Novel synthesis and functionalization of ortho-ortho disubstituted biphenyls and a highly condensed novel heterocycle using radical cyclization reaction

Article abstract of DOI:10.1016/j.tet.2012.09.036

This paper describes a novel synthetic route for the preparation of ortho-ortho disubstituted biphenyls and compounds possessing highly condensed ring system represented by structures X and Y, respectively. Several approaches, such as intermolecular Grubb's olefin metathesis, Heck and, Suzuki reactions were incorporated to functionalize the core structures of X and Y making it suitable for the preparation of a library of compounds.

Full text of DOI:10.1016/j.tet.2012.09.036

Tetrahedron 68 (2012) 9750e9762
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel synthesis and functionalization of orthoeortho disubstituted biphenyls
and a highly condensed novel heterocycle using radical cyclization reaction
,
a
a
a
a
b
b
C.H. Wang a , A.R. White , S.N. Schwartz , S. Alluri , T.M. Cattabiani , L.K. Zhang , T.M. Chan ,
*
A.V. Buevich b, A.K. Ganguly a
,
*
a Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, Castle Point on Hudson, Hoboken, NJ 07030, USA
b Merck Research Laboratories, Kenilworth, NJ 07033-1300, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2012
Received in revised form 6 September 2012
Accepted 7 September 2012
Available online 16 September 2012
This paper describes a novel synthetic route for the preparation of orthoeortho disubstituted biphenyls
and compounds possessing highly condensed ring system represented by structures X and Y, re-
spectively. Several approaches, such as intermolecular Grubb’s olefin metathesis, Heck and, Suzuki re-
actions were incorporated to functionalize the core structures of X and Y making it suitable for the
preparation of a library of compounds.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Radical cyclization
Atropisomerism
Heck reaction
Grubb’s metathesis
Suzuki reaction
1. Introduction
novel ring system. Compounds 11aec were formed presumably
through the intermediacy of 9 (Scheme 2).
orthoeortho Disubstituted biphenyls incorporating a median
size (six- to nine-membered) lactam ring are found in several
pharmacologically active natural products1e3 (i.e., Rhazinilam and
Steganacin) and synthetic drug candidates (i.e., LY 411575).4 In re-
cent publications5,6 we reported a novel route for the synthesis of
orthoeortho disubstituted biphenyls containing an eight-
membered lactam ring represented by structure X (Fig. 1). Our
approach toward the synthesis of these compounds involved rad-
ical cyclization of the compounds represented by structures 3aed,
using tributyltin hydride (TBTH) and 2,20-azobisisobutyronitrile
(AIBN). We speculated that the conversion of 3aed to biphenyls
7aed proceeded via intermediates 4, 5, and 6. Radical precursors
3aed were prepared by C-alkylation of imines 2aed using indium
and allyl bromide. The imines 2aed were prepared in turn by the
reactions of the corresponding isatins and substituted 2-
bromoanilines (Scheme 1).
2. Present study
Structures represented by 7a, 10a, and 11a are novel and have
many desirable attributes of drug like molecules, such as molecular
weights below 500, several sites of hydrogen bond acceptors and
donors. They also represent highly condensed ring systems with
rigid conformations, which might provide advantages in binding to
receptors and enzymes. Thus we decided to explore our chemistry
further and determine whether a library of compounds with dif-
ferent substitutions in rings A, B, and C of 10a and 11a could be
prepared for biological testing. The chemistry disclosed will also
allow synthesis of 7a with different substitutions in rings A and C.
We have already noted that the substitution in ring C could be
easily achieved by using different anilines for the preparation of the
imines represented, for example, by the structure 2d. For making
different substitutions on ring A of 7a, 10a, and 11a we needed to
develop a convenient synthesis of substituted isatins starting with
compound 12 and using Suzuki reaction. It should be noted that the
method disclosed in the present paper for the preparation of isatins
15aeg is general and the yields are good to excellent. Different
approaches were also necessary to bring changes in ring B than the
one disclosed in our previous publication because preparation of
substituted cinnamyl bromides following published procedures7
Similarly, the imines 2aec when reacted with indium and
substituted cinnamyl bromides yielded 8aec. Radical cyclization of
8aec produced the orthoeortho disubstituted biphenyls 10aec
along with the compounds 11aec, representing a highly condensed
* Corresponding authors. Tel.: þ1 201 216 5540; fax: þ1 201 216 8240; e-mail
address: akganguly1@aol.com (A.K. Ganguly).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.036

C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
9751
OH
O
N
H
N
F
N
N
CH3
H
O
N
O
CH3
O
H
F
(-)-rhazinilam
LY411575
gama secretase inhibitor
antimitotic activity
O
R2
O
OAc
H
N
H
H
R
NH
O
MeO
R2
R
R1
R1
H
O
HN
O
MeO
N
O
H
MeO
Steganacin
antimitotic activity
X
Y
Fig. 1. Examples of orthoeortho disubstituted biphenyls.
R1
O
R
H
R1
O
C
R1
NH
N
1a: R=H
1b: R=OCF3
1c: R=F
7a: R=R1=H (93
7b: R=OCF3 R1=H (61
7c: R=F, R1=H (94
7d: R=H, R1=F (87
)
N
R
R
)
H
)
)
A
R1
O
R1
N
H
6
N
cat. PTSA
H
R1
NH2
O
CHCl3
reflux
R1
Br
H
H
R1
R1
R1
N
N
TBTH
cat. AIBN
In, NaI, DMF
Br
Br
R1
R
R
C
R1
HN
toluene
reflux
R1
R1
O
O
R
N
H
Br
A
N
N
H
5
4
O
R
2a: R=R1=H
N
3a: R=R1=H (59
3b: R=OCF3 R1=H (53
3c: R=F, R1=H (54
3d: R=H, R1=F (49
)
O
2b: R=OCF3 R1=H
2c: R=F, R1=H
2d: R=H, R1=F
)
H
N
)
)
H
Scheme 1. Synthesis of novel orthoeortho disubstituted biphenyls 7aed.
C
R1
R
C
NH
A
B
Br
B
R1
O
TBTH
cat. AIBN
HN
In, NaI
Cinnamyl bromide
HN
O
H
R
Br
N
toluene
reflux
10a R = H (71
10b R = OCF3 (18
10c R = F (16
H
)
R
H
A
O
+
THF
)
N
N
)
N
R
H
H
H
N
8a R = H (50
8b R = OCF3 (17
8c R = F (47
)
O
2a: R=R1=H
2b: R=OCF3 R1=H
2c: R=F, R1=H
N
H
B
)
C
R
9
)
A
O
N
11a R = H (18
11b R = OCF3 (41
11c R = F (42
)
H
)
)
Scheme 2. Synthesis of novel orthoeortho disubstituted biphenyls 10aec and highly condensed compounds 11aec.
proved difficult because of the inherent instability of the com-
pounds. To overcome this problem we explored the possible use of
Heck reaction and Grubbs olefin metathesis of the synthone 3a to
prepare 21aee. In the present paper we wish to report the details of
our findings and we believe using the chemistry described, a library
of compounds represented by 7a, 10a, and 11a could be conve-
niently prepared for biological testing.
2.1. Modification of ring A
A convenient method of preparation of substituted isatins was
necessary for studying the substituent effects in ring A. As we could
not reproduce the Suzuki reaction on 5-bromoisatin reported in the
literature,8 we reasoned that the free carbonyl (ketone) group
presented the problem. Thus 5-bromoisatin 12 was converted to

9752
C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
O
O
O
R
O
aromatic boronic acids
cat. Pd(PPh3)2Cl2
O
R
Br
ethylene glycol
cat. PTSA
O
Br
conc. HCl
O
O
O
O
N
MeOH, reflux
DME:H2O(1:1)
N
N
toluene, reflux
N
H
H
H
H
13 (99
)
12
2-bromoaniline
cat. PTSA
CHCl3 reflux
15a: R=C6H5 (99
15b: R=4-CH3O-C6H4 (99
15c: R=4-CN-C6H4 (70
15d: R=4-F-C6H4 (93
)
14a: R=C6H5 (81
14b: R=4-CH3O-C6H4 (61
14c: R=4-CN-C6H4 (48
14d: R=4-F-C6H4 (69
)
)
)
)
)
)
)
15e: R=2-Thiophene (88
15f: R=4-CF3-C6H4 (97
15g: R=4-CH3-C6H4 (93
)
)
)
14e: R=2-Thiophene (33
14f: R=4-CF3-C6H4 (52
14g: R=4-CH3-C6H4 (58
)
)
)
Br
R
Br
N
HN
NH
O
allyl bromide, In, NaI
THF
R
cat. AIBN, TBTH
toluene, reflux
R
O
HN
O
)
N
N
H
H
16a: R=C6H5
18a: R=C6H5 (46
18b: R=4-CH3O-C6H4 (60
18c: R=4-CN-C6H4 (63
18d: R=4-F-C6H4 (63
18e: R=2-Thiophene (69
18f: R=4-CF3-C6H4 (34
18g: R=4-CH3-C6H4 (30
)
17a: R=C6H5 (39
17b: R=4-CH3O-C6H4 (90
17c: R=4-CN-C6H4, (15
16b: R=4-CH3O-C6H4
16c: R=4-CN-C6H4
16d: R=4-F-C6H4
16e: R=2-Thiophene
16f: R=4-CF3-C6H4
16g: R=4-CH3-C6H4
)
)
)
)
)
17d: R=4-F-C6H4 (78
)
)
17e: R=2-Thiophene (53
17f: R=4-CF3-C6H4 (94
17g: R=4-CH3-C6H4 (58
)
)
)
)
)
Scheme 3. Synthesis of novel derivatives with modification of ring A.
the ketal9 13, with ethylene glycol in the presence of catalytic
amounts of p-toluenesulphonic acid, which proved to be a suitable
substrate for the Suzuki reactions (Scheme 3).
Compound 13 underwent Suzuki cross-coupling with corre-
sponding arylboronic acids to yield 14aeg, which upon heating
under reflux with hydrochloric acid yielded structurally-diverse
isatins 15aeg Treatment of 15aeg with 2-bromoaniline yielded
the imines 16aeg, which without purification were treated with
allyl bromide and indium to yield 17aeg. Radical cyclization of
17aeg afforded substituted orthoeortho disubstituted biphenyls
18aeg with different substituents in ring A.
solution without the presence of cesium carbonate (Scheme 5).
Further alkylation of the lactam eNHe of 24 was then carried out
with methyl iodide in the presence of cesium carbonate to yield
25a. Treatment of 24 with benzylbromide, cesium carbonate, and
sodium iodide in DMF solution yielded 25b and 25c as atro-
pisomers (Fig. 2). The structures of 25b and 25c were deduced by
NMR spectroscopy. Briefly, atropisomer 25b showed long range
NOE’s between H3 and H15, H12 and H23 and H6 and H25, thus the
H3 proton occupied axial geometry relative to the plane of the
eight-membered ring. Atropisomer 25c had the H3 proton in the
equatorial configuration with respect to the plane of the eight-
membered ring. The rate of interconversion of the atropisomers
25b and 25c was very slow at 65 ꢀC. Ring closure metathesis of 25b
yielded 26a whereas that of 25c yielded 26b. NOE experiments
were utilized to help assign the conformations of 26a and 26b
(Fig. 3). We believe the new analogs reported in this paper will also
be substrates for the preparation of analogs of atropisomers 25b
and 25c, which could in turn be converted to analogs of 26a and
26b. Thus a rich library of drug like molecules can be prepared
using the chemistry disclosed in the present paper.
2.2. Modification of ring B
In our earlier publication6 we encountered difficulties pre-
paring, substituted cinnamyl bromides required for the C-alkyl-
ation of imines 2aec, perhaps due to their inherent instabilities.
Thus we investigated two alternative approaches to modify the B
ring of structure 8aec involving intermolecular Heck Reaction and
Grubb’s olefin metathesis of 3a, respectively (Scheme 4).
Under Heck reaction conditions, 3a underwent intramolecular
coupling and yielded spirooxindole 28. Intermolecular Heck re-
action of 3a with bromobenzene yielded 8a. Similarly, 21a and 21b
were prepared from 3a via intermolecular Heck reaction with the
corresponding substituted bromobenzenes. We did not detect the
formation of 28 during the intermolecular Heck reaction sequence.
This might be due to the fact that in general the yields during the
Heck reaction were poor to modest. Radical reaction of 21a yielded
22a and 23a, whereas the radical reaction of 21b yielded 22b and
23b. We would also like to point out that 7a under Heck reaction
conditions with bromobenzene yielded 10a.
For the Grubb’s metathesis sequence we needed substituted
styrenes 20aed, which were synthesized via the Stille reaction of
substituted bromobenzenes 19aed, respectively. Grubb’s metath-
esis of 3a and 20a yielded 21c. Similarly, 3a with 20d yielded 21d,
whereas 3a with 20b yielded 21e. Interestingly under radical re-
action conditions 21d yielded only 22c and 21e yielded only 22d.
In our earlier communication6 we noted that compound 7a
could be converted to 24 by treatment with allyl bromide in DMF
3. Experimental section
3.1. General
All the reactions were performed under nitrogen with magnetic
stirring. Air- and moisture-sensitive reagents were transferred us-
ing disposable syringes available from Aldrich Chemical Co. Anhy-
drous solvents were obtained from Aldrich and Pharmco Co. and
used without further drying. All commercially-available chemicals
were used without further purification. TLC was performed on glass
plates coated with Analtech silica gel (250 microns) and com-
pounds were visualized using UV light or exposure to iodine vapors.
NMR spectra were recorded with Varian 400 MHz and 600 MHz
spectrometers. Chemical shifts are reported in parts per million
relative to TMS, and coupling constants (J) are reported in Hz. The
compositions of all the compounds disclosed in this paper were
confirmed using mass spectrometry.

