Palladium-catalyzed direct 1,4-addition of heteroarenes to α,β-unsaturated ketones via C-H activation

Article abstract of DOI:10.1055/s-0031-1290382

Palladium-catalyzed direct conjugate additions of heteroarenes to α,β-unsaturated ketones via C-H activation are described. The reactions of heteroarenes with α,β-unsaturated ketones proceeded smoothly in the presence of PdClas a catalyst under mild conditions to give the corresponding Michael adducts in moderate to excellent yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290382

LETTER
▌1605
letter
Palladium-Catalyzed Direct 1,4-Addition of Heteroarenes to α,β-Unsaturated
Ketones via C–H Activation
Direct 1,4-Addition of Heteroarenes to α,β-Unsaturated Ketones
Xuan Zhang, Xiaoqiang Yu,* Xiujuan Feng, Ming Bao*
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, P. R. of China
Fax +86(411)84986180; E-mail: yuxiaoqiang@dlut.edu.cn; E-mail: mingbao@dlut.edu.cn
Received: 13.03.2012; Accepted after revision: 26.04.2012
product 3a was obtained in 50% yield (Table 1, entry 1).
Abstract: Palladium-catalyzed direct conjugate additions of het-
The use of Pd(acac)2, Pd(PPh3)2Cl2, and PdCl2 as Pd
eroarenes to α,β-unsaturated ketones via C–H activation are de-
source, instead of Pd(OAc)2, did not give the desired
product in high yield (45% to 53%, Table 1, entries 2–4).
scribed. The reactions of heteroarenes with α,β-unsaturated ketones
proceeded smoothly in the presence of PdCl2 as a catalyst under
mild conditions to give the corresponding Michael adducts in mod- No reaction was observed in the absence of a palladium
erate to excellent yields.
catalyst (Table 1, entry 5). The solvents were then
screened using PdCl2 as the catalyst (Table 1, entries 6–9).
Both aprotic nonpolar (toluene and CH2Cl2) and polar sol-
vents (DMF and MeCN) resulted in no reaction. Gratify-
ingly, the desired reaction proceeded smoothly in a protic
solvent methanol (MeOH) to afford product 3a in 97%
yield (Table 1, entry 10). Therefore, the subsequent reac-
tions of oxygen-, nitrogen-, and sulfur-atom-containing
five-membered heteroarenes with α,β-unsaturated ke-
tones were performed in the presence of PdCl2 as the cat-
alyst in MeOH at room temperature under a nitrogen
atmosphere.
Key words: palladium catalyst, direct conjugate addition, hetero-
arene, unsaturated ketone, C–H activation
Heteroaryl groups are frequently found in various bioac-
tive molecules and functional materials.1 The develop-
ment of a convenient and efficient method for the
synthesis of heteroaryl-group-containing compounds is
still a challenge in organic synthesis.2 Among the new
C(heteroaryl)–C(aryl or alkyl) bond-forming processes, palladi-
um-catalyzed coupling reactions via the C–H activation of
heteroarenes have recently emerged as an extremely pow-
erful tool for the synthesis of heteroarene derivatives.
These reactions include the cross-coupling reaction of
heteroarenes with aryl halides3 or pseudohalides4 and ar-
ylboronic reagents,5 the oxidative coupling between dif-
ferent heteroarenes,6 the alkenylation of heteroarenes with
alkenes,7 and the alkynylation of heteroarenes with al-
kynes.8 The palladium-catalyzed direct carbonylation of
heteroarenes via the C–H activation of heteroarenes has
also been reported recently.9 To the best of our knowl-
edge, no report on the palladium-catalyzed direct 1,4-ad-
dition of heteroarenes to α,β-unsaturated ketones via C–H
activation is currently available.10 From the mechanistic
analysis of these cross-coupling reactions, the palladium-
catalyzed direct conjugate addition of heteroarenes to α,β-
unsaturated ketones is anticipated to occur via C–H acti-
vation. Thus, the palladium-catalyzed direct 1,4-addition
of five-membered heteroarenes to α,β-unsaturated ke-
tones via C–H activation was investigated in the present
study, and the results are reported herein.
