Transformation of Alkynes into α- Or β-Difluorinated Alkyl Azides by an Efficient One-Pot Two-Step Procedure

Article abstract of DOI:10.1021/acs.orglett.9b03593

Reported herein an unprecedented 1,2-azide migratory hydroazidation and subsequent gem-difluorination of alkynes accessing β-difluorinated alkyl azides. Importantly, functional group controlled 1,2-azide or 1,2-aryl migration was observed in the case of a

Full text of DOI:10.1021/acs.orglett.9b03593

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Transformation of Alkynes into α- or β‑Difluorinated Alkyl Azides by
an Efficient One-Pot Two-Step Procedure
†
,‡
†
,†,‡
Huaizhi Li, Bhoomireddy Rajendra Prasad Reddy, and Xihe Bi*
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
‡
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
*
S Supporting Information
ABSTRACT: Reported herein an unprecedented 1,2-azide migratory
hydroazidation and subsequent gem-difluorination of alkynes accessing β-
difluorinated alkyl azides. Importantly, functional group controlled 1,2-azide
or 1,2-aryl migration was observed in the case of aromatic alkynes.
Moreover, the azide group is sustained up to the final product. The method
can be easily adapted for large-scale preparation, and the resulting products
can be readily transformed into gem-difluoro group containing amine and
triazole derivatives.
harmaceutical compounds with one or more fluorine
P
atoms have become popular. It is well recognized that the
presence of fluorine atoms in a bioactive molecule greatly
improves its metabolic stability, lipophilicity, and bioavail-
1
ability. Given the importance of fluorine functionalization,
new practical methods that allow access to a more diverse
range of medicinally relevant fluorinated building blocks are of
2
particular importance. β-Fluoroalkyl amines are a class of
fluorinated compounds that are very attractive elements in
3
drug candidates. In particular, β-difluorinated alkyl amines are
found in a variety of medicinally relevant bioactive molecules
(Figure 1) and constitute important synthetic motifs in the
design of anticancer, anticholinergic, and anti-inflammatory
4
drugs. Moreover, the geminal difluoro group in these
molecules shows valuable properties as a chemically and
metabolically inert isostere of a variety of polar functional
1
e
groups. From a synthetic perspective, the available
approaches to access β-difluorinated alkyl amines require
4c
tedious multistep transformations. However, this multistep
process has been limited due to the competitive side process of
deoxyfluorination adjacent amines to give the corresponding β-
keto amines. Therefore, it is highly desirable to develop a
straightforward synthesis of these compounds.
Figure 1. Bioactive molecules containing a β-difluorinated alkyl amine
moiety.
Recently, several groups have reported hypervalent iodine-
mediated selective gem-difluorination of styrene derivatives.
2m,5
migration via aziridine-N-diazonium ions instead of 1,2-aryl
migration (Figure 2b). Such aziridine-N-diazonium ions were
The conversion of an aryl alkenyl group into a 2,2-
difluoroethyl group accompanied by 1,2-aryl migration via
bridged ethylenearenium ions (Figure 2a) is quite convenient
8
first postulated by Streitwieser and Pulver and subsequently
9
observed by other groups. Herein, we describe the successful
6
realization of this process via a hydroazidation and subsequent
gem-difluorination of alkynes. Notably, functional group-
directed whether 1,2-azide or 1,2-aryl migration was observed
when using aryl alkynes. Electron-withdrawing groups
and useful in organic synthesis. In our recent studies on
developing novel organic reactions using alkynes, we
established a silver-catalyzed hydroazidation of alkynes with
7
TMSN to afford vinyl azides. In light of this knowledge, we
3
hypothesized whether azides generated from alkynes could
undergo a similar type of gem-difluorination to deliver gem-
difluorinated alkyl azides accompanied by selective 1,2-azide
Received: October 11, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03593
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
oxidant
F source
solvent
T (°C)
yield of 2h (%)
1
2
3
4
5
6
7
8
9
none
Py·HF
Py·HF
Py·HF
Py·HF
AgF
DCM
DCM
DCM
DCM
DCM
DCM
DMSO
DMF
DCE
25
25
25
25
25
25
25
25
25
−30
0
0
60
26
80
0
0
0
0
57
24
50
34
PhIO
PIFA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
CsF
Figure 2. Previous studies and our strategy.
