An efficient intramolecular 1,3-dipolar cycloaddition involving 2-(1,2-dichlorovinyloxy)aryldiazomethanes: A one-pot synthesis of benzofuropyrazoles from salicylaldehydes

Article abstract of DOI:10.1021/jo802193z

A novel intramolecular 1,3-dipolar cycloaddition strategy for a rapid entry into benzofuropyrazoles is described. In a three- step sequence, (E)-2-(1,2-dichlorovinyloxy)aryldiaz- omethanes were generated in situ from the corresponding salicylaldehydes. In

Full text of DOI:10.1021/jo802193z

SCHEME 1. Classical Route to Benzofuropyrazoles
An Efficient Intramolecular 1,3-Dipolar
Cycloaddition Involving
2-(1,2-Dichlorovinyloxy)aryldiazomethanes: A
One-Pot Synthesis of Benzofuropyrazoles from
Salicylaldehydes
zothieno- and benzofuropyrazolyl compounds have also been
identified as modulators of the 5HT2c receptor. Potentially
treatable disorders associated with this receptor are obesity,
eating disorders, and obesity-related diabetes.4 New synthetic
methods that allow efficient access to this class of fused
heterocycles is therefore of great value especially in the early
stages of drug discovery and structure-activity studies. We wish
to report herein an efficient intramolecular dipolar cycloaddition
strategy for a rapid, one-pot assembly of benzofuropyrazoles
starting from the corresponding salicylaldehydes.
Zachary S. Sales and Neelakandha S. Mani*
Johnson & Johnson Pharmaceutical Research and
DeVelopment, L.L.C., 3210 Merryfield Row,
San Diego, California 92121
nmani@its.jnj.com
ReceiVed October 03, 2008
Despite their gaining prominence, preparation of this class
of fused pyrazoles has relied mostly on the Knorr pyrazole
synthesis involving the condensation of a 1,3-dicarbonyl
substrate with hydrazine5 (Scheme 1).
This condensation involving an acylbenzofuranone is not
always very efficient due to other competing reaction pathways
such as deacylation and ring opening.5 In our experience, these
side reactions appear to be particularly dominant in the case of
those acylbenzofuranones that contain electron-donating sub-
stituents on the aromatic ring. These difficulties prompted us
to explore novel disconnections that might be more efficient.
1,3-Dipolar cycloaddition of nitrile imines or diazo compounds
with olefinic or acetylenic dipolarophiles has been reported to
offer an alternative method to construct pyrazoles.6 Kirmse and
Dietrich7 have reported that 2-(allyloxy)phenyldiazomethane
undergoes intramolecular 1,3-dipolar cycloaddition to form a
fused benzopyranopyrazoline derivative. Subsequently, Padwa
and Ku8 showed that thermolysis of a 2-(2- alkenyl)phenyldia-
zomethane gave tetrahydroindenopyrazole cycloadduct in high
yields. More recently, Aggarwal9 and Chandrasekharan10 have
reported cycloaddition of aryldiazomethanes with dipolarophiles
in which they describe a safe, in situ generation of aryldiaz-
omethanes by the base-mediated decomposition of tosylhydra-
zones under mild conditions. We thus envisaged an intramo-
lecular 1,3-dipolar cycloaddition involving an in situ generated
2-(vinyloxy)aryldiazomethane 3 as outlined in Scheme 2. The
initial pyrazoline adduct 4 was then proposed to be aromatized
A novel intramolecular 1,3-dipolar cycloaddition strategy for
a rapid entry into benzofuropyrazoles is described. In a three-
step
sequence,
(E)-2-(1,2-dichlorovinyloxy)aryldiaz-
omethanes were generated in situ from the corresponding
salicylaldehydes. Intramolecular cycloaddition followed by
dehydrohalogenation garnered 3-chlorobenzofuropyrazoles
in excellent yields. By careful choice of solvent, base, and
reaction conditions, the entire sequence can be carried out
in a one-pot procedure.
