High-intensity ultrasound-promoted reformatsky reactions

Article abstract of DOI:10.1021/jo0261395

Reformatsky reactions of a phenyl ketone, an α-bromoester, zinc dust, and a catalytic amount of iodine in dioxane under high-intensity ultrasound (HIU) irradiation from an ultrasonic probe give high yields of β-hydroxyesters in short reaction times. A ser

Full text of DOI:10.1021/jo0261395

High -In ten sity Ultr a sou n d -P r om oted Refor m a tsk y Rea ction s
Nathan A. Ross and Richard A. Bartsch*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409
richard.bartsch@ttu.edu
Received J uly 3, 2002
Reformatsky reactions of a phenyl ketone, an R-bromoester, zinc dust, and a catalytic amount of
iodine in dioxane under high-intensity ultrasound (HIU) irradiation from an ultrasonic probe give
high yields of â-hydroxyesters in short reaction times. A series of alkyl phenyl ketones with
increasing steric demands of the alkyl group are evaluated as potential electrophiles for the reactions
with several R-bromoesters, also having increasing steric demands. The Reformatsky reaction under
HIU is found to be concentration dependent.
SCHEME 1. Refor m a tsk y Rea ction
In tr od u ction
A classic reaction in organic chemistry is the zinc-
induced formation of â-hydroxyesters from R-haloesters
and aldehydes or ketones known as the Reformatsky
reaction (Scheme 1).1 The scope of the Reformatsky
reaction has progressed through the years and is the
subject of several reviews.2-5 An underlying problem with
the classical protocol of using zinc dust is its low
reactivity. It is necessary to “activate” the zinc dust to
initiate the reaction. Control of the resulting exothermic
reaction has also been a problem. Improvements in yields
of the Reformatsky reaction have been achieved when
freshly prepared zinc powder,6 a heated column of zinc
dust,7 a trimethyl borate-THF solvent system,8 a cop-
per-zinc couple,9 acid-washed zinc,10 and trimethylchlo-
rosilane11 were utilized.
In some instances, ultrasonic irradiation can be utilized
to advantage as an alternative for organic reactions
ordinarily accomplished by heating.12,13 Han and Boud-
jouk14 reported that the use of a low-intensity ultrasonic
(LIU) laboratory cleaning bath greatly improved the rates
and yields for Reformatsky reactions of simple aldehydes
and ketones with ethyl bromoacetate. However, the zinc
dust still had to be “activated” using the “Cava” method,15
and the reported conditions called for dried, distilled
dioxane as the optimal solvent.
LIU from an ultrasonic cleaner has considerably less
power when compared to high-intensity ultrasound (HIU)
from a direct immersion horn.16 This can lead to repro-
ducibility problems due to the lower power involved for
LIU.17 We now report results from our study of HIU-
promoted Reformatsky reactions.
Resu lts a n d Discu ssion
The HIU Reformatsky reactions were conducted in a
20 °C thermostated cooling bath to control the exothermic
reaction and cool the contents from frictional heating
produced from the direct introduction of high-intensity
ultrasound irradiation. The reaction flask was partially
immersed in the cooling bath during ultrasonication, and
the in situ temperature was 41-42 °C as determined by
a calorimetry experiment. The HIU Reformatsky reac-
tions were performed with unactivated zinc, a phenyl
ketone, 1.5 equiv of the R-bromoester, and a catalytic
amount of iodine (0.2 equiv) in undistilled, reagent-grade
dioxane. A series of six ketones, 1-6 (Chart 1), with
increasing steric demands were evaluated as potential
electrophiles for reactions with R-bromoesters (ethyl
bromoacetate, ethyl R-bromopropionate, and ethyl R-bro-
moisobutyrate), also with increasing degrees of steric
bulk.
(1) Reformatsky, S. Chem. Ber. 1887, 20, 1210.
(2) Shriner, R. L. Org. React. 1942, 1, 1.
(3) Gaudemar, M. Organomet. Chem. Rev., A 1972, 8, 183.
(4) Rathke, M. W. Org. React. (N.Y.) 1975, 22, 423.
(5) Fu¨rstner, A. Synthesis 1989, 571.
(6) Rieke, R. D.; Ulm, S. J . Synthesis 1975, 22, 452.
(7) Ruppert, J . F.; White, J . D. J . Org. Chem. 1974, 39, 269.
(8) Rathke, M. W.; Lambert, A. J . Org. Chem. 1970, 35, 3966.
(9) Santaniello, E.; Manzocchi, A. Synthesis 1977, 698.
(10) Frankenfeld, J . W.; Werner, J . J . J . Org. Chem. 1969, 34, 3689.
(11) Picotin, G.; Miginiac, P. J . Org. Chem. 1987, 52, 4796.
(12) Rathke, M. W.; Weipert, P. In Comprehensive Organic Synthe-
sis; Trost, B. M., Fleming, K., Eds.; Pergamon: New York, 1991; Vol.
2, pp 277-299.
(13) Luche, J . L.; Bianchi, C. Synthetic Organic Sonochemistry;
Plenum: New York, 1998.
(14) Han, B.-H.; Boudjouk, P. J . Org. Chem. 1982, 47, 5030.
(15) Kerdesky, F. A. J .; Ardecky, R. J .; Lakshmikanthan, M. W.;
Cava, M. P. J . Am. Chem. Soc. 1981, 103, 1992.
(16) Suslick, K. S.; Flint, E. B. In Experimental Organometallic
Chemistry; Wayda, A., Darenbourg, M. Y., Eds.; American Chemical
Society: Washington DC, 1987; p 195.
(17) Pugin, B. Ultrasonics 1987, 25, 50.
10.1021/jo0261395 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/28/2002
360
J . Org. Chem. 2003, 68, 360-366

Ultrasound-Promoted Reformatsky Reactions
CHART 1. Str u ctu r es of th e P h en yl Keton es
The very hindered phenyl trityl ketone (6) gave no
reaction with even the simplest R-bromoester, ethyl
bromoacetate, after 60 min of HIU irradiation (entry 16).
