Three-component 3-(phosphoryl)methylindole synthesis from indoles, H-phosphine oxides and carbonyl compounds under metal-free conditions

Article abstract of DOI:10.1039/c8gc03530j

The first facile and efficient acid-catalyzed three-component reaction of indoles, H-phosphine oxides and carbonyl compounds has been developed, providing a general, one-pot approach to structurally diverse C3-alkylated indole derivatives accompanied by concurrent C-P/C-C bond formation with remarkable functional group tolerance and excellent regioselectivity.

Full text of DOI:10.1039/c8gc03530j

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Three-component 3-(phosphoryl)methylindoles synthesis from
indoles, H-phosphine oxides and carbonyl compounds under
metal-free conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Jiaoting Pan,a Ruimin Zhao,b Jiami Guo,b Dumei Ma,b Ying Xia,a Yuxing Gao,*a Pengxiang Xu*a and
DOI: 10.1039/x0xx00000x
Yufen Zhaoa
www.rsc.org/
The first facile and efficient acid-catalyzed three-component
reaction of indoles, H-phosphine oxides and carbonyl compounds
has been developed, providing a general, one-pot approach to
structurally diverse C3-alkylated indole derivatives accompanied
by concurrent C-P/C-C bond formation with remarkable
functional group tolerance and excellent regioselectivity.
of functional groups, thus limiting their further applications
for the synthesis and discovery of novel 3-
(phosphoryl)methylindoles
of
biological
importance.
Therefore, the development of practical, economic and
efficient methods to access these interesting skeletons
starting from simple indoles and other readily available
starting substrates under base- and metal-free conditions is
highly desirable, and thus it might significantly extend the
scope of the synthesis of 3-(phosphoryl)methylindoles for
chemical biology research.
Substituted indoles have attracted significant attention in
organic and medicinal chemistry over the past several
decades because of their unique structural features and
diverse biological activities.1 Moreover, it is well-known that
phosphorus substituents could regulate significantly
biological, medicinal and material functions.2 Thus, 3-
(phosphoryl)methylindole skeleton containing a indole ring
and a phosphorus substituent represents a key structural
motif of a number of biologically active molecules, which are
valued for their great potential as novel chymase inhibitors,3
NAALADase inhibitors,4 hepatitis C virus inhibitors,5 treating
glutamate abnormality,6 inhibitors of prostate cancer cells7
and antioxidants.8 Yet, the known methods for synthesizing
these motifs are relatively lacking. At present, 3-
(phosphoryl)methylindoles are mainly obtained from
previously prepared 3-(1-arylsulfonylalkyl)indoles with P(O)H
compounds.9 In addition, three-component reactions for
making 3-(phosphoryl)methylindoles from 1H-indole-3-
carbaldehyde and trialkylphosphites or P(O)H have been
reported sporadically under metal or metal-free catalysis
conditions,10 and other procedures are also described
sporadically.11 Despite their usefulness, almost all of the
aforementioned synthetic methods suffer from the need of
complex or well-defined functionalized indole precursors,
poor substrate scope, using excess strong bases or
environmentally unfriendly metal catalysts, or poor tolerance
Previous work: NaH-promoted substitution of 3-(1-arylsulfonylalkyl)indoles
HN
HN
H
O
R2
N
R1CHO
ArSO2H
NaH (2 equiv)
SO2Ar
P
R2
HP(O)R2
2
R1
R1
R
R
R
This work: Acid-catalyzed three-component reaction of indoles, H-phosphine
oxides and carbonyl compounds
HN
H
O
R3
O
N
O
H2SO4 (20 mol %)
P
R3
P
R3
H
+
+
2R3
- H2O
metal free
base free
R1 R2
1 R
R
R
R
Scheme 1 Synthetic strategies toward 3-(phosphoryl)methyl-
indoles
Over the past several years, direct functionalization of
unreactive C-H bonds for selective C-C and C-heteroatom
bond formation has emerged as one of the most promising
strategies for synthesizing a variety of valuable molecular
frames in modern synthesis chemistry owing to its
remarkable advantages such as avoiding substrate pre-
functionalization, high step- and atom-economy and
environmental sustainability in industrial process and green
chemistry.12 Among them, direct C-H bond functionalization
of indoles has attracted continuous attention for synthetic
chemists since indole derivatives are versatile structural
motifs in biologically active natural products and
pharmaceutical
drugs.1b,13
Furthermore,
direct
aDepartment of Chemistry and Key Laboratory for Chemical Biology of Fujian
Province, College of Chemistry and Chemical Engineering, Xiamen University,
functionalization at the C3 position of free (N-H) indoles
remains challenging since it usually suffers from some
competing reactions at C2 and N1 positions.14 On the other
hand, the development of metal-free transformations has
become one of the most active research topics in organic
Xiamen
361005,
Fujian,
China.
