Synthesis of 3-arylideneindolin-2-ones from 2-aminophenols by Ugi four-component reaction and Heck carbocyclization

Article abstract of DOI:10.1055/s-0028-1083505

2-Aminophenols underwent the Ugi four-component reaction (U-4CR) with trans-cinnamic acids, aromatic aldehydes and isocyanides in MeOH (50°C, 48 h) to give the linear α-[N-(2-hydroxyphenyl)-substituted amido] carboxamides in 54-80% yields. Treatment of the 2-hydroxyphenyl moiety in the U-4CR products with NaH and PhNTf₂ afforded the corresponding aryl triflates (77-100%), which were subjected to the intramolecular Heck reaction (IMHR) catalyzed by 3-5 mol% Pd(OAc)₂-BINAP (MeCN, 180 °C, 30-60 min) under microwave heating to furnish a-(3-arylidene-2-oxindol-1-yl) carboxamides in 52-77% yields.

Full text of DOI:10.1055/s-0028-1083505

2716
LETTER
Synthesis of 3-Arylideneindolin-2-ones from 2-Aminophenols by
Ugi Four-Component Reaction and Heck Carbocyclization1
S
ynthesis of 3-Arylideneindolin-2-o
i
nes fro
-
m
2-Am
M
inophenols in Dai,*a,b Jianyu Shi,a Jinlong Wua
a
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953128; E-mail: chdai@zju.edu.cn
b
Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR,
P. R. of China
Received 1 July 2008
metrical 3-diarylmethyleneindolin-2-ones 1 with com-
plete stereocontrol. Müller and co-workers6a assembled a
tandem Heck carbocyclization–Sonogashira cross-cou-
pling approach for the reaction of 5a with 1-alkynes 6c,
Abstract: 2-Aminophenols underwent the Ugi four-component re-
action (U-4CR) with trans-cinnamic acids, aromatic aldehydes and
isocyanides in MeOH (50 °C, 48 h) to give the linear a-[N-(2-hy-
droxyphenyl)-substituted amido] carboxamides in 54–80% yields.
Treatment of the 2-hydroxyphenyl moiety in the U-4CR products furnishing the oxindoles 1 possessing an exocyclic conju-
gated enyne moiety (R4 = alkynyl) at C3. By using func-
with NaH and PhNTf2 afforded the corresponding aryl triflates (77–
100%), which were subjected to the intramolecular Heck reaction
tionalized 6c, the initially formed enynes could enter the
(IMHR) catalyzed by 3–5 mol% Pd(OAc)2–BINAP (MeCN, 180
subsequent cascade of reactions to yield rigid spirocy-
°C, 30–60 min) under microwave heating to furnish a-(3-arylidene-
2-oxindol-1-yl) carboxamides in 52–77% yields.
cles.6
Key words: 2-aminophenol, aryl triflate, Heck reaction, 2-oxin-
dole, Ugi four-component reaction
R3
G
R4
R3
R1
O
+
R1
CO
+
+
N
R2
O
CuBr2
(CuCl2)
NH2
3-Substituted methyleneindolin-2-ones 1 belong to the
privileged bicyclic heterocycles of the indole family, de-
livering a diverse spectrum of biological activity.2,3a–f
Among the synthetic methodologies as shown in
Scheme 1, condensation of 3-unsubstituted 2-oxindoles
2b with carbonyl compounds 3 is the most direct and con-
venient preparation of 1.3 A variation has been reported
based on a Horner–Wadsworth–Emmons (HWE) olefina-
tion of the 3-diethoxyphosphoryl-2-oxindoles 2a, which
were formed in situ by a hemolytic aromatic substitution.4
The undesired aspect of these syntheses is the lack of ste-
reocontrol over the geometry of the exocyclic double
bond, resulting in formation of a mixture of stereoisomers
