Synthesis of substituted 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles and 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles by intramolecular nitrilimine cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2014.02.068

Both substituted 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles and 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles have been synthesized by the 3+2 intramolecular dipolar cycloaddition of nitrilimines to alkynes. This cyclization has been extended to more versatile 3-bromo derivatives by the use of alkynylbromides as dipolarophiles.

Full text of DOI:10.1016/j.tetlet.2014.02.068

Tetrahedron Letters 55 (2014) 2150–2153
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of substituted 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles
and 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles by intramolecular
nitrilimine cycloaddition
⇑
Michael P. Winters , Christopher A. Teleha, Zhihua Sui
Janssen Research and Development, LLC, 1400 McKean Rd., Spring House, PA 19477, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Both substituted 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles and 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles
have been synthesized by the 3+2 intramolecular dipolar cycloaddition of nitrilimines to alkynes. This
cyclization has been extended to more versatile 3-bromo derivatives by the use of alkynylbromides as
dipolarophiles.
Received 9 January 2014
Revised 14 February 2014
Accepted 18 February 2014
Available online 28 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Nitrilimine
Intramolecular 3+2 dipolar cycloaddition
Tetrahydrocyclopentylpyrazoles
Tetrahydropyrrolopyrazoles
N-type Calcium Channel
We were interested in synthesizing fused bicyclic pyrazoles 1
where X = C or N1 as inhibitors of N-type Calcium Channel, a target
for neuropathic pain (Fig. 1).2 One of the most common methods
for the synthesis of pyrazoles is the intermolecular condensation
of hydrazines with 1,3-dicarbonyl compounds or their derivatives.3
This approach, though robust, often gives regioisomers such as 2
that require purification with subsequent lower yields. The intra-
molecular condensation of nitrilimines with tethered alkenes and
alkynes to give annulated pyrazoles has gained favor in recent
years due to the regiospecificity of the reaction.4 Also, this reaction
has enabled the synthesis of many targets that would be difficult to
make by traditional routes. In this Letter, we discuss the synthesis
of 2,3-diaryl-2,4,5,6-tetrahydrocyclopenta[c]pyrazoles 1 (X = C)
and 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles 1 (X = N) via the
intramolecular condensation of nitrilimines with tethered alkynes.
Before our attempts to synthesize 1 using an intramolecular
1,3-dipolar addition reaction, we tried the addition of 2-methoxy-
phenylhydrazine to 1,3-dione 3 (Scheme 1). Under both basic and
acidic conditions, a 2:1 regioisomeric mix of 4 to 5 was the best
that we achieved. Attempts to duplicate this synthetic route with
intermediates that would give a more robust synthetic handle at
the 5-position of the heterocycle, functionality such as ketone or
hydroxy, were unsuccessful due to difficulties in accessing these
particular 1,3-dicarbonyl intermediates. These issues led us to pur-
sue intramolecular 3+2 cycloadditions to make the desired com-
pounds using a synthesis based on the ring closure of hydrazonyl
chlorides 6 and 7 to bicyclic pyrazoles 8 and 9.
The general scheme for the synthesis of 2,4,5,6-tetrahydrocy-
clopenta[c]pyrazoles 18 is shown below (Scheme 2). Treatment
of 4-chlorophenylacetylene 10 with n-BuLi/Et2AlCl followed by
addition to the terminal carbon of epoxide 11 gives the addition
product 12 in 60% yield as a single regioisomer.5 Protection of
the alcohol with TIPS followed by hydrolysis of the ethyl ester
gives the acid 13 in good yield. Formation of the hydrazonyl chlo-
ride 15 was accomplished by condensation of the acid 13 with a
phenylhydrazine 14 followed by treatment with Ph3P/CCl4.6 The
key intramolecular 3+2 dipolar cycloaddition was accomplished
R2
R2
N
X
R1
N
N
R1
N
X
R3
R3
2
1
X = C, N
⇑
Corresponding author. Tel.: +1 215 628 7843; fax: +1 215 540 4611.
E-mail address: mwinter4@its.jnj.com (M.P. Winters).
Figure 1. Possible pyrazole regioisomers.
http://dx.doi.org/10.1016/j.tetlet.2014.02.068
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M. P. Winters et al. / Tetrahedron Letters 55 (2014) 2150–2153
2151
tile intermediate for the synthesis of many N-type Calcium Chan-
nel inhibitors. It should be noted that the use of commercially
available (R)- or (S)-10 in the reaction sequence gives the chiral
5-hydroxycyclopentylpyrazole.
OMe
OMe
MeO
N
NHNH2
O
O
Ar
N
N
N
Ar
Ar
+
After the success we had in making the cyclopentylpyrazoles,
we applied similar chemistry to the synthesis of 2,4,5,6-tetrahy-
dropyrrolo[3,4-c]pyrazoles 26 (Scheme 3). Treatment of alkyne
19 with 20 under Sonagashira conditions gives 21. Coupling of
21 with aryl hydrazines 22 gives the hydrazide, which can be con-
verted to the hydrazonyl chloride 23 by treatment with Ph3P/CCl4.
Heating 23 to 100 °C in the presence of triethylamine generates the
1,3-dipolar intermediate 24 which reacts with the alkyne to give
the desired 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole 25 as a single
regioisomer in excellent yield.8 Deprotection of the Boc furnishes
versatile intermediate 26.
Comparative yields for various R groups on the arylhydrazine
are shown (Tables 1 and 2). Overall, purified yields for the intramo-
lecular 1,3-dipolar cycloaddition reaction were very good, most
above 80%. A few exceptions were noted for 2-dimethylamino 43,
2-nitro 44, and 2,3-methylenedioxy 45 in the formation of the pyr-
rolopyrazoles. For the cyclopentylpyrazoles, it is worth noting that
2-methoxy 28 consistently gave yields in the 70% range in toluene,
but switching to dioxane gave an increase to 96%. When using
phenylhydrazine in both syntheses, the intermediate hydrazonyl
HOAc,
EtOH, 80°C
3
Ar = 4-chlorophenyl
4
5
R3
X
R2
Cl
R1
N
X
R1
N
N
NH
6 X = C
7 X = N
8 X = C
9 X = N
R3
R2
Scheme 1. Comparison of pyrazole syntheses.
by heating 15 in the presence of triethylamine to generate the
intermediate nitrilimine 16, which reacts in an intramolecular
fashion with the tethered alkyne to give the desired 2,4,5,6-tetra-
hydrocyclopenta[c]pyrazole 17 in excellent yield as
a single
isomer.7 Deprotection of the TIPS gives the free alcohol 18, a versa-
1)
NHNH2
HO
TIPSO
n-BuLi, Et2AlCl
14
R
1) TIPSOTf, DIEA
2) NaOH, EtOH
O
CO2Et
12, 61%
CO2H
Cl
i-BuOCOCl, NMM
2) CCl4, Ph3P
CO2Et
Cl
Cl
10
13, 92%
11
TIPSO
TIPSO
R
R
Cl
Cl
Cl
TEA, 100oC
N
N
HCl, 80oC
N+
N-
N
Cl
N
N
Cl
NH
OH
OTIPS
R
R
16
Scheme 2. Synthesis of 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles.
15
17
18
1)
R
NHNH2
I
Cl
R
20
Cl
O
22
Cl
O
HN
Cl
N
N
N
HO
Boc
EDC, HOBt
HO
Boc
21, 62%
(Ph3P)2PdCl2, CuI
TEA, 80oC
N
2) Ph3P, CCl4
Boc
19
23
Boc
N
R
R
Cl
Cl
TEA, toluene
100oC
N
N
N
TFA, DCM
N
N+
N-
N
Cl
N
H
Boc
R
25
26
24
Scheme 3. Synthesis of 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles.

