Iridium-catalyzed allylic fluorination of trichloroacetimidates

Article abstract of DOI:10.1021/ja2087213

A rapid allylic fluorination method utilizing trichloroacetimidates in conjunction with an iridium catalyst has been developed. The reaction is conducted at room temperature under ambient air and relies on Et ₃N?3HF reagent to provide branched allylic fluorides with complete regioselectivity. This high-yielding reaction can be conducted on a multigram scale and shows considerable functional group tolerance. The use of [¹⁸F]KF?Kryptofix allowed ¹⁸F^- incorporation in 10 min.

Full text of DOI:10.1021/ja2087213

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Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates
Joseph J. Topczewski,† Timothy J. Tewson,‡ and Hien M. Nguyen*,†
†Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
‡PET Imaging Center, Department of Radiology, University of Iowa College of Medicine, Iowa City, Iowa 52242, United States
S Supporting Information
b
Table 1. Screening of Catalysts and Fluoride Sourcesa
ABSTRACT: A rapid allylic fluorination method utilizing
trichloroacetimidates in conjunction with an iridium catalyst
has been developed. The reaction is conducted at room
temperature under ambient air and relies on Et3N 3HF
3
reagent to provide branched allylic fluorides with complete
regioselectivity. This high-yielding reaction can be con-
ducted on a multigram scale and shows considerable func-
tional group tolerance. The use of [18F]KF Kryptofix
3
allowed 18FÀ incorporation in 10 min.
he past decade has seen an explosion in the use of selectively
fluorinated molecules for applications in pharmaceuticals
T
and medical imaging.1,2 The fluorine atom has unique properties
that make it an ideal bioisostere for hydrogen or oxygen. This
substitution imparts fluorinated products with improved potency,
metabolic stability, and pharmacokinetics.1 In addition, 18F atom
appears to be an ideal isotope for use in positron emission tomo-
graphy (PET) imaging because of its low-energy emission, ease
of preparation from [18O]water, and 110 min half-life.2 These
characteristics, although advantageous to the product, make
incorporation of fluorine challenging.1e,3,4 As a result, fluorina-
tion methods have not been adequately developed in comparison
to other protocols that form carbonÀheteroatom bonds.1e,3,4 This
warrants the discovery of general and rapid strategies for fluorine
incorporation into bioactive molecules.1,2
a All reactions were conducted at 0.3 M. b 5 mol % catalyst was used in
the reaction. c Yields were determined by 19F NMR analysis using PhCF3
as an internal standard. d Isolated yields. e 4 g scale, 2.5 mol % Ir catalyst.
Many elegant approaches have been developed for the forma-
tion of aryl fluorides5 and α-fluorocarbonyl compounds.6 Despite
their potential applications as valuable building blocks in a variety
of pharmaceutical compounds, only a few methods for the pre-
paration of allylic fluorides are available.7 Allylic fluorides are
traditionally prepared by displacement of allylic alcohols with
(diethylamino)sulfur trifluoride. This transformation is not regio-
selective or enantioselective.7 Other strategies for the synthesis of
allylic fluorides have been developed, including electrophilic
desilylation.8 Transition-metal-catalyzed fluorination of allylic
electrophiles would be a conceptually novel approach for the
regio- and enantioselective preparation of branched allylic fluor-
ides. This approach has not been fully explored because of a
number of anticipated challenges. First, the nucleophilicity of the
fluoride ion is significantly decreased in its solvated form, reduc-
ing the efficacy of fluorine incorporation into the target molecule.1,2c,7
Second, competitive elimination is often observed, as the desolva-
ted fluoride ion can act as a strong base.9b Third, because
palladium and platinum are known to form π-allyl complexes
with allylic fluorides,9 employing transition metals in these reactions
was not thought to be possible.9a Despite these challenges, the
recent work of Doyle has shown that Pd-catalyzed fluorination
of allylic halides is possible.10 The 24À48 h fluorination time
precludes the use of this method for [18F] labeling. Another
report by Gouverneur has also shown the feasibility of Pd-
catalyzed fluorination reactions of allylic p-nitrobenzoates,11 in
which primary allylic fluorides are formed in moderate to good
yields. Herein we report a complementary iridium-catalyzed
fluorination leading to secondary and tertiary allylic fluorides.
