Synthesis of withasomnines and their non-natural analogues from aldehydes and 4-nitro-1-butanol in three steps

Article abstract of DOI:10.1021/jo400207u

Total synthesis of all three pyrazole-based withasomnine alkaloids and selected examples of their non-natural analogs has been achieved from readily available aldehydes and 4-nitro-1-butanol in three steps. Since 4-nitro-1-butanol in turn is prepared in t

Full text of DOI:10.1021/jo400207u

Note
pubs.acs.org/joc
Synthesis of Withasomnines and Their Non-natural Analogues from
Aldehydes and 4‑Nitro-1-butanol in Three Steps
Deepti Verma, Rahul Kumar, and Irishi N. N. Namboothiri*
Department of Chemistry, Indian Institute of Technology, Bombay, Mumbai 400 076, India
S
* Supporting Information
ABSTRACT: Total synthesis of all three pyrazole-based
withasomnine alkaloids and selected examples of their non-
natural analogs has been achieved from readily available
aldehydes and 4-nitro-1-butanol in three steps. Since 4-nitro-
1-butanol in turn is prepared in two steps via Michael addition
of nitromethane to acrylate followed by borane reduction of the
ester group and the key 1,3-dipolar cycloaddition step is carried
out with commercially available TMSCHN2, this approach is a very convenient and economical one.
As part of our efforts to develop novel and efficient
methodologies for the synthesis of functionalized and fused
pyrazoles,12,13 we recently reported a novel approach for the
synthesis of withasomnine 5a based on base-mediated 1,3-
dipolar cycloaddition of nitroester 10 or bromonitroalkene 11a
with diazosulfone 12 (Scheme 2).13 However, this required
ithasomnine 5a, isolated from the roots of the Indian
Wmedicinal plant Withania somnifera, belonging to the
Solanaceae family,1 has been used in traditional Ayurvedic
medicine for the treatment of enlarged spleen, migraines, and
many infections and as an aphrodisiac. The analgesic as well as
CNS and circulatory system depressant properties of with-
asomnine 5a and its analogues 5b,c, isolated from similar plant
sources, are described in more recent literature.2 These
biological properties of withasomnines 5a−c motivated many
research groups to pursue their synthesis. Most of the
approaches targeted withasomnine 5a and involved reactions
such as intramolecular alkylation,3 oxidative coupling,4 sydnone
cycloaddition,5,6 hydrazine-1,3-dicarbonyl cyclization,7 conver-
sion of cyclopropanols to pyrazoles,8 radical cyclization,9
multicomponent coupling,10 and Claisen rearrangement11 as
the key steps (Scheme 1). A diverse array of starting materials
(e.g., 1−4 and 6−8), and conditions were employed in those
schemes which often required complex reagents and numerous
synthetic operations.
Scheme 2
diazosulfone 12 to be prepared in two steps from commercially
available chloroacetone, and the sulfonyl group had to be
removed in the final step. Second, possible generalization of our
methodology to synthesis of other natural and non-natural
analogues of withasomnine 5a was not investigated. In fact,
there is only one report on the total synthesis of withasomnine
analogs 5b,c in the literature which is based on 1,3-dipolar
cycloaddition of sydnones with acetylenes (Schemes 1, 4 to 5).6
Against the above background, we report here the total
synthesis of all three withasomnine natural products 5a−c and
their three other non-natural analogues through a general and
highly efficient strategy from commercially available starting
materials in five steps. Our retrosynthetic analysis suggested
that withasomnine 5a could be synthesized from pyrazole 13a
via intramolecular alkylation of 13a in which X is a good leaving
group (Scheme 3). Pyrazole 13a in turn would be accessible via
1,3-dipolar cycloaddition of nitroalkene 11 with a diazoalkane
14.14 Nitroalkene 11 would arise from condensation of
benzaldehyde 15a with a suitable aliphatic nitro compound 16.
Scheme 1
Received: January 30, 2013
Published: February 25, 2013
© 2013 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 3
Table 1. Preparation of Nitroalkenols 19
a
entry
15, R
time (h)
19, % yield
1
2
3
4
5
6
15b, 4-OMePh
15c, 4-OHPh
15d, 4-ClPh
34
34
36
36
48
21
19b, 73
19c, 64
19d, 74
19e, 68
19f, 65
19g, 65
In practice, we prepared nitroester 9 in 73% yield following a
known procedure via HMPT-mediated Michael addition of
nitromethane 18 to ethyl acrylate 17 (Scheme 4).15 Reduction
15e, 2-furyl
15f, cyclohexyl
15g, 4-NO2Ph
a
Isolated yield after purification by silica gel column chromatography.
