Synthesis of β-Difluoroalkyl Azides via Elusive 1,2-Azide Migration

Full text of DOI:10.1016/j.chempr.2019.12.004

Article
Synthesis of b-Difluoroalkyl Azides via Elusive
1,2-Azide Migration
Yongquan Ning, Paramasivam
Sivaguru, Giuseppe Zanoni,
Edward A. Anderson, Xihe Bi
bixh507@nenu.edu.cn
HIGHLIGHTS
Rapid synthesis of b-difluorinated
alkyl azides
Elusive 1,2-azide migration of
a-vinyl azides
Late-stage modifications of
natural products and drugs
Novel mechanism via a three-
membered transition state
An unprecedented 1,2-azide migration has been developed through gem-
difluorination of the easily available a-vinyl azides with in situ-generated PhIF2,HF.
This approach provides a platform for the downstream synthesis of b-difluorinated
alkyl azides in high yields with broad substrate scope and excellent functional
group tolerance. The DFT calculations suggest 1,2-azide migration occur via a
three-membered azacyclic transition state.
Ning et al., Chem 6, 1–11
February 13, 2020 ª 2019 Elsevier Inc.
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Please cite this article in press as: Ning et al., Synthesis of b-Difluoroalkyl Azides via Elusive 1,2-Azide Migration, Chem (2019), https://doi.org/
10.1016/j.chempr.2019.12.004
Article
Synthesis of b-Difluoroalkyl Azides
via Elusive 1,2-Azide Migration
Yongquan Ning,1 Paramasivam Sivaguru,1 Giuseppe Zanoni,2 Edward A. Anderson,3 and Xihe Bi1,4,5,
*
SUMMARY
The Bigger Picture
The development of azide
migration reactions is a
The development of azide migration reactions is a formidable challenge
because of the potential competition of side processes driven by the release
of molecular nitrogen. Here, we report a conceptually novel 1,2-azide migration
in an unprecedented gem-difluorination of the readily available a-vinyl azides, a
transformation that enables the synthesis of a range of novel b-difluorinated
alkyl azides. The practicality of the method is demonstrated by broad substrate
scope, excellent functional group compatibility, and high yields. The migrating
group selectivity can be tuned through electronic effects, and DFT calculations
suggest 1,2-azide migration occurs via a three-membered azacyclic transition
state. By using routine protocols, the b-difluorinated alkyl azide products can
be easily transformed to biologically relevant b-difluorinated amines—common
structural motifs in pharmaceuticals, thus demonstrating the utility of these
fluorinated organic azides for pharmaceutical synthesis as well as other synthet-
ically useful derivatives.
formidable challenge, and the
only sole exception is the
pericyclic 1,3-allylic azide
rearrangement. This is probably
because of the liable
decomposition of azides by the
release of molecular nitrogen. In
this article, we introduce a
conceptually novel 1,2-azide
migration through gem-
difluorination of the readily
available a-vinyl azides mediated
by Py,HF and PIDA, allowing for
the synthesis of b-difluorinated
alkyl azides. This novel
INTRODUCTION
rearrangement reaction displays
high reaction efficiency, broad
substrate scope, and excellent
functional group tolerance.
Further transformations of these
fluorinated azide products could
afford a variety of gem-
The construction of carbon-nitrogen (C–N) bonds is one of the most important
transformations in organic chemistry because of the prevalence of nitrogen-
containing compounds in pharmaceuticals, natural products, and organic mate-
rials.1–3 Organic azides are widely recognized as convenient tools in such pro-
cesses because of their superior ability to participate in a variety of C–N bond
forming reactions.4–12 Among their many applications,13,14 organic azides are
easily transformed into amines, and readily undergo C–N bond formation via nitro-
gen-centered reactive intermediates (e.g., nitrenoid chemistry, driven by the
release of molecular nitrogen),15–18 or as a 1,3-dipole (e.g., click reactions).12,15
In contrast, transformations in which the azide functionality remains intact in the
final product are almost unknown, the sole exception being a pericyclic 1,3-allylic
azide rearrangement,19–24 which is limited in utility because of the generation of
mixtures of allylic azide products (Figure 1A). The development of new azide
migration reactions would therefore be of great value, not only because they
would provide an ideal approach to organic azides inaccessible by existing
methods but also due to the conceptual challenge of avoiding the highly entropi-
cally favorable loss of N2.13,14
difluorinated nitrogen-containing
molecules of potential interest in
medicinal chemistry. Therefore,
the discovery described here
represents a conceptual advance
in azide preparation and has
opened up an avenue to the azide
migration highly desired by
synthetic chemists.
