Synthetic applications of the β-lithiation of β-Aryl secondary amides: Diastereoselective and enantioselective substitutions

Article abstract of DOI:10.1021/jo952223r

The sequence of β-lithiation and electrophilic substitution of β-aryl secondary amides is reported. The lithiations occur regioselectively at the β-position, and the resulting lithiated intermediates can be reacted with a wide range of electrophiles to give substituted products. Reactions of β-lithiated amides bearing an α-substituent provide substituted products with high diastereoselectivity. Electrophilic substitutions of β-lithiated N-methylamides in the presence of the chiral diamine (-)-sparteine provide highly enantioenriched products. The methodology is used to synthesize enantioenriched β-aryl β-substituted amides, acids, and lactones.

Full text of DOI:10.1021/jo952223r

4542
J . Org. Chem. 1996, 61, 4542-4554
Syn th etic Ap p lica tion s of th e â-Lith ia tion of â-Ar yl Secon d a r y
Am id es: Dia ster eoselective a n d En a n tioselective Su bstitu tion s†
Gary P. Lutz, Hua Du, Donald J . Gallagher, and Peter Beak*
Department of Chemistry, Roger Adams Laboratory, University of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
Received December 18, 1995X
The sequence of â-lithiation and electrophilic substitution of â-aryl secondary amides is reported.
The lithiations occur regioselectively at the â-position, and the resulting lithiated intermediates
can be reacted with a wide range of electrophiles to give substituted products. Reactions of
â-lithiated amides bearing an R-substituent provide substituted products with high diastereose-
lectivity. Electrophilic substitutions of â-lithiated N-methylamides in the presence of the chiral
diamine (-)-sparteine provide highly enantioenriched products. The methodology is used to
synthesize enantioenriched â-aryl â-substituted amides, acids, and lactones.
The â-lithiation of carboxamides provides lithiated
formed with high enantioenrichments.4 These reactions
can be used to provide diastereoenriched and enantioen-
riched lactone and lactam products.
intermediates which are synthetic equivalents of ho-
moenolates.1 We have previously reported â-lithiations
of R-substituted diisopropylamides 1.2 These reactions
are characterized by a kinetically directed deprotonation
of a â-hydrogen instead of deprotonation of the thermo-
dynamically more acidic hydrogen R to the amide carbo-
nyl.3 The lithiated intermediate 2 was shown to react
with electrophiles to provide the â-substituted products
3 with high diastereoselectivity. The relative stereo-
chemistry of 3 was found to be dependent on the elec-
trophile.
Resu lts a n d Discu ssion
Lith ia tion s of â-P h en yl Secon d a r y Am id es. Lithi-
ations of â-phenyl tertiary amides which do not have an
R-substituent occur at the R-position.2 We expected that
lithiation of the corresponding secondary amides would
result in the initial formation of the N-lithio species
which should discourage formation of the enolate species.
As shown below, lithiation of either N-methyl-3-phenyl-
propanamide (4) or N-isopropyl-3-phenylpropanamide (5)
with 2 equiv of s-BuLi in THF at -78 °C for 1 h produced
a dianion which on reaction with CH3OD provided either
the â-substituted product 6 in 88% yield and 97% d1 or 7
in 98% yield and 96% d1.
The synthetic utility of these reactions is limited by
the difficulty in removing the diisopropylamide function-
ality. As part of an ongoing effort to extend remote
directed lithiation/substitution methodology, we have
investigated â-aryl secondary amides. In this report, we
show that lithiations of these compounds occur regiose-
lectively in the â-position. Substitution reactions of the
lithiated intermediates proceed with high diastereose-
lectivity in the presence of R-substituents. In the absence
of R-substituents and in the presence of the chiral
diamine (-)-sparteine the â-substituted products are
A wide range of electrophiles have been assayed in this
reaction, and formation of products 8-30 is summarized
in Table 1. Most of these electrophilic substitutions
proceed in good yield from either 4 or 5 with no detectable
substitution at the anionic amide nitrogen. The dilithi-
ated intermediate reacts with alkyl halides in good yields
(Table 1, entries 1-10). Reactions with bromochloroal-
kanes (Table 1, entries 5-7) illustrate that alkyl chlorides
remain intact under the reaction conditions. Alkylations
using the corresponding dibromoalkanes provided lower
yields of the desired products and sideproducts including
debrominated material and cross-coupling products.
† Dedicated to Clayton H. Heathcock on the occasion of his 60th
birthday.
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
(1) For leading references and reviews on homoenolates, see: Ku-
wajima, I.; Nakamura, E. Topics Curr. Chem. 1991, 155, 1. Stowell, J .
C. Chem. Rev. 1984, 84, 409.
(2) Lutz, G. P.; Wallin, A. P.; Kerrick, S. T.; Beak, P. J . Org. Chem.
1991, 56, 4938. Beak, P.; Hunter, J . E.; J un, Y. M.; Wallin, A. P. J .
Am. Chem. Soc. 1987, 109, 5403. Beak, P.; Hunter, J . E.; J un, Y. M.
J . Am. Chem. Soc. 1983, 105, 6350.
(3) Kinetic deprotonation of a less thermodynamically acidic hydro-
gen has been rationalized in terms of a complex-induced proximity
effect (CIPE). Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
(4) For a preliminary report of this work, see: Beak, P.; Du, H. J .
Am. Chem. Soc. 1993, 115, 2516.
S0022-3263(95)02223-7 CCC: $12.00 © 1996 American Chemical Society

â-Lithiation of â-Aryl Secondary Amides
J . Org. Chem., Vol. 61, No. 14, 1996 4543
Ta ble 1. â-Lith ia tion s a n d Electr op h ilic Su bstitu tion s of
Ta ble 2. â-Lith ia tion a n d Electr op h ilic Su bstitu tion of 9
4 a n d 5
entry
E+
E
product
yielda (%)
1
2
3
4
5
CH3OD
CH3I
Ph2CO
PhCHO
DMF
D
CH3
Ph2C(OH)
PhCH(OH)
34
35
36
37
38
87 (86 d1)
91
yielda
(%)
entry
R
E+
E
product
61
66b
71c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Me CH3I
i-Pr CH3I
Me n-BuI
i-Pr n-BuI
i-Pr Cl(CH2)3Br
i-Pr Cl(CH2)4Br
i-Pr Cl(CH2)5Br
CH3
CH3
n-Bu
n-Bu
8
9
93
70
94
93
79
80
77
78
55
91
87
75
78
82
90
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
a
Isolated yields of analytically pure material unless otherwise
b
noted. Isolated as lactone 39 as two diastereomers in 66% overall
Cl(CH2)3
Cl(CH2)4
Cl(CH2)5
yield. c Isolated as lactam 38 in 71% yield.
Me CH2)CHCH2Cl CH2)CHCH2
methanol-d and methyl iodide as electrophiles (Table 2,
entries 1 and 2) provided 87% and 91% yields of 34 and
35, respectively. Use of benzophenone and benzaldehyde
as electrophiles (Table 2, entries 3 and 4) provided
moderate yields of substituted products.
The crude product 37 from reaction with benzaldehyde
was converted to lactone 39 to provide two separable
diastereomers in 66% overall yield. Use of DMF as the
electrophile (entry 5) provided a 71% yield of 38 as one
diastereomer of undetermined relative stereochemistry.
Me PhCH2Cl
i-Pr PhCH2Cl
Me TMSCl
PhCH2
PhCH2
TMS
TMS
i-Pr TMSCl
Me Me2PhSiCl
Me Bu3SnCl
Me Ph2CO
Me2PhSi
Bu3Sn
Ph2C(OH)
Ph2C(OH)
PhCH(OH)
PhCH(OH)
(CH3)2C(OH)
(CH3)2C(OH)
(CH2)5COH
PhCO
i-Pr Ph2CO
96
Me PhCHO
i-Pr PhCHO
Me (CH3)2CO
i-Pr (CH3)2CO
Me (CH2)5CO
i-Pr PhCO2CH3
i-Pr n-BuCOCl
78b
81b
50
>48c
67
70
53
n-BuCO
a
b
Yield of isolated material unless otherwise noted. Obtained
as a 1:1 mixture of diastereomers. c Product 27 was not purified
but converted to the lactone 31 in 48% overall yield.
Lithiation/substitution of 4 using TMSCl as an elec-
trophile (Table 1, entry 11) provided the expected product
18 in 87% yield, while the lithiation/substitution of 5 with
TMSCl (Table 1, entry 12) provided a 75% yield of 19.
Carbonyl compounds also functioned as efficient electro-
philes (Table 1, entries 15-23). Use of benzophenone
and benzaldehyde (Table 1, entries 15-18) provided good
yields of substituted products. The initial product 27
from the use of acetone as the electrophile was not
purified but was cyclized to lactone 31 in 48% overall
yield.
The chloro derivatives 13 and 14 (Table 1, entries 6
and 7) were found to undergo â-lithiation followed by an
intramolecular cyclization on warming to provide the
cyclopentane derivative 40 and the cyclohexane deriva-
tive 41. When the deprotonation-cyclization sequence
was attempted at -78 °C, only unchanged starting
materials were recovered. Addition of the s-BuLi to 13
and 14 at -40 °C followed by very gradual warming to
-10 °C overnight afforded the desired cyclized products
40 and 41 in 95% and 79% yields, respectively.
When DMF was used as the electrophile the unstable
lactam 32 was found to be the major product. Treatment
of crude 32 sequentially with silica gel and p-toluene-
sulfonic acid provided the R,â-unsaturated lactam 33 in
88% overall yield from 5.
Dia ster eoselectivity in th e P r esen ce of r-Su bstit-
u en ts. The diastereoselectivity of the â-lithiation in the
presence of an R-methyl substituent was investigated.
Amide 42 was lithiated with 2-2.3 equiv of s-BuLi in
THF at -78 °C for 30 min followed by reaction with an
electrophile to provide the â-substituted amides 43-47
(Table 3) in 70-95% yields with moderate to high
diastereoselectivity. As shown in entry 1 (Table 3), the
addition of CH3OD provided the â-deuterated amide 43
in 95% yield as 92.5% d1 material. Amide 43 was
obtained as a 75:25 mixture of diastereomers based on
1
the H NMR spectrum. The â-protons of 42 appear as
The sequence of lithiation/substitution at the tertiary
benzylic position of 9 was investigated. Treatment of 9
with 2 equiv of s-BuLi followed by reactions with elec-
trophiles provided moderate to good yields of â-substi-
tuted products 34-38 as shown in Table 2. Use of
two distinct sets of doublets of doublets at 2.67 and 2.92
ppm while the â-proton of 43 appears as a multiplet at
2.65 ppm which integrates as 0.25 of a proton and as a
doublet at 2.90 ppm which integrates as 0.75 of a proton.
The position of deuteration was further verified by the

4544 J . Org. Chem., Vol. 61, No. 14, 1996
Lutz et al.
Ta ble 3. â-Lith ia tion a n d Electr op h ilic Su bstitu tion
Ta ble 4. Yield s a n d en a n tioselectivities for th e
lith ia tion of 4 in th e p r esen ce of 49
of 42
entry
E+
E
product
43
(R*,S*)-44
yielda (%)
1
2
3
4
5
CH3OD
CH3I
Br(CH2)4Br
Ph2CO
D
CH3
95 (93 d1)
87b
Br(CH2)3CH2 (R*,S*)-45c 79
Ph2C(OH)
PhCH(OH)
yielda eec
(R*,S*)-46c 95
47
70d
entry
E+
E
product
(%)
(%)
PhCHO
1
2
3
4
5
6
7
8
9
10
11
12
13
CH3I
(CH3)2SO4
n-C4H9I
n-C4H9Cl
PhCH2Br
CH2)CHCH2Cl CH2)CHCH2
(CH3)3SiCl
(CH3)2PhSiCl
(n-C4H9)3SnCl
PhCHO
Ph2C(O)
(CH2)5C(O)
(CH3)2C(O)
CH3
CH3
n-C4H9
n-C4H9
PhCH2
(R)-8
(R)-8
84b
80
78
59
88
10
80
80
94
80
60
65d
73e
54
60
a
b
Isolated yield of analytically pure material. Yield corrected
for 14% recovered starting material. c Relative stereochemistry
(R)-10
(R)-10
(R)-16
(R)-15
(R)-18
(R)-20
(R)-21
(R)-24
(R)-22
(R)-28
(R)-26
77b
76
d
assigned by analogy to 44. Yield corrected for 22% recovered
starting material.
78b
74
(CH3)3Si
86b
68
observance of a triplet for the â-carbon resonance at 40.3
ppm in the 13C NMR spectrum of 43. The stereochem-
istries of the diastereomers were not assigned. The
assignment of the regiochemistry for the remainder of
(CH3)2PhSi
(n-C4H9)3Sn
PhCH(OH)
Ph2C(OH)
(CH2)5C(OH)
(CH3)2C(OH)
84
63b
84b
65
1
the products in Table 3 was similarly based upon H and
13C NMR spectra and upon analogy to the â-deuterated
product 43. Use of methyl iodide as the electrophile
provided the R,â-dimethyl amide 44 in 75% yield. The
amide 44 was obtained as a single diastereomer and was
determined to be of the R*,S* configuration based upon
1H and 13C NMR comparison to authentic R*,R* material.5
The â-lithiated intermediate from 42 reacts with
Br(CH2)4Br to provide the bromide 45 in 79% yield as a
single diastereomer based on 1H NMR and 13C NMR
analysis. Use of benzophenone as the electrophile af-
forded 46 in 95% yield also as a single diastereomer as
shown in entry 4 (Table 3). The relative configurations
of 45 and 46 are tentatively assigned as (R*,S*) by
analogy to 44. The corresponding reaction sequence
using benzaldehyde provided only one of the four possible
diastereomers of 47 in 55% yield. The assignment of the
relative stereochemistry of 47 is based on an X-ray crystal
structure of the lactone 48 resulting from cyclization of
47. The formation of 47 as a single diastereomer il-
lustrates the potential of this reaction to be used for
diastereoselective synthesis of three contiguous stereo-
genic centers in a single transformation.
45
a
Isolated yields. b From ref 4. c The ee’s and absolute configura-
d
tions were determined as described in the text. The ee of the
product was determined by conversion of 24 to 53 as described in
the text and analysis by CSP HPLC. e Recrystallization of the
product 22 from EtOAc provided 84% ee.
Yields and enantioselectivities for the lithiation/
substitution of 4 in the presence of (-)-sparteine are
summarized in Table 4. As can be seen in Table 4, yields
are generally good, and the products can be obtained in
54-94% enantiomeric excesses. The degree of enan-
tioenrichment was a function of the electrophile. For
example, the use of methyl iodide (Table 4, entry 1)
provides 84% yield of (R)-8 in 78% ee, whereas dimethyl
sulfate (Table 4, entry 2) provides comparable yields but
a 59% ee. The difference between the use of n-butyl
iodide (88% ee, Table 4, entry 3) and n-butyl chloride
(10% ee, Table 4, entry 4)) also illustrates this effect. In
general, electrophilic substitution with alkyl or silyl
halides proceeded in good yield and enantioselectivities.
In contrast, stannyl and carbonyl electrophiles (Table 4,
entries 9-13) gave somewhat lower enantiomeric ex-
cesses. Electrophilic substitution with benzaldehyde
(Table 4, entry 10) provided a 1:1 mixture of diastereo-
mers.
En a n tioselectivity in th e P r esen ce of (-)-Sp a r -
tein e. We have previously reported as preliminary
results observations that the lithiation/substitutions of
4 provide â-substituted products in high enantioselec-
tivities when the reactions are carried out in the presence
of the chiral diamine (-)-sparteine (49).4,6 If the lithia-
tion reactions were carried out in the absence of (-)-
sparteine and the chiral diamine was added to the
reaction mixture prior to the addition of the electrophile,
the products were obtained in high enantiomeric excess.7
(5) Hunter, J . E. Ph.D. Dissertation, University of Illinois at
Urbana-Champaign, 1986.
(6) For related work, see: Hoppe, D.; Kramer, T. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 69. Thayumanavan, S.; Lee, S.; Liu, C.; Beak,
P. J . Am. Chem. Soc. 1994, 116, 9755. Hoppe, I.; Marsch, M.; Harms,
K.; Boche, G.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 2158
and references cited therein.
The enantiomeric excesses for (R)-8, (R)-10, and (R)-
16 were determined by hydrolysis of the methyl amides
to the corresponding acids as discussed below. Amidation

