On the mechanism of conversion of 4-carboxy-3,4-dihydro-3-phenyl-1(2H)-isoquinolones to indeno[1,2-c]isoquinolines by thionyl chloride

Article abstract of DOI:10.1016/j.tet.2006.07.072

It has been known for a long time that thionyl chloride can effectively mediate the transformation of 4-carboxy-3,4-dihydro-3-phenyl-1(2H)-isoquinolones to indeno[1,2-c]isoquinolines. The mechanism of this unique transformation, however, remains to be established. Evidence is presented to demonstrate that (1) the two-electron dehydrogenation precedes Friedel-Crafts cyclization and (2) the two-electron dehydrogenation occurs via H-4 deprotonation and subsequent O-sulfinylation of the lactam moiety instead of C-sulfinylation of the carbon α to the carboxyl group.

Full text of DOI:10.1016/j.tet.2006.07.072

Tetrahedron 62 (2006) 9705–9712
On the mechanism of conversion of 4-carboxy-3,4-dihydro-3-
phenyl-1(2H)-isoquinolones to indeno[1,2-c]isoquinolines
by thionyl chloride
Xiangshu Xiao,a Andrew Morrell,a Phillip E. Fanwickb and Mark Cushmana,
*
aDepartment of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, School of Pharmacy
and Pharmaceutical Sciences, Purdue University, West Lafayette, IN 47907, USA
bDepartment of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Received 10 March 2006; revised 20 July 2006; accepted 24 July 2006
Available online 21 August 2006
Abstract—It has been known for a long time that thionyl chloride can effectively mediate the transformation of 4-carboxy-3,4-dihydro-3-
phenyl-1(2H)-isoquinolones to indeno[1,2-c]isoquinolines. The mechanism of this unique transformation, however, remains to be established.
Evidence is presented to demonstrate that (1) the two-electron dehydrogenation precedes Friedel–Crafts cyclization and (2) the two-electron
dehydrogenation occurs via H-4 deprotonation and subsequent O-sulfinylation of the lactam moiety instead of C-sulfinylation of the carbon
a to the carboxyl group.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
In 1978, the direct transformation of cis acid 1 to indeno-
[1,2-c]isoquinoline2 by thionyl chloridewas reported.1 Since
the establishment of compound 2 as a novel non-campto-
thecin topoisomerase I inhibitor,2 a number of analogs of 2
have been synthesized using this thionyl chloride-mediated
oxidation/Friedel–Crafts cyclization methodology.3–9 De-
spite its effectiveness in providing access to different
substituted indenoisoquinolines, the exact mechanism of
the thionyl chloride-mediated oxidation/Friedel–Crafts cy-
clization of 1 is still not established. Herein, detailed studies
are described on the mechanism of this conversion employing
differentially substituted substrate analogs to support a mech-
anism in which dehydrogenation precedes Friedel–Crafts
cyclization and the lactam functionality plays an essential
role in the dehydrogenation process.
To determine if SOCl2-mediated oxidation can proceed
without prior Friedel–Crafts acylation, cis acid 7 with a
less-activated 3-phenyl ring than 1 was designed and synthe-
sized (Scheme 1). Condensation of 3,4-dimethoxyhomoph-
thalic anhydride (6)1 with Schiff base 5, prepared from
MOM-protected aldehyde 4 and MeNH2, yielded the cis
acid 7, whose relative stereochemistry was determined
by the observed 6.2 Hz coupling constant for the two me-
thine protons.10 Treatment of the cis acid 7 with SOCl2
gave three isolated compounds 8, 9, and 10 in 11, 31,
and 28% yields, respectively. Therefore, it is clear that
the SOCl2-mediated dehydrogenation step can proceed
without prior Friedel–Crafts cyclization. Previous studies
indicated that the dehydrogenated intermediate derived
from 1 could undergo Friedel–Crafts cyclization in the
presence of thionyl chloride to afford 2, but the Friedel–
Crafts product derived from 1 did not undergo dehydroge-
nation to yield 2 with thionyl chloride.1 These results, in
combination with the present study, make it clear that
dehydrogenation precedes the Friedel–Crafts acylation
during the conversion of 1 to 2 by thionyl chloride.
What remains to be determined is the mechanism of the
dehydrogenation step.
O
9
O
11
O
HOOC
O
8
1
4
MeO
MeO
MeO
MeO
4
1
O
3
2
N
5 N
CH3
CH3
O
O
1
2
Compounds 9 and 10 are novel macrocyclic systems con-
taining 16-membered and 24-membered rings with either
two or three benzene rings, respectively. Interestingly, the
chemical shifts of the four protons in the substituted benzene
Keywords: Thionyl chloride; Oxidation; Indenoisoquinoline; Intramolecular
Friedel–Crafts reaction.
