Facile and efficient synthesis of indazole derivatives by 1,3-cycloaddition of arynes with diazo compounds and azomethine imides

Article abstract of DOI:10.1135/cccc2009014

N-Unsubstituted indazoles 3 and 1-arylindazoles 4 are readily available in good to high yields through [3+2] cycloaddition of 2-(trimethylsilyI)aryl triflates 1 and diazo compounds in the presence of KF or CsF under mild reaction conditions. Furthermore, we found that azomethine imides also underwent cycloaddition reaction with 2-(trimethylsilyl)phenyl triflates (la) in the presence of KF to afford indazolone derivatives 6 in moderate yields.

Full text of DOI:10.1135/cccc2009014

Synthesis of Indazole Derivatives
957
FACILE AND EFFICIENT SYNTHESIS OF INDAZOLE DERIVATIVES BY
1,3-CYCLOADDITION OF ARYNES WITH DIAZO COMPOUNDS AND
AZOMETHINE IMIDES
1,
2,
Tienan JIN *, Fan YANG and Yoshinori YAMAMOTO *
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578,
1
2
Japan; e-mail: tjin@mail.tains.tohoku.ac.jp; yoshi@mail.tains.tohoku.ac.jp
Received February 18, 2009
Accepted April 14, 2009
Publish ed on lin e Jun e 18, 2009
Dedicated to Dr. Alfred Bader on the occasion of his 85th birthday in recognition of his outstanding
contributions to the science of chemistry.
N-Un substituted in dazoles 3 an d 1-arylin dazoles 4 are readily available in good to h igh
yields th rough [3+2] cycloaddition of 2-(trim eth ylsilyl)aryl triflates 1 an d diazo com poun ds
in th e presen ce of KF or CsF un der m ild reaction con dition s. Furth erm ore, we foun d th at
azom eth in e im ides also un derwen t cycloaddition reaction with 2-(trim eth ylsilyl)ph en yl
triflates (1a) in th e presen ce of KF to afford in dazolon e derivatives 6 in m oderate yields.
Keyw ord s: [3+2] Cycloaddition ; 1,3-Dipolar cycloaddition ; Aryn es; Diazo com poun ds;
Azom eth in e im ides; In dazoles.
1H-In dazoles are an im portan t class of h eterocycles th at display a wide
ran ge of ph arm acological activities, in cludin g an tifertility, an tiarth ritic,
an ti-in flam m atory, an d con traceptive activity, as well as an tagon istic activ-
ity to th e 5-HT3 receptor1. Owin g to th eir poten tial usefuln ess, con siderable
effort h as been devoted to th e developm en t of efficien t m eth ods for th e
con struction of in dazole skeleton s (Sch em e 1)2. Th e com m on preparation
routes are diazotization of th e correspon din g 2-alkylan ilin es2a an d
n itrosation of th e N-acetyl derivatives of 2-alkylan ilin es (Jacobson m odifi-
cation )2b–2d. An oth er attractive route is th e con den sation of 2-substituted
ben zaldeh ydes with h ydrazin e2e,2f. However, th e reaction con dition s of
th ese m eth ods are fairly h arsh , usually stron g acids or h igh tem peratures
are n eeded. An in terestin g m eth od is th e 1,3-dipolar cycloaddition of
ben zyn e (gen erated from diazotized an th ran ilic acid) with diazoalkan es3
an d azom eth in e im in es4. For exam ple, α-diazoketon es react with ben zyn e
to give 3-acyl-3H-in dazoles, wh ich furth er isom erize to 2-acyl-2H-in dazoles
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972
© 2009 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2009014

958
Jin, Yang, Yamamoto:
SCHEME 1
Gen eral m eth ods for th e syn th esis of 1H-in dazoles
(Eq. (1))3c–3e. In addition , azom eth in e im in es also reported to un dergo
cycloaddition reaction with ben zyn e precursor, ben zen e-1-diazon ium -
2-carboxylate, to afford in dazolon e derivatives (Eq. (2))4b. However, th ese
cycloaddition approach es often em ployed explosive an d h azardous
ben zyn e precursors, an d n ecessarily h ave n ot wide scope. Th erefore, th e de-
velopm en t of an efficien t an d gen eral syn th etic m eth od to in dazole deriva-
tives is m uch desirable.
(1)
(2)
It is well kn own th at ben zyn e is gen erated in situ from 2-(trim eth yl-
silyl)ph en yl triflate (1a) un der very m ild reaction con dition s5. Accordin gly,
a variety of syn th etic m eth ods usin g 1a (via a ben zyn e in term ediate) h ave
been in vestigated, in cludin g cycloaddition s6, an d n ucleoph ilic addition re-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