â-Lithiation of â-Aryl Secondary Amides
J . Org. Chem., Vol. 61, No. 14, 1996 4545
Ta ble 5. Effect of Lith ia tion Con d ition s on th e
F or m a tion of (R)-18 fr om th e Lith ia tion /Su bstitu tion of 4
in th e P r esen ce of (-)-Sp a r tein e (49)
with 3,5-dimethylaniline provided the dimethylanilide
derivatives which were analyzed by chiral stationary
phase (CSP) HPLC. The absolute stereochemistries of
(R)-8, (R)-10, and (R)-16 were assigned by comparison
of the optical rotations of the acids to known values. The
enantiomeric excess of (R)-15 was determined directly
by CSP HPLC and the absolute stereochemistry assigned
by analogy with (R)-8, (R)-10, and (R)-16.
The enantiomeric excesses of (R)-18, (R)-20, and (R)-
21 were determined directly by CSP HPLC analysis.
Amide (R)-20 was converted to the ester 50, which was
then oxidized using HBF4 and m-CPBA to the hydroxy
ester 51.9,10 Assignment of the absolute stereochemistry
of (R)-51 was based on comparison of the optical rotation
literature values.11 The assignments of absolute stere-
ochemistry to (R)-18 and (R)-21 were made by analogy
to (R)-20.
condnsc
equiv (T (°C), yield ee
entry basea
solvent
of 49b time (h)) (%) (%)
1
2
3
4
5
6
6
7
8
9
s-BuLi THF
1.1 -78, 1.5
2.5 -78, 1.5
79
78
74
67
82
82
88
90
89
80
s-BuLi THF
s-BuLi THF
s-BuLi THF
t-BuLi THF
s-BuLi Et2O
s-BuLi THF/Et2O (1:1)
s-BuLi THF/MTBE (1:1)
s-BuLi THF/MTBE (1:1)
s-BuLi THF/MTBE (1:1)
5
-78, 1.5
-78, 1.5
10
2.5 -78, 1.5
2.5 -78, 1.5
2.5 -78, 1.5
2.5 -78, 1.5
73
84
86
70
86
92
94
82
5
5
-78, 1.5
-40, 1.5
a
2.2 equiv of organolithium was used for the deprotonation.
b Number of equivalents relative to 4. c Conditions for the lithiation
reaction.
The ee’s of (R)-26 and (R)-28 were determined by
conversion to the corresponding lactones (vida infra) and
analysis by CSP HPLC. The benzaldehyde adduct (R)-
24 was converted to the known acid 53 by treatment of
the 1:1 mixture of diastereomers with Boc-O-Boc under
basic conditions to provide a mixture of diastereomeric
lactones 52. Hydrogenolysis provided the known acid 53.
The dimethylanilide derivative of 53 was determined by
CSP HPLC analysis to be of 65% ee. Comparison of the
optical rotation of 53 led to the absolute stereochemistry
of the â-benzylic carbon assignment as R. Assignments
of the absolute stereochemistry of (R)-22, (R)-26, and (R)-
28 are made by analogy to (R)-24.
could also be carried out with t-BuLi (Table 5, entry 5).
The reaction did not proceed in Et2O where a precipitate,
which is most likely the initially deprotonated amide, is
formed. Mixed solvents of THF/Et2O or THF/MTBE were
found to provide good yields and enantiomeric excesses
of (R)-18. The optimum conditions for the conversion of
4 to (R)-18, listed as entry 8 (Table 5), utilize a 1:1 THF/
MTBE solvent mixture, 5 equiv of (-)-sparteine, and 2.5
equiv of s-BuLi and provide a 94% ee as compared to the
reaction in THF with 1.2 equiv of (-)-sparteine which
provided 82% ee. The reaction possesses some tolerance
for higher temperatures as shown by entry 9 (Table 5)
in which carrying out the lithiation and substitution steps
at -40 °C provides (R)-18 in 70% yield and 82% ee.
Syn th etic Tr a n sfor m a tion s of th e En a n tioen -
r ich ed P r od u cts. Conversions of the enantioenriched
â-substituted carboxamides into other chiral compounds
have been carried out. Asymmetric syntheses of (R)-3-
phenylalkanoic acids (R)-54, (R)-55, and (R)-53 are shown
below. The syntheses of these compounds have previ-
ously utilized chiral auxiliary methodologies involving
Michael additions of organometallic reagents to chiral
R,â-unsaturated amides,12-14 esters,15 and oxazolines.16
The enantioenriched amides 8, 10, and 16 were converted
to the N-Boc derivatives and then treated with 1 M
NaOH in THF at room temperature17 to provide the
known acids (R)-54, (R)-55, and (R)-53 in 60%, 58%, and
62% yields and 78%, 88%, and 80% enantiomeric ex-
cesses, respectively.
A series of reactions carried out to optimize the
lithiation conditions for the formation of (R)-18 from 4
are summarized in Table 5. Entries 1-4 illustrate the
effect of increasing the amount of (-)-sparteine. Some
improvement in enantiomeric excess was found upon
increasing the equivalents of (-)-sparteine to 2.5, but
additional (-)-sparteine had little effect. The reaction
(7) These results indicated that these reactions proceed through an
asymmetric substitution pathway in which the chiral diamine induces
asymmetry in the substitution step. This is in contrast to an asym-
metric deprotonation pathway.8 Work is currently underway exploring
the mechanistic issues of these asymmetric substitution reactions, and
the results will be presented in due course.
The alcohols produced by electrophilic substitution
with ketones could be cyclized to the enantioenriched
(8) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl.
1990, 102, 1257. Kerrick, S. T.; Beak, P. J . Am. Chem. Soc. 1991, 113,
9708. Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J . J . Am. Chem. Soc. 1994,
116, 3231.
(12) Touet, J .; Baudouin, S.; Brown, E. Tetrahedron: Asymmetry
1992, 3, 587-590.
(13) Soai, K.; Ookawa, A. J . Chem. Soc., Perkin Trans. 1 1986, 759.
Soai, K.; Ookawa, A.; Nohara, Y. Synth. Commun. 1983, 13, 27-334.
(14) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 913-916.
(15) Fang, C.; Ogawa, T.; Suemune, H.; Sakai, K. Tetrahedron:
Asymetry 1991, 2, 389-398.
(16) Meyers, A. I.; Smith, R. K.; Whitten, C. E. J . Org. Chem. 1979,
44, 2250-2254. Meyers, A. I.; Whitten, C. E. J . Am. Chem. Soc. 1975,
97, 6266-6267.
(17) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983, 48,
2424-2426.
(9) The phenyldimethylsilyl group can be converted in two steps into
a
hydroxyl group with retention of configuration. This oxidation
10
procedure is known to proceed with retention of configuration.
(10) For recent applications of this reaction, see: Chan, T. H.; Pellon,
P. J . Am. Chem. Soc. 1989, 111, 8737-8738. Pearson, A. J .; O’Brien,
M. K. J . Org. Chem. 1989, 54, 4663-4673. Overman, L. E.; Wild, H.
Tetrahedron Lett. 1989, 30, 647-650.
(11) Oppolzer, W.; Mills, R. J .; Pachinger, W.; Stevenson, T. Helv.
Chim. Acta 1986, 69, 1542-1545.

4546 J . Org. Chem., Vol. 61, No. 14, 1996
Lutz et al.
Ta ble 6. Lith ia tion of 60 w ith s-Bu Li/49 a n d Asym m etr ic
Syn th eses of (R)-4-Su bstitu ted Hyd r ocou m a r in s 66-68
stituted products 61-64 were hydrolyzed to the
corresponding carboxylic acids by treatment with Boc-
O-Boc, followed by 1 M NaOH. Demethylation of 61-
63 and cyclization with BBr3 provided enantioenriched
4-substituted hydrocoumarin products 66-68 in moder-
ate yields over the three steps (42-51%). Attempted
demethylation and cyclization of the allyl-substituted
product 65 resulted in the formation of an intractable
mixture. The results of the lithiation and hydrocou-
marin-forming reactions are presented in Table 6.
yield of
ee of
yield of
coumarin
(%)
product amidea amideb
amide
product
R
(%)
(%)
coumarinc
PhCH2
CH3
Bu
TMS
61
62
63
64
65
71
63
67
68
67
80
80
83
80
86
66
67
68
51
49
46
H2CdCHCH2
a
b
Isolated yields. For determination of enantiomeric excesses,
see ref 21. c Overall isolated yield from the substituted amides 61-
63.
lactones using either 5% HCl in THF or by treatment
with Boc-O-Boc. Using the latter procedure, (R)- 22 was
converted to lactone (R)-56 in 87% yield and 84% ee.
Similarly, treatment of (R)-26 and (R)-28 provided 82%
and 79% yields of (R)-57 and (R)-58 in 60% ee and 54%
ee, respectively. The enantiomeric excesses of 56-58
were determined directly by CSP HPLC and the absolute
configurations assigned by analogy to (R)-24.
We have briefly investigated other â-aryl-substituted
systems. The p-methoxy-substituted amide 69 was lithi-
ated using s-BuLi/(-)-sparteine to provide 72 in 88%
yield and 80% ee. Use of the o-methyl- and o-chloro-
substituted amides 70 and 71 provided 66% isolated
yields of 73 and 74, but the enantiomeric excesses of the
products were 0% and 15% for 73 and 74, respectively.
Although the lithiation/substitution protocol was suc-
cessful with the o-methoxy group present, this methodol-
ogy is apparently not general for all ortho-substituted
systems.
Iodolactonization18 of the â-allyl-substituted amide (R)-
15 provided only the syn-diastereomer of â,δ-disubsti-
tuted-δ-lactone 59 in 67% yield.19 The cis stereochem-
istry was assigned by H NMR spectroscopy using NOE
effects and the enantiomeric excess is assigned as 74%
1
ee based on that of the starting amide (R)-15.
Enantioenriched 4-substituted hydrocoumarins can be
synthesized using this methodology.20 Treatment of
o-methoxy-substituted amide 60 with s-BuLi/49 in 1:1
MTBE/THF at -78 °C followed by electrophilic substitu-
tion provides the (R)-substituted products 61-65 in 63-
71% yields and 80-86% enantiomeric excesses.21 Sub-
In summary, the present work shows that lithiation/
substitution sequences with â-phenyl secondary amides
can be carried out with high regioselectivity, diastereo-
selectivity, and enantioselectivity under controlled reac-
tion conditions. The applications of this methodology
should provide useful approaches for the enantioselective
syntheses of â-aryl-substituted amides, acids, and lac-
tones.
(18) For recent reports on highly diastereoselective iodolactonization
see: Hoffmann, R. W.; Stu¨rmer, R.; Harms, K. Tetrahedron Lett. 1994,
35, 6263-6266. Friesen, R. W.; Kolaczewska, A. E. J . Org. Chem. 1991,
56, 4888-4895. Pearson, A. J .; Hsu, S-Y. J . Org. Chem. 1986, 51,
2505-2511. Metz, P. Tetrahedron 1993, 49, 6367-6374.
(19) The relative configuration of 59 was determined by a difference
1H NMR NOE experiment detailed in the Experimental Section.
(20) Previous asymmetric syntheses of 4-substituted hydrocou-
marins: Grimshaw, J .; Millar, P. G. J . Chem. Soc. 1970, 2324. Abe,
S.; Nonaka, T.; Fuchigami, T. J . Am. Chem. Soc. 1983, 105, 3630-
3632. Schoo, N.; Schafer, H.-J . Liebig. Ann. Chem. 1993, 601-607.
Syntheses of racemic 4-substituted hydrocoumarins: Bergdahl, M.;
Eriksson, M.; Nisson, M.; Olsson, T. J . Org. Chem. 1993, 58, 7238-
7244. Patra, A.; Misra, S. K. Indian J . Chem. 1988, 272-273.
(21) The enantiomeric excesses of amides 61-65 were determined
by hydrolysis of the amides to the corresponding acids and then
formation of the (S)-R-methylbenzylamide derivatives, which were
analyzed for diastereomeric excess by gas chromatography. The
absolute configuration of 62 and 67 was determined by comparison of
the optical rotation of (R)-67 to the known rotation for (R)-67.20 The
absolute configurations of 61, 63-66, 68, and 69 are assigned by
analogy to (R)-67.
Exp er im en ta l Section
All reactions involving organometallic reagents were carried
out under a nitrogen or argon atmosphere in glassware which
was either flame dried or dried in an oven and cooled under a
nitrogen atmosphere. All solvents and reagents were obtained
from commercial sources and were used without further
purification except where noted. Tetrahydrofuran (THF) was
distilled from sodium/benzophenone under a nitrogen atmo-
sphere before use. The s-BuLi solutions were titrated using
the method of Suffert.22
(22) Suffert, J . J . Org. Chem. 1989, 54, 509.