* Corresponding author. Tel.: +1 765 494 1465; fax: +1 765 494 6790;
e-mail: cushman@pharmacy.purdue.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.072

9706
OH
X. Xiao et al. / Tetrahedron 62 (2006) 9705–9712
OMOM
NMR results indicate that the conformational mobility of
OMOM
MeNH2
Et3N
MOM-Cl
NaOH
Adogen
45%
O
the macrodilide ring of 9 is limited by the p–p stacking
interaction of the two aromatic rings, and this conclusion
is also consistent with the AM1 calculation (Fig. 1). The
predominant formation of this macrodilide in the reaction
mixture is likely due to the effect of a combination of pre-
disposed orientation of 3-phenyl and 4-carboxyl groups in
MeO
MeO
+
MgSO4
100%
O
CHO
O
CHO
MeN
H
4
3
6
5
OMOM
13 and product stability rendered by the p–p stacking inter-
HOOC
8
action of the C and C0 rings, which have an appropriate
MeO
MeO
CHCl3
36%
1) SOCl2
14
˚
distance of 3.45 A for stacking.
2) Work-up and
N
CH3
chromatography
O
O
7
Originally, we proposed the oxidation step involving Mech-
anism 1 as shown in Scheme 2 on the basis of the reported
SOCl2 dehydrogenation reactions of substrates lacking lac-
tam functionality.1 However, two alternative Mechanisms
2 and 3 involving participation of the lactam functionality
are also intriguing,15 especially because Mechanism 1 en-
tails the formation of a quaternary carbon in a very sterically
congested environment. In order to distinguish these mech-
anisms, two interrupting analogs 1716 and 18 were designed
and synthesized. When 17 was treated with SOCl2 at room
temperature for 5 h, the typical time frame to convert cis-1
to 2,1 followed by methanol work up, only ester 1916 was
obtained quantitatively. However, prolonged reaction of 17
with SOCl2 for 36 h resulted in the formation of 18% chlo-
rinated compound 20 and 77% of ester 19 (Scheme 3). The
failure to observe the formation of 21, or a derivative of it,
argues against Mechanism 2 (Scheme 2). Based on the rela-
tively high pKa of H-3 compared to H-4, which is doubly
activated by both carboxyl group and lactam, Mechanism
2 requiring deprotonation at H-3 in the presence of H-4 is
also not favored.
OMe
OMe
Me
N
B'
A'
OH
HOOC
C'
MeO
MeO
O
O
N
O
O
CH3
C
O
MeO
MeO
8
A
B
N
9
Me
O
MeO
OMe
O
O
N
Me
O
Me
N
O
O
O
O
O
OMe
MeO
MeO
OMe
N
O
O
HOOC
HOOC
Me
Me
Me
10
MeO
MeO
O
N
N
Scheme 1.
CH3
CH3
O
17
O
18
ring C of macrodilide 9 are different from each other11 and
one of the protons is significantly shifted upfield to
5.60 ppm. The C and C0 rings are equivalent so that the eight
protons on the two rings appear as four doublets of doublets.
In order to understand the unusual 1H NMR spectrum of this
compound, the geometry was optimized at the AM1 theory
level in Gaussian03.12 It is reasonable to assume that the op-
timized AM1 structure (Fig. 1) would provide a valid model
on which to base the interpretation of the 1H NMR data. Due
to the differential shielding effect from the C0 ring, the two
pairs of protons on the C ring are no longer identical, and
vice versa. Furthermore, since the proton labeled ‘a’ in
Figure 1 is located directly over the ring current from ring
C0, it experiences an unusually strong shielding effect and
O
OMe
Me
O
OMe
Me
MeOOC S
O
MeO
MeO
O
N
O
N
CH3
CH3
Cl
O
21
22
To avoid the complications resulting from the nucleophilic
aromatic rings present in 17, a simplified analog 18 was
designed and synthesized (Scheme 4). Ketimine formation
between acetophenone and methylamine in the presence of
1
thus appears more upfield in the H NMR spectrum. The
17
TiCl4 afforded 24, which was condensed with homo-
phthalic anhydride (25) to give a pair of diastereomers 26
and 18 in 16 and 3% yields, respectively. The corresponding
methyl esters were furnished by treating the individual acids
with TMSCHN2 in MeOH–benzene. The relative configura-
tions of 18, 26, 27, and 28 were determined primarily by the
chemical shift differences of H-4, 3-Me, and 4-COOMe due
to the shielding effect of the 3-phenyl ring and the electron-
withdrawing effect of the 4-carbonyl (Table 1).18,19 The
structure of compound 28 was further confirmed by single
crystal X-ray analysis (see Supplementary data).
Figure 1. AM1 optimized geometry of compound 9.

X. Xiao et al. / Tetrahedron 62 (2006) 9705–9712
9707
O
O
NMe
CH3
O
O
MeNH2
O
CH3
Me
O
25
O
H
TiCl4
76%
MeO
MeO
CHCl3
H
Me
23
24
N
O
HOOC
HOOC
Me
O
Cl
1) SOCl2
2) MeOH
30
Me
Me
N
N
+
N
CH3
CH3
Mechanism 1
O
O
O
26
O
S
18
29
O
O
O
Cl
H
TMSCHN2
99%
HOOC
MeO
Cl
MeO
MeO
O
MeOOC
MeOOC
O
SOCl2
Me
Me
N
N
N
O
MeO
O
CH3
Cl
CH3
11
O
N
1
O
CH3
CH3
O
O
O
O
O
O
28 (X-ray)
27
MeO
MeO
MeO
MeO
Scheme 4.
