Phosphonylpyrazoles from bestmann-ohira reagent and nitroalkenes: synthesis and dynamic nmr studies

Article abstract of DOI:10.1021/jo902595e

Application of diethyl 1-diazo-2-oxopropylphosphonate (Bestmann-Ohira reagent) as a cycloaddition partner with nitroalkenes has been extensively investigated. Base-mediated reaction of the Bestmann-Ohira reagent with various nitroalkenes such as β-substit

Full text of DOI:10.1021/jo902595e

pubs.acs.org/joc
Phosphonylpyrazoles from Bestmann-Ohira Reagent and Nitroalkenes:
Synthesis and Dynamic NMR Studies
Rajendran Muruganantham and Irishi Namboothiri*
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India
irishi@iitb.ac.in
Received December 8, 2009
Application of diethyl 1-diazo-2-oxopropylphosphonate (Bestmann-Ohira reagent) as a cycload-
dition partner with nitroalkenes has been extensively investigated. Base-mediated reaction of the
Bestmann-Ohira reagent with various nitroalkenes such as β-substituted, R,β-disubstituted, and
nitroethylene that are part of a carbocyclic or heterocyclic ring provided functionalized phospho-
nylpyrazoles through a one-pot regioselective reaction at room temperature in high yield. The
substituted nitroalkenes employed in these reactions also included Morita-Baylis-Hillman
adducts of conjugated nitroalkenes with various electrophiles. Detailed dynamic NMR studies
were performed on the prototropic tautomerism exhibited by the phosphonylpyrazoles using
CDCl3 and DMSO-d6 as solvents and 1H and 31P as the probe nuclei. These studies unraveled the
existence of two tautomers in solution with a small energy difference but considerable barrier to
interconversion.
Introduction
non-nucleoside HIV-1 reverse transcriptase inhibitors,4
COX-2 inhibitors,5 antihyperglycemic agents,6 cannabinoid
antagonists,7 and cytotoxic agents8 has been reported in the
recent literature. Other enzyme inhibitory,9 antimicrobial,
antiviral, and anticancer10 properties of pyrazoles also made
them a prominent class of heterocycles. The natural product
withasomnine, which is an analgesic and a CNS depressant,
Heterocyclic compounds are popular targets for synthetic
chemists primarily because of their diverse and potent
biological properties.1 Pyrazoles, in particular, have been
reported to exhibit a wide range of biological properties.2
Their therapeutic effects in areas such as CNS diseases,
metabolic diseases, endocrine functions, and oncology have
been highlighted.3 The efficacy of pyrazoles to behave as
(6) Kees, K. L.; Fitzgerald, J. J.; Steiner, K. E.; Mattes, J. F.; Mihan, B.;
Tosi, T.; Mondoro, D.; McCaleb, M. L. J. Med. Chem. 1996, 39, 3920.
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Dolzhenko, A. V.; Chui, W.-K. Heterocycles 2008, 75, 1575. (d) Elgemeie,
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DOI: 10.1021/jo902595e
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Published on Web 03/10/2010
J. Org. Chem. 2010, 75, 2197–2205 2197
2010 American Chemical Society

Muruganantham and Namboothiri
JOCArticle
possesses a pyrazole moiety.11 Several pyrazole-containing
compounds such as Viagra, Celebrex, and Acomplia are
much sought after drugs in the world market. The versatility
of pyrazoles as ligands in coordination chemistry has been
recently reviewed.12
SCHEME 1
The pivotal role of organophosphorus compounds13 as
biomolecules, metabolic probes,14 peptide mimetics,15 antibio-
tic and pharmacological agents,16 and other molecules of
biological relevance17 is well-documented. The organopho-
sphorus compounds to which a heterocyclic moiety is attached
often display greater biological activity.18 Among phosphorus
compounds, phosphonates regulate important biological func-
tions by mimicking carboxylic acid groups.19 Various hetero-
cyclic phosphonates20 exhibit a wide range of bioactivities such
as Edg receptor antagonistic,21 bone-resorption inhibitory,22
antibiotic,23 antibacterial, and antifungal properties.24
Synthesis of phosphonylpyrazoles appeared an attractive
objective in view of the above-mentioned properties of the
individual components and the possible and unpredictable
changes in such properties in the hybrid system. The reported
methods for the synthesis of phosphonylpyrazoles are by and
large based on the cyclocondensation of 1,3-difunctional
species bearing phosphorus substituent with hydrazine deri-
vatives25 or 1,3-dipolar cycloaddition of alkenyl or alkynyl
phosphonate with diazo compounds.26 Although these are
based on the methods for the synthesis of pyrazoles,27,28
synthesis of the phosphorus/phosphonate precursors in-
volves multisteps and the key cyclization/cycloaddition step
often proceeds with poor regioselectivity.29
We recently disclosed a one-pot regioselective synthesis of
phosphonylpyrazoles 3 via base-mediated reaction of the
Bestmann-Ohira reagent 2 with nitroalkenes 1 (Scheme 1).30
In fact, the reaction of 2,31 which is a synthetic equivalent of
diethyl diazomethylphosphonate (Seyferth-Colvin-Gilbert
reagent),32 with aldehydes in the presence of a suitable base
is a convenient way of generating acetylenes.33,34 However,
possible application of 2 as a cycloaddition partner received
scant attention.35 This article, which is a full version of our
preliminary communication,30 describes the scope and appli-
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TABLE 1. 1,3-DC Reaction of β-Substituted Nitroethylenes 1 with
BOR 2 in the Presence of NaOEt in EtOH at Room Temperature
TABLE 2. 1,3-DC Reaction of R,β-Disubstituted Nitroethylenes 4 with
BOR 2 in the Presence of NaOEt in EtOH at Room Temperature
% yielda
entry nitroalkene
R1
benzo[d][1,3]dioxole Me 15 min
R2
time
% yielda
entry
1
R
time
1
2
3
4
5
4a
4b
4c
4d
4e
70
65
68
62
56
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1f
1g
1h
1i
benzo[d][1,3]dioxole
4-OMe-Ph
4-Cl-Ph
4-NO2-Ph
3-NO2-Ph
2-NO2-Ph
Ph
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
30 min
2 h
77
66
61
64
61
67
62
55b
49b
64
53
58
60
4-Cl-Ph
4-NO2-Ph
Ph
Me 15 min
Me 15 min
Me 15 min
Ph
Ph
2 h
aIsolated yield after purification by recrystallization.
