Cobalt-catalyzed synthesis of tertiary azides from α,α- disubstituted olefins under mild conditions using commercially available reagents

Article abstract of DOI:10.1055/s-2007-1000817

The use of commercially available azide sources is presented for the cobalt-catalyzed hydroazidation reaction. α,α-Disubstituted olefins with a variety of functional groups were employed as substrates, providing tertiary azides in useful yields. Georg Thi

Full text of DOI:10.1055/s-2007-1000817

PAPER
3839
Cobalt-Catalyzed Synthesis of Tertiary Azides from a,a-Disubstituted Olefins
under Mild Conditions Using Commercially Available Reagents
TertiaryAzides
f
o
a
,
a
-Disu
r
bstitute
d
O
lefin
s
s
Gaspar, Jérôme Waser, Erick M. Carreira*
Laboratorium für Organische Chemie, ETH Hönggerberg, HCI G336, 8093 Zürich, Switzerland
Fax +41(1)6321328; E-mail: carreira@org.chem.ethz.ch
Received 12 September 2007
lectivity was observed and, importantly, tertiary azides
Abstract: The use of commercially available azide sources is pre-
sented for the cobalt-catalyzed hydroazidation reaction. a,a-Disub-
stituted olefins with a variety of functional groups were employed
as substrates, providing tertiary azides in useful yields.
were accessible by this method when geminally disubsti-
tuted and trisubstituted olefins were employed. In this pa-
per, we describe the azidation of olefins under milder
conditions with commercially available reagents, which
are marketed as safe alternatives to TsN3 (Scheme 1).
Key words: alkenes, hydroazidation, homogeneous catalysis, co-
balt, silanes
In our ongoing investigations we have conducted a de-
tailed study into the effect of catalyst, silane and tert-butyl
hydroperoxide (t-BuOOH) additives, including mechanis-
tic investigations.12 Furthermore, we observed that the
structure of the azide source had a significant influence on
the reaction. The arylsulfonyl azide scaffold proved to be
the best and three compounds were recognized as efficient
hydroazidating agents. All of them however, had to be
prepared in advance and, therefore, we decided to test the
more readily available arylsulfonyl azides. Such an azide
source would render the method even more practical as all
the components, including ligand 2, would be commer-
cially available.
The use of organic azides as nucleophiles, electrophiles or
nitrene precursors demonstrates their unique position in
organic chemistry.1 Their synthetic utility is represented
by their easy conversion to amines2 and by cycloaddition
reactions.3 Recently, they attracted much attention espe-
cially in biochemistry for the Staudinger ligation4 and
click chemsitry.5 Primary and secondary alkyl azides are
commonly prepared by classic nucleophilic substitution,
but tertiary azides are more difficult to access by this ap-
proach.1 Moreover, substrates with a suitable leaving
group are usually not readily available and have to be pre-
pared. The hydroazidation of olefins represents a more di-
rect access to these interesting compounds. Such an
approach, however, is limited to alkenes that give rise to
stabilized carbocations and requires excess hydrazoic acid
(HN3),6 trimethylsilyl azide (TMSN3)7 or zeolite-support-
ed sodium azide (NaN3).8 Conjugate additions to
unsaturated carbonyl compounds9 and several multi-
functionalization methods have been developed as well.10
Given the limitations of the known processes, a new azi-
dation protocol was deemed desirable.
Using our standard conditions13 and 4-phenylbutene (1a)
as a test substrate, we examined four different commer-
cially available azide sources 4–7 (Scheme 2).14
4-Acetamidobenzenesulfonyl azide (4) was the best re-
agent, giving azide 3a in 82% yield after 1.5 hours. 4-Carb-
oxybenzenesulfonyl azide (5) and benzenesulfonyl azide
functionalized silica (7) were less active, providing the
hydroazidation product 3a in 48% and 59% yield, respec-
tively. Polymer-bound benzenesulfonyl azide (6) failed to
give any product at all. With sulfonyl azide 4, we could
improve the yield of 3a to 92% by conducting the reaction
at 0 °C. Nonetheless, when submitting the sterically more
challenging disubstituted olefin 1b, we were not able to
get high conversions to the product 3b, even after varying
the reaction conditions. It was apparent that sulfonyl azide
We have recently described a cobalt-catalyzed hydroazi-
dation reaction of unactivated olefins 1 using tosyl azide
(TsN3) and a silane.11 We discovered that the diphenyl-
glycine-derived ligand 2 provided the highest reactivity in
the hydroazidation reaction. Excellent Markovnikov se-
Ph
N
Ph
CO2K
t-Bu
OH
2 (6 mol%)
R3
R1
R1
R2
t-Bu
R3
ArSO2N3
+
H
R2
Co(BF4)2⋅6H2O (6 mol%)
t-BuOOH (30 mol%), silane
EtOH, 23 °C
N3
1
3
Scheme 1
SYNTHESIS 2007, No. 24, pp 3839–3845
x
x.
x
x
.