Table 1 Catalyst and Solvent Screeninga
MeO
H
MeO
S
O
1a
S
O
n-C5H11
catalyst (5 mol%)
solvent, r.t., 24 h
2a
n-C5H11
3a
Entry
Catalyst
Solvent
Yield (%)b
1
2
Pd(OAc)2
Pd(acac)2
Pd(PPh3)2Cl2
PdCl2
AcOH
AcOH
AcOH
AcOH
AcOH
toluene
CH2Cl2
DMF
50
52
3
45
4
53
5c
6
none
n.r.d
n.r.d
n.r.d
n.r.d
n.r.d
97
PdCl2
7
PdCl2
In our initial studies, the reaction of 2-methoxythiophene
(1a) with (E)-non-3-en-2-one (2a) was selected as a mod-
el reaction for optimizing the reaction conditions. The re-
sults are shown in Table 1. The reaction of 1a with 2a was
carried out under similar conditions as that employed in
the palladium-catalyzed direct arylation of heteroarenes
with aryl boronic acids reported by Shi et al.11 The desired
8
PdCl2
9
PdCl2
MeCN
MeOH
10
PdCl2
a Reaction conditions: 1a (57.1 mg, 0.5 mmol), 2a (35.1 mg, 0.25
mmol), catalyst (5 mol%), solvent (2 mL) at r.t. under a nitrogen
atmosphere.
b Isolated yield.
SYNLETT 2012, 23, 1605–1608
Advanced online publication: 13.06.2012
c Reaction mixture stirred in the absence of catalyst.
d No reaction observed; starting materials recovered.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290382; Art ID: ST-2012-W0233-L
© Georg Thieme Verlag Stuttgart · New York

1606
X. Zhang et al.
LETTER
The reactions of five-membered heteroarenes 1a–d with The reactions of 2-methylfuran (1b) with α,β-unsaturated
α,β-unsaturated ketones 2a and 2b were performed under ketones 2a and 2b proceeded smoothly to give addition
optimized reaction conditions. The results are summa- products 3c and 3d in excellent yields (98%, Table 2, en-
rized in Table 2.12 The reaction of five-membered hetero- tries 3 and 4, respectively). When furan (1c) was used as
arene 1a with α,β-unsaturated ketone (E)-4-phenylbut-3- starting material, the double-alkylated product was isolat-
en-2-one (2b) yielded 76% desired adduct 3b (Table 2, ed along with the monoalkylated product. Adducts 3e (Ta-
entry 2).
ble 2, entry 5) and 3f (Table 2, entry 6) were obtained as
Table 2 Palladium-Catalyzed Direct 1,4-Addition of Heteroarenes 1 to α,β-Unsaturated Ketones 2a
R1
O
PdCl2 (5 mol%)
X
R2
+
R1
H
O
R2
CH3OH, r.t., 24 h
X
1
2
3
Entry
1
Heteroarene 1
Ketone 2
Product 3
Yield (%)b
MeO
O
S
1a
2a
2b
3a
97
MeO
O
S
n-C5H11
n-C5H11
MeO
O
S
2
1a
3b
76
O
O
Ph
Ph
O
3
4
1b
1b
2a
2b
3c
98
98
O
n-C5H11
O
3d
O
Ph
O
O
5
6
7
8
1c
1c
1d
1d
2a
2b
2a
2b
3e
3f
67c
45d
70
O
n-C5H11
O
O
Ph
N
Me
O
3g
3h
N
Me
n-C5H11
N
Me
42e
O
Ph
a Reaction conditions: five-membered heteroarene 1 (1.0 mmol), α,β-unsaturated ketone 2 (0.5 mmol), PdCl2 (4.4 mg, 5 mol%), MeOH (2 mL)
at r.t. for 24 h under a nitrogen atmosphere.
b Isolated yield.
c Double alkylated product isolated in 15% yield.
d Double alkylated product isolated in 22% yield.
e Starting material 2b recovered in 33% yield.
Synlett 2012, 23, 1605–1608
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct 1,4-Addition of Heteroarenes to α,β-Unsaturated Ketones
1607
major products in 67% and 45% yields, respectively. The catalyzed direct conjugate addition of heteroarenes to α,β-
related double-alkylated products were isolated with 15% unsaturated ketones proceeded smoothly under mild reac-
and 22% yields, respectively (Table 2, entries 5 and 6). By tion conditions to give Michael adducts in moderate to ex-
contrast, when the N-methylated pyrrole 1-methyl-1H- cellent yields. The present study is the first to demonstrate
pyrrole (1d) was examined, a sole monoalkylated product the use of the catalytic C–H activation protocol in the di-
was obtained. Desired product 3g was isolated in 70% rect conjugate addition of heteroarenes to α,β-unsaturated
yield from the reaction of 1d with 2a (Table 2, entry 7). ketones. Further studies on the extension of the reaction
α,β-Unsaturated ketone 2b exhibited low reactivity in the scope and the asymmetric direct conjugate addition are
conjugate addition reaction with 1d, which led to the for- currently under way.
mation of monoalkylated product 3h in only 42% yield;
2b was recovered in 33% yield (Table 2, entry 8).
