Highly Efficient Synthesis of Enantiomerically Pure (S)-2-Amino-1,2,2-triphenylethanol. Development of a New Family of Ligands for the Highly Enantioselective Catalytic Ethylation of Aldehydes

Article abstract of DOI:10.1021/jo982442n

The reaction of (S)-triphenylethylene oxide (3) with diisopropoxytitanium(IV) diazide in benzene solution at 70°C takes place readily in a completely regioselective and stereospecific manner to afford (S)-2-azido-1,2,2-triphenylethanol (6). Reduction of the azide by catalytic hydrogenation leads to (S)-2-amino-1,2,2-triphenylethanol (5) that, by N,N-dialkylation with 1,4-dibromobutane, 1,5-dibromopentane, 1,5-dibromo-3-oxapentane, α,α′-dibromo-o-xylene, and methyl iodide, affords the corresponding (S)-2-dialkylamino-1,2,2-triphenylethanols (7a-e). On the other hand, the reaction of 5 with benzyl bromide or 1-iodobutane takes place as a monoalkylation, leading to the corresponding (S)-2-alkylamino-1,2,2-triphenylethanols (8f,g). The performance of amino alcohols 7a-e as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehyde has been studied, with enantioselectivities of 94-97% being recorded. The best performing ligands in this family, 7a [(S)-1,2,2-triphenyl-2-(1-pyrrolidinyl)-ethanol] and 7c [(S)-2-morpholino-1,2,2-triphenylethanol] have been studied in the addition of Et₂Zn to a representative family of aldehydes. With 7a, a 96.6% mean ee is recorded for a family of 16 α-substituted aldehydes and a 92.8% mean ee for a family of six α-unsubstituted aldehydes. With 7c working on the same families of aldehydes, the mean enantioselectivities are 96.8% and 91.8%, respectively.

Full text of DOI:10.1021/jo982442n

J . Org. Chem. 1999, 64, 3969-3974
3969
High ly Efficien t Syn th esis of En a n tiom er ica lly P u r e
(S)-2-Am in o-1,2,2-tr ip h en yleth a n ol. Develop m en t of a New F a m ily
of Liga n d s for th e High ly En a n tioselective Ca ta lytic Eth yla tion
of Ald eh yd es§
Katamreddy Subba Reddy, Llu´ıs Sola`, Albert Moyano, Miquel A. Perica`s,* and Antoni Riera
Unitat de Recerca en S´ıntesi Asime`trica, Departament de Qu´ımica Orga`nica, Universitat de Barcelona,
c/ Martı´ i Franque`s, 1-11, 08028 Barcelona, Spain
Received December 14, 1998
The reaction of (S)-triphenylethylene oxide (3) with diisopropoxytitanium(IV) diazide in benzene
solution at 70 °C takes place readily in a completely regioselective and stereospecific manner to
afford (S)-2-azido-1,2,2-triphenylethanol (6). Reduction of the azide by catalytic hydrogenation leads
to (S)-2-amino-1,2,2-triphenylethanol (5) that, by N,N-dialkylation with 1,4-dibromobutane, 1,5-
dibromopentane, 1,5-dibromo-3-oxapentane, R,R′-dibromo-o-xylene, and methyl iodide, affords the
corresponding (S)-2-dialkylamino-1,2,2-triphenylethanols (7a -e). On the other hand, the reaction
of 5 with benzyl bromide or 1-iodobutane takes place as a monoalkylation, leading to the
corresponding (S)-2-alkylamino-1,2,2-triphenylethanols (8f,g). The performance of amino alcohols
7a -e as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehyde has been
studied, with enantioselectivities of 94-97% being recorded. The best performing ligands in this
family, 7a [(S)-1,2,2-triphenyl-2-(1-pyrrolidinyl)-ethanol] and 7c [(S)-2-morpholino-1,2,2-triphenyle-
thanol] have been studied in the addition of Et2Zn to a representative family of aldehydes. With
7a , a 96.6% mean ee is recorded for a family of 16 R-substituted aldehydes and a 92.8% mean ee
for a family of six R-unsubstituted aldehydes. With 7c working on the same families of aldehydes,
the mean enantioselectivities are 96.8% and 91.8%, respectively.
In tr od u ction
Enantiomerically pure â-amino alcohols represent one
of the most widely employed types of ligands for asym-
metric catalysis.1 Besides the classically used members
of this family of compounds, which derive from natural
products, enantiomerically pure amino alcohols of syn-
thetic origin are gaining progressive importance.2
In this context, we have recently reported the synthesis
of new families of enantiomerically pure â-amino alcohols
through the regioselective and stereospecific ring opening
of epoxides arising from the Sharpless3 (1)4 and the
J acobsen5 (2)6 epoxidations. When the use of these
substances as ligands is considered, they offer the clear
advantage of their modular construction, this character-
istic being important for the fine-tuning of catalytic
properties through structural variation.
Among these ligands, 2-dialkylamino-1,1,2-triphenyle-
thanols6 (2) obtained from readily available, enantiopure
triphenylethylene oxide7 (3) possess superb characteris-
tics of turnover and enantioselectivity in the addition of
diethylzinc to R-substituted aldehydes, in addition to a
great ease of preparation.
