Fluorination of methyl 3-oxopentanoate (MOP) using difluorobis(fluoroxy)methane, BDM

Article abstract of DOI:10.1135/cccc20021416

Difluorobis(fluoroxy)methane, BDM, is an electrophilic fluorinating agent that is capable of affecting selective monofluorination of 1,3-dicarbonyls such as diketones and ketoesters with very high regioselectivity. For example, in highly acidic anhydrous HF (AHF) solvent, fluorination of methyl 3-oxopentanoate (MOP) with BDM provides methyl 2-fluoro-3-oxopentanoate (MFOP) with 100% conversion and 95% selectivity. In mixtures of HF and methanol, fluorination conversions and selectivity are markedly lower. In comparison, direct fluorination of MOP with dilute F₂ typically affords a fluorinated product that is less pure, being contaminated with radical fluorination byproducts that are difficult to separate. Fluorination of MOP with dilute mixtures of BDM and F₂ is generally more selective than using dilute F₂ alone.

Full text of DOI:10.1135/cccc20021416

1
416
Bailey, Casteel, Syvret:
FLUORINATION OF METHYL 3-OXOPENTANOATE (MOP)
USING DIFLUOROBIS(FLUOROXY)METHANE, BDM
1
2
3,
Wade H. BAILEY III , William J. CASTEEL, Jr. and Robert G. SYVRET *
1
Air Products and Chemicals, Inc., Allentown, PA 18195, U.S.A.; e-mail: baileywh@apci.com,
casteewj@apci.com, syvretrg@apci.com
2
3
Received Jun e 24, 2002
Accepted October 6, 2002
This paper is dedicated to the memory of Professor Miloš Hudlický who shall always be remembered as
a kind gentleman and a skilled fluorine chemist.
Difluorobis(fluoroxy)m eth an e, BDM, is an electroph ilic fluorin atin g agen t th at is capable of
affectin g selective m on ofluorin ation of 1,3-dicarbon yls such as diketon es an d ketoesters
with very h igh regioselectivity. For exam ple, in h igh ly acidic an h ydrous HF (AHF) solven t,
fluorin ation of m eth yl 3-oxopen tan oate (MOP) with BDM provides m eth yl 2-fluoro-3-oxo-
pen tan oate (MFOP) with 100% con version an d 95% selectivity. In m ixtures of HF an d m eth -
an ol, fluorin ation con version s an d selectivity are m arkedly lower. In com parison , direct
fluorin ation of MOP with dilute F2 typically affords a fluorin ated product th at is less pure,
bein g con tam in ated with radical fluorin ation byproducts th at are difficult to separate. Fluor-
in ation of MOP with dilute m ixtures of BDM an d F2 is gen erally m ore selective th an usin g
dilute F2 alon e.
Keyw ord s: Electroph ilic fluorin ation ; Fluoroxy com poun ds; Dicarbon yl fluorin ation ; Fluori-
n ated com poun ds; Keto esters.
Difluorobis(fluoroxy)m eth an e, BDM, CF (OF) , an d to a m uch greater ex-
2
2
ten t trifluoro(fluoroxy)m eth an e, FTM, CF OF, h ave been used to carry out a
3
n um ber of electroph ilic fluorin ation s; h owever, th eir use for th e fluorin a-
1
–5
tion of 1,3-dicarbon yl com poun ds h as n ot been previously reported . An -
oth er O–F bon d con tain in g com poun d, acetyl h ypofluorite, h as been used
successfully in th e fluorin ation of ketoesters an d th eir en olate salts, givin g
0–80% of th e desired m on ofluoro product6 ; h owever, th ere are safety
,7
7
con cern s with th e large-scale use of th is reagen t. Sim ilarly, cesium fluoroxy
sulfate, CsSO (OF) gave a 44% yield of th e desired m on ofluorin ated prod-
3
uct an d 19% of th e difluorin ated product on reaction with th e relatively
8
n ucleoph ilic substrate, 2,4-pen tan edion e .
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20021416