N
N
CH3
CH3
Cl
O
O
12
Table 1. Chemical shift differences (ppm) between 18, 26, 27, and 28
2
Mechanism 2
Compound
H-4
3-Me
4-COOMe
18
26
27
28
3.82
4.12
4.18
3.75
1.66
1.86
1.81
1.58
N/A
N/A
3.62
3.14
O
Cl
O
Cl
O
H
MeO
O
O
MeO
MeO
O
N
N
MeO
CH3
CH3
Cl
Cl
O
O
O
S
cyclization instead of cyclizing from the original sp3-hybrid-
ization state, which does not cyclize as evidenced by the fail-
ure to form any cyclized product derived from 17, and failure
to form 30 from 1 under similar treatment.1 The failure to
form even a trace of the sulfinate ester 22 and formation of
29 suggests that Mechanism 3 is the most likely one account-
ing for the oxidation step mediated by SOCl2.
Cl
S
O
O
13
14
Cl
H
Cl
O
MeO
MeO
12
O
N
CH3
O
15
Mechanism 3
Further evidence to support Mechanism 3 comes from the
reactions of methanesulfinyl chloride20 with various esters
(Scheme 5). Reaction of the enolate derived from ester 31
with methanesulfinyl chloride resulted in the formation of
dehydrogenated product 32 in 75% yield. On the other hand,
treatment of methyl 3-phenylpropionate (33) with NaHMDS
followed by methanesulfinyl chloride gave methyl sulfoxide
34 diastereoselectively, whose structure was confirmed by
single crystal X-ray analysis (see Supplementary data).
Cl
Cl
Cl
Cl
H
O
O
H
O
O
MeO
MeO
MeO
O
O
N
N
CH3
Cl
MeO
CH3
O
O
Cl
S
O
Cl
13
S
16
O
12
Scheme 2.
The formation of 34 is expected since elimination of sul-
finic acid usually is slow21,22 and requires high temperature
compared to elimination of selenic acid.23,24 If the oxida-
tion reaction were to involve Mechanism 1, then similar
treatment of ester 28 with methanesulfinyl chloride would
generate the corresponding methyl sulfoxide. However,
this treatment only resulted in the recovery of starting
material. These observations indicate the mechanism shown
in Scheme 6 for the formation of 29. The acyl chloride 35
undergoes a reversible reaction with SOCl2 to give O-sulfini-
lated species 36, whose C-4 is in an sp2 hybridization state,
followed by cyclization to afford 37. Chloride addition
and elimination of sulfur monoxide from 37 provide the
observed chloride 29.
Cl
O
MeOOC
MeOOC
Me
N
Me
O
MeO
MeO
MeO
MeO
1) SOCl2
2) MeOH
O
+
17
O
N
CH3
CH3
O
19
O
20
Scheme 3.
When acid 18 was treated with SOCl2 at room temperature
for 5 h, followed by methanol treatment, the only product
formed was the ester 28. On the other hand, when the reac-
tion time of SOCl2 treatment was prolonged to 36 h, a minor
product 29 (5%) was also formed besides the ester 28 (92%).
The formation of cyclized product 29 is very informative as
it suggests that C-4 must become sp2-hybridized before
More direct evidence to support the participation of the
amide functionality in the oxidation process is the

9708
X. Xiao et al. / Tetrahedron 62 (2006) 9705–9712
O
O
O
MeOOC
O
MeOOC
MeO
MeO
MeO
O
1) n-BuLi, -78°C
N
N
O
CH3
MeO
CH3
S
2)
O
32
Me
Cl
31
O
O
1) NaHMDS, -78°C
O
OMe
O
COOMe
:
S
S
2)
Me
Cl
Me
34 (X-ray)
33
MeOOC
Me
N
1) n-BuLi, -78°C
no reaction
O
CH3
S
O
28
2)
Me
Cl
Scheme 5.
oxidations mediated by thionyl chloride,25–31 Mechanism
3 involving deprotonation at H-4 and subsequent O-sulfiny-
lation of the amide is the most likely one accounting for the
dehydrogenation of cis acid 1 based on the present experi-
mental data presumably due to the sterics and the presence
of an additional amide functionality.
Cl
Me
O
Cl
Cl
H
O
N
Me
CH3
CH3
Cl
N
O
O
S
Cl
Cl
S
O
O
36
35
4. Experimental
4.1. 4-Methoxymethoxybenzaldehyde (4)32
O
Cl
Method A: a solution of NaOH (1.3 g in 16 mL H2O) was
added to a stirred solution of 4-hydroxybenzaldehyde
(2.0 g, 16.4 mmol) and AdogenÒ (1.3 g) in CH2Cl2
(50 mL). Then MOM-Cl (1.98 g, 24.5 mmol) was added.