2
0
0
7
Advanced online publication: 28.11.2007
DOI: 10.1055/s-2007-1000817; Art ID: E19407SS
© Georg Thieme Verlag Stuttgart · New York

3840
B. Gaspar et al.
PAPER
N3
Co(BF4)2⋅6H2O, ligand 2
azide source
+
Ph
Ph
t-BuOOH, TMDSO
EtOH, 23 °C
1a
3a
azide source:
HN
O
SO2N3
SO2N3
HO2C
benzenesulfonyl azide
6 (polymer-bound) 0%
7 (functionalized silica) 59%
4
5
82%
48%
Scheme 2
SO2N3
Co(BF4)2⋅6H2O, ligand 2
O
+
O
TBDPS
N3
TBDPS
t-BuOOH, TMDSO
EtOH, 23 °C
3b
1b
COONa
92%
8
Scheme 3
Table 1 Hydroazidation of Geminally Disubstituted Olefins with 8a
(continued)
5 could be easily modified given the carboxylic function-
ality. Deprotonation with sodium ethoxide provided the
corresponding sodium salt 8 as a bench-stable, amorphous
solid. To our delight, 1.5 equivalents of 8 with 6 mol% of
catalyst, 30 mol% of t-BuOOH and two equivalents of tet-
ramethyldisiloxane (TMDSO), was able to completely
convert the disubstituted olefin 1b into the corresponding
azide 3b in 92% yield (Scheme 3).
N3
R
R
1
3
Entry Alkene
Product Time (h) Yield (%)
5
6
7
3f
4
8
8
70
84
73
Ph
O
It is important to note that the reaction was heterogeneous
since 8 was poorly soluble in ethanol. Next, we optimized
the synthesis in order to obtain 8 in reasonable purity. Us-
ing sodium hydride in tetrahydrofuran at room tempera-
ture, we could obtain sodium 4-azidosulfonylbenzoate (8)
O
1f
3g
3h
O
Ph
O
O
1
1g
in 86% yield and 95% purity (confirmed by H NMR).
With a reliable procedure in hand, we proceeded to exam-
ine the scope of the hydroazidation reaction (Table 1).
Ph
N
H
Table 1 Hydroazidation of Geminally Disubstituted Olefins with 8a
1h
O
8
9
3i
11
9
74
75
78
H
N
N3
Boc
O
R
R
1i
1
3
3j
3k
O
H
N
Entry Alkene
1
Product Time (h) Yield (%)
Boc
O
3c
3b
3d
7
4
7
94
92
71
1j
Ph
10
7
O
1c
H
N
2
O
O
O
O
TBDPS
Ph
1b
1k
Boc
1l
3
OH
11
3l
9
52
O
H
N
HO
1d
4
3e
7
48
Ph
O
a Reagents and conditions: Co(BF4)2·6H2O (6 mol%), ligand 2 (6
mol%), alkene (0.5 mmol), azide 8 (0.75 mmol), t-BuOOH (28
mol%), TMDSO (1 mmol), EtOH (2.5 mL), argon, 23 °C.
O
1e
Synthesis 2007, No. 24, 3839–3845 © Thieme Stuttgart · New York

PAPER
Tertiary Azides from a,a-Disubstituted Olefins
3841
In our investigations we found that geminally disubstitut- 6). These results indicate that the two protocols are com-
ed olefins were especially good substrates for the reaction, plementary, with the pre-formed azide 8 being slightly
and as these compounds provide tertiary azides, which are more active and the in situ protocol being more straight-
difficult to prepare by other methods, we decided to focus forward. An advantage of both protocols is the easy re-
on this class of alkene.
moval of any excess reagent in the aqueous work-up.
All olefins showed excellent Markovnikov selectivity as
linear azides were never observed. A simple alkene and a
protected alcohol were good substrates for the reaction
(entries 1 and 2). In contrast to the protocol using tosyl
azide (TsN3), free alcohols could be employed, providing
the corresponding azides in good yields (entries 3 and 11).
Esters (entries 4–6) and amides were well tolerated (entry
7) and substrates with an alkene functionality connected
to either the O-end of an amino acid through an ester link-
age (entries 8, 9 and 11) or to the N-end through an amide
bond (entry 10), give interesting products in useful yields.
Alkenes conjugated to stabilizing groups such as an ester
or a phenyl showed no conversion at all and thus represent
a limitation of the process.
Table 2 Hydroazidation of Geminally Disubstituted Olefins with
Triethylammonium 4-Azidosulfonylbenzoate Formed in situa
N3
R
R
1
3
Entry Alkene
Product Time (h) Yield (%)
1
3c
7
6
99
93
Ph
1c
2
3b
3e
O
TBDPS
1b
Although sodium 4-azidosulfonylbenzoate (8) is an easy
to handle, stable solid, we were interested in forming the
reagent in situ, thus avoiding the pre-formation and isola-
tion process. Formation of the sodium salt of carboxyben-
zenesulfonyl azide 5 in situ resulted in a very dense
heterogeneous mixture and the stirring was not efficient.
Interestingly, when using the pre-formed sodium salt 8,
the mixture was less dense and stirring was never prob-
lematic. Finally, mixing azide 5 with triethylamine in eth-
anol formed the triethylammonium salt as a clear
Ph
O
3
18
6
76
62
57
O
1e
Ph
O
4
3f
3i
O
1f
O
H
N
5
6
11
Boc
O
homogeneous
mixture.