2152
M. P. Winters et al. / Tetrahedron Letters 55 (2014) 2150–2153
Table 1
Comparative yields for the nitrilimine cyclization to form 2,4,5,6-tetrahydrocyclo-
penta[c]pyrazoles 17 and 18
Br
O
1) NBS, AgNO3
2) i-BuOCOCl, NMM
HN
NH
OH
OMe
O
Compd no.
R
Solvent
Yielda (%)
OMe
27
28
28
29
30
31
32
2-OCF3
2-OMe
2-OMe
2-OEt
2-OMe-4-Cl
2,3-Dihydrofuran
H
Toluene
Toluene
Dioxane
Toluene
Dioxane
Dioxane
69
64–72
96
TIPSO
48
OTIPS
49, 76%
NHNH2
85
95
93
37b
Br
OMe
HN
N
a
Cl
N
OMe
PS-Ph3P,
Br
Yield includes deprotection of TIPS by heating with 1 N HCl in dioxane.
Cyclization occurred during the Ph3P/CCl4 step.
TEA, dioxane
100oC
N
b
CCl4, 50oC
OTIPS
OTIPS
51,
84%
50,
75%
Table 2
Comparative yields for the nitrilimine cyclization to form 2,4,5,6-tetrahydropyrrol-
o[3,4-c]pyrazoles 25 and 26
Compd no.
R
Yield (%)
OMe
OMe
Cl
(Ph3P)4Pd, Na2CO3
1 N HCl
4-Cl-PhB(OH)2
N
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
2-Ethyl
2-CF3
2-OCF3
2-OMe
91
90
92
N
N
Br
N
dioxane, 80oC
84
2-OEt
98a
90
OH
2-Me-4-OMe
2-OMe-4-F
2-OMe-4-Me
2-F-4-OMe
2-OMe-4-Cl
2-NMe2
OH
53,
71%
52,
95%
85
93
95
99
Scheme 4. Synthesis of 3-bromocyclopentylpyrazole 51.
58
2-NO2
71
59a
91a
17b
OMe
NHNH2
Br
2,3-Methylenedioxy
2,3-Dihydrofuran
H
Boc
Br2, KOH
N
O
Boc
a
N
Yield includes deprotection of the Boc by treatment with TFA/DCM.
Cyclization occurred during the Ph3P/CCl4 step.
HO
i-BuOCOCl, NMM
b
HO
19
O
54, 47%
chloride could not be isolated from the Ph3P/CCl4 reactions, and in-
stead the cyclized cyclopentylpyrazole 32 and pyrrolopyrazole 47
products were isolated directly from the reaction mixture.9
One limitation of this chemistry was the necessity to carry the
aryl group on the alkyne through many synthetic steps. To enable
the synthesis of analogs at the 3-position of the pyrazole later in
the synthesis, 3-bromo-cyclopentylpyrazole 51 was targeted
(Scheme 4). The 3+2 dipolar cycloaddition of a nitrilimine with
an alkynylbromide to form a bromopyrazole is unprecedented,
either by intra- or intermolecular reaction. Treatment of 48 with
NBS and silver nitrate followed by coupling with 2-methoxyphenyl
hydrazine gives bromohydrazide 49.10 Reaction of 49 with Ph3P/
CCl4 gives a low yield due to loss of bromine from the alkyne.
Attempts to remedy this by changing solvent, amounts of reagents,
and surveying other reaction conditions were initially unsuccess-
ful. However, substitution of Ph3P with polymer-bound Ph3P and
heating to 50 °C in acetonitrile gives the desired hydrazonyl chlo-
ride 50 in 75% yield. Cyclization using TEA in dioxane at 100 °C
gives the 2-aryl-3-bromocyclopentylpyrazole 51 in 98% yield, an
important intermediate for the synthesis of diverse N-type inhibi-
tors 53 via palladium coupling reactions.
OMe
1) PS-Ph3P,
CCl4, 45%
N
MeO
N
Br
Br
HN
O
NH
2) TEA, toluene
100oC, 74%
N
N
Boc
Boc
55,
77%
56
Scheme 5. Synthesis of 3-bromopyrrolopyrazole 56.
for the dipolar cycloaddition reaction, and the formation of a single
regioisomer in that reaction, are considerable improvements on
the traditional ways to synthesize pyrazole derivatives. We have
also extended the chemistry to include alkynylbromides as the
dipolarophile giving the versatile 2-aryl-3-bromo derivatives that
enable the synthesis of a variety of analogs at the 3-position of
the pyrazole. Lastly, we have shown that PS-Ph3P can be an impor-
tant reagent to use in the Wolkoff reaction to generate sensitive
hydrazonyl chlorides.
Supplementary data
For the pyrrolopyrazole series, treatment of the alkyne 19 with bro-
mine and KOH gives the bromoalkyne 54 (Scheme 5).11 Following the
same general synthetic scheme described previously gives the desired
3-bromopyrrolopyrazole 56 in 45% yield for the chlorination and 74%
yield for the intramolecular 1,3-dipolar cycloaddition reaction.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02
.068. These data include MOL files and InChiKeys of the most
important compounds described in this article.
We have shown that the intramolecular 3+2 dipolar cycloaddi-
tion of nitrilimines to tethered alkynes is a versatile way to
synthesize a variety of substituted 2,3-diaryl-cyclopentyl- and
pyrrolopyrazole derivatives. The ease of synthesis of intermediates
References and notes
1. Aubert, T.; Tabyaoui, B.; Farnier, M.; Guilard, R. Synthesis 1988, 742.

