Stereoselective conjugate addition reactions of α,β-unsaturated tert- butyl esters with aryllithium reagents

Full text of DOI:10.1021/jo971723c

3120
J . Org. Chem. 1998, 63, 3120-3124
was found that the use of Gilman-type cuprates for this
Ster eoselective Con ju ga te Ad d ition
transformation was not always practical. In particular,
the requirement of 2 equiv of cuprate for full conversion
results in the waste of 3 equiv of transferable ligand.11
Also, in our hands, more hindered aryl cuprates (e.g.,
ortho-substituted aryl cuprates) were either difficult to
form or did not react cleanly.12 Although aryllithium
reagents are easily prepared and are highly reactive,
their use in this reaction has not been reported, presum-
ably due to competing 1,2-addition with R,â-unsaturated
ethyl esters.13 It was proposed that use of the corre-
sponding tert-butyl esters would minimize the 1,2 mode
of addition.14 Therefore, we decided to investigate the
reactions of aryllithium reagents with R,â-unsaturated
tert-butyl esters (e.g., 3b/3c) possessing chiral imidazo-
lidine (3b) or oxazolidine (3c) auxiliaries in order to
develop a general method for enantioselective synthesis
of chiral â,â-diarylpropanoates 4 (Scheme 1). The chiral
imidazolidine and oxazolidines 3b/3c were selected for
initial studies since they are prepared from aldehyde 3a 15
and the readily available and inexpensive starting ma-
terials (1R,2R)-bis-N-methylamino cyclohexane and
(1S,2S)-pseudoephedrine, respectively.
Our studies began with a comparison of the reactions
of Ph2CuLi and PhLi with unsaturated ester 3b using
Et2O as the solvent (Table 1, entries 1 and 3). As
expected, the reaction involving PhLi (2 equiv)16 was
complete within 1 h at -78 °C, while the reaction
involving Ph2CuLi (2 equiv) required warming to 0 °C.
After workup (aqueous NH4Cl), the auxiliaries were
removed (THF-aqueous HOAc, 25 °C), and the products
were purified by silica gel chromatography. The enan-
tiomeric excesses were determined using chiral super-
critical fluid chromatography (SFC) on the purified
products. It was found that PhLi and Ph2CuLi reacted
with 3b in Et2O to give the 1,4-addition product 5 (<5%
Rea ction s of r,â-Un sa tu r a ted ter t-Bu tyl
Ester s w ith Ar yllith iu m Rea gen ts†
Lisa F. Frey,* Richard D. Tillyer,*
Alain-Sebastien Caille, David M. Tschaen,
Ulf-H. Dolling, Edward J . J . Grabowski, and
Paul J . Reider
Department of Process Research, Merck Research
Laboratories, Merck & Co., Inc., Rahway, New J ersey 07065
Received September 16, 1997 (Revised Manuscript Received
March 3, 1998)
Chiral â,â-diaryl propionic acid derivatives and related
compounds have significant and diverse biological activ-
ity. This structural element is present in compounds
which have reported activities as antiarrhythmics,1,2
vasodilators (Ca-modulin antagonists),1,3 antidepres-
sives,1,4,5 antihistamines,1 and controllers of cerebral
insufficiency.6 As such, synthetic methods are required
for the preparation of a wide variety of compounds of this
general structure,1,2,4,6-10 especially in an optically pure
form.5,7-9 In this regard we were attracted to methodol-
ogy developed by Alexakis involving stereoselective 1,4-
addition of lithium diphenyl cuprate to R,â-unsaturated
ethyl ester 1 possessing a neighboring chiral controller
(chiral imidazolidine).8
This chemistry features high stereoselectivity, facile
attachment and removal of the chiral auxiliary, and the
aldehyde function in the product 2 provides a handle for
further functionalization. However, for our purposes, it
(11) This problem may be avoided by use of a mixed cuprate with a
nontransferable ligand. See footnote 9 and also Lipshutz, B. H.;
Koerner, M.; Parker, D. A. Tetrahedron Lett. 1987, 28, 945-948.
(12) For example, the cuprate prepared from 4-bromo-3-methyl
anisole did not react cleanly with 1, providing mainly the 1,2-1,4-over
addition product.
† Presented at the ACS National Meeting in Las Vegas, NV,
September 1997.
(1) Mueller, A. L.; Moe, S. T.; Balandrin, M. F.; Delmar, E. G.;
Vanwagenen, B. C.; Artman, L. D.; Barmore, R. M.; Smith, D. L. Patent
WO 96/40097, J une 5, 1995.
(13) Reaction of p-methoxyphenyllithium with 1 provided mainly
the products of 1,2-addition (including the 1,2-addition product, and
the 1,2-1,4 and 1,2-1,2-over addition products). For
a review of
organolithium chemistry, see: Wakefield, B. J . The Chemistry of
Organolithium Compounds; Pergamon Press: New York, 1974.
