Direct Difluorination-Hydroxylation, Trifluorination, and C(sp2)-H Fluorination of Enamides

Article abstract of DOI:10.1021/acs.orglett.7b03994

A direct double functionalization involving both difluorination and hydroxylation of enamides is reported. With the appropriate combination of an electrophilic fluorinating reagent and H₂O, the most convenient and ecofriendly hydroxylating agent, the preparation of 3-(difluoroalkyl)-3-hydroxyisoindolin-1-ones was achieved under basic or Br?nsted acidic conditions. Suitable conditions for trifluorination as well as C(sp²)-H fluorination were also identified. Subsequent asymmetric functionalization of the obtained gem-difluorinated products has also been demonstrated.

Full text of DOI:10.1021/acs.orglett.7b03994

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Difluorination−Hydroxylation, Trifluorination, and C(sp2)−H
Fluorination of Enamides
Socrates B. Munoz,† Vinayak Krishnamurti,† Pablo Barrio,‡ Thomas Mathew,†
and G. K. Surya Prakash*,†
†Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California
90089, United States
‡Departamento de Quimica Organica, Universidad de Valencia, E-46100 Burjassot, Spain
S
* Supporting Information
ABSTRACT: A direct double functionalization involving both difluorination and hydroxylation of enamides is reported. With
the appropriate combination of an electrophilic fluorinating reagent and H2O, the most convenient and ecofriendly hydroxylating
agent, the preparation of 3-(difluoroalkyl)-3-hydroxyisoindolin-1-ones was achieved under basic or Brønsted acidic conditions.
Suitable conditions for trifluorination as well as C(sp2)−H fluorination were also identified. Subsequent asymmetric
functionalization of the obtained gem-difluorinated products has also been demonstrated.
ncorporation of fluorine into organic molecules imparts
1
Iunique physicochemical and biological properties. Hence,
organofluorine compounds are of increasing interest in medicinal
chemistry.2 gem-Difluoromethylene3 compounds have drawn
increasing attention as the −CF2− unit can serve as a bioisostere
to an oxygen atom in various functionalities such as alcohols,4a
carbonyl groups,4b and phosphates.5 The isoindolin-1-one
scaffold is present in many naturally occurring products6 as
well as designed pharmaceuticals,7 and it plays a key role in their
specific biological properties (Figure 1). Surprisingly, methods
for the preparation of fluorinated isoindolinones are scarce.8,9
Vicinal difunctionalization of unsaturated systems is one of the
most direct, atom-economical, and synthetically important
transformations.10 Fluoro functionalization using pyridinium
Figure 1. Naturally occurring and FDA-approved isoindolin-1-ones.
poly(hydrogen fluoride) (PPHF, Olah’s reagent) in combination
proposed α-fluoroiminium intermediate A would enable facile
deprotonation, followed by subsequent oxyfluorination, resulting
in the preparation of α,α-difluoro-N,O-aminal products 2
(Scheme 1).
To validate this hypothesis, isoindolinone 1a was selected as a
model substrate and reacted with several electrophilic fluorine
sources (N−F reagents) under varied reaction conditions (Table
1).
with several electrophilic reagents stands as a powerful strategy
for the efficient preparation of fluorine-containing molecules.11
The advent of electrophilic (or radical) fluorinating reagents12
(primarily N−F reagents) has allowed for several alternative
protocols.13
Because of our longstanding interest in organofluorine and
heterocyclic chemistry,14 we set out to develop a direct gem-
difluorination−hydroxylation protocol for the preparation of
CF2-containing heterocycles. Inspired by an elegant work by
Toste and co-workers13d on oxyfluorination of enamides 1, we
envisaged that the increased acidity of the α-proton (Hα) in the
Received: December 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
products. Notably, II emerged as the only reagent capable of
promoting formation of the desired product 2a, without the
detection of trifluorinated derivative 3a.17 The optimized
conditions were thus selected on the basis of this result (method
A, Table 1, entry 5).
