Synthesis of indole derivatives by cyclization of oxo N-acyliminium ions

Article abstract of DOI:10.1055/s-2008-1072532

The reaction of indole-containing hydroxamates with aldehydes in the presence of Lewis acid leads to oxo N-acyliminium ions, which cyclize to the corresponding N-O fused [1,2]oxazino[4,5-b]indole, [1,2]oxazepino[4,5-b]indole, and [1,2]oxazocino[4,5-b]indo

Full text of DOI:10.1055/s-2008-1072532

PAPER
1345
Synthesis of Indole Derivatives by Cyclization of Oxo N-Acyliminium Ions
C
yclization of
Oxo
i
N
-Acy
u
liminium
I
o
f
ns to Ind
a
oles ng Zheng,a Junbiao Chang,*a,b Kang Zhao*a
a
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. of China
Department of Chemistry, Zhengzhou University, Zhengzou 450001, P. R. of China
Fax +86(22)27890968; E-mail: kangzhao@tju.edu.cn
b
Received 26 November 2007; revised 30 January 2008
O
O
n
n
Abstract: The reaction of indole-containing hydroxamates with al-
dehydes in the presence of Lewis acid leads to oxo N-acyliminium
ions, which cyclize to the corresponding N–O fused [1,2]oxazi-
no[4,5-b]indole, [1,2]oxazepino[4,5-b]indole, and [1,2]oxazoci-
no[4,5-b]indole derivatives in good yields.
O
O
HN
N+
RCHO
OMe
Lewis acid
N
OMe
N
R
PG
PG
3
4
Key words: oxo N-acyliminium ions, cyclization, hydroxamate, in-
dole, Lewis acid
PG = Boc, Me
R = alkyl, aryl
n = 1, 2, 3
O
n
O
N
N-Acyliminium ions 1 (Figure 1) are important, reactive
species in organic synthesis for the construction of car-
bon–carbon and carbon–heteroatom bonds.1 Indeed, the
well-known Pictet–Spengler2 reaction is an excellent and
extensively exploited method for the synthesis of tetrahy-
droisoquinolines (THIQ) and tetrahydrocarbolines, which
are present in numerous natural products and synthetic
medical compounds possessing biological activities. To
the best of our knowledge, the cyclization of oxo N-
acyliminium ions 2 has received less attention.3 In at-
tempting to extend the N-acyliminium ion chemistry, we
observed and previously communicated that excellent
yields of 1H-2,3-benzoxazines could be obtained from the
Lewis acid catalyzed reaction of hydroxamates with alde-
hydes.4 Due to the electronic feature of oxygen atom, the
N–O fused 1H-2,3-benzoxazines, which appear to be
structurally similar to THIQs, can dramatically change the
electronic property of the nitrogen atom in the molecule,
and may present interesting physical properties.5
OMe
N
R
PG
5
Scheme 1
Ph
N
O
O
N
PhNO
Ph
+
N
N
R
N
R
R
Scheme 2
reaction with nitrosobenzene, but two isomers were ob-
tained in this process (Scheme 2).6
Many polycyclic heteroarenes containing the indole nu-
cleus exhibit important pharmacological properties and
thus constitute synthetically interesting target mole-
cules.6,7 Therefore, we considered that the design of a nov-
el access to [1,2]oxazino[4,5-b]indole series by indole-
based oxo N-acyliminium ion cyclization would be desir-
able. The required hydroxamates 3 for this approach were
conveniently prepared according to the reported process
from commercial materials.6,8
O
O
R2
R2
OR1
+
N
+N
R1
1
Figure 1 N-Acyliminium ions 1 and oxo N-acyliminium ions 2
Initial studies were directed toward finding a general set
of reaction conditions that could be applied to a wide va-
riety of indole-fused hydroxamates and aldehydes. Since
the reaction conditions such as TMSCl/NaI in MeCN can
promote the generation of 1H-2,3-benzoxazines success-
fully,4 we turned our attention to optimizing that process.
Firstly, the reaction of 3a with benzaldehyde was carried
out with three equivalents of TMSCl/NaI at –40 °C, and
the cyclized product 5a was obtained in 94% yield
(Table 1, entry 1). Although the N-Boc group is sensitive
to high acidity,9 prolonged exposure of 5a to these condi-
tions did not promote the deprotection process.
