Convenient Access to Primary Amines by Employing the Barbier-Type Reaction of N-(Trimethylsilyl)imines Derived from Aromatic and Aliphatic Aldehydes

Article abstract of DOI:10.1021/jo971061r

A new versatile preparation of primary amines via benzylation of aromatic and aliphatic aldimines is described. Sonochemical and traditional methods for generation of the reactive intermediates are compared and contrasted. Competitive reactions were analyzed via free energy relationships to support the proposed alkylative mechanism.

Full text of DOI:10.1021/jo971061r

2824
J . Org. Chem. 1998, 63, 2824-2828
Con ven ien t Access to P r im a r y Am in es by Em p loyin g th e
Ba r bier -Typ e Rea ction of N-(Tr im eth ylsilyl)im in es Der ived fr om
Ar om a tic a n d Alip h a tic Ald eh yd es
Ferenc Gyenes, Kathryn E. Bergmann, and J ohn T. Welch*
Department of Chemistry, University at Albany, SUNY Albany, New York 12222
Received J une 12, 1997 (Revised Manuscript Received February 26, 1998)
A new versatile preparation of primary amines via benzylation of aromatic and aliphatic aldimines
is described. Sonochemical and traditional methods for generation of the reactive intermediates
are compared and contrasted. Competitive reactions were analyzed via free energy relationships
to support the proposed alkylative mechanism.
In this paper we describe a simple method for the
reaction of halides with carbonyl compounds such as
aldehydes, ketones, and esters in the presence of a metal.
Highly reactive, sterically strained tertiary alcohols13
have been prepared by the Barbier reaction. Although
magnesium13 has been employed as the reductant metal,
the use of lithium has been found not only to increase
the yield of the Barbier reaction but also to suppress side
reactions. Sonication was successfully applied to lithium-
Barbier reactions14 in 1980 with the superiority of the
method strikingly evident. Although organic halides in
which the halogen atom is bound to a single asymmetric
carbon atom react with metals with complete loss of
stereochemical integrity, the formation of enantiomeric
alcohols under ultrasonic Barbier conditions has been
reported.15 While a variety of organohalides have been
employed, the use of benzylic halides has remained
problematic.
synthesis of primary amines, which avoids catalysts,
difficult reaction conditions, or multistep procedures,
using a variant of the Barbier procedure to effect the
addition of a benzyl group to imines. While the addition
of organolithium, organocopper, and Grignard reagents
to the imine carbon is a useful method for the preparation
of amines,1-5 the low electrophilicity of the imine carbon
has frequently hindered these reactions. The reactivity
of imines has been improved by N-acylation or N-
alkylation6 to form reactive iminium salts3 or by com-
plexation with Lewis acids.5
Only a few examples of the addition of benzyl organo-
metallics to imines are known; typical of these is Grig-
nard addition to N-(trimethylsilyl)imines.7 The methods
described in these examples, some of which require
inconvenient, long reaction times or low temperatures,
proceed in fair to good yield. The preparation of the
necessary benzyl organometallics is particularly trouble-
some since Wurtz coupling reactions are facile. Benzyl
organometallics have been prepared by metalation of
toluene with 1:1 mixture of n-BuLi/MOtBu (M ) K, Rb)
at ambient temperature8 or treatment of toluene with
n-BuLi and TMEDA.9 The reductive cleavage of dibenzyl
ether by lithium suspended in THF is also known.10
Resu lts
N-(Trimethylsilyl)benzaldimine was initially employed
in our search for the optimal Barbier reaction conditions
for the formation of an amine from in situ generated
imines. It was prepared from benzaldehyde via an
addition-elimination reaction with lithium hexameth-
yldisilazide (LiHMDS).8,16 N-(Trimethylsilyl)benzaldi-
mine was allowed to react without isolation or purifica-
tion with benzyl bromide in the presence of lithium wire
in refluxing ether under sonication.17 1,2-Diphenylethan-
amine was isolated in moderate to good yields following
aqueous workup. Solvents were screened in model
studies to determine the most suitable medium for the
sonication reaction. Initially, to optimize cavity forma-
The Barbier synthesis11 is a one-step alternative to the
Grignard reaction12 for the preparation of alcohols by the
(1) J ones, C. A.; J ones, I. G.; North, M.; Pool, C. R. Tetrahedron Lett.
1995, 36, 7885.
(2) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron Lett.
1992, 33, 235.
(3) Polniaszek, R. P.; Dillard, L. W. Tetrahedron Lett. 1990, 31, 797.
(4) (a) Yamamoto, Y.; Komatsu, T.; Maruyama, K. J . Org. Chem.
