Radical substitution with azide: TMSN3-PhI(OAc)2 as a substitute of in3

Article abstract of DOI:10.1039/b500037h

TMSN₃ and PhI(OAc)₂ were found to promote high-yield azide substitution of ethers, aldehydes and benzal acetals. The reaction is fast and occurs at zero to ambient temperature in acetonitrile. However, it is essential for the reaction that TMSN₃ is added subsequent to the mixture of PhI(OAc)₂ and the substrate. A primary deuterium kinetic isotope effect was found for the azidonation of benzyl ethers both with TMSN₃-PhI(OAc)₂ and with IN₃. Also a Hammett free energy relationship study of this reaction showed good correlation with σ⁺ constants giving with ρ-values of -0.47 for TMSN ₃-PhI(OAc)₂ and -0.39 for IN₃. On this basis a radical mechanism of the reaction was proposed. The Rayal Society of Chemistry 2005.

Full text of DOI:10.1039/b500037h

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A R T I C L E
Radical substitution with azide: TMSN3–PhI(OAc)2 as a substitute
of IN3†
Christian Marcus Pedersen, Lavinia Georgeta Marinescu and Mikael Bols*
Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000, Aarhus C,
Denmark. E-mail: mb@chem.au.dk
Received 6th January 2005, Accepted 12th January 2005
First published as an Advance Article on the web 27th January 2005
TMSN3 and PhI(OAc)2 were found to promote high-yield azide substitution of ethers, aldehydes and benzal acetals.
The reaction is fast and occurs at zero to ambient temperature in acetonitrile. However, it is essential for the reaction
that TMSN3 is added subsequent to the mixture of PhI(OAc)2 and the substrate . A primary deuterium kinetic isotope
effect was found for the azidonation of benzyl ethers both with TMSN3–PhI(OAc)2 and with IN3. Also a Hammett
free energy relationship study of this reaction showed good correlation with r+ constants giving with q-values of
−0.47 for TMSN3–PhI(OAc)2 and −0.39 for IN3. On this basis a radical mechanism of the reaction was proposed.
of higher rate at milder conditions, higher yields in some cases
Introduction
and overall safer reaction conditions, since IN3 is avoided. The
The azido group is a highly useful functionality in organic
only drawback is that PhI and excess reagent have to be removed
synthesis due to its ready conversion to an amino group and
by chromatography.
its photochemical and cycloaddition reactions.1 Besides the well
known nucleophilic introduction of azide using azide ions, the
Results and discussion
introduction of azide by substitution of active hydrogen atoms
employing azide radicals2,3 has also been reported.4–17 Thus, a-
While it occurred to us early on that azidonation of aldehydes,
azidonation of enolic double bonds and amines with PhIO–
TMSN3 at low temperature have been reported,5–8 while an
azidoiodinane has also been shown to azidonate alkanes.9 In
these reactions an azidoiodine compound is believed to be the
azidonating species. Kita et al. reported that PhI(OOCCF3)2–
TMSN3 can azidonate certain activated benzylic positions.11
Chen showed that PhI(OAc)2–NaN3 transforms aldehydes to
acyl azides in good yield, but also that the reaction appears
only to work on aromatic aldehydes.12 The mechanisms of these
reactions have been suggested to occur through (1) formation
of PhI(N3)2 (or equivalent), (2) homolysis of the I–N bond to
form azide radicals, (3) abstraction of active hydrogen and (4)
reaction of the carbon radical with a PhIN3• radical giving alkyl
azide and iodobenzene.11,12
benzyl ethers and acetals might also be possible with TMSN3 or
NaN3 and a hypervalent iodine species, attempts to carry out this
reaction under many of the conditions published for successful
azidonation of other substrates failed to give a satisfactory (or
any) result. However it was found that the order of addition
of the azide source, hypervalent iodine species and substrate is
crucial in order to obtain a successful result. Mixing of TMSN3
and PhI(OAc)2 either at low or ambient temperature before
adding the substrate completely fails to produce any products,
presumably because the reagents decompose before reaction.
However when PhI(OAc)2 and substrate are mixed at room
temperature and TMSN3 is added subsequently, azidonation
products are obtained in high yield.
