Simple protocol for enhanced (E)-selectivity in Julia-Kocienski reaction

Article abstract of DOI:10.1016/j.tetlet.2011.02.086

A short and efficient Julia-Kocienski olefination protocol, based upon the use of chelating agents (18-crown-6 or TDA-1 for K⁺; 12-crown-4 or HMPA for Li⁺), was developed. This protocol enhances the (E)-selectivity of the reaction an

Full text of DOI:10.1016/j.tetlet.2011.02.086

Tetrahedron Letters 52 (2011) 2348–2352
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Tetrahedron Letters
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Simple protocol for enhanced (E)-selectivity in Julia–Kocienski reaction
⇑
ˇ
Jirí Pospíšil
Institute of Condensed Matter and Nanosciences—Molecules, Solids and Reactivity (IMCN/MOST), Université catholique de Louvain, Place Louis Pasteur, 1 bte 2,
1348 Louvain-la-Neuve, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and efficient Julia–Kocienski olefination protocol, based upon the use of chelating agents (18-
crown-6 or TDA-1 for K+; 12-crown-4 or HMPA for Li+), was developed. This protocol enhances the (E)-
selectivity of the reaction and the desired olefins are obtained generally with >10:1 (E/Z)-selectivity.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 26 January 2011
Revised 15 February 2011
Accepted 18 February 2011
Available online 26 February 2011
Keywords:
Julia–Kocienski reaction
Olefins
Selectivity
Chelation
The formation of C@C double bonds is of paramount importance
in the field of organic chemistry.1 The reason for this lies not only
in the fact that this structural motif (olefin) is present in various
natural and nonnatural bioactive compounds, but also in the fact
that olefins can be easily transformed into a wide variety of differ-
ent functional groups.
Recently, Julia–Kocienski reaction has become a very popular
method to achieve the double bond formation thanks to its wide
functional group tolerance and possibility to perform the transfor-
mation under very mild reaction conditions. As a consequence, this
reaction has become one of the most favorite late stage coupling
methods used in total synthesis (Scheme 1).2
In general, the Julia–Kocienski reaction yields olefins predomi-
nantly in (E)-configuration on newly formed double bond. How-
ever, low, missing, or even inversed selectivity ((Z)-isomer
formed as the major one) was also observed when the standard
reaction conditions were used.
N
N
N
N
Ph
N
O[M]
R2
N
N
O
N
Ph
slow
R1
O
H
[M]
[M]
R1
R2
SO2
H
S
O
R1
O
H
SO2PT
5
R2
H
anti-4
anti-4
H
R1
PTO
SO2[M]
R2
R2
R1
O
[M]
E-3
H
6
+
PT
R2
S
O2
R1
R2
R1
PTO
SO2[M]
R1
R2
1
2
H
Z-3
8
H
N
O2
S
O
base
N
R1
R1
+
R2
N
R2
N
N
N
N
N
1
Ph
N
2
3
O[M]
N
N
Ph
Ph
fast
N
R1
O
[M]
R2
O
H
[M]
S
Scheme 1. Julia–Kocienski olefination.
1 O
SO2
R2
O
R1
H
R
SO2PT
R2
H
7
H
syn-4
syn-4
⇑
Tel.: +32 10 472 919; fax: +32 10 472 788.