Since it appeared that steric factors were responsible
for the formation of â-lactone 19 from isobutyrophenone
(3), the effect of alkyl R-bromoester variation (alkyl )
methyl, ethyl, isopropyl, and tert-butyl) was determined.
Results are shown in Table 2. Increasing the size of the
ester alkyl group from Me to t-Bu had no significant effect
in the R-bromoacetate series with 95-100% yields of the
â-hydroxyester isolated after HIU treatment for 35 min
(entries 1-4). However, for a corresponding R-bromoisobu-
tyrate series, sensitivity to the identity of the ester alkyl
group was observed. The methyl ester gave the â-lactone
adduct 19 as the only product in an isolated 74% yield
(entry 6) compared with a 66% isolated yield of 19 from
the ethyl ester (entry 7). Increasing the bulk with an
isopropyl ester resulted in a mixture of products (entry
8). Analysis of the crude product by 1H NMR and IR
spectroscopy and GC showed an approximately equal
mixture of â-lactone 19, the corresponding â-hydroxyester
24, and unreacted 3. With the bulkiest tert-butyl ester,
no â-lactone product was observed (entry 9). Analysis of
For acetophenone (1) and propiophenone (2), reactions
with ethyl bromoacetate proceeded in less than 5 min to
provide very high to quantitative yields of the corre-
sponding â-hydroxyesters (Table 1) after minimal puri-
fication. Increasing the steric bulk of the R-bromoester
component in the series ethyl bromoacetate < ethyl
R-bromopropionate < ethyl R-bromoisobutyrate had no
effect on the reaction time or yield for either ketone
reactant (entries 1-6). When ethyl chloroacetate was
used as the R-haloester component with 1, no reaction
took place even after HIU irradiation for 60 min.
In contrast, LIU irradiation of 1 and ethyl bromoac-
etate following the Han and Boudjouk method14 in dried,
distilled dioxane in an ultrasonic cleaning bath for 30
min gave only 8-33% yields18 of â-hydroxyester 7, with
the remainder being recovered reactants.
Benzophenone (5) exhibited reactivity similar to those
of 1 and 2 under HIU irradiation with short reaction
times (5 min) and very high yields (entries 13-15). When
ethyl chloroacetate was used as the R-haloester compo-
nent with 5, no reaction took place under HIU irradiation
for 5 or 60 min. Thus, R-chloroesters are judged to be
ineffective R-haloester components for HIU-promoted
Reformatsky reactions.
1
the crude product by H NMR and IR spectroscopy and
GC showed a mixture of â-hydroxyester 25 in 58-62%
GC yield and unreacted 3. Increasing the reaction time
from 35 to 70 min had no effect on the reactant consump-
tion or product distribution.
Ster eoch em istr y. Considerable research has been
performed on the stereochemistry of the thermal Refor-
matsky reaction.21 With DL-ethyl R-bromopropionate as
the R-bromoester component, a mixture of diastereoiso-
1
meric â-hydroxyesters is possible. Analysis by H NMR
spectroscopy reveals complementary sets of signals for
the pair of diastereomers produced during the addition
reaction. These stereoisomers are designated threo and
erythro (Scheme 3), and their ratio is determined by
integration of the 1H NMR spectrum. J acques and co-
workers22 report a 3:2 threo:erythro ratio for reactions of
1 and 2 with ethyl bromoacetate. The diastereomer ratio
for HIU-promoted Reformatsky reactions of 1 and 2 with
ethyl bromoacetate (entries 2 and 5, Table 1, respectively)
was found to be the same as in the thermal reactions.22
From 3 and ethyl bromoacetate (entry 8, Table 1), a 1:4
threo:erythro ratio was observed for the HIU-promoted
Reformatsky reaction.
Con cen tr a tion Dep en d en ce Stu d ies. During the
course of this study, it was noted that Reformatsky
reactions under HIU are concentration dependent. Per-
formance of several different reactions using varying
concentrations of reactants led to the realization that
minimal reactant concentrations were required for the
reaction to proceed efficiently. This concentration depen-
dence was observed also with other ketones.23 The
concentration dependence is illustrated by the data in
Table 3. Entry 1 represents the standard HIU conditions
with THF as the solvent and gives a 93% yield of
Isobutyrophenone (3) required a longer reaction time
under HIU irradiation to induce complete consumption
of the ketone reactant. Both ethyl bromoacetate and
ethyl R-bromopropionate gave quantitative yields of
â-hydroxyesters from 3 after 35 min of irradiation
(entries 7 and 8). With ethyl R-bromoisobutyrate as the
R-bromoester component, â-lactone 19 was isolated in
66% yield (entry 9) after 35 min of HIU irradiation.19
A
mechanism for the formation of 19 is shown in Scheme
2. Subsequently, it was observed that after 5 min of HIU
treatment, the crude product mixture, as determined by
1H NMR spectroscopy, consisted of 19 and the corre-
sponding â-hydroxyester in a 4:1 ratio together with
unreacted starting materials.
For the even more hindered pivalophenone (4), reaction
with ethyl bromoacetate gave a high yield of the â-hy-
droxyester after irradiation for 35 min (entry 10). Reac-
tion of 4 with ethyl R-bromopropionate for 35 min gave
1
a mixture of products (entry 11). As determined by H
NMR and IR spectroscopy and GC, the mixture was
mainly recovered pivalophenone and the corresponding
â-lactone 20. Increasing the reaction time from 35 to 70
min gave the same results. The most hindered ester,
ethyl R-bromoisobutyrate, did not react with 4 (entry 12).
(20) Schick, H.; Ludwig, R.; Schwarz, K.-H.; Kleiner, K.; Kunath,
A. J . Org. Chem. 1994, 59, 3161.
(21) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Wiley: New York, 1983; Vol. 3, p 144.
(22) Canceill, J .; Basselier, J . J .; J acques, J . Bull. Soc. Chim. Fr.