Related to this work with hypervalent iodine species, we
have found that iodine azide can be used to promote radical
azidonation (or azidation) of aldehydes,13 benzal acetals14 and
ethers.15–17 These reactions also follow radical mechanisms and
have been proposed to occur by (1) bond homolysis of the weak
I–N3 bond to radicals, (2) attack of iodine or azide radical on
active hydrogen atoms, (3) a propagating reaction step of the
resulting carbon radical, with iodine azide forming an alkyl
azide (or alternatively an alkyl iodide that is finally substituted
by azide ions).
While the parallels in the above literature are obvious,
it has been difficult to reach a clear-cut consistency in the
methods. Thus, PhI(OAc)2–NaN3 has been reported only to
azidonate aromatic aldehydes,12 whereas IN3 reacts well with
aliphatic aldehydes,13 and, unlike PhIO–TMSN3, IN3 does not
give smooth azidonation of amines.15 Since IN3, perhaps not
entirely justifiably, is notorious for being a hazardous reagent,
we made attempts to see if substitution of iodine azide with
hypervalent iodine reagents in the azidonation of benzyl ethers
and aldehydes was possible, and here report that iodine azide
can indeed be substituted with PhI(OAc)2 and TMSN3 in these
reactions. This is a useful modification as it has the advantages
Ethers
When benzyl methyl ether (1) and PhI(OAc)2 are treated with
TMSN3 in MeCN at 0–5 ◦C and subsequently allowed to warm
to room temperature, an 88% yield of azide 2 is formed in an
essentially instantaneous reaction (Scheme 1). For comparison,
IN3 gives a 93% yield by 20 min reflux. A range of different
benzyl ethers and related compounds were tried, and the results
are shown in Table 1. PhI(OAc)2 and TMSN3 are used in
equimolar amounts and in excess, between 1.3 to 4 equivalents,
compared to the substrate; at least 1 equivalent of these reagents
is necessary. In general the reaction gives similar yield to IN3.
Particularly noteworthy is the selectivity of monoazidonation of
dibenzyl ether (7). The chiral silyl ethers 11 and 13 were also
azidonated, but without induction of much diastereoselectivity:
The diastereomeric ratio was 1 : 1 in 12 and 1 : 3 in 14. Also
it should be noted that, unlike IN3, PhI(OAc)2–TMSN3 can
convert a substrate like 15. with a free OH group, as it is silylated
† Electronic supplementary information (ESI) available: NMR spectra,
Hammett plots and data, spectral data for known compounds. See
http://www.rsc.org/suppdata/ob/b5/b500037h/
Scheme 1
8 1 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 1 6 – 8 2 2
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Table 1 Substitution of ethers using PhI(OAc)2–TMSN3
Yield with
PhI(OAc)2–
Number TMSN3/%
Substrate
Number PhI(OAc)2–TMSN3 Product
Yield with IN3/%
9315
1
2.5 : 2.5
2
88
3
2 : 4
4
71
7415
5
2.5 : 2.5
6
79
7116
7
9
2 : 2
8
89
50
—
—
1.3 : 1.3
10
11
3 : 3
12
84
—
13
15
5 : 5
14
16
51
82
—
—
2.5 : 2.5
by TMSN3. The optimal solvent is acetonitrile, though benzene
and dichloromethane could also be used. THF gave no reaction
presumably because of hydrogen abstraction from the solvent.2
Some mechanistic experiments were performed to provide
an insight into the reaction and to compare it with other
conditions. The reaction is inhibited by addition of N-tert-butyl-
a-phenylnitrone in accordance with the radical nature of the
mechanism. Adding more TMSN3, beyond the first equivalent
(compared to PhI(OAc)2) has no positive effect. Also, TMSN3
could not be replaced by sodium azide in this reaction even
though NaN3 has some solubility in acetonitrile. However, a
product could be obtained with PhI(OAc)2–NaN3 in a slow
overnight reaction, when 15-crown-5-ether was also added.
Adding 1.5 equivalents of TMSCN to the reaction of 7 still
only gave product 8 and no nitrile containing products, showing
that no nucleophilic step was involved in the mechanism. On the
other hand, when diphenyl diselenide (1.5 eq.) was added the
corresponding selenide, PhCH(SePh)OBn (17), was obtained in
varying amounts depending on how fast the TMSN3 was added.
The slower the addition of TMSN3, the higher the proportion
of 17 compared to 8. This supports the presence of benzylic
radicals in the mechanism.
