO3 (30 mL) and
then EtOAc (100 mL) was added. The suspension was passed
through a bed of Celite and the filtrate was partitioned in a sepa-
rating funnel. The organic layer was separated, dried (Na2SO4) and
concentrated to afford a residue, which was purified by silica gel
chromatography using hexane/EtOAc (80:20, v/v) as eluent to af-
ford 27a as brown oil.
d
¼151.45, 146, 40, 133.67, 130.52, 130.00, 129.37, 129.09, 128.86,
127.74, 127.69, 127.41, 126.73, 124.53, 124.02, 123.43, 122.86, 115.63.
Mass (FAB) m/z 401 (Mþþ1). Anal. Calcd for C21H13BrN4: C, 62.86; H,
3.27; N, 13.96. Found: C, 62.72; H, 3.32; N, 13.84.
4.11.3. 7-Methyl-3-phenyl-4-p-tolyl-[1,2,3]triazolo[1,5-a]-
quinoxaline (28c)
Yield 62%; off white solid; mp 220–221 ꢀC; Rf¼0.38 (3:7 EtOAc/
hexane); IR nmax (KBr) 3048, 2922, 2867, 1601, 1352 cmꢂ1; 1H NMR
(300 MHz, CDCl3):
d¼8.63 (d, J¼8.3 Hz, 1H, ArH), 8.12 (d, J¼8.3 Hz,
1H, ArH), 7.58 (dd, J¼8.3, 1.6 Hz, 1H, ArH), 7.35 (d, J¼8.1 Hz, 2H,
ArH), 7.30–7.26 (overlapped, 3H, ArH), 7.23–7.20 (m, 2H, ArH), 7.02
(d, J¼8.1 Hz, 2H, ArH), 2.69 (s, 3H, CH3), 2.35 (s, 3H, CH3). 13C
4.10.1. 2-(4-Phenyl-[1,2,3]triazol-1-yl)-phenylamine (27a)
Yield 82%; brown oil; Rf¼0.32 (1:4 EtOAc/hexane); IR nmax (neat)
(75 MHz, CDCl3):
d¼151.64, 142.43, 139.48, 138.86, 133.53, 132.19,
3322, 1631, 1530 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼8.06 (s, 1H,
129.29, 129.08, 128.74, 128.27, 128.06, 127.70, 127.45, 126.91, 123.69,
121.43, 114.03, 20.71, 20.09. Mass (ESþ) m/z 351 (Mþþ1). Anal. Calcd
for C23H18N4: C, 78.83; H, 5.18; N, 15.99. Found: C, 78.52; H, 5.37; N,
16.02.
ArH), 7.92 (d, J¼8.1 Hz, 2H, ArH), 7.50–7.45 (m, 2H, ArH), 7.41–7.38
(m, 1H, ArH), 7.29–7.24 (overlapped, 2H, ArH), 6.93–6.83 (m, 2H,
ArH), 4.60 (br s, 2H, NH2). Mass (ESþ) m/z 237.2 (Mþþ1). Anal. Calcd
for C14H12N4: C, 71.17; H, 5.12; N, 23.71. Found: C, 71.32; H, 5.18; N,
23.88.
4.11.4. 4-(4-Bromo-phenyl)-7-methyl-3-phenyl-[1,2,3]triazolo-
[1,5-a]quinoxaline (28d)
4.10.2. 5-Methyl-2-(4-phenyl-[1,2,3]triazol-1-yl)-
phenylamine (27b)
Yield 62%; white solid; mp 183–185 ꢀC; Rf¼0.52 (3:7 EtOAc/
hexane); IR nmax (KBr) 2926, 2872, 1595, 1351 cmꢂ1 1H NMR
;
Yield 84%; brown oil; Rf¼0.25 (1:4 EtOAc/hexane); IR nmax (neat)
(300 MHz, CDCl3):
7.61 (d, J¼8.4 Hz, 1H, ArH), 7.37–7.32 (overlapped, 4H, ArH), 7.28–
7.24 (m, 5H, ArH), 2.70 (s, 3H, CH3). 13C (75 MHz, CDCl3):
d
¼8.63 (s, 1H, ArH), 8.11 (d, J¼8.40 Hz, 1H, ArH),
3458, 3363, 1630, 1518 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
¼8.07 (s,
1H, ArH), 7.93 (d, J¼8.10 Hz, 2H, ArH), 7.51–7.46 (m, 2H, ArH), 7.42–
7.39 (m, 1H, ArH), 7.11–7.08 (overlapped, 2H, ArH), 6.83 (d, J¼8.1 Hz,
1H, ArH), 4.43 (br s, 2H, NH2), 2.33 (s, 3H, CH3). Mass (ESþ) m/z 251.1
d
¼150.29,
142.27, 140.05, 133.82, 133.41, 129.95, 129.35, 129.22, 128.72, 128.37,
127.31, 126.67, 123.78, 123.20, 121.18, 114.08, 20.72. Mass (ESþ) m/z

8684
B. Saha et al. / Tetrahedron 64 (2008) 8676–8684
415 (Mþ). Anal. Calcd for C22H15BrN4: C, 63.63; H, 3.64; N, 13.49.
