A chiral Rh-phosphite complex displaying high activity in the enantioselective Rh-catalyzed addition of arylboronic acids to carbonyl compounds: When and why atropos is better than tropos

Article abstract of DOI:10.1016/j.tetasy.2010.11.009

The use of deoxycholic acid derived tropos and atropoisomeric phosphites as chiral ligands in the Rh-catalyzed enantioselective addition of arylboronic acids to arylaldehydes and 2,2,2-trifluoroacetophenone is presented. Screening of these phosphites showed the high activity of the Rh-complex obtained starting from one of the two atropoisomeric ligands, which afforded complete conversion of the carbonyl compounds in short reaction times under mild reaction conditions and with ee's of up to 84%. A study aimed at getting information about the different behavior of tropos and atropoisomeric ligands is also reported.

Full text of DOI:10.1016/j.tetasy.2010.11.009

Tetrahedron: Asymmetry 21 (2010) 2775–2781
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A chiral Rh–phosphite complex displaying high activity in the
enantioselective Rh-catalyzed addition of arylboronic acids to carbonyl
compounds: when and why atropos is better than tropos
⇑
Varsha R. Jumde, Sarah Facchetti, Anna Iuliano
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of deoxycholic acid derived tropos and atropoisomeric phosphites as chiral ligands in the Rh-
catalyzed enantioselective addition of arylboronic acids to arylaldehydes and 2,2,2-trifluoroacetophenone
is presented. Screening of these phosphites showed the high activity of the Rh-complex obtained starting
from one of the two atropoisomeric ligands, which afforded complete conversion of the carbonyl
compounds in short reaction times under mild reaction conditions and with ee’s of up to 84%. A study aimed
at getting information about the different behavior of tropos and atropoisomeric ligands is also reported.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 13 September 2010
Accepted 10 November 2010
Available online 6 December 2010
1. Introduction
rhodium catalyzed asymmetric addition of arylboronic acids to
arylaldehydes, such as phosphites,8 mono and bis phosphorami-
The asymmetric rhodium catalyzed addition of aryl boronic acids
to electrophilic acceptors represents a useful and practical method
to promote the carbon–carbon bond formation in an enantioselec-
tive way.1 The increasing interest in this approach is mainly due to
robustness, stability, ready availability, and compatibility with a
great variety of functional groups of these organometallic reagents,
which permit us to obtain a great variety of products, under unde-
manding reaction conditions. In this context, the rhodium catalyzed
asymmetric addition of arylboronic acids to arylaldehydes, first
introduced by Miyaura,2 represents an extremely attractive topic,
because the diarylmethanol products are intermediates in the syn-
thesis of bioactive compounds, such as (R)-orphenadrine and (R)-
neobenodine, which display antihistaminic activity;3 in addition,
chiral diarylmethanols can be used as precursors of compounds
possessing the chiral diarylmethane nucleus, which behave as
antimuscarinics,4 antidepressants,5 and endothelin antagonists.6
However, despite the noticeable usefulness of the method, the
progress of the enantioselective addition of arylboronic acids to
arylaldehydes has been slow, especially if compared to the devel-
opment of the analogous conjugate addition to electron-poor
alkenes,7 because of the lack of suitable catalytic systems. As a
matter of fact, arylaldehydes are more demanding substrates with
respect to enones and, hence, a chiral rhodium catalyst can be less
active or less enantioselective than in the conjugate addition. Nev-
ertheless, some efficient chiral ligands have been developed for the
dites9, and dienes,10 affording high yields and good ee’s of diaryl-
methanols. Arylketones are even more demanding substrates for
this reaction: indeed, only very few examples of the Rh-catalyzed
asymmetric addition of arylboronic acids to highly electrophilic
ketones, such as aryl-trifluoromethyl ketones11 or isatin,12 have
been reported.
Recently, using monodentate deoxycholic acid derived tropos
biphenylphosphites as chiral ligands in the rhodium catalyzed
asymmetric conjugate addition of arylboronic acids to cyclic enon-
es, we found that two different coordination modes are possible
leading to mono or disubstituted rhodium complexes, which act
as catalysts in different reactions.13 In fact, both complexes are able
to promote the conjugate addition but, in addition, the disubsti-
tuted ones are able to afford a double (1,2 plus 1,4) addition to
cyclohexenone leading to diastereomerically pure 1,4-diarylcy-
clohexanols with good ee’s.14 Since these catalytic precursors
succeeded in promoting the addition to a carbonyl group, we
considered it highly probable that the same disubstituted com-
plexes could be also effective in the rhodium catalyzed addition
of arylboronic acids to arylaldehydes and highly electrophilic
ketones and, hence, became interested in checking their activity
and enantioselectivity in this reaction.
