Synthesis of β-Alkoxy Ketones and α′-Functionalized β-Alkoxy Ketones Utilizing Benzotriazole-Stabilized Acyl Anion Synthons

Article abstract of DOI:10.1021/jo971630v

1-(α-Alkoxyalkyl)benzotriazoles 1a-d add to phenyl vinyl ether to form key intermediates 4a-d, which readily undergo lithiation and subsequent trapping by a variety of electrophiles to give the expected substituted derivatives 7a-d, 9a-c, 11, 13, 15, and 18 in high yields. Subsequent hydrolysis of these compounds provides a novel high-yield acyl anion synthon approach for the synthesis of β-alkoxy ketones 8 or α′-functionalized β-alkoxy ketones 10, 12, 14, 16, and 19 by short procedures from readily available starting materials.

Full text of DOI:10.1021/jo971630v

J . Org. Chem. 1998, 63, 1473-1477
1473
Syn th esis of â-Alk oxy Keton es a n d r′-F u n ction a lized â-Alk oxy
Keton es Utilizin g Ben zotr ia zole-Sta bilized Acyl An ion Syn th on s
Alan R. Katritzky,* Daming Feng, and Ming Qi
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received September 3, 1997
1-(R-Alkoxyalkyl)benzotriazoles 1a -d add to phenyl vinyl ether to form key intermediates 4a -d ,
which readily undergo lithiation and subsequent trapping by a variety of electrophiles to give the
expected substituted derivatives 7a -d , 9a -c, 11, 13, 15, and 18 in high yields. Subsequent
hydrolysis of these compounds provides a novel high-yield acyl anion synthon approach for the
synthesis of â-alkoxy ketones 8 or R′-functionalized â-alkoxy ketones 10, 12, 14, 16, and 19 by
short procedures from readily available starting materials.
Sch em e 1
Previous work in our group has demonstrated that
benzotriazole is a versatile and reliable synthetic auxil-
iary for the synthesis of complex organic compounds,
including classes difficult to prepare via other methods.1
For example, N-(ethoxybenzyl)benzotriazole (1a ) adds to
ethyl vinyl ether to form intermediate 2, which undergoes
subsequent reactions to give 1,3-diethers 3 (Scheme 1).2
However, while N-(ethoxymethyl)benzotriazoles3a-c and
N-(phenoxymethyl)-benzotriazoles3d are convenient, func-
tionalized acyl anion synthon equivalents, as expected,3d
2 cannot be further lithiated at the methine group. We
now find that 1a -d add to phenyl vinyl ether to form
intermediates 4a -d (Scheme 2), which can now be
readily lithiated and reacted with a wide range of
electrophiles. Subsequent hydrolysis gives â-ethoxy ke-
tones and R′-functionalized â-alkoxy ketones.
Sch em e 2
Resu lts
Ad d ition of 1-(1-Alk oxy-1-a r ylm eth yl)ben zotr ia -
zoles (1) to P h en yl Vin yl Eth er . 1-(1-Alkoxy-1-aryl-
methyl)benzotriazoles 1a -d were prepared in good to
excellent yields from the reaction of aromatic aldehydes
and benzotriazole with the corresponding alcohol or (in
three cases) an ortho-ester (triethyl orthoformate for
1a ,b; trimethyl orthoformate for 1c) in THF with a few
drops of concentrated sulfuric acid as catalyst, according
to our previous report.4
Treatment of compound 1a with 1.2 equiv of phenyl
vinyl ether at 50-60 °C for 12 h, without either solvent
or catalyst, gave [1-(benzotriazol-1-yl)-3-ethoxy-3-phenyl]-
propyl phenyl ether (4a ), as a mixture of two diastereo-
mers (ratio 1:1), in 74% yield (Scheme 2) and 10% of
byproduct [1-(benzotriazol-1-yl)]ethyl phenyl ether (5).
When the reaction was carried out with a catalytic
amount of p-toluenesulfonic acid hydrate (PTS), only 43%
yield of product 4a was obtained, together with 40% of
byproduct 5. [1-(Benzotriazol-1-yl)-3-ethoxy-3-(p-chlo-
rophenyl)]propyl phenyl ether (4b) was prepared in a
similar manner in the absence of PTS from 1b in 71%
yield, with a very small amount of byproduct 5. No
reaction was observed between compounds 1c,d and
phenyl vinyl ether in the absence of PTS, even at 80-90
°C for an extended time (48 h). However, with small
amounts of PTS (∼5%), compounds 1c,d added to phenyl
vinyl ether at 60-70 °C to afford 4c,d in 60% and 67%
yields, respectively; byproduct 5 was also formed in about
10% yield in both cases. The more severe reaction
conditions needed for the addition of compounds 1c,d to
vinyl ether correspond to their higher stabilities and
longer shelf life compared to 1a ,b, which need refrigera-
tion for long-term storage.
(1) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem. Rev.
1997, in press.
(2) Katritzky, A. R.; Rachwal, S.; Rachwal, B.; Steel, P. J . J . Org.
Chem. 1992, 57, 4925.
(3) (a) Katritzky, A. R.; Zhang, G.; J iang, J . J . Org. Chem. 1995,
60, 7589. (b) Katritzky, A. R.; Lang, H. J . Org. Chem. 1995, 60, 7612.
(c) Katritzky, A. R.; Yao, J .; Qi, M. J . Org. Chem. 1997, 23, 8201-
8204. (d) Katritzky, A. R.; Lang, H.; Wang, Z.; Zhu, L. J . Org. Chem.
1996, 61, 7551.
