Activator-free and one-pot C-allylation by simple palladium catalyst in water

Article abstract of DOI:10.1016/j.tetlet.2012.01.022

For atom economic and green chemistry concepts, we develop a reaction that involves one-pot and one step to construct the C-C bond without the help of any activating reagents for allylic alcohols in water. The palladium-catalyzed allylation of cyclic 1,3-

Full text of DOI:10.1016/j.tetlet.2012.01.022

Tetrahedron Letters 53 (2012) 1380–1384
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Tetrahedron Letters
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Activator-free and one-pot C-allylation by simple palladium catalyst in water
⇑
Yi-Jen Shue, Shyh-Chyun Yang
School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
For atom economic and green chemistry concepts, we develop a reaction that involves one-pot and one
step to construct the C–C bond without the help of any activating reagents for allylic alcohols in water.
The palladium-catalyzed allylation of cyclic 1,3-diones using allylic alcohols directly gave the corre-
sponding allylated products in 8–99% yields.
Received 17 November 2011
Revised 26 December 2011
Accepted 5 January 2012
Available online 13 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Activator-free
Allylic alcohols
Palladium
Water
Cyclic 1,3-diones
Allylic substitution is a fundamental transformation in organic
synthesis and also is one of the most powerful tools for the forma-
tion of carbon–carbon and carbon–heteroatom bonds.1 Transition-
metal-mediated C- and N-allylation reactions are very constructive
for further investigating because of their broad substrate scope. For
instance, Tsuji–Trost reaction has served as a pivotal reaction to
To determine the optimal reaction conditions, the palladium-
catalyzed allylation of 1,3-cyclohexadione (1a) with cinnamyl alco-
hol (2a) was investigated under various conditions. Initially, using
Pd(acac)2 instead of Pd(OAc)2 under the same conditions gave
nearly the same total yields (entry 1 in Table 1). The yields were
increased when we prolonged the reaction time to 30 min (entry
2). Providing increasing the 2a stoichiometry to 1.2 mmol in
conjunction with Pd(acac)2 (0.05 mmol) and PPh3 (0.2 mmol) in
water (5 mL) refluxed for 30 min, it gave excellent yields of prod-
ucts 3a and 4a to 56% and 40%, respectively (entry 3). However,
it was observed that lower reaction temperature would decrease
the yield of the products (entry 4). The reaction did not occur in
the absence of the palladium species (entry 5), phosphine ligand
(entry 6), or water (entry 7). The effect of water may activate allyl
alcohol via hydration of the hydroxy group and stabilize the result-
ing hydroxide ion by strong solvation with water. In water, the
hydroxide ion can leave with hydrating water molecules and the
negative charge can be delocalized in the water cluster.7b As ex-
pected, increasing the relative amount of cinnamyl alcohol would
favor the formation of the desired diallylated product 4a (entry
8). Using MeOH as solvent gave only moderate yields of products
(entry 9). Then, all of Pd reagents in our lab were investigated (en-
tries 3 and 10–16). However, using Pd(0) complex Pd2(dba)3 with
extra PPh3 as catalyst has increased the yield of products (entries
16). PdCl2(PhCN)2 was employed as the palladium source, and a
screening of monodentate (entries 17–22) and bidentate phos-
phine ligands (entries 23–25) was undertaken.
construct C–C bonds by using a (p-allyl)metal intermediate in this
regard.2 Palladium-catalyzed conversion of allylic alcohols directly
into allylation products are highly beneficial, especially from the
standpoint of the atom economy.3 We have reported our attempts
and some successful applications of a process involving the C–O
bond cleavage by palladium complexes in the presence of Ti(OPri)4
in benzene.4 Due to inherent low aptitude of the hydroxy group,
the precedent protocols require stoichiometric or catalytic activa-
tors for allyl alcohols.3b,5 Recently, more and more particular cata-
lysts or ligands have been developed for enabling such conversion
without the aid of activators.3a,5g,6 Furthermore, water has become
as a highly recommended solvent for organic reactions in terms of
cost, safety, availability, and environmental concerns.7 We have
recently disclosed a new catalytic system for palladium/carboxylic
acid-catalyzed allylation of cyclic 1,3-diones with allylic alcohols
using water as the solvent.7a However, it gave only moderate yields
of products without the presence of carboxylic acid as an activator.
Oshima’s report provided an incentive for further studies of reac-
tions under ‘no-activator’ condition.8 In this Letter, we display a
reaction which was taken place in distilled water without any
other activators involved.
