I2-mediated C3-formylation of indoles by tertiary amine and H2O

Article abstract of DOI:10.1016/j.tetlet.2014.08.024

An I₂-promoted 3-formylation of free (N-H) and N-substituted indoles with tetramethylethylenediamine (TMEDA) and H₂O as the carbonyl source is achieved, providing 3-formylindole in moderate to excellent yields with good functional gr

Full text of DOI:10.1016/j.tetlet.2014.08.024

Tetrahedron Letters 55 (2014) 5618–5621
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
I2-mediated C3-formylation of indoles by tertiary amine and H2O
⇑
Bo Zhang, Bin Liu, Jianbin Chen, Jiehui Wang, Miaochang Liu
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325035, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An I2-promoted 3-formylation of free (N–H) and N-substituted indoles with tetramethylethylenediamine
(TMEDA) and H2O as the carbonyl source is achieved, providing 3-formylindole in moderate to excellent
yields with good functional group tolerance. This procedure represents an exceedingly attractive
alternative to the traditional formylation methods.
Received 19 May 2014
Revised 22 July 2014
Accepted 8 August 2014
Available online 28 August 2014
Ó 2014 Published by Elsevier Ltd.
Keywords:
Iodine
3-Formylindole
Tertiary amine
Iminium ion
The indole nucleus is an omnipresent component of numerous
natural and synthetic molecules with significant biological
activity.1 Therefore, chemo- and regioselective functionalization
of indoles has always been of tremendous value in organic synthe-
sis for the diversity of indole derivatives.2 3-Formylindoles are not
only key intermediates for the preparation of biologically active
molecules3 and indole alkaloids4 but also important precursors
for the synthesis of a variety of indole derivatives because their
carbonyl groups can facilely undergo C–C and C–N coupling reac-
tions and reductions.5 However, a series of well-established classi-
cal methods such as Vilsmeier–Haack4a,5a,6 Reimer–Tiemann,7
Rieche,5b,8 and Duff9 reactions for the construction of 3-formylin-
doles suffer from several drawbacks such as using environmentally
unfriendly POCl3,4a,6b,10 strong bases4a,6,7 or acids9 in workup pro-
cesses, lack of functionality tolerance,4a,10c,5a,11 low selectivity,10a,d
and tedious procedures.4a,7,10,11a,5b Accordingly, the development
of general and operationally simple approaches using environmen-
tally benign reagents for the formylation of indoles is still highly
desirable.
Recently, Cheng and Su reported Cu or Ru catalyzed
C3-formylation of indoles using amine as the carbonyl source inde-
pendently.12 However, the utility of metal catalysts would result in
several problems involved in removing the residual metals from
the final products, which was usually a difficult and tedious pro-
cess, limiting the practical applications of these procedures. Very
recently, Cheng reported the NH4OAc-promoted formylation of
indole by DMSO and H2O at elevated temperatures.13 The
n-Bu4NI-catalyzed 3-formylation of indoles with tert-butyl
peroxybenzoate (TBPB) as oxidant and N-methylaniline as a car-
bonyl source demonstrated by Wang was an important advance-
ment.14 However, excess pivalic acid (PivOH) was indispensable
in Su or Wang’s strategies which was incompatible with the func-
tional groups labile under acidic conditions. We envisioned that
the development of a simple metal-free system, using common
cheaper and milder molecular iodine as the promotor, might
tremendously improve the practicality of formylation reactions.
Herein, we report our study on it.
From the outset of this work, 1-methyl-1H-indole 1a with
tetramethylethylenediamine (TMEDA) was selected as the test
substrates in combination with I2 as the oxidant (Table 1). To our
delight, the reaction proceeded smoothly in the presence of
1.1 equiv of I2 with Na2CO3 (2.0 equiv) as the additive in 1,4-diox-
ane at 75 °C under 1 atm of O2 affording the desired product in
moderate yield (58%, entry 1). Encouraged by this result, we simply
increased the loading of I2 to 1.5 or 2.0 equiv, and formylated
indole 2a was delivered in good to excellent yields (66% and 83%,
entries 2 and 3). Among the bases tested, Na2CO3 was the best, pro-
viding the formylation product in 91% yield (entry 12), and the
yield dramatically decreased to 10% in the absence of base (entry
6). In the presence of 1, 2, and 3 equiv of TMEDA, the formylation
product was isolated in 30%, 79%, and 83% yields, respectively. It
was worth noting that solvent was critical owing to only traces
of 2a provided in MeNO2 (entry 8), albeit with moderate yield in
toluene (52%, entry 7). In contrast, the use of nBu4NI or KI13 previ-
ously reported to be an excellent catalyst for formylation of
indoles, could not give any products (entries 9 and 10). Attempt
to develop a catalytic system failed, as the yield dramatically
decreased to 34% and 33% under 100 °C and 75 °C, respectively
(entries 13 and 14).
⇑
Corresponding author. Tel./fax: +86 577 88368280.
E-mail address: mcl@wzu.edu.cn (M. Liu).
http://dx.doi.org/10.1016/j.tetlet.2014.08.024
0040-4039/Ó 2014 Published by Elsevier Ltd.

