Application of chiral 2,6-bis(thiazolinyl)pyridines in asymmetric Ru-catalyzed cyclopropanations with diazoesters

Article abstract of DOI:10.1016/j.tetasy.2004.06.039

Chiral 2,6-bis(thiazolinyl)pyridines were examined as ligands for ruthenium-catalyzed asymmetric catalytic cyclopropanation of olefins with diisopropyl diazomethylphosphonate and ethyl diazoacetate. Enantioselectivities of up to 84% for the trans-cyclopro

Full text of DOI:10.1016/j.tetasy.2004.06.039

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2569–2573
Application of chiral 2,6-bis(thiazolinyl)pyridines in asymmetric
Ru-catalyzed cyclopropanations with diazoesters
a
Paul Le Maux, Isabelle Abrunhosa, Mathieu Berchel, G e´ rard Simonneaux,
b
a
a,
*
b
Mihaela Gulea and Serge Masson
b,
*
a
Laboratoire de Chimie Organom e´ tallique et Biologique, UMR CNRS 6509, Universit e´ de Rennes 1, 35042 Rennes Cedex, France
Laboratoire de Chimie Mol e´ culaire et Thio-organique, UMR CNRS 6507, Universit e´ de Caen et ISMRA, F-14050 Caen, France
b
Received 10 June 2004; accepted 28 June 2004
Available online 3 August 2004
Abstract—Chiral 2,6-bis(thiazolinyl)pyridines were examined as ligands for ruthenium-catalyzed asymmetric catalytic cyclopropa-
nation of olefins with diisopropyl diazomethylphosphonate and ethyl diazoacetate. Enantioselectivities of up to 84% for the trans-
cyclopropylphosphonate were observed.
ꢀ
2004 Elsevier Ltd. All rights reserved.
1
. Introduction
using ethyl diazoacetate, as well as diisopropyl diazo-
methylphosphonate. It should be emphasized that cyclo-
propylphosphonates display interesting biological
activity such as inhibition for deaminases and alanine
The asymmetric cyclopropanation of alkenes with dia-
zoesters catalyzed by transition metals has been inten-
sively studied since the first report by Nozaki et al. of
enantioselective cyclopropanation with a chiral cop-
per(II) chelate. Over the last decade, ruthenium com-
plexes have been redeveloped. This is partly due to
the design of ruthenium catalysts that possess chiral
bis(oxazolinyl)pyridine (Pybox) ligands described by
1
10
racemase.
2
,3
2. Results and discussion
Homochiral 2,6-bis(thiazolinyl)pyridines 1a–c (Scheme
1) were synthesized from dithioesters and commercial
enantiopure 2-aminoalcohols, as previously reported
4
Nishiyama et al. This catalytic system gives high trans-
4
,5
selectivity with high enantioselectivity. In contrast, a
limited number of chiral bis(thiazoline) ligands has been
7
for 1d.
6
,7
synthesized while their uses in catalytic reactions have
been rarely examined. Two remarkable exceptions are
the Rh(I)-catalyzed asymmetric hydrosilylation of
acetophenone and the Pd-catalyzed allylic substitution
7
reaction. Moreover, some of us have recently compared
6
S
S
N
the behaviour of several bis(thiazolines) and the corre-
sponding bis(oxazolines) as ligands in the Pd-catalyzed
Tsuji–Trost allylic substitution reaction with important
differences concerning the reactivity and asymmetric
N
1a-d
N
R
R
Ligand 1
1a
R
Et
iPr
Bn
Ph
Configuration
(R,R)
(S,S)
(S,S)
(R,R)
8
induction being observed. As part of our continuing
efforts to promote ruthenium complexes in asymmetric
1
b
9
1c
catalysis, we herein report the use of chiral ruthenium
1
d
2,6-bis(thiazolinyl)pyridine complexes as catalysts for
the asymmetric cyclopropanation of styrene derivatives
Scheme 1.
