Palladium-catalyzed regioselective allylation of five-membered heteroarenes with allyltributylstannane

Article abstract of DOI:10.1039/c4cc10373d

Palladium-catalyzed allylation reactions of 2-(chloromethyl)thiophenes, 2-(chloromethyl)furans, and N-protected 2-(chloromethyl)-1H-pyrroles with allyltributylstannane were described in this study. This type of allylation reaction regioselectively occurred on the heteroarene rings to produce allylated dearomatization products or allylated heteroarenes with satisfactory yields.

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ARTICLE TYPE
Palladium-catalyzed Regioselective Allylation of Five-membered
Heteroarenes with Allyltributylstannane
Sheng Zhang,a Xiaoqiang Yu,a Xiujuan Feng,a Yoshinori Yamamoto,a,b Ming Bao*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Palladiumꢀcatalyzed allylation reactions of 2ꢀ(chloromethyl)thiophenes, 2ꢀ(chloromethyl)furans, and Nꢀ
protected 2ꢀ(chloromethyl)ꢀ1Hꢀpyrroles with allyltributylstannane were described in this study. This type
of allylation reaction regioselectively occurred on the heteroarene rings to produce allylated
dearomatization products or allylated heteroarenes with satisfactory yields.
10 Nꢀ, Oꢀ, and Sꢀcontaining fiveꢀmembered heteroarene moieties are
common skeletons in drug molecules and natural products.1,2
In Yamamoto's study, it was determined that benzyl chlorides
react with allyltributylstannane through η3ꢀbenzylpalladium
Therefore, development of efficient and convenient methods for 35 intermediates to produce paraꢀallylated dearomatization
functionalization of these compounds has gained considerable
attention.2 Among the methods developed, allylation has become
15 an important technique for functionalization of fiveꢀmembered
heteroarenes because of the versatility of the allyl group as a
products.8 Based on this discovery, we hypothesized that 2ꢀ
(chloromethyl)furans, 2ꢀ(chloromethyl)thiophenes, and Nꢀ
protected 2ꢀ(chloromethyl)ꢀ1Hꢀpyrroles may also react with
allyltributylstannane in the presence of palladium catalyst
handle to access various functional groups. Over the past decades, 40 through a similar pathway as benzyl chlorides. As expected, the
two main methods have been developed for allylation of fiveꢀ
membered heteroarenes. One method involves the Friedel–Crafts
20 reactions using allylic alcohol or its acetate derivative as
allylating reagents in the presence of Brønsted3 or Lewis acid4
catalysts (Eq. 1). Another method involves transition metalꢀ
catalyzed Tsuji–Trostꢀtype allylation reaction of fiveꢀmembered
heteroarenes with allylic alcohol derivatives (Eq. 2).5ꢀ7 These
25 procedures are valuable to introduce an allyl group onto
heteroarene rings. However, the substrates of these
transformations are restricted to benzopyrrole (indole),
benzofuran, and benzothiophene derivatives. Allylation of simple
heteroarenes, such as pyrrole, furan, and thiophene derivatives,
30 has been rarely investigated.
target reaction occurred to produce allylated dearomatization
products or allylated heteroarenes with satisfactory yields under
optimized reaction conditions (Eq. 3). The results are reported in
the current work.
