Synthesis of N-Alkylated and N-Arylated Derivatives of 2-Amino-2′-hydroxy-l, 1′-binaphthyl (NOBIN) and 2,2′-Diamino-1, 1′'-binaphthyl and Their Application in the Enantioselective Addition of Diethylzinc to Aromatic Aldehydes a

Article abstract of DOI:10.1021/jo9807565

High-yield reductive alkylation of CR)-(+)-l and (R)-(+)-2 has been accomplished with a series of ketones (even as bulky as 2-adamantanone) and NaBH₄/H₂SO₄ in THF at room temperature to give the respective N-alkylated binaphthyls 6a-c, 9a-c, and 10a-c. Related W-phenyl derivatives 14, 16, and 17 were obtained via the Pd(0)-catalyzed coupling of (R)-(+)-l and (R)-(+)-2, respectively, with PhBr; no racemization was observed. Subsequent reductive methylation with CH₂O and NaBH₄/H₂SO₄ afforded the bidentate ligands 8a-c, 12a-c, 13a-c, 15, 18, and 19, which comprise a new class of binaphthyls. Their utility as chiral ligands has been demonstrated for the addition of Et₂Zn to benzaldehyde and its congeners; the highest level of asymmetric induction was observed for N.N-dimethyl NOBIN (R)-(+)-3 (3 mol %) in conjunction with n-BuLi (5.4 mol %), which gave CR)-(+)-21a in 88% ee. Derivatives of the amino phenol 1 (NOBIN) proved more efficient than the corresponding diamines derived from 2. The stereochemical outcome and the enhancement of asymmetric induction by Li⁺ are discussed in terms of the chelated transition state 26.

Full text of DOI:10.1021/jo9807565

J . Org. Chem. 1998, 63, 7727-7737
7727
Syn th esis of N-Alk yla ted a n d N-Ar yla ted Der iva tives of
2-Am in o-2′-h yd r oxy-1,1′-bin a p h th yl (NOBIN) a n d
2,2′-Dia m in o-1,1′-bin a p h th yl a n d Th eir Ap p lica tion in th e
En a n tioselective Ad d ition of Dieth ylzin c to Ar om a tic Ald eh yd es†
Sˇteˇpa´n Vyskocˇil,*,‡,§ Stanislav J aracz,‡ Martin Smrcˇina,‡ Martin Sˇt´ıcha,‡ Vladim´ır Hanusˇ,|
Miroslav Pola´sˇek,| and Pavel Kocˇovsky´*,§,
Department of Organic Chemistry, Charles University, 128 40, Prague 2, Czech Republic,
Department of Chemistry, University of Leicester, Leicester LE1 7RH, U.K., and J . Heyrovsky´ Institute of
Physical Chemistry and Electrochemistry, Academy of Sciences of the Czech Republic,
182 23 Prague 8, Czech Republic
Received April 21, 1998
High-yield reductive alkylation of (R)-(+)-1 and (R)-(+)-2 has been accomplished with a series of
ketones (even as bulky as 2-adamantanone) and NaBH4/H2SO4 in THF at room temperature to
give the respective N-alkylated binaphthyls 6a -c, 9a -c, and 10a -c. Related N-phenyl derivatives
14, 16, and 17 were obtained via the Pd(0)-catalyzed coupling of (R)-(+)-1 and (R)-(+)-2, respectively,
with PhBr; no racemization was observed. Subsequent reductive methylation with CH2O and
NaBH4/H2SO4 afforded the bidentate ligands 8a -c, 12a -c, 13a -c, 15, 18, and 19, which comprise
a new class of binaphthyls. Their utility as chiral ligands has been demonstrated for the addition
of Et2Zn to benzaldehyde and its congeners; the highest level of asymmetric induction was observed
for N,N-dimethyl NOBIN (R)-(+)-3 (3 mol %) in conjunction with n-BuLi (5.4 mol %), which gave
(R)-(+)-21a in 88% ee. Derivatives of the amino phenol 1 (NOBIN) proved more efficient than the
corresponding diamines derived from 2. The stereochemical outcome and the enhancement of
asymmetric induction by Li+ are discussed in terms of the chelated transition state 26.
In tr od u ction
prominence. In contrast to the wide use of these binaph-
thyls, the diamine 27 has enjoyed relatively less popular-
ity despite its straightforward, one-step synthesis from
2-naphthol and hydrazine and its ready resolution into
enantiomers.8
The 1,1′-binaphthyl-based ligands owe their success in
asymmetric reactions to the chiral cavity they create
around the metal center.1 Within this class, the prime
role is played by C2-symmetrical 2,2′-disubstituted 1,1′-
binaphthyls bearing identical coordinating groups, in
particular Noyori’s BINOL2 and BINAP.3 Their con-
geners with nonidentical substituents at positions 2 and
2′ (which are no longer C2-symmetrical) have only
recently emerged, and among them, Hayashi’s MOP (with
2-OMe and 2′-PPh2)4 and our NOBIN5,6 (1) have risen to
We reasoned that introducing bulky, lipophilic sub-
stituent(s) at the amino groups of 1 and 2 should restrict
the conformational freedom, thereby creating a more
rigid chiral cavity and, in the case of the diamine,
enhancing the C2 twist. A metal catalyst, based on this
class of ligands, can therefore be expected to exhibit
raised levels of asymmetric induction. Moreover, im-
proved solubility of both the ligands and the complexes
in common organic solvents can also be anticipated.
† In memoriam Vladimir Prelog.
‡ Charles University.
§ University of Leicester.
We have recently shown that the NH2 group of 2-hy-
droxy-2′-amino-1,1′-binaphthyl (NOBIN, 1) can be readily
dimethylated on reaction with 40% aqueous CH2O and
| J . Heyrovsky´ Institute.
E-mail: PK10@Le.ac.uk.
(1) (a) Morrison, J . D. Asymmetric Synthesis; Academic Press: New
York, 1983-1985, Vols. 1-5. (b) Kocˇovsky´, P.; Turecˇek, F.; Ha´j´ıcˇek, J .
Synthesis of Natural Products: Problems of Stereoselectivity; CRC
Press: Boca Raton, FL, 1986; Vols. 1 and 2. (c) Nogrady, M. Stereo-
selective Synthesis; VCH: Weinheim, 1987. (d) Ojima, I. Asymmetric
Catalysis; VCH: New York, 1993. (e) Noyori, R. Asymmetric Catalysis
in Organic Synthesis; Wiley & Sons: New York, 1994.
(2) (a) Noyori, R.; Tomino, I.; Tanimoto, Y. J . Am. Chem. Soc. 1979,
101, 3129. (b) Noyori, R. Pure Appl. Chem. 1981, 53, 2315. (c) Noyori,
R.; Tomino, I.; Tanimoto, Y.; Nishizawa M. J . Am. Chem. Soc. 1984,
106, 6709. (d) Noyori, R.; Takaya, H. Chem. Scr. 1985, 25, 83. (e) Wang,
J . T.; Fan, X.; Quian, Y. M. Synthesis 1989, 292. (f) Reetz, M. T.; Kyung,
S. H.; Bolm, C.; Zierke, T. Chem. Ind. (London) 1986, 824.
(3) (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.;
Souchi, T.; Noyori, R. J . Am. Chem. Soc. 1980, 102, 7932. (b) Miyashita,
A.; Takaya, H.; Souchi, T.; Noyori, R. Tetrahedron 1984, 40, 1245. (c)
Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.;
Taketomi, T.; Akutagawa, S.; Noyori, R. J . Org. Chem. 1986, 51, 629.
(d) Takaya, H.; Akutagawa, S.; Noyori, R. Org. Synth. 1988, 67, 20.
(4) (a) Uozumi, Y.; Hayashi, T. J . Am. Chem. Soc. 1991, 113, 9887.
(b) Hayashi, T.; Iwamura, H.; Naito, M.; Matsumoto, Y.; Uozumi, Y.;
Miki, M.; Yanagi, K. J . Am. Chem. Soc. 1994, 116, 775. (c) For a review,
see: Hayashi, T. Acta Chem. Scand. 1996, 50, 259.
(5) (a) Smrcˇina, M.; Lorenc, M.; Hanusˇ, V.; Kocˇovsky´, P. Synlett
1991, 231. (b) Smrcˇina, M.; Lorenc, M.; Hanusˇ, V.; Sedmera, P.;
Kocˇovsky´, P. J . Org. Chem. 1992, 57, 1917. (c) Smrcˇina, M.; Pola´kova´,
J .; Vyskocˇil, Sˇ.; Kocˇovsky´, P. J . Org. Chem. 1993, 58, 4534. (d) Smrcˇina,
M.; Vyskocˇil, Sˇ.; Ma´ca, B.; Pola´sˇek, M.; Claxton, T. A.; Abbott, A. P.;
Kocˇovsky´, P. J . Org. Chem. 1994, 59, 2156. (e) Smrcˇina, M.; Vyskocˇil,
Sˇ.; Pol´ıvkova´, J .; Pola´kova´, J .; Kocˇovsky´, P. Collect. Czech. Chem.
Commun. 1996, 61, 1520. (f) Vyskocˇil, Sˇ.; Smrcˇina, M.; Lorenc, M.;
Hanusˇ, V.; Pola´sˇek, M.; Kocˇovsky´, P. Chem. Commun. 1998, 585.
(6) For ligands derived from NOBIN, see: (a) Carreira, E. M.; Singer,
R. A.; Wheeseong, L. J . Am. Chem. Soc. 1994, 116, 8837. (b) Carreira,
E. M.; Wheeseong, L.; Singer, R. A. J . Am. Chem. Soc. 1995, 117, 3649.
(c) Singer, R. A.; Carreira, E. M. J . Am. Chem. Soc. 1995, 117, 12360.
For the corresponding methyl ether and imines derived from it, see:
(d) Kno¨lker, H.-J .; Hermann, H. Angew. Chem., Int. Ed. Engl. 1996,
35, 341.
(7) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis
1992, 503.
(8) Miyano, S.; Nawa, M.; Mori, A.; Hashimoto, H. Bull. Chem. Soc.
J pn. 1984, 57, 2171.
10.1021/jo9807565 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/16/1998

7728 J . Org. Chem., Vol. 63, No. 22, 1998
Vyskocˇil et al.
Ch a r t 1
Sch em e 1a
NaBH4/H2SO4 in THF9 to give its N,N-dimethyl analogue
3 (84%),9a whereas the classical Eschweiler-Clarke reac-
tion gave much less satisfactory results.9a The per-
methylated diamine 5 was originally prepared by Snyder
from 2 via the Eschweiler-Clarke methylation in modest
yield,10 and we assumed that our NaBH4-mediated
reductive methylation,9 which proved superior in the case
of NOBIN, would also be successful here.9b
Herein, we report the synthesis of the nitrogen-
alkylated or phenylated amines derived from 1 and 2
with alkyl groups of different sizes and their application
in the ligand-accelerated addition of diethylzinc to aro-
matic aldehydes. Also reported are the effects of catalytic
amounts of n-butyllithium, and the superiority of amino
phenols over diamines is demonstrated.
a
Ketone ) acetone, cyclohexanone, or 2-adamantanone.
8c (86%), respectively, demonstrating that the second
alkylation of the Ar-NHR group can only be attained
with a sterically less demanding aldehyde.
Resu lts a n d Discu ssion
Reductive alkylation of the diamine (R)-(+)-2 (g99%
ee) with the above ketones and NaBH4/H2SO4 in THF
has also been found to occur readily at room temperature,
affording mixtures of N,N′-bisalkylated and N-mono-
alkylated products (Scheme 2). Thus, the reaction of (R)-
(+)-2 with acetone gave predominantly the N,N′-bisiso-
propyldiamine 9a (82%), accompanied by a small amount
of the monoalkylated product 10a (15%). Enhancing the
steric demands of the ketone led to a gradual increase
in the proportion of monoderivatization; with cyclohex-
anone, a ∼2:1 mixture of the bis- and monoalkylated
diamines 9b (64%) and 10b (28%) was obtained, whereas
2-adamantanone gave mainly the monoalkylated product
10c (71%), with the bisderivative 9c being formed in a
mere 15% yield. As in the case of 6c, all attempts to
improve the yield of 9c failed. Glutaric dialdehyde, on
the other hand, readily afforded the corresponding bis-
piperidine derivative 11 (98%).11 As expected, formal-
dehyde produced (R)-(+)-5 in high yield (88%).9b
The bisalkylated diamines 9a -c were then permeth-
ylated with CH2O (aq) under the same conditions (NaBH4,
H2SO4, THF, rt) to give 12a (76%), 12b (75%), and 12c
(59%), respectively. Similarly, the monoalkylated di-
amines 10a -c were converted into 13a (65%), 13b (68%),
and 13c (64%), respectively.
Syn th esis of th e N-Ar yla ted Bin a p h th yls. Ap-
pending an alkyl substituent to a nitrogen atom is one
of the classical synthetic transformations that can be
accomplished, e.g., via a nucleophilic substitution or by
reductive alkylation (vide supra). By contrast, N-aryl-
ation is much more difficult to attain so that this strategy
is normally avoided.12 It was not only until very recently
that a new method emerged, being independently devel-
oped by Hartwig13 and Buchwald.14 With the aid of a
number of simple model substrates, the latter authors
have demonstrated that amines can be arylated by aryl
Syn th esis of th e N-Alk yla ted Bin a p h th yls. Since
the reductive methylation of NOBIN (1) with formalde-
hyde and NaBH4 proved very efficient,9 it was desirable
to explore the scope of this reaction, in particular its
feasibility with other carbonyl partners of increased bulk.
