The organocatalytic addition of bis(arylsulfonyl)methane to α,β-unsaturated aldehydes and the synthesis of optically-enriched 3-methyl-alkanols

Article abstract of DOI:10.1039/b908963b

An indirect organocatalytic method for the β-methylation of α,β-unsaturated aldehydes that involves the addition of bis(arylsulfonyl)methane catalyzed by prolinol derivatives and further elimination of the chameleonic sulfonyl groups is presented. The Roy

Full text of DOI:10.1039/b908963b

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The organocatalytic addition of bis(arylsulfonyl)methane to
a,b-unsaturated aldehydes and the synthesis of optically-enriched
3-methyl-alkanolsw
´ ´ ´
´
Jose Luis Garcıa Ruano,* Vanesa Marcos and Jose Aleman*
Received (in Cambridge, UK) 6th May 2009, Accepted 22nd May 2009
First published as an Advance Article on the web 12th June 2009
DOI: 10.1039/b908963b
An indirect organocatalytic method for the b-methylation of
a,b-unsaturated aldehydes that involves the addition of
bis(arylsulfonyl)methane catalyzed by prolinol derivatives and
further elimination of the chameleonic sulfonyl groups is presented.
The same strategy could be used for introducing alkyl
groups at the b-position of a,b-unsaturated aldehydes 6.
Surprisingly, the reactions of bis(arylsulfonyl)methanes 5 as
nucleophiles with a,b-unsaturated aldehydes catalyzed by
proline derivatives have never been reported. In this work,
we present the first organocatalytic asymmetric addition of
bis(phenylsulfonyl)methane to a,b-unsaturated aldehydes, and
their subsequent reduction and desulfonylation to obtain
3-methyl-1-alkanoles (Scheme 2).
In the last few years, organocatalysis has proved to be a
powerful tool in the development of a large number of enantio-
selective reactions.1 Among them, asymmetric 1,4-conjugate
addition has emerged as a powerful strategy to easily obtain
chiral organic compounds.2 In this field, covalent strategies
have mainly been used for the b-functionalization of a,b-
unsaturated aldehydes.3 These processes are usually based on
the activation of the carbonyl group by the formation of
iminium ions with chiral amines,3 which react with doubly-
activated methylenes such as b-ketoesters.3b Despite the large
number of reactions describing the b-functionalization of
a,b-unsaturated aldehydes, the introduction of simple alkyl
groups has never been reported. The importance of the problem
has a special significance in the case of methylation. 3-Methyl-
alkanols, obtained by the b-methylation of a,b-unsaturated
aldehydes and subsequent reduction, are themselves important
pheromones,4 building blocks5 or are directly implicated in the
synthesis of various different terpenoids in the fragrance industry.6
These compounds are currently prepared from citronellal by
various different synthetic sequences involving a large number
of steps.7
Scheme 1 The a-functionalization of aldehydes with a,b-unsaturated
bis-sulfones.
Scheme 2 The organocatalytic enantioselective approach of this
work.
When we tried the reaction of aldehyde 6a with bis(phenyl-
sulfonyl)methane (5) catalyzed by proline derivative 8a
(entry 1, Table 1), we did not observe any change in the
reaction mixture. This would explain the absence of references
Taking advantage of the chameleonic ability of sulfones to be
transformed into different functionalities,8 they have been used
in enamine-type organocatalysis. Thus, starting in 2005,
Alexakis et al. published the reaction of aldehydes with a,b-
unsaturated bis-sulfones catalyzed by N-i-Pr-2,20-bipyrrolidine.9
Interestingly, in 2008–2009, the groups of Palomo,10a Alexakis10b
and Lu10c independently published the addition of aldehydes to
vinyl-bis-sulfones catalyzed by silyl-biaryl prolinol ethers11
(Scheme 1), affording a-functionalized aldehydes in high enantio-
meric excesses. In all of these cases, the electrophiles were
activated by the sulfonyl group, which could be transformed
(or simply removed) at the end of the sequence, converting the
obtained compounds into alkyl derivatives (Scheme 1).