In this context, we decided to extend our research focus-
ing on developing a new approach to the preparation of
N–O fused indole derivatives 5, such as [1,2]oxazino[4,5-
b]indoles (n = 1), [1,2]oxazepino[4,5-b]indoles (n = 2),
and [1,2]oxazocino[4,5-b]indoles (n = 3), via cyclization
of oxo N-acyliminium ions 4 (Scheme 1). Among these
compounds, the [1,2]oxazino[4,5-b]indoles can be pre-
pared from indole-2,3-quinodimethanes by Diels–Alder
SYNTHESIS 2008, No. 9, pp 1345–1350
x
x
.
x
x
.2
0
0
8
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-1072532; Art ID: F21907SS
© Georg Thieme Verlag Stuttgart · New York

1346
X. Zheng et al.
PAPER
Table 1 Reaction of Hydroxamates 3 with Aldehydes in the Presence of Lewis Acid (Scheme 1)a
Entry
1
Hydroxamate
Aldehyde
PhCHO
Product
Yield (%)b
94
O
O
O
O
N
HN
3a
5a
OMe
N
OMe
N
Ph
Boc
Boc
O
N
O
CHO
Cl
2
3
3a
3a
5b
5c
82
97
OMe
N
Boc
Cl
O
N
O
CHO
OMe
N
Boc
Cl
Cl
O
N
O
CHO
OMe
N
4
5
6
3a
3a
3a
5d
5e
5f
95
94
99
Boc
Cl
Cl
O
N
O
CHO
OMe
N
Boc
NO2
NO2
O
N
O
CHO
OMe
N
Boc
MeO
OMe
MeO
OMe
O
N
O
CHO
7
8
3a
3a
5g
5h
84
85
OMe
N
O
O
S
Boc
O
N
O
CHO
S
OMe
N
Boc
O
N
O
9
3a
3a
n-PrCHO
5i
5j
65
54
OMe
N
Pr
Boc
O
N
O
10
(HCHO)n
OMe
N
Boc
Synthesis 2008, No. 9, 1345–1350 © Thieme Stuttgart · New York

PAPER
Cyclization of Oxo N-Acyliminium Ions to Indoles
1347
Table 1 Reaction of Hydroxamates 3 with Aldehydes in the Presence of Lewis Acid (Scheme 1)a (continued)
Entry
11
Hydroxamate
Aldehyde
Product
Yield (%)b
79
O
O
N
3a
i-PrCHO
5k
OMe
N
H
H
N
O
N
O
O
O
O
12
13
14
3b
3c
3d
PhCHO
PhCHO
PhCHO
5l
47
73
27
O
MeO
N
N
Ph
Ph
OMe
Boc
Boc
H
N
O
N
5m
5n
O
MeO
N
N
OMe
Me
Me
O
O
N
HN
N
N
O
O
Ph
Boc
Boc
MeO
OMe
a Reaction conditions: see experimental section.
b Isolated yield.
We subjected the hydroxamates 3 and a wide range of al- (entry 10). However, complicated result was obtained
dehydes to this process to determine its scope and limita- when hindered isobutyraldehyde was used, and no desired
tions. As indicated in Table 1, this approach to N–O fused product was isolated. BF3·Et2O was found to efficiently
indole derivatives 5 is very versatile. A wide variety of ar- promote the reaction, and a deprotected compound 5k was
omatic aldehydes have been reacted successfully (entries obtained in 79% yield (entry 11).
1–8). We have been able to obtain high yields using benz-
aldehydes with electron-withdrawing or electron-donat-
ing groups on benzene ring. However, when the hindered
Next, in order to investigate the scope of the presented
methodology, the hydroxamates 3b, 3c, and 3d were pre-
pared with different side chains. Formation of seven-
2-chlorobenzaldehyde was employed, a slightly lower
membered rings in arene cyclization can be trouble-
yield of 5b was observed (entry 2). It is particularly note-
some,10 but the cyclized product 5l was readily obtained
worthy that 3a undergoes this cyclization process with
from 3b in a moderate 47% yield after treatment with
furan-2-carbaldehyde and thiophen-2-carbaldehyde to af-
TMSCl/NaI (entry 12). Given the higher reactivity of N-
methyl indole (compared to N-Boc indole), dramatic im-
provement in yield was observed when the reaction of 3c
ford the corresponding 5g and 5h in good yields (entries 7
and 8).