If successful, this method would open a straightforward
entry into an array of binaphthyl-based ligands. In this
combinatorial-like approach, amino phenol5 (R)-(+)-1 and
diamine7,8 (R)-(+)-2 were employed as linchpins (Chart
1), onto whose nitrogen atoms we intended to attach
various alkyls; acetaldehyde, acetone, cyclohexanone,
2-adamantanone, and glutaric dialdehyde, in addition to
formaldehyde, were selected as representative carbonyl
partners.
Reductive alkylation of (R)-(+)-1 (g99% ee) with acet-
aldehyde and NaBH4/H2SO4 in THF proceeded at ambi-
ent temperature in the same way as observed with
formaldehyde to afford N,N-diethyl-NOBIN 4 (91%) as
the product of dialkylation (Chart 1). By contrast, only
monoalkylation was observed with the sterically more
demanding ketones. Thus, acetone and cyclohexanone
furnished 6a (89%) and 6b (90%), respectively (Scheme
1), as the result of an essentially quantitative conversion
of the starting material, whereas 2-adamantanone gave
a rather lower yield of 6c (57%). In the latter instance,
the reaction did not proceed to completion; extending the
reaction period, varying the temperature, and employing
an excess of 2-adamantanone and/or NaBH4 had little
effect. On the other hand, glutaric dialdehyde readily
afforded the corresponding piperidine derivative 7 (96%).
The monoalkylated amino phenols 6a -c were then
methylated with CH2O (aq) under the same conditions
(NaBH4, H2SO4, THF, rt) to give 8a (96%), 8b (95%), and
(9) (a) Smrcˇina, M.; Vyskocˇil, Sˇ.; Pol´ıvkova´, J .; Pola´kova´, J .; Sejbal,
J .; Hanusˇ, V.; Pola´sˇek, M.; Verrier, H.; Kocˇovsky´, P. Tetrahedron:
Asymmetry 1997, 8, 537. (b) Vyskocˇil, Sˇ.; Smrcˇina, M.; Kocˇovsky´, P.
Collect. Czech. Chem. Commun. 1998, 63, 515.
(10) Benson, S. C.; Cai, P.; Colon, M.; Haiza, M. A.; Tokles, M.;
Snyder, J . K. J . Org. Chem. 1988, 53, 5335.
(11) With NaBH3CN, only one of the amino groups was converted
into the piperidine ring: Kawakami, Y.; Hiratake, J .; Yamamoto, Y.;
Oda, J . J . Chem. Soc., Chem. Commun. 1984, 779.

High-Yield Reductive Alkylation
J . Org. Chem., Vol. 63, No. 22, 1998 7729
Sch em e 2a
Sch em e 3
stituents but if successful with these relatively complex
and sterically congested, enantiopure substrates, our
experiments would further broaden the scope of this
promising methodology.15
N-Phenylation, using the Hartwig-Buchwald proto-
col,13,14 was first attempted with (R)-(+)-1. On reaction
with bromobenzene, catalyzed by the racemic complex
of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP)
and Pd(0) at 90 °C for 2 h, the latter substrate readily
produced the expected N-phenyl derivative 14 in 71%
yield (Scheme 3); no traces of the starting amino phenol
were detected in the crude reaction mixture.16 In ac-
cordance with a recent report,14e no loss of enantiopurity
was observed. Standard reductive methylation (CH2O,
NaBH4, H2SO4, THF, rt) of the amino phenol 14 thus
obtained led to N-methyl-N-phenyl-NOBIN 15 (81%). The
Hartwig-Buchwald method proved equally successful
with the diamine (R)-(+)-2, which under the same condi-
tions, afforded mainly the N,N′-bisphenyl derivative 16
(70%),17 contaminated by the monophenylated product
17 (18%). Reductive methylation of each of these di-
amines furnished the respective permethylated deriva-
tives 18 (85%) and 19 (61%).
a
Ketone ) acetone, cyclohexanone, or 2-adamantanone.
halides or triflates in a reaction catalyzed by certain Pd(0)
complexes that have a suitable bite angle of the ligand.
This new procedure, involving an oxidative addition to
the N-H bond, seemed ideally suited to our binaphthyls;
not only would it extend the existing array of available
ligands by incorporating an important class of N sub-
(12) (a) Paradisi, C. In Comprehensive Organic Chemistry; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, p 433. (b)
March, J . Advanced Organic Chemistry; J . Wiley & Sons: New York,
1992; p 641. For facilitating the nucleophilic substitution via activation
of the aromatic nucleus by coordination to transition metals, see, e.g.:
(c) Pauson, P. L.; Segal, J . A. J . Chem. Soc., Dalton Trans. 1975, 1677,
1683. For use of ArMgX reagents, see: (d) Nishiyama, K.; Tanaka, N.
J . Chem. Soc., Chem. Commun. 1983, 1322. (e) Mori, S.; Aoyama, T.;
Shiori, T. Tetrahedron Lett. 1984, 25, 429. For the reaction of ArI with
(Me3Si)2NCu, see: (f) King, F. D.; Walton, D. R. M. J . Chem. Soc.,
Chem. Commun. 1983, 256. For the high-pressure-enforced reaction
of amines with electron-poor aromatic halides, see: (g) Ibata, T.;
Isogami, Y.; Toyoda, J . Chem. Lett. 1987, 1187. For the preparation of
aromatic amines on reaction of phenols with 4-chloro-2-phenylquinazo-
line (AM-ex-OL), see: (h) Scherrer, R. A.; Beatty, H. R. J . Org. Chem.
1972, 37, 1681. For arylation using bismuth reagents, such as Ph3Bi-
(OAc)2, in conjunction with Cu(II) catalysis, see: (i) Barton, D. H. R.;
Finet, J .-P.; Khamsi, J . Tetrahedron Lett. 1989, 30, 937. (j) Anderson,
J . C.; Harding, M. Chem. Commun. 1998, 393.
(13) Halides: (a) Louie, J .; Hartwig, J . F. Tetrahedron Lett. 1995,
36, 3609. (b) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1996,
118, 7217. (c) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1997,
119, 8232. (d) Mann, G.; Hartwig, J . F.; Driver, M. S.; Ferna´ndez-Rivas,
C. J . Am. Chem. Soc. 1998, 120, 827. Triflates: (e) Louie, J .; Driver,
M. S.; Hamann, B. C.; Hartwig, J . F. J . Org. Chem. 1997, 62, 1268.
For reviews, see: (f) Hartwig, J . F. Synlett 1997, 329. Hartwig, J . F.
Angew. Chem., Int. Ed. Engl. 1998, 37, 2046.
The Hartwig-Buchwald method is known to be sensi-
tive to the ligand, with BINAP and the ferrocenyl-derived
Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 8451. (f) Singer, R. A.;
Sadighi, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 213.
Triflates: (g) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997, 62,
1264. Ni: (h) Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997,
119, 6054.
(15) For an early application of the Hartwig-Buchwald protocol by
another group, see: Ma, D.; Yao, J . Tetrahedron: Asymmetry 1996, 7,
3075.
(16) Interestingly, when 2-amino-2′-diphenylphosphino-1,1′-binaph-
thyl (MAP) was used as the ligand instead of BINAP, the reaction was
complete at 60 °C in 5 min, suggesting that aminophosphines may
become the ligands of choice for the Hartwig-Buchwald coupling. For
the preparation of MAP, see the adjacent paper.
(17) The IR, NMR, and mass spectra of this product were identical
to those of an authentic sample of (()-16 prepared by the oxidative
coupling of N-phenyl-2-aminonaphthalene.5d No loss of enantiomeric
purity was observed for (R)-16 by chiral HPLC.
(14) Halides: (a) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1996,
61, 1133. (b) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem.
Soc. 1996, 118, 7215. (c) Wolfe, J . P.; Rennels, R. A.; Buchwald, S. L.
Tetrahedron 1996, 52, 7525. (d) Marcoux, J .-F.; Wagaw, S.; Buchwald,
S. L. J . Org. Chem. 1997, 62, 1568. (e) Wagan, S.; Rennels, R. A.;

7730 J . Org. Chem., Vol. 63, No. 22, 1998
Vyskocˇil et al.
Sch em e 4
bisphosphine dppf being identified to give the best
results.13,14 Naturally, if a nonchiral target compound
is to be synthesized, economic criteria would dictate that
the inherently chiral BINAP be used in its racemic
form.13,14 This raises the question of whether application
of the enantiomerically pure BINAP would, in the case
of a racemic substrate, lead to any kinetic resolution. To
address this issue, racemic NOBIN (()-1 was treated
under the Hartwig-Buchwald conditions (vide supra) in
the presence of (S)-BINAP, at a lower temperature than
originally, to slow the reaction and increase the chance
for resolution. Analysis of the reaction mixture at ∼35%
conversion (60 °C, 15 min) by HPLC on a Diacel Chiral-
pak AD column revealed a preferential formation of (R)-
14 in 27% ee, demonstrating the feasibility of this
approach. At ∼60% conversion (60 °C, 45 min), the
enantioselectivity dropped to 11% ee. Analogous experi-
ments with (()-2 gave (R)-16 of 17% ee at ∼45% conver-
sion (60 °C, 1 h).9b Although these enantioselectivities
could be in principle improved by fine tuning of the ligand
and the reaction conditions, this issue was not further
pursued in view of the straightforward synthesis of the
enantiomerically pure starting materials (R)-(+)-15 and
(R)-(+)-2.8 On the other hand, successful kinetic resolu-
tion of this type may prove useful in the synthesis of other
enantiopure compounds, where the classical resolution
of the corresponding racemate is more difficult than in
the present case.
tatives of the binaphthyl series.26 This is hardly surpris-
ing, for there was no simple and efficient route to
NOBIN-like structures until recently. The scene has now
changed owing to our one-step synthesis of NOBIN via
the highly selective cross-coupling of 2-naphthol with
2-naphthylamine.5,27 With the series of the NOBIN-
derived amino phenols 3, 4, 7, 8a -c, and 15, whose
syntheses were described above, we could embark on a
systematic investigation of the substituent effect on the
level of asymmetric induction in the R2Zn addition to a
set of aromatic aldehydes.28 The corresponding diamines
5, 11, 12a -c, 13a -c, 18, and 19 were also explored to
complete the study.
En a n tioselective Ad d ition of Dieth ylzin c to Se-
lected Ar om a tic Ald eh yd es. In contrast to Grignard
reagents and alkyllithiums, which react instantaneously
with carbonyl compounds, dialkylzinc reagents are inert
even to aldehydes at room temperature or below. How-
ever, perturbing the rod-type geometry of the stable, sp-
hybridized R2Zn by coordination, followed by replacement
of one of the R groups with an electronegative substituent
of the bidentate ligand, increases the nucleophilicity of
the remaining R group and, at the same time, the Lewis
acidity of the Zn atom.18 As a result, the zinc complexes
thus generated in situ become reactive toward aldehydes.
This ligand-enhanced reactivity18,19 has been demon-
strated for amino alcohols (particularly those possessing
a tertiary amino group) and, to some extent, for diamines.
Since R2Zn itself is inert, only a substoichiometric
amount of the ligand is needed to facilitate the reaction,
which has an obvious practical advantage in the asym-
metric version of the reaction; although it is stoichiomet-
ric with respect to the nonexpensive organometallic
reagent, it is catalytic in the precious chiral ligand.
Following the pioneering work of Oguni and Omi,20
numerous chiral amino alcohols have been surveyed as
ligands in the R2Zn addition to aldehydes and some
spectacular enantioselectivities have been reported (90-
99% ee),18,19,21-25 especially with DAIB21,22 and DBNE.23,24
However, inspection of the impressively long list of these
ligands reveals an almost total absence of the represen-
The N,N-dimethylamino phenol (R)-(+)-3 and benzal-
dehyde (20a ) were chosen for the initial experiments
(Scheme 4). The addition of Et2Zn to 20a was carried
out at ambient temperature in the presence of 3 mol %
of the ligand and was completed in 36 h to give (R)-(+)-
1-phenyl-2-propanol (21a ) in 68% ee (Table 1, entry 1).
Better enantioselectivities were observed for the catalyst
generated in situ from (R)-(+)-3 and n-BuLi.29 An
optimum was found for 1.8 equiv of n-BuLi (counted with
respect to the ligand) and 3 mol % of (R)-(+)-3, which
(25) For the use of amino thiols as ligands, see, ref 12j and the
following: (a) Hof, R. P.; Poelert, M. A.; Peper, N. C. M. W.; Kellog, R.
M. Tetrahedron: Asymmetry 1994, 5, 31. (b) Kang, J .; Kim, D. S.; Kim,
J . I. Synnlett 1994, 842. (c) Kang, J .; Lee, J . W.; Kim, J . I. J . Chem.
Soc., Chem. Commun. 1994, 2009. (d) Rijnberg, E.; J astrzebski, J . T.
