Highly efficient and stereoselective Julia-Kocienski protocol for the synthesis of α-fluoro-α,β-unsaturated Esters and Weinreb amides employing 3,5-bis(trifluoromethyl)phenyl (BTFP) sulfones

Article abstract of DOI:10.1002/adsc.200800194

: α-Fluoroacetates 3 and Weinreb amide 4, bearing a α-[3,5-bis(trifluoromethyl)phenyl]sulfonyl (BTFP-sulfonyl) group at the α-position, are employed in the highly stereoselective synthesis of α-fluoro-α,β-unsaturated alkenoates and Weinreb amides, respectively. Aromatic and aliphatic aldehydes are condensed under extremely mild and simple reaction conditions using potassium carbonate in dimethylformamide at room temperature under solid-liquid phase-transfer catalysis conditions in good yields and high Z-diastereoselectivities, specially in the case of the fluorinated Weinreb amides. A detailed computational mechanistic study suggests a final non-concerted elimination of sulfur dioxide and 3,5-bis(trifluoromethyl)phenoxide and explains the observed high stereoselectivities for the reaction on the basis of thermodynamic and kinetic considerations.

Full text of DOI:10.1002/adsc.200800194

FULL PAPERS
DOI: 10.1002/adsc.200800194
Highly Efficient and Stereoselective Julia–Kocienski Protocol for
the Synthesis of a-Fluoro-a,b-unsaturated Esters and Weinreb
Amides Employing 3,5-Bis(trifluoromethyl)phenyl (BTFP)
Sulfones
Diego A. Alonso,a,* Mónica Fuensanta,a Enrique Gómez-Bengoa,b
and Carmen Nµjeraa,*
a
Departamento de Química Orgµnica and Instituto de Síntesis Orgµnica (ISO), Facultad de Ciencias, Universidad de
Alicante, Apartado 99, 03080, Alicante, Spain
Fax : (+34)-96-590-3549; e-mail: diego.alonso@ua.es or cnajera@ua.es
Departamento de Química Orgµnica I, Facultad de Química, Universidad del País Vasco, Apdo. 1072, 20080, San
b
Sebastiµn, Spain
Fax : (+34)-94-301-5270
Received: March 31, 2008; Published online: July 24, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: a-Fluoroacetates 3 and Weinreb amide 4, ly in the case of the fluorinated Weinreb amides. A
bearing a a-[3,5-bis(trifluoromethyl)phenyl]sulfonyl detailed computational mechanistic study suggests a
(BTFP-sulfonyl) group at the a-position, are em- final non-concerted elimination of sulfur dioxide and
ployed in the highly stereoselective synthesis of a- 3,5-bis(trifluoromethyl)phenoxide and explains the
fluoro-a,b-unsaturated alkenoates and Weinreb observed high stereoselectivities for the reaction on
amides, respectively. Aromatic and aliphatic alde- the basis of thermodynamic and kinetic considera-
hydes are condensed under extremely mild and tions.
simple reaction conditions using potassium carbonate
in dimethylformamide at room temperature under
solid-liquid phase-transfer catalysis conditions in Keywords: alkenes; esters; Julia–Kocienski olefina-
good yields and high Z-diastereoselectivities, special- tion; sulfones; Weinreb amides
Introduction
defluorination of allylic gem-difluorides.[9] Very re-
cently, the Julia–Kocienski olefination[10] has been suc-
Fluorine plays a very important role in the design of cesfully used for the synthesis of fluoro olefins such
new compounds since it is well-established that it as vinyl fluorides[11] and a-fluoroacrylates[12] employ-
strongly modifies their chemical, physical, and biolog- ing fluorinated 1,3-benzothiazol-2-yl (BT) sulfones 1
ical properties. However, fluorinated compounds are (Figure 1).