in some cases. Several groups have recently reported syn-
thesis of 3-diarylmethyleneindolin-2-ones 1 starting from
arylpropynamides 5a,b. Player and co-workers5a dis-
closed a tandem Heck carbocyclization–Suzuki cross-
coupling approach by using 5a and arylboronic acids 6a
under the catalysis of Pd(PPh3)4 and copper(I) thiophene-
2-carboxylate (CuTC). Stereoselectivity in the range of
4:1 to 100:0 was achieved. Takemoto and co-workers5b
extended the tandem reaction strategy to Heck–carbony-
lative Suzuki and Heck–Heck sequences for preparation
of 1 with R4 being arylcarbonyl and vinyl groups, respec-
tively. In another work, Takemoto and co-workers5c es-
tablished tandem indium-mediated carbometalation of 5a
and palladium-catalyzed cross-coupling reaction of the
vinylindium intermediate with 6b to synthesize unsym-
2a G = P(O)(OEt)2
2b G = H
3
4
R4
R3
4
3
R1
O
2
N
7
R2
1
R3
X
X
O
R1
R1
R4Y
+
R3
N
O
N
R2
R2
6a R4Y = ArB(OH)2
6b R4Y = ArI
5a X = I
5b X = H
7 X = Br, I
8 X = OTf (this work)
6c R4Y = 1-alkyne
Scheme 1 Synthesis of 3-substituted methyleneindolin-2-ones 1
In contrast to using iodides 5a, Zhu and co-workers7a de-
veloped a sequence of intermolecular carbopalladation,
C–H activation, and C–C bond formation for the reactions
of 5b (R3 = aryl) with aryl iodides 6b to afford 1 in 59–
93% yields. If propynamides 5b (R3 = H) were used to re-
act with two different aryl iodides under palladium catal-
ysis, a three-component synthesis of 1 was realized.7b
Similarly, Li, Wang, and co-workers7c,d reported the syn-
thesis of 1 (R4 = N-/O-substituted) from 5b, phthalimide,
SYNLETT 2008, No. 17, pp 2716–2720
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083505; Art ID: W10408ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Arylideneindolin-2-ones from 2-Aminophenols
2717
and carboxylic acids via the sequence of intermolecular subjected to IMHR catalyzed by 10 mol% Pd(OAc)2 and
amino/carboxy palladation, C–H activation, and C–C 20 mol% Ph3P (MeCN, 80 °C, 24 h) to furnish 1 in 35–
bond formation. 2-Alkynylanilines 4 and 2-alkynylanil- 63% overall yields. The ratios of E- and Z-isomers were
ides are the key intermediates to 2-substituted indoles via not given. The U-4CR–IMHR process enables incorpora-
base- and metal-mediated heteroannulation.8 It is interest- tion of two points of diversity for R2 (vide infra) attached
ing to note that Li and co-workers9 developed a carbony- to the N1-position of 1. We report here on synthesis of 3-
lative annulation toward formation of 1 (R2 = H; R4 = Br, arylideneindolin-2-ones 1 (R4 = H) based on U-4CR of 2-
Cl) in the presence of CO and PdX2–CuX2. Alternatively, aminophenols13 and microwave-assisted IMHR of 2-car-
Kamijo, Yamamoto, and co-workers9b reported the boamidoaryl triflates 8 (Scheme 1).11c,14 The E- and Z-iso-
Pd(OAc)2–dppe-catalyzed intramolecular carbopallada- mers of 1 (R4 = H) have been separated and characterized
tion between 2-alkynylaryl isocyanates and 1-alkynes 6b in our work, allowing estimation of stereoselectivity of
to afford conjugated enynes 1 (R4 = alkynyl). Murakami the Heck carbocyclization under microwave heating.