We recently reported the novel use of trichloroacetimidate as
the leaving group in rhodium-catalyzed allylic substitution with
unactivated anilines.12,13 The amination proceeded with excellent
regioselectivity. We postulated that this reaction manifold and
the unique properties of the trichloroacetimidate leaving group
might lead to an efficient fluorination reaction. To test our hypo-
thesis, allylic trichloroacetimidate 1 (Table 1) was chosen as a
Received: September 15, 2011
Published: November 07, 2011
r
2011 American Chemical Society
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|

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Scheme 1. Control Studies
Table 2. Survey of Secondary Allylic Imidatesa
model substrate because the 4-fluorobenzoate group would
provide a means of monitoring the reaction by 19F NMR analysis
of the crude reaction mixture.14 Initial efforts utilizing RhCl-
(P(OPh)3)312,15 and a variety of fluoride sources (CsF, TBAT,
and TEA 3HF) did not afford allylic fluoride 2 (entries 1À3).
3
A number of Rh(I) catalysts were screened. Both RhCOD2OTf
and RhCOD2BF4 (entries 6 and 7) provided 2 in moderate yields
along with elimination product 3. In all cases, the linear allylic
fluoride was not detected by crude 19F NMR analysis. Subsequent
efforts to suppress the competing elimination reaction were met
with success when the solvent was varied. Use of nonpolar sol-
vents (Et2O, MTBE, and PhCH3) resulted in a biphasic mixture.
This phase separation not only simplified the purification of
allylic fluoride 2, eliminating the need for an aqueous workup, but
also provided 2 in the highest yield (entries 10À12). Additional
studies showed that [IrClCOD]2 was a better catalyst than
RhCOD2BF4, and product 2 was isolated in 93% yield (entry 13).
A control experiment (entry 14) without iridium catalyst was per-
formed, and no reaction was apparent after 18 h. The application
to a large scale was explored utilizing 4 g of imidate 1 (entry 15),
and allylic fluoride 2 was obtained in 88% yield.
To evaluate the unique nature of the trichloroacetimidate
potentially to act as both the leaving group and the directing
group, allylic acetate 4 (Scheme 1a) was subjected to our reaction
conditions, and no reaction was observed after 12 h. Methyl ether
6 (Scheme 1b) was the major product when allylic carbonate 5
was used in the fluorination. To determine whether iridium acts
as a Lewis acid, we explored the reaction of imidate 1 with 10 mol %
a All reactions were conducted at 0.3 M in Et2O for 1À2 h. b Fluorina-
tion with RhCOD2BF4 proceeded to completion in 30 min, and the
isolated yields were 50À65% forimidates 7À15. c Quenched with 3 equiv
of TEA.
BF3 OEt2 (Scheme 1c). Less than 6% yield of allylic fluoride 2
3
azide, which can be incorporated into a variety of biomolecules.17
Allylic fluoride 24 (entry 8), a functionality that has been intro-
duced into prostaglandin analogues,18 was isolated in 90% yield.
The azide group in imidate 15 (entry 9) was stable under the
fluorination conditions, and fluoride 25 (entry 9) was isolated in
64% yield. This azide can undergo “Cu-free” cycloaddition with
strained cyclooctynes.19,20 These secondary allylic fluorides can be
stored at ambient temperature for weeks without decomposition.