b-difluoroalkylamines are key structural motifs in a variety of medicinally important
compounds such as anticancer, anticholinergic, and anti-inflammatory therapeutic
agents (Figure 1B);25–31 however, current synthetic approaches require tedious
multi-step operations.25 We questioned whether the readily available a-vinyl
azides—a class of structurally unique functionalized alkene that displays a rich
reactivity profile6—could offer a much more rapid entry to b-difluoroalkylamines
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Figure 1. Development of 1,2-Azide Migration Reactions
(A) Applications of organic azides in organic synthesis.
(B) Examples of bioactive molecules containing a gem-difluoroalkylamine motif.
(C) Planned gem-difluorination of vinyl azides with in situ-generated PhIF2,HF via an unprecedented 1,2-azide migration process (this work).
via a gem-difluorination and 1,2-azide migration (Figure 1C). The related gem-di-
fluorination and 1,2-aryl migration of styrenes, recently been described by Jacob-
sen32,33 and others,34–38 provides an efficient and powerful means to access the
gem-difluoroalkyl motif, a useful bioisostere of common polar functional groups.39
However, with the exception of isolated examples involving benzyl ether (OBn)
and sulfonamide (NHTs) groups,40 these rearrangements proceed almost exclu-
sively via arene migration. Under similar oxidative fluorination conditions (pyridi-
ne,HF and hypervalent iodine),36 we report herein a conceptually novel 1,2-azide
migration, which enable the efficient synthesis of a wide range of gem-difluorinated
alkyl azides (Figure 1C). The migratory preference can be tuned through electronic
effects, enabling a product switch in the reactions of a-aryl vinyl azides (i.e., azide
migration versus arene migration). Further, the product gem-difluoroalkylazides
can be readily converted to the corresponding biologically relevant gem-
difluoroalkylamines.41,42
RESULTS AND DISCUSSION
We first sought to establish conditions for the gem-difluorination and 1,2-azide migra-
tion reaction by using vinyl azide 1aa as a model substrate (Table 1). Subjection of 1aa
to oxidative fluorination conditions employed for gem-difluorination and 1,2-aryl
migration of styrenes36 (pyridine,HF as fluorine source, bis(acetoxy)iodobenzene
(PIDA) as oxidant in CH2Cl2 at 25ꢀC) afforded the 1,2-azide migration product 2aa
in excellent yield (entry 1). An oxidant was essential (entry 2), whereas other potential
fluorine sources (e.g., AgF,43 CsF,44 Et3N,HF45) led to no reaction (entries 3–5).
1Department of Chemistry, Northeast Normal
University, Changchun 130024, China
Changing the oxidant to the more potent bis(trifluoroacetoxy)iodobenzene (PIFA)34
resulted in a significantly reduced yield of 2aa (30%, entry 6), whereas use of PhIO44
2Department of Chemistry, University of Pavia,
Viale Taramelli 12, Pavia 27100, Italy
offered no advantage (entry 7). A brief survey of other solvents revealed poor or no
3Chemistry Research Laboratory, University of
Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
temperature to À40ꢀC or À78ꢀC led to reduced yields (entries 10 and 11).
