Broad Scope Synthesis of Ester Precursors of Nonfunctionalized Chiral Alcohols Based on the Asymmetric Hydrogenation of α,β-Dialkyl-, α,β-Diaryl-, and α-Alkyl-β-aryl-vinyl Esters

Article abstract of DOI:10.1021/acs.joc.7b00710

The catalytic asymmetric hydrogenation of trisubstituted enol esters using Rh catalysts bearing chiral phosphine-phosphite ligands (P-OP) has been studied. Substrates covered comprise α,β-dialkyl, α-alkyl-β-aryl, and α,β-diarylvinyl esters, the corresponding hydrogenation products being suitable precursors to prepare synthetically relevant chiral nonfunctionalized alcohols. A comparison of reactivity indicates that it decreases in the order: α,β-dialkyl > α-alkyl-β-aryl > α,β-diaryl. Based on the highly modular structure of P-OP ligands employed, catalyst screening identified highly enantioselective catalysts for α,β-dialkyl (95-99% ee) and nearly all of α-alkyl-β-aryl substrates (92-98% ee), with the exception of α-cyclohexyl-β-phenylvinyl acetate which exhibited a low enantioselectivity (47% ee). Finally, α,β-diarylvinyl substrates showed somewhat lower enantioselectivities (79-92% ee). In addition, some of the catalysts provided a high enantioselectivity in the hydrogenation of E/Z mixtures (ca. Z/E = 75:25) of α,β-dialkylvinyl substrates, while a dramatic decrease on enantioselectivity was observed in the case of α-methyl-β-anisylvinyl acetate (Z/E = 58:42). Complementary deuteration reactions are in accord with a highly enantioselective hydrogenation for both olefin isomers in the case of α,β-dialkylvinyl esters. In contrast, deuteration shows a complex behavior for α-methyl-β-anisylvinyl acetate derived from the participation of the E isomer in the reaction.

Full text of DOI:10.1021/acs.joc.7b00710

Article
pubs.acs.org/joc
Broad Scope Synthesis of Ester Precursors of Nonfunctionalized
Chiral Alcohols Based on the Asymmetric Hydrogenation of α,β-
Dialkyl‑, α,β-Diaryl‑, and α‑Alkyl-β-aryl-vinyl Esters
Felix Leon,† Pedro J. Gonzalez-Liste,‡ Sergio E. García-Garrido,‡ Inmaculada Arribas,† Miguel Rubio,†,§
́
́
́
Victorio Cadierno,*,‡ and Antonio Pizzano*,†
†Instituto de Investigaciones Químicas (IIQ) and Centro de Innovacion
Universidad de Sevilla, Americo Vespucio 49, 41092 Sevilla, Spain
‡Laboratorio de Compuestos Organometal
icos y Catalisis (Unidad Asociada al CSIC), Centro de Innovacion
ica e Inorganica, Instituto Universitario de Química Organometal
́
en Química Avanzada (ORFEO−CINQA), CSIC,
́
́
́
́
en Química Avanzada
ica “Enrique
(ORFEO−CINQA), Departamento de Química Organ
́
́
́
Moles”, Universidad de Oviedo, 33006 Oviedo, Spain
S
* Supporting Information
ABSTRACT: The catalytic asymmetric hydrogenation of trisubstituted enol esters using Rh catalysts bearing chiral phosphine-
phosphite ligands (P-OP) has been studied. Substrates covered comprise α,β-dialkyl, α-alkyl-β-aryl, and α,β-diarylvinyl esters, the
corresponding hydrogenation products being suitable precursors to prepare synthetically relevant chiral nonfunctionalized
alcohols. A comparison of reactivity indicates that it decreases in the order: α,β-dialkyl > α-alkyl-β-aryl > α,β-diaryl. Based on the
highly modular structure of P-OP ligands employed, catalyst screening identified highly enantioselective catalysts for α,β-dialkyl
(95−99% ee) and nearly all of α-alkyl-β-aryl substrates (92−98% ee), with the exception of α-cyclohexyl-β-phenylvinyl acetate
which exhibited a low enantioselectivity (47% ee). Finally, α,β-diarylvinyl substrates showed somewhat lower enantioselectivities
(79−92% ee). In addition, some of the catalysts provided a high enantioselectivity in the hydrogenation of E/Z mixtures (ca. Z/E
= 75:25) of α,β-dialkylvinyl substrates, while a dramatic decrease on enantioselectivity was observed in the case of α-methyl-β-
anisylvinyl acetate (Z/E = 58:42). Complementary deuteration reactions are in accord with a highly enantioselective
hydrogenation for both olefin isomers in the case of α,β-dialkylvinyl esters. In contrast, deuteration shows a complex behavior for
α-methyl-β-anisylvinyl acetate derived from the participation of the E isomer in the reaction.
feasibility of this option is, however, strongly dependent on the
nature of R1 and R2 substituents. Thus, the hydrogenation of
aryl-alkyl ketones constitutes one of the highest achievements
in asymmetric catalysis due to the exceptional levels of catalyst
activity and enantioselectivity reached.4 As well, very efficient
catalysts have been described for the hydrogenation of tert-
alkyl−alkyl ketones.5 Nonetheless, the hydrogenation of dialkyl
ketones characterized by less bulky alkyl substituents has a
considerable difficulty and high enantioselectivities have only
been achieved in a limited number of cases.4i,6,7 Likewise,
INTRODUCTION
■
Catalytic asymmetric hydrogenation constitutes one of the
most efficient tools for the preparation of chiral building blocks
with high enantioselectivity.1,2 As well, due to the inherent
advantages that usually characterize these kind of processes
(e.g., high catalyst efficiency, perfect atom economy, simple
workup), they have extensively been used in industrial
applications.3 Among diverse classes of compounds prepared
using asymmetric hydrogenation reactions, a particularly
remarkable one corresponds to nonfunctionalized chiral
alcohols of general structure A (R1, R2 = alkyl, aryl; Figure 1).
A very convenient and direct route to alcohols A is provided
by the asymmetric hydrogenation of ketones B (path a). The
Received: March 27, 2017
Published: May 8, 2017
© XXXX American Chemical Society
A
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Figure 1. Hydrogenation routes to alcohols A.
benzyl-alkyl ketones constitutes another class of problematic
substrates and no satisfactory hydrogenation catalysts have so
far been reported.8,9 However, chiral alkanols and homo-
benzylic alcohols are very versatile building blocks for
synthesis,10 therefore the development of efficient methods to
obtain them in a high enantiomeric purity has a considerable
interest. Toward this aim, the asymmetric hydrogenation of
enol esters C constitutes an appealing alternative, as esters D
can trivially be converted into alcohols A through deacylation
(path b).11 Although the hydrogenation of B and C are
mechanistically different reactions, the preparation of A with
high enantioselectivity by either path a or b ultimately depends
on an effective discrimination of prochiral substrate faces by the
corresponding hydrogenation catalyst. In this regard, the
hydrogenation of enol esters is characterized by substrate
chelation, which enables a powerful recognition of the olefinic
substrate.12 In contrast, the differentiation of enantiotopic faces
of ketones bearing not very dissimilar R1 and CH2R2
substituents is an extremely difficult task, as evidenced by the
background mentioned above. In this context, a meaningful
case is provided by the hydrogenation of α-alkylvinyl esters (C,
R1 = alkyl, R2 = H), which has enabled a broad scope and
highly efficient route for the synthesis of chiral 2-alkanols.13
A highly valuable expansion of path b route corresponds to
the hydrogenation of trisubstituted substrates C (R1, R2 = alkyl,
aryl), as it may provide access to a vast range of chiral esters
considering the countless possible combinations of R1 and R2.
Nevertheless, the inclusion of a substituent in β position of the
vinyl fragment introduces fundamental reactivity aspects to
study. First, in comparison with widely studied disubstituted
substrates,14 increase in olefin substitution should be
accompanied by a reduced catalyst activity,15 further to the
relatively low reactivity of enol esters.16 Second, the
enantioselectivity of the hydrogenation may critically be
dependent on the olefin configuration,17 which can limit
severely the usefulness of this approach as enol esters are often
obtained as E/Z mixtures and their separation is usually
cumbersome. On the other hand, nearly all enol esters
examined in asymmetric hydrogenation possess an α-electron-
withdrawing substituent (carboxylate, phosphonate, trifluor-
omethyl, cyano, or aryl), which is an important element in the
course of the reaction.18 As a result of this background, there is
very little information in the literature about the enantiose-
lective hydrogenation of trisubstituted substrates bearing an
alkyl substituent in α position.19,20 Precedents are limited to a
study on the hydrogenation of α-alkyl-β-methylvinyl esters, as
mixtures of the corresponding E and Z isomers, described by
Goossen and co-workers. Thus, these authors have reported
enantioselectivities up to 98% ee in the case of the α-methyl-
substituted substrates, as well as a decrease down to 82 and
78% ee for esters bearing α-nPr and α-nBu substituents,
respectively.19 Finally, we would like to remark also here that
no precedents of the asymmetric hydrogenation of α,β-
diarylvinyl esters have been described so far in the literature.
In a preliminary contribution we studied the synthesis and
hydrogenation of α-alkyl-β-aryl-substituted substrates C2
(Figure 2),21 using Rh catalysts based on chiral phosphine−
Figure 2. General structures of enol esters C1−C3.
phosphite ligands (P-OP).22 Herein we present a broader study
on the hydrogenation of trisubstituted enol esters covering in
addition those of types C1 and C3. Moreover, the reduction of
mixtures of E/Z-isomers, providing information about the
influence of substrate configuration on the reaction, has also
been studied in detail.
RESULTS AND DISCUSSION
■
Synthesis of Substrates. In order to examine the scope of
the asymmetric hydrogenation of trisubstituted enol esters of
types C1−C3, a wide range of substrates covering the three
types of structures has been prepared (Figure 3). Thus,
regarding those of type C1, compounds 1a and 1b have been
prepared by a gold catalyzed addition of benzoic acid to 2-
butyne (Scheme 1a), following the procedure described by Kim
and Chary.23,24 Also based on the work of these authors, 1c and
1d were synthesized by a gold catalyzed tandem addition-
isomerization reaction (Scheme 1b). Worth to note, 1a and 1b
were obtained as the pure Z isomers, while 1c and 1d as
mixtures with a Z/E ratio of 74:26 and 72:28, respectively.
Regarding substrates of type C2, we have previously prepared
α-methyl-β-aryl vinyl acetates 1e−1i, with generally good yields
and selectivity (Z:E ≥ 95:5) upon the acylation of methyl
benzyl ketones.21,25 Moreover, a range of 1-alkyl-2-arylvinyl
substrates (1k−1q, 1t−1z) were stereoselectively prepared as
the Z isomers by a Suzuki coupling over (Z)-β-iodoalkenyl
acetates.21,26 In order to complete the set of compounds C2,
new substrate 1j bearing a 1-ethyl substituent has been
prepared in good yield (62%) by the former method. Likewise,
compounds 1r and 1s, possessing 2-phenylethyl and 3-
phenylpropyl substituents, have been prepared by the Suzuki
coupling route in good yields from the corresponding iodo-
alkenes 2 (75 and 79%, respectively; Scheme 2).
B
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Figure 3. Range of enol esters 1 covered in the present study.
Scheme 1. Synthesis of Enol Esters 1a−1d and 1aa
Scheme 2. Synthesis of New Enol-Esters by a Suzuki
Coupling on 2-Iodoalkenyl Acetates
This reaction provided the (Z)-enol ester 1af, albeit in a rather
low yield (Scheme 3).
Range of Catalysts Examined. In previous contributions
we have reported the application of bidentate phosphine−
phosphite ligands 3 (P-OP, Figure 4) in asymmetric hydro-
genation reactions.22,28 These ligands are characterized by a
To widen the range of substrates, several examples of type
C3 have also been prepared. Initially, diphenyl substrate 1aa
was prepared in moderate yield by the reaction of Scheme 1a.
