An expedient synthesis of regioisomeric pyrazole-fused cycloalkanones

Article abstract of DOI:10.1055/s-2008-1032086

Described herein is a novel one-pot procedure for the synthesis of pyrazoles through the in situ generation of a monohydrazone of cyclic 1,3-diones and subsequent cyclization with N,N-dimethylformamide dimethyl acetal. This route provides pyrazoles that have limited accessibility by other methods. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032086

600
LETTER
An Expedient Synthesis of Regioisomeric Pyrazole-Fused Cycloalkanones
S
ynthesis of Re
a
w
Pyrazole-FusedC
r
ycloalka
e
nones nce J. Kennedy*
Metabolic Diseases Chemistry, Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ, 08543-5400, USA
Fax +1(609)8183460; E-mail: lawrence.kennedy@bms.com
Received 16 October 2007
clization to 3.1a However, it seems equally plausible that
Abstract: Described herein is a novel one-pot procedure for the
pyrazole 3 could arise from attack of the secondary amino
group at the exocyclic carbon, followed by cyclization to
3.
synthesis of pyrazoles through the in situ generation of a monohy-
drazone of cyclic 1,3-diones and subsequent cyclization with N,N-
dimethylformamide dimethyl acetal. This route provides pyrazoles
that have limited accessibility by other methods.
Based on literature reports, treatment of an acyclic, sym-
metrical enaminedione 1 with methylhydrazine affords a
mixture of regioisomeric pyrazoles 2/3 (Scheme 1, X,
Y = alkyl, aryl, R1 = H).1a,2b However, the analogous reac-
tion with phenylhydrazine is generally regiospecific,
forming only pyrazole 2.1a,5 Five-membered cyclic enam-
inediones and hydrazines are often quite reluctant to pro-
vide pyrazoles.1a,2a In six-membered cyclic systems
(Scheme 1, X–Y = alkyl, substituted alkyl, R1 = H) regio-
isomer 2 again predominates, and 3 is rarely observed re-
gardless of the substitution of the hydrazine (2/3 = 19:1 to
>99:1).1a,2a Only one example has been previously report-
ed in the literature for seven-membered cyclic systems.2a
Key words: pyrazole, hydrazine, hydrazone, fused-ring system, di-
one
Though rarely found in nature, pyrazoles receive consid-
erable attention from the synthetic and medicinal chemis-
try communities. The employment of enaminediones 1 for
generating polysubstituted pyrazoles 2 and 3 is well estab-
lished (Scheme 1).1–5 Use of this synthon has flourished
since its introduction.1a The ability of enaminediones and
1,2- and 1,3-dinucleophiles to form diverse heterocycles
continues to attract attention and innovation.2a The prepa-
ration of pharmaceutically relevant pyrazoles from enam-
inediones has been the focus of recent medicinal
chemistry efforts.4
Heterocycle-fused cycloalkanones were required as part
of a structure–activity relationship survey in a medicinal
chemistry program.6 Cycloheptapyrazolones, such as 2a–
d and 3a–d (vide infra), were identified as desirable inter-
mediates. The use of enaminediones was selected as a ver-
satile means of accessing the preferred pyrazoles. The
prerequisite enaminedione 1a was prepared from 1,3-cy-
cloheptane dione and N,N-dimethylformamide dimethyl
acetal (DMFDMA).1a Treatment of 1a at 0 °C with meth-
ylhydrazine in methanol afforded pyrazoles 2a/3a in good
yield as a 5:1 mixture of regioisomers (Table 1, entry 1).7–
Enaminediones 1 are typically more reactive than enami-
nones. This heightened reactivity has been attributed to
resonance stabilization from delocalization of the nega-
tive charge across two carbonyls, as depicted by the me-
someric structure 4 (Scheme 2).1a,3 This configuration is
thought to favor attack of the primary amino group of a
substituted hydrazine at the exocyclic carbon, leading to
pyrazole 2 (Scheme 1).1a,2a This reaction proceeds via ini-