45
Table 1 Reaction condition screeninga
Entry
1
2
Catalyst
Pd(PPh3)4
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Hexane
Acetone
CH3OH
CH3CN
THF
Yield (%)b
60
50
56
65
74
0d
80
38
79
20
0d
Pd(OAc)2/PPh3
Pd(acac)2/PPh3
Pd2(dba)3/PPh3
Pd2(dba)3/PPh3
Pd2(dba)3/PPh3
Pd2(dba)3/PPh3
Pd2(dba)3/PPh3
Pd2(dba)3/PPh3
Pd2(dba)3/PPh3
None
3
4
5c
6c
7c
8c
9c
10c
11
Acetone
aReaction conditions: 2ꢀ(chloromethyl)ꢀ5ꢀ(phenylethynyl)thiophene (1h,
0.5 mmol, 116.4 mg), allyltributylstannane (0.5 mmol, 165.6 mg),
50 Pd2(dba)3 (2.5 mol%, 11.5 mg), Pd(OAc)2 (5 mol%, 5.6 mg), Pd(acac)2
(5 mol%, 7.6 mg), Pd(PPh3)4 (5 mol%, 28.9 mg), and PPh3 (10 mol%,
13.1 mg) in solvent (3.0 mL) at room temperature under an N2
atmosphere for 10 h. bIsolated yield. cPd2(dba)3 (5 mol%) and PPh3
(20 mol%) were used. dba = trans,transꢀdibenzylideneacetone. acac =
55 acetylacetonate. dStarting materials were recovered.
Initially, the allylation reaction of 2ꢀ(chloromethyl)ꢀ5ꢀ
(phenylethynyl)thiophene (1h) with allyltributylstannane was
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selected as a model to optimize the reaction conditions (Table 1).
was tested. The strong electronꢀwithdrawing group NO2 linked to
The allylated dearomatization product 2h was obtained in 60% 60 the thiophene ring may have hindered the generation of the η3ꢀ
yield when the model reaction was conducted in CH2Cl2 in the
presence of catalyst Pd(PPh3)4 at room temperature for 10 h
(Entry 1). The model reaction was then tested using Pd(OAc)2,
Pd(acac)2, and Pd2(dba)3 as precatalysts combined with PPh3 in
CH2Cl2 (Entries 2 to 4). Pd2(dba)3/PPh3 was more suitable
catalyst system for the target reaction. The desired product 2h
was obtained in 65% yield (Entry 4). We observed that the yield
allylpalladium intermediate, thereby, hindered the occurrence of
the target reaction.
5
Table 2 Palladiumꢀcatalyzed allylation reaction of 2ꢀ(chloromethyl)ꢀ
thiophenes with allyltributylstannanea,b
10 of 2h increased with the increase in Pd2(dba)3 loading (Entry 5).
Nonpolar (CH2Cl2 and hexane) and polar [acetone, CH3CN,
CH3OH, and tetrahydrofuran (THF)] solvents were examined for
solvent screening (Entries 5 to 10). The results obtained indicated
that the product 2h was obtained in almost the same good yield
15 when the reaction was conducted in acetone or CH3CN (Entries 7
and 9, 80% vs. 79%). The acetone solvent could be easily
removed from the reaction mixture because of its relatively lower
boiling point than that of CH3CN. Therefore, acetone was
selected as reaction solvent. No reaction was observed in the
20 absence of palladium catalyst (Entry 11). The subsequent
65
2a, 60%, 12 h
2d, 58%, 12 h
2b, 82%, 10 h
2e, 50%, 12 h
2c, 75%, 10 h
2f, 51%, 12 h
reactions
of
2ꢀ(chloromethyl)thiophenes
with
allyltributylstannane were conducted in the presence of Pd2(dba)3
(5 mol%) and PPh3 (20 mol%) in acetone solvent at room
temperature.
2g, 78%, 10 h
2h, 80%, 10 h
2i, 75%, 10 h
25
The reactions of 2ꢀ(chloromethyl)thiophenes 1a–1o with
allyltributylstannane were conducted under optimized conditions.