Found: C, 63.81; H, 3.53; N, 13.50.
Sui, Z. Org. Lett. 2005, 7, 2043–2046; (g) Srinivasan, N.; Ganesan, A. Chem.
Commun. 2003, 916–917; (h) Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett.
2003, 44, 543–547; (i) Kane, T. R.; Ly, C. Q.; Kelly, D. E.; Dener, J. M. J. Comb.
Chem. 2004, 6, 564–572; (j) Zhou, H.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6, 249–
252; (k) Nielsen, T. E.; Meldal, M. J. Comb. Chem. 2005, 7, 599–610.
7. Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Wu, G. S.; Yamanaka, E.;
Hutchins, L.; DiePierro, M.; Cook, J. M. J. Org. Chem. 1979, 44, 535–545.
8. (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.;
Schenker, K. Tetrahedron 1963, 19, 247–257; (b) Jackson, A. H.; Smith, A. E.
Tetrahedron 1968, 24, 403–413; (c) Harrison, D. M. Tetrahedron Lett. 1981, 22,
2501–2504.
9. (a) Kundu, B.; Sawant, D.; Chhabra, R. J. Comb. Chem. 2005, 7, 317–321; (b)
Kundu, B.; Sawant, D.; Partani, P.; Kesarwani, A. P. J. Org. Chem. 2005, 70, 4889–
4892; (c) Duggineni, S.; Sawant, D.; Saha, B.; Kundu, B. Tetrahedron 2006, 62,
3228–3241; (d) Sharma, S.; Saha, B.; Sawant, D.; Kundu, B. J. Comb. Chem. 2007,
9, 783–792.
4.11.5. 4-(4-Chloro-phenyl)-3-phenyl-[1,2,3]triazolo[1,5-a]-
quinoxaline (28e)
Yield 61%; brown solid; mp 227–230 ꢀC; Rf¼0.50 (3:7 EtOAc/
hexane); IR nmax (KBr) 1597 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
¼8.80 (dd, J¼7.6, 1.9 Hz, 1H, ArH), 8.21 (dd, J¼7.5, 1.9 Hz, 1H, ArH),
7.90 (dd, J¼7.1, 1.7 Hz, 1H, ArH), 7.83–7.77 (m, 2H, ArH), 7.47–7.34
(m, 2H, ArH), 7.30–7.18 (m, 6H, ArH). 13C (75 MHz, CDCl3):
d¼151.38,
142.50, 135.22, 135.42, 133.19, 129.18, 129.10, 128.87, 128.74, 127.70,
127.42, 127.24, 126.73, 124.51, 123.98, 119.20, 115.60. Mass (FAB) m/z
357 (Mþþ1). Anal. Calcd for C21H13ClN4: C, 70.69; H, 3.67; N, 15.70.
Found: C, 70.44; H, 3.51; N, 15.73.
10. (a) Duncton, M. A. J.; Smith, L. M.; Burdzovic-Wizeman, S.; Burns, A.; Liu, H.;
Mao, Y.; Wong, W. C.; Kiselyov, A. S. J. Org. Chem. 2005, 70, 9629–9631; (b)
Zheng, L.; Xiang, J.; Daang, Q. D.; Bai, X. J. Comb. Chem. 2005, 7, 813–815; (c)
David, E.; Pellet-Rostaing, S.; Marc Lemaire, M. Tetrahedron 2007, 63, 8999–
9006; (d) Wang, X. L.; Zheng, X. F.; Liu, R. H.; Reiner, J.; Chang, J. B. Tetrahedron
2007, 63, 3389–3394.
Acknowledgements
11. (a) Katritzky, A. R. In Comprehensive Heterocyclic Chemistry; Katritzky, Rees,
Eds.; 1984; Vol. 5, pp 41–110; (b) Metzger, J. V. In Comprehensive Heterocyclic
Chemistry; Katritzky, Rees, Eds.; 1984; Vol. 6, pp 235–330.
