Conformationally rigid chiral pyridine N-oxides as organocatalyst: Asymmetric allylation of aldehydes

Article abstract of DOI:10.1002/adsc.201200115

A pyridine unit with a conformationally rigid chiral backbone has been designed and synthesized in an enantiomerically pure form to utilize in the Lewis base-catalyzed Sakurai-Hosomi-Denmark-type allylation reaction. The chiral pyridine N-oxide in 1:1 mix

Full text of DOI:10.1002/adsc.201200115

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DOI: 10.1002/adsc.201200115
Conformationally Rigid Chiral Pyridine N-Oxides as
Organocatalyst: Asymmetric Allylation of Aldehydes
Elumalai Gnanamani,a Nagamalla Someshwar,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: February 12, 2012; Revised: April 30, 2012; Published online: && &&, 0000
Dedicated to Professor Mariappan Periasamy on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200115.
Abstract: A pyridine unit with a conformationally
rigid chiral backbone has been designed and synthe-
sized in an enantiomerically pure form to utilize in
the Lewis base-catalyzed Sakurai–Hosomi–Den-
mark-type allylation reaction. The chiral pyridine
N-oxide in 1:1 mixture of chloroform and 1,1,2,2-
tetrachloroethane produced the homoallylic alco-
hols in up to 98% yield and up to 94% ee.
the allylation reaction. Most of these chiral pyridine
N-oxides are synthesized through difficult synthetic
processes whilst some of them are from natural sour-
ces.[7b] The enantioselectivity of the allylation reaction
often depends on the electronic property of the car-
bonyl compounds as well as the catalyst used. It has
been documented that catalysts with an electron-rich
aromatic ring attached at the position 6 of the pyri-
dine N-oxide display increased enantioselectivity
when reacting with electron-deficient benzaldehyde
derivatives. This has been rationalized through arene-
arene interactions.[7a] Later studies had shown that the
electron-rich aldehydes also deliver homoallylic alco-
hols in high enantioselectivity.[7b]
Keywords: activation of allylsilanes; catalyst design;
chiral pyridine N-oxides; homoallylic alcohols.; or-
ganocatalysts
We have initiated our effort to develop a conforma-
tionally rigid novel chiral pyridine N-oxide to catalyze
The design and synthesis of novel catalysts for the the asymmetric allylation reaction, which resulted in
enantioselective activation of electrophiles/nucleo- two important observations: (i) with an electron-rich
philes is one of the challenges in asymmetric organo- catalyst, the electron-rich benzaldehyde produced
catalysis.[1] Activation of a carbonyl group towards nu- higher enantioselectivity; (ii) a mixture of solvents en-
cleophiles is generally achieved by Lewis acids or or- hances the yield and enantioselectivity. Based on the
ganocatalysts. Lewis base activation of nucleophiles is steric requirements, the designer catalyst with a con-
one of the promising complimentary technologies to formationally rigid chiral backbone possessing a pyri-
[2]
À
establish new C C bonds with carbonyl groups. Or- dine unit was synthesized in racemic form from an-
ganocatalytic enantioselective allylation reactions are thracene 1 and dienophile 2 in the presence of alumi-
considered to be one such tool to produce homoallylic num chloride. The racemic pyridine derivative 3 was
alcohols which are, in turn, used to synthesize biologi- resolved to obtain the corresponding antipodes in
cally active molecules as well as for the assemblage of enantiomerically pure forms using l-(+)-tartaric acid
complex natural products.[3]
(Scheme 1).[11]
Due to the advantages associated with pyridine N-
The enantiomerically pure N-oxide (11S,12S)-(+)-4
oxides over other Lewis base activators such as phos- was easily generated in 95% yield by treating
phoramides,[4] sulfoxides,[5] formamides,[6] etc., consid- (11S,12S)-(+)-3 with meta-chloroperbenzoic acid (m-
erable attention has been paid to both the develop- CPBA) in dichloromethane at room temperature for
ment of novel chiral pyridine N-oxides and examina- 6 h (Scheme 2). The catalyst (11S,12S)-(+)-4 was then
tion of their efficacy in catalyzing the Sakurai– evaluated for the enantioselective allylation reaction
Hosomi–Denmark-type allylation reaction.[7–10] For with 4-methoxybenzaldehyde using allyltrichlorosi-
example, Nakajima,[8] Hayashi,[9] Malkov,[7] and Ko- lane, diisopropylethylamine (DIPEA) and tetrabuty-
[7]
ˇ
´
covsky have introduced successful catalysts to effect lammonium iodide (TBAI) in the presence of
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Scheme 1. Synthesis of chiral pyridine derivative 3.
