Synthetic studies of the formation of pyrazoloisoquinolines

Article abstract of DOI:10.1016/S0040-4020(02)00587-2

Diazotization of 7-amino-5,8-dimethyl-6-(phenylthio)isoquinoline unexpectedly led to the formation of a new ring system, 3H-pyrazolo[3,4-h]isoquinoline as its 5-methyl-6-phenylthio derivative. In this work, the parent ring system was synthesized and chara

Full text of DOI:10.1016/S0040-4020(02)00587-2

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 6061±6067
Synthetic studies of the formation of pyrazoloisoquinolines
²
R. Bryan Miller, Joseph G. Stowell, Sundeep Dugar, Thomas E. Moock, Christopher W. Jenks,p
Steven C. Farmer, Bach Phan, Chad E. Wujcik and Marilyn M. Olmstead
Department of Chemistry, University of California, Davis, CA 95616 USA
Received 7 March 2002; revised 1 June 2002; accepted 6 June 2002
AbstractÐDiazotization of 7-amino-5,8-dimethyl-6-(phenylthio)isoquinoline unexpectedly led to the formation of a new ring system, 3H-
pyrazolo[3,4-h]isoquinoline as its 5-methyl-6-phenylthio derivative. In this work, the parent ring system was synthesized and characterized,
along with its 5-methyl, 6-bromo-5-methyl, and 5-methyl-6-phenylthio derivatives. The mechanism for the transformation is explored.
q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
It was discovered long ago that 2-methylaniline 1
(R1ˆR2ˆH) formed indazole 2 (R1ˆR2ˆH) in very low
yield when diazotized in AcOH (Scheme 1). Yields were
improved when the amine 1 bore an electron-withdrawing
substituent for R1 or R2, when the pH was increased, or
when the reaction was carried out in chloroform in the
presence of tetramethylammonium acetate.1
An improved method of cyclization converted amide 3 into
nitroso derivative 4, which then cyclized to indazole 2 upon
Scheme 2. (a) NOCl, Ac2O, HOAc, NaOAc. (b) Anhydrous benzene, heat.
heating in anhydrous benzene (Scheme 2).2 Good yields
were generally obtained with a variety of substituents, and
line 5c was diazotized in cold AcOH and then treated with
NaN3 (Scheme 3). Instead of the expected azide 8, a mixture
was obtained, containing as its major component the
pyrazoloisoquinoline 6c, which contains a new ring system.6
consequently this indazole synthesis has been popular.
Successful substrates similar to those in this article include
aminomethylpyridines,3 1-methyl-2-naphthylamine4 and
3-amino-4-methylquinoline.5 Unfortunately, the method is
less convenient, more hazardous, and more costly than
simple diazotization of the amine in AcOH.
Although the biological properties of 6c are unexplored,
isomeric pyrazoloisoquinolines have shown promise as anti-
biotics,7 anti-in¯ammatory agents,8 and benzodiazepine
antagonists.9 The unexpected conversion of isoquinoline
5c into pyrazoloisoquinoline 6c without the presence of an
electron-withdrawing group suggests that the improved
method through the nitroso derivative may not be necessary
for isoquinolines, or even polycyclic systems in general.
The present paper explores which substituents on iso-
quinoline are necessary to allow pyrazoloisoquinolines to
form, and therefore begins with the synthesis of a series of
isoquinolines with varying substituents at the 5 and 6
positions.
As part of testing a route to isoellipticine 9, adaptable to the
synthesis of 9-substituted ellipticines 7, the aminoisoquino-
Scheme 1.
Keywords: indazoles; isoquinolines; cyclisation; diazo compounds.
Corresponding author. Tel.: 11-530-759-8855;
2. Results and discussion
p
e-mail: chris@jenks.name
Deceased.
²
A practical route to aminoisoquinoline 5c was developed,
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00587-2

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R. B. Miller et al. / Tetrahedron 58 (2002) 6061±6067
Scheme 3.
Scheme 4.
beginning with cyclization of substituted xylene 10b to
5-bromo-4,7-dimethylindanone (11b, Scheme 4). Subse-
quent nitration with fuming nitric acid gave nitroindanone
12b, which was then reduced to indanol 13b. Dehydration
with catalytic p-TsOH in re¯uxing benzene led to indene
14b. Ozonolysis in the presence of MeOH, followed by
reduction with Me2S and treatment with conc. NH4OH
furnished 6-bromo-5,8-dimethyl-7-nitroisoquinoline 15b
in 89% yield. Treatment of isoquinoline 15b with NaSPh
in hot DMF led to 5,8-dimethyl-7-nitro-6-(phenylthio)iso-
quinoline 15c. Limiting the reaction time prevented dis-
placement of the nitro group by thiophenoxide. Reduction
of the nitro group using hydrazine and catalytic Raney
nickel in re¯uxing EtOH gave amine 5c in 33% overall
yield. Similar processes were used to prepare 7-amino-
5,8-dimethylisoquinoline 5a (54%) and 7-amino-6-bromo-
5,8-dimethylisoquinoline 5b (35%) from 10a and 10b,
respectively.
of imine 17 using hot H2SO4/P2O5 (Scheme 5). The cycliza-
tion step gave very poor yield (8.5, 6.6% overall) and purity
of product.
