Carbolithiation of o-amino-(E)-stilbenes: Diastereoselective electrophile substitution with applications to quinoline synthesis

Article abstract of DOI:10.1021/jo7017679

(Chemical Equation Presented) A regioselective carbolithiation of o-amino-(E)-stilbenes has been achieved with a series of alkyllithiums when THF is employed as the reaction solvent. The use of other solvents, such as diethyl ether or hydrocarbons, leads to a pronounced loss in regioselectivity. Moreover, high levels of diastereoselectivity have been obtained following reaction of the lithiated intermediate in THF with different electrophiles such as MeOD, CO₂, and Bu₃SnCl. It was shown that diastereoselectivity was influenced by the orthoamino substituent and the alkyllithium utilized for carbolithiation with N-Boc substituent and t-BuLi proving optimal. In the case of carbolithiated intermediate 3a, obtained from the reaction of N-Boc substituted stilbene with t-BuLi, ¹H and ¹³C NMR analysis revealed predominantly one diastereoisomer which was stable at room temperature. Application of the carbolithiation/electrophile reaction methodology to the synthesis of six-membered quinoline ring systems is demonstrated with substituted 3,4-dihydroquinolin-2-ones, 1,2,3,4-tetrahydroquinolines, 1,4-dihydroquinolines, and quinolines all prepared by a common cascade route.

Full text of DOI:10.1021/jo7017679

Carbolithiation of o-Amino-(E)-Stilbenes: Diastereoselective
Electrophile Substitution with Applications to Quinoline Synthesis
Anne-Marie L. Hogan and Donal F. O’Shea*
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, UniVersity
College Dublin, Belfield, Dublin 4, Ireland
donal.f.oshea@ucd.ie
ReceiVed August 13, 2007
A regioselective carbolithiation of o-amino-(E)-stilbenes has been achieved with a series of alkyllithiums
when THF is employed as the reaction solvent. The use of other solvents, such as diethyl ether or
hydrocarbons, leads to a pronounced loss in regioselectivity. Moreover, high levels of diastereoselectivity
have been obtained following reaction of the lithiated intermediate in THF with different electrophiles
such as MeOD, CO2, and Bu3SnCl. It was shown that diastereoselectivity was influenced by the ortho-
amino substituent and the alkyllithium utilized for carbolithiation with N-Boc substituent and t-BuLi
proving optimal. In the case of carbolithiated intermediate 3a, obtained from the reaction of N-Boc
substituted stilbene with t-BuLi, 1H and 13C NMR analysis revealed predominantly one diastereoisomer
which was stable at room temperature. Application of the carbolithiation/electrophile reaction methodology
to the synthesis of six-membered quinoline ring systems is demonstrated with substituted 3,4-
dihydroquinolin-2-ones, 1,2,3,4-tetrahydroquinolines, 1,4-dihydroquinolines, and quinolines all prepared
by a common cascade route.
Introduction
unactivated alkene, ethene, was achieved.2 Subsequently, the
carbolithiation of other substituted alkenes such as styrene,
â-methylstyrene, and trans-stilbene has been described in detail.3
Intermolecular alkene carbolithiation facilitates the generation
of a carbon-carbon bond and carbon-lithium center in a single
transformation. The synthetic utility of this transformation lies
in the fact that the tandem formation of C-C and C-Li bonds
allows for further in situ reactions. Indeed, one of the first uses
for alkene carbolithiation was in the anionic polymerization of
styrene.1 The development of carbolithiation chemistry for
nonpolymer applications can be traced to the reports of Bartlett
et al. in which the intermolecular carbolithiation of the simplest
(3) (a) Okamoto, Y.; Kato, M.; Yuki, H. Bull. Chem. Soc. Jpn 1969, 42,
760. (b) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T. V.;
Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc. 1991, 113, 5720. (c)
Superchi, S.; Sotomayor, N.; Miao, G.; Joseph, B.; Campbell, M. G.;
Snieckus, V. Tetrahedron Lett. 1996, 37, 6061. (d) Wei, X.; Taylor, R. J.
K. Chem. Commun. 1996, 187. (e) Klein, S.; Marek, I.; Poisson, J. F.;
Normant, J. F. J. Am. Chem. Soc. 1995, 117, 8853. (f) Norsikian, S.; Marek,
I.; Normant, J. F. Tetrahedron Lett. 1997, 38, 7523. (g) Norsikian, S.; Marek,
I.; Klein, S.; Poisson, J. F.; Normant, J. F. Chem.sEur. J. 1999, 5, 2055.
(h) Marek, I. J. Chem. Soc., Perkin Trans 1 1999, 535. (i) Wei, X.; Johnson,
P.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans 1 2000, 1109. (j) Peters,
J. G.; Seppi, M.; Fro¨hlich, R.; Wibbeling, B.; Hoppe, D. Synthesis 2002,
381. (k) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon
Press: Oxford, U.K., 2002; pp 273-335. (l) Normant, J. F. Topics
Organomet. Chem. 2003, 5, 287.
(1) Ziegler, K.; Gellert, H. G. Justus Liebigs Ann. Chem. 1950, 567,
195.
(2) (a) Bartlett, P. D.; Friedman, S.; Stiles, M. J. Am. Chem. Soc. 1953,
75, 1771. (b) Bartlett, P. D.; Tauber, S. J.; Weber, W. P. J. Am. Chem. Soc.
1969, 91, 6362.
10.1021/jo7017679 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/15/2007
J. Org. Chem. 2007, 72, 9557-9571
9557

Hogan and O’Shea
SCHEME 1. Regioselectivity of Alkene Carbolithiation
SCHEME 3. Carbolithiation Initiated Quinoline Synthesis
It has been shown that carbolithiation of unsymmetrical alkenes
such as styrene and â-methylstyrene, which offer two potential
regioisomer products, is regiospecific, with the more stabilized
benzylic lithiated species generated exclusively in both cases
(eq 1, Scheme 1). In contrast, the carbolithiation of unsym-
metrical stilbenes (Ar * Ar1) poses a considerable selectivity
challenge as two possible benzylic lithiated regioisomers could
be generated from the reaction (eq 2, Scheme 1). We were
attracted to investigate this issue for the specific case of ortho-
aryl-substituted stilbenes to determine if selective carbolithiation
could be achieved and to utilize it for the synthesis of fused
ring systems.
The value of lithiated compounds (generated by deprotona-
tion) as synthetic intermediates for heterocyclic systems is
indisputable, with the motifs of ortho hetero-substituted aryl-
and benzylic-lithium species being common intermediates in
the synthesis of fused ring systems (eqs 1 and 2, Scheme 2).4-6
lithium species (eq 1, Scheme 2),4 while treatment of o-
tolylcarbamic acid tert-butyl ester with s-BuLi in the same
solvent results in lithiation at the R-benzylic position (eq 2).5
Electrophile reaction at the aryl or benzylic lithium center and
subsequent cyclization with the ortho-substituent has been
reported for the synthesis of five-, six-, seven-, and eight-
membered fused ring systems, the ring size being dependent
upon the electrophile employed, the ortho-substituent, and
whether the lithium is at the ortho or R position.
A less common approach, developed in our laboratory, is the
generation of benzylic lithiated species via alkene carbolithiation
followed by in situ reaction to provide routes to heterocycles
(eq 3, Scheme 2). We have recently reported the carbolithiation
of ortho-amino substituted styrenes, â-methylstyrenes, and vinyl-
pyridines with applications to indole8 and 7-azaindole synthesis.9
Carbolithiation offers improved atom efficiency over utilizing
the alkyllithium as a base as the product includes an additional
functionality incorporated from the carbolithiation step.
What is more unusual and synthetically more challenging to
achieve is lithiation at the position â to the ortho-substituted
aryl ring especially via a directed deprotonation reaction (eq 4,
Scheme 2). Yet, if this lithiation pattern could be achieved it
would provide access to a different series of ring systems
following electrophile reaction. Herein we report our findings
on achieving this lithiation pattern via carbolithiation for the
specific case of ortho-amino-(E)-stilbenes (DG ) NR, eq 4)
and its subsequent application to a new synthetic entry into the
quinoline ring system at various oxidation levels (Scheme 3).10
SCHEME 2. Approaches to Lithiated Aryls and Benzylic
Compounds (DG ) Directing Group)
Results and Discussion
Synthesis of Starting Substrates. The required N-substituted
ortho-bromoanilines 1a, b were both prepared from com-
mercially available 2-bromoaniline. Reaction with di-tert-butyl
dicarbonate at reflux in THF for 24 h yielded (2-bromophenyl)-
carbamic acid tert-butyl ester 1a, while introduction of the
benzyl group was accomplished by reductive amination with
benzaldehyde in a methanol/sodium borohydride mixture.8b Our
method of choice for the synthesis of the starting substrates tert-
butoxycarbonyl and benzyl N-substituted ortho-amino-(E)-
stilbenes 2a and 2b was the stereoselective Suzuki-Miyaura
Heteroatom containing functional groups which have shown the
ability to direct lithiations include methoxy, amines, and amides
as well as oxygen and nitrogen carbamates.7 For example, taking
the specific case of N-Boc as the directing group (DG ) N-Boc,
Scheme 2), ortho-lithiation of phenylcarbamic acid tert-butyl
ester can be achieved using t-BuLi in THF to generate the aryl
(4) (a) Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 4798.
(b) Stanetty, P.; Koller, H.; Mihovilovic, M. J. Org. Chem. 1992, 57, 6833.
(5) Clark, R. D.; Muchowski, J. M.; Souchet, M.; Repke, D. B. Synlett
1990, 4, 207.
(6) (a) Houlihan, W. J.; Parrino, V. A.; Uike, Y. J. Org. Chem. 1981,
46, 4511. (b) Smith, K.; El-Hiti, G. A.; Pritchard, G.; Hamilton, A. J. Chem.
Soc., Perkin Trans. 1 1999, 2299. (c) Clark, R. D.; Jahangir. Tetrahedron
1993, 49, 1351. (d) Wender, P. A.; White, A. W. Tetrahedron 1983, 39,
3767. (e) Wender, P. A.; White, A. W. Tetrahedron Lett. 1981, 22, 1475.
(7) (a) Slocum, D. W.; Jennings, C. A. J. Org. Chem. 1976, 41, 3653.
(b) Snieckus, V. Chem. ReV. 1990, 90, 879. (c) Clayden, J. Organolithi-
ums: SelectiVity for Synthesis; Pergamon Press: Oxford, U.K., 2002; p28-
59.
(8) (a) Coleman, C. M.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125,
4054. (b) Kessler, A.; Coleman, C. M.; Charoenying, P.; O’Shea, D. F. J.
Org. Chem. 2004, 69, 7836. (c) Hogan, A.-M. L.; O’Shea, D. F. J. Am.
Chem. Soc. 2006, 128, 10360.
(9) (a) Cottineau, B.; O’Shea, D. F. Tetrahedron Lett. 2005, 46, 1935.
(b) Cottineau, B.; O’Shea, D. F. Tetrahedron 2007, 63, 10354.
(10) (a) Hogan, A.-M. L.; O’Shea, D. F. Org. Lett. 2006, 8, 3769. (b)
For the directed deprotonation of o-amino-(Z)-stilbenes, see; Cotter, J.;
Hogan, A.-M. L.; O’Shea, D. F. Org. Lett. 2007, 9, 1493.
9558 J. Org. Chem., Vol. 72, No. 25, 2007

