Enantioselective synthesis of 2-ethyl-2,3-dihydrobenzofuran carboxylic acid, direct precursor of (+)-efaroxan, from a Baylis-Hillman adduct

Article abstract of DOI:10.1016/j.tetlet.2005.07.099

We describe herein a new and straightforward enantioselective approach to R-(+)-2-ethyl-2,3-dihydrofuran carboxylic acid, the direct precursor of (+)-efaroxan, an α₂ adrenoreceptor antagonist, which is indicated to be used for the treatment of

Full text of DOI:10.1016/j.tetlet.2005.07.099

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6477–6481
Enantioselective synthesis of
2-ethyl-2,3-dihydrobenzofuran carboxylic acid, direct precursor
of (+)-efaroxan, from a Baylis–Hillman adduct
Gabriel P. de Carvalho e Silveira and Fernando Coelho*
Campinas State University, Chemistry Institute, Organic Chemistry Department, PO Box 6154, 13084-971 Campinas, SP, Brazil
Received 24 June 2005; revised 18 July 2005; accepted 20 July 2005
Abstract—We describe herein a new and straightforward enantioselective approach to R-(+)-2-ethyl-2,3-dihydrofuran carboxylic
acid, the direct precursor of (+)-efaroxan, an a2 adrenoreceptor antagonist, which is indicated to be used for the treatment of neuro-
degenerative diseases (Alzheimer and Parkinson), migraine and type II diabetes. Our goal was accomplished using a Baylis–Hillman
adduct as starting material. The dihydrobenzofuran acid was obtained in eight steps with an overall yield of 14%.
Ó 2005 Elsevier Ltd. All rights reserved.
It is well known that some imidazoline-containing
ligands have an affinity for binding sites distinct from
a-adrenoreceptors and two discrete imidazoline recep-
tors (designated I1 and I2) are well characterized.1
Recently, a third imidazoline binding site (putatively
designed as I3) was identified in pancreatic b-cells and
this receptor is associated with control of insulin secre-
tion.2 Insulin secretagogue activity mediated by imidazo-
line agonists is known to be associated with closure of
ATP-sensitive potassium (KATP) channels, leading to
membrane depolarization and Ca+2 influx.3
N
O
O
N
O
O
N
H
N
N
H
R1
H
KU14R (3)
4, R1= CH3
5, R1= CH2CH3
(R)-Efaroxan (1)
CO2H
O
(2)
Figure 1. 2-Ethyl-2,3-dihydrobenzofuran 2 as key intermediate to the
synthesis of efaroxan and derivatives.
Apparently, the biological effects exerted by (R)-(+)-
efaroxan (1, Fig. 1)4 are directly related to its a2-adreno-
receptor antagonism, while those demonstrated by its
(ꢀ)-enantiomer are mediated by the I3 receptor.5
lute configuration of the quaternary asymmetric centre.
The preparation of efaroxan in its enantiomerically pure
form was initially achieved by resolution of racemic 2.3,7
Only recently, Imbert and co-workers8 have described
the first successful approach for the preparation of
(R)-2-ethyl-2,3-dihydrobenzofuran carboxylic acid (2).
The high pharmacological potentiality of efaroxan (1)
and derivatives (3–5) have motivated the development
of several approaches to their total syntheses.6 In most
of them, the 2,3-dihydrobenzofuran carboxylic acid (2,
Fig. 1) has been used as key intermediate.
The pharmacological relevance of efaroxan associated
with a research program focused on exploiting the syn-
thetic potentiality of the Baylis–Hillman adducts as
starting materials for the synthesis of valuable com-
pounds9 stimulated us to proposing an alternative enan-
tioselective approach for the preparation of the
dihydrobenzofuran acid 2. Our intention was to develop
a versatile strategy that could guarantee the access to the
The biological activities exhibited by efaroxan (1) and
also by their derivatives are clearly related to the abso-
Keywords: Baylis–Hillman; Heterocycles; Asymmetric synthesis;
Dihydrobenzofuran; Efaroxan.
