Two-step azidoalkenylation of terminal alkenes using iodomethyl sulfones

Article abstract of DOI:10.3390/molecules24224184

The radical azidoalkylation of alkenes that was initially developed with α-iodoesters and α-iodoketones was extended to other activated iodomethyl derivatives. By using iodomethyl aryl sulfones, the preparation of γ-azidosulfones was easily achieved. Faci

Full text of DOI:10.3390/molecules24224184

molecules
Article
Two-Step Azidoalkenylation of Terminal Alkenes
Using Iodomethyl Sulfones
Nicolas Millius, Guillaume Lapointe and Philippe Renaud *
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland;
Nicolas.Millius@dsm.com (N.M.); guillaume.lapointe@novartis.com (G.L.)
* Correspondence: philippe.renaud@dcb.unibe.ch
Academic Editor: Chryssostomos Chatgilialoglu
Received: 31 October 2019; Accepted: 11 November 2019; Published: 18 November 2019
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: The radical azidoalkylation of alkenes that was initially developed with
α
-iodoesters
and
α
-iodoketones was extended to other activated iodomethyl derivatives. By using iodomethyl
-azidosulfones was easily achieved. Facile conversion of these
aryl sulfones, the preparation of
γ
azidosulfones to homoallylic azides using a Julia–Kocienski olefination reaction is reported, making
the whole process equivalent to the azidoalkenylation of terminal alkenes.
Keywords: radical reaction; azidoalkylation; carboazidation; sulfones; azides; Julia–Kocienski
olefination
1. Introduction
Organic alkyl azides are highly versatile compounds for synthesis [
towards a broad range of reaction conditions but, under dedicated conditions, they may become
nitrene [ ] and aminyl radical precursors [ 11] as well as suitable substrates for Schmidt reaction [12 14],
aza-Wittig [15] reaction, and 1,3-dipolar cycloaddition [16,17].
1–4]. They are unreactive
5
6–
–
They are commonly prepared via nucleophilic substitution of halides and related electrophiles
using inorganic azides [18]. For tertiary alkyl azides, the nucleophilic substitution approach is
often difficult, and free radical processes have proven to be a very convenient alternative. Radical
azidation reactions are run under mild conditions, and they are compatible with a broad range of
functional groups [19
transform terminal alkenes into functionalized alkyl azides [22]. It is performed under chain transfer
conditions and has been employed as a key step in several alkaloids syntheses [20 23 29]. Alternatively,
carboazidation using under transition metal catalysis has also been reported [30 34]. Except for one
reaction involving CCl3Br [22], the reaction has mainly been used with -iodoesters and -iodoketones
(Scheme 1I) under ditin [35 36] or triethylborane [37 38] mediation. More recently, a very efficient
desulfitative approach was reported starting from -azidosulfonyl esters [26]. This approach is the
–21]. The carboazidation of alkenes represents a particularly attractive method to
,
–
–
α
α
,
,
α
best in terms of atom economy and efficiency, but it is less convenient to test the applicability of
the method with a broad range of substituted radicals since every starting azide has to be prepared
separately. The iodide approach remains very attractive in terms of availability of the starting material
(the starting iodide and the azidating agents are either commercially available or easily prepared), and
it can be easily used to introduce of variety of functional groups. Here, we report the extension of
the carboazidation process for the preparation of azido-nitriles, -phosphonates, -phthalimides, and
sulfones according to Scheme 1II. The reaction with sulfones is particularly attractive since it allows
one to prepare homoallylic azides.
Molecules 2019, 24, 4184; doi:10.3390/molecules24224184
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Scheme 1. The radical carboazidation reaction.
2. Results
Iodoacetonitrile
1, N-iodomethylphthalimide
2, diethyl iodomethanephosphonate
3, and
iodomethyl phenyl sulfones
information). They were tested for the carboazidation of terminal alkenes
triethylborane (B) conditions (Scheme 2). Under ditin-mediated conditions A, reactions of
methylenecyclohexane 5a worked fine and provided the desired tertiary azide 6a 9a in good yields.
Azidonitrile 6a is a potential precursor for 1,4-diamines, and azidophthalimide 7a is a bis-protected
1,3-diamine. -Azidophosphonates such as 8a are interesting precursors of -aminophosphonic
acids, a well-established class of biologically active compounds [39]. Finally, the rich chemistry of
sulfones renders -azidosulfones such as 9a as potential precursors for a broad range of functionalized
amines. The reaction of iodomethylsulfone with 5a mediated by Et3B (method B) provided the
azidosulfones 9a in an increased 92% yield. Sulfone was also employed for the carboazidation of
methylenecycloheptene 5b and the two substituted methylenecyclohexanes 5c and 5d as well as the
monosubstituted terminal alkene 5e under conditions B. The tertiary azides 9b 9d were obtained in
4
are either commercially available or easily prepared (see supporting
under ditin (A) or
with
5
1–4
–
γ
γ
γ
4
4
–
moderate to good yields, and the level of stereoselectivity observed for 9c and 9d (2–3:1) corresponded
to expectations [40]. The secondary azidosulfone 9e was obtained in 45% yield under conditions B.
The crude product was contaminated with the iodide 10e (9%) and the alcohol 11e (13%). The alcohol
13e presumably resulted from a sulfone assisted hydrolysis of the iodide 10e, but reaction of the
intermediate radical with oxygen could not be excluded. When the reaction was run at a higher
temperature according to method A, no azide 9e was obtained, and the iodine atom transfer product
10e (34% yield) was the only isolated product.