C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
9753
H
H
H
R2
N
R3
R4
O
substituted bromobenzene
Pd(OAc)2, PPh3, TEA
N
H
Br
Br
11a:R2=R3=R4=H (18
)
22a:R2=R3=H, R4=OCH3 (49
22b:R2=OCH3, R3=R4=H (27
)
)
Dioxane:H2O(3:1), reflux
NH
NH
R2
22c:R2=R3=H, R4=CN (65
)
22d:R2=CN, R3=F, R4=H (61
)
cat. AIBN
TBTH
O
O
NH
R4
NH
R3
20a-d
Grubbs cat. (2nd gen.)
3a
toluene
reflux
R2
8a:R2=R3=R4=H (24
)
Dioxane:H2O
(3:1)
reflux
R4
Pd(OAc)2,
PPh3, TEA
DCM, reflux
21a:R2=R3=H, R4=OCH3(27
21b:R2=OCH3, R3=R4=H(25
21c:R2=R3=H, R4=OCF3 (25
21d:R2=R3=H, R4=CN (20
)
)
)
NH
NH
)
)
R3
O
21e:R2=CN, R3=F, R4=H (24
)
10a: (59
Br
10a:R2=R3=R4=H (71
23a:R2=R3=H, R4=OCH3 (19
23b:R2=OCH3, R3=R4=H (24
)
)
)
NH
Pd(PPh3)4
Tributyl(vinyl)tin
Pd(OAc)2 , PPh3 , TEA
CH3CN:H2O (3:1)
Reflux
R4
R2
R3
Br
R3
O
R4
R2
N
H
28: 13
DMF
reflux
20a:R2=R3=H, R4=OCF3 (60
20b:R2=CN, R3=F, R4=H (38
20c:R2=R3=H, R4=OCH3 (30
)
)
)
19a:R2=R3=H, R4=OCF3
19b:R2=CN, R3=F, R4=H
19c:R2=R3=H, R4=OCH3
19d:R2=R3=H, R4=CN
NH
20d:R2=R3=H, R4=CN(99
)
NH
7a
O
Scheme 4. Synthesis of novel derivatives with modification of ring B.
Grubbs cat.
(1st gen.)
R
R
N
N
RX
N
Cs2CO3, R'X
DMF
NH
DCM
reflux
DMF
N
N
N
N
H
O
O
R'
R'
O
R'
O
7a
25a: R= -CH2-CH=CH2 ; R'= CH3 (77
25b: R= -CH2-CH=CH2 ; R'= CH2Ph (51
25c: R= -CH2-CH=CH2 ; R'= CH2Ph (24
)
)
)
26a: R'= CH2Ph (76
26b: R'= CH2Ph (72
)
)
24: R= -CH2-CH=CH2, R'=H (80
)
Scheme 5. Synthesis of atropisomers 26a & 26b.
Fig. 2. NOE in atropisomers 25b & 25c.

9754
C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
Fig. 3. NOE in atropisomers 26a & 26b.
3.2. General procedure for synthesis of Schiff bases (for ex-
ample 16g)
and 2-bromoaniline, following the general procedure for synthesis
of Schiff bases. The compound was carried on to the next step
without further purification.
3.2.1. 3-((2-Bromophenyl)imino)-5-(p-tolyl)indolin-2-one (16g). To
a solution of 15g (379 mg, 1.60 mmol) and 2-bromoaniline (825 mg,
4.80 mmol) in chloroform (14 mL), p-toluenesulphonic acid
(5.95 mg, 0.03 mmol) was added. The above mixture was placed
under nitrogen atmosphere and allowed to reflux for 48 h. The
reaction mixture was evaporated to dryness and used in the next
step without further purification.
3.2.8. 4-(3-((2-Bromophenyl)imino)-2-oxoindolin-5-yl)benzonitrile
(16c). The title compound was prepared from compound 15c and
2-bromoaniline, following the general procedure for synthesis of
Schiff bases. The compound was carried on to the next step without
further purification.
3.2.9. 3-((2-Bromophenyl)imino)-5-(4-fluorophenyl)indolin-2-one
(16d). The title compound was prepared from compound 15d and
2-bromoaniline, following the general procedure for synthesis of
Schiff bases. The compound was carried on to the next step without
further purification.
3.2.2. 3-((2-Bromophenyl)imino)indolin-2-one (2a). The title com-
pound was prepared from compound 1a and 2-bromoaniline, fol-
lowing the general procedure for synthesis of Schiff bases. The
compound was carried on to the next step without further
purification.
3.2.10. 3-((2-Bromophenyl)imino)-5-(thiophen-2-yl)indolin-2-one
(16e). The title compound was prepared from compound 15e and
2-bromoaniline, following the general procedure for synthesis of
Schiff bases. The compound was carried on to the next step without
further purification.
3.2.3. 3-[(2-Bromophenyl)imino]-5-(trifluoromethoxy)-1,3-dihydro-
2H-indol-2-one (2b). The title compound was prepared from
compound 1b and 2-bromoaniline, following the general pro-
cedure for synthesis of Schiff bases. The compound was carried on
to the next step without further purification.
3.2.11. 3-((2-Bromophenyl)imino)-5-(4-(trifluoromethyl)phenyl)in-
dolin-2-one (16f). The title compound was prepared from com-
pound 15f and 2-bromoaniline, following the general procedure for
synthesis of Schiff bases. The compound was carried on to the next
step without further purification.
3.2.4. 3-[(2-Bromophenyl)imino]-5-fluoro-1,3-dihydro-2H-indol-2-
one (2c). The title compound was prepared from compound 1c and
2-bromoaniline, following the general procedure for synthesis of
Schiff bases. The compound was carried on to the next step without
further purification.
3.3. General procedure for C-alkylation using allyl bromide:
(for example preparation of 3a)
3.2.5. 3-[(2-Bromo-4,6-difluorophenyl)imino]-1,3-dihydro-2H-indol-
2-one (2d). The title compound was prepared from compound 1a
and 2-bromo-4,6-difluoroaniline, following the general procedure
for synthesis of Schiff bases. The compound was carried on to the
next step without further purification.
3.3.1. 3-Allyl-3-((2-bromophenyl)amino)indolin-2-one (3a). To a so-
lution of compound 2a (600 mg, 2.00 mmol) in DMF (or THF), indium
(229 mg, 2.0 mmol), and sodium iodide (450 mg, 3.00 mmol) were
added. To the stirred reaction mixture allyl bromide (362 mg,
3.00mmol)wasadded dropwise. Afterthereactionwascomplete, the
reactionmasswasfilteredandevaporatedtodryness. Theresiduewas
diluted with DCM and washed with 30% HCl. The aqueous layer was
extracted with DCM three times. The combined organic extracts were
dried over anhydrous sodium sulfate, filtered, and evaporated to yield
the crude compound, which was purified bycolumn chromatography
to yield 3a. Yield: 59%. Crystals were obtained from DCM and hexane.
3.2.6. 3-((2-Bromophenyl)imino)-5-phenylindolin-2-one (16a). The
title compound was prepared from compound 15a and 2-
bromoaniline, following the general procedure for synthesis of
Schiff bases. The compound was carried on to the next step without
further purification.
3.2.7. 3-((2-Bromophenyl)imino)-5-(4-methoxyphenyl)indolin-2-
one (16b). The title compound was prepared from compound 15b
Mp 180e182 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.89 (s, 1H), 7.38 (dd,

C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
9755
J¼7.9, 1.5 Hz, 1H), 7.28e7.24 (m, 1H), 7.19 (dd, J¼7.4, 0.6 Hz, 1H), 7.02
(dt, J¼7.6,1.0 Hz,1H), 6.93 (d, J¼7.8 Hz,1H), 6.79 (dt, J¼8.4,1.4 Hz,1H),
6.52e6.45 (m,1H), 5.95e5.82 (m, 2H), 5.42e5.27 (m, 2H), 5.20 (s,1H),
136.15, 132.97, 132.48, 130.30, 129.96, 128.24, 127.77, 127.38, 122.20,
121.86, 119.10, 114.15, 112.70, 110.87, 110.65, 63.75, 55.30, 44.76;
HRMS: calcd for
449.0847.
C
24H2279BrN2O2 [MþH]þ: 449.0859, found:
2.82e2.65(m, 2H); 13CNMR(400MHz,CDCl3)
d179.48,141.90,139.47,
132.48, 130.00, 129.58, 129.11, 128.22, 123.88, 123.06, 121.82, 119.05,
112.65, 110.86, 110.70, 63.70, 44.63; HRMS: calcd for C17H1679BrN2O
[MþH]þ: 343.0446, found: 343.0430.
3.3.7. 4-(3-Allyl-3-((2-bromophenyl)amino)-2-oxoindolin-5-yl)ben-
zonitrile (17c). The title compound was prepared from compound
16c, following the general procedure for C-alkylation using allyl
3.3.2. 3-Allyl-3-((2-bromophenyl)amino)-5-(trifluoromethoxy)in-
dolin-2-one (3b). The title compound was obtained from com-
pound 2b, following the general procedure for C-allylation using
bromide. Yield: 15%. 1H NMR (400 MHz, CDCl3)
d 8.53 (s, 1H), 7.78
(d, J¼8.3 Hz, 2H), 7.70 (d, J¼8.3 Hz, 2H), 7.63 (dd, J¼8.0, 1.7 Hz, 1H),
7.55 (d, J¼1.1 Hz, 1H), 7.50 (dd, J¼7.8, 0.8 Hz, 1H), 7.16 (d, J¼8.1 Hz,
1H), 6.93 (t, J¼7.7 Hz, 1H), 6.62 (t, J¼7.42 Hz, 1H), 6.10e6.01 (m, 2H),
5.52e5.47 (m, 2H), 5.33 (s, 1H), 2.93 (dd, J¼13.3, 7.0 Hz, 1H), 2.80
allyl bromide. Yield: 53%. 1H NMR (400 MHz, CDCl3)
d 8.56 (s, 1H),
8.06e8.01 (m, 3H), 7.39e7.17 (m, 2H), 7.12 (d, J¼8.21 Hz, 1H), 6.88
(d, J¼8.39 Hz, 1H), 5.94e5.47 (m, 1H), 5.22e5.00 (m, 2H), 3.70 (b,
(dd, J¼13.3, 7.7 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 179.87, 142.75,
1H), 2.68 (m, 2H); 13C NMR (400 MHz, CDCl3)
d
179.97, 145.04,
141.94, 140.29, 135.72, 132.48, 132.40, 129.41, 129.37, 128.25, 126.85,
125.51, 124.82, 123.28, 119.42, 118.75, 112.80, 111.36, 110.93, 110.63,
62.88, 45.74; HRMS: calcd for C24H1979BrN3O [MþH]þ: 444.0706,
found: 444.0692.
141.61, 138.09, 132.68, 131.30, 129.29, 128.29, 122.47, 122.30, 121.70,
119.50, 119.14, 117.66, 112.42, 111.56, 110.96, 64.16, 44.51; HRMS:
calcd for C18H1579BrF3N2O2 [MþH]þ: 427.0269, found: 427.0251.
3.3.3. 3-Allyl-3-((2-bromophenyl)amino)-5-fluoroindolin-2-one
(3c). The title compound was prepared from compound 2c, fol-
lowing the general procedure for C-alkylation using allyl bromide.
Yield: 54%. Crystals were obtained from DCM and hexane. Mp
3.3.8. 3-Allyl-3-((2-bromophenyl)amino)-5-(4-fluorophenyl)indolin-
2-one (17d). The title compound was prepared from compound
16d, following the general procedure for C-alkylation using allyl
bromide. Yield: 78%. 1H NMR (400 MHz, CDCl3)
d 9.35 (s, 1H),
160e162 ꢀC; 1H NMR (400 MHz, CDCl3)
d
9.19 (s,1H), 7.39 (dd, J¼7.9,
7.52e7.39 (m, 5H), 7.16e7.05 (m, 2H), 6.98 (d, J¼8.1 Hz, 1H), 6.81 (t,
J¼7.61 Hz, 1H), 6.49 (t, J¼7.66 Hz, 1H), 6.01e5.85 (m, 2H), 5.43e5.32
(m, 2H), 5.25 (s, 1H), 2.84 (dd, J¼13.3, 7.2 Hz, 1H), 2.69 (dd, J¼13.3,
1.4 Hz, 1H), 6.99e6.89 (m, 2H), 6.89e6.74 (m, 2H), 6.51 (dt, J¼7.7,
1.4 Hz, 1H), 6.09e5.72 (m, 2H), 5.41e5.31 (m, 2H), 5.19 (s, 1H),
2.84e2.71 (m, 1H), 2.67e2.59 (m, 1H); 13C NMR (400 MHz, CDCl3)
7.2 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 178.99, 163.52, 161.07,
d
179.69, 160.58, 158.17, 141.65, 135.36, 135.34, 132.63, 131.49,
141.87, 138.58, 136.56, 136.53, 135.55, 132.56, 130.48, 129.87, 128.38,
128.30, 128.27, 128.18, 127.82, 122.45, 121.99, 119.19, 115.70, 115.48,
112.64, 110.92, 110.80, 63.77, 44.77; HRMS: calcd for
C23H1979BrFN2O [MþH]þ: 437.0659, found: 437.0648.
131.42, 129.51, 128.28, 122.26, 119.35, 115.79, 115.55, 112.46, 111.91,
111.67, 111.57, 111.50, 110.90, 64.12, 44.53; HRMS: calcd for
C17H1579BrFN2O [MþH]þ: 361.0352, found: 361.0349.
3.3.4. 3-Allyl-3-((2-bromo-4,6-difluorophenyl)amino)indolin-2-one
(3d). The title compound was prepared from compound 2d, fol-
lowing the general procedure for C-alkylation using allyl bromide.
Yield: 49%. Crystals were obtained from DCM and hexane. Mp
3.3.9. 3-Allyl-3-((2-bromophenyl)amino)-5-(thiophen-2-yl)indolin-
2-one (17e). The title compound was prepared from compound
16e, following the general procedure for C-alkylation using allyl
bromide. Yield: 53%. 1H NMR (400 MHz, CDCl3)
d 8.58e8.25 (b, 1H),
187e189 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.62 (s, 1H), 7.17 (ddd,
7.55 (d, J¼8.0, 1H), 7.48 (s, 1H), 7.41 (dd, J¼7.9, 1.5 Hz, 1H), 7.27e7.21
(m, 2H), 7.06 (dd, J¼5.0, 3.7 Hz, 1H), 6.97 (dd, J¼8.1, 1.5 Hz, 1H), 6.85
(t, J¼7.8 Hz, 1H), 6.53 (t, J¼7.61 Hz, 1H), 6.02e5.84 (m, 2H),
5.49e5.27 (m, 2H), 5.23 (s, 1H), 2.90e2.73 (m, 2H); 13C NMR
J¼7.8, 6.5, 2.4 Hz, 1H), 7.01 (ddd, J¼7.7, 2.8, 2.0 Hz, 1H), 6.95e6.80
(m, 3H), 6.45 (ddd, J¼11.3, 8.3, 2.9 Hz, 1H), 5.87 (tdd, J¼17.2, 10.0,
7.4 Hz, 1H), 5.42e5.25 (m, 2H), 4.56 (s, 1H), 2.82 (dd, J¼13.4, 7.8 Hz,
1H), 2.65 (dd, J¼13.4, 7.1 Hz, 1H); 13C NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d 179.90, 144.53, 142.90, 140.95, 135.20, 134.89,
d
180.68,180.65,157.15,157.02,154.71,154.58,152.10,151.98,140.49,
133.96, 133.42, 129.86, 129.17, 128.14, 125.89, 125.60, 125.50, 123.93,
123.52, 119.30, 118.26, 117.35, 65.63, 45.56; HRMS: calcd for
C21H1879BrN2OS [MþH]þ: 425.0318, found: 425.0301.
130.24, 129.16, 128.96, 128.68, 123.83, 123.78, 122.17, 122.10, 122.04,
115.52, 115.45, 115.41, 115.34, 115.20, 115.17, 114.96, 114.92, 110.42,
104.23, 103.97, 103.72, 65.55, 44.85; HRMS: calcd for
C17H1479BrF2N2O [MþH]þ: 379.0252, found: 379.0247.
3.3.10. 3-Allyl-3-((2-bromophenyl)amino)-5-(4-(trifluoromethyl)
phenyl)indolin-2-one (17f). The title compound was prepared from
compound 16f, following the general procedure for C-alkylation
3.3.5. 3-Allyl-3-((2-bromophenyl)amino)-5-phenylindolin-2-one
(17a). The title compound was prepared from compound 16a, fol-
lowing the general procedure for C-alkylation using allyl bromide.
using allyl bromide. Yield: 94%. 1H NMR (400 MHz, CDCl3)
d 8.82 (s,
1H), 7.60e7.52 (m, 4H), 7.50 (dd, J¼8.1, 1.6 Hz, 1H), 7.43 (s, 1H), 7.38
(d, J¼8.0 Hz,1H), 7.02 (d, J¼8.0 Hz,1H), 6.81 (t, J¼7.7 Hz,1H), 6.49 (t,
J¼7.6 Hz, 1H), 5.91e5.84 (m, 2H), 5.42e5.32 (m, 2H), 5.23 (s, 1H),
2.82 (dd, J¼13.3, 7.2 Hz, 1H), 2.68 (dd, J¼13.3, 7.2 Hz, 1H); 13C NMR
Yield: 39%. 1H NMR (400 MHz, CDCl3)
d 8.80 (s, 1H), 7.67e7.23 (m,
8H), 7.02 (d, J¼8.1 Hz,1H), 6.83 (t, J¼7.8 Hz,1H), 6.50 (t, J¼7.6 Hz,1H),
6.02e5.85 (m, 2H), 5.43e5.32 (m, 2H), 5.24 (s, 1H), 2.92e2.64 (m,
2H); 13C NMR (400 MHz, CDCl3)
d
178.94, 141.91, 140.41, 138.59,
(400 MHz, CDCl3) d 179.09, 149.51, 143.88, 141.85, 139.47, 134.95,
136.52, 132.54, 130.39, 129.95, 129.25, 128.76, 128.28, 127.94, 127.14,
126.78, 122.65, 121.96, 119.18, 112.72, 110.73, 63.78, 44.79; HRMS:
calcd for C23H2079BrN2O [MþH]þ: 419.0754, found: 419.0742.
132.62, 130.71, 129.76, 129.01, 128.56, 128.30, 128.26, 127.03, 125.74,
125.71, 125.70, 122.67, 122.14, 119.31, 112.63, 111.03, 108.24, 63.82,
44.75; HRMS: calcd for C24H1979BrF3N2O [MþH]þ: 487.0627,
found: 487.0619.
3.3.6. 3-Allyl-3-((2-bromophenyl)amino)-5-(4-methoxyphenyl)in-
dolin-2-one (17b). The title compound was prepared from com-
pound 16b, following the general procedure for C-alkylation using
3.3.11. 3-Allyl-3-((2-bromophenyl)amino)-5-(p-tolyl)indolin-2-one
(17g). The title compound was prepared from compound 16g, fol-
lowing the general procedure for C-alkylation using allyl bromide.
allyl bromide. Yield: 90%. 1H NMR (400 MHz, CDCl3)
d 8.80 (s, 1H),
7.50e7.35 (m, 5H), 7.11e6.91 (m, 3H), 6.81 (t, J¼7.3 Hz, 1H), 6.49 (t,
J¼7.2 Hz, 1H), 5.98e5.82 (m, 2H), 5.43e5.32 (m, 2H), 5.23 (s, 1H),
3.83 (s, 3H), 2.82 (dd, J¼13.3, 7.2 Hz, 1H), 2.69 (dd, J¼13.3, 7.9 Hz,
Yield: 58%. 1H NMR (400 MHz, CDCl3)
d
8.22 (s, 1H), 7.51 (dd, J¼8.0,
1.6 Hz, 1H), 7.43e7.19 (m, 4H), 7.22 (d, J¼8.1 Hz, 2H), 7.00 (d,
J¼7.8 Hz, 1H), 6.83 (t, J¼7.6 Hz, 1H), 6.51 (t, J¼7.4 Hz, 1H), 5.94e5.85
(m, 2H), 5.42e5.33 (m, 2H), 5.23 (s, 1H), 2.83 (dd, J¼13.2, 7.2 Hz,
1H); 13C NMR (400 MHz, CDCl3)
d 178.88, 158.98, 141.90, 137.99,

