Catalytic asymmetric synthesis using feedstocks: An enantioselective route to 2-arylpropionic acids and 1-arylethyl amines via hydrovinylation of vinyl arenes

Article abstract of DOI:10.1021/jo900198b

A three-step procedure for the synthesis of 2-arylpropionic acids (profens) from vinyl arenes in nearly enantiomerically pure form has been developed. Excellent yields (>97%), regioselectivities (>99%), and enantioselectivities (>97% ee) for the desired branched products were obtained in the asymmetric hydrovinylation reactions of vinyl arenes, and the products from these reactions were transformed into 2-arylpropionic acids via oxidative degradation. Subsequent Curtius or Schmidt rearrangements of these acids provided highly valued 1-arylethyl amines, including a prototypical primary amine with an α-chiral tertiary N-alkyl group, in very good yields.

Full text of DOI:10.1021/jo900198b

Catalytic Asymmetric Synthesis Using Feedstocks: An
Enantioselective Route to 2-Arylpropionic Acids and 1-Arylethyl
Amines via Hydrovinylation of Vinyl Arenes
Craig R. Smith and T. V. RajanBabu*
Department of Chemistry, The Ohio State UniVersity, 100 W 18th AVenue, Columbus, Ohio 43210
rajanbabu.1@osu.edu
ReceiVed January 29, 2009
A three-step procedure for the synthesis of 2-arylpropionic acids (profens) from vinyl arenes in nearly
enantiomerically pure form has been developed. Excellent yields (>97%), regioselectivities (>99%),
and enantioselectivities (>97% ee) for the desired branched products were obtained in the asymmetric
hydrovinylation reactions of vinyl arenes, and the products from these reactions were transformed into
2-arylpropionic acids via oxidative degradation. Subsequent Curtius or Schmidt rearrangements of these
acids provided highly valued 1-arylethyl amines, including a prototypical primary amine with an R-chiral
tertiary N-alkyl group, in very good yields.
Introduction
enantiomer selectively targets γ-secretase lowering Aꢀ42,5
which may retard amyloid plaque formation in Alzheimer’s
disease, without inducing COX inhibition. Currently, (R)-
flurbiprofen was one time in phase III clinical trials as a
Nonsteroidal antiinflammatory drugs (NSAIDs) are the most
frequently prescribed analgesics with annual worldwide sales
estimated to exceed $20 billion.1 Among these, 2-arylpropionic
acids are the most important class of compounds. Biological
activity of the 2-arylpropionic acids is largely, if not entirely,
stereospecific with the (S)-enantiomer being more active2 in the
inhibition of prostaglandin biosynthesis through nonselective
inhibition of cyclooxygenase (both COX-1 and COX-2 en-
zymes).3 The enzymatic bioinversion of (R)-(-)-ibuprofen and
other chiral 2-arylpropionic acids to the biologically active (S)-
enantiomer has been proven to be a unidirectional process4
producing compounds with the desired analgesic effects. Flur-
biprofen among other NSAIDs has unique properties, as the
(S)-enantiomer is an antiinflammatory agent and the (R)-
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Sagi, S. A.; Smith, T. E.; Weggen, S.; Das, P.; McLendon, D. C.; Ozols, V. V.;
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3066 J. Org. Chem. 2009, 74, 3066–3072
10.1021/jo900198b CCC: $40.75 2009 American Chemical Society
Published on Web 03/24/2009

Catalytic Asymmetric Synthesis Using Feedstocks
Selective Aꢀ42 Lowering Agent (SALA)6 under the trade name
Flurizan (generic name: tarenflurbil).
SCHEME 1. Synthesis of (S)-Ibuprofen from
4-Isobutylstyrene
Our recent work in fine-tuning of hemilabile phosphoramidites
in the asymmetric hydrovinylation (HV)7a eliminated the
isomerization and polymerization problems that in the past had
plagued this important carbon-carbon bond forming reaction.7b
As we begin to seek applications of asymmetric hydrovinylation
reaction for natural product synthesis, transformations of the
vinyl group are becoming important in these synthetic efforts.
Oxidative cleavage of the 3-arylbutenes for the synthesis of
NSAIDs is thus a natural progression of this work. Because of
the diverse nature of the aryl units, this oxidative degradation
was found to be more difficult than anticipated. For example,
the most direct and practical ozonolysis route that works well
for ibuprofen and flurbiprofen, was found not to be applicable
for the electron-rich aromatic precursors of naproxen and
fenoprofen. Thus, we examined the most optimal oxidative
methods for the syntheses of five of the most common
2-arylpropionic acids.8
Many amines bearing an R-chiral benzylic group are known
to possess a wide range of therapeutic activities.9 Several
successful drugs such as Zoloft and Sensipar belong to this class
of compounds. Typically, chiral 1-arylethyl amines are produced
via classical resolution of salts,10 asymmetric reduction (i.e.,
hydrogenation) of CdN bonds,11 and biotechnological trans-
formations, such as transamination12 and enzymatic kinetic
resolutions.13 As each of these methods for the production of
chiral 1-arylethyl amines has advantages, each also suffers from
distinct disadvantages. New enabling technologies are needed
when substrates are structurally complex, when the parent
compounds have strongly electron-withdrawing groups attached,
for amines carrying N-tertiary alkyl groups, and in cases where
enzymes cannot produce the desired enantiomer of the amine
with high selectivity. Access to enantiomerically pure 2-aryl-
propionic acids opens a facile route to these compounds via
Curtius,14 Schmidt,15 or related reactions.
In this paper we provide the details of the syntheses of
prototypical enantiopure 2-arylpropionic acids from 3-aryl-
butenes, and the subsequent transformations of these acids to
1-arylethyl amines.
Results and Discussion
Synthesis of 2-Arylpropionic Acids. During our initial
investigations, mild, highly tolerant reaction conditions for the
asymmetric hydrovinylation of vinylarenes were developed (eq
1).7,16 Using ligand L1 under the optimized conditions described
in eq 1, the 3-arylbutenes were prepared. Racemic compounds
were prepared in reactions of ethylene and the vinylarenes of
interest in the presence of a catalytic amount of [(allyl)NiBr]2,
ligand L2 [an equimolar mixture of simplified ligand (RcRc) and
(ScSc) enantiomers] and sodium tetrakis[(3,5-trifluorometh-
yl)phenyl]borate [NaBARF].
(7) (a) Smith, C. R.; RajanBabu, T. V. Org. Lett. 2008, 10, 1657. For a review,
see: (b) RajanBabu, T. V. Chem. ReV. 2003, 103, 2845. Ligand synthesis: (c)
Smith, C. R.; Mans, D.; RajanBabu, T. V. Org. Synth. 2008, 85, 238.
(8) For a review of synthesis of 2-arylpropionic acids, see: Stahly, G. P.;
Starrett, R. M. In Chirality in Industry II; Collins, A. N., Sheldrake, G. N., Crosby,
J., Ed.; John Wiley: Chichester, 1997.