and co-workers9c prepared vinyl boron 1 (R4 = B) from
In connection with our research program in microwave-
the Rh(I)-catalyzed reaction of 2-alkynylaryl isocyanates
accelerated, diversity-oriented synthesis,15 we have fo-
with bis(pinacolato)diboron. Grigg and co-workers9d used
cused on synthesis of heterocycles by using multicompo-
(2-ethynylphenyl)carbamoyl chlorides in the reactions
nent reactions of 2-aminophenols followed by post
with alkynyl, aryl, and vinyl stannanes via palladium-cat-
annulations,13,16 such as intramolecular SN2, SNAr, Pd-cat-
alyzed cyclization–anion capture approach to prepare 3-
alyzed amidation, and Pd-catalyzed direct arylation.17 For
substituted methyleneindolin-2-ones 1 (R4 = H).
the synthesis of the aryl triflates 14 (Scheme 2) of type 8
The palladium-catalyzed tandem reactions using readily as mentioned in Scheme 1, we examined four different 2-
available starting materials 4, 5a,b¸and 6a–c enable ste- aminophenols 9 in the U-4CR with three aromatic alde-
reoselective synthesis of 1. However, structural variation hydes 10, two cinnamic acids 11, and two isocyanides 12.
on R2 has been very limited.5–7,9 Balasubramanian and co- The U-4CR was performed in MeOH at 50 °C for 48
workers10a reported a solid-phase synthesis of 3-arylid- hours and the product phenols 13a–g were obtained in 54–
eneindolin-2-ones 1 (R4 = H) via an intramolecular Heck 80% yields (Scheme 2 and Table 1).18
reaction (IMHR)11 of the resin-bound crotonamides and
cinnamamides 7 (X = I; R2 = H, Bn, CH2CHMe2) in the
R1
OH
R4
presence of Pd(OAc)2, Ag2CO3, and Ph3P in DMF at 100
°C (Scheme 1). A mixture of E- and Z-isomers was ob-
tained in the ratios of 73:27 to 85:15. Hirama and co-
workers10b used IMHR of 7 (X = Br; R2 = Boc) for syn-
thesis of a 3-alkylideneindolin-2-one 1 (R4 = H) in 86%
yield and in a Z/E ratio of >20:1 during the total synthesis
of TMC-95A. In contrast, an analogous N-unprotected
substrate 7 (X = Br; R2 = H) gave only 5–15% yield,10c in-
dicating a remarkable influence of R2 on IMHR. In 2006,
Umkehrer and co-workers12c reported a one-pot synthesis
of 1 (R1 = H, 6-NO2; R3 = Me, Ph; R4 = H) via U-4CR and
IMHR.12 The U-4CR of 2-bromoanilines, aldehydes, car-
boxylic acids, and isocyanides was carried out in
CF3CH2OH at 50 °C for 24 hours to give b-substituted
acrylamides 7 (X = Br). The latter, without isolation, were
R2
NH2
9
+
R1
R2
X
N
R5NC
12
CHO
O
O
MeOH
50 °C, 48 h
R3
10
HN
R3
R5
+
O
13 X = OH
14 X = OTf
NaH, PhNTf2
HO
THF, 0 °C to r.t.
30 min
R4
11
Scheme 2 Synthesis of aryl triflates 14 via U-4CR products 13
Table 1 Yields of U-4CR Products 13 and Triflates 14
Entry
R1
H
R2
R3
H
R4
Me
H
R5
13
Yield (%)a 14
Yield (%)b
1
2
3
4
5
6
7
H
Cy
Cy
Cy
Bn
Bn
Bn
Bn
13a
13b
13c
13d
13e
13f
13g
82
54
65
80
56
61
63
14a
100
100
77
Me
Me
H
H
H
14b
14c
14d
14e
14f
H
H
Me
H
Me
Me
Me
t-Bu
H
90
H
Cl
MeO
H
H
96
H
H
91
H
H
14g
87
a Isolated yields of the U-4CR products 13.
b Isolated yields of aryl triflates 14.
Synlett 2008, No. 17, 2716–2720 © Thieme Stuttgart · New York

2718
W.-M. Dai et al.
