Synthesis of methanes having four different carbon substituents utilizing indium-catalyzed cleavage of carbon-pyrrolyl bonds

Article abstract of DOI:10.1002/ejoc.200900246

A pyrrolyl group bound to an sp³ carbon atom in gem-dipyrrolylalkanes was found to be successfully replaced by a certain range of carbon nucleophiles in the presence of an indium catalyst. The reaction can also be performed efficiently as a thr

Full text of DOI:10.1002/ejoc.200900246

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900246
Synthesis of Methanes Having Four Different Carbon Substituents Utilizing
Indium-Catalyzed Cleavage of Carbon–Pyrrolyl Bonds
Teruhisa Tsuchimoto,*[a] Taku Ainoya,[a] Kazuki Aoki,[a] Tatsuya Wagatsuma,[a] and
Eiji Shirakawa*[b]
Keywords: Indium / C–C activation / Nucleophilic substitution / Alkynes / Heterocycles
A pyrrolyl group bound to an sp3 carbon atom in gem-dipyr-
rolylalkanes was found to be successfully replaced by a cer- to synthesize methanes having four different carbon substitu-
bon nucleophiles in one batch. The strategy is highly useful
tain range of carbon nucleophiles in the presence of an in-
dium catalyst. The reaction can also be performed efficiently
as a three-component assembly of alkynes, pyrroles, and car-
ents.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
5. This provides methanes 6 having four different carbon
substituents, one of which is a β-pyrrolyl group.[6]
Introduction
Under acidic conditions, tertiary alkyl groups are well
known to transfer between aromatic rings by C(sp3)–
C(aryl) bond cleavage–bond formation sequences through
some cationic species.[1,2] In this context, the tBu group on
aromatic rings has played a crucial role as a “positional
protective group” to direct incoming electrophiles. Thus far,
however, the tBu group has been disposed of after the trans-
alkylation to other aromatic compounds.[3] To the best of
our knowledge, such cleavage reactions have been utilized
only for synthesis of aromatic compounds with regioselec-
tively introduced substituents. We envisaged that in situ
trapping of the released tertiary alkyl groups with carbon
nucleophiles would generate quaternary carbon centers
connected with all carbon substituents.
We have reported that indium triflate [In(OTf)3, Tf =
SO2CF3] catalyzes the double addition of N-methylpyrrole
(2a) to alkynes 1, giving isomeric mixtures of gem-dipyrro-
lylalkanes (DPAs) [Scheme 1, In(OTf)3 = In].[4,5] Under in-
dium catalysis, α,βЈ-adduct 3 readily isomerizes to β,βЈ-iso-
Scheme 1. Working hypothesis for trapping of intermediate A with
5.
mer 4, in which cationic species A was proposed to be an Results and Discussion
intermediate.[2a] Herein we disclose the first carbon–carbon
In order to verify our working hypothesis, we first tested
bond-forming reaction through C(sp3)–C(pyrrolyl) bond
the reaction of 2,2-bis(N-methylpyrrol-3-yl)octane (4a)[7]
with 2-methylfuran (5a) (Table 1). Thus, treatment of 4a
and 5a with In(OTf)3 (10 mol-%) in 1,4-dioxane at 85 °C
cleavage followed by capture of A with carbon nucleophiles
[a] Department of Applied Chemistry, School of Science and Tech- for 1.5 h gave 2-(5-methylfuran-2-yl)-2-(N-methylpyrrol-3-
yl)octane (6a) in 80% yield (Table 1, Entry 1).[8–10] Notably,
nology, Meiji University,
Higashimita, Tama-ku, Kawasaki, 214-8571, Japan
neither α-pyrrolyl isomer 7a nor double substitution prod-
uct 8a was produced. DPAs 4b–4e having other alkyl
groups, including bulkier secondary and tertiary ones, at
the quaternary carbon center similarly reacted with 5a
(Table 1, Entries 2–5). Interestingly, 1,1,1-triarylethanes 6f
and 6g having three different aryl groups can be readily
prepared, where aryl moieties such as the phenyl and
Fax: +81-44-934-7228
E-mail: tsuchimo@isc.meiji.ac.jp
[b] Department of Chemistry, Graduate School of Science, Kyoto
University,
Sakyo-ku, Kyoto 606-8502, Japan
Fax: +81-75-753-3988
E-mail: shirakawa@kuchem.kyoto-u.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2009, 2437–2440
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Tsuchimoto, T. Ainoya, K. Aoki, T. Wagatsuma, E. Shirakawa
SHORT COMMUNICATION
thienyl groups do not act as leaving groups (Table 1, En-
tries 6 and 7). The reaction of 4a with 2-methoxythiophene
