Chiral triphenylprolinol ligands for the efficient catalytic asymmetric arylation of aldehydes

Article abstract of DOI:10.1002/ejoc.201000336

The synthesis of new chiral amino alcohols by Heck arylation of an enecarbamate is described. These compounds were used as chiral ligands for the catalytic asymmetric arylation of aldehydes and can be easily recovered. Chiral, nonracemic diarylmethanols were obtained in high yields and enantioselectivities.

Full text of DOI:10.1002/ejoc.201000336

FULL PAPER
DOI: 10.1002/ejoc.201000336
Chiral Triphenylprolinol Ligands for the Efficient Catalytic Asymmetric
Arylation of Aldehydes
Angélica Venturini Moro,[a] Edward R. T. Tiekink,[b] Julio Zukerman-Schpector,[c]
Diogo S. Lüdtke,*[d] and Carlos Roque D. Correia*[a]
Keywords: Asymmetric synthesis / Amino alcohols / Heck reaction / Chirality / Aldehydes
The synthesis of new chiral amino alcohols by Heck arylation
of an enecarbamate is described. These compounds were
used as chiral ligands for the catalytic asymmetric arylation
of aldehydes and can be easily recovered. Chiral, nonrace-
mic diarylmethanols were obtained in high yields and
enantioselectivities.
Introduction
Among the methods available for the generation of reac-
tive arylzinc intermediates, the boron-to-zinc exchange re-
action[8] is one of the most interesting, as a number of aryl-
boronic acids are commercially available or can be easily
prepared, which allows the synthesis of a number of substi-
tuted diarylmethanols.[9,10] Moreover, this methodology al-
lows the synthesis of both enantiomers of a given product
by using the same chiral ligand through the appropriate
choice of arylboronic acid and aromatic aldehyde reaction
partners.
Among the chiral ligands described to catalyze the asym-
metric aryl transfer reaction with high enantioselectivity, β-
amino alcohols have been the most effective.[11] Considering
the proline motif as a privileged framework for the develop-
ment of asymmetric catalysts,[12] we decided to apply the
Heck reaction of arenediazonium salts (Heck–Matsuda re-
The asymmetric addition of arylzinc reagents to aromatic
aldehydes has received much attention over the past few
years, because enantioenriched diarylmethanols are present
in a number of biologically and pharmacologically active
compounds.[1] For example, this unit can be found in the
structure of (R)-orphenadrine and (R)-neobenodine,[2]
which display antihistaminic and anticholinergic activity,
and in (S)-BMS 184394, which is active against breast can-
cer and leukemia.[3] In addition to their direct applications,
the chiral diarylmethanol nucleus can serve as a precursor
for diarylmethane derivatives through SN2 substitution at
the CO bond without erosion in enantiomeric purity.[4]
Compounds possessing a chiral diarylmethane nucleus be-
have as antimuscarinics,[5] antidepressants,[6] and endothelin
antagonists (Figure 1).[7]
Figure 1. Structure of bioactive diarylmethanol derivatives.
[a] Instituto de Química, Universidade Estadual de Campinas,
UNICAMP,
action) for the synthesis of new chiral arylated amino
alcohols and apply them as chiral ligands for the asymmet-
ric arylation of aldehydes (Scheme 1).
The palladium-catalyzed Heck reaction of arenediazon-
ium salts with electron-rich olefins is an important tool for
the synthesis of natural products and biologically important
compounds.[13,14] Arenediazonium salts offer several advan-
tages over the more traditionally employed aryl halides; ar-
ylations are usually milder, easier to manipulate, faster, and
more economic.[15] Even more important is the fact
C.P. 6154, CEP. 13084-917 Campinas, Brazil
E-mail: roque@iqm.unicamp.br
[b] Department of Chemistry, University of Malaya,
Kuala Lumpur 50603, Malaysia
[c] Departamento de Química, Universidade Federal de São
Carlos,
São Carlos, Brazil
[d] Faculdade de Ciências Farmacêuticas, Universidade de São
Paulo, USP, CEP
05508-900 São Paulo, Brazil
E-mail: dsludtke@usp.br
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000336.
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Chiral Triphenylprolinol Ligands for Asymmetric Arylation of Aldehydes
Table 1. Heck reaction of enecarbamate 1 and arenediazonium
salts.
Entry
Ar
Yield [%]
trans/cis[a]
Scheme 1. General structure of the chiral ligands prepared by Heck
arylation.
1
2
3
4
Ph
85
90
82
70
45:55
85:15
44:56
42:58
4-MeOC6H4
4-FC6H4
2-naphthyl
that they undergo extremely facile oxidative addition with
Pd0, operating under “ligand-free” conditions to generate a
highly reactive cationic ArPdII species.
[a] The trans/cis ratio was determined by GC–MS analysis or by
1H NMR spectroscopy.
treated with LiAlH4 to reduce the N-Boc group to N-Me,
affording the desired amino alcohols in 40–60% yield over
Results and Discussion
The desired chiral ligands were synthesized by a short three steps. At this point, diastereoisomeric chiral amino
and efficient synthetic sequence starting from chiral ene- alcohols 5a–9a and 5b–9b were easily separated by flash
carbamate 1.[16] First, Heck arylation with arenediazonium chromatography (Scheme 2).
salts proceeded smoothly in the presence of Pd2(dba)3
Attempts to unequivocally determine the stereochemistry
(4 mol-%) as catalyst, delivering the arylated product as a of the chiral N-Me amino alcohols by H and 13C NMR
mixture of diastereoisomers in high yields (Table 1). With spectroscopy met with problems. To attribute the absolute
the exception of the Heck arylation with the 4-methoxyben- stereochemistry of the new chiral ligands, the diastereoiso-
zenediazonium tetrafluoroborate, the arylation process is meric mixture of N-Boc amino alcohol 4 (Ar = Ph, R =
unselective and almost equimolar mixtures of the cis and Ph) was separated into the trans and cis isomers. The cis
trans diastereoisomers were obtained. The lack of stereose- isomer furnished a suitable crystal, which allowed its stereo-
lectivity in our case is attractive, as it allows the synthesis chemistry to be determined by X-ray diffraction analysis
of a stereochemically diverse set of ligands with modular (Figure 2). Next, both pure diastereoisomers were con-
character. This is an important feature of the synthetic se- verted separately into their corresponding amino alcohols
quence, because it permits fine-tuning of catalytic activity trans-5a and cis-5b. Therefore, the stereochemistry of all
1
through refinement of the ligand structure.
compounds was attributed. The stereochemistry of remain-
Interestingly, lower stereoselectivity (Table 1, Entries 1, 3, ing ligands 6–9 was attributed by comparison of their NMR
and 4) seems to reflect the stability of the cationic aryl pal- spectra with those of trans-5a and cis-5b.
ladium intermediate. We hypothesize that the less-stable cat-
With the amino alcohols in hands, we turned our atten-
ionic aryl palladium intermediates complex rather ef- tion to evaluate their behavior as chiral ligands for the aryl-
ficiently with the ester group at C-2, which helps to promote ation of p-tolualdehyde with phenylboronic acid. The re-
the migratory insertion from the same side of the ester sults of these studies are depicted in Table 2.
group.