*
0
Corresponding authors. Tel.: +33-(0)2-99286285; fax: +33-(0)2-
9281646; e-mail: simonnea@univ-rennes1.fr
The asymmetric cyclopropanation of styrene and diazo-
ethylacetate was carried out using a solution of the
9
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.039

2570
P. Le Maux et al. / Tetrahedron: Asymmetry 15 (2004) 2569–2573
N2
Ph
Ru/thiapybox
2
1
2
1
Ph
+
+
H
CO Et
Ph
CO Et
CO Et
2
2
2
cis
trans
Scheme 2.
1
1
homochiral ligand and [Ru(p-cymene)Cl2]2 as an in
situ catalyst, in a protocol similar to that reported for
slightly alters the enantiomeric excess of the cyclo-
propane derivatives. Varying the substituents in the
para-phenyl position of the styrene does not change sig-
nificantly the enantiomeric excess, showing the weak
electronic effect of the substrate upon enantioselectivity.
In contrast, a remote electronic control in asymmetric
cyclopropanation with chiral Ru–Pybox was found,
4
bis(oxazolinyl)Ru complexes (Scheme 2). Four different
chiral 2,6-bis(thiazolinyl)pyridines 1a–d were used as lig-
ands (Scheme 1). For example, the addition of homochi-
ral ligand 1a or 1b to a solution of [Ru(p-cymene)Cl2]2
gave a dark red solution, which was stirred for 5h at
room temperature before addition of styrene and diazo-
acetate. By contrast, 1h of stirring was only necessary
with R = Bn and Ph substituted ligands 1c and 1d to ob-
tain the optimal conditions (see Experimental section).
The results are reported in Table 1.
1
2
with substituted bis(oxazoline)Ru.
These Ru–thia–Pybox complexes can also be applied
to catalyze styrene cyclopropanation with diisopropyl
diazomethylphosphonate (Scheme 3). Cyclopropylphos-
phonates are very convenient intermediates for the syn-
1
3
As it is evident from the data, the two ligands 1a
R = Et) and 1b (R = iPr) are superior to 1c (R = Bn)
thesis of diphenylmethylene-cyclopropane derivatives
1
4
(
by the Wadsworth–Emmons reaction. Since our first
catalytic enantioselective cyclopropanation of an olefin
with diisopropyl diazomethylphosphonate by a chiral
porphyrin ruthenium complex, only one study using
Ru-bis(oxazoline) catalytic system with diazomethyl-
phosphonate has been mentioned as a work to be pub-
lished in a review. Good enantiomeric excesses up to
90% were obtain. Herein, with R = Et, the yield and
the enantiomeric excesses compare well with those ob-
tained with ethyl diazoacetate (see Table 1). In this case,
however, the reaction time is longer (12h), as we have
and 1d (R = Ph). In all cases, the cyclopropanation is
very selective in favour of the trans-isomer, which is also
obtained with better enantiomeric excesses than its cis-
isomer (Scheme 2). With ligands 1a and 1b ee >80%
are observed and they are comparable to those previ-
ously reported for cyclopropanation using ruthenium
1
5
1
6
5
bis(oxazolinyl) complexes. By contrast, % ee values
for 1c (R = Bn) or 1d (R = Ph) reached only moderate
levels. A diagram allowing a comparison between the
two catalytic systems is shown below.
100
8
4
8
2
6
9
5
9
5
6
5
4
50
41
2
8
(
1R ,2R)
(1R ,2S)
0
ee (trans)
1S ,2S)
ee (cis)
-
15
(
(1S ,2R)
-24
-50
-
60
-
64
-
68
-
78
-
86
-
88
-
-
100
150
Et (R ,R )
i -Pr (S ,S )
Bnz (S ,S)
Ph (R, R)
ee (trans) ThiaPybox
ee (trans) Pybox
ee (cis) Thiapybox
ee (cis) Pybox
Although we could anticipate a different electronic den-
sity between the two ligands that is thia–Pybox and
Pybox, due to the presence of a sulfur atom in the
five-membered ring of the former, it appears in this
Ru-catalyzed cyclopropanation reaction that this modi-
fication does not change the preferred configuration and
previously observed with cyclopropanation of styrene
1
catalyzed by ruthenium porphyrins.