2-furyl
2-thienyl
NMe2
suggests that while aromatic nitroalkenes 1a-g with a
variety of substituents (entries 1-7) provide pyrazoles
3a-g in 61-77% yield, the product yields are marginally
lower in the case of heteroaromatic nitroalkenes 1h-i. The
pyrazoles 3j-m were isolated in satisfactory yields in the case
of enaminonitroalkene 1j, β-alkyl nitroethylene 1k, and
nitrodienes 1l-m (entries 10-13, Table 1).
1j
1k
1l
cyclohexyl
PhCHdCHc
2-MeO-PhCHdCHc
1m
2 h
aIsolated yield after purification by silica gel column chromatogra-
phy. bPart of 1 polymerized. c(E) configuration.
by 3. Multinuclear (1H and 31P), variable-temperature (VT),
and solvent-dependent NMR studies were performed on a
representative system to unravel the tautomeric equilibrium in
phosphonylpyrazoles.
Having successfully employed a diverse array of β-sub-
stituted nitroethylenes 1a-m, we proceeded to investigate
the reactivity of BOR 2 with a variety of R,β-disusbtituted
nitroethylenes 4a-e36,37 under the optimized conditions
(Table 2). It may be noted that nitroethylenes 4a-e with
methyl and phenyl substituents at the R-position and aro-
matic rings with electron-withdrawing and -donating groups
at the β-position react with BOR 2 to afford pyrazoles 5a-e
in good yield (56-70%, entries 1-5, Table 2).
Reaction of BOR 2 with nitroethylenic moiety 6 which is
part of various carbo- and heterocyclic rings appeared to be
an attractive strategy for the synthesis of phosphonylpyr-
azoles 7 which are fused to carbo- and heterocycles (Table 3).
Thus, we were pleased to observe the formation of phospho-
nyl pyrazoles angularly fused to chromene skeleton 7a-c in
good yield when nitrochromenes 6a-c38 were reacted with
BOR 2 (entries 1-3, Table 3). While nitroquinoline 6d and
nitronaphthalene 6e also reacted with BOR 2 over 24 h and
delivered the pyrazoles 7d and 7e, respectively, in good to
moderate yield (entries 4 and 5), our attempts to react
nitrobenzene 6f and m-dinitrobenzene 6g with BOR 2
under similar conditions were unsuccessful (entries 6 and 7,
Table 3). The inertness of nitrobenzene 6f and m-dinitro-
benzene 6g in their base-mediated reaction with BOR 2 is
attributable to their greater aromaticity as compared to
nitroquinoline 6d and nitronaphthalene 6e.
Results and Discussion
The commercially available 2-oxopropylphosphonate was
transformed in one step to the Bestmann-Ohira reagent
(BOR) 2.34 Our extensive optimization studies using 1a as the
model substrate revealed that the regioselective formation of
pyrazole 3a in 77% yield from nitroalkene 1a and BOR 2
takes place in the presence of sodium ethoxide in ethanol at
room temperature in 15 min (Table 1). The requirement of a
nucleophilic base and protic solvent was apparent from our
experiments. According to the proposed mechanism,30 the
nucleophilic base mediated acyl cleavage of BOR 2 followed
by cycloaddition of the resulting diazomethylphosphonate
anion with nitroalkene 1a provides initial cycloadduct which
undergoes elimination to afford phosphonylpyrazole 3a.
After confirming the structure of 3a by 1H-1H-NOESY
and single-crystal X-ray diffraction analysis,30 we reacted
a variety of other nitroalkenes 1b-m with BOR 2 under the
optimized conditions (Table 1). Examination of Table 1
(33) The diazomethylphosphonate anion, generated in situ by a nucleo-
philic base, reacts with the aldehyde in a Horner-Wadsworth-Emmons
fashion to afford acetylenes. For recent reviews, see: (a) Zanatta, S. D. Aust.
J. Chem. 2007, 60, 963. (b) Eymery, F.; Iorga, B.; Savignac, P. Synthesis 2000,
It should be noted that in the reactions discussed so far, the
pyrazoles are formed via elimination of the NO2 group, a
€
185. For recent articles, see: (c) Roth, G. J.; Liepold, B.; Muller, S. G.;
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Ravikumar, V.; Pujari, S. A. Tetrahedron Lett. 2006, 47, 981. (l) For a recent
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2008, 49, 6904.
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of 2 to aromatic nitriles involves loss of diazo group in 2: Gong, D.; Zhang,
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J. Org. Chem. Vol. 75, No. 7, 2010 2199

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TABLE 3. 1,3-DC Reaction of Nitroheterocycles and Aromatics 6 with
BOR 2 in the Presence of NaOEt in EtOH at Room Temperature
TABLE 4. 1,3-DC Reaction of r-Bromonitrostyrenes 8 with BOR 2 in
the Presence of NaOEt in EtOH
entry
8
Ar
% yield of 9 þ 10a 9/10 ratiob
1
2
3
4
8a Ph
47
54
38
50
100:0
61:39
100:0
52:48
8b 4-OMe-Ph
8c 4-Cl-Ph
8d benzo[d][1,3]dioxole
aIsolated yield after purification by silica gel column chromatogra-
phy. Part of 8 polymerized. bDetermined by 31P NMR of the crude
mixture.