(14) Conjugate addition reactions of unsaturated sec- and tert-butyl
esters: (a) Cooke, M. P., J r. J . Org. Chem. 1984, 49, 1144-1146. (b)
Munch-Petersen, J . J . Org. Chem., 1957, 22, 170-176. (c) Unsaturated
esters of 2,6-di-tert-butyl-4-methoxyphenol undergo conjugate addition
reactions with organolithium reagents: Cooke, M. P. J . Org. Chem.
1986, 51, 1637-1638. (d) Conjugate addition reactions of trityl enones
with organolithium derivatives: Seebach, D.; Ertas, M.; Locher, R.;
Schweizer, W. B. Helv. Chim. Acta 1985, 68, 264-282. (e) 1,4-addition
of organolithiums in charge-directed systems: Cooke, M. P., J r.;
Pollock, C. M. J . Org. Chem. 1993, 58, 474-7481.
(2) J ohnson, R. E.; Busacca, C. A. U.S. Patent 5,098,901, March 24,
1991.
(3) Mannhold, R.; Caldirola, P. L.; Bijloo, G. J .; Timmerman, H. Eur.
J . Med. Chem. 1993, 28, 727-734.
(4) J ones, G.; Maisey, R. F.; Somerville, A. R.; Whittle, B. A. J . Med.
Chem. 1971, 14, 161-164.
(5) Corey, E. J .; Gant, T. G. Tetrahedron Lett. 1994, 35, 5373-5376.
(6) Aschwanden, W.; Imhof, R.; J akob-Roetne, R.; Kyburz, E. U.S.
Patent 5,017,608, May 21, 1991.
(7) For reviews of conjugate addition chemistry: (a) Rossiter, B. E.
and Swingle, N. M. Chem. Rev. 1992, 92, 771. (b) Lee, V. J . In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 4, pp 69-198.
(8) Diastereoselective conjugate addition of R2CuLi to cinnamates
bearing a chiral imidazolidine or an oxazolidine auxiliary: Alexakis,
A.; Sedrani, R.; Mangeney, P.; Normant, J . F. Tetrahedron Lett. 1988,
29, 4411.
(15) 3a was prepared from 2-bromo-5-methoxybenzaldehyde via
Heck reaction: see Experimental Section.
(9) (a) Christenson, B.; Hallnemo, G.; Ullenius, C. Tetrahedron 1991,
47, 4739. Stereoselective conjugate addition using chiral cuprates: (b)
Malmberg, H.; Nilsson, M.; Ullenius, C. Tetrahedron Lett. 1982, 23,
3823. (c) Andersson, S.; J agner, S.; Nilsson, M.; Urso, F. J . Organomet.
Chem. 1986, 301, 257-267.
(10) Nosseir, M. H.; Aziz, G.; Doss, N. L.; Rish, A. S. Indian J . Chem.
1974, 12, 668-670.
(16) Reactions were carried out with 2 equiv of ArLi to guarantee
complete reaction. When 1 equiv of ArLi was used, the ee of the final
product was similar to that obtained using 2 equiv of ArLi, but the
reactions did not proceed to completion.
S0022-3263(97)01723-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/09/1998

Notes
J . Org. Chem., Vol. 63, No. 9, 1998 3121
Ta ble 1. Rea ction sa of Ar yl Or ga n om eta llic Rea gen ts
w ith 3b/3c
Sch em e 1
1,2-addition products were observed)17 with similar ste-
reoselectivity and with the same absolute stereochemis-
try (assigned the R configuration in accordance with the
work of Alexakis).8,18 Further examination of the 1,4-
addition reactions involving PhLi indicated that improved
enantioselectivity could be obtained by use of the imida-
zolidine 3b in THF (entry 2) or by use of the (1S,2S)-
pseudoephedrine-based oxazolidine 3c in Et2O (entry 4).
At this point the conclusion was made that the use of
copper-based reagents for this transformation is not
essential, and that high stereoselectivity might generally
be attainable using aryllithium reagents. Thus, we
investigated the reactions of substituted aryllithium
reagents 6-10 with 3b/3c using both THF and Et2O as
the solvent (Table 1, entries 6-25). Several points should
be made regarding these data. First, the reactions
proceeded efficiently in most cases to give good yields of
the 1,4-adducts 11-15, with little (<5%) 1,2-addition
being observed. The 1H NMR spectra of compounds 5
and 11-15 (Eu(hfc)3, C6D6) consistently showed upfield
shifts for the major enantiomer (early eluting relative to
minor enantiomer by SFC), implying that these products
have the same absolute configuration (assigned as R).
