Stereoselective radical azidooxygenation of alkenes

Article abstract of DOI:10.1021/ol402106x

Radical azidooxygenation of various alkenes is described. A readily prepared N₃-iodine(III) reagent acts as a clean N₃-radical precursor. Radical generation is achieved with TEMPONa acting as a mild organic reducing reagent. The C-radical generated after N₃-radical addition is efficiently trapped by in situ generated TEMPO. Yields are good to excellent, and for cyclic systems azidooxygenation occurs with excellent diastereoselectivity.

Full text of DOI:10.1021/ol402106x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Stereoselective Radical Azidooxygenation
of Alkenes
Bo Zhang and Armido Studer*
€
Institute of Organic Chemistry, Westfalische Wilhems-University, Corrensstrasse 40,
48149, Mu€nster, Germany
studer@uni-muenster.de
Received July 25, 2013
ABSTRACT
Radical azidooxygenation of various alkenes is described. A readily prepared N3-iodine(III) reagent acts as a clean N3-radical precursor. Radical
generation is achieved with TEMPONa acting as a mild organic reducing reagent. The C-radical generated after N3-radical addition is efficiently
trappedby in situ generatedTEMPO. Yields are good toexcellent, and for cyclic systems azidooxygenation occurswith excellent diastereoselectivity.
Organic azides are highly important compounds which
have gained renewed attention due to their intensive use as
coupling partners in azide/alkyne cycloaddition (bona fide
click reaction).1 Moreover, azides are easilytransformedto
amines and serve as starting materials for other useful
transformations.2 Alkyl azides are generally prepared via
ionic substitution of alkyl halides with an inorganic
azide as a nucleophile.3 Hydroazidation of alkenes can
be achieved with HN3,4a TMSN3,4b TosN3,4c and NaN3.4d
Renaud nicely demonstrated the efficiency of radical
chemistry for the introduction of azide functionality.5
In these reactions, alkyl or arylsulfonyl azides were used
as C-radical acceptors. However, azidation via a reaction
of the electrophilic azidyl radical6a with an alkene has not
been well explored. Azido-phenylselenylation was achieved
by radical azidation with PhI(OAc)3/NaN3 in the presence
of PhSeSePh.6b In polar solvents, in situ generated N3I
reacts with alkenes to the corresponding vicinal azidoio-
dides via an ionic mechanism.7 In apolar solvents radical
type addition can be achieved as judged by the regiochem-
ical outcome of the vicinal difunctionalization.8 Reaction
of NaN3 with ceric ammonium nitrate (CAN) and an
alkene was reported to give the corresponding R-azido-β-
nitratoalkene likely via an initial azidyl radical addition.6c,d
However, in many cases the azidyl radical was used for
C-radical generation via H-abstraction and CꢀN-bond
(1) Reviews: (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2001, 40, 2004–2021. (b) Barner-Kowollik, C.; Du Prez,
F. E.; Espeel, P.; Hawker, C. J.; Junkers, T.; Schlaad, H.; Van Camp, W.
Angew. Chem., Int. Ed. 2011, 50, 60–62.
(6) (a) Worketin, M. S.; Wagner, B. D.; Lusztyk, J.; Wayner,
D. D. M. J. Am. Chem. Soc. 1995, 117, 119–126. (b) Tingoli, M.; Tiecco,
M.; Chianelli, D.; Balducci, R.; Temperini, A. J. Org. Chem. 1991, 56,
6809–6813 and references cited. (c) Trahanovsky, W. S.; Robbins, M. D.
J. Am. Chem. Soc. 1971, 93, 5256–5257. (d) Lemieux, R. U.; Ratcliffe,
R. M. Can. J. Chem. 1979, 57, 1244–1251.
(2) Pinho e Melo, T. M. V. D. In Organic Azides: Syntheses and
€
Applications; Brase, S., Banert, K., Eds.; Wiley-VCH: 2010; pp 53ꢀ94.
€
(3) Brase, S., Banert, K., Eds. Organic Azides: Syntheses and Applica-
(7) Hassner, A. Acc. Chem. Res. 1971, 4, 9–16. (b) Barluenga, J.;
ꢀ
Alvarez-Perez, M.; Fananas, F. J.; Gonzalez, J. M. Adv. Synth. Catal.
