Palladium-catalyzed coupling of optically active amines with aryl bromides

Article abstract of DOI:10.1021/ja971583o

The coupling of enantiomerically enriched amines with aryl bromides produces the corresponding N-aryl derivatives. The choice of ligand in the palladium-catalyzed coupling is critical to the formation of the anilines without loss of enantiomeric purity. W

Full text of DOI:10.1021/ja971583o

J. Am. Chem. Soc. 1997, 119, 8451-8458
8451
Palladium-Catalyzed Coupling of Optically Active Amines with
Aryl Bromides
Seble Wagaw, Roger A. Rennels, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed May 15, 1997X
Abstract: The coupling of enantiomerically enriched amines with aryl bromides produces the corresponding N-aryl
derivatives. The choice of ligand in the palladium-catalyzed coupling is critical to the formation of the anilines
without loss of enantiomeric purity. While LnPd (L ) P(o-tolyl)3) successfully catalyzes the intramolecular aryl
amination of R-subsituted optically pure amines, intermolecular coupling reactions with this catalyst system gives
racemized products. In contrast, intermolecular N-arylations employing LnPd (L ) (()-BINAP) gives products in
good yields with no erosion of enantiopurity. A mechanism for the observed racemization is proposed. The utility
of the intramolecular process is demonstrated by the synthesis of 5, an intermediate in the formal synthesis of 6, a
potent ACE inhibitor.
Introduction
bromides with enantiomerically enriched amines with stereo-
genic centers R to the nitrogen gives cyclized products without
loss of stereochemical integrity. In addition, Pd/bis(phosphine)
catalysts effect the intermolecular coupling of aryl bromides
with enantiomerically enriched R-substituted amines with to give
products without erosion of enantiopurity. The utility of these
methods is demonstrated by the preparation of a variety of
enantiomerically enriched aniline and indoline derivatives.
Recently, the palladium-catalyzed intramolecular and inter-
molecular coupling of aryl halides with amines has been shown
to be a mild and efficient method for the synthesis of a variety
of aniline derivatives.1-5 Initial reports on the palladium-
catalyzed amination of aryl halides utilized Pd/P(o-tolyl)3
catalysts, where the use of P(o-tolyl)3 was key to the success
of the reaction. Subsequently, Pd/bis(phosphine) catalysts have
been shown to effect the amination of aryl halides and have
been found to give superior results over those obtained in
reactions catalyzed by Pd/P(o-tolyl)3 for several classes of
substrates.6-9
It would be desirable to extend the palladium-catalyzed
carbon-nitrogen bond forming reaction to the preparation
enantiomerically enriched aniline derivatives by coupling enan-
tiomerically enriched amines with aryl bromides. Such com-
pounds are common structural units in agricultural and phar-
maceutical chemistry.10-16 We now report that the use of Pd/
P(o-tolyl)3 catalysts for the intramolecular coupling of aryl
Results
Initial investigations into the Pd2(DBA)3/P(o-tolyl)3 catalyzed
coupling of aryl bromides with enantiomerically enriched
R-substituted amines gave promising results. A previously
reported procedure for intramolecular carbon-nitrogen bond
formation, utilizing catalytic Pd2(DBA)3/P(o-tolyl)3, successfully
cyclizes enantiomerically enriched amine and amide substrates
with either endocyclic or exocyclic chiral centers with no
decrease in enantiomeric excess (ee).17 For example, Pd2-
(DBA)3/P(o-tolyl)3 catalyzes the cyclization of 1 (96% ee) in
high yield and without loss of enantiopurity (eq 1).
X Abstract published in AdVance ACS Abstracts, August 15, 1997.
(1) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927-928.
(2) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901-
7902.
(3) Guram, A. S.; Rennels, R. R.; Buchwald, S. L. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1348-1350.
(4) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969-
5970.
(5) Louie, J.; Hartwig, J. F. Tetrahedron Lett 1995, 36, 3609-3612.
(6) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240-7241.
(7) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 7215-7216.
The utility of this methodology was further demonstrated in
the preparation of (S)-N-acetylindoline-2-carboxylate methyl
ester 5 (Scheme 1), a key intermediate in the synthesis of the
ACE inhibitor 6.11 The stereochemistry of 4 is retained under
the mild cyclization reaction conditions to give 5 in 99% ee.
Optically active 4 is prepared by a Heck coupling reaction of
o-bromoiodobenzene with methyl-2-acetamidoacrylate to pro-
duce 3,18 followed by an asymmetric hydrogenation of the
resulting eneamide.19 Alternate methods for the synthesis of
(8) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217-
7218.
(9) Marcoux, J. F.; Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1997,
62, 1568-1569.
(10) Gupton, J. T.; Tarrant, J. G.; Yu, R. H.; Solarz, T. L. Synth. Comm.
1992, 22, 3205-3214.
(11) Grundfeld, N.; Stanton, J. L.; Yuan, A. M.; Ebetino, F. H.; Browne,
L. J.; Gude, C.; Huebner, C. F. J. Med. Chem. 1983, 26, 1277-1293.
(12) LaMontagne, M. P.; Blumbergs, P.; Smith, D. C. J. Med. Chem.
1989, 32, 1728-1732.
(13) Wender, P. A.; Zercher, C. K. J. Am. Chem. Soc. 1991, 113, 2311-
2313.
(14) Carmeli, S.; Moore, R. E.; Patterson, G. M. L. J. Am. Chem. Soc.
1990, 112, 8195-8197.
(15) Queener, S. F.; Bartlett, M. S.; Nasar, M.; Smith, J. W. Antimicrob.
Agents Chemother. 1993, 37, 2166-2172.
(16) Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114, 10997-
8.
(17) For previous exmaples of palladium-catalyzed intramolecular aryl
aminations and aryl amidations, see: Wolfe, J. P.; Rennels, R. A.; Buchwald,
S. L. Tetrahedron 1996, 52, 7525-7546.
(18) Harrington, P. J.; Hegedus, L. S.; McDaniel, K. F. J. Am. Chem.
Soc. 1987, 109, 4335-4338.
S0002-7863(97)01583-7 CCC: $14.00 © 1997 American Chemical Society

8452 J. Am. Chem. Soc., Vol. 119, No. 36, 1997
Wagaw et al.
Scheme 1
Table 1. Palladium-Catalyzed Coupling of Optically Active
enantiopure 6 require either a low-yielding fractional recrys-
tallization or an enantioselective enzymatic hydrolysis of the
racemic ester 5.20
R-Substituted Amines with Aryl Bromidesg
We attempted to apply the Pd(0)/P(o-tolyl)3 protocol to the
intermolecular coupling of enantiomerically enriched amines
with aryl bromides. Given the success of the Pd2(DBA)3/P(o-
tolyl)3-catalyzed intramolecular coupling reactions, we were
surprised to find that Pd2(DBA)3/P(o-tolyl)3-catalyzed intermo-
lecular coupling of enantiomerically enriched R-chiral amines
with aryl bromides yields products which are partially to fully
racemized. For instance, when (R)-R-methylbenzylamine (98%
ee) is coupled with 4-bromobiphenyl using this catalyst system,
aniline 7 was obtained with 70% ee (eq 2). A racemic product
is formed with this catalyst when (S)-2-phenylpyrrolidine (98%
ee) and 4-bromobiphenyl are used as substrates (eq 3).
While determining which aspects of the reaction protocol in
eq 2 were responsible for the observed racemization, we
discovered that the intermolecular N-arylation of enantiomeri-
cally enriched R-substituted amines catalyzed by LnPd/(()-
BINAP gives coupled products without erosion of optical
activity (Table 1, entries 1,6,9-14).21 For example, (R)-R-
methylbenzylamine (1.2 mmol, >99% ee) and 4-bromobiphenyl
(1 mmol) are coupled using NaOt-Bu (1.4 equiv), Pd2(DBA)3
(2 mol %, 4 mol % Pd), and (()-BINAP (4 mol %) in toluene
at 70 °C to give (R)-N-(R-methylbenzyl)-4-phenylaniline in 86%
yield and >99% ee (Table 1, entry 1). The use of lower catalyst
loadings (1 mol % Pd2(DBA)3, 2 mol % Pd) and higher reaction
temperatures (100 °C) give the coupled product in 65% yield
and >99% ee (Table 1, entry 2).
a Yields and ee’s refer to the average of two isolated yields of >99%
1
purity as determined by H NMR and elemental analysis. b Reactions
were run with 1 mol % Pd2(DBA)3, 2 mol % (()-BINAP, 1.4 equiv of
NaOt-Bu, 0.5 M in toluene at 100 °C. c Reactions were run with 5 mol
% (DPPF)PdCl2‚CH2Cl2, 15 mol % DPPF, 1.25 equiv of NaOt-Bu, 1
M in THF at 100 °C. d Reactions were run with 5 mol % Pd(OAc)2,
20 mol % DPPF, 1.25 equiv of NaOt-Bu, 1 M in THF at 100 °C.
e Reactions were run with 5 mol % Pd(OAc)2, 5 mol % DPPF, 1.25
equiv of NaOt-Bu, 1 M in THF at 100 °C. f Three equiv of 2-bro-
mopyridine were used. g Reactions were run with 2 mol % Pd2(DBA)3,
4 mol % (()-BINAP, 1.4 eequiv of NaOt-Bu, 0.5 M in toluene at 70
°C unless otherwise stated.
