Conformationally rigid chiral bicyclic skeleton-tethered bipyridine N,N'-dioxide as organocatalyst: Asymmetric ring opening of meso-epoxides

Article abstract of DOI:10.1002/adsc.201400029

The conformationally rigid chiral bicyclic skeleton tethered bipyridine NN'-dioxide (-)-9 has been designed, synthesized and examined as an organocatalyst in the enantioselective ring opening of meso-epoxides using tetrachlorosilane (SiCl₄). The catalyst (-)-9 is found to exhibit good enantioselectivity for substituted cis-stilbene epoxides; whereas, the saturated cyclic meso-epoxides display a moderate enantioselectivity. At -30 °C in chloroform, the catalyst (-)-9 with 0.5 mol % loading generated the chlorohydrins in up to 97 % yield with up to 93 % ee. The possible creation of transient axial chiral environment around hypervalent silicon species due to the presence of conformationally rigid chiral bicyclic skeleton tethered bipyridine N,N'-dioxide may be responsible for such enantioselectivity observed in the desymmetrization of meso-epoxides.

Full text of DOI:10.1002/adsc.201400029

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DOI: 10.1002/adsc.201400029
Conformationally Rigid Chiral Bicyclic Skeleton-Tethered
Bipyridine N,N’-Dioxide as Organocatalyst: Asymmetric Ring
Opening of meso-Epoxides
Elumalai Gnanamani,a Nagamalla Someshwar,a Jayakumar Sanjeevi,a
and Chinnasamy Ramaraj Ramanathana,*
a
Department of Chemistry, Pondicherry University, Puducherry – 605 014, India
Fax : (+91)-413-265-6740; phone: (+91)-413-265-4416; e-mail: crrnath.che@pondiuni.edu.in
Received: January 9, 2014; Revised: March 1, 2014; Published online: && &&, 0000
In memory of Professor A. Srikrishna for his outstanding contribution in organic synthesis.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400029.
Abstract: The conformationally rigid chiral bicyclic
skeleton tethered bipyridine N,N’-dioxide (À)-9 has
been designed, synthesized and examined as an or-
ganocatalyst in the enantioselective ring opening of
meso-epoxides using tetrachlorosilane (SiCl4). The
catalyst (À)-9 is found to exhibit good enantioselec-
tivity for substituted cis-stilbene epoxides; whereas,
the saturated cyclic meso-epoxides display a moder-
ate enantioselectivity. At À308C in chloroform, the
catalyst (À)-9 with 0.5 mol% loading generated the
chlorohydrins in up to 97% yield with up to 93%
ee. The possible creation of transient axial chiral en-
vironment around hypervalent silicon species due
to the presence of conformationally rigid chiral bi-
cyclic skeleton tethered bipyridine N,N’-dioxide
may be responsible for such enantioselectivity ob-
served in the desymmetrization of meso-epoxides.
a Lewis base to generate non-racemic chlorohydrins.
This observation resulted in the introduction of other
types of Lewis base catalysts such as phosphine
oxides[4] and N-oxides[5–10] for enantioselective ring
opening of meso-epoxides.
Since then, different types of chiral pyridine N-
oxides a–f (Figure 1) have been introduced by several
groups, including those of Fu et al.,[5] Nakajima
et al.,[6] Chelucci et al.,[7] Takenaka et al.,[8] Malkov
et al.,[9] and Kotora et al.,[10] to effect the desymmetri-
Keywords: asymmetric synthesis; catalyst design;
chiral bipyridine N,N’-dioxide; desymmetrization of
meso-epoxides; organocatalysis
The stereoselective ring opening of oxiranes with nu-
cleophiles such as carbon, nitrogen, oxygen, halogen,
etc., generates products with two contiguous stereo-
genic centers of diverse functional groups: alcohols,
amino alcohols, alkoxy alcohols, diols, halohydrins
etc.[1] Andrews et al., and Fu et al. introduced the
Lewis base-catalyzed ring opening of epoxides with
chloride as nucleophile to generate chlorohydrins.[2]
Based on this method Denmark et al.[3] reported the
ring opening of epoxides with chloride as nucleophile
Figure 1. Chiral pyridine N-oxides for asymmetric ring open-
under the influence of chiral phosphoramides as ing of meso-epoxides.
