In-depth structure-selectivity investigations on asymmetric, copper-catalyzed oxidative biaryl coupling in the presence of 5-cis-substituted prolinamines

Article abstract of DOI:10.1039/c4cy01676a

Thirteen new and 25 known prolinamines carrying an additional 5-cis substituent were evaluated as the chiral ligands in asymmetric copper-catalyzed, oxidative biaryl coupling of 3-hydroxy-2-naphthoates. Comprehensive structure-selectivity investigations r

Full text of DOI:10.1039/c4cy01676a

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In-depth structure–selectivity investigations
on asymmetric, copper-catalyzed oxidative
biaryl coupling in the presence of
Cite this: DOI: 10.1039/c4cy01676a
5
-cis-substituted prolinamines†
a
b
b
a
Felix Prause, Benjamin Arensmeyer, Benjamin Fröhlich and Matthias Breuning*
Thirteen new and 25 known prolinamines carrying an additional 5-cis substituent were evaluated as the
chiral ligands in asymmetric copper-catalyzed, oxidative biaryl coupling of 3-hydroxy-2-naphthoates.
Comprehensive structure–selectivity investigations revealed that a phenyl group in the 5-cis position and a
small substituent at the pyrrolidine nitrogen (e.g., Me) are essential for high levels of chirality transfer. The
sense of the asymmetric induction depends on the steric demand of the exocyclic amino function. In the
coupling of methyl 2-hydroxy-3-naphthoate, a primary amino group permitted up to 36% ee in favor
of the P-enantiomer, while up to 64% ee in favor of the M-enantiomer was reached with secondary and
Received 15th December 2014,
Accepted 16th January 2015
tertiary amino functions (e.g. NMe , IJS)-NHCHIJMe)Ph). A fully linear relationship between the enantiomeric
2
excess of the prolinamine and the binaphthol was observed.
A mechanism consistent with all
stereochemical findings is proposed, indicating that 3-hydroxy-2-naphthoates with bulkier ester groups
should permit better stereocontrol. Indeed, the enantiomeric excess was raised to good 87% when
tert-butyl 3-hydroxy-2-naphthoate was used as the substrate.
DOI: 10.1039/c4cy01676a
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of a complex generated from CuCl and the prolinamine 3,
provided the 1,1′-binaphthyl-2,2′-ol 2a in good 85% yield and
Introduction
A chiral biaryl axis is the characteristic and dominating fea-
1
ture of a wide variety of bioactive natural products and
2
privileged ligands for enantioselective synthesis. During the
past three decades, many efficient and strategically diverse
methods for the stereoselective construction of chiral biaryl
bonds have been developed, from the desymmetrization of
achiral, but rotationally hindered biaryls and the stereo-
chemical fixation of configurationally labile ones through the
atroposelective construction of aromatic rings to diastereo-
3
,4
and enantioselective biaryl coupling reactions.
Among the latter approaches, oxidative coupling reactions
3
c
of 2-naphthols in the presence of chirally modified copper
5
–7
catalysts have received particular attention,
since these
reactions offer a direct access to the important class of axially
2
chiral 1,1′-binaphthol derivatives. A first breakthrough in
8
–10
this field was achieved by Nakajima et al. in 1995.
The
oxidative coupling of the naphthol 1a, catalyzed by 10 mol%
a
Organic Chemistry Laboratory, University of Bayreuth, Universitätsstraße 30,
9
5447 Bayreuth, Germany. E-mail: matthias.breuning@uni-bayreuth.de
b
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074
Würzburg, Germany
Electronic supplementary information (ESI) available: Experimental procedures,
Scheme 1 The oxidative biaryl coupling of 1a to 2a, a selection of
successfully used chiral diamines (3–6), the metal complex 7 and the
new 5-cis-substituted prolinamines 8–10.
†
HPLC and NMR spectra. See DOI: 10.1039/c4cy01676a
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8% ee (Scheme 1). As for most copper–diamine catalysts
developed so far, the additional ester group at C2
or another coordinating electron-withdrawing group
allowing bidentate binding) is crucial for a high level of
prompted us to study the performance of 8–10 in the enantio-
selective, copper-catalyzed oxidative biaryl coupling of 1 to 2.
With the broad variety of derivatives available, in-depth inves-
tigations on structure–selectivity relationships should
be possible.
(
1
1
enantioselection.
Further seminal work was done by
-symmetric 1,5-diaza-cis-
The CuI complex of 4 proved to be a highly
enantioselective catalyst, providing, for example, the model
Kozlowski et al. introducing the C
2
1
2,13
decalin 4.
Results and discussion
Synthesis of the prolinamines
1
2
biaryl 2a in good 85% yield and excellent 93% ee. This
system was successfully applied in the total synthesis of
We recently developed three tailor-made routes to prolinamines
of type 8–10 that all start from cheap L-pyroglutamic acid (11),
but differ in the order of introduction of the substituent at the
1
3
several axially chiral biaryl natural products. Among all
other diamines evaluated so far in the enantioselective,
1
4
1
2
copper-catalyzed oxidative coupling of 1a, only the CuCl
5
-cis position (R ), at the pyrrolidine nitrogen atom (R ), and at
3
4 20
complex of Ha's C -symmetric BINAM IJ1,1′-binaphthyl-2,2′-
1
the exocyclic aminomethyl function (R , R ). The high flexibil-
ity and applicability of these approaches was demonstrated in
the preparation of more than 25 derivatives with widely varying
substitution patterns. Some of these compounds were used in
this study. The new prolinamines 8a, b and 9b–l (Table 1)
were all synthesized from the amino alcohol 12, which is
diamine) derivative 5 was able to provide binaphthol 2a in
1
5
comparable 94% ee.
induction (97% ee) was recently reported by Sekar et al.,
using a 2 : 1 ratio of C -symmetric BINAM (6) and CuCl in
combination with the stable radical additive TEMPO
The highest level of asymmetric
2
1
6
19,20
IJ(2,2,6,6-tetramethylpiperidin-1-yl)oxyl).
In the course of our investigations on conformationally
rigid diamines we became interested in prolinamines of
available from 11 in seven steps and 49% overall yield
and possesses a 5-cis-phenyl substituent and an N-methyl
group at the pyrrolidine. Activation of the hydroxy function
of 12 by mesylation and subsequent treatment with an
1
7
general types 8–10, which possess, as compared to other pro-
1
3
4
line derived ligands, an additional substituent R in the 5-cis
excess of the respective amine HNR R afforded the target
21
position. Upon chelation of a metal (see complex 7), this sub-
prolinamines in one pot operations. Two bulky tertiary
amines (8a, b), ten secondary amines (9b–k) with varying ste-
ric demand and, in part, additional stereogenic centers, and
one aniline substituent (9l) were thus introduced in accept-
able to good 47–78% yield.
1
stituent R should shield the upper left face, which might
result in enhanced levels of stereocontrol in asymmetric syn-
thesis. This assumption was recently corroborated by copper-
1
8
catalyzed, enantioselective Henry reactions of nitromethane
with a series of aromatic, heteroaromatic, vinylic, and ali-
1
9
phatic aldehydes. The CuCl and CuBr complexes of the
2
2
1
2
4
3
Validation of the enantiomer analysis
simple prolinamine 9a (R = Ph; R , R = Me; R = H) pro-
vided the corresponding β-nitro alcohols with 99% ee in all
cases (36 examples). This successful application and the
Initially, an accurate determination of the enantiomeric
excess of the stereochemically enriched binaphthyl 2a by
2
2
structural similarity of 8–10 to Nakajima's diamine
3
HPLC on chiral phase proved to be difficult. Just picking a
Table 1 Preparation of the prolinamines 8a, b and 9b–l from 12
3
4
a
Entry
Cmpd.
