Direct preparation of Z-1,3-enyne systems with a TMS-propargylic sulfone: Application of a one-pot Julia olefination

Article abstract of DOI:10.1055/s-2006-948196

A benzothiazolyl TMS-propargylic sulfone was subjected to one-pot Julia olefinations with a variety of aliphatic and aromatic aldehydes. Predominant Z-selectivity up to 98:2 and good chemical yields were obtained in a facile route to the desired Z-1,3-eny

Full text of DOI:10.1055/s-2006-948196

LETTER
2079
Direct Preparation of Z-1,3-Enyne Systems with a TMS-Propargylic Sulfone:
Application of a One-Pot Julia Olefination
T
MS-Propargylic
a
BT-Sulfon
r
e
for the
l
Synth
o
Z
-1,3-Enyn
B
s
onini,* Lucia Chiummiento, Valeria Videtta
Dipartimento di Chimica, Università degli Studi della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
Fax +39(0971)202223; E-mail: bonini@unibas.it
Received 22 March 2006
Abstract: A benzothiazolyl TMS-propargylic sulfone was sub-
jected to one-pot Julia olefinations with a variety of aliphatic and
aromatic aldehydes. Predominant Z-selectivity up to 98:2 and good
chemical yields were obtained in a facile route to the desired Z-1,3-
enyne moieties.
N
OR
n
3-alkoxymethylindolizines
(3)
Key words: enynes, olefination, aldehydes, propargylic sulfones,
natural products
N
n
TMS
cyclooctatetraenophanes
Vinylacetylenes are important and direct precursors of
(2)
conjugated p-systems, including dienic, diacetylenic and
aromatic compounds which are common features in
natural products.1 Frameworks like 1 (Scheme 1) are
frequently used in multistep syntheses of polyunsaturated
CH3
H
TMS
N
1
R
compounds, suitable for subsequent coupling reactions af-
ter silyl deprotection. For example, the Z-1,3-enyne sys-
tem is used in the preparation of cyclooctatetraenophanes
(2)2 and of 3-alkoxymethylindolizines (3),3 the latter are
quinolizidine 217A
(4)
potential new calcium entry blockers, chemotherapeutics
and cardiovascular agents. The same moiety 1 is the key
m
n
OH
m = 4, n = 2,
intermediate in several total syntheses of natural bioactive
compounds like the alkaloid quinolizidine 217A (4)4 and
OH
(–)-siphonodiol
the (–)-siphonodiol (5),5 an antifungal and antibacterial
(5)
polyacetylene.
Scheme 1
As part of our ongoing projects on natural product synthe-
ses we are interested in the development of an efficient
propargylic sulfones are alkyl-substituted at the end of the
method for the construction of such Z-1,3-enyne system
starting from an appropriate acetylenic compound, and in
the subsequent stereocontrolled formation of the con-
jugated double bond. For highly regio- and stereoselective
double-bond formation, compatible with multifunctional-
ized compounds, the most generally applicable methods
involve the direct olefination of carbonyl compounds as in
the Wittig,6 Peterson,7 Johnson,8 classical Julia9 and one-
pot Julia10 reactions, or the more recently developed olefin
metathesis11 and transition-metal-catalyzed cross-
coupling12 reactions.
acetylenic bond (n-Bu and Me, respectively).
We have recently developed a simple and highly efficient
procedure for the preparation of different propargylic sul-
fones starting from the corresponding propargylic alco-
hols.14 We have chosen the TMS-propargylic sulfone for
a general application of the one-pot Julia reaction. With
both benzothiazoyl (BT) sulfones and phenyltetrazoyl
(PT) sulfones in hand, we have attempted the olefination
with benzaldehyde (Table 1), which was not used with
propargylic sulfones in the previously reported olefina-
tions.10,13
Together with the seminal work on modified Julia olefina-
tion,10c we have found only a recent report13 on the prepa-
ration of such enyne systems via one-pot reaction of
propargylic sulfones with a,b-unsaturated aldehydes, but
no applications in total syntheses. Moreover, the reported
In the first attempts, olefination of sulfone 6a was con-
ducted at –55 °C in THF using KHMDS, according to the
premetallated15 or Barbier procedure.16 Reactions afford-
ed the required enyne 7 in 50% and 80% yields, with Z/E
ratios of 87:13 and 96:4, respectively (Table 1, entries 1
and 2).
The same Z-selectivity was obtained in the olefination of
sulfone 6a with benzaldehyde using DME as solvent
(31% yield, 98:2 Z/E ratio, entry 3 in Table 1). When
SYNLETT 2006, No. 13, pp 2079–2082
Advanced online publication: 09.08.2006
DOI: 10.1055/s-2006-948196; Art ID: G10306ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.0
8
.2
0
0
6

2080
C. Bonini et al.
LETTER
1d in 23–44% yield with excellent Z-selectivity (Z/E =
93:7 ratio) and with a significant amount of self-conden-
sation product.
Table 1 Yields and Z/E Ratios for the One-Pot Julia Olefination of
6a,b with PhCHO
KHMDS,
solvent, –55 °C
+ PhCHO
SO2Het
Subsequently, in order to introduce chiral centers upon the
enyne system, attempts were also made using functional-
ized enantiopure aldehydes like the known compounds
8e19 and 8f,20 which we had prepared for the stereoselec-
tive synthesis of natural products.
TMS
TMS
Ph
6a: Het = BT
6b: Het = PT
7
N
N
S
N
N
BT =
PT =
N
Using only method A, the same stereochemical trend was
observed (entries 5 and 6 in Table 2): the obtained yields
remained good and the Z-selectivity was still very high
(56–76% in yields, >99:1 and 86:14 in Z/E ratios, for 1e
and 1f, respectively).21
Ph
Entry
Sulfone Solvent Method Ratio Z/Ec Yields(%)
Aa or Bb
of 7d
1
2
3
4
6a
6a
6a
6b
THF
THF
DME
THF
A
B
A
B
87:13
96:4
98:2
98:2
50
The moderate yields obtained in our protocols, although
superior to the previously reported yields with similar
substrates, are probably due to the formation of several
by-products. Since the BT-sulfones particularly suscepti-
ble to nucleophilic attack at C2,10 self-condensation and
side reaction of the sulfone 6a are likely. In fact, the unre-
acted aldehydes were recovered, while the sulfone disap-
peared completely. This was further demonstrated when
6a and the base reacted under the typical conditions and
resulted in volatile compounds and by-products. More-
over, under Barbier conditions utilized in many cases to
improve the yields and to avoid side reactions, we ob-
tained olefins 1a–d with excellent Z/E ratios (from 93:7 to
only Z isomer), without a general improvement in yields.
80
31
38
a Method A: premetallated conditions: base added to sulfone, alde-
hyde added thereafter.
b Method B: Barbier conditions: base added to sulfone and aldehyde.
c The ratios were determined by GC-MS analysis.
d Yields (%) after chromatographic purification on silica gel.
PT-sulfone 6b was used under the Barbier conditions in
THF, enyne 7 was obtained in 38% yield and 98:2 Z/E
ratio (entry 4).
Considering the results obtained in this preliminary study,
we decided to utilize the more suitable sulfone 6a17 with
different aldehydes.
The stereochemical outcome of the one-pot Julia olefina-
tion is generally substrate-dependent (in this reaction,
sulfone and aldehyde) and influenced by the reaction con-
ditions. However, in our case, the reaction appeared to be
controlled mainly by the propargylic sulfone 6, and al-
most not influenced by the reacting aldehydes and by the
reaction conditions.
In Scheme 2 we report our general strategy for the con-
struction of Z-1,3-enyne systems like 1, using aromatic,
a,b-unsaturated and linear or branched alkyl aldehydes of
type 8.
Remarkably, compound 1b, recently prepared by a differ-
ent protocol,22 was obtained with our direct procedure in
higher yield and stereoselectivity.
R1
OHC
In summary, we have applied a direct and highly stereo-
specific methodology for the synthesis of Z-1,3-enynes,
via a general one-pot Julia olefination of aldehydes.
Different substituents in the aldehydes are also tolerated
in the construction of the 1,3-enyne moieties, and a net
increase in chemical yields has been observed with
respect to previous reports.10c,13
or
OHC
OHC
SO2-BT
+
X
TMS
R
TMS
1
6a
or
8
Scheme 2 One-pot Julia olefination with propargylic BT-sulfone 6a
Typical Premetallated Procedure
A solution of sulfone 6a (1 equiv, 0.13 mmol) in THF (3 mL) at
–55 °C was treated dropwise with KHMDS (0.5 M in toluene 1.2
equiv, 0.32 mL). The resulting brown solution was stirred at –55 °C
for 30 min, and then aldehydes 8a–f (1.5 equiv, 0.20 mmol) were
slowly introduced. The mixture was stirred at –55 °C for 2–3 h, al-
lowed to warm to r.t. for 1 h, and then diluted with Et2O and washed
with H2O. The aqueous solution was extracted with Et2O and the
combined organic layers were washed with brine and dried over
Na2SO4. Evaporation of the solvent followed by purification of the
crude product by column chromatography on silica gel (PE–Et2O,
95:5) gave olefins 1a–f as yellow oils.
Table 2 shows the results of the one-pot Julia olefination
of a variety of aldehydes (1.5–1.6 equiv) using sulfone 6a
(1 equiv). Aromatic and a,b-unsaturated18 aldehydes 8a–
c (entries 1–3), under both premetallated and Barbier con-
ditions, led to enynes 1a–c in 41–46% yields, in good to
high Z-selectivities.
We then examined the reaction of 6a with the linear and
branched aliphatic aldehydes 8d–f (entries 4–6, Table 2).
Aldehyde 8d, under Barbier conditions, afforded olefin
Synlett 2006, No. 13, 2079–2082 © Thieme Stuttgart · New York