Scheme 4
Table 2. Preparation of Bromonitroalkenes 11
a
entry
19, R
11, % yield
1
2
3
4
5
6
19b, 4-OMePh
19c, 4-OHPh
19d, 4-ClPh
11b, 93
11c, 82
11d, 92
11e, 94
11f, 92
11g, 80
19e, 2-furyl
19f, cyclohexyl
19g, 4-NO2Ph
a
Isolated yield after purification by silica gel column chromatography.
of nitroester 9 with BH3·Me2S in THF afforded nitrobutanol 16
in 80% yield.15 Henry condensation of nitrobutanol 16 with
benzaldehyde 15a proceeded well to provide nitroalkenol 19a
in 71% yield. It appeared prudent to convert the OH group in
19a to a better leaving group Br at this stage. Thus, 19a was
converted to bromonitroalkene 11a in excellent yield (91%)
under mild conditions using CBr4 and Ph3P. The key step in
our synthetic sequence, i.e., 1,3-dipolar cycloaddition of
bromide 11a, was performed using commercially available
TMSCHN2 14a. Although this reaction took 4 days for
completion, our attempts to carry out the intramolecular
alkylation in the same pot by treating the intermediate pyrazole
13a (R = H, X = Br) with NaOEt under reflux met with
success, and we were pleased to isolate withasomnine 5a in 60%
yield (for two steps).
the conversion of nitroalkenols 19b,d−f to bromonitroalkenes
11b,d−f, respectively (entries 1, 3−5). Slightly lower yields
(80−82%) were encountered in the preparation of bromides
11c and 11g from alcohols 19c and 19g, respectively.
Having prepared a variety of bromonitroalkenes 11b−g in
two steps from commercially available aldehydes 15b−g and
easily accessible nitrobutanol 16, we proceeded to execute the
one-pot 1,3-dipolar cycloaddition−elimination−intramolecular
alkylation protocol to accomplish the synthesis of witha-
somnine analogues 5b−g (Table 3). Thus, bromonitroalkenes
11b−g were refluxed with TMSCHN2 14a in THF for 4 days
during which time the 1,3-dipolar cycloaddition and aromatiza-
tion via elimination were complete. The reaction mixture was
then refluxed with NaOEt in THF for 24 h for the cyclization
via intramolecular alkylation to take place. We were gratified to
The good overall yield of the above sequence involving
practically five steps starting from ethyl acrylate 17 and
nitromethane 18 prompted us to pursue the synthesis of other
natural and non-natural analogues of withasomnine 5a and
generalize our methodology. Thus, various commercially
available aldehydes 15b−g were condensed with nitrobutanol
16 to afford the nitroalkenols 19b−g in good yield (64−74%,
Table 1). Aldehydes with strong electron-donating groups 15b
and 15c as well as those with weakly and strongly deactivating
groups 15d and 15g, respectively, afforded corresponding
nitroalkenols 19b, 19c, 19d, and 19g in good yield (64−74%,
entries 1−3 and 6). Representative heteroaromatic aldehyde
15e and aliphatic aldehyde 15f also underwent smooth Henry
condensation with nitrobutanol 16 to provide nitroalkenols 19e
and 19f, respectively, in good yields (65−68%, entries 4 and 5).
The nitroalkenols 19b−g were subsequently converted to
bromides 11b−g in excellent yield (80−94%) using CBr4 and
Ph3P (Table 2). The yields were particularly high (92−93%) in
Table 3. Synthesis of Withasomnine Analogues 5
a
b
entry
11, R
5, % yield
overall % yield for five steps
1
2
3
4
5
6
11b, 4-OMePh
11c, 4-OHPh
11d, 4-ClPh
5b, 64
5c, 60
5d, 66
5e, 65
5f, 55
25
18
26
25
19
11e, 2-furyl
11f, cyclohexyl
11g, 4-NO2Ph
c
5g, −
a
Isolated yield after purification by silica gel column chromatography.
Starting from ethyl acrylate 17 and nitromethane 18. Complex
b
c
mixture.