E-mail:
gaoxingchem@xmu.edu.cn,
xpengxiang@xmu.edu.cn
bDepartment of Chemical and Biochemical Engineering, College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, China
Electronic Supplementary Information (ESI) available: Experimental, spectral data
and copies of spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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synthesis and green chemistry because the metal-free
catalytic process is favourable to cost saving, elimination of
metal toxicity and reducing environmental pollution.15
Moreover, given the influences of trace metals on human
consumption drugs and the performance of organic
electronic devices, developing metal-free catalytic system for
the direct functionalization of indoles is greatly important
and meaningful. Meanwhile, in view of the low cost and a
wide range of commercially available indoles, their use as
starting materials for 3-(phosphoryl)methylindoles synthesis
is highly attractive. As part of our continuing efforts to
develop new methods for the synthesis of phosphorus-
containing compounds,16 we herein disclosed the first
example of a one-pot preparation of structurally diverse 3-
(phosphoryl)methylindoles via a facile and efficient Brønsted
acid-catalyzed three-component direct C3-alkylation of
indoles (Scheme 1b) with readily available carbonyl
compounds and P(O)H compounds under metal-free
conditions with remarkable functional group tolerance, high
regioselectivity and good to excellent yields. This metal-free
strategy provided a simple and rapid access to various new 3-
(phosphoryl)methylindoles, which were not easily accessible
by the known methods, through direct indole C-H
functionalization along with the formation of one C-C and
one C-P bond. To the best of our knowledge, this method has
not been reported to date.
Our initial investigation focused on the three-component
reaction of indole 1a, benzaldehyde 2a and
View Article Online
DOI: 10.1039/C8GC03530J
diphenylphosphine oxide 3a as summarized in Table 1.
Preliminary attempts using Cu(OTf)2 as a catalyst in toluene
at 80 oC for 10 h under an argon atmosphere led to the
formation of the desired C3-alkylated product 4a in 81% yield
(entry 1). Encouraged by this promising result, other copper
salts such as CuSO4 and Cu(OAc)2 were also studied, whereas
they were entirely ineffective (entries 2-3). To advance the
process further, other catalysts including TfOH, TsOH, H2SO4,
H3PO4 and AcOH were also investigated, with the finding that
TfOH, TsOH and H2SO4 gave similar yields of 83%, 81% and
82%, respectively, while H3PO4 and AcOH were less effective
(entries 4-8). In addition, no product was observed in the
absence of H2SO4 (entry 9). These results revealed that strong
acid was essential to achieve a high yield of product 4a.
Subsequently, we checked the effect of various solvents and
found that a slight decrease in yield was observed using DCE,
dioxane, acetonitrile and EtOH, but the use of water
completely suppressed this reaction (entries 10-14). An
increase in the H2SO4 loading did not promote the reaction,
and a low loading gave rise to a decrease of the yield (entries
15 and 16). Similarly, increasing or decreasing the
o
temperature from 80 C resulted in reduced yield (entries 17
and 18). Under air, the reaction still gave 80% yield, indicating
that it is not sensitive to air and moisture (entry 19).
