Efficient synthesis of 1-Benzyloxyphenyl-3-phenylacetones

Article abstract of DOI:10.1055/s-2000-6414

1-[(Benzyloxy)phenyl]-3-phenylacetones 1a-c have been conveniently synthesized by acylation of the PhCH₂Li-DABCO complex with their respective N-methyl O-methyl hydroxamates 5a-c. In four steps, ketones 1a-c having ortho-, meta- and para-benzyloxy substituents were obtained in 42-51% overall yields from commercially available 2-(hydroxyphenyl)acetic acids.

Full text of DOI:10.1055/s-2000-6414

1214
SHORT PAPER
Efficient Synthesis of 1-Benzyloxyphenyl-3-phenylacetones
Els Mannekens,a* Dirk Tourwé,a William D. Lubellb*
a Vrije Universiteit Brussel, Laboratorium voor Organische Chemie, Pleinlaan 2, 1050 Brussel, Belgium
b Département de chimie, Université de Montréal C. P. 6128, Succursale Centre Ville, Montréal, Québec, Canada H3C 3J7
Fax +32(2)6293304; E-mail: emmannek@vub.ac.be
Received 21 December 1999; revised 11 April 2000
of acid 4b into N-methyl-O-methyl hydroxamate 5b was
Abstract: 1-[(Benzyloxy)phenyl]-3-phenylacetones 1a-c have
first examined using 1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide hydrochloride (WSC) and N-methyl O-me-
thyl hydroxylamine hydrochloride in a THF/water (1:1)
been conveniently synthesized by acylation of the PhCH2Li-DAB-
CO complex with their respective N-methyl O-methyl hydroxam-
ates 5a-c. In four steps, ketones 1a-c having ortho-, meta- and
para-benzyloxy substituents were obtained in 42-51% overall solution. 2-[3-(Benzyloxy)phenyl]-N-methyl-O-methyl
yields from commercially available 2-(hydroxyphenyl)acetic acids.
hydroxamate (5b) was obtained in 80% yield; however,
chromatography was needed to isolate pure material.
Switching coupling agents from the carbodiimide to the
oxonium salt 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetrame-
thyluronium tetrafluoroborate (TBTU)10 allowed for the
preparation of amide 5b in higher yield without chroma-
tography. Treatment of acids 4a-c with TBTU, DIEA and
MeON(Me)H•HCl in acetonitrile gave hydroxamates
5a-c in 82-96% yield. For the final step, benzyllithium
was initially generated in the presence of 1,4-diazabicyc-
lo[2,2,2]octane (DABCO) to form the corresponding
BnLi-DABCO complex.11 In the pot, n-BuLi was added to
a toluene solution containing the diamine and the mixture
was heated to 80 °C, when bright yellow crystals formed.
The solution was then cooled to room temperature and
treated with hydroxamate 5, the crystals disappeared, and
the presence of ketone was detected as a higher Rf product
by TLC. After an aqueous quench and chromatography,
ketones 1a-c were isolated in 68-71% yields.
Key words: ketones, N-methoxy-N-methylamides, benzyllithium,
acylation, 1-[(benzyloxy)phenyl]-3-phenylacetone
Protected 1-[(hydroxy)phenyl]-3-phenylacetones are at-
tractive targets because of the importance of 1,3-diben-
zylketone as a starting material for the synthesis of
polyphenylenes1,2 and pipecolates.3 Previous syntheses of
O-protected 1-[(hydroxy)phenyl]-3-phenylacetones have,
however, suffered from low yields and the use of toxic or-
ganocadmium reagents.4-7 Contrary to the low yields ob-
tained in acylations of organocadmium and Grignard
reagents,5-8 acylation of methyllithium with methyl 2-[(3-
benzyloxy)phenyl]-N-methyl-O-methyl
hydroxamate
(5b) gave (3-benzyloxy)phenylacetone in 85% yield.9 In-
spired by this result, we examined the acylation of benzyl-
lithium with N-methyl O-methyl hydroxamates 5a-c. By
using benzyllithium-DABCO complex in this reaction,
we have developed an effective means for synthesizing
1-[(benzyloxy)phenyl]-3-phenylacetones 1a-c (Scheme).