(4) (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. J . Chem. Soc.,
Perkin Trans. 1 1987, 791. (b) Katritzky, A. R.; Bayyuk, S. I.; Rachwal,
S. Synthesis 1991, 279. (c) Katritzky, A. R.; Xie, L.; Serdyuk, L. J . Org.
Chem. 1996, 61, 7564. (d) Katritzky, A. R.; Rachwal, S.; Rachwal, B.
J . Org. Chem. 1989, 54, 6022.
S0022-3263(97)01630-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/18/1998

1474 J . Org. Chem., Vol. 63, No. 5, 1998
Katritzky et al.
Sch em e 3
Sch em e 4
hydrolyzed at 50-60 °C to provide the corresponding R′-
hydroxy-â-alkoxy or R′-amino-â-alkoxy ketones 10a ,b, 12,
and 14. When 15 was hydrolyzed at 50-60 °C, cin-
namoyltrimethylsilane (17) was obtained in 44% yield,
together with 11% of 16.
To introduce further unsaturation into the R′-position
of the ketone, an isothiocyanate, an isocyanate, or ethyl
chloroformate was reacted with carbanion 6a to give
products 18, 20, and 22, respectively, in 90-95% yields
(Scheme 4). Compounds 18, 20, and 22 have low solubil-
ity in EtOH-H2O (1:1) at reflux; they are difficult to
hydrolyze with dilute HCl in EtOH-H2O (1:1). However,
the use of HCl in CH3CN-H2O (1:1) solution hydrolyzed
compound 18 smoothly to give N-phenyl 4-phenyl-4-
ethoxy-2-oxobutyrothioamide (19) in 95% yield. In con-
trast, no desired R-keto ester 21 was obtained from
compound 20. â,γ-Unsaturated R-keto amide 23 was the
only product from the hydrolysis (in CH3CN-H2O) of
intermediate 22, whereas both 23 and â,γ-unsaturated
R-keto ester 24 were formed when hydrolysis of 22 was
carried out in EtOH-H2O. Compound 24 was formed
from the esterification of the amide 23 in ethanol.
P r ep a r a tion of â-Alk oxy Keton es. As expected,3d
1-(benzotriazol-1-yl)-3-alkoxy-3-arylpropyl phenyl ethers
4a ,c can easily be lithiated site-specifically at the position
R to both the benzotriazolyl and phenoxy groups to form
intermediates 6 (Scheme 2). Intermediates 6 can be
trapped with 1.0 equiv of methyl or ethyl iodide at -78
°C for 10 min to give products 7a -c in 82-96% yields.
Subsequent hydrolysis of 7a -c in dilute HCl in EtOH-
H2O (1:1) at room temperature for 5-7 h produced
â-alkoxy-substituted ketones 8a -c in 76-96% yields.
Treatment of 4a with 1.0 equiv of n-BuLi at -78 °C and
then reaction with 1.0 equiv of 1-iodohexane at -78 °C
for 5 h, followed by warming to room temperature for 1
h, gave product 7d in 66% yields. If 1-iodohexane was
replaced by 1-bromohexane, only 15% of 7d was obtained,
regardless of whether 1-bromohexane was added before
n-BuLi or after. Further hydrolysis of 7d under the same
conditions for 12 h produced â-ethoxy-substituted ketones
8d in 93% yield.
Discu ssion
P r ep a r a tion of r′-F u n ction a lized â-Alk oxy Ke-
ton es. Intermediates 6a ,d can also react with ketones,
an aldehyde, N-[(4-methyl)benzylidene]aniline, and chlo-
rotrimethylsilane to give compounds 9a -c, 11, 13, and
15, respectively (Scheme 3), all of which were isolated
by column chromatography. In the carbonyl compound
reactions, the aromatic ketone or aldehyde gave excellent
yields of product 9a or 11; however, when aliphatic
ketones were used as electrophiles, 50% of starting
materials 4a or 4d was recovered. The yields reported
of 9b,c are based on the consumed starting materials.
As mentioned above, compounds 7a -d can be hydro-
lyzed at room temperature, and compounds 9c and 15
under similar conditions gave 10c and â-alkoxyacylsilane
16. However, some substituted analogues need elevated
temperatures. Thus, compounds 9a ,b, 11, and 13 were
â-Alkoxy ketone units frequently occur in antibiotics,
such as lasalocid A.5 They are usually prepared by one
of two methods: (i) ether exchange of â-alkoxy ketones6
or (ii) the reaction of silyl enol ethers with acetals7 or
(5) Ireland, R. E.; Thaisrivongs, S.; Vanier, N.; Wilcox, C. S. J . Org.
Chem. 1980, 45, 48.
(6) Pulkkinen, J . T.; Vepsa¨la¨inen, J . J . J . Org. Chem. 1996, 61, 8604
and references therein.
(7) (a) Hosomi, A.; Hashimoto, H.; Kobayashi, H.; Sakurai, H. Chem.
Lett. 1979, 245. (b) Dawe, R. D.; Fraser-Reid, B. J . Chem. Soc., Chem.
Commun. 1981, 1180. (c) Teijin Ltd. J pn. Kokai Tokyo Koho J P 81,-
108,726, 1981; Chem. Abstr. 1982, 96, 142461g. (d) Mukaiyama, T.;
Kobayashi, S.; Murakami, M. Chem. Lett. 1984, 1759. (e) Iwasawa,
N.; Mukaiyama, T. Chem. Lett. 1987, 463. (f) Murata, S.; Suzuki, M.;
Noyori, R. Tetrahedron 1988, 44, 4259. (g) Tester, R.; Varghese, V.;
Montana, A. M.; Khan, M.; Nicholas, K. M. J . Org. Chem. 1990, 55,
186. (h) Yoshimatsu, M.; Shimizu, H.; Kataoka, T. J . Chem. Soc., Chem.