Herein, we report the results obtained using the disubstituted
complexes of tropos and atropoisomeric ligands 1–7, derived from
deoxycholic acid (Fig. 1), in the rhodium catalyzed conjugate addi-
tion of arylboronic acids to arylaldehydes and 2,2,2-trifluoacetoph-
enone; the different behavior of the tropos ligands with respect to
the atropoisomeric ones is also discussed.
⇑
Corresponding author. Tel.: +39 050 2219231; fax: +39 050 2219260.
E-mail address: iuliano@dcci.unipi.it (A. Iuliano).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.009

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V. R. Jumde et al. / Tetrahedron: Asymmetry 21 (2010) 2775–2781
R
R'
O
O
P
R
O
O
P
O
O
O
O
R'
OCH3
1: R = R' = H
OCH3
2: R = Ph, R' = H
3: R = COPh, R' = H
4: R = H, R' = Ph
5: R = R' = t-Bu
H3COCO
6a: (R)-Binaphthyl
6b: (S)-Binaphthyl
H3COCO
OCH3
O
O
Ph
O
O
P
O
7
O
Figure 1. Deoxycholic acid derived tropos and atropoisomeric ligands.
of the binaphthylphosphite unit on the cholestanic backbone
(entries 12 and 13), as already observed in other reactions.15 The
high activity exhibited by the catalytic species derived from 6b
that allows the product to be obtained in only 1 h at 0 °C using a
very low amount of rhodium could suggest the formation, during
the catalytic cycle, of a co-ordinatively unsaturated species bearing
only one phosphite ligand on the rhodium, which must be highly
reactive.16 To shed light on this point, the monosubstituted
Rh-complex of 6b was prepared ‘in situ’ as previously described,13
and used as a catalytic precursor for the reaction (entry 14). How-
ever, under these reaction conditions, only traces of the racemic
product were obtained after 7 h, suggesting that a monosubsti-
tuted complex cannot be involved in the addition reaction.
Phosphites 2–4, possessing a tropos substituted biphenyl moiety
werelessactiveandenantioselectivethan6b(entries15–19):longer
reaction times were required for obtaining complete conversion of
8a, especially in toluene, and the highest ee of 10aa was a modest
17% reached by using 2 in toluene, as the reaction solvent (entry
17). All of the tropos phosphites gave an (S)-configured addition
product, as the mismatched atropoisomeric ligand 6a. The low ee’s
obtained using tropos ligands cannot be explained simply taking into
account the non-selective complexation of these phosphites to
[Rh(C2H4)2Cl]2 giving rise to a couple of diastereomeric complexes
in a 1:1 ratio,14 which are both active in the addition of phenylbo-
ronic acid to 1-naphthaldehyde and produce opposite enantiomers
of the product, as suggested by the results obtained using the
atropoisomeric ligands 6a and 6b (entries 2 and 3). In fact, as shown
inFigure2, wherethekineticprofile ofthereactionspromotedbythe
diastereomeric ligands 6a and 6b is reported, the reaction rates are
different and the fastest reaction, promoted by 6b, is also the most
enantioselective (entry 3).