Synthesis of Indazole Derivatives
959
action s7. Recen tly, we h ave developed catalytic, gen eral syn th etic protocols
for useful n itrogen -con tain in g h eterocycles, such as tetrazoles an d 1,2,3-tri-
azoles, th rough th e [3+2] cycloaddition s of alkyn es, n itriles, an d ison itriles
with trim eth ylsilyl azide8. In con tin uation of our in terest in th e develop-
m en t of efficien t m eth ods for th e syn th esis of useful h eterocycles, an d in
ben zyn e ch em istry6c–6f, we in vestigated th e cycloaddition of ben zyn e with
diazo com poun ds an d azom eth in e im ides. Th e [3+2] cycloaddition of aryn es,
gen erated from silylaryl triflates 1, an d various diazom eth an e derivatives 2
proceeded sm ooth ly un der very m ild con dition s, depen din g m erely on th e
con dition s, to give N-un substituted 1H-in dazoles 3 or 1-aryl in dazoles 4 in
good to h igh yields (Eq. (3))9a. Furth erm ore, th e cycloaddition of 2-(tri-
m eth ylsilyl)ph en yl triflate (1a) with azom eth in e im ides 5 un der sim ilar
reaction con dition s afforded th e tricyclic in dazolon e derivatives 6 in m od-
erate yields (Eq. (4)). Herein , we report a detailed in vestigation of th ese
cycloaddition syn th etic m eth ods.
(3)
(4)
RESULTS AND DISCUSSION
Synthesis of N-Unsubstituted 1H-Indazoles from 2-(Trimethylsilyl)aryl
Triflates and Diazomethanes
In itially, in th e cycloaddition of com m ercially available 2-(trim eth ylsilyl)-
ph en yl triflate (1a) an d eth yl diazoacetate (2a), we focused on screen in g
th e fluoride sources for th e form ation of N-un substituted 1H-in dazole 3a.
Treatm en t of 1a with 2a (1.2 equiv.) in th e presen ce of KF (3.0 equiv.) an d
18-crown -6 (3.5 equiv.) in THF at room tem perature for 24 h afforded
3-(eth oxycarbon yl)-1H-in dazole (3a)10a in 80% yield (Table I, en try 1). Al-
th ough CsF or Bu4NF could be used in stead of KF to gen erate ben zyn e in
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

960
Jin, Yang, Yamamoto:
situ from 1a, th e yield of 3a decreased to 63 an d 54%, respectively (Table I,
en tries 2 an d 3).
With th e optim ized reaction con dition s in h an d, th is cycloaddition reac-
tion was exten ded to various diazo com poun ds 2 an d th e substituted aryn e
precursors 1b–1f to explore th e regioselectivity of th e reaction an d to test
wh eth er th e m eth odology is gen eral for th e syn th esis of fun ction alized
1H-in dazoles or n ot10b. Wh en th e reaction of 1a with 2b was carried out
un der th e stan dard reaction con dition s, th e correspon din g in dazole 3b was
obtain ed in a h igh yield (Table I, en try 4). Diazo(trim eth ylsilyl)m eth an e (2c)
un derwen t th e cycloaddition reaction in th e presen ce of CsF in a m ixture
of CH3CN an d MeOH to give th e 50% yield of 3-un substituted in dazole 3c
with loss of th e TMS group (Table I, en try 5), wh ile n o desired product was
obtain ed in th e absen ce of MeOH. Th e reaction was also applied to diazo-
(ph en yl)m eth an e (2d ), affordin g 3-ph en yl-1H-in dazole 3d in 90% yield
(en try 6). It is n oteworth y th at 3-m eth oxy-2-(trim eth ylsilyl)ph en yl triflate
(1b) reacts sm ooth ly with 2a to afford th e correspon din g in dazole 3e as a
sin gle product in 83% yield with out form ation of th e regioisom er (en try 7).
However, in th e case of ben zyn e precursors 1c an d 1d , th e reaction gave
a ca. 1:1 m ixture of regioisom ers (en tries 8 an d 9). Th e regioselective form a-
tion of 3e can be explain ed by th e electron ic effect of th e 3-OMe group
on th e n ucleoph ilic attack of ben zyn e, an d a favorable steric effect7e. Th e
ben zyn e precursors 1e an d 1f efficien tly un derwen t th e cycloaddition reac-
tion , givin g th e in dan e 3h an d ph en an th ren e derivatives 3i in 90 an d 70%
yields, respectively (en tries 10 an d 11).
Synthesis of 1-aryl-1H-Indazoles from 2-(Trimethylsilyl)aryl
Triflates and Diazomethanes
1-Aryl-1H-in dazoles are frequen tly foun d in im portan t ph arm aceuticals
with biological activities1. Recen tly, som e useful m eth odologies for syn th e-
sis of 1-aryin dazoles h ave been developed in cludin g th e Pd-catalyzed
cyclization of arylh ydrazon es of 2-h aloben zaldeh ydes11 an d Cu-catalyzed
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

Synthesis of Indazole Derivatives
961
TABLE I
Syn th esis of N-un substituted 1H-in dazoles 3a
En try
1
2
R2
Product
3
Yield, %b
1
1a
1a
1a
1a
2a
2a
2a
2b
CO2Et
CO2Et
CO2Et
CO2t-Bu
3a
3a
3a
3b
80
63
54
89
2c
3d
4
5e
6
1a
1a
1b
2c
2d
2a
TMS
Ph
3c
3d
3e
50
90
83
7
CO2Et
8f
1c
1d
1e
2a
2a
2a
CO2Et
CO2Et
CO2Et
3f
82
3f′
(1:1)
9
3g
70
3g′
(1:1)
10
3h
90
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