Reactions catalyzed by (DPPF)PdCl2‚CH2Cl2 in the presence
of excess DPPF give yields and ee’s similar to those obtained
when Pd2(DBA)3/(()-BINAP is used to couple primary R-sub-
stituted amines with aryl bromides (entries 3 and 8).8 The in
situ generation of the active catalyst from Pd(OAc)2 and an
excess of DPPF gives similar results to those obtained with
(DPPF)PdCl2‚CH2Cl2/DPPF (entry 4). Without an excess of
DPPF, however, the yield is significantly lower though the ee
remains high (entry 5).
Acyclic secondary amine substrates give lower yields of
coupled products than those obtained with primary amines or
cyclic secondary amine substrates in reactions catalyzed by Pd2-
(DBA)3/(()-BINAP and generally require electron-deficient aryl
bromides for complete conversion (entry 6). In these cases the
side products, imine and hydrodehalogenated arene, result from
(19) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125-10138.
(20) Tombo, G. M. R.; Scha¨r, H. P.; Ghisalba, O. Agric. Biol. Chem.
1987, 51, 1833-1838.
(21) The use of less expensive bis(phosphine) ligands, such as 1,2-bis-
(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, and 1,2-
bis(diphenylphosphino)benzene, also prevents racemization in these reac-
tions. However, the yields of coupled products are significantly lower due
to poor conversion and an increase of side products which arise from
â-hydride elimination from Pd(II)-amido complexes. See ref 7.

Pd-Catalyzed Coupling of Amines with Aryl Bromides
J. Am. Chem. Soc., Vol. 119, No. 36, 1997 8453
â-hydride elimination from an intermediate Pd(II)-amido com-
plex. However, higher yields of coupled products may be
obtained by raising the reaction temperature to 100 °C (entry
7). The use of (DPPF)PdCl2‚CH2Cl2/DPPF as a catalyst at 100
°C also gives improved yields of coupled products with acyclic
secondary amine substrates (entry 8).
Scheme 2
Due to the importance of amino alcohols in the pharmaceuti-
cal industry, we hoped to extend this methodology to the
selective N-arylation of enantiomerically enriched amino alco-
hols. However, protection of the hydroxyl group was required
in order to obtain the desired product in good yield. A variety
of protecting groups were surveyed, and we found that amino
alcohols protected as their tert-butyl ethers underwent efficient
coupling (entries 13 and 14).22
In order to probe the mechanism of racemization in inter-
molecular coupling reactions of enantiomerically enriched
R-substituted amines with aryl bromides using the Pd2(DBA)3/
P(o-tolyl)3 catalyst, the reaction protocol in eq 2 was varied in
order to examine which reaction parameters have an effect on
the ee of the coupled product. The following observations were
made: (1) The ratio of Pd2(DBA)3:P(o-tolyl)3 had little effect
on the ee of the coupled product. (2) The use of other
monodentate phosphine ligands such as P(1-naphthyl)3, P(o-
methoxyphenyl)3, and PPh3 gave products with similar ee’s as
those obtained with P(o-tolyl)3. (3) Racemization was found
to be temperature dependent, where higher reaction temperatures
gave a more extensively racemized product. (4) Control
experiments showed that amine racemization requires a pal-
ladium complex and an aryl bromide, which suggested that an
(aryl)(Br)Pd(II)Ln (L ) P(o-tolyl)3) complex is involved in
amine racemization. (5) A sample of 7 (>99% ee) was
subjected to typical reaction conditions for 24 h and did not
undergo racemization, indicating that amine racemization occurs
prior to or during the coupling reaction and not after the product
is formed. (6) When the coupling reaction was carried out in
the presence of an excess of the enantiomerically enriched
R-substituted amine, the recovered unreacted amine was partially
racemized (eq 4). (7) When a deuterated imine was added to
a Pd2(DBA)3/P(o-tolyl)3 catalyzed aryl amination, no deuterium
was incorporated into coupled product as detected by 2H NMR
(eq 5).23,24
Scheme 3
ladium-mediated racemization of optically active amines has
been observed by several research groups, where reversible
â-hydride elimination of Pd(0)-amino or Pd(II)-amido com-
plexes is responsible for racemization.28,29
Reports on the mechanism of Pd/P(o-tolyl)3-catalyzed aryl
amination reactions suggest that the use of P(o-tolyl)3 favors
the formation of mono(phosphine) palladium intermediates
which are believed to be the catalytically active species (Scheme
2).27 Oxidative addition of an aryl bromide then forms a dimeric
Pd(II) species, which has been shown to form monomeric Pd-
(II)-amino complexes upon addition of an amine. Deproto-
nation then forms Pd(II)-amido complex 10a which can
undergo reductive elimination to give the coupled product.
Alternately, if 10a possesses â-hydrogens, reversible â-hydride
elimination from 10a can lead to the formation of imine and
hydrodehalogenated arene, which are common side products in
this reaction.
Though â-hydride elimination from Pd(II)-amido complex
10a (Scheme 3) initially forms the π-coordinated imine 11a,
σ-coordination through the lone pair on nitrogen is favored for
late transition metal-imine complexes.30 An equilibrium
between π-coordinated Pd(II)-imine complex 11a and σ-co-
ordinated Pd(II)-imine complex 12 provides a pathway for the
formation of the π-coordinated imine complexes 11a and 11b,
where either face of the prochiral imine is bound to the metal
center.31 Migratory insertion of the π-coordinated imine into
the palladium-hydride bond of 11a and 11b then forms
enantiomeric Pd(II)-amido complexes 10a and 10b.32 Reduc-
tive elimination then produces a racemized mixture of the
coupled product. Alternately, Pd(II)-amido complexes 10a and
10b can undergo exchange with another equivalent of amine,
Discussion
â-Hydride elimination is known to be a facile and reversible
process for late transition metal-amido complexes.25-27 Pal-
(22) Overman has recently used our methodology to aid in the deter-
mination of the absolute configuration of an amino alcohol derivative.
See: Calter, M.; Hollis, T. K.; Overman, L. E.; Ziller, J.; Zipp, G. G. J.
Org. Chem. 1997, 62, 1449-1456.
(26) Diamond, S. E.; Mares, F. J. Organomet. Chem. 1977, 142, C55-
C57.
(27) Hartwig, J. F.; Richards, S.; Baran˜o, D.; Paul, F. J. Am. Chem. Soc.
1996, 118, 3626-3633.
(23) The addition of imine inhibits the coupling reaction; therefore, only
10 mol % imine was used.
(28) Murahashi, S. I.; Yoshimura, N.; Tsumiyama, T.; Kojima, T. J. Am.
Chem. Soc. 1983, 105, 5002-5011.
(24) Similarly, it has been shown that Pt-bound butene produced by
â-hydride elimination from (DPPF)PtBu2 does not undergo exchange with
free butene in solution. See: Whitesides, G. M.; Gaasch, J. F.; Stedronsky,
E. R. J. Am. Chem. Soc. 1972, 94, 5258-5270.
(29) Walker, H. W.; Kresge, C. T.; Ford, P. C.; Pearson, R. G. J. Am.
Chem. Soc. 1979, 101, 7429-7430.
(30) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principles
and Applications of Organotransition Metal Chemistry; University Science
Books: Mill Valley, CA, 1987.
(25) Bryndza, H. E.; Tam, W. Chem. ReV. 1988, 88, 1163-1188.

8454 J. Am. Chem. Soc., Vol. 119, No. 36, 1997
Wagaw et al.
Scheme 4
producing a new Pd(II)-amido complex plus racemized un-
the aryl halide to palladium, followed by deprotonation of the
amine. It has been shown that five- and six-membered late
transition metal metallacycles, even those with exocyclic alkyl
groups, are significantly more resistant toward â-hydride
elimination than their acyclic analogs.35 If reversible â-hydride
elimination is not competitive with reductive elimination, then
no pathway for racemization exists. Therefore bis(phosphine)
ligands are not required to obtain unracemized coupled products
in intramolecular coupling reactions.
coupled amine (eq 4).33
An equilibrium between 11a and 11b could also result from
the exchange of a palladium-bound imine with free imine in
solution. However, the lack of deuterium incorporation in eq
5 indicates that the palladium-bound imine is not exchanging
with free imine in solution. Therefore the equilibrium between
11a and 11b must proceed through the σ-coordinated Pd(II)-
imine complex 12.