B. H.; J anssen, M. D.; Boersma, J .; van Koten, G. Tetrahedron Lett.
1994, 35, 6521. For the most recent examples of amino alcohols, see,
e.g.: (e) J ones, G. B.; Guzel, M.; Chapman, B. J . Tetrahedron:
Asymmetry 1998, 9, 901.
(26) The only example of a binaphthyl-type amino alcohol, namely
(S)-(2,2′-[2-(2-hydroxyethyl)-2-azapropane-1,3-diyl]-1,1′-binaphtha-
lene, exhibited modest enantioselectivity (49% ee): Noyori, R.; Suga,
S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.; Hayashi, M.;
Kaneko, T.; Matsuda, Y. J . Organomet. Chem. 1990, 382, 19.
(27) For a modified version producing (()-NOBIN, see ref 5f and
the following: Ding, K.; Xu, Q.; Wang, Y.; Liu, J .; Yu, Z.; Du, B.; Wu,
Y.; Koshima, Y.; Matsuura, T. Chem. Commun. 1997, 693.
(28) Benzaldehyde and its congeners are the standards against
which the success of new ligands is measured. Other aldehydes have
also been studied but usually found to exhibit lower enantioselectivites.
In contrast to the wealth of examples of the reactions of aldehydes,
there are only sporadic reports on the corresponding aldimines: (a)
Soai, K.; Hatanaka, T.; Miyazawa, T. J . Chem. Soc., Chem. Commun.
1992, 1097. (b) Andersson, P. G.; Guijarro, D.; Tanner, D. Synlett 1996,
727. (c) Andersson, P. G.; Guijarro, D.; Tanner, D. J . Org. Chem. 1997,
62, 7364. (d) Guijarro, D.; Pinho, P.; Andersson, P. G. J . Org. Chem.
1998, 63, 2530.
(18) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49.
(19) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
(20) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823.
(21) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J . Am. Chem.
Soc. 1986, 108, 6071.
(22) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J . Am. Chem.
Soc. 1989, 111, 4028.
(23) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J . Am. Chem. Soc.
1987, 109, 7111.
(29) For the use of lithium alkoxides of amino alcohols as ligands
in dialkylzinc additions, see refs 18, 19, 23, and the following: (a) de
Vries, E. F. J .; Brussee, J .; Kruse, C. C.; van der Gen, A. Tetrahedron:
Asymmetry 1993, 4, 1987. (b) Mehler, T.; Martens, J .; Wallbaum, S.
Synth. Commun. 1993, 23, 2691. (c) De Parrodi, C. A.; J uaristi, E.;
Quintero-Corte´s, L.; Amador, P. Tetrahedron: Asymmetry 1996, 7,
1915. (d) Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A. J . Org.
Chem. 1997, 62, 4970.
(24) Soai, K.; Yokoyama, S.; Hayasaka, T. J . Org. Chem. 1991, 56,
4264.

High-Yield Reductive Alkylation
J . Org. Chem., Vol. 63, No. 22, 1998 7731
Ta ble 1. En a n tioselective Ad d ition of Dieth ylzin c to
Ben za ld eh yd e Ca ta lyzed by Com p lexes of Am in op h en ols
3, 4, 8a -c, 15, n -Bu Li, a n d Dia m in es 11, 12a -c, 13a -c, 18,
19a
Ta ble 2. En a n tioselective Ad d ition of Dieth ylzin c to
Ald eh yd es 20a -j Ca ta lyzed by th e Com p lex of (R)-3 a n d
n -Bu Lia
% yield
of 21
%
ee
configuration
% yield
of 21a
%
configuration
entry
aldehyde 20
C6H5CHOc
of 21b
entry
catalyst
(R)-3
(R)-3/n-BuLi
(R)-4/n-BuLi
(R)-5
eeb
of 21a c
1
2
3
4
5
6
7
8
9
96
95
93
93
93
96
81
94
87
89
88d
75e
62d
83d
79e
82e
81e
79f
79e
83e
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
1
2
3
89
96
79
94d,e
74
92
81
74
34
64
48
40
69
47
43
55
41
35
68
88
45
63e
58
75
71
15
23
13
19
16
41
2
(R)
(R)
(R)
(R)e
(R)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
4-MeO-C6H5CHO
2-MeO-C6H5CHO
4-Cl-C6H5CHO
2-Cl-C6H5CHO
4-Me-C6H5CHO
2-Me-C6H5CHO
4-F-C6H5CHO
1-C10H7CHO
4
5
6
7
8
(R)-7/n-BuLi
(R)-8a /n-BuLi
(R)-8b/n-BuLi
(R)-8c/n-BuLi
(R)-11
(R)-12a
(R)-12b
(R)-12c
(R)-13a
(R)-13b
(R)-13c
(R)-15/n-BuLi
(R)-18
(R)-19
9
10
2-C10H7CHO
10
11
12
13
14
15
16
17
18
a
Reactions were carried out in a 2:1 mixture of toluene and
hexanes at room temperature for 36 h with 3 mol % of the ligand
b
and 5.4 mol % of BuLi. Determined by comparison of specific
rotations with literature data (see the Experimental Section).
d
c Copied from Table 1. Determined by GC analysis of diastereo-
∼0
19
8
isomeric menthoxycarbonyl esters; see ref 33. e Determined by
chiral HPLC (see the Experimental Section). f Determined by 1H
NMR integration of characteristic proton signals in the presence
of the chiral shift reagent Eu(hfc)3.
(R)
(R)
(S)
22
a
Reactions were carried out in a 2:1 mixture of toluene and
hexanes at room temperature for 36 h with 3 mol % of the ligand
diamines,18 the binaphthyl derivative 5 has been reported
to facilitate the formation of 21a with the promising 63%
ee (entry 4).31 Therefore, we have explored the potential
of our new tetrasubstituted diamines 11, 12a -c, 13a -
c, 18, and 19. However, in all instances, the reactions
turned out to be much slower than those carried out with
the corresponding amino phenols, and the yields and
enantioselectivities were inferior (entries 9-15, 17, and
18).
Finally, we employed our champion catalytic system,
i.e., (R)-(+)-3 and 1.8 equiv of n-BuLi, in reactions with
a series of aromatic aldehydes 20 aiming to elucidate the
substituent effect on the level of asymmetric induction
(Scheme 4). In all the cases examined, the (R)-3 ligand
proved to induce formation of the secondary alcohols 21
of (R) configuration (Table 2). In general, introducing a
substituent to the aromatic ring resulted in a decrease
in enantioselectivity. As expected, the effect of ortho
substitution proved slightly more adverse than that of
the same para substitution (compare entries 2 vs 3 and
4 vs 5 in Table 2); however, the difference for the o- and
p-methyl-benzaldehydes 20f and 20g was negligible
(entries 6 and 7). An electron-donating group (MeO)
turned out to reduce the level of asymmetric induction
rather more than an electron-withdrawing substituent
(F, Cl) both in the para (compare entries 2 vs 4 and 8 in
Table 2) and ortho series (compare entries 3 vs 5).32 This
result is in accord with earlier reports by Noyori21 and
Soai23 and in conflict with the behavior of Fre´chet’s
polymer-bound ligands34b and with the recent report by
Chan,32d who observed enhancement of enantioselection
b
and 5.4 mol % of BuLi. Determined by GC analysis of diastereo-
d
isomeric menthoxycarbonyl esters; see ref 33. c See ref 21. NMR
yield. e See ref 31.
led to 88% ee (Table 1, entry 2); with 1 equiv of n-BuLi,
the ee dropped to 80%, whereas 2.5 equiv gave 81% ee,
and 0.5 equiv led to 74% ee. Employing more than 3 mol
% of (R)-(+)-3 did not improve the asymmetric induction,
whereas with only 1 mol % it dropped to 67% ee. In
accord with the earlier observations,18,19 running the
reaction at lower temperature (0 °C) resulted in lower
conversion, practically not affecting the enantioselectiv-
ity.
Since the initial experiments with 3 were promising,
it was desirable to examine the binaphthyls with bulky
groups, in particular 4, 7, 8a -c, and 15, as chiral ligands
for the same reaction.30 The reactions were performed
under the optimal conditions identified for the ligand 3
(vide supra), including addition of n-BuLi to the ligand
as specified above (i.e., 1.8 equiv of n-BuLi counted with
respect to the ligand). However, both the conversions and
enantioselectivities turned out to be generally rather
lower than those obtained in the case of (R)-(+)-3 (Table
1, entries 3, 5-8, and 16), with the highest asymmetric
induction in the formation of (R)-(+)-21a being attained
with the N-isopropyl-N-methyl amino phenol (R)-(+)-8a
(75% ee; entry 6) and the lowest with the N-phenyl-N-
methyl derivative (R)-(+)-15 (19% ee; entry 16). Inter-
estingly, the N-adamantyl-N-methyl amino phenol 8c
gave the addition product with an opposite configuration,
i.e., (S)-(-)-21a (15% ee; entry 8), which apparently
reflects a change of mechanism. This finding also shows
that caution must be exercised when predicting the
configuration of the resulting alcohol18,19 even within a
series of closely related ligands.
(31) Rosini, C.; Franzini, L.; Iuliano, A.; Pini, D.; Salvadori, P.
Tetrahedron: Asymmetry 1991, 2, 363.
(32) For electronic effects in asymmetric reduction of substituted
benzophenones, see: (a) Corey, E. J .; Helal, C. J . Tetrahedron Lett.
1995, 36, 9153. (b) Corey, E. J .; Helal, C. J . Tetrahedron Lett. 1996,
37, 5675. For electronic effects in asymmetric cyclopropanation cata-
lyzed by Rh, see: (c) Park, S.-B.; Murata, K.; Matsumoto, H.; Nish-
iyama, H. Tetrahedron: Asymmetry 1995, 6, 2487. For electronic effects
in addition of Et2Zn to para substituted benzaldehydes catalyzed by a
chiral R-pyridylphenol, see: (d) Zhang, H.; Xue, F.; Mak, T. C. W.;
Chan, K. S. J . Org. Chem. 1996, 61, 8002.
(33) Westley, J . W.; Halpern, B. J . Org. Chem. 1968, 33, 3979.
(34) (a) Itsuno, S.; Fre´chet, J . M. J . J . Org. Chem. 1987, 52, 4142.
(b) Itsuno, S.; Sakurai, Y.; Ito, K.; Maruyama, T.; Nakahama, S.;
Fre´chet, J . M. J . J . Org. Chem. 1990, 55, 304. See also: (c) Watanabe,
M.; Araki, S.; Butsugan, Y.; Uemura, M. J . Org. Chem. 1991, 56, 2218.
Although amino alcohol ligands typically exhibit higher
enantioselectivities in dialkylzinc additions than aprotic
(30) For the effect of the size of the N substituents on the enantio-
selectivity of Et2Zn addition, see refs 12j, 23, 28d, and the following:
(a) Muchow, Y.; Vannoorenberghe, G. B. Tetrahedron Lett. 1987, 28,
6163. (b) Chaloner, P. A.; Perera, S. A. R. Tetrahedron Lett. 1987, 28,
3013. (c) Itsuno, S.; Fre´chet, J . M. J . J . Org. Chem. 1987, 52, 4140. (d)
Soai, K.; Yokoyama, S.; Ebihara, K.; Hayasaka, T. J . Chem. Soc., Chem.
Commun. 1987, 1690.

7732 J . Org. Chem., Vol. 63, No. 22, 1998
Vyskocˇil et al.
Ch a r t 2
Ch a r t 3
for benzaldehydes bearing strongly electron-withdrawing
groups. On the other hand, little substituent electronic
effect (F vs MeO) was recently found by Perica`s for
1-aminopropane-2,3-diol-type ligands.29d Hence, it ap-
pears that the relationship is rather complex and de-
pendent on the actual ligand, the solvent used, etc.23
1-Naphthaldehyde displayed the same enantioselectivity
as o-chlorobenzaldehyde (79% ee; compare entries 9 and
5 in Table 2), while 2-naphthaldehyde gave the same
enantioselectivity as p-chlorobenzaldehyde (83% ee, com-
pare entries 10 and 4 in Table 2).
Mech a n istic Con sid er a tion s. The addition of di-
alkylzinc reagents to aldehydes, facilitated by amino
alcohols as bidentate ligands, is generally accepted to
occur via dinuclear species. Several transition-state
models have been proposed to account for the observed
enantioselectivity,22,23,34,35 which differ in the way the
alkyl is transferred to the aldehyde (Chart 2). According
to Noyori’s mechanism 22,22 it is the bridging alkyl
originating from the zinc atom coordinated to both
nitrogen and oxygen atoms of the amino alcohol (ZnA)
that migrates to the aldehyde, since the ZnA-Rbridging
linkage is more polarized than the ZnB-Rterminal bond. By
contrast, Fre´chet34 proposed that the alkyl from the other
zinc atom (ZnB) is transferred, i.e., that coordinated to
oxygen (23). The third model (24), postulated by Soai23
and Corey,35 differs from 23 in lacking the coordination
of the aldehyde oxygen to ZnB.36,37
transition state. The latter effect is likely to improve the
enantioselection, which is consonant with the experi-
mental data (compare entries 1 and 2 in Table 1).
