Controlled Single and Double Iodofluorination of Alkynes with DIH- and HF-Based Reagents

Article abstract of DOI:10.1021/acs.orglett.8b00321

A novel protocol for the regio- and stereoselective iodofluorination of internal and terminal alkynes using 1,3-diiodo-5,5,-dimethylhydantoin and HF-based reagents is disclosed. This approach is used to prepare a fluorinated tamoxifen derivative in two steps from commercially available starting materials. A facile method enabling controlled regioselective double iodofluorination of terminal alkynes is also presented.

Full text of DOI:10.1021/acs.orglett.8b00321

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Controlled Single and Double Iodofluorination of Alkynes with DIH-
and HF-Based Reagents
Lukas Pfeifer and Veronique Gouverneur*
́
Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: A novel protocol for the regio- and stereoselective iodofluorination of internal and terminal alkynes using 1,3-
diiodo-5,5,-dimethylhydantoin and HF-based reagents is disclosed. This approach is used to prepare a fluorinated tamoxifen
derivative in two steps from commercially available starting materials. A facile method enabling controlled regioselective double
iodofluorination of terminal alkynes is also presented.
Scheme 1. Au-Mediated Bromofluorination of Alkynes
classical strategy for the halofluorination of alkynes uses
A
electrophilic halogenating reagents in combination with
sources of HF.1 These methods are typically associated with
low yields,1c,e,f poor selectivity,1d−f and a substrate scope
restricted to unfunctionalized hydrocarbons.1e,f These limita-
tions have prompted the use of alternative reagents such as
hypervalent iodine species.2 These reactions that proceed via
the formation of (E)-(fluoroalkenyl)iodonium fluorides2b suffer
from byproduct formation for terminal alkyne substrates.2c
Rozen and co-workers reported the addition of BrF and IF,
generated from the elements, to unfunctionalized alkynes,
leading to the formation of stereoisomeric mixtures, and in
some cases uncontrolled single and double addition products.3
Isolated examples of iodofluorination of 3-hexyne employing
bis(pyridine)iodonium tetrafluoroborate and fluoride salts,4 or
a combination of elemental iodine and XeF2, have also been
disclosed.5 In quest of a reliable simpler protocol, the cis-
bromofluorination of terminal alkynes using N-bromosuccini-
mide and an excess of AgF was developed by Jiang,6 and Hara
reported the iodofluorination of internal and terminal alkynes
using IF5−pyridine−HF.7 From this survey, it is apparent that
the development of a regioselective iodofluorination method
compatible with functionalized alkynes and using easily
accessible reagents is still highly desirable.
of the preformed gold(I)−alkyne π-complex 4 with NBS and
either NEt3·3HF or (Me2N)3S(Me)3SiF2 (TASF) gave 2 in
18% and 64% yield, respectively (Scheme 1b).
These results encouraged further investigation. The reaction
of 3-hexyne with NBS in the presence of [Au(SIPr)BF4] (5
mol %) led to no (TASF) or only traces (NEt3·3HF) of
bromofluorinated product 2 (Table 1, entries 1 and 2). The
replacement of NBS with 1,3-dibromo-5,5,-dimethylhydantoin
(DBH) afforded the desired product in 54% yield, and a control
experiment revealed that 6a was also formed in the absence of a
Au-catalyst (Table 1, entries 3 and 4). Screening of alternative
sources of fluoride, electrophilic bromine sources, and solvents
identified NEt3·3HF and DBH in DCM as optimum for this
reaction (Table 1, entries 5−7; Tables S2−S5). Only HF-based
reagents were effective (Table S2). By lowering the temper-
ature to 0 °C (Table 1, entry 8) and increasing the amount of
NEt3·3HF to 3 equiv (Table 1, entries 9 and 10), 6a was
isolated in 80% yield but as a mixture with 15% of (E)-5,6-
