Platinum-catalyzed multistep reactions of indoles with alkynyl alcohols

Article abstract of DOI:10.1002/chem.200700589

PtCl₂ effectively catalyzes the multistep reaction of N-methyl indole (1a) with pent-3-yn-1-ol (2a) in THF at room temperature for 2 h to give indole derivative 3a, which contains a five-membered cyclic ether group at C3 in 93 % yield. Under similar reaction conditions, various substituted N-methyl indoles 1b-h and indole (1i) reacted efficiently with 2 a to afford the corresponding indole derivatives 3b-h and 3i in 48-91 and 72 % yields. The results showed that N-methyl indoles with electron-donating substituents were more reactive affording higher product yields than those with electron-withdrawing groups. Likewise, various substituted but-3-yn-1-ols 2b-e and other longer chain alkynyl alcohols 2 f-i also underwent a cyclization-addition reaction with N-methyl indole (1a) to provide the corresponding cyclization-addition products 3j-m and 3a, 3j, and 3n-o in good to excellent yields. The present platinum-catalyzed cyclization-addition reaction can be further extended into N-methyl pyrrole. Mechanistically, the catalytic reaction proceeds by an intramolecular hydroalkoxylation of alkynyl alcohol to afford cyclic enol ether followed by the addition of the C-H bond of indole to the unsaturated moiety of cyclic enol ether providing the final product. Experimental evidence to support this proposed mechanism is provided.

Full text of DOI:10.1002/chem.200700589

FULL PAPER
DOI: 10.1002/chem.200700589
Platinum-Catalyzed MultistepReactions of Indoles with Alkynyl Alcohols
Sivakolundu Bhuvaneswari, Masilamani Jeganmohan, and Chien-Hong Cheng*[a]
Abstract: PtCl2 effectively catalyzes
the multistep reaction of N-methyl
indole (1a) with pent-3-yn-1-ol (2a) in
THF at room temperature for 2 h to
give indole derivative 3a, which con-
substituents were more reactive afford-
ing higher product yields than those
ucts 3j–m and 3a, 3j, and 3n–o in
good to excellent yields. The present
platinum-catalyzed cyclization–addition
reaction can be further extended into
N-methyl pyrrole. Mechanistically, the
catalytic reaction proceeds by an intra-
molecular hydroalkoxylation of alkynyl
alcohol to afford cyclic enol ether fol-
with
electron-withdrawing
groups.
Likewise, various substituted but-3-yn-
1-ols 2b–e and other longer chain al-
kynyl alcohols 2 f–i also underwent a
cyclization–addition reaction with N-
methyl indole (1a) to provide the cor-
responding cyclization–addition prod-
tains
a five-membered cyclic ether
group at C3 in 93% yield. Under simi-
lar reaction conditions, various substi-
tuted N-methyl indoles 1b–h and
indole (1i) reacted efficiently with 2a
to afford the corresponding indole de-
rivatives 3b–h and 3i in 48–91 and
72% yields. The results showed that N-
methyl indoles with electron-donating
À
lowed by the addition of the C H
bond of indole to the unsaturated
moiety of cyclic enol ether providing
the final product. Experimental evi-
dence to support this proposed mecha-
nism is provided.
Keywords: catalysis · electrophilic
metallation · gold · Lewis acids ·
platinum
Introduction
halogenation is required. Indeed, if the above two highly ef-
ficient transition-metal-catalyzed transformations occur in
one pot without isolating the intermediate and changing the
reaction conditions, it would be very useful in organic syn-
thesis for maximized molecular complexity with minimized
organic wastes.[7]
With the assistance of metal complexes such as palladium,
platinum, and gold, alkynyl alcohols are capable of undergo-
ing intramolecular hydroalkoxylation reactions to give cyclic
enol ether derivatives.[8] In addition, these metal complexes
The transition-metal-catalyzed intramolecular nucleophilic
addition of an O H bond to a carbon–carbon multiple bond
À
(hydroalkoxylation reaction) is a practical method to con-
struct complex cyclic ethers under mild reaction condi-
tions.[1] Many polycyclic ether-based biologically active com-
pounds and natural products[2] as well as antiviral nucleo-
sides[3] and oligosaccharides[4] were synthesized by using this
methodology. The development of mild and convenient
methods for the functionalization of arenes and heteroar-
enes is fundamentally important in organic synthesis. The
À
also readily activate the unreactive C H bond of arenes or
heteroarenes which further endures addition reactions with
carbon–carbon multiple bonds to give the corresponding hy-
droarylation product.[5–7,9] Although a number of reports de-
À
transition-metal-catalyzed direct addition of the C H bond
of arenes or heteroarenes to carbon–carbon multiple bonds
through electrophilic metallation is one of the convenient
methods for functionalizing arenes or heteroarenes.[5,6,9]
These types of reactions are highly atom-economical and en-
vironmentally friendly as no prefunctionalization, such as
À
scribe the addition reaction of the C H bond of arenes, het-
eroarenes, or active methylenes to carbon–carbon multiple
bonds (alkynes and alkenes),[5–7,9] the addition reaction with
cyclic enol ether is still rare. Recently, Li et al. reported a
À
gold-catalyzed addition reaction of the C H bond of active
methylenes with cyclic enol ethers.[10]
[a]S. Bhuvaneswari, Dr. M. Jeganmohan, Prof. Dr. C.-H. Cheng
Department of Chemistry, National Tsing Hua University
Hsinchu 30013 (Taiwan)
Our continuous interest in metal-catalyzed multistep reac-
tions prompted us to investigate the possibility of carrying
out the above two transformations in one pot.[11–12] In this ar-
ticle, we wish to report a platinum-catalyzed domino reac-
tion of indole with alkynyl alcohol to give an indole deriva-
tive with a cyclic ether group at the 3-position through two
Fax : (+886)3-572-4698
E-mail: chcheng@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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8285

À
À
consecutive O H and C H bond additions. Nitrogen or
oxygen-containing heterocycles are important building
blocks in natural products and various pharmaceutical
agents. The present reaction provides an efficient method
for the functionalization of indoles and pyrrole.