â-Lithiation of â-Aryl Secondary Amides
J . Org. Chem., Vol. 61, No. 14, 1996 4547
High-pressure liquid chromatography (HPLC) was per-
formed using Rainin HPXL pump systems. Preparative scale
HPLC was performed on a Dynamax 60-A 8 µm silica column
(Rainin Instrument Co., Woburn, MA, 25 cm × 21.4 mm i.d.).
Flash chromatography was performed with Merck 50-200 µm
silica gel. Medium-pressure liquid chromatography (MPLC)
was performed using columns of different sizes packed with
Merck silica gel (32-63 mesh) whose length and diameter
depended on the amount of material and the difficulty of the
separation.
145.71, 170.67. Anal. Calcd for C13H19NO: C, 76.06; H, 9.33;
N, 6.82. Found: C, 76.10; H, 9.31; N, 6.89.
N-Isop r op yl-3-p h en ylh ep ta n a m id e (11) was obtained
using butyl iodide as the electrophile and was purified by
MPLC (30% EtOAc/hexane) to afford a 93% yield of 11: 1H
NMR (300 MHz) δ 0.82 (t, J ) 7.2 Hz, 3H), 0.85 (d, J ) 6.5
Hz, 3H), 1.01 (d, J ) 6.6 Hz, 3H), 1.07-1.37 (om, 4H), 1.55-
1.75 (m, 2H), 2.31 (dd, J 1 ) 13.7 Hz, J 2 ) 8.9 Hz, 1H), 2.47
(dd, J 1 ) 13.5 Hz, J 2 ) 6.4 Hz, 1H), 3.02-3.12 (m, 1H), 3.92
(m, J ) 6.6 Hz, 1H), 5.35-5.47 (bd, 1H), 7.10-7.35 (om, 5H);
13C NMR (75 MHz) δ 13.77, 22.25, 22.42, 29.40, 35.62, 40.77,
42.88, 44.80, 126.15, 127.34, 128.24, 144.24, 170.69. Anal.
Calcd for C16H25NO: C, 77.69; H, 10.19; N, 5.66. Found: C,
77.89; H, 10.00; N, 5.71.
Compounds were fully characterized as either the racemic
mixtures or as enantiomerically enriched material. When
microanalysis data were not available, the purity of title
1
compounds was judged to be >90% by H-NMR, GC analysis,
and/or 13C-NMR unless otherwise stated.
6-Ch lor o-N-isop r op yl-3-p h en ylh exa n a m id e (12) was
obtained using 1-bromo-3-chloropropane as the electrophile
and was purified by recrystallization from hexane/EtOAc to
afford a 79% yield of 12 as a white solid: mp 108-110 °C; 1H
NMR (300 MHz) δ 0.85 (d, J ) 6.6 Hz, 3H), 1.02 (d, J ) 6.6
Hz, 3H), 1.55-1.95 (om, 4H), 2.31 (dd, J 1 ) 13.6 Hz, J 2 ) 8.6
Hz, 1H), 2.46 (dd, J 1 ) 13.6 Hz, J 2 ) 6.4 Hz, 1H), 3.05-3.15
(m, 1H), 3.46 (t, J ) 6.2 Hz, 2H), 3.93 (m, J ) 6.7 Hz, 1H),
En a n tiom er ic P u r ity An a lyses. Enantiomeric purity
analyses were carried out with both racemic and enantioen-
riched compounds. Optical rotations were obtained on a
J ASCO Model DIP-370 digital polarimeter (J ASCO Inc.,
Easton, MD) in a cylindrical glass cell (3.5 mm i.d. × 50 mm)
with quartz windows. Analytical chiral stationary phase (CSP)
HPLC was performed on Pirkle-concept chiral columns (Regis
Chemical Co., Morton Grove, IL, 25 cm × 4.6 mm i.d.): (R,R)-
â-Gem 1, D-phenylglycine or (S,S)-Whelk-O1 columns using
mixtures of 2-propanol (i-PrOH) and hexane. Diastereomeric
purity analyses determined by GC were performed on an HP-5
fused silica column.
4.95-5.10 (b, 1H), 7.15-7.25 (om, 3H), 7.25-7.35 (m, 2H); 13
C
NMR (75 MHz) δ 22.43, 22.58, 30.41, 33.03, 41.01, 42.44, 44.95,
45.06, 126.67, 127.39, 128.61, 143.36, 170.30. Anal. Calcd for
C15H22ClNO: C, 67.28; H, 8.28; N, 5.23; Cl, 13.24. Found: C,
67.38; H, 8.34; N, 5.20; Cl, 13.32.
7-Ch lor o-N-isop r op yl-3-p h en ylh ep ta n a m id e (13) was
obtained using 1-bromo-4-chlorobutane as the electrophile and
was purified by MPLC (30% EtOAc/hexane) to afford an 80%
yield of 13 as a clear oil: 1H NMR (300 MHz) δ 0.85 (d, J )
6.5 Hz, 3H), 1.01 (d, J ) 6.6 Hz, 3H), 1.20-1.40 (m, 2H), 1.60-
1.80 (om, 4H), 2.31 (dd, J 1 ) 13.6 Hz, J 2 ) 8.7 Hz, 1H), 2.46
(dd, J 1 ) 13.6 Hz, J 2 ) 6.4 Hz, 1H), 3.02-3.17 (m, 1H), 3.44
(t, J ) 6.7 Hz, 2H), 3.92 (m, J ) 6.7 Hz, 1H), 5.10-5.25 (b,
1H), 7.15-7.37 (om, 5H); 13C NMR (75 MHz) δ 22.35, 22.49,
24.56, 32.30, 35.00, 40.90, 42.71, 44.68, 44.82, 126.44, 127.33,
128.44, 143.71, 170.46. Anal. Calcd for C16H24ClNO: C, 68.19;
H, 8.58; N, 4.97; Cl, 12.58. Found: C, 68.28; H, 8.61; N, 4.96;
Cl, 12.65.
8-Ch lor o-N-isop r op yl-3-p h en ylocta n a m id e (14) was ob-
tained using 1-bromo-5-chloropentane as the electrophile and
was purified by MPLC (30% EtOAc/hexane) to afford a 77%
yield of 14 as a white solid: mp 45-46 °C; 1H NMR (300 MHz)
δ 0.85 (d, J ) 6.5 Hz, 3H), 1.01 (d, J ) 6.6 Hz, 3H), 1.07-1.27
(m, 2H), 1.27-1.47 (m, 2H), 1.57-1.80 (om, 4H), 2.30 (dd, J 1
) 13.6 Hz, J 2 ) 8.7 Hz, 1H), 2.45 (dd, J 1 ) 13.6 Hz, J 2 ) 6.4
Hz, 1H), 3.02-3.17 (m, 1H), 3.45 (t, J ) 6.7 Hz, 2H), 3.92 (m,
J ) 6.7 Hz, 1H), 5.23 (bd, 1H), 7.15-7.35 (om, 5H); 13C NMR
(75 MHz) δ 22.31, 22.46, 26.51, 26.60, 32.26, 35.64, 40.84,
42.79, 44.87, 126.32, 127.32, 128.36, 143.93, 170.53. Anal.
Calcd for C17H26ClNO: C, 69.02; H, 8.86; N, 4.73; Cl, 11.98.
Found: C, 68.94; H, 8.90; N, 4.71; Cl, 12.08.
Gen er a l P r oced u r e for th e Lith ia tion of 4 or 5 w ith
s-Bu Li in THF . To a stirring solution of 4 or 5 (0.05 M in
THF) cooled to -78 °C was added 2.2 equiv of s-BuLi. The
solution was allowed to stir for 0.5-1.4 h, and then the
electrophile (1.1-1.5 equiv) was added. The solution was
allowed to warm slowly to room temperature before 2% HCl
and Et2O were added. The aqueous layer was washed twice
with 10 mL portions of Et2O . The combined Et2O layers were
dried over MgSO4, filtered, and concentrated under reduced
pressure to afford the crude products, which were purified as
indicated below.
3-Deu ter io-N-m eth yl-3-ph en ylpr opan ecar boxam ide (6)
was obtained using methanol-d as the electrophile in 93% yield
and was found to contain 96% d1 and 4% d0 material by FIMS
isotope ratios: 1H NMR (300 MHz) δ 2.52 (d, J ) 7.8 Hz, 2H),
2.75 (bs, 3H), 2.94 (t, J ) 7.5 Hz, 1H), 6.40-6.70 (b, 1H), 7.15-
7.30 (om, 5H); 13C NMR (75 MHz) δ 26.33, 31.42 (t, J ) 19.7
Hz), 37.81, 126.17, 128.18, 128.41, 140.52, 173.43.
3-Deu ter io-N-isop r op yl-3-p h en ylp r op a n a m id e (7) was
obtained using methanol-d as the electrophile in 98% yield as
a thick oil which was found to contain 96.0% d1 and 4.0% d0
material by FIMS isotope ratios: 1H NMR (200 MHz) δ 1.06
(d, J ) 6.7 Hz, 6H), 2.41 (d, J ) 8.1 Hz, 2H), 2.93 (bt, 1H),
4.02 (m, J ) 6.7 Hz, 1H), 5.38-5.53 (bs, 1H), 7.15-7.35 (om,
5H): 13C NMR (50 MHz) 22.58, 31.44 (t, J ) 20 Hz), 38.54,
41.11, 126.07, 128.27, 128.36, 140.79, 171.12.
3,4-Dip h en yl-N-isop r op ylbu ta n eca r boxa m id e (17) was
obtained using benzyl chloride as the electrophile and was
purified by MPLC (30% EtOAc/hexane) to afford a 91% yield
N-Meth yl-3-p h en ylbu ta n a m id e (8) was obtained using
methyl iodide as the electrophile and was purified by MPLC
(35% EtOAc/hexane) to give an 84% yield of 8 as a white
1
1
of 17 as a white solid: mp 96-98 °C; H NMR (300 MHz) δ
solid: mp 61-63 °C; H NMR (300 MHz) δ 1.29 (d, J ) 7.0
0.82 (d, J ) 6.5 Hz, 3H), 0.97 (d, J ) 6.6 Hz, 3H), 2.37 (dd, J 1
) 13.8 Hz, J 2 ) 9.0 Hz, 1H), 2.51 (dd, J 1 ) 13.8 Hz, J 2 ) 6.2
Hz, 1H), 2.9-3.0 (om, 2H), 3.41 (m, 1H), 3.90 (m, J ) 6.8 Hz,
1H), 5.50-5.90 (b, 1H), 6.95-7.30 (om, 10H); 13C NMR (75
MHz) δ 22.14, 22.24, 40.65, 42.40, 42.89, 44.43, 125.72, 126.19,
127.33, 127.82, 128.05, 128.92, 139.38, 143.21, 170.32. Anal.
Calcd for C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C,
81.12; H, 8.29; N, 4.92.
N-Isopr opyl-3-ph en yl-3-tr im eth ylsilylpr opan am ide (19)
was obtained using TMSCl as the electrophile, and the reaction
mixture was purified by MPLC (30% EtOAc/hexane) to afford
a 75% yield of 19 as a white solid: mp 64-68 °C; 1H NMR
(300 MHz, the internal Si(CH3)3 signal was set to be 0.00 ppm)
δ 0.00 (s, 9H), 0.69 (d, J ) 6.5 Hz, 3H), 0.75 (d, J ) 6.5 Hz,
3H), 2.40-2.60 (om, 3H), 3.74 (m, J ) 6.7 Hz, 1H), 5.45 (bd,
1H), 6.90-7.00 (m, 3H), 7.10-7.20 (m, 2H); 13C NMR (75 MHz)
δ -3.27, 22.18, 22.24, 33.11, 36.76, 40.72, 124.67, 127.20,
128.11, 142.17, 171.38. Anal. Calcd for C15H25NOSi: C, 68.39;
H, 9.56; N, 5.32. Found: C, 68.66; H, 9.72; N, 5.30.
Hz, 3H), 2.34-2.48 (m, AB portion of an ABX spin system,
2H), 2.69 (d, J ) 4.8 Hz, 3H), 3.26-3.33 (m, 1H), 5.60-5.80
(b, 1H), 7.15-7.35 (om, 5H); 13C NMR (75 MHz) δ 21.48, 26.10,
36.80, 45.55, 126.27, 126.62, 128.44, 145.91, 172.34. Anal.
Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C,
74.59; H, 8.54; N, 7.90.
N-Isop r op yl-3-p h en ylbu ta n a m id e (9)23 was obtained us-
ing methyl iodide as the electrophile and was purified by
MPLC (40% EtOAc/hexane) to afford a 93% yield of 9 as a
white solid: mp 43-45 °C; 1H NMR (200 MHz) δ 0.95 (d, J )
6.2 Hz, 3H), 1.06 (d, J ) 6.7 Hz, 3H), 1.29 (d, J ) 7.0 Hz, 3
Hz), 2.39 (d, J ) 7.6 Hz, 2H), 3.29 (m, 1H), 4.00 (m, 1H), 5.80-
6.20 (b, 1H), 7.10-7.30 (om, 5H); 13C NMR (50 MHz) 21.20,
22.15, 22.28, 36.79, 40.72, 45.38, 125.98, 126.51, 128.13,
(23) The 1H and 13C NMR spectra of 9 were consistent with
previously reported data. De Kimpe, N.; Sulmon, P.; Moens, L.;
Schamp, N.; Declercq, J .-P.; Meerssche, M. V. J . Org. Chem. 1986, 51,
3839.