TABLE 5. 1,3-DC Reaction of R-Hydroxymethylated Nitrostyrenes 11
with BOR 2 in the Presence of NaOEt in EtOH
aIsolated yield after purification by silica gel column chromatogra-
phy. b22% of 6e was recovered. cNo reaction. m- and p-nitrotoluene also
did not react under our experimental conditions.
entry
11
R
% yielda
synthetically useful functionality, from the initial cyclo-
adduct. Therefore, it was felt that in the event of the starting
nitroalkene possessing a leaving group that is better than
NO2 group at the R-position, it would be possible to isolate
nitropyrazole. In order to achieve this objective, R-bromoni-
troalkenes 8a-d37 were reacted with BOR 2 under the
optimized conditions (Table 4). These reactions proceeded
in moderate to good yield (38-54%). Interestingly, nitro-
alkenes 8a and 8c provided nitropyrazoles 9a and 9c as the
exclusive products (entries 1 and 3, Table 4). On the other
hand, in the case of R-bromonitrostyrenes with electron-
donating groups on the aromatic ring mixtures of nitropyr-
azole and bromopyrazole were isolated (entries 2 and 4,
Table 4). This was explained primarily in terms of the
elimination of HBr by an E2 mechanism and HNO2 by an
E1cB mechanism from the initial cycloadducts. It turns out
that in the case of 8a and 8c E2 elimination leads to the
exclusive formation of 9a and 9c, respectively. However, in
the case of 8b and 8d, a competing E1cB mechanism is also
operative which leads to the formation of a mixture of 9
and 10.30
1
2
3
11a
11b
11c
benzo[d][1,3]dioxole
4-OMe-Ph
2-furyl
61
55
57
aIsolated yield after purification by silica gel column chromatogra-
phy.
The above strategy was extended to other MBH adducts
arising from reaction of nitroalkenes with electrophiles such
as tosyl imines, methyl vinyl ketone, azo dicarboxylate, and
acrylate40 (Table 6). Reaction of these MBH adducts 13a-f
with BOR 2 proceeded well to afford pyrazoles 14a-f in
good to excellent yield (51-75%). In the case of MBH
adducts 13e-f the initial cycloadduct underwent sponta-
neous cyclization to the lactams 14e-f.
Dynamic NMR Studies. Besides biological and ligand
properties (vide supra), an interesting property of pyrazoles
is their tautomerism,41 but the energy difference between
the two tautomers is generally small.42 Additionally, the
(40) MBH adducts of nitroalkenes with: (a) Tosyl imines: Rastogi, N.;
Mohan, R.; Panda, D.; Mobin, S. M.; Namboothiri, I. N. N. Org. Biomol.
Chem. 2006, 4, 3211. (b) Activated alkenes such as MVK and acrylate:
Dadwal, M.; Mohan, R.; Panda, D.; Mobin, S. M.; Namboothiri, I. N. N.
Chem. Commun. 2006, 338. (c) Azodicarboxylates: Dadwal, M.; Mobin,
S. M.; Namboothiri, I. N. N. Org. Biomol. Chem. 2006, 4, 2525.
(41) (a) Elguero, J.; Marzin, C.; Linda, P.; Katritzky, A. R. The Tautomerism
of Heterocycles; Academic Press: New York, 1976; pp 655. (b) Cornago, P.;
Cabildo, P.; Claramunt, R. M.; Bouissane, L.; Pinilla, E.; Torres, M. R.; Elguero, J.
New J. Chem. 2009, 33, 125 and references cited therein. (c) O'Connell, M. J.;
Ramsay, C. G.; Steel, P. J. Aust. J. Chem. 1985, 38, 401 and references cited
therein. (d) Fahmy, H. M.; Elnagdi, M. H.; Mahgoub, A. E.; Kasem, A.; Ghali,
E. A. J. Chin. Chem. Soc. 1985, 32, 99. (e) Witanowski, M.; Stefaniak, L.;
Januszewski, H.; Elguero, J. J. Chim. Phys. Phys.-Chim. Biol. 1973, 70, 697;
Chem. Abstr. 1973, 79, 31082.
Our methodology found applications in the synthesis of
fully functionalized pyrazoles. At the outset, R-hydroxy-
methylated nitroalkenes 11a-c,39 which were conveniently
generated via Morita-Baylis-Hillman (MBH) reaction of
nitroalkenes with formaldehyde, were employed as the cyclo-
addition partners with BOR 2 under the optimized condi-
tions (Table 5). The fully functionalized pyrazoles 12a-c
were isolated in good yield (55-61%).
(39) (a) Rastogi, N.; Namboothiri, I. N. N.; Cojocaru, M. Tetrahedron
Lett. 2004, 45, 4745. (b) Mohan, R.; Rastogi, N.; Namboothiri, I. N. N.;
Mobin, S. M.; Panda, D. Bioorg. Med. Chem. 2006, 14, 8073.
(42) Abboud, J. L. M.; Cabildo, P.; Canada, T.; Catalan, J.; Claramunt,
R. M.; De Paz, J. L. G.; Elguero, J.; Homan, H.; Notario, R. J. Org. Chem.
1992, 57, 3938.