Moreover, several examples characterized by a α-Ph and diverse
aryl or heteroaryl fragments in β position have been synthesized
by the Suzuki coupling route (1ab−1ae; Scheme 2). Finally,
with the intention to explore the introduction of an alkyl
substituent in position β of the CC bond, a Negishi type
coupling was studied using (Z)-α-benzyl-β-iodovinyl acetate.27
Scheme 3. Preparation of Substrate 1af
C
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Scheme 4. Synthesis of Ligands 3g−3i
Figure 4. Structure of phosphine−phosphite ligands 3a−3f.
highly modular structure which facilitates the fine-tuning of
diverse key elements of the structure of the catalyst, (e.g., the
steric effects produced by each P-fragment, the basicity of the
phosphine, or the flexibility of the backbone). According to this
background we have chosen a wide set of catalyst precursors of
general formula [Rh(diene)(P-OP)]BF4 [diene = NBD, P-OP
= 3a (4a), 3c−3e (4c-4e); diene = COD, P-OP = 3b (4b), 3f−
3i (4f-4i)] to study the hydrogenation of substrates 1. All
ligands 3 possess an atropisomeric biaryl fragment in the
phosphite, while ligands 3h and 3i (Scheme 4), introduced in
our preliminary communication,21 also possess a P-stereogenic
P(tBu)Me fragment, which is present in several highly efficient
hydrogenation catalysts.29 For comparison with 3h and 3i, the
novel ligand 3g characterized by a PtBu2 fragment has also been
included in the set. Ligands 3h and 3i were prepared by
reaction of (S)-tert-butyl-(2-hydroxyethyl)-methylphosphine
borane (PB−OH, R = Me; Scheme 4)30 with each enantiomer
of 3,3′-di-tert-butyl-5,5′,6,6′-tetramethyl-2,2′-bisphenoxy-phos-
phorus chloride (PCl), followed by deboronation with
DABCO, while 3g was prepared in an analogous manner
starting from di-tert-butyl-(2-hydroxyethyl)-phosphine borane
it is moreover observed that the phosphite fragment has a
dominant role in the induction of chirality and controls the
product enantiomer. Thus, catalysts characterized by a
phosphite fragment with configuration S produce (S)-5a (and
conversely an R product for an R phosphite). On the other
hand, in good accord with the positive effect of 1,2-
dichloroethane (DCE) in these hydrogenations (see below),
no decrease in enantioselectivity was observed in this solvent
(entries 8 and 9). Moreover, it was also possible to develop a
more practical synthesis of 5a with a low catalyst loading (S/C
= 1000) and high enantioselectivity (95% ee, entry 10) under
20 bar H2. Substrate 1b constitutes another interesting case,
since it could provide a convenient access to enantiopure 3-
hexanol, highly difficult to obtain from 3-hexanone.32a As
shown for 1a, catalyst precursors 4a and 4d provided
satisfactory results in the hydrogenation of 1b, affording (R)-
5b and (S)-5b, respectively, with complete conversion and an
outstanding enantioselectivity (97−99% ee; entries 11, 12).
Considering that some of the substrates of type C1 can be
obtained in a simple manner, although unselectively, as
mixtures of E and Z isomers, an interesting goal in this topic
corresponds to the development of highly enantioselective
hydrogenations with these mixtures. Accordingly we examined
the reaction of a mixture of Z and E isomers of 1c in a 74:26
ratio using several catalysts. For instance, 4a provided full
conversion in DCE, with an outstanding enantioselectivity
(99% ee, entry 13), while a decrease down to 90% ee was
observed in the case of 4d (entry 14). Moreover, an important
mismatching effect was detected with the couple of complexes
4h and 4i, being the former considerably more enantioselective
than the latter (92 and 55% ee, respectively; entries 15 and 16).
In addition, the hydrogenation of 1d (Z:E = 72:28),
characterized by a bulky aliphatic substituent in β position,
t
(PB−OH, R = Bu).
Hydrogenation of α,β-Dialkylvinyl Esters. Initially, we
chose ester 1a as an example of a C1 type structure. It is
noteworthy that the asymmetric hydrogenation of this substrate
has a high interest due to the importance of enantiopure 2-
butanol and,31 as well, to the fact that its production represents
a highly challenging synthetic goal, even by the enzymatic
reduction of 2-butanone.32 Thus, some reactions were prepared
in dichloromethane (DCM) using standard reaction conditions
(S/C = 100, 4 bar H2, 40 °C) and diverse catalyst precursors
(entries 1−7, Table 1). With the exception of 4b, all the
catalysts examined provided full conversion to 5a and
enantioselectivities over 94% ee, giving 4d the best
enantioselectivity (99% ee, entry 4). Along the catalyst series
D
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Finally, complexes 4e, 4f, and 4g were also tested (entries 19−
21), although they did not provide better results than 4a.
These results, together with those reported in the hydro-
genation of α-alkylvinyl substrates,13d clearly illustrate the high
value of Rh catalysts bearing P-OP ligands for the synthesis of
ester precursors of aliphatic alcohols, due to the wide range of
products obtained with high levels of enantioselectivity and, as
well, to the straightforward application of the reaction to the
synthesis of the desired product enantiomer.
Table 1. Hydrogenation of α,β-Dialkylvinyl Esters
Performed with Catalyst Precursors 4
a
subs.
entry (Ak, Ak′) cat. prec. solvent
S/C conv (%) % ee (conf)
Enantioselective Synthesis of Homobenzylic Esters by
Asymmetric Hydrogenation. In our preliminary study we
investigated the hydrogenation of a wide set of substrates of
type C2, taking 1n as a representative substrate for the
optimization of the catalytic system. For the sake of
completeness, we include herein some results of this study to
recall the more relevant aspects of the hydrogenation of 1n, and
of the scope of the hydrogenation of substrates of type C2.
Worth to note, catalyst screening for 1n in our preliminary
communication not only included complexes 4a−4e, 4h, and 4i
based on P-OP ligands, but also some catalysts based on
commercial chiral ligands,33 finally pointing to catalyst from 4h
as the more efficient one which could reduce 1n under mild
conditions (4 bar H2, 40 °C, DCE, S/C = 100−250, 24 h) with
98% ee (entries 10, 11, Table 2). A relevant feature of 1n is a
1
2
3
4
5
6
7
8
9
10
1a (Me,
4a
4b
4c
4d
4e
4h
4i
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
100
100
100
100
100
100
100
100
100
1000
100
98 (R)
Me)
1a (Me,
Me)
37
n.d.
1a (Me,
Me)
97
94 (S)
99 (S)
97 (S)
98 (S)
95 (R)
95 (S)
98 (S)
95 (S)
1a (Me,
Me)
100
100
100
100
100
100
100
1a (Me,
Me)
1a (Me,
Me)
1a (Me,
Me)
1a (Me,
Me)
4h
4d
4d
1a (Me,
Me)
DCE
b
1a (Me,
Me)
DCE
Table 2. Hydrogenation of 1n Performed with Catalyst
a
Precursors 4
11
12
13
1b (Et, Et)
1b (Et, Et)
4a
4d
4a
DCE
DCE
DCE
100
100
100
100
100
100
99 (R)
97 (S)
99 (R)
1c (Me,
nPen)
14
15
16
1c (Me,
4d
4h
4i
DCE
DCE
DCE
100
100
100
100
100
100
90 (S)
92 (S)
55 (R)
nPen)
1c (Me,
nPen)
entry
cat. prec.
solvent
conv (%)
% ee (conf)
1
2
4a
4b
4c
4d
4e
4f
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
13
<5
<5
<5
62
59
34
79
38
100
98
n.d.
1c (Me,
nPen)
n.d.
17
18
19
20
21
22
23
1d (Me,
Cy)
4a
4d
4e
4f
DCE
DCE
DCE
DCE
DCE
DCE
DCE
100
100
100
100
100
100
100
100
100
100
100
100
100
44
95 (R)
92 (S)
89 (S)
90 (S)
70 (S)
78 (S)
68 (S)
3
n.d.
4
n.d.
1d (Me,
Cy)
5
96 (S)
92 (R)
94 (S)
98 (S)
94 (R)
98 (S)
98 (S)
6
1d (Me,
Cy)
7
4g
4h
4i
8
1d (Me,
Cy)
9
1d (Me,
Cy)
4g
4h
4i
10
4h
b
11
4h
DCE
1d (Me,
Cy)
a
Reactions at 40 °C, [Rh] = 1 × 10−3 M, S/C = 100, 4 bar H2 initial
pressure, and 24 h reaction time, unless otherwise stated. Conversion
1d (Me,
Cy)
determined by 1H NMR and enantiomeric excess by chiral HPLC. See
b
Experimental Section for determination of configuration. [Rh] = 1 ×
a
Reactions at 40 °C, [Rh] = 1 × 10−3 M, substrate to catalyst ratio (S/
C), solvent, and 4 bar H2 unless otherwise indicated. 24 h reaction
time. Conversion determined by 1H NMR and enantiomeric excess by
chiral HPLC. Configuration was determined by comparison of the
optical rotation sign with literature data. Reaction performed under
20 bar H2.
10−3 M, S/C = 250.
b
markedly lower reactivity than that of 1a toward hydrogenation
(entries 1−5, 8, and 9). In contrast, the attainment of a good
enantioselectivity is not as demanding and relatively good
enantioselectivities, with values between 92 and 98% ee, were
obtained with catalysts 4e, 4h, and 4i (entries 5, 8, and 9,
respectively). As well, a positive effect on conversion was
observed when DCE was used as solvent (entry 10). Since the
incorporation of the P-stereogenic phophine fragment is the
most demanding aspect of the preparation of the P-OP ligand
3h, we explored the behavior of catalysts based on ligands 3f
and 3g, characterized by a nonstereogenic trialkylphosphine
fragment and by a less elaborated synthesis, as a possible
was also studied. First, catalyst precursors 4a and 4d afforded
full conversion and high enantioselectivity, with values of 95
and 92% ee, respectively (entries 17 and 18). Moreover,
complex 4h provided a complete reaction as well, but with a
substantially lower enantioselectivity (78% ee, entry 22), while
diastereomeric 4i exhibited a mismatching effect manifested
both in catalyst activity and enantioselectivity (entry 23).
E
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practical improvement. However, corresponding catalyst
precursors 4f and 4g provided lower conversion values than
4h, pointing again to the achievement of a suitable catalyst
activity as a challenging aspect of the present catalytic system.
Notwithstanding that, 4f and 4g showed relatively good
enantioselectivities, 92 and 94% ee, respectively (entries 6, 7).
Regarding substrate scope, 4h provided high enantioselectiv-
ities with a wide range of substrates (Table 3). Thus,
observed in the hydrogenation of 4-phenyl-1-buten-2-yl
benzoate13d and it is probably related to the formation of low
reactive Rh-η6-arene species.11a,16b In contrast, full conversion
and good enantioselectivities were observed under 20 bar H2
for 1r (93% ee, entry 16) and 1s (88% ee, entry 18).
Finally, a limitation of the present reaction was found with
the α-cyclohexyl-substituted substrate 1q. This compound
exhibited a markedly low reactivity and only a good conversion
was obtained with 4i under 20 bar H2 (90%), while both 4h
and 4i provided a rather low enantioselectivity (40−47% ee,
entries 13, 14).
a
Table 3. Hydrogenation of α-Alkyl-β-arylvinyl Esters
Enabled by the rather versatile synthetic procedures for
substrates 1, an appealing application of the present system is
the hydrogenation of 1af, which switches the position of the
olefin substituent containing the aryl fragment and should then
provide the corresponding homobenzylic ester 5af with
opposite configuration (with regard to that observed in the
hydrogenation of 1j−1o with 4h; entries 6−11 in Table 3).
Gratifyingly, hydrogenation of 1af with 4h under our standard
reaction conditions provided (R)-5af with excellent conversion
and enantioselectivity (Scheme 5).
cat.
H2
entry
subs. (Ak, Ar)
prec.
(bar) % conv. % ee (conf.)