962
Jin, Yang, Yamamoto:
TABLE I
(Continued)
En try
11
1
2
R2
Product
3
Yield, %b
1f
2a
CO2Et
3i
70
a
Th e reaction of 1 (0.5 m m ol) an d 2 (0.6 m m ol) was carried out in th e presen ce of KF
(3 equiv.) an d 18-crown -6 (3.5 equiv.) in 0.25 M THF at r.t. for 24 h un less oth erwise n oted.
b
c
Yields of th e isolated product. Th e reaction was carried out in th e presen ce of CsF
d
(2.0 equiv.) in CH3CN. Th e reaction was carried out in th e presen ce of Bu4NF (2.0 equiv.)
e
in CH3CN. Th e reaction was carried out in th e presen ce of CsF (3.0 equiv.) in CH3CN/
MeOH (10:1, 0.25 M). Th e ratio of regioisom ers was determ in ed by 1H NMR spectroscopy.
f
N-arylation of in dazoles12. However, th ese reaction s usually required h igh
tem peratures an d are lim ited to th e form ation of 3-un substituted in dazoles.
More recen tly, Liu an d Larock reported a sim ple N-arylation of various
am in es with 2-silylph en yl triflates un der very m ild con dition s7d,7e. We as-
sum e th at a com bin ation of our n ew m eth od (Table I) an d th e protocol of
Liu an d Larock would provide a sim ple, efficien t an d on e-pot procedure for
N-arylated 1H-in dazoles (Table II).
As expected, 1-ph en yl-1H-in dazole (4a) was readily obtain ed in 62%
yield with out form ation of N-un substituted in dazole wh en 1a (2.0 equiv.)
was treated with 2a in th e presen ce of an excess KF/18-crown -6 at room
tem perature (Table II, en try 1). However, wh en CsF was used in stead of
KF/18-crown -6 to gen erate ben zyn e, th e yield in creased to 79% an d th e
reaction was com plete in a m uch sh orter tim e (24 h ) (en try 2). Un der th e
optim al reaction con dition s, diazo(ph en yl)m eth an e (2d ) also reacted
well with 1a to afford 1,3-diph en ylin dazole 4b in 56% yield (en try 3).
Sim iliarly, th e reaction of ben zoyl(diazo)m eth an e (2e) with 1a afforded
th e correspon din g 1-arylin dazole 4c in a h igh yield (en try 4). Th e an alo-
gous reaction with th e un sym m etrical silylaryl triflate 1b afforded th e
meta-isom er 4d in 68% yield with excellen t regioselectivity (en try 5). Th is
result clearly in dicates th at th e n ucleoph ile reacts at th e meta position to
a m eth oxy group rath er th an ortho position .
Mechanism: A proposed reaction m ech an ism for th e form ation of N-
un substituted in dazoles 3 an d N-ph en ylin dazoles 4 is sh own in Sch em e 2.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

Synthesis of Indazole Derivatives
963
TABLE II
Syn th esis of 1-ph en yl-1H-in dazoles 4a
En try
1
2
R2
Product
4
Yield, %b
1c
2
1a
1a
2a
2a
CO2Et
CO2Et
4a
62
79
3
4
5
1a
1a
1b
2d
2e
2a
Ph
4b
54
4-CF3C6H4CO
4c
4d
89
50
CO2Et
a
Th e reaction of 1 (0.5 m m ol) an d 2 (0.25 m m ol) was carried out in th e presen ce of CsF
b
(6.0 equiv.) in CH3CN (2 m l) at r.t. for 24 h un less oth erwise stated. Yield of th e isolated
product. Th e reaction was carried out in th e presen ce of KF (6.0 equiv.) an d 18-crown -6
c
(7.0 equiv.) in THF for 48 h .
Th e h igh ly active ben zyn e in term ediate A is form ed in situ from 2-(tri-
m eth ylsilyl)ph en yl triflate (1a) in th e presen ce of a fluoride source. Th e
[3+2] cycloaddition of ben zyn e A with 1,3-dipoles such as diazom eth an es 2
affords th e in term ediate B wh ich un dergoes a 1,3-h ydrogen sh ift to give th e
correspon din g N-un substituted in dazoles 3. In th e presen ce of an excess of
ben zyn e A, th e furth er h ydroam in ation of 3 to ben zyn e would occur to
form th e N-ph en ylin dazoles 4.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

964
Jin, Yang, Yamamoto:
SCHEME 2
A proposed m ech an ism for th e form ation of N-un substituted in dazoles 3 an d N-ph en yl-
in dazoles 4
Synthesis of Tricyclic Indazolone Derivatives 6 from 2-(Trimethylsilyl)aryl
Triflates and Azomethine Imides
Azom eth in e im ides such as 3-oxopyrazolidin -1-ium -2-ides 5 are readily
available from th e reaction of pyrazolidin -3-on e with an aldeh yde. Th ey are
stable, easy-to-h an dle com poun ds13. 1,3-Dipolar cycloaddition of th ese di-
poles with ben zyn e is often con ducted at elevated tem peratures an d explo-
sive ben zyn e precursors such as ben zen e-1-diazon ium -2-carboxylates are
used4. In spired by th e successful syn th esis of various in dazoles, we furth er
in vestigated th e [3+2] cycloaddition of 2-(trim eth ylsilyl)ph en yl triflate (1a)
with azom eth in e im ide derivatives 5. In an in itial in vestigation , we exam -
in ed th e reaction of silylph en yl triflate 1a with azom eth in e im in e 5a by
usin g several fluoride sources. In th e presen ce of KF com bin ed with
18-crown -6 or CsF at room tem perature, cycloadduct 6a was obtain ed in 40
or 38% yield, respectively (Table III, en tries 1 an d 2). In con trast, Bu4NF
failed to give an y desired product 6a, an d 1a was decom posed un der th e
reaction con dition s (en try 3). Next, we h ave determ in ed th e scope of th e
KF/18-crown -6 prom oted cycloaddition of 1a with a ran ge of im ides of
dipoles 5b–5g. Th e reaction of th e azom eth in e im ides bearin g electron -
with drawin g (5b, 5c) an d electron -don atin g (5d , 5e) ph en yl groups at th e
im ide group gave cycloadducts 6b–6e in good yields regardless of para- or
ortho-substituen ts on ben zen e rin gs (en tries 4 to 7). Com poun d 5f with
disubstituted ph en yl in th e m olecule also reacted with 1a sm ooth ly, afford-
in g th e in dazolon e derivative 6f in 58% yield (en try 8). Th e styryl-
substituted azom eth in e im ide 5g was also a suitable dipole for th e form a-
tion of th e cycloaddition product 6g (en try 9). Un fortun ately, th e reaction
of 1a with alkyl-substituted im ides 5 (R3 = Et, t-Bu) failed to give an y de-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

