Vanadium-Catalyzed Coupling of Allenols with Electrophilic Halide Sources for the Formation of α-Halo-α′,β′-unsaturated Ketones

Article abstract of DOI:10.1021/acs.orglett.9b00195

A vanadium-catalyzed coupling of allenylic alcohols with electrophilic halide sources to form α-halo-α′,β′-unsaturated ketones is described. The process proceeds through a metal enolate formed from the 1,3-transposition of an allenol that is initiated by

Full text of DOI:10.1021/acs.orglett.9b00195

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Vanadium-Catalyzed Coupling of Allenols with Electrophilic Halide
Sources for the Formation of α‑Halo-α′,β′-unsaturated Ketones
Barry M. Trost,* Jacob S. Tracy,† and Tas Yusoontorn†
Department of Chemistry, Stanford University, 333 Campus Drive, Stanford, California 94305, United States
S
* Supporting Information
ABSTRACT: A vanadium-catalyzed coupling of allenylic
alcohols with electrophilic halide sources to form α-halo-
α′,β′-unsaturated ketones is described. The process proceeds
through a metal enolate formed from the 1,3-transposition of
an allenol that is initiated by a cheap and earth-abundant
vanadium oxo catalyst. Fluorine, chlorine, and bromine
electrophiles can be utilized, and the resulting products can
give rise to the introduction of nitrogen, oxygen, sulfur, and
iodine nucleophiles α to the ketone through substitution chemistry.
he α-halo-α′,β′-unsaturated ketone motif, especially those
T
adorned with fluorine, have begun to receive significant
attention in the patent literature as key intermediates in the
synthesis of biologically active targets.1 However, their
synthesis is generally plagued by multistep reaction sequences
and/or the need to use specialized reagents that are often
difficult to access.2 While the direct electrophilic halogenation
of α,β-unsaturated ketones is an appealing method, the use of
enolate chemistry is particularly challenging due to issues
associated with overhalogenation that occur because of the
increased acidity of α-protons following the first halogenation.3
While judicious choice of stoichiometric strong base and the
use of cryogenic reaction temperatures can help to limit
overhalogenation, most approaches rely upon the use of
stoichiometric silyl or boron activating agents that typically
necessitate cryogenic reaction temperatures in addition to
stoichiometric strong base.4
Figure 1. Proposed catalytic cycle.
Our group has developed a very mild and regioselective
method for the in situ, catalytic generation of enolates starting
from allenyl5 or propagyl6 alcohols that negates the need for
stoichiometric activation, strong base, and cryogenic reaction
temperatures. In this method, which can be termed
“sigmatropic functionalization”, a vanadium oxo complex
catalyzes the 1,3-transposition of the alcohol to form a metal
enolate that can undergo trapping by a series of electrophiles in
preference to a competing simple protonation pathway that
would lead to the Meyer−Schuster product. Given the mild
reaction conditions and high functional group tolerance
previously observed, we wondered whether the vanadium
enolates generated from readily available allenyl alcohols7
would be able to successfully trap electrophilic halide sources
to generate α-halo-α′,β′-unsaturated ketones and overcome
the issues of regioselectivity and overhalogenation typically
observed in base-promoted processes (Figure 1).
expensive gold catalyst, and the inability to install halides other
than fluorine (Scheme 1).8 Use of our group’s earth-abundant
vanadium catalyst would provide an economical method for
the generation of a wide range of α-halo-α′,β′-unsaturated
ketones.
We began our studies with allenol 1. Treatment with 5 mol
% of OV(OSiPh3)3, 1.2 equiv of N-fluorobenzenesulfonimide
(NFSI), and 3 equiv of freshly ground sodium carbonate in
1,2-dichloroethane (DCE) at 65 °C for 19 h resulted in clean
formation of monofluorinated product 2 in 68% isolated yield
(Table 1, entry 1). No difluorinated adduct 3 was observed,
and the remaining material could be accounted for by
formation of the Meyer−Schuster product. Increasing the
amount of electrophile was beneficial, with 2 equiv of NFSI
yielding the desired product in 84% yield (entry 2). The
Previous attempts to utilize allenylic alcohols as precursors
for α-halo-α′,β′-unsaturated ketones have been plagued by the
need to utilize a three-step reaction sequence, the use of an
Received: January 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00195
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Use of Allenols for the Synthesis of α-Halo-α′,β′-
Scheme 2. One-Pot Control Experiment
unsaturated Ketones
in DCE at rt until complete conversion to the Meyer−Schuster
product was observed. At this point, NFSI and freshly ground
sodium carbonate were added to the reaction flask, and the
mixture was allowed to stir at 65 °C for 23 h. Under these
conditions, only 3% of fluorinated product 2 was obtained.
This control clearly supports the reaction pathway presented in
Figure 1.