2. Results and discussion
Both tropos and atropoisomeric phosphites were assayed in the
rhodium catalyzed addition of phenylboronic acid, 9a, to 1-naph-
thaldehyde, 8a, as a test reaction, in order to evaluate the activity
and the enantioselectivity of their complexes and the results are
reported in Table 1. At first, the optimized reaction conditions for
the double addition reaction to cyclohexenone were used:14 thus,
in a typical procedure the disubstituted complex was prepared
by stirring in dioxane [Rh(C2H4)2Cl]2 and the ligand in 1:2 Rh:P
ratio at room temperature for 30 min (catalyst loading: 3 mol %),
then water (solvent/H2O 10:1), base (1 equiv), phenylboronic acid
(2 equiv), and 1-naphthaldehyde were added: all of the reactions
were stopped at complete substrate conversion or when it did
not proceed any further. By using the tropos phosphite 1 as a chiral
ligand, complete conversion of the substrate was observed in 4 h at
room temperature, but disappointingly the addition product was
obtained in only 5% ee (entry 1). The use of the two diastereomeric
phosphites 6a and 6b, which can be considered as the atropoiso-
meric analogs of 1, showed the existence of a matched–mis-
matched effect on the outcome of the reaction. As a matter of
fact, even if both the ligands afforded complete conversion of the
aldehyde, by using 6a a (S)-configured addition product having
only 10% ee was obtained (entry 2), whereas 6b afforded
(R)-10aa in 66% ee in a shorter reaction time (entry 3). The high
activity displayed by the complex obtained from 6b, which gave
complete conversion in 1.5 h is noteworthy. Lowering of the
reaction temperature to 0 °C, in the presence of THF as solvent
(entry 4), only had the effect of slightly slowing down the reaction
without the improvement of the enantioselectivity. The decrease of
the catalyst loading (entry 5) neither slowed the reaction to a great
extent nor altered the asymmetric induction capability, so con-
firming the high activity of the catalytic species derived from 6b.
Variation of the organic solvent showed that both in t-butanol at
rt (entry 8) and in toluene at 0 °C (entry 10) the addition is faster
and more enantioselective than in other solvents, whereas using
KF instead of KOH as a base did not affect the outcome of the reac-
tion (entry 11). The use of 7 showed that activity and enantioselec-
tivity of these ligands depend not only on the absolute
configuration of the binaphthyl moiety but also on the position
On the basis of these results one should expect that tropos
ligands afford higher ee’s even in the presence of a non-selective
complexation. However it must be considered that the reactions
promoted by tropos ligands 1–4 were slower and (S)-10aa is
obtained in prevalence, whereas (R)-10aa is obtained using the
matched atropoisomeric ligand 6b. A slower addition means that
both the reaction rates for the additions promoted by the two dia-
stereomeric forms of the tropos complexes are slower and likely
closer to each other, giving rise to an addition product having a

V. R. Jumde et al. / Tetrahedron: Asymmetry 21 (2010) 2775–2781
2777
Table 1
Rh-catalyzed asymmetric addition of phenylboronic acid to 1-naphthaldehyde in the presence of ligands 1–7a
O
H
OH
B(OH)2
*
[Rh(C2H4)2Cl]2
KOH (1 equiv),
L* (L*
solvent:H2O 10:1
+ 2
:Rh 2:1)
10aa
9a
8a
*
Entry
L
Solvent
T (°C)
Rh (mol %)
Time (h)
%eeb (absolute configuration)c
1
2
3
4
5
6
7
8
9
10
11d
12
13
14
15
16
17
18
19
20
1
Dioxane
Dioxane
Dioxane
THF
25
25
25
0
0
25
0
25
25
0
0
0
25
0
25
25
0
0
25
0
3
3
3
3
4
2
1.5
2
3
2
6
1
0.75
1
5 (S)
6a
6b
6b
6b
6b
6b
6b
6b
6b
6b
7
7
6b
2
3
2
10 (S)
66 (R)
65 (R)
63 (R)
47 (R)
54 (R)
69 (R)
68 (R)
72 (R)
71 (R)
15 (R)
23 (R)
Racemic
Racemic
Racemic
17 (S)
6 (S)
THF
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5f
1.5
1.5
1.5
1.5
1.5
1.5
2-Propanol
2-Propanol
t-Butanol
Toluene
Toluene
Toluene
Toluene
t-Butanol
Toluene
t-Butanol
t-Butanol
Toluene
Toluene
t-Butanol
Toluene
1
6e
7
7g
3
1
6
3
2
3
4
5
6 (S)
22 (S)
7
a
Pre-catalyst was formed by stirring the solvent mixture of [Rh(C2H4)2Cl]2 and ligand for 30 min, then the other reactives were added and the reactions were continued
until TLC analysis showed complete substrate conversion; under these conditions the isolated yield of the product was always around 90%.
b
Determined by HPLC analysis on Chiralcel OD-H.8
Assigned on the basis of the elution order of the enantiomers by comparison with literature data.8
c
d
KF was used as base.
e
Conversion was 56%, determined by 1H NMR.
f
L*:Rh ratio was 1:1 and pre-catalyst was prepared as described previously.13
g
Product was obtained in trace amounts.