4State Key Laboratory of Elemento-Organic
conversion in acetonitrile and DMSO (entries 8 and 9); similarly, lowering the reaction
Chemistry, Nankai University, Tianjin 300071,
China
Having identified optimal conditions (Table 1, entry 1), the scope of this gem-
5Lead Contact
difluorination/1,2-azide migration was first explored with a range of a-alkyl vinyl
*Correspondence: bixh507@nenu.edu.cn
azides (Figure 2). As shown in Figure 2A, vinyl azides with primary alkyl (1ab, 1ac,
https://doi.org/10.1016/j.chempr.2019.12.004
and 1ah), secondary alkyl (1ad, 1ae, 1af, and 1ai), or benzyl (1ag) groups were
2
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Table 1. Optimization of the Reaction Conditions
Entry
Oxidant
PIDA
none
PIDA
PIDA
PIDA
PIFA
Fluorinating Agent
Py,HF
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
DMSO
CH2Cl2
CH2Cl2
T (ꢀC)
25
Yield (%)a
1
92
0
2
Py,HF
25
3
AgF
25
0
4
CsF
25
0
5
Et3N,HF
Py,HF
25
0
6
25
30
90
47
0
7
PhIO
PIDA
PIDA
PIDA
PIDA
Py,HF
25
8
Py,HF
25
9
Py,HF
25
10
11
Py,HF
À40
À78
60
30
Py,HF
Reaction conditions: 1aa (0.5 mmol), PIDA (0.6 mmol), and Py,HF (2.5 mmol) in CH2Cl2 (5 mL) at 25ꢀC for
1 min.
aIsolated yield.
smoothly converted to products 2ab–2ai in 75%–95% yield. a-alkyl vinyl azides
featuring a variety of functionalities on the terminal carbon of the alkyl chain (e.g.,
chloro, nitro, cyano, sulfonyl, ester, carboxylic acid, and ether groups) also proved
to be suitable substrates, giving products 2aj–2au in 62%–95% yield. This included
tolerance of other potentially reactive azides on the alkyl chains (substrates 1ak
and 1au), which afforded the rearrangement products 2ak and 2au in 80% and
85% yields, respectively. Substrates with a-substituents such as acrylic ester (1ba),
cyclohexenyl (1bb), and internal alkynyl (1bc) moieties (Figure 2B) also selectively
delivered the corresponding gem-difluorination and 1,2-azide migration products
(2ba–2bc) in good yield, without detrimental fluorination of the other unsaturated
functionality of the a-substituents. These intriguing results clearly reveal that if the
compound contains two unsaturated groups, olefins bearing an azide group have
higher reactivity than free unsaturated groups.
We applied this methodology to the late-stage modification of natural product de-
rivatives bearing a vinyl azide (Figure 2C). Substrates derived from menthol (1ca),
vitamin E (1cb), and diacetone-D-galactose (1cc) afforded the desired products
2ca–2cc in 62%–89% yields. These examples highlight the potential utility of this
method in the straightforward derivatization of bioactive molecules. This difluoroa-
zidation methodology can also be used to build polyfunctionalized products; as de-
picted in Figure 2D, 2,7-diazidoocta-1,7-diene (1da) and 2,8-diazidonona-1,8-diene
(1db) provided the bis-difluoroazides, 2da and 2db, in 84% and 85% yield, respec-
tively. Even a substrate containing four vinyl azide units (1dc) was converted to the
desired product (2dc) in good yield (75%). Such azides are potentially useful building
blocks for the synthesis of linear and poly(triazole) dendrimers via click chemistry,
opening up applications in material science and medicinal chemistry.46–48
Spurred on by the positive results obtained with a-alkyl vinyl azides, and with previous
reports on styrene gem-difluorination/1,2-aryl migration in mind,32–38 we next
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Figure 2. Scope of 1,2-Azide Migratory gem-difluorinations
(A) Varying the a-alkyl group.
(B) Unsaturated substrates.
(C) Natural product derivatives bearing a vinyl azide moiety.
