An efficient synthesis of fluorinated azaheterocycles by aminocyclization of alkenes

Article abstract of DOI:10.1021/ol4003866

A general and efficient approach to important fluorinated azaheterocycles has been developed by incorporating nucleophilic fluorination into alkene difunctionalization. This intramolecular aminofluorination transformation of alkenes has been achieved via the aminocyclization of reactive unsaturated N-iodoamines, which can be generated in situ from either unsaturated N-chloramines or their amine precursors in a one-pot protocol.

Full text of DOI:10.1021/ol4003866

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
An Efficient Synthesis of Fluorinated
Azaheterocycles by Aminocyclization
of Alkenes
Hai-Tsang Huang, Tyler C. Lacy, Barbara Bzachut, Gerardo X. Ortiz Jr., and Qiu Wang*
Department of Chemistry, Duke University, Durham, North Carolina 27708,
United States
qiu.wang@duke.edu
Received February 8, 2013
ABSTRACT
A general and efficient approach to important fluorinated azaheterocycles has been developed by incorporating nucleophilic fluorination into
alkene difunctionalization. This intramolecular aminofluorination transformation of alkenes has been achieved via the aminocyclization of
reactive unsaturated N-iodoamines, which can be generated in situ from either unsaturated N-chloramines or their amine precursors in a one-pot
protocol.
Azaheterocycles, such as piperidines, have long been
recognizedasprivileged pharmacophoresfor their remark-
able biological activities and extensive use in synthetic
pharmaceuticals.1 Fluorinated azaheterocycles not only
are isosteric to parent molecules but also can achieve im-
proved bioavailability, lipophilicity, and metabolic stability.2
Furthermore, the fluorine-18 radiolabeled azaheterocycles
have innumerable applications in positron emission tomo-
graphy (PET) and are valuable tools in drug discovery and
biomedical research.3 Therefore, developing effective and
rapid fluorination methods to access fluorinated azahe-
terocycles is important and highly desired.
Although the synthesis of fluorinated azaheterocyles has
received much attention,2À4 fluorination methods to con-
struct such azaheterocycles remained largely unexplored.5,6
The incorporation of a fluorination step into alkene difunc-
tionalization would represent a general and effective route
as olefin functionalization has proved to be a powerful
(1) (a) Gilligan, P. J.; Cain, G. A.; Christos, T. E.; Cook, L.;
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Dewhirst, M. W. J. Nucl. Med. 2011, 52, 165. (d) Koudih, R.; Gilbert,
G.; Dhilly, M.; Abbas, A.; Barre, L.; Debruyne, D.; Sobrio, F. Org.
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r
10.1021/ol4003866
XXXX American Chemical Society

approach to access azaheterocycles.7 Several alkene fluor-
ination transformations have been recently achieved using
an electrophilic fluoride.8,9 Note that nucleophilic fluor-
inations would offer a higher specific radioactivity for 18F-
labeled radiomolecules than electrophilic fluorination.3a
However, alkene difunctionalization incorporating nu-
cleophilic fluorination has hardly been explored for pre-
paring fluorinated azahetereocycles. The first example of
using fluoride ions in alkene difunctionalization was re-
ported by Liu’s group on a Pd(II)-catalyzed oxidative
aminofluorination, which was efficient but was restricted
to terminal alkenes and required extended reaction time
(24 h).6 New strategies to effectively incorporate nucleo-
philic fluorination into alkene functionalization will not
only offer a new method for the CÀF bond formation but
also greatly benefit the development of general and rapid
routes to the important fluorinated azaheterocycles.10
In this paper, we describe the development of a new
approach to important fluorinated azaheterocycles by an
intramolecular aminofluorination reaction of a diverse
range of terminal and internal alkenes (Scheme 1). This
transformation would involve an initial amino cyclization
step of unsaturated N-iodoamines (I)11 and a subsequent
rearrangement of the pyrrolidine intermediate (II) to form
the aziridinium intermediate (III) followed by a nucleo-
philic fluoride ring-opening in either endo or exo fashion.12
This approach diminishes intrinsic toxicity concerns asso-
ciated with transition metals, which is highly desired for
practical use in biomedical and materials science. We have
also established a one-pot protocol for a rapid fluorination
step (<30 min) that represents great potential for preparing
18F-labeled azaheterocycles as novel PET imaging tools.