Unlike reactions catalyzed by Pd2(DBA)3/P(o-tolyl)3, LnPd/
bis(phosphine) catalysts presumably have two phosphines on
the palladium center throughout the catalytic cycle.7,8 This
precludes three-coordinate palladium intermediates in the
catalytic cycle and creates a more sterically crowded metal
center. We believe that the success of LnPd/bis(phosphine)
catalysts in coupling optically active amines with aryl halides
without loss of enantiopurity is due to their ability to prevent
the equilibration between the π-bound palladium imine complex
14a and its diastereomer 14c (Scheme 4). The formation of
the σ-coordinated Pd(II)-imine complex 14b may be prohibited
for steric reasons. The formation of 14b would require a Pd-
N-C-CH3 dihedral angle of 0°, placing the methyl group
toward the sterically crowded metal center, in contrast to 14a
where the dihedral angle is 90° and the methyl group is pointed
away from the metal center. If 14b is not formed, the major
pathway for facial equilibration of a π-coordinated Pd(II)-imine
complex is eliminated. Instead 14a reforms 13 without race-
mization. Alternately, 14a may lose the coordinated imine prior
to hydride reinsertion, due to steric reasons, followed by
reductive elimination of the hydrodehalogenated arene. This
side reaction leads to a lower yield but no loss of enantiomeric
purity of the product. The use of chelating (bis)phosphine
ligands minimizes â-hydride elimination from Pd(II)-amido
complexes. That â-hydride elimination is not entirely sup-
pressed is evidenced by the formation of products resulting from
this process: imine and hydrodehalogenated arene.34
Recently, it has been reported that catalytic mixtures of Pd-
[P(o-tolyl)3]2Cl2 or Pd(PPh3)4 with stoichiometric amounts of
CuI under phase transfer conditions catalyze the coupling of
optically active amino acids with aryl bromides and iodides
without racemization.36 The reaction does not proceed without
CuI, though its role in the reaction is unknown. In contrast to
our findings, products arising from â-hydride elimination are
not reported. Copper ions are known to form chelates with
amino acids through the carboxyl and amino groups. Formation
of a chelate complex may disfavor â-hydride elimination due
to geometric constraints, therefore preventing racemization of
the amino acid during the coupling reaction.
Conclusion
Pd2(DBA)3/P(o-tolyl)3 catalyzes the intramolecular coupling
of optically active R-substituted amine substrates without
racemization. However, LnPd/bis(phosphine) catalysts are
required to obtain unracemized products in intermolecular
coupling reactions of optically active R-chiral amines with aryl
In intramolecular Pd2(DBA)3/P(o-tolyl)3 catalyzed aryl ami-
nations, we believe that â-hydride elimination is not competitive
with reductive elimination of the aryl amine. The metallacycle
intermediate 15 (eq 6) is formed by the oxidative addition of
(34) For example, when 2-phenylpyrrolidine and 4-bromobiphenyl were
coupled using 2 mol % Pd2(DBA)3, 4 mol % (()-BINAP, and 1.4 equiv
of NaOt-Bu in toluene at 70 °C, a mixture of 46% 2-phenyl-1-pyrroline,
36% biphenyl, and 18% N-(p-biphenyl)-2-phenylpyrrolidine was obtained
as determined by GC analysis. The percentages were corrected for the
response factors of each component of the mixture.
(31) A similar π-σ-π equilibrium has been observed. See: Boone,
B. J.; Klein, D. P.; Seyler, J. W.; Mendez, N. Q.; Arif, A. M.; Gladysz, J.
A. J. Am. Chem. Soc. 1996, 118, 2411-2421.
(35) McDermott, J. X.; White, J. F.; Whitesides, G. M. J. Am. Chem.
Soc. 1976, 98, 6521-6528.
(32) It is believed that π-coordination in metal-imine complexes is
required for insertion reactions to occur. See: Fryzuk, M. D.; Piers, W. E.
Organomet. 1990, 9, 986-998.
(36) Ma, D.; Yao, J. Tetrahedron: Asymm. 1996, 7, 3075-3078.
(37) Verdaguer, X.; Lange, U. E.; Reding, M. T.; Buchwald, S. L. J.
Am. Chem. Soc. 1996, 118, 6784-6785.
(33) Bryndza, H. E.; Calabrese, J. C.; Marsi, M.; Roe, D. C.; Tam, W.;
Bercaw, J. E. J. Am. Chem. Soc. 1986, 108, 4805-4813.
(38) Vedejs, E.; Gingras, M. J. Am. Chem. Soc. 1994, 116, 579-588.
(39) Fry, D. F.; Fowler, C. B.; Dieter, R. K. SynLett 1994, 836-838.

Pd-Catalyzed Coupling of Amines with Aryl Bromides
J. Am. Chem. Soc., Vol. 119, No. 36, 1997 8455
solution was added dropwise (8.4 mL, 1 M in THF, 8.4 mmol, 2.7
equiv), and the solution was heated to reflux for 8 h. THF was removed
under vacuum, the solution was acidified to pH ) 1 with 10% HCl,
and the reaction mixture was stirred for 30 min. The solution was
made basic (pH ) 14) with 1 M NaOH, stirred for 15 min, and then
extracted with Et2O (3 × 15 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated to give the crude product
as a yellow oil. Flash column chromatography (10% EtOAc/Hex)
afforded the product as a clear oil (862 mg, 95% yield). 1H NMR δ
7.50 (d, J ) 7.5 Hz, 1 H), 7.17-7.31 (m, 7 H), 7.01-7.07 (m, 1 H),
3.82 (q, J ) 6.5 Hz, 1 H), 2.69-2.93(m, 4 H), 1.47 (s, 1 H), 1.35 (d,
J ) 6.6 Hz, 3 H); 13C{1H} NMR δ 145.5, 139.4, 132.8, 130.6, 128.4,
127.8, 127.3, 126.9, 126., 58.0, 47.2, 36.8, 24.4; IR (neat) 3059, 3024,
2960, 2837, 1470, 1449 cm-1; Anal. Calcd for C16H18NBr: C, 63.17;
H, 5.96. Found: C, 62.90; H, 5.96. [R]24 +46° (c 3.1, CHCl3).
(R)-N-(r-Methylbenzyl)indoline (2). (R)-2-(o-bromophenyl)-N-(R-
methylbenzyl)ethylamine (101 mg, 0.33 mmol, 96% ee), Pd2(DBA)3
(6 mg, 0.007 mmol, 4 mol % Pd), P(o-tolyl)3 (8 mg, 0.026 mmol, 8
mol %), and NaOt-Bu (41 mg, 0.43 mmol, 1.3 equiv) in 0.6 mL of
toluene were heated to 100 °C in an oven dried Schlenk flask under
nitrogen for 12 h. The crude reaction solution was diluted with Et2O
(5 mL) and filtered through Celite, the Celite was rinsed with Et2O,
and the combined organic layers were concentrated. Purification by
flash column chromatography (1% EtOAc/Hex) gave the product as a
clear oil (67 mg, 86 % yield). 1H NMR δ 7.24-7.41 (m, 5 H), 7.04
(d, J ) 7.05 Hz, 1 H), 6.98 (t, J ) 7.5 Hz, 1 H), 6.59 (t, J ) 6.9 Hz,
1 H), 6.35 (d, J ) 8.8 Hz, 1 H), 4.71 (dd, J ) 6.8, 13.6 Hz, 1 H),
3.27-3.40 (m, 2H), 2.94 (t, J ) 8.4 Hz, 2 H), 1.53 (d, J ) 6.9 Hz, 3
H); 13C{1H} NMR δ 151.6, 143.1, 130.3, 128.6, 127.3, 127.2, 127.1,
124.6, 117.1, 107.4, 77.6, 77.2, 76.8, 54.7, 48.1, 28.4, 16.7; IR (neat)
3025, 2973, 2932, 2843, 1606 cm-1: Anal. Calcd for C12H13N: C,
86.05; H, 7.76. Found: C, 86.27; H, 7.72. The product was found to
be of 96% ee as determined by Chiral GC analysis with a Alltech G-TA
column, 110 °C isotherm, and a 2 mL/min flow rate. [R]26 +67° (c
1.1, CHCl3).