5
It has already been reported that cyclopropanation with
the Pybox-ruthenium system should proceed concert-
edly via an attack of styrene on the possible intermediate

P. Le Maux et al. / Tetrahedron: Asymmetry 15 (2004) 2569–2573
2571
Table 1. Asymmetric cyclopropanation of styrene and its derivatives with ethyl diazoacetate and isopropyl diazomethylphosphonate catalyzed by
a
Ru/thia–Pybox
Catalyst L =
Substrate
N
2
CHR R =
Products: trans- and cis-cyclopropyl esters
b
c
Yield (%)
Selectivity trans/cis
Ee (config.)
d
trans %
cis
Et
Styrene
Styrene
Styrene
Styrene
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
87
89
86
92
83
86
89
75
84
72
78
97
96
86
81
80
62
35
18
17
13.6
12.4
8.8
84 (1S,2S)
85 (1R,2R)
47 (1S,2S)
60 (1R,2R)
83 (1S,2S)
77 (1R,2R)
76 (1S,2S)
45 (1R,2R)
81 (1S,2S)
81 (1R,2R)
45 (1S,2S)
58 (1R,2R)
85 (1S,2S)
83 (1R,2R)
53 (1S,2S)
52 (1R,2R)
59 (1S,2R)
65 (1R,2S)
20 (1S,2R)
15 (1R,2S)
55 (1S,2R)
48 (1R,2S)
15 (1S,2R)
4 (1R,2S)
46 (1S,2R)
54 (1R,2S)
20 (1S,2R)
2 (1R,2S)
48 (1S,2R)
64 (1R,2S)
14 (1S,2R)
4 (1R,2S)
iPr
Ph
Bzyl
Et
10.1
19
p-CF
p-CF
p-CF
p-CF
3
3
3
3
styrene
styrene
styrene
styrene
styrene
styrene
styrene
styrene
iPr
Ph
12.5
16.2
12.1
10.5
9.6
Bzyl
Et
p-CH
p-CH
p-CH
p-CH
3
3
3
3
iPr
Ph
8.6
Bzyl
Et
11.5
10.5
11.6
7.7
p-OCH
p-OCH
p-OCH
p-OCH
3
3
3
3
styrene
styrene
styrene
styrene
iPr
Ph
Bzyl
Et
7.3
––
e
f
Styrene
Styrene
Styrene
Styrene
PO(OiPr)
PO(OiPr)
PO(OiPr)
PO(OiPr)
2
2
2
2
84
ND
iPr
Ph
––
––
64
17
17
ND
ND
ND
Bzyl
––
a
b
c
2 2
Reactions were performed in CH Cl at 35ꢁC for 1h with a catalyst:diazo:substrate molar ratio of 1:200:1000.
Isolated yields based on ethyl diazoacetate and isopropyl diazomethylphosphonate.
3
Determined by chiral GC (chiral column: Chrompack Chirasil-Dex CB) for styrene and p-CF styrene and by chiral HPLC (Chiralcel OJ-H column,
3
Daicel) for p-CH styrene and p-OMe styrene.
d
e
f
The configuration is given in parentheses.
The configuration has not been determined.
The cis-cyclopropyl esters were formed in too small quantities to be analyzed.
1
7
carbene complex without olefin coordination. Thus
carbene ruthenium intermediates can also be suggested
in these cyclopropanations as previously demonstrated
for the cyclopropanation observed with catalysts were
consistent with the alkene approach trajectories that
are depicted in Scheme 4. In these representations, the
complex orientates the carbon double bond of the
1
7
with bis(oxazoline) analogues. The enantioselectivities
N2
Ph
Ph
Ru/thiapybox
2
1
+
H
P(O)(OiPr)2
P(O)(OiPr)2
trans
Scheme 3.
