Asymmetric organocatalytic 1,4-addition reactions starting from enals with gem-difluoroalkyl side chains

Article abstract of DOI:10.1002/ejoc.201201427

gem-Difluoroenals are excellent substrates for asymmetric organocatalytic 1,4-additions of thiols and anilines. By using diarylsilylprolinol ether as a catalyst, good to excellent yields with ee values in the same range (up to 98 %) were obtained. The CF₂R group strongly activates the enals towards these organocatalytic additions. New chiral β-thio and β-amino aldehydes with CF₂R chains can be obtained in high yields with high ee values by asymmetric organocatalytic processes after selection of the appropriate catalyst and optimization of the reaction conditions. Copyright

Full text of DOI:10.1002/ejoc.201201427

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201427
Asymmetric Organocatalytic 1,4-Addition Reactions Starting from Enals with
gem-Difluoroalkyl Side Chains
Ali Khalaf,[a,b] Danielle Grée,[a] Hassan Abdallah,[b] Nada Jaber,[b] Ali Hachem,*[b] and
René Grée*[a]
Keywords: Asymmetric synthesis / Organocatalysis / Michael addition / Fluorine / Enals
gem-Difluoroenals are excellent substrates for asymmetric
organocatalytic 1,4-additions of thiols and anilines. By using
diarylsilylprolinol ether as a catalyst, good to excellent yields
with ee values in the same range (up to 98%) were obtained.
The CF2R group strongly activates the enals towards these
organocatalytic additions.
difluoroalkyl side chains.[9] Therefore, we became interested
in the use of such intermediates in asymmetric organocata-
lysis.
Introduction
Asymmetric organocatalysis has been strongly de-
veloping over the last 10 years, and a number of remarkable
synthetic applications have been documented.[1] Fluorine
chemistry has also become a major topic, especially in the
realms of bioorganic and medicinal chemistry.[2] Therefore,
the use of asymmetric organocatalysis for the preparation
of optically pure fluorine-containing molecules appears to
be of much interest, even if relatively few examples have
been published to date. Most representative are the asym-
metric monofluorination[3] and trifluoromethylation[4] reac-
tions, as well as the additions on trifluoromethylcrotonates
and the corresponding amides.[5] Very recently, an elegant
study was reported on the preparation of trifluorocrotonal-
dehyde and its use in various asymmetric organocatalytic
reactions.[6] Notably, the fluorine–iminium gauche effect can
also be used to control the enantioselectivity in organocata-
lytic epoxidation reactions.[7] However, to the best of our
knowledge, no examples of asymmetric organocatalysis has
been reported for derivatives containing gem-difluoro-
methyl or gem-difluoroalkyl systems. As part of our pro-
gram dealing with the use of propargylic systems for the
synthesis of fluorine-containing building blocks,[8] we de-
signed short and efficient routes to enals 1 bearing gem-
Results and Discussion
The purpose of this communication is to establish that,
after proper selection of the organocatalyst, highly enantio-
selective Michael additions of thiols and aniline derivatives
can be performed on gem-difluoroenals 1 (Scheme 1). We
will also demonstrate that introduction of fluorine atoms in
the chain has a positive effect on the efficiency of these
reactions relative to the efficiencies of reactions performed
with hydrogenated analogues.
[a] Université de Rennes 1, Institut des Sciences Chimiques de
Rennes, CNRS UMR 6226,
Scheme 1. Designed asymmetric organocatalysis starting from gem-
difluoroenals 1 and catalysts selected for this study.
Avenue du Général Leclerc, 35042 Rennes Cedex, France
Fax: +33-2-23236978
The gem-difluoroenals were prepared by using method-
ology that we reported previously for the synthesis of a di-
fluoro analogue of 13 HODE.[9a] Both 1a and 1b were ob-
tained, as described in Scheme 2, from commercially avail-
able propionaldehyde diethyl acetal (5) in four steps in 53
and 45% overall yield, respectively. In this synthesis, only
the E isomer of enals 1 was obtained.
E-mail: rene.gree@univ-rennes1.fr
[b] Laboratory for Medicinal Chemistry and Natural Products,
Lebanese University, Faculty of Sciences (1) and PRASE-
EDST,
Hadath, Beyrouth, Lebanon
Fax: +961-5-460-301
E-mail: ahachem@ul.edu.lb
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201427.
Eur. J. Org. Chem. 2013, 653–657
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
653

A. Khalaf, D. Grée, H. Abdallah, N. Jaber, A. Hachem, R. Grée
SHORT COMMUNICATION
Table 1. Asymmetric organocatalyzed 1,4-addition of benzylthiol
to gem-difluoroenal 1a by using catalysts 2 and 3.[a]
Entry Cat.
H2O
[equiv.]
T
[°C]
Time
[h]
Conv. 10a
10a ee[c]
[%]
[%]
1
2
3
4
2
2
2
2
3
3
–
–
–
r.t.
–15
0
r.t.
–15
–15
–15
0
24
46
44
24
48
24
46
44
87
Ͻ5
71
92
49
47
0/0
46
20
n.d.
14
26
16
26
–
0.1
0.1
0.1
–
0.1
0.1
0.1
5[b]
6[b]
7
8
0
[a] Reactions were performed in toluene. [b] Reaction performed
with addition of benzoic acid (10 mol-%). [c] The ee value was es-
tablished by analysis of the corresponding imidazolidines by 19F
NMR spectroscopy (see text); n.d.: not determined.
Scheme 2. Synthesis of gem-difluoroenals 1a and 1b.
Therefore, these imidazolidine-type catalysts are not ap-
propriate for the reaction under study. This could be due,
at least in part, to the competition between catalyzed and
uncatalyzed nucleophilic additions, as well as racemization
processes at room temperature.[13] We performed control ex-
periments without any catalyst and established that no reac-
tion occurred at –15 °C (Table 1, entry 7), whereas after
44 h at 0 °C the conversion was 46% and adduct 10a was
afforded in racemic form (Table 1, entry 8).
To develop the use of 1 in asymmetric 1,4-additions of
thiols and aniline derivatives, the first problem was the se-
lection of the organocatalyst and the optimization of the
reaction conditions. We chose 1a as a model, and consid-
ered three derivatives as catalysts: MacMillan’s imid-
azolidones 2 and 3[10] and Jørgensen’s diarylprolinol silyl
ether 4.[11] We screened different reaction conditions, and
the results are reported in Scheme 3 and Tables 1–3.
We then considered diarylprolinol silyl ether 4,[13] and
better results were obtained (Table 2). The reactions were
performed at –15 °C. Catalyst 4 alone gave low conversion
(Table 2, entry 1). In the presence of 0.1 equiv. of benzoic
acid, the reaction was complete after 16 h and gave 10a with
an excellent ee value (Table 2, entry 2). Similar results were
obtained after further addition of water (0.1 equiv.; Table 2,
entry 3). This gave us the optimized reaction conditions to
be used later, and they were extended to thiophenol ad-
ditions (compound 11a; Table 2, entry 5). Similarly, tert-
butylthiol gave good conversion to 12a with an excellent ee
value (Table 2, entry 6). Finally, these optimized conditions
were used with 1b to afford desired adduct 10b in excellent
yield and ee (Table 2, entry 7). So this catalyst is well suited
for such 1,4-additions to enals 1, which is in agreement with
literature results with nonfluorinated enals,[13] as well as
with trifluorocrotonaldehyde.[6]
Scheme 3. Asymmetric organocatalytic 1,4-additions to gem-di-
fluoroenals 1a and 1b. For conditions and results, see Tables 1–3.
The next step was extension of the reaction to aniline
derivatives (Scheme 3 and Table 3).[14] Starting from 1a and
For benzylthiol addition, hydrochloride salt catalyst 2 using catalyst 2, the reaction gave desired adduct 13a; how-
alone at room temperature gave good conversion but a low ever, only a moderate ee value was obtained (42%; Table 3,
ee value (Table 1, entry 1). It is well known that water and entry 1). On changing to catalyst 3 in the presence of benz-
some acids can enhance the reactivity in organocataly- oic acid, the addition product was obtained in lower yield
sis.[1e,12] Therefore, this reaction was performed with but with excellent ee (98%; Table 3, entry 2). In contrast,
10 mol-% water at –15 °C, but a very low conversion was with the use of catalyst 4 and the addition of benzoic acid
obtained (Table 1, entry 2). An improvement in reactivity (0.1 equiv.) and water (0.1 equiv.) at 35 °C, good to excellent
was observed at 0 °C (Table 1, entry 3) and room tempera- conversions and high ee values were obtained for adducts
ture (Table 1, entry 4) but the ee values still remained low. 13a–15a (87–98%; Table 3, entries 3–6). The same result
Then, catalyst 3 was tested in the presence of 0.1 equiv. of was obtained in the case of adduct 14b starting from enal
benzoic acid (Table 1, entry 5) and in the additional pres- 1b (Table 3, entry 7).