Synthesis of (S)-2-Methylcarboxylate-N-acetylindoline (5).18 2-Ac-
etamido-o-bromomethylcinnamate (3). 2-Acetamidoacrylate (555
mg, 3.9 mmol) was added to a solution of Pd(OAc)2 (39.6 mg, 0.18
mmol) and o-bromoiodobenzene (1 g, 3.53 mmol) in NEt3 (615 mL,
4.41 mmol) in a Schlenk flask under nitrogen. The solution was heated
to 100 °C for 2.5 h, cooled to room temperature, diluted with CH2Cl2
(50 mL), and washed with water (3 × 25 mL). The aqueous layer
was then extracted with CH2Cl2 (3 × 20 mL), and the combined organic
layers were dried over MgSO4, filtered, and concentrated under vacuum
to give the crude product. Recrystallization from CH2Cl2/Et2O afforded
the analytically pure product as a light brown solid (884 mg, 84% yield).
mp 142-144 °C. 1H NMR δ 7.62 (d, J ) 8.8 Hz, 1 H), 7.44 (s, 1 H),
7.40 (s, 1 H), 7.25 (t, J ) 13.55 Hz, 1 H), 7.17 (t, J ) 8.0 Hz, 1 H),
6.99 (s, 1 H), 3.88 (s, 3 H), 2.05 (s, 3 H); 13C{1H} NMR δ 168.7,
165.2, 134.4, 132.8, 130.0, 129.8, 129.5, 127.1, 126.2, 124.3, 52.7,
23.0; IR (KBr) 3211, 3000, 1722, 1654, 1521, 1507 cm-1; Anal. Calcd
for C12H12NO3Br: C, 48.34; H, 4.06. Found: C, 48.60; H, 4.28.
(S)-2-Bromo-N-acetylphenylalanine Methyl Ester (4). 2-Aceta-
mido-o-bromomethylcinnamate (298 mg, 1 mmol), [(COD)Rh]+OTf-
(0.47 mg, 1 × 10-3 mmol), and (S,S)-Et-DUPHOS (0.38 mg, 1.05 ×
10-3 mmol) were added to a Fisher-Porter bottle in a drybox. The
vessel was then closed, removed from the glovebox, and placed in the
fume hood. Anhydrous MeOH (1.3 mL) was added via syringe to the
sealed flask, which was then pressurized to 30 psig with H2 and then
carefully vented. This cycle was repeated two times. The reaction
was then pressurized to 30 psig, and the reaction mixture was stirred
at room temperature for 2.5 h. The H2 was carefully vented, and MeOH
was removed under vacuum. Flash column chromatography (50%
EtOAc/Hex) afforded the analytically pure product as a white solid
(285 mg, 95% yield). mp 95-100 °C. 1H NMR δ 7.54 (d, J ) 8.3
Hz, 1 H), 7.18-7.27 (m, 2 H), 7.11 (dt, J ) 1.8, 7.2 Hz, 1 H), 6.06 (d,
J ) 7.9 Hz, 1 H), 4.92 (dd, J ) 6.8 Hz, 1 H), 3.26 (ddd, J ) 6.8, 13.9,
41.4 Hz, 2 H), 1.96 (s, 3 H); 13C{1H} NMR δ 172.0, 169.8, 135.8,
132.7, 130.9, 128.5, 127.3, 124.7, 52.2, 37.6, 22.7. IR (KBr) 3275,
1747, 1652, 1557, 1539 cm-1; Anal. Calcd for C12H14NO3Br: C, 48.02;
H, 4.70. Found: C, 48.23; H, 4.86. The product was found to be of
99% ee as determined by HPLC analysis using a Chiralcel OJ column,
halides. The use of LnPd/(()-BINAP as a catalyst preserves
the optical purity of the starting amine, in addition to giving
higher yields of coupled products with primary amine substrates
than those obtained using the Pd2(DBA)3/P(o-tolyl)3 catalyst.
The comparison of these catalyst systems and substrates provides
insight into the mechanism for the palladium-mediated racem-
ization of R-substituted amines. Furthermore, this methodology
provides a simple and efficient method for the N-arylation of
optically active R-substituted amines and for the synthesis of
optically active indoline derivatives.
Acknowledgment. We thank Pfizer Inc. and the National
Science Foundation for their support of this research and Strem
Chemical for their generous gifts of (()-BINAP and (S,S)-Et-
DuPHOS. We thank Dr. Xavier Verdaguer for the synthesis
of (S)-2-phenylpyrrolidine.37 S.W. is the recipient of a Ford
Foundation Fellowship. R.A.R. was a NCI Postdoctoral Trainee
supported by NIH Cancer Training Grant CI T32CA09122.
Experimental Procedure
General Considerations. All reactions were run in oven-dried test
tubes under a nitrogen atmosphere unless otherwise stated. Toluene
was distilled from molten sodium under argon. Sodium tert-butoxide
was purchased from Aldrich Chemical Co., stored in a vacuum
atmospheres drybox under nitrogen, and weighed out in the air. All
reagents were commercially available and used without further purifica-
tion unless noted otherwise.
Preparative flash chromatography was performed using ICN Flash
Silica Gel, 230-400 mesh. Yields and ee’s refer to the average of
1
two isolated yields of 95% or higher purity as determined by GC, H
NMR, and elemental analysis (for new compounds). All products were
1
characterized by H NMR, 13C NMR, and infrared (IR) spectroscopy.
New compounds were further characterized by C, H analysis from E
1
& R Microanalytical Laboratories. All H NMR spectra (300 MHz)
are reported in δ units, ppm down field from tetramethylsilane as an
internal standard. All 13C NMR spectra (75 MHz) are reported in ppm
relative to the central line of the triplet for CDCl3 at 77 ppm. Gas
chromatography analyses were performed on a Hewlett-Packard 5890
gas chromatograph, with a FID, a 25 m capillary column with a
dimethylpolysiloxane stationary phase, and a 3392A integrator. Melting
points are uncorrected. Ee’s were determined by HPLC analyses using
a Hewlet Packard series 1050 HPLC with a 1040A detection system
using a Chiralcel OD or OJ column. Alternately, ee’s were determined
by GC analysis with an Alltech G-TA 20 m capillary column, with
0.13 µm thickness and 0.25 mm diameter. Optical rotations were
measured using a sodium lamp (589 nm) and are reported in degrees,
with concentration units of g/100 mL.
Synthesis of (R)-N-(r-methylbenzyl)indoline (2). (R)-2-Bromo-
N-(r-methyl)phenylacetamide. 2-Bromophenylacetic acid (2 g, 9.3
mmol) was added to SOCl2 (5 mL, 68 mmol) in a Schlenk flash under
argon at -78 °C, and the reaction mixture was stirred at room
temperature for 2 h. The excess SOCl2 was removed under vacuum,
and THF (10 mL) was added. The solution was then cooled to 0 °C,
and (R)-R-methylbenzylamine was added dropwise (3 mL, 23.25 mmol).
The solution was warmed to room temperature and stirred for 3 hours.
THF was removed under vacuum, CH2Cl2 (15 mL) was added, and
the solution was washed with a saturated NaHCO3 solution (2 × 10
mL). The organic layers were dried over Na2SO4, filtered, and
concentrated to give the title compound as a white solid (2.74 g, 93%
yield). mp 138-140 °C. 1H NMR δ 7.58 (d, J ) 7.7 Hz, 1 H), 7.20-
7.34 (m, 7 H), 7.15 (dt, J ) 1.8, 7.5 Hz, 1 H), 5.78 (d, J ) 6.2 Hz, 1
H), 5.11-5.29 (m, 1 H), 3.70 (s, 2 H), 1.43 (d, J ) 7.0 Hz, 3 H);
13C{1H} NMR δ 168.8, 143.1, 135.0, 133.3, 131.9, 129.3, 128.8, 128.2,
127.4, 126.2, 125.0, 48.9, 44.3, 21.8; IR (KBr) 3062, 2925, 1640, 1549,
1444, 1412 cm-1; Anal. Calcd for C16H17NOBr: C, 60.53; H, 5.07.
Found: C, 60.39; H, 5.07. [R]24°C +15° (c 1.3, CHCl3).
(R)-2-(o-Bromophenyl)-N-(r-methylbenzyl)ethylamine (1). (R)-
2-Bromo-N-(R-methyl)phenylacetamide (1 g, 3.14 mmol) was dissolved
in THF (10 mL) in a flame dried three-necked flask equipped with a
reflux condenser and cooled to 0 °C. Commercial borane-THF

8456 J. Am. Chem. Soc., Vol. 119, No. 36, 1997
Wagaw et al.
with a 10% IPA/hexane mobile phase, and a flow rate of 0.5 mL/min.
with Et2O. The product was found to have a 70% ee using the
procedure described for entry 1.
[R]25 +29° (c 2.6, CHCl3).
