Solvent free synthesis of 1,5-disubstituted tetrazoles derived from Baylis Hillman acetates as potential TNF-α inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.08.047

Solvent free multicomponent reaction of Baylis Hillman acetate, TMS azide and arylnitrile to produce 1,5-disubstituted tetrazole is described. Some of these tetrazoles are found to be potential TNF-α inhibitors.

Full text of DOI:10.1016/j.bmcl.2009.08.047

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5569–5572
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Solvent free synthesis of 1,5-disubstituted tetrazoles derived
from Baylis Hillman acetates as potential TNF-
a
inhibitors
a
a
a
a
b
P. Srihari a, , Palash Dutta , R. Srinivasa Rao , J. S. Yadav , S. Chandrasekhar , P. Thombare ,
*
J. Mohapatra b, A. Chatterjee b, Mukul R. Jain b,
*
a Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Zydus Research Centre, Sarkhej-Bavla N.H. No 8A, Moraiya, Ahmedabad 382 213, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Solvent free multicomponent reaction of Baylis Hillman acetate, TMS azide and arylnitrile to produce 1,5-
disubstituted tetrazole is described. Some of these tetrazoles are found to be potential TNF-a inhibitors.
Received 19 May 2009
Accepted 12 August 2009
Available online 15 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Click chemistry
Arthritis
Multicomponent
Michael reaction
Baylis Hillman
Tumor necrosis factor
a
(TNFa) is a potent proinflammatory
the synthesis of novel tetrazoles as new chemical entities and their
cytokine which by binding to its receptors, TNFR1 and TNFR2, re-
activities towards the inhibition of tumor necrosis factor a. We
sults in recruitment of signal transducers that activates at least
herein report the multicomponent addition reaction of Baylis Hill-
man acetates8 with azide followed by one pot click reaction with
nitriles to yield 1,5-disubstituted tetrazoles and evaluation to-
wards inhibition of tumor necrosis factor.
two transcription factors, AP-1 and NF-j
B.1 The transcription fac-
tors in turn regulate the production of many proinflammatory
cytokines and related proteins that are elevated in immune-
inflammatory diseases. As excessive or unregulated TNF-
tion implicates either in exacerbating/mediating number of disease
states, thus decreasing TNF- levels may become a valuable thera-
a
produc-
Our initial studies began with the addition of NaN3 to Baylis
Hillman acetate (1a, 1c) followed by aryl nitriles in the presence
of metal salts of CuCl or ZnCl2. We chose DMF as the solvent
9
a
peutic strategy for the treatment of many inflammatory, infectious,
immunological, or malignant diseases such as rheumatoid arthritis
and psoriasis.2
and found out that the reaction works with copper chloride to yield
the corresponding tetrazoles in ꢀ50% yield along with ꢀ10–15% of
the intermediate azido products. However, in the case of zinc chlo-
ride, there was no reaction and the starting material was com-
pletely recovered. We also investigated TBAF as the catalyst for
this transformation as this reagent is well known for promoting
Recently click chemistry has been much focused wherein con-
densation of alkynes with azides occur in presence of copper to
yield the triazoles.3 However, similar addition of cyanides with
azides to yield tetrazoles has not been much explored. Even
though, tetrazole containing molecules are not available naturally
and does not exhibit appreciable biological activity, they are found
to resist biological degradation, and this property has enabled tet-
razoles to form the isosteric substituent for various functional
groups in the development of biologically active substances.4 Tet-
razoles have been also found to have wide applications in propel-
lants,5 explosives,6 and pharmaceuticals.7
E
R
OAc
TMSN3,
N
TBAF.3H 2O, Ar-CN 2
E
N
70 oC, 15-19 h
70-85%
N
R
N
1
Ar
3
R = CH3, Ph, p-MeOC6H4, MeC6H4, furyl
Ar= Ph, m-BrC6H4, 3-pyridyl, 4-pyridyl
As part of our ongoing project for design and synthesis of small
molecules as therapeutics in rheumatoid arthritis, we investigated
E= CO2Et, CN
* Corresponding authors. Tel.: +91 4027191490 (P.S.).
