Deoxycholic acid-derived biaryl phosphites as versatile and enantioselective ligands in the rhodium-catalyzed conjugate addition of arylboronic acids to nitroalkenes

Article abstract of DOI:10.1002/adsc.201300619

A highly enantioselective conjugate addition of arylboronic acids to cyclic as well as acyclic aromatic and aliphatic nitroalkenes is presented. The rhodium complexes obtained from deoxycholic acid-derived binaphthyl and flexible biphenyl phosphites showed good activity as well as very high enantioselectivity (ee up to 99%) in the conjugated addition even in the presence of challenging substrates such as 1-nitrocyclohexene or aliphatic acyclic nitroalkenes. Copyright

Full text of DOI:10.1002/adsc.201300619

FULL PAPERS
DOI: 10.1002/adsc.201300619
Deoxycholic Acid-Derived Biaryl Phosphites as Versatile and
Enantioselective Ligands in the Rhodium-Catalyzed Conjugate
Addition of Arylboronic Acids to Nitroalkenes
Varsha R. Jumdea and Anna Iulianoa,*
a
Universitꢀ di Pisa – Dipartimento di Chimica e Chimica Industriale, via Risorgimento 35, 56126 Pisa, Italy
Fax : (+39)-050-221-9260; phone: (+39)-050-221-9231; e-mail: iuliano@dcci.unipi.it
Received: July 16, 2013; Revised: September 16, 2013; Published online: November 13, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300619.
Abstract: A highly enantioselective conjugate addi- even in the presence of challenging substrates such
tion of arylboronic acids to cyclic as well as acyclic as 1-nitrocyclohexene or aliphatic acyclic nitro-
aromatic and aliphatic nitroalkenes is presented. The
rhodium complexes obtained from deoxycholic acid-
derived binaphthyl and flexible biphenyl phosphites
ACHTUNGTRENNaUNG lkenes.
showed good activity as well as very high enantiose- Keywords: asymmetric catalysis; conjugate addition;
lectivity (ee up to 99%) in the conjugated addition nitroalkenes; phosphites; rhodium
Introduction
catalyzed conjugate additions of organoboronic acids
to nitroalkenes, likely because of the difficulty in con-
In recent years the use of transition metal-catalyzed trolling the reaction stereoselectivity.
asymmetric reactions has been an important tool for
Since Hayashiꢁs pioneering work on the asymmetric
the enantioselective carbon-carbon and carbon- addition to cyclic nitroalkenes using a rhodium/binap
heteroACHTUNGTRENNUNG
atom bond formation. Among them, the rhodi- catalyst was reported in 2000,[7] little progress has
um-catalyzed asymmetric conjugate addition of orga- been made in the reaction of cyclic nitroalkenes,[8] the
noboronic acids to electron-poor alkenes, pioneered research efforts focusing more on the conjugate addi-
by Miyaura, Hayashi, and co-workers,[1] has been es- tion to acyclic nitroalkenes, where only medium-level
tablished as one of the most powerful and convenient enantioselectivities (<50% ee) were obtained by
procedures for the enantioselective synthesis of b-sub- using phosphorus ligands.[9] More recently, high levels
stituted functionalized compounds. In particular, ex- of enantioselectivity have been reached in the conju-
cellent results were achieved in the addition to a,b- gate addition of arylboronic acids to acyclic nitroalk-
unsaturated carbonyl compounds[2] and related Mi-
ACHTUNGTRENNUNG
chael acceptors.[3]
Among the Michael acceptors, nitroalkenes are inductions have been observed in the conjugate addi-
good substrates for the rhodium-catalyzed asymmetric tion of arylboronic acids to dihydronitronaphthalenes
addition of organoboronic acids, due to the presence in the presence of a monodentate phosphoramidite
of the highly electron-withdrawing nitro group, which ligand.[13] However, despite the most recent achieve-
makes them good electrophilic acceptors. Moreover, ments in the reaction, efficient catalytic systems, pre-
the corresponding addition products can serve as ver- pared from readily available ligands and acting
satile substrates, which can undergo various transfor- toward a broad range of substrates are still lacking.