Commun. 1995, 149.

Synthesis of â-Alkoxy Ketones
J . Org. Chem., Vol. 63, No. 5, 1998 1475
R-chloro ethers.8 These two and other methods9 all
involved the formation for two components, i.e., O +
C-C-C(:O)-C or O-C + C-C(:O)-C. In our new
approach, the three components O-C + C-C(:O) + C are
combined using umpolung and a masked acyl anion
equivalent.
chromatography on silica gel (hexane/ethyl acetate, 13:1) to
give 4a , as two separable diastereomers. Isomer I: 33% yield;
1
colorless oil; H NMR δ 1.15 (t, 3 H, J ) 7.0 Hz), 2.71-2.82
(m, 1 H), 2.88-3.02 (m, 1 H), 3.10-3.87 (m, 2 H), 3.89 (dd, 1
H, J ) 9.6 and 4.3 Hz), 6.83-7.00 (m, 3 H), 7.02-7.50 (m, 10
H), 7.76 (d, 1 H, J ) 8.2 Hz), 8.04 (d, 1H J ) 8.3 Hz); 13C
NMR δ 15.2, 43.0, 64.4, 77.4, 85.6, 110.9, 116.5, 120.3, 122.9,
124.3, 126.4, 127.8, 128.0, 128.6, 129.6, 131.5, 140.9, 146.6,
156.0. Anal. Calcd for C23H23N3O2: C, 73.97; H, 6.21; N,11.25.
Found: C, 73.62; H, 6.43; N, 11.10.
There are few previous reports of R′-functionalized
â-alkoxy ketones of the type presently prepared. Isolated
examples of the synthesis of R′-hydroxy-â-alkoxy ketones
from the double hydroxylation of â-alkoxy vinyl bro-
mide,10 the oxidation of â-alkoxy trimethylsilyl enol
ether,11 and other routes12 have been reported. R′-Amino-
â-alkoxy ketones were prepared from R′-bromo-â-alkoxy
ketones13 and R′,â′-epoxy-â-alkoxy ketones,14 but no
general method has been published. The silyl enol ethers
of acylsilanes [RCHdC(SiMe3)OSiMe3] were reacted ef-
fectively with acetals in the presence of BF3‚Et2O to give
â-alkoxyacylsilanes;15 however, the starting material is
difficult to prepare. â,γ-Unsaturated R-keto amides have
been synthesized from palladium-catalyzed double-car-
bonylations of alkenyl halides,16 but only secondary
amides were reported.
Isomer II: 41% yield; white solid; mp 76-78 °C; 1H NMR δ
1.10 (t, 3 H, J ) 7.0 Hz), 2.46-2.61 (m, 1 H), 2.80-2.95 (m, 1
H), 3.15-3.46 (m, 2 H), 4.68 (dd, 1 H, J ) 10.3, 3.2 Hz), 6.86-
7.06 (m, 3 H), 7.10-7.51 (m, 10 H), 7.72 (d, 1 H, J ) 8.2 Hz),
8.01 (d, 1 H, J ) 8.2 Hz); 13C NMR δ 15.1, 43.5, 64.2, 77.4,
85.7, 110.9, 116.8, 120.0, 123.1, 124.1, 126.4, 127.5, 127.9,
128.6, 129.6, 131.5, 141.3, 146.6, 156.4. Anal. Calcd for
C
23H23N3O2: C, 73.97; H, 6.21; N, 11.25. Found: C, 73.72; H,
6.60; N, 10.77.
1-(Ben zotr ia zol-1-yl)eth yl p h en yl eth er (5) was obtained
as a byproduct from the reaction of compound 1a and phenyl
vinyl ether, in 10% yield: white solid; mp 60-62 °C; 1H NMR
δ 2.00 (d, 3 H, J ) 6.3 Hz), 6.88 (t, 1 H, J ) 7.4 Hz), 6.95 (d,
2 H, J ) 8.2 Hz), 7.02 (q, 1 H, J ) 6.3 Hz), 7.13 (t, 2 H, J )
7.5 Hz), 7.27 (t, 1 H, J ) 7.4 Hz), 7.40 (t, 1 H, J ) 7.2 Hz),
7.78 (d, 1 H, J ) 8.4 Hz), 7.99 (d, 1 H, J ) 8.2 Hz); 13C NMR
δ 20.9, 84.4, 110.8, 116.1, 119.8, 122.7, 124.0, 127.4, 129.4,
130.8, 146.4, 155.6. Anal. Calcd for C14H13N3O: C, 70.28; H,
5.48; N,17.56. Found: C, 70.32; H, 5.49; N, 17.78.
In comparison to these aforementioned routes, our new
approach provides a general and versatile method to
synthesize â-alkoxy ketones with or without an R′-
functional group.
[2-(Ben zotr iazol-1-yl)-4-ph en yl-4-eth oxy]-2-bu tyl P h en -
yl Eth er (7a ). To a solution of [1-(benzotriazol-1-yl)-3-ethoxy-
3-phenyl]propyl phenyl ether (4a , 1.12 g, 3 mmol) in dry THF
(50 mL) at -78 °C was added n-BuLi (1.6 M, 2.3 mL), then
the solution was stirred at this temperature for 5-10 min, and
methyl iodide (0.42 g, 3 mmol) was added. After stirring at
-78 °C for 10-30 min, the solution was quenched by water
(50 mL), extracted with ether, and washed with water. The
organic extracts were dried (MgSO4) and concentrated to give
a residue which was purified by column chromatography on
silica gel (hexane/ethyl acetate, 15:1) to give the pure product
(referred to as procedure A later in this paper), as two
separable diastereomers (ratio 1:1), in a total yield of 96%.