Isotope effects in the reaction were investigated using the
deuterated version of 7,1826 (Scheme 2). Reaction of 18 with
PhI(OAc)2–TMSN3 (1.5 and 2 eq., MeCN, 25 ◦C, 50 min) gave
a 1 : 5.2 ratio of 19 and 20 corresponding to a primary isotope
effect. Reaction of 18 with IN3 (2 eq., MeCN, 75 ◦C, 2 h.) gave
a 1 : 5.0 ratio of 19 and 20, also indicating a primary isotope
effect in this reaction. This means that hydrogen abstraction is
the rate determining step with both reagents.
Electronic effects were investigated using 21 and a series
of monosubstituted analogues of 7 (Scheme 2). The ratio of
isomeric products 22 and 23, obtained from 21, can be used to
determine the influence of the substituent X on the reaction,
i.e., the isomeric ratio is identical to the ratio between rates
of substituted and unsubstituted benzyl ethers. So isomeric
ratios were determined for X = p-MeO, m-MeO, p-Br, m-Br,
m-Cl, p-NO2 and m-NO2 and used to construct Hammett plots
correlating log (ratio) with r or r+. The reaction of 21 with
PhI(OAc)2–TMSN3 (1.5 and 2 eq., MeCN, 25 ◦C, 1 h) gave the
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 1 6 – 8 2 2
8 1 7

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Scheme 3
a benzylic radical is beyond doubt, these experiments suggest
that radicals formed from cyclisation cannot be converted into
azides, but rather reconvert to the benzylic radical.
Aldehydes
Scheme 2
Aldehydes are also readily azidonated. From aliphatic aldehyde
plots shown in Fig. 1 and S1. Plotting the data against r+ (Fig. 1)
gives a better correlation (r2 = 0.97) than the plot against r (r2 =
0.85, refer to the supplementary information) indicating that
resonance from the substituent plays a role in the transition state.
The q is −0.47, however, which is a very small value compared
to a reaction involving an ionic transition state.
27, the acyl azide 28 is obtained, but due to its instability
◦
during work-up, this primary product was heated to 83 C to
give Curtius rearrangement to isocyanate 29 that, under these
conditions, reacts with azide ions to give carbamoyl azide 30,
which was isolated in 84% yield (Scheme 4). For comparison
an 86% yield was obtained with IN3.11 For the azidonation
an excess of equimolar amounts of PhI(OAc)2 and TMSN3
was necessary, but an extra equivalent of TMSN3 was added
to form carbamoyl azide. A series of aliphatic and aromatic
aldehydes were converted to carbamoyl azides in good yield
with this procedure (Table 2). In general the yields with aromatic
aldehydes are slightly lower than those obtained with IN3. The
preferred solvent was MeCN, while dichloromethane, benzene,
EtOH and THF gave lower yields. The reaction is inhibited by
the radical trap N-tert-butyl-a-phenylnitrone.
Fig. 1 Hammett plot for the reaction of 21 with PhI(OAc)2–TMSN3.
This Hammett analysis was also performed for IN3 by reacting
the compound series 21 with IN3 in refluxing MeCN to generate
the isomeric product ratios of 22 and 23. Again, the Hammett
plot against r+ gives the best correlation (r2 = 1.00, Fig. 2), while
the correlation vs. r (supplementary information) is worse (r2 =
0.91). The q is −0.39 and thus IN3 behaves very similarly to
PhI(OAc)2–TMSN3, with respect to the low degree of charge in
the transition state.
Scheme 4
Benzal acetal
Benzal acetal 43 also reacted with PhI(OAc)2–TMSN3 giving 2-
azidoethyl benzoate 44 in 98% yield (Scheme 5), while IN3 only
gave 78% yield in this reaction.15
Fig. 2 Hammett plot for the reaction of 21 with IN3.