The transferable aryl group was generated by reaction of
Following our synthetic sequence, the diastereoisomeric phenylboronic acid with Et2Zn at 60 °C for 12 h.[17] All li-
mixture of the Heck adduct was then hydrogenated, fol- gands employed in the catalytic asymmetric arylation reac-
lowed by double Grignard addition, to result in the corre- tion furnished the product in good yield and varied levels
sponding amino alcohols 4. The crude products were then of enantioselectivity. Initially, the R group was held con-
Scheme 2. Completion of the synthesis of chiral amino alcohols 5–9.
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D. S. Lüdtke, C. R. D. Correia et al.
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conducting the reaction at 0 °C while maintaining the same
yield (Table 2, Entry 2). Further decrease in the temperature
did not improve the efficiency of the reaction, leading to a
decrease in yield or in the er (Table 2, Entries 4 and 5). The
influence of the stereochemistry at C-5 was then examined.
When using ligand 5b (cis relationship), a lower yield of the
chiral diarylmethanol was obtained with virtually the same
er. The addition of DiMPEG, an additive commonly used
to improve the enantioselectivity of organozinc ad-
ditions,[18] resulted in sluggish reactions and erosion in both
yield and er (Table 2, Entries 8 and 9). The influence of the
nature of the Ar group attached to C-5 was further evalu-
ated. Substituted aromatic rings led to diminished er values,
albeit furnishing the product in high yields in most cases
(Table 2, Entries 10–15). Among the ligands possessing a
substituted aryl ring, the best results were achieved with 8a
(Ar = naphthyl); chiral secondary alcohol 10a was obtained
in 95:5er in almost quantitative yield (Table 2, Entry 14).
Finally, the replacement of the R group from Ph to the
more sterically demanding ortho-tolyl derivative did not re-
sult in any improvement in the reaction outcome (Table 2,
Entries 16 and 17).
Importantly, direct comparison of the performance of li-
gands 5a and 5b with known diarylprolinol ligand 11[19]
reveals that smaller amounts of ligand are required to ob-
tain high enantioselectivity in the phenylation of p-tolual-
dehyde (Figure 3). Whereas 11 produced diarylmethanol
10a in 97:3er with a 20 mol-% loading, a significant de-
crease in the er to 67.5:32.5 was observed with 10 mol-%
loading. On the other hand, both ligands 5a and 5b pro-
vided a highly enantioselective aryl transfer reaction with
the use of a ligand loading of only 10 mol-% (up to 98:2er).
Figure 2. ORTEP drawing of cis-N-Boc amino alcohol 4b.
Table 2. Arylation of p-tolualdehyde with phenylboronic acid.
Entry Ligand (mol-%)
T [°C]
Yield [%] er (S)[a]
1
2
3
4
5
6
7
5a (10)
5a (10)
5a (5)
25
0
0
–40
–20
0
–20
0
0
0
0
0
98
98
72
60
99
86
80
51
46
97
99
85
99
99
99
81
81
88:12
98:2
87:13
99:1
95.5:4.5
97.5:2.5
95:5
92:8
91:9
93:7
92:8
93:7
89:11
95:5
91:9
91:9
5a (10)
5a (10)
5b (10)
5b (10)
5a (10)
5b (10)
6a (10)
6b (10)
7a (10)
7b (10)
8a (10)
8b (10)
9a (10)
9b (10)
8[b]
9[b]
10
11
12
13
14
15
16
17
Figure 3. Comparison between proline-based ligands.
0
0
0
0
With ligand 5a identified as the most active, we turned
our attention to exploit the potential of our system to a
broader variety of aldehydes and boronic acids with diverse
electronic and steric properties. The results are summarized
in Table 3. Reactions of o- and p-tolualdehyde underwent
smooth aryl addition, and the corresponding products were
isolated with high er values and yields (Table 3, Entries 1
and 2). Phenyl transfer to halogen-substituted aldehydes re-
sulted in good er values, albeit in lower levels of enantiose-
0
90:10
[a] Enantiomeric ratios determined by HPLC with a Chiralcel OD-
H column, λ = 254 nm, hexanes/iPrOH (90:10), 0.5 mLmin–1. Ab-
solute configuration determined by comparison with literature
data. [b] DiMPEG MW 2000 (dimethoxypolyethylene glycol,
10 mol-%) was used as additive.
stant as a phenyl group, and we studied the influence of lection when compared with p-tolualdehyde (Table 3, En-
the substitution pattern at C-5. Thus, ligand 5a (10 mol-%), tries 3–7). Interestingly, the position of the halogen in the
which presents the trans configuration, was used and the aryl ring did not seem to exert influence in the enantio-
diarylmethanol was obtained in 98% yield with 88:12er selectivity of the reaction. The arylation of the heteroaro-
(Table 2, Entry 1). A decrease in the reaction temperature matic 2-furaldehyde proceeded smoothly, and the corre-
proved to be beneficial to the enantioselectivity of the aryl- sponding phenyl-heteroarylmethanol was isolated in excel-
ation process, as the er was greatly improved to 98:2 by lent yield with an er of 96:4 (Table 3, Entry 9).
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Chiral Triphenylprolinol Ligands for Asymmetric Arylation of Aldehydes
Table 3. Catalytic asymmetric arylation of aldehydes with aryl- the reaction between biphenylboronic acid and 2-fural-
boronic acids.
dehyde produced the corresponding chiral secondary
alcohol in excellent yield and enantiomeric ratio (98% yield,
98.5:1.5er; Table 3, Entry 16).
Importantly, chiral ligand 5a could be completely reco-
vered by column chromatography and reused without any
loss in the catalytic activity or in the enantioselectivity of
the arylation reaction.
