Direct benzylation and allylic alkylation in high-temperature water without added catalysts

Article abstract of DOI:10.1016/j.tetlet.2010.01.112

In high-temperature water a series of benzyl and allylic alcohols reacted with 1,3-dicarbonyl compounds and activated aromatic compounds to give the alkylated products without added catalysts.

Full text of DOI:10.1016/j.tetlet.2010.01.112

Tetrahedron Letters 51 (2010) 1847–1851
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Direct benzylation and allylic alkylation in high-temperature water without
added catalysts
*
Tsunehisa Hirashita , Sho Kuwahara, Sota Okochi, Makoto Tsuji, Shuki Araki
¯
Omohi College, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In high-temperature water a series of benzyl and allylic alcohols reacted with 1,3-dicarbonyl compounds
and activated aromatic compounds to give the alkylated products without added catalysts.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 16 November 2009
Revised 22 January 2010
Accepted 29 January 2010
Available online 2 February 2010
The direct reaction of ROH and R0H to generate a new R–R0 bond
useful resources from organic wastes in near-critical water,13 organ-
ic synthetic reactions at high-temperature water have so far been
strictly limited. If the direct coupling reaction shown in Eq. 1 can
be realized in high-temperature water without added chemicals,
this process would be a clean chemical transformation.14
(Eq. 1) is
a
desirable process from
a
view point of Green
Chemistry.1
ROH þ R0H ! R-R0 þ H2O
ð1Þ
We initiated a reaction of benzhydrol and acetylacetone as test
substrates. A mixture of benzhydrol and acetylacetone in water
(15 mL) was put in a Teflon container (30 cm3) supported by a ves-
sel made of SUS 316, and heated in an electric dryer for several
hours.15
There is no need for preparing individual reactive species and
water as an only by-product seems to be highly attractive. These
type reactions have hitherto been achieved using Lewis acids,2–5
Brønsted acids,6 and iodine7 in organic solvents. Water is undoubt-
edly a greener solvent than organic solvents. The salient features of
water in organic syntheses, exemplified by acceleration of reac-
tions and enhancement of selectivities, have prompted organic
chemists to utilize water as an alternative solvent.8 However, a
broad range of catalysts used in organic solvents is often incompat-
ible with water and low solubility of common organic compounds
in water makes its practical use highly problematic. Recently, the
reactions as shown in Eq. 1 can be realized under aqueous condi-
tions by the aid of alkylbenzenesulfonic acid,9 which supports
the reaction by generating hydrophobic circumstances in water.
It is noted that simple Brønsted acids were not effective for the
coupling reaction under aqueous conditions.
In order to address the dilemma of water between an environ-
mental benign solvent and usability for performing organic reac-
tions, we focus on high-temperature water as a clean reaction
medium.10 As water is heated, its physical properties are dramati-
cally altered depending on temperature and pressure. For example,
increasing the temperature of water increases the ionic product and
reduces the dielectric constant; in other words, water itself plays
roles as a strong acid/base and becomes miscible with organic com-
pounds.11 Supercritical water has emerged in chemical process as an
environmentally attractive reagent/solvent for destruction of haz-
ardous and toxic materials due to its strong reactive nature.12
Although some reactions have been documented for regenerating
The reaction performed at 170 °C gave no coupling product,
whereas small amounts of the corresponding alkylated product
3a and the deacetylated product 4a were obtained at 180 °C (Table
1, entries 1 and 2). By prolonging the reaction time at 220 °C, the
yield of 4a increased with keeping the total yield (entries 3 and
4), which indicates that (1) the product 4a was derived from 3a
via elimination of acetic acid, and (2) acetylacetone was consumed
prior to the coupling with benzhydrol. The former possibility was
confirmed by the exposure of 3a under the identical conditions giv-
ing 4a in 60% yield. To reinforce the latter possibility that 1,3-dike-
tone easily undergoes hydrolysis under the present conditions, a
larger amount of acetylacetone (600 mol %) was employed in the
reaction, resulting in an improvement of the total yields (entries
5 and 6). However, longer reaction time did not give rise the total
yield again (entries 7 and 8). The reactions under refluxing at nor-
mal pressure as well as the hydrothermal reactions below 170 °C
gave no coupling product. Normally, deacetylation of diketones
has been performed in basic conditions.16,17 In the present reac-
tions, both the acid-catalyzed alkylation and the base-promoted
deacetylation simultaneously proceeded (Scheme 1).
Next, acyclic and cyclic diketones 2b–d were subjected to the
reaction in order to get some insight into this process (Scheme
2). Dibenzoylmethane (2b) was treated under hydrothermal condi-
tions to give benzoic acid and acetophenone in 87% and 46% yields,
respectively. The reaction of 2b in the presence of 1a provided a
mixture of 3b and 4b as the cases in Table 1.
* Corresponding author. Tel./fax: +81 52 735 5206.
E-mail address: hirasita@nitech.ac.jp (T. Hirashita).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.112