R
R
Yield (%)
1
2
3
4
5
6
7
8
9
8a
8b
9b
9c
9d
9e
9f
9g
9h
9i
Me
Me
H
H
H
H
H
H
H
H
H
H
H
tBu
Ph
Et
72
66
62
78
53
55
74
65
52
62
65
47
73
2
CH tBu
iPr
3-Pentyl
IJS)-CHIJMe)Ph
IJS)-CHIJEt)Ph
IJS)-CHIJMe)tBu
IJR)-CHIJMe)Ph
tBu
10
11
12
13
9j
9k
9l
2 3
CIJCH OBn)
Ph
a
Isolated yield.
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small sample from the product, which was obtained as a
slightly yellowish solid after column chromatography, and
dissolving it in the HPLC solvent led to huge derivations in
the ee measured. For example, the ee-values of a scalemic
sample with 63% ee varied between 27% and 80%,
depending on the position the material was taken from.
Thus, the solid material of 2a is not stereochemically
homogeneous, but a conglomerate of areas with different
enantiopurities. Furthermore, the low solubility of 2a in
typical HPLC solvents such as hexane, isopropanol, etha-
nol, or methanol in connection with the high tendency of
Optimization of the reaction conditions
All copper–diamine complexes were freshly prepared prior
to use by stirring a solution of the copper salt and the respec-
tive 5-cis-substituted prolinamine 8–10 in acetonitrile–
dichloromethane 0.9 : 1 for 20 min. After evaporation, the res-
idue was dissolved in the reaction solvent, providing a clear
green solution.
The reaction conditions were optimized using the simple
1
2
4
prolinamine 8c (R = Ph, R –R = Me) as the chiral ligand
(Table 2). Because of the close structural relationship of 8c
8
b
8b
2
a to form racemic (micro)crystals bears the risk of an
with diamine 3, we initially chose Nakajima's conditions
1
2a
exaggerated enantiomeric excess in the solution to be
measured.
(entry 1), but added mol sieves 4 Å, which is known
to be
beneficial to the reaction rate and yield. After 72 h at 20 °C,
the oxidative coupling of naphthol 1a afforded binaphthol 2a
in high 91% yield and acceptable 61% ee in favor of the
We solved these problems by using the following proce-
dure for sample preparation: the complete material of 2a
gathered from column chromatography was dissolved in
dichloromethane (ca. 1 mL per 10 mg) giving a homoge-
neous, clear solution. A small aliquot was taken, evapo-
8
b
M-enantiomer. In agreement with the literature,
the
enantiomeric excess of 2a was easily raised by trituration with
ethyl acetate, giving highly enriched (M)-2a (96% ee) in the
mother liquor.
Variation of the reaction parameters showed that chlori-
nated hydrocarbons and mol sieves 4 Å are essential for high
yields and enantioselectivities (entries 1–6). Small changes in
the relative stoichiometry CuCl/8c (1.2 : 1–0.9 : 1) had no
−
1
rated, and dissolved in methanol (ca. 50 μg mL ) under
ultra-sonification and warming. The resulting solution was
directly injected into HPLC, providing reliably and repro-
ducibly ee-values (Δee ≤ 1%) as checked by several control
measurements.
Table 2 Optimization of the reaction conditions for the oxidative biaryl coupling of 1a to 2a in the presence of 8c
a
b
Entry
Solvent
CH Cl
Conc. (M)
8c (mol%)
CuX (mol%)
Temp. (°C)
Oxidant
Yield (%)
ee (%)
c
1
2
3
4
5
2
2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.5
0.05
0.5
0.5
0.5
0.5
0.5
10
10
10
10
10
10
10
10
20
5
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (12)
CuCl (9)
CuCl (18)
CuCl (4.5)
CuCl (0.9)
CuI (9)
20
20
20
20
20
20
20
20
20
20
20
20
20
20
40
0
−20
20
20
20
20
20
20
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
91
80
83
45
22
67
87
94
94
59
23
61 (96)
IJCH Cl)
CHCl
MeCN
2
2
61
62
25
28
62
61
62
62
61
55
59
19
63
53
75
77
63
64
63
55
56
—
3
d
2
Et O
e
6
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
2
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1
f
10
10
10
10
10
20
10
10
10
10
10
10
43
55
f
MeCN
CH Cl
IJCH
CuI (9)
2
2
2 2
CuCl ĴH O (9)
81
78
g
2
Cl)
2
CuCl (9)
CuCl (9)
CH
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
2
2
65
56
h
CuCl (18)
CuCl (9)
CuCl (9)
CuCl (9)
CuCl (9)
CuCl (9)
CuCl (9)
85
91
84
12
77
0
Air
tBuOOH
AgCl
DDQ
a
b
c
d
e
f
Isolated yield. Determined by HPLC on chiral phase. After trituration with ethyl acetate. Suspension. Without mol sieves 4 Å. Side
g
h
products formed. Reaction time: 18 h. Reaction time: 7 days.
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4
measureable effect on the chirality transfer (entries 7 and 8).
Nine mol% of the catalyst was required; lower loadings
resulted in significantly reduced yields (entries 9–11). CuI
was not suited as the metal salt because of the formation of
side products (entries 12 and 13). CuCl Ĵ2H O (entry 14) and
CuCl gave comparable results, as expected from the redox
process CuIJI) ⇄ CuIJII) in the catalytic cycle, in which both
oxidation states are involved. The enantioselectivity of the
oxidative biaryl coupling can be enhanced to 75% ee by low-
ering the temperature from 20 °C to 0 °C (entry 16), albeit at
the price of a reduced yield (65% within 72 h). At −20 °C, a
drastic breakdown of the reaction rate was observed (56%
yield after 7 days in the presence of 18 mol% catalyst), in
combination with just a poor further gain in chirality control
enantioselectivity relationship. All four substituents R –R
were separately varied and their influence on the chirality
transfer was studied.
Prolinamines 8, which are characterized by a tertiary exo-
cyclic amino function (R , R ≠ H), were screened first
(Table 3). The bulkiness of the 5-cis substituent R was found
to exert a profound influence on the chirality transfer (entries
1–8). The enantiomeric excess of 2a rose from low 4% to
acceptable 62–64% by increasing the steric demand of R
from H (8d) to 4-methoxyphenyl (8h) and phenyl (8c). Larger
3
4
2
2
1
1
1
substituents R such as 3,5-IJbistrifluoromethyl)phenyl in 8i
and 1-naphthyl in 8j, however, resulted in a deterioration of
the chirality transfer (48% and 25% ee, respectively).
The N-methyl group at the pyrrolidine nitrogen atom is
2
2
(77% ee, entry 17). The dilution had no significant effect on
essential since all variations of R (8k–m, R = H, Et, Bn) led
to lower enantioselectivities (15–28% ee, entries 9–11). A sim-
the chirality transfer, although the best results at 20 °C (91%
yield, 64% ee) were obtained at higher concentration (c =
3
4
ilar small substituent tolerance was observed for R and R at
the exocyclic amino function (entries 12–17). Good enantio-
selectivities (63–64% ee) were only reached with the model
0
.5 M, entry 19). As the oxidant, air can be used instead of
oxygen, but the reaction rate slows somewhat down (entry 20).
tBuOOH and AgCl afforded lower yields and diminished
enantioselectivities, while no biaryl coupling was observed
with DDQ (entries 21–23).
The optimum conditions with respect to reaction rate,
yield, and stereoselectivity, which were used in the following
diamine screening, are thus as follows: diamine (10 mol%),
3
4
diamine 8c (R , R = Me) and the pyrrolidine derivative 8o.
Even a slight increase in the steric demand of one or both
substituents at the NR R group as, for example, in 8q
2
IJNR R = NEt ) and 8p IJNR R = piperidinyl) resulted in
drastically reduced enantioselectivities (6–42% ee). Finally, it
should be noted that the formation of the M-atropoenantiomer
of 2a was favored in all coupling reactions in the presence of
a diamine 8.
In the screening of the secondary prolinamines 9 (R = H),
we first kept the optimized substituents R = Ph and R = Me
3
4
3
4
3 4
CuCl (9 mol%), O
2 2 2
(1 bar), CH Cl (c = 0.5 M), mol sieves 4 Å,
2
0 °C, 72 h (entry 19).
