PtCl4-catalyzed cyclization reaction of β-allenols in the presence of indoles

Article abstract of DOI:10.1021/ol802838v

The highly regioselective PtCl₄-catalyzed reaction of indoles with β-allenols in THF at room temperature afforded indole derivatives containing a six-membered ether ring at the 3-position in moderate isolated yields. On the basis of a D-labelin

Full text of DOI:10.1021/ol802838v

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1213-1216
PtCl4-Catalyzed Cyclization Reaction of
ꢀ-Allenols in the Presence of Indoles
Wangqing Kong,† Jie Cui,‡ Yihua Yu,‡ Guofei Chen,† Chunling Fu,† and
Shengming Ma*,†
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang UniVersity, Hangzhou 310027, Zhejiang, People’s Republic of China, and
Shanghai Key Laboratory of Functional Magnetic Resonance Imaging, Department of
Physics, East China Normal UniVersity, Shanghai 200062, People’s Republic of China
masm@mail.sioc.ac.cn
Received December 9, 2008
ABSTRACT
The highly regioselective PtCl4-catalyzed reaction of indoles with ꢀ-allenols in THF at room temperature afforded indole derivatives containing
a six-membered ether ring at the 3-position in moderate isolated yields. On the basis of a D-labeling experiment, a mechanistic rationale was
proposed.
Indoles are key structural units in many natural products and
important pharmaceuticals.1 The development of new, ef-
ficient, and selective synthetic methods for the functional-
ization of indoles continues to receive considerable attention.2
Recently, we and others have developed the cyclization of
functionalized allenes in the presence of organic halides.3
Considering the easy functionalization at the 3-position of
indoles,4 we envisioned the cyclization of allenes with a
nucleophilic functional group in the presence of indoles
(Scheme 1). In this paper, we report our unexpected
observation that ꢀ-allenols may be cyclized in the presence
of indoles to give an indole derivative with a saturated six-
membered cyclic ether group at the 3-position.
Scheme 1
† Zhejiang University.
‡ East China Normal University.
(1) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (b)
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Our initial investigation was focused on the reaction of
indole 1a and 3,4-undecadien-1-ol 2a in THF under the
catalysis of AuCl3 (5 mol %), resulting in cycloisomerization
of 2a to afford 2-hexyl-5,6-dihydro-2H-pyran 4aa in 84%
isolated yield (entry 1, Table 1).5
When AuCl3 was replaced with AuCl(PPh3), 89% of indole
1a and 92% of ꢀ-allenol 2a were recovered (entry 2, Table
10.1021/ol802838v CCC: $40.75
Published on Web 02/12/2009
2009 American Chemical Society