100
90
80
consequence, at 0 °C, the temperature of the reaction. In fact, the
%10aa
31P NMR spectrum of 5, recorded at rt, shows the presence of
two signals at 155.7 and 149.8 ppm that broaden and coalesce at
50 °C (Fig. 3), attributable to the two M–P diastereomeric forms,
slowly equilibrating at rt. The integrated areas of the NMR peaks
give an 85:15 ratio between the two diastereoisomers.
6b
6a
70
60
50
40
30
20
10
0
The sense of twist of the biphenyl group of the prevailing
diastereoisomer was determined by CD spectroscopy. The CD
spectrum (Fig. 4) shows, in the absorbing region of the biphenylph-
osphite chromophore two negative Cotton effects at 285 nm (De
ꢀ1.8) and at 258 nm (
D
e
ꢀ12.5). This spectrum can be safely com-
0
20
40
60
80
100
120
140
pared to that of 1, whose relationship between the CD spectrum
and sense of twist of the biphenyl moiety is known,17 since the
presence of the t-butyl groups does not alter significantly the
polarization direction of the electronic transitions of the biphenyl-
phosphite chromophore,18 as confirmed also by the high similarity
of the UV spectra of 1 and 5.
Reaction time (min)
Figure 2. Kinetic profiles (experimental curves) for the addition of 9a to 8a
catalyzed by 6a and 6b.
On the basis of this comparison a prevalent P sense of twist of
the biphenylphosphite moiety, corresponding to (S) absolute con-
figuration, can be inferred.
lower ee. Furthermore, the achievement of (S)-10aa instead of its
enantiomer, as expected on the basis of the highest enantioselec-
tivity of the reaction promoted by the most active diastereomeric
complex (entry 3), should suggest a change in the asymmetric
induction mechanism in passing from binaphthyl to biphenyl
derivatives, which can result in a less efficient chirality transfer.
To confirm this point phosphite 5 was used as a ligand in the reac-
tion. This phosphite was chosen because it can be considered
atropoisomeric at room temperature, given that the interconver-
sion barrier between the M and P diastereoisomeric forms is suffi-
ciently high to prevent free rotation at this temperature and, of
The Rh-catalyzed addition of phenylboronic acid to 8a in the
presence of 5 as a ligand was slower than the reaction promoted
by 6 and afforded (S)-10 in 22% ee (entry 20). This result confirms
the hypothesis of a change of the asymmetric induction mecha-
nism in passing from binaphthylphosphite derivatives to biphenyl-
phosphites and suggests that the presence of a biphenyl moiety in
the ligand framework instead of a binaphthyl one makes these
phosphites less enantioselective.

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V. R. Jumde et al. / Tetrahedron: Asymmetry 21 (2010) 2775–2781
b
a
165.0
160.0
155.0
ppm
150.0
145.0
Figure 3. 31P NMR (121 MHz, toluene d8) spectra of 5 at 25 °C (a) and 50 °C (b).
From the screening of ligands, phosphite 6b emerged as the best
one, regarding both activity and enantioselectivity of its Rh-com-
plex in the addition of phenylboronic acid to 1-naphthaldehyde:
under optimized reaction conditions, (S)-10aa was obtained in
nearly quantitative yield and 72% ee at 0 °C, using a very low cat-
alyst loading. Therefore this ligand was used under the best reac-
tion conditions to test the applicability of the reaction to
different aldehydes and different arylboronic acids and the results
are reported in Table 2.
All of the reactions proceeded smoothly, affording complete
conversion of the substrates in 1–3 h with both electron-rich and
electron-poor aldehydes with the sole exception of 2-nitrobenzal-
dehyde, which was not completely converted to the corresponding
alcohol (entry 3). As far as enantioselectivity is concerned ortho-
substituted benzaldehydes were converted into the corresponding
diarylcarbinols with higher ee’s than the para-substituted
60000
25
20
15
10
5
ε
Δε
50000
40000
30000
20000
10000
0
0
-5
-10
-15
220
240
260
280
λ (nm)
300
320
340
Figure 4. UV (solid line) and CD (bold line) spectra of 5 in CH3CN solution.