2200 J. Org. Chem. Vol. 75, No. 7, 2010

Muruganantham and Namboothiri
JOCArticle
TABLE 6. 1,3-DC Reaction of Various MBH Adducts of Nitroalkenes
13 with BOR 2 in the Presence of NaOEt in EtOH
SCHEME 2. Tautomerism in Phosphonylpyrazoles
due to coupling of C5-H with the adjacent NH proton
was ruled out. However, appearance of these two peaks as
a doublet (J = 2.0 Hz) due to coupling of C5-H with
phosphorus could not be ruled out. When the spectrum
was recorded in DMSO-d6, the pattern dramatically chan-
ged to the two peaks appearing at 7.86 and 8.10 ppm,
respectively, in 1:4 ratio (Figure S1b, Supporting Infor-
mation). Additionally, there was no characteristic peak
for the N-H proton when the spectrum was recorded in
CDCl3, but it appeared at ∼13.60 ppm in DMSO-d6
(Figures S1a and S1b, Supporting Information). From
the above observation it appeared that the two peaks
centered at ∼7.80 ppm in CDCl3 (a) corresponded to the
C5-H of the two equally populated but fast interconvert-
ing tautomers 3a-P-3-P (pyrazole-3-phosphonate) and 3a-
P-5-P (pyrazole-5-phosphonate) of phosphonylpyrazole
3a on the NMR time scale (Scheme 2) or (b) due to
coupling of C5-H with phosphorus. In any event, if
tautomerism does exist in CDCl3 at room temperature
and the process is fast on the NMR time scale, it would
slow down in a strong hydrogen bonding acceptor solvent
such as DMSO-d6 with concomitant appearance of the
N-H signal and shifting of the equilibrium in favor of one
of the tautomers (Scheme 2).
aIsolated yield after purification by silica gel column chromatography.
activation barrier for the interconversion between the tau-
tomers is also generally low. The tautomerism involving
exclusively the ring proton attached to the nitrogen has been
extensively investigated both experimentally41 and theoreti-
cally.43 Although pyrazole tautomeric equilibrium constants
can be determined by NMR spectroscopy, to our knowledge,
the method has scarcely been used.44 An interesting case of a
tautomeric mixture whose equilibrium constant has been
determined by NMR spectroscopy is that of 3(5)-methyl-
and phenylpyrazoles.45 In this study, 3(5)-methylpyrazole
was found to exist in hexamethylphosphorotriamide
(HMPT) at -20 °C as a mixture of 46% of 3-methylpyrazole
and 54% of 5-methylpyrazole. To our knowledge, there was
no study on the tautomerism of pyrazole phosphonates.
Further, 31P NMR was rarely utilized to study the pyrazole
tautomerism.46 In this scenario, we decided to investigate the
tautomerism of our phosphonylpyrazoles by 1H NMR and
31P NMR analysis.
To further understand the tautomerism exhibited by
phosphonyl pyrazole 3 in solution, variable-temperature
NMR experiments (230-330 K) were performed both in
CDCl3 and in DMSO-d6 by choosing phosphonyl pyrazole
3a as the model substrate.
First, we recorded the 1H NMR spectra of 3a in the
temperature range of 228-318 K in CDCl3 (Figure 1a).
The pyrazole proton C5-H in 3a showed two peaks
of equal intensities at room temperature due to intermedi-
ate exchange on NMR time scale (vide supra, see also
Figure S1a). The two peaks are visible, though not clearly
separated due to fast exchange at 318 K as well. The same
experiment was performed at different low temperatures
(up to 228 K) at which the interconversion, if any, was
expected to gradually slow down so that the two peaks
corresponding to the two tautomeric pyrazoles 3a-P-3-P
and 3a-P-5-P could be followed by NMR. Unfortunately,
the peaks overlapped to form a single broad peak at lower
temperature. Appearance of a single peak even at the
lowest temperature studied is attributable either to acci-
dental overlap of the two peaks corresponding to two
tautomers or existence of only one tautomer (very slow
or no exchange on NMR time scale). However, consider-
able deshielding of the peak for the C5-H was observed on
lowering the temperature, suggesting that intermolecular
H-bonding with the participation of C5-H, besides N-H,
becomes stronger at lower temperature. An infinite net-
work of phosphonylpyrazole 3a involving intermolecular
hydrogen bonding and π-stacking was observed in the
solid state (Figure S2, Supporting Information)30 which
1
The H NMR spectrum of compound 3a recorded in
CDCl3 showed two peaks centered at ∼7.80 ppm in a 1:1
ratio and separated by 2.0 Hz for the C5-H (Figure S1a,
Supporting Information). These peaks remained unaf-
fected when the spectrum was recorded in CDCl3
D2O. Therefore, the possibility of these two peaks arising
þ
(43) (a) Alkorta, I.; Elguero, J.; Liebman, J. F. Struct. Chem. 2006, 17,
439. (b) Alkorta, I.; Elguero, J. Heteroatom Chem. 2005, 16, 628.
(44) (a) Nesmeyanov, A. N.; Zavelovich, E. B.; Babin, V. N.; Kochetkova,
N. S.; Fedin, E. I. Tetrahedron 1975, 31, 1461. (b) Nesmeyanov, A. N.; Babin,
V. N.; Zavelovich, E. V.; Kochetkova, N. S. Chem. Phys. Lett. 1976, 37, 184.
(45) (a) Cativiela, C.; Garcia-Laureiro, J. I.; Elguero, J.; Elguero, E. Gazz.
Chim. Ital. 1991, 121, 477. (b) Aguilar-parrilla, F.; Cativiela, C.; Diaz de
Villegas, M. D.; Elguero, J.; Foces-Foces, C.; Garcia, L.; Jose, I.; Hernandez,
C. F.; Limbach, H. H.; Smith, J. A. S.; Toiron, C. J. Chem. Soc., Perkin
Trans. 2 1992, 1737.
