Exclusive synthesis of β-alkylpyrroles under indium catalysis: Carbonyl compounds as sources of alkyl groups

Article abstract of DOI:10.1002/chem.201000733

No longer difficult: Just mixing readily available carbonyl compounds, pyr-roles, and nucleophiles with an indium catalyst was found to give β-alkylpyr-roles in a regiospecific manner. Removal of benzyl (Bn) and cumyl groups from the nitrogen atoms of the products enables access to nitrogen-unsubstituted β-alkylpyrroles (see scheme).

Full text of DOI:10.1002/chem.201000733

COMMUNICATION
DOI: 10.1002/chem.201000733
Exclusive Synthesis of b-Alkylpyrroles under Indium Catalysis:
Carbonyl Compounds as Sources of Alkyl Groups
Teruhisa Tsuchimoto,* Motohiro Igarashi, and Kazuki Aoki[a]
Dedicated to Professor Tamejiro Hiyama in commemoration of his retirement from Kyoto University
Introduction of alkyl groups onto aromatic rings is among
the most important transformations in organic synthesis.
Transition-metal-catalyzed cross-coupling must be a leading
option to make alkyl–aryl bonds at desired positions.[1] How-
ever, pre-activation of both fragments with halides and elec-
tropositive metals is required to secure the regioselectivities.
A realistic candidate to reduce our dependence on the pre-
activation would be electrophilic aromatic substitution
(EAS), that is, the Friedel–Crafts alkylation that replaces
the pre-activated arenes with simple arenes, while the
simple arenes for the EAS generally cause non-regioselec-
tive reaction, and, in addition, their reaction sites are nar-
rowed to more nucleophilic positions.[2] Therefore, develop-
ment of EAS enabling regioselective alkylation at desired
sites on arenes would be useful over the cross-coupling. In
this context, we recently reported the regiospecific b-alkyla-
tion of pyrroles through EAS, by the simple assembly of al-
kynes 1, pyrroles 2, and Et3SiH (3a) under indium catalysis
(Scheme 1).[3] b-Alkylpyrroles are structural motifs found in
many natural products[4] and functional organic materials,[5]
but b-alkylation of pyrroles by EAS has been a challenging
issue, due to dominant a-nucleophilicity of pyrroles.[6] De-
spite such characteristics of pyrroles, our recent finding,
which is the first example of catalytic b-alkylation of pyr-
roles in one-step, showed that b-alkylpyrroles 4 are formed
exclusively, via formation of dipyrrolylalkanes 5 as crucial
intermediates.[7,8] However, the scope of 1 has been restrict-
ed mainly to terminal alkynes, the terminal carbon atom of
which is inevitably incorporated as a methyl group into 4.[9]
We envisioned that replacing 1 with carbonyl compounds 6
Scheme 1. Indium-catalyzed reductive b-alkylation of pyrroles: alkynes
versus carbonyl compounds as sources of alkyl groups ([In]=indium
salt).
would drastically extend the diversity of alkyl groups instal-
lable onto 2.[10] Moreover, the use of 6, which is cheaper in
general than 1, would make the process highly attractive
and practical. Herein we disclose a new method for synthe-
sis of b-alkylpyrroles 4 using 6 as alkyl group suppliers.[11]
Due to the potent activity of InACHTUNRGTNEUNG(NTf2)3 (Tf=SO2CF3)
found in our preceding research,[3] research on this topic
began with its testing in the reaction of 2-decanone (6a) and
N-methylpyrrole (2a) with Et3SiH (3a), by the procedure
shown as method A: simultaneous treatment of 6, 2, 3 and
InACHTNUGTRENNUG(NTf2)3 (Table 1). Thus, the reaction with InACHTUNGTRENNUNG(NTf2)3
(10 mol%) in 1,4-dioxane at 858C for 3 h gave 3-(decan-2-
yl)-N-methylpyrrole (4a) as a single isomer in 92% yield
(entry 1). The absence of formation of its a-isomer is partic-
ularly noteworthy. Another important aspect is that the use
of 6a allowed to reduce the catalyst loading, compared with
reaction of the corresponding alkyne, 1-decyne, requiring
[a] Prof. Dr. T. Tsuchimoto, M. Igarashi, K. Aoki
Department of Applied Chemistry
School of Science and Technology
Meiji University, Higashimita
25 mol% of InACTHNUTRGNEUNG
(NTf2)3.[3] The 5-nonyl group, which is diffi-
cult to install regioselectively when an unsymmetrical
alkyne (4-nonyne) is used, is readily available from 5-nona-
none (entry 2). The cyclic structures that are inaccessible
from alkynes can be treated with ease (entries 3–5), while 2-
adamantanol (15% yield), resulting from direct reduction of
Tama-ku, Kawasaki 214-8571 (Japan)
Fax : (+81)44-934-7228
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000733.
