Asymmetric allylation of N-benzoylhydrazones promoted by novel C2-symmetric bis-sulfoxide organocatalysts

Article abstract of DOI:10.1016/j.tetlet.2006.09.113

Novel C₂-symmetric bis-sulfoxide/N-oxide (R,R)-5 was prepared in good yield according to the Andersen protocol with (S)-menthyl p-tolyl sulfinate (2 equiv) and the dilithium derivate of 2,6-dimethylpyridine N-oxide. Reduction of (R,R)-5 to pyri

Full text of DOI:10.1016/j.tetlet.2006.09.113

Tetrahedron Letters 47 (2006) 8235–8238
Asymmetric allylation of N-benzoylhydrazones promoted by novel
C -symmetric bis-sulfoxide organocatalysts
2
Fred Garc ´ı a-Flores, Luz S. Flores-Michel and Eusebio Juaristi*
Departamento de Qu ı´ mica, Centro de Investigaci o´ n y de Estudios Avanzados del Instituto Polit e´ cnico Nacional,
Apdo. Postal 14-740, 07000 M e´ xico, DF, Mexico
Received 25 August 2006; revised 20 September 2006; accepted 21 September 2006
Available online 10 October 2006
2
Abstract—Novel C -symmetric bis-sulfoxide/N-oxide (R,R)-5 was prepared in good yield according to the Andersen protocol with
(
S)-menthyl p-tolyl sulfinate (2 equiv) and the dilithium derivate of 2,6-dimethylpyridine N-oxide. Reduction of (R,R)-5 to pyridine/
0
bis-sulfoxide (R,R)-6 was accomplished by means of Katritzky’s procedure (Fe /AcOH). Both bis-sulfoxides (R,R)-5 and (R,R)-6
are efficient chiral organocatalysts in the asymmetric allylation of N-benzoyl hydrazones derived from both aldehydes and ketones.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1. Introduction
to the silicon atom of the allyltrichlorosilanes to form
hypervalent silicon intermediates. In particular, N,N-
7
The development of practical enantioselective syntheses
of chiral amines is of great relevance to synthetic organic
chemistry. In particular, enantiopure homoallylic
amines are useful intermediates for the preparation of
nitrogen-containing compounds, which are biologically
dimethylformamide (DMF),
hexamethylphosphor-
7
8
9
10
amide (HMPA), N-oxides, P-oxides, and ureas,
including their optically active derivatives for asymmet-
ric catalysis, promote the allylation of aldehydes.
6
b
1
active. In this regard, resonance-stabilized allyl organo-
Recently, the use of chiral sulfoxides 1–3 (Chart 1) as
metallics have been used with success in imine addition
reactions; nevertheless, metal-free organic molecule-
ligands in the enantioselective allylation of aldehydes and
2
catalyzed allylation reactions are most attractive in
terms of reagent stability and environmentally benign
Ph
nature relative to metal complex-catalysts.3
O
O
S
O
A major problem encountered in the addition of allyl-
N
S
4
metals to imines is competitive a-deprotonation. This
:
R1
Fe
1
¨
complication can be solved at least in part, by the use
R2
R
2
,5
of allylsilanes; nevertheless, their relative low reactiv-
ity usually requires the use of catalysts. In particular,
allyltrichorosilanes are essentially inert to the electro-
philic imines in the absence of external promoters.
Therefore, activation of the reaction has been achieved
in two ways: (1) by the use of Lewis acid catalysis,
including asymmetric variants using chiral Lewis acids,
O
S
R1
1
2
1
1
1 (R , R )
2 (R )
3 (R )
(R)-1a (Me, p-tolyl)
2a (Ph)
2 6 4
2b (p-O NC H )
3a (p-tolyl)
3b (t-Bu)
3c (i-Pr)
6
which activate the imine, and (2) by means of a Lewis
base, which activates the nucleophile via coordination
(
(
(
R)-1b (Et, p-tolyl)
R)-1c (i-Pr, p-tolyl)
S)-1d (o-tolyl, Me)
7
2c (2-C10H )
2d (p-MeOC
6
3
4
H )
Keywords: Organocatalysis; Chiral sulfoxide; Enantioselective allyl-
ation; Chiral sulfur reagents.
(S)-1e (o-MeOC
6
H
4
, Me)
, Me)
2e (2,4,6-Me
C
6
H
2
)
(
S)-1f (p-MeOC
6
H
4
2
2f (Me CH)
*
Corresponding author. Tel.: +52 55 5061 3722; fax: +52 55 5061
389; e-mail: juaristi@relaq.mx
3
Chart 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.113

