Masked allylic zinc reagents

Article abstract of DOI:10.1039/a805952g

The preparation of allylic zinc reagents using the fragmentation of sterically hindered tertiary homoallylic alcohols is described.

Full text of DOI:10.1039/a805952g

Masked allylic zinc reagents
Philip Jones, Nicolas Millot and Paul Knochel*
Fachbereich Chemie der Universität, Hans-Meerwein Strasse, D-35032 Marburg, Germany.
E-mail: knochel@ps1515.chemie.uni-marburg.de
Received (in Liverpool, UK) 29th July 1998, Accepted 22nd September 1998
The preparation of allylic zinc reagents using the fragmenta-
tion of sterically hindered tertiary homoallylic alcohols is
described
a-substituent reacted well, within 2 h at room temperature, to
give the desired allylated product in good yields (entries 3 and
4). Transfer of the allyl group to a ketone required slightly
longer reaction times, the reaction usually taking between 2 and
4 h at room temperature to go to completion. Reaction with
cyclohexanone gave the allylated adduct in 82% (entry 5), while
a,b-unsaturated ketones gave the desired products in reasonable
yields (entries 6 and 7). a-Tetralone also reacted well to give the
desired material in excellent yield (entry 8).
The development and use of allylic organometallic reagents in
synthesis has been an underlying theme of modern organic
synthesis.1,2 Despite the plethora of methods currently available
for the introduction of allylic moieties into complex molecules
several problems remain, most notably that of cross contamina-
tion of the product with the Wurtz coupling adduct. Secondly,
there are the problems associated with generating stoichio-
metric amounts of inorganic salts and thirdly, the functionally
group tolerance of the reagent due to the highly polar nature of
most carbon–metal bonds.
There are several reports in the literature that the addition of
allylic organometallics to electrophiles is reversible;3–6 in
particular one report by Miginiac has inspired us.5a Therefore it
was rationalised that generation of a zinc alkoxide of a sterically
hindered tertiary allyl alcohol would result in decomposition to
the parent ketone and an allyl zinc reagent, which in the
presence of a suitable electrophile could be utilised synthet-
ically. Recently, Nokami has described a related allyl transfer
reaction of homoallylic alcohols catalysed by tin(II) triflate
which has caused us to disclose our results.7
The reaction is not just limited to carbonyl compounds. It was
discovered that nitriles also react well to give b,g-unsaturated
ketones in good yields (Scheme 2). Generation of the zinc
alkoxide as previously and addition of the nitrile generates the
corresponding imine, which upon hydrolysis liberates the
ketones 3a–c in good yield; both aromatic and enolisable
nitriles reacted well.
b,g-Unsaturated amines can also be prepared using these
masked organozinc reagents through reaction with imines
(Scheme 3). Addition of BunLi and then zinc chloride to a
solution of the tertiary allyl alcohol 1b in THF generates the
Table 1 Reaction of masked organozinc reagent 1b with carbonyl
compounds
Accordingly a series of tertiary homallylic alcohols 1a,b
were prepared. Treatment of the tertiary alcohol bearing two
isopropyl groups 1a first with BunLi and then with zinc bromide
gave the zinc alkoxide. At room temperature no migration of the
allyl group was observed in the presence of benzaldehyde, but
after heating at reflux for 6 h the benzylic alcohol 2 could be
isolated in 70% yield (Scheme 1). Clearly, as hypothesised the
zinc alkoxide had fragmented in situ to give an allyl zinc
reagent. The reaction could be improved by the addition of a
polar co-solvent; after 6 h in a THF–HMPA mixture 98% of the
secondary alcohol 2 was observed. Increasing the steric
congestion around the zinc alkoxide also resulted in a faster
reaction; by using two tert-butyl groups 1b the migration was
complete within 1 h at room temperature, resulting in 89%
isolated yield of the secondary alcohol 2.† In both cases, control
experiments with lithium and magnesium alkoxides in the
absence of zinc salts showed no migration of the allyl group.
Inspired by this reaction the compatibility of these reagents
with a range of aldehydes and ketones was investigated (Table
1). Treatment of the zinc alkoxide with heptanal gave dec-1-en-
4-ol in 83% yield (entry 1), whilst an a,b-unsaturated aldehyde
was also tolerated (entry 2), giving exclusively the 1,2-addition
product in 84% yield. In a similar manner, aldehydes bearing an
Entry Electrophile
Product
Yield (%)a
OH
OH
1
2
C6H13CHO
CHO
83
C6H13
84
OH
CHO
3
4
82
85b
Ph
Ph
CHO
OH
OH
O
5
82
OH
O
6
7
74
73
(i) BuLi
OH
OH
(ii) ZnBr2
Ph
Ph
R1
R2
(iii) PhCHO
BrZn
HO
OH
Ph
O
1a,b
2
1a R1 = R2 = Pri
THF, room temp.
THF, 70 °C
O
0%
8
99
70%
98%
89%
THF–HMPA, 70 °C
THF, room temp.
1b R1 = R2 = But
a Isolated yield of analytically pure products. b 3:1 mixture of erythro:threo
isomers.
Scheme 1
Chem. Commun., 1998, 2405–2406
2405

O
(i) BuLi, –78 °C
(ii) PhCHO,
–78 °C
(i) BuLi, room temp.
(ii) ZnCl2
OH
OH
OH
OH
But
But
Ph
But
But
(iii) PhCN
(iv) H+
Ph
(CH2)4CO2Et
(CH2)4CO2Et
(iii) ZnCl2
1b
3a 73%
8 60%
6
–78 °C to
O
room temp.
O
OH
(i) BuLi, –78 °C
(ii) PhCHO, –78 °C
(iii) ZnCl2
Cl
But
But
Ph
(CH2)4CN
Br
(CH2)4CN
3b 74%
3c 62%
–78 °C to
7
9 56%
Scheme 2
room temp.
Scheme 6
(i) BuLi
HN
H
Me
(ii) ZnCl2
OH
prepared9 and treated with BuLi, benzaldehyde and zinc
chloride at 278 °C, followed by warming the reaction mixture
to room temperature. This gave the desired hydroxy ester 8 and
hydroxy nitrile 9 in 60 and 56% yields, respectively.
In summary, we have developed a method for the generation
of allylic organozinc reagents by exploiting a retro-addition
reaction. This method avoids entirely the problem of Wurtz
coupling during formation of the organometallic reagent. The
reaction is also very general and addition to a range of
electrophiles is possible. The mild conditions associated with
this reaction also make it compatible with a range of functional
groups and finally the reaction has been shown to be catalytic in
zinc salts.10
But
But
N-Bu
(iii)
Ph
Ph
1b
4a 97%
HN
Ph
HN
Ph
Me
c-Hex
Ph
N
Ph
H
4b 67%
4c 90%
4d 63%
Scheme 3
zinc alkoxide that fragments in a retro-allylation reaction to give
the allylzinc reagent in situ; in turn this reacts with benzylidene-
butylamine to give the secondary amine 4a in 97% yield.
Reaction with benzyl(1-phenylethylidene)amine generates 4b
in 67% yield, whilst the a,b-unsaturated imine, benzyl(3-
methylbut-2-enylidene)amine, reacts to give amine 4c in 90%
yield. The a-substituted imine benzyl(cyclohexyl)methylene-
amine also reacted in 63% yield to give 4d.
The authors thank the DFG (SFB 260 and Leibniz program)
for generous financial support, and the Royal Society for an
award (to P. J.) under the European Science Exchange
Programme.
Notes and references
Carbozincation reactions are also possible using this ap-
proach with masked organozinc reagents, indeed reaction of the
zinc alkoxide with trimethyl(prop-2-ynyloxy)silane at room
temperature gives, within 2 h, the 1,4-diene 5 in 74% yield after
hydrolysis (Scheme 4).
† Typical procedure: Preparation of 1-phenylbut-3-en-1-ol 2: A solution of
BunLi (2.71 mmol) in pentane (1.40
M, 1.94 ml) was added dropwise over
2 min to a stirred solution of 3-tert-butyl-2,2-dimethylhex-5-en-3-ol 1b
(500 mg, 2.71 mmol) in THF (4 ml) at 0 °C under argon. The resulting
solution was then stirred for 15 min and a solution of zinc bromide (610 mg,
2.71 mmol) in THF (2 ml) was added, followed by benzaldehyde (275 ml,
2.71 mmol). The reaction was allowed to warm to room temperature and
stirred for 1 h. Saturated aq. NH4Cl solution (15 ml) was added and the
resulting mixture was extracted with Et2O (3 3 15 ml). The combined