Enantioselectivities were highly dependent on the struc-
ture of the nucleophile and chiral auxiliary, as well as
on the solvent. In general, the enantioselectivities were
higher in THF than in Et2O for reactions involving the
(1R,2R)-bis-N-methylamino cyclohexane-based imidazo-
lidine 3b (entries 6 vs 7, 10 vs 11, 14 vs 15, 22 vs 23).
Conversely, the enantioselectivities were generally higher
in Et2O than in THF for reactions involving the (1S,2S)-
pseudoephedrine-based oxazolidine 3c (entries 8 vs 9, 12
vs 13, 24 vs 25). However, for a given aryllithium
reagent, it was not possible to predict which chiral
auxiliary and solvent combination would give the best
enantioselectivity. In each case, the enantioselectivity
(as high as 97% ee) was maximized experimentally by
appropriate matching of the solvent and auxiliary.
Next, the effect of structural variation of the oxazoli-
dine auxiliary was investigated. For this study the chiral
a
Reactions were run with 2 equiv of ArLi in Et2O/THF at -78
b
°C for 1 h or with 2 equiv of Ph2CuLi at 0 °C. PhLi was obtained
as a 1.8 M solution in cyclohexanes-ether. Aryllithium reagents
6-10 were generated by reaction of the corresponding aryl bromide
with 2 equiv of t-BuLi in Et2O/THF at -78 °C. c Isolated yields of
pure products after silica gel chromatography. The yields are for
three steps: protection, 1,4-addition, and deprotection. See Ex-
perimental Section. The ee was measured by supercritical fluid
chromatography on purified samples. Stationary phases dependent
on substrate. See Experimental Section.
(17) Less than 5% of 1,2-addition products as measured by 1H NMR
(represents the total of 1,2-addition product, 1,2-1,4-over addition
product, and 1,2-1,2-over addition product).
(18) The surprisingly low stereoselectivity observed in the reaction
of 3b with Ph2CuLi in Et2O is the result of an electronic effect in the
cuprate chemistry. The same reaction involving desmethoxy 3b
proceeded with high stereoselectivity (90% ee), in accordance with the
literature precedent.8 Interestingly, the aryllithium chemistry does not
show this electronic effect, since the reactions of phenyllithium with
3b and with desmethoxy 3b proceeded with similar stereoselectivity
(48% ee and 38% ee, respectively).
d
oxazolidines 3c-f (derived from (1S,2S)-pseudoephe-
drine, (1S,2R)-ephedrine, (1R,2S)-cis-1-methylamino-2-
indanol, and (1R,2S)-cis-1-benzylamino-2-indanol, re-
spectively) were reacted with aryllithium reagent 7 using

3122 J . Org. Chem., Vol. 63, No. 9, 1998
Notes
Ta ble 2. Rea ction sa of Ar yllith iu m 7 w ith Oxa zolid in es 3
Sch em e 2
Ta ble 3. Rea ction sa of Ar yllith iu m Rea gen ts w ith
Accep tor s 16b/16c
entry
16
ArLi
solvent
yield (%)b
ee (%) product
1
2
3
4
5
6
7
8
16b
16c
16b
16c
16b
16c
16b
16c
6
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
54
45
76
73
85
78
94
95
45
93
54
95
57
84
74
72
17
18
19
20
7
8
9
a
Reactions were run with 2 equiv of ArLi in Et2O/THF at -78
b
°C for 1 h. Isolated yields of pure products after silica gel
chromatography. The yields are for three steps: protection, 1,4-
addition, and deprotection. See Experimental Section.
to unsaturated esters 3b/3c and might behave differently
in this 1,4-addition chemistry. Thus, 16b/16c were
reacted with aryllithium reagents 6-9, using THF as the
solvent for reactions of imidazolidine 16b and Et2O as
the solvent for reactions involving oxazolidine 16c (Table
3). On the basis of our earlier observations (Tables 1 and
2), these solvent-auxiliary combinations were expected
to provide optimal enantioselectivities. Several points
should be made regarding the data in Table 3. First, in
each case, the 1,4-adducts 17-20 were obtained cleanly
and efficiently with minimal 1,2-addition.20 Also, for each
aryllithium reagent, the 16c-Et2O combination provided
the 1,4-adducts with higher enantioselectivities (up to
95% ee) than the 16b-THF combination. This is in
contrast to the 1,4-addition reactions of 3b/3c, which are
more sensitive to the nature of the aryllithium reagent.