As an extension of this work, we planned to accede the
enantiomerically pure 2-amino-1,1,2-triphenylethanol (4)
through the ring opening of 3 with an azide-delivering
reagent plus reduction. This useful amino alcohol, which
is normally prepared from (R)-phenylglycine by a process
not exempt of difficulties,8 has been employed by Garcia
and co-workers as starting material for the preparation
of efficient oxazaborolidine-type reducing agents9 and by
Braun and co-workers for the preparation of catalytically
active imine-alkoxytitanium (IV) complexes.10
* To whom correspondence should be addressed. E-mail: mpb@
ursa.qo.ub.es.
§ Dedicated to Professor J ose´ Elguero on the occasion of his 65th
birthday.
(1) For general reviews, see: (a) Chiral Auxiliaries and Ligands in
Asymmetric Synthesis; Seyden-Penne, J ., Ed.; J ohn Wiley & Sons: New
York, 1995. (b) Blaser, H. U. Chem. Rev. 1992, 92, 935-952.
(2) (a)Watanabe, M.; Araki, S.; Butsugan, Y. J . Org. Chem. 1991,
56, 2218-2224. (b) Qiu, J .; Guo, C.; Zhang, X. J . Org. Chem. 1997, 62,
2665-2668. (c) Dosa, P. I.; Ruble, J . C.; Fu, G. C. J . Org. Chem. 1997,
62, 444-445.
(3) For reviews, see: (a) Katsuki, T.; Mart´ın, V. S. Org. React. 1996,
48, 1-299. (b) J ohnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993; pp 101-
158.
We wish to report here on how the azide-induced ring
opening of 3 takes place in a completely unexpected
manner and how the amino alcohol, ultimately arising
from the ring opening plus reduction process, can be
(4) (a) Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera, A. J . Org.
Chem. 1997, 62, 4970-4982. (b) Vidal-Ferran, A.; Moyano, A.; Perica`s,
M. A.; Riera, A. Tetrahedron Lett. 1997, 38, 8773-8776.
(5) J acobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH Publishers: New York, 1993; pp 159-202.
(6) 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, 7078-7082.
(7) Brandes, B. D.; J acobsen, E. N. J . Org. Chem. 1994, 59, 4378-
4380.
(8) Bach, J .; Berenguer, R.; Garcia, J .; Loscertales, T.; Vilarrasa, J .
J . Org. Chem. 1996, 61, 9021-9025.
(9) Berenguer, R.; Garcia, J .; Vilarrasa, J . Tetrahedron: Asymmetry
1994, 5, 165-168.
(10) Fleischer, R.; Wunderlich, H.; Braun, M. Eur. J . Org. Chem.
1998, 1063, 3-1070.
10.1021/jo982442n CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/07/1999

3970 J . Org. Chem., Vol. 64, No. 11, 1999
Reddy et al.
Sch em e 1
F igu r e 1.
Sch em e 2
successfully used as starting material for the preparation
of a new family of amino alcohols with useful character-
istics as ligands for the highly enantioselective catalytic
alkylation of aldehydes.
Resu lts a n d Discu ssion
The starting material for our study, (S)-triphenyleth-
ylene oxide (3), is easily prepared in enantiopure form
(>99.9% ee) in multigram amounts from commercially
available triphenylethylene through J acobsen epoxida-
tion7 followed by a simple crystallization from hexane.
The ring opening of 3 was initially attempted with NaN3
as the azide source in conjunction with LiClO4 as a
promoter according to Crotti11 (Scheme 1), since these
reaction conditions are those normally providing the best
results in the ring opening of epoxyalcohols with azides.
Surprisingly, no reaction was detected at all, although
high temperatures and long reaction times were used. It
is important to note that this result is in sharp contrast
with the apparently similar and even more difficult
reactions with secondary amines, which take place in
high yields and with complete regioselectivity to afford
amino alcohols 2.6
In view of the failure of this procedure, we centered
our attention on the use of diisopropoxytitanium(IV)
diazide [Ti(iPrO)2(N3)2], a reagent first used by Sharpless
for similar purposes.12 When (S)-3 was treated with 1.2
equiv of this reagent at 70 °C in benzene solution, we
were pleased to observe that a fast reaction was taking
place (complete conversion after 0.5 h). The reaction
product was easily characterized as an azido alcohol, and
HPLC analysis (Chiralcel OD) established that it was
enantiomerically pure. Reduction of this azido alcohol
(H2/Pd-C) led in quantitative yield to an amino alcohol,
but this compound was clearly different from 2-amino-
1,1,2-triphenylethanol (4).8 The analysis of the spectro-
scopic data of this material allowed its structural assign-
ment as the regioisomer of 4, 2-amino-1,2,2-
triphenylethanol (5):13 Surprisingly enough, the ring-
opening process had taken place by nucleophilic attack
at the more hindered, doubly benzylic position leading
to the azido alcohol 6. This behavior could be interpreted
as indicative of an intermediate O-titanyl species, re-
sponsible for the activation of the epoxide, possessing an
important carbocationic character at the more substi-
tuted position (Figure 1).