20 mol% of catalyst at À408C in various solvents. The
homoallylic alcohol 7a was produced in 33–54% ee
and up to 89% yield (Table 1, entries 1–5). To in-
crease the enantioselectivity of allylation reaction, the
sterically crowded groups such as phenyl, 1-naphthyl
and 9-anthracenyl groups were introduced at the posi-
tion 6 of the pyridine ring of the catalyst (11S,12S)-
Scheme 2. Preparation of pyridine N-oxide (+)-4.
Table 1. Effect of catalyst/solvent on efficiency and enantioselectivity of allylation of 4-methoxybenzaldehyde 5a with allyltri-
chlorosilane 6.[a]
Entry Catalyst[b] Solvent
Yield [%][c] ee [%][d] Entry Catalyst[b] Solvent
Yield [%][c] ee [%][d]
1
2
3
4
5
6
7
8
(+)-4
(+)-4
(+)-4
(+)-4
CH3CN
CH2Cl2
CHCl3
60
78
89
33
47
54
34
47
56
42
40
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
(À)-12e
Cl2(CH)2Cl2
6
5
28[f]
56[f]
60
76
76
50
78
72
74
76
77
83
nd
nd
79
82
87
86
86
85
84
(À)-12f[e] CH3CN
(+)-12g
(+)-12g
(+)-12g
(+)-12g
(+)-12g
(+)-12h
(+)-12h
(+)-12h
(+)-12h
(+)-12h
(+)-12h
(+)-12h
(+)-12h
(+)-12h
(+)-12h
(+)-12h
(+)-12h
(+)-12h
(+)-12h
CH3CN
CH2Cl2
CHCl3
ClACHTNGUTRENNU(G CH2)2Cl
Cl2(CH)2Cl2
CH3CN
CH2Cl2
CHCl3
Cl2(CH)2Cl2
ClACHTNGUTRENNU(G CH2)2Cl
20
17
16
8
48
64
63
84
88
15
nr
nr
Cl
N
(+)-4
Cl2(CH)2Cl2 85
(+)-12a
(+)-12a
(+)-12a
(+)-12a
(+)-12a
CH3CN
CH2Cl2
CHCl3
2
4
5
9
Cl
N
nd
20
10
11
12
13
14
15
16
17
18
19
20
21
Cl2(CH)2Cl2
5
(À)-12b[e] CH3CN
(À)-12c[e] CH3CN
nr
nr
22
6
nd
nd
63[f]
67[f]
45[f]
nd
66[f]
nd
40[f]
35[f]
nd
(À)-12d
(À)-12d
(À)-12d
(À)-12d
(À)-12d
(À)-12e
(À)-12e
(À)-12e
(À)-12e
CH3CN
CH2Cl2
CHCl3
toluene
THF
5
CHCl3:Cl2(CH)2Cl2 (1:1) 96
CHCl3:Cl2(CH)2Cl2 (1:1) 91
CHCl3:Cl2(CH)2Cl2 (1:1) 84
CHCl3:Cl2(CH)2Cl2 (1:2) 76
CHCl3:Cl2(CH)2Cl2 (1:3) 39
CHCl3: Cl2(CH)2Cl2 (2:1) 85
CHCl3:Cl2(CH)2Cl2 (3:1) 86
Cl
N
37[g]
38[h]
39[h]
40[h]
41[h]
42[h]
Cl2(CH)2Cl2
CH3CN
CH2Cl2
CHCl3
ClACTHNURGTNEUGN(CH2)2Cl nr
9
trace
3
2
[a]
All reactions were performed with 5a (0.25 mmol, 1 equiv.), 6 (1.2 equiv.), catalyst 4 or 12a–h (20 mol%) and (i-Pr)2NEt
(5 equiv.) in solvents (0.76 mL) at À408C for 24 h.