The application of the fluorination process was further
investigated with tertiary allylic imidates 26À28 (Table 3).12b In
contrast to secondary substrates, tertiary allylic fluorides 29À31
were unstable toward isolation, and polymerization/decomposi-
tion was observed.22 Nevertheless, the reaction was fast and
proceeded with excellent regioselectivity. Use of imidate 26
(entry 1) provided tertiary fluoride 29 in 67% yield [branched
(b)/linear (l) = 25:1]. Reaction of imidate 28 (entry 3) afforded
a 73% yield (b/l = 10:1) of fluoromonoterpenoid 31, a potential
was detected along with decomposition. No reaction was ob-
served with the milder Lewis acids Zn(OTf)2 and Cu(OTf)2.
Use of the palladium catalysts Pd(PPh3)4 and Pd-[COP-OAc]13a
led to decomposition of the starting material. To elucidate the
stereochemical outcome of the fluorination, enantiopure allylic
imidate 7 was investigated (Scheme 1d). Fluoride 17 was isolated
with nearly complete racemization (12% ee).16
To establish the scope of the fluorination, secondary allylic
imidates 7À15 (Table 2) were studied. A variety of functional
groups were tolerated, affording branched allylic fluorides 17À25
in good yields as single regioisomers. For instance, fluorination of
imidate 10 (entry 4) provided fluoride 208a in 89% yield. The
silyl ether group in imidate 1212 (entry 6) proved to be stable
under iridium conditions, and fluoride 22 was obtained in 78%
yield. Imidate 13 containing the terminal alkyne group (entry 7)
was also compatible, and allylic fluoride 23 was obtained in 68%
yield. This alkyne is capable of conjugating to bioorthogonal
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Table 3. Survey of Tertiary Allylic Imidatesa
In summary, we have developed a novel method for the syn-
thesis of secondary and tertiary allylic fluorides. The reaction is
simple in operation and provides allylic fluorides in high yields
with excellent regioselectivities. Efforts to render the fluorination
enantioselective, further application to the preparation of [18F]-
labeled allylic fluoride radiotracers, and mechanistic studies will
be reported in due course.
’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental details and
b
spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
hien-nguyen@uiowa.edu
a All reactions were conducted at 0.3 M in Et2O under ambient air for 1 h.
b Yields were determined by 19F NMR analysis using PhCF3 as an
internal standard; “b/l” is the ratio of branched and linear regioisomers.
’ ACKNOWLEDGMENT
This work is dedicated to Professor Barry Trost on the occa-
sion of his 70th birthday. We thank Professor Geert-Jan Boon at
the University of Georgia for providing 4-dibenzocyclooctynol,
the ACS Division of Medicinal Chemistry for the graduate
fellowship to J.J.T, and the University of Iowa for financial
support.
Scheme 2. Fluorination with KF Kryptofix
3
’ REFERENCES
(1) (a) M€uller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(b) Gouverneur, V. Science 2009, 325, 1630. (c) Furuya, T.; Kamlet,
A. S.; Ritter, T. Nature 2011, 473, 470. (d) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(2) (a) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem.,
Int. Ed. 2008, 47, 8998. (b) Ametamey, S. M.; Honer, M.; Schubiger,
P. A. Chem. Rev. 2008, 108, 1501. (c) Cai, L.; Lu, S.; Pike, V. W. Eur. J.
Org. Chem. 2008, 2853. (d) Adam, M. J.; Wilbur, D. S. Chem. Soc. Rev.
2005, 34, 153.
(3) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
(4) (a) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160. (b) Grushin,
V. V. Chem.—Eur. J. 2002, 8, 1007.
lead for the synthesis of insecticide analogues.21 To illustrate the
utility of tertiary allylic fluorides, crude product 30 (entry 2) was
derivatized via hydrogenation over Pd/C, and the corresponding
tertiary alkyl fluoride was isolated in 50% yield over two steps.
