Hindered ester formation by SN2 azidation of N-acetoxy-N-alkoxyamides and N-alkoxy-N-chloroamides-novel application of HERON rearrangements

Article abstract of DOI:10.1039/b111250n

Treatment of N-acetoxy-N-alkoxyamides or N-alkoxy-N-chloroamides with sodium azide in aqueous acetonitrile results in S_N2 displacement of chloride and the formation of reactive N-alkoxy-N-azidoamides. The reaction with N-acetoxy-N-benzyloxybenzamide has been studied kinetically (k₂₉₄ = 2 L mol^-1 s^-1) and azidation of N-formyloxy-N-methoxyformamide has been modeled computationally at the pBP/DN*//HF/6-31G* level of theory. The anomeric amides N-alkoxy-N-azidoamides decompose intermolecularly and spontaneously to esters and two equivalents of nitrogen. This extremely exothermic process facilitates the formation, in excellent yields, of highly hindered esters.

Full text of DOI:10.1039/b111250n

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Hindered ester formation by SN2 azidation of N-acetoxy-N-
alkoxyamides and N-alkoxy-N-chloroamides—
novel application of HERON rearrangements
2
Stephen A. Glover* and Guoning Mo
Division of Chemistry, School of Biological, Biomedical and Molecular Sciences,
University of New England, Armidale 2351, New South Wales, Australia
Received (in Cambridge, UK) 10th December 2001, Accepted 31st July 2002
First published as an Advance Article on the web 30th August 2002
Treatment of N-acetoxy-N-alkoxyamides or N-alkoxy-N-chloroamides with sodium azide in aqueous acetonitrile
results in SN2 displacement of chloride and the formation of reactive N-alkoxy-N-azidoamides. The reaction with
N-acetoxy-N-benzyloxybenzamide has been studied kinetically (k294 = 2 L molϪ1 sϪ1) and azidation of N-formyloxy-
N-methoxyformamide has been modeled computationally at the pBP/DN*//HF/6-31G* level of theory. The
anomeric amides N-alkoxy-N-azidoamides decompose intramolecularly and spontaneously to esters and two
equivalents of nitrogen. This extremely exothermic process facilitates the formation, in excellent yields, of highly
hindered esters.
alkoxyamides with aromatic amines8,9 and in the thermal
Introduction
decomposition of N,NЈ-diacyl-N,NЈ-dialkoxy hydrazines.3,6,10
N,N-Bisheteroatom-substituted amides constitute an unusual
class of amides whose properties have recently been studied
Where the heteroatom is a part of a good leaving group, these
amides undergo substitution reactions. We have reported both
both experimentally and theoretically.1–7 They are character-
SN1-type (AAl1 acid-catalysed solvolysis) reactivity11–13 and
ised, among other things, by an unusual degree of pyramidality
SN2-type reactivity for one such class of compounds, the bio-
at the amide nitrogens resulting in reduced conjugation between
the nitrogen lone pair and the carbonyl π bond. Direct con-
logically active dioxo-substituted amides, N-acyloxy-N-alkoxy-
amides.8,9,13 Aromatic amines and hydroxide ions have both
sequences of this are much lower amide isomerisation barriers
been found to displace acetate or benzoate in a classical SN2
and high carbonyl stretch frequencies in their infrared spectra
(Fig. 1a). While these effects arise out of the additional electron
reaction at nitrogen and recently we have also discovered that
these mutagens react by an SN2 process with the cellular conju-
gating agent, glutathione (Scheme 2).14 SN2 reactions with
Fig.
1
(a) Pyramidalisation and (b) anomeric interactions in
bisheteroatom-substituted amides.
demand by two electronegative atoms, this geminal substitution
pattern also facilitates unusual anomeric interactions through
the amide nitrogen. A lone pair on one heteroatom can overlap
with the neighbouring σ*-orbital between the second hetero-
atom and nitrogen (Fig. 1b). This is particularly effective
where one heteroatom is more electronegative than the other, in
which case it results in anomeric weakening of one of the bonds
to nitrogen.1,5 In N-alkoxy-N-aminoamides, such interactions
have been found to result in the unusual HERON† rearrange-
ment (Scheme 1).3,7,8 Since alkoxides are poor leaving groups,
the negative hyperconjugation results in a migration of the
oxygen from nitrogen to carbon. HERON rearrangements
have been found in the reactions of mutagenic N-acyloxy-N-
Scheme 2
amines and glutathione have been modeled computationally
and are characterised by a non-synchronous concerted process
involving strong charge separation in the transition states which
have long N–OAc bonds and partial nitrenium ion character at
the amide nitrogen.15
Recently we have also discovered that in aqueous-organic
mixtures, both N-acyloxy-N-alkoxyamides as well as N-alkoxy-
N-chloroamides undergo substitution reactions with azide.16
Substitution of chloride or acetate leads to intermediate
Scheme 1
† Heteroatom Rearrangements on Nitrogen.
1728
J. Chem. Soc., Perkin Trans. 2, 2002, 1728–1739
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b111250n

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N-alkoxy-N-azidoamides which readily decompose to esters
with the evolution of nitrogen (Scheme 3). The reaction
involves a HERON-type reaction of a 1-acyl-1-alkoxydiazene
intermediate. We now report on the kinetic and theoretical
details of the formation and decomposition of N-alkoxy-N-
azidoamides, the energetics and mechanism of which enable
the synthesis of highly hindered esters that are unavailable by
classical ester formation reactions.
would involve rate limiting formation of an acylalkoxy-
nitrenium ion 6 and the overall rate would be independent of
the concentration of azide. When the reaction was carried out
in aqueous acetonitrile in a closed system, progress of the
reactions could be monitored dilatometrically but the reaction
with N-alkoxy-N-chlorobenzamides 5a as substrates was pro-
hibitively fast, even at low temperatures and low concentrations
of both reagents. However, the acetoxy derivatives 5b reacted
more slowly under the same conditions and a kinetic study of
the reaction of sodium azide with N-acetoxy-N-benzyloxy-
benzamide 8 was possible.
Scheme 3
Results and discussion
Azide trapping of carbocations and nitrenium ions in aqueous
solution, a diffusion-controlled process, provides solvolysis rate
constants in water, kw, and a number of research groups have
utilised this competition method for the evaluation of solvolysis
rate constants for a variety of arylnitrenium ions.17–23 In an
attempt to determine the lifetimes of N-acyl-N-alkoxy-
nitrenium ions in aqueous solution using similar methods, we
found that N-acetoxy-N-butoxybenzamide 1a, upon treatment
with an aqueous-acidic solution of sodium azide afforded a
near quantitative yield of butyl benzoate 3a. The extremely
rapid reaction was accompanied by liberation of two equiv-
alents of nitrogen gas. A crossover experiment using N-acetoxy-
N-ethoxy-p-toluamide 2a and 1a afforded exclusively the
non-crossover esters, ethyl p-toluate 4a and butyl benzoate 3a
(Scheme 4). N-Chlorohydroxamic esters reacted similarly and
a crossover experiment with sodium azide and a mixture of
N-benzyloxy-N-chlorobenzamide 1b and N-chloro-N-ethoxy-
p-nitrobenzamide 2b in aqueous acetonitrile gave exclusively
benzyl benzoate 3b and ethyl p-nitrobenzoate 4b as the only
ester products (Scheme 4). Ester formation does not involve
generation, in solution, of an acylating agent and alcohol since
this would have resulted in mixed esters.
Two reactions of 8 and sodium azide were carried out in a
250 mL homogeneous acetonitrile–water solution at the initial,
identical reagent concentrations of 0.0005 M and 0.0010 M,
respectively. The volume of evolved nitrogen was measured
dilatometrically at 750 mm. Since there is a proportionality
between the concentrations, [c]t, of 8 and azide and the remain-
ing nitrogen in the reaction mixtures, [c]t was derived from the
volumes of nitrogen liberated at time t and the total volume of
nitrogen liberated upon completion of the reaction [eqn. (1)]:
Reactant concentration [c]t =
[N2(total) Ϫ N2(evolved)] × [c]0/N2(total) (1)
With [8]0 = [N3Ϫ]0 = 1 × 10Ϫ3 M and at 294.5 K, a plot of the
reciprocal of concentrations (1/[c]t) of 8 or azide versus time
was linear with gradient equal to the rate constant, k, of 1.88 L
molϪ1 sϪ1 and t1/2 = 4.9 × 102 s [Fig. 2(a)]. With starting concen-
trations of [8]0 = [N3Ϫ]0 = 5 × 10Ϫ4 M a similar rate constant was
obtained (Table 1) but t1/2 = 1.06 × 103 s. ‡
Kinetic results
Similar rate constants were obtained at this temperature for
the reaction of 8 and azide under pseudo first order conditions,
N-Alkoxy-N-azidobenzamides 7 were postulated as unstable
intermediates which decompose spontaneously to alkyl benz-
oate and nitrogen, and SN1 and SN2 limiting mechanisms for
their formation are depicted in Scheme 5. The SN1 reaction
‡ For bimolecular reactions with identical concentrations, t = 1/[c]0k,
½
thus halving the concentrations doubles t .