At 110 °C. The experiment described above was repeated at 110
°C. The product was found to have a 40% ee using the procedure
described for entry 1.
(S)-2-Methylcarboxylate-N-acetylindoline (5). 2-Bromo-N-acetylphe-
nylalanine methyl ester (100 mg, 0.33 mmol), Pd2(DBA)3 (15.7 mg,
0.017 mmol, 10 mol % Pd), P(o-tolyl)3 (18.3 mg, 0.06 mmol, 20 mol
%), and Cs2CO3 (215 mg, 0.66 mmol) in toluene (0.6 mL) were heated
to 100 °C in an oven-dried Schlenk flask under nitrogen for 15 h. The
reaction mixture was then cooled to room temperature, directly loaded
onto a chromatographic column, and purified by flash column chro-
matography (50% EtOAc/Hex) to give the product as a clear oil (69
mg, 98% yield). 1H NMR 1.3:1 ratio of rotamers: δ major 8.21 (d, J
) 7.8 Hz, 0.57 H) minor 7.13 (d, J ) 7.3 Hz, 0.43 H), 7.19-7.28 (m,
2 H), 7.01 (t, J ) 7.4, 1 H), major 4.91 (d, J ) 9.7 Hz, 0.57 H) minor
5.15 (dd, J ) 3.1, 11.1 Hz, 0.43 H), major 3.75 (s, 1.7 H) minor 3.71
(s, 1.3 H), 3.41-3.63 (m, 1 H), major 3.24 (d, J ) 16.1 Hz, 0.57 H)
minor 3.08 (dd, J ) 2.7, 16.8 Hz, 0.43 H), major 2.15 (s, 1.7 H) minor
2.47 (s, 1.3 H); 13C{1H} NMR δ 171.6, 168.7, 168.2, 142.4, 141.0,
130.6, 128.3, 127.6, 125.5, 124.1, 123.8, 123.2, 117.0, 113.6, 61.1,
59.9, 52.7, 52.2, 33.3, 31.2, 24.3, 23.5; IR (neat) 2918, 2849, 1868,
1682, 1652 cm-1; Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98.
Found: C, 65.86; H, 6.12. The product was found to be of 99% ee as
determined by HPLC analysis with a Diacel OJ column, with a 10%
isopropyl alcohol/hexane mobile phase and a flow rate of 0.5 mL/min.
[R]26 -48° (c 0.8, CHCl3).
Mechanistic Experiments. (1) The Effect of Pd:P(o-tolyl)3 Ratios
on Product ee’s. Ratio of 2:1 (Eq 3). 4-Bromobiphenyl (233 mg, 1
mmol), (S)-2-phenylpyrrolidine (172 mg, 1.2 mmol, 98% ee), Pd2-
(DBA)3 (18 mg, 0.02 mmol, 4 mol % Pd), P(o-tolyl)3 (24 mg, 0.08
mmol, 8 mol %), NaOt-Bu (134 mg, 1.4 mmol, 1.4 equiv), and toluene
(9 mL) were added to an oven-dried Schlenk flask which was capped
with a septum, purged with nitrogen, and then heated to 100 °C under
nitrogen until the aryl bromide was consumed as determined by GC
analysis. The reaction mixture was then allowed to cool to room
temperature, diluted with Et2O (5 mL), and filtered through Celite, and
the Celite was rinsed with Et2O. The filtrate was dried over MgSO4
and concentrated to give the crude product. The product was found to
be racemic using the procedure described for entry 1.
(4) Control Experiments. Eq 2 without Pd2(DBA)3. 4-Bromo-
biphenyl (233 mg, 1 mmol), (R)-R-Methylbenzylamine (0.1 mL, 1.2
mmol, > 99% ee), Pd2(DBA)3 (9 mg, 0.01 mmol, 4 mol % Pd), P(o-
tolyl)3 (24 mg, 0.08 mmol, 8 mol %), NaOT-Bu (67 mg, 0.7 mmol,
1.4 equiv), and toluene (9 mL) were added to an oven-dried test tube
which was capped with a septum, purged with nitrogen, and then heated
to 100 °C under nitrogen for 12 h. The reaction mixture was then
allowed to cool to room temperature and worked up as described above.
The naphthylamide was found to be of 99% ee as determined by HPLC
analysis using the procedure described above.
Eq 2 without an Aryl Bromide. 4-Bromobiphenyl (233 mg, 1
mmol), (R)-R-methylbenzylamine (0.1 mL, 1.2 mmol, >99% ee), P(o-
tolyl)3 (24 mg, 0.08 mmol, 8 mol %), NaOt-Bu (134 mg, 1.4 mmol,
1.4 equiv), and toluene (9 mL) were added to an oven-dried Schlenk
flask which was capped with a septum, purged with nitrogen, and then
heated to 100 °C under nitrogen for 12 h. The reaction mixture was
then allowed to cool to room temperature, diluted with Et2O (5 mL),
and filtered through Celite, and the Celite was rinsed with Et2O, and
the solution was concentrated under vacuum. CH2Cl2 (10 mL) was
added to the crude reaction mixture, followed by an excess of NEt3
(∼0.5 mL) and 1-napthoyl chloride (∼0.2 mL). The mixture was stirred
at room temperature for 30 min and washed with saturated brine (1 ×
10 mL), and the organic layer was separated, passed through silica
gel, and concentrated under vacuum. The resulting naphthoyl amide
was found to have a 99% ee as determined by HPLC analysis using a
Chiracel OD column, with a 10% IPA/hexane mobile phase, and a flow
rate of 0.5 mL/min.
(5) Lack of Racemization of 7. A sample of 7 (136 mg, 0.5 mmol,
>99% ee), Pd2(DBA)3 (9 mg, 0.01 mmol, 4 mol % Pd), P(o-tolyl)3
(12 mg, 0.04 mmol, 8 mol %), NaOt-Bu (67 mg, 0.7 mmol, 1.4 equiv),
and toluene (5 mL) were added to an oven-dried Schlenk flask which
was capped with a septum, purged with nitrogen, and then heated to
100 °C for 16 h. The reaction mixture was then allowed to cool to
room temperature, diluted with Et2O (5 mL), and filtered through Celite,
and the Celite was rinsed with Et2O. The filtrate was dried over MgSO4
and concentrated to give the crude product. Purification by flash
column chromatography (2% EtOAc/hexane) afforded the product. The
product was found to be >99% ee as determined by HPLC analysis
using the procedure described above.
(6) Racemization of (R)-r-Methylbenzylamine (Eq 4). 4-Bro-
mobiphenyl (233 mg, 1 mmol), (R)-R-methylbenzylamine (0.5 mL, 5
mmol, >99% ee), Pd2(DBA)3 (18 mg, 0.02 mmol, 4 mol % Pd), P(o-
tolyl)3 (24 mg, 0.08 mmol, 8 mol %), NaOt-Bu (134 mg, 1.4 mmol,
1.4 equiv), and toluene (9 mL) were added to an oven-dried Schlenk
flask which was capped with a septum, purged with nitrogen, and then
heated to 100 °C under nitrogen until the aryl bromide was consumed
as determined by GC analysis. The reaction mixture was then allowed
to cool to room temperature, diluted with Et2O (5 mL), and filtered
through Celite, the Celite was rinsed with Et2O, and the combined
organic layer was concentrated under vacuum. Distillation of the
resulting crude reaction mixture (70 °C, 1 mmHg) afforded the
unreacted starting amine (197 mg, 33%). The 1-naphthylamide was
prepared using the procedure described above and was found to have
an 80% ee as determined by HPLC analysis using a Chiracel OD
column, with a 10% IPA/hexane mobile phase, and a flow rate of 0.5
mL/min.
Ratio of 3:1. The procedure described above was repeated using
12 mol % P(o-tolyl)3 (36 mg, 0.012 mmol, 12 mol %). The product
was found to be racemic using the procedure described for entry 1.
(2) Pd-Catalyzed Coupling of r-Chiral Amines with Aryl
Bromides Using Monodentate Phosphine Ligands Other than P(o-
tolyl)3. P(1-naphthyl)3. 4-Bromobiphenyl (233 mg, 1 mmol), (S)-2-
phenylpyrrolidine (172 mg, 1.2 mmol, 98% ee), Pd2(DBA)3 (18 mg,
0.02 mmol, 4 mol % Pd), P(1-naphthyl)3 (34 mg, 0.08 mmol, 8 mol
%), NaOt-Bu (134 mg, 1.4 mmol, 1.4 equiv), and toluene (9 mL) were
added to an oven-dried Schlenk flask which was capped with a septum,
purged with nitrogen, and then heated to 65 °C under nitrogen until
the aryl bromide was consumed as determined by GC analysis. The
reaction mixture was then allowed to cool to room temperature, diluted
with Et2O (5 mL), and filtered through Celite, and the Celite was rinsed
with Et2O. The filtrate was dried over MgSO4 and concentrated to
give the crude product. The product was found to be racemic using
the procedure described for entry 1.