Synthesis of Indazole Derivatives
965
Table III
Syn th esis of tricyclic in dazolon e derivatives 6a
En try
5
R3
Product
6
Yield, %b
1
5a
5a
5a
Ph
Ph
Ph
6a
40
38
0
2c
3d
4
5
6
7
5b
5c
5d
5e
4-ClC6H4
2-BrC6H4
4-MeC6H4
2-MeC6H4
6b
6c
6d
6e
43
63
50
46
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

966
Jin, Yang, Yamamoto:
Table III
(Continued)
En try
8
5
R3
Product
6
Yield, %b
58
5f
2-Br-4-MeC6H3
6f
9
5g
(E)-styryl
6g
45
a
Th e reaction of 1a (0.2 m m ol) an d 5 (0.24 m m ol) was carried out in th e presen ce of KF
(3 equiv.) an d 18-crown -6 (3.5 equiv.) in 1 M THF at r.t. for 12 h un less oth erwise stated.
b
c
Yield of th e isolated product. Th e reaction was carried out in th e presen ce of CsF
d
(3.0 equiv.) in CH3CN. Th e reaction was carried out in th e presen ce of Bu4NF (3.0 equiv.)
in THF.
sired products an d both 1a an d im ides were decom posed un der th e reac-
tion con dition s.
Next, we exam in ed th e reaction of th e substituted ben zyn e precursors,
1b, 1d , an d 1e, with azom eth in e im ide 5c un der th e stan dard reaction con -
dition s. Th e reaction of 3-m eth oxy-2-(trim eth ylsilyl)ph en yl triflate (1b)
with 5c gave th e correspon din g in dazolon e product 6h in 30% yield as
a sin gle regioisom er in wh ich th e m eth oxy group was away from th e h in -
dered 2-brom oph en yl substituen t (Eq. (5)). Treatm en t of 1-(trim eth yl-
silyl)n aph th yl-2-triflate (1d ) with azom eth in e im ide 5c afforded a n early
(5)
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

Synthesis of Indazole Derivatives
967
1:1 m ixture of two regioisom ers (Eq. (6)). Th e structures of regioisom ers 6h
an d 6i′ were determ in ed un am biguously by NOE experim en t as well as
HMBC an d DEPT an alysis (Fig. 1). A sim ilar reaction with th e sym m etrical
silylaryl triflate 1e produced th e correspon din g diazain dacen on e derivative
6j in 52% yield (Eq. (7)).
(6)
(7)
An efficien t, facile, an d gen eral m eth od for th e syn th esis of N-un sub-
stituted in dazoles an d 1-arylin dazoles via th e 1,3-dipolar cycloaddition of
aryn es with diazom eth an es h as been developed. By ch an gin g th e reaction
con dition s, th e con trolled syn th esis of eith er of th e two products is possi-
ble. Furth erm ore, we h ave succeeded in th e developm en t of syn th esis of
tricyclic in dazolon e derivatives th rough th e cycloaddition of 2-silylph en yl
triflate with azom eth in e im ides un der very m ild reaction con dition s. Fur-
th er studies on th e application of th e presen t m eth od to th e syn th esis of
biologically active com poun ds are in progress.
FIG. 1
NOE experim en t of com poun ds 6h an d 6i′
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

968
Jin, Yang, Yamamoto:
EXPERIMENTAL
1H an d 13C NMR spectra were recorded on JEOL JMTC-270/54/SS (JASTEC, 300 an d 500 MHz)
spectrom eters. 1H NMR spectra are reported as follows: ch em ical sh ift in ppm (δ) relative to
CDCl3 at 7.26 ppm , in tegration , m ultiplicities (s, sin glet; d, doublet; t, triplet; q, quartet;
m , m ultiplet; br, broaden ed), an d couplin g con stan ts (J) in Hz. 13C NMR spectra reported in
ppm (δ) relative to th e cen tral lin e of triplet for CDCl3 at 77 ppm . IR spectra were recorded
on a Sh im adzu FTIR-8200A spectrom eter; absorption s are reported in cm –1. High -resolution
m ass spectra were obtain ed on a Bruker APEXIII spectrom eter. Meltin g poin ts were m easured
by MRK (No. 8026). Colum n ch rom atograph y was carried out em ployin g Silica gel 60 N
(sph erical, n eutral, 40–100 m m , Kan to Ch em ical Co.). An alytical th in -layer ch rom atograph y
(TLC) was perform ed on precoated plate with 0.2 m m Kieselgel 60 F254 (Merck). An h ydrous
aceton itrile (Wako), Tetrah ydrofuran (Kan to), KF, CsF (Wako), 18-crown -6 (TCI), eth yl
diazoacetate (2a), tert-butyl diazoacetate (2b), diazo(trim eth ylsilyl)m eth an e (2c) (2.0 M solu-
tion in dieth yl eth er), 2-(trim eth ylsilyl)ph en yl triflate (1a) (Aldrich ), pyrazolidin -3-on e h ydro-
ch loride (Across), were purch ased an d used as received. Aryn e precursors 1b, 1c, 1d , 1f 14
,
,
1e 15, diazo(ph en yl)m eth an e (2d )16 an d diazo[4-(trifluorom eth yl)ben zoyl]m eth an e (2e)17
13
an d 3-oxopyrazolidin -1-ium -2-ides 5a–5g
were prepared accordin g to th e literature proce-
dure. Th e procedures an d ch aracterization of fin al products 3a–3i an d 4a–4d are available
from ref.9a
.
Typical Procedure for th e Syn th esis of In dazolon e Derivatives 6
2-(Trim eth ylsilyl)ph en yl triflate (1a) (50 µl, 0.2 m m ol) was added to a THF (1 m l) solution of
1-ben zyliden e-3-oxopyrazolidin -1-ium -2-ide (5a) (41.8 m g, 0.24 m m ol), KF (35 m g, 0.6 m m ol),
an d 18-crown -6 (185 m g, 0.7 m m ol) in a pressure vial. After stirrin g at room tem perature for
12 h , th e reaction m ixture was filtered th rough a sh ort pad of Florisil an d eluted with eth yl
acetate. Th e filtrate was con cen trated, an d th e residue purified by ch rom atograph y on silica
gel usin g a m ixture of h exan e/EtOAc (5:1 to 3:1) as eluen t to afford 6a as a wh ite solid
(20 m g, 40%).
2,3-Dih ydro-5-ph en yl-1H,5H-pyrazolo[1,2-a]in dazol-1-on e (6a)
Wh ite solid, m .p. 154–158 °C. 1H NMR (300 MHz, CDCl3): 2.85–2.73 m , 1 H (-CH-C(O));
3.17–3.01 m , 2 H (N-CH-, -CH-C(O)); 3.64–3.54 m , 1 H (N-CH-); 5.09 s, 1 H (-CH-Ph );
6.85–6.83 m , 1 H (arom atic); 7.04–7.00 m , 1 H (arom atic); 7.30–7.23 m , 1 H (arom atic);
7.42–7.37 m , 5 H (arom atic); 7.60 d, 1 H, J = 7.8 (arom atic). 13C NMR (75 MHz, CDCl3):
36.61, 52.21, 74.42, 112.72, 123.73, 124.82, 128.37, 128.59, 128.68, 128.82, 133.67, 135.01,
138.28, 162.60. IR (n eat): 1687, 1603, 1482, 1463, 761, 698. HRMS (ESI): calculated for
C
16H14N2O (M + Na)+ 273.0998, foun d 273.0997.
5-(4-Ch loroph en yl)-2,3-dih ydro-1H,5H-pyrazolo[1,2-a]in dazol-1-on e (6b)
Wh ite solid, m .p. 142–144 °C. 1H NMR (300 MHz, CDCl3): 2.86–2.77 m , 1 H (-CH-C(O));
3.16–3.02 m , 2 H (N-CH-, -CH-C(O)); 3.64–3.57 m , 1 H (N-CH-); 5.09 s, 1 H (-CH-Ph -Cl);
6.82 d, 1 H, J = 7.8 (arom atic); 7.07–7.02 m , 1 H (arom atic); 7.34–7.26 m , 1 H (arom atic);
7.38 m , 4 H (arom atic); 7.61 d, 1 H, J = 7.8 (arom atic). 13C NMR (75 MHz, CDCl3): 36.54,
52.21, 73.75, 112.79, 123.58, 124.87, 128.88, 129.02, 129.67, 133.62, 124.47, 134.53,
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

