4
P. Singh et al. / Tetrahedron Letters xxx (2017) xxx–xxx
2-((4-Chlorophenyl)(phenyl)methyl)-5-methylbenzene-1,4-diol (4af)
Yield: 138 mg (85%) as brown viscous liquid; IR (KBr): vmax
3429, 3027, 2923, 2849, 1603, 1452, 1189 cmÀ1 1H NMR
;
(500 MHz, CDCl3): 7.33 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 8.0 Hz, 3H),
7.13 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.60 (s, 1H), 6.24
(s, 1H), 5.74 (s, 1H), 4.97 (s, 1H, OH), 2.18 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): d 147.6, 146.8, 142.5, 141.5, 132.4, 130.8,
129.4, 128.7, 128.6, 126.9, 123.6, 118.7, 117.0, 49.7, 15.7 ppm;
HRMS (ESI+): m/z calcd for C20H17ClO2 [M+Na]+: 347.0809, found
347.0805.
Scheme 2. Gram-scale synthesis of benzylated hydroquinone 3ab.
R1
OH
R1
R1
OH
OH
OH
TsOH•H2O
2-Methoxy-5-(1-phenylethyl)benzene-1,4-diol (4bh)
R2
R2
R2
R
R
OH
3/4
2
5
1
Yield: 107 mg (88%) as brown viscous liquid; IR (KBr): vmax
3435, 3062, 2929, 2854, 1640, 1450, 1368, 1118 cmÀ1 1H NMR
;
Scheme 3. Plausible reaction mechanism.
(400 MHz, CDCl3): d 7.30–7.18 (m, 5H), 6.84 (s, 1H), 6.36 (s, 1H),
4.24 (q, J = 7.2 Hz, 1H), 3.76 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H), ppm;
13C NMR (100 MHz, CDCl3): d 146.7, 145.7, 145.5, 139.5, 129.0,
127.6, 126.7, 124.4, 113.8, 100.9, 56.2, 38.6, 21.5 ppm; HRMS (ESI
+): m/z calcd for C15H16O3 [M+H]+: 245.1172, found 245.1153.
Additionally, the dehydrative substitution of 2-methyl hydro-
quinone (1a) and benzhydryl alcohol (2b) could be performed at
5 mmol scale under the optimized conditions to produce the corre-
sponding 2-benzyl-5-methylbenzene-1,4-diol (3ab) in a very good
yield (Scheme 2).
Acknowledgement
On the basis of our results and literature reports,17 a plausible
mechanism is outlined in Scheme 3 to account for the benzylation
of hydroquinones. These reactions presumably proceed via dehy-
drative SN1 mechanism. A benzyl carbocation 5 generated from
diaryl carbinol 2 in the presence of PTSA and 5 could be attacked
by hydroquinone 1 to afford the products 3 and 4.
We are grateful to SERB, India for financial support and DST for
providing the HRMS facility in the FIST program. P. S. thanks UGC,
New Delhi, for a research fellowship.
References
In conclusion, we have developed a simple and straightforward
sustainable method for the direct nucleophilic substitution of
hydroquinones to benzhydryl alcohols using PTSA as a catalyst in
water. The established metal-free and eco-friendly process is one
of the most efficient synthetic routes for the functionalization of
hydroquinones. The demonstrated protocol shows compatibility
of benzhydrols bearing substituents of different electronic nature
with a variety of hydroquinones. Large-scale preparation of func-
tionalized hydroquinones with high atom economy under aerobic
conditions marked the clear and practical utility of this economic
synthetic process.
General procedure for the synthesis of benzylated hydroquinones 3
and 4
A mixture of hydroquinones 1 (0.5 mmol), TsOHÁH2O (2 mol%)
and benzhydryl alcohols 2 (0.6 mmol) in H2O (2 mL) was heated
at 40 °C for 1 h. Then it was cooled, the reaction mixture was
poured into water and extracted with EtOAc. The organic layer
was dried over anhyd. Na2SO4, and concentrated in a rotatory
evaporator. The residue was purified by silica gel column chro-
matography (step gradient with 10–20% ethyl acetate in hexanes
as the eluent) to afford the desired products 3 and 4.
w0067-l.
2-(Di-p-tolylmethyl)-5-methylbenzene-1,4-diol (3aa)
Yield: 146 mg (92%) as white solid; mp: 147–148 °C; IR (KBr):
vmax 3412, 3026, 2922, 2860, 1597, 1415, 1187 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d 7.11 (d, J = 7.6 Hz, 4H), 7.02 (d, J = 8.0 Hz,
4H), 6.61 (s, 1H), 6.19 (s, 1H), 5.54 (s, 1H), 4.27 (s, 1H, OH), 4.25
(s, 1H, OH), 2.33 (s, 6H), 2.18 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): d 147.5, 147.0, 139.5, 136.4, 129.4, 129.3, 129.2, 123.2,
118.8, 116.8, 50.1, 21.1, 15.6 ppm; HRMS (ESI+): m/z calcd for
C
22H22O2 [M+H]+: 319.1692, found: 319.1697.