1
2
3
4
5
1e (Me, 4-MeO-C6H4)
1f (Me, 4-Me-C6H4)
1g (Me, 4-F-C6H4)
4e
4e
4e
4e
4h
4
100
100
100
100
100
97 (S)
91 (S)
98 (S)
99 (S)
93 (S)
10
4
1h (Me, 2-MeO-C6H4)
4
1i [Me, 3,4-(MeO)2-
C6H3]
4
Scheme 5. Hydrogenation of 1af
6
1j (Et, Ph)
4h
4h
4h
4h
4h
4h
4h
4h
4i
4
100
100
100
100
100
100
100
50
94 (S)
94 (S)
98 (S)
98 (S)
98 (S)
98 (S)
92 (n.d.)
47 (n.d.)
40 (n.d.)
96 (S)
93 (S)
87 (S)
88 (S)
96 (S)
93 (S)
93 (S)
95 (S)
96 (S)
95 (S)
7
1k (nPr, Ph)
1l (nBu, Ph)
1m (nPen, Ph)
1n (nHex, Ph)
4
8
4
9
4
10
11
4
i
1o [(CH2)2 Pr, Ph]
4
b
12
1p (cC3H5, Ph)
4
c
13
c
1q (Cy, Ph)
20
20
4
14
1q (Cy, Ph)
90
Hydrogenation of α,β-Diarylvinyl Esters. To complete
this exploratory analysis we next examined the hydrogenation
of 1aa as an example of structure of type C3. Reactions
performed in DCM under our standard conditions (4 bar H2,
40 °C and S/C = 100) with several catalyst precursors (entries
1−6, Table 4), afforded rather low conversion values, being
only moderate in the case of 4h (entry 5). However, full
conversion and good enantioselectivity was observed when
DCE was used as solvent (92% ee, entry 7). Despite the
similitude between DCM and DCE, it is noteworthy that a
significant increase on conversion with the latter is both
observed with representative substrates 1n and 1aa, further
providing satisfactory results for the series of substrates C2 and
C3. In this context it is pertinent to mention that an
enhancement on enantioselectivity was observed by the group
of Ding in the hydrogenation of related enol esters when using
DCE instead of DCM,13b while a significantly better perform-
ance in DCE over DCM in the hydrogenation of an acyl
hydrazone with a Rh-diphosphine catalyst has been reported by
Haddad and co-workers.34 We have not found an explanation
to the solvent effect observed herein, but it should be noted
that despite DCE and DCM are rather similar solvents,
characterized by a poorly coordinating character, the former has
some ability to act as a chelating ligand.35 As intermediates
containing coordinated solvent are proposed in the hydro-
genation catalytic cycle, it is not unreasonable to expect a
different influence of these solvents in the catalytic process.
In addition, some α,β-diarylvinyl substrates of type C3 were
examined to complete the results obtained with 1aa. By
comparison with these results, it appears that substitution of
aryl ring of position β is detrimental for conversion (substrates
1ab−1ad; entries 8, 11, 14; Table 4). This is both observed
15
16
17
18
19
1r [(CH2)2Ph, Ph]
1r [(CH2)2Ph, Ph]
1s [(CH2)3Ph, Ph]
1s [(CH2)3Ph, Ph]
1t (nHex, 4-F-C6H4)
1u (nHex, 4-MeO-C6H4)
1v (nHex, 4-Me-C6H4)
1w (nHex, 4-Cl-C6H4)
1x (nHex, 4-Ph-C6H4)
4h
4h
4h
4h
4h
4h
4h
4h
4h
4h
89
20
4
100
84
20
4
100
100
100
100
100
100
100
d
20
4
21
22
23
24
20
4
4
1y [nHex, 3,4-(MeO)2-
20
C6H3]
25
1z [nHex, 3,5-(MeO)2-
4h
4
100
96 (S)
C6H3]
a
Hydrogenations performed at 40 °C in DCE, [Rh] = 1 × 10−3 M, S/
C = 100, at initial pressure (bar H2) indicated, and 24 h reaction time
unless otherwise stated. Conversion determined by 1H NMR and
enantiomeric excess by chiral HPLC. See Experimental Section for
b
c
determination of configuration. Reaction performed at 30 °C. 48 h
d
reaction time. [Rh] = 2 × 10−3 M, S/C = 100.
compounds 1i (entry 5), 1k−1p (entries 7−12), and 1t−1z
(entries 19−25) were hydrogenated with enantioselectivities
between 93 and 98% ee using our standard or similar reaction
conditions (see footnotes of Table 3 for details). Worth to
note, 4h provided a somewhat lower enantioselectivity in the
case of 1e (91% ee, not shown), outperformed by 4e (97% ee,
entry 1). Upon this result, 4e was used with satisfactory results
in the case of substrates 1f−1h (entries 2−4).
Regarding newly added substrates, 1j was satisfactorily
hydrogenated with 4h (94% ee, entry 6), while 1r and 1s
showed a lower reactivity under standard conditions leading to
uncompleted reactions (entries 15, 17). A similar decrease was
F
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Table 4. Hydrogenation of Diaryl-Substituted Substrates C3
Performed with Catalyst Precursors 4
Scheme 6. Comparison of Product Configuration Observed
in the Hydrogenation of 1
a
entry
subs. (Ar)
1aa (Ph)
cat. prec. solvent conv (%) % ee (conf)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4h
4i
DCM
DCM
DCM
DCM
DCM
DCM
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
6
n.d.
1aa (Ph)
<5
7
n.d.
1aa (Ph)
n.d.
1aa (Ph)
8
n.d.
1aa (Ph)
51
93 (R)
91 (S)
92 (R)
87 (R)
90 (R)
91 (R)
86 (R)
82 (R)
77 (R)
69 (R)
71 (R)
88 (R)
71 (R)
79 (R)
1aa (Ph)
43
1aa (Ph)
4h
4h
4h
4h
4h
4h
4h
4h
4h
4h
4h
4h
100
67
1ab (4-CF3-C6H4)
1ab (4-CF3-C6H4)
1ab (4-CF3-C6H4)
1ac (4-MeO-C6H4)
1ac (4-MeO-C6H4)
1ac (4-MeO-C6H4)
1ad (4-PhO-C6H4)
1ad (4-PhO-C6H4)
1ad (4-PhO-C6H4)
1ae (3-thienyl)
1ae (3-thienyl)
b
9
100
100
37
catalyst to both isomers of the substrate or, alternatively, to the
existence of an E-Z olefin isomerization process prior to the
hydrogenation.37 Following well established cis addition of
hydrogen to the olefin bond,38 the deuteration of E and Z
isomers will produce different diastereomers (Scheme 7), which
c
10
11
b
12
c
100
100
35
13
14
b
15
c
100
100
44
Scheme 7. Stereoisomers of Dideuterated 5-d2 Resulting
from cis Deuteration of Z and E Isomers of Enol Esters 1
16
17
c
18
100
a
Reactions at 40 °C, [Rh] = 1 × 10−3 M, S/C = 100, 4 bar H2 initial
pressure, and 24 h reaction time, unless otherwise stated. Conversion
determined by 1H NMR and enantiomeric excess by chiral HPLC. See
b
Experimental Section for determination of configuration. [Rh] = 4 ×
c
10−3 M, S/C = 100. Reactions performed under 20 bar H2.
with electron-donor and electron-withdrawing substituents and
may be then attributed to steric effects. Overall, substrates of
type C3 seem less reactive than those of type C2. However, full
conversion reactions were obtained at higher substrate
concentration or under 20 bar of H2. Thus, enantioselectivities
up to 91% ee (1ab, entry 10), 82% ee (1ac, entry 12), and 88%
ee (1ad, entry 16) were observed.36 In addition, the thienyl-
substituted enol ester 1ae also provided full conversion and a
relatively good enantioselectivity (79% ee, entry 18).
Mechanistic Considerations. The catalyst screening
performed with representative substrates 1a, 1n, and 1aa
indicates that product configuration is determined by the
configuration of the biaryl fragment of the phosphite. Thus, for
catalysts with a configuration S of this fragment, S enantiomers
are observed for products proceeding from dialkylvinyl
substrates (1a−1d, Scheme 6). Likewise, S enantiomers are
selectively formed from α-alkyl-β-aryl vinyl esters (1e−1z)
using 4h or 4e. On the other hand, R products are obtained in
the case of the hydrogenation of diaryl vinyl substrates (1aa-
1ae) catalyzed by 4h. Therefore, the sense of hydrogen
addition is coincident for the three types of products (the
changes in product configuration are due to the change of
priority order of substituents of the stereogenic carbon). It
should be finally added that this stereochemical relation
between phosphite configuration and the sense of hydrogen
addition is analogous to that observed in the hydrogenation of
structurally related olefins (enamides and α-acyloxyphospho-
nates) and discussed in detail elsewhere.22a,b
could eventually be distinguished by NMR. As a requisite for
this analysis, diastereotopic protons at position β should
generate separate signals. This was observed for 5c (as well as
for 5e, see below) while 5d exhibited overlapped signals. Thus,
the deuteration of 1c with 4a showed a 72:28 ratio of
1
diastereomers by H NMR, labeled at positions α and β,
namely M-5c-d2 and m-5c-d2 (major and minor, respec-
tively).39 This ratio is rather close to that of isomers of the
starting material (74:26) and is in accord with the absence of a
significant isomerization between the isomers of the starting
material. Moreover, analysis by ESI-MS did not show
appreciable amounts of trideuterated products, typically formed
in olefin isomerization reactions by a reversible olefin insertion
step.37a In this context, it is also pertinent to recall that the
variation on enantioselectivity upon deuteration has been taken
as an indication of competing mechanistic pathways in
asymmetric olefin hydrogenation reactions catalyzed by Rh
complexes.40 This seems not to occur in the present case, as a
value of 96% ee was observed in the deuteration of 1c, slightly
lower to that obtained in the standard hydrogenation (99% ee;
entry 13 in Table 1). Overall, the results obtained are in good
accord with an independent hydrogenation of each isomer of
1c by 4a both producing (R)-5c with high enantioselectivity.
In our preliminary communication we observed only
moderate enantioselectivities in the hydrogenation of a mixture
The high enantioselectivity obtained in the hydrogenation of
mixtures of olefin isomers of 1c and 1d with 4a is remarkable.
This can be attributed to an efficient transfer of chirality of
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of isomers of 1e in a Z:E = 58:42 ratio,41 in sharp contrast with
results obtained in the hydrogenation of 1c and 1d. This
committed us to investigate in more detail the hydrogenation of
1e. To this aim mixtures with Z:E = 95:5 and 58:42 ratios were
tested with several catalyst precursors (Table 5). Remarkably,
with 4h, no complete conversions were observed in the rest of
the hydrogenations (entries 1−3, 5). Moreover, an analysis of
the remaining unreacted substrate in these reactions showed an
enrichment in isomer E, indicating a slower reaction of the
latter compared with the Z isomer. Accordingly, the decrease in
enantioselectivity observed in reactions performed with 4d and
4e is attenuated by uncompleted reactions.