Scheme 1. Working Hypothesis
As a suitable alternative approach to this process, we
envisioned that 1 could undergo a tandem hydroxyfluorina-
tion−dehydration−hydroxyfluorination sequence in the pres-
ence of Brønsted acids to afford the corresponding α,α-difluoro-
N,O-aminal 2, without requiring strictly anhydrous conditions. A
practical, benchtop protocol can thus be developed via such a
tandem sequence (eq 1).
a
Table 1. Selected Optimization Studies
Toward this end, several Brønsted acids were examined using
commercially available Selectfluor (I) under benchtop con-
ditions (Table 1, entries 9−12). To our delight, it was found that
the use of trifluoroacetic acid (TFA) afforded 2a with 95% yield
in 4 h at 50 °C, whereas H3PO4 required 40 h at room
temperature to provide a similar yield of 2a. Stronger acids such
as BF3·H2O or trifluoromethanesulfonic acid, provided complex
reaction mixtures. Therefore, TFA was selected for further
studies (method B, Table 1, entry 10).15 Next, the reaction scope
and limitations were examined using both methods A and B, and
the results are shown in Scheme 2.
A variety of N-substituted-3-benzylideneisoindolinones were
subjected to both optimized reaction conditions, and we found
that, except for N-OMe isoindolinone 1e, which failed to furnish
the desired gem-difluorinated product, both methods were
applicable to substrates bearing a variety of substituents on
nitrogen including N-Me, N-Bn, and free N-H groups (Scheme
2, 2a−c). In the case of N−Ph substituted isoindolinone 1d, only
method A under basic anhydrous conditions proved effective.
Substitution at the benzylidene moiety was next studied, and
method A was found particularly effective for substrates bearing
electron-donating as well as electron-withdrawing and heteroaryl
functionalities. Accordingly, methoxy-, CF3-, fluoro-, bromo-,
acetyl-, and pyridyl-substituted isoindolinones 1f−k smoothly
reacted and afforded the desired gem-difluoro products 2f−k
after 30 min at room temperature (Scheme 2).
b
yield (%)
F source
(equiv)
time
(h)
entry
additive (equiv)
2a
45
24
3a
4a
cd
,
1
2
3
4
I (2.0)
I (2.0)
I (3.2)
I (2.0)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
1
1
1
1
40
63
80
80
13
3
15
14
K2CO3 (1.2), KF
(1.0)
5
II (2.2)
III (2.2)
IV (2.2)
V (2.2)
I (2.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
H3PO4 (10)
TFA (10)
0.5
12
12
12
40
4
90
trace
dec
dec
94
6
7
8
d
9
de
,
10
I (2.2)
I (2.2)
95
d
11
12
BF3/H2O (10)
TfOH (10)
com2plex mixture
com2plex mixure
d
I (2.2)
a
Reactions were carried out with 1a (0.25 mmol) and 3 Å molecular
b
sieves (250 mg). Determined by 19F NMR using fluorobenzene
c
d
internal standard. MeCN (0.05 M) was used Reaction performed in
the absence of molecular sieves. H2O (100 μL was added after 1 h at
50 °C. See the Supporting Information for full details. TFA =
e
trifluoroacetic acid, TfOH = trifluoromethanesulfonic acid.
We next explored the effect of substituents on the
isoindolinone ring and were pleased to find that the Cl-
substituted substrate smoothly afforded the corresponding
product 2m. Similarly, both CF3- and Me-substituted gem-
difluoroisoindolinones 2l and 2n, respectively, could be easily
obtained in high yields. The use of halo-substituted (Br and Cl)
isoindolinones 1i and 1m is notable, as it allows for further
product functionalization.
Next, parallel studies were performed using method B under
Brønsted acidic conditions. In this case, the reactions are
conveniently set up on the benchtop using commercially
available I. Upon formation of derivatives 4 as detected by 19F
NMR (15 min), addition of TFA (10 equiv) to this reaction
mixture effectively promotes a dehydration process, giving rise to
difluorinated products 2.15 This approach was the method of
choice for the substrates containing N-Me, N-Bn and N-H
groups, affording the corresponding products 2a−c in excellent
yields, without any trace of monofluoro derivatives. Substrates
bearing electron-donating (OMe) and electron-withdrawing
groups (CF3, F, Br, and acetyl) at the benzylidene ring also
Initials studies using Selectfluor, I (2.0 equiv), as the
electrophilic fluorine source and K2CO3 (1.2 equiv) as the base
in anhydrous MeCN afforded α,α-difluoro-N,O-aminal 2a as the
major product (Table 1, entry 1). However, the selectivity
toward 2a was rather poor, and varying quantities of monofluoro
and trifluorinated derivatives (4a and 3a, respectively) were also
obtained.15 Performing the reaction in the presence of 3 Å
molecular sieves inhibited the formation of 4a and afforded 2a
and 3a in 24% and 63% yield, respectively (Table 1, entry 2).