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C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
1H), 2.70 (dd, J¼13.6, 7.6 Hz, 1H), 2.38 (s, 3H); 13C NMR (400 MHz,
The above mixture was allowed to reflux for 2 h. The mixture was
then evaporated to dryness. The residue was diluted with DCM and
washed with water. The aqueous layer was extracted with DCM
three times. The combined organic extracts were dried over an-
hydrous sodium sulfate, filtered, and evaporated. The crude mix-
ture was purified using column chromatography to yield 7a. Yield:
93%. Crystals were obtained from DCM and hexane. Mp 179e181 ꢀC.
CDCl3)
d 179.21, 141.94, 138.38, 137.54, 136.92, 136.44, 132.52,
130.30, 130.00, 129.45, 128.29, 127.68, 126.60, 122.42, 121.92, 119.14,
112.74, 110.90, 110.80, 63.84, 44.78, 21.03; HRMS: calcd for
C24H2279BrN2O [MþH]þ: 433.0910, found: 433.0902.
3.4. General procedure for C-alkylation using cinnamyl bro-
mide: (for example preparation of 8a)
1H NMR (400 MHz, CDCl3)
d 8.00 (s, 1H), 7.48e7.32 (m, 3H),
7.18e7.05(m, 2H), 6.89e6.72 (m, 2H), 6.62 (d, J¼8.1 Hz, 1H),
5.79e5.65 (m, 1H), 5.16e4.86 (m, 2H), 4.33 (dd, J¼16.4, 7.1 Hz, 1H),
3.82 (d, J¼9.5 Hz, 1H), 2.61e2.45 (m, 1H), 2.41e2.32 (m, 1H); 13C
3.4.1. 3-((2-Bromophenyl)-amino)-3-cinnamylindolin-2-one
(8a). To a solution of compound 2a (1.5 g, 4.37 mmol) dissolved in
DMF (or THF), indium (502 mg, 4.37 mmol), and sodium iodide
(982 mg, 6.55 mmol) were added followed by the addition of cin-
namyl bromide (292 mg, 6.55 mmol) dropwise. The mixture was
allowed to react for 3 h at room temperature. After the reaction was
complete, the reaction mass was filtered and evaporated to dryness.
The crude reaction mixture was diluted with DCM and washed with
30% HCl. The aqueous layer was extracted with DCM three times.
The combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and evaporated to yield the crude compound,
which was purified by column chromatography to yield 8a. Yield:
50%. Crystals were obtained from DCM and hexane. Mp
NMR (400 MHz, CDCl3)
d 173.62, 145.46, 140.57, 135.74, 134.00,
133.37, 132.66, 129.00, 128.46, 128.37, 125.48, 124.31, 119.38, 118.15,
117.87, 52.72, 35.48; HRMS: calcd for C17H1779N2O [MþH]þ:
265.1341, found: 265.1357.
3.5.2. 7-Allyl-2-(trifluoromethoxy)-7,8-dihydrodibenzo[e,g][1,4]diaz-
ocin-6(5H)-one (7b). The title compound was prepared from
compound 3b, following the general procedure for radical cycliza-
tion. Yield: 61%. 1H NMR (400 MHz, CDCl3)
d 8.33 (s, 1H), 7.24e7.02
(m, 5H), 6.88e6.75 (m, 2H), 6.62 (d, J¼7.90 Hz, 1H), 5.76e5.63 (m,
1H), 5.15e4.88 (m, 2H), 4.31 (ddd, J¼9.36, 7.57, 6.42 Hz, 1H), 3.90 (d,
J¼9.49 Hz, 1H), 2.57e2.48 (m, 1H), 2.46e2.25 (m, 1H); 13C NMR
163e165 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.31 (s, 1H), 7.47e7.13 (m,
8H), 7.04 (t, J¼7.5 Hz, 1H), 6.93 (d, J¼7.7 Hz, 1H), 6.78e6.70 (m, 2H),
6.48 (dt, J¼7.7, 1.4 Hz, 1H), 6.24 (td, J¼15.5, 7.6 Hz, 1H), 5.88 (dd,
J¼8.2, 1.3 Hz, 1H), 5.31 (s, 1H), 2.93 (dd, J¼13.8, 7.0 Hz, 1H), 2.77 (dd,
(400 MHz, CDCl3) d 173.80, 148.76, 15.74, 148.72, 145.40, 142.44,
134.50, 133.88, 133.11, 129.57, 126.65, 124.87, 122.86, 121.65, 120.49,
119.53, 119.08, 118.32, 118.12, 52.61, 35.37; HRMS: calcd for
C18H16F3N2O2 [MþH]þ: 349.1164, found: 349.1152.
J¼13.4, 7.8 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 179.86, 141.99,
139.62, 136.74, 136.67, 132.48, 129.66, 129.21, 128.59, 128.30, 127.81,
126.47, 123.85, 123.11, 121.26, 119.17, 112.81, 110.95, 110.85, 64.14,
43.87; HRMS: calcd for C23H2079BrN2O [MþH]þ: 419.0759, found:
419.0769.
3.5.3. 7-Allyl-2-fluoro-7,8-dihydrodibenzo[e,g][1,4]diazocin-6(5H)-
one (7c). The title compound was prepared from compound 3c,
following the general procedure for radical cyclization. Yield: 94%.
Crystals were obtained from DCM and hexane. Mp 191e193 ꢀC; 1H
3.4.2. (Z)-3-((2-Bromophenyl)amino)-3-(3-phenylallyl)-5-(tri-
fluoromethoxy)indolin-2-one (8b). The title compound was pre-
pared from compound 2b, following the general procedure for C-
alkylation using cinnamyl bromide. Crystals were obtained from
DCM and hexane. Mp 139e141 ꢀC; Yield: 17%. 1H NMR (400 MHz,
NMR (400 MHz, CDCl3) d 7.68 (s, 1H), 7.18e6.97 (m, 4H), 6.87e6.74
(m, 2H), 6.61 (d, J¼8.1 Hz,1H), 5.81e5.54 (m,1H), 5.11e5.02 (m, 2H),
4.37e4.22 (m, 1H), 3.89 (d, J¼9.4 Hz, 1H), 2.59e2.45 (m, 1H),
2.43e2.27 (m, 1H); 13C NMR (400 MHz, CDCl3)
d 173.78, 163.40,
160.94, 145.39, 142.75, 142.67, 133.70, 133.25, 131.90, 131.87, 129.43,
127.08, 126.99, 123.27, 119.44, 119.32, 119.10, 118.35, 118.00, 115.15,
114.93, 52.63, 35.36; HRMS: calcd for C17H16FN2O [MþH]þ:
283.1241, found: 283.1240.
CDCl3)
d 9.01 (s, 1H), 7.42e7.21 (m, 6H), 7.15e7.08 (m, 2H),
6.94e6.87 (m, 1H), 6.84e6.76 (m, 1H), 6.66 (d, J¼15.8 Hz, 1H), 6.51
(dt, J¼7.8, 1.3 Hz, 1H), 6.33e6.02 (m, 1H), 5.82 (dd, J¼8.2, 1.2 Hz, 1H),
5.27 (s, 1H), 3.02e2.68 (m, 2H); 13C NMR (400 MHz, CDCl3)
d 179.77,
145.07, 145.05, 141.67, 138.09, 137.22, 136.41, 132.66, 131.47, 128.63,
128.31, 128.01, 126.42, 122.39, 120.24, 119.60, 117.68, 112.56, 111.55,
110.97, 64.49, 43.78; HRMS: calcd for C24H1979BrF3N2O2 [MþH]þ:
503.0582, found: 503.0603.
3.5.4. 7-Allyl-9,11-difluoro-7,8-dihydrodibenzo[e,g][1,4]diazocin-
6(5H)-one (7d). The title compound was prepared from compound
3d, following the general procedure for radical cyclization. Yield:
87%. Crystals were obtained from DCM and hexane. Mp
156e158 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.59 (s, 1H), 7.49e7.29 (m,
3.4.3. 3-((2-Bromophenyl)amino)-3-cinnamyl-5-fluoroindolin-2-one
(8c). The title compound was prepared from compound 2c, fol-
lowing the general procedure for C-alkylation using cinnamyl
bromide. Crystals were obtained from DCM and hexane. Mp
3H), 7.17e7.10 (m, 1H), 6.88e6.74 (m, 1H), 6.50e6.39 (m, 1H),
5.81e5.60 (m, 1H), 5.23e4.96 (m, 2H), 4.37e4.19 (m, 1H), 4.03e3.90
(m, 1H), 2.64e2.51 (m, 1H), 2.49e2.37 (m, 1H); 13C NMR (400 MHz,
CDCl3)
d 173.12, 155.73, 155.60, 153.35, 153.22, 152.71, 152.59,
214e216 ꢀC; Yield: 47%. 1H NMR (400 MHz, DMSO)
d
10.86 (s, 1H),
150.30, 150.18, 138.44, 138.43, 135.60, 133.02, 132.31, 129.27, 128.71,
125.89, 118.18, 115.01, 114.98, 114.79, 114.76, 103.63, 103.38, 103.12,
52.34, 35.35; HRMS: calcd for C18H15F2N2O [MþH]þ: 301.3106,
found: 301.1139.
7.48e7.05 (m, 8H), 7.02e6.87 (m, 2H), 6.62 (d, J¼15.8 Hz, 1H),
6.58e6.47 (m, 1H), 6.19e6.11 (m, 1H), 5.75 (d, J¼7.7 Hz, 1H), 5.32 (s,
1H), 2.96e2.84 (m, 2H); 13C NMR (400 MHz, CDCl3)
d 178.70,160.62,
158.21, 141.70, 136.99, 136.52, 135.19, 135.17, 132.61, 131.69, 131.62,
128.58, 128.25, 127.92, 126.45, 120.47, 119.47, 115.85, 115.61, 112.61,
112.04, 111.79, 111.20, 111.12, 110.94, 64.34, 43.85; HRMS: calcd for
C23H1979BrFN2O [MþH]þ]: 438.3122, found: 437.0651.
3.5.5. 7-Cinnamyl-7,8-dihydrodibenzo[e,g][1,4]diazocin-6(5H)-one
(10a) and 5-benzyl-4a,5,6,7-tetrahydro-1,6a-(epiminomethano)-in-
deno[1,7a-b]indol-12-one (11a). The title compounds were pre-
pared from compound 8a, following the general procedure for
radical cyclization. Yields-10a: 71% and 11a: 18%.
3.5. General procedure for radical cyclization: (for example
preparation of 7a)
Compound 10a: Crystals were obtained from DCM and hexane.
Mp 195e197 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.00 (s, 1H), 7.53e7.03
3.5.1. 7-Allyl-7,8-dihydrodibenzo[e,g][1,4]diazocin-6(5H)-one
(7a). Compound 3a (90 mg, 0.26 mmol) was dissolved in toluene.
AIBN (8.61 mg, 0.052 mmol) was added at 80 ꢀC followed by slow
addition of TBTH (83.9 mg, 0.28 mmol) at the same temperature.
(m, 10H), 6.88e6.75 (m, 2H), 6.63 (d, J¼7.8 Hz, 1H), 6.41 (d,
J¼15.9 Hz, 1H), 6.16e6.06 (m, 1H), 4.40 (dd, J¼7.5, 7.1 Hz, 1H), 3.86
(d, J¼8.8 Hz, 1H), 2.72e2.64 (m, 1H), 2.60e2.48 (m, 1H); 13C NMR
(400 MHz, CDCl3)
d 173.51, 145.43, 140.57, 137.01, 135.67, 133.99,