(9) Importance of chiral amines: (a) Lawrence, S. A. Amines, Synthesis
Properties and Applications; Cambridge University Press: Cambridge, 2004. (b)
Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keꢀeler, M.; Stu¨rmer, R.;
Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788, and references cited therein.
(10) (a) Jacques, J.; Collett, A.; Wilen, S. Enantiomers, Racemates, and
Resolutions; Wiley & Sons: New York, 1980. (b) Ingersoll, A. W. Org. Synth.
Coll. Vol. II 1950, 506. (c) Ault, A. Org. Synth. Coll. Vol. V 1973, 932. (d)
Bryker, W.; Avila, L. A. U.S. Patent 4983771, 1989 (Chem. Abstr. 1991, 114,
206739). (e) Yamakawa, Y. K. Japanese Patent 56026848, 1979 (Chem. Abstr.
1981, 95, 115012). (f) Brown, E.; Voit, F. Tetrahedron Lett. 1985, 26, 4451. (g)
Vries, T.; Wynberg, H.; van Echten, E.; Koek, J.; ten Hoeve, W.; Kellogg, R. M.;
Broxterman, Q. B.; Minnaard, A.; Kaptein, B.; van der Sluis, S.; Hulshof, L.;
Kooistra, J. Angew. Chem., Int. Ed. 1998, 37, 2349.
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(b) Lensink, C.; de Vries, J. G. Tetrahedron: Asymmetry 1993, 4, 215. (c) Burk,
M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084. (d) Spindler, F.;
Blaser, H.-U. AdV. Synth. Catal. 2001, 343, 68. (e) Krzyzanowska, B.; Stec,
W. J. Synthesis 1978, 521. (f) Krzyzanowska, B.; Stec, W. J. Synthesis 1982,
270. (g) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.; Tijani,
A. J. Am. Chem. Soc. 1994, 116, 4061.
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1989 (Chem. Abstr. 1991, 114, 41044). (b) Matcham, G. W.; Rozzell, J. D.;
Sterling, D. I.; Zeitlin, A. L. U. S. Patent 5169780, 1990 (Chem. Abstr. 1993,
118, 190144). (c) Iwasaki, A.; Yamada, Y.; Kizaki, N.; Ikenaka, Y.; Hasegawa,
J. Appl. Microbiol. Biotechnol. 2006, 69, 499.
(13) (a) Phillips, G. T.; Shears, J. H. European Patent 399589, 1989 (Chem.
Abstr. 1991, 115, 69951). (b) Schmidt, H.; Fischer, A.; Fischer, P.; Schmidt,
R. D.; Stelzer, U. European Patent 812363, 1995 (Chem. Abstr. 1996, 125,
219744). (c) Balkenhohl, F.; Ditrich, K.; Hauer, B.; Ladner, W. J. Prakt. Chem.
1997, 339, 381. (d) Ditrich, K.; Ladner, W.; Melder, J.-P. German Patent
19913256, 1999 (Chem. Abstr. 2000, 133, 252151). (e) Ditrich, K. Synthesis
2008, 2283.
Initial experiments were conducted with 3-(4-isobutylphenyl)-
1-butene (2), the precursor for ibuprofen (Scheme 1). In the
(14) (a) Buchner, E.; Curtius, T. Chem. Ber. 1885, 18, 2371. (b) Curtius, T.
Chem. Ber. 1890, 23, 3023. (c) Smith, P. A. S. Org. React. 1946, 3, 337. (d)
Nagumo, S.; Nishida, A.; Yamazaki, C.; Matoba, A.; Murashige, K.; Kawahara,
N. Tetrahedron 2002, 58, 4917. (e) Boger, D. L.; Cassidy, K. C.; Nakahara, S.
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Org. Chem. 2001, 66, 2667.
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85, 248.
J. Org. Chem. Vol. 74, No. 8, 2009 3067

Smith and RajanBabu
TABLE 1. Asymmetric Hydrovinylation of Vinylarenesa
TABLE 2. Oxidation of Hydrovinylation Products and Synthesis
of 2-Arylpropionic Acidsa
a See Experimental Section for details. b Conversion and selectivities
determined by GC analysis. c Yields determined by isolated mass after
column chromatography. d Selectivity for the branched HV product.
e Determined by GC except for 4, which was determined by HPLC.
f Configuration assigned by comparison to GC and HPLC data with
authentic samples (2 and 4). Others assigned by analogy.
a See Experimental Section for details. b Yields determined by isolated
mass after column chromatography. c Determined by GC. d Decompo-
sition of starting alkene. e Enantiomeric excess assigned by comparison
to literature rotation (ref 21).
in 92% yield (97% ee) over three steps (Scheme 1). The
configuration and enantiomeric excess were established by
conversion to the known (L)-menthyl esters.18 Gas chromato-
graphic analysis of the (L)-menthyl esters (10) of ibuprofen using
a Cyclodex-ꢀ column revealed baseline separation, with a
diastereomeric excess of 96% for the (S)-ibuprofen ester. This
confirms the overall selectivity and absolute configuration of
the hydrovinylation product. Oxidative degradation using RuCl3/
NaIO4 gave 96% of the acid from 2.
Table 2 lists the conditions for the oxidative cleavage of all
the hydrovinylation products. Only compounds 2, 3 and 6
underwent clean ozonation and subsequent oxidation under
modified Pinnick conditions to afford the acids without epimer-
ization (Table 2, entries 1, 2 and 5). Substrates containing
electron-rich aryl units, 4 and 5 proved to be incompatible with
ozonolysis, presumably due to over oxidation of the aromatic
ring, even when controlled ozonolysis was attempted.19 Hiyama
has reported that olefins in proximity to electron-rich aromatic
systems could be oxidatively cleaved and subsequently oxidized
to the desired carboxylic acid at low temperatures with KM-
original preparation of this alkene, complete conversion of
4-isobutylstyrene 1 to 2 was achieved in 98% yield and 96%
ee after reaction with ethylene in the presence of 0.014 equiv.
of a precatalyst produced from (S)-2,2′-binaphthoyl-benzyl-(R)-
[1-(1-naphthylethyl)]aminoylphosphine (L1), [(allyl)NiBr]2 and
NaBARF at -78 °C (2 h).7a,16 Under these conditions, no (E)
or (Z) olefins arising via isomerization of the primary product
or byproduct from oligomerization were observed. Hydroviny-
lation of a number of vinyl arenes, giving 3-arylbutenes 2-7,
all precursors to 2-arylpropionic acids, were carried out under
optimal conditions and the results are shown in Table 1. In all
cases, the conversions, yields, and selectivities were highly
reproducible, with best values realized at low temperatures. In
a typical example, selectivities of >96% ee and 92% ee were
observed for the formation of 2 at -78 °C and at 0 °C
respectively under otherwise identical conditions.