[b]
The catalysts (+)-12(a, g and h) were synthesized from (11S,12S)-(+)-3 and the catalysts (À)-12
ACHTUNGERTN(NUNG b–f) were synthesized
from (11R,12R)-(À)-3.
[c]
[d]
Isolated yield.
The ee was determined by chiral HPLC analysis and the product 7a produced in all experiments is of the (S)-(À)-configu-
ration (unless otherwise stated), as revealed by the comparison of HPLC retention times,[14a] with the literature value.
The catalysts were also studied in other solvents but they are ineffective.
[e]
[f]
The products were of the (R)-(+)-configuration.[14a]
[g]
[h]
Reaction was carried out at À558C for 24 h.
Reactions were carried out at À788C for 24 h; nr=no reaction, nd=not determined.
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Conformationally Rigid Chiral Pyridine N-Oxides as Organocatalyst
Scheme 3. Synthesis of chiral pyridine N-oxides 12a–h.
(+)-4 via chlorination of pyridine N-oxide 4 followed tion reaction. This has been supported by the fact
by Suzuki coupling of isomer 8 with the respective that the introduction of either alkyl or aryl groups at
boronic acids 10a–c (Scheme 3). As an encourage- the positions 2 and/or 6 of the pyridine ring reduces
ment, when the catalyst 12a was examined for the al- the nucleophilicity/basicity of the pyridine and conse-
lylation reaction at À408C, the homoallylic alcohol 7a quently reduces the nucleophilicity of the correspond-
was produced with improved enantioselectivity (56% ing N-oxide.[12] Hence the electron-rich aryl rings (me-
ee) but disappointingly very low yield (Table 1, en- thoxy-substituted benzene group) have been intro-
tries 6–10). The enhancement of enantioselectivity duced at the 6 position of the pyridine ring in
may be due to the involvement of an arene-arene in- (11S,12S)-(+)-4 to afford the chiral biaryls 11d–11h,
teraction as claimed by earlier reports.[7a] Unfortu- which may enhance both reactivity and selectivity. A
nately, the 1-naphthyl-substituted 12b and 9-anthra- single crystal X-ray crystallographic analysis exposed
cenyl-substituted 12c chiral pyridine N-oxides even the presence of a cavity-like structure after the intro-
failed to catalyze the reaction (Table 1, entries 11 and duction of an aryl moiety at the position 6 of the pyri-
12), which may be due to the combined electronic dine ring in 4 (Figure 1).[13] Oxidation of 11d–11h
and steric effects infulencing negatively on the allyla-
Figure 1. ORTEP representations of the X-ray crystal structures of 12b and 11h.
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Table 2. Asymmetric allylation of aldehydes with allyltrichlorosilane catalyzed by (+)-12h.[a]
Entry
Aldehyde
R
Yield [%][b]
ee [%][c]
Configuration[d]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-MeO-C6H4
2-MeO-C6H4
C6H5
9-anthryl
piperonyl
3,4-dimethoxy
4-NO2-C6H4
4-Cl-C6H4
2-thienyl
3-thienyl
2-furyl
84
95
87
62
58
81
47
98
71
67
52
37
64
87
80
83
92
81
94
25
76
92
89
93
71
33
S
S
S
S
S
S
S
S
R
S
R
S
S
9
10
11
12
13
5j
5k
5l
(E)-C6H5CH=CH
cyclohexyl
5m
[a]
All reactions were performed with 5 (0.25 mmol, 1 equiv.), 6 (1.2 equiv.), catalyst (+)-12h, (i-Pr)2NEt (5 equiv.) and TBAI
(1 equiv.) in 1:1 mixture of chloroform:1,1,2,2-tetrachloroethane (0.76 mL) at À788C for 24 h.
Isolated yield.
[b]
[c]
[d]
The ee was determined by chiral HPLC analysis.
Absolute configurations were assigned by comparing the HPLC retention time with the literature data.[14,8a]
using m-CPBA produced the chiral pyridine N-oxides hance the enantioselectivity without diminishing the
12d–12h (Scheme 3).
yield.