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Scheme 2.
Radical carboazidation with cyano-, phthalimido-, diethoxylphosphonyl-, and
benzenesulfonyl-substituted radicals.
To illustrate the utility of
with lithium hexamethyldisilazane (LiHMDS) and diphenyl disulfide (PhSSPh). The sulfide 12
was easily converted to the unsaturated -azido vinyl sulfone 13, an attractive and versatile
γ-azidosulfones, compound 9c was sulfurized to 12 by treatment
γ
building block for synthesis, upon oxidation to the sulfoxide and standing in CDCl3 (Scheme 3).
The whole reaction sequence allowed us to convert a terminal 2,2-disubsituted alkene into a tertiary
1-sufonylated allylic azide. Attempts to convert 12 into a β-azido ester upon treatment successively
with meta-chloroperbenzoic acid (m-CPBA) and trifluoroacetic acid (TFA) to promote a Pummerer
rearrangement according to a procedure reported by Barton and co-workers failed to give the desired
product [41].
Scheme 3. Preparation of unsaturated γ-azido vinyl sulfone 13 from the azidosulfone 9c.
The carboazidation with sulfones also offers a potential approach for the preparation of homoallylic
azides [42] by taking advantage of the Julia–Kocienski olefination process [43
1-phenyl-1H-tetrazole-5-yl iodomethyl sulfone 14 was prepared from the commercially available
1-phenyl-1H-tetrazole-5-thiol [45 46]. Carboazidation was then tested with methylene cyclohexene
5a and 2-butyl-1-hexene 5f using the ditin procedure (Scheme 4). With 5a, the tertiary azide 15a
,44]. For this purpose,
,

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was obtained in high yield. The reaction with 2-butyl-1-hexene 5f proved to be more challenging.
The desired azide 15f was isolated in 31% yield together with a side product identified as being 16f in 20%
yield. Compound 16f most likely resulted from the ipso attack of a tin radical to the 1H-tetrazole-5-yl
sulfone followed by reaction of the primary alkanesulfonyl radical with 3-pyridinesulfonyl azide.
A related intermolecular ipso substitution was recently reported by Kamijo and co-workers [47].
Scheme 4. Tin mediated azidoalkylation with 1-phenyl-1H-tetrazole-5-yl iodomethyl sulfone 14.
Following this observation, all carboazidation reactions involving 14 and different alkenes
were using the Et3B method B. Results are summarized in Scheme 5, and moderate to good yields
were observed for the formation of -azidosulfones 15 with a broad range of 2,2-substituted alkenes.
5
γ
No side product resulting from an ipso substitution at the tetrazole could be detected in those reactions.
The radical nature of the process was demonstrated by formation of the ring-opening reaction product
15j from (–)-β-pinene.
Scheme 5. Cont.