the least abundant natural organohalides.[1] Therefore,
We have recently demonstrated that the 3,5-bis(tri-
fluorinated analogues of natural products, building fluoromethyl)phenyl (BTFP)-sulfonyl group is an ex-
blocks, or simple fluorine-containing organic mole- cellent nucleofuge in base-promoted b-elimination
cules have become highly desirable compounds.[2] In processes.[13] On the other hand, BTFP sulfones (2,
this context, structures with the fluoro olefin moiety Figure 1) are excellent partners for the stereoselective
are gaining importance due to their interesting biolog- synthesis of di-, tri- and tetrasubstituted olefins
ical properties.[1,3] Different approaches have been de- through the Julia–Kocienski olefination of carbonyl
veloped for the synthesis of fluorine-containing ole- compounds under simple reaction conditions using
fins such as the electrophilic fluorination of vinyllithi- KOH and phosphazenes as bases.[14] Very recently,
ums[4] or stannanes,[5] fluorodesilylation of vinylsi- BTFP sulfones have also been successfully used for
lanes,[6] the Horner–Wadsworth–Emmons reaction of the stereoselective synthesis of a,b-unsaturated esters
a-fluorophosphonates with carbonyls,[7] the Peterson and Weinreb amides under solid-liquid PTC condi-
olefination,[8] and the palladium-catalyzed reductive tions.[15,16] Herein we report the synthesis of a-(BTFP
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This could be the reason for the moderate yields ob-
served in the fluorination process. Compound 6 af-
forded the best yield, probably due to the higher sta-
bility of the corresponding enolate intermediate.
Synthesis of a-Fluoro-a,b-Unsaturated Esters
With the fluorinated sulfones prepared, different reac-
tion conditions were first assayed for the synthesis of
fluorinated acrylate 7aa via one-pot Julia olefination
of benzaldehyde with BTFP sulfone 3a. Since previ-
ously studies with unfluorinated BTFP sulfones 5b
and 6[15] had shown K2CO3 (9 equiv.) and TBAB
(0.1 equiv.) in DMF under Barbier conditions (addi-
tion of the base over the solution of the sulfone and
the aldehyde) as the most efficient olefination meth-
odology, the optimization experiments with 3a and
Figure 1. BT and BTFP sulfones 1–4.
sulfonyl)-a-fluoroacetates 3 and Weinreb amide 4 and benzaldehyde were carried out under these solid-
their use as efficient reagents for a highly stereoselec- liquid PTC conditions at room temperature. The ob-
tive synthesis of a-fluoro-a,b-unsaturated esters and tained yields and Z/E ratios are displayed in Table 1,
Weinreb amides, respectively.
entries 1–4. Under the typical reaction conditions, a
66% conversion of the desired olefin 7aa was ob-
tained with an excellent Z stereoselectivity (Z/E: 92/
8) [19F NMR: JF,H =35.3 Hz (Z-7aa), JF,H =27.3 Hz (E-
7aa)] along with considerable amounts of decarboxy-
lated 3,5-[bis(trifluoromethyl)phenyl] fluoromethyl
sulfone (8) (Table 1, entry 1). Under anhydrous condi-
Results and Discussion
Synthesis of Fluorinated Sulfones
Fluorinated BTFP sulfones 3a, 3b, and 4 were pre- tions, the yield was fairly improved but still giving
pared in good yields from commercially available 3,5- substantial amounts of the decarboxylated sulfone 8
bis(trifluoromethyl)benzenethiol[17] by NaH mediated (Table 1, entry 2). Finally, the yield of the olefination
S-alkylation with methyl bromoacetate, tert-butyl bro- was found to be very high when working under non-
moacetate, and 2-bromo-N-methoxy-N-methylacet- Barbier conditions (Table 1, entry 3) and especially if
ACHTREUNG
amide,[18] respectively. Oxidation with either 30% the sulfone was used in two-fold excess, conditions
H2O2/NaHCO3/MnSO4·H2O[19] or oxoneꢁ,[20] of the which afforded the desired (Z)-7aa in 95% yield with
corresponding sulfanes and final electrophilic fluori- no traces of decarboxylated product 8 in the crude re-
nation of 5 and 6 with NaH/Selectfluorꢁ afforded the action mixture (Table 1, entry 4).
desired sulfones (Scheme 1). Significant quantities of
Under the optimized reaction conditions, the syn-
unreacted non-fluorinated starting material (~20%) thesis of a-fluoroacrylates through the modified Julia
were recovered from all the fluorination reactions. olefination with methyl and tert-butyl esters 3a and 3b
was next investigated (Table 1, entries 5–19). As
shown, the fluorinated BTFP sulfone reagents 3 were
significantly more reactive than the non-fluorinated
congeners 5[15] probably due to the alpha effect of the
fluorine atom. Condensation of BTFP sulfones 3a and
3b with selected aldehydes gave, in general, good
yields of the corresponding a-fluoro-a,b-unsaturated
esters 7a and 7b, respectively. Z-configurated olefins
were mainly obtained from aromatic aldehydes
(Table 1, entries 4–13), the selectivity being lower for
t-Bu ester 3b (compare entries 4, 6, 8, and 11 with 5,
7, 9, and 12) and for electron-rich aldehydes such as
4-methoxybenzaldehyde (Table 1, entry 10). The ste-
reoselectivity but not the yield was independent of
the steric demands of the electrophile as demonstrat-
ed in the olefination of 2-chlorobenzaldehyde
Scheme 1. Synthesis of fluorinated BTFP sulfones 3 and 4.
(Table 1, entry 13).
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Highly Efficient and Stereoselective Julia–Kocienski Protocol
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Table 1. Synthesis of a-fluoro-a,b-unsaturated esters.
atives to generate in very good yields and selectivities
(Z)-a-fluoro-a,b-unsaturated alkenoates under very
mild reaction conditions. This is an important result
since the previously employed BT sulfone 1 (Figure 1,
R=t-BuO,[12a]) affords (E)-a-fluoro-a,b-unsaturated
alkenoates in the presence of DBU as base in CH2Cl2
at room temperature. On the other hand, (Z)-a-
fluoro-a,b-unsaturated alkenoates can be obtained
with BT sulfone 1 (Figure 1, R=Et,[12b]) employing
DBU as base but in the presence of stoichiometric
amounts of MgBr2.
Entry
X
RCHO
No. Yield (%)[a] Z/E[b]
1
2
3
4
5
6
7
8
Me PhCHO
Me PhCHO
Me PhCHO
Me PhCHO
7aa 63 [34][c]
7aa 85 [6][c,d]
7aa 95 [5][d]
92/8
92/8
93/7
Synthesis of a-Fluoro-a,b-Unsaturated Weinreb
Amides
7aa >95 [0][d,e] 93/7
t-Bu PhCHO
7ba 75[d,e]
7ab 50[d,e]
7bb 42[d,e]
7ac 60[d,e]
7bc 68[d,e]
82/18
94/6
Me 4-CF3C6H4CHO
t-Bu 4-CF3C6H4CHO
Me 4-ClC6H4CHO
t-Bu 4-ClC6H4CHO
The synthesis of a-fluoro-a,b-unsaturated Weinreb
amides with BTFP sulfone 4 was next investigated
under the optimized reaction conditions. Sulfone 4 re-
acted with aryl and alkyl aldehydes in good yields to
afford the corresponding diastereomerically pure (Z/
E>99/1) Z-unsaturated Weinreb amides (Table 2).
The stereochemistry was independent of the electron-
ic character or the steric demands of the aldehyde
(Table 2, entries 1–7). However, the yield of the reac-
tion was lower for electron-rich aldehydes such as, 4-
methoxybenzaldehyde and 6-methoxy-2-naphthalde-
hyde (Table 2, entries 4 and 6). With respect to ali-
phatic aldehydes, branching at the a- or b-position
did not affect the reaction yield or the stereoselectiv-
ity (Table 2, entries 8–13).