C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
9757
132.99, 132.69, 129.02, 128.52, 128.42, 127.27, 126.12, 125.53, 124.84,
124.29, 119.40, 118.187, 53.09, 34.87; HRMS: calcd for C23H21N2O
[MþH]þ: 341.1648, found: 341.1653.
following the general procedure for radical cyclization. Yield: 46%.
1H NMR (400 MHz, CDCl3)
8.11 (s, 1H), 7.70e7.07 (m, 9H), 6.92 (d,
d
J¼6.8 Hz, 1H), 6.81 (t, J¼7.41 Hz, 1H), 6.66 (d, J¼8.0 Hz, 1H),
5.83e5.67 (m, 1H), 5.17e5.00 (m, 2H), 4.44e4.40 (m, 1H), 3.90 (d,
J¼9.5 Hz, 1H), 2.62e2.39 (m, 2H); 13C NMR (400 MHz, CDCl3)
Compound 11a: 1H NMR (400 MHz, CDCl3)
d 8.31 (s, 1H),
7.32e7.07 (m, 7H), 6.69 (t, J¼7.3 Hz, 1H), 6.62 (d, J¼8.1 Hz, 1H), 6.12
(dd, J¼9.4, 5.3 Hz, 1H), 5.69 (dd, J¼8.5, 4.7 Hz, 1H), 5.45 (d, J¼5.3 Hz,
1H), 4.90 (s, 1H), 2.89 (dd, J¼13.4, 4.5 Hz, 1H), 2.65 (dd, J¼13.4,
8.4 Hz, 1H), 2.45e2.30 (m, 2H), 2.28e2.17 (m, 1H), 1.83 (dd, J¼13.9,
d
173.66, 145.48, 141.44, 140.90, 139.72, 134.83, 134.06, 133.35,
131.37, 129.15, 128.89, 127.73, 126.99, 126.91, 125.86, 124.25, 119.48,
118.22, 118.02, 52.77, 35.56; HRMS: calcd for C23H21N2O [MþH]þ:
341.1648, found: 341.1643.
11.1 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 180.33, 148.91, 140.31,
138.20,129.41, 128.96, 128.73, 128.32, 126.09,124.56, 123.85, 123.21,
119.55, 110.42, 97.88, 78.00, 60.96, 49.66, 49.62, 40.72, 40.63;
HRMS: calcd for C23H21N2O [MþH]þ: 341.1648, found: 341.1653.
3.5.9. 7-Allyl-2-(4-methoxyphenyl)-7,8-dihydrodibenzo[e,g][1,4]di-
azocin-6(5H)-one (18b). The title compound was prepared from
compound 17b, following the general procedure for radical cycli-
3.5.6. 7-Cinnamyl-2-(trifluoromethoxy)-7,8-dihydrodibenzo[e,g][1,4]
diazocin-6(5H)-one (10b) and rac-(4aS,5R,6aS,11bS)-5-benzyl-4-
(trifluoromethoxy)-4a,5,6,7-tetrahydro-1,6a-(epiminomethano)in-
deno[1,7a-b]indol-12-one (11b). The title compound was prepared
from compound 8b, following the general procedure for radical
cyclization. Yields-10b: 18% and 11b: 41%.
zation. Yield: 60%. 1H NMR (400 MHz, CDCl3)
d 7.62e7.52 (m, 4H),
7.24 (s, 1H), 7.16e7.10 (m, 2H), 7.00 (d, J¼7.8 Hz, 2H), 6.93 (d,
J¼7.8 Hz,1H), 6.81 (t, J¼7.4 Hz,1H), 6.65 (d, J¼8.2 Hz,1H), 5.81e5.72
(m,1H), 5.12e5.05 (m, 2H), 4.42 (dd, J¼15.5, 7.8 Hz,1H), 3.87 (s, 3H),
3.78 (d, J¼7.3 Hz, 1H), 2.62e2.53 (m, 1H), 2.43e2.38 (m, 1H); 13C
NMR (400 MHz, CDCl3)
d 173.43, 159.48, 145.45, 141.08, 140.89,
Compound 10b: 1H NMR (400 MHz, CDCl3)
d
7.95 (s, 1H),
134.13, 133.98, 133.36, 132.20, 130.84, 129.11, 128.03, 126.41, 125.86,
124.37, 119.47, 118.23, 118.00, 114.32, 55.34, 52.75, 35.59; HRMS:
calcd for C24H23N2O2 [MþH]þ: 371.1754, found: 371.1744.
7.37e7.05 (m, 9H), 6.82e6.71 (m, 2H), 6.62 (d, J¼8.1 Hz,1H), 6.45 (d,
J¼15.9 Hz, 1H), 6.18e6.6.09 (m, 1H), 4.42e4.37 (m, 1H), 3.85 (d,
J¼7.5 Hz, 1H), 2.74e2.56 (m, 2H); 13C NMR (400 MHz, CDCl3)
d
179.77, 145.07, 145.05, 141.67, 138.09, 137.22, 136.41, 132.66, 131.47,
3.5.10. 4-(7-Allyl-6-oxo-5,6,7,8-tetrahydrodibenzo[e,g][1,4]diazocin-
2-yl)benzonitrile (18c). The title compound was prepared from
compound 17c, following the general procedure for radical cycli-
128.63, 128.31, 128.01, 126.42, 122.39, 120.24, 119.60, 117.68, 112.56,
111.55, 110.97, 54.49, 33.78; HRMS: calcd for C24H20F3N2O2
[MþH]þ: 425.1477, found: 425.1475.
zation. Yield: 63%. 1H NMR (400 MHz, CDCl3)
d 7.76e7.70 (m, 3H),
Compound 11b: 1H NMR (400 MHz, CDCl3)
d
8.37 (s, 1H),
7.60e7.54 (m, 2H), 7.44 (s, 1H), 7.20 (d, J¼8.8 Hz, 2H), 7.14 (dt, J¼8.1,
1.7 Hz, 1H), 6.87 (dd, J¼7.7, 1.5 Hz, 1H), 6.80 (t, J¼7.4 Hz, 1H), 6.63 (d,
J¼7.8 Hz, 1H), 5.79e5.68 (m, 1H), 5.12e5.07 (m, 2H), 4.36 (dd,
J¼15.2, 7.3 Hz, 1H), 3.75 (d, J¼9.7 Hz, 1H), 2.62e2.56 (m, 1H),
7.32e7.08 (m, 7H), 6.74 (t, J¼7.4 Hz, 1H), 6.62 (d, J¼8.1 Hz, 1H), 6.06
(d, J¼4.9 Hz, 1H), 5.37 (d, J¼6.0 Hz, 1H), 4.89 (s, 1H), 3.12 (d,
J¼10.10 Hz, 1H), 2.71e2.45 (m, 3H), 2.25e2.13 (m, 1H), 1.85 (dd,
J¼14.0, 10.3 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d
180.48, 148.84,
2.48e2.40 (m, 1H); 13C NMR (400 MHz, CDCl3)
d 173.89, 160.23,
146.71, 139.63, 136.99, 129.96, 128.74, 128.42, 127.78, 126.26, 123.78,
121.70, 120.00, 119.13, 110.60, 109.73, 94.83, 77.89, 62.74, 51.99,
48.62, 40.02, 39.80; HRMS: calcd for C24H20F3N2O2 [MþH]þ:
425.1477, found: 425.1476.
147.45, 141.56, 140.23, 134.02, 133.78, 133.38, 131.20, 130.62, 129.10,
127.69, 126.40, 125.56, 124.37, 119.40, 118.02, 117.10, 116.82, 56.34,
36.74; HRMS: calcd for C24H20N3O [MþH]þ: 366.1601, found:
366.1591.
3.5.7. 7-Cinnamyl-2-fluoro-7,8-dihydrodibenzo[e,g][1,4]diazocin-
6(5H)-one (10c) and rac-(4aS,5R,6aS,11bS)-5-benzyl-4-fluoro-
4a,5,6,7-tetrahydro-1,6a-(epiminomethano)indeno[1,7a-b]indol-12-
one (11c). The title compounds were prepared from compound 8c,
following the general procedure for radical cyclization. Yields-10b:
16% and 11b: 42%.
3.5.11. 7-Allyl-2-(4-fluorophenyl)-7,8-dihydrodibenzo[e,g][1,4]diazo-
cin-6(5H)-one (18d). The title compound was prepared from
compound 17d, following the general procedure for radical cycli-
zation. Yield: 63%. 1H NMR (400 MHz, CDCl3)
d 7.95(s, 1H),
7.63e7.53 (m, 4H), 7.21e7.10 (m, 4H), 6.91 (dd, J¼7.7, 1.3 Hz, 1H),
6.81 (t, J¼7.3 Hz, 1H), 6.64 (d, J¼8.1 Hz, 1H), 5.80e5.72 (m, 1H),
5.18e5.04 (m, 2H), 4.45e4.40 (b, 1H), 3.87e3.80 (b, 1H), 2.58 (td,
J¼14.12, 5.9 Hz, 1H), 2.41 (td, J¼13.5, 6.7 Hz, 1H); 13C NMR
Compound 10c: Crystals were obtained from THF and hexane.
Mp 108e110 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.91 (s, 1H), 7.35e7.01
(m, 9H), 6.86e6.73 (m, 2H), 6.63 (d, J¼8.1 Hz, 1H), 6.42 (d,
J¼15.9 Hz, 1H), 6.17e6.00 (m, 1H), 4.42e4.35 (m, 1H), 3.88 (d,
J¼7.5 Hz, 1H), 2.72e2.52 (m, 2H); 13C NMR (400 MHz, CDCl3)
(400 MHz, CDCl3) d 173.22, 161.46, 145.44, 141.09, 140.52, 134.74,
133.94, 133.29, 131.23, 129.24, 128.64, 128.56, 126.78, 125.96, 124.11,
119.53, 118.28, 118.07, 115.91, 115.70, 52.76, 35.61; HRMS: calcd for
C23H20FN2O [MþH]þ: 359.1554, found: 359.1542.
d
173.54, 163.48, 161.01, 145.37, 142.85, 142.76, 136.98, 133.70,
133.22, 131.80, 131.77, 129.50, 128.50, 127.40, 127.22, 127.13, 126.18,
124.68, 123.29, 119.54, 119.42, 119.19, 118.45, 115.25, 115.03, 53.07,
34.84; HRMS: calcd for C23H20FN2O [MþH]þ: 359.1560, found:
359.1557.
3.5.12. 7-Allyl-2-(thiophen-2-yl)-7,8-dihydrodibenzo[e,g][1,4]diazo-
cin-6(5H)-one (18e). The title compound was prepared from com-
pound 17e, following the general procedure for radical cyclization.
Compound 11c: Crystals were obtained from THF and hexane.
Yield: 69%. 1H NMR (400 MHz, CDCl3)
d 8.31 (s, 1H), 7.60e7.50(m,
Mp>235 ꢀC; 1H NMR (400 MHz, d6-DMSO-CDCl3)
d
7.84 (s, 1H),
2H), 7.35e7.25 (m, 2H), 7.17e7.01 (m, 3H), 6.89 (dd, J¼7.7, 1.5 Hz,
1H), 6.85e6.75 (m, 1H), 6.64 (d, J¼8.1 Hz, 1H), 5.78e5.65 (m, 1H),
5.08e5.00 (m, 2H), 4.46e4.38 (m, 1H), 3.93 (d, J¼9.4 Hz, 1H),
7.21e6.91 (m, 7H) 6.54e6.48 (m, 2H), 6.11 (s, 1H), 5.71 (dd, J¼11.3,
5.9 Hz, 1H), 5.17 (dd, J¼5.8, 4.9 Hz, 1H), 2.94 (dd, J¼13.5, 3.8 Hz, 1H),
2.58e2.42 (m, 2H), 2.35e2.22 (m, 1H), 1.99 (dd, J¼13.8, 7.3 Hz, 1H),
2.60e2.35 (m, 2H); 13C NMR (400 MHz, CDCl3)
d 173.90, 145.53,
1.74e1.67 (m, 1H); 13C NMR (400 MHz, d6-DMSO-CDCl3)
d
178.22,
142.94, 140.96, 135.00, 134.59, 133.96, 133.32, 129.86, 129.18, 128.15,
125.89, 125.59, 125.37, 123.93, 123.59, 119.40, 118.17, 117.95, 52.80,
35.47; HRMS: calcd for C21H19N2OS [MþH]þ: 347.1213, found:
347.1202.
160.34, 157.69, 148.13, 138.04, 135.03, 135.01, 127.97, 127.36, 126.79,
126.64, 124.60, 121.84, 116.70, 108.24, 107.02, 100.27, 100.07, 91.38,
91.31, 77.19, 76.31, 76.29, 61.00, 49.92, 49.69, 46.23, 46.21; HRMS:
calcd for C23H20FN2O [MþH]þ: 359.1560, found: 359.1567.
3.5.13. 7-Allyl-2-(4-(trifluoromethyl)phenyl)-7,8-dihydrodibenzo
[e,g][1,4]diazocin-6(5H)-one (18f). The title compound was pre-
pared from compound 17f, following the general procedure for
3.5.8. 7-Allyl-2-phenyl-7,8-dihydrodibenzo[e,g][1,4]diazocin-6(5H)-
one (18a). The title compound was prepared from compound 17a,

