Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral Auxiliary for Asymmetric C(sp3)?H Bond Activation

Article abstract of DOI:10.1002/chem.201603507

An original and recyclable chiral bidentate aniline-sulfoxide-based directing group has been developed. This auxiliary allows challenging stereoselective Pd-catalyzed direct functionalization of small cycloalkanes through C–aryl and C–alkyl bond formation. Although moderate diastereoselectivities are observed, both optically pure enantiomers of the highly functionalized products can be obtained separately by simple silica gel chromatography and cleavage of the chiral auxiliary. This strategy was further applied to the preparation of enantiomerically pure 1,2,3-trisubstituted cyclopropane carboxylic acid derivatives, with three stereogenic centers and bearing both alkyl and aromatic substituents. These molecular scaffolds are not yet reported in the literature. The synthetic utility of this approach is validated by the chiral auxiliary being readily cleaved and recovered posteriori to the C?H activation step, without deterioration of its optical purity. Finally, an unprecedented palladacycle intermediate generated through C?H activation of the cyclopropane moiety has been isolated and fully characterized. Initial DFT calculations shed additional light on the reactivity of this original intermediate.

Full text of DOI:10.1002/chem.201603507

DOI: 10.1002/chem.201603507
Full Paper
&
Asymmetric Catalysis |Hot Paper|
Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral
3
Auxiliary for Asymmetric C(sp )ÀH Bond Activation
[a]
[a]
[a]
[b]
Soufyan Jerhaoui, Faouzi Chahdoura, Clꢀmence Rose, Jean-Pierre Djukic,
[a]
[a]
Joanna Wencel-Delord,* and FranÅoise Colobert*
Abstract: An original and recyclable chiral bidentate aniline-
sulfoxide-based directing group has been developed. This
auxiliary allows challenging stereoselective Pd-catalyzed
direct functionalization of small cycloalkanes through C–aryl
and C–alkyl bond formation. Although moderate diastereo-
selectivities are observed, both optically pure enantiomers
of the highly functionalized products can be obtained sepa-
rately by simple silica gel chromatography and cleavage of
the chiral auxiliary. This strategy was further applied to the
preparation of enantiomerically pure 1,2,3-trisubstituted cy-
clopropane carboxylic acid derivatives, with three stereogen-
ic centers and bearing both alkyl and aromatic substituents.
These molecular scaffolds are not yet reported in the litera-
ture. The synthetic utility of this approach is validated by
the chiral auxiliary being readily cleaved and recovered pos-
teriori to the CÀH activation step, without deterioration of
its optical purity. Finally, an unprecedented palladacycle in-
termediate generated through CÀH activation of the cyclo-
propane moiety has been isolated and fully characterized.
Initial DFT calculations shed additional light on the reactivity
of this original intermediate.
[8]
Introduction
aliphatic motifs. Intermolecular catalytic systems in which
a chiral induction is attained by differentiation of stereotopic
protons of a methylene bridge are even more challenging. To
achieve this goal, several research groups focused on the func-
tionalization of chiral amino acid derivatives, imposing the
chiral induction by the presence of a proximal stereogenic
The extraordinary advances achieved over the last decade in
the field of CÀH bond activation render this approach a truly
useful strategy for the synthesis of complex molecules from
[
1,2]
simple and non-prefunctionalized starting materials.
In clear
[9]
contrast, the stereoselective outcome of such transformations
has remained a niche topic for years and it is only recently
that this field has been attracting a growing interest from the
center. Yu discovered that monoprotected amino acids may
also play the role of chiral ligands in the enantioselective trans-
II
0
[10]
formations occurring through a Pd /Pd mechanism. Recent-
ly, enantioselective functionalization of cyclopropylmethyla-
mine cores was achieved by Yu using monoprotected amino
[
3]
scientific community. Accordingly, several catalytic systems
have been devised to allow, for example, the generation of ax-
[
4]
[5]
[11]
ially chiral, planar-chiral, and stereogenic spirocyclic-type
acids, and Duan reported functionalization of aliphatic linear
[
6]
2
[12]
molecules by means of C(sp )ÀH bond activation. The direct
functionalization of aliphatic CÀH bonds is recognized to be
substrates by employing phosphoric amides ligands. As the
monoprotected amino acids clearly stand out as a privileged
more challenging than those of aromatic ones and therefore,
chirality source in asymmetric CÀH activation, Hong astutely
3
accessing stereogenic carbons by means of asymmetric C(sp )À installed this motif directly on a substrate as a directing group,
[
7]
[13]
H bond activation presents an additional difficulty. The initial
targeting diastereoselective reactions.
3
key achievements in C(sp )ÀH activation concerned mainly in-
With regard to the widely recognized potential of bicoordi-
nating directing groups to facilitate challenging functionaliza-
tramolecular reactions in which a chiral catalyst, preinstalled
on a molecule, was prompted to differentiate two stereotopic
[14]
tion of aliphatic substrates, the conception of original chiral
bidentate directing groups, implying different sources of chiral-
[
a] S. Jerhaoui, Dr. F. Chahdoura, C. Rose, Dr. J. Wencel-Delord, Prof. F. Colobert
Laboratoire de Chimie Molꢀculaire (UMR CNRS 7509)
Universitꢀ de Strasbourg, ECPM
ity from the commonly used amino acid scaffolds, is highly ap-
[15]
pealing.