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Elumalai Gnanamani et al.
to be moderate. Is this because of the presence of per-
manent axial and central chiralities disfavouring the
formation of an appropriate chiral environment
around the hypervalent silicon species due to confor-
mational restrictions? If so, would the avoidance of
permanent axial chirality provide the conformational
freedom around the bipyridyl N,N’-dioxide unit? This
conformational freedom in bipyridine N,N’-dioxide
may lead to effective bidentate coordination with SiCl4.
During this process, the presence of bulky stereogenic
groups at the 3,3’-positions in bipyridine N,N’-dioxide
may direct the generation of a transient axial chiral en-
vironment around the hypervalent silicon species.
Figure 2. CRCB skeleton-attached pyridine N-oxides.
zation of meso-epoxides. The enantioselectivity in the Hence, we presume that this transient axial chiral en-
desymmetrization of meso-epoxides is realized due to vironment may assist the enantioselective desymmet-
the presence of chiral elements such as planar chirali- rization of meso-epoxides.
ty, axial chirality, central chirality, helical chirality as
well as the combination of both axial and central chir- symmetric bipyridine N,N’-dioxide (À)-9 possessing
ality in organocatalysts. a bulky stereogenic group, the CRCB skeleton, at the
Based on this hypothesis, we have designed a C2-
All these catalysts exhibit good enantioselectivity 3,3’-positions. The chiral bipyridine (À)-7 was success-
for the ring opening of cis-stilbene oxides, except fully prepared in 79% yield through biaryl coupling
c and e which are moderately effective for meso-epox- of the chiral molecule (À)-6[11a] using NiCl2/PPh3 and
ides derived from cycloalkenes. Furthermore, the re- Zn in DMF at 708C for 12 h.[13] The bipyridine (À)-7
ported catalysts require very low temperatures on treatment with m-CPBA in dichloromethane pro-
(À788C to À908C) to exert enantioselectivity.[5–10] vided both mono-N-oxide (À)-8 and N,N’-dioxide
Thus, the design and development of a catalyst system (À)-9 in 10% and 81% yields, respectively
exhibiting better enantioselectivity and efficiency for (Scheme 1).
both structural classes is still warranted.
Both N-oxides were separated through column
Recently, we have engineered a family of confor- chromatography and examined for desymmetrization
mationally rigid chiral bicyclic (CRCB) skeleton-sub- of meso-epoxides. The catalytic efficiency as well as
stituted pyridine N-oxides, 3–5, with an appropriate the enantiomeric purity of chlorohydrin 2a generated
stereoelectronic environment for organocatalytic
enantioselective allylation of aldehydes (Figure 2).[11]
The presence of a pyridine N-oxide unit on the
CRCB skeleton prompted us to examine this class of
molecules for the enantioselective ring opening of
meso-epoxides using SiCl4. Hence, the catalysts 3–5
were screened for desymmetrization of cis-stilbene
oxide, using SiCl4/diisopropylethylamine at À408C in
dichloromethane. The steric factor and nucleophilicity
of the catalysts 3–5 dictated the reactivity as well as
the enantioselectivity. The catalyst 3, after 18 h, su-
cessfully generated the chlorohydrin 2a in 32% ee.
The reaction was very sluggish in the presence of cat-
alyst 4 (even after 24 h only 82% conversion of 1a
was observed) and the chlorohydrin 2a was obtained
only in 5% ee. This may due to the presence of unfav-
ourable nucleophilicity and steric crowding compared
to the catalyst 3. Quite interestingly, the catalyst 5
with strong nucleophilic character delivered the chlor-
ohydrin 2a, although only in moderate enantioselec-
tivity (42% ee, 12 h).
These results prompted us to modify the catalyst
structure for better selectivity. Even though the cata-
lyst f, reported by Kotora et.al,[10] possess both axial
and central chirality, the enantioselectivities obtained
in the desymmetrization of meso-epoxides were found Scheme 1. Synthesis of bipyridine derivatives.