E-mail address: srihari@iict.res.in (P. Srihari).
Scheme 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.08.047

5570
P. Srihari et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5569–5572
Table 1
In-vitro TNF-
a
inhibition at 100
l
M and 10
lM concentration in human whole blood assay
Entry
Baylis Hillmann acetates
Nitriles
Producta
Product ratiob (E:Z)
Time (h)
18
Yieldc (%)
COOMe
OAc
CN
COOMe
N
N
1
100:0
75
N
1a
2a
3a
N
Ph
COOMe
OAc
CN
N
N
COOMe
N
N
2
100:0
15
72
N
2b
1a
3b
N
COOEt
OAc
N
N
CN
N
COOEt
3
4
5
100:0
100:0
100:0
16
18
16
75
78
80
N
Ph
1b
2c
3c
Ph
COOMe
OAc
CN
COOMe
N
N
MeO
N
1c
2a
N
MeO
Ph
3d
COOMe
OAc
CN
N
N
COOMe
MeO
N
N
N
1c
2b
MeO
3e
N
COOMe
OAc
N
N
CN
MeO
COOMe
N
N
6
100:0
19
82
1c
N
2d
MeO
3f
N
COOEt
OAc
Br
CN
O
N
N
COOEt
N
7
100:0
15
85
N
O
1d
2e
Br
3g

P. Srihari et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5569–5572
5571
Table 1 (continued)
Entry
Baylis Hillmann acetates
Nitriles
Producta
Product ratiob (E:Z)
Time (h)
18
Yieldc (%)
OAc
CN
CN
CN
CN
8
17:83
70
72
75
80
10
N
N
2a
N
N
1e
H3C
MeO
O2N
CN
3h
H3C
Br
CN
OAc
CN
9
10
11
12
10:90
24:76
38:62
23:77
17
16
12
18
1f
N
Br
N
N
2e
3i
CN
N
N
OAc
CN
N
N
N
2d
N
N
1g
CN
MeO
3j
OAc
CN
CN
N
2a
N
1h
CN
N
N
3k
N
N
OAc
CN
N
N
2b
1i
CN
N
N
3l
O2N
a
b
c
All products were characterized by 1H NMR, 13C NMR, mass and IR spectroscopy.
Product ratio determined by crude 1H NMR spectra.
Calculated after purification by column chromatography.
both Michael reactions10 as well as click chemistry.11 Thus we
started with adduct 1a (1 mmol), which was treated with TMSN3
(1 mmol) in presence of TBAF in DMF and benzonitrile (1 mmol)
at 85 °C for 18 h. A neat spot was observed which was isolated
and characterized as the tetrazole 3a in 65% yield. There was 5–
10% increase in yield when the solvent was changed from DMF
to THF or toluene.
Interestingly, the reaction also worked well in absence of sol-
vent to give the product in 75% yield (Table 1 entry 1) and hence
we chose to evaluate further scope of the reaction without any sol-
vent media (Scheme 1). Thus, different Baylis Hillman acetates
with ester moiety were investigated with several aryl nitriles
(2a–e) in the presence of trimethylsilyl azide and found to produce
the corresponding tetrazoles (3a–g) in good yields (Table 1).12,13
Even the Baylis Hillman acetates (BHA) with nitrile moiety (1e–
i) reacted similarly to produce the corresponding substituted tetra-
zoles (3h–l). Substitution in aromatic ring of BHA did not change
the yields significantly. However, the reaction of nitro containing
aryl Baylis Hillman adduct 1i gave poor yield when treated with
4-cyano pyridine 2b (entry 12). It was found that E isomer was
the only product formed with Baylis Hillman acetates containing
ester moiety. Whereas nitrile containing Baylis Hillman acetates
ended up with mixture of diastereomers with Z isomer as the ma-
jor product.14 The overall yield when compared for individual reac-
tions for Michael reaction and Click reaction were found to be less
than the one pot Michael followed by Click reaction.
