Copper-catalyzed aerobic methyl/methylene oxygenation and C-H formylation with a DABCO-DMSO system for the synthesis of carbonyl indoles and pyrroles

Article abstract of DOI:10.1055/s-0031-1290815

Copper-catalyzed aerobic methyl/methylene oxygenation of substituted indoles and pyrroles was developed using 1,4-diazabicyclo[2.2.2]octane (DABCO) as an additive in dimethyl sulfoxide (DMSO). Similar aerobic catalytic conditions could also be utilized for direct C-H formylation of C(3) on indoles and C(2) on pyrroles.

Full text of DOI:10.1055/s-0031-1290815

1526▌
SPECIAL TOPIC
sCpeociapl tpopeicr-Catalyzed Aerobic Methyl/Methylene Oxygenation and C–H
Formylation with a DABCO–DMSO System for the Synthesis of Carbonyl
Indoles and Pyrroles
Yi-Feng Wang, Feng-Lian Zhang, Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, 637371 Singapore, Singapore
Fax +65(6791)1961; E-mail: shunsuke@ntu.edu.sg
Received: 17.02.2012; Accepted after revision: 09.03.2012
tions with tetramethylethylenediamine (TMEDA) and 4-
Abstract: Copper-catalyzed aerobic methyl/methylene oxygen-
(N,N-dimethylamino)pyridine (DMAP) did not proceed at
ation of substituted indoles and pyrroles was developed using 1,4-
all (Table 1, entries 2 and 3), the yield of 2a was dramati-
cally improved to 83% by using DABCO (1 equiv) as an
diazabicyclo[2.2.2]octane (DABCO) as an additive in dimethyl
sulfoxide (DMSO). Similar aerobic catalytic conditions could also
be utilized for direct C–H formylation of C(3) on indoles and C(2) additive (entry 4). The use of quinuclidine (1-azabicy-
on pyrroles.
Table 1 Optimization of Reaction Conditionsa
Key words: aldehydes, copper, oxygen, oxygenation, formylation
O
H
Cu salts
additive
Among nitrogen-containing heterocycles, indoles1,2 and
pyrroles3,4 are an omnipresent component of numerous
natural alkaloids and potent pharmaceutical drugs. Ac-
cordingly, chemo- and regioselective functionalization of
rather simple and readily available indole and pyrrole de-
rivatives are of great value in their further derivatization.5
Herein, we report the copper-catalyzed aerobic meth-
yl/methylene oxygenation and C–H formylation of indole
and pyrrole derivatives in the presence of 1,4-diazabicyc-
lo[2.2.2]octane (DABCO) in dimethyl sulfoxide (DMSO)
for the synthesis of their oxygenated/carbonylated deriva-
tives.6
conditions
100 °C
under O2 (1 atm)
N
N
Me
Me
2a
1a
Entry Cu salt (mol%)
Additive
(equiv)
Solvent
Time Yield
(%)b
(h)
1
CuBr·SMe2
(15)
–
DMSO
DMSO
DMSO
DMSO
29
9
(49)c
2
CuBr·SMe2
(15)
TMEDA
(1.0)
29
29
29
52
24
29
23
23
34
27
0
(89)c
3
CuBr·SMe2
(15)
DMAP
(1.0)
0
(72)c
We have recently been interested in copper-catalyzed aer-
obic oxidation and oxygenation of various carbon–hydro-
gen and carbon–carbon unsaturated bonds.7 During the
course of these studies, we became interested in oxidative
functionalization of indole and pyrrole nuclei under cop-
per-catalyzed aerobic conditions. We began our investiga-
tion with the copper-catalyzed aerobic reactions of 1,3-
dimethylindole (1a; Table 1). Interestingly, when 1a was
treated with 15 mol% CuBr·SMe2 in DMSO at 100 °C un-
der an O2 atmosphere, oxygenation of the C-3 methyl
group was observed, affording 3-formylindole (2a) in 9%
yield (entry 1). Although there have been reports on the
direct oxygenation of benzylic methyl and methylene
moieties by metal–peroxide systems8 as well as hyperva-
lent iodine reagents,9 these methods have seldom been ap-
plied for the oxidation of indole and pyrrole derivatives,
probably due to their highly electron-rich and nucleophil-
ic natures.10 With this background, the above mentioned
unprecedented aerobic oxygenation prompted us to opti-
mize the reaction conditions further. Whereas the reac-
CuBr·SMe2
(15)
DABCO
(1.0)
4
83
5
CuBr·SMe2
(15)
Quinuclidine DMSO
(1.0)
38
(45)c,d
6
CuBr·SMe2
(10)
DABCO
(1.0)
DMSO
64
7
CuBr·SMe2
(15)
DABCO
(1.0)
DMF
66
(17)c
8
CuCl
(20)
DABCO
(1.0)
DMSO
DMSO
DMSO
DMSO
78
64
68
63
9
CuBr2
(20)
DABCO
(1.0)
10
11
Cu(OCOCF3)2
(20)
DABCO
(1.0)
Cu(OTf)2
(20)
DABCO
(2.0)
a The reactions were carried out using 0.5 mmol of 1a under O2 (1 atm).
b Isolated yield.
c Recovery yield of 1a.
d NMR yield.
