Synthetic aspects of the oxidative amidation of phenols

Article abstract of DOI:10.1016/j.tet.2010.05.020

The oxidative amidation of phenols effects the conversion of appropriately substituted phenols into 4-amidodienones ('para-oxidative amidation') or 2-amidodienones ('ortho-oxidative amidation') by the action of hypervalent iodine reagents. The reagent, (diacetoxyiodo)benzene ('DIB') is especially effective in these transformations. This paper focuses on techniques for the desymmetrization of the dienoes thus obtained, leading to the stereocontrolled creation of N-substituted spiro carbons. The methodology creates new opportunities in alkaloid synthesis, as apparent from a number of examples. DIB=PhI(OAc)₂. The reaction may be carried out in the intra- or the intermolecular mode.

Full text of DOI:10.1016/j.tet.2010.05.020

Tetrahedron 66 (2010) 5884e5892
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Synthetic aspects of the oxidative amidation of phenols
y
*
Huan Liang , Marco A. Ciufolini
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada V6T Oxford St., Cambridge, MA 02138, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2010
Received in revised form 6 May 2010
Accepted 7 May 2010
Available online 13 May 2010
The oxidative amidation of phenols effects the conversion of appropriately substituted phenols into
4-amidodienones (‘para-oxidative amidation’) or 2-amidodienones (‘ortho-oxidative amidation’) by
the action of hypervalent iodine reagents. The reagent, (diacetoxyiodo)benzene (‘DIB’) is especially
effective in these transformations. This paper focuses on techniques for the desymmetrization of the
dienoes thus obtained, leading to the stereocontrolled creation of N-substituted spiro carbons. The
methodology creates new opportunities in alkaloid synthesis, as apparent from
examples.
a number of
Keywords:
Hypervalent iodine
Oxidative amidation
Phenols
Ó 2010 Elsevier Ltd. All rights reserved.
Amides
Alkaloids
1. Introduction
The oxidative amidation of phenols1 entails the conversion of
phenolic substrates such as 1 or 2 into aza-substituted dienones 3
or 4, respectively. Group N in 1e2 represents a suitable nitrogen
nucleophile, while in 3e4 it stands for an amide-type group. The
dashed circles indicate that ‘N’ may be tethered to the phenolic ring
or it may be independent. In the first case, the reaction will be
intramolecular, in the second, bimolecular. Hypervalent iodine re-
agents,2 especially PhI(OCOCH3)2 (DIB) but also PhI(OCOCF3)2
(PIFA), are uniquely competent in oxidative amidation chemistry,
which constitutes a special case of oxidative dearomatization of
phenols.3 The reaction may be thought to proceed via electrophilic
intermediates 5e6, which are nucleophilically intercepted by the
‘N’ group (Scheme 2, but see Ref. 3 for a more detailed mechanistic
discussion). Extensive precedent exists for the oxidation of a phenol
to a transient electrophilic species such as 5 and for its capture by
a suitable nucleophile.4 Indeed, Barton5 disclosed initial examples
of this chemistry beginning in the late 1950s.6 Over time, more
effective oxidants steadily improved the efficiency of these re-
actions,7 but it is the advent of hypervalent iodine reagents that
permitted a veritable quantum leap in the field. Noteworthy con-
tributions by Kita,8 Pelter,9 Barrett,10 and Wipf,11 speak eloquently
to that effect.
Scheme 1. The oxidative amidation of phenols.
Scheme 2. Mechanistic hypothesis for the oxidative amidation of phenols.
We stress that oxidative amidation reactions proceeding as
detailed in Scheme 2 differ at a mechanistic level from related
transformations that predate them, and that involve the interaction
of an electrophilic nitrogen atom with a nucleophilic aromatic
nucleus. Such processes emanated from the work of Kikugawa,12
Glover,13 and Prabhakar14 (Fig.1). Their full synthetic potential be-
came apparent later thanks to the work of Wardrop.15
* Corresponding author. Tel.: þ1 604 822 2417; fax: þ1 604 822 8710; e-mail
address: ciufi@chem.ubc.ca (M.A. Ciufolini).
y
Current address: Department of Chemistry and Chemical Biology, Harvard
University, 12 Oxford St., Cambridge, MA 02138, USA
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.020

H. Liang, M.A. Ciufolini / Tetrahedron 66 (2010) 5884e5892
5885
Sorensen24 and Honda25 developed oxidative cyclizations of phenolic
secondary amines (Scheme 5) in connection with their own total
syntheses of FR-901683 and of TAN-1251 compounds.
O
O
O
Z
Z
Z
N
H
N
N
[ O ]
RO
RO
O
7
Z = MeO
Z = PhtN
9
10 Z = MeO
11 Z = PhtN
8
Figure 1. Kikugawa-Glover-type reactions.
Oxidative amidation according to the format of Scheme 1 was
developed in our laboratory during research on the synthesis of
azaspirocyclic natural products such as FR-90168316 and TAN-
1251C.17 These efforts have been thoroughly reviewed.1,18
Accordingly, we eschew further discussion of this chemistry and
simply remind the reader thatour investigationsproducedthe modes
of oxidative amidation outlined in Scheme 3; namely the cyclization
Scheme 5. The Sorensen (Ref. 24) and Honda (Ref. 25) oxidative cyclization of phenolic
secondary amines.
This article constitutes
a personal account of recent de-
velopments in oxidative amidation chemistry. The recognition that
the methodology could simplify the assembly of certain nitroge-
nous architectures to a significant degree, and the desire to adduce
tangible proof of this in the form of total syntheses of various al-
kaloids, has encouraged us to expand the scope of oxidative ami-
dation and to research appropriate refinements of original
procedures. Such is the focus of this review.
