Allene synthesis via C-C fragmentation: Method and mechanistic insight

Article abstract of DOI:10.1021/ja906189h

A new method of allene synthesis is described. Suitably functionalized vinyl triflates undergo fragmentation to give allenes in high yield. Computational and experimental data provide a mechanistic framework for allene formation and the complementary form

Full text of DOI:10.1021/ja906189h

Published on Web 08/25/2009
Allene Synthesis via C-C Fragmentation: Method and Mechanistic Insight
Robert V. Kolakowski, Madhuri Manpadi, Yue Zhang, Thomas J. Emge, and Lawrence J. Williams*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received July 23, 2009; E-mail: lawjw@rci.rutgers.edu
The rich structural and reactive properties of allenes complement
the chemistry of alkenes and alkynes and render them uniquely
versatile synthetic intermediates.1-4 Allenes are also present in
many natural products5 and are relevant to certain biosynthetic
pathways.6 The importance of allenes in synthesis is attenuated by
the lack of methods for their preparation and strategies for their
application. The most generally useful stereoselective methods for
allene synthesis are the SN2′ displacement of propargylic esters by
organocuprates and rearrangement of propargyl diazenes.1,7 In the
course of our studies,8 we identified instances where available
approaches are not expedient and, consequently, developed a new
entry to allenes via C-C fragmentation, as described below.
Olefin-forming C-C fragmentation (1f2, Figure 1) was rec-
ognized in natural product degradation studies, for example by
Prelog,9 and significantly developed by Grob.10 Recently, Dudley
reported that ꢀ-triflyl-R,ꢀ-unsaturated ketones also undergo efficient
C-C fragmentation to give alkynes (3f4).11 This fragmentation
strategy has not been applied to allene synthesis. Allenes have been
accessed by a variety of anion-initiated and thermolytic fragmenta-
tion reactions of suitably functionalized alkenes.7b,12-15 We
wondered whether vinyl triflates would fragment to give the
corresponding allenes via a framework that complements the Grob
and Dudley reactions (5f6) and whether this transformation could
be used to prepare allenes stereospecifically.
preparation of compounds 8 and 9, fragmentation appears rate
limiting for at least some substrates. For example, when a reaction
mixture of 7 with CeCl3 (2.5 equiv) and PhLi (2.5 equiv) at -78
°C was quenched after 10 min, the nonfragmented tertiary alcohol
10 was isolated in 20% yield (Table 1, see inset). These data
demonstrate that allenes form rapidly from carbon nucleophile
addition/vinyl triflate fragmentation for suitable substrates.
a
Table 1
a 1.0 equiv of PhLi, 45 min, THF -78 °C - rt, 1 h. b 1.3 equiv of
NaHMDS, 1.3 equiv of PhCOCH3, THF, -78 °C, 15 min. c 1.4 equiv of
LiHMDS, 1.3 equiv of EtOAc, THF, -78 °C, 15 min. d 1.1 equiv of
nBuLi, 1.2 equiv of dithiane, THF, -78 °C-rt, 1 h. e 1.1 equiv of
nBuLi, 1.2 equiv of TMSCCH, THF, -78 °C-rt, 1 h. f 3.0 equiv of
CeCl3, 3.0 equiv of PhMgBr, THF, -78 °C-rt, 1 h. g 3.0 equiv of
CeCl3, 3.0 equiv of nBuLi, THF, -78 °C-rt. h 3.0 equiv of nBuLi, 3.0
equiv of dithiane, THF, -78 °C-rt.
Figure 2 shows the conversion of other vinyl triflates to allenes
and that stereogenic allenes form stereospecifically. Exposure of
carvone-derived silyl ether 11 to fluoride led to rapid and clean
formation of allenic aldehyde. For convenience, the reaction mixture
was then treated with reducing agent, which gave the corresponding
acyclic alcohol 12. Excess phenyl magnesium bromide smoothly
added to cyclopentenone 13 to give allenic alcohol 14. Ten-
membered cyclic allene 16 was prepared by fluoride-induced
fragmentation from bicyclic silyl ether17,18 and was obtained as a
single isomer. The reaction efficiency for these more complex
substrates is primarily a reflection of triflate hydrolysis as a
competing side reaction. Thus, the precursor used to prepare 15
was also isolated from the reaction mixture (see 21). The yield of
16, based on recovered 21, was 85%.
Figure 1. Fragmentation to alkenes, alkynes, and allenes.
Addition of carbon nucleophiles to the carbonyl of 7 generated
a transient alkoxide that induced fragmentation/allene formation
(Table 1). Use of approximately stoichiometric quantities of
nucleophile gave allenic ketones 8a-e. Use of excess reagent gave
allenic alcohols 9a-c. Organolithium and Grignard reagents,