SYNTHESIS 2012, 44, 1526–1534
Advanced online publication: 20.04.2012
DOI: 10.1055/s-0031-1290815; Art ID: SS-2012-C0163-ST
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

SPECIAL TOPIC
Oxygenation and C–H Formylation of Indoles
1527
clo[2.2.2]octane) in place of DABCO rendered the reaction even after 120 h (entry 6). Similarly, the reaction of indole
more sluggish (entry 5). Lower catalyst loading (10 1g bearing a benzyl moiety with a 4-methoxycarbonyl
mol%; Table 1, entry 6) or conducting the reaction in N,N- group at C(3) proceeded with a slow reaction rate (entry
dimethylformamide (DMF) as a solvent instead of DMSO 7). In the case of 4-pyridylmethyl derivative 1h, 14%
(entry 7) resulted in lower yield of 2a. Other copper salts yield of dimer 2h′11 (Figure 1) was also isolated along
also performed well as a catalyst in the present oxygen- with the oxygenated product 2h (entry 8). The methylene
ation, regardless of their oxidation states (i.e., CuI or CuII; oxygenation of 3,5-dimethyl-5,10-dihydroindeno[1,2-
Table 1, entries 8–11), although the yields from CuII salts b]indole (1i) proceeded smoothly to give 2i in 93% yield
were slightly reduced (entries 9–11).
(entry 9). Interestingly, 3-allylindole 1j could be convert-
ed into 3-indolylacrylaldehyde 2j through oxygenation of
the terminal carbon (entry 10). We next examined the re-
actions of 2,3-dimethylindole (1k) and 2-methyl-3-ben-
zylindole (1l; entries 11 and 12). In these cases, 3-
carbonylindoles 2k and 2l were formed as the major prod-
uct. The oxygenation of 2,5-dimethylpyrrole (1m) deliv-
ered mono-oxygenated pyrrole 2m in 57% yield (entry
13). It should be noted that oxygenation of other hetero-
aromatic compounds such as benzofuran, benzotiophene,
oxazoles, and imidazoles did not occur under the present
reaction conditions.
With the optimized reaction conditions in hand (Table 1,
entry 4), we next examined the scope and limitations of
the oxygenation reaction of 3-alkylindoles (Table 2). As a
substituent on the nitrogen atom, a benzyl group could
also be introduced instead of a methyl group (Table 2, en-
try 2). 3-Acetyl- and 3-benzoylindoles, 2c and 2d, respec-
tively, could be prepared from the corresponding 3-ethyl
and 3-benzyl derivatives 1c and 1d (entries 3 and 4). In-
stallation of a methoxyl group on C(5) of the indole core
accelerated the reaction to give indole 2e in 92% yield
(entry 5), whereas a bromine substituent on C(5) render
the reaction sluggish, affording indole 2f in 75% yield
Table 2 Copper-Catalyzed Aerobic Oxygenationa
Product, yield (%)b
Entry
Substrate
Time (h)
O
H
2a 83
2b 77c
1
2
1a R = Me
1b R = Bn
29
47
N
R
N
R
O
3
1c
30
2c 65
N
Me
N
Me
O
R
R
Ph
Ph
2d 87
2e 92
2f 75 (22)c
4
5
6
1d R = H
29
1e R = OMe
1f R = Br
24
120
N
N
Me
Me
O
CO2Me
CO2Me
2g 39 (31)c
7
8
9
1g
1h
1i
72
6.5
4
N
N
Me
Me
O
N
N
2h 47d
N
N
Me
Me
O
2i 93
N
N
Me
Me
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1526–1534

1528
Y.-F. Wang et al.
SPECIAL TOPIC
Table 2 Copper-Catalyzed Aerobic Oxygenationa (continued)
Product, yield (%)b
Entry
10
Substrate
Time (h)
27
O
H
1j
2j 48
N
Me
N
Me
O
H
11
1k
4
2k 63
2k′ 22
2l 50
N
Me
N
Me
O
N
Me
H
O
Ph
Ph
12
1l
5
N
Me
N
Me
Ph
O
2l′ 39
N
Me
H
O
13
1m
3
2m 57
N
N
Me
H
Me
a Reaction conditions: 1 (0.5 mmol ), CuBr•SMe2 (15 mol%), DABCO (1 equiv), DMSO, 100 °C.
b Isolated yield.
c Recovery yield of 1.
d 14% yield of dimer 2h′ (dr = 10:1) was also isolated (Figure 1).
18O
N
standard
conditions
H
MeN
under 18O2
N
N
N
Me
1a
Me
2a (87%)
N
Me
Scheme 1 Reagents and conditions: 1a (0.5 mmol), CuBr·SMe2 (15
mol%), DABCO (1 equiv) in DMSO, 100 °C, 18O2 (1 atm).