Table 1. Iodide-Catalyzed Aminofluorination of Unsaturated
N-Chloramine 1aa
yieldb (%)
entry IÀ source (equiv) solvent temp (°C) time (h) 2a
4a
1c
2
NaI (0.1)
NaI (0.1)
None
CHCl3
50
50
50
50
50
50
70
1
À
50
À
97
43
À
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
4
3
4
4
Bu4NI (0.1)
NaI (0.5)
NaI (0.1)
NaI (0.1)
5
12
81
64
75
12
À
5
4
5e
0.75e
6d
7d
À
À
a Reaction conditions: 1a (1.0 equiv, 0.1 mmol, 0.2 M), AgF
(3.0 equiv). b Determined by 1H NMR spectroscopy with DMF as a
quantitative internal standard. Neither 3-iodopiperidine nor exo-
product 3a was detected by NMR. c Reaction in the absence of AgF.
d Stepwise addition: upon complete conversion of 1a to 4a promoted
by NaI (<1 h), AgF was added. e Reaction time after the addition of
AgF.14
generating N-iodoamine catalytically in situ from the treat-
ment of the more stable but less reactive N-chloramine13
precursors with an iodide source (Table 1).14 To this end,
NaI was found to be effective for the conversion of
N-chloramine 1a to 3-chloropiperidine 4a in the absence
of fluoride sources. We next examined the NaI-catalyzed
aminofluorination of 1a in the presence of AgF using
various solvents (e.g., CHCl3, THF, MeCN, and t-BuOH).14
Encouragingly, the aminofluorinated product 2a was ob-
tained in 50% yield in t-BuOH (entry 2), which proved to
be the best solvent for this reaction and is also known
to enhance the efficiency of nucleophilic fluorination.15
Among all fluoride sources tested, AgF was the most
efficient fluorination reagent. This suggests the role of
silver salt in facilitating the rearrangement/aziridinium
ring-opening step. Control experiments showed that the
iodide catalyst was essential for this transformation (entry 3)
while NaI was more effective than Bu4NI11a as the iodide
source (entry 4). We later noticed that the conditions with
10 mol % NaI (entry 2) occasionally provided much lower
Scheme 1. Proposed Aminofluorination of N-Iodoamine
Alkenes
Considering the high reactivity and instability of the
N-iodoamine intermediate I, we initiated our studies by
(8) Examples for intramolecular alkene electrophilic fluorination: (a)
Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science
2011, 334, 1681. (b) Phipps, R. J.; Hiramatsu, K.; Toste, F. D. J. Am.
Chem. Soc. 2012, 134, 8376. (c) Xu, T.; Mu, X.; Peng, H. H.; Liu, G. S.
Angew. Chem., Int. Ed. 2011, 50, 8176.
(9) Examples for intermolecular alkene electrophilic fluorination: (a)
Qiu, S. F.; Xu, T.; Zhou, J.; Guo, Y. L.; Liu, G. S. J. Am. Chem. Soc.
2010, 132, 2856. (b) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2011, 50, 9120. (c) Wang, X.; Ye, Y. X.; Zhang, S. N.; Feng, J. J.; Xu,
Y.; Zhang, Y.; Wang, J. B. J. Am. Chem. Soc. 2011, 133, 16410. (d) Zhu,
R.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 12462.
(10) During the preparation of this manuscript, two intramolecular
aminofluorination reactions of alkenes were reported. (a) Using PhI-
(OPiv)2/hydrogen fluorideÀpyridine: Wang, Q.; Zhong, W. H.; Wei, X.;
Ning, M. H.; Meng, X. B.; Li, Z. J. Org. Biomol. Chem. 2012, 10, 8566.