According to this model, the zinc atom is assumed to
coordinate to the soft π-electrons of the carbonyl oxygen,
whereas Li+, a harder Lewis acid, reaches for its hard
and more Lewis-basic n orbital.38 In contrast to this
analysis, the two other models (23 and 24), although also
predicting the correct configuration of the product 21, do
not easily accommodate the Li+ chelation so that its
influence on the level of enantioselection would be
difficult to rationalize. Moreover, the corresponding
transition state 27 can be assumed to be less rigid than
26 and, consequently, to lead to lower stereoselectivity.
In the instance of the N-methyl-N-alkyl-NOBIN de-
rivatives 8a -c and 15, the larger alkyl group (R′′ in the
transition state 26) can be predicted to attain the exo
(37) A titanium(IV) complex of 2,2′-dihydroxy-1,1′-binaphthyl (BINOL)
has recently been shown to also catalyze asymmetric addition of Et2-
Zn to aldehydes, thus breaking the hegemony of amino alcohol ligands
in this area. The mechanism is believed to involve transmetalation so
that the ethyl is first transferred from the zinc atom to the titanium
chelated by the diol ligand. Presumably, the latter chiral species then
reacts with the aldehyde: (a) Mori, M.; Nakai, T. Tetrahedron Lett.
1997, 38, 6233. Even more recently, functionalized polyBINOLs have
been demonstrated to be capable of catalyzing the same reaction
without the need of an additive: (b) Hu, Q.-S.; Huang, W.-S.; Vitha-
rana, D.; Zheng, X.-F.; Pu, L. J . Am. Chem. Soc. 1997, 119, 12454. (c)
Huang, W.-S.; Hu, Q.-S.; Pu, L. J . Org. Chem. 1998, 63, 1364. High
enantioselectivities were reported for N,N,N′,N′-tetraalkyl-2,2′-dihy-
droxy-1,1′-binaphthyl-3,3′-dicarboxamides employed as ligands in the
Et2Zn addition; additional coordination of the zinc by amide carbonyls
has been proposed: (d) Kitajima, H.; Ito, K.; Katsuki, T. Chem. Lett.
1996, 343. For the most recent report on the use of diols as well as
amino alcohols as ligands, see: (e) Bringmann, G.; Breuning, M.
Tetrahedron: Asymmetry 1998, 9, 667. 1,2-Bis(trifluoromethane-
sulfonamido)cyclohexane is another “non-amino alcohol” exhibiting
high enantioselectivity in the addition of organozinc reagents to
aldehydes: (f) Lutz, C.; Knochel, P. J . Org. Chem. 1997, 62, 7895. For
other bissulfonamide-type ligands, see: (g) Cernerud, M.; Skrinning,
A.; Be´rge`re, I.; Moberg, C. Tetrahedron: Asymmetry 1997, 8, 3437.
For oxazoline-type ligands, see: (h) Allen, J . V.; Frost, C. G.; Williams,
J . M. J . Tetrahedron: Asymmetry 1993, 4, 649-650. (i) Macedo, E.;
Moberg, C. Tetrahedron: Asymmetry 1995, 6, 549. (j) Nakamura, M.;
Hirai, A.; Nakamura, E. J . Am. Chem. Soc. 1996, 118, 8489. For a
ferrocene-derived amino aldehyde as the ligand, see: (k) Fukuzawa,
S.; Kato, H. Synlett 1998, 727.
The effect of added BuLi has previously been demon-
strated on several occasions.18,19,23,29 While in some
instances its addition resulted in notable enhancement
of asymmetric induction,18,19,23,29b-d in other cases it either
caused lowering of the ee or reversed the sense of
chirality,29a thus confirming the mechanistic importance
of Li+.
Our results, obtained with the NOBIN-derived ligands
(Table 1), can best be interpreted using the Noyori model
22. When applied to our system (Chart 3), it shows that
the axial twist imposed by the binaphthyl scaffold
determines the annulation of the dinuclear chelate (25).
The downward pointing angular ethyl adjacent to ZnB
must then be directly responsible for determining the
stereochemical outcome of the reaction as the aldehyde
approaches in a way avoiding repulsive interactions
between the Ar and the latter alkyl (i.e., it exposes its re
face), producing (R)-21. If Li+ is taken into account (26),
we can envisage its chelation between the carbonyl and
the naphtholate oxygen, thereby further stabilizing the
(35) (a) Corey, E. J .; Hannon, F. J . Tetrahedron Lett. 1987, 28, 5237.
(b) Corey, E. J .; Yuen, P.-W.; Hannon, F. J .; Wierda, D. A. J . Org. Chem.
1990, 55, 784.
(36) An entirely different mechanism operates in the recently
reported reaction of Et2Zn and PhCHO in the presence of (S)-(-)-2,2-
dimethyl-5,5-diphenyl-4-isopropyl-1,3-oxazolidine, which apparently
involves zinc amide as the reactive species lacking chelation: Prasad,
K. R. K.; J oshi, N. N. J . Org. Chem. 1997, 62, 3770.
(38) For the basicity of π and n orbitals of the CdO group and its
manifestation, see: (a) Suga, T.; Imamura, K.; von Rudolf, E. J . Chem.
Soc., Perkin Trans. 1 1972, 962. (b) Golfier, M. In Stereochemistry;
Kagan, H. B., Ed.; Thieme: Stutgart, 1977; Vol. 1, p 39. (c) Tichy´, M.
Adv. Org. Chem. 1965, 5, 115. (d) Kocˇovsky´, P.; Stary´, I. J . Org. Chem.
1990, 55, 3236. For the ab initio calculations, see: (e) J aisen, P. G.;
Stevens, W. J . J . Chem. Phys. 1986, 84, 3271.

High-Yield Reductive Alkylation
J . Org. Chem., Vol. 63, No. 22, 1998 7733
position in order to avoid clashing with the binaphthyl
skeleton (note that, upon chelation, the nitrogen atom
becomes stereogeneous). However, the larger the N-alkyl
(R′′), the more serious repulsive interaction with the Ar
group of the incoming aldehyde can be identified in the
(re)-facial approach of ArCHO (26).39 This effect should
gradually reduce the degree of enantioselectivity owing
to the competing (si)-approach. Indeed, the enantio-
selectivity decreases in the following order 3 > 8a > 8b
> 7 > 15 (Table 1, entries 2, 5-7, 16), with the extreme
of the N-(2-adamantyl) derivative 8c, which preferen-
tially gives the opposite enantiomer. However, for the
(si)-approach, another serious clash can be identified, this
time with the nontransferable ethyl at ZnB, which is in
accord with the low enantioselectivity observed for 8c
(Table 1, entry 8). The increasing steric congestion is
reflected in the reaction rate, expressed by the yields
attained in the standard period of time (compare, for
example, entries 6-8 in Table 1).
The effect of the steric bulk of the N-alkyls on the
enantioselectivity of Et2Zn addition to carbonyl com-
pounds has been the subject of several studies.23,28d,30
While ephedrine-type amino alcohols with NMeR (R )
Me, i-Pr, PhCH2) or NBu2 groups turned out to exhibit
little difference (within 10% ee),30a-d proline derived
ligands showed a dramatic increase when the N-methyl
group was replaced by N-neopentyl (from 72 to 100%
ee).23 Similar improvement was attained with amino
thiols.12j Interestingly, Andersson has recently reported
on the reversal of the configuration of the resulting
alcohol 21a as a function of the steric bulk of the N
substituent in 2-azanorbornylmethanols as ligands. Thus,
while the N-Me derivative afforded (R)-21a of 24% ee,
the N-Et, N-Pri, and N-CH2Ph ligands produced (S)-21a
of 48, 53, and 75% ee, respectively.28d This behavior was
rationalized in the way similar to that in the present
study, i.e., by increasing the steric clash of the N-R
substituent with the Ph group of benzaldehyde.
complished with ketones even as bulky as 2-adaman-
tanone and NaBH4/H2SO4 in THF at room temperature
and have established its scope (Schemes 1 and 2); NaBH4
proved to be more efficient than NaBH3CN. Related
N-phenyl derivatives were obtained via the Pd(0)-
catalyzed coupling of (R)-(+)-1 and (R)-(+)-2 with PhBr
(Scheme 3). It can be envisaged that the appendices
attached to the nitrogen atom(s) via our methodology
could bring additional functional group(s), which might
further assist the coordination of the metal6a-c and
enhance the chirality of its environment. We have
further demonstrated that our chiral binaphthyls com-
prise a new, promising class of ligands to be used in
asymmetric catalysis. As an example, we have studied
the prototype addition of Et2Zn to benzaldehyde and its
congeners in the presence of these ligands; the highest
level of asymmetric induction was observed for N,N-
dimethyl NOBIN (R)-(+)-3 (3 mol %) in conjunction with
n-BuLi (5.4 mol %), which gave (R)-(+)-21a in 88% ee
(Table 1, entry 2). The reactions were carried out at
ambient temperature; no increase in the level of enan-
tioselectivity was detected at 0 °C or below, which has
obvious practical implications. Generally, derivatives of
the amino phenol 1 proved more efficient than the
corresponding diamines derived from 2. The observed
enantioselectivities are in the same range as those for
established ligands reported by other groups.18,19,29 The
stereochemical outcome and the effect of Li+ are consis-
tent with the Noyori-type18,22 transition-state model 26.
Investigation of further applications of the NOBIN-
derived complexes in asymmetric catalysis is on the way
and will be reported in due course.40,41
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed under a
dry argon atmosphere. Sodium borohydride, diethylzinc (1 M
solution in hexanes), n-BuLi (1.6 M solution in hexanes42), and
aldehydes 20 were purchased from Aldrich. Toluene was
freshly distilled from a sodium benzophenone still under dry
argon. Melting points were determined on a Kofler block and
are uncorrected. The optical rotations were measured in THF,
CHCl3, benzene, or toluene with an error of < ( 0.1 at 25 °C.
Bidentate chelation of the diamine ligands can also be
assumed. However, the present data do not allow the
proposition of a sound hypothesis in view of the rather
low enantioselectivities generally observed with di-
amines. Nevertheless, the trend in this series is similar
to that observed for amino phenolssa gradual decrease
of enantioselectivity with the increasing steric demands
of the N substituents (e.g., 13a > 13b; Table 1, entries
13 and 14) leading, eventually, to the reversal of the
product configuration with ligands possessing two bulky
N,N′-substituents (e.g., 12a -c; Table 1, entries 10-12).
As expected, the increased steric bulk of the substituents
resulted in lower conversions (compare, for example, the
yields in entries 4, 10-12; Table 1).
1
The H NMR spectra were recorded on 250, 300, or 400 MHz
instruments (FT mode) for CDCl3 solutions at 25 °C with TMS
as an internal reference. The 13C NMR spectra were recorded
on 63 MHz instrument (FT mode) for CDCl3 solutions at 25
°C. The IR spectra were measured in chloroform or dichloro-
methane. The high-resolution mass spectra (EI) were meas-
ured on a double focusing spectrometer (70 eV, 50 µA) using
direct inlet and the lowest temperature enabling evaporation;
the accuracy was e5 ppm. Yields are given in milligrams of
isolated product, showing one spot on a chromatographic plate
and no impurities detectable in the NMR spectrum. Semi-
preparative HPLC analyses were carried out on a Magnum 9
Con clu sion s
(40) During the preparation of this manuscript, two papers appeared
on the addition of dialkyl zinc reagents to ketones rather than
aldehydes. Fu has reported on the successful addition of Ph2Zn to
ketones in the presence of the Noyori’s DAIB ligand with 58-83% ee.41a
Tagliavini has apparently found a more general approach, in which
the addition of Et2Zn and other Knochel-type zinc reagents to ketones
is boosted by Me3SiCl and related silylating agents41b (note that a
similar effect is known in cuprate chemistry). The latter approach is
awaiting its chiral version, thereby opening an exciting new avenue
to our NOBIN-derived ligands.
(41) (a) Dosa, P. I.; Fu, G. C. J . Am. Chem. Soc. 1998, 120, 445. (b)
Alvisi, C.; Casolari, S.; Costa, A. L.; Ritiani, M.; Tagliavini, E. J . Org.
Chem. 1998, 63, 1330.
(42) The actual concentration of n-BuLi was determined using
titration with o-phenanthroline as an indicator. For the method, see:
Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 9, 165.
We have demonstrated that a simple, high-yield reduc-
tive alkylation of (R)-(+)-1 and (R)-(+)-2 can be ac-
(39) Bulky groups attached to the nitrogen normally tend to increase
the enantioselectivity of this reaction.24 The opposite trend, observed
in our series, can be understood if N,N-dimethyl NOBIN (3) is assumed
to be the upper limit for tolerating the steric bulk; further increasing
the steric hindrance apparently has an adverse effect. Alternatively,
the bulky N substituent may impair the metal coordination to the
sterically hindered nitrogen atom, thereby loosening the transition
state. A similarly detrimental effect of the Ph3C group has been
reported for the aziridino alcohols employed as ligands in the Et2Zn
addition to imines.28b,c

7734 J . Org. Chem., Vol. 63, No. 22, 1998
Vyskocˇil et al.
column (Partisil 10, Whatman) using petroleum ether-ethyl
acetate mixtures and refractive index detection. Chiral HPLC
analyses were carried out on a Chiralpak AD column (Daicel)
using hexanes-ethanol mixtures and UV detection at 254 nm.