2h'
Figure 1 Dimer 2h′
species.13 This higher oxidation state Cu(II) species un-
dergoes one-electron oxidation of indole 1 to afford cation
radical I. Homolytic cleavage of the C–H bond on the
C(3) substituent forms carbon radical II, which could be
further converted into Cu-peroxo species III. Formation
of C(3)-carbonyl indole 2 occurs from III along with for-
mation of [CuI]-OH, which is responsible for maintaining
the catalytic cycle further.
A labeling experiment using an 18O2 atmosphere revealed
that the oxygen atom might be incoporated into the car-
bonyl group from atmospheric oxygen (Scheme 1).
Based on these observations, a proposed reaction mecha-
nism for the present oxygenation is described in Scheme
2. In this scenario, the Cu(I)–DABCO complex12 (de-
scribed as [CuI]) is first generated, which reacts with mo-
lecular oxygen to give a Cu(II) superoxo or peroxo
Synthesis 2012, 44, 1526–1534
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Oxygenation and C–H Formylation of Indoles
1529
mechanism of these oxygenative fragmentation reactions,
it might proceed from putative peroxy intermediates III
(see Scheme 2) through radical fragmentation.14
CuBr•SMe2
O
+
DABCO
R
R
O2
[CuI]X
X [CuII]O
N
O
N
Me
O
Me
O
2
1
(X = Br or OH)
H
standard
conditions
(a)
[CuI]
X–
•
N
H
N
O
O
Me
2a
Me
1o
H
R
[CuI]O
28 h, 33%
R
•
O
O
N
Me
N
H
[CuI]O
I
standard
conditions
Me
III
•
O
(b)
N
N
•
Me
R
Me
1p
2a
HX
99 h, 37%
N
Me
II
standard conditions: 0.5 mmol of 1 with 15 mol% of CuBr•SMe2,
1 equiv of DABCO in DMSO at 100 °C under O2 (1 atm)
Scheme 2 Proposed reaction mechanism
The reaction of 3-aminomethylindole (1n) provided 3-
formylindole (2a) in 98% yield through C–N bond cleav-
age probably via formation of the iminium cation generat-
ed by further one-electron oxidation of the resulting
putative radical intermediate followed by its hydrolysis
(Scheme 3).
CuBr•SMe2 (1 equiv)
DABCO (1 equiv)
DMSO, 100 °C
under O2 (1 atm)
N
Me
(c)
1q (0.5 mmol)
O
O
+
H
NEt2
standard
conditions
H
O
N
N
Me
2q (14%)
Me
N
N
Me
Me
1n
2q' (29%)
2a
24 h, 98%
Scheme 4
H2O
During the course of this study, it was found that direct in-
dole C(3)-H formylation of 1-methylindole (3a) could
also proceed to give 3-formylindole 4a (= 2a) in 34%
yield under the same reaction conditions [CuBr·SMe2 (20
mol%), DABCO (2 equiv), DMSO, 100 °C], where
DMSO most likely acted as a carbon source for the result-
ing formyl group. Conventional C(3)-H formylation of in-
doles has relied exclusively on the Vilsmeier reaction
using toxic phosphoryl chloride (POCl3) and DMF.15 This
copper-catalyzed aerobic direct C(3)-H formylation of in-
dole 3a in DMSO prompted us to investigate in more de-
tail the optimization of the reaction conditions and the
scope of the reaction (Table 3).16,17 Screening of copper
salts revealed that the use of Cu(OCOCF3)2 was optimal
for this direct C(3)-H formylation (entry 6), giving 4a (=
2a) in 50% yield. Interestingly, addition of DABCO (2
equiv) was crucial, and other nitrogen bases did not work
well for this transformation (entries 9 and 10).
NEt2
NEt2
– e–
N
N
Me
Me
Scheme 3 Reagents and conditions: 1n (0.5 mmol), CuBr·SMe2 (15
mol%), DABCO (1 equiv), DMSO, 100 °C, O2 (1 atm).
Interestingly, indoles bearing 3-butanoyl (for 1o) and 3-
methyl-3-butenyl (for 1p) moieties at C(3) were both con-
verted into 2a through oxygenative C–C bond cleavage
(Scheme 4, a and b). The reaction of 3-(2-tetrahydronaph-
thyl)indole (1q) with one equivalent of CuBr·SMe2 and
DABCO also underwent a similar fragmentation with C–C
bond cleavage to give 3-acylindole 2q bearing a newly
formed benzaldehyde moiety along with generation of 3-
naphthylindole 2q′, although the yield was low (Scheme
4, c). Although we are still uncertain as to the reaction
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1526–1534

1530
Y.-F. Wang et al.