Py·HF
Py·HF
Py·HF
Py·HF
Py·HF
Py·HF
promoted the 1,2-azide migration, whereas electron-donating
groups favored 1,2-aryl migration. This new reaction readily
affords difluoro alkyl azides, which can be readily transformed
to the corresponding amine for use in pharmaceutical
applications or reacted further to produce a triazole ring.
To test our hypothesis, 2-propynylbenzene (1h) was chosen
as the model substrate. Alkyne hydroazidation was carried out
10
11
12
DCM
DCM
DCM
40
a
Reaction conditions: (a) 1h (1.0 mmol), TMSN (2.0 mmol), AgN
5 mol %), and H O (2.0 mmol) in 2 mL of DMSO at 80 °C for 90
min. (b) Oxidant (1.5 mmol), and F source (5.0 mmol) in 3 mL of
3
3
(
2
b
solvent for 1 min. Isolated yield.
7
on the basis of our previous reports, and 2-propynylbenzene
(
1.0 mmol) was reacted with TMSN , AgN , and water in
3 3
DMSO at 80 °C to afford the corresponding vinyl azide.
Subsequently, without further purification of vinyl azide, we
examined different hypervalent iodine reagents (1.5 mmol) in
the presence of pyridine·HF complex (Py·HF) (5.0 mmol) as
the fluorine source in DCM at 25 °C for 1 min. Interestingly,
the reaction proceeded very rapidly and was completed in 1
min. No improvement in yield was achieved when the reaction
was allowed to proceed for a longer time. A blank test showed
that no gem-difluorination takes place without hypervalent
iodine reagents (entry 1). Iodosylbenzene (PhIO) was added
as a hypervalent iodine reagent, which gave 2h in a 60% yield
including 2-propynylbenzene, were successfully converted to
products 2h−2j in 65 to 85% yield. Aliphatic alkynes
containing a variety of functional groups at the terminal
carbon of their alkyl chain, such as chloro, ester, and ether
groups, also proved to be suitable reaction partners, leading to
the desired products 2k−2o in 70−81% yield.
We next examined the scope of arylalkynes under identical
reaction conditions. Notably, these substrates exhibited 1,2-
aryl and/or 1,2-azide migration depending on the electronic
nature of the aryl moiety. Aryl alkynes bearing strongly
electron-withdrawing groups on the benzene ring (such as 4-
CN, 4-NO , and 4-SO CH , 1p−1r) simply underwent 1,2-
(
entry 2). When iodosobenzene bis(trifluoroacetate) (PIFA)
2
2
3
was used, the yield was decreased to 26% (entry 3). The best
yield (80%) was achieved when employing iodobenzene
diacetate (PIDA) (entry 4). Next, we examined fluorine
sources using PIDA. The inorganic fluorine sources failed to
afford the desired product (entries 5 and 6), and among the
examined fluorine sources, Py·HF was found to be an efficient
fluorinating agent. Furthermore, various solvents were
screened, but none were found to be as effective as DCM
azide migration and delivered β-difluorinated alkyl azides 2p−
2r in moderate yields. In contrast, aryl alkynes containing
weakly electron-withdrawing groups on the benzene ring (such
as 3/4-AcO- and 4-formyl, 1s−1u) generated a mixture of
products from both 1,2-azide and 1,2-aryl migration pathways,
although 1,2-azide migration occur majorly (2s−2u vs 3s−3u).
Aryl alkynes substituted with electron-donating groups on the
benzene ring (methyl and phenyl, 1w−1z), including simple
phenylacetylene (1v), were effectively transformed into the
1,2-aryl migration products: α-difluorinated alkyl azides (3v−
3z). To our surprise, compounds with p-halyl substituents on
the benzene ring, solely transformed into the 1,2-aryl migration
products (3aa−3ac). 2-Naphthyl and 3-thienyl alkynes reacted
smoothly to give the corresponding α-difluorinated alkyl azides
(3ad, 3ae). Unfortunately, the aryl alkynes, containing a
phenolic hydroxyl, an amide, and a sulfonamide group, only
afforded the vinyl azide products in good yields in the
hydroazidation step; however, an unidentified mixture was
obtained in the following treatment of vinyl azide with PIDA
and Py·HF.