2. Trifluoroacetic acid as a solvent or co-solvent in the
oxidative amidation of phenols
Our foremost objective has been the identification of a medium
suitable for the conduct of oxidative amidation reactions on large
scale. The transformations seen in Schemes 3 and 4 were initially
carried out in solvents such as 2,2,2-trifluoroethanol (TFE) or
1,1,1,3,3,3-hexafluoroisopropanol (HFIP). The choice of these fluo-
roalcohols segued from the work of Kita,8 who had shown that
a number of DIB-promoted phenolic oxidations proceed best in such
solvents. Unfortunately, TFE and HFIP are costly, and especially so the
latter: the need for fluoroalcohol solvents had to be suppressed.
Bimolecular oxidative amidations stood to benefit the most from the
development of a fluoro-alcohol-free protocol. The first-generation
method for the conduct of these reactions entailed operating in dilute
solutions using 1:1 HFIP/MeCNas the solvent.21a This is not an obstacle for
runs involving less than 300 mg of substrate, but the cost of HFIP rapidly
becomes prohibitive upon scale-up. Attempts to circumvent the problem
by working at concentrations higher than about 0.05 M surrendered
products contaminated with much polymeric matter, imposing the need
for costly, impractical purifications that cause unacceptable losses.
The search for alternative solvents led to the identification of
inexpensive trifluoroacetic acid (TFA) as a superb promoter. In vir-
tually all cases examined to date, the reaction proceeded much
better in MeCN containing 1.3e1.5 equiv of TFA relative to DIB.21b
Scheme 3. Modes of oxidative amidation of phenols devised in the authors’ laboratory.
of phenolic oxazolines19 that of para- and ortho-phenolic sulfon-
amides,20 and the bimolecular oxidative amidation of 4-substituted
phenols in the presence of nitriles.21 Related processes include the
oxidative cyclization of indolic oxazolines22 and sulfonamides23
(Scheme 4). All these reactions are promoted by DIB. Independently,
Table
1 compares representative examples of small-scale bi-
molecular oxidative amidation of phenols under the original and the
new conditions. In some cases, a trebling of the yield was achieved.
Only phenols incorporating a para-alkyl substituent of elevated mi-
gratory aptitude, such as an isopropyl group (30h) reacted less effi-
ciently. This appears to be due to a more facile dienone/phenol
rearrangement of the resultant 31h in the presence of TFA.21b It is
worthy of note that DIB was generally superior to the more reactive,
but also more costly, PIFA. The reactions were best carried out by
slow addition of the phenol to a solution of DIB in MeCN/TFA at room
temperature. The examples listed in the table were run to a final
Scheme 4. Oxidative cyclization of indolic oxazolines and sulfonamides.

5886
H. Liang, M.A. Ciufolini / Tetrahedron 66 (2010) 5884e5892
Table 1
Representative bimolecular oxidative amidations of para-alkylphenols with DIB in
the presence of HFIP or TFAa
Entry
R
Yieldc (%, HFIP)
Yieldc (%, TFA)
Scheme 7. Oxidative cyclization of sulfonamides in fluoroalcohol solvents.
a
b
c
d
e
f
CH2CN
(CH2)3CN
(CH2)2Br
(CH2)2NHTs
CH2COOMe
Me
31
71
<10
53
58
56
86
81
57
59
86
89
82
40d
A thorough study of the reaction27 determined that one could
achieve quantitative spirocyclization by adding the phenol to a so-
lution of DIB in TFA at room temperature, to a final formal con-
centration of substrate equal to 0.3 M. Yields of purified products
around 90% are common. Tables 2 and 3 summarize the results of
a representative number of such experiments.28 The electronic or
steric properties of the sulfonyl group appear to have little or no
influence on the course of the reaction. For instance, even sub-
strates incorporating sterically demanding sulfonamides react in
good yield (cf. 36c, 36j, Table 2). By contrast, bulky substituents on
the side chain are not tolerated (cf. 38c, 38g, Table 3). Groups of
small or moderate steric size are acceptable, and even aldehyde 38f
cyclized in high yield.
g
h
n-Pr
i-Pr
54
62
a
All reactions run at room temperature. See the Experimental section for rep-
resentative procedures.
b Co-solvent¼HFIP (50% vol/vol) or TFA (1.5 equiv vs DIB).
c
After column chromatography.
Chromatographic purification also afforded 4-acetamido-3-isopropyl- phenol
d
(product of dienone/phenol rearrangement of 31h) in 30% yield.
formal concentration of substrate equal to 8e10 mM. Of course, such
dilute conditions are inappropriate for preparative work, but we
found that the final substrate concentration could be increased up to
about 0.15 M with minor erosion of yields. More importantly, the
procedure was readily scalable and robust. For instance, compound
31e, an important intermediate in one of our current projects, was
consistently obtained in 65e70% yield from runs involving 10e30 g
batches of starting phenol 30e. On the other hand, phenols 32
(Scheme 6) reacted poorly. Substrates 32a,b incorporate carbonyl
groups that compete effectively with external nucleophiles (MeCN in
this case) for the presumed electrophilic intermediate 5 (cf. Scheme
2). This shuts down the oxidative amidation pathway in favor of
other outcomes.26 Sterically demanding substituents at the phenolic
para-position (entry 32d) are damaging in two ways. First, they
probably retard the nucleophilic attack of MeCN onto 5. Second, after
nucleophilic capture (i.e., at the stage of 21) they are quite prone to
dienone/phenol migration. Substitution at both ortho-phenolic po-
sitions with sterically demanding alkyls (entry 32h) retards the in-
teraction of DIB with the OH group. Phenols displaying carbonyl
groups at the para-position (entries 32f,g) were slowly converted
into intractable mixtures containing none of the desired amidodie-
none. Finally, unlike bromide analog 30c, iodide 32e degraded rap-
idly in MeCN solution, possibly due to ionization anchimerically
assisted by the electron-rich phenyl group.
