α-fluoroallenoate synthesis via N-heterocyclic carbene-catalyzed fluorination reaction of alkynals

Article abstract of DOI:10.1021/acs.orglett.5b03615

The first catalytic α-fluoroallenoate synthesis is described. With a suitable combination of N-heterocyclic carbene precatalyst, base, and fluorine reagent, the reaction proceeded smoothly to yield a wide range of α-fluoroallenoates with excellent chemose

Full text of DOI:10.1021/acs.orglett.5b03615

Letter
pubs.acs.org/OrgLett
α‑Fluoroallenoate Synthesis via N‑Heterocyclic Carbene-Catalyzed
Fluorination Reaction of Alkynals
Xu Wang, Zijun Wu, and Jian Wang*
Department of Pharmacology and Pharmaceutical Science, School of Medicine, Tsinghua University, Beijing 117543, China
S
* Supporting Information
ABSTRACT: The first catalytic α-fluoroallenoate synthesis is
described. With a suitable combination of N-heterocyclic
carbene precatalyst, base, and fluorine reagent, the reaction
proceeded smoothly to yield a wide range of α-fluoroallenoates
with excellent chemoselectivity. These substituted α-fluori-
nated allenoates have been synthesized for the first time, and
they are versatile synthetic intermediates toward other useful fluorine-containing building blocks.
t has become increasingly evident that fluorine has a
I
significant impact on drug discovery.1 The incorporation of
fluorine in a potential drug can lead to a dramatic change in the
molecule’s properties. For example, fluorine can increase the
efficacy of the drug and can make the administration process
convenient.1 Consequently, the insertion of fluorine into organic
molecules has drawn long-standing attention from medicinal
chemists. In addition, allenes have also been proven to be highly
valuable synthons in preparative organic chemistry due to their
ability to undergo a variety of transformations.2 We speculated
that, if the fluorine atom can be installed into the allene scaffold, a
variety of fluorinated functional molecules could be feasibly
accessed through a late-stage transformation (Figure 1b).
Although significant progress has been made toward the
production of C−F bonds, there remains a great need for further
development of novel methodology for the construction of
diversified functional molecules.3 For example, the efficient
incorporation of fluorine into the allenoate backbone remains
unknown. In the process of proving the hypothesis, several
challenges may be encountered: (1) both α and γ positions of the
N-heterocyclic carbene (NHC)−trienolate are nucleophilic; (2)
instead of C−F bond formation, the NHC−trienolate can
undergo protonation at the α position to afford a nonfluorinated
product.
NHCs are well-known for their unique capability to reverse the
polarity of aldehydes.4,5 On this basis, the Rovis group developed
an elegant example of NHC-catalyzed directed hydration of α,β-
unsaturated aldehydes, leading to a variety of α-fluoro carboxylic
acids.6 In 2012, Sun and co-workers reported a catalytic efficient
synthesis of β,γ-unsaturated α-fluoroesters catalyzed by NHCs.7
More recently, the Wang8a and the Sun groups8b independently
disclosed a progress regarding the NHC-catalyzed α-fluorination
of aliphatic aldehydes for the synthesis of α-fluoroesters, amides
and thioesters (Figure 1). In brief, the above reactions afforded α-
fluoro carbonyls through an NHC-catalyzed Csp3−F bond
forming process. To the best of our knowledge, the example of
Figure 1. (a) Methods for allenoate synthesis. (b) Our strategy for α-
fluorinated allenonate synthesis.
We first undertook the screening of achiral carbene precursors,
including thiazoliums, imidazoliums, and triazoliums. Results
from our catalyst evaluation are shown in Table 1. Although cat.
III and IV10 indicated moderate to good reactivity, low levels of
chemoselectivity were obtained (entries 3 and 4). However, cat.
2
NHC-catalyzed Csp −F bond forming process has not yet been
reported by far. With this goal, we set out to efficiently construct
Received: December 21, 2015
α-fluoroallenoates9 by using a catalytic umpolung strategy.9
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a c
,
Table 1. Optimization of the Reaction Conditions
Table 2. Scope of Symmetric Germinal Disubstituted
Alkynals
a
b
entry NHC
ROH
base
“F”
F/H
2 (%)
1
I
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
K2CO3
F-5
F-5
F-5
F-5
F-5
F-5
F-5
F-5
F-5
F-5
F-5
F-5
F-5
F-5
N.D.
N.D.
1:1
<5 (2a)
<5 (2a)
40 (2a)
74 (2a)
71 (2a)
<5 (2a)
23 (2a)
60 (2a)
43 (2a)
32 (2a)
91 (2b)
98 (2b)
61 (2c)
<5 (2d)
2
II
III
IV
V
VI
V
V
V
V
V
V
V
V
K2CO3
3
K2CO3
4
K2CO3
3:1
5
K2CO3
8:1
6
K2CO3
N.D.
2:5
7
Cs2CO3
NaHCO3
NaOMe
PhCO2Na
NaHCO3
NaHCO3
NaHCO3
NaHCO3
8
>19:1
1:1
9
10
11
12
13
14
1:1
>19:1
>19:1
>19:1
N.D.
d
EtOH
iPrOH
nBuOH
a
Reaction conditions: A mixture of 1a (0.10 mmol), catalyst (20 mmol
a
Reaction conditions: alkynal 1(0.5 mmol), cat. V (0.1 mmol), NFSI
%), fluorine reagent (0.15 mmol), base (0.2 mmol) in MeOH (1.0
b
b
(1.0 mmol), NaHCO3 (1.0 mmol), EtOH (5.0 mL), rt, 12 h. Yield in
parentheses was obtained at a scale of 5.0 mmol.
mL) was stirred at room temperature for 12 h. Isolated yield after
c
flash chromatography. Under standard conditions, other F-reagents
d
(F-1 to F-4) gave no desired product 2a or 2b. F-5 (0.2 mmol %).
approach (2b, 2e−2j). In addition, two specific α-fluoroalle-
noates, built on scaffolds of azabicyclooctane and adamantine,
had been successfully constructed (Table 2, 2k and 2l, 95% and
92%, respectively). Moreover, introduction of symmetric acyclic