Table 2 Reaction scope of carbonyl compounds with 1a and 3aa
Table 1 Optimization of the reaction conditionsa
CHO
HN
H
HN
O
H
O
O
P
Ph
N
O
O
Ph
N
H2SO4 (20 mol %), toluene
Ar, 80 oC, 10 h
catalyst
P
P
Ph
+
H
+
Ph
+
P
H
+
Ph
R1
R2
solvent, temp
Ph
Ph
3a
R1 R2
4
Ph
3a
Ph
4a
1a
2
1a
2a
HN
HN
O
HN
O
P
O
P
entry
1
2
catalyst
Cu(OTf)2
CuSO4
Cu(OAc)2
TfOH
solvent
toluene
yield (%)b
81
0
HN
Ph
Ph
Ph
Ph
O
P
P
Ph
Ph
Ph
Ph
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
3
0
I
Cl
, 83%
Br
, 90%
4
83
81
82
4
4a
HN
, 82 %
4b
4c
4d
, 94%
5
TsOH
HN
HN
HN
O
O
O
P
O
P
Ph
Ph
Ph
Ph
Ph
Ph
6
H2SO4
H3PO4
AcOH
P
P
Ph
Ph
7
8
0
9
0
—
NO2
, 55%
COOMe
, 82%
Me
OH
4h, 82%
4e
4f
4g
, 67%
10
11
12
13
14
15c
16d
17e
18f
19g
H2SO4
77
78
72
73
0
HN
HN
HN
O
P
O
O
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
dioxane
HN
Ph
Ph
Ph
Ph
O
P
P
P
Ph
acetonitrile
Ph
Ph
Ph
EtOH
S
H2O
NMe2
, 79%
OMe
, 82%
toluene
toluene
toluene
toluene
toluene
63
74
63
77
80
b
4k
4l
4i
4j
, 90%
O
, 80%
HN
HN
O
P
HN
HN
O
Ph
Ph
O
P
Ph
Ph
Ph
P
P
Ph
Ph
Ph
Ph
c
d
e
4p
, 75%
4m
4n
4o
, 68%
, 69%
, 51%
aReaction conditions: indole 1a (0.4 mmol), benzaldehyde 2a (0.48
aReaction conditions: indole 1a (0.4 mmol), carbonyl compounds 2 (0.48
mmol), diphenylphosphine oxide 3a (0.6 mmol), H2SO4 (20 mol %) and
mmol), diphenylphosphine oxide 3a (0.6 mmol), catalyst (20 mol %)
c
and solvent (1 mL) at 80 oC for 10 h under Ar. b Isolated yields. H2SO4
o
b
toluene (1 mL) at 80 C for 10 h under Ar. Isolated yields. MeOH (1 mL).
cTfOH (20 mol %), dichloroethane (1 mL). dTfOH (20 mol %). e120 oC.
(30 mol %). dH2SO4 (10 mol %). eAt 60 oC. fAt 100 oC. gUnder air.
2 | J. Name., 2012, 00, 1-3
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With the optimized conditions in hand (footnote a, Table 2),
we first investigated the substrate scope of the acid-catalyzed
three-component reaction of indole 1a, diphenylphosphine
oxide 3a with a variety of carbonyl compounds. As shown in
Table 2, the approach was found to be quite general and
various aromatic aldehydes having election-withdrawing
groups including Cl, Br, I, NO2 and COOMe and electron-
donating groups such as CH3, OH, NMe2 and OMe, were all
compatible with the reaction conditions and afforded the
desired products (4b-4j) in good to excellent yields, indicating
that electronic effect was not evident in this reaction. The
conjugated aromatic aldehyde 2k was also a suitable
substrate for this method, producing the corresponding
product 4k in an excellent yield of 90%. A heterocyclic
aromatic aldehyde 2l smoothly reacted with 1a and 3a to
provide 4l in a high yield. Interestingly, when using TfOH (20
mol %) as the catalyst, aliphatic aldehydes such as
butyraldehyde and pivalaldehyde also efficiently gave the
expected products 4m and 4n in moderate yields. In addition,
apart from aldehydes, some ketones (2o and 2p) were also
suitable reaction partner and afforded the desired products
4o and 4p in 68% and 75% yields, respectively.
OH, Cl, Br, I, OMe, COOMe, CH3 and OBn substituents were
all well tolerated. Notably, chloro-, bromo- and iodo-
View Article Online
DOI: 10.1039/C8GC03530J
substituted indoles could be successfully converted into the
corresponding products (4r-4t), allowing to access more
complex molecules through next coupling of these halide
products. To our delight, 2-methyl-1H-indole and 1-methyl-
1H-indole still underwent a similar process to give the desired
products 4w and 4x in excellent yields. Fortunately, the
product 4z was recrystallized from ethyl acetate/n-hexane as
colorless crystals, and the molecular structure of 4z was
confirmed by X-ray diffraction analysis.17 To gain more insight
into the substrate scope, some H-phosphine oxides were also
evaluated. Apart from 3a, other H-phosphine oxides including
3b, 3c, 3d and 3e were all suitable reaction partners, and the
corresponding products 4aa, 4ab, 4ac and 4ad were obtained
in 90%, 90%, 68% and 67% yields, respectively. Yet, under the
standard conditions, phosphites as substrates did not afford
the desired products since the phosphites are less
nucleophilic than phosphine oxides leading to no generation
of the key intermediate α-hydroxy phosphonates. However,
in the presence of bases, treatment of 4-
methoxybenzaldehyde 2j or 1-(4-methoxyphenyl)ethanone
2q with diethyl phosphonate 3f could generate the
corresponding α-hydroxy phosphonates in situ18. Without
isolation of the α-hydroxy phosphonates, reaction with TfOH
and indole 1a in alcohol gave the desired products 4ae and
4af in 27% and 30% yields, respectively (Scheme 2). This
constitutes a facile one-pot method for the synthesis of
diethyl ((1H-indol-3-yl)methyl)phosphonates.