The results are summarized in Table 2. The reaction of 2ꢀ
(chloromethyl)thiophene (1a), the simplest thiophene ringꢀ
containing substrate, with allyltributylstannane proceeded
2j, 75%, 20 h
2k, 71%, 20 h
2n, 74%, 6 hc
2l, 64%, 12 h
2o, 0%, 24 hd
O
MeO
S
30 smoothly to produce the desired allylated product 2a in moderate
yield (60%). This low isolated yield may be ascribed to the low
boiling point of 2a. Allylated products 2b and 2c were obtained
in good yields (82% and 75%, respectively) from the reactions of
3ꢀbromoꢀ2ꢀ(chloromethyl)thiophene (1b) and 3ꢀchloroꢀ2ꢀ
35 (chloromethyl)thiophene (1c), respectively. However, the
reaction of 4ꢀbromoꢀ2ꢀ(chloromethyl)thiophene (1d) with
allyltributylstannane produced the desired product 2d in low yield
(58%). The reason for this behavior remains unclear. Notably, the
Br and Cl atoms linked to the thiophene rings were maintained in
40 the structures of the products 2b–2d under the allylation reaction
conditions, indicating that further manipulation may produce
useful compounds. Allylated dearomatization products 2e and 2f
were obtained in moderate yield (50% and 51%, respectively)
when the substrates 1e and 1f bearing an electronꢀdonating group
45 (methyl or normal butyl) on the 5ꢀposition were examined. The
relatively low yields of 2e and 2f may be attributed to the
instability of 1e and 1f under the reaction conditions. We
observed that the 2ꢀ(chloromethyl)thiophene substrate could
become stable under the reaction conditions with the appropriate
50 electronꢀwithdrawing group linked to the 5ꢀposition and provided
the allylated dearomatization product in relatively high yield.
Dearomatization products 2g–2l were obtainedin 64% to 80%
yields. The formation of the double allylated dearomatization
product 2n was observed in the reaction of 5ꢀchloroꢀ2ꢀ
55 (chloromethyl)thiophene with allyltributylstannane. It was
considered that the double allylation was proceeded through
allylative dearomatization and Stille coupling successively. No
reaction was observed when 5ꢀnitroꢀ2ꢀ(chloromethyl)thiophene
2m, 71%, 8 h
aReaction conditions: 2ꢀ(chloromethyl)thiophenes (1, 0.5 mmol),
allyltributylstannane (0.5 mmol, 165.6 mg), Pd2(dba)3 (5 mol%, 22.9 mg),
and PPh3 (20 mol%, 26.2 mg) in acetone (3.0 mL) at room temperature
under
an
N2
atmosphere.
bIsolated
yield.
c2ꢀChloroꢀ5ꢀ
70 (chloromethyl)thiophene was used as a starting material. dStarting
materials were recovered.
Successful allylation of the 2ꢀ(chloromethyl)thiophene
75 substrates encouraged us to examine the allylation reaction of 2ꢀ
(chloromethyl)furans and Nꢀprotected 2ꢀ(chloromethyl)ꢀ1Hꢀ
pyrroles. The results are summarized in Tables 3 and 4.
Considering the low boiling point of the 2ꢀ(chloromethyl)furan
substrates and the poor solubility of the Nꢀprotected 2ꢀ
80 (chloromethyl)ꢀ1Hꢀpyrrole substrates in acetone, CH2Cl2 was
utilized as the solvent instead of acetone. Allylated
dearomatization products 4a–4h were obtained in low to
moderated yields (25% to 57%) from the allylation reactions of 2ꢀ
(chloromethyl)furan substrates 3a–3h. These results may also be
85 attributed to the instability of 3a–3h under the reaction
conditions. Notably, the allylation reactions of Nꢀprotected 2ꢀ
(chloromethyl)ꢀ1Hꢀpyrroles 5a–5g proceeded smoothly to
produce the corresponding allylated pyrrole derivatives 6a–6g in
satisfactory yields (67% to 84%). Finally, the allylated
90 dearomatization product 6h was isolated in 45% yield from the
2
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reaction of Nꢀprotected
5ꢀsubstituted 2ꢀ(chloromethyl)ꢀ1Hꢀ
According to the above experimental results and previous
report,9 a plausible mechanism for the palladiumꢀcatalyzed
regioselective allylation of fiveꢀmembered heteroarenes with
25 allyltributylstannane is shown in Scheme 1. The oxidative
addition of a 2ꢀ(chloromethyl)thiophene to a Pd(0) species could
produce the η3ꢀallylpalladium chloride intermediate A, which
could undergo transmetalation with allyltributylstannane to
generate intermediate B . Isomerization of intermediate B could
30 occur to produce intermediate C. Finally, the reductive
elimination of intermediate C through coupling of the Cꢀ3
terminus of the η1ꢀallyl ligand with the Cꢀ5 of the η3ꢀ
methylenethiophene ligand9 could occur to produce allylated
dearomatization product (R ≠ H) or allylated thiophene derivative
35 (R = H) via 1,5ꢀhydrogen migration and to regenerate a Pd(0)
catalyst.