However, when designing a synthetically useful
system, it is essential to use a chiral inductor/directing group
that may be easily installed and cleaved posteriori to the func-
tionalization event (Figure 1). Ideally, the chiral auxiliary should
also be recyclable without alteration of its optical purity. Nota-
bly, generation of diastereomeric products gives a unique op-
portunity for their convenient separation while allowing isola-
tion of the desired product with a total optical purity. If these
conditions were met, such a diastereoselective transformation
2
5 Rue Becquerel, 67087 Strasbourg (France)
E-mail: wenceldelord@unistra.fr
francoise.colobert@unistra.fr
[
b] Dr. J.-P. Djukic
LCSOM, Institut de Chimie de Strasbourg (UMR 7177)
Universitꢀ de Strasbourg
4
, rue Blaise Pascal, 67070 Strasbourg Cedex (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603507.
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would be synthetically as appealing as an enantioselective re-
action, because no additional steps are required and the chiral
source is regenerated. Considering these criteria and encour-
aged by our recent work showing the potential of a sulfoxide
moiety to allow highly atropo-diastereoselective CÀH activatio-
exchange of N-(2-bromophenyl)pivalamide, followed by an
electrophilic trapping with 2, and deprotection, afforded 1 in
70% yield (Scheme 1A). Targeting a more atom-economical
pathway, a sequence of directed ortho-lithiation of N-phenylpi-
valamide/electrophilic trapping with 2 was evaluated, but
under these conditions, 1 was isolated in a lower yield of 35%
over 2 steps. The third approach, inspired by Lloyd-Jones and
[
4a–d]
n,
we designed a 2-(p-tolylsulfinyl)aniline (1) moiety as
a precursor for an original bicoordinating directing group
Figure 2). The chiral induction might be anticipated by coordi-
[17]
(
Booker-Milburn, consisted of a one-pot generation of a urea
derivative, followed by ortho-lithiation and quenching with 2.
However, no product formation was observed.
nation of the stereogenic sulfur atom to the Pd-catalyst. We
expect that the primary amine motif would allow its handy in-
stallation on a carboxylic acid derived substrate through amide
coupling (Path A) and ensure a second coordination site. Alter-
natively, the aliphatic amide-sulfoxide derivatives may be con-
structed in two steps (Path B), 1) preparation of N-(2-bromo-
phenyl)-aliphatic carboxamide, followed by 2) lithium/bromine
exchange and an electrophilic trapping with an enantiopure
sulfoxide precursor.
Scheme 1. Synthesis of enantiopure 1 (Tol=tolyl).
With the enantiopure 1 in hand, we embarked on an evalua-
tion of its potential for the direct asymmetric activation of cy-
Figure 1. Diastereoselective CÀH activation using a traceless and recyclable
[18]
clopropane derivatives, because they are important scaffolds
chiral DG.
[19]
in pharmaceutical and agrochemical industry. Accordingly, N-
2-(p-tolylsulfinyl)phenyl]cyclopropanecarboxamide (3) was pre-
[
pared by amide coupling between 1 and cyclopropanecarbon-
yl chloride (retrosynthetic pathway A, Figure 2) in quantitative
yield. Notably, the alternative approach (retrosynthetic path-
way B, Figure 2) based on an initial construction of N-(2-bro-
mophenyl)cyclopropanecarboxamide, followed by lithium/bro-
mine exchange and an electrophilic trapping with 2 was also
effective, delivering enantiopure 3 in 71% yield.
Promisingly, the first attempt of a direct functionalization of
3
, using Pd(OAc) catalyst, AgOAc as base (OAc=acetate), 4-io-
2
doanisole (4a, 4 equiv) as coupling partner, and conducting
the reaction in toluene at 1208C, showed the formation of the
desired product 5, but in trace amounts (Table 1, entry 1). A
significantly higher reactivity was observed when an electron-
poor aryl iodide, such as 4-iodoacetophenone (4b), was em-
ployed. The arylation occurred with 80% conversion and 64:36
diastereomeric ratio, together with 3% of the biarylated side
product (Table 1, entry 2). Replacing the toluene solvent by di-
chloromethane or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) al-
lowed for a decrease in the reaction temperature to 100 and
808C, respectively, but maintained the high conversion
(Table 1, entries 3–4). The addition of 0.5 equiv of NaTFA
(TFA=trifluoroacetate) resulted in a further improvement of
Figure 2. Retrosynthetic pathways for the preparation of aliphatic substrates
bearing the chiral aniline-sulfoxide-based DG.
Results and Discussion
Our work commenced with the preparation of (S)-2-(p-tolylsul-
finyl)aniline 1. As no general synthetic pathway to access
[16]
a chiral primary sulfinyl aniline was known in the literature,
we evaluated three different strategies, using (1R,2S,5R)-(À)-
menthyl-(S)-p-toluenesulfinate (2) as an easily accessible pre-
cursor (Scheme 1). The first strategy applying bromine/lithium
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[
a]
Table 1. Optimization of the diastereoselective arylation of 3.