It is speculated that, for 16b/16c, the substrate confor-
mation overrides contributions from the aryllithium
reagent (steric effects, aggregation phenomena) in de-
termining the stereoselectivities, while, for 3b/3c, the
stereoselectivities arise from a subtle balance of these
effects.
a
Reactions were run with 2 equiv of ArLi in Et2O/THF at -78
b
°C for 1 h. Isolated yields of pure products after silica gel
chromatography. The yields are for three steps: protection, 1,4-
addition, and deprotection. See Experimental Section.
both Et2O and THF as the solvent (Table 2). In each
case, the yields of 1,4-adduct 12 were high, and the
enantioselectivities were found to be dependent on the
structure of the oxazolidine and on the solvent. Interest-
ingly, a general trend was again observed (consistent
with the data in Table 1) for optimal enantioselectivities
being obtained in the reactions of the oxazolidines 3c-f
in Et2O as the solvent (entries 1, 3, 5, and 7). The best
result was obtained using the (1S,2S)-pseudoephedrine-
based oxazolidine 3c in Et2O (entry 1). These results are
in general agreement with the model proposed by Alex-
akis (for the cuprate reactions) in which the conformation
of the unsaturated ester, relative to the chiral auxiliary,
is important for high stereoselectivity. It is likely that
the oxazolidines 3c-f have quite different conformational
preferences, resulting in the observed variation in reac-
tion stereoselectivity.
In summary, it has been shown that aryllithium
reagents react rapidly and efficiently with â-aryl-R,â-
unsaturated tert-butyl esters bearing a chiral imidazo-
lidine or oxazolidine to give the 1,4-addition products in
high yield and optical purity. This chemistry is practi-
cal,21 utilizes readily available and inexpensive chiral
To further probe the importance of substrate confor-
mation on the reaction stereoselectivity, the reactions of
aryllithium reagents with the R,â-unsaturated esters
16b/16c, which bear an o-methyl substituent, were
studied (Scheme 2).19 It was predicted that these sub-
strates would have different conformational preferences
(20) The absolute configurations of these 1,4-addition products were
not determined. Either product enantiomer can be prepared by using
the appropriate enantiomer of pseudoephedrine/bis-N-methylamino
cyclohexane, both of which are readily available.
(21) This reaction can be perfomed on
example, the 1,4-addition of 9 to 3c in THF was carried out on a 5-g
scale to give 14 in 87% isolated yield and 92% ee.
a multigram scale. For
(19) 16a was prepared from 2-bromo-3-methylbenzaldehyde and tert-
butyl acrylate, via Heck reaction: see Experimental Section.

Notes
J . Org. Chem., Vol. 63, No. 9, 1998 3123
the reaction temperature below -70 °C. After being aged for 1
h, the mixture was quenched into saturated aqueous NH4Cl (25
mL), EtOAc (25 mL) was added, and the layers were separated.
The aqueous phase was extracted with EtOAc (10 mL), and the
organic phases were combined, washed with brine (25 mL), and
concentrated. The mixture was dissolved in THF (3 mL), water
(0.8 mL), and HOAc (1.7 mL), and the solution was stirred at
25 °C for 1 h. The mixture was diluted with water (25 mL) and
EtOAc (25 mL), the layers were separated, and the aqueous
phase was extracted with EtOAc (10 mL). The combined organic
phases were washed with brine (25 mL), dried (MgSO4), and
concentrated. The crude product was purified by silica gel
chromatography (eluted with toluene/EtOAc) to give 11 (317 mg,
72% yield, 74% ee). The same procedure was followed using
Et2O as the solvent for the 1,4-addition reaction to give 11 in
79% yield and 52% ee: 1H NMR (C6D6) δ 10.42 (s, 1H), 7.31 (d,
J ) 2.8, 1H), 7.10 (d, J ) 8.6, 1H), 7.03 (d, J ) 8.6, 2H), 6.85
(dd, J ) 2.8, 8.5, 1H), 6.70 (d, J ) 8.6, 2H), 5.57 (t, J ) 8.1, 1H),
auxiliaries, and can be used to prepare a wide variety of
structurally complex chiral â,â-diaryl propanoates. The
levels of stereoselectivity observed in this process are
dependent on the structure of the imidazolidine/oxazo-
lidine, on the substitution in the acceptor/nucleophile,
and on the solvent. For any given combination of
aryllithium reagent and acceptor, optimal selectivities
were obtained by matching the auxiliary and solvent
effects.