Since the chiral center in (S)-3 is not involved in the
reaction, the absolute configuration of 5 was assigned as
S. With this enantiomerically pure amino alcohol in hand,
the possibility of preparing a new family of ligands (7)
by N-alkylation became apparent. Given the regioiso-
meric relationship between 7 and 2, a comparison of the
enantioselectivities recorded with both families of com-
pounds in a common situation could help in the under-
standing of the mechanism of the considered processes.
The alkylation of 5 was performed under standard
conditions by reaction with a series of R,ω-dibromides and
alkyl halides in ethanol solution in the presence of
potassium carbonate (Scheme 2). The results of these
reactions have been summarized in Table 1.
(11) Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovani, E.;
Macchia, F.; Pineschi, M. J . Org. Chem. 1993, 58, 1221-1227.
(12) Caron, M.; Carlier, P. R.; Sharpless, K. B. J . Org. Chem. 1988,
53, 5185-5187.
(13) After this paper was submitted for publication, an alternative
preparation of enantiomerically pure 2-amino-1,2,2-triphenylethanol
starting from mandelic acid has been reported: Fleischer, R.; Braun,
M. Synlett 1998, 1441-1443.
Compounds 7a -d , where the nitrogen atom in the
dialkylamino residue is part of a ring, were selected as

Catalytic Ethylation of Aldehydes
J . Org. Chem., Vol. 64, No. 11, 1999 3971
Sch em e 3
Sch em e 4
para-substituted), aliphatic, and R,â-unsaturated speci-
mens (Scheme 4 and Table 3). It is worth noting that the
optimum reaction medium varied from one ligand to the
other. Thus, when using ligand 7c, toluene was found to
be the solvent where the reactions took place with higher
enantioselectivity, whereas with ligand 7a , the use of
hexane as the solvent resulted in a slightly higher (ca.
1%) enantioselectivity. Consequently, all additions in-
volving the use of ligand 7c were performed in toluene,
and additions using ligand 7a were run in hexane. Also
from a practical perspective, in all experiments involving
ligand 7c a 6% molar amount of ligand was used,
whereas with 7a a 10% molar amount of ligand was used
in some instances.
As can be seen, excellent results are obtained for the
set of R-substituted aldehydes (9a -p ), irrespectively of
their nature being aromatic, aliphatic, or R,â-unsatur-
ated. For this family of compounds, the resulting alcohols
are obtained in g 95% ee. With 7c, a mean enantiomeric
excess of 96.8%, with a standard deviation of 0.8%, is
recorded for the set of 16 R-substituted aldehydes (9a -
p ), while for 7a the mean enantiomeric excess is 96.6%
and the standard deviation is 0.9% with the same set of
aldehydes.
A very interesting characteristic of 7a and 7c is their
behavior in the addition to R-unsubstituted aldehydes.
These are, in general, substrates that experience catalytic
ethylation with low enantioselectivity, and probably for
this reason they are not well represented in the lists of
substrates on which newly developed ligands are tested.
Up to now, only the procedures developed by Seebach17
and by Pu18 provide consistently high enantioselectivities
in this particular situation, albeit at the expenses of using
a high percentage of ligand at rather inconveniently low
temperatures17 or involving the use of a difficultly avail-
able ligand.18
With the readily available ligands 7a and 7c, when
R-unsubstituted aldehydes, either R,â-unsaturated (9q)
or aliphatic (9r -v), are employed as substrates for the
reaction, the addition proceeds for all examples with high
enantioselectivity at the convenient temperature of 0 °C.
Thus, using 7c with the six considered R-unsubstituted
substrates, the mean ee is 91.8%, with a standard
deviation of 2%, while with 7a the mean ee is 92.8%, with
the even lower standard deviation of 1.3%.
Ta ble 2. Scr een in g of Liga n d s 7a -e a n d 8f,g in th e
Ca ta lytic En a n tioselective Ad d ition of Dieth ylzin c to
Ben za ld eh yd e
ligand
conversiona (%)
selectivityb (%)
eec (%)
7a
100
98
97
7b
7c
98
100
97
97
95
97
7d
7e
8f
100
99
99
93
97
99
97
94
17
74
8g
100
100
a
Determined by integration of residual 9a in front of all new
b
products in the gas chromatogram of the reaction crude. Deter-
mined by integration of 10a (both enantiomers in front of all new
products in the gas chromatogram of the reaction crude. c Deter-
mined by GC on a â-DEX 120 column.
targets bearing in mind the excellent catalytic results
provided by this type of amino residues in the regioiso-
meric products 26 and in related ligands.2a,4,14 The
preparation of 7a -d was achieved without problem with
the yields reported in Table 1, which have not been
optimized. On the other hand, when simple halides were
used as alkylating agents, dialkylation could only be
achieved with methyl iodide (7e); with benzyl bromide
and 1-iodobutane, the reactions were very slow leading
to secondary amines 8f and 8g as the result of a
monoalkylation.