When aliphatic aldehydes were employed, the results with benzaldehyde was carried out in the same conditions,
were generally inferior to those of aromatic aldehydes. and the corresponding 5m was isolated in 73% yield. In
The reaction of 3a with n-butyraldehyde dramatically this approach, it is possible for the cyclization of 3d with
lowers the yield of 5i (entry 9). The reaction proceeded benzaldehyde to produce a new eight-membered ring 5n
well when paraformaldehyde was employed, but only the in 27% yield (entry 14).
a-hydroxy intermediate 6 was obtained in 58% yield
In summary, a synthesis of diverse N–O fused indole de-
rivatives 5 via the cyclization of oxo N-acyliminium ions
methodology has been developed. The TMSCl/NaI sys-
tem proved to be efficient for the cyclization of hydrox-
(Scheme 3), which can be cyclized to the desired com-
pound 5j in 78% yield by treatment with TFA. Reasonable
yield of 5j was also obtained by the reaction of 3a with
paraformaldehyde using just TFA at room temperature
amates 3 and aromatic aldehydes regardless of the
O
O
O
O
O
O
TFA (2.0 equiv)
HN
(HCHO)n
N
N
CH2Cl2
r.t., 5 h
OMe
TMSCl, NaI
MeCN
–40 °C to r.t.
OMe
OMe
N
N
N
OH
6 58%
Boc
Boc
Boc
3a
5j 78%
Scheme 3
Synthesis 2008, No. 9, 1345–1350 © Thieme Stuttgart · New York

1348
X. Zheng et al.
PAPER
J = 7.5, 1.0 Hz, 1 H), 7.37 (dd, J = 8.5, 1.0 Hz, 1 H), 7.40 (td,
J = 7.5, 1.5 Hz, 1 H), 8.23 (d, J = 8.5 Hz, 1 H).
substitution on benzene ring. Aliphatic aldehydes can be
used in the cyclization in the presence of BF3·Et2O. A se-
ries of novel [1,2]oxazino[4,5-b]indoles (5a–k, n = 1), 13C NMR (125 MHz, CDCl3): d = 27.85, 53.56, 57.62, 67.22, 84.94,
114.69, 116.10, 118.09, 123.26, 125.16, 125.81, 126.64, 128.25,
[1,2]oxazepino[4,5-b]indoles (5l, 5m, n = 2), and [1,2]ox-
azocino[4,5-b]indoles (5n, n = 3) were obtained by appli-
128.51, 129.46, 129.83, 134.16, 136.14, 140.60, 149.26, 155.47.
cation of this procedure.
5-tert-Butyl 3-Methyl 4-(4-Chlorophenyl)-[1,2]oxazino[4,5-
b]indole-3,5(1H,4H)-dicarboxylate (5d)
Colorless solid; mp 76–78 °C.
MeCN and CH2Cl2 were distilled from CaH2. TMSCl, BF3·Et2O,
TFA and all aldehydes were commercially available. All the hy-
1H NMR (500 MHz, CDCl3): d = 1.43 (s, 9 H), 3.85 (s, 3 H), 5.05,
5.36 (AB, J = 13.5 Hz, 2 H), 6.79 (s, 1 H), 7.19–7.20 (m, 2 H), 7.25–
7.30 (m, 3 H), 7.35–7.40 (m, 2 H), 8.21 (d, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 27.87, 53.51, 57.54, 67.25, 84.87,
114.64, 116.06, 118.06, 123.25, 125.11, 125.82, 128.38, 129.78,
130.15, 133.93, 136.11, 137.16, 149.23, 155.49.
1
droxamates 3 were prepared according to the literature. H NMR
(500 MHz) and 13C NMR (125 MHz) spectra were recorded on
Varian Inova 500 MHz instrument. Melting point was not corrected.
High-resolution mass spectra (HRMS) were recorded on a Q-TOF
micro (water) apparatus.
Cyclization of Hydroxamates 3 and Aldehydes in the Presence
of TMSCl/NaI; General Procedure
5-tert-Butyl 3-Methyl 4-(4-Nitrophenyl)-[1,2]oxazino[4,5-b]in-
dole-3,5(1H,4H)-dicarboxylate (5e)
Pale yellow solid; mp 100–102 °C.