[
c]
Entry
4
Base
Solvent
T
Conversion
[%]
5A:5B
Mono:
biarylation [%]
[
b]
[c]
[
8C]
1
2
3
4
4a
4b
4b
4b
4b
4b
4b
4b
4b
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
PhMe
PhMe
DCM
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
120
120
100
80
80
80
80
100
100
13
80
60
88
100
78
40
80
85
nd
nd
64:36
65:35
63:37
61:39
61:39
52:48
66:34
64:36
97:3
96:4
96:4
95:5
97:3
96:4
97:3
97:3
[
d]
5
6
7
8
9
Ag
2
CO
3
AgTFA
AgOAc
AgOAc
[
[
e]
f]
1
[
[
a] General reaction conditions: 3 (0.15–0.30 mmol), 4 (4 equiv), Pd(OAc)
c] Determined by chiral HPLC; nd=not determined. [d] 0.5 equiv of NaTFA was added. [e] Pd(TFA)
2
(10 mol%), AgOAc (4 equiv), solvent (0.15m), 18 h. [b] Determined by H NMR.
. [f] Pd(OPiv) . Ac=acetyl, Piv=pivaloyl.
2
2
the reactivity of this catalytic system allowing full consumption
of 3 (Table 1, entry 5). Neither solvent nor temperature signifi-
cantly impacted the diastereoselectivity of this transformation.
Also, no improvement was evidenced when modifying the pal-
ladium catalyst or silver salt (Table 1, entries 6–9). Undesired
biarylation could be avoided by lowering the excess of the io-
doarene partner 4.
[
a]
Table 2. Influence of steric hindrance of the chiral auxiliary.
Considering that the chiral information is transferred from
the stereogenic sulfoxide moiety, we speculated that a modifi-
cation of the steric hindrance on the sulfur atom should direct-
ly impact the diastereoselectivity of this transformation
[
c]
Entry
Substrate
R
Conversion
A:B
[
b]
[
%]
1
2
3
4
5
6
7
3
6
7
8
9
p-tolyl
2,4,6-mesityl
3,5-xylyl
p-t-buylphenyl
isopropyl
cyclohexyl
t-butyl
90
45
70
55
42
35
30
60:40
70:30
65:35
65:35
70:30
85:15
90:10
(Table 2). Thus, several racemic N-[2-(sulfinyl)phenyl)]cyclopro-
panecarboxamide substrates 6–11 were synthesized (retrosyn-
thetic pathway B, Figure 2). Replacement of the p-tolyl sub-
stituent of the sulfoxide by other aromatics, such as 2,4,6-tri-
methylbenzene (6), 3,5-dimethylbenzene (7), or 4-tert-butyl-
benzene (8) only slightly improved the stereoselectivity
10
11
[a] General reaction conditions:
Pd(OAc)
08C, 18 h. [b] Determined by H NMR. [c] Determined by H NMR.
3
(0.15–0.30 mmol),
4
(1.5 equiv),
(Table 2, entries 2–4). In contrast, arylation of the substrates
2
(10 mol%), NaTFA (0.5 equiv), AgOAc (4 equiv), HFIP (0.15m),
1
1
8
10–11, with sulfoxide moieties bearing more sterically hinder-
ing aliphatic substituents, such as cyclohexyl and tert-butyl, oc-
curred with high diastereoselectivities of 85:15 and 90:10 re-
spectively, but with dramatically decreased yields (30–35%,
Table 2, entries 6–7). Disappointingly, an extensive optimization
study did not improve the reactivity of 11 towards this CÀH
functionalization.
system was obtained by adding a small amount of water as
co-solvent. Use of this solvent mixture also permitted the re-
duction of catalyst and silver salt loadings (down to 5 mol%
and 2.2 equiv, respectively). Under these reoptimized reaction
conditions, the direct arylation of 3 using a large panel of io-
doarenes 4 was performed (Table 3). When para-substituted
aryl iodides were employed, the chiral cyclopropane com-
pounds were usually generated in high yields but with modest
diastereoselectivities of approximately 60:40 (Table 3, en-
tries 1–6). However, both diastereoisomers could be isolated
separately, thus allowing access to optically pure enantiomeric
compounds. Importantly, the steric hindrance of the aryl cou-
Considering both the antagonism between efficiency and
stereoselectivity of this catalytic system and the formation of
diastereomeric products easily separable by simple silica-gel
column chromatrography, we decided to evaluate the scope of
this transformation using 3 with the 2-(p-tolylsulfinyl)aniline
(APS) auxiliary as the standard substrate. Unexpectedly, when
4-iodoacetophenone coupling partner 4b was replaced by
methyl 4-iodobenzoate (4c) the desired arylated product was
generated in trace amounts. Rewardingly, a more robust
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pling partner also influences the stereoselectivity of the overall
transformation; ArÀI bearing a nitro- or chloro- substituent in
the meta position (4i, 4k) or ester or aldehyde functionaliza-
tion in the ortho position (4n, 4o) delivered the functionalized
cyclopropanes with significantly improved diastereoselectivity
of 80:20 (Table 3, entries 8, 10, 13, 14). Remarkably, several syn-
thetically useful functionalities were well tolerated, such as
ester or chloro motifs. Additionally, iodoarenes bearing sub-
stituents such as trifluoromethyl (Table 3, entry 4) or nitro
(Table 3, entries 6, 8, 12, 15), which can be considered as an
amine precursor, important motifs in agrochemistry and phar-
maceutical industry, also worked well under our reaction con-
ditions. 4-bromoiodobenzene (4 f) could also be used as the
coupling partner (Table 3, entry 5), generating a product
equipped to undergo further functionalization, albeit in signifi-
cantly lower yield.
s C15
Figure 3. ORTEP-type diagram of the structure of (S R SC17)-5Ab.