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Table 1. Indium-catalyzed reductive b-alkylation of pyrroles with carbonyl compounds and Et3SiH.[a]
Entry
1
Method
A
t [h]
Product, yield[b]
Entry
12[d,e]
Method
B
t [h]
Product, yield[b]
t2 =1
t3 =5
t1 =3
t2 =1
t3 =5
2
3
4
5
A
A
A
A
t1 =7
t1 =3
t1 =3
t1 =3
13[e]
B
B
A
B
t2 =20
t3 =1
14
15
t1 =3
t2 =1
t3 =3
16
t2 =20
t3 =1
6
B
17
A
t1 =7
7
8
A
B
t1 =7
18
19
A
A
t1 =3
t1 =3
t2 =1
t3 =20
9[c]
A
t1 =7
20[f]
A
t1 =24
t2 =1
t3 =4
10
B
B
21
A
A
t1 =10
t1 =20
t2 =1
t3 =3
11[d]
22[c]
[a] Reagents (unless otherwise specified): 6 (0.30 mmol), 2 (0.90–1.2 mmol), 3a (0.45 mmol), InACHTNUGTRENNG(U NTf2)3 (0.030–0.075 mmol) for entries 1–16 or InACHTUNGTRENNUNG(ONf)3
(0.030–0.075 mmol) for entries 17–22, 1,4-dioxane (0.5 mL). See Supporting Information for further details. [b] Isolated yield based on 6. [c] Performed
at 608C. [d] Carried out in the presence of MgSO4 (3.0 equiv). [e] The process after the addition of 3a was performed at 1008C. [f] 3a (2.4 mmol) was
used.
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Indium Catalysis
COMMUNICATION
2-adamantanone by 3a, was contaminated in the case of
entry 5. The undesired reduction was suppressed entirely by
the simple alteration of method A to method B, in which 3
is added after consumption of 6, leading to in situ formation
of dipyrrolylalkanes 5 as intermediates (entry 6).[12] A range
of functional groups, sulfide, ester, alkenyl, boryl {[B]=
B(pinacolate)}, cyano, and alkoxy, are compatible with the
strategy (entries 4, 7–9, 11, 12, 20, and 22). For aryl and het-
eroaryl ketones, method B is valid to exclude a-alkylation
(entries 10–13).[13] Pyrroles bearing a benzyl (Bn), tBu, Ph,
or cumyl (2-phenylisopropyl) group on the nitrogen atom
also participated well in this protocol (entries 14–22). One
of the major highlights is to ensure access to primary alkyl
groups that are impossible to handle in our previous
system,[3] since terminal alkynes 1 accept 2 at the internal
fect b-selective manner in all cases. In the cases of 3d, the
bicyclic ring was formed at once through regioselective
three carbon–carbon bond-forming cascades, in which a ben-
zylic cation generated after nucleophilic attack of the C=C
bond of 3d is likely to accept the a-carbon of the pyrrolyl
group.