Under
NaAuCl4·2H2O exhibited substantial catalytic activity giving
3a in 70 and 75% yields, but AuCl(PPh3) was totally inac-
tive (entries 1–3). However, if the chloride in AuCl(PPh3)
similar
reaction
conditions,
[AuCl3]and
AHCTREUNG
ACHTREUNG
(5 mol%) was removed by AgSbF6 (20 mol%), the gold
complex became active for the reaction giving 3a in 45%
yield (entry 4). Thus, PtCl2 appears to show the highest cata-
lytic activity among these platinum and gold complexes
(entry 5). Several solvents were tested for the [PtCl2]-cata-
lyzed reaction of 1a with 2a at room temperature. The re-
sults revealed that THF was the solvent of choice giving 3a
in 97% yield (entry 5). CH3CN was also effective affording
3a in 85% yield (entry 6). Other solvents, DCE (1,2-di-
chloroethane), toluene, and MeOH provided 3a in 60, 55,
and 35% yields, respectively (entries 7–9).
Results and Discussion
In the presence of platinum dichloride (5 mol%), N-methyl
indole (1a) reacted with pent-3-yn-1-ol (2a) in THF at room
temperature for 2 h to give indole derivative 3a containing a
five-membered ether ring group attached at C3 in 93% iso-
lated yield (Scheme 1). This product, thoroughly character-
This platinum-catalyzed addition reaction was successfully
extended to different substituted indoles 1b–i and substitut-
ed alkynyl alcohols 2b–e. The results of these studies are
listed in Table 2. Treatment of 5-methoxy-substituted indole
1b with 2a provided the expected product 3b in 91% yield
(entry 1). Similarly, 6-methoxy (1c), 7-methoxy (1d), 5-
bromo (1e), 5-iodo (1 f), and 5-nitro- (1g) substituted in-
doles reacted with 2a affording products 3c–g in 58–90%
yields, respectively (entries 2–6). The reaction of 1h possess-
ing a methyl group at the C2-position with 2a also proceed-
ed smoothly to give the addition product 3h albeit in lower
yield (entry 7). The nature of the substituents on the N-
moiety of indole greatly influences the yield of the product.
While N-methyl indole (1a) gave 3a in the highest, 93%,
yield (Scheme 1), indole (1i) was comparatively less effec-
tive affording 3i in 72% yield (entry 8). N-acetyl indole and
N-sulphonyl indole were totally ineffective. These results in-
dicate that an electron-donating substituent at the benzo-
ring or at the nitrogen atom of the indole moiety favors
product formation, while an electron-withdrawing group
greatly hinders the reaction (entries 1–8).
Scheme 1. Platinum-catalyzed cyclization–addition reaction of N-methyl
indole (1a) with pent-3-yn-1-ol (2a).
1
ized by H and 13C NMR spectroscopy and mass spectrome-
À
try, appears to result from an intramolecular O H bond ad-
À
dition and an intermolecular C H bond addition of indole
(1a) to the unsaturated moiety of the alkynyl alcohol. The
reaction is completely atom economic with no loss of any
atom in the product compared with the two reactants. In
this reaction, the cyclization step is likely to occur by means
of the attack of the hydroxy group at C4 of the alkynyl alco-
hol 2a (a 5-endo-dig pathway) to give a five-membered
ether ring group.[13]
In view of the fact that some gold complexes show similar
Lewis acid catalytic activity to that of PtCl2, we also exam-
Under the optimized reaction conditions, other but-3-yn-
1-ol derivatives that have substituents, such as Et (2b), Ph
(2c), and 2-thienyl (2d) at one of the alkyne carbons also
reacted efficiently with N-methyl indole (1a), providing 3j–l
in 73–89% yields (entries 9–11). The substituent at one of
the alkyne carbons of 2 shows a substantial steric effect on
the yield of product 3. Thus, Et-substituted alkynyl alcohol
2b affords 3j in 89% yield, but the bulkier Ph or 2-thienyl-
substituted alkynyl alcohol 2c and 2d provide 3k and 3l in
75 and 73% yields, respectively. In addition to 3k, a non-
cyclized addition product 3k’ containing an E and Z mixture
ined the catalytic activities of AuCl3, AuCl(PPh3), and
A
NaAuCl4·2H2O for the reaction of 1a with 2a (Table 1).