[
a]
Table 3. Scope of the arylation of 3.
The APS-based bicoordinating directing group also allows
a direct arylation of a cyclobutane derivative 12 (Scheme 2). In
this case, however, a selective monofunctionalization turned
out to be more challenging. Under the standard reaction con-
ditions, the coupling with 4-iodoacetophenone (4b) afforded
the monoarylated 13 in 40% yield and a moderate diastereo-
selectivity of 70:30, together with the diarylated compound 14
in 18% yield.
[
b]
Entry Ar
d.r.
5A(a–q)
5B(a–q)
yield [%]
Total yield
[%]
[
c]
[c]
[d]
(
crude) yield [%]
1
2
3
4
5
6
7
8
9
0
4b: 4-Ac-C
4c: 4-CO Me-C
4d: 4-CN-C
4e: 4-CF -C
4 f: 4-Br-C
4g: 4-NO
4h: 3-Ac-C
4i: 3-NO -C
4j: 3-CF -C
4k: 3-Cl-C
4l: 3,5-di-Cl-C
4m: 3,5-di-NO
4n: 2-CO Me-C
4o: 2-CHO-C
4p: 2-NO -C
4q: C
6
H
4
60:40
60:40
60:40
65:35
60:40
60:40
70:30
80:20
70:30
80:20
70:30
70:30
80:20
80:20
70:30
60:40
54
54
52
45
26
54
55
70
55
56
32
41
36
37
33
90
91
85
62
26
82
77
91
80
74
43
58
45
53
88
48
2
6 4
H
6
H
4
[
e]
3
6
H
4
17
nd
28
22
21
25
18
11
17
6
H
4
2
6 4
-C H
6
H
4
2
6 4
H
[
[
[
e]
e]
e]
3
6 4
H
1
6 4
H
1
1
6 3
H
12
13
14
15
16
2 6 3
-C H
Scheme 2. Arylation of cyclobutane derivative 12.
2
6
H
4
45 (A+B mixture)
6
H
4
40
66
31
13
12
17
[
e]
2
6 4
H
6
H
5
The cyclohexane substrate also underwent direct arylation
under the optimized reaction conditions with a diastereoselec-
tivity of 70:30. Nevertheless, considering that both cis and
[
(
8
a] General reaction conditions: 3 (0.23 mmol), 4 (1.2 equiv), Pd(OAc)
5 mol%), NaTFA (0.5 equiv), AgOAc (2.2 equiv), HFIP:H O 9:1 (0.1m),
08C, 8–24 h. [b] Determined by H NMR. [c] Isolated yield. [d] Total isolat-
2
2
1
[21]
trans cyclopalladations occur, four separable products were
ed yield of A + B. [e] Isolated together with a small amount of 3; for de-
tails, see the Supporting Information.
obtained in a combined yield of 57% (cis products: 23 and
[22]
16% yield, trans products: 10 and 8% yield).
Although direct arylation by means of CÀH activation is
amongst the most frequently studied transformations, closely
related alkylations are much more challenging. In particular, ex-
Notably, this arylation reaction is equally efficient on gram
scale, rendering it synthetically applicable in multistep synthe-
sis. Using standard reaction conditions, non-distilled solvent
and under air, we were pleased to isolate the desired 5Ab and
3
3
amples of C(sp )ÀH activation/C(sp ) couplings are scarce.
Thus, we pursued our study by investigating the alkylation re-
action of small cyclic substrates bearing our aniline-sulfoxide-
derived directing group (APS) (Scheme 3). Remarkably, in the
presence of ethyl iodoacetate, the alkylation of 3 occurred
smoothly yielding diastereomeric products 15A and 15B in
34% and 24% yield, respectively, (overall yield of 58% and
60:40 d.r. of the crude mixture; d.r.=diastereomeric ratio).
Moreover, cyclobutane substrate 12 was also compatible with
this transformation and, contrary to the CÀAr coupling, selec-
5
Bb in the unchanged yields of 54 and 36%, respectively.
To assign the absolute configuration of the major and minor
products obtained, 5Ab was recrystallized from a mixture of
DCM:CHCl :Et O, providing monocrystals. The X-ray diffraction
3
2
[
20]
analysis showed a (SsRC15SC17) configuration of 5Ab. The ab-
solute configuration for the other products was attributed ac-
cordingly (Figure 3).
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Table 4. Scope of the arylation of trans-alkyl-substituted cyclopropane
[
a]
acid derivatives.
Entry
R
Product
A yield
B yield
[%]
Total yield
[%]
[
b]
[b]
[c]
[
%]
1
2
3
4
5
6
Me
Me
Me
Me
nPr
nPr
19b: 4-Ac-C
19h: 3-Ac-C
6
H
H
4
52
56
54
50
56
47
31
36
31
36
34
40
83
92
85
86
90
87
6
4
19i: 3-NO
19q: Ph
2 6 4
-C H
3
1
Scheme 3. C(sp )ÀH alkylation. [a] d.r. of crude product measured by H
21b: 4-Ac-C
6
H
4
NMR.