ꢀ
ꢀ
ꢀ
tions; Wiley-VCH: 2010.
2001, 343, 335–337.
(8) Kirschning, A.; Hashem, M. A.; Monenschein, H.; Rose, L.;
(4) (a) Hassner, A.; Fibiger, R.; Andisik, D. J. Org. Chem. 1984, 49,
4237–4244. (b) Breton, G. W.; Daus, K. A.; Kropp, P. J. J. Org. Chem.
1992, 57, 6646–6649. (c) Waser, J.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 8294–8295. (d) Leggans, E. K.; Barker, T. J.; Duncan, K. K.;
Boger, D. L. Org. Lett. 2012, 14, 1428–1431.
€
Schoning, K.-U. J. Org. Chem. 1999, 64, 6522–6526. (b) Curini, M.;
Epifano, F.; Marcotullio, M. C.; Rosati, O. Tetrahedron Lett. 2002, 43,
1201–1203.
(5) (a) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2000, 122, 6496–
6497. Reviews: (b) Ranchaud, P.; Chabaud, L.; Landais, Y.; Ollivier, C.;
Renaud, P.; Zigmantas, S. Chem.;Eur. J. 2004, 10, 3606–3614. (c)
Lapointe, G.; Kapat, A.; Weidner, K.; Renaud, P. Pure Appl. Chem.
2012, 84, 1633–1641.
(9) (a) Fontana, F.; Minisci, F.; Yan, Y. M.; Zhao, L. Tetrahedron
Lett. 1993, 34, 2517–2520. (b) Viuf, C.; Bols, M. Angew. Chem., Int. Ed.
2001, 40, 623–625. (c) Marinescu, L. G.; Pedersen, C. M.; Bols, M.
Tetrahedron 2005, 61, 123–127. See also (d) Harschneck, T.; Hummel, S.;
Kirsch, S. F.; Kahn, P. Chem.;Eur. J. 2011, 18, 1187–1193.
r
10.1021/ol402106x
XXXX American Chemical Society

formation in such transformations occurs via a subsequent
ionic process.9 Herein we report radical azidooxygenation
of various alkenes using azidoiodine(III) reagent 110 as
a N3-radical precursor under mild reductive conditions
(Scheme 1).11,12
Table 1. Azidooxygenation of Styrene under Various Conditions
Scheme 1. Radical Azidooxygenation of Alkenes
1
2
time
(h)
temp
(°C)
yield
(%)a
entry
(equiv)
(equiv)
1
2
3
4
5
6
7
8
1.5
2
2
3
3
3
3
3
2
1.5
2
3
2
3
3
3
3
2
4
4
4
4
4
3
5
6
6
6
6
6
20
20
20
20
20
20
20
20
20
20
0
50
57
57
56
65
53
75
94
74
90
21
93
9
10
11
12
2.5
3
3
2.5
3
3
40
We have recently shown that the CF3-radical can be
cleanly generated from a CF3-iodine(III) reagent (Togni
reagent)13 by single electron transfer (SET) using TEM-
PONa 214 as an organic reducing reagent.15 Based on that
result we decided to investigate azidyl radical generation
from azidoiodine(III) reagent 1 by reduction with 2. If SET
is conducted in the presence of an alkene, the N3-radical
should add to the alkene and the adduct radical generated
will be trapped by the 2,2,6,6-tetramethylpiperidine-N-
oxyl radical (TEMPO)16 which is formed as a byproduct
in the initial SET to eventually give the azidooxygenation
product 3 (Scheme 1). Selective cross-coupling of the
a Isolated yields.
