Synthesis of (E)-3-styryl-2,5-dihydro-1H-pyrrole derivatives via Pd-catalyzed addition of indoles to hydroxy 1,6-enynes

Article abstract of DOI:10.1039/c3ra47647b

A mild Pd-catalyzed addition of indoles to hydroxy 1,6-enynes has been developed. In this reaction, hydroxy 1,6-enynes were selectively transformed into (E)-3-styryl-2,5-dihydro-1H-pyrrole derivatives. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ra47647b

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Synthesis of (E)-3-styryl-2,5-dihydro-1H-pyrrole
derivatives via Pd-catalyzed addition of indoles to
hydroxy 1,6-enynes†
Cite this: RSC Adv., 2014, 4, 8914
Received 15th December 2013
Accepted 21st January 2014
*
Mei-Jin Zhong, Hai-Tao Zhu, Pin Gao, Yi-Feng Qiu and Yong-Min Liang
DOI: 10.1039/c3ra47647b
www.rsc.org/advances
A mild Pd-catalyzed addition of indoles to hydroxy 1,6-enynes has of various phosphine ligands revealed that electron-with-
been developed. In this reaction, hydroxy 1,6-enynes were selectively drawing groups on the ligand were benecial for this reaction,
transformed into (E)-3-styryl-2,5-dihydro-1H-pyrrole derivatives.
(C6F5)3P improved the yield to 59% (entries 2–5). Although other
Pd catalysts were also tested, no better result was obtained
(entries 6–8). To our surprise, solvent investigations revealed
that AcOH was essential for this reaction and no reaction
occurred in other solvents (entries 9–11). With this result in
mind, we tested cosolvents. Using MeNO2 as a cosolvent with
AcOH improved the yield of 3aa. Aer certain optimization of
the MeNO2/AcOH, the yield improved to 66% under MeNO2–
AcOH (1 : 1) (entries 12–14). When the temperature reduced to
Pd-catalyzed cycloisomerization of 1,6-enynes has emerged as a
powerful method for the construction of ve- and six- membered
heterocycles and carboncycles in recent years.1 These
compounds are important intermediates for the synthesis of
pharmaceutically and biologically active molecules, such as
(À)-domoic acid,2a isodomoic acid H,2b kainic acid,2c con-
essine2d,e and (+)-intricarene.2f–h Lately, attack of a nucleophile
toward 1,6-enynes has expanded the diversity of these products.
However, most of the Pd-catalyzed reactions were restricted to
water,3a halogen3b–e and OAc3f–j as nucleophiles. Several years
ago, Echavarren group reported gold(I)-catalyzed addition reac-
tions of electron-rich arenes and indoles to the 1,6-enynes.4a,b
Veronique Michelet also developed asymmetric gold-catalyzed
hydroarylation/cyclization reactions.4c To our knowledge, Pd-
catalyzed intermolecular reaction of 1,6-enynes and indoles has
not yet been reported. In the context of our ongoing efforts on
Pd-catalyzed cyclization of enynols to construct hetero- and
carbo-cyclic structures,1i,5a,b we wish to report the Pd-catalyzed
addition of indoles to the hydroxyl 1,6-enynes.
Our initial investigations were focused on 1,6-enynol 1a due
to its stability and reactivity. Aer some optimization, we were
pleased to nd that treatment of 1a with 3 equiv. of N-methyl
indole, 1 equiv. of TBHP, 10 mol% of Pd(acac)2 in AcOH at 70 ꢀC
gave the product 3aa (E)-1-methyl-3-(phenyl(4-styryl-1-tosyl-2,5-
dihydro-1H-pyrrol-3-yl)methyl)-1H-indole in 47% yield aer
1.5 h (Table 1, entry 1). The structure of 3aa was unambiguously
conrmed by X-ray crystallographic analysis (see ESI†). A screen
ꢀ
60 C, we could get a higher yield to 71%, lower temperature
gave a negative result (entries 14–16). Other cosolvents showed
to be less effective (entries 17–18). As expected, no reaction
occurred in the absence of Pd catalyst (entry 19).