The resulting biphasic mixture was stirred at room tempera-
ture for 20 h. CH2Cl2 (100 mL) was added and the organic
phase was separated and then washed successively with 1 N
HCl (2ꢀ25 mL), H2O (2ꢀ25 mL), and brine (2ꢀ25 mL)
and dried over Na2SO4. The solution was filtered and evapo-
rated in vacuo and the resulting residue was subjected to flash
columnchromatography, elutingwithn-hexane–ethyl acetate
(10:1), furnishing 4 as a colorless oil (1.2 g, 45%): 1H NMR
(300 MHz, CDCl3) d 9.87 (s, 1H), 7.80 (d, J¼8.7 Hz, 2H),
7.11 (d, J¼8.7 Hz, 2H), 5.22 (s, 2H), 3.46 (s, 3H); ESIMS
m/z (rel intensity) 167 (MH+, 100). Method B: 4-hydroxyben-
zaldehyde (2.000 g, 16.37 mmol) was dissolved in dry DMF
(50 mL) and cooled to 0 ꢁC. Sodium hydride (60% dispersion
in mineral oil) (0.786 g, 19.65 mmol) was carefully added
and the reaction mixture was allowed to stir at 0 ꢁC for
30 min. MOM-Cl (1.582 g, 19.65 mmol) was added drop-
wise and the reaction mixture was allowed to stir at 0 ꢁC for
1 h, then at room temperature for 1 h. The reaction was
quenched with the addition of saturated aq NH4Cl (50 mL)
and the solution was extracted with EtOAc (3ꢀ25 mL). The
combined organic layers were washed with saturated aq
K2CO3 (3ꢀ25 mL), saturated aq NH4Cl (3ꢀ25 mL), and
brine (25 mL). The organic layer was dried over sodium sul-
fate, filtered, and concentrated to provide a crude yellow oil
that was purified by flash column chromatography (SiO2),
eluting with a gradient of hexanes to 30% EtOAc/hexanes,
29
Me
N
CH3
O
Cl
S
O
37
Scheme 6.
observation that treatment of 2,3-diphenyl-propionic acid
(38) with SOCl2, followed by MeOH, only resulted in the
formation of the corresponding methyl ester 39 (Scheme
7). No oxidation product was observed in this case. The
acid 38 is a simplified analog of 1 lacking the lactam func-
tionality, and the inability of 38 to undergo the oxidation
reaction indicates lactam participation in the oxidation of
1 by SOCl2.
MeOOC
HOOC
1) SOCl2, rt, 12 h
2) MeOH, rt, 2 h
38
39
Scheme 7.
3. Conclusions
The transformation from cis acid 1 to indenoisoquinoline 2
by thionyl chloride involves a two-electron dehydrogenation
followed by Friedel–Crafts cyclization. Although Mecha-
nism 1 (Scheme 2) has been proposed for most of the

X. Xiao et al. / Tetrahedron 62 (2006) 9705–9712
9709
to provide a colorless oil (2.374 g, 87%) identical to the
material furnished by Method A.
141.1, 130.6 (2C), 128.3, 124.8, 117.8, 115.2 (2C), 112.9,
107.3, 104.3, 55.6 (2C), 33.5; IR (KBr) 3489, 3441, 3137,
2956, 1685, 1609, 1512, 1274, 1225, 1176 cmꢂ1; ESIMS
m/z (rel intensity) 356 (MH+, 100). Anal. Calcd for
C19H17NO6$1.5H2O: C, 59.68; H, 5.27; N, 3.66. Found: C,
4.2. (4-Methoxymethoxy-benzylidene)methylamine (5)
1
Anhydrous MgSO4 (1.8 g) and aldehyde 4 (817.5 mg,
4.92 mmol) were added sequentially to a stirred solution
of MeNH2 (2 M in methanol, 3.0 mL, 6.0 mmol) and Et3N
(1 mL, 7.39 mmol) in CHCl3 (10 mL). The resulting mixture
was stirred at room temperature for 18 h. CH2Cl2 (50 mL)
was added and the solution was washed with H2O
(2ꢀ10 mL) and brine (2ꢀ10 mL). The organic phase was
dried over Na2SO4, filtered, and concentrated in vacuo
59.93; H, 5.05; N, 3.51. Product 9: mp 383–385 ꢁC. H
