Formal highly enantioselective organocatalytic addition of fluoromethyl anion to α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/chem.200900991

The first organocatalytic enantioselective fluoro(bis-phenlsulfonyl) methylation of α-β-unsaturated aldehydes in high yields and enantioselective fluoro(bis-phenylsulfonyl) methylation of α-β- unsaturated aldehydes in high yields and enantioselectivity wa

Full text of DOI:10.1002/chem.200900991

COMMUNICATION
DOI: 10.1002/chem.200900991
Formal Highly Enantioselective Organocatalytic Addition of Fluoromethyl
Anion to a,b-Unsaturated Aldehydes
Andrea-Nekane Alba, Xavier Companyꢀ, Albert Moyano,* and Ramon Rios*[a]
The selective introduction of fluorine (or of fluorine-bear-
ing building blocks) into organic molecules and polymers
can dramatically alter their physical, chemical and biological
properties. Thus, the unique behavior exhibited by many or-
ganofluorinated synthetic compounds has fostered their use
in life and materials sciences. Therefore, extensive studies
have been carried out seeking new synthetic fluorination
methodologies during the past 30 years.[1] The most common
strategies rely on the use of electrophilic fluorine sources,
that presently allow the highly regio- and stereocontrolled
introduction of a fluorine atom in a variety of organic com-
pounds.[2] On the other hand, nucleophilic fluoroalkylation,
that involves the addition of a fluorinated carbanion to an
electrophile, has become one of the most important and
fast-growing fields in fluorine chemistry. In 2008, Hu and
co-workers successfully accomplished the nucleophilic fluo-
roalkylation of a,b-enones, arynes, and activated alkynes
with fluorinated sulfones in racemic form.[3] It is worth
noting, however, that for a,b-unsaturated aldehydes such as
cinnamaldehyde, only 1,2-addition products were obtained.
In the same year, Prakash and Olah reported on the phos-
phine- or base-catalyzed Michael addition of a-substituted
fluoro(phenylsulfonyl)methane derivatives to a variety of
a,b-unsaturated compounds (again with the exception of
a,b-unsaturated aldehydes).[4] The same authors had previ-
ously disclosed an enantiospecific monofluoromethylation of
secondary alcohols by using a fluorocarbon nucleophile in a
Mitsunobu reaction.[5] There are, however, very few asym-
metric nucleophilic fluorination methods reported in litera-
ture. In 2006, Shibata et al. disclosed an elegant palladium-
catalyzed allylic fluoromethylation with excellent yields and
enantioselectivities;[6] the same group reported in 2007 the
first enantioselective monofluoromethylation of N-Boc
imines,[7] and, more recently, the first enantioselective fluo-
romethylation of enones using cinchona alkaloid derivatives
as organocatalysts.[8,9] An organocatalytic asymmetric di-
fluoromethylation of aromatic aldehydes has been described
by Hu[10] with moderate enantioselectivities.
Therefore, the enantioselective Michael addition of fluo-
roalkyl pronucleophiles to a,b-unsaturated aldehydes (1) ap-
peared as a worthy synthetic objective. Based in the previ-
ous works of Shibata[6–8] and others,[3,4] we hypothesized that
fluorobis(phenylsulfonyl)methane (2) could be an excellent
nucleophile, and that the use of iminium catalysis[11] would
result in the exclusive formation of 1,4-addition products.[12]
Moreover, the facility of removal of the phenylsulfonyl
moiety[8] makes this reactant a perfect choice in order to
carry out the future conversion of the resulting compounds
(3) into attractive and interesting products for medicinal
chemistry such as fluorinated building blocks, fluoro-labeled
natural products as shown in Scheme 1.
Initially, we studied the nucleophilic addition of fluoro
ACHTUNGTRENNUNGbis-
AHCTUNGTREG(NNUN phenylsulfonyl)methane (2) to 2-heptenal (1d), catalyzed
by TMS-protected diphenylprolinol (VII). In an initial sol-
vent screening (Table 1), we found that the reaction renders
the expected addition product in good conversions and
enantioselectivities when toluene or CH2Cl2 were used (en-
tries 1 and 2). On the other hand, when protic solvents such
as methanol or 2,2,2-trifluoroethanol were tested no reac-
tion was observed (entries 3 and 4). Furthermore, the addi-
tion of Cs2CO3 as additive increased the rate of the reaction,
but the enantioselectivity decreased dramatically (entries 5
and 6).
[a] A.-N. Alba, X. Companyꢀ, Prof. A. Moyano, Dr. R. Rios+,++
Department of Organic Chemistry
Universitat de Barcelona
Martꢁ i Franquꢂs 1-11, 08028 Barcelona (Spain)
Fax : (+34-933397878)
Once we determined that toluene is a suitable solvent for
the addition reaction, we screened different amines as cata-
lysts (Table 2). The reaction is efficiently catalyzed by proli-
nol (III) or prolinamide (IV) (entries 3 and 4). When pro-
line (I), diphenylprolinol (II) or cinchonidine (VI) were
used, only traces of the product were detected after four
E-mail: rios.ramon@icrea.cat
a.moyano@ub.edu
[+] ICREA Researcher at UB
[
++] ICC-UB Researcher
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900991.
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7035