The amounts of the additive and N-methyl indole were also
important, 3 equiv. of N-methyl indole and 1 equiv. of TBHP was
optimum (Table 2, entries 4–9). It is worth mentioning that the
reaction could proceed in the absence of oxidant (entry 4). The
result indicates that TBHP only plays a supporting role in the
reaction. Thus, the optimized reaction conditions were affirmed
as follows: 3 equiv. of indole as nucleophile, 10 mol% Pd(acac)2
as catalyst, 20 mol% (C6F5)3P as ligand and 1 equiv. of TBHP as
the additive under Ar in MeNO2/AcOH (1 : 1) at 60 ꢀC for 1.5 h.
Having identied the optimal conditions, we next examined
the scope and limitations of the Pd-catalyzed cyclization reac-
tion. As can be seen in Table 3, the reaction tolerated both
electron-withdrawing and -donating groups on the aromatic R2,
the corresponding products 3ba–3ea were obtained in moderate
yields (Table 3, entries 2–5). Compound 1e, containing a
naphthalene moiety, was a good substrate for this reaction, and
3ea was obtained in 74% yield (entry 5). The substrates with an
aliphatic or a heterocyclic R2 group can also smoothly converted
into the corresponding products in moderate yields (entries 6–
7). Substrate 1 h, with aliphatic R1 and R2 groups, affords the
desired product in 50% yield (entry 8). The reaction efficiency
was somewhat affected by the substituents on the C–C double
bond. Terminal olen 1i only provides 3ia in 27% yield (entry 9).
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, China. E-mail: liangym@lzu.edu.cn; Fax: +86-931-8912582
† Electronic supplementary information (ESI) available: Experimental procedures
and analysis data for new compounds. CCDC 969442–969443. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ra47647b
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Table 1 Pd-catalyzed reactions of 1a with indole under various conditionsa
Entry
Catalyst
Ligand
Solvent
T/ꢀC
t/h
Yieldb/%
1
2
3
4
5
6
7
8
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(OAc)2
Pd(CF3CO2)2
PdCl2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
—
—
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
70
70
70
70
50
70
70
70
70
70
70
70
70
70
60
50
70
60
60
1.5
1
2
2.5
5
3.5
3.5
1
1
1
1
2
1.5
1.5
1.5
5
2.5
1
47
47
54
52
59
44
51
P(2-furyl)3
X-Phos
P[O(o-tol)]3
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
(C6F5)3P
c
—
9
MeCN
DCE
THF
—
—
—
63
64
66
71
30
56
59
—
10
11
12
13
14
15
16
17
18
19
MeNO2–AcOH (10 : 1)
MeNO2–AcOH (1 : 10)
MeNO2–AcOH (1 : 1)
MeNO2–AcOH (1 : 1)
MeNO2–AcOH (1 : 1)
DCE–AcOH (1 : 1)
DCM–AcOH (1 : 1)
MeNO2–AcOH (1 : 1)
1
a
Unless otherwise noted, all of the reaction were carried out using 0.1 mmol of 1a, 3 equiv. of 2a, 10 mol% catalyst, 20 mol% ligand and 1 equiv. of
TBHP (t-butyl hydroperoxide) under Ar in 1 mL solvent. b Isolated yields. c No reaction.
Notably, carbon-tethered 1,6-enynol were also applicable to this
reaction, giving 3ja in 63% yield (entry 10).
To further expand the scope of this reaction, unprotected
Table 2 Optimization studies for the amounts of reagentsa
indole was tested. To our delight, the reaction proceeds
smoothly under the standard condition (entry 11). Therefore,
we investigated a range of indoles and N-methyl indoles. A weak
electron-donating or electron-withdrawing group is most
favorable for this reaction (entries 14, 16 and 17), but a strong
electron-donating or electron-withdrawing group is less effec-
tive (entries 12, 13 and 15). N-benzyl-substituted indole lead to a
good result in 70% yield (entry 18). We also attempted other
nucleophiles, such as furan and 2,6-dimethylphenol. To our
Oxidant
Entry (equiv.)
Pd(acac)2 (C6F5)3P Equiv.
disappointment, no desired product was observed.
(mol%)
(mol%)
of 2a
t/h
Yieldb/%
To gain more insight into the mechanism of the present
reaction, we applied the optimal condition on 1a without
nucleophiles, AcOH react with the 1,6 enyne 1a and gave the
product 4a (Scheme 1, eqn (1)). Meanwhile, we investigated the
origin of the proton incorporated into the cyclic product by
using deuterium labeled AcOH. Deuterium labeled product 4a-
d4 was obtained when AcOH-d4 was used in the absence of
nucleophiles (Scheme 1, eqn (2)). However, when treating 1a
and indole 2g with AcOH-d4, a 60 : 40 mixture of 3ag-d4 and 3ag
was obtained in 50% yield (Scheme 1, eqn (3)). The low deute-
rium incorporation observed in the reaction with indole and
AcOH-d4 could be due to H/D exchange between the acidic
proton of the acid and the proton in C-3 of the indole. So pro-
tonolysis of a C–Pd bond was involved in the mechanism.
