One-pot synthesis of substituted indole N-oxides: TiCl4-mediated Baylis-Hillman reaction of α-oxo cyclic ketene-S,S-acetal with o-nitrobenz-aldehydes and subsequent intramolecular cyclization

Article abstract of DOI:10.1055/s-2006-939074

One-pot synthesis of substituted indole N-oxides 3 has been developed based on the TiCl₄-mediated Baylis-Hillman reaction of α-oxo cyclic ketene-S,S-acetal 1 with o-nitrobenzaldehydes 2 and subsequent intramolecular cyclization reaction. Georg

Full text of DOI:10.1055/s-2006-939074

1090
LETTER
One-Pot Synthesis of Substituted Indole N-Oxides: TiCl4-Mediated Baylis–
Hillman Reaction of a-Oxo Cyclic Ketene-S,S-acetal with o-Nitrobenz-
aldehydes and Subsequent Intramolecular Cyclization
O
ne-Pot Synthesis of Su
e
bstitute
d
In
i
dole
N
-Oxide
P
s
an, Dewen Dong,* Shaoguang Sun, Qun Liu*
Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. of China
Fax +86(431)5098635; E-mail: dongdw663@nenu.edu.cn
Received 21 January 2006
During the course of our studies on the chemistry of a-oxo
Abstract: One-pot synthesis of substituted indole N-oxides 3 has
been developed based on the TiCl4-mediated Baylis–Hillman reac-
tion of a-oxo cyclic ketene-S,S-acetal 1 with o-nitrobenzaldehydes
2 and subsequent intramolecular cyclization reaction.
ketene-S,S-acetals, we are interested in the a-functional-
ization reactions at a-position of such compounds.19 Our
recent work revealed that 1-(1,3-dithiolan-2-ylidene)pro-
pan-2-one (1) could be obtained from the deacylation
reaction of 3-(1,3-dithiolan-2-ylidene)pentane-2,4-dione
or the decarboxylation reaction of 2-(1,3-dithiolan-2-
ylidene)-3-oxobutanoic acid. It is noted that compound 1
shows promising structural feature as an activated alkene
due to the highly polarized push (RS)–pull (C=O) effect
on the C–C double bond. Accordingly, we developed a
novel Baylis–Hillman type reaction to build the C–C bond
at the a-position of 1.20 The results and our continued
interest in the development of new general methods for
biologically important heterocycles21 prompted us to
explore the feasibility of the B–H reaction of 1 with o-ni-
trobenzaldehydes for the synthesis of azaheterocycles. In
the present work, we wish to describe our preliminary
findings in this area.
Key words: Baylis–Hillman reaction, indole N-oxides, a-oxo
ketene-S,S-acetals, TiCl4
In the past two decades, the Baylis–Hillman (B–H) reac-
tion has been recognized as one of the most useful and
economical C–C bond-forming reactions in organic syn-
thesis and reviewed in several recent articles and mono-
graphs.1 Indeed, it is a coupling reaction of an activated
alkene or alkyne with an aldehyde or ketone catalyzed by
a tertiary amine or phosphane.2 However, the reaction
traditionally suffers from slow reaction rate and limited
substrate scope. Recent work has revealed that the combi-
nation of Lewis base such as amines,3 phosphanes,4 or-
ganic chalcogenides,5 bisoxazolines6 and quaternary
ammonium halides7 with Lewis acid TiCl4 can signifi-
cantly improve the B–H reaction, and much research at-
tention is directed towards the catalytic, asymmetric
version of B–H reaction and the applications of the B–H
adducts.1e,8 The versatility of the functionality, i.e. hy-
droxy (or amino), alkene, and electron-withdrawing
groups, makes the B–H adducts valuable intermediates in
Friedel–Crafts reaction,9 Heck reaction,10 hydride addi-
tion,11 hydrogenation,12 aminohydroxylation,13 radical re-
action,14 photochemical reaction.15 In fact, some of these
methodologies are also successfully employed in the syn-
thesis of a variety of biologically active molecules and
natural products.1e
The reaction of o-nitrobenzaldehyde 2a with 1 (1.0 equiv)
was performed in dichloromethane at room temperature in
the presence of TiCl4 (Scheme 1). As indicated by TLC,
the reaction proceeded sluggishly. A product was formed,
but most of the substrates could not be consumed even
after prolonged reaction time (Table 1, entry 1). Then the
reaction was halted, a pure yellow solid was obtained after
workup and column chromatography of the resulting re-
action mixture along with 72% recovery of 2a. The only
product was characterized as substituted indole N-oxide
3a (8% yield) on the basis of its elemental analysis, NMR
and mass spectral and single crystal X-ray analytical data
(Figure 1). It was of interest to note that the desired B–H
adduct was not even detectable in the reaction system. In-
deed, substituted indole N-oxides are important organic
molecules present in numerous natural products along
with bio- and pharmacological activities.22 The reactions
of 2a with 1 (4.0 equiv) were then carried out under vari-
ous conditions to optimize the yields, some of the results
are summarized in Table 1. It was found that the reactions
could proceed in some polar solvent such as DMF, THF
and MeCN, but failed in strong polar solvent DMSO.