Table 1. Effect of catalyst and solvent on the cyclization–addition reac-
tion of N-methyl indole (1a) with pent-3-yn-1-ol (2a).[a]
Entry
Catalyst
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
AuCl3
THF
THF
THF
THF
THF
CH3CN
DCE
toluene
MeOH
70
0
AuCl
A
NaAuCl4·2H2O
75
45[c]
97
85
60
55
35
AuCl
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
A
[a]All reactions were carried out by using N-methyl indole (1a)
(1.00 mmol), pent-3-yn-1-ol (2a) (1.20 mmol), catalyst (0.005 mmol,
5 mol%) and THF (3.0 mL) at room temperature for 10 h. [b]Yields
were measured from crude products by the 1H NMR spectroscopic inte-
gration method by using mesitylene as an internal standard. [c]Additive
AgSbF6 (0.020 mmol, 20 mol%) was added in the reaction mixture.
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Platinum-Catalyzed Multistep Reactions
FULL PAPER
Table 2. Results of the platinum-catalyzed cyclization–addition reaction of substituted indoles 1b–i with alkyn-
yl alcohols 2a–i.[a]
in a 80:20 ratio in 15% com-
bined yield was also observed
from the reaction of 2c with
1a. Similarly, addition product
3l’ with an E/Z ratio of 78:22 in
17% combined yield was also
observed for the reaction of 2d
with 1a. For but-3-yn-1-ol de-
rivative 2e, which contains an
ethyl group at one of the
alkyne carbons and a methyl
group at the a-position to the
alcohol group affords the corre-
sponding cyclization–addition
product 3m in 85% yield. The
product consists of a 1:1 ratio
of diastereomers (entry 12). All
of these reactions are highly re-
gioselective, giving only five-
membered cyclization products
(entries 1–12). While various in-
ternal alkynyl alcohols 2a–e
react smoothly with 1 to give
cyclization–addition product 3,
terminal alkynyl alcohol but-3-
yn-1-ol showed no activity with
indoles 1a and 1i under the op-
timized reaction conditions.
Surprisingly, for the terminal
alkyne,[7d] pent-4-yn-1-ol (2 f),
which is one carbon longer than
but-3-yn-1-ol, the cyclization–
addition reaction with 1a pro-
ceeded successfully to give
product 3a in 85% yield
(Table 2, entry 13). The product
is exactly the same as that from
1a and pent-3-yn-1-ol (2a)
(Scheme 1). Similarly, indole 1i
reacts with 2 f to afford 3i in
79% yield (entry 14).[5f,g] The
product is also exactly the same
as that from 1i and pent-3-yn-1-
ol (2a) (entry 8). Internal al-
kynyl alcohol 2g also undergoes
a cyclization–addition reaction
smoothly, but to give two prod-
ucts, 3j and 3n (Scheme 2). The
former is the major product in
67% yield and shows a struc-
ture the same as that from 1a
and 2b (entry 9), while the
latter is minor and is a six-
membered cyclic ether ring
(entry 15). It is noteworthy that
the reaction of 1a or 1i with
substituted pent-4-yn-1-ol 2 f af-
Entry
1
2
Product 3
Yield [%][b]
1
1b
91
2
3
1c
85
90
1d
4
5
6
7
8
9
1e
1 f
1g
1h
1i
89
90
58
48
72
89
1a
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C.-H. Cheng et al.
fords only five-membered cyclic
ether ring products (entries 13–
14), whereas the reaction of 1a
with 2g gives five-membered as
well as six-membered ring
products 3j and 3n, respective-
ly (entry 15, Table 2 and
Scheme 2).
Table 2. (Continued)
Entry
1
2
Product 3
Yield [%][b]
10
1a
75[c]
The present catalytic reaction
was further tested with longer
chain alkynyl alcohols by using
hex-5-yn-1-ol (2h) and hept-5-
yn-1-ol (2i, see Scheme 2). In
both cases, the catalytic reac-
tion proceeded smoothly and is
highly regioselective. For exam-
ple, the reaction of 2h with 1a
afforded six-membered ether
ring 3n exclusively in 87%
yield (entry 16). In a similar
manner, 2i reacted with 1a pro-
viding product 3o, which con-
tains a six-membered ether ring
in 85% yield (entry 17). It is
important to say that in the re-
action of 2i with 1a, only a six-
membered ether ring product is
observed and no seven-mem-
bered-ring product formed.