P(o-methoxyphenyl)3. The experiment described above was re-
peated using 8 mol % P(o-methoxyphenyl)3 (28 mg, 0.08 mmol). The
product was found to be racemic using the procedure described for
entry 1.
PPh3. The experiment described above was repeated using 8 mol
% PPh3 (21 mg, 0.08 mmol). The product was found to be racemic
using the procedure described for entry 1.
(7) Exchange Experiment (Eq 5). 4-Bromobiphenyl (233 mg, 1
mmol), 2-phenylpyrrolidine (172 mg, 1.2 mmol), 2-(d5-phenyl)-1-
pyrroline (15 mg, 0.1 mmol) Pd2(DBA)3 (18 mg, 0.02 mmol, 4 mol %
Pd), P(o-tolyl)3 (24 mg, 0.08 mmol, 8 mol %), NaOt-Bu (134 mg, 1.4
mmol, 1.4 eq), and toluene (5 mL) were added to an oven-dried Schlenk
flask which was capped with a septum, purged with nitrogen, and then
heated to 70 °C under nitrogen until the aryl bromide was consumed
as determined by GC analysis. The reaction mixture was then allowed
to cool to room temperature, diluted with Et2O (5 mL), and filtered
through Celite, and the Celite was rinsed with Et2O. The filtrate was
dried over MgSO4 and concentrated to give the crude product.
(3) The Effect of Reaction Temperature on Product ee’s. At
100 °C (Eq 2). 4-Bromobiphenyl (233 mg, 1 mmol), (R)-R-methyl-
benzylamine (0.1 mL, 1.2 mmol, > 99% ee), Pd2(DBA)3 (18 mg, 0.02
mmol, 4 mol % Pd), P(o-tolyl)3 (24 mg, 0.08 mmol, 8 mol %), NaOt-
Bu (134 mg, 1.4 mmol, 1.4 equiv), and toluene (9 mL) were added to
an oven-dried Schlenk flask which was capped with a septum, purged
with nitrogen, and then heated to 100 °C under nitrogen until the aryl
bromide was consumed as determined by GC analysis. The reaction
mixture was then allowed to cool to room temperature, diluted with
Et2O (5 mL), and filtered through Celite, and the Celite was rinsed

Pd-Catalyzed Coupling of Amines with Aryl Bromides
J. Am. Chem. Soc., Vol. 119, No. 36, 1997 8457
Purification by flash column chromatography (2% EtOAc/Hex) afforded
the product. 2H NMR showed that no deuterated coupled product was
formed.
product. Purification by flash column chromatography (2% EtOAc/
Hex) afforded the product as a white solid (112 mg, 82% yield). The
product was found to be of >99% ee using the procedure described
for entry 1.
Pd-Catalyzed Coupling of r-Substituted Optically Active Amines
with Aryl Bromides. Procedure A. The aryl bromide (0.5 mmol),
amine (0.6 mmol), Pd2(DBA)3 (9 mg, 0.01 mmol, 4 mol % Pd), (()-
BINAP (12 mg, 0.02 mmol, 4 mol %), NaOt-Bu (67 mg, 0.7 mmol,
1.4 eq), and toluene (5 mL) were added to an oven-dried test tube which
was capped with a septum, purged with nitrogen, and then heated to
70 °C under nitrogen until the aryl bromide was consumed as
determined by GC analsis. The reaction mixture was then allowed to
cool to room temperature, diluted with Et2O (5 mL), and filtered through
Celite, and the Celite was rinsed with Et2O. The filtrate was dried
over MgSO4 and concentrated to give the crude product. Purification
by flash column chromatography afforded the pure product.
Procedure B. In the drybox, the aryl bromide (0.5 mmol), (DPPF)-
PdCl2‚CH2Cl2, (20.5 mg, 0.025 mmol, 5 mol % Pd), DPPF (42 mg,
0.075 mmol, 15 mol %), and NaOt-Bu (60 mg, 0.625 mmol, 1.25 equiv)
were added to an oven-dried sealable Schlenk flask. The flask was
then sealed, removed from the glovebox, and attached to a Schlenk
line. The amine (0.625 mmol) and THF were added under positive
argon pressure. The flask was then sealed and heated to 100 °C, behind
a blast shield, for 4 h. The reaction mixture was then allowed to cool
to room temperature, diluted with Et2O (5 mL), and filtered through
Celite, and the Celite was rinsed with Et2O. The filtrate was then dried
over MgSO4 and concentrated to give the crude product. Purification
by flash column chromatography afforded the pure product.
(R)-N-(r-Methylbenzyl)-4-phenylaniline (Entry 5). 4-Bromobi-
phenyl (177 mg, 0.5 mmol), Pd(OAc)2 (6 mg, 0.025 mmol, 5 mol %
Pd), DPPF (14 mg, 0.025 mmol, 5 mol %), and NaOt-Bu (60 mg, 0.625
mmol, 1.25 equiv) were added to an oven-dried Schlenk flask in a
drybox under nitrogen. The flask was then capped with a septum,
removed from the glovebox, and attached to a Schlenk line. (R)-R-
Methylbenzylamine (0.08 mL, 0.625 mmol, 1.25 equiv, >99% ee) and
THF (0.5 mL) were added under positive argon pressure. The flask
was then sealed and heated to 100 °C, behind a blast shield, for 12 h.
The reaction mixture was then allowed to cool to room temperature,
diluted with Et2O (5 mL), and filtered through Celite, and the Celite
were rinsed with Et2O. The filtrate was then dried over MgSO4 and
concentrated to give the crude product. Purification by flash column
chromatography (2% EtOAc/Hex) afforded the product as a white solid
(54 mg, 40% yield). The product was found to be of >99% ee using
the procedure described for entry 1.
(R)-N-(4-Benzotrifluoro)-N-r-dimethylbenzylamine (Entry 6).
Procedure A was used to convert 4-bromobenzotrifluoride and (R)-N-
R-methylbenzylamine (96% ee) to the title compound. Purification by
flash column chromatography (1% EtOAc/Hex) gave the product as a
white solid (61 mg, 44% yield). mp 72-74 °C. 1H NMR δ 7.45 (d,
J ) 8.8 Hz, 2 H), 7.33 (d, J ) 6.0 Hz, 2 H), 7.27 (d, J ) 8.3 Hz, 3 H),
6.82 (d, J ) 9.0 Hz, 2 H), 5.18 (qd, J ) 6.7, 13.8 Hz, 1 H), 2.74 (s,
3 H), 1.57 (d, J ) 6.7 Hz, 3 H); 13C{1H} NMR δ 152.3, 142.1, 128.8,
127.3, 126.9, 126.8, 126.73, 126.68, 126.64, 111.8, 56.3, 32.2, 16.9;
IR (neat) 2981, 2914, 2832, 1613 cm-1; Anal. Calcd for C16H16NF3:
C, 68.81; H, 5.77. Found: C, 68.59; H, 5.45. The product was found
to be of 96% ee as determined by HPLC analysis using a Chiralcel OJ
column with a 10% IPA/hexane mobile phase and a flow rate of 0.5
mL/min. [R]26 +138° (c 1.0, CHCl3).
(R)-N-(4-Benzotrifluoro)-N-r-dimethylbenzylamine (Entry 7).
4-Bromobenzotrifluoride (0.5 mmol, 0.07 mL), (R)-N-R-methylbenzy-
lamine (0.6 mmol, 0.06 mL, 96% ee), Pd2(DBA)3 (4.5 mg, 0.005 mmol,
2 mol % Pd), (()-BINAP (6 mg, 0.02 mmol, 2 mol %), NaOt-Bu (67
mg, 0.7 mmol, 1.4 eq), and toluene (5 mL) were added to an oven-
dried test tube which was capped with a septum, purged with nitrogen,
and then heated to 100 °C under nitrogen until the aryl bromide was
consumed as determined by GC analysis. The reaction mixture was
then allowed to cool to room temperature, diluted with Et2O (5 mL),
and filtered through Celite, and the Celite was rinsed with Et2O. The
filtrate was dried over MgSO4 and concentrated to give the crude
product. Purification by flash column chromatography (1% EtOAc/
Hex) afforded the pure product (88 mg, 63% yield). The product was
found to be of >99% ee using the procedure described for entry 6.
(R)-N-(4-Benzotrifluoro)-N-r-dimethylbenzylamine (Entry 8).
Procedure B was used to convert 4-bromobenzotrifluoride and (R)-N-
R-methylbenzylamine (96% ee) to the title compound (78 mg, 56%
yield). The product was found to be of 96% ee as determined by the
procedure described in entry 6.