Exp er im en ta l Section
Gen er a l Meth od s. All manipulations were carried out under
a positive atmosphere of dry nitrogen. Dry THF and Et2O were
used (KF <150 µg/mL). NMR data was obtained in C6D6 from
a Bruker AM300 spectrometer. Coupling constants are reported
in hertz. Enantioselectivities were determined using supercriti-
cal fluid chromatography (Hewlett-Packard HP1205A SFC). All
chemicals were procured from Aldrich Chemical Co. and were
used without further purification. 2-Bromo-5-methoxybenzal-
dehyde was prepared from methyl-2-bromo-5-methoxybenzoate
via DIBAL reduction22 followed by PCC oxidation.23 2-Bromo-
3-methylbenzaldehyde was prepared in 50% yield from 2-bromo-
m-xylene by a published procedure.24 (1R,2R)-bis-N-methylami-
no cyclohexane was prepared from (1R,2R)-N,N-cyclohexane-
diamine by a published procedure.25 (1R,2S)-cis-1-Amino-2-
indanol was used to prepare (1R,2S)-cis-1-methylamino-2-in-
danol25 and (1R,2S)-cis-1-benzylamino-2-indanol.26
3-(2-F or m yl-4-m et h oxyp h en yl)-2-p r op en oic Acid 1,1-
Dim eth yleth yl Ester (3a ). To a solution of 2-bromo-5-meth-
oxybenzaldehyde (2.49 g, 11.6 mmol) in toluene (40 mL) at 25
°C were added, successively, tert-butyl acrylate (2.55 mL, 17.4
mmol), NaOAc (2.85 g, 34.8 mmol), (o-tolyl)3P (353 mg, 1.16
mmol), and (allyl)2PdCl2 (212 mg, 0.58 mmol), and the mixture
was heated to reflux. After 8 h, the mixture was concentrated,
and the crude product was purified by silica gel chromatography
(eluted with hexanes/EtOAc) to give 3a (2.43 g, 80% yield): 1H
NMR (C6D6) δ 9.93 (s, 1H), 8.61 (d, J ) 15.7, 1H), 7.07 (m, 2H),
6.65 (dd, J ) 2.8, 8.6, 1H), 6.28 (d, J ) 15.7, 1H), 3.13 (s, 3H),
1.50 (s, 9H); 13C NMR (C6D6) δ 190.0, 165.6, 161.0, 139.0, 135.5,
129.2, 123.3, 120.7, 114.1, 80.1, 54.9, 28.2; HR-MS calcd for
3.29 (s, 1H), 3.23 (s, 1H), 2.87 (d, J ) 8.2, 2H), 1.24 (s, 9H); 13
C
NMR (C6D6) δ 190.9, 170.4, 158.7, 138.8, 136.0, 135.2, 129.7,
129.2, 120.8, 114.3, 114.2, 80.1, 54.8, 54.7, 42.6, 39.6, 27.9; HR-
MS calcd for C22H26O5 m/ z 370.1780, found m/ z 370.1812.
Enantioselectivity data was determined by SFC using a Chiralcel
OD(H) column at 35 °C, 300 bar, and 1 mL/min and with MeOH
as the modifier.
Gen er a l p r oced u r e B. 1,4-Ad d ition Rea ction In volvin g
Oxa zolid in es. P r ep a r a tion of (11). To a solution of 3a (270
mg, 1.15 mmol) in toluene (8 mL) were added (1S,2S)-pseu-
doephedrine (209 mg, 1.27 mmol) and 1 drop of concd HCl, and
the mixture was refluxed for 3.5 h. The mixture was quenched
into saturated aqueous NaHCO3 (15 mL), EtOAc (10 mL) was
added, and the organic phase was washed with brine (15 mL),
dried (MgSO4), filtered, and concentrated to give 3c (422 mg)
as an oil. To a cold (-78 °C) solution of 4-bromoanisole (0.26
mL, 2.07 mmol) in Et2O (7 mL) was added tert-BuLi (1.7 M
solution in pentane, 2.42 mL, 4.15 mmol), maintaining the
temperature below -70 °C. After this mixture was aged for 1
h, a solution of 3c (422 mg, 1.03 mmol) in Et2O (7 mL) was
added, maintaining the reaction temperature below -70 °C.
After being aged for 1 h, the mixture was quenched into
saturated aqueous NH4Cl (25 mL), EtOAc (25 mL) was added,
and the layers were separated. The aqueous phase was ex-
tracted with EtOAc (10 mL), and the organic phases were
combined, washed with brine (25 mL), and concentrated. The
mixture was dissolved in THF (3 mL), water (0.8 mL), and HOAc
(1.7 mL), and the solution was stirred at 25 °C for 1 h. The
mixture was diluted with water (25 mL) and EtOAc (25 mL),
the layers were separated, and the aqueous phase was extracted
with EtOAc (10 mL). The combined organic phases were washed
with brine (25 mL), dried (MgSO4), and concentrated. The crude
product was purified by silica gel chromatography (eluted with
toluene/EtOAc) to give 11 (203 mg, 46% yield, 66% ee). The
same procedure was followed using THF as solvent for the 1,4-
addition reaction to give 11 in 54% yield and 2% ee.
C
15H18O4 m/ z 262.1205, found m/ z 262.1211.