12
concerning this topic. Taking into account the similar pKa
value for 5 (12.2) and b-ketoesters (B14.2), the scarce reactivity
of the bis(arylsulfonyl)methane was intriguing and we decided
to investigate. The only reason to explain the different reactivity
of b-ketoesters and bis-sulfones with a,b-unsaturated alde-
hydes must be related to the equilibration of the esters with
their enolic forms, which are weak nucleophiles that are able
to react with the iminium intermediates. A similar process is
not possible with bis-sulfones, and a significant amount of
a-sulfonyl carbanion must not be generated under standard
iminium catalytic conditions (usually performed in the
presence of weak acids such as PhCO2H or AcOH). These
latter conditions were also unfruitful, as applied to the reaction
of 5 with 6a (entry 2, Table 1). This fact suggests that reactions
could be possible in the presence of an appropriate base that is
able to deprotonate the methylenic proton of 5 and be
compatible with the organocatalytic reaction. Surprisingly,
the addition of LiOAc13 allowed us to detect the desired
Departamento de Quı´mica Orga´nica (C-I), Universidad Auto´noma de
Madrid, Cantoblanco, 28049-Madrid, Spain.
E-mail: joseluis.garcia.ruano@uam.es, jose.aleman@uam.es;
Fax: +34 914973966
w Electronic supplementary information (ESI) available: Further
experimental details, characterisation data and spectra. See DOI:
10.1039/b908963b
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Table 1 The screening of various reaction conditionsa
Table 2 The scope of various unsaturated aldehydesa
Entry
R
Product
Yield (%)
ee (%)b
1
2
3
4
5
6
7
8
Me (6a)
Et (6b)
Et (6b)
n-Pr (6c)
n-Bu (6d)
n-Pentyl (6e)
n-Hexyl (6f)
n-Nonyl (6g)
i-Pr (6h)
7a
7b
ent-7b
7c
7d
7e
95
80c
92 (91)c
97
96
91 (91)c
Entry
Catalyst
Additive
Solvent
Yield (%)
erb
ꢁ90d
1
2
3
4
5
6
7
8
8a
8a
8a
8b
8b
ent-8b
8b
8c
8c
8c
8c
8c
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
EtOH
nr
nr
5o
nrc
60
—
—
—
—
75 : 25
24 : 76
—
85 : 15
—
—
90
90
96
94
96
90
90
—
PhCO2H
—
—
99
83
83
73
7f
LiOAc
LiOAc
LiOAc
LiOAc
PhCO2H
AcOH
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
7g
7h
7i
42
9
10
11
70
63
nrc
50
PhCH2CH2 (6i)
Ph (6j)
7j
nre
9
nrc
nrc
50
a
Performed with 5 (0.20 mmol), 6 (0.40 mmol), LiOAc (100 mol%)
b
and 8c (20 mol%) as the catalyst in 0.2 mL of THF at rt. Enantio-
10
11
12
13
14
15
16
85 : 15
82 : 18
ndd
c
meric excess determined by chiral stationary phase HPLC. Reaction
50
d
e
performed at 0 1C. ent-8c was used as the catalyst. No reaction.
8c
8c
8c
8c
CH3CN
H2O
THF
5o
nrc
68
—
85 : 15
90 : 10
Consequently, we studied the behaviour of the rest of the
aldehydes only at rt. When the size of the R group at the
double bond of the aldehyde was larger, better enantio-
selectivities were observed (compare entry 1 with the other
entries in Table 2). Interestingly, compound ent-7b (the
enantiomer of 7b) could be easily obtained by using catalyst
ent-8c (entry 3, Table 2). Almost quantitative yields (91–99%)
and high enantiomeric excesses (90–91%) were obtained from
aldehydes 6b–d (entries 2–5, Table 2), whereas the yield was
slightly decreased (73–83%) and the stereoselectivity was
increased in the reactions of 6e–6g (94–96% ee; entries 6–8,
Table 2). The results were analogously good for compounds
with bulkier groups, such as 6h (i-Pr; entry 9, Table 2) or 6i
(PhCH2CH2; entry 10, Table 2). Unfortunately, no reaction
was observed for aromatic a,b-unsaturated aldehydes
(entry 11, Table 2).