ꢀ
(46) Claramunt, R. M.; Lopez, C.; Elguero, J.; Rheingold, A. L.; Zakharov,
L. N.; Trofimenkoc, S. ARKIVOC 2003, 209.
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Muruganantham and Namboothiri
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FIGURE 1. VT 1H NMR spectra of 3a (a) in CDCl3 and (b) DMSO-d6.
is likely to be present in solution (CDCl3) as well at low
temperature.
equations were used for calculating the kinetic constants at
coalescence.49
After completing our VT 1H NMR analysis of 3a in
CDCl3, we proceeded to investigate the behavior of 3a in a
strong H-bonding acceptor solvent such as DMSO-d6 in
anticipation that the two tautomers that interconverted
rapidly (fast exchange on NMR time scale) in CDCl3 at
different temperatures would exhibit differential stability
and population as a result of selective stabilization of one
kA ¼ 1=2τavð1-ΔnÞ and τA ¼ 1=kA
kB ¼ 1=2τavð1 þ ΔnÞ and τB ¼ 1=kB
ð2Þ
ð3Þ
ꢀ
ΔGA ¼ 4:57Tc½10:62 þ log 2πΔντA=2πð1 -ΔnÞ
þ logðTc=ΔνÞꢁ
ð4Þ
1
of them by DMSO-d6.47 Thus, the H NMR spectra of 3a
ꢀ
ΔGB ¼ 4:57Tc½10:62 þ log 2πΔντB=2πð1 þ ΔnÞ
were recorded in the temperature range of 298-333 K in
DMSO-d6 (Figure 1b). The spectrum recorded at 298 K
showed two signals appearing at 7.86 ppm and 8.10 ppm
with a ratio of ∼1:4 (see also Figure S1b, Supporting
Information). When the temperature was raised, the two
peaks coalesced at 318 K and became a broad single peak.
The VT 1H NMR spectra recorded in DMSO-d6 (Figure 1b)
allow us to estimate the average rate constant kav and
average lifetime τav at the coalescence temperature Tc by
the following equation:48
þ logðTc=ΔνÞꢁ
ð5Þ
where Δn is nB - nA, the difference in mole fractions of the two
species.
Using the above equations, we calculated the free energies
of activation at coalescence (Tc = 318 K) for the tautomer-
1
ism of 3a-P-3-P to 3a-P-5-P and vice versa from H NMR
recorded in DMSO-d6 as 17.52 and 15.66 kcal mol-1
,
respectively (Tables S1 and S3, Supporting Information).
The 31P NMR spectrum recorded in CDCl3 at room
temperature shows a single peak at 7.03 ppm, while in
DMSO-d6 two signals at 7.78 and 12.07 ppm corresponding
to two tautomers with relative intensity of ∼1:3 are observed
(Figure S3, Supporting Information).
kav ¼ 2:22ðΔνÞ and τav ¼ 1=kav
ð1Þ
This relates to two given signals absorbing with a frequency
difference Δν. However, since two kinetic processes are
involved for unequally populated two-site exchange between
3a-P-3-P and 3a-P-5-P, the following modified Eyring’s
Subsequently, we recorded the variable-temperature 31P
NMR spectrum in two different solvents, i.e., CDCl3 and
DMSO-d6 (Figure 2). In the case of DMSO-d6 at room
temperature, the rate of tautomerism between 3a-P-5-P
and 3a-P-3-P was found to be slow on the NMR time scale
showing two clearly distinguishable peaks in ∼1:3 ratio
(Figure 2a and Figure S3, Supporting Information). When
the temperature was gradually raised from 298 to 343 K, the
peaks turned broad, especially the one corresponding to the
minor tautomer, making it extremely difficult to assess the
coalescence.
(47) For NMR studies on the tautomerism of pyrazoles in strong hydro-
gen bonding acceptor solvents such as DMSO and HMPT, see: (a) Gonzalez,
E.; Faure, R.; Vincent, E. J.; Espada, M.; Elguero, J. Org. Magn. Reson.
1979, 12, 587. (b) Litchman, W. M. J. Am. Chem. Soc. 1979, 101, 545.
(c) Chenon, M. T.; Coupry, C.; Grant, D. M.; Pugmire, R. J. J. Org. Chem.
1977, 42, 659.
(48) Atta-ur-Rahman. Nuclear Magnetic Resonance: Basic Principles;
Springer Verlag: New York, 1986.
(49) Shanan-Atidi, H.; Bar-Eli, K. H. J. Phys. Chem. 1970, 74, 961. This
is a convenient method to calculate kinetic constants at coalescence for
unequally populated two site exchange as compared to the cumbersome line
shape analysis. For a discussion, see: Eliel, E. L.; Wilen, S. H.; Mander, L. S.
Stereochemistry of Organic Compounds; John Wiley and Sons, Singapore,
2003, pp 504. For an application, see: Zhang, P. C.; Wang, Y. H.; Liu, X.; Yi,
X.; Chen, R. Y.; Yu, D. Q. Chin. Chem. Lett. 2002, 13, 645.
The 31P NMR spectra of 3a were then recorded in CDCl3
over the temperature range 223-300 K (Figure 2b). The RT
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Muruganantham and Namboothiri
JOCArticle
FIGURE 2. VT 31P NMR spectra of 3a in (a) DMSO-d6 and (b) CDCl3.
31P NMR spectrum (300 K) showed a single peak either due
the fast interconversion between the two tautomers 3a-P-5-P
and 3a-P-3-P or due to the existence of only one tautomer.