88/12
92/8
83/17
61/39
91/9
79/21
90/10
48/52
23/77
43/57
19/81
93/7
9
10
11
12
13
14
15
16
17
18
19
t-Bu 4-MeOC6H4CHO 7bd 94[d,e]
Me 2-naphthaldehyde 7ae 47[d,e]
t-Bu 2-naphthaldehyde 7be 72[d,e]
Me 2-ClC6H4CHO
Me Ph(CH2)2CHO
t-Bu Ph(CH2)2CHO
7af 68[d,e]
7ag 66[d,e]
7bg 92[d,e]
7ah 61[d,e]
7bh 75[d,e]
7ai 71[d,e]
7bi 91[d,e]
ACHTREUNG
ACHTREUNG
Me Citronellal
t-Bu Citronellal
Me c-C6H11CHO
t-Bu c-C6H11CHO
85/15
[a]
Isolated yield after flash chromatography. In brackets
isolated yield for decarboxylated compound 8.
[b]
1
Relative ratio determined by HNMR over the crude re-
action mixture.
[c]
[d]
[e]
Barbier-type conditions were used.
The reaction was performed under anhydrous conditions.
2 Equivalents of sulfone were used.
Table 2. Synthesis of (Z)-a-fluoro-a,b-unsaturated Weinreb
amides.
The reaction of BTFP sulfones 3 with aliphatic al-
dehydes such as 3-phenylpropanal afforded better
yields and E-selectivities for tert-butyl ester 3b than
for methyl ester 3a (Table 1, entries 14 and 15). The
change in stereoselectivity with respect to aromatic al-
dehydes was confirmed in the reaction of the b-
branched aldehyde citronellal which gave, especially
in the case of sulfone 3b, a significantly increased E-
selectivity (Table 1, entry 17). Finally, the reaction
with cyclohexanecarbaldehyde, an a-branched sub-
strate, reversed the stereochemistry in favor of the Z-
fluoro-a,b-unsaturated esters 7ai and 7bi (Table 1, en-
tries 18 and 19). In general, all the studied examples
showed an increased E-selectivity for t-Bu ester 3b
with respect to the results observed for 3a.
Entry
RCHO
No.
Yield (%)[a]
1
2
3
4
5
6
7
8
PhCHO
9a
9b
9c
9d
9e
9f
9g
9h
9i
83
63
62
45
81
55
99
56
57
46
51
65
63
4-CF3C6H4CHO
4-ClC6H4CHO
4-MeOC6H4CHO
2-naphthaldehyde
6-MeO-2-naphthaldehyde
2-ClC6H4CHO
n-C9H19CHO
9
PhACHTER(UNG CH2)2CHO
10
11
12
13
PhCH(Me)CHO
c-C5H9CHO
c-C6H11CHO
citronellal
9j
9k
9l
The results obtained with BTFP sulfones 3a and 3b
in the one-pot Julia olefination of aromatic and ali-
phatic aldehydes emphasize the ability of these deriv-
9m
[a]
Isolated yield after flash chromatography.
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Diego A. Alonso et al.
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The Z configurations of compounds 9 were as- Computational Mechanistic Studies
signed by 19F NMR spectroscopy (see Supporting In-
formation) and confirmed by X-ray analysis for (Z)-2- Computational studies were performed for the olefi-
fluoro-N-methoxy-N-methyl-3-phenylacrylamide[21]
(9a, Figure 2).
nation of benzaldehyde with sulfone 3a using the
functional B3LYP and the 6-311++G** basis set as
implemented in Gaussian 03.[22] As we have previous-
ly shown for the olefination of aromatic aldehydes
with non-fluorinated sulfones 5 and 6,[15] the reaction
proceeds through a two-step mechanism (Scheme 2).
The first one (TS1) corresponds to the nucleophilic
addition of enolate I to benzaldehyde and generating
a high-in-energy alkoxy intermediate (II-type). The
second step involves the nucleophilic aromatic substi-
tution of the sulfonyl group by the formed alkoxide
(TS2)[23] and lies at the highest point along the reac-
tion coordinate. Introduction of solvent effects does
not significantly alter the results. In DMF the energy
of II-type intermediates decreases, increasing the acti-
vation barrier for the second step. IRC calculation un-
doubtedly connects TS2 with the final alkene 7aa
through an asynchronous elimination of SO2 and
Figure 2. X-ray structure of 9a.
