Electronic and steric control in regioselective addition reactions of organolithium reagents with enaldimines

Article abstract of DOI:10.1021/jo015766b

A reaction mode of imines derived from naphthalene-1-carbaldehyde and acyclic α,β-unsaturated aldehydes with organolitium reagents was dependent on the characteristic nature of a substituent on the imine nitrogen atom. An imine having an electron-withdrawing aryl group on the nirtogen atom behaves as a 1,2-directing imine toward organolithium reagents. In contrast, an imine bearing an alkyl or a bulky aryl group favors 1,4-addition of organolithium reagents. Electronic and steric tuning of a substituent on the imine nitrogen atom for a reaction mode was rationalized on the basis of molecular orbital calculations.

Full text of DOI:10.1021/jo015766b

J . Org. Chem. 2001, 66, 7051-7054
7051
Electr on ic a n d Ster ic Con tr ol in Regioselective Ad d ition
Rea ction s of Or ga n olith iu m Rea gen ts w ith En a ld im in es†
Kiyoshi Tomioka,* Yoshito Shioya, Yasuo Nagaoka, and Ken-ichi Yamada
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Sakyo-ku, Kyoto 606-8501, J apan
tomioka@pharm.kyoto-u.ac.jp
Received May 17, 2001
A reaction mode of imines derived from naphthalene-1-carbaldehyde and acyclic R,â-unsaturated
aldehydes with organolitium reagents was dependent on the characteristic nature of a substituent
on the imine nitrogen atom. An imine having an electron-withdrawing aryl group on the nirtogen
atom behaves as a 1,2-directing imine toward organolithium reagents. In contrast, an imine bearing
an alkyl or a bulky aryl group favors 1,4-addition of organolithium reagents. Electronic and steric
tuning of a substituent on the imine nitrogen atom for a reaction mode was rationalized on the
basis of molecular orbital calculations.
Sch em e 1. 1,2- a n d 1,4-Selective Ad d ition
Rea ction s
In tr od u ction
A conjugate addition reaction of organometallic re-
agents with R,â-unsaturated carbonyl compounds and
their equivalents is a powerful and fundamental method
in forming a carbon-carbon bond.1 These substrates are,
however, ambident in their nature and undergo 1,4- and
1,2-additions. An oxazoline trick has been demonstrated
by Meyers as a milestone toward a modern carbanion and
heterocyclic chemistry applicable to a 1,4-selective asym-
metric conjugate addition reaction of organolithium
reagents.2 It was further and considerable progress to
extend this trick to a 1,4-selective addition reaction of
organolithium reagents with a naphthalene nucleus.3,4
Steric modification in a carbonyl moiety has been proven
as an alternative methodology effective for a 1,4-selective
conjugate addition of organolithium reagents.5 Pioneering
works by Seebach6 and Cooke7 have demonstrated that
sterically hindered R,â-unsaturated trityl ketones and
BHA esters serve as the Michael acceptors, affording the
corresponding 1,4-selective addition products.8 The BHA
method was also extended to a 1,4-selective addition
reaction of a naphthalenecarboxylate.9,10 Steric masking
and nucleophilic activation of naphthalenyl ketone by an
external aluminum-based bulky Lewis acid has been
impressive advance of 1,4- and 1,6-selective addition
reactions.11 An enaldimine 4 derived from an enal and
an amine has been also developed as a good Michael
acceptor equivalent to the corresponding R,â-unsaturated
aldehyde (Scheme 1).12 The imine method was also
extended to a 1,4-selective reaction of imines 1 bearing
a naphthalene nucleus.13 The 1,2- and 1,4-selectivity has
been shown to be dependent on a type of organometallic
reagents14 and the ion-pair structure of organometallic
reagents.15 It was interesting for us to learn that the 1,2-
† We dedicate this work to Prof. A. I. Meyers for his accomplishment
of oxazoline- and imine-based methodology on the occasion of his
retirement.
