Pure & Appl. Chem., Vol. 64,No. 3, pp. 387-392, 1992.

Printed in Great Britain.

@ 1992 IUPAC

Stereochemical aspects on the formation of chiral

allenes from propargylic ethers and epoxides
Alex Alexakis
Laboratoire de Chimie des Organo-ElCments,associC au CNRS UA 473 Universitt
P. et M. Curie, 4,Place Jussieu ,F-75252 Paris Cedex 05, France

Abstract - Chiral propargylic ethers react with organocopper reagents to afford

optically active allenes by a u addition to the triple bond followed by an anti p-
elimination of the resulting alkenyl copper species. However, the same reaction, run
with a Grignard reagent and a catalytic amount of copper (I) salt affords allenes
through an anti or svn process. The crucial step is the p-elimination of the
intermediate alkenyl metal species, which is of & type with FWa and of type
with RMgCJ. Propargylic acetates, which also afford allenes in this reaction, but
through a Cu(II1) intermediate, are not sensitive to this "halogen effect". By close
analogy to ethers, propargylic epoxides react with Grignard reagents and catalytic
amount of Cu(1) salt, leading to a-allenic alcohols. The reaction is highly
diastereoselective and its stereochemical outcome can be fully controlled.The
diastereomer, probably arising through an addition-elimination mechanism, is better
obtained with RM&l and copper (I) bromide, whereas the anti diastereomer is best
obtained with RM& and a complexed copper (I) salt.

The synthesis of chiral allenes 3 is often done by reaction of an organocopper derivative with a chiral
propargylic substrate 1 (where X is a good leaving group) (ref 1). Mechanistically, these reactions are
thought to proceed through a CuIII intermediate 2 resulting from an anti S"2 nucleophilic attack of the CuI
atom. This intermediate collapses by reductive elimination to allene 3 with retention of configuration.(ref 2)
The overall result is an anti process (Scheme I) :

Scheme I

X = halide, OAc, OCOOR, OSOR, OS02R, OPO(OR)p

During our work on the carbocupration of alkynes (ref 3), we had the opportunity to demonstrate that
the formation of dibutyl allene 6 from propargylic ether 4 follows a different path. A syn addition first takes
place producing an alkenyl copper reagent 5Cu , which can be trapped by various electrophiles. This alkenyl
copper species undergoes, then, a p-elimination to afford allene 6 (ref 4)(Scheme 11). The nature of this p-
elimination was studied with a chiral substrate 4 and was found to be a (ref 5). The overall process
occured with >96%chirality transfer (or optical yield) :
Scheme II
Bu

BuMgBr
CUB~,ZP(OE~)~
Et20
-
BuCu,MgBr2,2P(OEt)3
4,)~
4 BU Cu
OMe ~

4 O 0 , 30min
Y

5cu
U-
6';;
>-<:' Bu

H
6
ANTI

Some years later, we needed to prepare large amounts of chiral dibutyl allene 6 and we thought more
convenient to use another optically pure propargylic ether. Indeed, Johnson et al (ref 6 ) ,reported an elegant
synthesis of propargylic ethers, such as 7, bypassing the need of preparing first an optically active
propargylic alcohol (Scheme III). Such an approach is particularly attractive since it allows also the recovery
of the chiral diol, used as auxiliary.
387

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388 A. ALEXAKIS

Scheme 111

- -pH
Bu Bu
l)TiCI, BU~CU" BU
Me3Si-SiMe3 + o&
,
H
6
.
However, repetition of the experiment described in Scheme 11, gave, largely, the undesired regioisomer 8
instead of the expected allene (Scheme IV). Since Gaudemar et al (ref 7) have shown that the same allene
synthesis can be carried out with a Grignard reagent and a catalytic amount of copper salt, we also tried this
procedure. Indeed, we obtained, this time, the desired dibutyl allene 6 but, surprisingly, through a SYI-I
overall process ! (Scheme IV):

Thus, the catalytic process, seems to be sensitive to various factors which not only affect the
regioselectivity of this reaction but also its stereoselectivity.In order to have a closer view of these factors,
we studied in more details all the parameters of this reaction on a more simple substrate : propargylic ether 4 .
It was reported, in 1979, by Claesson et al (ref 8), that the catalytic version of the reaction shown in
Scheme I1 occured with a low chirality transfer, giving an allene of 16% optical purity, through an overall
anti process. It was also postulated that extensive racemization took place, by the organocopper reagent (ref
F o r copper (0) (ref lo), also found in these reactions, through a SET process. Our first idea was that
stabilization of the reacting organocopper species by appropriate ligands should avoid such racemization.
Indeed, as shown in Scheme V, on the scale, trivalent phosphorus ligands allow, now, an excellent chirality
transfer with an optical yield of 90% for the anti process. Tributyl phosphine is known to be a better ligand
than methyl phosphite (ref 11) and the results corroborate this fact. Thus, the catalytic procedure allows,
now, a very efficient synthesis of optically active allenes through an process.

Scheme V

BuMgBr + 5%CuBr,nL +
Et2O
-40°-OoC, l h
*
Bu
>-<: ANTI
4 OMe H 6

Optical yield % 16 43 55 72 80 90

I
Ligand none 2 P(OE1)s P(NMe2)3 2 P(NMe2)3 PBu3 2 PBu3

The surprise came when we varied the nature of the copper salt and most strikingly, when we changed
the halogen of the Grignard reagent. We found that BUM@always lead to the allene 6 , whereas B u M d
allways lead to the a allene 6 ! More impressively, as shown in Scheme VI, BuMgk gave highly variable
results, depending only upon the catalytic amount (5%) of the copper (I) salt, giving the s y allene ~ ~ 6 with
CuCN (0.y. 41%) or the & one with CuBr (0.y. 43%). These results are summarized on the three scales in
Scheme VI
All these reactions proceed through an addition-eliminationmechanism, as in the stoichiometric case
(Scheme 11) since it is possible to isolate, after hydrolysis at an intermediate stage of the reaction, -30% of 5-
methoxy-E,6-~ndecene.The addition step is still a carbocupration ; it is, therefore, the type of p-elimina-
tion of the alkenyl-metal intermediate that determines the overall stereochemistry. The amount, of this

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 Stereochemical aspects of the formation of chiral allenes 389

Scheme VI
BuMgX + 5%CuX,2P(OEt)3 + +,H
OMe
Bu EtZO

-4O"-OOC, l h - uB
:u-H
6

BuMgCl
SYN
-
CuX
0.y. 60 54 49
I
Br I
l l
CN
33
I
CI
0
I ANTI

BuMgBr
SYN
-
CUX
O.Y.
41
I
CN
22
I
C I I
13
I
0
I
43
I
Br
ANTI
*

BuMal
0
- 51 58 63 80
SYN 0.Y.
t I I I I I ANTI c

CUX CI CNI Br

intermediate (30%)compared with the 5% of CuX, indicates that this intermediate should be mainly an
alkenyl Grignard reagent. We were, thus, led to study the nature of the p-elimination of alkenyl Grignard
reagents of type 5Mg in the absence of any copper salt.
As shown in Scheme VII, the iodination of alkenyl copper reagent 5Cu (Scheme 11) gave, in 70%
yield, the iodide 9 (ref 4), which, after metal-halogen exchange, affords the lithium reagent 5Li.
Transmetallation to the Grignard reagent by addition of MgI2 or MgC12 salts lead respectively to the anti or to
the ~ 1 allene
4 6 . In a simplified view it may be admitted that the small size and the electronegativity of the
chlorine atom allow a cyclic transition state where the greater Lewis acidity of MgC12 (ref 12) plays a role in
favor of a syll elimination. On the other hand, the size of the iodine atom does not allow such a cyclic
arrangement and the elimination becomes predominently (Scheme VII).