Scheme 5
To investigate possible intramolecular trapping of an inter-
mediate benzylic radical, the three homoallylic substrates 24a–
c22–25 were prepared (Scheme 3). Reaction of the unsubstituted
derivative 24a24 gave 54% of monoazide 25a and 41% of diazide
26a, but with no cyclisation products being formed. Compound
26a is a product of radical addition to the double bond. Reaction
of enol ether 24b22,23 gave diazide 26b in low yield (13%) as well as
a number of by-products, none of which could be identified. The
unsaturated ester 24c25 gave, according to mass spectrometry,
monoazide 25c together with an unidentified by-product that
however did not fit with a cyclic structure. Since formation of
Mechanism
The inhibition of the reactions by addition of a radical trap
and the deuterium primary kinetic isotope effect seen show
that this is a radical mechanism with the rate determining step
involving hydrogen abstraction. It is reasonable to suppose that
this abstraction is being carried out by azide radicals as was
suggested by others.2,4,5 The very low negative value of q in the
Hammett plot supports a purely radical reaction, as does the
8 1 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 1 6 – 8 2 2

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Table 2 Conversion of aldehydes to carbamoyl azides using either (1) PhI(OAc)2–TMSN3 and heating or (2) IN3 at 83 ◦
C
Yield with
PhI(OAc)2–TMSN3/%
Substrate
Number PhI(OAc)2–TMSN3
Product
Number
Yield with IN3/%
8613
27
1.5 : 2.5
30
84
31
1.5 : 2.5
32
34
36
77
7313
9713
9613
33
35
1.5 : 2.5
1.5 : 2.5
81
84
37
39
1.5 : 2.5
1.5 : 2.5
38
40
58
74
—
7013
41
2 : 4
42
41
—
lack of any success in substituting azide with cyanide when
TMSCN is added to the reaction. The better correlation of
the Hammett data to r+ values suggest some ionic character
of the transition state. These data fit the mechanism shown in
Scheme 6, which is similar to what has been proposed previously,
and is one of simplest that can be suggested. The mixture
of TMSN3 and PhI(OAc)2 lead to formation of PhI(N3)2 that
decomposes giving azide radicals. The chain propagating steps
are reactions (3) and (4) with (3) being the rate determining step.
Since the behaviour of PhI(OAc)2–TMSN3 and iodine azide
is extremely similar in terms of reaction yields, kinetic isotope
effect and Hammett correlations, it is compelling that the
mechanism should be similar. It is therefore very probable that
azide radicals are also involved in the hydrogen abstraction
with this reagent and not iodine radicals as have previously
been suggested.13 We therefore propose the mechanism shown
in Scheme 6. In this mechanism the chain propagating steps are
(3), (6) and (7), the latter step being necessary to produce new
azide radicals. Alternatively it might be suggested that in step
(6) iodine was abstracted by the carbon radical producing azide
radicals directly and giving an alkyl iodide. This iodide would
subsequently be substituted by azide ions. However there is with
IN3 no evidence for the intermediacy of iodides or any indication
of a ionic component in the reaction.
In summary PhI(OAc)2–TMSN3 is a valuable substitute for
IN3 in azidonation reactions. The reaction is faster and milder,
and the reaction conditions are safer. The yields are slightly
lower for aldehydes but higher for ethers and acetals.
Experimental
General procedure for benzyl ethers (A)
Into a 7 ml sample vial equipped with a septum, ca. 100 mg of
benzyl ether was dissolved in 4 ml acetonitrile under a nitrogen
atmosphere. 1.5 eq. of iodobenzene diacetate (with respect to
ether) was added, and the mixture was stirred until complete
dissolution. The vial was then cooled down on an ice bath, 2 eq.
of TMSN3 was added dropwise via syringe and the mixture was
allowed to reach room temperature. After the gas had finished
developing, the reaction mixture was concentrated in vacuo to
give a crude oil containing the product and iodobenzene. The
product was purified by column chromatography (iodobenzene
was removed with pentane and the product was eluated with
Scheme 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 1 6 – 8 2 2
8 1 9

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pentane : dichloromethane, 5 : 1) and obtained as a colourless
oil.
(m, 28H, Ar), 5.03 (s, 2H, H1a/H1b), 4.69 (d, J = 14, 2H, BnHa),
4.54 (d, J = 14, 2H, BnHb), 3.66 (s, 6H, OMe), 0.48 (s, 6H,
Me2C<). 13C-NMR (CDCl3): d = 156.3 (Ar-1), 147.2 (Ar-2),
142.6 (Ph-), 129,5, 128.8, 128.2, 127.9, 127.6 127.5, 127.3, 127.2,
127.1 (Ar, Ph), 120.7 (Ar-4), 113.7 (Me2C<), 109.8 (Ar-3),
82.5 (Ph2C<), 81.2 (C1a/C1b), 61.0 (PhCH2-), 55.4 (OMe), 27.3
(Me2C<). IR (NaCl)/cm−1: m = 3059 (Ar C–H sp2), 2992, 2935,
2836 (C–H sp3), 1603, 1590, 1493 (Ar C–H sp2). MS(ES): calc.
for (M + Na) = 789.2859, found 789.5275.