(D) Polyazide substrates.
interrogated the reactivity of a-aryl vinyl azides 3. As shown in Figure 3, these sub-
strates exhibited migration selectivity that could be turned by the electronic nature
of the arene substituent: specifically, difluorination was accompanied by 1,2-migra-
tion of either the azide or aryl group, leading to b-difluoroalkylazides 4 or a-difluoroal-
kylazides 5, respectively (Figure 3A). Azides with strong electron-withdrawing groups
(EWGs) on the aryl moiety (3aa–3ad) underwent the expected gem-difluorination and
1,2-azide migration at 40ꢀC to afford the corresponding products 4aa–4ad in moder-
ate to good yields (62%–82%, Figure 3B; inferior yields were obtained at 25ꢀC).
Certain disubstituted aryl vinyl azides, including 3,5-bis-trifluoromethyl- (3ae) and
3,5-difluoroarenes (3af), also afforded the azide migration products (4ae and 4af),
whereas substrates bearing formyl, acetyl, or ester groups at the p- or m-positions
of the aryl ring (3ag–3aj) afforded mixtures of competing 1,2-azide and 1,2-aryl migra-
tions, in favor of the former (4ag–4aj versus 4ag’–4aj’), and the structure of azide
migration product 4ah was unambiguously confirmed by single-crystal X-ray crystal-
lography. Realizing that the electronic nature of the arene could be used to control
the chemoselectivity of the migration, other substituted arenes were tested.
A meta-chloro substituent (3ak) again gave rise to a mixture of the products of the
1,2-migration (4ak and 4ak’); however, chloro, bromo, and fluoro substituents at the
p-position of the aryl ring all exclusively delivered the gem-difluorinated products
of 1,2-aryl migration (4al–4an, 72%–79%). Despite the inductive electron-withdrawing
nature of these substituents, this selectivity likely arises from mesomeric stabilization
of developing positive charge at the para position during arene migration. This
switch in product selection allowed us to prepare a variety of previously inaccessible
a-difluoroalkylazides 5, thus providing an entry to novel a-difluoroalkylamins.
This switch in selectivity was conveniently extended to a range of a-aryl vinyl azides
equipped with electron-donating substituents (EDGs) on the aryl moiety (Figure 3B).
a-aryl vinyl azides featuring alkyl and alkoxy groups at any position on the aryl ring
(3ba–3bi) were efficiently transformed into the corresponding 1,2-aryl migration
products (a-difluoroalkylazides 5ba–5bi) in good to excellent yields, and no 1,2-
azide migration products were observed. Substrates with additional sp2 substituents
(2-naphthyl, phenyl, and 3-thienyl; 3bj–bl) were also smoothly converted to equiva-
lent products (5bj–5bl) in high yields, and the structure of 5bk was confirmed by
single-crystal X-ray crystallography. Overall, these results illustrate the connection
between migratory aptitude and the arene substituent (EWG versus EDG).
The vinyl azides employed in this chemistry are readily derived by hydroazidation of
the corresponding terminal alkynes,49 and many tandem hydroazidation reactions of
terminal alkynes have been established.50,51 Accordingly, we questioned whether it
would be possible to access the difluoroalkylazide products directly from alkynes in a
two-step, one-pot process consisting of hydroazidation, followed by gem-difluori-
nation/1,2-azide migration. Using alkyne 6 as substrate, both steps indeed pro-
ceeded efficiently, giving gem-difluorinated alkyl azide 2aa in 80% yield (Figure 4A).
This sequenced approach offers a step economic and operationally simple method
for the synthesis of gem-difluorinated alkyl azides.