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Note
(E)-4-Nitro-5-phenylpent-4-en-1-ol (19a):13 yellow liquid; yield
71% (1.470 g); IR (neat, cm−1) 3378 (m), 2934 (w), 1652 (w), 1518
(s), 1450 (w), 1325 (s), 1217 (w), 1063 (m), 761 (m); 1H NMR (400
MHz, CDCl3) 1.88−1.95 (m, 2H), 2.09 (br s, 1H), 2.97 (t, J = 7.6 Hz,
2H), 3.74 (t, J = 3.1 Hz, 2H), 7.43−7.47 (m, 5H), 8.08 (s,1H); 13C
NMR (100 MHz, CDCl3) δ 24.0, 30.8, 62.0, 129.2, 130.0, 130.3, 132.3,
134.2, 151.7. Consistent with literature data.13
(E)-5-(4-Methoxyphenyl)-4-nitropent-4-en-1-ol (19b): yellow
solid; yield 73% (1.730 g); mp 75−76 °C; IR (KBr, cm−1) 3324
(m), 3247 (m), 2942 (m), 2876 (w), 1640 (m), 1604 (s), 1518 (s),
1500 (m), 1440 (w), 1306 (vs), 1262 (vs), 1179 (s), 1061 (m), 1034
(m), 830 (m); 1H NMR (400 MHz, CDCl3) δ 1.72 (br s, 1H), 1.88−
1.96 (m, 2H), 3.02 (t, J = 7.8 Hz, 2H), 3.76 (t, J = 6.0 Hz, 2H), 3.86
(s, 3H), 6.98 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 8.06 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 24.0, 30.6, 55.5, 61.9, 114.7,
124.4, 132.2, 134.2, 149.4, 161.4; MS (ES+) m/z (rel intensity) 260
(MNa+, 90), 238 (MH+, 91), 192 (100); HRMS (ES+) calcd for
C12H16NO4 (MH+) 238.1079, found 238.1070.
note the formation of withasomnine analogues 5b−f in 55−
66% yield (for two steps, entries 1−5). Unfortunately,
bromonitroalkene 11g afforded only a complex mixture
(entry 6). In fact, the yields are in the range of 60−65% for
bromonitroalkenes 11b−e with a variety of R groups, viz., an
aromatic ring with strongly electron-donating groups 11b and
11c (entries 1 and 2), weakly deactivating aromatic ring 11d
(entry 3), and a heteroaromatic ring 11e (entry 4). A slightly
lower yield (55%) was encountered only when R was aliphatic
(cyclohexyl, entry 5).
The proposed mechanism involves regio- and presumably
stereoselective 1,3-dipolar cycloaddition of TMSCHN2 14a
with bromonitroalkene 11 to form the initial cycloadduct I
(Scheme 5). Elimination of TMSNO2 directly (path a) or after
Scheme 5
(E)-4-(5-Hydroxy-2-nitropent-1-enyl)phenol (19c): yellow solid;
yield 64% (1.427 g); mp 124−125 °C; IR (KBr, cm−1) 3434 (br m),
2929 (m), 1603 (s), 1519 (m), 1445 (w), 1375 (w), 1314 (w), 1279
1
(m), 1174 (m), 1022 (m); H NMR (400 MHz, CD3OD) δ 1.79−
1.86 (m, 2H), 2.93−2.98 (m, 2H), 3.66 (t, J = 6.2 Hz, 2H), 6.87 (d, J =
8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.99 (s, 1H); 13C NMR (100
MHz, CD3OD) δ 23.8, 30.3, 61.0, 115.7, 123.1, 132.3, 133.7, 148.8,
159.8; MS (ES+) m/z (rel intensity) 246 (MNa+, 95), 224 (MH+, 48),
214 (35), 206 (50), 178 (100); HRMS (ES+) calcd for C11H14NO4
(MH+) 224.0923, found 224.0931.
(E)-5-(4-Chlorophenyl)-4-nitropent-4-en-1-ol (19d): light yellow
solid; yield 74% (1.783 g); mp 78−79 °C; IR (KBr, cm−1) 3550 (m),
3251 (br vs), 2939 (m), 2873 (m), 1648 (s), 1590 (m), 1506 (s), 1489
(s), 1451 (m), 1316 (s), 1278 (m), 1089 (s), 1066 (s), 1023 (m), 840
1
(m), 817 (m); H NMR (400 MHz, CDCl3) δ 1.86−1.94 (m, 2H),
2.95−2.99 (m, 2H), 3.75 (t, J = 5.8 Hz, 2H), 7.41−7.46 (m, 4H), 8.01
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 23.9, 30.5, 61.7, 129.4, 130.6,
131.2, 132.8, 136.3, 151.9; MS (ES+) m/z (rel intensity) 244 ([MH
+2]+, 20), 242 (MH+, 60), 226 (33), 224 (100); HRMS (ES+) calcd
for C11H13NO3Cl (MH+) 242.0584, found 242.0580.
(E)-5-(Furan-2-yl)-4-nitropent-4-en-1-ol (19e): yellow liquid; yield
68% (1.340 g); IR (neat, cm−1) 3432 (br m), 2945 (m), 1647 (m),
1510 (s), 1472 (m), 1315 (vs), 1065 (m), 1024 (s), 757 (s); 1H NMR
(400 MHz, CDCl3) 1.79 (br s, 1H), 1.85−1.94 (m, 2H), 3.14−3.18
(td, J = 7.5, 1.0 Hz, 2H), 3.74 (t, J = 6.1 Hz, 2H), 6.59 (dd, J = 3.5, 1.8
Hz, 1H), 6.91 (d, J = 3.5 Hz, 1H), 7.65−7.66 (m, 1H), 7.87 (d, J = 1.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.2, 30.8, 61.9, 113.1,
119.8, 121.0, 146.6, 147.7, 148.0; MS (ES+, Ar) m/z (rel intensity)
220 (MNa+, 21), 198 (MH+, 42), 180 (100), 152 (25); HRMS (ES+,
Ar) calcd for C9H12NO4 (MH+) 198.0766, found 198.0766.