*
Corresponding author. Tel.: +55 19 3788 3085; fax: +55 19 3788
3023; e-mail: coelho@iqm.unicamp.br
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.099

6478
G. P. C. Silveira / Tetrahedron Letters 46 (2005) 6477–6481
both enantiomers of 2, since they both exhibit interest-
ing pharmacological properties.
adduct in dry dichloromethane was treated with acetyl
chloride, DMAP and triethylamine to furnish the acety-
lated derivative (9) in 90% yield (Scheme 2). To our sur-
prise, the treatment of 9 with lithium dimethyl cuprate
at 0 °C led to the formation of a mixture of two prod-
ucts (11 and 12; ratio 3:2), in 40% yield. The olefin 11
was the product required for our strategy. By-product
12 could be formed through a dimerization step, most
probably involving the intermediates of the cuprate
addition (Scheme 2).12,13 To overcome the low yield
and avoid the formation of 12, several experimental
modifications were tested. In Table 1 we summarize
the results achieved for the optimization of cuprate
addition reaction.
2-Ethyl-2,3-dihydrobenzofuran carboxylic acid (2), in
which the absolute stereochemistry of the quaternary
centre was already controlled, could be prepared
through a base-catalyzed cyclization reaction (via a
nucleophilic aromatic substitution reaction) of the chiral
fluorinated hydroxyacid 6, which in turn, could be
obtained from epoxyalcohol 7. A Sharpless asymmetric
epoxidation on the a-substituted allylic alcohol 8 could
furnish the intermediate epoxy 7, in its enantiomerically
pure form. The preparation of 8 could be assured
through a Michael addition of an organocuprate on
the terminal double bond of acetylated Baylis–Hillman
adduct 9, following by in situ elimination of an acetate
group. A Baylis–Hillman reaction between methyl acryl-
ate and 2-fluorobenzaldehyde followed by an acetyl-
ation reaction could secure the formation of 9, as
depicted below (Scheme 1).
The 1,4 addition of the lithium dimethylcuprate reagent
is quite fast as is the formation of the byproduct 12. At
ꢀ50 °C, the formation of 12 could be minimized, how-
ever it was not possible to completely avoid it. A similar
observation has been reported by Ullenius, when she
tried to add lithium dimethylcuprate to ortho-substi-
tuted methyl cinnamates.14
Besides the atom efficiency, the success of this strategy
could provide convenient access to enantiomerically
pure derivatives of efaroxan, simply changing the alde-
hyde used in the Baylis–Hillman reaction. Use of enan-
tiomeric tartarate in the Sharpless reaction would allow
the easy preparation of the minus enantiomers of 2.
The cinnamate derivative 11 was reduced with DIBAL-
H, at ꢀ78 °C in dichloromethane to furnish the corre-
Table 1. Optimization of cuprate 1,4-addition reaction on acetylated
Baylis–Hillman adduct 9
We report herein the sequence, which led to the asym-
metric total synthesis of dihydrobenzofuran carboxylic
acid 2.
Entry
Temperature
(°C)
Time
(min)
Ratio product
11:12
Yields (%)
11/12a,b
1
2
3
4
0
ꢀ20
ꢀ30
ꢀ50
1
8
15
20
42:58
45:55
58:42
70:30
39/50
40/50
44/38
68/25
The Baylis–Hillman reaction10 between commercial 2-
fluorobenzaldehyde and methyl acrylate, in the presence
of a catalytic amount of DABCO and ultrasound radia-
tion11 gave the adduct 10 in 90% yield, after chromato-
graphic purification. A solution of the Baylis–Hillman
a Isolated and purified product.
b Fully characterized by 1H, 13C NMR and MS.