(1) For reviews, see: (a) Tomioka, K.; Nagaoka, Y. In Comprehensive
Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999; Vol. III, Chapter 31. (b) Tomioka, K. In
Modern Carbonyl Chemistry; Otera, J ., Ed.; Wiley-VCH: Weinheim,
2000; Chapter 12. (c) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
8033-8061.
(2) For reviews on oxazolines chemistry, see: (a) Gant, T. G.; Meyers,
A. I. Tetrahedron 1994, 50, 2297-2360. (b) Meyers, A. I. J . Heterocycl.
Chem. 1998, 35, 991-1002.
(3) For the use of 1,3-oxazoline as an activating group for naphtha-
lene additions, see: (a) Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner,
B. A.; Laucher, D. J . Am. Chem. Soc. 1988, 110, 4611-4624. (b)
Rawson, D. J .; Meyers, A. I. J . Org. Chem. 1991, 56, 2292-2294. (c)
Kolotuchin, S. V.; Meyers, A. I. J . Org. Chem. 2000, 65, 3018-3026.
(4) Interesting 1,6-addition of lithium amides has been reported. (a)
Shimano, M.; Meyers, A. I. J . Org. Chem. 1996, 61, 5714-5715. (b)
Shimano, M.; Matsuo, A. Tetrahedron 1998, 54, 4787-4810.
(5) (a) Tomioka, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1990,
31, 1739-1740. (b) Tomioka, K.; Shindo, M.; Koga, K. J . Org. Chem.
1990, 55, 2276-2277.
(9) Shindo, M.; Koga, K.; Asano, Y.; Tomioka, K. Tetrahedron 1999,
55, 4955-4968.
(10) Application of the bulky ester in the nucleophilic aromatic
substitution reaction has been extensively studied by Miyano. A
review: Hattori, T.; Miyano, S. J . Synth. Org. Chem. 1997, 55, 121-
131. Leading reference: Hattori, T.; Komuro, Y.; Hayashizaka, N.;
Takahashi, H.; Miyano, S. Enantiomer 1997, 2, 203-213.
(11) Maruoka, K.; Ito, M.; Yamamoto, H. J . Am. Chem. Soc. 1995,
117, 9091-9092.
(12) Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron
1981, 37, 3951-3956.
(13) For the use of oxazolidine/imine system as an activating group
for naphthalene additions, see: (a) Mokhallatie, M. K.; Muralidha-
ran, K. R.; Pridgen, L. N. Tetrahedron Lett. 1994, 35, 4267-4270. (b)
Meyers, A. I.; Brown, J . D.; Laucher, D. Tetrahedron Lett. 1987, 28,
5283-5286. (c) Tomioka, K.; Shindo, M.; Koga, K. J . Am. Chem. Soc.
1989, 111, 8266-8268.
(6) Seebach, D.; Ertas, M.; Locher, R.; Schweizer, W. B. Helv. Chim.
Acta 1985, 68, 264-282.
(7) Cooke, M. P., J r. J . Org. Chem. 1986, 51, 1637-1638.
(8) Xu, F.; Tillyer, R. D.; Tschaen, D. M.; Grabowski, E. J . J .; Reider,
P. J . Tetrahedron: Asymmetry 1998, 9, 1651-1654.
(14) (a) Pridgen, L. N.; Mokhallatie, M. K.; Wu, M.-J . J . Org. Chem.
1992, 57, 1237-1241. (b) Meyers, A. I.; Brown, J . D.; Laucher, D.
Tetrahedron Lett. 1987, 28, 5279-5282.
10.1021/jo015766b CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/21/2001

7052 J . Org. Chem., Vol. 66, No. 21, 2001
Tomioka et al.