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points were determined on
a hot stage apparatus without correction. 1H (300 MHz) and
13C NMR (75 MHz) spectra were recorded in CDCl3 with TMS
or CDCl3, respectively, as the internal reference. Column
chromatography was carried out on MCB silica gel (230-400
mesh). Tetrahydrofuran (THF) was freshly distilled from
sodium-benzophenone. Lithiation reactions were carried out
under the protection of dry nitrogen.
The preparation and characterization of 1-(1-alkoxybenzyl)-
benzotriazoles 1a -c have been reported by this laboratory.4a-c
1-[(1-Bu toxy-1-p h en yl)m eth yl]ben zotr ia zole (1d ) was
prepared from benzotriazole, benzaldehyde, and n-butanol by
the method previously reported,4d in 54% yield: colorless oil;
1H NMR δ 0.84 (t, 3 H, J ) 7.3 Hz), 1.25-1.47 (m, 2 H), 1.50-
1.68 (m, 2 H), 3.31-3.44 (m, 1 H), 3.65-3.77 (m, 1 H), 7.28 (s,
1 H), 7.24-7.50 (m, 8 H), 8.01-8.12 (m, 1 H); 13C NMR δ 13.6,
19.1, 31.1, 69.0, 89.6, 111.5, 119.7, 124.0, 125.8, 127.2, 128.4,
128.8, 130.9, 136.3, 146.9. Anal. Calcd for C17H19N3O: C,
72.57; H, 6.81; N, 14.93. Found: C, 72.73; H, 6.95; N, 15.15.
[1-(Ben zotr ia zol-1-yl)-3-eth oxy-3-p h en yl]p r op yl P h en -
yl Eth er (4a ). 1-(1-Ethoxybenzyl)benzotriazole (1a , 2.53 g,
10 mmol) was mixed with phenyl vinyl ether (1.2 equiv) and
the mixture was stirred at 60-70 °C for 12 h. The reaction
mixture was cooled, extracted with ether, and washed with
water. The organic extracts were dried (MgSO4) and concen-
trated to give a residue which was purified by column
1
Isomer I: colorless oil; H NMR δ 0.84 (t, 3 H, J ) 7.0 Hz),
2.28 (s, 3 H), 2.66 (dd, 1 H, J ) 14.8, 1.9 Hz), 2.90 (dd, 1 H, J
) 14.8, 9.1 Hz), 2.97-3.23 (m, 2 H), 4.58 (dd, 1 H, J ) 9.1, 1.9
Hz), 6.97 (d, 2 H, J ) 7.1 Hz), 6.92-7.13 (m, 3 H), 7.14-7.53
(m, 7 H), 7.97 (d, 1 H, J ) 8.3 Hz), 8.09 (d, 1 H, J ) 8.1 Hz);
13C NMR δ 14.9, 23.5, 49.3, 63.9, 77.9, 95.1, 113.1, 119.8, 120.8,
124.0, 126.2, 127.4, 127.6, 128.5, 129.3, 129.4, 132.6, 142.3,
146.9, 153.6. Anal. Calcd for C24H25N3O2: C, 74.39; H, 6.50;
N,10.84. Found: C, 74.07; H, 6.81; N, 10.66.
1
Isomer II: white solid; mp 79-81 °C; H NMR δ 1.08 (t, 3
H, J ) 7.1 Hz), 2.30 (s, 3 H), 2.75-2.95 (m, 2 H), 2.97-3.30
(m, 2 H), 3.72 (dd, 1 H, J ) 8.3, 3.6 Hz), 6.41 (d, 2 H, J ) 7.8
Hz), 6.85-7.29 (m, 8 H), 7.37-7.53 (m, 2 H), 7.94 (d, 1 H, J )
7.8 Hz), 8.12 (d, 1 H, J ) 7.7 Hz); 13C NMR δ 15.1, 23.6, 49.9,
64.2, 77.6, 95.5, 113.0, 115.5, 120.0, 121.3, 124.2, 126.0, 127.5,
127.7, 128.4, 129.4, 132.4, 141.9, 146.9, 153.4. Anal. Calcd for
C
24H25N3O2: C, 74.39; H, 6.50; N, 10.84. Found: C, 74.51; H,
6.68; N, 10.82.
(8) Hosomi, A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1983, 405.
(9) Takahashi, M.; Suzuki, H.; Moro-Oka, Y.; Ikawa, T. Tetrahedron
Lett. 1982, 23, 1079.
(10) Fattori, D.; Guchteneere, E.; Vogel, P. Tetrahedron Lett. 1989,
30, 7415.
(11) Cox, P. J .; Simpkins, N. S. Synlett 1991, 321.
(12) Brehm, M.; Dauben, W. G.; Ko¨hler, P.; Lichtenthaler, F. W.
Angew. Chem., Int. Ed. Engl. 1987, 26, 1271.
(13) Danishefsky, S.; Morris, J .; Mullen, G.; Gammill, R. J . Am.
Chem. Soc. 1980, 102, 2838.
(14) Zvonok, A. M.; Kuz′menok, N. M.; Stanishevskii, L. S. Chem.
Heterocycl. Compd. (Engl. Transl.) 1988, 250.
(15) Sato, T.; Arai, M.; Kuwajima, I. J . Am. Chem. Soc. 1977, 99,
5827.
(16) (a) Ozawa, F.; Soyama, H.; Yamamoto, T.; Yamamoto, A.
