Highly enantioselective fluoromalonate addition to α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2009.06.092

A highly enantioselective organocatalytic fluoromalonate addition to α,β-unsaturated aldehydes is reported. The reaction is catalyzed by simple and commercially available secondary amines, affording the corresponding 1,4-adducts with high yields and enant

Full text of DOI:10.1016/j.tetlet.2009.06.092

Tetrahedron Letters 50 (2009) 5021–5024
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Highly enantioselective fluoromalonate addition to a,b-unsaturated aldehydes
a,
a,c,
Xavier Companyó a, Monika Hejnová b, Martin Kamlar b, Jan Vesely b, , Albert Moyano , Ramon Rios
*
*
*
a Departament de Química Orgànica, Universitat de Barcelona, Facultat de Química, C. Martí i Franquès 1-11, 08028 Barcelona, Catalonia, Spain
b Department of Organic Chemistry, Charles University, Hlavova 2030, 128 00 Prague, Czech Republic
c Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08018-Barcelona, Castalonia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective organocatalytic fluoromalonate addition to
a,b-unsaturated aldehydes is
Received 30 May 2009
Revised 15 June 2009
Accepted 17 June 2009
Available online 21 June 2009
reported. The reaction is catalyzed by simple and commercially available secondary amines, affording
the corresponding 1,4-adducts with high yields and enantioselectivities.
Ó 2009 Elsevier Ltd. All rights reserved.
The stereoselective introduction of fluorine (or of fluorine-con-
taining building blocks) into organic molecules and polymers can
dramatically alter their physical, chemical, and biological proper-
ties. This is mainly due to the highly polarized nature of the C–F bond
that usually has strong stereoelectronic interactions with neighbor-
ing bonds or with electron lone pairs of neighboring atoms.1 Many
organofluorated synthetic compounds exhibit unique physical,
chemical, and biological properties that have found wide application
in life sciences, in materials science, and in related disciplines. For
example, fluorination is commonly used in medicinal chemistry to
improve metabolic stability, bioavailability, and protein-drug inter-
actions.2 As a result, extensive research has been carried out seeking
new synthetic fluorination methodologies during the past 30
years.3,1 The specific incorporation of fluorine in a regio- and stere-
oselective fashion can be achieved both by nucleophilic and by elec-
trophilic fluorination. Nucleophilic fluoroalkylation has become one
of the most important and fast growing fields in fluorine chemistry,
and most often involves the transfer of a fluorinated carbanion to an
electrophile. For example, in 2008 Hu and co-workers described a
The most common way relies on the use of electrophilic fluorine
sources: for example, the asymmetric -fluorination of aldehydes
a
was achieved almost simultaneously by Jørgensen,8 MacMillan,9
and Barbas III,10 in high yields and enantioselectivities. While Bar-
bas III and MacMillan used imidazoline derivatives as catalysts,
Jørgensen found that diphenylprolinolsilyl ether was an efficient
catalyst for this transformation. However, there is only one exam-
ple of asymmetric organocatalytic nucleophilic addition of fluo-
rine-containing moieties to
in our laboratory: the enantioselective conjugate addition of fluoro
bis(phenylsulfonyl)methane to ,b-unsaturated aldehydes, a reac-
a,b-unsaturated aldehydes, developed
a
tion with excellent results.11 In the context of an ongoing research
program in our group, devoted to the development of new asym-
metric methodologies based on organocatalysis,12 we are focused
in uncovering new strategies that allow us to form C–C bonds in
an enantioselective fashion. Based on the previous works of Nic-
hols on the fluoromalonate addition to nitroalkenes catalyzed by
chiral magnesium salts,13 the addition of 2-fluoromalonates to
enones catalyzed by phase transfer catalysts by Kim14 and taking
into account the recent reports of Wang and Lu15 on the addition
of 2-fluoroketoesters to nitrostyrenes catalyzed by Cinchona alka-
loids, we turned our attention to the addition of 2-fluoromalonates
convenient fluoroalkylation of a,b-enones, arynes, and activated al-
kynes with fluorinated sulfones in racemic form.4 There are however
few enantioselective fluorination methods reported in the litera-
ture. In 2006, Shibata and co-workers disclosed an elegant palla-
dium-catalyzed allylic fluoromethylation that takes place with
excellent yields and enantioselectivities;5 the same author reported
in 2008 the first enantioselective 1,4-fluoromethylation of enones,
using Cinchona alkaloid derivatives as organocatalysts.6 Sodeoka
has described the direct asymmetric fluorination of oxindoles cata-
lyzed by palladium, with excellent results.7
to
a,b-unsaturated aldehydes as an easy and versatile entry to
interesting products for medicinal chemistry such as building
blocks for drug synthesis, and fluoro-labeled natural products
(Scheme 1).