Ta ble 1. 1,2- a n d 1,4-Selective Ad d ition Rea ction s w ith
Im in e 1
and 1,4-regioselectivity was dependent on the nature of
an imine.16 An imine prepared by condensation of an aryl
aldehyde with an amine is a typical example to realize
amine dependency of the reaction pattern. Thus, the
imine 1 derived from naphthalene-1-carbaldehyde and
an alkylamine such as cyclohexylamine undergoes 1,4-
selective conjugate-type addition with organolithium
reagents giving 2-alkylated 1,2-dihydronaphthalenecar-
baldehydes, after hydrolysis of 3. In contrast, the imine
1 derived from an arylamine such as 4-methoxyaniline
undergoes 1,2-selective addition reaction with organo-
lithium giving the corresponding alkylated amine 2. It
was also more interesting to learn that 1-substituted
2-naphthaleneimine was a good 1,4-selective acceptor
giving a nucleophilic aromatic substitution product in a
high yield.17 Similar reaction pattern dependency has
been observed in the reaction of an imine 4 derived from
R,â-unsaturated aldehyde, affording 1,4- and 1,2-selective
products 6 and 5.
Selectivity control in a bond-forming reaction is the
focus in the recent synthetic chemistry. Electronic and
steric factors are the elements for regioselectivity control.
We have already described that the degree of a LUMO
coefficient is an essential factor in the reaction of orga-
nolithium reagents with naphthalenecarbaldehyde imi-
nes.18,19 The current report summarizes our efforts to
address the relationship between 1,2- and 1,4-regiose-
lectivity and imine variables. One goal of the studies was
to define the essential electronic and structural features
of the R,â-unsaturated imines required for high 1,2- and
1,4-regioselectivity.
run
1
R
Nu T/°C time/h 2/% 7/%
x:y
1
2
3
4
5
6
7
8
9
a
a
b
b
c
c
d
d
e
e
c-Hex
Bu -78
Ph -45
Bu -78
Ph -45
3
3
3
3
1
1
1
1
1
1
<1
0
5
83
57
64
76
6
4
6
1
0
74:9
24:33
64:0
39:37
6:0
4:0
4:2
0:1
0:0
c-Hex
n-Bu
n-Bu
0
4-MeOC6H4 Bu -78
79
90
83
99
89
99
4-MeOC6H4 Ph -78
Ph
Ph
Bu -78
Ph -78
Bu -78
Ph -78
4-CF3C6H4
4-CF3C6H4
10
0
0:0
In contrast, arylimines 1c,d ,e (R ) 4-MeOC6H4, Ph,
4-CF3C6H4) were 1,2-selective acceptors giving the cor-
responding amines 2 as major products (Table 1, runs
5-10). 4-Methoxyphenyl and phenylimines 1c,d (R )
4-MeOC6H4, Ph) were not perfect 1,2-selective acceptors,
giving a small amount of 1,4-products 7, while 4-trifluo-
romethylphenylimine 1e (R ) 4-CF3C6H4) was a perfect
acceptor giving 1,2-addition amine 2 without production
of 1,4-adduct 7 (Table 1, runs 9 and 10). Electronic control
is apparently a factor determining 1,2- and 1,4-selectivity.
The most electron-withdrawing group, CF3, favors a 1,2-
addition. An electron-donating MeO group is still in favor
of 1,2-addition, though the relative ratio of 1,4-addition
is increased.
Resu lts a n d Discu ssion
Alkylimines 1a ,b of naphthalene-1-carbaldehyde were
1,4-selective acceptors predominantly affording the cor-
responding alcohols 7 (Table 1, run 1-4). Treatment of
cyclohexylimine 1a (R ) c-Hex) with butyllithium in THF
at -78 °C for 3 h and acidic hydrolysis followed by sodium
borohydride reduction of the aldehyde provided 2-buty-
lated alcohols 7 as a mixture of dihydro and aromatized
naphthalenes 7x,y in 83% yield (Table 1, run 1). A trace
amount of the 1,2-addition product (<1%) was observed
Understanding the factors governing regioselectivity
is a long-standing challenge21,22 and essential for further
development of more effective asymmetric reactions of
the enimines. We carried out molecular orbital calcula-
tions of 1.23
1
by H NMR in basic extracts from the reaction mixture.