To a solution of hydroxamate 3 (500 mg) in anhyd MeCN (10 mL
per 1.0 mmol of 3) was added the appropriate aldehyde (1.5 equiv)
in one portion followed by NaI (3.0 equiv). The resulting mixture
was chilled to –40 °C and TMSCl (3.0 equiv) was added dropwise
under N2. The mixture was allowed to warm to r.t. slowly and treat-
ed with aq 20% NaHSO3 (20 mL) and extracted with EtOAc (3 × 20
mL). The organic phases were collected, washed with aq sat.
NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4), and evaporat-
ed under reduced pressure. The residue was chromatographed on a
silica gel column to afford the desired N–O fused indole derivatives
5.
1H NMR (500 MHz, CDCl3): d = 1.46 (s, 9 H), 3.87 (s, 3 H), 5.09,
5.41 (AB, J = 14.0 Hz, 2 H), 6.89 (s, 1 H), 7.31 (td, J = 7.5, 0.5 Hz,
1 H), 7.30 (td, J = 7.5, 1.5 Hz, 1 H), 7.42 (td, J = 7.5, 1.0 Hz, 1 H),
7.46–7.48 (m, 2 H), 7.14–7.18 (m, 3 H).
13C NMR (125 MHz, CDCl3): d = 27.95, 53.71, 57.51, 67.36, 85.17,
114.97, 116.14, 118.26, 123.42, 125.37, 125.77, 129.42, 129.54,
135.92, 145.69, 147.62, 149.24, 155.39.
HRMS (ESI): m/z calcd for C23H23N3O7 + Na [M + Na]+: 476.1428;
found: 476.1425.
5-tert-Butyl 3-Methyl 4-Phenyl-[1,2]oxazino[4,5-b]indole-
3,5(1H,4H)-dicarboxylate (5a)
Colorless solid; mp 121–123 °C.
5-tert-Butyl 3-Methyl 4-(3,4-Dimethoxyphenyl)-[1,2]oxazi-
no[4,5-b]indole-3,5(1H,4H)-dicarboxylate (5f)
Colorless solid; mp 144–146 °C.
1H NMR (500 MHz, CDCl3): d = 1.42 (s, 9 H), 3.82 (s, 3 H), 3.83
(s, 3 H), 3.86 (s, 3 H), 5.06, 5.37 (AB, J = 13.5 Hz, 2 H), 6.62 (dd,
J = 8.0, 2.0 Hz, 1 H ), 6.73 (d, J = 8.0 Hz, 1 H), 6.77 (s, 1 H), 6.93
(d, J = 2.0 Hz, 1 H), 7.28 (td, J = 7.5, 1.0 Hz, 1 H), 7.36 (dd, J = 7.5,
1.5 Hz, 1 H), 7.39 (td, J = 7.5, 1.0 Hz, 1 H), 8.25 (d, J = 8.5 Hz, 1
H).
13C NMR (125 MHz, CDCl3): d = 27.84, 53.44, 55.86, 55.98, 57.92,
67.18, 84.64, 110.52, 111.79, 114.35, 115.99, 117.97, 120.66,
123.14, 124.95, 125.86, 130.64, 131.20, 136.21, 148.86, 148.95,
149.32, 155.71.
1H NMR (500 MHz, CDCl3): d = 1.37 (s, 9 H), 3.86 (s, 3 H), 5.06,
5.38 (AB, J = 13.5 Hz, 2 H), 6.82 (s, 1 H), 7.22–7.24 (m, 2 H), 7.27–
7.30 (m, 4 H), 7.36 (dd, J = 8.5, 1.0 Hz, 1 H), 7.40 (d, J = 8.5 Hz, 1
H), 8.26 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 27.74, 53.43, 58.09, 67.19, 84.70,
114.50, 116.01, 117.96, 123.16, 124.96, 125.89, 128.05, 128.23,
128.33, 130.38, 136.24, 138.59, 149.31, 155.59.
HRMS (ESI): m/z calcd for C23H24N2O5 + Na [M + Na]+: 431.1577;
found: 431.1586.