LETTER
Treatment of the phenols 13a–g with NaH and PhNTf2 in A and B (entries 1 and 2, Table 2). By using Pd(OAc)2 and
THF afforded the 2-carboamidoaryl triflates 14a–g in 77– ( )-BINAP as the catalyst (methods C and D), 15d was
100% yields.19 We investigated IMHR of the known aryl obtained in 73% and 77% yields at 80 °C for 24 hours and
bromide 1612c and our aryl triflate 14d under four sets of at 180 °C for 30 minutes, respectively (entries 3 and 4,
reaction conditions (methods A–D) with thermal and mi- Table 2). The ratio of the E- and Z-isomers are similar for
crowave heating.20 The results are given in Table 2. Meth- the IMHR of 14d and 16 under the four sets of reaction
od A was used by Umkehrer and co-workers12c and it conditions, suggesting a thermodynamic control of stereo-
consists of 10 mol% Pd(OAc)2 and 20 mol% Ph3P. By us- selectivity.
ing method A, the aryl bromide 16 was converted into the
Next, we used method D for the IMHR of aryl triflates
IMHR product 17 in 97% combined yield and in a E/Z ra-
14d–g (R2 = alkyl)21 and the results are summarized in
tio of 78:22 (entry 1, Table 2). A 54% yield was reported
Table 3 (entries 4–7). The products 15d–g were formed in
52–77% combined yields and in the E/Z ratios of 71:29 to
for the one-pot synthesis of 17,12c indicating that the yield
for the U-4CR product 16 is around 56%. Under the reac-
83:17. The chlorine atom in 15e (R3 = Cl) survived under
tion conditions of method B, the yield of 17 was visibly
the microwave heating at 180 °C in the presence of palla-
diminished to 63% but the E/Z ratio remained the same
even though after being heated at 180 °C for 30 minutes
(entry 2, Table 2). When Pd(OAc)2 and ( )-BINAP (5
mol% each) were used as the catalyst, a low yield of 36%
dium species although the yield is slightly low. A similar
low yield was obtained for 15g (R2 = t-Bu) and the reason
is not clear. We found that a longer reaction time was re-
quired for the IMHR of 14a (R4 = Me) to afford 15a in
was obtained for 17 with an E/Z ratio of 81:12 after react-
70% yield and in a 90:10 isomeric ratio (entry 1, Table 3).
ing for 24 hours at 80 °C (method C; entry 3, Table 2).
We tried 3 mol% (instead of 5 mol%) of Pd(OAc)2 for the
The results may be interpreted by a ‘neutral pathway’ as-
reactions of aryl triflates 14b and 14c. After heating at 180
°C for 20 minutes, 14b was transformed into 15b in 55%
yield and in a 91:9 isomeric ratio (entry 2, Table 3). A
61% yield was achieved for the product 15c after prolong-
ing the reaction time of 14c to 40 minutes (entry 3,
Table 3). Finally, the stereoisomers of 15a–g were sepa-
rated in all cases and the E-and Z-isomers were assigned
sociated with bidentate ligands.11c Due to competing coor-
dination of halide anions with an olefinic residue, the
IMHR was significantly retarded. At high reaction tem-
perature used in method D, the negative halide effect was
suppressed and 17 was isolated in 65% yield and in an
E/Z ratio of 74:26 (entry 4, Table 2).