Nitrogen-unsubstituted b-alkylpyrroles also are easily ac-
cessible by the removal of the benzyl or cumyl group in b-al-
kylpyrroles synthesized thus far (Scheme 3).[14] For example,
[11c]
ꢀ
carbon of the C C bond.
In fact, linear and a-branched
aliphatic aldehydes as well as an aromatic one reacted with
2 and 3a over InACHTUNGTRENNUNG(ONf)3 (Nf=SO2C4F9) as a catalyst to give
b-alkylpyrroles 4p–4u exclusively (entries 17–22). Here the
bulkiness on the nitrogen atom of 2 is crucial for complete
b-selectivities and also high conversion of intermediates 5.
In these cases, InACHTUNGTRENNUNG(NTf2)3 is less effective, due mainly to
lower conversion of 5. Utility of the strategy can be demon-
strated by performing scale up synthesis. For example, 4m
(667 mg, 76% yield) and 4t (520 mg, 53% yield) can be pre-
pared in virtually the same yield, compared to those ob-
tained in entries 14 and 21 of Table 1, by tenfold scale-up re-
action.
Besides hydride nucleophile 3a, carbon nucleophiles
[Nu(C)] 3, such as Me3SiCN (3b), 2,3-dimethylthiophene
(3c) and 4-vinylanisole (3d), can be adopted for extension
of a carbon–carbon bond (Scheme 2).[11f] Their use enables
installation of tertiary alkyl units onto 2, here again in a per-
Scheme 3. Synthesis of nitrogen-unsubstituted b-alkylpyrroles 8a–8c. Re-
agents and conditions: a) TiCl3 (2.0 equiv), Li (13 equiv), I2 (1.0 equiv),
THF, RT, 16 h.
the treatment of 4m, 4t, or 7 f with TiCl3/Li/I2 in THF at
room temperature gave 8a, 8b, or 8c, respectively,[15] indi-
cating that the debenzylation and decumylation allow us to
gain nitrogen-unsubstituted b-alkylpyrroles with all types of
alkyl groups, that is, primary, secondary and tertiary ones.
We next performed some reactions to get insight into the
reaction mechanism (Scheme 4). Thus, the indium-catalyzed
reaction of 6a with 2a, but without 3, gave an isomeric mix-
ture of 5a, as already observed in the reactions using meth-
od B (vide supra). Subsequently, treating 5a, 3a, and H2O
with InACHTNUGTRENUNG(NTf2)3 (10 mol%) provided b-(decan-2-yl)pyrrole
4a exclusively.[16] These results indicate that dipyrrolylal-
kanes 5 are intermediates in the three-component reaction
using 6, 2, and 3. On the basis of these results and our previ-
Scheme 2. Indium-catalyzed b-alkylation of pyrroles with carbonyl com-
pounds and carbon nucleophiles (3b: Me3SiCN, 3c: 2,3-dimethylthio-
phene, 3d: 4-vinylanisole).
Scheme 4. Indium-catalyzed synthesis of dipyrrolyldecanes 5a, and
indium-catalyzed synthesis of b-(decan-2-yl)pyrrole 4a starting from 5a.
Chem. Eur. J. 2010, 16, 8975 – 8979
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T. Tsuchimoto et al.
ous ones,[3,11f]
a plausible mechanism is depicted in
Experimental Section
Scheme 5, in which one pyrrolyl ring in 5 is fixed as the b-
pyrrolyl ring, due actually to no formation of a-alkylpyrroles
Synthesis of 4a (Table 1, entry 1): InACHTNUTRGNEUNG(NTf2)3 (28.7 mg, 30.0 mmol) was
heated in a 20 mL Schlenk tube at 1508C in vacuo for 2 h. Under argon,
1,4-dioxane (0.5 mL), 2-decanone (46.9 mg, 0.300 mmol), N-methylpyr-
role (73.0 mg, 0.900 mmol) and Et3SiH (52.3 mg, 0.450 mmol) were added
to the Schlenk tube. The mixture was stirred at 858C for 3 h, and then a
saturated NaHCO3 aqueous solution (0.3 mL) was added and the aque-
ous phase was extracted with EtOAc (3ꢁ5 mL). The combined organic
layer was washed with brine (1 mL) and then dried over anhydrous
Na2SO4. Filtration and evaporation of the solvent followed by column
chromatography on silica gel (hexane/EtOAc=60:1) gave 3-(decan-2-yl)-
N-methylpyrrole (4a) (61.1 mg, 92% yield).