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Conformationally Rigid Chiral Bicyclic Skeleton-Tethered Bipyridine
Table 1. Effect of catalyst loading and temperature on effi-
plete conversion also increased from 20 min at
5 mol% catalyst loading to 105 min at 0.5 mol% cata-
lyst loading. Further lowering of catalyst loading to
0.25 and 0.1 mol% resulted in slight decreases in
enantioselectivity (84% ee for 0.1 mol% catalyst load-
ing) as well as drastic increases in reaction time (18 h)
for complete conversion of meso-epoxide (Table 1,
entries 5 and 6). Both 0.5 mol% and 1 mol% catalyst
loading furnished the chlorohydrin in 89% ee at
À408C (Table 1, entries 3 and 4). Even though
0.5 mol% of (À)-9 required a longer reaction time
(105 min) compared to 1 mol%, which required
60 min, we have chosen 0.5 mol% catalyst loading for
optimization studies owing to the advantage of using
a smaller amount of catalyst.
ciency and enantioselectivity.[a]
Entry (À)-9
[mol%]
Temp.
[8C]
Time
Conv.
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
9
10
5
2.5
1
0.5
0.25
0.1
0.5
0.5
0.5
0.5
À40
À40
À40
À40
À40
À40
À60
À50
À30
À20
20 min 100
30 min 100
85
89
89
89
88
84
74
82
89
83
1 h
100
105 min 100
5 h
100
100
62
18 h
24 h
8 h
With 0.5 mol% catalyst loading the experiments
were carried out at various temperatures such as
À608C, À508C, À308C, and À208C to realize the
better enantioselectivity (Table 1, entries 4, 7–9). The
100
70 min 100
35 min 100
[a]
All the reactions were performed with 1a (0.25 mmol, reaction at À608C was found to be unfavourable in
1 equiv.), SiCl4 (lM in dichloromethane, 0.38 mL,
1.5 equiv.) with (i-Pr)2NEt (5 equiv.) in the presence of
various amounts of catalyst (À)-9 in chloroform (0.8 mL)
at À408C.
terms of both rate of the reaction and the enantiose-
lectivity (Table 1, entry 7). Gradual increases of reac-
tion temperature from À608C to À308C were accom-
panied by increases in the rate of the reaction (24 h
to 70 min) as well as the enantioselectivity from 74%
to 89% (Table 1, entries 4, 7–9). Further increase of
the reaction temperature from À308C to À208C
caused a decrease in enantioselectivity from 89% ee
to 83% ee (Table 1, entry 10). Therefore, the catalytic
efficiency and enantioselectivity was found to be opti-
[b]
[c]
1
Determined from H NMR spectra.
Determined by chiral HPLC analysis and the product 2a
produced in all experiments is of the (1R,2R)-(À)-config-
uration, as revealed by a comparison of HPLC retention
times.[4a]
from 1a in the presence of (À)-8 was not effective mum at À308C. The quantity of base, diisopropyle-
(after 24 h, only 45% conversion of 1a to 2a with 0% thylamine, is also known to exhibit crucial role in
ee was observed in dichloromethane). Meanwhile, both reactivity as well as enantioselectivity. Hence,
20 mol% of catalyst (À)-9 completely converted the the experiments were performed with various equiva-
epoxide 1a to the corresponding chlorohydrin 2a with lents (1 equiv. to 20 equiv.) of diisopropylethylamine
76% ee upon reaction with SiCl4 and diisopropylethyl- in the presence of catalyst (À)-9 (0.5 mol%) at
amine in dichloromethane at À408C in just 10 min. À308C in chloroform.[13] This study reveals that the
Lower catalyst loading, for example, 5 mol% of (À)-9 optimum amount of diisopropylethylamine required
also exhibited 100% conversion in 20 min to produce to realize better enantioselectivity (93% ee) was
2a in 85% ee (Table 1, entry 1).