NMR (300 MHz, CDCl3) d 7.85 (s, 2H), 7.60 (dd, J¼8.4,
2.4 Hz, 2H), 7.45 (dd, J¼8.4, 2.4 Hz, 2 H), 7.29 (dd,
J¼8.1, 2.1 Hz, 2H), 7.23 (s, 2H), 5.60 (dd, J¼8.1, 2.1 Hz,
2H), 4.02 (s, 6H), 4.00 (s, 6H), 3.35 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 165.9 (2C), 161.7 (2C), 154.1 (2C),
150.8 (2C), 149.9 (2C), 142.6 (2C), 133.2 (2C), 131.0
(2C), 130.4 (2C), 128.3 (2C), 123.8 (2C), 122.7 (2C),
118.8 (2C), 110.7 (2C), 108.2 (2C), 103.7 (2C), 56.3 (2C),
34.2 (2C), 29.7 (2C); ESIMS m/z (rel intensity) 1349
(2M+H+, 53), 675 (MH+, 100); IR (film) 2963, 2905,
1732, 1651, 1609, 1502, 1415, 1260, 1094, 1019, 799,
703 cmꢂ1. Anal. Calcd for C38H30N2O10: C, 67.65; H,
4.48; N, 4.15. Found: C, 67.34; H, 4.46; N, 3.98. Product
10: mp 402–404 ꢁC. 1H NMR (300 MHz, CDCl3) d 7.87 (s,
3H), 7.58 (s, 3H), 7.36 (d, J¼9.0 Hz, 6H), 7.04 (d,
J¼9.0 Hz, 6H), 4.03 (s, 9H), 3.95 (s, 9H), 3.31 (s, 9H); 13C
NMR (125 MHz, CDCl3) d 167.5 (3C), 162.2 (3C), 157.4
(3C), 154.0 (3C), 149.7 (3C), 142.5 (3C), 130.7 (6C), 129.0
(3C), 126.3 (3C), 118.5 (3C), 116.0 (6C), 112.5 (3C), 107.9
(3C), 104.2 (3C), 56.3 (6C), 34.5 (3C); ESIMS m/z (rel
intensity) 1012 (MH+, 100); IR (film) 2921, 2851, 1722,
1647, 1610, 1501, 1422, 1312, 1267, 1200, 1147, 1053,
1023 cmꢂ1. Anal. Calcd for C57H45N3O15: C, 67.65; H,
4.48; N, 4.15. Found: C, 67.46; H, 4.32; N, 3.96.
1
giving 5 as a colorless oil (882.8 mg, 100%): H NMR
(300 MHz, CDCl3) d 8.19 (s, 1H), 7.62 (d, J¼8.7 Hz, 2H),
7.03 (d, J¼8.7 Hz, 2H), 5.18 (s, 2H), 3.46 (s, 6H); 13C
NMR (75 MHz, CDCl3) d 161.7, 159.1, 130.2, 129.3 (2C),
116.1 (2C), 94.2, 56.1, 48.1; IR (KBr) 2938, 1652, 1607,
1510, 1237, 1153, 1081, 1003 cmꢂ1; ESIMS m/z (rel inten-
sity) 180 (MH+, 100). Anal. Calcd for C10H13NO2: C, 67.02;
H, 7.31; N, 7.82. Found: C, 67.37; H, 7.18; N, 7.59.
4.3. cis-4-Carboxy-6,7-dimethoxy-3-(4-methoxy-
methoxy-phenyl)-2-methyl-1-oxo-1,2,3,4-tetrahydro-
isoquinoline (7)
Anhydride 6 (269 mg, 1.2 mmol) was added in one portion
to a stirred solution of imine 5 (217.2 mg, 1.2 mmol) in
CHCl3 (1.2 mL). The solution became clear and 3 h later
a light yellow precipitate formed in the reaction mixture.
The precipitate was collected and washed with CHCl3
(1 mL) giving 7 as an off-white powder (173 mg, 36%):
mp 218–220 ꢁC. 1H NMR (300 MHz, DMSO-d6) d 7.51 (s,
1H), 7.11 (s, 1H), 6.96 (d, J¼8.7 Hz, 2H), 6.87 (d,
J¼8.7 Hz, 2H), 5.12 (s, 2H), 5.01 (d, J¼6.2 Hz, 1H), 4.59
(d, J¼6.2 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.32 (s, 3H),
2.87 (s, 3H); 13C NMR (75 MHz, DMSO-d6) d 170.8,
163.0, 156.5, 151.2, 147.7, 130.1, 128.9 (2C), 127.2, 121.5,
115.8 (2C), 110.8, 109.8, 93.6, 62.6, 55.6, 55.5 (2C), 47.5,
33.4; ESIMS m/z (rel intensity) 402 (MH+, 100); IR (film)
2939, 1739, 1596, 1511, 1489, 1287, 1230, 1147, 1079,
754, 624 cmꢂ1. Anal. Calcd for C21H23NO7$H2O: C,
60.14; H, 6.01; N, 3.34. Found: C, 60.45; H, 5.64; N,
3.36.
4.5. cis-3-(2-Chloro-4,5-methylenedioxyphenyl)-1,2,3,4-
tetrahydro-6,7-dimethoxy-4-methoxycarbonyl-2,4-di-
methyl-1-oxo-isoquinoline (20)
SOCl2 (1 mL) was added to a stirred solution of acid 17
(10 mg, 0.025 mmol) at room temperature. The resulting
mixture was stirred at room temperature for 36 h and then
the excess SOCl2 was evaporated under reduced pressure.