(R)-N-(4-Benzophenone)-1-cyclohexylethylamine (Entry 9). Pro-
cedure A was used to convert 4-bromobenzophenone and (R)-1-
(cyclohexyl)ethylamine (>99% ee) to the title compound. Purification
by flash column chromatography (10% EtOAc/Hex) gave the product
as a viscous yellow oil (131 mg, 89% yield). 1H NMR δ 7.69-7.75
(m, 4 H), 7.41-7.54 (m, 3 H), 6.53 (dt, J ) 5.8 Hz, 3.15 Hz, 2 H),
4.17 (d, J ) 8.4 Hz), 3.43 (dd, J ) 6.3 Hz, 14.3 Hz, 1 H), 1.66-1.84
(m, 5H), 1.44-1.46 (m, 1 H), 0.99-1.26 (m, 8 H); 13C{1H} NMR δ
195.1, 151.9, 139.5, 133.3, 131.2, 129.6, 128.2, 125.6, 111.6, 52.9,
43.3, 29.8, 28.7, 26.7, 26.5, 26.4, 17.6; IR (neat) 3346, 2926, 2850,
1590, 1493 cm-1; Anal. Calcd for C21H25NO: C, 82.04; H, 8.20.
Found: C, 82.06; H, 8.37. The product was found to be >99% ee as
determined by HPLC analysis using a Chiralcel OJ column, with a 2%
IPA/hexane mobile phase, and a flow rate of 0.7 mL/min. [R]25 +11°
(c 0.4, CHCl3).
(R)-N-(r-Methylbenzyl)-4-phenylaniline (Table 1, Entry 1). Pro-
cedure A was used to convert 4-bromobiphenyl and (R)-R-methylben-
zylamine (>99% ee) to the title compound. Purification by flash
column chromatography (2% EtOAc/Hex) gave the product as a white
solid (119 mg, 88% yield). mp 98-100 °C. 1H NMR δ 7.47 (d, J )
7.4 Hz, 2 H), 7.29-7.39 (m, 8 H), 7.21 (m, 2 H), 6.56 (dd, J ) 5.2,
2.0 Hz, 2 H), 4.51 (q, J ) 6.9 Hz, 1 H), 4.12 (s, 1 H), 1.52 (d, J ) 6.9
Hz, 3 H); 13C{1H} NMR δ 146.8, 145.2, 141.36, 130.23, 128.8, 128.7,
127.9, 127.1, 126.4, 126.1, 125.9, 113.7, 53.6, 25.1; IR (neat) 2920,
1460, 1377 cm-1
. Anal. Calcd for C20H19N: C, 87.87; H, 7.01.
Found: C, 87.84; H, 7.25. The product was found to be of >99% ee
as determined by HPLC analysis using a Chiralcel OD column, with a
10% isopropyl alcohol (IPA)/hexane mobile phase, and a flow rate of
0.5 mL/min. [R]24 +54° (c 0.5, CHCl3).
(R)-N-(r-Methylbenzyl)-4-phenylaniline (Entry 2). 4-Bromobi-
phenyl (0.5 mmol, 117 mg), (R)-R-methylbenzylamine (0.6 mmol, 0.05
mL, >99% ee), Pd2(DBA)3 (4.5 mg, 0.005 mmol, 2 mol % Pd), (()-
BINAP (6 mg, 0.01 mmol, 2 mol %), NaOt-Bu (67 mg, 0.7 mmol, 1.4
equiv), and toluene (5 mL) were added to an oven-dried test tube which
was capped with a septum, purged with nitrogen, and then heated to
100 °C under nitrogen until the aryl bromide was consumed, as
determined by GC analysis. The reaction mixture was then allowed
to cool to room temperature, diluted with Et2O (5 mL), and filtered
through Celite, and the Celite was rinsed with Et2O. The filtrate was
dried over MgSO4 and concentrated to give the crude product.
Purification by flash column chromatography (2% EtOAc/Hex) afforded
the pure product (89 mg, 65% yield). The product was found to be of
>99% ee using the procedure described for entry 1.
(R)-N-(r-Methylbenzyl)-4-phenylaniline (Entry 3). Procedure B
was used to convert 4-bromobiphenyl and (R)-R-methylbenzylamine
(>99% ee) to the title compound (110 mg, 80% yield). The product
was found to be of >99% ee using the procedure described for entry
1.
(R)-N-(r-Methylbenzyl)-4-phenylaniline (Entry 4). 4-Bromobi-
phenyl (177 mg, 0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol, 5 mol %
Pd), DPPF (55.5 mg, 0.01 mmol, 20 mol %), and NaOt-Bu (60 mg,
0.625 mmol, 1.25 equiv) were added to an oven-dried sealable Schlenk
flask in a drybox under nitrogen. The flask was then sealed, removed
from the drybox, and attached to a Schlenk line. (R)-R-Methylben-
zylamine (80 µL, 0.625 mmol, >99% ee) and THF (0.5 mL) were
added under positive argon pressure. The flask was sealed and heated
to 100 °C, behind a blast shield for 4 h. The reaction mixture was
then allowed to cool to room temperature, diluted with Et2O (5 mL),
and filtered through Celite, and the Celite was rinsed with Et2O. The
filtrate was dried over MgSO4 and concentrated to give the crude
(S)-N-(4-Chlorophenyl)-2-phenylpyrrolidine (Entry 10). Proce-
dure A was used to convert 4-bromochlorobenzene and (S)-2-phe-
nylpyrrolidine37 (>99% ee) to the title compound. Purification by flash
column chromatography (2% EtOAc/Hex) gave the product as white

8458 J. Am. Chem. Soc., Vol. 119, No. 36, 1997
Wagaw et al.
solid (101 mg, 79% yield). mp 50-52 °C. 1H NMR δ 7.16-7.29
(m, 6 H), 7.05 (d, J ) 8.7 Hz, 2 H), 6.37 (d, J ) 8.7 Hz, 2 H), 4.67 (d,
J ) 7.7 Hz, 1 H), 3.65 (dt, J ) 8.04 Hz, 2.75 Hz, 1 H), 3.36 (dd, J )
15.78 Hz, 8.81 Hz, 1 H), 2.35-2.40 (m, 1 H), 1.89-2.04 (m, 3 H);
13C{1H} NMR δ 145.8, 144.2, 128.9, 128.7, 126.9, 126.0, 120.7, 113.6,
63.2, 49.4, 36.3, 23.3; IR (neat) 2968, 2849, 1596, 1490 cm-1. Anal.
Calcd for C16H16NCl: C, 74.56; H, 6.26. Found: C, 74.34; H, 6.43.
The product was found to be of >99% ee as determined by HPLC
analysis using a Chiralcel OD column, with a 2% IPA/hexane mobile
phase and a flow rate of 0.5 mL/min. [R]25 -99° (c 2.8, CHCl3).
(R)-N-(sec-Butyl)-2-aminonaphthalene (Entry 11). Procedure A
was used to convert 2-bromonaphthalene and (R)-sec-butylamine (94%
ee) to the title product. Purification by flash column chromatography
(2% EtOAc/Hex) gave the product as a light brown oil (70 mg, 70%
yield). 1H NMR δ 7.57-7.66 (m, 3H), 7.31-7.36 (m, 1 H), 7.16 (dt,
J ) 7.2 Hz, 2.0 Hz, 1 H), 6.83 (dd, J ) 2.5 Hz, 8.8 Hz, 1 H), 6.77 (d,
J ) 1.6 Hz, 1 H), 3.62 (s, 1 H), 3.49-3.58 (m, 1 H), 1.50-1.71 (m,
2 H), 1.23 (d, J ) 5.5 Hz, 3 H), 0.99 (t, J ) 7.2 Hz, 3 H); 13C{1H}
NMR δ 145.5, 135.5, 129.1, 127.8, 127.4, 126.4, 125.9, 121.8, 118.5,
104.8, 49.9, 29.7, 20.3, 10.6; IR (neat) 3404, 3050, 2963, 2929, 2874,
1628, 1520, 1484, 1398 cm-1. Anal. Calcd for C14H17N: C, 84.37;
H, 8.60. Found: C, 84.59; H, 8.76. The product was found to be of
94% ee as determined by HPLC analysis using a Chiralcel OD column,
with a 5% IPA, 0.05% diethylamine/hexane mobile phase, and a flow
rate of 0.5 mL/min. [R]25 +35° (c 3.2, CHCl3).