In summary, this four step route featuring acylation of
BnLi-DABCO complex with N-methyl-O-methyl hy-
droxamates 5 has furnished 1,3-diphenylacetones 1 with
o-, m- and p-benzyloxy substituents in 47%, 51% and
42% respective overall yields.
Commercially available (hydroxyphenyl)acetic acids 2
were alkylated with benzylbromide and K2CO3 in DMF to
afford, in 83-84% yields, benzyl benzyloxyphenylace-
tates 3 that were saponified in MeOH/water (9:1) to their
corresponding acids 4 in 85-94% yields. Transformation
PhCH2-Br, K2CO3
DMF, 80 °C
MeON(Me)H.HCl
TBTU, DIEA, CH3CN, rt
OMe
Me
COOH
COOR
N
HO
BnO
2a-c
83-84 %
BnO
82-96 %
O
a = ortho
b = meta
c = para
5a-c
3a-c: R = Bn
4a-c: R = H
KOH, MeOH/H2O (9:1)
85-94 %
toluene
nBuLi, DABCO
68-71 %
BnO
O
1a-c
Scheme
Synthesis 2000, No. 9, 1214–1216 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Efficient Synthesis of 1-Benzyloxyphenyl-3-phenylacetones
1215
Unless stated otherwise, solvents and reagents were used as sup-
plied. Toluene was distilled from Na and diisopropylethylamine
(DIEA) from CaH2. Final reaction solutions were dried over
Na2SO4. Flash-column chromatography was performed on 230-
400 mesh silica gel; TLC was performed on aluminium-backed sil-
ica plates with visualization by UV-light, iodine vapour or a ceric
ammonium molybdate spray. Mass spectral data, HRMS (FAB)
were obtained by the Université de Montréal Mass Spec. Facility.
1H and 13C NMR spectra were recorded in CDCl3 at 300 MHz and
100 MHz, respectively. Chemical shifts are in ppm relative to inter-
with sat. NaHCO3 (30 mL) and discarded. The alkaline layer was
acidified to pH 2 with 1 N HCl and extracted with Et2O (3 ¥ 30 mL).
Similarly the first H2O phase was acidified to pH 2 with 1 N HCl
and extracted with Et2O (3 ¥ 20 mL). The organic layers were com-
bined, dried and evaporated to a solid that was crystallized from
Et2O/hexanes.
2-[2-(Benzyloxy)phenyl]acetic Acid (4a)
Yield: 88% (3.22 g); mp: 94.0-94.6 °C (Lit.13 94 °C); Rf 0.80
(EtOAc).
1H NMR: d = 3.74 (s, 2H), 5.09 (s, 2H), 6.94-7.00 (m, 2H), 7.23-
7.42 (m, 7H).
13C NMR: d = 36.2, 70.1, 112.0, 121.0, 122.9, 127.2, 127.9, 128.7,
129.0, 131.3, 137.1, 156.7, 178.7.
HRMS: calcd for C15H14O3 (M+) 242.0943. Found: 242.0953.
nal TMS for 1H NMR spectra and relative to solvent signals for 13
C
NMR spectra. Mps were determined on a Gallenkamp melting point
apparatus with a digital thermometer.
Benzyl 2-[(Benzyloxy)phenyl]acetates (3); General Procedure
A solution of acid 2 (5.00 g, 32.9 mmol) and K2CO3 (18.00 g,
131.0 mmol) in DMF (25 mL) was stirred for 15 min. at r.t., treated
with benzylbromide (20 mL, 164.5 mmol), stirred for 72 h at 80 °C,
cooled to r.t. and quenched with H2O (20 mL). The pH was adjusted
to 4 with citric acid (0.5 N), and the mixture was extracted with
Et2O (3 ¥ 40 mL). The organic phases were combined, washed with
sat. NaHCO3 (40 mL) and brine (40 mL), dried and evaporated.