Acknowledgment
To confirm the presented reaction of five-membered het-
We are grateful to the National Natural Science Foundation of
eroarenes with α,β-unsaturated ketones processed via C–
China (No. 21002010) for their financial support. This work was
also supported by the Fundamental Research Funds for the Central
H activation, 1H NMR analysis of a solution of 1a in deu-
teromethanol (CD3OD), and a mixture of PdCl2, 1a, and
CD3OD were performed. The results are shown in Figure
1. A double resonance for the Ha of 1a was observed at
δ = 6.60 ppm in the 1H NMR spectrum (Figure 1, A). As
expected, the resonance peak of Ha reduced with increas-
ing PdCl2 amount. The 1H NMR spectrum of 1a was de-
Universities [DUT10RC(3)28].
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
termined in the presence of 0.5 equivalents of PdCl2. At References
the same time, the resonance peak of Ha was reduced to
half (Figure 1, B), compared with that in the H NMR
(1) For selected reviews, see: (a) Henry, G. D. Tetrahedron
2004, 60, 6043. (b) Michael, J. P. Nat. Prod. Rep. 2005, 22,
627. (c) Hamada, Y.; Shioiri, T. Chem. Rev. 2005, 105,
4441. (d) Miyashita, K.; Imanishi, T. Chem. Rev. 2005, 105,
4515. (e) Gaumont, A.-C.; Gulea, M.; Levillain, J. Chem.
Rev. 2009, 109, 1371. (f) Pedersen, D. S.; Abell, A. Eur. J.
Org. Chem. 2011, 2399. For selected examples, see:
1
(Figure 1, A). Furthermore, the resonance peak of Ha al-
most disappeared, when 1a was treated with one equiva-
lent of PdCl2 in CD3OD (Figure 1, C). The reaction of
heteroarene 1a with PdCl2 is believed to form a new pal-
ladium species 4 (Scheme 1), which could undergo a 1,4-
addition reaction with a α,β-unsaturated ketone.13
(g) Helms, B.; Mynar, J. L.; Hawker, C. J.; Frechet, J. M. J.
J. Am. Chem. Soc. 2004, 126, 15020. (h) Moorhouse, A. D.;
Santos, A. M.; Gunaratnam, M.; Moore, M.; Neidle, S.;
Moses, J. E. J. Am. Chem. Soc. 2006, 128, 15972. (i) De S,
K.; Stebbins, J. L.; Chen, L.-H.; Riel-Mehan, M.; Machleidt,
T.; Dahl, R.; Yuan, H.; Emdadi, A.; Barile, E.; Chen, V.;
Murphy, R.; Pellecchia, M. J. Med. Chem. 2009, 52, 1943.
(j) Pedersen, D. S.; Abell, A. Eur. J. Org. Chem. 2011, 2399.
(2) For recent reviews on heterocyclic synthesis, see:
(a) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev.
2004, 104, 3341. (b) Coldham, I.; Hufton, R. Chem. Rev.
2005, 105, 2765. (c) Singh, G. S.; D’hooghe, M.; De Kimpe,
N. Chem. Rev. 2007, 107, 2080. (d) Patil, N. T.; Yamamoto,
Y. Chem. Rev. 2008, 108, 3395; and references cited
therein. (e) Gaumont, A.-C.; Gulea, M.; Levillain, J. Chem.
Rev. 2009, 109, 1371. (f) Godoi, B.; Schumacher, R. F.;
Zeni, G. Chem. Rev. 2011, 111, 2937; and references cited
therein. (g) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111,
PR215; and references cited therein.
(3) For selected reviews, see: (a) Seregin, I. V.; Gevorgyan, V.
Chem. Soc. Rev. 2007, 36, 1173. (b) Joucla, L.; Djakovitch,
L. Adv. Synth. Catal. 2009, 351, 673. (c) Bellina, F.; Rossi,
R. Tetrahedron 2009, 65, 10269. For selected examples, see:
(d) Lebrasseur, N.; Larrosa, L. J. Am. Chem. Soc. 2008, 130,
2926. (e) Martin, T.; Verrier, C.; Hoarau, C.; Marsais, F.
Org. Lett. 2008, 10, 2909. (f) Wasa, M.; Worrell, B. T.; Yu,
J.-Q. Angew. Chem. Int. Ed. 2010, 49, 1275. (g) Guo, P. F.;
Joo, J. M.; Rakshit, S.; Sames, D. J. Am. Chem. Soc. 2011,
133, 16338; and references cited therein . (h) Duric, S.;
Tzschucke, C. C. Org. Lett. 2011, 13, 2310. (i) Ackermann,
L.; Punji, B.; Song, W. Adv. Synth. Catal. 2011, 353, 3325.
(j) Zhang, G.; Zhao, X.; Yan, Y.; Ding, C. Eur. J. Org.
Chem. 2012, 669. (k) Carrier, A.; Brinet, D.; Florent, J.-C.;
Rousselle, P.; Bertounesque, E. J. Org. Chem. 2012, 77,
Figure 1 1H NMR spectra obtained in deuteromethanol (CD3OD).
A: 1a; B: 1a + PdCl2 (0.5 equiv); C: 1a + PdCl2 (1.0 equiv).
CD3OD
PdCl2
+
+ HCl
H
MeO
PdCl
MeO
r.t.
S
S
1a
4
Scheme 1
In summary, a convenient and efficient method for the
synthesis of heteroaryl-group-containing compounds via
the palladium-catalyzed C–H activation of heteroarenes
has been developed in the present study. The palladium-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1605–1608

1608
X. Zhang et al.
LETTER
1316. (l) Bheeter, C. B.; Beza, J. K.; Doucet, H. Tetrahedron
2012, 53, 509.
(11) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi,
Z.-J. Angew. Chem. Int. Ed. 2008, 47, 1473.
(4) For a review, see: (a) Ref. 3c. For selected examples, see:
(b) Ackermann, L.; Barfüsser, S.; Pospech, J. Org. Lett.
2010, 12, 724; and references cited therein. (c) Strotman,
N. A.; Chobanian, H. R.; Guo, Y.; He, J.; Wilson, J. E. Org.
Lett. 2010, 12, 3578. (d) Ackermann, L.; Fenner, S. Chem.
Commun. 2011, 47, 430. (e) Zhang, M. L.; Zhang, S. H.; Liu,
M. C.; Cheng, J. Chem. Commun. 2011, 47, 11522; and
references cited therein.
(12) General Procedure
To a mixture of PdCl2 (0.025 mol, 4.4 mg), α,β-unsaturated
ketone 2 (0.5 mmol), and MeOH (2.0 mL), heteroarene 1
(1.0 mmol, 2.0 equiv) was added. After the resultant mixture
was stirred at r.t. for 24 h, the solvent was removed under
vacuum. The residue was purified by flash chromatography
on silica gel (eluent: PE–EtOAc = 10:1 to 20:1, v/v) to afford
the desired product 3.
(5) For a review, see: (a) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
Commun. 2010, 46, 677; and references cited therein. For
selected examples, see: (b) Zhao, J. L.; Zhang, Y. H.; Cheng,
K. J. Org. Chem. 2008, 73, 7428. (c) Schnapperelle, I.;
Breitenlechner, S.; Bach, T. Org. Lett. 2011, 13, 3640.
(d) Kirchberg, S.; Tani, S.; Ueda, K.; Yamaguchi, J.; Studer,
A.; Itami, K. Angew. Chem. Int. Ed. 2011, 50, 2387.
(6) For several reviews, see: (a) You, S.-L.; Xia, J.-B. Top.
Curr. Chem. 2010, 292, 165. (b) Cho, S. H.; Kim, J. Y.;
Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. For
selected examples, see: (c) Potavathri, S.; Dumas, A. S.;
Dwight, T. A.; Naumiec, G. R.; Hammann, J. M.; DeBoef,
B. Tetrahedron Lett. 2008, 49, 4050; and references cited
therein. (d) Wang, Z.; Li, K. Z.; Zhao, D. B.; Lan, J. B.; You,
J. S. Angew. Chem. Int. Ed. 2011, 50, 5365; and references
cited therein . (e) Gong, X.; Song, G. Y.; Zhang, H.; Li, X.
W. Org. Lett. 2011, 13, 1766.
(7) For selected reviews, see: (a) Rossi, R.; Bellina, F.; Lessi, M.
Synthesis 2010, 4131. For selected examples, see: (b) Kong,
A. D.; Han, X. L.; Lu, X. Y. Org. Lett. 2006, 8, 1339. (c) Wu,
J. L.; Cui, X. L.; Chen, L. M.; Jiang, G. J.; Wu, Y. J. J. Am.
Chem. Soc. 2009, 131, 13888; and references cited therein.