To obtain the 2-arylpropionic acids from the branched HV
products, we envisioned oxidative cleavage of the olefin
followed by further oxidation of the intermediate aldehyde to
the corresponding carboxylic acid (Scheme 1). A variety of
methods are available for such oxidations.17 The enantiomeric
excess of (S)-ibuprofen was verified by three independent
methods (chiral stationary phase GC of 2 and (L)-(-)-menthyl
esters 10, [R]D of 9) to be within experimental error at two
different stages in the three step synthesis from 4-isobutylsty-
rene. Ozonolysis of 2 in a solution of CH2Cl2 and pyridine
followed by reductive workup afforded the desired aldehyde
(8), which was treated with NaClO2 to afford (S)-ibuprofen (9)
(17) (a) Bailey, P. S. Ozonation in Organic Chemistry; Academic: San Diego,
1982; Vol. 2. (b) Pryor, W. A.; Giamalva, D.; Church, D. F. J. Am. Chem. Soc.
1983, 105, 6858. (c) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless,
K. B. J. Org. Chem. 1981, 46, 3936. (d) Fraunhoffer, K. J.; White, M. C. J. Am.
Chem. Soc. 2007, 129, 7274. (e) Ramminger, C.; Zim, D.; Lando, V. R.; Fassina,
V.; Monteiro, A. L. J. Braz. Chem. Soc. 2000, 11, 105. (f) Lee, D. G.; Lamb,
S. E.; Chang, V. S. Org. Synth. 1981, 60, 11.
(18) Park, H.; Kumareswaran, R.; RajanBabu, T. V. Tetrahedron 2005, 61,
6352.
(19) Veysoglu, T.; Mitschler, L. A.; Swayze, J. K. Synthesis 1980, 807.
3068 J. Org. Chem. Vol. 74, No. 8, 2009

Catalytic Asymmetric Synthesis Using Feedstocks
SCHEME 2. Synthesis of Ketoprofen from 3-Bromostyrene
methyl-2-phenylbutanoic acid (15), prepared from the corre-
sponding hydrovinylation adduct 7 (Table 2, entry 6), upon
reaction with diphenylphosphoryl azide22 in benzene, followed
by capture of the isocyanate with benzyl alcohol, yields the
CBZ-derivative 18 in 81% yield (eq 2). Schmidt reaction of
the acid 15 with hydrazoic acid gives the corresponding free
amine upon aqueous work up. This product was trapped and
identified as the corresponding propionamide 19. Products 20-
22 were also prepared by similar routes. Careful HPLC analysis
of 22 was conducted to guarantee that the configuration of the
asymmetric carbon of 3 as derived from the hydrovinylation
remained unaltered both in the oxidative cleavage to 11 and
the subsequent rearrangement to the amide. The true advantage
of this procedure lies in the ability to generate quaternary
heteroatom-substituted chiral centers and in the ability to create
chiral 1-artylethyl amines with a wide variety of structural and
electronic features for the generation of analog libraries for
pharmaceutical evaluation.
nO4.20 This method proved most successful in the oxidation of
4 to form naproxen, 12. Other common oxidants led to substrate
decomposition. Synthesis of (S)-fenoprofen from 5 (entry 4)
was best achieved under Sharpless improved conditions for
ruthenium tetroxide-catalyzed oxidations of organic com-
pounds,17c which afforded 13 in 91% overall yield from the
3-phenoxystyrene. Ibuprofen and flurbiprofen can also be made
by using RuCl3, even though the ozonolysis route has clear
advantages if large scale synthesis is to be attempted. For 5,
the fenoprofen precursor, KMnO4/NaIO4 oxidation gave only
40% yield. The acid 15 is best prepared by the RuCl3-mediated
oxidation of the corresponding alkene.
We have reported that 3-(bromoaryl)-butenes can serve as
precursors for 2-arylpropionic acids with substituents on the
aromatic ring. For example, 3-(4-bromophenyl)-1-butene has
been converted into ibuprofen by Ni-catalyzed cross-coupling
(Kumada Coupling) with i-butylmagnesium bromide followed
by oxidation.18 Likewise, 3-(3-bromophenyl)-1-butene (6),
prepared in >99% yield by asymmetric hydrovinylation of
3-bromostyrene can serve as a precursor for another important
2-arylpropionic acid, (S)-ketoprofen. A viable sequence for
the synthesis of ketoprofen from the 3-bromoaryl-butene in the
racemic series is shown in Scheme 2. Lithium halogen exchange
reaction, followed by the addition of benzaldehyde gives the
diastereomeric alcohol(s) 16. Subsequent global oxidation of
the alcohols without further purification led to ketoprofen (17)
in 72% overall yield in three steps from commercially available
materials.
FIGURE 1. Curtius (20 and 21) and Schmidt (22) reaction products.
Conclusions
Enantiopure 2-arylpropionic acids ibuprofen, naproxen, flur-
biprofen, and fenoprofen were prepared from the corresponding
3-arylbutenes by oxidative degradation of the vinyl group. This
approach represent the highest overall selectivity obtained in
the enantioselective syntheses of the title compounds that does
not rely upon classical resolution or dynamic kinetic resolution.23
Curtius and Schmidt rearrangements of the carboxylic acids also
produce the corresponding 1-aryletheyl amine derivatives in high
enantiomeric purity.
Experimental Section
General Methods. See Supporting Information.
Typical Procedure for Asymmetric Hydrovinylation.7a,16 The
precatalyst was prepared as follows in a gloVebox: To [di(µ-
bromo)bis(η-allyl)nickel(II)24 (2.6 mg, 0.007 mmol for substrate
1) in CH2Cl2 (1 mL) was added a solution of ligand (L1, 0.014
(22) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94,
6203. (b) Shioiri, T.; Yamada, S. Org. Synth. Coll. Vol. VII 1990, 7, 206.
(23) For the best asymmetric routes to date, Naproxen via Ru-catalyzed
asymmetric hydrogenation of 2-arylacrylic acids: (a) Ohta, T.; Takaya, H.;
Kitamura, M.; Nagai, K.; Noyori, R. J. Org. Chem. 1987, 52, 3174 (98% ee) Ni-
catalyzed asymmetric hydrocyanation: (b) RajanBabu, T. V.; Casalnuovo, A. L.
J. Am. Chem. Soc. 1996, 118, 6325, and references cited therein (95% ee)
Ibuprofen via Ru-catalyzed hydrogenation: (c) Uemura, T.; Zhang, X.; Mat-
sumura, K.; Sayo, N.; Kumobayashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J.
Org. Chem. 1996, 61, 5510 (97% ee) Rh-catalyzed asymmetric hydroformylation:
(d) Nozaki, K.; Sakai, N.; Nanno, T.; Higashijima, T.; Mano, S.; Horiuchi, T.;
Takaya, H. J. Am. Chem. Soc. 1997, 119, 4413 (92% ee) Hydrovinylation: (e)
Zhang, A.; RajanBabu, T. V. Org. Lett. 2004, 6, 1515 (91%) Zn-Cu catalyzed
allylic substitution: (f) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel,
F. F.; Knochel, P. Org. Lett. 2003, 5, 2111 (97% ee) Flurbiprofen via DKR:
(g) Norinder, J.; Boga´r, K.; Kanupp, L.; Ba¨ckvall, J.-E. Org. Lett. 2007, 9,
5095 (>97% ee). No useful catalytic asymmetric methods are known for other
(S)-2-arylpropionic acid precursors.