Table 5. Hydrogenation of 1e (Z:E = 58:42) Performed with
a
In addition, we have studied the deuteration of the isomer
mixtures of 1e differing in the E/Z ratio with 4h, as this
precursor provides the only catalyst able to complete the
reaction in both cases. In contrast to the experiment with 1c,
the deuteration of the Z:E = 58:42 mixture not only showed the
expected M-5e-d2 and m-5e-d2, but as well a third isotopomer
5e′-d2 labeled at positions α and β′ (Scheme 8, see SI for NMR
spectra), with a 59:28:13 respective ratio. Worth to note, an
analysis by MS-ESI did not show an appreciable presence of tri-
or monodeuterated species, confirming the dideuterated nature
of the three isomers. In contrast, compound 5e′-d2 was hardly
visible in the deuteration of the 95:5 mixture and a ratio M-5e-
d2:m-5e-d2:5e′-d2 of 92:5:3, respectively, could be estimated
Catalyst Precursors 4
b
c
d
entry cat. prec. conv (%) Z:E (%)
% ee (conf)
% ee (conf)
1
2
3
4
5
4a
4d
4e
4h
4i
94
75
0:100
0:100
12:88
58 (R)
80 (S)
81 (S)
44 (S)
55 (R)
78 (R)
95 (S)
97 (S)
91 (S)
74 (R)
76
100
89
23:77
a
Reactions at 40 °C in DCE, [Rh] = 1 × 10−3 M, S/C = 100, 4 bar H2
initial pressure, and 24 h reaction time. Conversion determined by 1H
NMR and enantiomeric excess by chiral HPLC. Configuration was
determined by comparison of the optical rotation sign with literature
data. Z/E ratio of remaining substrate. % ee of 5e obtained in the
hydrogenation of Z/E-1e. % ee of 5e obtained in the hydrogenation
b
c
d
1
(5e′-d2 is detected as an AB quartet in the H NMR, partially
of the Z:E = 95:5 ratio mixture.
overlapped with singlets of M-5e-d2 and m-5e-d2). As well, no
tri- or monodeuterated products were detected by MS-ESI. A
comparison of the ratio of isotopomers obtained in the
deuteration of the two isomer mixtures indicates that 5e′-d2 is
mainly formed from E-1e, although some formation from Z-1e
cannot be ruled out. Enantioselectivity for deuteration of the
Z:E = 95:5 mixture was 89% ee, which is only slightly lower
than the value obtained in the standard hydrogenation (91% ee;
entry 4 in Table 5). In contrast, an appreciable difference was
observed in the case the Z:E = 58:42 mixture, providing 54% ee
in the deuteration and 44% ee in the hydrogenation (entry 4,
the hydrogenation of the Z:E = 58:42 mixture provided
significantly lower enantioselectivities with all catalysts tested
(|Δ% ee| = 15−47% ee) than those performed with the Z:E =
95:5 mixture, indicating that the hydrogenation of E-1e is
appreciably less enantioselective with catalysts 4 than that of Z-
1e. The difference is particularly dramatic in the case of 4h, for
which values of 44 and 91% ee, respectively, were observed
(entry 4). As well, slower reactions with the 58:42 mixture were
observed. Thus, with the exception of the reaction prepared
Scheme 8. Deuteration Reactions of 1e by Complex 4h
H
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Scheme 9. Proposed Formation of Products M-5e-d2, m-5e-d2, and 5e′-d2
Table 5), suggesting a complex behavior of E-1e in the catalytic
process.
consequence of this mechanistic scheme, the exchange between
allyl complexes Rh−Al and Rh−Al′ would enable an E-Z
isomerization of 1e. It is interesting to note, in addition, that
free 1e′ is expected to be thermodynamically less stable than
parent E-1e,45 but the complex of the former should be
sterically less congested, driving the hydrogenation of 1e′.42
Moreover, previous studies with catalysts 4 demonstrate a faster
hydrogenation of 1-benzylvinyl benzoate, closely related to 1e′,
than observed for 1e in the present study.13d
Most interestingly, the pathway involving Rh-1e′ should lead
to a product enantioreversal giving the R enantiomer. In this
regard, hydrogenation of closely related 1-benzylvinyl benzoate
provided the R product with complexes 4d and 4e.13d Likewise,
4h produced the R enantiomer with 68% ee in the
hydrogenation of the latter substrate (Scheme 10). It is
worth noting, finally, that the 1e→1e′ isomerization is made
possible by the methyl substituent at position α, while α-
acyloxyacrylates mentioned above possess a carboxylate group
at this position and showed a clean cis deuteration of both
olefin isomers.11a
Regarding the products formed in the deuteration of 1e, the
main ones M-5e-d2 and m-5e-d2 should be formed by cis
deuteration on olefin complexes Rh-Z-1e and Rh-E-1e,
respectively (steps a′ and a, Scheme 9), while a reasonable
pathway leading to 5e′-d2 would be the deuteration of 3-(p-
methoxyphenyl)-1-propen-2-yl acetate (1e′), generated by an
olefin migration process in 1e. From the lack of observation of
trideuterated species, a typical reversible insertion pathway can
be disregarded. Alternatively, a mechanism for olefin isomer-
ization through η3-allyl hydride intermediates has been well
documented in the literature.42−44 Particularly interesting in
this regard, Budzelaar et al. have observed an equilibrium
between olefin and hydrido allyl Rh complexes bearing
diiminate ligands, while deuteration of 2,3-dimethyl-2-butene
by these complexes produced 1,2-dideutero-2,3-dimethylbu-
tane, resulting from an olefin isomerization to 2,3-dimethyl-1-
butene prior to the reduction.43 According to this background,
an isomerization through a η3-allyl hydride intermediate Rh−Al
from Rh-E-1e olefin complex (b) may be proposed. In a
subsequent step, Rh−Al could produce β-alkyl complex Rh−
Ak (c) which after C−H formation and olefin coordination
would finally render Rh-1e′ (d). Moreover, the sequence of
steps b−d results in a 1,3-H migration, in good accord with the
experimental observations. Despite results suggest that 5e′-d2 is
mainly formed from E-1e, an analogous transformation from
Rh-Z-1e (steps b′, c′, and d) may also be possible. As a
Scheme 10. Hydrogenation of 1-Benzylvinyl Benzoate
I
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reaction mixture stirred at 60 (1a−b) or 110 °C (1aa) for 15 h. After
that time, the solvent was removed in vacuo and the crude reaction
mixture purified by column chromatography over silica gel using
diethyl ether/hexane (1:10) as eluent, yielding the corresponding enol
esters as pure Z isomers.
CONCLUSIONS
■
A broad scope and practical method for the preparation of
chiral esters 5 by the asymmetric hydrogenation of trisub-
stituted enol esters 1 has been described. The set of substrates
analyzed comprises α,β-dialkyl, α-alkyl-β-aryl, and α,β-diary-
lvinyl esters, while catalysts used are based on Rh complexes
bearing chiral phosphine−phosphite ligands (P-OP). A
comparison of the reactivity between the different types of
enol esters studied indicates that it decreases in the order: α,β-
dialkyl > α-alkyl-β-aryl > α,β-diarylvinyl (the asymmetric
hydrogenation of the latter has been addressed for the first
time in the literature). Enabled by a highly precise tuning of the
P-OP ligand, suitable catalysts have been identified for each
type of substrate. Thus, for α,β-dialkylvinyl esters 4a provided
high enantioselectivities both for the Z isomer and for Z/E
mixtures. On the other hand, for Z-α-alkyl-β-aryl and Z-α,β-
diaryl substrates best results were provided by catalyst
precursor 4h. The latter is characterized by a highly basic P-
stereogenic trialkylphosphine fragment and shows important
mismatching effects in catalyst activity with respect to
diastereomeric 4i. Notwithstanding that, for some of the α-
Me-β-aryl substrates (1e-1h) more satisfactory enantioselectiv-
ities were obtained with catalyst precursor 4e. In contrast to the
behavior shown by Z/E mixtures of α,β-dialkylvinyl esters, the
hydrogenation of such a mixture of an α-alkyl-β-aryl substrate
(1e, Z/E = 58:42) showed a significantly poorer enantiose-
lectivity than in the reaction performed with nearly pure Z
isomer (Z/E = 95:5). The decrease is particularly dramatic in
the case of catalyst precursor 4h (44 vs 91% ee). Deuteration
experiments indicate the existence of a secondary route in the
hydrogenation of 1e, mainly associated with E-1e, characterized
by a product enantioreversal, justifying the decrease on
enantioselectivity observed with the mixture of isomers of 1e.
(Z)-But-2-en-2-yl Benzoate (1a).19,24 Colorless oil. Yield: 0.118 g
(67%).
(Z)-Hex-3-en-3-yl Benzoate (1b).24,46 Pale yellow oil. Yield: 0.131 g
(64%).
(Z)-1,2-Diphenylvinyl Heptanoate (1aa).24 White solid. Yield:
0.163 g (53%).
General Procedure for the Synthesis of Enol Esters 1c,d.
Under an argon atmosphere, the corresponding terminal alkyne (1.2
mmol) and benzoic acid (0.122 g, 1 mmol), [AuCl(PPh3)] (0.024 g,
0.05 mmol), AgOTf (0.016 g, 0.05 mmol), and toluene (5.0 mL) were
stirred at room temperature for 15 h. After that time, the solvent was
removed in vacuo and the crude reaction mixture purified by column
chromatography over silica gel using diethyl ether/hexane (1:10) as
eluent. The corresponding enol esters 1c,d were obtained as a mixture
of stereoisomers in 62−84% yield. Configuration of corresponding
isomers was assigned by 2D-NOESY experiments.
Oct-2-en-2-yl Benzoate (1c).47 Pale yellow oil. Yield: 0.195 g (84%,
Z/E = 74:26). Z-1c: 1H NMR (CDCl3, 300 MHz): δ = 8.10 (m, 2H),
7.58 (m, 1H), 7.45 (m, 2H), 5.11 (t, J(H,H) = 6.8 Hz, 1H), 2.00 (s,
3H), 1.97 (m, 2H), 1.31 (m, 6H), 0.86 (t, J(H,H) = 6.9 Hz, 3H) ppm.
13C{1H} NMR (CDCl3, 75 MHz): δ = 164.5, 145.0, 133.3, 130.0
(3C), 128.5 (2C), 117.5, 31.5, 28.9, 25.5, 22.5, 19.7, 14.0 ppm. E-1c:
1H NMR (CDCl3, 300 MHz): δ = 8.10 (m, 2H), 7.58 (m, 1H), 7.45
(m, 2H), 5.26 (t, J(H,H) = 7.7 Hz, 1H), 2.09 (q, J(H,H) = 7.8 Hz,
2H), 1.97 (s, 3H), 1.31 (m, 6H), 0.89 (t, J(H,H) = 7.4 Hz, 3H) ppm.
13C{1H} NMR (CDCl3, 75 MHz): δ = 165.4, 145.5, 133.2, 130.3,
129.9 (2C), 128.4 (2C), 118.0, 31.7, 29.3, 26.7, 22.6, 15.4, 14.1 ppm.
1-Cyclohexylprop-1-en-2-yl Benzoate (1d). Pale yellow oil. Yield:
0.151 g (62%, Z/E = 72:28). Z-1d: 1H NMR (CDCl3, 300 MHz): δ =
8.10 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 4.97 (d, J(H,H) = 9.2 Hz,
1H), 2.20 (m, 1H), 1.98 (d, J(H,H) = 0.5 Hz, 3H), 1.68 (m, 5H), 1.20
(m, 5H) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 164.7, 143.6,
133.2, 130.0 (3C), 128.5 (2C), 123.1, 35.0, 32.9 (2C), 26.0, 25.8 (2C),
19.7 ppm. E-1d: 1H NMR (CDCl3, 300 MHz): δ = 8.10 (m, 2H), 7.58
(m, 1H), 7.45 (m, 2H), 5.12 (d, J(H,H) = 9.7 Hz, 1H), 2.20 (m, 1H),
2.0 (d, J(H,H) = 0.8 Hz, 3H), 1.68 (m, 5H), 1.20 (m, 5H) ppm.
13C{1H} NMR (CDCl3, 75 MHz): δ = 165.3, 143.6, 133.1, 130.6,
129.9 (2C), 128.4 (2C), 123.5, 36.2, 33.3 (2C), 26.0 (2C), 25.9, 15.5
ppm. HRMS (ESI) m/z: [M+H]+ Calcd for C16H21O2 245.1542;
Found 245.1538.
Synthesis of Enol Ester 1j. Over a suspension of NaH (0.35 g, 60%
in mineral oil, 8.8 mmol), washed with pentane (3 × 10 mL) in dry
1,2-dimethoxyethane (10 mL), was added dropwise a solution of 1-
phenylbutan-2-one (0.78 g, 5.2 mmol) in 1,2-dimethoxyethane (10
mL). The resulting mixture was stirred for 1 h, giving a bright yellow
suspension, which was allowed to stand for 1 h. The supernatant was
added slowly over distilled acetic anhydride (1.0 mL, 10 mmol) cooled
at 0 °C. After all the supernatant enolate solution was transferred, the
residual sodium hydride was washed with additional 1,2-dimethoxy-
ethane (5 mL), the mixture allowed to stand for 30 min and the
resulting supernatant added to the acetic anhydride solution. The
mixture obtained was stirred at room temperature for 0.5 h and poured
into a mixture of n-hexane (25 mL), water (25 mL), and NaHCO3
(2.5 g, 30 mmol). Phases obtained were separated and the aqueous
one was extracted with n-hexane (30 mL). The combined n-hexane
fractions were dried over anhydrous MgSO4 overnight, filtered, and
solvent evaporated. The resulting oil was purified by column
chromatography over silica gel using n-hexane/AcOEt (90:10) as
eluent, yielding 1j as the pure Z isomer in 62% yield.