E-mail address: jiri.pospisil@uclouvain.be
Scheme 2. Proposed mechanism of Julia–Kocienski olefination.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.086

J. Pospíšil / Tetrahedron Letters 52 (2011) 2348–2352
2349
PT
S
PT
S
PT
S
O
O
R2
O
O
O
R2
KO
H
O
O
S
SO2PT
R2
R1
H
H
R2
H
K
R2
PT
R1
R1
O
R1
H
anti-
SO2PT
k1
R1
H
R2
O
R1
H
9
anti-
9
OLi
O
TS-1
O
H
O
N
TS-1
anti-4
N
N
Ph
N
N
TS-1
R2
H
R2
R1
R1
SO2
O
R1
R2
E-isomer is prefered for the opened TS:
SO2
H
PTO
R2
15
R1
polar solvents, large counter-ions (K)
E-3
3
E-
H
14
H
N
N
N
N
N
Ph
SO2PT
R2
R2
H
N
N
R1
R2
R1
Ph
SO2
O
H
R1
R1
H
R1
R2
SO2
R2
S
Li
PTO
H
17
3
Z-
O
O
O
R1
OLi
Z-3
16
H
R2
syn-4
H
TS-2
PT
S
PT
S
Z-isomer is prefered for the closed TS:
non-polar solvents, small counter-ions (Li)
O
R2
O
O
R2
O
O
k2
k
R1
H
R2
SO2PT
H
Scheme 3. Proposed guidelines for the reaction selectivity.
R1
H
R1
H
1 < k2
O
O
syn-9
syn-9
For this reason, it became important to postulate some guide-
lines that would allow us to predict the reaction selectivity. Such
guidelines, based on the generally accepted Julia–Kocienski reac-
tion mechanisms2,3 (Scheme 2), and some additional experimental
observations,4 were proposed (Scheme 3). It was stated that if the
TS-3
Scheme 5. Addition of anion generated from
a-monosubstituted sulfone to
aldehyde.
of the transformation. This assumption was based upon the expec-
tation that selective cation chelation will create ‘naked’ sulfonyl
anion 13. As a consequence, the highly reactive intermediate 13
can either undergo a rapid self-condensation (Scheme 4, path a)
or it can react with aldehyde 2 (Scheme 4, path b). To favor the
addition (path b) over the self-condensation (path a), the aldehyde
has to be added to the reaction mixture rapidly after the base. On
the other hand, we have to let some time to the chelating agents to
chelate the specific alkali metal cation to generate the more reac-
tive ‘naked’ carbon-based anion 13.
We believe that if we would find good reaction conditions
where the chelating agent would have enough time to chelate
the corresponding cation but the self-condensation of 13 would
be sufficiently slow, then the addition of 13 to aldehyde 2 should
proceed via an open TS-1 to yield adduct anti-9 (Scheme 5). We ex-
pect that TS-1 will be preferred over the other possible open tran-
sition state TS-3. In TS-3 the groups R1 and R2 suffer from severe
steric repulsions. Additionally, we expect that the addition of 13
to aldehyde 2 is an irreversible process, since the retro-addition
would form highly unstable ‘free’ carbon-based anion species.
The presence of a chelating agent should play an important role
even after the addition step, since under standard reaction condi-
addition of aliphatic a-metalated sulfones to aldehydes is a nonre-
versible process, then the stereochemical outcome of the reaction
directly depends upon the syn/anti selectivity of the addition
step.2,5 By other means, if the addition of
a-sulfonyl anion proceeds
via an open TS-1 (K+-bases/polar solvent), formation of (E)-olefin
should be observed. Contrary, if a closed TS-2 (Li+-bases/nonpolar
solvents) is preferred, Z-olefins should be obtained.
These statements are based on observations that the rest of the
sequence, namely the transformation of the anti- and syn-4 ad-
ducts to the corresponding olefins 3, via a Smiles rearrangement/
elimination sequence, is stereospecific (Scheme 2).2,5
However, there are exceptions to these guidelines. In some
cases, the best (E)-selectivity (addition via open TS-1) was
achieved when a Li+-containing base (LiHMDS) was used in combi-
nation with polar solvents (DMF/HMPA).6,7 Thus, in general, it is
difficult to predict with high level of confidence the selectivity out-
come of the reaction; this situation being rather inconvenient
when the coupling of two complex fragments is desired. Therefore,
we decided to develop a new protocol that would allow the Julia–
Kocienski reaction to proceed with high (E)-selectivity.
We assumed that the addition of selective metal–cation chelat-
ing species into the reaction mixture might increase the selectivity
O2
R1
S
N
N
N
Ph
Ph
N
Ph
N
N
N
N
N
N
N
N
N
N
N
base
N
N
N
N
Ph
path a
N
R1
R2
Ph
S
S
R1
R1
S
chelating
agent
O2
O2
O2
1
13
14
O
path b
2
R1
R2
3
Scheme 4. Julia–Kocienski reaction in the presence of chelating agents: two plausible competitive pathways.

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J. Pospíšil / Tetrahedron Letters 52 (2011) 2348–2352
Table 1
Reaction conditions optimization
Ph
Ph
N
N
N
+
Ph
SO2
0.1M, -78°C
O
N
10a
11a
12a
Entry
Conditions
Solvent
Yielda
(E/Z)b
1
2
3
4
5
6
7
8
9
KHMDS (1.1 equiv)
THF
THF
THF
88%
86%
84%
87%
78%
83%
78%
81%
90%
79%
92%
88%
4.3:1
15:1
>50:1
>50:1
>50:1
>50:1
4:1
4:1
2.1:1
3:1
KHMDS (1.1 equiv), 18-crown-6 (1.1 equiv)
KHMDS (1.1 equiv), 18-crown-6 (2.0 equiv)
KHMDS (1.1 equiv), 18-crown-6 (2.0 equiv)
KHMDS (1.1 equiv), 18-crown-6 (2.0 equiv)
KHMDS (1.1 equiv)
NaHMDS (1.1 equiv), 18-crown-6 (2.0 equiv)
NaHMDS (1.1 equiv)
LiHMDS (1.1 equiv)
Toluene
DMF
DMF/TDA-1 3:1c
THF
DMF/TDA-1 3:1c
THF
10
11c
12c
LiHMDS (1.1 equiv), 12-crown-4 (2.0 equiv)
LiHMDS (1.1 equiv)
LiHMDS (1.1 equiv)
THF
DMF/HMPA 3:1
DMF/DMPU 3:1
5:1
4.4:1
a
b
c
Average of three runs; refers to pure isolated compounds.
Average of three runs; based on crude 1H NMR spectra.
Reaction performed at ꢀ60 °C.
Table 2
Preliminary scope and limitations—1,2-disubstituted olefins
Entry
Sulfone
PTO2S
10a
Carbonyl compound
Product
Conditiona
Yield (E/Z)
O
1
2
A
B
81% (21:1)
82% (>50:1)
H
12b
OTBDPS
OBn
OTBDPS
11b
O
3
4
A
B
78% (19:1)
75% (>50:1)
H
12c
OBn
11c
PTO2S
O
C3H7
5
6
A
B
74% (5:1)
86% (>50:1)
Ph
10b
C3H7
Ph
12d
11a
O
O
C3H7
7
8
A
B
68% (9:1)
63% (>50:1)
12e
12f
H
OBn
OBn
11c
O
PTO2S
9
10
A
B
72% (8:1)
62% (>50:1)
Ph
10c
Ph
11a
11
12
A
B
76% (4:1)
75% (19:1)
OBn
H
12g
OBn
11c
PTO2S
O
Cl
13
14
A
B
47% (50:1)
65% (25:1)
10b C3H7
C3H7
C3H7
C3H7
11d
O
12g
Cl
NO2
15
16
A
B
54% (30:1)
67% (20:1)
11e
12h
NO2
O
OMe
MeO
17
18
A
B
59% (>50:1)
64% (>50:1)
11f
12i
O
NO2
19
20
A
B
61% (19:1)
74% (10:1)
NO2
11g
C3H7
12j
a
Conditions: (A) KHMDS (1.1 equiv), THF; (B) KHMDS (1.1 equiv), 18-crown-6 (2.0 equiv), THF.