These results suggested that the reaction favored the reac-
tion medium with an appropriate polarity. Further experi-
ments revealed that the mixed solvent of CH2Cl2 and
MeCN (1:1) was the most efficient medium among those
Recently, Kim,16 Kaye8c and Basavaiah17 reported some
attractive synthesis of quinoline or quinoline N-oxides
from the B–H adducts derived from o-nitrobenzalde-
hydes, respectively. These achievements provide useful
entries for the quinoline chemistry. Similarly, Horn and
Nicholas realized some interesting transformations of
such B–H adducts into indole derivatives, albeit in low
yields and under harsh conditions.18
SYNLETT 2006, No. 7, pp 1090–1094
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939074; Art ID: W02006ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of Substituted Indole N-Oxides
1091
O
O
H
S
S
+
NO2
2b
1
6 h
15 min
(65%)
45 min
(68%)
(43%)
(12%)
S
O
O
S
O
S
OH
S
S
S
S
S
S
ii
S
S
6b
N
H
O
S
98%
NO2
N
O
NO2
O
NO2
O
6b
3b
4b
5b
iii (6 h)
53%
iii + 1 (4 h)
81%
Scheme 1 Reagents and conditions: i) TiCl4, CH2Cl2–MeCN, 0 °C to r.t.; ii) TiCl4, MeCN, r.t., 1 h; iii) TiCl4, CH2Cl2, r.t.
Table 1 The TiCl4-Mediated Reactions of 2a with 1 at 0 °C to
Room Temperature
out.23 From the results summarized in Table 2, it was not
hard to find that all the selected aromatic aldehydes could
be converted into the corresponding indole N-oxides of
type 3 in the presence of TiCl4 in moderate yields. In com-
parison to the reaction of 2a, the latter reactions are far
more complicated. In the case of o-nitrobenzaldehyde
(2b), the reaction was performed in the mixed solvent of
CH2Cl2 and MeCN (1:1 by v/v) at 0 °C to room tempera-
ture, several compounds were formed and isolated at dif-
ferent stages (Scheme 1). When 2b reacted with 1 (4.0
equiv) in the presence of TiCl4 for 15 minutes at 0 °C,
workup and column chromatography of the resulting
mixture furnished a white solid (65% yield). The product
was characterized as 3-(1,3-dithiolan-2-ylidene)-4-hy-
droxy-4-(2-nitrophenyl)butan-2-one (4b), a B–H adduct,
on the basis of its spectral and analytical data. When the
O
S
O
O
S
O
O
O
O
S
S
H
TiCl4
+
S
S
0 °C to r.t.
N
O
NO2
3a
1
2a
Entry
Solvent a
CH2Cl2
DMF
THF
TiCl4 (equiv) Time (h)
Yield (%)b
1
2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
1.5
24
12
12
12
24
8
8
30
30
55
0
3
4
MeCN
DMSO
10:1
5
6
40
56
62
75
38
7
3:1
8
8
1:1
8
9
1:1
6
10
1:2
6
a Mixed solvents of CH2Cl2–MeCN employed in the entries of 6–10.
b Isolated yields.
examined (entry 8). In addition, an appropriate amount
excess of TiCl4 could result in a slightly fast transforma-
tion to 3a along with a good yield (75%, entry 9).