(b) Using difluoroiodonium salts: Kong, W.; Feige, P.; de Haro, T.;
Nevado, C. Angew. Chem., Int. Ed. 2013, 52, 2469.
(12) (a) A recent review on aziridium ring-opening reactions: Metro,
T. X.; Duthion, B.; Pardo, D. G.; Cossy, J. Chem. Soc. Rev. 2010, 39, 89.
For some additional examples, see: (b) Dekimpe, N.; Boelens, M.;
Piqueur, J.; Baele, J. Tetrahedron Lett. 1994, 35, 1925. (c) Tehrani,
K. A.; Van Syngel, K.; Boelens, M.; Contreras, J.; De Kimpe, N.;
Knight, D. W. Tetrahedron Lett. 2000, 41, 2507. (d) Graham, M. A.;
Wadsworth, A. H.; Thornton-Pett, M.; Rayner, C. M. Chem. Commun.
2001, 966. (e) Jarvis, S. B.; Charette, A. B. Org. Lett. 2011, 13, 3830.
(13) For reviews on N-chloramines see: (a) Kovacic, P.; Lowery,
M. K.; Field, K. W. Chem. Rev. 1970, 70, 639. (b) Stella, L. Angew.
Chem., Int. Ed. 1983, 22, 337.
(14) See the Supporting Information for a detailed description of
optimization studies.
(11) (a) Noack, M.; Gottlich, R. Eur. J. Org. Chem. 2002, 3171. (b)
Minakata, S. Acc. Chem. Res. 2009, 42, 1172.
(15) Kim, D. W.; Jeong, H. J.; Lim, S. T.; Sohn, M. H. Angew. Chem.,
Int. Ed. 2008, 47, 8404.
B
Org. Lett., Vol. XX, No. XX, XXXX

yields. However, the use of 50 mol % of NaI consistently
gave a higher yield (entry 5). A comparable yield of 2a was
also obtained consistently with 10 mol % of NaI when a
stepwise reaction was performed, where AgF was added
upon consumption of the N-chloramine 1a (entry 6). This
indicated the presence of AgF may hinder cyclization by
coordination with the iodide catalyst. Using this stepwise
protocol, we observed a faster conversion of the cyclized
intermediates into ring-opened products at elevated tem-
peratures. The fluorination reaction at 70 °C (45 min)
provided 2a in 75% yield (entry 7).
Table 2. Synthesis of Fluorinated Azaheterocycles by Amino-
fluorination of Unsaturated N-Chloramines
With the effective conditions for aminofluorination
identified, we examined the generality and efficiency of
this transformation with a range of substrates containing
different substitution on the nitrogen atom, olefin moiety,
and alkyl backbone (Table 2). For 1aÀ1c substrates bear-
ing various alkyl groups on nitrogen, all formed 3-fluor-
opiperidine products with excellent yields and high endo
selectivity (entries 1À3). Substrates 1d and 1e, containing a
ring at the β-position, both effectively provided the spiro
products with endo selectivity (entries 4 and 5). The reac-
tion of substrate 1f, which lacks substitution at the
β-position, also afforded the aminofluorination products
but without regioselectivity (entry 6). These results suggest
that substitution at the β-position favors the endo nucleo-
philic ring opening.16 The hexenyl compound 1g was also a
viable substrate that gave the aminofluorination products
with modest selectivity favoring the 7-membered endo-
ring-opened product 2g (entry 7). Next we examined the
effects of substitution on the alkene and the backbone. For
disubstituted olefins 1hÀ1j, their reactions all successfully
afforded the desired products with modest regioselectivity
and excellent diastereoselectivity (entries 8À10). The Z
alkene exclusively gave the cis-aminofluorinated cyclic
amine, and the E alkene gave only the trans product. For
the effects of backbone substitution, monosubstitution at
the β-position resulted in good regio- and diastereoselec-
tivity and favored the formation of the endo ring-opened
product 2k with cis stereoselectivity (entry 11).16 For
monosubstitution at the R- and γ-positions, little or mod-
est regioselectivity was observed while the 3-fluoropiper-
idine products showed higher diastereoselectivity than did
the 2-(fluoromethyl)pyrrolidine products (entries 12 and 13).