In attempting to prepare azide 8 as a precursor to isoellipti-
cide 9 (Scheme 3), diazotization of 7-amino-5,8-dimethyl-
The fortunate availability of 3-acetamido-2-methylbenzal-
dehyde10 16 allowed convenient synthesis of 7-amino-8-
methylisoquinoline 5d through condensation with amino-
acetaldehyde diethyl acetal and subsequent cyclization11
Scheme 5.

R. B. Miller et al. / Tetrahedron 58 (2002) 6061±6067
6063
Scheme 6.
Table 1. Diazotization of 5c (XˆSPh) under various conditions
Structure
HOAc, no azidea (%)
HOAc1azideb (%)
HCl, no azidea (%)
HCl1azideb (%)
5c
6c
18
8
20
58
21
0
7
5
68
27
0
21
2
1
75
32
36
25
Yields were determined by 1H NMR of the crude reaction mixture. Structures 5c, 6c, 18 and 8 accounted for almost all the peaks, so the total of their
integrations was de®ned as 100% yield.
a
Aqueous ammonia was added the day following diazotization.
Azide was added 10 min after diazotization.
b
6-(phenylthio)-isoquinoline 5c in cold AcOH led instead to
mixture of 5-methyl-6-phenylthio-3H-pyrazolo[3,4-
try AcOH as a solvent. The ratio of 6c and 18 in HOAc (58±
21%) was different when the reaction was run on a larger
scale (41±34% following chromatography), possibly
because the concentration of water in the reaction was
lower. The ratio was also affected by the presence of
NaN3, perhaps due to increased pH.
a
h]isoquinoline 6c and thiaellipticine12 18 (Scheme 6).
Attempts to add NaN3 solution quickly after diazotization
usually led to the same mixture and little or no azide
derivative 8. Although the azide derivative 8 did form in
one instance, this result could not be reproduced. In dilute
HCl, however, clean conversion to azide 8 was obtained.
The other aminoisoquinolines (5a, 5b, 5d) were diazotized
in AcOH in the same manner as 5c (Table 2). Since
electron-withdrawing groups facilitate cyclization of aniline
derivatives,1 it was surprising that the bromo group (5b) led
to a lower yield than the corresponding unbrominated
substrate 5a. On the other hand, 7-amino-8-methylisoquino-
line 5d produced the prototype ring system 6d in excellent
yield (96%), showing that a substituent at the 6-positon is
unnecessary for cyclization.
The effects of acid type and of added NaN3 are demon-
strated in Table 1. The purpose of adding azide was to
show the extent of cyclization after 10 min of reaction.
Cyclization was mostly complete in acetic acid after
10 min, but in HCl the reaction took overnight. The yields
of cyclization products (6c and 18) were higher in HCl, and
this may be the acid of choice for some substrates, but poor
solubility of amine 5c in HCl was the original motivation to
Based on studies of the formation of indazole,2 the expected
mechanism involves diazotization followed by deprotona-
tion of the ortho methyl group which is facilitated by the
strongly electron-withdrawing diazo group and any other
groups in a position to withdraw electrons through
Table 2. Cyclization of diazotized aminoisoquinolines 5a±d
Product
X
R
% Yield
6a
6b
6c
6d
H
Br
SPh
H
C
H
83
66
3
CH3
CH3
H
41a
96
a
Plus 34% thiaellipticine 18.
Scheme 7.

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R. B. Miller et al. / Tetrahedron 58 (2002) 6061±6067
resonance. In the case of isoquinolines, deprotonation may
be facilitated by the electron-accepting ability of the ring
nitrogen when protonated (Scheme 7). The need for a base
to initiate the cyclization explains the sluggishness of
cyclization in strong acid.
1105 cm21. Anal. calcd for C11H11NO3: C, 64.38; H, 5.40;
N, 6.83. Found: C, 64.24; H, 5.43; N, 6.77.
3.1.3.
5-Bromo-2,3-dihydro-4,7-dimethyl-6-nitro-1H-
indene-1-one (12b, XˆBr). Chromatography on Florisile
(2:3 CH2Cl2/pentane) gave white solid (66% yield): mp
(MeOH) 159±1618C; H NMR d 2.44 (s, 3H), 2.54 (s,
1
The present work establishes that 7-amino-8-methyliso-
quinolines, which may bear various substituents, cyclize
to pyrazoloisoquinolines in good yield upon diazotization,
unlike most 2-methylanilines 1.
3H), 2.75 (br t, 2H, Jˆ6.0 Hz), 3.08 (br t, 2H, Jˆ6.0 Hz);
13CNMR d 11.9, 18.2, 25.1, 36.8, 120.6, 128.0, 133.5,
135.4, 152.2, 155.9, 205.7; IR (CH2Cl2) 1710, 1640, 1565,
1540, 1380, 1110 cm21. Anal. calcd for C11H10BrNO3: C ,
46.50; H, 3.55; N, 4.93. Found: C, 46.48; H, 3.62; N, 4.88.