1985, 50, 3115. (b) Ukaji, Y.; Kume, K.; Watai, T.; Fujisawa, T. Chem.
Lett. 1991, 173.
(5) (a) Lashat, S.; Kunz, H. J . Org. Chem. 1991, 56, 5883. (b) Hallett,
D. J .; Thomas, E. J . J . Chem. Soc., Chem. Commun. 1995, 657.
(6) (a) Hatanaka, M.; Ueda, I. Chem. Lett. 1991, 61. (b) Wang, D.-
K.; Dai, L.-X.; Hou, X.-L. Tetrahedron Lett. 1995, 36, 8649.
(7) Cainelli, G.; Giacomini, D.; Mezzina, E.; Panunzio, M.; Zaran-
tonello, P. Tetrahedron Lett. 1991, 32, 2967.
(12) (a) Molle, G. R.; Bauer, P. J . Am. Chem. Soc. 1982, 104, 3481.
(b) Pearce, P. J .; Richads, D. H.; Scilly, N. F. J . Chem. Soc., Perkin
Trans. 1 1972, 1655. (c) Blomberg, C.; Hartog, F. A. Synthesis 1977,
18. (d) Pearce, P. J .; Richards, D. H.; Scilly, N. F. J . Chem. Soc., Chem.
Commun. 1970, 1160.
(13) Choi, H.; Pinkerton, A. A.; Fry, J . L. J . Chem. Soc., Chem.
Commun. 1990, 991.
(8) (a) Desponds, O.; Schlosser, M. J . Organomet. Chem. 1991, 409,
93. (b) Hoffman, D.; Bauer, W.; Hampel, F.; Scheleyer, P. von R.; van
Eikema Hommes; N. J . R.; Otto, P.; Pieper, U.; Stalke, D.; Wright, D.
S.; Snaith, R. J . Am. Chem. Soc. 1994, 116, 528.
(9) Lubell, W. D.; Rapoport, H. J . Am. Chem. Soc. 1988, 110, 7447.
(10) Medic-Mijacevic, L.; Miljkovic, D. A.; Kovacevic, R.; Stankovic,
S. M.; Gasi, K. M. J . Serb. Chem. Soc. 1993, 58, 615.
(11) (a) Barbier, P. L. C. R. Hebd. Seances Acad. Sci. 1898, 128,
110. (b) Blomberg, C. The Barbier Reaction and Related One-Step
Processes; Springer-Verlag: Berlin Heidelberg, 1993.
(14) Luche, J .-L.; Damiano, J .-C. J . Am. Chem. Soc. 1980, 102, 7927.
(15) Souza-Barboza, J . C.; Luche, J .-L.; Petrier, J . C. Tetrahedron
Lett. 1987, 28, 2013.
(16) (a) Suga, K.; Watanabe, S.; Pan, T. P. Aust. J . Chem. 1968, 21,
2341. (b) Watanabe, S.; Suga, K.; Suzuki, T. Can. J . Chem. 1969, 47,
2343.
(17) (a) Mason, T. J .; Lorimer, J . P. Sonochemistry Theory, Applica-
tions and Uses of Ultrasound in Chemistry; Ellis Horwood Limited:
Chichester, 1988; pp 32-35. (b) Ley, S. V.; Low, C. M. R. Ultrasound
in Synthesis; Springer-Verlag: Berlin Heidelberg, 1989; pp 2-10.
S0022-3263(97)01061-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/14/1998

Convenient Access to Primary Amines
J . Org. Chem., Vol. 63, No. 9, 1998 2825
Ta ble 1. Solven t Op tim iza tion
Sch em e 1
Li,
equiv
benzylbromide,
yield,a
%
entry
solvent
equiv
1
2
3
4
5
6
7
8
diethyl ether
THF
pentane
DMPU
dioxane
di-n-butyl ether
DME
ether/DMF 1:1
4
4
4
4
4
4
4
4
2
2
2
2
2
2
2
2
35
18
0.0
0.5
0.0
0.7
0.1
0.0
a
Yields are determined by mass balance and gas chromato-
graphic analysis.
Ta ble 2. Effect of th e Tem p er a tu r e
entry
solvent
ether
THF
ether
THF
ether
THF
ether/THF 1:2
ether
T, °C
yield %a
Ta ble 4. In flu en ce of Su bstitu en ts a t th e P a r a P osition
on Am in e F or m a tion
1
2
3
4
5
6
7
8
0
0
0.0
0.0
35
14
61
52
50
73
entry
imine
R1
R2
amine
yield, %a
0-5
0-5
reflux
reflux
reflux
60b
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3d
3d
3d
3d
4
N(CH3)2
H
H
H
H
H
H
H
H
5a
5b
5c
5d
5d
5d
5d
5d
6
92
69
31
63
41b
48c
55d
60e
8
OCH3
CH3
H
H
H
H
H
H
F
a
b
See footnote Table 1. Reaction was run in a sealed tube with
the bath temperature at 60 °C.