Fluorination of Methyl 3-Oxopentanoate
1417
Previously, 1,3-dicarbon yls h ave been fluorin ated directly with fluorin e
in acidic solven ts or in polar solven ts con tain in g acidic, or weakly basic,
9
–11
polar additives
. Wh ile th is fluorin ation m eth odology is reason ably
selective, th e desired 2-fluoro product still con tain s sign ifican t am oun ts
of im purities, wh ich m ost com m on ly result from radical fluorin ation of
th e pen dan t alkyl groups on th e substrate, at substrate loadin gs of on ly
5
–10 wt.%. Oth ers h ave dem on strated th at th e substrate loadin g, in th e
specific case of m eth yl 3-oxopen tan oate, can be substan tially in creased in
very stron g acids (up to 88 wt.% MOP in h igh ly acidic triflic acid); h owever,
th e product still con tain ed up to 16 wt.% fluorin ated im purities, in cludin g
1
2
th e 2,2-difluoro derivative . Th ere are oth er m eth ods for th e preparation
of fluorin ated dicarbon yl com poun ds; h owever, th ese m eth ods gen erally
em ploy m ultiple steps. For exam ple, th e dicarbon yl com poun d is ch lori-
1
3
n ated an d th en fluorin e in troduced by h alogen exch an ge . Un fortun ately,
th is m eth od gives on ly m oderate yields of fluorin ated product, 30–80%,
1
3
th at m ust still be purified by fraction al distillation . Man y popular m eth -
ods for th e selective fluorin ation of dicarbon yl com poun ds usin g reagen t
based ch em istry h ave been developed, for exam ple, in th e work of Hara,
3
Yon eda, an d coworkers usin g (difluoro-λ -iodan yl)toluen e an d HF·pyridin e
1
4
com plex , an d in th e work of Prof. E. Ban ks an d coworkers usin g
1
5
Selectfluor® fluorin ation agen t . A com preh en sive review of electroph ilic
fluorin ation , wh ich in cludes several exam ples of α-fluoro carbon yl com -
poun d form ation , h as recen tly been publish ed16
.
Despite a sign ifican t am oun t of work reported in th e literature, th ere re-
m ain s th e n eed for a selective m eth od of fluorin atin g th e im portan t
1
,3-dicarbon yl com poun d, MOP, th at produces th e m on ofluoro product,
m eth yl 2-fluoro-3-oxopen tan oate, MFOP, in h igh yield an d with out radical
fluorin ation im purities th at are troublesom e, if n ot im possible, to separate.
RESULTS AND DISCUSSION
In th e presen t work, depicted in Eq. (1), we h ave in vestigated fluorin ation
of th e 1,3-dicarbon yl com poun d, MOP, in HF, an d in som e cases HF/MeOH
solven t at low tem peratures, an d com pared results obtain ed usin g N2-
diluted BDM, BDM an d F m ixtures, an d F . Th e results are sum m arized in
2
2
Table I.
O
O
O
O
HF or HF/MeOH
"
F"
+
O
o
O
(1)
–
20 to –30 C
F
MOP
"F" = CF2(OF)2 or F2
FMOP
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