(R)-(+)-2-(Dieth ylam in o)-2′-h ydr oxy-1,1′-bin aph th yl, (R)-
(+)-4. A solution of (R)-(+)-NOBIN (1) (285 mg, 1 mmol, g99%
ee) in THF (10 mL) and solid NaBH4 (530 mg, 14 mmol) were
slowly added (simultaneously) to a solution of acetaldehyde
(616 mg, 14 mmol) and 20% aqueous H2SO4 (2 mL) in THF (5
mL) over a period of 15 min. The reaction mixture was stirred
for an additional 15 min and then poured into 2% aqueous
KOH (100 mL). The resulting suspension was extracted with
ethyl acetate (3 × 20 mL), and the extract was dried with
MgSO4 and evaporated. The crude product was purified by
flash chromatography on silica gel (20 g) with toluene to give
(R)-(+)-4 (310 mg, 91%): [R]D +13.1 (c 0.5, THF); 1H NMR (250
MHz) δ 0.86 (t, J ) 7.1 Hz, 6 H), 2.87-3.05 (m, 4 H), 7.00-
7.05 (m, 2 H), 7.09-7.18 (m, 2 H), 7.21-7.38 (m, 3 H), 7.48 (d,
J ) 9.1 Hz, 1 H), 7.80-7.94 (m, 4 H); 13C NMR δ 12.26 (q),
46.75 (t), 118.47 (s), 119.53 (d), 120.28 (d), 123.06 (d), 124.42
(d), 125.21 (s), 125.61 (d), 126.12 (d), 126.15 (d), 126.28 (d),
127.78 (d), 128.11 (d), 129.18 (d), 129.25 (s), 129.56 (d), 130.32
(s), 134.10 (s), 134.21 (s), 147.35 (s), 151.37 (s); IR (CH2Cl2) ν
3525 (OH), 1621 and 1597 (CdC arom) cm-1; MS m/z (%) 341
(M•+, 47), 326 (100).
Gen er a l P r oced u r e for t h e R ea ct ion of NOBIN (R)-
(+)-1 w ith Keton es a n d Na BH 4. A solution of (R)-(+)-
NOBIN (1) (285 mg, 1 mmol, g99% ee) in THF (10 mL) and
solid NaBH4 (265 mg, 7 mmol) were slowly added (simulta-
neously) to a solution of the ketone (7 mmol) and 20% aqueous
H2SO4 (1 mL) in THF (5 mL) over a period of 15 min at room
temperature. The reaction mixture was stirred for an ad-
ditional 15 min and then poured into 2% aqueous KOH (100
mL). The resulting suspension was extracted with ethyl
acetate (3 × 20 mL), and the extract was dried with MgSO4
and evaporated. The crude product was purified by flash
chromatography on silica gel (20 g) with toluene to give the
monosubstituted amino phenols 6.
127.08 (d), 127.17 (s), 128.13 (d), 128.19 (d), 129.46 (s), 130.30
(d), 130.49 (d), 133.41 (s), 134.39 (s), 144.28 (s), 151.95 (s); IR
(CHCl3) ν 3511 (OH), 3418 (NH), 1620 and 1599 (CdC arom)
cm-1; MS m/z (%) 419 (M•+, 100).
(R)-(+)-2-(N-P iper idin yl)-2′-h ydr oxy-1,1′-bin aph th yl, (R)-
(+)-7 (340 m g, 96%): [R]D +6.3 (c 0.8, THF); 1H NMR (250
MHz) δ 1.39 (bs, 6 H), 2.84-2.97 (m, 4 H), 7.05-7.31 (m, 6
H), 7.41-7.46 (m, 2 H), 7.79-7.94 (m, 4 H), 8.12 (bs, 1 H); 13
C
NMR δ 23.96 (t), 26.20 (t), 53.32 (t), 118.55 (s), 118.65 (d),
120.28 (d), 123.05 (d), 124.35 (d), 125.06 (s), 125.86 (d), 126.02
(d), 126.15 (d), 126.41 (d), 127.82 (d), 128.07 (d), 129.27 (s),
129.53 (d), 129.73 (d), 130.46 (s), 133.71 (s), 134.14 (s), 149.02
(s), 151.66 (s); IR (CHCl3) ν 3527 (OH), 1620 and 1595 (CdC
arom) cm-1; MS m/z (%) 353 (M•+, 100).
Gen er a l P r oced u r e for Meth yla tion of th e Am in o
P h en ols (R)-6. A solution of the amino phenol (1 mmol) in
THF (10 mL) and solid NaBH4 (265 mg, 7 mmol) were slowly
added (simultaneously) to a solution of 40% aqueous formal-
dehyde (1 mL; 12 mmol) and 20% aqueous H2SO4 (1 mL) in
THF (5 mL) over a period of 15 min at room temperature. The
reaction mixture was stirred for an additional 15 min and then
poured into 2% aqueous KOH (100 mL). The resulting
suspension was extracted with ethyl acetate (3 × 20 mL), and
the extract was dried with MgSO4 and evaporated. The crude
product was purified by flash chromatography on silica gel (20
g) with toluene to give the amino phenols 8.
(R)-(+)-2-(N-Isopr opyl-N-m eth ylam in o)-2′-h ydr oxy-1,1′-
bin a p h th yl, (R)-(+)-8a (327 m g, 96%): mp 106-8 °C (tolu-
ene); [R]D +20.7 (c 0.3, THF); 1H NMR (400 MHz) δ 0.70 (d, J
) 6.4 Hz, 3 H), 0.77 (d, J ) 6.4 Hz, 3 H), 2.66 (s, 3 H), 3.16-
3.24 (m, 1 H), 7.01-7.17 (m, 4 H), 7.21-7.28 (m, 2 H), 7.36 (d,
J ) 8.8 Hz, 1 H), 7.44 (d, J ) 8.8 Hz, 1 H), 7.75-7.87 (m, 4
H); 13C NMR δ 16.68 (q), 19.78 (q), 31.21 (q), 54.04 (d), 118.65
(s), 119.66 (d), 120.20 (d), 123.05 (d), 123.95 (s), 124.22 (d),
125.65 (d), 126.12 (d), 126.15 (d), 126.27 (d), 127.79 (d), 128.10
(d), 129.20 (s), 129.40 (d), 129.54 (d), 130.13 (s), 133.93 (s),
134.10 (s), 149.23 (s), 151.50 (s); IR (CHCl3) ν 3526 (OH), 1620
and 1596 (CdC arom) cm-1; MS m/z (%) 341 (M•+, 29), 326
(100).
(R)-(+)-2-(Isop r op yla m in o)-2′-h yd r oxy-1,1′-b in a p h t h -
yl, (R)-(+)-6a (291 m g, 89%): mp 50-2 °C (toluene); [R]D +119
(R)-(+)-2-(N-Cycloh exyl-N-m et h yla m in o)-2′-h yd r oxy-
1,1′-bin a p h th yl, (R)-(+)-8b (364 m g, 95%): mp 103-4 °C
(toluene); [R]D +30.1 (c 0.4, THF); 1H NMR (400 MHz) δ 0.04-
0.15 (m, 1 H), 0.49-0.59 (m, 1 H), 0.64-0.75 (m, 1 H), 0.91-
0.98 (m, 1 H), 1.03-1.19 (m, 3 H), 1.21-1.27 (m, 2 H), 1.37-
1.43 (m, 1 H), 2.63 (s, 3 H), 2.65-2.73 (m, 1 H), 6.99-7.14 (m,
4 H), 7.19-7.23 (m, 2 H), 7.26 (d, J ) 8.8 Hz, 1 H), 7.38 (d, J
) 9.0 Hz, 1H), 7.71-7.83 (m, 4 H); 13C NMR δ 25.62 (t), 25.72
(t), 27.83 (t), 30.55 (t), 32.74 (q), 63.12 (d), 118.71 (s), 119.14
(d), 120.20 (d), 122.47 (s), 123.10 (d), 124.07 (d), 125.44 (d),
125.77 (d), 126.26 (d), 126.42 (d), 127.80 (d), 128.08 (d), 129.24
(s), 129.39 (d), 129.47 (d), 129.94 (s), 134.12 (s), 149.78 (s),
149.82 (s), 151.14 (s); IR (CHCl3) ν 3526 (OH), 1620 and 1596
(CdC arom) cm-1; MS m/z (%) 381 (M•+, 61), 338 (100).
(R )-(-)-2-[N -(2′′-Ad a m a n t yl)-N -m e t h yla m in o]-2′-h y-
d r oxy-1,1′-bin a p h th yl, (R)-(-)-8c (372 m g, 86%): mp 206-8
1
(c 0.4, THF); H NMR (400 MHz) δ 0.99 (d, J ) 6.3 Hz, 3 H),
1.06 (d, J ) 6.3 Hz, 3 H), 3.42 (bs, 1 H), 3.71-3.82 (m, 1 H),
5.16 (bs, 1 H), 6.92 (d, J ) 7.5 Hz, 1 H), 7.10-7.40 (m, 7 H),
7.77 (d, J ) 7.5 Hz, 1 H), 7.80-7.93 (m, 3 H); 13C NMR δ 23.04
(q), 23.13 (q), 44.52 (d), 108.43 (s), 114.09 (s), 114.85 (d), 117.58
(d), 122.12 (d), 123.51 (d), 123.55 (d), 124.58 (d), 126.79 (d),
127.07 (d), 127.41 (s), 128.08 (d), 128.17 (d), 129.46 (s), 130.27
(d), 130.54 (d), 133.37 (s), 134.24 (s), 144.81 (s), 151.92 (s); IR
(CHCl3) ν 3515 (OH), 3403 (NH), 1620 and 1598 (CdC arom)
cm-1; MS m/z (%) 327 (M•+, 69), 312 (100).
(R)-(+)-2-(Cycloh exyla m in o)-2′-h yd r oxy-1,1′-b in a p h -
th yl, (R)-(+)-6b (330 m g, 90%): mp 54-5 °C (toluene); [R]D
+118 (c 0.4, THF); 1H NMR (250 MHz) δ 0.70-1.05 (m, 4 H),
1.10-1.36 (m, 2 H), 1.43-1.61 (m, 2 H), 1.74-1.91 (m, 2 H),
3.30-3.43 (m, 1 H), 3.47 (bs, 1 H), 5.19 (bs, 1 H), 6.91 (d, J )
8 Hz, 1 H), 7.05-7.37 (m, 7 H), 7.61-7.88 (m, 4 H); 13C NMR
δ 24.72 (2 × t), 25.84 (t), 33.36 (t), 33.42 (t), 51.71 (d), 108.27
(s), 114.09 (s), 114.82 (d), 117.54 (d), 121.97 (d), 123.42 (d),
123.49 (d), 124.57 (d), 126.72 (d), 126.98 (d), 127.32 (s), 128.04
(d), 128.13 (d), 129.39 (s), 130.19 (d), 130.37 (d), 133.36 (s),
134.29 (s), 144.59 (s), 151.89 (s); IR (CHCl3) ν 3514 (OH), 3405
1
°C (toluene); [R]D -67.5 (c 0.4, THF); H NMR (400 MHz) δ
0.53-0.62 (m, 1 H), 0.83-0.88 (m, 1 H), 1.13-1.69 (m, 11 H),
2.01-2.07 (m, 1 H), 3.09 (s, 3 H), 3.49 (bs, 1 H), 3.70-3.76 (m,
1 H), 6.79 (d, J ) 8.5 Hz, 1 H), 7.05-7.28 (m, 4 H), 7.38-7.42
(m, 1 H), 7.70 (d, J ) 8.8 Hz, 1 H), 7.77-7.88 (m, 4 H), 7.99
(d, J ) 9.1 Hz, 1 H); 13C NMR δ 26.18 (d), 26.56 (d), 28.66 (d),
28.88 (d), 30.23 (t), 30.52 (t), 36.56 (t), 36.83 (t), 37.01 (t), 43.12
(q), 70.23 (d), 113.20 (s), 119.30 (d), 120.57 (d), 122.92 (d),
124.77 (d), 125.48 (s), 126.23 (d), 126.33 (d), 126.87 (d), 126.93
(d), 127.62 (s), 128.02 (d), 128.26 (d), 128.69 (s), 130.46 (d),
130.97 (d), 132.15 (s), 133.35 (s), 134.17 (s), 153.51 (s); IR
(CHCl3) ν 3537 (OH), 1623 and 1597 (CdC arom) cm-1; MS
m/z (%) 433 (M•+, 100).
(NH), 1619 and 1598 (CdC arom) cm-1; MS m/z (%) 367 (M•+
,
100).