Table 2. Catalyst screening (see Table 1 for reaction scheme).[a]
Entry
Catalyst
Conversion [%][b]
e.r.[c]
1
2
3
4
5
6
7
I
II
<10
traces
83
40
5
traces
57
5
51:49
n.d.
84:16
60:40
65:35
n.d.
96:4
97:3
97:3
III
IV
V
VI
VII
VIII
VII
8
9[d]
52
[a] In all cases, 2 (1 equiv) in toluene was added to a mixture of 1d
(1.5 equiv) and catalyst (I–VIII) at room temperature. [b] Determined by
NMR. [c] Determined by chiral HPLC analysis. [d] Reaction run at 48C.
Scheme 1. Versatility of the present methodology.
Table 1. Solvent screening.[a]
Table 3. Catalyst screening.[a]
Entry
Aldehyde
Product
Yield [%][b]
e.r.[c]
1
2
3
4
3a
3b
3c
3d
96
87
91
93
98:2
97:3
95:5
96:4
Entry
Solvent
Conversion [%][b]
e.r.[c]
1
2
3
4
toluene
CH2Cl2
MeOH
CF3CH2OH
toluene
CH2Cl2
57
80
traces
traces
100
96:4
90:10
n.d.
n.d.
57:43
57:43
5
6
3e
3 f
63
77
98:2
98:2
5[d]
6[d]
100
[a] In all cases, 2 (1 equiv) in solvent (1 mL) was added to a mixture of
1d (1.5 equiv) and catalyst VII (0.2 equiv) at room temperature. [b] De-
termined by NMR. [c] Determined by chiral HPLC analysis. [d] 1 equiv
of Cs2CO3 was added.
7
8
3g
3h
66
64
96:4[d]
95:5
days (entries 1, 2 and 6, respectively). To our delight, when
compounds VII and VIII were used, the reaction was effi-
ciently catalyzed, showing high levels of enantioselectivity.
Interestingly, we found a slight increase of enantioselectivi-
ties without appreciable loss of conversion at 48C (entry 9).
However, catalyst VIII showed very low conversion after
four days. For this reason, we selected catalyst VII and tolu-
ene at 48C as the best system for the monofluorination reac-
tion.
With these optimized conditions already established, the
scope of the reaction in terms of substrates was investigated
next (Table 3). We found that the conditions used constitute
a very general catalytic system for the asymmetric addition
of fluorobis(phenylsulfonyl)methane (2) to a broad range of
a,b-unsaturated aldehydes (1a–j) (Table 3).
9
3i
3j
73
90
95:5
98:2
10
[a] In all cases, 2 (1 equiv) in toluene was added to a mixture of 1a–j
(1.5 equiv) and catalyst VIII (0.2 equiv) at room temperature. [b] Isolated
yield. [c] Determined by chiral HPLC analysis. [d] HPLC analysis of re-
duction product.
(entries 1, 2, 3 and 4), affording the desired adducts in up to
98:2 enantiomeric ratio. When aromatic aldehydes were
used, the reaction became slower and the yields slightly de-
creased. When electron-withdrawing groups were placed in
the aromatic ring, the reaction took place with good yields
and enantioselectivities (entries 6 and 7); on the other hand,
when Br or Cl where placed in the aromatic ring the yields
were moderate and the enantioselectivities decreased to
95:5 e.r. (entries 8 and 9). Finally, it is noteworthy that the
The reaction takes place with excellent levels of enantio-
selectivity and high yields when aliphatic aldehydes are used
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Chem. Eur. J. 2009, 15, 7035 – 7038