V. R. Jumde et al. / Tetrahedron: Asymmetry 21 (2010) 2775–2781
2779
Table 2
Rh-catalyzed addition of arylboronic acids to arylaldehydesa
OH
*
[Rh(C2H4)2Cl]2 (0.75 mol%)
O
+ 2 ArIB(OH)2
Ar
ArI
6b (3 mol%), KOH (1 equiv)
toluene-H2O 10:1, 0ºC
Ar
H
9a-g
8a-h
10
Entry
Product
Ar
ArI
Time (h)
%eeb (absolute configuration)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
10aa
10ba
10ca
10da
10ea
10fa
10ga
10ha
10eb
10ec
10ed
10ee
10ef
10eg
1-Naphthyl
4-NO2–Ph
2-NO2–Ph
4-Cl–Ph
2-CH3–Ph
4-OCH3–Ph
2-OCH3–Ph
4-F–Ph
2-CH3–Ph
2-CH3–Ph
2-CH3–Ph
2-CH3–Ph
2-CH3–Ph
2-CH3–Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1
3
6e
2
1
2
2
1
1
1
1
4
3
2
70 (R)
49 (R)d
71 (R)
40 (R)
84 (R)
52 (R)
65 (R)
40 (R)
65 (R)
28 (R)
56 (R)
31 (+)f
60 (+)f
61 (R)
4-CH3–Ph
4-OCH3–Ph
1-Naphthyl
2-Naphthyl
3-OCH3–Ph
4-Cl–Ph
a
The reactions were carried on until complete conversion of the substrate: isolated yields, after column chromatography (SiO2; CH2Cl2 or CH2Cl2/hexane 97:3) were in the
range 85–95%.
b
Determined by enantioselective HPLC: for chromatographic conditions, see Section 4.
c
d
e
f
Absolute configuration was determined on the basis of the elution orders of the enantiomers by comparison with literature data.
Absolute configuration was assigned on the basis of the sign of the specific rotation.19
The reaction was not complete and the product was obtained in 34% yield.
Absolute configuration not determined.
substrates (entries 3,5 and 7), suggesting that steric hindrance near
the carbonyl group is a determining factor for asymmetric induc-
tion, as also observed with other kinds of phosphite ligands.8
ortho-Tolualdehyde was the substrate affording the highest ee (en-
try 5) and, hence, was used for the screening of arylboronic acids.
Changing the structure of the arylboronic acid had a scarce ef-
fect on the activity of the catalytic species obtained from 6b and
ortho-tolualdehyde was completely converted into the different
diarylcarbinols in at the most 4 h. No correlation of the enantiose-
lectivity of the reaction with the structure of the arylboronic acid
could be found: in fact differently hindered arylboronic acids affor-
ded similar ee’s of the products (entries 11, 13 and 14), whereas
arylboronic acids having similar steric hindrance near the reaction
site gave very different ee’s (entries 9 and 10). Anyway, the highest
ee was obtained using phenylboronic acid (entry 5) suggesting that
its structure is the most suitable for reaching high levels of asym-
metric induction.
the Rh-catalyzed addition of arylboronic acids to arylketones, more
challenging substrates than arylaldehydes. The optimized reaction
conditions were used for the addition of different arylboronic acids
to 2,2,2-trifluoroacetophenone and the results are reported in
Table 3.
Although the addition of the arylboronic acids to 11 was slower
than the addition to aldehydes, complete conversion of the sub-
strate was obtained in short reaction times at room temperature.
To the best of our knowledge these are the mildest reaction condi-
tions and the shortest reaction times to perform the addition of
arylboronic acids to ketones: this result confirms the high activity
exhibited by the Rh-complex obtained from 6b. The high activity of
the catalytic species is flanked by only a moderate enantioselectiv-
ity, the highest ee being 54% (entry 5). No dependence of the reac-
tion rate on the structural characteristics of the arylboronic acid
can be found, since the time to obtain complete conversion of
the substrate was very different with arylboronic acids having sim-
ilar steric hindrance (entries 3 and 4). Longer reaction times and a
higher amount of arylboronic acid were required to obtain good
The high activity of 6b-derived catalyst prompted us to check
activity and enantioselectivity of the Rh-complex of 6b toward
Table 3
Rh-catalyzed addition of arylboronic acids to 2,2,2-trifluoroacetophenonea
O
HO
Ar
[Rh(C2H4)2Cl]2 (0.75 mol%)
+ ArB(OH)2
CF3
CF3
6b (3 mol%), KOH (1 equiv)
toluene-H2O 10:1, rt
9b-g
12b-g
11
Entry
Compound
Ar
Time (h)
Yieldb (%)
eec (%)
Specific rotationd
1
2
3
4
5
6
12f
3-OMe–Ph
4-OMe–Ph
4-Cl–Ph
3 h
2 h
7 h
1 h
7 h
7 h
95
93
70
87
90f
90f
11
27
39
27
54
36
(+)
12c
12g
12b
12d
12e
(ꢀ)
(+)
4-Me–Ph
(ꢀ)
(ꢀ)
(ꢀ)
1-Naphthyle
2-Naphthyle
a
b
c
d
e
f
Reactions were carried on until complete conversion of the substrate (TLC).