(E)-5-Cyclohexyl-4-nitropent-4-en-1-ol (19f): yellow liquid; yield
65% (1.385 g); IR (neat, cm−1) 3417 (br s), 2932 (vs), 2855 (m),
1551 (m), 1519 (vs), 1449 (m), 1333 (s), 1267 (m), 1061 (m), 738
(vs); 1H NMR (400 MHz, CDCl3) 1.16−1.42 (m, 6H), 1.66−1.95 (m,
6H), 2.22−2.37 (m, 2H), 2.61−2.73 (m, 2H), 3.67 (t, J = 6.1 Hz, 2H),
6.97 (d, J = 10.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 23.0, 25.2,
25.6, 31.1, 32.0, 37.5, 61.6, 141.8, 149.9; MS (ES+, Ar) m/z (rel
intensity) 215 ([MH + 1]+, 14), 214 (MH+, 100), 213 (5), 212 (23);
HRMS (ES+, Ar) calcd for C11H20NO3 (MH+) 214.1443, found
214.1434.
a Brook rearrangement (path b) would provide intermediate
III. Tautomerization of III gives IV which in the presence of
NaOEt cyclizes to afford withasomnine 5.
In conclusion, a simple, highly efficient, and general method
for the synthesis of all three withasomnine alkaloids and their
selected non-natural analogues has been developed for the first
time. The key step in the synthesis is a 1,3-dipolar cycloaddition
of α-bromopropyl nitroalkenes with commercially available
TMSCHN2. The bromonitroalkenes in turn are prepared via
nitroaldol (Henry) condensation of commercially available
aldehydes with 4-nitro-1-butanol. An overall yield of 18−26%
for five steps was observed for the six examples reported here,
making this approach a very attractive one.
EXPERIMENTAL SECTION
■
General Methods. The melting points recorded are uncorrected.
The 1H NMR spectra were recorded at 400 MHz, and the 1H
decoupled 13C NMR spectra were recorded at 100 or 75 MHz with
TMS as the internal standard. The coupling constants (J values) are
given in Hz. The high-resolution mass spectra were recorded under
ESI Q-TOF conditions. TMSCHN2 was commercially available.
General Procedure for the Preparation of Nitroalkenols 19.
To a stirred solution of nitrobutanol 16 (1.2 g, 10 mmol) and
aldehyde (11 mmol) in benzene (80 mL) were added piperidine (1.71
g, 20.08 mmol) and acetic acid (6 mL). The reaction mixture was
refluxed overnight under Dean−Stark conditions. After completion of
the reaction (monitored by TLC), the mixture was diluted with water
(10 mL), and the aqueous layer was extracted with EtOAc (5 × 20
mL) and dried over Na2SO4. After evaporation of the solvent in vacuo,
the crude residue was purified by silica gel column chromatography
(60−120 mesh, 70/30 pet ether/ethyl acetate) to afford pure product.
(E)-4-Nitro-5-(4-nitrophenyl)pent-4-en-1-ol (19g): light yellow
solid; yield 65% (1.638 g); mp 94−95 °C; IR (KBr, cm−1) 3557
(m), 3308 (m), 2934 (w), 2876 (w), 1651 (w), 1597 (w), 1516 (vs),
1
1492 (m), 1449 (w), 1344 (s), 1305 (m), 1061 (m); H NMR (400
MHz, CDCl3) 1.84−1.93 (m, 2H), 2.96 (t, J = 7.8 Hz, 2H), 3.73 (t, J =
5.8 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 8.04 (s, 1H), 8.29 (d, J = 6.7 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 24.1, 30.6, 61.7, 124.3, 130.6,
131.3, 138.8, 148.3, 154.3; MS (ES+, Ar) m/z (rel intensity) 253
(MH+, 55), 251 (70), 249 (100); HRMS (ES+, Ar) calcd for
C11H13N2O5 (MH+) 253.0824, found 253.0834.
General Procedure for the Preparation of Bromides 11. To a
stirred solution of alcohol 19 (2 mmol) and CBr4 (1.658 g, 5 mmol) in
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Note
CH2Cl2 (20 mL) was added PPh3 (1.310 g, 5 mmol) solution in
CH2Cl2 (5 mL) at 0 °C. Then the reaction mixture was stirred until
complete consumption of starting material (∼45 min). The solvent
was evaporated and the crude residue was purified by silica gel column
chromatography (60−120 mesh, 95/5 petroleum ether/ethyl acetate)
to get pure bromides 11.
Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 8.10 (s, 1H), 8.31 (d, J = 8.6 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 26.2, 30.6, 32.8, 124.3, 130.5,
132.2, 138.4, 148.4, 153.0; MS (ES+, Ar) m/z (rel intensity) 235 ([M
− Br]H+, 100), 205 (30), 158 (25); HRMS (ES+, Ar) calcd for
C11H11N2O4 ([M − Br]H+) 235.0719, found 235.0712.
General Procedure for the Conversion Bromide 11 to
Withasomnine and Its Analogues 5. To a stirred solution of
bromide 11 (0.5 mmol) in dry THF (20 mL) was added a 2.0 M
solution of trimethylsilyldiazomethane 14a in hexane (0.5 mL, 1
mmol), and the reaction mixture was refluxed for 2 days. On the third
and fourth day, an additional quantity of trimethylsilyldiazomethane
14a (0.2 mL, 0.4 mmol) was added and reflux continued until
complete consumption of 11 (∼4 d). NaOEt (272 mg, 4 mmol) was
then added, and the reaction mixture was refluxed for another 12 h.
The mixture was then concentrated in vacuo, and the crude residue
was directly subjected to silica gel column chromatography (60−120
mesh, 70/30 ethyl acetate/petroleum ether) to afford pure with-
asomnine 5.
(E)-(5-Bromo-2-nitropent-1-enyl)benzene (11a):13 yellow liquid;
yield 91% (491 mg); IR (neat, cm−1) 3060 (w), 2926 (m), 2852 (w),
1651 (m), 1521 (vs), 1449 (m), 1325 (vs), 1255 (m), 1216 (m), 700
(m); 1H NMR (400 MHz, CDCl3) 2.18−2.25 (m, 2H), 3.01−3.05 (m,
2H), 3.50 (t, J = 6.1 Hz, 2H), 7.45−7.48 (m, 5H), 8.11 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 26.4, 30.7, 33.0, 129.3, 130.0, 130.5, 132.0,
134.9, 150.5. Consistent with literature data.13
(E)-1-(5-Bromo-2-nitropent-1-enyl)-4-methoxybenzene (11b):
yellow solid; yield 93% (558 mg); mp 67−68 °C; IR (KBr, cm−1)
2969 (m), 2940 (m), 2840 (w), 1643 (w), 1605 (s), 1519 (m), 1501
(vs), 1446 (m), 1430 (m), 1311 (vs), 1265 (m), 1251 (m), 1181 (m),
1027 (s), 838 (s); 1H NMR (400 MHz, CDCl3) δ 2.18−2.27 (m, 2H),
3.03−3.07 (m, 2H), 3.54 (t, J = 6.2 Hz, 2H), 3.86 (s, 3H), 6.98 (d, J =
8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 8.08 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 26.5, 30.5, 33.3, 55.6, 114.8, 124.1, 132.3, 134.9,
148.2, 161.6; MS (ES+) m/z (rel intensity) 302 ([MH + 2]+, 100),
300 (MH+, 100); HRMS (ES+) calcd for C12H15NO3Br (MH+)
300.0235, found 300.0240.
3-Phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (5a):.1−11,13
white solid; yield 60% (56 mg); mp 115−116 °C (lit.6 mp 114−116
°C); IR (KBr, cm−1) 2985 (m), 2912 (m), 1604 (w), 1462 (w), 1411
(s), 1296 (m), 1160 (m), 1075 (m), 862 (m), 695 (s); 1H NMR (400
MHz, CDCl3) δ 2.61−2.69 (quintet, J = 7.3 Hz, 2H), 3.06 (t, J = 7.3
Hz, 2H), 4.15 (t, J = 7.3 Hz, 2H), 7.16−7.21 (m, 1H), 7.33−7.37 (m,
2H), 7.43−7.46 (m, 2H), 7.82 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 23.9, 26.5, 47.6, 115.3, 125.1, 125.7, 128.9, 133.5, 140.9, 142.7.