Enantioselective Organocatalysis
COMMUNICATION
addition to dienal 1j was completely regioselective (only b-
addition product was observed), and took place with good
yield and excellent enantioselectivity (entry 10).
situ” to obtain the corresponding 4-fluoro-2-amino-1-hy-
droxy compounds (10). These compounds can be easily
modified to obtain the free amino acid, or amino acid deriv-
atives.[13,14]
With a range of enantiomerically enriched g-fluoro-bis-
A
It is noteworthy that this amination methodology allows
us to prepare with almost equal efficiently anti and syn
amino alcohol derivatives (10e and 10e’, respectively)
simply by using d- or l- proline as the catalyst.
In order to expand the utility of the reaction, we decided
to prepare more derivatives such as esters or amines. Com-
pound 3d was easily oxidized by known procedures to acid
7d in quantitative yield; after treatment with dicyclohexyl-
carbodiimide (DCC) and (À)-menthol this acid afforded
ester 8d in moderate yield. Moreover, compound 3d can be
transformed to an amine deriv-
to investigate the reductive desulfonylation of compounds 3
to complete the sequence of enantioselective monofluoro-
methylation.
In order to show the viability of this sequence, we chose
compounds 3a, 3b, and 3e; these compounds were reduced
with sodium borohydride to afford the corresponding alco-
hols 4, and then treated with Mg in methanol[6] for the re-
moval of sulfonyl groups. We obtained compounds 5 in
almost quantitative yield from the aldehydes 3 (Scheme 2).
ative 6d by reductive amination
in good yield (Scheme 3).
The absolute configuration of
adducts was ascertained by
chemical correlation. Thus, ad-
dition of phenylmagnesium
chloride to aldehyde 3a and
subsequent oxidation gave com-
pound 12a as shown in
Scheme 4. Comparison with the
literature data[8] revealed that
the absolute configuration of
the known ketone 12a is (2R)
([a]2D5 =+30.4 (c = 1.2, CHCl3),
lit. (ref. [6]) ([a]2D5 =+24.1 (c =
1.0, CHCl3)).
The stereochemical outcome
can be rationalized by the
Scheme 2. Synthesis of fluorinated alcohols.
mechanistic proposal outlined
in Scheme 5. Thus, efficient
shielding of the Re face of the
chiral iminium intermediate 13
by the bulky aryl groups of VII
leads to stereoselective Si-facial
nucleophilic conjugate attack
on the b-carbon of 13. This
mechanism is in accordance
with those proposed for other
amine-catalyzed reactions be-
tween nucleophiles and enals.[15]
In conclusion, we have de-
scribed the first organocatalytic
enantioselective
fluoro(bis-
Scheme 3. Synthetic applications of adducts 3.
A
ACHTUNGTRENNUNG
a,b-unsaturated aldehydes in
high yields and enantioselectivities. The resulting com-
pounds were converted into a wide range of derivatives to
show the applicability of this new methodology. Moreover,
we synthesized valuable 4-fluoro-2-amino-1-alkanols that
can be easily transformed to fluoroaminoACTHNUTRGNEaNUG cids or fluoroami-
noalcohols by known procedures. Mechanistic studies, syn-
thetic applications of this transformation as well as develop-
Moreover, we synthesized d-fluoro-b-aminoalcohols in a
few steps and, more important, in highly diastereo- and
enantioselective fashion. Compound 5e was oxidized by pyr-
idinium chlorochromate in CH2Cl2, and the resulting alde-
hyde 9e was a-aminated following the procedures described
by Jorgensen[13] and List,[14] using proline and diethyl azodi-
carboxylate (DEAD). The resulting crude was reduced “in
Chem. Eur. J. 2009, 15, 7035 – 7038
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7037

A. Moyano, R. Rios et al.
Acknowledgements
We thank the Spanish Ministry of Science and Education for financial
support (Project AYA2006-15648-C02-01). A.N.A. is grateful to the UB
for a predoctoral fellowship.
Scheme 4. Determination of absolute configuration.
Keywords: enantioselectivity · fluorine · organocatalysis ·
nucleophilic addition · stereoselectivity
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Scheme 5. Proposed mechanism.
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Experimental Section
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An ordinary vial equipped with a magnetic stirring bar was charged with
catalyst VII (16 mg, 0.05 mmol) and toluene. Then, the solution was
cooled to 48C and the a,b-unsaturated aldehyde 1a–j (0.375 mmol) and
fluorobis(phenylsulfonyl)methane (2; 78 mg, 0.25 mmol) were added. The
stirring was maintained at 48C for 1–4 d until completion of the reaction
1
(monitored by H NMR) and then directly purified by flash chromatogra-
phy to afford the products 3a–j.
Compound 3a: Colorless oil; 1H NMR (400 MHz, CDCl3, TMSint): d =
1.52 (dd, J=6.9, J’=1.7 Hz, 3H), 3.19 (dd, J=19.1, J’=9.6 Hz, 1H),
3.44–3.37 (m, 1H), 3.73 (dd, J=19.1, J’=2.1 Hz, 1H), 7.73–7.66 (m, 6H),
8.00–7.98 (m, 2H), 8.09–8.05 (m, 2H), 9.88 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3): d = 14.9 (d, J=8.4 Hz), 31.4 (d, J=18.7 Hz), 45.3 (d,
J=5.7 Hz), 116.0 (d, J=256 Hz), 128.9, 129.0, 131.0, 135.2,
135.3,198.5 ppm; 19F NMR (376 MHz, CDCl3): d=À134.7 ppm; HRMS:
m/z: calcd for [C17H17FO5S2Na]+: 407.0394; found: 407.0391; [a]2D5 =À65
(c=0.5, CHCl3, 96% ee); HPLC: Chiralpack IA hexane/isopropanol
90:10, 1 mLminÀ1, tR = 42 and 45 min.
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Received: April 14, 2009
Published online: June 23, 2009
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Chem. Eur. J. 2009, 15, 7035 – 7038