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Bailey, Casteel, Syvret:
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Fluorination of Methyl 3-Oxopentanoate
1419
In Table I, th e first four en tries represen t experim en ts don e usin g dilute
<5 vol.%) BDM for fluorin ation of MOP in eith er n eat HF, or HF/MeOH
(
m ixtures. Com parin g en tries 1 an d 4 th at were don e in stron g acid solu-
tion , <1% radical fluorin ation im purities are observed at 10 wt.% MOP
loadin g, h owever, just 83% con version was obtain ed. On th e oth er h an d,
1
00% con version of MOP was obtain ed at 80 wt.% loadin g, wh ich essen -
tially represen ts fluorin ation of th e substrate in th e absen ce of solven t but
in th e presen ce of a sm all am oun t of acid, an d just 4% fluorin ation im puri-
ties (in cludin g 2,2-difluoro MOP) were obtain ed. Radical fluorin ation im pu-
rities are observed to in crease if th e acid solven t is diluted with m eth an ol
(
en try 2), an d at h igh er levels of m eth an ol dilution (en try 3), th e substrate
becom es deactivated towards fluorin ation , with th e result bein g lower con -
version of MOP substrate.
If th e dilute BDM stream con tain s som e fluorin e, selectivity of th e fluori-
n ation reaction is reduced; h owever, BDM/F /N m ixtures (en tries 5–7) still
2
2
perform better th an F /air or F /N at relatively h igh substrate loadin gs.
2
2
2
Th us, a 50 wt.% substrate solution in HF (en try 6) sh owed on ly 3 wt.% radi-
cal fluorin ation im purities wh en fluorin ated with a 55 : 45 m ixture of
BDM/F diluted with N , com pared to 11wt. % radical fluorin ation im puri-
2
2
ties for a 38 wt.% substrate solution fluorin ated with F /air (en try 8) an d
2
1
4–15 wt.% radical fluorin ation im purities for a 26 wt.% solution fluori-
n ated with F /N (en try 10).
2
2
Fin ally, we foun d th at by addition of oxygen to th e dilutin g gas, th e
levels of radical fluorin ation im purities could be sign ifican tly reduced.
Th us, com parin g en tries 9 an d 10, just 5% radical im purities were obtain ed
wh en a 26 wt.% MOP solution in HF was fluorin ated at –30 °C with 10% F2
diluted with O /N , wh ereas with out O in th e diluen t gas (en try 10), th e
2
2
2
am oun t of radical fluorin ation im purities was in creased sign ifican tly to
1
4–15 wt.%.
A process is described wh erein low tem perature (–20 °C) selective fluor-
in ation of con cen trated (80 wt.%) m eth yl 3-oxopen tan oate in an h ydrous
HF with BDM provides m eth yl 2-fluoro-3-oxopen tan oate with 100% con -
version , 95% selectivity, an d just 4% radical fluorin ation byproducts.
EXPERIMENTAL
5
BDM was produced in a flow system as previously described . MOP (Wacker Ch em ical) an d
F2 (Air Products) were used as received.
1
19
H an d F NMR spectra were recorded on a Bruker DMX-500 NMR spectrom eter operat-
1
in g at 500.243 an d 470.696 MHz, respectively. H NMR spectra were referen ced in tern ally to
th e deuterated solven t an d F NMR spectra were referen ced extern ally to CFCl . Ch em ical
1
9
3
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

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Bailey, Casteel, Syvret:
sh ifts are reported in ppm (δ-scale), couplin g con stan ts (J) in Hz. A positive ch em ical sh ift
den otes a reson an ce to low field of th e referen ce.
Fluorin ation of MOP in HF with BDM
In a typical experim en t, m eth yl-3-oxopen tan oate is ch arged to a 100 m l FEP reactor
equipped with a valve. Th e reactor an d con ten ts are extern ally cooled to ca –35 °C an d th e
required am oun t of an h ydrous HF is tran sferred in un der static vacuum . Followin g th is,
–
1
BDM (≈1 eq.) as a 5% BDM/N2 stream is delivered at 225 m l m in in to th e reactor at –20 °C,
with th e effluen t from th e reactor bein g directed th rough a soda-lim e scrubber. Wh en th e
BDM addition is com plete, th e HF solven t is pum ped off th rough a soda-lim e scrubber. Th e
reactor is th en open ed an d th e con ten ts poured in to 30 m l H O. Th e resultin g aqueous solu-
2
tion is n eutralized with NaHCO3 an d th e product extracted in to dieth yl eth er. After rem oval
of eth er, a portion of th e resultin g yellow liquid product is dissolved in CDCl solven t an d
3
1
19
subsequen tly an alyzed by H an d F NMR spectroscopy. Th e results are sh own in Table I.
NMR param eters are sum m arized below.
Meth yl 2-fluoro-3-oxopen tan oate. H NMR (CDCl ): 5.04 d, J = 48.5; 3.47 s; 2.35 m ;
1
3
0
.68 t, J = 7.4. 19F NMR (CDCl ): –197.2 d, J = 48.5.
3
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