8236
F. Garc ı´ a-Flores et al. / Tetrahedron Letters 47 (2006) 8235–8238
hydrazones has been explored by several researchers,11–13
with observed enantioselectivities that vary from poor to
very good enantiomeric excesses.
(7) was promoted by achiral dimethylsulfoxide
(DMSO), by chiral monosulfoxide (R)-methyl p-tolyl
sulfoxide (MTS), and by C -symmetric bis-sulfoxides
2
(
R,R)-5 and (R,R)-6. The conditions employed by
1
1
Attracted by the wide applicability of enantiopure sulf-
Kobayashi et al. were followed, using 1.5 or 3.0 equiv
of the sulfoxides.
1
4
23
oxides in asymmetric carbon–carbon bond formation,
and intrigued by the possibility of bidentate complex
formation between the silicon moiety in allyltrichloro-
Analysis of the observations collected in Table 1 reveals
that bis-sulfoxide/N-oxide (R,R)-5 is quite efficient in
promoting the enantioselective allylation of hydrazone
7a with allyltrichlorosilane (er = 12:88, entry 3 in Table
1). By contrast, lower enantioinduction is observed with
bis-sulfoxide (R,R)-6. Indeed, the er = 20:80 of the ally-
lated hydrazide (entry 4 in Table 1) is essentially the
same as the one achieved with (R)-methyl p-tolyl sulf-
oxide (er = 21:79, entry 2 in Table 1). Although the yield
of the allylation reaction in the presence of (R,R)-6 is
lower than those achieved with monosulfoxide (R)-MTS,
it should be mentioned that no allylation takes place
in the absence of sulfoxide activator.
1
5
silane and C -symmetric chiral ligands, we undertook
2
the synthesis of novel bis-sulfoxides (R,R)-5 and (R,R)-
6
and the examination of their potential as promoters in
the asymmetric allylation of N-benzoyl hydrazones
derived from aldehydes and ketones.
2
. Results and discussion
The synthesis of novel bis-sulfoxides (R,R)-5 and (R,R)-6
was carried out following the general method developed
1
6
by Andersen. Thus, (S)-(ꢀ)-menthyl p-tolylsulfinate, 4,
1
7
was prepared according to the literature procedure and
was made to react with the dilithium derivate of 2,6-
Table 2 compiles the results of the allylation reaction
(allyltrichlorosilane) of various prochiral N-benzoyl-
hydrazones 7a–f in the presence of chiral bis-sulfoxides
(R,R)-5 and (R,R)-6.
1
8
dimethylpyridine N-oxide. The desired bis-sulfoxide/
N-oxide (R,R)-5, arising from the inversion of configura-
1
9
tion at the sulfinate’s stereogenic sulfur, was obtained
2
0
as white solid in a good yield. Bis-sulfoxide (R,R)-6
0
was prepared from (R,R)-5 by the reduction with Fe /
The configuration of the major enantiomeric N-benzoyl
hydrazide 8b was assigned as (S) by comparison of its
optical rotation with that already assigned in the litera-
CH CO H according to the general method of Katritzky
3
2
2
1,22
and co-workers
(Scheme 1).
1
1a
ture. Because of the similitude in optical rotation and
2
4
Table 1 summarizes the results obtained when allylation
chromatographic (chiral HPLC) retention times, the
of the N-benzoyl hydrazone derived from benzaldehyde
predominant enantiomeric products 8a and 8c were also
n-BuLi (2 equiv.)
N
O
N
THF, 0 ºC
Li
Li
O
O
S
p-tol
O
4
(2 equiv.)
Feº / AcOH
N
N
O
S
S
S
S
p-tol
O
O
p-tol
p-tol
O
O
p-tol
(
R,R)-6, 78 % yield
(R,R)-5, 76 % yield
Scheme 1.