SPECIAL TOPIC
Table 3 Direct C(3)-H Formylation of N-Methylindolea
Table 4 Scope of the Copper-Catalyzed Aerobic Direct Formyl-
ationa,b
O
O
H
Cu salts (20 mol%)
additive
H
R2
R2
Cu(OCOCF3)2 (15 mol%)
DABCO (2.0 equiv)
DMSO
100 °C
under O2 (1 atm)
N
N
R3
R3
Me
Me
DMSO, 100 °C
under O2 (1 atm)
N
R1
3
N
R1
4
4a (= 2a)
3a
Yield (%)b
34
Entry Cu salt
Additive (equiv) Time (h)
O
O
O
Br
1
2
3
4
5
6
7
8
9
10
CuBr·SMe2
DABCO (2.0)
DABCO (2.0)
DABCO (2.0)
DABCO (2.0)
DABCO (2.0)
DABCO (2.0)
DABCO (3.0)
DABCO (1.0)
DMAP (2.0)
41
42
19
18
26
26
24
34
23
23
H
H
H
18 (23)c
CuI
N
N
N
12 (55)c
38
Me
Cu(OAc)2
Me
Me
MeO
4b: 54%
4d: 41%
Cu(hfacac)2
Cu(OTf)2
4c: 47%
O
O
O
44
H
H
H
Cu(OCOCF3)2
Cu(OCOCF3)2
Cu(OCOCF3)2
Cu(OCOCF3)2
Cu(OCOCF3)2
50
N
N
N
46
Me
Me
Ph
4f: 42%
4g (= 2k): 33%
33
4e (= 2b): 41%
0
O
O
H
TMEDA (2.0)
26
N
H
a The reactions were carried out using 0.5 mmol of 3a under O2 (1 atm).
b Isolated yields.
N
Me
c Recovery yield of 3a.
4h: 42%
4i: 29%
a The reactions were carried out using 0.5 mmol of 3.
The C(3)-selective formylation was observed in moderate
yields with a series of indoles 3b–h, however, the reaction
of N-phenylpyrrole (3i) afforded only 2-formylpyrrole 4i
in low yield (Table 4).
b Isolated yields are given.
Cu-Catalyzed Aerobic Methyl/Methylene Oxygenation of
Indoles and Pyrrole; Typical Procedure
In summary, chemoselective copper-catalyzed aerobic
methyl/methylene oxygenation of substituted indoles and
pyrrole in the presence of DABCO in DMSO was ex-
plored. Similar aerobic catalytic conditions could be ap-
plied for the direct C–H formylation of C(3) on indoles
and C(2) on pyrrole. Further investigations on the scope
and reaction mechanism of the present oxidation is under
way.
To a solution of 1,3-dimethyl-1H-indole (1a; 72.5 mg, 0.500 mmol)
in DMSO (5.0 mL) was added CuBr·SMe2 (15.4 mg, 0.075 mmol)
and DBACO (56.1 mg, 0.500 mmol). The reaction mixture was then
stirred for 29 h at 100 °C under an O2 atmosphere. The resulting
mixture was quenched with pH 9 ammonium buffer and extracted
twice with EtOAc. The combined organic extracts were washed
with brine, dried over MgSO4 and concentrated. Purification of the
crude product by flash column chromatography (silica gel; hexane–
EtOAc, 70:30) afforded 2a.
1-Methyl-1H-indole-3-carbaldehyde (2a)18
1H NMR spectra were measured with a Bruker Avance 400 spec-
trometer in CDCl3 [CHCl3 (δ = 7.26 ppm) as internal standard], or
in DMSO-d6 [DMSO (δ = 2.50 ppm) as internal standard]. 13C NMR
spectra were measured with a Bruker Avance 400 MHz spectrome-
ter in CDCl3 [CDCl3 (δ = 77.0 ppm) as internal standard] or in
DMSO-d6 [DMSO (δ = 39.5 ppm) as internal standard]. The follow-
ing abbreviations are used for the multiplicities: s = singlet, d = dou-
blet, t = triplet, q = quartet, m = multiplet, br = broad. IR spectra
were recorded with a Shimadzu IR Prestige-21 FT-IR spectrometer.
High-resolution mass spectra were obtained with a Q-Tof Premier
LC HR mass spectrometer. Melting points are uncorrected and were
recorded with a Büchi B-54 melting point apparatus. Flash column
chromatographic purification was performed using Silicycle 60 sil-
ica gel and distilled eluting solvents. DMF, DMSO, copper salts,
DABCO, and compound 1m were purchased from Sigma–Aldrich,
Pte. Ltd. For the synthesis of starting materials 1 and 3, see the Sup-
porting Information.
Yield: 66.1 mg (0.415 mmol, 83%); pale-yellow solid.
1H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H), 7.30–7.34 (m, 3 H),
7.60 (s, 1 H), 8.28–8.30 (m, 1 H), 9.93 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 33.6, 109.8, 117.9, 121.9, 122.8,
123.9, 125.1, 137.8, 139.3, 184.4.