Conclusions
Entry
R1
Ar
Yield [%]
er[a]
98:2 (S)
96:4 (S)
93.5:6.5 (S)
92.5:7.5 (S)
93:7 (S)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
4-Me
4-Ph
4-MeO
4-Br
4-MeO
4-Cl
4-Ph
4-MeC6H4
2-MeC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
2-BrC6H4
3-FC6H4
4-MeOC6H4
2-furyl
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
4-MeC6H4
2-furyl
98
91
94
93
94
92
75
91
89
90
98
83
96
71
98
98
In summary, we have described the synthesis of new and
recyclable chiral amino alcohols by using a mild and ef-
ficient Heck arylation of an enecarbamate as the key step.
Furthermore, these compounds were efficiently used as chi-
ral ligands in the catalytic asymmetric aryl transfer reac-
tions of arylboronic acids to aromatic aldehydes. Chiral,
nonracemic diarylmethanols were obtained in high yields
and enantioselectivities. Applications of these new chiral
amino alcohols as organocatalysts are ongoing and will be
reported in due course.
93:7 (S)
90:10 (S)
93.5:6.5 (S)
96:4 (S)
92:8 (R)
98:2 (R)
88.5:11.5 (R)
96:4 (R)
86.5:13.5 (S)
96:4 (R)
9
10
11
12
13
14
15
16
Experimental Section
98.5:1.5 (S)
Materials and Methods: 1H NMR spectra were obtained at 250
and 500 MHz. Spectra were recorded in CDCl3 solutions. Chemical
shifts are reported in ppm and referenced to the solvent peak of
residual CHCl3 or tetramethylsilane (TMS). Data are reported as
follows: chemical shift (δ), multiplicity, coupling constant (J), and
integrated intensity. 13C NMR spectra were obtained at 62.5 and
125 MHz. Spectra were recorded in CDCl3 solutions. Chemical
shifts are reported in ppm and referenced to the solvent peak
CDCl3. Abbreviations to denote the multiplicity of a particular sig-
[a] Enantiomeric ratios determined by HPLC, see Supporting In-
formation for details. Absolute configuration determined by com-
parison with literature data.
To examine the competence of our catalytic system in the
transfer of substituted aryl groups, we examined the reac-
tion of a variety of boronic acids with benzaldehyde under
our standard conditions. Gratifyingly, we could observe
that the efficiency of the catalytic system was maintained. nal are s (singlet), d (doublet), t (triplet), dd (doublet of doublets),
and m (multiplet). Column chromatography was performed by
using silica gel (230–400 mesh) following the methods described by
Still.[20] Thin-layer chromatography (TLC) was performed by using
silica gel GF254, 0.25 mm thickness. For visualization, TLC plates
were either placed under ultraviolet light or treated with phos-
phomolybdic acid followed by heating. Air- and moisture-sensitive
reactions were conducted in flame-dried or oven-dried glassware
equipped with tightly fitted rubber septa and under a positive at-
mosphere of dry argon. Reagents and solvents were handled by
using standard syringe techniques. Temperatures above room tem-
For example, reaction of 4-biphenylboronic acid and 4-bro-
mophenylboronic acid with benzaldehyde resulted in the
corresponding product in very high er (Table 3, Entries 11
and 13). Exception to these high levels of selectivity is the
reaction with 4-methoxyphenylboronic acid, which resulted
in a decrease in the er (Table 3, Entry 12; 88.5:11.5er). An-
other important feature of this methodology is its ability to
prepare both enantiomers of a given product by using the
same chiral ligand. In fact, this could be accomplished by
using our catalytic system. For example, addition of p-tolyl- perature were maintained by use of a mineral oil bath heated on a
hotplate. Enantiomeric excesses were determined by HPLC with a
chiral stationary phase. All measurements were performed at a col-
umn temperature of 20 °C by using a UV detector at 254 nm, ex-
cept noted otherwise.
boronic acid and p-bromophenylboronic acid to benzalde-
hyde proceeded smoothly. The corresponding diarylmeth-
anols were obtained in high yields and high enantio-
selectivities (Table 3, Entry 1 vs. 10, Entry 5 vs. 13).
General Procedure for the Heck Arylation of Enecarbamate 1 with
Arenediazonium Salts: To a round-bottomed flask (or a test tube)
Finally, the synthesis of chiral diarylmethanols with sub-
stituents other than hydrogen in both aryl rings was pur-
sued. Effectively, this goal was achieved and structural vari-
ation was made simultaneously at the boronic acid and at
the aldehyde. The arylation reaction occurred uneventfully,
and the chiral secondary alcohols were generally obtained
in high yields and enantioselectivities. For example, reaction
of 4-chlorophenylboronic acid with p-tolualdehyde fur-
nished the corresponding product in high er (96:4) in essen-
was added enecabamate
1 (1.13 g, 5 mmol) and acetonitrile
(23 mL). To the resulting suspension was then added Pd2(dba)3·dba
(4 mol-%, 200 mg), sodium acetate (3 equiv., 1.6 g, 15 mmol), and
the arenediazonium salt (1.3 equiv., 6.5 mmol). The reaction was
stirred at room temperature, and the reaction progress was moni-
tored by the evolution of N2. After the nitrogen bubbling had
stopped, the crude reaction mixture was filtered through a plug of
silica gel and concentrated under reduced pressure. The product
tially quantitative yield (Table 3, Entry 15). Additionally, was purified by flash chromatography (hexanes/ethyl acetate) to
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D. S. Lüdtke, C. R. D. Correia et al.
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provide arylated products 2a and 2b, as an inseparable mixture of
diastereoisomers, which was directly used in the next step.
[(2S,5R)-5-(4-Methoxyphenyl)-1-methylpyrrolidin-2-yl]diphenyl-
methanol (6b): Yield: 0.097 g (9%). [α]2D0 = +118 (c = 1.0, CHCl3).
1H NMR (250 MHz, CDCl3): δ = 1.64 (s, 3 H, N-CH3), 1.69–1.84
(m, 2 H, CH2), 1.88–2.04 (m, 2 H, CH2), 3.50 (dd, J = 10.3, 5.8 Hz,
1 H, CH), 3.78 (s, 3 H, OCH3), 3.87 (dd, J = 9.3, 4.3 Hz, 1 H,
CH), 4.99 (br. s, 1 H, OH), 6.86 (d, J = 8.8 Hz, 2 H, Ar), 7.07–
7.18 (m, 2 H, Ar), 7.23–7.32 (m, 6 H, Ar), 7.56 (d, J = 8.5 Hz, 2
H, Ar), 7.67 (d, J = 8.5 Hz, 2 H, Ar) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 28.1, 34.5, 40.8, 55.2, 72.4, 72.8, 77.8, 113.8, 125.3,
125.4, 126.1, 126.2, 127.9, 128.0, 128.1, 134.5, 146.7, 148.1,
General Procedure for the Synthesis of the Ligands: To a round-
bottomed flask, under a hydrogen atmosphere, was added Heck
adduct 2 (3 mmol) and dry methanol (60 mL), followed by the ad-
dition of 10% Pd/C (20 wt.-%, 0.18 g). The reaction was stirred at
room temperature for 24 h. After this time, the crude reaction mix-
ture was filtered through a plug of Celite and concentrated under
reduced pressure. The resulting product was used without further
purification. To a round-bottomed flask, under an argon atmo-
sphere, a solution of RMgBr (1  in THF, 15 mL, 15 mmol,
5 equiv.) was added to a THF (10 mL) solution of ester 3 (3 mmol)
at 25 °C, and the mixture was stirred for 4 h before being quenched
by careful addition of 2  NaOH. The heterogeneous mixture was
filtered through a pad of Celite and washed with dichloromethane
(3ϫ50 mL). The combined organic phase was dried with MgSO4,
filtered, and concentrated. The resulting product was used without
further purification. In a round-bottomed flask, under an argon
atmosphere, containing a suspension of lithium aluminum hydride
(1.14 g, 30 mmol) in THF (15 mL), cooled to 0 °C, was added a
solution of N-Boc alcohol 4 in THF (5 mL). The resulting mixture
was heated at reflux for 12 h. After this time, the mixture was co-
oled to 0 °C and 4  NaOH was added. The mixture was filtered
through a pad of Celite and washed with ethyl acetate. The organic
158.8 ppm. IR (KBr): ν = 3371, 3283, 1512, 1248 cm–1. MS (EI):
˜
m/z = 355, 190. HRMS (EI): calcd. for C25H25NO [M – H2O]
355.1936; found 355.1935.
[(2S,5S)-5-(4-Fluorophenyl)-1-methylpyrrolidin-2-yl]diphenyl-
methanol (7a): Yield: 0.224 g (21%). [α]2D0 = +9 (c = 1.0, CHCl3).
1H NMR (250 MHz, CDCl3): δ = 1.59 (s, 3 H, N-CH3), 1.63–1.72
(m, 1 H), 1.76–1.88 (m, 1 H), 2.13–2.31 (m, 2 H, CH2), 4.23 (dd,
J = 8.5, 4.8 Hz, 1 H, CH), 4.29 (d, J = 6.8 Hz, 1 H, CH), 6.96–
7.06 (m, 2 H, Ar), 7.09–7.17 (m, 4 H, Ar), 7.18–7.31 (m, 4 H, Ar),
7.61 (d, J = 8.5 Hz, 2 H, Ar), 7.68 (d, J = 8.5 Hz, 2 H, Ar) ppm.
13C NMR (62.5 MHz, CDCl3): δ = 28.9, 31.5, 38.3, 70.3, 70.5, 77.2,
115.1 (d, J = 21.25 Hz), 125.2, 125.2, 126.1, 126.1, 128.0, 128.1,
129.2 (d, J = 7.5 Hz), 138.3 (d, J = 3.1 Hz), 146.9, 148.2, 161.7 (d,
J = 243.12 Hz) ppm. IR (KBr): ν = 3292, 1508, 709 cm–1. MS (EI):
˜
layer was separated, and the filtrate was extracted with ethyl acetate m/z = 343, 182, 178, 165, 105, 77. HRMS (EI): calcd. for C24H22FN
(3ϫ50 mL). The combined organic phase was dried with MgSO4,
filtered, and concentrated. The crude product was purified by flash
chromatography (hexanes/ethyl acetate, 95:05).
[M – H2O] 343.1736; found 343.1714.
[(2S,5R)-5-(4-Fluorophenyl)-1-methylpyrrolidin-2-yl]diphenyl-
methanol (7b): Yield: 0.285 g (26%). [α]2D0 = +116 (c = 1.0, CHCl3).
1H NMR (250 MHz, CDCl3): δ = 1.64 (s, 3 H, N-CH3), 1.69–1.85
(m, 2 H, CH2), 1.88–2.08 (m, 2 H, CH2), 3.52 (dd, J = 10.5, 5.8 Hz,
1 H, CH), 3.89 (dd, J = 9.0, 4.3 Hz, 1 H, CH), 4.87 (br. s, 1 H,
OH), 6.94–7.03 (m, 2 H, Ar), 7.06–7.19 (m, 2 H, Ar), 7.22–7.31
(m, 6 H, Ar), 7.57 (d, J = 8.5 Hz, 2 H, Ar), 7.67 (d, J = 8.5 Hz, 2
H, Ar) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 28.1, 34.6, 40.9,
72.4, 72.7, 77.8, 115.3 (d, J = 21.25 Hz), 125.3, 125.4, 126.1, 126.2,
[(2S,5S)-1-Methyl-5-phenylpyrrolidin-2-yl]diphenylmethanol
(5a):
Yield: 0.278 g (27%). [α]2D0 = +12 (c = 1.0, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 1.62 (s, 3 H, N-CH3), 1.66–1.88 (m, 2 H,
CH2), 2.14–2.35 (m, 2 H, CH2), 4.25–4.34 (m, 2 H, 2 CH), 7.06–
7.36 (m, 11 H, Ar), 7.61 (dd, J = 8.3, 1.5 Hz, 2 H, Ar), 7.69 (dd, J
= 8.3, 1.5 Hz, 2 H, Ar) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
29.0, 31.5, 38.4, 70.6, 71.2, 77.3, 125.25, 125.26, 126.1, 126.1, 126.9,
127.8, 128.0, 128.1, 128.3, 142.8, 147.0, 148.3 ppm. IR (film): ν = 128.0, 128.1, 128.4 (d, J = 7.5 Hz), 138.2 (d, J = 3.1 Hz), 146.5,
˜
3415, 1490, 705 cm–1. MS (ESI): m/z = 344, 331, 326. HRMS (ESI): 147.9, 162.0 (d, J = 243.75 Hz) ppm. IR (film): ν = 3352, 1508,
˜
calcd. for C24H25NO + H 344.2014; found 344.2012.
1223 cm–1. MS (EI): m/z = 343, 178, 167, 165, 105. HRMS (EI):
calcd. for C24H22FN [M – H2O] 343.1736; found 343.1731.