mations,[4] making optically active nitroalkanes useful
Quite recently we developed deoxycholic acid-de-
chiral building blocks in the synthesis of pharmaco- rived tropos and atropoisomeric biaryl monophos-
logically interesting compounds as well as natural phites, which have proven their effectiveness as chiral
products.[5] Owing to this behaviour, the conjugate ad- ligands in the Rh-catalyzed asymmetric conjugate ad-
dition products to nitroalkenes have been described ditions of arylboronic acids to cyclic enones.[14] These
as “synthetic chameleons’’.[6] However, despite the phosphites represent really appealing ligands because
great synthetic importance of optically active nitro they are readily synthesized starting from economic
compounds, there are relatively few reports on Rh- materials with simple experimental procedures and
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Varsha R. Jumde and Anna Iuliano
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obtained (entry 2) and no reaction was observed
using LiF under anhydrous conditions even at higher
temperatures (entry 3): in line with most 1,4-addition
processes, the outcome of this reaction suggests that
a small amount of water is essential for good conver-
sion.[10]
These disappointing results were attributed to side
reactions which the just formed 2-phenylnitrocyclo-
hexane 7a undergoes in the reaction medium, likely
promoted by the base. In order to suppress these side
reactions it was judged essential to isolate as much as
possible the reaction product from the basic medium
and this could be easily performed by using a reaction
solvent immiscible with water, such as toluene or di-
chloromethane. Hence by using aqueous KOH as
a well performing base, the reactions were carried out
at reflux of CH2Cl2 and at 608C (entries 4 and 5).
Using dichloromethane, we observed, after long reac-
tion times, 47% conversion and comparable yield of
the product, but poor diastereomeric ratio (cis/trans
42:58) and moderate ee (55% for cis); when toluene
was used as solvent, 47% yield was obtained after
24 h, along with an increase in distereoselectivity
(81:19), while the enantioselectivity remained un-
changed.
Figure 1. Structures of the phosphite ligands.
By lowering the temperature to 458C both the con-
are quite stable. In view of these characteristics and version and cis:trans ratio were improved (entry 6),
considering their effectiveness as Rh ligands in differ- but the ee remained unaffected. On further lowering
ent asymmetric reactions,[15] we became interested in of the temperature to room temperature (entry 7),
checking their use in the asymmetric conjugate addi- the diastereoselectivity remained almost same, with-
tion of arylboronic acids to nitroalkenes having differ- out any considerable change in the ee, suggesting that
ent structures. Herein we report the results obtained ee is not very sensitive to temperature change. But
in the Rh-catalyzed conjugate addition of arylboronic yield was differently affected on lowering the temper-
acids to cyclic as well as acyclic aliphatic and aromatic ature (compare entries 5, 6 and 7). These results can
nitroalkenes using the deoxycholic acid-derived be explained taking into account that at higher tem-
monophosphites 1–4 as chiral ligands (Figure 1.
perature in the presence of water under basic condi-
tions, as Hayashi reported, the main side reaction is
the proto-de-boronation of the boronic acid, which
consumes the reagent: this reaction is slowed down at
lower temperature.[2b] However, to obtain acceptable
Results and Discussion
The results concerning the use of the chiral phosphite conversion at room temperature, about the double
ligands 1–4 in the Rh-catalyzed conjugate addition of period of time was required and yield dropped down
arylboronic acid to 1-nitrocyclohexene are reported in to 35%. The best compromise was reached by work-
Table 1. The effect of different reaction parameters ing at 458C, where the hydrolysis of phenylboronic
was investigated using 1 as ligand in the conjugate ad- acid can be reduced to such an extent that it is not
dition of phenylboronic acid and the reactions were competitive with the main conjugate addition reac-
carried out until complete substrate conversion or tion, so that a large excess of arylboronic acid is not
when it did not proceed further.
The reaction initially was carried out using as Rh and better conversion can be obtained in shorter
source [RhCl(C2H4)2]2 with 1M KOH (0.5 equiv.), in time.