adduct radical by TEMPO is steered by the persistent
radical effect.17
The reaction was optimized using styrene as a test
substrate. The concentration, solvent, and stoichiometry
of the reagents were systematically varied, and 3a was
isolated by purification using SiO2-chromatography. Re-
actions were conducted by slowly adding a freshly pre-
pared THF solution of TEMPONa (0.875 M) to a CH2Cl2
solution (0.2 M) of styrene and 1 at rt togive 3a. Pleasingly,
with 1.5 equiv of 1 and 2 each for 4 h the targeted
azidooxygenation product 3a was isolated in a promising
50% yield (Table 1, entry 1). Increasing the amount of
reagents 1 and 2 led to a further improvement of the yield,
and the best result was achieved upon using a 3-fold excess
of 1 and 2 (Table 1, entries 2ꢀ5, 9, 10). It is likely that the
in situ generated azidyl radical is trapped in a side reaction
by TEMPO to give an unstable N3-TEMPO derivative
which however could not be detected by mass spectro-
metric analysis. We found that a 6 h reaction time is ideal
for this transformation (Table 1, entries 6ꢀ8). Other
solvents such as CH3CN, THF, and trifluorotoluene pro-
vided lower yields (not shown), and running the reaction
at a lower temperature afforded a lower yield (Table 1,
entry 11). Increasing the temperature to 40 °C did not
affect the yield to a large extent (Table 1, entry 12); there-
fore all other experiments were conducted at rt.
(10) 1 was prepared according to: Akai, S.; Okuno, T.; Egi, M.;
Takada, T.; Tohma, H.; Kita, Y. Heterocycles 1996, 42, 47–51.
(11) Applications of azido iodine(III) reagents: (a) Magnus, P.;
Lacour, J. J. Am. Chem. Soc. 1992, 114, 767–769. (b) Magnus, P.; Lacour,
J.; Weber, W. J. Am. Chem. Soc. 1993, 115, 9347–9348. (c) Kita, Y.;
Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mitoh, S.; Sakurai, H.;
Oka, S. J. Am. Chem. Soc. 1994, 116, 3684–3691. (d) Tingoli, M.;
Temperini, A.; Testaferri, L.; Tiecco, M. Synlett 1995, 1129–1130. (e)
Chen, D.-J.; Chen, Z.-C. Tetrahedron Lett. 2000, 41, 7361–7363. (f)
Chung, R.; Yu, E. S.; Incarvito, C. D.; Austin, D. J. Org. Lett. 2004, 6,
ꢀ
3881–3884. (g) Barluenga, J.; Campos-Gomez, E.; Rodrıguez, D.;
´
ꢀ
ꢀ
Gonzalez-Bobes, F.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2005, 44,
5851–5854. (h) Li, X.-Q.; Wang, W.-K.; Zhang, C. Adv. Synth. Catal.
2009, 351, 2342–2350. (i) Zhou, W.; Zhang, L.; Jiao, N. Angew. Chem., Int.
Ed. 2009, 48, 7094–7097. (j) Li, X.-Q.; Wang, W.-K.; Han, Y.-X.; Zhang,
C. Adv. Synth. Catal. 2010, 352, 2588–2598. (k) Matcha, K.; Antonchick,
A. P. Angew. Chem., Int. Ed. 2013, 52, 2082–2086. (l) Antonchick, A. P.;
Burgmann, L. Angew. Chem., Int. Ed. 2013, 52, 3267–3271.
(12) (a) Reviews on iodine(III) chemistry: (a) Wirth, T. Angew.
Chem., Int. Ed. 2005, 44, 3656–3665. (b) Zhdankin, V. V.; Stang, P. J.
Chem. Rev. 2008, 108, 5299–5358. (c) Yusubov, M. S.; Zhdankin, V. V.
Curr. Org. Synth. 2012, 9, 247–272.
(13) (a) Eisenberger, P.; Gischig, S.; Togni, A. Chem.;Eur. J. 2006,
12, 2579–2586. (b) Wiehn, M. S.; Vinogradova, E. V.; Togni, A.
J. Fluorine Chem. 2010, 131, 951–957. (c) Matousek, V.; Togni, A.;
Bizet, V.; Cahard, D. Org. Lett. 2011, 13, 5762–5765 and references cited
therein.
(14) Inokuchi, T.; Kawafuchi, H. Tetrahedron 2004, 60, 11969–
11975.
(15) (a) Li, Y.; Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8221–
8224. (b) See also: Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950–
8958.
Under optimized conditions various terminal alkenes
were tested in the radical azidooxygenation reaction to
give the corresponding products 3bꢀv (Table 2). Styrene
derivatives bearing electron-donating substituents at the
para-position afforded the azides 3c (4-Me), 3e (4-t-Bu),
(17) (a) Fischer, H. Chem. Rev. 2001, 101, 3581–3610. (b) Studer, A.