EXPERIMENTAL SECTION
■
General Information. All reactions and manipulations were
performed under nitrogen or argon, either in a Braun Labmaster
100 glovebox or using standard Schlenk-type techniques. All solvents
were distilled under nitrogen with the following desiccants: sodium-
benzophenone-ketyl for diethyl ether and tetrahydrofuran (THF);
sodium for hexanes and toluene; CaH2 for dichloromethane and
isopropanol. Rh complexes 4a−4b,22a 4c,28 4d,22b 4e,11d and 4f22c
were prepared as described previously. Moreover, the synthesis and
characterization of enol esters 1e−i, 1k−q, and 1t−z, their
corresponding hydrogenation products 5, the ligands 3h−i, and the
catalyst precursors 4h−i have been included in our preliminary
communication.21 With the exception of the (Z)-β-iodoenol acetates
2,26 all other reagents were purchased from commercial suppliers and
used as received. IR spectra were recorded on a PerkinElmer 1720-
XFT or in a Bruker Vector 22 spectrometer. NMR spectra were
obtained on a Bruker DPX-300, DRX-400, DRX-500, or Ascend 600
spectrometers. 31P{1H} NMR shifts were referenced to external 85%
H3PO4 and 19F{1H} NMR to CFCl3, while 13C{1H} and H shifts
1
were referenced to the residual signals of deuterated solvents. All data
are reported in ppm downfield from Me4Si. All NMR measurements
were carried out at 25 °C, unless otherwise stated. HPLC analyses
were performed at 30 °C by using a Waters 2690 chromatograph.
HRMS data were obtained on a Thermo Scientific Q Exactive hybrid
quadrupole-Orbitrap mass spectrometer in the General Services of
Universidad de Sevilla (CITIUS). Optical rotations were measured on
a PerkinElmer Model 341 polarimeter.
General Procedure for the Synthesis of Enol Esters 1a, 1b,
and 1aa. Under an argon atmosphere, the corresponding internal
alkyne (1.2 mmol) and carboxylic acid (1 mmol), [AuCl(PPh3)]
(0.024 g, 0.05 mmol), AgPF6 (0.013 g, 0.05 mmol), and toluene (3.0
mL) were introduced into a Teflon-capped sealed tube, and the
(Z)-1-Phenylbut-1-en-2-yl Acetate (1j). Pale orange oil. Yield:
1
0.600 g (62%). H NMR (CDCl3, 400 MHz): δ = 7.38 (d, J(H,H) =
7.7 Hz, 2H), 7.31 (t, J(H,H) = 7.9 Hz, 2H), 7.21 (t, J(H,H) = 7.5 Hz,
1H), 5.99 (s, 1H), 2.42 (q, J(H,H) = 7.6 Hz, 2H), 2.19 (s, 3H), 1.17
(t, J(H,H) = 7.7 Hz, 3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ
J
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Article
= 168.7, 151.4, 134.6, 128.4, 128.3 (2C), 127.0 (2C), 114.9, 27.5, 21.2,
11.4 ppm. IR (film): ν = 1757 (s, CO), 1679 (m, CC) cm−1.
HRMS (ESI) m/z: [M+Na]+ Calcd for C12H14O2Na 213.0886; Found
213.0882.
product extracted with dichloromethane, dried over MgSO4 and the
solvent removed in vacuo. The crude reaction mixture was then
purified by column chromatography over silica gel using diethyl ether/
hexane (1:50) as eluent, yielding (Z)-1af in 10% yield.
General Procedure for the Synthesis of Enol Esters 1r−s and
1ab−1ae. Under an argon atmosphere, the corresponding (Z)-β-
iodoenol acetate 2 (1.0 mmol), [Pd(PPh3)4] (0.058 g, 0.05 mmol),
and toluene (3.0 mL) were introduced into a Teflon-capped sealed
tube, and the mixture was stirred at room temperature for 10 min.
Then, 0.5 mL of a 4.0 M NaOH aqueous solution (2.0 mmol of
NaOH) and the corresponding boronic acid (1.5 mmol) were added
to the sealed tube and the reaction mixture stirred at 80 °C for 12 h.
After that time, the solvent was removed in vacuo and the crude
reaction mixture purified by column chromatography over silica gel
using diethyl ether/hexane (1:100) as eluent. The corresponding enol
esters 1r−s and 1aa−1ad were obtained as pure Z isomers in 42−80%
yield.
(Z)-1,4-Diphenylbut-1-en-2-yl Acetate (1r). Orange oil. Yield:
0.200 g (75%). 1H NMR (CDCl3, 400 MHz): δ = 7.46 (m, 2H), 7.41
(m, 4H), 7.32 (m, 4H), 6.07 (s, 1H), 2.99 (t, J(H,H) = 7.7 Hz, 2H),
2.83 (t, J(H,H) = 7.7 Hz, 2H), 2.22 (s, 3H) ppm. 13C{1H} NMR
(CDCl3, 100 MHz): δ = 168.5, 149.0, 140.9, 134.3, 128.4 (4C), 128.3
(2C), 128.2 (2C), 127.1, 126.1, 116.4, 36.1, 33.3, 20.9 ppm. IR (film):
ν = 1757 (s, CO), 1602 (m, CC) cm−1. HRMS (ESI) m/z: [M
+Na]+ Calcd for C18H18O2Na 289.1204; Found 289.1199.
(Z)-1,5-Diphenylpent-1-en-2-yl Acetate (1s). Orange oil. Yield:
0.221 g (79%). 1H NMR (CDCl3, 400 MHz): δ = 7.47 (m, 2H), 7.40
(m, 4H), 7.30 (m, 4H), 6.08 (s, 1H), 2.80 (t, J(H,H) = 10.2 Hz, 2H),
2.54 (t, J(H,H) = 10.2 Hz, 2H), 2.26 (s, 3H), 1.99 (m, 2H) ppm.
13C{1H} NMR (CDCl3, 100 MHz): δ = 168.5, 149.4, 141.8, 134.4,
128.5 (2C), 128.4 (4C), 128.2 (2C), 127.1, 125.9, 116.2, 35.2, 33.9,
28.5, 21.1 ppm. IR (film): ν = 1755 (s, CO), 1602 (m, CC)
cm−1. HRMS (ESI) m/z: [M+Na]+ Calcd for C19H20O2Na 303.1361;
Found 303.1356.
(Z)-1-Phenyldec-2-en-2-yl Acetate (1af). Yellow oil. Yield: 0.047 g
(10%). 1H NMR (CDCl3, 300 MHz): δ = 7.31 (m, 2H), 7.23 (m, 3H),
5.03 (t, J(H,H) = 7.3 Hz, 1H), 3.51 (s, 2H), 2.09 (s, 3H), 1.93 (q,
J(H,H) = 7.1 Hz, 2H), 1.31 (m, 10H), 0.88 (t, J(H,H) = 6.5 Hz, 3H)
ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 169.0, 147.4, 137.6, 129.2
(2C), 128.5 (2C), 126.7, 118.6, 40.0, 31.9, 29.3, 29.2, 29.1, 25.6, 22.8,
20.8, 14.2 ppm. IR (film): ν = 1760 (s, CO), 1605 (m, CC)
cm−1. HRMS (ESI) m/z: [M+Na]+ Calcd for C18H26O2Na 297.1830;
Found 297.1825.
General Procedure for Asymmetric Hydrogenation. In a
glovebox, a solution of 4 (0.5 μmol) and substrate 1 (0.05 mmol) in
1,2-dichloroethane (0.5 mL) was placed in a HEL CAT-18 or in a
HEL 16 mL reactor. The reactor was purged with hydrogen and finally
pressurized at 4 bar. Deuteration reactions were prepared in the 16 mL
reactor, deoxygenating it with argon and vacuum cycles and finally
pressurizing it under 4 bar D2. The reaction was heated at 40 °C and
magnetically stirred for 24 h. Then, the reactor was depressurized and
the resulting solution slowly evaporated under vacuum. The remaining
residue was analyzed by 1H NMR to determine conversion and
subsequently dissolved in a i-PrOH/n-hexane (1:10) mixture and
passed through a short pad of silica gel to remove catalyst
decomposition products. The solution obtained was carefully
evaporated and the residue obtained was analyzed by chiral
chromatography to determine enantiomeric excess as described
below. Racemic mixtures were obtained by hydrogenation of 1 with
commercially available [Rh(COD)(DiPFc)]BF4 [DiPFc = 1,1′-bis-
(diisopropylphosphino)ferrocene] with the exception of 5p. In the
hydrogenation of 1p a complex mixture was observed and (rac)-5p
was alternatively prepared by acylation of 1-cyclopropyl-2-phenyl-
ethan-1-ol.21
(Z)-1-Phenyl-2-(4-(trifluoromethyl)phenyl)vinyl Acetate (1ab).
Yellow solid. mp: 46−49 °C. Yield: 0.129 g (42%). 1H NMR
(CDCl3, 400 MHz): δ = 7.62 (brs, 4H), 7.56 (m, 2H), 7.41 (m, 3H),
6.73 (s, 1H), 2.32 (s, 3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ
= 168.4, 148.5, 138.1, 135.2, 129.4 (q, J(C,F) = 32.4 Hz), 129.3, 128.9
(4C), 125.6 (q, 2C, J(C,F) = 3.6 Hz), 125.1 (2C), 124.2 (q, J(C,F) =
270.3 Hz), 115.6, 21.2 ppm. 19F{1H} NMR (CDCl3, 376 MHz): δ =
−62.6 ppm. IR (KBr): ν = 1753 (s, CO), 1615 (m, CC) cm−1.
HRMS (ESI) m/z: [M+Na]+ Calcd for C17H13F3O2Na 329.0765;
Found 329.0761.
sec-Butyl Benzoate (5a). Chiralcel OB-H, n-hexane, flow 1.0 mL/
min, t1 = 7.6 min (R), t2 = 8.2 min (S).
Hexan-3-yl Benzoate (5b). Chiralcel AD-H, 99:1 n-hexane:i-PrOH,
flow 0.5 mL/min, t1 = 9.2 min (R), t2 = 9.4 min (S).
Octan-2-yl Benzoate (5c). Chiralcel AD-H, n-hexane, flow 1.0 mL/
min, t1 = 20.0 min (R), t2 = 21.8 min (S).
1-Cyclohexylpropan-2-yl Benzoate (5d). Chiralcel OB-H, n-
hexane, flow 1.0 mL/min, t1 = 5.2 min (R), t2 = 6.3 min (S).
1-(4-Methoxyphenyl)propan-2-yl Acetate (5e). Chiralcel AD-H,
99:1 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 10.4 min (R), t2 = 11.0
min (S).
1-(4-Methylphenyl)propan-2-yl Acetate (5f). Chiralcel AD-H, 99:1
n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 12.4 min (R), t2 = 15.6 min
(S).
1-(4-Fluorophenyl)propan-2-yl Acetate (5g). Chiralcel AD-H, n-
hexane, flow 1.0 mL/min, t1 = 22.0 min (R), t2 = 24.7 min (S).
1-(2-Methoxyphenyl)propan-2-yl Acetate (5h). Chiralcel OB-H, n-
hexane, flow 1.0 mL/min, t1 = 29.2 min (S), t2 = 32.8 min (R).
1-(3,4-Dimethoxyphenyl)propan-2-yl Acetate (5i). Chiralcel AD-
H, 98:2 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 22.9 min (R), t2 =
24.9 min (S).
