trans-hydroalumination/alkylation: One-pot synthesis of trisubstituted allylic alcohols

Article abstract of DOI:10.1021/ol0613721

Described herein is a method of stereoselective synthesis of trisubstituted allylic alcohols by alkylation of alkenyl alanates, formed in situ through treatment of propargyl alcohols with Vitride (Red-Al). This technique represents the first of its kind to feature a trans-hydrometalation, and is particularly effective for the formation of 1,4-dienes. Applications involving primary, secondary, and tertiary alcohols are discussed, as well as limitations regarding both alkyne and electrophile components.

Full text of DOI:10.1021/ol0613721

ORGANIC
LETTERS
2
006
Vol. 8, No. 17
761-3764
trans-Hydroalumination/Alkylation:
One-Pot Synthesis of Trisubstituted
Allylic Alcohols
3
Neil F. Langille and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
tfj@mit.edu
Received June 5, 2006
ABSTRACT
Described herein is a method of stereoselective synthesis of trisubstituted allylic alcohols by alkylation of alkenyl alanates, formed in situ
through treatment of propargyl alcohols with Vitride (Red-Al). This technique represents the first of its kind to feature a trans-hydrometalation,
and is particularly effective for the formation of 1,4-dienes. Applications involving primary, secondary, and tertiary alcohols are discussed, as
well as limitations regarding both alkyne and electrophile components.
Alkyne hydrometalation reactions are among the most vital
and reliable methods of stereoselective alkene synthesis.
As part of ongoing research in our laboratories exploring
the synthetic utility of skipped polyenes, we required
1
5
Among these methods, those that utilize the transient
alkenylmetal species directly for carbon-carbon bond for-
mation are particularly powerful, resulting in highly substi-
tuted alkene products that may otherwise be accessible only
through tedious multistep synthetic transformations. Indeed,
a number of protocols have been developed to meet this
challenge, including some involving alkylation of activated
vinyl alanates.2 However, each of these hydroalumination/
alkylation methods incorporates the emerging carbon-carbon
bond cis to the hydrogen.4
trisubstituted alkenes bearing the hydrogen atom positioned
trans to a newly formed carbon-carbon bond. trans-Selective
hydroalumination reactions of alkynols are well-understood
transformations that have been frequently utilized since
6
Corey’s pioneering syntheses of farnesol and the C18
7
Cecropia juvenile hormone. However, previous studies
involved quenching the intermediate vinyl alanes exclusively
with H O, D O, or iodine. A logical extension of existing
,3
2
2
methods would be the direct alkylation of a vinyl alane or
alanate derived from a trans-hydroalumination of an alkynol.
Such a sequence would provide the requisite alkene structures
(1) Review: (a) Hudrlik, P. F.; Hudrlik, A. M. The Chemistry of the
Carbon-Carbon Triple Bond; Patai, S., Ed.; John Wiley and Sons: New
York, 1978; Part 1, Chapter 7, pp 199-273. See also: (b) Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
(4) For a similar carbometalation example with Me3Al, see: Hu, T.;
Schaus, J. V.; Lam, K.; Palfreyman, M. G.; Wuonola, M.; Gustafson, G.;
Panek, J. S. J. Org. Chem. 1998, 63, 2401-2406.
(
2) With i-Bu2AlH: (a) Lynd, R. A.; Zweifel, G. Synthesis 1974, 658-
6
2
2
1
1
59. (b) Eisch, J. J.; Damasevitz, G. A. J. Org. Chem. 1976, 41, 2214-
215. (c) Uchida, K.; Utimoto, K.; Nozaki, H. J. Org. Chem. 1976, 41,
215-2217. (d) Baba, S.; Van Horn, D. E.; Negishi, E. Tetrahedron Lett.
976, 17, 1927-1930. (e) Ziegler, F. E.; Mikami, K. Tetrahedron Lett.
984, 25, 131-134.
(5) (a) Heffron, T. P.; Jamison, T. F. Org. Lett. 2003, 5, 2339-2442.
(b) Simpson, G. L.; Heffron, T. P.; Merino, E.; Jamison, T. F. J. Am. Chem.
Soc. 2006, 128, 1056-1057.
(6) Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H. J. Am. Chem.
Soc. 1967, 89, 4245-4247.
(7) Corey, E. J.; Katzenellenbogen, J. A.; Gilman, N. W.; Roman, S.
A.; Erickson, B. W. J. Am. Chem. Soc. 1968, 90, 5618-5620.
(3) With LiAlH4: Sato, F.; Kodama, H.; Sato, M. J. Organomet. Chem.
1
978, 157, C30-C32.
1
0.1021/ol0613721 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/29/2006