[(2S,5R)-1-Methyl-5-phenylpyrrolidin-2-yl]diphenylmethanol
(5b):
Yield: 0.340 g (33%). [α]2D0 = +115 (c = 1.02, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 1.66 (s, 3 H, N-CH3), 1.68–1.83 (m, 2 H,
CH2), 1.92–2.03 (m, 2 H, CH2), 3.54 (dd, J = 10.8, 6.0 Hz, 1 H,
CH), 3.89 (dd, J = 9.8, 4.0 Hz, 1 H, CH), 4.97 (br. s, 1 H, OH),
7.09 (t, J = 7.0 Hz, 1 H, Ar), 7.13 (t, J = 7.0 Hz, 1 H, Ar), 7.19–
7.33 (m, 9 H, Ar), 7.58 (dd, J = 8.5, 1.0 Hz, 2 H, Ar), 7.68 (dd, J
= 8.5, 1.0 Hz, 2 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): δ =
28.2, 34.5, 41.0, 72.5, 73.4, 77.8, 125.3, 125.4, 126.1, 126.2, 126.9,
[(2S,5S)-1-Methyl-5-(naphthalen-2-yl)pyrrolidin-2-yl]diphenyl-
methanol (8a): Yield: 0.272 g (23%). [α]2D0 = +1 (c = 1.0, CHCl3).
1H NMR (250 MHz, CDCl3): δ = 1.67 (s, 3 H, N-CH3), 1.75–1.94
(m, 2 H, CH2), 2.23–2.42 (m, 2 H, CH2), 4.38 (dd, J = 8.5, 4.3 Hz,
1 H, CH), 4.50 (d, J = 5.3 Hz, 1 H, CH), 7.06–7.35 (m, 8 H, Ar),
7.43–7.51 (m, 2 H, Ar), 7.60–7.66 (m, 3 H, Ar), 7.71 (d, J = 8.5 Hz,
2 H, Ar), 7.82 (d, J = 8.5 Hz, 2 H, Ar) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 29.1, 31.6, 38.5, 70.9, 71.2, 77.3, 125.3, 125.3, 125.7,
127.2, 128.0, 128.1, 128.4, 142.6, 146.6, 148.0 ppm. IR (film): ν = 126.0, 126.1, 126.2, 126.2, 126.6, 127.6, 127.8, 128.0, 128.1, 128.2,
˜
3428, 3263, 1449 cm–1. MS (ESI): m/z = 209, 167. HRMS (ESI):
calcd. for C24H25NO + H 344.2014; found 344.2083.
132.5, 133.2, 140.4, 147.0, 148.3 ppm. IR (KBr): ν = 3432, 1449,
˜
746 cm–1. MS (EI): m/z = 375, 210, 182, 105. HRMS (EI): calcd.
for C28H25N [M – H2O] 375.1987; found 375.1984.
[(2S,5S)-5-(4-Methoxyphenyl)-1-methylpyrrolidin-2-yl]diphenyl-
methanol (6a): Yield: 0.552 g (49%). [α]2D0 = +1 (c = 1.0, CHCl3).
[(2S,5R)-1-Methyl-5-(naphthalen-2-yl)pyrrolidin-2-yl]diphenyl-
1H NMR (250 MHz, CDCl3): δ = 1.59 (s, 3 H, N-CH3), 1.64–1.89 methanol (8b): Yield: 0.377 g (32%). [α]2D0 = +110 (c = 1.0, CHCl3).
(m, 2 H, CH2), 2.11–2.31 (m, 2 H, CH2), 3.76 (m, 3 H, OCH3), 1H NMR (250 MHz, CDCl3): δ = 1.70 (s, 3 H, N-CH3), 1.77–1.91
4.19–4.28 (m, 2 H, 2 CH), 6.85 (d, J = 8.5 Hz, 2 H, Ar), 7.05–7.15
(m, 4 H, Ar), 7.19–7.30 (m, 4 H, Ar), 7.60 (d, J = 8.5 Hz, 2 H,
(m, 2 H, CH2), 1.97–2.06 (m, 2 H, CH2), 3.73 (dd, J = 9.5, 6.0 Hz,
1 H, CH), 3.96 (dd, J = 9.3, 4.5 Hz, 1 H, CH), 5.06 (br. s, 1 H,
Ar), 7.68 (d, J = 8.5 Hz, 2 H, Ar) ppm. 13C NMR (62.5 MHz, OH), 7.09–7.19 (m, 2 H, Ar), 7.25–7.34 (m, 4 H, Ar), 7.41–7.52
CDCl3): δ = 29.0, 31.4, 38.3, 55.1, 70.3, 70.4, 77.2, 113.6, 125.1,
125.2, 126.1, 126.1, 127.9, 128.0, 128.9, 134.5, 147.0, 148.9, Ar), 7.79–7.85 (m, 3 H, Ar) ppm. 13C NMR (62.5 MHz, CDCl3):
158.4 ppm. IR (film): ν = 3352, 1511, 1246 cm–1. MS (EI): m/z =
δ = 28.3, 34.4, 41.0, 72.5, 73.5, 77.8, 124.8, 125.3, 125.4, 125.6,
355, 276, 190, 105, 77. HRMS (EI): calcd. for C25H25NO [M – 126.0, 126.0, 126.2, 126.2, 127.6, 127.6, 128.0, 128.1, 128.4, 133.0,
H2O] 355.1936; found 355.1919.
133.3, 140.0, 146.7, 148.0 ppm. IR (KBr): ν = 3424, 1449, 708 cm–1.
(m, 3 H, Ar), 7.60 (d, J = 8.5 Hz, 2 H, Ar), 7.69–7.73 (m, 3 H,
˜
˜
3700
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3696–3703

Chiral Triphenylprolinol Ligands for Asymmetric Arylation of Aldehydes
MS (EI): m/z = 375, 296, 210. HRMS (EI): calcd. for C28H25N
[M – H2O] 375.1987; found 375.1945.
arylmethanols, as well as recovery of the chiral amino alcohol in
good yields (Ͼ90%). Enantiomeric ratios were measured by HPLC.