Isolated yield after chromatographic purification.
Determined by enantioselective HPLC (for chromatographic conditions see Section 4).
Sign of the specific rotation.
Three equivalents of arylboronic acid were used.
Gas chromatographic yield.

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V. R. Jumde et al. / Tetrahedron: Asymmetry 21 (2010) 2775–2781
yields in the case of 9d and 9e (entries 5 and 6), due to competitive
hydrolysis reaction of these arylboronic acids. The high difference
between the reaction rate of 9g and that of 9b (entries 3 and 4)
can be attributed to the different electronic character of chloro
and methyl substituents: as a matter of fact, the addition reaction
did not work using arylboronic acids possessing strong electron
withdrawing substituents. As far as the extent of the asymmetric
induction is concerned, the highest ee value was obtained in the
addition of 1-naphthylboronic acid, suggesting that the steric hin-
drance of the boronic acid plays a major role in determining the
stereochemical outcome of the reaction.
hydroxy-5b-cholan-24-ate22 were prepared according to literature
procedures and matched the reported characteristics.
4.2. Methyl 3a-acetyloxy-12a
-[(3,30,5,50-tetratertbutylbiphenyl-
2,20-diyl)-phosphite]-5b-cholan-24-ate, 5
A solution of dry 3,30,5,50-tetratertbutyl-2,20-dihydroxybiphenyl
(0.35 g, 1.02 mmol) in dry toluene (13 mL) was dropwise added at
0 °C to a solution of PCl3 (0.089 mL, 1.11 mmol), dry pyridine
(0.165 mL, 2.05 mmol) in dry toluene (5 mL) and the mixture
was stirred overnight at room temperature, then filtered under
nitrogen atmosphere. The filtrate was dropwise added to a solution
of DMAP (0.136 g, 1.11 mmol) and Et3N (0.51 mL, 3.6 mmol) in dry
3. Conclusion
toluene (25 mL) at ꢀ60 °C then methyl-3
a-acetyloxy-12a-hydro-
xy-5b-cholan-24-ate (0.45 g, 1.11 mmol) was added; the mixture
was then warmed at 80 °C and stirred for 24 h. After cooling the
mixture to room temperature, the solvent was removed under
reduced pressure and the crude product was purified by flash chro-
matography under nitrogen (SiO2, toluene), giving 110 mg of pure
7 (0.12 mmol, 12%).
Screening of tropos and atropoisomeric phosphites, derived
from deoxycholic acid, as chiral ligands in the Rh-catalyzed asym-
metric addition of arylboronic acids to carbonyl compounds, al-
lowed us to obtain, starting from phosphite 6b, which possesses
an atropoisomeric (S)-binaphthyl moiety, a Rh-complex displaying
a high catalytic activity. As a matter of fact, not only arylaldehydes
were completely converted into the corresponding diarylmetha-
nols in short reaction times (1–4 h) at 0 °C, but also the reaction
of arylboronic acids with the highly demanding substrate 2,2,2-tri-
fluoroacetophenone proceeded smoothly at rt, giving high yields of
the products in at most 7 h. The enantioselectivity of the reaction
depended strongly on the substrate structure and the higher ee’s,
up to 84%, were obtained with aldehydes. Investigation on the dif-
ferent activity and enantioselectivity displayed by tropos ligands
with respect to atropoisomeric ones evidenced a different asym-
metric induction mechanism in passing from binaphthylphosph-
ites to biphenylphosphites, likely responsible for the failure of
the tropos systems in this reaction.