General procedure for aldehydes (B)
Into a 7 ml sample vial equipped with a septum, to a solution
of ca. 100 mg aldehyde in 4 ml acetonitrile under nitrogen,
iodobenzene diacetate (1.5 eq., with respect to aldehyde) was
added and stirred until complete dissolution. The mixture was
then cooled to 0 ◦C on an ice bath and TMSN3 (2.5 eq.) was
added dropwise to the mixture. After the resulting evolution
of gas was completed, the reaction mixture was allowed to
reach room temperature and the reaction was followed by TLC
showing the formation of acyl azide. The vial was then heated
to 83 ◦C for ca. 30 min to obtain the Curtius rearrangement
followed by formation of carbamoyl azide. The reaction mixture
was concentrated in vacuo and the product was isolated by
column chromatography (pentane for removing the iodobenzene
and than pentane : ethyl acetate, 10 : 1).
6-(a-Azido-2-methoxybenzyloxy)-6-(2-methoxybenzyloxy)-2,2-
dimethyl-4,4,8,8-tetraphenyl-tetrahydro-[1,3]dioxolo[4,5-e][1,3,2]-
dioxasilepine (14). Prepared from 13 using general procedure
A. Colorless oil. Yield: 27 mg (51%). Diastereomeric ratio
1
1 : 3. H-NMR (CDCl3): d = 6.6–7.6 (m, 28H, Ar), 6.0/6.1
(s, 1H, N3-C-H/N3–C–Hꢀ), 5.04 (m, 2H, H1, H2), 4.72/4.69
ꢀ
(d, J = 13.6, 1H, BnHa/ BnHa ), 4.55/4.53 (d, J = 13.6, 1H,
ꢀ
BnHb/BnHb ), 3.66, 3.67, 3.68, 3.69 (s, 6H, –OMe), 0.43, 0.47,
0.48, 0.49 (s, 6H, Me2C<). 13C-NMR (CDCl3): d = 156.1
(Ar-1), 146.7 (Ar-2), 142.3 (Ph-), 130.0, 129.4, 129.3 128.3,
128.2 128.0, 127.9 127.5, 127.4, 127.3, 127.3, 127.1, 127.1 (Ar,
Ph), 120.7 (Ar-4), 113.8 (Me2C<), 110.3 (Ar-3), 109.7 (C–N3),
82.9/81.9 (Ph2C<), 81.1/81.0 (C1a/C1b), 61.3/61.1 (PhCH2–),
55.6/55.3 (OMe), 27.2 (Me2C<). IR (NaCl)/cm−1: m = 2105
(–N3), 1602, 1559, 1492 (Ar C–H sp2). MS(ES): calc. for (M +
Na) = 830.2874, found 830.1154.
a-Azidobenzyl methylether (2)15. Prepared from commer-
cially available 1 using general procedure A. Colorless oil. Yield:
123 mg (88%).
(R,S)-a-Azido-benzyl 2-O-acetyl-3,4-O-isopropylidene-b-D-
arabinopyranoside (4)15. Prepared from 318 using general
procedure A. Colorless oil. Yield: 75 mg (71%).
a-Azidobenzyl 3-trimethylsilanoxypropyl ether (16). Pre-
3-(Azido-phenyl-methoxy)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester (6)16. Prepared from 516 using
general procedure A. Clear colourless oil. Yield: 89 mg (79%).
a-Azidobenzyl benzyl ether (8)19. Prepared from commer-
cially available 7 using general procedure A. Colourless oil.
Yield: 120 mg (89%).
pared from 1521 using general procedure A. Colorless oil. Yield:
1
102 mg (82%). H-NMR (CDCl3): d = 7.36–7.47 (m, 5H, Ar),
5.43 (s, 1H, N3–C–H), 3.96 (m, 1H, H1a), 3.65–3.75 (m, 3H, H1b,
H3), 1.91 (m, 2H, H2), 0.11 (s, 9H, OTMS). 13C-NMR (CDCl3):
d = 137.8(Ar-1), 129.2(H3), 128.9(H4), 126.6(H2), 93.2 (>C–N3),
66.4 (C3), 59.7 (C1), 33.1 (C2), 0.0(TMS). IR (NaCl)/cm−1: m =
2956 (C–H sp3), 2105(vs) (N3) MS(ES): calc. for (M + Na) =
302.1322, found 302.1301.