3. Experimental
3.1. General
3.1.4. 2,3-Dihydro-4,7-dimethyl-6-nitro-1H-indene-1-ol
(13a, XˆH). A solution of 12a (0.2196 g, 1.07 mmol) in
MeOH (11 mL) was cooled in an ice bath and NaBH4
(0.0607 g, 1.61 mmol) was added over 2 min with stirring.
After 10 min the solvent was evaporated without heating
and H2O (10 mL) was added. The aqueous mixture was
extracted with EtOAc and the combined organic layers
were washed with brine and poured through a ®lter contain-
ing anhyd Na2SO4, decolorizing carbon, and silica gel. The
®ltrate was evaporated to give 0.2142 g (97% yield) of 13a
(XˆH) as light yellow solid: mp 71±728C; 1H NMR d 1.99
(bs, 1H), 2.09±2.18 (m, 1H), 2.28 (s, 3H), 2.35±2.49 (m,
1H), 2.56 (s, 3H), 2.81 (ddd, 1H, Jˆ17.1, 9.7, 2.7 Hz),
3.03±3.14 (m, 1H), 5.36 (d, 1H, Jˆ6.0 Hz), 7.68 (s, 1H);
13CNMR d 15.3, 18.4, 29.2, 34.6, 75.1, 125.7, 128.1, 132.6,
145.1, 148.5, 148.7; IR 3245br, 1518, 1442, 1346, 1047,
Reactions were generally run unprotected from the air. IR
spectra were taken on NaCl, and NMR spectra were taken in
CDCl3, unless noted otherwise. Silica gel used for chroma-
tography was 230±400 mesh.
3.1.1. 5-Bromo-2,3-dihydro-4,7-dimethyl-1H-indene-1-
one (11b, XˆBr). A solution of 1-bromo-2,5-dimethyl-
benzene (10b, XˆBr) (37.0 g, 200 mmol) and 3-chloro-
propionyl chloride (24.46 g, 210 mmol) in 50 mL of CS2
was added slowly over 1 h to a powerfully stirred slurry
of AlCl3 (30.0 g, 240 mmol) in 150 mL of CS2 under a
dry atmosphere. After 16 h, the solvent was removed
under reduced pressure and 250 mL of conc. H2SO4 was
added slowly. Constant vigorous stirring was required to
contain the foaming. The mixture was stirred at 808Cfor
1 h, after which the evolution of gas subsided. The cooled
mixture was quenched with 250 g of crushed ice and
extracted with CH2Cl2. The combined extracts were washed
with saturated NaHCO3, dried (Na2SO4) and evaporated to a
dark residue. Chromatography through 300 g of Florisile
(3:7 CH2Cl2/pentane) gave 40.3 g (85% yield) of light
yellow solid. Recrystallization (MeOH) gave light yellow
needles of 11b (XˆBr): mp 105±1068C; 1H NMR d 2.31 (s,
3H), 2.52 (s, 3H), 2.62 (br t, 2H, Jˆ5.3 Hz), 2.94 (br t, 2H,
Jˆ5.3 Hz), and 7.26 (s, 1H); 13CNMR d 17.3, 25.0, 30.7,
36.6, 131.0, 132.6, 132.9, 133.2, 136.7, 155.7, 206.9; IR
(capillary melt) 1700, 1565, 1465, 1255, 1185 cm21. Anal.
calcd for C11H11OBr: C, 55.25; H, 4.63. Found: C, 55.17; H,
4.67.
969 cm21
.
3.1.5.
5-Bromo-2,3-dihydro-4,7-dimethyl-6-nitro-1H-
indene-1-ol (13b, XˆBr). Crude product was yellow solid
(99% yield). Recrystallization (MeOH) gave large yellow
hexagonal rods: mp 162±162.58C; 1H NMR d 1.74 (s, 1H),
2.10 (qt, 1H, Jˆ9.3, 3.4 Hz), 2.35 (s, 3H), 2.36 (s, 3H), 2.45
(d of sextets, 1H, Jˆ7.1, 1.9 Hz), 2.85 (dq, 1H, Jˆ9.0,
3.6 Hz), 3.13 (q, 1H, Jˆ8.1 Hz), 5.31 (dd, 1H, Jˆ6.9,
1
2.6 Hz); H NMR (acetone-d6) d 1.95±2.10 (m, 1H), 2.30
(s, 3H), 2.33 (s, 3H), 2.35±2.50 (m, 1H), 2.77±2.90 (m, 1H),
3.03±3.17 (m, 1H), 2.90 (br d, 1H, Jˆ4.3 Hz); 13CNMR
(acetone-d6) d 13.6, 19.6, 30.8, 35.4, 75.2, 114.0, 126.3,
134.1, 145.4, 146.7, 152.5, 206.5; IR (CH2Cl2) 3630,
2980, 1640, 1540, 1390, 1380 cm21
.