(R,R)-trans-N,N,N′-(Tri-2-pyridyl)-1,2-cyclohexyldiamine (Entry
12). 2-Bromopyridine (0.3 mL, 3 mmol), (R,R)-trans-1,2-cyclohexy-
ldiamine (0.12 mL, 1 mmol, >99% ee), Pd2(DBA)3 (14 mg, 0.015
mmol, 6 mol % Pd), (()-BINAP (20 mg, 0.03 mmol), and NaOt-Bu
(327 mg, 3.4 mmol, 3.4 eq) were heated to 70 °C in an oven-dried
Schlenk flask under argon for 18 h. The reaction mixture was allowed
to cool to room temperature, diluted with Et2O (10 mL), and washed
with saturated brine (3 × 10 ml), and the organic layer was dried over
MgSO4 and concentrated to give the crude product. Purification by
flash column chromatography (15% EtOAc/Hex, with 5% NEt3)
afforded the product as a yellow solid (258 mg, 77% yield). mp 104-
105 °C. 1H NMR δ 8.37 (d, J ) 4.1 Hz, 2 H), 7.93 (d, J ) 4.4 Hz,
1 H), 7.37 (dt, J ) 7.76 Hz, 2 H), 7.19 (dt, J ) 7.74 Hz, J ) 1.77 Hz,
1H), 6.86 (dd, J ) 6.55 Hz, J ) 5.2 Hz, 2 H), 6.58 (d, J ) 8.06 Hz,
2 H), 6.37 (dd, J ) 6.2 Hz, J ) 5.2 Hz, 1 H), 6.09 (d, J ) 8.4 Hz, 1
H), 5.49 (d, J ) 7.4 Hz, 1 H), 5.03 (dt, J ) 11.4 Hz, J ) 3.7 Hz, 1 H),
3.91-3.95 (m, 1 H), 2.31-2.34 (m, 1 H), 2.03-2.08 (m, 1 H), 1.71-
1.79 (m, 3 H), 1.30-1.44 (m, 3 H); 13C{1H} NMR δ 158.5, 157.8,
148.4, 148.0, 137.6, 136.8, 117.8, 117.7, 111.7, 107.4, 59.7, 53.8, 33.9,
32.0, 26.2, 24.9; IR (nujol) 2971, 2880, 2836, 1465 cm-1; Anal. Calcd
for C21H23N5: C, 73.02; H, 6.71. Found: C, 73.29; H, 6.98. The
product was found to be of >99% ee as determined by HPLC analysis
using a Chiralcel OD column, with a 10% IPA/hexane mobile phase
and a flow rate of 0.5 mL/min. [R]25 +149° (c 0.9, CHCl3).
NO2: C, 80.59; H, 7.54. Found: C, 80.81; H, 7.70. The product was
found to be of >99% ee as determined by HPLC analysis using a
Chiralcel OD column, with a 5% IPA/hexane mobile phase and a flow
rate of 0.5 mL/min. [R]26 -100° (c 2.1, CHCl3).
tert-Butyl Ether of (S)-N-(3-(2-(1,3-Dioxolanyl))phenyl)prolinol
(Entry 14). Procedure A was used to couple the tert-butyl ether of
(S)-prolinol (99% ee) with 2-(3-bromophenyl)-1,3-dioxolane to give
the title product. Purification by flash column chromatography (10%
EtOAc/Hex) afforded the title product as a thick clear oil (106 mg,
70% yield). 1H NMR δ 7.22 (t, J ) 7.3 Hz, 1 H), 6.74-6.79 (m, 2
H), 6.63 (dd, J ) 2.3 Hz, 14.3 Hz, 1 H), 5.78 (s, 1 H), 4.00-4.12 (m,
4 H), 3.79-3.86 (m, 1 H), 3.51 (dd, J ) 3.4 Hz, 8.7 Hz, 1 H), 3.03-
3.14 (m, 2 H), 1.96-2.06 (m, 4 H), 1.19 (s, 9 H); 13C{1H} NMR δ
147.6, 138.9, 129.2, 113.5, 112.6, 109.5, 104.2, 72.8, 65.2, 61.6, 58.9,
48.3, 28.7, 27.5, 23.2; IR (neat) 2971, 2875, 1606 cm-1; Anal. Calcd
for C18H27NO3: C, 70.79; H, 8.91. Found: C, 70.40; H, 8.89. The
product was found to be of 99% ee as determined by HPLC analyses
with a Diacel OD column, with a 10% isopropyl alcohol/hexane mobile
phase and a flow rate of 0.5 mL/min. [R]25 +136° (c 0.5, CHCl3).
Preparation of Starting Materials. tert-Butyl Ether of (S)-
Phenylalaninol. Isobutylene (∼10 mL) was added to Fisher-Porter
bottle charged with (S)-phenylalaninol (5 g, 33 mmol) and H2SO4 (2.12
mL, 40 mmol) in CH2Cl2 (10 mL) and stirred at room temperature for
12 h. The isobutylene was carefully vented, and 1 N NaOH was added
till the solution reached pH ) 12. The aqueous layer was extracted
with Et2O (3 × 10 mL), and the combined organic layers were dried
over anhydrous K2CO3, filtered, and concentrated under vacuum to give
the crude product as a yellow oil. Purification by Kugelrohr distillation
gave the product as a clear oil (4.22 g, 62% yield). 1H NMR δ 7.20-
7.33 (m, 5 H), 3.35-3.37 (m, 1 H), 3.1503.22 (m, 2 H), 2.79 (dd, J )
4.4, 13.1 Hz, 1 H0, 2.52 (dd, J ) 8.1, 13.5 Hz, 1 H), 1.39 (s, 2 H),
1.19 (s, 9 H); 13C{1H} NMR δ 139.22, 129.22, 128.36, 126.13, 72.68,
66.33, 52.77, 40.84, 27.55; IR (neat) 2973, 1363, 1198, 1083 cm-1
.
Anal. Calcd for C13H21NO: C, 75.32; H, 10.21. Found: C, 75.24; H,
10.42. [R]25°C -9° (c 1.3, CHCl3).
tert-Butyl Ether of (S)-Prolinol. The procedure described above
was used to convert (S)-prolinol (2.5 g, 25 mmol), isobutylene (∼10
mL), and H2SO4 (1.6 mL, 30 mmol) to the title product (1.25 g, 32%
yield). Spectral data was in accord with that reported by Vedejs.38
2-(d5-Phenyl)-1-pyrroline (9).39 Bromobenzene-d5 (0.65 mL, 6.17
mmol) was dissolved in Et2O (5 mL) and added dropwise to a solution
of Mg shavings (151 mg, 6.17 mmol) and an I2 crystal in Et2O (5 mL)
in a three-necked flask equipped with a reflux condenser. The solution
was stirred at room temperature until the magnesium was consumed
(2 h). 4-Chlorobutyronitrile (0.46 mL, 5.14 mmol) was then added,
and the solution was heated to reflux for 2 h. The reaction mixture
was cooled to room temperature, and Et2O (20 mL) was added. The
ether solution was washed with saturated brine (2 × 20 mL), stired
with charcoal, dried over MgSO4, filtered, and concentrated in Vacuo
to give the crude product as a yellow oil. Purification by Kugelrohr
distillation gave the product as a white solid (632 mg, 68% yield). 1H
NMR δ 4.04-4.10 (m, 2 H), 2.92-2.98 (m, 2 H), 1.99-2.09 (m, 2
H); 13C{1H} NMR (125 MHz) δ 173.16, 134.29, 129.67 (t, J ) 0.2
Hz, 1 H), 127.79 (t, J ) 0.2 Hz, 1 H), 127.05 (t, J ) 0.2 Hz, 1 H),
61.44, 34.81, 22.56; IR(KBr) 2966, 2919, 2849, 1613, 1537, 1446, 1431,
tert-Butyl Ether of (S)-N-(4-Benzophenone)phenylalaninol (Entry
13). Procedure A was used to convert the tert-butyl ether of
(S)-phenylalaninol (>99% ee) and 4-bromobenzophenone to the title
compound. Purification by flash column chromatography (10% EtOAc/
1
Hex) gave the product as a thick yellow oil (190 mg, 98% yield). H
NMR δ 7.73 (t, J ) 7.9 Hz, 4 H), 7.42-7.52 (m, 3 H), 7.23-7.33 (m,
5 H), 6.61 (d, J ) 8.7 Hz, 2 H), 4.66 (d, J ) 8.9 Hz, 1 H); 13C{1H}
NMR δ 195.0, 151.3, 139.2, 138.4, 133.1, 131.1, 129.4, 129.3, 128.5,
128.0, 126.4, 125.9, 111.8, 73.1, 61.1, 53.8, 37.0, 27.6; IR (nujol) 2972,
2928, 1639, 1590, 1526, 1317, 1282 cm-1; Anal. Calcd for C26H29-
1400 cm-1
.
JA971583O