Stilbene Carbolithiation
SCHEME 4. Synthesis of N-Substituted o-Amino-(E)-
Stilbenes
While the reactions with n-Bu and EtLi were regioselective,
the isolated yields of 5b and c were low due to a competing
intramolecular cyclization of intermediates 3b, c to form the
3,4-dihydro-1H-quinolin-2-ones 11b and 11c in 45% and 26%
yields, respectively (see later for a more detailed discussion).
The additive N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PM-
DTA) was utilized to retard the intramolecular cyclization of
3b, c, and improved yields of 5b and 5c (62 and 76%,
respectively) were obtained (compare entries 3 and 4 with 9
and 10, respectively).13 In both cases the addition of PMDTA
significantly reduced the isolated yields of 11b, c to 10% and
7%. The addition of PMDTA to the reaction of 2b with n-BuLi
improves the carbolithiation reactivity of the alkyllithium giving
a higher yield of 5e (compare entries 6, 11). It is noteworthy
that in each case the use of PMDTA did not alter the
regioselectivity of the addition.
The remarkable solvent dependency of this regioselectivity
is illustrated by entries 12-18 (Table 1). When reactions were
carried out using diethyl ether or the hydrocarbon cumene as
solvent, mixtures of both regioisomers were obtained. For these
solvents the degree of regioselectivity varied for different
stilbene derivatives, alkyllithiums, and additives. For example
the reaction of 2a and 2b with t-BuLi in diethyl ether provided
a mixture of 5a/6a and 5d/6d in ratios of 90:10 and 60:40,
respectively (entries 12, 13). Interestingly, when PMDTA was
added a greater loss in selectivity was observed when compared
to ether alone, with 5a/6a obtained in a ratio of 75:25 (entry
14). A further decrease in selectivity was noted when the
reaction was performed in cumene/PMDTA (entry 15). No
carbolithiation products were obtained for the reaction of 2b
with t-BuLi in either diethyl ether/PMDTA or cumene/PMDTA
(entries 16, 18). However carbolithiation was achieved when
diethyl ether/(-)-sparteine was employed but with poor regi-
oselectivity (entry 17).
The regioisomer assignments were confirmed by indepen-
dently synthesizing compounds 6a, b, d, and e as outlined in
Scheme 5. Lithiation of o-tolylcarbamic acid tert-butyl ester 7,
followed by addition of 2,2-dimethylpropiophenone or vale-
rophenone, afforded the alcohol products 8a (R1 ) t-Bu) and
8b (R1 ) n-Bu) in 67% and 81% yields, respectively. Reaction
with thionyl chloride provided the trisubstituted alkenes 9a, b,
which following olefin hydrogenation yielded the regioisomers,
6a, b. Nitrogen benzylation of 6a, b was achieved by treatment
with NaH/benzyl bromide, and subsequent removal of the Boc
group with TFA gave the authentic samples of the regioisomers
6d, e.
Diastereoselectivity of Carbolithiation-Electrophile Sub-
stitution Sequence. The carbolithiation of unsymmetrical 1,2-
disubstituted alkenes such as stilbenes (Scheme 1, Ar *
Ar1) generates an organolithium species with two contiguous
stereocenters; therefore the possibility of introducing diastereo
and/or enantioselectivity into the reaction sequence was ex-
plored. Treatment of lithiated intermediate 3a (formed by the
carbolithiation of 2a with t-BuLi) with a series of electro-
philes was investigated for diastereoselectivity of the electro-
phile substitution reaction. We were pleased to discover that
cross-coupling of 1a, b with commercially available trans-2-
phenylvinylboronic acid (Scheme 4). Using the cross-coupling
conditions of 5% Pd(PPh3)4 as catalyst, Na2CO3 as base, and a
4:1 ratio of DME/water as solvent, 2a was isolated in a low
yield of 38%, yet 2b was obtained in a good yield of 82%. The
poor yield for the case of 2a was in part due to competitive
homocoupling of the boronic acid to generate trans,trans-1,4-
diphenylbuta-1,3-diene in significant amounts. We found that
homocoupling of the boronic acid could be reduced, and a higher
67% isolated yield of 2a achieved, by changing the solvent ratio
to 2:1 DME/water.
Regioselectivity of Carbolithiation. Our first aim was to
determine conditions to provide optimal regioselectivity of
alkyllithium addition to starting substrates 2a, b. As a convenient
method of studying the effect of temperature, solvent, and
additive on the carbolithiation regioselectivity, the inter-
mediate lithiated species were treated with methanol and the
crude reaction products were analyzed by 1H NMR and HPLC
(Table 1).
Initial studies of the reaction of t-BuLi with 2a revealed that
the carbolithiation was regioselective in THF across the tem-
perature range from -78 to -25 °C. The optimal temperature
was determined as -25 °C (entry 2, Table 1) with lower
temperatures such as -78 °C resulting in a poor conversion to
product for the same reaction time of 1 h (entry 1). As such all
other reactions were performed at -25 °C. To test the scope
and limitations of the reaction, carbolithiation with five alky-
llithiums of varying reactivity and steric bulk from tertiary to
primary were investigated, in combination with the two ortho-
substituted stilbenes 2a, b. The ortho-substituents chosen were
NBoc, which is a moderately strong directing group, and NBn,
which to the best of our knowledge has not been reported to
have any directing effect.11
We were pleased to discover that, with THF as solvent, a
single regioisomer 5a-f was generated from the reaction across
the range of alkyllithiums: t-Bu, s-Bu, n-Bu, and EtLi (entries
1-7, Table 1). Significantly, in all cases the regioisomer formed
had the alkyl group on the carbon R to the aniline ring, which
would be consistent with the formation of the lithiated inter-
mediates 3a-f in the carbolithiation step. This carbolithiation
selectivity is opposite from that observed for our previously
reported corresponding styrene and â-methylstyrene sub-
strates.8,12 Reaction of methyllithium with 2a resulted only in
the recovery of starting material (entry 8).
(11) Lithiation of N-monoalkylanilines has been achieved by first
generating the N-alkyl-carbamate. The carbamate acts as an intermediate
carbanion stabilizing group which is removed following lithiation. Katritzky,
A. R.; Fan, W-Q.; Akutagawa, K. Tetrahedron 1986, 42, 4027.
(12) During the course of this work we became aware of a similar finding
in which carbolithiation of o-methoxystilbene with n-BuLi in cumene and
(-)-sparteine gave a 94:6 ratio of regioisomers, with the major isomer
having the butyl group substituted at the carbon R to the o-methoxy
functionalized benzene ring. (a) Norsikian, S. Ph.D. Thesis, 1999, Universite´
Pierre et Marie Curie, Paris, France. (b) Prof. I. Marek, Department of
Chemistry, Technion-Israel Institute of Technology, Israel, private com-
munication.
(13) For examples of the use of PMDTA as additive in organolithium
reactions, see: (a) Fukuda, T.; Mine, Y.; Masatomo, I. Tetrahedron 2001,
57, 975. (b) Barluenga, J.; Alonso, J.; Fananas, F. J. J. Am. Chem. Soc.
2003, 125, 2610. (c) Reich, H. J.; Green, D. P.; Medina, M. A.; Goldenberg,
W. S.; Gudmundsson, B. O.; Dykstra, R. R.; Phillips, N. H. J. Am. Chem.
Soc. 1998, 120, 7201. (d) Reich, H. J.; Goldenberg, W. S.; Sanders, A. W.;
Jantzi, K. L.; Tzschucke, C. C. J. Am. Chem. Soc. 2003, 125, 3509.
J. Org. Chem, Vol. 72, No. 25, 2007 9559

Hogan and O’Shea
TABLE 1. Investigation of Regioselectivity of Carbolithiation of 2a, b
entry
sm
temp, °C
R2
solvent
additive
product
ratio 5:6a
yield,b %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2a
2a
2a
2a
2b
2b
2b
2a
2a
2a
2b
2a
2b
2a
2a
2b
2b
2b
-78
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
t-Bu
t-Bu
n-Bu
Et
t-Bu
n-Bu
s-Bu
Me
THF
THF
THF
THF
THF
THF
THF
THF
-
-
-
-
-
-
-
5a/6a
5a/6a
5b/6b
5c/6c
5d/6d
5e/6e
5f/6f
-
99:1
99:1
99:1
99:1
99:1
99:1
99:1
-
20c
87
40d
43e
79
33f
81
g
PMDTA
PMDTA
PMDTA
PMDTA
-
-
n-Bu
Et
THF
THF
5b/6b
5c/6c
5e/6e
5a/6a
5d/6d
5a/6a
5a/6a
-
99:1
99:1
99:1
90:10
60:40
75:25
45:55
-
62h
76i
61k
72
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
THFj
Et2Oj
Et2Oj
Et2Oj
cumenej
Et2Oj
Et2Oj
cumenej
-
30l
72
PMDTA
PMDTA
PMDTA
(-)-sparteine
PMDTA
71
m
-
5d/6d
-
40:60
-
39n
o
-
a Ratios determined by 1H NMR and confirmed by HPLC (220 nm); a ratio of 99:1 indicates that only a single regioisomer was observed. bIsolated
purified yield (combined yield of both isomers where relevant). cRemainder was unreacted starting material. dCompound 11b was also isolated in 45% yield
(see Table 4). eCompound 11c was also isolated in 26% yield. fStarting material recovered in 50% yield. gReaction at 0 °C, 87% starting material recovered.
hCompound 11b was also isolated in 10% yield. iCompound 11c was also isolated in 7% yield. jReaction time 2 h. kStarting material recovered in 29% yield.
lStarting material recovered in 41% yield. mStarting material recovered in 83% yield. nStarting material recovered in 37% yield. oStarting material recovered
in 94% yield.
SCHEME 5. Synthesis of Regioisomers 6a, b, d, and e
2.5 Hz, and the electrophile and t-Bu group anti (Scheme 6,
Table 2, entry 1).
SCHEME 6
X-ray crystal structure analysis of 10a (Figure 1) shows the
two aromatic rings in a gauche conformation in the solid state,
and comparison of the 1H NMR spectra and coupling constants
of 10a with the nondeuterated analogue 5a indicates the
Newman projection shown for the product. The interesting diaryl
gauche conformation has been previously observed for other
1,2-diarylethanes containing ortho-substituted aryl rings.14 The
chemical shift of the t-Bu substituent (1.0 ppm) would indicate
that this conformer also predominates in solution at room
temperature (a deshielding of the t-Bu group by the neighboring
phenyl ring, as reflected by an upfield shifted t-Bu resonance,
is not observed).15
In addition, utilizing the electrophiles CO2 or Bu3SnCl in
reaction with 3a resulted in the formation of compounds 10b
(14) Antolini, L.; Folli, U.; Iarossi, D.; Mucci, A.; Sbardellati, S.; Taddei,
F. J. Chem. Soc., Perkin Trans 2 1995, 1007 and references therein.
(15) Davies, H. M. L.; Ren, P. Tetrahedron Lett. 2001, 42, 3149.
deuteration of 3a with MeOD gave 10a as a single diastereoi-
1
somer by H NMR, with a CHtBu-CHD coupling constant of
9560 J. Org. Chem., Vol. 72, No. 25, 2007

Stilbene Carbolithiation
SCHEME 7. Cyclization of Compound 10b to 3,4-trans
Quinolinone 11a
FIGURE 1. X-ray crystal structure (thermal ellipsoids drawn at the
50% probability level) and Newman projection of 10a.
and 10c as single diastereoisomers as judged by 1H NMR
(Figure 2, Table 2, entries 2, 3). The products 10b and 10c were
characterized with CH-CH coupling constants of 11.6 and 11.5
Hz and upfield shifted t-Bu resonances at 0.6 and 0.7 ppm,
respectively. The variation in the CH-CH coupling constant
and t-Bu chemical shift of 10b and 10c in comparison to those
of the deuterated example 10a can be explained by the favored
conformations of the products. In the case of the 1,1,2,2-tetra-
substituted ethanes 10b and c, the favored conformer placed
the two aryl rings antiperiplanar resulting in an increased
dihedral angle between the alkane protons and a deshielding
effect of the phenyl ring on the t-Bu group accounting for the
chemical shift difference from 10a (Figure 2). As such, the
electrophilic substitution with CD3OD, CO2, and Bu3SnCl all
Confirmation of this assignment was achieved by intramo-
lecular cyclization of compound 10b to generate the quinolinone
11a (Scheme 7, route A). The reaction was performed under
acidic conditions using aqueous HCl to Boc deprotect and effect
the intramolecular cyclization with 11a isolated exclusively as
the 3,4-trans isomer, which is consistent with the formation of
the diastereoisomer as shown in the Newman projection (Figure
2). As interconversion of 3,4-cis and 3,4-trans quinolinone
isomers can occur under acidic conditions (see later), the Boc
deprotection of 10b was also carried out under the neutral
conditions of trimethylsilyl chloride/sodium iodide followed by
intramolecular coupling with 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide (EDCI) which exclusively provided the same
trans isomer of 11a (Scheme 7, route B).16
1
occurred with retention of configuration. The use of H NMR
chemical shifts has been previously reported for conformational
analysis and stereochemical assignment of tetra-substituted
ethanes.15
To further explore the scope of this diastereoselective
transformation the effect of variation in alkyllithium and ortho-
N-substituent on the selectivity obtained was determined (Table
2). Carbolithiation of 2a with the less sterically bulky n-BuLi
and EtLi, followed by deuteration of the lithiated intermediates
3b and 3c, gave the same excellent diastereoselectivity as
observed for the t-Bu example (Table 2, entries 4, 5). The
stereochemistry of deuterated products 10d and 10e was
assigned by comparison with their corresponding protonated
compounds 5b and 5c and was found to be the same as that
observed for 10a. However, when CO2 was employed as the
electrophile in reaction with 3b (from carbolithiation of 2a with
n-BuLi), no diastereoselectivity was observed and the substitu-
tion products were isolated as an equal mixture of diastereoi-
FIGURE 2. Newman projections of 10b, c.
TABLE 2. Scope of Diastereoselective Substitution
1
somers 10f-(i) and 10f-(ii). H NMR analysis showed similar
CH-CH coupling constants of 11.9 and 11.1 Hz for the two
isomers indicating differences in conformations of the two
diastereoisomers. This was supported by a variation in the
chemical shift of the CH3(CH2)2CH2 protons for the two isomers
with 10f-(i) at 1.29-1.06 ppm and 10f-(ii) at 1.89-1.72 ppm.
As such, one of the isomers, 10f-(i), with a coupling constant
of 11.9 Hz and deshielded CH2 signal at 1.29-1.06 ppm, is
assigned the same relative configuration and conformation of
the aryl rings as the t-Bu example 10b, while the other isomer,
10f-(ii), has the opposing relative configuration and a gauche
conformation of the aryl rings. In addition an X-ray crystal
structure of 10f-(ii) was obtained to support this structural
carbolithiated
entry intermediate
R1
R2
E
product yield,a %
drb
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3c
3b
3d
3d
Boc t-Bu
Boc t-Bu CO2H 10b
Boc t-Bu SnBu3 10c
Boc n-Bu
Boc Et
Boc n-Bu CO2H 10f
Bn t-Bu 10g
Bn t-Bu CO2H 10h
D
10a
85c
78
95:5
95:5
95:5
95:5
95:5
50:50
95:5
60:40
34d
61e
75f
56g
70h
64
D
D
10d
10e
D
a Isolated purified yield. bDiastereomeric ratios determined by 1H NMR.
(16) (a) Kato, T.; Marumoto, S.; Sato, T.; Kuwajima, I. Synlett 1990,
671. (b) Mu¨ck-Lichtenfeld, C.; Ahlbrecht, H. Tetrahedron 1996, 52, 10025.
(c) Mu¨ck-Lichtenfeld, C.; Ahlbrecht, H. Tetrahedron 1999, 55, 2609. (d)
For review see; Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. 2002,
41, 716.
c91% deuterium incorporation. dCompound 5a was also recovered in
e
f
61% yield. 94% deuterium incorporation. 71% deuterium incorporation.
gCompound 11b was also isolated in 16% yield. h81% deuterium incorpora-
tion.
(17) (a) Schade, S.; Boche, G. J. Organomet. Chem. 1998, 550, 359.
J. Org. Chem, Vol. 72, No. 25, 2007 9561

Hogan and O’Shea
FIGURE 3. Newman projections of diastereoisomers 10f-(i) and 10f-
(ii) with X-ray crystal structure (thermal ellipsoids drawn at the 50%
probability level) of 10f-(ii).
assignment (Figure 3). Cyclization of a diastereoisomer mixture
of 10f-(i) and -(ii) to the quinolinone 11b by Boc deprotection
with trimethylsilyl chloride/sodium iodide and subsequent amide
coupling with EDCI (as per Scheme 7, route B) gave the product
as the corresponding mixture of 3,4-trans and 3,4-cis isomers
which is consistent with the Newman projections shown in
Figure 3.
FIGURE 4. 1H NMR and gCOSY spectrum of 3a at -15 °C in THF-
d8 (X unknown).
The influence of the N-substituent upon diastereoselectivity
was examined by reaction of the N-benzyl substituted lithiated
intermediate 3d with MeOD and CO2 as electrophiles. Deu-
teration provided the product 10g as a single diastereoisomer
ppm. Examination of the gCOSY spectrum reveals the coupling
between aromatic protons HA, HB, HC, and HD of the ortho-
substituted aryl ring with HD showing an heteronuclear multiple-
bond correlation (HMBC) to CHtBu. The five hydrogens of the
unsubstituted phenyl ring, labeled HE, HF, and HG are assigned
by coupling in the gCOSY spectrum. The informative aromatic
signal shifted upfield to 4.87 ppm represents HG (corresponding
carbon signal at 98.6 ppm) and is indicative of charge delocal-
ization into the ring which is a characteristic of a benzylic
lithium species.17 The inequivalence of the two HF protons
(chemical shifts) suggests that the molecule may be conforma-
tionally fixed with restricted rotation of some of the bonds. The
1H NMR spectrum indicates that the lithiated intermediate 3a
exists predominantly in a stabilized conformation and, while
not conclusive, does support the proposed formation of a hetero-
chelated ring as shown in Figure 5. The Newman projection
1
by H NMR (J ) 2.6 Hz and chemical shift of t-Bu group at
1.04 ppm) with the stereochemistry assigned by analogy to be
the same as that of 10a (Table 2, entry 7). However, reaction
with CO2 resulted in a lower selectivity and isolation of 10h as
a 60:40 mixture of diastereoisomers (entry 8). The CH-CH
coupling constants of the two isomers had similar values of 11.1
and 10.4 Hz, but significant differences in the chemical shifts
of the t-Bu groups were observed at 0.57 and 1.02 ppm for
major and minor isomers, respectively. Comparison of the t-Bu
chemical shift of the major isomer with that of 10b (Figure 2)
indicates that the same diastereoisomer is favored in both cases.
As might be expected, reducing the temperature of the solution
to -78 °C prior to addition of CO2 resulted in an improved
diastereoselectivity of 70:30. Overall these results indicate that
a combination of the t-Bu group and N-Boc ortho-substituent
is optimal for achieving the highest diastereoselectivities with
a broad range of electrophiles.
The variation in diastereoselectivity observed for the two
ortho-substituents (N-Boc and N-Benzyl) prompted an examina-
tion of the lithiated compounds 3a and 3d by NMR. Figure 4
shows the 1H NMR and the gCOSY spectra of 3a in THF-d8 at
-15 °C at the same concentration as the reaction conditions.
The 1H NMR of 3a shows remarkable resolution for a lithiated
species at this temperature indicating a highly conformationally
organized compound, and in fact the spectrum remained virtually
unchanged up to 20 °C (Supporting Information). The key CH
protons, CHPh and CHtBu, appear as sharp doublets at 2.68
and 3.73 ppm, respectively, with a coupling constant of 10.7
Hz. Their corresponding carbon atoms resonate at 61.7 and 45.4
FIGURE 5. Proposed structure (solvent coordinations not shown) and
Newman projection of 3a.
would be analogous to that of the carboxylic acid derivative
10b which would facilitate the intramolecular chelation between
the benzylic lithium and ortho N-Boc substituent. Diastereose-
lectivity could be envisaged by this arrangement due to a locking
of the benzylic lithium in a preferred configuration. As the
recorded coupling constant of 3a is not conclusive for this
9562 J. Org. Chem., Vol. 72, No. 25, 2007