M. P. Winters et al. / Tetrahedron Letters 55 (2014) 2150–2153
2153
2. Yamamoto, T.; Takahara, A. Curr. Top. Med. Chem. 2009, 9, 377.
3. (a) Fustero, S.; Simon-Fuentes, A.; Sanz-Cerveram, J. F. Org. Prep. Proced. Int.
2009, 41, 253; (b) Yoon, J.-Y.; Lee, S.; Shin, H. Curr. Org. Chem. 2011, 15, 657; (c)
Makino, K.; Kin, H. S.; Kurasawa, Y. J. Heterocycl. Chem. 1998, 35, 489; (d)
Kumar, S.; Yadav, S.; Raghava, B.; Saraiah, B.; Ila, H.; Rangappa, K.; Hazra, A. J.
Org. Chem. 2013, 78, 4960.
4. Broggini, G.; Molteni, G.; Zecchi, G. Heterocycles 1998, 47, 541.
5. Trost, B. M.; Ball, Z. T.; Laemmerhold, K. M. J. Am. Chem. Soc. 2005, 127, 10028.
6. Wolkoff, P. Can. J. Chem. 1975, 53, 1333.
8. Molteni, G. Heterocycles 2004, 63, 1423.
9. These were single reactions and are unoptimized. Perhaps the electron-
donating effects of the substituents commonly used (necessary for N-type
calcium channel activity) destabilize the nitrilimine intermediate, while
neutral phenyl stabilizes it and thus encourages the cyclization at rt. Or
perhaps the ortho-substituent twists the aryl out of plane from the nitrilimine
destabilizing it, while the phenyl remains in the plane and stabilizes the
nitrilimine by delocalizing the charge.
10. Leroy, J. Synth. Commun. 1992, 22, 567.
7. Padwa, A.; Nahm, S.; Sato, E. J. Org. Chem. 1978, 43, 1664.
11. Brandsma, L.; Verkruijsse, H. D. Synthesis 1990, 11, 984.