3-(2-F or m yl-6-m eth ylp h en yl)-2-p r op en oic a cid 1,1-d im -
eth yleth yl ester (16a ): prepared using the procedure described
above and starting with 2-bromo-3-methylbenzaldehyde. 16a
was obtained in 78% yield: 1H NMR (C6D6) δ 10.01 (s, 1H), 7.88
(d, J ) 16.0, 1H), 7.70 (dd, J ) 1.6, 7.0, 1H), 6.85 (m, 2H), 5.76
(d, J ) 16.1, 1H), 1.88 (s, 3H), 1.43 (s, 9H); 13C NMR (C6D6) δ
190.7, 164.7, 139.4, 138.1, 137.5, 135.3, 135.0, 129.6, 128.4, 126.9,
80.5, 28.1, 19.6; HR-MS calcd for C15H18O3 m/ z 246.1256, found
m/ z 246.1262.
Gen er a l P r oced u r e A. 1,4-Ad d ition Rea ction In volvin g
Im id a zolid in es. P r ep a r a tion of 2-F or m yl-4-m eth oxy-â-(4-
m eth oxyp h en yl)ben zen ep r op a n oic Acid 1,1-Dim eth yleth -
yl Ester (11). To a solution of 3a (312 mg, 1.19 mmol) in CH2Cl2
(5 mL) at 25 °C were added (1R,2R)-bis-N-methylamino cyclo-
hexane (169 mg, 1.19 mmol) and 4 Å powdered molecular sieves
(140 mg). After 3 h, the mixture was filtered and washed with
CH2Cl2, and the solvent was evaporated to give 3b (460 mg) as
an oil. To a cold (-78 °C) solution of 4-bromoanisole (0.30 mL,
2.38 mmol) in THF (7 mL) was added tert-BuLi (1.7 M solution
in pentane, 2.80 mL, 4.76 mmol), maintaining the temperature
below -70 °C. After the mixture was aged for 1 h, a solution of
3b (460 mg, 1.19 mmol) in THF (7 mL) was added, maintaining
The following compounds were prepared by either general
procedure A or B. Yields and enantioselectivities are listed in
Tables 1-3. Spectral data is given below.
2-For m yl-4-m eth oxy-â-ph en ylben zen epr opan oic acid 1,1-
d im eth yleth yl ester (5): prepared using a commercially
available solution of PhLi (1.8 M in cyclohexanes-ether); 1H
NMR (C6D6) δ 10.36 (s, 1H), 7.29 (d, J ) 2.9, 1H), 7.07 (m, 6H),
6.80 (dd, J ) 2.9, 8.6, 1H), 5.61 (t, J ) 8.1, 1H), 3.19 (s, 3H),
2.85 (m, 2H), 1.22 (s, 9H); 13C NMR (C6D6) δ 190.9, 170.3, 158.7,
144.0, 138.3, 135.2, 129.8, 128.8, 128.2, 126.7, 120.8, 114.4, 80.2,
54.8, 42.4, 40.3, 27.9; HR-MS calcd for C21H24O4 m/ z 340.1674,
found m/ z 340.1667. Enantioselectivity data was determined
by SFC using three Chiralpak AS columns in sequence at 35
°C, 200 bar, and 1 mL/min and with MeOH as the modifier.
2-F or m yl-4-m eth oxy-â-(4-m eth oxy-2-m eth ylp h en yl)ben -
zen ep r op a n oic a cid 1,1-d im eth yleth yl ester (12): 1H NMR
(C6D6) δ 10.40 (s, 1H), 7.32 (d, J ) 2.8, 1H), 7.08 (m, 2H) 6.78
(dd, J ) 2.7, 8.6, 1H), 6.67, (m, 2H), 5.70, (t, J ) 7.9, 1H), 3.38
(22) Yoon, N. M.; Gyoung, Y. S. J . Org. Chem. 1985, 50, 2443.
(23) (a) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 35, 2647.
(b) Cainelli, G.; Cardillo, G. Chromium Oxidations in Organic Chem-
istry; Springer: Berlin, 1984.
(24) Miyano, S.; Fukushima, H.; Inagawa, H.; Hashimoto, H. Bull.
Chem. Soc. J pn. 1986, 10, 3285.
(25) (a) Benson, S. C.; Cai, P.; Colon, M.; Haiza, M. A.; Tokles, M.;
Snyder, J . K. J . Org. Chem. 1988, 53, 5335-5341. (b) Kashiwabara,
D.; Hanaki, K.; Fujita, J . Bull Chem. Soc. J pn. 1980, 53, 2275-2280.
(26) J ian, L. S.; Aiqiao, M.; Guishu, Y.; Yaozhong, J . Synth.
Commun. 1992, 22, 1497-1503.