Fused pyrazoles such as benzofuropyrazoles are structural
motifs increasingly found in a wide array of medicinal chemistry
programs. For example, 1H-benzofuro[3,2]pyrazolyl-3-amine
derivatives have been reported to have analgesic and anticon-
vulsant properties due to their ability to inhibit selectively the
cyclooxygenase 2 (COX 2) enzyme.1 A class of 3-arylbenzo-
furopyrazoles has been developed as inhibitors of certain
tyrosine kinases for the treatment of diseases and disorders
associated with abnormal cell proliferation.2 Fused pyrazoles,
including benzothieno- and benzofuropyrazoles, have been
identified as selective histamine H3 antagonists, which are
potentially useful in the treatment of a host of CNS disorders
such as ADHD, Parkinson’s disease, memory, Alzheimer’s,
narcolepsy, sleep apnea, insomnia, etc.3 A number of ben-
(4) Ladoucur, G. H.; Choi, S.; Wang, Y. WO 2003/057161, A2 PCT/US02/
41859.
(5) (a) Mosher, W. A.; Serridge, P. M.; Lipp, D. W. J. Org. Chem. 1972,
37, 2402–2405. (b) Gatta, F.; Settimj, G. J. Heterocycl. Chem. 1984, 21, 937–
943.
(6) (a) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John Wiley & Sons:
New York, 1984; Vol. 1. (b) Regitz, M.; Maas, G. Diazo Compounds: Properties
and Synthesis; Academic Press: London, 1996. (c) Maas, G. In Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products; Padwa, A., Taylor, E. C., Pearson, W. H., Eds.; John Wiley
& Sons: New York, 2002.
(7) Kirmse, W.; Dietrich, H. Chem. Ber. 1967, 100, 2710–2718.
(8) Padwa, A.; Ku, H. J. Org. Chem. 1980, 45, 3756–3766. We are grateful
to the reviewers for bringing the earlier works of Kirmse and Padwa to our
attention.
(1) (a) Philipp, A.; Jirkowsky, I.; Martel, R. US Patent 4420,476 (December
1983), Appl. No 380,973. (b) Talley, J.; Stephen, R. WO 96/09304, PCT/US
95/11403. (c) Caruso, F. S. WO 00/29023, PCT/US 98/24317.
(2) (a) Murata, K.; Kumagai, H.; Kawashima, T.; Tamitsu, K.; Irie, M.;
Nakajima, H.; Suzu, S.; Shibuya, M.; Kamihira, S.; Nosaka, T.; Asano, S.;
Kitamura, T. J. Biol. Chem. 2003, 278, 32892–32898. (b) Donald, S.; Whartenby,
K.; Pardoll, D. WO 2006/020145, PCT/US 2005/025318and references cited
therein.
(9) Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. J. Org. Chem. 2003, 68,
5381–5383.
(3) Bennani, Y. L.; Campbell, M. G.; Dastrup, D.; Porterhuck, E. WO 2007/
094962, A2 PCT/US2007/002547.
(10) Chandrasekhar, S.; Rajaiah, G.; Srihari, P. Tetrahedron Lett. 2001, 42,
6599–6601.
10.1021/jo802193z CCC: $40.75
Published on Web 12/03/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 891–894 891

SCHEME 2. 1,3-Dipolar Cycloaddition Strategy toward
Benzofuropyrazoles
SCHEME 4. Synthesis of
(E)-2-(1,2-Dichlorovinyloxy)benzaldehyde
SCHEME 3. Proposed Route to Benzofuropyrazoles from
Salicylaldehyde
TABLE 1. Synthesis of
(E)-2-(1,2-Dichlorovinyloxy)arylcarboxaldehydes
to the pyrazole either by oxidation (X ) H) or by base-induced
elimination (X ) halogen).