5-tert-Butyl 3-Methyl 4-(2-Chlorophenyl)-[1,2]oxazino[4,5-
b]indole-3,5(1H,4H)-dicarboxylate (5b)
Colorless solid; mp 88–91 °C.
HRMS (ESI): m/z calcd for C25H28N2O7 + Na [M + Na]+: 491.1789;
found: 491.1797.
1H NMR (500 MHz, CDCl3): d = 1.37 (s, 9 H), 3.87 (s, 3 H), 5.99,
5.45 (AB, J = 13.3 Hz, 2 H), 6.78 (dd, J = 7.5, 1.5 Hz, 1 H), 6.99
(br, 1 H), 7.10 (td, J = 7.5, 1.0 Hz, 1 H), 7.25 (td, J = 7.5, 1.5 Hz, 1
H), 7.29 (td, J = 7.5, 1.0 Hz, 1 H), 7.39 (td, J = 8.0, 1.5 Hz, 2 H),
7.44 (dd, J = 8.0, 1.0 Hz, 1 H), 8.29 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 27.79, 53.68, 56.33, 66.34, 84.82,
114.78, 116.17, 117.98, 123.25, 125.24, 125.85, 126.43, 129.49,
129.99, 130.02, 134.46, 135.87, 136.30, 149.29, 156.00.
5-tert-Butyl 3-Methyl 4-(Furan-2-yl)-[1,2]oxazino[4,5-b]indole-
3,5(1H,4H)-dicarboxylate (5g)
Colorless solid; mp 132–134 °C.
1H NMR (500 MHz, CDCl3): d = 1.48 (s, 9 H), 3.88 (s, 3 H), 5.06
(d, J = 13.5 Hz, 1 H), 5.35 (dd, J = 13.5, 1.0 Hz, 1 H), 6.02 (td,
J = 7.5, 1.0 Hz, 1 H ), 6.30 (ddd, J = 3.5, 2.0, 0.5 Hz, 1 H), 6.80 (s,
1 H), 7.28 (td, J = 7.5, 1.0 Hz, 1 H), 7.36–7.39 (m, 2 H), 7.40 (dd,
J = 2.0, 1.0 Hz, 1 H), 8.28 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 27.79, 52.96, 53.62, 67.14, 84.77,
109.49, 110.52, 114.61, 115.98, 118.04, 123.18, 125.18, 125.72,
128.53, 136.30, 142.24, 149.22, 151.21, 155.61.
HRMS (ESI): m/z calcd for C23H23ClN2O5 + Na [M + Na]+:
465.1188; found: 465.1188.
5-tert-Butyl 3-Methyl 4-(3-Chlorophenyl)-[1,2]oxazino[4,5-
b]indole-3,5(1H,4H)-dicarboxylate (5c)
Colorless solid; mp 181–183 °C.
HRMS (ESI): m/z calcd for C21H22N2O6 + Na [M + Na]+: 421.1370;
found: 421.1371.
1H NMR (500 MHz, CDCl3): d = 1.43 (s, 9 H), 3.86 (s, 3 H), 5.07,
5.38 (AB, J = 14.0 Hz, 2 H), 6.78 (s, 1 H), 7.15 (td, J = 7.5, 1.0 Hz,
1 H), 7.23 (td, J = 7.5, 0.5 Hz, 1 H), 7.25–7.26 (m, 2 H), 7.29 (td,
5-tert-Butyl 3-Methyl 4-(Thiophen-2-yl)-[1,2]oxazino[4,5-b]in-
dole-3,5(1H,4H)-dicarboxylate (5h)
Colorless solid; mp 102–104 °C.
Synthesis 2008, No. 9, 1345–1350 © Thieme Stuttgart · New York

PAPER
Cyclization of Oxo N-Acyliminium Ions to Indoles
1349
1H NMR (500 MHz, CDCl3): d = 1.49 (s, 9 H), 3.87 (s, 3 H), 5.10
(d, J = 13.5 Hz, 1 H), 5.36 (dd, J = 13.5, 1.5 Hz, 1 H), 6.87 (dd,
J = 3.5, 1.0 Hz, 1 H), 6.90 (dd, J = 5.0, 3.5 Hz, 1 H), 6.96 (s, 1 H),
7.23 (dd, J = 5.0, 1.5 Hz, 1 H), 7.28 (td, J = 7.5, 1.0 Hz, 1 H), 7.36
(dd, J = 7.5, 1.5 Hz, 1 H), 7.38–7.40 (m, 1 H), 8.22 (d, J = 8.0 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 27.84, 53.53, 54.31, 67.45, 84.83,
114.32, 115.99, 118.15, 123.17, 125.12, 125.68, 126.32, 127.23,
130.91, 136.19, 141.00, 149.28, 155.42.