pyrrole substrate 5h with allyltributylstannane. The results
obtained indicated that pꢀtoluenesulfonyl and tꢀbutoxycarbonyl
could be used as Nꢀprotecting groups in the pyrrole substrates.
5
Table 3 Palladiumꢀcatalyzed allylation reaction of 2ꢀ(chloromethyl)furans
with allyltributylstannanea,b
4a, 47%
4d, 45%
4b, 53%
4e, 25%
4c, 57%
4f, 55%
4g, 50%
4h, 55%
aReaction conditions: 2ꢀ(chloromethyl)furans (3, 0.5 mmol),
10 allyltributylstannane (0.5 mmol, 165.6 mg), Pd2(dba)3 (5 mol%, 22.9 mg),
and PPh3 (20 mol%, 26.2 mg) in CH2Cl2 (3.0 mL) at room temperature
under an N2 atmosphere for 12 h. bIsolated yield.
Scheme 1. Proposed mechanism for the allylation of fiveꢀmembered
40 heteroarenes.
Table
4
Palladiumꢀcatalyzed
allylation
reaction
of
2ꢀ
15 (chloromethyl)pyrroles with allyltributylstannanea,b
In summary, we developed a new method for the regioselective
allylation of fiveꢀmembered heteroarenes using palladium
catalyst. This novel protocol exhibited good tolerance for various
45 functional groups linked to fiveꢀmembered heteroarenes, such as
ester, carbonyl, and alkynyl. The commercial availability of the
catalyst, mild reaction conditions, and experimental simplicity are
the features of the catalytic method presented in the current paper.
Further studies focusing on the threeꢀcomponent reactions of
50 fiveꢀmembered heteroarenes bearing a chloromethyl substituent
on the 2ꢀposition, allyltributylstannane, and carbon dioxide are
currently ongoing.
6a, 80%
6b, 84%
6c, 79%
We are grateful to the National Natural Science Foundation of
China (Nos. 21173032 and 21372035) for their financial support.
55
Notes and references
a
State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Dalian 116023, China. Fax: +86ꢀ0411ꢀ84986181; Tel: +86ꢀ
0411ꢀ84986180; Eꢀmail: mingbao@dlut.edu.cn
60 WPIꢀAIMR (WPIꢀAdvanced Institute for Materials Research), Tohoku
6d, 75%
6e, 76%
6f, 67%
b
Ph
University, Sendai 980ꢀ8577, Japan
†
Electronic Supplementary Information (ESI) available: Experimental
N
procedures and spectroscopic data for isolated compounds. See
DOI: 10.1039/b000000x/
Boc
6h, 45%
6g, 71%
65
1
For a book, see: T. Eicher and S. Hauptmann, The Chemistry of
Heterocycles: Structures, Reactions, Synthesis, and Applications, 2nd
ed. WileyꢀVCH: Weinheim, 2003.
For selected references, see: (a) H. Wang, N. Schröder, and F.
Glorius, Angew. Chem., Int. Ed., 2013, 52, 5386; (b) A. J. Eberhart,
aReaction conditions: 2ꢀ(chloromethyl)pyrroles (5, 0.5 mmol),
allyltributylstannane (0.5 mmol, 165.6 mg), Pd2(dba)3 (5 mol%, 22.9 mg),
and PPh3 (20 mol%, 26.2 mg) in CH2Cl2 (3.0 mL) at room temperature
20 under an N2 atmosphere for 12 h. bIsolated yield.
2
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DOI: 10.1039/C4CC10373D
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15
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3
4
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5
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7
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4
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