1,4-dioxane (entry 1) at 508C, under the same reac- Finally, to check if a monosubstituted Rh complex
necessary to obtain satisfactory yields of product 7a,
ACHTUNGTRENNUNG
tion conditions used in the conjugate addition of phe- can work also in this reaction as in the conjugate ad-
nylboronic acid to cyclohexenone.[14] However, the dition to cyclohexenone[14] a reaction was carried out
result was disappointing: after 60 h, 67% conversion by preparing the monosubstituted catalytic precursor
was obtained but the yield was so low that no product {by stirring the [RhClACTHNUGTRNE(UNG C2H4)2]2 and 1 at L*/Rh=
was isolated. Changing the base did not help the reac- 1 molar ratio in toluene under nitrogen for 24 h at
tion to proceed: with K2CO3, very low conversion was room temperature)[14] (entry 8): a detrimental effect
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Deoxycholic Acid-Derived Biaryl Phosphites as Versatile and Enantioselective Ligands
Table 1. Rh-catalyzed asymmetric conjugate addition of arylboronic acids to 1-nitrocyclohexene.[a]
Entry L* Ar
Base (equiv.) Solvent
T [8C] t [h] Conv. (Yield) [%][b] cis:trans[c] ee (cis) [%][d]
1
2
3
4
5
6
1
1
1
1
1
1
1
1
2
2
2
2
3
4
3
2
3
2
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
KOH (0.5)
K2CO3 (0.5)
LiF (10)[g]
KOH (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.25)
KOH (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.5)
dioxane 50
dioxane 60
dioxane reflux
60
24
63
97
24
27
43
30
25
25
23
24
51
51
37
37
45
27
70
67[f]
<10
Nr
–
–
–
–
–
–
DCM
reflux
60
4.5
r.t.
45
45
45
45
45
45
45
45
45
45
45
45
47 (34) 7a
59 (47) 7a
67 (50) 7a
41 (35) 7a
15 (<10) 7a
63 (53) 7a
22 (17) 7a
80 (68) 7a
79 (70) 7a
68 (67) 7a
37 (36) 7a
25[k] 7b
42/58
81/19
87/13
88/12
73/27
88/12
77/23
86/14
80/20
87/13
78/22
80/20
78/22
86/14
85:15
64:36
55 (R,R)[e]
55 (R,R)[e]
55 (R,R)[e]
52 (R,R)[e]
42 (R,R)[e]
83 (R,R)[e]
19 (R,R)[e]
79 (R,R)[e]
75 (R,R)[e]
96 (R,R)[e]
71 (S,S)[e]
94
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
7
8[h]
9
10
11[i]
12[i,j]
13[i]
14[i]
15[i]
16[i]
17[i]
18[i]
19[i]
3-MeOC6H4 KOH (0.5)
3-MeOC6H4 KOH (0.5)
3-MeOC6H4 KOH (0.5)
4-MeOC6H4 KOH (0.5)
78[k] 7b
65
96
70
88
20[k] 7c
40[k] 7c
4-CF3C6H4
KOH (0.5)
23[k] 7d
[a]
The reaction was carried out with nitroalkene 5 (1 mmol), arylboronic acid 6 (2 equiv.), base (0.5 mmol) in a given solvent
system (2.5:0.25 mL sol:H2O) at the given temperature in the presence of 1.5 mol% of the catalyst generated from
ACHTUNGTRENNUNG[RhClACHTUNGTRENNUNG(C2H4)2]2 and ligand (Rh:L*=1:2) unless otherwise noted.
[b]
[c]
[d]
Conversion into product determined by GC, yield of isolated product.
1
Determined by H NMR.
Determined by HPLC analysis with chiral stationary phase columns (Lux-1, n-hexane:2-propanol 92:8, l=220 nm, flow
rate 1 mLminÀ1, temperature 208C).
Absolute configuration, assigned by comparing the sign of optical rotation with the literature data.
The yield was very low; no product was isolated.
Anhydrous conditions were used.
[e]
[f]
[g]
[h]
[i]
Rh:L* 1:1.
Toluene:H2O 1:0.1 mL.
5 mol% of catalyst.
Only the yield is reported. Nr=no reaction
[j]
[k]
on yield was observed together with a significant drop of both yield and ee of the product, whereas the use
in ee, and diastereoselectivity. of a lower amount of solvent while maintaining the
Using the optimized reaction conditions, that is, 10:1 ratio toluene:H2O as before, to our delight im-
458C, toluene as solvent with L*/Rh=2 molar ratio, proved the yield from 53% to 68%, although a minor
the activity and enantioselectivity of complexes of the drop in the ee was observed. By contrast no improve-
ligands 2–4 in the conjugate addition of phenylboron- ment of the outcome of the reaction was observed on
ic acid to 5 were checked. The cis product is obtained increasing the catalyst loading (entry 12). Therefore,
as major diastereomer in all the cases. Phosphite 2 activity and enantioselectivity of the catalysts derived
having phenyl groups at the 5,5’ positions of the bi- from the diastereomeric binaphthyl phosphites 3 and
phenyl moiety was a better performing ligand as far 4 were checked using these newly optimized reaction
as enantioselectivity was concerned, giving 83% ee conditions. In the presence of phosphite 3 possessing
(entry 9). Using this phosphite the effect of reducing an (S) configured binaphthyl moiety, 67% yield and
the amount of base (entry 10) as well as of increasing excellent ee of the cis product 7a were obtained in
the concentration of the reaction mixture (entry 11) 51 h (entry 13), with a cis:trans ratio 87:13. On the
or the catalyst loading (entry 12) were checked. The other hand, the diastereomeric ligand 4, having an
use of half the amount of base resulted in a lowering (R) configured binaphthyl moiety, in 51 h gave only
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36% of yield and 71% ee, with a cis:trans ratio 78:22 rise to low conversion. Timely added extra boronic
(entry 14), showing the presence of a strong matched/ acid in the reaction did not help to improve the con-
mismatched effect between the cholestanic backbone version level. Excellent enantioselectivity was ob-
and the biaryl moiety. It is worthy of note that with tained (entry 17) when 3 was used, albeit the yield
the atropoisomeric phosphites longer reaction times was very low.