Synthesis of Indazole Derivatives
969
136.97, 162.55. IR (n eat): 1688, 1605, 1478, 1403, 1089, 845, 747. HRMS (ESI): calculated for
C
16H13ClN2O (M + Na)+ 307.0609, foun d 307.0608.
5-(2-Brom oph en yl)-2,3-dih ydro-1H,5H-pyrazolo[1,2-a]in dazol-1-on e (6c)
Colorless oil. 1H NMR (300 MHz, CDCl3): 2.84–2.77 m , 1 H (-CH-C(O)); 3.14–3.02 m , 1 H
(-CH-C(O)); 3.32–3.22 m , 1 H (N-CH-); 3.66–3.60 m , 1 H (N-CH-); 5.78 s, 1 H (-CH-Ph -Br);
7.06–6.97 m , 2 H (arom atic); 7.35–7.20 m , 3 H (arom atic); 7.65–7.56 m , 3 H (arom atic).
13C NMR (75 MHz, CDCl3): 36.58, 52.60, 72.27, 112.74, 123.98, 124.10, 124.77, 128.05,
128.78, 129.78, 130.34, 132.85, 133.84, 133.86, 138.12, 162.83. IR (n eat): 1687, 1604, 1483,
1463, 1404, 1025, 744. HRMS (ESI): calculated for C16H13BrN2O (M + Na)+ 351.0103, foun d
351.0103.
2,3-Dih ydro-5-(4-m eth ylph en yl)-1H,5H-pyrazolo[1,2-a]in dazol-1-on e (6d )
Yellowish solid, m .p. 155–160 °C. 1H NMR (300 MHz, CDCl3): 2.82 s, 3 H (-CH3); 2.86–2.76 m ,
1 H (-CH-C(O)); 3.18–3.01 m , 2 H (N-CH-, -CH-C(O)); 3.63–3.53 m , 1 H (N-CH-); 5.08 s, 1 H
(-CH-Ph -Me); 6.86 d, 1 H, J = 7.5 (arom atic); 7.04 dd, 1 H, J1 = 7.5, J2 = 7.5 (arom atic);
7.32–7.20 m , 5 H (arom atic); 7.62 d, 1 H, J = 7.5 (arom atic). 13C NMR (75 MHz, CDCl3):
21.16, 36.62, 52.10, 74.20, 112.71, 123.73, 124.78, 128.31, 128.60, 129.51, 133.72, 135.21,
135.22, 138.44, 162.56. IR (n eat): 1688, 1604, 1478, 1404, 842, 803. HRMS (ESI): calculated
for C17H16N2O (M + Na)+ 287.1155, foun d 287.1155.
2,3-Dih ydro-5-(2-m eth ylph en yl)-1H,5H-pyrazolo[1,2-a]in dazol-1-on e (6e)
Wh ite solid, m .p. 129–133 °C. 1H NMR (500 MHz, CDCl3): 2.41 s, 3 H (-CH3); 2.85–2.80 m ,
1 H (-CH-C(O)); 3.19–3.06 m , 2 H (N-CH-, -CH-C(O)); 3.63–3.59 m , 1 H (N-CH-); 5.41 s, 1 H
(-CH-Ph -Me); 6.84 d, 1 H, J = 7.5 (arom atic); 7.04 dd, 1 H, J1 = 7.5, J2 = 7.5 (arom atic);
7.31–7.24 m , 4 H (arom atic); 7.46 d, 1 H, J = 7.5 (arom atic); 7.65 d, 1 H, J = 7.5 (arom atic).
13C NMR (125 MHz, CDCl3): 19.55, 36.70, 52.56, 71.63, 112.76, 123.45, 124.76, 126.44,
128.22, 128.54, 129.09, 130.94, 133.90, 134.94, 136.01, 136.77, 162.67. IR (n eat): 1683,
1603, 1483, 1412, 1065, 761. HRMS (ESI): calculated for C17H16N2O (M + Na)+ 287.1155,
foun d 287.1153.
5-(2-Brom o-4-m eth ylph en yl)-2,3-dih ydro-1H,5H-pyrazolo[1,2-a]in dazol-1-on e (6f)
Yellowish solid, m .p. 116–118 °C. 1H NMR (300 MHz, CDCl3): 2.34 s, 3 H (-CH3); 2.84–2.75 m ,
1 H (-CH-C(O)); 3.12–3.00 m , 1 H (-CH-C(O)); 3.30–3.21 m , 1 H (N-CH-); 3.63–3.57 m , 1 H
(N-CH-); 5.73 s, 1 H (-CH-Ph -Me(Br)); 6.96 d, 1 H, J = 7.8 (arom atic); 7.04 dd, 1 H, J1 = 6.9,
J2 = 6.9 (arom atic); 7.14 d, 1 H, J = 6.9 (arom atic); 7.29 dd, 1 H, J3 = 7.5, J4 = 7.5 (arom atic);
7.42 d, 1 H, J = 7.8 (arom atic); 7.46 m , 1 H (arom atic); 7.62 d, 1 H, J = 7.8 (arom atic).
13C NMR (75 MHz, CDCl3): 20.74, 36.58, 52.50, 72.04, 112.74, 123.95, 123.98, 124.78,
128.71, 128.96, 130.05, 133.23, 133.90, 134.15, 134.96, 140.15, 162.83. IR (n eat): 1686,
1601, 1480, 1408, 1067, 752. HRMS (ESI): calculated for C17H15BrN2O (M + Na)+ 365.0260,
foun d 365.0260.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

