Synthesis of acyl fluorides via photocatalytic fluorination of aldehydic C-H bonds

Article abstract of DOI:10.1039/c8cc06375c

Acyl fluorides are versatile acylating agents owing to their unique stability. Their synthesis, however, can present challenges and is typically accomplished through deoxyfluorination of carboxylic acids. Here, we demonstrate that acyl fluorides can be prepared directly from aldehydes via a C(sp²)-H fluorination reaction involving the inexpensive photocatalyst sodium decatungstate and electrophilic fluorinating agent N-fluorobenzenesulfonimide. This convenient fluorination strategy enables direct conversion of aliphatic and aromatic aldehydes into acylating agents.

Full text of DOI:10.1039/c8cc06375c

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Synthesis of acyl fluorides via photocatalytic
fluorination of aldehydic C–H bonds†
Cite this:DOI: 10.1039/c8cc06375c
Michael Meanwell,‡a Johannes Lehmann,‡a Marc Eichenberger,‡b
a
Rainer E. Martin *b and Robert Britton
*
Received 5th August 2018,
Accepted 11th August 2018
DOI: 10.1039/c8cc06375c
rsc.li/chemcomm
Acyl fluorides are versatile acylating agents owing to their unique
While the conversion of aldehydes into acyl fluorides has
stability. Their synthesis, however, can present challenges and is been described,11 the typically harsh reaction conditions (e.g.,
typically accomplished through deoxyfluorination of carboxylic CsSO4F,11a UF6,11b difluoro(aryl)-l3-bromane,11e F2 gas11d,11f
)
acids. Here, we demonstrate that acyl fluorides can be prepared have limited the widespread adoption of these strategies. As a
directly from aldehydes via a C(sp2)–H fluorination reaction involving notable exception, Banks and Lawrence reported that refluxing
the inexpensive photocatalyst sodium decatungstate and electrophilic a solution of 4-chlorobenzaldehyde and Selectfluor in MeCN
fluorinating agent N-fluorobenzenesulfonimide. This convenient afforded the corresponding acyl fluoride after 70 hours.11c In
fluorination strategy enables direct conversion of aliphatic and general, however, acyl fluorides are prepared via nucleophilic
aromatic aldehydes into acylating agents.
addition to activated carboxylic acids (deoxyfluorination)12 or
through halide exchange reactions with acyl chlorides (Fig. 1).13
Late-stage C–H halogenation has become an enabling tool with Importantly, some acyl fluorides are stable to chromatographic
a wide range of applications relevant to both natural product purification and thus represent attractive alternatives to acid
synthesis1 and medicinal chemistry.2 In particular, C–H fluorination chlorides or anhydrides for the preparation of amides,14 esters,15
reactions provide unique opportunities to optimize the physico- and thioesters.15 Moreover, acyl fluorides are the smallest acyl
chemical properties and metabolic stability of drug leads3 or transfer group, providing certain advantages in systems where
access 18F radiotracers for positron emission tomography (PET) traditional coupling strategies are unsuccessful.16 Finally, while
imaging.3a,4 Among the many C(sp3)–H fluorination strategies,4 a acyl fluorides are generally reacted in organic solvents,17 their
growing family of late-stage transformations involve the generation stability in water has inspired investigations of their use as
of a carbon-centered radical followed by fluorine atom transfer from electrophilic tags for bioconjugation.18 Here, we describe the
reagents such as N-fluorobenzenesulfonimide (NFSI) or Selectfluor, optimization and scope of a direct aldehyde C(sp2)–H fluorination
a process first demonstrated by Paquin and Sammis.5 For example, and contrast the stability of benzoyl fluoride to a sulfonyl fluoride, a
Lectka,6a Tan,6b and others7 have described both aliphatic6 and commonly used functional group for bioconjugation studies.
benzylic7 C(sp3)–H fluorination reactions using Selectfluor as
Previously, we have reported that photoactivated tetra-n-butyl-
the fluorine atom source. In addition, we have reported the ammonium decatungstate (TBADT) catalyzes the conversion of
decatungstate-catalyzed8 fluorination of both aliphatic9a,9b and
benzylic9c C(sp3)–H bonds by exploiting the fluorine atom
transfer capacity of NFSI. In a single example, we also demon-
strated the utility of this system for the fluorination of aldehydic
C(sp2)–H bonds10 in the conversion of benzaldehyde into benzoyl
fluoride.9a
a Department of Chemistry, Simon Fraser University, Burnaby, British Columbia,
V5A 1S6, Canada. E-mail: rbritton@sfu.ca
b Medicinal Chemistry, Roche Pharma Research and Early Development (pRED),
Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124,
CH-4070 Basel, Switzerland. E-mail: rainer_e.martin@roche.com
† Electronic supplementary information (ESI) available: Experimental procedures
Fig. 1 Synthesis of acyl fluorides from carboxylic acids and the direct
conversion of aldehydes to acyl fluorides via acyl radical intermediates.
and characterization data for all new compounds. See DOI: 10.1039/c8cc06375c
‡ These authors contributed equally.