1967, 1024.
(23) Ross, N. A.; Bartsch, R. A. J . Heterocycl. Chem. 2001, 38, 1255.
(18) Han and Boudjouk report formation of a 90% yield of â-hydroxy-
ester 7 from 1 after 30 min of LIU irradiation.14
(19) Schick and co-workers20 report the formation of both â-lactone
and â-hydroxyester products in reactions of 2, phenyl propyl ketone,
butyl phenyl ketone, or 5 with ethyl R-bromoisobutyrate and zinc in
DMF.
J . Org. Chem, Vol. 68, No. 2, 2003 361

Ross and Bartsch
TABLE 1. HIU-P r om oted Refor m a tsk y Rea ction s of r-Br om oester s w ith P h en yl Keton es 1-6
PhC(O)R
R
R′R′′CBrCO2Et
R′ R′′
yielda (%)
reaction time
(min)
entry
product
â-hydroxyester
â-lactone
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Me
Me
Me
Et
Et
Et
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
Ph
H
H
H
Me
H
H
Me
H
H
Me
H
H
Me
H
H
Me
H
5
5
5
5
5
7
8
9
93
99b
100
99
0
0
0
0
0
0
0
0
Me
Me
H
Me
Me
H
Me
Me
H
Me
Me
H
10
11
12
13
14
19
15
20
NRe
16
17
18
NRe
96b
99
5
35
35
35
35
35, 70
35
5
5
10
60
100
100c
0
94
0
66
0
26, 23d
95
99
100
0
0
0
Ph
Me
Me
H
Ph
Trf
a
d
Isolated yield. b A 3:2 mixture of threo/erythro diastereomers. c A 1:4 mixture of threo/erythro diastereomers. GC yield of crude reaction
product after workup (unreacted pivalophenone present). e No reaction, only recovered ketone starting material. f Tr ) Trityl.
SCHEME 2. Mech a n ism for F or m a tion of
â-La cton e 19
work, dried, distilled THF and undistilled, reagent-grade
dioxane were utilized as solvents for thermal reactions
with ethyl bromoacetate to allow for direct comparison
with the HIU experiments, since THF and dioxane are
equally compatible solvents for HIU-induced Refor-
matsky reactions. Thermal reactions were performed
with 1 and ethyl bromoacetate in both refluxing THF and
dioxane. From reaction in THF for 20 h, a 58% GC yield
of â-hydroxyester 7 was observed together with uncon-
sumed ketone reactant. The reaction in refluxing dioxane
failed completely, and no product was detected by 1H
NMR spectroscopic analysis of the crude product mixture.
Thermal reactions were also performed with 5 and ethyl
bromoacetate at reflux in both anhydrous THF and
reagent-grade dioxane. From reaction in THF at reflux
for 20 h, a 65% GC yield of the â-hydroxyester 18 was
obtained together with unconsumed ketone reactant.
Reaction in refluxing dioxane for 23 h gave a 9% GC yield
in the crude product mixture, with the majority being
unreacted ketone reactant.
A trimethyl borate-THF solvent system8 has been
shown to improve the conventional Reformatsky reaction.
Reaction at room temperature reduces base-catalyzed
side reactions of the starting materials that were at least
partially responsible for the low yields.25 Reactions of 1
with the three ethyl R-bromoesters, zinc dust, and
trimethyl borate-THF (1:1) were conducted for 20 h at
room temperature. The results (Table 4) show that, as
the bulkiness of the R-bromoester increases on going from
ethyl bromoacetate to ethyl R-bromopropionate, the â-hy-
droxyester yield drops from 76% to 40%. With ethyl
R-bromoisobutyrate, only a trace (∼3%) of the â-hydroxy-
ester product was detected by GC analysis of the crude
reaction mixture. Reaction of 5, ethyl bromoacetate, zinc
dust, and trimethyl borate-THF (1:1) for 20 h at room
â-hydroxyester 7 from sonication of 1 and ethyl bromoac-
etate for 5 min when the weight percent of zinc was 4.1.
Reducing the concentrations of the reactants uniformly
by one-third reduced the yield from 93% to 78% (entry
2). Further reduction resulted in inhibition of the reac-
tion, and only unreacted starting materials were recov-
ered (entries 3 and 4). Changing the solvent from THF
to dioxane had no effect on the reaction in the case where
the weight percent of zinc was 1.4 (entry 4). These results
reveal that only a small difference in the weight percent
of zinc (0.8) makes a difference as to whether the reaction
proceeds.
The concentration dependence may be attributed to the
zinc density.24 For the successful reactions, the amounts
of zinc were 4.1 (entry 1) and 3.0 (entry 2) wt %.
Decreasing the amount of zinc to 2.2 wt % (entry 3) and
lower (entry 4) gave no reaction. Apparently, below a
minimal zinc density, metal collisions are minimized,
which slows or halts surface activation of the metal.
Com p a r ison w ith Th er m a l Rea ction s. The conven-
tional thermal Reformatsky reaction involves refluxing
the mixture in benzene or diethyl ether and gives modest
to low yields for a variety of â-hydroxyesters.2 In this
(24) Suslick, K. S. Department of Chemistry, University of Illinois,
Urbana-Champaign. Personal communication, 2001.
(25) Hussey, A. S.; Newman, M. S. J . Am. Chem. Soc. 1948, 70, 3024.
362 J . Org. Chem., Vol. 68, No. 2, 2003

Ultrasound-Promoted Reformatsky Reactions
TABLE 2. HIU-P r om oted Refor m a tsk y Rea ction s of r-Br om oester s a n d Isobu tyr op h en on e (3)
yielda (%)
reaction time
(min)
entry
R′
R′′
R′′′
product
â-hydroxyester
â-lactone
1
2
3
4
5
6
7
8
9
H
H
H
H
Me
Me
Me
Me
Me
H
H
H
H
Me
Et
i-Pr
t-Bu
Et
Me
Et
i-Pr
t-Bu
35
35
35
35
35
35
35
35
21
13
22
23
14
19
19
100
100
97
95
100
0
0
0
0
0
0
74
66
30b
0
H
Me
Me
Me
Me
0
24 + 19
34b
58, 62b
35, 70
25c
a
b
Isolated yield. GC yields in crude reaction mixture after workup. Unreacted isobutyrophenone present. c A small amount of 25 was
isolated from the unreacted ketone in the product by recrystallization from hexane.