Lowering the reaction temperature generally en-
Promisingly, the catalysts 12d and 12e gave the ho-
moallylic alcohol in increased enantiomeric excess, up hances the enantioselectivity of the reaction (vide
to 67% ee with poor yield when the reactions were infra). But the freezing points of chloroform and
carried out in various solvents, whereas the catalyst 1,1,2,2-tetrachloroethane, respectively, are À63.58C
12f failed to catalyze the reaction (Table 1, en- and À448C and this hindered the use of these solvents
tries 13–23). The low yield may probably be due to at À788C. Mixing of two solvents is known to reduce
the insufficient nucleophilicity of the Lewis bases the freezing point of the mixture thus enabling the ex-
12d–12f. Hence the additional methoxy group con- periment to be conducted at À788C.[15] Therefore the
taining molecules 12g and 12h were screened for ally- preliminary experiments were carried out with 1:1
lation of 4-methoxybenzaldehyde under the estab- mixtures of chloroform and 1,1,2,2-tetrachloroethane
lished conditions using allyltrichlorosilane, DIPEA at À408C, À558C and À788C in the presence of the
and TBAI in various electrophilic, nucleophilic and catalyst (+)-12h (Table 1, entries 36–38). The homoal-
neutral solvents (Table 1, entries 24–35). Between lylic alcohol was produced in 84% yield with 87% ee
these two catalysts, the catalyst 12h enhanced the when the experiment was carried out at À788C
enantioselectivity of the reaction and increased the (Table 1, entry 38). Increasing the concentration of
yield of the homoallylic alcohol (Table 1, entries 29– 1,1,2,2-tetrachloroethane reduces the yield of the
33). Reactions in solvents such as chloroform and product (Table 1, entries 39 and 40), while retaining
1,1,2,2-tetrachloroethane furnished the homoallylic al- the enantiomeric purity of the homoallylic alcohol.
cohol in higher enantiomeric purity with good yield. Increasing the percentage of chloroform marginally
On the other hand 1,2-dichloroethane produced the increases the yield, but reduces the enantiomeric
homoallylic alcohol in 83% ee with poor yield (15%) purity of the homoallylic alcohol (Table 1, entries 41
(Table 1, entry 33). Hence the solvents chloroform and 42). This study, without compromising the yield,
and 1,1,2,2-tetrachloroethane were selected for fur- showed better enantioselectivity in a 1:1 mixture of
ther optimization of the reaction conditions to en- chloroform and 1,1,2,2-tetrachloroethane (Table 1,
entry 38).
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Conformationally Rigid Chiral Pyridine N-Oxides as Organocatalyst
Scheme 4. Crotylation of 4-methoxybenzaldehyde.
Having identified the appropriate solvent combina- the opposite configuration in contrast to the reported
tion, we tried to identify the appropriate base, addi- stereochemical outcome (Table 2, entries 9 and
tives and the amount of catalyst required for better 11).[10e,7e] This stereochemical outcome may be ex-
yield and enantioselectivity.[16] After extensive experi- plained by the involvement of an axial orientation of
mentation based on the above variables, the best con- the heterocycles in such a way that the lone pair of
ditions were found to be 20 mol% catalyst loading, electrons on either O/S is stabilizing the positive
with TBAI (1 equiv.) as additive and DIPEA charge of the b-carbon of allyl reagent as well as en-
(5 equiv.) as base in a 1:1 mixture of chloroform and suring exposure of the re-face of the aldehyde to the
1,1,2,2-tetrachloroethane
entry 38).