THF
95e
a
Performed at room temperature with 5 (0.20 mmol), 6a (0.40 mmol),
catalyst 8 (20 mol%), additive (100 mol%) and solvent (0.2 mL) in each
b
case. Enantiomeric ratio determined by chiral stationary phase
c
d
e
HPLC. No reaction. Not determined. Reaction performed at 0 1C.
addition product in the crude mixture,14 although the conver-
sion was very low (entry 3, Table 1). The reaction with the
catalyst’s TMS derivative, 8b, was also unfruitful in the
absence of base (entry 4, Table 1), but the addition of LiOAc
afforded 7a in a 60% yield as a 75 : 25 mixture of enantiomers
(entry 5, Table 1). Interestingly, a similar result was obtained
when this reaction was catalyzed by ent-8b; the alkanol
enantiomer (ent-7a) was obtained with a similar result
(entry 6, Table 1). The reaction did not work by using toluene
instead of CH2Cl2 as the solvent (entry 7, Table 1).
Elimination of the chameleonic sulfonyl group8 in
compounds
7 provides products corresponding to the
The best stereoselectivity was obtained by using the bulkier
catalyst, 8c,11 in CH2Cl2 (50% yield and 85 : 15 er; entry 8,
Table 1). With this catalyst, the addition of AcOH or PhCO2H,
which usually improves other catalytic processes via iminium
ions, had a negative influence (entries 9 and 10, Table 1). The
choice of solvent therefore seems to be very important. Thus,
results in CHCl3 or EtOH (entries 11 and 12, Table 1) were
similar to those obtained in CH2Cl2, but the conversion was
very poor in H2O and CH3CN (entries 13 and 14, Table 1). The
best results were obtained in THF (entries 15 and 16, Table 1)
with a 65% yield (85 : 15 er) at rt and a 95% yield (90 : 10 er) at
0 1C. Reaction times were longer (5 d) at 0 1C than at rt (3 d).
We then studied the reactions of alkyl aldehydes 6a–j with 5
catalyzed by 8c11 under the optimized conditions of Table 1;
the results are shown in Table 2. Starting from 6b, the
observed enantioselectivity at rt was substantially higher than
that from 6a (compare entries 1 and 2, Table 2). We also
studied the reaction of 6b at 0 1C (entry 2, Table 2), but the
selectivity and yield remained unaltered (value in brackets of
entry 2, Table 2), and the reaction time increased from 3 to 5 d.
b-methylation of the a,b-unsaturated aldehydes. In order to
assign the configuration of compounds 7, we transformed 7b
into 3-methylpentanol (9b) by a reaction with Mg/MeOH
(entry 1, Table 3). The sign of the specific rotation of 9b was
the opposite of that reported for (S)-3-methylpentanol,15
which supports the (R)-configuration of 9b and therefore
7b.15 This configuration is the one expected by assuming the
stereochemical models reported for the b-functionalization of
a,b-unsaturated aldehydes catalyzed by 8.3,11
The use of similar conditions should allow 3-methyl-1-
alkanols to be obtained in high optical purity (the reaction
conditions do not affect the chiral center). We have illustrated
this possibility by preparing compounds that exhibit the most
interesting features (entries 2–6, Table 3). Alkanol 9c has been
employed in the synthesis of the pheromone of the southern
corn rootworm,16 and was obtained in 40% yield. Interestingly,
longer alkyl chains provided better yields (entries 3–6,
Table 3). Thus, 9d (R = n-Bu), used as a building block in
the synthesis of HUN-72935c and as intermediate in the
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Table 3 Desulfonylation of various alcohols 7b–g
2007, 1701; (b) D. Almasi, D. A. Alonso and C. Najera, Tetra-
hedron: Asymmetry, 2007, 18, 299; (c) M. Shimizu, I. Hachiya and
I. Mizota, Chem. Commun., 2009, 874.
3 See, for example: (a) S. Mayer and B. List, Angew. Chem., Int. Ed.,
2006, 45, 4193; (b) S. Brandau, A. Landa, J. Franzen, M. Marigo
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2006, 45, 4305;