Synthesis of 1-Arylethyl Amines. Curtius14 and Schmidt15
reactions are widely used methods for the conversion of acids
to amines with one less carbon atom. These methods were
chosen as each allows for the synthesis of either the free amine,
or a number of other synthetically and pharmaceutically useful
derivatives including carbamates, ureas, and amides. Further,
the configuration of the R-carbon of the amine derivative is
reliably predictable since the migration to the electron-deficient
nitrogen proceeds with retention of configuration. Thus, (S)-2-
(20) Hiyama, T.; Wakasa, N. Tetrahedron Lett. 1985, 26, 3259.
(21) Koul, S.; Parshad, R.; Taneja, S. C.; Qazi, G. N. Tetrahedron: Asymmetry
2003, 14, 2459.
(24) Herrmann, W. A.; Bo¨hm, V. P. W.; Reisinger, C.-P. J. Organomet.
Chem. 1999, 576, 23.
J. Org. Chem. Vol. 74, No. 8, 2009 3069

Smith and RajanBabu
mmol for substrate 1) in CH2Cl2 (1 mL) at ambient temperature.
The resulting solution was added to a suspension of NaBARF25,16
(12.4 mg, 0.014 mmol for 4-isobutylstyrene) dissolved in dichlo-
romethane (1 mL) and the mixture was stirred at ambient temper-
ature in a 10 mL pear shaped flask for 2 h affording a dark brown
solution containing a small amount of fine particulate (NaBr).
(s, 3H), 3.62-3.59 (m, 1H), 1.45 (d, J ) 7.20 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 157.3, 143.3, 140.7, 133.2, 129.1, 129.0,
22
126.8, 126.7, 125.0, 118.7, 113.2, 105.6, 55.3, 43.0, 20.7. [R]D
) -18.9 ( 0.02 (c 1.00, CHCl3). HRMS 212.1207 (M+·; calcd
for C15H16O 212.1201). GC [poly(dimethylsiloxane] conditions: 5
min at 100 °C, 10 °C/min, 10 min at 250 °C; retention time (min):
18.90. HPLC (chiral) conditions: (Chiracel OJ-H) hexanes:isopro-
panol ) 95:5, 0.50 mL/min; retention time (min): 25.52 (R), 26.80
(S).
In a fumehood, a 25 mL three-necked round bottomed flask
equipped with a rubber septum, flow-controlled nitrogen inlet, a
temperature probe, and a magnetic stirring bar was flame-dried and
purged with nitrogen. The flask was then charged with 5 mL of
dry dichloromethane. The catalyst solution prepared above now
removed from the drybox, was introduced to the vessel via cannula.
The flask containing the catalyst solution was further rinsed with 2
mL of CH2Cl2, and this solution was also transferred to the reaction
mixture. Upon completion of precatalyst transfer, the system was
closed at the flow-controlled stopcock and cooled to -78 °C,
creating a vacuum. Dry ethylene (passed through a 0.5” × 4”
column of Drierite) was introduced via needle through the serum
stopper and the vessel atmosphere was slowly evacuated 3 times
with a 20 mL syringe. After cooling the solution to -78 °C, a
solution of p-isobutylstyrene (160 mg, 1.00 mmol) in 2 mL dry
CH2Cl2 was introduced dropwise into the solution of precatalyst
over a one minute period via syringe followed by a 1 mL rinse
with CH2Cl2. The vessel was then maintained at -78 °C for a period
of 1 h. At the end of this period, the ethylene line is removed and
the system exposed to nitrogen. Deionized H2O (1 mL) was
introduced into the flask, the septum was pierced with a needle,
and nitrogen was blown through the flask to remove any remaining
ethylene. The biphasic solution was then poured into a 100-mL
separatory funnel containing 20 mL H2O and the CH2Cl2 was
collected. The aqueous layer was then extracted with three 10 mL
portions of diethyl ether. The organic layers were combined, dried,
filtered through a sintered glass funnel and the volume was reduced
by rotary evaporation, yielding a free-flowing yellow oil. The
resulting oil was filtered by flash column chromatography (eluted
with isocratic pentane) to afford the desired crude hydrovinylation
product as a colorless oil, which was then used to acquire all
analytical data without further purification.
1
1-Phenoxy-3-[(R)-1-methylallyl]benzene (5). Clear liquid, H
NMR (400 MHz, CDCl3): δ 7.34 (t, J ) 7.80 Hz, 2H), 7.26 (t, J
) 7.80 Hz, 1H), 7.10 (t, J ) 7.40 Hz, 1H), 7.01 (d, J ) 7.60 Hz,
2H), 6.97 (d, J ) 8.00 Hz, 1H), 6.92 (s, 1H), 6.83 (dd, J ) 8.00,
2.40 Hz, 1H), 6.03-5.95 (m, 1H), 5.08-5.03 (m, 2H), 3.47-3.44
(m, 1H), 1.35 (d, J ) 6.80 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 157.3, 157.2, 147.8, 142.8, 129.7, 129.6, 123.0, 122.2, 118.7,
22
118.0, 116.5, 113.4, 43.1, 20.7. [R]D ) -7.8 ( 0.02 (c 1.00,
CHCl3). HRMS 224.1197 (M+·; calcd for C16H16O 224.1201). GC
[poly(dimethylsiloxane] conditions: 5 min at 100 °C, 5 °C/min, 5
min at 250 °C; retention time (min): 24.81. GC (chiral) conditions:
(Cyclodex-ꢀ) 100 min at 100 °C, 0.3 °C/min, 91.67 min at 125
°C; retention time (min): 215.68 (R), 216.85 (S).
1-Bromo-3-[(R)-1-methylallyl]benzene (6). Clear liquid, 1H
NMR (400 MHz, CDCl3): δ 7.36-7.32 (m, 2H), 7.19-7.14 (m,
2H), 6.00-5.92 (m, 1H), 5.09-7.07 (m, 1H), 5.06-5.04 (m, 1H),
3.47-3.41 (m, 1H), 1.35 (d, J ) 6.80 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 147.9, 142.3, 130.4, 130.0, 129.2, 126.0, 122.5,
113.8, 42.9, 20.6. [R]D22 ) -23.3 ( 0.02 (c 1.00, CHCl3). HRMS
210.0040 (M+·; calcd for C10H11Br 210.0044). GC [poly(dimeth-
ylsiloxane] conditions: 5 min at 100 °C, 5 °C/min, 5 min at 200
°C; retention time (min): 20.38. GC (chiral) conditions: (Cyclodex-
ꢀ) 70 min at 85 °C (isothermal); retention time (min): 54.01 (R),
55.81 (S).