Table 3 Reaction scope of 2, indoles and H-phosphine oxidesa
CHO
HN
O
P
R3
H
O
P
N
H2SO4 (20 mol %), toluene
Ar, 80 oC, 10 h
R3
R3
H
+
R
+
R3
R
R1
4
1
2
3
, R = Ph; , R3 = 4-OMe-Ph;
3
3
R1
3a
3b
, R = 3,5-dimethyl-Ph; , R = 4-F-Ph; , R3 = 4-Me-Ph
3
3c
3d
3e
HN
HN
HN
HN
O
P
O
P
O
P
O
P
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
HN
a):
TfOH (50 mol %)
indole (0.4 mmol)
O
O
P
HO
Cl
Br
I
K3PO4 (15 mol %)
rt, 5 min
P(OEt)2
MeO
MeO
CHO
4q
, 57%
+ EtO
H
4r,
4s
4t,
76%
93%
, 86%
EtOH (1 mL)
Ar, 130 oC, 10 h
OEt
Ph-OMe-4
HN
HN
O
P
O
P
2j
3f
4ae
, 27%
, 0.8 mmol
, 0.8 mmol
HN
Ph
Ph
N
O
O
Ph
Ph
Ph
HN
b):
TfOH (20 mol %)
indole (3 mmol)
O
P
O
P
O
Ph
Ph
n-BuLi (0.2 mol %)
P(OEt)2
Ph
Ph
, 92%
Ph
, 70%
EtO
P H
+
rt, 15 min
Ph
EtOH (5 mL)
Ar, 80 oC, 10 h
Ph
MeOOC
HN
MeO
OEt
, 6 mmol
Ph-OMe-4
4v
4w
, 98%
4x, 94%
4u
3f
2q
, 5 mmol
4af
, 30%
OMe
O
Ph
HN
HN
Scheme 2 One-pot Synthesis of diethyl ((1H-indol-3-yl)methyl)phos-
phonates from 2j or 2q with 1a and diethyl phosphonate 3f
O
P
O
P
Ph
P
Ph
Ph
Ph
Ph
Cl
Very interestingly, increasing the reaction temperature from
80 oC to 120 oC led to the formation of promising
bifunctionalized indole derivatives in the presence of TfOH
(Table 4),1b,19 which may serve as attractive motifs with
diverse biological activities. The coupling reaction of indole
1a with butyrophenone 2r and 3a in the presence of TfOH (20
mol %) at 120 oC in toluene (1 mL) for 10 h under argon could
furnish a new product diphenyl(3-(1-phenylbutyl)-1H-indol-2-
yl)phosphine oxide 5a in 51% yield without the observation of
product 4. The substrates having Cl, COOMe and MeO groups
on the indole ring were tolerated (5b-5f). In addition to 3a,
dibutylphosphine oxide 3g could also react with indole 1a and
ketones (2o and 2u) to generate the corresponding products
(5h and 5i) in 74% and 44% yields, respectively. Yet,
aldehydes as the coupling partners only gave poor yields (5j
and 5k), probably due to the steric hindrance. Luckily, the
molecular structure of 5b was determined by X-ray diffraction
analysis,17 which was recrystallized from CH2Cl2/CH3OH as
colorless crystals. The result clearly revealed that the
OBn
OMe
, 90%
Cl
4y
4z, 84%
HN
, 50%
O
4aa
F
Me
HN
HN
O
O
P
P
P
Ph
Ph
Ph
F
Me
, 67%
4ab,
4ac
4ad
90%
, 68%
aReaction conditions: 1 (0.4 mmol), 2 (0.48 mmol), 3 (0.6 mmol), H2SO4
(20 mol %) and toluene (1 mL) at 80 oC for 10 h under Ar. Isolated yields.