(c) P. T. Franke, B. Richter and K. A. Jørgensen, Chem.–Eur. J.,
2008, 14, 6317; (d) M. Rueping, E. Sugionoa and E. Merino,
Chem.–Eur. J., 2008, 14, 6329; (e) S. Cabrera, E. Reyes,
J. Aleman, A. Milelli, S. Kobbelgaard and K. A. Jørgensen,
J. Am. Chem. Soc., 2008, 130, 12031; (f) J. Wang, A. Ma and
D. Ma, Org. Lett., 2008, 10, 5425.
4 (a) G. Y. Ishmuratov, M. P. Yakovleva, R. Y. Kharisov and
G. A. Tolstikov, Russ. Chem. Rev., 1997, 66, 987; (b) K. Mori, Eur.
J. Org. Chem., 1998, 1479; (c) P. H. G. Zarbin, J. A. F. P. Villar
and A. G. Correa, J. Braz. Chem. Soc., 2007, 18, 1100.
Entry
R
Product
Yield (%)
1
2
3
4
5
6
Et (7b)
n-Pr (7c)
n-Bu (7d)
n-Pentyl (7e)
n-Hexyl (7f)
n-Nonyl (7g)
9b
9c
9d
9e
9f
51
40
92
75
87
96
9g
5 3-Methyl-alkanols are quite commonly used building blocks. See,
for example: (a) T.-Z. Wang, E. Pinard and L. A. Paquette, J. Am.
Chem. Soc., 1996, 118, 1309; (b) A. B. Smith III, S. A. Kozmin and
D. V. Paone, J. Am. Chem. Soc., 1999, 121, 7423; (c) D. L. Boger,
H. Keim, B. Oberhauser, E. P. Schreiner and C. A. Foster, J. Am.
Chem. Soc., 1999, 121, 6197; (d) D. R. Williams, A. L. Nold and
R. J. Mullins, J. Org. Chem., 2004, 69, 5374; (e) D. F. Taber and
synthesis of different pheromones,17 was obtained in 92%
yield. An intermediate of the sex attractant of the yellow
mealworm, 9e (R = n-pentyl),18 was obtained in 75% yield
(entry 4, Table 3). Alcohol 9f (R = n-hexyl), used as an
intermediate in the synthesis of the sex pheromones of the
western hemlock looper,19a of the red flour beetle19b and of
some marine lipids,19c was obtained in 87% yield (entry 5,
Table 3). Finally, 9g (R = n-nonyl), which has been used in the
synthesis of pheromones,20 could be obtained in an almost
quantitative yield (entry 6, Table 3). The present procedure for
preparing all of these compounds involves two steps from
commercially available materials, and therefore it is much
more simple and efficient than those methods so far reported,
usually requiring much longer synthetic sequences.
W. Tian, J. Org. Chem., 2008, 73, 7560.
A different but
complementary iminium-based methodology for the enantio-
selective construction of chiral 3-methyl-alkanols, based on the
hydride reduction of enals, have been also reported. See:
(f) J. W. Yang, M. T. Hechavarria-Fonseca, N. Vignola and
B. List, Angew. Chem., Int. Ed., 2005, 44, 108; (g) S. Ouellet,
J. B. Tuttle and D. W. C. MacMillan, J. Am. Chem. Soc., 2005,
127, 32.
6 The Chemistry of Fragrances, ed. D. Pybus and C. Sell, Royal
Society of Chemistry, Cambridge, 1999.
7 D. J. Lenardao, G. V. Botteselle, F. Azambuja, G. Perin and
R. G. Jacob, Tetrahedron, 2007, 63, 6671.
8 (a) B. Trost, Bull. Chem. Soc. Jpn., 1998, 61, 107;
(b) J. C. Carretero, R. Arrayas and J. Adrio, in Sulfones in
Asymmetric Catalysis, ed. T. Toru and C. Bolm, Wiley, 2008,
ch. 9, pp. 291.
9 (a) S. Mosse and A. Alexakis, Org. Lett., 2005, 7, 4361;
(b) S. Mosse, M. Laars, K. Kriis, T. Kanger and A. Alexakis,
Org. Lett., 2006, 8, 2559; (c) A. Quintard, C. Bournaud and
A. Alexakis, Chem.–Eur. J., 2008, 14, 7504.
10 (a) A. Landa, M. Maestro, C. Masdeu, A. Puente, S. Vera,
M. Oiarbide and C. Palomo, Chem.–Eur. J., 2009, 15, 1562;
(b) S. Mosse, A. Alexakis, J. Mareda, G. Bollot, G. Bernardinelli
and Y. Filinchuk, Chem.–Eur. J., 2009, 15, 3204; (c) Q. Zhu and
Y. Lu, Org. Lett., 2008, 10, 4803.
11 For a general review of the use of silyldiarylprolinol ethers as
catalysts see: A. Mielgo and C. Palomo, Chem.–Asian J., 2008, 3,
922.