tial addition–elimination amine-exchange of the dimeth-
ylamino group by the hydrazine to afford the
hydrazinomethylene adduct 5, which then undergoes con-
11
In an attempt to improve the regioselectivity the reac-
tion was repeated at –78 °C, which unexpectedly reversed
the regioselectivity, now favoring formation of pyrazole
3a (2a/3a = 1:3). The reaction of 1a and methylhydrazine
in refluxing methanol provided pyrazoles 2a/3a with im-
proved regioselectivity (2a/3a = 10:1), though in reduced
yield. Other substituted hydrazines varied from this result
(Table 1).10
comitant cyclodehydration to afford pyrazole
2
(Scheme 2). Alternately, it has been suggested that regio-
isomer 3 originates from attack of the primary amino
group of the hydrazine first with a carbonyl, forming an
intermediate hydrazone 6 (Scheme 2), followed by cy-
R1
R1
R1
O
O
O
RNHNH2
N
R
N
X
N
X
+
X
N
N
O
Y
Y
Y
R
1
2
3
Scheme 1
SYNLETT 2008, No. 4, pp 0600–0604
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032086; Art ID: S08407ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Regioisomeric Pyrazole-Fused Cycloalkanones
601
that enaminedione 1a reacts via the mesomeric structure
4, one would anticipate the regioselectivity to favor pyra-
zole 2d (vide supra). This is in agreement with experimen-
tal observations. For alkyl hydrazines one might expect
pyrazole 3 to predominate, given that the secondary ami-
no group is the more nucleophilic nitrogen.13 However,
pyrazole 2 is the major product observed experimentally.
This observation would suggest that steric effects override
any nucleophilic advantage the secondary amino group
might possess at temperatures ≥ 0 °C. The reversal in re-
gioselectivity witnessed at –78 °C with methylhydrazine
suggests that conditions were favorable for attack by the
secondary amino group, or a change in reactivity of 1a has
occurred. For the latter, enaminedione 1a would react
more like 1 than 4, leading to hydrazone 6, then ultimately
to pyrazole 3a (Scheme 2).
O
Y
O
Y
N
N
O
X
X
NH
X
N
NHR
NHR
O
Y
O
5
6
4
O
O
X
X
N
R
N
N
N
Y
Y
R
2
3
Scheme 2
Table 1 Cycloheptapyrazolones7,10
In general the hydrazinomethylene intermediate 5 was not
observed during the course of the reactions, except in the
case of R = benzyl where 5 was observed by LCMS
(Scheme 2). The presumed conversion of 5 (R = Bn) to 2c
was monitored over the course of several hours at reduced
temperatures. The mass corresponding to adduct 6 was
not observed for any hydrazine at any temperature.
O
O
O
N
RNHNH2
MeOH
4
R
4
N
1 N
N
1
+
N
O
8
8
R
2a–d
3a–d
1a
Since neither 2a nor 3a were obtained in adequate regioi-
someric excess, it was necessary to develop a scalable
separation method. Cycloheptapyrazolone 2a was crystal-
lized from an enriched mixture of 2a/3a to high regioiso-
meric excess (>99:1). Similarly, 2a was precipitated from
an enriched mixture of 2a/3a and the filtrate concentrated
to afford 3a in high regioisomeric excess (19:1).
Entry
R
Ratio of 2/3 (yield, %)
–78 °C
0 °C
65 °C
1
2
3
4
Me (a)
Et (b)
Bn (c)
Ph (d)
1:3
5:1
10:1
(56)
(91)
(86)
11:1
(83)
>19:1
(79)
>19:1
(60)
In view of the fact that pyrazole 3 was poorly accessible
via enaminedione 1a, it was necessary to develop an alter-
nate route. It was envisioned that pyrazole 3 might be
available by essentially reversing the employment of the
same reagents used to synthesize pyrazole 2. In that, form-
ing a monohydrazone from a substituted hydrazine and a
1,3-dione followed by cyclization with DMFDMA to af-
ford pyrazole 3. This hypothesis was tested by first gener-
ating hydrazone 7 from 1,3-cyclohexanedione and
phenylhydrazine.14 Cyclization to pyrazole 3h with ex-
cess DMFDMA in refluxing THF proceeded in good yield
(Scheme 3).