O
OH
CO2H
OH
CO2H
O
F
F
6
2
7
OAc
CO2CH3
OH
Baylis-Hillman
reaction
F
F
9
8
Scheme 1. Retrosynthetic analysis for the preparation of 2.
R
CO2CH3
CHO
a, b
CO2CH3
R1
c
+
CO2CH3
F
F
F
F
F
11
10, R=OH; R1= CO2CH3
9, R=OAc,R1= CO2CH3
12
Scheme 2. Reagents and conditions: (a) methyl acrylate, DABCO, MeOH, ultrasound, 16 h, 90%; (b) acetyl chloride, DMAP, NEt3, CH2Cl2, 12 h,
90%; (c) Li(CH3)2Cu, diethyl ether, ꢀ30 °C, 20 min, 68%.

G. P. C. Silveira / Tetrahedron Letters 46 (2005) 6477–6481
6479
O
CO2CH3
OH
a
b
OH
F
F
F
7
8
11
[α]2D0
+ 0.5 (c = 0.1, MeOH)
˚
Scheme 3. Reagents and conditions: (a) DIBAL-H, ꢀ78 °C, CH2Cl2, 2 h, 85%; (b) L-(+)-DIPT, Ti(O–iPr)4, THBP, molecular sieves (4 A), CH2Cl2,
ꢀ35 °C, 8 h, 75%, 89% ee.
O
O
sponding allylic alcohol 8, in 85% yield, which was used,
after purification, as substrate for a Sharpless–Katsuki
epoxidation reaction.15 Unfortunately, the chemical
yield of this oxidation reaction was very low (45%,
Scheme 3). An additional study was carried out, in
which three reaction parameters were varied (molar
ratio of titanium isoproxide and tartarate and the tem-
perature of the reaction). The results are summarized
in Table 2.
O
O
O
b
H
a
OH
OH
F
F
F
13
7
6
[α]2D0
c
+ 0.5 (c= 0.1, MeOH)
O
d
OH
CO2H
OH
O
F
The best yield and reproducibility were attained when
diisopropyl tartarate (60 mol %) was used, at ꢀ35 °C,
with 50 mol % of titanium isopropoxide (entry 5). The
epoxide-alcohol 7 was prepared in 75% of yield and
89% ee.
2
14
Scheme 4. Reagents and conditions: (a) TPAP, N-methyl morfoline-N-
oxide (NMO), dichloromethane, rt, 1 h, 85%; (b) NaClO2, NaH2PO4,
2-methyl-2-butene, acetone, 0 °C ! rt, 4 h, 90%; (c) Pd/C 5%, EtOH,
rt, 12 h, 80%; (d) NaH, toluene/DMF (8:2), 110 °C, 16 h, 65%.
The enantiomeric purity of this epoxide was determined
by GC using a chiral column (Chiral HP column—
b-cyclodextrin).
14, as the sole isolable product in 80% yield. The cycli-
zation reaction was carried out with NaH in DMF to
furnish 2, in 65% yield (Scheme 4). The diidrobenzo-
furan ring was formed through a nucleophilic aromatic
substitution reaction (SNAr). In this type of nucleophilic
attack fluorine used to be the best leaving group. The
most likely explanation is that the first step of the SNAr
mechanism is usually the rate determining, and this step
is promoted by groups with strong ꢀI effects. This
would explain why fluoro is such a good leaving group
when this mechanism is operating.19
At this stage, the stereochemistry of the quaternary car-
bon was already controlled. Based on the rationalization
proposed by Sharpless, the oxygen of the hydroperoxide
should be transferred to the Si face of the double bond
to produce epoxide with (S,S)-configuration.