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Scheme 5. Et3B mediated azidoalkylation with 1-phenyl-1H-tetrazole-5-yl iodomethyl sulfone 14.
Finally, the 1-phenyl-1H-tetrazole sulfones 15 were submitted to the Julia–Kocienski olefination.
Deprotonation of the sulfones 15 with LiHMDS followed by treatment with aldehydes afforded the
homoallylic tertiary azides 17
with aromatic (17), aliphatic (18
the homoallylic tertiary azides 17
–
,
21. Moderate to good yields and high E selectivity were obtained
19), and -unaturated (20 21) aldehydes (Scheme 6). Interestingly,
21 were found to be stable and easily purified by column
α
,β
,
–
chromatography on silicagel.
Scheme 6. Julia–Kocienski olefination of γ-azidosulfones 15 with aldehydes, a formal 4-component
azidovinylation of alkenes.

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3. Experimental Procedures
3.1. General Methods
All glassware was oven-dried at 160 ◦C and assembled hot or flame dried under vacuum, and
allowed to cool under a nitrogen atmosphere. Unless otherwise stated, all the reactions were performed
under a nitrogen atmosphere. For flash chromatography (FC) silica gel P60 (40–63 µm) (Silicycle, Basel,
Switzerland) was used. Thin layer chromatography (TLC) was performed on silica gel F-254 plates
(Silicycle, Basel, Switzerland) visualisation under UV (254 nm) or by staining. Staining solutions: (1)
KMnO4 (1.5 g), K2CO3 (10 g) and NaOH 10% (1.25 mL) in H2O (200 mL); (2) ammonium molybdate
tetrahydrate (50 g), CeSO4 (2 g) and conc. H2SO4 (100 mL) in H2O (900 mL); (3) p-anisaldehyde
(3.7 mL), acetic acid (1.5 mL) and conc. H2SO4 (5 mL) in EtOH (135 mL). 1H and 13C NMR spectra were
recorded on a Bruker Advance 300 (1H: 300.18 MHz, 13C: 75.48 MHz) (Bruker BioSpin AG, Fällanden,
Switzerland). Chemical shifts (d) were reported in parts per million (ppm) with the residue solvent
peak used as internal standard (CHCl3: d = 7.26 ppm, C6H6: d = 7.16 ppm and THF: d = 1.72 ppm
for 1H NMR spectra and CHCl3: d = 77.00 ppm, C6H6: d = 128.00 ppm and THF: d = 67.21 ppm
for 13C NMR spectra). Multiplicities were abbreviated as follows: s (singlet), d (doublet), t (triplet),
q (quadruplet), m (multiplet) and br (broad). Coupling constants (J), are reported in Hz. 13C NMR
measurements were run using a proton-decoupled pulse sequence. The number of carbon atoms for
each signal is indicated only when more than one. High-resolution mass spectrometry (HRMS) analyses
were measured on an Applied Biosystems Sciex QSTAR Pulsar (hybrid quadrupole time-of-flight
mass spectrometer using electrospray ionisation (ESI) (Sciex, Baden, Switzelrand). Low resolution
mass-spectrometry (LRMS) analyses were performed Finnigan Trace GC-MS (Thermo Scientific,
Schlieren, Switzerland) (EI mode at 70 eV); GC column: Optima Delta 3 0.25 µm, 20 m, 0.25 mm
(Macherey-Nagel, Oensingen, Switzerland). The infrared measurements were performed on a Jasco
FTIR-460 Plus spectrometer equipped with a Specac MKII Golden Gate Single Reflection Diamond ATR
System and are reported in wave numbers (cm−1). All reagents were obtained from commercial sources
and used without further purification, unless otherwise mentioned. All reactions solvents (distilled
THF, distilled Et2O, distilled dichloromethane, commercial toluene and benzene) were filtered over
columns of activated alumina under a positive pressure of argon. Solvents for flash chromatography
and extractions were of technical grade and were distilled prior to use. Hexamethyldisilazane (HMDS)
was fractionally distilled under a nitrogen atmosphere before use. 1,2-Dichloroethane (DCE) was
distilled over CaH2 under a nitrogen atmosphere.
3.2. General Procedures
Hexabutylditin-mediated carboazidation (procedure A)
Di-tert-butyl hyponitrite (DTBHN) [48] (0.1 equiv) was added in one portion to a solution of
alkene (2–4 equiv), iodomethyl derivative (1 equiv), (Bu3Sn)2 (1.2 equiv), and ArSO2N3 [49] (3 equiv.)
in benzene (0.5 M). The solution was stirred at 70 ◦C for 3 h. The crude mixture was directly purified
by flash chromatography (FC) using KF/silica [50].
Et3B-mediated carboazidation (procedure B)
A 1 M solution of Et3B (3–4 equiv) was added at room temperature (rt) over 2 h via syringe pump
to an open flask and then charged with a vigorously stirred mixture of alkene (2–4 equiv), iodomethyl
derivative (1 equiv), and 3-PySO2N3 [49] (3 equiv) in solvent (0.66 M). Caution: the needle should be
immersed into the reaction mixture in order to avoid direct contact of Et3B drops with air. The reaction
vessel should be protected from direct light exposure by aluminum foil. After 1 h stirring, H2O and
CH2Cl2 were added, and the layers were separated. The aqueous layer was extracted with CH2Cl2
(3×). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was
removed under reduced pressure, and the crude product was purified by FC.