1
(R)-3-Methyl-3-phenyl-1-pentene (7). Clear liquid, H NMR
(500 MHz, CDCl3): δ 7.34-7.28 (m, 4 H), 7.21-7.16 (m, 1 H),
6.03 (dd, J ) 17.40, 10.40 Hz, 1 H), 5.10 (dd, J ) 10.70, 1.20 Hz,
1 H), 5.04 (dd, J ) 17.60, 1.20 Hz, 1 H), 1.89-1.72 (ABX3; νAB
) 0.035, νA ) 1.84, νB ) 1.77; JAB ) 13.70 Hz, JAX ) 7.40 Hz,
JBX ) 7.40 Hz; 2 H), 1.35 (s, 3H), 0.77 (t, J ) 7.40 Hz, 3 H). 13
C
1
1-Isobutyl-4-[(R)-1-methylallyl]benzene (2). Clear liquid, H
NMR (125 MHz, CDCl3): δ 147.4, 146.9, 128.0, 126.7, 125.7,
111.7, 44.5, 33.4, 24.4, 8.9. [R]D22 ) -22.3 (c 1.05, CHCl3). HRMS
160.1250 (M+·; calcd for C12H16 160.1252). GC [poly(dimethyl-
siloxane] conditions: 5 min at 100 °C, 5 °C/min, 5 min at 200 °C,
retention time (min): 10.61. GC (chiral) conditions: (Cyclodex-ꢀ)
40 min at 70 °C, 5 °C/min, 10 min at 90 °C, retention time (min):
53.90 (R), 55.65 (S).
Typical Procedure for the Oxidation of 2-Arylpropionic
Acid Precursors. Procedure 1.26 A solution of 1-isobutyl-4-[(R)-
1-methylallyl]benzene (100 mg, 0.53 mmol) in dichloromethane-
pyridine (9:1, 30 mL) was cooled to -78 °C, and ozone was passed
through the solution until the blue color persisted. It was stirred
for 20 min at -78 °C, while nitrogen was passed through the
solution to remove excess ozone, then dimethylsulfide (0.5 mL)
was added to the mixture. The resulting mixture was permitted to
warm to 0 °C, and stirring was continued for 1 h at 0 °C and for
another hour at ambient temperature. It was concentrated under
reduced pressure, diluted with water, and extracted with diethyl
ether (3 × 15 mL). The organic extract was washed with saturated
aqueous sodium bicarbonate, dried over magnesium sulfate, and
concentrated to dryness in vacuo to afford 106 mg of the
intermediate aldehyde as a colorless oil. The crude product was
used for the next step without further purification.
NMR (400 MHz, CDCl3): δ 7.13-7.07 (m, 4H), 6.05-5.97 (m,
1H), 5.07-5.00 (m, 2H), 3.48-3.41 (m, 1H), 2.44 (d, J ) 6.80
Hz, 2H), 1.85 (septet, J ) 6.80 Hz, 1H), 1.35 (d, J ) 7.20 Hz,
3H), 0.90 (d, J ) 6.80 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ
143.5, 142.7, 139.4, 129.1, 126.9, 112.8, 45.0, 42.8, 30.2, 22.4,
20.7. [R]D22 ) -9.1 ( 0.02 (c 0.50, CHCl3). HRMS 188.1562 (M+·
;
calcd for C14H20 188.1565). GC [poly(dimethylsiloxane] conditions:
5 min at 100 °C, 5 °C/min, 5 min at 200 °C; retention time (min):
15.23. GC (chiral) conditions: (Cyclodex-ꢀ) 45 min at 100 °C
(isothermal); retention time (min): 37.72 (R), 38.37 (S).
2-Fluoro-1-phenyl-4-[(R)-1-methylallyl]benzene (3). Clear liq-
uid, 1H NMR (400 MHz, CDCl3): δ 7.56-7.54 (m, 2H), 7.46-7.42
(m, 2H), 7.38-7.34 (m, 2H), 7.08 (dd, J ) 7.60, 1.60 Hz, 1H),
7.02 (dd, J ) 8.00, 1.60 Hz, 1H), 6.06-5.97 (m, 1H), 5.14-5.08
(m, 2H), 3.53-3.50 (m, 1H), 1.40 (d, J ) 6.80 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 161.0, 147.3, 142.4, 135.8, 130.6, 130.5,
129.0, 128.9, 128.4, 127.4, 123.2, 114.9, 114.7, 113.8, 42.7, 20.6.
[R]D ) -18.7 ( 0.02 (c 1.00, CHCl3). HRMS 249.1051 (M+·
;
22
calcd for C16H15F + Na 249.1055). GC [poly(dimethylsiloxane]
conditions: 5 min at 100 °C, 5 °C/min, 5 min at 200 °C; retention
time (min): 25.14. GC (chiral) conditions: (Cyclodex-ꢀ) 120 min
at 130 °C (isothermal); retention time (min): 91.98 (R), 93.24 (S).
2-Methoxy-6-[(R)-1-methylallyl]naphthalene (4). Crystalline
1
To a solution of crude aldehyde in diethyl ether (3 mL) was
added 2,3-dimethyl-2-butene (2 mL) and was cooled to 0 °C.
Sodium chlorite (90 mg, 1.00 mmol) which had been finely
powdered, was added and the resulting mixture was stirred
solid, mp < 10 °C; H NMR (400 MHz, CDCl3): δ 7.69 (d, J )
9.60 Hz, 2H), 7.58 (s, 1H), 7.33 (dd, J ) 8.40, 1.60 Hz, 1H),
7.15-7.12 (m, 2H), 6.13-6.04 (m, 1H), 5.13-5.06 (m, 2H), 3.92
(25) (a) Kobayashi, H.; Sonoda, A.; Iwamoto, H.; Yoshimura, M. Chem.
Lett. 1981, 10, 579. (b) Brookhart, M.; Grant, B.; Volpe, A. F., Jr. Organome-
tallics 1992, 11, 3920–3922.
(26) (a) Criegee, R. Angew. Chem., Int. Ed. Engl. 1975, 87, 745. (b) Tietze,
L. F.; Bratz, M. Org. Synth. 1993, 71, 214.
3070 J. Org. Chem. Vol. 74, No. 8, 2009

Catalytic Asymmetric Synthesis Using Feedstocks
vigorously. The reaction mixture was allowed to warm to ambient
temperature and was stirred for a further 15 min, at which time
water (5 mL) was added and stirred for three minutes. Sulfuric
acid (3 mL of a 10% v:v solution) was added and the solution was
stirred for an additional ten minutes before the slurry was extracted
into diethyl ether (3 × 10 mL). The combined organic extracts
were dried over anhydrous MgSO4, filtered through a sintered glass
funnel, and concentrated to afford 107 mg (98%) of (S)-(+)-
ibuprofen.
44.8, 18.0. [R]D22 ) 41.2 ( 0.02 (c 1.00, CHCl3). HRMS 244.0904
(M+·; calcd for C15H13O2F 244.0900). GC (chiral) conditions, (L)-
menthyl esters: (Chirasil-S-Val) 120 min at 200 °C (isothermal);
retention time (min): 82.24 (R), 87.37 (S).
