Stereoselective preparation of deuteriated dienes by ring fragmentation of metallated cyclopropylcarbinols

Article abstract of DOI:10.1055/s-2004-822918

The hydroalumination reaction of cyclopropenylcarbinols initially leads to the alumino-cyclopropylcarbinol derivatives, which is followed by an elimination reaction to give the corresponding substituted dienes as unique isomers and in good yields. The use

Full text of DOI:10.1055/s-2004-822918

1
288
LETTER
Stereoselective Preparation of Deuteriated Dienes by Ring Fragmentation of
Metallated Cyclopropylcarbinols
S
E
tereoselective
l
P
repara
i
tion of
n
D
euteriated
o
D
ienes r Zohar, Mirit Ram, Ilan Marek*
Department of Chemistry and Institute of Catalysis Science and Technology, Technion-Israel Institute of Technology, Technion City,
2000 Haifa, Israel
3
Fax +972(4)8293709; E-mail: chilanm@tx.technion.ac.il
Received 15 February 2004
The reduction of 1 occurs diastereoselectively in Et O at
2
Abstract: The hydroalumination reaction of cyclopropenyl-
carbinols initially leads to the alumino-cyclopropylcarbinol deriva-
tives, which is followed by an elimination reaction to give the
corresponding substituted dienes as unique isomers and in good
4
0 °C to yield the anti-cyclopropylcarbinol 2 as a single
diastereoisomer. The regioselectivity of the hydroalumi-
nation on the cyclopropenyl ring has been mapped out by
yields. The use of LiAlD as reducing agent provides stereoselec- deuterium labeling experiments (Scheme 1).
4
tively substituted deuteriodienes.
However, when the reaction mixture is heated at higher
Key words: dienes, deuteriodienes, reducing agent, cyclopropane,
cyclopropene
temperature (80 °C in benzene) or in Et O for a longer pe-
2
riod of time, the intermediate cyclopropylaluminum spe-
cies 3a–k undergo an elimination reaction to yield the
corresponding dienes 4a–k in excellent yields and as
unique geometrical isomers (Scheme 2).
As the conjugated diene system represents not only an im-
portant structural feature of many insect pheromones and
other biologically active compounds but also a versatile
16
1
building skeleton for the construction of complicated mol-
ecules via the Diels–Alder reaction, numerous methods
H3C CH3
n-BuLi
(2 equiv)
2
H C
X
CHBr3, NaOH
X
Br
3
have been developed for their stereoselective synthesis.
These methodologies are based on either the Wittig-type
H3C
R2
Cetrimide, H O
2
R2
Br
X = Cl, Br
3
approach, the selective reduction of acetylenic units of
H3C CH3
H3C CH3
3
H C
CH3
4
1
,3-enynes or the direct coupling reaction of two vinyl
3
LiAlH4
R CHO
R3
R3
OH
groups. The latter method, namely the metal-catalyzed
cross-coupling reaction between a stereodefined vinyl
halide with a stereodefined alkenyl organometallic com-
R2
Li
R2
Et O, +40 °C
R2
2
1
2
then H3O+
OH
LiAlD4
5
6
7
pound such as vinylborane, -zinc, -cuprates, -alumi-
3
Et2O, +40 °C
then H3O+
R = Et
8
9
10
11
num, -zirconium, -magnesium or -tin reagents, has
found outstanding applications in organic synthesis.
H3C CH3
The stereoselective preparation of deuterium-labelled di-
enyl systems is particularly important for the structural
H
D
R = CH3; %(d) > 98; 72%
R = H; %(d) > 98; 80%
Et
R
12
determination of fragments in mass spectroscopy, and is
generally more troublesome since pure stereospecifically
deuteriated alkenyl halides and/or alkenyl metals have to
OH
Scheme 1
1
3
be synthesized. In this letter, we would like to report an
unusual but straightforward stereoselective preparation of
deuteriated dienes in only a few chemical steps from com-
mercially available starting materials.
R1 R1
R2
R1 R1
H
R1
LiAlH4(D4)
benzene,
+80 o
"Al"
H (D)
R
R3
R3
3
R2
R2
R1
H(D)
We have recently developed the diastereoselective re-
OH
a–g
C
O"Al"
duction of cyclopropenylcarbinol 1 to anti-cyclopropyl-
1
3a–k
4a–k
1
4
carbinol derivatives 2 (Scheme 1); the cyclopropenyl-
carbinols 1 are themselves obtained from 1,1,2-trihalocy-
clopropanes (prepared by reaction of substituted vinyl
bromide derivatives with bromoform) by treatment with
two equivalents of n-BuLi and reaction with various alde-
Scheme 2
The scope of the reaction is rather broad as compiled in
Table 1.
1
5
hydes as summarized in Scheme 1.
The reaction was first tested with non-deuteriated LiAlH4
on the fully substituted cyclopropenylcarbinol 1a (R = R
= Me, R = Ph, entry 1, Table 1). After heating for 19
hours in benzene, the corresponding diene 4a was ob-
tained in 85% yield as unique (E)-isomer (J = 16 Hz).
1
2
3
SYNLETT 2004, No. 7, pp 1288–1290
0
3.
0
6.
2
0
0
4
Advanced online publication: 27.04.2004
DOI: 10.1055/s-2004-822918; Art ID: G04904ST
Georg Thieme Verlag Stuttgart · New York
©

LETTER
Stereoselective Preparation of Deuteriated Dienes
1289
Table 1 Stereoselective Preparation of Dienes
Entry
1
R1
R2
R3
LiAlH /LiAlD
Product
Yield (%)a
85
4
4
CH3
CH3
C H
LiAlH4
CH3
6
5
5
H3C
H3C
Ph
Ph
Ph
Et
4
a
2
3
4
5
6
7
8
9
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
(CH2)5
CH3
CH3
C H
LiAlD4
CH3
D
84
80
75
67
75
70
65
65
55
65
6
H3C
H3C
4
b
H
C H
LiAlD4
LiAlH4
LiAlD4
LiAlH4
LiAlD4
LiAlH4
LiAlD4
LiAlH4
LiAlH4
H
6
5
5
5
H3C
H3C
D
4
c
CH3
CH3
CH3
CH3
H
C H
CH3
2
H3C
H3C
H
4
d
C H
CH3
2
H3C
H3C
Et
D
4
e
c-C H
CH3
6
11
11
11
11
H3C
H3C
H
4
f
c-C H
CH3
6
H3C
H3C
D
4
g
c-C H
H
6
H3C
H3C
H
4
h
H
c-C H
H
6
H3C
H3C
D
4
i
1
1
0
1
CH3
CH3
C H
CH3
2
5
Et
H
CH3
H
4
j
CH CH=CHC H
5
2
2
H3C
H3C
Et
4
k
a
Yields determined after purification by chromatography on silica gel.
Synlett 2004, No. 7, 1288–1290 © Thieme Stuttgart · New York