10-tert-Butyl 2-Methyl 1-Phenyl-4,5-dihydro-1H-[1,2]oxazepi-
no[4,5-b]indole-2,10-dicarboxylate (5l)
Colorless oil.
1H NMR (500 MHz, CDCl3): d = 1.41 (s, 9 H), 3.07–3.19 (m, 2 H),
3.86 (s, 3 H), 4.29–4.31 (m, 2 H), 7.13 (s, 1 H), 7.14 (d, J = 1.5 Hz,
1 H), 7.24–7.36 (m, 5 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.62 (s, 1 H),
8.17 (d, J = 8.0 Hz, 1 H).
HRMS (ESI): m/z calcd for C24H26N2O5 + Na [M + Na]+: 445.1734;
found: 445.1749.
HRMS (ESI): m/z calcd for C21H22N2O5S + Na [M + Na]+:
437.1142; found: 437.1147.
Methyl 10-Methyl-1-phenyl-4,5-dihydro-1H-[1,2]oxazepi-
no[4,5-b]indole-2(10H)-carboxylate (5m)
Colorless solid; mp 155–157 °C.
1H NMR (500 MHz, CDCl3): d = 3.18 (dt, J = 16.5, 4.0 Hz, 1 H),
3.25–3.31 (m, 1 H), 3.51 (s, 9 H), 3.84 (s, 3 H), 4.27–4.32 (m, 1 H),
4.44–4.49 (m, 1 H), 6.83 (s, 1 H), 7.15–7.30 (m, 8 H), 7.57 (d,
J = 7.5 Hz, 1 H).
5-tert-Butyl 3-Methyl 4-Propyl-[1,2]oxazino[4,5-b]indole-
3,5(1H,4H)-dicarboxylate (5i)
Colorless oil.
1H NMR (500 MHz, CDCl3): d = 0.98 (t, J = 7.5 Hz, 3 H), 1.52–
1.64 (m, 2 H), 1.71 (s, 9 H), 1.88–1.97 (m, 2 H), 3.81 (s, 3 H), 4.95
(d, J = 13.5 Hz, 1 H), 5.31 (br, 1 H), 5.62 (br, 1 H), 7.22 (td, J = 7.0,
1.0 Hz, 1 H), 7.28–7.32 (m, 2 H), 8.14 (d, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.84, 17.90, 28.24, 35.22, 53.27,
55.70, 66.74, 84.53, 112.06, 115.98, 117.73, 123.02, 124.51,
126.25, 134.14, 135.77, 149.69, 156.27.
HRMS (ESI): m/z calcd for C20H20N2O3 + Na [M + Na]+: 359.1366;
found: 359.1377.
11-tert-Butyl 2-Methyl 1-Phenyl-5,6-dihydro-[1,2]oxazoci-
no[4,5-b]indole-2,11(1H,4H)-dicarboxylate (5n)
Colorless oil.
1H NMR (500 MHz, CDCl3): d = 1.56 (s, 9 H), 1.83–1.90 (m, 1 H),
1.98–2.06 (m, 1 H), 2.82–2.91 (m, 2 H), 3.70 (td, J = 12.0, 4.5 Hz,
1 H), 3.89 (s, 3 H), 4.31 (dd, J = 13.0, 5.0 Hz, 1 H), 7.27–7.33 (m,
6 H), 7.38 (td, J = 7.0, 1.0 Hz, 1 H), 7.55 (d, J = 7.5 Hz, 1 H), 7.81
(s, 1 H), 8.17 (d, J = 7.5 Hz, 1 H).
HRMS (ESI): m/z calcd for C20H27N2O5 [M + H]+: 375.1914; found:
375.1928.