1848
T. Hirashita et al. / Tetrahedron Letters 51 (2010) 1847–1851
Table 1
220 ºC, 6 h
H2O
Hydrothermal reaction of benzhydrol and acetylacetonea
+
PhCOMe
46%
PhCO2H
87%
Ph
Ph
Ph
O
Ph
Ph
O
Ph
Ph
Ph
Δ
Ph
O
Ph
Ph
Ph
+
O
O
+
1a
O
O
H2O
OH
1a
2b
Ph
Ph Ph
+
220 ºC, 6 h
O
2a
3a
4a
H2O
O
O
3b: 6%
Entry
Conditions
Yields (%)
4b: 41%
2a (mol %)
T (°C)
t (h)
3a
4a
1a (recovery)
Scheme 2. Carbon–carbon bond coupling and cleavage of 2b under hydrothermal
conditions.
1
2
3
4
5
6
7
8
200
200
200
200
600
600
600
600
170
180
220
220
220
220
220
220
12
6
6
48
2
6
0
3
15
0
16
31
13
0
0
1
5
19
3
26
49
68
91
72
58
45
73
29
27
28
CO2Me
O
R
O
O
12
24
5c: R = H, 12%
1. 220 ºC, 6 h/H2O
2. TMSCHN2
5d: R = Ph, 28% (45%)a
a
All reactions were performed with benzhydrol (1.0 mmol) and acetylacetone in
ion-exchanged water (15 mL).
O
+
R
2c: R = H
O
R
O
2d: R = Ph
The reaction of cyclic diketone 2c performed with 1 mmol scale
in water (15 mL) gave linear d-keto carboxylate 5c in 12% yield
after the esterification with TMSCHN2 (Scheme 3). When cyclic
diketone 2d carrying a phenyl group was employed, the yield
was slightly improved to afford the corresponding methyl carbox-
ylate 5d in 28% yield. With 10-times lower concentration
(0.1 mmol scale), the yield was increased up to 45%. In the reac-
tions of cyclic diketones 2c and 2d, unexpected diketo esters 6c
and 6d were isolated. On the basis of 13C NMR analysis, 6d was
found to be a 1:1 mixture of the diastereomers. The most plausible
reaction mechanism for the formation of 6c and 6d is depicted in
Scheme 4. The aldol condensation of 2 generates A,18 which is fol-
lowed by hydrolysis leading to the formation of 6 according to the
sequence mentioned above.19
As active methylene compounds including a 1,3-diketone moi-
ety prove to be highly sensitive under the present conditions, we
turned our attention to aromatic electrophilic substitution in
high-temperature water (Table 2).
The reaction of indole (7a) and benzyl alcohol at 220 °C did not
occur and the starting materials remained intact. However, the
reaction of 1a with 7a under hydrothermal conditions gave the
alkylated product 8aa quantitatively (Table 2, entry 1). 1-Methyl-
indole (7b) afforded the corresponding product 8ba in high yield
at 220 °C (entry 2). The reaction of 4-methoxybenzyl alcohol (1b)
MeO
R
6c: R = H, 23%
6d: R = Ph, 44% (29%)a
a Under diluted conditions.
Scheme 3. Carbon–carbon bond coupling and cleavage of cyclic diketones 2c and
2d under hydrothermal conditions.
O
O
O
HO
O
OH
2
H2O
R
R
H
A
R
R
O
O
O
O
HO
R
6
R
O
Scheme 4. Proposed mechanism for the formation of 6.
with 7a under reflux conditions resulted in a recovery of 1b and
7a, whereas under hydrothermal conditions, 8ab was obtained in
a
H2O
4a
1a
moderate yield along with 4,40-dimethoxydiphenylmethane
(17%) as a major by-product (entry 3). 1-Phenylethanol (1c) affor-
ded the alkylated product 8ac in 52% yield under hydrothermal
conditions (entry 4). The reaction of triphenylmethanol (1d) with
7b under refluxing resulted in a quantitative recovery of 1d,
whereas under hydrothermal conditions the corresponding alkyl-
ated product 8bd was obtained in high yield (entry 5). The reaction
of cinnamyl alcohol (1e) gave a mixture of regioisomers 8be and
8be0 in a moderate yield (entry 6). Cyclic alcohol 1f afforded 8bf
(entry 7). However, the alkylation failed with crotyl alcohol, but-
3-en-2-ol and 2-methylbut-3-en-2-ol. 1,3-Diphenylpropen-1-ol
(1g) proved to be susceptible to heating under aqueous conditions;
just refluxing of 1g with 7b for 15 h reached a high level of conver-
sion into the corresponding alkylated product 8bg in 82% yield. In
contrast, the reaction of 1g and 7b in toluene at 100 °C gave no
coupling product. The reaction performed in water at 220 °C gave
the better yield (entry 8).20 Next, 1,3,5-trimethoxybenzene (7c)
was submitted to the hydrothermal reaction. The reaction of 1a
Ph
Ph
O
H
Ph
Ph
O
H2O
+
OH
AcOH
OH
3a
Scheme 1. Proposed mechanism for the acid- and base-catalyzed reactions under
hydrothermal conditions.