On a side note, the presence of a sulfonyl group on the N atom of
products 37e39 raises legitimate concerns about the survival of the
sensitive dienone during attempted N-deblocking, and by
Table 2
Oxidative cyclization of phenolic sulfonamidesa
Entry
R
Yieldb
%
a
b
c
d
e
f
g
h
i
Me
CF3
t-Bu
95
94
85
90
94
95
93
93
85
83
cyclo-C3H6
4-MeeC6H4
2-O2NeC6H4
4-BreC6H4
4-NCeC6H4
4-MeOeC6H4
2,4,6-Triisopropylphenyl
j
a
Representative procedures are provided in the Experimental section.
After column chromatography.
b
Table 3
Oxidative cyclization of phenolic sulfonamides bearing substituents on the NeAr
tethera
Scheme 6. Poor substrates for the bimolecular reaction.
Entry
R1
R2
R3
Yieldb (%)
a
b
c
d
e
f
Me
4-MeC6H4
Me
Me
Me
H
H
Bn
H
H
H
H
NHTs
NHTs
H
CH2OH
CH2OMe
CHO
83
80
d
A second process that would greatly benefit from a fluoro-al-
cohol-free procedure is the oxidative spirocyclization of phenolic
sulfonamides (Scheme 3, 16/17). In its original form, the reaction
was carried out with DIB in neat HFIP.20 Only in this costly solvent
were we able to suppress solvolysis of presumed intermediate 5
(Scheme 2). For instance, oxidative cyclization of 33 with DIB in TFE
gave about 15% of 35 in addition to the desired 34, while in HFIP
only 34 was formed (Scheme 7).
95
95
94
d
Me
Me
g
CH2OTBDPS
a
Representative procedures are provided in the Experimental Section.
After column chromatography.
b

H. Liang, M.A. Ciufolini / Tetrahedron 66 (2010) 5884e5892
5887
extension, about the synthetic usefulness of these spirocyclic in-
termediates. In fact, facile release of the sulfonyl group may be
achieved using Fukuyama nitrosulfonamides.29 Moreover, in
a number of cases the sulfonamide becomes an integral part of the
ultimate target, bypassing the need for N-deblocking at the stage of
37e39. Examples will be detailed later.
Phenolic phosphoramides such as 40a also undergo oxidative
cyclization23,27 (Scheme 8), but curiously, structurally similar dia-
lkyl phosphinamides 40b and 40c do not.27
substituted dienones (entries b,c) reflects the substantially efficiency
of the oxidative cyclization step, and not of the IMDA one. It is also
worthy of note that dienic sulfonamides (entries d,e) expressed only
dienophilic reactivity toward the dienone. A related transformation
combines a para-oxidative cyclization of a 1-butadienyl-sulfonamide
with an IMDA event (Scheme 9). Substrates 48 are readily made by
Tozer-type condensation32 on an N-Boc methanesulfonamide such
as 47 with acrolein. Rather than isolating intermediate 49, we found
it expedient to dilute the reaction mixture resulting from the oxi-
dative step with toluene, and to heat to reflux to trigger the con-
version of 49 into 50.33
Scheme 8. Oxidative cyclization of phosphoramides.
The oxidative cyclizations seen thus far occur at the para-posi-
tion of a phenol, but as indicated earlier in Schemes 1 and 2, ortho-
oxidative amidation is also viable (albeit less efficient). Neat TFA, as
opposed to HFIP,23 proved to be a good solvent for this reaction as
well. Table 4 lists representative examples. Yields are lower than in
the para-mode, normally hovering around 50%, and they drop
further if electron-withdrawing groups are present on the aromatic
nucleus (entry b). Sterically demanding sulfonamides may fail al-
together to cyclize (entry d).
Scheme 9. Tandem para-oxidative cyclization/IMDA of phenolic sulfonamides.
Table 4
ortho-Oxidative cyclization of phenolic sulfonamidesa
3. Desymmetrization of ‘locally symmetrical’ dienones
obtained by oxidative amidation of phenols
A second objective of considerable import has been the explo-
ration of artifices that permit the desymmetrization of dienones
arising through para-oxidative cyclization of phenolic sulfon-
amides. As apparent from Scheme 10, such a transform enables the
creation a tetrasubstituted nitrogen-bearing carbon atom of a spe-
cific configuration. Generally speaking, the stereoselective assem-
bly of such carbon centers is difficult. In the present case, the stated
goal is achievable through the selective addition of a generic agent
Entry
R1
R2
Yieldb (%)
a
b
c
H
Me
Me
Me
60
29
47
d
Br
Me
H
d
4-O2NeC6H4
XeY either to the pro-(R) or the pro-(S)
p bond of dienone 51.
a
Representative procedures are provided in the Experimental section.
After column chromatography.
b
The moderate yields are partly attributable to the sensitive nature
of dienones 43, which, for instance, display poor tolerance of chro-
matographic operations. On the other hand, the s-cis arrangement of
double bonds imparts marked Diels/Alder reactivity to these spe-
cies.30 This enables the conduct of tandem ortho-oxidative cycliza-
tions/intramolecular Diels/Alder (IMDA)31 reactions of substrates
incorporating vinylsulfonamide moieties. Relevant examples appear
in Table 5. Notice that the moderate yields obtained with Brr and Me-
Table 5
Tandem ortho-oxidative cyclization/intramolecular DielseAlder reaction of phenolic
sulfonamidesa
Scheme 10. Dienone desymmetrization.