The reaction using 3.2 equiv of I provided 3a in 80% yield. A
similar result was obtained when the reaction was conducted with
I (2 equiv) in the presence of anhydrous KF (1 equiv) as an
external fluoride source16 (Table 1, entries 3 and 4). At this point,
our attention shifted to alternative electrophilic fluorine sources,
including F-TEDA-PF6 (II), N-fluorobenzenesulfonimide
(NFSI, III), and N-fluoropyridinium salts (IV and V) (Table
1, entries 5−8). From these reagents, III afforded traces of 2a,
while the use of pyridinium salts IV and V led to decomposition
B
DOI: 10.1021/acs.orglett.7b03994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The utility of our approach was further demonstrated by the
preparation of a series of hitherto unknown fluoroolefins 5 and
trifluorinated products 3. A C(sp2)−H olefinic fluorination was
successfully performed under conditions similar to those of
method B, except that only 1 equiv of I was used. In addition, a
trifluorination reaction of isoindolinones was achieved by the
combination of I with KF as external fluoride source under basic,
anhydrous conditions (Scheme 3).
Scheme 2. Tandem Difluorination−Hydroxylation of
a
Isoindolin-1-ones
Scheme 3. C(sp2)−H Olefinic Fluorination and
Trifluorination of Isoindolinones
a
See the Supporting Information for full details. Z/E ratio shown in
parentheses.
Since iminium ion intermediates are prominent and well
established versatile species,19 accessing them from our products
could greatly expand the utility of our method and enable
molecular diversification by the addition of a variety of
nucleophilic species. Accordingly, products 2 derived from this
protocol are very well suited for this purpose.20 To this end, 2b
was subjected to several chiral Brønsted acid-catalyzed
nucleophilic addition reaction conditions.21 An extensive
experimental investigation showed that catalyst A promotes the
enantioselective addition of p-methoxythiophenol (PMP-SH) in
moderate yield and high enantiomeric excess (Scheme 4).22 In
Scheme 4. Asymmetric Chemical Elaboration of 3-Hydroxy-3-
a
difluoroalkylisoindolin-1-ones
a
Reactions performed using 1 (0.25 mmol, 1 equiv). See the
Supporting Information for full details.
a
See the Supporting Information. Tf = trifluoromethanesulfonyl; PMP
underwent the desired transformation after 20 h at room
temperature leading to 2f−j in good yields (65−83%). On the
other hand, 2-pyridyl-substituted isoindolinone 1k required
prolonged heating (60 h at 65 °C) to furnish 2k in 55% yield. In
some cases, slightly inferior yields were obtained compared to
method A (2f−j and 2m), but the practicality, scalability,18a and
ease of setup of method B make it an attractive approach.
Importantly, controlling the initial amount of H2O present in the
system at the onset of the reaction is critical for the success of this
method.18b
The results obtained from these parallel studies showed that
both developed methods are complementary. In general, method
A allows for a rapid synthesis (30 min) of gem-difluorinated
products using II [F-TEDA-PF6] under basic anhydrous
conditions, and it is particularly effective in the cases where
method B proved to be challenging (e.g., 2d, 2k, and 2l). On the
other hand, method B requires longer reaction times (4−60 h)
and in some cases elevated temperatures were also necessary to
afford products 2 in practical reaction times.
= p-methoxyphenyl.
contrast to previously reported methodologies using 3-
hydroxyisoindolin-1-one derivatives as substrates for chiral
BINOL-derived phosphoric acid catalysis, 2b required the use
of more acidic triflimide derivative A.23 This is not surprising
given the deactivating effect of the gem-difluoro unit vicinal to the
hemiaminal functionality.24
In conclusion, we have developed efficient methods for double
functionalization (fluoro-functionalization) of enamides. Two
complementary methods for difluorination−hydroxylation
(under basic or Brønsted acidic conditions) were developed.