P h ysica l a n d An a lytica l Meth od s. 1H NMR and 13C NMR
SCHEME 3. Dia ster eom er ic â-Hyd r oxyester s
P r od u ced in Refor m a tsk y Rea ction s w ith DL-Eth yl
r-Br om op r op ion a te
spectra were recorded at 499.7 and 125.7 MHz, respectively,
in deuteriochloroform. Chemical shifts are given in δ values
(ppm) with TMS as the internal standard. HIU irradiation was
provided by an ultrasonic processor probe system (20 kHz, 600
W, 13 mm tip diameter at a power level of 7) from that was
modified in-house for insertion into a custom-designed and
-fabricated, four-armed, 15 or 25 mL glass sonochemical
reaction vessel. During irradiation, the reaction vessel was
cooled in a 20 °C circulating temperature bath. LIU was
produced with an ultrasonic laboratory cleaner (40 kHz, 100
W). GC analysis was performed with a 30 m × 0.32 mm ×
0.25 mm capillary column using a temperature ramp program
from 45 to 250 °C at 10 °C/min. Elemental analyses were
performed by Desert Analytics, Inc. (Tucson, AZ).
Gen er a l P r oced u r e for Refor m a tsk y Rea ction s u n d er
HIU Ir r a d ia tion . The 25 mL, four-armed sonochemical
reaction flask capped with rubber septa was flushed with
nitrogen for several minutes. Zinc dust (1.18 g, 18 mmol) and
iodine (0.50 g, 2.0 mmol) were added to the flask. Half of the
dioxane (12.5 mL) was added, and nitrogen was bubbled
through the solution. The ketone (10 mmol) and R-bromoester
(15 mmol) were added, followed by the remaining solvent (12.5
mL). The flask was attached to the probe, and the lower
portion was immersed in a 20 °C ethylene glycol/water (1:1)
constant-temperature bath. The reaction mixture was soni-
cated for the specified period in a 6 s pulse mode.
At the end of the reaction period, the flask was detached
from the probe and the contents were poured into a beaker
containing distilled water/ice (200 mL). The mixture was
transferred to a 1 L separatory funnel. The beaker was rinsed
with 2% aq HCl (100 mL), and the rinsings were added to the
separatory funnel. The sonochemical flask was rinsed with
CH2Cl2, and the rinsings were added to the separatory fun-
nel. The mixture in the separatory funnel was extracted with
CH2Cl2 (2 × 200 mL). The combined CH2Cl2 layers were dried
over MgSO4 and evaporated in vacuo. The residue was dried
in vacuo to give the crude product that was subjected to short-
path column chromatography on alumina with EtOAc or
EtOAc/hexanes as eluent and, if necessary, Kugelrohr evapo-
ration of the remaining volatile impurities under high vacuum
(0.3 Torr) to give the â-hydroxyester.
temperature was also attempted. No product formation
1
was evident by H NMR spectroscopic analysis.
Con clu sion s
Irradiation of a mixture of a phenyl ketone, an R-bro-
moester, zinc dust, and iodine in dioxane with an HIU
horn gave very high yields of â-hydroxyesters in short
reaction times. Only when the reactants became ex-
tremely bulky did the HIU-promoted Reformatsky reac-
tion fail. It was not necessary to activate the zinc, and
undistilled, reagent-grade dioxane was used. These fac-
tors, as well minimal purification of the crude products,
make the HIU method attractive for performing Refor-
matsky reactions.
Exp er im en ta l Section
Ma ter ia ls. The ketones and R-haloesters were used as
obtained from commercial sources unless otherwise stated.
Zinc dust (99.9%) was used directly unless otherwise noted.
THF was distilled from sodium-benzophenone ketyl radical.
Iodine crystals and trimethyl borate were used directly as
obtained from commercial sources. Reagent-grade dioxane was
stored over activated 4 Å molecular sieves and used without
distillation unless specified. The methyl and isopropyl R-bro-
moisobutyrate esters were synthesized from the commercially
available R-bromo-R-methylpropionyl bromide using a stan-
dard procedure.26
For reactions conducted in the 15 mL, four-armed sonochem-
ical flask, a total of 12.5 mL of solvent was utilized.
Eth yl 3-h yd r oxy-3-p h en ylbu tyr a te (7)2 was prepared
from 1 in 93% yield after chromatography on alumina with
EtOAc/hexanes (1:1) as eluent: colorless oil; IR (neat) 3502,
1
1715 cm-1; H NMR (CDCl3) δ 1.11 (t, J ) 7.1 Hz, 3H), 1.54
(26) Allen, F. C.; Kalm, M. J . Organic Syntheses; Wiley & Sons: New
York, 1963; Collect. Vol. IV, p 608.
(s, 3H), 2.87 (dd, J ) 15.9, 15.9 Hz, 2H), 4.04 (q, J ) 7.1 Hz,
J . Org. Chem, Vol. 68, No. 2, 2003 363

Ross and Bartsch
TABLE 3. Con cen tr a tion Effect in HIU-P r om oted Refor m a tsk y Rea ction s
solvent
zinc
ketone
isolated
reaction
entry
solvent
vol (mL)
concn (wt %)
concn (M)
yield (%)
time (min)
1
2
3
4
THFa
THFa
THFa
25
4.1
3.0
2.2
1.4
0.400
0.266
0.191
0.116
93
5
5
5
12.5
12.5
25
78
NRc
NRc
THFa or dioxaneb
30
a
b
Distilled from Na-benzophenone ketyl. Undistilled, reagent-grade. c No reaction.