(
entries 7−9). Finally, a brief temperature study was carried
out, which found that decreasing or increasing the reaction
temperature did not provide a higher yield (entries 10−12).
We thus selected the reaction conditions shown in Table 1,
entry 4, as the optimum conditions for subsequent assessment
of the substrate scope.
With the optimized conditions obtained above (Table 1,
entry 4), we then explored the substrate scope and limitations
of this hydroazidation/gem-difluorination with a variety of
terminal alkynes (Scheme 1). Aliphatic alkynes promoted 1,2-
azide migration and produced β-difluorinated alkyl azides.
Aliphatic chain alkynes (1a, 1b) were very compatible with this
method and were converted to 2a and 2b at 51% and 80%
yields, respectively. Aliphatic chain 1,7-and 1,8-dialkynes (1c,
The practicality of the method was demonstrated by the
gram-scale synthesis of β-difluorinated alkyl azide 2h under
identical reaction conditions (Scheme 2). Further synthetic
manipulations of the azide group in the product allowed the
synthesis of diverse difluoro-containing compounds. The azide
group is a versatile functional group in organic chemistry, and
compounds derived from organic azides have found various
1
d) reacted smoothly to form bis(difluoro azides) in good
yields. 2-Propynylcyclohexane (1e) was readily transformed to
the desired product with a 64% yield. In addition to simple n-
alkyl alkynes, cycloalkyl alkynes (1f, 1g) were well tolerated by
this method, producing the expected β-difluorinated alkyl azide
in reasonable yields. Aliphatic alkynes featuring a phenyl group,
10
11
12
applications in biology, medicine, and materials science.
B
DOI: 10.1021/acs.orglett.9b03593
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of α-or β-Difluorinated Alkyl Azides
from Alkynes
product could be reduced to a β-difluorinated alkyl amine (4)
with PPh3 and readily underwent a 1,3-dipolar cycloaddition
a,
e,f
13
with dimethyl acetylenedicarboxylate (DMAD) to provide the
1
4
corresponding 1,2,3-triazole (5) in excellent yield.
To explore the mechanism of the gem-difluorination
reaction, we prepared a deuterated vinyl azide analogue of 1-
(
1-azidovinyl)-4-methylbenzene (6), by substituting H O for
2
2
15
D O in the hydroazidation step. Approximately 60% degree
of deuterium incorporation was observed. The reaction of the
[
D ]-6 gave a difluorinated product ([D ]-3y) with the
2
2
deuterium atoms incorporated at the benzylic position
Scheme 3). This result suggested that 1,2-aryl migration
(
took place with electron-rich aryl group.
a
Scheme 3. Deuterium-Labeling Experiments
a
Reaction conditions: (a) 1 (1.0 mmol), TMSN (2.0 mmol), AgN
3
3
(
5 mol %), and D O (2.0 mmol) in 2 mL of DMSO at 80 °C for 90
2
min; (b) PIDA (1.5 mmol) and Py·HF (5.0 mmol) in 3 mL of DCM
at 25 °C for 1 min. Yields are of isolated products.
On the basis of these experimental results and relevant
literature, the possible reaction pathways are proposed
(
Scheme 4). Initially, regioselective vicinal fluoroiodination
Scheme 4. Proposed Mechanism
a
Reaction conditions: (1) 1 (1.0 mmol), TMSN (2.0 mmol), H O
3
2
(
2.0 mmol), and AgN (5 mol %) in 2 mL of DMSO at 80 °C for 90
3
b c
min. 20 mol % Ag CO was used, and t = 50 min. 20 mol %
Ag CO was used, and t = 80 min. 20 mol % Ag CO was used, and t
2
3
d
2
3
2
3
=
5 h. (2) Further removal of Ag catalyst and DMSO from the residue
were added DCM (3 mL), Py·HF (5.0 mmol), and PIDA (1.5 mmol)
at 25 °C for 1 min. Isolated yield. Two-step yield.
e
f
Scheme 2. Gram-Scale Synthesis and Further Reactions of
a
2
h
of the vinyl azide using PhIF ·HF (which is generated in situ
2
from the reaction of PIDA and Py·HF) delivers intermediate I.