Scheme VII
Bu SYN
0.y. 35%
H
6

Bu
mn
O.Y. 65%
H
6

Whatever the case, it is synthetically important to be able, with the same substrate, to change the stereo-
chemical course of this reaction. Improvement of the optical yield of the syn process was, thus, required.
Reaction of B u M g a with propargylic ether 4, under 5% CuBr catalysis, gave the syn allene 6 with 41%
optical yield. When CuBr,2P(OEt)j was used, the optical yield climbed to 60%.However, a better ligand
such as PBu3 gave worse results (0.y. 24%). Thus, the effect of PBu3 was not, as we initially thought, to
prevent racemization of the formed allene ; it intrinsically favors an elimination. Finally we found that in
situ generation of more MgC12 has a strongly beneficial effect. Thus, when the reaction was run with 5%
CuBr, 1 eq. of TMSCl and in a mixture of Et2O/pentane (50/50), a 76%optical yield of syn allene 6 could be
attained.
Considering the various aspects of all the factors that affect the stereochemical course of this reaction,
the following general explanation may account for all the above results. The Grignard reagent undergoes,
first, a transmetallation to a copper species which adds to the triple bond of the propargylic ether leading to an
alkenyl copper complex 5Cu (Scheme VIII). This copper intermediate 5Cu may undergo a p-elimination

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390 A. ALEXAKIS

which is of & type as shown in the stoichiomemc case (Scheme II). However, 5Cu must transmetallate
also to an alkenyl Grignard species 5Mg since at an intermediate stage of the reaction 5Cu + 5Mg amount to
30%of the reaction products with only 5% Cu(1) salt present. According to the nature of the halogen of the
Grignard intermediate 5Mg a or an anti p-elimination takes place (Scheme VIII). The rate of the
exchanges 5Cu + 5Mg and the kinetics of the p-elimination (the irreversible step) of 5Cu or 5Mg
determine the final proportion of the w or the anti allene 6.We have already noted the accelerating effect of
a good ligand in the p-elimination of the alkenyl copper intermediate 5Cu (ref 4). Thus, a good ligand such
as PBu3 will favor the p-elimination of 5Cu and therefore the anti process, rather than the transmetallation to
5Mg which, with C1 as halogen, would favor the w process.

Scheme Vlll

BuMgBr + CuX - Bu"Cu"

Bu
ANTI

Bu
\=(
MgX
.Bu - \=( - Bu

H
SYN

5Mg bMe

It was of interest to check if this intriguing "halogen effect" of the Grignard reagent was operative in
other organocopper reaction, particularly those involving a different mechanistic pathway. Propargylic
acetates, as well as other propargylic substrates having a good leaving group, are known to afford allenes
through a Cu(II1) intermediate following an overall d process (Scheme I). The reaction was also known to
occur with a catalytic amount of Cu(1) salt (ref 8). When we performed this reaction with acetate 10, under
our best conditions, we obtained the & allene 6 with an excellent optical yield (Scheme IX). Thus, a
reaction that proceed through a Cu(1II) intermediate is always an & substitution, whatever the halogen of
the Grignard reagent RMgX.

Scheme IX
Hex MgBr
10% CuBr / Et20
- Hex ANTI
0.y. 79% ref8
H

BuMgCl Bu ANTI
/
O.Y. 96%
5% CuBr,2P(OEt):, H
10 Et2O 6

This different behaviour of the two mechanisms (addition-eliminationor Cu(II1) intermediate) can be
used for the determination of the mechanism of other reactions in organocopper and organomagnesium
chemistry. One such interesting case is that of propargylic epoxides. Ortiz de Montellano (ref 13) has shown,
first, that these compounds react with lithium diorganocuprates to afford anti a-allenic alcohols 10 (ref 14).
As major by-product he obtained an unsubstituted allenol 11. Such reduction by-products are typical of a
Cu(1II) intermediate (Scheme X).