3
1
2
Structure–selectivity studies
4
and varied R at the exocyclic amino group (Table 4). To our
The facile and modular access to various prolinamines of
surprise and in contrast to the results with all tertiary
type 8–10 permitted in-depth investigations on the structure–
diamines 8 (see Table 3), the P-atropoenantiomer of 2a was
Table 3 Oxidative biaryl coupling of 1a in the presence of the tertiary prolinamines 8
1
2
3
4
a
b
Entry
8
R
R
R
R
Yield (%)
ee (%)
1
2
3
4
5
d
e
f
g
h
c
i
j
k
l
m
n
a
b
o
p
q
H
Me
Bn
iPr
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
–IJCH
–IJCH
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
95
95
95
73
98
91
74
59
64
81
93
74
46
20
77
54
73
4
7
22
28
62
64
48
25
15
28
19
12
10
10
63
42
6
4-MeOC
Ph
3,5-IJCF ) C H
3 2 6 3
1-Naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6 5
H
c
6
7
8
9
10
11
12
13
14
15
16
17
Et
Bn
Me
Me
Me
Me
Me
Me
tBu
Ph
2
)
)
4
–
–
2
5
Et
a
b
c
Isolated yield. Determined by HPLC on chiral phase. See Table 2, entry 19.
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preferentially formed (19% ee) in the presence of 9a, which
An increase in P-selectivity might also result if the steric
3
4
possesses the sterically least hindered secondary amino-
demand at the exocyclic NR R group is minimized, as in the
4
3 4
methyl function (R = Me, entry 1). Even a slight increase in
2
primary diamines 10a–f IJNR R = NH , entries 4–9). Indeed,
4
the bulkiness of R deteriorated the P-preference and a race-
derivative 10e delivered, compared to corresponding second-
ary amine 9a, the binaphthol (P)-2a with an improved
P-selectivity (36% ee vs. 19% ee for 9a). Increasing the size of
4
mic mixture was obtained with 9b (R = Et, entry 2). More
4
demanding α-branched substituents R tilted the sense of
1
1
stereoinduction in favor of the M-enantiomer. A broad
maximum plateau in the range of 58–61% ee was reached
R as in 10f (R = 1-naphthyl) as well as decreasing it as in
1
10b–10d (R = iPr, Bn, Me) resulted in diminished enantio-
4
for R = 3-pentyl, IJS)-1-phenylethyl, IJS)-1-phenylpropyl, and
selectivities, while the formation of the M-atropoisomer was
slightly favored for the 5-cis-unsubstituted prolinamine 10a
IJS)-3,3-dimethylbutan-2-yl (9e–h, entries 5–8). The configura-
tion of the stereocenter in the α-position in 9f–h was also of
importance, as seen in the reaction with 9i, which carries,
compared to 9f, the enantiomeric IJR)-1-phenylethyl side
chain, and provided (M)-2a in lower 49% ee (entry 9). A fur-
1
(R = H, 8% ee).
The structure–enantioselectivity relationships found show
that there is a complex interplay between the relative and
1
4
absolute steric bulk of the substituents R –R . Significant
4
ther increase in the steric demand in R was not favorable.
findings are: (i) the catalyst system is highly sensitive to steric
2
3
With bulky α-tertiary substituents such as tBu (9j) and
CIJCH OBn) (9k), the stereoinduction sharply dropped to
overcrowding. In particular at the positions R and R , only
2
3
the small substituents (R = Me and R = Me, H) are toler-
ated. (ii) The stereoselection rises with an enhanced steric
2
3
4
2% and 22% ee, respectively (entries 10 and 11). The reac-
1
tion rates, which roughly correspond to the isolated yields
after 72 h, also decreased with the rising steric demand of
demand of R . This accounts for the M-selective prolinamines
as well as for the P-selective ones. (iii) In the prolinamine
4
1
2
R . The aniline derivative 9l failed to induce a good chirality
series with R = Ph and R = Me (8a–c, n–q, 9a–l and 10e),
transfer (38% ee, entry 12).
the sense of stereoinduction can be steered by the size and
3
4
Curious by the reversed stereoinduction observed with
the prolinamine 9a, we wondered whether the P-preference
could be raised by the appropriate choice of the substitu-
degree of substitution of the exocyclic NR R group. Tertiary
diamines of type 8 generally provide the M-enantiomer of 2a,
but good levels of enantioselection require small substituents
2
3 4
ents. Since an increase in the size of R at the pyrrolidine
2
as in 8c and 8o IJNR R = NMe , pyrrolidinyl). Roughly the
nitrogen atom had led to a loss of chirality transfer with
same chirality transfer is achieved with the secondary
the M-selective prolinamines 8l and 8m (see Table 3, entries
diamines 9e–h possessing a sterically more demanding,
α-branched alkyl substituent R . (iv) P-configured 2a is prefer-
4
1
0 and 11), we anticipated that the opposite effect, an
enhanced P-selectivity, should occur with the analogous
derivatives of 9a. However, just slightly higher 24% ee
entially formed, albeit with lower stereocontrol, if an NHMe
group as in 9a and 9m or a primary NH group as in 10b–f is
2
(
vs. 19% ee for 9a) was found for the N-ethyl diamine 9m,
present. (v) A hydrogen bridging between the catalyst and the
naphthols to be coupled can be excluded for the M-selective
prolinamines since the best ligand, 8c, does not possess an
acidic proton; for the P-selective ligands 9a, m and 10b–f
whereas the sense of stereoinduction switched back to M
for 9n and 9o carrying the larger N-benzyl and N-isopropyl
groups (Table 5, entries 1–3).
Table 4 Oxidative biaryl coupling of 1a in the presence of the secondary prolinamines 9a–l
4
a
b
Entry
9
R
Yield (%)
ee (%)
Config.
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
Me
Et
CH
iPr
96
99
60
81
64
72
73
77
68
61
38
49
19
0
P
—
M
M
M
M
M
M
M
M
M
M
2
tBu
42
47
58
61
61
61
49
42
22
38
3-Pentyl
IJS)-CHIJMe)Ph
IJS)-CHIJEt)Ph
IJS)-CHIJMe)tBu
IJR)-CHIJMe)Ph
tBu
10
11
12
j
k
l
2 3
CIJCH OBn)
Ph
a
b
Isolated yield. Determined by HPLC on chiral phase.
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Table 5 Oxidative biaryl coupling of 1a in the presence of the primary and secondary prolinamines 9m–o and 10a–f
1
2
4
a
b
Entry
Diamine
R
R
R
Yield (%)
ee (%)
Config.
1
2
3
4
5
6
7
8
9
9m
9n
9o
10a
10b
10c
10d
10e
10f
Ph
Ph
Ph
H
Me
Bn
iPr
Ph
Et
Me
Me
Me
H
H
H
H
H
H
96
90
74
90
91
89
93
85
82
24
3
15
8
19
29
33
36
19
P
Bn
iPr
Me
Me
Me
Me
Me
Me
M
M
M
P
P
P
P
P
c
Naph
a
b
c
Isolated yield. Determined by HPLC on chiral phase. Naph = 1-naphthyl.
3
4
IJNR R = NH ), however, such an additional prefixation
because the amount of (M)-2 isolated was by far larger than
the amount of the catalyst used. A subsequent deracemization
by atropodiastereomerization of configurationally unstable
copper complexes, namely CuClĴ8cĴIJM/P)-2 to CuClĴ8cĴIJM)-2,
can be ruled out since there was no change in the optical
purity if scalemic or racemic 2a were treated with the catalyst
for several days.
2
might be possible.
Furthermore, the screening revealed that there are signifi-
cant differences between our prolinamines and the known
diamines 3 and 4. For example, both latter ligands require
at least one secondary amino function for high levels of
asymmetric induction, while 8c has just tertiary ones. In
addition, the optimum reaction conditions elaborated for
diamine 4 (CuI, solvent MeCN) gave only unsatisfying results
with our prolinamine 8c (see Table 2, entries 4, 12, and 13).