What inspired us to pursue such an objective is an observation
recorded during research on phenolic oxazolines. Specifically, we
found that on standing, spirolactam 54 undergoes spontaneous, and
highly diastereoselective, Michael cyclization to 55 (Scheme 11).19b
The stereochemical outcome of this reaction is consistent with the
known preference for an axial orientation for substituents occupy-
ing a position adjacent to the N atom in N-acylpiperidines and re-
lated structures, such as the N-acylmorpholine segment of 55.34 In
the present case, this proclivity can be satisfied only if the OH group
were to attack the pro-(R)-double bond of the dienone, thereby
establishing the (R)-configuration of the spiro center. Thus, one can
harness conformational effects to elicit selective reactivity at a par-
Entry
R1
R2
Y
Yieldb (%)
a
b
c
d
e
H
H
H
H
H
H
H
H
40
31
43
34
27
Br
Me
H
CH2]CHe
H
CH2]CHe
H
a
Representative procedures are provided in the Experimental section.
After column chromatography.
b
ticular diastereotopic
p system of a ‘locally symmetrical’ dienone.

5888
H. Liang, M.A. Ciufolini / Tetrahedron 66 (2010) 5884e5892
the reason delineated in Scheme 14. This diagram retraces the ar-
gument presented earlier in Scheme 12. Thus, the IMDA reaction of
65 may occur from either of two conformers: anti-67 and syn-67.
But conformer syn-67 suffers from a greater degree steric com-
pression between the sulfonyl group and the R substituent;
therefore, it is disfavored relative to anti-67. Diels/Alder cyclization
is thus more likely to occur from the latter, leading to the selective
formation of the correct product 64.
Scheme 11. Stereoselective Michael cyclization of 13d.
The foregoing principle invites the exploration of previously
uncharted strategies in alkaloid synthesis. An example is apparent
in our synthesis of (ꢀ)-cylindricine C, 60.20b,23 A key step in this
effort was the desymmetrization of the dienone in 56. This objec-
tive appeared to be attainable by a stereocontrolled Michael cycli-
zation of the anion of the methanesulfonamide (Scheme 12). This
reaction was anticipated to favor formation of isomer 58. Indeed,
the metalated sulfonamide, 57, may add to the enone from what
may be described as an anti conformation [attack on the pro-(R)
double bond] or a syn one [attack on the pro-(S) double bond],
leading, respectively to 58 or 59. Conformer syn-57 suffers from
greater steric compression between sulfonyl and CH2OP groups.
This should favor reaction from anti-57, translating into preferential
formation of 58. This is indeed the case. Furthermore, consistent
with the model of Scheme 12, the selectivity for 58 improved with
increasing steric demand of the protecting group P and with
diminishing temperature, peaking at a 7:1 ratio when the P¼TBDPS
variant of 56 was cyclized at ꢀ100 ꢁC.20b,23 The emerging 58 was
then reductively elaborated to 60. The introduction of the
remaining fragments of the molecule relied on the anionic chem-
istry of the cyclic sulfonamide. The C atom of the mesyl group thus
became an integral part of the final target, suppressing any need to
desulfonylate the sensitive dienone 56.
Scheme 13. Approach to the himandrine core.
Scheme 14. Predicted course of the IMDA step.
An investigation designed to address the foregoing hypothesis
started with 39d (Scheme 15), wherein the configuration of the N-
bearing carbon is opposite that of 66. But of course, here we are
concerned with issues of diastereoselectivity, so the absolute con-
figuration of the substrate is immaterial. Tozer condensation in-
stalled the dienic sulfonamide. A subsequent one-pot oxidative
cyclization/IMDA sequence surrendered an 8:1 mixture of 72
Scheme 12. Strategy for the synthesis of cylindricine.
More recent work has addressed dienone desymmetrization
through cycloaddition chemistry. These studies were motivated by
a desire to incorporate oxidative amidation technology in possible
syntheses of himandrine35 and of tetrodotoxin.36 As seen in
Scheme 13, the spirocyclic core of himandrine, 62, contains subunit
63. One could envisage 64 as a precursor of 63. Relative to the
natural product, 64 displays the cis-fusion of the decaline segment,
but of course epimerization of the position adjacent to the C]O
group at an appropriate juncture would presumably furnish the
thermodynamically more favorable trans-isomer. The chemistry of
Scheme 9 suggests that 64 may be accessible through a tandem
oxidative amidation/IMDA reaction of 66. In particular, the IMDA
cyclization of 65 should occur diastereoselectively to furnish 64 for
Scheme 15. Dienone desymmetrization via intramolecular Diels/Alder reaction.

H. Liang, M.A. Ciufolini / Tetrahedron 66 (2010) 5884e5892
5889
(desired)37 and 73 in a moderate 32% yield. Interestingly, the
products were obtained as the trans-fused isomers. Evidently,
epimerization of the primary Diels/Alder adduct had occurred in
situ, probably through acid-catalyzed enolization of the enone.
Four new stereogenic carbons, including a spiro center, were thus
created stereoselectively in a single operation.
Considering that nitrile oxides are available by oxidation of
oximes, we questioned whether DIB could promote a tandem oxi-
dative amidation/INOC sequence of appropriately tailored oximi-
nophenols. The success of this process is conditional to the
occurrence of the oxidative amidation step at a rate much faster
than that of oxime oxidation. Indeed, the nascent nitrile oxide must
undergo instant intramolecular capture by the preformed dienone,
otherwise it will rapidly dimerize. We knew that the oxidative
amidation of the phenol occurs very rapidly (minutes) but we had
no knowledge of whether DIB (or PIFA) would oxidize oximes to
nitrile oxides, and at which rate. We were also cognizant that the
The bimolecular oxidative amidation of phenols offers perhaps
the widest range of possibilities in the synthesis of nitrogenous
natural products. Tandem oxidative reactions that might elaborate
a simple starting material into a product of considerable molecular
complexity serve to multiply such tactical opportunities. To illus-
trate the point with a somewhat extreme example, imagine re-
leasing both ortholactone and guanidine moieties in the molecule
of tetrodotoxin, 74 (Scheme 16). The resultant 75 could be obtained
from 77, which is the product of oxidative amidation of 76
(G¼oxygenated functionality or forerunner thereof). The ‘north-
western’ OH tetrad in 75 could be installed by osmylation chem-
istry once the keto group of 77 has been transformed into an
exomethylene (Wittig reaction). A more interesting problem relates
to the introduction of the C-2 OH and the C-3 CHO groups selec-
tively onto the pro-S double bond of 77, an operation that again
would result in desymmetrization of a locally symmetrical dienone.