(d) García-Rubia, A.; Arrayás, R. G.; Carretero, J. C. Angew.
Chem. Int. Ed. 2009, 48, 6511; and references cited therein.
(e) Aouf, C.; Thiery, E.; Bras, J. L.; Muzart, J. Org. Lett.
2009, 11, 4096.
4-(5-Methoxythiophen-2-yl)-4-phenylbutan-2-one (3b)
Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.19–7.31
(m, 5 H), 6.37 (d, J = 3.8 Hz, 1 H), 5.94 (d, J = 3.8 Hz, 1 H),
4.62 (t, J = 7.4 Hz, 1 H), 3.80 (s, 3 H), 3.18 (dd, J = 16.6, 7.5
Hz, 1 H), 3.07 (dd, J = 16.6, 7.3 Hz, 1 H), 2.10 (s, 3 H). 13
NMR (100 MHz, CDCl3): δ = 206.4, 165.1, 143.4, 134.0,
C
128.7, 127.6, 126.9, 121.2, 102.8, 60.2, 50.6, 42.0, 30.7. IR
(neat): 3413, 3026, 2925, 1715, 1559, 1505, 1451, 1430,
1355, 1203, 1153, 990, 762, 698 cm–1. HRMS (EI): m/z calcd
for C15H16O2S [M]+: 260.0871; found: 260.0876.
4-(Furan-2-yl)nonan-2-one (3e)
Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.28 (dd, J =
1.8, 0.8 Hz, 1 H), 6.25 (dd, J = 3.1, 1.9 Hz, 1 H), 5.98 (dd,
J = 3.2, 0.8 Hz, 1 H), 3.22–3.30 (m, 1 H), 2.78 (dd, J = 16.3,
7.6 Hz, 1 H), 2.63 (dd, J = 16.3, 6.6 Hz, 1 H), 2.07 (s, 3 H),
1.49–1.66 (m, 2 H), 1.21–1.26 (m, 6 H), 0.85 (t, J = 6.8 Hz,
3 H). 13C NMR (100 MHz, CDCl3): δ = 207.6, 157.5, 140.9,
110.0, 105.1, 48.0, 34.5, 34.0, 31.6, 30.3, 26.8, 22.5, 14.0. IR
(neat): 2956, 2929, 2858, 1719, 1360, 1159, 1148, 1010, 729
cm–1. ESI-HRMS: m/z calcd for C13H20O2 [M + Na]+:
231.1361; found: 231.1364.
4-(1-Methyl-1H-pyrrol-2-yl)nonan-2-one (3g)
Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 6.45 (t, J =
1.8, 1.9 Hz, 1 H), 6.04 (t, J = 3.1, 3.0 Hz, 1 H), 5.84 (dd, J =
3.2, 1.8 Hz, 1 H), 3.57 (s, 3 H), 3.19–3.26 (m, 1 H), 2.74 (dd,
J = 16.7, 7.5 Hz, 1 H), 2.65 (dd, J = 16.6, 6.5 Hz, 1 H), 2.04
(s, 3 H), 1.50–1.56 (m, 2 H), 1.19–1.26 (m, 6 H), 0.84 (t, J =
6.5 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 208.3, 136.7,
120.9, 106.8, 104.1, 50.2, 36.6, 33.9, 32.0, 31.8, 31.0, 27.1,
22.7, 14.2. IR (neat): 2954, 2927, 2856, 1716, 1489, 1359,
1299, 1162, 702 cm–1. ESI-HRMS: m/z calcd for C14H23NO
[M + Na]+: 244.1677; found: 244.1684.
(8) Kim, S. H.; Yoon, J. Org. Lett. 2011, 13, 1474; and
references cited therein.
(9) Zhang, H.; Liu, D.; Chen, C. Y.; Liu, C.; Lei, A. W. Chem.–
Eur. J. 2011, 17, 9581; and references cited therein.
(10) Au(III)-promoted addition reactions of heteroarenes to enals
have been reported. See: (a) Nair, V.; Vidya, N.; Abhilash,
K. G. Synthesis 2006, 3647. (b) Nair, V.; Vidya, N.;
Abhilash, K. G. Tetrahedron Lett. 2006, 47, 2871.
(13) (a) Lu, X. Y.; Lin, S. H. J. Org. Chem. 2005, 70, 9651.
(b) Lerebours, R.; Wolf, C. Org. Lett. 2007, 9, 2737. (c) Lin,
S. H.; Lu, X. Y. Org. Lett. 2010, 12, 253.
Synlett 2012, 23, 1605–1608
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.