As an initial estimate of their performance, dialky-
laminoethanols 7a -e and alkylaminoethanols 8f-g were
tested as ligands in the enantioselective addition of
diethylzinc to benzaldehyde15 (9a ) in toluene solution
(Scheme 3 and Table 2). We were most pleased to find
that, at 0 °C, all dialkylated ligands (7a -e) exhibited a
high catalytic activity, the reactions being complete after
3 h, and displayed a very high level of enantioselection,
affording (S)-1-phenylpropanol (10a ) of 94-97% ee. On
the other hand, as anticipated for monoalkylaminoetha-
nols,16 enantioselectivities were substantially lower when
ligands 8f and 8g were used.
Among the dialkylaminoethanols, best results were
recorded for ligands 7a and 7c. Ligand 7d , albeit provid-
ing a comparable enantioselectivity, induces slightly less
selective reactions than 7a and 7c. Noteworthy is the
very high enantioselectivity observed with the ligand
containing a 1-pyrrolidinyl module (7a ), since this struc-
tural unit did not provide particularly good results in the
previously studied family of amino alcohols, 1.4
Con clu sion s
The best performing ligands resulting from this pre-
liminary screening, 7a and 7c, were subsequently tested
in the addition of diethylzinc to a representative family
of aldehydes, comprising aromatic (ortho-, meta-, and
In summary, the unexpected regiochemistry of the ring
opening of (S)-triphenylethylene oxide with diisopro-
poxytitanium(IV) diazide has allowed, after hydrogena-
tion of the resulting azido compound 6, the development
of a straightforward synthesis of enantiomerically pure
(S)-2-amino-1,2,2-triphenylethanol (5). The alkylation of
(14) (a) Kang, J .; Lee, S. W.; Kim, J . I. J . Chem. Soc., Chem.
Commun. 1994, 2009-2010. (b) Hayashi, M.; Kaneko, T.; Oguni, N.
J . Chem. Soc., Perkin Trans. 1 1991, 25-28.
(15) For reviews, see: (a) Soai, K. Chem. Rev. 1992, 92, 833-856.
(b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; J ohn Wiley
& Sons: New York, 1994; pp 255-297.
(17) (a) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991,
30, 1321-1323. (b) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed.
Engl. 1991, 30, 99-101.
(18) Huang, W. S.; Hu, Q. S.; Pu, L. J . Org. Chem. 1998, 63, 1364-
1365.
(16) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49-69.

3972 J . Org. Chem., Vol. 64, No. 11, 1999
Reddy et al.
Ta ble 3. Ca ta lytic En a n tioselective Ad d ition of Et2Zn to Ald eh yd es 9a -v Lea d in g to Alcoh ols 10a -v Med ia ted by
Liga n d s 7a a n d 7c
ligand 7a
ligand 7c
starting aldehyde
benzaldehyde (9a )
resulting alcohol conversiona (%) selectivityb (%) eec (%) conversiona (%) selectivityb (%) eec (%)
(S)-10a
(S)-10b
(S)-10c
(S)-10d
(S)-10e
(S)-10f
100
99
97
92
91
96
97
98
97
98
97
99
91
99
99
89
89
97
90
98
96
99
99
98
97
98
95
96
97
97
96
97
97
98
96
96
96
98
96
96
90
94
94
93
93
93
100
100
100
100
98
100
100
100
100
85
97
90
88
95
96
97
98
98
99
99
90
98
99
89
89
96
98
96
98
99
96
95
97
98
95
96
97
96
97
98
97
97
97
97
96
97
98
96
90
94
94
93
91
89
o-tolualdehyde (9b)
o-chlorobenzaldehyde (9c)
o-methoxybenzaldehyde (9d )
m-tolualdehyde (9e)
m-fluorobenzaldehyde (9f)
m-methoxybenzaldehyde (9g)
p-tolualdehyde (9h )
pfluorobenzaldehyde (9i)
p-methoxybenzaldehyde (9j)
1-naphtaldehyde (9k )
2-naphtaldehyde (9l)
2-furfuraldehyde (9m )
2-ethylbutyraldehyde (9n )
cyclohexanecarbaldehyde (9o)
(E)-R-methylcinnamaldehyde (9p )
cinnamaldehyde (9q)
dihydrocinnamaldehyde (9r )
isovaleraldehyde (9s)
hexanal (9t)
100
100
100
100
100
100
100
100g
99
(S)-10g
(S)-10h
(S)-10i
(S)-10j
(S)-10k d
(S)-10ld
(S)-10m e
(S)-10n e
(S)-10of
(S)-10p e
(S)-10qd
(S)-10r f
(S)-10sf
(S)-10t
99
99
100
100
84
85
84
93
99
99
100
100
85
95g
99g
93
95
96
99
80
80
heptanal (9u )
nonanal (9v)
(S)-10u e
(S)-10ve
99g
96g
a
b
Determined by integration of residual 9 in front of all new products in the gas chromatogram of the reaction crude. Determined by
integration of 10 (both enantiomers) in front of all new compounds in the gas chromatogram of the reaction crude. c Determined by GC
on a â-DEX 120 column unless otherwise specified. Determined by HPLC on a Chiralcel OD column. e The alcohol was converted into
d
its acetate derivative and analyzed by GC on a â-DEX 120 column. f Determined by GC on a a-DEX 120 column. A 10% molar amount
g
of ligand was used.