T. Hirashita et al. / Tetrahedron Letters 51 (2010) 1847–1851
1849
Table 2
Electrophilic substitution reaction under hydrothermal conditionsa
Entry
NuH
Alcohol
Products and yield
Ph
Ph
Ph
1
N
H
Ph
OH
1a
7a
7b
N
8aa: 99%
Ph
H
Ph
2
1a
N
Me
N
8ba: 98%
Me
p-MeOC6H4
p-MeOC6H4
3b
7a
7a
OH
1b
8ab: 44%
N
H
Me
Ph
Me
8ac: 52%
Ph
OH
4
1c
N
H
Ph
Ph
Ph
Ph
Ph
Ph
OH
5
6
7b
7b
1d
8bd: 87%
N
Me
R2
Ph
R1
OH
OH
1e
54%
(8be:8be' = 52:48)
N
Me
8be: R1 = H, R2 = Ph
8be': R1 = Ph, R2 = H
7
7b
1f
8bf: 61%
N
Me
Ph
Ph
OH
Ph
Ph
1g
8
9
7b
8bg: 90%
N
Me
OMe
OMe Ph
Ph
1a
MeO
OMe
MeO
OMe
8ca: >99%
7c
(continued on next page)

1850
T. Hirashita et al. / Tetrahedron Letters 51 (2010) 1847–1851
Table 2 (continued)
Entry
NuH
Alcohol
Products and yield
OMe
Ph
10
7c
1e
MeO
OMe
8ce: 66%
Ph
11
7c
8ce: 77%
OH
1e'
a
All reactions were performed with NuH 7 (1.2 mmol) and alcohol 1 (1.0 mmol) in ion exchanged water (15 mL) at 220 °C for 6 h.
b
4,40-Dimethoxydiphenylmethane (17%) was also obtained.
References and notes
Table 3
Intramolecular reaction of 9 under hydrothermal conditionsa
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Ph
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3046–3052.
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OH
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11
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Entry
Conditions
Yields (%)
11b
T (°C)
t (h)
10b
9 (recovery)
1
2
3
4
5
6
7
rfx
18
6
0
0
0
0
0
0
96
98
98
95
0
150
160
170
170
180
220
6
6
4
Trace
16
6
48
6
61
19
57
51
0
6
20
a
All reactions were performed with
(15 mL).
9
(1.0 mmol) in ion-exchanged water
b
NMR yields estimated from a mixture of 10 and 11.
9. Shirakawa, S.; Kobayashi, S. Org. Lett. 2007, 9, 311–314.
gave 8ca in a quantitative yield (entry 9). The regioisomeric alco-
hols 1e and 1e0 gave coinciding results (entries 10 and 11). p-Dime-
thoxybenzene was found to be inactive at 220 °C.
The aromatic compounds that can be applied in this alkylation
are limited to electron-rich aromatics, indicating that the transient
intermediates are not electrophilic and/or stable enough under the
conditions to promote the alkylation. We anticipated that an intra-
molecular reaction would open the possibility of using non-acti-
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Watanabe, M.; Sato, T.; Inomata, H.; Smith, R. L., Jr.; Arai, K.; Kruse, A.;
Dinjus, E. Chem. Rev. 2004, 104, 5803–5821; (f) Comisar, C. M.; Savage, P. E.
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vated aromatic units as
a substrate. Thus, alcohol 9 was
subjected to the hydrothermal reaction with altering temperature
and the results are compiled in Table 3. The reactions under reflux-
ing and the thermal reactions below 170 °C, 9 remained intact (en-
tries 1–3). A small amount of cyclization product 10 was obtained
at 170 °C for 6 h and prolonging the time allowed to consume 9
affording 10 in 61% yield along with a dehydrated product 11 (en-
tries 4 and 5). Reactions at higher temperature gave better yields in
a shorter time (entries 6 and 7). The above results show that a non-
activated aromatic has a potential for the hydrothermal alkylation