21g: 4-NO -C
2
6
H
4
[
(
8
a] General reaction conditions: 16 (0.23 mmol), 4 (4 equiv), Pd(OAc)
10 mol%), NaTFA (0.5 equiv), AgOAc (4 equiv), HFIP:H O 9:1 (0.1m),
08C, 24 h; [b] Isolated yield. [c] Total isolated yield of A and B.
2
2
tive monofunctionalization was effective, yielding separately
both diastereomers of 16 in 46% and 21% yield, respectively.
Remarkably, although the diastereoselectivity remains moder-
ate (70:30), this reaction is, to the best of our knowledge, the
3
3
first example of the direct C(sp )ÀC(sp ) coupling of cyclobu-
tane derivative. Noteworthy is the significant increase of the
diastereoselectivity observed using a more sterically demand-
ing chiral directing group. Alkylation of 11 occured with high
were separated by a simple silica-gel column chromatography,
affording enantiomerically pure compounds containing three
C-stereocenters, in 52 and 31% yields, respectively. Subse-
quently, the generality of this challenging transformation was
illustrated by performing the coupling with several different io-
doarenes 4. In all cases, the reactions occur smoothly, deliver-
ing both diastereomers separately in decent yields. Moreover,
other aliphatic substituent on the cyclopropane ring, such as
an n-propyl chain, was also well tolerated (Table 4, entries 5-6);
the arylated product 21b and 21g were generated in total
yields of 90 and 87%, respectively. Both diastereomers 21Ab
and 21Bb were isolated in respective yields of 56 and 34%,
whereas 21Ag and 21Bg were isolated in 47 and 40% yields,
respectively. In addition, trisubsituted 2,3-dialkyl-cyclopropane
carboxylic acid may also be prepared employing our approach.
Alkylation of 20 with iodoethylacetate afforded 22 in a total
yield of 62%, isolated as 22A and 22B in respective yields of
40 and 22% (Scheme 4).
9
0:10 chiral induction but, as observed with the arylation, the
product 17 was isolated in a low yield of 13%.
Regarding the high reactivity of our catalytic system and the
usually very convenient separation of the two diastereomeric
products, this approach seems to be particularly well adapted
to prepare both enantiomers of optically pure 1,2,3-trisubsti-
tuted cyclopropane carboxylic acid derivatives from racemic
precursors. Notably, cyclopropane carboxylic acids bearing
both alkyl and aryl substituents are key biologically active scaf-
folds, used as epoxide hydrolase inhibitors involved in cardio-
[23,24]
vascular disease treatment and pyrethroid insecticides.
Ad-
ditionally, they may be applied as conformationally restricted
[
25]
peptide isosters. However, in spite of their importance, syn-
thesis of such scaffolds with cis configuration between the car-
boxylic acid and an aromatic ring and trans configuration rela-
tive to the alkyl moiety remains, to the best of our knowledge,
unexplored not only in enantioselective but also in a racemic
[
26]
manner.
Notably, because of the potential biological and
agrochemical reactivity of such a scaffold, straightforward
access to both enantiomers is highly desirable. Accordingly,
the direct CÀH arylation of trans-2-alkylcyclopropane-1-carbox-
ylic acid derivatives bearing the APS auxiliary, could pave the
way towards such a challenging goal.
Scheme 4. Direct alkylation of the substituted cyclopropane substrate 20.
Following this target, trans-(S)-2-methyl-N-(2-(p-tolylsulfinyl)-
[
27]
phenyl)cyclopropane-1-carboxamide (18),
was prepared in
one step from a racemic trans-2-methylcyclopropane-1-carbox-
ylic acid and our chiral auxiliary 1. Although under our stan-
dard conditions the reaction failed, increasing the amount of
the aryliodide 4b, the loading of the palladium catalyst (up to
Finally, the essential prerequisite rendering the present strat-
egy synthetically useful involves a straightforward cleavage of
the APS directing group and its recovery without alteration of
its optical purity. As expected, the removal of the sulfinyl ani-
line auxiliary 1 from 5Ab occurred readily using 1m KOH solu-
tion in EtOH at 808C. Rewardingly, this mild deprotection
allows the isolation and separation of both the enantiopure,
10mol%), and the silver salt allowed the formation of the ex-
pected product 19b in 83% yield, and, as expected, as two
diastereomers (Table 4, entry 1). Importantly, 19Ab and 19Bb
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highly functionalized cyclopropane carboxylic acid 23 and the
chiral inductor 1 in high yields by a simple acido-basic workup
clopropane-based palladacycle has been reported. In our initial
attempts, the substrate 3 was reacted with a stoichiometric
(86 and 97% respectively). Notably, as 1 was isolated without
amount of Pd(OAc) in acetonitrile at 608C. Encouragingly, for-
2
loss of its chiral purity, this moiety can indeed be considered
as a truly recyclable chiral source (Scheme 5).
mation of the palladacyclic intermediates was confirmed by
1
H NMR, but a mixture of OAc- and CH CN-ligated complexes
3
was evidenced. The addition of pyridine displaced weakly coor-
dinating ligands and the expected organometallic molecule
was formed cleanly as a mixture of two diastereoisomers in an
approximate 60:40 ratio. 24 is surprisingly stable and could be
purified by silica gel chromatography. Furthermore, (RsSC15SC17)-
2
4 afforded monocrystals and its structure could be further
[20]
confirmed by X-Ray diffraction analysis.