Table 1. Optimization of trans-Hydrometalation/Alkylation
Table 2. trans-Hydrometalation/Alkylation: Electrophile
Scope
1
a
entry
MeLi (mol %)
Cu source (mol %)
2a: H quench
1
2
3
4
none
250
125
125
125
125
CuI‚P(OEt)3 (100)
CuI‚P(OEt)3 (100)
CuI‚P(OEt)3 (100)
CuI‚P(OEt)3 (50)
CuI‚P(OEt)3 (100)
CuCl (100)
0.5:1
2:1
8:1
1.3:1
>20:1
>20:1
b
5
b
6
a
Determined by 1H NMR analysis of crude reaction mixture after
b
aqueous workup. 300 mol % allyl bromide used.
directly from readily available alkyne starting materials, and
would complement existing i-Bu
2 4
AlH and LiAlH -based
strategies which involve cis-hydroalumination.
To test the viability of this concept, propargyl alcohol 1
8
was subjected to hydrometalation, with Vitride as the metal
hydride source. Representative examples are shown in Table
1
. Subsequent experiments identified Ziegler’s CuI‚P(OEt)
3
2
e,9
salt as ideal for this transformation, providing excellent
conversion to the desired diene 2a with only 100 mol %
allyl bromide used as the electrophilic component.
The stereochemical configuration of diene 2a was readily
determined to be E by nOe experiments, indicating that the
geometry of the trans-hydrometalated alkene was maintained
1b
through the alkylation step. In accord with related precedent,
we observed exclusive metal incorporation onto the carbon
distal to the hydroxymethyl substituent. It should be noted
that substoichiometric amounts of the copper salt (entry 4)
proved less effective, although the actual conversion suggests
a catalytic role for the copper species. Further, CuCl
displayed efficacy similar to CuI‚P(OEt) , indicating potential
3
application to substrates impeded by difficult chromato-
graphic separation from trialkyl phosphite residue. Inferior
additives included CuCN‚2LiCl, Fe(acac) , and InCl . Im-
3 3
portantly, full conversion was readily achieved when excess
allyl bromide was utilized (entries 5 and 6).
With successful reaction conditions in hand, we sought
to define the electrophile scope of this transformation (Table
2). A number of allyl halides proved effective in this
sequence, resulting in good yields of the desired 1,4-diene
structures (entries 1-4). Importantly, substitution on the
proximal or distal carbon of the electrophile was well
tolerated. Similarly, unactivated alkyl halides also partici-
pated in this reaction (entries 5 and 6), although full
conversion to trisubstituted alkene products remained elusive.
Additionally, although allene products dominated when
a
Standard conditions: (i) Vitride, Et2O (0.5 M), 0 °C to room
temperature, 6 h; (ii) MeLi, Et2O, 0 °C to room temperature, 1.5 h; (iii)
R-X, Cu source, THF (0.2 M), -78 °C to room temperature, 20 h.
Isolated yield after purification (SiO2 chromatography). Reflects ratio
b
c
1
1
of product: H quench (measured by H NMR analysis of crude reaction
mixture). d para-Formaldehyde used as the electrophile.
1
-bromo-2-butyne was utilized (not shown), propargyl
halides bearing silyl substituents on the alkyne resulted in
the formation of 1,4-enynes in moderate yield (entries 7 and
8
). Finally, para-formaldehyde proved competent in this
(8) Vitride is the common name for sodium bis(2-methoxyethoxy)-
aluminum hydride, also known as SMEAH or Red-Al.
protocol, resulting in installation of a hydroxymethyl sub-
3762
Org. Lett., Vol. 8, No. 17, 2006