8
12
A fully linear relationship between the enantiomeric
excess of the prolinamine 8c and the product 2a was found
2
8
(Fig. 1). The absence of a nonlinear effect makes the exis-
tence of dimeric or oligomeric catalyst species as well as a
participation of two molecules of the catalyst in the stereo-
chemically decisive biaryl coupling step unlikely (although
both possibilities cannot fully be ruled out).
Mechanistic and stereochemical considerations
1
2
Kozlowski et al. did extensive studies on the mechanism of
enantioselective, oxidative biaryl coupling in the presence
of their catalyst CuI·4, finding first order dependences on the
2
3
Based on the aforementioned mechanistic investigations
and our studies we propose the following mechanism for
the oxidative biaryl coupling of 1a in the presence of our
prolinamine-derived copper catalysts (Scheme 2). For simpli-
fication of the discussion, a phenyl group in the 5-cis posi-
1
2d
oxygen and catalyst concentrations.
step of the catalytic cycle is the reoxidation of the catalyst by
The rate determining
1
2d
O ,
2
which presumably involves several oxygenated dimeric
2
4,25
1
or oligomeric species.
The stereochemically decisive for-
tion (R = Ph) and an N-methyl group at the pyrrolidine nitro-
2
mation of the biaryl axis is proposed to proceed in two con-
secutive steps, a face-selective coupling of two naphthyl radi-
gen atom (R = Me), which are both essential for good levels
of stereoselection, and a secondary or primary exocyclic
2
6
3
4
4
cals, of which at least one is chelated to a tetrahedral
amino function are set. The ligands 9e–h IJNR R = NHR ;
diamine–Cu-complex, followed by a central-to-axial chirality
1
2c,27
transfer upon rearomatization.
Since the counter ion has
no effect on the stereoselection, it is likely that the reaction
1
2b
takes place at a cationic metal complex.
Finally, a positive
2
8
nonlinear effect was observed, hinting at dimeric or oligo-
This assumption was
furthermore corroborated by VPO measurements.
1
2b
meric catalyst species in solution.
1
2b
Our mechanistic studies started with the proof that the
6
4% ee in the product (M)-2a, as achieved with the catalyst
CuCl·8c, is based on a stereodifferentiating coupling step,
and not, as observed for coupling with stoichiometric amounts
9
of chirally modified Cu complexes, on a non-stereoselective
coupling followed by resolution or deracemization of the
primarily formed, racemic biaryl. A mere diastereoselective
crystallization of CuClĴ8cĴIJM)-2 can safely be excluded
Fig. 1 Fully linear relationship between the enantiomeric excess of the
prolinamine 8c and the binaphthol 2a.
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Scheme 2 Proposed mechanism for the M- and P-selective oxidative biaryl coupling of 1a in the presence of the prolinamines 9e–h and 10e.
4
R
= secondary alkyl, 58–61% ee in favor of M) and 10e
group does. As a consequence of this arrangement depicted
3
4
IJNR R = NH
2
, 36% ee in favor of P) fulfill these premises.
in 13, the lower right quadrant is shielded by the phenyl
4
Taking the relative and absolute steric demands of the sub-
group and the upper left one by R (see “front view”). In the
1
4
4
stituents R –R into account, this mechanism can be
extended to all prolinamines that provided significant levels
of asymmetric induction.
case of 10e with R = H, only the repulsion by the phenyl
group exists, thus favoring the formation of 14B, while in the
4
cases of 9e–h (R = secondary alkyl), the higher steric
4
Initial chelation of the chiral prolinamine to CuCl pro-
demand of R dominates, thus favoring the orientation
vides the bicyclic, C
1
-symmetric complex 13, to which the
shown in 14A.
naphthol 1a principally can bind in two different orienta-
The following steps are identical for both catalytic cycles.
2
9
24
12d,25
tions, as illustrated in the tetrahedral complexes 14A and
Multistage and rate-limiting
oxidation of the copperIJI)
3
0
1
4B. The preference for one or the other is controlled by
atom in 14 by O affords the copperIJII) complexes 15, which
2
steric factors. On the side of the naphthol 1a, the methoxy
group of the ester function is more demanding than the two
carbon atoms C-4 and C-4a of the aryl ring. On the side of
the chiral catalyst, it is reasonable that, in the energetically
most favored conformation, the larger substituents at the
two nitrogen atoms (R and the annelated pyrrolidine)
occupy opposite positions with respect to the central copper
heterocycle and align pseudo-equatorially, as the phenyl
can undergo electron transfer from the naphthol to the cop-
per atom to give the naphthyl radicals 16. In both complexes,
the backside of the naphthyl radical is efficiently shielded by
the phenyl group, possibly supported by some π-stacking,
which directs the attack of a second naphthyl radical [1a˙] to
the front side, thus leading to 17. It should be noted that the
4
2
6
true nature of [1a˙] is still unclear, although the observed
absence of a nonlinear effect (see Fig. 1) makes the
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complexation of [1a˙] to a second, chirally modified copper
atom and, thus, a coupling between two molecules of 16,
unlikely.
radical in 16A and 16B (see Scheme 2), which is in good
agreement with the mechanism proposed.
During the rearomatization process via twofold ketoenol
tautomerism, the two (pre)aromatic moieties have to rotate
in order to reach the orthogonal alignment in biaryls. This
rotation follows the pathway of the least steric hindrance,
which means that the carbonyl groups pass each other and
Consequences of the mechanism
Under the assumption that the backside-shielding in 16 and
the central-to-axial chirality transfer occur with high selectiv-
ity, the resulting enantiomeric excess in the binaphthol 2a is
thus determined by the orientation of 1a during binding to
18 (and 13 in the starting sequence). As a consequence, the
enantioselection of the M-selective catalysts should increase
if the steric differentiation in the naphthol substrate is more
pronounced, which can be achieved by raising the steric bulk
of the ester group at C-2. In order to consolidate this theory,
we synthesized the naphthol esters 1b–d and subjected these
compounds to the coupling procedures (Table 6). Indeed, the
levels of stereoselection significantly increased by using the
sterically more hindered esters. The binaphthol 2d (R = tBu)
was produced in good 78% and 75% ee with the pro-
linamines 8c and 9f as the chiral ligands (entries 4 and 8).
This trend is in sharp contrast to the observations made in
other oxidative biaryl coupling reactions in the presence of
diamine–copper catalysts, in which the chirality transfer
1
2c,27
not the aromatic rings (repulsion of the peri-H).
Conse-
quently, the rotation is clockwise in 17A, leading to
M-configuration at the newly created biaryl axis in 18A,
whereas an anticlockwise rotation takes place in 17B, creat-
ing the P-configured biaryl axis in 18B. Final exchange of the
binaphthol 2a against naphthol 1a completes the catalytic
cycle. For the orientation of 1a upon complexation, the very
same steric arguments apply as in the chelation of 1a to 13
giving 14A and 14B.
Since most of the prolinamines 8–10 used in this study
favored the formation of (M)-2a, the top faces of the respec-
tive copper complexes must be more strongly shielded than
the bottom faces, which forces the incoming naphthol 1a to
bind in a fashion shown in 14A. This also means that the ste-
1
ric demand of the annelated, R -substituted pyrrolidine can-
8b,12c,14a,16
not be high, probably due to its pseudo-equatorial orienta-
tion with respect to the central copper heterocycle. The size
dropped when the size of the ester group was increased.
By lowering the reaction temperature to 0 °C, the enantio-
meric excess in the CuCl·8c catalyzed coupling of 1d to 2d
was further improved to 87%, without any noticeable loss in
yield (96%, entry 9). The latter result is the best asymmetric
induction so far reached with the naphthyl ester 1d.