To explore the scope of this novel system, allylation of a series
of cyclic 1,3-diones (1b–h) with cinnamyl alcohol (2a) using
PdCl2(PhCN)2 and PPh3 in water is summarized in Table 2. Dime-
done (1b) has been extensively used as precursors of potential
⇑
Corresponding author. Tel.: +886 7 3121101; fax: +886 7 3210683.
E-mail address: scyang@kmu.edu.tw (S.-C. Yang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.022

Y.-J. Shue, S.-C. Yang / Tetrahedron Letters 53 (2012) 1380–1384
1381
antidiabetic drugs9 and tyrosinase inhibitor,10 and it would under-
go mono- and di-allylation while providing excellent yields of
products 3b and 4b in 55% and 44%, respectively (entry 1). When
the relative amount of 2a was increased, the selective diallylation
product 4b could be obtained in a 95% yield (entry 2). Based on our
observation, there were given only diallylated products when the
ring contained heteroatoms. Such as 1,3-dioxane-4,6-dione 1c, fur-
an-2,4-dione 1d, and pyrimidine-2,4,6-trione 1e. Compound 1c,
the core of phospholipase A2 inhibitors,11 it gave product 4c in a
77% yield (entry 3), and compound 1d afforded moderate yields
of 4d (entry 4), and 1e, a novel chemical scaffold for amyotrophic
lateral sclerosis (ALS),12 also gave only diallylated product 4e in
high yields (entry 5). The approach of ‘no activator’ is more selec-
tive than previous report,7a especially for compound 1e. Then, we
chose the coumarin derivatives to treat this reaction because of
their anticoagulantic, spasmolytic, antifungal, and anti-HIV activi-
ties.13 4-Hydroxycoumarin (1f) gave monoallylated products 3f
and 5 in 55% and 30% yields, respectively (entry 6). Compound 5
may be produced via diallylated product 4f, which was hydrolyzed
and then decarboxylated to compound 5.7a 6-Chloro-4-hydroxy-
coumarin (1g) reacted as 1f, affording the corresponding products
3g and 6 in 49% and 39% yields, respectively (entry 7). The solubil-
ity of the cyclic 1,3-diones 1d–h can be problematic. It can be alle-
viated by using a 2:3 methanol/H2O mixture as the solvent (entries
4–8). 2,4-Quinolinediol (1h) gave the desired products in rare
yields, but using (3-MeC6H4)3P instead of PPh3 as ligand would
give moderate results (entry 8). Compound 1h is a major core of
the anti-HCV reagent.13,14
Table 1
Allylation of 1,3-cyclohexadione (1a) with cinnamyl alcohol (2a)a
Ph
Ph
Ph
O
HO
Ph
HO
O
2a
HO
O
+
O
Pd, P-ligand
H2O
1a
3a
4a
Entry
Palladium
Ligand
Yieldb (%) (3a:4a)
1c,d
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
—
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(OAc)2
PdCl2(1,10-phen)
PdCl2(MeCN)2
PdCl2(PhCN)2
Pd(propionate)2
Pd2(dba)3
PPh3
PPh3
PPh3
PPh3
PPh3
—
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
—
63 (11:89)
74 (95:5)
96 (58:42)
56 (16:84)
0
2c
3
4e
5
6
0
0
7f
8g
9h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
99 (5:95)
55 (58:42)
68 (24:76)
95 (17:83)
90 (26:74)
99 (41:59)
90 (38:62)
14 (0:100)
89 (8:92)
97 (38:62)
85 (9:91)
99 (28:72)
91 (40:60)
90 (41:59)
95 (18:82)
0
Pd2(dba)3
PPh3
(2-furyl)3P
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
(2-pyridyl)Ph2P
(3-MeC6H4)3P
(4-MeC6H4)3P
(4-MeOC6H4)3P
(4-FC6H4)3P
Dpppi
Dppbj
98 (41:59)
84 (71:29)
Dpphk
The results for allylation of 1,3-cyclohexadione (1a) with both
aromatic and aliphatic alcohols 2b–j in the presence of a catalytic
amount of PdCl2(PhCN)2 associated with (3-MeC6H4)3P in water
are summarized in Table 3. In addition to the parent cinnamyl alco-
hol (2a), the regioisomer 2b also reacted to give the same products
3a and 4a in excellent yields of 51% and 48%, respectively (entry 1).