We proposed that a suitably substituted aryldiazomethane 3
could be generated in situ starting from the corresponding
salicylaldehyde as shown in Scheme 3.
After considering a variety of groups that could serve as an
internal dipolarophile, we chose the dichlorovinyloxy group as
the most suitable for our purpose. The main considerations
which guided our selection were as follows: (1) A leaving group
at the 3a-position of the initially formed pyrazoline adduct 4 is
highly desirable as it could eliminate HX to form the pyrazole
5. (2) A second leaving group retained at the 3-position of the
pyrazole is needed for further substitution reactions leading to
more complexity. (3) Accessibility from readily available
precursors as well as stability toward reagents needed for
generating the proposed aryldiazomethane is also critical.
Formation of aryl dichlorovinyl ethers by reaction of phenols
with readily available trichloroethylene has been reported.
Extensive studies by Kende,11 Pielichowski,12 and Green13 have
shown that under strongly basic conditions trichloroethylene
undergoes dehydrohalogenation to form highly reactive dichlo-
roacetylene, and this readily reacts with nucleophiles such as
alcohols and phenols to form the corresponding dichlorovinyl
ethers. However, initial attempts following a reported proce-
dure12 gave only modest yields of the desired vinyloxy
derivative. Thus, heating a mixture of salicylaldehyde and
trichloroethylene in a biphasic medium (aqueous NaOH and
heptane) in the presence of a phase-transfer catalyst gave a 40%
yield of the desired (E)-(1,2-dichlorovinyloxy)benzaldehyde 9
as a single isomer. The regio- and stereochemical assignments
were based on the elimination-addition mechanism established
by Kende and co-workers.11 After considerable experimentation
involving a number of solvent and base combinations, we
determined that optimum yields could be obtained by reacting
salicylaldehyde with a slight excess of trichloroethylene in DMF
using K2CO3 as the base at 70-80 °C (Scheme 4).
SCHEME 5. Synthesis of Benzofuropyrazoles
electron-donating substituents gave very good yields of the
dichlorovinlyl ethers, whereas strong electron-withdrawing
groups (see entry 8) appeared to be less favored.
With an efficient method for the synthesis of dichlorovinyl
ethers in hand, we examined the intramolecular cycloaddition.
Treatment of 2-(1,2-dichlorovinyloxy)benzaldehyde 9 with
benzenesulfonyl hydrazide in acetonitrile at room temperature
resulted in fast conversion to the corresponding hydrazone 10
(Scheme 5). Upon adding a slight excess of aqueous NaOH
solution and heating to 50 °C, the diazo compound was
generated in situ, which then spontaneously cyclized to form
the chloropyrazole 11 in almost quantitative yield. A number
of substrates were examined, and all of them gave uniformly
excellent yields of the desired benzofuropyrazoles (Table 2).
A number of dichlorovinyl ethers were thus prepared by this
method as outlined in Table 1. In general, substrates with
(11) Kende, A. S.; Fludzinski, P.; Hill, J. H.; Swenson, W.; Clardy, J. J. Am.
Chem. Soc. 1984, 106, 3551–3562.
(12) Pielichowski, J.; Bogdal, D. Pol. J. Chem. 1988, 62, 483–487.
(13) (a) Moyano, A.; Charbonnier, F.; Greene, A. E. J. Org. Chem. 1987,
52, 2919–2922. (b) Imbroglio, J. E.; Rainier, J. D. Tetrahedron Lett. 2001, 42,
6987–6900.
892 J. Org. Chem. Vol. 74, No. 2, 2009

TABLE 2. Synthesis of Benzofuropyrazoles
SCHEME 7. Elaboration of the Pyrazole by
Palladium-Catalyzed Cross-Coupling with Phenylboronic
Acid
SCHEME 8. Elaboration of the Pyrazole by
Palladium-Catalyzed Amination with Benzylamines
to a variety of benzofuropyrazoles. These can then be further
elaborated by substitution using palladium catalyzed coupling
strategies.15 To demonstrate this utility, we investigated cross-
coupling reaction of chloropyrazole 11 with phenylboronic acid.