At this point, different hypothesis can be proposed to ra-
tionalize the modest diastereoselectivity observed. Firstly, the
X-Ray structure of 24A (Figure 4, view b), shows that the p-
tolyl group on the sulfinyl moiety is orientated above the cy-
clopropane core. Therefore, the steric interaction with protons
on C17 is minimized compared to the interaction with protons
at C16, yet favoring formation of 24A (Scheme 7). In line with
this, a significantly more sterically demanding tert-butyl group
on the sulfinyl auxiliary leads to more pronounced steric con-
gestion with the proton on C16, clearly disfavoring this inter-
mediate and resulting in an improved diastereoselectivity of
90:10 (Table 2, entry 7). Nevertheless, as the CÀH activation
step is reversible, the overall stereoselectivity may also result
from the different rates of oxidative addition and reductive
elimination steps (for the proposed catalytic cycle, see Figure 6
ahead). In particular, the clear improvement of the diastereose-
lectivity for the arylation with 2-substituted iodoarenes 4n and
4o (Table 3, entries 13,14) further supports this hypothesis.
Scheme 5. Deprotection of the functionalized carboxylic acid and recovery
of the chiral auxiliary 1.
As the sulfoxide-aniline moiety has never been used before
3
in the context of the asymmetric activation of C(sp )ÀH bonds,
we have subsequently undertaken some mechanistic investiga-
tions (Scheme 6). Targeting kinetic isotope effect studies, we
first focused on the preparation of the cis-1,2-deuterated sub-
strate 3-d . Remarkably, this original molecule could be synthe-
2
sized very easily using the CÀH activation strategy. When 3
was reacted with Pd(OAc) catalyst (5 mol%) and deuterated
2
acetic acid, in [D ]acetonitrile, a double cis-deuteration pro-
3
ceeded efficiently, providing 3-d in 88% yield, with >99% cis-
2
D purity. 3-d was then subjected to our standard arylation re-
2
action in the absence of the ArÀI coupling partner. Total deute-
rium/proton exchange was observed in only 8 h suggesting
a reversible character of this metallation step. In parallel, the
initial rates of the arylation of 3 and 3-d were measured. The
2
k /k ratio of 1.28 further suggests that in our catalytic system,
H
D
3
the C(sp )ÀH bond cleavage is probably not the rate determin-
ing step.
Scheme 7. Formation of diastereoisomeric palladacyclic species 24A and
2
4B (for clarity, the pyridine ligand is not represented for 24B) and pro-
posed origin of diastereoselectivity.
Scheme 6. Study of the reversibility of the CÀH activation step and determi-
nation of the kinetic isotope effect.
This crystallographic data provides key information about
the original cyclopropane-derived palladacycle. Firstly, the bi-
dentate character of the APS directing group is proven and
the amide group coordinates through its deprotonated form.
Moreover, although the sulfoxide moiety contains potentially
two chelating atoms, that is, O and S, the PdÀS coordination is
favored resulting in the formation of 5,5-bicyclic species. Im-
portantly, the rare examples of isolated palladacycle intermedi-
Regarding the smooth deuteration of 3 in acetonitrile and
the strongly coordinating nature of our bidentate DG, we
speculated that isolation of a metallacyclic intermediate could
be possible. The isolation and characterization of such an or-
ganometallic compound is undeniably appealing, as only very
3
few examples of palladacyclic species resulting from C(sp )ÀH
[
28]
3
activation are described in the literature. In particular, no cy-
ates generated through C(sp )ÀH activation of aliphatic, linear
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substrates bearing quinolin-8-amine derived N,N-bicoordinat-
[
28a,b]
ing (QA) DG show related 5,5-bicyclic structures.
A rapid
comparison of 24A with the literature-reported structures indi-
cates that APS moiety leads to formation of a larger metallacy-
clic species; for 24A the amide–Pd bond is 2.014 ꢂ, whereas
[
28b]
[28a]
for the QA intermediate, the values of 1.971
and 1.969 ꢂ
were determined (Figure 4). In addition, the SÀPd bond of
2
.329 ꢂ is significantly longer than the N(quinoline)ÀPd linkag-
[28b] [28a]
es (2.126
and 2.124 ꢂ ). In contrast, the PdÀC bond in 24
is shorter in comparison to its quinolin-8-amine congeners
[
28b]
[28a]
(2.001 vs. 2.023
and 2.012 ꢂ ). The N(1)-Pd-C(17) angle of
83.18 shows distortion from an idealized square planar geome-
try at the palladium center, which is coherent with the litera-
[
28a]
ture.
In addition, slight torsion of the second ring is ob-
served, as suggested by the S(1)-Pd-N(1) angle of 84.09 ꢂ, and
S(1)-C(8)-C(13) and C(8)-C(13)-N(1) angles of 118.928 and
117.098 respectively, together with the S(1)-C(8)-C(13)-N(1) tor-
sion of À0.908.