We tried to directly oxidize the epoxide-alcohol 7 to the
corresponding carboxylic acid 6, with Jones reagent at
0 °C. However, in our hands the acid was obtained in
only 40% yield, with an intense degradation of the reac-
tion medium. Based on a previous experience of our lab-
oratory, we decided first to oxidize the alcohol to an
aldehyde and then to the acid, using mild experimental
conditions.16 Treatment of alcohol 7 with TPAP/NMO
gave the epoxy-aldehyde 13 in 85% yield.17 Acid 6 was
obtained from aldehyde 13 through treatment with
sodium chlorite, NaH2PO4 and 2-methyl-2-butene in
90% yield (Scheme 4).18 Reductive opening of 7 was
completely regioselective and gave the a-hydroxy acid
To confirm the optical purity and the absolute configu-
ration of the dihydrobenzofuran 2 we decided to use the
strategy described by Imbert and co-workers.7 The chi-
ral acid 2 was then treated with an equimolar amount
of (S)-(+)-2-phenylglycinol in ethyl acetate. The crystal-
line solid salt was filtered and recrystallized twice in
methylethylketone. The solid was dissolved in methanol
20
and its specific rotation was measured {½aꢁD 54.8 (c 0.3,
20
MeOH); Lit.7 ½aꢁD 55.9 (c 0.3, MeOH)}.
Table 2. Sharpless–Katsuki reaction with allylic alcohol 8
Entry
Ti(O–iPr)4 (mol %)
Tartaratea (mol %)
Temperature (°C)
Time (h)
Yieldb (%)/% eec
1
2
3
4
5
6
100
100
100
100
50
(+)-DET (100)
(+)-DET (100)
(+)-DET (120)
(+)-DIPT (120)
(+)-DIPT (60)
(+)-DIPT (30)
ꢀ25
ꢀ25
ꢀ25
ꢀ35
ꢀ35
ꢀ35
12
12
12
8
8
8
45/89
52/89
58/87
75/89
75/89
70/85
25
a
˚
All reactions were carried out in the presence of molecular sieves (4 A), using 0.5 mmol of allylic alcohol 8.
b The yields are for purified and isolated products.
c The enantiomeric purity was determined by GC using a chiral column (using a racemic product for comparison).

6480
G. P. C. Silveira / Tetrahedron Letters 46 (2005) 6477–6481
Gouverneur, V.; Couture, K.; Lesimple, P.; Autret,
J.-M. WO Patent 15624, 2000; Chem. Abstr. 2000, 132,
222438; For an example of the synthesis of an efaroxan
derivative, see: (g) Mayer, P.; Loubat, C.; Imbert, T.
Heterocycles 1998, 48, 2529–2534.
Based on these data our product has an optical purity
>95% ee. The synthesis of the (R)-(+)-2-ethyl-2,3-
dihydrobenzofuran carboxylic acid 2 was accomplished
in eight steps, from the Baylis–Hillman adduct, with
an overall yield of 14%.20 The utilization of the commer-
cial (ꢀ)-DIPT in the place of (+)-DIPT should permit
access to the (S)-(ꢀ)-enantiomer using the same
synthetic strategy.21,22 Our strategy should also permit
the preparation of several derivatives of both the enan-
tiomers of efaroxan, substituted in aromatic ring.
7. For some examples of the resolution of racemic
dihydrobenzofuran carboxylic acid, see: Imbert, T.;
Mayer, P. WO Patent 35682 1996; Chem. Abstr. 1997,
126, 59852.
8. For the asymmetric synthesis of (R)-efaroxan, see: (a)
Mayer, P.; Imbert, T.; Couture, K.; Gouverneur, V.;
Mioskowski, C. WO Patent 0002836, 2000; Chem. Abstr.
2000, 132, 93199.
Finally this simple and straightforward strategy exem-
plifies clearly the synthetic potentially of the Baylis–Hill-
man reaction for the preparation of chiral compounds
of pharmaceutical interest.
9. For a recent example that demonstrates the potentiality of
the Baylis–Hillman adduct in the total synthesis of antibio-
tics, see: Mateus, C. R.; Coelho, F. C. J. Braz. Chem. Soc.