Using the catalyst system Pd(OAc)2/S-Phos/K3PO4, the cross-
coupling went smoothly to furnish the 3-aryl derivative 13, a
known tyrosine kinase inhibitor GTP-14564,2 in 86% yield
(Scheme 7).
Unlike the Suzuki-Miyaura coupling reactions, palladium-
catalyzed aminations appeared to be more capricious. The nature
of palladium catalyst, ligand, solvent, and base used all appeared
to have some influence on the outcome. Thus, for the amination
with benzylamines, best results were obtained using the catalyst
system Pd2(dba)3/t-Bu-X-Phos/LiHMDS.16 In the two cases,
which we examined, poor to moderate yields were obtained
(Scheme 8). A considerable amount of dehalogenation was
observed indicating an unfavorable reductive elimination step.
Further optimization of this chemistry is currently ongoing.
SCHEME 6. One-Pot Synthesis of Benzofuropyrazoles
In conclusion, an efficient construction of the benzofuropy-
razole skeleton using an intramolecular 1,3-dipolar cycloaddition
strategy has been accomplished. The methodology appears to
be suited for preparing a wide variety of pharmaceutically active
benzofuropyrazoles by further elaborations using palladium-
catalyzed coupling strategies. Application of this methodology
toward our ongoing medicinal chemistry program will be
reported in due course.
The efficient one-pot conversion of 2-(1,2-dichlorovinlyloxy-
)benzaldehydes to benzofuropyrazoles under basic conditions
suggested the possibility of carrying out this reaction using the
same solvent-base combination (DMF-K2CO3) used for the
first step, namely the preparation of the dichlorovinyl ether.
Starting from salicylaldehyde, this would allow the entire
sequence to be carried out in a one-pot operation.14 Indeed, this
turned out to be quite feasible in a test experiment as outlined
in Scheme 6. Thus, salicylaldehyde was reacted with trichlo-
roethylene in presence of K2CO3 at 70 °C in DMF. After the
dichlorovinyl ether formation was judged complete by monitor-
ing the reaction by TLC, the mixture was cooled to room
temperature and benzenesulfonyl hydrazide was added directly
to the reaction flask. Formation of the hydrazone 10 was
complete in about 2 h, and when this reaction mixture was
warmed to 50 °C, we were delighted to observe steady
consumption of the hydrazone and formation of the desired
chloropyrazole. After completion, workup followed by chro-
matography furnished 11 in 55% overall yield.
Experimental Section
General Procedure for the Synthesis of (E)-2-(1,2-
Dichlorovinyloxy)arylcarboxaldehydes (Table 1). Trichloroeth-
ylene (13.5 mL, 0.150 mol) was added over 30 min to a
mechanically stirred suspension of a substituted salicylaldehyde
(0.050 mol), powdered potassium carbonate (20.8 g, 0.150 mol),
(15) (a) Miyaura, N. Top. Curr. Chem. 2002, 219, 11–59. (b) Barder, T. E.;
Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
4685–4696. (c) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.;
Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101–4111. (d) Billingsley, K.;
Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358–3366.
(16) (a) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417–3419. (b) Harris,
M. C.; Huang, X.; Buchwald, S. L. Org. Lett. 2002, 4, 2885–2888. (c) Hooper,
M. W.; Hartwig, J. F. Organometallics 2003, 22, 3394–3403. (d) Charles, M. D.;
Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7, 3965–3968. (e) Anderson, K. W.;
Tundel, R. E.; Ikawa, T.; Altman, R. A.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2006, 45, 6523–6527.
With a large collection of substituted o-hydroxy benzalde-
hydes readily available, the above protocol allows a rapid entry
(14) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 302–312. (b)
Broadwater, S. J.; Roth, S. L.; Price, K. E.; Kobaslija, M.; McQade, D. T. Org.