Subsequently, the versatility of the reaction was further
explored for the three-component reaction of a variety of
indole derivatives with different H-phosphine oxides and
aldehydes and the results were summarized in Table 3.
Likewise, various indoles bearing electron-withdrawing and
electron-donating substituents at the indole ring could be
used to generate the expected products (4q-4y) in moderate
to excellent yields. Thus, various functional groups such as
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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phosphoryl moiety was preferentially installed at the C2-
positions of indoles in this reaction.
View Article Online
DOI: 10.1039/C8GC03530J
H
HN
a):
b):
c):
N
H2SO4 (20 mol %)
Table 4 Synthesis of (3-(1-alkyl)-1H-indol-2-yl)phosphine oxides from
carbonyl compounds with indole derivatives and H-phosphine oxidesa
H
OH
+
CHO
toluene (1 mL)
Ar, 80 °C, 10 h
Ph
, 0%
1a
2a
, 0.4 mmol
1a
0.4 mmol
, 0.48 mmol
O
5
O
N
H
O
R1 R2
2
R3
O
P
H2SO4 (20 mol %)
P
N
TfOH (20 mol %), toluene
Ar, 120 oC, 10 h
R3
H
Ph
P
H
no reaction
R3
+
+
R
+
R
toluene (1 mL)
Ar, 80 °C, 10 h
R3
Ph
, 0.6 mmol
R2
R1
1
3
5
3a
O
,
R1 = Ph, R2 = n-Pr; , R1 = 4-Cl-Ph, R2
= n-Pr;
2r
2s
P(Ph)2
OH
toluene (1 mL)
Ar, 80 °C, 10 h
, R1 = 4-Cl-Ph, R2
=
Et;
R1 = 4-Br-Ph, R2
2u
,
=
Me; , R3 = Bu-n.
2t
3g
CHO
3a
+
H
H
H
O
P
O
O
N
N
N
2a
0.6 mmol
, 0.48 mmol
6
, 93%
O
Ph
P
Ph
P
Ph
O
HN
Cl
Ph
Ph
d):
e):
Ph
H2SO4 (20 mol %)
P(Ph)2
6
1a
OMe
+
toluene (1 mL)
Ar, 80 °C, 10 h
Ph
, 70%
0.48 mmol
4a
0.4 mmol
5a
5b
, 73%
, 51%
5c
, 61%
H
H
H
H
N
H
N
O
P
O
O
H
O
N
N
N
O
N
Ph
P
Ph
P
Ph
TfOH (20 mol %)
P
Ph
P(Ph)2
2t
3a
+
+
O
Ph Cl
Ph
Cl
Ph
Ph
toluene (1 mL)
Ar, 80 °C, 10 h
Cl
1c
Et
Ph-Cl-4
Cl
, 0.4 mmol
0.48 mmol 0.6 mmol
4ag
, 87%
Cl
5d
Cl
Cl
toluene (1 mL)
f):
5g
, 0%
5e
5f
no reaction
, 41%
H
N
, 65%
H
, 52%
4ag
4ag
(0.4 mmol)
H
N
Ar, 120 °C, 10 h
TfOH (20 mol %)
O
H
H
N
O
P
O
O
P
O
P
N
N
g):
P(Ph)2
Bu-n
P
Bu-n
Bu-n
Bu-n
(0.4 mmol)
Cl
5f
Bu-n
Bu-n
Bu-n
Bu-n
toluene (1 mL)
Ar, 120 °C, 10 h
Ph-Cl-4
, 48%
Et
Br
Cl
Scheme 4 Control experiments
5k
5h
, 21%
, 74%
5i
5j
, 20%
, 44%
under Ar (Scheme 4f). To our delight, the expected [1,3]-P
migration product 5f was obtained in a moderate yield of
48% in the presence of TfOH under heating at 120 oC for 10 h
under Ar (Scheme 4g). These results indicated that a 3-
(phosphoryl)methylindole species was generated firstly,
followed by a rearrangement to afford the final product (3-(1-
alkyl)-1H-indol-2-yl)phosphine oxides.
aReaction conditions: 1 (0.4 mmol), 2 (0.48 mmol), 3 (0.6 mmol), TfOH (20
mol %) and toluene (1 mL) at 120 oC for 10 h under Ar. Isolated yields.