The practicality of the process was readily tested by conducting a multigram scale
synthesis of 2aa (Figure 4B, 15 mmol scale, 2.7 g, 87%). 2aa can be used to
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Figure 3. Divergent Migration Pathways in the gem-difluorination of a-Aryl Vinyl Azides
synthesize various previously unknown gem-difluorinated compounds of potential
interest as useful building blocks in medicinal chemistry: for instance, reduction of
the azide group produced b-difluoroalkylamine 7 in excellent yield,42 whereas
base-mediated 1,3-dipolar cycloaddition of 2aa with malononitrile52 or dimethyl
acetylenedicarboxylate (DMAD)53 gave the trisubstituted 1,2,3-triazole derivatives
8 and 9 in 65% and 95% yields, respectively. 1,3-dipolar cycloaddition of 2aa with
benzoyl cyanide afforded 1,5-disubstituted tetrazole 10 in good yield,54 whereas
addition of an alkyllithium afforded triazene 11 in 90% yield,55 the practical dipolar
cycloaddition could further promote their use in bioconjugation.12,56 These results
clearly illustrate the potential of b-difluorinated alkyl azides to access nitrogen-con-
taining b-difluorinated products, which could influence physical and biological prop-
erties such as conformation, lipophilicity, and metabolic stability.57–59 Otherwise,
positron emission tomography (PET) and single photon emission computed tomog-
raphy (SPECT) are subfields of nuclear imaging that emerged from the combined ef-
forts of national laboratories, academia, and industries.60,61 Fluorine-18 (18F, t1/2
=
109.7 min) is the most widely used nuclide for positron emission tomography
(PET). Our methodology has quite a rapid reaction time, even occurring at speeds
<1 min. Such a short reaction time should be essential for the efficient introduction
of 18F-radiolabel into organic molecules.[62]
6
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Figure 4. Tandem Hydroazidation/Difluorination, Gram Scale Synthesis, and Further Product Transformations
(A) gem-difluorination and 1,2-azide migration of terminal alkynes. Reaction conditions: 6 (0.5 mmol), TMSN3 (1.0 mmol), Ag2CO3 (10% mol), in DMSO
(2.0 mL) and H2O (2.0 equiv) at 80ꢀC for 90 min; then DCM (2 mL), Py,HF (2.5 mmol), PIDA (1.0 mmol), 25ꢀC. PIDA = (Diacetoxyiodo)benzene; Py = pyridyl.
(B) Gram scale synthesis and further reactions of the b-difluoroalkylazides to access products relevant to medicinal chemistry applications. Reaction
conditions: (a) 2aa (0.5 mmol), PPh3 (1.0 mmol), H2O (200 mL) in THF (2.0 mL) at 50ꢀC for 3 h. (b) 2aa (0.5 mmol), malononitrile (0.6 mmol), K2CO3
(1.0 mmol) in DMSO at 45ꢀC. (c) 2aa (0.5 mmol), dimethyl acetylenedicarboxylate (0.6 mmol) in water (8 mL) at 70ꢀC. (d) 2aa (0.5 mmol) and benzoyl
cyanide (1.2 mmol) at 120ꢀC under Ar. (e) 2aa (0.5 mmol), n-BuLi (0.6 mmol) in THF atÀ78ꢀC under Ar. THF = tetrahydrofuran.
The mechanism of azide group migration is intriguing. To explore this, the gem-
difluorination/1,2-azide migration was investigated with deuterium-labeled
substrate [D2]-1aa (Figure 5A), which under the standard conditions produced
difluorinated product [D2]-2aa in 95% yield with exclusive deuteration at the carbon
atom bearing the azide group. No indication of deuterium scrambling was observed
by 1H NMR spectroscopic analysis, suggesting the involvement of a 1,2-azide migra-
tion rather than an elimination process. A mechanism is proposed that involves
initial 1,2-iodofluorination of the vinyl azide with PhIF2,2HF (generated in situ
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Figure 5. Mechanistic Study and Proposal for the gem-difluorination/1,2-Azide Migration of Vinyl Azides
The energy profile was obtained by DFT calculations at the M062X/6-31G(d, p)/LANL2DZ level.
from reaction of PIDA with Py,HF), forming intermediate I (Figure 5B). The similar
activation of different molecules of HF to PhIF2 has been investigated by Zhou
et al.,33 and they found that the two-molecule activation model is the most favored.