½
Scheme 4
Scheme 5
J. Chem. Soc., Perkin Trans. 2, 2002, 1728–1739
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Table 1 Rate constants at 294.5 K for the reaction sodium azide and N-acetoxy-N-benzyloxybenzamide in acetonitrile–water
Experiment
[Azide]/10Ϫ4 M
[Acetoxy]/10Ϫ4 M
k/L molϪ1 sϪ1
Calc. methoda
1
2
3
4
5.0
10.0
50.0
5.0
5.0
10.0
5.0
1.91
1.88
1.81
2.08
(1)
(1)
(2)
(3)
50.0
a k calculated according to eqns. (1)–(3).
reactions. The gas-phase activation energy for the SN2
reaction of ammonia with N-formyloxy-N-methylformamide
(148.65 kJ molϪ1) is double that of the reaction of ammonia
with N-formyloxy-N-methoxyformamide (72.37 kJ molϪ1).15
Interestingly, neither N-butyl-N-chlorobenzamide 9a nor
N-benzoyloxy-N-benzylbenzamide 9b reacted with azide in the
same manner. Upon reaction in acetonitrile–water parent
hydroxamic ester was formed indicating alternative reaction
pathways. Destablisation of the N–Cl or N–OAc bond through
negative hyperconjugation facilitates attack at nitrogen by
azide with the displacement of chloride or acetate. The sp3
nature of the amide nitrogen in 5a and 5b also facilitates this
process. 9a and 9b, on the other hand should be closer to sp2
hybridised at the amide nitrogen and exhibit substantially more
lone pair conjugation with the carbonyl. The ease of SN2 reac-
tions at such nitrogens might therefore be compared to the
energetically unfavourable bimolecular substitution at vinylic
carbons.
Theoretical properties
The SN2 reaction of azide has been modelled theoretically at
the pBP/DN*//HF/6-31G* level by the reaction of azide with
N-formyloxy-N-methoxyformamide 10 (Scheme 6). In the gas
phase the transition state is preceded by an ion–molecule com-
plex (Fig. 3a) which is at a minimum on the reaction coordinate
and in which the azide anion is 3.7 Å from the amide nitrogen,
and approaching the axis of the formyloxy–nitrogen (N1–O9)
bond. The early nature of this interaction is demonstrated by
the largely unchanged geometry of the amide molecule. The
average angle at nitrogen of 109.7Њ, which reflects a character-
istically high degree of pyramidality at N1, and the N1–O9
bond length of 1.383 Å are similar to those computed for the
ground state structure for 10 (109.8Њ and 1.376 Å). Energies and
thermodynamic values are given in Tables 2 and 3. Including
zero point energies, the reaction is computed to be exothermic
in the gas phase at 0 K (∆E = Ϫ58.5 kJ molϪ1) but the transition
state, while at a saddle-point, is lower in energy than the ion–
molecule complex (EA = Ϫ18.4 kJ molϪ1) in accord with the
expected stabilisation due to charge delocalisation; the charge
on azide (Ϫ1) is shared by both the azide (Ϫ0.76) and the
formate group (Ϫ0.62) in the transition state. Decreased solvent
stabilization of the transition state relative to the intermediate
complex should be important and inclusion of AM1 solvation
energies resulted in a small positive EA. At 298 K, and including
enthalpy and entropy terms, ∆H‡ is computed to be Ϫ18.7 kJ
molϪ1 but, in accord with the associative transition state, ∆S‡ is
Ϫ14.5 J KϪ1 molϪ1 and ∆G‡ is computed to be Ϫ14.3 kJ molϪ1
without solvation effects. By comparison, at the HF/6-31G*
level of theory, ∆G and ∆G‡ are computed to be Ϫ86.4 and
125.5 kJ molϪ1 respectively.
Fig. 2 (a) Second order plot for the reaction of N-acetoxy-N-
benzyloxybenzamide 8 with sodium azide in acetonitrile–water (3 : 1,
250 mL) at 294.5 K. [8]0 = [N3Ϫ]0 = 1 × 10Ϫ3 M; (b) Pseudo first order
plot for the reaction of 8 (5 × 10Ϫ4 M) and N3Ϫ(5 × 10Ϫ3 M) in
acetonitrile–water (3 : 1, 250 mL) at 294.5 K.
both with a ten-fold excess of azide or a ten-fold excess of
acetoxy compound. A plot of the natural logarithm of the con-
centrations of acetoxy compound ([8]0 = 5 × 10Ϫ4 M, [N3Ϫ]0 =
5 × 10Ϫ3 M) versus time [eqn. (2)] was linear (Fig. 2(b)).
ln[8] = ln[8]0 Ϫ k[N3Ϫ] × t
ln[N3Ϫ] = ln[N3Ϫ]0Ϫ k[8] × t
(2)
(3)
The second order rate constant, k, calculated from the gradient
of the line of best fit was 1.81 L molϪ1 sϪ1 with t = 69 s. With a
½
ten-fold excess of mutagen and reverse concentrations, the
value was similar with a t = 60 s (Table 1).
½
The reaction of 8 and azide is therefore dependent upon first
order concentrations of both reagents. Since N-alkoxy-N-
chlorobenzamides solvolyse relatively slowly under aqueous
organic conditions,6,24 their facile reaction in the presence of
sodium azide must also follow bimolecular kinetics.
The N-alkoxy-N-azidoamide intermediates from these reac-
tions, though readily generated, are clearly unstable. However,
since non-crossover products were obtained from mixtures of
N-acetoxy and N-chloro precursors, ester formation from the
N-alkoxy-N-azidoamides must be an intramolecular process.
Recent calculations on the energetics of SN2 reactions at
nitrogen confirm the role of the N-alkoxy group in these
The computed energetics suggest a facile SN2 reaction in
agreement with the experimental findings. Rate constants for
the reaction of N-acyloxy-N-alkoxyamides with aromatic
amines or glutathione are slower by two to three orders of
magnitude.8,14
In the computed transition state 11 (Fig. 4a) the azide and
formyloxy groups are approaching collinearity (N2–N1–O9 =
158.6Њ) and the SN2 displacement is predicted to be concerted
but non-synchronous. The increase in negative charge of the
1730
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Table 2 pBP/DN*//HF/6-31G* and HF/6-31G* energiesa, enthalpies, entropies for reactants, gas-phase complexes, transition states and productsb
and AM1 solvation energies for the reaction of azide with N-formyloxy-N-methoxyformamide (10) and N-formyloxy-N-methylformamide (14).
ZPE/kJ molϪ1
Eelec/au
H/kJ molϪ1
S/J KϪ1 molϪ1
Esolv/kJ molϪ1
HCON(OCHO)OMe 10
233.0
(261.5)
28.0
(32.6)
264.2
(299.4)
256.7
(291.1)
204.7
(230.7)
53.7
(59.0)
233.0
(252.3)
254.9
(287.8)
246.7
Ϫ473.05455
(Ϫ470.2843)
Ϫ164.31803
(Ϫ163.26100)
Ϫ637.39671
(Ϫ633.57434)
Ϫ637.40085
(Ϫ633.52633)
Ϫ448.09735
(Ϫ445.39062)
Ϫ189.29648
(Ϫ188.18263)
Ϫ397.86254
(Ϫ395.49629)
Ϫ562.20473
(Ϫ558.7831)
Ϫ562.17967
(Ϫ558.70577)
246.0
(284.7)
34.9
(39.2)
284.5
(331.1)
276.7
(322.4)
219.2
(251.2)
61.6
(66.7)
236.4
(271.0)
272.0
(317.0)
265.0
316.1
(380.8)
213.5
(211.5)
390.0
(487.4)
375.5
(461.9)
324.8
(371.2)
244.8
(243.9)
307.4
(352.5)
357.8
(464.4)
360.4
Ϫ34.0
Ϫ314.9
Ϫ293.7
Ϫ254.7
Ϫ43.8
Ϫ
N3
[10–N3]Ϫ complex
T.s. 11
HCON(N3)OMe 12
HCO2Ϫ 13
Ϫ320.3
Ϫ41.7
HCON(OCHO)Me (14)
[14–N3]Ϫ complex
T.s 15
Ϫ303.1
Ϫ246.8
(279.3)
(305.0)
(411.8)
a HF/6-31G* values in parentheses. b N-Azido-N-methylformamide 16 was unstable at the HF/6-31G* level of theory decomposing to N2 and
1-formyl-1-methyldiazene.
Scheme 6
Fig. 3 HF/6-31G* geometries of azide complexes with (a) N-formyloxy-N-methoxyformamide (10); (b) N-formyloxy-N-methylformamide (14).
formate group [∆qformate = Ϫ0.65] is larger than the decrease in
negative charge over the azide group [∆qazide = ϩ0.24] which is
indicative of more N1–O9 bond stretching than N2–N1 bond
formation. In this respect the transition state is similar to that
reported for the corresponding reactions of ammonia or
methanethiol with the same mutagen model.15 However, the
transition states for those reactions, involving neutral nucleo-
philes, exhibited significant charge separation as opposed to the
charge delocalisation in the azide reaction transition state. Near
coplanarity of O8–C7–N1–O5–C6 indicates that the lone pair
on N1 is completely out of conjugation with the carbonyl at the
transition state and both the C7 and O5 p-orbitals are aligned
with the partial bonds between N1 and the incoming azide and
departing formate.
The reaction of azide with N-formyloxy-N-methylformamide
(14) (Scheme 7) likewise involves an intermediate ion–molecule
J. Chem. Soc., Perkin Trans. 2, 2002, 1728–1739
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Fig. 4 HF/6-31G* transition state geometries for the reaction of azide anion with (a) N-formyloxy-N-methoxyformamide and (b) N-formyloxy-N-
methylformamide.