1-Benzyl-1H-indole-3-carbaldehyde (2b)19
Yield: 90.2 mg (77% from 1b); white solid.
1H NMR (400 MHz, CDCl3): δ = 5.30 (s, 2 H), 7.14–7.16 (m, 2 H),
7.26–7.31 (m, 6 H), 7.65 (s, 1 H), 8.31–8.33 (m, 1 H), 9.95 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 50.8, 110.3, 118.3, 122.0, 123.0,
124.1, 125.3, 127.1, 128.2, 129.0, 135.2, 137.3, 138.6, 184.6.
1-(1-Methyl-1H-indol-3-yl)ethanone (2c)20
Yield: 56.6 mg (65% from 1c); yellow solid.
Synthesis 2012, 44, 1526–1534
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Oxygenation and C–H Formylation of Indoles
1531
1H NMR (400 MHz, CDCl3): δ = 2.51 (s, 3 H), 3.83 (s, 3 H), 7.26–
7.34 (m, 3 H), 7.68 (s, 1 H), 8.36–8.38 (m, 1 H).
2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 8.27–8.28
(m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 27.6, 33.4, 109.6, 116.9, 122.5
(overlapped), 123.3, 126.2, 135.7, 137.4, 192.9.
13C NMR (100 MHz, CDCl3): δ (major isomer) = 32.8, 47.5, 109.2,
114.9, 118.8, 119.0, 121.7, 123.8, 126.6, 127.2, 136.8, 149.5, 152.3.
HRMS (ESI): m/z [M + H]+ calcd for C30H27N4: 443.2236; found:
443.2241.
(1-Methyl-1H-indol-3-yl)(phenyl)methanone (2d)21
Yield: 102.5 mg (87% from 1d); yellow solid.
1H NMR (400 MHz, CDCl3): δ = 3.77 (s, 3 H), 7.30–7.33 (m, 3 H),
7.43–7.47 (m, 3 H), 7.51–7.53 (m, 1 H), 7.77–7.79 (m, 2 H), 8.41–
8.44 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 33.4, 109.6, 115.4, 122.6 (over-
lapped), 123.5, 127.1, 128.2, 128.5, 131.0, 137.4, 137.9, 140.8,
190.7.
3,5-Dimethylindeno[1,2-b]indol-10(5H)-one (2i)
Yield: 116.0 mg (93% from 1i); pale-yellow solid; mp 223–224 °C.
1H NMR (400 MHz, CDCl3): δ = 2.25 (s, 3 H), 3.72 (s, 3 H), 6.82–
6.84 (m, 2 H), 7.07–7.14 (m, 3 H), 7.18 (d, J = 7.6 Hz, 1 H), 7.68
(d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.8, 31.5, 110.4, 115.0, 119.7,
120.3, 122.71 (overlapped), 122.75, 123.2, 129.2, 134.8, 138.5,
142.4, 142.7, 158.4, 185.0.
3-Benzyl-5-methoxy-1-methyl-1H-indole (2e)22
Yield: 123.6 mg (92% from 1e); yellow solid.
1H NMR (400 MHz, CDCl3): δ = 3.74 (s, 3 H), 3.90 (s, 3 H), 6.96
(dd, J = 2.4, 8.8 Hz, 1 H), 7.20 (d, J = 8.8 Hz, 1 H), 7.41–7.51 (m,
4 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.97 (d, J = 2.4 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H14NO: 248.1075; found:
248.1072.
(E)-3-(1-Methyl-1H-indol-3-yl)acrylaldehyde (2j)23
Yield: 44.1 mg (48% from 1j); yellow solid.
13C NMR (100 MHz, CDCl3): δ = 33.6, 55.7, 103.7, 110.4, 114.0,
115.0, 127.9, 128.2, 128.4, 130.9, 132.4, 138.0, 140.8, 156.5, 190.8.
1H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H), 6.70 (dd, J = 8.0,
15.6 Hz, 1 H), 7.24–7.27 (m, 1 H), 7.29–7.34 (m, 2 H), 7.41 (s,
1 H), 7.60 (d, J = 15.6 Hz, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 9.57 (d,
J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 33.3, 110.2, 112.3, 120.4, 121.9,
123.4, 124.0, 125.8, 134.1, 138.2, 146.4, 194.0.
3-Benzyl-5-bromo-1-methyl-1H-indole (2f)
Yield: 116.5 mg (75% from 1f); pale-yellow solid; mp 180–181 °C.
IR (KBr): 3053, 2986, 1632, 1526, 1462, 1422, 1365, 1265 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.83 (s, 3 H), 7.22 (d, J = 8.6 Hz,
1 H), 7.43 (dd, J = 2.0, 8.6 Hz, 1 H), 7.47–7.56 (m, 4 H), 7.78 (d,
J = 8.4 Hz, 2 H), 8.60 (d, J = 2.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 33.7, 111.1, 114.9, 116.4, 125.2,
126.5, 128.3, 128.5, 128.6, 131.2, 136.1, 138.4, 140.4, 190.3.
1,2-Dimethyl-1H-indole-3-carbaldehyde (2k)24
Yield: 55.0 mg (63% from 1k); pale-yellow solid.
1H NMR (400 MHz, CDCl3): δ = 2.56 (s, 3 H), 3.59 (s, 3 H), 7.21–
7.27 (m, 3 H), 8.23–8.25 (m, 1 H), 10.07 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 10.4, 29.5, 109.1, 114.0, 120.7,
HRMS (ESI): m/z [M + H]+ calcd for C16H1379BrNO: 314.0181;
found: 314.0177.
122.6, 123.0, 125.5, 136.8, 147.7, 183.9.
Methyl 4-(1-Methyl-1H-indole-3-carbonyl)benzoate (2g)
1,3-Dimethyl-1H-indole-2-carbaldehyde (2k′)25
Yield: 20.1 mg (22% from 1k); pale-yellow solid.
1H NMR (400 MHz, CDCl3): δ = 2.62 (s, 3 H), 4.03 (s, 3 H), 7.14
(dd, J = 7.2, 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.41 (dd, J =
7.2, 8.0 Hz, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 10.15 (s, 1 H).
Yield: 59.8 mg (39% from 1g); pale-yellow solid; mp 130–132 °C.
IR (KBr): 3053, 2986, 1720, 1624, 1524, 1466, 1422, 1369, 1265,
1115 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H), 3.97 (s, 3 H), 7.35–
7.40 (m, 3 H), 7.50 (s, 1 H), 7.85 (d, J = 8.0 Hz, 2 H), 8.16 (d, J =
8.0 Hz, 2 H), 8.40–8.42 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 8.5, 31.5, 110.1, 120.0, 121.2,
126.4, 126.8, 127.3, 131.2, 139.7, 181.5.
13C NMR (100 MHz, CDCl3): δ = 33.6, 52.4, 109.7, 115.4, 122.7,
123.0, 123.9, 127.0, 128.4, 129.5, 132.1, 137.6, 138.1, 144.7, 166.5,
189.9.
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO3: 294.1130; found:
294.1126.
(1,2-Dimethyl-1H-indol-3-yl)(phenyl)methanone (2l)22
Yield: 58.8 mg (50% from 1l); pale-yellow solid.
1H NMR (400 MHz, CDCl3): δ = 2.53 (s, 3 H), 3.66 (s, 3 H), 7.05
(dd, J = 7.2, 8.0 Hz, 1 H), 7.18 (dd, J = 7.2, 8.0 Hz, 1 H), 7.27 (d,
J = 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.42 (dd, J = 7.6, 7.6 Hz,
2 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.73 (d, J = 7.6 Hz, 2 H).
(1-Methyl-1H-indol-3-yl)(pyridin-4-yl)methanone (2h)
Yield: 54.8 mg (47% from 1h); yellow solid; mp 150 °C (dec).
13C NMR (100 MHz, CDCl3): δ = 12.4, 29.5, 109.1, 113.4, 120.8,
121.3, 121.9, 126.9, 128.1, 128.9, 131.3, 136.4, 141.4, 144.6, 192.7.
IR (KBr): 3053, 2986, 1632, 1526, 1466, 1422, 1371, 1265, 1115
cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H), 7.36–7.40 (m, 3 H),
7.49 (s, 1 H), 7.59–7.61 (m, 2 H), 8.41–8.44 (m, 1 H), 8.77–8.78
(m, 2 H).
3-Benzyl-1-methyl-1H-indole-2-carbaldehyde (2l′)
Yield: 47.0 mg (39% from 1l); pale-yellow solid; mp 79–81 °C.
IR (KBr): 3053, 2986, 1656, 1614, 1528, 1472, 1418, 1382, 1265,
1132 cm–1.
13C NMR (100 MHz, CDCl3): δ = 33.6, 109.8, 114.8, 122.1, 122.5,
1H NMR (400 MHz, CDCl3): δ = 4.05 (s, 3 H), 4.44 (s, 2 H), 7.10
(dd, J = 7.2, 8.0 Hz, 1 H), 7.15–7.18 (m, 1 H), 7.20–7.25 (m, 4 H),
7.33 (d, J = 8.0 Hz, 1 H), 7.39 (dd, J = 7.2, 8.0 Hz, 1 H), 7.62 (d,
J = 8.0 Hz, 1 H), 10.17 (s, 1 H,).
13C NMR (100 MHz, CDCl3): δ = 29.5, 31.6, 110.3, 120.5, 121.6,
126.2, 126.4, 127.2, 128.1, 128.5, 128.6, 131.2, 139.8, 140.3, 181.8.
123.1, 124.0, 126.6, 137.6, 138.2, 147.4, 150.1, 188.5.
HRMS (ESI): m/z [M + H]+ calcd for C15H13N2O: 237.1028; found:
237.1027.