(Z)-2-(4-Methoxyphenyl)-1-phenylvinyl Acetate (1ac).48 Yellow
solid. Yield: 0.201 g (75%).
(Z)-2-(4-Phenoxyphenyl)-1-phenylvinyl Acetate (1ad). Yellow
solid. mp: 122−124 °C. Yield: 0.238 g (72%). 1H NMR (CDCl3,
300 MHz): δ = 7.51 (m, 4H), 7.35 (m, 5H), 7.14 (m, 1H), 7.05 (m,
2H), 6.99 (m, 2H), 6.68 (s, 1H), 2.33 (s, 3H) ppm. 13C{1H} NMR
(CDCl3, 75 MHz): δ = 168.7, 157.0, 156.8, 146.0, 135.7, 130.3 (2C),
130.0 (2C), 129.4, 128.8 (2C), 128.7, 124.7 (2C), 123.8, 119.4 (2C),
118.7 (2C), 116.2, 21.3 ppm. IR (KBr): ν = 1761 (s, CO), 1607 (m,
CC) cm−1. HRMS (ESI) m/z: [M+Na]+ Calcd for C22H18O3Na
353.1154; Found 353.1149.
(Z)-1-Phenyl-2-(thiophen-3-yl)vinyl Acetate (1ae). Yellow solid.
mp: 103−105 °C. Yield: 0.195 g (80%). 1H NMR (CDCl3, 300 MHz):
δ = 7.55 (m, 2H), 7.37 (m, 6H), 6.80 (s, 1H), 2.38 (s, 3H) ppm.
13C{1H} NMR (CDCl3, 75 MHz): δ = 168.6, 145.7, 135.3, 135.2,
128.7 (2C), 128.6, 127.8, 125.7, 124.6 (2C), 124.4, 111.3, 21.2 ppm.
IR (KBr): ν = 1755 (s, CO), 1595 (m, CC) cm−1. HRMS (ESI)
m/z: [M+Na]+ Calcd for C14H12O2SNa 267.0456; Found 267.0449.
Synthesis of (Z)-1-Phenyldec-2-en-2-yl Acetate (1af). Under an
argon atmosphere, [Pd(PPh3)4] (0.04 g, 0.034 mmol) and THF (5.0
mL) were introduced into a Teflon-capped sealed tube, followed by
TMEDA (0.280 mL; 1.9 mmol) and (Z)-1-iodo-3-phenylprop-1-en-2-
yl acetate (0.5 g, 1.7 mmol). n-Heptylzinc bromide (0.5 M in THF; 3.8
mL, 1.9 mmol) was then added dropwise to the sealed tube and the
reaction mixture stirred at room temperature for 12 h. After that time,
the reaction was quenched with saturated NH4Cl solution and the
1-Phenylbutan-2-yl Acetate (5j). Chiralcel AD-H, n-hexane, flow
1.0 mL/min, t1 = 23.3 min (S), t2 = 25.8 min (R).
1-Phenylpentan-2-yl Acetate (5k). Chiralcel OB-H, n-hexane, flow
1.0 mL/min, t1 = 14.8 min (S), t2 = 16.9 min (R).
1-Phenylhexan-2-yl Acetate (5l). Chiralcel OB-H, n-hexane, flow
1.0 mL/min, t1 = 16.8 min (R), t2 = 18.1 min (S).
1-Phenylheptan-2-yl Acetate (5m). Chiralcel OB-H, n-hexane, flow
1.0 mL/min, t1 = 18.2 min (R), t2 = 22.8 min (S).
1-Phenyloctan-2-yl Acetate (5n). Chiralcel OB-H, n-hexane, flow
1.0 mL/min, t1 = 9.7 min (R), t2 = 10.8 min (S).
5-Methyl-1-phenylhexan-2-yl Acetate (5o). Chiralcel OB-H, n-
hexane, flow 1.0 mL/min, t1 = 12.8 min (R), t2 = 15.3 min (S).
1-Cyclopropyl-2-phenylethyl Acetate (5p). Chiralcel OB-H, 99:1
n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 17.5 min (S), t2 = 18.8 min
(R).
K
DOI: 10.1021/acs.joc.7b00710
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1-Cyclohexyl-2-phenylethyl Acetate (5q). Chiralcel OB-H, n-
hexane, flow 1.0 mL/min, t1 = 7.3 min (R), t2 = 8.1 min (S).
1,4-Diphenylbutan-2-yl Acetate (5r). Chiralcel AD-H, 99.5:0.5 n-
hexane:i-PrOH, flow 1.0 mL/min, t1 = 10.6 min (R), t2 = 11.7 min (S).
1,5-Diphenylpentan-2-yl Acetate (5s). Chiralcel AD-H, 99.5:0.5 n-
hexane:i-PrOH, flow 1.0 mL/min, t1 = 8.6 min (S), t2 = 12.0 min (R).
1-(4-Fluorophenyl)octan-2-yl Acetate (5t). Chiralcel AD-H, 98:2
n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 13.9 min (S), t2 = 15.0 min
(R).
1-(4-Methoxyphenyl)octan-2-yl Acetate (5u). Chiralcel OB-H,
99:1 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 9.9 min (R), t2 = 11.5
min (S).
1-(4-Methylphenyl)octan-2-yl Acetate (5v). Chiralcel OB-H, n-
hexane, flow 1.0 mL/min, t1 = 14.4 min (R), t2 = 18.2 min (S).
1-(4-Chlorophenyl)octan-2-yl Acetate (5w). Chiralcel OB-H, n-
hexane, flow 1.0 mL/min, t1 = 15.5 min (R), t2 = 20.7 min (S).
1-([1,1′-Biphenyl]-4-yl)octan-2-yl Acetate (5x). Chiralcel AD-H,
98:2 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 12.5 min (S), t2 = 14.0
min (R).
1-(3,4-Dimethoxyphenyl)octan-2-yl Acetate (5y). Chiralcel OB-H,
95:5 n-hexane:i-PrOH, flow 0.7 mL/min, t1 = 20.0 min (R), t2 = 22.9
min (S).
1-(3,5-Dimethoxyphenyl)octan-2-yl Acetate (5z). Chiralcel AD-H,
98:2 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 12.9 min (S), t2 = 13.5
min (R).
1,2-Diphenylethyl Heptanoate (5aa). Chiralcel OB-H, n-hexane,
flow 1.0 mL/min, t1 = 7.7 min (R), t2 = 8.3 min (S).
1-Phenyl-2-(4-(trifluoromethyl)phenyl)ethyl Acetate (5ab). Chir-
alcel AD-H, 99:1 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 7.2 min (S),
t2 = 8.9 min (R).
2-(4-Methoxyphenyl)-1-phenylethyl Acetate (5ac). Chiralcel AD-
H, 99:1 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 14.0 min (R), t2 =
21.5 min (S).
(R)-2,3-Dideutero-octan-2-yl Benzoate (5c-d2). Obtained accord-
ing to the general procedure (S/C = 100) as a pale yellow oil using 4a
under 4 bar D2 (11.1 mg, 93% yield, 96% ee). H NMR (CDCl3, 400
1
MHz): δ = 8.04 (d, J(H,H) = 8.1 Hz, 2H), 7.55 (t, J(H,H) = 7.3 Hz,
1H), 7.44 (t, J(H,H) = 7.7 Hz, 2H), 1.71 (m, 0.7 H, CDH major
diastereomer), 1.58 (m, 0.3 H, CDH minor diastereomer), 1.32 (m,
2
11H), 0.87 (t, J(H,H) = 6.5 Hz, 3H) ppm. H NMR (CHCl3, 61
MHz): δ = 5.14 (brs), 1.71 (brs, CDH minor diastereomer), 1.59 (brs,
CDH major diastereomer) ppm. 13C{1H} NMR (CDCl3, 100 MHz):
δ = 166.3, 132.8, 131.1 (2C), 129.6 (2C), 128.4, 70.1 (t, J(C,D) = 19
Hz), 35.7 (t, J(C,D) = 19 Hz), 31.9, 29.3, 25.6, 22.7, 20.1, 14.2 ppm.
IR (film): ν = 1717 (s, CO) cm−1. HRMS (ESI) m/z: [M+Na]+
Calcd for C15H20D2O2Na 259.1638; Found 259.1641.
(R)-1-Cyclohexylpropan-2-yl Benzoate (5d).11d Obtained accord-
ing to the general procedure using 4a (S/C = 100) as a pale yellow oil
(11.1 mg, 90% yield, 95% ee).
(S)-1,2-Dideutero-1-(4-methoxyphenyl)propan-2-yl Acetate (5e-
d2). Obtained according to the general procedure (S/C = 100) as a
light orange oil using 4h under 4 bar D2 (9.5 mg, 95% yield, 89% ee).
Major diastereomer: 1H NMR (CDCl3, 400 MHz): δ = 7.10 (d,
J(H,H) = 8.0 Hz, 2H), 6.83 (d, J(H,H) = 8.05 Hz, 2H), 3.79 (s, 3H),
2.86 (brs, 1H, CHD), 2.00 (s, 3H), 1.19 (s, 3H) ppm; minor
diastereomer: 2.69 (brs, CHD). 2H NMR (CHCl3, 61 MHz): δ = 5.06
(brs, CDO), 2.69 (brs, CHD) ppm. 13C{1H} NMR (CDCl3, 151
MHz): δ = 170.6, 158.3, 130.4 (2C), 129.7, 113.8 (2C), 71.4 (t,
J(C,D) = 22 Hz), 55.4, 41.0 (t, J(C,D) = 20 Hz), 21.5, 19.3 ppm. IR
(film): ν = 1731 (s, CO) cm−1. HRMS (ESI) m/z: [M+Na]+ Calcd
for C12H14D2O3Na 233.1117; Found 233.1117.
(S)-1-Phenylbutan-2-yl Acetate (5j). Obtained according to the
general procedure (S/C = 100) as a pale yellow oil using 4h (9.2 mg,
96% yield, 94% ee). [α]D20 = +5.8° (c 0.9, CHCl3, 94% ee). 1H NMR
(CDCl3, 400 MHz): δ = 7.31 (m, 2H), 7.23 (m, 3H), 5.04 (m, 1H),
2.86 (m, 2H), 2.02 (s, 3H), 1.60 (m, 2H), 0.94 (t, J(H,H) = 7.5 Hz,
3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ = 170.7, 137.7, 129.4
(2C), 128.3 (2C), 126.4, 75.9, 40.1, 26.4, 21.2, 9.7 ppm. IR (film): ν =
1737 (s, CO) cm−1. HRMS (ESI) m/z: [M+Na]+ Calcd for
C12H16O2Na: 215.1043; Found 215.1039.
(S)-1,4-Diphenylbutan-2-yl Acetate (5r). Obtained according to
the general procedure (S/C = 100) as a pale yellow oil using 4h under
20 bar H21(12.6 mg, 94% yield, 93% ee). [α]D20 = +2.3° (c 0.9, CHCl3,
93% ee). H NMR (CDCl3, 400 MHz): δ = 7.30 (m, 5H), 7.20 (m,
5H), 5.17 (quint, J(H,H) = 6.2 Hz, 1H), 2.95 (m, 1H), 2.95 (m, 1H),
2.68 (m, 2H), 2.03 (s, 3H), 1.91 (m, 2H) ppm. 13C{1H} NMR
(CDCl3, 100 MHz): δ = 170.8, 141.6, 137.5, 129.6 (2C), 128.5 (2C),
128.5 (2C), 128.4 (2C), 126.6, 126.0, 74.5, 40.7, 35.3, 31.9, 21.3 ppm.
IR (film): ν = 1736 (s, CO) cm−1. HRMS (ESI) m/z: [M+Na]+
Calcd for C18H20O2Na 291.1356; Found 291.1353.
2-(4-Phenoxyphenyl)-1-phenylethyl Acetate (5ad). Chiralcel AD-
H, 97:3 n-hexane:i-PrOH, flow 0.6 mL/min, t1 = 13.3 min (S), t2 =
14.2 min (R).