were required, maybe due to their bulkiness. The ab-
The optimized reaction conditions for the conjugate
solute configuration of the prevailing enantiomer of addition of arylboronic acids to nitrocyclohexene
the cis product 7a obtained with 3, bearing an (S) were slightly modified for the reaction with acyclic ar-
configured binaphthyl moiety, was cis-(R,R), whereas omatic nitroalkenes, such as nitrostyrene 8a and its
the binaphthyl phosphite 4, possessing an (R) config- analogues, and the results are collected in Table 2. All
ured binaphthyl moiety, afforded a prevalence of cis- the reactions were carried out until GC showed com-
(S,S) product. This suggests that the sense of asym- plete conversion of the substrate or when the reaction
metric induction is determined by the absolute config- did not proceed further.
uration of the biaryl moiety of the phosphite, as al-
At first, phosphite 3, the most enantioselective
ready observed in other reactions.[14b,16] Nevertheless ligand for the arylation of nitrocyclohexene, was used
the role of the cholestanic moiety is fundamental to in the asymmetric conjugate addition of p-methoxy-
the asymmetric induction: the strong matched-mis- phenylboronic acid 6c to nitrostyrene 8a, obtaining
matched effect is due to the presence of this moiety. the product 9ac in high yield and 91% ee in long reac-
In addition, we have already demonstrated that when tion time (entry 1). When the catalytic complex of
the deoxycholic acid is replaced by the achiral cyclo- tropos phosphite 2, which had proven to be the most
hexanol moiety the resulting ligand was much less active, was tested for the same reaction, high yield of
enantioselective.[16]
9ac was obtained in only 6 h, even if the ee was lower
Catalysts obtained with phosphites 1 and 2, bearing and, surprisingly, its absolute configuration was the
a flexible biphenyl moiety, gave rise to the prevailing opposite (entry 2), unlike what was observed in the
formation of the cis-(R,R) product, with good ees, reaction of nitrocyclohexene. However, when phos-
albeit lower than those obtained with the catalyst de- phite 4, diastereomer of 3, was used as chiral ligand,
rived from 3. This suggests that although both rapidly we were pleased to observe that 9ac was obtained in
interconverting diastereomeric complexes are formed high yield and excellent ee in only 6 h (entry 3): the
in a 1:1 ratio,[14b] the most active and enantioselective absolute configuration of 9ac was the same as that of
is that one in which the biphenyl moieties of the li- the product obtained with the tropos phosphite. These
gands assume the P sense of twist [corresponding to results point out the strong matched effect on the out-
the (S)-configuration] and determines the stereo- come of the reaction of the combination (R)-binaph-
chemical outcome of the reaction.
thylphosphite/deoxycholic acid of phosphite 4; in ad-
Afterwards, the general applicability of the reaction dition, given that the opposite configuration of the
was explored under the optimized reaction conditions, product was obtained using the diastereomeric phos-
by performing the arylation of 1-nitrocyclohexene phites 3 and 4, again the sense of asymmetric induc-
with different arylboronic acids in the presence of tion of the ligand must depend on the absolute config-
phosphite 3, which gave the highest ees, and phosphite uration of the binaphthyl moiety. The same trend was
2, which gave the highest conversions.