3.1.6. 4,7-Dimethyl-5-nitro-1H-indene (14a, XˆH). A
solution of 13a (0.2142 g, 1.03 mmol) in benzene
(2.5 mL) containing p-TsOH (0.0026 g, 0.01 mmol) was
heated to re¯ux, and the condensate was returned through
a Dean±Stark trap containing anhyd CaCl2 pellets. After
16 h, the reaction mixture was allowed to cool, and
EtOAc (15 mL) and H2O (15 mL) were added. The organic
layer was washed with brine and evaporated to a light brown
solid. Chromatography on silica gel (1:4 EtOAc/petroleum
ether) gave 0.1895 g (97% yield) of 14a (XˆH) as light
yellow solid. Recrystallization (heptane) gave ¯uffy yellow
needles: mp 62.5±63.58C; 1H NMR d 2.37 (s, 3H), 2.59 (s,
3H), 3.36 (t, 2H, Jˆ2.0 Hz), 6.70 (dt, 1H, Jˆ5.7, 2.0 Hz),
7.03 (dt, 1H, Jˆ5.7, 2.0 Hz), 7.61 (s, 1H); 13CNMR d 15.6,
18.2, 38.7, 122.0, 123.0, 130.2, 131.0, 135.6, 145.6, 147.2,
148.8; IR 1514, 1382, 1337br, 866, 755, 691 cm21. Anal.
calcd for C11H11NO2: C, 69.83; H, 5.86; N, 7.40. Found: C,
69.62; H, 5.86; N, 7.41.
3.1.2.
2,3-Dihydro-4,7-dimethyl-6-nitro-1H-indene-1-
one (12a, XˆH). Fuming 90% nitric acid (29 mL,
625 mmol) was cooled to 2208Cand 2,3-dihydro-4,7-
dimethyl-1H-indene-1-one13 (11a, XˆH) (2.502 g,
15.6 mmol) was added portionwise over 5 min with stirring.
After 5 min the reaction mixture was poured over ice and
extracted with 1:1 EtOAc/heptane. The combined extracts
were washed with saturated NaHCO3 until the washings
remained basic, then they were washed with brine, dried
(Na2SO4) and evaporated to a red±brown solid (3.7 g).
Chromatography on silica gel (CHCl3) gave 2.1058 g
(66% yield) of orange solid. Recrystallization (i-PrOH)
gave dark yellow needles of 12a (XˆH): mp 111.5±
1
112.58C; H NMR d 2.40 (s, 3H), 2.67 (s, 3H), 2.75 (t,
2H, Jˆ6.0 Hz), 3.04 (t, 2H, Jˆ6.0 Hz), 7.79 (s, 1H); 13C
NMR d 12.1, 16.9, 23.7, 36.7, 128.9, 130.4, 134.1, 134.8,
148.9, 159.0, 206.0; IR 1716, 1515, 1378, 1358, 1258,

R. B. Miller et al. / Tetrahedron 58 (2002) 6061±6067
6065
3.1.7. 6-Bromo-4,7-dimethyl-5-nitro-1H-indene (14b,
XˆBr). Chromatography on Florisile (2:3 CH2Cl2/
pentane) gave white solid (86% yield): mp (MeOH)
3.1.11. 7-Amino-5,8-dimethylisoquinoline (5a, XˆH). A
mixture of 15a (2.5535 g, 12.54 mmol), hydrazine mono-
hydrate (3.77 g, 75 mmol), and 80% Raney nickel in H2O
(1.13 g, 15 mmol) in EtOH (75 mL) was re¯uxed for 2 h, by
which time the reaction was con®rmed to be complete by
TLC. Most of the EtOH was boiled away, and the cooled
mixture was diluted with EtOAc and ®ltered through celite.
The ®ltrate was extracted with dilute HCl and the combined
aqueous layers were basi®ed with NaHCO3. The aqueous
mixture was extracted with EtOAc, dried (Na2SO4) and
evaporated to give 1.9979 g (92% yield) of orange solid.
Recrystallization (MeOH) gave 5a (XˆH) as ¯at orange
1
134±1358C; H NMR d 2.33 (s, 3H), 2.40 (s, 3H), 3.36
(br s, 2H), 6.69 (br d, 1H, Jˆ3.6 Hz), 6.90 (br d, 1H,
Jˆ3.9 Hz); 13CNMR d 13.9, 19.3, 39.7, 110.8, 120.3,
129.6, 132.0, 136.2, 143.4, 144.3, 151.5; IR (CH2Cl2)
2940, 1535, 1385, 950, 880 cm21. Anal. calcd for
C11H10BrNO2: C, 49.23; H, 3.76; N, 5.22. Found: C,
49.09; H, 3.85; N, 5.25.
3.1.8. 5,8-Dimethyl-7-nitroisoquinoline (15a, XˆH). A
solution of 14a (6.3083 g, 33.3 mmol) in MeOH (167 mL)
and CH2Cl2 (167 mL) was cooled to 2788Cand treated with
ozone until the solution turned blue. The solution was
purged with oxygen until the blue color disappeared, then
added to Me2S (16.7 mL) and NaHCO3 (3.33 g), and the
sealed ¯ask was stirred for 4 h at room temperature. Conc.