at
À788C
(Table 1, g-carbon of allyl reagent, which then facilitates the
transfer of the allyl group from a hypervalent silicon
Based on these conditions, the versatility of catalyst complex to the re-face of the carbonyl group.[18]
(+)-12h was examined for the enantioselective allyla-
In summary, we have designed and synthesized
tion reaction with various aromatic, heterocyclic and a series of enantiomerically pure pyridine N-oxides
aliphatic aldehydes (Table 2). Interestingly the aro- and evaluated their ability to promote the Sakurai–
matic aldehydes with electron-releasing functional Hosomi–Denmark-type allylation of aldehydes with
groups or benzaldehyde produced better yields and allyltrichlorosilane. An electron-rich pyridine N-oxide
higher levels of asymmetric induction (Table 2, en- is a prerequisite for high enantioselectivity and good
tries 1–3), even though the aldehydes and catalysts yield. The notable observation of the present article
are not electronically complementary to each other. contemplates the beneficial effect of a mixture of sol-
To further exemplify this observation, the reaction vents on the enantioselectivity. The stabilizing effect
was carried out with an electron-withdrawing group- of a partial positive charge on the b-carbon by the
containing benzaldehyde such as 4-nitrobenzaldehyde, lone pair electrons of the S/O atoms of the hetero-
which generated the corresponding homoallylic alco- cyles in 2-thiophenecarbaldehyde and 2-furancarbal-
hol in poor yield and low optical purity (Table 2, dehyde, respectively, accounts for the excellent enan-
entry 7). Condensed polycyclic aromatic aldehyde, for tioselectivity and opposite configuration of the homo-
example, anthracene-9-carboxaldehyde, generated the allylic alcohol produced. Further studies on modifica-
corresponding homoallylic alcohol in 62% yield with tion of the catalyst structure to enhance the enantio-
good enantioselectivity (92% ee), which strongly sug- selectivity of all class of aldehydes are in progress in
gests the involvement of steric factors in the enantio- this laboratory.
selectivity.
All the aldehydes, except 2-thiophenecarbaldehyde
5i and 2-furancarbaldehyde 5k, produced homoallylic
alcohols with the S configuration in the presence of
(+)-12h. This showed the involvement of a six-mem-
Experimental Section
bered chair-like cyclic transition state which, in turn,
facilitated the transfer of the allyl nucleophile to the
si-face of the prochiral aldehydes (Table 2, entries 1–
General Experimental Procedure for the Asymmetric
Allylation of Aldehydes
8, 10, 12, and 13). Furthermore, this conclusion was Allyltrichorosilane (44 mL, 0.3 mmol) was added dropwise to
the solution of catalyst (+)-12h (26.8 mg, 0.05 mmol), diiso-
propylethylamine (0.21 mL, 1.25 mmol), tetra-n-butylammo-
nium iodide (92.3 mg, 0.25 mmol) and aldehyde (0.25 mmol)
in chloroform:1,1,2,2-tetrachloroethane (1:1, 0.76 mL) under
nitrogen atmosphere at À788C with stirring. After 24 h the
reaction mixture was quenched with aqueous saturated
NaHCO3 (2 mL). The organic layer was separated and then
the aqueous layer was extracted with diethyl ether (3ꢁ
5 mL). The combined organic layer was washed with brine,
dried over anhydrous Na2SO4, filtered and the solvent was
corroborated by treating the 4-methoxybenzaldehyde
with crotyltrichlorosilane (E/Z=82:18)[17] in the pres-
ence of catalyst (À)-12h, which produced the anti/syn
alcohols in an 81:19 ratio (Scheme 4).
Electron-rich heterocyclic carboxaldehydes such as
furan- and thiophenecarbaldehydes 5i–5k successfully
furnished the homoallylic alcohols 7i–7k in excellent
enantioselectivity (Table 2, entries 9–11). As a sur-
prise, the thiophene-2-carbaldehyde and 2-furfural
produced the corresponding homoallylic alcohols in evaporated on a rotary evaporator under reduced pressure.
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The residue was purified through silica gel column chroma-
tography to afford the homoallylic alcohols.
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Acknowledgements
We thank DST, New Delhi for financial support. E. G. and
N. S. thank CSIR, New Delhi for SRF and JRF respectively.
We gratefully acknowledge Prof. M. L. N. Rao, IITK,
Kanpur, Prof. K. R. Prasad, IISc, Bengaluru, and Depart-
ment of Chemistry, IITM, Chennai for HR-MS analyses;
CIF, Pondicherry University for NMR/IR data; and the single
crystal XRD facility (DST-FIST), Department of Chemistry,
Pondicherry University for XRD data.
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6
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Conformationally Rigid Chiral Pyridine N-Oxides as
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Organocatalyst: Asymmetric Allylation of Aldehydes
Adv. Synth. Catal. 2012, 354, 1 – 7
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