observed in the conjugate addition of other arylbor-
The reaction promoted by 3 gave lower yield of the onic acids to nitrostyrene (entries 4–9 and 12–14) and
products, suggesting that the presence of the bi- also in the conjugate addition to different aromatic ni-
naphthyl moiety makes the catalytic active species troalkenes (entries 17–19) where the tropos phospite
more crowded, so lowering the turnover of the reac- 2 gave a catalyst showing comparable activity to the
tion; as a matter of fact, when the less reactive 4-tri- catalyst obtained from 4 and enantioselectivity in line
fluoromethylphenylboronic acid was used, the conju- or superior than the catalyst obtained from mis-
gated addition took place with good enantioselectivity matched phosphite 3. These results are different from
only in the presence of 2 (entry 19). Good yield of the those obtained in the conjugate addition to nitrocy-
product was obtained with 3-methoxyphenylboronic clohexene, where ligand 3 gave the most enantioselec-
acid using the tropos phosphite ligand 2, but the ee tive rhodium complex. This behaviour can be ex-
was only 65%; on the other hand in the presence of 3 plained by considering that a substrate-dependent
as ligand, even though the yield was low, the product asymmetric activation takes place. This means that
was obtained in 94% ee. Higher ee, but only 40% when the substrate is nitrocyclohexene the faster cata-
yield were achieved with 4-methoxyphenylboronic lytic cycle is that one involving the Rh complex of
acid in the presence of tropos phosphite ligand 2 ligand 3. By contrast when the substrate is nitrostyr-
(entry 18), suggesting that in this case the competitive ene the faster catalytic cycle is the one taking place
proto-de-boronation reaction is faster and most of the with the Rh complex of 4. It must be considered that
boronic acid was consumed in the side reaction giving when the tropos phosphite 2 is used as Rh ligand two
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Deoxycholic Acid-Derived Biaryl Phosphites as Versatile and Enantioselective Ligands
Table 2. Rh-catalyzed asymmetric conjugate addition of arylboronic acids to aromatic nitroalkenes.[a]
Entry
Ligand
Ar’
Ar
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3
2
4
3
2
4
3
2
4
3
4
3
2
4
2
4
3
2
4
2
4
2
4
2
4
2
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
3-ClC6H4
3-ClC6H4
4-CF3C6H4
4-CF3C6H4
4-CF3C6H4
2-Np
2-Np
2-Np
2-Np
2-Np
Ph
Ph
4-MeOC6H4
4-MeOC6H4
Ph
Ph
Ph
46
6
6
40
13
6
38
6
6
45
6
48
19
21
24
6
27
6
6
18
5
21
4
6
3
6
5
92 (9ac)
87 (9ac)
91 (9ac)
89 (9ab)
84 (9ab)
95 (9ab)
79 (9ae)
63 (9ae)
98 (9ae)
53 (9af)
92 (9af)
25 (9ad)
60 (9ad)
86 (9ad)
93 (9ag)
89 (9ag)
60 (9bg)
86 (9bg)
82 (9bg)
60 (9ca)
89 (9ca)
91 (9dc)
90 (9dc)
89 (9ba)
87 (9ba)
45 (9ea)
95 (9ea)
91 (+)[d]
81 (À)[d]
97 (À)[d]
83 (À)[d]
85 (+)[d]
94 (+)[d]
85 (À)[d]
80 (+)[d]
97 (+)[d]
87 (À)[d]
99 (+)[d]
83 (À)[d]
90 (+)[d]
97 (+)[d]
88 (+)[d]
99 (+)[d]
61 (À)[d]
90 (+)[d]
99 (+)[d]
88 (À)[d]
97 (À)[d]
84 (À)[d]
97 (À)[d]
82 (+)[d]
98 (+)[d]
82 (+)[d]
98 (+)[d]
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
2-naphthyl
2-naphthyl
4-MeOC6H4
4-MeOC6H4
4-FC6H4
4-FC6H4
Ph
[a]
The reactions were carried out with nitroalkene (1 mmol), arylboronic acid (2 equiv.) KOH (0.1 equiv.) in 2:0.2 mL tolue-
ne:H2O at 458C in the presence of 1.5 mol% of the catalyst generated by reacting [RhCl
1:2) at room temperature for 30 min.
Yield of the isolated product.
Determined by HPLC analysis on chiral stationary phase (see the Supporting Information).
Sign of the optical rotation of the prevailing enantiomer.