Overall, the rapid fluorination conditions and broad functional
group tolerance indicate the potential application of this method
for use in labeling of allylic compounds with 18FÀ. Accordingly,
(5) For representative examples of ArÀF bond formation, see:
(a) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-Fortanet,
J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661. (b) Ball, N. D.;
Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 3796. (c) Furuya, T.; Ritter,
T. J. Am. Chem. Soc. 2008, 130, 10060. (d) Furuya, T.; Strom, A. E.;
Ritter, T. J. Am. Chem. Soc. 2009, 131, 1662. (e) Tang, P.; Furuya, T.;
Ritter, T. J. Am. Chem. Soc. 2010, 132, 12150. (f) Tang, P.; Wang, W.;
Ritter, T. J. Am. Chem. Soc. 2011, 133, 11482.
(6) For representative examples of α-fluorination of carbonyl
compounds, see: (a) Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 1738. (b) Marigo, M.;
Fielenbach, D.; Braunton, A.; Kjærsgaard, A.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 3703. (c) Steiner, D. D.; Mase, N.; Barbas, C. F.,
III. Angew. Chem., Int. Ed. 2005, 44, 3706. (d) Jiang, H.; Falcicchio, A.;
Jensen, K. L.; Paix~ao, M. W.; Bertelsen, S.; Jørgensen, K. A. J. Am. Chem.
Soc. 2009, 131, 7153. (e) Erb, J.; Paull, D. H.; Dudding, T.; Belding, L.;
Lectka, T. J. Am. Chem. Soc. 2011, 133, 7536.
the reaction of allylic imidate 1 (Scheme 2a) with “cold” [19F]KF
3
Kryptofix [2.2.2] complex 322a was explored. This KF Kryptofix
3
complex was selected because it is the most commonly used
source of 18FÀ for radiolabeling studies.2a Typically, under [18F]-
labeling conditions, the target substrate is used in 100À1000 fold
excess relative to 18FÀ.2a Therefore, 10 equiv of imidate 1 was
used with 1 equiv of “cold” [19F]KF Kryptofix in the presence of
3
[IrClCOD]2 and camphorsulfonic acid (CSA) (Scheme 2a).
Fluoride incorporation was observed in 20 min, and compound 2
was obtained in 82% yield.23 Encouraged by this result, initial
(7) Pacheco, M. C.; Purser, S.; Gouverneur, V. Chem. Rev. 2008,
108, 1943.
trials with “hot” [18F]KF Kryptofix complex were conducted on
3
(8) (a) Thibaudeau, S.; Gouverneur, V. Org. Lett. 2003, 5, 4891.
(b) Greedy, B.; Paris, J. M.; Vidal, T.; Gouverneur, V. Angew. Chem., Int. Ed.
2003, 42, 3291. (c) Thibaudeau, S.; Fuller, R.; Gouverneur, V. Org.
Biomol. Chem. 2004, 2, 1110. (d) Boldon, S.; Moore, J. E.; Gouverneur,
V. Chem. Commun. 2008, 3622.
allylic trichloroacetimidate 7 (Scheme 2b). The decay-corrected
radiochemical yield (RCY) of allylic fluoride 17 was determined
to be 38%, which is competitive with those obtained using other
methods.11
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(9) (a) Hintermann, L.; L€ang, F.; Maire, P.; Togni, A. Eur. J. Inorg.
Chem. 2006, 1397. (b) Hazari, A.; Gouverneur, V.; Brown, J. M. Angew.
Chem., Int. Ed. 2009, 48, 1296. (c) Oh, Y. H.; Ahn, D. S.; Chung, S. Y.;
Jeon, J. H.; Park, S. W.; Oh, S. J.; Kim, D. W.; Kil, H. S.; Chi, D. Y.; Lee, S.
J. Phys. Chem. A 2007, 111, 10152.
(10) (a) Katcher, M. H.; Doyle, A. G. J. Am. Chem. Soc. 2010,
132, 17402. (b) After we submitted this paper, an excellent method for
generating branched acyclic allylic fluorides via palladium catalysis was
reported. See: Katcher, M. H.; Sha, A.; Doyle, A. G. J. Am. Chem. Soc.