(S)-(+)-Naproxen (12). White solid, mp 154-155 °C; 1H NMR
(400 MHz, CDCl3): δ 7.72 (s, 1H), 7.69 (s, 2H), 7.42 (dd, J )
8.40, 1.60 Hz, 1H), 7.15 (dd, J ) 8.80, 1.60 Hz, 1H), 7.11 (d, J )
2.00 Hz, 1 H), 3.92 (s, 3H), 3.88 (q, J ) 7.20 Hz, 1H), 1.60 (d, J
) 7.20 Hz). 13C NMR (100 MHz, CDCl3): δ 180.8, 157.7, 134.8,
133.8, 129.3, 128.9, 127.2, 126.2, 126.1, 119.0, 105.6, 55.3, 45.3,
Procedure 2.7c A solution of 1-phenoxy-3-[(R)-1-methylallyl]-
benzene (90 mg, 0.40 mmol) in 1:2 CCl4:H2O (10 mL) was added
NaIO4 (0.427 g, 2.0 mmol). A solution of RuCl3-H2O (0.80 mg,
0.004 mmol) in CH3CN (4 mL) was added in a dropwise fashion
to the biphasic solution containing the olefin. The reaction was
stirred at ambient temperature for 3 h at which time it was poured
into a 100 mL separatory funnel containing CH2Cl2 (20 mL) and
10% H2SO4 (20 mL). The DCM was drained off and the remaining
aqueous solution was extracted with DCM (2 × 15 mL). The
resulting organic layers were combined, dried over anhydrous
MgSO4, filtered, and concentration by rotary evaporation. The crude
material was purified by column chromatography (6:1 hexanes/
ethyl acetate) to afford (S)-fenoprofen (88 mg, 91%).
18.1. [R]D22 ) 66.5 ( 0.02 (c 1.00, CHCl3). HRMS 248.1045 (M+·
calcd for C14H14O3 + H2O 248.1049).
;
(S)-(+)-Fenoprofen (13). Beige solid, mp 169-170 °C; 1H NMR
(400 MHz, CDCl3): δ 11.48 (br s, 1H), 7.33-7.28 (m, 2H),
7.25-7.20 (m, 2H), 7.09 (t, J ) 7.20 Hz, 1H), 7.04 (d, J ) 7.60
Hz, 1H), 7.01-6.97 (m, 3H), 6.87 (dd, J ) 8.00, 2.40 Hz, 1H),
3.69 (q, J ) 7.20 Hz, 1H), 1.49 (d, J ) 7.20 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 180.5, 157.5, 156.9, 141.6, 129.9, 129.7,
123.4, 122.3, 119.0, 118.2, 117.5, 45.2, 18.0. [R]D22 ) 22.3 ( 0.02
(c 0.50, CHCl3). HRMS 265.0836 (M+·; calcd for C15H14O3 + Na
265.0841). GC (chiral) conditions, (L)-menthyl esters: (Chirasil-
S-Val) 120 min at 195 °C (isothermal); retention time (min): 94.33
(R), 95.81 (S).
Procedure 3.27 To a solution of 2-(3-bromophenyl)-1-butene
(100 mg, 0.46 mmol) in 1:2 t-BuOH/H2O (36 mL), was added
KMnO4 (216 mg, 1.38 mmol), NaIO4 (1.76 g, 8.2 mmol) and K2CO3
(446 mg, 3.2 mmol). The pH of the reaction solution was adjusted
to 8 with 2 M KOH aqueous solution. The reaction was stirred for
3 h at ambient temperature. Concentrated HCl was added to adjust
the pH of the solution to 1, and NaHSO3 was added to reduce
KMnO4 until the reaction mixture turned yellow. The mixture was
extracted with dichloromethane and the CH2Cl2 layer was extracted
with 2 M KOH aqueous solution (5 mL). The aqueous layer was
acidified with 10% H2SO4 and then was extracted with CH2Cl2 (3
× 15 mL). The dried organic layer was evaporated and the product
was subjected to flash column chromatography (10:1 CH2Cl2/
MeOH) to afford 2-(3-bromophenyl)-propionic acid (100 mg, 93%).
(S)-2-(3-Bromophenyl)-propionic acid (14). Light-yellow oil,
1H NMR (400 MHz, CDCl3): δ 10.17 (br s, 1H), 7.48 (s, 1H), 7.40
(d, J ) 8.00 Hz, 1H), 7.25 (d, J ) 8.80 Hz, 1H), 7.20 (d, J ) 8.00
Hz, 1H), 3.70 (q, J ) 7.20 Hz, 1H), 1.50 (d, J ) 7.20 Hz, 3H). 13
C
NMR (100 MHz, CDCl3): δ 179.9, 141.8, 130.8, 130.6, 130.2,
22
126.3, 122.7, 45.0, 18.0. [R]D ) 33.8 ( 0.02 (c 1.00, CHCl3).
HRMS 249.9600 (M+·; calcd for C9H8O2Br + Na 249.9605). GC
(chiral) conditions, (L)-menthyl esters: (Chirasil-S-Val) 45 min at
190 °C (isothermal); retention time (min): 25.77 (R), 26.70 (S).
Synthesis of (()-Ketoprofen from Racemic 6. A 25 mL three-
necked round bottomed flask equipped with a rubber septum, flow-
controlled nitrogen inlet, a temperature probe, and a magnetic
stirring bar was flame-dried and purged with nitrogen. The flask
was then charged with 6 (0.10 g, 0.46 mmol) and freshly distilled
hexanes (5 mL) and the vessel was subsequently cooled to -78
°C, at which time, t-BuLi (0.92 mmol, 0.55 mL of 1.7 M solution
in hexanes) was added to the stirred mixture in a dropwise fashion,
maintaining the temperature below -75 °C. After addition was
complete, the solution was allowed to stir for 1 h before addition
of benzaldehyde (0.06 mL, 0.55 mmol). Upon completion of
addition, the vessel was warmed to ambient temperature and allowed
to react for 18 h. Upon completion of reaction, the mixture was
poured into water (20 mL) and washed with diethyl ether (3 × 20
mL). The ethereal layers were combined and washed with an
ethanolic solution of NaHSO3 (20 mL). The ethereal portion was
dried with Na2SO4 (1.5 g), filtered, and reduced. The crude alcohol
(0.100 g, 0.45 mmol) was used without further purification. The
olefin was suspended in a solution of 2:1 H2O:t-BuOH (36 mL)
with vigorous stirring in a 100 mL single-necked round bottomed
flask. When the mixture became homogeneous, the solution was
cooled to 0 °C and the olefin was treated with KMnO4 (0.213 g,
1.35 mmol), NaIO4 (1.73 g, 8.10 mmol), and K2CO3 (0.44 g, 3.20
mmol), which were added as a single portion. The pH was adjusted
to 8 with a solution of 2 M KOH. The reaction was stirred for 2 h
at 0 °C. Concentrated HCl was added to adjust the pH of the
solution to 1, and NaHSO3 was added to reduce KMnO4 until the
reaction mixture turned yellow. The mixture was extracted with
dichloromethane and the CH2Cl2 layer was extracted with 2 M KOH
aqueous solution. The aqueous layer was acidified with concentrated
10% H2SO4 and then was extracted with CH2Cl2 (3 × 15 mL).
The dried organic layer was evaporated and the product was
subjected to chromatography (10:1 CH2Cl2/MeOH) to afford
racemic ketoprofen (83 mg, 72%) as a white crystalline solid.
(()-Ketoprofen (17). White solid, mp 94-96 °C; 1H NMR (400
MHz, CDCl3): δ 7.81-7.78 (m, 3H), 7.69 (d, J ) 7.60 Hz, 1H),
7.61-7.56 (m, 2H), 7.49-7.43 (m, 3H), 3.83 (q, J ) 7.20 Hz,
1
(S)-(+)-Ibuprofen (9). White solid, mp 76-77 °C; H NMR
(400 MHz, CDCl3): δ 11.13 (br s, 1H), 7.22 (d, J ) 8.00 Hz, 2H),
7.10 (d, J ) 8.00 Hz, 2H), 3.71 (q, J ) 7.20 Hz, 1H), 2.44 (d, J )
7.20 Hz, 2H), 1.85 (septet, J ) 6.80 Hz, 1H), 1.50 (d, J ) 7.20
Hz, 3H), 0.89 (d, J ) 6.80 Hz, 6H). 13C NMR (100 MHz, CDCl3):
22
δ 181.3, 140.8, 137.0, 129.4, 127.3, 45.0 (2), 30.1, 22.4, 18.1. [R]D
) 55.1 ( 0.02 (c 1.00, CHCl3). HRMS 229.1200 (M+·; calcd for
C13H18O2 + Na 229.1204). To ascertain the absolute configuration
and the enantioselectivity, the crude product (0.5 mg in 100 µL of
dichloromethane) was converted to the corresponding ibuprofen
(-)-menthyl esters by mixing with 100 µL of an esterification
solution, prepared as described below, and then stirring the resulting
mixture for 30 min. The esterification solution was prepared by
dissolving 3.5 g of (-)-menthol, 0.12 g of dicyclohexylcarbodi-
imide, 6 mg of 4-dimethylaminopyridine, and 25 µL of 1 M HCl
in 1 mL of dichloromethane. GC (chiral stationary phase, Cyclodex-
ꢀ) conditions for the (L)-menthyl esters, 60 min at 160 °C
(isothermal): retention time (min): 39.55 (S), 42.55 (R). The major
acid isomer was identified as S-ibuprofen (96% ee) by comparison
of retention times with that of authentic samples. The diastereomeric
menthyl esters were prepared from commercially available racemic
ibuprofen using the esterification solution. A slight preference for
the formation of one of the diastereomeric esters was noticed in
this preparation.
1
(S)-(+)-Flurbiprofen (11). White solid, mp 115-117 °C; H
NMR (400 MHz, CDCl3): δ 11.48 (br s, 1H), 7.55-7.52 (m, 2H),
7.46-7.35 (m, 4H), 7.19-7.14 (m, 2H), 3.79 (q, J ) 7.20 Hz,
1H), 1.57 (d, J ) 7.20 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
179.9, 140.9, 135.4, 130.9, 128.9, 128.4, 127.7, 123.7, 115.5, 115.3,
(27) (a) Lemieux, R. U.; von Rudloff, E. Can. J. Chem. 1955, 33, 1701. (b)
von Rudloff, E. Can. J. Chem. 1965, 43, 1784. (c) von Rudloff, E. Can. J. Chem.
1956, 34, 1413. (d) von Rudloff, E. Can. J. Chem. 1965, 43, 2660. (e) Suga, T.;
von Rudloff, E. Can. J. Chem. 1969, 47, 3682.
J. Org. Chem. Vol. 74, No. 8, 2009 3071

Smith and RajanBabu
1H), 1.56 (d, J ) 7.20 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
196.4, 179.9, 140.1, 137.9, 137.4, 132.5, 131.6, 130.1, 129.3, 129.2,
128.6, 128.3, 45.2, 18.1. HRMS 276.0761 (M+·; calcd for C16H13O3
+ Na 276.0762).
(S)-2-Methyl-2-phenylbutanoic Acid (15). Beige solid, mp
67-69 °C; 1H NMR (400 MHz, CDCl3): δ 11.68 (br s, 1H),
7.40-7.32 (m, 4H), 7.27-7.24 (m, 1H), 2.16-1.95 (m, 2H), 1.57
(s, 3H), 0.86 (t, J ) 7.60 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 182.5, 142.8, 128.4, 126.9, 126.3, 50.4, 31.6, 21.7, 9.0. HRMS
196.1095 (M+·; calcd for C11H16O3 196.1099).
Typical Procedure for the Schmidt Rearrangement of
2-Arylpropionic Acids.15 A 10 mL two-necked round bottomed
flask equipped with a magnetic stirring bar, rubber septum, reflux
condenser, and a gas inlet was evacuated, flame-dried, and purged
with nitrogen. The flask was then charged with (S)-2-methyl-2-
phenylbutanoic acid (15, 0.100 g, 0.56 mmol), and chloroform (4
mL) distilled from calcium hydride and the reaction was cooled to
0 °C. Methanesulfonic acid (0.36 mL, 5.60 mmol) was then
introduced over a period of 10 min. Once addition was complete,
the reaction was stirred for 10 min before sodium azide (0.18 g,
2.80 mmol) was added as a single portion, maintaining the
temperature at 0 °C. The reaction mixture was then warmed to reflux
for a period of 12 h. Upon completion, the reaction was cooled to
ambient temperature and the solution was neutralized via addition
of 1 M NaOH (3 mL). The mixture was then poured into deionized
H2O (10 mL) and extracted into DCM (3 × 10 mL). The organic
layers were then combined, dried over MgSO4, filtered, and reduced
to a syrup which was then dissolved in DCM (3 mL). Propionyl
chloride (0.5 mL) was then added to the solution in a dropwise
fashion and stirred for 1 h. The reaction was then neutralized with
saturated NaHCO3 (10 mL). The product was extracted into DCM
(3 × 10 mL). The combined organic layers were washed with 1 M
NAOH (10 mL), and then brine (10 mL). The organic layer was
then dried over MgSO4, filtered, and reduced in Vacuo. The product
was then purified by passage through a silica gel column (4:1
hexanes/ethyl acetate) to afford 74 mg (64%) of the amide as a
clear oil.
