Manganese-promoted β-elimination reactions: Totally stereoselective synthesis of (E)-α,β-unsaturated esters

Article abstract of DOI:10.1055/s-2005-923592

Stereoselective β-elimination of 2-bromo-3-hydroxy-esters is achieved by using non-preactivated manganese and trimethylsilyl chloride, to yield (E)-α,β-unsaturated esters with total diastereoselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-923592

LETTER
315
Manganese-Promoted b-Elimination Reactions: Totally Stereoselective
Synthesis of (E)-a,b-Unsaturated Esters
Manganesoe-Promoted
b
-Elimina
é
tion
R
eactions M. Concellón,* Humberto Rodríguez-Solla, Vicente del Amo
Dpto. Química Orgánica e Inorgánica, Universidad de Oviedo, C/ Julián Clavería 8, 33006, Oviedo, Spain
E-mail: jmcg@fq.uniovi.es
Received 17 October 2005
out in our laboratory is reported. In addition, a mechanism
to explain this b-elimination process is also proposed.
Abstract: Stereoselective b-elimination of 2-bromo-3-hydroxy-
esters is achieved by using non-preactivated manganese and tri-
methylsilyl chloride, to yield (E)-a,b-unsaturated esters with total
diastereoselectivity.
So, when a solution of several 2-bromo-3-hydroxyesters 1
in dry THF was treated with Mn granules (325 mesh, pro-
Key words: alkenes, diastereoselectivity, esters, eliminations, vided by Aldrich, 1.5 equiv), chlorotrimethylsilane (1.75
manganese
equiv) and refluxed for five hours, the corresponding a,b-
unsaturated esters 2 were isolated, after hydrolysis, with
total stereoselectivity and in high yield (Scheme 1).12
The development of new methods for the stereoselective
formation of carbon–carbon double bonds is one of the
OH
most demanding subjects in organic chemistry.1 Our
Mn(0)
CO2Et
CO2Et
Br R2
R1
R1
group has reported the preparation of a,b-unsaturated es-
TMSCl, THF
reflux
R2
ters with total E selectivity from a-halo-b-hydroxyesters
2
promoted by either SmI2 or CrCl2.3 Although these meth-
1
2
odologies worked obtaining (E)-a,b-unsaturated esters in
good yield and with total diastereoisomeric excess (de)
presented two drawbacks: a) the high cost of these metal
halides,4 and b) the high sensitivity to air oxidation or
moisture of SmI2 and CrCl2, and for this reason, these
reagents require careful manipulation and storage.
Scheme 1 Synthesis of (E)-a,b-unsaturated esters 2
The starting materials 1 were easily prepared by reaction
of the corresponding lithium enolates of 2-bromoesters
(generated by treatment of 2-bromoesters 3 with LDA at
–85 °C) with aldehydes at the same temperature
(Scheme 2).2,3,12
In contrast to Sm(II),5 Cr(II)6 or other metals, Mn(0) has
not yet found such a wide acceptance in organic synthesis,
possibly due to the inherent passivity exhibited by this
metal, which is coated by an outer shell of oxide.7 To
overcome this limitation, many approaches have been de-
veloped to increase its reactivity and generally the use of
Mn(0) has implied the previous preparation of active man-
ganese in processes which are somewhat lengthy and
cumbersome.8 So, active manganese has been employed
in the generation of diverse organomanganese derivatives
for synthetic use9 including the Reformatsky reaction.10
However, very scarce synthetic applications of non-acti-
vated manganese have been described,11 and to the best of
our knowledge, manganese has not been used to date to
promote b-elimination reactions.
O
OH
R2
1) LDA
CO2Et
R1
OEt
2) R1CHO
3) H3O+
Br R2
Br
3
1
Scheme 2 Preparation of starting compounds 1
It is noteworthy that although the 2-bromo-3-hydroxy-
esters 1 were prepared and used as mixtures of diastereo-
isomers (roughly 1:1), the corresponding a,b-unsaturated
esters 2 were obtained with total stereoselectivity.
The diastereoisomeric excess (de) in compounds 2 was
determined on the crude reaction products by H NMR
1
Motivated from our studies on the preparation of new or-
ganometallic reagents derived from active metals, in this
paper we report a new general approach for the prepara-
tion of a,b-unsaturated esters with total E stereoselectivity
from 2-bromo-3-hydroxyesters promoted by the cheap
manganese. A comparison of this reaction with other b-
elimination reactions promoted by SmI2 or CrCl2 carried
spectroscopy (300 MHz). The E stereochemistry of the
carbon–carbon double bond in products 2 was assigned on
the basis of the value of the 1H NMR coupling constants
between the olefinic protons 2a–c. This stereochemistry
was also unambiguously confirmed by comparison of
NMR data of compounds 2a–h with similar materials
previously prepared.13
This proposed methodology to obtain a,b-unsaturated
esters is general: R1 and R2 can be varied widely. So,
aliphatic (linear, branched, or cyclic), unsaturated, or
aromatic a,b-unsaturated esters can be prepared starting
SYNLETT 2006, No. 2, pp 0315–0317
Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923592; Art ID: G34005ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
2.
2
0
0
6

316
J. M. Concellón et al.
LETTER
from the corresponding compounds 1. In turn, structures membered ring.15 Also, this chelation of the MnII centre
can be varied starting from the suitable aldehyde or with the oxygen atom of the alcohol group increases the
bromoester 3.
ability of the hydroxyl group as a leaving group. Tenta-
tively, we surmise that the chair-like transition state mod-
el A might be involved, with the R1 group in an equatorial
orientation. As depicted in B (Newman projection of A
through atoms C2 and C3), R1 and R2 show a cis relation-
ship. A concerted elimination process as that shown in the
tautomeric equilibrium I in Scheme 4 afforded the (E)-
a,b-unsaturated esters 2. The generation of a Mn-enolate
in the presence of an OH group can be rationalised assum-
ing that the elimination process takes place faster than the
competing hydrolysis of the C–Mn(II) bond, moreover
when the elimination is assumed to go through a rigid
chelated transition state.
When this process was carried out in the absence of
TMSCl, no reaction took place. On the other hand, when
lower quantities (0.4 equiv with respect to bromohydrin 1)
of TMSCl were employed the reaction did indeed proceed
although it required a longer time (ca. 12 h). These obser-
vations suggest that TMSCl plays some role as manganese
activating agent7 but does not interfere with the reaction
mechanism.
Table 1 Synthesis of a,b-Unsaturated Esters 2 with Mn
Entry R1
R2
Yield (%)a
Mn
SmI2
70
–
CrCl2
65
–
MnBr
O
OH
OH
H
2a
2b
2c
2d
2e
2f
C7H15
H
82
85
51
75
83
90
78
91
Mn/TMSCl
O
CO2Et
CO2Et
R1
2
R1
R1
OEt
BrMn R2
Cy
H
Br R2
R2
p-MeO-C6H4
C7H15
H
–
–
1
I
Me
75
87
86
90
–
64
–
H
H
O
O
R1
R2
O
CH3CH(Ph)
Ph
C6H13
C6H13
C6H13
C6H13
R1
MnII
OEt
O
OEt
MnII
R2
65
–
H
H
A
B
2g
2h
MeCH=CH
PhCH=CH
Scheme 4 Chelation control model for the conversion of 1 into 2
–
a Isolated yield after column chromatography based on compounds 1;
all products were isolated with >98% de, determined by 1H NMR
and/or GC-MS of the crude products 2.
This mechanism would explain the high levels of stereo-
selectivity shown in this reaction (de >98%). Synthesis of
2 with total stereoselectivity from a mixture of diastereo-
isomers of 1 could be explained by assuming that after the
reaction of 1 with Mn, only one stereoisomer is afforded
with the appropriate relative configuration for the coordi-
nation of the manganese centre with the oxygen atom
from the free alcohol. In this sense, the two starting dia-
stereoisomers 1 are transformed into two enolate enantio-
mers, which afford a single E diastereoisomer through a
b-elimination reaction.
Table 1 also shows results obtained when the b-elimina-
tion process took place using SmI2 or CrCl2 as a metalat-
ing reagent. In general, the yield of the obtained a,b-
unsaturated esters 2 with the Mn/TMSCl system is higher
than when using SmI2 (entries 2a, 2d–g) or CrCl2 (entries
2a, 2d, and 2f). In addition, the reagents utilised to pro-
mote this b-elimination reaction, are cheaper than SmI2 or
CrCl2.
When the reaction was performed on a,b-epoxyesters,
only starting material was recovered in the reaction out-
come. So, a mechanism proceeding via an epoxide must
be ruled out.
Mechanism: we could surmise that the stereochemistry of
this b-elimination reaction is ruled by the thermodynamic
stability of the obtained alkene, affording the E diastereo-
isomer (Scheme 3).
In conclusion, an efficient, general and very cheap meth-
odology has been developed to synthesise a,b-unsaturated
esters with total E diastereoselectivity from easily avail-
able 2-bromo-3-hydroxyesters promoted by non-preacti-
vated manganese and trimethylsilyl chloride. Attempts to
carry out other elimination processes by using the ready
available, cheap and stable Mn metal, are currently under
investigation in our laboratory.
OH
CO2Et
CO2Et
Mn/TMSCl
R1
R1
OH
Br R2
R2
1,2-elimination
CO2Et
BrMn R2
R1
1
2
Scheme 3 b-Elimination for the conversion of 1 into 2
Alternatively, and similarly to other b-elimination reac-
tions,2,3 we could also propose a mechanism based on a
chelation control model (Scheme 4). Thus, metallation of
Acknowledgment
We thank to Ministerio de Educación y Cultura (CTQ2004-01191/
the C–Br bond takes place, and a manganese enolate inter- BQU) for financial support. J.M.C. thanks Carmen Fernández-
mediate is generated.14 Chelation of the MnII centre with
Flórez for her time, and H.R.S. to Ministerio de Educación y
Ciencia (Ramón y Cajal Program).
the oxygen atom of the alcohol group generates a six-
Synlett 2006, No. 2, 315–317 © Thieme Stuttgart · New York

LETTER
Manganese-Promoted b-Elimination Reactions
317
(11) For some examples of synthetic applications of non-
References and Notes
activated manganese, see: (a) Cahiez, G.; Chavant, P.-Y.
Tetrahedron Lett. 1989, 30, 7373. (b) Hiyama, T.;
Sawahata, M.; Obayashi, M. Chem. Lett. 1983, 1237.
(c) See also ref. 7, 9c.
(1) The Chemistry of Alkenes, Vol. 2; Patai, S., Ed.;
Interscience: New York, 1968.
(2) Concellón, J. M.; Pérez-Andrés, J. A.; Rodríguez-Solla, H.
Angew. Chem. Int. Ed. 2000, 39, 2773.
(3) Concellón, J. M.; Rodríguez-Solla, H.; Méjica, C.
Tetrahedron Lett. 2004, 45, 2977.
(4) Aldrich catalogue (2005–2006): manganese (325 mesh):
250 g – 30.50 €; samarium (40 mesh): 50 g – 325.20 €;
chromium dichloride: 25 g – 541.80 €.
(5) (a) Concellón, J. M.; Rodríguez-Solla, H. Chem. Soc. Rev.
2004, 33, 599. (b) Kagan, H. B. Tetrahedron 2003, 59,
10351. (c) Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001,
2727. (d) Molander, G. A.; Harris, C. R. Chem. Rev. 1996,
96, 307.
(6) (a) Matsubara, S.; Oshima, K. In Modern Carbonyl
Olefination; Takeda, T., Ed.; WileyVCH: Weinheim, 2004,
Chap. 5. (b) Fürstner, A. Chem. Rev. 1999, 99, 991.
(c) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1.
(7) For a publication about the effect of TMSCl concerning the
activation of Mn0, see: Takai, K.; Ueda, T.; Hayashi, T.;
Moriwake, T. Tetrahedron Lett. 1996, 37, 7049.