1
2
3
4
5
6
7
8
K2S2O8 (1)
O2 (1 atm)
BQ (1)
10
10
10
10
20
20
20
20
20
20
20
20
20
10
10
30
3
3
3
3
3
3
1.1
2
5
4.5 65
4.5 66
c
1
4
3
5
3
3
3
6
2
2
—
—
64
68
55
64
69
70
63
65
57
TBHP (0.2) 10
TBHP (2)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
10
10
10
10
5
9
10
11
12
3
3
3
10
10
a
Unless otherwise noted, all of the reaction were carried out using 0.1
mmol of 1, N-methyl indole, Pd(acac)2, (C6F5)3P and TBHP under Ar
in 1 mL MeNO2–AcOH (1 : 1) at 60 ꢀC. b Isolated yields. c No reaction.
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Table 3 Pd-catalyzed reactions of hydroxy 1,6-enynes with nucleophilesa
Entry
Enyne
X
R1
R2
R3
Indole
R4
R5
Product
t/h
Yieldb/%
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
C(CO2Me)2
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
H
H
H
H
H
H
H
H
H
H
H
5-OMe
5-CN
7-Me
4-OMe
6-Cl
7-Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
H
H
H
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
1.5
3
3
3
3
1.5
5
12
2
4
2.5
4
12
2.5
4
4
71
65
64
60
74
64
62
50
27
63
66
50
44
63
53
63
70
70
4-Me Ph
4-Br Ph
4-OMe Ph
1-Naphthyl
1-Furyl
n-C6H13
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9
10
11
12
13
14
15
16
17
18
1j
3ja
1a
1a
1a
1a
1a
1a
1a
1a
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
2g
2h
2i
4
2
Bn
a
Unless otherwise noted, all of the reaction were carried out using 0.1 mmol of 1, 3 equiv. of 2, 10 mol% Pd(acac)2, 20 mol% (C6F5)3P and 1 equiv. of
b
TBHP under Ar in 1 mL MeNO2–AcOH (1 : 1) at 60 ꢀC. Isolated yields.
Scheme 1 Mechanism investigation.
Scheme 2 Reaction mechanism of Pd(acac)2-catalyzed reaction of
1,6-enyne with N-methyl indole.
Based on the above observations together with previous
literature reports,6 a plausible mechanism for this reaction is
proposed (Scheme 2). Coordination of catalyst with ligand
affords active PdL2X2 species. The PdL2X2 would coordinate to product 3aa.7 It is worth to notice that H/D exchange between
the enyne to form complex 5. Cyclization of 5 would give the acidic proton of the acid and the proton in C-3 of the indole
cyclopropylpalladium carbene complex 6. The attack of indole leads to the low deuterium incorporation observed in the
at the cyclopropyl carbon give the intermediate 7 and a proton is reaction with indole and AcOH-d4. However, when the reaction
released at the same time. 8 would formed from the proto- carried out in the absence of indole, AcOH attack the interme-
nolysis of 7, which undergoes 1,4-elimination to give the nal diate 6 to form 9, which undergoes 1,4-elimination to give 10. In
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this case, AcOH is the sole origin of proton and deuterium
labeled product would obtained in the solvent AcOH-d4.
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Conclusions
In summary, we have developed a mild Pd-catalyzed addition of
indoles to hydroxyl 1,6-enynes. In this reaction, 1,6-enynes were
selectively transformed into (E)-3-styryl-2,5-dihydro-1H-pyrrole
derivatives. A variety of substituted enynes and indoles can
proceed this reaction in moderate yields. We are currently
investigating Pd-catalyzed addition of other nucleophiles to 1,6-
enynes.
Acknowledgements
The authors gratefully acknowledge National Basic Research
Program of China (973 program) and “111” program of MOE.
We thank the NSF (NSF-21072080, NSF-20732002) for nancial
support. We also thank Project and Program for Changjiang
Scholars and innovative Research Team in University (IRT1138).
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