CH3
H
H
Ta ble 3. Tim e Dep en d en ce of th e Rea ction
10
11
12
3e
3f
3g
5e
5f
5g
30
21
4
Cl
CF3
entry
t, min
yield, %a
H
1
2
3
4
15
30
45
60
18
63
69
40
a
b
Isolated yields. The reaction was done without sonication.
c Slow addition of the benzyl bromide-imine mixture to a solution
d
of lithium naphthalide in ether with no sonication. Slow addition
in THF with no sonication. e Slow addition of the reagent in
refluxing ether under sonication.
a
See footnote Table 1.
tion,17b temperatures between 0 and 5 °C were employed
with ethereal solvents (entries 1 and 2) in Table 1.
Subsequently, nonpolar pentane (entry 3) and highly
polar 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone
(DMPU) (entry 4) as well as ethereal solvents with varied
boiling points and viscosities were employed neat (entries
5-7) and as mixtures (entry 8). As can be seen from the
table, diethyl ether was superior to tetrahydrofuran,
while none of the other solvents was satisfactory.
At elevated temperatures, the reaction proceeded bet-
ter with diethyl ether than with tetrahydrofuran in all
cases (Table 2). A mixture of these two solvents gave
results consistent with those found with the major
component alone. At 60 °C the yield of the reaction in
experiments with diethyl ether as solvent in a sealed tube
increased, but because of the associated inconvenience,
all further reactions were conducted under reflux at
atmospheric pressure obviating the difficulty in main-
taining a stable temperature in a sonication bath. The
side reaction normally observed, Wurtz coupling, was
minimized at higher temperatures.
necessary to maximize amine formation. The reaction
is apparently relatively unaffected by concentration.
N-(Trimethylsilyl)imines with carefully selected para
substituents (Scheme 1) were prepared in situ from the
appropriate aromatic aldehydes and lithium hexameth-
yldisilazide.7,16 In the imine-forming step, at no time was
it possible to detect the aldehyde by infrared spectroscopy
after as few as 15 min. It can therefore be concluded
that differences in the rate of imine formation cannot
account for the observed differences of amine formation.
N-(Trimethylsilyl)imines were reacted with benzyl
bromide in the presence of lithium wire under the
optimized conditions. The resultant primary amines
were isolated in moderate to good yields following aque-
ous workup (Table 4). It can be seen that imines bearing
electron-donating groups in the para position gave much
higher yields than those having electron-withdrawing
groups. While it was anticipated that the reaction would
involve nucleophilic attack of a benzyllithium reagent,
these results suggest that the reaction proceeds via a
different mechanism.
Since the reaction times of sonochemically promoted
reactions can have a profound effect on yield, a survey
of reaction times was undertaken to determine the length
of time for the reaction (Table 3). Reaction times greater
than 30 min resulted in only a modest increase in the
yield of the process (entry 3), and at 60 min the yield
decreased considerably (entry 4).
Quantities of benzyl halide and lithium in excess of
that required stoichiometrically are necessary for the best
yield in the process. Two equivalents of benzyl bromide
are sufficient to compensate for the side reaction of Wurtz
coupling. However, eight equivalents of lithium were
The reaction also proceeds without sonication, however,
in lower yield, and with longer reaction times (entry 5).
Prolongation of the reaction time is accompanied by
consumption of the benzyl bromide, as well as by decom-
position of the imine at the elevated temperature em-
ployed. In light of the fact that the benzyl halide is not
used efficiently in this reaction, slow addition of a
mixture of imine and benzyl bromide to refluxing ether
under sonication improved the yield of amine to 60%
(entry 8). As mentioned previously benzyllithium is
difficult to prepare by direct reaction of a benzyl halide
with lithium metal because of the marked tendency for

2826 J . Org. Chem., Vol. 63, No. 9, 1998
Gyenes et al.
Ta ble 5. Alip h a tic Im in es in th e Ba r bier -Typ e Rea ction
Sch em e 2
imine
R1
R2
R3
amine
yield, %a
8a
8b
8c
8d
8e
8f
H
CH3
CH3
CH3
C2H5
(CH2)4
C3H7
H
H
H
H
H
CH3
H
9a
9b
9c
9d
9e
9f
23
52
88
61
44
51
52
CH3
CH3
C2H5
CH2
CH3
H
H
8g
9g
a
Isolated yields.