Chem.;Eur. J. 2001, 7, 1159–1164. (c) Studer, A. Chem. Soc. Rev. 2004,
33, 267–273. (d) Studer, A.; Schulte, T. Chem. Rec. 2005, 5, 27–35.
(16) Reviews: (a) Vogler, T.; Studer, A. Synthesis 2008, 1979–1993.
(b) Tebben, L.; Studer, A. Angew. Chem., Int. Ed. 2011, 50, 5034–5068.
B
Org. Lett., Vol. XX, No. XX, XXXX

and 3f (4-MeO) in good to excellent yields (85ꢀ98%,
Table 2, entries 1, 4, 5). Ortho- and meta-substituted
congeners showed similar reactivity (Table 2, entries 2, 3).
As expected due to the electrophilic nature of the N3-
radical, styrene derivatives carrying electron-withdrawing
substituents provided slightly lower but still good yields
(see 3gꢀi, 3lꢀn, Table 2, entries 6ꢀ8, 11ꢀ13).
(Figure 1). Selectivity was determined by 1H NMR analy-
sis of the crudeproduct. β-Methylstyrene reacted under the
standard conditions with complete regioselectivity to 3w
which was isolated in 95% yield. Azide 3wwas formedwith
4.3:1 diastereoselectivity, and assignment of the relative
configuration was based on the allylic A[1,3]-strain
model.18,19 Very low selectivity but good yield was ob-
tained in the transformation of trans-stilbene (3x, dr =
1:1.1, 88%). Dihydronaphthalene and indene reacted with
excellent trans-selectivity and complete regioselectivity to
produce the corresponding azides 3y and 3z in excellent
yields. Complete trans-selectivity but slightly lower yields
were achieved for the radical azidooxygenation of cyclo-
hexene and dihydropyran (see 3aa and 3ab). For electronic
reasons only one regioisomer was formed in the reaction of
the cyclic enol ether. Norbornene was transformed with
complete exo-selectivity for the initial N3-radical addition
and perfect trans-selectivity in the TEMPO trapping step
(3ac), and also benzofuran reacted with complete regio-
and diastereoselectivity (3ad) in good yield.
Table 2. Radical Azidooxygenation of Terminal Alkenes
entry
R1
R2
compd
yield (%)a
1
2
3
4
5
6
7
8
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
4-t-BuC6H4
4-CH3OC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-PhC6H4
β-naphthyl
4-NCC6H4
4-CF3C6H4
4-AcOC6H4
4-pyridyl
PhCH2CH2
BuO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3b
3c
3d
3e
3f
3g
3h
3i
85
89
94
97
98
88
84
88
73
90
60
72
52
57
35b
66
84
96
77
80
80
9
3j
3k
3l
10
11
12
13
14
15
16
17
18
19
20
21
3m
3n
3o
3p
3q
3r
3s
3t
N-carbazyl
C6H5
C2H5
-CH2(CH2)4CH2-
2-AllylC6H4
H
CH3
C2H5
3u
3v
H
a Isolated yields. b Using 5 equiv of 1 and 5 equiv of 2.
Figure 1. Products obtained by diastereoselective radical azi-
dooxygenation of internal alkenes.
β-Vinylnaphthalene afforded a 90% yield of 3k, and a
slightly lower yield was achieved with para-vinylbiphenyl
(see 3j, 73%) likely due to the inductive effect exerted by
the second phenyl group (Table 2, entries 9, 10). However,
the aliphatic alkene, 4-phenylbut-1-ene, was not a good
substrate and 3p was isolated in only a 35% yield (Table 2,
entry 15). It is known that the azidyl radical reacts
slowly with unactivated aliphatic terminal alkenes.6a Im-
portantly, this reactivity difference can be used for highly
regioselective azidooxygenation as shown in the reaction
of ortho-allylstyrene to give the benzylic alkoxyamine 3v in
good yield (80%, entry 21). Azidation at the less reactive
allyl group did not occur under the applied conditions.
Electron rich enol ethers or enamines gave good results
(Table 2, entries 16, 17). Terminal aliphatic alkenes if
activated by an additional alkyl group at the β-position
such as in 2-ethylbut-1-ene or methenylcyclohexane afford
in good to excellent yields the corresponding tertiary
alkoxyamines (see 3t,u in Table 2, entries 19, 20).