For the P-selective catalyst CuCl·10e, the enantioselection
achieved with the methyl ester 1a and the t-butyl ester 1d was
virtually identical (entries 10 and 11). This result is also in
1
of R at this ring, however, exerts a drastic effect on the level
of stereoselection. Since the same trends – decreasing the
1
bulkiness of R led to a reduced chirality transfer (see 8d–j,
Table 3, and 10a–f, Table 5) – were observed for the M- and
the P-directing prolinamines, this substituent cannot play an
important role in the binding of 1a, but must be decisive in
the shielding of the backside of the complexed naphthyl
Table 6 Oxidative biaryl coupling of 1a–d in the presence of the prolinamines 8c, 9f and 10e
a
b
Entry
Biaryl 1, 2
R
Diamine
Temp. (°C)
t (day)
Yield (%)
ee (%)
Config.
c
1
1a
1b
1c
1d
2a
2b
2c
2d
1d
1a
1d
Me
iPr
Bn
tBu
Me
iPr
Bn
tBu
tBu
Me
tBu
8c
8c
8c
8c
9f
9f
9f
9f
20
20
20
20
20
20
20
20
0
3
3
3
6
3
5
5
7
8
3
5
91
94
93
99
72
94
99
94
96
85
99
64
69
73
78
61
75
72
75
87
36
36
M
M
M
M
M
M
M
M
M
P
2
3
4
d
5
6
7
8
9
8c
10e
10e
e
1
1
0
1
20
20
P
a
b
c
d
e
Isolated yield. Determined by HPLC on chiral phase. See Table 2, entry 19. See Table 4, entry 6. See Table 5, entry 8.
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good agreement with the proposed catalytic cycle, since the
interaction between the ester group and the chiral backbone
is just weak (see 14B, Scheme 2).
ESI (electronspray ionization). The enantiomeric excess of the
binaphthols 2a–d was determined by HPLC analysis (Waters
Alliance HPLC; Waters 2695 Separation Module, Waters 2487
Dual λ Absorbance Detector) on chiral phase (Daicel Chiralpak
AD-H).
The synthesis of 9f and the general procedure for the
oxidative biaryl coupling under optimized conditions are
described here exemplary. For the preparation of all other
new compounds, see the ESI.†
Conclusions
A series of 38 prolinamines 8–10, which differ in the substitu-
1
2
ents R at the 5-cis position, R at the pyrrolidine nitrogen
3
4
atom, and R R at the exocyclic amino function, were evalu-
ated in their performance as chiral ligands in the copper-
catalyzed oxidative biaryl coupling of the naphthol 1a. Essen-
tial for good enantioselectivities were a 5-cis-phenyl (R ) and
an N-methyl group (R ). With these two substituents given,
1
IJ2R,5S)-1-Methyl-2-phenyl-5-IJ(IJ(S)-1-
phenylethyl)amino)methyl)pyrrolidine (9f)
2
the level and sense of the asymmetric induction can be
steered by the NR R group. Good 58–64% ee in favor of the
M-enantiomer of 2a were reached with the tertiary amine 8c
NEt3 (197 μL, 143 mg, 1.41 mmol) and MsCl (87.4 μL,
129 mg, 1.13 mmol) were added at 0 °C to a solution of the
3
4
1
9
alcohol 12 (180 mg, 941 μmol) in anhydrous CH Cl (8 mL).
2
2
3
4
3 4
IJNR R = NMe ) and the secondary amines 9e–h IJNR R
=
After 1 day at r.t., the solution was treated with IJS)-1-phenyl-
ethylamine (2.40 mL, 2.28 g, 18.8 mmol) and stirring was con-
tinued for 5 days. The solvent was removed under reduced pres-
sure and the crude material was directly subjected to column
chromatography (1. silica gel, CH Cl /MeOH, 100 : 0–97 : 3,
2 2
2. silica gel, EtOAc). Filtration through a pad of basic alumina
2
4
4
NHR , with R = secondary alkyl), while the P-enantiomer of
a was preferentially formed with the primary amine 10e
36% ee, NR R = NH ). A mechanism, in which the steric
demand of the NR R group of the chiral ligand determines
the orientation of 1a upon complexation to the copper atom
and, thus, the sense of the chirality transfer, was proposed.
2
(
3
4
2
3
4
(activity I, CH Cl /MeOH, 9 : 1) delivered the prolinamine 9f
2
2
1
The 5-cis-phenyl group (R ) plays the decisive role in the face-
(205 mg, 697 μmol, 74%) as a yellowish oil.
2
1
selective C,C-coupling step by shielding one side of the
R 0.65 (EtOAc). [α]
8.2 (c 0.50 in MeOH). IR (ATR)
f
D
−
1
complexed naphthyl radical. As
a consequence of the
νmax/cm 2968w, 2784w, 1491w, 1450s, 1122w, 1041w, 1027w,
757s, 697vs; H NMR δ (500 MHz; CDCl ) 1.43 (3 H, d, J =
H 3
1
structure–enantioselectivity investigations, we concluded that
naphthols with bulkier ester groups should permit better
stereocontrol. Indeed, the enantiomeric excess of the oxida-
6.7 Hz, CHCH ), 1.67 (1 H, m, 3-HH), 1.83 (1 H, m, 4-HH),
3
1.98 (1 H, m, 4-HH), 2.05 (1 H, m, 3-HH), 2.06 (3 H, s,
tive coupling of 1d (CO
2
R = CO
2
tBu) was improved to up to
3
1-CH ), 2.52 (1 H, dd, J = 11.1, 6.4 Hz, 5-CHH), 2.58 (1 H, m,
8
7% ee by using CuCl·8c as the chiral catalyst.
5-H), 2.75 (1 H, dd, J = 11.1, 3.1 Hz, 5-CHH), 3.27 (1 H, dd,
J = 9.7, 6.7 Hz, 2-H), 3.82 (1 H, q, J = 6.7 Hz, CHCH ), 7.26
3
1
3
(
(
2 H, m, Ar–H), 7.33 (8 H, m, Ar–H) ppm. C NMR δ
125 MHz, CDCl ) 24.4 (CHCH ), 28.1 (C-4), 34.3 (C-3), 39.3
C
Experimental
3
3
All reactions with moisture-sensitive reagents were carried
out under an argon atmosphere in anhydrous solvents, pre-
IJ1-CH ), 50.7 IJ5-CH ), 58.8 (CHCH ), 65.9 (C-5), 72.6 (C-2),
3 2 3
126.7, 127.0, 127.1, 127.4, 128.4, 128.6 (CH–Ar), 143.9, 145.9
3
1
+
pared using standard procedures. Commercially available
reagents (highest quality available) were used as received.
Reactions were monitored by thin layer chromatography on
precoated silica gel (Macherey-Nagel, Alugram SIL G/UV254).
Spots were visualized by UV light (254 nm) or by staining
(C -Ar) ppm. HRMS (ESI, pos.) m/z calcd for C H N [M + H]
q
20 27 2
295.2169, found 295.2169.
General procedure for the oxidative biaryl coupling under
optimized conditions
4
with aqueous KMnO , vanillin, or ceric ammonium molyb-
date. Silica gel (Macherey-Nagel, particle size 40–63 μm) was
used for column chromatography. Melting points were mea-
sured by a Stuart SMP10 digital or a Thermo Scientific 9300
melting point apparatus and are uncorrected. Optical rota-
tions were recorded on a Jasco P-1020 polarimeter (10 cm
cell). NMR spectra were taken on a Bruker Avance 300, a
Bruker Avance 400, or a Bruker Avance III HD 500 instrument
and calibrated using the residual undeuterated solvent as
Oxidative coupling. A solution of CuCl (4.46 mg, 45.0 μmol,
9 mol%) in MeCN (450 μL) was added to a solution of the
prolinamine 8c, 9f, or 10e (50.0 μmol, 10 mol%) in anhydrous
CH Cl (500 μL). After stirring for 20 min, the solvent was
2
2
removed in vacuo and the residue was dissolved in anhydrous
CH Cl (1 mL) to give a greenish solution. The temperature
2
2
was adjusted to 20 °C or 0 °C and the naphthols 1a–d
(500 μmol, 101 mg in the case of 1a) and powdered mol
sieves 4 Å (30 mg) were added. After 3–8 days under an O
2
1
an internal reference. The peak assignments in the H and
1
3
C NMR data were performed on the basis of 2D NMR
atmosphere (1 bar), the reaction mixture was diluted with
CH Cl (5 mL) and directly subjected to column chromatogra-
methods (COSY, HSQC, HMBC). Infrared spectra were
recorded on a Jasco FT-IR-410 or a PerkinElmer Spectrum
2
2
phy (for 2a: silica gel, petroleum ether/EtOAc, 10 : 1–2 : 1;
for 2b–d: silica gel, petroleum ether/CH Cl , 3 : 1–1 : 9), deliv-
1
00 FT-IR spectrometer, high resolution mass spectra on a
2
2
8
b
Bruker Daltonics micrOTOF focus mass spectrometer using
ering the product 2a–d as a yellowish solid.