TABLE 4. Th er m a l Refor m a tsk y Rea ction s Con d u cted in a Tr im eth yl Bor a te-THF Solven t System
entry
R
R ′
product
yielda (%)
1
2
3
H
Me
Me
H
H
Me
7
8
9
76b
40
3
a
b
GC yield in the crude reaction mixture after workup (incomplete reaction). Isolated yield.
2H), 4.40 (s, 1H), 7.19-7.24 (m, 1H), 7.28-7.35 (m, 2H), 7.41-
7.47 (m, 2H); 13C NMR (CDCl3) δ 13.8, 30.5, 46.3, 60.6, 72.6,
124.3, 126.7, 128.0, 146.8, 172.5. Anal. Calcd for C12H16O3: C,
69.21; H, 7.74. Found: C, 68.86; H, 7.55.
(CDCl3) δ 7.7, 13.9, 35.8, 44.9, 60.6, 75.1, 125.1, 126.6, 128.0,
145.1, 172.9. Anal. Calcd for C13H18O3: C, 70.24; H, 8.16.
Found: C, 69.91; H, 8.31.
Eth yl 3-h ydr oxy-2-m eth yl-3-ph en ylpen tan oate (11) was
prepared from 2 in 96% yield as a 3:2 mixture of threo/erythro
diastereomers, after chromatography on alumina with EtOAc/
hexanes (1:1) as eluent and flash Kugelrohr distillation up to
Eth yl 3-h yd r oxy-2-m eth yl-3-p h en ylbu tyr a te (8)2 was
prepared from 1 in 99% yield as a 60:40 mixture of threo/
erythro diastereomers after chromatography on alumina with
EtOAc/hexanes (1:1) as eluent and flash Kugelrohr distillation
up to 100 °C ot (oven temperature): clear oil; IR (neat) 3502,
1715 cm-1; 1H NMR (CDCl3) δ 0.94 (t, J ) 7.1 Hz, threo), 1.29
(t, J ) 7.1 Hz, erythro, threo + erythro ) 3H), 0.95 (d, J ) 7.2
Hz, erythro), 1.33 (d, J ) 7.1, threo, threo + erythro ) 3H),
1.45 (s, threo), 1.56 (s, erythro, threo + erythro ) 3H), 2.83 (q,
J ) 7.1 Hz, erythro), 3.0 (q, J ) 7.2 Hz, threo, threo + erythro
) 1H), 3.82-3.93 (m, threo), 4.15-4.27 (m, erythro, threo +
erythro ) 2H), 3.94 (s, erythro), 4.09 (s, threo, threo + erythro
) 1H), 7.16-7.25 (m, 1H), 7.27-7.38 (m, 2H), 7.38-7.47 (m,
2H); 13C NMR (CDCl3) δ 12.2, 12.6, 13.7, 14.0, 26.7, 29.8, 48.4,
49.2, 60.3, 60.7, 74.2, 74.5, 124.6, 124.8, 126.5, 126.6, 127.9,
128.0, 145.0, 147.5, 176.6, 177.1. Anal. Calcd for C13H18O3‚
2H2O: C, 69.16; H, 8.21. Found: C, 69.52; H, 7.85. (The
presence of H2O in the analytical sample was evident in its
1H NMR spectrum.)
110 °C ot: clear oil; IR (neat) 3497, 1709 cm-1 1H NMR
;
(CDCl3) δ 0.61-0.72 (m, 3H), 0.84-0.98 (m, 3H), 1.32 (t, J )
7.2 Hz, erythro, 1H), 1.36 (d, J ) 7.1 Hz, threo, 2H), 1.61-
1.81 (m, 1H), 1.85-1.98 (m, 1H), 2.86 (q, J ) 7.1 Hz, erythro),
3.05 (q, J ) 7.2 Hz, threo, threo + erythro ) 1H), 3.75 (s,
erythro), 4.06 (s, threo, threo + erythro ) 1H), 3.77-3.94 (m,
threo), 4.17-4.30 (m, erythro, threo + erythro ) 2H), 7.14-
7.26 (m, 1H), 7.28-7.37 (m, 2H), 7.37-7.43 (m, 2H); 13C NMR
(CDCl3) δ 7.4, 7.8, 11.9, 12.6, 13.7, 14.1, 31.4, 34.4, 47.5, 48.8,
60.3, 60.7, 76.9, 77.1, 125.4, 125.5, 126.3, 126.5, 127.8, 127.9,
142.5, 145.2, 176.9, 177.6. Anal. Calcd for C14H20O3: C, 71.16;
H, 8.53. Found: C, 70.79; H, 8.27.
Eth yl 3-h yd r oxy-2,2-d im eth yl-3-p h en ylp en ta n oa te (12)
was prepared from 2 in 99% yield after chromatography on
alumina with EtOAc/hexanes (1:1) as eluent and flash Kugel-
rohr distillation up to 110 °C ot: colorless oil; IR (neat) 3472,
1693 cm-1; 1H NMR (CDCl3) δ 0.75 (t, J ) 7.3 Hz, 3H), 1.1 (s,
3H), 1.16 (s, 3H), 1.22 (t, J ) 7.1 Hz, 3H), 1.97 (doublet of
sextets, 2H), 4.08-4.19 (m, 2H), 4.40 (s, 1H), 7.20-7.26 (m,
1H), 7.28-7.34 (m, 2H), 7.38-7.47 (m, 2H); 13C NMR (CDCl3)
δ 7.9, 13.9, 21.4, 21.8, 28.2, 50.3, 61.0, 79.8, 126.6, 127.1, 128.0,
140.1, 178.8. Anal. Calcd for C15H22O3: C, 71.97; H, 8.86.
Found: C, 71.91; H, 8.86.