9758
C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
radical cyclization. Yield: 34%. 1H NMR (400 MHz, CDCl3)
d
7.99 (s,
1H), 6.42 (d, J¼15.9 Hz, 1H), 6.17e6.00 (m, 1H), 4.37 (m, 1H),
3.88 (d, J¼7.5 Hz, 1H), 3.26 (s, 3H), 2.72e2.52 (m, 2H); 13C NMR
1H), 7.79e7.68 (m, 4H), 7.62e7.59 (m, 2H), 7.20e7.13 (m, 2H), 6.90
(d, J¼7.2 Hz, 1H), 6.81 (t, J¼7.4 Hz, 1H), 6.65 (d, J¼8.2 Hz, 1H),
5.80e5.70 (m, 1H), 5.10e5.00 (m, 2H), 4.41 (dd, J¼16.3, 7.3 Hz, 1H),
3.86 (d, J¼9.5 Hz, 1H), 2.63e2.52 (m, 1H), 2.45e2.35 (m, 1H); 13C
(400 MHz, CDCl3)
d 179.55, 159.72, 141.94, 139.52, 138.16, 136.50,
132.45, 129.61, 129.54,129.19,128.25, 123.87, 123.10, 121.57,
119.16, 119.08, 113.22, 112.79, 111.98, 110.85, 110.79, 64.07, 55.19,
33.74; HRMS: calcd for C24H23N2O2 [MþH]þ: 371.1760, found:
371.1767.
NMR (400 MHz, CDCl3)
d 173.58, 145.52, 143.24, 143.23, 141.20,
139.88, 135.86, 134.01, 133.27, 131.55, 129.32, 127.28, 127.07, 126.03,
125.89, 125.86, 125.82, 125.78, 123.90, 119.54, 118.27, 118.08, 52.82,
35.57; HRMS: calcd for C24H20F3N2O [MþH]þ: 409.1522, found:
409.1508.
3.5.17. rac-4-(((4aS,5S,6aR,11bR)-12-oxo-4a,5,6,7-Tetrahydro-1,6a-
(epiminomethano)indeno[1,7a-b]indol-5-yl)methyl)benzonitrile
(22c). The title compound was prepared from compound 21d,
following the general procedure for radical cyclization. Yield: 65%.
3.5.14. 7-Allyl-2-(p-tolyl)-7,8-dihydrodibenzo[e,g][1,4]diazocin-
6(5H)-one (18g). The title compound was prepared from com-
pound 17g, following the general procedure for radical cyclization.
1H NMR (400 MHz, CDCl3)
d
8.84 (s, 1H), 7.52 (d, J¼8.3 Hz, 2H), 7.19
(d, J¼8.2 Hz, 2H), 7.12e7.02 (m, 2H), 6.68 (dt, J¼7.5, 0.8 Hz, 1H), 6.60
(d, J¼7.9 Hz, 1H), 6.12 (dd, J¼9.4, 5.3 Hz, 1H), 5.62 (dd, J¼9.4, 5.6 Hz,
1H), 5.45 (d, J¼5.3 Hz, 1H), 4.95 (s, 1H), 2.91 (dd, J¼13.5, 4.4 Hz, 1H),
2.68 (dd, J¼13.5, 8.6 Hz, 1H), 2.38e2.15(m, 2H), 2.15 (dd, J¼13.9,
Yield: 30%. 1H NMR (400 MHz, CDCl3)
d 8.21 (s, 1H), 7.59e7.54 (m,
4H), 7.27 (d, J¼7.7 Hz, 2H), 7.12 (d, J¼7.8 Hz, 2H), 6.91 (d, J¼7.3 Hz,
1H), 6.80 (t, J¼7.4 Hz, 1H), 6.65 (d, J¼8.2 Hz, 1H), 5.79e5.65 (m, 1H),
5.10e5.06 (m, 2H), 4.44 (dd, J¼16.2, 7.2 Hz, 1H), 3.92 (d, J¼9.5 Hz,
1H), 2.57 (td, J¼14.0, 8.8 Hz, 1H), 2.47e2.37 (m, 4H); 13C NMR
6.6 Hz, 1H), 1.80e1.72 (m, 1H); 13C NMR (400 MHz, CDCl3)
d 180.73,
149.08,146.25,138.60,132.45,129.82,129.76,128.89,125.35,124.12,
122.79, 119.93, 119.14, 110.71, 110.32, 98.31, 78.25, 61.12, 49.83,
49.32, 41.07, 40.70; HRMS: calcd for C24H20N3O [MþH]þ: 366.1601,
found: 366.159.
(400 MHz, CDCl3)
d 173.87, 145.52, 141.22, 140.77, 137.53, 136.84,
134.66, 134.06, 133.39, 131.07, 129.58, 129.05, 126.77, 126.62, 125.76,
124.34, 119.38, 118.16, 117.91, 52.77, 35.52, 21.08; HRMS: calcd for
C24H23N2O [MþH]þ: 355.1805, found: 355.1796.
3.5.18. rac-4-Fluoro-3-(((4aS,5S,6aR,11bR)-12-oxo-4a,5,6,7-
tetrahydro-1,6a-(epiminomethano)indeno[1,7a-b]indol-5-yl)methyl)
benzonitrile (22d). The title compound was prepared from
compound 21e, following the general procedure for radical cy-
3.5.15. rac-(4aR,5R,6aS,11bS)-5-(4-Methoxybenzyl)-4a,5,6,7-
tetrahydro-1,6a-(epiminomethano)indeno[1,7a-b]indol-12-one (22a)
and 7-(3-(4-methoxyphenyl)allyl)-7,8-dihydrodibenzo[e,g][1,4]diaz-
ocin-6(5H)-one (23a). The title compounds were prepared from
compound 21a, following the general procedure for radical cycli-
zation. Yields-22a: 49%. and 23a: 19%.
clization. Yield: 61%. 1H NMR (400 MHz, CDCl3þDMSO)
d 8.89 (s,
1H), 7.55e7.42 (m, 2H), 7.18e7.07 (m, 3H), 6.65 (t, J¼7.4 Hz, 1H),
6.59 (d, J¼7.8 Hz, 1H), 6.14 (dd, J¼9.3, 5.3 Hz, 1H), 5.58 (dd,
J¼9.4, 5.6 Hz, 1H), 5.43 (d, J¼5.3 Hz, 1H), 4.93 (s, 1H), 2.85 (dd,
J¼13.3, 5.3 Hz, 1H), 2.78 (dd, J¼13.7, 8.0 Hz, 1H), 2.42e2.36 (m,
2H), 2.29 (dd, J¼13.6, 6.9 Hz, 1H), 1.83 (dd, J¼13.2, 11.2 Hz, 1H);
Compound (22a): 1H NMR (400 MHz, CDCl3)
d 8.38 (s, 1H),
7.09e7.05 (m, 2H), 7.02 (d, J¼8.5 Hz, 2H), 6.78 (d, J¼8.5 Hz, 2H), 6.69
(t, J¼7.4 Hz, 1H), 6.61 (d, J¼8.1 Hz, 1H), 6.11 (dd, J¼9.4, 5.3 Hz, 1H),
5.68 (dd, J¼9.3, 5.3 Hz, 1H), 5.44 (d, J¼5.3 Hz, 1H), 4.90 (s, 1H), 3.77
(s, 3H), 2.82 (dd, J¼13.9, 4.3 Hz, 1H), 2.60 (dd, J¼13.7, 7.9 Hz, 1H),
2.39e2.30 (m, 2H), 2.22 (dd, J¼13.9, 6.5 Hz, 1H), 1.81 (dd, J¼13.7,
13C NMR (400 MHz, CDCl3)
d 179.82, 164.62, 162.07, 148.97,
138.84, 135.29, 135.23, 132.48, 132.39, 129.53, 129.41, 129.36,
128.75, 125.39, 123.84, 121.79, 119.48, 118.04, 116.82, 116.58,
110.41, 108.35, 108.31, 97.50, 77.78, 60.78, 49.43, 47.83, 40.441,
33.00; HRMS: calcd for C24H19FN3O [MþH]þ: 384.1507, found:
384.1493.
10.8 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 180.43, 157.95, 148.92,
138.22, 132.39,129.65,129.39,129.02, 124.47,123.85,123.32,119.53,
113.73, 110.40, 97.89, 78.01, 60.95, 55.20, 49.82, 49.57, 40.58, 39.73;
HRMS: calcd for C24H23N2O2 [MþH]þ: 371.1760, found: 371.1747.
Compound (23a): 1H NMR (400 MHz, CDCl3)
d
8.32 (s, 1H),
3.6. Preparation of 50-bromospiro[[1,3]dioxolane-2,30-in-
dolin]-20-one (13)
7.55e7.35 (m, 9H), 6.82e6.70 (m, 2H), 6.63 (d, J¼8.1 Hz,1H), 6.42 (d,
J¼15.9 Hz, 1H), 6.17e6.00 (m, 1H), 4.54 (m, 1H), 3.75 (d, J¼7.5 Hz,
1H), 3.20 (s, 3H), 2.69e2.52 (m, 2H); 13C NMR (400 MHz, d6-DMSO)
To a solution of 5-bromoisatin (1 g, 4.42 mmol) in toluene
(40 mL), ethylene glycol (4.9 mL, 84.48 mmol) and p-toluene-
sulphonic acid (38.1 mg, 0.22 mmol) were added. The reaction
mixture was refluxed for 5 h and then evaporated to dryness.
The residue was diluted with DCM and washed with saturated
sodium bicarbonate solution. The aqueous layer was extracted
with DCM three times. The combined organic extracts were
dried over anhydrous sodium sulfate, filtered, and evaporated.
The crude mixture was purified using column chromatography
d
178.27, 159.62, 142.78, 141.56, 135.66, 133.07, 130.19, 129.96,
129.82, 129.08, 128.11, 124.17, 122.86, 120.02, 119.43, 114.75, 112.94,
111.01, 110.31, 56.99, 55.78, 33.82; HRMS: calcd for C24H23N2O2
[MþH]þ: 371.1760, found: 371.1750.
3.5.16. rac-(4aR,5R,6aS,11bS)-5-(3-Methoxybenzyl)-4a,5,6,7-
tetrahydro-1,6a-(epiminomethano)indeno[1,7a-b]indol-12-one (22b)
and 7-(3-(3-methoxyphenyl)allyl)-7,8-dihydrodibenzo[e,g][1,4]diaz-
ocin-6(5H)-one (23b). The title compounds were prepared from
compound 21b, following the general procedure for radical cycli-
zation. Yields-22b: 27% and 23b: 24%.
to yield 13. Yield: 99%. 1H NMR (400 MHz, CDCl3)
d 8.03 (d,
J¼6.7 Hz, 1H), 7.46e7.41 (m, 2H), 6.71 (d, J¼8.3 Hz, 1H),
4.60e4.52 (m, 2H), 4.38e4.30 (m, 2H); 13C NMR (400 MHz,
Compound 22b: 1H NMR (400 MHz, CDCl3)
d
8.17(s, 1H),
CDCl3) d 176.24, 140.64, 134.36, 128.54, 126.37, 115.82, 112.11,
7.21e7.13 (m, 1H), 7.12e7.07 (m, 2H), 6.75e6.60 (m, 5H), 6.19 (dd,
J¼9.4, 5.4 Hz, 1H), 5.74 (dd, J¼9.3, 5.9 Hz, 1H), 5.41 (d, J¼5.4 Hz, 1H),
4.89 (s, 1H), 3.78 (s, 3H), 2.94e2.82 (m, 1H), 2.61 (dd, J¼13.3, 8.9 Hz,
1H), 2.42e2.32 (m, 2H), 2.29e2.20 (m, 1H), 1.90e1.82 (m, 1H); 13C
112.05, 65.96; HRMS: calcd for C10H979BrNO3 [MþH]þ: 269.9760,
found: 269.9749.
3.7. General procedure for Suzuki reaction: (for example
preparation of 14a)
NMR (400 MHz, CDCl3)
d 180.23, 159.55, 148.92, 141.93, 138.18,
129.42, 129.30, 128.96, 124.60, 123.85, 123.19, 121.18, 119.56, 114.66,
111.21, 110.43, 97.86, 77.98, 60.96, 55.12, 49.66, 49.50, 40.74, 40.66;
HRMS: calcd for C24H23N2O2 [MþH]þ: 371.1760, found: 371.1762.
3.7.1. 50-Phenylspiro[[1,3]dioxolane-2,30-indolin]-20-one (14a). To
a solution of 13 (500 mg, 1.85 mmol) in ethylene glycol dimethyl
ether (5 mL), dichlorobis(triphenylphosphine)palladium (II)
(39 mg, 0.0555 mmol) was added. The reaction mixture was
Compound 23b: 1H NMR (400 MHz, d6-benzene)
d 7.91
(s, 1H), 7.35e7.01 (m, 9H), 6.86e6.73 (m, 2H), 6.63 (d, J¼8.1 Hz,