Simple
addition
of
Co(BF4)2·6H2O (6 mol%), ligand 2 (6 mol%), t-BuOOH
(30 mol%), TMDSO (2 equiv) and alkene 1b (1 equiv) to
this clear solution (1.5 equiv of azide 5 and 1.43 equiv
Et3N), resulted in a smooth reaction providing tertiary
azide 3b in 93% yield (Scheme 4).
1i
O
H
N
3j
9
57
Boc
O
1j
In order to compare the two reagents [sodium 4-azidosul-
fonylbenzoate (8) versus triethylammonium azidosulfo-
nyl benzoate], several alkenes were submitted to the
hydroazidation reaction with the in situ formed triethyl-
ammonium azidosulfonyl benzoate (Table 2).
a Reagents and conditions: azide 5 (0.75 mmol), Et3N (0.715 mmol),
Co(BF4)2·6H2O (6 mol%), ligand 2 (6 mol%), alkene (0.5 mmol),
t-BuOOH (28 mol%), TMDSO (1 mmol), EtOH (2.5 mL), argon,
23 °C.
Alkenes 1b and 1c gave practically the same yields as
with the pre-formed azide 8 (Table 2, entries 1 and 2). Es-
ters gave comparable results as well, with 1e being slight-
ly more active (Table 2, entries 3 and 4). However,
substrates where the alkene functionality was connected
to an amino acid through an ester bond provided the cor-
responding azide in lower yields (Table 2, entries 5 and
In summary, we have extended our hydroazidation reac-
tion to commercially available azide sources, thus making
the method more practical. We showed that geminally di-
substituted olefins are good substrates for the reaction
leading to tertiary azides, which are difficult to prepare by
other methods. Especially interesting is the hydroazida-
tion of the amino acid derivatives as they open up new
SO2N3
Co(BF4)2⋅6H2O, ligand 2
O
+
O
TBDPS
N3
TBDPS
t-BuOOH, TMDSO
EtOH, 23 °C
3b
1b
COO–
+
Et3NH
5 + Et3N
Scheme 4
Synthesis 2007, No. 24, 3839–3845 © Thieme Stuttgart · New York

3842
B. Gaspar et al.
PAPER
stirred for 20 min at this temperature and then at r.t. for 4.5 h.
CH2Cl2 (10 mL) was added, the precipitate was filtered off and the
resulting homogeneous solution was washed with HCl (10%, 15
mL) and sat. aq NaHCO3 (15 mL). The solvent was evaporated and
the crude product was purified by flash chromatography (hexane–
Et2O, 7:3) to give 1j.
possibilities for drug discovery in the context of click
chemistry and permits their use in bioconjugation via
Staudinger ligation. Studies in order to better understand
the similarities and differences between the processes,
employing various azide sources, are being conducted.
Yield: 1.176 g (91%); pale-yellow oil; Rf = 0.37 (hexane–Et2O, 7:3);
[a]D26 –10.9 (c 1, CHCl3).
All reactions were carried out under an atmosphere of argon or ni-
trogen. All chemicals were purchased from commercial suppliers
and used as such unless stated otherwise. Compounds 1b, 1c, 2, 3a,
3b, 3c11 and compounds 1e, 1f, 1g and 1i15 were synthesized accord-
ing to literature procedures. Flash chromatography was performed
using Brunschwig silica 32–63, 60 Å. TLC was performed on
Merck silica gel 60 F254 TLC glass plates and visualized with UV
light and permanganate stain. Melting points were measured on a
Büchi 510 melting point apparatus using open glass capillaries; the
data are uncorrected. Optical rotation measurements were carried
out on a Jasco DIP-1000 polarimeter. 1H NMR spectra were record-
ed on a Varian Mercury 300 MHz spectrometer in CDCl3 or
DMSO-d6, all signals are reported in ppm with the internal CHCl3
signal at 7.26 ppm or the internal DMSO signal at 2.50 ppm as stan-
IR: 3371 (m), 3078 (w), 2978 (s), 2936 (m), 1720 (s), 1650 (w),
1512 (m), 1452 (m), 1391 (m), 1367 (m), 1344 (m), 1307 (w), 1250
(m), 1166 (s), 1068 (m), 1026 (w), 893 (w) cm–1.
1H NMR (CDCl3, 300 MHz): d = 5.02 (br s, 1 H, NH), 4.81 (s, 1 H,
C=CH), 4.37 (s, 1 H, C=CH), 4.33–4.17 (m, 3 H, NCH and OCH2),
3
2.35 (t, J = 6.9 Hz, 2 H, CH2), 1.75 (s, 3 H, CCH3), 1.44 [s, 9 H,
C(CH3)3], 1.37 (d, 3J = 7.3 Hz, 3 H, CH3).
13C NMR (CDCl3, 75 MHz): d = 173.27, 155.03, 141.23, 112.47,
79.71, 63.28, 49.19, 36.59, 28.28, 22.35, 18.74.
MS (ESI): m/z = 280.1 [M + Na].
Anal. Calcd for C13H24NO4: C, 60.68; H, 9.01; N, 5.44. Found: C,
60.51; H, 9.04; N, 5.67.
1
dard. 13C NMR spectra were recorded with H-decoupling on a
Varian Mercury 75 MHz spectrometer in CDCl3 or DMSO-d6, all
signals are reported in ppm with the internal CHCl3 signal at 77.0
ppm or the internal DMSO signal at 39.5 ppm as standard. IR spec-
tra were recorded on a Perkin–Elmer Spectrum RX-I FT-IR spectro-
photometer as thin films unless stated otherwise. CAUTION:
Azides are potentially hazardous compounds and adequate safety
measures should be taken. Reactions, especially when involving
larger quantities or heating, should be conducted behind safety
shields.