2005, 16, 386–396 (available free of charges at http://
jbcs.sbq.org.br/online/2005/vol16_n3A/11-238-04.pdf).
10. For comprehensive reviews on the Baylis–Hillman reac-
tion see: (a) Basavaiah, D.; Rao, A. J.; Satyanarayama, T.
Chem. Rev. 2003, 103, 811–891; (b) Almeida, W. P.;
Coelho, F. Quim. Nova 2000, 23, 98–105; Chem. Abstr.
2000, 132, 236562e; (c) Ciganek, E. Org. React. 1997, 51,
201; (d) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001–8062. For some new insights
about the mechanism of the Baylis–Hillman reaction
see: (e) Santos, L. S.; Pavam, C. H.; Almeida, W. P.;
Coelho, F.; Eberlin, M. N. Angew. Chem., Int. Ed. 2004,
43, 4330–4333; (f) Price, K. E.; Broadwater, S. J.;
Walker, B. J.; McQuade, D. T. J. Org. Chem. 2005, 70,
3980–3987; (g) Aggarwal, V. K.; Fulford, S. Y.; Llyod-
Jones, G. C. Angew. Chem., Int. Ed. 2005, 44, 1706–
1708.
Acknowledgements
The authors thank Fapesp for a grant to G.P.C.S.
(Fapesp no. 01/01250-0) and for financial support
(Fapesp 04/09745-0 and 02/00461-3). F.C. thanks CNPq
for a research grant and financial support (CNPq
302758/2004-6 and 475652/2004-5). The authors are
grateful to Professor C. H. Collins for English revision
of this text.
References and notes
11. (a) Almeida, W. P.; Coelho, F. Tetrahedron Lett. 1998, 39,
8609–8612; (b) Coelho, F.; Almeida, W. P.; Veronese, D.;
Lopes, E. C. S.; Silveira, G. P. C.; Rossi, R. C.; Pavam,
C. H. Tetrahedron 2002, 58, 7437–7447.
1. (a) Regunathan, S.; Reis, D. J. Annu. Rev. Pharmacol.
Toxicol. 1996, 36, 511–544; (b) Eglen, R. M.; Hudson, A.
L.; Kendall, D. A.; Nutt, D. J.; Morgan, N. G.; Wilson, V.
G.; Dillon, M. P. Trends Pharmacol. Sci. 1998, 19, 381–
390; (c) To know more about the indication of efaroxan
for the treatment of Parkinson disease see: Colpaert, F.;
Briley, M.; Imbert, T. WO Patent 00145 1995; Chem.
Abstr. 1995, 122, 123150; (d) For the use of efaroxan in the
treatment of Alzheimer disease, see: Colpaert, F.; Briley,
M.; Imbert, T. WO Patent 01791 1995; Chem. Abstr. 1995,
122, 151400; (e) Yoshida, M.; Mariano, P. S. J. Org.
Chem. 1996, 61, 4439–4449.
2. (a) Morgan, N. G. Exp. Opin. Invest. Drugs 1999, 8, 575;
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05171, 1992; Chem. Abstr. 1992, 117, 131200.
12. For a recent discussion about the mechanism of cuprate
addition, see: (a) Woodward, S. Chem. Soc. Rev. 2000, 29,
393–401, and reference cited therein; (b) Yamanaka, M.;
Nakamura, E. Organometallics 2001, 20, 5675–5681.
13. There are in the literature some controversies concerning
the mechanism of the 1,4-addition of organocuprate
reagent on a,b-unsaturated compounds. Based on avail-
able theoretical evidences, compound 12 perhaps could be
formed as shown below. Further studies should be done to
confirm this proposition.
Li
Li
OAc O
OAc O
OAc O
R
OCH3
R
OCH3
R
OCH3
Cu(CH3)2
III
Cu(CH3)2
oxidative addition (16)
π-complex (15)
9
4. To some insights into the action mechanism of insulin, see:
Laborde, E.; Manchem, V. P. Curr. Med. Chem. 2002, 9,
2231–2242.