J. Pospíšil / Tetrahedron Letters 52 (2011) 2348–2352
2351
Table 3
Preliminary scope and limitations—trisubstituted olefins
Entry
Sulfone
Carbonyl compound
Product
Conditiona
Yield (E/Z)
PTO2S
O
Cl
1
2
C
D
Nr
76% (1.6:1)
10b C3H7
3
4
E
F
87% (2.6:1)
73% (2.6:1)
C3H7
11i
Cl
12l
PTO2S
O
5
6
C
E
Nr
Ph
97% (1.2:1)
C5H11
C5H11
10d C5H11
Ph
12m
11a
OHC
7
8
C
E
Nr
NO2
75% (1.2:1)
NO2
11h
12n
a
Conditions: (C) KHMDS, various conditions; (D) LiHMDS (1.1 equiv), THF; (E) LiHMDS (1.1 equiv), 12-crown-4 (2.0 equiv), THF; (F) LiHMDS (1.1 equiv), 12-crown-4
(2.0 equiv), toluene.
reaction selectivity (Table 1, entries 3–5). Additionally, TDA-19 was
used as 18-crown-6 surrogate, yielding olefin 12a in excellent yield
and exquisite (E/Z)-selectivity (Table 1, entry 6). In all these exper-
iments, aldehyde 11a was added 0.5 min after the base (to avoid
the undesired self-condensation reaction).
Control experiments to clarify if the 18-crown-6 and the TDA-1
behave as K+ scavengers were also performed. First, we replaced
KHMDS in the standard reaction conditions set (KHMDS/18-
crown-6/THF or KHMDS/DMF:TDA-1 = 3:1) with NaHMDS (Table
1, entries 7 and 8). As expected, the (E/Z)-selectivity of both reac-
tions dropped and the original 4:1 (E/Z)-ratio was recuperated (Ta-
ble 1, entry 1).
Additionally, the olefination reaction between sulfone 10a and
aldehyde 11a, promoted by LiHMDS, was investigated (Table 1, en-
tries 9–11). As expected, the addition of 12-crown-4 (Table 1, entry
10) or HMPA as a co-solvent (Table 1, entry 11) increased the (E)-
selectivity of the coupling, but the influence of these additives was
less pronounced when compared with the KHMDS/18-crown-6
system. We believe that this is due to a slower chelation of the
Li+ cation by 12-crown-4 or HMPA when compared to the K+/18-
crown-6 system.10
Addition of anion generated from
monosubstituted sulfone to ketone
PT
S
PT
S
O
R2
O
O
R3
O
R3
R2
R1
H
R1
H
O
TS-4
O
TS-5
Two possible open transition states
Addition of anion generated from α
disubstituted sulfone to aldehyde
PT
S
PT
S
O
R3
O
O
R3
O
H
H
R1
R2
R2
R1
O
O
TS-6
TS-7
Having optimized the reaction conditions, the preliminary
scope and limitations of our protocol were established (Tables 2
and 3). First, the (E/Z)-selectivity of 1,2-disubstituted olefins pre-
pared from linear or b-branched sulfones 10a–c reacting with lin-
Two possible open transition states
Scheme 6. Proposed TS for
a-monosubstituted sulfones addition to ketones and a-
disubstituted sulfones to aldehydes.
ear and/or
a-substituted aldehydes 11a–c under our reaction
tions (reaction performed without the presence of any chelating
agent), the adduct anti-9 should undergo the Smiles rearrangement
only very slowly (due to the steric repulsion between R1 and R2 as
showed in adduct anti-4, see Scheme 2). In our case, the rearrange-
ment of adduct anti-9 should proceed with faster reaction rate due
to enhanced nucleophilic character of alkoxide anion. Similarly, the
fragmentation of intermediate 15 should proceed faster than when
chelating agents are not used.
To test our hypothesis, the olefination reaction of sulfone 10a
with aldehyde 11a was investigated (Table 1).8 Under the standard
reaction conditions (KHMDS used as a base); the desired olefin 12a
was obtained in 88% yield with a 4.3:1 (E/Z)-selectivity (Table 1,
entry 1). However, when the reaction was performed in the pres-
ence of 1.0 equiv of 18-crown-6, olefin 12a was isolated in 86%
yield and with a greater than 15:1 (E/Z)-selectivity (Table 1, entry
2). Further increase in 18-crown-6 loading yielded alkene 12a in
comparable yield and with an excellent >50:1 (E/Z)-selectivity (Ta-
ble 1, entry 2). Interestingly, no solvent effect was observed on the
conditions were examined (Table 2, entries 1–12). In all studied
cases, the olefins 12b–g, that were prepared using KHMDS/18-
crown-6 conditions, were furnished with very good to excellent
(E)-selectivity. It is important to note that the observed (E/Z)-selec-
tivities were always superior to those obtained under the classical
reaction conditions (KHMDS/THF).
Next, the reaction of sulfone 10b with aromatic aldehydes 11d–
g was examined (Table 2, entries 13–20). Surprisingly, in these
cases, the (E/Z)-selectivity of the olefin formation was worse if
the chelating agents were used. On the other hand, the reaction
yields were in general 10% higher.
Finally, the stereoselective synthesis of trisubstituted olefins
was attempted (Table 3). First, the reaction between
a-monosub-
stituted sulfone 10b and ketone 11i was attempted (Table 3,
entries 1–4). Interestingly, if KHMDS was used as a base, the for-
mation of olefin 12l was not observed. In contrast to this result,
the use of LiHMDS provided the desired olefin 12l in very good
yield (Table 3, entries 2–4). The same situation occurred if a-disub-

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J. Pospíšil / Tetrahedron Letters 52 (2011) 2348–2352
PT
O
Eq 1
PTO2S
PTO2S
C3H7
14b
(29%)
KHMDS
C3H7
11i
Cl
PTO2S
13b
C3H7
+
O
18-crown-6
THF
10b
Cl
(82%)
11i
Eq 2
O
O
KHMDS
C5H11
Ph
Ph
(42%)
PTO2S
10d
Ph
PTO2S
13d
C5H11
18-crown-6
THF
11a
15
Scheme 7. Side products obtained during the KHMDS-mediated attempts of trisubstituted olefin synthesis.
stituted sulfone 10d reacted with aromatic or aliphatic aldehyde
11h or 11a (Table 3, entry 5). Also in this case, the use of LiHMDS
as a base furnished the desired olefins 12m and 12n in good to
excellent yields (Table 3, entries 6 and 7). In all these cases, very
low or virtually missing (E)-selectivity was observed. We believe
that the missing selectivity can be attributed to the fact that both
possible open transition states, by which the reaction can proceed,
suffer from rather severe steric restrictions (Scheme 6).
Recherche Scientific (Chargé de Recherche F.N.R.S.) is gratefully
acknowledged.
Supplementary data
Supplementary data (full experimental details and characteriza-
tion data of synthetic compounds) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2011.02.086.
As shown in Table 3, if the synthesis of trisubstituted olefins
via Julia–Kocienski olefination reaction was attempted under our
KHMDS/18-crown-6 or KHMDS/TDA-1 conditions, no olefin for-
mation was observed (Scheme 7). In all cases, only the products
of sulfone self-condensation (product 14) or aldol condensation
reaction (compound 15 if aldehyde was used as the coupling
partner), were obtained. It was suggested that the formation of
these undesired products might be caused either by the low
reactivity of the electrophilic partner (ketone vs aldehyde) or
by the steric hindrance presented around the generated anion.
In both cases, the addition of anion 13b to ketone 11i (Scheme 7,
Eq. 1) or of anion 13d to aldehyde 11a is kinetically less favored
than the addition of anion 13b to aldehyde 11a (Scheme 7, Eq.
2) due to steric reasons. As a consequence, a competitive depro-
References and notes
1. (a) Dumeunier, R.; Markó, I. E. In Modern Carbonyl Olefination; Takeda, T., Ed.;
Wiley-VCH: Weinheim, Germany, 2004; pp 104–161; (b) Kocienski, P. J. In
Comp. Org. Synth.; Trost, B. M., Fleming, I., Eds., 1991; 6, pp 987–1000.