4548 J . Org. Chem., Vol. 61, No. 14, 1996
Lutz et al.
4-Hydr oxy-N-isopr opyl-3,4,4-tr iph en ylbu tan am ide (23)
was obtained using benzophenone as the electrophile and was
purified by MPLC (first 5% EtOAc/hexane, then 30% EtOAc/
hexane) to afford a 96% yield of 23 as a white solid: mp 160-
199.22. Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74.
Found: C, 77.01; H, 7.28; N, 4.84.
P r ep a r a tion of 3,4-Did eh yd r o-1-isop r op yl-4-p h en yl-2-
p yr r olid in on e (33). To a stirring solution of 0.482 g (2.52
mmol) of 5 in 50 mL of THF at -78 °C was added 5.0 mL (5.5
mmol) of s-BuLi. After 50 min, 0.58 mL (7.5 mmol) of N,N-
dimethylformamide (DMF) was added. After 1 h, 30 mL of
saturated NH4Cl in 2% HCl was added, and the mixture was
allowed to warm to room temperature overnight before 30 mL
of ether was added. The layers were separated, and the
aqueous layer was washed with 30 mL of ether. The combined
ether layers were dried over MgSO4, filtered, and concentrated
under reduced pressure to give a crude solid. To a stirring
solution of the solid in 20 mL of EtOAc was added 2 g of silica
gel. The mixture was allowed to stir for 5 h before the silica
gel was removed by filtration. The EtOAc was concentrated
under reduced pressure to afford an off-white solid. To a
stirring solution of the off-white solid in 40 mL of benzene was
added 0.85 g (4.5 mmol) of p-toluenesulfonic acid monohydrate.
After the solution was allowed to stir overnight, 20 mL of
saturated NaHCO3 was added. The benzene was removed
under reduced pressure before 20 mL of ether was added. The
layers were separated, and the aqueous layer was washed
twice with 20 mL portions of ether. The combined ether layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure to give a crude solid. The solid was purified
by MPLC separation using 20% EtOAc/hexane as the eluant.
The EtOAc backwash was collected and concentrated under
reduced pressure to give 0.45 g (88% yield) of 33 as a white
solid: 1H NMR (300 MHz) δ 1.27 (d, J ) 6.8 Hz, 6H), 4.30 (d,
J ) 0.9 Hz, 2H), 4.52 (m, J ) 6.8 Hz, 1H), 6.41 (s, 1H), 7.40-
7.48 (m, 3H), 7.48-7.57 (m, 2H); 13C NMR (75 MHz) δ 20.88,
42.22, 47.39, 120.61, 125.53, 128.81, 129.87, 131.83, 153.77,
170.84. Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96.
Found: C, 77.51; H, 7.52; N, 6.98.
1
162 °C; H NMR (200 MHz) δ 0.74 (d, J ) 6.7 Hz, 3H), 0.84
(d, J ) 6.7 Hz, 3H), 2.50-2.72 (m, AB portion of ABX system,
2H), 3.75 (m, J ) 6.7 Hz, 1H), 4.32 (dd, J 1 ) 8.0 Hz, J 2 ) 8.0
Hz, X portion of ABX system, 1H), 4.51 (s, 1H), 5.17 (bd, 1H),
6.90-7.40 (om, 13H), 7.65-7.75 (m, 2H); 13C NMR (75 MHz)
δ 22.13, 22.14, 39.47, 41.09, 50.55, 80.13, 125.72, 125.97,
126.05, 126.58, 127.49, 127.71, 128.26, 129.91, 139.51, 145.87,
146.37, 171.34. Anal. Calcd for C25H27NO2: C, 80.40; H, 7.29;
N, 3.75. Found: C, 80.17; H, 7.45; N, 3.66.
3,4-Dip h en yl-4-h yd r oxy-N-isop r op ylbu ta n a m id e (25)
was obtained using benzaldehyde as the electrophile and was
purified by MPLC (30% EtOAc/hexane) to afford a 42% yield
of the less polar diastereomer of 25 as a white solid: mp 128-
1
130 °C; H NMR (300 MHz) δ 0.87 (d, J ) 6.5 Hz, 3H), 0.99
(d, J ) 6.6 Hz, 3H), 2.37 (dd, J 1 ) 8.2 Hz, J 2 ) 14.3 Hz, 1H),
2.52 (dd, J 1 ) 6.6 Hz, J 2 ) 14.3 Hz, 1H), 2.75-2.95 (b, 1H),
3.49 (m, J 1 ) 6.6 Hz, J 2 ) 8.2 Hz, J 3 ) 6.3 Hz, 1H), 3.80-4.00
(m, 1H), 4.92 (d, J ) 6.3 Hz, 1H), 5.00-5.20 (bd, 1H), 7.10-
7.35 (om, 10H); 13C NMR (75 MHz) δ 22.45, 22.50, 35.95, 39.82,
41.23, 50.06, 77.37, 126.76, 127.08, 127.63, 128.08, 128.38,
128.78, 139.91, 141.70, 170.63. Anal. Calcd for C19H23NO2:
C, 76.74; H, 7.80; N, 4.71. Found: C, 76.70; H, 7.75; N, 4.72.
The MPLC separation also gave 39% yield of the more polar
diastereomer of 25 as a white solid: mp 127-129 °C; 1H NMR
(300 MHz) δ 0.93 (d, J ) 6.5 Hz, 3H), 1.01 (d, J ) 6.6 Hz, 3H),
2.60 (dd, J 1 ) 6.3 Hz, J 2 ) 14.8 Hz, 1H), 2.79 (dd, J 1 ) 6.3 Hz,
J 2 ) 14.8 Hz, 1H), 3.34 (m, J 1 ) 6.3 Hz, J 2 ) 6.3 Hz, J 3 ) 7.9
Hz, 1H), 3.80-4.00 (m, 1H), 4.20-4.60 (b, 1H),4.80 (d, J )
7.9 Hz, 1H), 5.40-5.55 (b, 1H), 7.00-7.30 (om, 10H). Anal.
Calcd for C19H23NO2: C, 76.74; H, 7.80; N, 4.71. Found: C,
76.75; H, 7.79; N, 4.73.
Rep r esen ta tive Lith ia tion of Ca r boxa m id e 9: P r ep a -
r a t ion of 3-Deu t er io-N-isop r op yl-3-p h en ylb u t a n a m id e
(34). To a stirring solution of 0.074 g (0.36 mmol) of 9 in 7.4
mL of THF at -78 °C was added 0.56 mL (0.79 mmol) of
s-BuLi. The solution was allowed to stir for 1 h before 0.20
mL (4.8 mmol) of CH3OD was added. After the solution was
allowed to stir for 1 h, 10 mL of saturated NH4Cl in 2% HCl
and 10 mL of ether were added. The layers were separated,
and the aqueous layer was washed with 10 mL of ether. The
combined ether layers were dried over MgSO4, filtered, and
concentrated under reduced pressure to afford 0.064 g (87%
yield) of 34 which was determined to contain 86% d1 and 14%
d0 material by FIMS isotope ratios: 1H NMR (200 MHz) δ 0.93
(d, J ) 6.7 Hz, 3H), 1.05 (d, J ) 6.7 Hz, 3H), 1.30 (s, 3H), 2.39
(s, 1H), 3.29 (m, 0.1H), 3.97 (m, J ) 6.7 Hz, 1H), 5.45-5.62
(b, 1H), 7.15-7.35 (om, 5H); 13C NMR (50 MHz) δ 21.38, 22.41,
22.56, 41.16, 45.78, 126.36, 126.76, 128.46, 145.68, 170.90.
N-Isop r op yl-3-m eth yl-3-p h en ylbu ta n a m id e (35) was
obtained using methyl iodide as the electrophile following a
procedure similar to that reported for the preparation of 34.
The crude product was purified by MPLC (30% EtOAc/hexane)
to afford a 91% yield of 35 as a clear oil: 1H NMR (200 MHz)
δ 0.83 (d, J ) 6.8 Hz, 6H), 1.45 (s, 6H), 2.44 (s, 2H), 3.83 (m,
J ) 6.8 Hz, 1H), 4.70-4.85 (b, 1H), 7.15-7.45 (om, 5H); 13C
NMR (50 MHz) δ 22.22, 28.60, 37.28, 40.51, 51.58, 125.64,
126.00, 128.29, 147.91, 169.75. Anal. Calcd for C14H21NO: C,
76.67; H, 9.65; N, 6.39. Found: C, 76.32; H, 9.64; N, 6.53.
4-Hyd r oxy-N-isop r op yl-3-m eth yl-3,4,4-tr ip h en ylbu ta n -
a m id e (36) was obtained using benzophenone as the electro-
phile following a procedure similar to that reported for the
preparation of 34. The crude mixture was purified by MPLC
(20% EtOAc/hexane, the solid was dissolved in CH2Cl2 before
being loaded onto the MPLC column) to afford a 61% yield of
N-Isop r op yl-4-k eto-3-p h en ylh ep ta n a m id e (30) was pre-
pared using butyryl chloride as the electrophile and was
purified by MPLC separation (35% EtOAc/hexane) to give 0.18
g (53% yield) of 30 as a clear oil: 1H NMR (300 MHz) δ 0.78
(t, J ) 7.5 Hz, 3H), 1.01 (d, J ) 6.5 Hz, 3H), 1.09 (d, J ) 6.5
Hz, 3H), 1.42-1.60 (m, 2H), 2.30-2.50 (om, 3H), 2.99 (dd, J 1
) 9.3 Hz, J 2 ) 14.7 Hz, 1H), 3.98 (m, J ) 6.7 Hz, 1H), 4.28
(dd, J 1 ) 9.3 Hz, J 2 ) 5.4 Hz, 1H), 5.60-5.75 (b, 1H), 7.20-
7.35 (om, 5H); 13C NMR (75 M Hz) δ 13.36, 16.97, 22.44, 39.54,
41.14, 43.54, 54.44, 127.32, 128.09, 128.86, 137.95, 170.03,
209.71. Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N, 5.36.
Found: C, 73.42; H, 8.80; N, 5.30.
4-Hyd r oxy-4-m eth yl-3-p h en ylp en ta n oic a cid γ-la cton e
(31).24 Lithiation of 5 followed by electrophilic substitution
with acetone provided a crude oil. The oil was dissolved in 10
mL of toluene, and the solution was heated at reflux temper-
atures for 18 h. After the toluene was removed under reduced
pressure, the crude product was purified by MPLC (15%
EtOAc/hexane) to give a 48% yield of 31 as a white solid: mp
89-91 °C; 1H NMR (200 MHz) δ 1.04 (s, 3H), 1.55 (s, 3H),
2.95 [center of AB portion of an ABX spin system, J AB ) 17.6
Hz, J AX ) 8.5 Hz, J BX ) 9.6 Hz, (νA - νB) ) 31.5 Hz, 2H], 3.52
(center of X portion of ABX spin system, 1H), 7.15-7.45 (om,
5H); 13C NMR (50 MHz), 23.08, 27.57, 34.34, 51.01, 87.12,
127.61, 127.67, 128.54, 136.54, 175.30. Anal. Calcd for
C12H14O2: C, 75.76; H, 7.42. Found: C, 75.86; H, 7.52.
3,4-Dip h en yl-N-isop r op yl-4-k etobu ta n a m id e (29) was
obtained using methyl benzoate as the electrophile and was
purified by MPLC (30% EtOAc/hexane) to afford a 70% yield
of 29 as a white solid: mp 111-114 °C; 1H NMR (200 MHz) δ
1.01 (d, J ) 6.3 Hz, 3H), 1.06 (d, J ) 6.7 Hz, 3H), 2.56 (dd, J 1
) 14.5 Hz, J 2 ) 5.7 Hz, 1H), 3.11 (dd, J 1 ) 14.5 Hz, J 2 ) 9.0
Hz, 1H), 3.98 (m, 1H), 5.20 (dd, J 1 ) 8.9 Hz, J 2 ) 5.7 Hz, 1H),
5.40-5.60 (bd, 1H), 7.10-7.50 (om, 8H), 7.97 (d, J ) 7.1 Hz,
2H); 13C NMR (50 MHz) δ 22.54, 41.11, 41.28, 50.01, 127.25,
128.04, 128.40, 128.84, 129.05, 132.92, 136.12, 138.50, 170.07,
1
36 as a white solid: mp 176-178 °C; H NMR (200 MHz) δ
0.87 (d, J ) 6.7 Hz, 3H), 0.91 (d, J ) 6.7 Hz, 3H),1.57 (s, 3H),
2.68 (d, J ) 13.9 Hz, 1H), 3.05 (d, J ) 13.9 Hz, 1H), 3.90 (m,
J ) 6.7 Hz, 1H), 4.90-5.05 (bd, 1H), 5.70 (s, 1H), 6.90-7.00
(m, 2H), 7.10-7.30 (om, 9H), 7.30-7.40 (m, 2H), 7.40-7.52
(m, 2H) 13C NMR (CDCl3/DMSO, 50 MHz) δ 21.58, 21.65,
21.79, 40.72, 45.89, 49.51, 81.62, 125.81, 125.89, 126.00,
126.16, 126.33, 126.46, 128.25, 128.41, 128.97, 144.18, 144.90,
(24) The melting point, 1H NMR spectrum, and mass spectrum of
31 were consistent with previously reported data. Campaigne, E.; Ellis,
R. L. J . Org. Chem. 1967, 32, 2372. Baumann, N.; Sung, M.; Ulman,
E. F. J . Am. Chem. Soc. 1968, 90, 4157.

