A novel route to fully substituted 1H-pyrazoles

Article abstract of DOI:10.1021/jo051319a

A novel one-step synthesis route to fully substituted pyrazol-4-ols is reported. This simple yet nonobvious method for the construction of pyrazol-4-ols by the condensation-fragmentation-cyclization-extrusion reactions of thietanones with 1,2,4,5-tetrazin

Full text of DOI:10.1021/jo051319a

A Novel Route to Fully Substituted 1H-Pyrazoles
Yat Fan Suen,† Håkon Hope,† Michael H. Nantz,† Makhluf J. Haddadin,‡ and
Mark J. Kurth*,†
Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616,
and Department of Chemistry, American University of Beirut, Beirut, Lebanon
mjkurth@ucdavis.edu
Received June 27, 2005
A novel one-step synthesis route to fully substituted pyrazol-4-ols is reported. This simple yet
nonobvious method for the construction of pyrazol-4-ols by the condensation-fragmentation-
cyclization-extrusion reactions of thietanones with 1,2,4,5-tetrazines is reported. All of the elements
of the thietanone except its sulfur are incorporated in these novel products.
Introduction
Synthetic heterocyclic compounds afford solutions to
a wide variety of important pharmaceutical1 and agro-
chemical2 problems. As a consequence, extensive research
efforts are continually directed at the discovery of novel,
small molecule heterocycles with appropriate biological
effects. Of special relevance to this work are three
substituted pyrazoles (Figure 1):3 HIV-1 reverse tran-
scriptase inhibitors (e.g., PNU-32945),4 sodium ion ex-
changer NHE-1 inhibitors (e.g., zoniporide),5 and cyclooxy-
genase-2 COX-2 inhibitors (e.g., celecoxib).6 In that
context, we report here an intriguing new route to 1H-
FIGURE 1. Pyrazoles with reverse transcriptase HIV-1,
NHE-1, and COX-2 inhibitor properties.
pyrazoles which derives from the base-mediated reaction
between thietanones and 1,2,4,5-tetrazines.
The reactions of electrophilic tetrazines are well docu-
mented.7 For example, in previous work we reported the
reactions of 3,6-diphenyl-1,2,4,5-tetrazine (1a) with eno-
late anions as an effective method for pyridazine syn-
thesis (3; eq 1).8 However, we found that when employing
the enolate of cyclobutanone, the reaction led not to a
pyridazine but to a [1,2]diazocin-4-one (5; eq 2).9
† University of California.
‡ American University of Beirut.
(1) See, for example: (a) Vullo, D.; Voipio, J.; Innocenti, A.; Rivera,
C.; Ranki, H.; Scozzafava, A.; Kaila, K.; Supuran, C. T. Bioorg. Med.
Chem. Lett., 2005, 15, 971-976. (b) Pillai, A. D.; Rani, S.; Rathod, P.
D.; Xavier, F. P.; Vasu, K. K.; Padh, H.; Sudarsanam, V. Bioorg. Med.
Chem. 2005, 13, 1275-1283. (c) Broughton, Howard B.; Watson, Ian
A. J. Mol. Graphics Modell. 2004, 23, 51-58.
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G. J. Spec. Chem. 1996, 16, 256-258. (c) Fischer, H.-P.; Buser, H.-P.;
Chemla, P.; Huxley, P.; Lutz, W.; Mirza, S.; Ramos Tombo, G. M.; Van
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2005, 3, 1844-1849.
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1034-1040.
(5) Guzman-Perez, A.; Wester, R. T.; Allen, M. C.; Brown, J. A.;
Buchholz, A. R.; Cook, E. R.; Day, W. W.; Hamanaka, E. S.; Kennedy,
S. P.; Kinght, D. R.; Kowalczyk, P. J.; Marala, R. B.; Mularski, C. J.;
Novomisle, W. A.; Ruggeri, R. B.; Tracey, W. R.; Hill, R. J. Bioorg.