(S)-Methyl 2-(3-Methylbut-3-enamido)-3-phenylpropanoate
(1k)
Et3N (352 mL, 2.50 mmol, 1.00 equiv) was added to L-phenylala-
nine hydrochloride (539 mg, 2.50 mmol, 1.00 equiv) in CHCl3 (3
mL) at r.t. under argon, followed by 3-methylbut-3-enoic acid (250
mg, 2.50 mmol, 1.00 equiv). The solution was cooled to 0–5 °C (ice
bath) and DCC (516 mg, 2.50 mmol, 1.00 equiv) was added fol-
lowed by a second portion of CHCl3 (1 mL). The reaction mixture
was stirred at this temperature for 1 h and then at r.t. for 24 h. The
precipitate formed was filtered off and washed with CHCl3 (10 mL).
The organic phase was washed with HCl (10%, 8 mL) and sat. aq
NaHCO3 (8 mL), the solvent was evaporated and the crude product
was purified by two flash chromatographic separations (hexane–
EtOAc, 1:1) to give 1k.
3-Methyl-N-phenylbut-3-enamide (1h)
3-Methylbut-3-enoic acid (250 mg, 2.50 mmol, 1.00 equiv) was dis-
solved in CH2Cl2 (3 mL) at r.t. under argon. DMAP (8 mg, 0.063
mmol, 0.025 equiv) and aniline (458 mL, 5.00 mmol, 2.00 equiv)
were added, the mixture was cooled to 0–5 °C (ice bath) and DCC
(516 mg, 2.50 mmol, 1.00 equiv) was added. The mixture was
stirred for 15 min at this temperature and then at r.t. for 4 h. CH2Cl2
(8 mL) was added, the precipitate was filtered off and the resulting
homogeneous solution was washed with HCl (10%, 10 mL) and sat.
aq NaHCO3 (10 mL). The solvent was evaporated and the crude
product was purified by flash chromatography (hexane–EtOAc,
2:1) to give 1h.
Yield: 302 mg (46%); colorless solid; Rf = 0.52 (hexane–EtOAc,
1:1); mp 59–61 °C; [a]D27 +48.6 (c 1, CHCl3).
IR: 3280 (m), 3070 (w), 2958 (w), 2346 (w), 1737 (m), 1646 (m),
1540 (m), 1435 (m), 1355 (m), 1234 (s), 1004 (m), 891 (m), 692 (s)
cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.31–7.21 (m, 3 H, ArH), 7.10–
7.07 (m, 2 H, ArH), 6.12 (d, 3J = 7.2 Hz, 1 H, NH), 4.94–4.84 (m,
3 H, C=CH2 and NCH), 3.73 (s, 3 H, OCH3), 3.16 (dd, 2J = 14.1 Hz,
Yield: 348 mg (79%); colorless solid; Rf = 0.5 (hexane–EtOAc,
2:1); mp 72–75 °C.
2
3J = 6.0 Hz, 1 H, PhCH), 3.06 (dd, J = 14.1 Hz, 3J = 6.3 Hz, 1 H,
IR: 3297 (m), 3199 (m), 3140 (m), 3082 (w), 2971 (w), 2934 (w),
1654 (s), 1618 (m), 1599 (s), 1544 (s), 1498 (s), 1443 (s), 1420 (m),
1353 (m), 1309 (m), 1251 (m), 1210 (w), 1183 (w), 956 (w), 898
(m), 754 (m), 734 (w), 692 (w) cm–1.
PhCH), 2.94 (s, 2 H, CH2), 1.70 (s, 3 H, CH3).
13C NMR (CDCl3, 75 MHz): d = 171.96, 169.72, 139.94, 135.90,
129.18, 128.26, 127.09, 115.51, 52.99, 52.13, 46.03, 37.94, 22.22.
1H NMR (CDCl3, 300 MHz): d = 7.52–7.49 (m, 2 H, ArH), 7.47 (br
s, 1 H, NH), 7.35–7.29 (m, 2 H, ArH), 7.13–7.08 (m, 1 H, ArH),
5.08 (m, 1 H, C=CH), 5.02 (br s, 1 H, C=CH), 3.14 (s, 2 H, CH2),
1.87 (s, 3 H, CH3).
HRMS (EI): m/z calcd for C15H19NO3: 261.1360; found: 261.1359.
(S)-2-Methylallyl 2-(tert-Butoxycarbonylamino)-3-hydroxypro-
panoate (1l)
Et3N (556 mL, 4.00 mmol, 1.00 equiv) was added to N-Boc-L-serine
(821 mg, 4.00 mmol, 1.00 equiv) in CH2Cl2 (8 mL) at r.t. under ar-
gon followed by 3-bromo-2-methylprop-1-ene (403 mL, 4.00 mmol,
1.00 equiv). The reaction mixture was stirred at r.t. for 24 h then
CH2Cl2 (10 mL) was added and the mixture was washed with HCl
(10%, 10 mL) and brine (15 mL). The solvent was evaporated and
the crude product was purified by flash chromatography (hexane–
EtOAc, 1:1) to give 1l.