2011, 133, 15902.
(11) Hollingworth, C.; Hazari, A.; Hopkinson, M. N.; Tredwell, M.;
Benedetto, E.; Huiban, M.; Gee, A. D.; Brown, J. M.; Gouverneur, V.
Angew. Chem., Int. Ed. 2011, 50, 2613.
(12) (a) Arnold, J. S.; Stone, R. F.; Nguyen, H. M. Org. Lett. 2010,
12, 4580. (b) Arnold, J. S.; Cizio, G. T.; Nguyen, H. M. Org. Lett. 2011,
13, 5576.
(13) For applications of the trichloroacetimidate group in palladium-
catalyzed allylic substitution reactions, see: (a) Kirsch, S. F.; Overman,
L. E. J. Am. Chem. Soc. 2005, 127, 2866. (b) Kirsch, S. F.; Overman, L. E.;
White, N. S. Org. Lett. 2007, 9, 911. (c) Olson, A. C.; Overman, L. E.;
Sneddon, H. F.; Ziller, J. W. Adv. Synth. Catal. 2009, 351, 3186.
(d) Cannon, J. S.; Kirsch, S. F.; Overman, L. E. J. Am. Chem. Soc. 2010,
132, 15185.
(14) Liu, Q.; Burton, D. J. J. Fluorine Chem. 2010, 131, 1082.
(15) For previous work with this rhodium catalyst, see: (a) Evans,
P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 39, 1725. (b) Evans, P. A.;
Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761.
(16) We also performed the control experiments with both the E and
Z linear isomers of branched allylic imidate 7 in the presence of 5 mol %
[IrClCOD]2 and TEA HF. Crude 1H and 19F NMR analyses showed
3
that less than 10% yield of secondary allylic fluoride 17 was present
after 12 h.
(17) Sharpless, K. B.; Manetsch, R. Expert Opin. Drug Discovery
2006, 1, 525.
(18) (a) Klimko, P.; Hellberg, M.; McLaughlin, M.; Sharif, N.;
Severns, B.; William, G.; Haggard, K.; Liao, J. Bioorg. Med. Chem.
2004, 12, 3451. (b) Fujimura, K.; Sasabuchi, Y. ChemMedChem 2010,
5, 1254.
(19) (a) Sanders, B. C.; Friscourt, F.; Ledin, P. A.; Mbua, N. E.;
Arumugam, S.; Guo, J.; Boltje, T. J.; Popik, V. V.; Boons, G. J. J. Am.
Chem. Soc. 2011, 133, 949. (b) Jewett, J. C.; Bertozzi, C. R. Chem. Soc.
Rev. 2010, 39, 1272. (c) Codelli, J. A.; Baskin, J. M.; Agard, N. J.;
Bertozzi, C. R. J. Am. Chem. Soc. 2008, 130, 11486.
(20) See the Supporting Information for a specific example of
“Cu-free” cycloaddition of azide 25 with 4-dibenzocyclooctynol to form
the corresponding triazole product.
(21) Banthorpe, D. V.; Ireland, M. J. J. Prakt. Chem. 1996, 338, 279.
(22) (a) Lee, E.; Yandulov, D. V. J. Fluorine Chem. 2009, 130, 474.
(b) W€ust, M.; Little, D. B.; Schalk, M.; Croteau, R. Arch. Biochem.
Biophys. 2001, 387, 125.
(23) In the absence of [IrClCOD]2, only decomposition resulted,
with less than 5% of allylic imidate 1 being converted to fluoride 2. When
a second control experiment was conducted with KF (3 equiv), CSA
(3 equiv), and imidate 1 in the presence of 5 mol % [IrClCOD]2, a 45%
yield of allylic fluoride 2 was present in the reaction mixture.
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