Chelation-induced catalytic multiple arylation of allylic 2-pyridyl sulfones

Article abstract of DOI:10.1002/adsc.200404180

The development of a chelation-assisted, transition metal-catalyzed protocol for the sequential multiarylation of cyclic allyl sulfones is described. The metal-coordinating ability of the 2-pyridyl group on the sulfone promotes the otherwise difficult int

Full text of DOI:10.1002/adsc.200404180

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Chelation-Induced Catalytic Multiple Arylation of Allylic
2-Pyridyl Sulfones
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Tomas Llamas, Ramon Gomez Arrayas, Juan Carlos Carretero*
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Departamento de Química Organica, Facultad de Ciencias, Universidad Autonoma de Madrid
Cantoblanco, 28049 Madrid, Spain
Fax: (þ34)-91-497-3966, e-mail: juancarlos.carretero@uam.es
Received: June 16, 2004; Accepted: September 17, 2004
Dedicated to the memory of Dr. Juan Carlos del Amo.
Abstract: The development of a chelation-assisted,
transition metal-catalyzed protocol for the sequen-
tial multiarylation of cyclic allyl sulfones is describ-
ed. The metal-coordinating ability of the 2-pyridyl
group on the sulfone promotes the otherwise difficult
intermolecular Heck monoarylation and diarylation
of trisubstituted alkenes, as well as the copper-cata-
lyzed allylic arylation with Grignard reagents.
ity, typically a nitrogen-containing group, with the tran-
sition metal induces its transfer to the reactive center in
an intramolecular fashion.[6] We envisaged that allylic
sulfones bearing a metal coordinating group could func-
tion as an excellent platform for the regiocontrolled as-
sembly of structurally complex molecules through se-
quential Heck reactions and copper-catalyzed allylic ar-
ylations (Scheme 1). In this communication we report
the crucial role of the metal coordinating 2-pyridylsul-
fonyl group to accomplish this goal, whereas the typical
allyl phenyl sulfones proved unsuccessful.
Keywords: allylic substitution; chelation-induced;
copper; Heck reaction; palladium; pyridyl sulfone
The starting point of our research was to define an ap-
propriate chelating functionality and to identify the op-
timal reaction conditions. We chose cyclopentenes 1–3
as model alkene substrates to evaluate potential coordi-
The Heck and the allylic alkylation reactions have nating groups (Table 1). Compounds 1–3 were readily
proved to be among the most powerful and versatile obtained in good overall yield (65–94%) by condensa-
C C bond forming tools.[1,2] The intermolecular variant tion of cyclopentanone with the corresponding methyl
À
of these transformations, however, has some limitations sulfonyl carbanion (n-BuLi, THF, À78 8C), followed
due to its great sensitivity to the substitution pattern of by dehydration of the resulting alcohols (TFAA,
the alkene scaffold, steric factors becoming prevalent DMAP, Et3N, CH2Cl2, room temperature) and in situ
over electronics. As a result, the assembly of complex isomerization of the vinyl to the allyl sulfone (DBU,
and sterically congested molecules through the Heck re- CH2Cl2, room temperature).[7] Examination of the
action of trisubstituted alkenes has been essentially re- Heck reaction with iodobenzene under different condi-
stricted to its intramolecular version.[1,3] The use of al- tions led us to find that a combination of Pd(OAc)2 as
kenes carrying a removable coordinating group has palladium source, Ag2CO3 as halide abstractor and
been reported by several groups,[4] including ours,[5] as base, and DMFor CH CN as solvents provided the
3
a successful strategy to overcome the reluctance of sub- best results.[8] Table 1 highlights the crucial role of chela-
stituted alkenes to participate in the intermolecular tion on the reactivity of substituted cyclopentenes.
Heck reaction and/or to control the stereoselectivity of While the reaction of phenyl sulfone 1 and sulfonamide
the process. The association of such directing functional- 2 reached about 50% conversion after 24 h, 2-pyridyl
sulfone 3 underwent smooth Heck reaction to afford a
91:9 mixture of the expected product 6 and the diarylat-
ed compound 7 within just 2 h (92% conversion). This
dramatic acceleration effect, together with the forma-
tion of the double-Heck product 7, suggests a strong che-
lating interaction of the pyridine moiety with the aryl-
palladium oxidative addition complex.
This chelation-assisted Heck protocol was next ex-
tended to a range of electronically varied iodoarenes
(Table 2). Further optimization of the reaction condi-
tions by means of reducing the amount of Ag2CO3 to
Scheme 1. Concept of proposed chelation-assisted multiary-
lation protocol.
Adv. Synth. Catal. 2004, 346, 1651–1654
DOI: 10.1002/adsc.200404180
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Tomas Llamas et al.
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Table 1. Screening of different sulfonyl groups for the Heck arylation.
Entry
Substrate (R)
Time [h]
Conversion [%][a]
Mono-/Diarylation[a]
1
2
3
1 (Ph)
2 (NEt2)
3 (2-Py)
24
24
2
50
56
92
4 (100)/–
5 (100)/–
6 (91)/7 (9)
[a]
1
Measured by H NMR [%].
Table 2. Heck monoarylation of allylic (2-pyridyl)sulfonylcy-
clopentenes.
Entry Ar-X
Yield[a] Mono-/Diarylation[b]
Scheme 2. Heck monoarylation of cyclohexene derivatives.
1
2
3
Ph-I
6, 92% 98/2
8, 85% 96/4
9, 89% 93/7
10, 89% 95/5
(m-F)C6H4-I
(p-Me)C6H4-I
(p-OMe)C6H4-I
(p-OMe)C6H4-N2BF4
4
5[c]
–
76/24
[a]
Isolated yield after chromatography (mono-/diarylation
mixtures).
Measured by H NMR [%].
[b]
[c]
1
1.1 equivalents of diazonium salt at room temperature. 7%
Scheme 3. Heck diarylation of allylic (2-pyridyl)sulfonylcy-
clopentenes.
of 3 was recovered.
ficiently in the Heck arylation reaction with substrate
0.5 equivalents led to complete conversion without an 12 (products 15 and 16).
increase of the diarylation product (less than 7%). Un-
Encouraged by the observation of some diarylation
der these conditions, a number of arylated sulfonylcy- during the course of our investigation, especially in the
clopentenes could be obtained in good yields[9] regard- arylation of cyclopentenes with diazonium salts as re-
less of the electronic nature of the iodoarene used. agents, we set out to develop a sequential double Heck
The use of diazonium salts instead of iodoarenes pro- arylation protocol. Gratifyingly, the Heck reaction of 6
duced an increased amount of the diarylation product with aryldiazonium salts of varied electronic nature oc-
(entry 5).
curred within 24 h at 120 8C, affording 2,5-diarylcyclo-
To test the efficiency of this coordinating system to- pentenes in good yield. Disappointingly, the Heck aryla-
ward less reactive substrates, we briefly explored the tion ofthe cyclohexene derivative 14 did not succeed to a
Heck reaction of cyclohexene derivatives 11 and 12. practical extent (30% conversion after 24 h).
These reactions proved to require harsher reaction con-
To fully realize the synthetic potential of these allyl (2-
ditions.[10] As shown in Scheme 2, phenyl sulfone 11 pro- pyridyl)sulfones, finally we decided to investigate the
vided only a 23% conversion after 48 h (15% isolated copper-catalyzed allylic substitutions of such substrates
yield), whereas the pyridyl analogue 12 reached 92% with Grignard reagents.[11,12] This process would allow
conversion under the same reaction conditions to afford the elimination of the sulfonyl group with concomitant
À
a 94:6 mixture of the mono- and diarylation products, formation of a new C C bond. While allylic halides
respectively (84% isolated yield). Interestingly, both and allylic alcohol derivatives have been widely used
the electron-deficient (m-fluoro)iodobenzene and the as substrates for copper-catalyzed allylic substitution
electron-rich (p-methoxy)iodobenzene participated ef- with non-stabilized nucleophiles,[13] this transformation
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Adv. Synth. Catal. 2004, 346, 1651–1654

Multiple Arylation of Allylic 2-Pyridyl Sulfones
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Table 3. Cu-catalyzed substitution of allyl 2-pyridyl sulfones
with Grignard reagents.
in CH3CN (1 mL) was added iodobenzene (20 mL,
0.178 mmol). The mixture was stirred at 70 8C for 24 h, then al-
lowed to reach room temperature and Et2O (10 mL) was add-
ed. After filtration through Celite, the filtrate was evaporated
and the residue was purified by flash chromatography (n-hex-
ane-EtOAc, 4:1) to afford a 98:2 mixture of 6 and 7 (yield:
24.5 mg, 92%) as a solid.
Complete separation by further reverse phase silica (Merck,
lichroprep RP-18, MeOH-H2O, 4:1) afforded pure 6 as a white
Entry Sub- Ar1
strate
R2 Ar3
Yield[a]
1
solid; yield: 15 mg (57%); mp 73–74 8C; H NMR: d¼8.74–
8.79 (m, 1H), 8.07–8.02 (m, 1H), 7.98–7.90 (m, 1H), 7.58–
7.51 (m, 1H), 7.33–7.16 (m, 3H), 7.14–7.07 (m, 2H), 5.84 (s,
1H), 4.25 (d, 1H, J¼14.1 Hz), 3.97 (m, 1H), 3.72 (d, 1H, J¼
14.1 Hz), 2.58–2.23 (m, 3H), 1.97–1.78 (m, 1H); 13C NMR:
d¼156.8, 149.9, 143.8, 137.7, 136.5, 133.1, 128.4, 127.5, 127.1,
126.3, 122.3, 52.7, 52.1, 33.6, 31.7; MS (APCIþ, 60 V): m/z¼
300 (Mþ þH, 100), 157 (Mþ ÀPySO2, 50), 144 (88).
1
2
3
4
5
6
6
6
6
7
17
18
Ph
Ph
Ph
Ph
H
H
H
Ph
19, 98%
(p-OMe)C6H4 20, 60%
(p-F)C6H4
21, 90%
22, 83%
23, 76%
Ph Ph
(p-OMe)C6H4 Ph (p-F)C6H4
(m-Br)C6H4
Ph (p-OMe)C6H4 24, 55%
1
[a]
Compound 7: yellow solid; mp 139–140 8C; H NMR: d¼
Isolated yield after chromatography.
8.43–8.38 (m, 1H), 8.00–7.95 (m, 1H), 7.90–7.82 (m, 1H),
7.45–7.38 (m, 1H), 7.35–7.15 (m, 10H), 4.57 (d, 1H, J¼
13.9 Hz), 4.38 (m, 1H), 3.72 (d, 1H, J¼13.9 Hz), 2.97 (m,
2H), 2.61–2.45 (m, 1H), 2.00–1.86 (m, 1H); 13C NMR: d¼
157.3, 150.0, 148.1, 144.3, 137.6, 136.5, 128.7, 128.4, 127.8,
127.7, 127.5, 127.4, 127.1, 126.5, 122.3, 54.1, 51.2, 37.2, 32.7;
MS (APCIþ, 30 V): m/z¼376 (Mþ þH, 100), 233 (Mþ ÀPy-
SO2, 45), 144 (17).
has been little explored in the case of allyl sulfones,[14] al-
ways involving typical non-coordinating phenyl or p-tol-
uenesulfonyl derivatives. Allylic substitutions were ini-
tially probed on mono-Heck product 6 by addition of
PhMgBr (1.5 equivs.) in the presence of a 10 mol % of
a copper salt in THFat room temperature. The excellent
catalyst-directing aptitude of the 2-pyridylsulfonyl
group was also found to be determinant in this copper-
catalyzed process.[15] Whereas phenyl sulfone 1 gave
rise to the recovery of unaltered starting material after
24 h, pyridyl sulfone 6 produced a smooth substitution
reaction generating with complete selectivity the SN2-
type products 19–21 (Table 3, entries 1–3). As expect-
ed, the reaction was completely suppressed in the ab-
sence of copper source. The four copper salts examined
[CuCN, CuBr·SMe2, Cu(OAc)2 ·(H2O) and CuTC][16]
proved to be efficient catalyst for this transformation,
the highly soluble CuTC providing slightly better re-
sults.[17] Interestingly, the sterically congested double
Heck products were also suitable substrates for the ary-
lation reaction affording the triarylated cyclopentenes
22–24 (entries 4–6), which clearly shows the efficiency
of the allyl (2-pyridyl)sulfonyl moiety in sequential met-
al-catalyzed arylation processes.
Typical Procedure for the Cu-Catalyzed Allylic
Arylation: 5-Phenyl-1-benzylcyclopent-1-ene (19)
To a room temperature solution of allyl sulfone 6 (20 mg,
0.066 mmol) and CuTC[16] (1.3 mg, 0.0066 mmol) in THF
(1 mL) was added a 1 M solution of phenylmagnesium bromide
in THF(99 mL, 0.099 mmol). The mixture was stirred at room
temperaturefor24 h,itwasquenchedwithwater(severaldrops)
and CH2Cl2 (10 mL) was added. After filtration through Celite,
the filtratewas dried(Na2SO4) and concentratedto dryness. The
residue was purified by flash chromatography (n-hexane) to af-
1
ford 19 as a colourless oil; yield: 15 mg (98%); H NMR: d¼
7.64–7.58 (m, 1H), 7.49–7.42 (m, 1H), 7.39–7.13 (m, 6H),
7.10–7.04 (m, 2H), 5.50 (s, 1H), 3.64 (m, 1H), 3.30 (d, 1H, J¼
15.3 Hz), 3.00 (d, 1H, J¼15.3 Hz), 2.55–2.28 (m, 3H), 1.93–
1.78 (m, 1H); 13C NMR: d¼145.6, 129.0, 128.7, 128.4, 128.1,
127.8, 127.2, 126.0, 125.8, 53.1, 36.1, 34.4, 31.4.
In summary, allyl sulfones bearing a 2-pyridyl group
serve as versatile scaffolds for the efficient regiocontrol-
ledconstructionofhighlyfunctionalizedcycloalkenesun-
der smooth reaction conditions by means of chelation-as-
sistedintermolecularHeckarylationsandfurther Cu-cat-
alyzed allylic substitution with Grignard reagents.
Acknowledgements
This work was supported by the MEC (project BQU2003–
0508). T. L. thanks the Comunidad de Madrid for a predoctoral
fellowship. R. G. A. thanks the MEC for a Ramon y Cajal con-
tract. Johnson Mattey PLC is gratefully acknowledged for a gen-
erous loan of Pd(OAc)2.
´
Experimental Section[18]
References and Notes
Typical Procedure for the Heck Monoarylation: 5-
Phenyl-1-[(2-pyridylsulfonyl)methyl]cyclopent-1-ene (6)
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Tomas Llamas et al.
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to the better leaving group nature of the 2-pyridylsulfon-
yl group compared to the typical phenylsulfonyl group.
Investigation directed towards differentiate between
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[17] Among the various solvents examined, THFand CH 2Cl2
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ethyl ether or toluene provided very low conversions.
[7] A similar synthetic approach has been reported for the
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[8] Pd(OAc)2 turned out to be better than Pd2(dba)3 ·CHCl3.
Other silver salts such as AgNO3 or AgOAc provided
similar results, whereas i-Pr2EtN, KOAc, K2CO3 or
K3PO4 led to much lower conversions. For a discussion
on the role of Agþ in the Heck reaction, see: K. Karabe-
˜
[18] For general remarks, see: O. García Mancheno, J. Priego,
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´
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