13C NMR (CDCl3, 75 MHz): d = 168.55, 140.24, 137.72, 128.89,
124.27, 119.72, 115.99, 47.30, 22.40.
HRMS (EI): m/z calcd for C11H13NO: 175.0992; found: 175.0991.
N-Boc-L-alanine 3-Methylbutenyl Ester (1j)
N-Boc-L-alanine (946 mg, 5.00 mmol, 1.00 equiv) was dissolved in
CH2Cl2 (6 mL) at r.t. under argon. DMAP (15 mg, 0.125 mmol,
0.025 equiv) and 3-methylbut-3-en-1-ol (1 mL, 10.00 mmol, 2.00
equiv) were added, the mixture was cooled to 0–5 °C (ice bath) and
DCC (1.03 g, 5.00 mmol, 1.00 equiv) was added. The mixture was
Yield: 526 mg (51%); colorless oil; Rf = 0.54 (hexane–EtOAc, 1:1);
[a]D28 –1.5 (c 1, CHCl3).
Synthesis 2007, No. 24, 3839–3845 © Thieme Stuttgart · New York

PAPER
Tertiary Azides from a,a-Disubstituted Olefins
3843
IR: 3435 (m), 2979 (m), 2936 (m), 1716 (s), 1506 (s), 1456 (m),
1393 (m), 1368 (s), 1345 (m), 1251 (m), 1164 (s), 1062 (m), 953
(w), 907 (w), 857 (w), 780 (w) cm–1.
equiv) were added followed by a second portion of EtOH (0.5 mL).
Finally TMDSO (182 mL, 1.00 mmol, 2.00 equiv) was added and
the resulting homogeneous dark-brown reaction mixture was stirred
at r.t. and monitored by TLC (hexane–Et2O, 40:1). Upon comple-
tion, the reaction was quenched with H2O (0.5 mL). Sat. aq
NaHCO3 (3 mL) and brine (2 mL) were added and the reaction mix-
ture was extracted with Et2O (3 × 10 mL). The solvent was removed
under reduced pressure (40 mbar, 40 °C) and the crude product was
purified by flash chromatography (hexane–Et2O, 40:1) to afford
3-azido-3-methylbutylbenzene (3c; 94 mg, 99%) as a pale-yellow
liquid. All the spectroscopical data were consistent with those pre-
viously reported.11
1H NMR (CDCl3, 300 MHz): d = 5.47 (br s, 1 H), 5.00 (s, 1 H,
C=CH), 4.95 (s, 1 H, C=CH), 4.62 (d, 2J = 13.2 Hz, 1 H, CO2CH),
4.56 (d, 2J = 13.2 Hz, 1 H, CO2CH), 4.41 (br s, 1 H), 4.03–3.88 (m,
3
2 H, OCH2), 2.45 (t, J = 6.3 Hz, 1 H, NCH), 1.76 (s, 3 H, CH3),
1.45 [s, 9 H, C(CH3)3].
13C NMR (CDCl3, 75 MHz): d = 170.49, 155.73, 139.17, 113.57,
80.31, 68.81, 63.60, 55.77, 28.25, 19.38.
MS (ESI): m/z = 282.1 [M + Na].
Anal. Calcd for C12H21NO5: C, 55.58; H, 8.16; N, 5.40. Found: C,
55.41; H, 8.19; N, 5.43.
(1R,2S,5R)-2-(2-Azidopropan-2-yl)-5-methylcyclohexanol (3d)
Rf = 0.24 (hexane–Et2O, 4:1); [a]D27 +18.9 (c 1, CHCl3).
IR: 3446 (w), 2952 (m), 2923 (m), 2871 (m), 2105 (s), 1457 (w),
1388 (w), 1372 (w), 1256 (m), 1147 (w), 1093 (w), 1055 (w), 1029
(w), 1013 (w) cm–1.
Sodium 4-Azidosulfonylbenzoate (8)
A solution of 4-azidosulfonylbenzoic acid (5; 97% Aldrich, 422 mg,
1.80 mmol, 1.00 equiv) in anhydrous THF (5 mL) was added slowly
to a stirred suspension of NaH (95% Aldrich, 41 mg, 1.62 mmol,
0.90 equiv) in anhydrous THF (5 mL) at r.t. under argon. A precip-
itate was formed and a little warming was observed. The reaction
mixture was stirred at r.t. for 20 min then the precipitate was fil-
tered, washed with Et2O (2 × 10 mL) and dried under high vacuo to
yield 8, which was used without further purification.
3
1H NMR (CDCl3, 300 MHz): d = 3.75 (d, J = 1.5 Hz, 1 H, OH),
3.65–3.56 (m, 1 H, OCH), 2.00–1.93 (m, 1 H), 1.76–1.62 (m, 2 H),
1.50–1.32 (m, 2 H), 1.36 (s, 3 H, CH3), 1.29 (s, 3 H, CH3), 1.05–
0.81 (m, 3 H), 0.91 (d, 3J = 6.6 Hz, 3 H, CH3).
13C NMR (CDCl3, 75 MHz): d = 71.64, 64.84, 51.44, 44.08, 34.36,
31.00, 26.22, 25.49, 21.89, 21.44.