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Scheme 1 NaDT-catalyzed C(sp2)–H fluorination of benzaldehyde.
benzaldehyde into benzoyl fluoride under UV irradiation (l =
365 nm) in the presence of NFSI (Scheme 1).9a Here, fluorine
atom transfer5 from NFSI to the intermediate acyl radical 7
generated from C–H abstraction by photoactivated decatungstate
(W*)8 provides a direct route to benzoyl fluoride (11). While the
crude acyl fluoride could be characterized by a diagnostic reso-
nance (d = 17 ppm, CD3CN) in the 19F NMR spectrum, it was
directly reacted with benzylamine to provide N-benzylbenzamide
(12) in good yield (Table 1, entry 1).9a It is notable that
Fagnoni8b,8d and Orfanopoulos8c have also exploited decatung-
state catalysis in the generation of acyl radicals for the purpose of
C–C bond formation. Our interest in further exploring this route
to acyl fluorides prompted us to reexamine this reaction. As
summarized in Table 1, sodium decatungstate (NaDT)8h proved
equally efficient (entry 2) for the formation of benzoyl fluoride,
while the addition of NaHCO3 (entry 3) or other additives
commonly used in decatungstate-catalyzed C–H fluorination
reactions9 failed to further improve the yield of 11. The use of
radical initiators under thermal conditions (e.g., AIBN or
tBuOOH, entries 4 and 5) resulted in markedly decreased yields
of 11. In the interest of exploring other bench stable fluorinating
reagents capable of radical chain propagation, we also examined
Fig. 2 Synthesis of (hetero)aromatic and aliphatic acyl fluorides. a Yields of
acyl fluorides determined using quantitative 19F NMR and 1,3,5-tris(trifluoro)-
b
methylbenzene (TTMB) as an internal standard; isolated yield of N-benzyl
amide over two steps from aldehyde.
19
the use of XeF2 alone, which afforded benzoyl fluoride (11)
albeit in a modest yield of 38% (entry 6). Considering radical chain
propagation is operative in the fluorination of benzaldehyde
with Selectfluor,11c we examined the equivalent fluorination
using NFSI alone. As highlighted in entry 7, without the
photocatalyst NaDT no benzoyl fluoride was observed under
UV-irradiation or thermal conditions (80 1C). These results indicate
that the NFSI-derived nitrogen-centered radical 9 (Scheme 1) is
incapable of chain propagation9c in the fluorination of aldehydes,
and that decatungstate catalysis plays a key role in this process.
As depicted in Fig. 2, we further examined the conversion of
a collection of aliphatic and aromatic aldehydes into acyl
fluorides. Surprisingly, in only a small number of cases were
we able to isolate and purify the acyl fluoride by flash column
Table 1 Conversion of benzaldehyde into benzoylfluoride
Entry Catalyst or initiator Additive Fluorine source Yielda (%)
1b
2b
3b
4c
5d
6e
7f
TBADT
NaDT
NaDT
AIBN
tBuOOH
—
—
—
NFSI
NFSI
79
79
78
NaHCO3 NFSI
—
—
—
—
NFSI
NFSI
XeF2
NFSI
o2
10
38
o2
—
a
Yields determined using quantitative 19F NMR spectroscopic analysis
and 1,3,5-tris(trifluoro)methylbenzene (TTMB) as an internal standard. chromatography. While the isolation of acyl fluorides 13–17
b
NFSI (1.1 equiv.), decatungstate salt (2 mol%), CH3CN, 365 nm LED
highlight the unique stability of these acyl halides, the majority
of acyl fluorides decomposed during isolation and/or purification,
or proved challenging to isolate owing to their volatility. Instead, the
c
d
lamp, 2 h. NFSI (1.1 equiv.), AIBN (20 mol%), CH3CN, 80 1C. NFSI
(1.1 equiv.), tBuOOH (4 equiv.), CH3CN, 80 1C. e XeF2 (1 equiv.), CH3CN. f NFSI
(1.1 equiv.), CH3CN, 365 nm lamp or 80 1C, 2 h.
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crude acyl fluorides were characterized by 19F NMR spectroscopy
then directly converted into amides by reaction with benzylamine
(see ESI† for details). Following this strategy, variously substituted
benzaldehydes could be directly transformed into acyl fluorides
13–16 and 18–21. Likewise, several aliphatic aldehydes were directly
converted into the corresponding acyl fluorides including the
unusual cyclopropanecarbonyl fluoride 28. Interestingly, here the
major product 28 derives from trapping of the acyl radical inter-
mediate with NFSI rather than fragmentation.20 It is notable
that the generation of acyl radicals from aliphatic aldehydes is
often accompanied by varying amounts of decarbonylation.8b
Consequently, the acyl fluorides 24 and 29 were produced along
with small amounts (o10%) of the corresponding decarbony-
lative fluorination products (i.e., aliphatic fluorides), while
production of the acyl fluoride 25 was accompanied by 24% of
Scheme 2 Decatungstate-promoted radical decarbonylation of phenyl-
acetaldehydes.