Given our interest in transition metal mediated C−F bond
formation,8 our initial approach considered Au-catalysis to
activate the alkyne. Hashmi9 reported that an alkenyl-Au(I)
species can undergo halodeauration when treated with an
electrophilic halogen source, and Sadighi10 demonstrated that
internal alkynes reversibly form β-(fluorovinyl)gold(I) com-
plexes in the presence of [Au(SIPr)F]. Building on these
precedents, a preliminary experiment consisted of adding N-
bromosuccinimide (NBS) to the equilibrium mixture of 3-
hexyne and β-(fluorovinyl)gold(I) complex 1; this reaction led
to 32% of (E)-3-bromo-4-fluorohex-3-ene, 2, and 15% of (Z)-3-
fluorohex-3-ene, 3 (Scheme 1a), being formed. The treatment
Received: January 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Halofluorination of 5a
Scheme 2. Halofluorination of Internal Alkynes
a
entry
bc
F− source (equiv)
“X+” source (equiv) t [°C] 6a/7a [%]
,
1
2
3
4
5
6
7
8
9
TASF (1)
NBS (1)
NBS (1)
DBH (1)
DBH (1)
DBH (1)
DBH (1)
DBH (1)
DBH (1)
DBH (1)
DBH (1)
DBH (1)
DIH (1)
DIH (1)
DIH (1)
rt
rt
rt
rt
rt
rt
rt
0
0
bc
,
NEt3·3HF (1)
NEt3·3HF (1)
NEt3·3HF (1)
<5
bc
,
54
45
d
pyr/HF (3)
29
e
f
NEt3·3HF (1)
NEt3·3HF (1)
NEt3·3HF (1)
NEt3·3HF (2)
NEt3·3HF (3)
32
43
53
0
72
g
10
11
12
13
14
0
81 (80)
8
d
DMPU/HF (3)
0
NEt3·3HF (3)
NEt3·3HF (3)
0
30
40
91 (91)
d
pyr/HF (3)
−20
81
a
Determined by 1H and 19F NMR of crude reaction mixture (1-fluoro-
3-nitrobenzene as internal reference). Isolated yields in parentheses.
b
3-Hexyne is used as substrate affording bromofluorinated alkene 2.
c
d
e
With 5 mol % of [Au(SIPr)BF4]. Amount (equiv) of HF. In DCE.
f
g
In CHCl3. Isolated in a mixture with 15% of (E)-5,6-dibromodec-5-
ene.
dibromodec-5-ene, which could not be separated by silica gel
column chromatography (Conditions A). DMPU/HF was not
satisfactory for this reaction (Table 1, entry 11).11 When using
1,3-diiodo-5,5,-dimethylhydantoin (DIH) instead of DBH, the
reaction was best performed using NEt3·3HF at 40 °C and gave
(E)-5-fluoro-6-iododec-5-ene, 7a, isolated pure in 91% yield
(Conditions B) (Table 1, entries 12−14; Table S6).
These conditions applied to the terminal alkyne 1-hexyne 8a
afforded the iodofluoroalkene 9a in 35% yield as a single
diastereomer (Table 2, entry 1). Increasing the amount of
a
b
Conditions used are shown in parentheses. Yield determined by 19
F
c
Table 2. Optimization of Selective Single and Double
Iodofluorination of Terminal Alkynes
NMR (hexafluorobenzene as internal reference). 93% on 5 mmol
scale. Reaction at rt using pyr/HF (4 equiv of HF).
d
An increase of the amount of pyr/HF to 9 equiv led to the
exclusive formation of double iodofluorinated product 10a in
80% yield using 1 equiv of DIH (Conditions D) (Table 2, entry
7). This later transformation absorbs fully the iodine content of
this reagent.12
In this study, the difference in reactivity of the DIH/NEt3·
3HF and DIH/pyr/HF systems is notable. It is known that
halogenating reagents can be activated either with Brønsted and
Lewis acids or with nucleophilic promoters. Brønsted acid
activation is more plausible for DIH/pyr/HF (pKaH(pyr) = 5.2)
than for DIH/NEt3·3HF (pKaH(NEt3) = 10.7).13 In contrast,
nucleophilic activation could be more effective for DIH/NEt3·
3HF than DIH/pyr/HF considering the reduced hydrogen
bond accepting potential of pyridine (pKBHX = 1.86) versus
NEt3 (pKBHX = 1.98).14
a
a
entry
F− source (equiv)
t [°C]
9a [%]
10a [%]
1
2
3
4
5
6
7
NEt3·3HF (3)
NEt3·3HF (5)
NEt3·3HF (3)
40
40
rt
35
0
28
0
31
0
b
pyr/HF (3)
rt
14
29
b
pyr/HF (3)
0
33
20
b
pyr/HF (3)
−20
−20
77 (74)
0
8
b
pyr/HF (9)
87 (80)
a
Determined by 1H and 19F NMR of crude reaction mixture (1-fluoro-
3-nitrobenzene as internal reference). Amount (equiv) of HF.
b
NEt3·3HF or lowering the temperature had detrimental effects
on the outcome of the reaction (Table 2, entries 2 and 3).