Interestingly, when the spectrum was recorded at 223 K, the
slow interconversion on the NMR time scale between the two
tautomers was evident from the appearance of two peaks,
respectively, at 7.61 and 12.29 ppm in a ratio of ∼1:7
(Figure 2b). These two peaks coalesced at 238 K and became
a single peak, due to fast exchange on NMR time scale,
centered at δ 8.36 at higher temperature. This confirmed that
two tautomers do exist in CDCl3 as well, but they inter-
convert slowly at low temperature enabling us to distinguish
between them. An averaged single peak, indicating their
faster interconversion on the NMR time scale, is observed
at higher temperature. The activation barriers for the inter-
conversion of 3a-P-3-P to 3a-P-5-P and vice versa calculated
from 31P NMR recorded in CDCl3 at coalescence (Tc = 238
K) are, respectively, 13.48 and 10.81 kcal mol-1 (Tables S2
and S3, Supporting Information).
bonding involving the N-H and C5-H of the phosphonylpyr-
azole and DMSO-d6 could stabilize 3a-P-3-P over 3a-P-
5-P (Scheme 3). This intermolecular hydrogen bonding
becomes weaker as the temperature is increased. Hence,
1H NMR in DMSO-d6 at room temperature showed two
peaks of unequal intensities for C5-H corresponding to
major and minor tautomers. It is important to note that the
peak for the major tautomer is deshielded as compared to
that for the minor tautomer in all the analogues 3a-m
(Table S4, Supporting Information). On the other hand, it
showed an average signal for two tautomers at elevated
temperature. The same trend was observed in the case of
31P NMR as well.
As a consequence of overlapping of peaks for C5-H in 1H
NMR at low temperature in CDCl3 (Figure 1a), we cannot
unambiguously assign the major tautomer. However, 31P
NMR in CDCl3 clearly shows two separate peaks in ∼1:7
ratio for two different tautomers due to slow exchange on
NMR time scale at lower temperature (Figure 2b). This is
presumably due to the intermolecular hydrogen bonding
between C5-H of one molecule and PdO of another molecule
Variable-temperature 1H NMR spectra suggested that, in
DMSO-d6 at room temperature, intermolecular hydrogen
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Muruganantham and Namboothiri
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SCHEME 3. Stabilization of Pyrazole 3-Phosphonate of 3a in
DMSO-d6
by TLC, see also Tables 1-6) which was then diluted with water
(15 mL), neutralized with 5% HCl (10 mL), and extracted with
ethyl acetate (3 ꢂ 15 mL). The combined organic layers were then
washed with brine (2 ꢂ 10 mL), dried over anhyd Na2SO4, and
then concentrated in vacuo. The crude residue was purified by
column chromatography (silica gel, n-hexane/ethylacetate 3:1) to
afford pure pyrazole 3, 5, 7, 9-10, 12, or 14. Representative
experimental data are provided below. For complete data, see the
Supporting Information.
Diethyl 4-cyclohexyl-1H-pyrazol-3-ylphosphonate (3k): color-
less solid; yield 151 mg (53%); mp 136 °C; IR (KBr, cm-1) 3170
(m), 2926 (s), 1240 (m), 1225 (s), 1023 (s), 974 (m), 576 (m); 1H
NMR (400 MHz, CDCl3) δ 1.32 (t, J = 7.0 Hz, 6H), 1.35-1.40
(m, 6H), 1.72-1.92 (m, 4H), 2.77-2.83 (m, 1H), 4.04-4.24 (m,
4H), 7.64 (d, J = 2.0 Hz, 1H); 1H NMR (300 MHz, DMSO-d6) δ
1.22 (t, J = 6.9 Hz, 6H), 1.28-1.31 (m, 5H), 1.72-1.85 (m, 5H),
2.76 (m, 1H), 3.95 (dq collapsed to quintet, J = 7.0 Hz, 4H),
7.54/7.70 (br s/br s, minor/major, 1H), 13.28 ((br s/br s, major/
becoming stronger with lowering of temperature. This type
of hydrogen bonding is also present in the solid state (see the
crystal structure of 3a, Figure S2, Supporting Information),
and hence, we believe that 3a-P-3-P is stabilized over 3a-P-
5-P in CDCl3 at lower temperature as well. This is consistent
with the general trend that the tautomer in the solid state and
the most stable tautomer in solution are identical.50
minor, 1H); 13C NMR (100 MHz, CDCl3) δ 16.2 (d, JC-P
6.9 Hz), 26.0, 26.7, 33.9, 34.9, 62.2 (d, JC-P = 4.6 Hz), 130.2
=
Analysis of 1H and 31P NMR spectra of pyrazoles 3b-m
recorded in CDCl3 and in DMSO-d6 at room temperature
revealed that 3b-m also exhibit tautomerism similar to that
of 3a (Table S4, Supporting Information).51
(br), 133.2 (d, JC-P = 22.8 Hz), 134.7 (d, JC-P = 220.0 Hz); 31
P
NMR (121.4 MHz, CDCl3) δ 10.04; 31P NMR (121.4 MHz,
DMSO-d6) δ 12.35 (br); MS (ESþ) m/e (rel intensity) 325 (MKþ,
5), 309 (MNaþ, 100), 287 (MH, 5); HRMS (ESþ) calcd for
C13H23N2O3PNa (MNaþ) 309.1344, found 309.1340.