In conclusion, we report here the first organocatalytic
additions of a bis(arylsulfonyl)methane, catalyzed by the
diarylprolinol ether 8c in the presence of LiOAc, to a wide-
range of a,b-unsaturated aldehydes. The reactions take place
with excellent yields and high enantioselectivities (up to 96% ee).
Further in situ reduction and elimination of the sulfonyl
groups provides an indirect method for the organocatalytic
b-methylation of a,b-unsaturated aldehydes. This sequence
allows the synthesis of highly important 3-methyl-1-alkanols
in high optical purity from commercially available reagents.
This work was made possible by the Spanish Government
(Grant BQU2006-04012). J. A. and V. M. thank the ‘‘Ministerio
de Ciencia e Innovacion’’ for a ‘‘Juan de la Cierva’’ contract and
a pre-doctoral fellowship, respectively.
12 pKa values were obtained from D. A. Evans’ pKa table
(http://www2.lsdiv.harvard.edu/labs/evans/pdf/evans_pKa_table.pdf).
13 The use of LiOAc in aminocatalysis has been previously reported.
See, for example: Y. Wang, P. Li, X. Liang, T. Y. Zhang and J. Ye,
Chem. Commun., 2008, 1232.
Notes and references
14 All of the reactions described here of a,b-unsaturated aldehydes 6
with bisulfones 5 using proline derivatives as the organocatalyst
were followed by NMR. The resulting sulfonyl aldehydes were
in situ-reduced to their respective alcohols since direct isolation of
the aldehydes was difficult.
1 For recent reviews on organocatalysis see, for example:
(a) P. I. Dalko and P. L. Moisan, Angew. Chem., Int. Ed., 2004,
43, 5138; (b) A. Berkessel and H. Groger, Asymmetric Organo-
catalysis: From Biomimetic Concepts to Applications in
Asymmetric
Synthesis,
Wiley-VCH,
Weinheim,
2004;
15 K. Mori and T. Sugai, Synthesis, 1982, 752.
(c) J. Seayed and B. List, Org. Biomol. Chem., 2005, 3, 719;
(d) Acc. Chem. Res., 2004, 37(8), special issue on organocatalysis;
(e) B. List and J.-W. Yang, Science, 2006, 313, 1584;
(f) M. J. Gaunt, C. C. C. Johansson, A. McNally and N. C. Vo,
Drug Discovery Today, 2007, 2, 8; (g) B. List, Chem. Commun.,
2006, 819; (h) Enantioselective Organocatalysis: Reactions and
Experimental Procedures, ed. P. I. Dalko, Wiley-VCH, Weinheim,
2007; (i) P. Melchiorre, M. Marigo, A. Carlone and G. Bartoli,
Angew. Chem., Int. Ed., 2008, 47, 6138.
16 S. Senda and K. Mori, Agric. Biol. Chem., 1983, 47, 795.
17 See, for example: B. V. Burger and W. G. B. Petersen, J. Chem.
Ecol., 2002, 28, 501.
18 T. Kitahara and S.-H. Kang, Proc. Jpn. Acad., Ser. B, 1994, 70,
181.
19 (a) J. Li, G. Gries, R. Gries, J. Bikic and K. N. Slessor, J. Chem.
Ecol., 1993, 19, 2547; (b) T. Suzuki, J. Ozaki and R. Sugawara,
Agric. Biol. Chem., 1983, 47, 869; (c) D. Raederstorff, A. Y. L. Shu,
J. E. Thompson and C. Djerassi, J. Org. Chem., 1987, 52, 2337.
20 K. Mori and J. Wu, Liebigs Ann. Chem., 1991, 5, 439.
2 For recent reviews on conjugated additions using iminium-ion
activation see, for example: (a) S. B. Tsogoeva, Eur. J. Org. Chem.,
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