Switching to pyr/HF gave 14% of monoiodofluorinated 9a
along with 29% of double iodofluorinated 10a (Table 2, entry
4). By lowering the temperature to −20 °C, 9a could be
isolated in 74% yield (Conditions C) (Table 2, entries 5 and 6).
Having established the optimum conditions for the
iodofluorination of internal and terminal alkynes, we studied
the substrate scope of these transformations. For internal
alkynes (Scheme 2), conditions B (3 equiv of NEt3·3HF,
40 °C) gave good to excellent yields for the iodofluorination of
electron-neutral as well as electron-rich substrates 5a−5c, 5h−
B
DOI: 10.1021/acs.orglett.8b00321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
5j, 5n, 5s, and 5u, with a lower yield of 26% for furan derivative
5t. The p-Cl-substituted alkyne 5g gave almost identical yields
regioisomers 7qa and 7qb, which were obtained in a 1.7:1 ratio,
favoring fluoride attack on the more electron-rich position as
confirmed by 19F−1H heteronuclear NOE (HOESY) analysis.
When placing a primary and a secondary carbon substituent on
the triple bond (5u) a 2.6:1 ratio of regioisomers was obtained,
favoring fluoride attack on the less sterically congested alkyne
carbon.16 The presence of a tertiary carbon substituent (5v)
resulted in only a trace amount of product being formed under
conditions B or C. Both 5a and 5b underwent successful
bromofluorination under conditions A. The iodofluorination of
5a was performed starting from 5.00 mmol of alkyne giving
1.32 g (93%) of 7a, demonstrating the robustness of this
protocol toward scale-up.
Table 3. Substrate Scope for the Single and Double
Iodofluorination of Internal Alkynes
Next, we examined the substrate scope for the single and
double iodofluorination of terminal alkynes (Table 3). Good
yields were obtained with unfunctionalized alkyl and aryl
substrates 8a−8d (Table 3, entries 1−4), chloro- and cyano-
substituted compounds 8e and 8f (Table 3, entries 5 and 6),
and electron-poor alkyne 8i (Table 3, entry 9). Alkyne 8g
bearing a carboxylic acid functionality gave lower yields
especially in the monoiodofluorination (Table 3, entry 7).
For the single iodofluorination of 4-Ph- and 4-OMe-substituted
phenylacetylenes 8h and 8j, conditions C only gave trace
amounts of the desired products, whereas conditions B resulted
in yields of 35% and 12%, respectively (Table 3, entries 8 and
10). Likewise, double iodofluorination gave 17% (10h) and a
trace amount (10j) of the desired products, respectively.
Products 10 bearing the 1,1-diiodo-2,2-difluoroethyl function-
ality are rare and accessed from the reaction of 1-hexyne or
phenylacetylene with IF.3 These products hold great potential
as versatile intermediates, for example, for subsequent use in
olefinations under Takai’s conditions17 or via reaction with α-
sulfinyl carbanions,18 as well as double functionalization with a
Grignard19 or organozinc20 reagent followed by quenching with
an electrophile. The (E)-configuration of 7b and 9d was
unambiguously confirmed using NOESY and 19F−1H HOESY
NMR experiments.21
Iodofluoroalkenes are useful products for the preparation of
highly substituted fluoroalkenes as they are amenable to Suzuki,
Sonogashira, or Ullmann-type cross-couplings (Scheme 3A).21
Scheme 3. Cross-Coupling Reactions with 7a, and Two-Step
Synthesis of Fluorinated Tamoxifen Derivative 11 from
Alkyne 5d
a
b
Conditions are shown in parentheses. Yield determined by 19F
NMR (hexafluorobenzene as internal reference).