B. Zhang et al. / Tetrahedron Letters 55 (2014) 5618–5621
5619
Table 1
Screening the optimized reaction conditionsa
CHO
N
N
N
N
2a
1a
Entry
Iodide source
Additive
Solvent
T (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
I2 (1.1 equiv)
I2 (1.5 equiv)
I2 (2.0 equiv)
I2 (2.0 equiv)
I2 (2.0 equiv)
I2 (2.0 equiv)
I2 (2.0 equiv)
I2 (2.0 equiv)
nBu4NI (2.0 equiv)
KI (2.0 equiv)
—
Na2CO3 (2.0 equiv)
Na2CO3 (2.0 equiv)
Na2CO3 (2.0 equiv)
NaOH (2.0 equiv)
NaOtBu (2.0 equiv)
—
Na2CO3 (2.0 equiv)
Na2CO3 (2.0 equiv)
Na2CO3 (2.0 equiv)
Na2CO3 (2.0 equiv)
Na2CO3 (2.0 equiv)
Na2CO3 (2.0 equiv)
Na2CO3 (2.0 equiv)
Na2CO3 (2.0 equiv)
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
75
75
75
75
75
75
75
75
75
75
75
100
100
75
58
66
83
15
70
10
52
<5
0
MeNO2
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
0
0
I2 (2.0 equiv)
I2 (20 mol %)
I2 (20 mol %)
91(68)b (53)c (30)d (79)e (83)f
34g
33g
a
Reaction conditions: 1-methyl-1H-indole 1a (0.2 mmol), TMEDA (0.5 mmol, 2.5 equiv), iodide source with indicated equivalents, H2O (100 lL), additive (2.0 equiv),
solvent (0.5 mL), indicated temperature, O2 (1 atm), 36 h, isolated yield.
b
Air.
N2.
c
d
TMEDA (1 equiv).
TMEDA (2 equiv).
TMEDA (3 equiv).
TBHP (4 equiv).
e
f
g
Next, some other amine or amide was tested in this formylation
reaction, as shown in Scheme 1.
and nitro groups on the aromatic moiety were tolerated well with
yields ranging from moderate to excellent (40–76%, 3a–3i). Simi-
larly, substrates bearing a methyl at the C2 position did not dimin-
ish the reactivity (63%, 3j).
To learn about the generality of this newly developed protocol,
a number of indoles were tested and the results are shown in
Table 2. Firstly, substrates bearing different kind of N-protecting
groups were surveyed and yields ranged from 50% to 83%
(2a–2d). The substitution on the aromatic ring of indole was then
studied, and formylated products were obtained in moderate to
excellent yields from the corresponding indoles possessing elec-
tron-donating or electron-withdrawing groups on the aromatic
ring (2e–2p). However, electron-donating groups such as methyl
and methoxy appeared more effective than electron-withdrawing
groups such as nitro and cyano when substitution at C5 (2e, 2h
vs 2i, 2j). To our delight, a diversity of halogen functional groups
were tolerated with good to excellent yields which offer handles
for other valuable manipulations (62–76%, 2l–2p). Particularly,
the heteroaryl indoles, such as N-methyl-1H-pyrrolo[2,3-b]
pyridine 1q, produced 2q smoothly in 60% yield. Importantly,
groups such as phenyl and acylamino on the pyrrole ring of indole
were not detrimental to this process as exemplified by 2r and 2s
(65% and 50%, respectively). In light of these results, we extend
our efforts on the scope of free (N–H) indoles. As expected, elec-
tron-poor or -rich substrates bearing a series of functional groups
such as methyl, methoxy, fluoro, chloro, bromo, formyl, cyano,
In order to acquire preliminary understanding of this process,
several control experiments were conducted (Scheme 2). Initially,
the extra added H2O was replaced by D2O and 2a was generated
in 90% GC–MS yield which indicated that the hydrogen atom of
carbonyl groups did not come from H2O (Eq. 1). The blank
experiment showed that the reaction did not run in the absence
of TMEDA. It demonstrated that the carbon atom in the carbonyl
group may derive from the added TMEDA (Eq. 2). Subsequently,
radical trapping experiments were studied by employing 2,2,6,
6-tetramethyl-1-piperidinyloxy (TEMPO) as a radical scavenger
and the result confirmed that no change of the reaction outcome
happened (Eq. 3), which excluded the radical route. The photo-
initiated singlet oxygen was usually involved in the aerobic oxida-
tion reaction system.15 Hence, 1,4-diazabicyclo-[2.2.2]octane
(DABCO) as a singlet oxygen inhibitor was added to the model
reaction. However, the approach did not inhibit and run well in
100% conversion, indicating that singlet molecular oxygen might
not be involved in our system (Eq. 4).
On the basis of the results described above and previous stud-
ies12a,16, a tentative mechanism is illustrated in Scheme 3. Firstly,
N
NH
N
N
N
trace
N
trace
trace
O
42%
O
NH2
NH HN
N
N
DMAc
trace
DMF
trace
trace
23%
Scheme 1. Screening of amine or amide for the formylation reaction.