LETTER
TMS-Propargylic BT-Sulfone for the Synthesis of Z-1,3-Enynes
2081
Table 2 Yields and Z/E Ratios for the One-Pot Julia Olefination of 6a with Aldehydes 8a–f
KHMDS, THF, –55 °C
6a
+
RCHO
method A or B
TMS
R
8a–f
1a–f
Entry
1
Aldehyde 8
Product 1
A or B
Ratio Z/Ea
Yields (%)b
OHC
A
B
78:22
97:3
51
43
1a
OMe
8a
OHC
A
B
95:5
Only Z
50
41
2
3
1b
1c
O
8b
OHC
A
B
66:43
94:6
42
46
8c
OHC(CH2)4OBn
8d
A
B
79:21
93:7
44
4
5
1d
1e
23c
OTBS
OHC
OPMB
A
A
Only Z
56
76
8e
OTBS
6
1f
86:14
OHC
OTBS
8f
a The ratios were determined by GC-MS analysis.
b Yields (%) after chromatographic purification on silica gel.
c A considerable amount of self-condensation product of the aldehyde was isolated after purification.
Typical Barbier Procedure
(4) Maloney, K. M.; Danheiser, R. L. Org. Lett. 2005, 7, 3115.
(5) López, S.; Fernández-Trillo, F.; Midón, P.; Castedo, L.; Saá,
C. J. Org. Chem. 2005, 70, 6346.
(6) (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(b) Wittig, G.; Geissler, G. Justus Liebigs Ann. Chem. 1953,
580, 44.
(7) (a) Van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc.
Rev. 2002, 31, 195. (b) Peterson, D. J. J. Org. Chem. 1968,
33, 780.
(8) Johnson, C. R.; Shanklin, J. R.; Kirchhoff, R. A. J. Am.
Chem. Soc. 1973, 95, 6462.
To a stirred solution of sulfone 6a (1 equiv, 0.07 mmol) and alde-
hyde 8a–d (1.6 equiv, 0.08 mmol) in THF (2 mL) at –55 °C KH-
MDS 0.5 M in toluene (1.2 equiv, 0.12 ml) was dropwise added.
The resultant yellow solution was stirred at –55 °C for 4 h and al-
lowed to warm to r.t. for 1 h. The mixture was then diluted with
Et2O and washed with H2O. The aqueous solution was extracted
with Et2O and the combined organic layers were washed with brine
and dried over Na2SO4. Evaporation of the solvent followed by pu-
rification of the crude product by column chromatography on silica
gel (PE–Et2O, 95:5) gave olefins 1a–d as yellow oils.
(9) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 4833.
(10) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.;
Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336. (c) Baudin, J.
B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 856. (d) Baudin, J. B.; Hareau, G.;
Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175.
(11) For recent reviews of the alkene-metathesis reaction, see:
(a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.
Int. Ed. 2005, 44, 4490. (b) Schmidt, B.; Hermanns, J. Top.
Organomet. Chem. 2004, 7, 223. (c) Fürstner, A. Angew.
Chem. Int. Ed. 2000, 39, 3012. (d) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413.
Acknowledgment
Thanks are due to the University of Basilicata and the MIUR
(FIRB-Progettazione, preparazione e valutazione biologica e far-
macologica di nuove molecole organiche quali potenziali farmaci
innovativi grant) for financial supports.
References and Notes
(1) (a) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
(b) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901.
(2) Moriarty, R. M.; Pavlović, D. J. Org. Chem. 2004, 69, 5501.
(3) Kaloko, J.; Hayford, A. Org. Lett. 2005, 7, 4305.
Synlett 2006, No. 13, 2079–2082 © Thieme Stuttgart · New York