Scheme 5. A plausible reaction mechanism.
Acknowledgements
Financial support from the Ministry of Education, Culture, Sports, Sci-
ence and Technology by a grant-in-aid for Scientific Research (No.
21750107) is gratefully acknowledged. We also acknowledge partial finan-
cial support from Nissan Chemical Industries.
derived inevitably from a,a’-5. The indium salt [In] first as-
sembles 6 and 2 into 5,[17] one pyrrolyl group of which coor-
dinates to the indium salt and then eliminates to give cation-
ic species b-9 by way of the CACTHNUGTRNENUG ACHUTGNTREN(NGUN pyrrolyl) bond cleav-
(sp3)–C
À
Keywords: aldehydes · C C activation · indium · ketones ·
nucleophilic substitution
age. The trapping of b-9 by nucleophile (Nu) 3 affords final
product 4 or 7. The origin of the perfect b-selectivities is at-
tributed to the following two synergistic effects, as previous-
ly noted:[3,11f] 1) dominant formation of b-9 being much
more stable than alternative cationic species a-9
(Scheme 5), which has 1,3-allylic-type strain between R1 and
R3,[18] and 2) superior leaving ability of an a-pyrrolyl group
to a b-pyrrolyl group. In fact, only 4a is produced, even
from a,b’-5a, which is a possible precursor for 4a and its a-
isomer (Scheme 6).
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In conclusion, we have disclosed a new robust and simple
synthetic method for b-alkylpyrroles by the choice of car-
bonyl compounds as alkyl group sources, through tandem
À
C=O and C C bond activations under indium catalysis. The
regioselectivities on both pyrrole rings and alkyl units are
perfectly controlled. The striking feature is that the indium-
catalyzed b-alkylation in combination with the debenzyla-
tion offers all six variations including nitrogen-substituted
and -unsubstituted b-alkylpyrroles with primary, secondary,
and tertiary alkyl groups. Application of the strategy to an
asymmetric variant is currently underway, and the result will
be reported in due course.
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Indium Catalysis
COMMUNICATION
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[12] Disappearance of 6 followed by formation of 5 can be confirmed by
GC analysis.
[13] For example, the reaction of acetophenone (R1 =Ph, R2 =Me), 2a
and 3a by using method A gives a 98:2 mixture of b- and a-(1-phe-
nylethyl)pyrroles in 88% yield (see entry 10).
[14] Unfortunately, application of the strategy to pyrrole (R3 =H) result-
ed in low yield and b-selectivity: treatment of 6a, pyrrole, 3a
(1:3:1.5) and InACTHUNTRGNE(UNG NTf2)3 (10 mol%) at 858C for 20 h by using meth-
od A gives a 54:46 mixture of b- and a-(decan-2-yl)pyrroles in 28%
yield.
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[9] Although 4-octyne is available as a source of an alkyl group, its use
imposes higher loadings of a pyrrole and indium catalyst at higher
temperature, compared to standard reaction conditions.
[10] Carbonyl compounds have much higher skeletal and substitutional
diversities than alkynes as commercial sources. See, for example,
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com/chemistry/chemistry-products.html?TablePage=16273490.
[16] The process of the indium-catalyzed reaction of 6a with 2a produces
one molar equivalent of H2O along with 5a. Accordingly, the reac-
tion was carried out in the presence of H2O (1 equiv).
[17] Synthesis of dipyrrolylalkanes upon treatment of carbonyl com-
pounds and pyrroles with acid catalysts is a well-established reac-
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À
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Received: March 24, 2010
Published online: July 6, 2010
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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