The resulting residue was treated with MeOH (5 mL) and
the reaction mixture was heated under reflux for 2 h. Meth-
anol was evaporated and the residue was separated by
preparative TLC, developing with CHCl3–MeOH (100:1),
yielding compound 20 (2 mg, 18%) and ester 19 (8 mg,
77%). Compound 20 was isolated as a viscous oil that be-
came a white solid upon standing: mp 145–146 ꢁC. 1H
NMR (300 MHz, CDCl3) d 7.70 (s, 1H), 6.78 (s, 1H), 6.75
(s, 1H), 6.41 (s, 1H), 5.88 (d, J¼1.2 Hz, 1H), 5.86 (d,
J¼1.2 Hz, 1H), 5.18 (s, 1H), 3.95 (s, 3H), 3.87 (s, 3H),
3.51 (s, 3H), 3.00 (s, 3H), 1.78 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 172.8, 162.7, 152.2, 148.3, 148.2,
147.1, 132.9, 128.4, 125.6, 120.2, 110.4, 109.9, 109.2,
107.7, 102.0, 65.5, 56.1, 52.2, 34.1, 29.7; IR (film) 3451,
2925, 2854, 1736, 1651, 1602, 1508, 1479, 1283, 1237,
1120, 1038, 928, 782 cmꢂ1; ESIMS m/z (rel intensity) 450
(37ClꢂMH+, 34), 448 (35ClꢂMH+, 100); HRESIMS m/z
calcd for 448.1163, found 448.1161.
4.4. 4-Carboxy-1,2-dihydro-3-(4-hydroxyphenyl)-6,7-
dimethoxy-2-methyl-1-oxo-isoquinoline (8), dilide (9)
and trilide (10)
Acid 7 (39.5 mg, 0.098 mmol) was treated with thionyl chlo-
ride (0.4 mL) at room temperature for 4 h. Then excess thio-
nyl chloride was evaporated in vacuo and benzene (3ꢀ3 mL)
was added and evaporated in vacuo. The residue was
subjected to flash column chromatography, eluting with
CHCl3–MeOH (100:0–4:1), to provide a white powder 8
(4 mg) and a mixture of 9 and 10. The mixture of 9 and 10
was further purified by preparative TLC on silica gel
[CHCl3–MeOH (50:1)] giving 9 (10 mg) and 10 (9 mg) as
white powders. Product 8: mp>254 ꢁC (dec). 1H NMR
(300 MHz, DMSO-d6) d 9.90 (br s, 1H), 7.87 (s, 1H), 7.40
(d, J¼8.4 Hz, 2H), 7.05 (s, 1H), 6.86 (d, J¼8.4 Hz, 2H),
3.89 (s, 3H), 3.84 (s, 3H), 3.18 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 168.2, 160.6, 158.0, 153.2, 148.9,
4.6. Phenylethylidene-N-methylamine (24)33
MeNH2 (2.0 M in THF, 15 mL, 30 mmol) was added to
a stirred solution of acetophenone (23) (1.2 g, 10 mmol) in
toluene (10 mL) at ꢂ10 ꢁC. A solution of TiCl4 (0.55 mL,

9710
X. Xiao et al. / Tetrahedron 62 (2006) 9705–9712
5 mmol) in toluene (2 mL) was then added dropwise to the
reaction mixture. The reaction mixture was allowed to
warm to room temperature and then heated at 90 ꢁC for
2 h. After cooling to room temperature, the reaction mixture
was allowed to stand overnight, filtered, and washed with
toluene (100 mL). Evaporation of toluene yielded 24 as
4.53. Found: C, 74.02; H, 6.36; N, 4.39. Summary of X-ray
˚
crystal data: C19H11NO3; FW¼309.37; a¼11.4459(3) A;
ꢁ
˚
˚
b¼7.8559(2) A; c¼18.1780(5) A; b¼104.6058(17) ; vol¼
3
˚
1581.70(7) A ; monoclinic; space group P21/n; Z¼4; crystal
size¼0.41ꢀ0.39ꢀ0.35 mm; GOF¼1.071; R(Fo)¼0.039,
Rw(Fo2)¼0.107. Product 27: a white solid, mp 153–154 ꢁC.
1H NMR (300 MHz, CDCl3) d 8.10 (td, J¼6.3, 1.2 Hz, 1H),
7.12–7.33 (m, 7H), 6.95 (dd, J¼6.9, 1.8 Hz, 1H), 4.18 (s,
1H), 3.62 (s, 3H), 3.12 (s, 3H), 1.81 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 170.6, 165.5, 142.9, 132.8, 131.8, 129.2,
128.7 (2C), 128.5, 128.3, 127.5, 126.7, 125.4 (2C), 63.3,
57.4, 52.4, 30.4, 24.8; ESIMS m/z (rel intensity) 310 (MH+,
100); HRESIMS m/z calcd for 310.1443, found 310.1444.
1
a blood-red oil (1.0 g, 76%): H NMR (300 MHz, CDCl3)
d 7.71–7.76 (m, 2H), 7.33–7.40 (m, 3H), 3.34 (s, 3H), 2.23
(s, 3H); IR (film) 3057, 2961, 1635, 1445, 1285, 1026,
761, 694; EIMS m/z (rel intensity) 133 (MH+, 8), 118
(100), 91 (33), 77 (88), 51 (62).