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Julia–Kocienski olefination
The phenyltetrazole sulfone derivative (1 equiv) was dissolved/diluted in THF (0.15 M) and
cooled to
78 ◦C. A freshly prepared LiHMDS solution in THF (1.5 equiv) was added slowly and
stirred for a further 30 min at
78 ◦C. Aldehyde (2 equiv) was added neat and stirred for a further
3 h at
78 ◦C. The reaction mixture was allowed to reach rt and was further stirred at rt overnight.
H2O and Et2O were added to the reaction suspension, and the layers were separated. The aqueous
phase was extracted with Et2O (3 ). The combined organic layers were washed with brine and dried
−
−
−
×
over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified
by FC.
5-((2-(1-Azidocyclohexyl)ethyl)sulfonyl)-1-phenyl-1H-tetrazole (15a)
According to the procedure A from di-tert-butylhyponitrite (17 mg, 0.10 mmol),
methylenecyclohexane 5a (0.24 mL, 2.00 mmol), 5-((iodomethyl)sulfonyl)-1-phenyl-1H-tetrazole 14
(350 mg, 1.00 mmol), hexabutylditin (0.61 mL, 1.20 mmol), and 3-PySO2N3 (552 mg, 3.00 mmol) in
benzene (2.0 mL). The crude mixture was directly purified by FC using KF/silica gel (cyclohexane/EtOAc,
95:5) to afford 15a (325 mg, 90%).
According to the procedure B from a 1 M solution of Et3B in CH2Cl2 (4.00 mL, 4.00 mmol),
methylenecyclohexane 5a (0.24 mL, 2.00 mmol), 5-((iodomethyl)sulfonyl)-1-phenyl-1H-tetrazole 14
,
(350 mg, 1.00 mmol), 3-PySO2N3 (552 mg, 3.00 mmol), and CH2Cl2 (0.50 mL). Purification by FC
(cyclohexane/EtOAc, 95:5) afforded 15a (260 mg, 72%). The NMR spectra of some compounds are in
the Supplementary Materials.
Colorless crystals: m.p. 90.9–93.6 ◦C. 1H NMR (300 MHz, CDCl3):
3H), 3.90–3.84 (m, 2H), 2.24–2.18 (m, 2H), 1.81–1.73 (m, 2H), 1.69–1.29 (m, 8H). 13C NMR (75 MHz,
δ = 7.76–7.72 (m, 2H), 7.69–7.62 (m,
CDCl3):
δ = 153.31, 132.96, 131.50, 129.75 (2C), 125.00 (2C), 62.45, 51.61, 34.41 (2C), 31.72, 25.07, 21.96
(2C). IR (neat): 2933, 2856, 2098, 1497, 1337, 1253, 1150. HRMS (ESI): calcd. for [M + H]+: C15H20N7O2S
calcd 362.1394; found: 362.1400.
(3-(1-Azidocyclohexyl)prop-1-en-1-yl)benzene (17a)
According to the Julia–Kocienski procedure from 15a (260 mg, 0.72 mmol), LiHMDS in THF
(1.66 mL, 1.08 mmol), benzaldehyde (0.15 mL, 1.44 mmol), and THF (3.00 mL). Purification by FC