Scheme 7
complex (Fig. 3b) but activation energies and ∆G‡ are com-
puted to be significantly greater than those for the reaction of
azide with (10) at both the pBP/DN*//HF/6-31G* and HF/
6-31G* levels of theory (Table 3). This could be attributable, in
part, to a stronger N1–O8 bond (no anomeric destabilisation)
as well as to a loss in amide resonance in this case, since lone
pair resonance with the carbonyl is also lost in the transition
state (Fig. 4(b)). Computational results therefore predict that a
similar reaction with 14 would be much less favourable than the
reaction of azide with 10 which is in accord with the failure of
9a and 9b to react.
N-Alkoxy-N-azidoamides constitute a special class of NNO
anomeric amides in which anomeric overlap could be
1
nN–σ*NO
.
However, while one resonance form [Fig. 5(b)]
Fig. 5 Anomeric effects in N-azido-N-alkoxyamides.
generates anionic nitrogen adjacent to the amide nitrogen,
the strongly electron-withdrawing effect of the quaternary
ammonium centre [Fig. 5(a)] could both reduce the donor
capacity of this nitrogen, as well as result in a reverse nO–σ*NN
anomeric effect through a lowering of the C(O)N–N σ* orbital
energy.
N-Azido-N-methoxyformamide is predicted to be a stable
point on the energy surface. At the pBP/DN*//HF/6-31G* level
the E- form is computed to be 5 kJ molϪ1 lower in energy than
the Z-form and its geometry is illustrated in Fig. 6(a). Like other
anomeric amides,1,2,4,5 it has a strongly pyramidal amide nitro-
gen and Newman projections in Fig. 6(b) and Fig. 6(c) indicate
only one anomeric alignment, namely that between the p-type
lone pair on the alkoxy oxygen and the N–N σ*orbital. This
Fig.
6
HF/6-31G* optimised geometry for (a) (E)-N-azido-N-
methoxyformamide; (b) Newman projection along the O7–N1 bond; (c)
Newman projection along the N2–N1 bond.
geometry is similar to that described in the accompanying
paper where a full analysis of the energetics of ground state
reactants, products, and reactivity of N-azido-N-methoxy-
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formamide 11, at B3LYP/6-31G* hybrid density functional
level of theory, is given.25
By analogy with concerted decompositions of N-alkoxy-
N-aminoamides or N,NЈ-diacyl-N,NЈ-dialkoxyhydrazines,3,6,8
ester formation could occur by a normal HERON process
(Scheme 8, pathway A). However, with N-alkoxy-N-azido-
Scheme 8
amides an alternative process is possible; initial loss of nitrogen
followed by a HERON reaction of the intermediate 1,1-
disubstituted diazene 17 would lead to the same products
(Scheme 8, Path B). 17 is also formed as intermediate from
the three-centre rearrangement of N,N Ј-diacyl-N,N Ј-dialkoxy-
hydrazines.
Becke3LYP/6-31G* calculations on these and other possible
reaction pathways of 12 show that path B, which proceeds in
two steps is computed to be the lowest energy process and,
significantly, the overall transformation of 11 into two mole-
cules of nitrogen and ester is computed to be exothermic by 584
kJ molϪ1 25
Such favourable energetics should facilitate the
.
formation of high energy esters. The driving force for the
formation of 17 and the subsequent HERON rearrangement to
esters (Scheme 8, Path B) is derived from the liberation of two
molecules of N2 and should facilitate coupling of sterically
hindered alkoxy and acyl substituents.
Synthesis of sterically hindered esters
In classical Fischer esterification reactions, bulky groups on
either the carboxylic acid or the alcohol slow down the reaction
considerably.26–28 The tetrahedral intermediate in these reac-
tions imparts significant steric compression at the acyl carbon
when either the acyl side chain of the acid or the alkyl group of
the alcohol, or both of these are bulky or have branching
adjacent to the carboxylic acid and hydroxy functionality.
Similarly, there are impediments in hindered ester formation
from alcohols and acid chlorides. There is therefore continued
interest in new methods to activate the carboxy group toward
facile esterification. Parish and coworkers have presented a
simple method for the esterification of hindered carboxylic
acids involving the reaction of trifluoroacetic anhydride with
alcohol.29 However, because of the strongly acidic reaction
conditions, the esterification could not be achieved in some
cases, especially those involving aliphatic tertiary alcohols.
Kaiser and coworkers reported a synthesis in which alcohols
were converted into their lithium alkoxide salts with n-butyl-
lithium and then heated briefly with an appropriate acid chlor-
ide.30 This method is restricted to acid chlorides without labile
α-hydrogen atoms, and to those halides whose corresponding
ketenes (intermediates in the reaction) are not volatile or do not
readily dimerise. The method of Rossi and coworkers involving
two-step reactions by means of potassium alkoxides is only
applicable to the preparation of benzoate esters of appropriate
tertiary alcohols but not demonstrated for other cases.31 Silver
cyanide was employed by Takimoto and coworkers in the prep-
aration of sterically hindered esters from the corresponding
acid chlorides and alcohols.32 This method is excellent and
complementary to the methods developed previously when
J. Chem. Soc., Perkin Trans. 2, 2002, 1728–1739
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Table 4 Ester (RCOORЈ) formation from the reaction of alkyl
N-alkoxy-N-chloroamides (RCONClORЈ) with sodium azide in
aqueous acetonitrile
considering the high yields and the speed of the reaction, but it
is not suitable for some other cases under mild conditions. The
efficient synthesis of macrocyclic lactones and esters by the
activation of thiol esters with metal salts such as HgII, CuI, CuII,
and AgI in the presence of alcohols has been reported by
Masamune and coworkers.33 However, the reaction depends
largely on the nature of the thiol esters and metal salts
employed. Kim and coworkers introduced a synthesis of steric-
ally hindered esters by the reaction of S-2-pyridyl thioates and
2-pyridyl esters with alcohols in the presence of cupric brom-
ide.34 More recently Barton and coworkers have demonstrated
that decomposition of N,N Ј-diacyl-N,N Ј-dialkoxyhydrazines
could be fashioned as a synthesis of highly hindered esters.10
However, the generation of considerable amounts of the corre-
sponding acids in the course of formation of highly hindered
esters, offsets the advantages in this method.
Ester
R
RЈ
Isolated crude yield (%)
21a
21b
21c
21d
21e
21f
21g
21h
21i
Ph
(CH3)3C
(CH3)3C
(CH3)3C
Cyclohexyl
(CH3)2CH
PhCH2
PhCH2
Et
87
30a
82b
97
92
93
92
94
94
(CH3)3C
1-Adamantyl
(CH3)3C
Ph
Ph
CH3
p-NO2C6H4
Ph
Et
a GLC analysis; reaction accompanied by formation of pivalic acid
29%. b Traces of adamantanecarboxylic acid were also detected.
In contrast to carboxylic ester formation, we have found that
bulky substituents present little barrier to the synthesis of
hydroxamic esters, either by reaction of acid chlorides with
alkoxyamines or by alkylation of sodium salts of hydrox-
amic acids. The additional heavy atom between the acyl
and alkoxy side chains reduces the influence of steric effects.
Similarly, N-chlorination of hydroxamic esters with tert-butyl
hypochlorite is not impeded by sterically demanding groups in
the hydroxamic ester. We envisaged that treatment of N-alkoxy-
N-chloroamides with sodium azide would therefore provide an
energetically favourable route to sterically hindered esters.
tert-Butyl hydroxamates (19a–c) were prepared through the
treatment of O-(tert-butyl) hydroxylamine hydrochloride with
the appropriate acid chloride in the presence of pyridine, in
anhydrous conditions at 0 ЊC.10 Other hydroxamic esters (19d–i)
have been prepared previously by condensation of alkyl halides
and potassium benzohydroxamates. Treatment of 19a–i with a
three molar excess of tert-butyl hypochlorite in anhydrous
DCM in the dark at room temperature for 3–12 hours (at 0 ЊC
in the cases of 19b and 19c), followed by removal of the solvent
under reduced pressure (room temperature) afforded the appro-
priate N-chlorohydroxamates 20a–i as yellow oils (Scheme 9).
corresponding tert-butyl carboxylic esters. The reaction has
the advantage that it is easy to perform and, in most cases, the
products are readily isolated from the reaction mixtures by
extraction with organic solvents.
Sterically crowded esters formed by this process and their
yields are summarised in Table 4. tert-Butyl pivalate 21b and to
a lesser extent, tert-butyl adamantane-1-carboxylate 21c were
accompanied by formation of some of their parent carboxylic
acid. Since the esters were stable under the reaction condi-
tions, acid formation is most likely derived from the N-chloro
precursor prior to azide reaction.