Stilbene Carbolithiation
conformation and assignment of the t-Bu group could not be
achieved due to masking by solvents, alternative dimeric
structures cannot be ruled out at this time.
Synthesis of Quinolinone and Quinoline Ring Systems.
Substituted quinolinones, dihydroquinolines, tetrahydroquino-
lines, and quinolines are common motifs found in natural
products and pharmaceutical agents and as such continue to
attract considerable attention from synthetic and medicinal
chemists.19 Thus, preparation of each structural class (quinoli-
nones, dihydroquinolines, tetrahydroquinolines, and quinolines)
via a common route would be of high synthetic value. As such
the application of our regio- and diastereoselective carbolithia-
tion-electrophile substitution reaction sequence was investigated
for the synthesis of quinolinone and quinoline ring systems.
As previously demonstrated treatment of the acyclic car-
boxylic acids 10d, f with aqueous 12 M HCl, effecting
deprotection of the Boc group and intramolecular cyclization,
allowed the isolation of 3,4-dihydro-1H-quinolin-2-ones 11a and
11b, respectively (Table 3, entries 1 and 2, route A). Compound
11a was isolated exclusively as the 3,4-trans isomer while the
n-alkyl derivative 11b was obtained as a 60:40 mixture of the
3,4-trans/3,4-cis isomers. It was found that generation of the
carboxylic acids 10d, f was not necessary for access to this ring
system, as intramolecular nucleophilic substitution of the
benzylic lithium center of 3a-c at the Boc group was readily
achieved by raising the reaction temperature to either 0 °C or
room temperature for 1 to 6 h (Table 3, entries 3-5, route B).
1
In contrast the H NMR spectrum (THF-d8, -15 °C) of the
corresponding N-benzyl compound 3d is considerably more
complex containing a mixture of broad and well-defined peaks
(Supporting Information). Significantly, the well resolved por-
tions of the spectrum show an alkane CHPh proton of the major
component at 2.67 ppm with a coupling constant of 11.7 Hz,
which is comparable to that observed for 3a. These spectral
characteristics would be consistent with the lower recorded
diastereoselectivity following electrophilic substitution (Table
2, compare entries 2 and 8).
Related diastereoselectivities from electrophilic substitution
of hetero-substituted benzyllithium compounds (generated via
carbolithiation) are known within the literature.3g,17 Selectivity
is attributed to intramolecular heteroatom locked conformations
within five-membered rings from which diastereoselective
substitutions can be achieved. For example carbolithiation of
dimethyl-(3-phenylallyl)amine with n-BuLi provides a heteroa-
tom locked conformation from which highly diastereoselective
substitutions are obtained (Scheme 8).3g
SCHEME 8. Carbolithiation of
Dimethyl-(3-phenylallyl)amine
TABLE 3. Synthesis of 3,4-Dihydro-1H-quinolin-2-ones
Having studied the regio- and diastereoselectivity of the
reaction sequence, attempts to achieve enantioselectivity were
carried out. The chiral diamine (-)-sparteine is a common chiral
additive used in conjunction with alkyllithiums for asymmetric
transformations.18 Unfortunately (-)-sparteine mediated asym-
metric carbolithiations are typically not successful in achieving
high enantioselectivities in the presence of a strongly coordinat-
ing solvent such as THF. As it was determined that THF is
essential for regioselective carbolithiation of our stilbenes, we
anticipated that this would be incompatible with achieving
enantioselective carbolithiations. As expected, the reaction of
n-BuLi with either 2a or 2b in THF with 3 equiv of (-)-
sparteine at -25 °C generated racemic products.
entry sm route temp, °C time, h
R1
product yield,a %
1
2
3
4
5
10d
10f
3a
3b
3c
A
A
B
B
B
rt
rt
rt
0
24
16
6
1
2
t-Bu
n-Bu
t-Bu
n-Bu
Et
11a
11b
11a
11b
11c
76
68
22b
90
84
0
(18) For reviews of (-)-sparteine in organolithium chemistry, see: (a)
Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc.
Chem. Res. 1996, 29, 552. (b) Hoppe, D.; Hense, T. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2282.
a Isolated purified yield. bCompound 5a was also isolated in 51% yield.
(19) For examples, see: quinolin-2-ones: (a) Carling, R. W.; Leeson,
P. D.; Moore, K. W.; Smith, J. D.; Moyes, C. R.; Mawer, I. M.; Thomas,
S.; Chan, T.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, I. M.; Marshall,
G. R.; Tricklebank, M. D.; Saywell, K. L. J. Med. Chem. 1993, 36, 3397.
(b) Rowley, M.; Kulagowski, J. J.; Watt, A. P.; Rathbone, D.; Stevenson,
G. I.; Carling, R. W.; Baker, R.; Marshell, G. R.; Kemp, J. A.; Foster, A.
C.; Grimwood, S.; Hargreaves, R.; Hurley, C.; Saywell, K. L.; Tricklebank,
M. D.; Leeson, P. D. J. Med. Chem. 1997, 40, 4053. (c) Foucaud, B.; Laube,
B.; Schemm, R.; Kreimeyer, A.; Goeldner, M.; Betz, H. J. Biol. Chem.
2003, 278, 24011. Tetrahydroquinolines: (d) Katritzky, A.; Rachwal, S.;
Rachwal, B. Tetrahedron 1996, 52, 15031. Dihydroquinolines: (e) Michne,
W. F.; Guiles, J. W.; Treasurywala, A. D.; Castonguay, L. A.; Weigelt, C.
A.; O’Connor, B.; Volberg, W. A.; Grant, A. M.; Chadwick, C. C.; Krafte,
D. S.; Hill, R. J. J. Med. Chem. 1995, 38, 1877. (f) Gaillard, S.; Papamicael,
C.; Marsais, F.; Dupas, G.; Levacher, V. Synlett 2005, 441. (g) van Straten,
N. C. R.; van Berkel, T. H. J.; Demont, D. R.; Karstens, W.-J. F.; Merkx,
R.; Oosterom, J.; Schulz, J.; van Someren, R. G.; Timmers, C. M.; van
Zandvoort, P. M. J. Med. Chem. 2005, 48, 1697. Quinolines: (h) Michael,
J. P. Nat. Prod. Rep. 2003, 20, 476.
The reactivity of the Boc protecting group has previously
been exploited for the synthesis of fused ring systems,4a,20 and
the intermolecular nucleophilic substitution of the Boc group
of phenylcarbamic acid tert-butyl ester with n-BuLi has been
reported.4b However, to the best of our knowledge this is the
first example of formation of a six-membered ring by nucleo-
philic substitution of a benzylic lithium center on a Boc group.
Following this intramolecular cyclization the 3,4-dihydro-1H-
quinolin-2-one 11a was obtained solely as the 3,4-trans isomer
with compounds 11b, c isolated crude as a 60:40 ratio of 3,4-
trans (J ) 1.2 and 1.8 Hz, respectively)/3,4-cis (J ) 5.3 and
5.4 Hz, respectively). During purification by silica gel chro-
(20) For a review of the synthetic exploitation of the Boc protecting
group, see: Agami, C.; Couty, F. Tetrahedron 2002, 58, 2701.
J. Org. Chem, Vol. 72, No. 25, 2007 9563

Hogan and O’Shea
TABLE 4. Synthesis of 1,2,3,4-Tetra-Substituted
Tetrahydroquinolines, 2,3- and 3,4- Disubstituted and 3-Substituted
Quinolines
TABLE 5. Synthesis of 1,3,4-Tri- and 1,2,3,4-Tetra-Substituted
1,4-Dihydroquinolines
lithiated
intermediate
entry
R1
R2
product
yield,a %
1
2
3
4
3d
3e
3f
t-Bu
n-Bu
s-Bu
t-Bu
H
H
H
14a
14b
14c
14d
82
51
84
50b
3d
COCH3
b
a Isolated purified yield. Acidification with saturated NH4Cl followed
by 5 M HCl for 30 min.
entry
sm
route
product
R1
R2
yield,a %
1
2
3
4
5
6
7
8
9
3a
3b
3c
12a
12b
12c
3a
3b
3c
-
-
-
A
A
A
B
B
B
B
12a
12b
12c
13a
13b
13c
13a
13b
13c
13d
t-Bu
n-Bu
Et
H
n-Bu
Et
H
n-Bu
Et
-
-
-
H
H
H
H
H
H
76
63
71
78
78
61
63
51
36
21
complete conversion from 2,3-trans-3,4-trans-12a to 2,3-cis-
3,4-trans-12a could be achieved by treatment with 2 M HCl in
THF at room temperature for 6 h.
Dehydration of 12a-c by treatment with aqueous HCl (12
M) enabled the preparation of substituted quinoline rings (Table
4, route A, entries 4-6). Compounds 12b and 12c were
dehydrated and in situ oxidized to yield as expected the 3,4-
disubstituted quinolines, 13b and 13c, respectively. Surprisingly,
the t-Bu substituted analogue 12a yielded only the monosub-
stituted 3-phenylquinoline 13a, indicating that the aromatic ring
was generated by loss of the t-Bu group. Even when milder
acidification conditions were employed (5 M HCl in THF), only
13a was isolated with the 3,4-di-substituted quinoline again not
observed. A similar loss of a t-Bu group from dihydroquinolines
and porphyrins has been previously observed.22
Compounds 13a-c could also be prepared directly from
intermediates 3a-c in similar overall yields without the isolation
of 12a-c (Table 4, route B, entries 7-9). The use of 4-meth-
oxybenzonitrile as electrophile in reaction with 3a with subse-
quent acidification demonstrated the use of this approach for
the direct generation of the quinoline 13d with a 2,3-di-substi-
tution pattern following in situ loss of the t-Bu group (entry
10).
Reaction of the N-benzyl substituted di-lithiated intermediates
3d-f with the electrophile DMF or diethoxypropionitrile pro-
vided a direct entry into the 1,4-dihydroquinoline class. Treat-
ment of 3d-f with DMF, followed by a mild aqueous acidifi-
cation, resulted in ring closure and an in situ dehydration to
the 1,4-dihydroquinolines 14a-c without isolation of their tetra-
hydro precursors (Table 5, entries 1-3). A representative exam-
ple of a nitrile electrophile, diethoxypropionitrile, was utilized
in reaction with 3d to generate the C-2 keto substituted 1,2,3,4-
tetra-substituted-1,4,-dihydroquinoline 14d. In this example,
following the reaction cascade sequence to generate the 1,4-
dihydroquinoline ring, a further in situ deprotection of the acetal
protecting group occurred thereby generating the 2-keto sub-
stituent.
10
3a
H
4-MeOC6H4
a Isolated purified yield.
matography, the isomer mixture of 11b and 11c converted to a
90:10 and 80:20 ratio, respectively, in favor of the thermody-
namic trans isomer. The acidity of the C-3 proton adjacent to
the amide bond (CHPh) creates a potential site for deprotonation
thus allowing interconversion of cis and trans isomers.19a,21
Notably, resubjecting the purified trans isomer of 11b to the
reaction conditions ((i) n-BuLi in THF at 0 °C for 1 h, (ii)
MeOH) resulted in the isolation of 11b in a trans/cis isomer
ratio of 30:70.
To further extend the synthetic utility of the carbolithiation
reaction we found that treatment of lithiated intermediates 3a-c
with DMF followed by acidification with aqueous acid provided
a versatile synthesis of the 1,2,3,4-tetrasubstituted-tetrahydro-
quinolines 12a-c in purified yields of 63-76% (Table 4, entries
1-3). Two diastereomeric products were isolated, 2,3-cis-3,4-
trans and 2,3-trans-3,4-trans; however in all cases the alkyl
and phenyl groups were trans to each other with the difference
being in the relative orientation of the phenyl and alcohol groups.
This result is consistent with generation of the aldehyde
intermediate with anti selectivity, which following acidification
and in situ cyclization affords the tetrahydroquinoline as the
3,4-trans isomer. Both isomers of 12a showed a coupling
constant between the C-3 and C-4 protons of 4.0 Hz. The
corresponding coupling constants for the n-Bu derivative are
11.5 and 9.4 Hz for 2,3-cis-3,4-trans-12b and 2,3-trans-3,4-
trans-12b, respectively. The differences in the coupling con-
stants for the t-Bu and n-alkyl derivatives can be explained by
differing conformations of the nitrogen containing ring as
evidenced by X-ray crystal structure (Supporting Information).
The ratio of isomers obtained was dependent on the acidification
temperature, with low temperatures (-78 °C) favoring the 2,3-
trans-3,4-trans isomer and increased temperatures yielding 2,3-
cis-3,4-trans as the major isomer. A single isomer, 2,3-cis-3,4-
trans, of 12a was isolated when the reaction mixture was
brought to room temperature before acidification. Alternatively
Conclusion
In summary, we have shown that a general carbolithiation
of ortho-amino-(E)-stilbenes can be achieved in THF to provide
(21) Kim, Y.; Shin, E.; Beak, P.; Park, Y. S. Synthesis, 2006, 22, 3805.
(22) (a) Anne, A.; Fraoua, S.; Moiroux, J.; Save´ant, J.-M. J. Am. Chem.
Soc. 1996, 118, 3938. (b) Neya, S.; Funasaki, N. Tetrahedron Lett. 2002,
43, 1057.
9564 J. Org. Chem., Vol. 72, No. 25, 2007