Ph
X
Ph
Ph
re
si
Ph
2R
2S
1R
Cl
CO R
2
S
Ph
i-PR
N
H
re
si
N
Ru
OR
N
i-Pr
O
1R
S
Ph
CO R
2
Cl
X
Scheme 4.

2572
P. Le Maux et al. / Tetrahedron: Asymmetry 15 (2004) 2569–2573
substrate to a front side approach of the metallocarbene,
as indicated in Scheme 4, yielding to the trans-isomer.
The reverse approach of the substrate produces the
cis-isomer. Similar orientations have been previously
proposed for the asymmetric cyclopropanation of styr-
ene catalyzed by chiral Ru-bis(oxazoline) complexes.
The unexpected decrease in the ees for the trans-product
with phenyl and benzyl substituted ligands could be ex-
plained by the larger steric interactions between the aryl
group of the ligand and the phenyl group of the incom-
ing substrate.
sodium D line at 20ꢁC. Microanalyses were performed
at Caen with an automatic apparatus ThermoQuest.
Synthesized products were purified by flash column
chromatography on silica gel. Styrene derivatives were
purchased from Aldrich, Acros and Lancaster. Before
being used, chloroform, dichloromethane and benzene
were distilled under argon over K CO , CaH and Na/
2
3
benzophenone, respectively.
4
.2. Preparation of pyridine-2,6-bis(thiazoline) 1a–d
Pyridine-2,6-bis(thiazoline) 1a–c have been prepared
using the general method already described for analo-
3
. Conclusion
7
gous compounds with R = tBu, Ph (1d), in two steps,
starting from dimethyl 2,6-pyridine bis(dithiocarboxyl-
The most probable mechanism of the transition-metal-
complex-catalyzed cyclopropanation is generally divided
in two main steps. First, a transition metal complex
reacts with diazoacetates to generate a carbene complex
as an intermediate and then the intermediate reacts with
alkenes to give cyclopropanes. As suggested recently by
19
ate) and 2equiv of (S)-valinol. They were purified
by silica gel flash chromatography (pentane/diethyl
ether).
4
.2.1. (R,R)-2,6-Bis[4-ethyl-4,5-dihydro-2-thiazolyl]pyr-
20
1
8
idine 1a. Yellow solid, mp = 179ꢁC, ½aꢁ
D
¼ þ135 (c
, acetone), overall yield = 75%. H NMR (400MHz,
CDCl ): 1.09 (t, 6H, J = 7.4Hz, 2 · CH CH ), 1.70–
a theoretical analysis, the nature of the metal–carbene
bond may be quite important, in particular in regards to
the diastereoselectivity and enantioselectivity. Thus,
substituting an oxygen atom by a sulfur atom in the
five-membered ring of the chiral ligands could lead to
a different situation as has been observed for the biden-
tate bis(thiazolines) in the Pd-catalyzed allylic alkyl-
1
1
3
3
3
2
2
.00 (m, 4H, 2 · CH CH ), 3.05 (dd, 2H, J = 11Hz,
3
2
2
J = 8.3Hz, 2 · CHHS), 3.45 (dd, 2H, J = 11.0Hz,
3
2
J = 8.7Hz, 2 · CHHS), 4.67 (dt, 2H, J = 7.4Hz,
3
3
J = 8.3Hz, 2 · CHN), 7.35 (t, 1H, J = 7.6Hz, H ),
3
3
4
1
3
8
7.72 (d, 2H, J = 7.6Hz, H
3
and H
5
).