ence of 0.1 equiv. of water (Table 1, entry 6). After 24 h at
–15 °C, conversions were only moderate and the ee values measurement of the enantiomeric excess (Scheme 4). As a
remained low (16–26%). result of the presence of an aldehyde in the final product,
An important point to note is the method used for the
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Eur. J. Org. Chem. 2013, 653–657

Asymmetric Organocatalytic 1,4-Addition Reactions
Table 2. Asymmetric organocatalyzed 1,4-addition of thiols to gem- amines will give the stereoisomers in a ratio (de) that will
difluoroenals 1 by using catalyst 4.
transfer directly to the ee of the starting aldehyde. A key
Entry Enal R1 Conditions[a] Time Product Conv./yield ee[b]
advantage of this very simple and efficient method is that
it avoids any purification step.[16]
[h]
[%]
[%]
An interesting point is the effect of the gem-difluoro
group in the asymmetric catalytic process. Thus, we have
compared the reactivity and selectivity of our compounds
with the same derivatives with two hydrogen atoms in the
allylic position (Scheme 5 and Table 4). The results clearly
indicate that the presence of the two fluorine atoms strongly
accelerates the reactions in both cases. In the addition of
BnSH, complete conversion of 1a was observed after 16 h,
whereas after the same amount of time, conversion of hy-
drogeno analogue 1aH was only 44% complete (Table 4,
entries 1 and 2). The ee value was also slightly lower in the
latter case (82 vs. 98% ee). In the addition of N,N-dimeth-
ylaniline (Table 4, entries 3 and 4), the difference was even
more striking, as there was no reaction at all starting from
hydrogeno analogue 1aH, whereas addition was highly suc-
cessful with 1a.
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1b
Bn
Bn
Bn
Ph
Ph
tBu
Bn
A
B
C
B
C
C
C
16
16
16
24
21
40
16
10a
10a
10a
11a
11a
12a
10b
40/nd
100/nd
100/98
84/nd
92/88
35
96
98
70
95
94
96
76/71
100/94
[a] Reactions performed in toluene at –15 °C. Conditions A: Cata-
lyst (10 mol-%) alone; conditions B: catalyst (10 mol-%) and ben-
zoic acid (10 mol-%); conditions C: catalyst (10 mol-%), H2O
(10 mol-%), and benzoic acid (10 mol-%); nd = not determined.
[b] The ee value was established by analysis of the corresponding
imidazolidines by 19F NMR spectroscopy (see text).
Table 3. Asymmetric organocatalyzed 1,4-addition of aniline deriv-
atives to gem-difluoroenals 1a and 1b.
Entry Cat./enal RЈ
R2 Time
[h][a]
Product Conv./yield ee[d]
[%]
[%]
1[c]
2
2/1a
3/1a
4/1a
4/1a
4/1a
4/1a
4/1b
Me
Me
Me
Me
H
H
H
H
26
48
48
48
13a
13a
13a
13a
14a
15a
14b
90/n.d.
38/n.d.
58/n.d.
82/77
95/87
53/40
42
98
94
98
98
87
98
3[c]
4
5
6
7
Me OMe 24
[b]
–
H
51
Me OMe 24
88/84
Scheme 5. Reactivity comparison between gem-difluoroenal 1a and
hydrogeno analogue 1aH during representative asymmetric organ-
ocatalyzed 1,4-additions.
[a] Reactions were performed in CHCl3 at 35 °C; nd = not deter-
mined. [b] NRЈ2 = 1-pyrrolidino. [c] Reaction was performed with-
out water. [d] The ee value was established by analysis of the corre-
sponding imidazolidines by 19F NMR spectroscopy (see text).
Table 4. Comparison of asymmetric organocatalyzed 1,4-addition
to gem-difluoroenal 1a and non-fluorinated molecules 1aH.
it is possible to use diastereoisomeric imidazolidines to de-
termine the ee values, and these derivatives are easily ana-
lyzed by NMR spectroscopy. Condensation of enantiopure
aldehyde 16 with enantiopure diamine (R,R)-17[15] gives sin-
gle diastereoisomer 18. The same condensation performed
with the racemic diamine gives a mixture of 18 and 19, and
this mixture produces well-separated signals in the 19F
NMR spectrum.