In contrast to the aryl bromide 16, the aryl triflate 14d
failed to form the IMHR product 15d with both methods
Table 3 Microwave-Assisted IMHR of Aryl Triflates 14a–g
R4
Table 2 Comparison of IMHR with Thermal and Microwave
Heating
R4
Ph
Ph
H
H
X
R1
R2
OTf
N
R1
R2
Pd(OAc)2 (5 mol%)
rac-BINAP (5 mol%)
Et3N (4 equiv)
Pd
O
O
R2
N
O
O
R2
N
IMHR
O
N
MeCN, MW
180 °C, 30–60 min
O
O
O
Ph
Ph
HN
HN
R5
R5
HN
HN
R3
R5
R3
R5
14d R2 = Me, R5 = Bn, X = OTf
16 R2 = H, R5 = t-Bu, X = Br
15d R2 = Me, R5 = Bn
17 R2 = H, R5 = t-Bu
14a–g
15a–g
Entry Time
Yield of (E)-15 Yield of (Z)-15 Combined E/Z
Entry
Method
Aa
Yield of 15d (%),e E/Z Yield of 17 (%),e E/Z
(min) (%)a
(%)a
yield (%) ratiob
f
1
2
3
4
–
–
97; 78:22
63; 76:24
36;g 81:12
65; 74:26
1
2
3
4e
5
6
7
60c
20c,d
40c,d
30
(E)-15a 63
(Z)-15a 7
(Z)-15b 5
(Z)-15c 18
(Z)-15d 15
(Z)-15e 15
(Z)-15f 16
(Z)-15g 9
70
55
61
77
52
73
54
90:10
Bb
f
(E)-15b 50
(E)-15c 43
(E)-15d 62
(E)-15e 37
(E)-15f 57
(E)-15g 45
91:9
Cc
73; 77:23
77; 81:19
70:30
81:19
71:29
78:22
83:17
Dd
a Method A: Pd(OAc)2 (10 mol%), Ph3P (20 mol%), Et3N (4 equiv),
MeCN, 80 °C, 24 h. The conditions were adopted from ref. 11c.
b Method B: Pd(OAc)2 (10 mol%), Ph3P (20 mol%), Et3N (4 equiv),
MeCN, MW, 180 °C, 30 min.
30
30
c Method C: Pd(OAc)2 (5 mol%), ( )-BINAP (5 mol%), Et3N (4
equiv), MeCN, 80 °C, 24 h.
30
a Isolated yields.
d Method D: Pd(OAc)2 (5 mol%), ( )-BINAP (5 mol%), Et3N (4
equiv), MeCN, MW, 180 °C, 30 min.
b Calculated based on the isolated products.
c DIPEA was used instead of Et3N.
e Isolated combined yields of E- and Z-isomers.
f Starting materials (75–81%) were recovered.
d The amount of 3 mol% each Pd(OAc)2 and ( )-BINAP were used.
e Data taken from the entry 4 of Table 2.
g Some starting materials were recovered.
Synlett 2008, No. 17, 2716–2720 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Arylideneindolin-2-ones from 2-Aminophenols
2719
Varoli, L.; Calonghi, N.; Cappadone, C.; Farruggia, G.; Zini,
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zene ring which is attached to the exocyclic double bond.
The protons for the E-isomers appear at high field (d = ca.
7.70 ppm) than those (d = ca. 8.30 ppm) of the Z-iso-
mers.3a
(5) For a tandem Heck carbocyclization–Suzuki cross-coupling
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In summary, we have established an alternative synthesis
of 3-arylideneindolin-2-ones 15 starting from readily
available 2-aminophenols via U-4CR and the microwave-
accelerated IMHR. By using 3–5 mol% Pd(OAc)2–( )-
BINAP as the catalyst, IMHR of aryl triflates 14 took
place at 180 °C for 20–60 minutes. It is a significant im-
provement over the reaction conditions [Pd(OAc)2 (10
mol%), Ph3P (20 mol%), 24 h, 80 °C] used for IMHR of
the corresponding aryl bromides.12c Moreover, the present
synthesis offers additional points of structural diversity on
the benzene ring of 2-oxindole skeleton. The U-4CR and
IMHR sequence enables generation of 3-substituted
methyleneindolin-2-ones possessing diverse subunits at
N1-position as compared to other robust metal-catalyzed
annulations.5–7,9
(6) For a tandem Heck carbocyclization–Sonogashira cross-
coupling approach to 3-disubstituted methyleneindolin-2-
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The Laboratory of Asymmetric Catalysis and Synthesis is esta-
blished under the Cheung Kong Scholars Program of The Ministry
of Education of China. This work is supported in part by the re-
search grants from The National Natural Science Foundation of
China (Grant No. 20672092), Zhejiang University, and Zhejiang
University Education Foundation.