HRMS (EI): m/z [M – N3]+ calcd for C10H19N3O: 155.1431; found:
155.1433.
Yield: 384 mg (86%; purity of 95% by 1H NMR); colorless amor-
phous solid;
IR: 3619 (w), 3369 (w), 2352 (w), 2127 (s), 1605 (s), 1558 (m),
1393 (s), 1302 (m), 1166 (s), 1084 (m), 1016 (w), 845 (w), 743 (s),
688 (w), 606 (s) cm–1.
2-Azido-2-methylpropyl Benzoate (3e)
Rf = 0.47 (hexane–Et2O, 7:1).
1H NMR (DMSO-d6, 300 MHz): d = 8.16 (d, J = 8.7 Hz, 2 H,
3
IR: 2095 (s), 1726 (s), 1602 (w), 1469 (w), 1452 (m), 1396 (w),
1374 (m), 1315 (m), 1273 (s), 1177 (m), 1112 (s), 1071 (m), 1028
(m), 975 (w), 775 (w), 711 (s), 686 (w), 676 (w), 612 (w), 563 (w)
cm–1.
ArH), 7.93 (d, 3J = 8.4 Hz, 2 H, ArH).
13C NMR (DMSO-d6, 75 MHz): d = 167.59, 147.01, 137.12,
130.33, 126.63.
1H NMR (CDCl3, 300 MHz): d = 8.09–8.06 (m, 2 H, ArH), 7.61–
7.56 (m, 1 H, ArH), 7.49–7.44 (m, 2 H, ArH), 4.26 (s, 2 H, OCH2),
1.39 (s, 6 H, 2 × CH3).
HRMS (ESI): m/z [M – Na] calcd for C7H4N3NaO4S: 225.9923;
found: 225.99298.
13C NMR (CDCl3, 75 MHz): d = 165.93, 133.14, 129.64, 129.48,
Hydroazidation Reaction; Typical Procedure A
Co(BF4)2·6H2O (10 mg, 0.03 mmol, 0.06 equiv) and ligand 2 (14
mg, 0.03 mmol, 0.06 equiv) were dissolved in EtOH (1 mL) at r.t.
under argon. After 10 min, 3-methylbut-3-enylbenzene (1c; 73 mg,
0.50 mmol, 1.00 equiv) was added to the homogeneous solution,
followed by sodium 4-azidosulfonylbenzoate (8; 195 mg, 0.75
mmol, 1.50 equiv) and tert-butyl hydroperoxide (5.50 M solution in
decane, 25 mL, 0.14 mmol, 0.28 equiv). A second portion of EtOH
(1.5 mL) was added to the suspension followed by TMDSO (182
mL, 1.00 mmol, 2.00 equiv). The resulting dark-brown suspension
was stirred at r.t. and the reaction was monitored by TLC (hexane–
Et2O, 40:1). Upon completion, the reaction was quenched with H2O
(0.5 mL). Sat. aq NaHCO3 (3 mL) and brine (2 mL) were added and
the reaction mixture was extracted with Et2O (3 × 10 mL). The sol-
vent was removed under reduced pressure (40 mbar, 40 °C) and the
crude product was purified by flash chromatography (hexane–Et2O,
40:1) to afford 3-azido-3-methylbutylbenzene (3c; 89 mg, 94%) as
a pale-yellow liquid. All spectroscopic data were consistent with
those previously reported.11
128.38, 71.14, 60.23, 23.46.
HRMS (EI): m/z [M – N3]+ calcd for C11H13N3O2: 177.0911; found:
177.0911.
3-Azido-3-methylbutyl Benzoate (3f)
Rf = 0.44 (hexane–Et2O, 7:1).
IR: 2101 (s), 1721 (s), 1451 (w), 1316 (w), 1276 (s), 1176 (w), 1146
(w), 1114 (m), 1071 (w), 1027 (w), 711 (s), 688 (w), 676 (w) cm–1.
1H NMR (CDCl3, 300 MHz): d = 8.05–8.02 (m, 2 H, ArH), 7.59–
7.54 (m, 1 H, ArH), 7.47–7.42 (m, 2 H, ArH), 4.45 (t, 3J = 6.6 Hz,
2 H, OCH2), 1.99 (t, 3J = 6.6 Hz, 2 H, CH2), 1.39 (s, 6 H, 2 × CH3).
13C NMR (CDCl3, 75 MHz): d = 166.24, 132.85, 129.97, 129.39,
128.25, 61.24, 60.26, 39.77, 26.45.
HRMS (EI): m/z [M – N3]+ calcd for C12H15N3O2: 191.1067; found:
191.1068.
Anal. Calcd for C12H15N3O2: C, 61.79; H, 6.48; N, 18.01. Found: C,
62.05; H, 6.53; N, 17.77.
Typical Procedure B
4-Azidosulfonylbenzoic acid (5; 176 mg, 0.75 mmol, 1.50 equiv)
was suspended in EtOH (2 mL) at r.t. under argon. Et3N (101 mL,
0.715 mmol, 1.43 equiv) was added and the mixture was stirred un-
til the mixture became a clear colorless solution (15–20 min).