temperature and benzene was removed under reduced pres-
sure. The concentrate was dissolved in 250 mL of diethyl ether,
300 mL of 5% H2SO4 was added, and the resulting mixture
was stirred until two phases formed (ca. 1h). Phases were
separated; the aqueous phase was extracted with diethyl ether
(4 × 100 mL), and the combined ethereal phases were dried
(Na2SO4) and concentrated. The residual solid was purified
by column chromatography to afford 12.50 g (99% yield) of 6
as a white solid: The enantiomeric purity was determined by
HPLC analysis (column, Chiralcel-OD; eluent, hexane/2-pro-
panol 90:10; flow rate, 1 mL/min; S isomer, tR 7.3 min, and R
5 with R,ω-dibromides allows the construction of a cycle
at nitrogen, and the resulting (S)-2-dialkylamino-1,2,2-
triphenylethanols (7a -d ) present interesting properties
as catalytic ligands for the enantioselective addition of
diethylzinc to aldehydes. In concrete, 7a , containing a
1-pyrrolydinyl fragment, and 7c, containing a morpholino
fragment, turn out to be among the best ligands described
to date for this reaction. The ease of preparation of these
substances, along with the convenience of the experi-
mental conditions involved in their use, should foster the
search for new catalytic applications. Work along these
lines is being undertaken in our laboratories and will be
reported in due course.
isomer, tR 9.9 min) and found to be >99.9%: mp 101 °C; [R]23
D
1
) -105.0 (c ) 1.35 in CHCl3); H NMR (300 MHz, CDCl3) δ
7.49-6.93 (m, 15H), 5.64 (d, J ) 3.1 Hz, 1 H), 2.41 (d, J ) 3.1
Hz, 1H, OH); 13C NMR (75 MHz, CDCl3) δ 140.8 (C), 140.1
(C), 139.1 (C), 128.8 (CH), 128.3 (CH), 128.0 (CH), 127.9 (CH),
127.8 (CH), 127.5 (CH), 127.4 (CH), 79.0 (CH), 75.9 (C); IR
Exp er im en ta l Section
(KBr) 3560, 2116, 1447, 698 cm-1; MS (CI, NH3) m/z (relative
Gen er a l Meth od s. Optical rotations were measured at
room temperature (23 °C) (concentration in g/100 mL). Melting
points were determined in open capillary tubes and are
uncorrected. Infrared spectra were recorded using NaCl film
or KBr pellet techniques. 1H NMR were recorded at 200 or
300 MHz (s ) singlet, d ) doublet, t ) triplet, m ) multiplet,
b ) broad). 13C NMR were recorded at 50.3 or 75.4 MHz.
Carbon multiplicities have been assigned by distortionless
enhancement by polarization transfer (DEPT) experiments.
High-resolution mass spectra (CI) were measured by the
Servicio de Espectrometr´ıa de Masas, Universidad de Co´rdoba.
Elemental analyses were performed by the Servei de Mi-
croana`lisi del CSIC de Barcelona. Chromatographic separa-
tions were carried out using NEt3 pretreated (2.5% v/v) SiO2
(70-230 mesh), eluting (unless otherwise stated) with hex-
anes-ethyl acetate mixtures of increasing polarity. HPLC
analyses were performed on an instrument equipped with a
Chiralcel OD (25 cm) column. Optically pure (S)-triphenyl-
ethylene oxide (3) was prepared according to the procedure
described by J acobsen et al.7 followed by recrystallization.
(S)-2-Azid o-1,2,2-tr ip h en yleth a n ol, 6. A solution of (S)-3
(10.88 g, 40 mmol, >99.9% ee) in dry benzene (100 mL) was
added to a suspension of [Ti(OiPr)2(N3)2] (12.0 g, 48 mmol) in
100 mL of benzene under argon at 70 °C. After being stirred
for 30 min, the reaction mixture was allowed to cool to room
+
intensity) 333 (C20H17N3O‚NH4
, 100). Anal. Calcd for
C
20H17N3O: C, 76.17; H, 5.43; N, 13.32. Found: C, 75.95; H,
5.42; N, 13.30.
(S)-2-Am in o-1,2,2-tr ip h en yleth a n ol, 5. A solution of 6
(12.0 g, 38 mmol) in MeOH (200 mL) was added on
a
suspension of 10% Pd/C (1.44 g) in MeOH (200 mL) under
hydrogen. The suspension was vigorously stirred for 10 h at
room temperature and then filtered through a pad of Celite
and concentrated under reduced pressure to furnish the crude
amino alcohol 5 in quantitative yield. Purification of this
product by column chromatography, eluting with
a 19:1
mixture of chloroform/MeOH, afforded 10.95 g (99% yield) of
5 as a white crystalline solid: mp 166 °C; [R]23 ) -237.0 (c
D
) 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.64-6.87 (m,
15H), 5.65 (s, 1 H), 3.10 (b, 1H, OH), 1.90 (b, 2H, NH2); 13C
NMR (50 MHz, CDCl3) δ 145.7 (C), 145.2 (C), 139.6 (C), 128.2
(CH), 127.8 (CH), 127.7 (CH), 127.3 (CH), 127.2 (CH), 126.7
(CH), 126.4 (CH), 77.4 (CH), 65.6 (C); IR (KBr) 3390, 3367,
1447, 700 cm-1; MS (CI, NH3) m/z (relative intensity) 290
(C20H19NO‚H+, 100). Anal. Calcd for C20H19NO: C, 83.01; H,
6.62; N, 4.84. Found: C, 83.00; H, 6.69; N, 4.86.