NH4OH (167 mL) was added and the resealed ¯ask was
stirred overnight. The mixture was mostly evaporated and
the remaining aqueous suspension was extracted with
CHCl3 and the combined organic layers were washed with
brine, dried (Na2SO4) and evaporated to give 6.3196 g (94%
yield) of orange±yellow solid. Recrystallization (EtOAc)
gave 15a (XˆH) as bright yellow needles: mp 161±
1
rods: mp 201.5±202.58C; H NMR d 2.45 (s, 3H), 2.56 (s,
3H), 3.88 (bs, 2H), 6.98 (s, 1H), 7.60 (d, 1H, Jˆ5.7 Hz),
8.35 (d, 1H, Jˆ5.7 Hz), 9.31 (s, 1H); 13CNMR d 10.6, 18.3,
110.6, 117.1, 123.0, 128.9, 130.3, 132.2, 139.4, 142.0,
147.8; IR 3197br, 1645, 1609, 1386, 874, 809 cm21. Anal.
calcd for C11H12N2: C, 76.71; H, 7.02; N, 16.27. Found: C,
76.55; H, 6.97; N, 16.23.
3.1.12. 7-Amino-6-bromo-5,8-dimethylisoquinoline (5b,
XˆBr). Chromatography on silica gel (2% MeOH/CHCl3)
gave yellow solid (82% yield). Recrystallization (CH3CN)
gave ¯uffy white clumps: mp 163±1648C; 1H NMR d 2.49
(s, 3H), 2.70 (s, 3H), 4.48 (bs, 2H), 7.60 (dd, 1H, Jˆ5.9,
0.6 Hz), 8.33 (d, 1H, Jˆ5.9 Hz), 9.28 (d, 1H, Jˆ0.6 Hz);
13CNMR d 12.0, 18.9, 111.9, 117.1, 120.6, 127.2, 129.4,
131.7, 139.9, 140.1, 148.0; IR 3328br, 1627, 1381, 1235,
1005, 805 cm21. Anal. calcd for C11H11BrN2: C, 52.61; H,
4.41; N, 11.16. Found: C, 52.96; H, 4.28; N, 11.42.
1
1628C; H NMR d 2.69 (s, 3H), 2.88 (s, 3H), 7.79 (m,
2H), 8.73 (d, 1H, Jˆ6.0 Hz), 9.63 (d, 1H, Jˆ0.6 Hz); 13C
NMR d 13.4, 18.3, 117.1, 124.3, 127.3, 128.6, 133.8, 136.8,
145.4, 147.7, 151.0; IR 1521, 1386, 1365, 1348, 879,
824 cm21. Anal. calcd for C11H10N2O2: C, 65.34; H, 4.98;
N, 13.85. Found: C, 65.37; H, 4.97; N, 13.87.
3.1.13. 7-Amino-5,8-dimethyl-6-(phenylthio)isoquinoline
(5c, XˆSPh). Crude product (82% yield) was recrystallized
(i-PrOH) to give dark yellow needles: mp 141±141.58C; 1H
NMR d 2.51 (s, 3H), 2.83 (s, 3H), 4.78 (bs, 2H), 7.00 (d, 2H,
Jˆ8.1 Hz), 7.11 (t, 1H, Jˆ7.2 Hz), 7.20 (t, 2H, Jˆ7.2 Hz),
7.69 (d, 1H, Jˆ6.0 Hz), 8.36 (d, 1H, Jˆ6.0 Hz), 9.37 (s,
1H); 13CNMR d 11.8, 17.1, 111.0, 117.8, 123.0, 125.6,
126.2, 128.8, 129.2, 129.3, 135.6, 139.1, 139.6, 144.2,
148.2; IR 3312, 1631, 1563, 1477, 1375, 738 cm21. Anal.
calcd for C17H16N2S: C, 72.82; H, 5.75; N, 9.99. Found: C,
72.85; H, 5.93; N, 9.96.
3.1.9. 6-Bromo-5,8-dimethyl-7-nitroisoquinoline (15b,
XˆBr). Chromatography on basic alumina (9:1 CH2Cl2/
petroleum ether) gave yellow-tan solid (89% yield).
Recrystallization (EtOAc) followed by sublimation gave
1
15b (XˆBr) as a pale yellow solid: mp 194±1978C; H
NMR d 2.65 (s, 3H), 2.76 (s, 3H), 7.78 (d, 1H,
Jˆ5.9 Hz), 8.70 (d, 1H, Jˆ6.0 Hz), 9.42 (s, 1H); 13C
NMR d 13.2, 18.6, 115.8, 117.2, 125.4, 125.8, 134.5,
135.3, 145.6, 150.2, 157.4; IR 1604, 1532, 1387,
835 cm21. Anal. calcd for C11H9BrN2O2: C, 47.17; H,
2.88; N, 10.00. Found: C, 46.84; H, 3.09; N, 9.72.
3.1.14. 5-Methyl-3H-pyrazolo[3,4-h]isoquinoline (6a,
XˆH, RˆCH3). A stirring solution of 5a (0.4516 g,
2.62 mmol) in AcOH (20.7 mL) was placed in an ice bath.