Co(BF4)2·6H2O (10 mg, 0.03 mmol, 0.06 equiv) and ligand 2 (14
mg, 0.03 mmol, 0.06 equiv) were added. After 10 min, 3-methylbut-
3-enylbenzene (1c; 73 mg, 0.50 mmol, 1.00 equiv) and tert-butyl
hydroperoxide (5.5 M solution in decane, 25 mL, 0.14 mmol, 0.28
3-Azido-3-methylbutanoic Acid Benzyl Ester (3g)
Rf = 0.61 (hexane–Et2O, 3:1).
IR: 3035 (w), 2976 (m), 2102 (s), 1738 (s), 1498 (w), 1456 (w),
1373 (w), 1348 (w), 1258 (m), 1216 (m), 1143 (m), 1118 (m), 1004
(w), 750 (w), 698 (m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.38–7.35 (m, 5 H, ArH), 5.15 (s,
2 H, OCH2), 2.55 (s, 2 H, CH2), 1.40 (s, 6 H, 2 × CH3).
Synthesis 2007, No. 24, 3839–3845 © Thieme Stuttgart · New York

3844
B. Gaspar et al.
PAPER
13C NMR (CDCl3, 75 MHz): d = 169.72, 135.58, 128.55, 128.30,
2J = 13.8 Hz, 3J = 5.7 Hz, 1 H, PhCH), 3.06 (dd, 2J = 13.8 Hz,
3J = 6.9 Hz, 1 H, PhCH), 2.30 (s, 2 H, CH2), 1.36 (s, 3 H, CH3), 1.27
(s, 3 H, CH3).
13C NMR (CDCl3, 75 MHz): d = 171.73, 168.75, 135.64, 129.01,
128.47, 127.06, 59.90, 53.10, 52.34, 48.05, 37.82, 26.02, 25.86.
66.49, 59.49, 45.56, 26.21.
MS (ESI): m/z = 256.2 [M + Na].
Anal. Calcd for C12H15N3O2: C, 61.79; H, 6.48; N, 18.01. Found: C,
61.86; H, 6.50; N, 17.92.
HRMS (EI): m/z [M]+ calcd for C15H20N4O3: 304.1530; found:
3-Azido-3-methyl-N-phenylbutanamide (3h)
Rf = 0.11 (hexane–Et2O, 2:1).
304.1530.
N-Boc-L-serine 3-Methyl-3-azidopropyl Ester (3l)
Rf = 0.22 (hexane–Et2O, 2:3); mp 73–75 °C; [a]D –6.1 (c 1,
CHCl3).
IR: 3252 (m), 3131 (w), 3071 (w), 2972 (w), 2096 (s), 1654 (s),
1597 (m), 1539 (s), 1438 (s), 1341 (m), 1237 (s), 1107 (w), 972 (w),
904 (w), 851 (w), 739 (s) cm–1.
28
IR: 3398 (m), 2980 (w), 2942 (w), 2892 (w), 2136 (w), 2094 (s),
2037 (w), 1752 (s), 1677 (s), 1513 (s), 1462 (w), 1370 (m), 1345
(m), 1264 (m), 1210 (s), 1156 (s), 1065 (s), 981 (w), 930 (w), 892
(w), 862 (w), 828 (w), 771 (w), 633 (m), 613 (m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.83 (br s, 1 H, NH), 7.53–7.51
(m, 2 H, ArH), 7.36–7.30 (m, 2 H, ArH), 7.14–7.09 (m, 1 H, ArH),
2.49 (s, 2 H, CH2), 1.48 (s, 6 H, 2 × CH3).
13C NMR (CDCl3, 75 MHz): d = 167.64, 137.58, 128.93, 124.38,
120.03, 60.23, 49.36, 26.00.
HRMS (EI): m/z [M]+ calcd for C11H14N4O: 218.1163; found:
218.1162.
1H NMR (CDCl3, 300 MHz): d = 5.43 (br s, 1 H), 4.44 (br s, 1 H),
2
4.19 (d, J = 11.1 Hz, 1 H, CO2CH), 4.07–3.91 (m, 2 H, OCH2),
4.02 (d, 2J = 11.1 Hz, 1 H, CO2CH), 2.25 (br s, 1 H, NCH), 1.46 [s,
9 H, C(CH3)3], 1.32 (s, 6 H, 2 × CH3).
13C NMR (CDCl3, 75 MHz): d = 170.40, 155.63, 80.37, 71.26,
N-Boc-L-alanine 3-Methyl-3-azidopropyl Ester (3i)
Rf = 0.23 (hexane–Et2O, 7:3); mp 35–37 °C; [a]D –17.4 (c 0.5,
CHCl3).
63.52, 60.03, 55.75, 28.27, 23.26, 23.06.
27
MS (ESI): m/z = 325.24 [M + Na].
IR: 2096 (s), 2037 (w), 1763 (m), 1694 (s), 1514 (s), 1455 (m), 1386
(m), 1369 (m), 1351 (w), 1298 (w), 1252 (m), 1216 (m), 1164 (s),
1118 (m), 1069 (s), 1022 (m), 979 (w), 868 (m), 782 (w), 764 (w),
613 (w) cm–1.
Anal. Calcd for C12H22N4O5: C, 47.67; H, 7.33; N, 18.53. Found: C,
47.72; H, 7.39; N, 18.62.