C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
9759
stirred at room temperature for 15 min. Phenylboronic acid
(338 mg, 2.775 mmol), sodium bicarbonate (466.6 mg,
5.55 mmol), and water (5 mL) were added. The reaction mixture
was refluxed for 2 h and then evaporated to dryness. The residue
was diluted with DCM and washed with 10% sodium hydroxide
solution. The aqueous layer was extracted with DCM three times.
The combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and evaporated. The crude mixture was purified
using column chromatography to yield 14a. Yield: 81%. 1H NMR
125.75, 125.71, 125.56, 125.20, 124.25, 122.85, 111.03, 102.08, 65.92;
HRMS: calcd for C17H13F3NO3 [MþH]þ: 336.0842, found: 336.0828.
3.7.7. 50-(p-Tolyl)spiro[[1,3]dioxolane-2,30-indolin]-20-one
(14g). The title compound was prepared from compound 13 and 4-
methylphenylboronic acid, following the general procedure for
Suzuki reaction. Yield: 58%. 1H NMR (400 MHz, CDCl3)
d 7.75 (s, 1H),
7.56 (s, 1H), 7.50 (dd, J¼8.1,1.7 Hz,1H), 7.41 (d, J¼8.0 Hz, 2H), 7.21 (d,
J¼8.0 Hz, 2H), 6.86 (d, J¼8.1 Hz, 1H), 4.58 (t, J¼6.7 Hz, 2H), 4.34 (t,
J¼6.7 Hz, 2H), 2.37 (s, 3H); 13C NMR (400 MHz, d6-acetone)
(400 MHz, CDCl3) d 7.82 (s, 1H), 7.59 (s, 1H), 7.55e7.48 (m, 3H), 7.41
(t, J¼7.6 Hz, 2H), 7.32 (t, J¼7.3 Hz, 1H), 6.89 (d, J¼8.1 Hz, 1H), 4.59
d 175.35, 159.04, 140.18, 136.64, 132.90, 129.87, 127.77, 124.80,
(dt, J¼6.1, 4.2 Hz, 2H), 4.35 (dt, J¼6.3, 4.2 Hz, 2H); 13C NMR
123.82, 114.18, 110.56, 65.85, 55.30, 22.25; HRMS: calcd for
(400 MHz, CDCl3)
d
175.13, 140.86, 140.32, 136.93, 130.36, 128.75,
C17H16NO3 [MþH]þ: 282.1125, found: 282.1116.
127.16, 126.746, 124.91, 124.16, 110.77, 102.21, 65.87; HRMS: calcd
for C16H14NO3 [MþH]þ: 268.0968, found: 268.0959.
3.8. General procedure for ketal deprotection: (for example
preparation of 15a)
3.7.2. 50-(4-Methoxyphenyl)spiro[[1,3]dioxolane-2,30-indolin]-20-one
(14b). The title compound was prepared from compound 13 and 4-
methoxyphenylboronic acid, following the general procedure for
3.8.1. 5-Phenylindoline-2,3-dione (15a). To
a solution of 14a
(630 mg, 2.36 mmol) in methanol (12 mL), concd HCl (5 mL) was
added and the mixture was allowed to reflux for 4 h. The reaction
mixture was evaporated to dryness. The residue was diluted with
DCM and washed with saturated sodium bicarbonate solution. The
aqueous layer was extracted with DCM three times. The combined
organic extracts were dried over anhydrous sodium sulfate, filtered,
and evaporated. The crude mixture was purified using column
chromatography to yield 15a. Yield: 99%. 1H NMR (400 MHz, DMSO)
Suzuki reaction. Yield: 61%. 1H NMR (400 MHz, CDCl3)
d 9.44 (s, 1H),
7.32 (s, 1H), 7.30e7.25 (m, 3H), 6.76 (d, J¼8.7 Hz, 2H), 6.69 (d,
J¼8.1 Hz, 1H), 4.39 (dd, J¼8.2, 5.2 Hz, 2H), 4.15 (dd, J¼7.9, 5.6 Hz,
2H), 3.65 (s, 3H); 13C NMR (400 MHz, d6-acetone)
d 175.54, 160.17,
142.76, 136.45, 133.74, 130.41, 128.45, 126.66, 124.10, 115.18, 111.65,
103.07, 66.56, 55.67; HRMS: calcd for C17H16NO4 [MþH]þ: 298.1074,
found: 298.1062.
d
7.90 (d, J¼8.2 Hz, 1H), 7.75 (s, 1H), 7.69e7.61 (m, 2H), 7.52e7.40
(m, 2H), 7.40e7.36 (m, 1H), 7.03e6.97 (m, 1H); 13C NMR (400 MHz,
d6-acetone) 183.91, 159.09, 149.88, 139.28, 136.65, 136.10, 128.93,
3.7.3. 4-(20-Oxospiro[[1,3]dioxolane-2,30-indolin]-50-yl)benzonitrile
(14c). The title compound was prepared from compound 13 and 4-
cyanophenylboronic acid, following the general procedure for
d
127.48, 126.37, 122.61, 118.66, 112.69; HRMS: calcd for C14H10NO2
Suzuki reaction. Yield: 48%. 1H NMR (400 MHz, CDCl3)
d
7.78e7.58
[MþH]þ: 224.0706, found: 224.0698.
(m,7H), 6.93 (d, J¼8.1 Hz, 1H), 4.60 (dt, J¼6.0, 4.1 Hz, 2H), 4.36 (dt,
J¼6.3, 4.2 Hz, 2H); 13C NMR (400 MHz, CDCl3)
d
175.43, 144.68,
3.8.2. 5-(4-Methoxyphenyl)indoline-2,3-dione (15b). The title com-
pound was prepared from compound 14b, following the general
procedure for ketal deprotection. Yield: 99%. 1H NMR (400 MHz,
CDCl3)
1H), 7.41 (d, J¼8.8 Hz, 2H), 6.93 (dd, J¼8.4, 6.9 Hz, 3H), 3.81 (s, 3H);
13C NMR (400 MHz, d6-acetone)
184.09, 142.89, 140.56, 137.42,
136.93, 136.881, 135.66, 130.11, 129.45, 128.72, 126.56, 124.83,
123.93, 110.71, 58.85; HRMS: calcd for C15H12NO3 [MþH]þ:
254.0812, found: 254.0801.
142.10, 134.67, 132.63, 130.65, 127.24, 125.93, 125.32, 124.30, 118.81,
110.99, 110.81, 65.90; HRMS: calcd for C17H13N2O3 [MþH]þ:
293.0921, found: 293.0922.
d
10.23 (s, 1H), 7.70 (d, J¼1.3 Hz, 1H), 7.66 (dd, J¼8.1, 2.0 Hz,
3.7.4. 50-(4-Fluorophenyl)spiro[[1,3]dioxolane-2,30-indolin]-20-one
(14d). The title compound was prepared from compound 13 and 4-
fluorophenylboronic acid, following the general procedure for
d
Suzuki reaction. Yield: 69%. 1H NMR (400 MHz, CDCl3)
d 8.06 (s, 1H),
7.53e7.45 (m, 4H), 7.13e7.05 (m, 2H), 6.89 (d, J¼8.1 Hz, 1H), 4.60
(dd, J¼8.3, 5.1 Hz, 2H), 4.36 (dd, J¼7.9, 5.5 Hz, 2H); 13C NMR
3.8.3. 4-(2,3-Dioxoindolin-5-yl)benzonitrile (15c). The title com-
pound was prepared from compound 14c, following the general
procedure for ketal deprotection. Yield: 70%. 1H NMR (400 MHz,
(400 MHz, CDCl3)
d 175.12, 163.55, 161.10, 140.88, 136.48, 136.45,
135.95, 130.24, 128.35, 128.27, 124.96, 124.03, 115.72, 115.51, 110.82,
65.86; HRMS: calcd for C16H13FNO3 [MþH]þ: 286.0874, found:
286.0862.
CDCl3)
d
9.73 (s, 1H), 7.79 (s, 1H), 7.76 (dd, J¼8.3, 1.8 Hz, 1H), 7.70 (d,
J¼8.4 Hz, 2H), 7.64 (d, J¼8.2 Hz, 2H), 7.03 (d, J¼8.1 Hz, 1H); 13C NMR
(400 MHz, d6-acetone)
d 183.96, 159.10, 149.65, 137.20, 136.41,
3.7.5. 50-(Thiophen-2-yl)spiro[[1,3]dioxolane-2,30-indolin]-20-one
(14e). The title compound was prepared from compound 13 and
2-thiopheneboronic acid, following the general procedure for
136.09, 134.15, 131.79, 129.56, 126.22, 122.34, 118.63, 112.62; HRMS:
calcd for C15H9N2O2 [MþH]þ: 249.0659, found: 249.0655.
Suzuki reaction. Yield: 33%. 1H NMR (400 MHz, CDCl3)
d
7.82e7.65
3.8.4. 5-(4-Fluorophenyl)indoline-2,3-dione (15d). The title com-
pound was prepared from compound 14d, following the general
procedure for ketal deprotection. Yield: 93%. 1H NMR (400 MHz,
(m, 3H), 7.28e7.20 (m, 2H), 7.05 (dd, J¼4.9, 3.8 Hz, 1H), 6.83 (d,
J¼8.0 Hz, 1H), 4.59 (dt, J¼6.3, 4.9 Hz, 2H), 4.37 (dt, J¼7.6, 4.4,
1.8 Hz, 2H); 13C NMR (400 MHz, d6-acetone)
d
175.42, 144.48,
CDCl3)
d
9.14 (s, 1H), 7.75 (s, 1H), 7.70 (dd, J¼8.0, 2.0 Hz, 1H),
143.39, 132.38, 130.25, 129.84, 129.13, 126.85, 125.98, 125.36,
123.70, 123.39, 111.89, 66.63; HRMS: calcd for C14H12NO3S
[MþH]þ: 274.0532, found: 274.052.
7.50e7.42 (m, 2H), 7.13 (t, J¼8.6 Hz, 2H), 6.98 (d, J¼8.1 Hz, 1H); 13C
NMR (400 MHz, d6-acetone)
d 185.81, 165.61, 163.17, 160.98, 151.81,
138.50, 137.64, 136.99, 130.36, 130.28, 126.42, 124.90, 124.51, 120.58,
117.64, 117.43, 114.63; HRMS: calcd for C14H9FNO2 [MþH]þ:
242.0612, found: 242.0601.
3.7.6. 50-(4-(Trifluoromethyl)phenyl)spiro[[1,3]dioxolane-2,30-in-
dolin]-20-one (14f). The title compound was prepared from com-
pound 13 and 4-trifluoromethlyphenylboronic acid, following the
general procedure for Suzuki reaction. Yield: 52%. 1H NMR
3.8.5. 5-(Thiophen-2-yl)indoline-2,3-dione (15e). The title com-
pound was prepared from compound 14e, following the general
procedure for ketal deprotection. Yield: 88%. 1H NMR (400 MHz,
(400 MHz, CDCl3)
1H), 4.75e4.63 (m, 2H), 4.51e4.41 (m, 2H); 13C NMR (400 MHz,
CDCl3) 175.15,143.76,141.76,135.31,130.63,129.40,129.08, 126.97,
d
8.23 (s, 1H), 7.80e7.68 (m, 6H), 7.02 (d, J¼8.1 Hz,
CDCl3)
d
9.16 (s, 1H), 7.81 (s, 1H), 7.76 (dd, J¼8.2, 1.9 Hz, 1H),
d
7.32e7.22 (m, 2H), 7.07 (dd, J¼4.8, 3.8 Hz, 1H), 6.92 (d, J¼7.8 Hz,