Tetrahedron Lett. 1982, 23, 3383. (b) Son, T.-i.; Yanagihara, H.; Ozawa,
F.; Yamamoto, A. Bull. Chem. Soc. J pn. 1988, 61, 1251.
Gen er a l P r oced u r e for th e P r ep a r a tion of 8a -d .
Compounds 7 (1-2 mmol) were dissolved in a mixture of
ethanol (25 mL), water (25 mL), and concentrated HCl (1 mL)
and stirred at rt for 12 h. The resulting solution was extracted
with ether and washed with saturated aqueous Na2CO3
solution. The organic extracts were dried (MgSO4) and
concentrated to give a residue which was separated by column
chromatography (hexane/ethyl acetate 15:1) (referred to as
procedure B later in this paper).
1-P h en yl-1-eth oxy-3-bu ta n on e (8a ): 76% yield; colorless
oil; 1H NMR δ 1.14 (t, 3 H, J ) 7.1 Hz), 2.16 (s, 3 H), 2.60 (dd,
1 H, J ) 15.7, 4.2 Hz), 2.97 (dd, 1 H, J ) 15.7, 9.0 Hz), 3.25-
3.44 (m, 2 H), 4.75 (dd, 1 H, J ) 9.1, 4.4 Hz), 7.22-7.45 (m, 5
H); 13C NMR δ 15.1, 31.0, 52.1, 64.3, 77.8, 126.4, 127.7, 128.5,

1476 J . Org. Chem., Vol. 63, No. 5, 1998
Katritzky et al.
141.8, 206.6. Anal. Calcd for C12H16O2: C, 74.97; H, 8.39.
Found: C, 74.91; H, 8.54.
130.2, 131.4, 134.1, 138.0, 141.2, 146.1, 148.6, 203.8 and 204.3.
Anal. Calcd for C25H27NO2: C, 80.40; H, 7.29; N, 3.75.
Found: C, 80.33; H, 7.32; N, 3.13.
1,1,4-Tr ip h e n yl-2-(b e n zot r ia zol-1-yl)-2-p h e n oxy-4-
eth oxybu ta n ol (9a ) was obtained from the reaction of 4a and
benzophenone (procedure A) in 90% yield: white microcrystals;
mp 173-176 °C; 1H NMR (two diastereomers, 1:1) δ 1.01 (t, J
) 6.9 Hz) and 1.15 (t, J ) 7.2 Hz) (total 3 H), 2.26-2.37 (m)
and 2.89-3.51 (m) (total 4 H), 4.05 (dd, J ) 17.1, 9.9 Hz) and
4.56 (d, J ) 9.6 Hz) (total 1 H), 5.91 (br s) and 6.18 (d, J ) 7.8
Hz) (total 1 H), 6.45-7.44 (m, 21 H), 7.84 (d, J ) 7.8 Hz) and
7.93 (d, J ) 7.8 Hz) (total 1 H), 8.10 (d, 2 H, J ) 7.2 Hz); 13C
NMR δ 14.7 and 14.9, 43.2 and 44.0, 63.4 and 64.2, 76.3 and
79.3, 81.9 and 82.5, 100.5 and 102.4, 113.8, 118.5, 118.6, 118.9,
119.4, 123.0, 123.1, 123.5, 125.6, 126.4, 126.6, 126.9, 127.0,
127.1, 127.2, 127.3, 127.7, 127.9, 128.0, 128.4, 128.5, 128.7,
129.1, 129.6, 129.8, 134.3, 141.3, 141.5, 141.7, 142.6, 144.1,
145.1, 153.2, 153.9. Anal. Calcd for C36H33N3O3: C, 77.81; H,
5.99; N, 7.56. Found: C, 77.54; H, 6.37; N, 7.41.
[1-(Be n zot r ia zol-1-yl)-1-t r im e t h ylsilyl-3-p h e n yl-3-
eth oxy]p r op yl p h en yl eth er (15) was obtained from the
reaction of compound 4a and chlorotrimethylsilane (procedure
A, except the reaction mixture was warmed to rt before being
quenched) in 71% yield: white microcrystals; mp 59-61 °C;
1H NMR (two diastereomers, about 1:1) δ 0.25 (s) and 0.29 (s)
(total 9 H), 0.61 (t, J ) 7.1 Hz) and 0.78 (t, J ) 7.1 Hz) (total
3 H), 2.57-2.71 (m) and 2.98-3.11 (m) (total 1 H), 2.75-2.97
(m) and 3.30-3.53 (m) (total 3 H), 4.42 (d, J ) 8.8 Hz) and
4.57 (dd, J ) 7.6, 2.7 Hz) (total 1 H), 6.46 (d, 1 H, J ) 7.7 Hz),
6.52 (d, 1 H, J ) 7.9 Hz), 6.85-7.42 (m, 10 H), 7.58 (d, J ) 8.2
Hz) and 7.72-7.75 (m) (total 1 H), 7.97-8.08 (m, 1 H); 13C
NMR δ -0.8 and -0.1, 14.5, 45.6 and 47.9, 63.3, 76.9, 94.9
and 95.4, 113.5, 114.0, 119.4, 119.5, 120.5 and 120.6, 123.3
and 123.4, 123.7, 126.0 and 126.2, 126.9, 127.3 and 127.4,
128.3, 129.0 and 129.2, 133.9 and 134.0, 142.5 and 142.8, 146.0,
155.5 and 155.9. Anal. Calcd for C26H31N3O2Si: C, 70.08; H,
7.01; N, 9.43. Found: C, 69.67; H, 6.97; N, 9.25.