C NMR
ation. Comparative evaluation of enantiocontrol for
(
62.9MHz, CDCl3): 11.2 (2 · CH CH ), 28.6
3
2
cyclopropanation of styrene with chiral ruthenium
bis(oxazoline) and bis(thiazoline) shows many similari-
ties with, in some cases, good enantiomeric excess. These
surveys also illustrate that chiral bis(thiazoline) are ver-
satile ligands, which may be used in many different reac-
tions involving carbene transfer. These encouraging
results should open up the way to other catalytic sys-
tems. Their development should be considerably wid-
ened in the future, with application in asymmetric
catalysis.
(2 · CH CH ), 35.8 (2 · CH S), 80.3 (2 · CHN), 123.8,
3
2
2
1
1
37.5, 150.6, 169.1 (SAC@N). IR (KBr): 2950, 2870,
605 (mSAC@N), 1460, 1370. Anal. Calcd for
C H N S : C, 58.98; H, 6.27; N, 13.76; S, 20.99.
Found: C, 58.47; H, 6.32; N, 13.48; S, 20.60.
1
5
19
3 2
4
.2.2.
yl]pyridine
(S,S)-2,6-Bis[4-isopropyl-4,5-dihydro-2-thiazol-
1b. Yellow solid,
mp = 190ꢁC,
20
1
½
aꢁ ¼ ꢀ125 (c 1, acetone), overall yield = 70%.
H
NMR (400MHz, CDCl ): 1.04 and 1.13 (2d, 12H,
D
3
J = 6.7Hz, 2 · CH(CH ) ), 2.13 (oct, 2H, J = 6.7Hz,
3
3 2
3
2
2
2
7
· CH(CH ) ), 3.11 (t, 2H, J = 10.4Hz, J = 9.3Hz,
4
. Experimental
3 2
2
3
· CHHS), 3.38 (dd, 2H, J = 10.4, J = 9.3Hz,
2
3
· CHHS), 4.53 (td, 2H, J = 9.3, 6.7Hz, 2 · CHN),
4
.1. General
3
.83 (t, 2H, J = 7.7Hz, H ), 8.16 (d, 2H, J = 7.7Hz,
3
4
3
1
3
H and H ). C NMR (62.9MHz, CDCl ): 19.0 and
3
1
Reactions were carried out under an argon atmosphere
with magnetic stirring. H NMR spectra were recorded
5
3
1
9.7 (2 · (CH ) CH), 33.4 (2 · CH(CH ) ), 34.1
3 2
3 2
(2 · CH S), 84.0 (2 · CHN), 122.7, 136.9, 150.6, 167.9
(SAC@N). IR (KBr): 2960, 2870, 1600 (m
in CDCl or CD Cl on a Bruker AC 400 spectrometer.
3
2
2
2
), 1450,
SAC@N
360, 1310, 1020. Anal. Calcd for C H N S : C,
17 23 3 2
1.22; H, 6.95; N, 12.60. Found: C, 60.91; H, 6.92; N,
2.78.
The chemical shifts (d) are expressed in ppm relative to
TMS. The coupling constants (J) are given in hertz.