Conclusions
Diethyl 4-(benzo[d][1,3]dioxol-5-yl)-5-methyl-1H-pyrazol-3-
yl-3-phosphonate (5a): colorless solid; yield 235 mg (70%); mp
153 °C; IR (KBr, cm-1) 3412 (br, m), 3081 (w), 2980 (w), 2925
(w), 1693 (s), 1604 (m), 1541 (s), 1462 (w), 1291 (w), 1260 (w),
1172 (m), 1027 (s), 760 (m); 1H NMR (400 MHz, CDCl3) δ 1.19
(t, J = 7.0 Hz, 6H), 2.30 (s, 3H), 3.96-4.15 (m, 4H), 5.99 (s, 2H),
6.79-6.88 (m, 3H); 1H NMR (300 MHz, DMSO-d6) δ 1.10 (t,
J = 6.9 Hz, 6H), 2.16/2.21 (s/s, minor/major in 1:4.6 ratio, 3H),
4.03 (dq collapsed to quintet, J = 7.3 Hz, 4H), 6.02 (s, 2H), 6.89
(ABq, J = 6.2 Hz, 2H), 6.92 (s, 1H), 13.30 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 10.8, 16.0 (d, JC-P = 6.9 Hz), 62.6 (d,
The regioselective synthesis of fused and highly functio-
nalized phosphonylpyrazoles through a one-pot base-
mediated reaction at room temperature between the Best-
mann-Ohira reagent (BOR) and nitroalkenes has been
carried out. These studies establish the hitherto unexplored
role of BOR as a 1,3-dipolar cycloaddition partner with
nitroalkenes. The scope and potential of the cycloaddition
has been demonstrated with a variety of nitroethylenes and
nitrodienes. The tautomerism exhibited by many of the
pyrazole phosphonates in solution was investigated in detail
by dynamic NMR studies which showed that the two
tautomers underwent faster interconversion in CDCl3. But,
in a hydrogen bonding acceptor solvent such as DMSO-d6,
selective stabilization of one of the tautomers, which was
identical to the only tautomer observed in solid state (X-ray),
was discernible. Investigations on the base-mediated cyclo-
addition of BOR with other activated alkenes are currently
underway in our laboratory.
J
C-P = 4.6 Hz), 101.0, 108.0, 110.4, 123.4, 124.8 (d, JC-P = 21.3 Hz),
125.9, 134.0 (d, JC-P = 210.5 Hz), 142.7 (br), 146.7, 147.2; 31
P
NMR (161.8 MHz, CDCl3) δ 7.76; 31P NMR (121.4 MHz,
DMSO-d6) δ 7.37/11.76 (minor/major in 1:3.6 ratio); MS
(ESþ) m/e (rel intensity) 339 (MHþ, 100); HRMS (ESþ) calcd
for C15H20N2O5P (MHþ) 339.1110, found 339.1112.
Diethyl-7-methyl-3H-pyrazolo[4,3-f]quinolin-1-ylphosphonate
(7d): light yellow solid; yield 165 mg (52%); mp 190 °C; IR (KBr,
cm-1) 3440 (br, m), 2989 (w), 1596 (w), 1545 (w), 1441 (w), 1375
(w), 1246 (m), 1232 (s), 1048 (vs), 1023 (vs); 1H NMR (300 MHz,
CDCl3) δ 1.33 (t, J = 7.1 Hz, 6H), 2.78 (s, 3H), 4.17-4.37 (m,
4H), 7.46 (d, J = 8.5, Hz, 1H), 7.96 (ABq, J = 9.1, the upfield
half is further split into d, J = 2.2 Hz, 2H), 9.26 (d, J = 8.5 Hz,
1H); 1H NMR (300 MHz, DMSO-d6) δ 1.24 (t, J = 7.1 Hz, 6H),
2.60 (s, 3H), 4.15 (dq collapsed to quintet, J = 7.3 Hz, 4H), 7.59
(d, J = 8.4 Hz, 1H), 7.94 (ABq, J = 9.1 Hz, the downfield half is
further split into d, J = 1.8 Hz, 2H), 9.27 (d, J = 8.4 Hz, 1H),
Experimental Section
General Procedure for the 1,3-DC Reaction of Nitroalkenes
and Nitrodienes with Bestmann-Ohira Reagent.52 NaOEt
(102 mg, 1.5 mmol) was added to a stirred solution of nitroalkene
1, 4, 6, 8, 11, or 13 (1 mmol) and BOR 2 (264 mg, 1.2 mmol) in dry
EtOH (5 mL) at room temperature under N2. The resulting
mixture was stirred until the reaction was complete (monitored
14.34 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 16.2 (d, JC-P
6.6 Hz), 24.7, 63.1 (d, JC-P = 5.4 Hz), 115.1, 119.9 (d, JC-P
=
=
23.7 Hz), 120.3, 122.7, 129.4, 134.0, 134.6 (d, JC-P = 232.6),
139.9, 146.0, 157.0; 31P NMR (121.4 MHz, CDCl3) δ 9.21; 31P
NMR (121.4 MHz, DMSO-d6) δ 11.4; MS (ESþ) m/e (rel intensity)
320 ((MHþ, 100); HRMS (ESþ) calcd for C15H19N3O3P (MHþ)
320.1164, found 320.1153.
(50) (a) Minkin, V. I.; Garnovskii, A. D.; Elguero, J.; Katritzky, A. R.;
Denisko, O. V. Adv. Heterocycl. Chem. 2000, 76, 157. (b) Claramunt, R. M.;
Lopez, C.; Santa Maria, M. D.; Sanz, D.; Elguero, J. Prog. Nucl. Magn.
Reson. Spec. 2006, 49, 169. (c) Claramunt, R. M.; Cornago, P.; Santa Maria,
M. D.; Torres, V.; Pinilla, E.; Torres, M. R.; Elguero, J. Supramol. Chem.
2006, 18, 349. (d) Szabo, A.; Cesljevic, V. I.; Kovacs, A. Chem. Phys. 2001,
270, 67. (e) See also ref 41b.
(51) For a detailed discussion on the tautomerism of 3b-m, 5, 7, 9, 10, 12,
and 14 based on their room-temperature 1H and/or 31P NMR recorded in
CDCl3 and in DMSO-d6, see the Supporting Information.