1,1,4-Tr ip h en yl-1-h yd r oxy-4-eth oxy-2-bu ta n on e (10a )
was obtained from the hydrolysis of 9a (procedure B) in 89%
1
yield: colorless oil; H NMR δ 1.07 (t, 3 H, J ) 7.2 Hz), 2.52
(dd, 1 H, J ) 15.6, 4.2 Hz), 3.17-3.46 (m, 3 H), 4.77 (dd, 1 H,
J ) 9.3, 4.2 Hz), 5.29 (s, 1 H), 7.07-7.38 (m, 13 H), 7.40-7.52
(m, 2 H); 13C NMR δ 14.9, 47.1, 64.3, 78.2, 85.0, 126.3, 127.5,
127.6, 127.7, 127.9, 128.1, 128.3, 128.7, 128.8, 140.7, 141.3,
142.1, 208.7. Anal. Calcd for C24H24O3: C, 79.97; H, 6.71.
Found: C, 79.91; H, 7.08.
(3-P h en yl-3-eth oxy)p r op a n oyltr im eth ylsila n e (16) was
obtained from the hydrolysis of 15 (procedure B, except at rt
for 4 h) in 67% yield: orange oil; 1H NMR δ 0.17 (s, 9 H), 1.12
(t, 3 H, J ) 7.1 Hz), 2.65 (dd, 1 H, J ) 15.7, 4.4 Hz), 3.21-
3.37 (m, 3 H), 4.78 (dd, 1 H, J ) 8.5, 4.4 Hz), 7.22-7.45 (m, 5
H); 13C NMR δ -3.5, 15.2, 55.9, 64.1, 77.1, 126.4, 127.4, 128.4,
142.4, 246.9. Anal. Calcd for C14H22O2Si: C, 67.15; H, 8.86.
Found: C, 67.35; H, 8.98.
1,4-Dip h en yl-2-(b en zot r ia zol-1-yl)-2-p h en oxyl-4-et h -
oxybu ta n ol (11) was obtained from the reaction of 4a and
benzaldehyde (procedure A). A single diastereomer was
isolated by recrystallization from diethyl ether/hexanes in 83%
Cin n a m oyltr im eth ylsila n e (17) was obtained from the
hydrolysis of compound 15 using procedure B in 44% yield
1
1
yield: white microcrystals; mp 204-206 °C; H NMR δ 1.28
(together with 11% of compound 16): orange oil; H NMR δ
(t, 3 H, J ) 7.2 Hz), 3.20 (d, 1 H, J ) 16.5 Hz), 3.41 (q, 2 H, J
) 7.2 Hz), 3.59 (dd, 1 H, J ) 16.5, 9.9 Hz), 4.65 (d, 1 H, J )
9.9 Hz), 5.59 (s, 1 H, OH), 5.64 (s, 1 H), 6.66 (d, 2 H, J ) 8.1
Hz), 6.70-6.80 (m, 2 H), 6.86-7.08 (m, 8 H), 7.09-7.24 (m, 7
H), 7.90 (d, 1 H, J ) 8.4 Hz); 13C NMR δ 14.9, 44.1, 64.5, 76.5,
80.4, 97.5, 113.5, 118.6, 118.9, 123.3, 123.5, 125.6, 127.2, 127.4,
127.8, 128.0, 128.1, 128.5, 129.9, 134.1, 137.1, 141.3, 145.4,
154.3; HRMS (CI) m/z calcd for C30H29N3O3 + H 480.2287,
found 480.2283.
0.31 (s, 9 H), 6.88 (d, 1 H, J ) 16.5 Hz), 7.21-7.43 (m, 4 H),
7.44-7.58 (m, 2 H); 13C NMR δ -2.1, 128.2, 128.9, 130.4, 131.2,
134.9, 142.7, 236.0. Anal. Calcd for C12H16OSi: C, 70.53; H,
7.89. Found: C, 70.14; H, 7.79.
N-P h en yl-[2-(ben zotr ia zol-1-yl)-2-p h en oxy-4-p h en yl-4-
eth oxy]bu tyr oth ioa m id e (18) was obtained from the reac-
tion of compound 4a and phenyl isothiocyanate (procedure A)
in 93% yield (two diastereomers, ratio 1.7:1): green micro-
1
crystals; mp 168-171 °C; H NMR δ 0.91 (t, J ) 7.1 Hz) and
1,4-Dip h en yl-1-h yd r oxy-4-eth oxy-2-bu ta n on e (12) was
obtained from the hydrolysis of 11 (procedure B) in 54%
yield: green microcrystals; mp 40-42 °C; 1H NMR (single
isomer) δ 1.10 (t, 3 H, J ) 7.2 Hz), 2.61 (dd, 1 H, J ) 15.4, 5.8
Hz), 2.96 (dd, 1 H, J ) 15.4, 8.0 Hz), 3.21-3.40 (m, 2 H), 4.42
(d, 1 H, J ) 3.6, Hz), 4.71 (dd, 1 H, J ) 7.9, 6.1 Hz), 4.90 (d,
1 H, J ) 3.3 Hz), 7.15-7.45 (m, 10 H); 13C NMR δ 15.1, 46.6,
64.3, 77.8, 80.0, 126.4, 127.4, 128.0, 128.5, 128.6, 128.8, 137.4,
140.9, 207.3. Anal. Calcd for C18H20O3: C, 76.03; H, 7.09.
Found: C, 76.32; H, 7.35.