F. Garc ı´ a-Flores et al. / Tetrahedron Letters 47 (2006) 8235–8238
Table 1. Allylation of N-benzoyl-N -benzyledene-hydrazone with allyltrichlorosilane using various sulfoxides (L) as promoters
8237
0
a
NHCOPh
NHCOPh
N
HN
L (equiv.)
SiCl
3
+
*
CH Cl / -78 ºC
2
2
Ph
H
Ph
b
Entry
L
(equiv)
Yield
Enantiomeric ratio (R:S)
1
2
3
4
DMSO
3
3
1.5
1.5
98
94
89
73
(50:50)
(21:79)
(12:88)
(20:80)
c
(R)-MTS
(R,R)-5
(R,R)-6
a
b
c
11
Half equivalent of 2-methyl-2-butene was added to suppress the racemization of the chiral sulfoxides.
Determined by chiral HPLC.
24
(
R)-Methyl-p-tolyl sulfoxide.
Table 2. Allylation of various N-benzoyl-hydrazones 7a–f with allyltrichlorosilane under catalysis by C
2
-symmetric organocatalysts (R,R)-5 and
a
(
R,R)-6
NHCOPh
NHCOPh
N
HN
L* (1.5 equiv.)
CH Cl / -78 ºC
SiCl
3
+
*
R1
R2
2
2
R1
R2
7
a-f
8a-f
1
2
b
Entry
Substrate (R /R )
L*
Yield of 8
Enantiomeric ratio (R:S)
1
2
3
4
5
6
7
8
9
7a (Ph/H)
7a
(R,R)-5
(R,R)-6
(R,R)-5
(R,R)-6
(R,R)-5
(R,R)-6
(R,R)-5
(R,R)-6
(R,R)-5
(R,R)-6
(R,R)-5
(R,R)-6
89
73
80
72
93
68
84
54
81
56
82
30
12:88
21:79
14:86
30:70
18:82
30:70
7b (p-MeOC
7b
6
H
4
/H)
6 4
7c (m-MeOC H
/H)
7c
7d (2-Furyl/H)
7d
c
16:84
c
45:55
c
7e (Me
2
CHCH
2
/H)
74:26
10
11
12
7e
7f (Ph/Me)
7f
50:50
20:80
87:13
a
b
c
11
Half equivalent of 2-methyl-2-butene was added to suppress the racemization of the chiral sulfoxides.
Determined by chiral HPLC.
This configurational assignment is tentative (see text).
24
assigned as (S). The absolute configuration in hydrazide
selective allylation of N-benzoyl hydrazones derived
from both aldehydes and ketones. The potential applica-
tion of these chiral Lewis bases in other asymmetric C–C
bond forming reactions is being explored.
5
b
(
R)-(+)-8f was determined by Leighton et al. Interest-
ingly, organocatalysts (R,R)-5 and (R,R)-6 induce the
formation of enantiomeric products of opposite config-
uration, suggesting that coordination to the N ! O
group is operative and determinant. The configurational
assignments of hydrazides 8d and 8e are tentatively
assigned in Table 2 on the basis of optical rotation
and chromatographic behavior.
Acknowledgments
We are indebted to Roberto Melgar-Fern a´ ndez for
performing the HPLC analyses. We are also grateful
to Conacyt, M e´ xico, for financial support via grant
Salient observations from the results compiled in Table 2
are (1) the ability of both bis-sulfoxides (R,R)-5 and
45157-Q.
(
R,R)-6 to catalyze the allylation of N-benzoyl hydraz-
ones derived from both aliphatic and aromatic aldehydes
and ketones; (2) the efficiency of N-oxide/bis-sulfoxide
References and notes
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(
R,R)-5 is generally higher relative to the exhibited by
pyridine/bis-sulfoxide (R,R)-6. This finding might sug-
gest an effective coordination by the N ! O group.
1
In summary, novel C -symmetric bis-sulfoxides (R,R)-5
2
and (R,R)-6 are efficient organocatalysts in the enantio-