½
a 2D8
ꢂ
¼ þ92:4 (c 0.75, CH2Cl2); 1H NMR (300 MHz, benzene-d6, d):
0.49 (s, 3H), 0.74 (s, 3H), 1.24 (s, 9H), 1.30 (s, 9H), 1.54 (s, 9H), 1.60 (s,
9H), 1.69 (s, 3H), 2.27–0.93 (m, 29H), 3.32 (s, 3H), 4.65 (br, 1H), 4.80
(br, 1H), 7.28 (d, J 2.4 Hz, 1H), 7.33 (d, J 2.4 Hz, 1H), 7.53 (d, J 2.4 Hz,
1H), 7.57 (d, J 2.4 Hz, 1H); 13C NMR (75 MHz, benzene-d6, d): 12.4,
20.9, 23.0, 23.8, 26.4, 27.2, 27.3, 31.2, 31.3, 31.4, 31.5, 31.7, 32.7,
34.3, 34.5, 35.3, 35.5, 35.7, 36.2, 42.0, 46.4, 46.9, 48.3, 50.7, 74.0,
78.2, 124.0, 124.2, 126.9, 127.3, 133.6, 134.0, 140.1, 140.2, 140.3,
146.3, 169.5, 173.5. 31P NMR (121.5 MHz, toluene-d8, d): 155.7,
149.8. Anal. Calcd. for C55H83O7P: C, 74.46; H, 9.43; P, 3.49. Found:
C, 74.29; H, 9.45; P, 3.51.
4.3. General optimized procedure for the asymmetric Rh(I)-
catalyzed addition of arylboronic acids to arylaldeydes and
2,2,2-trifluoroacetophenone
4. Experimental
4.1. General procedures and materials
Under nitrogen atmosphere toluene (1 mL) was added to
[RhCl(C2H4)2]2 (0.75 mol %) and the phosphite (3 mol %). The mix-
ture was stirred for 30 min, then water (0.1 mL), 2 M KOH
(0.25 mL), phenylboronic acid (2 equiv), and the carbonyl com-
pound (0.5 mmol) were added. The mixture was stirred at 0 °C
(aldehydes) or 25 °C (ketone) and the reaction was monitored by
TLC. After complete conversion, the mixture was poured into 1 M
NaHCO3 and extracted three times with diethyl ether. The com-
bined organic layers were washed with brine, dried over anhy-
drous Na2SO4, filtered, and evaporated to yield the crude product.
Chromatography on silica gel (CH2Cl2 for compounds 10, CH2Cl2–
hexane mixtures for compounds 12) gave the pure diarylcarbinol.
The spectroscopic characteristics of the known products were in
agreement with literature data.
The ee was determined by HPLC analyses on chiral stationary
phases. The absolute configuration of the prevailing enantiomer
was assigned on the basis of the chromatographic elution order
or on the basis of the sign of the specific rotations, by comparison
with literature data as specified for each compound. 10aa,8 10ba,22
10ca,8 10da,8 10ea,8 10fa,8 10ga,23 10ha,24 10eb,23 10ec,23 10ed,10
10ee,25 10ef,26 and 10eg.23
1H, 31P and 13C NMR spectra were recorded on a Varian Gemini-
300 300 MHz NMR spectrometer, using TMS as an external stan-
dard. 31P NMR chemical shifts are referred to H3PO4 as an external
standard. The temperature was controlled to 0.1 °C by means of
the Varian unity control.
The following abbreviations are used: s = singlet, d = doublet,
dd = double doublet, t = triplet, m = multiplet, br = broad. HPLC
analyses were performed on a JASCO PU-980 intelligent HPLC
pump equipped with JASCO UV-975 detector. Optical rotations
were measured with a JASCO DIP-360 digital polarimeter. GC anal-
yses were performed on a Perkin–Elmer Autosystem XL chromato-
graph equipped with
a
l
BP-1 dimethyl polysiloxane column
m), using nitrogen as transport gas. Peak
(25 m ꢁ 0.25 mm ꢁ 0.25
identification was performed using independently synthesized
samples.
Circular dichroic (CD) and UV spectra were obtained using a
0.1 cm path length cell and spectropolarimetric grade CH3CN sol-
vent, at 25 °C. Sample concentration for UV and CD analysis was
4 ꢁ 10ꢀ4 M.