In an initial catalyst screening, we ran the addition reaction of
diethyl 2-fluoromalonate (2) to cinnamaldehyde (1a) in CHCl3
and we used different commercially available secondary amines
as catalysts (Table 1). Simple proline was able to catalyze the reac-
tion although with low enantioselectivities (entry 1). The proline-
derived diamine II gave only slightly better enantioselectivity
(entry 2), and MacMillan first generation catalyst IV (entry 4) did
not catalyze the reaction. Gratifyingly, when the diphenyl prolinol
derivative III was used, the reaction was efficiently catalyzed,
achieving full conversion after 3 days and affording the conjugate
In the realm of organocatalysis, many efforts have been devoted
in the past few years to the enantioselective synthesis of fluorine-
containing compounds using aldehydes as the starting materials.
* Corresponding authors. Tel.: +34 934021245; fax: +34 933397878 (R.R.).
E-mail addresses: jxvesely@natur.cuni.cz (J. Vesely), amoyano@ub.edu (A.
Moyano), rios.ramon@icrea.cat, riosramon@yahoo.com (R. Rios).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.092

5022
X. Companyó et al. / Tetrahedron Letters 50 (2009) 5021–5024
Table 2
F
*
R"
R
R"
*
Conditions screeninga
CO2H
F
EtO2C
Ph
CO2Et
CHO
3a
EtO2C
CO2Et
III
Catalyst (20%)
CHO
Ph
+
NH2
1a
F
Solventr.t.,
F
*
O
NaOAc1.0equiv
R'O2C
R
CO2R'
CHO
F
2
N
H
R'O2C
cat.
O
CHO
*
R
Entry
Solvent
Time (d)
Conversionb (%)
eec (%)
R
F
*
F
1
2
3
4
5
6
CHCl3
CH2Cl2
DMF
ACN
MeOH
Toluene
3
1
7
7
7
2
100
100
26
71
58
92
96
90
90
88
n.d.
O
R'O2C
CO2R'
R'O2C
R'''
N
*
R
*
31
Scheme 1. Synthetic potential of the addition of 2-fluoromalonates to
a,b-
unsaturated aldehydes.
a
Experimental conditions: a mixture of 1a–g (0.5 mmol), catalyst III (20%), and
2a (0.25 mmol) in the selected solvent (1 mL) was stirred at rt for the time shown in
the Table. After full conversion the crude product was purified by column
chromatography.
Table 1
b
Isolated yield.
Catalyst screeninga
c
Ee determined by chiral HPLC analysis.
F
EtO2C
Ph
CO2Et
CHO
EtO2C
CO2Et
Catalyst (20%)
CHO
+
Ph
Gratifyingly, in all cases the 2-fluoromalonate addition took
place with moderate to good yields and with high enantioselectiv-
ities. For example, when para-nitro cinnamaldehyde was used, the
addition product was obtained with 69% yield and with 94% ee (en-
try 3). The reaction works well with cyanide (entry 2) or halogen
substituents in the para position of the aromatic ring (entries 5
and 6). It is noteworthy that the reaction performs well when
ortho-bromo cinnamaldehyde was used, affording the malonate
1a
F
CHCl3, r.t.,
NaOAc 1.0 equiv
3a
2
O
Ph
Ph
OTMS
N
COOH
N
H
II
N
H
I
N
N
H
N
H
III
Bn
IV
Entry
Catalyst
Time (d)
Conversionb (%)
eec (%)
Table 3
1
2
3
4
I
II
III
IV
7
7
3
7
64
53
100
Traces
15
32
92
n.d.
Aldehyde scopea
F
EtO2C
Ph
CO2Et
CHO
EtO2C
CO2Et
III
Catalyst (20%)
CHO
+
R
F
CH2Cl2, r.t.,
NaOAc 1.0 equiv
a
Experimental conditions: a mixture of 1a–g (0.5 mmol), catalyst III (20%), and
2a (0.25 mmol) in CHCl3 (1 mL) was stirred at rt for the time shown in the Table.
After full conversion the crude product was purified by column chromatography.
1a-g
2
3a
-g
b
Isolated yield.
Ee determined by chiral HPLC analysis.
Entry
Product
R
Time (d)
1
Yieldb (%)
eec (%)
c
1
2
3
4
5
6
7
3a
66
96
93
94
94
95
94
96
addition product with a 92% ee. However, the reaction did not
work without using stoichiometric amounts of a basic additive.
Further optimization of the reaction conditions showed that the
role of the base is crucial: 1 equiv of NaOAc produced the best re-
sults, while KOAc, Et3N, or NaHCO3 gave inferior conversions and/
or enantioselectivities. When the amount of catalyst was decreased
the reaction became extremely slow. We proceeded next to the
optimization of the solvent, taking again the addition of diethyl
2-fluoromalonate (2) to cinnamaldehyde (1a) (Table 2) as a bench-
mark reaction.
Diphenylprolinol derivative III afforded the best results when
the reaction was run in dichloromethane, achieving full conversion
after 3 days and with 96% enantiomeric excess (entry 2). It should
be noticed that the reaction works well in other solvents such as
acetonitrile (entry 4), or methanol (entry 5). The use of dimethyl-
formamide (entry 3) or of toluene (entry 6) led to a substantial
lowering of the reaction rate.
3b
3c
3d
3e
3f
3
3
4
3
3
2
68
69
39
75
73
78
NC
O2N
Br
Cl
3g
Br
Once we uncovered suitable reaction conditions for the enantio-
selective addition of diethyl 2-fluoromalonate to cinnamic alde-
hyde, we studied the scope of the process with different
unsaturated aldehydes. The reaction did not work when aliphatic
unsaturated aldehydes were used, probably due to their instability
in the reaction conditions, but cinnamaldehyde derivatives gave
excellent results as shown in Table 3.
a
Experimental conditions: A mixture of 1a–g (0.5 mmol), catalyst III (20%), and
2a (0.25 mmol) in CH2Cl2(1 mL) was stirred at ꢀ40 °C for the time shown in the
Table. After full conversion the crude product was purified by column
chromatography.
b
Isolated yield.
c
Ee determined by chiral HPLC analysis.

X. Companyó et al. / Tetrahedron Letters 50 (2009) 5021–5024
5023
EtO2C
Ph
CO2Et
CHO
catalyst III
CHO
EtO2C
CO2Et
+
Ph
ref 6
HO
OH
4
1a
5a
p-TsOH, toluene
F
CO2Et
EtO2C
Ph
CO2Et
7a
EtO2C
Ph
NaH, THF
Select Fluor
HO
OH
F
O
EtO2C
Ph
CO2Et
p-TsOH, toluene
O
CHO
6a
O
O
3a
Scheme 2. Determination of absolute configuration.
product in 78% yield and 96% ee (entry 7). On the other hand, when
the b-naphthyl derivative 3d was used the yield of the reaction
dropped dramatically probably due to steric interactions (entry 4).
The absolute configuration of adducts was ascertained by
chemical correlation (Scheme 2). Following the procedure devel-
oped by Jørgensen and co-workers,16 we prepared the highly
enantiopure compound 5a, with an (R) absolute configuration.
After protection of the aldehyde in acetal form and fluorination
by of the malonate moiety by treatment with sequential sodium
hydride and SelectfluorÒ we obtained compound 7a that exhib-
Acknowledgments
We thank the Spanish Ministry of Science and Innovation for
financial support (Project AYA2006-15648-C02-01) and the Minis-
try of Education of the Czech Republic for financial support, Grant
No. MSM0021620857.