B.S., S.S. and D.S. are thankful to CSIR, New Delhi for providing
fellowship.
12. Stokker, G. E. Tetrahedron Lett. 1996, 37, 5453–5456.
13. Zhang, L.; Meier, W.; Wats, E.; Costello, T. D.; Ma, P.; Ensinger, C. L.; Rodgers,
J. M.; Jacobson, I. C.; Rajagopalan, P. Tetrahedron Lett. 1995, 36, 8387–8390.
14. (a) Butler, R. N. In Comprehensive Heterocyclic Chemistry; Katritzky, Rees, Eds.;
1984; Vol. 5, pp 816–818; (b) Wahoff, H. In Comprehensive Heterocyclic Chem-
istry; Katritzky, Rees, Eds.; 1984; Vol. 5, pp 697–700.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.07.003.
15. (a) Sarges, R.; Howard, H. R.; Brown, R. C.; Label, L. A.; Seymour, P. A. J. Med.
Chem. 1990, 33, 2240–2254; (b) Bailly, C.; Echepare, S.; Gargo, F.; Raring, M. J.
Anti-Cancer Drug Des. 1999, 15, 219–222; (c) Sakata, G.; Makino, K.; Kurasawa, Y.
Heterocycles 1998, 27, 2481–2485; (d) Buckle, D. R.; Rockell, C. J. M. J. Chem. Soc.,
Perkin Trans. 1 1982, 627–630; (e) Buckle, D. R.; Outred, D. J.; Rockell, C. J. M.;
Smith, H.; Spicer, B. A. J. Med. Chem. 1983, 26, 251–254; (f) Buckle, D. R.; Outred,
D. J.; Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med. Chem. 1986, 29, 2262–2267;
(g) Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.; Emmert, D. E.;
Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.; Hutchinson, D. K.; Morris,
J.; Reischer, R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert,
D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953–970; (h) Alvarez, R.; Velazquez, S.;
San-Felix, A.; Aquaro, S.; De Clercq, E.; Perno, C. F.; Karlsson, A.; Balzarini, J.;
Camarasa, M. J. J. Med. Chem. 1994, 37, 4185–4194.
16. (a) Kauer, J. C.; Sheppard, W. A. J. Org. Chem. 1967, 32, 3580–3592; (b) LeBlanc,
B. W.; Jursic, B. S. Synth. Commun. 1998, 28, 3591–3593; (c) Markgraf, J. H.;
Sadighi, J. P. Heterocycles 1995, 40, 583–586.
17. (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, NY, 1984; (b) Bock, V. D.; Hiemstra, H.; Maarseveen, J. H. V. Eur. J. Org.
Chem. 2006, 51–68; (c) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 114, 2708–2711; (d) Chan, T. R.; Robert, H.;
Sharpless, K. B.; Fokin, V. V. Org. Lett. 2004, 6, 2653–2855; (e) Feldman, A. K.;
Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6, 3897–3899; (f) Prasad, A.; Wim, D.;
Fokin, V. V.; Eycken, E. V. Org. Lett. 2004, 6, 4223–4225.
18. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596–2599; (b) Tornoe, C. W.; Hristensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057–3064; (c) Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri,
M. R. J. Am. Chem. Soc. 2004, 126, 15366–15367; (d) Manetsch, R.; Krasinski, A.;
Radic, Z.; Raushel, J.; Taylor, P.; Sharpless, K. B.; Kolb, H. C. J. Am. Chem. Soc.
2004, 126, 12809–12818; (e) Zhou, Z.; Fahrni, C. J. J. Am. Chem. Soc. 2004, 126,
8862–8863; (f) Punna, S.; Kuzelka, J.; Wang, Q.; Finn, M. G. Angew. Chem., Int. Ed.
2005, 44, 2215–2220.
19. Saha, B.; Sharma, S.; Sawant, D.; Kundu, B. Synlett 2007, 1591–1594.
20. Nielsen, T. E.; Meldal, M. J. Org. Chem. 2004, 69, 3765–3773.
21. Lanter, J. C.; Sui, Z. Org. Lett. 2005, 7, 2043–2046.
22. (a) Ferna´ndez, D.; Ahaidar, A.; Danelo´ n, D.; Cironi, P.; Marfil, M.; Pe´rez, O.;
Cuevas, C.; Albericio, F.; Joule, J. A.; lvarez, M. A. Monatsh. Chem. 2004, 135,
615–627; (b) Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. Lett. 2002, 10,
2415–2434; (c) Balaban, A. T.; Oniciu, D. C.; Katritzky, A. R. Chem. Rev. 2004, 104,
2777–2812; (d) Chen, J. J.; Fang, H. Y.; Duh, C. Y.; Chen, I. S. Planta Med. 2005, 71,
470–475; (e) Nicolaou, K. C.; Baran, P. S.; Yong, Y. L.; Sugita, K. J. Am. Chem. Soc.