Gen er a l P r oced u r e for th e Alk yla tion of 5: (S)-1,2,2-
Tr ip h en yl-2-(1-p yr r olid in yl)eth a n ol, 7a . A mixture of 5
(2.89 g, 10 mmol), 1,4-dibromobutane (4.32 g, 20 mmol), K2-

Catalytic Ethylation of Aldehydes
J . Org. Chem., Vol. 64, No. 11, 1999 3973
CO3 (2.76 g, 20 mmol), and absolute ethanol (10 mL) was
refluxed for 48 h under N2. The reaction mixture was allowed
to cool to room temperature and filtered and the precipitate
washed with ethanol. The solution was concentrated under
reduced pressure, and the residue was purified by column
chromatography to afford 2.41 g (70% yield) of 7a as an oil
that solidified on standing at room temperature: mp 122-
MHz, CDCl3) δ 140.4 (C), 136.9 (C), 133.2 (C), 130.9 (CH), 130.7
(CH), 127.7 (CH), 127.1 (CH), 126.6 (CH), 126.5 (CH), 120.0
(CH), 76.4 (C), 71.1 (CH), 39.5 (CH3); IR (KBr) 3403, 1441,
710 cm-1; MS (CI, NH3) m/z (relative intensity) 318 (C22H23
-
NO‚H+, 100); HRMS (CI) calcd for C22H22N [M+ - OH]
300.1749, found 300.1752.
123 °C; [R]23 ) -20.9 (c ) 1.06, CHCl3); 1H NMR (300 MHz,
(S)-2-Ben zyla m in o-1,2,2-tr ip h en yleth a n ol, 8f. A mixture
of 5 (450 mg, 1.56 mmol), benzyl bromide (720 mg, 0.5 mL,
4.2 mmol), K2CO3 (538 mg, 3.9 mmol), and absolute ethanol
(5 mL) was refluxed for 48 h under N2 and treated as described
for 7a to afford, after purification by column chromatography,
D
CDCl3) δ 7.42-6.88 (m, 13H), 6.72-5.69 (m, 2 H), 5.91 (s, 1H),
4.68 (b, 1H, OH), 2.48 (b, 4H), 1.63 (b, 4H); 13C NMR (75 MHz,
CDCl3) δ 140.1 (C), 137.4 (C), 133.9 (C), 130.9 (CH), 128.1 (CH),
127.1 (CH), 126.7 (CH), 126.6 (CH), 125.9 (CH), 74.6 (C), 72.4
(CH), 45.9 (CH2), 22.1 (CH2); IR (KBr) 3405, 1493, 710 cm-1
;
250 mg (42% yield) of 8f as an oil: [R]23 ) -3.78 (c ) 1.47,
D
MS (CI, NH3) m/z (relative intensity) 344 (C24H25NO‚H+, 100).
Anal. Calcd for C24H25NO: C, 83.93; H, 7.34; N, 4.08. Found:
C, 83.89; H, 7.33; N, 4.20.
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.45-7.42 (m, 2H), 7.31-
7.20 (m, 12H), 7.12-7.01 (m, 4H), 6.74 (d, J ) 8.4 Hz, 2H),
5.66 (s, 1H), 3.51 (part A of AB system, J ) 12.8 Hz, 1H), 3.46
(part B of AB system, J ) 12.8 Hz, 1H), 3.45 (b, 1H, OH), 1.95
(b, 1H, NH); 13C NMR (75 MHz, CDCl3) δ 142.1 (C), 141.5 (C),
140.6 (C), 140.1 (CH), 129.8 (CH), 129.3 (CH), 128.4 (CH),
128.2 (CH), 127.9 (CH), 127.5 (CH), 127.3 (CH), 127.1 (CH),
127.0 (CH), 126.9 (CH), 126.9 (CH), 77.5 (CH), 70.8 (C), 47.6
(CH2); IR (KBr) 3559, 3426, 1495, 698 cm-1; MS (CI, NH3) m/z
(relative intensity) 379 (C27H25NO+, 100), 380 (C27H25NO‚H+,
24). Anal. Calcd for C27H25NO: C, 85.45; H, 6.64; N, 3.69.
Found: C, 85.27; H, 6.74; N, 3.57.