The comparable yields indicate that sterically hindered
esters are formed with similar ease relative to less hindered
esters. The HERON-type reaction of 1,1-disubstituted dia-
zenes, which proceeds through a three-centered transition state
involving extrusion of a stable nitrogen molecule, is not only
extremely exothermic, its concerted nature can avoid the limit-
ing formation of a tetrahedral intermediate since the CO–N
bond is broken as the O–CO bond is formed. Theoretical
modelling of these reactions and the unusual properties of
N-alkoxy-N-azidoamides forms the basis of the accompanying
publication.25
Experimental
Melting points were determined on a Reichert Microscopic
Hot-Stage and are uncorrected. Infrared spectra were recorded
on a Perkin-Elmer 1725X Fourier-transform instrument. 300
1
MHz H and 75 MHz 13C NMR spectra were recorded on a
Bruker AC-300P FT spectrometer or a Bruker Avance 300 FT
spectrometer. Deuterated chloroform (CDCl3) was com-
mercially obtained from Aldrich. All routine samples for struc-
tural analysis were run at 300 K in CDCl3, with tetramethyl-
silane (0.1%) or CHCl3 as an internal standard. Chemical shifts
are reported in ppm downfield of TMS. Abbreviations used
to indicate spectral multiplicity are: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), br (broad). GLC analyses
were performed on a Shimadzu Gas Chromatograph (GC-8A)
instrument. Thin layer chromatography (TLC) was performed
on aluminium sheets pre-coated with 0.2 mm of silica gel 60
F254 (Merck). Preparative plate chromatography was carried out
centrifugally on a Harrison 7924T Research Chromatotron.
Mass spectral data were obtained on a Kratos MS902
spectrometer from the Mass Spectrometry Unit, School of
Chemistry, the University of Sydney. Microanalyses were
performed at the Microanalytical Unit, Research School of
Chemistry, Australian National University.
Scheme 9
N-tert-Butoxy-N-chloro-2,2-dimethylpropanamide 20b and
N-tert-butoxy-N-chloroadamantane-1-carboxamide 20c were
unstable at room temperature in the dark and partially decom-
posed in the course of the chlorination reaction. N-Chlorin-
ation of 19b and 19c was however successfully effected below
0 ЊC. The chlorides were formed cleanly in high yields and were
characterised by IR (high carbonyl frequencies: 1715–1740
1
1
cmϪ1
) and H NMR. These chlorides were used directly in
subsequent reactions.
The reaction of N-tert-butoxy-N-chloroamides 20a–i with
excess sodium azide in aqueous acetonitrile (H2O–CH3CN =
1 : 3) proceeded rapidly and was essentially complete within a
few minutes (Scheme 9). Nitrogen gas evolved during the course
of the reaction was measured by dilatometry and nearly two
equivalents were evolved in each case. Extraction of the mix-
tures with DCM afforded, after drying and concentration, the
Computational methods
Molecular orbital calculations were executed with MACSPAR-
TAN PRO and SPARTAN 5 molecular modelling software.35
Geometries were optimised at the HF/6-31G* level of theory.
1734
J. Chem. Soc., Perkin Trans. 2, 2002, 1728–1739

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Energies were obtained from single point density functional
calculations from non-local density calculations using the BP86
functional of Becke and Perdew36,37 in which the non-local
corrections are introduced perturbatively (pBP method). The
numerical polarisation basis set, DN*, which is comprised of
atomic solutions supplemented by d-type functions on heavy
atoms, was used throughout.35,38 Frequency calculations at the
HF/6-31G* level were carried out to verify stationary points as
minima (all positive force constants) and transition states (one
negative force constant) and HF/6-31G* and pBP/DN* fre-
quency calculations with force constant analysis were used to
determine zero point vibrational energies (ZPE) at 0 K and
enthalpy (H) and entropy (S ) thermodynamic quantities at
298.15 K and 1 atmosphere. Aqueous solvation energies were
estimated semiempirically for HF/6-31G* optimised geometries
using the SM2 method of Cramer and Truhlar within Spartan
5.39 Group charges (qformate and qazide) were derived from the sum
of electrostatic charges computed at the HF/6-31G* level of
theory and changes in group charges (∆q) were determined
from the difference between total electrostatic charge on azide
and formate in the transition state and that on the same group
in the ground state of azide and N-formyloxy-N-methoxy-
formamide (10).
tert-Butyl adamantane-1-carbohydroxamate 19c. To a stirred
solution of O-(tert-butyl)hydroxylamine hydrochloride (1.00 g,
0.008 mol) in dry pyridine (10 mL) at 0 ЊC was added, dropwise,
a chilled solution of adamantane-1-carbonyl chloride (2.59 g,
0.013 mol) in anhydrous THF. The reaction mixture was stirred
overnight at room temperature, filtered and concentrated under
reduced pressure with gentle heating. The residue was dissolved
in DCM (50 mL) which was washed with 10% Na2CO3 (50 mL),
water (200 mL), dried with anhydrous sodium carbonate and
concentrated to give the crude title compound. Recrystallis-
ation from benzene gave pure tert-butyl adamantane-1-carbo-
hydroxamate as colourless crystals (1.56 g, 78%), mp 164–166
ЊC (Found: C, 72.23%; H, 9.52%; N, 5.57%. C15H25O2N requires
C, 71.67%; H, 10.02%; N, 5.57%); νmax(CHCl3)/cmϪ1 3413 (NH)
and 1682 (C᎐O); νmax(Nujol)/cmϪ1 3260 (NH), 1655 (C᎐O),
᎐
᎐
1187, 1013, 930, 860 and 810; δH(CDCl3) 1.27 (9H, s, CH3),
1.71–1.78 (6H, m, CH–CH2–CH), 1.90–1.92 (6H, m, CH–CH2–
C), 2.01–2.12 (3H, m, CH), 7.76 (1H, br, NH); δC(CDCl3) 26.30
(q, CH3), 28.00 (t, CH2), 36.50 (t, CH2), 39.10 (d, CH), 40.50 (s,
C–CO), 81.80 (s, –O–C(CH3)3), 176.60 (s, CO). The product
was consistent spectroscopically (IR, 1H, 13C NMR) with the oil
reported for the same compound by Barton and coworkers.10
The synthesis of N-acetoxy-N-butoxybenzamide (1a),11,40
Synthesis of cyclohexyl 2,2-dimethylpropanohydroxamate42
N-benzyloxy-N-chlorobenzamide (1b),11,12 N-acetoxy-N-benzyl-
A solution of potassium trimethylacetohydroxamate (64.95 g,
0.42 mol),43 cyclohexyl bromide (68.22 g, 0.42 mol), sodium
carbonate (21 g), methanol (200 mL) and water (150 mL) was
stirred for 24 hours then refluxed for 2 hours. Removal of
methanol under reduced pressure, acidification and extraction
with DCM afforded the crude cyclohexyl 2,2-dimethyl-
propanohydroxamate upon concentration (10.75 g, 13%).
Recrystallisation from benzene gave pure cyclohexyl 2,2-
dimethylpropanohydroxamate as colourless crystals, mp 159–
160 ЊC (Found: C, 65.51%; H, 10.19%; N, 7.07%. C11H21O2N
requires C, 66.30%; H, 10.62%; N, 7.03%); νmax(CHCl3)/cmϪ1
oxybenzamide
(8),11,12
N-chloro-N-isopropoxybenzamide
(20e),11 ethyl p-methylbenzohydroxamate,3 ethyl p-nitrobenzo-
hydroxamate,3 benzyl acetohydroxamate3 and N-chloro-N-
ethoxybenzamide (20i)11 have been described previously.
Synthesis of tert-butyl hydroxamates10
tert-Butyl benzohydroxamate 19a. To a stirred solution of
O-(tert-butyl)hydroxylamine hydrochloride (1.00 g, 0.008 mol)
in dry pyridine (10 mL) at 0 ЊC was added, dropwise, a chilled
solution of benzoyl chloride (1.12 g, 0.008 mol) in anhydrous
THF. The reaction mixture was stirred overnight at room
temperature, and filtered and concentrated under reduced
pressure with gentle heating. The residue was dissolved in DCM
(50 mL) which was washed with 10% Na2CO3 (50 mL), water
(100 mL), dried with anhydrous sodium carbonate, and concen-
trated to give the crude title compound. Recrystallisation
from diethyl ether gave pure tert-butyl benzohydroxamate as
colourless crystals (0.54 g, 35%), mp 132 ЊC (Lit.41mp 134–
3433 (NH) and 1686 (C᎐O); δ (CDCl ) 1.22 (9H, s, CH ), 1.20–
᎐
H
3
3
1.98 (10H, m, CH2), 3.82–3.88 (1H, m, CH), 8.16 (1H, br, NH);
δC(CDCl3) 23.70 (q, CH3), 25.60 (t, CH2), 27.30 (t, CH2), 30.60
(t, CH2), 38.10 (s, C(CH3)3–), 83.00 (d, CH), 176.40 (s, CO); m/z
199 (Mϩ, 10%), 83 (cyclohexyl, 48), 57 (tert-butyl, 100).
General synthesis of N-chlorohydroxamates11
A solution of the appropriate hydroxamate and excess tert-
butyl hypochlorite44 in DCM was stirred in the dark under
anhydrous condition for 3–5 hours. The solvent and excess tert-
butyl hypochlorite were removed under reduced pressure at
room temperature to give the N-chlorohydroxamate in near
quantitative yields, as a yellow oil. Since these are generally
thermally unstable as well as light sensitive, they were character-
135 ЊC); νmax(CHCl3)/cmϪ1 3382 (NH) and 1684 (C᎐O);
᎐
δH(CDCl3) 1.35 (9H, s, CH3), 7.42 (2H, t, m-ArH), 7.51 (1H, t,
p-ArH), 7.75 (2H, d, JAB = 8 Hz, o-ArH), 8.42 (1H, br, NH);
δC(CDCl3) 26.40 (q, CH3), 82.40 (s, CCH3)3), 127.10 (d, m-C),
128.60 (d, o-C), 131.80 (d, p–C), 132.60 (s, ipso-C), 167.90
(s, CO).