References and Notes
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C.; Hubbard, S.; Tang, F.; Lipson, K.; Schreck, R.; Zhou, Y.;
McMahon, G.; Tang, C. J. Med. Chem. 2000, 43, 2655.
(d) Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T.;
Cui, J.; Fukuda, J. Y.; Chu, J.-Y.; Nematalla, A.; Wang, X.;
Chen, H.; Sistla, A.; Luu, T. C.; Tang, F.; Wei, J.; Tang, C.
J. Med. Chem. 2003, 46, 1116. (e) Andreani, A.; Burnelli,
S.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.;
Rambaldi, M.; Varoli, L.; Kunkel, M. W. J. Med. Chem.
2006, 49, 6922. (f) Andreani, A.; Burnelli, S.; Granaiola,
M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.;
(13) For U-4CR of 2-aminophenols, see: (a) Xing, X.; Wu, J.;
Feng, G.; Dai, W.-M. Tetrahedron 2006, 62, 6774.
(b) Xing, X.; Wu, J.; Luo, J.; Dai, W.-M. Synlett 2006, 2099.
Synlett 2008, No. 17, 2716–2720 © Thieme Stuttgart · New York

2720
W.-M. Dai et al.
LETTER
1652, 1601, 1366, 1212, 1139 cm–1. 1H NMR (400 MHz,
(14) For use of 2-carboamidoaryl triflates in indole synthesis,
see: (a) Dai, W.-M.; Guo, D.-S.; Sun, L.-P. Tetrahedron
Lett. 2001, 42, 5275. (b) Dai, W.-M.; Sun, L.-P.; Guo, D.-S.
Tetrahedron Lett. 2002, 43, 7699; and references cited in
refs. 8a,b.
(15) Dai, W.-M.; Shi, J. Comb. Chem. High Throughput
Screening 2007, 10, 837.
CDCl3): d [major atropisomer (83% in CDCl3 at r.t.)] =
7.96–7.90 (br s, 1 H), 7.67 (d, J = 15.6 Hz, 1 H), 7.35–7.10
(m, 16 H), 6.88 (d, J = 8.4 Hz, 1 H), 6.78–6.64 (br s, 1 H),
6.30–6.23 (br s, 1 H), 6.24 (d, J = 15.6 Hz, 1 H), 4.62–4.41
(m, 2 H), 2.39 (s, 3 H). 13C NMR (100 MHz, CDCl3): d [
major atropisomer (83% in CDCl3 at r.t.)] = 170.1, 166.8,
144.1, 143.5, 139.2, 138.1, 135.3, 135.0, 132.4, 131.3,
131.0, 130.9 (2×), 129.6, 128.7, 128.5 (2×), 128.4 (2×),
128.0 (2×), 127.9 (2×), 127.3 (2×), 127.1, 120.6, 118.2,
118.1 (q, JC–F = 317.9 Hz), 65.2, 43.6, 20.8. MS (ESI+): m/z
(%) = 631 (100) [M + Na+]. Anal. Calcd for C32H27F3N2O5S:
C, 63.15; H, 4.47; N, 4.60. Found: C, 63.17; H, 4.43; N, 4.51.
(20) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002,
35, 717.
(16) For a recent review on post-Ugi transformations, see:
Akritopoulou, I.; Djuric, S. W. Heterocycles 2007, 73, 125.
(17) For microwave-assisted synthesis of 3,4-dihydro-3-oxo-2H-
1,4-benzoxazines from 2-aminophenols, see: (a) Dai,
W.-M.; Wang, X.; Ma, C. Tetrahedron 2005, 61, 6879.
(b) Feng, G.; Wu, J.; Dai, W.-M. Tetrahedron 2006, 62,
4635. (c) Feng, G.; Wu, J.; Dai, W.-M. Tetrahedron Lett.
2007, 48, 401. (d) Wu, J.; Nie, L.; Luo, J.; Dai, W.-M.
Synlett 2007, 2728. (e) For microwave-assisted 3CR-aza-
DA of 2-aminophenols, see: Xing, X.; Wu, J.; Dai, W.-M.
Tetrahedron 2006, 62, 11200.
(18) General Procedure for Synthesis of U-4CR Products 13
A solution of a 2-aminophenol 9 (3.0 mmol) and an aldehyde
10 (3.0 mmol) in MeOH (5 mL) was stirred at r.t. for 15 min.
To the resultant mixture was added a carboxylic acid 11 (3.0
mmol) followed by stirring for 5 min. An isocyanide 12 (3.0
mmol) was then added to the above mixture followed by
stirring at 50 °C for 48 h. The white precipitate of the U-4CR
product 13 was collected by filtration and the solid was
washed with MeOH (3 mL). The combined filtrate was
concentrated under reduced pressure, and the residue was
purified by flash column chromatography over silica gel
[eluting with 20% EtOAc in PE (bp 60–90 °C)] to give
additional portion of the U-4CR product 13. The yields of
U-4CR 13a–g are given in Table 1.
(21) General Procedure for Microwave-Accelerated
Synthesis of IMHR Products 15
A 10 mL pressurized process vial was charged with the aryl
triflate 14 (0.26 mmol), Pd(OAc)2 (1.3·10–2 mmol, 5 mol%),
and ( )-BINAP (1.3·10–2 mmol, 5 mol%). The vial was
sealed with a cap containing a silicon septum. The vial was
evacuated and backfilled with N2 (repeated for three times)
through the cap using a needle. To the degassed vial was
added degassed anhyd MeCN (5 mL) and Et3N (1.04 mmol)
through the cap using a syringe. The loaded vial was then
placed into the microwave reactor cavity and was heated at
180 °C for 20–60 min. After cooling to r.t. the reaction
mixture was concentrated under reduced pressure and the
residue was purified by flash column chromatography over
silica gel [eluting with 17% EtOAc in PE (bp 60–90 °C)] to
give the 3-arylideneindolin-2-ones (E)-15 and (Z)-15. The
yields of 15a–g and E/Z isomer ratios are given in Table 3.
Characterization Data for (E)-15d
Characterization Data for 13d
White solid; mp 233–236 °C (CHCl3–hexane); Rf = 0.26
(20% EtOAc–hexane). IR (KBr): 3326, 3030, 1654, 1649,
1363 cm–1. 1H NMR (400 MHz, CDCl3): d [major
atropisomer (76% in CDCl3 at r.t.)] = 10.71 (s, 1 H), 7.61 (d,
J = 15.6 Hz, 1 H), 7.32–7.13 (m, 15 H), 6.86 (d, J = 2.0 Hz,
1 H), 6.82 (s, 1 H), 6.71 (t, J = 5.6 Hz, 1 H), 6.29 (s, 1 H),
6.23 (d, J = 15.6 Hz, 1 H), 6.12 (d, J = 1.2 Hz, 1 H), 4.60 and
4.49 (ABqd, J = 15.2, 6.0 Hz, 2 H), 1.95 (s, 3 H). 13C NMR
(100 MHz, CDCl3): d [major atropisomer (76% in CDCl3 at
r.t.)] = 173.1, 167.6, 153.6, 143.4, 137.2, 134.9, 133.1,
132.0, 130.8, 130.1 (2×), 129.6, 129.4, 129.3, 128.6 (2×),
128.5 (2×), 128.4 (2×), 128.0 (2×), 127.6 (2×), 127.5, 124.4,
117.7, 117.3, 65.5, 44.1, 19.9. MS (ESI–): m/z (%) = 475
(100) [M – H]. Anal. Calcd for C31H28N2O3: C, 78.13; H,
5.92; N, 5.88. Found: C, 78.13; H, 5.91; N, 5.84.