11
12
13
1a
1a
1a
73[c]
85[d]
85
14
15
1i
79
Unlike 2h and 2i, the reac-
tion of 2j with indoles 1a and
1i did not give the expected
seven-membered cyclic ether
derivatives. Instead, the reac-
tion products are bis(3-indolyl)
species 3p and 3q in 85 and
1a
67+20
79%
yields,
respectively
(Scheme 3).
The scope of the present plat-
inum-catalyzed cyclization–ad-
dition reaction can be further
extended to N-methyl pyrrole.
Treatment of N-methyl pyrrole
(1j) (4.0 mmol) with pent-3-yn-
1-ol (2a) (1.0 mmol) in the
presence of PtCl2 in CH3CN at
room temperature for 30 min
afforded 2-substituted pyrrole
derivative 3r in 75% yield
(Scheme 4). When the reaction
was carried out in nearly an
equal ratio of 1j (1.0 mmol) to
2a (1.2 mmol), multicyclic ether
substituted pyrrole products
were observed. These products
cannot be separated by column
chromatography.
16
17
1a
1a
87[e]
85[e]
[a]All reactions were carried out by using indoles 1 (1.00 mmol), alkynyl alcohol 2 (1.20 mmol), PtCl2
(0.005 mmol, 5 mol%) and THF (3.0 mL) at room temperature for 2 h. [b]Isolated yields. [c]Reaction was
carried out at room temperature for 8 h. [d]Diasteroisomeric ratio 1:1. [e]Reaction was carried out at 60 8C
for 8 h.
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Platinum-Catalyzed Multistep Reactions
FULL PAPER
À
C H bond addition of indole to intermediate 6 catalyzed by
PtCl2 again leads to the final product 3a.
For the intimate mechanism of the intramolecular hydro-
alkoxylation of alkynyl alcohol, PtCl2 likely acts as a Lewis
acid to which the carbon–carbon triple bond of alkynyl alco-
hol 2a is coordinated to give intermediate 4. Intramolecular
nucleophilic addition of the OH bond to alkyne in inter-
mediate 4 by an 5-endo-dig cyclization affords intermediate
5. Protonation of the resulting organoplatinum complex 5
affords cyclic enol ether 6 and regenerates PtCl2.
For the mechanism of the addition of indole 1a to the
cyclic enol ether 6, there are two possible routes
(Scheme 5). One involves an electrophilic metallation reac-
tion of indole 1a with PtCl2 to form complex 7,[6] followed
by insertion of the carbon–carbon double bond of cyclic
enol ether 6 to give complex 8. Subsequent protonation of
complex 8 affords product 3a and regenerates PtCl2. The
other possible pathway is the coordination of the carbon–
carbon double bond of cyclic enol ether 6 to PtCl2 to afford
À
intermediate 9. C H addition of indole 1a at the coordinat-
ed double bond in 9 provides intermediate 8. Protonation of
complex 8 gives product 3 with regeneration of the catalyst.
The proposed key intermediate 6 is strongly supported by
the results of the following re-
Scheme 2. Platinum-catalyzed cyclization–addition reaction of substituted
indoles 1a and 1i with substituted pent-4-yn-1-ols 2 f–g and hex-5-yn-1-
ols 2h–i.
actions. Treatment of indole 1a
(1.0 mmol) with 2,3-dihydro-5-
methylfuran (6) available com-
mercially (3 mmol) in the pres-
ence of PtCl2 at room tempera-
ture gave product 3a in 91%
yield (Scheme 6). Interestingly,
as the relative amount of 1a to
6 increases, another product 3s,
a product from double addition
of indole 1a to 6, starts to
appear. To explain the forma-
tion of 3s, product 3a was fur-
Scheme 3. Platinum-catalyzed addition reaction of substituted indoles 1a and 1i with hept-6-yn-1-ol 2j.
ther treated with indole 1a in
the presence of PtCl2 further
transforming 3a to the double-
addition product 3s in 85% yield (Scheme 6). In agreement
with the results of the reaction of excess 1a with 6, the reac-
tion of indole 1a (2.00 mmol) with alkynyl alcohol 2
(1.00 mmol) (Scheme 1) also gave only the double-addition
product 3s in 82% yield (Scheme 6). The formation of 3s
can be explained by the coordination of the oxygen of 3a to
Scheme 4. Platinum-catalyzed cyclization–addition reaction of N-methyl
pyrrole (1j) with pent-3-yn-1-ol (2a).
À
PtCl2 followed by C H addition of indole to the highly sub-
stituted carbon of the cyclic ether of 3a to give double-addi-
tion product 3s with regeneration of the catalyst. The selec-
tive ring-opening of cyclic ether has been a subject of in-
tense interest in organic synthesis for the past few de-
cades.[14] In the present reaction, we have reported for the
first time that the catalytic amount of PtCl2 selectively
Based on the known chemistry of the metal-catalyzed in-
tramolecular hydroalkoxylation of alkynyl alcohols[1,8] and
À
the metal-catalyzed C H bond addition of arenes to carbon-
carbon multiple bonds,[5–7,9] a possible mechanism for the
present platinum-catalyzed reaction of alkynyl alcohol 2a
with indole 1a is proposed in Scheme 5. First, a PtCl2-cata-
lyzed intramolecular hydroalkoxylation of alkynyl alcohol
likely occurs to give 2,3-dihydro-5-methylfuran (6). Then, a
À
cleaves the C O quaternary carbon of cyclic ether under
mild reaction conditions.