5. For the determination of the absolute stereochemistry of
the biologically active (R)-efaroxan, see: Belin, C.; Chau-
vet, A.; Leloup, J. M.; Ribet, J. P.; Maurel, J. L. Acta
Crystallogr. 1995, C51, 2439–2441.
R= 2-FC6H4
O
R
OCH3
CO2CH3
R
III
Cu(CH3)2
(Me)2Cu
O
Compound 12
R
OCH3
III
Cu(CH3)2
copper (III) complex (17)
6. For the racemic synthesis of efaroxan, see: (a) Edwards, C.
R.; Readhead, M. J.; Tweddle, N. J. J. Heterocycl. Chem.
1987, 24, 495–496; (b) Mayer, P.; Brunel, P.; Imbert, T.
Bioorg. Med. Chem. Lett. 1999, 9, 3021–3022; (c) Couture,
K.; Gouverneur, V.; Mioskowski, C. Bioorg. Med. Chem.
Lett. 1999, 9, 3023–3026; (d) Clews, J.; Morgan, N. G.;
Ramsden, C. A. J. Heterocycl. Chem. 2001, 38, 519–521;
(e) Chapleo, C. B.; Myers, P. L.; Butler, R. C. M.; Davis,
J. A.; Doxey, J. C.; Higgins, S. D.; Myers, M.; Roach, A.
G.; Smith, C. F. C.; Stillings, M. R.; Welbourn, A. P. J.
Med. Chem. 1984, 27, 570–576; (f) Mioskowski, C.;
14. Christenson, B.; Hallnemo, G.; Ullenius, C. Tetrahedron
1991, 47, 4739–4752.
15. (a) Sharpless, K. B.; Gao, Y.; Hanson, R. M.; Klunder, J.
M.; Ko, S. Y.; Masamune, H. J. Am. Chem. Soc. 1987,
109, 5765–5780; (b) Sharpless, K. B.; Carlier, P. R. J. Org.
Chem. 1989, 54, 4016–4018.
16. Rossi, R. C.; Coelho, F. Tetrahedron Lett. 2002, 43, 2800–
2897.

G. P. C. Silveira / Tetrahedron Letters 46 (2005) 6477–6481
6481
17. (a) Ley, S. V.; Norman, J.; Griffith, W.; Marsden, S. P.
Synthesis 1994, 639–666; (b) Ley, S. V.; Griffith, W.;
Whitcombe, G. P.; White, A. D. J. Chem. Soc. Chem.
Commun. 1987, 1625–1627.
18. (a) Pinnick, H. W.; Childers, W. E.; Balkrishna, S. B.
Tetrahedron 1981, 37, 2091–2096; (b) Dalcane, E. J. Org.
Chem. 1986, 51, 567–569.
1245 cmꢀ1
;
HRMS (m/z) Calcd for C12H13FO2
208.08995; found 208.09003. Compound 7: 75% yield;
89% ee (chiral HP column); [a]D 0.5 (c 0.1, MeOH); 1H
NMR (300 MHz, CDCl3) d 7.35–7.02 (m, 4H), 4.31 (s,
1H), 3.94 (d, J = 12.4 Hz, 1H), 3.80 (d, J = 12.4 Hz, 1H),
1.93 (broad s, 1H), 1.55 (qd, J = 7.5 Hz, 1H), 1.29 (qd,
J = 7.5 Hz, 1H), 0.83 (t, J = 7.5 Hz, 3H). 13C NMR
(75.4 MHz, CDCl3) d 161.8, 159.8, 128.2, 123.7, 123.2,
129.0, 114.9, 66.6, 62.4, 56.2, 20.9; IR (kmax, film) 3355,
1118 cmꢀ1. HRMS (m/z) calcd for C11H13FO2 196.08996;
found 196.08978. Compound 12: 25% yield; 1H NMR
(500 MHz, CDCl3) d 6.6 (s, 1H), 7.26 (m, 1H), 7.10 (m,
1H), 7.01 (m, 2H), 6.89 (m, 4H), 6.31 (s, 1H), 5.62 (s, 1H),
4.49 (dd, J = 9.46 and 5.8 Hz, 1H), 3.80 (s, 3H), 3.59 (s,
3H), 3.02 (ddd, J = 13.13, 9.46 and 5.8 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 167.7, 168.6, 161.8, 160.6, 159.9,
158.7, 141.6, 134.14, 132.8, 129.9, 128.9, 128.1, 128.0,
19. March, J. Advanced Organic Chemistry, 3rd ed.; John
Wiley & Sons: New York, 1985, Chapter 13, pp 576–607.