Ta ble 6. Com p etitive Rea ction s of Ar om a tic Im in es for
th e Ha m m ett P lot
Wurtz coupling. This difficulty has been overcome by
forming a lithium-electron acceptor complex either in
ether or THF before addition of the reactant mixture. To
employ this strategy, lithium was added to a solution of
naphthalene12b,18 in ether and THF. When the benzyl
bromide-imine mixture was added slowly to an excess
of this complex, Wurtz coupling was minimized. With an
addition time of 30 min, the result of the reaction under
these conditions is comparable to those obtained on
sonication. The yield was 48% in ether (entry 6) and 55%
in THF (entry 7). Reaction with acetophenone (entry 9)
failed (Table 4). Failure of acetophenone to react may
be a consequence of the presence of acidic R-protons
which interfere with imine formation as lithium hexa-
methyldisilazide is a potent base. Attempts to avoid the
use of N-(trimethylsilyl)imines by employing a preformed
imine from the reaction of benzaldehyde and benzylamine
resulted in only an 8% yield of amine product.
entry
R1
σa
σ+ a
log(K/K0)b,c log(K/K0)b,d
1
2
3
4
5
6
7
N(CH3)2 -0.63
-1.70
-0.78
+1.49
-0.15
-0.36
0.0
-0.03
-0.81
-1.25
0.4
e
e
0.0
-0.05
e
-0.95
OCH3
CH3
H
-0.27
-0.017 -0.31
0.0
0.0
F
Cl
CF3
+0.06
+0.23
+0.54
-0.17
+0.11
+0.54
a
b
The σ values were taken from ref 25. The values were
calculated from the competition reactions. c The reactions were
d
carried out at the boiling point of ether. The temperature was
kept between 0 and 5 °C. e These reactions were not performed.
Steric hindrance might be invoked in rationalizing the
decrease in yield in the reactions of 8e through 8g as
well.
Discu ssion
Aliphatic aldehydes, both with and without acidic
The Barbier reaction is generally accepted19 to proceed
either via an organometallic compound (polar (PL) route)
or via a radical intermediate occurring on the surface of
the metal. The latter pathway involves two steps, an
electron transfer (ET) step followed by a radical coupling
(RC) step (Scheme 2). Whether a reaction involves
organometallic compounds (PL route) or radical inter-
mediates (the ET-RC route) is dependent upon the
nature of the nucleophile as well as the structure of the
carbonyl compounds, with the determination of the
dominant pathway quite difficult in some cases. In the
case of the reactions of benzaldehyde derivatives under
Barbier conditions, the proposed mechanism of the
process is mainly considered to involve polar addition (PL
addition), with no evidence for the ET mechanism.20
From Scheme 2 it is clear that any of three steps are
potentially rate limiting.21 The PL mechanism, the ET-
RC mechanism with rate-determining ET, and the ET-
RC mechanism with rate-determining RC can be distin-
guished.
R-protons, were also employed in the reaction.
Competitive enolization of the aldehyde during the
preparation of silylimine and/or competitive deprotona-
tion of the product imine to the corresponding azaenolate
may be suppressed by effecting the imine formation at
-30 °C.16
With enolizable aldehydes bearing increasingly less
acidic protons (entries 8a thru 8c, Table 5), the yield of
amine product follows the predicted ease of imine forma-
tion. In the case of aldehydes with especially reactive
hydrogens, even imine formation at -30 °C and Barbier
reaction at 35 °C cannot compete with the deprotonation
process. The absence of an R-proton does not necessarily
result in an improvement in yield (entry 8d ) as the yield
in this case is slightly decreased relative to entry 8c.
In an effort to develop a better understanding of the
process involved in the reaction of aldimines, two sets of
competitive experiments at different temperatures were
conducted with N-(trimethylsilyl)imines derived from
benzaldehyde and a substituted benzaldehyde. The
product ratios in these cases were used to generate the
data shown in Table 6 and to establish the free energy
relationship shown in Figure 1.
In those cases involving the ET-RC mechanism with
ET and rate-determining step, the process would be
predicted to have a very small F value. Since the reaction
(18) (a) Hirao, A.; Hattori, I.; Yamaguchi, K.; Nakahama, S.;
Yamazaki, N. Synthesis 1982, 461. (b) Hart, D. J .; Kanai, K-i.;
Thomas, D. G.; Yang, T.-K. J . Org. Chem. 1983, 48, 289. (c) Cainelli,
G.; Giacomini, D.; Panunzio, M.; Martelli, G.; Spunta, G. Tetrahedron
Lett. 1987, 28, 5369.