ACHTUNGNERTN(UNG C2H4)2]2 and ligand (Rh:L*=
[b]
[c]
[d]
diastereoisomeric Rh complexes are formed, which
The opposite situation was found in the arylation of
are in fast equilibrium between themselves and in nitrocyclohexene, where 3, possessing an (S)-bi-
a 1:1 molar ratio.[14] In the case of nitrostyrene aryla- naphthyl phosphite moiety gives rise to the most
tion, the diastereomeric complex, where the biaryl active and enantioselective catalyst. In this case, when
moieties are twisted in M sense [corresponding to (R) the tropos ligand is used, the diastereomeric complex
absolute configuration], gives the most active catalyst, in which the biaryl moieties are twisted in the P sense
which enters in the fastest catalytic cycle. As a conse- affords the most active catalyst. It, in turn, enters in
quence, the equilibrium between the two diastereo- the fastest catalytic cycle, so that the equilibrium is
meric complexes is shifted towards the one giving the continuously shifted toward this: in this case, the
most active catalyst, so that the product is obtained product is obtained through the catalytic cycle II.
by means of the catalytic cycle I (Figure 2). Therefore
Taking into account only the formation of homochi-
the absolute configuration of the product is the same ral Rh complexes should appear as an oversimplifica-
as that obtained using the most active and enantiose- tion of the tropos equilibria, which can give rise also
lective atropoisomeric phosphite 4.
to the formation of heterochiral Rh complexes (i.e.,
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were present on the nitroalkene or on the arylboronic
acid. This effect is more evident when the tropos
phosphite 2 and the mismatched phosphite 3 were
used, whereas the phosphite 4 gave an Rh catalyst
showing high activity throughout.
By contrast, a dependence of the enantioselectivity
of the reaction on the electronic character of the ni-
troalkenes cannot be found, as also observed with
other kinds of ligands reported in the literature.[10,11]
For instance, in the reaction of p-methoxynitrostyrene
and p-fluoronitrostyrene almost the same ees were ob-
tained (entries 25 and 27). The ee values were excel-
lent, ranging from 94 to 99%, in all the reactions cata-
lyzed by the Rh complex of 4, superior to those ob-
served with the best performing ligands reported in
the literature.[10–12] It is worth of note that the excel-
lent ees obtained with this ligand, independently of
the nature of both nitroalkene and arylboronic acid,
allowed us to obtain both the enantiomers of the
same products almost optically pure, simply by ex-
changing the aryl groups of alkene and organometal-
lic reagent (entries 3 and 25, 19 and 23).
The excellent results obtained in the conjugate ad-
dition of arylboronic acids to acyclic nitroalkene
prompted us to extend the reaction to some more
challenging substrates such as aliphatic and hetero-
AHCTUNGTREGUNaNN romatic acyclic nitroalkenes: Table 3 reports on
these results.
In line with the results obtained with aromatic ni-
troalkenes, the reaction of 3-methyl-1-nitrobutene,
10a, with phenylboronic acid, was fast and highly
Figure 2. Catalytic cycles with tropos Rh-complexes (for the
sake of simplicity the cis-trans equilibria are not shown; S is
solvent).
having both M and P twisted ligands). However the enantioselective, when phosphite 4 was used as chiral
high ees obtained with tropos ligands suggest that ligand (entry 1), slower and less enantioselective
even if the heterochiral complexes are formed their when both the diastereomeric 3 and the tropos phos-
activity must be very low, so that their formation can phite 2 were employed (entries 2 and 3): again, a de-
be reasonably neglected.
pendence of the absolute configuration of the prevail-
The catalyst obtained from phosphite 4 gave always ing enantiomer on the stereochemistry of the biaryl
fast reactions (almost complete after about 6 h) with moiety was observed (entries 2 and 3). The matched-
excellent yields of the products.
mismatched effect between cholestanic and binaphth-
It was observed that when p-methoxyphenylboronic yl moieties of phosphites 3 and 4 was more pro-
acid and 2-naphthylboronic acid, which are prone to nounced in the arylation of nitroalkene 10b, where no
give, under the reaction conditions, proto-de-borona- reaction was observed in the presence of 3 (entry 5),
tion and homocoupling, were used, the addition of an whereas 4 gave a high yield of product 11ba, which
extra equivalent of boronic acid in the corresponding was obtained in excellent ee (entry 4). Surprisingly,
reactions promoted by phosphite 2 or 3 provided the Rh complex of tropos ligand 2 was unable to cata-
good yields of the products (up to 93%). By contrast, lyze the reaction (entry 6), whereas tropos phosphite
when phosphite 4 was used as ligand for the reaction 1, having a less crowded structure, gave an Rh cata-
a high yield of the product (up to 91%) was obtained lyst that was active and enantioselective (entry 7).
in 6 h of reaction, so that it was not necessary to add The results obtained in the arylation of the heteroaro-
extra equivalents of boronic acid (entries 3, 16, 19, matic nitroalkene were comparable to those observed
23).