1
ised by H NMR and IR spectroscopy. Relative to precursor
tert-Butyl 2,2-dimethylpropanohydroxamate 19b. To a stirred
solution of O-(tert-butyl)hydroxylamine hydrochloride (1.00 g,
0.008 mol) in dry pyridine (10 mL) at 0 ЊC was added, dropwise,
a chilled solution of pivaloyl chloride (1.54 g, 0.013 mol) in
anhydrous THF. The reaction mixture was stirred overnight at
room temperature, filtered and concentrated under reduced
pressure with gentle heating. The residue was dissolved in DCM
(50 mL) which was washed with 10% Na2CO3 (50 mL), water
(100 mL), dried with anhydrous sodium carbonate and concen-
trated to give the crude title compound. Recrystallisation from
benzene gave pure tert-butyl 2,2-dimethylpropanohydroxamate
as colourless needles (0.30 g, 22%), mp 84–95 ЊC (Found: C,
61.83%; H, 11.10%; N, 8.10%. C9H19O2N requires C, 62.39%;
H, 11.05%; N, 8.08%); νmax(CHCl3)/cmϪ1 3416 (NH), 1690
hydroxamic esters, protons β- and γ- to the alkoxy oxygen
undergo a downfield shift in their 1H NMR spectrum. As ano-
meric amides, the carbonyls of N-alkoxy-N-chloroamides
appear between 40 and 60 wave numbers higher in frequency
than the corresponding hydroxamic esters.1
N-tert-Butoxy-N-chlorobenzamide 20a. tert-Butyl benzo-
hydroxamate (0.0510 g, 2.59 × 10Ϫ4 mol) and tert-butyl hypo-
chlorite (2.05 g, 1.89 × 10Ϫ2 mol) gave the title compound as a
yellow oil in a good yield (0.058 g, 98%). νmax(CDCl3)/cmϪ1
1723 (C᎐O); δ (CDCl ) 1.40 (9H, s, CH ), 7.46 (2H, t, m-ArH),
᎐
H
3
3
7.56 (1H, t, p-ArH), 7.84 (2H, d, o-ArH); δC(CDCl3) 26.70 (q,
CH3), 78.10 (s, C(CH3)3), 118.70 (d, m–C), 128.20 (d, o–C),
129.50 (d, p–C), 132.60 (s, ipso-C), CO not present.
(C᎐O); δ (CDCl ) 1.24 (9H, s, CH –C–C(O)–), 1.27 (9H, s,
᎐
H
3
3
CH3–C–O–), 7.81 (1H, br, NH); δC(CDCl3) 26.30 (q, CH3),
27.40 (q, CH3), 38.30 (s, (CH3)3C–CO–), 81.90 (s, –O–C(CH3)3),
177.30 (s, CO); m/z 173 (Mϩ, 3%), 85 (pivaloyl, 11), 57 (tert-
butyl, 100).
N-tert-Butoxy-N-chloro-2,2-dimethylpropanamide 20b. tert-
Butyl 2,2-dimethylpropanohydroxamate (0.130 g, 7.50 × 10Ϫ4
mol) and tert-butyl hypochlorite (4.50 g, 0.041 mol) gave the
title compound as a yellow oil in a good yield (0.156 g, 100%).
J. Chem. Soc., Perkin Trans. 2, 2002, 1728–1739
1735

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νmax(CDCl3)/cmϪ1 1732 (C᎐O); δ (CDCl ) 1.36 (9H, s, CH –C–
Ester formation from N-chlorohydroxamic esters
᎐
H
3
3
C(O)–), 1.39 (9H, s, CH3–C–O–); δC(CDCl3) 26.88 (q, CH3),
28.01 (q, CH3), 41.17 (s, (CH3)3C–CO–), 84.70 (s, –O–C(CH3)3),
CO not present. This N-chloro derivative was unstable at room
temperature and upon standing for some time in the dark
converted back to 19b.
tert-Butyl benzoate 21a. To a solution of N-tert-butoxy-N-
chlorobenzamide (0.058 g, 2.55 × 10Ϫ4 mol) in CH3CN (5 mL)
was added a solution of sodium azide (0.20 g, 3.08 × 10Ϫ3 mol)
in CH3CN–water (1 : 1, 20 mL). A pale pink colour was formed
immediately. The reaction mixture was stirred at room temper-
ature for 2 hours during which nitrogen (9.7 mL, 85%) was
collected. The reaction solution was extracted with DCM
(50 mL) which was dried and concentrated to give tert-butyl
benzoate as a yellow oil (0.04 g, 87%) which was consist-
N-tert-Butoxy-N-chloroadamantane-1-carboxamide 20c. tert-
Butyl adamantane-1-carbohydroxamate (0.13 g, 5.17 × 10Ϫ4
mol) and tert-butyl hypochlorite (3.10 g, 0.029 mol) in dry
DCM (50 mL) were stirred at 0 ЊC in an ice bath in the dark for
5 hours. Removal of solvent on a rotary evaporator in vacuo
provided the title compound as a yellow oil in a good yield (0.15
30,31,34
ent, spectroscopically, with previously reported data.
νmax(CHCl3)/cmϪ1 1707 (C᎐O); δ (CDCl ) 1.62 (9H, s, CH ),
᎐
H
3
3
7.44 (2H, t, m-ArH), 7.54 (1H, t, p-ArH), 8.01 (2H, d, JAB
=
g, 100%). νmax(CHCl3)/cmϪ1 1740 (C᎐O); δ (CDCl ) 1.38 (9H,
᎐
H
3
7 Hz, o-ArH); δC(CDCl3) 27.90 (q, CH3), 80.90 (s, C(CH3)3),
128.10 (d, m-C), 129.40 (d, o-C), 132.10 (d, p-C), 132.40
(s, ipso-C), 165.80 (s, CO).
s), 1.71–1.76 (6H, m, CH–CH2–CH), 2.05–2.10 (3H and 6H,
m, CH, CH–CH2–C); δC(CDCl3) 26.90 (q, CH3), 28.10 (t, CH2),
36.40 (t, CH2), 39.10 (d, CH), 43.80 (s, C–CO), 84.60 (s,
–O–C(CH3)3), 186.10 (s, CO). Upon standing at room temper-
ature, N-tert-butoxy-N-chloroadamantane-1-carboxamide con-
verted back to its N–H parent precursor 19c and in aqueous
solution, it reverted to adamantane-1-carboxylic acid.
tert-Butyl 2,2-dimethylpropanoate 21b. Reaction 1: N-tert-
butoxy-N-chloro-2,2-dimethylpropanamide was prepared from
2,2-dimethylpropanohydroxamate (0.18 g, 1.04 × 10Ϫ3 mol) and
tert-butyl hypochlorite as described previously. Treatment with
a solution of sodium azide (0.09 g, 2.14 × 10Ϫ3 mol) in CH3CN–
water (1 : 1, 1.2 mL) led to an immediate evolution of nitrogen
and development of a pink colouration. The CH3CN was
separated and made up to 2.5 mL in a volumetric flask and
analysed by GLC. tert-Butyl 2,2-dimethylpropanoate (30%)
and pivalic acid (29%) were detected by comparison with
standard solutions of authentic materials.
Reaction 2: to N-tert-butoxy-N-chloro-2,2-dimethylpropan-
amide (0.156 g, 7.50 × 10Ϫ4 mol) was added a solution of
sodium azide (0.07 g, 1.08 × 10Ϫ3 mol) in CD3CN (0.50 g)–D2O
(0.50 g). Nitrogen gas was evolved immediately after which the
solution was dried with anhydrous sodium carbonate. NMR
analysis of the d3-acetonitrile layer indicated the presence
of ester. Removal of CD3CN by distillation at 60 ЊC on an
BÜCHI GKR-50 distillation apparatus afforded tert-butyl
2,2-dimethylpropanoate as the major component with minor
quantities of decomposition products. νmax(CDCl3)/cmϪ1 1714
N-Chloro-N-cyclohexyloxy-2,2-dimethylpropanamide 20d.
Cyclohexyl 2,2-dimethylpropanohydroxamate (1.06 g, 5.32 ×
10Ϫ2 mol) and tert-butyl hypochlorite (4.65 g, 4.28 × 10Ϫ2 mol)
gave
N-chloro-N-cyclohexyloxy-2,2-dimethylpropanamide
(1.22 g, 98%) as a yellow oil. νmax(CHCl3)/cmϪ1 1715 (C᎐O);
᎐
δH(CDCl3) 1.32 (9H, s, CH3), 1.20–2.14 (10H, m, CH2), 4.11–
4.20 (1H, m, CH); δC(CDCl3) 24.00 (q, CH3), 25.40 (t, CH2),
27.40 (t, CH2), 30.60 (t, CH2), 41.40 (s, C(CH3)3–), 83.00 (d,
CH), 183.70 (s, CO).
N-Chloro-N-ethoxy-p-nitrobenzamide 2b. Ethyl p-nitro-
benzohydroxamate (0.25 g, 1.19 × 10Ϫ3 mol) and tert-butyl
hypochlorite (1.94 g, 0.018 mol) gave N-chloro-N-ethoxy-p-
nitrobenzamide (0.27 g, 93%) as a yellow oil. νmax(CHCl3)/cmϪ1
1723 (C᎐O); δ (CDCl ) 1.26 (3H, t, CH ), 4.21 (2H, q, CH ),
᎐
H
3
3
2
7.93 (2H, d, JAB = 8 Hz, o-ArH), 8.32 (2H, d, JAB = 9 Hz,
m-ArH); δC(CDCl3) 12.80 (q, CH2CH3), 71.00 (t, CH2CH3),
123.50 (d, m-C), 130.20 (d, o-C), 137.20 (s, ipso-C), 150.00
(s, p-C), 171.90 (s, CO).