The addition reaction of indole 1a with cyclic enol ether 6
is a crucial step for the present reaction (Scheme 6). It is
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8289

C.-H. Cheng et al.
indole to 6 is an irreversible
process leading to 3a instead of
10a as the final product. This is
strongly supported by the fol-
lowing experiment in which the
reaction of 1a with tetrahydro-
2-(pent-3-ynyloxy)-2H-pyran
(10b) in the presence of PtCl2
in THF at room temperature
for 3 h gave products 3a and 3t
in 88 and 80% yields, respec-
tively (Scheme 7). The above
reaction clearly revealed that in
the presence of PtCl2, 10b is
cleaved into two moieties, al-
kynyl alcohol 2a and cyclic
enol ether 11. Alkynyl alcohol
2a then reacted with 1a in the
presence of PtCl2 to give 3a by
Scheme 5. Proposed mechanism for the cyclization–addition reaction of indole 1 with alkynyl alcohol 2.
the
pathway
shown
in
Scheme 5. In meantime, 11 re-
acted with two molecules of
indole 1a to afford a double-
addition product which further
reacted with another molecule
of 11 to give product 3t by the
pathway shown in Scheme 6. It
is noteworthy that the same
product 3t in 88% yield was
also observed from the reaction
of 1a (1.0 mmol) with 11
(1.2 mmol) in the presence of
PtCl2 (Scheme 7).
An alternative mechanism
can also be proposed for the
present addition–cyclization re-
action of indole 1 with alkynyl
alcohol
2
(Scheme 8). The
carbon–carbon triple bond of
alkynyl alcohol 2a reacts first
with indole 1a catalyzed by
PtCl2 to give intermediate 12.
Protonolysis of 12 affords 13
and regenerates PtCl2. Subse-
quently, the carbon–carbon
double bond of alkene in 13 is
Scheme 6. Result of the platinum-catalyzed addition reaction of N-methylindole (1a) with 2,3-dihydro-5-meth-
ylfuran (6).
well known that cyclic enol ether is an excellent protecting
reagent for alcohols.[15] With the assistance of PtCl2, alkynyl
alcohol 2a underwent an intramolecular hydroalkoxylation
reaction to give cyclic enol ether 6 (Scheme 5). Once, cyclic
enol ether 6 is formed in the reaction mixture, there is a
competition from the nucleophilic addition of the OH bond
of alkynyl alcohol 2a.[8a–b] It is likely that in the presence of
PtCl2, the nucleophilic addition of an OH bond of alkynyl
alcohol 2a to cyclic enol ether 6 to give 10a is faster than
activated by PtCl2 and is followed by intramolecular nucleo-
philic addition of an OH bond to alkene by a 5-endo-trig
pathway[13] to yield intermediate 8. This intermediate further
undergoes protonolysis to give the final product 3a and re-
generates PtCl2. This mechanism can not be totally ruled
out, but is highly unlikely on the basis of following studies.
In the reaction of N-methyl indole (1a) with 4-phenylbut-
3-yn-1-ol (2c), in addition to the expected cyclic ether deriv-
ative 3k, alkenyl alcohol 3k’ (E and Z mixture) was ob-
tained in 15% combined yield. The corresponding addition
products were further treated with PtCl2 in THF at room
À
the indole C H bond addition (Scheme 7), but the reaction
is reversible. On the other hand, the addition of N-methyl
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Chem. Eur. J. 2007, 13, 8285 – 8293

Platinum-Catalyzed Multistep Reactions
FULL PAPER
sequence of the substrates. The
mechanism in Scheme 5, in
which the intramolecular cycli-
zation of alkynyl alcohol 2 to
give the corresponding cyclic
À
enol ether occurs before the C
H addition of indole, explains
very well the regiochemistry
and the ring size of the substi-
tuted cyclic ether groups in the
products based on the known
Baldwinꢁs rule.[13] On the other
hand,
the
mechanism
in
À
Scheme 8, in which the C H
addition to the alkyne moiety
of 2 occurs first, cannot distin-
guish the two alkynyl carbons
and would lead to two different
products (13 and 14). This is in
contrast to the results shown in
Table 2 in which the reactions
show very high regioselectivity
for the formation of a cyclic
ether group.
Scheme 7. Results of the addition reaction of N-methyl indole (1a) with 3-tetrahydro-2-(pent-3-ynyloxy)-2H-
pyran (10b).