1,2-Bis(1-methyl-1H-indol-3-yl)-1,2-di(pyridin-4-yl)ethane
(2h′)
Yield: 30.5 mg (14% from 1h); dr = 10:1; yellow solid; mp 280 °C
(dec).
HRMS (ESI): m/z [M + H]+ calcd for C17H16NO: 250.1232; found:
1H NMR (400 MHz, CDCl3): δ (major isomer) = 3.63 (s, 6 H), 4.92
(s, 2 H), 6.90 (s, 2 H), 7.00–7.03 (m, 6 H), 7.18 (dd, J = 7.2, 8.0 Hz,
250.1236.
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Y.-F. Wang et al.
SPECIAL TOPIC
1,5-Dimethyl-1H-pyrrole-2-carbaldehyde (2m)26
Yield: 36.2 mg (57% from 1m); pale-yellow oil.
7-Methoxy-1-methyl-1H-indole-3-carbaldehyde (4c)
Yield: 44.3 mg (47% from 3c); pale-yellow solid; mp 124–126 °C.
1H NMR (400 MHz, CDCl3): δ = 2.27 (s, 3 H), 3.87 (s, 3 H), 6.02
(d, J = 4.0 Hz, 1 H), 6.83 (d, J = 4.0 Hz, 1 H), 9.41 (s, 1 H).
IR (KBr): 3053, 2986, 1653, 1616, 1541, 1498, 1366, 1265, 1107
cm–1.
13C NMR (100 MHz, CDCl3): δ = 12.1, 32.3, 109.7, 124.6, 131.7,
140.6, 178.6.
1H NMR (400 MHz, CDCl3): δ = 3.92 (s, 3 H), 4.08 (s, 3 H), 6.72
(d, J = 8.0 Hz, 1 H), 7.18 (dd, J = 8.0, 8.0 Hz, 1 H), 7.49 (s, 1 H),
7.86 (d, J = 8.0 Hz, 1 H), 9.93 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 37.7, 55.4, 104.7, 114.3, 117.7,
123.6, 127.3, 127.6, 139.8, 147.6, 184.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H12NO2: 190.0868; found:
190.0867.
2-[3-(1-Methyl-1H-indol-3-yl)-3-oxopropyl]benzaldehyde (2q)
Yield: 14.2 mg (14% from 1q); white solid; mp 118–120 °C.
IR (KBr): 3053, 2986, 1693, 1645, 1601, 1531, 1465, 1421, 1373,
1265, 1085 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.15 (t, J = 8.0 Hz, 2 H), 3.50 (t,
J = 8.0 Hz, 2 H), 3.84 (s, 3 H), 7.30–7.34 (m, 3 H), 7.39–7.43 (m,
2 H), 7.52 (dd, J = 7.6, 7.6 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.88
(s, 1 H), 8.39–8.41 (m, 1 H), 10.28 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.8, 33.5, 41.7, 109.6, 116.1,
122.58, 122.59, 123.3, 126.3, 126.8, 131.6, 133.5, 133.8, 134.0,
135.9, 137.4, 144.2, 193.1, 194.2.
5-Bromo-1-methyl-1H-indole-3-carbaldehyde (4d)27
Yield: 49.1 mg (41% from 3d); pale-yellow solid.
1H NMR (400 MHz, CDCl3): δ = 3.87 (s, 3 H), 7.23 (d, J = 8.4 Hz,
1 H), 7.44 (dd, J = 2.0, 8.4 Hz, 1 H), 7.68 (s, 1 H), 8.47 (d, J =
2.0 Hz, 1 H), 9.96 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 33.8, 111.3, 116.5, 117.3, 124.5,
126.6, 126.9, 136.4, 139.7, 184.1.
HRMS (ESI): m/z [M + H]+ calcd for C19H18NO2: 292.1338; found:
292.1332.
1-Benzyl-1H-indole-3-carbaldehyde (4e = 2b)
Yield: 48.2 mg (41% from 3e).
1-Methyl-3-(naphthalen-2-yl)-1H-indole (2q′)
Yield: 26.6 mg (29% from 1q); pale-yellow solid; mp 87–89 °C.
The analytical data for product obtained by this method were iden-
IR (KBr): 3051, 2983, 1629, 1600, 1541, 1477, 1423, 1377, 1265,
1087 cm–1.
tical to those obtained for 2b reported above.
1-Methyl-1H-benzo[g]indole-3-carbaldehyde (4f)
Yield: 43.7 mg (42% from 3f); pale-yellow solid; mp 154–156 °C.
1H NMR (400 MHz, CDCl3): δ = 3.88 (s, 3 H), 7.25 (dd, J = 8.0,
7.6 Hz, 1 H), 7.33 (dd, J = 8.0, 7.2 Hz, 1 H), 7.37 (s, 1 H), 7.41 (d,
J = 8.0 Hz, 1 H), 7.45 (dd, J = 8.0, 6.8 Hz, 1 H), 7.51 (dd, J = 8.0,
6.8 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.88–7.93 (m, 3 H), 8.09 (d,
J = 8.0 Hz, 1 H), 8.14 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 32.9, 109.6, 116.6, 120.00,
120.02, 122.1, 124.9, 125.1, 126.1, 126.2, 126.4, 127.0, 127.66,
127.70, 128.2, 131.9, 133.1, 134.0, 137.6.