Orange crystals; mp 180–182 °C (acetone–hexane);
Rf = 0.34 (20% EtOAc–hexane). IR (KBr): 3326, 1685,
1619, 1445, 1153 cm–1. 1H NMR (400 MHz, DMSO-d6):
d = 8.97 (t, J = 5.6 Hz, 1 H), 7.76 (s, 1 H), 7.72 (d, J = 7.2
Hz, 2 H), 7.55–7.45 (m, 4 H), 7.40–7.22 (m, 10 H), 6.68 (s,
1 H), 6.67 (d, J = 6.8 Hz, 1 H), 6.38 (s, 1 H), 4.45 and 4.38
(ABqd, J = 14.8, 5.6 Hz, 2 H), 2.11 (s, 3 H). 13C NMR (100
MHz, DMSO-d6): d = 167.8, 167.2, 142.7, 139.4, 139.1,
135.6, 135.3, 134.5, 129.7, 129.3 (2×), 128.8 (2×), 128.4
(2×), 128.3 (2×), 128.2 (2×), 127.8, 127.4 (2×), 126.8, 126.2,
122.2, 121.7, 118.1, 112.5, 57.5, 42.7, 21.6. MS (ESI+): m/z
(%) = 481 (100) [M + Na+]. Anal. Calcd for C31H26N2O2: C,
81.20; H, 5.72; N, 6.11. Found: C, 81.35; H, 5.52; N, 5.94.
Characterization Data for (Z)-15d
Orange needles; mp 180–182 °C (acetone–hexane);
Rf = 0.39 (20% EtOAc–hexane). IR (KBr): 3314, 1669,
1612, 1452, 1170 cm–1. 1H NMR (400 MHz, DMSO-d6):
d = 8.91 (t, J = 6.0 Hz, 1 H), 8.37 (d, J = 8.0 Hz, 1 H), 8.36
(d, J = 7.2 Hz, 1 H), 7.85 (s, 1 H), 7.66 (d, J = 7.6 Hz, 1 H),
7.50–7.45 (m, 3 H), 7.40–7.20 (m, 10 H), 6.83 (d, J = 7.6 Hz,
1 H), 6.58 (s, 1 H), 6.30 (s, 1 H), 4.43 and 4.32 (ABqd,
J = 14.8, 6.0 Hz, 2 H), 2.16 (s, 3 H). 13C NMR (100 MHz,
DMSO-d6): d = 167.3, 165.7, 140.6, 139.1, 138.1, 136.3,
135.4, 133.9, 131.8 (2×), 130.3, 128.3 (2×), 128.3 (2×),
128.1 (2×), 128.1 (2×), 127.7, 127.4 (2×), 126.7, 125.2,
122.2, 121.6, 119.3, 111.8, 57.2, 42.6, 21.6. MS (ESI–): m/z
(%) = 457 (100) [M – H]. Anal. Calcd for C31H26N2O2: C,
81.20; H, 5.72; N, 6.11. Found: C, 81.31; H, 5.65; N, 6.10.
The 1H NMR and 13C NMR spectra of 15a–g can be found
in the Supporting Information.
(19) General Procedure for Formation of Aryl Triflates 14
To a suspension of NaH (1.5 mmol) in dry THF (3 mL)
cooled in an ice–water bath was added a solution of the
U-4CR product 13 (1.0 mmol) in dry THF (7 mL) under a
nitrogen atmosphere. After stirring for 10 min, a solution of
PhNTf2 (1.2 mmol) in dry THF (8 mL) was added via a
syringe. The resultant mixture was stirred at r.t. for 1 h. The
reaction mixture was concentrated under reduced pressure,
and the residue was purified by flash column chromatog-
raphy over silica gel [eluting with 20% EtOAc in PE (bp 60–
90 °C)] to give the aryl triflate 14. The yields of aryl triflates
14a–g are given in Table 1.
Characterization Data for 14d
Colorless crystals; mp 146–148 °C (EtOAc–hexane);
Rf = 0.29 (20% EtOAc–hexane). IR (KBr): 3322, 1681,
Synlett 2008, No. 17, 2716–2720 © Thieme Stuttgart · New York

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