Notably, a gram-scale experiment was performed by
employing 1a (10 mmol, 1.17 g) with 2a (12 mmol, 1.27 g)
and 3a (15 mmol, 3.03 g) under the optimal reaction
conditions. The desired product 4a was obtained in a high
yield of 81%, revealed that this approach could be easily
adopted for the large-scale synthesis with high efficiency
(Scheme 3).
path a:
HN
HN
O
O
O
O
H
H+
- H2
1a
3a
HO
P(Ph)2
P(Ph)2
P(Ph)2
P(Ph)2
CHO
- H+
O
Ph
Ph
Ph
Ph
6
7
4a
2a
8
O
O
path b:
O
H
O
P(Ph)2
HN
H
N
P(Ph)2
N
P(Ph)2
Isomerization
TfOH
TfOH
Et
Et
R
HN
O
1c, 3a
[1,3]-P migration
R
Et
R
Et
H
N
Cl
Ph
O
P
H2SO4 (20 mol %)
toluene, Ar, 80 oC, 10 h
2t
4ag
R = Ph-Cl-4
9
5f
Cl
Cl
Cl
CHO
Ph
P
H
+
+
Ph
Ph
4a
, 3.30 g, 81% yield
Ph
3a
, 3.03 g
Scheme 5 Proposed reaction mechanism
1a
2a
, 1.27 g
, 1.17 g
Based on the above experimental results and previous
reports,20,21 a plausible mechanism was proposed in Scheme
5. Initially, the intermediate 6 was easily formed by the
addition of 3a to benzaldehyde 2a under heating.20 Then, the
critical carbocation intermediate 7, which would be stabilized
by inductive/conjugation effect of adjacent substituents,
Scheme 3 Gram-scale preparation of 4a
To gain preliminary insight into the reaction mechanism,
several control experiments were conducted. Treatment of
1a with 2a under standard conditions without 3a gave no the
expected product 5 (Scheme 4a). The reaction of 1a with 3a
did not occur (Scheme 4b). Yet, without H2SO4, 2a could
smoothly react with 3a under heating, leading to the product
6 in an excellent yield of 93% (Scheme 4c).20 Further
treatment of 6 with 1a could afford the targeted product 4a
in 70% yield (Scheme 4d), showing 6 should be the key
intermediate for the reaction. In addition, the three-
component reaction of 1c with bulkier ketone 2t and 3a at 80
oC for 10 h could produce the product 4ag in a high yield of
87% (Scheme 4e). Next, without TfOH, treatment of 4ag
could be gained by the elimination of OH group with the
21a,b
assistance of
a
Brønsted acid, H2SO4.
Next, the
nucleophile indole 1a attacked 7 to provide the intermediate
8, followed by the elimination of H+ to afford the desired
product 4a (path a).21c The bulky ketones such as 2t as the
reaction partner might undergo another pathway to form the
product 5f. As shown in path b, the intermediate 4ag was
generated firstly with the help of TfOH via path a, followed by
[1,3]-P migration to form the intermediate 9 with the
assistance of TfOH21d,e. Finally, 9 easily isomerizated to more
stable isomer 5f.21f,g
o
provided no new product under heating at 120 C for 10 h
4 | J. Name., 2012, 00, 1-3
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Conclusions
In conclusion, we have developed the first facile and efficient
Brønsted acid-catalyzed three-component direct C3-alkylation of
indoles with readily available aldehydes and P(O)H compounds
under metal-free conditions, furnishing a new and rapid route to
structurally diverse and biologically important C3-alkylated indoles
via sequential P-H/C-H functionalization along with concurrent C-P
bond and C-C bond formation. Importantly, the present method
avoids metals and other additives, and a wide range of valuable 3-
(phosphoryl)methylindole moieties could be conveniently
obtained in a simple one-pot process. Most attractively, directly
utilizing C3-unfunctionalized free (C-H) indoles without the
requirement of prepared well-defined indole precursors, greatly
enhancing the reaction efficiency, represents a prominent
advantage of this method. In addition, the operational simplicity,
the remarkable functional group tolerance, excellent
regioselectivity and good to excellent yields mean that this
protocol will open a new avenue for the synthesis of potential
biological active 3-(phosphoryl)methylindoles and should find a
widespread application in synthetic and medicinal chemistry.
Moreover, an interesting [1,3]-P migration/isomerization was
observed. Further mechanistic investigations and application
researches will be pursued.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank Chinese National Natural Science Foundation
(21202135, 21642010, 41576081) and Fundamental Research
Funds for the Central Universities (20720180083, 20720160034)
for financial support.
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View Article Online
DOI: 10.1039/C8GC03530J
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