Towards our goal for identification of small molecules for rheu-
matoid arthritis therapy, few of these new small molecules (substi-
tuted tetrazoles) synthesized (3a, 3b, 3d–f) were tested for in vitro
TNF-a
-inhibition studies15 (Table 2) and found that compound 3b
and 3d were significantly active.
In conclusion, we have developed a new strategy for synthesis
of functionalized 1,5-disubstituted tetrazoles starting from Baylis
Hillman acetates under solvent free reaction conditions. Based on

5572
P. Srihari et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5569–5572
8.23 (d, J = 8.3 Hz, 2H), 8.17 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.64–755 (m, 4H),
Table 2
7.48–7.39 (m, 5H), 7.38–7.31 (m, 1H), 5.64 (s, 2H), 4.27 (q, J = 6.7 Hz, 2H), 1.30
(t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 165.9, 164.7, 146.0, 142.9, 140.2,
133.8, 129.7, 129.0, 128.9, 128.8, 127.7, 127.4, 127.2, 127.0, 126.2, 124.3, 61.5,
49.9, 14.1; MS-ESIMS: m/z 411 (M+H+); HRMS calcd for C25H23N4O2: 411.1815,
In-vitro TNF-
assay
a
inhibition at 100
Compound
l
M and 10
l
M concentration in human whole blood
S.No.
% of TNF-
a
inhibition (SEM)
10
found 411.1816. Compound 3d: light green sticky liquid; IR (neat):
m 2922,
100
l
M
lM
2848, 1709, 1601, 1511, 1442, 1254, 1176, 1026, 836, 731 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d 8.19–8.14 (m, 2H), 8.13 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.47
(m, 3H), 6.95 (d, J = 8.8 Hz, 2H), 5.68 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 166.8, 164.9, 161.0, 146.1, 131.3, 130.2, 128.7, 127.3, 126.8,
126.1, 121.5, 114.4, 55.3, 52.4, 50.1; MS-ESIMS: m/z 373 (M+Na+); HRMS calcd
for C19H18N4O3: 373.1276, found 373.1271. Compound 3e: light green sticky
1
2
3
4
5
3a
3b
3d
3e
3f
35.1 (1.9)
67.0 (3.6)
46.3 (5.6)
12.9 (24.0)
30.2 (3.0)
14.6 (1.8)
18.2 (12.1)
22.2 (0.4)
8.6 (7.0)
5.4 (19.8)
liquid; IR (neat):
m ;
2921, 2851, 1714, 1634, 1442, 1252, 1026, 805, 731 cmÀ1
1H NMR (300 MHz, CDCl3): d 8.77 (d, J = 4.3 Hz, 2H), 8.16 (s, 1H), 8.04 (d,
J = 6.0 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.72 (s, 2H), 3.84
(s, 3H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3): d 166.7, 162.9, 161.1, 150.4,
146.4, 134.7, 131.2, 125.9, 121.1, 120.8, 114.4, 55.3, 52.4, 50.4; MS-ESIMS: m/z
352 (M+H+); HRMS calcd for C18H17N5O3: 352.1411, found 352.1404.
the preliminary reports obtained by us, further evaluation for SAR/
lead identification towards arthritis is currently being investigated.
Compound 3f: white crystalline solid, mp: 105–108 °C; IR (KBr):
m 2929,
1538, 1401, 1350, 1220, 1182, 840, 772 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
Acknowledgements
9.30 (s, 1H), 8.63 (s, 1H), 8.35 (dt, J = 7.9, 1.7 Hz, 1H), 8.06 (s, 1H), 7.46 (d,
J = 8.6 Hz, 2H), 7.30–7.38 (m, 1H), 6.88 (d, J = 8.6 Hz, 2H), 5.63 (s, 2H), 3.75 (s,
3H), 3.73 (s, 3H); 13C NMR (75 MHz, CDCl3): d 166.7, 162.6, 161.0, 151.0, 148.0,
146.2, 134.0, 131.2, 125.9, 123.5, 121.1, 114.4, 55.3, 52.4, 50.2; MS-ESIMS: m/z
374 (M+Na+); HRMS calcd for C18H17N5O3: 374.1239, found 374.1229.