found to be 15 equivalents. Further increases of base
With this encouraging result, the catalytic efficiency equivalents decreased the rate of the reaction as well
of (À)-9 with a 5 mol% loading was examined in as the enantioselectivity.
other commonly employed solvents, such as acetoni-
Therefore, the catalyst (À)-9 (0.5 mol%), SiCl4
trile, 1,1,2,2-tetrachloroethane and 1,2-dichloro- (1.5 equiv.), DIPEA (15 equiv.) at À308C in chloro-
ethane; the chlorohydrin 2a was produced in 39% ee, form is found to be the optimized conditions for the
84% ee and 64% ee, respectively. Hence, chloroform enantioselective desymmetrization of meso-epoxides
is found to be an ideal solvent.[13] The decrease in cat- (Scheme 2).
alyst loading enhanced the enantioselectivity with
only a slight increase in reaction time. This observa-
tion rendered the opportunity to perform the reaction
in chloroform at À408C by varying the catalyst (À)-9
loading from 5 mol% to 0.1 mol% to improve the
enantioselectivity (Table 1, entries 1–6). Indeed, the
enantiomeric purity of the chlorohydrin 2a produced
was increased from 85% to 89% while decreasing the
catalyst loading from 5 mol% to 0.5 mol%. At the
same time, the reaction time required for the com- bene oxide.
Scheme 2. Optimized conditions for ring opening of cis-stil-
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Elumalai Gnanamani et al.
Table 2. Desymmetrization of meso-epoxides with SiCl4 cat-
alyzed by (À)-9.[a]
Figure 3. Proposed coordination of N,N’-dioxide with SiCl4.
Entry
R
Time Yield ee
Configur-
AHCTUNGTRENNUNG
[min] [%][b] [%] ation
1
2
3
4
5
6
7
C6H5 (1a)
3-CH3O-C6H4 (1b) 90
4-CH3-C6H4 (1c)
4-F-C6H4 (1d)
-(CH2)3- (1e)
-(CH2)4- (1f)
-(CH2)6- (1g)
120
94
96
92
97
67
65
84
93[c] 1R,2R[e]
89[c] 1R,2R[e]
89[c] 1S,2S[e]
The enantioselectivity and differences in the rate of
desymmetrization reaction of cis-stilbene oxide effect-
ed by the catalysts 4, 5 and 9, intrigued us to specu-
late the possible coordination of catalyst and sub-
strate with SiCl4 in the transition state. The rate of de-
symmetrization of cis-stilbene oxide in the presence
of 4 (20 mol%) was found to be very slow (only 82%
conversion even after 24 h). A similar rate could have
been prevailed with catalyst (À)-9, because the nucle-
ophilicity of both N-oxides might have been reduced
inductively by each other and hence overall. On the
contrary, the conversion of cis-stilbene oxide in the
presence of (À)-9 (20 mol%) was very fast (10 min
for 100% conversion).[13] This observation may be ra-
tionalized through the involvement of bidentate coor-
dination of N,N’-dioxide with SiCl4 (Figure 3) and
hence the creation of a transient axial chiral environ-
ment around the silicon species to exert the enantio-
selectivity in desymmetrization of meso-epoxides.
In summary, we have successfully designed a bipyri-
dine N,N’-dioxide with chiral substituents at the 3,3’-
positions exhibiting excellent reactivity in the desym-
metrization of meso-epoxides using SiCl4 in chloro-
form at À308C and producing chlorohydrins in up to
93% ee. It is interesting to note that the reaction re-
105
180
45
60
90
78[c] 1S,2S[e]
[f]
22[d]
-
42[d] 1R,2R[g]
69[d] 1R,2R[g]
[a]
All reactions were performed with
1 (0.25 mmol,
1 equiv.), SiCl4 (lM in dichloromethane, 0.38 mL,
1.5 equiv.), (i-Pr)2NEt (15 equiv.) in the presence of cata-
lyst (À)-9 (0.5 mol%) in chloroform (0.8 mL) at À308C.
Yields are of isolated product.
[b]
[c]
[d]
The ee values were determined by chiral HPLC analysis.