(5b) also mainly gave monothienyl product 6h,[11] but a
small amount of 8b was produced through double substitu-
tion (Table 1, Entry 8). Importantly, stepwise replacement
of the two pyrrolyl groups of 4 also was found to be feasible
in this strategy. For example, 6a, which has been synthe-
sized in Entry 1 of Table 1, reacted with 5b to give 2-furyl-
2-thienyloctane 9 [Equation (1)]. The potential of this
method can be demonstrated by using carbon nucleophiles
other than heteroarenes. The introduction of an allyl or cy-
ano group was thus achieved by the reaction of 4a with
tetraallyltin (5c) or trimethylsilyl cyanide (5d), respectively
[Equations (2) and (3)]. In the reaction of 4c with 4-vinylan-
isole (5e), two carbon–carbon bonds were formed in one
batch, where a benzylic cation generated after nucleophilic
attack of the C=C bond of 5e is likely to accept the α-
position of the remaining pyrrolyl group [Equation (4)].
These results direct us toward further extension of the scope
of nucleophiles, and thus are quite promising.
Table 1. In(OTf)3-catalyzed reaction of DPAs with carbon nucleo-
philes 5.[a]
of the assembly of alkynes and two different heteroarenes,
which can be regarded as their substrate-selective addition
to CϵC bonds. Aliphatic terminal alkynes having an ace-
Table 2. In(OTf)3-catalyzed three-component reaction of alkynes,
pyrroles, and carbon nucleophiles.[a]
Entry
R1
R2
5
t [h]
Yield [%] of 6[b]
1
Hex
Me
Pr
iPr
tBu
Ph
Me (4a)
Me (4b)
Pr (4c)
Me (4d)
Me (4e)
Me (4f)
Me (4g)
Me (4a)
5a
5a
5a
5a
5a
5a
5a
5b
1.5
4
1.5
2.5
5
18
4
1.5
80 (6a)
78 (6b)
72 (6c)
64 (6d)
73 (6e)
72 (6f)
78 (6g)
49 (6h)
2[c]
3
4
5
6
7[d]
8[d,e]
3-thienyl
Hex
Entry R1
R2
5[b]
method, t [h] Yield [%][c] (6/7)[d]
[a] Reaction conditions: 4 (0.13 mmol), 5 (0.52 mmol), In(OTf)3
(13 µmol), 1,4-dioxane (1.0 mL). [b] Isolated yield based on 4.
[c] Performed at 60 °C. [d] Performed in 1,4-dioxane (0.35 mL).
[e] Compound 8b also was generated in 4% yield.
1
2
Hex
Hex
Me
Me
Me
Me
Me
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5d[i]
A, x = 2.5
B, y = 2.5
A, x = 12
B, y = 18
A, x = 12
A, x = 12
A, x = 7
71 (97:3)
62 (97:3)
58 (98:2)
50 (98:2)
50 (98:2)
51 (96:4)
56 (96:4)
[e]
[e]
3
4
5
AcO(CH2)3
AcO(CH2)3
NC(CH2)3
The procedure requiring the presynthesis of the DPAs
can be modified to a more simple protocol, which is a one-
pot reaction without the isolation of the DPAs (Table 2).
Treatment of 1-octyne (1a) and N-methylpyrrole (2a) with
In(OTf)3 as a catalyst at 85 °C for 2 h, followed by the ad-
dition of 2-methylfuran (5a) gave 6a in a good yield, though
α-isomer 7a was slightly co-produced (Table 2, Entry 1;
method A).[12] The one-pot reaction can be performed also
by a different procedure, shown as method B in Table 2.
Thus, simultaneous treatment of 1a, 2a, 5a, and a catalytic
amount of In(OTf)3 at 85 °C for 2.5 h gave the mixture in
62% yield with the same ratio (Table 2, Entry 2; method B).
6
p-MeOC6H4 Me
7
8
3-thienyl
Hex
Me
Bn[f]
tBu
Ph
A, x = 0.5
A, x = 2.5
A, x = 0.5
A, x = 150
72 (Ͼ99:Ͻ1)
70 (Ͼ99:Ͻ1)
57 (Ͼ99:Ͻ1)
50 (Ͼ99:Ͻ1)
9
Hex
Hex
CH3(CH2)9
10[g]
11[h]
Me
[a] Reaction conditions:
1
(0.25 mmol),
2
(1.0 mmol),
5
(0.75 mmol), In(OTf)3 (63 µmol), 1,4-dioxane (2.0 mL, method A;
0.70 mL, method B). [b] 5a: 2-methylfuran, 5d: Me3SiCN. [c] Iso-
lated yield based on 1. [d] Determined by GC. [e] Ac = acetyl. [f] Bn
= benzyl. [g] The temperature was lowered to 70 °C after the ad-
dition of 5a. [h] The reaction was performed in 1,4-dioxane
(0.70 mL) and the temperature was elevated to 100 °C after the
To the best of our knowledge, this is the first demonstration addition of 5d. [i] 5d (4 equiv.) was used.
2438 Eur. J. Org. Chem. 2009, 2437–2440
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Methanes Having Four Different Carbon Substituents
toxy or cyano group similarly accepted one molecule of 2a tions of 4a and 3a, clearly indicating that 7a is the only
and of 5a (Table 2, Entries 3–5). Aryl and heteroaryl acetyl- precursor to 8a.[13] This is most likely a result of the leaving
enes also participated in the strategy (Table 2, Entries 6 and ability of the α-pyrrolyl group being higher than that of the
7). A bulkier substituent such as –Bn, –tBu, or –Ph on the β-pyrrolyl group.