4.7. cis-4-Carboxy-1,2,3,4-tetrahydro-2,3-dimethyl-
3-phenyl-1-oxo-isoquinoline (18) and trans-4-carboxy-
1,2,3,4-tetrahydro-2,3-dimethyl-3-phenyl-1-oxo-
isoquinoline (26)
4.9. 12-Chloro-5,6,12,13-tetrahydro-6,13-dimethyl-5,11-
dioxo-11H-indeno[1,2-c]isoquinoline (29)
Homophthalic anhydride (25) (520 mg, 3.2 mmol) was
added to a stirred solution of ketimine 24 (427 mg,
3.2 mmol) in CHCl3 (4 mL) at room temperature. The mix-
ture was heated at reflux for 5 h. CHCl3 was evaporated and
the residue was subjected to flash column chromatography,
eluting with CHCl3 and CHCl3–MeOH (10:1), yielding
acid 18 (150 mg, 16%) and acid 26 (30 mg, 3%). Product
The acid 18 (90 mg, 0.3 mmol) was treated with SOCl2
(2 mL) at room temperature for 36 h. Then the excess
SOCl2 was evaporated to afford a residue, which was imme-
diately dissolved in anhydrous MeOH (2 mL). The mixture
was stirred at room temperature for 2 h. MeOH was removed
in vacuo and the residue was subjected to flash column chro-
matography, eluting with n-hexane–EtOAc (3:1), yielding
ester 28 (87 mg, 92%) and 29 (5 mg, 5%). Product 29: awhite
1
18: a white solid, mp>200 ꢁC (dec). H NMR (300 MHz,
1
CDCl3) d 8.14 (d, J¼6.6 Hz, 1H), 7.35–7.45 (m, 4H),
7.07–7.22 (m, 4H), 3.82 (s, 1H), 2.83 (s, 3H), 1.66 (s, 3H);
13C NMR (75 MHz, CDCl3) d 174.2, 165.9, 140.0, 133.0,
132.1, 128.9, 128.6, 128.5, 128.4 (2C), 128.0, 127.2, 127.0
(2C), 64.9, 58.3, 32.4, 24.0; IR (film) 2983, 1727, 1622,
1575, 1385, 1165, 1028, 760, 703; ESIMS m/z (rel intensity)
296 (MH+, 100); HRESIMS m/z calcd for 296.1287, found
solid, mp 158–160 ꢁC. H NMR (300 MHz, CDCl3) d 8.11
(d, J¼7.8 Hz, 1H), 7.76 (d, J¼7.8 Hz, 1H), 7.67 (t,
J¼7.5 Hz, 2H), 7.59 (t, J¼7.5 Hz, 1H), 7.52 (td, J¼7.5,
1.5 Hz, 1H), 7.44 (t, J¼7.5 Hz, 1H), 7.41 (td, J¼7.5,
1.5 Hz, 1H), 3.39 (s, 3H), 1.83 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 163.5, 159.1, 142.9, 135.9 (2C), 133.7, 132.8,
131.8, 129.8, 129.6, 128.9, 128.1, 125.1, 123.8, 76.8, 67.1,
30.4, 26.8; ESIMS m/z (rel intensity) 312 (35ClMH+, 100),
314 (37ClMH+, 31);HRESIMS m/z calcdfor C18H14 35ClNO2
311.0713, found 311.0720.
1
296.1281. Product 26: a white solid, mp>186 ꢁC (dec). H
NMR (300 MHz, CDCl3) d 8.06 (d, J¼6.6 Hz, 1H), 7.08–
7.30 (m, 7H), 6.98–7.00 (m, 1H), 4.12 (s, 1H), 3.10 (s,
3H), 1.86 (s, 3H); 13C NMR (75 MHz, CDCl3) d 173.4,
165.8, 142.7, 132.6, 132.0, 129.2, 128.8 (2C), 128.5 (2C),
127.5, 127.0, 125.3 (2C), 63.0, 57.1, 29.3, 25.4; IR (film)
3406, 2983, 1723, 1626, 1575, 1381, 1218, 1029, 762,
700; ESIMS m/z (rel intensity) 296 (MH+, 100); HRESIMS
m/z calcd for 296.1287, found 296.1287.
4.10. 6,7-Dimethoxy-4-methoxycarboxy-N-methyl-3-
(30,40-methylenedioxyphenyl)-1(2H)-isoquinolone (32)
n-BuLi (0.16 mL, 2.5 M in hexane, 0.39 mmol) was slowly
added to a stirred solution of ester 31 (129 mg, 0.32 mmol)
in THF (2 mL) at ꢂ78 ꢁC. The resulting solution was then
stirred at ꢂ78 ꢁC for 15 min and then a solution of methane-
sulfinyl chloride (32 mg, 0.32 mmol) in THF (0.5 mL) was
added. The reaction mixture was stirred at ꢂ78 ꢁC for 1 h.