After 2 min a solution of NaNO2 (0.199 g, 2.88 mmol) in
H2O (2.62 mL) was added over 4 min. The ice bath was
allowed to warm to room temperature overnight. The dark
red solution was diluted with H2O (50 mL) and basi®ed
using dilute NH4OH. Once cool, the mixture was extracted
with CH2Cl2 and the organic layer was dried (Na2SO4) and
directly chromatographed on silica gel (0±5% MeOH/
CHCl3) to give 18 mg (4% recovery) of starting material
and 0.401 g (83% conversion, 87% yield based on recovered
starting material) of product. Recrystallization (CHCl3, then
MeOH) gave light brown needles of 6a (XˆH, RˆCH3)
which were further puri®ed by sublimation at 1558Cunder
high vacuum: mp 292±2938C(dec.); 1H NMR (Me2SO-d6)
d 2.66 (s, 3H), 7.76 (s, 1H), 7.86 (d, 1H, Jˆ5.7 Hz), 8.57 (d,
1H, Jˆ5.7 Hz), 8.70 (s, 1H), 9.70 (s, 1H), 13.50 (bs, 1H); 1H
NMR (CD3CO2D) d 2.58 (s, 3H), 7.76 (s, 1H), 8.08 (d, 1H,
Jˆ6.4 Hz), 8.51 (s, 1H), 8.58 (d, 1H, Jˆ6.4 Hz), 9.55 (s,
3.1.10. 5,8-Dimethyl-7-nitro-6-(phenylthio)isoquinoline
(15c, XˆSPh). A solution of 15b (141 mg, 0.500 mmol),
thiophenol (111 mg, 1.01 mmol), NaOMe (28.5 mg,
0.528 mmol) and DMF (3 mL) were heated on a steam
bath for 6 h. The cooled mixture was diluted with H2O
(25 mL) and extracted with Et2O. The combined extracts
were washed with saturated NaHCO3, H2O, and brine,
dried and evaporated to a tan solid. Chromatography on
basic alumina (8:1 CH2Cl2/hexanes) gave 146 mg (94%
yield) of yellow-beige solid. Recrystallization (MeOH)
gave 15c (XˆSPh) as light yellow needles: mp
1
155.5±156.58C; H NMR d 2.69 (s, 3H), 2.76 (s, 3H),
7.1±7.3 (m, 5H), 7.83 (d, 1H, Jˆ6.6 Hz), 8.72 (d, 1H,
Jˆ5.7 Hz) and 9.53 (s, 1H); 13CNMR d: 13.1, 16.7,
117.6, 124.6, 125.0, 126.5, 126.7, 128.0, 129.1, 135.2,
135.5, 140.9, 145.3, 150.2, 153.6; IR 1533, 1440, 1361,
837, 739, 684 cm21. Anal. calcd for C17H14N2O2S:
C, 65.69; H, 4.49; N, 8.97. Found: C, 65.79; H, 4.55; N,
9.03.

6066
R. B. Miller et al. / Tetrahedron 58 (2002) 6061±6067
1H); 13CNMR (CD 3CO2D) d 20.0, 116.8, 122.5, 123.1,
124.0, 132.8, 135.2, 136.0, 138.2, 141.2, 142.5; IR
3118br, 2901, 1611, 1260, 936, 848 cm21. Anal. calcd for
C11H9N3: C, 72.11; H, 4.95; N, 22.94. Found: C, 72.21; H,
4.91; N, 23.12.
wrapped in aluminum foil. The ice bath was allowed to
warm to room temperature overnight. EtOAc (40 mL) was
added to the clear yellow solution and the aqueous layer was
basi®ed by adding aqueous NaHCO3. The aqueous layer
was extracted with EtOAc, and the combined extracts
were washed with brine, dried (Na2SO4), ®ltered and evapo-
rated. Chromatography on silica gel (1:1 EtOAc/petroleum
ether) followed by recrystallization (EtOAc) gave 14.3 mg
(65% yield) of 8 as long yellow needles: mp 114±114.58C;
1H NMR d 2.78 (s, 3H), 2.87 (s, 3H), 7.05 (d, 2H,
Jˆ7.0 Hz), 7.15 (t, 1H, Jˆ7.3 Hz), 7.22 (t, 2H,
Jˆ7.4 Hz), 7.80 (dd, 1H, Jˆ5.9, 0.6 Hz), 8.62 (d, 1H,
Jˆ5.9 Hz), 9.48 (s, 1H); 13CNMR d 13.4, 17.1, 117.7,
126.0, 126.9, 127.0, 128.0, 129.2, 131.3, 133.8, 136.4,
138.7, 139.6, 143.4, 149.8; IR 2112, 1478, 1439, 1363,
3.1.15. 6-Bromo-5-methyl-3H-pyrazolo[3,4-h]isoquino-
line (6b, XˆBr, RˆCH3). Chromatography on silica gel
(0±7% MeOH/1% Et3N/CHCl3) gave 6b (XˆBr, RˆCH3)
as yellow solid (66% yield). Recrystallization (CHCl3) gave
1
yellow needles: mp .3008C; H NMR (Me2SO-d6) d 2.70
(s, 3H), 7.89 (d, 1H, Jˆ5.7 Hz), 8.57 (d, 1H, Jˆ5.7 Hz),
8.85 (bs, 1H), 9.66 (s, 1H), 13.84 (bs, 1H); 1H NMR
(CD3CO2D) d 2.84 (s, 3H), 8.41 (d, 1H, Jˆ6.5 Hz), 8.77
(d, 1H, Jˆ6.5 Hz), 8.91 (s, 1H), 9.84 (s, 1H); 13CNMR
(CD3CO2D) d 19.1, 117.1, 120.5, 123.8, 124.0, 132.9,
134.6, 137.2, 139.0, 143.1, 143.2; IR 1596, 1446, 1208,
936, 821, 716 cm21. Anal. calcd for C11H8BrN3: C, 50.41;
H, 3.08; N, 16.03. Found: C, 50.54; H, 3.04; N, 15.78.