9760
C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
1H); 13C NMR (400 MHz, d6-acetone)
d
184.76, 159.94, 150.69,
7.8, 1.3 Hz, 1H), 6.00 (td, J¼15.5, 7.6, 7.6 Hz, 1H), 5.77 (dd, J¼8.2,
1.2 Hz, 1H), 5.30 (s, 1H), 3.72 (s, 3H), 2.76e2.70 (m, 2H); 13C NMR
(400 MHz, d6-DMSO) d 178.27, 159.62, 142.78, 141.56, 135.66, 133.07,
130.19, 129.96, 129.82, 129.08, 128.11, 124.17, 122.86, 120.02, 119.43,
114.75, 112.94, 111.01, 110.31, 63.99, 55.78, 43.82; HRMS: calcd for
C24H2279BrN2O2 [MþH]þ: 449.0865, found: 449.0854.
143.30, 139.27, 136.20, 129.30, 126.00, 124.42, 122.17, 119.61, 113.82;
HRMS: calcd for C12H8NO2S [MþH]þ: 230.0270, found: 230.0269.
3.8.6. 5-(4-(Trifluoromethyl)phenyl)indoline-2,3-dione (15f). The ti-
tle compound was prepared from compound 14f, following the
general procedure for ketal deprotection. Yield: 97%. 1H NMR
(400 MHz, CDCl3)
1H), 7.70 (d, J¼8.4 Hz, 2H), 7.64 (d, J¼8.2 Hz, 2H), 6.95 (d, J¼8.1 Hz,
1H); 13C NMR (400 MHz, d6-acetone)
183.88, 163.68, 161.25,
149.88, 136.57, 136.54, 135.72, 135.06, 128.43, 128.35,122.97, 122.58,
118.65, 115.71, 115.50, 112.70; HRMS: calcd for C15H9F3NO2 [MþH]þ:
292.0580, found: 292.0578.
d
10.73 (s, 1H), 7.79 (s, 1H), 7.76 (dd, J¼8.3, 1.8 Hz,
3.10.2. (E)-3-((2-Bromophenyl)amino)-3-(3-(3-methoxyphenyl)allyl)
indolin-2-one (21b). The title compound was prepared from com-
pound 3a and 3-bromoanisole, following the general procedure for
intermolecular Heck reaction. Yield: 25%. 1H NMR (400 MHz, CDCl3)
d
d
9.02 (s, 1H), 7.36 (d, J¼7.9 Hz, 1H), 7.30e7.18 (m, 3H), 7.04 (t,
J¼7.5 Hz, 1H), 6.94e6.70 (m, 5H), 6.63 (d, J¼15.9 Hz, 1H), 6.48 (t,
J¼7.64 Hz, 1H), 6.19 (td, J¼15.4, 7.7, 7.7 Hz, 1H), 5.86 (d, J¼8.1 Hz,
1H), 5.25 (s, 1H), 3.80 (s, 3H), 2.92 (dd, J¼13.4, 7.3 Hz, 1H), 2.77 (dd,
3.8.7. 5-(p-Tolyl)indoline-2,3-dione (15g). The title compound was
prepared from compound 14g, following the general procedure for
J¼13.5, 8.1 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d 179.55, 159.72,
ketal deprotection. Yield: 93%. 1H NMR (400 MHz, CDCl3)
d
9.42 (s,
141.94, 139.52, 138.16, 136.50, 132.45, 129.61, 129.54, 129.19, 128.25,
123.87, 123.10, 121.57, 119.16, 119.08, 113.22, 112.79, 111.98, 110.85,
110.79, 64.07, 55.19, 43.74; HRMS: calcd for C24H2279BrN2O2
[MþH]þ: 449.0865, found: 449.0852.
1H), 7.82 (s,1H), 7.76 (d, J¼8.3 Hz,1H), 7.41 (d, J¼8.4 Hz, 2H), 7.28 (d,
J¼8.2 Hz, 2H), 6.95 (d, J¼8.1 Hz, 1H), 2.40 (s, 3H); 13C NMR
(400 MHz, d6-acetone)
d 183.95, 159.10, 149.65, 137.21, 136.42,
136.09, 134.15, 129.57, 126.23, 122.35, 118.64, 112.63, 20.11; HRMS:
calcd for C15H12NO2 [MþH]þ: 238.0863, found: 238.0863.
3.11. General procedure for Stille reaction: (for example
preparation of 20a)
3.9. Intramolecular Heck reaction: (preparation of 28)
3.11.1. 1-(Trifluoromethoxy)-4-vinylbenzene (20a). To a solution of
1-bromo-4-trifluoromethoxybenzene 19a (345.5 mg, 1.43 mmol)
in DMF (3 mL), tributyl(vinyl)tin (500 mg, 1.58 mmol) and tet-
rakis(triphenylphosphine)palladium(0) (82.8 mg, 0.072 mmol)
were added. The reaction mixture was then refluxed for 2 days
and then evaporated to dryness. The residue was diluted with
DCM and washed with saturated aqueous sodium chloride. The
aqueous layer was extracted with DCM three times. The com-
bined organic extracts were dried over anhydrous sodium sulfate,
filtered, and evaporated. The crude compound was purified by
column chromatography to give 20a. Yield 60%. 1H NMR
3.9.1. 40-Methylene-30,40-dihydro-1’H-spiro[indoline-3,20-quinolin]-
2-one (28). To a solution of 3a (200 mg, 0.58 mmol) in CH3CN
(9 mL) and water (3 mL), Pd(OAc)2 (6.54 mg, 0.03 mmol),
PPh3(15.3 mg, 0.06 mmol), and triethylamine (0.10 mL, 2.56 mmol)
were added. The reaction mixture was refluxed for 24 h and then
evaporated to dryness. The residue was diluted with DCM and
washed with water. The aqueous layer was extracted with DCM
three times. The combined organic extracts were dried over an-
hydrous sodium sulfate, filtered, and evaporated. The crude com-
pound was purified by column chromatography to yield 28. Yield:
13%. 1H NMR (400 MHz, CDCl3)
d
8.30 (s, 1H), 7.56 (d, J¼7.9 Hz, 1H),
(400 MHz, CDCl3)
d
7.37 (d, J¼8.8 Hz, 2H), 7.12 (d, J¼8.8 Hz, 2H),
7.22 (t, J¼7.8 Hz, 1H), 7.17e7.07 (m, 2H), 6.96 (t, J¼7.6 Hz, 1H), 6.88
(d, J¼7.7 Hz, 1H), 6.78 (t, J¼7.6 Hz, 1H), 6.57 (d, J¼8.1 Hz,1H), 5.64 (s,
1H), 4.87 (s, 1H), 4.24 (s, 1H), 3.01 (d, J¼14.0 Hz, 1H), 2.60 (d,
6.65 (dd, J¼17.6, 10.9 Hz, 1H), 5.68 (d, J¼17.6 Hz, 1H), 5.24 (d,
J¼10.4 Hz, 1H).
J¼13.5 Hz, 1H); 13C NMR (400 MHz, d6-acetone)
d
177.82, 143.73,
3.11.2. 4-Fluoro-3-vinylbenzonitrile (20b). The title compound was
prepared from compound 19b, following the general procedure for
140.99, 137.41, 133.60, 129.46, 128.93, 124.42, 124.15, 122.10, 119.33,
117.28, 115.32, 109.73, 108.41, 60.40, 39.52; HRMS: calcd for
C17H15N2O [MþH]þ: 263.1179, found: 263.1168.
Stille reaction. Yield: 38%. 1H NMR (400 MHz, CDCl3)
d 7.79 (dd,
J¼6.9, 1.8 Hz, 1H), 7.53 (ddd, J¼8.3, 4.6, 2.1 Hz, 1H), 7.15 (dd, J¼9.6,
8.8 Hz, 1H), 6.82 (dd, J¼17.7, 11.0 Hz, 1H), 5.89 (d, J¼17.8 Hz, 1H),
5.52 (d, J¼11.2 Hz, 1H).
3.10. General procedure for intermolecular Heck reaction:
(for example preparation of 8a)
3.11.3. 1-Methoxy-4-vinylbenzene (20c). The title compound was
prepared from compound 19c, following the general procedure for
To a solution of 3a (300 mg, 0.87 mmol) in CH3CN (24 mL) and
water (8 mL), Pd(OAc)2 (9.8 mg, 0.05 mmol) and PPh3(25.2 mg,
0.09 mmol) were added. The reaction mixture was stirred under
nitrogen to which triethylamine (0.14 mL, 0.96 mmol) and bro-
mobenzene (0.33 mL, 2.56 mmol) were added dropwise. The
mixture was refluxed for 2 days and then evaporated to dryness.
The residue was diluted with DCM and washed with water. The
aqueous layer was extracted with DCM three times. The combined
organic extracts were dried over anhydrous sodium sulfate, filtered,
and evaporated. The crude compound was purified by column
chromatography to yield 8a. Yield 24%.
Stille reaction. Yield: 30%. 1H NMR (400 MHz, CDCl3)
d 7.38 (d,
J¼9.1 Hz, 2H), 6.78 (d, J¼9.1 Hz, 2H), 6.66 (dd, J¼17.6, 10.9 Hz, 1H),
5.61 (dd, J¼17.6, 0.9 Hz, 1H), 5.12 (dd, J¼10.9, 0.9 Hz, 1H), 3.81
(s, 3H).
3.11.4. 4-Vinylbenzonitrile (20d). The title compound was prepared
from compound 19d, following the general procedure for Stille
reaction. Yield: 99%. 1H NMR (400 MHz, CDCl3)
d 7.63e7.59 (m, 2H),
7.55e7.48 (m, 2H), 6.72 (dd, J¼17.6, 10.9 Hz, 1H), 5.87 (d, J¼17.6 Hz,
1H), 5.44 (d, J¼10.9 Hz, 1H).
3.10.1. (E)-3-((2-Bromophenyl)amino)-3-(3-(4-methoxyphenyl)allyl)
indolin-2-one (21a). The title compound was prepared from com-
pound 3a and 4-bromoanisole, following the general procedure for
intermolecular Heck reaction. Yield: 27%. Crystals were obtained
from DCM and hexane. Mp 199e200 ꢀC; 1H NMR (400 MHz,
3.12. General procedure for intermolecular Grubb’s metath-
esis: (for example preparation of 21d)
3.12.1. (E)-4-(3-(3-((2-Bromophenyl)-amino)-2-oxoindolin-3-yl)
prop-1-en-1-yl)benzonitrile (21d). To a solution of 3a (201.6 mg,
1.56 mmol) in DCM (20 mL), 20d (535.7 mg, 1.56 mmol) and
second generation Grubb’s catalyst (66.2 mg, 0.08 mmol) were
d6-DMSO)
d
10.84 (s, 1H), 7.38 (dd, J¼7.9, 1.3 Hz, 1H), 7.32e7.17
(m, 4H), 7.03e6.80 (m, 5H), 6.58 (d, J¼15.8 Hz, 1H), 6.48 (dt, J¼7.8,