Conclusion
We have developed a highly re-
gioselective platinum-catalyzed
multistep reaction of indoles
with alkynyl alcohols. The
methodology offers
a simple
and mild method for the prepa-
ration of 3-substituted five-
membered tetrahydrofuran and
six-membered tetrahydro-2H-
pyran indole derivatives. Ring
closure of these alkynyl alco-
hols is highly regioselective.
Based on these observations, a
mechanism involving successive
PtCl2-catalyzed cyclization of
alkynyl alcohol to give the cor-
responding cyclic enol ether
and addition of indole deriva-
tive to the cyclic enol ether is
Scheme 8. Alternative mechanism for the addition and cyclization reaction of indole 1 with alkynyl alcohol 2.
temperature for 12 h, but no 3k was observed. This observa-
tion clearly indicates that the formation of 3k did not go
through 3k’ as the intermediate. Thus, the mechanism pro-
posed in Scheme 8 is highly unlikely.
The regiochemistry and the ring size of the cyclic ether
group in products 3 (see Table 2) also favors the proposed
mechanism shown in Scheme 5. The main difference be-
tween the two proposed mechanisms (Schemes 5 and 8) for
the PtCl2-catalyzed cyclization and addition is the reaction
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C.-H. Cheng et al.
121.55 (C), 121.03 (CH), 119.85 (C), 108.64 (CH), 92.84 (CH), 81.71 (C),
67.20 (CH2), 55.71 (O-CH3), 38.47 (CH2), 32.62 (N-CH3), 28.70 (CH3),
26.04 ppm (CH2); HRMS: m/z: calcd for C15H19O2N: 245.1416; found:
245.1425.
proposed to account for the present platinum-catalyzed re-
action of indole with alkynyl alcohols. The proposed mecha-
nism is strongly supported by the following reactions: 1) ad-
dition reaction of N-methyl indole with 2,3-dihydro-5-meth-
ylfuran and 2) E and Z mixture of 4-(1-methyl-1H-indol-3-
yl)-4-phenylbut-3-en-1-ol derived from the reaction of N-
methyl indole with 4-phenylbut-3-yn-1-ol do not give the
corresponding cyclization product. Further extension of this
work to the addition reaction of arenes or heteroarenes to
propargyl alcohols and alkynyl amines, and the detailed
study of the mechanism are in progress.
3-(Tetrahydro-2-methylfuran-2-yl)-1-methyl-1H-indole (3i): 1H NMR
À
(500 MHz, CDCl3): d=8.19 (s, 1H; N H), 7.74 (d, J=7.6 Hz, 1H; HC=),
7.32 (d, J=8.0 Hz, 1H; HC=), 7.20 (t, J=7.2 Hz, 1H; HC=), 7.14 (t, J=
À
7.2 Hz, 1H; HC=), 7.06 (d, J=2.4 Hz, 1H; HC=), 4.04–3.99 (m, 2H; O
CH2), 2.40–2.38 (m, 1H; CH2), 2.07–1.97 ppm (m, 3H; CH2), 1.68 ppm (s,
3H; CH3); 13C NMR (100 MHz, CDCl3): d=137.00 (C), 124.95 (C),
122.81 (CH), 121.65 (CH), 120.43 (CH), 120.20 (CH), 119.23 (CH),
111.23 (CH), 81.81 (C), 67.21 (CH2), 38.30 (CH2), 28.40 (CH3), 26.02 ppm
(CH2); HRMS: m/z: calcd for C13H15ON: 201.1154; found: 201.1152.
3-(2-Ethyl-tetrahydrofuran-2-yl)-1-methyl-1H-indole
(3j):
1H NMR
(500 MHz, CDCl3): d=7.71 (d, J=8.0 Hz, 1H; HC=), 7.30 (d, J=8.4 Hz,
1H; HC=), 7.22 (t, J=8.0 Hz, 1H; HC=), 7.10 (t, J=8.4 Hz, 1H; HC=),
Experimental Section
À
À
6.96 (s, 1H; HC=), 3.98–3.93 (m, 2H; O CH2), 3.76 (s, 3H; N CH3),
2.35–2.32 (m, 1H; CH2), 2.08–1.90 (m, 5H; CH2), 0.82 ppm (t, J=7.2 Hz,
3H; CH3); 13C NMR (125 MHz, CDCl3): d=137.67 (C), 126.22 (CH),
125.63 (C), 121.17 (CH), 120.46 (CH), 119.74 (C), 118.59 (CH), 109.18
General: All reactions were conducted under a nitrogen atmosphere on a
dual-manifold Schlenk line unless otherwise mentioned by using oven-
dried glass ware. Reagents and chemicals were used as purchased without
further purification. Substituted indoles 1b–h,[16a] alkynyl alcohols 2g,[15]
2i[15] and 2j,[16b] and tetrahydro-2-(pent-3-ynyloxy)-2H-pyran (10b)[15]
were synthesized according to the reported procedures.