Acknowledgment
1H NMR (CDCl3, 300 MHz): d = 5.01 (br s, 1 H, NH), 4.39–4.34
(m, 1 H, NCH), 4.11 (d, 2J = 11.4 Hz, 1 H, OCH), 4.00 (d, 2J = 11.1
This research was supported by a Swiss National Science Founda-
tion grant. The authors thank Sigma–Aldrich for providing all the
azide sources.
3
Hz, 1 H, OCH), 1.45 [s, 9 H, C(CH3)3], 1.43 (d, J = 7.5 Hz, 3 H,
CHCH3), 1.31 (s, 3 H, N3CCH3), 1.30 (s, 3 H, N3CCH3).
13C NMR (CDCl3, 75 MHz): d = 172.92, 155.04, 79.89, 71.11,
59.86, 49.26, 28.26, 23.15, 18.43.
References
MS (ESI): m/z = 309.14 [M + Na].
(1) (a) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
(b) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
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Anal. Calcd for C12H22N4O4: C, 50.34; H, 7.74; N, 19.57. Found: C,
50.45; H, 7.96; N, 19.28.
(2) (a) Rao, H. S. P.; Siva, P. Synth. Commun. 1994, 24, 549.
(b) Corey, E. J.; Nicolaou, K. C.; Balanson, R. D.; Machida,
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N-Boc-L-alanine 3-Methyl-3-azidobutyl Ester (3j)
Rf = 0.74 (CH2Cl2–MeOH, 15:1); [a]D28 –9.3 (c 1, CHCl3).
(3) (a) Huisgen, R.; Knorr, R.; Mobius, L.; Szeimies, G. Chem.
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K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.
(4) Kohn, M.; Breinbauer, R. Angew. Chem. Int. Ed. 2004, 43,
3106.
IR: 2101 (s), 1743 (m), 1714 (s), 1512 (m), 1502 (m), 1452 (w),
1391 (w), 1368 (m), 1301 (w), 1252 (s), 1166 (s), 1069 (m), 1025
(m), 975 (w), 851 (w), 782 (w) cm–1.
1H NMR (CDCl3, 300 MHz): d = 5.01 (br s, 1 H, NH), 4.32–4.22
3
3
(m, 1 H, NCH), 4.24 (t, J = 6.9 Hz, 2 H, OCH2), 1.84 (t, J = 6.9
3
Hz, 2 H, CH2), 1.44 [s, 9 H, C(CH3)3], 1.37 (d, J = 7.2 Hz, 3 H,
CHCH3), 1.32 (s, 6 H, 2 × CH3).
13C NMR (CDCl3, 75 MHz): d = 173.03, 154.92, 79.82, 61.58,
60.80, 49.25, 39.58, 28.38, 26.38, 18.66.
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MS (ESI): m/z = 323.04 [M + Na].
(6) Hassner, A.; Fibiger, R.; Andisik, D. J. Org. Chem. 1984, 49,
Anal. Calcd for C13H24N4O4: C, 51.99; H, 8.05; N, 18.65. Found: C,
52.29; H, 8.21; N, 18.26.
4237.
(7) Breton, G. W.; Daus, K. A.; Kropp, P. J. J. Org. Chem. 1992,
57, 6646.
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Commun. 1997, 1133.
(9) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999,
121, 8959. (b) Horstmann, T. E.; Guerin, D. J.; Miller, S. J.
Angew. Chem. Int. Ed. 2000, 39, 3635.
(10) (a) Hassner, A.; Levy, L. A. J. Am. Chem. Soc. 1965, 87,
4203. (b) Magnus, P.; Lacour, J.; Evans, P. A.; Roe, M. B.;
Hulme, C. J. Am. Chem. Soc. 1996, 118, 3406. (c) Tiecco,
M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.;
(S)-Methyl-2-(3-azido-3-methylbutanamido)-3-phenyl Pro-
panoate (3k)
Rf = 0.43 (hexane–EtOAc, 3:2); [a]D27 +32.9 (c 1, CHCl3).
IR: 3314 (m), 3065 (w), 3031 (w), 2974 (m), 2103 (s), 1747 (s),
1652 (s), 1538 (m), 1437 (m), 1372 (m), 1258 (m), 1219 (m), 1178
(m), 1136 (m), 1081 (w), 1032 (w), 744 (w), 701 (m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.33–7.22 (m, 3 H, ArH), 7.15–
3
7.13 (m, 2 H, ArH), 6.42 (d, J = 7.5 Hz, 1 H, NH), 4.88 (ddd,
3J = 7.7, 6.9, 5.7 Hz, 1 H, NCH), 3.73 (s, 3 H, OCH3), 3.17 (dd,
Synthesis 2007, No. 24, 3839–3845 © Thieme Stuttgart · New York

PAPER
Bagnoli, L.; Temperini, A. Angew. Chem. Int. Ed. 2003, 42,
Tertiary Azides from a,a-Disubstituted Olefins
3845
(13) Co(BF4)2·6H2O (6 mol%), ligand 2 (6 mol%), alkene (0.5
mmol), azide source (1.5 mmol), t-BuOOH (30 mol%),
TMDSO (1 mmol), EtOH (2.5 mL).
3131. (d) Mahoney, J. M.; Smith, C. R.; Johnston, J. N.
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(11) Waser, J.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc.
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Synthesis 2007, No. 24, 3839–3845 © Thieme Stuttgart · New York