a-Azidophthalan (10). Prepared from commercially avail-
able 9 using general procedure A. Colorless oil. Yield: 67 mg
1
(50%). H-NMR (CDCl3): d = 7.32–7.56 (m, 4H, Ar), 6.34 (s,
General procedure for preparation of substituted dibenzyl ethers
(21)
1H, N3–C–H), 5.33 (d, J = 12.4, 1H, Ar–CHa–O), 5.13 (d, J =
12.4, 1H, Ar–CHb-O). 13C-NMR (CDCl3): d = 139.3 (Ar-2),
136.4 (Ar-1), 129.8 (Ar-6), 128.3 (Ar-3), 122.7 (Ar-4). 121.4 (Ar-
5), 96.0 (C–N3), 73.9 (PhCH2). IR (NaCl)/cm−1: m = 3081, 3051
(Ar C–H sp2), 2926, 2875 (C–H sp3), 2099(vs) (N3).
Substituted benzyl alcohol (1 eq.) was dissolved in dry DMF
under nitrogen atmosphere. The mixture was cooled on an ice
bath and pre-washed NaH (2 eq.) was slowly added. After
stirring for 30 min, benzyl bromide (1.2 eq.) was added slowly
by syringe, and the mixture was allowed to come to room
temperature. After stirring overnight, the reaction was quenched
with water and extracted with ether. The combined organic
fractions were washed with brine, dried (MgSO4), concentrated
in vacuo and purified by flash chromatography (DCM : pentane,
1 : 3) to give colorless to pale yellow oils.
(a-Azido-(2-methoxybenzyl)oxy)tris(((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl)oxy)silane (12). Prepared from 1120 using
general procedure A. Colorless oil. Yield: 89 mg (84%).
1H-NMR(CDCl3): d = 7.58 (dt, J = 1.6, J = 6.1, 1H, Ar),
7.31 (tt, J = 2.1, J = 7.8, 1H, Ar), 6.98 (dt, J = 3.4, J = 7.3,
1H, Ar), 6.88 (dd, J = 1.8, J = 8.0, 1H, Ar), 6.38/6.36 (s,
1H, BnH/BnHꢀ), 3.86/3.85 (s, 3H, OMe/OMeꢀ), 3.71 (m, 3H,
H1a), 2.24 (m, 3H, H7), 2.1/2.0 (bd, J = 11.8, 2H, H2a, H2aꢀ),
1.55–1.65 (m, 6H, H6), 1.33 (m, 3H, H4e), 1.20 (m, 3H, H3e), 1.04
(m, 3H, H5a), 0.84–1.0 (m, 24H, Me2C–, H3a, H4a), 0.70/0.78
(d, 3H, Me/Meꢀ). 13C-NMR (CDCl3): d = 156.0 (Ar-1), 129.9
(Ar-5), 127.8 (Ar-2), 126.4 (Ar-3), 120.5 (Ar-4), 110.4 (Ar-6),
81.2 (C-N3), 74.0 (C1), 55.5 (OMe), 49.8/49.7 (C2), 44.9 (C4),
34.6, 31.8, 25.5, 22.8, 22.3, 21.3, 15.8/15.7 (C3, C5, C6, Me,
Me2C, Me2C). IR (NaCl)/cm−1: m = 2954, 2923, 2870 (C–H
sp3), 2103(vs) (–N3), 1604, 1592, 1494 (Ar C–H sp2). MS(ES):
calc. for (M + Na) = 694.5656, found 694.5656.
a,a-D2 dibenzyl ether (18) was prepared according to literature
procedures.26
Selectivity and isotope effect experiments with dibenzylethers
(18/21)
General procedure for PhI(OAc)2–TMSN3
Into a 7 ml sample vial equipped with a septum, ca. 100 mg
of benzyl ether was dissolved in 4 ml acetonitrile under a
nitrogen atmosphere. 1.5 eq. of iodobenzene diacetate (with
respect to ether) was added and the mixture was stirred until
complete dissolution. TMSN3 (2 eq.) was then added dropwise
by syringe. After the gas had finished developing, the reaction
mixture was concentrated in vacuo to give a crude oil containing
the two products and iodobenzene. The ratio of products was
determined by comparing integrals in 1H-NMR.
(6,6-bis(2-Methoxybenzyloxy)-2,2-dimethyl-4,4,8,8-tetra-
phenyl-tetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxasilepine
(13).