1-Phenyl-2-(thiophen-3-yl)ethyl Acetate (5ae). Chiralcel OB-H,
97:3 n-hexane:i-PrOH, flow 1.0 mL/min, t1 = 10.0 min (R), t2 = 12.3
min (S).
1-Phenyldecan-2-yl Acetate (5af). Chiralcel AD-H, 99:1 n-
hexane:i-PrOH, flow 1.0 mL/min, t1 = 6.6 min (R), t2 = 7.5 min (S).
Determination of Configuration of Products 5. For products
5a,49 5c,11d 5d,11d 5e,50 5g,51 and 5h52 configuration was assigned by
comparison of the sign of optical rotation with that described in the
literature. For compounds 5b, 5f, 5i, and 5j configuration was assigned
by analogy with the previous data. For ester 5n configuration was
determined by deacylation and comparison of the sign of optical
rotation of the resulting alcohol with that described in the literature.53
For compounds 5k−5m, 5o, and 5r−5z configuration was assigned
assuming an analogous stereochemical course of the hydrogenation
with that of 5n. In addition, configuration of 5ac was assigned upon
comparison of the sign of optical rotation with that described in the
literature,54 while configuration of products 5aa, 5ab, 5ad, and 5ae
were assigned by analogy with the latter data. Finally, for 5af,
configuration was assigned assuming an analogous stereochemical
course of the hydrogenation with that of 5b and 5c.
(S)-1,5-Diphenylpentan-2-yl Acetate (5s). Obtained according to
the general procedure (S/C = 100) as a pale yellow oil using 4h under
20 bar H2 (13.3 mg, 94% yield, 88% ee). [α]D20 = +1.3° (c 1.1, CHCl3,
1
88% ee). H NMR (CDCl3, 400 MHz): δ = 7.25 (m, 10H), 5.15
(quint, J(H,H) = 6.2 Hz, 1H), 2.87 (m, 2H), 2.62 (m, 2H), 2.02 (s,
3H), 1.69 (m, 4H) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ =
170.6, 142.1, 137.6, 129.4 (2C), 128.4 (2C), 128.3 (4C), 126.4, 125.8,
74.5, 40.6, 35.6, 33.1, 27.3, 21.2 ppm. IR (film): ν = 1737 (s, CO)
cm−1. HRMS (ESI) m/z: [M+Na]+ Calcd for C19H22O2Na 305.1512;
Found 305.1506.
Characterization of Compounds 5. Full characterization of
products 5e−i, 5k−q, and 5t−z has been reported in our preliminary
communication.21
(R)-1,2-Diphenylethyl Heptanoate (5aa). Obtained according to
the general procedure (S/C = 100) as a pale yellow oil using 4h (14.1
(S)-sec-Butyl Benzoate (5a).49 Obtained according to the general
procedure (S/C = 100) as a pale yellow oil using 4d and DCM,
instead of DCE, as solvent (8.4 mg, 94% yield, 99% ee). Alternatively,
obtained using 0.5 mmol 1a and 0.5 μmol 4d in DCE (0.5 mL) under
20 bar H2 at 40 °C for 24 h (83.0 mg, 93% yield, 95% ee).
(R)-Hexan-3-yl Benzoate (5b).19 Obtained according to the general
procedure (S/C = 100) as a pale yellow oil using 4a (9.8 mg, 95%
20
1
mg, 91% yield, 92% ee). [α]D = +6.4° (c 0.8, CHCl3, 92% ee). H
NMR (CDCl3, 400 MHz): δ = 7.29 (m, 8H), 7.14 (m, 2H), 5.99 (m,
1H), 3.22 (m, 1H), 3.09 (m, 1H), 2.29 (t, J(H,H) = 7.5 Hz, 2H), 1.55
(m, 2H), 1.26 (m, 6H), 1.26 (t, J(H,H) = 6.8 Hz, 3H) ppm. 13C{1H}
NMR (CDCl3, 100 MHz): δ = 173.0, 140.4, 137.2, 129.6 (2C), 128.5
(2C), 128.3 (2C), 129.0 (2C), 126.7, 126.6, 76.4, 43.2, 34.7, 31.6, 28.8,
25.0, 22.6, 14.2 ppm. IR (film): ν = 1737 (s, CO) cm−1. HRMS
(ESI) m/z: [M+Na]+ Calcd for C21H26O2Na 333.1825; Found
333.1815.
20
yield, 99% ee). [α]D = −2.1° (c 1.1, CHCl3, 99% ee).
(R)-Octan-2-yl Benzoate (5c).11d Obtained according to the general
procedure (S/C = 100) as a pale yellow oil using 4a (11.7 mg, 94%
yield, 99% ee).
(R)-1-Phenyl-2-(4-(trifluoromethyl)phenyl)ethyl Acetate (5ab).
Obtained according to the general procedure (S/C = 100) as a pale
L
DOI: 10.1021/acs.joc.7b00710
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Article
yellow oil using 4h under 20 bar H2 (14.9 mg, 97% yield, 91% ee).
Alternatively, obtained using 0.1 mmol 1ab and 1 μmol 4h in DCE
(0.25 mL) under 4 bar H2 at 40 °C for 24 h (27.7 mg, 90% yield, 90%
borane (20 mg, 0.1 mmol) and Et3N (30 μL, 0.22 mmol) in toluene (2
mL) was added dropwise a solution of (S)-3,3′-di-tert-butyl-5,5′,6,6′-
tetramethyl-2,2′-bisphenoxyphosphorous chloride (41 mg, 0.1 mmol).
The mixture was stirred for 24 h and the resulting suspension was
evaporated, dissolved in Et2O, and filtered through a short pad of
neutral alumina. Alumina was washed with Et2O (2 × 5 mL), ethereal
phases collected and evaporated yielding 3g-BH3 as a white powder
20
1
ee). [α]D = +2.0° (c 0.8, CHCl3, 91% ee). H NMR (CDCl3, 400
MHz): δ = 7.52 (d, J(H,H) = 7.9 Hz, 2H), 7.33 (m, 5H), 7.23 (d,
J(H,H) = 8.2 Hz, 2H), 5.98 (m, 1H), 3.98 (m, 1H), 3.14 (m, 1H),
2.06 (s, 3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ = 170.0,
141.1, 139.5, 129.8 (2C), 128.9 (q, J(C,F) = 32 Hz), 128.5 (2C),
128.2, 126.5 (2C), 125.1 (q, J(C,F) = 4 Hz, 2C), 124.2 (q, J(C,F) =
272 Hz), 76.0, 42.7, 21.1 ppm. 19F{1H} NMR (CDCl3, 380 MHz): δ =
−62.4 ppm. IR (film): ν = 1743 (s, CO) cm−1. HRMS (ESI) m/z:
[M+Na]+ Calcd for C17H15O2F3Na 331.0916; Found 331.0915.
(R)-2-(4-Methoxyphenyl)-1-phenylethyl Acetate (5ac).54 Obtained
according to the general procedure (S/C = 100) as a pale yellow oil
using 4h under 20 bar H2 (12.1 mg, 90% yield, 77% ee). Alternatively,
obtained using 0.1 mmol 1ac and 1 μmol 4h in DCE (0.25 mL) under
4 bar H2 at 40 °C for 24 h (24.8 mg, 92% yield, 82% ee).
1
(49 mg, 88% yield). H NMR (C6D6, 500 MHz): δ = 7.29 (s, 1H),
7.21 (s, 1H), 4.15 (m, 1H), 3.91 (m, 1H), 2.23 (s, 3H), 2.07 (s, 3H),
1.98 (m, 1H), 1.86 (s, 3H), 1.81 (m, 1H), 1.70 (s, 3H), 1.59 (s, 9H),
1.58 (s, 9H), 0.93 (d, J(H,P) = 2.5 Hz, 9H), 0.91 (d, J(H,P) = 2.5 Hz,
9H) ppm (BH3 signal partially observed as a broad hump at 0.65
ppm). 31P{1H} NMR (C6D6, 162 MHz): δ = 126.3, 41.3 (bd, J(P,B) =
62 Hz) ppm. 13C{1H} NMR (C6D6, 125 MHz): δ = 146.2 (d, J(C,P) =
4 Hz), 146.2 (d, J(C,P) = 3 Hz), 138.2 (d, J(C,P) = 2 Hz), 137.4,
135.6, 134.9, 132.7, 132.6, 132.2 (d, J(C,P) = 5 Hz), 131.2 (d, J(C,P)
= 2 Hz), 129.1, 128.3, 62.9 (dd, J(C,P) = 9 Hz, J(C,P) = 5 Hz), 35.0,
34.9, 31.9 (d, J(C,P) = 8 Hz), 31.7 (d, J(C,P) = 8 Hz), 31.6 (d, J(C,P)
= 5 Hz), 31.3, 27.5 (d, J(C,P) = 16 Hz), 27.5 (d, J(C,P) = 16 Hz), 20.8
(d, J(C,P) = 25 Hz), 20.5, 20.4, 16.8, 16.5 ppm. HRMS (ESI) m/z: [M
+H]+ Calcd for C34H58O3BP2 587.3949; Found 587.3960.
(R)-2-(4-Phenoxyphenyl)-1-phenylethyl Acetate (5ad). Obtained
according to the general procedure (S/C = 100) as a pale yellow oil
using 4h under 20 bar H2 (15.1 mg, 91% yield, 88% ee). Alternatively,
obtained using 0.1 mmol 1ad and 1 μmol 4h in DCE (0.25 mL) under
20
4 bar H2 at 40 °C for 24 h (31.9 mg, 96% yield, 71% ee). [α]D
=
2-(Ditert-butylphosphinoethyl)-(S)-1,1′-(3,3′-ditert-butyl-
5,5′,6,6′-tetramethyl)biphen-2,2′-diyl Phosphite (3g). A mixture of
2-(di-tert-butylphosphinoethyl)-(S)-1,1′-(3,3′-di-tert-butyl-5,5′,6,6′-
tetramethyl)biphen-2,2′-diyl phosphite borane (20 mg, 0.03 mmol)
and 1,4-diazabicyclo[2.2.2]octane (18.4 mg, 0.16 mmol) in toluene (2
mL) was heated for 72 h at 70 °C. The resulting suspension was
evaporated, dissolved in Et2O, and filtered through a short pad of
neutral alumina. Alumina was washed with Et2O (2 × 5 mL), and the
ethereal phases collected and evaporated yielding 3g as a white foamy
+5.2° (c 1.0, CHCl3, 88% ee). 1H NMR (CDCl3, 400 MHz): δ = 7.35
(m, 7H), 7.10 (m, 3H), 7.01 (d, J(H,H) = 8.4 Hz, 2H), 6.92 (d,
J(H,H) = 8.4 Hz, 2H), 5.95 (m, 1H), 3.21 (m, 1H), 3.06 (m, 1H),
2.07 (s, 3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ = 170.2,
157.5, 155.9, 140.1, 132.1, 130.9 (2C), 129.8 (2C), 128.5 (2C), 128.1,
126.7 (2C), 123.2, 118.9 (2C), 118.8 (2C), 76.8, 42.4, 21.3 ppm. IR
(film): ν = 1739 (s, CO) cm−1. HRMS (ESI) m/z: [M+Na]+ Calcd
for C22H20O3Na 355.1305; Found 355.1298.