Figure 5. Maps of electrostatic potential (MEP) drawn on an isosurface of
the electron density (0.06 e/bohr ) and the related gas phase singlet ground
3
state geometries (ZORA-PBE-D3(BJ)/all electron TZP) of pre-24A (a) and 24A
(
b). The MEP of pre-24A was drawn on a flipped (rotated) geometry to em-
phasize the peculiar charge density depletion around the amide H atom.
Carbon and hydrogen atoms are colored in grey and white, respectively, in
the right hand side drawn geometries. Selected interatomic distances (ꢂ) for
pre-24A: PdÀN 2.133, PdÀC 2.028, PdÀS 2.369, PdÀO 2.043, CÀO 1.210, SÀO
1
.496. Selected interatomic distances (ꢂ) for 24A: PdÀN 2.032, PdÀC 2.035,
PdÀS 2.323, PdÀNpy 2.073, CÀO 1.237, SÀO 1.507.
(
noted pre-24A,B), indicates, however, that the N-bound
proton bears a rather high positive charge that makes it poten-
tially prone to abstraction by any moderate base such as the
acetate. This can be intuitively noted from the map of electro-
static potential drawn in Figure 5a, which denotes a dark blue
colored isosurface area indicative here of an important charge
density depletion at the amide proton. Deprotonation of this
position is key to the stabilization of the palladacycle as it re-
leases the nitrogen lone electron pair leading to enhanced
electron conjugation and planarization of the whole chelate.
Natural charges [extracted from Natural Bonding Orbital (NBO)-
Figure 4. Ortep-type diagram of the structure of 24A with full atom num-
bering. Ellipsoids are drawn at the 30% level. Selected interatomic distances
(
ꢂ) and angles (deg): S1ÀPd1 2.3289(13), O1ÀS1 1.477(4), N2ÀPd1 2.065 (4),
N1ÀPd1 2.014(4), C17ÀPd1 2.001(6), C16ÀC17 1.471(11), C8ÀC13 1.409(7),
N1-Pd1-S1 84.09(13), C17-Pd1-N1 83.1(2), C17-Pd1-S1 165.81(17), N1-Pd1-N2
176.12(18).
[31]
Furthermore, preliminary density functional theory (DFT-D)
Natural Population analysis ] clearly support the acidic char-
acter of this position (q(Hamide)= +0.43, q(H)average ~ +0.22) in
pre-24A. When comparing relevant interatomic distances
around the central Pd atom in going from pre-24A to 24 A,
one can note that the largest variation of distance is observed
by order of importance for the NamideÀPd bond (shortening by
0.10 ꢂ), the SÀPd bond (shortening by 0.05 ꢂ) and the CÀPd
bond (shortening by 0.01 ꢂ). As a consequence the amide CÀO
and sulfoxide SÀO distances undergo a slight elongation by
about 0.010-0.020 ꢂ. Further NBO analysis of 24A indicates
that in the assumed Lewis structure, the lowest bond electron
populations around the Pd center are found for the SÀPd and
computations were carried out without thorough investigation
of the reaction energy profile (Figure 5). Given the conditions
required for the catalysis to take place and the central role of
palladacyclic intermediates in the overall process, a mere com-
parison of the energies of metallacycles 24A and 24B that are
formed indicated that they were almost all isoenergetic within
À1
2
kcalmol (gas phase ground state geometries at 298.15 K,
[
29,30]
ZORA-PBE-D3(BJ)
/all electron TZP), with a slight bias in
favour of the tridentate complex 24A depicted in Figure 4 in
which the cyclopropyl methylene orientation is antara-facial
with respect to the sulfoxide oxygen atom. As a matter of fact,
in the present stage of the study, it was not possible to con-
firm that the deprotonation of the amidic NH position that
leads to neutral 24A took place before the cyclopalladation
step or after.
N
ÀPd bonds, which fall below the detection threshold of
pyridine
1.7 e. Their Wiberg bond indices (NBO), w, are w(SÀPd)=0.14
and w(N
ÀPd)=0.05, respectively. Interestingly, in the com-
pyridine
puted NBO Lewis structure, the bonds that actually seem to
Computation of the energies of the two low-lying tridentate
palladium acetate chelates, i.e., the precursors of 24A,B
support the chelate are the NamideÀPd and C
ÀPd, which
cyclopropyl
are both computed as the following linear combinations of
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2
.99
atom-centered orbitals: y(N
ÀPd) (1.89 e)=0.90(sp ) +
amide
N
Conclusion
0.95
0
.43(sd ) , w(Namide-Pd)=0.10; y(C
ÀPd) (1.83 e)=
Pd
cyclopropyl
3.54
1.21
0
.78(sp )C +0.62(sd ) , w(CÀPd)=0.53.