The reaction was quenched by slow addition of a saturated
solution of NH4Cl (5 mL) and the product was extracted
with CHCl3 (3ꢀ20 mL). The combined organic layers
were washed with H2O (2ꢀ5 mL) and brine (2ꢀ5 mL).
The organic solution was dried over anhydrous Na2SO4, fil-
tered, and concentrated. The residue was subjected to flash
column chromatography, eluting with CHCl3, yielding 32
as a light yellow solid (92 mg, 72%), which displayed iden-
tical physical data with an authentic sample of 32 obtained
differently.15
4.8. trans-1,2,3,4-Tetrahydro-4-methoxycarbonyl-2,3-
dimethyl-1-oxo-3-phenylisoquinoline (27) and cis-
1,2,3,4-tetrahydro-4-methoxycarbonyl-2,3-dimethyl-1-
oxo-3-phenylisoquinoline (28)
TMSCHN2 (2.0 M in hexane, 25 mL, 0.044 mmol) was
added to a stirred suspension of acid 18 or 26 (10 mg,
0.033 mmol) in MeOH–benzene (1:3.5 mL) at room temper-
ature. The resulting mixture was stirred at room temperature
for 30 min and the solution became clear. The solvent was re-
moved under reduced pressure and the residue was subjected
to flash column chromatography, eluting with CHCl3–MeOH
(20:1), yielding a white solid (10 mg, 99%). Product 28:
a chunk crystal (from n-hexane–EtOAc), mp 174–175 ꢁC.
1H NMR (300 MHz, CDCl3) d 8.10 (dd, J¼6.0, 3.3 Hz,
1H), 7.17–7.34 (m, 7H), 7.00 (dd, J¼6.0, 3.3 Hz, 1H), 3.75
(s, 1H), 3.14 (s, 3H), 2.77 (s, 3H), 1.58 (s, 3 H); 13C NMR
(75 MHz, CDCl3) d 170.3, 165.6, 140.7, 133.1, 132.0,
128.8, 128.7, 128.5 (3C), 128.0, 127.1, 126.8 (2C), 65.1,
58.5, 52.0, 32.3, 23.9; ESIMS m/z (rel intensity) 310 (MH+,
100). Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N,
4.11. ( )-Methyl 2(R)-benzyl-2-(S)-methanesulfinyl-3-
oxo-5-phenylpentanoate (34)
NaHMDS (3.04 mL, 1.0 M in THF, 3.04 mmol) was slowly
added to a stirred solution of ester 33 (415 mg, 2.53 mmol)
in THF (5 mL) at ꢂ78 ꢁC. The resulting solution was then
stirred at ꢂ78 ꢁC for 30 min when methanesulfinyl chloride

X. Xiao et al. / Tetrahedron 62 (2006) 9705–9712
9711
(299 mg, 3.04 mmol) was added. The reaction mixture was
then stirred at ꢂ78 ꢁC for 1 h. The reaction was quenched
byslowaddition ofH2O (5 mL)andtheproductwasextracted
with EtOAc (3ꢀ30 mL). The combined organic layers were
washed with H2O (2ꢀ10 mL) and brine (2ꢀ10 mL). The
organic solution was dried over anhydrous Na2SO4, filtered,
and concentrated. The residue was subjected to flash column
chromatography, eluting with n-hexane–EtOAc (4:1), yield-
ing a white solid 34 as colorless needles (320 mg, 71%):
this article can be found in the online version, at
doi:10.1016/j.tet.2006.07.072.
References and notes
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1
mp 119–120 ꢁC. H NMR (300 MHz, CDCl3) d 7.20–7.36
(m, 10H), 3.83 (d, J¼13.8 Hz, 1H), 3.71 (s, 1H), 3.46 (d, J¼
13.8 Hz, 1H), 3.08–3.21 (m, 2H), 2.95–3.03 (m, 2H), 2.41 (s,
3H). Summary of X-ray crystal data: C20H22O4S; FW¼
˚
˚
˚
358.46; a¼24.0662(7) A; b¼6.2232(2) A; c¼26.5189(9) A;
3
ꢁ
˚
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Thionyl chloride (1 mL) was added to acid 38 (116 mg,
0.5 mmol) at room temperature. The mixture was stirred at
room temperature for 12 h. Excess thionyl chloride was
removed under reduced pressure. The residue was treated
with methanol (2 mL) and stirred at room temperature for
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a colorless oil (120 mg, 100%): 1H NMR (300 MHz,
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1H), 3.45 (s, 3H), 3.31 (dd, J¼13.8, 8.7 Hz, 1H), 2.91 (dd,
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4.13. X-ray crystallographic data for 28 and 34
Crystallographic data (excluding structure factors) for the
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bridge Crystallographic Data Centre as supplementary pub-
lication numbers CCDC 601047 and 601048, respectively.
Copies of the data can be obtained, free of charge, on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
This work was made possible by the National Institutes of
Health (NIH) through support of this work with Research
Grant UO1 CA89566. This research was conducted in a
facility constructed with support from Research Facilities
Improvement Program Grant Number C06-14499 from the
National Center for Research Resources of the National
Institutes of Health.
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