[(2S,5S)-1-Methyl-5-phenylpyrrolidin-2-yl]di(o-tolyl)methanol (9a):
Yield: 0.200 g (18%). [α]2D0 = +154 (c = 1.5, CHCl3). 1H NMR
Phenyl(p-tolyl)methanol (10a and 10j): Yield: 10a, 0.059 g (98%);
10j, 0.054 g (90%). H NMR (250 MHz, CDCl3): δ = 2.27 (br. s, 1
1
(250 MHz, CDCl3): δ = 1.50 (s, 3 H, N-CH3), 1.63–1.70 (m, 1 H), H, OH), 2.31 (s, 3 H, CH3), 5.77 (s, 1 H, CH), 7.12 (d, J = 8.0 Hz,
2.02–2.29 (m, 8 H), 2.30–2.46 (m, 1 H), 4.22–4.32 (m, 2 H, 2 CH),
2 H, Ar), 7.22–7.37 (m, 7 H, Ar) ppm. 13C NMR (62.5 MHz,
6.88 (d, J = 7.0 Hz, 1 H, Ar), 6.93–7.28 (m, 10 H, Ar), 7.50–7.69 CDCl3): δ = 21.1, 76.0, 126.4, 126.5, 127.4, 128.4, 129.1, 137.2,
(m, 2 H, Ar) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 21.7, 22.7, 140.9, 143.9 ppm. HPLC (Chiralcel OD-H; hexane/iPrOH, 90:10;
29.9, 32.4, 38.4, 70.2, 71.1, 77.2, 123.8, 124.9, 126.72, 126.76,
126.82, 127.7, 128.3, 128.3, 129.0, 132.2, 132.5, 136.0, 138.5, 142.0,
0.5 mLmin–1): tR = 16.5 (S), 18.2 (R) min.
Phenyl(o-tolyl)methanol (10b): Yield: 0.055 g (91 %). 1H NMR
(250 MHz, CDCl3): δ = 2.17 (br. s, 1 H, OH), 2.42 (s, 3 H, CH3),
6.00 (s, 1 H, CH), 7.11–7.38 (m, 8 H, Ar), 7.51 (d, J = 7.0 Hz, 1
H, Ar) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 19.4, 73.4, 126.1,
126.2, 127.1, 127.5, 127.6, 128.5, 130.5, 135.3, 141.4, 142.8 ppm.
143.2, 143.7 ppm. IR (film): ν = 3399, 1454, 739 cm–1. MS (EI):
˜
m/z = 353, 195, 160. HRMS (EI): calcd. for C26H27N [M – H2O]
353.2144; found 353.2112.
[(2S,5R)-1-Methyl-5-phenylpyrrolidin-2-yl]di(o-tolyl)methanol (9b):
Yield: 0.245 g (22%). [α]2D0 = +87 (c = 1.0, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 1.42 (s, 3 H, N-CH3), 1.55–1.73 (m, 1 H),
1.90–2.02 (m, 1 H), 2.03–2.26 (m, 8 H), 3.47 (dd, J = 11.5, 5.5 Hz,
1 H, CH), 3.81 (dd, J = 8.8, 3.8 Hz, 1 H, CH), 4.45 (br. s, 1 H,
OH), 6.86 (d, J = 7.0 Hz, 1 H, Ar), 6.95–7.30 (m, 11 H, Ar), 7.32–
7.42 (m, 1 H, Ar) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 21.5,
22.8, 29.6, 35.8, 41.3, 73.5, 73.5, 77.2, 123.8, 125.2, 126.6, 126.8,
126.8, 127.0, 127.2, 128.5, 128.5, 129.1, 132.0, 132.6, 135.4, 139.0,
HPLC (Chiralcel OD-H; hexane/iPrOH, 98:02; 0.5 mLmin–1): tR
28.3 (R), 30.9 (S) min.
=
(4-Chlorophenyl)(phenyl)methanol (10c): Yield: 0.062 g (94%). 1H
NMR (250 MHz, CDCl3): δ = 2.51 (br. s, 1 H, OH), 5.74 (s, 1 H,
CH), 7.22–7.33 (m, 9 H, Ar) ppm. 13C NMR (62.5 MHz, CDCl3):
δ = 75.5, 126.5, 127.7, 127.8, 128.5, 128.6, 133.2, 142.1, 143.3 ppm.
HPLC (Chiralpak AD-H; hexane/iPrOH, 90:10; 1.0 mLmin–1): tR
= 8.3 (R), 9.0 (S) min.
(2-Chlorophenyl)(phenyl)methanol (10d): Yield: 0.061 g (93%). 1H
NMR (500 MHz, CDCl3): δ = 2.35 (d, J = 3.5 Hz, 1 H, OH), 6.23
(d, J = 3.5 Hz, 1 H, CH), 7.22 (dt, J = 7.5, 1.5 Hz, 1 H, Ar), 7.25–
7.32 (m, 3 H, Ar), 7.34 (d, J = 7.5 Hz, 2 H, Ar), 7.39 (d, J = 7.5 Hz,
2 H, Ar), 7.60 (dd, J = 8.0, 1.5 Hz, 1 H, Ar) ppm. 13C NMR
(125 MHz, CDCl3): δ = 72.7, 126.9, 127.1, 127.8, 128.0, 128.5,
128.8, 129.5, 132.5, 141.0, 142.2 ppm. HPLC (Chiralcel OD-H;
hexane/iPrOH, 95:05; 1.0 mLmin–1): tR = 10.2 (R), 11.6 (S) min.
142.7, 143.5 ppm. IR (film): ν = 3422, 1490, 1455 cm–1. MS (EI):
˜
m/z = 353, 195, 160. HRMS (EI): calcd. for C26H27N [M – H2O]
353.2144; found 353.2118.
(2S,5S)-tert-Butyl 2-(Hydroxydiphenylmethyl)-5-phenylpyrrolidine-
1-carboxylate (4a): [α]2D0 = –135 (c = 0.68, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 0.74–0.97 (m, 1 H), 1.10 (s, 9 H, 3 CH3),
1.14–1.41 (m, 1 H), 1.87–1.95 (m, 1 H), 2.28–2.46 (m, 1 H), 4.50
(d, J = 8.3 Hz, 1 H, CH), 5.33 (dd, J = 7.8, 1.5 Hz, 1 H, CH), 6.33
(br. s, 1 H, OH), 7.04 (dd, J = 6.8, 1.5 Hz, 2 H, Ar), 7.17–7.42 (m,
11 H, Ar), 7.48 (dd, J = 8.1, 1.5 Hz, 2 H, Ar) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 27.2, 27.8, 32.2, 63.8, 65.9, 80.7, 82.1,
124.8, 124.8, 126.4, 127.1, 127.3, 127.7, 127.8, 128.3, 128.5, 143.8,
(4-Bromophenyl)(phenyl)methanol (10e and 10m): Yield: 10e, 0.074 g
(94%); 10m, 0.076 g (96%). 1H NMR (250 MHz, CDCl3): δ = 2.41
(br. s, 1 H, OH), 5.65 (s, 1 H, CH), 7.13 (d, J = 8.5 Hz, 2 H, Ar),
7.16–7.26 (m, 5 H, Ar), 7.35 (d, J = 8.5 Hz, 2 H, Ar) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = 75.6, 121.3, 126.5, 127.8, 128.2,
128.6, 131.5, 142.6, 143.3 ppm. HPLC (Chiralcel OB; hexane/
iPrOH, 90:10; 0.5 mLmin–1): tR = 23.4 (R), 33.1 (S) min.