Under identical conditions as for 2a (Table 1, entry 9), the
reactions of 1 with various o-nitrobenzaldehydes 2b–d
bearing different type substituted groups were carried
Figure 1 ORTEP drawing of indole N-oxide 3a
Synlett 2006, No. 7, 1090–1094 © Thieme Stuttgart · New York

1092
W. Pan et al.
LETTER
reaction time was prolonged to 45 minutes, 3,5-di-(1,3- Nevertheless, the present protocol provides a facile and
dithiolan-2-ylidene)-4-(2-nitrophenyl)heptane-2,6-dione convenient route to construct five-membered indole N-
(5b), a double B–H type adduct, was obtained in 68% iso- oxides of type 3 through one-pot B–H reaction of o-ni-
lated yield. It is worthy noting that the formation of com- trobenzaldehydes 2 with 1 unlike the work reported by
pound 4 or 5 can be easily controlled by reaction time. Kim,16 Kaye8c and Basavaiah17 to yield six-membered
Furthermore, when allowing the reaction mixture warmed quinoline N-oxides. This suggests that they might follow
to room temperature, and prolonging the reaction time to different reaction mechanisms. Consequently, two more
six hours, substituted indole N-oxide 3b and N-[2-(1,3- reactions were carried out as shown also in Scheme 1. In
dithiolan-2-ylidene)-1-(2-nitrophenyl)-3-oxobutyl]acet- one case, the mixture of B–H adduct 4b and 1 (1.0 equiv)
amide (6b) were obtained in 43% and 12% isolated yields, was stirred in the presence of TiCl4 (1.5 equiv) in CH2Cl2
respectively. Apparently, the small amount of 6b was at room temperature for four hours, the double B–H
formed through a three-component reaction involving se- adduct 5b was obtained in 81% yield. In another one, 5b
quential B–H and Ritter reactions, which is consistent could be transformed into 3b in 53% yield when subjected
with the results of our recent work.20b
to TiCl4 (1.5 equiv) in CH2Cl2 at room temperature for six
hours. On the basis of the above results together with our
previous work,20 the entire reaction sequence involves the
formation of Baylis–Hillman adducts 4 and 5, followed by
an intramolecular cyclization through intermediate 7
under surprisingly mild conditions affording substituted
indole N-oxides 3 directly without isolation of the adducts
(Scheme 2).
Table 2 The Reactions of Various o-Nitrobenzaldehydes 2 with 4.0
Equivalents of 1
O
S
O
O
S
TiCl4
H
S
S
+
R
S
S
R
0 °C to r.t.
NO2
N
O
O
S
1
2
3
O
S
S
Entry
Substrate 2 R
Product 3 Time (h) Yield (%)a
TiCl4
H
S
+
R
1
R
1
2
3
4
2a
2b
2c
2d
3,4-O2CH2 3a
6
6
6
6
75
43
57
53
O
NO2
N
O
O
H
3b
3c
3d
5
2
5-Cl
4-NO2
TiCl4 – MeCOCl
S
O
O
S
a Isolated yields.
S
S
H
S
S
– TiCl3(OH)
R
R
In the same fashion, the B–H adduct 4-(5-chloro-2-nitro-
phenyl)-3-(1,3-dithiolan-2-ylidene)-4-hydroxybutan-2-
one (4c) was obtained in 74% yield when the reaction of
5-chloro-2-nitrobenzaldehyde (2c) with 1 was performed
in the presence of TiCl4 at 0 °C for 30 minutes, where-
as the double B–H type adduct 4-(5-chloro-2-nitro-
phenyl)-3,5-di(1,3-dithiolan-2-ylidene)heptane-2,6-dione
(5c) was isolated in 70% yield when increasing the
reaction time to one hour. Substituted indole N-oxide 3c
and N-[1-(5-chloro-2-nitrophenyl)-2-(1,3-dithiolan-2-
ylidene)-3-oxobutyl]acetamide (6c) were obtained in
57% and 10% isolated yield, respectively, when the reac-
tion was continued and proceeded at room temperature for
six hours. The reaction of 2,4-dinitrobenzaldehyde (2d)
and 1 was carried out under the identical conditions, sub-
stituted indole N-oxide 3d was obtained in 53% yield.
