Synthesis of pyrazole-fused polycyclic systems via intramolecular 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.1016/j.tet.2013.03.099

Synthesis of a variety of pyrazole-fused systems starting from 4-iodopyrazolecarbaldehydes is described. The general strategy involves Suzuki coupling of 2-formyl aryl boronic acid with the 4-iodopyrazole derivatives generated from either Morita-Baylis-Hillman, Horner-Wadsworth-Emmons or Knoevenagel reactions followed by 1,3-dipolar cycloaddition reaction either by azomethine ylide or nitrile oxide. Interestingly, the cycloaddition reaction in substrates generated through Morita-Baylis-Hillman and Knoevenagel chemistries were diastereoselective for syn isomer. In contrast, the substrates prepared from Horner-Wadsworth-Emmons chemistry upon cycloaddition reactions afforded a mixture of syn and anti isomers in varying ratios.

Full text of DOI:10.1016/j.tet.2013.03.099

Tetrahedron 69 (2013) 5029e5043
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Synthesis of pyrazole-fused polycyclic systems via intramolecular
1,3-dipolar cycloaddition reactionsq,qq
,
Maloy Nayak a, Neeraj Rastogi b, Sanjay Batra a
*
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, PO Box 173, Lucknow 226 001, India
b Centre of Biomedical Magnetic Resonance, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow 226 014, UP,
India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of a variety of pyrazole-fused systems starting from 4-iodopyrazolecarbaldehydes is described.
The general strategy involves Suzuki coupling of 2-formyl aryl boronic acid with the 4-iodopyrazole
derivatives generated from either MoritaeBayliseHillman, HornereWadswortheEmmons or Knoeve-
nagel reactions followed by 1,3-dipolar cycloaddition reaction either by azomethine ylide or nitrile oxide.
Interestingly, the cycloaddition reaction in substrates generated through MoritaeBayliseHillman and
Knoevenagel chemistries were diastereoselective for syn isomer. In contrast, the substrates prepared
from HornereWadswortheEmmons chemistry upon cycloaddition reactions afforded a mixture of syn
and anti isomers in varying ratios.
Received 16 October 2012
Received in revised form 5 March 2013
Accepted 18 March 2013
Available online 1 April 2013
Keywords:
Pyrazole
MoritaeBayliseHillman
HornereWordswortheEmmons
Knoevenagel
Ó 2013 Elsevier Ltd. All rights reserved.
Cycloaddition
1. Introduction
As a consequence, there has been continued interest to develop
methodologies for the synthesis of a variety of pyrazole-based com-
Generation of complexity from readily available simple starting
materials has been the mainstay of chemical research. In particular,
of significant interest to any medicinal chemistry program is the
synthesis of a chemical library incorporating sufficient diversity
from readily available substrates via straightforward approaches. In
this context, the intramolecular 1,3-dipolar cycloaddition reactions
either through azomethine ylide or via nitrile oxide are considered
to be convenient approaches for the construction of structurally
complex, fused, heterocyclic ring systems with simultaneous gen-
eration of several stereogenic centers.1 The popularity of these
strategies have grown manifold since they lead to polycyclic
nitrogen-containing compounds, which are represented in various
alkaloids and pharmacologically active compounds in a highly
regio- and stereocontrolled way.
pounds.4 In this context, halogenated pyrazoles are considered to be
of great importance as they provide opportunity for a variety of
transition-metal based coupling reactions, which either leads to new
fused-pyrazoles or provide a viable intermediate for further com-
plexity generating reactions.4a In a project aiming at development of
protocols for the preparation of pyrazole-fused architectures we have
successfully accomplished the synthesis of pyrazolo[4,3-b]pyridin-5-
ones,5 pyrazolo[4,3-b]pyridines,6 pyrazolo-fused benzodiazepines
and benzoxazoazepines,7 pyrazolo[4,3-d]pyrimidines and pyrazolo
[4,3-d]pyrimidin-7(6H)-ones,8 fused-pyrazoloazepines,9 and pyrro-
lopyrazoles10 using either copper-mediated cross coupling reactions
or Pd-catalyzed heteroarylation of the heteroarene CeH bonds.
Continuing with our exploratory studies to unfold the synthetic po-
tential of 4-iodopyrazolecarbaldehydes we have developed a set of
new polycyclic fused-pyrazoles, which may be employed for the bi-
ological screening. We envisaged that the derivatives prepared from
the MoritaeBayliseHillman (MBH), HornereWadswortheEmmons
(HWE), and Knoevenagel chemistries of 4-iodopyrazolecar-
baldehydes upon Suzuki coupling with 2-formyl phenyl boronic
acid would result into substrates amenable for intramolecular cy-
cloaddition either through azomethine ylide or nitrile oxide forma-
tion.11 Working toward these goals we observed that the key
intramolecular cycloadditions, which employ azomethine ylides de-
Pyrazole-derivatives are important from the viewpoint of their
pharmacological properties. They have been known to display anti-
anxiety, antipyretic, analgesic, PDE-4, antimicrobial, and anti-
inflammatory activities.2 They are also employed as agrochemicals.3
q
CDRI Communication no. 8429.
This work was presented at INDIGO Conference held at Mahabalipuram,
qq
Chennai between 12 and 16 February 2012.
* Corresponding author. Tel.: þ91 522 2612411 18x4234, 4368; fax: þ91 522
rived from MBH derivatives and secondary a-amino esters resulted in
2623405; e-mail addresses: batra_san@yahoo.co.uk, s_batra@cdri.res.in (S. Batra).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.099

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M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
diastereoselective preparation of polycyclic pyrazoles. In contrast
similar cycloadditions, which employ the azomethine ylides derived
from HWE derivatives and secondary
a-amino esters afforded
a mixture of syn and anti diastereomers in varying ratios. The details
of results of these studies are being presented herein.
2. Results and discussion
2.1. Studies for synthesis of fused pyrazoles employing the
MBH-derivatives
The first stage of this study concerns with use of the MBH de-
rivatives for the desired cycloaddition reactions. The required MBH
derivatives 2aede3aec were prepared from 1aed following the
reported procedure.5 The Suzuki coupling of 2aede3aec with 2-
formyl phenyl boronic acid in the presence of tetrakis(-
triphenylphosphine)palladium (0) proceeded smoothly to give the
formyl derivatives 4aede5aec in good yields (Scheme 1). With
4aede5aec in hand, the attention was directed toward con-
structing the polycyclic pyrazoles via intramolecular cycloaddition
of azomethine ylide. The investigation for identifying the optimized
conditions with respect to solvent and temperature for trans-
formation of 4e6 was initiated by reacting 4a with sarcosine. It was
satisfying to note that the reaction of 4a with sarcosine in toluene
under heating at reflux for 2 h was clean and yielded a product,
which was readily isolated in pure form by filtering through a small
column containing silica gel. Based on the spectral analysis, the
structure of the product was established to be 6a. The reaction was
found to be diastereoselective for syn stereochemistry at the ring
junction in 6a as ascertained by result of the X-ray diffraction
analysis (Fig. 1).12 This observation is in line with earlier reports
wherein the 1,3-dipolar cycloadditions in MBH derivatives have
been disclosed to afford the syn-product exclusively.11c,e,f,g
With optimized conditions in hand, the scope of reaction was
evaluated by treating 4aede5aec with sarcosine and proline. It
was a delight to note that all reactions were diastereoselective to
afford only the syn product of the respective pyrazoloindazole
derivatives (6aede7aec, 8aede9aec) in good yields.
Encouraged by the success of the strategy we decided to ex-
amine the protocol for the intramolecular 1,3-dipolar cycloaddition
via formation of nitrile oxide using 4aede5aec as the starting
materials. Accordingly, compounds 4aede5aec were treated with
hydroxylamine hydrochloride in ethanol at room temperature to
afford the corresponding oximes in 30 min, which without any
purification were treated with hypochlorite solution in the pres-
ence of Et3N for 16e18 h resulting into the formation of a new 2-
isoxazoline systems 10aede11aec in good yields.
Further, to probe the generality of the protocol with heteroaryl
aldehyde in place of benzaldehyde, Suzuki reaction of 2a with
2-formyl-3-thiopheneboronic acid was carried out to generate 12.
Similar to the earlier results, 1,3-dipolar cycloaddition reactions of
12 with sarcosine and proline afforded the fused-pyrazoles 13 and
14, respectively, as syn-isomer exclusively whereas the reaction
with nitrile oxide gave the isoxazoline 15 (Scheme 2).
Scheme 1. Reagent and conditions: (i) (a) methyl acrylate or acrylonitrile, DABCO,
neat, rt, 24e48 h. (b) AcCl, pyridine, 3 h, rt. (c) DABCO, NaBH4, THF/H2O, rt, 1 h; (ii) 2-
formyl phenyl boronic acid (1.1 equiv), Pd(PPh3)4 (0.05 equiv), Na2CO3 (3 equiv), DMF,
90 ꢀC, 3 h; (iii) sarcosine (1.5 equiv), PhMe, 110 ꢀC, 2 h; (iv) L-proline (1.5 equiv), PhMe,
110 ꢀC, 1.5 h; (v) (a) NH2OH∙HCl (1.2 equiv), NaOAc (1.2 equiv), EtOH, rt, 30 min; (b)
NaOCl (2 equiv), Et3N (1.5 equiv), CH2Cl2, rt, 14 h.
2.2. Studies for synthesis of fused pyrazoles employing the
HWE-derivatives
In the next stage of the study we turned our attention to another
set of substrates, which could be obtained from HWE chemistry of
substituted 4-iodo-3-pyrazolecarbaldehydes. Essentially in the first
step, aldehydes 1a,b,e,f were treated with triethylphosphonoace-
tate to afford the corresponding HWE-products 16.1a,b,e,f, 16.2a,e
(Scheme 3). The Suzuki-coupling of these substrates (16.1a,b,e,f,
16.2a,e) with 2-formyl phenyl boronic acid in the presence of Pd(0)
yielded the respective coupling products 17.1a,b,e,f, 17.2a,e in good
Fig. 1. Ortep diagram for 6a at 35% probability level.

M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
5031
Scheme 2. Reagent and conditions: (i) (a) acrylonitrile, DABCO, neat, rt, 24 h. (b) AcCl,
pyridine, 3 h, rt. (c) DABCO, NaBH4, THF/H2O, rt, 1 h; (ii) 2-formyl 3-thiopheneboronic
acid (1.1 equiv), Pd(PPh3)4 (0.05 equiv), Na2CO3 (3 equiv), DMF, 90 ꢀC, 3 h; (iii) sar-
cosine (1.5 equiv), PhMe, 110 ꢀC, 2 h; (iv) L-proline (1.5 equiv), PhMe, 110 ꢀC, 1.5 h; (v)
(a) NH2OH∙HCl (1.2 equiv), NaOAc (1.2 equiv), EtOH, rt, 30 min; (b) NaOCl (2 equiv),
Et3N (1.5 equiv), CH2Cl2, rt, 14 h.
yields. With starting material for the envisaged cycloaddition re-
action in hand we proceed to optimize the protocol employing
17.1a and sarcosine as the model substrate. Like the reaction with
MBH derivatives, it was found that condensation of 17.1a with
sarcosine was successful in refluxing toluene. However unlike the
MBH derivatives, 17.1a afforded a mixture of two products, which
were readily separated via column chromatography. Spectroscopic
characterization of the separated products indicated them to be
a mixture of relative stereoisomers. Based on the coupling con-
stants of the ring-junction protons the major product (91%) was
identified to be syn-18.1a whereas the minor product (9%), which
was relatively polar was identified as anti-18.1a. In order to test the
generality of the protocol compounds 17.1b,e,f, 17.2a,e were sub-
jected to similar reaction with sarcosine. Gratifyingly all reactions
furnished a mixture of two products, which were readily separated
via column chromatography. In each case the major products were
identified as syn-18.1b,e,f, 18.2a,e while the minor products were
the anti-18.1b,e, 18.2a,e. Essentially to unambiguously assign the
relative stereochemistry of the products detailed NMR experiments
with 18.1e were carried out (Fig. 2) (see Supplementary data).
These results implied that the 1,3-dipolar cycloaddition reactions of
these substrates with sarcosine were regio- and diastereoselective
in nature and in all cases the syn diastereoisomer is formed in
major amount. Such diastereoselectivity in favor of syn-isomer
during the intramolecular cycloaddition reaction can be explained
on the basis of preferential formation of E-ylide as compared to Z-
ylide as reported recently by Ghandi et al. (Fig. 3).13
Scheme 3. Reagents and conditions: (i) (EtO)3P(O)CH2CO2Et (1.2 equiv), NaH (3 equiv),
THF, 0 ꢀCert, 6 h; (ii) 2-formyl phenyl boronic acid (1.1 equiv), Pd(PPh3)4 (0.05 equiv),
Na2CO3 (3 equiv), DMF, 90 ꢀC, 3 h; (iii) sarcosine (1.5 equiv), PhMe, 110 ꢀC, 2 h; (iv) L-
Proline (1.5 equiv), PhMe, 110 ꢀC, 1.5 h; (v) (a) NH2OH∙HCl (1.2 equiv), NaOAc (1.2 equiv),
EtOH, rt, 30 min; (b) NaOCl (2 equiv), Et3N (1.5 equiv), CH2Cl2, rt, 14e16 h.
In the next stage the cycloaddition reactions of 17.1a,b,e,f,
17.2a,e with
17.1a,b,e,f, 17.2a,e were treated with
Unlike reactions of sarcosine, reactions of
L
-proline were investigated. Accordingly, compounds
-proline in refluxing toluene.
-proline, in each case,
L
L
yielded a mixture of diastereoisomeric products (syn-19.1a,b,e,f,
19.2a,e and anti-19.1a,b,e,f, 19.2a,e) in excellent yields but
in w45:55 diastereoisomeric ratio in favor of anti. A detailed NMR
experiments with syn-19.1b and anti-19.1b confirmed the assigned
stereochemistry (Figs. 4 and 5). Finally the stereochemistry was
unambiguously assigned on the basis of result of the X-ray dif-
fraction analysis for syn-19.2a (Fig. 6).14 The stereochemical out-
come for the intramolecular dipolar cycloaddition reaction of
proline can be attributed to the preferential formation of W-shaped
intermediate over S-shaped intermediate (Fig. 7).13
Fig. 2. NOE correlations in syn-18.1e.
formation. As a consequence 17.1a,b,e,f, 17.2a,e were treated with
hydroxylamine hydrochloride in ethanol at room temperature for
30 min to yield the respective oximes, which without any purifi-
cation were immediately treated with hypochlorite solution for
Subsequently 17.1a,b,e,f, 17.2a,e were also investigated for
intramolecular 1,3-dipolar cycloaddition via nitrile oxide

5032
M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
Fig. 7. Transition state model to explain the formation of anti- and syn-isomers of 19.1.
Fig. 3. Transition state model to explain diastereoselectivity during the formation
of 18.1.
Fig. 4. NOE relations in syn-19.1b.
Fig. 5. NOE relations in anti-19.1b.
Scheme 4. Reagents and conditions: (i) (EtO)3P(O)CH2CO2Et (1.2 equiv), NaH (3 equiv),
THF, 0 ꢀCert, 6 h; (ii) 2-formyl phenyl boronic acid (1.1 equiv), Pd(PPh3)4 (0.05 equiv),
Na2CO3 (3 equiv), DMF, 90 ꢀC, 3 h; (iii) sarcosine (1.5 equiv), PhMe, 110 ꢀC, 2 h; (iv) L-
proline (1.5 equiv), PhMe, 110 ꢀC, 1.5 h; (v) (a) NH2OH∙HCl (1.2 equiv), NaOAc
(1.2 equiv), EtOH, rt, 30 min; (b) NaOCl (2 equiv), Et3N (1.5 equiv), CH2Cl2, rt, 16e18 h.
23a,b with -proline yielded 25a,b, respectively, in excellent yields
L
as a mixture of syn and anti isomers. As observed earlier, here too
the diastereomers were formed in w45:55 ratio in favor of anti
isomer. Similar to earlier results, reactions of 23a,b with hydrox-
ylamine hydrochloride in the presence of sodium acetate gave the
corresponding oximes, which were immediately treated with hy-
pochlorite and Et3N in CH2Cl2 to furnish the expected fused-
isoxazole derivatives 26a,b in good yields.
Fig. 6. Ortep diagram for syn-19.2a at 35% probability level.
16e18 h to furnish the isoxazole derivatives 20.1a,b,e,f, 20.2a,e,
respectively.
The scope of the protocol for accessing fused-pyrazoles was also
studied with the regioisomeric pyrazole derivatives 23a,b, which
were prepared smoothly via the Suzuki coupling of 2-formyl phenyl
boronic acid with 4-iodopyrazole derivatives 22a,b (Scheme 4).
Treating 23a,b with sarcosine gave the expected benzo[e]pyrrolo
[2,3-g]indazole derivatives 24a,b in excellent yields in a diaster-
eoselective fashion in favor of syn. On the other hand reactions of
2.3. Studies for synthesis of fused pyrazoles employing
Knoevenagel derivatives
Finally to illustrate more application of the strategy, the formyl
substrate prepared from the Knoevenagel product 27 of 1a was
investigated. In a representative example Knoevenagel reaction of