1-[1-(p-Tolyl)-2-(ben zotr ia zol-1-yl)-2-p h en oxy-4-p h en -
yl-4-eth oxy]bu tyla n ilin e (13) was obtained as one predomi-
nant isomer from the reaction of 4a and N-[(4-methyl)-
benzylidene]aniline (procedure A) in 92% yield: yellow
microcrystals; mp 98-101 °C; 1H NMR δ 1.16 (t, 3 H, J ) 7.2
Hz), 2.15 (s, 3 H), 3.20 (q, 2 H, J ) 7.0 Hz), 3.29 (dd, 1 H, J )
15.9, 9.3 Hz), 3.69 (dd, 1 H, J ) 15.6, 3.6 Hz), 4.77 (dd, 1 H, J
) 9.3, 3.6 Hz), 5.12 (d, 1 H, J ) 8.1 Hz), 5.32 (d, 1 H, J ) 8.4
Hz), 6.48 (d, 2 H, J ) 8.4 Hz), 6.53-6.80 (m, 7 H), 6.81-7.43
(m, 12 H), 7.76 (d, J ) 7.8 Hz), 7.95 (d, J ) 8.4 Hz) (total 2 H);
13C NMR δ 15.4, 20.9, 39.9, 62.7, 64.0, 78.2, 98.5, 113.4, 113.8,
117.7, 118.1, 119.0, 119.7, 123.0, 123.7, 126.5, 127.2, 127.7,
128.3, 128.4, 128.7, 129.1, 133.1, 137.6, 141.8, 146.0, 154.1.
Anal. Calcd for C37H36N4O2: C, 78.14; H, 6.38; N, 9.85.
Found: C, 78.42; H, 6.37; N, 9.70.
1.22 (t, J ) 6.9 Hz) (total 3 H), 3.06-3.22 (m) and 4.03 (dd, J
) 15.5, 10.2 Hz) (total 3 H), 3.57 (dd, J ) 15.4, 2.5 Hz) and
3.69 (dd, J ) 15.6, 2.4 Hz) (total 1 H), 4.87 (dd, J ) 10.7, 2.8
Hz) and 4.69 (dd, J ) 10.0, 2.2 Hz) (total 1 H), 6.61 (t, 2 H, J
) 7.8 Hz), 6.47-6.85 (m, 14 H), 8.01-8.11 (m, 3 H), 11.14 (s)
and 10.96 (s) (total 1 H); 13C NMR δ 15.5 and 15.0, 42.4 and
43.7, 64.2, 76.8 and 78.6, 97.2 and 98.8, 111.4 and 111.9, 119.2
and 120.3, 120.2 and 122.1, 122.4 and 122.6, 124.3 and 124.6,
125.5, 126.4 and 126.5, 127.1 and 127.4, 127.8, 127.9 and 128.0,
128.4 and 128.5, 129.1 and 129.3, 129.4 and 129.8, 131.9 and
132.3, 137.9 and 138.1, 141.3 and 141.5, 146.6 and 146.7, 152.2
and 152.5, 191.3 and 192.9. Anal. Calcd for C30H28N4O2S: C,
70.84; H, 5.55; N, 11.02. Found: C, 70.91; H 5.76; N, 10.74.
N-P h en yl (2-oxo-4-ph en yl-4-eth oxy)bu tyr th ioam ide (19)
was obtained from the hydrolysis of 15 (procedure B, except
1
at rt for 4 h) in 95% yield: red oil; H NMR δ 1.14 (t, 3 H, J
) 7.1 Hz), 3.32-3.42 (m, 2 H), 3.46 (dd, 1 H, J ) 16.8, 4.4
Hz), 3.82 (dd, 1 H, J ) 16.8, 9.0 Hz), 4.91 (dd, 1 H, J ) 9.0,
4.4 Hz), 7.18-7.60 (m, 8 H), 7.97 (d, 2 H, J ) 7.8 Hz), 10.5 (s,
1 H); 13C NMR δ 15.0, 45.3, 64.2, 77.8, 121.6, 126.5, 126.9,
127.7, 128.4, 128.8, 137.6, 141.2, 184.6, 190.8. Anal. Calcd for
C
18H19NO2S: C, 68.98; H, 6.11; N, 4.47. Found: C, 69.23; H,
6.09; N, 4.68.
Eth yl [2-(ben zotr iazol-1-yl)-2-ph en oxy-4-eth oxy-4-ph en -
yl]bu tyr oa te (20) was obtained from the reaction of 4a and
ethyl chloroformate (procedure A) in 89% yield: yellow mi-
crocrystals; mp 113-116 °C; 1H NMR (two diastereomers, 1:1)
δ 1.03 (t, J ) 7.0 Hz) and 1.08 (t, J ) 7.1 Hz) (total 3 H), 1.17
(t, J ) 7.1 Hz) and 1.28 (t, J ) 7.1 Hz) (total 3 H), 2.95-3.62
(m, 4 H), 4.14-4.41 (m, 2 H), 4.72 (dd, J ) 10.4, 1.2 Hz) and
4.86 (dd, J ) 8.8, 2.3 Hz) (total 1 H), 6.37 (d, 1 H, J ) 7.7 Hz),
6.59 (d, 1 H, J ) 8.0 Hz), 6.82-7.63 (m, 10 H), 7.67 (d, J ) 8.2
Hz) and 7.78 (d, J ) 8.2 Hz) (total 1 H), 8.07 (d, J ) 8.2 Hz)
and 8.12 (d, J ) 8.2 Hz) (total 1 H); 13C NMR δ 13.7 and 13.8,
1-(p -Tolyl)-1-p h e n yla m in o-4-p h e n yl-4-e t h oxy-2-b u -
ta n on e (14) was obtained from the hydrolysis of 13 (procedure
B) in 64% yield: green oil; 1H NMR (two diastereomers, about
1:1) δ 1.11 (t, 3 H, J ) 7.2 Hz), 2.26 (s) and 2.30 (s) (total 3 H),
2.32-3.05 (m, 2 H), 3.28-3.44 (m, 2 H), 4.76 (dd, 1 H, J )
8.7, 4.2 Hz), 5.07 (s, 1 H), 5.37 (s, 1 H), 6.45-6.66 (m, 3 H),
7.01-7.95 (m, 11 H); 13C NMR δ 15.1, 21.0 and 21.8, 47.8, 64.1
and 64.4, 67.7 and 68.4, 78.1, 113.3, 117.4, 122.5, 126.2, 126.5,
127.6, 127.8, 128.0, 128.4, 128.5, 128.8, 129.0, 129.6, 129.8,