5620
B. Zhang et al. / Tetrahedron Letters 55 (2014) 5618–5621
Table 2
The scope for 3-formylation of indolesa
CHO
R2
I2 (2.0 equiv)
Na2CO3 (2.0 equiv)
R2
R3
R3
N
N
N
N
H2O (100 μL), O2 (1 atm.)
R1
R1
1,4-dioxane (0.5 mL)
2 or 3
1
100 o
C
CHO
CHO
CHO
CHO
R3
Me
F
N
N
N
N
R1
R1= Me 2a 83%, 36 h
R1= Et 2b 74%, 37 h
R3 = MeO 2h 71%, 60 h
R3 = NO2 2i 39%, 48 h
2e
2l
5-Me
80%, 48 h
5-F 64%, 38 h
6-Me 2f 56%, 37 h
7-Me 2g 73%, 38 h
6-F 2m 62%, 38 h
R1= Allyl 2c 50%, 37 h
R3 = CN 2j 54%, 60 h
1
3
2d
2k
R = Bn
70%, 37 h
R = CHO
60%, 68 h
CHO
CHO
Br
CHO
CHO
R2
Cl
N
N
N
N
N
R2 = Ph
65%, 64 h
2r
2q 60%, 36 h
2n
2o
2p
5-Cl
6-Cl
72%, 65 h
76%, 36 h
70%, 60 h
R2 = CONHMe 2s 50%, 61 h
CHO
CHO
CHO
CHO
R3
R3
X
N
H
N
H
N
H
N
H
R3 = H
75%
3b
72%
70%
R3 = NO2
40%
70%
3d
3j
63%
5-F
76%
3a
3g
6-Cl 3e 72%
5-Br 3f 74%
3
R3 = MeO
R = CHO
3h
3
R3 = Me
R = CN 52%
3c
3i
a
Reaction conditions: indole 1 (0.2 mmol), TMEDA (0.5 mmol, 2.5 equiv), I2 (0.4 mmol, 2.0 equiv), H2O (100 lL),
Na2CO3 (0.4 mmol, 2.0 equiv), 1,4-dioxane (0.5 mL), 100 °C, O2 (1 atm), indicated time and 36 h for free (N–H) indole,
isolated yield.
CHO
I2 (2.0 equiv)
Na2CO3 (2.0 equiv)
N
N
N
N
D O
(100 μL), O2 (1 atm.)
2
1,4-dioxane (0.5 mL)
100 oC, 36 h
90%
eq (1)
CHO
I2 (2.0 equiv)
Na2CO3 (2.0 equiv)
N
N
N
H2O (100 μL), O2 (1 atm.)
1,4-dioxane (0.5 mL)
100 oC, 36 h
0% Con. GC-MS eq (2)
CHO
I2 (2.0 equiv)
Na2CO3 (2.0 equiv)
N
N
N
H2O (100 μL), O2 (1 atm.)
1,4-dioxane (0.5 mL)
100 oC, 36 h
TEMPO 50 mol %, 100% Con. GC-MS eq (3)
DABCO 50 mol %, 100% Con. GC-MS
DABCO 100 mol %, 100% Con. GC-MS eq (4)
Scheme 2. Isotope labeling experiments and preliminary mechanism study.

B. Zhang et al. / Tetrahedron Letters 55 (2014) 5618–5621
5621
1/2 I2 and O2
N
N
N
R
R
R
HI
B
B'
N
H
R
N
R
N
H
N
H
B
C
CHO
N
N
R
1/2 I2 and O2
HI
H2O
R
N
H
N
H
N
H
3a
E
D
Scheme 3. A tentative mechanism.
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the oxidation of a tertiary amine by I2/O2 took place forming imin-
ium ion intermediate B and B0. Secondly, because intermediate B
was more stable, the nucleophilic attack of iminium ion B rather
than B0 by indole occurred to deliver species C, which generated
compound D by the loss of H+. Subsequently, in the presence
another molecular iodine and O2, species D was oxidized to a
new iminium ion intermediate E which was hydrolyzed by H2O
to produce 3-formylindole 3a.12a
In summary, we develop a molecular I2-promoted 3-formyla-
tion of indole approach. This procedure represents an exceedingly
attractive alternative to the traditional formylation methods with
excellent function group tolerance and good to excellent yields.
Investigations aimed at broadening the scope of this transforma-
tion and further delineating the mechanism are currently in
progress.
Acknowledgments
We thank the National Natural Science Foundation of China (no.
21372177), the University Students’ Scientific Innovation Founda-
tion of Zhejiang Province (no. KZ1304052) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.08.
024.
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