1334, 741 cm21
.
3.2.2. 3-(2,2-Diethoxyethyliminomethyl)-2-methylaceta-
nilide (17). A stirring mixture of 3-acetamido-2-methyl-
benzaldehyde
(16)
(0.2249 g,
1.27 mmol)
and
3.1.16.
quinoline (6c, XˆSPh, RˆCH3) and 6-thiaellipticine
(18). Chromatography on activity basic alumina
5-Methyl-6-phenylthio-3H-pyrazolo[3,4-h]iso-
aminoacetaldehyde diethyl acetal (0.369 mL, 2.54 mmol)
was placed in a 1608Coil bath under a re¯ux condenser.
After 90 min the ¯ask was allowed to cool and a stream of
air was used to remove remaining acetal. The solid
recrystallized (i-PrOH) to give 0.2892 g (78% yield) of 17
as a bulky white ¯uff: mp 130.5±1318C; 1H NMR d 1.20 (t,
6H, Jˆ7.0 Hz), 2.08 (s, 3H), 2.23 (s, 3H), 3.58 (dq, 2H,
Jˆ9.3, 7.0 Hz), 3.73 (dq, 2H, Jˆ9.3, 7.0 Hz), 3.77 (d, 2H,
Jˆ5.3 Hz), 4.79 (t, 1H, Jˆ5.3 Hz), 7.12 (t, 1H, Jˆ7.8 Hz),
7.36 (d, 1H, Jˆ7.7 Hz), 7.64 (d, 1H, Jˆ7.6 Hz), 8.08 (s,
1H), 8.50 (s, 1H); 13CNMR d 13.0, 15.1, 23.3, 62.5, 64.7,
101.8, 125.4, 125.8, 127.4, 131.8, 135.1, 135.8, 162.1,
I
(CH2Cl2) gave 6-thiaellipticine (18) side product (34%
yield). Further elution with methanol gave product 6c
(41% yield). Recrystallization (CHCl3) of 6c gave yellow
prisms: mp 219.5±220.58C; 1H NMR d 2.90 (s, 3H), 7.05±
7.25 (m, 5H), 7.88 (d, 1H, Jˆ6.0 Hz), 8.52 (s, 1H), 8.70 (d,
1H, Jˆ5.7 Hz), 9.62 (s, 1H), 11.35 (bs, 1H); 13CNMR d
16.3, 102.9, 116.1, 118.8, 122.3, 126.5, 127.4, 129.5, 133.4,
133.6, 134.7, 138.6, 140.4, 143.7, 147.6; IR 1582, 1477,
1439, 931, 817, 736 cm21. The structure was veri®ed by
single crystal X-ray analysis.
169.1; IR 3268br, 2974, 1648, 1541, 1371, 1073 cm21
.
3.2.3. 7-Amino-8-methylisoquinoline (5d, XˆH, RˆH).
A stirring mixture of P2O5 (8.94 g) and conc. H2SO4
(5 mL) was heated in a 1608Coil bath. Portions of conc.
H2SO4 (45 mL) were used to dissolve 17 (1.30 g, 4.5 mmol)
as rapidly as possible (about 25 min) and then added
through a re¯ux condenser to the reaction mixture. The
solution was allowed to react until 30 min after the addition
was started. The cooled black mire was poured onto ice
(300 mL) and basi®ed using Na2CO3. The mixture was
extracted with CHCl3 and the combined organic layers
were extracted with 2% HCl. The combined aqueous layers
were basi®ed with aqueous Na2CO3 and the resulting
mixture was extracted with CHCl3. The combined organic
layers were dried (Na2SO4) and evaporated to a brown resi-
due. Chromatography on silica gel (0.5% conc. NH4OH/2%
MeOH/CHCl3) gave 0.060 g (8.5% yield) of 5d (XˆH,
3.2. Measurement of azide formation for 7-amino-5,8-
dimethyl-6-(phenylthio)isoquinoline
Four reactions of equivalent scale were set up and each was
designated a letter A, B, C, or D. In each of reactions A and
B, a solution of 5c (11.0 mg, 0.039 mmol) was prepared in
H2O (1 drop) and AcOH (0.31 mL). In reactions Cand D,
the same amount of amine was dissolved in H2O (1 mL) and
conc. HCl (0.3 mL). All four solutions were cooled in an ice
bath and then an aqueous solution (44 mL) of NaNO2
(2.98 mg, 0.043 mmol) was injected in one portion into
each one. After 10 min, an aqueous solution (56 mL) of
NaN3 (5.61 mg, 0.086 mmol) was injected into each of reac-
tions B and D. At the same time, H2O (56 mL) was injected
into reactions A and Cas a control. All ¯asks were wrapped
in aluminum foil to protect them from light and the ice bath
was allowed to warm to room temperature overnight. Each
reaction mixture was separately poured into dilute NH4OH
and con®rmed to be basic before being extracted with
CHCl3. The combined organic layers were washed with
brine, dried (Na2SO4) and evaporated. The composition of
each product mixture was measured using the integrations
of the most cleanly integrated peaks on the NMR spectrum.