(C᎐O); δ (CDCl ) 1.15 (9H, s, CH –C–C(O)–), 1.44 (9H, s,
᎐
H
3
3
CH3–C–O–);30 δC(CDCl3) 28.03 (q, CH3), 29.68 (q, CH3), 38.60
(s, (CH3)3C–CO–), 79.30 (s, –O–C(CH3)3), CO not present; m/z
173 (Mϩ, <1%), 85 (pivaloyl, 20), 57 (tert-butyl, 100).
Reaction 3: N-tert-butoxy-N-chloro-2,2-dimethylpropan-
amide (0.042 g, 2.03 × 10Ϫ4 mol) was reacted with sodium azide
(0.10 g, 1.54 × 10Ϫ3 mol) in CH3CN–water (3 : 1, 50 mL) to give
N2 (8.85 mL, 98%) by dilatometry.
N-Benzyloxy-N-chloroacetamide 20g. Benzyl acetohydrox-
amate (0.45 g, 2.70 × 10Ϫ3 mol) and tert-butyl hypochlorite
(1.00 g, 9.21 × 10Ϫ3 mol) gave N-benzyloxy-N-chloroacetamide
(0.54 g, 99%) as a yellow oil. νmax(CHCl3)/cmϪ1 1729 (C᎐O);
᎐
δH(CDCl3) 2.13 (3H, s, CH3), 5.03 (2H, s, CH2), 7.30–7.52 (5H,
m, ArH); δC(CDCl3) 21.60 (q, CH3), 77.30 (t, CH2), 128.50 (d,
p-C), 129.90 (d, o-C), 133.60 (d, m-C), 149.10 (s, ipso-C), 175.40
(s, CO).
tert-Butyl adamantane-1-carboxylate 21c. To a solution of
N-tert-butoxy-N-chloroadamantane-1-carboxamide (0.15 g,
5.17 × 10Ϫ4 mol) in CH3CN (5 mL) was added a solution of
sodium azide (0.25 g, 3.85 × 10Ϫ3 mol) in CH3CN–water (1 : 1,
10 mL) with immediate evolution of nitrogen (21.2 mL, 92%)
and development of a pink colouration. The reaction solution
was extracted with DCM (50 mL) which was dried and concen-
trated to give a crude product as a pale yellow oil (0.10 g,
82%). Centrifugal chromatography (EtOAc–hexane, 5% : 95%)
afforded tert-butyl adamantane-1-carboxylate as a colourless
oil which was consistent, spectroscopically, with previously
reported data.34 νmax(CHCl3)/cmϪ1 1708 (C᎐O); δ (CDCl ) 1.44
Synthesis of N-acetoxy-N-ethoxy-p-toluamide 2a
Ethyl p-toluohydroxamate (0.22 g, 1.23 × 10Ϫ3 mol) and tert-
butyl hypochlorite (0.53 g, 4.9 × 10Ϫ3 mol) reacted according to
the standard procedure in DCM (25 mL) afforded N-chloro-N-
ethoxy-p-toluamide. νmax(neat)/cmϪ11719 (C᎐O); δ (CDCl )
᎐
H
3
1.28 (3H, t, CH3), 2.43 (3H, s, CH3), 4.18 (2H, q, CH2), 7.26
(2H, d, m-H), 7.72 (2H, d, o-H). The N-chloro-N-ethoxy-p-
toluamide was stirred overnight in dry acetone (20 mL) with
sodium acetate (0.58 g, 7.0 × 10Ϫ3 mol). After filtration, the
solution was concentrated under reduced pressure to give
N-acetoxy-N-ethoxy-p-toluamide as a pale yellow oil (0.17 g,
60%) which was a single component by both TLC and 1H
NMR. νmax(neat)/cmϪ1 1791 (C᎐O), 1721 (C᎐O); δ (CDCl )
᎐
H
3
(9H, s, CH3), 1.68–1.74 (6H, m, CH–CH2–CH), 1.85–1.90 (6H,
m, CH–CH2–C), 2.00–2.22 (3H, m, CH); δC(CDCl3) 28.00
(q, CH3), 28.10 (t, CH2), 36.60 (t, CH2), 38.90 (d, CH), 41.10
(s, C–CO), 79.30 (s, –O–C(CH3)3), 177.10 (s, CO).
᎐
᎐
H
3
1.34 (3H, t, CH3), 2.12 (3H, s, COCH3), 2.42 (3H, s, ArCH3),
4.5 (2H, q, CH2), 7.43 (2H, d, ArH), 7.70 (2H, d, ArH);
δC(CDCl3) 13.5 (q, CH3), 18.7 (q, CH3), 21.50 (q, CH3), 71.00 (t,
CH2), 128.70 (s, ipso-C), 129.00 (d), 129.10 (d), 143.60 (s, p-C),
168.10 (s, amide CO), 174.10 (s, ester CO).
Cyclohexyl 2,2-dimethylpropanoate 21d. To a solution of
N-chloro-N-cyclohexyloxy-2,2-dimethylpropanamide (0.93 g,
3.98 × 10Ϫ3 mol) in CH3CN (50 mL) was added a solution of
sodium azide (1.20 g, 0.019 mol) in CH3CN–water (3 : 1, 100
mL). The reaction mixture was stirred at room temperature for
1736
J. Chem. Soc., Perkin Trans. 2, 2002, 1728–1739

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5 min, extracted with DCM (100 mL) which was dried and
concentrated to give cyclohexyl 2,2-dimethylpropanoate as a
pale yellow oil (0.71 g, 97%) which was consistent, spectro-
scopically, with previously reported data;34 νmax(CHCl3)/cmϪ1
150.40 (s, p-C), 164.60 (s, CO). In addition 0.040 g (1.64 × 10Ϫ4
mol) of N-ethoxy-N-chloro-p-nitrobenzamide reacted with
sodium azide (0.10 g, 1.54 × 10Ϫ3 mol) in CH3CN–water (3 : 1,
50 mL) in a dilatometric apparatus evolved N2 (6.90 mL, 94%).
1714 (C᎐O); δ (CDCl ) 1.20 (9H, s, CH ), 1.20–1.79 (10H, m,
᎐
H
3
3
Ethyl benzoate 21i. To a solution of N-ethoxy-N-chloro-
benzamide (0.58 g, 2.91 × 10Ϫ3 mol) in CH3CN (50 mL) was
added a solution of sodium azide (1.80 g, 0.028 mol) in
CH3CN–water (3 : 1, 100 mL). The reaction mixture was stirred
at room temperature for 5 min and extracted with DCM (50
mL) which was dried with anhydrous sodium carbonate and
concentrated to give ethyl benzoate as a yellow oil (0.41 g, 94%)
CH2), 4.67–4.71 (1H, m, CH); δC(CDCl3) 23.30 (q, CH3), 25.40
(t, CH2), 27.10 (t, CH2), 31.30 (t, CH2), 38.60 (s, C(CH3)3–),
71.70 (d, CH), 177.80 (s, CO). In addition 0.042 g (1.80 × 10Ϫ4
mol) of N-chloro-N-cyclohexyloxy-2,2-dimethylpropanamide
reacted with sodium azide (0.10 g, 1.54 × 10Ϫ3 mol) in CH3CN–
water (3 : 1, 50 mL) to give N2 (7.55 mL, 94%) by dilatometry.
identical to authentic ester. νmax(CHCl3)/cmϪ1 1713 (C᎐O);
Isopropyl benzoate 21e. To a solution of N-isopropoxy-N-
chlorobenzamide (0.92 g, 4.31 × 10Ϫ3 mol) in CH3CN (50 mL)
was added a solution of sodium azide (1.10 g, 0.017 mol) in
CH3CN–water (3 : 1, 100 mL). The reaction mixture was stirred
at room temperature for 5 min, extracted with DCM (100 mL)
which was dried and concentrated to give isopropyl benzoate as
a pale yellow oil (0.65 g, 92%) which was identical to authentic
᎐
δH(CDCl3) 1.41 (3H, t, CH3), 4.40 (2H, q, CH2), 7.45 (2H, t,
m-ArH–), 7.56 (1H, t, p-ArH), 8.07 (2H, d, JAB = 8 Hz, o-ArH);
δC(CDCl3) 14.30 (q, CH2CH3), 60.90 (t, CH2CH3), 128.00 (d,
m-C), 129.50 (d, o-C), 130.50 (d, p-C), 132.80 (s, ipso-C), 166.60
(s, CO). In addition 0.040 g (2.00 × 10Ϫ4 mol) of N-ethoxy-N-
chlorobenzamide reacted with sodium azide (0.13 g, 2.00 × 10Ϫ3
mol) in CH3CN–water (3 : 1, 20 mL) and gave N2 (8.52 mL,
95%) by dilatometry.
material; νmax(CHCl3)/cmϪ1 1710 (C᎐O); δ (CDCl ) 1.39 (6H, d,
᎐
H
3
CH3), 5.28 (1H, septet, CH), 7.44 (2H, t, m-ArH), 7.56 (1H, t,
p-ArH), 8.06 (2H, d, JAB = 8 Hz, o-ArH);31 δC(CDCl3) 21.90 (q,
CH3), 68.30 (d, CH), 128.20 (d, m-C), 129.50 (d, o-C), 131.00
(d, p-C), 132.60 (s, ipso-C), 166.10 (s, CO). In addition 0.039 g
(1.83 × 10Ϫ4 mol) of N-isopropoxy-N-chlorobenzamide reacted
with sodium azide (0.10 g, 1.54 × 10Ϫ3 mol) in CH3CN–water
(3 : 1, 50 mL) and gave N2 (7.60 mL, 93%) by dilatometry.