(R)-(+)-2-[(2′′-Adam an tyl)am in o]-2′-h ydr oxy-1,1′-bin aph -
th yl, (R)-(+)-6c (240 m g, 57%): mp 153-5 °C (toluene); [R]D
1
+87 (c 0.4, THF); H NMR (300 MHz) δ 1.10-1.14 (m, 1 H),
1.20-1.22 (m, 1 H), 1.23-1.27 (m, 1 H), 1.30-1.36 (m, 2 H),
1.48-1.52 (m, 1 H), 1.58-1.62 (m, 1 H), 1.74-1.78 (m, 4 H),
1.79-1.82 (m, 2 H), 1.90-1.94 (m, 1 H), 3.65 (bs, 1 H), 4.02
(bs, 1 H), 5.19 (bs, 1 H), 6.95-7.00 (m, 1 H), 7.14-7.34 (m, 6
H), 7.38 (d, J ) 8.8 Hz, 1 H), 7.74-7.78 (m, 1 H), 7.83-7.87
(m, 2 H), 7.91 (d, J ) 8.8 Hz, 1 H); 13C NMR δ 26.92 (d), 27.25
(d), 31.12 (t), 31.17 (t), 31.77 (d), 31.92 (d), 37.23 (t), 37.35 (t),
37.48 (t), 56.47 (d), 107.81 (s), 114.21 (s), 114.49 (d), 117.45
(d), 121.87 (d), 123.35 (d), 123.57 (d), 124.72 (d), 126.79 (d),
Gen er a l P r oced u r e for th e Rea ction of Dia m in e (R)-
(+)-2 w ith Keton es a n d Na BH4. A solution of diamine (2)
(284 mg, 1 mmol) in THF (10 mL) and solid NaBH4 (530 mg,
14 mmol) were slowly added (simultaneously) to a solution of
the ketone (14 mmol) and 20% aqueous H2SO4 (2 mL) in THF
(5 mL) over a period of 15 min at room temperature. The
reaction mixture was stirred for an additional 15 min and then

High-Yield Reductive Alkylation
J . Org. Chem., Vol. 63, No. 22, 1998 7735
poured into 2% aqueous KOH (100 mL). The resulting
suspension was extracted with ethyl acetate (3 × 20 mL), and
the extract was dried with MgSO4 and evaporated. The crude
product was purified by flash chromatography on silica gel (20
g) with toluene to give the disubstituted diamines 9 or 11 and
the monosubstituted diamines 10, respectively.
δ 27.00 (d), 27.31 (d), 31.08 (t), 31.25 (t), 31.88 (d), 32.08 (d),
37.35 (t), 37.41 (t), 37.54 (t), 56.65 (d), 112.20 (s), 112.45 (s),
114.70 (d), 118.09 (d), 121.55 (d), 122.31 (d), 123.66 (d), 124.23
(d), 126.58 (d), 126.60 (d), 127.30 (s), 127.97 (d), 128.02 (d),
128.40 (s), 129.32 (d), 129.42 (d), 133.85 (s), 133.96 (s), 142.90
(s), 143.34 (s); IR (CHCl3) ν 3486 (NH2, asym), 3392 (NH2 sym,
(R)-(+)-2,2′-Bis(isop r op yla m in o)-1,1′-bin a p h th yl, (R)-
(+)-9a (301 m g, 82%): mp 83-4 °C (toluene); [R]D +89 (c 0.4,
THF); 1H NMR (400 MHz) δ 0.96 (d, J ) 6.3 Hz, 6 H), 1.04 (d,
J ) 6.3 Hz, 6 H), 3.40 (bs, 2 H), 3.73-3.86 (m, 2 H), 6.91 (dd,
J ) 8.1 Hz, J ) 0.9 Hz, 2 H), 7.08-7.22 (m, 4 H), 7.25 (d, J )
9.0 Hz, 2 H), 7.75 (dd, J ) 8.1 Hz, J ) 0.9 Hz, 2 H), 7.85 (d, J
) 9.0 Hz, 2 H); 13C NMR δ 23.20 (q), 44.49 (d), 112.38 (s),
114.95 (d), 121.76 (d), 123.99 (d), 126.46 (d), 127.54 (s), 127.88
(d), 129.42 (d), 134.03 (s), 144.04 (s); IR (CHCl3) ν 3398 (NH),
1619 and 1599 (CdC arom) cm-1; MS m/z (%) 368 (M•+, 100).
(R)-(+)-2,2′-Bis(cycloh exyla m in o)-1,1′-bin a p h th yl, (R)-
(+)-9b (288 m g, 64%): mp 66-8 °C (toluene); [R]D +70.5 (c
NH), 1620 and 1598 (CdC arom) cm-1; MS m/z (%) 418 (M•+
,
100).
(R)-(-)-2,2′-Bis(N-p ip er id in yl)-1,1′-bin a p h th yl, (R)-(-)-
11 (412 m g, 98%): [R]D -229 (c 0.5, THF); 1H NMR (400
MHz) δ 0.99-1.18 (m, 8 H), 1.21-1.30 (m, 4 H), 2.70 (t, J )
5.2 Hz, 8 H), 7.14-7.18 (m, 4 H), 7.22-7.31 (m, 2 H), 7.48 (d,
J ) 8.7 Hz, 2 H), 7.81 (d, J ) 7.8 Hz, 2 H), 7.87 (d, J ) 8.7 Hz,
2 H); 13C NMR δ 24.28 (t), 26.38 (t), 52.89 (t), 120.77 (d), 123.35
(d), 125.64 (d), 126.14 (d), 127.76 (d), 128.21 (d), 129.01 (s),
130.15 (s), 134.23 (s), 150.29 (s); IR (CHCl3) ν 1620 and 1593
(CdC arom) cm-1; MS m/z (%) 420 (M•+, 100).
Gen er a l P r oced u r e for Meth yla tion of Dia m in es (R)-9
a n d (R)-10. A solution of the diamine (1 mmol) in THF (10
mL) and solid NaBH4 (795 mg, 21 mmol) were slowly added
(simultaneously) to a solution of 40% aqueous formaldehyde
(2 mL, 24 mmol) and 20% aqueous H2SO4 (2 mL) in THF (5
mL) over a period of 15 min at room temperature. The
reaction mixture was stirred for an additional 15 min and then
poured into a 2% aqueous KOH (100 mL). The resulting
suspension was extracted with ethyl acetate (3 × 20 mL), and
the extract was dried with MgSO4 and evaporated. The crude
product was purified by flash chromatography on silica gel (20
g) with toluene to give the tetrasubstituted diamines 12 or
13, respectively.
1
0.4, THF); H NMR (300 MHz) δ 0.72-1.11 (m, 6 H), 1.15-
1.34 (m, 4 H), 1.47-1.68 (m, 6 H), 1.80-2.01 (m, 4 H), 3.32-
3.41 (m, 2 H), 3.55 (bs, 2 H), 6.92 (d, J ) 8.3 Hz, 2 H), 7.09-
7.19 (m, 4 H), 7.24 (d, J ) 8.8 Hz, 2 H), 7.73 (dd, J ) 8.3 Hz,
J ) 2.2 Hz, 2 H), 7.85 (d, J ) 8.8 Hz, 2 H); 13C NMR δ 24.88
(t), 24.96 (t), 25.65 (t) 33.58 (t), 33.68 (t), 51.92 (d), 112.24 (s),
114.91 (d), 121.65 (d), 123.96 (d), 126.40 (d), 127.49 (s), 127.86
(d), 129.30 (d), 134.07 (s), 143.89 (s); IR (CHCl3) ν 3396 (NH),
1618 and 1599 (CdC arom) cm-1; MS m/z (%) 448 (M•+, 100).
(R)-(+)-2,2′-Bis[(2′′-a d a m a n t yl)a m in o]-1,1′-b in a p h t h -
yl, (R)-(+)-9c (82 m g, 15%): mp 292-4 °C (toluene); [R]D
+16.8 (c 0.2, THF); 1H NMR (400 MHz) δ 0.82-0.90 (m, 2 H),
1.08-1.12 (m, 2 H), 1.13-1.16 (m, 2 H), 1.25-1.29 (m, 6 H),
1.41-1.45 (m, 2 H), 1.56-1.59 (m, 4 H), 1.73-1.86 (m, 10 H),
3.61-3.65 (m, 2 H), 4.09 (bs, 2 H), 6.97-7.05 (m, 2 H), 7.09-
7.17 (m, 4 H), 7.21 (d, J ) 9.1 Hz, 2 H), 7.72-7.80 (m, 2 H),
7.83 (d, J ) 9.1 Hz, 2 H); 13C NMR δ 27.00 (d), 27.34 (d), 31.04
(t), 31.28 (t), 31.97 (d), 32.26 (d), 37.37 (t), 37.54 (t), 37.56 (t),
56.65 (d), 112.15 (s), 114.47 (d), 121.50 (d), 123.97 (d), 126.41
(d), 127.27 (s), 127.91 (d), 129.31 (d), 134.14 (s), 143.63 (s); IR
(CHCl3) ν 3414 (NH), 1619 and 1598 (CdC arom) cm-1; MS
m/z (%) 552 (M•+, 100).
(R)-(-)-2,2′-Bis(N-isop r op yl-N-m et h yla m in o)-1,1′-b i-
n a p h th yl, (R)-(-)-12a (301 m g, 76%): mp 121-3 °C (tolu-
1
ene); [R]D -159 (c 0.3, THF); H NMR (300 MHz) δ 0.33 (d, J
) 6.9 Hz, 6 H), 0.69 (d, J ) 6.9 Hz, 6 H), 2.53 (s, 6 H), 2.84-
2.92 (m, 2 H), 7.13-7.17 (m, 4 H), 7.22-7.30 (m, 2 H), 7.45 (d,
J ) 8.8 Hz, 2 H), 7.77-7.86 (m, 4 H); 13C NMR δ 17.04 (q),
19.73 (q), 31.50 (q), 52.81 (d), 122.12 (d), 123.11 (d), 125.60
(d), 126.03 (d), 127.66 (2 × d), 128.29 (s), 129.78 (s), 134.48
(s), 150.13 (s); IR (CHCl3) ν 1619 and 1593 (CdC arom) cm-1
MS m/z (%) 396 (M•+, 12), 353 (100).
;
(R)-(+)-2-Am in o-2′-(isop r op yla m in o)-1,1′-b in a p h t h yl,
(R)-(-)-2,2′-Bis(N-cycloh exyl-N-m et h yla m in o)-1,1′-b i-
(R)-(+)-10a (50 m g, 15%): mp 158-61 °C (toluene); [R]D +137
n a p h th yl, (R)-(-)-12b (357 m g, 75%): mp 143-5 °C (tolu-
1
1
(c 0.2, THF); H NMR (400 MHz) δ 0.98 (d, J ) 6.0 Hz, 3 H),
ene); [R]D -161 (c 0.4, THF); H NMR (400 MHz) δ -0.26 to
1.05 (d, J ) 6.0 Hz, 3 H), 3.42 (bs, 1 H), 3,64 (bs, 2 H), 3.75-
3.83 (m, 1 H), 6.96 (d, J ) 7.5 Hz, 1 H), 7.03 (d, J ) 8.1 Hz, 1
H), 7.20-7.23 (m, 5 H), 7.27 (d, J ) 9.0 Hz, 1 H), 7.75-7.82
(m, 3 H), 7.86 (d, J ) 9.0 Hz, 1 H); 13C NMR δ 23.18 (q), 23.33
(q), 44.77 (d), 112.31 (s), 112.85 (s), 115.26 (d), 118.20 (d),
121.90 (d), 122.34 (d), 123.81 (d), 124.10 (d), 126.62 (d), 126.67
(d), 127.65 (s), 128.02 (2 × d), 128.44 (s), 129.45 (2 × d), 133.71
(s), 133.92 (s), 142.88 (s), 144.01 (s); IR (CHCl3) ν 3485 (NH2,
-0.09 (m, 2 H), 0.28-0.33 (m, 2 H), 0.49-0.59 (m, 2 H), 0.63-
0.75 (m, 2 H), 0.83-0.90 (m, 2 H), 1.14-1.21 (m, 6 H), 1.35-
1.44 (m, 4 H), 2.33-2.38 (m, 2 H), 2.62 (s, 6 H), 7.16-7.24 (m,
4 H), 7.26-7.31 (m, 2 H), 7.44 (d, J ) 8.8 Hz, 2 H), 7.78-7.84
(m, 4 H); 13C NMR δ 25.66 (t), 25.83 (t), 25.87 (t), 27.86 (t),
30.89 (t), 32.59 (q), 61.94 (d), 122.09 (d), 123.06 (d), 125.70 (d),
125.93 (d), 127.50 (d), 127.72 (d), 128.20 (s), 129.78 (s), 134.84
(s), 150.30 (s); IR (CHCl3) ν 1619 and 1592 (CdC arom) cm-1
;
asym), 3393 (NH2 sym, NH), 1620 and 1598 (CdC arom) cm-1
MS m/z (%) 326 (M•+, 75), 311 (100).
;
MS m/z (%) 476 (M•+, 13), 393 (100).