P.D. thanks CSIR, New Delhi for financial assistance. The authors
thank DST, New Delhi for sponsoring the project.
Compound 3g: white crystalline solid, mp: 105–108 °C; IR (KBr):
m
2924,
References and notes
2854, 1705, 1636, 1446, 1252, 1212, 1098, 1021, 885, 764 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d 8.25 (t, J = 2.2 Hz, 1H), 8.05 (dt, J = 8.3, 1.5 Hz, 1H), 7.74 (s,
1H), 7.60–7.50 (m, 2H), 7.31 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.53 (dd,
J = 3.7, 2.2 Hz, 1H), 5.96 (s, 2H), 4.26 (q, J = 7.5 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 166.1, 163.3, 149.8, 146.1, 132.8, 130.5, 129.5,
129.3, 125.2, 122.6, 119.2, 118.5, 112.4, 61.3, 49.7, 14.0; MS-ESIMS: m/z 403
(M+H+); HRMS calcd for C17H15N4O3Br: 403.0409, found 403.0327. Compound
1. Baud, V.; Karin, M. Trends Cell Biol. 2001, 11, 372.
2. Möller, B.; Villiger, P. M. Springer Semin Immunopathol. 2006, 27, 391.
3. (a) Demko, Z. P.; Sharpless, K. B. Angew. Chem. 2002, 114, 2217; (b) Demko, Z.
P.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2113; (c) Demko, Z. P.;
Sharpless, K. B. Angew. Chem. 2002, 114, 2214.
4. (a) Bond, A. D.; Fleming, A.; Kelleher, F.; McGinkley, J.; Prajapati, V. Tetrahedron
2006, 62, 9577; (b) Herr, R. J. Bioorg. Med. Chem 2002, 10, 3379.
3h: white crystalline solid, mp: 93–95 °C; IR (KBr):
m 2924, 2853, 2211, 1604,
1446, 1343, 1187, 1022, 926, 811, 727, 698 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
5. Brown, M. US Patent 3338,915, 1967; Chem. Abstr. 1968, 87299.
6. Tarver, C. M. Goodale, T. C.; Shaw, R.; Cowperthwaite, M. Off. Nav. Res. (Tech.
Rep.) ACR (US), ACR-221, Proc. Symp. Int. Detonation 6th, 231, 1976; Chem.
Abstr. 1980, 92, 8480b; Henry, R. A. US Patent 3096, 312, 1963.
8.19–8.14 (m, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.53–7.45 (m, 3H), 7.31 (s, 1H), 7.25
(d, J = 7.5 Hz, 2H), 5.52 (s, 2H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3): d 165.8,
149.1, 142.5, 130.5, 129.7, 129.4, 129.2, 128.8, 126.9, 116.7, 101.7, 56.1, 29.6,
21.5; MS-ESIMS: m/z 324 (M+Na+); HRMS calcd for C18H15N5: 324.1236, found
7. (a) Bradbury, R. H.; Allott, C. P.; Dennis, M.; Girdwood, J. A.; Kenny, P. W.; Major,
J. S.; Oldham, A. A.; Ratcliffe, A. H.; Rivett, J. E. J. Med. Chem. 1993, 36, 1245; (b)
Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.;
Price, W. A.; Santella, J. B.; Wells, G. J. J. Med. Chem. 1991, 34, 2525; (c) Koyama,
M.; Ohtani, N.; Kai, F.; Moriguchi, I.; Inouye, S. J. Med. Chem. 1987, 30, 552; (d)
Maxwell, J. R.; Wasdahl, D. A.; Wolfson, A. C.; Stenberg, V. I. J. Med. Chem. 1984,
27, 1565; (e) Pande, K.; Tandon, M.; Bhalla, T. N.; Parmar, S. S.; Barthwal, J. P.