2-[3-(Benzyloxy)phenyl]acetic Acid (4b)
Yield: 94% (3.44 g); mp: 123.5-124.0 °C (Lit.14 123-125 °C); Rf
0.71 (MeCN/MeOH/H2O, 4:1:1).
HRMS: calcd for C15H15O3 (MH+) 243.1021. Found: 243.1016.
2-[4-(Benzyloxy)phenyl]acetic Acid (4c)
Yield: 85% (3.11 g); mp 119.0-119.5 °C (Lit.15 120-121 °C); Rf
0.71 (EtOAc).
Benzyl 2-[2-(benzyloxy)phenyl]acetate (3a)
Purified by crystallization from Et2O/hexanes.
Yield: 83% (8.80 g); mp: 74.4-74.6 °C; Rf 0.72 (hexanes/EtOAc,
1H NMR: d = 3.60 (s, 2H), 5.06 (s, 2H), 6.95 (d, 2H, J = 8.4 Hz),
4:1).
7.20 (d, 2H, J = 8.4 Hz), 7.26-7.44 (m, 5H).
1H NMR: d = 3.76 (s, 2H), 5.07 (s, 2H), 5.11 (s, 2H), 6.93-6.97 (m,
2H), 7.23-7.40 (m, 12H).
13C NMR: d = 36.4, 66.5, 70.0, 111.9, 120.9, 123.5, 127.2, 127.9,
128.2, 128.5, 128.6, 128.7, 131.2, 136.2, 137.2, 156.8, 171.8.
13C NMR: d = 40.4, 70.2, 115.2, 125.8, 127.6, 128.1, 128.8, 130.6,
137.1, 158.3, 178.7.
HRMS: calcd for C15H14O3 (M+) 242.0943. Found: 242.0935.
HRMS: calcd for C22H21O3 (MH+) 333.1491. Found: 333.1502.
2-(Benzyloxy)phenyl-N-methoxy-N-methylacetamides (5);
General Procedure
Anal. calcd for C22H20O3: C, 79.50; H, 6.06. Found: C, 79.08; H,
A stirred solution of acid 4 (3.00 g, 12.4 mmol) in CH3CN (100 mL)
was treated with TBTU (4.78 g, 14.9 mmol), DIEA (8.6 mL,
49.6 mmol) and N,O-dimethylhydroxylamine∑HCl (1.45 g, 14.9
mmol), then stirred at r.t. overnight. The volatiles were removed on
a rotary evaporator and the residue was dissolved in EtOAc (50
mL), washed with 0.1 N HCl (2 ¥ 20 mL), 4% aq NaHCO3
(2 ¥ 20 mL) and brine (20 mL), dried and concentrated to provide
N-methyl O-methylhydroxamate 5 suitable for use in subsequent re-
actions.
6.21.
Benzyl 2-[3-(benzyloxy)phenyl]acetate (3b)
Purified by chromatography using a gradient of pure hexanes to
hexanes/EtOAc (95:5).
Yield: 83% (8.80 g); Rf 0.46 (hexanes/EtOAc, 4:1).
1H NMR: d = 3.66 (s, 2H), 5.04 (s, 2H), 5.15 (s, 2H), 6.90-6.95 (m,
3H), 7.23-7.46 (m, 11H).
13C NMR: d = 41.5, 66.7, 70.0, 113.8, 115.9, 122.1, 127.6, 128.1,
2-[2-(Benzyloxy)phenyl]-N-methoxy-N-methylacetamide (5a)
Isolated as a liquid that solidified on standing. The solid was crys-
tallized from EtOAc/hexanes.
128.3, 128.4, 128.7, 129.7, 135.5, 136.0, 137.1, 159.1, 171.3.
HRMS: calcd for C22H20O3 (M+) 332.1412. Found: 332.1424.
Yield: 94% (3.31 g); mp: 69.5-71.0 °C; Rf 0.32 (CH2Cl2/hexanes,
Benzyl 2-[4-(benzyloxy)phenyl]acetate (3c)
9:1).