2002, 124, 2212–2220.
References and notes
1. Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030–2036.
2. (a) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761–793; (b) Allen, J. R.;
Holmstedt, B. R. Phytochemistry 1979, 19, 1573–1582; (c) Braestrup, C.; Nielsen,
M.; Olsen, C. E. Proc. Natl. Acad. Sci. U.S.A. 1980, 77, 2288–2292; (d) Schlecker,
W.; Huth, A.; Ottow, E.; Mulzer, J. Synthesis 1995, 1225–1227; (e) Molina, P.;
Fresneda, P. M. J. Chem. Soc., Perkin Trans. 1 1988, 1819–1822; (f) Molina, P.;
Fresneda, P. M.; Zafra, G. S.; Almendros, P. Tetrahedron Lett. 1994, 35, 8851–8854.
3. For reviews, see: (a) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311–
2352; (b) Nielsen, T. E.; Diness, F.; Meldal, M. Curr. Opin. Drug Discovery Dev.
2003, 6, 801–814; (c) Cox, E. D.; Cook, J. Chem. Rev. 1995, 95, 1797–1842; (d)
Larghi, E. L.; Amongero, M.; Bracca, A. B. J.; Kauffman, T. S. Arkivoc 2005, xii,
98–153.
4. Czarnocki, Z.; MacLean, D. B.; Szarek, W. A. Can. J. Chem. 1986, 64, 2205–2210;
(b) Czarnocki, Z.; Suh, D.; MacLean, D. B.; Hultin, P. G.; Szarek, W. A. Can. J.
Chem. 1992, 70, 1555–1561; (c) Czarnocki, Z.; Mieckzkowsi, J. B.; Kiegiel, J.;
´
Arazny, Z. Tetrahedron: Asymmetry 1995, 6, 2899–2902; (d) Czarnocki, Z.;
Araz´ny, Z. Heterocycles 1999, 51, 2871–2879; (e) Rozwadowska, M. D. Hetero-
cycles 1994, 39, 903–931; (f) Singh, K.; Deb, P. K.; Venugopalan, P. Tetrahedron
2001, 57, 7939–7949.
5. (a) Sandrin, J.; Soerens, D.; Mokry, P.; Cook, J. M. Heterocycles 1977, 6, 1133–
1139; (b) Dai, W. M.; Zhu, H. J.; Hao, X. J. Tetrahedron Lett. 1996, 37, 5971–5974;
(c) Czerwinski, K. M.; Deng, L.; Cook, J. M. Tetrahedron Lett. 1994, 33, 4721–4724;
(d) Zhang, L. H.; Bi, Y. Z.; Yu, F. X.; Menzia, G.; Cook, J. M. Heterocycles 1992, 34,
517–547; (e) Ungemach, F.; DiPierro, M.; Weber, R.; Cook, J. M. J. Org. Chem.
1981, 46, 164–168; (f) Jawdosiuk, M.; Cook, J. M. J. Org. Chem. 1984, 49, 2699–
2701; (g) Bonnet, D.; Ganesan, A. J. Comb. Chem. 2002, 4, 546–548; (h) Wang,
H.; Ganesan, A. Org. Lett. 1999, 1, 1647–1649; (i) Zawadzka, A.; Leniewski, A.;
Maurin, J. K.; Wojtasiewicz, K.; Czarnocki, Z. Org. Lett. 2001, 3, 997–999; (j)
Gremmen, C.; Wanner, M. J.; Koommen, G. J. Tetrahedron Lett. 2001, 42, 8885–
8888; (k) Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. Org. Lett.
2000, 2, 1955–1958.
6. (a) Hegedus, A.; Hell, Z. Tetrahedron Lett. 2004, 45, 8553–8555; (b) Yen, Y.-H.;
Chu, Y.-H. Tetrahedron Lett. 2004, 45, 8137–8140; (c) Bianchi, D. A.; Rua, F.;
Kaufman, T. S. Tetrahedron Lett. 2004, 45, 411–415; (d) Taylor, M. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 10558–10559; (e) Gonzalez, J. F.; Cuesta, E.;
Avendano, C. Tetrahedron 2004, 60, 6319–6326; (f) Zhang, X.; Li, X.; Lanter, J. C.;