nitrogen atom of 2 effectively promotes the exclusive forma-
tion of 6 (Table 2, Entries 8–10). Me3SiCN (5d) also is avail-
able as a nucleophile in the three-component reaction
(Table 2, Entry 11).
The time course studies on the reaction of DPA 4a, 3a,
or 10 with 5a are summarized in Table 3. Both of the reac-
tions of β,βЈ-DPA 4a and α,βЈ-DPA 3a gave only β-pyrrolyl
isomer 6a, and even α,αЈ-DPA 10 was transformed into 6a
selectively, along with a small amount of α-isomer 7a and
difuryloctane 8a. The reactivity order of the three DPAs
was found to be 3a Ͼ 4a Ͼ 10. Scheme 2 illustrates possible
routes from the DPAs to the products. In the case of 3a,
cationic species β-A and α-A are possible intermediates;
these result in 6a and 7a, respectively. The exclusive forma-
tion of 6a suggests that β-A is much more stable than α-A,
which has serious steric repulsion between the two hydrogen
atoms. The reaction of 4a, which inevitably forms β-A upon
the elimination of a pyrrolyl group, also gives 6a exclusively.
Considering that the difference between 4a and 3a is the
leaving group, the fact that the reaction of 3a is faster than
that of 4a indicates that the α-pyrrolyl group has a superior
leaving ability to the β-pyrrolyl group. α,αЈ-DPA 10, despite
having two α-pyrrolyl groups, was slowly consumed, sug-
gesting that the primary factor contributing to the reactivity
of the DPAs is the formation of β-A over α-A rather than
the release of the α-pyrrolyl group over the β-pyrrolyl
group. Difuryloctane 8a was not produced from the reac-
Scheme 2. Possible routes from DPAs to products.
Conclusions
We demonstrated the first carbon–carbon bond-forming
reaction by the cleavage of the C(sp3)–C(pyrrolyl) bond,
where a certain range of carbon nucleophiles are available.
The reaction can be performed also as a three-component
assembly in an easy manner. The important aspect dis-
closed herein is the selective formation of intermediary β-A
from DPAs; this contributes to the high selectivities of β-
isomers 6. Further synthetic applications by utilizing the
effect of the β-pyrrolyl group are in progress in our labora-
tory.
Table 3. Time course studies on reaction of DPAs with 2-methylfu-
ran.
Experimental Section
Synthesis of 6a: Under an argon atmosphere, a mixture of 4a
(35 mg, 0.13 mmol), 5a (43 mg, 0.52 mmol), and In(OTf)3 (7.3 mg,
13 µmol) in 1,4-dioxane (1.0 mL) was stirred at 85 °C for 1.5 h. To
this was added a saturated NaHCO3 aqueous solution (0.5 mL),
and the aqueous phase was extracted with EtOAc (3ϫ5 mL). The
combined organic layer was dried with anhydrous Na2SO4. Fil-
tration and evaporation of the solvent followed by column
chromatography on silica gel (hexane/EtOAc, 50:1) gave 6a (28 mg,
80% yield; Table 1, Entry 1).
DPA
t
Conv. [%] of DPAs
GC yield [%] of GC yield [%]
[min]
(4a/3a/10)[a]
6a + 7a (6a/7a)
of 8a
4a
5
15
60
5
15
40
5
52 (92:8:Ͻ1)
88 (90:10:Ͻ1)
98
76 (90:10:Ͻ1)
93 (87:13:Ͻ1)
98
20 (Ͻ1:Ͻ1:Ͼ99)
49 (2:Ͻ1:98)
82 (9:Ͻ1:91)
95
34 (Ͼ99:Ͻ1)
67 (Ͼ99:Ͻ1)
86 (Ͼ99:Ͻ1)
59 (Ͼ99:Ͻ1)
79 (Ͼ99:Ͻ1)
86 (Ͼ99:Ͻ1)
3 (33:67)
Ͻ1
Ͻ1
Ͻ1
Ͻ1
Ͻ1
Ͻ1
Ͻ1
1
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and characterization data;
1H and 13C NMR spectra for all new compounds.
3a
10
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DPAs.
Eur. J. Org. Chem. 2009, 2437–2440
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2439

T. Tsuchimoto, T. Ainoya, K. Aoki, T. Wagatsuma, E. Shirakawa
SHORT COMMUNICATION
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[8]
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[12] After consumption of 1a upon reaction with 2a was confirmed,
5a was added to the reaction mixture. Other entries using
method A also were carried out in a similar way.
[13] The contamination of α-isomer 7 in several three-component
reactions is likely to be related to the increasing content of
α,αЈ-isomers among the remaining DPAs during the reaction
(Table 2). For example, before and after the addition of 2-meth-
ylfuran (5a) in the reaction of Entry 1, the ratio of β,βЈ-, α,βЈ-
, and α,αЈ-DPA changed from 86:13:1 to 82:11:7 (10 min later)
and then to 78:10:12 (20 min later).
Received: March 7, 2009
Published Online: April 14, 2009
2440
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2437–2440