Pharmacology 1987, 35, 333.
8. For our earlier work with Baylis Hillman acetates, see: (a) Srihari, P.; Singh, A.
P.; Jain, R.; Yadav, J. S. Synthesis 2006, 2772; (b) Srihari, P.; Singh, A. P.; Basak, A.
K.; Yadav, J. S. Tetrahedron Lett. 2007, 48, 5999; (c) Yadav, J. S.; Singh, A. P.;
Bhunia, D. C.; Basak, A. K.; Srihari, P. Chem. Lett. 2008, 37, 624; (d)
Chandrasekhar, S.; Basu, D.; Rambabu, Ch. Tetrahedron Lett. 2006, 47, 3059.
9. (a) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945; (b) Demko, Z. P.;
Sharpless, K. B. Org. Lett. 2002, 4, 2525.
324.1225. Compound 3i: pale yellow sticky liquid; IR (neat):
m 2924, 2853,
2210, 1458, 1219, 1038, 771.cmÀ1 1H NMR (300 MHz, CDCl3): d 8.28 (d,
;
J = 1.5 Hz, 1H), 8.08 (dd, J = 7.5, 1.5 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.35 (t,
J = 7.5 Hz, 1H), 6.58 (t, J = 7.5 Hz, 1H), 5.34 (s, 2H), 2.58–2.43 (m, 2H), 1.16 (t,
J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 164.4, 156.4, 133.4, 130.4, 129.8,
128.7, 125.4, 122.9, 114.7, 107.4, 54.5, 25.2, 12.5; MS-ESIMS: m/z 318 (M+H+);
HRMS calcd for C12H12BrN5: 318.0348, found 318.0335. Compound 3j: white
crystalline solid, mp: 122–125 °C; IR (KBr):
m
2924, 2853, 2201, 1741, 1599,
;
1513, 1434, 1262, 1180, 1025, 829, 750 cmÀ1
1H NMR (300 MHz, CDCl3): d
9.39 (d, J = 1.5 Hz, 1H), 8.71 (dd, J = 5.2, 1.5 Hz, 1H), 8.46 (dt, J = 7.5, 1.5 Hz, 1H),
7.57 (s, 1H), 7.52 (d, J = 9.0 Hz, 2H), 7.46–7.40 (m, 1H), 6.99 (d, J = 9.0 Hz, 2H),
5.61 (s, 2H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3): d 163.4, 161.7, 151.4,
150.0, 148.1, 134.2, 131.3, 124.6, 123.6, 118.2, 114.7, 104.2, 55.4, 51.0, 29.6;
MS-ESIMS: m/z 341 (M+Na+); HRMS calcd for C17H14N6O: 341.1139, found
341.1126. Compound 3k: amorphous yellow solid, mp: 99–103 °C; IR (KBr):
m
2924, 2854, 2215, 2096, 1740, 1447, 1337, 1272, 1036, 849, 775, 688 cmÀ1 1H
;
10. For few references on TBAF mediated Michael reactions, see: (a) Liu, L.-P.; Xu,
B.; Hammond, G. B. Org. Lett. 2008, 10, 3887; (b) Sharma, G. V. M.; Reddy, V. G.;
Chander, A. S.; Reddy, K. R. Tetrahedron: Asymmetry 2002, 13, 21.
11. Amantini, D.; Beleggia, R.; Fringueslli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem.
2004, 69, 2896.