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Enantiomer analysis. Sample preparation: the complete
material of 2a–d gathered from column chromatography
was dissolved in CH Cl (1 mL per 10 mg). A small aliquot
50 μL) was taken, evaporated, and dissolved in MeOH
10 mL) under warming and ultra-sonification. This solution
Tetrahedron Lett., 2011, 52, 4221; ( f ) S. Ogaki, Y. Shibata,
K. Noguchi and K. Tanaka, J. Org. Chem., 2011, 76, 1926; (g)
M. Leibeling and D. B. Werz, Chem. – Eur. J., 2012, 18, 6138; (h)
A. Ros, B. Estepa, A. Bermejo, E. Álvarez, R. Fernández and
J. M. Lassaletta, J. Org. Chem., 2012, 77, 4740; (i) Y. Kasai,
N. Michihata, H. Nishimura, T. Hirokane and H. Yamada,
Angew. Chem., Int. Ed., 2012, 51, 8026; ( j) Z.-H. Shan, J. Liu,
L.-M. Xu, Y.-F. Tang, J.-H. Chen and Z. Yang, Org. Lett.,
2012, 14, 3712; (k) M. Groh, D. Meidlinger, G. Bringmann and
A. Speicher, Org. Lett., 2012, 14, 4548; (l) F. R. Leroux,
A. Berthelot, L. Bonnafoux, A. Panossian and F. Colobert,
Chem. – Eur. J., 2012, 18, 14232; (m) S. Postikova, M. Sabbah,
D. Wightman, I. T. Nguyen, M. Sanselme, T. Besson,
J.-F. Brière, S. Oudeyer and V. Levacher, J. Org. Chem., 2013, 78,
8191; (n) G.-Q. Li, H. Gao, C. Keene, M. Devonas, D. H. Ess and
L. Kürti, J. Am. Chem. Soc., 2013, 135, 7414; (o) N. Kadoya,
M. Murai, M. Ishiguro, J. Uenishi and M. Uemura, Tetrahedron
Lett., 2013, 54, 512; (p) A. Link and C. Sparr, Angew. Chem., Int.
Ed., 2014, 53, 5458; (q) G. Xu, W. Fu, G. Liu, C. H. Senanayake
and W. Tang, J. Am. Chem. Soc., 2014, 136, 570; (r) Y. Zhou,
X. Zhang, H. Liang, Z. Cao, X. Zhao, Y. He, S. Wang, J. Pang,
Z. Zhou, Z. Ke and L. Qiu, ACS Catal., 2014, 4, 1390; (s)
C. K. Hazra, Q. Dherbassy, J. Wencel-Delord and F. Colobert,
Angew. Chem., Int. Ed., 2014, 53, 13871.
2
2
(
(
was directly used for HPLC analysis on chiral phase (Daicel
Chiralpak AD-H). HPLC conditions: 2a: n-hexane/iPrOH 8 : 2,
−
1
1
.0 mL min , 254 nm: t IJP-enantiomer) = 8.8 min; t
R R
8
b
IJM-enantiomer) = 14.3 min; 2b: n-hexane/iPrOH 98 : 02,
−
1
1
.0 mL min , 254 nm: t IJP-enantiomer) = 7.9 min; tR
R
IJM-enantiomer) = 9.5 min; the absolute configuration of 2b
was determined after transesterification of 2b into 2a; 2c:
−
1
n-hexane/iPrOH 9 : 1, 1.0 mL min , 254 nm: t IJP-enantiomer)
R
8b
=
9
14.6 min; t IJM-enantiomer) = 23.1 min; 2d: n-hexane/iPrOH
R
8: 02, 1.0 mL min , 254 nm: t IJM-enantiomer) = 6.8 min; t
R R
−1
8b
IJP-enantiomer) = 7.6 min.
Acknowledgements
The financial support of the German Research Foundation
DFG) is gratefully acknowledged.
(
Notes and references
1
Reviews: (a) U. Weiss, L. Merlini and G. Nasini, Prog. Chem.
Org. Nat. Prod., 1987, 52, 1; (b) G. Bringmann, C. Günther,
M. Ochse, O. Schupp and S. Tasler, Prog. Chem. Org. Nat.
Prod., 2001, 82, 1; (c) O. Baudoin and F. Guéritte, Stud. Nat.
Prod. Chem., 2003, 29(Part J), 355; (d) H. Aldemir, R. Richarz
and T. A. M. Gulder, Angew. Chem., Int. Ed., 2014, 53, 8286.
Reviews: (a) L. Pu, Chem. Rev., 1998, 98, 2405; (b) R. Noyori,
Asymmetric Catalysis in Organic Synthesis, Wiley, New York,
5 For selected examples of oxidative biaryl couplings catalyzed
by chiral vanadium complexes, see: (a) S.-W. Hon, C.-H. Li,
J.-H. Kuo, N. B. Barhate, Y.-H. Liu, Y. Wang and C.-T. Chen,
Org. Lett., 2001, 3, 869; (b) C.-Y. Chu, D.-R. Hwang,
S.-K. Wang and B.-J. Uang, Chem. Commun., 2001, 980; (c)
Z. Luo, Q. Liu, L. Gong, X. Cui, A. Mi and Y. Jiang, Chem.
Commun., 2002, 914; (d) N. B. Barhate and C.-T. Chen, Org.
Lett., 2002, 4, 2529; (e) C.-Y. Chu and B.-J. Uang,
Tetrahedron: Asymmetry, 2003, 14, 53; ( f ) H. Somei,
Y. Asano, T. Yoshida, S. Takizawa, H. Yamataka and
H. Sasai, Tetrahedron Lett., 2004, 45, 1841; (g) M. Tada,
T. Taniike, L. M. Kantam and Y. Iwasawa, Chem. Commun.,
2004, 2542; (h) M. Tada, N. Kojima, Y. Izumi, T. Taniike and
Y. Iwasawa, J. Phys. Chem. B, 2005, 109, 9905; (i) Q.-X. Guo,
Z.-J. Wu, Z.-B. Luo, Q.-Z. Liu, J.-L. Ye, S.-W. Luo, L.-F. Cun
and L.-Z. Gong, J. Am. Chem. Soc., 2007, 129, 13927; ( j)
S. Takizawa, T. Katayama, H. Somei, Y. Asano, T. Yoshida,
C. Kameyama, D. Rajesh, K. Onitsuka, T. Suzuki,
M. Mikami, H. Yamataka, D. Jayaprakash and H. Sasai,
Tetrahedron, 2008, 64, 3361; (k) S. Takizawa, J. Kodera,
Y. Yoshida, M. Sako, S. Breukers, D. Enders and H. Sasai,
Tetrahedron, 2014, 70, 1786.
2
1
994; (c) C. Rosini, L. Franzini, A. Raffaelli and P. Salvadori,
Synthesis, 1992, 503; (d) T. Hayashi, Acc. Chem. Res., 2000,
3, 354; (e) J. M. Brunel, Chem. Rev., 2005, 105, 857; ( f )
3
M. Berthod, G. Mignani, G. Woodward and M. Lemaire,
Chem. Rev., 2005, 105, 1801.