Consistent with literature data.6
(E)-4-(5-Bromo-2-nitropent-1-enyl)phenol (11c): light yellow
solid; yield 82% (469 mg); mp 104−105 °C; IR (KBr, cm−1) 3391
(br m), 1640 (w), 1605 (vs), 1585 (m), 1518 (s), 1504 (s), 1446 (m),
1
1380 (w), 1317 (m), 1279 (m), 1218 (m), 1174 (s); H NMR (400
3-(4-Methoxyphenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
(5b):6 yellow solid; yield 64% (69 mg); mp 124−126 °C (lit.6 mp
123−125 °C); IR (KBr, cm−1) 2928 (vs), 2857 (m), 1665 (w), 1564
(w), 1503 (m), 1460 (w), 1257 (m), 1103 (m), 1031 (s), 830 (m); 1H
NMR (400 MHz, CDCl3) δ 2.62 (quint, J = 7.5 Hz, 2H), 3.00 (t, J =
7.5 Hz, 2H), 3.80 (s, 3H), 4.12 (t, J = 7.5 Hz, 2H), 6.89 (d, J = 8.7 Hz,
2H), 7.34 (d, J = 8.7 Hz, 2H), 7.73 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 23.9, 26.5, 47.6, 55.3, 114.3, 115.0, 126.1, 126.2, 140.5,
142.0, 157.7. Consistent with literature data.6
MHz, CDCl3) δ 2.18−2.25 (m, 2H), 3.03−3.08 (m, 2H), 3.53 (t, J =
6.2 Hz, 2H), 6.17 (br s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.8
Hz, 2H), 8.09 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 26.5, 30.5,
33.3, 116.5, 124.2, 132.6, 135.3, 148.2, 158.2; MS (ES+) m/z (rel
intensity) 288 ([MH + 2]+, 23), 286 (MH+, 22), 174 (35), 123 (100);
HRMS (ES+) calcd for C11H13NO3Br (MH+) 286.0079, found
286.0090.
(E)-1-(5-Bromo-2-nitropent-1-enyl)-4-chlorobenzene (11d): light
yellow solid; yield 92% (560 mg); mp 74−75 °C; IR (KBr, cm−1)
2924 (w), 1644 (m), 1590 (m), 1514 (vs), 1492 (s), 1450 (m), 1314
4-(5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)phenol (5c):6 off-
white solid; yield 60% (60 mg); mp 230−231 °C (lit.6 mp 232−234
°C); IR (KBr, cm−1) 3507 (vs), 2951 (m), 2925 (s), 2854 (m), 1656
1
(vs), 1092 (m), 828 (m); H NMR (400 MHz, CDCl3) δ 2.18−2.24
(m, 2H), 3.00−3.04 (m, 2H), 3.51 (t, J = 6.2 Hz, 2H), 7.41 (d, J = 8.6
Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 8.05 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 26.4, 30.6, 33.0, 129.6, 130.4, 131.2, 133.6, 136.7, 150.9; MS
(ES+) m/z (rel intensity) 226 ([M + 2]+, 33), 224 (100, M+), 179
(20), 177 (45); HRMS (ES+) calcd for C11H11NO2Cl (M+) 224.0478,
found 224.0481.
1
(vs), 1462 (w), 1267 (m), 764 (m). H NMR (400 MHz, DMSO-d6)
2.56 (quint, J = 7.2 Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 4.03 (t, J = 7.2
Hz, 2H), 4.06 (br s, 1H), 6.73 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz,
2H), 7.69 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 23.2, 26.1, 47.0,
1
114.5, 115.6, 124.2, 125.9, 139.6, 141.4, 155.3; H NMR (400 MHz,
CDCl3/CD3OD, 1:1) δ 2.67 (quint, J = 7.3 Hz, 2H), 3.03 (t, J = 7.3
Hz, 2H), 3.34 (br s, 1H), 4.10 (t, J = 7.3 Hz, 2H), 6.81 (d, J = 8.6 Hz,
2H), 7.27 (d, J = 8.6 Hz, 2H), 7.68 (s, 1H); 13C NMR (100 MHz,
CDCl3/CD3OD, 1:1) δ 22.9, 25.7, 46.7, 115.0, 115.1, 124.1, 125.7,
139.3, 141.9, 154.8. Consistent with literature data.6
(E)-2-(5-Bromo-2-nitropent-1-enyl)furan (11e): yellow liquid; yield
94% (488 mg); IR (neat, cm−1) 2929 (m), 2857 (w), 1648 (s), 1513
(m), 1310 (m), 750 (vs); 1H NMR (400 MHz, CDCl3) 2.15−2.22 (m,
2H), 3.19−3.52 (m, 2H), 4.44 (t, J = 6.8 Hz, 2H), 6.60 (dd, J = 3.5, 1.8
Hz, 1H), 6.91 (d, J = 3.5 Hz, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.88 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 26.8, 31.0, 32.9, 113.2, 120.3,
121.4, 146.8, 146.9, 147.5; MS (ES+, Ar) m/z (rel intensity) 262 ([M
+ 2]H+, 45), 260 (MH+, 45), 241 (63), 167 (25), 149 (63), 97 (100);
HRMS (ES+, Ar) calcd for C9H11NO3Br (MH+) 259.9922, found
259.9925.