8238
F. Garc ı´ a-Flores et al. / Tetrahedron Letters 47 (2006) 8235–8238
2
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4
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20. Preparation of (R,R)-2,6-bis(p-toluen-4-sulfenylmethyl)-
pyridine-1-oxide (R,R)-5. To a solution of 2,6-dimethyl-
pyridine N-oxide (0.166 g, 1.35 mmol) in 5 mL of THF at
0 ꢁC was added dropwise a solution of n-BuLi in hexane
(2.5 M, 1.0 mL, 2.70 mmol). The resulting mixture was
stirred at 0 ꢁC for 1 h and then transferred via cannula to a
flask containing (S)-(ꢀ)-menthyl p-tolylsulfinate (1.0 g,
3.34 mmol) in 5.0 mL of THF at 0 ꢁC. The reaction
mixture was stirred for 1 h at 0 ꢁC before quenching with
aqueous saturated ammonium chloride solution. The
product was extracted with methylene chloride, dried over
anhyd sodium sulfate, concentrated at reduced pressure,
and purified by silica gel column chromatography
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5
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(
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b) Hoffmann, R. W.; Endesfelder, A. Liebigs Ann. Chem.
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ences cited therein; (b) Denmark, S. E.; Fu, J. Chem. Rev.
(EtOAc–CHCl –i-PrOH, 8:2:1). Bis-sulfoxide (R,R)-5
3
2
003, 103, 2763.
. Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59,
620.
crystallized from hexane–EtOAc (1:1) to afford 0.40 g
24
7
8
(76% yield) of product, mp 175–176 ꢁC. ½aꢁ +313.0 (c 1.0,
D
1
6
3 3
CHCl ). H NMR (400 MHz, CDCl ) d 2.40 (s, 6H), 4.08
. (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J.
Am. Chem. Soc. 1998, 120, 6419; (b) Nakajima, M.; Saito,
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(d, J = 12.1 Hz, 2H), 4.49 (d, J = 12.1 Hz, 2H), 7.16–7.18
13
(m, 1H), 7.31–7.34 (m, 6H), 7.57–7.60 (m, 4H). C NMR
(100 MHz, CDCl ) d 21.6, 60.8, 123.9, 124.7, 128.2, 130.1,
3
+
2449; (c) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T.
140.6, 142.1, 142.9. MS m/z 399 (M ). Anal. Calcd for
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Farrugia, L.; Kocovsky, P. Angew. Chem., Int. Ed. 2003,
C H NO S : C, 63.13; H, 5.30; N, 3.51; S, 16.05. Found:
C, 63.07; H, 5.36; N, 3.55; S, 16.19.
2
1
21
3 2
4
2, 3674; (e) Malkov, A. V.; Kocovsky, P. Eur. J. Org.
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22. Preparation of (R,R)-2,6-bis(p-toluen-4-sulfenylmethyl)-
pyridine (R,R)-6. To a solution of N-oxide (R,R)-5
(399 mg, 1.0 mmol) in 1.0 mL of acetic acid was added
reduced iron (168 mg, 3.0 mmol) at 0 ꢁC. The resulting
mixture was stirred at rt for 30 min and then neutralized
4
46.
0. Chataigner, I.; Piarulli, U.; Gennari, C. Tetrahedron Lett.
999, 40, 3633.
1
1
1
3
by the addition of satd aq NaHCO , keeping the temper-
1. (a) Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M.
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ature at 0–5 ꢁC. The reaction product was extracted with
CH Cl (3 · 100 mL), dried over anhyd Na SO , and
2
2
2
4
concentrated at reduced pressure. The reduced product
was purified by silica gel column chromatography
1
023.
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1
(EtOAc–CHCl –i-PrOH, 8:2:1) followed by crystallization
3
2
from hexane–EtOAc (1:1) to give 0.30 g (78% yield) of
2
D
4
1
H. Tetrahedron Lett. 2006, 47, 1829.
(R,R)-6, mp 159–160 ꢁC. ½aꢁ +217.0 (c 1, CHCl
3
). H
1
1
3. Fern a´ ndez, I.; Valdivia, V.; Gori, B.; Alcudia, F.; Alvarez,
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3
NMR (400 MHz, CDCl ) d 2.39 (s, 6H), 4.09 (d, J = 12.1,
2H), 4.13 (d, J = 12.4 Hz, 2H), 7.08 (d, J = 7.7 Hz, 2H),
13
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7.26–7.42 (m, 8H), 7.55 (t, J = 7.6 Hz, 1H). C NMR
(100 MHz, CDCl ) d 21.6, 65.7, 124.3, 124.7, 129.9, 137.0,
3
+
140.1, 141.9, 151.2. MS m/z 383 (M ). Anal. Calcd for
C H NO S : C, 65.77; H, 5.52; N, 3.65. Found: C, 65.89;
2
1
21
2 2
H, 5.76; N, 3.68.
23. Bis-sulfoxides (R,R)-5 and (R,R)-6 may be recovered by
silica gel column chromatography: following the elution of
the allylated hydrazides, the bis-sulfoxides are eluted with
2 2
CH Cl –EtOAc (2:1) in 72–87% yields.
1
1
5. (a) Whitesell, J. K. Chem. Rev. 1989, 89, 1581; (b)
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24. HPLC: Chiralcel OD, 0.46 cm · 25 cm, hexane–2-propa-
nol (90:10), flow 1.0 mL/min, UV detector at 230 nm.
Elution times: (R)-8a, 8.8 min; (S)-8a, 9.8 min. (R)-8b,
12.7 min; (S)-8b, 14.6 min. (R)-8c, 16.5 min; (S)-8c, 21.2
min. (R)-8d, 11.1 min; (S)-8d, 16.2 min. (R)-8e, 12.0 min;
(S)-8e, 10.0 min. (S)-8f, 10.8 min; (R)-8f, 13.6 min.
5637; See, also: (b) Drabowicz, J.; Bujnicki, B.; Mikolajc-