(R)-(-)-2,2′-Bis[N-(2′′-a d a m a n tyl)-N-m eth yla m in o]-1,1′-
bin a p h th yl, (R)-(-)-12c (342 m g, 59%): mp 275-8 °C; [R]D
(R)-(+)-2-Am in o-2′-(cycloh exyla m in o)-1,1′-b in a p h t h -
yl, (R)-(+)-10b (102 m g, 28%): mp 224-6 °C (toluene); [R]D
+122 (c 0.4, THF); 1H NMR (300 MHz) δ 0.79-0.90 (m, 1 H),
0.93-1.09 (m, 2 H), 1.14-1.35 (m, 2 H), 1.47-1.65 (m, 3 H),
1.79-1.88 (m, 1 H), 1.90-1.98 (m, 1 H), 3.32-3.42 (m, 1 H),
3.68 (bs, 3 H), 6.97 (d, J ) 7.2 Hz, 1 H), 7.02 (d, J ) 7.2 Hz,
1 H), 7.11-7.26 (m, 5 H), 7.32 (d, J ) 9.0 Hz, 1 H), 7.75-7.81
(m, 3 H), 7.86 (d, J ) 9.0 Hz, 1 H); 13C NMR δ 24.90 (t), 24.98
(t), 25.63 (t), 33.58 (t), 33.76 (t), 52.01 (d), 112.35 (s), 112.62
(s), 115.21 (d), 118.19 (d), 121.78 (d), 122.33 (d), 123.74 (d),
124.13 (d), 126.59 (d), 126.66 (d), 127.58 (s), 127.98 (d), 128.01
(d), 128.41 (s), 129.36 (d), 129.41 (d), 133.77 (s), 133.93 (s),
142.87 (s), 143.77 (s); IR (CHCl3) ν 3485 (NH2, asym), 3390
(NH2 sym, NH), 1620 and 1599 (CdC arom) cm-1; MS m/z (%)
366 (M•+, 100).
(R)-(+)-2-Am in o-2′-[(2′′-a d a m a n tyl)a m in o]-1,1′-bin a p h -
th yl, (R)-(+)-10c (298 m g, 71%): mp 230-3 °C (toluene); [R]D
+107 (c 0.2, THF); 1H NMR (400 MHz) δ 1.10-1.14 (m, 1 H),
1.16-1.19 (m, 1 H), 1.25-1.29 (m, 1 H), 1.31-1.35 (m, 2 H),
1.44-1.49 (m, 1 H), 1.57-1.61 (m, 2 H), 1.74-1.82 (m, 5 H),
1.90-1.95 (m, 1 H), 3.62-3.75 (m, 3 H), 4.05 (bs, 1 H), 7.00-
7.09 (m, 2 H), 7.12-7.24 (m, 6 H), 7.73-7.85 (m, 4 H); 13C NMR
1
-116 (c 0.1, THF); H NMR (400 MHz) δ -0.29 to -0.24 (m,
2 H), 0.40-0.47 (m, 2 H), 1.15-1.25 (m, 12 H), 1.35-1.45 (m,
2 H), 1.51-1.63 (m, 6 H), 1.65-1.73 (m, 2 H), 2.10-2.18 (m, 2
H), 2.78 (s, 6 H), 2.90-2.95 (m, 2 H), 6.92-7.05 (m, 4 H), 7.26-
7.33 (m, 2 H), 7.71-7.81 (m, 4 H), 7.92 (d, J ) 8.8 Hz, 2 H);
13C NMR δ 27.30 (d), 27.41 (d), 30.07 (d), 30.29 (d), 30.78 (t),
31.68 (t), 26.92 (t), 37.36 (t), 38.10 (t), 42.65 (q), 69.60 (d),
123.40 (d), 124.40 (d), 124.75 (d), 127.30 (d), 128.37 (d), 128.91
(d), 131.43 (s), 133.40 (s), 134.55 (s), 151.53 (s); IR (CHCl3) ν
1619 and 1598 (CdC arom) cm-1; MS m/z (%) 580 (M•+, 1),
445 (100).
(R)-(-)-2-(N-Isop r op yl-N-m et h yla m in o)-2′-(d im et h yl-
a m in o)-1,1′-bin a p h th yl, (R)-(-)-13a (239 m g, 65%): mp
182-5 °C (toluene); [R]D -109 (c 0.1, THF); 1H NMR (400 MHz)
δ 0.44 (d, J ) 6.6 Hz, 3 H), 0.71 (d, J ) 6.6 Hz, 3 H), 2.34 (s,
6 H), 2.50 (s, 3 H), 2.93-3.09 (m, 1 H), 7.09-7.29 (m, 6 H),
7.42-7.47 (m, 2 H), 7.75-7.85 (m, 4 H); 13C NMR δ 17.50 (q),
19.77 (q), 32.03 (q), 43.38 (2 × q), 52.70 (d), 120.57 (d), 122.02
(d), 123.10 (d), 123.32 (d), 125.74 (d), 125.77 (d), 125.84 (s),
125.89 (d), 126.26 (d), 127.67 (d), 127.70 (d), 127.93 (d), 128.09
(s), 128.23 (d), 129.68 (s), 129.76 (s), 134.52 (s), 134.76 (s),

7736 J . Org. Chem., Vol. 63, No. 22, 1998
Vyskocˇil et al.
149.61 (s), 150.22 (s); IR (CHCl3) ν 1619 and 1595 (CdC arom)
cm-1; MS m/z (%) 368 (M•+, 19), 325 (100).
(s), 134.38 (s), 146.94 (s), 148.60 (s), 151.27 (s); IR (CHCl3) ν
3546 (OH), 1621 and 1600 (CdC arom) cm-1; MS m/z (%) 375
(M•+, 100).
(R)-(-)-2-(N-Cycloh exyl-N-m eth yla m in o)-2′-(d im eth yl-
a m in o)-1,1′-bin a p h th yl, (R)-(-)-13b (277 m g, 68%): color-
less oil [R]D -120 (c 0.2, THF); 1H NMR (250 MHz) δ -0.09-
0.00 (m, 1 H), 0.42-0.55 (m, 2 H), 0.58-0.72 (m, 1 H), 0.85-
1.05 (m, 2 H), 1.08-1.51 (m, 4 H), 2.44 (s, 6 H), 2.43-2.50 (m,
1 H), 2.61 (s, 3 H), 7.12-7.30 (m, 6 H), 7.40-7.48 (m, 2 H),
7.78-7.85 (m, 4 H); 13C NMR δ 25.68 (t), 25.83 (2 × t), 27.92
(t), 30.78 (t), 32.79 (q), 43.47 (2 × q), 61.59 (d), 121.00 (d),
121.74 (d), 123.16 (d), 123.23 (d), 125.79 (d), 125.81 (d), 125.97
(d), 126.11 (d), 126.62 (s), 127.51 (s), 127.66 (d), 127.74 (2 ×
d), 128.22 (d), 129.56 (s), 129.89 (s), 134.73 (s), 134.83 (s),
149.57 (s), 150.35 (s); IR (CHCl3) ν 1618 and 1593 (CdC arom)
cm-1; MS m/z (%) 408 (M•+, 16), 325 (100).
(R)-(-)-2-[N-(2′′-Adam an tyl)-N-m eth ylam in o]-2′-(dim eth -
yla m in o)-1,1′-bin a p h th yl, (R)-(-)-13c (294 m g, 64%): mp
173-6 °C (toluene); [R]D -146 (c 0.3, THF); 1H NMR (250 MHz)
δ 0.11-0.17 (m, 1 H), 0.60-0.65 (m, 1 H), 1.12-1.26 (m, 3 H),
1.31-1.48 (m, 5 H), 1.58-1.68 (m, 3 H), 2.00-2.06 (m, 1 H),
2.49 (s, 6 H), 2.57 (s, 3 H), 2.86 (m, 1 H), 6.84 (d, J ) 8.5 Hz,
1 H), 6.97-7.03 (m, 1 H), 7.15-7.39 (m, 4 H), 7.46 (d, J ) 8.8
Hz, 1 H), 7.67 (d, J ) 8.8 Hz, 1 H), 7.75 (d, J ) 7.9 Hz, 1 H),
7.82-7.93 (m, 3 H); 13C NMR δ 27.27 (d), 27.37 (d), 29.96 (d),
30.18 (d), 30.65 (t), 31.02 (t), 36.98 (t), 37.37 (t), 37.52 (t), 41.13
(q), 43.47 (2 × q), 66.92 (d), 118.84 (d), 122.86 (d), 124.51 (d),
124.57 (d), 125.23 (d), 125.47 (s), 125.71 (d), 126.36 (d), 127.51
(d), 127.60 (d), 127.66 (d), 128.41 (d), 128.49 (d), 129.62 (s),
131.25 (s), 133.29 (s), 134.64 (s), 134.89 (s), 150.36 (s), 150.43
(s); IR (CHCl3) ν 1619 and 1596 (CdC arom) cm-1; MS m/z
(%) 460 (M•+, 7) 325 (100).
(R)-(+)-2-(P h en ylam in o)-2′-h ydr oxy-1,1′-bin aph th yl, (R)-
(+)-14. Bis(dibenzylidene acetone)palladium (0.05 mmol, 29
mg, 5 mol %), (()-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
(BINAP; 0.075 mmol, 49 mg), sodium tert-butoxide (6 mmol,
576 mg), NOBIN (1) (1 mmol, 285 mg), and bromobenzene (5
mmol, 785 mg, 523 µL) were placed in a Schlenk tube under
an argon atmosphere and dissolved in dry toluene (5 mL). The
tube was heated at 90 °C with stirring for 2 h. After cooling,
the mixture was purified by flash chromatography on silica
gel (20 g) with toluene as eluent to give (R)-(+)-14 (255 mg,
71%) as an amorphous solid: [R]D +146 (c 0.3, THF); 1H NMR
(250 MHz) δ 5.13 (bs, 1 H), 5.50 (bs, 1 H), 6.89-7.00 (m, 3 H),
7.05 (d, J ) 8.2 Hz, 1 H), 7.13-7.36 (m, 8 H), 7.61 (d, J ) 9.1
Hz, 1 H), 7.75-7.91 (m, 4 H); 13C NMR δ 112.42 (s), 113.81
(s), 117.32 (d), 117.73 (d), 120.53 (2 × d), 122.60 (d), 123.51
(d), 123.75 (d), 124.13 (d), 124.29 (d), 127.15 (d), 127.32 (d),
128.21 (d), 128.35 (d), 129.15 (s), 129.24 (2 × d), 129.49 (s),
130.11 (d), 130.58 (d), 133.34 (s), 134.12 (s), 141.46 (s), 141.95
(s), 151.90 (s); IR (CHCl3) ν 3526 (OH), 3407 (NH), 1624 and
1596 (CdC arom) cm-1; MS m/z (%) 361 (M•+, 100). Chroma-
tography on Daicel Chiralpak AD (elution hexane-2-propanol)
9:1, flow rate 1 mL/min, UV detection at 256 nm) showed 99%
ee (tR ) 7.5 min, tS ) 9 min).
(R)-(+)-2,2′-Bis(p h en yla m in o)-1,1′-bin a p h th yl, (R)-(+)-
16. Bis(dibenzylidene acetone)palladium (58 mg, 0.1 mmol, 5
mol %), (()-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BI-
NAP; 98 mg, 0.15 mmol), sodium tert-butoxide (1.152 g, 12
mmol), diamine 2 (284 mg, 1 mmol, >99% ee), and bromoben-
zene (1.57 g, 1.046 mL, 10 mmol) were placed in a Schlenk
tube under an argon atmosphere and dissolved in dry toluene
(5 mL). The tube was heated at 90 °C with stirring for 2 h.
After cooling, the mixture was purified by flash chromatog-
raphy on silica gel (50 g) with toluene as eluent to give (R)-
(+)-16 (304 mg, 70%) as an amorphous solid: [R]D +63.4 (c
0.4, THF); 1H NMR (250 MHz) δ 5.47 (bs, 2 H), 6.79-6.89 (m,
6 H), 7.05-7.24 (m, 10 H), 7.59 (d, J ) 9.1 Hz, 2 H), 7.73-
7.81 (m, 4 H); 13C NMR δ 116.38 (s), 117.83 (d), 119.94 (2 ×
d), 122.13 (d), 123.43 (d), 124.42 (d), 127.01 (d), 128.19 (d),
129.20 (2 × d), 129.36 (d), 129.41 (s), 133.96 (s), 140.37 (s),
142.49 (s); IR (CHCl3 ν 3402 (NH), 1620 and 1596 (CdC arom);
MS m/z (%) 436 (M•+, 100).17 Chromatography on Daicel
Chiralpak AD (elution hexanes-ethanol 19:1, flow rate 1 mL/
min, UV detection at 256 nm) showed 98% ee (tS ) 4.3 min, tR
) 5.5 min).
(R)-(+)-2-Am in o-2′-(p h en yla m in o)-1,1′-bin a p h th yl, (R)-
(+)-17. (R)-(+)-17 (65 mg, 18%) was isolated from the previous
experiment as a slower moving byproduct: mp 240-1 °C
1
(toluene); [R]D +131 (c 0.4, THF); H NMR (400 MHz) δ 3.75
(bs, 2 H), 5.60 (bs, 1 H), 6.91-6.95 (m, 1 H), 6.98-7.02 (m, 2
H), 7.09-7.12 (m, 2 H), 7.14 (d, J ) 8.8 Hz, 1 H), 7.18-7.32
(m, 5 H), 7.70 (d, J ) 9.1 Hz, 1 H), 7.76-7.88 (m, 5 H); 13C
NMR δ 112.03 (s), 116.82 (s), 117.86 (d), 118.27 (d), 119.80 (2
× d), 121.95 (d), 122.53 (d), 123.33 (d), 123.85 (d), 124.52 (d),
126.85 (d), 126.99 (d), 128.13 (d), 128.17 (d), 128.44 (s), 129.09
(d), 129.20 (2 × d), 129.44 (s), 129.75 (d), 133.74 (s), 133.93
(s), 140.19 (s), 142.77 (s), 142.82 (s); IR (CHCl3) ν 3487 (NH2
asym), 3397 (NH2 sym, NH), 1621 and 1595 (CdC arom) cm-1
MS m/z (%) 360 (M•+, 100).