(19) Bauer, P.; Molle, G. Tetrahedron Lett. 1978, 48, 4853.
(20) Yamataka, H.; Nishikawa, K.; Hanafusa, T. Bull. Chem. Soc.
J pn. 1992, 65, 2145.
(21) (a) Yamataka, H.; Yamaguchi, K.; Takatsuka, T.; Hanafusa,
T. Bull. Chem. Soc. J pn. 1992, 65, 1157. (b) Yamataka, H.; Nishikawa,
K.; Hanafusa, T. Bull. Chem. Soc. J pn. 1994, 67, 242.
(22) March, J . Advanced Organic Chemistry; J ohn Wiley & Sons:
New York, 1992; p 280.

Convenient Access to Primary Amines
J . Org. Chem., Vol. 63, No. 9, 1998 2827
imine is often more difficult than that to an aldehyde
since the imine is less reactive toward the addition of an
anion. One the other hand, the imine can be reduced in
a one-electron-transfer step to an intermediate radical
anion. Although the reduction potentials of benzalde-
hyde and the corresponding imines are very close, shifts
in the reduction potential can be expected in the case of
the Schiff bases. Reduction of the carbon-nitrogen
double bond in these cases is facilitated by electron-
withdrawing substituents24 on either portion of the imine
bond. Following electron transfer to the carbon-nitrogen
double bond, the radical anion may also be stabilized by
the trimethylsilyl group. The reactivity of the resultant
anion is most significantly moderated by the substituents
on the aromatic ring. Obviously it is the effect of the
substituents on the reactivity of the anion that is
reflected in the linear free energy relationship, rather
than the effect of the substituents on the redox potential
of the imine.
F igu r e 1. Substituent effects for the Barbier-type reaction
of aromatic imines with benzyl bromide in the presence of
lithium.
Con clu sion
In situ prepared (trimethylsilyl)imines have been found
to react with benzyl bromide in the presence of lithium
metal upon sonication to give primary amines in fair to
good yield. The optimum solvent for the reaction was
diethyl ether with the best yields occurring when the
reaction was conducted at 60 °C. Competitive experi-
ments suggest that the rate-limiting step involves attack
of a nucleophilic species (formed by reduction of the imine
reactant) on benzyl bromide. The reaction was extended
to encompass imines prepared from aliphatic aldehydes.
has a significant Hammett F value, the radical mecha-
nism with rate-determining ET can likely be excluded.
From Figure 1, it is clear that the reaction of the imine
occurs with a large negative F value at 35 °C (F ) -2.39,
corr coef ) 0.97 excluding the CH3O group). With the
observation that electron-releasing groups enhance the
reactivity while electron-withdrawing groups retard the
reactivity, polar addition of a benzyl anion is also
unlikely.
The negative slope of the plot in Figure 1 is indicative
of two possibilities. First, the reaction is being studied
at temperatures beneath the isokinetic temperature. It
is known that F values will approach zero when the
temperature of the measurement is close to the isokinetic
temperature and will change sign below that tempera-
ture.23 From competitive reactions studied between 0
and 5 °C (Table 6), the value of F was determined to be
-1.11. Since the value of F approached zero at this lower
temperature, it was a clear indication that measurements
at both 35 and 0-5 °C are above the isokinetic temper-
ature. The correlation coefficient of 0.94 associated with
the data obtained at lower temperature is worse than
that for the data obtained under reflux as a consequence
of the difficulty of controlling the temperature of the
sonication bath. Second, the results suggest that the
reaction process involves attack of an electrophile in a
rate-determining step on the substituted imine. The
negative slope associated with the plot suggests that the
imine reactant acts as a nucleophile since electron-
releasing groups are accelerating the reaction. A rapid
electron transfer to the imine carbon from the surface of
the metal to form a radical anion which then reacts as a
nucleophile with benzyl bromide fits the observed data
better than the assumption that the benzyl bromide is
converted to an organometallic species.
Exp er im en ta l Section
1H, 13C, and 19F NMR spectra were recorded at 300, 75, and
282 MHz, respectively. 19F NMR chemical shifts were refer-
enced to CFCl3. Diethyl ether was distilled from sodium in
the presence of sodium benzophenone ketyl. Hexamethyl-
disilazane was dried with calcium hydride. Aldehydes were
distilled before use. The imines were prepared immediately
before utilization in the Barbier reaction. All reactions were
carried out under an argon atmosphere. Lithium wire (sodium
content 1%) was purchased from Aldrich. The sonication was
carried out in a Branson 2200 type ultrasonic cleaning bath.