with conditions B and C (pyr/HF, −20 °C). Conditions C
were superior for the iodofluorination of electron-poor
substrates 5d−5f, 5k−5m, and 5o−5q. Overall, different
functionalities, among them unprotected alcohols (7j) and
carboxylic acids (7l) as well as esters (7k), cyano groups (7o),
ketones (7f), and aromatic halides (7g, 7m, and 7q), are
tolerated under these conditions. The 19F−1Halkyl coupling
constants <4 Hz for products derived from alkyl aryl alkynes
served to determine the sense of regiocontrol of the reaction. α-
Ketoalkyne 5r also underwent regioselective iodofluorination
using 4 equiv of pyr/HF at rt, affording 7r in 48% yield.15 The
influence of electronics on regioselectivity was studied using the
unsymmetrically substituted stilbene derivative 5q. Under
conditions C 5q gave an inseparable mixture of the two
C
DOI: 10.1021/acs.orglett.8b00321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) (a) Emer, E.; Pfeifer, L.; Brown, J. M.; Gouverneur, V. Angew.
Chem., Int. Ed. 2014, 53, 4181. (b) Tredwell, M.; Preshlock, S. M.;
Taylor, N. J.; Gruber, S.; Huiban, M.; Passchier, J.; Mercier, J.;
Genicot, C.; Gouverneur, V. Angew. Chem., Int. Ed. 2014, 53, 7751.
(c) Khotavivattana, T.; Verhoog, S.; Tredwell, M.; Pfeifer, L.;
Calderwood, S.; Wheelhouse, K.; Collier, T. L.; Gouverneur, V.
Angew. Chem., Int. Ed. 2015, 54, 9991. (d) Verhoog, S.; Pfeifer, L.;
Khotavivattana, T.; Calderwood, S.; Collier, T. L.; Wheelhouse, K.;
Tredwell, M.; Gouverneur, V. Synlett 2015, 27, 25. (e) Preshlock, S.;
Calderwood, S.; Verhoog, S.; Tredwell, M.; Huiban, M.; Hienzsch, A.;
Gruber, S.; Wilson, T. C.; Taylor, N. J.; Cailly, T.; Schedler, M.;
Collier, T. L.; Passchier, J.; Smits, R.; Mollitor, J.; Hoepping, A.;
Mueller, M.; Genicot, C.; Mercier, J.; Gouverneur, V. Chem. Commun.
2016, 52, 8361. (f) Schuler, M.; Silva, F.; Bobbio, C.; Tessier, A.;
Gouverneur, V. Angew. Chem., Int. Ed. 2008, 47, 7927.
This chemistry was applied to the preparation of the fluorinated
tamoxifen derivative 11, a compound shown to exhibit higher
growth inhibition against four tested human cancer cell lines
compared to the parent compound.22 By applying our
methodology, 7d was prepared and subsequently coupled to
boronic acid 12 to afford 11 in 48% overall yield (Scheme 3B).
This two linear steps synthesis constitutes a significant
improvement from the original six-step procedure, for which
no overall yield was provided.22
In conclusion, we have developed synthetic protocols
enabling controlled iodofluorination of internal and terminal
alkynes relying on the unique reactivity of the DIH/“HF”
system. Our method for single iodofluorination tolerates a wide
range of functionalities and has successfully been performed on
gram scale. It allowed facile access to a potent fluorinated
tamoxifen derivative in two steps from commercially available
starting materials. We have also developed a highly efficient
strategy for double iodofluorination using the entire iodine
content of DIH.
(9) Hashmi, A. S. K.; Ramamurthi, T. D.; Rominger, F. J. Organomet.
Chem. 2009, 694, 592.
(10) Akana, J. A.; Bhattacharyya, K. X.; Muller, P.; Sadighi, J. P. J. Am.
̈
Chem. Soc. 2007, 129, 7736.
(11) Okoromoba, O. E.; Han, J.; Hammond, G. B.; Xu, B. J. Am.
Chem. Soc. 2014, 136, 14381.