M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
5033
1a with acetyl acetone was performed to generate 27, which was
subjected to Suzuki coupling as described earlier to obtain 28.
Heating 28 with sarcosine in toluene at reflux temperature resulted
into the required product 29 as syn isomer in 85% yields exclusively
(Scheme 5).
and Pd(PPh3)4 (0.09 mmol, 10 mg) were added to the reaction mix-
ture under nitrogen atmosphere. The reaction mixture was stirred at
90 ꢀC for 3 h. After completion, the reaction mass was diluted with
water (50 mL) and extracted with EtOAc (3ꢁ25 mL). The organic
layers were pooled, washed with brine dried over Na2SO4, and
concentrated under reduced pressure to furnish a residue. Column
chromatography of the residue over silica gel (hexanes/EtOAc, 85:15,
v/v) afforded pure 4a as a white solid (69%, 496 mg).
4.2.1. 2-((4-(2-Formylphenyl)-1,5-diphenyl-1H-pyrazol-3-yl)methyl)
acrylonitrile (4a). [found: C, 80.00; H, 4.70; N, 11.02. C26H19N3O
(Exact mass: 389.1528) requires C, 80.18; H, 4.92; N, 10.79%]. Mp
130e132 ꢀC; Rf (hexanes/EtOAc, 80:20, v/v) 0.28; nmax (KBr) 1693
(CHO), 2226 (CN) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
¼3.62 (q, 2H,
J¼15.3 Hz, CH2), 5.68 (s, 1H, ]CH), 5.84 (s, 1H, ]CH), 6.93 (d, 2H,
J¼7.0 Hz, ArH), 7.13e7.21 (m, 3H, ArH), 7.31e7.36 (m, 6H, ArH), 7.46
(t, 1H, J¼7.3 Hz, ArH), 7.61 (t, 1H, J¼7.4 Hz, ArH), 7.89 (d, 1H,
J¼7.6 Hz, ArH), 9.87 (s, 1H, CHO); 13C NMR (50 MHz, CDCl3):
¼32.2,
d
111.7, 118.4, 120.3, 125.2, 127.8, 128.2, 128.6, 128.6, 128.8, 128.84,
129.1, 130.0, 132.1, 132.6, 134.2, 134.6, 135.8, 139.6, 142.4, 146.5,
191.4; mass (ESþ) m/z¼390.3 (Mþþ1).
Scheme 5. Reagents and conditions: (i) acetylacetone (1.2 equiv), piperidine (1 equiv),
THF, rt, 5 h; (ii) 2-formyl phenyl boronic acid (1.1 equiv), Pd(PPh3)4 (0.05 equiv),
Na2CO3 (3 equiv), DMF, 90 ꢀC, 3 h; (iii) sarcosine (1.5 equiv), PhMe, 110 ꢀC, 3 h.
4.2.2. 2-{[5-(4-Chlorophenyl)-4-(2-formylphenyl)-1-phenyl-1H-pyr-
azol-3-yl]methyl}prop-2-enenitrile (4b). Yield 75% as colorless oil
(356 mg from 500 mg); [found: C, 73.89; H, 4.43; N, 9.70.
C26H18ClN3O (Exact mass: 423.1138) requires C, 73.67; H, 4.28; N,
9.91%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.29; nmax (Neat) 1695 (CHO),
3. Conclusions
In summary we have disclosed a facile protocol for the synthesis
of a variety of pyrazole-fused polycyclic systems from halogenated
pyrazoles via cycloaddition chemistry. It was observed that the
cycloaddition reaction in the derivatives produced from the MBH or
Knoevenagel chemistries are highly diastereoselective to afford
only the syn-isomer. Unlike, reactions of the substrates generated
from the HWE chemistry gave products as a mixture of di-
astereomers the ratio of which was influenced by the nature of the
reactants. Although we have demonstrated the application of the
methodology with substrates derived from MBH, HWE, and
Knoevenagel reactions, it is assumed that it should successful with
many more substrates, which may carry double bond in the side
chain in pyrazole nucleus.
2225 (CN) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼3.60 (q, 2H,
J¼16.0 Hz, CH2), 5.68 (s, 1H, ]CH), 5.84 (s, 1H, ]CH), 6.85 (d, 2H,
J¼8.5 Hz, ArH), 7.13 (d, 2H, J¼8.5 Hz, ArH), 7.28e7.38 (m, 6H, ArH),
7.49 (t, 1H, J¼7.5 Hz, ArH), 7.62 (dt, 1H, J1¼1.3 Hz, J2¼7.5 Hz, ArH),
7.91 (dd, 1H, J1¼0.9 Hz, J2¼7.7 Hz, ArH), 9.87 (s, 1H, CHO); 13C NMR
(50 MHz, CDCl3):
d
¼32.2, 118.0, 118.3, 120.3, 125.3, 127.4, 128.1,
128.6, 128.8, 129.1, 129.3, 131.2, 132.1, 132.6, 134.3, 134.7, 135.0,
135.3, 139.4, 141.2, 146.7, 191.2; mass (ESþ) m/z¼424.4 (Mþþ1).
4.2.3. 2-{[4-(2-Formylphenyl)-1-methyl-1H-pyrazol-3-yl]methyl}
prop-2-enenitrile (4c). Yield 73% as colorless oil (336 mg from
500 mg); [found: C, 71.62; H, 5.38; N,16.68. C15H13N3O (Exact mass:
251.1059) requires C, 71.70; H, 5.21; N, 16.72%]; Rf (hexanes/EtOAc,
70:30, v/v) 0.18; nmax (Neat) 1690 (CHO), 2231 (CN) cmꢂ1; 1H NMR
4. Experimental section
4.1. General
(300 MHz, CDCl3):
d
¼3.52 (s, 2H, CH2), 3.97 (s, 3H, NCH3), 5.64 (s,
1H, ]CH), 5.82 (s, 1H, ]CH), 7.34 (d, 1H, J¼7.6 Hz, ArH), 7.40 (s, 1H,
ArH), 7.49 (t, 1H, J¼7.5 Hz, ArH), 7.62 (dt, 1H, J1¼1.4 Hz, J2¼7.5 Hz,
ArH), 7.99 (dd, 1H, J1¼1.0 Hz, J2¼7.8 Hz, ArH); 13C NMR (50 MHz,
General Melting points are uncorrected and were determined in
capillary tubes on a Precision melting point apparatus containing
silicon oil. IR spectra were recorded using a Perkin Elmer’s RX I FTIR
spectrophotometer. 1H NMR and 13C NMR spectra were recorded
either on a Bruker DPX-200 or Bruker Avance DRX-300 MHz FT or
Bruker 400 MHz spectrometers or Bruker 800 MHz spectrometers,
CDCl3):
d
¼31.9, 39.4, 117.5, 120.8, 128.1, 128.3, 131.7, 131.9, 134.1,
145.2, 192.2; mass (ESþ) m/z¼252.1 (Mþþ1).
4.2.4. 2-((4-(2-Formylphenyl)-1-(4-methoxyphenyl)-5-phenyl-1H-
pyrazol-3-yl)methyl)acrylonitrile (4d). Yield 82% as yellow oil
(522 mg from 670 mg); [found: C, 77.42; H, 5.22; N, 9.93. C27H21N3O
(Exact mass: 419.1634) requires C, 77.31; H, 5.05; N, 10.02.]; Rf
(hexanes/EtOAc, 80:20, v/v) 0.28; nmax (Neat) 1691 (CHO), 2227 (CN)
using TMS as an internal standard (chemical shifts in d). The ESMS
were recorded on MICROMASS Quadro-II LCMS system. The HRMS
spectra were recorded either as ESI-HRMS on Agilent 6520 Q-TOF,
LCeMS/MS mass spectrometer or as DART-HRMS (recorded as ESþ)
on a JEOL-AccuTOF JMS-T100LC mass spectrometer having DART
(Direct Analysis in Real Time) source. The stereochemistry shown in
the structures corresponds to the relative stereochemistry only.
One of the compounds anti-18.1b could be isolated in very low yield
and hence data corresponding to it is not included.
cmꢂ1; 1H NMR(400 MHz, CDCl3):
d
¼3.61 (q, 2H, J¼19.2 Hz, CH2), 3.80
(s, 3H, CH3), 5.68 (s, 1H, ]CH), 5.83 (s, 1H, ]CH), 6.81e6.85 (m, 2H,
ArH), 6.90e6.92 (m, 2H, ArH), 7.13e7.23 (m, 5H, ArH), 7.35 (d, 1H,
J¼7.6 Hz, ArH), 7.46 (t,1H, J¼7.1 Hz, ArH), 7.59e7.62 (m,1H, ArH), 7.89
(d, 1H, J¼7.7 Hz, ArH), 9.86 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
d
¼32.2, 55.6,114.3,120.5,126.7,128.1,128.5,128.7,128.9,130.0,130.1,
132.0, 132.6, 132.8, 134.2, 134.6, 136.0, 142.4, 146.1, 159.1, 191.5; mass
4.2. General procedure for the synthesis of compounds 4aed,
5aec, 12, 17.1a,b,e,f, 17.2a,e, 23a,b, and 28 as exemplified 4a
(ESþ) m/z¼419.4 (Mþþ1).
4.2.5. Methyl 2-{[4-(2-formylphenyl)-1,5-diphenyl-1H-pyrazol-3-yl]
methyl}prop-2-enoate (5a). Yield 72% as colorless oil (342 mg from
500 mg); [found: C, 76.99; H, 5.00; N, 6.84. C27H22N2O3 (Exact mass:
422.1630) requires C, 76.76; H, 5.25; N, 6.63%]; Rf (hexanes/EtOAc,
A solution of compound 2a (1.85 mmol, 760 mg) and Na2CO3
(5.55 mmol, 2 M) in DMF (10 mL) was degassed with nitrogen for
15 min. Thereafter 2-formyl phenylboronic acid (2.04 mmol, 280 mg)

5034
M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
80:20, v/v) 0.29; nmax (KBr) 1637 (CHO), 1692 (CO2Me) cmꢂ1
NMR (300 MHz, CDCl3):
;
1H
4.44; N, 6.37. C27H21ClN2O3 (Exact mass: 456.1241) requires C, 70.97;
H, 4.63; N, 6.13%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.31; nmax (KBr)
d
¼3.62e3.69 (m, 5H, CO2Me & CH2), 5.57 (d,
1H, J¼1.2 Hz, ]CH), 6.21 (d, 1H, J¼0.8 Hz, ]CH), 6.91 (dd, 2H,
J1¼1.1 Hz, J2¼7.8 Hz, ArH), 7.10e7.22 (m, 3H, ArH), 7.27e7.37 (m, 5H,
ArH), 7.42 (t, 1H, J¼7.5 Hz, ArH), 7.58 (dt, 1H, J1¼1.4 Hz, J2¼7.5 Hz,
1648 (CHO), 1700 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d¼1.27
(t, 3H, J¼7.1 Hz, CH3), 4.19 (q, 2H, J¼7.1 Hz, OCH2), 6.46 (d, 1H,
J¼16.1 Hz, CH), 6.84 (d, 2H, J¼8.5 Hz, ArH), 7.13 (d, 2H, J¼8.5 Hz, ArH),
7.29e7.34 (m, 6H, ArH), 7.47e7.54 (m, 2H, ArH & ]CH), 7.61e7.67 (m,
1H, ArH), 7.94 (d, 1H, J¼7.7 Hz, ArH), 9.86 (s, 1H, CHO); 13C NMR
ArH), 7.86 (dd, 1H, J1¼1.0 Hz, J2¼7.7 Hz, ArH), 9.83 (s, 1H, CHO); 13
C
NMR (50 MHz, CDCl3):
d
¼29.3, 52.1, 117.6, 125.2, 127.0, 127.5, 127.7,
128.2,128.6,128.6,128.7,129.0,129.2,130.1,132.6,134.0,136.7,137.8,
(50 MHz, CDCl3):
d
¼14.4, 60.7, 119.2, 121.0, 125.2, 127.0, 128.4, 128.6,
139.8, 142.1, 149.3, 167.2, 191.7; mass (ESþ) m/z¼423.2 (Mþþ1).
129.0,129.2,129.3,131.2,132.7,133.9,134.4,134.5,134.9,135.2,139.2,
141.7, 146.5, 166.9, 191.2; mass (ESþ) m/z¼457.2 (Mþþ1).
4.2.6. Methyl 2-{[5-(4-chlorophenyl)-4-(2-formylphenyl)-1-phenyl-
1H-pyrazol-3-yl]methyl}prop-2-enoate (5b). Yield 73% as yellow oil
(348 mg from 500 mg); [found: C, 70.77; H, 4.80; N, 6.35.
C27H21ClN2O3 (Exact mass: 456.1241) requires C, 70.97; H, 4.63; N,
6.13%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.26; nmax (Neat) 1638 (CHO),
4.2.11. Ethyl (2E)-3-[4-(2-formylphenyl)-5-(4-methylphenyl)-1-
phenyl-1H-pyrazol-3-yl]prop-2-enoate
(17.1e). Yield
78%
as
a white solid (304 mg from 500 mg); mp 137e138 ꢀC; [found: C,
77.24; H, 5.78; N, 6.21. C28H24N2O3 (Exact mass: 436.1787) requires
C, 77.04; H, 5.54; N, 6.42%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.30;
1702 (CO2Me) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼3.60e3.72 (m,
5H, CO2Me & CH2), 5.57 (s, 1H, ]CH), 6.21 (s, 1H, ]CH), 6.84 (d, 2H,
J¼8.4 Hz, ArH), 7.11 (d, 2H, J¼8.4 Hz, ArH), 7.26e7.34 (m, 6H, ArH),
7.45 (t, 1H, J¼7.4 Hz, ArH), 7.59 (t, 1H, J¼6.8 Hz, ArH), 7.89 (d, 1H,
nmax (KBr) 1649 (CHO), 1706 (CO2Et) cmꢂ1 1H NMR (300 MHz,
;
CDCl3):
d
¼1.27 (t, 3H, J¼7.1 Hz, CH3), 2.24 (s, 3H, CH3), 4.19 (q, 2H,
J¼7.1 Hz, OCH2), 6.46 (d, 1H, J¼16.1 Hz, ]CH), 6.84 (d, 2H, J¼8.5 Hz,
ArH), 7.13 (d, 2H, J¼8.5 Hz, ArH), 7.29e7.34 (m, 6H, ArH), 7.47e7.54
(m, 2H, ArH & ]CH), 7.61e7.67 (m, 1H, ArH), 7.94 (d, 1H, J¼7.7 Hz,
J¼7.4 Hz, ArH), 9.83 (s, 1H, CHO); 13C NMR (50 MHz, CDCl3):
¼29.2,
d
52.0, 117.8, 125.2, 127.0, 127.7, 128.0, 128.4, 129.0, 129.1, 131.2, 132.5,
134.1, 134.5, 134.7, 136.2, 137.6, 139.5, 140.8, 149.3, 167.0, 191.5; mass
(ESþ) m/z¼457.2 (Mþþ1).
ArH), 9.86 (s, 1H, CHO); 13C NMR (50 MHz, CDCl3):
d
¼14.4, 60.7,
119.2, 121.0, 125.2, 127.0, 128.4, 128.6, 129.0, 129.2, 129.3, 131.2,
132.7, 133.9, 134.4, 134.5, 134.9, 135.2, 139.2, 141.7, 146.5, 166.9,
191.2; mass (ESþ) m/z¼437.2 (Mþþ1).
4.2.7. Methyl
2-{[4-(2-formylphenyl)-1-methyl-1H-pyrazol-3-yl]
methyl}prop-2-enoate (5c). Yield 71% as colorless oil (264 mg from
400 mg); [found: C, 67.80; H, 5.81; N, 9.67. C16H16N2O3 (Exact mass:
284.1161) requires C, 67.59; H, 5.67; N, 9.85%]; Rf (hexanes/EtOAc,
4.2.12. Ethyl (2E)-3-[4-(2-formylphenyl)-1-(4-nitrophenyl)-1H-pyr-
azol-3-yl]prop-2-enoate (17.1f). Yield 77% as a yellow solid (292 mg
from 400 mg); mp 137e138 ꢀC; [found: C, 64.66; H, 4.62; N, 10.53.
C21H17N3O5 (Exact mass: 391.1168) requires C, 64.45; H, 4.38; N,
10.74%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.32; nmax (KBr) 1690 (CHO),
70:30, v/v) 0.16; nmax (Neat) 1694 (CHO), 1708 (CO2Me) cmꢂ1 1H
;
NMR (300 MHz, CDCl3):
d
¼3.59 (s, 2H, CH2), 3.66 (s, 3H, CO2Me),
3.93 (s, 3H, NCH3), 5.47 (d, 1H, J¼1.2 Hz, ]CH), 6.18 (s, 1H, ]CH),
7.34 (t, 2H, J¼3.4 Hz, ArH), 7.53e7.70 (m, 2H, ArH), 7.96e7.99 (m,
1718 (CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼1.21
1H, ArH), 10.0 (s, 1H, CHO); 13C NMR (100 MHz, CDCl3):
d
¼29.1, 39.1,
(t, 3H, J¼7.1 Hz, CH3), 4.13 (q, 2H, J¼7.1 Hz, OCH2), 5.75 (d, 1H,
J¼16.2 Hz, ]CH), 7.43 (d, 1H, J¼7.6 Hz, ArH), 7.48 (d, 1H, J¼16.2 Hz,
]CH), 7.60 (t, 1H, J¼7.4 Hz, ArH), 7.69e7.78 (m, 4H, ArH), 8.08 (d,
1H, J¼7.7 Hz, ArH), 8.43 (d, 2H, J¼8.9 Hz, ArH); 13C NMR (50 MHz,
52.0, 117.0, 126.7, 127.9, 131.5, 131.8, 132.1, 133.9, 134.6, 136.7, 138.1,
147.8, 167.1, 192.5; mass (ESþ) m/z¼285.1 (Mþþ1).
4.2.8. 2-((4-(2-Formylthiophen-3-yl)-1,5-diphenyl-1H-pyrazol-3-yl)
methyl)acrylonitrile (12). Yield 80% as yellow oil (384 mg from
500 mg); found: [C, 72.76; H, 4.41; N, 10.51. C24H17N3OS (Exact
mass: 395.1092) requires C, 72.89; H, 4.33; N, 10.63.]; Rf (hexanes/
CDCl3):
d
¼14.3, 61.3, 121.6, 123.7, 125.2, 125.9, 129.0, 129.1, 129.3,
131.9, 134.2, 134.6, 134.9, 135.7, 143.1, 143.9, 147.3, 165.7, 191.3;
mass (ESþ) m/z¼392.2 (Mþþ1).
EtOAc, 80:20, v/v) 0.26; nmax (Neat) 1694 (CHO), 2229 (CN) cmꢂ1
;
4.2.13. Methyl (2E)-3-[4-(2-formylphenyl)-1,5-diphenyl-1H-pyrazol-
3-yl]prop-2-enoate (17.2a). Yield 71% as a white solid (67 mg from
100 mg); mp 173e174 ꢀC; [found: C, 76.66; H, 5.10; N, 6.63.
C26H20N2O3 (Exact mass: 408.1474) requires C, 76.45; H, 4.94; N,
6.86%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.52; nmax (KBr) 1647 (CHO),
1H NMR (300 MHz, CDCl3):
d
¼3.68 (s, 2H, CH2), 5.77 (s, 1H, ]CH),
5.91 (s, 1H, ]CH), 6.98 (d, 2H, J¼7.3 Hz, ArH), 7.03 (d, 1H, J¼4.9 Hz,
ArH), 7.19e7.32 (m, 8H, ArH), 7.75 (d, 1H, J¼4.9 Hz, ArH), 9.53 (s, 1H,
CHO); 13C NMR (75 MHz, CDCl3):
d
¼32.4, 114.2, 118.4, 120.3, 125.3,
128.0, 128.7, 128.9, 129.1, 129.2, 130.0, 131.6, 132.2, 134.8, 139.5,
1697 (CO2Me) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼3.73 (s, 3H,
139.6, 141.1, 142.7, 146.6, 183.3; mass (ESþ) m/z¼396.4 (Mþþ1).
CO2Me), 6.50 (d, 1H, J¼16.1 Hz, ]CH), 6.91 (d, 2H, J¼6.8 Hz, ArH),
7.13e7.23 (m, 3H, ArH), 7.31e7.38 (m, 6H, ArH), 7.50 (t, 1H, J¼7.4 Hz,
ArH), 7.54 (d, 1H, J¼16.1 Hz, ]CH), 7.64 (dt, 1H, J1¼1.4 Hz, J2¼7.5 Hz,
ArH), 7.91e7.94 (m, 1H, ArH), 9.86 (s, 1H, CHO); 13C NMR (50 MHz,
4.2.9. Ethyl (2E)-3-[4-(2-formylphenyl)-1,5-diphenyl-1H-pyrazol-3-
yl]prop-2-enoate (17.1a). Yield 76% as a white solid (560 mg from
800 mg); mp 149e150 ꢀC; [found: C, 76.95; H, 5.00; N, 6.44.
C27H22N2O3 (Exact mass: 422.1630) requires C, 76.76; H, 5.25; N,
6.63%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.45; nmax (KBr) 1637 (CHO),
CDCl3):
d
¼51.8, 119.2, 125.3, 128.3, 128.6, 128.8, 129.0, 129.2, 130.1,
132.8, 134.2, 134.4, 134.7, 135.4, 139.5, 143.0, 146.4, 167.3, 191.2;
mass (ESþ) m/z¼409.2 (Mþþ1).
1706 (CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.27 (t,
3H, J¼7.1 Hz, CH3), 4.19 (q, 2H, J¼7.1 Hz, OCH2), 6.49 (d, 1H,
J¼16.1 Hz, ]CH), 6.91 (d, 2H, J¼6.8 Hz, ArH), 7.13e7.23 (m, 3H,
ArH), 7.34e7.38 (m, 6H, ArH), 7.47e7.51 (m, 1H, ArH), 7.54 (d, 1H,
J¼16.1 Hz, ]CH), 7.64 (dt, 1H, J1¼1.4 Hz, J2¼7.5 Hz, ArH), 7.92 (dd,
1H, J1¼1.0 Hz, J2¼7.7 Hz, ArH), 9.85 (s, 1H, CHO); 13C NMR (75 MHz,
4.2.14. Methyl (2E)-3-[4-(2-formylphenyl)-5-(4-methylphenyl)-1-
phenyl-1H-pyrazol-3-yl]prop-2-enoate
(17.2e). Yield
67% as
a white solid (510 mg from 800 mg); mp 156e157 ꢀC; [found: C,
76.55; H, 5.50; N, 6.85. C27H22N2O3 (Exact mass: 422.1630) requires
C, 76.76; H, 5.25; N, 6.63%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.38;
CDCl3):
d
¼14.4, 60.7, 119.1, 121.0, 125.3, 128.2, 128.3, 128.6, 128.79,
nmax (KBr) 1653 (CHO), 1707 (CO2Me) cmꢂ1 1H NMR (300 MHz,
;
128.93, 129.0, 129.2, 130.1, 132.8, 134.2, 134.24, 134.7, 135.4, 139.6,
CDCl3):
d
¼2.24 (s, 3H, CH3), 3.73 (s, 3H, CO2Me), 6.48 (d, 1H,
143.1, 146.5, 166.9, 191.2; mass (ESþ) m/z¼423.2 (Mþþ1).
J¼16.1 Hz, ]CH), 6.78 (d, 2H, J¼8.0 Hz, ArH), 6.95 (d, 2H, J¼7.9 Hz,
ArH), 7.34e7.37 (m, 6H, ArH), 7.49 (t, 1H, J¼7.4 Hz, ArH), 7.53 (d, 1H,
J¼16.1 Hz, ]CH), 7.63 (dt, 1H, J1¼1.4 Hz, J2¼7.5 Hz, ArH), 7.93 (dd,
1H, J1¼0.9 Hz, J2¼7.7 Hz, ArH), 9.85 (s, 1H, CHO); 13C NMR (50 MHz,
4.2.10. Ethyl (2E)-3-[5-(4-chlorophenyl)-4-(2-formylphenyl)-1-
phenyl-1H-pyrazol-3-yl]prop-2-enoate (17.1b). Yield 74% as a white
solid (350 mg from 500 mg); mp 144e145 ꢀC; [found: C, 70.75; H,
CDCl3):
d¼21.4, 51.8, 118.9, 120.3, 125.3, 125.5, 128.1, 128.2, 128.7,

M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
5035
129.1, 129.6, 129.9, 132.8, 134.3, 134.5, 134.6, 135.6, 139.0, 139.6,
d
¼26.6, 33.3, 34.0, 43.2, 52.4, 55.4, 64.5, 120.3, 124.9, 125.4, 126.6,
143.2, 146.3, 167.4, 191.3; mass (ESþ) m/z¼423.3 (Mþþ1).
127.3, 127.4, 127.8, 128.6, 128.8, 128.82, 128.9, 129.0, 129.4, 129.8,
129.9, 130.2, 130.3, 132.2, 138.5, 139.9, 148.9; mass (ESþ) m/z¼443.4
(Mþþ1); ESI-HRMS: MHþ, found: 443.2283. C30H27N4 requires
443.2236.
4.2.15. Ethyl (2E)-3-[3-4-(2-formylphenyl)-1,3-diphenyl-1H-pyrazol-
5-yl]prop-2-enoate (23a). Yield 72% as a white solid (353 mg from
500 mg); mp 119e120 ꢀC; [found: C, 76.94; H, 5.46; N,
6.40.C27H22N2O3 (Exact mass: 422.1630) requires C, 76.76; H, 5.25;
N, 6.63%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.41; nmax (KBr) 1633
4.3.2. (2R,6R)-11-(4-Chlorophenyl)-3-methyl-10-phenyl-3,9,10-
triazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(13),8,11,14,16-pentaene-
6-carbonitrile (6b). Yield 90% as a white solid (107 mg from
120 mg), mp 224e225 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.24; nmax
(CHO), 1704 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d¼1.18 (t, 3H,
J¼7.1 Hz, CH3), 4.09 (q, 2H, J¼7.1 Hz, OCH2), 5.53 (d, 1H, J¼16.3 Hz,
]CH), 7.22 (dd, 3H, J1¼1.6 Hz, J2¼5.1 Hz, ArH), 7.36e7.39 (m, 2H,
ArH), 7.42e7.63 (m, 8H, ArH & ]CH), 7.69e7.74 (m, 1H, ArH), 8.07
(d, 1H, J¼7.7 Hz, ArH), 9.95 (s, 1H, CHO); 13C NMR (50 MHz, CDCl3):
(KBr) 2230 (CN) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼2.01 (s, 3H,
NCH3), 2.32e2.37 (m, 3H, CH2 & CHHN), 2.95e3.08 (m, 3H, CH2
&
CHHN), 3.44 (s, 1H, NCH), 6.73 (d, 1H, J¼6.5 Hz, ArH), 7.03 (d, 2H,
d
¼14.3, 60.9, 117.5, 121.8, 126.1, 127.8, 128.4, 128.6, 128.7, 129.2,
J¼8.4 Hz, ArH), 7.12e7.35 (m, 9H, ArH), 7.42 (d, 1H, J¼6.7 Hz, ArH);
129.3, 129.7, 130.1, 131.7, 132. 5, 134.6, 134.9, 136.6, 139.1, 151.2,
13C NMR (75 MHz, CDCl3):
d
¼30.1, 34.2, 34.7, 40.5, 55.3, 77.6, 121.1,
166.2, 191.4; mass (ESþ) m/z¼423.2 (Mþþ1).
124.8, 125.2, 126.8, 127.4, 128.6, 128.8, 129.1, 129.2, 130.2, 131.6,
132.5, 133.2, 134.8, 135.6, 137.4, 139.6, 147.6; mass (ESþ) m/z¼451.4
(Mþþ1); ESI-HRMS: MHþ, found 451.1670. C28H24ClN4 requires
451.1689.
4.2.16. Ethyl (2E)-3-[3-(4-chlorophenyl)-4-(2-formylphenyl)-1-
phenyl-1H-pyrazol-5-yl]prop-2-enoate (23b). Yield 68% as a white
solid (356 mg from 500 mg); mp 151e152 ꢀC; [found: C, 71.16; H,
4.41; N, 6.00. C27H21ClN2O3 (Exact mass: 456.1241) requires C,
70.97; H, 4.63; N, 6.13%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.40; nmax
4.3.3. (2R,6R)-3,10-Dimethyl-3,9,10-triazatetracyclo[11.4.0.02,6.08,12
]
heptadeca-1(13),8,11,14,16-pentaene-6-carbonitrile (6c). Yield 82%
(KBr) 1696 (CHO), 1717 (CO2Et) cmꢂ1 1H NMR (300 MHz, CDCl3):
;
as a white solid (45 mg from 50 mg), mp 119e120 ꢀC; Rf (hexanes/
d
¼1.18 (t, 3H, J¼7.1 Hz, CH3), 4.09 (q, 2H, J¼7.1 Hz, OCH2), 5.53 (d,
EtOAc, 70:30, v/v) 0.19; nmax (KBr) 2236 (CN) cmꢂ1 1H NMR
;
1H, J¼16.3 Hz, ]CH), 7.19 (d, 2H, J¼8.6 Hz, ArH), 7.31 (d, 2H,
J¼8.6 Hz, ArH), 7.40e7.46 (m, 2H, ArH & ]CH), 7.49e7.65 (m, 6H,
ArH), 7.73 (dt, 1H, J1¼1.1 Hz, J2¼7.4 Hz, ArH), 8.08 (d, 1H, J¼6.7 Hz,
(400 MHz, CDCl3):
d
¼1.79 (s, 3H, NCH3), 2.11e2.24 (m, 3H, CH2),
2.80 (d, 1H, J¼10.5 Hz, NCHH), 2.89e2.96 (m, 2H, NCHH & CHH),
3.27 (s, 1H, NCH), 3.81 (s, 3H, NCH3), 7.13e7.19 (m, 3H, ArH), 7.27 (s,
ArH), 9.93 (s, 1H, CHO); 13C NMR (50 MHz, CDCl3):
d¼14.3, 61.0,
1H, ArH), 7.34 (s,1H, ArH); 13C NMR (100 MHz, CDCl3):
d¼33.8, 34.9,
117.5, 122.0, 126.1, 128.9, 129.0, 129.3, 129.5, 129.8, 129.9, 130.4,
132.4, 134.4, 134. 6, 135.0, 136.2, 137.0, 139.0, 150.0, 166.1, 191.3;
mass (ESþ) m/z¼457.2 (Mþþ1).
39.2, 40.8, 49.7, 55.4, 81.0, 121.5, 125.2, 126.6, 127.2, 129.1, 129.3,
133.1, 133.6, 134.7, 146.1; mass (ESþ) m/z¼279.2 (Mþþ1); ESI-
HRMS: MHþ, found 279.1617. C17H19N4 requires 279.1610.
4.2.17. 2-[3-(2-Acetyl-3-oxobut-1-en-1-yl)-1,5-diphenyl-1H-pyr-
azol-4-yl]benzaldehyde (28). Yield 65% as a white solid (155 mg
from 250 mg); mp 155e157 ꢀC; [found C, 77.62; H, 5.29; N, 6.20.
C28H22N2O3 (Exact mass: 434.1630) requires C, 77.40; H, 5.10; N,
6.45%]; Rf (hexanes/EtOAc, 80:20, v/v) 0.26; nmax (KBr) 1668 (COCH3
4.3.4. (4bR,7aR)-10-(4-Methoxyphenyl)-5-methyl-11-phenyl-5,6,7,7a,
8,10-hexahydro-4bH-benzo[3,4]pyrrolo[20,30:5,6]cyclohepta[1,2-c]pyr-
azole-7a-carbonitrile (6d). Yield 92% as a white solid (98 mg from
100 mg); mp 220e222 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.27; nmax
(KBr) 2227 (CN) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼2.05 (s, 3H,
& CHO) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼2.28 (s, 3H, COCH3),
CH3), 2.36e2.38 (m, 3H, CHHN & CH2), 2.97e3.11 (m, 3H, CH2
&
2.55 (s, 3H, COCH3), 6.91 (d, 2H, J¼7.0 Hz, ArH), 7.05 (s, 1H, ]CH),
7.16e7.34 (m, 9H, ArH), 7.51 (t, 1H, J¼7.5 Hz, ArH), 7.64 (t, 1H,
J¼6.9 Hz, ArH), 7.94 (d, 1H, J¼6.9 Hz, ArH), 9.86 (s, 1H, CHO); 13C
CHHN), 3.46 (s, 1H, NCH), 3.82 (s, 3H, CH3), 6.76 (d, 1H, J¼7.5 Hz,
ArH), 6.84 (d, 2H, J¼8.2 Hz, ArH), 7.11e7.21 (m, 6H, ArH), 7.32e7.37
(m, 3H, ArH), 7.43 (d, 1H, J¼6.5 Hz, ArH); 13C NMR (75 MHz, CDCl3):
NMR (50 MHz, CDCl3):
d
¼26.5, 31.4, 120.9, 124.7, 126.5, 128.1, 128.3,
d
¼34.2, 34.8, 40.4, 49.1, 55.3, 55.6, 56.5, 111.6, 114.1, 120.3, 122.6,
128.5, 128.9, 129.95, 129.1, 129.2, 129.7, 130.0, 132.8, 134.2, 134.4,
134.7, 139.2, 142.6, 143.1, 144.4, 191.0, 196.2, 204.9; mass (ESþ) m/
z¼435.4 (Mþþ1).
125.0,126.4,126.5,127.2,128.5,128.7,128.9,130.2,130.4,133.1,135.4,
138.7, 147.0, 158.6; mass (ESþ) m/z¼447.3 (Mþþ1); ESI-HRMS: MHþ,
found: 447.2171. C29H27N4O requires 447.2185.
4.3. General procedure for the synthesis of compounds 6aed,
7aec, 13, 18.1a,b,e,f, 18.2a,e, 24a,b and 29 as exemplified 6a
4.3.5. Methyl (2R,6R)-3-methyl-10,11-diphenyl-3,9,10-triazatetracyc-
lo[11.4.0.02,6.08,12]heptadeca-1(13),8,11,14,16-pentaene-6-carboxylate
(7a). Yield 87% as a white solid (88 mg from 100 mg); mp
119e120 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.25; nmax (KBr) 1730
To a stirred solution of compound 4a (0.26 mmol, 100 mg) in
toluene (15 mL) was added sarcosine (0.39 mmol, 30 mg) and
stirred at 110 ꢀC for 3 h. Thereafter reaction mixture was cool to
room temperature and extracted with EtOAc (3ꢁ10 mL) and water
(30 mL). The organic layers were combined, washed with brine
dried over Na2SO4, and concentrated under reduced pressure.
Column chromatography of the residue over silica gel (hexanes/
EtOAc, 70:30, v/v) afforded pure 6a as a white solid (92%, 98 mg).
(CO2Me) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.98 (s, 3H, NCH3),
2.14e2.21 (m, 2H, CH2), 2.27e2.33 (m, 1H, CHHN), 2.84e3.05 (m,
3H, CH2 & CHHN), 3.43 (s, 1H, NCH), 3.76 (s, 3H, CO2Me), 6.71 (d, 1H,
J¼6.5 Hz, ArH), 7.03e7.08 (m, 1H, ArH), 7.11e7.15 (m, 3H, ArH),
7.19e7.29 (m, 9H, ArH); 13C NMR (50 MHz, CDCl3):
d
¼33.2, 33.5,
40.8, 52.5, 55.9, 61.7, 79.5, 121.2, 125.1, 126.1, 126.8, 127.8, 128.4,
128.7, 128.8, 130.0, 130.5, 130.7, 133.1, 133.2, 137.8, 138.2, 140.2,
149.4, 177.1; mass (ESþ) m/z¼450.3 (Mþþ1); DART-HRMS: MHþ,
found 450.2144. C29H28N3O2 requires 450.2182.
4.3.1. (2R,6R)-3-Methyl-10,11-diphenyl-3,9,10-triazatetracyclo
[11.4.0.02,6.08,12]heptadeca-1(13),8,11,14,16-pentaene-6-carbonitrile
(6a). Mp 119e120 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.44; nmax
4.3.6. Methyl (2R,6R)-11-(4-chlorophenyl)-3-methyl-10-phenyl-3,9,
10-triazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(13),8,11,14,16-
pentaene-6-carboxylate (7b). Yield 82% as a white solid (83 mg
from 100 mg); mp 205e206 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.26;
(KBr) 2226 (CN) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.78 (s, 2H,
CH2), 1.93e2.01 (m, 3H, CH2), 2.34e2.35 (m, 2H, CH2), 2.75 (d, 1H,
J¼14.1 Hz, CHH), 2.92e3.08 (m, 2H, NCH2), 3.20 (d, 1H, J¼14.0 Hz,
CHH), 3.66 (s, 1H, NCH), 6.73 (d, 1H, J¼7.1 Hz, ArH), 7.06e7.43 (m,
12H, ArH), 7.60 (d, 1H, J¼7.5 Hz, ArH); 13C NMR (50 MHz, CDCl3):
nmax (KBr) 1726 (CO2Me) cmꢂ1; 1H NMR (300 MHz, CDCl3):
(s, 3H, NCH3), 2.13e2.19 (m, 2H, CH2), 2.27e2.33 (m, 1H, CHHN),
d
¼1.97

5036
M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
2.84e3.03 (m, 3H, CH2 & CHHN), 3.43 (s, 1H, NCH), 3.76 (s, 3H,
CO2Me), 6.70 (d, 1H, J¼7.3 Hz, ArH), 7.05e7.18 (m, 4H, ArH),
(KBr) 1730 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d¼1.32 (t, 3H,
J¼7.1 Hz, CH3), 2.31 (s, 3H, NCH3), 2.54 (t, 1H, J¼8.6 Hz, CH), 3.40 (d,
1H, J¼5.6 Hz, CHHN), 3.57 (dd, 1H, J¼9.3 Hz, CH), 3.95e3.99 (m, 2H,
CHHN & NCH), 4.24 (q, 2H, J¼7.1 Hz, OCH2), 7.08e7.38 (m,13H, ArH);
7.24e7.32 (m, 8H, ArH); 13C NMR (200 MHz, CDCl3):
d
¼33.1, 33.4,
40.9, 52.6, 55.9, 61.5, 79.6, 121.4, 125.2, 126.4, 127.1, 128.0, 129.0,
129.1,129.9,131.8,132.8, 133.4,134.5,137.0,137.8,139.8,149.5,177.1;
mass (ESþ) m/z¼484.3 (Mþþ1); ESI-HRMS: MHþ, found 484.1780.
C29H27ClN3O2 requires 484.1792.
13C NMR (50 MHz, CDCl3):
114.8,123.3,125.4,125.8,127.3,128.5,129.0,129.4,129.8,130.2,131.6,
132.1,135.2,137.3,139.8,151.9,175.1; mass (ESþ) m/z¼484.1 (Mþþ1);
ESI-HRMS: MHþ, found 484.1800. C29H27ClN3O2 requires 484.1792.
d
¼14.5, 40.1, 40.8, 46.8, 58.7, 61.2, 69.7,
4.3.7. Methyl (2R,6R)-3,10-dimethyl-3,9,10-triazatetracyclo[11.4.0.
0
2,6.08,12]heptadeca-1(13),8,11,14,16-pentaene-6-carboxylate
4.3.12. Ethyl (2R,6R)-10-(4-chlorophenyl)-3-methyl-9-phenyl-3,8,9-
triazatetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaene-
5-carboxylate (anti-18.1b). Yield 2% as a white solid (2 mg from
100 mg); mp 160e161 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.3; nmax
(KBr) 1730 (CO2Et) cmꢂ1; mass (ESþ) m/z¼484.1 (Mþþ1); ESI-
HRMS: MHþ, found 484.1805. C29H27ClN3O2 requires 484.1792.
(7c). Yield 89% as colorless oil; Rf (hexanes/EtOAc, 50:50, v/v)
0.25, nmax (Neat) 1724 (CO2Me) cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
¼1.79 (s, 3H, NCH3), 2.11e2.24 (m, 3H, CH2), 2.80 (d, 1H,
J¼10.5 Hz, NCHH), 2.89e2.96 (m, 2H, NCHH & CHH), 3.27 (s, 1H,
NCH), 3.81 (s, 3H, NCH3), 7.13e7.19 (m, 3H, ArH), 7.27 (s, 1H, ArH),
7.34 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3):
d
¼33.8, 34.9, 39.2,
40.8, 49.7, 55.4, 81.0121.5, 125.2, 126.6, 127.2, 129.1, 129.3, 133.1,
133.6, 134.7, 146.1; mass (ESþ) m/z¼312.2 (Mþþ1); ESI-HRMS:
MHþ, found 312.1710. C18H22N3O2 requires 312.1712.
4.3.13. Ethyl (2S,6R)-3-methyl-10-(4-methylphenyl)-9-phenyl-3,8,9-
triazatetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaene-
5-carboxylate (syn-18.1e). Yield 85% as a white solid (90 mg from
100 mg), mp 165e167 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.31; nmax
4.3.8. (7aR,10aS)-10-Methyl-4,5-diphenyl-7,7a,8,9,10,10a-hexahy-
dro-5H-pyrrolo[20,30:5,6]thieno[30,20:3,4]cyclohepta[1,2-c]pyrazole-
7a-carbonitrile (13). Yield 91% as a white solid (68 mg from 70 mg);
mp 194e196 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.25; nmax (KBr)
(KBr) 1730 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
¼1.32 (t, 3H,
J¼7.1 Hz, CH3), 2.31 (s, 3H, NCH3), 2.40 (s, 3H, CH3), 2.53 (t, 1H,
J¼8.7 Hz, CH), 3.39 (d,1H, J¼5.8 Hz, CHHN), 3.58 (t,1H, J¼9.4 Hz, CH),
3.95e4.00 (m, 2H, CHHN & NCH), 4.24 (q, 2H, J¼7.1 Hz, OCH2),
7.06e7.15 (m, 3H, ArH), 7.17e7.26 (m, 10H, ArH); 13C NMR (50 MHz,
2234 (CN) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼2.26e2.30 (m, 2H,
CH2), 2.36 (s, 3H, CH3), 2.55e2.63 (m, 1H, CHHN), 2.94 (d, 1H,
J¼14.0 Hz, CHH), 3.17e3.20 (m, 1H, CHHN), 3.24 (d, 1H, J¼14.0 Hz,
CHH), 3.85 (s, 1H, NCH), 6.48 (d, 1H, J¼5.1 Hz, ArH), 7.09 (d, 1H,
J¼5.1 Hz, ArH), 7.18 (d, 2H, J¼7.4 Hz, ArH), 7.29e7.33 (m, 8H, ArH);
CDCl3):
d
¼14.5,21.6, 40.1, 40.9, 46.8,58.8, 61.1, 69.7,114.4,123.4,125.3,
125.4,126.9,128.3,128.4,128.8,129.7,130.5,130.6,131.5,132.0,138.7,
138.9, 140.2, 151.7, 175.1; mass (ESþ) m/z¼464.1 (Mþþ1); DART-
HRMS: MHþ, found 464.2331. C30H30N3O2 requires 464.2338.
13C NMR (75 MHz, CDCl3):
d
¼34.4, 35.9, 41.6, 52.1, 54.8, 72.2, 117.4,
124.6, 124.8, 125.1, 127.3, 128.4, 128.7, 129.0, 129.9, 130.2, 130.7,
137.8, 138.4, 139.8, 148.0; mass (ESþ) m/z¼423.3 (Mþþ1); ESI-
HRMS: MHþ, found: 423.1670. C26H23N4S requires 423.1643.
4.3.14. Ethyl (2R,6R)-3-methyl-10-(4-methylphenyl)-9-phenyl-3,8,9-
triazatetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaene-
5-carboxylate (anti-18.1e). Yield 7% as a white solid (7 mg from
100 mg), mp 154e155 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.28; nmax
4.3.9. Ethyl (2S,6R)-3-methyl-9,10-diphenyl-3,8,9-triazatetracyclo
[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaene-5-carboxylate
(syn-18.1a). Yield 82% as a white solid (87 mg from 100 mg); mp
145e146 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.27; nmax (KBr) 1729
(KBr) 1730 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3)
d¼1.32 (t, 3H,
J¼7.1 Hz, CH3), 1.61 (s, 1H, CH), 1.72 (s, 3H, NCH3), 1.90 (s, 3H, CH3),
2.04 (s,1H, CH), 2.92e2.98 (m, 2H, CHHN), 4.20e4.25 (m, 3H, NCH &
OCH2), 7.07 (s, 2H, ArH), 7.11e7.17 (m, 3H, ArH), 7.22e7.26 (m, 3H,
ArH), 7.36 (s, 5H, ArH); mass (ESþ) m/z¼464.1 (Mþþ1); DART-
HRMS: MHþ, found 464.2322. C30H30N3O2 requires 464.2338.
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼1.33 (t, 3H, J¼7.1 Hz,
CH3), 2.31 (s, 3H, NCH3), 2.54 (t, 1H, J¼8.6 Hz, CH), 3.40 (d, 1H,
J¼5.6 Hz, CHHN), 3.58 (t, 1H, J¼9.3 Hz, CH), 3.96e4.01 (m, 2H, CH &
CHHN), 4.25 (q, 2H, J¼7.1 Hz, OCH2), 7.05e7.14 (m, 3H, ArH),
7.20e7.22 (m, 6H, ArH), 7.39 (s, 5H, ArH); 13C NMR (50 MHz, CDCl3):
4.3.15. Ethyl (2S,6R)-3-methyl-9-(4-nitrophenyl)-3,8,9-triazatetra-
cyclo[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaene-5-carboxy-
late (syn-18.1f). Yield 95% as a yellow solid (204 mg from 200 mg),
mp 200e201 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.22; nmax (KBr) 1727
d
¼14.4, 40.1, 40.8, 46.8, 58.7, 61.1, 69.7, 114.6, 123.3, 125.2, 125.5,
127.0, 128.4, 128.4, 128.8, 130.0, 130.5, 130.7, 131.3, 131.5, 132.0, 138.
6, 140.0, 151.7, 175.1; mass (ESþ) m/z¼450.1 (Mþþ1); DART-HRMS:
MHþ, found 450.2186. C29H28N3O3 requires 450.2182.
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.13 (t, 3H, J¼7.1 Hz,
CH3), 2.18 (s, 3H, NCH3), 2.23e2.26 (m, 1H, CH), 2.85e2.91 (m, 1H,
CH), 3.27 (t, 1H, J¼9.1 Hz, CH), 3.39 (d, 1H, J¼6.8 Hz, CHHN),
3.94e4.12 (m, 2H, OCH2), 4.45 (dd, 1H, J1¼2.9 Hz, J2¼6.6 Hz, CHHN),
7.21e7.26 (m, 2H, ArH), 7.38e7.42 (m,1H, ArH), 7.59 (d,1H, J¼7.5 Hz,
ArH), 7.66 (d, 2H, J¼8.9 Hz, ArH), 8.05 (s, 1H, ArH), 8.30 (d, 2H,
4.3.10. Ethyl (2R,6R)-3-methyl-9,10-diphenyl-3,8,9-triazatetracyclo
[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaene-5-carboxylate
(anti-18.1a). Yield 8% as a white solid (9 mg from 100 mg); mp
168e170 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.20; nmax (KBr) 1729
J¼8.8 Hz, ArH); 13C NMR (75 MHz, CDCl3):
¼14.1, 39.4, 39.5, 47.1,
d
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼1.31 (t, 3H, J¼7.1 Hz,
58.5, 61.4, 69.5, 119.1, 123.4, 124.1, 124.9, 125.9, 129.1, 129.3, 130.0,
130.7,137.2,140.1,144.7,146.3,173.7; mass (ESþ) m/z¼419.2 (Mþþ1);
ESI-HRMS: MHþ, found 419.1725. C23H23N4O4 requires 419.1719.
CH3), 2.70 (s, 3H, NCH3), 3.06e3.12 (m, 1H, CH), 3.51e3.57 (m, 3H,
CH & NCH2), 3.81 (dd, 1H, J1¼6.4 Hz, J2¼12.1 Hz, CH), 4.25 (q, 2H,
J¼7.1 Hz, OCH2), 6.93 (d, 1H, J¼7.4 Hz, ArH), 7.00e7.07 (m, 1H, ArH),
7.16e7.39 (m, 11H, ArH), 7.51 (d, 1H, J¼7.5 Hz, ArH); 13C NMR
4.3.16. Methyl (2S,6R)-3-methyl-9,10-diphenyl-3,8,9-triazatetracyclo
[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaene-5-carboxylate
(syn-18.2a). Yield 83% as a white solid (89 mg from 100 mg), mp
145e146 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.36; nmax (KBr) 1734
(50 MHz, CDCl3):
d
¼14.4, 42.1, 44.0, 44.9, 61.1, 62.0, 72.8, 117.0,
123.3, 124.2, 125.3, 126.2, 126.7, 127.1, 128.8, 129.0, 129.1, 130.2,
130.8, 139.9, 173.5; mass (ESþ) m/z¼450.1 (Mþþ1); DART-HRMS:
MHþ, found 450.2187. C29H28N3O3 requires 450.2182.
(CO2Me) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼2.31 (s, 3H, NCH3),
2.56 (t, 1H, J¼8.7 Hz, CH), 3.39 (d, 1H, J¼6.0 Hz, CHHN), 3.56 (dd, 1H,
J1¼9.1 Hz, J2¼9.4 Hz, CH), 3.79 (s, 3H, CO2Me), 3.95e4.02 (m, 2H,
CHHN & NCH), 7.06e7.14 (m, 3H, ArH), 7.16e7.24 (m, 6H, ArH), 7.39
4.3.11. Ethyl (2S,6R)-10-(4-chlorophenyl)-3-methyl-9-phenyl-3,8,9-
triazatetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaene-
5-carboxylate (syn-18.1b). Yield 91% as a white solid (115 mg from
120 mg); mp 149e150 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.34; nmax
(s, 5H, ArH); 13C NMR (50 MHz, CDCl3):
d¼21.6, 31.3, 52.3, 63.6,
118.0, 125.7, 126.4, 126.8, 127.9, 128.3, 128.6, 128.7, 129.0, 129.8, 40.1,

M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
5037
40.9, 467, 52.3, 58.6, 69.7, 114.5, 123.4, 125.2, 125.5, 120, 128.5, 128.8,
129.0, 129.1, 130.4, 130.7, 131.3, 131.5, 131.9, 138.6, 140.0, 151.7, 175.5;
mass (ESþ) m/z¼436.2 (Mþþ1); DART-HRMS: MHþ, found
436.2020. C28H26N3O2 requires 436.2025.
145e147 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.24; nmax (KBr) 1731
(CO2Et) cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
¼1.13 (t, 3H, J¼7.1 Hz,
CH3), 2.63 (s, 3H, NCH3), 2.85e2.99 (m, 2H, CH & CH2), 3.39e3.43
(m, 1H, CH), 3.60 (d, 1H, J¼13.3 Hz, NCH), 3.76e3.89 (m, 2H, OCH2),
3.92e4.00 (m, 1H, NCHH), 7.15 (t, 1H, J¼7.4 Hz, ArH), 7.22 (d, 1H,
J¼7.5 Hz, ArH), 7.34e7.37 (m, 1H, ArH), 7.42e7.44 (m, 8H, ArH), 7.52
(d, 1H, J¼7.5 Hz, ArH), 7.76 (d, 2H, J¼7.8 Hz, ArH); 13C NMR (50 MHz,
4.3.17. Methyl (2R,6R)-3-methyl-9,10-diphenyl-3,8,9-triazatetracyclo
[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaene-5-carboxylate
(anti-18.2a). Yield 8% as a white solid (8 mg from 100 mg), mp
157e158 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.30; nmax (KBr) 1734
CDCl3):
d
¼14.1, 41.3, 43.1, 43.5, 61.1, 63.0, 73.2, 116.2, 123.2, 124.5,
125.9, 126.8, 127.1, 128.4, 128.7, 128.9, 129.1, 129.3, 131.3, 133.6,
135.9, 139.5, 143.2, 173.0; mass (ESþ) m/z¼450.2 (Mþþ1); DART-
HRMS: MHþ, found 450.2198. C29H28N3O3 requires 450.2182.
(CO2Me) cmꢂ1
;
1H NMR (800 MHz, CDCl3)
d¼2.72 (s, 3H, NCH3),
3.12e3.13 (m, 1H, CH), 3.56 (d, 1H, J¼9.2 Hz, CHHN), 3.62 (s, 1H, CH),
3.78 (s, 3H, CO2Me), 3.80e3.82 (s, 2H, CHHN & NCH), 6.93 (d, 1H,
J¼7.4 Hz, ArH), 7.04 (t, 1H, J¼7.4 Hz, ArH), 7.19 (t, 1H, J¼7.5 Hz, ArH),
7.22e7.30 (m, 7H, ArH), 7.36e7.41 (m, 3H, ArH), 7.52 (d, 1H,
4.3.22. Ethyl (2S,6R)-10-(4-chlorophenyl)-3-methyl-8-phenyl-3,8,9-
triazatetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),7(11),9,12,14-penta-
ene-5-carboxylate (syn-24b). Yield 85% as a white solid (94 mg from
100 mg), mp 190e191 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.33; nmax
J¼7.7 Hz, ArH); 13C NMR (200 MHz, CDCl3)
¼41.8, 43.8, 44.8, 52.5,
d
61.8, 72.7, 117.0, 123.4, 124.3, 125.5, 126.2, 126.8, 127.2, 128.9, 129.0,
129.1, 130.2, 130.3, 130.6, 138.5, 139.8, 151.9, 174.0; mass (ESþ) m/
z¼436.2 (Mþþ1); DART-HRMS: MHþ, found 436.2006. C28H26N3O2
requires 436.2025.
(KBr) 1726 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d¼1.13 (t, 3H,
J¼7.0 Hz, CH3), 2.18 (t, 1H, J¼9.2 Hz, CH), 2.25 (s, 3H, NCH3), 2.97 (t,
1H, J¼7.4 Hz, CH), 3.29e3.37 (m, 2H, CHHN & NCH), 3.87e4.04 (m,
2H, OCH2), 4.37 (d, 1H, J¼4.0 Hz, CHHN), 7.17e7.26 (m, 3H, ArH),
7.41e7.46 (m, 8H, ArH), 7.69 (d, 2H, J¼8.2 Hz, ArH); 13CNMR (50 MHz,
4.3.18. Methyl
(2S,6R)-3-methyl-10-(4-methylphenyl)-9-phenyl-
3,8,9-triazatetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-
pentaene-5-carboxylate (syn-18.2e). Yield 85% as a white solid
(86 mg from 100 mg); mp 164e165 ꢀC; Rf (hexanes/EtOAc, 70:30, v/
v) 0.28; nmax (KBr) 1736 (CO2Me) cmꢂ1; 1H NMR (300 MHz, CDCl3):
CDCl3):
d
¼14.3, 39.5, 39.7, 47.0, 59.1, 61.1, 70.2, 114.4, 123.6, 124.9,
125.5,128.2,128.7,128.8,129.6,130.8,130.9,131.3,132.9,134.4,139.8,
142.1,148.3,173.8; mass (ESþ) m/z¼484.1 (Mþþ1); ESI-HRMS: MHþ,
found 484.1797. C29H27ClN3O2 requires 484.1792.
d
¼2.31 (s, 3H, NCH3), 2.40 (s, 3H, CH3), 2.56 (t, 1H, J¼8.7 Hz, CH),
3.39 (d, 1H, J¼5.8 Hz, CHHN), 3.56 (t, 1H, J¼9.2 Hz, CH), 3.79 (s, 3H,
4.3.23. Ethyl (2R,6R)-10-(4-chlorophenyl)-3-methyl-8-phenyl-3,8,9-
triazatetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),7(11),9,12,14-
pentaene-5-carboxylate (anti-24b). Yield 8% as a white solid (10 mg
from 100 mg), mp 136e137 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v)
CO2Me), 3.94e4.02 (m, 2H, CH & CHHN), 7.09e7.13 (m, 3H, ArH),
7.17e7.26 (m, 10H, ArH); 13C NMR (50 MHz, CDCl3):
d¼21.6, 40.1,
40.9, 46.7, 52.3, 58.7, 69.7, 114.4, 123.4, 125.3, 125.4, 126.9, 128.2,
128.4, 128.7, 129.7, 130.5, 130.6, 131.5, 131.9, 138.7, 138. 9, 140.2,
151.7, 175.6; mass (ESþ) m/z¼450.2 (Mþþ1); DART-HRMS: MHþ,
found 450.1796. C27H24N3O3 requires 450.1818.
0.26; nmax (KBr) 1726 (CO2Et) cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
¼1.15 (t, 3H, J¼7.1 Hz, CH3), 2.65 (s, 3H, NCH3), 2.86e3.00 (m, 2H,
CH & CHHN), 3.40e3.44 (m, 1H, CHHN), 3.60 (d, 1H, J¼13.3 Hz,
NCH), 3.74e3.89 (m, 2H, OCH2), 3.93e4.03 (m, 1H, CH), 7.17e7.26
(m, 3H, ArH), 7.33e7.37 (m, 1H, ArH), 7.41e7.46 (m, 6H, ArH), 7.54
(d, 1H, J¼7.5 Hz, ArH), 7.73 (d, 2H, J¼8.4 Hz, ArH); 13C NMR
4.3.19. Methyl (2R,6R)-3-methyl-9,10-diphenyl-3,8,9-triazatetracyclo
[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaene-5-carboxylate
(anti-18.2e). Yield 9% as a white solid (10 mg from 100 mg); mp
167e168 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.18; nmax (KBr) 1735
(50 MHz, CDCl3):
d
¼14.1, 41.2, 43.1, 43.5, 61.1, 63.0, 73.2, 116.2,
123.3, 124.3, 125.4, 126.1, 126.9, 127.0, 128.9, 129.3, 130.2, 131.0,
132.1, 134.4, 136.0, 139.3, 143.4, 147.9, 172.9; mass (ESþ) m/z¼484.1
(Mþþ1); ESI-HRMS: MHþ, found 484.1782. C29H27ClN3O2 requires
484.1792.
(CO2Me) cmꢂ1
;
1H NMR (800 MHz, CDCl3):
d
¼2.39 (s, 3H, NCH3),
2.70 (s, 3H, CH3), 3.08 (s, 1H, CH), 3.54e3.57 (m, 3H, CH & NCH2),
3.78 (s, 3H, CO2Me), 3.81 (s, 1H, NCH), 6.97 (d, 1H, J¼6.9 Hz, ArH),
7.04 (s, 1H, ArH), 7.17 (s, 5H, ArH), 7.22e7.26 (m, 5H, ArH), 7.51 (d,
1H, J¼6.3 Hz, ArH); 13C NMR (200 MHz, CDCl3):
d
¼21.6, 41.8, 43.9,
4.3.24. 1-[(2S,6R)-5-Acetyl-3-methyl-9,10-diphenyl-3,8,9-triazatet-
racyclo[10.4.0.02,6.07,11]hexadeca-1(16),7,10,12,14-pentaen-5-yl]ethan-
1-one (29). Yield 85% as a white solid (90 mg from 100 mg), mp
140e142 ꢀC; [found C, 78.07; H, 5.07; N, 8.89. C30H27N3O2 (Exact
mass: 461.2103) requires C, 78.07; H, 5.90; N, 9.10%]; Rf (hexanes/
44.9, 52.5, 62.0, 72.8, 116.8, 123.2, 124.2, 125.5, 126.1, 126.7, 127.1,
127.5, 128.9, 129.8, 130.0, 130.5, 138.6, 139.0, 139. 9, 152.0, 174.1;
mass (ESþ) m/z¼450.2 (Mþþ1); DART-HRMS: MHþ, found
450.1800. C27H24N3O3 requires 450.1818.
EtOAc, 70:20, v/v) 0.32; nmax (KBr) 1668 (COCH3) cmꢂ1
;
1H NMR
4.3.20. Ethyl (2S,6R)-3-methyl-8,10-diphenyl-3,8,9-triazatetracyclo
[10.4.0.02,6.07,11]hexadeca-1(16),7(11),9,12,14-pentaene-5-carboxyl-
ate (syn-24a). Yield 88% as a white solid (93 mg from 100 mg), mp
184e185 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.35; nmax (KBr) 1731
(300 MHz, CDCl3):
d
¼2.26 (s, 3H, COCH3), 2.28 (s, 3H, COCH3), 2.41
(s, 3H, NCH3), 2.60 (d, 1H, J¼11.2 Hz, CHHN), 3.40 (d, 1H, J¼2.2 Hz,
CH), 4.11 (d, 1H, J¼10.5 Hz, CHHN), 4.65 (d, 1H, J¼4.4 Hz, CH),
7.00e7.17 (m, 9H, ArH), 7.35e7.41 (m, 5H, ArH); 13C NMR (75 MHz,
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.13 (t, 3H, J¼7.1 Hz,
CDCl3):
d
¼26.8, 29.8, 40.6, 42.2, 50.9, 57.8, 70.1, 115.8, 123.3, 124.2,
CH3), 2.18 (t, 1H, J¼9.1 Hz, CH), 2.26 (s, 3H, NCH3), 2.99 (dd, 1H,
J1¼5.8 Hz, J2¼8.5 Hz, CH), 3.29e3.37 (m, 2H, CHHN & NCH),
3.87e4.04 (m, 2H, OCH2), 4.38 (d, 1H, J¼3.8 Hz, CHHN), 7.14 (d, 2H,
J¼3.3 Hz, ArH), 7.22e7.23 (m, 1H, ArH), 7.36e7.50 (m, 9H, ArH), 7.74
124.8, 125.5, 125.6, 126.6, 128.6, 128.8, 128.9, 129.0, 129.1, 129.2,
130.2, 130.3, 130.5, 130.8, 131.0, 131.4, 138.1, 204.7; mass (ESþ) m/
z¼462.1 (Mþþ1).
(d, 2H, J¼5.4 Hz, ArH); 13C NMR (50 MHz, CDCl3):
d
¼14.3, 39.5, 39.7,
4.4. General procedure for the synthesis of compounds 8aed,
9aec, 14, 19.1a,b,e,f, 19.2a,e and 25a,b as exemplified 8a
47.0, 59.1, 61.1, 70.2, 114.4, 123.7, 125.0, 125.3, 128.1, 128.4, 128.6,
128.7, 129.6, 130.7, 131.1, 131.2, 134.4, 139.9, 141.8, 149.6, 173.9; mass
(ESþ) m/z¼450.2 (Mþþ1); DART-HRMS: MHþ, found 450.2178.
C29H28N3O3 requires 450.2182.
To a stirred solution of compound 4a (0.26 mmol, 0.10 g) in tol-
uene (15 mL) was added L-proline (0.39 mmol, 0.05 g) and stirred at
reflux temperature for 4 h. Thereafter reaction mixture was cool to
room temperature and extracted with EtOAc (3ꢁ10 mL) and water
(30 mL). The organic layers were combined, washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
4.3.21. Ethyl (2R,6R)-3-methyl-8,10-diphenyl-3,8,9-triazatetracyclo
[10.4.0.02,6.07,11]hexadeca-1(16),7(11),9,12,14-pentaene-5-carboxyl-
ate (anti-24a). Yield 8% as a white solid (9 mg from 100 mg), mp

5038
M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
Column chromatography of the residue over silica gel (hexanes/
EtOAc, 70:30, v/v) afforded pure 8a as white solid (90%, 0.102 g).
(CO2Me) cmꢂ1
;
1H NMR (200 MHz, CDCl3):
d
¼1.60e1.67 (m, 1H,
CHH), 1.72e1.77 (m, 1H, CHH), 1.84e1.89 (m, 1H, CHH), 1.94e2.04
(m, 1H, CHH), 2.19e2.25 (m, 1H, CHH), 2.31 (t, 1H, J¼11.1 Hz, CHH),
2.43e2.49 (m, 1H, CHH), 2.79e2.88 (m, 1H, NCH), 3.03 (s, 3H,
CO2Me), 3.28e3.36 (m, 2H, NCH2), 3.68 (s, 1H, NCH), 3.76e3.82 (m,
1H, NCHH), 6.71 (d, 1H, J¼7.7 Hz, ArH), 6.82 (t, 1H, J¼7.0 Hz, ArH),
7.08e7.14 (m, 3H, ArH), 7.18e7.22 (m, 4H, ArH), 7.24e7.32 (m, 4H,
4.4.1. (1R,14R)-9,10-Diphenyl-10,11,20-triazapentacyclo[12.6.0.02,7.08,12
16,20]icosa-2,4,6,11-tetraene-14-carbonitrile (8a). Mp 119e120 ꢀC; Rf
(hexanes/EtOAc, 70:30, v/v) 0.44; nmax (KBr) 2226 (CN) cmꢂ1; 1H NMR
(300 MHz, CDCl3):
.
0
d
¼1.78 (s, 2H, CH2), 1.93e2.01 (m, 3H, CH2),
2.34e2.35 (m, 2H, CH2), 2.75 (d, 1H, J¼14.1 Hz, CHH), 2.92e3.08 (m,
2H, NCH2), 3.20 (d, 1H, J¼14.0 Hz, CHH), 3.66 (s, 1H, NCH), 6.73 (d, 1H,
J¼7.1 Hz, ArH), 7.06e7.43 (m, 12H, ArH), 7.60 (d, 1H, J¼7.5 Hz, ArH);
ArH), 7.41 (d, 1H, J¼7.6 Hz, ArH); 13C NMR (50 MHz, CDCl3):
¼26.0,
d
28.8, 38.1, 39.8, 47.6, 51.6, 61.3, 70.9, 71.4, 118.2, 125.5, 125.6, 125.9,
127.2, 128.6, 128.8, 128.9, 129.2, 130.2, 131.1, 131.4, 136.6, 140.0,
140.6, 149.1, 175.3; mass (ESþ) m/z¼476.3 (Mþþ1); ESI-HRMS:
MHþ, found 476.2348. C31H30N3O2 requires 476.2338.
13C NMR (50 MHz, CDCl3):
d¼26.6, 33.3, 34.0, 43.2, 52.4, 55.4, 64.5,
120.3,124.9, 125.4, 126.6, 127.3, 127.4, 127.8, 128.6, 128.8, 128.82, 128.9,
129.0, 129.4, 129.8, 129.9, 130.2, 130.3, 132.2, 138.5, 139.9, 148.9; mass
(ESþ) m/z¼443.4 (Mþþ1); ESI-HRMS: MHþ, found 443.2283.
C30H27N4 requires 443.2236.
4.4.6. Methyl (1R,14R)-9-(4-chlorophenyl)-10-phenyl-10,11,20-
triazapentacyclo[12.6.0.02,7.08,12.016,20]icosa-2(7),3,5,8,11-pentaene-
14-carboxylate (9b). Yield 81% as a white solid (90 mg from 100 mg),
mp 175e176 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.33; nmax (KBr) 1725
4.4.2. (1R,14R)-9-(4-Chlorophenyl)-10-phenyl-10,11,20-triazapenta-
cyclo[12.6.0.02,7.08,12.016,20]icosa-2,4,6,11-tetraene-14-carbonitrile
(8b). Yield 85% as a white solid (143 mg from 150 mg), mp
193e194 ꢀC; Rf 0.42 (hexanes/EtOAc, 70:30, v/v); nmax (KBr) 2234
(CO2Me) cmꢂ1
;
1H NMR (200 MHz, CDCl3):
d
¼1.83e1.95 (m, 2H,
CH2), 2.16e2.41 (m, 2H, CH2), 2.55e2.79 (m, 2H, CH2), 2.98 (dd, 2H,
J1¼13.8 Hz, J2¼26.9 Hz, CHH), 3.21e3.35 (m, 1H, NCH2), 3.73 (s, 3H,
CO2Me), 4.30 (s, 1H, NCH), 6.72 (d, 1H, J¼7.3 Hz, ArH), 7.04e7.16 (m,
(CN) cmꢂ1; 1H NMR (200 MHz, CDCl3):
d
¼1.76 (s, 2H, CH2), 2.00 (m,
2H, CH2), 2.35e2.37 (m, 2H, CH2), 2.77 (d, 1H, J¼14.0 Hz, CHH), 2.91
(m,1H, NCH2), 3.02 (s,1H, CH2), 3.18 (d,1H, J¼14.1 Hz, CHH), 3.61 (m,
1H, CH2), 4.37 (s,1H, NCH), 6.73 (d,1H, J¼7.2 Hz, ArH), 7.06e7.14 (m,
3H, ArH), 7.20e7.34 (m, 8H, ArH), 7.60 (d,1H, J¼7.5Hz, ArH);13C NMR
4H, ArH), 7.19e7.38 (m, 9H, ArH); 13C NMR (50 MHz, CDCl3):
d
¼25.9,
28.7, 38.0, 39.7, 47.6, 51.5, 61.2, 70.9, 71.3, 118.4, 125.6, 126.0, 127.2,
127.5,128.9,129.0,129.2,129.5,129.8,131.6,132.3,134.7,136.6,139.2,
139.6,149.2,175.2; mass (ESþ) m/z¼510.3 (Mþþ1); ESI-HRMS: MHþ,
found 510.1954. C31H29ClN3O2 requires 510.1948.
(50 MHz, CDCl3):
d
¼26.5, 33.3, 34.0, 43.2, 52.4, 55.3, 64.5, 120.6,
124.8,125.5,126.8,127.6,127.9,128.4,129.1,129.3,130.0,131.6,131.9,
134.7, 137.4, 138.5, 139.6, 149.0; mass (ESþ) m/z¼477.4 (Mþþ1); ESI-
HRMS: MHþ, found 477.1846. C30H26ClN4 requires 477.1846.
4.4.7. Methyl (1R,14R)-10-methyl-10,11,20-triazapentacyclo[12.6.0.02,7
8,12.016,20]icosa-2(7),3,5,8,11-pentaene-14-carboxylate (9c). Yield 89%
as yellow oil (53 mg from 50 mg); Rf (hexanes/EtOAc, 50:50, v/v) 0.16;
nmax (Neat) 1728 (CO2Me) cmꢂ1 1H NMR (800 MHz, CDCl3):
.
0
4.4.3. (1R,14R)-10-Methyl-10,11,20-triazapentacyclo[12.6.0.02,7.08,12
16,20]icosa-2,4,6,11-tetraene-14-carbonitrile (8c). Yield 86% as
a white solid (52 mg from 50 mg), mp 119e120 ꢀC; Rf (hexanes/
EtOAc, 50:50, v/v) 0.26; nmax (KBr) 2231 (CN) cmꢂ1 1H NMR
(400 MHz, CDCl3):
.
;
0
d
¼1.59e1.64 (m, 1H, CHH), 1.77 (s, 1H, CHH), 1.83 (s, 2H, CH2),
2.11e2.17 (m, 1H, NCHH), 2.23 (t, 1H, J¼11.1 Hz, NCHH), 2.42 (s, 1H,
NCHH), 2.78 (s,1H, NCHH), 3.07 (s, 3H, CO2Me), 3.16 (d,1H, J¼16.2 Hz,
CHH), 3.29 (s, 1H, NCHH), 3.40 (s, 1H, NCH), 3.60 (d, 1H, J¼16.2 Hz,
CHH), 3.90 (s, 3H, NCH3), 7.17e7.21 (m, 2H, ArH), 7.38 (d,1H, J¼7.1 Hz,
ArH), 7.41 (d,1H, J¼7.0 Hz, ArH), 7.57 (s,1H, ArH); 13C NMR (200 MHz,
;
d
¼1.60e1.68 (m, 2H, CH2), 2.09e2.15 (m, 2H,
CH2), 2.49 (d, 1H, J¼14.2 Hz, CH2), 2.67e2.70 (m, 1H, CHH), 2.79 (s,
1H, CHH), 2.94 (d, 1H, J¼14.1 Hz, CHH), 3.11e3.36 (m, 1H, NCHH),
3.45e3.48 (m, 1H, NCHH), 3.77 (s, 4H, NCH3 & NCHH), 4.04 (s, 1H,
NCH), 7.04e7.16 (m, 4H, ArH), 7.05e7.15 (m, 4H, ArH), 7.43 (d, 1H,
CDCl3):
d¼22.9, 28.6, 29.9, 37.7, 39.1, 39.7, 48.0, 51.6, 72.1, 77.4, 119.9,
125.8, 126.0, 126.9, 128.9, 130.3, 147.6, 175.0; mass (ESþ) m/z¼338.2
(Mþþ1); ESI-HRMS: MHþ, found 338.1863. C20H24N3O2 requires
338.1869.
J¼7.1 Hz, ArH); 13C NMR (100 MHz, CDCl3):
¼26.2, 32.9, 33.9, 39.1,
d
42.9, 52.7, 55.4, 64.6, 76.2, 121.2, 126.7, 127.0, 127.9, 128.2, 128.4,
130.1,132.4, 137.7,147.7; mass (ESþ) m/z¼305.2 (Mþþ1); ESI-HRMS:
MHþ, found 305.1760. C19H21N4 requires 305.1766.
4.4.8. (7aR,12aS)-4,5-Diphenyl-7,7a,8,8a,9,10,11,12a-octahydro-5H-
pyrazolo[40,30:5,6]thieno[20,30:3,4]cyclohepta[1,2-b]pyrrolizine-7a-
carbonitrile (14). Yield 87% as a white solid (69 mg from 70 mg);
mp 200e202 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.22; nmax (KBr)
4.4.4. (8aR,13aR)-6-(4-Methoxyphenyl)-5-phenyl-8,8a,9,9a,10,11,12,
13a-octahydro-6H-benzo[3,4]pyrazolo[40,30:5,6]cyclohepta[1,2-b]pyr-
rolizine-8a-carbonitrile (8d). Yield 85% as a white solid (96 mg from
100 mg); mp 202e204 ꢀC; [found: C, 78.95; H, 5.88; N, 11.70.
C31H28N4O (Exact mass: 472.2263) requires C, 78.79; H, 5.97; N,
11.86.]; Rf (hexanes/EtOAc, 70:30, v/v) 0.24; nmax (KBr) 2236 (CN)
2231 (CN) cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼1.84e1.89 (m, 2H,
CH2), 2.01 (s, 2H, CH2), 2.36e2.45 (m, 2H, CH2), 2.72 (d, 1H,
J¼11.7 Hz, CHH), 3.03 (s, 1H, NCH2), 3.32 (d, 2H, J¼14.2 Hz, CHH),
3.86 (s, 1H, CH), 4.54 (s, 1H, NCH), 6.43 (d, 1H, J¼5.2 Hz, ArH), 6.97
(d, 1H, J¼5.0 Hz, ArH), 7.14e7.27 (m, 10H, ArH); 13C NMR (75 MHz,
cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d¼1.78e1.84 (m, 2H, CH2),
2.00e2.04 (m, 2H, CH2), 2.30e2.40 (m, 2H, CH2), 2.75 (d, 1H,
J¼14.0 Hz, CHH), 2.91e2.93 (m,1H, NCH2), 3.04e3.07 (m,1H, NCH2),
3.18 (d,1H, J¼14.0 Hz, CHH), 3.64 (s,1H, CH), 3.80 (s, 3H, CH3), 4.38 (s,
1H, NCH), 6.74 (dd, 1H, J1¼1.0 Hz, J2¼7.5 Hz, ArH), 6.82 (d, 2H,
J¼9.0 Hz, ArH), 7.06e7.10 (m, 1H, ArH), 7.13e7.17 (m, 2H, ArH),
7.17e7.22 (m, 3H, ArH), 7.28e7.34 (m, 3H, ArH), 7.60 (d,1H, J¼7.5 Hz,
CDCl3):
d
¼22.9, 26.6, 32.5, 34.9, 43.5, 56.6, 64.9, 72.6, 116.8, 124.5,
125.3, 127.4, 128.0, 128.7, 128.8, 128.9, 130.0, 130.3, 138.8, 139.9,
142.9, 148.7; mass (ESþ) m/z¼449.3 (Mþþ1); ESI-HRMS: MHþ,
found: 449.1826. C28H25N4S requires 449.1800.
4.4.9. Ethyl (1R,13S)-4,5-diphenyl-3,4,14-triazapentacyclo[11.6.0.02,6
.
ArH); 13C NMR (75 MHz, CDCl3):
d
¼26.6, 33.3, 34.0, 43.1, 52.5, 55.4,
0
7,12.014,18]nonadeca-2,5,7,9,11-pentaene-19-carboxylate (syn-19.1a).
55.6, 64.5, 76.2, 114.1, 119.9, 125.0, 126.5, 126.8, 127.8, 128.5, 128.7,
129.4,129.7,130.0,130.3,132.4,133.1,138.5,138.8,148.5,158.7; mass
(ESþ) m/z¼473.3 (Mþþ1).
Yield 34% as a white solid (38 mg from 100 mg), mp 160e161 ꢀC;
[found: C, 78.36; H, 6.04; N, 8.71. C31H29N3O2 (Exact mass: 475.2260)
requires C, 78.29; H, 6.15; N, 8.84%]; Rf (hexanes/EtOAc, 70:30, v/v)
0.24; nmax (KBr) 1722 (CO2Et) cmꢂ1 1H NMR (300 MHz, CDCl3):
;
4.4.5. Methyl (1R,14R)-9,10-diphenyl-10,11,20-triazapentacyclo
[12.6.0.02,7.08,12.016,20]icosa-2(7),3,5,8,11-pentaene-14-carboxylate
(9a). Yield 88% as a yellow solid (119 mg from 120 mg); mp
119e120 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.34; nmax (KBr) 1727
d
¼1.18e1.26 (m, 1H, CHH), 1.32 (t, 3H, J¼7.1 Hz, CH3), 1.90e2.04 (m,
3H, CHH & CH2), 2.92e3.02 (m, 2H, CH), 3.99e4.02 (m, 3H, NCH &
NCH2), 4.20e4.24 (m, 3H, NCH & OCH2), 6.99e7.11 (m, 3H, ArH),
7.14e7.26 (m, 5H, ArH), 7.35e7.39 (m, 6H, ArH); 13C NMR (50 MHz,

M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
5039
CDCl3):
d
¼14.5, 27.4, 28.9, 42.5, 45.6, 53.4, 60.7, 66.2, 68.2, 115.2,
100 mg), mp 166e167 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.14, nmax
(KBr) 1726 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3):
123.3, 125.3, 126.1, 127.1, 127.9, 128.8, 128.9, 129.0, 129.8, 130.8, 131.4,
d¼1.34 (t, 3H,
140.1, 174.0; mass (ESþ) m/z¼476.2 (Mþþ1).
J¼7.1 Hz, CH3), 1.65e1.72 (m, 1H, CHH), 1.84e1.93 (m, 2H, CH2),
2.09e2.18 (m, 1H, CHH), 2.39 (s, 3H, CH3), 2.77 (dd, 1H, J1¼7.7 Hz,
J2¼17.5 Hz, CH), 3.41e3.48 (m, 2H, NCHH & NCH), 3.63 (dd, 1H,
J1¼11.1 Hz, J2¼13.6 Hz, CH), 4.21e4.28 (m, 4H, NCH & NCHH),
7.00e7.04 (m, 2H, ArH), 7.19e7.22 (m, 10H, ArH), 7.56 (d, 1H,
4.4.10. Ethyl
(1R,13R)-4,5-diphenyl-3,4,14-triazapentacyclo[11.6.0.
0
2,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-19-carboxylate (anti-
19.1a). Yield 57% as a white solid (64 mg from 100 mg), mp
171e172 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.15; nmax (KBr) 1723
J¼7.2 Hz, ArH); 13C NMR (50 MHz, CDCl3):
¼14.5, 21.6, 26.2, 28.7,
d
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼1.34 (t, 3H, J¼7.1 Hz,
39.2, 49.2, 50.7, 60.9, 67.9, 69.0, 116.4, 123.9, 125.3, 126.0, 126.2,
126.8, 126.9, 128.0, 128.7, 129.8, 130.2, 130.9, 135.1, 138.8, 138.9,
140.0, 150.8, 173.1; mass (ESþ) m/z¼490.2 (Mþþ1); DART-HRMS:
MHþ, found 490.2505. C32H32N3O2 requires 490.2494.
CH3), 1.18e1.26 (m, 1H, CHH), 1.90e2.04 (m, 3H, CHH & CH2),
2.92e3.02 (m, 2H, CH), 3.99e4.02 (m, 3H, NCH & NCH2), 4.20e4.24
(m, 3H, NCH & OCH2), 6.99e7.11 (m, 3H, ArH), 7.14e7.26 (m, 5H,
ArH), 7.35e7.39 (m, 6H, ArH); 13C NMR (50 MHz, CDCl3):
d¼14.5,
27.4, 28.9, 42.5, 45.6, 53.4, 60.7, 66.2, 68.2, 115.2, 123.3, 125.3, 126.1,
127.1, 127.9, 128.8, 128.9, 129.0, 129.8, 130.8, 131.4, 140.1, 174.0; mass
(ESþ) m/z¼476.2 (Mþþ1); ESI-HRMS: MHþ, found 476.2346.
C31H30N3O2 requires 476.2338.
4.4.15. Ethyl (1R,13S)-4-(4-nitrophenyl)-3,4,14-triazapentacyclo
[11.6.0.02,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-19-carboxylate
(syn-19.1f). Yield 42% as a yellow solid (42 mg from 100 mg), mp
157e158 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.21; nmax (KBr) 1724
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.11 (t, 3H, J¼6.9 Hz,
4.4.11. Ethyl (1R,13S)-5-(4-chlorophenyl)-4-phenyl-3,4,14-triaza-
pentacyclo[11.6.0.02,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-19-
carboxylate (syn-19.1b). Yield 40% as a white solid (67 mg from
150 mg), mp 140e142 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.22; nmax
CH3), 1.43e1.50 (m, 1H, CHH), 1.75e1.86 (m, 2H, CH2), 1.99e2.00 (m,
1H, CHH), 2.88e2.93 (m, 1H, CH), 3.05e3.06 (m, 2H, CH), 3.59e3.67
(m, 1H, NCH), 3.94e3.96 (m, 2H, OCH2), 4.29e4.31 (m, 1H, NCHH &
NCH) 7.24e7.36 (m, 2H, ArH), 7.49e7.54 (m, 2H, ArH), 7.72 (d, 2H,
J¼8.6 Hz, ArH), 8.04 (s, 1H, ArH), 8.34 (d, 2H, J¼8.7 Hz, ArH); 13C
(KBr) 1720 (CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼1.24e1.26
(m, 1H, CHH), 1.32 (t, 3H, J¼7.1 Hz, CH3), 1.90e2.04 (m, 3H, CHH &
CH2), 2.92e3.01 (m, 2H, CH2), 3.92e4.01 (m, 3H, NCH & NCH2),
4.20e4.25 (m, 3H, NCH & OCH2), 7.07 (s, 2H, ArH), 7.11e7.18 (m, 3H,
ArH), 7.22e7.29 (m, 3H, ArH), 7.36 (s, 5H, ArH); 13C NMR (50 MHz,
NMR (50 MHz, CDCl3):
d
¼14.3, 25.5, 28.1, 39.5, 51.8, 52.9, 61.1, 65.0,
66.6, 119.8, 123.2, 125.0, 126.8, 128.4, 129.1, 133.6, 137.3, 149.2, 145.1,
146.5, 172.6; mass (ESþ) m/z¼445.3 (Mþþ1); ESI-HRMS: MHþ,
found 445.1879. C25H25N4O4 requires 445.1876.
CDCl3):
d
¼14.5, 27.4, 28.9, 42.5, 50.5, 53.4, 60.7, 66.2, 68.1, 115.4,
123.2,125.3,126.3,127.3,127.9,128.0,129.1,129.3,129.8,129.9,132.1,
135.1,135.4,137.3,139.8,150.3,174.0; mass (ESþ) m/z¼510.2 (Mþþ1);
ESI-HRMS: MHþ, found 510.1937. C31H29ClN3O2 requires 510.1948.
4.4.16. Ethyl (1R,13R)-4-(4-nitrophenyl)-3,4,14-triazapentacyclo
[11.6.0.02,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-19-carboxylate
(anti-19.1f). Yield 54% as a yellow solid (61 mg from 100 mg), mp
162e163 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.13; nmax (KBr) 1724
4.4.12. Ethyl (1R,13R)-5-(4-chlorophenyl)-4-phenyl-3,4,14-triazap-
entacyclo[11.6.0.02,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-19-
carboxylate (anti-19.1b). Yield 57% as a white solid (96 mg from
150 mg), mp 150e151 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.14; nmax
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.10 (t, 3H, J¼7.1 Hz,
CH3), 1.42e1.45 (m, 1H, CHH), 1.77e1.88 (m, 2H, CH2), 2.00e2.10 (m,
1H, CHH), 2.74 (dd, 1H, J1¼7.7 Hz, J2¼17.2 Hz, CH), 2.99 (t, 1H,
J¼10.4 Hz, CH), 3.37e3.44 (m, 1H, NCHH), 3.55e3.66 (m, 1H, NCH),
3.77e3.99 (m, 2H, OCH2), 4.11e4.18 (m, 1H, NCHH), 4.36 (d, 1H,
J¼14.0 Hz, NCH), 7.30e7.36 (m, 2H, ArH), 7.53e7.60 (m, 4H, ArH),
7.99 (s, 1H, ArH), 8.30 (d, 1H, J¼8.7 Hz, ArH); 13C NMR (50 MHz,
(KBr) 1723 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
¼1.34 (t, 3H,
J¼7.1 Hz, CH3), 1.65e1.69 (m, 1H, CHH), 1.84e1.93 (m, 2H, CH2),
2.09e2.21 (m, 1H, CH), 2.71e2.80 (m, 1H, CH), 3.40e3.47 (m, 2H,
CH2), 3.58e3.66 (m, 1H, CH), 4.21e4.35 (m, 4H, NCH, NCHH &
OCH2), 6.95 (d, 1H, J¼7.5 Hz, ArH), 7.04 (t, 1H, J¼7.4 Hz, ArH),
7.18e7.29 (m, 8H, ArH), 7.36 (d, 2H, J¼8.5 Hz, ArH), 7.58 (d, 2H,
CDCl3):
d
¼14.1, 25.6, 28.5, 39.4, 48.9, 50.7, 61.0, 68.6, 70.1, 120.8,
123.2,124.5,126.1,126.8,127.7,128.1,129.2,129.9,130.3,133.0,134.6,
137.0, 140.6, 145.0, 147.7, 172.8; mass (ESþ) m/z¼445.3 (Mþþ1); ESI-
HRMS: MHþ, found 445.1885. C25H25N4O4 requires 445.1876.
J¼7.6 Hz, ArH); 13C NMR (50 MHz, CDCl3):
¼14.5, 26.2, 28.7, 39.1,
d
49.2, 50.7, 60.9, 67.9, 68.9, 116.7, 123.8, 125.4, 126.28, 126.34, 126.9,
127.3,128.9,129.4,129.5,130.4,131.7,135.1,135.3,137.3,139.6,150.9,
173.0; mass (ESþ) m/z¼510.2 (Mþþ1); ESI-HRMS: MHþ, found
510.1938. C31H29ClN3O2 requires 510.1948.
4.4.17. Methyl (1R,13S)-4,5-diphenyl-3,4,14-triazapentacyclo
[11.6.0.02,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-19-carboxylate
(syn-19.2a). Yield 41% as a white solid (93 mg from 200 mg), mp
210e211 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.30; nmax (KBr) 1732
4.4.13. Ethyl (1R,13S)-5-(4-methylphenyl)-4-phenyl-3,4,14-triaza-
pentacyclo[11.6.0.02,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-19-
carboxylate (syn-19.1e). Yield 40% as a white solid (45 mg from
100 mg), mp 198e199 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.23; nmax
(CO2Me) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼1.58e1.63 (m, 2H,
CHH),1.90 (s, 2H, CH2), 2.92e3.01 (m, 3H, CHH), 3.77 (s, 3H, CO2Me),
3.96e4.02 (m, 3H, NCHH & NCH), 4.26e4.27 (m,1H, NCH), 7.01e7.23
(m, 9H, ArH), 7.35e7.39 (m, 6H, ArH); 13C NMR (50 MHz, CDCl3):
(KBr) 1726 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
¼1.32 (t, 3H,
d
¼27.4, 28.9, 42.5, 50.6, 51.8, 53.5, 66.1, 68.2,115.1,123.3,125.2,126.1,
J¼7.1 Hz, CH3), 1.60 (s, 1H, CHH), 1.90e2.04 (m, 3H, CH2), 2.40 (s, 3H,
CH3), 2.92e3.01 (m, 3H, CHH), 3.98e4.01 (m, 3H, NCHH & NCH),
4.20e4.24 (m, 3H, NCH & NCHH), 7.02 (t, 1H, J¼7.5 Hz, ArH), 7.11 (t,
2H, J¼7.4 Hz, ArH), 7.18e7.28 (m, 9H, ArH), 7.35 (d, 1H, J¼7.4 Hz,
127.0,127.8,128.8,128.9,129.0,129.3,129.8,130.7,131.3,135.1,138.6,
140.0, 149.9, 174.5; mass (ESþ) m/z¼462.2 (Mþþ1); DART-HRMS:
MHþ, found 462.2146. C30H28N3O2 requires 462.2185.
ArH); 13C NMR (50 MHz, CDCl3):
d
¼14.5, 21.6, 27.4, 28.9, 42.5, 50.6,
4.4.18. Methyl (1R,13R)-4,5-diphenyl-3,4,14-triazapentacyclo
[11.6.0.02,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-19-carboxylate
(anti-19.2a). Yield 59% as a white solid (133 mg from 200 mg), mp
185e186 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.15; nmax (KBr) 1732
53.4, 60.6, 66.1, 68.2, 115.0, 123.3, 125.2, 125.9, 126.9, 127.8, 128.2,
128.8, 129.5, 129.6, 129.8, 130.6, 135.2, 138.77, 138.84, 140.1, 150.0,
174.1; mass (ESþ) m/z¼490.2 (Mþþ1); DART-HRMS: MHþ, found
490.2505. C32H32N3O2 requires 490.2494.
(CO2Me) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼1.60e1.68 (m, 1H,
CHH), 1.84e1.91 (m, 2H, CH2), 2.10e2.21 (m, 1H, CHH), 2.74e2.82
(m, 1H, CH), 3.41e3.52 (m, 2H, NCHH & NCH), 3.60e3.68 (dd, 1H,
J¼11.0, 13.3 Hz, CH), 3.81 (s, 3H, CO2Me), 4.28e4.35 (m, 2H, NCH &
NCHH), 6.95e7.03 (m, 2H, ArH), 7.15e7.28 (m, 9H, ArH), 7.37e7.39
4.4.14. Ethyl (1R,13R)-5-(4-methylphenyl)-4-phenyl-3,4,14-triaza-
pentacyclo[11.6.0.02,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-19-
carboxylate (anti-19.1e). Yield 55% as a white solid (61 mg from

5040
M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
(m, 3H, ArH), 7.57 (d, 1H, J¼7.6 Hz, ArH); 13C NMR (50 MHz, CDCl3):
142.4, 149.2, 172.6; mass (ESþ) m/z¼476.2 (Mþþ1); DART-HRMS:
d¼21.6, 26.1, 28.9, 39.2, 49.2, 50.4, 52.1, 68.0, 68.9, 116.4, 123.9,
MHþ, found 476.2322. C31H30N3O2 requires 476.2338.
125.3, 125.7, 126.0, 126.2, 126.9, 127.0, 127.8, 128.7, 129.8, 130.2,
130.8, 134.6, 138.9, 139.0, 149.9, 150.4, 173.3; DART-HRMS: MHþ,
found 462.2176. C30H28N3O2 requires 462.2185.
4.4.23. Ethyl (1R,13S)-5-(4-chlorophenyl)-3-phenyl-3,4,14-tria-
zapentacyclo[11.6.0.02,6.07,12.014,18]nonadeca-2(6),4,7,9,11-pentaene-
19-carboxylate (syn-25b). Yield 42% as a white (49 mg from
100 mg) solid, mp 209e210 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.31;
4.4.19. Methyl (1R,13S)-5-(4-methylphenyl)-4-phenyl-3,4,14-
triazapentacyclo[11.6.0.02,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-
19-carboxylate (syn-19.2e). Yield 38% as a white solid (88 mg from
200 mg), mp 167e168 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.29; nmax
nmax (KBr) 1718 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d¼1.12 (t,
3H, J¼6.8 Hz, CH3), 1.50e1.53 (m, 1H, CHH), 1.76e1.84 (m, 2H, CH2),
1.99e2.04 (m, 1H, CHH), 2.99e3.10 (m, 3H, CH &CHHN), 3.62e3.65
(m, 1H, NCH), 3.90e3.92 (m, 2H, NCH), 4.23e4.29 (m, 2H, OCH2),
7.14 (s, 2H, ArH), 7.35e7.49 (m, 9H, ArH), 7.70 (d, 2H, J¼7.7 Hz, ArH);
(KBr) 1730 (CO2Me) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d¼1.26e1.34
(m, 1H, CHH), 1.89e2.04 (m, 3H, CH2), 2.40 (s, 3H, CH3), 2.94e3.01
(m, 3H, CHH), 3.77 (s, 3H, CO2Me), 3.99e4.01 (m, 3H, NCHH & NCH),
4.25 (s, 1H, NCH), 7.04 (d, 1H, J¼6.8 Hz, ArH), 7.11 (t, 2H, J¼6.3 Hz,
ArH), 7.20e7.26 (m, 9H, ArH), 7.36 (d, 1H, J¼6.9 Hz, ArH); 13C NMR
13C NMR (50 MHz, CDCl3):
d
¼14.4, 25.3, 27.8, 39.6, 51.1, 52.3, 60.8,
65.4, 66.5, 114.9, 123.4, 125.0, 126.1, 127.9, 128.3, 128.8, 129.4, 129.5,
129.8, 130.8, 132.9, 133.9, 134.3, 139.9,141.0, 148.3,172.7; mass (ESþ)
m/z¼510.2 (Mþþ1); ESI-HRMS: MHþ, found 510.1932.
C31H29ClN3O2 requires 510.1948.
(50 MHz, CDCl3):
d
¼21.6, 27.4, 28.9, 42.5, 50.6, 51.7, 53.5, 66.2, 68.2,
115.0, 123.3, 125.2, 126.0, 127.0, 127.8, 128.2, 128.7, 129.5, 129.7,
129.8, 130.6, 138.9, 140.1, 150.1, 174.5; mass (ESþ) m/z¼476.2
(Mþþ1); DART-HRMS: MHþ, found 476.2333. C31H30N3O2 requires
476.2338.
4.4.24. Ethyl (1R,13R)-5-(4-chlorophenyl)-3-phenyl-3,4,14-triaza-
pentacyclo[11.6.0.02,6.07,12.014,18]nonadeca-2(6),4,7,9,11-pentaene-19-
carboxylate (anti-25b). Yield 55% as a yellow solid (59 mg from
100 mg), mp >250 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.19; nmax
4.4.20. Methyl (1R,13R)-5-(4-methylphenyl)-4-phenyl-3,4,14-
triazapentacyclo[11.6.0.02,6.07,12.014,18]nonadeca-2,5,7,9,11-pentaene-
19-carboxylate (anti-19.2e). Yield 56% as a white solid (122 mg
from 200 mg), mp 187e188 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.14;
(KBr) 1718 (CO2Et) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d¼1.11 (t, 3H,
J¼7.1 Hz, CH3), 1.43e1.47 (m, 1H, CHH), 1.77e1.85 (m, 2H, CH2),
2.00e2.13 (m, 1H, CHH), 2.74 (dd, 1H, J1¼8.2 Hz, J2¼16.6 Hz, CH),
2.99 (t, 1H, J¼10.3 Hz, CH), 3.36e3.44 (m, 1H, NCHH), 3.55e3.66 (m,
1H, NCH), 3.75e3.95 (m, 2H, OCH2), 4.12e4.17 (m, 1H, NCHH), 4.40
(d, 1H, J¼13.7 Hz, NCH), 7.14 (t, 1H, J¼7.4 Hz, ArH), 7.20 (d, 1H,
J¼7.6 Hz, ArH), 7.31 (d, 1H, J¼7.3 Hz, ArH), 7.38e7.44 (m, 7H, ArH),
7.55 (d, 1H, J¼7.4 Hz, ArH), 7.62 (m, 2H, J¼8.3 Hz, ArH); 13C NMR
;
nmax (KBr) 1730 (CO2Me) cmꢂ1 1H NMR (300 MHz, CDCl3):
d
¼1.61e1.67 (m, 1H, CHH), 1.88e1.93 (m, 2H, CH2), 2.10e2.20 (m,
1H, CHH), 2.39 (s, 3H, CH3), 2.80 (dd, 1H, J1¼7.0 Hz, J2¼16.5 Hz, CH),
3.47e3.53 (m, 2H, NCHH & NCH), 3.65 (t, 1H, J¼12.3 Hz, CH), 3.81 (s,
3H, CO2Me), 4.33e4.38 (m, 2H, NCH & NCHH), 7.01 (d, 2H, J¼5.6 Hz,
ArH), 7.16e7.26 (m, 9H, ArH), 7.57 (d, 1H, J¼7.4 Hz, ArH); 13C NMR
(50 MHz, CDCl3):
d
¼14.1, 25.5, 28.1, 39.6, 48.5, 50.3, 60.6, 69.1, 70.0,
(50 MHz, CDCl3):
d
¼21.6, 26.1, 28.8, 39.2, 49.2, 50.4, 52.1, 68.0, 68.9,
115.6, 124.1, 125.9, 126.2, 127.0, 128.0, 128.9, 129.2, 129.3, 130.5,
130.9, 132.4, 133.8, 134.3, 139.5, 142.6, 148.0, 172.5; mass (ESþ) m/
z¼510.2 (Mþþ1); ESI-HRMS: MHþ, found 510.1952. C31H29ClN3O2
requires 510.1948.
116.3, 123.9, 125.3, 125.4, 126.0, 126.2, 126.9, 127.0, 127.8, 128.7,
129.8, 130.2, 130.8, 134.6, 138.9, 139.0, 149.9, 150.4, 173.3; mass
(ESþ) m/z¼476.2 (Mþþ1); DART-HRMS: MHþ, found 476.2339.
C31H30N3O2 requires 476.2338.
4.5. General procedure for the synthesis of compounds
10aed, 11aec, 15, 20.1a,b,e,f, 20.2a,e and 26a,b as exemplified
10a
4.4.21. Ethyl (1R,13S)-3,5-diphenyl-3,4,14-triazapentacyclo[11.6.0.02,6
7,12.014,18]nonadeca-2(6),4,7,9,11-pentaene-19-carboxylate
(syn-
.
0
25a). Yield 37% as a white solid (42 mg from 100 mg), mp
143e144 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.29; nmax (KBr) 1727
To a stirred solution of compound 4a (0.51 mmol, 200 mg) in
EtOH (15 mL) was added hydroxylamine hydrochloride (0.62 mmol,
43 mg) and sodium acetate (0.62 mmol, 51 mg) and the reaction
was continued at room temperature for 30 min. Thereafter EtOH
was evaporated and the residue was extracted with EtOAc
(3ꢁ15 mL) and water (30 mL). The organic layers were combined
washed with brine, dried over Na2SO4, and evaporated under re-
duced pressure. Subsequently the reaction mixture was diluted
with CH2Cl2 (15 mL) followed by addition of Et3N (0.77 mmol,
0.11 mL) and NaOCl (1.02 mmol, 0.068 mL) and stirred at rt for
overnight. After completion of the reaction water (30 mL) was
added and layers were separated. The aqueous layer was again
extracted with CH2Cl2 (2ꢁ15 mL). The organic layers were com-
bined, washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. Column chromatography of the residue
over silica gel (hexanes/EtOAc, 90:10, v/v) afforded pure 10a as
a white solid (65%, 134 mg).
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.12 (t, 3H, J¼7.1 Hz,
CH3), 1.51e1.53 (m,1H, CHH), 1.73e1.84 (m, 2H, CH2), 1.98e2.00 (m,
1H CHH), 2.97e3.13 (m, 3H, CH & CHHN), 3.63e3.66 (m, 1H, NCH),
3.89e3.92 (m, 2H, NCH), 4.23e4.33 (m, 2H, OCH2), 7.09e7.16 (m,
2H, ArH), 7.38e7.53 (m, 10H, ArH), 7.73e7.75 (m, 2H, ArH); 13C
NMR (50 MHz, CDCl3):
d
¼14.4, 25.3, 27.8, 39.7, 51.2, 52.4, 60.7, 65.4,
66.6, 114.8, 123.5, 125.1, 125.9, 127.9, 128.1, 128.4, 128.6, 129.2,
129.5, 130.1, 134.4, 140.0, 149.5, 172.8; mass (ESþ) m/z¼476.2
(Mþþ1); DART-HRMS: MHþ, found 476.2322. C31H30N3O2 requires
476.2338.
4.4.22. Ethyl
0
(1R,13R)-3,5-diphenyl-3,4,14-triazapentacyclo[11.6.0.
2,6.07,12.014,18]nonadeca-2(6),4,7,9,11-pentaene-19-carboxylate
(anti-25a). Yield 7% as a white solid (64 mg from 100 mg), mp
199e200 ꢀC; Rf (hexanes/EtOAc, 70:30, v/v) 0.19; nmax (KBr) 1727
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼1.12 (t, 3H, J¼7.2 Hz,
CH3), 1.43e1.49 (m, 1H, CHH), 1.77e1.87 (m, 2H, CH2), 2.00e2.10 (m,
1H, CHH), 2.74 (dd, 1H, J1¼8.0 Hz, J2¼16.2 Hz, CH), 3.00 (t, 1H,
J¼10.3 Hz, CH), 3.36e3.44 (m, 1H, NCHH), 3.56e3.67 (m, 1H, NCH),
3.76e3.95 (m, 2H, OCH2), 4.11e4.16 (m, 1H, NCHH), 4.41 (d, 1H,
J¼13.7 Hz, NCH), 7.11 (t, 1H, J¼7.5 Hz, ArH), 7.20 (t, 1H, J¼7.3 Hz,
ArH), 7.34 (d,1H, J¼7.7 Hz, ArH), 7.40e7.44 (m, 8H, ArH), 7.54 (d,1H,
J¼7.5 Hz, ArH), 7.66e7.68 (m, 2H, ArH); 13C NMR (50 MHz, CDCl3):
4.5.1. 10,11-Diphenyl-4-oxa-3,9,10-triazatetracyclo[11.4.0.02,6.08,12
heptadeca-1(17),2,8,13,15-pentaene-6-carbonitrile (10a). Mp 158e159
ꢀC; Rf (hexanes/EtOAc, 80:20, v/v) 0.57; nmax (KBr) 2212 (CN) cmꢂ1
1H NMR (300 MHz, CDCl3):
]
;
d
¼3.40e3.50 (m, 2H, CH2), 4.41 (d, 1H,
J¼9.3 Hz, OCHH), 5.00 (d, 1H, J¼9.2 Hz, OCHH), 6.86 (d, 1H, J¼7.7 Hz,
ArH), 7.09 (d, 2H, J¼6.9 Hz, ArH), 7.19e7.35 (m, 10H, ArH), 7.73 (d, 1H,
d
¼14.1, 25.5, 28.1, 39.6, 48.5, 50.4, 60.6, 69.1, 70.1, 115.5, 124.3, 125.8,
J¼6.8 Hz, ArH); 13C NMR (50 MHz, CDCl3):
¼29.8, 30.4, 56.7, 117.9,
d
126.0, 126.9, 128.0, 128.4, 128.6, 129.1, 129.2, 131.1, 133.8, 139.5,
119.0, 125.4, 125.7, 127.4, 127.9, 128.6, 129.0, 129.1, 129.2, 129.3, 129.8,

M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
5041
130.4, 130.9, 132.0, 139.3, 141.9, 145.3, 156.8; mass (ESþ) m/z¼403.3
(Mþþ1); ESI-HRMS [MH]þ, found 403.1572. C26H19N4O requires
403.1559.
9H, ArH), 7.63 (d, 1H, J¼7.3 Hz, ArH); 13C NMR (50 MHz, CDCl3):
d
¼29.0, 53.3, 69.7, 119.4, 125.4, 127.2, 127.9, 128.5, 129.2, 129.8,
130.0, 131.7, 135.1, 139.2, 139.9, 147.1, 159.8, 171.8; mass (ESþ) m/
z¼470.1 (Mþþ1).
4.5.2. 11-(4-Chlorophenyl)-10-phenyl-4-oxa-3,9,10-triazatetracyclo
[11.4.0.02,6.08,12]heptadeca-1(17),2,8,13,15-pentaene-6-carbonitrile
(10b). Yield 66% as a white solid (102 mg from 150 mg), mp
121e122 ꢀC; Rf (hexanes/EtOAc, 80:20, v/v) 0.54; nmax (KBr) 2235
4.5.7. Methyl 10-methyl-4-oxa-3,9,10-triazatetracyclo[11.4.0.02,6.08,12
]
heptadeca-1(17),2,8,11,13,15-hexaene-6-carboxylate (11c). Yield 69%
as a white solid (144 mg from 200 mg), mp 167e168 ꢀC; Rf (hexanes/
(CN) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
¼3.38e3.49 (m, 2H, CH2),
EtOAc, 70:30, v/v) 0.34; nmax (KBr) 1724 (CO2Me) cmꢂ1 1H NMR
;
4.39 (d, 1H, J¼9.2 Hz, OCHH), 4.99 (d, 1H, J¼9.2 Hz, OCHH), 6.86
(d, 1H, J¼6.9 Hz, ArH), 7.02 (d, 2H, J¼8.5 Hz, ArH), 7.18e7.37 (m,
9H, ArH), 7.75 (dd, 1H, J1¼1.2 Hz, J2¼7.5 Hz, ArH); 13C NMR
(800 MHz, CDCl3):
d
¼3.17 (d, 1H, J¼14.9 Hz, CHH), 3.54 (s, 3H,
CO2Me), 3.58 (d, 1H, J¼15.6 Hz, CHH), 3.88 (s, 3H, NCH3), 4.50 (d, 1H,
J¼5.8 Hz, OCHH), 4.77 (d,1H, J¼5.9 Hz, OCHH), 7.24 (s, 1H, ArH), 7.38
(s, 1H, ArH), 7.52 (d, 1H, J¼4.3 Hz, ArH), 7.70 (s, 1H, ArH), 7.88 (d, 2H,
(50 MHz, CDCl3):
d
¼29.9, 30.3, 56.8, 117.8, 119.2, 125.3, 125.5,
125.8, 127.7, 128.2, 128.9, 129.1, 129.3, 129.4, 129.9, 131.1, 131.7,
132.0, 135.5, 139.1, 140.6, 145.4, 156.7; mass (ESþ) m/z¼437.3
(Mþþ1); ESI-HRMS: MHþ, found 437.1180. C26H18ClN4O requires
437.1169.
J¼4.3 Hz, ArH); 13C NMR (200 MHz, CDCl3):
¼33.3, 39.2, 53.0, 62.3,
d
79.4, 119.4, 125.5, 126.3, 126.6, 129.5, 129.9, 130.3, 130.5, 145.6, 159.8,
171.1; mass (ESþ) m/z¼298.0 (Mþþ1); ESI-HRMS: MHþ, found
298.1198. C16H16N3O3 requires 298.1192.
4.5.3. 10-Methyl-4-oxa-3,9,10-triazatetracyclo[11.4.0.02,6.08,12]hepta-
deca-1(17),2,8,13,15-pentaene-6-carbonitrile (10c). Yield 67% as
a white solid (142 mg from 200 mg), mp 136e137 ꢀC; Rf (hexanes/
4.5.8. 4,5-Diphenyl-5,7,7a,8-tetrahydropyrazolo[30,40:4,5]thieno
[30,20:6,7]cyclohepta[1,2-c]isoxazole-7a-carbonitrile (15). Yield 60%
as a white solid (124 mg from 200 mg), mp 136e138 ꢀC; Rf (hexanes/
EtOAc, 70:30, v/v) 0.24; nmax (KBr) 2234 (CN) cmꢂ1
;
1H NMR
EtOAc, 80:20, v/v) 0.42, nmax (KBr) 2242 (CN) cmꢂ1 1H NMR
;
(400 MHz, CDCl3):
d
¼3.27 (d, 1H, J¼15.4 Hz, CHH), 3.52 (d, 1H,
(400 MHz, CDCl3)
OCHH), 6.01 (s,1H, ArH), 6.48 (s,1H, ArH), 7.00 (s,1H, ArH), 7.25e7.32
(m, 9H, ArH); 13C NMR (100 MHz, CDCl3)
118.7, 121.1, 125.4, 125.6, 126.9, 127.7, 128.5, 128.6, 128.8, 129.1, 130.3,
131.9, 140.0, 144.5, 147.9; mass (ESþ) m/z¼409.3 (Mþþ1); ESI-HRMS
calcd for C24H17N4OS [MH]þ: 409.1123; found: 409.1127.
d
¼3.72 (s, 2H, CH2), 4.82 (s,1H, OCHH), 5.95 (s,1H,
J¼15.4 Hz, CHH), 3.92 (s, 3H, NCH3), 4.69 (d, 1H, J¼8.8 Hz, OCHH),
4.86 (d, 1H, J¼8.8 Hz, OCHH), 7.28 (s, 1H, ArH), 7.45 (t, 1H, J¼7.2 Hz,
ArH), 7.64 (d, 1H, J¼7.8 Hz, ArH), 7.87 (d, 2H, J¼11.6 Hz, ArH); 13C
d¼32.7, 33.8, 60.0, 107.2,
NMR (100 MHz, CDCl3):
d
¼35.5, 39.4, 48.9, 79.2, 117.1, 119.3, 122.6,
126.6, 126.8, 130.2, 130.3, 130.4, 131.6, 143.8, 157.4; mass (ESþ) m/
z¼265.0 (Mþþ1); ESI-HRMS: MHþ, found 265.1095. C15H13N4O
requires 265.1089.
4.5.9. Ethyl 9,10-diphenyl-4-oxa-3,8,9-triazatetracyclo
[10.4.0.02,6.07,11]hexadeca-1(16),2,5,7,10,12,14-heptaene-5-carboxylate
(20.1a). Yield 70% as a yellow solid (68 mg from 100 mg); Rf¼0.37
(hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1736 (CO2Et) cmꢂ1; 1H NMR
4.5.4. 10-(4-Methoxyphenyl)-11-phenyl-7,7a,8,10-tetrahydrobenzo
[6,7]pyrazolo[30,40:4,5]cyclohepta[1,2-c]isoxazole-7a-carbonitrile
(10d). Yield 65% as a white solid (67 mg from 100 mg); mp
134e135 ꢀC; Rf (hexanes/EtOAc, 80:20, v/v) 0.43; nmax (KBr) 2238
(300 MHz, CDCl3):
d
¼1.52 (t, 3H, J¼7.1 Hz, CH3), 4.60 (q, 2H, J¼7.1 Hz,
OCH2), 7.27e7.52 (m, 13H, ArH), 8.54 (d, 1H, J¼7.7 Hz, ArH); 13C NMR
(CN) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼3.44 (s, 2H, CH2), 3.78
(50 MHz, CDCl3):
d
¼14.4, 62.5, 112.3, 117.0, 121.0, 123.6, 125.2, 125.7,
(s, 3H, CH3), 4.41 (d, 1H, J¼9.2 Hz, OCHH), 4.99 (d, 1H, J¼9.4 Hz,
OCHH), 6.80e6.87 (m, 3H, ArH), 7.07e7.17 (m, 4H, ArH), 7.22 (d,
1H, J¼8.0 Hz, ArH), 7.31e7.37 (m, 4H, ArH), 7.73 (d, 1H, J¼7.4 Hz,
126.6, 127.9, 128.8, 129.4, 129.6, 129.8, 130.5, 130.9, 138.4, 139.0, 139.9,
152.9, 157.6, 158.7; mass (ESþ) m/z¼434.2 (Mþþ1); ESI-HRMS: MHþ,
found 434.1518. C27H20N3O3 requires 434.1505.
ArH); 13C NMR (50 MHz, CDCl3):
d
¼30.4, 32.1, 55.6, 56.8, 114.3,
118.6, 125.7, 126.8, 127.4, 129.0, 129.1, 129.8, 130.4, 130.9, 132.1,
141.9, 144.9, 159.2; mass (ESþ) m/z¼433.3 (Mþþ1); ESI-HRMS:
MHþ, found: 433.1642. C27H21N4O2 requires 433.1665.
4.5.10. Ethyl 10-(4-chlorophenyl)-9-phenyl-4-oxa-3,8,9-triazatetra-
cyclo[10.4.0.02,6.07,11]hexadeca-1(16),2,5,7,10,12,14-heptaene-5-
carboxylate (20.1b). Yield 68% as a yellow solid (66 mg from
100 mg); Rf (hexanes/EtOAc, 80:20, v/v) 0.38; nmax (KBr) 1728
4.5.5. Methyl 10,11-diphenyl-4-oxa-3,9,10-triazatetracyclo[11.4.0.02,6
.
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.51 (t, 3H, J¼7.1 Hz,
0
8,12]heptadeca-1(17),2,8,11,13,15-hexaene-6-carboxylate (11a). Yield
CH3), 4.59 (q, 2H, J¼7.1 Hz, OCH2), 7.33e7.50 (m, 12H, ArH), 8.55 (d,
70% as a white (72 mg from 100 mg) solid, mp 108e110 ꢀC; Rf
1H, J¼7.4 Hz, ArH); 13C NMR (50 MHz, CDCl3):
¼14.4, 62.5, 112.1,
d
(hexanes/EtOAc, 80:20, v/v) 0.47; nmax (KBr) 1735 (CO2Me) cmꢂ1; 1H
117.0, 121.1, 123.4, 125.3, 125.5, 125.8, 126.8, 128.0, 128.2, 129.0,
129.3, 129.8, 130.5, 131.8, 132.3, 136.0, 137.7, 138.5, 139.6, 153.0,
157.5, 158.6; mass (ESþ) m/z¼468.1 (Mþþ1); ESI-HRMS: MHþ,
found 468.1117. C27H19ClN3O3 requires 468.1115.
NMR (300 MHz, CDCl3):
d¼3.25e3.36 (m, 2H, CH2), 3.80 (s, 3H,
CO2Me), 4.38 (d, 1H, J¼9.1 Hz, OCHH), 4.98 (d, 1H, J¼9.0 Hz, OCHH),
6.79 (d,1H, J¼7.1 Hz, ArH), 7.07e7.10 (m, 2H, ArH), 7.19e7.33 (m,10H,
ArH), 7.61e7.64 (m,1H, ArH); 13C NMR (50 MHz, CDCl3):
d¼29.1, 30.8,
53.2, 69.7, 119.2, 125.3, 127.0, 127.6, 128.4, 128.7, 128.8, 128.9, 129.0,
129.5, 129.6, 129.9, 130.4, 132.1, 133.5, 139.5, 141.2, 146.9, 160.0, 171.9;
mass (ESþ) m/z¼436.2 (Mþþ1); ESI-HRMS: MHþ, found 436.1665.
C27H22N3O3 requires 436.1661.
4.5.11. Ethyl 10-(4-methylphenyl)-9-phenyl-4-oxa-3,8,9-triazatet-
racyclo[10.4.0.02,6.07,11]hexadeca-1(16),2,5,7,10,12,14-heptaene-5-
carboxylate (20.1e). Yield 71% as a yellow solid (69 mg from
100 mg); Rf (hexanes/EtOAc, 80:20, v/v) 0.36; nmax (KBr) 1720
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.52 (t, 3H, J¼7.1 Hz,
4.5.6. Methyl 11-(4-chlorophenyl)-10-phenyl-4-oxa-3,9,10-triaza-
tetracyclo[11.4.0.02,6.08,12]heptadeca-1(17),2,8,11,13,15-hexaene-6-
carboxylate (11b). Yield 68% as a white solid (84 mg from 120 mg),
mp 154e155 ꢀC; [found C, 69.12; H, 4.36; N, 8.71. C27H20ClN3O3
(Exact mass: 469.1193) requires C, 69.01; H, 4.29; N, 8.94%]; Rf
CH3), 4.60 (q, 2H, J¼7.1 Hz, OCH2), 7.26e7.44 (m, 11H, ArH), 7.50 (d,
1H, J¼8.0 Hz, ArH), 8.54 (d, 1H, J¼7.5 Hz, ArH); 13C NMR (50 MHz,
CDCl3):
d
¼14.4, 21.7, 62.5, 117.0, 121.0, 123.6, 125.2, 125.7, 126.6,
127.8, 127.9, 128.8, 129.8, 130.2, 130.5, 130.7, 139.2, 139.8, 140.0,
152.9, 157.7, 158.8; mass (ESþ) m/z¼448.1 (Mþþ1); ESI-HRMS:
MHþ, found 448.1671. C28H22N3O3 requires 448.1661.
(hexanes/EtOAc, 80:20, v/v) 0.46; nmax (KBr) 1737 (CO2Me) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼3.24e3.35 (m, 2H, CH2), 3.79 (s, 3H,
CO2Me), 4.36 (d, 1H, J¼9.0 Hz, OCHH), 4.98 (d, 1H, J¼9.0 Hz, OCHH),
6.79 (d, 1H, J¼7.4 Hz, ArH), 7.01 (d, 2H, J¼8.3 Hz, ArH), 7.19e7.31 (m,
4.5.12. Ethyl 9-(4-nitrophenyl)-4-oxa-3,8,9-triazatetracyclo[10.4.0.
0
2,6.07,11]hexadeca-1(16),2,5,7,10,12,14-heptaene-5-carboxylate

5042
M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
(20.1f). Yield 74% as a yellow solid (72 mg from 100 mg); Rf (hex-
anes/EtOAc, 80:20, v/v) 0.32; nmax (KBr) 1720 (CO2Et) cmꢂ1 1H
NMR (200 MHz, CDCl3):
Authors also acknowledge the guidance extended by Prof. Raja Roy,
CBMR, SGPGI, Lucknow for elucidating the structures via detailed
NMR experiments. We acknowledge the help extended by Prof.
Sandeep Verma, IIT Kanpur and his student Mr. Venkatesh K. for the
X-ray analysis of compounds.
;
d
¼1.27 (t, 3H, J¼7.1 Hz, CH3), 4.01 (q, 2H,
J¼7.1 Hz, OCH2), 7.58e7.65 (m, 1H, ArH), 7.72e7.79 (m, 3H, ArH),
8.10 (d, 1H, J¼7.9 Hz, ArH), 8.37 (d, 2H, J¼9.0 Hz, ArH), 8.52 (s, 1H,
ArH), 8.61 (d, 1H, J¼7.7 Hz, ArH); 13C NMR (50 MHz, CDCl3):
¼14.2,
d
63.0, 107.8, 120.1, 122.6, 123.8, 124.1, 125.2, 127.7, 128.2, 128.6, 131.4,
137.3, 146.8, 147.0, 153.2, 157.4, 157.8; mass (ESþ) m/z¼403.1
(Mþþ1); ESI-HRMS: MHþ, found 403.1031. C21H15N4O5 requires
403.1042.
Supplementary data
Remaining spectroscopic data and copies of 1H and 13C NMR
spectra of all new compounds are provided. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.03.099. These data include MOL files and InChiKeys of the
most important compounds described in this article.
4.5.13. Methyl 9,10-diphenyl-4-oxa-3,8,9-triazatetracyclo[10.4.0.02,6
7,11]hexadeca-1(16),2,5,7,10,12,14-heptaene-5-carboxylate
(20.2a). Yield 71% as a yellow solid (73 mg from 100 mg); Rf
(hexanes/EtOAc, 80:20, v/v) 0.36; nmax (KBr) 1725 (CO2Me) cmꢂ1
.
0
;
References and notes
1H NMR (300 MHz, CDCl3):
d
¼4.13 (s, 3H, CO2Me), 7.28e7.51 (m,
13H, ArH), 8.54 (d, 1H, J¼7.1 Hz, ArH); 13C NMR (75 MHz, CDCl3):
1. Only a few representative citations: (a) 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, NY, 1984; (b) Carruthers, W. In Cycloaddition
Reactions in Organic Synthesis Tetrahedron Organic Chemistry Series; Pergamon:
Oxford, UK, 1990, pp 1e373; (c) Wade, P. A. In Comprehensive Organic Synthesis;
Pergamon: Oxford, UK, 1991; Vol. 4, pp 1111e1168; (d) Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa,
A., Pearson, W. H., Eds.; Wiley: New York, NY, 2003; (e) Coldham, I.; Hufton, R. Chem.
Rev. 2005, 105, 2765e2809; (f) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108,
2887e2902; (g) Appukkuttan, P.; Mehta, V. P.; Van der Eycken, E. V. Chem. Soc.
Rev. 2010, 39, 1467e1477; (h) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev.
2006, 106, 4484e4517; (i) Pellissier, H. Tetrahedron 2007, 63, 3235e3285; (j)
Heaney, F. Eur. J. Org. Chem. 2012, 3043e3058 and references cited therein.
2. A few examples only: (a) Xu, L.-L.; Zheng, C.-J.; Sun, L.-P.; Miao, J.; Piao, H.-R.
Eur. J. Med. Chem. 2012, 48, 174e178; (b) Reddy, T. S.; Kumar, K. S.; Meda, C. L.
T.; Kandale, A.; Rambabu, D.; Rama Krishna, G.; Hariprasad, C.; Rao, V. V.;
Venkataiah, S.; Reddy, C. M.; Naidu, A.; Dubey, P. K.; Parsa, K. V. L.; Pal, M.
Bioorg. Med. Chem. Lett. 2012, 22, 3248e3255; (c) Thaher, B. A.; Arnsmann, M.;
d
¼52.9, 112.1, 116.8, 120.8, 123.4, 125.0, 125.5, 126.4, 127.7, 128.6,
129.2, 129.4, 129.6, 130.3, 130.7, 138.2, 138.8, 139.7, 152.7, 157.4,
158.5; mass (ESþ) m/z¼420.2 (Mþþ1); ESI-HRMS: MHþ, found
420.1348. C26H18N3O3 requires 420.1348.
4.5.14. Methyl 10-(4-methylphenyl)-9-phenyl-4-oxa-3,8,9-triaza-
tetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),2,5,7,10,12,14-heptaene-5-
carboxylate (20.2e). Yield 69% as a yellow solid (71 mg from
100 mg); Rf (hexanes/EtOAc, 80:20, v/v) 0.36; nmax (KBr) 1728
(CO2Me) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
¼2.46 (s, 3H, CH3), 4.13
(s, 3H, CO2Me), 7.29e7.44 (m, 11H, ArH), 7.50 (d, 1H, J¼8.0 Hz, ArH),
8.53 (d, 1H, J¼7.9 Hz, ArH); 13C NMR (50 MHz, CDCl3):
¼21.6, 53.1,
d
116.9, 120.9, 123.6, 125.2, 125.7, 126.6, 127.7, 127.9, 128.9, 129.8,
130.2, 130.5, 130.7, 138.3, 139.3, 139.8, 140.0, 158.0, 158.8; mass
(ESþ) m/z¼434.1 (Mþþ1); ESI-HRMS: MHþ, found 434.1505.
C27H20N3O3 requires 434.1505.
€
Totzke, F.; Ehlert, J. E.; Kubbutat, M. H. G.; Schachtele, C.; Zimmermann, M. O.;
€
Koch, P.; Bockler, F. M.; Laufer, S. A. J. Med. Chem. 2012, 55, 961e965; (d)
ꢀ
ꢀ
ꢁ
ꢀ
ꢀ
ꢁ
ꢁ
Vujasinovic, I.; Paravic-Radicevic, A.; Mlinaric-Majerski, K.; Brajsa, K.; Bertosa,
€
B. Bioorg. Med. Chem. 2012, 20, 2101e2110; (e) C¸ alıs¸ kan, B.; Luderer, S.; Ozkan,
Y.; Werz, O.; Banoglu, E. Eur. J. Med. Chem. 2011, 46, 5021e5033; (f)
El-Dakdouki, M. H.; Adamski, N.; Foster, L.; Hacker, M.; Erhardt, P. W. J. Med.
Chem. 2011, 54, 8224e8227; (g) Pasin, J. S. M.; Ferreira, A. P. O.; Saraiva, A. L. L.;
Ratzlaff, V.; Andrighetto, R.; Machado, P.; Marchesan, S.; Zanette, R. A.;
Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P.; Ferreira, J.; Mello, C. F.; Braz, J.
Med. Biol. Res. 2010, 43, 1193e1202; (h) Elguero, J.; Goya, P.; Jagerovic, N.; Silva,
A. M. S. Pyrazoles as Drugs: Facts and Fantasies Attanasi, O. A., Spinelli, D.,
Eds.. Targets in Heterocyclic Systems; Italian Society of Chemistry: Roma, Italy,
2002; Vol. 6, pp 52e98; (i) Xia, Y.; Chackalamannil, S.; Czarniecki, M.; Tsai, H.;
Vaccaro, H.; Cleven, R.; Cook, J.; Fawzi, A.; Watkins, R.; Zhang, H. J. Med. Chem.
1997, 40, 4372e4377.
4.5.15. Ethyl 8,10-diphenyl-4-oxa-3,8,9-triazatetracyclo[10.4.0.02,6
7,11]hexadeca-1(16),2,5,7(11),9,12,14-heptaene-5-carboxylate
(26a). Yield 62% as a white solid (64 mg from 100 mg); Rf (hexanes/
EtOAc, 80:20, v/v) 0.52; nmax (KBr) 1734 (CO2Et) cmꢂ1 1H NMR
(300 MHz, CDCl3):
.
0
;
d
¼1.21 (t, 3H, J¼7.2 Hz, CH3), 3.82 (q, 2H,
J¼7.2 Hz, OCH2), 7.43e7.60 (m, 8H, ArH), 7.63 (d, 2H, J¼7.2 Hz, ArH),
7.70e7.73 (m, 2H, ArH), 7.84e7.87 (m, 1H, ArH), 8.60 (dd, 1H,
€
3. (a) Theodoridis, G. In Modern Crop Protection Compounds; Kramer, W., Schirmer,
J1¼1.7 Hz, J2¼7.2 Hz, ArH); 13C NMR (50 MHz, CDCl3):
¼14.1, 62.8,
d
U., Eds.; Wiley-VCH: Weinheim, Germany, 2007; Vol.1, pp 153e186; (b) Shiga, Y.;
Okada, I.; Ikeda, Y.; Takizawa, E.; Fukuchi, T. J. Pestic. Sci. 2003, 28, 313e314; (c)
Lindell, S. D.; Moloney, B. A.; Hewitt, B. D.; Earnshaw, C. G.; Dunfield, P. J.; Dancer,
J. E. Bioorg. Med. Chem. Lett.1999, 9,1985e1990; (d) Vicentini, C. B.; Romagnoli, C.;
Andreotti, E.; Mares, D. J. Agric. Food Chem. 2007, 55,10331e10338; (e) Fustero, S.;
106.8, 117.9, 120.2, 123.76, 124.0, 125.2, 126.8, 128.4, 129.0, 129.2,
129.8, 129.9, 130.0, 130.7, 134.0, 141.8, 150.4, 153.8, 157.9, 158.0;
mass (ESþ) m/z¼434.3 (Mþþ1); ESI-HRMS: MHþ, found 434.1527.
C27H20N3O3 requires 434.1505.
ꢀ
ꢀ
Roman, R.; Sanz-Cervera, J. F.; Simon-Fuentes, A.; Bueno, J.; Villanova, S. J. Org.
Chem. 2008, 73, 8545e8552; (f) Dutra, G. A.; Hamper, B. C.; Mitschke, D. A.;
Moedritzer, K.; Rogers, K. D., PCT Int. Appl., WO 9206962,1992. Chem. Abstr.1992,
117, 69859.
4.5.16. Ethyl 10-(4-chlorophenyl)-8-phenyl-4-oxa-3,8,9-triaza-
tetracyclo[10.4.0.02,6.07,11]hexadeca-1(16),2,5,7(11),9,12,14-heptaene-
5-carboxylate (26b). Yield 60% as a yellow solid (62 mg from
100 mg); Rf (hexanes/EtOAc, 80:20, v/v) 0.51; nmax (KBr) 1731
4. (a) Janin, Y. L. Chem. Rev. 2012, 112, 3924e3958 and references cited therein; (b)
ꢀ
ꢀ
ꢀ
Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A. Chem. Rev. 2011, 111,
6984e7034 and references cited therein; (c) Guillou, S.; Bonhomme, F. J.; Er-
_
molenko, M. S.; Janin, Y. L. Tetrahedron 2011, 67, 8451e8457; (d) Vilkauskaite, G.;
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.21 (t, 3H, J¼7.1 Hz,
ꢁ
ꢁ
Sackus, A.; Holzer, W. Eur. J. Org. Chem. 2011, 5123e5133; (e) Guillou, S.; Janin, Y. L.
Chem.dEur. J. 2010, 16, 4669e4677; (f) Yet, L. Five-Membered Ring Systems:
With More than One N Atom Gribble, G. W., Joule, J. A., Eds.. Progress in Het-
erocyclic Chemistry; Elsevier: 2009; Vol. 21, pp 224e260; (g) Yet, L. In Compre-
hensive Heterocyclic Chemistry; Katrizky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Eds.; Pergamon: London, UK, 2008; Vol. 4, 4.01, pp 1e141; and
CH3), 3.83 (q, 2H, J¼7.1 Hz, OCH2), 7.44e7.55 (m, 7H, ArH), 7.61 (d,
2H, J¼7.4 Hz, ArH), 7.67 (d, 2H, J¼8.4 Hz, ArH), 7.82e7.85 (m, 1H,
ArH), 8.59e8.62 (m, 1H, ArH); 13C NMR (50 MHz, CDCl3):
d
¼14.1,
62.9, 106.7, 117.8, 120.2, 123.7, 123.8, 125.3, 126.9, 128.5, 129.1, 129.2,
129.5, 130.0, 130.8, 131.4, 132.4, 135.3, 141.7, 149.2, 153.9, 157.9,
158.0; mass (ESþ) m/z¼468.2 (Mþþ1); ESI-HRMS: MHþ, found:
468.1117. C27H19ClN3O3 requires 468.1115.
€
references cited therein; (i) Schnurch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mi-
hovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283e3307.
5. Nag, S.; Nayak, M.; Batra, S. Adv. Synth. Catal. 2009, 351, 2715e2723 and ref-
erences cited therein.
6. Nayak, M.; Batra, S. RSC Adv. 2012, 2, 3367e3373.
7. Nayak, M.; Batra, S. Adv. Synth. Catal. 2010, 352, 3431e3437.
8. Nayak, M.; Rastogi, N.; Batra, S. Eur. J. Org. Chem. 2012, 1360e1366.
9. Nayak, M.; Batra, S. Eur. J. Org. Chem. 2012, 3677e3683.
Acknowledgements
10. Nayak, M.; Batchu, H.; Batra, S. Tetrahedron Lett. 2012, 53, 4206e4208.
11. Representative citations only: (a) Mishra, A.; Rastogi, N.; Batra, S. Tetrahedron 2012,
68, 2146e2154; (b) Arumugam, N.; Raghunathan, R.; Almansour, A. I.; Karama, U.
Bioorg. Med. Chem. Lett. 2012, 22, 1375e1379; (c) Kathiravan, S.; Vijayarajan, D.;
Raghunathan, R. Tetrahedron Lett. 2010, 51, 3065e3070; (d) Sirisha, N.;
Two of the authors (M.N. and N.R.) gratefully acknowledges the
financial support from Council of Scientific and Industrial Research,
New Delhi. Authors gratefully acknowledge the SAIF Division of
CDRI for recording all the spectroscopic and analytical data.

M. Nayak et al. / Tetrahedron 69 (2013) 5029e5043
5043
Raghunathan, R. Tetrahedron Lett. 2010, 51, 2515e2518; (e) Kathiravan, S.; Ramesh,
E.; Raghunathan, R. Tetrahedron Lett. 2009, 50, 2389e2391; (f) Ramesh, E.; Raghu-
nathan, R. Tetrahedron Lett. 2008, 49,1125e1128; (g) Bakthadoss, M.; Sivakumar, N.;
Sivakumar, G.; Murugan, G. Tetrahedron Lett. 2008, 49, 820e823; (h) Pedrosa, R.;
Andres, C.; Nieto, J.; Perez-Cuadrado, C.; San Francisco, I. Eur. J. Org. Chem. 2006,
3259e3265.
can be obtained from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK (CCDC deposition no. 927231).
13. Ghandi, M.; Taheri, A.; Bozcheloei, A. H.; Abbasi, A.; Kia, R. Tetrahedron 2012, 68,
3641e3648.
ꢀ
ꢀ
14. Crystal data of compound 19.2a: C30H27N3O2, M¼461.55, triclinic, Pꢂ1, a¼9.
ꢂ
233(2), b¼10.647(2), c¼13.105(3) A,
a¼99.208(3),
b
¼108.350(4), ¼100.080(4),
g
3
ꢂ
12. Crystal data of compound 6a: C28H24N4, M¼416.51, Monoclinic, P 21/n, a¼8.
V¼1171.5(4) A , Z¼2, Dcalcd¼1.308 g cmꢂ3, m (Mo-Ka)¼0.083 mmꢂ1, F (000)¼
488, yellow block, dimension 0.42ꢁ0.40ꢁ0.38 mm, 6660 reflections measured
(Rint¼0.0347), 4510 unique, wR2¼0.2095, conventional R¼0.0669 on F2 values
of 2817 reflections with I>2s(I), S¼1.003 for all data and 316 parameters. Unit
ꢂ
8122(17), b¼19.571(4), c¼12.739(2) A,
a
¼90,
b
¼93.974(4),
g
¼90, V¼2191.
8(7) A , Z¼4, Dcalcd¼1.262 mg/m3, m (Mo-Ka)¼0.076 mmꢂ1, F (000)¼880, col-
orless block, dimension 0.21ꢁ0.2ꢁ0.19 mm, 14,415 reflections measured
(Rint¼0.0687), 5388 unique, wR2¼0.2140, conventional R¼0.0698 on F2 values
3
ꢂ
cell determination and intensity data collection (2
q
¼50ꢀ) were performed on
of 3132 reflections with I>2s(I), (
D/
s
)
¼000), S¼1.095 for all data and 289
a Bruker P4 diffractometer at 100 (2) K. Structure solutions by direct methods
and refinements by full-matrix least-squares methods on F2. Programs: ZSCANS
(Siemens Analytical X-ray Instrument Inc.: Madison, WI, USA, 1996) for data
collection and data processing; SHELXTL-NT (Bruker AXS Inc.: Madison, Wis-
consin, USA, 1997) for structure determination, refinements and molecular
graphics. Further details of the crystal structure investigation can be obtained
from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK (CCDC deposition no. 927230).
max
parameters. Unit cell determination and intensity data collection (2
q
¼50ꢀ)
were performed on a Bruker P4 diffractometer at 293(2) K. Structure solutions
by direct methods and refinements by full-matrix least-squares methods on F2.
Programs: XSCANS (Siemens Analytical X-ray Instrument Inc.: Madison, WI,
USA, 1996) for data collection and data processing; SHELXTL-NT (Bruker AXS
Inc.: Madison, Wisconsin, USA, 1997) for structure determination, refinements
and molecular graphics. Further details of the crystal structure investigation