NMR (300 MHz, CDCl3): d 8.19–8.14 (m, 2H), 7.81 (dd, J = 6.0, 2.2 Hz, 2H), 7.52–
7.41 (m, 6H), 7.25 (s, 1H), 5.51 (s, 2H); 13C NMR (75 MHz, CDCl3): d 165.8,
149.0, 131.9, 131.7, 130.5, 129.4, 129.0, 128.8, 126.9, 116.4, 103.2, 56.0, 29.6;
MS-ESIMS: m/z 288 (M+H+); HRMS calcd for C17H13N5: 288.1248, found
12. General procedure for multicomponent reaction: Baylis Hillman acetate
(1 mmol), TBAFÁ3H2O (0.5 mmol), and TMSN3 (1 mmol) were stirred at room
temperature for half an hour and to this mixture was added aryl nitrile
(1 mmol) and the mixture was heated to 85 °C till completion of the reaction
(as given in Table 1). The compound was diluted with ethyl acetate and water
was added. The aqueous layer was extracted with ethyl acetate. The solvent
was evaporated under reduced pressure and the crude product was purified by
column chromatography.
288.1244. Compound 3l: pale yellow sticky liquid; IR (KBr):
m
2923, 2853,
;
2212, 1740, 1604, 1522, 1461, 1346, 1261, 1099, 799, 652 cmÀ1
1H NMR
(300 MHz, CDCl3): d 8.78 (dd, J = 4.5, 1.5 Hz, 2H), 8.34 (d, J = 8.3 Hz, 2H), 8.06–
7.91 (m, 4H), 7.31 (s, 1H), 5.59 (s, 2H); MS-ESIMS: m/z 334 (M+H+); HRMS calcd
for C16H11N7O2: 334.1052, found 334.1047.
14. The diastereomeric mixture of a representative sample (3j) was separated and
their respective geometries were characterized by NOE studies.
15. Procedure for assay: inhibition of TNF-
a in human whole blood assay: fresh
13. Analytical data for compounds 3a: light green sticky liquid; IR (neat):
m 2925,
blood was collected aseptically in the presence of heparin by venipuncture
from healthy adult volunteers. Two microliters of either a test compound
2850, 1711, 1604, 1512, 1459, 1256, 1178, 838, 754 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d 8.2 (s, 1H), 8.14–8.19 (m, 2H), 7.54–7.59 (m, 2H), 7.50–7.40 (m, 6H),
5.64 (s, 2H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3): d 166.4, 164.9, 146.3,
133.7, 130.2, 129.8, 129.1, 128.9, 128.7, 126.8, 123.9, 113.8, 52.5, 49.9; MS-
ESIMS: m/z 321 (M+H+); HRMS calcd for C18H16N4O2: 343.1183, found
solution (10, 100
blood and incubated at 37 °C for 1 h. Following this,
lipopolysaccharide (dissolved in phosphate-buffered
concentration of 1 ng/ml) were added in each microtube. The blood mixture
along with LPS was further incubated at 37 °C for 5 h. The reactions were
terminated by placing the samples over ice for 10 min. At study completion,
the plasma was separated by centrifugation at 3000 rpm for 10 min at 4 °C and
stored at À70 °C until further analysis. Concentrations of tumor necrosis
factor-alpha in the plasma were determined by enzyme-linked
immunosorbent assays (BD Biosciences, USA).
l
M) or dimethyl sulfoxide was mixed with 246-
of 125 ng/ml
saline; final
ll aliquot of
2 ll
343.1170. Compound 3b: Dark brown sticky liquid; IR (neat):
m 2921, 2851,
1715, 1611, 1456, 1257, 1206, 1106, 834, 757 cmÀ1 1H NMR (300 MHz, CDCl3):
;
d 8.67 (s, 2H), 8.11 (s, 1H), 7.93 (s, 2H), 7.30–7.50 (m, 5H), 5.58 (s, 2H), 3.71 (s,
3H); 13C NMR (75 MHz, CDCl3): d 166.1, 162.7, 150.2, 146.4, 134.6, 133.3,
129.8, 128.8, 123.4, 120.7, 52.3, 50.1; MS-ESIMS: m/z 344 (M+Na+); HRMS calcd
for C17H15N5O2: 344.1133, found 344.1123. Compound 3c: light green sticky
liquid; IR (neat):
m ;
2928, 1711, 1219, 772 cmÀ1 1H NMR (300 MHz, CDCl3): d