3
For reviews about the atroposelective synthesis of axially
chiral biaryls (methodology and application), see: (a)
G. Bringmann, A. J. Price Mortimer, P. A. Keller,
M. J. Gresser, J. Garner and M. Breuning, Angew. Chem., Int.
Ed., 2005, 44, 5384; (b) O. Baudoin, Eur. J. Org. Chem., 2005,
4
223; (c) M. C. Kozlowski, B. J. Morgan and E. C. Linton,
Chem. Soc. Rev., 2009, 38, 3193; (d) G. Bringmann,
T. Gulder, T. A. M. Gulder and M. Breuning, Chem.
Rev., 2011, 111, 563; (e) S. E. Allen, R. R. Walvoord,
R. Padilla-Salinas and M. C. Kozlowski, Chem. Rev.,
6 For oxidative biaryl couplings catalyzed by other chiral
transition metal complexes, see: Ru: (a) T. Hamada,
H. Ishida, S. Usui, Y. Watanabe, K. Tsumura and K. Ohkubo,
J. Chem. Soc., Chem. Commun., 1993, 909; (b) R. Irie,
K. Masutani and T. Katsuki, Synlett, 2000, 1433; Fe; (c)
H. Egami and T. Katsuki, J. Am. Chem. Soc., 2009, 131, 6082;
(d) H. Egami, K. Matsumoto, T. Oguma, T. Kunisu and
T. Katsuki, J. Am. Chem. Soc., 2010, 132, 13633.
2
013, 113, 6234.
4
For selected recent developments in the atroposelective
synthesis of biaryls, see: (a) X. Shen, G. O. Jones, D. A. Watson,
B. Bhayana and S. L. Buchwald, J. Am. Chem. Soc., 2010, 132,
1
1278; (b) J. L. Gustafson, D. Lim and S. J. Miller, Science, 2010,
3
28, 1251; (c) F. Guo, L. C. Konkol and R. J. Thomson, J. Am.
Chem. Soc., 2011, 133, 18; (d) N. Asakura, S. Fujimoto,
N. Michihata, K. Nishii, H. Imagawa and H. Yamada, J. Org.
Chem., 2011, 76, 9711; (e) P. Wessig, C. Pick and U. Schilde,
7 For other types of enantioselective oxidative biaryl couplings,
see: Electrochemically: (a) T. Osa, Y. Kashiwagi, Y. Yanagisawa
Catal. Sci. Technol.
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Paper
and J. M. Bobbitt, J. Chem. Soc., Chem. Commun., 1994, 2535;
enzymatic; (b) M. Takemoto, Y. Suzuki and K. Tanaka,
Tetrahedron Lett., 2002, 43, 8499; (c) F. Trotta, G. Cravotto and
S. Rossignoli, J. Inclusion Phenom. Macrocyclic Chem., 2002, 44,
14 For the oxidative biaryl coupling of 1 catalyzed by other
chiral copper–diamine complexes, see: (a) A. Caselli,
G. B. Giovenzana, G. Palmisano, M. Sisti and T. Pilati,
Tetrahedron: Asymmetry, 2003, 14, 1451; (b) J. Illesinghe,
R. Ebeling, B. Ferguson, J. Patel, E. M. Campi, W. R. Jackson
and A. J. Robinson, Aust. J. Chem., 2004, 57, 167; (c) S. Arai,
S. Takita and A. Nishida, Eur. J. Org. Chem., 2005, 5262; (d)
L. Chen, J.-b. Lan and R.-g. Xie, Hecheng Huaxue, 2006, 14,
581; (e) P. Yan, Y. Sugiyama, Y. Takahashi, H. Kinemuchi,
T. Temma and S. Habaue, Tetrahedron, 2008, 64, 4325; ( f )
Y. Yusa, I. Kaito, K. Akiyama and K. Mikami, Chirality,
2010, 22, 224; (g) S. Sabarinathan, G. Vasuki and P. S. Rao,
Eur. J. Chem., 2010, 1, 360; (h) G. Grach, G. Pieters, A. Dinut,
V. Terrasson, R. Medimagh, A. Bridoux, V. Razafimahaleo,
A. Gaucher, S. Marque, J. Marrot, D. Prim, R. Gil,
J. G. Planas, C. Viñas, I. Thomas, J.-P. Roblin and Y. Troin,
Organometallics, 2011, 30, 4074.
2
93; (d) F. Trotta, G. Cravotto and G. Casile, Environ. Sci.
Pollut. Res., 2003, 10, 144.
8
9
(a) M. Nakajima, K. Kanayama, I. Miyoshi and
S.-I. Hashimoto, Tetrahedron Lett., 1995, 36, 9519; (b)
M. Nakajima, I. Miyoshi, K. Kanayama, S.-I. Hashimoto,
M. Noji and K. Koga, J. Org. Chem., 1999, 64, 2264.
The atroposelectivities observed in earlier biaryl couplings of
2
-naphthols mediated by an (over)stoichiometric amount of
a copper–diamine complex are not the result of an asymmet-
ric coupling step, but of a succeeding dynamic kinetic reso-
lution or a diastereoselective crystallization of the initially
formed biaryl–copper–diamine complexes: (a) J. Brussee and
A. C. A. Jansen, Tetrahedron Lett., 1983, 24, 3261; (b) J. Brussee,
J. L. G. Groenendijk, J. M. te Koppele and A. C. A. Jansen,
Tetrahedron, 1985, 41, 3313; (c) M. Smrčina, M. Lorenc,
V. Hanuš, P. Sedmera and P. Kočovský, J. Org. Chem.,
15 K. H. Kim, D.-W. Lee, Y.-S. Lee, D.-H. Ko and D.-C. Ha,
Tetrahedron, 2004, 60, 9037.
16 S. K. Alamsetti, E. Poonguzhali, D. Ganapathy and G. Sekar,
Adv. Synth. Catal., 2013, 355, 2803.
1
992, 57, 1917; (d) M. Smrčina, J. Poláková, Š. Vyskočil and
P. Kočovský, J. Org. Chem., 1993, 58, 4534.
0 The first truly asymmetric oxidative biaryl coupling was
17 (a) M. Breuning, D. Hein, M. Steiner, V. H. Gessner and
9
1
C. Strohmann, Chem. – Eur. J., 2009, 15, 12764; (b)
9
d
reported in 1993 by Smrčina and Kočovský et al.
the presence of 10 mol% of a sparteine-CuCl complex and
with AgCl as the stoichiometric oxidant, the product biaryl
was obtained in low 32% ee.
In
M. Breuning, M. Steiner, C. Mehler, A. Paasche and D. Hein,
J. Org. Chem., 2009, 74, 1407; (c) M. Breuning, T. Häuser,
C. Mehler, C. Däschlein, C. Strohmann, A. Oechsner and
H. Braunschweig, Beilstein J. Org. Chem., 2009, 5(81); (d)
M. Breuning, A. Paasche, M. Steiner, S. Dilsky,
V. H. Gessner, C. Strohmann and B. Engels, J. Mol. Struct.,
2011, 1005, 178; (e) M. Breuning and D. Hein, Eur. J. Org.
Chem., 2013, 7575.
2
1
1 For a copper-catalyzed, enantioselective oxidative biaryl
coupling of 1-naphthol, see: J. Gao, J. H. Reibenspies and
A. E. Martell, Angew. Chem., Int. Ed., 2003, 42, 6008.
2 (a) X. Li, J. Yang and M. C. Kozlowski, Org. Lett., 2001, 3,
1
1
137; (b) M. C. Kozlowski, X. Li, P. J. Carroll and Z. Xu,
18 Reviews: (a) J. Boruwa, N. Gogoi, P. P. Saikia and
N. C. Barua, Tetrahedron: Asymmetry, 2006, 17, 3315; (b)
C. Palomo, M. Oiarbide and A. Laso, Eur. J. Org. Chem.,
2007, 2561; (c) G. Blay, V. Hernández-Olmos and J. R. Pedro,
Synlett, 2011, 1195; (d) G. Chelucci, Coord. Chem. Rev.,
2013, 257, 1887; (e) N. Ananthi and S. Velmathi, Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem., 2013, 52, 87.