The conditions were also efficient for the cyclic substrate 1n,
providing fluorinated bridged heterocyclic product 2n in
good yield and stereoselectivity (entry 14).
We next looked into developing a one-pot protocol
for chlorination and aminofluorination of unsaturated
amines, as elimination of the N-chloramine isolation step
would be attractive.17 It was hypothesized that when the
N-chlorosuccinimide (NCS) oxidizes the amine to the
N-chloramine, the succinimide byproduct would be a
spectator in the subsequent reactions. To test this, unsat-
urated amines were first treated with NCS followed by
treatment with NaI in t-BuOH while AgF was added upon
a Isolated yields for both products 2 and 3. b Regioselectivity (ratio of 2/3)
and diastereoselectivity (dr) were determined by 1H NMR spectroscopy
and/or GCÀMS analysis of the reaction mixture. Major diastereomer is
shown. c Yields determined by 1H NMR spectroscopy with DMF as a
quantitative internal standard.
(16) Origins of the observed endo selectivity for those substitutions on
alkene and backbone are under investigation.
(17) Barker, T. J.; Jarvo, E. R. J. Am. Chem. Soc. 2009, 131, 15598.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. One-Pot Protocol for Chlorination and
NaI-Catalyzed Aminofluorination of Unsaturated Amines
Scheme 3. Rapid Aminofluorination via Stoichiometric
Formations of Unsaturated N-Iodoaminesa
a Yields (combined for products 2 and 3) and regioselectivity deter-
mined by 1H NMR spectroscopy with DMF as a quantitative internal
standard. b Isolated yield.
consumption of the N-chloramine (Scheme 2). With this
one-pot procedure, aminofluorination products 2c, 2d, 2g,
and 2o were all formed effectively. These results demon-
strated that the aminofluorination of alkenes can be achieved
from either N-chloramines or their amine precursors.
a Results listed as the major product in isolated yield.
to the pharmaceutical and chemical industries. The amino-
fluorination reactions ofa broadscope of alkene substrates
have been achieved via the reactive N-iodoamine inter-
mediates formed in situ, either catalytically from N-chlor-
aminesand NaI or stoichiometricallyfrom amine and NIS.
In particular, the latter protocol allows for a more rapid
fluorination step, suggesting its great promise in synthesiz-
ing 18F-labeled azaheterocycles for PET imaging. Further-
more, this approach can serve as a general strategy to
incorporate a variety of nucleophiles to access diversely
functionalized azaheterocycles in a modular fashion.
To explore this transformation for its applications in
synthesizing 18F-labeled azaheterocycles (∼110 min half-
life), we examined if the nucleophilic fluorination could be
accelerated by the stoichiometric formation of reactive
3-iodopiperidine intermediates through a one-pot N-iodo-
succinimide (NIS) iodination18 and aminofluorination
protocol. We also examined the combined treatment of
TBAF or KF with different silver salts for alternative
fluorination conditions, since either [18F]TBAF or [18F]KF
is readily available (commercially),3 while [18F]AgF is not.
We were encouraged to observe that the fluorination step
using a 1:1 ratio of TBAF and AgOTf led to the rapid
formation of aminofluorinated products (15À30 min).
This protocol was effective across a variety of acyclic and
cyclic substrates (Scheme 3). These results suggest this
method holds great potential in preparing 18F-labeled
azaheterocycles to develop novel PET imaging tools.
In summary, we have developed an efficient alkene
aminofluorination approach to synthesize fluorinated
piperidines and other azaheterocycles of great importance
Acknowledgment. Financial support was provided by
Duke University. B.B. thanks Duke University for support
provided through the Howard Hughes Research Fellows
Program, and G.X.O. thanks Duke University for support
provided through the Dean’s Fellowship.
Supporting Information Available. Experimental pro-
cedures, additional screening data, and characterization
data for new compounds including 1H, 13C, and 19F
NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465, 1027.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX