Regioselective 1,6-conjugate addition of boronic acids and grignard reagents to dienylpyridines

Article abstract of DOI:10.1055/s-0030-1261183

Functionalization of the lateral chain of dienylpyridines was achieved by the regioselective 1,6-addition of boronic acids catalyzed by rhodium(I) or Grignard reagents under iron(II) catalysis. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261183

2234
LETTER
Regioselective 1,6-Conjugate Addition of Boronic Acids and Grignard
Reagents to Dienylpyridines
R
egioselective
i
1,6-C
l
v
e
A
ddition to
i
Dieny
a
lpyridines Roscales, Irene G. Salado, Aurelio G. Csákÿ*
Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3945030; E-mail: csaky@quim.ucm.es
Received 13 May 2011
R2M
H+
R2
R2
Abstract: Functionalization of the lateral chain of dienylpyridines
was achieved by the regioselective 1,6-addition of boronic acids
catalyzed by rhodium(I) or Grignard reagents under iron(II) cataly-
sis.
N
R1
N
R1
N
R1
M
conjugate addition to vinylpyridines
Key words: addition, catalysis, pyridines, rhodium, iron
R2
N
R1
The conjugate addition reaction of carbon nucleophiles to
electron-deficient alkenes has become one of the most im-
portant C–C bond-forming reactions in organic synthesis.
The most common functional groups used to activate al-
kenes toward conjugate addition include carbonyl groups,
nitriles, sulfones, phosphonates, and nitro groups. How-
ever, other less common groups such as electron-deficient
aromatic heterocycles have also been reported as activat-
ing groups for alkenes enabling the reaction with carbon
nucleophiles.1–3 Aromatic heterocyclic compounds are
present in numerous biologically active natural products,
agrochemicals, pharmaceuticals, and functional mole-
cules. Therefore, new methods for the functionalization of
this type of compounds are highly important.
i) R2M
ii) H+
2
1,4-adducts
N
R1
R2
1
N
R1
3
conjugate addition to dienylpyridines
1,6-adducts
Scheme 1
On the basis of previous reports on the addition of boronic
acids to vinylpyridines and reactions of dienoic esters and
ketones catalyzed by rhodium(I) in aqueous solvents,2 at
the onset of our study we considered the reaction of
boronic acids with 2-(1,3-butadienyl)pyridine (1a). The
results are gathered in Table 1. After testing several cata-
lytic systems and reaction conditions,6 we found that reac-
tion was successful when using [(cod)RhCl]2 (2 mol%) as
catalyst in the presence of the water-soluble bis(p-sul-
fonatophenyl)phenylphosphine dihydrate dipotassium
salt (TPDS, 8 mol%) and using Na2CO3 (2.0 equiv) as
base in water together with sodium dodecylsulfate (SDS,
0.5 equiv) at 80 °C.
In comparison with other heterocycles, pyridine rings
have been reported as particularly challenging substrates
for the activation of conjugate additions, as there is a con-
siderable loss in aromaticity upon formation of the reac-
tion intermediate. Also, this type of reaction has been
found difficult in b-substituted compounds due to steric
reasons.3
In comparison with alkenes, the addition to dienes has
been much less considered in the literature4 and consti-
tutes a topic of current synthetic interest. These types of
reactions are complicated by the multiple electrophilic
sites of electron-deficient dienes, which may lead to 1,6-
or 1,4-addition modes together with direct addition to the
activating functional group.
Table 1 Rhodium(I)-Catalyzed Additions of R2B(OH)2 to 1a,b
R2B(OH)2
[(cod)RhCl]2
(2 mol%)
R2
TPDS (8 mol%)
N
R1
N
R1
Na2CO3
(2.0 equiv)
H2O
SDS (0.5 equiv)
80 °C, 18 h
Despite success in the additions of carbon nucleophiles to
alkenyl heterocycles, the possibility of functionalizing di-
enyl heterocycles by nucleophilic addition has received
no attention. We report herein our findings in the regio-
selective additions of arylboronic acids and Grignard
reagents to dienylpyridines5 (Scheme 1).
1
2
Entry
1
R1
H
R2
Yield of 2 (%, E/Z ratio)
2a 75 (60:40)
2b 70 (60:40)
2c 65 (60:40)
–
1
2
3
4
1a
1a
1a
1b
Ph
H
4-MeOC6H4
4-F3CC6H4
Ph
H
SYNLETT 2011, No. 15, pp 2234–2236
x
x
.x
x
.2
0
1
1
Advanced online publication: 12.08.2011
DOI: 10.1055/s-0030-1261183; Art ID: D14611ST
Me
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective 1,6-Conjugate Addition to Dienylpyridines
2235
Under these reaction conditions the reaction of 1a was pounds were obtained as mixtures of the corresponding
achieved for phenylboronic acid (Table 1, entry 1) and ei- E- and Z-isomers.
ther for boronic acids with electron-releasing (Table 1,
In conclusion, we have developed a new method which
entry 2) or electron-withdrawing substituents (Table 1,
permits the functionalization of the lateral chain of di-
entry 3). The 1,6-conjugate addition product was obtained
enylpyridines, which could be of use in the synthesis of
as the only adduct, with no traces of the 1,4-adduct. How-
new heterocycles.
ever, the reaction failed for d-substituted systems as ex-
emplified for 1b (Table 1, entry 4).
Acknowledgment
In the search for a more reactive catalytic system, we
Projects CTQ2010-16170 from the Spanish government and GR35/
10-A from UCM are gratefully acknowledged for financial support.
found that these types of reactions could be carried out in
a general fashion using Grignard reagents under iron(II)
catalysis (Table 2).7,8 Thus, electron-donating or electron-
withdrawing groups were tolerated in the aryl moiety of
the Grignard reagent, as well as steric hindrance in ortho
position.9
References and Notes
(1) See, for example: (a) Hoffman, A.; Farlow, M. W.; Fuson,
R. C. J. Am. Chem. Soc. 1933, 55, 2000. (b) Gilman, H.;
Gainer, G. C. J. Am. Chem. Soc. 1949, 71, 2327.
(c) Mathis, C.; Hogen-Esch, T. E. J. Am. Chem. Soc. 1982,
104, 634. (d) Dryanska, V.; Ivanov, C. Synthesis 1983, 143.
(e) Houpis, I. N.; Lee, J.; Dorziotis, I.; Molina, A.; Reamer,
B.; Volante, R. P.; Reider, P. J. Tetrahedron 1998, 54, 1185.
(f) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. Tetrahedron 1988, 44, 2021. (g) Clariana, J.;
Gálvez, N.; Marchi, C.; Moreno-Mañas, M.; Vallribera, A.;
Molins, E. Tetrahedron 1999, 55, 7331. (h) Baschieri, A.;
Bernardi, L.; Ricci, A.; Suresh, S.; Adamo, M. F. A. Angew.
Chem. Int. Ed. 2009, 48, 9342. (i) Mineyama, K.;
Maekawa, H.; Kohsaka, A.; Yamamoto, Y.; Nishiguchi, I.
Tetrahedron 2009, 65, 7706. (j) Sun, H.-W.; Liao, Y.-H.;
Wu, Z.-J.; Wang, H.-Y.; Zhang, X.-M.; Yuan, W.-C.
Tetrahedron 2011, 67, 3991.
Table 2 Iron(II)-Catalyzed Additions of R2MgBr to 1
R2MgBr
FeCl2 (10 mol%)
R2
0 °C, 10 min
r.t., 60 min
N
R1
N
R1
R3
R3
1
2
Entry 1
R1
H
R2
Ph
R3
H
Yield of 2 (%, E/Z ratio)
2a 80 (60:40)
2b 75 (65:35)
2c 60 (50:50)
2d 60 (60:40)
2e 80 (60:40)
2f 70 (75:35)
2g 70 (80:20)
2h 65 (60:40)
2i 65 (50:50)
2j 60 (50:50)
2k 75 (60:40)
2l 80 (50:50)
2m 80 (0:100)
2n 65 (0:100)
1
2
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1d
1d
1e
1e
H
4-MeOC6H4
4-FC6H4
H
3
H
H
(2) (a) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-
4
H
2-MeOC6H4
Ph
H
Matute, B. J. Am. Chem. Soc. 2001, 123, 5358.
(b) Amengual, R.; Michelet, V.; Genêt, J.-P. Tetrahedron
Lett. 2002, 43, 5905.
5
Me
Me
Me
Me
Ph
Ph
i-Pr
i-Pr
Et
H
(3) (a) Pattison, G.; Piraux, G.; Lam, H. W. J. Am. Chem. Soc.
2010, 132, 14373. (b) Kobayashi, T.; Yorimitsu, H.;
Oshima, K. Chem. Asian J. 2010, 6, 669.
6
4-MeOC6H4
4-FC6H4
H
7
H
(4) Csákÿ, A. G.; de la Herrán, G.; Murcia, M. C. Chem. Soc.
8
2-MeOC6H4
4-MeOC6H4
4-FC6H4
H
Rev. 2010, 39, 4080.
(5) For the synthesis of starting materials (1) from 2-methyl-
pyridine, see: Braun, M.; Mroß, S.; Schwarz, I. Synthesis
1998, 83.
9
H
10
11
12
13
14
H
(6) Recovery of starting material was observed when treating 1a
with PhB(OH)2 using [Rh(cod)]2BF4 or [Rh(cod)Cl]2 as
catalysts (5 mol%) in the presence of Ba(OH)2, K3PO4, or
KOH (1.0 equiv) at 50 °C in dioxane–H2O (4:1) for 18 h.
(7) (a) Fukuhara, K.; Urabe, H. Tetrahedron Lett. 2005, 46,
603. (b) Okada, S.; Arayama, K.; Murayama, R.; Ishizuka,
T.; Hara, K.; Hirone, N.; Hata, T.; Urabe, H. Angew. Chem.
Int. Ed. 2008, 47, 6860.
4-MeOC6H4
4-FC6H4
H
H
4-MeOC6H4
4-FC6H4
Me
Me
Et
(8) Recovery of starting material was observed when treating 1a
with PhMgBr in THF in the presence of CuI (10 mol%) or in
the absence of catalyst at r.t. for 18 h.
(9) Typical Procedure for the Addition of Grignard
Reagents to Dienylpyridines (1)
Substitution of the diene moiety at d-position was possible
(Table 2, entries 5–12), and even simultaneous substitu-
tion at d- and g-positions was tolerated (Table 2, entries
14 and 15). In all cases the 1,6-adducts were obtained ex-
clusively even in the presence of bulky phenyl or isopro-
pyl groups at d-position. No conjugation of the newly
generated C=C bond of the lateral chain with the pyridine
ring was observed. With the exception of 2m,n, which
were obtained as a single Z-isomer,10 the rest of com-
Synthesis of (Z)-2-[4-(p-Methoxyphenyl)-3-methylhex-2-
enyl]pyridine (2m)
To a stirred solution of 1e (86.6 mg, 0.5 mmol) and FeCl2
(6.4 mg, 0.05 mmol) in anhyd THF (3.5 mL) under Ar was
added p-methoxyphenylmagnesium bromide (1.0 M in THF,
0.9 mmol, 0.9 mL) at 0 °C. The solution was stirred at 0 °C
for 15 min and at r.t. for 1 h. The reaction was terminated by
Synlett 2011, No. 15, 2234–2236 © Thieme Stuttgart · New York