organic extracts were washed with brine (10 ml), dried and concentrated
under reduced pressure to give a crude residue, which was purified by
column chromatography on silica using 15% Et2O–hexanes as eluent to give
the desired alcohol 2 (356 mg, 89%) as a colourless oil.
(i) BuLi
(ii) ZnBr2
OH
HO
(iii)
But
But
OSiMe3
1b
5 74%
Scheme 4
1 W. R. Roush, in Comprehensive Organic Synthesis, ed. B. M. Trost, I.
Fleming and C. H. Heathcock, Pergamon, Oxford, 1991, vol. 2, pp.
1–53.
Although we had eliminated the problems associated with
Wurtz coupling, our reagents were not environmentally
friendly, generating 1 equiv. of zinc waste; consequently we
were delighted to discover that the reaction could be made to
function using catalytic amounts of zinc salts—reduction to 50
mol% gave the benzylic alcohol 2 in 95% yield after 6 h, whilst
further reductions to 10 mol% gave no loss in efficiency, with
the secondary alcohol being isolated in 92%, again within 6 h
(Scheme 5). However, all efforts to make the reaction catalytic
in base have to date been unsuccessful.
2 Y. Yamamoto and N. Asao, Chem. Rev., 1993, 93, 2207.
3 For reaction of Grignard reagents see: R. A. Benkeser and M. P. Siklosi,
J. Org. Chem., 1976, 41, 3212; R. A Benkeser, M. P. Siklosi and E. C.
Mozdzen, J. Am. Chem. Soc., 1978, 100, 2134; R. A Benkeser, W. G.
Young, W. E. Broxterman, D. A. Jones and S. J. Piaseczynski, J. Am.
Chem. Soc., 1969, 91, 132; F. Barbot and P. Miginiac, Bull. Chim. Soc.
Fr., 1977, 113.
4 F. Gerard and P. Miginiac, Bull. Chim. Soc. Fr., 1974, 2527; F. Gerard
and P. Miginiac, Bull. Chim. Soc. Fr., 1974, 1924.
5 (a) F. Barbot and P. Miginiac, Tetrahedron Lett., 1975, 3829; (b) P.
Miginiac and C. Bouchoule, Bull. Chim. Soc. Fr., 1968, 4675; (c) F.
Barbot and P. Miginiac, J. Organomet. Chem., 1977, 132, 445.
6 For reversible addition to imines, see A. Bocoum, D. Savoia and A.
Umani-Ronchi, J. Chem. Soc., Chem. Commun. 1993, 1542.
7 J. Nokami, K. Yoshizane, H. Matsuura and S. Sumida, J. Am. Chem.
Soc., 1998, 120, 6609.
8 P. Knochel, J. J. Almena Perea and P. Jones, Tetrahedron, 1998, 54,
8275.
9 These reagents were prepared from 3-tert-butyl-2,2,5-trimethylhex-
5-en-3-ol by NBS allylic bromination and displacement with the
appropriate zinc-copper reagent (ref. 11).
OH
(i) BuLi
OH
But
But
(ii) ZnBr2 (X mol%)
(iii) PhCHO
Ph
1b
2
100 mol% 89%
50 mol% 95%
10 mol% 92%
Scheme 5
10 A patent has been filed with Chemetall Gmbh (Frankfurt).
11 P. Knochel, M. C. P. Yeh, S. C. Berk and J. Talbert, J. Org. Chem.,
1988, 53, 2390.
A further advantage with this concept is the ability of these
reagents to tolerate functional groups, in a similar manner to
other organozinc reagents.8 The tertiary alcohols 6 and 7 were
Communication 8/05952G
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Chem Commun., 1998