During the reaction process, several intermediates were
formed as indicated by TLC. However, the attempt to
separate them was not successful since they were quite
unstable. Thus, B–H adducts 4d and 5d were not obtained
from the reaction system.
N
N
S
S
O
O
TiCl3
O
7
3
Scheme 2 A proposed mechanism for the one-pot synthesis of the
substituted indole N-oxides 3
In summary, a facile one-pot synthesis of substituted
indole N-oxides 3 has been developed based on the se-
quential TiCl4-mediated Baylis–Hillman reactions of a-
oxo cyclic ketene-S,S-acetal 1 with o-nitrobenzaldehydes
2 and intramolecular cyclization reaction. Further investi-
gations on the scope and application of the protocol are in
progress.
Acknowledgment
Financial support of this research by the NNSFC (20572013), the
Key Project of the Ministry of Education of China (105061) and the
Key Grant Project of the Ministry of Education of China (10412) is
greatly acknowledged.
Synlett 2006, No. 7, 1090–1094 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Substituted Indole N-Oxides
1093
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(22) Myers, A. G.; Herzon, S. B. J. Am. Chem. Soc. 2003, 125,
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(23) Typical Procedure for the Synthesis of Substituted
Indole N-Oxides 3 (3b as an Example).
To a solution of 1 (4.0 mmol) and 2b (1.0 mmol) in mixed
solvent of CH2Cl2 (5 mL) and MeCN (5 mL) was added
TiCl4 (1.5 mmol) at 0 °C. The mixture was stirred at 0 °C for
about 45 min until substrate 1 was consumed as indicated by
TLC. The reaction was then allowed to warm to r.t. and
stirred for 6 h. The reaction mixture was quenched with sat.
aq Na2CO3 (10 mL) and extracted with CH2Cl2 (3 × 15 mL).
The combined organic extracts were washed with sat. aq
NaCl (3 × 20 mL), dried over MgSO4, filtered and
concentrated in vacuo to give a yellowish solid. Purification
was carried out by flash silica gel chromatography using PE–
Et2O (4:1) as eluent to give product 3b (0.17 g, 43%).
Compound 3b: yellowish solid; mp 140–142 °C. 1H NMR
(500 MHz, CDCl3): d = 1.80 (s, 3 H), 3.34–3.59 (m, 8 H),
6.85 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 7.5 Hz, 1 H), 7.52 (d,
J = 7.5 Hz,1 H), 7.70 (d, J = 8.0 Hz, 1 H). 13C NMR (125
MHz, CDCl3): d = 26.04, 35.88, 37.82, 38.18, 41.10, 109.81,
119.87, 120.53, 121.49, 124.75, 127.10, 134.88, 139.40,
149.26, 171.57, 179.55, 193.97. IR (KBr): 3424, 2924, 2361,
1645, 1521, 1465, 1368 cm–1. MS (EI): m/z = 393.9 [M + 1]+.
Anal. Calcd for C17H15NO2S4: C, 51.88; H, 3.84; N, 3.56.
Found: C, 51.83; H, 3.88; N, 3.53.
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6427.
Selected Data for Other Compounds.
Compound 3a: yellowish solid; mp 138–140 °C. 1H NMR
(500 MHz, CDCl3): d = 1.93 (s, 3 H), 3.30–3.58 (m, 8 H),
6.00 (s, 2 H), 6.28 (s, 1 H), 7.20 (s 1 H). 13C NMR (125 MHz,
CDCl3): d = 25.67, 35.57, 37.49, 37.79, 40.82, 90.57,
101.87, 102.29, 114.33, 119.66, 127.50, 138.27, 143.22,
147.66, 154.55, 171.54, 177.59, 193.58. IR (KBr): 3424,
2924, 2361, 1645, 1521, 1465, 1386 cm–1. MS (EI): m/z =
438.0 [M + 1]+. Anal. Calcd for C18H15NO4S4: C, 49.41; H,
3.46; N, 3.20. Found: C, 49.46; H, 3.48; N, 3.23.