â-Lithiation of â-Aryl Secondary Amides
J . Org. Chem., Vol. 61, No. 14, 1996 4549
145.02, 171.73. Anal. Calcd for C26H29NO2: C, 80.59; H, 7.54;
N, 3.61. Found: C, 80.19; H, 7.46; N, 3.57.
in 2% HCl and 10 mL of ether were added. The layers were
separated, and the aqueous layer was washed with two 10 mL
portions of ether. The combined ether layers were dried over
MgSO4, filtered, and concentrated under reduced pressure to
afford a clear oil. The crude material was purified by MPLC
separation using 30% EtOAc/hexane as the eluant to afford
P r epar ation of 5-Hydr oxy-1-isopr opyl-4-m eth yl-4-ph en -
yl-2-p yr r olid in on e (38). To a stirring solution of 0.269 g
(1.31 mmol) of 9 in 26 mL of THF at -78 °C was added 2.1
mL (2.9 mmol) of s-BuLi. The solution was allowed to stir for
45 min before 0.30 mL (3.9 mmol) of DMF was added. After
the solution was allowed to stir at ambient temperature
overnight, 20 mL of saturated NH4Cl in 2% HCl and 20 mL of
ether were added. The layers were separated, and the aqueous
layer was washed with two 20 mL portions of ether. The
combined ether layers were dried over MgSO4, filtered, and
concentrated under reduced pressure to afford a crude solid.
The crude solid was purified by recrystallization from hexane/
EtOAc to afford 0.22 g (71% yield) of 38 as a white solid: mp
1
0.089 g (79% yield) of 41 as a white solid: mp 72-74 °C; H
NMR (300 MHz) δ 0.78 (d, J ) 6.5 Hz, 6H), 1.35-1.52 (om,
4H), 1.52-1.68 (m, 2H), 1.68-1.83 (m, 2H), 2.13-2.24 (m, 2H),
2.35 (s, 2H) 3.76 (m, J ) 6.6 Hz, 1H), 4.17-4.30 (b, 1H), 7.19-
7.40 (om, 5H); 13C NMR (75 MHz) δ 22.21, 22.32, 26.19, 36.13,
40.62, 41.02, 51.74, 125.96, 126.88, 128.50, 145.71, 169.60.
Anal. Calcd for C17H25NO: C, 78.72; H, 9.71; N, 5.40.
Found: C, 78.44; H, 9.62; N, 5.22.
Rep r esen ta tive Lith ia tion of Ca r boxa m id e 42: P r ep a -
r a tion of (R*,S*)-N-isop r op yl-2-m eth yl-3-p h en ylbu ta n a -
m id e ((R*,S*)-44). To a stirring solution of 0.384 g (1.87
mmol) of 42 in 37 mL of THF at -78 °C was added 2.7 mL of
s-BuLi. After 50 min, 0.13 mL (2.1 mmol) of iodomethane was
added. After 1.5 h, 20 mL of saturated NH4Cl in 2% HCl and
20 mL of ether were added. The aqueous layer was washed
twice with 20 mL portions of ether. The three combined ether
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure to give a crude solid. Purification was
accomplished by MPLC separation using 30% EtOAc/hexane
followed by HPLC separation using 25% EtOAc/hexane as the
eluant to give 0.053 g (14% recovery) of 42 and 0.31 g (75%
yield) of (R*,S*)-44 as a white solid: mp 107-109 °C; 1H NMR
(200 MHz) δ 0.62 (d, J ) 6.7 Hz, 3H), 0.95 (d, J ) 6.7 Hz, 3H),
1.21 (d, J ) 6.7 Hz, 3H), 1.28 (d, J ) 7.0 Hz, 3H), 2.23 (dq, J 1
) 6.6 Hz, J 2 ) 9.5 Hz, 1H), 2.92 (dq, J 1 ) 6.9 Hz, J 2 ) 9.9 Hz,
1H), 3.77 (m, J ) 6.7 Hz, 1H), 4.80-5.00 (bd, 1H), 7.10-7.35
(om, 5H); 13C NMR (50 MHz) δ 15.28, 18.37, 22.14, 22.43,
40.44, 40.52, 43.08, 49.34, 126.16, 127.21, 128.22, 145.70,
174.22. Anal. Calcd for C14H21NO: C, 76.67; H, 9.65; N, 6.39.
Found: C, 76.77; H, 9.64; N, 6.41.
1
135-136 °C; H NMR (300 MHz) δ 1.00 (d, J ) 6.8 Hz, 3H),
1.26 (d, J ) 6.8 Hz, 3H), 1.52 (s, 3H), 2.75 (AB quartet, ∆xAB
) 28.6 Hz, 33.1 Hz, 2H), 3.83 (d, J ) 8.2 Hz, 1H), 4.18 (m, J
) 6.8 Hz, 1H), 5.11 (d, J ) 8.2 Hz, 1H), 7.20-7.45 (om, 5H);
13C NMR (75 MHz) δ 19.33, 21.76, 22.70, 43.06, 43.42, 45.20,
89.31, 125.46, 126.73, 128.59, 145.77, 173.91. Anal. Calcd for
C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found C, 72.14; H,
8.18; N, 6.01.
P r ep a r a tion of 3,4-Dip h en yl-4-h yd r oxy-3-m eth ylbu -
ta n oic Acid γ-La cton e (39a ,b). To a stirring solution of 0.41
g (2.0 mmol) of 9 in 40 mL of THF at -78 °C was added 3.2
mL (4.4 mmol) of s-BuLi. The solution was allowed to stir for
50 min before 0.48 mL (4.6 mmol) of benzaldehyde was added.
After the solution was allowed to warm to ambient tempera-
ture overnight, 25 mL of saturated NH4Cl in 2% HCl and 30
mL of ether were added. The layers were separated, and the
aqueous layer was washed with 30 mL of ether. The combined
ether layers were dried over MgSO4, filtered, and concentrated
under reduced pressure to give 37 as a crude oil. The crude
mixture was partially purified by MPLC separation using 30%
EtOAc/hexane as the eluant to afford a clear oil. The oil was
dissolved in 10 mL of toluene, and the solution was heated at
reflux temperatures for 18 h. After the toluene was removed
under reduced pressure, the crude product was purified by
MPLC separation using 30% EtOAc/hexane as the eluant to
give 0.21 g (42% yield) of 39a as a white solid: mp 133-135
3-Deu t er io-N-isop r op yl-2-m et h yl-3-p h en ylp r op a n a -
m id e (43) was obtained using methanol-d as the electrophile
following a procedure similar to that reported for the prepara-
tion of 44. The deuterated product 43 was obtained in 95%
yield as a white solid which was determined to contain 93%
d1 and 8% d0 material by FIMS isotope ratios: mp 114-116
1
°C; H NMR (300 MHz) δ 1.15 (s, 3H), 2.72 (d, J ) 17.1 Hz,
1
1H), 3.31 (d, J ) 17.1 Hz, 1H), 5.66 (s, 1H), 6.98 (d, J ) 6.4
Hz, 2H), 7.23-7.44 (om, 8H); 13C NMR (75 MHz) δ 20.50,
45.28, 47.69, 89.47, 125.68, 126.30, 127.37, 128.02, 128.21,
128.79, 134.45, 141.51, 175.25. Anal. Calcd for C17H16O2: C,
80.93; H, 6.39. Found: C, 81.19; H, 6.15. The MPLC separa-
tion also gave 0.12 g (24% yield) of 39b as a white solid: mp
°C; H NMR (200 MHz) δ 0.91 (d, J ) 6.2 Hz, 3H), 1.04 (d, J
) 6.2 Hz, 3H), 1.17 (d, J ) 6.6 Hz, 3H), 2.34 (m, 1H), 2.65 (m,
0.25H), 2.90 (d, J ) 8.6 Hz, 0.75H), 3.96 (d, J ) 6.1 Hz, 0.5H),
4.00 (d, J ) 6.1 Hz, 0.5H), 5.00-5.10 (bs, 1H), 7.10-7.35 (om,
5H); 13C NMR (50 MHz) δ 17.64, 22.55, 22.64, 40.3 (t), 40.90,
43.90, 126.16, 128.29, 128.92, 139.89, 174.6;7.75, 128.37,
128.49, 131.55, 135.07, 141.87, 172.58.
1
112-114 °C; H NMR (300 MHz) δ 1.72 (s, 3H), 2.81 (d, J )
17.2 Hz, 1H), 3.26 (d, J ) 17.2 Hz, 1H), 5.41 (s, 1H), 6.80-
6.90 (om, 4H), 7.05-7.18 (om, 6H); 13C NMR (75 MHz) δ 25.78,
43.05, 48.67, 90.58, 126.08, 126.51, 126.86, 127.64, 127.90,
128.06, 134.82, 140.16, 176.37. Anal. Calcd for C17H16O2: C,
80.93; H, 6.39. Found: C, 81.11; H, 6.06.
7-B r o m o -N -is o p r o p y l-2-m e t h y l-3-p h e n y lh e p t a n a -
m id e (45) was obtained using 1,4-dibromobutane as the
electrophile following a procedure similar to that reported for
the preparation of 44. The crude oil was purified by MPLC
(30% EtOAc/hexane) to afford a 79% yield of 45 as a white
1
P r ep a r a tion of 1-P h en yl-1-[[(N-isop r op yla m in o)ca r -
boxy]m eth yl]cyclop en ta n e (40). To a stirring solution of
0.149 g (0.529 mmol) of 13 in 11 mL of THF at -40 °C was
added 0.94 mL (1.2 mmol) of s-BuLi. The solution was allowed
to stir overnight at -40 to -10 °C before 10 mL of saturated
NH4Cl in 2% HCl and 10 mL of ether were added. The layers
were separated and the aqueous layer was washed twice with
10 mL of ether. The combined ether layers were dried over
MgSO4, filtered and concentrated under reduced pressure to
afford 0.124 g (95% yield) of 40 as a white solid: mp 58-60
°C; 1H NMR (200 MHz) δ 0.79 (d, J ) 6.3 Hz, 6H), 1.60-1.90
(om, 4H), 1.90-2.20 (om, 4H), 2.40 (s, 2H) 3.78 (m, J ) 6.6
Hz, 1H), 4.37-4.52 (b, 1H), 7.15-7.40 (om, 5H); 13C NMR (50
MHz) δ 22.25, 22.73, 37.38, 40.58, 48.86, 50.13, 125.99, 126.79,
128.22, 147.32, 170.06. Anal. Calcd for C16H23NO: C, 78.32;
H, 9.45; N, 5.71. Found: C, 78.10; H, 9.60; N, 5.44.
solid: mp 68-70 °C; H NMR (200 MHz) δ 0.58 (d, J ) 6.7
Hz, 3H), 0.93 (d, J ) 6.7 Hz, 3H), 1.23 (d, J ) 6.7 Hz, 3H),
1.05-1.28 (m, 2H), 1.45-1.68 (m, 1H), 1.70-1.95 (om, 3H),
2.28 (dq, J 1 ) 9.9 Hz, J 2 ) 6.9 Hz, 1H), 2.74 (om, J 1 ) 3.0 Hz,
J 2 ) 10.6 Hz, J 3 ) 10.0 Hz, 1H), 3.29 (t, J ) 7.0 Hz, 2H), 3.74
(m, J ) 6.7 Hz, 1H), 4.85-5.05 (bd, 1H), 7.10-7.30 (om, 5H);
13C NMR (50 MHz) δ 15.55, 22.01, 22.30, 25.87, 30.97, 32.53,
33.38, 40.38, 48.35, 48.84, 126.25, 127.92, 128.16, 143.01,
173.98. Anal. Calcd for C17H26BrNO: C, 60.00; H, 7.70; N,
4.12; Br, 23.48. Found: C, 60.02; H, 7.72; N, 4.08; Br, 23.23.
4-Hyd r oxy-N-isop r op yl-2-m eth yl-3,4,4-tr ip h en ylbu ta n -
a m id e (46) was obtained using benzophenone as the electro-
phile following a procedure similar to that reported for the
preparation of 44. The crude product was purified by MPLC
(first 5% EtOAc/hexane, then 40% EtOAc/hexane) to afford a
1
95% yield of 46 as a white solid: mp 158-162 °C; H NMR
P r ep a r a tion of 1-P h en yl-1-[[(N-isop r op yla m in o)ca r -
boxy]m et h yl]cycloh exa n e (41). To a stirring solution of
0.128 g (0.433 mmol) of 14 in 9 mL of THF at -70 °C was
added 0.80 mL (1.0 mmol) of s-BuLi. The resulting solution
was allowed to warm to -40 °C and was then allowed to stir
overnight at -40 to -10 °C before 10 mL of saturated NH4Cl
(200 MHz) δ 0.78 (d, J ) 6.7 Hz, 3H), 0.94 (d, J ) 6.7 Hz, 3H),
1.06 (d, J ) 6.9 Hz, 3H), 3.02 (dq, J 1 ) 1.2 Hz, J 2 ) 7.4 Hz,
1H), 3.78 (s,1H), 3.89 (m, J 1 ) 7.9 Hz, J 2 ) 6.7 Hz, 1H), 5.01
(bd, J ) 7.9 Hz, 1H), 6.85-7.25 (om, 7H), 7.30-7.50 (om, 6H),
7.80-7.88 (om, 2H); 13C NMR (75 MHz) δ 17.17, 21.64, 22.19,
41.48, 41.71, 58.11, 80.14, 125.36, 125.55, 125.75, 126.23,

4550 J . Org. Chem., Vol. 61, No. 14, 1996
Lutz et al.
126.40, 127.19, 127.36, 128.23, 131.01, 136.99, 145.98, 148.63,
174.77. Anal. Calcd for C26H29NO2: C, 80.59; H, 7.54; N, 3.61.
Found: C, 80.69; H, 7.61; N, 3.34.
The acid was converted to the 3,5-dimethylanilide according
to Pirkle’s method.26 To a solution of (R)-54 (48 mg, 0.29 mmol)
in methylene chloride (6 mL) were added dicyclohexylcarbo-
diimide (64 mg, 0.30 mmol) and 3,5-dimethylaniline (50 µL,
0.40 mmol). The reaction mixture was stirred at room tem-
perature for 12 h and then concentrated in vacuo. The
resulting mixture was then dissolved in 1/1 (v/v) EtOAc/hexane
and passed through a short plug of silica to give a light yellow
oil. Purification by flash chromatography (5% EtOAc/hexane)
gave the 3,5-dimethylanilide derivative as a colorless oil (50
mg, 65%): 1H NMR (CDCl3, 300 MHz) δ 1.37 (d, 3Η, J ) 6.9
Hz, CH3), 2.26 (s, 6H, CH3Ar), 2.53-2.65 (m, 2H, CH2), 3.34-
3.41 (m, 1H, CH), 6.72 (s, 1H, NH), 6.89 (s, 1H, Ar), 6.99 (s,
2H, Ar), 7.20-7.35 (m, 5H, Ar). The enantiomeric excess of
the 3,5-dimethylanilide derivative was determined to be 78%
by CSP HPLC ((R,R)-â-Gem column, 24/1 hexane/i-PrOH, 2.0
mL/min). The major enantiomer (R) had a retention time of
36.4 min and the minor enantiomer (S) had a retention time
of 45.8 min.
3,4-Dip h en yl-4-h yd r oxy-N-isop r op yl-2-m eth ylbu ta n a -
m id e (47) was obtained using benzaldehyde as the electrophile
following a procedure similar to that reported for the prepara-
tion of 44. The crude oil was purified by MPLC (30% EtOAc/
hexane) to afford a 22% recovery of the starting amide 42 and
1
55% yield of 47 as a white solid: mp 107-108 °C; H NMR
(200 MHz) δ 1.05 (d, J ) 7.4 Hz, 3H), 1.11 (d, J ) 6.7 Hz, 3H),
1.12 (d, J ) 6.2 Hz, 3H), 3.03 (dd, J 1 ) 9.3 Hz, J 2 ) 4.7 Hz,
1H), 3.18 (dq, J 1 ) 7.4 Hz, J 2 ) 4.7 Hz, 1H), 4.11 (m, J ) 6.2
Hz, 0.5H), 4.15 (m, J ) 6.7 Hz, 0.5H), 5.07 (dd, J 1 ) 9.3 Hz, J 2
) 4.5 Hz, 1H), 5.27 (d, J ) 4.5 Hz, 1H), 5.45-5.55 (bd, 1H),
6.90-7.05 (om, 2H), 7.05-7.20 (om, 8H); 13C NMR (75 MHz)
δ 15.32, 22.29, 22.57, 41.31, 41.46, 57.99, 75.58, 126.56, 126.82,
126.95, 127.79, 127.92, 129.33, 139.04, 143.17, 174.37. Anal.
Calcd for C20H25NO2: C, 77.14; H, 8.09; N, 4.50. Found: C,
76.90; H, 8.13; N, 4.43.
(R)-N-Meth yl-3-p h en ylh ep ta n a m id e ((R)-10) was ob-
tained using butyl iodide as the electrophile following a
procedure similar to that reported for the preparation of (R)-
8. The crude product was purified by MPLC (30% EtOAc/
hexane) to give a 77% yield of (R)-10 as an oil: 1H NMR
(CDCl3, 300 MHz) δ 0.80 (t, 3H, J ) 7.1 Hz, CH3), 1.06-1.29
(m, 4H, CH2CH2), 1.55-1.68 (m, 2H, CH2), 2.35 (dd, 1H, J )
5.7 Hz, J ) 8.2 Hz, CH2), 2.47 (dd, 1H, J ) 7.3 Hz, J ) 6.7 Hz,
CH2), 2.63 (d, 3H, J ) 4.8 Hz, NCH3), 3.03-3.13 (m, 1H, CH),
5.48 (bs, 1H, NH), 7.15-7.29 (m, 5H, Ar); 13C NMR (CDCl3,
75 MHz) δ 13.86, 22.53, 26.06, 29.51, 35.66, 42.68, 44.61,
126.26, 127.32, 128.33, 144.44, 172.37; [R]26D -22.8° (c ) 2.00,
CHCl3). Anal. Calcd for C14H21NO: C, 76.67; H, 9.65; N, 6.38.
Found: C,76.54; H, 9.73; N, 6.44. The absolute configuration
and enantiomeric excess of (R)-10 was determined following
the hydrolysis/dimethylanilide derivatization protocol de-
scribed above for (R)-8. The acid 55 was assigned the absolute
configuration of (R) by comparison of the optical rotation of
R ep r esen t a t ive Lit h ia t ion of Ca r b oxa m id e 4 w it h
s-Bu Li/(-)-Sp a r tein e: P r ep a r a tion of (R)-N-Meth yl-3-
p h en ylbu ta n a m id e ((R)-8). To (-)-sparteine (1 mL, 3.8
mmol) in THF (4 mL) at -78 °C was added s-BuLi (2.8 mL,
3.4 mmol). The reaction mixture was stirred for 20 min at
-78 °C and then was transferred to a solution of N-methyl-
3-phenylpropanamide (4) (222 mg, 1.36 mmol) in THF (8 mL)
at -78 °C. The resulting reaction mixture was stirred at -78
°C for 50 min, and then iodomethane (0.14 mL, 2.2 mmol) was
added. This mixture was allowed to stir for 2 h at -78 °C.
HCl (5%, 15 mL) and Et2O (20 mL) were added. The mixture
was allowed to warm to ambient temperature, and then the
layers were separated. The aqueous layer was extracted with
ether (2 × 20 mL). The combined ether layers were dried over
anhydrous MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by MPLC (30% EtOAc/
hexane) to give (R)-8 as a white solid (216 mg, 89%): mp 61-
63 °C; 1H and 13C NMR spectral data were consistent with
55 [[R]20 -31.4° (c ) 2.20, benzene)] to the known rotation
the racemic product reported above; [R]22 -25.4° (c ) 1.68,
D
D
for (R)-55 [[R]23 -35.2° (c ) 8, benzene)].25 The dimethyla-
D
CHCl3). The enantiomeric excess of (R)-8 was determined to
be 78% by hydrolysis to the acid 54, conversion of 54 to the
dimethylanilide derivative, and CSP HPLC analysis as de-
scribed below.
nilide of 55 was analyzed by CSP HPLC ((R,R)-â-Gem column,
24/1 hexane/i-PrOH, 2.0 mL/min) and found to have an
enantiomeric excess of 88%. The major enantiomer (R) had a
retention time of 30.5 min, and the minor enantiomer (S) had
a retention time of 42.6 min.
Rep r esen ta tive Hyd r olysis of th e Am id es to th e Cor -
r esp on d in g Acid s a n d P r ep a r a tion of th e Dim eth yla n il-
id e Der iva tives: P r ep a r a tion of (R)-3-P h en ylbu tyr ic
Acid ((R)-54). To a 0.5 M solution of (R)-8 (194 mg, 1.09
mmol) in methylene chloride was added triethylamine (0.15
mL, 1.09 mmol), di-tert-butyl dicarbonate (0.5 mL, 2.18 mmol),
and 4-(dimethylamino)pyridine (150 mg, 1.11 mmol). The
solution was stirred for 8 h at room temperature. The volatiles
were removed, and the residue was purified by flash chroma-
tography (1/20 (v/v) EtOAc/hexane) to afford the desired (R)-
N-Boc-N-methyl-3-phenylbutanamide (210 mg, 70%): 1H NMR
(CDCl3, 300 MHz) δ 1.29 (d, J ) 6.9 Hz, 3H, CH3), 1.52 (s, 9H,
O-t-Bu), 3.07 (s, 3H, NCH3), 3.10-3.38 (m, 3H, CHCH2), 7.18-
7.29 (m, 5H, Ar).
(R)-N-Meth yl-3-p h en yl-5-h exen a m id e ((R)-15) was ob-
tained using allyl chloride as the electrophile following a
procedure similar to that reported for the preparation of (R)-
8. The crude product was purified by MPLC (30% EtOAc/
hexane) to give a 74% yield of (R)-15 as an oil: 1H NMR
(CDCl3, 300 MHz) δ 2.32-2.50 (m, 3H, CH2 and 1H of CH2),
2.53-2.64 (m , 1H, 1H of CH2), 2.63 (d, 3H, J ) 5.1 Hz, CH3),
3.18-3.27 (m, 1H, CH), 4.92-5.00 (m, 2H, CH2), 5.51-5.71
(m, 2H, CH and NH), 7.16-7.30 (m, 5H, C6H5); 13C NMR
(CDCl3, 75 MHz) δ 26.11, 40.26, 42.17, 43.26, 116.63, 126.44,
127.33, 128.41, 136.01, 143.73, 172.16. Anal. Calcd for C17H19
-
NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.81; H, 8.45; N,
6.90. The enantiomeric excess of (R)-15 was determined
directly by CSP HPLC analysis ((S,S)-Whelk-O1 column, 15%
i-PrOH/hexane, 2.0 mL/min) to be 74%. The major enantiomer
(R)-15 had a retention time of 6.6 min, and the minor
enantiomer (S)-15 had a retention time of 7.8 min.
(R)-N-Meth yl-3,4-d ip h en ylbu ta n a m id e ((R)-16) was ob-
tained using benzyl bromide as the electrophile following a
procedure similar to that reported for the preparation of (R)-
8. The crude product was purified by MPLC (30% EtOAc/
hexane) to give a 78% yield of (R)-16 as an oil: 1H NMR
(CDCl3, 300 MHz) δ 2.41 (dd, 1H, J ) 5.6, 8.7 Hz, CH2), 2.55
(dd, 1H, J ) 8.2, 6.1 Hz, CH2), 2.62 (d, 3H, J ) 4.9 Hz, NCH3),
2.87-3.00 (m, 2H, CH2), 3.39-3.46 (m, 1H, CH), 5.16-5.23
(bs, 1H, NH), 7.03-7.28 (m, 10H, Ar); 13C NMR (CDCl3, 75
MHz) δ 26.14, 42.66, 42.90, 44.30, 126.01, 126.50, 127.47,
128.09, 129.19, 139.56, 143.60, 172.03; [R]26D +27.8° (c ) 1.94,
CHCl3). Anal. Calcd for C17H19NO: C, 80.60; H, 7.56; N, 5.53.
A 0.2M solution of N-Boc derivative (175 mg, 0.63 mmol) in
THF (4 mL), under N2 atmosphere, was cooled to 0 °C. To
this solution was added 1 N lithium hydroxide (2.0 mL, 2.0
mmol). The reaction mixture was allowed to stir for 6 h. After
removal of THF in vacuo, the basic residue was acidified with
5% HCl and extracted with ether (3 × 15 mL). The combined
ether layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was puri-
fied by bulb-to-bulb distillation (110-120 °C /1.2 mmHg) to
give the desired acid (R)-54 (85 mg, 85%): 1H NMR (CDCl3,
300 MHz) δ 1.36 (d, 3H, J ) 7.0 Hz, CH3), 2.46-2.75 (m, 2H,
CH2), 3.28-3.35 (m, 1H, CH), 7.22-7.37 (m, 5H, Ar), 10.78 (s,
1H, COOH); 13C NMR (CDCl3, 75 MHz) δ 21.80, 36.07, 42.56,
126.44, 126.64, 128.50, 145.36, 178.78. The absolute config-
uration of 54 was assigned as R by comparison of the optical
rotation of 54 [[R]22D -39.2° (c ) 2.33, benzene)] to the known
rotation for (R)-54 [[R]23 -54.5° (c ) 10, benzene)].25
D
(25) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 913-916.
(26) Pirkle, W. H.; McCune, J . F. J . Chromatogr. 1989, 479, 419.