Eth yl 3-h yd r oxy-2,2-d im eth yl-3-p h en ylbu tyr a te (9) was
prepared from 1 in 100% yield after chromatography on
alumina with EtOAc/hexanes (1:1) as eluent and flash Kugel-
rohr distillation up to 110 °C ot: colorless oil; IR (neat) 3482,
1
1695 cm-1; H NMR (CDCl3) δ 1.14 (s, 3H), 1.15 (s, 3H), 1.21
(t, J ) 7.1 Hz, 3H), 1.61 (s, 3H), 4.08-4.18 (m, 2H), 4.52 (s,
1H), 7.19-7.26 (m, 1H), 7.27-7.32 (m, 2H), 7.41-7.48 (m, 2H);
13C NMR (CDCl3) δ 13.9, 21.5, 21.6, 24.8, 49.9, 60.9, 76.9, 126.7,
127.0, 127.1, 143.4, 178.4. Anal. Calcd for C14H20O3: C, 71.16;
H, 8.53. Found: C, 70.85; H, 8.58.
Eth yl 3-h ydr oxy-4-m eth yl-3-ph en ylpen tan oate (13) was
prepared from 3 in 100% yield after chromatography on
alumina with EtOAc/hexanes (1:1) as eluent: colorless oil; IR
Eth yl 3-h yd r oxy-3-p h en ylp en ta n oa te (10)2,4 was pre-
pared from 2 in 99% yield after chromatography on alumina
with EtOAc/hexanes (1:1) as eluent: colorless oil; IR (neat)
(neat) 3496, 1712 cm-1 1H NMR (CDCl3) δ 0.79 (d, J ) 6.9
;
Hz, 3H), 0.91 (d, J ) 6.8 Hz, 3H), 1.03 (t, J ) 7.1 Hz, 3H),
1.94 (septet, J ) 6.7 Hz, 1H), 2.92 (dd, J ) 15.6, 15.6 Hz, 2H),
3.89-4.01 (m, 2H), 4.32 (s, 1H), 7.15-7.24 (m, 1H), 7.26-7.34
(m, 2H), 7.34-7.42 (m, 2H); 13C NMR (CDCl3) δ 13.8, 16.8,
17.1, 38.6, 42.3, 60.5, 77.2, 125.7, 126.6, 127.7, 144.8, 173.3.
1
3503, 1712 cm-1; H NMR (CDCl3) δ 0.77 (t, J ) 7.4 Hz, 3H),
1.08 (t, J ) 7.2 Hz, 3H), 1.72-1.89 (m, 2H), 2.87 (dd, J ) 15.7,
15.7 Hz, 2H), 4.01 (q, J ) 7.1 Hz, 2H), 4.34 (s, 1H), 7.16-7.25
(m, 1H), 7.27-7.36 (m, 2H), 7.36-7.43 (m, 2H); 13C NMR
364 J . Org. Chem., Vol. 68, No. 2, 2003

Ultrasound-Promoted Reformatsky Reactions
Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 70.82;
H, 8.59.
135.2, 175.4. Anal. Calcd for C14H18O2: C, 77.03; H, 8.31.
Found: C, 77.32; H, 8.24.
Eth yl 3-h yd r oxy-2,4-d im eth yl-3-p h en ylp en ta n oa te (14)
was prepared from 3 in 100% yield as a 1:4 mixture of threo/
erythro diastereomers, after chromatography on alumina with
EtOAc as eluent and flash Kugelrohr distillation up to 100 °C
Met h yl 3-h yd r oxy-4-m et h yl-3-p h en ylp en t a n oa t e (21)
was prepared from 3 in 100% yield after chromatography on
alumina with EtOAc as eluent: colorless oil; IR (neat) 3500,
1
1716 cm-1; H NMR (CDCl3) δ 0.79 (d, J ) 6.8 Hz, 3H), 0.90
1
ot: colorless oil; IR (neat) 3496, 1709 cm-1; H NMR (CDCl3)
(d, J ) 6.8 Hz, 3H), 1.94 (septet, J ) 6.8 Hz, 1H), 2.5 (dd, J )
15.9, 15.9 Hz, 2H), 3.48 (s, 3H), 4.31 (s, 1H), 7.15-7.22 (m,
1H), 7.25-7.32 (m, 2H), 7.35-7.40 (m, 2H); 13C NMR (CDCl3)
δ 16.7, 17.0, 38.5, 41.9, 51.5, 77.0, 125.5, 126.5, 127.6, 144.7,
173.7. Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C,
70.37; H, 8.06.
δ 0.69 (d, J ) 6.7 Hz, threo), 0.77 (d, J ) 6.6 Hz, erythro, threo
+ erythro ) 3H), 0.81 (d, J ) 7.0 Hz, threo), 0.86 (d, J ) 6.8
Hz, erythro, threo + erythro ) 3H), 0.95 (t, J ) 7.1 Hz, threo),
1.28 (t, J ) 7.1 Hz, erythro, threo + erythro ) 3H), 1.01 (d, J
) 7.1 Hz, erythro), 1.37 (d, J ) 7.1 Hz, threo, + erythro ) 3H),
1.99 (septet, J ) 6.8 Hz, erythro), 2.16 (septet, J ) 6.9 Hz,
threo, threo + erythro ) 1H), 3.25 (q, J ) 7.1 Hz, erythro), 3.39
(q, J ) 7.1 Hz, threo, threo + erythro ) 1H), 3.78-3.92 (m,
threo), 4.11-4.28 (m, erythro, threo + erythro ) 2H), 3.98 (s,
erythro, 0.8H), 7.13-7.26 (m, 1H), 7.26-7.35 (m, 2H), 7.34-
7.52 (m, 2H); 13C NMR (CDCl3) δ 11.5, 13.2, 13.7, 14.0, 16.6,
17.0, 17.2, 18.0, 33.2, 37.6, 44.2, 45.1, 60.4, 60.8, 78.6, 79.3,
126.3, 126.4, 126.7, 126.8, 127.2, 127.4, 140.6, 142.8, 177.3,
177.4. Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C,
71.80; H, 8.70.