>19:1
(85)
>19:1
(76)
>19:1
(61)
>19:1
(85)
>19:1
(81)
>19:1
(68)
Treatment of enaminedione 1a with ethylhydrazine gave
markedly different results from methylhydrazine at all
three temperatures investigated (Table 1, entry 2). How-
ever, the regioselectivity at –78 °C was diminished
(2b/3b = 11:1), suggesting at least a slight shift towards
3b. Both benzyl and phenylhydrazine afforded 2c,d in
high regioselectivity irrespective of the temperature
(Table 1, entries 3 and 4). The regioisomeric pyrazoles
3c,d were not observed in either crude reaction mixtures
or purified products.
In an attempt to further improve the utility of this synthet-
ic sequence the reaction was performed in a one-pot man-
ner. To this end, 1,3-cyclohexanedione was treated with
one equivalent of phenylhydrazine for two hours, then ex-
cess DMFDMA was added and the reaction was refluxed
overnight (Table 2). Pyrazole 3h was isolated in 50%
yield, which is comparable to the overall yield for the two-
The primary amino group of phenylhydrazine is more nu-
cleophilic than the secondary amino group due to the elec-
tron-withdrawing nature of the phenyl ring.12 Assuming
O
O
O
DMFDMA
THF, reflux
PhNHNH2
H2O
4
N
Ph
H
1
83%
68%
N
N
O
N
Ph
3h
7
Scheme 3
Synlett 2008, No. 4, 600–604 © Thieme Stuttgart · New York

602
L. J. Kennedy
LETTER
Table 2 Synthesis of pyrazoles 3a–h15–18
1) RNHNH2, THF, r.t.
O
O
or
RNHNH2(2HX), Et3N, MeOH–THF, r.t.
4
N
R
1
N
2) DMFDMA, reflux
n
n
O
n = 2, 3a–d
n = 1, 3e–h
2–
X = 2Cl– or C2O4
Entry
R
n
2
2
2
2
1
1
1
1
Pyrazole
3a
Yield (%)
1
2
3
4
5
6
7
8
Me
Et
61
52
47
48
66
64
59
50
3b
Bn
Ph
Me
Et
3c
3d
3e
3f
Bn
Ph
3g
3h
step sequence (56%, Scheme 3). The generality of this manuscript, with the exception of 2d and 3h, are previous-
one-pot reaction was explored using the three other previ- ly unreported in the literature.9b,20,21
ously employed hydrazines and also examining two dif-
ferent ring sizes (Table 2).15–17
Acknowledgment
The hydrazines and diones investigated provided modest
to good yields for the one-pot procedure. In general, the
yields for cyclohexanedione (Table 2, entries 5–8) were
I would like to thank Mr. Richard Sulsky and Drs. Bruce Ellsworth
and Jun Li for many helpful discussions. I would also like to thank
Mr. Lawrence Dombrowsky for the accurate mass measurements,
slightly higher than for cycloheptanedione (Table 2, en-
tries 1–4). Methylhydrazine gave the highest yields for
both diones. Ethylhydrazine was comparable in yield to
methylhydrazine for cyclohexanedione, but was consider-
ably lower for cycloheptanedione. The two-step reaction
sequence seems to be unaffected by the presence of
MeOH, (Et3NH)+X–, and dimethylamine in this one-pot
procedure.
and Ms. Sarah Traeger for initial 2D NMR experiments.
References and Notes
(1) (a) Schenone, P.; Mosti, L.; Menozzi, G. J. Heterocycl.
Chem. 1982, 19, 1355. (b) Lemke, T. L.; Sawhney, K. N.
J. Heterocycl. Chem. 1982, 19, 1335. (c) Dawood, K. M.;
Faraq, A. M.; Kandeel, Z. E. J. Chem. Res., Synop. 1999, 88.
(2) (a) Molteni, V.; Hamilton, M. M.; Long, M.; Crane, C. M.;
Termin, A. P.; Wilson, D. A. Synthesis 2002, 1669; also
includes a one-pot procedure under microwave irradiation.
(b) Touzot, A.; Soufyane, M.; Berber, H.; Toupet, L.;
Mirand, C. J. Fluorine Chem. 2004, 125, 1299.
(3) For related examples of pyrazoles from enaminones, see:
(a) Olivera, R.; SanMartin, R.; Dominguez, E. J. Org. Chem.
2000, 65, 7010. (b) Ulrich, T.; Dersch, C. M.; Rothman, R.
B.; Jacobson, A. E.; Rice, K. C. Bioorg. Med. Chem. Lett.