2082
C. Bonini et al.
LETTER
(12) For general reviews, see: (a) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442.
(b) Negishi, E.-I.; Liu, F. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998, 1. (c) Farina, V.; Krishnamurthy,
V.; Scott, W. J. Org. React. (NY) 1997, 50, 1. (d) Miyaura,
N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(19) Smith, A. B. III; Freeze, B. S.; LaMarche, M. J.; Hirose, T.;
Brouard, I.; Xian, M.; Sundermann, K. F.; Shaw, S. J.;
Burlingame, M. A.; Horwitz, S. B.; Myles, D. C. Org. Lett.
2005, 7, 315.
(20) Preparation of aldehyde 8f, starting from the alcohol 9
(Scheme 3). Alcohol 9 was prepared according to: Bonini,
C.; Chiummiento, L.; Videtta, V.; Colobert, F.; Solladié, G.,
manuscript in preparation.
(13) Sorg, A.; Brückner, R. Synlett 2005, 289.
(14) Bonini, C.; Chiummiento, L.; Videtta, V. Synlett 2005, 3067.
(15) Premetallated conditions: base added to sulfone, then
aldehyde added.
(16) Barbier conditions: base added to the mixture of sulfone and
aldehyde.
(17) Pent-2-ynyl BT-sulfone, reacting with benzaldehyde
according to method A, afforded the corresponding enyne in
only 18% yield but with 94:6 Z/E ratio.
OTBS
OTBS
1. TBSCl
2. DDQ
HO
PMBO
OTBS
OH
73%
10
9
Dess–Martin
periodinane
OTBS
OHC
OTBS
78%
8f
(18) For other examples with high cis-selectivity during the one-
pot Julia olefination of allyl benzothiazolyl sulfones with
a,b-unsaturated aldehydes, see: (a) Furuichi, N.; Hara, H.;
Osaki, T.; Mori, H.; Katsumura, S. Angew. Chem. Int. Ed.
2002, 41, 1023. (b) Furuichi, N.; Hara, H.; Osaki, T.;
Nakano, M.; Mori, H.; Katsumura, S. J. Org. Chem. 2004,
69, 7949. (c) Ref. 13. (d) Vaz, B.; Alvarez, R.; Souto, J. A.;
de Lera, A. R. Synlett 2005, 294. (e) Vaz, B.; Alvarez, R.;
Brückner, R.; de Lera, A. R. Org. Lett. 2005, 7, 545.
Scheme 3
(21) No b-elimination product was observed for aldehyde 8e.
Moreover, the optical rotation for the unreacted aldehyde 8f
shows the same the value of the starting aldehyde, thus
indicating that no epimerization reaction occurs.
(22) Hayford, A.; Kaloko, J. Jr.; El-Kazaz, S.; Bass, G. Org. Lett.
2005, 7, 2671.
Synlett 2006, No. 13, 2079–2082 © Thieme Stuttgart · New York