(s, 3H), 3.29 (s, 3H), 2.84 (m, 2H), 2.08 (s, 3H), 1.24 (s, 9H); 13
C
NMR (C6D6) δ 191.2, 170.6, 158.7, 158.6, 138.2, 137.9, 134.9,
133.8, 130.4, 120.5, 116.8, 115.0, 111.3, 80.1, 54.9, 54.7, 42.5,
36.8, 27.9, 19.8; HR-MS calcd for C23H28O5 m/ z 384.1937, found
m/ z 384.1959. Enantioselectivity data was determined by SFC

3124 J . Org. Chem., Vol. 63, No. 9, 1998
Notes
using a Chiralcel OD(H) column at 35 °C, 300 bar, and 1 mL/
min and with MeOH as the modifier.
2-F or m yl-â-(4-m et h oxy-2-m et h ylp h en yl)-6-m et h ylb en -
zen ep r op a n oic a cid 1,1-d im eth yleth yl ester (18): 1H NMR
(C6D6) δ 10.34 (s, 1H), 7.65 (d, J ) 6.3, 1H), 7.28 (d, J ) 8.5,
1H), 6.92 (m, 2H), 6.63 (d, J ) 6.6, 1H), 6.55 (s, 1H), 5.36 (m,
1H), 3.34 (s, 3H), 3.13 (dd, J ) 10.0, 15.4, 1H), 2.65 (dd, J ) 5.5,
15.5, 1H), 2.12 (s, 3H), 1.69 (s, 3H), 1.28 (s, 9H); 13C NMR (C6D6)
δ 191.4, 170.7, 158.8, 144.3, 138.6, 137.8, 136.5, 136.4, 132.9,
128.7, 127.0, 117.3, 110.9, 80.4, 54.7, 40.2, 39.1, 27.9, 20.8, 20.2;
HR-MS calcd for C23H28O4 m/ z 368.1987, found m/ z 368.2014.
Enantioselectivity data was determined by SFC using a Chiralcel
OD(H) column at 35 °C, 300 bar, and 1 mL/min and with i-PrOH
as the modifier.
2-F or m yl-6-m e t h yl-â-[2-(1-m e t h yle t h yl)p h e n yl]b e n -
zen ep r op a n oic a cid 1,1-d im eth yleth yl ester (19): 1H NMR
(C6D6) δ 10.31 (s, 1H), 7.64 (m, 1H), 7.40 (d, J ) 7.7, 1H), 7.08
(d, J ) 4.0, 2H), 7.03 (m, 1H), 6.91 (m, 2H), 5.72 (m, 1H), 3.15
(dd, J ) 10.2, 15.8, 1H), 2.88 (m, 1H), 2.67 (dd, J ) 5.6, 15.8,
1H), 2.09 (s, 3H), 1.26 (s, 9H), 1.07 (d, J ) 6.8, 3H), 0.64 (d, J )
6.7, 3H); 13C NMR (C6D6) δ 191.5, 170.5, 147.8, 144.8, 138.8,
137.7, 136.5, 129.3, 127.6, 127.3, 127.0, 126.6, 125.7, 80.4, 40.3,
39.0, 29.0, 27.9, 24.6, 22.8, 20.9; HR-MS calcd for C24H30O3 m/ z
366.2195, found m/ z 366.2194. Enantioselectivity data was
determined by SFC using a Chiralcel OD(H) column at 35 °C,
300 bar, and 1 mL/min and with i-PrOH as the modifier.
â-(2-F or m yl-6-m eth ylp h en yl)[1,1′-bip h en yl]-2-p r op a n o-
ic a cid 1,1-d im eth yleth yl ester (20): 1H NMR (C6D6) δ 10.00
(s, 1H), 7.49 (d, J ) 7.9, 1H), 7.42 (d, J ) 7.3, 1H), 7.14 (m, 1H),
7.02 (m, 2H), 6.78 (m, 7H), 5.74 (m, 1H), 3.17 (dd, J ) 10.4, 15.8,
1H), 2.62 (dd, J ) 5.3, 15.9, 1H), 1.74 (s, 3H), 1.30 (s, 9H); 13C
NMR (C6D6) δ 191.0, 170.7, 144.2, 143.5, 142.3, 140.4, 138.0,
136.3, 135.9, 131.1, 128.8, 128.7, 128.5, 127.9, 127.3, 127.2, 126.7,
126.6, 80.3, 39.2, 38.9, 27.9, 20.6; HR-MS calcd for C23H20O3 (M
+ -C4H8) m/ z 344.1412, found m/ z 344.1429. Enantioselec-
tivity data was determined by SFC using a Chiralcel OD(H)
column at 35 °C, 300 bar, and 1 mL/min and with i-PrOH as
the modifier.