Biomol. Chem. 2005, 3, 2889–2906.
J. Org. Chem. Vol. 74, No. 2, 2009 893

and DMF (35 mL) at 60 °C and under N2. The resulting mixture
was heated to 70 °C and stirred for 15 h. Upon cooling to room
temperature, it was partitioned between 150 mL of EtOAc and 100
mL of H2O. The organic layer was dried over MgSO4 and filtered
and the solvent removed under vacuum (30 °C, 100-10 mmHg).
Purification of the resulting residue by column chromatography
(silica gel; 0-30% EtOAc in hexanes) yielded the title compound.
In most cases, the products were isolated as low-melting solids.
General Procedure for the Synthesis of 3-Chloro-1H-benzo-
furo[3,2-c]pyrazoles (Table 2). Benzenesulfonyl hydrazide (0.39
g, 2.3 mmol) was added all at once to a solution of the 2-(1,2-
dichlorovinyloxy)arylcarboxaldehyde (2.1 mmol) in acetonitrile (21
mL) at room temperature. After the solution was stirred for 2 h,
aqueous NaOH (2 M, 2.1 mL, 4.2 mmol) was added dropwise over
10 min. The solution was heated to 50 °C and stirred for 1 h. After
the solution was cooled to room temperature, the solvents were
removed under vacuum (30 °C, 100-10 mmHg). The residue was
partitioned between 20 mL of EtOAc and 15 mL of H2O. The
organic layer was dried over MgSO4 and filtered and solvent
removed under vacuum yielding the title compound. In most cases,
the products isolated were crystalline solids of excellent purity, and
no chromatographic purification was necessary.
was heated to 70 °C and stirred for 15 h. Upon cooling to room
temperature, benzenesulfonyl hydrazide (6.03 g, 0.035 mol) was
added all at once. After 2 h, the reaction mixture was heated to 50
°C and stirred for 15 h. This heterogeneous mixture was then cooled
to room temperature and partitioned between 200 mL EtOAc and
100 mL H2O. The organic layer was dried over MgSO4 and filtered
and the solvent removed under vacuum (30 °C, 100-10 mmHg).
Purification via column chromatography (silica gel; 20-40% EtOAc
in hexanes) yielded the title compound as a tan solid (4.24 g, 55%
1
yield): mp 222-223 °C; H NMR (THF-d8, 600 MHz) δ (ppm)
7.31 (m, 1H), 7.41 (m, 1H), 7.59 (d, J ) 8.4 Hz, 1H), 7.72 (d, J )
7.2 Hz, 1H), 12.44 (s, 1H); 13C NMR (THF-d8, 150 MHz) δ (ppm)
114.1, 117.9, 119.6, 120.2, 124.1, 127.4, 135.7, 144.0, and 162.9.
Anal. Calcd for C9H5ClN2O: C, 56.12; H, 2.62; Cl, 18.41; N, 14.54.
Found: C, 56.14; H, 2.52; Cl, 18.14; N, 14.38.
Acknowledgment. We thank Dr. Jiejun Wu, Ms. Bita Naderi,
and Ms. Heather McAllister for analytical support.
Supporting Information Available: Experimental proce-
dures for the synthesis of 13, 15, and 17, copies of 1H and 13
C
One-Pot Synthesis of 3-Chloro-1H-benzofuro[3,2-c]pyra-
zole (11). Trichloroethylene (10.8 mL, 0.120 mol) was added over
30 min to a mechanically stirred suspension of salicylaldehyde 6
(4.26 mL, 0.040 mol), powdered potassium carbonate (16.6 g, 0.120
mol), and DMF (28 mL) at 60 °C under N2. The resulting mixture
NMR spectra, and analytical data of all new compounds (Tables
1 and 2). This material is available free of charge via the Internet
at http://pubs.acs.org.
JO802193Z
894 J. Org. Chem. Vol. 74, No. 2, 2009