Freshly distilled tetrachlorosilane (57 ll, 0.5 mmol) was added
to a solution of R,R-TADDOL (0.233 mg, 0.5 mmol) in 20 ml
of dry toluene under a nitrogen atmosphere. Pyridine (0.12 ml,
1.5 mmol) was then added and the reaction mixture was stirred
overnight. After this, o-methoxy-benzylic alcohol (0.13 ml, 1
mmol) was added. The mixture was stirred overnight, filtered
through celite and concentrated in vacuo. The product was
purified by flash chromatography (pentane : ether 10 : 1 to 1 : 1)
as a white solid (0.213 g, 56%). 1H-NMR (CDCl3): d = 6.6–7.6
General procedure for IN3
In a 7 ml vial equipped with a septum, ICl (2 eq.) was dissolved
in 4 ml ◦dry acetonitrile under nitrogen atmosphere and cooled
to −10 C. Sodium azide (2.3 eq.) was added and the mixture
8 2 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 1 6 – 8 2 2

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(s, 3H, Me), 1.88 (m, 2H, H3), 1.83 (m, 2H, H2). 13C-NMR
was stirred for 15 min, then ca. 100 mg benzyl ether (1 eq.)
was added via syringe and the mixture was heated to 75 ◦C for
1 h. The crude mixture was transferred to a separation funnel
containing ca. 15 ml Na2S2O3 (5% solution), extracted 3 times
with ca. 20 ml DCM. The combined organic fractions were
washed with brine, dried (MgSO4) and concentrated in vacuo to
give the crude product as a colorless/pale yellow oil.
The ratio of products was determined by comparing integrals
in 1H-NMR.
(CDCl3): d = 137.1 (Ar-1), 129.3 (Ar-4), 128.8, 126.2 (Ar-2,
Ar-3, Ar-5, Ar-6), 94.0 (PhCN3), 92.6 (C4), 68.3 (C1), 56.8 (Me),
31.5 (C3), 24.9 (C2). IR (NaCl)/cm−1: m = 3066, 3034 (Ar C–
H sp2), 2834, 2878 (C–H sp3), 2105(vs) (N3). MS(ES): calc. for
(M + Na) = 299.1239, found 299.1254.
Heptyl carbamoylazide (30)13. Prepared from commercial 27
using general procedure B. Colourless oil. Yield: 120 mg (84%).
2-Phenylethyl carbamoylazide (32)13. Prepared from com-
mercial 31 using general procedure B. White crystals. Yield:
108 mg (77%).
1-((4-Methoxybut-3-enyloxy)methyl)benzene (24b)22,23
.
4-
Benzyloxybut-1-ene (24a) was prepared in a 92% yield according
to the protocol of Six.24 To a solution of 4-benzyloxybut-1-ene
(5.13 g, 31.6 mmol) in 280 ml THF–H2O (4 : 3) was added
NaIO4(14.9 g, 67.7 mmol). The reaction mixture was cooled
Phenyl carbamoylazide (34)13. Prepared from commercial 33
using general procedure B. White crystals. Yield: 124 mg (81%).
mp = 107.1 ◦C.
t
in an ice bath, stirred for 30 min OsO4 (0.6 ml 2% in BuOH)
was then added dropwise via syringe. After a while the solution
turned light yellow and then white. The reaction was carefully
followed by TLC and quenched with NaHSO3 (10%) after ca.
2 h. The mixture was extracted with ether and the combined
organic phases were washed with Na2S2O3, brine and dried over
MgSO4. Flash chromatography (DCM–Pentane gradient, 1:1
to 1:0) provided 3-benzyloxy propanal as a colorless oil. Yield:
3.14 g (61%).
To a THF solution (10 ml) of di-isopropylamine (1.1 ml,
7.61 mmol) at 0 ◦C was added 5.1 ml n-BuLi (1.5 M in hexane,
7.61 mmol). After stirring at 0 ◦C for 5 min the mixture was
transferred via syringe to a 10 ml solution of (methoxymethyl)-
triphenylphosphonium chloride (2.61 g, 7.61 mmol). After
stirring the mixture at 0 ◦C for 30◦min and at room temperature
for 30 min it was cooled to −78 C and 3-benzyloxy propanal
(0.50 g, 3.05 mmol) dissolved in 3 ml THF was added. The
mixture was allowed to come to room temperature. When
no more starting material appeared on TLC the mixture was
quenched with water and extracted with ether. The combined
organic phases were washed with NH4Cl (sat.), brine, dried
(MgSO4) and concentrated in vacuo to give the crude product.