to the 3-position of indole 1a. Surprisingly, the connection
to indole was made at the 5-position of the starting alcohol
2a; i.e., the hydrogen atom at this position was removed,
and no CdC bond remained in the final product (Figure 1).
Table 1. Effect of Catalyst and Solvent on the Cyclization
Reaction of 3,4-Undecadien-1-ol 2a in the Presence of Indole 1a
NMR yield
catalyst
(mol %)
2a
time
(%) of
entry
solvent
THF
(equiv) (h)
3aaa
b
c
1
2
3
4
5
6
7
8
9
10
a
AuCl3 (5)
AuCl(PPh3) (5) THF
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.2
4
27
4
PtCl4 (5)
PtCl4 (5)
PtCl4 (5)
PtCl4 (5)
PtCl4 (5)
PtCl4 (5)
PtCl4 (5)
PtCl4 (3)
THF
77 (74d)
e
DMSO
CH3CN
ClCH2CH2Cl
toluene
MeOH
THF
19
3.5
4
60
64
7
72
f
24
6
60d
THF
22.5 59d
1H NMR yield using CH2Br2 as the internal standard. b 3aa was not
formed, and the reacion afforded 4aa in 84% isolated yield. c The recoveries
of indole 1a and ꢀ-allenol 2a were 89% and 92%, respectively. d Isolated
yield. e The recoveries of indole 1a and ꢀ-allenol 2a were 100% and 94%,
respectively. f The recovery of indole 1a was 80%, and ꢀ-allenol 2a
decomposed.
Figure 1. ORTEP representation of the product 3aa.
In terms of solvent effect, THF is better than other solvents
screened, such as DMSO, CH3CN, DCE, toluene, etc. We
also observed that 1.2 equiv of ꢀ-allenol 2a is necessary
(compare entry 9 with entry 3, Table 1). When 3 mol % of
PtCl4 was used, the yield of 3aa was lower with a prolonged
reaction time (compare entry 10 with entry 3, Table 1). Thus,
we defined the experimental protocol for the cyclization of
ꢀ-allenols with indoles under the catalysis of 5 mol % of
PtCl4 in THF at room temperature as the standard reaction
conditions to afford indole derivatives with a cyclic ether at
the 3-position.
This new transformation was quite general. Some of the
typical results are listed in Table 2. With the N-unprotected
simple indole 1a, the cyclization of ꢀ-allenols 2a-2d
afforded the products 3aa-3ad in 71-74% isolated yields
(entries 1-4, Table 2). Other N-unprotected indoles with
substituents at the 5-position 1b-1d can also successfully
afford the corresponding products 3ba-3da (entries 5-8,
Table 2). A methyl group may be introduced to the 2-position
of indole (entry 8, Table 2). The 1-position of indoles may
also be substituted with an alkyl (entries 9-13, Table 2) as
well as a phenyl group (entries 14 and 15, Table 2). However,
a tosyl group inhibited this cyclization reaction (entry 16,
Table 2).
1). Fortunately, when PtCl4 was applied, an unexpected 1:1
cyclization product was isolated in 77% NMR yield (entry
3, Table 1). The structure was further established by the
X-ray studies of this product6 to be 3-(2-hexyl-tetrahydro-
2H-pyran-2-yl)-1H-indole 3aa, indicating the ꢀ-allenols were
cyclized to form a six-membered ring, which was attached
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(6) Crystal data for 3aa: C19H27NO, MW ) 285.43, Monoclinic, space
group P2(1)/c, final R indices [I > 2σ(I)], R1 ) 0.0377, wR2 ) 0.0881, a
) 7.4333(5) Å, b ) 15.8825(13) Å, c ) 15.0972(10) Å, R ) 90°, ꢀ )
106.1198(16)°, γ ) 90°, V ) 1712.3(2) Å3, T ) 296(1) K, Z ) 4, number
of reflections collected/unique: 3868/1300 (Rint ) 0.077), number of
observations [I > 2σ(I)] 3868, parameters: 191. Supplementary crystal-
lographic data have been deposited at the Cambridge Crystallographic Data
Center. CCDC702025.
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Org. Lett., Vol. 11, No. 6, 2009