À
(CH), 85.14 (C), 67.14 (CH2), 36.79 (CH2), 33.79 (CH2), 32.63 (N CH3),
25.86 (CH2), 9.21 ppm (CH3); HRMS: m/z: calcd for C15H19ON:
229.1467; found: 229.1471.
3-(Tetrahydro-2-methyl-2H-pyran-2-yl)-1-methyl-1H-indole
(3n):
General procedure for the cyclization–addition reaction of indole 1 with
1H NMR (400 MHz, CDCl3): d=7.96 (d, J=8.0 Hz, 1H; HC=), 7.31 (d,
J=8.0 Hz, 1H; HC=), 7.26 (t, J=8.0 Hz, 1H; HC=), 7.14 (t, J=8.0 Hz,
alkynyl alcohol 2:
A 25 mL round-bottomed flask containing PtCl2
À
(0.050 mmol, 5.0 mol%) was evacuated and purged with nitrogen gas
three times. Freshly distilled THF (3.0 mL), indole (1.00 mmol) and al-
kynyl alcohol (1.20 mmol) were sequentially added to the system and the
reaction mixture was stirred at room temperature for 2 h. The mixture
was filtered through a short Celite and silica-gel pad and washed with di-
chloromethane several times. The filtrate was concentrated and the resi-
due was purified on a silica gel column by using hexanes/ethyl acetate as
an eluent to afford the cyclization product 3. Products 3a–k were synthe-
sized according to this procedure, but for products 3l–m the reactions
proceeded for 8 h at room temperature, for products 3n–o for 8 h at
608C, and for products 3p–q, N-methyl indole (2.00 mmol) was used for
8 h at 608C. Product 3r was synthesized according to a similar procedure
by using pyrrole 1j (4.0 mmol) instead of indole.
1H; HC=), 6.88 (s, 1H; HC=), 3.75 (s, 3H; N CH3), 3.74–3.73 (m, 1H;
À
À
O CH2), 3.54–3.48 (m, 1H; O CH2), 2.24–2.20 (m, 1H; CH2), 1.83–1.63
(m, 4H; CH2), 1.59 (s, 3H; CH3), 1.46–1.44 ppm (m, 1H; CH2); 13C NMR
(100 MHz, CDCl3): d=137.39 (C), 126.35 (CH), 126.27 (C), 121.57 (CH),
121.42 (CH), 118.87 (CH), 118.29 (C), 118.31 (C), 109.03 (CH), 74.15
À
(C), 62.69 (CH2), 35.49 (CH2), 32.68 (N CH3), 31.46 (CH3), 25.70 (CH2),
20.20 ppm (CH2); HRMS: m/z: calcd for C15H19ON: 229.1467; found:
229.1473.
3-(2-Ethyl-tetrahydro-2H-pyran-2-yl)-1-methyl-1H-indole (3o): 1H NMR
(400 MHz, CDCl3): d=7.97 (d, J=8.0 Hz, 1H; HC=), 7.32 (d, J=8.4 Hz,
1H; HC=), 7.25 (t, J=8.0 Hz, 1H; HC=), 7.12 (t, J=8.0 Hz, 1H; HC=),
6.85 (s, 1H; HC=), 3.74 (s, 3H; N CH3), 3.73–3.72 (m, 1H; O CH2),
3.57–3.51 (m, 1H; O CH2), 2.23–2.20 (m, 1H; CH2), 2.05–2.01 (m, 1H;
CH2), 1.81–1.63 (m, 5H; CH2), 1.44–1.41 (m, 1H; CH2), 0.73 ppm (t, J=
7.6 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=137.46 (C), 127.54
(CH), 126.68 (C), 121.81 (CH), 121.30 (CH), 118.79 (CH), 116.05 (C),
109.67 (CH), 77.66 (C), 62.59 (CH2), 36.23 (CH2), 33.09 (N-CH3), 32.67
(CH3), 22.95 (CH2), 20.03 (CH2), 8.43 ppm (CH3); HRMS: m/z: calcd for
C16H21ON: 243.1623; found: 243.1627.
À
À
À
Spectral data of compounds 3a–c, 3i–j, 3n–p, and 3r are listed bellow.
Experimental procedure for the preparation of compounds 3s and 3t,
spectral data of remaining compounds, and copies of 1H and 13C NMR
spectra of all compounds are given in the Supporting Information.