40
conversion of oximes into nitrile oxides with PhIO39 and PhICl2
had been documented, but these reagents are unsuitable for oxi-
dative amidation chemistry. Fortunately, DIB proved to be quite
effective for the oxidation of oximes into nitrile oxides.41 The re-
action was best run in MeOH containing a catalytic amount of TFA.
Pertinent examples appear in Table 6, while Scheme 18 illustrates
three cases of INOC processes. Happily, oxime oxidation was rela-
tively slow (ca. 1 h at rt), engendering optimism for the feasibility of
the tandem sequence. Indeed, exposure of 90 to DIB in MeOH/TFA
produced 91 in 51% yield,42 while treatment with DIB in MeCN/TFA
furnished 92 in 71% yield (Scheme 19). More importantly, (ꢂ)-93
reacted with DIB in MeCN/TFA to afford (ꢂ)-94 in moderate yield
(44%), but as a single diastereomer. The stereochemical outcome of
this reaction is consistent with the logic of Scheme 17.
Table 6
DIB oxidation of oximes to nitrile oxides and cycloaddition thereof to alkenesa
Entry
a
R1
Alkene
Ph
Product type
Yieldb (%)
71
Scheme 16. Retrosynthetic hypothesis for tetrodotoxin.
N
N
N
O
O
O
Ph
R1
R1
R1
Ph
Ph
Ph
The simultaneous introduction of an OH and an equivalent of
the formyl groupdin the form of CN unitdmay be achieved by an
intramolecular nitrile oxide cycloaddition (INOC)38 followed by
isoxazoline cleavage. Selectivity for the pro-S double bond could be
secured through a new incarnation of the principle delineated in
Schemes 12 and 14. To illustrate, suppose that substituent A in
nitrile oxide 78 (Scheme 17) were a sterically demanding group
with a reactivity profile conducive to a subsequent fragmentation
of the nascent isoxazoline ring. The INOC event can occur either
from conformer 79a or from 79b. In the latter, the bulky A moiety is
forced within the concavity of the developing bowl-shaped cyclo-
adduct, thereby engendering significant steric congestion, whereas
cyclization from 79a occurs in such a way that A remains external to
the developing tricyclic framework. This alleviates nonbonding
interactions and promotes selectivity in favor of cycloadduct 81.
b
c
3-O2NeC6H4
n-C5H11
91
74
Ph
Ph
N
O
d
e
Ph(CH2)2
Ph
63
95
R1
Ph
Ph
O
N
R1
O
O
N
f
3-O2NeC6H4
n-C5H11
77
91
R1
N
g
R1
O
O
O
N
h
i
Ph(CH2)2
t-Bu
79
75
90
R1
N
R1
N
j
4-MeOeC6H4
R1
N
O
k
Ph
83
(CH2)4Br
R1
(CH2)4Br
a
Representative procedures are provided in the Experimental section.
After column chromatography.
b
Scheme 17. Predicted course of the INOC reaction of 78.

5890
H. Liang, M.A. Ciufolini / Tetrahedron 66 (2010) 5884e5892
N-benzylsulfonamide into a carbonyl group, and ensuing isoxazo-
line fragmentation would deliver nonracemic 99e100. Such a goal
is being actively pursued as of this writing.
4. Conclusion
This article has highlighted key aspects of the oxidative amidation
of phenols, a technique that encompasses a suite of reactions devised
in our laboratory in response to specific synthetic problems. The new
methodology provides access to valuable enantioenriched building
blocks for nitrogenous substances. Numerous applications in natural
product synthesis and in medicinal chemistry may be envisaged. We
emphasize that the driving force behind this effort wasdand
remaindthe élan toward efficient syntheses of architecturally in-
triguing natural products through previously unexplored strategies.
Scheme 18. DIB-promoted INOC reactions.
5. Experimental section
5.1. Experimental protocols
Unless otherwise noted, NMR spectra were recorded in CDCl3 at
300 MHz for 1H and 75 MHz for 13C. Chemical shift (
d) are in parts
per million, and coupling constants (J) are in hertz. Multiplicities
are reported as: ‘s’ (singlet), ‘d’ (doublet), ‘t’ (triplet), ‘q’ (quartet),
‘m’ (multiplet), ‘br’ broad. IR spectra (cmꢀ1) were measured on
a Perkin/Elmer 1720-X FTIR from CHCl3 solutions. Low- and high
resolution mass spectra (m/e) were obtained in the CI (isobutane),
EI (70 eV), LSIMS (Csþ), or ESI mode, as specified. Optical rotation
were measured in CHCl3, with concentrations (c) expressed in g/
100 mL. All reactions were run under argon, and monitored by TLC.
Reagents and solvents were commercial products and were used as
received, except: THF (freshly dist. Na/benzophenone); CH2Cl2,
Et3N (dist. CaH2).
Scheme 19. Tandem oxidative dearomatization/INOC reaction of phenols promoted by
DIB.