970
Jin, Yang, Yamamoto:
2,3-Dih ydro-5-(E)-styryl-1H,5H-pyrazolo[1,2-a]in dazol-1-on e (6g)
Yellow solid, m .p. 128–132 °C. 1H NMR (500 MHz, CDCl3): 2.84–2.77 m , 1 H (-CH-C(O));
3.15–3.06 m , 2 H (-CH-C(O), N-CH-); 3.77–3.70 m , 1 H (N-CH-); 4.74 s, 1 H, J2 = 8.0
(-CH-styryl); 6.32 dd, 1 H, J1 = 16.0, J2 = 8.0 (-CH=); 6.73 d, 1 H, J1 = 16.0 (=CHPh ); 7.10 d,
2 H, J3 = 4.5 (arom atic); 7.32–7.29 m , 2 H (arom atic); 7.36 dd, 2 H, J = 7.0, J = 7.0 (aro-
m atic); 7.46 d, 2 H, J = 7.0 (arom atic); 7.60 d, 1 H, J = 7.0 (arom atic). 13C NMR (125 MHz,
CDCl3): 36.53, 52.17, 73.19, 112.96, 123.50, 124.78, 125.83, 126.68, 128.29, 128.69, 128.85,
133.70, 133.87, 134.67, 135.86, 162.64. IR (n eat): 1672, 1605, 1485, 1459, 1410, 1074, 750.
HRMS (ESI): calculated for C18H16N2O (M + Na)+ 299.1155, foun d 299.1154.
5-(2-Brom oph en yl)-2,3-dih ydro-9-m eth oxy-1H,5H-pyrazolo[1,2,a]in dazol-1-on e (6h )
Wh ite solid, m .p. 180–183 °C. 1H NMR (500 MHz, CDCl3): 2.77–2.72 m , 1 H (-CH-C(O));
2.92–2.85 m , 1 H (-CH-C(O)); 3.31–3.25 m , 1 H (N-CH-); 3.42–3.38 m , 1 H (N-CH-); 3.55 s,
3 H (-OCH3); 5.88 s, 1 H (-CH-Ph Br); 6.58- 6.56 m , 1 H (arom atic); 7.14–7.11 m , 2 H (aro-
m atic); 7.28–7.20 m , 3 H (arom atic); 7.56–7.55 m , 1 H (arom atic). 13C NMR (125 MHz,
CDCl3): 36.45, 51.90, 55.47, 69.64, 105.52, 107.71, 119.93, 124.53, 127.74, 129.48, 130.41,
130.79, 132.63, 135.88, 137.55, 155.44, 163.72. IR (n eat): 2841, 1688, 1600, 1471, 1394,
1264, 1084, 765. HRMS (ESI): calculated for C17H15BrN2O2 (M + Na)+ 381.0209, foun d
381.0209.
7-(2-Brom oph en yl)-8,9-dih ydro-7H-7a,10a-diazapen talen o[1,2-a]n aph th alen -10-on e (6i′)
Yellowish solid, m .p. 74–77 °C. 1H NMR (500 MHz, CDCl3): 2.97–2.91 m , 1 H (-CH-C(O));
3.25–3.17 m , 1 H (-CH-C(O)); 3.41–3.35 m , 1 H (N-CH-); 3.71–3.67 m , 1 H (N-CH-); 5.98 s,
1 H (-CH-Ph Br); 7.02 d, 1 H, J = 8.5 (arom atic); 7.22 dd, 1 H, J1 = 7.5, J1 = 7.5 (arom atic);
7.31 dd, 1 H, J1 = 7.5, J1 = 7.5 (arom atic); 7.60–7.48 m , 4 H (arom atic); 7.66 d, 1 H, J1 = 7.5
(arom atic); 7.79 d, 1 H, J1 = 7.5 (arom atic); 8.98 d, 1 H, J = 8.5 (arom atic). 13C NMR
(125 MHz, CDCl3): 36.76, 51.86, 73.07, 120.73, 121.73, 124.36, 126.42, 126.54, 126.67,
126.99, 127.92, 128.11, 129.85, 130.68, 130.73, 131.95, 132.89, 134.23, 138.31, 163.74.
IR (n eat): 3059, 2845, 1686, 1408, 1355, 1095, 1024, 808, 752. HRMS (ESI): calculated for
C
20H15BrN2O (M + Na)+ 401.0260, foun d 401.0260.
10-(2-Brom oph en yl)-8,9-dih ydro-10H-6b,9a-diazapen talen o[2,1-a]n aph th alen -7-on e (6i)
Yellow solid, m .p. 71–75 °C. 1H NMR (500 MHz, CDCl3): 2.88–2.82 m , 1 H (-CH-C(O));
3.03–2.95 m , 1 H (-CH-C(O)); 3.46–3.40 m , 1 H (N-CH-); 3.58–3.51 m , 1 H (N-CH-); 6.38 s,
1 H (-CH-Ph Br); 7.07 d, 2 H, J = 8.5 (arom atic); 7.21–7.19 m , 2 H (arom atic); 7.39–7.26 m ,
2 H (arom atic); 7.71–7.68 m , 1 H (arom atic); 7.80 d, 1 H, J = 8.5 (arom atic); 7.90 d, 1 H, J =
8.5 (arom atic); 7.95 d, 1 H, J= 8.5 (arom atic). 13C NMR (125 MHz, CDCl3): 36.44, 51.90,
71.01, 112.59, 123.05, 124.37, 124.72, 125.32, 127.36, 128.33, 128.82, 129.00, 130.07,
130.51, 131.29, 131.74, 132.91, 132.93, 137.75, 163.73. IR (n eat): 3056, 2850, 1692, 1519,
1472, 1407, 1067, 1025, 812, 738. HRMS (ESI): calculated for C20H15BrN2O (M + Na)+
401.0260, foun d 401.0261.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