5-tert-Butyl 3-Methyl [1,2]Oxazino[4,5-b]indole-3,5(1H,4H)-di-
carboxylate (5j)
To a solution of hydroxamate 3a (500 mg, 1.56 mmol) in anhyd
CH2Cl2 (20 mL) was added paraformaldehyde (70 mg, 2.33 mmol)
in one portion. TFA (0.24 mL, 3.12 mmol) was added dropwise at
r.t. After stirring for 10 h, the solvent was evaporated under reduced
pressure and the residue was chromatographed on silica gel column
to afford 5j as a colorless oil.
1H NMR (500 MHz, CDCl3): d = 1.69 (s, 9 H), 3.84 (s, 3 H), 5.05
(s, 2 H), 5.12 (t, J = 1.5 Hz, 2 H), 7.23 (td, J = 7.0, 1.0 Hz, 1 H),
7.30–7.33 (m, 2 H), 8.15 (d, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 28.24, 46.38, 53.45, 67.30, 84.67,
113.43, 115.70, 117.71, 123.04, 124.49, 126.28, 129.44, 135.60,
149.77, 156.22.
HRMS (ESI): m/z calcd for C17H20N2O5 + Na [M + Na]+: 355.1264;
found: 355.1273.
HRMS (ESI): m/z calcd for C25H28N2O5 + Na [M + Na]+: 459.1890;
found: 459.1890.
Methyl [N-(1-tert-Butoxycarbonylindol-3-yl)]methoxy(hy-
droxymethyl)carbamate (6)
Colorless solid; mp 136–137 °C.
1H NMR (500 MHz, CDCl3): d = 1.67 (s, 9 H), 3.18 (t, J = 7.5 Hz,
1 H, OH), 3.81 (s, 3 H), 4.87 (d, J = 7.5 Hz, 2 H), 5.07 (d, J = 0.5
Hz, 2 H), 7.28 (td, J = 8.0, 1.0 Hz, 1 H), 7.34 (td, J = 8.0, 1.5 Hz, 1
H), 7.65 (s, 1 H), 7.74 (d, J = 7.5 Hz, 1 H), 8.13 (d, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 28.17, 53.45, 68.18, 73.88, 84.07,
115.09, 115.30, 119.47, 123.06, 124.83, 126.50, 129.59, 135.61,
149.51, 157.39.
Methyl 4-Isopropyl-[1,2]oxazino[4,5-b]indole-3(1H,4H,5H)-
carboxylate (5k)
Acknowledgment
To a solution of hydroxamate 3a (500 mg, 1.56 mmol) in anhyd
CH2Cl2 (20 mL) was added isobutyraldehyde (0.21 mL, 2.34 mmol)
in one portion. The resulting mixture was cooled to –78 °C and
BF3·OEt2 (0.4 mL, 3.12 mmol) was added dropwise under N2. The
mixture was allowed to warm to r.t. slowly and quenched with Et3N
(0.5 mL). The solvent was evaporated under reduce pressure and the
residue was chromatographed on silica gel column to afford 5k as a
colorless solid; mp 202–204 °C.
J.C. acknowledges the National Natural Science Foundation of
China (#20672030), the Program of New Century Excellent Talent,
and the Ministry of Education of China (NCET 050613) for finan-
cial support. K.Z. acknowledges the Tianjin Municipal Science and
Technology Commission and the Cheung Kong Scholars Pro-
gramme for financial support.
1H NMR (500 MHz, CDCl3): d = 1.03 (d, J = 6.5 Hz, 3 H), 1.12 (d,
J = 7.0 Hz, 3 H), 2.26 (td, J = 13.5, 6.5 Hz, 1 H), 3.82 (s, 3 H), 4.98
(br, 1 H), 5.02 (d, J = 13.5 Hz, 1 H), 5.31 (d, J = 12.5 Hz, 1 H), 7.10
(td, J = 8.0, 1.0 Hz, 1 H), 7.18 (td, J = 8.0, 1.0 Hz, 1 H), 7.35 (dt,
J = 8.0, 1.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 8.26 (br, 1 H).
13C NMR (125 MHz, CDCl3): d = 19.22, 19.47, 32.91, 53.39, 59.77,
67.74, 106.80, 111.23, 117.92, 119.95, 122.20, 124.19, 130.79,
135.87, 156.60.
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Synthesis 2008, No. 9, 1345–1350 © Thieme Stuttgart · New York