and the cationic intermediate was practically generated from ben-
zylic alcohols even at 170 °C.
13. Abdelmoez, W.; Nakahasi, T.; Yoshida, H. Ind. Eng. Chem. Res. 2007, 46, 5286–
5294.
14. Recent examples of synthetic reactions in water: (a) Mehta, B. K.; Kumamoto,
K.; Yanagisawa, K.; Kotsuki, K. Tetrahedron Lett. 2005, 46, 6953–6956; (b)
Habib, P. M.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. Tetrahedron Lett. 2008, 49, 7005–
7007; (c) Wang, Z.; Cui, Y-T.; Xu, Z-B.; Qu, J. J. Org. Chem. 2008, 73, 2270–2274;
(d) Liu, Y.-L.; Liu, L.; Wang, Y.-L.; Han, Y.-C.; Wang, D.; Chen, Y.-J. Green Chem.
2008, 10, 635–640; (e) Ghosh, S.; Dey, R.; Chattopadhyay, K.; Ranu, B. C.
Tetrahedron Lett. 2009, 50, 4892–4895; (f) Ko, K.; Nakano, K.; Watanabe, S.;
Ichikawa, Y.; Kotsuki, H. Tetrahedron Lett. 2009, 50, 4025–4029.
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2000, 73, 2687–2693; (b) Yamasaki, Y.; Hirayama, T.; Oshima, K.; Matsubara, S.
Chem. Lett 2004, 864–865.
In summary, the direct coupling of alcohols and aromatic com-
pounds in high-temperature water has been achieved. Water un-
der hydrothermal conditions would open opportunities for
alcohols as an alkylating agent without added chemicals.21
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Acknowledgment
17. The cleavage of 1,3-diketone under aquathermolysis conditions (15% sodium
formate, 315 °C) was proposed to explain
a formation of decomposition
products. Siskin, M.; Brons, G.; Vaughn, S. N.; Katritzky, A. R.; Balasubramanian,
M.; Greenhill, J. V. Energy Fuels 1993, 7, 589–597.
We thank Professor Y. Yamasaki (Hosei University) for intro-
ducing us the autoclave and helpful discussion.

T. Hirashita et al. / Tetrahedron Letters 51 (2010) 1847–1851
1851
18. (a) Koyama, T.; Fukuoka, S.; Hirota, T.; Maeyama, J.; Ohmori, S.; Yamato, M.
Chem. Pharm. Bull. 1976, 24, 591–595; (b) Stetter, H.; Siehnhold, E. Chem. Ber.
1953, 86, 1308–1311.
19. The formation of the dimeric acid from 1,3-cyclohexanedione in the presence
of sodium bicarbonate was documented: Conrow, K. J. Org. Chem. 1966, 31,
1050–1053.
20. The reaction of 1g with 7a under reflux conditions gave the corresponding
product in 63% yield. However, the reaction performed at 220 °C resulted in a
formation of a complicated mixture.
21. General experimental procedure: All reactions were carried out in ion-exchanged
water (<0.08 mS/cm), which was obtained by an ORGANO PURE LITE PRB-
002A. The autoclave was purchased from Shikokurika Co., Ltd. Representative
procedure for reaction screening (Table 2, entry 2): A mixture of benzhydrol
(0.18 g, 1.0 mmol), 1-methylindole (0.15 mL, 1.2 mmol), and ion-exchanged
water (15 mL) was introduced into an autoclave with a volume filling factor of
50%. The autoclave was heated at 220 °C in an electric drier for 6 h. After the
reactor was cooled down to room temperature, the product was extracted with
ether. The organic solution was washed with brine and concentrated under
reduced pressure giving a crude product (321 mg), from which excess 1-
methylindole was removed by distillation (150 °C, 20 mmHg) to afford 3-(1,1-
diphenylmethyl)-1-methylindole (8ba, 291 mg, 98%).