(cyclohexane/EtOAc, 98:2) afforded the alkene 17a as an inseparable mixture of isomers (141 mg, E/Z >
95:5, 81%). Colorless oil.
1
(E)-17a (major): H NMR (300 MHz, CDCl3):
δ = 7.39–7.20 (m, 5H), 6.47 (d, J = 15.8 Hz, 1H), 6.24 (dt,
J = 15.8, 7.4 Hz, 1H), 2.46 (dd, J = 7.4, 1.2 Hz, 2H), 1.72 (d, J = 13.1 Hz, 2H), 1.65–1.39 (m, 7H), 1.32–1.21
(m, 1H). 13C NMR (75 MHz, CDCl3): = 137.24, 133.74, 128.51 (2C), 127.29, 126.17 (2C), 124.36, 64.22,
43.93, 34.52 (2C), 25.33, 22.07 (2C).
1
Characteristic signals for (Z)-17a (minor): H NMR (300 MHz, CDCl3):
δ = 2.55 (d, J = 5.8 Hz, 2H). IR
(neat): 3027, 2931, 2858, 2096, 1495, 1447, 1254, 1138, 1102, 1029. EI-MS m/z (%): M–N2: 213.3 (21),
198.3 (7), 170.3 (20), 156.3 (16), 128.3 (10), 117.3 (100), 115.3 (73), 96.3 (63), 91.3 (40), 69.3 (34), 55.3 (39).
HRMS (ESI): calcd. for [M + H]+: C15H20N3: 242.1652; found: 242.1655.
4. Conclusions
In conclusion, we demonstrated that the azidoalkylation of terminal alkenes is not limited to
α
-iodoester and α-iodoketones. The reaction also works well with nitriles, phosphonates, phthalimides,
and aryl sulfones. This last class of compounds is particularly interesting in terms of potential synthetic
applications. This point was illustrated by the preparation of homoallylic azides by merging the
azidoalkylation process with a Julia–Kocienski olefination reaction. Recently, 1-phenyl-1H-tetrazole
sulfones have also been shown to be privileged substrates for reductive cross-coupling processes,
opening new opportunities for further functionalization [51,52].

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Supplementary Materials: Detailed experimental procedures and NMR spectra of all compounds are available
online at http://www.mdpi.com/1420-3049/24/22/4184/s1.
Author Contributions: Conceptualization and methodology, N.M., G.L. and P.R.; Experimental work N.M., G.L.;
writing—original draft preparation, N.M.; Writing—review and editing, P.R.; Supervision, project administration
and funding acquisition, P.R.
Funding: This research was funded by the Swiss National Science Foundation (Project 200020_172621).
Conflicts of Interest: The authors declare no conflict of interest.
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