including alkyl, aryl, and alkynyl nucleophiles, smoothly added and
induced fragmentation. Ketone and ester enolates also added as
did dithiane anions. Use of cerium chloride was necessary to
suppress competitive enolate formation of this substrate in instances
where hard carbon nucleophiles were used.16 Addition of alkoxides
or lithiated amines as nucleophiles for carbonyl addition, which in
principle would give ester or amide products, gave recovered 7 or
complex mixtures (not shown). As suggested by the selective
The fragmentations are stereospecific. Highly enantioenriched
acyclic vinyl triflates 17 and 19 fragmented upon treatment with
fluoride to give the corresponding enantioenriched allenes. Mosher
ester analysis showed that in this fragmentation allene 20 was not
formed from 17f18 and allene 18 was not formed from 19f20.18
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12910 J. AM. CHEM. SOC. 2009, 131, 12910–12911
10.1021/ja906189h CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
We close with observations regarding the mechanism of frag-
mentation (Figure 3). In principle, anionic O-triflyl piperidone 22
could give an allene of type 23 or an alkyne of type 24 (cf. Dudley
fragmentation). The corresponding trifluoroacetate salt was treated
with excess PhMgBr in diethyl ether at -20 °C.18,19 Only 23 was
observed after 5 min (>20:1, 23:24, 5% yield, 5% conversion). As
the reaction proceeded, 24 became evident and the ratio of 23:24
gradually decreased. After 1 h the ratio of 23:24 was 3:1 (82%
yield, 82% conversion). The increase in alkyne is readily understood
in terms of the known propensity of terminal allenes to isomerize
to terminal alkynylides under strongly basic conditions.1 These data
demonstrate that fragmentation of this system favors allene over
alkyne formation.
with the anionic nitrogen and, as a result, allene formation becomes
the kinetically more facile pathway.
We have shown that suitably functionalized vinyl triflates serve
as precursors to allenes by way of direct fragmentation or as part
of an addition/cascade reaction. Mechanistic studies provide a
framework for understanding this reaction in relation to other known
modes of fragmentation, and as such, these findings complement
methods of alkene and alkyne synthesis that rely upon C-C
fragmentation. This work is complementary to allene synthesis
methods that use alkyne precursors, provides access to highly
enantioenriched allenes, including cyclic allenes, and is stereospecific.
Acknowledgment. Financial support from Merck & Co. is
gratefully acknowledged.
Supporting Information Available: Complete ref 20a, synthetic
methods, and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Figure 2. Vinyl triflate-to-allene fragmentation.
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(18) See Supporting Information for details.
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Figure 3. Fragmentation and mechanistic insight of vinyl triflate 22.
Why does the allene form faster than the alkyne? Computed
transition states were found for allene and alkyne formation using
B3LYP/6-31G+(2d,2p).20 The δ∆H‡calc for the computed transition
structures TSI and TSII was 2.39 kcal/mol, favoring allene
formation.21,22 Moreover, the optimized ground state energy of 25
indicates, by NBO analysis, a greater positive charge on C5 than
on C1.20a,23 Hence the calculated transition structures are consistent
with a rationale wherein the triflate polarizes the carbon framework.
Despite proper stereoelectronics for both pathways, the sp3 network,
being more polarized than the sp2 network, interacts more strongly
(21) Caution must be exercised in light of the known difficulties in calculating
allene and alkyne ground states. (See: Wodrich, M. D.; Corminboeuf, C.;
Schleyer, P. V. R. Org. Lett. 2006, 8, 3631. ). The good correlation between
∆H‡calc and experiment is likely due in part to the degree of separation that
exists between the transition states and the product ground states.
(22) Transition states for chlorine and fluorine substituted piperidines were
calculated and compared with the bromine substituted TS I (see Supporting
Information). The enthalpy of the reaction for the series was-F 13.5 kcal/
mol,-Cl 9.2 kcal/mol, and-Br 8.3 kcal/mol, consistent with leaving group
ability.
(23) Weinhold, F. Landis, C. Valency and Bonding; Cambridge University Press:
Cambridge, U.K., 2005.
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