Ester crossover experiments
Experiment with 1a and 2a. A solution of N-acetoxy-N-
butoxybenzamide (0.5 g, 2 × 10Ϫ3 mol) and N-acetoxy-N-
ethoxy-p-toluamide (0.45 g, 2 × 10Ϫ3 mol) was reacted with
sodium azide (1.0 g, 0.015 mol) in 50 mL acetonitrile–water.
Once evolution of nitrogen had subsided, the acetonitrile was
removed under reduced pressure and the mixture was extracted
with chloroform (100 mL) which was separated, dried and con-
centrated to an oil. NMR analysis using an internal standard
indicated the presence of butyl benzoate and ethyl p-toluate in
near quantitative yield.
Benzyl benzoate 21f. To a solution of N-benzyloxy-N-
chlorobenzamide (0.28 g, 1.07 × 10Ϫ3 mol) in CH3CN (50 mL)
was added a solution of sodium azide (0.70 g, 0.011 mol) in
CH3CN–water (1 : 1, 100 mL). The reaction mixture was then
stirred at room temperature for 5 min, extracted with DCM
(100 mL) which was dried and concentrated under reduced
pressure to give benzyl benzoate as a pale yellow oil (0.21 g,
93%) which was identical to authentic material; νmax(CHCl3)/
Experiment with 1b and 2b. A solution of N-ethoxy-
N-chloro-p-nitrobenzamide (0.65 g, 2.66 × 10Ϫ3 mol) and
N-benzyloxy-N-chlorobenzamide (0.67 g, 2.56 × 10Ϫ3 mol) was
treated with a solution of sodium azide (1.05 g, 0.016 mol) in
50 mL acetonitrile–water (3 : 1). The reaction was complete
within a minute and the mixture was extracted with DCM
(100 mL). Removal of solvent under reduced pressure provided
cmϪ1 1716 (C᎐O); δ (CDCl ) 5.40 (2H, s, CH ), 7.28–7.58 (8H,
᎐
H
3
2
m, ArH), 8.11 (2H, d, o-ArH–CO–); δC(CDCl3) 66.70 (t, CH2),
128.20 (s, ipso-C), 128.30 (d, pЈ-C), 128.40 (d, mЈ-C), 128.60 (d,
oЈ-C), 129.70 (d, m-C), 130.20 (d, o-C), 133.00 (d, p-C), 136.20
(s, ipsoЈ-C), 166.40 (s, CO). In addition N2 (43.50 mL, 91%) was
collected by dilatometry.
1
a crude mixture which by H NMR analysis contained ethyl
p-nitrobenzoate and benzyl benzoate and a complete lack of
the crossover esters, ethyl benzoate and benzyl p-nitrobenzoate.
Separation of the crude mixture by centrifugal chromatography
(5% EtOAc–95% hexane) gave ethyl p-nitrobenzoate as a
colourless solid (0.43 g, 83%) and benzyl benzoate as a colour-
less oil (0.41 g, 76%), both consistent, spectroscopically, with
authentic samples.
Benzyl acetate 21g. To a solution of N-benzyloxy-N-
chloroacetamide (0.45 g, 2.25 × 10Ϫ3 mol) in CH3CN (50 mL)
was added a solution of sodium azide (1.50 g, 2.31 × 10Ϫ2 mol)
in CH3CN–water (1 : 1, 100 mL). The reaction mixture was
then stirred at room temperature for 5 min, and extracted with
DCM (50 mL) which was dried with anhydrous sodium car-
bonate, and concentrated to give benzyl acetate as a pale yellow
oil (0.31 g, 92%) identical to authentic material. νmax(CHCl3)/
Rate studies. An appropriate quantity of sodium azide in
water was added rapidly by syringe to a solution of the required
amount of N-acetoxy-N-benzyloxybenzamide (8) in aceto-
nitrile–water such that the final volume was 250 mL and final
solvent composition of acetonitrile–water was 3 : 1. The closed
system was attached to a dilatometry apparatus and the volume
of evolved nitrogen was monitored throughout the reaction at
atmospheric pressure (Tables 5–8).
cmϪ1 1730 (C᎐O); δ (CDCl ) 2.13 (3H, s, CH ), 5.13 (2H, s,
᎐
H
3
3
CH2), 7.28–7.45 (5H, m, ArH); δC(CDCl3) 20.90 (q, CH3), 66.30
(t, CH2), 128.40 (d, p-C), 128.70 (d, o-C), 136.10 (d, m-C),
148.90 (s, ipso-C), 170.80 (s, CO). In addition 0.042 g (2.10 ×
10Ϫ4 mol) of N-benzyloxy-N-chloroacetamide reacted with
sodium azide (0.15 g, 2.31 × 10Ϫ3 mol) in CH3CN–water (1 : 1,
50 mL) gave N2 (8.30 mL, 88%) by dilatometry.
Ethyl p-nitrobenzoate 21h. To a solution of N-ethoxy-N-
chloro-p-nitrobenzamide (0.19 g, 7.77 × 10Ϫ4 mol) in CH3CN
(50 mL) was added a solution of sodium azide (0.50 g, 7.69 ×
10Ϫ3 mol) in CH3CN–water (3 : 1, 100 mL). The reaction mix-
ture was stirred at room temperature for 5 min and extracted
with DCM (50 mL) which was dried with anhydrous sodium
carbonate and concentrated to give ethyl p-nitrobenzoate as a
pale yellow oil (0.14 g, 94%) identical to authentic material.
Preparation of N-butyl-N-chlorobenzamide 9a
Treatment of N-butylbenzamide (2.24 g, 1.3 × 10Ϫ2 mol) in
DCM (100 mL) with tert-butyl hypochlorite (4.12 g, 3.8 × 10Ϫ2
mol) gave a 2 : 1 mixture (3.4 g) of N-butyl-N-chlorobenzamide
1
and N-butylbenzamide (by H NMR). Purification by centri-
fugal chromatography (10% EtOAc–hexane) afforded pure title
compound (1.33 g, 48%) which was analysed for positive chlor-
ine iodometrically (Found: Cl, 16.6%. C11H14ClNO requires Cl,
16.75%); δH(CDCl3) 0.90 (3H, t, CH3), 1.31 (2H, sextet, CH2),
1.75 (2H, quintet, CH2), 3.71 (2H, t, OCH2), 7.28–7.53 (5H, m,
ArH).
νmax(CHCl3)/cmϪ1 1723 (C᎐O); δ (CDCl ) 1.44 (3H, t, CH ),
᎐
3
3
4.45 (2H, q, CH2), 8.22 (2H, d, JABH = 8 Hz, o-ArH), 8.30 (2H, d,
JAB = 8 Hz, m-ArH); δC(CDCl3) 14.10 (q, CH2CH3), 61.90 (t,
CH2CH3), 123.40 (d, m-C), 130.60 (d, o-C), 135.80 (s, ipso-C),
J. Chem. Soc., Perkin Trans. 2, 2002, 1728–1739
1737

View Article Online
Table 5 Data for reaction of N-acetoxy-N-benzyloxybenzohydroxamate 8 (5 × 10Ϫ4 M) and sodium azide (5 × 10Ϫ4 M) in acetonitrile–water (3 : 1)
(250 mL) at 21.5 ЊC
Time/s
N2(lib.)/mLa
N2(rem.)/mLb
N2(rem.)/N2 (total)
[c]t/10Ϫ4Mc
[c1] /103 MϪ1
t
0
15
25
60
90
120
150
240
360
480
600
900
1200
1500
1800
2400
3000
0.00
0.16
0.22
0.42
0.60
0.77
0.88
1.06
1.32
1.54
1.73
2.12
2.38
2.65
2.82
3.21
3.49
4.61
4.45
4.39
4.19
4.01
3.84
3.73
3.55
3.29
3.07
2.88
2.49
2.23
1.96
1.79
1.40
1.12
1.00
0.97
0.95
0.91
0.87
0.83
0.81
0.77
0.71
0.67
0.63
0.54
0.48
0.43
0.39
0.30
0.24
5.00
4.83
4.76
4.54
4.35
4.16
4.05
3.85
3.57
3.33
3.12
2.70
2.42
2.13
1.94
1.52
1.21
2.00
2.07
2.10
2.20
2.30
2.40
2.47
2.60
2.80
3.00
3.20
3.70
4.13
4.70
5.15
6.59
8.23
a Nitrogen liberated at time t. b Nitrogen remaining in the reaction mixtures at time t. c Concentrations [c] of 8 and N3Ϫ at time t.