Moreover, with appropriate selection of the reaction conditions,
either an olefinic C(sp2)−H fluorination or a trifluorination
reaction can be accomplished. The utility of the obtained
products was further demonstrated with the synthesis of
enantioenriched N,S-aminal (+)-6.
C
DOI: 10.1021/acs.orglett.7b03994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(12) Baudoux, J.; Cahard, D. Electrophilic Fluorination with N−F
Reagents. In Organic Reactions; John Wiley & Sons, Inc.: 2004; Vol. 69,
pp 347.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03994.
■
S
(13) (a) Crossley, S. W. M.; Obradors, C.; Martinez, R. M.; Shenvi, R.
A. Chem. Rev. 2016, 116, 8912. (b) Miro, J.; del Pozo, C.; Toste, F. D.;
Fustero, S. Angew. Chem., Int. Ed. 2016, 55, 9045. (c) For a recent
review, see: Chen, P.; Liu, G. Eur. J. Org. Chem. 2015, 2015, 4295.
(d) Honjo, T.; Phipps, R. J.; Rauniyar, V.; Toste, F. D. Angew. Chem., Int.
Ed. 2012, 51, 9684. (e) For a related mono-fluorination of chiral
enamides, see: Xu, Y.-S.; Tang, Y.; Feng, H.-J.; Liu, J.-T.; Hsung, R. P.
Org. Lett. 2015, 17, 572.
Experimental procedures as well as NMR spectra and
characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gprakash@usc.edu.
ORCID
(14) (a) Prakash, G. K. S.; Papp, A.; Munoz, S. B.; May, N.; Jones, J.-P.;
Haiges, R.; Esteves, P. M.; Mathew, T. Chem. - Eur. J. 2015, 21, 10170.
(b) Munoz, S. B.; Aloia, A. N.; Moore, A. K.; Papp, A.; Mathew, T.;
Fustero, S.; Olah, G. A.; Surya Prakash, G. K. Org. Biomol. Chem. 2016,
14, 85. (c) Prakash, G. K. S.; Zhang, Z.; Wang, F.; Munoz, S.; Olah, G. A.
J. Org. Chem. 2013, 78, 3300. (d) Surya Prakash, G. K.; Munoz, S. B.;
Papp, A.; Mathew, T.; Olah, G. A. Asian J. Org. Chem. 2012, 1, 146.
(e) Munoz, S. B.; Ni, C.; Zhang, Z.; Wang, F.; Shao, N.; Mathew, T.;
Olah, G. A.; Prakash, G. K. S. Eur. J. Org. Chem. 2017, 2017, 2322.
Thomas Mathew: 0000-0002-2896-1917
G. K. Surya Prakash: 0000-0002-6350-8325
Notes
The authors declare no competing financial interest.
́
(f) Mathew, T.; Papp, A. A.; Paknia, F.; Fustero, S.; Surya Prakash, G. K.
ACKNOWLEDGMENTS
■
Chem. Soc. Rev. 2017, 46, 3060.
Financial support by the Loker Hydrocarbon Research Institute
is gratefully acknowledged. S.B.M. acknowledges financial
support from a USC−CONACyT postdoctoral fellowship.
(15) See the Supporting Information for full experimental details.
(16) These results suggest that the fluorine atom α to nitrogen
−
originates from nucleophilic fluoride attack from BF4 (in the case of
entry 3) or KF (entry 4) and not from the N−F unit.
(17) Though PF6− could release fluoride under certain conditions, the
ability of II to selectively afford 2a could be rationalized by the relative
Lewis acidity strength of BF3 vs PF5 (fluoride ion affinity = 83.1 kcal/mol
vs 94.9 kcal/mol, respectively). See: Christe, K. O.; Dixon, D. A.;
McLemore, D.; Wilson, W. W.; Sheehy, J. A.; Boatz, J. A. J. J. Fluorine
Chem. 2000, 101, 151.
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DOI: 10.1021/acs.orglett.7b03994
Org. Lett. XXXX, XXX, XXX−XXX