1
RˆH) as a yellow solid: mp 170±1728C; H NMR d 2.49
(s, 3H), 3.90 (bs, 2H), 7.15 (d, 1H, Jˆ8.7 Hz), 7.50 (d, 1H,
Jˆ5.6 Hz), 7.54 (d, 1H, Jˆ8.8 Hz), 8.32 (d, 1H, Jˆ5.6 Hz),
9.34 (s, 1H); 13CNMR d 10.9, 112.9, 120.7, 122.5, 125.5,
128.7, 130.7, 139.4, 142.6, 147.4; IR 3361, 3188br, 1617,
1598, 1404, 833 cm21
158.0844, found 158.0845.
; HRMS calcd for C10H10N2
3.2.4. 3H-Pyrazolo[3,4-h]isoquinoline (6d, XˆH, RˆH).
Chromatography on silica gel (0.5% conc. NH4OH/3±5%
MeOH/CH2Cl2) gave off-white solid (96% yield): mp 244±
3.2.1. 7-Azido-5,8-dimethyl-6-(phenylthio)isoquinoline
(8). A stirred solution of 5c (20.0 mg, 0.071 mmol) in
H2O (36 mL) and conc. HCl (0.46 mL) was cooled to 48C
and NaNO2 (7.4 mg, 0.107 mmol) was added. After 10 min,
NaN3 (93 mg, 1.43 mmol) was added and the ¯ask was
1
244.58C; H NMR (CD3CO2D) d 7.92 (d, 1H, Jˆ9.3 Hz),
8.23 (d, 1H, Jˆ9.3 Hz), 8.28 (d, 1H, Jˆ6.3 Hz), 8.71 (d, 1H,

R. B. Miller et al. / Tetrahedron 58 (2002) 6061±6067
6067
Jˆ6.3 Hz), 8.81 (s, 1H), 9.86 (s, 1H); 13CNMR (CD CO2D)
2. Zollinger, H. Diazo Chemistry I: Aromatic and Hetero-
aromatic Compounds; VCH: New York, 1994 pp 137±141.
3. (a) Foster, H. E.; Hurst, J. J. Chem. Soc., Perkin Trans. 1 1973,
3, 2901±2907. (b) Chapman, D.; Hurst, J. J. Chem. Soc,
Perkin Trans. 1 1980, 11, 2398±2404.
3
d 117.7, 123.8, 123.9, 126.3, 127.5, 132.8, 135.4, 138.6,
141.4, 142.5; IR 3122br, 2937br, 2855br, 2788br, 938,
828 cm21. Anal. calcd for C10H7N3: C, 70.99; H, 4.17; N,
24.84. Found: C, 70.94; H, 4.12; N, 24.79.
4. Bailey, R. J.; Card, P. J.; Shechter, H. J. Am. Chem. Soc. 1983,
105, 6096±6103.
3.3. Supplementary material
5. Ockenden, D. W.; Scho®eld, K. J. Chem. Soc. 1953, 1915±
1919.
Crystallographic data (excluding structure factors) for
5-methyl-6-phenylthio-3H-pyrazolo[3,4-h]isoquinoline (6c,
RˆCH3, XˆSPh) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 182/288. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: 144-(0)1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
6. Miller, R. B.; Stowell, J. G.; Jenks, C. W.; Farmer, S. C.;
Wujcik, C. E.; Olmstead, M. M. J. Chem. Soc., Chem.
Commun. 1996, 24, 2711±2712.
7. Cruz, R.; Arias, M. S.; Arias, M. E.; Soliveri, J. J. Antibiot.
1996, 49 (7), 700±702.
8. Hassan, A. A.; Mekheimer, R.; Mohamed, N. K. Pharmazie
1997, 52 (8), 589±593.
9. Cecchi, L.; Colotta, V.; Melani, F.; Palazzino, G.; Filacchioni,
G.; Martini, C.; Giannaccini, G.; Lucacchini, A. J. Pharm. Sci.
1989, 78, 437.
Acknowledgements
10. (a) Ducrocq, C.; Bisagni, E.; Rivalle, C.; Lhoste, J. M.
J. Chem. Soc., Perkin Trans. 1 1979, 1, 142±145. (b) Rivalle,
C.; Ducrocq, C.; Lhoste, J. M.; Bisagni, E. J. Org. Chem.
1980, 45 (11), 2176±2180.
We thank the Chemistry Department at the University of
California at Davis for funding this research.
11. (a) Gensler, W. J. Org. React. 1951, 6, 191±206. (b) Sengupta,
D.; Anand, N. Indian J. Chem. 1986, 25B, 72±75. (c) Balkau,
F.; Elmes, B. C.; Loder, J. W. Aust. J. Chem. 1969, 22, 2489±
2492.
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