References and notes
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In summary, we have reported a highly enantioselective 2-flu-
oromalonate addition to aromatic
a
,b-unsaturated aldehydes.18
The reaction is efficiently catalyzed by commercially available chi-
ral pyrrolidine derivatives and gives the corresponding adducts
with moderate to good yields and with excellent enantioselectivi-
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doi:10.1002/chem.200900991; For an authoritathive and excellent review of
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Moyano, A.; Rios, R. Eur. J. Org. Chem. 2009, 199–203; (c) Valero, G.; Schimer, J.;
Cisarova, I.; Vesely, J.; Moyano, A.; Rios, R. Tetrahedron Lett. 2009, 50, 1943–
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b900777f; For 2-fluoromalonate addition to nitrostyrenes see: (c) Li, H.; Zu, L.;
Xie, H.; Wang, W. Synthesis 2009. doi:10.1055/s-0028-1088124.
16. Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2006, 45, 4305–4309.
EtO2C
CO2Et
Ph
Ph
OTMS
OH-
R
N+
2
F
O
8
1
H2O
R
Ph
Ph
OTMS
Ph
N
Ph
OTMS
N
H
III
R
EtO2C
CO2Et
9
F
17. (a) Ibrahem, I.; Córdova, A. Angew. Chem, Int. Ed. 2006, 45, 1952–1956; (b)
Vesely, J.; Rios, R.; Ibrahem, I.; Zhao, G. -L.; Eriksson, L.; Córdova, A. Chem Eur. J.
2008, 14, 2693–2698; (c) Zhao, G. -L.; Córdova, A. Tetrahedron Lett. 2006, 47,
7417–7421; (d) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2004, 43, 1272–1277; (e) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J.
Am. Chem. Soc. 2005, 127, 15710–15711; (f) Yamamoto, Y.; Momiyama, N.;
Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962–5963; (g) Marigo, M.; Franzén,
F
EtO2C
R
CO2Et
H2O
CHO
3
Scheme 3. Proposed mechanism and stereochemical outcome.

5024
X. Companyó et al. / Tetrahedron Letters 50 (2009) 5021–5024
J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964–
4.06–3.94 (m, 2H), 3.05 (ddd, J1 = 1.5 Hz, J2 = 9.9 Hz, J3 = 17.2 Hz, 1H), 2.96
(ddd, J1 = 1.5 Hz, J2 = 5.2 Hz, J3 = 17.2 Hz, 1H), 1.33 (t, J = 7.0 Hz, 3H), 1.01 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz. CDCl3): d (ppm) = 198.8, 165.5, 165.1, 164.8,
164.5, 136.4, 129.3, 129.3, 128.6, 128.1, 98.1, 95.4, 63.2, 62.5, 44.4, 43.7, 43.5,
36.9, 36.8, 13.9, 13.7.19F NMR (282 MHz, CDCl3): d (ppm) ꢀ174.2 (d, J = 5.2 Hz)
6965; (h) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441,
861; (i) Sundén, H.; Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2006, 47, 99–103;
(j) Rios, R.; Sundén, H.; Ibrahem, I.; Zhao, G. -L.; Córdova, A. Tetrahedron Lett.
2006, 47, 8679–8682; (k) Rios, R.; Sundén, H.; Ibrahem, I.; Córdova, A.
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G.-L.; Córdova, A. Tetrahedron Lett. 2007, 48, 5701–5705; (m) Rios, R.; Vesely, J.;
Sundén, H.; Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2007, 48, 5835–5839.
18. Compound 3a: Colorless oil. 1H NMR (400 MHz. CDCl3): d (ppm) 9.56 (q,
J = 1.5 Hz, 1H), 7.38–7.23 (m, 5H), 4.40–4.24 (m, 1H), 4.33 (q, J = 7.2 Hz, 2H),
½ ꢁ
a 2D5 +14.7 (c 1.0, CHCl3, 99% ee). HRMS (ESI): Calcd for [C16H19FNaO5]+:
333.1109; found: 333.1113. HPLC (ChiralpakÒ IC, 1 mL minꢀ1, hexanes:IPA
80:50, 220 nm): tR = 5.9 min (minor), 7.1 min (major).