(E)-(5-Bromo-2-nitropent-1-enyl)cyclohexane (11f): yellow liquid;
yield 92% (508 mg); IR (neat, cm−1) 3055 (m), 2933 (m), 2987 (w),
2855 (w), 1732 (w), 1552 (w), 1520 (m), 1436 (w), 1422 (w), 1335
(w), 1264 (s), 735 (vs); 1H NMR (400 MHz, CDCl3) 1.18−1.40 (m,
5H), 1.63−1.81 (m, 5H), 2.04−2.12 (m, 2H), 2.33−2.43 (m, 1H),
2.76−2.80 (m, 2H), 3.43 (t, J = 6.1 Hz, 2H), 7.02 (d, J = 10.7 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 25.1, 25.3, 25.6, 31.0, 32.1, 32.9,
37.7, 142.7, 148.7; MS (ES+, Ar) m/z (rel intensity) 279 ([MH + 3]+,
76), 278 ([MH + 2]+, 100), 276 (14), 262 (23); HRMS (ES+, Ar)
calcd for C11H19NO2Br (MH+) 276.0599, found 276.0600.
3-(4-Chlorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (5d):
light yellow solid; yield 66% (72 mg); mp 105−106 °C; IR (KBr,
cm−1) 2951 (m), 2923 (s), 2852 (m), 1556 (w), 1490 (w), 1395 (w),
1
1163 (w), 1093 (m), 825 (s); H NMR (400 MHz, CDCl3) δ 2.66
(quint, J = 7.4 Hz, 2H), 3.02 (t, J = 7.4 Hz, 2H), 4.14 (t, J = 7.4 Hz,
2H), 7.29 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.76 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 23.9, 26.5, 47.7, 114.3, 126.2, 129.0,
131.2, 132.0, 140.8, 142.8; MS (ES+) m/z (rel intensity) 221 ([MH +
2]+, 34), 219 (MH+, 100); HRMS (ES+) calcd for C12H12N2Cl (MH+)
219.0689, found 219.0679.
3-(Furan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (5e): yellow
liquid; yield 65% (57 mg); IR (neat, cm−1) 2956 (m), 2928 (m), 1640
(vs), 1546 (w), 1438 (m), 1421 (m), 1338 (m), 1267 (w), 1157 (m),
1019 (m), 736 (s); 1H NMR (400 MHz, CDCl3) 2.47 (quintet, J = 7.3
Hz, 2H), 3.02 (t, J = 7.3 Hz, 2H), 4.14 (t, J = 7.3 Hz, 2H), 6.20 (d, J =
3.2 Hz, 1H), 6.39−6.40 (m, 1H), 7.34−7.35 (m, 1H), 7.71 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 23.3, 26.4, 47.9, 102.7, 107.6, 111.2,
140.1, 140.5, 142.5, 149.0; MS (ES+, Ar) m/z (rel intensity) 176
([MH + 1]+, 15), 175 (MH+, 100); HRMS (ES+, Ar) calcd for
C10H11N2O (MH+) 175.0871, found 175.0868.
(E)-1-(5-Bromo-2-nitropent-1-enyl)-4-nitrobenzene (11g): light
yellow solid; yield 80% (504 mg); mp 85−86 °C; IR (KBr, cm−1)
3122 (w), 2930 (w), 1604 (m), 1539 (s), 1523 (vs), 1347 (vs), 1331
(vs), 1316 (s), 1253 (m), 1046 (w), 929 (w), 839 (w); 1H NMR (400
MHz, CDCl3) 2.17−2.24 (m, 2H), 3.99−3.03 (m, 2H), 3.49 (t, J = 6.0
3485
dx.doi.org/10.1021/jo400207u | J. Org. Chem. 2013, 78, 3482−3486

The Journal of Organic Chemistry
Note
3-Cyclohexyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (5f): yellow
liquid; yield 55% (52 mg); IR (neat, cm−1) 2923 (vs), 2853 (s), 1720
(m), 1554 (w), 1448 (m), 1415 (m), 1338 (w); 1H NMR (400 MHz,
CDCl3) 1.14−1.38 (m, 5H), 1.66−1.90 (m, 5H), 2.38−2.44 (m, 1H),
2.56 (quint, J = 7.3 Hz, 2H), 2.83 (t, J = 7.3 Hz, 2H), 4.05 (t, J = 7.3
Hz, 2H), 7.31 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 23.3, 26.3,
26.5, 26.7, 34.1, 34.5, 47.4, 120.2, 141.6, 142.1; MS (ES+, Ar) m/z (rel
intensity) 191 (MH+, 100); HRMS (ES+, Ar) calcd for C12H19N2
(MH+) 191.1548, found 191.1543.