(52) The reactions of all the nitroalkenes 1, 4, 6, 8, 11, and 13 with BOR 2
were carried out under identical conditions, at 1 mmol scale under N2 (for
reaction times, see Tables 1-6). All the pyrazole phosphonates are stable and
can be stored in the refrigerator for several months without any decomposi-
tion. The yields dropped gradually on scale up of the reaction between 1a and
BOR 2 as follows: 1 mmol, 77%; 3 mmol, 68% and 5 mmol, 61%.
Diethyl 4-(4-Chlorophenyl)-1H-pyrazol-3-ylphosphonate (9c):
colorless solid; yield 137 mg (38%); mp 216-218 °C; IR (KBr,
cm-1) 3440 (br, m), 3093 (br, w), 2983 (w), 2923 (m), 1679 (m),
1523 (m), 1413 (w), 1388 (w), 1247 (m), 1026 (s), 842 (m), 769
1
(m); H NMR (300 MHz, CDCl3) δ 1.20 (t, J = 7.1 Hz, 6H),
3.99-4.17 (m, 4H), 7.32 (ABq, J = 8.4 Hz, 4H), 14.05 (br s, 1H);
1H NMR (300 MHz, DMSO-d6) δ 1.09 (t, J = 6.9 Hz, 6H),
3.87-4.02 (m, 4H), 7.46 (ABqt, J = 7.7, 2.1 Hz, 4H), 15.01 (br s,
2204 J. Org. Chem. Vol. 75, No. 7, 2010

Muruganantham and Namboothiri
JOCArticle
1H); 13C NMR (100 MHz, CDCl3) δ 16.0 (d, JC-P = 6.8 Hz),
64.2 (d, JC-P = 5.3 Hz), 122.2 (d, JC-P = 17.6 Hz), 126.9, 128.5,
1438 (m), 1397 (m), 1264 (s), 1221 (s), 1026 (m); 1H NMR (400 MHz,
CDCl3) δ 1.14 (t, J = 7.0 Hz, 6H), 2.70 (t, J = 5.9 Hz, 2H), 2.98
131.5, 132.7 (d, JC-P = 217.3 Hz), 135.2, 154.0 (d, JC-P
=
(t, J = 5.9 Hz, 2H), 3.92-4.10 (m, 4H), 7.33-7.43 (m, 5H); 13
C
18.3 Hz); 31P NMR (121.4 MHz, CDCl3) δ 0.29; 31P NMR
(121.4 MHz, DMSO-d6) δ 3.02; MS (ESI) m/e (rel intensity) 360
(MHþ, 78), 332 (10); (ESþ) calcd for C13H16N3O5PCl (MHþ)
360.0516, found 360.0517.
NMR (75 MHz, CDCl3) δ 16.0 (d, JC-P = 6.7 Hz), 19.0, 33.7,
62.7 (d, JC-P = 5.3 Hz), 125.4 (d, JC-P = 22.1 Hz), 127.7, 128.3,
130.2, 131.4, 137.2 (d, JC-P = 220.0 Hz), 142.5 (d, JC-P =
11.2Hz), 176.4; 31P NMR (121.4 MHz, CDCl3) δ 8.09;MS(ESþ)
Diethyl 4-(benzo[d][1,3]dioxol-5-yl)-5-(hydroxymethyl)-1H-
pyrazol-3-ylphosphonate (12a): dark brown liquid; yield 216 mg
(61%); IR (KBr, cm-1) 3429 (br, w), 2983 (m), 2935 (w), 1614 (s),
1560 (m), 1513 (m), 1465 (m), 1443 (m), 1371 (m), 1249 (s), 1027
(s), 839 (s), 738 (s); 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J =
6.9 Hz, 6H), 3.91-4.11 (m, 4H), 4.64 (s, 2H), 5.99 (s, 2H),
m/e (rel intensity) 353 ([MH H2O]þ, 100), 335 (MHþ, 5), 279
3
(90), 253 (8); HRMS (ESþ) calcd for C16H20N2O4P (MHþ)
335.1161, found 335.1169.
Acknowledgment. I.N. thanks DST and DAE/BRNS,
India, for financial assistance. R.M. thanks IIT Bombay for
a senior research fellowship. We thank SAIF, IIT Bombay,
and TIFR, Mumbai, for selected NMR data and Prof. Y. U.
Sasidhar for helpful discussions. Dedicated to Prof. H. Ila on
the occasion of her 66th birthday.
1
6.83-6.96 (m, 3H); H NMR (300 MHz, DMSO-d6) δ 1.11 (t,
J = 7.0 Hz, 6H), 3.89-4.05 (m, 4H), 4.41 (s, 2H), 5.38 (br s, 1H),
6.03 (s, 2H), 6.90-7.10 (m, 3H), 13.61 (br s, 1H); 13C NMR
(CDCl3) δ 16.1 (d, JC-P = 6.1 Hz), 54.6, 62.9, 101.3, 108.2, 110.7,
123.8, 124.7 (d, JC-P = 21.3 Hz), 125.0, 136.4 (d, JC-P = 226.5
Hz), 144.9, 147.2, 147.5; 31P NMR (121.4 MHz, CDCl3) δ 8.80;
31P NMR (121.4 MHz, DMSO-d6) δ 11.47; MS (ESþ) m/e
(rel intensity) 355 (MHþ, 100), 337 (12); HRMS (ESþ) calcd
for C15H20N2O6P (MHþ) 355.1059, found 355.1044.
Supporting Information Available: Complete characteriza-
tion data, tables of energy calculations, copies of NMR spectra
for all new compounds, and 1H and 31P VT NMR spectra for a
representative compound 3a. This material is available free of
charge via the Internet at http://pubs.acs.org.
Diethyl 6-oxo-3-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-
2-ylphosphonate (14e): colorless solid; yield 183 mg (55%); mp
148 °C; IR (KBr, cm-1) 3056 (m), 2986 (m), 1717 (s), 1654 (w),
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