Synthesis of â-Alkoxy Ketones
J . Org. Chem., Vol. 63, No. 5, 1998 1477
14.7 and 14.8, 41.4 and 43.4, 62.2 and 62.6, 63.9 and 64.5, 76.1
and 77.0, 91.1 and 92.7, 112.4 and 114.1, 115.4, 119.8, 120.0
and 121.3, 124.1 and 124.4, 124.5 and 124.7, 125.9, 126.5, 127.6
and 127.7, 127.8 and 128.2, 128.3 and 129.2, 129.3 and 129.4,
132.1 and 132.9, 141.2 and 141.7, 146.2, 152.2 and 152.7, 166.0
and 166.2. Anal. Calcd for C26H27N3O4: C, 70.10; H, 6.11; N,
9.43. Found: C, 70.25; H, 6.34; N, 8.89.
N-Isop r op yl-2-oxo-4-p h en yl-bu t-3-en a m id e (23) was ob-
tained from the hydrolysis of compound 22 (procedure B,
except in refluxing CH3CN-H2O (1:1) for 12 h) in 75% yield:
1
green microcrystals; mp 72-73 °C; H NMR δ 1.24 (d, 6 H, J
) 6.6 Hz), 4.03-4.22 (m, 1 H), 7.05 (br s, 1 H), 7.32-7.54 (m,
3 H), 7.59-7.63 (m, 2 H), 7.78 (d, 1 H, J ) 16.1 Hz), 7.94 (d,
1 H, J ) 16.1 Hz); 13C NMR δ 22.4, 41.7, 118.8, 129.0, 129.1,
131.3, 134.4, 147.7, 160.4, 185.8. Anal. Calcd for C13H15NO2:
C, 71.87; H, 6.96; N, 6.45. Found: C, 72.09; H, 7.21; N, 6.07.
Eth yl 2-oxo-4-p h en yl-bu t-3-en oa te (24)17 was obtained
as a byproduct from the hydrolysis of 22 (procedure B) in 46%
N-Isop r op yl-[2-(ben zotr ia zol-1-yl)-2-p h en oxy-4-p h en -
yl-4-eth oxy]bu tyr a m id e (22) was obtained from the reaction
of 4a and isopropyl isocyanate (procedure A) in 95% yield:
1
white microcrystals; mp 183-186 °C; H NMR (two diastere-
1
omers, 1:1) δ 1.03-1.22 (m, 3 H), 1.23-1.50 (m, 6 H), 3.00 (dd,
J ) 15.1, 9.8 Hz) and 3.64 (dd, J ) 15.4, 10.2 Hz) (total 1 H),
3.15-3.48 (m, 3 H), 4.12-4.37 (m, 1 H), 4.60 (d, J ) 9.9 Hz)
and 4.68 (d, J ) 9.6 Hz) (total 1 H), 6.43 (d, 1 H, J ) 7.6 Hz),
6.53 (d, 1 H, J ) 8.0 Hz), 6.90-7.17 (m, 4 H), 7.18-7.55 (m, 7
H), 7.67 (d, J ) 8.2 Hz) and 7.74 (d, J ) 8.2 Hz) (total 1 H),
8.05 (d, J ) 8.2 Hz) and 8.09 (d, J ) 8.4 Hz) (total 1 H); 13C
NMR δ 15.0 and 15.3, 22.4 and 22.5, 22.7 and 22.8, 41.2, 42.2
and 42.4, 63.8 and 64.1, 76.1 and 77.7, 92.7 and 93.5, 111.5
and 111.6, 119.1 and 120.1, 121.9, 124.2 and 124.3, 125.0, 126.2
and 126.4, 127.7, 127.6 and 127.8, 128.4, 129.3 and 129.7, 132.2
and 132.5, 141.5 and 142.0, 146.5 and 146.6, 151.9 and 152.5,
165.1 and 165.2. Anal. Calcd for C27H30N4O3: C, 70.72; H,
6.59; N, 12.22. Found: C, 70.97; H, 6.93; N, 12.25.
yield (together with 35% of 23): colorless oil; H NMR δ 1.42
(t, 3 H, J ) 7.1 Hz), 4.40 (q, 2 H, J ) 7.1 Hz), 7.24-7.53 (m,
4 H), 7.54-7.73 (m, 2 H), 7.87 (d, 1 H, J ) 16.2 Hz); 13C NMR
δ 14.0, 62.4, 120.7, 129.0, 129.1, 131.6, 134.1, 148.4, 162.2,
182.9.
Su p p or tin g In for m a tion Ava ila ble: Full detailed analy-
sis data (1H NMR, 13C NMR, and microanalysis) of compounds
1
4b-d , 7b-d , 8b-d , 9b,c, and 10b,c, and H NMR, 13C NMR,
and HRMS spectra for intermediate 11 (8 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information and Internet access instructions.
(17) Sugimura, H.; Yoshida, K. Bull. Chem. Soc. J pn. 1992, 65, 3209.
J O971630V