γ-disubstituted alkynals could be tolerated without loss in yield or
chemoselectivity (2m−2o). A large scale synthesis of 2h was also
examined and provided a good chemical yield (Table 2, 80%,
data in parentheses).
Lastly, we turned our attention to unsymmetric γ-disubstituted
alkynal. It should be noted that this new protocol has yet to be
successfully implemented with this type of alkynals, bearing
unsymmetric disubstitution at the alkynal γ-position. Using
alkyl−alkyl γ-disubstituted alkynals, high conversions were
observed (4a−4f, 85−95%). With respect to functional group
tolerance, protected alcohols and aldehydes are readily tolerated
using these mild reaction conditions (4g and 4h, 61% and 78%,
respectively). Importantly, we have found that this new protocol
can be readily applied to alkyl−aryl γ-disubstituted alkynals (4i,
65%). Moreover, γ-monosubstituted alkynals were also found to
be suitable partners and afforded the corresponding products in
good chemical yields (4j and 4k, 60% and 62%, respectively).
Having successfully examined a series of commonly used
alkynals, we next directed our standard fluorination conditions
to more complex substrates. Remarkably, an array of cyclic γ-
disubstituted alkynals was successfully fluorinated, affording the
V11 provided 2a in a 71% yield and also with a ratio of 2a/3a =
8:1 (entry 5). Based on these findings, we further investigated
other reaction parameters, such as base and fluorination reagent,
in order to achieve a better chemoselectivity and a higher
chemical yield. Pleasingly, NaHCO3 was found to be an ideal
base for this α-fluorination study (entry 8, ratio of 2a/3a > 19:1).
Examination of a range of fluorination reagents revealed that N-
fluorobenzenesulfonimide (NFSI) was superior with respect to
reaction efficiency. The use of other fluorine reagents, such as N-
fluoropyridine salts (F−1, F−2, and F−3) and Selectfluor (F−
4), resulted in poor yield or no reaction. Further improvement
was achieved via the use of EtOH (a replacement of MeOH) and
2 equiv of NFSI (product 2b, 98% yield, >19:1 chemoselectivity).
The critical effect of the size of alcohols was demonstrated by
comparison to various dimensional alcohols (2c and 2d, 61% and
<5%, respectively). Moreover, a brief survey of different leaving
groups at the alkynal γ-position, e.g., OMe, OAc, and OTs,
reveals that the methyl carbonate group (OCO2Me) is the most
suitable one.
We then investigated the scope of this method. In general,
symmetric cyclic γ-disubstituted alkynals were efficiently
converted to desired products (Tables 2 and 3). Notably, a
wide array of carbocyclic and heterocyclic γ-disubstitutedalkynals
(six-, seven-, eight-, and 12-membered) is amenable to this
B
DOI: 10.1021/acs.orglett.5b03615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Scope of Unsymmetrical γ-Substituted Alkynals
Figure 3. Postulated mechanism.
formation of by product 3b. The observed excellent chemo-
selectivity (>19:1) was attributed to below two plausible reasons.
First, NFSI exhibits a high electrophilicity,15 thus facilitating the
nucleophilic substitution reaction and resulting in the desired
C−F bond; Second, the potential π−π stacking between NFSI
(phenyl ring) and intermediate B (perfluorophenyl group)
allows the C−F bond generation to be an intramolecular-like
reaction.
In summary, we have developed an efficient α-fluorination of
azolium allenols that were generated from various γ-substituted
alkynals. With a suitable combination of NHC precatalyst, base,
and fluorine reagent, the reaction proceeded smoothly to yield a
wide range of α-fluoroallenoates with excellent chemoselectivity.
NFSI serves as the fluorine source in the reactions. These
substituted α-fluorinated allenoates have been synthesized for
the first time, and they are useful synthetic intermediates toward
other fluorine-containing building blocks
a
Reaction conditions: alkynal 3 (0.5 mmol), cat. V (0.1 mmol), NFSI
b
(1.0 mmol), NaHCO3 (1.0 mmol), EtOH (5.0 mL), rt, 12 h. MeOH
(5.0 mL) as solvent.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03615.
■
corresponding α-fluoroallenoates 4l−4o in good to high yields
and moderate dr. Additionally, the α-fluoroallenoates can be
smoothly transformed into other useful fluorinated molecules
(Figure 2).
S
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Figure 2. Synthetic transformations.
*E-mail: wangjian2012@tsinghua.edu.cn.
Notes
A postulated mechanism is depicted in Figure 3. The catalytic
cycle begins with the addition of NHC catalyst V to alkynal 2a in
the presence of NaHCO3. The resulting Breslow intermediate A
then undergoes elimination to afford a cumulative allenol B.12,13
Nucleophilic addition of intermediate B to NFSI generates a
NHC-bound α-fluorinated intermediate C.14 Further acyl
substitution by ethanol proceeds via intermediate C to form
the desired product 2b and regenerate the NHC catalyst. In
addition, a plausible competition reaction could take place in the
conversion of intermediate B to C. As highlighted in Figure 3, the
nucleophilic addition of intermediate B to proton, generated
from the NHC catalyst in the presence of base, could lead to the
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the “Thousand Plan” Youth program, the Bayer
Investigator Fellowship, the Tsinghua-Peking centre for life
sciences (CLS), and the Tsinghua University for generous
financial support.
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DOI: 10.1021/acs.orglett.5b03615
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