An isotopic distribution experiment was performed on the
reaction of N-methyl indole 1e and ꢀ-allenol 2a-D. To our
surprise, the result showed that 28% and 25% D incorporated
into the C3′ and C1′′ position (Scheme 4, see Supporting
Information file for the determination of isotopic distribution).
Table 2. PtCl4-Catalyzed Cyclization Reaction of ꢀ-Allenols in
the Presence of Indoles
Scheme 4
yield
1
2
time (%) of
entry
R1
R2
R3
R4
R5
(h)
3a
1
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
n-C4H9
Ph
H
H (1a)
H (1a)
H (1a)
H (1a)
n-C6H13 H (2a)
n-C5H11 H (2b)
4
10
11
74 (3aa)
74 (3ab)
74 (3ac)
2
H
H
H
H
H
H
3
CH3
Ph
H (2c)
4
CH3 (2d) 21.3 71 (3ad)
5
OH (1b) n-C6H13 H (2a)
OH (1b) n-C5H11 H (2b)
OBn (1c) n-C6H13 H (2a)
4.6
1.8
5
67 (3ba)
77 (3bb)
72 (3ca)
42 (3da)
With this evidence in hand, we proposed a rationale for this
transformation (Scheme 5). The reaction of PtCl4 with 1e
would form indolyl platinum trichloride 5, which would
undergo carbometalation with allenol 2a-D to afford vinylic
platinum intermediate 6. Subsequent ꢀ-D elimination would
afford indole-containing allenol 7. Hydrometalation of 7 with
DPtCl3 would afford π-allylic platinum 8,10 which may
undergo ꢀ-H elimination to afford conjugated diene 10.
6
7
8b
9
CH3 Cl (1d)
n-C6H13 H (2a)
n-C6H13 H (2a)
n-C5H11 H (2b)
19
H
H
H
H
H
H
H
H
H (1e)
H (1e)
H (1e)
H (1e)
H (1f)
H (1g)
H (1g)
H (1h)
14.2 70 (3ea)
10
11
12
13
14
15
16
6
12
50 (3eb)
68 (3ec)
47 (3ed)
55 (3fa)
50 (3ga)
CH3
Ph
H (2c)
CH3 (2d) 23
n-C6H13 H (2a)
n-C6H13 H (2a)
n-C5H11 H (2b)
n-C6H13 H (2a)
19
10
Ph
Ts
12
55 (3gb)
c
18.6
a Isolated yield. b PtCl4 (10 mol %) and 2 (2 equiv) were added. c The
recovery of indole 1h was 100%, and ꢀ-allenol 2a decomposed.
Scheme 5
Further study revealed that no reaction was observed
between indole 1a and 2-hexyl-5,6-dihydro-2H-pyran 4aa,
which rules out the possibility of initial cyclization of
ꢀ-allenol followed by the subsequent connection to indole
(Scheme 2).
Scheme 2
To gain further insight into the mechanism, we prepared
the deuterium-labeled ꢀ-allenol 2a-D. First, Jones oxidation
of non-1-yn-3-ol afforded the corresponding alkynyl ketone,7
which was subsequently reduced by LiAlD4.8 Finally, an
ortho-Claisen rearrangement followed by reduction with
LiAlH4 afforded 2a-D (Scheme 3).9
Hydrometalation of 10 with DPtCl3 with a reversed regi-
oselectivity would afford π-allylic platinum intermediate 11,
Scheme 3
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Org. Lett., Vol. 11, No. 6, 2009
1215

which would undergo intermolecular allylic substitution,11
hydrometalation of 12, and protonolysis12 to afford the
product 3ea-D with regeneration of the catalytically active
species PtCl4. Of course, intermediate 8 may also cyclize to
afford the monocyclic 9, which undergoes similar transfor-
mation of 12 to afford the 3′-monodeuterated product 3.
Likewise, the 1″-monodeuterated product may also be formed
from 7 via hydrometalation with HPtCl3, ꢀ-hydrometalation,
hydrometalation with DPtCl3, etc. The lower level of
D-incorporation may be caused by the coexistence of HPtCl3
and DPtCl3 (Scheme 5).
In summary, we have observed a unique cyclization of
ꢀ-allenols in the presence of indoles. Due to the easy
availability of the starting allenols9 and indoles and the
potential of the products, this method may be useful in
organic synthesis. We also proposed a possible mechanism
based on a D-labeling study. Further studies in this area are
being carried out in our laboratory.
Acknowledgment. Financial support from the Major State
Basic Research and Development Program (2009CB825300),
the National Natural Science Foundation of China (20732005),
and Science and Technology Commission of Shanghai
Municipality (No. 07DZ22937) is greatly appreciated. Sheng-
ming Ma is a Qiu Shi Adjunct Professor at Zhejiang
University. We thank Mr. Xinpeng Jiang in this group for
reproducing the results presented in entries 2, 5, 12, and 15
of Table 2.
Note Added after ASAP Publication. The version
published ASAP on February 12, 2009 contained errors. In
the version published ASAP on February 18, 2009, a
correction was made to entry 9 in Table 1 and the last
sentence was added to the acknowledgment.
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Supporting Information Available: Typical experimental
procedure and analytical data for all products not listed in
the text. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL802838V
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Org. Lett., Vol. 11, No. 6, 2009