â-Lithiation of â-Aryl Secondary Amides
J . Org. Chem., Vol. 61, No. 14, 1996 4551
Found: C, 80.30; H, 7.68; N, 5.49. The absolute configuration
and enantiomeric excess of (R)-16 were determined following
the hydrolysis/ dimethylanilide derivatization protocol de-
scribed above for (R)-8. The acid 53 was assigned the absolute
configuration of R by comparison of the optical rotation of 53
EtOH). Anal. Calcd for C23H23NO2: C, 79.97; H, 6.71; N, 4.05.
Found: C, 79.63; H, 6.76; N, 4.06. The enantiomeric purity
of (R)-22 was determined to be 84% by CSP HPLC of the
corresponding γ-lactone 56 as described below.
(3R )-N -Me t h yl-4-h yd r oxyl-3,4-d ip h e n ylb u t a n a m id e
((3R)-24) was obtained using benzaldehyde as the electrophile
following a procedure similar to that reported for the prepara-
tion of (R)-8. The crude product was purified by HPLC (60%
EtOAc/hexane) to give the less polar diastereomer as a
semisolid (33%): 1H NMR (CDCl3, 300 MHz) δ 2.57-2.7 (m,
4H, CH3 and CH2), 2.82 (dd, 1H, J ) 15.1, 6.4 Hz, CH2), 3.31-
3.37 (m, 1H, CH), 4.7-5.5 (bs, 1H, OH), 4.76 (d, 1H, J ) 7.8
Hz, CH), 6.99 (s, 1H, NH), 7.03-7.35 (m, 10H, Ar); 13C NMR
(CDCl3, 75 MHz) δ 26.30, 39.06, 50.14, 78.26, 126.42, 126.59,
127.10, 127.84, 128.14, 128.22, 141.58, 143.02, 173.56. Anal.
Calcd for C23H23NO2: C, 75.81; H, 7.11; N, 5.20. Found: C,
75.59; H, 7.16; N, 5.05. The more polar diastereomer (30%)
was isolated as a semisolid: 1H NMR (CDCl3, 300 MHz) δ 2.40
(dd, 1H, J ) 14.6, 7.5 Hz, CH2), 2.55-2.62 (m, 4H, CH2 and
CH3N), 3.20 (bs, 1H, OH), 3.46-3.53 (m, 1H, CH), 4.89 (d, 1H,
J ) 5.9 Hz, CH), 5.64 (s, 1H, NH), 7.05-7.27 (m, 10H, Ar);
13C NMR (CDCl3, 75 MHz) δ 26.26, 39.10, 49.65, 77.08, 126.71,
126.96, 127.50, 127.96, 128.26, 128.71, 139.92, 141.68, 172.41.
Anal. Calcd for C23H23NO2: C, 75.81; H, 7.11; N, 5.20.
Found: C, 75.54; H, 7.13; N, 5.13.
Ster eoch em istr y a n d En a n tiom er ic P u r ity Assa y of
(3R )-N -Me t h y l-4-h y d r o x y l-3,4-d ip h e n y lb u t a n a m id e
((3R)-24): Syn th esis of 52. To a solution of the less polar
diastereomer of (3R)-24 (98 mg, 0.36 mmol) in methylene
chloride (5 mL) were added triethylamine (0.05 mL, 0.35
mmol), di-tert-butyl dicarbonate (0.16 mL, 0.70 mmol), and
4-(dimethylamino)pyridine (46 mg, 0.35 mmol). The solution
was stirred for 12 h at room temperature. The volatile
materials were removed in vacuo, and the residue was purified
by flash chromatography (1/10 (v/v) EtOAc/hexane) to afford
the desired γ-lactone 52 (62 mg, 73%) as a white solid: mp
107-109 °C; 1H NMR (CDCl3, 300 MHz) δ 2.93 (m, 1H, CH2),
3.07 (m, 1H, CH2), 3.56-3.62 (m, 1H, CH), 5.43 (d, 1H, J )
8.6 Hz, CH), 7.17-7.39 (m, 5H, Ar); 13C NMR (CDCl3, 75 MHz)
δ 37.10, 50.53, 87.39, 125.58, 127.32, 127.84, 128.60, 129.06,
137.66, 137.85, 175.30.
[[R]22 +52.5° (c ) 1.07, benzene)] to the known rotation for
D
(S)-53 [R]22 -60° (benzene)].27 The enantiomeric excess was
D
determined to be 80% by CSP HPLC ((R,R)-â-Gem column,
24/1 hexane/i-PrOH, 2.0 mL/min) analysis of the dimethyl-
anilide of 53. The major enantiomer (R) had a retention time
of 42.0 min, and the minor enantiomer (S) had a retention time
of 66.2 min.
(R )-N -Me t h yl-3-p h e n yl-3-(t r im e t h ylsilyl)p r op a n a -
m id e ((R)-18) was obtained using TMSCl as the electrophile
following a procedure similar to that reported for the prepara-
tion of (R)-8. The crude product was purified by MPLC (30%
EtOAc/hexane) to give an 86% yield of (R)-18 as an oil: 1H
NMR (CDCl3, 300 MHz) δ 0 (s, 9H, Si(CH3)3), 2.57-2.70 (m,
6H, CH2CH2 and NCH3), 5.26-5.42 (bs, 1H, NH), 7.06-7.32
(m, 5H, Ar); 13C NMR (CDCl3, 75 MHz) δ -3.14, 26.18, 32.92,
36.66, 124.9, 127.17, 128.27, 142.29, 173.17. [R]26 -17.6° (c
D
) 2.82, CHCl3). Anal. Calcd for C13H21NOSi: C, 66.33; H,
8.99; N, 5.95. Found: C, 66.42; H, 8.96; 5.81. The enantio-
meric excess of (R)-18 was determined directly by CSP HPLC
analysis ((S,S)-Whelk-O1 column, 10% i-PrOH/hexane, 2.0 mL/
min) to be 94%. The major enantiomer (R)-18 had a retention
time of 13.5 min, and the minor enantiomer (S)-18 had a
retention time of 9.0 min.
(R)-N-Meth yl-3-ph en yl-3-(dim eth ylph en ylsilyl)pr opan -
a m id e ((R)-20) was obtained using dimethylphenylsilyl chlo-
ride as the electrophile following a procedure similar to that
reported for the preparation of (R)-8. The crude product was
purified by MPLC (30% EtOAc/hexane) to give a 68% yield of
(R)-20 as an oil: 1H NMR (CDCl3, 300 MHz) δ 0.23 (s, 3H,
SiCH3), 0.24 (s, 3H, SiCH3), 2.52-2.59 (m, 5H, NCH3 and CH2),
2.76-2.81 (m, 1H, CH), 5.41 (bs, 1H, NH), 7.07-7.40 (m, 10H,
Ar); 13C NMR (CDCl3, 75 MHz) δ -5.46, -4.24, 25.95, 32.37,
36.41, 124.83, 127.34, 127.50, 128.04,129.08, 133.94, 136.29,
141.51,172.76. Anal. Calcd for C18H23NOSi: C, 72.68; H, 7.79;
N, 4.71. Found: C, 72.75; H, 7.82; N, 4.75. The enantiomeric
excess of (R)-20 was determined directly by CSP HPLC
analysis ((S,S)-Whelk-O1 column, 10% i-PrOH/hexane, 2.0 mL/
min) to be 80%. The major enantiomer (R)-20 had a retention
time of 16.1 min, and the minor enantiomer (S)-20 had a
retention time of 11.2 min.
(R)-N-Me t h yl-3-p h e n yl-3-(t r ib u t ylst a n n yl)p r op a n a -
m id e ((R)-21) was obtained using tributyltin chloride as the
electrophile following a procedure similar to that reported for
the preparation of (R)-8. The crude product was purified by
MPLC (30% EtOAc/hexane) to provide an 84% yield of (R)-21
as an oil: 1H NMR (CDCl3, 300 MHz) δ 0.67-0.93 (m, 15H,
3CH3CH2), 1.10-1.29 (m, 6H, 3CH2), 1.30-1.46 (m, 6H, 3CH2),
2.67 (d, 3H, J ) 4.9 Hz, NCH3), 2.69-2.97 (m, 3H, CHCH2),
5.45 (bs, 1H, NH), 6.98-7.269 (m, 5H, C6H5); 13Η NMR (CDCl3,
75 MHz) δ 9.40, 13.62, 26.26, 27.41, 28.94, 29.3, 38.95, 123.89,
125.59, 145.69, 173.46. Anal. Calcd for C22H39SnNO: C,
58.43; H, 8.69; N, 3.10; Sn, 26.25. Found: C, 58.44; H, 8.74;
N, 3.16; Sn, 26.16. The enantiomeric excess of (R)-21 was
determined directly by CSP HPLC analysis (D-phenylglycine,
10% i-PrOH/hexane, 1.0 mL/min) to be 60%. The major
enantiomer (R)-21 had a retention time of 55.1 min, and the
minor enantiomer (S)-21 had a retention time of 63.6 min.
(R)-N-Met h yl-4-h yd r oxy-3,4,4-t r ip h en ylb u t a n a m id e
((R)-22) was obtained using benzophenone as the electrophile
following a procedure similar to that reported for the prepara-
tion of (R)-8. The crude product was recrystallized from EtOAc
to provide an 84% yield of (R)-22 as a white solid: mp 182-
184 °C; 1H NMR (CDCl3, 300 MHz) δ 2.56 (d, 3H, J ) 4.8 Hz,
CH3), 2.67 (m, 2H, CH2), 3.87 (s, 1H, OH), 4.39 (dd, 1H, J )
5.7Hz, J ) 1.5 Hz, CH), 5.07-5.16 (bs, 1H, NH), 7.00-7.73
(m, 15H, Ar); 13C NMR (d6-acetone, 75 MHz) δ 25.92, 39.68,
50.69, 80.82, 126.10, 126.52, 126.69, 126.97, 127.84, 128.71,
131.08, 141.48, 147.83, 149.08, 172.91. [R]22D 105.5° (c ) 0.47,
To a solution of the γ-lactone 52 (97 mg, 0.41 mmol) in EtOH
(10 mL) was added 5% Pd in carbon (80 mg). The mixture
was allowed to stir under H2 atmosphere for 4 h and then
passed through a short plug of Celite. The resulting solution
was concentrated to give 53 (96 mg, quantitative yield) as a
colorless oil. [R]22 +41.4° (c ) 2.62, benzene). Acid 53 was
D
converted to the 3,5-dimethylanilide and the enantiomeric
excess determined to be 65% by CSP HPLC as described above.
(R)-N-Met h yl-4-h yd r oxy-4-m et h yl-3-p h en ylp en t a n a -
m id e ((R)-26) was obtained using acetone as the electrophile
following a procedure similar to that reported for the prepara-
tion of (R)-8. The crude product was recrystallized from EtOAc
to provide 45% of (R)-26 as a white solid: mp 122-124 °C; 1H
NMR (CDCl3, 300 MHz) δ 1.10 (s, 3H, CH3), 1.21 (s, 3H, CH3),
2.53-2.62 (m, 4H, CH3 and 1H of CH2), 2.87-2.94 (m, 1H, 1H
of CH2), 3.16-3.21 (m, 1H, CH), 5.75 (bs, 1H, NH), 7.18-7.30
(m, 5H, C6H5); 13C NMR (CDCl3, 75 MHz) δ 26.30, 26.65, 29.27,
34.49, 37.92, 51.16, 52.88, 72.36, 126.74, 128.16, 129.02,
141.51, 173.43. Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65;
N, 6.32. Found: C, 70.46; H, 8.54; N, 6.09. The enantiomeric
purity of (R)-26 was determined to be 60% by CSP HPLC of
the corresponding γ-lactone 57 as described below.
(R)-N-Met h yl-3-(1-h yd r oxycycloh exyl)-3-p h en ylp r o-
p a n a m id e ((R)-28) was obtained using cyclohexanone as the
electrophile following a procedure similar to that reported for
the preparation of (R)-8. The crude product was purified by
MPLC (50% EtOAc/hexane) to afford a 65% yield of (R)-28 as
an oil: 1H NMR (CDCl3, 300 MHz) δ 1.08-1.71 (m, 10H,
(CH2)5), 2.28 (bs, 1H, OH), 2.51-2.59 (m, 4H, CH3 and 1H of
CH2), 2.86 (dd, J ) 5.2 Hz, J ) 9.4 Hz, 1H, 1H of CH2), 3.13-
3.18 (m, 1H, CH), 5.69 (bs, 1H, NH), 7.17-7.29 (m, 5H, C6H5);
13C NMR (CDCl3, 75 MHz) δ 21.70, 21.91, 25.53, 26.27, 35.25,
36.18, 37.28, 52.28, 72.72, 126.64, 128.12, 129.28, 141.21,
173.36. Anal. Calcd for C16H23NO2: C, 73.52; H, 8.87; N, 5.36.
Found: C, 73.22; H, 8.83; N, 5.46. The enantiomeric purity
(27) Touet, J .; Baudouin, S.; Brown, E. Tetrahedron: Asymmetry
1992, 3, 587-590.

4552 J . Org. Chem., Vol. 61, No. 14, 1996
Lutz et al.
of (R)-28 was determined to be 54% by CSP HPLC of the
corresponding γ-lactone 58 as described below.
13C NMR (CDCl3, 75 MHz) δ 23.22, 27.74, 34.52, 51.20, 87.26,
127.79, 128.70, 136.69, 175.39. Anal. Calcd for C12H14O2: C,
75.76; H, 7.42. Found: C, 75.80; H, 7.44. The enantiomeric
excess of (R)-57 was determined to be 54% by CSP HPLC
analysis (1% i-PrOH/hexane, 2.0 mL/min) using a prototype
CSP HPLC column from Professor William Pirkle. The major
enantiomer (R)-57 had a retention time of 19.3 min, and the
minor enantiomer (S)-57 had a retention time of 22.2 min.
(R)-4-(spir o-Cycloh exyl)-3-ph en yl-γ-bu tyr olacton e ((R)-
58) was prepared from (R)-28 following a procedure similar
to that reported for the preparation of (R)-56. The crude
product was purified by MPLC (30% EtOAc/hexane) to provide
a 79% yield of (R)-58 as a white solid: mp 95-96 °C; 1H NMR
(CDCl3, 300 MHz) δ 0.86-1.92 (m, 10H, (CH2)5), 2.94 (d, 2H,
J ) 8.6 Hz, CH2), 3.40 (t, 1H, J ) 8.9 Hz, CH), 7.16-7.38 (m,
5H, C6H5); 13C NMR (CDCl3, 75 MHz) δ 21.63, 22.55, 24.88,
32.29, 34.71, 36.73, 51.16, 88.55, 127.63, 128.10, 128.59,
St er eoch em ica l Assa y of (R )-N-Met h yl-3-p h en yl-3-
(d im eth ylp h en ylsilyl) p r op a n a m id e ((R)-20): Syn th esis
of (R)-51. To a 0.5 M solution of (R)-20 (947 mg, 3.18 mmol)
in methylene chloride were added triethylamine (0.44 mL, 3.18
mmol), di-tert-butyl dicarbonate (1.39 g, 6.36 mmol), and
4-(dimethylamino)pyridine (388 mg, 3.18 mmol). The solution
was stirred for 7 h at room temperature. The volatiles were
removed in vacuo, and the residue was purified by flash
chromatography (1/20 (v/v) EtOAc/Hexane) to afford the
desired (R)-N-Boc-N-methyl-3-(dimethylphenylsilyl)-3-phenyl-
propanamide (850 mg, 67%): 1H NMR (CDCl3, 300 MHz) δ
0.20 (s, 3H, SiCH3), 0.26 (s, 3H, SiCH3), 1.51 (s, 9H, O-t-Bu),
2.91 (s, 3H, NCH3), 2.97-3.15 (m, 2H, CH2), 3.40-3.50 (m,
1H, CH), 6.95-7.43 (m, 10H, Ar).
A solution of the N-Boc derivative (530 mg, 1.33 mmol) in
methanol (3 mL), under N2 atmosphere, was cooled to 0 °C.
To this solution was added 0.5 mL (2.44 mmol) of a 25 wt %
solution of sodium methoxide in methanol. The reaction
mixture was stirred for 40 min and then poured into 15 mL of
brine. The layers were separated, and the aqueous layer was
extracted with ether (3 × 15 mL). The combined ether layers
were dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography (1/50 (v/v) EtOAc/hexane) to give (R)-50 (226
137.05, 175.80. Anal. Calcd for C15
H18O2: C, 78.23; H, 7.88.
Found: C, 78.19; H, 7.87. The enantiomeric excess of (R)-58
was determined to be 54% by CSP HPLC analysis (1% i-PrOH/
hexane, 2.0 mL/min) using a prototype CSP HPLC column
from Professor William Pirkle. The major enantiomer (R)-58
had a retention time of 16.3 min, and the minor enantiomer
(S)-58 had a retention time of 21.1 min.
P r ep a r a tion of (3R,5S)-3-P h en yl-5-(iod om eth yl)-δ-la c-
ton e (59). To a stirring solution of (R)-15 (182 mg, 0.89 mmol)
in THF (8 mL) and Et2O (8 mL) was added saturated NaHCO3
solution (16 mL). The mixture was allowed to stir for 10 min
before being cooled to 0 °C. Iodine (909 mg, 3.58 mmol) was
added, and the mixture was stirred overnight at 0 °C. Et2O
(150 mL) was added, and the organic layer was washed with
NaS2O3 solution (50 mL), H2O (50 mL), and brine (50 mL),
dried over MgSO4, filtered, and concentrated to give a yellow
oil. Purification by MPLC (25% EtOAc/hexane) gives the
product as a yellow semisolid (189 mg, 67% yield): 1H NMR
(CDCl3, 300 MHz) δ 1.84 (m, 1H, 1H of CH2), 2.41 (m, 1H, 1H
of CH2), 2.56 (m, 1H, 1H of CH2), 2.91 (m, 1H, 1H of CH2),
3.23 (m, 1H, CH), 3.44 (m, 2H, CH2), 4.40 (m, 1H, CH), 7.20-
7.39 (m, 5H, C6H5); 13C NMR (CDCl3, 75 MHz) 7.81, 36.18,
36.85, 37.11, 78.330, 126.32, 127.33, 128.94, 141.98, 169.66.
1
mg, 57%); H NMR (CDCl3, 300 MHz) δ 0.21 (s, 3H, SiCH3),
0.24 (s, 3H, SiCH3), 2.60-2.87 (m, 3H, CHCH3), 3.46 (s, 3H,
OCH3), 6.93-7.41 (m, 10H, Ar).
To a 0.1 M solution of (R)-50 (183 mg, 0.6 mmol) in
methylene chloride was added tetrafluoroboric acid-diethyl
ether complex (1 g, 6 mmol). The mixture was stirred at room
temperature for 3 h. The volatile materials were removed in
vacuo to give (R)-3-(fluorodimethylsilyl)-3-phenyl propyl meth-
yl ester (105 mg) as an oil: 1H NMR (CDCl3, 300 MHz) δ 0.14
(d, J ) 7.5 Ηz, 3H, SiCH3), 0.19 (d, J ) 7.4 Hz, 3H, SiCH3),
2.79-2.87 (m, 3H, CHCH2), 3.58 (s, 3H, OCH3), 7.09-7.29 (m,
5H, Ar). The material was used without further purification.
To a solution of the crude fluorosilane (100 mg, 0.42 mmol)
in DMF (1.2 mL) were added m-chloroperbenzoic acid (624 mg,
3.6 mmol) and anhydrous potassium fluoride (133 mg, 2.3
mmol). The mixture was stirred at room temperature for 5 h.
The crude product was purified by MPLC (10% EtOAc/hexane)
to afford (R)-3-hydroxy-3-phenylpropyl methyl ester ((R)-51)
1
The relative configuration was determined by a difference H
NMR NOE experiment. Irradiation at δH 3.23 ppm (1H,
benzylic CH) caused enhancement at δH 4.40 ppm (1H, CH,
10.2%). Irradiation at δH 4.40 ppm (1H, CH) caused enhance-
ment at δH 3.23 ppm (1H, benzylic CH, 11.0%). Anal. Calcd
for C13H16NO2I: C, 45.59; H, 4.16. Found: C, 45.88; H, 4.16.
Rep r esen ta tive Lith ia tion of N-Meth yl-3-(o-m eth oxy-
p h en yl)p r op a n a m id e (60): P r ep a r a tion of (R)-N-Meth yl-
3-(o-m et h oxyp h en yl)-4-p h en ylbu t a n a m id e ((R)-61). To
(-)-sparteine (0.64 mL, 2.78 mmol) in THF (5 mL) and tert-
BuOMe (5 mL) at -78 °C was added s-BuLi (2.43 mL, 2.55
mmol). The reaction mixture was stirred for 20 min at -78
°C and then was transferred to a solution of N-methyl-3-(o-
methoxyphenyl)propanamide (60) (214 mg, 1.11 mmol) in THF
(5 mL) and tert-BuOMe (5 mL) at -78 °C. The resulting
reaction mixture was stirred at -78 °C for 1 h, and then benzyl
bromide (0.17 mL, 1.44 mmol) was added. This mixture was
then allowed to warm to ambient temperature overnight. HCl
(5%, 5 mL) was added, and then the layers were separated.
The aqueous layer was extracted with ether (3 × 20 mL). The
(70 mg, 71% total) as an oil: [R]25 +12.4° (c ) 2.66, EtOH);
D
1H NMR (CDCl3, 300 MHz) δ 2.73-2.77 (m, 2H, CH2), 3.72 (s,
3H, OCH3), 4.2-4.7 (bs, 1H, OH), 5.12-5.17 (dd, 1H, J ) 4.2
Hz, J ) 4.5 Hz, CH), 7.29-7.39 (m, 5H, Ar); 13C NMR (CDCl3,
75 MHz) δ 43.1, 51.9, 70.27, 125.61, 127.81, 128.53, 142.39,
172.78. The [R]25 for (S)-51 was reported to be -18.4.11
D
Rep r esen ta tive Syn th esis of Bu tyr ola cton es: P r ep a -
r a tion of (R)-3,4,4-Tr ip h en ylbu tyr ola cton e ((R)-56). To
a 0.5 M solution of (R)-22 (121 mg, 0.35 mmol) in methylene
chloride were added triethylamine (0.05 mL, 0.35 mmol), di-
tert-butyl dicarbonate (0.16 mL, 0.70 mmol), and 4-(dimethyl-
amino)pyridine (43 mg, 0.35 mmol). The solution was stirred
for 8 h at room temperature. The volatiles were removed, and
the residue was purified by flash chromatography (1/20 (v/v)
EtOAc/hexane) to afford the desired γ-lactone (R)-56 (96 mg,
87%): mp 140-142 °C; 1H NMR (CDCl3, 300 MHz) δ 2.80 (dd,
1H, J ) 17.5, 4.6 Hz, CH2), 3.00 (dd, J ) 17.5, 8.0 Hz, CH2),
4.47-4.51 (m, 1H, CH), 6.93-7.67 (m, 15H, Ar); 13C NMR
(CDCl3, 75 MHz) δ 37.39, 50.90, 92.91, 126.02, 126.19, 127.14,
127.28, 127.62, 128.13, 128.29, 128.49, 128.64, 138.43, 139.87,
143.05, 175.79. The enantiomeric excess of (R)-56 was deter-
mined directly by CSP HPLC analysis (D-phenylglycine, 200/1
(v/v) i-PrOH/hexane, 1.0 mL/min) to be 60%. The major
enantiomer (R)-56 had a retention time of 51.6 min, and the
minor enantiomer (S)-56 had a retention time of 57.1 min.
(R)-4,4-Dim eth yl-3-p h en yl-γ-bu tyr ola cton e ((R)-57) was
prepared from (R)-26 following a procedure similar to that
reported for the preparation of (R)-56. The crude product was
purified by MPLC (30% EtOAc/hexane) to provide an 85% yield
combined ether layers were dried over anhydrous MgSO4
,
filtered, and concentrated under reduced pressure. The
residue was purified by MPLC (30% EtOAc/hexane) to give
(R)-61 as an oil (223 mg, 71%): 1H NMR (CDCl3, 300 MHz) δ
2.55-2.58 (m, 2H, CH2Ph), 2.62 (d, 3H, J ) 4.8 Hz, CH3),
2.87-3.00 (m, 2H, CH2CO), 3.72-3.82 (m, 4H, OCH3 and CH),
5.41 (bs, 1H, NH), 6.81-6.89 (m, 2H, Ar), 7.05-7.26 (m, 7H,
Ar and C6H5); 13C NMR (CDCl3, 75 MHz) 26.15, 38.01, 41.08,
41.27, 55.43, 110.83, 120.75, 125.86, 127.47, 127.97, 128.15,
129.21, 131.54, 140.12, 157.00, 172.45; [R]22 28.1° (c ) 1.2,
D
CHCl3). Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N, 4.94.
Found: C, 76.27; H, 7.66; N, 4.85. The enantiomeric excess
of (R)-61 was determined to be 80% by conversion to the (S)-
R-methylbenzylamide derivative and analysis by GC.21
(R)-N-Met h yl-3-(o-m et h oxyp h en yl)b u t a n a m id e ((R)-
62) was obtained using methyl iodide as the electrophile
1
of (R)-57 as a white solid: mp 100-102 °C; H NMR (CDCl3,
300 MHz) δ 1.04 (s, 3H, CH3), 1.55 (s, 3H, CH3), 2.84-3.06
(m, 2H, CH2), 3.49-3.55 (m, 1H, CH), 7.20-7.39 (m, 5H, C6H5);