2236
S. Roscales et al.
LETTER
the addition of a sat. NH4Cl aq solution (5 mL). The organic
products were extracted with Et2O (3 × 5 mL). The
3 H), 3.78 (s, 3 H), 1.66–1.96 (m, 2 H), 1.54 (d, J = 1.0 Hz,
3 H), 0.90 (t, J = 7.3 Hz, 3 H). 13C NMR (75 MHz, CDCl3):
d = 12.4, 18.9, 24.2, 36.9, 46.2, 55.3, 113.7 (2 C), 121.2,
122.7, 123.0, 128.7 (2 C), 135.8, 136.6, 139.7, 149.4, 157.9,
161.5.
combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The crude product was
chromatographed on silica gel (hexane–EtOAc = 8:2). 1H
NMR (300 MHz, CDCl3): d = 8.55 (d, J = 4.7 Hz, 1 H), 7.60
(td, J = 7.7, 1.8 Hz, 1 H), 7.07–7.22 (m, 4 H), 6.82 (dt,
J = 8.7, 2.1 Hz, 2 H), 5.55 (t, J = 7.1 Hz, 1 H), 3.72–3.90 (m,
(10) Determined by NOE measurement upon irradiation of the
vinyl-H signal.
Synlett 2011, No. 15, 2234–2236 © Thieme Stuttgart · New York

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