To document the potential of the azidooxygenation
products as building blocks in the synthesis we investigated
the follow up chemistry. Chemical modification of the azide
functionality was studied first using 3a as the substrate
(Scheme 2). Azide reduction was achieved by treating 3a
with CuSO4/NaBH4 in MeOH at0 °C to provide amine 4 in
95% yield.20 Benzotriazole 5 (82%) was readily obtained
by the reaction of in situ generated benzyne with 3a,21 and
as expected, 3a was a suitable substrate for a Cu-catalyzed
[3 þ 2] alkyne/azide cycloaddition (CAAC; see 6, 84%).1
The alkoxyamine moiety in these azidooxygenation
products offers unique and diverse reactivity.16b For
example, oxidation of that functionality in 3a with
meta-chloroperbenzoic acid (MCPBA) at rt afforded the
(18) Curran, D. P.; Thoma, G. J. Am. Chem. Soc. 1992, 114, 4436–4437.
(19) All compounds reported were prepared as racemates.
(20) Rao, H. S. P.; Siva, P. Synth. Commun. 1994, 24, 549–555.
(21) Reddy, B. V. S.; Praneeth, K.; Yadav, J. S. Carbohydr. Res. 2011,
346, 995–998.
To address the diastereoselectivity of the novel process
we investigated the azidooxygenation of internal alkenes
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Transformation of the Azide Functionality in 3a
Scheme 4. NMP of Styrene Using 12 as Initiator/Regulator
Scheme 3. Diverse Reactivity of the Alkoxyamine Functionality
temperature are cleanly homolytically cleaved.17 Heating
of alkoxyamine 6 in the presence of PhSH as a radical
reducing reagent provided the deoxygenated triazole 11 in
quantitative yield.
To further document the potential of these bifunctional
aminoxygenation products we successfully used 3a for the
preparation of a diblock copolymer. CAAC of 3a with a
pegylated alkyne gave alkoxyamine 12 (72%, see Support-
ing Information) which was thenusedasa radical initiator/
mediator for the nitroxide mediated radical polymeriza-
tion of styrene (NMP, Scheme 4).17 NMP using 1 mol % of
12 in neat styrene at 130 °C for 3 h provided the diblock
copolymer 13 (Mn = 4900 g/mol, PDI = 1.10, 51%
conversion) convincingly documenting that the chemistry
presented is very well suited for the preparation of NMP
initiators.
In conclusion, we reported a novel method for radical
azidation using readily prepared N3ꢀI(III)-reagent 1 and
TEMPONa, generated from commercially available TEMPO
and sodium. In these processes TEMPONa first acts as a mild
organic reducing reagent (SET) for N3-radical generation
under formation of TEMPO which subsequently reacts as
an oxidant for adduct C-radical trapping. The azidooxygena-
tion works efficiently on various styrene derivatives and on
electron-rich alkenes. Experiments are easy to conduct, and
products are generally obtained in good to excellent yields.
For cyclic systems the vicinal difunctionalization occurs
with excellent diastereoselectivity. Importantly, the products
obtained are highly useful materials for further chemical
manipulations as documented by various transformations.
R-azidoketone 7 in 90% yield (Scheme 3).22 The NꢀO
bond in alkoxyamines can be readily cleaved under mild
conditions. Alkoxyamine 8,23 obtained by CAAC of 3ac
with phenyl acetylene, was converted to alcohol 9 by using
Zn in AcOH/H2O at rt.24 In analogy, we obtained alcohol
10 starting from triazole 6. TEMPO-derived benzylic
alkoxyamines have weak CꢀO bonds which at higher
(22) Hartmann, M.; Li, Y.; Studer, A. J. Am. Chem. Soc. 2012, 134,
16516–16519.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (DFG) for supporting our work.
(23) The structure of 8 was also characterized by X-ray analysis.
CCDC 936564 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge at www.ccdc.cam.ac.
uk/-conts/retrieving.html [or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(internat.) þ44(1223)336-033, E-mail: deposit@ccdc.cam.ac.uk].
(24) NꢀO cleavage leaving the azide functionality intact was not
possible.
Supporting Information Available. Experimental details
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX