Chromium(III) catalyzed synthesis of allenes from propargyl derivatives via a carbometalation-elimination sequence

Article abstract of DOI:10.1016/j.tetlet.2005.01.143

The syn-carbometalation/syn-elimination of propargyl substrates to form allenes has been achieved using cationic chromium(III) catalysts activated by alkylaluminums. The mechanism and scope of this transformation are presented.

Full text of DOI:10.1016/j.tetlet.2005.01.143

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2345–2349
Chromium(III) catalyzed synthesis of allenes from propargyl
derivatives via a carbometalation–elimination sequence
Gary A. Molander* and Erin M. Sommers
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Received 13 October 2004; revised 26 January 2005; accepted 26 January 2005
Abstract—The syn-carbometalation/syn-elimination of propargyl substrates to form allenes has been achieved using cationic
chromium(III) catalysts activated by alkylaluminums. The mechanism and scope of this transformation are presented.
ꢀ 2005 Elsevier Ltd. All rights reserved.
During the past two decades, our laboratory has con-
centrated research efforts on adapting organometallic,
specifically organolanthanide, complexes for small mole-
cule synthesis. Despite the wide array of attractive
transformations that have been achieved with organo-
lanthanide catalysts,1 several inherent limitations exist.
The highly Lewis acidic organolanthanide complexes de-
mand strict exclusion of moisture and oxygen and are
intolerant of many functional groups, including terminal
alkynes. In addition, the lanthanides catalyze intramo-
lecular carbon–carbon bond-forming reactions but only
following an initial hydrometalation step. This sequence
forbids a single-step intermolecular carbometalation
reaction. To expand our organometallic catalysis pro-
gram and circumvent the obstacles of the lanthanide
methods, we desired a new catalyst system that would
display increased tolerance for functional groups using
straightforward benchtop manipulations leading to a
carbometalation rather than hydrometalation event.
We envisioned known chromium olefin polymerization
catalysts (1–3) as viable alternatives to the lanthanides
and other group 4 carbometalation catalysts.2,3 As later
transition metals, chromium complexes were expected to
be easier to synthesize and handle and more tolerant of a
wider range of functionality than the lanthanides and
group 4 metal systems. We began this program by
exploring the utility of chromium(III) complexes in the
carbometalation of alkynes. Although we were able to
effect the desired transformation (Eq. 1), organochro-
mium complexes also proved to have low tolerance for
functionality. In addition to this shortcoming, the chro-
mium(III) complexes showed little regioselectivity with
internal alkynes. However, we were able to synthesize
several 1,1-disubstituted alkenes successfully in moder-
ate yields using chromium(III) complexes. Despite their
limitations, a curious result prompted us to explore the
utility of these complexes for the synthesis of allenes.
When propargyl alcohol derivatives were subjected to
the reaction conditions, allenes were produced instead
of the expected alkene products (Eq. 1). This transfor-
mation contrasts starkly to the carbometalation reaction
reported by Negishi and co-workers with a-heterosubsti-
tuted substrates.3b Because allenes are present in many
natural products and serve as useful synthons for syn-
thetic transformations, the efficient synthesis of the allen-
yl functional group is an attractive pursuit.4a,b Many
syntheses of allenes have been reported. However, the
most widely used methods stem from organocuprate dis-
placement of propargylic leaving groups.4c Therefore,
we sought to explore the mechanism and scope of this
unanticipated reaction. Herein we report the synthesis
of stereodefined allenes through a syn-carbometalation/
syn-elimination sequence.
CrCl2
CrCl2
Keywords: Chromium(III) complexes; Allenes; Propargylic com-
pounds.
N
R
N
R
*
Corresponding author. Tel.: +1 215 573 8604; fax: +1 215 573
7165; e-mail: gmolandr@sas.upenn.edu
See Supplementary material for summary.
1, R = Me
2, R = -(CH2)4
3
-
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.143