C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
9761
added. The solution was then refluxed for 1 day. The reaction
3.14. General procedures for alkylation of amide nitrogen:
(for example preparation of 25a)
mass was diluted with DCM and washed with water. The
aqueous layer was extracted with DCM three times. The com-
bined organic extracts were dried over anhydrous sodium sul-
fate, filtered, and evaporated. The crude compound was purified
by column chromatography to give 21d. Yield: 20%. 1H NMR
3.14.1. 7,8-Diallyl-5-methyl-7,8-dihydrodibenzo[e,g][1,4]diazocin-
6(5H)-one (25a). To a solution of 24 (100 mg, 0.33 mmol) in DMF,
cesium carbonate (214 mg, 0.65 mmol) and methyl iodide (0.04 mL,
0.65 mmol) were added. The reaction mixture was stirred for 18 h.
The mixture was then evaporated to dryness, diluted with DCM and
the organic layer was washed with water. The aqueous layer was
extracted with DCM three times. The combined organic extracts
were dried over anhydrous sodium sulfate, filtered, and evaporated.
The crude mixture was purified using column chromatography to
(400 MHz, CDCl3)
d
8.43 (s, 1H), 7.58 (d, J¼8.4 Hz, 2H), 7.41 (d,
J¼8.3 Hz, 2H), 7.36 (dd, J¼7.9, 1.5 Hz, 1H), 7.31e7.21 (m,2H), 7.07
(dt, J¼7.5, 0.9 Hz, 1H), 6.94 (d, J¼7.8 Hz, 1H), 6.79 (dt, J¼8.3,
1.4 Hz, 1H), 6.66 (d, J¼15.8 Hz, 1H), 6.50 (dt, J¼7.7 1.4 Hz, 1H),
6.36 (ddd, J¼15.5, 8.1, 7.1 Hz, 1H), 5.87 (dd, J¼8.2, 1.4 Hz, 1H),
5.18 (s, 1H), 2.93 (ddd, J¼13.4, 6.9, 1.2 Hz, 1H), 2.83 (ddd, J¼13.4,
8.3, 0.8 Hz, 1H); 13C NMR (400 MHz, CDCl3)
d
178.67, 141.75,
give 25a. Yield: 77%. 1H NMR (400 MHz, CDCl3)
d 7.52e7.33 (m, 3H),
140.94, 139.29, 134.72, 132.48, 132.40, 129.41, 129.37, 128.23,
126.85, 125.51, 123.82, 123.28, 119.42, 118.75, 112.80, 111.06,
110.93, 110.63, 63.88, 43.74; HRMS: calcd for C24H1979BrN3O
[MþH]þ: 444.0706, found: 444.0694.
7.29e7.23 (m, 2H), 7.16e7.08 (m, 2H), 7.02 (dd, J¼7.7, 1.5 Hz, 1H),
5.80e5.67 (m, 1H), 5.65e5.50 (m, 1H), 5.11e4.79 (m, 4H), 3.83 (dd,
J¼9.6, 3.6 Hz, 1H), 3.48e3.24 (m, 2H), 2.98 (s, 3H), 2.87e2.67 (m,
1H), 2.49e2.33 (m, 1H); 13C NMR (400 MHz, CDCl3)
d 170.63, 148.17,
142.17, 140.10, 136.15, 135.36, 135.06, 130.90, 130.59, 130.36, 129.15,
127.77, 125.55, 125.08, 116.77, 116.54, 63.84, 57.47, 36.51, 36.11;
HRMS: calcd for C21H23N2O [MþH]þ: 319.1805, found: 319.1802.
3.12.2. (E)-3-((2-Bromophenyl)amino)-3-(3-(4-(trifluoromethoxy)
phenyl)allyl)indolin-2-one (21c). The title compound was pre-
pared from compound 3a and 20a, following the general pro-
cedure for intermolecular Grubbs Metathesis. Yield: 25%. 1H NMR
3.14.2. 7,8-Diallyl-5-benzyl-7,8-dihydrodibenzo[e,g][1,4]diazocin-
6(5H)-one atropisomers of (25b) and (25c). The title compound was
prepared from compound 24 and benzylbromide, following the
general procedure for alkylation of amide nitrogen. (25b: 51% and
25c: 24%).
(400 MHz, CDCl3)
d 8.29 (s, 1H), 7.40e7.00 (m, 8H), 6.94 (d,
J¼7.8 Hz, 1H), 6.79 (dt, J¼8.3, 1.4 Hz, 1H), 6.66 (d, J¼15.8 Hz, 1H),
6.50 (dt, J¼7.7, 1.4 Hz, 1H), 6.36 (ddd, J¼15.5, 8.1, 7.1 Hz, 1H), 5.87
(dd, J¼8.2, 1.4 Hz, 1H), 5.18 (s, 1H), 2.93e2.83 (m, 2H); 13C NMR
(400 MHz, CDCl3)
d 179.76, 141.89, 139.58, 135.40, 135.03, 132.47,
Compound 25b: 1H NMR (CDCl3, 600 MHz)
d
7.40 (1H, td, J¼7.5,
130.01, 129.54, 129.11, 128.63, 128.31, 128.01, 126.42, 122.39,
120.24, 119.60, 117.68, 112.80, 112.56, 111.55, 110.97, 110.84, 64.10,
43.75; HRMS: calcd for C24H1979BrF3N2O2 [MþH]þ: 503.0577,
found: 503.0568.
1.8 Hz), 7.36 (1H, td, J¼7.5, 1.7 Hz), 7.26 (1H, dd, J¼1.8, 7.4 Hz), 7.18 (1H,
td, J¼7.6, 1.8 Hz), 7.17 (1H, dd, J¼7.7, 1.5 Hz), 7.12 (1H, tt, J¼1.8, 7.3 Hz),
7.07 (1H, dd, J¼1.6, 8.0 Hz), 7.02 (2H, t, J¼7.8 Hz), 6.85 (1H, td, J¼7.5,
1.7 Hz), 6.81 (2H, d, J¼7.8 Hz), 6.35 (1H, dd, J¼1.8, 7.5 Hz), 5.79 (1H, m),
5.55(1H, m), 5.07(1H, dq, J¼17.3,1.8Hz), 5.04 (1H, bd, J¼10.3Hz), 4.97
(1H, d, J¼14.3 Hz), 4.87 (1H, dq, J¼17.0,1.7 Hz), 4.84 (1H, bd, J¼9.9 Hz),
4.44(1H, d,J¼14.3Hz),3.83(1H,dd, J¼3.5,9.7Hz),3.38(1H,ddt,J¼5.1,
14.9, 1.6 Hz), 3.28 (1H, dd, J¼7.9, 14.9 Hz), 2.82 (1H, m), 2.45 (1H, m);
3.12.3. (E)-3-(3-(3-((2-Bromophenyl)amino)-2-oxoindolin-3-yl)
prop-1-en-1-yl)-4-fluorobenzonitrile (21e). The title compound was
prepared from compound 3a and 20b, following the general pro-
cedure for intermolecular Grubbs Metathesis. Yield: 24%. 1H NMR
13C NMR (400 MHz, CDCl3)
d 170.31, 147.66, 140.86, 140.25, 136.45,
(400 MHz, CDCl3)
d
8.98 (s, 1H), 7.37 (dd, J¼7.8, 1.0 Hz, 1H),
136.32, 135.23, 135.02, 130.77, 130.08, 128.81, 128.51, 128.10, 127.70,
126.96,125.74,125.02,116.89,116.51, 63.87, 57.71, 52.23,36.67;HRMS:
calcd for C27H27N2O [MþH]þ: 395.2118, found: 395.2111.
7.24e7.17 (m, 3H), 7.18 (d, J¼7.3 Hz, 1H), 7.01 (t, J¼7.5 Hz, 1H), 6.92
(d, J¼7.7 Hz, 1H), 6.78 (t, J¼7.4 Hz, 1H), 6.48 (dt, J¼7.9, 0.9 Hz, 1H),
5.92e5.82 (m, 2H), 5.42e5.30 (m, 2H), 5.20 (s, 1H), 2.78 (dd, J¼13.3,
7.4 Hz, 1H), 2.64 (dd, J¼13.2, 7.5 Hz, 1H); 13C NMR (400 MHz, CDCl3)
Compound 25c: 1H NMR (CDCl3, 600 MHz)
d
7.40 (1H, td, J¼7.5,
1.6 Hz), 7.35 (1H, td, J¼7.5, 1.4 Hz), 7.26 (1H, td, J¼1.6, 7.3 Hz), 7.23
(1H, dd, J¼7.8, 1.4 Hz), 7.19 (1H, dd, J¼8.1, 1.3 Hz), 7.17 (1H, tt, J¼1.4,
7.5 Hz), 7.12 (1H, dd, J¼1.8, 7.5 Hz), 7.08 (2H, t, J¼7.6 Hz), 6.87 (1H, td,
J¼7.4, 1.3 Hz), 6.81 (2H, d, J¼7.9 Hz), 6.47 (1H, dd, J¼1.6, 7.4 Hz), 5.80
(1H, m), 5.45 (1H, m), 5.10e5.15 (2H, m), 4.91 (1H, d, J¼14.2 Hz),
4.87e4.93 (2H, m), 4.38 (1H, d, J¼14.2 Hz), 3.97 (1H, dd, J¼5.1,
10.5 Hz), 3.78 (1H, ddt, J¼6.7, 15.6, 1.4 Hz), 3.59 (1H, ddt, J¼4.2, 15.6,
2.0 Hz), 2.40 (1H, m), 2.05 (1H, m); 13C NMR (400 MHz, CDCl3)
d
180.70,160.52,158.21,142.70, 137.99,136.32,134.19, 134.17,132.41,
131.39, 131.60, 128.78, 128.45, 127.95, 127.45, 120.48, 119.47, 115.85,
115.61, 112.61, 111.79, 111.20, 111.12, 110.94, 63.34, 42.85; HRMS:
calcd for C24H1879BrFN3O [MþH]þ: 462.0612, found: 462.0598.
3.13. Preparation of 24
3.13.1. 7,8-Diallyl-7,8-dihydrodibenzo[e,g][1,4]diazocin-6(5H)-one
(24). To a solution of 7a (25 mg, 0.09 mmol) in DMF, allyl bro-
mide (0.01 mL, 0.11 mmol) and sodium iodide (21.2 mg,
0.14 mmol) were added. The resulting mixture was stirred at
room temperature for 16 h. The reaction mixture was then
evaporated to dryness, diluted with DCM and the organic layer
was washed with water. The aqueous layer was extracted with
DCM three times. The combined organic extracts were dried over
anhydrous sodium sulfate, filtered, and evaporated. The crude
mixture was purified by column chromatography to yield 24.
d 169.78, 147.66, 140.74, 140.23, 136.66, 136.44, 135.36, 133.96,
129.23, 128.92, 128.64, 128.59, 128.04, 128.00, 127.48, 127.05, 125.88,
123.91,122.52,117.34,116.61, 73.59, 54.67, 54.49, 35.84; HRMS: calcd
for C27H27N2O [MþH]þ: 395.2118, found: 395.2111.
3.15. General procedure for ring closing metathesis: (for ex-
ample preparation of 26a)
3.15.1. 11-Benzyl-9,9a-dihydro-6H-dibenzo[e,g]pyrido[1,2-a][1,4]di-
azocin-10(11H)-one (26a). To
a solution of 25b (127.9 mg,
Yield: 80%. 1H NMR (400 MHz, CDCl3)
d
7.48e6.97 (m, 8H),
0.32 mmol) in DCM (10 mL), first generation Grubb’s catalyst
(13.3 mg, 0.02 mmol) was added. The reaction mass was refluxed
for 2 h. The mixture was then diluted with DCM and washed with
water. The aqueous layer was extracted with DCM three times. The
combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and evaporated. The crude mixture was purified
using column chromatography to give 26a. Yield: 76%. 1H NMR
5.90e5.68 (m, 1H), 5.58e5.24 (m, 1H), 5.18e4.93 (m, 2H),
4.92e4.73 (m, 2H), 3.95e3.75 (m, 1H), 3.57 (d, J¼4.4 Hz, 1H), 3.34
(d, J¼5.9 Hz, 1H), 2.81e2.28 (m, 2H); 13C NMR (400 MHz, CDCl3)
d
172.54, 147.17, 141.17, 139.10, 136.25, 136.36, 135.26, 131.90,
131.59, 130.86, 129.45, 127.97, 125.95, 125.28, 117.77, 116.94, 63.19,
57.35, 36.25; HRMS: calcd for C20H21N2O [MþH]þ: 305.1648,
found: 305.1644.
(600 MHz, CDCl3)
d
7.41 (1H, td, J¼7.6, 1.8 Hz), 7.19e7.27 (4H, m),

9762
C.H. Wang et al. / Tetrahedron 68 (2012) 9750e9762
7.15 (1H, tt, J¼1.4, 7.3 Hz), 7.10 (1H, t, J¼7.4 Hz), 6.99 (2H, t, J¼7.8 Hz),
6.85 (1H, td, J¼7.4, 1.8 Hz), 6.79 (2H, d, J¼7.8 Hz), 6.25 (1H, dd, J¼1.6,
7.6 Hz), 5.78 (1H, m), 5.58 (1H, m), 5.33 (1H, d, J¼14.3 Hz), 4.39 (1H,
d, J¼14.3 Hz), 3.86 (1H, dd, J¼3.2, 9.7 Hz), 3.52 (1H, m), 3.28 (1H, m),
would also like to thank Stevens Institute of Technology for the
award of undergraduate fellowships to A.W. and S.S. and a post-
doctoral fellowship to S.A.
2.93 (1H, m), 1.96 (1H, m); 13C NMR (400 MHz, CDCl3)
d 170.84,
References and notes
148.53, 140.31, 140.05, 136.30, 134.99, 132.01, 130.93, 129.61, 128.87,
128.83, 128.60, 128.10, 127.76, 126.97, 125.26, 125.08, 124.87, 124.86,
58.04, 55.90, 51.70, 30.36; HRMS: calcd for C25H23N2O [MþH]þ:
367.1805, found: 367.1798.
1. (a) Brecht, A.; Seitz, G.; Guenard, D.; Thoret, S. Bioorg. Med. Chem. 2000, 8,
557e562; (b) Bergemann, S.; Brecht, S.; Buttner, F.; Guenard, D.; Gust, R.; Seitz,
G.; Stubbsa, M.; Thoret, S. Bioorg. Med. Chem. 2003, 11, 1269e1281; (c)
€
Bringmann; Gunther, C.; Ochse, M.; Schupp, O.; Tasler, S. In Progress in the
Chemistry of Organic Natural Products; Herz, W., Falk, H., Kirby, G. W., Moore,
ꢀ
R. E., Eds.; Springer: Vienna, 2001; vol. 82, pp 1e249; (d) Baudoin, O.;Gueritte,F.
3.15.2. 11-Benzyl-9,9a-dihydro-6H-dibenzo[e,g]pyrido[1,2-a][1,4]di-
azocin-10(11H)-one (26b). The title compound was prepared from
compound 25c, following the general procedure for ring closing
In Studies in Natural Product Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
2003; vol. 29, pp 355e417.
2. Baudoin, O.; Guenard, D.; Gueritte, F. J. Org. Chem. 2000, 65, 9268e9271.
3. (a) Pasquinet, E.; Rocca, P.; Richalot, S.; Gueritte, F.; Guenard, D.; Godard,
A.; Marsais, F.; Queguiner, G. J. Org. Chem. 2001, 66, 2654e2661; (b)
metathesis. Yield: 72%. 1H NMR (600 MHz, CDCl3)
d 7.38 (1H, td,
ꢀ
ꢀ
ꢀ
J¼7.6, 1.7 Hz), 7.29e7.34 (3H, m), 7.25 (1H, dd, J¼7.9, 1.4 Hz), 7.17
(1H, tt, J¼1.4, 7.3 Hz), 7.11 (1H, dd, J¼1.5, 7.1 Hz), 7.07 (2H, t,
J¼7.6 Hz), 6.98 (1H, td, J¼7.6,1.6 Hz), 6.76 (2H, d, J¼7.8 Hz), 6.58 (1H,
dd, J¼1.7, 7.5 Hz), 5.63 (1H, m), 5.59 (1H, m), 5.13 (1H, d, J¼14.2 Hz),
4.28 (1H, d, J¼14.2 Hz), 3.91 (1H, dd, J¼3.4, 11.2 Hz), 3.83 (1H, m),
2.99 (1H, m), 2.46 (1H, m), 2.31 (1H, m); 13C NMR (400 MHz, CDCl3)
Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J. Org. Chem. 2002, 67,
1199e1207.
4. Fuwa, H.; Okamura, Y.; Morohashi, Y.; Tomita, T.; Iwatsubo, T.; Kan, T.; Fukuyama,
T.; Natsugari, H. Tetrahedron Lett. 2004, 45, 2323e2326.
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1879e1881.
6. Wang, C. H.; Reilly, J.; Brand, N.; Schwartz, S.; Alluri, S.; Chan, T. M.; Buevich, A.
V.; Ganguly, A. K. Tetrahedron Lett. 2010, 51, 6213e6215.
d
171.03, 148.30, 140.41, 140.17, 137.42, 136.40, 128.95, 128.87,
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128.26, 128.19, 128.04, 127.34, 127.04, 125.73, 125.61, 124.91, 123.77,
121.47, 69.37, 55.24, 50.66, 30.05; HRMS: calcd for C25H23N2O
[MþH]þ: 367.1805, found: 367.1799.
Acknowledgements
We wish to thank Schering-Plough Research Institute (presently
Merck Research Laboratories), for generous financial assistance. We