Gen er a l Meth od for Alip h a tic Im in e F or m a tion . To a
solution of lithium hexamethyldisilazide (4.3 mmol) in 8 mL
of diethyl ether at -30 °C was added the appropriate aliphatic
aldehyde (3.9 mmol) dropwise in 3 mL of diethyl ether. The
reaction mixture was stirred at this temperature for 30 min.
Gen er a l Meth od for Ar om a tic Im in e F or m a tion . These
compounds were prepared under the same conditions as the
aliphatic compounds except that the temperature was 0 °C.
Gen er a l Meth od for th e Ba r bier -Typ e Rea ction . Dry
ethyl ether (20 mL) and lithium (16 mmol) cut into small pieces
were placed in a reaction flask equipped with a condenser. The
flask was immersed into an ultrasonic cleaning bath contain-
ing warm water. Sonication was started after the reflux in
the flask had begun. While under reflux, a mixture of imine
(2 mmol) and benzyl bromide (4 mmol) was added via syringe.
The reaction mixture was transferred into 20 mL of a
saturated NH4Cl solution and extracted with EtOAc. The
Preliminary results indicated that the product of Wurtz
coupling is also formed, implying that a second process
competes with the proposed alkylative mechanism. We
have shown that formation of the Wurtz coupling product
can be suppressed by raising the reaction temperature.
The proposed mechanism for the reaction of imines
accommodates that observation that polar addition to an
combined organic phase was extracted with
a 10% HCl
solution, and the aqueous phase was washed with EtOAc. The
pH of the aqueous phase was adjusted to 12, and the solution
was extracted with EtOAc. The organic layer was then
washed with water and brine and dried over MgSO4.
(24) Kuder, J . E.; Gibson, H. W.; Wychick, D. J . Org. Chem. 1975,
40, 875.
(23) Kwart, H.; Barnett, W. J . Am. Chem. Soc. 1977, 99, 614.

2828 J . Org. Chem., Vol. 63, No. 9, 1998
Gyenes et al.
Gen er a l Meth od for th e Rela tive Rea ctivity. A pair of
aldehydes (the parent and substituted, 1.95 mmol each) in 3
mL of dry ether were added to a solution of LiHMDS (4.3
mmol) in 5 mL of dry ethyl ether, and the solution was stirred
for 30 min. The Barbier-type reaction was performed in the
same manner as before. After aqueous workup of the reaction,
the ratio of the two amines was determined by GC from the
crude product.
cm-1; 1H NMR (CDCl3) δ 7.14 (m, 5H), 3.07 (m, 1H), 2.62 (dd,
J ) 5.6, 13.4 Hz, 1H), 2.43 (dd, J ) 8.2, 13.2 Hz, 1H), 1.75 (b,
2H), 1.03 (d, J ) 6.2 Hz, 3H); 13C NMR (CDCl3) δ 139.4, 129.0,
128.1, 125.9, 48.3, 46.4, 23.3.
1-P h en ylbu ta n -2-a m in e28 (9b): IR (neat) 3352, 3264 cm-1
;
1H NMR (CDCl3) δ 7.22 (m, 5H), 4.30 (br, 2H), 3.05 (m, 1H),
2.83 (dd, J ) 13.4, 6.2 Hz, 1H), 2.73 (dd, J ) 13.2, 7.8 Hz,
1H), 1.53 (m, 2H), 0.98 (t, J ) 7.3 Hz, 3H); 13C NMR (CDCl3)
δ 138.0, 129.1, 128.3, 126.2, 54.2, 41.6, 27.8, 10.1.
1-(4-(N′,N′-Dim et h yla m in o)p h en yl)-2-p h en ylet h a n -1-
1
a m in e (5a ): IR (neat) 3363, 3300 cm-1; H NMR (CDCl3) δ
3-Meth yl-1-p h en ylbu ta n -2-a m in e29 (9c): IR (neat) 3375,
3307 cm-1; 1H NMR (CDCl3) δ 7.18 (m, 5H), 2.78 (dd, J ) 10.0,
4.1 Hz, 1H), 2.41 (dd, J ) 14.1, 10.0 Hz, 1H), 2.28 (br, 2H),
1.64 (m, 1H), 0.94 (dd, J ) 6.2, 6.2 Hz, 6H); 13C NMR (CDCl3)
δ 139.7, 129.1, 128.3, 126.0, 58.1, 40.6, 32.4, 19.2, 17.3.