;
(R)-(+)-2,2′-Bis(N-m eth yl-N-p h en yla m in o)-1,1′-bin a p h -
th yl, (R)-(+)-18. A solution of the diamine 16 (436 mg, 10
mmol) in THF (10 mL) and solid NaBH4 (530 mg, 14 mmol)
were slowly added (simultaneously) to a solution of 40%
aqueous formaldehyde (2 mL, 24 mmol) and 20% aqueous
H2SO4 (2 mL) in THF (5 mL) over a period of 15 min. The
reaction mixture was stirred for an additional 15 min at room
temperature and then poured into a 2% aqueous KOH (100
mL). The resulting suspension was extracted with ethyl
acetate (3 × 20 mL), and the extract was dried with MgSO4
and evaporated. The crude product was purified by flash
chromatography on silica gel (20 g) with toluene to give (R)-
(+)-18 (395 mg, 85%): mp 162-4 °C (toluene); [R]D +401 (c
1
0.2, THF); H NMR (400 MHz) δ 2.64 (s, 6 H), 6.40-6.49 (m,
6 H), 6.74-6.81 (m, 4 H), 7.17 (d, J ) 8.8 Hz, 2 H), 7.22-7.28
(m, 2 H), 7.39-7.44 (m, 2 H), 7.46 (d, J ) 8.8 Hz, 2 H), 7.82-
7.88 (m, 4 H); 13C NMR δ 39.09 (q), 115.09 (2 × d), 117.64 (d),
125.00 (d), 126.26 (d), 126.39 (d), 126.82 (d), 127.82 (2 × d),
128.13 (d), 129.12 (d), 130.85 (s), 131.65 (s), 134.51 (s), 146.17
(R)-(+)-2-(N-Met h yl-N-p h en yla m in o)-2′-h yd r oxy-1,1′-
bin a p h th yl, (R)-(+)-15. A solution of the amino phenol 14
(361 mg, 1 mmol) in THF (10 mL) and solid NaBH4 (265 mg,
7 mmol) were slowly added (simultaneously) to a solution of
40% aqueous formaldehyde (1 mL, 12 mmol) and 20% aqueous
H2SO4 (1 mL) in THF (5 mL) over a period of 15 min at room
temperature. The reaction mixture was stirred for an ad-
ditional 15 min and then poured into 2% aqueous KOH (100
mL). The resulting suspension was extracted with ethyl
acetate (3 × 20 mL), and the extract was dried with MgSO4
and evaporated. The crude product was purified by flash
chromatography on silica gel (20 g) with toluene to give (R)-
(+)-15 (304 mg, 81%) as an amorphous solid: [R]D +137 (c 0.2,
THF); 1H NMR (400 MHz) δ 2.78 (s, 3 H), 4.95 (s, 1 H), 6.55-
6.64 (m, 2 H), 6.93-7.19 (m, 9 H), 7.33-7.45 (m, 1 H), 7.46 (d,
(s), 148.56 (s); IR (CH2Cl2) ν 1605 and 1580 (CdC arom) cm-1
;
MS m/z (%) 464 (M•+, 27), 246 (100).
(R)-(+)-2-(N-Meth yl-N-p h en yla m in o)-2′-(d im eth yla m i-
n o)-1,1′-bin a p h th yl, (R)-(+)-19. A solution of the diamine
17 (360 mg, 1 mmol) in THF (10 mL) and solid NaBH4 (795
mg, 21 mmol) were slowly added (simultaneously) to a solution
of 40% aqueous formaldehyde (3 mL, 36 mmol) and 20%
aqueous H2SO4 (3 mL) in THF (5 mL) over a period of 15 min.
The reaction mixture was stirred for an additional 15 min and
then poured into a 2% aqueous KOH (100 mL). The resulting
suspension was extracted with ethyl acetate (3 × 20 mL), and
the extract was dried with MgSO4 and evaporated. The crude
product was purified by flash chromatography on silica gel (20
g) with toluene to give (R)-(+)-19 (246 mg, 61%) as an
amorphous solid: [R]D +335 (c 0.6, THF); 1H NMR (250 MHz)
δ 2.19 (s, 6 H), 2.42 (s, 3 H), 6.60-6.64 (m, 3 H), 7.01-7.18
(m, 4 H), 7.20-7.25 (m, 2 H), 7.31-7.46 (m, 3 H), 7.54 (d, J )
8.8 Hz, 1 H), 7.76-7.82 (m, 2 H), 7.87-7.91 (m, 2 H); 13C NMR
J ) 8.8 Hz, 1 H), 7.68-7.73 (m, 2 H), 7.80-7.90 (m, 2 H); 13
C
NMR δ 39.16 (q), 114.83 (2 × d), 116.19 (s), 116.52 (s), 117.80
(d), 118.35 (d), 123.24 (d), 125.07 (d), 125.73 (d), 125.79 (d),
126.33 (d), 126.93 (d), 126.96 (d), 128.07 (d), 128.10 (d), 128.75
(2 × d), 129.10 (s), 129.78 (d), 130.32 (d), 131.90 (s), 133.66

High-Yield Reductive Alkylation
J . Org. Chem., Vol. 63, No. 22, 1998 7737
δ 38.34 (q), 43.25 (2 × q), 113.49 (2 × d), 116.66 (d), 119.54
(d), 123.25 (d), 124.68 (s), 125.14 (d), 125.44 (d), 126.13 (d),
126.18 (d), 126.70 (d), 128.00 (2 × d), 128.11 (d), 128.15 (2 ×
d), 128.52 (d), 128.76 (d), 129.67 (s), 131.91 (s), 133.14 (s),
134.14 (s), 135.14 (s), 145.02 (s), 148.84 (s), 150.75 (s); IR
(CHCl3) ν 1621 and 1594 (CdC arom) cm-1; MS m/z (%) 402
(M•+, 28), 184 (100).
(R)-(+)-1-(2′-Ch lor op h en yl)-1-p r op a n ol (21e): [R]D +37.1
(c 4, CHCl3). In this case, the absolute configuration is
assumed but not rigorously proven.
(R)-(+)-1-(4′-Meth ylp h en yl)-1-p r op a n ol (21f): [R]D +29.8
(c 1, benzene) [lit.44 -23.9 (c 5.85, benzene) for the (S)
enantiomer, 61% ee].
(R)-(+)-1-(2′-Meth ylp h en yl)-1-p r op a n ol (21g): [R]D +44.8
(c 1, benzene) [lit.45 -57.51 (c 4, benzene) for the (S) enanti-
omer].
Gen er a l P r oced u r e for Ad d ition of Dieth ylzin c to
Ald eh yd es Usin g th e Am in o P h en ols 3, 4, 7, 8, a n d 15 a s
Ch ir a l Liga n d s. The (R) ligand (0.03 mmol) was placed in a
Schlenk tube and dissolved in degassed toluene (3 mL). The
solution was stirred for 5 min, 1.6 M BuLi in hexanes (0.054
mmol, 0.034 mL, 1.8 equiv) was added, and the resulting
mixture was stirred for an additional 5 min at room temper-
ature. A 1.0 M solution of diethylzinc in hexanes (2.2 mmol,
2.2 mL) was then added, and after the mixture was stirred
for 5 min, a solution of the aldehyde 20 (1 mmol) in degassed
toluene (5 mL) was added. The reaction mixture was stirred
for 36 h at room temperature and quenched by the addition of
5% aqueous HCl (20 mL), and the product was extracted into
ethyl acetate (3 × 10 mL). The combined extracts were
washed successively with water, 5% aqueous KHCO3, and
water and dried with MgSO4, and the solvent was evaporated
in vacuo. The crude product was purified by a semipreparative
HPLC (silica gel, Magnum 9 Whatman column, a 4:1 hexanes-
ethyl acetate mixture as an eluent) to give the pure alcohol
21 as a colorless oil. The enantiomeric purities were deter-
mined by GC analysis of the corresponding menthoxycarbonyl
esters33 or by chiral HPLC (vide infra). The yields are given
in Tables 1 and 2.
(R)-(+)-1-(4′-F lu or op h en yl)-1-p r op a n ol (21h ): [R]D +29.7
(c 3, CHCl3) [lit.25 +51.2 (c 2.5, CHCl3)].
(R)-(+)-1-(1′-Na p h th yl)-1-p r op a n ol (21i): [R]D +39.9 (c 2,
CHCl3) [lit.46 -55.2 (c 8, CHCl3) for the (S) enantiomer, 87%
ee].
(R)-(+)-1-(2′-Na p h th yl)-1-p r op a n ol (21j): [R]D +22 (c 3,
benzene) [lit.34c gives -26.6 (c 3.35, benzene) for the (S)
enantiomer, 97% ee].
Ack n ow led gm en t. We thank the GACˇ R for Grants
203/97/1009, 203/97/0351 and 203/98/1185, GAUK for
Grants 86/95 and 18/98, British Council and the Uni-
versity of Leicester for additional support, and Mr.
Andrew J . Matthews for initial experiments with (()-
2. We also thank J ohnson-Matthey for the loan of
(dba)2Pd.
Su p p or tin g In for m a tion Ava ila ble: MS and HRMS
1
data, characterization of 20a -j, and H and 13C NMR spectra
of the new compounds prepared (53 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Gen er a l P r oced u r e for Ad d ition of Dieth ylzin c to
Ald eh yd es Usin g th e Dia m in es 5, 11-13, 16, 18, a n d 19
a s Ch ir a l Liga n d s. The (R) ligand (0.03 mmol) was placed
in a Schlenk tube and dissolved in degassed toluene (3 mL).
The solution was stirred for 5 min, a 1.0 M solution of
diethylzinc in hexanes (2.2 mmol, 2.2 mL) was then added,
and, after the mixture was stirred for 5 min, a solution of the
aldehyde 20 (1 mmol) in degassed toluene (5 mL) was added.
The reaction mixture was stirred for 36 h at room temperature
and quenched by the addition of 5% aqueous HCl (20 mL), and
the product was extracted into ethyl acetate (3 × 10 mL). The
combined extracts were washed successively with water, 5%
aqueous KHCO3, and water and dried with MgSO4, and the
solvent was evaporated in vacuo. The crude product was
purified by a semipreparative HPLC (silica gel, Magnum 9
Whatman column, a 4:1 mixture hexanes-ethyl acetate as
eluent) to give pure alcohol 21 as a colorless oil. The
enantiomeric purities were determined by GC analysis of the
corresponding menthoxycarbonyl esters33 or by chiral HPLC
(vide infra). The yields are given in Tables 1 and 2.
(R)-(+)-1-P h en yl-1-pr opan ol (21a): [R]D +38.8 (c 2, CHCl3)
[lit.21 -47.6 (c 6.11, CHCl3) for the (S) enantiomer, 98% ee].
(R)-(+)-1-(4′-Meth oxyph en yl)-1-pr opan ol (21b): [R]D +23.9
(c 3, benzene) [lit.21 -32.1 (c 1.25, benzene) for the (S)
enantiomer, 93% ee].
Not e Ad d ed in P r oof: (a) While this paper was in
press, Buchwald reported on acceleration of the amina-
tion of aryl bromides similar to that we have observed
for MAP (see ref 16). In his case, the acceleration was
due to a biphenyl analogue of MAP (9), namely 2-(di-
methylamino)-2′-(dicyclohexylphosphino)-1,1′-biphenyl.
See: Old, D. V.; Wolfe, J . P.; Buchwald, S. L. J . Am.
Chem. Soc. 1998, 120, 9722. (b) The first successful
resolution of a racemate via the Hartwig-Buchwald
coupling has been accomplished in the presence of
[2.2]phanephos. See: Rossen, K.; Pye, P. J .; Maliakal,
A.; Volante, R. P. J . Org. Chem. 1997, 62, 6462. (c)
Recently, Perica`s reported a new, highly efficient amino
alcohol to promote enantioselective addition of Et2Zn. See
Sola´, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.;
Perica`s, M. A.; Riera, A.; Alvarez-Larena, A.; Piniella,
J .-F. J . Org. Chem. 1998, 63, 7078.
(R)-(+)-1-(2′-Meth oxyph en yl)-1-pr opan ol (21c): [R]D +27.3
(c 2, toluene) [lit.43 -44.9 (c 1, toluene) for the (S) enantiomer,
83% ee].
J O9807565
(R)-(+)-1-(4′-Ch lor op h en yl)-1-p r op a n ol (21d ): [R]D +17.8
(c 3, benzene) [lit.21 -23.5 (c 0.82, benzene) for the (S)
enantiomer, 93% ee].
(44) Soai, K.; Watanabe, M. J . Chem. Soc., Chem. Commun. 1990,
43.
(45) Chelucci, G.; Conti, S.; Falorni, M.; Giacomelli, G. Tetrahedron
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