Stilbene Carbolithiation
1
also isolated in 10% yield.) H NMR (CDCl3, 400 MHz) δ: 7.45
single regioisomers containing carbon-lithium centers at the â
position from the ortho-substituted aryl ring. Subsequent elec-
trophile substitution reactions show exceptional diastereoselec-
tivity with a range of electrophiles and investigation of the
lithiated intermediates by NMR permitted an insight into the
source of this selectivity. The scope of this regio- and diaste-
reoselective reaction methodology has been demonstrated by
the development of new synthetic routes to substituted quinolin-
2-ones, 1,2,3,4-tetrahydroquinolines, 1,4-dihydroquinolines, and
quinolines from common lithiated reaction intermediates. Uti-
lization of this approach for the generation of other heterocycles
by modification of the reacting pair of ortho-substituent and
electrophile is ongoing.
(bs, 1H), 7.25-7.12 (m, 6H), 6.99-6.96 (m, 2H), 5.56 (bs, 1H),
3.00-2.92 (m, 2H), 2.74-2.68 (m, 1H), 1.80-1.61 (m, 2H), 1.45
(s, 9H), 1.29-1.20 (m, 2H), 1.19-1.12 (m, 2H), 0.82 (t, 3H, J )
7.1 Hz). 13C NMR (CDCl3, 100 MHz) δ: 153.9, 140.7, 136.0,
129.2, 129.2, 128.6, 126.7, 126.5, 126.4, 125.4, 80.1, 43.9, 41.8,
35.2, 30.0, 28.5, 23.0, 14.2. IR (KBr disc): 1450, 1522, 1674, 2860,
2926, 2949, 3026, 3226 cm-1. ES-MS: m/z 376.2 [M + Na]+.
HRMS [M + Na]+: 376.2249, C23H31NO2Na requires 376.2252.
Analysis calcd for C23H31NO2:C, 78.15; H, 8.84; N, 3.96. Found:
C, 78.20; H, 8.94; N, 3.76.
[2-(1-Benzylpropyl)phenyl]carbamic Acid tert-Butyl Ester, 5c.
A solution of 2a (146.9 mg, 0.50 mmol) in THF (6 mL) was cooled
to -25 °C, and PMDTA (0.31 mL, 1.48 mmol) was added. EtLi
(0.92 mL, 1.50 mmol) was added dropwise over 15 min, during
which time a red color developed. The reaction mixture was stirred
at -25 °C for 1 h and treated with methanol (1 mL). The reaction
mixture was allowed to warm to room temperature, and the THF
was removed under reduced pressure. The residue was dissolved
in diethyl ether (10 mL) and washed with hydrochloric acid (1 M,
10 mL). The organic layer was dried over sodium sulfate and
concentrated to dryness. Chromatography on alumina (eluent: 1/1
pentane/diethyl ether) gave the purified product as a colorless solid
(123.7 mg, 76%), mp 70-73 °C. (Note: compound 11c was also
isolated in 7% yield.) 1H NMR (400 MHz) δ: 7.46 (bs, 1H), 7.25-
7.13 (m, 6H), 7.00-6.98 (m, 2H), 5.61 (bs, 1H), 2.97-2.88 (m,
2H), 2.74-2.69 (m, 1H), 1.85-1.74 (m, 1H), 1.73-1.63 (m, 1H),
1.46 (s, 9H), 0.81 (t, 3H, J ) 7.4 Hz). 13C NMR (100 MHz) δ:
153.8, 140.7, 136.1, 129.2, 128.6, 126.7, 126.6, 126.4, 125.4, 80.1,
43.6, 43.5, 28.6, 28.2, 12.3. IR (neat): 1514, 1697, 1730, 2873,
2937, 2966, 3027, 3062, 3394 cm-1. ES-MS: m/z 326.2 [M + H]+.
HRMS [M + H]+: 326.2135, C21H28NO2 requires 326.2120.
Analysis calcd for C21H27NO2: C, 77.50; H, 8.36; N, 4.30. Found:
C, 77.67; H, 8.38; N, 4.21.
Experimental Section
NMR Analysis of 3a. t-BuLi (0.10 mL, 0.17 mmol) was added
to a solution of 2a (17.1 mg, 0.06 mmol) in THF-d8 (0.75 mL) at
-20 °C. The temperature was increased to -15 °C, and the mixture
was transferred to an NMR tube. NMR data were collected at -15
°C on a Varian 500 MHz instrument. 1H NMR (THF-d8, 500 MHz,
-15 °C) δ: 7.22 (dd, 1H, J ) 7.8/2.0 Hz, HD), 6.72-6.65 (m, 2H,
HB and HC), 6.57 (dd, 1H, J ) 7.8/2.0 Hz, HA), 6.15-6.11 (m,
1H, HF), 6.04-6.01 (m, 1H, HF), 5.82-5.79 (m, 2H, HE), 4.88-
4.85 (m, 1H, HG), 3.73 (d, 1H, J ) 10.7 Hz, CHtBu), 2.68 (d, 1H,
J ) 10.7 Hz, CHPh). The signals for the t-Bu groups were not
identified due to the presence of pentane in the sample (from the
t-BuLi). [Note: Spectrum referenced from THF signal at 3.58 ppm.]
13C NMR (THF-d8, 125 MHz, -15 °C) δ: 151.6, 149.1, 143.8,
129.7, 129.7, 128.4, 126.1, 123.6, 121.1, 115.7, 111.2, 109.0, 98.6,
74.8, 61.7, 45.4. The signals corresponding to the two t-Bu groups
were not identified. Variable temperature NMR was performed on
the sample from -15 to 20 °C following which the sample was
treated with methanol and compound 5a was isolated.
Benzyl-[2-(1-benzyl-2,2-dimethylpropyl)phenyl]amine, 5d. A
solution of 2b (144.0 mg, 0.50 mmol) in THF (6 mL) was cooled
to -25 °C. t-BuLi (1.15 mL, 1.51 mmol) was added dropwise over
15 min, during which time a red color developed. The reaction
mixture was stirred at -25 °C for 1 h and treated with methanol
(1 mL). The reaction mixture was allowed to warm to room
temperature, and the THF was removed under reduced pressure.
The residue was dissolved in diethyl ether (10 mL) and washed
with hydrochloric acid (1 M, 10 mL). The organic layers were dried
over sodium sulfate and concentrated to dryness. Silica gel
chromatography (eluent: 9/1 pentane/diethyl ether) gave the product
[2-(1-Benzyl-2,2-dimethylpropyl)phenyl]carbamic Acid tert-
Butyl Ester, 5a. A solution of 2a (247.8 mg, 0.84 mmol) in THF
(10 mL) was cooled to -25 °C. t-BuLi (1.70 mL, 2.53 mmol) was
added dropwise over 15 min, during which time a red color
developed. The reaction mixture was stirred at -25 °C for 1 h and
treated with methanol (1 mL). The reaction mixture was allowed
to warm to room temperature, and the THF was removed under
reduced pressure. The residue was dissolved in dichloromethane
(10 mL) and washed with water (10 mL). The organic layer was
dried over sodium sulfate and concentrated to dryness. Silica gel
chromatography (eluent: 8/2 pentane/diethyl ether) gave the purified
1
as a colorless solid (136.4 mg, 79%), mp 103-106 °C. H NMR
1
(CDCl3, 400 MHz) δ: 7.30-7.28 (m, 1H), 7.26-7.19 (m, 3H),
7.13-7.08 (m, 3H), 7.01-6.97 (m, 2H), 6.96-6.93 (m, 3H), 6.73-
6.69 (m, 1H), 6.41-6.39 (m, 1H), 4.18 (d, 1H, J ) 14.8 Hz), 4.10
(d, 1H, J ) 14.8 Hz), 3.80 (bs, 1H), 3.15 (dd, 1H, J ) 13.1/ 2.6
Hz), 2.94-2.87 (m, 1H), 2.78 (dd, 1H, J ) 11.4/ 2.6 Hz), 1.04 (s,
9H). 13C NMR (CDCl3, 100 MHz) δ: 146.9, 142.2, 139.9, 129.0,
128.7, 128.4, 128.2, 127.5, 127.3, 127.0, 126.8, 125.7, 117.0, 111.6,
50.2, 48.5, 37.4, 35.7, 28.5. IR (KBr disc): 1510, 1603, 2864, 2900,
2956, 3464 cm-1. ES-MS: m/z 344.2 [M + H]+. HRMS [M +
H]+: 344.2378, C25H30N requires 344.2369. Analysis calcd for
C25H29N: C, 87.41; H, 8.51; N, 4.08. Found: C, 87.21; H, 8.38;
N, 3.87.
product as a colorless solid (257.8 mg, 87%), mp 63-64 °C. H
NMR (CDCl3, 300 MHz) δ: 7.40-7.37 (m, 1H), 7.34 (bs, 1H),
7.13-7.04 (m, 5 H), 6.90-6.88 (m, 2H), 5.61 (bs, 1H), 3.18 (dd,
1H, J ) 12.9/2.7 Hz), 2.96-2.80 (m, 2H), 1.43 (s, 9H), 1.00 (s,
9H). 13C NMR (CDCl3, 100 MHz) δ: 153.9, 141.7, 136.8, 128.7,
128.4, 128.2, 126.4, 125.9, 124.7, 80.2, 51.2, 37.2, 35.2, 28.5, 28.5.
IR (KBr disk): 1366, 1690, 2947, 3431 cm-1. ES-MS: m/z 352.2
[M - H]-. HRMS [M - H]-: 352.2290, C23H30NO2 requires
352.2277. Analysis calcd for C23H31NO2: C, 78.15; H, 8.84; N,
3.96. Found: C, 78.41; H, 8.92; N, 3.97.
[2-(1-Benzylpentyl)phenyl]carbamic Acid tert-Butyl Ester, 5b.
A solution of 2a (150.0 mg, 0.51 mmol) in THF (6 mL) was cooled
to -25 °C, and PMDTA was (0.32 mL, 1.53 mmol) added. n-BuLi
(0.60 mL, 1.54 mmol) was added dropwise over 30 min, during
which time a red color developed. The reaction mixture was stirred
for 1 h at -25 °C and treated with methanol (1 mL). The reaction
mixture was allowed to warm to room temperature, and the THF
was removed under reduced pressure. The residue was dissolved
in dichloromethane (10 mL) and washed with hydrochloric acid (1
M, 10 mL). The organic layer was dried over sodium sulfate and
concentrated to dryness. Silica gel chromatography (eluent: 1/1
cyclohexane/diethyl ether) gave the purified product as a colorless
solid (112 mg, 62%), mp 51-54 °C. (Note: compound 11b was
Benzyl-[2-(1-benzylpentyl)phenyl]amine, 5e. A solution of 2b
(143.9 mg, 0.50 mmol) in THF (6 mL) was cooled to -25 °C, and
PMDTA (0.31 mL, 1.48 mmol) was added. n-BuLi (0.61 mL, 1.51
mmol) was added dropwise over 15 min, during which time red
color developed. The reaction mixture was stirred at -25 °C for 2
h and treated with methanol (1 mL). The reaction mixture was
allowed to warm to room temperature, and the THF was removed
under reduced pressure. The residue was dissolved in diethyl ether
(10 mL) and washed with hydrochloric acid (1 M, 10 mL). The
organic layer was dried over sodium sulfate and concentrated to
dryness. Silica gel chromatography (eluent: 99/1 pentane/diethyl
J. Org. Chem, Vol. 72, No. 25, 2007 9565