Entry Enal
NuH
Time Product Conv./yield ee[c]
[h]
[%]
[%]
1[a]
2[a]
3[b]
4[b]
1a
1aH
1a
BnSH
BnSH
C6H5NMe2
C6H5NMe2
16
16
48
48
10a
10aH
13a
100/98
44/40
82
98
82
98
nd
1aH
13aH
0/nd
[a] Reactions were performed in toluene at –15 °C. [b] Reactions
were performed in CHCl3 at 35 °C. [c] The ee values was estab-
lished by analysis of the corresponding imidazolidines by 19F NMR
1
and H NMR spectroscopy (see text).
In-depth mechanistic studies have been performed on
these types of asymmetric organocatalytic reactions.[1,17] On
the basis of these data, it is possible to propose an explana-
tion for the effect of the CF2R groups: The increase in reac-
tivity with enals 1 is likely connected to the electronegativity
of the fluorine atoms, which should increase the electrophi-
licity of the iminium intermediates. Moreover, the larger
size of F as compared to that of H should also increase the
steric effects during these reactions and improve the
enantioselectivity. Further, electronic effects, for instance
through repulsions as a result of the electron pairs of fluor-
ine, could also participate to the improved selectivity of 1a
Scheme 4. NMR method used to measure the ee values of the 1,4-
adducts.
Therefore, starting from the crude reaction mixtures, versus 1aH.
condensation reactions performed with racemic diamines
The (S) absolute configuration at the new stereogenic
will give two set of signals corresponding to the two dia- center of the 1,4-adducts was attributed by analogy with
stereoisomers, whereas condensation with enantiopure di- previous results from the literature with related enals. Start-
Eur. J. Org. Chem. 2013, 653–657
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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655

A. Khalaf, D. Grée, H. Abdallah, N. Jaber, A. Hachem, R. Grée
SHORT COMMUNICATION
ee). [α]2D2 = –10.9 (c = 1.53, CHCl3). Rf = 0.33 (pentane/diethyl
ether = 85:15). H NMR (400 MHz, CDCl3): δ = 9.54 (br. s, 1 H,
ing from catalyst 4, the same configuration was obtained in
the series of enals with alkyl chains[13] and in the series of
enals with the CF3 group.[6] These data are also in agree-
ment with the mechanism proposed for these reactions.
1
CHO), 7.17–7.13 (m, 2 H, CHarom), 7.09–7.00 (m, 4 H, CHarom),
6.23 [dd, J = 2.5, 8.6 Hz, 1 H, (CH3)2NCCHCH], 6.12 [d, J =
2.5 Hz, 1 H, CHC(OCH3)], 4.22 (dddd, J = 5.6, 9.1 Hz, JHF = 5.4,
27.0 Hz, 1 H, CF2CH), 3.74 (s, 3 H, OCH3), 3.01 (ddd, J = 1.9,
5.6, 16.7 Hz, 1 H, CH2CHO), 2.86 [s, 6 H, N(CH3)2], 2.81–2.59 (m,
2 H, PhCH2), 2.71 (ddd, J = 2.4, 9.1, 16.7 Hz, 1 H, CH2CHO),
2.02–1.79 (m, 2 H, CH2CF2) ppm. 13C NMR (100 MHz, CDCl3): δ
= 201.1 (CHO), 157.9 [C(OCH3)], 151.2 [CN(CH3)2], 141.0 (Carom),
129.3 [d, J = 3.1 Hz, (CH3)2NCCHCH], 128.3 (2 CHarom), 128.25
(2 CHarom), 126.0 [C(CH)2CH], 125.4 (dd, J = 245.7, 247.8 Hz,
CF2), 112.9 [d, J = 9.3 Hz, (CH3O)CC], 105.4 [(CH3)2NCCHCH],
95.7 (CHCOCH3), 55.5 (OCH3), 43.4 (dd, J = 2.3, 3.6 Hz
CH2CHO), 40.5 [(CH3)2N], 36.8 (t, J = 24.8 Hz, CH2CF2), 36.7
(dd, J = 22.8, J = 25.7 Hz, CF2CH), 28.1 (dd, J = 4.3, 5.9 Hz,
PhCH2) ppm. 19F NMR (282 MHz, CDCl3): δ = –99.14 (dddd, JHF
= 5.4, 15.5, 21.5, JFF = 239.1 Hz), –107.05 (dddd, JHF = 10.2, 19.5,
Conclusions
We have shown that gem-difluoroenals are excellent sub-
strates for asymmetric organocatalyzed 1,4-additions by
using Jørgensen’s catalyst 4.[18] The desired adducts were
obtained in fair to good yields with good to excellent ee
values. It was also established that the CF2R group strongly
activates the enals towards these organocatalytic 1,4-ad-
ditions. Further, a very simple and efficient method based
on NMR spectroscopy was used to establish the ee values
directly on the crude reaction mixtures. Taking into account
the large number of reactions that can be used in asymmet-
ric organocatalysis, these enals could be of much interest
for the preparation of various types of bioactive molecules
with gem-difluoroalkyl side chains. Corresponding studies
are ongoing in our groups and will be reported in due
course.