with the aromatic substrates: the Rh complexes of
As a general trend, the presence of electron-with- both phosphites 2 and 4 gave high yields of optically
drawing substituents on the aromatic ring of the nitro- active product in good to excellent ees (entries 12 and
alkene or on the arylboronic acid had a slightly nega- 13). The Rh complex of ligand 4 gave very good re-
tive impact on the conversion of the substrates (en- sults, as far as both yield and ee were concerned, in
tries 10–14 and 26), whereas the conjugate addition the arylation of the three nitroalkenes also on chang-
worked better when electron-donating substituents ing the arylboronic acid structure (entries 14–16):
3480
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Adv. Synth. Catal. 2013, 355, 3475 – 3483

Deoxycholic Acid-Derived Biaryl Phosphites as Versatile and Enantioselective Ligands
Table 3. Asymmetric conjugated addition of arylboronic acids to aliphatic and heteroaromatic nitroalkenes.[a]
Entry
Ligand
R
Ar
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4
3
2
4
3
2
1
4
3
2
1
4
2
4
4
4
i-Pr
i-Pr
i-Pr
c-C6H11
c-C6H11
c-C6H11
c-C6H11
Pr
Pr
Pr
Pr
2-thienyl
2-thienyl
2-thienyl
c-C6H11
i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4
99 (11aa)
83 (11aa)
69 (11aa)
91 (11ba)
Nr
Nr
95 (11ba)
Nr
78 (11ca)
50 (11ca)
97 (11ca)
98 (11dc)
98 (11dc)
73 (11de)
79 (11bc)
88 (11ac)
96 (À)[d]
78 (+)[d]
68 (À)[d]
91 (À)[d]
Nd
28
21
4
45
47
6
45
23
24
5
4
4
18
4
7
Nd
82 (À)[d]
Nd
9
Ph
Ph
Ph
81 (+)[d]
45 (À)[d]
27 (À)[d]
98 (À)[d]
88 (À)[d]
95 (+)[d]
89 (À)[d]
96 (À)[d]
10
11
12
13
14
15
16
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
[a]
The reactions were carried out with nitroalkene (1 mmol), arylboronic acid (2 equiv.), KOH (0.1 equiv.) in 2:0.2 mL tolu-
ene: H2O at 458C in the presence of 1.5 mol% of the catalyst generated by reacting [RhCl
1:2) at room temperature for 30 min.
Yield of isolated product.
Determined by HPLC analysis on a chiral stationary phase (see the Supporting Information).
Sign of the optical rotation of the prevailing enantiomer.
ACHTUNGNERTN(UNG C2H4)2]2 and ligand (Rh:L*=
[b]
[c]
[d]
only the addition of p-tolylboronic acid to 10d re- tive is the one where the biphenyl moieties of the li-
quired a longer reaction time to obtain a satisfactory gands of the Rh catalyst are P-twisted, a configuration
yield of the product (entry 14). Completely different opposite to that of the binaphthyl moiety of the most
results were obtained using the linear nitroalkene 10c active binaphthyl phosphite 3.
as substrate. Phosphite 3 gave the most active Rh cat-
alyst (entry 9), as in the case of nitrocyclohexene,
and, more surprisingly, the Rh catalysts obtained from Conclusions
tropos phosphites 1 and 2 gave the opposite enantio-
mer of the product, in low ee (entries 10 and 11). A catalytic system showing high activity and excellent
These results point out again a strong dependence of enantioselectivity toward the Rh-catalyzed asymmet-
the asymmetric activation on the structure of the ni- ric conjugate addition of arylboronic acids to nitroal-
troalkene. In fact, when tropos ligands were used in kenes has been developed starting from easily accessi-
the arylation of nitroalkenes branched at the 3-posi- ble and economic deoxycholic acid-derived biaryl
tion as well as of the heteroaromatic substrate, the phosphites. The Rh catalysts obtained from phos-
products had the same absolute configuration as phites 1–4 were able to give the conjugate addition
those obtained with 4 (entries 3, 7, 13). Thus these re- products under mild reaction conditions. The high
actions proceeded through the catalytic cycle I versatility of the catalytic system was demonstrated in
(Figure 2), in which the biphenyl units of the ligands the conjugate addition not only to various nitrostyr-
of the catalytic complex are twisted in the M sense of enes, but also to more challenging substrates, such as
twist, corresponding to the (R) absolute configuration aliphatic acyclic nitroalkenes and 1-nitrocyclohexene.
of the binaphthyl moiety of ligand 4.