2001, 11, 2883. (c) Olivera, R.; SanMartin, R.; Dominguez,
E. Tetrahedron Lett. 2000, 41, 4353.
(4) For recent examples of enaminediones in the synthesis of
pyrazoles of pharmaceutical relevance, see: (a) D’Alessio,
R.; Bargiotti, A.; Metz, S.; Brasca, G.; Cameron, A.; Ermoli,
A.; Marsiglio, A.; Polucci, P.; Roletto, F.; Tibolla, M.;
Vazquez, M. L.; Vulpetti, A.; Pevarello, P. Bioorg. Med.
Chem. Lett. 2005, 15, 1315. (b) Menozzi, G.; Merello, L.;
Fossa, P.; Schenone, S.; Ranise, A.; Mosti, L.; Bondavalli,
F.; Loddo, R.; Murgioni, C.; Mascia, V.; La Colla, P.;
Tamburini, E. Bioorg. Med. Chem. 2004, 12, 5465.
The opposite regioisomers were not observed, with the
exception of entry 3.16 Benzylhydrazine and cyclohep-
tanedione afforded traces of the regioisomeric pyrazole 2c
(25:1 by 1H NMR). Pyrazole 2c may have arisen through
incomplete hydrazone formation, resulting in some re-
maining benzylhydrazine and cycloheptanedione at the
time of DMFDMA addition. Subsequently, DMFDMA
can react with cycloheptanedione to form 1a, which in
turn can react with benzylhydrazine to form 2c
(Scheme 3).
In conclusion, a temperature-dependent regioselectivity
was observed in the addition of methylhydrazine to enam-
inedione 1a to form pyrazoles 2a/3a. It was shown that all
other hydrazines examined provided predominantly pyra-
zole 2, regardless of temperature. These results prompted
the development of a novel one-pot procedure for the syn-
thesis of pyrazoles 3a–h through the in situ generation of
the monohydrazone of 1,3-diones and subsequent cycliza-
tion with DMFDMA.19 All pyrazoles described in this
(5) There are few reports of regioisomers obtained from
phenylhydrazine. These examples can most likely be
Synlett 2008, No. 4, 600–604 © Thieme Stuttgart · New York

LETTER
Synthesis of Regioisomeric Pyrazole-Fused Cycloalkanones
603
attributed to the electrophilicity of the ketone carbonyls
(10) (a) All reactions were performed on a 0.5 mmol scale (0.10
M) using 1.1 equiv hydrazine. Reaction conditions are not
optimized. (b) Ratio of 2/3 from HPLC analysis of crude
reaction mixture. (c) Ethylhydrazine oxalate and
(Scheme 1, X = CF3, Y = CF3 or aryl), see: (a) Soufyane,
M.; Mirand, C.; Levy, J. Tetrahedron Lett. 1993, 34, 7337.
(b) Okada, E.; Masuda, R. Heterocycles 1992, 34, 791.
(c) Also see ref. 2b.
benzylhydrazine·2HCl were pretreated with Et3N (2.2
equiv). (d) A solution of the hydrazine was added to a
refluxing solution of 1a for reactions run at elevated
temperature.
(6) Shi, Y.; Robl, J. A.; Kennedy, L. J.; Malley, M. F.
Tetrahedron Lett. 2007, 48, 555.
(7) Representative Experimental Procedure for Pyrazoles
2a–d
(11) The identical reaction at 0 °C with methylhydrazine sulfate
and Et3N (2.2 equiv) also favored 2a (2a/3a = 5:1).
(12) Kenny, P. W.; Robinson, M. J. T. Tetrahedron 1987, 43,
4043; and pertinent references cited therein.
(13) The secondary amino group of methylhydrazine was
determined experimentally to be the more nucleophilic site,
see: Gregory, M. J.; Bruice, T. C. J. Am. Chem. Soc. 1967,
89, 4400; and pertinent references cited therein.
(14) Martin, M. J.; Trudell, M. L.; Arauzo, H. D.; Allen, M. S.;
LaLoggia, A. J.; Deng, L.; Schultz, C. A.; Tan, Y.-C.; Bi, Y.;
Narayanan, K.; Dorn, L. J.; Koehler, K. F.; Skolnick, P.;
Cook, J. M. J. Med. Chem. 1992, 35, 4105.
(15) Representative Experimental Procedure for Pyrazoles
3a–h
A solution of 1,3-cycloheptanedione (15.1 g, 120 mmol) in
DMFDMA (48 mL, 360 mmol) was heated to reflux for 3 h.
The reaction mixture was concentrated at reduced pressure,
then dried under high vacuum (3 d, <1 mmHg) until 1a
formed as an amber solid (20.6 g, 95%). 1H NMR (400 MHz,
CDCl3): d = 7.73 (s, 1 H), 3.31 (s, 3 H), 2.81 (s, 3 H), 2.62–
2.58 (m, 4 H), 1.88–1.85 (m, 4 H). 13C NMR (100 MHz,
CDCl3): d = 200.57, 159.94, 113.20, 48,39, 43.61, 40.85,
22.58. HRMS: m/z calcd for C10H16NO2 [M + H]+: 182.1181;
found: 182.1178.
To a solution of 1a (507 mg, 2.8 mmol) in MeOH (22 mL)
cooled to 0 °C was added a solution of methylhydrazine (164
mL, 3.08 mmol) in MeOH (6 mL) over 5 min. After 1 h the
reaction mixture was concentrated in vacuo (2a/3a = 6:1).
Purification by flash chromatography (SiO2, eluting with
10–20% acetone–CH2Cl2) afforded 2a as a pale-yellow solid
(0.355 g, 77%) which was dissolved in warm EtOAc (3 mL),
then hexanes (9 mL) was added, and the resulting solution
was placed in a –20 °C freezer. The resulting solid was
filtered, then dried in vacuo to afford 2a as small pale-yellow
needles (0.278 g); 2a/3a >99:1 by HPLC analysis. 1H NMR
(400 MHz, CDCl3): d = 7.91 (s, 1 H), 3.79 (s, 3 H), 2.91 (t,
J = 6.3 Hz, 2 H), 2.71 (t, J = 6.1 Hz, 2 H), 2.07–2.02 (m, 2
H), 1.95–1.90 (m, 2 H). 13C NMR (100 MHz, CDCl3): d =
196.58, 145.01, 141.05, 122.69, 44.55, 37.08, 27.41, 25.72,
22.95. HRMS: m/z calcd for C9H13N2O [M + H]+: 165.1028;
found: 165.1029.
(a) Pyrazole 3h: To a solution of 1,3-cyclohexanedione (112
mg, 1.0 mmol) in THF (4 mL) under argon was added a
solution of phenylhydrazine (99 mL, 1.0 mmol) in THF (1
mL) quickly. After 2 h, DMFDMA (402 mL, 3.00 mmol) was
added quickly and the resulting solution heated to reflux.
After 16 h the reaction mixture was concentrated in vacuo
and purified via flash chromatography (12 g SiO2, 0–60%
EtOAc–hexanes) to afford 3h as an off-white solid (106 mg,
50%). 1H NMR (400 MHz, CDCl3): d = 8.35 (s, 1 H), 7.69
(d, J = 7.7 Hz, 2 H), 7.48 (t, J = 8.0 Hz, 2 H), 7.36 (t, J = 7.4
Hz, 1 H), 2.95 (t, J = 6.1 Hz, 2 H), 2.57 (t, J = 6.6 Hz, 2 H),
2.19 (quin, J = 6.3 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
d = 194.66, 158.08, 139.28, 129.59, 127.65, 126.66, 120.64,
119.73, 38.85, 23.49, 22.99. HRMS: m/z calcd for
C13H13N2O [M + H]+: 213.1028; found: 213.1018.
Pyrazole 3a (pale-yellow solid): 1H NMR (400 MHz,
CDCl3): d = 7.83 (s, 1 H), 3.85 (s, 3 H), 2.97–2.94 (m, 2 H),
2.70–2.67 (m, 2 H), 1.98–1.90 (m, 4 H). 13C NMR (100
MHz, CDCl3): d = 197.28, 153.75, 134.02, 122.83, 43.19,
39.03, 27.79, 25.34, 22.79. HRMS: m/z calcd for C9H13N2O
[M + H]+: 165.1028; found: 165.1023.
Pyrazole 2b: 1H NMR (400 MHz, CDCl3): d = 7.93 (s, 1 H),
4.10 (q, J = 7.2 Hz, 2 H), 2.93 (t, J = 6.4 Hz, 2 H), 2.71 (t,
J = 6.1 Hz, 2 H), 2.07–2.02 (m, 2 H), 1.95–1.90 (m, 2 H),
1.42 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d =
196.13, 143.79, 140.68, 122.78, 44.31, 43.83, 26.43, 25.26,
22.48, 14.89. HRMS: m/z calcd for C10H15N2O [M + H]+:
179.1184; found: 179.1180.
Pyrazole 2c: 1H NMR (400 MHz, CDCl3): d = 8.00 (s, 1 H),
7.39–7.25 (m, 3 H), 7.14–7.09 (m, 2 H), 5.30 (s, 2 H), 2.82
(t, J = 6.4 Hz, 2 H), 2.82 (t, J = 6.1 Hz, 2 H), 1.98–1.92 (m,
2 H), 1.90–1.84 (m, 2 H). 13C NMR (100 MHz, CDCl3): d =
196,18, 144.75, 141.00, 135.77, 128.91, 122.97, 126.71,
122.82, 53.55, 43.99, 26.78, 25.24, 22.46. HRMS: m/z calcd
for C15H17N2O [M + H]+: 241.1341; found: 241.1344.
Pyrazole 2d: 1H NMR (400 MHz, CDCl3): d = 8.10 (s, 1 H),
7.53–7.40 (m, 5 H), 2.96–2.93 (m, 2 H), 2.77–2.75 (m, 2 H),
1.98–1.95 (m, 4 H). 13C NMR (100 MHz, CDCl3): d =
196.26, 145.76, 141.61, 138.85, 129.24, 128.76, 125.67,
123.36, 43.35, 27.26, 25.39, 22.56. HRMS: m/z calcd for
C14H15N2O [M + H]+: 227.1184; found: 227.1179.
(8) The identical reaction at 21 °C favored 2a (2a/3a = 6:1).
(9) (a) Regioisomer 2 was assigned based on the NOE observed
between the R group and the C8 protons (Table 1).
(b) Pyrazole 2d was found to be identical to that previously
described in the literature (see ref. 2a).
Pyrazole 3b (pale-yellow viscous oil): 1H NMR (400 MHz,
CDCl3): d = 7.86 (s, 1 H), 4.11 (q, J = 7.3 Hz, 2 H), 2.99–
2.94 (m, 2 H), 2.72–2.67 (m, 2 H), 2.01–1.88 (m, 4 H), 1.49
(t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d =
197.37, 153.45, 132.25, 122.46, 47.12, 43.18, 27.85, 25.32,
22.79, 15.07. HRMS: m/z calcd for C10H15N2O [M + H]+:
179.1184; found: 179.1179.
Pyrazole 3c (pale-yellow viscous oil): 1H NMR (400 MHz,
CDCl3): d = 7.81 (s, 1 H), 7.39–7.32 (m, 3 H), 7.29–7.23 (m,
2 H), 5.21 (s, 2 H), 3.00–2.94 (m, 2 H), 2.71–2.65 (m, 2 H),
2.00–1.86 (m, 4 H). 13C NMR (100 MHz, CDCl3): d =
197.37, 153.78, 134.93, 133.26, 128.96, 128.51, 128.18,
122.94, 56.20, 43.18, 27.82, 25.29, 22.73. HRMS: m/z calcd
for C15H17N2O [M + H]+: 241.1341; found: 241.1334.
Pyrazole 3d (pale-yellow viscous oil): 1H NMR (400 MHz,
CDCl3): d = 8.39 (s, 1 H), 7.68 (d, J = 7.7 Hz, 2 H), 7.46 (t,
J = 8.0 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H), 3.10–3.05 (m, 2
H), 2.78–2.73 (m, 2 H), 2.05–1.93 (m, 4 H). 13C NMR (100
MHz, CDCl3): d = 197.46, 154.67, 139.12, 130.42, 129.53,
127.35, 122.62, 119.44, 43.19, 27.82, 25.19, 22.71. HRMS:
m/z calcd for C14H15N2O [M + H]+: 227.1184; found:
227.1179.