Scheme 2. Proposed mechanism for the fluoro-Julia–Kocienski olefination of aldehydes with BTFP sulfones.
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Highly Efficient and Stereoselective Julia–Kocienski Protocol
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BTF-phenoxide. No intermediates could be detected amides 9 and the lower selectivity observed (see
during the elimination process that leads to the irre- Table 1) for 3b when compared with the methyl deriv-
versible formation of the final products.
ative 3a (DG0rot =3.7 Kcal/mol). Then, according to
Comparison of the energies at TS1 and II-type the calculation studies, the rotation process in inter-
structures reveals the existence of a ca. 1:1 equilibri- mediate III is more favored for 3a and 4, which in
um between the diastereomeric syn and anti inter- concert with the biggest energy gap between the III-
mediates, which would not lead to any selectivity. In syn and III-anti intermediates for the Weinreb amide
contrast, the data show that TS2-syn is kinetically fa- would explain the higher Z-selectivity obtained when
vored over TS2-anti by 1.3 kcalmolÀ1 due to the BTFP sulfone 4 is employed in the olefination reac-
minor steric interactions between the phenyl and tion. Cartesian coordinates for transition states and
ester moieties, predicting the formation of the experi- reactant complexes are included in the Supporting In-
mentally encountered Z-isomer. These data indicate formation
that TS2 might be the selectivity-determining step.
À
Alternatively, the rotation around the C C bond
after elimination of SO2 and prior to the elimination Conclusions
of ArOÀ would eventually lead to the thermodynamic
convergence of both pathways to the more stable Z- In summary, we have shown that the Julia–Kocienski
isomer through III-syn via an E1cB-type elimination. olefination is an efficient strategy for the selective
The rotation barrier is low (6.2 kcalmolÀ1),[24] suggest- preparation of (Z)-a-fluoro-a,b-unsaturated esters
ing that the rotation might indeed be important. and Weinreb amides employing BTFP sulfones under
Nonetheless, both kinetic considerations at TS2 and solid-liquid PTC conditions at room temperature. The
thermodynamic factors during elimination after TS2, reaction is highly diastereoselective, particularly in
merge at the formation of the same isomer (Z-7aa) the case of Weinreb amides, allowing the olefination
and account for the high Z-diastereoselectivity ob- of both aromatic and aliphatic aldehydes. According
served in the process.
to computational studies, the reaction mechanism in-
The energies for the rotation process after elimina- volves a non-concerted elimination of SO2 and 3,5-
tion of SO2 and prior to the elimination of ArOÀ for bis(trifluoromethyl)phenoxide. Furthermore, both ki-
tert-butyl ester 3b and Weinreb amide 4 were also cal- netic and thermodinamic considerations point to spi-
culated in order to explain the lower selectivity ob- rocyclic TS2, which is closely related to the Smiles re-
served in the olefination of aldehydes with 3b and the arrangement, being responsible for the high Z-diaste-
exclusive formation of Z-amides from 4 (Figure 3). reoselectivity of the reaction.