Synthesis of Indazole Derivatives
971
9-(2-Brom oph en yl)-1,2,5,6,7,9-h exah ydro-3a,9a-diazacyclopen ta[a]-s-in dacen -3-on e (6j)
Yellow solid, m .p. 149–150 °C. 1H NMR (500 MHz, CDCl3): 2.08–2.01 m , 2 H (Ar-C-CH2-C-Ar);
2.90–2.72 m , 5 H (-CH-C(O), Ar-CH2-C-CH2-Ar)); 3.09–3.02 m , 1 H (-CH-C(O)); 3.26–3.20 m ,
1 H (N-CH-); 3.61–3.57 m , 1 H (N-CH-); 5.70 s, 1 H (-CH-Ph Br); 6.78 s, 1 H (arom atic);
7.22–7.18 m , 1 H (arom atic); 7.34–7.31 m , 1 H (arom atic); 7.50 s, 1 H (arom atic); 7.63–7.58 m ,
2 H (arom atic). 13C NMR (125 MHz, CDCl3): 25.72, 32.42, 32.74, 36.52, 52.50, 72.24,
109.03, 119.70, 124.10, 128.04, 129.65, 130.36, 132.36, 132.45, 132.78, 138.48, 141.09,
145.24, 162.35. IR (n eat): 1696, 1608, 1482, 1405, 1314, 1083, 762. HRMS (ESI): calculated
for C19H17BrN2O (M + Na)+ 391.0416, foun d 391.0416.
W e thank the Instrumental Analysis Center at Tohoku University for the measurements of
NMR spectra and mass spectra.
REFERENCES AND NOTES
1. a) Wrobleski S. T., Chen P., Hynes J., Jr., Lin S., Norris D. J., Pandit C. R., Spergel S., Wu H.,
Tokarski J. S., Chen X., Gilloly K. M., Kiener P. A., McIntyre K. W., Patil-Koota V.,
Shuster D. J., Turk L. A., Yang G., Leftheris K.: J. Med. Chem. 2003, 46, 2110;
b) Bermudez J., Fake C. S., Joiner G. F., Joiner K. A., King F. D., Miner W. D., Sanger G. J.:
J. Med. Chem. 1997, 33, 1924; c) Boehm H.-J., Boehringer M., Bur D., Gmuender H.,
Huber W., Klaus W., Kostrwa D., Kuehne H., Luebbers T., Meunier-Keller N., Mueller F.:
J. Med. Chem. 2000, 43, 2664; d) Corsi G., Palazzo G., Germani C., Barcellona P. S.,
Silvestrini B.: J. Med. Chem. 1976, 19, 778; e) Bistochi G. A., De Meo G., Pedini M.,
Ricci A., Brouilhet H., Bucherie S., Rabaud M., Jacquignon P.: Farmaco Ed. Sci. 1981, 36,
315.
2. a) Stadlbauer W.: Sci. Synthesis 2002, 12, 227; b) Jacobson P., Huber L.: Ber. Dtsch. Chem.
Ges. 1908, 41, 660; c) Rüchardt C., Hassmann V.: Liebigs Ann. Chem. 1980, 908;
d) Yoshida T., Matsuura N., Yamamoto K., Doi M., Shimada K., Morie T., Kato S.:
Heterocycles 1996, 43, 2701; e) Caron S., Vazquez E.: Synthesis 1999, 588; f) Jukin K., Hsu
M. C., Fernando D., Leanna M. R.: J. Org. Chem. 2006, 71, 8166; g) Elguero J. in:
Comprehensive Heterocyclic Chemistry (A. R. Katrizky and C. W. Rees, Eds), Vol. 5, pp.
167–303. Pergamon, New York 1984.
3. a) Baum G., Bernard R., Shechter H.: J. Am. Chem. Soc. 1967, 89, 5307; b) Baum G.,
Shechter H.: J. Org. Chem. 1976, 41, 2120; c) Yamazaki T., Shechter H.: Tetrahedron Lett.
1972, 13, 4533; d) Yamazaki T., Shechter H.: Tetrahedron Lett. 1973, 14, 1417;
e) Yamazaki T., Baum G., Shechter H.: Tetrahedron Lett. 1974, 15, 4421.
4. a) Huisgen R., Knorr R.: Naturwissenschaften 1961, 48, 716; b) Taylor E. C., Sobieray D. M.:
Tetrahedron 1991, 47, 9599.
5. Himeshima Y., Sonoda T., Kobayashi H.: Chem. Lett. 1983, 1211.
6. a) Kitamura T., Yamane M.: J. Chem. Soc., Chem. Commun. 1995, 983; b) Peñ a D.,
Escudero S., Pérez D., Guitián E., Castedo L.: Angew. Chem., Int. Ed. 1998, 37, 2659;
c) Yoshikawa E., Radhakrishnan K. V., Yamamoto Y.: J. Am. Chem. Soc. 2000, 122, 7280;
d) Yoshikawa E., Yamamoto Y.: Angew. Chem. Int. Ed. 2000, 39, 173; e) Yoshikawa E.,
Radhakrishnan K. V., Yamamoto Y.: Tetrahedron Lett. 2000, 41, 729; f) Radhakrishnan
K. V., Yoshikawa E., Yamamoto Y.: Tetrahedron Lett. 1999, 40, 7533; g) Yoshida H.,
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972