Typical Procedure for the Curtius Rearrangement of
2-Arylpropionic Acids.14 A 10 mL two-necked round bottomed
flask equipped with a magnetic stirring bar, rubber septum, reflux
condenser, and a gas inlet was evacuated, flame-dried, and purged
with nitrogen. The flask was then charged with (S)-2-methyl-2-
phenylbutanoic acid (15, 0.100 g, 0.56 mmol), diphenylphosphoryl
azide (0.24 mL, 1.12 mmol), triethylamine (0.12 mL, 0.84 mmol),
and benzene (4 mL). The solution was then heated to reflux and
maintained for 12 h, at which time benzyl alcohol (0.29 mL, 2.80
mmol) was added in a single portion and the reaction was
maintained at reflux for an additional 6 h. Upon completion, the
reaction was cooled to ambient temperature, treated with 1 M NaOH
(4 mL), and the slurry was poured into a separatory funnel
containing deionized H2O (15 mL). The solution was then extracted
with dichloromethane (3 × 10 mL). The organic layers were then
combined and washed with 10% H2SO4 (20 mL). The organic layer
was then dried with MgSO4, filtered, and reduced. The product was
then subjected to chromatography (6:1 hexanes/ethyl acetate) to
afford (S)-benzyl-2-phenylbutan-2-ylcarbamate (18, 128 mg, 81%)
as a clear oil.
1
(S)-N-(2-Phenylbutan-2-yl)propionamide (19). Clear oil, H
NMR (500 MHz, CDCl3): δ 7.34-7.31 (m, 4H), 7.25-7.21 (m,
1H), 4.14 (q, J ) 7.00 Hz, 1H), 2.15-2.08 (m, 1H), 1.99-1.92
(m, 1H), 1.53 (s, 3H), 1.19 (t, J ) 7.00 Hz, 3H), 0.85 (t, J ) 7.00
Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 176.2, 144.0, 128.2, 126.5,
126.0, 60.6, 50.6, 31.8, 22.2, 14.1, 9.1. IR (neat) cm-1: 3447, 2879,
1
(S)-Benzyl-2-phenylbutan-2-ylcarbamate (18). Clear oil, H
NMR (500 MHz, CDCl3): δ 7.37-7.31 (m, 9H), 7.24-7.22 (m,
1H), 5.11 (br s, 1H), 5.04 (s, 2H), 2.04-1.99 (m, 1H), 1.92-1.88
(m, 1H), 1.70 (s, 3H), 0.80 (t, J ) 7.50 Hz, 3H). 13C NMR (125
MHz, CDCl3): δ 154.4, 145.7, 136.7, 129.8, 128.4, 128.2, 128.1,
127.7, 126.5, 125.2, 120.1, 66.2, 58.3, 34.8, 25.1, 8.2. IR (neat)
cm-1: 3432, 3344, 2974, 1718, 1497, 737. [R]D22 ) 1.4 ( 0.02 (c
1.00, CHCl3). HRMS 283.1570 (M+ · ; calcd for C18H21NO2
283.1572).
22
1272, 1265, 738. [R]D ) 2.0 ( 0.02 (c 0.50, CHCl3). HRMS
205.1463 (M+·; calcd for C13H19NO 205.1467).
(S)-N-(1-(2-Fluorobiphenyl-4-yl)ethyl)propionamide (22). Clear
1
oil, H NMR (500 MHz, CDCl3): δ 7.55 (d, J ) 8.00 Hz, 2H),
7.45 (t, J ) 7.50 Hz, 2H), 7.42-7.35 (m, 2H), 7.16 (t, J ) 8.00
Hz, 2H), 4.23-4.12 ([(ABq)q]; νAB ) 0.036, νA ) 4.21, νB ) 4.14;
JAB ) 11.50, JAX ) 7.00, JBX ) 7.00 Hz; 2H), 3.75 (q, J ) 7.00
Hz, 1H), 1.54 (d, J ) 7.00 Hz, 3H), 1.25 (d, J ) 7.00 Hz, 3H). 13
C
(S)-Ethyl-2-(4-isobutylphenyl)butan-2-ylcarbamate (20). Clear
1
oil, H NMR (500 MHz, CDCl3): δ 7.21 (d, J ) 8.00 Hz, 2H),
NMR (125 MHz, CDCl3): δ 174.0, 159.7 (d, JC-F ) 246.0 Hz),
142.0, 135.5, 130.7, 128.9, 128.4, 127.8, 127.6, 123.5, 115.3, 115.1,
61.0, 45.1, 18.4, 14.1. IR (neat) cm-1: 3445, 2981, 1730, 1484,
1183, 737. [R]D22 ) 22.7 ( 0.02 (c 1.00, CHCl3). HRMS 271.1370
(M+·; calcd for C17H18NOF 271.1372). HPLC (chiral) conditions:
(Chiralpak AD-H) isocratic hexanes, 0.50 mL/min; retention time
(min): 42.82 (R), 47.43 (S).
7.10 (d, J ) 8.00 Hz, 2H), 4.99 (br s, 1H), 4.83 (br s, 1H),
4.14-4.07 (m, 2H), 2.45 (d, J ) 7.50 Hz, 2H), 1.85 (septet, J )
7.00 Hz, 1H), 1.47 (d, J ) 6.50 Hz, 3H), 1.22 (t, J ) 7.00 Hz,
3H), 0.90 (d, J ) 6.50 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ
155.8, 140.8, 140.6, 129.3, 125.7, 60.6, 50.5, 50.2, 45.0, 30.1, 22.3,
14.5. IR (neat) cm-1: 3437, 3334, 2957, 1713, 1510, 740. [R]D
)
22
12.1 ( 0.02 (c 1.00, CHCl3). HRMS 277.2045 (M+ · ; calcd for
C17H27NO2 277.2042).
Acknowledgment. Financial assistance for this research by
NSF (CHE-0610349) and NIH (General Medical Sciences, R01
GM075107) is gratefully acknowledged. We also thank the ACS
Organic Division for a graduate fellowship sponsored by The
Schering Plough Corporation to Craig Smith.
(S)-Ethyl-2-(3-phenoxyphenyl)butan-2-ylcarbamate (21). Light-
yellow oil, 1H NMR (500 MHz, CDCl3): δ 7.33 (dt, J ) 8.50, 1.50
Hz, 2H), 7.28 (t, J ) 8.00 Hz, 1H), 7.10 (t, J ) 7.50 Hz, 1H), 7.04
(d, J ) 8.00 Hz, 1H), 7.01-6.98 (m, 3H), 6.86 (dd, J ) 8.00, 2.00
Hz, 1H), 4.94 (d, J ) 7.00 Hz, 1H), 4.82 (br s, 1H), 4.13-4.07
(m, 2H), 1.45 (d, J ) 6.50 Hz, 3H), 1.22 (t, J ) 7.00 Hz, 3H). 13
C
Supporting Information Available: Spectroscopic and
chromatographic data for characterization of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
NMR (125 MHz, CDCl3): δ 157.5, 157.1, 155.8, 146.0, 129.9,
129.8, 123.3, 120.8, 118.9, 117.4, 116.4, 60.9, 50.4, 22.6, 14.6. IR
(neat) cm-1: 3442, 3329, 3015, 2981, 1704, 1584, 1245, 757. [R]D
22
) -42.8 ( 0.02 (c 0.50, CHCl3). HRMS 313.1674 (M+·; calcd
for C19H23NO3 313.1678).
JO900198B
3072 J. Org. Chem. Vol. 74, No. 8, 2009