Isopr opyl 3-h ydr oxy-4-m eth yl-3-ph en ylpen tan oate (22)-
was prepared from 3 in 97% yield after chromatography on
alumina with EtOAc as eluent and flash Kugelrohr distillation
1
up to 123 °C ot: colorless oil; IR (neat) 3491, 1707 cm-1; H
NMR (CDCl3) δ 0.79 (d, J ) 6.8 Hz, 3H), 0.89 (d, J ) 6.2 Hz,
3H), 0.92 (d, J ) 6.8 Hz, 3H), 1.07 (d, J ) 6.3 Hz, 3H), 1.93
(septet, J ) 6.7 Hz, 1H), 2.89 (dd, J ) 15.3, 15.4 Hz, 2H), 4.35
(s, 1H), 4.81 (septet, J ) 6.2 Hz, 1H), 7.14-7.21 (m, 1H), 7.24-
7.32 (m, 2H), 7.36-7.42 (m, 2H); 13C NMR (CDCl3) δ 16.8, 17.0,
21.2, 21.3, 38.5, 42.7, 67.9, 77.2, 125.7, 126.5, 127.6, 144.8,
172.8. Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C,
72.31; H, 9.05.
Eth yl 3-h yd r oxy-4,4-d im eth yl-3-p h en ylp en ta n oa te (15)
was prepared from 4 in 94% yield after chromatography on
alumina with EtOAc/hexanes (1:1) as eluent and flash
Kugelrohr distillation up to 110 °C ot: colorless oil; IR (neat)
tert-Bu tyl 3-h yd r oxy-4-m eth yl-3-p h en ylp en ta n oa te (23)
was prepared from 3 in 95% yield after chromatography on
alumina with EtOAc as eluent and flash Kugelrohr distillation
3488, 1713 cm-1 1H NMR (CDCl3) δ 0.92 (s, 9H), 1.01
;
1
up to 100 °C ot: colorless oil; IR (neat) 3486, 1702 cm-1; H
(t, J ) 7.2 Hz, 3H), 3.05 (dd, J ) 15.7, 15.7 Hz, 2H), 3.93 (q,
J ) 7.1 Hz, 2H), 4.38 (s, 1H), 7.13-7.23 (m, 1H), 7.23-7.30
(m, 2H), 7.30-7.57 (m, 2H); 13C NMR (CDCl3) δ 13.8, 25.4,
37.9, 39.9, 60.5, 77.3, 126.5, 127.0, 127.3, 143.6, 173.8. Anal.
Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 72.05; H,
9.00.
NMR (CDCl3) δ 0.78 (d, J ) 7.0 Hz, 3H), 0.92 (d, J ) 6.8 Hz,
3H), 1.18 (s, 9H), 1.91 (septet, J ) 6.8 Hz, 1H), 2.83 (dd, J )
15.1, 15.1 Hz, 2H), 4.33 (s, 1H), 7.12-7.23 (m, 1H), 7.23-7.33
(m, 2H), 7.36-7.42 (m, 2H); 13C NMR (CDCl3) δ 16.8, 17.0,
27.6, 38.6, 43.7, 77.3, 81.4, 125.9, 126.4, 127.5, 145.0, 172.6.
Anal. Calcd for C16H24O3: C, 72.69; H, 9.15. Found: C, 72.91;
H, 9.17.
E t h yl 3-h yd r oxy-3,3-d ip h en ylp r op ion a t e (16)2,4 was
prepared from 5 in 95% yield after chromatography on alumina
with EtOAc/hexanes (1:1) as eluent: white solid; mp 78-79
°C; IR (deposit from CH2Cl2 onto a NaCl plate) 3476, 1690
cm-1; 1H NMR (CDCl3) δ 1.12 (t, J ) 7.1 Hz, 3H), 3.25 (s, 2H),
4.06 (q, J ) 7.2 Hz, 2H), 5.10 (s, 1H), 7.15-7.23 (m, 2H), 7.23-
7.32 (m, 4H), 7.38-7.45 (m, 4H); 13C NMR (CDCl3) δ 13.9, 45.5,
60.9, 76.3, 125.6, 127.0, 128.1, 145.9, 172.7. Anal. Calcd for
tert-Bu tyl 3-h ydr oxy-2,2,4-tr im eth yl-3-ph en ylpen tan oate
(25) was isolated from reaction of 3 and R-bromoisobutyrate
in a small amount from the crude product mixture after
recrystallization from hexanes: white solid; mp 80-82 °C; IR
1
(deposit from CH2Cl2 onto a NaCl plate) 3404, 1723 cm-1; H
NMR (CDCl3) δ 0.65 (d, J ) 6.6 Hz, 3H), 0.87 (s, 3H), 1.01 (d,
J ) 6.8 Hz, 3H), 1.22 (s, 3H), 1.48 (s, 9H), 2.57 (septet, J )
6.6 Hz, 1H), 6.03 (s, 1H), 7.16-7.26 (m, 1H), 7.27-7.37 (m,
2H), 7.37-7.88 (br m, 2H); 13C NMR (CDCl3) δ 17.4, 18.7, 20.2,
25.5, 27.5, 27.6, 33.8, 47.3, 77.0, 81.9, 126.2, 127.0, 127.9, 143.2,
179.7. Anal. Calcd for C18H28O3: C, 73.93; H, 9.65. Found: C,
74.26; H, 9.85.
C
17H18O3: C, 75.53; H, 6.71. Found: C, 75.71; H, 6.47.