A possible mode of isoxazoline fragmentation was demon-
strated by the use of intermediate 97, which was prepared from
dienone 31e as detailed in Scheme 20. A key step in this sequence
was a Torssell cyclization43 of nitroketone 96. Treatment of 97 or its
5.2. Representative procedure for small-scale bimolecular
oxidative amidation of phenols using DIB in MeCN/TFA:
compound 31e21b
A MeCN (20 mL) solution of 30e (53 mg, 320
added over 10 min (syringe pump) to a solution of DIB (123 mg,
380 mol, 1.2 equiv) and TFA (47 mg, 400 mol, 1.3 equiv vs DIB) in
mmol, 1 equiv) was
m
m
MeCN (20 mL), at room temperature with good stirring. The final
concentration was equal to 8 mmol of substrate/L. At the end of the
addition, the solution was light yellow. Solid NaHCO3 (107 mg,
1.3 mmol, 4 equiv) was added and the mixture was stirred for
15 min, then it was filtered through Celite and concentrated.
Chromatographic purification (1% MeOH in EtOAc) gave 61 mg
(280 m
mol, 86%) of 31e, off-white solid, mp 100e102 ꢁC.
5.3. Representative procedure for preparative-scale
bimolecular oxidative amidation of phenols using DIB in
MeCN/TFA: compound 31e21b
A MeCN (20 mL) solution of 30e (9.1 g, 55.0 mmol, 1 equiv) was
added over 3 h (syringe pump) to a solution of DIB (23.9 g,
74.0 mmol, 1.3 equiv) and TFA (6.4 mL, 82.5 mmol, 1.5 equiv vs DIB)
in MeCN (480 mL), at rt with good stirring (final concen-
tration¼0.11 M). The progress of the reaction was monitored by 1H
NMR. At the end of the addition, the solution had become light
brown. The mixture was evaporated (rotavap) and the residue was
taken up with toluene (10 mL). The suspension was concentrated
(rotavap) and the procedure was repeated to azeotropically remove
all residual TFA. The brown residue was filtered through a silica pad
(45 g) using first 300 mL of Et2O (removal of brown tar and iodo-
benzene) and then 300 mL Et2O/CH3CN (2.5:1, elution of product).
Scheme 20. Keto-isoxazoline fragmentation with methanolic Li2CO3.
congener 98 with Li2CO3/MeOH provided 99 and 100, re-
spectively.44 This observation suggests that an enantioselective
route to 99e100, and consequently to 74, may be possible starting
with enantioenriched 93, available in turn from (
L)-tyrosine.
Oxidative conversion into scalemic 94, elaboration of the

H. Liang, M.A. Ciufolini / Tetrahedron 66 (2010) 5884e5892
5891
Concentration (rotavap) afforded a brown solid, which was re-fil-
tered through fresh silica gel using the same procedure (complete
removal of polymeric material). The solid residue was taken up
with 20 mL of EtOAc and kept at ꢀ20 ꢁC for 5 h. The resulting
precipitate was essentially pure product. Concentration of the
mother liquor afforded a second crop of crystalline material. A total
of 8.2 g (36.3 mmol, 66.0%) of product was obtained. A sample
recrystallized from 2:1 EtOAc/hexanes had mp 100e102 ꢁC. 1H
(acetone-d6): 7.54 (br, 1H); 7.17 (d, J¼10.3, 2H); 6.15 (d, J¼10.3, 2H);
3.62 (s, 3H); 3.02 (s, 2H); 1.88 (s, 3H). 13C (acetone-d6): 184.3; 169.4;
169.0; 148.8; 128.1; 53.3; 51.1; 41.7; 22.5. IR: 3200, 1738, 1666.
HRMS: calcd for C11H13NO4Na [MþNa]þ 246.0737; found 246.0742.
EA calcd for C11H15NO4 C 59.19, H 5.87, N 6.27; found C 58.96, H
5.80, N 6.18.
concentration of substrate¼0.1 M) and heated to reflux. Upon the
completion of the reaction (several hours), the mixture was evap-
orated (rotavap). Silica gel chromatography of the residue (1:1:3
EtOAc/hexanes/toluene) afforded 46a (40%) as a pale yellow solid,
mp 121e122 ꢁC. IR: 1735; 1304; 1133. 1H (acetone-d6): 6.55e6.48
(m, 1H); 6.39e6.32 (m, 1H); 3.77e3.63 (m, 2H); 3.47e3.38 (m, 2H);
3.04e2.92 (m, 1H); 2.87 (dt, J¼14, 2.5, 1H); 2.32e2.19 (m, 1H);
2.16e1.93 (m, 3H); 1.64e1.54 (m, 1H). 13C (acetone-d6): 202.4;
134.2; 130.0; 71.2; 56.8; 46.3; 44.8; 43.9; 30.8; 27.2; 27.0. HRMS:
calcd for C11H13NO3SNa [MþNa]þ 262.0514; found 262.0515.
5.8. Representative procedure for tandem para-oxidative
cyclization/IMDA of phenolic sulfonamides: compound 7233
Solid DIB (70 mg, 216
mmol) was added slowly at rt to a 0.2 M TFA
(0.9 mL) solution of 70(54 mg,180
m
mol) at roomtemperature. After
5.4. Representative procedure for para-oxidative cyclization
30 min, toluene (2.5 mL) was added and the mixture was heated to
reflux for 10 h, whereupon the IMDA reaction was complete. The
mixture was evaporated to dryness (rotavap) and the residue was
chromatographed over silica gel (ca. 3 g) with 3:1 EtOAc/hexanes to
of phenolic sulfonamides with DIB in TFA: compound 39d27
Solid DIB (1.5 g, 4.8 mmol, 1.1 equiv) was added slowly and
portionwise at rt to a well stirred 0.3 M solution of 38d (1.0 g,
4.4 mmol, 1.0 equiv) in TFA. Upon completion of the reaction (TLC),
the mixture was evaporated (rotavap). Silica gel (ca. 30 g) chro-
matography of the residue (1% MeOH in AcOEt) afforded 942 mg
give 17 mg (58 mmol, 32%) of an 8:1 a mixture of 72 and 73. A fraction
enriched in 72 deposited crystals suitable for an X-ray study that
confirmed the structure. Compound 72. IR: 3290; 1709; 1358; 1219.