Mass spectra were obtained using a Nermag R 10H
spectrometer. GC analysis were performed on a VAR-
IAN CP-3380 gas chromatography (using helium as
the carrier gas) equipped with a CP-1177 Injector and
a Flame Ionization Detector (FID). A WCOT fused sil-
ica Chrompack capillary column coating CP-Chirasil-
Dex CB (25m*0.25mm i.d.; 0.25lm film thickness)
was used. Analytic HPLC data were obtained using a
VARIAN Prostar 218 system equipped with a Chiralcel
OJ-H column (Daicel, 0.46cm i.d.*25cm). IR spectra
were recorded on a Perkin–Elmer 16 PC spectrophoto
1
6
1
4.2.3. (R,R)-2,6-Bis[4-benzyl-4,5-dihydro-2-thiazolyl]pyr-
20
idine 1c. Yellow solid, mp = 191ꢁC, ½aꢁ ¼ ꢀ102 (c 1,
D
1
acetone), overall yield = 67%. H NMR (400MHz,
CDCl3): 2.88 (dd, 2H, J2 = 13.6Hz, J3 = 9.0Hz,
2 · CHHPh), 3.14 (dd, 2H, J = 13.6Hz, J = 8.1Hz,
2
3
2 · CHHPh), 3.33 (dd, 2H, J = 11.3Hz, J = 8.6Hz,
2
3
2 · CHHS), 3.34 (dd, 2H, J = 11.3Hz, J = 8.6Hz,
2
3
2 · CHHS), 4.99–5.07 (m, 2H, 2 · CHN), 7.20–7.36
(m, 10H, 2C H ), 7.86 (t, 1H, J = 7.7Hz, H ), 8.16 (d,
ꢀ
1
meter, m (cm ) are given. Optical rotations were measured
on a Perkin–Elmer model 241 polarimeter for the
6
5
3
1
4
3
2H, J = 7.7Hz, H and H5). C NMR (62.9MHz,
3 3

P. Le Maux et al. / Tetrahedron: Asymmetry 15 (2004) 2569–2573
2573
CDCl ): 36.1 (CH Ph) 40.2 (2 · CH S), 79.4 (2 · CHN),
References
3
2
2
1
1
1
22.9, 126.5, 128.5, 129.4, 137.1, 138.4, 150.6,
69.6 (SAC@N). IR (KBr): 3060, 3020, 2920, 2860,
600 (mSAC@N), 1570, 1490, 1450, 1320, 1150, 1030.
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2
3
4
Anal. Calcd for C H N S : C, 69.89; H, 5.40; N,
2
5
23
3 2
9
1
.78; S, 14.93. Found: C, 69.84; H, 5.41; N, 9.52; S,
4.11.
5
. Nishiyama, H.; Itoh, Y.; Suwagara, Y.; Matsumoto, H.;
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.3. General procedure for the asymmetric catalytic
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1
262.
. Helmchen, G.; Krotz, A.; Ganz, K. T.; Hansen, D. Synlett
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6
7
8
1
A solution of complex [RuCl (p-cymene)] (3.1mg,
2
2
. Abrunhosa, I.; Gulea, M.; Levillain, J.; Masson, S.
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lmol) and (S,S)-2,6-bis[4-isopropyl-4,5-dihydro-2-thi-
azolyl]pyridine 1b (4.7mg, 14lmol) in dichloromethane
0.1mL) was stirred at room temperature for 5h under
(
argon. The reaction mixture was heated at 35ꢁC and styr-
ene (104mg, 1mmol) then added. Ethyl diazoacetate
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22.8mg, 0.2mmol) in dichloromethane (0.2mL) was
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next added over 30min and the reaction mixture stirred
for an additional 30min. The enantiomeric excess was
determined by chiral GC with a Chirasil-Dex CB col-
umn (Chrompack, 25m).
1
1
1
1
1
For the p-CH styrene and p-OMe styrene compounds,
3
the enantiomeric excess was determined by chiral HPLC
with a Chiralcel OJ-H column (Daicel, 25cm). The cy-
clopropyl esters formed were analyzed by GC and puri-
fied by flash chromatography with a suitable mixture of
pentane and ether (5:1) as the eluant. The same proce-
dure was applied for the cyclopropanation of styrene
with the isopropyl diazophosphonate and a reaction
time of 5h.
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1
072.
The reaction time with the chiral ligand 2,6-pyridyl bis-
thiazoline and the complex [RuCl (p-cymene)] was 5h
when the ligand was 1a (R = Et) and 1h when the ligand
was 1c (R = Bn) or 1d (R = Ph).
1
8. Ikeno, T.; Iwakura, I.; Yamada, T. J. Am. Chem. Soc.
2002, 124, 15152–15153.
19. Abrunhosa, I.; Gulea, M.; Masson, S. Synthesis 2004, 6,
2
2
928–936.