(8) (a) Fürstner, A.; Brunner, H. Tetrahedron Lett. 1996, 37,
7009. (b) Kim, S.-H.; Hanson, M. V.; Rieke, R. D.
Tetrahedron Lett. 1996, 37, 2197.
(12) (a) Typical Procedure for Compound 2h.
When a solution of 1h (0.4 mmol, 1 equiv) in dry THF (2.5
mL), in the presence of Mn granules (325 mesh, 0.6 mmol,
1.5 equiv), and TMSCl (0.7 mmol, 1.75 equiv), was refluxed
for 5 h, compound 2h was obtained after hydrolysis with >98
% de and 91% yield. For spectroscopic data of 1h see ref.
12b.
Compound 2h: 1H NMR (300 MHz, CDCl3): d = 7.52–7.27
(6 H, m), 7.09 (1 H, dd, J = 15.3, 10.9 Hz), 6.89 (1 H, d, J =
15.3 Hz), 4.26 (2 H, q, J = 7.4 Hz), 2.53 (2 H, t, J = 7.4 Hz),
1.61–1.29 (8 H, m), 1.35 (3 H, t, J = 7.4 Hz), 0.92 (3 H, t,
J = 6.1 Hz). 13C NMR (75 MHz, CDCl3): d = 168.1 (C),
138.9 (CH), 138.1 (C), 136.5 (C), 132.5 (CH), 128.7 (CH),
128.5 (CH), 126.9 (CH), 123.7 (CH), 60.4 (CH2), 31.5
(CH2), 29.7 (CH2), 29.1 (CH2), 27.0 (CH2), 22.5 (CH2), 14.2
(CH3), 14.0 (CH3). HRMS: m/z calcd for C19H26O2:
286.1933; found: 286.1904. IR (neat): 2958, 2871, 1461,
1375 cm–1. (b) Concellón, J. M.; Bernad, P. L.; Rodríguez-
Solla, H. Angew. Chem. Int. Ed. 2001, 40, 3897.
(13) Concellón, J. M.; Concellón, C.; Méjica, C. J. Org. Chem.
2005, 70, 6111; see also ref. 2, 3, 12.
(9) (a) Kakiya, H.; Nishimae, S.; Shinokubo, H.; Oshima, K.
Tetrahedron 2001, 57, 8807. (b) Kim, S.-H.; Rieke, R. D. J.
Org. Chem. 2000, 65, 2322. (c) Guijarro, A.; Gómez, C.;
Yus, M. Trends Org. Chem. 2000, 8, 65. (d) Cahiez, G.;
Martin, A.; Delacroix, T. Tetrahedron Lett. 1999, 40, 6407.
(e) Kim, S.-H.; Rieke, R. D. Synth. Commun. 1998, 28,
1065. (f) Kim, S.-H.; Rieke, R. D. J. Org. Chem. 1998, 63,
6766. (g) Tang, J.; Shinokubo, H.; Oshima, K. Synlett 1998,
1075. (h) Rieke, R. D.; Kim, S.-H. J. Org. Chem. 1998, 63,
5235. (i) Kim, S.-H.; Rieke, R. D. Tetrahedron Lett. 1997,
38, 993.
(14) Manganese(II) enolates and related species have been
proposed as intermediates in other manganese-promoted
transformations. See: (a) Dessole, G.; Bernardi, L.; Bonini,
B. F.; Capitò, E.; Fochi, M.; Herrera, R. P.; Ricci, A.;
Cahiez, G. J. Org. Chem. 2004, 69, 8525. (b) Tang, J.;
Shinokubo, H.; Oshima, K. Tetrahedron 1999, 55, 1893.
(c) Cahiez, G.; Figadère, B.; Cléry, P. Tetrahedron Lett.
1994, 35, 6295.
(15) Similar transition state models have been proposed to
explain the selectivity in other Mn(II)-promoted reactions:
Oshima, K. J. Organomet. Chem. 1999, 575, 1.
(10) Suh, Y.; Rieke, R. D. Tetrahedron Lett. 2004, 45, 1807.
Synlett 2006, No. 2, 315–317 © Thieme Stuttgart · New York