Hogan and O’Shea
ether) gave the purified product as a colorless oil (105.1 mg, 61%).
(Note: Starting material 2b was also recovered in 29% yield.) H
mmol) was added dropwise over 15 min, during which time
a red color developed. The reaction mixture was stirred at
-25 °C for 1 h and treated with solid carbon dioxide. The re-
action mixture was allowed to warm to room temperature, and
the THF was removed under reduced pressure. The residue was
dissolved in dichloromethane (10 mL) and washed with water
(10 mL). The organic layer was dried over sodium sulfate
and concentrated to dryness. Chromatography on alumina (eluent:
diethyl ether followed by methanol) gave the purified product
as a colorless solid (158.5 mg, 78%), mp 145-147 °C. 95:5 dr.
1H NMR (CDCl3, 400 MHz) δ: 7.45-7.43 (m, 2H), 7.27-7.24
(m, 1H), 7.21-7.13 (m, 4H), 6.96-6.92 (m, 1H), 6.88-6.84
(m, 1H), 3.81 (d, 1H, J ) 11.6 Hz), 3.56 (d, 1H, J ) 11.6
Hz), 3.09 (bs, 1H), 1.57 (s, 9H), 0.60 (s, 9H). 13C NMR
(CDCl3, 100 MHz) δ: 180.3, 155.2, 142.6, 140.0, 136.1,
129.2, 128.3, 127.8, 126.7, 126.1, 125.2, 80.5, 59.3, 50.3,
35.3, 29.8, 28.7. IR (neat): 1367, 1574, 1684, 2932, 2959, 3389
cm-1. ES-MS: m/z 398.2 [M + H]+. HRMS [M + H]+: 398.2332,
C24H32NO4 requires 398.2331.
{2-[2,2-Dimethyl-1-(phenyltributylstannanylmethyl)propyl]-
phenyl}carbamic Acid tert-Butyl Ester, 10c. A solution of 2a
(105.5 mg, 0.36 mmol) in THF (4.3 mL) was cooled to -25 °C.
t-BuLi (0.64 mL, 1.09 mmol) was added dropwise over 15 min,
during which time a red color developed. The reaction mixture was
stirred at -25 °C for 1 h and treated with tributyltin chloride (0.29
mL, 1.07 mmol). Stirring continued at -25 °C for 10 min before
the reaction mixture was allowed to warm to room temperature,
and the THF was removed under reduced pressure. The residue
was dissolved in diethyl ether (10 mL) and washed with water (10
mL). The organic layer was dried over sodium sulfate and
concentrated to dryness. Silica gel chromatography (eluent: 99/1
pentane/diethyl ether) gave the purified product as a colorless oil
(77.6 mg, 34%). 95:5 dr. (Note: Compound 5a was also recovered
in 61% yield.) 1H NMR (CDCl3, 400 MHz) δ: 7.78-7.76 (m, 1H),
7.26-7.14 (m, 6H), 7.10-7.06 (m, 1H), 7.02-6.98 (m, 1H), 6.42
(bs, 1H), 3.49 (d, 1H, J ) 11.5 Hz), 3.35 (d, 1H, J ) 11.5 Hz),
1.56 (s, 9H), 1.12-1.07 (m, 12H), 0.79-0.75 (m, 9H), 0.70 (s,
9H), 0.32-0.19 (m, 6H). 13C NMR (CDCl3, 100 MHz) δ: 153.4,
148.1, 135.5, 128.8, 128.5, 128.5, 127.9, 126.8, 124.1, 123.9, 123.8,
80.7, 49.5, 40.4, 38.6, 29.6, 29.2, 28.7, 27.6, 13.8, 10.5. IR (neat):
1694, 1738, 2871, 2927, 2955, 3061, 3467 cm-1. ES-MS: m/z 644.3
[M + H]+. HRMS [M + H]+: 644.3517, C35H58NO2Sn requires
644.3490.
1
NMR (CDCl3, 400 MHz) δ: 7.32-7.23 (m, 3H), 7.21-7.13 (m,
6H), 7.07-7.03 (m, 1H), 6.99-6.96 (m, 2H), 6.78-6.74 (m, 1H),
6.55-6.53 (m, 1H), 4.19 (d, 1H, J ) 14.1 Hz), 4.07 (d, 1H, J )
14.1 Hz), 3.67 (bs, 1H), 2.92-2.79 (m, 3H), 1.73-1.67 (m, 2H),
1.29-1.17 (m, 4H), 0.82 (t, 3H, J ) 7.0 Hz). 13C NMR (CDCl3,
100 MHz) δ: 146.1, 141.1, 139.8, 129.7, 129.3, 128.8, 128.4, 127.7,
127.3, 126.9, 126.7, 126.2, 117.9, 111.4, 48.8, 43.3, 40.7, 34.8,
30.0, 23.1, 14.3. IR (neat): 1506, 1603, 2856, 2927, 2954, 3028,
3061, 3444 cm-1. ES-MS: m/z 344.2 [M + H]+. HRMS [M +
H]+: 344.2365, C25H30N requires 344.2378. Analysis calcd for
C25H29N: C, 87.41; H, 8.51; N, 4.08. Found: C, 87.66; H, 8.43;
N, 4.15.
Benzyl-[2-(1-benzyl-2-methylbutyl)phenyl]amine, 5f. A solu-
tion of 2b (144.5 mg, 0.51 mmol) in THF (6 mL) was cooled
to -25 °C. s-BuLi (1.09 mL, 1.49 mmol) was added dropwise
over 15 min, during which time red color developed. The reaction
mixture was stirred at -25 °C for 1 h and treated with methanol
(1 mL). The reaction mixture was allowed to warm to room
temperature, and the THF was removed under reduced pressure.
The residue was dissolved in diethyl ether (10 mL) and washed
with hydrochloric acid (1 M, 10 mL). The organic layer was dried
over sodium sulfate and concentrated to dryness. Silica gel
chromatography (eluent: 95/5 pentane/diethyl ether) gave the
purified product as a colorless oil (142.2 mg, 81%). (Note: The
product was analyzed as an equal mixture of diastereoisomers.) 1H
NMR (CDCl3, 400 MHz) δ: 7.29-7.21 (m, 3H), 7.15-7.08 (m,
6H), 7.01-6.98 (m, 1H), 6.93-6.91 (m, 2H), 6.73-6.70 (m, 1H),
6.46-6.44 (m, 1H), 4.16-4.11 (m, 1H), 4.02-3.97 (m, 1H), 3.58
(bs, 1H), 3.18-3.14 (m, 1H), 2.79-2.73 (m, 2H), 1.79-1.75 (m,
1H includes both isomers, 0.5H, isomer 1), 1.43-1.37 (m, 0.5H,
isomer 2), 1.32-1.24 (m, 0.5H, isomer 1), 1.08 (d, 1.5H, J ) 6.7
Hz, isomer 1), 1.09-1.04 (m, 0.5H, isomer 2), 0.96-0.87 (m, 1.5H,
isomer 1), 0.86-0.80 (m, 3H, isomer 2). 13C NMR (CDCl3, 100
MHz) δ: 146.6, 146.4, 141.6, 141.5, 139.9, 139.8, 129.2, 129.1,
128.9, 128.7, 128.3, 128.2, 127.6, 127.5, 127.2, 127.1, 126.7, 125.9,
125.8, 117.6, 111.5, 111.4, 48.7, 39.6, 39.4, 39.2, 38.8, 27.6, 27.3,
17.2, 17.1, 11.7, 11.6. IR (neat): 1452, 1506, 1603, 2873, 2927,
2958, 3026, 3062, 3438 cm-1. ES-MS: m/z 344.2 [M + H]+.
HRMS [M + H]+: 344.2374, C25H30N requires 344.2378. Analysis
calcd for C25H29N: C, 87.41; H, 8.51; N, 4.08. Found: C, 87.46;
H, 8.50; N, 4.10.
[2-(1-Benzyl-2,2-dimethylpropyl)phenyl]carbamic Acid tert-
Butyl Ester-d1, 10a. A solution of 2a (94.1 mg, 0.32 mmol) in
THF (3.8 mL) was cooled to -25 °C. t-BuLi (0.56 mL, 0.95 mmol)
was added dropwise over 15 min, during which time a red color
developed. The reaction mixture was stirred at -25 °C for 1 h and
treated with methanol-d4 (0.7 mL). The reaction mixture was
allowed to warm to room temperature, and the THF was removed
under reduced pressure. The residue was dissolved in dichlo-
romethane (10 mL) and washed with water (10 mL). The organic
layer was dried over sodium sulfate and concentrated to dryness.
Silica gel chromatography (eluent: 8/2 pentane/diethyl ether) gave
the purified product as a colorless solid (96.9 mg, 85%), mp 61-
62 °C. 95:5 dr. (Deuterium incorporation: 91%, determined by 1H
2-(1-Benzylpentyl)phenyl]carbamic Acid tert-Butyl Ester-d1,
10d. A solution of 2a (80.8 mg, 0.27 mmol) in THF (3 mL) was
cooled to -25 °C, and PMDTA (0.17 mL, 0.81 mmol) was added.
n-BuLi (0.58 mL, 0.80 mmol) was added dropwise over 15 min,
during which time a red color developed. The reaction mixture was
stirred for 1 h at -25 °C and treated with methanol-d4 (0.5 mL).
The reaction mixture was allowed to warm to room temperature,
and the THF was removed under reduced pressure. The residue
was dissolved in diethyl ether (10 mL) and washed with hydro-
chloric acid (1 M, 10 mL). The organic layer was dried over sodium
sulfate and concentrated to dryness. Silica gel chromatography
(eluent: 1/1 cyclohexane/diethyl ether) gave the purified product
as a colorless solid (58.7 mg, 61%), mp 49-50 °C. 95:5 dr.
(Deuterium incorporation: 94%, determined by 1H NMR.) 1H NMR
(CDCl3, 400 MHz) δ: 7.44 (bs, 1H), 7.25-7.13 (m, 6H), 6.99-
6.96 (m, 2H), 5.56 (bs, 1H), 3.00-2.95 (m, 1H), 2.92 (d, 1H, J )
5.6 Hz), 1.79-1.63 (m, 2H), 1.45 (s, 9H), 1.30-1.20 (m, 2H),
1.20-1.12 (m, 2H), 0.82 (t, 3H, J ) 7.1 Hz). 13C NMR (CDCl3,
100 MHz) δ: 153.8, 140.7, 136.0, 129.2, 129.2, 128.6, 126.7, 126.5,
126.4, 125.4, 80.1, 43.6 (t, JCD ) 19.1 Hz), 41.7, 35.2, 30.0, 28.5,
23.0, 14.2. IR (neat): 1451, 1514, 1675, 1730, 2859, 2930, 2958,
3402. ES-MS: m/z 355.3 [M + H]+. HRMS [M + H]+: 355.2508,
C23H33NO2 requires 355.2511. Analysis calcd for C23H30DNO2: C,
77.92; H, 9.10; N, 3.95. Found: C, 77.65; H, 8.84; N, 3.84.
[2-(1-Benzylpropyl)phenyl]carbamic Acid tert-Butyl Ester-
d1, 10e. A solution of 2a (98.6 mg, 0.33 mmol) in THF (4 mL)
1
NMR.) H NMR (CDCl3, 400 MHz) δ: 7.41-7.38 (m, 1H), 7.35
(bs, 1H), 7.14-7.05 (m, 5H), 6.90-6.88 (m, 2H), 5.61 (bs, 1H),
3.17 (d, 1H, J ) 2.5 Hz), 2.93 (s, 1H, J ) 2.5 Hz), 1.43 (s, 9H),
1.00 (s, 9H). 13C NMR (CDCl3, 100 MHz) δ: 153.6, 141.6, 136.7,
128.7, 128.4, 128.2, 126.4, 125.9, 124.7, 80.2, 51.1, 36.8 (t, JCD
)
19.5 Hz), 35.2, 28.5, 28.5. IR (neat): 1366, 1450, 1693, 1733, 2871,
2971, 3027, 3062, 3451 cm-1. ES-MS: m/z 355.3 [M + H]+.
HRMS [M + H]+: 355.2502, C23H33NO2 requires 355.2511.
Analysis calcd for C23H30DNO2: C, 77.92; H, 9.10; N, 3.95.
Found: C, 77.63; H, 8.83; N, 3.94.
3-(2-tert-Butoxycarbonylaminophenyl)-4,4-dimethyl-2-phenyl-
pentanoic Acid, 10b. A solution of 2a (150.7 mg, 0.51 mmol)
in THF (6 mL) was cooled to -25 °C. t-BuLi (0.90 mL, 1.53
9566 J. Org. Chem., Vol. 72, No. 25, 2007