(S)-1,2,2-Tr ip h en yl-2-p ip er id in oeth a n ol, 7b. A mixture
of 5 (289 mg, 1 mmol), 1,5-dibromopentane (506 mg, 2.2 mmol),
K2CO3 (304 mg, 2.2 mmol), and CH3CN (2 mL) was refluxed
for 42 h under N2 and treated as described for 7a to afford,
after purification by column chromatography, 148 mg (41%
yield) of 7b as a white solid: mp 130-131 °C; [R]23 ) +2.7 (c
D
) 1.05, CHCl3); 1H NMR (300 MHz, CDCl3, 50 °C) δ 7.48-
6.71 (m, 15H), 6.08 (s, 1H), 4.64 (b, 1H, OH), 2.38 (b, 3H), 1.69
(b, 5H), 1.38 (b, 2H); 13C NMR (75 MHz, CDCl3, 50 °C) δ 140.8
(C), 137.4 (C), 134.6 (C), 130.5 (CH), 127.6 (CH), 127.1 (CH),
126.8 (CH), 126.7 (CH), 126.5 (CH), 77.2 (C), 70.8 (CH), 49.0
(S)-2-Bu tyla m in o-1,2,2-tr ip h en yleth a n ol, 8g. A mixture
of 5 (200 mg, 0.69 mmol), n-butyl iodide (368 mg, 0.25 mL, 2
mmol), K2CO3 (194 mg, 1.4 mmol), and absolute ethanol (2
mL) was refluxed for 48 h under N2 and treated as described
for 7a to afford, after purification by column chromatography,
(CH2), 26.8 (CH2), 24.9 (CH2); IR (KBr) 3397, 2927, 708 cm-1
;
MS (CI, NH3) m/z (relative intensity) 358 (C25H27NO‚H+, 100).
Anal. Calcd for C25H27NO: C, 83.99; H, 7.61; N, 3.92. Found:
C, 83.80; H, 7.67; N, 4.06.
(S)-2-Mor p h olin o-1,2,2-tr ip h en yleth a n ol, 7c. A mixture
of 5 (1.5 g, 5.2 mmol), bis(2-bromoethyl) ether (2.4 g, 10.4
mmol), K2CO3 (1.44 g, 10.4 mmol), and absolute ethanol (6 mL)
was refluxed for 48 h under N2 and treated as described for
7a to afford, after purification by column chromatography,
0.901 g (48% yield) of 7c as a colorless oil that solidified on
standing at room temperature: mp 175-176 °C; [R]23D ) -0.69
(c ) 2.02, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.35-6.88 (m,
13H), 6.67 (d, J ) 6.9 Hz, 2H), 6.01 (s, 1H), 4.46 (b, 1H, OH),
3.80-3.78 (m, 4H), 2.89-2.05 (b, 4H); 13C NMR (75 MHz,
CDCl3) δ 140.1 (C), 136.1 (C), 133.7 (C), 133.7 (CH), 130.6 (CH),
127.7 (CH), 127.5 (CH), 126.9 (CH), 126.8 (CH), 126.3 (CH),
76.6 (C), 70.4 (CH), 67.4 (CH2), 47.9 (CH2); IR (KBr) 3411,
1115, 710 cm-1; MS (CI, NH3) m/z (relative intensity) 359
(C24H25NO2‚H+, 100). Anal. Calcd for C24H25NO2: C, 80.19; H,
7.01; N, 3.90. Found: C, 80.34; H, 7.06; N, 3.92.
130 mg (38% yield) of 8g as an oil: [R]23 ) -125.6 (c ) 0.72,
D
CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.40-7.00 (m, 13H), 6.78
(d, J ) 11.4 Hz, 2H), 5.59 (s, 1H), 2.29-2.24 (m, 2H), 1.8-0.4
(b, 2H, OH + NH), 1.42-1.22 (m, 4H), 0.84 (t, J ) 7.4 Hz,
3H); 13C NMR (50 MHz, CDCl3) δ 142.0 (C), 141.8 (C), 140.1
(C), 129.7 (CH), 129.3 (CH), 128.1 (CH), 127.3 (CH), 127.1
(CH), 126.9 (CH), 76.5 (CH), 70.7 (C), 42.7 (CH2), 32.9 (CH2),
20.5 (CH2), 14.1 (CH3); IR (KBr) 3421, 3300, 700 cm-1; MS (CI,
NH3) m/z 346 (C24H27NO‚H+, 100). Anal. Calcd for C24H27NO:
C, 83.44; H, 7.88; N, 4.05. Found: C, 83.47; H, 8.04; N, 4.08.
En a n tioselective Am in o Alcoh ol-Ca ta lyzed Ad d ition
of Dieth yzin c to Ald eh yd es. Gen er a l P r oced u r e. To a
solution of the chiral catalyst (0.06 mmol, 6 mol %) in toluene
(2 mL) was added the aldehyde (1 mmol) at room temperature.
The mixture was stirred for 20 min and then cooled to 0 °C.
Diethylzinc (2.2 mL of a 1 M hexanes solution, 2.2 mmol) was
added dropwise. The mixture was stirred for the corresponding
reaction time under N2. The reaction was quenched by the
addition of a saturated NH4Cl solution (10 mL). The mixture
was then extracted with CH2Cl2 (3 × 10 mL), and the combined
organic extracts were dried and concentrated in vacuo. Con-
version, selectivity, and enantiomeric purity of the resulting
alcohols were determined from the crude mixture by GC or
HPLC analysis. Conditions of GC analyses: Supelco â-DEX
or R-DEX 120 column, 30 m length, 0.25 mm inner diameter,
isotherm temperature program, He as carrier gas (2.4 mL/
min). For 10a -b,d -l,n -p ,r -s,u , conditions of analysis and
retention times of the R and S isomers have been reported
elsewhere.6 For 1-(2-chlorophenyl)propanol (10c): â-DEX 120
column, 135 °C, tR R isomer 47.1 min, tR S isomer 51.4 min.