3′,3-Dim eth yl-1-p h en ylbu ta n -2-a m in e (9d ): IR (neat)
3385, 3325 cm-1; 1H NMR (CDCl3) δ 7.25 (m, 5H), 2.98 (dd, J
) 13.2, 2.1 Hz, 1H), 2.69 (dd, J ) 11.0, 2.3 Hz, 1H), 2.22 (dd,
J ) 13.2, 11.0 Hz, 1H), 1.21 (br, 2H), 1.01 (s, 9H); 13C NMR
(CDCl3) δ 140.7, 128.9, 128.2, 125.8, 61.8, 38.4, 34.0, 26.1. Anal.
Calcd for C12H19N: C, 81.30; H, 10.80. Found: C, 81.40; H,
11.00.
7.4-6.7 (br, 9H), 4.15 (dd, J ) 8.7, 4.8 Hz, 1H), 3.05 (dd, J )
13.2, 5.1 Hz, 1H), 2.98 (s, 6H), 2.87 (dd, J ) 13.1, 8.9 Hz, 1H),
1.83 (br, 2H); 13C NMR (CDCl3) δ 149.6, 139.3, 133.2, 129.1,
128.1, 126.9, 126.0, 112.4, 56.7, 46.2, 40.5. Anal. Calcd for
C
16H20N: C, 79.95; H, 8.38. Found: C, 79.88; H, 8.34.
1-(4-Meth oxyp h en yl)-2-p h en yleth a n -1-a m in e25 (5b): IR
(neat) 3373, 3316 cm-1; H NMR (CDCl3) δ 7.3-7.1 (br, 9H),
1
4.16 (dd, J ) 7.9, 6.0 Hz, 1H), 3.78 (s, 3H), 3.01 (dd, J ) 13.3,
5.7 Hz, 1H), 2.90 (dd, J ) 13.2, 8.2 Hz, 1H), 2.67 (br, 2H); 13
C
NMR (CDCl3) δ 158.5, 138.6, 136.4, 129.2, 128.2, 127.5, 126.2,
113.6, 56.9, 55.1, 45.9. Anal. Calcd for C15H17N: C, 79.26; H,
7.54. Found: C, 79.09; H, 7.50.
3-Eth yl-1-p h en ylp en ta n -2-a m in e (9e): IR (neat) 3374,
3310 cm-1; 1H NMR (CDCl3) δ 7.22 (m, 5H), 3.19 (dd, J ) 7.9,
4.3 Hz, 1H), 2.85 (dd, J ) 13.5, 5.0 Hz, 1H), 2.59 (dd, J ) 12.8,
9.3 Hz, 1H), 1.49 (m, 2H), 1.36 (m, 2H), 1.24 (br, 2H), 0.95 (t,
J ) 7.2 Hz, 3H), 0.90 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ
139.4, 129.1, 128.4, 126.1, 54.2, 45.4, 39.9, 22.3, 21.5, 12.0, 11.9.
Anal. Calcd for C13H21N: C, 81.61; H, 11.06. Found: C, 81.46;
H, 10.93.
1-(4-Meth ylp h en yl)-2-p h en yleth a n -1-a m in e26 (5c): IR
1
(neat) 3356, 3287 cm-1; H NMR (CDCl3) δ 7.2-7.0 (br, 9H),
4.08 (dd, J ) 7.0, 7.0 Hz, 1H), 3.62 (br, 2H), 2.94 (dd, J ) 13.2,
6.2 Hz, 1H), 2.87 (dd, J ) 13.3, 7.9 Hz, 1H), 2.21 (s, 3H); 13C
NMR (CDCl3) δ 140.0, 138.2, 136.9, 129.2, 129.0, 128.2, 126.5,
126.3, 57.2, 45.0, 21.0.
2-P h en yleth a n -1-a m in e25 (5d ): IR (neat) 3375, 3300 cm-1
;
1H NMR (CDCl3) δ 7.28 (m, 10H), 4.22 (dd, J ) 8.8, 4.9 Hz,
1H), 3.03 (dd, J ) 13.3, 4.9 Hz, 2H), 2.85 (dd, J ) 13.3, 8.9
Hz, 1H), 1.66 (b, 2H); 13C NMR (CDCl3) δ 145.5, 138.9, 129.2,
128.3, 127.0, 126.35, 126.31, 57.4, 46.0.