Med. Chem. Lett. 2001, 11, 803-807.
(6) Penning, T. D. ; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G.
D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson,
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Results and Discussion
Based on these observations, we were intrigued by the
possibility of introducing an additional heteroatom using
10.1021/jo051319a CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/17/2005
8468
J. Org. Chem. 2005, 70, 8468-8471

A Novel Route to Fully Substituted 1H-Pyrazoles
SCHEME 1
a functionalized cyclobutanone as the starting substrate.
Since a reliable route to thietanone 6 was available,10 we
set out to explore its base-mediated reaction with 1,2,4,5-
tetrazines. As with observations from 1a + 4 f 5, the
reaction of thietanone 6 with tetrazine 1a in 5% metha-
nolic KOH resulted in the immediate evolution of nitro-
gen gas as well as the discharge of the tetrazine-derived
red color of the reaction mixture. However, to our
surprise, 2H-[1,4,5]thiadiazocin-7-one (7) was not isolated
from the reaction (eq 3). Rather, the major product from
TABLE 1. Synthesis of Fully Substituted 1H-Pyrazoles
this reaction displayed a downfield methyl group (∼3.5
ppm), suggesting the incorporation of a methoxy from
1
methanolic solvent. H NMR also revealed three indi-
vidual protons at 5.1, 5.2, and 5.6 ppm, and the APT
spectrum established that the two protons at 5.2 and 5.6
ppm were attached to the same carbon with a coupling
constant of 0.8 Hz. The 13C NMR showed only one CdN
and clearly ruled out the possibility of a CdO moiety. IR
also confirmed the absence of a carbonyl functional group,
but it did display a broad signal consistent with an OH
moiety. Low-resolution MS established a mass of 382 m/z
(interestingly, a molecular weight consistent with 2H-
[1,4,5]thiadiazocin-7-one (7)).
1,2,4,5-tetrazine
solvent
1H-pyrazole
1a
1a
1b
1b
1c
1c
MeOH
10 (R ) Me, 56%)
11 (R ) Et, 45%)
12 (R ) Me, 48%)
EtOH
MeOH
HOCH2CH2OH 13 (R ) CH2CH2OH, 35%)
MeOH
14 (R ) Me, 15%)
HOCH2CH2OH 15 (R ) CH2CH2OH, 9%)
as the 13C NMR requirement that there be only one C,N-
double bond.
In light of these data, it was our conjecture that the
sulfur atom in thietanone 6 was eliminated during the
reaction. However, because of the addition of methanol,
the product had the same mass as the anticipated
thiadiazocinone (7). Sulfur extrusion in analogous het-
erocycle chemistry has been observed previously. For
example, the [4 + 2] reactions of tetrazines with R2CdS
heterodienophiles delivers 6H-[1,3,4]thiadiazines which
can extrude sulfur (Scheme 1).11
On the basis of this information, we hypothesized that
the product of this thietanone reaction may be a 4H-[1,2]-
diazepine formed by a ring contraction-based sulfur
extrusion with subsequent Michael addition of methanol
and enolization to form (9a) (R ) Me; eq 4). Indeed,
reacting 1a + 6 in ethanolic KOH delivered the analogous
ethoxy-containing heterocycle, consistent with our hy-
pothesis (9b, R ) Et; eq 4). However, this diazepine
structure is inconsistent with both the observed 1H NMR
coupling constant for the geminal protons (0.8 Hz) as well
The lack of proton coupling information required us
to pursue an X-ray crystallography structure determi-
nation. As outlined in Table 1, the reactions of 6 with
aryl-substituted tetrazines 1a-c in methanol, ethanol,
or ethylene glycol delivered the sulfur-extruded product.