20. For
a recent example concerning the synthesis of
dihydrobenzofurans, see: Kuethe, J. F.; Wong, A.; Jour-
net, M.; Davies, I. W. J. Org. Chem. 2005, 70, 3727–3729,
and references cited therein.
21. The synthesis of (S)-enantiomer of 2 has been recently
reported using a different approach, see: Guo S., Yong
T. WO Patent 010936 2004; Chem. Abstr. 2004, 140,
145991.
22. The spectroscopic data (1H, 13C NMR, HRMS) for all
intermediates are compatible with the proposed structures.
125.2, 123.7, 115.5, 115.3, 52.0, 51.7, 37.9, 31.2; IR (kmax,
film) 1689, 1672 cmꢀ1; HRMS (m/z) calcd for C23H22F2O4
400.14862; found 400.14848. Compound 13: 85% yield; 1H
NMR (300 MHz, CDCl3) d 9.1 (s, 1H), 7.40–7.05 (m, 4H),
4.5 (s, 1H), 2.85 (m, 1H), 1.88 (m, 1H), 0.95 (t, J = 6.9 Hz,
3H); IR (kmax, film) 2800, 1750 cmꢀ1; HRMS (m/z) Calcd
for C11H11FO2 194.07431; found 194.07401. Compound 2:
1
Compound 10: 80% yield; H NMR (300 MHz, CDCl3) d
7.47–7.02 (m, 4H), 6.33 (s, 1H). 5.87 (s, 1H), 5.75 (s, 1H),
3.75 (s, 3H), 2.90 (s, 1H); 13C NMR (75.4 MHz, CDCl3) d
166.6, 161.4, 158.1, 140.6, 128.1, 127.9, 126.4, 124.1, 115.1,
67.0, 52.0. IR (kmax, film) 3437, 1721 cmꢀ1. HRMS (m/z)
Calcd for C11H11O3F 210.06922; found 210.06904; Com-
20
20
65% yield; {½aꢁD 54.8 (c 0.3, MeOH); Lit.7 ½aꢁD 55.9
(c 0.3, MeOH)—(S)-phenylglycinol salt}; 1H NMR (300
MHz, CDCl3) d 7.5–7.30 (m, 2H), 7.19–7.08 (m, 2H), 3.71
(d, J = 16.5 Hz, 1H), 3.43 (d, J = 16.5 Hz, 1H), 2.29 (m,
J = 7.3 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H). IR (kmax, KBr):
1
pound 11: 65% yield; H NMR (300 MHz, CDCl3) d 7.65
(s, 1H), 7.4–7.05 (m, 4H), 3.83 (s, 3H), 2.48 (q, J = 7.4 Hz,
2H), 1.14 (t, J = 7.4 Hz, 3H); 13C NMR (75.4 MHz,
CDCl3) d 167.9, 161.7, 158.4, 136.6, 131.0, 129.8, 123.7,
115.6, 51.9, 30.3, 21.2, 13.7. IR (kmax
,
film) 1719,
1728 cmꢀ1
.