The ee value was established by 19F NMR analysis of the
corresponding Mosherꢁs esters and the Mosher esterifica-
tion was quantitative as revealed by TLC analysis and
1H NMR spectra of the crude products, which excludes
a possible ee amplification during this derivatization.
Absolute configurations were assigned by comparing the
HPLC retention time with the literature data.[4]
The absolute configuration of chlorohydrin is not deter-
mined.
[e]
[f]
[g]
Absolute configurations were assigned by comparing the
sign of optical rotation with the literature data.[3a,12]
Based on these conditions, the versatility of catalyst quires only À308C to produce the chlorohydrins in
(À)-9 was evaluated for the enantioselective ring good yield with better enantioselectivity, unlike the
opening of meso-epoxides of various structural classes other reported organocatalysts that require very low
at À308C in chloroform (Table 2). The substituted cis- temperatures (À788C to À908C) to realize a reasona-
stilbene oxides, 1b–d, generated the corresponding ble enantioselectivity. Studies on further structural
chlorohydrins, 2b–d, in excellent yields, 92–97%, with modifications to get a better enantioselectivity for de-
good enantioselectivities, 78–89% (Table 2, entries 2– symmetrization of meso-epoxides are progressing in
4). The efficiency of the catalyst (À)-9 was further ex- this laboratory.
amined for the ring opening of cyclic meso-epoxides
such as cyclopentene oxide, cyclohexene oxide and cy-
clooctene oxide using SiCl4. All these substrates suc-
cessfully produced the corresponding chlorohydrins
Experimental Section
2e–g in moderate yields with moderate enantioselec-
General Experimental Procedure for the Ring
Opening of meso-Epoxides
tivity in short reaction times at À308C in chloroform
(Table 2, entries 5–7). One of the challenging sub-
Tetrachlorosilane (0.38 mL, 1M in dichloromethane,
0.38 mmol) was added dropwise to a stirred solution of ep-
strates, cyclooctene oxide 1g successfully furnished
the corresponding chlorohydrin 2g in 84% yield with
oxide
(0.25 mmol),
diisopropylethylamine
(0.64 mL,
69% ee. Based on the observation as reported by
Malkov et al.,[9] we have examined the efficiency of
mono N-oxide (À)-8 (0.5 mol%) for ring opening of
cyclooctene oxide 1g using SiCl4 and found it to pro-
duce 2g in 43% yield with 5% ee after 36 h at
À308C.[13]
3.75 mmol) and bipyridine N,N’-dioxide (À)-9 (0.93 mg,
0.00125 mmol) in dry chloroform (0.8 mL) at À308C, under
a nitrogen atmosphere. After stirring for the required time,
the reaction mixture was quenched with saturated aqueous
solutions of KF and K2HPO4 (1:1, 3 mL). The organic layer
was separated and then the aqueous layer was extracted
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Conformationally Rigid Chiral Bicyclic Skeleton-Tethered Bipyridine
with diethyl ether (5 mLꢂ3). The combined organic layer
was washed with brine, dried over anhydrous MgSO4, fil-
tered and the solvent was evaporated on a rotary evaporator
under reduced pressure. The residue was purified through
silica gel column chromatography to afford the correspond-
ing chlorohydrins.
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Acknowledgements
We thank DST, New Delhi, India for financial support. E. G.
and N. S. thank CSIR (New Delhi) for SRF and J. S. thanks
DST for SRF. We thank Dr. Bala. Manimaran and Dr. M.
Bakthadoss for valuable discussion. We gratefully acknowl-
edge the Department of Chemistry, IIT – Madras for HR-MS
analysis and CIF, Pondicherry University for NMR/IR data.
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6 Conformationally Rigid Chiral Bicyclic Skeleton-Tethered
Bipyridine N,N’-Dioxide as Organocatalyst: Asymmetric
Ring Opening of meso-Epoxides
Adv. Synth. Catal. 2014, 356, 1 – 6
Elumalai Gnanamani, Nagamalla Someshwar,
Jayakumar Sanjeevi, Chinnasamy Ramaraj Ramanathan*
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