19 D. Scharnagel, F. Prause, J. Kaldun, R. G. Haase and
M. Breuning, Chem. Commun., 2014, 50, 6623.
Organometallics, 2002, 21, 4513; (c) X. Li, J. B. Hewgley,
C. A. Mulrooney, J. Yang and M. C. Kozlowski, J. Org. Chem.,
2
003, 68, 5500; (d) J. B. Hewgley, S. S. Stahl and
M. C. Kozlowski, J. Am. Chem. Soc., 2008, 130, 12232.
3 Applications of diamine 4 in the atroposelective synthesis
of biaryl natural products: (a) C. A. Mulrooney, X. Li,
E. S. DiVirgilio and M. C. Kozlowski, J. Am. Chem. Soc.,
1
2
003, 125, 6856; (b) M. C. Kozlowski, E. C. Dugan,
E. S. DiVirgilio, K. Maksimenka and G. Bringmann, Adv.
Synth. Catal., 2007, 349, 583; (c) E. S. DiVirgilio, E. C. Dugan,
C. A. Mulrooney and M. C. Kozlowski, Org. Lett., 2007, 9,
20 F. Prause, J. Kaldun, B. Arensmeyer, B. Wennemann,
B. Fröhlich, D. Scharnagel and M. Breuning, Synthesis,
2015, DOI: 10.1055/s-0034-1379457.
3
85; (d) E. M. O'Brien, B. J. Morgan and M. C. Kozlowski,
21 The structures of the products 8 and 9 prepared by hydroxy–
amine exchange were unambiguously confirmed by 2D NMR
experiments. Rearrangements of 12 to β-amino piperidines
via the sequence of mesylation–aziridinium formation–
nucleophilic attack at C-2 under ring enlargement were not
observed. It had been shown that such rearrangements
do not occur under mild mesylation conditions and with
amines as the nucleophiles, see: (a) D. G. Pargo and
J. Cossy, Chem. – Eur. J., 2014, 20, 4516. See also: (b)
R. H. Reitsema, J. Am. Chem. Soc., 1949, 71, 2041; (c)
J. H. Biel, W. K. Hoya and H. A. Leiser, J. Am. Chem. Soc.,
1959, 81, 2527; (d) C. F. Hammer, S. R. Heller and
J. H. Craig, Tetrahedron, 1972, 28, 239.
Angew. Chem., Int. Ed., 2008, 47, 6877; (e) B. J. Morgan,
S. Dey, S. W. Johnson and M. C. Kozlowski, J. Am. Chem.
Soc., 2009, 131, 9413; ( f ) C. A. Mulrooney, B. J. Morgan,
X. Li and M. C. Kozlowski, J. Org. Chem., 2010, 75, 16; (g)
B. J. Morgan, C. A. Mulrooney, E. M. O'Brien and
M. C. Kozlowski, J. Org. Chem., 2010, 75, 30; (h)
B. J. Morgan, C. A. Mulrooney and M. C. Kozlowski, J. Org.
Chem., 2010, 75, 44; (i) E. M. O'Brien, B. J. Morgan,
C. A. Mulrooney, P. J. Carroll and M. C. Kozlowski, J. Org.
Chem., 2010, 75, 57; ( j) E. E. Podlesny and M. C. Kozlowski,
Org. Lett., 2012, 14, 1408; (k) E. E. Podlesny and
M. C. Kozlowski, J. Org. Chem., 2013, 78, 466.
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II
2
2 To our surprise, this problem has not yet been mentioned
free, catalytically active Cu -species. This pathway is also
fully consistent with the experimental results. We therefore
did not include an oxidized naphthol ligand in our mecha-
nistic model.
8
,12,14a–d, f–h,15,16
in any other publication
dealing with the
enantiomer analysis of 2.
2
2
3 For proposed transition states in the presence of other
chiral diamines, see ref. 8b,12a–c,14g and 15.
26 The product distribution in competition experiments is
1
2a,c
4 (a) Ref. 12b, and 14f; (b) L. M. Mirica, X. Ottenwaelder and
T. D. P. Stack, Chem. Rev., 2004, 104, 1013; (c) V. Mahadevan,
Z. Hou, A. P. Cole, D. E. Root, T. K. Lal, E. I. Solomon and
T. D. P. Stack, J. Am. Chem. Soc., 1997, 119, 11996; (d)
S. Mahapatra, J. A. Halfen and W. B. Tolman, J. Am. Chem.
Soc., 1996, 118, 11575; (e) V. Mahadevan, M. J. Henson,
E. I. Solomon and T. D. P. Stack, J. Am. Chem. Soc., 2000, 122,
most consistent with a radical–radical coupling.
In
contrast, a radical–anion coupling seems to occur in the
presence of a stoichiometric amount of a copper–diamine
complex, see: (a) M. Hovorka, J. Günterová and J. Závada,
Tetrahedron Lett., 1990, 31, 413; (b) M. Smrčina, Š. Vyskočil,
B. Máca, M. Polášek, T. A. Claxton, A. P. Abbott and
P. Kočovský, J. Org. Chem., 1994, 59, 2156.
1
2
0249; ( f ) S. Dong, J. Zhu and J. A. Porco Jr., J. Am. Chem. Soc.,
008, 130, 2738; (g) P. Kang, E. Bobyr, J. Dustman,
27 (a) A. I. Meyers and K. A. Lutomski, J. Am. Chem. Soc.,
1982, 104, 879; (b) A. I. Meyers and D. G. Wettlaufer, J. Am.
Chem. Soc., 1984, 106, 1135.
28 (a) C. Girard and H. B. Kagan, Angew. Chem., Int. Ed.,
1998, 37, 2922; (b) D. Heller, H.-J. Drexler, C. Fischer,
H. Buschmann, W. Baumann and B. Heller, Angew. Chem.,
Int. Ed., 2000, 39, 495; (c) D. G. Blackmond, Acc. Chem. Res.,
2000, 33, 402; (d) H. B. Kagan, Synlett, 2001, 888.
K. O. Hodgson, B. Hedman, E. I. Solomon and T. D. P. Stack,
Inorg. Chem., 2010, 49, 11030; (h) J. Jover, P. Spuhler, L. Zhao,
C. McArdle and F. Maseras, Catal. Sci. Technol., 2014, 4, 4200.
2
5 Kozlowski et al. also observed a fast uptake of O
2
and 1a in
the beginning of the reaction, but without any product
formation.
1
2d
On this basis they proposed that the
catalytically active Cu-species contains an additional, oxi-
dized naphthyl ligand, presumably an ortho-quinonic spe-
cies, which functions like a cofactor in enzymes. We do
not think that this is the only possible explanation for the
observation made. We suppose that there is a fast ligand
exchange at and oxygenation of the initially applied complex
CuI·4 (“burst phase”), leading to a catalytically inactive, oxy-
29 A catalytic cycle via octahedral copper species cannot be
fully excluded, but is very unlikely. For a short discussion,
see footnote 58 in ref. 12c.
30 An oxidation of the copperIJ ) atom in 13 prior to the
I
chelation of 1a is also possible (and stereochemically not of
relevance). This sequence, however, seems to be less likely
since the oxidation is slow (rate-limiting step in the catalytic
12d
genated copper complex of type ijCuO Ĵ4Ĵ1a]n (resting state;
cycle).
x
for examples of oxygenated di- and oligomeric Cu-complexes,
see ref. 24), which only slowly breaks down to the oxygen-
31 W. L. F. Armarego and D. D. Perrin, Purification of Laboratory
Chemicals, Butterworth-Heinemann, Oxford, 4th edn, 2000.
Catal. Sci. Technol.
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