972
Jin, Yang, Yamamoto:
Watanabe M., Fukushima H., Ohshita J., Kunai A.: Org. Lett. 2004, 6, 4049; h) Yoshida H.,
Fukushima H., Ohshita J., Kunai A.: Angew. Chem. Int. Ed. 2004, 43, 3935; i) Yoshida H.,
Fukushima H., Ohshita J., Kunai A.: J. Am. Chem. Soc. 2006, 128, 11040.
7. a) Yoshida H., Shirakawa E., Honda Y., Hiyama T.: Angew. Chem. Int. Ed. 2002, 41, 3247;
b) Yoshida H., Watanabe M., Ohshita J., Kunai A.: Chem. Commun. 2005, 3292; c) Peñ a D.,
Pérez D., Guitián E.: Angew. Chem. Int. Ed. 2006, 45, 2; and references therein; d) Liu Z.,
Larock R. C.: Org. Lett. 2003, 5, 4673; e) Liu Z., Larock R. C.: J. Org. Chem. 2006, 71, 3198.
8. a) Jin T., Kamijo S., Yamamoto Y.: Tetrahedron Lett. 2004, 45, 9435; b) Kamijo S., Jin T.,
Yamamoto Y.: J. Org. Chem. 2002, 67, 7413; c) Jin T., Kamijo S., Yamamoto Y.: Eur. J.
Org. Chem. 2004, 3789; d) Kamijo S., Jin T., Huo Z., Yamamoto Y.: J. Org. Chem. 2004,
69, 2386; e) Kamijo S., Jin T., Huo Z., Yamamoto Y.: J. Am. Chem. Soc. 2003, 125, 7786.
9. a) Jin T., Yamamoto Y.: Angew. Chem. Int. Ed. 2007, 46, 3323; b) Liu Z., Shi F., Martinez
P. D. G., Raminelli C., Larock R. C.: J. Org. Chem. 2008, 73, 219.
10. a)The 1H and 13C NMR spectra of compound 3a are identical with the literature data.
Shmidt A., Merkel L., Eisfeld W.: Eur. J. Org. Chem. 2005, 2124; b) The structures of 3e,
3f, 3f′, 3g, 3g′ and 4d were unambiguously confirmed by spectroscopic methods,
especially by NOE, COSY and HMBC analysis, see ref.9a
.
11. Recent examples for the synthesis of 1-aryl-1H-indazoles, see: a) Lebedev A. Y.,
Khartulyari A. S., Voskoboynikov A. Z.: J. Org. Chem. 2005, 70, 596; b) Cho C. S., Lim D. K.,
Heo N. H., Kim T.-J., Shim S. C.: Chem. Commun. 2004, 104; c) Song J. J., Yee N. K.,
Tetrahedron Lett. 2001, 42, 2937.
12. For N-arylation of indazoles, see: a) Antilla J. C., Baskin J. M., Barder T. E., Buchwald
S. L.: J. Org. Chem. 2004, 69, 5578; b) Collot V., Bovy P. R., Rault S.: Tetrahedron Lett.
2000, 41, 9053.
13. a) Shintani R., Fu G. C.: J. Am. Chem. Soc. 2003, 125, 10778; b) Dorn H., Otto A.: Chem.
Ber. 1968, 101, 3287; c) Dorn H., Otto A.: Angew. Chem., Int. Ed. Engl. 1968, 7, 214.
14. a) Peñ a D., Pérez D., Guitián E., Castedo L.: J. Am. Chem. Soc. 1999, 121, 5827; b) Peñ a D.,
Pérez D., Guitián E., Castedo L.: J. Org. Chem. 2000, 65, 6944.
15. Yoshida H., Sugiura S., Kunai A.: Org. Lett. 2002, 4, 2767.
16. Zrig S., Andrioletti B., Rose E., Colin J.: Tetrahedron Lett. 2005, 46, 1103.
17. Su G., Mu H., Za D., Zeng L., Cativiela C., Hammer R. P., Yu K.: Synth. Commun. 2003,
33, 2873.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 957–972