For 1-(2-furyl)propanol (10m ): (acetate derivative) â-DEX 120
column, 100 °C, tR S isomer 20.9 min, tR R isomer 22.2 min.
For 3-octanol (10t): (acetate derivative) â-DEX 120 column,
80 °C, tR S isomer 32.9 min, tR R isomer 36.0 min. For
3-undecanol (10v): (acetate derivative) â-DEX 120 column, 112
°C, tR S isomer 53.2 min, tR R isomer 56.8 min. Conditions of
HPLC analyses: Chiralcel-OD column, 25 cm, 30 °C. For 1-(1-
naphthyl)propanol (10k ): eluent, hexane/2-propanol 90:10;
flow rate, 1 mL/min; S isomer, tR 7.8 min and R isomer, tR
13.7 min. For 1-(2-naphthyl)propanol (10l): eluent, hexane/
(S)-2-(1,3-Dih yd r oisoin d ol-2-yl)-1,2,2-t r ip h en ylet h a -
n ol, 7d . A mixture of 5 (200 mg, 0.69 mmol), R,R′-dibromo-o-
xylene (400 mg, 1.52 mmol), K2CO3 (194 mg, 1.40 mmol), and
absolute ethanol (2 mL) was refluxed for 48 h under N2 and
treated as described for 7a to afford, after purification by
column chromatography, 115 mg (43% yield) of 7d as white
crystals: mp 159-160 °C; [R]23 ) -46.3 (c ) 1.52, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 7.52 (d, J ) 7.8 Hz, 2H), 7.37 (t,
J ) 7.5 Hz, 2H), 7.29-7.00 (m, 11H), 6.94 (t, J ) 7.5 Hz, 2H),
6.75 (d, J ) 7.8 Hz, 2H), 5.99 (s, 1H), 4.46 (b, 1H, OH), 4.11
(d, J ) 11.9 Hz, 2H), 3.98 (bd, J ) 11.9 Hz, 2H); 13C NMR (50
MHz, CDCl3) δ 139.7 (C), 138.8 (C), 136.4 (C), 134.2 (CH), 131.3
(CH), 130.9 (CH), 128.4 (CH), 127.4 (CH), 127.2 (CH), 126.9
(CH), 126.9 (CH), 126.8 (CH), 126.6 (CH), 126.3 (CH), 122.1
(CH), 74.9 (C), 72.9 (CH), 51.6 (CH2), 70.8 (CH), 49.0 (CH2),
26.8 (CH2), 24.9 (CH2); IR (KBr) 3378, 752, 712 cm-1; MS (CI,
NH3) m/z (relative intensity) 391 (C28H25NO+, 100), 392
(C28H25NO‚H+, 30); HRMS (CI) calcd for C28H24N [M+ - OH]
374.1890, found 374.1909.
(S)-2-Dim eth yla m in o-1,2,2-tr ip h en yleth a n ol, 7e. A mix-
ture of 5 (200 mg, 0.69 mmol), methyl iodide (320 mg, 0.14
mL, 2.25 mmol), K2CO3 (194 mg, 1.4 mmol), and absolute
ethanol (2 mL) was heated at 50 °C for 48 h under N2 and
treated as described for 7a to afford, after purification by
column chromatography, 200 mg (91% yield) of 7e as white
crystals: mp 103 °C; [R]23D ) -12.1 (c ) 1.5, CHCl3); 1H NMR
(200 MHz, CDCl3) δ 7.41-6.85 (m, 13H), 6.69 (d, J ) 8 Hz,
2H), 5.96 (s, 1H), 4.58 (b, 1H, OH), 2.12 (s, 6H); 13C NMR (50

3974 J . Org. Chem., Vol. 64, No. 11, 1999
Reddy et al.
2-propanol 95:5; flow rate, 1 mL/min; S isomer, tR 15.3 min
and R isomer, tR 17.0 min. For (E)-1-phenyl-1-penten-3-ol:
eluent, hexane/2-propanol 90:10; flow rate, 1 mL/min; R
isomer, tR 7.5 min and S isomer, tR 11.4 min. For 10a -l,n -
p ,r ,s,u , the establishment of the absolute configuration of the
major enantiomer resulting from the reaction has been per-
formed as already reported.6 For (S)-1-(2-furyl)propanol (10m ),18
(S)-3-octanol (10t),18 and (S)-3-undecanol (10v),18 retention
times of the acetate derivatives were compared with reported
values. For (S,E)-1-phenyl-1-penten-3-ol (10q),18 retention
times were compared with reported values.
Ack n ow led gm en t. We thank DGICYT (PB95-0265)
and CIRIT (1996SGR 00013) for financial support.
K.S.R. thanks MEC for a fellowship under the program
“Estancias Temporales de Cient´ıficos y Tecno´logos Ex-
tranjeros en Espan˜a”.
J O982442N