Stilbene Carbolithiation
was cooled to -25 °C, and PMDTA (0.21 mL, 1.00 mmol) was
added. EtLi (0.58 mL, 0.99 mmol) was added dropwise over 15
min, during which time a red color developed. The reaction mixture
was stirred at -25 °C for 1 h and treated with methanol-d4 (0.5
mL). The reaction mixture was allowed to warm to room temper-
ature, and the THF was removed under reduced pressure. The
residue was dissolved in diethyl ether (10 mL) and washed with
hydrochloric acid (1 M, 10 mL). The organic layer was dried over
sodium sulfate and concentrated to dryness. Chromatography on
alumina (eluent: 1/1 pentane/diethyl ether) gave the purified product
as a colorless solid (81.3 mg, 75%), mp 68-69 °C. 95:5 dr.
(Deuterium incorporation: 71%, determined by 1H NMR.) 1H NMR
(400 MHz) δ: 7.46 (bs, 1H), 7.25-7.13 (m, 6H), 7.00-6.98 (m,
2H), 5.61 (bs, 1H), 2.94-2.88 (m, 2H), 1.85-1.74 (m, 1H), 1.73-
1.64 (m, 1H), 1.46 (s, 9H), 0.81 (t, 3H, J ) 7.4 Hz). 13C NMR
(100 MHz) δ: 153.8, 140.7, 136.1, 129.2, 128.5, 126.7, 126.5,
126.4, 125.4, 80.1, 43.4, 43.2 (t, JCD ) 19.1 Hz), 28.6, 28.1, 12.3.
IR (neat): 1517, 1699, 1730, 2874, 2931, 2966, 3026, 3335, 3402
cm-1. ES-MS: m/z 325.2 [M - H]-. HRMS [M - H]-: 325.2018,
) 2.6 Hz), 2.78 (d, 1H, J ) 2.6 Hz), 1.04 (s, 9H). 13C NMR (CDCl3,
100 MHz) δ: 146.9, 142.1, 139.9, 128.9, 128.7, 128.3, 128.2, 127.4,
127.3, 127.0, 126.7, 125.7, 117.0, 111.5, 50.2, 48.5, 37.0 (t, JCD
)
19.1 Hz), 35.7, 28.5. IR (neat): 1506, 1602, 2868, 2905, 2958,
3027, 3062, 3458 cm-1. ES-MS: m/z 345.2 [M + H]+. HRMS [M
+ H]+: 345.2427, C25H29DN requires 345.2441. Analysis calcd
for C25H28DN: C, 87.16; H, 8.78; N, 4.07. Found: C, 86.93; H,
8.48; N, 4.08.
3-(2-Benzylaminophenyl)-4,4-dimethyl-2-phenylpentanoic Acid,
10h. A solution of 2b (161.3 mg, 0.56 mmol) in THF (6 mL) was
cooled to -25 °C. t-BuLi (1.12 mL, 1.68 mmol) was added
dropwise over 15 min, during which time a red color developed.
The reaction mixture was stirred at -25 °C for 1 h and treated
with solid carbon dioxide. The reaction mixture was allowed to
warm to room temperature, and the THF was removed under
reduced pressure. The residue was dissolved in dichloromethane
(10 mL) and washed with water (10 mL). The organic layer was
dried over sodium sulfate and concentrated to dryness. Chroma-
tography on alumina (eluent: diethyl ether followed by methanol)
gave the purified product as a colorless oil (138.7 mg, 64%). 60:
C211H25DNO2 requires 325.2026. Analysis calcd for C21H26DNO2:
1
C, 77.26; H, 8.64; N, 4.29. Found: C, 77.15; H, 8.37; N, 4.16.
3-(2-tert-Butoxycarbonylaminophenyl)-2-phenylheptanoic Acid,
10f. A solution of 2a (149.2 mg, 0.51 mmol) in THF (6 mL) was
cooled to -25 °C, and PMDTA (0.32 mL, 1.53 mmol) was added.
n-BuLi (0.71 mL, 1.54 mmol) was added dropwise over 15 min,
during which time a red color developed. The reaction mixture was
stirred for 1 h at -25 °C and treated with solid carbon dioxide.
The reaction mixture was allowed to warm to room temperature,
and the THF was removed under reduced pressure. The residue
was dissolved in dichloromethane (15 mL) and washed with
hydrochloric acid (1 M, 10 mL). The organic layer was dried over
sodium sulfate and concentrated to dryness. The impurities were
removed by tritration with pentane to give the purified product as
a colorless solid (102.8 mg, 56%), mp 149-150 °C. 50:50 dr.
40 dr. H NMR (CDCl3, 500 MHz) δ: 7.36-7.07 (m, 10H syn
isomer, 9H anti isomer), 6.91-6.85 (m, 2H anti isomer), 6.74-
6.67 (m, 1H syn isomer, 1H, anti isomer), 6.63-6.61 (m, 1H syn
isomer), 6.44-6.41 (m, 1H anti isomer), 6.33-6.30 (m, 2H syn
isomer), 6.24-6.21 (m, 1H anti isomer), 4.84 (bs, 1H syn isomer),
4.51 (bs, 1H anti isomer), 4.39 (d, 1H, J ) 15.7 Hz, syn isomer),
4.33 (d, 1H, J ) 15.7 Hz, syn isomer), 4.17 (d, 1H, J ) 13.4 Hz,
anti isomer), 4.05 (d, 1H, J ) 13.4 Hz, anti isomer), 3.88 (d, 1H,
J ) 10.4 Hz, syn isomer), 3.78-3.76 (m, 1H syn isomer, 1H anti
isomer), 3.22 (d, 1H, J ) 11.1 Hz, anti isomer), 1.02 (s, 9H, syn
isomer), 0.57 (s, 9H, anti isomer). 13C NMR (CDCl3, 125 MHz)
δ: 182.7, 181.3, 146.8, 146.3, 142.4, 140.6, 139.6, 131.4, 130.7,
129.2, 128.9, 128.7, 128.5, 127.9, 127.7, 127.6, 127.5, 127.2, 127.0,
126.9, 126.6, 126.0, 125.8, 117.3, 116.0, 112.8, 110.9, 59.7, 57.6,
49.2, 48.9, 48.5, 48.1, 36.2, 35.6, 29.7, 29.0. IR (neat): 1383, 1505,
1581, 1600, 2869, 2954, 3391, 3601 cm-1. ES-MS: m/z 388.2
[M + H]+. HRMS [M + H]+: 388.2283, C26H30NO2 requires
388.2277.
1
(Note: Compound 11b was also isolated in 16% yield.) H NMR
(CD3OD, 500 MHz) δ: 7.48-7.46 (m, 1H, anti isomer), 7.39-
7.36 (m, 2H, anti isomer), 7.32-6.99 (m, 9H syn isomer, 6H anti
isomer), 3.82 (d, 1H, J ) 11.1 Hz, syn isomer), 3.77 (d, 1H, J )
11.9 Hz, anti isomer), 3.72-3.67 (m, 1H, syn isomer), 3.61-3.57
(m, 1H, anti isomer), 1.89-1.84 (m, 1H, syn isomer), 1.76-1.72
(m, 1H, syn isomer), 1.54 (s, 9H, anti isomer), 1.51 (s, 9H, syn
isomer), 1.29-1.06 (m, 4H syn isomer, 6H anti isomer), 0.81 (t,
3H, J ) 7.3 Hz, syn isomer), 0.64 (t, 3H, J ) 7.4 Hz, anti isomer).
[10f-(i) anti isomer; 10f-(ii) syn isomer.] 13C NMR (CD3OD, 100
MHz) δ: 176.4, 176.3, 155.2, 155.1, 138.4, 138.0, 136.3, 136.2,
129.8, 128.6, 128.4, 128.3, 127.9, 127.4, 126.8, 126.4, 126.1, 125.8,
125.3, 80.0, 79.8, 29.0, 27.5, 23.3, 22.6, 21.9, 13.1, 13.0. [Note:
Peaks under solvent signal could not be identified.] IR (neat): 1660,
1712, 2872, 2932, 2952, 3299 cm-1. ES-MS: m/z 396.1 [M - H]-.
HRMS [M + H]+: 398.2330, C24H32NO4 requires 398.2331.
Suitable crystals were grown by the slow evaporation of a solution
of 10f in diethyl ether.
trans-4-tert-Butyl-3-phenyl-3,4-dihydro-1H-quinolin-2-one, 11a.
Method A: Compound 10b (21.5 mg, 0.05 mmol) was dissolved
in ethyl acetate (2.25 mL), and hydrochloric acid (12 M, 1 mL)
was added. The mixture was stirred at room temperature for 24 h.
Sodium hydrogen carbonate (1 M, 20 mL) was added slowly
(caution: CO2 eVolVed), and the aqueous layer was extracted with
ethyl acetate (2 × 10 mL). The combined organic layers were dried
over sodium sulfate, and the solvent was evaporated to dryness.
Silica gel chromatography (eluent: diethyl ether) gave the purified
product (10.6 mg, 76%). Method B: A solution of 10b (52.9 mg,
0.13 mmol), sodium iodide (77.8 mg, 0.52 mmol), and chlorotri-
methylsilane (0.06 mL, 0.47 mmol) in chloroform (3 mL) was
stirred at room temperature for 1 h. The reaction mixture was diluted
with dichloromethane (5 mL) and washed with water (5 mL). The
organic layer was separated, dried over sodium sulfate, and
concentrated to dryness. The crude reaction mixture was dissolved
in dichloromethane (2 mL) and treated with EDCI (27.4 mg, 0.14
mmol) and DMAP (22.2 mg, 0.18 mmol). The reaction was stirred
at room temperature for 3 h. The reaction mixture was diluted with
dichloromethane (5 mL) and washed with water (5 mL). The
organic layer was separated, dried over sodium sulfate, and
concentrated to dryness. Crude 1H NMR showed the product, 11a,
exclusively as the 3,4-trans isomer. After washing with hydrochloric
acid (1 M) 11a was obtained as a pale yellow oil (24.2 mg, 67%).
Method C: A solution of 2a (150.6 mg, 0.51 mmol) in THF (6
mL) was cooled to -25 °C. t-BuLi (1.00 mL, 1.49 mmol) was
added dropwise over 15 min, during which time a red/brown color
developed. The mixture was allowed to warm to room temperature
and stirred for 6 h, by which time the color had faded to orange/
red, and treated with methanol (1 mL). The THF was removed under
reduced pressure. The residue was dissolved in dichloromethane
Benzyl-[2-(1-benzyl-2,2-dimethylpropyl)phenyl]amine-d1, 10g.
A solution of 2b (82.8 mg, 0.29 mmol) in THF (3.6 mL) was cooled
to -25 °C. t-BuLi (0.61 mL, 0.87 mmol) was added dropwise over
15 min, during which time a red/brown color developed. The
reaction mixture was stirred at -25 °C for 1 h and treated with
methanol-d4 (1 mL). The reaction mixture was allowed to warm to
room temperature, and the THF was removed under reduced
pressure. The residue was dissolved in diethyl ether (10 mL) and
washed with hydrochloric acid (1 M, 10 mL). The organic layers
were dried over sodium sulfate and concentrated to dryness. Silica
gel chromatography (eluent: 9/1 pentane/diethyl ether) gave the
purified product as a colorless solid (69.1 mg, 70%), mp 106-108
1
°C. 95:5 dr. (Deuterium incorporation: 81%, determined by H
NMR.) 1H NMR (CDCl3, 400 MHz) δ: 7.31-7.28 (m, 1H), 7.26-
7.20 (m, 3H), 7.14-7.08 (m, 3H), 7.02-6.98 (m, 2H), 6.96-6.94
(m, 3H), 6.73-6.70 (m, 1H), 6.41-6.39 (m, 1H), 4.18 (d, 1H, J )
14.8 Hz), 4.11 (d, 1H, J ) 14.8 Hz), 3.81 (bs, 1H), 3.14 (d, 1H, J
J. Org. Chem, Vol. 72, No. 25, 2007 9567

Hogan and O’Shea
(10 mL) and washed with water (10 mL). The organic layer was
dried over sodium sulfate and concentrated to dryness. Silica gel
chromatography (eluent: 3/1 diethyl ether/pentane) gave the purified
product as a pale yellow oil (31.9 mg, 22%). (Note: Compound
13C NMR (CDCl3, 100 MHz) δ: 171.6, 138.7, 135.9, 129.5, 128.9,
127.9, 127.6, 127.4, 126.1, 123.6, 115.8, 52.1, 51.0 (cis isomer),
46.0, 44.5 (cis isomer), 28.8, 20.9 (cis isomer), 11.9 (cis isomer),
11.6. IR (KBr disc): 1491, 1593, 1678, 2872, 2918, 2966, 3061,
3215 cm-1. ES-MS: m/z 252.1 [M + H]+. HRMS [M + H]+:
252.1396, C17H18NO requires 252.1388.
1
5a was also isolated in 51% yield.) H NMR (CDCl3, 500 MHz)
δ: 8.57 (bs, 1H), 7.26-7.10 (m, 6H), 7.09-7.07 (m, 1H), 7.00-
6.94 (m, 1H), 6.84-6.80 (m, 1H), 4.11 (s, 1H), 2.77 (s, 1H), 1.02
(s, 9H). 13C NMR (CDCl3, 75 MHz) δ: 172.6, 139.7, 136.9, 132.2,
128.7, 127.9, 127.1, 127.0, 122.7, 122.5, 115.6, 55.4, 48.2, 35.6,
27.8. IR (KBr disc): 1493, 1593, 1672, 2868, 2914, 2956, 3406
cm-1. ES-MS: m/z 280.2 [M + H]+. HRMS [M + H]+: 280.1688,
C19H22NO requires 280.1701.
4-tert-Butyl-2-hydroxy-3-phenyl-3,4-dihydro-2H-quinoline-1-
carboxylic Acid tert-Butyl Ester, 12a. A solution of 2a (409.1
mg, 1.38 mmol) in THF (18 mL) was cooled to -25 °C. t-BuLi
(2.75 mL, 3.47 mmol) was added dropwise over 15 min, during
which time a brown color developed. The reaction mixture was
stirred at -25 °C for 1 h and DMF (1.0 mL, 12.9 mmol) was added.
Stirring continued at -25 °C for 15 min. Hydrochloric acid (1M,
10 mL) was added, and the reaction mixture was warmed to room
temperature over 10 min. The THF was removed under reduced
pressure, and the aqueous layer was extracted with diethyl ether (2
× 10 mL). The combined organic layers were dried over sodium
sulfate and concentrated to dryness. Silica gel chromatography
(eluent: 95/5 cyclohexane/diethyl ether) gave the purified product
as two diastereoisomers. 2,3-cis-3,4-trans-12a was isolated as a
colorless solid (258.1 mg, 49%), mp 154-155 °C; 2,3-trans-3,4-
trans-12a was isolated as a colorless solid (141.0 mg, 27%), mp
71-72 °C. (Combined yield of both isomers 76%.) (Note: The
ratio of isomers obtained was dependent on the acidification
temperature, with lower temperatures giving higher yields of 2,3-
trans-3,4-trans-12a and increased temperatures resulting in im-
proved yields of 2,3-cis-3,4-trans-12a.) 2,3-cis-3,4-trans-12a: 1H
NMR (CDCl3, 300 MHz) δ: 7.43 (d, 1H, J ) 8.1 Hz), 7.28-7.16
(m, 6H), 7.12-7.07 (m, 2H), 6.00-5.97 (m, 1H), 3.79-3.76 (m,
1H), 2.83 (d, 1H, J ) 4.0 Hz), 2.36 (d, 1H, J ) 4.7 Hz), 1.52 (s,
9H), 0.88 (s, 9H). 13C NMR (CDCl3, 125 MHz) δ: 152.9, 142.0,
136.9, 132.0, 131.1, 129.2, 128.3, 126.7, 126.6, 125.9, 123.8, 81.3,
79.2, 53.8, 49.9, 36.3, 28.4, 27.8. IR (KBr disk): 3465, 2963, 1671
cm-1. ES-MS m/z 380.2 [M - H]-. HRMS [M - H]-: 380.2212,
C24H30NO3 requires 380.2226. Analysis calcd for C24H31NO3: C,
75.56; H, 8.19; N, 3.67. Found: C, 75.27; H, 7.94; N, 3.65. 2,3-
trans-3,4-trans-12a: 1H NMR (CDCl3, 300 MHz) δ: 7.34-7.12
(m, 9H), 6.38 (d, 1H, J ) 9.2 Hz), 4.72 (t, 1H, J ) 8.9 Hz), 3.50
(dd, 1H, J ) 8.9/4.0 Hz), 2.88 (d, 1H, J ) 4.0 Hz), 1.48 (s, 9H),
0.89 (s, 9H). 13C NMR (CDCl3, 75 MHz) δ: 154.9, 144.7, 140.7,
132.4, 131.3, 128.5, 128.3, 126.5, 126.5, 125.8, 124.7, 88.9, 82.0,
trans/cis-4-Butyl-3-phenyl-3,4-dihydro-1H-quinolin-2-one, 11b.
Method A: Compound 10f (56.9 mg, 0.14 mmol) was dissolved
in ethyl acetate (4 mL), and hydrochloric acid (12 M, 2 mL) was
added. The mixture was stirred at room temperature for 24 h.
Sodium hydrogen carbonate (1 M, 20 mL) was added slowly
(caution: CO2 eVolVed), and the aqueous layer was extracted with
ethyl acetate (2 × 10 mL). The combined organic layers were dried
over sodium sulfate, and the solvent was removed under reduced
pressure to give the pure product as a pale yellow solid (26.4 mg,
68%). Method B: A solution of 2a (100.9 mg, 0.34 mmol) in THF
(5 mL) was cooled to -25 °C. n-BuLi (0.51 mL, 1.02 mmol) was
added dropwise over 15 min, during which time a red color
developed. The mixture was allowed to warm to 0 °C and stirred
for 1 h by which time the color had faded to pale yellow, and treated
with methanol (1 mL). The THF was removed under reduced
pressure. The residue was dissolved in dichloromethane (10 mL)
and washed with water (10 mL). The organic layer was dried over
sodium sulfate and concentrated to dryness. Silica gel chromatog-
raphy (eluent: diethyl ether) gave the purified product as a pale
yellow solid (86.1 mg, 90%), mp 78-82 °C. [The product was
1
analyzed as a 90:10 mixture of trans/cis-11b.] H NMR (CDCl3,
500 MHz) δ: 8.32 (bs, 1H, trans isomer), 8.13 (bs, 1H, cis isomer),
7.19-7.14 (m, 6H, trans isomer), 7.10-7.07 (m, 1H, trans isomer),
7.05-7.02 (m, 1H, cis isomer), 7.00-6.97 (m, 1H, trans isomer),
6.83-6.81 (m, 1H, cis isomer), 6.78-6.77 (m, 1H, trans isomer),
4.03 (d, 1H, J ) 5.3 Hz, cis isomer), 3.84 (d, 1H, J ) 1.2 Hz,
trans isomer), 3.10-3.06 (m, 2H, both isomers), 1.76-1.68 (m,
1H, trans isomer), 1.68-1.60 (m, 1H, trans isomer), 1.45-1.38
(m, 1H, trans isomer), 1.35-1.28 (m, 3H, trans isomer), 0.88 (t,
3H, J ) 7.1 Hz, trans isomer), 0.79 (t, 3H, J ) 7.1 Hz, cis isomer).
13C NMR (CDCl3, 150 MHz) of trans isomer δ: 171.3, 138.4,
135.7, 129.2, 128.7, 127.6, 127.3, 127.2, 126.4, 123.4, 115.5, 52.1,
44.3, 35.5, 29.0, 22.6, 13.9. IR (KBr disc): 1489, 1597, 1676, 2856,
2920, 2947, 3246 cm-1. ES-MS: m/z 280.2 [M + H]+. HRMS [M
+ H]+: 280.1702, C19H22NO requires 280.1701.
57.6, 51.9, 36.8, 28.4, 27.8. IR (KBr disk): 3446, 2963, 1675 cm-1
.
ES-MS m/z 382.2 [M + H]+. HRMS [M + H]+: 382.2364, C24H32-
NO3 requires 382.2382. Analysis calcd for C24H31NO3: C, 75.56;
H, 8.19; N, 3.67. Found: C, 75.26; H, 7.99; N, 3.69.
4-Butyl-2-hydroxy-3-phenyl-3,4-dihydro-2H-quinoline-1-car-
boxylic Acid tert-Butyl Ester, 12b. A solution of 2a (398.6 mg,
1.35 mmol) in THF (15 mL) was cooled to -25 °C. PMDTA (0.85
mL, 4.06 mmol) was added followed by n-BuLi (2.40 mL, 4.10
mmol), added dropwise over 15 min. The reaction mixture was
stirred at -25 °C for 1 h and DMF (1.05 mL, 13.55 mmol) was
added. Stirring continued at -25 °C for 15 min. Hydrochloric acid
(1 M, 10 mL) was added, and the reaction mixture warmed to room
temperature over 10 min. The THF was removed under reduced
pressure, and the aqueous layer was extracted with diethyl ether (2
× 10 mL). The combined organic layers were dried over sodium
sulfate and concentrated to dryness. Silica gel chromatography
(eluent: 9/1 cyclohexane/diethyl ether) gave the purified product
as a colorless solid (326.9 mg, 63%), mp 95-103 °C. (The product
was isolated and characterized as a 1:1 mixture of two diastereoi-
somers 2,3-cis-3,4-trans-12b and 2,3-trans-3,4-trans-12b.) 1H NMR
(CDCl3, 500 MHz) δ: 7.63 (d, 1H, J ) 8.0 Hz, 2,3-trans-3,4-
trans isomer), 7.45-7.44 (m, 1H, 2,3-cis-3,4-trans isomer), 7.36-
7.17 (m, 7H 2,3-cis-3,4-trans isomer, 7H 2,3-trans-3,4-trans
isomer), 7.14-7.11 (m, 1H, 2,3-cis-3,4-trans isomer), 7.07-7.04
(m, 1H, 2,3-trans-3,4-trans isomer), 5.98-5.97 (m, 1H, 2,3-trans-
3,4-trans isomer), 5.77 (dd, 1H, J ) 7.6/3.6 Hz, 2,3-cis-3,4-trans
isomer), 3.42 (bs, 1H, 2,3-cis-3,4-trans isomer), 3.37-3.34 (m, 1H,
2,3-trans-3,4-trans isomer), 3.23 (dd, 1H, J ) 9.4/3.6 Hz, 2,3-trans-
trans/cis-4-Ethyl-3-phenyl-3,4-dihydro-1H-quinolin-2-one, 11c.
A solution of 2a (148.7 mg, 0.50 mmol) in THF (6 mL) was cooled
to -25 °C. EtLi (0.94 mL, 1.50 mmol) was added dropwise over
15 min, during which time a red color developed. The reaction
mixture was warmed to 0 °C and stirred for 2 h, by which time the
color had faded to pale orange, and treated with methanol (1 mL).
The THF was removed under reduced pressure. The residue was
dissolved in diethyl ether (10 mL) and washed with hydrochloric
acid (1 M, 10 mL). The organic layer was dried over sodium sulfate
and concentrated to dryness. Silica gel chromatography (eluent:
diethyl ether) gave the product as a pale yellow oil (106.1 mg,
84%). (The product was analyzed as an 80:20 mixture of trans:
cis-11c; 13C NMR signals quoted refer to the trans isomer unless
1
otherwise stated.) H NMR (CDCl3, 400 MHz) δ: 8.51 (bs, 1H,
trans isomer), 8.28 (bs, 1H, cis isomer), 7.33-7.25 (m, 1H, trans
isomer), 7.22-7.15 (m, 5H, trans isomer), 7.11-7.09 (m, 1H, trans
isomer), 7.06-7.02 (m, 1H, cis isomer), 7.00-6.97 (m, 1H, trans
isomer), 6.84-6.82 (m, 1H, cis isomer), 6.80-6.78 (m, 1H, trans
isomer), 4.06 (d, 1H, J ) 5.4 Hz, cis isomer), 3.85 (d, 1H, J ) 1.8
Hz, trans isomer), 3.03-2.95 (m, 2H, both isomers), 1.84-1.72
(m, 1H, trans isomer), 1.71-1.60 (m, 1H, trans isomer), 0.98 (t,
3H, J ) 7.4 Hz, trans isomer), 0.84 (t, 3H, J ) 7.4 Hz, cis isomer).
9568 J. Org. Chem., Vol. 72, No. 25, 2007

Stilbene Carbolithiation
3,4-trans isomer), 2.85-2.81 (m, 1H, 2,3-cis-3,4-trans isomer), 2.71
(d, 1H, J ) 4.4 Hz, 2,3-trans-3,4-trans isomer), 2.67 (dd, 1H, J )
11.5/7.6 Hz, 2,3-cis-3,4-trans isomer), 1.81-1.79 (m, 1H, 2,3-trans-
3,4-trans isomer), 1.59-1.54 (m, 2H 2,3-cis-3,4-trans isomer, 1H
2,3-trans-3,4-trans isomer), 1.54 (s, 9H, 2,3-trans-3,4-trans isomer),
1.51 (s, 9H, 2,3-cis-3,4-trans isomer), 1.43-1.08 (m, 4H 2,3-cis-
3,4-trans isomer, 4H 2,3-trans-3,4-trans isomer), 0.79 (t, 3H, J )
7.2 Hz, 2,3-cis-3,4-trans isomer), 0.77 (t, 3H, J ) 7.2 Hz, 2,3-
trans-3,4-trans isomer). 13C NMR (CDCl3, 125 MHz) of both
isomers δ: 154.5, 153.1, 141.3, 140.5, 136.7, 135.8, 134.9, 131.9,
129.3, 128.7, 128.6, 128.3, 127.9, 127.8, 127.0, 126.1, 126.0, 124.7,
124.6, 124.4, 124.2, 123.9, 85.3, 81.9, 81.8, 79.4, 54.8, 49.8, 39.0,
38.6, 32.4, 28.6, 28.5, 28.4, 27.7, 27.3, 22.9, 22.8, 13.9, 13.9. IR
(KBr disc): 1676, 2929, 2960, 3464 cm-1. ES-MS m/z 404.2 [M
+ Na]+. HRMS [M + Na]+: 404.2220, C24H31NO3Na requires
404.2202. Analysis calcd for C24H31NO3: C, 75.56; H, 8.19; N,
3.67. Found: C, 75.47; H, 8.09; N, 3.72. Suitable crystals were
grown by the slow evaporation of a solution of 12b in dichlo-
romethane.
developed. The reaction mixture was stirred at -25 °C for 1 h and
DMF (0.39 mL, 5.03 mmol) was added. Stirring continued at -25
°C for 15 min. Hydrochloric acid (1 M, 1 mL) was added, and the
reaction mixture warmed to room temperature. The THF was
removed under reduced pressure, and the aqueous layer was
extracted with diethyl ether (2 × 10 mL). The residue was dissolved
in ethyl acetate (6 mL), treated with hydrochloric acid (12 M, 3
mL), and stirred at room temperature for 16 h. Sodium hydrogen
carbonate (1 M, 30 mL) was added slowly (caution: CO2 eVolVed),
and the aqueous layer was extracted with ethyl acetate (2 × 10
mL). The combined organic layers were dried over sodium sulfate
and concentrated to dryness. Chromatography on alumina (eluent:
9/1 to 1/1 pentane/diethyl ether) gave the purified product as a
1
yellow oil (64.9 mg, 63%). H NMR (CDCl3, 300 MHz) δ: 9.19
(d, 1H, J ) 2.3 Hz), 8.31 (d, 1H, J ) 2.3 Hz), 8.15 (d, 1H, J ) 8.4
Hz), 7.90-7.87 (m, 1H, J ) 8.1 Hz), 7.76-7.71 (m, 3H), 7.70-
7.51 (m, 3H), 7.46-7.42 (m, 1H). 13C NMR (CDCl3, 125 MHz)
δ: 150.2, 147.6, 138.2, 134.1, 133.5, 129.6, 129.5, 129.4, 128.4,
128.3, 128.2, 127.7, 127.2. IR (neat): 1493, 2868, 2972, 3032, 3059
cm-1. ES-MS m/z 206.1 [M + H]+. HRMS [M + H]+: 206.0974,
C15H12N requires 206.0970.
4-Ethyl-2-hydroxy-3-phenyl-3,4-dihydro-2H-quinoline-1-car-
boxylic Acid tert-Butyl Ester, 12c. A solution of 2a (148.3 mg,
0.50 mmol) in THF (6 mL) was cooled to -25 °C. PMDTA (0.31
mL, 1.48 mmol) was added followed by EtLi (1.00 mL, 1.50 mmol),
added dropwise over 15 min. The reaction mixture was stirred at
-25 °C for 1 h and DMF (0.39 mL, 5.03 mmol) was added. Stirring
continued at -25 °C for 15 min. Hydrochloric acid (1 M, 10 mL)
was added, and the reaction mixture warmed to room temperature
over 10 min. The THF was removed under reduced pressure, and
the aqueous layer was extracted with diethyl ether (2 × 10 mL).
The combined organic layers were dried over sodium sulfate and
concentrated to dryness. Silica gel chromatography (eluent: 9/1
pentane/diethyl ether) gave the purified product as two diastereoi-
somers. 2,3-cis-3,4-trans-12c was isolated as a colorless solid (67.4
mg, 54%), mp 117-118 °C; 2,3-trans-3,4-trans-12c was isolated
as a colorless solid (29.3 mg, 17%), mp 119-121 °C. (Combined
yield of both isomers 71%.) 2,3-cis-3,4-trans-12c: 1H NMR
(CDCl3, 500 MHz) δ: 7.45 (d, 1H, J ) 8.0 Hz), 7.37-7.33 (m,
2H), 7.29-7.21 (m, 5H), 7.14-7.11 (m, 1H), 5.77 (dd, 1H, J )
7.6/3.6 Hz), 3.44 (bs, 1H), 2.85-2.80 (m, 1H), 2.70 (dd, 1H, J )
11.7/7.6 Hz), 1.75-1.67 (m, 1H), 1.63-1.54 (m, 1H), 1.52 (s, 9H),
0.91 (t, 3H, J ) 7.4 Hz). 13C NMR (CDCl3, 125 MHz) δ: 154.5,
141.2, 136.7, 134.4, 128.7, 128.7, 127.1, 126.0, 124.7, 124.6, 124.2,
85.3, 82.0, 54.3, 39.6, 28.4, 20.6, 10.5. IR (KBr disc): 1344, 1496,
1678, 2933, 2978, 3064 cm-1. ES-MS m/z 352.2 [M - H]-. HRMS
[M - H]-: 352.1897, C22H26NO3 requires 352.1913. 2,3-trans-
3,4-trans 12c: 1H NMR (CDCl3, 500 MHz) δ: 7.65 (d, 1H, J )
8.3 Hz), 7.37-7.29 (m, 4H), 7.27-7.17 (m, 3H), 7.08-7.05 (m,
1H), 5.99-5.98 (m, 1H), 3.41-3.40 (m, 1H), 3.21 (dd, 1H, J )
10.0/ 3.1 Hz), 2.64 (d, 1H, J ) 4.3 Hz), 1.93-1.86 (m, 1H), 1.62-
1.56 (m, 1H), 1.54 (s, 9H), 0.73 (t, 3H, J ) 7.4 Hz). 13C NMR
(CDCl3, 125 MHz) δ: 153.0, 140.5, 136.0, 131.2, 129.3, 128.3,
127.8, 127.0, 126.1, 124.3, 123.9, 81.8, 79.4, 48.9, 39.3, 28.4, 24.8,
4-Butyl-3-phenylquinoline, 13b. Method A: A solution of 12b
(51.4 mg, 0.13 mmol) in ethyl acetate (5 mL) and hydrochloric
acid (12 M, 2 mL) was stirred at room temperature for 16 h. Sodium
hydrogen carbonate (1 M, 20 mL) was added slowly (caution: CO2
eVolVed), and the aqueous layer was extracted with ethyl acetate
(2 × 10 mL). The combined organic layers were dried over sodium
sulfate and concentrated to give the pure product as a colorless oil
(26.6 mg, 78%). Method B: A solution of 2a (146.6 mg, 0.50
mmol) in THF (6 mL) and PMDTA (0.31 mL, 1.48 mmol) was
cooled to -25 °C. n-BuLi (0.85 mL, 1.50 mmol) was added
dropwise over 15 min, during which time a red color developed.
The reaction mixture was stirred at -25 °C for 1 h and DMF (0.39
mL, 5.03 mmol) was added. Stirring continued at -25 °C for 15
min. Hydrochloric acid (1 M, 1 mL) was added, and the reaction
mixture warmed to room temperature. The THF was removed under
reduced pressure, and the aqueous layer was extracted with diethyl
ether (2 × 10 mL). The residue was dissolved in ethyl acetate (6
mL), treated with hydrochloric acid (12 M, 3 mL) and stirred at
room temperature for 16 h. Sodium hydrogen carbonate (1 M, 30
mL) was added slowly (caution: CO2 eVolVed), and the aqueous
layer was extracted with ethyl acetate (2 × 10 mL). The combined
organic layers were dried over sodium sulfate and concentrated to
dryness. Chromatography on alumina (eluent: 3/1 to 1/1 pentane/
diethyl ether) gave the purified product as a colorless oil (66.8 mg,
51%). 1H NMR (CDCl3, 300 MHz) δ: 8.79-8.76 (m, 1H), 8.16-
8.10 (m, 2H), 7.74-7.70 (m, 1H), 7.64-7.58 (m, 1H), 7.52-7.45
(m, 3H), 7.43-7.35 (m, 2H), 3.06-2.99 (m, 2H), 1.66-1.60 (m,
2H), 1.38-1.28 (m, 2H), 0.83 (t, 3H, J ) 7.5 Hz). 13C NMR
(CDCl3, 75 MHz) δ: 151.7, 147.6, 145.6, 139.0, 134.3, 130.3,
129.7, 128.8, 128.4, 127.6, 127.1, 126.7, 124.3, 33.4, 28.6, 23.2,
13.6. IR (neat): 1499, 2870, 2928, 2957, 3061 cm-1. ES-MS m/z
262.2 [M + H]+. HRMS [M + H]+: 262.1607, C19H20N requires
262.1596.
4-Ethyl-3-phenylquinoline, 13c. Method A: A solution of 12c
(12.4 mg, 0.04 mmol) in ethyl acetate (1 mL) and hydrochloric
acid (12 M, 0.4 mL) was stirred at room temperature for 16 h.
Sodium hydrogen carbonate (1 M, 10 mL) was added slowly
(caution: CO2 eVolVed), and the aqueous layer was extracted with
ethyl acetate (2 × 10 mL). The combined organic layers were dried
over sodium sulfate and concentrated to give the pure product as a
colorless solid (5.0 mg, 61%), mp 87-88 °C. Method B: A solution
of 2a (146.4 mg, 0.50 mmol) in THF (6 mL) and PMDTA (0.31
mL, 1.48 mmol) was cooled to -25 °C. EtLi (0.94 mL, 1.50 mmol)
was added dropwise over 15 min, during which time a red color
developed. The reaction mixture was stirred at -25 °C for 1 h and
DMF (0.39 mL, 5.03 mmol) was added. Stirring continued at -25
°C for 15 min. Hydrochloric acid (1 M, 1 mL) was added, and the
reaction mixture warmed to room temperature. The THF was
9.2. IR (KBr disc): 1369, 1495, 1666, 2924, 2981, 3032 cm-1
.
ES-MS m/z 352.2 [M - H]-. HRMS [M - H]-: 352.1906, C22H26-
NO3 requires 352.1913. Suitable crystals were grown by the slow
evaporation of a solution of 2,3-cis-3,4-trans-12c in ethanol.
3-Phenylquinoline,23 13a. Method A: A solution of 12a (50.4
mg, 0.13 mmol) in ethyl acetate (9 mL) and hydrochloric acid (12
M, 4 mL) was stirred at room temperature for 5 h. Sodium hydrogen
carbonate (1 M, 60 mL) was added slowly (caution: CO2 eVolVed),
and the aqueous layer extracted with ethyl acetate (2 × 10 mL).
The combined organic layers were dried over sodium sulfate and
concentrated to give the pure product as a yellow oil (20.7 mg,
78%). Method B: A solution of 2a (146.2 mg, 0.50 mmol) in THF
(6 mL) was cooled to -25 °C. t-BuLi (0.85 mL, 1.50 mmol) was
added dropwise over 15 min, during which time a brown color
(23) Mongin, F.; Mojovic, L.; Guillamet, B.; Trecourt, F.; Quegiuner,
G. J. Org. Chem. 2002, 67, 8991.
J. Org. Chem, Vol. 72, No. 25, 2007 9569

Hogan and O’Shea
removed under reduced pressure, and the aqueous layer was
extracted with diethyl ether (2 × 10 mL). The residue was dissolved
in ethyl acetate (6 mL), treated with hydrochloric acid (12 M, 3
mL), and stirred at room temperature for 16 h. Sodium hydrogen
carbonate (1 M, 30 mL) was added slowly (caution: CO2 eVolVed),
and the aqueous layer was extracted with ethyl acetate (2 × 10
mL). The combined organic layers were dried over sodium sulfate
and concentrated to dryness. Chromatography on alumina (eluent:
3/1 pentane/diethyl ether) gave the purified product as a colorless
oil (41.5 mg, 36%). 1H NMR (CDCl3, 400 MHz) δ: 8.76 (s, 1H),
8.16-8.11 (m, 2H), 7.74-7.70 (m, 1H), 7.63-7.59 (m, 1H), 7.52-
7.44 (m, 3H), 7.40-7.38 (m, 2H), 3.05 (q, 2H, J ) 7.6 Hz), 1.27
(t, 3H, J ) 7.6 Hz). 13C NMR (CDCl3, 100 MHz) δ: 151.9, 147.9,
146.8, 139.1, 134.3, 130.5, 129.8, 129.0, 128.7, 127.8, 127.0, 126.9,
124.5, 22.3, 15.7. IR (neat): 1616, 2927, 2958, 3232 cm-1. ES-
MS m/z 234.2 [M + H]+. HRMS [M + H]+: 234.1289, C17H16N
requires 234.1283.
to -25 °C, and PMDTA (0.31 mL, 1.48 mmol) was added. n-BuLi
(0.60 mL, 1.51 mmol) was added dropwise over 15 min, during
which time a red color developed. The reaction mixture was
stirred at -25 °C for 2 h and DMF (0.39 mL, 5.03 mmol) was
added. Stirring continued at -25 °C for 30 min. Hydro-
chloric acid (1 M, 10 mL) was added, and the reaction mixture
was allowed to warm to room temperature over 10 min. The THF
was removed under reduced pressure, and the aqueous layer
was extracted with diethyl ether (2 × 10 mL). The combined
organic layers were dried over sodium sulfate and concentrated
to dryness. Chromatography on alumina (eluent: 95/5 pentane/
diethyl ether) gave the purified product as a colorless oil (90.0 mg,
51%). (Note: Starting material was also recovered in 24% yield.)
1H NMR (CDCl3, 400 MHz) δ: 7.44-7.42 (m, 2H), 7.32-
7.22 (m, 7H), 7.15-7.12 (m, 2H), 7.06-7.02 (m, 1H), 6.92-
6.88 (m, 1H), 6.72 (s, 1H), 6.68-6.66 (m, 1H), 4.88 (d, 1H, J )
16.9 Hz), 4.77 (d, 1H, J ) 16.9 Hz), 4.10-4.06 (m, 1H), 1.61-
1.57 (m, 2H), 1.29-1.16 (m, 4H), 0.82-0.78 (m, 3H). 13C NMR
(CDCl3, 100 MHz) δ: 139.9, 139.6, 138.1, 130.1, 129.5, 129.0,
128.8, 127.4, 126.7, 126.7, 125.9, 125.3, 124.2, 121.1, 112.6, 111.9,
54.5, 39.9, 37.3, 28.1, 23.1, 14.4. IR (neat): 1597, 1743, 2868,
2927, 2954, 3028, 3061 cm-1. ES-MS m/z 352.2 [M + H]+.
HRMS [M + H]+: 352.2059, C26H26N requires 352.2065. The
nominal and accurate masses measured are of the oxidized quinoline
cation.
1-Benzyl-4-sec-butyl-3-phenyl-1,4-dihydroquinoline, 14c. A
solution of 2b (142.1 mg, 0.50 mmol) in THF (6 mL) was cooled
to -25 °C. s-BuLi (1.09 mL, 1.49 mmol) was added dropwise over
15 min, during which time a red color developed. The reaction
mixture was stirred at -25 °C for 1 h and DMF (0.39 mL, 5.03
mmol) was added. Stirring continued at -25 °C for 30 min.
Hydrochloric acid (1 M, 10 mL) was added, and the reaction
mixture was allowed to warm to room temperature over 15 min.
The THF was removed under reduced pressure, and the aqueous
layer was extracted with diethyl ether (2 × 10 mL). The combined
organic layers were dried over sodium sulfate and concentrated to
dryness. Chromatography on alumina (eluent: 99/1 pentane/diethyl
ether) gave the purified product as a colorless oil (147.9 mg, 84%).
(The product was analyzed as an equal mixture of diastereoisomers.)
1H NMR (CDCl3, 400 MHz) δ: 7.45-7.41 (m, 2H), 7.34-7.22
(m, 7H), 7.15-7.06 (m, 2H), 7.05-7.02 (m, 1H), 6.92-6.87 (m,
1H), 6.77 (s, 0.5H), 6.72 (s, 0.5H), 6.67-6.65 (m, 1H), 4.84-4.73
(m, 2H), 4.16 (d, 0.5H, J ) 3.1 Hz), 4.11 (d, 0.5H, J ) 3.4 Hz),
1.62-1.59 (m, 1H), 1.58-1.50 (m, 0.5H), 1.49-1.43 (m, 0.5H),
1.22-1.17 (m, 0.5H), 0.94-0.86 (m, 3H), 0.74-0.67 (m, 3.5H).
13C NMR (CDCl3, 125 MHz) δ: 141.3, 140.9, 138.1, 138.0, 131.3,
130.8, 130.3, 130.2, 129.2, 129.2, 129.0, 129.0, 128.8, 128.7, 128.7,
127.6, 127.4, 126.9, 126.8, 126.7, 125.3, 125.3, 124.8, 124.5, 124.4,
122.9, 120.9, 120.8, 112.3, 112.1, 111.9, 111.8, 54.7, 54.6, 45.8,
44.4, 43.6, 41.9, 27.0, 25.7, 16.4, 15.1, 12.5, 12.5. IR (neat): 1489,
1597, 1647, 2872, 2931, 2956, 3030, 3062 cm-1. ES-MS m/z 352.2
[M + H]+. HRMS [M + H]+: 352.2054, C26H26N requires
352.2065. The nominal and accurate masses measured are of the
oxidized quinoline cation.
2-(4-Methoxyphenyl)-3-phenylquinoline, 13d.
A solution
of 2a (145.1 mg, 0.49 mmol) in THF (6 mL) was cooled to
-25 °C. t-BuLi (0.88 mL, 1.48 mmol) was added dropwise over
15 min, during which time a brown color developed. The re-
action mixture was stirred at -25 °C for 1 h and 4-methoxy-
benzonitrile (0.60 mL, 4.91 mmol) was added. Stirring con-
tinued at -25 °C for 15 min. Hydrochloric acid (1M, 10 mL) was
added, and the reaction mixture warmed to room temperature
over 10 min. The THF was removed under reduced pressure, and
the residue was dissolved in ethyl acetate (5 mL) and treated with
hydrochloric acid (12 M, 2 mL). The solution was stirred at room
temperature for 16 h. Sodium hydrogen carbonate (1 M, 20 mL)
was added slowly (caution: CO2 eVolVed), and the aqueous
layer was extracted with ethyl acetate (2 × 10 mL). The combined
organic layers were dried over sodium sulfate and concentrated to
dryness. Chromatography on alumina (eluent: 95/5 pentane/diethyl
ether) gave the purified product as a colorless oil (32.1 mg, 21%).
1H NMR (CDCl3, 400 MHz) δ: 8.22-8.18 (m, 2H), 7.88-7.86
(m, 1H), 7.76-7.72 (m, 1H), 7.59-7.55 (m, 1H), 7.33-7.25
(m, 5H), 7.20-7.16 (m, 1H), 7.04-7.00 (m, 2H), 6.85-6.82 (m,
1H), 3.65 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ: 159.4, 158.4,
147.5, 141.9, 140.3, 137.8, 134.8, 129.9, 129.8, 129.7, 129.2, 128.5,
127.7, 127.5, 127.4, 127.0, 122.9, 115.2, 114.8, 55.3. IR (neat):
1600, 1728, 2858, 2926, 2954, 3024, 3060 cm-1. ES-MS m/z 312.1
[M + H]+. HRMS [M + H]+: 312.1390, C22H18NO requires
312.1388.
1-Benzyl-4-tert-butyl-3-phenyl-1,4-dihydroquinoline, 14a.
A solution of 2b (144.8 mg, 0.51 mmol) in THF (6 mL) was
cooled to -25 °C. t-BuLi (0.79 mL, 1.52 mmol) was added
dropwise over 15 min, during which time a red color developed.
The reaction mixture was stirred at -25 °C for 1 h and DMF (0.40
mL, 5.16 mmol) was added. Stirring continued at -25 °C for 30
min. Hydrochloric acid (1 M, 10 mL) was added, and the reaction
mixture was allowed to warm to room temperature over 10 min.
The THF was removed under reduced pressure, and the aqueous
layer was extracted with diethyl ether (2 × 10 mL). The combined
organic layers were dried over sodium sulfate and concentrated to
dryness. Chromatography on alumina (eluent: 99/1 pentane/diethyl
ether) gave the purified product as a colorless solid (145.6 mg,
82%), mp 98-101 °C. 1H NMR (CDCl3, 400 MHz) δ: 7.44-7.41
(m, 2H), 7.31-7.22 (m, 7H), 7.18-7.16 (m, 1H), 7.10-7.06 (m,
2H), 6.95-6.92 (m, 1H), 6.73-6.71 (m, 1H), 6.68 (s, 1H), 4.81
(d, 1H, J ) 16.8 Hz), 4.75 (d, 1H, J ) 16.8 Hz), 3.91 (s, 1H), 0.75
(s, 9H). 13C NMR (CDCl3, 100 MHz) δ: 143.9, 142.0, 137.9, 132.4,
131.4, 128.9, 128.8, 127.4, 126.9, 126.7, 125.1, 125.0, 123.4, 120.4,
113.2, 111.8, 54.5, 50.9, 39.7, 28.0. IR (KBr disc): 1487, 1595,
1633, 2864, 2899, 2949, 3022, 3381, 3460 cm-1. ES-MS m/z 206.2
base peak [M + H - (C11H16)]+ (loss of t-Bu and Bn groups).
Analysis calcd for C26H27N: C, 88.34; H, 7.70; N, 3.96. Found:
C, 88.04; H, 7.85; N, 3.91.
1-(1-Benzyl-4-tert-butyl-3-phenyl-1,4-dihydroquinolin-2-yl)
ethanone, 14d. A solution of 2b (143.1 mg, 0.50 mmol) in
THF (6 mL) was cooled to -25 °C. t-BuLi (0.85 mL, 1.50
mmol) was added dropwise over 15 min, during which time
a red color developed. The reaction mixture was stirred at -25 °C
for 1 h and 2,2-diethoxypropionitrile (0.78 mL, 5.00 mmol) was
added. Stirring continued at -25 °C for 2 h. Saturated ammonium
chloride solution (10 mL) was added, and the reaction mixture was
allowed to warm to room temperature over 10 min. The organic
layer was separated; hydrochloric acid (5 M, 10 mL) was added,
and the mixture stirred at room temperature for 30 min. The reaction
mixture was diluted with diethyl ether (10 mL), and the organic
layer was separated, dried over sodium sulfate, and concentrated
to dryness. Chromatography on alumina (eluent: 9/1 pentane/diethyl
ether) gave the purified product as a yellow solid (98.7 mg, 50%),
1-Benzyl-4-butyl-3-phenyl-1,4-dihydroquinoline, 14b.
A
solution of 2b (143.1 mg, 0.50 mmol) in THF (6 mL) was cooled
9570 J. Org. Chem., Vol. 72, No. 25, 2007

Stilbene Carbolithiation
1
mp 123-125 °C. H NMR (CDCl3, 400 MHz) δ: 7.32-7.24 (m,
Level Institutions administered by the HEA. Thanks to Dr. D.
Rai of the CSCB Mass Spectrometry Centre and Dr. H. Mueller-
Bunz of the UCD Crystallographic Centre for analysis.
6H), 7.25-7.14 (m, 6H), 7.04-6.99 (m, 1H), 6.94-6.91 (m, 1H),
5.10 (d, 1H, J ) 17.4 Hz), 4.82 (d, 1H, J ) 17.4 Hz), 3.65 (s, 1H),
1.42 (s, 3H), 0.73 (s, 9H). 13C NMR (CDCl3, 100 MHz) δ: 204.6,
142.8, 142.4, 139.6, 138.5, 130.7, 129.4, 128.7, 128.7, 127.3, 127.0,
126.6, 124.7, 120.9, 114.3, 113.5, 54.9, 50.3, 39.1, 31.7, 27.9. IR
(neat): 1489, 1697, 2951, 3029, 3062 cm-1. ES-MS: m/z 396.2
[M + H]+. HRMS [M + H]+: 396.2338, C28H29NO requires
396.2327. Analysis calcd for C28H29NO: C, 85.02; H, 7.39; N, 3.54.
Found: C, 84.73; H, 8.53; N, 3.45.
Supporting Information Available: Experimental procedures
for preparation of compounds 2a, 2b, 6a, 6b, 6d, 6e, 8a, 8b, 9a,
and 9b. 1H and 13C NMR spectra of all compounds. Variable
temperature 1H NMR of 3a from -15 to 20 °C and 1H NMR of 3d
at -15 °C. X-ray crystallographic data of 10a, 10f, 10g, 12b, and
12c (CCDC 656706-656710) as CIF files. This material is free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. A.-M.L.H. thanks the Irish Research
Council for Science, Engineering and Technology for student-
ship. Funding support from the Program for Research in Third-
JO7017679
J. Org. Chem, Vol. 72, No. 25, 2007 9571