Selected crystal data for 3a: empirical formula:
C18H15O4NS4; formula weight: 437.0; crystal color, habit:
yellow, rectangular; crystal dimensions: 0.24 × 0.19 × 0.09
mm; crystal system: orthorhombic; lattice type: primitive;
lattice parameters: a = 12.5378 (17), b = 10.4037 (14),
c = 17.058 (2) Å, V = 2187.0(5) Å3; b = 100.618 (3)°; space
group: P21/c (#33); Z = 4; Dcalc = 1.373 g cm–3;
F(000) = 936.00; residuals: R = 0.0816, wR = 0.2024.
CCDC 285048.
Compound 3c: yellowish solid; mp 153–155 °C. 1H NMR
(500 MHz, CDCl3): d = 1.93 (s, 3 H), 3.31–3.59 (m, 8 H),
6.80 (d, J = 7.0 Hz, 1 H), 7.41 (d, J = 7.0 Hz, 1 H), 7.82 (m,
1 H). 13C NMR (125 MHz, CDCl3): d = 25.55, 35.45, 37.40,
37.81, 40.67, 110.65, 118.91, 121.92, 123.73, 125.62,
Synlett 2006, No. 7, 1090–1094 © Thieme Stuttgart · New York

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W. Pan et al.
LETTER
126.69, 134.26, 141.02, 146.80, 171.61, 177.54, 193.18. IR
(KBr): 3415, 2924, 1647, 1607, 1520, 1462 cm–1. MS (EI):
m/z = 428.0 [M + 1]+. Anal. Calcd for: C17H14ClNO2S4: C,
47.70; H, 3.30; Cl, 8.28; N, 3.27. Found: C, 47.75; H, 3.33;
Cl, 8.24; N, 3.23.
1 H), 7.45 (m, 1 H), 7.58 (m, 2 H), 7.79 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 23.19, 28.31, 37.31, 38.48,
52.25, 124.11, 125.00, 128.79, 129.17, 132.59, 134.15,
149.08, 164.48, 169.66, 195.03. IR (KBr): 3262, 2970, 1653,
1529, 1457, 1364, 1242, 1175 cm–1. Anal. Calcd for:
C15H16N2O4S2: C, 51.12; H, 4.58; N, 7.95. Found: C, 51.15;
H, 4.62; N, 7.90.
Compound 3d: amethyst solid; mp 127–129 °C. 1H NMR
(500 MHz, CDCl3): d = 1.94 (s, 3 H), 3.34–3.63 (m, 8 H),
7.70 (s, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 8.00 (d, J = 8.0 Hz,
1 H). 13C NMR (125 MHz, CDCl3): d = 26.02, 36.07, 38.03,
38.55, 41.26, 105.75, 115.21, 118.56, 125.21, 125.70,
127.83, 145.04, 147.89, 152.12, 173.18, 177.27, 193.04. IR
(KBr): 3436, 2924, 1618, 1529, 1454, 1348 cm–1. MS (EI):
m/z = 439.0 [M + 1]+. Anal. Calcd for C17H14N2O4S4: C,
46.56; H, 3.22; N, 6.39. Found: C, 46.59; H, 3.17; N, 6.43.
Compound 4b: yellowish solid; mp 152–154 °C. 1H NMR
(500 MHz,CDCl3): d = 2.23 (s, 3 H), 3.11–3.37 (m, 4 H),
6.62 (d, J = 8.0 Hz, 1 H), 7.68 (m, 1 H), 7.56 (m, 2 H), 7.84
(d, J = 8.0 Hz,1 H). 13C NMR (125 MHz, CDCl3): d = 29.07,
36.67, 38.58, 71.42, 124.87, 125.03, 128.95, 129.01, 132.69,
135.79, 149.44, 165.95, 194.99. IR (KBr): 3430, 2925, 1615,
1528, 1455 cm–1. Anal. Calcd for: C13H13NO4S2: C, 50.14;
H, 4.21; N, 4.50. Found: C, 50.19; H, 4.25; N, 4.45.