(E)-2-Methyl-3-phenylprop-2-en-1-ol (2c) reacted to give the
allylating product 7 in moderate yields (entry 2). Allylation of
1,3-cyclohexadione (1a) worked well with cinnamyl alcohols con-
taining electron donating groups, giving generally high yields of
the corresponding allylic products. (E)-3-(4-Methoxyphenyl)prop-
a
Reaction conditions: 1a (1 mmol), 2a (1.2 mmol), Pd catalyst (0.05 mmol), and
ligand (0.2 mmol) in water (5 mL) were refluxed for 30 min.
b
Isolated yield.
Compound 2a (0.8 mmol) was used.
Reflux for 15 min.
Stirred at 70 °C.
Without water.
Compound 2a (2 mmol) was used.
Using MeOH as solvent.
1,3-Bis(diphenylphosphino)propane.
c
d
e
f
g
h
i
j
1,4-Bis(diphenylphosphino)butane.
1,6-Bis(diphenylphosphino)hexane.
k
Table 2
Allylation of cyclic 1,3-diones (1b-h) with cinnamyl alcohol (2a)a
Entry
1
1
h
Product
Yieldsb (%)
55
O
O
OH
Ph
Ph
1b
0.5
3b
4b
O
Ph
O
44
O
2c
3
1b
1c
0.5
1
4b
4c
95
77
O
O
O
O
O
Ph
O
O
O
O
Ph
Ph
OH
O
4d
1d
2
4d
53
84
O
O
O
O
O
O
Ph
O
Ph
Ph
HN
HN
5d
6d
1e
1f
2
2
4e
3f
HN NH
O
O
OH
OH
Ph
55
O
O
O
O
(continued on next page)

1382
Y.-J. Shue, S.-C. Yang / Tetrahedron Letters 53 (2012) 1380–1384
Table 2 (continued)
Entry
1
h
Product
Yieldsb (%)
Ph
O
4f
Not obtained
Ph
O
O
O
Ph
5
30
OH
Ph
OH
O
OH
Cl
Cl
7d
1g
2
3g
4g
49
Ph
O
O
O
Ph
O
Not obtained
Cl
Cl
Ph
O
O
O
Ph
6
39
23
OH
Ph
OH
OH
Ph
8d,e
1h
2
3h
N
H
O
N
H
O
Ph
O
4h
37
Ph
N
H
O
a
Reaction conditions: 1 (1 mmol), 2a (1.2 mmol), PdCl2(PhCN)2 (0.05 mmol), and PPh3 (0.2 mmol) were refluxed in water (5 mL).
Isolated yields.
Compound 2a (2 mmol) was used.
Water (3 mL) and MeOH (2 mL) were used.
Ligand (3-MeC6H4)3P (0.2 mmol) was used.
b
c
d
e
Table 3
Reaction of 1,3-cyclohexadione (1a) with allylic alcohols 2a
Entry
2
h
Product
Yieldsb (%)
1
2b
1
3a
4a
51
48
OH
O
OH
2
3
2c
2
7
8
47
56
OH
O
OH
H3CO
2d
0.5
OH
OCH3
OCH3
O
OCH3
9
37
23
74
O
O
OCH3
OH
OCH3
4
2e
0.5
10
11
OH
H3CO
O
O
OCH3
OH
5
2f
24
—
O2N

Y.-J. Shue, S.-C. Yang / Tetrahedron Letters 53 (2012) 1380–1384
1383
Table 3 (continued)
Entry
2
h
Product
Yieldsb (%)
O2N
OH
NO2
O
6
2g
15
12
53
O
NO2
OH
7
8
2h
2i
2
2
2
13
14
15
42
40
O
OH
OH
O
O
OH
OH
9
2j
8(E/Z = 80/20)c
OH
a
Reaction conditions: 1 (1 mmol), 2a (1.2 mmol), PdCl2(PhCN)2 (0.05 mmol), and (3-MeC6H4)3P (0.2 mmol) were refluxed in water (5 mL).
Isolated yields.
Determined by GC.
b
c
H
O
δ-
R
OH
H
L
δ-
its simplicity in operation, economical, and environmentally
advantages, air-stable, and economical viable. The alkylation of
aromatic allylic alcohol worked well with cyclic 1,3-diones, giving
generally good to high yields of the corresponding allylic 1,3-
diones. However, the results of acyclic diketones such as acetylace-
tone were unsatisfied. Further investigations on other applications
are in progress.
R
2
O
(H2O)x
R
+
(H2O)x
Pd
Pd0Ln
H2O
Pd
L
A
L
L
B
R
O
R
L
L
PdII
H2O
O
O
O
[OH(H2O)x]-
C
Acknowledgments
1
This work was supported by a Grant from the National Science
Council of Republic of China (NSC98-2119-M-037-001-MY3). Chyi-
Jia Wang and Min-Yuan Hung are thanked for analytic support.
Scheme 1. Proposed mechanism of the allylation of cyclic 1,3-diones 1 with allylic
alcohols 2.
Supplementary data
Supplementary data (experimental procedures and data for
products) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2012.01.022.
2-en-1-ol (2d) gave mono- and diallylated products 8 and 9 in the
yields of 56% and 37%, respectively (entry 3). (E)-3-(2-Methoxy-
phenyl)prop-2-en-1-ol (2e) also gave the corresponding products
in overall 97% yield (entry 4). Using cinnamyl alcohol containing
electron-withdrawing groups gave lower yields. (E)-3-(4-Nitro-
phenyl) prop-2-en-1-ol (2f) did not conduct under reflux condition
for 24 h (entry 5). (E)-3-(2-Nitrophenyl) prop-2-en-1-ol (2g) gave
only diallylated product in a 53% yield under reflux for 15 h (entry
6). The secondary alcohols 2h and 2i gave 42% and 40% yields,
respectively (entries 7 and 8). Steric factors affected the yield.
Treatment of 1a with crotyl alcohol (2j) gave only stereoisomeric
product 15 in the yield of 8%, and the formation of regioisomeric
product was not observed (entry 9). As our observation, the reac-
tivity of aromatic alcohols was better than aliphatic alcohols.
We speculated reaction mechanism in which water activates al-
lyl alcohol via hydration of the hydroxy group and stabilizes the
resulting hydroxide ion by strong solvation with water (A?B),
since Oshima et al. reported that the hydroxide ion of water can
leave with hydrating water molecules and the negative charge
can be delocalized in the water cluster. (Scheme 1)8 Intermolecular
References and notes
1. (a) Malkov, A. V.; Baxendale, I.; Mansfield, D. J.; Kocovsky, P. Tetrahedron Lett.
1997, 38, 4895–4898; (b) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98,
1689–1708; (c) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345; (d)
de Armas, J.; Kolis, S. P.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 5977–5983;
(e) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–2944; (f) Okamoto,
S.; Tominaga, S.; Saino, N.; Kase, K.; Shimoda, K. J. Organomet. Chem. 2005, 690,
6001–6007; (g) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258–297; (h) Gao,
F.; McGrath, K. P.; Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 14315–
14320.
2. (a) Trost, B. M. Science 1991, 254, 1471–1477; (b) Trost, B. M. Angew. Chem., Int.
Ed. Engl. 1995, 34, 259–281; (c) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P.;
Sylvain, C. J. Am. Chem. Soc. 2004, 126, 11966–11983; (d) Pelly, S. C.; Govender,
S.; Fernandes, M. A.; Schmalz, H.-G.; de Koning, C. B. J. Org. Chem. 2007, 72,
2857–2864.
3. (a) Kayaki, Y.; Koda, T.; Ikariya, T. J. Org. Chem. 2004, 69, 2595–2597; (b) Patil, N.
C.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 3101–3103; (c) Komine, N.; Sako,
A.; Hirahara, S.; Hirano, M.; Komiya, S. Chem. Lett. 2005, 34, 246–247; (d)
Nencka, R.; Sinnaeve, D.; Karalic, I.; Martins, J. C.; Van Calenbergh, S. Org.
Biomol. Chem. 2010, 8, 5234–5246.
4. (a) Yang, S.-C.; Tsai, Y.-C. Organometallics 2001, 20, 763–770; (b) Shue, Y.-J.;
Yang, S.-C.; Lai, H.-C. Tetrahedron Lett. 2003, 44, 1481–1485; (c) Yang, S.-C.; Lai,
H.-C.; Tsai, Y.-C. Tetrahedron Lett. 2004, 45, 2693–2697; (d) Hsu, Y.-C.; Gan, K.-
H.; Yang, S.-C. Chem. Pharm. Bull. 2005, 53, 1266–1269.