Chromatography (pentane : EtOAc, 5 : 1) afforded 155 mg 24b
(26%) as an E : Z (2 : 1) mixture.
4-Methylphenyl carbamoylazide (36)13. Prepared from com-
mercial 35 using general procedure B. Light yellow crystals.
Yield: 122 mg (84%).
Naphthyl carbamoylazide (38). Prepared from commercial
37 using general procedure B. Colorless oil. Yield: 78 mg (58%).
1H-NMR (CDCl3): d = 8.05 (s, 1H, NH), 7.77 (m, 3H, c,e,h),
7.47 (c,f,g), 7.11 (s, 1H, a). 13C-NMR (CDCl3): d = 154.4 (C O),
=
134.5 (Ar-2), 133.9 (Ar-10), 131.0 (Ar-5), 129.3, 127.9, 127.8,
127.0, 125.6 (Ar-4, Ar-6, Ar-7, Ar-8, Ar-9), 119.3 (Ar-3), 115.4
(Ar-1). IR (NaCl)/cm−1: m = 3344(s) (NH), 3059 (Ar C–H
2
=
sp ), 2144 (N3), 1699, 1681(vs) (C O), 1588, 1560, 1502 (Ar).
MS(ES): calc. for (M + Na) = 235.0596, found 235.0592
4-Methoxyphenyl carbamoylazide (40)13. Prepared from
commercial 39 using general procedure B. White crystals. Yield:
100 mg (74%).
4-Nitrophenyl carbamoylazide (42). Prepared from commer-
cial 41 using general procedure B. Yellow crystals. Yield: 55 mg
(41%). 1H-NMR (CDCl3): d = 8.22 (d, J = 8.9, 2H, Ar-2, Ar-2ꢀ)
7.63 (d, J = 8.9, 2H, Ar-3, Ar-3ꢀ), 7.30 (s, 1H, NH). 13C-NMR
=
(CDCl3): d = 154.3(C O), 144.0, 143.1(Ar-1, Ar-2), 125.5(Ar-
3/Ar-3ꢀ), 118.9(Ar-2, Ar-2). IR (NaCl)/cm−1: m = 3316 (NH),
2
=
a-Azidobenzyl 3-butenyl ether (25a). Prepared from 24a24
using general procedure A. Isolated as the first product from
flash chromatography in pentane to CH2Cl2–pentane, 1 : 1.
Colorless oil. Yield: 74 mg (54%). 1H-NMR (CDCl3): d = 7.35–
7.47 (m, 5H, Ar), 5.87 (ddt, J = 17.1, J = 10.2, J = 6.7, 1H,
Ha), 5.46 (s, 1H, N3–C–H), 5.15 (ddd, J = 17.2, J = 3.25, J =
1.6, 1H, Hb), 5.09 (ddd, J = 10.2, J = 1.6, 1.1, 1H, Hc), 3.92
(dt, J = 9.3, J = 6.7, 1H, H1), 3.66 (dt, J = 9.3, J = 6.7, 1H,
3079 (Ar C–H sp ), 2165, 2136 (N3), 1691 (C O), 1549, 1505,
1346 (–NO2). MS(ES): calc. for (M + Na) = 219.0, found 219.0
(C8H8N2O4 from reaction with MeOH).
2-Azidoethyl benzoate (44)14. Prepared from commercial 43
using general procedure A. Colorless oil. Yield: 123 mg (98%).
Acknowledgements
H1 ), 2.47 (ddt, J = 6.6, J = 6.7, J = 1.1, 2H, H2). 13C-NMR
ꢀ
We thank the Lundbeck foundation, the Holm foundation and
SNF for financial support. We also thank Ib B. Thomsen and
Susan Nielsen for assistance with preliminary experiments.
(CDCl3): d = 137.2 (Ar-1), 134.8(C3), 129.3(Ar-4), 128.7(Ar-
3/Ar-3ꢀ), 126.3(Ar-2/Ar-2ꢀ), 117.1(C4), 92.6(C–N3), 68.4(C1),
34.1(C2). IR (NaCl)/cm−1: m = 2921 (C–H sp3), 2104(vs) (–N3).
MS(ES): calc. for (M + Na) = 226.0956, found 226.0958.
References
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1
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8 2 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 1 6 – 8 2 2