With respect to the rotation barrier (DG°rot), the
highest value was obtained for the tert-butyl ester 3b
(7.6 kcal/mol), while methyl ester 3a (6.2 kcal/mol)
Experimental Section
and Weinreb amide 4 (6.5 kcalmolÀ1) showed very
similar energies (Figure 3). However, calculated
General Procedure for the Synthesis of Sulfones 5a,
5b, and 6
DG0 for tert-butyl ester 3b and Weinreb amide 4
rot
were 2.3 kcal/mol and 6.3 cal/mol, respectively, which
would account for the exclusive formation of the Z-
To a room temperature stirred solution of NaH (95%,
150 mg, 6 mmol) in MeCN (15 mL), was dropwise added
3,5-bis(trifluoromethyl)benzenethiol (835 mL, 5 mmol) under
an argon atmosphere. After stirring of the reaction mixture
for 15 min, the corresponding alkyl bromide (5.5 mmol) was
added at the same temperature and the stirring was contin-
ued for 1 d. The reaction was quenched with H2O (20 mL)
and the mixture was extracted with EtOAc (2”20 mL). The
combined organic layers were dried (MgSO4), and evaporat-
ed to afford the corresponding 3,5-bis(trifluoromethyl)phen-
yl sulfanes, which were used in the next step without further
purification.
To a 0 8C stirred solution of the corresponding sulfane
(5 mmol) in a 1/1 mixture of MeOH/H2O (44 mL), was
slowly added oxoneꢁ (50 mmol, 31 g). The reaction mixture
was then stirred at room temperature for 1 d. After MeOH
had been evaporated, the residue was dissolved in CH2Cl2
(50 mL) and filtered through celite. After quenched with
water (50 mL), the mixture was extracted with CH2Cl2 (2”
Figure 3. Rotation energies (kcalmolÀ1) for intermediates
III for BTFP sulfones 3 and 4.
25 mL), washed with a saturated solution of NaCl (3”
50 mL), and dried with anhydrous MgSO4. Evaporation of
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Diego A. Alonso et al.
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the solvent afforded the corresponding pure crude sulfones References
5a, 5b, and 6 which were recrystallized in ether/hexane or
purified by flash chromatography (hexane/EtOAc). Products
5b[15] and 6[15] have been previously described and gave satis-
factory spectroscopic and physical data. For compound 5a
see Supporting Information.
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3a, 3b, and 4
To a 0 8C stirred slurry of NaH (95%, 140 mg, 5.5 mmol) in
THF (20 mL), a solution of the corresponding sulfone
(5 mmol) in THF (10 mL) was added under an argon atmos-
phere. After stirring for 30 min at the same temperature, se-
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aqueous solution of NaHCO3 (15 mL), NaCl (15 mL), and
finally with H2O (15 mL). The organic phase was then dried
(MgSO4). Evaporation of the solvent afforded the corre-
sponding crude sulfones 3a, 3b, and 4, which were purified
by flash chromatography (hexane/EtOAc). See Supporting
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General Procedure for Condensation of Aldehydes
with Fluorinated Sulfones 3a, 3b, and 4
Under an argon atmosphere, a DMF (3 mL) solution of flu-
orinated BTFP sulfone (0.3 mmol), K2CO3 (2.7 mmol) and
TBAB (0.03 mmol) was stirred at room temperature for
15 min. Then, neat aldehyde (0.15 mmol) was added and the
resulting reaction mixture was stirred at room temperature
for 18 h. After this time, the reaction was hydrolyzed with
saturated aqueous solution of NH4Cl (10 mmol) and extract-
ed with EtOAc (3”10 mL). The combined organic layers
were washed with H2O (3”10 mL), dried (MgSO4) and
evaporated to afford the crude reaction mixture which was
purified by flash chromatography to yield the corresponding
a-fluoro esters and a-fluoro Weinreb amides 7 and 9. See
Supporting Information for physical and spectrosocpic data.
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7ba,[12a] 7bc,[29] 7bd,[12a] and 7be[12a] have been previously de-
scribed and gave satisfactory spectroscopic and physical
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Acknowledgements
This work has been supported by the Dirección General de
Investigación of the Ministerio de Educación y Ciencia
(CTQ2004–00808/BQU, CTQ2007–62771/BQU), and Con-
solider INGENIO 2010 (CSD2007–00006), by the Generali-
tat Valenciana (GRUPOS05/11, GV05/144, GV/2007/142)
and the University of Alicante. We also thank SGI/IZO-
SGIker UPV/EHU for allocation of computational resources
and Dr. Tatiana Soler for solving the X-ray structure of 9a.
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