Table 1. Optimization for the Formation of α-
Fluoroenones
a
With a set of optimized conditions in hand (Table 1, entry
3), the scope of the process was explored (Scheme 3). Steric
Scheme 3. Scope of the Vanadium-Catalyzed Fluorination
a
of Allenols
b
entry
base
X
temp (°C)
Y
yield of 2 (%)
1
2
3
4
5
6
7
8
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
Cs2CO3
NaHCO3
MgO
3
3
2
1.05
2
2
2
2
2
65
65
65
65
65
65
65
rt
1.2
2
2
2
2
2
2
2
2
68
84
80
26
c
b
60 (10)
d
b
19 (4)
11
22
28
e
9
Na2CO3
65
a
Experiments run at a 0.2 mmol scale. The base was freshly ground
b
before use. Isolated yield of 2. If observed, isolated yield of 3 is given
in parentheses. The remainder of the mass balance could be
c
d
accounted for by Meyer−Schuster product. 80% conversion. 25%
e
conversion. Reaction run in toluene.
amount of base could be reduced to 2 equiv without any
significant impact on yield (entry 3). Further reducing the
amount of base to 1.05 equiv led to a significant increase in the
formation of the Meyer−Schuster product (entry 4). Choice of
base was very important to the outcome of the reaction.
Switching from sodium carbonate to potassium carbonate
resulted in lower conversion as well as the formation of 10% of
the difluorinated adduct 3 (entry 5). Cesium carbonate led to
an even lower conversion (25%) and also resulted in the
formation of a small amount of difluorinated adduct 3 (entry
6). While full conversion was obtained using sodium
bicarbonate and magnesium oxide, the desired product was
obtained in only 11 and 22% yield, respectively, with the
remainder of the material being composed of the Meyer−
Schuster product (entries 7 and 8). The ability of the reaction
to proceed at rt with magnesium oxide while requiring elevated
temperatures of 65 °C to obtain reactivity with carbonate bases
indicates that the carbonates are likely acting as Lewis bases to
the vanadium catalyst, reducing the Lewis acidity of the
catalyst and impacting its ability to ionize the allenylic alcohol
during the 1,3-transposition. Finally, solvent was found to play
a large role in the outcome of the reaction, with the use of
toluene yielding the desired product in just 28% yield.
a
Reactions performed at 0.2 mmol scale. The base was freshly ground
b
before use. In all cases, >20:1 E/Z olefin geometry is observed. 10
mol % of OV(OSiPh3)3. 5 mol % of OV(OSi[p-ClC6H4]3)3 used. 10
mol % of OV(OSi[p-ClC6H4]3)3 used. Reaction run in acetonitrile-
d6. NMR yield based upon mesitylene internal standard. 7.5 mol % of
c
d
e
f
OV(OSiPh3)3.
bulk on R2 was well tolerated, with an isopropyl group at that
position resulting in only a slight decrease in yield compared to
a methyl group (4). Both electron-deficient aryl (5 and 6) and
electron-rich aryl (7−9) and heteroaryl (10) groups were
tolerated at R1, although a modest decrease in yield is generally
seen in the case of electron-rich aryl groups. The functional
group tolerance of the reaction was found to be remarkably
high for a process that involves the trapping of a metal enolate
with an electrophilic halide under Lewis acidic and Brønsted
basic conditions. An allenol containing a methyl alkynyl ketone
underwent the desired transformation, with the alkynyl ketone
acting as neither an acceptor for the vanadium enolate nor a
nucleophile toward the NFSI (6). Silyl-protected alcohols
A control experiment was performed to ensure that the
fluorination reaction was not simply the result of a vanadium-
catalyzed Meyer−Schuster rearrangement followed by a
general base-promoted fluorination (Scheme 2). In this
experiment, the allenol and vanadium oxo catalyst were stirred
B
DOI: 10.1021/acs.orglett.9b00195
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
remained intact, as did free alcohols (8 and 9). Distal alkenes,
silyl protected alkynes, and terminal alkynes were all well
tolerated and showed no undesired fluorine incorporation (7,
11, and 12). Aryl substitution at R1 was not required for
reactivity. Using the more electron-deficient OV[OSi(p-
ClC6H4)3]3 catalyst, a phenethyl-substituted allenol gave the
desired product in good yield (13). In addition to secondary
allenylic alcohols, tertiary allenols also participated cleanly to
give trisubstituted double bonds (14−16). When a cyclic
allenol is utilized, exocyclic enones can be produced (15).
Likewise, when the two R1 substituents are sterically
differentiated, the resulting enone is formed exclusively with
the thermodynamic E-double-bond geometry (16).
Both secondary and tertiary allenyl alcohols successfully
participated in the process (Scheme 4A, 17, 19−22). Both
Scheme 4. Scope of the Vanadium-Catalyzed Chlorination
a
and Bromination of Allenols
We next turned our attention to expanding the scope of
electrophiles to include electrophilic chlorine sources. Treating
allenol 1 under the previously optimized fluorination
conditions (Table 1, entry 3) but switching the electrophile
from NFSI to N-chlorosuccinimide (NCS) resulted in the
formation of a 1:2 mixture of the desired chlorination product
17 and the overhalogenated product 18 (Table 2, entry 1).