Pyrazole 3e (pale-yellow oily solid): 1H NMR (400 MHz,
CDCl3): d = 7.81 (s, 1 H), 3.91 (s, 3 H), 2.83 (t, J = 6.3 Hz,
Synlett 2008, No. 4, 600–604 © Thieme Stuttgart · New York

604
L. J. Kennedy
LETTER
2 H), 2.53–2.46 (m, 2 H), 2.12 (quin, J = 6.3 Hz, 2 H). 13
NMR (100 MHz, CDCl3): d = 194.44, 157.32, 130.05,
C
of THF due to solubility issues. Otherwise, reactions were
run as described in the experimental section.
119.25, 39.18, 38.67, 23.62, 22.79. HRMS: m/z calcd for
(18) 1,3-Cycloheptanedione was purchased from Sigma-Aldrich,
or when unavailable, synthesized and distilled as described
in: Ragan, J. A.; Makowski, T. W.; am Ende, D. J.; Clifford,
P. J.; Young, G. R.; Conrad, A. K.; Eisenbeis, S. A. Org.
Process Res. Dev. 1998, 2, 379.
(19) A similar preparation of 3-aryl pyrazoles (Scheme 3) from
hydrazone 7 and substituted benzaldehydes has been
reported: (a) Teuber, H. J.; Worbs, E.; Cornelius, D. Chem.
Ber. 1968, 101, 3918. (b) Strakova, I.; Strakovs, A.;
Petrova, M. Chem. Heterocycl. Compd. (Engl. Transl.)
2005, 41, 1398.
(20) Pyrazole 3h has been previously synthesized by a different
route: Bajnati, A.; Kokel, B.; Hubert-Habart, M. Bull. Soc.
Chim. Fr. 1987, 2, 318.
(21) Pyrazoles 2a and 3a are erroneously reported in
Le Tourneau, M. E.; Peet, N. P. US Patent 4734430, 1998.
In example 3 of the patent, pyrazoles 2a and 3a are reported
as 5,6,7,8-tetrahydro-1-methyl-4(1H)-
C8H11N2O [M + H]+: 151.0871; found: 151.0867.
Pyrazole 3f (pale-yellow solid): 1H NMR (400 MHz,
CDCl3): d = 7.85 (s, 1 H), 4.17 (q, J = 7.2 Hz, 2 H), 2.84 (t,
J = 6.3 Hz, 2 H), 2.52–2.46 (m, 2 H), 2.13 (quin, J = 6.3 Hz,
2 H), 1.51 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
d = 194.54, 157.09, 128.43, 118.92, 47.38, 38.67, 23.65,
22.86, 15.17. HRMS: m/z calcd for C9H13N2O [M + H]+:
165.1028; found: 165.1022.
Pyrazole 3g (pale-yellow solid): 1H NMR (400 MHz,
CDCl3): d = 7.79 (s, 1 H), 7.39–7.32 (m, 3 H), 7.29–7.24 (m,
2 H), 5.26 (s, 2 H), 2.85 (t, J = 6.3 Hz, 2 H), 2.51–2.45 (m, 2
H), 2.12 (quin, J = 6.3 Hz, 2 H). 13C NMR (100 MHz,
CDCl3): d = 194.59, 157.37, 134.83, 129.44, 129.01, 128.58,
128.18, 119.37, 56.43, 38.72, 23.62, 22.89. HRMS: m/z
calcd for C14H15N2O [M + H]+: 227.1184; found: 227.1179
(16) The regioisomers of pyrazoles 3e–h were independently
synthesized via ref. 1a or 2a.
(17) (a) All reactions were performed on a 1.0 mmol scale (0.20
M) using 1.0 equiv hydrazine and 3.0 equiv DMFDMA.
Reaction conditions are not optimized. (b) Ethylhydrazine
oxalate and benzylhydrazine dihydrochloride were
pretreated with Et3N (2.2 equiv) for 10 min in MeOH instead
cycloheptapyrazolone and 5,6,7,8-tetrahydro-2-methyl-
4(2H)-cycloheptapyr-azolone, respectively. However, they
should have been reported as 5,6,7,8-tetrahydro-1,3-
dimethyl-4(1H)-cycloheptapyrazolone and 5,6,7,8-
tetrahydro-2,3-dimethyl-4(2H)-cycloheptapyrazolonebased
on the chemistry described therein.
Synlett 2008, No. 4, 600–604 © Thieme Stuttgart · New York

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