Table 6 Data for reaction of N-acetoxy-N-benzyloxybenzohydroxamate 8 (1 × 10Ϫ3 M) and sodium azide (1 × 10Ϫ3 M) in acetonitrile–water (3 : 1)
(250 mL) at 21.5 ЊC
Time/s
N2(lib.)/mLa
N2(rem.)/mLb
N2(rem.)/N2 (total)
[c]t/ 10Ϫ4 Mc
[c1] / 103 MϪ1
t
0
30
55
0.00
1.17
1.85
2.08
2.56
2.90
2.98
3.53
4.34
5.42
6.18
6.68
7.02
8.95
7.78
7.10
6.87
6.39
6.05
5.97
5.42
4.61
3.53
2.77
2.27
1.93
1.00
0.87
0.79
0.77
0.71
0.68
0.67
0.61
0.52
0.39
0.31
0.25
0.22
10.00
8.69
7.93
7.68
7.14
6.76
6.67
6.06
5.15
3.94
3.09
2.54
2.16
1.00
1.15
1.26
1.30
1.40
1.48
1.50
1.65
1.94
2.54
3.23
3.94
4.64
90
120
150
180
360
540
900
1200
1500
1800
a Nitrogen liberated at time t. b Nitrogen remaining in the reaction mixtures at time t. c Concentrations [c] of 8 and N3Ϫ at time t.
Table 7 Data for reaction of N-acetoxy-N-benzyloxybenzohydroxamate 8 (5 × 10Ϫ4 M) with sodium azide (5 × 10Ϫ3 M) in acetonitrile–water (3 : 1)
(250 mL) at 21.5 ЊC
Time/s
N2(lib.)/mLa
N2(rem.)/mLb
N2(rem.)/N2 (total)
[8]/10Ϫ5 M
ln[8]
0
30
60
0.00
1.95
2.52
3.25
3.55
3.83
4.25
4.56
4.70
4.92
4.98
5.08
5.10
5.11
5.13
3.18
2.61
1.88
1.58
1.30
0.88
0.57
0.43
0.21
0.15
0.05
0.03
0.02
1.00
0.62
0.51
0.37
0.31
0.25
0.17
0.11
0.08
0.04
0.03
0.01
0.01
0.00
50.00
31.00
25.40
18.30
15.40
12.70
8.58
5.56
4.19
2.05
1.46
Ϫ7.60
Ϫ8.08
Ϫ8.28
Ϫ8.61
Ϫ8.78
Ϫ8.97
Ϫ9.36
Ϫ9.80
Ϫ10.08
Ϫ10.80
Ϫ11.13
Ϫ12.23
Ϫ12.74
Ϫ13.15
90
120
150
180
240
300
360
420
480
540
600
0.49
0.29
0.19
a Nitrogen liberated at time t. b Nitrogen remaining in the reaction mixtures at time t.
benzoyl chloride (1.76 g, 0.013 mol) and triethylamine (1.27 g)
in DCM (50 mL) at 0 ЊC. The reaction mixture was stirred for a
further one hour after which it was washed with 10% aqueous
sodium carbonate, dilute HCl, dried with anhydrous sodium
carbonate and concentrated to give the crude product. Purifi-
cation by centrifugal chromatography (2% EtOAc–98% hexane)
afforded the title compound as colourless crystals (1.55 g, 37%),
mp 95 ЊC (Found: C, 76.14%; H, 5.22%; N, 4.47%. C21H17O3N
requires C, 76.12%; H, 5.17%; N, 4.23%); νmax(CHCl3)/cmϪ1
Preparation of N-benzoyloxy-N-benzylbenzamide 9b45
Benzoyl peroxide (3.33 g, 0.014 mol) in DCM (50 mL) was
added dropwise to a mixture of benzylamine (1.34 g, 0.013 mol)
and sodium carbonate (1.99 g) in DCM (50 mL) in an ice bath
and the reaction mixture was stirred for a further 2 hours at
room temperature. Progress of the reaction was monitored by
TLC. Inorganic materials were removed by filtration and the
filtrate was treated dropwise with a pre-chilled solution of
1738
J. Chem. Soc., Perkin Trans. 2, 2002, 1728–1739

View Article Online
Table 8 Data for reaction of N-acetoxy-N-benzyloxybenzohydroxamate 8 (5 × 10Ϫ3 M) with sodium azide (5 × 10Ϫ4 M) in acetonitrile–water (3 : 1)
(250 mL) at 21.5 ЊC
Ϫ
Time/s
N2(lib.)/mLa
N2(rem.)/mLb
N2(rem.)/N2 (total)
[N3Ϫ]/ 10Ϫ5 M
ln[N3 ]
0
10
45
60
90
120
150
180
240
300
360
420
480
540
600
0.00
0.56
1.82
2.37
2.88
3.45
3.95
4.35
4.68
4.80
4.81
4.88
4.91
4.92
4.93
4.94
4.38
3.12
2.57
2.06
1.49
0.99
0.59
0.26
0.14
0.13
0.06
0.03
0.02
0.01
1.00
0.89
0.63
0.52
0.42
0.30
0.20
0.12
0.05
0.03
0.03
0.01
0.01
0.00
0.00
50.00
44.30
31.60
26.00
20.90
15.10
10.00
5.97
2.63
1.42
1.32
0.61
Ϫ7.60
Ϫ7.72
Ϫ8.06
Ϫ8.25
Ϫ8.48
Ϫ8.80
Ϫ9.21
Ϫ9.73
Ϫ10.55
Ϫ11.16
Ϫ11.24
Ϫ12.01
Ϫ12.71
Ϫ13.11
Ϫ13.80
0.30
0.20
0.10
a Nitrogen liberated at time t. b Nitrogen remaining in the reaction mixtures at time t.
15 S. A. Glover, Arkivok, 2001 (http://www.arkat-usa.org/ark/journal/
Volume2/Part3/Tee/OT-308C/OT-308.htm).
16 G. Mo, Properties and Reactions of Anomeric Amides, Ph.D.,
University of New England, 1999.
17 M. Novak, M. J. Kahley, J. Lin, S. A. Kennedy and L. A. Swanegan,
J. Am. Chem. Soc., 1994, 116, 11626.
18 S. A. Kennedy, M. Novak and B. A. Kolb, J. Am. Chem. Soc., 1997,
119, 7654.
1764 and 1668 (C᎐O); δ (CDCl ) 5.12 (2H, s, CH ), 7.33–7.42
᎐
H
3
2
(10H, m, ArH), 7.58 (1H, t, p-ArH–COO–), 7.69 (2H, d, JAB = 8
Hz, o-ArH–CON-), 7.84 (2H, d, JAB = 8 Hz, o-ArH–COO–);
δC(CDCl3) 53.50 (t, CH2), 126.90 (s), 127.90 (d), 128.40 (d),
128.60 (d), 128.70 (d), 129.80 (s), 130.20 (d), 131.00 (d), 133.40
(d), 133.60 (d, p-C–CO), 134.10 (d, p-C–CO), 135.20 (s, ipso-C–
CH2O–), 164.30 (s, CO), 170.70 (s, CO); m/z 210 (M Ϫ 121ϩ,
9%), 105 (benzoyl, 100), 77 (phenyl, 25).
19 M. Novak, L. L. Xu and R. A. Wolf, J. Am. Chem. Soc., 1998, 120,
1643.
20 J. C. Fishbein and R. A. McClelland, J. Am. Chem. Soc., 1987, 109,
Reaction of 9a and 9b with sodium azide
2824.
21 R. A. Davidse, M. J. Kahley, R. A. McClelland and M. Novak,
J. Am. Chem. Soc., 1994, 116, 4513.
22 R. A. McClelland, P. A. Davidse and G. Hadzialic, J. Am. Chem.
Soc., 1995, 117, 4173.
23 R. A. McClelland, M. J. Kahley, P. A. Davidse and G. Hadzialic,
J. Am. Chem. Soc., 1996, 118, 4794.
24 J. Johns, Synthesis and Thermal Decomposition of N,N-dialk-
oxybenzamides, Honours thesis, University of New England, 1996.
25 Following paper: S. A. Glover and A. Rauk, J. Chem. Soc., Perkin
Trans. 2, 2002, DOI: 10.1039/b204232k.
Treatment of N-butyl-N-chlorobenzamide 9a with sodium
azide in aqueous acetonitrile, at rt or under reflux afforded
parent N-butylbenzamide as the sole product. Similarly,
N-benzoyloxy-N-benzylbenzamide 9b reverted to N-benzyl-
benzamide.
Acknowledgements
26 I. O. Sutherland, in Comprehensive Organic Chemistry,
ed. I. O. Sutherland, Pergamon Press, Oxford, 1979, p. 871.
27 J. Mulzer, in Comprehensive Organic Synthesis, ed. B. M. Trost,
Pergamon Press, Oxford, 1991, p. 323.
The authors are grateful to the Australian Research Council for
financial funding and to the University of New England for a
U.N.E. Scholarship to G.Mo.
28 J. Mulzer, in Comprehensive Organic Functional Group Trans-
formations, ed. C. J. Moody, Pergamon, Oxford, 1995.
29 R. C. Parish and L. M. Stock, J. Org. Chem., 1965, 30, 927.
30 E. M. Kaiser and R. A. Woodruff, J. Org. Chem., 1970, 35, 1198.
31 R. A. Rossi and R. H. de Rossi, J. Org. Chem., 1974, 39, 855.
32 S. Takimoto, J. Inanaga, T. Katsuki and M. Yamagughi, Bull. Chem.
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33 S. Masamune, Y. Hayase, W. Schilling, W. K. Chan and G. S. Bates,
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34 S. Kim and J. I. Lee, J. Org. Chem., 1984, 49, 1712.
35 SPARTAN, Version 5 and MacSPARTAN Pro, Verson 1.0.2,
Wavefunction, Inc., 18401 Van Karman Avenue, Suite 370, Irvine,
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1739