2-Cycloh exyl-1-p h en ylet h a n -2-a m in e (9f): IR (neat)
1
3374, 3305 cm-1; H NMR (CDCl3) δ 7.35-7.15 (br, 5H), 2.87
(dd, J ) 13, 3.9 Hz, 1H), 2.81 (dd, J ) 4.0, 3.4 Hz, 2H), 2.43
(dd, J ) 12.0, 9.6 Hz, 1H), 1.91 (br, 2H), 1.9-1.5 (br, 5H), 1.4-
0.9 (br, 6H); 13C NMR (CDCl3) δ 140.0, 129.2, 128.4, 126.1,
57.6, 43.1, 40.9, 29.7, 28.1, 26.5, 26.4, 26.3. Anal. Calcd for
1-(4-F lu or op h en yl)-2-p h en ylet h a n -1-a m in e (5e): IR
(neat) 3373, 3298 cm-1; 1H NMR (CDCl3) δ 7.15 (m, 9H), 4.21
(br, 1H), 2.98 (dd, J ) 13.0, 4.9 Hz, 1H), 2.84 (dd, J ) 13.2,
C
14H21N: C, 82.70; H, 10.41. Found: C, 82.49; H, 10.21.
8.5 Hz, 1H), 1.91 (b, 2H); 13C NMR (CDCl3) δ 161.8 (d, J 1
)
(l,u )-3-Meth yl-1-p h en ylh exa n -2-a m in e (9g): IR (neat)
C-F
245 Hz), 140.8, 138.5 (d, J 4
) 2.7 Hz), 129.2, 128.3, 127.9
3375, 3307 cm-1; 1H NMR (CDCl3) δ 7.2 (m, 5H), 3.0-2.7 (br,
2H), 2.41 (m, 1H), 1.6-1.3 (br, 3H), 1.3-1.1 (br, 4H), 0.93 (m,
6H); 13C NMR (CDCl3) δ 1140.1, 140.0, 129.0, 128.9, 128.2,
125.8, 57.2, 56.4, 41.6, 40.2, 37.9, 37.2, 35.9, 34.5, 20.4, 20.3,
15.4, 14.2, 14.1, 13.7. Anal. Calcd for C13H21N1: C, 81.61; H,
11.06. Found: C, 81.39; H, 11.03.
C-F
(d, J 3
) 8 Hz), 126.3, 115.0 (d, J 2
) 21.6 Hz), 56.8, 46.3;
C-F
C-F
19F NMR (CDCl3) δ -63.07. Anal. Calcd for C14H14N: C,
78.11; H, 6.56. Found: C, 78.35; H, 6.72.
1-(4-Ch lor op h en yl)-2-p h en yleth a n -1-a m in e26 (5f): IR
1
(neat) 3370, 3297 cm-1; H NMR (CDCl3) δ 7.4-7.1 (br, 9H),
4.19 (m, 1H), 3.03 (dd, J ) 13.5, 5.0 Hz, 1H), 2.82 (dd, J )
13.2, 8.5 Hz, 1H), 1.58 (br, 2H); 13C NMR (CDCl3) δ 143.9,
138.4, 132.4, 129.2, 128.3, 127.7, 126,3, 56.8, 46.3.
Ack n ow led gm en t. Financial support of this work
by the National Science Foundation Grant CHE-
8901986 and National Institute of Health Grant AI33690
is gratefully acknowledged. The authors are also grate-
ful for the helpful comments and suggestions of Prof.
Paul Toscano and Prof. Barry Carpenter.
1-(4-(r′,r′,r′-Tr iflu or om et h yl)p h en yl)-2-p h en ylet h a n -
1-a m in e (5g): IR (neat) 3364, 3283 cm-1; 1H NMR (CDCl3) δ
7.53 (m, 4H), 7.30-7.15 (br, 5H), 4.28 (dd, J ) 5.2, 8.4 Hz,
1H), 3.00 (dd, J ) 5.0, 13.5 Hz, 1H), 2.85 (dd, J ) 8.7, 13.2
Hz, 1H), 1.85 (br, 2H); 13C NMR (CDCl3) δ 149.4, 138.3, 161.8
(q, J 2
) 270 Hz), 129.3, 128.5, 126.8, 126.6, 125.3 (q J 1
C-F
C-F
J O971061R
) 270 Hz), 57.2, 46.3; 19F NMR (CDCl3) δ -62.9.
1-P h en ylp r op a n -2-a m in e27 (9a ): IR (neat) 3355, 3296
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S. C.; Yoon H. Tetrahedron Lett. 1994, 35, 3745.
(25) Gee, K. R.; Barmettler, P.; Rhodes, M. R.; McBurney, R. N.;
Reddy, N. L.; Hu, L.-Y.; Cotter, R. E.; Hamilton, P. N.; Weber, E.;
Keana, J . F. W. J . Med. Chem. 1993, 36, 1938-1946.
(26) Nagase, T.; Suzukamo, G.; Suzuki, Y. Ger. Offen. 2,442,845,
1975; Chem. Abstr. 1975, 83, 78820a.