Scheme X

\ cu'

..
On the other hand, Oehlschlager (ref 15) reported that the metal counterion of the cuprate reagent may
strongly affect the stereoselectivity of this reaction (Scheme XI), a result which is more compatible with an

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 Stereochemical aspects of the formation of chiral allenes 391

addition-elimination process instead. If one considers that epoxides are a special kind of ethers, then a
"halogen effect" could influence the steric course of the reaction.
Scheme XI

R H H $ . f ~ ~ 2 ~ ~
FM
b + >-<HOH ref 15
ANTI l3 SYN
R~CU~~JX 40 60
R2CuLi 96 4

R H

addition-elimination ?
H20

&OH

Our first experiments were done with ethynyl cyclohexene oxide 12 as model epoxide. Reaction with
Bu2CuLi, under the conditions described by Ortiz de Montellano (ref 13) gave three allenols : the reduction
product 13 (33%), and two alkylation products 14A and 14B (54% ; 81/19) distinguishable by l3C NMR
or by G.C. after acetylation. In view of the known propensity of organocopper reagents to promote
preferential & SN' (ref 16) substitution, we ascribed to the major isomer 14A the anti configuration
(Scheme XII).

12 13 14A 14B

Next, the catalytic procedure (ref 17) was examined under our best anti conditions. Optimization
studies allowed us to obtain the anti allenol 14A in 74% yield without any trace of the allenol 14B.
These conditions (RMgBr + 5% CuBr,2PBug + epoxide in Et2O) were then applied to a variety of
propargylic cyclohexene oxides and different Grignard reagent with an almost equal success (Scheme XIII).
On the other hand, the process was also optimized to give the allenol 14B in quantitative yield and
88% selectivity. These conditions (RMgC1t 5% CuBr + 1 eq. TMSCl + epoxide in Et20/pentane) were also
very effective on a variety of epoxides and different Grignard reagents (Scheme XIII).

Scheme Xlll

-
R H, Me, Ph, SiMea
R' = Me, Bu, iPr, tBu, Ph
R'Mgx
+ Yield : 65-100%

ANTI SYN
ANTI process : 95-100%
SYN process : 75-96%

We also found that monosubstituted propargylic epoxides sych as 12 can react with a Grignard reagent
without copper salt (!), although the reaction becomes very slow. With RMgCl and RMgBr the reaction is
highly selective. This procedure is the preffered one for the transfer of Me and Ph groups.
It was of interest to check if this stereochemical control was also operative in the acyclic series. To this
end, we synthesized the isomeric epoxides 15E and 152 in a very high state of purity (>99%). These two
epoxides were expected to give the same diastereomer when reacted under respectively anti and condi-
tions. The same should be true if we reverse the experimental conditions as summarized in Scheme XIV. The

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392 A. ALEXAKIS

results are in complete agreement with our expectations. In all cases high selectivities (>85%) and yields
(>84%) are obtained. It should, however, be noted that, with trans epoxide 15E the selectivities are higher,
particularly for the syn process.

Scheme XIV
SYN

Allenic alcohols, such as the ones shown above, are quite interesting synthons in that they contain
highly condensed stereochemical information (ref 1). Thus, they may be oxidized on the allenic skeleton to
afford, among others, cyclopentenone derivatives (ref 18), or stereoselectively alkylated (ref 19). Beyond the
synthetic interest of being able to obtain highly selectively either diastereomer starting from the same
propargylic substrate, these reactions reveal the subtility of behaviour of of “classical”organometallics such
as Grignard reagents.

Acknowledgements The work presented herein represents part of the thesis of Dr Ilane Marek (see ref 5,20
and 21) whose enthousiasm and perseverance made it all possible. My thanks are also expressed to my friend
and colleague Dr Pierre Mangeney for our continuing collaboration in this research.

REFERENCES

1. a) S.R. Landor : “TheChemistry of the Allenes”, Academic Press,NewYork, 1982

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