3-(Tetrahydro-2-methylfuran-2-yl)-1-methyl-1H-indole (3a): 1H NMR
(500 MHz, CDCl3): d=7.68 (d, J=8.5 Hz, 1H; HC=), 7.26 (d, J=8.0 Hz,
1H; HC=), 7.19 (t, J=7.0 Hz, 1H; HC=), 7.08 (t, J=8.0 Hz, 1H; HC=),
6,6-Bis(1-methyl-1H-indol-3-yl)heptan-1-ol (3p): 1H NMR (400 MHz,
À
À
6.94 (s, 1H; HC=), 4.00–3.92 (m, 2H; O CH2), 3.73 (s, 3H; N CH3),
2.39–2.36 (m, 1H; CH2), 2.05–1.89 (m, 3H; CH2), 1.66 ppm (s, 3H; CH3);
13C NMR (125 MHz, CDCl3): d=137.38 (C), 125.41 (C), 125.20 (CH),
121.58 (C), 121.30 (CH), 120.37 (CH), 118.73 (CH), 109.27 (CH), 81.77
CDCl3): d=7.39 (d, J=8.0 Hz, 2H; HC=), 7.25 (d, J=8.0 Hz, 2H; HC=),
À
7.10 (t, J=7.2 Hz, 2H; HC=), 6.88 (m, 4H; HC=), 3.75 (s, 6H; N CH3),
3.50 (t, J=7.2 Hz, 2H; OCH2), 2.36 (t, J=8.0 Hz, 2H; CH2), 1.83 (s, 3H;
CH3), 1.49–1.16 ppm (m, 6H; CH2); 13C NMR (100 MHz, CDCl3): d=
137.61 (C), 126.74 (C), 126.07 (CH), 122.84 (C), 121.38 (CH), 120.76
(CH), 117.92 (CH), 108.94 (CH), 62.96 (CH2), 40.59 (CH2), 38.37 (C),
À
(C), 67.22 (CH2), 38.48 (CH2), 32.61 (N CH3), 28.70 (CH3), 26.08 ppm
(CH2); HRMS: m/z: calcd for C14H17ON: 215.1310; found: 215.1305.
À
32.65 (CH2), 32.57 (N CH3), 27.25 (CH3), 26.23 (CH2), 24.28 ppm (CH2);
3-(Tetrahydro-2-methylfuran-2-yl)-5-methoxy-1-methyl-1H-indole (3b):
1H NMR (400 MHz, CDCl3): d=7.16 (s, 1H; HC=), 7.15 (d, J=8.0 Hz,
1H; HC=), 6.90 (s, 1H; HC=), 6.85 (d, J=8.0 Hz, 1H; HC=), 4.03–3.90
IR: n˜ =3471.24 cmÀ1 (OH); HRMS: m/z: calcd for C25H30ON2: 374.2358;
found: 374.2363.
À
À
À
(m, 2H; O CH2), 3.86 (s, 3H; O CH3), 3.69 (s, 3H; N CH3), 2.38–2.35
(m, 1H; CH2), 2.03–1.87 (m, 3H; CH2), 1.65 ppm (s, 3H; CH3); 13C NMR
(100 MHz, CDCl3): d=153.46 (C), 133.17 (C), 125.83 (CH), 125.70 (C),
120.85 (C), 111.26 (CH), 109.92 (CH), 102.82 (CH), 81.71 (C), 67.18
(CH2), 50.08 (O-CH3), 38.29 (CH2), 32.77 (N-CH3), 28.48 (CH3),
26.06 ppm (CH2); HRMS: m/z: calcd for C15H19O2N: 245.1416; found:
245.1417.
2-(Tetrahydro-2-methylfuran-2-yl)-1-methyl-1H-pyrrole (3r): 1H NMR
(500 MHz, CDCl3): d=6.53 (t, J=2.0 Hz, 1H; HC=), 5.98 (m, 2H; HC=
À
À
À
), 3.96–3.92 (m, 1H; O CH2), 3.75–3.71 (m, 4H; N CH3, O CH2), 2.43–
2.38 (m, 1H; CH2), 2.01–1.94 (m, 2H; CH2), 1.88–1.86 (m, 1H; CH2),
1.51 ppm (s, 3H; CH3); 13C NMR (125 MHz, CDCl3): d=135.94 (C),
123.92 (CH), 105.96 (CH), 105.77 (CH), 80.88 (C), 67.15 (CH2), 38.03
À
(CH2), 35.75 (N CH3), 27.58 (CH3), 25.54 ppm (CH2); HRMS: m/z:
calcd for C10H15ON: 165.1154; found: 165.1155.
3-(Tetrahydro-2-methylfuran-2-yl)-6-methoxy-1-methyl-1H-indole (3c):
1H NMR (500 MHz, CDCl3): d=7.55 (d, J=9.0 Hz, 1H; HC=), 6.82 (s,
1H; HC=), 6.75 (d, J=8.5 Hz, 1H; HC=), 6.71 (d, J=2.5 Hz, 1H; HC=),
À
À
À
3.99–3.92 (m, 2H; O CH2), 3.86 (s, 3H; O CH3), 3.66 (s, 3H; N CH3),
2.35–2.32 (m, 1H; CH2), 2.03–1.92 (m, 3H; CH2), 1.64 ppm (s, 3H, CH3);
13C NMR (125 MHz, CDCl3): d=156.08 (C), 138.36 (C), 124.05 (CH),
8292
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Chem. Eur. J. 2007, 13, 8285 – 8293

Platinum-Catalyzed Multistep Reactions
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Acknowledgement
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Received: April 16, 2007
Published online: August 23, 2007
Chem. Eur. J. 2007, 13, 8285 – 8293
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8293