The reaction with phenyllithium at -45 °C was more
selective, giving 2-phenylated naphthalenes 7 in 57%
yield without production of the 1,2-addition product
(Table 1, run 2). In this reaction, no 1,2-addition product
could be observed in basic extracts. Butylimine 1b (R )
Bu) was a less bulky 1,4-selective acceptor predominantly
giving 7 (Table 1, runs 3 and 4). It is reasonably
understandable that phenyllithium is a softer nucleo-
phile20 and reacts with 1a ,b in a 1,4-conjugate addition
pattern and that butyllithium is a harder nucleophile and
gave a small amount of 1,2-addition amines 2 as the side
product.
Structures 1 were fully optimized with MOPAC (PM3,
precise mode). MOPAC calculations were shown to be
comparable with the ab initio (HF/STO-3G) method
under the Cs constraint.24 Calculation of methylimine
1a b (R ) Me) as a model of cyclohexyl and butylimines
(20) Ho, T.-L. Hard and Soft Acids and Bases Principle in Organic
Chemistry; Academic Press: New York, 1977.
(21) Similar regioselectivity has been reported in the reaction of
ketimines without clear explanation. Keuk, B. P.; Mauze, B.; Miginiac,
L. Synthesis 1977, 638.
(22) For theoretical treatment for regioselectivity of electrophilic
addition to an ambident ketone or aldehyde, see: Lefour, J .-M.; Loupy,
A. Tetrahedron 1978, 34, 2597-2605 and references therein.
(23) Calculations were carried out with an IBM RS6000 using the
GAUSSIAN 92 program: Frisch, M. J .; Trucks, G. W.; Head-Gordon,
M.; Gill, P. M. W.; Wong, M. W.; Foresman, J . B.; J ohnson, B. G.;
Schlegel, H. B.; Robb, M. A.; Replogle, E. S.; Gomperts, R.; Andres, J .
L.; Raghavachari, K.; Binkley, J . S.; Gonzalez, C.; Martin, R. L.; Fox,
D. J .; Defrees, D. J .; Baker, J .; Stewart, J . J .; Pople, J . A. GAUSSIAN
92, Revision B; Gaussian Inc.: Pittsburgh, PA, 1992. PM3 calculations
were also carried out using MOPAC.
(24) Results for the s-trans isomers are nearly the same as s-cis,
and the difference in the method of calculation (HF/3-21G, HF/STO-
3G, and PM3) has little influence on a qualitative conclusion. Tomioka,
K.; Okamoto, T.; Kanai, M.; Yamataka, H. Tetrahedron Lett. 1994, 35,
1891-1892.
(15) (a) Cohen, T.; Abraham, W. D.; Myers, M. J . Am. Chem. Soc.
1987, 109, 7923-7924. (b) Reich, H. J .; Sikorski, W. H. J . Org. Chem.
1999, 64, 14-15.
(16) Inoue, I.; Shindo, M.; Koga, K.; Tomioka, K. Tetrahedron 1994,
50, 4429-4438.
(17) Shindo, M.; Koga, K.; Tomioka, K. J . Am. Chem. Soc. 1992, 114,
4, 8732-8733.
(18) Tomioka, K.; Okamoto, T.; Kanai, M.; Yamataka, H. Tetrahe-
dron Lett. 1994, 35, 1891-1892.
(19) For the use of a carboxylate as an activating group for
naphthalene additions, see: Plunain, B.; Mortier, J .; Vaultier, J . J .
Org. Chem. 1996, 61, 5206-5207.

Addition Reactions of Organolithium Reagents
J . Org. Chem., Vol. 66, No. 21, 2001 7053
Ta ble 2. LUMO Coefficien ts a n d Regioselectivity of 1
Ta ble 4. LUMO Coefficien ts a n d Regioselectivity of 4
|C2 LUMO| - 1,2/1,4
|C2 LUMO| - 1,2/1,4
R1
4
Φ/deg
C2
C4
|C4 LUMO| (PhLi)a
R
1
C2
C4
|C4 LUMO|
(PhLi)a
Me
Ph
a b
cd
+0.472 -0.560
+0.462 -0.377
-0.088
+0.085
+0.051
-0.070
0:100
100:0
0
Me
a b +0.212 -0.325
-0.113
-0.002
+0.006
+0.084
0:100
23:1
99:1
44.7 +0.454 -0.403
4-MeOC6H4
Ph
4-CF3C6H4
c
d
e
+0.320 -0.322
+0.330 -0.324
+0.382 -0.298
2,6-(i-Pr)2- ee 91
C6H3
+0.486 -0.556
0:100
100:0
a
a
These ratios correspond to the ratios of 5 to 8 in Table 3.