3-fluoropentane. Given that we have previously described the and fluorine atom transfer quickly looses fluoride to afford an
decatungstate catalyzed fluorination of aliphatic C(sp3)–H bonds, aldehyde in situ. A second sequence of C–H abstraction/fluorine
we were pleased to observe no off-site fluorination of aliphatic atom transfer then provides the intermediate acyl fluoride.
aldehydes9a,b and no competing benzylic fluorination9c or aldehyde
To gain additional mechanistic insight into this process, we
a-fluorination in any of the aldehydes explored. Unsurprisingly, the considered that decarbonylation of phenylacetaldehydes would
general incompatibility of NFSI with nitrogen nucleophiles21 provide evidence supporting the intermediacy of acyl radicals.8b,21
complicated fluorination of heteroaryl aldehydes (e.g., indole, As depicted in Scheme 2, when an MeCN solution of phenyl-
pyrimidine, imidazole, indazole), however, the pyridine- acetaldehyde (36) or 2-phenylpropionaldehyde (37) were irradiated
containing acyl fluorides 22 and 23 could be accessed in modest with catalytic NaDT and excess NFSI, the corresponding benzyl
yield using this process. Finally, we explored fluorination of an fluorides 44 and 45 were produced directly (Scheme 2). The
N-Cbz leucine-containing benzaldehyde ester. While we have relatively low yield for fluorotoluene 44 can be attributed to
previously reported rapid fluorination of leucine at the branched the coincident formation and subsequent fluorination of 1,2-
position,9b we observed no leucine fluorination or other off-site diphenylethane producing benzyl fluoride 42. Fluoroethylbenzene
fluorination (e.g., benzylic), and clean conversion to the corres- 45 was the major product derived from the fluorination of phenyl-
ponding acyl fluoride 31, which was subsequently reacted with propionaldehyde (37).
phenyl alanine methyl ester to afford the amide 32. Overall, these
Considering that acyl fluorides have recently demonstrated
mild reaction conditions represent a convenient alternative to utility as electrophilic tags for bioconjugation,18 we sought to
existing strategies for aldehyde fluorination that rely on strong contrast the stability of benzoyl fluorides to sulfonyl fluorides,
oxidants such as F2 gas11f or the highly electrophilic fluorinating which are commonly used for selective modification of proteins,
reagents BrF3 and CsSO4F.11a
target identification and validation, and mapping of enzyme
11i
Orfanopoulous22 has previously demonstrated that photo- active sites.23 As detailed in the ESI,† under acidic (pH = 4),
activated decatungstate in combination with various oxidants neutral (pH = 7), and basic (pH = 9) conditions, benzoyl fluoride
can effect oxidation of primary alcohols. Based on this precedent, proved to be moderately stable with a t1/2 B 90 h for conversion
we also examined the direct conversion of primary alcohols into to benzoic acid. Conversely, phenyl sulfonyl fluoride was com-
acyl fluorides via a one-pot procedure. As indicated in Fig. 3, both pletely unreactive under these conditions (see ESI†). We also
benzylic and aliphatic alcohols could be converted directly into compared the stability of benzoyl fluoride and benzenesulfonyl
acyl fluorides (using 2.5 equiv. of NFSI) and subsequently fluoride in the presence of cysteine methyl ester and found
N-benzyl amides via decatungstate catalysis in modest to good approximately 80% of benzoyl fluoride and 35% of benzenesul-
yield over these three steps. Here, the intermediate vicinal fonyl fluoride had reacted after 24 hours. While these data
fluorohydrin generated following sequential C–H abstraction suggest that acyl fluorides do not possess comparable stability
to phenylsulfonyl fluorides, they may still prove useful for
bioconjugation studies by tuning reactivity through addition
of ortho substituents or groups that deactivate the carbonyl.
In summary, we describe the direct preparation of acyl
fluorides from aldehydes through a process that relies on
photoactivated decatungstate catalysis and fluorine atom transfer.
Importantly, this straightforward process avoids use of highly
reactive reagents typically required for equivalent transformations
(e.g., F2, BrF3, UF6 and CsSO4F). We expect that this process
should prove complimentary to deoxyfluorination of carboxylic
acids typically adopted for acyl fluoride synthesis.
Fig. 3 Direct conversion of benzylic and aliphatic alcohols into amides
33–35.
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We would like to thank Mr Martin Binder (Roche Basel) for
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supported by an NSERC Discovery Grant to R. B., a MSFHR
Career Investigator Award to R. B., a Hoffmann-La Roche Fellowship
(RPF), a NSERC Post-Graduate Scholarship for M. M., J. L. was
funded by the Deutsche Forschungsgemeinschaft (DFG).
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Conflicts of interest
There are no conflicts to declare.
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