IR (KBr): 3053, 2988, 1662, 1539, 1479, 1408, 1357, 1265, 1124
cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.13 (s, 3 H), 7.43–7.53 (m, 3 H),
7.66 (d, J = 8.4 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 8.27 (d, J =
8.4 Hz, 1 H), 8.35 (d, J = 8.4 Hz, 1 H), 9.94 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 39.2, 117.9, 120.3, 120.4, 122.5,
HRMS (ESI): m/z [M + H]+ calcd for C19H16N: 258.1283; found:
258.1278.
123.0, 124.1, 124.3, 125.9, 129.2, 131.3, 131.9, 138.5, 184.9.
HRMS (ESI): m/z [M + H]+ calcd for C14H12NO: 210.0919; found:
210.0925.
Cu-Catalyzed Aerobic Formylation of Indoles and Pyrrole;
Typical Procedure
1,2-Dimethyl-1H-indole-3-carbaldehyde (4g = 2k)
Yield: 28.6 mg (33% from 3g).
To a solution of 1-methyl-1H-indole (3a; 66.0 mg, 0.503 mmol) in
DMSO (5.0 mL) was added Cu(OCOCF3)·xH2O (29.0 mg, 0.100
mmol as anhydrate form) and DBACO (112.2 mg, 1.00 mmol). The
reaction mixture was then stirred for 26 h at 100 °C under an O2 at-
mosphere. The resulting mixture was quenched with pH 9 ammonium
buffer and extracted twice with EtOAc. The combined organic ex-
tracts were washed with brine, dried over MgSO4 and concentrated.
Purification of the crude product by flash column chromatography
(silica gel; hexane–EtOAc, 70:30) afforded 4a.
The analytical data for product obtained by this method were iden-
tical to those obtained for 2k reported above.
1-Methyl-2-phenyl-1H-indole-3-carbaldehyde (4h)28
Yield: 49.6 mg (42% from 3h); pale-yellow solid.
1H NMR (400 MHz, CDCl3): δ = 3.67 (s, 3 H), 7.36–7.40 (m, 3 H),
7.48–7.50 (m, 2 H), 7.55–7.57 (m, 3 H), 8.43–8.45 (m, 1 H), 9.74
(s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 31.0, 109.7, 115.7, 122.1, 123.3,
124.0, 125.1, 128.57, 128.62, 129.8, 130.9, 137.3, 151.4, 186.6.
1-Methyl-1H-indole-3-carbaldehyde (2a)
Yield: 40.1 mg (0.252 mmol, 50%).
The analytical data for product obtained by this method were iden-
tical to those obtained for 2a reported above.
1-Phenyl-1H-pyrrole-2-carbaldehyde (4i)29
Yield: 25.5 mg (29% from 3i); pale-yellow solid.
1H NMR (400 MHz, CDCl3): δ = 6.41 (dd, J = 2.8, 3.2 Hz, 1 H),
7.08 (m, 1 H), 7.17 (d, J = 2.8 Hz, 1 H), 7.36 (d, J = 7.2 Hz, 2 H),
7.43–7.49 (m, 3 H), 9.57 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 110.8, 122.0, 126.0, 128.2, 129.1,
131.0, 132.5, 138.7, 179.0.
1,5-Dimethyl-1H-indole-3-carbaldehyde (4b)
Yield: 46.9 mg (54% from 3b): pale-yellow solid; mp 141–143 °C.
IR (KBr): 3053, 2986, 1647, 1624, 1535, 1487, 1400, 1366, 1265,
1145 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3 H), 3.81 (s, 3 H), 7.17
(d, J = 8.4 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 7.58 (s, 1 H), 8.10 (s,
1 H), 9.92 (s, 1 H).
Acknowledgment
13C NMR (100 MHz, CDCl3): δ = 21.4, 33.6, 109.4, 117.6, 121.7,
125.4, 125.5, 132.6, 136.2, 139.3, 184.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H12NO: 174.0919; found:
This work was supported by funding from the Nanyang Technolo-
gical University and the Singapore Ministry of Education.
174.0916.
Synthesis 2012, 44, 1526–1534
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Oxygenation and C–H Formylation of Indoles
1533
(6) During the preparation of this manuscript, Maes reported
copper- and iron-catalyzed aerobic oxygenation of the
methylene group of aryl(di)azinylmethanes, see: Houwer, J.
D.; Tehrani, K. A.; Maes, B. U. W. Angew. Chem. Int. Ed.
2012, 51, 2745.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. .iat. onf.
I
ngimonSiourntpfoaIrnt
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