Table 3. trans-Hydrometalation/Alkylation: Alkynol Scope
Scheme 1. trans- and cis-Hydrometalation/Alkylation
Sequences
a number of homopropargylic and bishomopropargylic
alcohols were ineffective. Despite these cases, this procedure
is well suited for a number of propargylic alcohol/electrophile
combinations.
Scheme 2. Limitations to trans-Hydrometalation/Alkylation
a
Standard conditions: (i) Vitride, Et2O (0.5 M), 0 °C to room
temperature, 6 h; (ii) MeLi, Et2O, 0 °C to room temperature, 1.5 h; (iii)
allyl bromide, Cu source, THF (0.2 M), -78 °C to room temperature, 20
b
h. Isolated yield after purification (SiO2 chromatography).
Having demonstrated this trans-hydroalumination/alkyla-
tion method on simple diene substrates, we applied this
protocol to the preparation of a more complex skipped 1,4,7-
dienyne structure. Accordingly, we synthesized allylic iodide
stituent on alkene 2i. In all cases, the alkene was generated
as a single regio- and stereoisomer.
A broad range of propargyl alcohols were also exposed
to this optimized reaction protocol (Table 3). Importantly,
complete regioselectivity was observed with a number of
primary, secondary, and tertiary alcohols, as well as two
diols, yielding products 3b and 3c (entries 2 and 3).
9
in two steps from the known compound 2,5-heptadiyn-1-
11
12
4
ol (8), via reduction with LiAlH in refluxing ether and
iodination under standard conditions (Scheme 3). Copper-
mediated reaction of 9 with the alkenyl alanate derived from
10
Interestingly, Me
the demonstration of divergent reaction pathways, where
employment of Vitride or i-Bu AlH resulted in formation
3
Si-substituted propargyl alcohol 4 allowed
1
, however, produced a mixture of products 10 and 10′, the
latter indicating that the alkylation reaction proceeded
through a S 2′ pathway. In this example, steric factors
2
N
of the complementary products 5 and 5′ (Scheme 1).
Two important limitations to this method deserve com-
ment. First, terminal alkynes were converted cleanly to the
corresponding 1,4-enynes (6) by this procedure, where simple
deprotonation/alkylation precluded reduction of the alkyne
function (Scheme 2, eq 1). Even forcing conditions (reflux,
conferred a minor effect on product distribution (51% isolated
yield of 10, 46% isolated yield of isomer 10′). This result
N
was not entirely unexpected, as S 2′ alkylation reactions of
13
organocopper reagents are well precedented. Despite this
mixture of products, the trans-hydrometalation/alkylation
sequence allowed the convergent synthesis of the target
dienyne 10 in four linear steps from commercially available
18 h) did not result in appreciable hydrometalation of these
substrates. A second limitation was observed in the attempted
hydrometalation of homopropargylic alcohols (eq 2), where
only minimal conversion was observed even after prolonged
reaction time. Indeed, Vitride-mediated hydrometalations of
14
material.
(11) Bushby, R. J.; Whitham, G. H. J. Chem. Soc. B 1970, 563-569.
(12) Aebi, J. D.; Deyo, D. T.; Sun, C. Q.; Guillaume, D.; Dunlap, B.;
Rich, D. H. J. Med. Chem. 1990, 33, 999-1009.
(
13) Reviews: (a) Magid, R. Tetrahedron 1980, 36, 1901-1930. (b)
(
9) Nishizawa, Y. Bull. Chem. Soc. Jpn. 1961, 34, 1170-1178.
Krause, N.; Gerold. A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186-284.
(14) Alkynol 1 was synthesized in three steps from 3-butyn-1-ol. See
the Supporting Information for details.
(10) For synthesis and trans-hydrometalation of alkynol 4, see: Jones,
T. K.; Denmark, S. E. Org. Synth. 1986, 64, 182-188.
Org. Lett., Vol. 8, No. 17, 2006
3763

Scheme 3. Synthesis and Alkylation Reaction of Iodide 9
Scheme 4. Synthesis of Alkenyl Silane Analogue 13a
a
Cp* ) pentamethylcyclopentadienyl.
We hypothesized that a second substituent on the distal
alkene carbon of the allylic iodide would promote exclusive
alkylation on the R-carbon, yielding a single dienyne isomer.
stereoselective formation of skipped polyene-containing
compounds. Investigations into the usefulness of these
products are currently underway, and the results of these
studies will be reported in due course.
N
Therefore, to suppress S 2′ displacement, we initiated the
synthetic route illustrated in Scheme 4. Trost’s Ru-catalyzed
15
trans-hydrosilylation and iodination afforded allylic iodide
2, representing a C3-silyl substituted congener of iodide 9.
1
Acknowledgment. We thank Dr. Graham L. Simpson
Gratifyingly, iodide 12 proved well-suited for the trans-
hydrometalation/alkylation protocol, producing compound 13
in 77% yield as a single 1,4,7-dienyne isomer. Products of
(
(
GlaxoSmithKline) for helpful discussions, and Dr. Li Li
MIT Department of Chemistry Instrumentation Facility,
which is supported in part by the NSF (CHE-9809061 and
DBI-9729592) and the NIH (1S10RR13886-01)) for obtain-
ing mass spectrometric data for all compounds. We thank
the National Institute of General Medical Sciences for support
of this work (GM-72566).
S
N
2′ displacement were not observed in this experiment.
In summary, we have developed a one-pot trans-hydroalu-
mination/alkylation sequence that affords trisubstituted allylic
alcohols as single geometric isomers in a highly controlled
fashion. Although best suited for simple activated electro-
philes, this new technique represents the first carbon-carbon
bond forming method of its kind to incorporate a trans-
hydrometalation and has proven quite effective for the
Supporting Information Available: Full experimental
procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(
15) (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644-
7655. (b) Chung, L. W.; Wu, Y.-D.; Trost, B. M.; Ball, Z. T. J. Am. Chem.
Soc. 2003, 125, 11578-11582.
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