2. (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585; (b) Aïssa, C.
Eur. J. Org. Chem. 2009, 1831–1844. and references cited therein..
3. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130,
336–357; (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 856–878; (c) Kocienski, P. J.; Bell, A. G.; Blakemore, P. R.
Synlett 2000, 365–366.
4. Blakemore, P. R.; Cole, W. J.; Kociensky, P. J.; Morley, A. Synlett 1998, 26–28.
5. Markó, I. E.; Pospíšil, J. In Science of Synthesis; de Meijere, A., Ed.; Georg Thieme
Verlag KG: Stuttgart, 2010; pp 105–160.
6. (a) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772–10773; (b)
Albrecht, B. K.; Williams, R. M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11949–
11954.
tonation of
a-carbonyl hydrogens might occur. The protonated
7. It was also reported that the addition of 18-crown-6 (for KHMDS promoted
sulfonyl species then might easily undergo the self-condensation
reaction with another molecule of metalated sulfone 10.
The same is true, of course, if LiHMDS is used as a base. How-
ever, in this case, the Li+ cation presumably serves as a Lewis acid
that activates carbonyl group and, therefore, facilitates the addi-
tion of generated lithium sulfonyl anion.
In conclusions, new conditions for the Julia–Kocienski olefin-
ation, that use specific metal cation chelating agents to enhance
the reaction0s (E)-selectivity, were developed.11 Even though the
exact role of chelating reagents is not clear at the moment and re-
quires further investigation, we believe that this new modification
of the standard olefination reaction will find a wide application in
the synthesis of complex natural products.
coupling) might increase the reaction selectivity if an
a O-alkyl substituted
aldehyde was used as a reaction substrate. It was suggested that the presence
of 18-crown-6 disabled possible stabilization of the adduct and so, prevented
the retro addition reaction. Ishigami, K.; Watanabe, H.; Kitahara, T. Tetrahedron
2005, 61, 7546–7553.
8. For complete reaction optimization table see Table S-1.
9. TDA-1 = tris[2-(2-methoxyethoxy)ethyl]amine; selective K+ chelating agent,
see e.g. Tamao, K.; Nakagawa, Y.; Ito, Y. Org. Synth. 1996, 73, 94–109.
10. (a) Bradshaw, J. S.; Izatt, R. M. Acc. Chem. Res. 1997, 30, 338–345; (b) Lucht, B.
L.; Collum, D. B. Acc. Chem. Res. 1999, 32, 1035–1042.
11. Typical procedure: A solution of sulfone 10a (50 mg, 0.188 mmol, 1.0 equiv) and
18-crown-6 (99.4 mg, 0.376 mmol, 2.0 equiv) in THF (2 mL, 0.1 M) was cooled
down to ꢀ78 °C and KHMDS (451
1.2 equiv) was added dropwise within 10 s. After additional 30 s, aldehyde
(73 mg, 0.21 mmol, 1.1 equiv) in THF (500 L) was added. The resulting
lL, 0.5 M solution in toluene, 1.2 mmol,
l
mixture was stirred at ꢀ78 °C for 30 min before saturated aqueous NH4Cl
(10 mL) was added. The resulting phases were separated and the aqueous layer
was extracted with EtOAc (2 ꢁ 10 mL). The combined organic layers were
washed with brine (5 mL), dried over MgSO4, filtered, and the solvents were
evaporated under reduced pressure. The residue was purified by flash column
chromatography (P.E./EtOAc = 100:0?20:1) yielding 54.4 mg (82%) of colorless
oil ((E/Z) = >50:1).
Acknowledgments
J.P. is grateful to Professor István E. Markó (Université catholiq-
ue de Louvain) for his continuous support. Financial support of this
work by the Université catholique de Louvain and the Fond de la