2-F or m yl-4-m et h oxy-â-[2-(1-m et h ylet h yl)p h en yl]b en -
zen ep r op a n oic a cid 1,1-d im eth yleth yl ester (13): 1H NMR
(C6D6) δ 10.36 (s, 1H), 7.26 (m, 2H), 7.12 (m, 3H), 7.00 (d, J )8.7,
1H), 6.66 (dd, J ) 2.9, 8.7, 1H), 6.12 (t, J ) 8.0, 1H), 3.30 (m,
1H), 3.18 (s, 3H), 2.92 (dd, J ) 2.9, 8.0, 2H), 1.24 (s, 9H), 1.23
(d, J ) 8.2, 3H), 0.90 (d, J ) 6.8, 3H); 13C NMR (C6D6)
δ 191.3, 170.4, 158.6, 147.4, 139.7, 138.7, 134.5, 130.9, 127.4,
127.3, 126.4, 125.8, 120.3, 116.1, 80.2, 54.8, 42.9, 36.8, 28.8, 27.9,
24.4, 23.4; HR-MS calcd for C20H22O4 (M + -C4H8) m/ z
326.1518, found m/ z 326.1489. Enantioselectivity data was
determined by SFC using two Chiralcel OD(H) columns in
sequence at 35 °C, 200 bar, and 1 mL/min and with iPrOH as
the modifier.
â-(2-For m yl-4-m eth oxyph en yl)[1,1′-biph en yl]-2-pr opan o-
ic a cid 1,1-d im eth yleth yl ester (14): 1H NMR (C6D6) δ 9.75
(s, 1H), 7.37 (d, J ) 7.7, 1H), 7.28 (d, J ) 2.9, 1H), 7.20 (m, 1H),
7.06 (m, 8H), 6.75 (dd, J ) 2.9, 8.7, 1H), 5.73 (t, J ) 8.0, 1H),
3.23 (s, 3H), 2.84 (m, 2H), 1.20 (s, 9H); 13C NMR (C6D6) δ 189.6,
170.3, 158.4, 143.2, 141.5, 140.6, 138.6, 134.8, 130.8, 130.6, 129.4,
128.5, 127.5, 127.0, 126.8, 121.0, 112.0, 80.3, 54.8, 42.7, 36.9,
27.9; HR-MS calcd for C27H28O4 m/ z 416.1987, found m/ z
416.1986. Enantioselectivity data was determined by SFC using
a Chiralcel OD(H) column at 35 °C, 300 bar, and 1 mL/min and
with i-PrOH as the modifier.
â-(2-F o r m y l-4-m e t h o x y p h e n y l)-1-n a p h t h a le n e p r o -
p a n oic a cid 1,1-d im eth yleth yl ester (15): 1H NMR (C6D6) δ
10.34 (s, 1H), 8.25 (d, J ) 8.0, 1H), 7.62 (d, J ) 7.3, 1H), 7.59 (d,
J ) 8.2, 1H), 7.24 (m, 5H), 7.06 (d, J ) 8.6, 1H), 6.62 (m, 2H),
3.19 (s, 3H), 3.00 (m, 2H), 1.21 (s, 9H); 13C NMR (C6D6) δ 191.5,
170.5, 158.7, 139.8, 137.8, 134.8, 134.6, 131.9, 130.3, 129.2, 127.9,
126.8, 125.9, 125.4, 125.2, 123.9, 120.2, 116.4, 80.2, 54.8, 42.4,
37.1, 27.9; HR-MS calcd for C25H26O4 m/ z 390.1831, found m/ z
390.1837. Enantioselectivity data was determined by SFC using
a Chiralcel OD(H) column at 35 °C, 300 bar, and 1 mL/min and
with i-PrOH as the modifier.
Ack n ow led gm en t. We would like to acknowledge
Amy Bernick and Deborah Zink for obtaining the HRMS
data.
2-F or m yl-â-(4-m e t h oxyp h e n yl)-6-m e t h ylb e n ze n e p r o-
p a n oic a cid 1,1-d im eth yleth yl ester (17): 1H NMR (C6D6)
δ 10.30 (s, 1H), 7.81 (d, J ) 7.2, 1H), 6.99 (m, 2H), 6.88 (d,
J ) 8.5, 2H), 6.64 (d, J ) 8.7, 2H), 5.45 (m, 1H), 3.31 (s, 3H),
3.08 (dd, J ) 7.4, 14.7, 1H), 2.73 (dd, J ) 8.6, 14.7, 1H), 2.16
(s, 3H), 1.19 (s, 9H); 13C NMR (C6D6) δ 191.5, 171.0, 158.4,
144.5, 138.7, 136.4, 135.0, 128.5, 127.9, 127.2, 114.3, 80.3,
54.7, 41.0, 38.6, 27.8, 20.7; HR-MS calcd for C18H18O4 (M +
-C4H8) m/ z 298.1205, found m/ z 298.1182. Enantioselectivity
data was determined by SFC using a Chiralcel OD(H) column
at 35 °C, 300 bar, and 1 mL/min and with i-PrOH as the
modifier.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 3a , 5, 11-15, 16a , and 17-20 (31 pages).
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