â-Lithiation of â-Aryl Secondary Amides
J . Org. Chem., Vol. 61, No. 14, 1996 4553
following a procedure similar to that reported for the prepara-
tion of (R)-61. The crude product was purified by MPLC (30%
EtOAc/hexane) to give a 63% yield of (R)-62 as an oil which
solidified upon standing: 1H NMR (CDCl3, 300 MHz) δ 1.27
(δ, 3Η, J ) 7.0 Hz, CH3), 2.31-2.39 (m, 1H, CH2), 2.46-2.60
(m, 1H, CH2), 2.73 (d, 3H, J ) 4.8 Hz, CH3), 3.58-3.65 (m,
1H, CH), 3.84 (s, 3H, OCH3), 5.49 (bs, 1H, NH), 6.85-6.94 (m,
2H, Ar), 7.16-7.26 (m, 2H, Ar); 13C NMR (CDCl3, 75 MHz)
20.12, 26.19, 30.34, 43.93, 55.31, 110.52, 120.70, 126.89,
127.24, 133.84, 156.63, 172.77. Anal. Calcd for C12H17NO2:
C, 69.53; H, 8.27; N, 6.75. Found: C, 69.80; H, 8.32; N, 6.72.
The enantiomeric excess of (R)-62 was determined to be 80%
by conversion to the (S)-R-methylbenzylamide derivative and
analysis by GC.21
10% NaOH (1.0 mL). The reaction mixture was allowed to
stir overnight. After removal of THF in vacuo, the basic
residue was acidified with 10% HCl and extracted with ether
(3 × 15 mL). The combined ether layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The crude acid (134 mg, 63% yield) was obtained
as an oil which was not purified but was used for cyclization.
To a solution of the acid (112 mg, 0.41 mmol) in dry
methylene chloride (12 mL) at 0 °C was added BBr3 (0.11 mL,
1.20 mmol) under N2 atmosphere. The reaction mixture was
stirred for 2.5 h, and then H2O (3 mL) was added. The
resulting mixture was allowed to warm to ambient tempera-
ture and neutralized by saturated NaHCO3. The aqueous
layer was extracted with CH2Cl2 (2 × 15 mL) and EtOAc (15
mL). The combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by MPLC (15% EtOAc/hexane) to give
(R)-66 as an oil (80 mg, 82% yield, 52% overall yield from (R)-
61): 1H NMR (CDCl3, 300 MHz) δ 2.70-2.78 (m, 3H, CH2 and
1H of CH2CO), 2.94-3.01 (dd, 1H, J ) 6.6, 13.5 Hz, CH2CO),
3.20-3.28 (m, 1H, CH), 7.01-7.10 (m, 2H, Ar), 7.22-7.33 (m,
2H, Ar); 13C NMR (CDCl3, 75 MHz) 33.73, 37.31, 41.25, 117.06,
124.32, 125.92, 126.77, 127.78, 128.48, 128.57, 129.21, 137.80,
151.26, 168.03. Anal. Calcd for C16H14O2: C, 80.65; H, 5.92.
Found: C, 80.49; H, 5.88.
(R)-N-Meth yl-3-(o-m eth oxyp h en yl)h ep ta n a m id e ((R)-
63) was obtained using butyl iodide as the electrophile
following a procedure similar to that reported for the prepara-
tion of (R)-61. The crude product was purified by MPLC (35%
EtOAc/hexane) to give a 67% yield of (R)-63 as an oil: 1H NMR
(CDCl3, 300 MHz) δ 0.81 (t, 3H, J ) 7.1 Hz, CH3), 1.03-1.30
(m, 4H, CH2CH2), 1.61-1.668 (m, 2H, CH2), 2.48 (d, 2H, J )
7.4 Hz, CH2), 2.66 (d, 3H, J ) 4.8 Hz, CH3), 3.40-3.47 (m,
1H, CH), 3.82 (s, 3H, OCH3), 5.50 (s, 1H, NH), 6.84-6.94 (m,
2H, Ar), 7.11-7.26 (m, 2H, Ar); 13C NMR (CDCl3, 75 MHz)
13.96, 22.60, 26.15, 29.56, 34.54, 35.75, 43.10, 43.15, 55.41,
110.69, 1120.79, 127.18, 127.85, 132.32, 157.10, 172.80. Anal.
Calcd for C15H23NO2: C, 72.25; H, 9.30; N, 5.62. Found: C,
(R)-4-Meth ylh yd r ocou m a r in ((R)-67) was prepared from
(R)-62 following the procedure detailed above for (R)-66. The
crude product was purified by MPLC (15% EtOAc/hexane) to
give (R)-67 as an oil in 49% overall yield from (R)-62: 1H NMR
(CDCl3, 300 MHz) δ 1.34 (d, 3H, J ) 7.0 Hz, CH3), 2.55-2.62
(dd, 1H, J ) 7.2 Hz, J ) 15.6 Hz, CH2), 2.81-2.88 (dd, 1H, J
) 5.4 Hz, J ) 15.8 Hz, CH2), 3.15-3.22 (m, 1H, CH), 7.04-
7.29 (m, 4H, Ar); 13C NMR (CDCl3, 75 MHz) 19.88, 29.46,
36.77, 116.97, 124.57, 126.48, 127.82, 128.24, 151.20, 168.35.
The absolute configuration of (R)-67 was determined by
72.30; H, 9.27; N, 5.64. [R]22 11.1° (c ) 1.5, CHCl3). The
D
enantiomeric excess of (R)-63 was determined to be 83% by
conversion to the (S)-R-methylbenzylamide derivative and
analysis by GC.21
(R)-N-Meth yl-3-(o-m eth oxyph en yl)-3-tr im eth ylsilyl pr o-
p a n a m id e ((R)-64) was obtained using TMSCl as the elec-
trophile following a procedure similar to that reported for the
preparation of (R)-61. The crude product was purified by
MPLC (30% EtOAc/hexane) to give a 68% yield of (R)-64 as a
comparison of the optical rotation([R]22 26.1° (c ) 1.07,
D
white solid: mp 111-113 °C. [R]22 -13.0° (c ) 1.5, CHCl3);
benzene) with the literature value ([R]20 32°) for (R)-67.20
D
D
1H NMR (CDCl3, 300 MHz) δ -0.06 (s, 9H, Si(CH3)3), 2.58-
2.77 (m, 5H, CH2 and CH3), 2.90-2.97 (m, 1H, CH), 3.81 (s,
3H, OCH3), 5.57 (bs, 1H, NH), 6.81-6.91 (m, 2H, Ar), 7.00-
7.21 (m, 2H, Ar); 13C NMR (CDCl3, 75 MHz) -2.99, 24.49,
26.19, 36.31, 55.05, 110.15, 120.70, 125.70, 127.20, 130.61,
156.12, 173.38. Anal. Calcd for C14H23NO2Si: C, 63.35; H,
8.73; N, 5.28. Found: C, 63.32; H, 8.74; N, 5.28. The
enantiomeric excess of (R)-64 was determined to be 80% by
conversion to the (S)-R-methylbenzylamide derivative and
analysis by GC.21
(R)-4-Bu tylh yd r ocou m a r in (68) was prepared from (R)-
63 following the procedure detailed above for (R)-66. The
residue was purified by MPLC (15% EtOAc/hexane) to give
(R)-68 as an oil in 46% overall yield from (R)-63: 1H NMR
(CDCl3, 300 MHz) δ 0.88 (t, 3H, J ) 6.6 Hz, CH3), 0.93-1.40
(m, 4H, CH2CH2), 1.50-1.63 (m, 2H, CH2), 2.71-2.87 (m, 2H,
CH2CO), 2.93-2.99 (m, 1H, CH), 7.04-7.29 (m, 4H, Ar); 13C
NMR (CDCl3, 75 MHz) 13.89, 22.52, 28.78, 34.34, 34.73, 35.11,
117.08, 124.25, 126.85, 127.78, 128.18, 151.24, 168.50. Anal.
Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.17; H,
8.13.
(R)-N-Meth yl-3-(o-m eth oxyp h en yl)-5-h exen a m id e ((R)-
65) was obtained using allyl chloride as the electrophile
following a procedure similar to that reported for the prepara-
tion of (R)-61. The crude product was purified by MPLC (40%
EtOAc/hexane) to give 67% yield of (R)-65 as an oil: 1H NMR
(CDCl3, 300 MHz) δ 2.39-2.44 (m, 2H, CH2), 2.49-2.52 (m,
2H, CH2), 2.65 (d, 3H, J ) 4.8 Hz, CH3), 3.55-3.60 (m, 1H,
CH), 3.81 (s, 3H, OCH3), 4.88-4.98 (m, 2H, CH2), 5.57-5.71
(m, 2H, NH and CH)CH2), 6.83-6.91 (m, 2H, Ar), 7.12-7.20
(m, 2H, Ar); 13C NMR (CDCl3, 75 MHz) 26.09, 35.71, 38.86,
41.59, 55.35, 110.72, 116.14, 120.63, 127.35, 127.95, 131.63,
N-Meth yl-3-(p-m eth oxyp h en yl)-3-(tr im eth ylsilyl)p r o-
p a n a m id e (72) was obtained starting from amide 69 and by
following the lithiation/substitution procedure described above
for the preparation of (R)-8, using TMSCl as the electrophile.
The crude product was purified by MPLC (40% EtOAc/hexane)
1
to give 72 as a white solid: mp 55-57 °C; H NMR (CDCl3,
300 MHz) δ -0.08 (s, 9H, Si(CH3)3), 2.43-2.59 (m, 6H, CHCH2
and CH3), 3.74 (s, 3H, OCH3), 5.58 (bs, 1H, NH), 6.75-6.79
(m, 2H, Ar), 6.92-6.96 (m, 2H, Ar); 13C NMR (CDCl3, 75 MHz)
-3.18, 26.13, 31.73, 36.76, 55.01, 113.74, 127.98, 134.05,
156.90, 173.32. Anal. Calcd for C14H23NO2Si: C, 63.35; H,
8.73; N, 5.28. Found: C, 63.36; H, 8.76; N, 5.24. The
enantiomeric excess of 72 was determined to be 80% by
conversion to the N-R-(methylbenzyl)amide derivative followed
by analysis of the diastereomeric excess by gas chromatogra-
phy.21
136.50, 156.97, 171.57; [R]22 -19.4° (c ) 1.0, CHCl3). Anal.
D
Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.01. Found: C,
71.92; H, 8.19; N, 6.00. The enantiomeric excess of (R)-65 was
determined to be 86% by conversion to the (S)-R-methylben-
zylamide derivative and analysis by GC.21
Rep r esen ta tive Con ver sion of a n (o-Meth oxyp h en yl)-
p r op a n a m id e to a Hyd r ocou m a r in : P r ep a r a tion of (R)-
4-Ben zylh yd r ocou m a r in ((R)-66). To a solution of (R)-61
(223 mg, 0.79 mmol) in methylene chloride (3 mL) were added
triethylamine (0.12 mL, 0.79 mmol), di-tert-butyl dicarbonate
(345 mg, 1.58 mmol), and 4-(dimethylamino)pyridine (98 mg,
0.79 mmol). The solution was stirred overnight at room
temperature. The volatile materials were removed, and the
residue was purified by flash chromatography (10% EtOAc/
hexane) to afford (R)-N-Boc-N-methyl-3-(o-methoxyphenyl)-4-
phenylbutanamide.
N-Meth yl-3-(o-m eth ylph en yl)-3-(tr im eth ylsilyl)pr opan -
a m id e (73) was obtained starting from amide 70 and by
following the lithiation/substitution procedure described above
for the preparation of (R)-8, using TMSCl as the electrophile.
The crude product was purified by MPLC (30% EtOAc/hexane)
to give 73 as an oil: 1H NMR (CDCl3, 300 MHz) δ -0.04 (s,
6H, Si(CH3)3), -0.05 (s, 3H, Si(CH3)3), 2.29-2.30 (bs, 3H, CH3-
Ar), 2.51-2.61 (m, 5H, CH2 and CH3), 2.85-2.90 (, m, 1H, CH),
5.35 (bs, 1H, NH), 6.97-7.12 (m, 4H, Ar); 13C NMR (CDCl3,
75 MHz) -2.87, 20.53, 26.20, 27.33, 37.70, 124.56, 125.59,
A solution of the N-Boc derivative in THF (2.5 mL), under
N2 atmosphere, was cooled to 0 °C. To this solution was added
125.91, 130.52, 135.62, 141.24, 173.32. Anal. Calcd for C14H23
-
NOSi: C, 67.41; H, 9.29; N, 5.62. Found: C, 67.38; H, 9.31;

4554 J . Org. Chem., Vol. 61, No. 14, 1996
Lutz et al.
N, 5.60. CSP HPLC analysis ((S, S)-Whelk-O1 column, 10%
i-PrOH/hexane, 2.0 mL/min) indicated 0% ee.
followed by analysis of the diastereomeric excess by gas
chromatography.21
N-Meth yl-3-(o-ch lor op h en yl)-3-(tr im eth ylsilyl)p r op a n -
a m id e (74) was obtained starting from amide 71 and by
following the lithiation/substitution procedure described above
for the preparation of (R)-8, using TMSCl as the electrophile.
The residue was purified by MPLC (30% EtOAc/hexane) to give
74 as an oil: 1H NMR (CDCl3, 300 MHz) δ -0.04 (s, 6H, Si-
(CH3)3), 2.58-2.75 (m, 5H, CH2and CH3), 3.17-3.23 (m, 1H,
CH), 5.81 (bs, 1H, NH), 6.97-7.32 (m, 4H, C6H4); 13C NMR
(CDCl3, 75 MHz) -3.06, 26.20, 28.10, 36.65, 125.83, 126.77,
Ack n ow led gm en t. We are grateful to the National
Institutes of Health and the National Science Founda-
tion for support of this work. We thank Professor
William Pirkle for the use of prototype CSP HPLC
columns.
Su p p or tin g In for m a tion Ava ila ble: Preparations of
amides 4, 5, 42, 60, 69, 70, and 71 and the X-ray crystal
structure for 48 (6 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
127.16, 129.61, 133.14, 140.36, 172.52. Anal. Calcd for C13H20
-
NOSiCl: C, 57.86; H, 7.47; N, 5.19. Found: C, 57.91; H, 7.37;
N, 5.13. The enantiomeric excess of 74 was determined to be
0% by conversion to the N-R-(methylbenzyl)amide derivative
J O952223R