Thus, we directly use this activation model to study the following processes in this
work. Subsequently, azide migration (promoted by the leaving group ability of iodo-
benzene) and concomitant fluorination appear to outcompete processes involving
azide decomposition driven by loss of N2. This 1,2-azide shift in intermediate I could
occur either via a five-membered ring transition state (TS-1, path a) or a three-
membered ring transition state (TS-2, path b). These transition states were studied
with density functional theory (DFT) calculations at the M062X/6-31G(d,p)/LANL2DZ
level. The calculations predict that path a (via TS-1, Figure 5B) presents a prohibi-
tively high energy barrier (67.0 kcal/mol) relative to path b (TS-2, 15.1 kcal/mol),
potentially because of (1) the torsional strain involved in the migration of the azide
group in TS-1 (q1 = 161.8ꢀ) makes its structure more destabilized than that of TS-2
(q2 = 174.4ꢀ); (2) the stronger hydrogen-bond interactions between F– and H as
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Figure 6. NCI analysis for the two key transition states TS-1 and TS-2
The colors blue, green, and red represent the attraction, weak interaction, and steric effect,
respectively, between the atoms.
well as the stronger electrostatic interactions between F– and I+ in TS-2 is more
favored than those in TS-1, the electrostatic interactions between FÀ and N2 on
+
the azide group was also found in TS-2, whereas it is absent in TS-1 (NCI analysis
in Figure 6). As such, path b is proposed to be favored. The calculations also show
that the second fluorination occurs exclusively by nucleophilic attack at the fluori-
nated carbon, and the azonium ion is the leaving group, completing 1,2-azide
migration to b-difluorinated alkyl azide product 2ab. We speculate that the avoid-
ance of azide decomposition could be explained by the intramolecular delivery of
the fluoride ion. Finally, in the case of a-aryl vinyl azides, the electronic character
of the substituent on the aryl ring plays a pivotal role in the migration selectivity.
Whereas electron-poor aromatics undergo equivalent azide migration, the ability
of electron-rich arenes to form a phenonium ion outcompetes 1,2-azide migration
and thus delivers a-difluorinated alkyl azides.
Conclusions
An unprecedented 1,2-azide migration has been developed in the gem-difluorina-
tion of the easily available a-vinyl azides with in situ-generated PhIF2,HF, providing
efficient access to a variety of previously inaccessible, synthetically useful b-difluori-
nated azides. The azide functionality in the products can easily undergo further
transformations to afford a variety of gem-difluorinated nitrogen-containing mole-
cules of potential interest in medicinal chemistry. The azide migration could lead
to those organic azides that are inaccessible by conventional methods; therefore,
the discovery described here represents a conceptual advance in azide preparation
and has opened up an avenue to the azide migration highly desired by synthetic
chemists.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
DATA AND CODE AVAILABILITY
The X-ray crystallographic coordinates for structures reported in this article have
been deposited at the Cambridge Crystallographic Data Center (4ah’’: 1960403,
5bk: 1893371). These data could be obtained free of charge from The Cambridge
Crystallographic Data Center via https://www.ccdc.cam.ac.uk/structures/.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2019.12.004.
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ACKNOWLEDGMENTS
Financial support by NSFC (21871043, 21961130376), Department of Science and
Technology of Jilin Province (20180101185JC and 20190701012GH), and the
Fundamental Research Funds for the Central Universities (2412019ZD001). E.A.A.
thanks the EPSRC for support (EP/M019195/1 and EP/S013172/1). X.B. and E.A.A.
thank Royal Society for a Newton Advanced Fellowship.
AUTHOR CONTRIBUTIONS
Y.N. and P.S. performed the experiments and the mechanistic studies. Y.N., G.Z.,
E.A.A., and X.B. conceived the concept, designed the project, analyzed the data,
and prepared this manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: June 13, 2019
Revised: September 8, 2019
Accepted: December 5, 2019
Published: December 30, 2019
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