Table 2. Optimization for the Formation of α-
a
Chloroenones
a
Reactions performed at 0.2 mmol scale. The base was freshly ground
b
before use. In all cases, >20:1 E/Z olefin geometry is observed. 5 mol
% of OV(OSi[p-ClC6H4]3)3 used. 15 mol % of OV(OSiPh3)3 used.
c
b
entry
base
solvent
X
temp (°C)
yield of 17 (%)
aryl and alkyl substitution at R1 were well tolerated. As was the
case with fluorination, no halogen incorporation into a
terminal alkyne was observed (20). Monoalkyl substitution
at R1 required use of the more electron-deficient OV(OSi[p-
ClC6H4]3)3 catalyst (21). Of note, benzyl substitution at R2
was well tolerated, and no overhalogenation was observed
(22). This result highlights the mild nature of these reaction
conditions, as the benzylic nature of the α proton of 22 makes
it particularly activated toward enolization that would lead to
overhalogenation. The corresponding bromination process
could also be performed utilizing slightly modified conditions:
1.2 equiv of dibromo-Meldrum’s acid as the electrophilic
bromine source in DCE at room temperature (see the
Supporting Information, Table S1). The scope of bromination
was equally broad, with secondary and tertiary allenyl alcohols
participating (Scheme 4B, 23−27). Once again, no undesired
halogenation of a pendant methyl alkynyl ketone was observed
under the mild reaction conditions (24).
b
1
2
3
4
5
6
7
8
Na2CO3
MgO
MgO
MgO
MgO
MgO
MgO
MgO
MgO
DCE
DCE
DCE
DCE
DCE
DCE
THF
PhMe
PhMe
2
3
2
2
1.2
1.0
1.0
1.0
1.0
65
65
45
rt
45
45
45
45
45
20 (46)
96
92
88
93
94
51
93
84
c
9
a
Experiments run at a 0.2 mmol scale. The base was freshly ground
before use. Isolated yield of 17. If observed, the isolated yield of 18 is
given in parentheses. The remainder of the mass balance could be
accounted for by Meyer−Schuster product. Reaction run at 1.0 M.
b
c
Believing the dichlorinated product to be arising from a general
base-promoted chlorination of desired product 17, we
switched the base from sodium carbonate to a milder
magnesium oxide base. Under these conditions, the desired
product was isolated in 96% yield and with no evidence of
overchlorination (entry 2). Lowering the reaction temperature
from 65 to 45 °C had no impact on reactivity (entry 3). While
the reaction could be run at rt with only a very small reduction
in yield, 45 °C was picked as the optimized temperature due to
the observation of consistently higher yields at this slightly
elevated temperature (entry 4). In the case of chlorination, the
amount of electrophile could be dropped all the way down to
1.0 equiv without impacting yield (entries 5 and 6). While use
of THF resulted in the formation of significant amounts of
Meyer−Schuster product (entry 7), use of toluene gave nearly
identical results as that of DCE (entry 8). Finally, attempts to
increase the reaction concentration from 0.5 to 1.0 M resulted
in a small 9% reduction in isolated yield (entry 9).
To showcase the scalability of the reaction, the fluorination
of 1 was run on a gram scale, and its corresponding
chlorination was run at 1 mmol scale (Scheme 5). No impact
on yield was observed, but the heterogeneous nature of the
Scheme 5. Gram-Scale Fluorination and Millimole Scale
Chlorination Reactions
To determine the scope of the process, a series of allenols
were subjected to our optimized conditions (Table 2, entry 8).
C
DOI: 10.1021/acs.orglett.9b00195
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
reaction mixture required an increase in the amount of base
utilized to minimize formation of the Meyer−Schuster product
at the larger scale.
The unique ability of our method to access α-bromo ketones
was exploited to obtain a wide range of α-heteroatom
substituted α′,β′-unsaturated ketones. Starting from bromo
ketone 23, treatment with nitrogen, oxygen, sulfur, and iodine
nucleophiles all led to the desired SN2 products (28−31) in
high yields (Scheme 6).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bmtrost@stanford.edu.
ORCID
Barry M. Trost: 0000-0001-7369-9121
Jacob S. Tracy: 0000-0001-9261-7865
Author Contributions
†J.S.T. and T.Y. contributed equally.
Notes
Scheme 6. SN2 Reactions To Form α-Heteroatom α′,β′-
Unsaturated Ketones
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
J.S.T. acknowledges support from the Franklin Veatch
Memorial Award.
■
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In summary, we have developed an efficient method for the
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00195.
Experimental details, characterization data, and spectra
(PDF)
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D
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