TLC analyses were performed on silica gel 60 sheets; flash chro-
matography separations were carried out on adequate size col-
umns using silica gel 60 (230–400 mesh). Toluene was refluxed
over sodium and distilled before the use. Pyridine and triethyl-
amine were refluxed over CaH2 and distilled before use. Unless
otherwise specified, the reagents were used without any purifica-
tion. Phosphites 1–4,17,20 615 and 715 were prepared as previously
described and matched the reported characteristics. 3,30,5,50-Tet-
4.3.1. 2,2,2-Trifluoro-1-(3-methoxyphenyl)-1-phenylethanol 12f
Yield: 95% (colorless oil) after chromatographic purification
(CH2Cl2/hexane 7:3), Rf 0.5. Chiralcel OD-H, 230 nm, 1 mL/min,
n-hexane/2-propanol 99:1, T 25 °C, tmaj = 14.0 min, tmin = 16.9 min.
½
a 3D1
ꢂ
¼ þ0:3 (c 0.99, CHCl3) for a sample having 11% ee. 1H NMR
(300 MHz,CDCl3, d): 3.61 (s, 1H), 3.74 (s, 3H), 6.93 (dt, J1 = 8.4 Hz,
J2 = 1.2 Hz,1H), 7.32 (t, 1H), 7.41–7.39 (m, 3H), 7.21–7.16 (m, 2H),
7.62–7.60 (m, 2H); 13C NMR (300 MHz, CDCl3, d): 79.4 (q, J 28.5 Hz),
ra-tert-butylbiphenyl-2,20-diol21 and methyl-3
a-acetyloxy-12a-

V. R. Jumde et al. / Tetrahedron: Asymmetry 21 (2010) 2775–2781
2781
113.6, 113.9, 119.9, 123.5, 127.3, 128.2, 128.6, 129.2, 131.1, 139.3,
140.9, 159.2.
extracted twice with diethyl ether. The organic extracts were dried
over anhydrous Na2SO4, then evaporated until 0.3 mL volume and
analyzed by GC. The results expressed as a percentage of 10aa are
reported in Figure 2.
4.3.2. 2,2,2-Trifluoro-1-(4-methoxyphenyl)-1-phenylethanol
12c
Yield: 93% (colorless oil) after chromatographic purification
(CH2Cl2/hexane 7:3), Rf 0.56. Chiralcel OD-H, 230 nm, 1 mL/min,
n-hexane/2-propanol 97:3, T 25 °C, tmaj = 8.9 min, tmin = 10.0 min.
Acknowledgments
This work was supported by the University of Pisa. Dr. Tiziana
Funaioli is gratefully acknowledged for providing [RhCl(C2H4)2]2.
½
a 3D1
ꢂ
¼ ꢀ2:3 (c 1.03, CHCl3) for a sample having 27% ee. Spectral
data matched the reported ones.11
References
4.3.3. 2,2,2-Trifluoro-1-(4-chlorophenyl)-1-phenylethanol 12g
Yield: 56% (yellowish oil) after chromatographic purification
(CH2Cl2/hexane 1:1), Rf 0.52. Chiralcel OJ, 230 nm, 1 mL/min,
n-hexane/2-propanol 99:1, T 25 °C, tmin = 32.8 min, tmaj = 37.2 min.
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½
a 3D1
ꢂ
¼ ꢀ2:2 (c 1.03, CHCl3) for a sample having 27% ee. 1H NMR
(300 MHz, CDCl3, d): 2.49 (s, 3H), 3.26 (s, 1H), 7.31 (m, 2H), 7.48
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129.0, 136.6, 138.6, 139.5.
4.3.5. 2,2,2-Trifluoro-1-(1-naphthyl)-1-phenylethanol 12d
Yield: 50% (white solid) after chromatographic purification
(CH2Cl2/hexane 7:3), Rf 0.6. Chiralcel OD-H, 230 nm, 1 mL/min,
n-hexane/2-propanol 99:1, T 25 °C, tmin = 15.8 min, tmaj = 36.9 min.
½
a 3D1
ꢂ
¼ ꢀ72:4 (c 1, CHCl3) for a sample having 54% ee. 1H NMR
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a 3D1
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5. Kinetic measurements
Under nitrogen atmosphere toluene (2 mL) was added to
[RhCl(C2H4)2]2 (1.5 mol %) and phosphite 6a or 6b (6 mol %). The
mixture was stirred for 30 min, then water (0.2 mL), 2 M KOH
(0.5 mL), phenylboronic acid (2 mmol), and 1-naphthaldehyde
(1 mmol) were added. The mixture was stirred at 0 °C and 0.2 mL
samples were taken, the first after 5 min and the others after
15 min intervals, and poured into 0.5 mL of 1 M NaHCO3 and