A substrate dependent asymmetric activation of the
By contrast, the stereochemical pathway of the ary- catalytic complexes was also shown, which allows the
lation of linear nitroalkene 10c must be different in achievement of high enantioselectivities with different
passing from binaphthyl to biphenyl phosphites. In alkene substrates simply by changing the absolute
the presence of this substrate both the catalytic cycles configuration of the biaryl moiety: as a matter of fact
are active and the most active and (or) enantioselec- all the conjugate addition products were obtained
Adv. Synth. Catal. 2013, 355, 3475 – 3483
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3481

Varsha R. Jumde and Anna Iuliano
FULL PAPERS
CDCl3); d=139.7, 129.4, 129.1, 128.4, 127.7, 81.3, 44.4, 35.4,
20.4, 14.1; HPLC (Chiralcel OD-H, 215 nm, 1 mLminÀ1, n-
hexane:2-propanol 98:2): t1 =10.7 min, t2 =16.4 min.
11ca obtained using ligand 1: [a]2D7: À5.7 (c=0.2, CHCl3)
for 27% ee.
with high ees. By using phosphite 3, ees ranging from
94 to 96% were obtained in the conjugate additions
to 1-nitrocyclohexene and 81% ee was achieved in the
arylation of the challenging substrate 1-nitropentene.
Ligand 4 was more efficient in the conjugate additions
to aromatic and heteroaromatic acyclic nitroalkenes,
giving ees ranging from 94 to 99%, as well as to bulky
aliphatic acyclic nitroalkenes, where ees up to 96%
were obtained.
11ca obtained using ligand 2: [a]2D7: À9.6 (c=0.2, CHCl3)
for 45% ee.
11ca obtained using ligand 3: [a]2D7: +17.2 (c=0.2, CHCl3)
for 81% ee.
2-(4-Methyl)phenyl-2-(2-thienyl)-1-nitroethane: Rf: 0.26;
1
(hexane/acetone 9:1); H NMR (200 MHz, CDCl3): d=7.42–
7.05 (m, 5H), 7.05–6.77 (m, 2H), 5.11 (dd, J=14.9, 6.4 Hz,
1H), 5.02–4.88 (m, 2H), 2.36 (s, 3H); 13C NMR (50 MHz,
CDCl3) d=142.9, 138.1, 135.9, 130, 127.6, 127.2, 125.4, 125.2,
80.3, 44.7, 21.4; HPLC (Chiralcel OD-H, 230 nm,
1 mLminÀ1, n-hexane:2-propanol 60:40): t1 =9.5 min, t2 =
15.0 min.
Experimental Section
General Methods and Materials
All the reactions involving sensitive compounds were car-
ried out under dry N2, in flame-dried glassware. Toluene,
CH2Cl2, 1,4-dioxane and THF were freshly distilled before
the use from the proper drying agent. The phosphite ligands
were synthesized as previously described and matched the
reported characteristics.[16,17] Aliphatic acyclic nitroalkenes
were prepared according to literature procedures and
matched the reported characteristics.[18] If not noted other-
wise, the other compounds were commercially available and
used as received. TLC analyses were carried out with Merk
60 F254 plates (0.2 mm) and chromatographic purifications
with Macherey–Nagel silica gel (70–230 mesh). 1H and
13C NMR spectra were recorded as CDCl3 solutions on
a Varian 200 instrument and chemical shifts are reported in
ppm relative to TMS (1H) or to the solvent (13C, CDCl3 at
77.16 ppm). For the GC analyses a BP-1 column (25 m) on
a Perkin–Elmer Autosystem gas chromatograph was used,
with nitrogen as the carrier gas. HPLC analyses were carried
out on a Jasco PU-1580 chromatograph, equipped with an
UV-1575 detector. Optical rotations were measured in 1 dm
cells at the sodium D line, using a Jasco DIP 360 polarime-
ter.
11de obtained using ligand 4: [a]2D7: + 5.0 (c=0.5, CHCl3)
for 95% ee.
Acknowledgements
Financial support from Dipharma Francis S.R.L. is gratefully
acknowledged. We thank Mr. Nicola Bargagli for helping
with the synthesis of ligand 2 and some nitroalkenes.
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Acids to Nitroalkenes
Under a nitrogen atmosphere toluene (1 mL or 2 mL) was
added to [RhClACHTUNGTRENNUNG(C2H4)2]2 (1.5 mol%) and the phosphite
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3483