In summary, we have devised an original and truly recyclable
chiral auxiliary, (S)-2-(p-tolylsulfinyl)aniline (1) to construct a ste-
reogenic bidentate directing group. This original enantiopure
N,S-coordinating moiety allows Pd-catalyzed diastereoselective
direct functionalization of aliphatic CÀH bond of cyclopropane
and cyclobutane carboxylic acid derivatives. Both arylation and
more challenging alkylation reactions have been investigated
and moderate to good levels of diastereoselectivity are ob-
served. However, the formation of diastereomeric products
easily separable by simple silica-gel column chromatography
allows isolation of both diastereomers separately, thus giving
access to both optically pure enantiomers in synthetically
useful yields. Subsequently, this approach paved the way to-
wards preparation of unique, enantiomerically pure 1,2,3-tri-
substituted cyclopropane carboxylic acid derivatives containing
three stereocenters by functionalization of racemic precursors.
Targeting the mechanistic studies, the first palladacyclic inter-
mediate resulting from the CÀH activation of the cyclopropane
core has been isolated, showing unambiguously N,S-bicoordi-
nating character of our APS auxiliary. APS chiral auxiliary, which
is easy to install, to cleave and to recover is therefore a unique
Pd
On the basis of this study and in accordance with literature
precedents, a simplified catalytic scenario can be proposed
Figure 6). A substrate binding to the metal by coordinating S-
(
and N-atoms is believed to initiate the overall transformation.
3
tool for challenging asymmetric C(sp )ÀH activations and syn-
thesis of unprecedented chiral cyclopropane scaffolds with
possible biological and agrochemical applications.
Figure 6. Proposed catalytic cycle.
Experimental Section
The chelation with the deprotonative amide group bearing
a negative charge, enhances formation of Pd-intermediate Int1
bearing one anionic acetate ligand and allows the CÀH preacti-
To a Schlenk flask were added compound 3 (0.23 mmol, 1 equiv),
coupling partner 4 (0.28 mmol, 1.2 equiv), silver(I) acetate (86 mg,
[
32]
0
0
.52 mmol, 2.2 equiv), sodium trifluoroacetate (17 mg, 0.12 mmol,
.5 equiv), and palladium(II) acetate (2.6 mg, 0.012 mmol, 5 mol%).
vation through favorable Pd-CH agostic geometry. However,
the order of the elemental steps of NH-deprotonation and pal-
ladation, remains ambiguous. Subsequently, the reversible CÀH
activation takes place, probably through a concerted metalla-
tion-deprotonation pathway, enhanced in the presence of
NaTFA additive. This metallation step is believed to be stereo-
determinant, because the same diastereomeric ratio of the pal-
ladacyclic intermediates Int2 and the arylated products were
usually observed. Subsequent oxidative addition of ArÀI leads
HFIP (2 mL) and water (0.2 mL) were then added and the mixture
was stirred at 808C during the appropriate time (typically between
8
and 18 h) under air. The mixture was then allowed to cool to
room temperature, diluted with EtOAc, filtered over celite and
evaporated in vacuo. The crude was purified by column chroma-
tography on silica gel with cyclohexane/EtOAc to obtain the two
diastereomers of the title compound as pure enantiomers.
IV
to the formation of Pd intermediates Int3 and a final reduc-
tive elimination delivers both diastereomers of the product
and the catalyst is regenerated in the presence of AgOAc. No-
tably, the scope of the arylation of 3 clearly indicates that the
diastereoselectivity is improved when meta- and ortho-substi-
tuted iodoarenes 4 are used (Table 3, entries 8, 10, 13–14). It
can be hypothesized that when more sterically demanding 4
variants are used, the rate of the oxidative addition of Int2A
and Int2B and/or reductive elimination from the two diaste-
reomeric metallacyclic Int3 is different. Accordingly, one diaste-
reomer of Int3 is converted into the final product more rapidly
and the reversibility of the previous steps allows the re-equili-
bration of the ratio Int3A:Int3B. Therefore, in this case, the
overall stereoinduction would be impacted by both the diaste-
reoselectivity of the CÀH activation step and the rate of the ox-
idative addition/reductive elimination from the two diastereo-
meric intermediates.
Acknowledgements
We thank the CNRS (Centre National de la Recherche Scientifi-
que), the “Ministꢃre de l’Education Nationale et de la Recher-
che,” and ANR (Agence Nationale de la Recherche) France for
financial support. S.J. is very grateful to the ANR (Agence Na-
tionale de la Recherche), France for a doctoral grant and F.C.
acknowledges Idex “Attractivity” for a postdoctoral grant. We
are also very grateful to Matthieu Chessꢀ for his help in analy-
sis of compounds by chiral HPLC, and Drs. Lydia Karmazin and
Corinne Bailly for single crystal X-ray diffraction analysis.
Keywords: CÀH activation · chiral auxiliaries · cyclopropane ·
sulfoxide
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Published online on && &&, 0000
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FULL PAPER
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Asymmetric Catalysis
S. Jerhaoui, F. Chahdoura, C. Rose,
J.-P. Djukic, J. Wencel-Delord,* F. Colobert*
&& – &&
Enantiopure Sulfinyl Aniline as
a Removable and Recyclable Chiral
3
Auxiliary for Asymmetric C(sp )ÀH
APS: Asymmetric cycloPropane Synthe-
sis via CÀH activation strategy has been
achieved using new stereogenic bicoor-
dinating, sulfoxide-based directing
group. Enantiopure small cycloalkanes
with up to three carbon stereocenters
were constructed with concomitant re-
covery of the chiral directing group.
Bond Activation
Chem. Eur. J. 2016, 22, 1 – 11
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ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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