27.0 Hz, JFF
= 239.1 Hz) ppm. HRMS (ESI): calcd. for
C21H25NO2F2Na [M + Na]+ 384.1751; found 384.1750.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures with spectral and analytical data for
1
all compounds and copies of the H NMR and 13C NMR spectra
for all key intermediates and final products.
Acknowledgments
Experimental Section
Preparation of 3-Benzylsulfanyl-4,4-difluorotridecanal (10a) as a
Representative Procedure for the Addition of Thiols: In a glass vial
equipped with a magnetic stirring bar, aldehyde 1a (100 mg,
0.43 mmol, 1.5 equiv.), catalyst 4 (17 mg, 10 mol-%), benzoic acid
(3.5 mg, 10 mol-%), and water (0.5 m in dioxane, 57 μL, 10 mol-%)
were dissolved in toluene (1 mL). The mixture was cooled to –15 °C
before benzyl mercaptan (34 μL, 1 equiv.) was added. The mixture
was stirred at this temperature for 16 h and then subjected to silica
gel flash column chromatography to afford 10a as a colorless oil
(100 mg, 98%, 98% ee). [α]2D2 = +5.1 (c = 0.25, CHCl3). Rf = 0.41
(pentane/diethyl ether = 9:1). 1H NMR (400 MHz, CDCl3): δ =
9.49 (dd, J = 0.8, 2.0 Hz, 1 H, CHO), 7.28–7.16 (m, 5 H, CHarom),
3.77 (s, 2 H, CH2S), 3.27 (dddd, J = 4.5, 9.4 Hz, JHF = 7.1, 19.4 Hz,
1 H, CF2CH), 2.82 (ddd, J = 0.8, 4.4, 17.8 Hz, 1 H, CH2CHO),
2.61 (ddd, J = 2.0, 9.4, 17.8 Hz, 1 H, CH2CHO), 1.91–1.78 (m, 2
H, CH2CF2), 1.36–1.20 (m, 14 H, 7 CH2), 0.82 (t, J = 6.9 Hz, 3 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 198.7 (CHO), 137.2
(CCH2), 129.2 (2 CHarom), 128.7 (2 CHarom), 127.5 [C(CH)2CH],
125.7 (t, J = 245.9 Hz, CF2), 43.4 (dd, J = 1.5, 4.1 Hz, CH2CHO),
42.9 (t, J = 27.2 Hz, CF2CH), 36.8 (CH2S), 33.7 (t, J = 24.6 Hz,
CH2CF2), 31.9, 29.4, 29.3, 29.28, 29.26, 22.7, 21.5 (dd, J = 3.8,
4.6 Hz, CH2CH2CF2), 14.1 (CH3) ppm. 19F NMR (376 and
282 MHz, CDCl3): δ = –98.78 (dddd, JHF = 7.1, 15.7, 23.0 Hz, JFF
= 244.6 Hz), –101.81 (dtd, JHF = 12.6, 19.4 Hz, JFF = 244.6 Hz)
ppm. HRMS (ESI): calcd. for C20H30OF2NaS [M + Na]+ 379.1883;
found 379.1890.
We thank the Centre National de la Recherche Scientifique
(CNRS) and University of Rennes 1 for financial support. We
thank the Centre Regional de Mesures Physiques (CRMPO,
Rennes) for mass spectral analyses.
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Preparation of 3-(4-Dimethylamino-2-methoxyphenyl)-4,4-difluoro-
6-phenylhexanal (14b) as a Representative Procedure for the Addition
of Anilines: In a glass vial equipped with a magnetic stirring bar,
aldehyde 1b (90 mg, 0.43 mmol), catalyst 4 (25.6 mg, 10 mol-%),
benzoic acid (5.3 mg, 10 mol-%), water (0.5 m in dioxane, 86 μL,
10 mol-%), and 3-methoxy-N,N-dimethylaniline (94 μL, 1.5 equiv.)
were dissolved in CHCl3 (1 mL). The mixture was stirred at 35 °C
for 24 h and then directly subjected to silica gel flash column
chromatography to afford 14b as a colorless oil (130 mg, 84%, 98%
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Published Online: December 19, 2012
Eur. J. Org. Chem. 2013, 653–657
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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