20
1
solid (16 mg, 89% yield). [α]D = +141° (c 0.1, THF). H NMR
(CD2Cl2, 500 MHz): δ = 7.18 (s, 1H), 7.16 (s, 1H), 3.66 (m, 1H),
3.51 (m, 1H), 2.25 (s, 3H), 2.24 (s, 3H), 1.81 (s, 3H), 1.75 (m, 4H),
1.58 (m, 1H), 1.47 (s, 9H), 1.43 (s, 9H), 1.03 (d, J(H,P) = 11.5 Hz,
9H), 0.93 (d, J(H,P) = 11.5 Hz, 9H) ppm. 31P{1H} NMR (CD2Cl2,
162 MHz): δ = 128.2, 18.1 ppm. 13C{1H} NMR (CD2Cl2, 125 MHz):
δ = 145.9 (d, J(C,P) = 4 Hz), 145.7 (d, J(C,P) = 2 Hz), 138.5 (d,
J(C,P) = 3 Hz), 137.3, 135.3 (d, J(C,P) = 1 Hz), 134.8 (d, J(C,P) = 1
Hz), 132.9 (d, J(C,P) = 1 Hz), 132.1 (d, J(C,P) = 1 Hz), 132.0 (d,
J(C,P) = 5 Hz), 130.9 (d, J(C,P) = 3 Hz), 128.5 (d, J(C,P) = 1 Hz),
128.1, 67.1 (d, J(C,P) = 50 Hz), 34.9, 34.9, 31.5 (d, J(C,P) = 5 Hz),
31.3, 31.2, 31.1 (d, J(C,P) = 10 Hz), 29.6 (d, J(C,P) = 6 Hz), 29.5 (d,
J(C,P) = 6 Hz), 24.8 (dd, J(C,P) = 22 Hz, J(C,P) = 2 Hz), 20.5, 20.5,
16.7, 16.5 ppm. HRMS (ESI) m/z: [M+H]+ Calcd for C34H55O3P2
573.3621; Found 573.3625.
(R)-1-Phenyl-2-(thiophen-3-yl)ethyl Acetate (5ae). Obtained
according to the general procedure (S/C = 100) as a pale yellow oil
20
using 4h under 20 bar H2 (11.3 mg, 92% yield, 79% ee). [α]D
=
+3.0° (c 1.0, CHCl3, 79% ee). 1H NMR (CDCl3, 400 MHz): δ = 7.30
(m, 5H), 7.20 (m, 1H), 6.89 (m, 1H), 6.84 (m, 1H), 5.93 (m, 1H),
3.24 (m, 1H), 3.10 (m, 1H), 2.05 (s, 3H) ppm. 13C{1H} NMR
(CDCl3, 100 MHz): δ = 170.3, 140.1, 137.3, 128.8, 128.5 (2C), 128.2,
126.7 (2C), 125.4, 122.5, 76.1, 37.4, 21.4 ppm. IR (film): ν = 1738 (s,
CO) cm−1. HRMS (ESI) m/z: [M+Na]+ Calcd for C14H14O2NaS
269.0607; Found 269.0608.
(R)-1-Phenyldecan-2-yl Acetate (5af). Obtained according to the
general procedure (S/C = 100) as a pale yellow oil using 4h (13.1 mg,
95% yield, 99% ee). [α]D20 = −1.7° (c 1.0, CHCl3, 99% ee). 1H NMR
(CDCl3, 400 MHz): δ = 7.31 (m, 2H), 7.23 (m, 3H), 5.10 (m, 1H),
2.86 (m, 2H), 2.01 (s, 3H), 1.55 (m, 2H), 1.30 (m, 12H), 0.90 (t,
J(H,H) = 7.1 Hz, 3H) ppm. 13C{1H} NMR (CDCl3, 100 MHz): δ =
170.7, 137.7, 129.4 (2C), 128.3 (2C), 126.4, 74.8, 40.6, 33.5, 31.8,
29.5, 29.4, 29.2, 25.4, 22.7, 21.2, 14.1 ppm. IR (film): ν = 1737 (s, C
O) cm−1. HRMS (ESI) m/z: [M+Na]+ Calcd for C18H28O2Na
299.1982; Found 299.1977.
[Rh(COD)(3g)]BF4 (4g). Over a stirred solution of bis(1,5-
cyclooctadiene)rhodium(I) tetrafluoroborate (17 mg, 0.042 mmol)
in dichlorometane (2 mL) was added 2-(di-tert-butylphosphinoethyl)-
(S)-1,1′-(3,3′-di-tert-butyl-5,5′,6,6′-tetramethyl)biphen-2,2′-diyl phos-
phite (24.5 mg, 0.042 mmol) and the mixture obtained stirred for 4 h.
The resulting suspension was concentrated to a fourth of the volume
and precipitated with Et2O, washed with additional Et2O (3 × 2 mL),
and the resulting solution evaporated under vacuum to yield 4g as an
Synthesis and Characterization of [Rh(COD)(3g)]BF4 (4g). Ditert-
butyl-(2-hydroxyethyl)-phosphine Borane. Over a stirring solution of
di-tert-butylphosphine borane (100 mg, 0.62 mmol) and 2-
bromoethanol (78 mg, 0.62 mmol) in THF (5 mL), n-butyllithium
(0.78 mL, 1.24 mmol) was added dropwise and the mixture stirred for
2 h. Excess of NH4Cl and deoxigenated water (1 mL) were then added
and the mixture stirred for 1 h. The solvent was then evaporated with
vacuum and the resulting residue dried with toluene (2 × 5 mL) under
vacuum, then disolved in Et2O and filtered in a short pad of Celite.
Evaporation of Et2O in vacuum gave the desired product as a whitish
oil (48 mg, 38% yield). 1H NMR (C6D6, 500 MHz): δ = 3.83 (m, 2H),
2.43 (br, 1H), 1.50 (m, 2H), 0.97 (s, 9H), 0.94 (s, 9H) ppm (BH3
signal partially observed as broad humps at 1.42 and 1.22 ppm).
31P{1H} NMR (C6D6, 162 MHz): δ = 39.9 (q, J(P,B) = 56 Hz) ppm.
1
orange solid (32 mg, 89% yield). H NMR (CD2Cl2, 400 MHz): δ =
7.30 (s, 1H), 7.21 (s, 1H), 6.24 (m, 1H), 5.99 (m, 1H), 5.54 (m, 1H),
4.57 (m, 1H), 4.39 (m, 1H), 3.45 (m, 1H), 2.44 (m, 2H), 2.34 (m,
2H), 2.30 (s, 3H), 2.24 (m, 7H), 2.10 (m, 1H), 2.01 (m, 1H), 1.80 (s,
3H), 1.69 (s, 3H), 1.62 (s, 9H), 1.59 (d, J(H,P) = 13.6 Hz, 9H), 1.38
(s, 9H), 1.26 (d, J(H,P) = 13.1 Hz, 9H) ppm. 31P{1H} NMR (CD2Cl2,
162 MHz): δ = 121.3 (dd, J(P,Rh) = 250 Hz, J(P,P) = 48 Hz), 23.9
(dd, J(P,Rh) = 134 Hz, J(P,P) = 48 Hz) ppm. 13C{1H} NMR
(CD2Cl2, 100 MHz): δ = 145.5 (d, J(C,P) = 8 Hz), 144.9 (d, J(C,P) =
14 Hz), 137.5 (d, J(C,P) = 2 Hz), 137.4 (d, J(C,P) = 4 Hz), 136.7 (d,
J(C,P) = 1 Hz), 136.0 (d, J(C,P) = 2 Hz), 134.5 (d, J(C,P) = 2 Hz),
134.4 (d, J(C,P) = 2 Hz), 129.5 (d, J(C,P) = 2 Hz), 129.5 (d, J(C,P) =
2 Hz), 128.9, 128.8, 114.2 (dd, J(C,P) = 11 Hz, J(C,Rh) = 5 Hz),
101.8 (dd, J(C,P) = 14 Hz, J(C,Rh) = 5 Hz), 99.3 (dd, J(C,P) = 10
Hz, J(C,Rh) = 4 Hz), 84.0 (dd, J(C,P) = 13 Hz, J(C,Rh) = 7 Hz), 65.2,
39.7 (d, J(C,P) = 14 Hz), 38.9 (d, J(C,P) = 11 Hz), 35.2, 35.0, 32.8,
32.2, 31.8, 31.6 (d, J(C,P) = 5 Hz), 30.1, 30.1, 29.9 (d, J(C,P) = 4 Hz),
13C{1H} NMR (C6D6, 125 MHz): δ = 59.4, 31.8 (d, J(C,P) = 27 Hz,
2C), 27.6 (6C), 21.6 (d, J(C,P) = 27 Hz) ppm. HRMS (ESI) m/z: [M
+Na]+ Calcd for C10H26OBNaP 227.1707; Found 227.1708.
2-(Ditert-butylphosphinoethyl)-(S)-1,1′-(3,3′-ditert-butyl-
5,5′,6,6′-tetramethyl)biphen-2,2′-diyl phosphite Borane (3g-BH3).
Over a stirring solution of di-tert-butyl-(2-hydroxyethyl)-phosphine
M
DOI: 10.1021/acs.joc.7b00710
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The Journal of Organic Chemistry
Article
27.8, 20.5, 20.3, 20.2 (dd, J(P,P) = 20 Hz, J(P,P) = 7 Hz), 16.6, 16.3
ppm. Elem Anal. Calcd (%) for C42H66BF4O3P2Rh C 57.94, H 7.64;
Found C 57.51, H 7.44.
Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508−6509. (d) Xu, Y.;
Alcock, N. W.; Clarkson, G. J.; Docherty, G.; Woodward, G.; Wills, M.
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Feringa, B. L.; de Vries, J. G. Adv. Synth. Catal. 2010, 352, 2621−2628.
(h) Li, Y.; Zhou, Y.; Shi, Q.; Ding, K.; Noyori, R.; Sandoval, C. A. Adv.
Synth. Catal. 2011, 353, 495−500. (i) Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00710.
■
S
Selected NMR spectra and chromatograms (PDF)
AUTHOR INFORMATION
■
(5) (a) Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei, Y.;
Corresponding Authors
*E-mail: vcm@uniovi.es.
*E-mail: pizzano@iiq.csic.es.
Muniz, K.; Noyori, R. J. Am. Chem. Soc. 2005, 127, 8288−8289.
̃
(b) Yamamura, T.; Nakatsuka, H.; Tanaka, S.; Kitamura, M. Angew.
Chem., Int. Ed. 2013, 52, 9313−9315.
(6) (a) Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem.,
Int. Ed. 1998, 37, 1100−1103. (b) Li, W.; Hou, G.; Wang, C.; Jiang, Y.;
Zhang, X. Chem. Commun. 2010, 46, 3979−3981. (c) Matsumura, K.;
Arai, N.; Hori, K.; Saito, T.; Sayo, N.; Ohkuma, T. J. Am. Chem. Soc.
2011, 133, 10696−10699.
ORCID
Victorio Cadierno: 0000-0001-6334-2815
Antonio Pizzano: 0000-0002-9269-4817
Present Address
§Repsol Technology Center, 28935 Mos
́
toles, Madrid, Spain.
(7) Alternatively, some examples of highly enantioselective transfer
hydrogenations of dialkyl ketones have been described: (a) Reetz, M.
T.; Li, X. J. Am. Chem. Soc. 2006, 128, 1044−1045. (b) Schlatter, A.;
Woggon, W.-D. Adv. Synth. Catal. 2008, 350, 995−1000. (c) Li, J.;
Tang, Y.; Wang, Q.; Li, X.; Cun, L.; Zhang, X.; Zhu, J.; Li, L.; Deng, J.
J. Am. Chem. Soc. 2012, 134, 18522−18525.
(8) (a) Abdur-Rashid, K.; Amoroso, D.; Guo, R.; Chen, X.; Sui-Seng,
C.; Tsang, C.-W.; Jia, W. Kanata Chemical Technologies, WO
2009055912 A1. (b) Lagaditis, P. O.; Sues, P. E.; Sonnenberg, J. F.;
Wan, K. Y.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2014, 136,
1367−1380.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully thank Ministerio de Economia, Industria y
Competitividad of Spain (Grants CTQ2013-42501-P,
CTQ2013-40591-P, CTQ2016-75193-P, CTQ2016-75986-P,
and CTQ2016-81797-REDC; AEI/FEDER, UE) and the
Regional Government of Asturias (Project GRUPIN14-006)
for financial support.
(9) For a highly enantioselective transfer hydrogenation of a benzylic
ketone, see: Wu, X.; Li, X.; Zanotti-Gerosa, A.; Pettman, A.; Liu, J.;
Mills, A. J.; Xiao, J. Chem. - Eur. J. 2008, 14, 2209−2222.
(10) For some synthetic applications of alkanols and homobenzylic
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