(12) The multiplicity as well as coupling constants of the 19F NMR
signals of 9a (td, J = 22.6, 17.8 Hz) and 10a (td, J = 16.6, 12.2 Hz)
were used to determine the regiochemistry of these products.
(13) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, 2nd ed.; John Wiley & Sons, Inc.: Weinheim, 2013.
(14) (a) Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J.-Y.;
Renault, E. J. Med. Chem. 2009, 52, 4073. (b) Liang, S.; Hammond, G.
B.; Xu, B. Chem.−Eur. J. 2017, 23, 17850.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00321.
■
S
Experimental procedures, optimization tables, character-
(15) 19F NMR: −66.3 ppm (tq, J = 22.8, 6.6 Hz).
(16) 19F NMR: −91.2 ppm (t, J = 23.8 Hz) (7ua) vs −105.3 ppm (d,
J = 28.9 Hz) (7ub).
1
ization data, and H, 13C, and 19F spectra of all novel
compounds (PDF)
(17) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(18) (a) Abramovitch, A.; Varghese, J. P.; Marek, I. Org. Lett. 2004, 6,
621. (b) Abramovitch, A.; Marek, I. Eur. J. Org. Chem. 2008, 2008,
4924. (c) Varghese, J. P.; Knochel, P.; Marek, I. Org. Lett. 2000, 2,
2849.
(19) Hoffmann, R. W.; Knopff, O.; Kusche, A. Angew. Chem., Int. Ed.
2000, 39, 1462.
(20) Shibli, A.; Varghese, J. P.; Knochel, P.; Marek, I. Synlett 2001,
2001, 818.
(21) See Supporting Information for details.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: veronique.gouverneur@chem.ox.ac.uk.
ORCID
Veronique Gouverneur: 0000-0001-8638-5308
Notes
́
The authors declare no competing financial interest.
(22) Malo-Forest, B.; Landelle, G.; Roy, J. A.; Lacroix, J.; Gaudreault,
R. C.; Paquin, J. F. Bioorg. Med. Chem. Lett. 2013, 23, 1712.
ACKNOWLEDGMENTS
■
Generous financial support by the EU (FP7-PEOPLE-2012-
ITN-RADIOMI-316882 to L.P.) is gratefully acknowledged.
V.G. thanks the Royal Society for a Wolfson Research Merit
Award (2013−2018).
REFERENCES
■
(1) (a) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes,
I.; Olah, J. A. J. Org. Chem. 1979, 44, 3872. (b) Olah, G. A.; Nojima,
M.; Kerekes, L. Synthesis 1973, 1973, 780. (c) Gregorcic, A.; Zupan,
M. Bull. Chem. Soc. Jpn. 1987, 60, 3083. (d) Eddarir, S.; Francesch, C.;
Mestdagh, H.; Rolando, C. Bull. Soc. Chim. Fr. 1997, 134, 741.
̌
(e) Dear, R. E. A. J. Org. Chem. 1970, 35, 1703. (f) Dolenc, D.; Sket, B.
Synlett 1995, 1995, 327.
(2) (a) Zupan, M. Synthesis 1976, 1976, 473. (b) Hara, S.; Yoshida,
M.; Fukuhara, T.; Yoneda, N. Chem. Commun. 1998, 965. (c) Conte,
P.; Panunzi, B.; Tingoli, M. Tetrahedron Lett. 2006, 47, 273.
(3) Rozen, S.; Brand, M. J. Org. Chem. 1986, 51, 222.
(4) Barluenga, J.; Rodríguez, M. A.; Gonzal
Asensio, G. Tetrahedron Lett. 1986, 27, 3303.
́
ez, J. M.; Campos, P. J.;
(5) Shellhamer, D. F.; Jones, B. C.; Pettus, B. J.; Pettus, T. L.;
Stringer, J. M.; Heasley, V. L. J. Fluorine Chem. 1998, 88, 37.
(6) Li, Y.; Liu, X.; Ma, D.; Liu, B.; Jiang, H. Adv. Synth. Catal. 2012,
354, 2683.
(7) Ukigai, H.; Hara, S. Tetrahedron Lett. 2016, 57, 1379.
D
DOI: 10.1021/acs.orglett.8b00321
Org. Lett. XXXX, XXX, XXX−XXX