Direct and stereospecific synthesis of allenes via reduction of propargylic alcohols with Cp2Zr(H)Cl

Article abstract of DOI:10.1021/ja8035527

Allenes can be synthesized via the direct S_N2′ addition of hydride to propargylic alcohols. Previous examples of this approach, however, have involved harsh reaction conditions and have suffered from incomplete transfer of central chirality to

Full text of DOI:10.1021/ja8035527

Published on Web 07/25/2008
Direct and Stereospecific Synthesis of Allenes via Reduction of Propargylic
Alcohols with Cp2Zr(H)Cl
Xiaotao Pu and Joseph M. Ready*
Department of Biochemistry, UniVersity of Texas Southwestern Medical Center, 5323 Harry Hines BouleVard,
Dallas, Texas 75390
Received May 16, 2008; E-mail: joseph.ready@utsouthwestern.edu
Table 1. Effect of Additives on the Reduction of Propargylic
Hydrozirconation of alkynes with the Schwartz reagent
[Cp2Zr(H)Cl] provides vinyl zirconium species in a stereospecific
and regioselective fashion. These intermediates can react with a
variety of electrophiles or participate in cross-coupling reactions.1
The least hindered vinyl zirconium product usually dominates under
either kinetically or thermodynamically controlled conditions.2
However, we recently discovered that lithium alkoxides can alter
the regioselectivity of these reactions. In particular, hydrozirconation
of terminal propargylic alcohols (1, X ) H) occurs with complete
selectivity for the branched products in the presence of BuLi and
ZnCl2 (Scheme 1, 1 f 2).3,4 In contrast, when internal propargylic
alcohols were treated under similar reaction conditions, substantial
quantities of disubstituted allenes were isolated in addition to
branched allylic alcohols (Scheme 1, 1 f 3). Here we demonstrate
that this direct synthesis of allenes is high-yielding, general, and
stereospecific.
Alcohols with Cp2Zr(H)Cl
yielda
(%)
ee
(%)
entry
base
equiv
solvent
1
2
3
MeLi + ZnCl2
Me2Zn
Me2Zn
Me2AlCl
None
MeLi
1/6
1
1
1
-
1
1
1
1
THF
THF
<5
15
58
-
-
benzene
benzene
benzene
benzene
benzene
benzene
toluene
toluene/THFe
64
78
93
95
90
98
98
90
4
∼50
5b
6
40
15
7
8
NaH
<20
EtMgCl
EtMgCl
Et2Zn + ZnCl2
70d
9
70d
72d
10c
0.5/0.5
Scheme 1
a Yield determined by 1H NMR except as indicated. b 2 equiv of
Cp2Zr(H)Cl. c 1.6 equiv of Cp2Zr(H)Cl. d Isolated yield. e 30:1 Tol/THF.
zirconium, lithium, and sodium alkoxides reacted sluggishly but
selectively (entries 5-7). Finally, we identified two conditions that
provided the allene in good yield and excellent optical purity:
deprotonation of 1 with either EtMgCl or EtZnCl (formed in situ
from Et2Zn and ZnCl2) in toluene prior to hydrozirconation (entries
9, 10). Further studies revealed that the two protocols were
complementary. In general, for allenes bearing two sp3-hybridized
substituents, optimal results were obtained when the propargylic
alcohol was deprotonated with EtMgCl. As indicated by the
difference between entries 9 and 10 in Table 1, lower ee was
observed when EtZnCl was used to deprotonate these substrates.
For allenes connected to one or two sp2-hybridized carbons,
deprotonation of the propargylic alcohol with EtZnCl was preferred.
The use of only 1 equiv of EtZnCl was critical as racemization of
the allene was observed in the presence of excess zinc salts.10
Additionally, the use of EtMgCl with aryl- or vinyl-substituted
substrates led to over-reduction of the allene. For both procedures,
toluene was found to offer the optimal balance of reactivity and
selectivity; halogenated solvents displayed higher reactivity, but
the allenes were isolated with lower ee. Finally, under optimized
conditions, little or no allylic alcohol was isolated, indicating that
the regioselectivity of the hydrometalation is high.
Allenes can be prepared via SN2′ addition to propargylic alcohols
or their derivatives.5 Conceptually, hydride addition is one of the
most attractive routes to disubstituted allenes. Indeed, traditional
hydride reagents have been used,6 and transition metal catalyzed
methods have been developed as well.7 Unfortunately, SN2 addition
often competes with SN2′ addition. Furthermore, when scalemic
propargylic alcohols are used as substrates, substantial deterioration
of optical purity accompanies reduction.6 An alternative approach,
developed by Myers and co-workers,8 involves a Mitsunobu
reaction between a propargylic alcohol and a sulfonyl hydrazine.
The allene is generated through a sigmatropic elimination of N2.
While stereospecific and high-yielding in many cases, this protocol
requires an unstable hydrazine and all the accoutrements of a
Mitsunobu reaction; additionally, it has not proved generally
effective for allylic, benzylic, or tertiary propargylic alcohols.9
To address some limitations of existing methodology we
optimized the reaction of internal propargylic alcohols with
Cp2Zr(H)Cl. Initial experiments utilized alcohol 1a (98% ee) and
revealed that both the yield and optical purity of the product
depended strongly on the base and solvent (Table 1). For example,
under conditions originally optimized for terminal propargylic
alcohols,3 conversion was low (entry 1). We observed increased
reactivity in hydrocarbon solvents, but inorganic salts still affected
both the selectivity and efficiency of the reaction. With zinc or
aluminum bases, 3a was formed in reasonable yields but in
unacceptable enantiomeric excess (entries 3, 4). Alternatively, the
Having identified conditions to convert propargylic alcohols into
enantiomerically enriched allenes, we evaluated the generality of
the reduction (Figure 1). Benzyl and silyl ethers were tolerated under
the reaction conditions (3a-3c), as were acetals and aminals
(3d-3f). Neither carbamates (3f, 3h, 3r) nor silyl esters (3m)
interfered with the reduction. Various aromatic and heteroaromatic
rings remained intact. Additionally, we detected no hydrozirconation
of olefins (3g, 3j, 3l) or other alkynes (3o) present in the substrates.
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10874 J. AM. CHEM. SOC. 2008, 130, 10874–10875
10.1021/ja8035527 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
the corresponding vinyl metal species formed from internal prop-
argylic alcohols (4) eliminates rapidly to form allene. We interpret
this difference as a manifestation of A1,3 strain as indicated in eq
1. Furthermore, substrates with weaker C-O bonds (e.g., benzylic
alcohols) suffer elimination even in the context of terminal alkynes
(see 3u).
In summary, we have identified two complementary sets of
conditions that generate allenes in high yield and with high
stereochemical purity. The method provides access to dialkyl-, aryl-
alkyl-, and diaryl-substituted allenes in excellent enantiomeric or
diastereomeric ratios. This approach provides direct and stereospe-
cific access to allenes from free propargylic alcohols and therefore
represents an attractive alternative to nonselective reductive methods
and substitution of propargylic esters.
Acknowledgment. We thank Donghui Zhang for key initial
experiments. Financial support was provided by NIGMS (R01-
GM074822) and the Welch Foundation.
Supporting Information Available: Complete experimental details
and characterization data for new compounds. Time-course experiments
related to racemization studies. This material is available free of charge
via the Internet (http://pubs.acs.org).
References
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Figure 1. Synthesis of allenes from propargylic alcohols. aIsolated yields.
Allenes are drawn such that the original alkyne substituent (R2) is on the
right. See Supporting Information for experimental details. b1 equiv of
EtMgCl; 0.2 M in toluene; 1.1 equiv of Cp2ZrHCl. c0.5 equiv each of Et2Zn,
ZnCl2; 0.2 M in toluene/THF 30:1; 1.6 equiv of Cp2ZrHCl. dValues in
parentheses represent ee or dr of starting material.
Finally, we have used the hydrozirconation to prepare silyl-
substituted allenes (3i), allenes derived from tertiary alcohols (3v),
and terminal allenes (3u), although the latter showed some evidence
of polymerization under the reaction conditions.
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About half of our substrates were optically active11 and in every
case studied to date, the allenes were isolated with nearly the same
optical purity as the starting propargylic alcohols (Figure 1). The
absolute stereochemistry of the allenes was assigned based on
optical rotation.12 The conversion of central chirality to axial
chirality is consistent with a cis addition of Zr-H to the alkyne
followed by a syn elimination of Cp2ZrO (eq 1).13
(10) See Supporting Information for details.
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R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
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assigned according to: Lowe, G. Chem Commun. 1965, 411.
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The difference in reactivity between terminal and internal
propargylic alcohols is noteworthy. Our previous study demon-
strated that the vinyl metal species derived from terminal propar-
gylic alcohols is sufficiently stable to be trapped with various
electrophiles (Scheme 1).3 In contrast, we demonstrate here that
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