Chemistry; Padwa, A., Ed.; Wiley Interscience: New York, 1984;
Chapter 4. (c) Zollinger, H. Diazo Chemistry II-Aliphatic, Inorganic and
Organometallic Compounds; VCH: Weinheim, 1995; p 11. (d) Die-
derrich, F.; Isaacs, L.; Philip, D. Chem. Soc. Rev. 1994, 23, 243.
(e) Trivedi, G. K. J. Ind. Chem. Soc. 2004, 81, 187. (f) Mullins, R. J. In
Name Reactions in Heterocyclic Chemistry II; Li, J. J., Ed.; Wiley: New
York, 2011; p 327. (g) Harju, K.; Yli-Kauhaluoma, J. In Solid-Phase
Organic Synthesis; Toy, P. H., Lam, Y., Ed.; Wiley: New York, 2012; p
355.
(15) Newkome, G. R.; Kim, H. J.; Moorefield, C. N.; Maddi, H.; Yoo,
K.-S. Macromolecules 2003, 36, 4345.
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectra for all the new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: irishi@iitb.ac.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
I.N.N.N. thanks DAE/BRNS India for financial assistance. D.V.
thanks IIT Bombay for an institute postdoctoral fellowship, and
R.K. thanks CSIR India for a senior research fellowship.
REFERENCES
■
(1) Schroter, H.-B.; Neumann, D.; Katritzky, A. R.; Swinbourne, F. J.
Tetrahedron 1966, 22, 2895.
(2) (a) Other plant sources of withasomnines, Newbouldia laevis:
Adesanya, S. A.; Nia, R.; Fontaine, C.; Pais, M. Phytochemistry 1994,
35, 1053. (b) Aladesanmi, A. J.; Nia, R.; Nahrstedt, A. Planta Med.
1998, 64, 90. (c) Houghton, P. J.; Pandey, R.; Hawkes, J. E. Phytochem.
1994, 35, 1602. (d) Elytraria: Ravikanth, V.; Ramesh, P.; Diwan, P. V.;
Venkateswarlu, Y. Biochem. Syst. Ecol. 2001, 29, 753. (e) Discopodium
penninervium: Wube, A. A.; Wenzig, E.-M.; Gibbons, S.; Asres, K.;
Bauer, R.; Bucar, F. Phytochemistry 2008, 69, 982.
(3) (a) Marimoto, A.; Noda, K.; Watanabe, T.; Takasugi, H.
Tetrahedron Lett. 1968, 9, 5707. (b) Takano, S.; Imamura, Y.;
Ogasawara, K. Heterocycles 1982, 19, 1223.
(4) Onaka, T. Tetrahedron Lett. 1968, 9, 5711.
(5) Ranganathan, D.; Bamezai, S. Synth. Commun. 1985, 15, 259.
(6) Foster, R. S.; Huang, J.; Vivat, J. F.; Browne, D. L.; Harrity, J. P.
A. Org. Biomol. Chem. 2009, 7, 4052.
(7) Guzman-Perez, A.; Maldonado, L. A. Synth. Commun. 1991, 21,
1667.
(8) Kulinkovich, O.; Masalov, N.; Tyvorskii, V.; De Kimpe, N.;
Keppens, M. Tetrahedron Lett. 1996, 37, 1095.
(9) (a) Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; McInally, T.
Tetrahedron Lett. 2002, 43, 4191. (b) Allin, S. M.; Barton, W. R. S.;
Bowman, W. R.; Bridge, E.; Elsegood, M. R. J.; McInally, T.; McKee,
V. Tetrahedron 2008, 64, 7745.
(10) Majumder, S.; Gipson, K. R.; Staples, R. J.; Odom, A. L. Adv.
Synth. Catal. 2009, 351, 2013.
(11) Ichikawa, H.; Watanabe, R.; Fujino, Y.; Usami, Y. Tetrahedron
Lett. 2011, 52, 4448.
(12) (a) Muruganantham, R.; Mobin, S. M.; Namboothiri, I. N. N.
Org. Lett. 2007, 9, 1125. (b) Muruganantham, R.; Namboothiri, I. N.
N. J. Org. Chem. 2010, 75, 2197. (c) Verma, D.; Mobin, S. M.;
Namboothiri, I. N. N. J. Org. Chem. 2011, 76, 4764. (d) Kumar, R.;
Verma, D.; Mobin, S. M.; Namboothiri, I. N. N. Org. Lett. 2012, 14,
4070.
(13) Kumar, R.; Namboothiri, I. N. N. Org. Lett. 2011, 13, 4016.
(14) Selected reviews on 1,3-dipolar cycloaddition of diazo
compounds with alkenes or alkynes: (a) Molteni, G. ARKIVOC
2007, 224. (b) Regitz, M.; Heydt, H. 1,3-Dipolar Cycloaddition
3486
dx.doi.org/10.1021/jo400207u | J. Org. Chem. 2013, 78, 3482−3486