1
290
E. Zohar et al.
LETTER
When the reduction is performed with LiAlD (Table 1,
Schpector, J.; Toloi, A. P.; Ferreira, M. L.; Brocksom, U.
Org. Synth.: Theory Appl. 2001, 5, 39.
3) Kolodiazhnyi, O. I. In Phosphorous Ylides; Wiley-VCH:
Weinheim, 1999.
4) (a) Naso, F. Pure Appl. Chem. 1988, 60, 79. (b) Fiandese,
V.; Marchese, G.; Naso, F.; Ronzini, L. Synthesis 1987,
4
entry 2), the deuteriated diene is similarly obtained and in
comparable yield with more than 98% of deuterium incor-
poration (both LiAlH and LiAlD are used in solution in
(
(
4
4
Et O from commercially available sources). The cyclo-
2
propenylcarbinol can also bear three substituents as in 1c
1034; and references cited therein.
1
2
3
(
Table 1, entry 3, R = Me, R = H, R = Ph) or be substi-
(5) Suzuki, A. Cross-Coupling Reactions of Organoboron
Compounds with Organic Halides, In Metal-Catalyzed
Cross-Coupling Reactions; Diederich, F.; Stang, P. J., Eds.;
Wiley-VCH: Weinheim, 1998, 49.
6) Negishi, E.; Liu, F. Palladium- or Nickel-Catalyzed Cross
Coupling with Organometals Containing Zinc, Magnesium,
Aluminium, and Zirconium, In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998, 1.
7) (a) Gardette, M.; Jabri, N.; Alexakis, A.; Normant, J. F.
Tetrahedron 1984, 40, 2741. (b) Normant, J. F.; Alexakis,
A. Synthesis 1981, 841.
8) Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.;
Okukado, N. J. Am. Chem. Soc. 1987, 109, 2393.
9) Lipshutz, B. H.; Pfeiffer, S. S.; Noson, K.; Tomioka, T.
Hydrozirconation and Further Transmetalation Reactions,
In Titanium and Zirconium in Organic Synthesis; Marek, I.,
Ed.; Wiley-VCH: Weinheim, 2002, 110.
10) Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856.
11) Mitchell, T. N. Organotin Reagents in Cross-Coupling, In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.;
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998, 167.
(12) Kuck, D.; Mormann, M. In Mass Spectrometry and Gas-
Phase Ion Chemistry of Dienes and Polyenes, In The
Chemistry of Dienes and Polyenes; Rappoport, Z., Ed.;
Wiley: Chichester, 2000, 1.
13) Duffault, J.-M.; Einhorn, J.; Alexakis, A. Tetrahedron Lett.
1995, 36, 2765.
tuted by a primary (entries 4 and 5 for LiAlH and LiAlD
4
4
1
2
3
respectively, R = Me, R = Me, R = Et) or a secondary
alkyl group (entries 6 and 7 for LiAlH and LiAlD re-
4
4
(
1
2
3
spectively, R = Me, R = Me, R = cyclohexyl) at the pre-
existing stereogenic center without altering the efficiency
of the reaction; dienes 4d and 4f, as well as dienes specif-
ically labeled in 2-positions such as 4c, 4e and 4g, are con-
sistently obtained in good yields and as unique
geometrical isomers. The combination of a cycloprope-
nylcarbinol with three substituents with a secondary alkyl
(
(
3
group for R also leads to the diene 4h and deuteriodiene
4
i as unique isomers (Table 1, entries 8 and 9). The gem-
(
1
dimethyl group for R can also be replaced by other sub-
stituents such as a cyclohexyl ring [Table 1, entry 10, R1
=
(CH ) ]; 4j was isolated in 55% yield as a unique iso-
2 5
(
(
mer. Additional functionality, such as (E)-double bond
Table 1, entry 11, R = Me, R = Me, R3
1
2
(
=
CH CH=CHEt), can be present on the carbon skeleton of
2
the cyclopropenylcarbinol. The reduction occurs
chemoselectively at the double bond of the three-mem-
bered ring unit and by subsequent thermal elimination, the
skipped triene 4k was obtained as a single isomer
(
Table 1, entry 11).
(
In conclusion, from common commercially available
starting materials (vinyl bromides, HCBr , aldehydes and
(14) Zohar, E.; Marek, I. Org. Lett. 2004, 6, 341.
3
(
(
(
15) (a) Baird, M. S.; Hussain, H. H.; Nethercott, W. J. Chem.
LiAlH or LiAlD ), the corresponding alumino-cyclopro-
4
4
Soc., Perkin Trans. 1 1986, 1845. (b) Baird, M. S.;
pylcarbinol derivatives are easily obtained by reduction of
the internal double bond in very few chemical steps. Just
by heating these intermediates, an elimination reaction oc-
curs in all cases to lead to diversely substituted dienes.
The major advantage of this methodology is that the
preparation of regiospecific deuteriodienes is easily
Nethercott, W. Tetrahedron Lett. 1983, 24, 605. (c) Baird,
M. S.; Hussain, H. H. Tetrahedron 1987, 43, 215. (d) Al-
Dulayymi, J. R.; Baird, M. S. Tetrahedron Lett. 1988, 29,
6147. (e) Al-Dulayymi, J. R.; Baird, M. S. Tetrahedron
1989, 45, 7601. (f) Al-Dulayymi, A. R.; Baird, M. S. J.
Chem. Soc., Perkin Trans. 1 1994, 1547.
1
7
16) Rearrangements of cyclopropanols into dienes under acidic
catalysis were reported: (a) Il’ina, N. A.; Kulinkovitch, O.
G. Zh. Org. Khim. 1992, 28, 1597. (b) Il’ina, N. A.;
Kulinkovitch, O. G. J. Org. Chem. USSR (Engl. Transl.)
achieved.
Acknowledgment
1
992, 28, 1272. (c) Kulinkovitch, O. G.; Tishchenko, I. G.;
Roslik, N. A.; Reznikov, I. V. Synthesis 1983, 383.
d) Patro, B.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1992,
3, 809.
This research was supported by the Israel Science Foundation
administrated by the Israel Academy of Sciences and Humanities
(
3
(
79/01-1) and by the Technion Research & Development.
17) General Procedure for the Preparation of Dienes from
Cyclopropenylcarbinols 1a–g: LiAlH (or LiAlD , 1 M
4
4
References
solution in Et O, 1 mmol) was added to a stirred solution of
2
(
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sequential reduction and elimination reactions were
1
977, 33, 1845. (c) Rossi, R. Synthesis 1977, 817.
followed by TLC. When the transformation was complete,
1 M aq solution of HCl (3 mL) was added and the aqueous
(
2) (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
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layer was extracted with Et
organic phases were dried over MgSO
4
2
O (3 × 5 mL). The combined
1668. (b) Brockson, T. J.; Correa, A. G.; Naves, R. M.;
, filtered and the
Silva, F. Jr.; Catani, V.; Ceschi, M. A.; Zukerman-
solvent was removed under reduced pressure.
Chromatography on silica gel (eluent: hexane) gave the
dienes 4a–k in yields indicated in Table 1.
Synlett 2004, No. 7, 1288–1290 © Thieme Stuttgart · New York