146.1, 147.0, 158.4 ppm. IR (film): ν = 3503, 1677, 1372, 1346,
˜
1165 cm–1. MS (EI): m/z = 452 [M + Na], 396, 378, 352, 334.
HRMS: calcd. for C28H31NO3 + Na 452.2201; found 452.2189.
(2S,5R)-tert-Butyl 2-(Hydroxydiphenylmethyl)-5-phenylpyrrolidine-
1-carboxylate (4b): [α]2D0 = –113 (c = 1.0, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 1.14 (s, 9 H, 3ϫCH3), 1.19–1.39 (m, 2 H,
CH2), 1.96 (dtd, J = 12.6, 7.1, 1.8 Hz, 1 H), 2.12–2.37 (m, 1 H),
4.64 (dd, J = 10.3, 7.0 Hz, 1 H, CH), 5.09 (dd, J = 9.3, 2.5 Hz, 1
H, CH), 6.44 (br. s, 1 H, OH), 6.85–6.89 (m, 2 H, Ar), 7.14–7.35
(m, 9 H, Ar), 7.44–7.48 (m, 2 H, Ar), 7.53–7.57 (m, 2 H, Ar) ppm.
13C NMR (62.5 MHz, CDCl3): δ = 27.8, 29.0, 34.1, 64.8, 67.9, 81.2,
81.3, 125.8, 126.3, 126.9, 127.0, 127.5, 127.5, 127.7, 127.8, 128.5,
1
(2-Bromophenyl)(phenyl)methanol (10f): Yield: 0.072 g (92%). H
NMR (500 MHz, CDCl3): δ = 2.38 (d, J = 4.0 Hz, 1 H, OH), 6.19
(d, J = 4.0 Hz, 1 H, CH), 7.14 (dt, J = 7.5, 1.5 Hz, 1 H, Ar), 7.27
(tt, J = 7.5, 1.5 Hz, 1 H, Ar), 7.30–7.36 (m, 3 H, Ar), 7.40 (d, J =
7.5 Hz, 2 H, Ar), 7.53 (dd, J = 8.0, 1.5 Hz, 1 H, Ar), 7.58 (dd, J =
8.0, 2.0 Hz, 1 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = 74.8,
122.8, 127.0, 127.7, 127.8, 128.4, 128.5, 129.1, 132.8, 142.1,
142.5 ppm. HPLC (Chiralcel OD-H; hexane/iPrOH, 90:10;
1.0 mLmin–1): tR = 9.3 (R), 10.8 (S) min.
143.4, 143.7, 147.2, 159.2 ppm. IR (film): ν = 3370, 1655,
˜
1350 cm–1. MS (EI): m/z = 357, 356, 313, 312, 216. HRMS: calcd. (3-Fluorophenyl)(phenyl)methanol (10g): Yield: 0.046 g (75%). 1H
for C28H31NO3 + H 430.2382; found 430.2340.
NMR (250 MHz, CDCl3): δ = 2.30 (s, 1 H, OH), 5.82 (s, 1 H, CH),
6.94 (tdd, J = 8.3, 2.5, 0.8 Hz, 1 H, Ar), 7.08–7.17 (m, 2 H, Ar),
7.24–7.37 (m, 6 H, Ar) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
75.6 (d, J = 1.9 Hz), 113.4 (d, J = 21.9 Hz), 114.4 (d, J = 21.3 Hz),
122.0 (d, J = 2.5 Hz), 126.5, 127.9, 128.6, 129.9 (d, J = 8.1 Hz),
143.3, 146.2, 163.0 (d, J = 243.7 Hz) ppm. HPLC (Chiralcel OB;
hexane/iPrOH, 95:05; 0.5 mLmin–1): tR = 23.1 (R), 24.6 (S) min.
General Procedure for the Asymmetric Arylation of Aldehydes: In
a round-bottomed flask, under an argon atmosphere, diethylzinc
(2.1 mmol, toluene solution) was added dropwise to a solution of
boronic acid (0.72 mmol) in toluene (1.5 mL) under an argon atmo-
sphere. After stirring for 12 h at 60 °C, the mixture was cooled to
room temperature and a toluene solution of chiral amino alcohol
(10 mol-%) was introduced. The reaction was stirred for an ad-
ditional 15 min, cooled to 0 °C, and the aldehyde (0.3 mmol) was
subsequently added. After stirring for 6 h at 0 °C, the reaction was
quenched with water and saturated NH4Cl. The aqueous layer was
extracted with dichloromethane, and the combined organic layer
was dried with MgSO4, filtered, and concentrated. Purification by
flash chromatography (hexanes/ethyl acetate) afforded the pure di-
(4-Methoxyphenyl)(phenyl)methanol (10h and 10l): Yield: 10h,
1
0.058 g (91%); 10l, 0.053 g (83%). H NMR (250 MHz, CDCl3): δ
= 2.22 (br. s, 1 H, OH), 3.78 (s, 3 H, OCH3), 5.80 (s, 1 H, CH),
6.86 (d, J = 8.5 Hz, 2 H, Ar), 7.24–7.39 (m, 7 H, Ar) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = 55.2, 75.8, 113.8, 126.4, 127.4,
127.9, 128.4, 136.1, 144.0, 159.0 ppm. HPLC (Chiralpak AD-H;
hexane/iPrOH, 90:10; 1.0 mLmin–1): tR = 11.9 (R), 12.8 (S) min.
Eur. J. Org. Chem. 2010, 3696–3703
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3701

D. S. Lüdtke, C. R. D. Correia et al.
FULL PAPER
Furan-2-yl(phenyl)methanol (10i): Yield: 0.047 g (89%). 1H NMR
(250 MHz, CDCl3): δ = 2.46 (br. s, 1 H, OH), 5.82 (s, 1 H, CH),
6.11 (dt, J = 3.3, 0.8 Hz, 1 H, CHfuryl), 6.31 (dd, J = 3.3, 1.8 Hz,
1 H, CHfuryl), 7.26–7.46 (m, 6 H, Ar and CHfuryl) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 70.1, 107.4, 110.2, 126.6, 128.1, 128.5,
140.7, 142.5, 155.9 ppm. HPLC (Chiralcel OD-H; hexane/iPrOH,
97:03; 1.0 mLmin–1): tR = 21.1 (S), 24.8 (R) min.
trowski, S. J. Currier, E. J. Pack, L. Hammer, T. Roaslvig, J. A.