1H: 6.72 (d, J¼10.3, 1H); 6.41e6.32 (m, 1H); 6.13 (d, J¼10.3, 1H);
5.93e5.85 (m, 1H); 4.35e4.23 (m, 1H); 3.99e3.91 (m, 1H); 3.86 (dd,
J¼11.8, 2.8, 1H); 3.68e3.46 (m, 2H); 2.77e2.59 (m, 2H); 2.38e1.88
(m, 6H). 13C: 197.8; 145.1; 135.7; 128.1; 115.3; 66.9; 66.0; 64.6; 58.0;
40.7; 40.4; 40.0; 26.0; 24.3. HRMS: calcd for C14H17NO4SNa[MþNa]þ
318.0776; found 318.0782.
(4.2 mmol, 95%) of 39d, low-melting, pale yellow solid, [
a
]
22 ꢀ20.3
D
(c 1.10, acetone). IR: 3417; 2929; 1667; 1328. 1H (acetone-d6): 7.26
(dd, J¼9.8, 3.0,1H); 7.04 (dd, J¼9.9, 3.0,1H); 6.16 (dd, J¼9.9, 2.3,1H);
6.10 (dd, J¼10.1, 2.1, 1H); 4.15 (br, 1H); 4.12e4.04 (m, 1H); 3.82e3.72
(m, 2H); 3.00 (s, 3H); 2.61e2.33 (m, 2H); 2.24e2.13 (m, 1H);
1.99e1.89 (m, 1H). 13C (acetone-d6): 184.4; 152.7; 148.7; 127.7;
127.3; 64.2; 63.9; 63.1; 39.3; 37.7; 26.5. HRMS: calcd for
C11H15NO4SNa [MþNa]þ 280.0619; found 280.0619.
5.9. Representative procedure for DIB oxidation of oximes to
nitrile oxides with bimolecular capture: compound 83a41
5.5. Representative procedure for para-oxidative cyclization
A solution of benzaldoxime (82a, 109 mg, 1 mmol) in MeOH
(1 mL) was added slowly (syringe pump, 1 h) at room temperature
to a stirred solution of DIB (354 mg, 1.1 equiv) and styrene (115 mg,
of phenolic phosphoramides with DIB in TFA: compound 4127
The above procedure was applied to the oxidative cyclization of
40, whereupon compound 41, pale yellow oil, was obtained in 88.0%
yield after chromatography (100:6 EtOAc/MeOH). IR: 3450; 1662;
1251; 1016. 1H: H NMR: 6.84 (d, J¼10.1, 2H); 6.16 (d, J¼10.1, 2H);
3.66 (s, 3H); 3.62 (s, 3H); 3.54e3.47 (m, 2H); 2.09e2.01 (m, 4H). 13C:
185.3; 151.5; 127.1; 62.0 overlapping with 61.9; 53.43 overlapping
with 53.36; 48.94 overlapping with 48.87; 40.4, 40.3; 25.1, 25.0.
HREIMS: calcd for C11H16NO4P 257.0817 [M]þ; found 257.0821.
126 mL, 1.1 equiv) in MeOH (2 mL) containing TFA (15 mL). A white
precipitate formed immediately and then slowly redissolved as the
reaction progressed. Upon consumption of starting oxime (TLC, ca.
1 h), the mixture was evaporated (rotavap). The residue was puri-
fied by column chromatography (step gradient: 5%e10%e20% ethyl
acetate/hexanes) to afford 158 mg (71%) of the known isoxazoline
83a, colorless crystals, mp 72e73 ꢁC.45 1H: 7.70 (m, 2H), 7.40 (m,
8H), 5.75 (dd, J¼11.2, 8.4, 1H), 3.79 (dd, J¼16.4, 11.2, 1H), 3.35 (dd,
J¼16.4, 8.2, 1H). 13C: 156.2, 141.1, 130.3, 129.6, 128.9, 128.9, 128.3,
126.9, 126.0, 82.7, 43.3. ESI-MS: 224 [MþH]þ, 246 [MþNa]þ. HRMS:
calcd for C15H13NONa [MþNa]þ 246.0895; found 246.0894.
5.6. Representative procedure for ortho-oxidative cyclization
of phenolic sulfonamides with DIB in TFA: compound 43a27
Solid DIB (151 mg, 470
a well stirred solution of 42a (98 mg, 427
m
mol, 1.1 equiv) was added slowly at rt to
5.10. Representative procedure for tandem DIB oxidation of
oximes to nitrile oxides/INOC: compound 8741
mmol, 1 equiv) in TFA
(1.3 mL). Upon completion of the reaction, the mixture was evap-
orated (rotavap). Chromatography of the residue (2:1 EtOAc/hex-
anes) afforded 58 mg (255 mmol, 60%) of 43a, pale yellow oil. IR:
A solution of oxime 85 (99 mg, 440
slowly added to a solution of DIB (156 mg, 484
(15 L) in MeOH (1 mL). The mixture was stirred at room temper-
m
mol) in MeOH (1 mL) was
mmol) and TFA
1655; 1318; 1147. 1H: 7.01 (ddd, J¼9.8, 5.8, 1.7, 1H); 6.55 (ddd, J¼9.6,
1.7, 0.8, 1H); 6.16 (ddd, J¼9.6, 5.8, 1.0, 1H); 6.05 (dt, J¼9.8, 0.8, 1H);
3.78e3.57 (m, 2H); 2.96 (s, 3H); 2.27e1.97 (m, 4H). 13C: 201.6;
146.1; 142.0; 124.9; 119.8; 73.2; 49.4; 39.7; 39.5; 22.8. HRMS: calcd
for C10H13NO3SNa [MþNa]þ 250.0514; found 250.0512.