Purified by crystallization from Et2O/hexanes.
1H NMR: d = 3.18 (s, 3H), 3.50 (s, 3H), 3.81 (s, 2H), 5.08 (s, 2H),
6.93-6.96 (m, 2H), 7.24-7.43 (m, 7H).
13C NMR: d = 32.3, 33.8, 61.0, 70.2, 111.7, 120.9, 124.4, 127.7,
127.9, 128.2, 128.5, 131.2, 137.2, 156.6, 172.7.
Yield: 84% (8.90 g); mp: 71.5-71.9 °C (Lit.12 69-70 °C); Rf 0.65
(hexanes/EtOAc, 4:1).
1H NMR: d = 3.48 (s, 2H), 4.91 (s, 2H), 5.00 (s, 2H), 6.81 (d, 2H,
J = 8.7 Hz), 7.08 (d, 2H, J = 8.7 Hz), 7.19-7.31 (m, 10H).
13C NMR: d = 40.5, 66.7, 70.1, 115.1, 126.4, 127.6, 128.1, 128.2,
128.3, 128.6, 128.7, 130.5, 136.0, 137.1, 158.1, 171.8.
HRMS: calcd for C22H20O3 (M+) 332.1412. Found: 332.1403.
HRMS: calcd for C17H20NO3 (MH+) 286.1443. Found: 286.1440.
Anal. calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C,
71.40; H, 6.99; N, 4.95.
2-[3-(Benzyloxy)phenyl]-N-methoxy-N-methylacetamide (5b)
2-[(Benzyloxy)phenyl]acetic Acids (4); General Procedure
A solution of ester 3 (5.00 g, 15.1 mmol) in MeOH/H2O (9:1,
50mL) was treated with KOH (1.43 g, 25.6 mmol) and THF (5 mL)
to improve solubility. The reaction mixture was stirred at r.t. until
TLC-analysis indicated the complete consumption of starting mate-
rial (6-8 h). H2O (40 mL) was added and the mixture was extracted
with Et2O (3 ¥ 30 mL). The Et2O layers were combined, extracted
Isolated as a liquid.9
Yield: 96% (3.38 g); Rf 0.60 (CH2Cl2/EtOAc/hexanes, 9:1:1).
13C NMR: d = 32.2, 39.4, 61.3, 69.9, 113.3, 115.8, 122.0, 127.5,
127.9, 128.6, 129.5, 136.5, 137.1, 158.9, 172.2.
HRMS: calcd for C17H20NO3 (MH+) 286.1443. Found: 286.1437.
Synthesis 2000, No. 9, 1214–1216 ISSN 0039-7881 © Thieme Stuttgart · New York

1216
E. Mannekens et al.
SHORT PAPER
2-[4-(Benzyloxy)phenyl]-N-methoxy-N-methylacetamide (5c)
Crystallized from EtOAc/hexanes.
Anal. calcd for C22H20O2: C, 83.52; H, 6.37. Found: C, 83.70; H,
6.59.
Yield: 82% (2.89 g); mp: 67.5-68.0 °C; Rf 0.39 (CH2Cl2/hexanes,
1-[4-(Benzyloxy)phenyl]-3-phenylacetone (1c)
9:1).
Crystallized from Et2O/petroleum ether.
1H NMR: d = 3.20 (s, 3H), 3.63 (s, 3H), 3.73 (s, 2H), 5.06 (s, 2H),
6.95 (d, 2H, J = 8.5 Hz), 7.25 (d, 2H, J = 8.5 Hz), 7.35-7.46 (m,
5H).
13C NMR: d = 32.3, 38.5, 61.3, 70.0, 114.9, 127.3, 127.5, 128.0,
128.6, 130.4, 137.1, 157.8, 172.7.
Yield: 71% (1.66 g); mp: 49.4-49.8 °C; Rf 0.43 (hexanes/EtOAc,
4:1).
1H NMR: d = 3.68 (s, 2H), 3.73 (s, 2H), 5.07 (s, 2H), 6.94-6.96 (m,
2H), 7.07-7.10 (m, 2H), 7.15-7.19 (m, 2H), 7.27-7.47 (m, 8H).