The yields were lower with pyridyl-substituted tetrazine
1c (<20%) both because this highly electrophilic tetrazine
decomposes in alcoholic KOH and the electron-withdraw-
ing 2-pyridyl group hampers the nucleophilicity of the
enamine nitrogen to effect ring cyclization to a pyrazole
moiety (see Scheme 2). While a number of these conden-
sation products were solids, we were consistently unable
to obtain crystals suitable for X-ray crystallography.
Eventually, repeated recrystallization attempts with a
variety of solvents on the product of 1c + 6 in ethylene
glycol produced a collection of feather-like crystals. Under
crossed polarizers, one of these appeared to be predomi-
(7) (a) Churakov, A. M.; Tartakovsky, V. A. Chem. Rev. 2004, 104,
2601-2616. (b) Hurst, D T. Prog. Heterocycl. Chem. 1998, 10, 275-
291. (c) Sauer, J. Comp. Heterocycl. Chem. II 1996, 6, 901-955, 1177-
1307. (d) Boger, D. L. Chem. Rev. 1986, 86, 781-793.
(8) Haddadin; M. J.; Firsan, S.; Nader, B. J. Org. Chem. 1979, 44,
629-630.
(9) Haddadin; M. J.; Agha, B.; Salka, M. S. Tetrahedron Lett. 1984,
25, 2577-2580.
(10) Krubsack, A. J.; Higa, T.; Slack, W. E. J. Am. Chem. Soc. 1970.
92, 5258-5259.
(11) (a) Seitz, G.; Kampchem, T. Arch. Pharm. (Weinheim) 1977,
310, 269-271. (b) Hanefeld, W.; Kluck, D. Arch. Pharm. (Weinheim)
1982, 315, 57-68. (c) Seitz, G.; Mohr, R.; Overheu, W.; Allmann, R.;
Nagel, M. Angew. Chem., Int. Ed. Engl. 1984, 23, 890-891. (d)
Schmidt, R. R.; Huth, H. Tetrahedron Lett. 1975, 16, 33-36.
J. Org. Chem, Vol. 70, No. 21, 2005 8469

Suen et al.
disorder.12 Thus, while it was difficult to arrive at a
unique interpretation of the NMR spectrum, our X-ray
determination afforded a rational answer to this struc-
tural problem despite the unusual appearance of the
crystal.
The structure solution shows the remarkable outcome
that these condensation reactions deliver fully substi-
tuted pyrazol-4-ols. This unprecedented pyrazole syn-
thesis poses interesting mechanistic questionssone which
we surmise proceeds through the process depicted in
Scheme 2. Briefly, we speculate that a Michael addition
to 7 initiates a cascade event leading to a ring-opened
thioketo/enamine structure. The nitrogen of this enamine
attacks the thioketo group which, perhaps via a three-
membered thiirane ring intermediate, ultimately ex-
trudes sulfur and delivers the pyrazol-4-ol product. In
any case, the spectroscopic data for products 10-15 are
consistent with the pyrazol-4-ol structural assignment
(see Figure 3) as conclusively determined by X-ray
crystallography.
FIGURE 2. Crystal of 15, viewed under crossed polarizers
with a λ plate. The left panel shows the crystal in a general
orientation. The right panel shows the crystal aligned to the
polarization plane, suggesting that the sample is essentially
one single crystal.
In conclusion, we have discovered a simple yet nonob-
vious method for the construction of pyrazol-4-ols by a
consecutive series of condensation-fragmentation-cy-
clization-extrusion reactions of thietanones with 1,2,4,5-
tetrazines. While all of the elements of the thietanone
except its sulfur are incorporated in these novel products,
the structure of the thietanone is wildly disassembled.
Experimental Section
Preparation of Thietanone 6.10 Thionyl chloride (20 g,
168 mmol) was added to a flask charged with benzyl acetone
(5 g, 33.8 mmol) and 0.2 mL of pyridine at 0 °C, and the
resulting mixture was stirred for 14 h at which time the
mixture was concentrated in vacuo. Ice-water was added to
quench the residual SOCl2, and the mixture was extracted with
DCM three times. The combined organic layer was washed
with water twice and then with brine. Flash chromatography
(SiO2, 5% EtOAc in hexanes f 15% EtOAc in hexanes) gave
6 (3.60 g, 61%) as a pale yellow solid: 1H NMR δ 7.40 (5H,
m), 7.26 (1H, s), 4.44 (2H, s); 13C NMR 188.5, 146.4, 134.2,
129.8, 129.7, 129.3, 122.5, 55.4. These NMR data matched with
the reported data.
FIGURE 3. X-ray crystal structure of 15. The fully outlined
part represents the main component, with 91% occupancy. The
two components are enantiomers. Displacement ellipsoids are
drawn at the 50% level (T ) 17 K).
SCHEME 2
General Procedure for Preparing Tetrazines.13 To a
solution of 4-bromobenzonitrile (1.5 g, 8.2 mmol) in 10 mL of
absolute ethanol containing S8 (0.18 g, 5.7 mmol) was added
hydrazine (0.52 g, 16.4 mmol). The mixture was refluxed for
3 h. The deep orange dihydro-3,6-bis(4-bromophenyl)[1,2,4,5]-
tetrazine was isolated by filtration and washed carefully with
cold ethanol. Acetic acid (10 mL) and 3 equiv of NaNO2 (1.76
g) were added to the resulting dihydrotetrazine mixture and
the mixture stirred for 20 min at which time the orange color
turned purple. The solid was washed with a copious amount
of water and then methanol. Upon drying, product 1b (0.88 g,
54%) was used in further reactions without additional puri-
fication. All spectral data matched the reported values.13 For
the 3,6-di-2-pyridyl[1,2,4,5]tetrazine (1c), a similar procedure
was followed (90% yield).
nantly a single crystal (Figure 2). At the time, the
diffractometer was set up for near-liquid He temperature
cooling (17 K). Reflections from the unusual-looking
crystal were readily indexed, and a data set was obtained.
The data yielded the structure shown in Figure 3. While
the sample as a whole is a racemic mixture, two enan-
tiomeric molecules are present in a 10:1 ratio in the
analyzed crystal. We believe that the very low temper-
ature contributed to a relatively simple resolution of the
General Procedure for Preparing Pyrazol-4-ol. To a
mixture of thietanone 6 (32 mg, 0.18 mmol) and tetrazine 1b
(140 mg, 0.36 mmol) in 6 mL of THF was added 2 mL of 5%
(12) Crystallographic data: colorless, monoclinic, space group P21/
c; a ) 8.5483(11) Å, b ) 11.9018(15) Å, c ) 20.470(3) Å, â ) 100.168-
(2)°, V ) 2050.0(5) Å3, T ) 17(2) K, Z ) 4; 6941 reflections, 5435 >
2σ(I), R ) 0.094; whole molecule disorder, 10:1. Data collection: Bruker
SMART APEX II. Structure solution and refinement: SHELXS97 and
SHELXL97, Sheldrick, G. M. University of Go¨ttingen, Germany, 1997.
8470 J. Org. Chem., Vol. 70, No. 21, 2005

A Novel Route to Fully Substituted 1H-Pyrazoles
KOH/MeOH. The mixture was stirred for 10 min until TLC
showed that all of the thietanone had disappeared. Another
three portions of thietanone (3 × 0.18 mmol) were added over
a 5 min interval. (In the case of tetrazine 1a, the reaction rate
was much faster.) The mixture was then diluted with water,
made slightly acidic with 3 M HCl (in the case of 1c, the
workup was done under basic conditions), and extracted with
DCM (3×). The combined organic layer was washed with brine,
dried over Na2SO4, and evaporated to dryness. Flash chroma-
tography (SiO2, 15-20% EtOAc/hexanes) delivered 12 as a
brown oil (93.5 mg, 48.5%).
Compound 13 (35%): 1H NMR δ 7.96 (2H, d, J ) 8.4 Hz),
7.51 (2H, d, J ) 8.4 Hz), 7.35 (2H, d, J ) 8.0 Hz), 7.28 (3H,
m), 7.18 (2H, m), 6.92 (2H, d, J ) 8.0 Hz), 5.51 (1H, d, J ) 0.8
Hz), 5.23 (1H, s), 5.18 (1H, d, J ) 0.8 Hz), 3.78 (2H, m), 3.60
(1H, m), 3.50 (2H, m); 13C NMR 144.5, 138.9, 138.8, 138.2,
135.0, 131.9, 131.7, 131.4, 129.2, 129.1, 128.2, 128.1, 128.1,
127.0, 123.8, 121.7, 113.3, 79.4, 70.3, 61.8; IR (neat) 3379, 2986,
2933, 2881, 2834, 1630, 1589, 1555, 1486, 1443, 1404, 1355,
1301, 1241, 1090, 1071, 1008, 912, 834, 735, 708 cm-1; HPLC
purity ) 93.6%; LRMS (ESI) calcd for C26H23Br2N2O3 (M +
H)+ 569.01, found 569.00.
Compound 14 (15%): 1H NMR δ 8.60 (1H, d, J ) 4.8 Hz),
8.50 (1H, d, J ) 5.2 Hz), 7.96 (1H, d, J ) 8.0 Hz), 7.74 (1H, td,
J ) 7.6, 1.6 Hz), 7.44 (1H, td, J ) 7.6, 2.0 Hz), 7.35 (2H, m),
7.18 (5H, m), 6.61 (1H, d, J ) 8.0), 6.58 (1H, s), 5.60 (1H, s),
5.37 (1H, s), 3.31 (3H, s); 13C NMR 154.1, 153.4, 149.5, 147.5,
144.6, 142.6, 139.3, 137.5, 136.8, 135.8, 128.3, 127.8, 127.7,
127.2, 123.6, 122.3, 121.0, 119.1, 118.0, 76.7, 57.2; IR (neat)
3061, 2995, 2971, 2933, 2895, 1598, 1582, 1566, 1517, 1489,
1449, 1423, 1370, 1312, 1272, 1218, 1147, 1115, 1089, 962, 914,
791, 735, 701 cm-1; HPLC purity ) 100%; LRMS (ESI) calcd
for C23H21N4O2 - HOCH3 (M + H - HOCH3)+ 353.14, found
353.17.
Spectral Data. Compound 10 (55.5%): 1H NMR δ 8.01 (2H,
d, J ) 8.0 Hz), 7.34 (2H, t, J ) 7.6 Hz), 7.21(7H, m), 7.11 (2H,
m), 7.05 (2H, m), 6.49 (1H, s), 5.47 (1H, d, J ) 0.8 Hz), 5.12
(1H, d, J ) 0.8 Hz), 5.02 (1H, s), 3.22 (3H, s); 13C NMR 145.5,
139.1, 139.0, 138.3, 136.2, 132.6, 129.5, 129.1, 128.9, 128.7,
128.6, 128.2, 127.6, 126.7, 126.6, 126.4, 112.6, 81.1, 57.3; IR
(neat) 3407, 3061, 3028, 2933, 2890, 2828, 1629, 1605, 1585,
1492, 1448, 1364, 1310, 1238, 1074, 1026, 952, 911, 777, 697
cm-1; HPLC purity ) 96.3%; LRMS (ESI) calcd for C25H23N2O2
(M + H)+ 383.18, found 383.24.