Thereafter, intramolecular nucleophilic attack of the C−I bond
by the aromatic ring or azide moiety results in the formation of
2
m,5,6
a bridged ethylenearenium ion (II)
diazonium ion (IV)
or aziridine-N-
depending on the nature of the
substituent. The stability of these three-membered cyclic ions
II and IV) may account for the observed migration: aryl vs
8
,9
(
azide. The stability of the intermediate II increases with an
electron-rich aromatic moiety but diminishes with an electron-
poor aromatic moiety. Therefore, in the latter case,
intermediate IV was predominantly formed over intermediate
II. Finally, the second regioselective fluoride attack results in
ring-opening, which is concomitant with a 1,2-migration of
either the azide or aryl group, providing an α/β-difluorinated
alkyl azides (III, V). Only azide migration was observed in the
case of aliphatic alkynes since it is extremely difficult to form
cyclic intermediates with alkyl groups.
a
Reaction conditions: (a) 2h (0.5 mmol), PPh (1.0 mmol), and H O
3
2
(
200 μL) in 2.0 mL of THF at 50 °C for 3 h; (b) 2h (0.5 mmol) and
DMAD (0.6 mmol) in 8.0 mL of water at 70 °C for 8 h.
Moreover, the gem-difluoro group greatly improves the
metabolic stability, ipophilicity, and bioavailability of such
compounds. For example, the β-difluorinated alkyl azide
1
C
DOI: 10.1021/acs.orglett.9b03593
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, sequential hydroazidation and gem-difluorina-
tion of alkynes was successfully developed. The protocol offers
efficient and straightforward access to α- or β-difluorinated
alkyl azides, accompanied by 1,2-aryl or 1,2-azide migration
depending on the substituents present on the alkyne. The
alkyl/electron-poor aromatics promoted 1,2-azide migration,
and the electron-rich aromatics favored 1,2-aryl migration. The
reaction is viable for large-scale syntheses, and utility of the
products was established by further conversion of the azide
group into triazoles and amines. Considering the importance of
the gem-difluoro group and the rich chemistry of alkyl azides,
this method should find widespread applications in organic
synthesis.
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ASSOCIATED CONTENT
Supporting Information
■
(
*
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03593.
̈
(c) Smith, G. R.; Brenneman, D. E.; Zhang, Y.; Du, Y.; Reitz, A. B. J.
Mol. Neurosci. 2014, 52, 446. (d) Cox, C. D.; Coleman, P. J.; Breslin,
M. J.; Whitman, D. B.; Garbaccio, R. M.; Fraley, M. E.; Buser, C. A.;
Walsh, E. S.; Hamilton, K.; Schaber, M. D.; Lobell, R. B.; Tao, W.;
Davide, J. P.; Diehl, R. E.; Abrams, M. T.; South, V. J.; Huber, H. E.;
Torrent, M.; Prueksaritanont, T.; Li, C.; Slaughter, D. E.; Mahan, E.;
Fernandez-Metzler, C.; Yan, Y.; Kuo, L. C.; Kohl, N. E.; Hartman, G.
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Experimental procedures and copies of spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bixh507@nenu.edu.cn.
ORCID
(5) (a) Kitamura, T.; Muta, K.; Oyamada, J. J. Org. Chem. 2015, 80,
1
0431. (b) Kitamura, T.; Yoshida, K.; Mizuno, S.; Miyake, A.;
Xihe Bi: 0000-0002-6694-6742
Notes
Oyamada, J. J. Org. Chem. 2018, 83, 14853. (c) Lv, W. X.; Li, Q.; Li, J.
L.; Li, Z.; Lin, E.; Tan, D. H.; Cai, Y. H.; Fan, W. X.; Wang, H. Angew.
Chem., Int. Ed. 2018, 57, 16544. (d) Zhao, Z.; Racicot, R.; Murphy, G.
K. Angew. Chem., Int. Ed. 2017, 56, 11620. (e) Scheidt, F.; Neufeld, J.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by NSFC (21871043,
1961130376), Department of Science and Technology of
Jilin Province (20180101185JC, 20190701012GH), and the
Fundamental Research Funds for the Central Universities
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DOI: 10.1021/acs.orglett.9b03593
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