These ratios correspond to the ratios of 2 to 7 in Table 1.
in a quantitative yield (Table 3, run 4). Reaction with
harder butyllithium was, however, not so selective, giving
8 in 69% yield along with a 1,2-addition product 5 (R1 )
c-Hex, R2 ) Ph, Nu ) Bu) in 25% yield (Table 3, run 3).
In contrast, phenylimines 4c,d (R1 ) Ph) reacted in a
1,2-selective mode except for the reaction of 4c with softer
phenyllithium (Table 3, run 6), affording the correspond-
ing amines 5c,d as a sole isomer (Table 3, runs 5, 7, and
8). It was impressive that arylimine 4e (R1 ) 2,6-
diisopropylphenyl), having two bulky isopropyl groups at
the 2,6-positions of a phenyl ring, directed a 1,4-selective
addition whether butyl- or phenyllithium was used (Table
3, runs 10 and 11). It was noteworthy that even meth-
yllithium selectively reacted in a 1,4-manner to provide
the corresponding adduct 8 (Table 3, run 9).
Cooperative 1,4-selectivity by cyclohexylimine and the
characteristic nature of softer phenyllithium favors 1,4-
addition, and competition with harder butyllithium al-
lows for a partial contamination of the 1,2-addition
pathway. It is also responsible for 1,2-addition that 1,4-
addition results in loss of resonance stabilizing energy
of cinnamaldehyde-derived imine 4b. The relative mag-
nitude of LUMO coefficients of these acyclic imines was
also useful in understanding reaction selectivity (Table
4). Calculations were carried out with imines of acrolein
4. Methylimine 4a b (R1 ) Me), as a model of cyclohexy-
limines 4a ,b, indicated that the C4 position has a
coefficient larger than C2, suggesting 1,4-selective reac-
tion as has been observed. Phenylimine 4cd , as a model
of 4c,d , is quite interesting in that rotation of an N-Ph
σ bond affects the relative magnitude of coefficients at
C2 and C4. Thus, the coefficient at C2 is larger than that
at C4 when the dihedral angle of C2-N-CdC(Ph) is 0
degree (Φ ) 0). This conformation is the most stable
structure of 4cd . Imaginative rotation of the N-Ph bond
from 0 to 44.7° dihedral angle increases the C4 coefficient
and decreases the C2 coefficient. Rotation of the N-Ph
bond brings about the slippage from the conjugate plane
of CdN and Ph (R1), corresponding to replacement of the
aryl group of the imine part by an alkyl group. The
dihedral angle of the most stable structure of 2,6-
diisopropylphenylimine 4ee (R1 ) 2,6-diisopropylphenyl)
is 91°, almost perpendicular due to the steric bulk of
isopropyl group, and conjugation of the imine CdN
double bond with the aryl group is completely lost (Figure
1). The absolute value of the calculated LUMO coefficient
at C4 is larger than that at C2, which indicates the 1,4-
selective reaction. Steric hindrance by the isopropyl group
and the frontier molecular orbital cooperate in directing
the 1,4-selective addition reaction.
Ta ble 3. 1,2- a n d 1,4-Selective Ad d ition Rea ction s w ith
Im in e 4
run
4
R1
R2
Nu
time/h
5/% 8/%
1
2
3
4
5
6
7
8
9
a
a
b
b
c
c
d
d
e
e
e
c-Hex
c-Hex
c-Hex
c-Hex
Ph
Ph
Ph
Ph
Me
Me
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
Bu
Ph
Bu
Ph
Bu
Ph
Bu
Ph
Mea
Bu
Ph
2
2
1
2
1
1
1
1
3
1
1
0
0
25
0
92
32
99
92
0
74
81
69
99
0
51
0
0
2,6-(i-Pr)2C6H3
2,6-(i-Pr)2C6H3
2,6-(i-Pr)2C6H3
61
92
91
10
11
0
0
a
The reaction was carried out at -20 °C.
1a ,b was carried out (Table 2). The values of LUMO
coefficients at each reaction site (2- and 4-positions) and
the absolute value differences between these coefficients
for the optimized geometries are summarized for com-
parison. Comparison of LUMO coefficients of 1a b (R )
Me) and 1c,d (R ) Ar) revealed that the experimentally
observed regioselectivity is rationalized by the relative
magnitude of the LUMO coefficients. The methylimine
1a b has a larger coefficient at the 4-position, and the
major reaction course for 1a ,b was 1,4-addition. The
arylimine 1e has a larger coefficient at the 2-position
than the 4-position, being consistent with the exclusive
1,2-addition for 1e. The coefficients are almost equal at
the 2- and 4-positions for the arylimines 1c,d , for which
the 1,2-adduct was the selective product along with
formation of a small amount of 1,4-adduct. This is easily
understandable by considering that the 1,4-addition leads
to the unfavorable transition state rather than the 1,2-
addition due to the breakdown of the naphthalene
aromaticity. The substituent R-dependency of the LUMO
coefficient magnitude of 1 is ascribable to the electron-
withdrawing nature of the aryl and the donating nature
of the alkyl groups of 1, respectively.
Acyclic enaldimines 4 derived from cinnamaldehyde
and crotonaldehyde were also examined their behavior
toward organolithium reagents (Table 3). Cyclohexy-
limine 4a (R1 ) c-Hex, R2 ) Me) was cleanly converted
to the corresponding 1,4-selective addition products 8 (R2
) Me, Nu ) Bu, Ph) (Table 3, runs 1 and 2). Reaction of
cinnamaldehyde imine 4b (R1 ) c-Hex, R2 ) Ph) with
phenyllithium was selective, giving 8 (R2 ) Ph, Nu ) Ph)
The 1,4-directing effect of a 2,6-diisopropylphenyl
group was demonstrated in an asymmetric conjugate

7054 J . Org. Chem., Vol. 66, No. 21, 2001
Tomioka et al.
Sch em e 2. Asym m etr ic 1,4-Ad d ition of
P h en yllith iu m to Im in e
F igu r e 1. Model for 4ee.
addition reaction of phenyllithium with imine 1f (Scheme
2). The reaction was conducted in the presence of a chiral
diether 925 in toluene at -45 °C and then was treated
with methyl iodide, giving 10 in 97% yield. Hydrolysis
afforded a chiral aldehyde 113a in 82% yield. The ee was
determined to be 93% by a chiral stationary-phase HPLC
of reduction alcohol 12.
We believe that LUMO coefficient as well as steric control
would become an essential methodology for designing a
selective reaction.
Con clu sion
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the Ministry of Education, Science,
Sports and Culture, J apan Society for Promotion of
Science (RFTF-96P00302), and the Science and Tech-
nology Agency, J apan. We are grateful to M. Shindo
(Tokushima University) and T. Okamoto (Osaka Uni-
versity) for contributions to the early stages of the work.
Thus, it became clear that the relative magnitude of
the LUMO coefficient is one of the essential factors
governing the substituent-dependent regioselectivity of
the ambident enimines. A bulky aryl group can increase
C4 LUMO coefficients through slippage from conjugation.
Cooperation of this electronic and steric control by the
aryl group directs a 1,4-selective addition reaction. An
electron-withdrawing aryl group can increase C2 LUMO
coefficients and directs a 1,2-selective addition reaction.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedure and spectroscopic and analytical data for the new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(25) Shindo, M.; Koga, K.; Tomioka, K. J . Org. Chem. 1998, 63,
9351-9357.
J O015766B