1
Compound 11 (45%): H NMR δ 8.02 (2H, d, J ) 8.4 Hz),
7.34 (2H, t, J ) 7.6 Hz), 7.21 (7H, m), 7.10 (2H, m), 7.05 (2H,
m), 6.70 (1H, s), 5.46 (1H, s), 5.12 (1H, s), 5.12 (1H, d, J ) 0.8
Hz), 3.36 (2H, m) 1.13 (3H, t, J ) 7.2 Hz); 13C NMR 145.5,
139.1, 139.0, 138.8, 136.2, 132.6, 129.4, 128.9, 128.9, 128.7,
128.6, 128.2, 127.6, 126.7, 126.58, 126.5, 112.6, 79.3, 65.3, 15.3;
IR (neat) 3417, 3052, 3038, 2976, 2924, 2871, 1633, 1604, 1586,
Compound 15 (9%): 1H NMR δ 8.54 (1H, d, J ) 5.2), 8.43
(1H, d, J ) 5.2), 7.89 (1H, d, J ) 8.4), 7.70 (1H, td, J ) 8.0,
1.6 Hz), 7.39 (1H, td, J ) 8.0, 2.0), 7.27 (2H, m), 7.15 (5H, m),
6.61 (1H, d, J ) 8.0), 6.44 (1H, s), 5.50 (1H, s), 5.41 (1H, s),
3.67 (1H, m), 3.52 (3H, m); 13C NMR 153.9, 153.5, 149.6, 147.5,
144.8, 142.1, 139.3, 137.6, 136.9, 135.9, 128.5, 128.1, 127.7,
127.3, 123.7, 122.4, 121.0, 119.1, 118.0, 76.0, 70.9, 62.1; IR
(neat) 3360, 3047, 2924, 1601, 1584, 1569, 1448, 1428, 1375,
1320, 1272, 1247, 1124, 1099, 1063, 792, 751, 701 cm-1; HPLC
purity ) 97.8%; LRMS (ESI) calcd for C24H23N4O3 - HOCH2-
CH2OH (M + H - HOCH2CH2OH)+ 353.14, found 353.11.
1493, 1446, 1361, 1239, 1067, 1020, 1002, 903, 773, 691 cm-1
;
HPLC purity ) 100%; LRMS (ESI) calcd for C26H25N2O2 (M +
H)+ 397.19, found 397.12.
1
Compound 12 (48%): H NMR δ 7.94 (2H, d, J ) 8.8 Hz),
7.52 (2H, J ) 8.8 Hz), 7.34 (2H, J ) 8.8 Hz), 7.26 (3H, m),
7.14 (2H, m), 6.90 (2H, J ) 8.8 Hz), 6.70 (1H, s), 5.55 (1H, d,
J ) 0.8 Hz), 5.20 (1H, d, J ) 0.8 Hz), 5.12 (1H, s), 3.30 (3H,
s); 13C NMR 144.5, 139.0, 138.3, 137.9, 134.9, 131.8, 131.7,
131.4, 129.2, 129.0, 128.3, 128.1, 128.1, 126.6, 123.7, 121.6,
113.2, 81.2, 57.2; IR (neat) 3360, 2971, 2947, 2834, 1630, 1584,
Acknowledgment. We thank the National Science
Foundation (CHE-0313888) for support of this work.
The 400- and 300-MHz NMR spectrometers used in this
study were funded in part by a grant from the NSF
(CHE-9808183).
Supporting Information Available: 1H NMR, 13C NMR,
and HPLC data for compounds 10-15 as well as X-ray
crystallographic data for 15. This material is available free of
charge via the Internet at http://pubs.acs.org.
1485, 1440, 1400, 1356, 1236, 1072, 1007, 834, 692, 622 cm-1
;
HPLC purity ) 100%; LRMS (ESI) calcd for C25H21Br2N2O2
(M + H)+ 539.00, found 538.90.
(13) (a) Hu, W. X.; Rao, G. W.; Sun, Y. Q. Bioorg. Med. Chem. Lett.
2004. 14. 1177-1181. (b) Cohen, V. I. J. Heteroccycl. Chem. 1978, 15,
1113-1116. (c) Soloducho, J.; Doskocz, J.; Cabaj, J.; Roszak, S.
Tetrahedron 2003, 59, 4761-4766.
JO051319A
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