Honeyman, D. R. Tortolani, P. R. Reczek, M. M. Mansuri,
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olz, A. Mitschler, D. Moras, J. Mol. Biol. 2000, 302, 155–170.
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Mathre, P. D. O’Shea, A. Roy, R. D. Tillyer, Org. Lett. 2004, 6,
111–114; b) P. D. O’Shea, C.-Y. Chen, W. R. Chen, P. Dagneou,
L. F. Frey, E. J. J. Grabowski, K. M. Marcantonio, R. A.
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L. Nilvebrandt, K.-E. Andersson, P.-G. Gillberg, M. Stahl, B.
Sparf, Eur. J. Pharmacol. 1997, 327, 195–207.
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P. C. Astles, T. J. Brown, F. Halley, C. M. Handscombe, N. V.
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C. Bolm, J. Rudolph, J. Am. Chem. Soc. 2002, 124, 14850–
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For a review on B–Zn exchange and its application in asym-
metric arylations, see: M. W. Paixão, A. L. Braga, D. S. Lüdtke,
J. Braz. Chem. Soc. 2008, 19, 813–830.
a) M. Srebnik, Tetrahedron Lett. 1991,22, 2449–2452; b) W.
Oppolzer, R. N. Radinov, Helv. Chim. Acta 1992, 75, 170–173;
c) W. Oppolzer, R. N. Radinov, J. Am. Chem. Soc. 1993, 115,
1593–1594; d) F. Langer, L. Schwink, A. Devasagayaraj, P.
Chavant, P. Knochel, J. Org. Chem. 1996, 61, 8229–8243; e) A.
Boudier, L. O. Bromm, M. Lotz, P. Knochel, Angew. Chem.
Int. Ed. 2000, 39, 4414–4435; f) O. Prieto, D. J. Ramón, M.
Yus, Tetrahedron: Asymmetry 2003, 14, 1955–1957; g) V. J. For-
rat, D. J. Ramón, M. Yus, Tetrahedron: Asymmetry 2005, 16,
3341–3344; h) V. J. Forrat, D. J. Ramón, M. Yus, Tetrahedron:
Asymmetry 2006, 17, 2054–2058; i) V. J. Forrat, O. Prieto, D. J.
Ramón, M. Yus, Chem. Eur. J. 2006, 12, 4431–4445; j) R. Mart-
inez, L. Zoli, P. G. Cozzi, D. J. Ramón, M. Yus, Tetrahedron:
Asymmetry 2008, 19, 2600–2607; k) V. J. Forrat, D. J. Ramón,
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Yus, Tetrahedron: Asymmetry 2009, 20, 65–67.
[4]
Biphenyl-4-yl(phenyl)methanol (10k): Yield: 0.077 g (98 %). 1H
NMR (250 MHz, CDCl3): δ = 2.41 (br. s, 1 H, OH), 5.74 (s, 1 H,
CH), 7.11–7.34 (m, 10 H, Ar), 7.42–7.48 (m, 4 H, Ar) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = 76.0, 126.5, 126.9, 127.0, 127.2,
127.3, 127.6, 128.5, 128.7, 140.4, 140.7, 142.8, 143.7 ppm. HPLC
(Chiralcel OB; hexane/iPrOH, 95:05; 1.0 mLmin–1): tR = 36.3 (R),
61.4 (S) min.
[5]
[6]
[7]
(4-Chlorophenyl)(4-methoxyphenyl)methanol (10n): Yield: 0.053 g
(71%). 1H NMR (250 MHz, CDCl3): δ = 2.40 (br. s, 1 H, OH),
3.77 (s, 3 H, OCH3), 5.73 (s, 1 H, CH), 6.85 (d, J = 8.8 Hz, 2 H,
ArOMe), 7.22 (d, J = 8.8 Hz, 2 H, ArOMe), 7.28 (s, 4 H, ArCl) ppm.
13C NMR (62.5 MHz, CDCl3): δ = 55.2, 75.1, 113.9, 127.7, 127.9,
128.5, 133.0, 135.7, 142.4, 159.1 ppm. HPLC (Chiralcel OD-H; λ
= 216 nm; hexane/iPrOH, 98:02; 0.5 mLmin–1): tR = 88.3 (S), 95.5
(R) min.
[8]
[9]
[10]
(4-Chlorophenyl)(p-tolyl)methanol (10o): Yield: 0.068 g (98%). 1H
NMR (250 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3), 5.70 (s, 1 H,
CH), 7.11 (d, J = 8.0 Hz, 2 H, ArMe), 7.18 (d, J = 8.0 Hz, 2 H,
ArMe), 7.26 (s, 4 H, ArCl) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
21.1, 75.3, 126.4, 127.7, 128.5, 129.2, 133.0, 137.5, 140.5,
142.3 ppm. HPLC (Chiralcel OD-H; hexane/iPrOH, 98:02;
0.5 mLmin–1): tR = 49.9 (R), 52.6 (S) min.
Biphenyl-4-yl(furan-2-yl)methanol (10p): Yield: 0.074 g (98%). 1H
NMR (250 MHz, CDCl3): δ = 2.58 (br. s, 1 H, OH), 5.85 (s, 1 H,
CH), 6.16 (d, J = 3.3 Hz, 1 H, CHfuryl), 6.32 (dd, J = 3.3, 2.0 Hz,
1 H, CHfuryl), 7.30–7.51 (m, 6 H, Ar), 7.55–7.62 (m, 4 H, Ar) ppm.
13C NMR (62.5 MHz, CDCl3): δ = 70.0, 107.5, 110.2, 127.0, 127.1,
127.2, 127.3, 128.7, 139.8, 140.7, 140.9, 142.6, 155.8 ppm. HPLC
(Chiralcel OB; hexane/iPrOH, 95:05; 1.0 mLmin–1): tR = 37.3 (S),
49.9 (R) min.
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Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR spectra of compounds 5–9; data of X-ray
diffraction analysis of N-Boc amino alcohol 4b.
Acknowledgments
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq) and Fundação de Amparo à Pes-
quisa do Estado de São Paulo (FAPESP) for financial support of
this work. FAPESP and CNPq are also acknowledged for a PhD
fellowship to A.V.M. and for research fellowships to D.S.L. and
C.R.D.C. We also thank Prof. Leandro H. Andrade (Chemistry In-
stitute, University of São Paulo) for assistance with the HPLC
analyses.
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Received: March 10, 2010
Published Online: May 19, 2010
Eur. J. Org. Chem. 2010, 3696–3703
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3703