Eth yl 3-h yd r oxy-2-m eth yl-3,3-d ip h en ylp r op ion a te (17)
was prepared from 5 in 99% yield after chromatography on
alumina with EtOAc/hexanes (1:1) as eluent: white solid; mp
90-93 °C; IR (deposit from CH2Cl2 onto a NaCl plate) 3489,
1
1698 cm-1; H NMR (CDCl3) δ 1.08 (t, J ) 7.1 Hz, 3H), 1.16
(d, 7.1 Hz, 3H), 3.65 (q, J ) 7.2 Hz, 1H), 3.95-4.10 (m, 2H),
4.73 (s, 1H), 7.07-7.18 (m, 2H), 7.21-7.31 (m, 4H), 7.44-7.49
(m, 2H), 7.53-7.59 (m, 2H); 13C NMR (CDCl3) δ 12.8, 13.8,
46.8, 60.7, 78.0, 125.2, 125.3, 126.5, 126.8, 128.0, 128.1, 144.1,
147.5, 177.3. Anal. Calcd for C18H20O3: C, 76.03; H, 7.09.
Found: C, 76.40; H, 7.01.
Gen er a l P r oced u r e for Refor m a tsk y Rea ction s u n d er
LIU Ir r a d ia tion . A 50 mL, round-bottom flask was flushed
with nitrogen for several minutes. Zinc (Cava-activated or
dust) (1.18 g, 18 mmol) and iodine (0.50 g, 2.0 mmol) were
added to the flask. Half of the dioxane (12.5 mL) solvent was
added. The ketone (10 mmol) and R-bromoester (15 mmol) were
added followed by the remaining solvent (12.5 mL). The flask
was partially submerged in the ultrasonic cleaning bath in a
position of maximum ultrasonic intensity. The reaction mix-
ture was sonicated for the specified period in a continuous
irradiation mode and was not thermostated. At the end of the
reaction period, the reaction mixture was worked up in the
same fashion as reported above for reactions conducted under
HIU irradiation, and the crude product was analyzed by 1H
NMR spectroscopy and GC.
Gen er a l P r oced u r e for Th er m a l Refor m a tsk y Rea c-
tion s.4 A 50 mL, three-necked flask equipped with a magnetic
stirring bar and a reflux condenser was flushed with nitrogen
for several minutes and kept under nitrogen throughout the
reaction. Zinc dust (1.18 g, 18 mmol) and iodine (0.50 g, 2.0
mmol) were added. Half of the solvent (12.5 mL) was added,
and stirring was initiated. The ketone (10 mmol) and R-bro-
moester (15 mmol) were added followed by the remaining
solvent (12.5 mL). The reaction mixture was refluxed overnight
(>19 h) and worked up in the same fashion as reported above
Eth yl 3-h yd r oxy-2,2-d im eth yl-3,3-d ip h en ylp r op ion a te
(18) was prepared from 5 in 100% yield after chromatography
on alumina with EtOAc/hexanes (1:1) as eluent and flash
Kugelrohr distillation up to 125 °C ot: opaque oil; IR (neat)
1
3556, 3468, 1732, 1698 cm-1; H NMR (CDCl3) δ 1.21 (t, J )
7.2 Hz, 3H), 1.33 (s, 6H), 4.18 (q, J ) 7.1 Hz, 2H), 5.13 (s,
1H), 7.17-7.27 (m, 6H), 7.31-7.39 (m, 4H); 13C NMR (CDCl3)
δ 13.9, 24.0, 48.9, 61.3, 82.1, 126.8, 127.1, 128.2, 128.6, 145.5,
179.6. Anal. Calcd for C19H22O3: C, 76.48; H, 7.43. Found: C,
76.85; H, 7.35.
4-Isopr opyl-3,3-dim eth yl-4-ph en yloxetan -2-on e (19) was
prepared from 3 in 74% yield (from the methyl ester) or 66%
yield (from the ethyl ester) after recrystallization from hex-
anes: white solid; mp 68-70 °C; IR (deposit from CH2Cl2 onto
a NaCl plate) 1807, 1207, 1040 cm-1; 1H NMR (CDCl3) δ 0.80
(d, J ) 6.6 Hz, 3H), 0.99 (d, J ) 7.0 Hz, 3H), 1.05 (s, 3H), 1.56
(s, 3H), 2.46 (septet, J ) 6.7 Hz, 1H), 6.85-7.04 (m, 1H), 7.29-
7.36 (m, 2H), 7.36-7.50 (m, 2H); 13C NMR (CDCl3) δ 17.3, 18.1,
18.3, 22.9, 34.7, 56.7, 91.2, 126.2, 126.5, 127.1, 127.4, 128.2,
J . Org. Chem, Vol. 68, No. 2, 2003 365

Ross and Bartsch
for reactions conducted under HIU irradiation, and the crude
product was analyzed by H NMR spectroscopy and GC.
rated. The aqueous layer was extracted with CH2Cl2 (100 mL),
and the organic layers were combined and dried over MgSO4.
The solvent was evaporated in vacuo, and the residue was
dried in vacuo to give the crude product, which was analyzed
1
Gen er a l P r oced u r e for Th er m a l Refor m a tsk y Rea c-
tion s in th e Tr im eth yl Bor a te-THF System .8 A 50 mL
flask equipped with a magnetic stirring bar was flushed with
nitrogen for several minutes and maintained under nitrogen
during the reaction. Zinc dust (1.18 g, 18 mmol) was added,
and the flask was immersed in a water bath at 25 °C. The
ketone (10 mmol), anhydrous THF (12.5 mL), and trimethyl
borate (12.5 mL) were added sequentially. Stirring was initi-
ated, and the R-bromoester (15 mmol) was added by syringe.
The reaction mixture was stirred overnight (20 h) and then
hydrolyzed by addition of a solution of 25 mL of concentrated
NH4OH and 25 mL of MeOH. After addition of CH2Cl2 (100
mL) and distilled H2O (50 mL), the organic layer was sepa-
1
by H NMR spectroscopy and GC.
Ack n ow led gm en t. This research was supported by
a grant from the PG Research Foundation. We thank
Professor Kenneth S. Suslick for providing insight into
the concentration effect and Professor Dominick J .
Casadonte for helpful discussions. We thank the NSF
for Grant CHE-9808436 that was used to purchase the
Varian Unity INOVA NMR spectrometer.
J O0261395
366 J . Org. Chem., Vol. 68, No. 2, 2003