nucleophilic substitution of nucleophiles 1 takes place at the
p-al-
lyl system (C) to produce 2-allylated-1,3-diones.15
In conclusion, we have developed that aqueous reaction media
enables the direct use of allylic alcohols as the allyl source without
the help of any activating reagents for C–C bond formation. More-
over, this method gives potential industrial significance because of
5. (a) Lu, X.; Jiang, X.; Tao, X. J. Organomet. Chem. 1988, 344, 109–118; (b) Lumin,
S.; Falck, J. R.; Capdevila, J.; Karara, A. Tetrahedron Lett. 1992, 33, 2091–2094; (c)
Satoh, T.; Ikeda, M.; Miura, M.; Nomura, M. J. Org. Chem. 1997, 62, 4877–4879;

1384
Y.-J. Shue, S.-C. Yang / Tetrahedron Letters 53 (2012) 1380–1384
(d) Stary, I.; Stara, I. G.; Kocovsky, P. Tetrahedron Lett. 1993, 34, 179–182; (e)
11. (a) Bryant, M. D.; Flick, K. E.; Koduri, R. S.; Wilton, D. C.; Stoddard, B. L.; Gelb, M.
H. Bioorg. Med. Chem. Lett. 1999, 9, 1097–1102; (b) Breitenstein, W.; Märki, F.;
Roggo, S.; Wiesenberg, I.; Pfeilschifter, J.; Furet, P.; Beriger, E. Eur. J. Med. Chem.
1994, 29, 649–658.
12. Xia, G.; Benmohamed, R.; Kim, J.; Arvanites, A. C.; Morimoto, R. I.; Ferrante, R.
J.; Kirsch, D. R.; Silverman, R. B. J. Med. Chem. 2011, 54, 2409–2421.
13. Manolov, I.; Maichle-Moessmer, C.; Danchev, N. Eur. J. Med. Chem. 2006, 41,
882–890.
14. (a) Tedesco, R.; Shaw, A. N.; Bambal, R.; Chai, D.; Concha, N. O.; Darcy, M. G.;
Dhanak, D.; Fitch, D. M.; Gates, A.; Gerhardt, W. G.; Halegoua, D. L.; Han, C.;
Hofmann, G. A.; Johnston, V. K.; Kaura, A. C.; Liu, N.; Keenan, R. M.; Lin-Goerke,
J.; Sarisky, R. T.; Wiggall, K. J.; Zimmerman, M. N.; Duffy, K. J. J. Med. Chem.
2006, 49, 971–983; (b) Stanchev, S.; Momekov, G.; Jensen, F.; Manolov, I. Eur. J.
Med. Chem. 2008, 43, 694–706; (c) Hamdi, N.; Puerta, M. C.; Valerga, P. Eur. J.
Med. Chem. 2008, 43, 2541–2548.
Sakamoto, M.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1996, 69, 1065–
1078; (f) Tamaru, Y.; Horino, Y.; Araki, M.; Tanaka, S.; Kimura, M. Tetrahedron
Lett. 2000, 41, 5705–5709; (g) Manabe, K.; Kobayashi, S. Org. Lett. 2003, 5,
3241–3244.
6. (a) Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji,
M. J. Am. Chem. Soc. 2002, 124, 10968–10969; (b) Usui, I.; Schmidt, S.; Keller,
M.; Breit, B. Org. Lett. 2008, 10, 1207–1210; (c) Yadav, J. S.; Reddy, B. V. S.; Rao,
T. S.; Rao, K. V. R. Tetrahedron Lett. 2008, 49, 614–618; (d) Tao, Y.; Zhou, Y.; Qu,
J.; Hidai, M. Tetrahedron Lett. 2010, 51, 1982–1984; (e) Yamaguchi, Y.;
Hashimoto, M.; Tohyama, K.; Kimura, M. Tetrahedron Lett. 2011, 52, 913–915;
(f) Ghosh, R.; Sarkar, A. J. Org. Chem. 2011, 76, 8508–8512.
7. (a) Gan, K.-H.; Jhong, C.-J.; Yang, S.-C. Tetrahedron 2008, 64, 1204–1212; (b)
Nishikata, T.; Lipshutz, B. H. Org. Lett. 2009, 11, 2377–2379.
8. Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 4085–4088.
9. Sethukumar, A.; Prakasam, B. A. J. Mol. Struct. 2010, 963, 250–257.
10. Khan, K. M.; Maharvi, G. M.; Khan, M. T. H.; Shaikh, A. J.; Perveen, S.; Begum, S.;
Choudhary, M. I. Bioorg. Med. Chem. 2006, 14, 344–351.
15. Ranu, B. C.; Chattopadhyay, K.; Adak, L. Org. Lett. 2007, 9, 4595–4598.