Compound 5b: yellowish solid; mp 149–151 °C. 1H NMR
(500 MHz, CDCl3): d = 2.10 (s, 6 H), 3.25 (m, 8 H), 6.55 (s,
1 H), 7.43 (m, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.54 (m, 1 H),
7.89 (d, J = 8.0 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d =
28.33, 37.59, 37.87, 49.22, 125.22, 129.10, 132.13, 133.27,
135.07, 150.42, 195.14. IR (KBr): 3446, 2921, 2361, 1636,
1522, 1235 cm–1. Anal. Calcd for: C19H19NO4S4: C, 50.31;
H, 4.22; N, 3.09. Found: C, 50.35; H, 4.17; N, 3.05.
Compound 6b: yellowish solid; mp 101–103 °C. 1H NMR
(500 MHz, CDCl3): d = 2.15 (s, 3 H), 2.43 (s, 3 H,), 3.21–
3.32 (m, 4 H), 6.28 (d, J = 8.5 Hz 1 H), 7.03 (d, J = 8.5 Hz,
Compound 4c: yellowish solid; mp 138–140 °C. 1H NMR
(500 MHz, CDCl3): d = 2.29 (s, 3 H), 3.01 (d, J = 6.5 Hz,
1 H), 3.29–3.36 (m, 4 H), 6.56 (d, J = 6.5 Hz, 1 H), 7.42 (d,
J = 8.5 Hz, 1 H), 7.68 (s, 1 H), 7.82 (d, J = 8.5 Hz,1 H).
13C NMR (125 MHz, CDCl3): d = 28.70, 36.59, 38.35, 70.89,
124.18, 126.22, 128.69, 129.03, 138.10, 139.05, 149.66,
165.44, 194.08. IR (KBr): 3467, 1522, 1458, 1465, 1349
cm–1. Anal. Calcd for C13H12ClNO4S2: C, 45.15; H, 3.50; Cl,
10.25; N, 4.05. Found: C, 45.19; H, 3.46; Cl, 10.29; N, 4.00.
Compound 5c: yellowish solid; mp: 119–120 °C. 1H NMR
(500 MHz, CDCl3): d = 2.14 (s, 6 H), 3.23–3.29 (m, 8 H),
6.54 (s, 1 H), 7.35 (d, J = 2.0 Hz, 1 H), 7.44 (dd, J1 = 2.0 Hz,
J2 = 9.0 Hz, 1 H), 7.88 (d, J = 9.0 Hz, 1 H). 13C NMR (125
MHz, CDCl3): d = 28.10, 37.34, 37.66, 48.91, 122.57,
126.45, 128.94, 131.59, 137.06, 139.55, 148.15, 165.11,
194.57. IR (KBr): 3853, 2734, 2360, 1635, 1521, 1235
cm–1. Anal. Calcd for C19H18ClNO4S4: C, 46.76; H, 3.72; Cl,
7.26; N, 2.87; found: C, 46.80; H, 3.76; Cl, 7.21; N, 2.83.
Compound 6c: yellowish solid, mp 109–111 °C, 1H NMR
(500 MHz, CDCl3): d = 2.18 (s, 3 H), 2.44 (s, 3 H), 3.24–3.35
(m, 4 H), 6.25 (d, J = 8.5 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 1 H),
7.41 (dd, J1 = 2.0 Hz, J2 = 8.5 Hz, 1 H), 7.57 (s, 1 H), 7.78
(d, J = 8.5 Hz, 1 H). Anal. Calcd for C15H15ClN2O4S2: C,
46.57; H, 3.91; Cl, 9.16; N, 7.24. Found: C, 46.61; H, 3.87;
Cl, 9.22; N, 7.29.
Synlett 2006, No. 7, 1090–1094 © Thieme Stuttgart · New York