13C NMR: d = 48.3, 49.1, 70.1, 115.2, 126.5, 127.1, 127.6, 128.1,
128.7, 128.8, 129.6, 130.7, 134.2, 137.1, 158.0, 206.1.
HRMS: calcd for C22H20O2 (M+) 316.1463. Found: 316.1470.
HRMS: calcd for C17H20NO3 (MH+) 286.1443. Found: 286.1440.
Anal. calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C,
71.06; H, 7.01; N, 4.96.
Anal. calcd for C22H20O2: C, 83.52; H, 6.37. Found: C, 83.51; H,
1-[(Benzyloxy)phenyl]-3-phenylacetones (1); General Proce-
dure
6.60.
A solution of n-BuLi (2.5 M in hexanes, 3.5 mL, 8.8 mmol) was
added rapidly to a stirred solution of DABCO (0.98 g, 8.8 mmol) in
anhyd toluene (25 mL). The color of the mixture became yellow and
after heating at 80 °C for 30 min., bright yellow needles were
formed indicative of the benzyllithium-DABCO complex. Hereaf-
ter, the mixture was cooled to r.t. and treated with a solution of hy-
droxamate 5 (2.09 g, 7.3 mmol) in dry toluene (21 mL). The yellow
needles soon disappeared and the reaction mixture was then stirred
for another 60 min., washed with citric acid (0.1 N, 30 mL), H2O
(30 mL), sat. NaHCO3 (30 mL) and brine (30 mL), dried and con-
centrated. Ketone 1 was purified by flash-column chromatography
using a gradient of pure hexanes to hexanes/EtOAc (95:5).
Acknowledgement
This research was supported in part by the Natural Sciences and En-
gineering Research Council (NSERC) of Canada, the Ministère de
l'Education du Québec, the Ministère des Relations Internationales
du Québec, and the Ministry of the Flemish Community, Science
and Innovation Administration (BIL 98/11).
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1-[2-(Benzyloxy)phenyl]-3-phenylacetone (1a)
Solid.
Yield: 69% (1.61 g); mp: 45.8-46.4 °C; Rf 0.64 (hexanes/EtOAc,
4:1).
1H NMR: d = 3.70 (s, 2H), 3.76 (s, 2H), 5.06 (s, 2H), 6.94-6.99 (m,
2H), 7.08-7.16 (m, 3H), 7.25-7.43 (m, 9H).
13C NMR: d = 44.1, 49.2, 70.0, 111.7, 120.9, 123.7, 126.8, 127.5,
128.0, 128.5 (2), 128.6, 129.5, 131.4, 134.3, 136.9, 156.5, 205.9.
HRMS: calcd for C22H21O2 (MH+) 317.1541. Found: 317.1547.
Anal. calcd for C22H20O2: C, 83.52; H, 6.37. Found: C, 82.88; H,
6.91.
1-[3-(Benzyloxy)phenyl]-3-phenylacetone (1b)
Crystallized from Et2O/c-hexane.
Yield: 68% (1.59 g); mp: 39.5-40.0 °C, Rf 0.48 (hexanes/EtOAc,
4:1).
1H NMR: d = 3.74 (s, 2H), 3.76 (s, 2H), 5.08 (s, 2H), 6.84 (m, 2H),
6.96 (m, 1H), 7.20-7.51 (m, 11H).
13C NMR: d = 49.1, 49.2, 70.0, 113.6, 116.1, 122.2, 127.1, 127.6,
Article Identifier:
1437-210X,E;2000,0,09,1214,1216,ftx,en;H10199SS.pdf
128.1, 128.7, 128.8, 129.6, 129.9, 134.1, 135.6, 137.0, 159.1, 205.6.
HRMS: calcd for C22H21O2 (MH+) 317.1541. Found: 317.1547.
Synthesis 2000, No. 9, 1214–1216 ISSN 0039-7881 © Thieme Stuttgart · New York