2346
G. A. Molander, E. M. Sommers / Tetrahedron Letters 46 (2005) 2345–2349
be eliminated based on our results, our previous carbo-
metalation of alkynes suggests a carbometalation occurs
followed by a syn elimination. Only one other example
of a syn-addition/syn-elimination sequence has been
reported in the organocuprate literature.7
5 mol% 1
2 equiv Me3Al
CH2Cl2
R
R
R
R = alkyl
OR
ð1Þ
R
An enantiomeric excess of 17% is not synthetically use-
ful. Therefore, we screened leaving groups that main-
tained the stereochemical integrity in the formed
allene. Table 1 highlights the results of this study. A gen-
eral trend emerges from the results; the poorer the leav-
ing group, the better the retention of stereochemical
integrity from substrate to product. For example, one
of the poorest leaving groups studied, tert-butyldimeth-
ylsilanoxy (entry 7), provides the highest optical yields.
The optical yield is also susceptible to changes in the
equivalents of Me3Al used. The highest optical yields
were obtained when only 1 equiv of Me3Al was used.
The excess of Me3Al may act as a Lewis acid, promoting
ionization of the leaving group in an SN1-type reaction.
Additionally, the temperature of the reaction affects the
outcome. Each leaving group showed poorer optical
yields when the temperature was raised beyond ambient
temperature. Even the tert-butyldimethylsilanoxy group
suffered from a dramatic loss of ee when the temperature
was raised to 55 ꢁC.
R
R = alkoxy
At the outset of our studies, 1,4-bisacetoxy-2-butyne, 4,
was subjected to 5 mol% of catalyst and 2 equiv of
Me3Al to yield 1-acetoxy-2-methyl-2,3-butadiene in
73% yield (Eq. 2).5 Allene product formation transpires
via substitution of an acetoxy leaving group. This substi-
tution could occur via several mechanistic pathways: a
syn-carbometalation/syn-elimination, a syn-carbometa-
lation/anti-elimination, an anti or syn SN20 reaction, or
a non-stereospecific SN1 reaction. We ventured to ex-
plore the details of this transformation with the reaction
shown in Table 1.
5 mol% 1
2 equiv Me3Al
AcO
CH2Cl2, rt
ð2Þ
OAc
OAc
4
5
Before proposing a mechanism, one other aspect bears
discussion. Surprisingly, the regiochemistry of organo-
metallic insertion on the alkyne is opposite to that ob-
served during our studies of the carbometalation of
non-directing, internal, unsymmetrical alkynes. In the
present transformation, the chromium with its bulky
substituents are placed at the more sterically congested
terminus of the alkyne. This observed phenomenon sug-
gests that the alkoxy substituent coordinates to the chro-
mium, directing it to the proximal carbon of the alkyne.
When the acetate derivative 6a (entry 1) was subjected to
5 mol% of 1 and 1.5 equiv of Me3Al, a chiral non-race-
mic allene 7a was formed in 17% ee based on chiral GC
analysis. To delineate the absolute stereochemistry of
the allene, we compared the chromium catalyzed reac-
tion with an organocuprate reaction. We subjected the
enantiomeric acetate 6b to organocuprate reaction con-
ditions known to afford 36% of a mixture of anti SN20
product (57% ee) and the reduced allene. The allene iso-
lated from this reaction was identical to that formed in
the chromium catalyzed reaction of 6a.6 These results
indicate that the reaction catalyzed by chromium likely
To rationalize the observed results, we propose the
mechanism shown (Fig. 1). Activation of 1 to give com-
plex A is a well-documented and accepted first step in
the olefin polymerization literature.8 Complex A, pos-
undergoes syn-carbometalation/syn-elimination or
a
syn SN20 reaction. While a syn SN20 mechanism cannot
Table 1. Leaving group studies
7-9 mol% 1
RO
Me3Al
*
CH2Cl2
*
TBSO
TBSO
6a (*=R)
6b (*=S)
7a (*=R)
7b (*=S)
Entry
R, configuration
Catalyst loading (mol%)
Me3Al (equiv)
Time
Temperature (ꢁC)
Optical yielda (% ee)
1
2
3
4
5
6
7
8
Ac, R
Bn, R
Bn, R
7
8
1.0
1.5
1.7
1.8
1.8
2.0
1.0
1.5
5.5 h
19 h
0 to rt
rt
19 (17)
56 (50)
36 (32)
0
8
2.5 h
30 min
30 min
9 h
55
rt
CO2Me, S
CO2NHPh, S
CO2NHt-Bu, S
TBS, R
10
10
10
7
rt
85 (73)
n/ab
rt
24 h
rt
55
96 (85)
67 (60)
TBS, R
9
6.5 h
a Optical yield = (ee product/ee substrate) · 100.
b The carbamate was removed under the reaction conditions.

G. A. Molander, E. M. Sommers / Tetrahedron Letters 46 (2005) 2345–2349
2347
no a-oxygenated substituent is present, the alkenylchro-
mium species is transmetalated to aluminum yielding an
alkenylaluminum intermediate, regenerating the active
species. However, when an a-oxygenated substituent is
present, a syn b-elimination occurs to release the allene
product and generate a chromium alkoxide intermediate
(D). This intermediate can be transformed to the active
species (A) in a manner analogous to that of the initial
precatalyst 1.
+
Me3Al
Cr
Cl
N
R'
Cl
1
Cr
OR
N
Me2AlCl2- or
Me2AlOR
D
+
+
Me
R'
After determining the optimal leaving group, the catal-
yst loading was optimized and the scope of the reaction
was explored. It should be noted that the reaction does
not proceed when the chromium(III) catalyst is absent
from the reaction mixture. Table 2 lists the results of
expanding this method to other substrates (entries 4–
10) and organometallic nucleophiles (entries 1–3, 11).
Different trialkylaluminum species, such as Et3Al and
i-Bu3Al, were able to effect the transformation in high
optical yield by transferring an ethyl and iso-butyl
group, respectively. To widen the utility of the transfor-
mation, Et2Zn was substituted for an alkylaluminum
species. The reactivity of Et2Zn was significantly attenu-
ated compared to the alkylaluminums. For example,
good leaving groups, such as acetate and methyl carbon-
ate, were necessary to achieve good yields of the allene
product. In contrast to Me3Al, Et2Zn reacted with the
TBS derivative in less than 10% yield (based on GC)
to yield a 1:2 mixture of allene and the regioisomeric
carbometalated alkene. In addition, the benzyloxy
Cr
Cr
N
Me
N
RO
A
C
RO
R'
+
Cr Me
N
R'
RO
B
Figure 1. Proposed catalytic cycle.
sessing an open coordination site, is poised to coordi-
nate an alkyne to give complex B. The alkyne then
undergoes a carbometalation reaction through a syn-
addition to give intermediate C. At this point, when
Table 2. Chromium catalyzed synthesis of allenes
Entry
Substrate (% ee)
Product
R–Ma
Me3Al
% Yield (% ee)
83 (86)b
TBSO
TBSO
1
7
TBSO
6 (88)
2
3
6 (90)
Et3Al
82 (85)
79 (82)
TBSO
TBSO
8
6 (90)
i-Bu3Al
9
TBSO
4
Me3Al
11a = 20 (81)
11b = 4
OTBS
11a
11b
10 (84)
AcO
5
i-Bu3Al
n/ac
13
12
(continued on next page)

2348
G. A. Molander, E. M. Sommers / Tetrahedron Letters 46 (2005) 2345–2349
Table 2 (continued)
Entry
Substrate (% ee)
Product
R–Ma
Me3Al
% Yield (% ee)
OAc
6
54
15
OBn
OBn
C8H17
14
16
O
O
HO
7
8
Me3Al
Et3Al
71
C8H17
O
17
AcO
19a = 19
19b = —d
OTBS
OTBS
OTBS
18
19a
19b
OAc
9
Me3Al
Et3Al
80
C10H21
C10H21
20
21
TBSO
Me
10
23a = 50e
23b = <1
OTBS
TBSO
TBSO
TBSO
TBSO
22 (90)
23a
23b
AcO
11
24 (90)
8
Et2Zn
59 (14)
a Reagents and conditions: 7–10 mol% 1, 1.0–2.0equiv Me3Al, CH2Cl2, rt.
b The alkene produced by the regioisomeric carbometalation was observed by GC/MS and crude NMR (<5%) but never isolated.
c Isolated in toluene due to the volatility of the product.
d Compound 19b is contaminated by an unidentifiable side product.
e Compound 23a could not be resolved by chiral GC.
derivative gave one turnover of the alkene product (by
GC). The diminished ee of the acetate derivative, regard-
less of the nucleophiles, indicates that the reaction
proceeds through a non-stereospecific ionization/substi-
tution pathway when the leaving group is readily
ionized. However, the regiospecificity of the Et2Zn
reactions is puzzling, and the actual mechanism is likely
more complicated than we propose; perhaps a bimetallic
species defines the active catalyst.
In conclusion, we have successfully synthesized allenes
from propargylic tert-butyldimethylsilyl ethers in mod-
est yields and high optical purity. The reaction appears
to proceed through a syn-carbometalation/syn-elimina-
tion sequence. Because allenes represent a useful class
of compounds both as natural products and synthons
for further transformations, efforts from our laboratory
continue to focus on the use of transition metal catalysis
to synthesize chiral, non-racemic allenes with broad sub-
strate scope.
Similar to our original studies, little functionality can be
present in the substrate. For example, a simple phenyl
ring (entry 4) initiates side reactions that lower the iso-
lated yield significantly. Entry 6 highlights an example
of the formation of a terminal allene. Because the prod-
uct allene is achiral, using the less atom economical tert-
butyldimethylsilanoxy leaving group is unnecessary.
Entries 8 and 9 illustrate how the steric environment
also affects the outcome of the reaction. The bulky
cyclohexyl group hinders allene formation, and only
the Reetz product is observed.9 In contrast, the dimethyl
analogue (entry 8) gives the allene as the minor product.
Finally, we attempted to access a chiral non-racemic
1,1,3-trisubstituted allene (entry 10). In addition to a
modest yield of the allene product, we isolated <1% of
the regioisomeric carbometalation product.
Acknowledgements
We are grateful for financial support from NIGMS
(GM 48580) and the Merck Research Laboratories. In
addition, E.S. is funded by a Department of Education
GAANN Fellowship.
Supplementary data
Full experimental details are available. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2005.01.143.

G. A. Molander, E. M. Sommers / Tetrahedron Letters 46 (2005) 2345–2349
2349
Catalyzed Cross-Coupling Reactions; De Meijere, Armin,
Diederich, Francois, Eds., 2nd ed.; Wiley-VCH: Weinheim,
2004.
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