m
ature for 45 min, then it was quenched with 5% aqueous NaHCO3
(1 mL) and 10% aqueous NaHSO3 (1 mL), and extracted with ether
(3ꢃ5 mL). The combined extracts were washed with water
(2ꢃ7 mL), dried (MgSO4), filtered, and evaporated (rotavap). Puri-
fication of the residue by flash chromatography (20% EtOAc in
hexanes) afforded 87 (58 mg, 60%) as a colorless oil. 1H: 4.74 (dt,
J¼9.0, 8.1, 1H), 4.17 (q, J¼4.2, 2H), 4.07 (d, J¼9.0, 1H), 2.64e2.45 (m,
3H), 2.34e2.26 (m, 1H), 2.16e2.09 (m, 1H), 2.04e1.93 (m, 1H),
1.54e1.44 (m, 1H), 1.41e1.19 (m, 2H), 1.26 (t, J¼7.2, 3H). 13C: 175.2,
170.7, 77.8, 61.2, 58.8, 48.5, 40.5, 30.5, 28.5, 19.8, 18.6, 14.2. ESI-MS:
446.3 [MþNa]þ. HRMS calcd for C12H17NO3Na [MþNa]þ 246.1106;
found 246.1106.
5.7. Representative procedure for tandem ortho-oxidative
cyclization/IMDA of phenolic sulfonamides: compound 46a33
Solid DIB (1.1 equiv) was added slowly and portionwise to a well
stirred 0.3 M TFA solution of 44a (1 equiv). The reaction was
monitored by TLC and upon disappearance of the substrate the
mixture was diluted with twice the volume of toluene (final formal

5892
H. Liang, M.A. Ciufolini / Tetrahedron 66 (2010) 5884e5892
18. (a) Ciufolini, M. A.; Canesi, S.; Ousmer, M.; Braun, N. A. Tetrahedron 2006, 62,
5318; (b) Ciufolini, M. A.; Liang, H. In Biomimetic Organic Synthesis; Poupon, E.,
Nay, B., Eds.; Wiley-VCH: Weinheim, 2010.
5.11. Representative procedure for tandem bimolecular
oxidative amidationdINOC of phenolic oximes: compound 9241
19. (a) Braun, N. A.; Ciufolini, M. A.; Peters, K.; Peters, E.-M. Tetrahedron Lett. 1998,
39, 4667; (b) Braun, N. A.; Ousmer, M.; Bray, J. D.; Bouchu, D.; Peters, K.; Peters,
E.-M.; Ciufolini, M. A. J. Org. Chem. 2000, 65, 4397.
20. (a) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M. A. Tetrahedron
Lett. 2002, 43, 5193; (b) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew. Chem., Int.
Ed. 2004, 43, 4336 See also Ref. 23.
A solution of 90 (62 mg, 375
added at rt to a well stirred solution of DIB (226 mg, 825
TFA (15 L) in acetonitrile (20 mL). The reaction was complete after
m
mol) in MeCN (5 mL) was slowly
mmol) and
m
1 h at room temperature. The mixture was evaporated (rotavap)
and the residue was purified by flash column chromatography (step
gradient: 25%e50%e100% ethyl acetate/hexanes) to afford 58 mg
21. (a) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175; (b) Liang, H.;
Ciufolini, M. A. J. Org. Chem. 2008, 73, 4299.
22. Braun, N. A.; Bray, J.; Ciufolini, M. A. Tetrahedron Lett. 1999, 40, 4985 See also
Ref. 19b.
23. Canesi, S. Ph.D. Dissertation, Université Claude Bernard Lyon 1, 2004.
24. (a) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593;
(b) Seike, H.; Sorensen, E. J. Synlett 2008, 695.
25. (a) Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T. Tetrahedron Lett. 2002, 43,
2411; (b) Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T. Heterocycles 2004, 62,
343; (c) Mizutani, H.; Takayama, J.; Honda, T. Synlett 2005, 328.
26. The capture of electrophilic intermediates of the type 5 with carbonyl nucle-
ophiles forms the basis of some noteworthy transformations: (a) Wong, Y.-S.
Chem. Commun. 2002, 686; (b) Peuchmaur, M.; Wong, Y.-S. J. Org. Chem. 2007,
72, 5374; (c) Peuchmaur, M.; Wong, Y.-S. Synlett 2007, 2902; (d) Peuchmaur, M.;
Saidani, N.; Botte, C.; Marechal, E.; Vial, H.; Wong, Y.-S. J. Med. Chem. 2008, 51,
4870; (e) Li, C.; Danishefsky, S. J. Tetrahedron Lett. 2006, 47, 385; (f) Chang, J.;
Chan, B.; Ciufolini, M. A. Tetrahedron Lett. 2006, 47, 3599.
27. Liang, H. Ph.D. Dissertation, University of British Columbia, 2009.
28. Liang, H.; Ciufolini, M.A., unpublished.
29. Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353 Ref. 23 describes some im-
plementations of this technology.
30. E.g.: (a) Drutu, I.; Njardson, J.; Wood, J. Org. Lett. 2002, 4, 493; (b) Bérubé, A.;
Drutu, I.; Wood, J. L. Org. Lett. 2006, 8, 5421 For Diels/Alder reactions of
structurally similar quinone monoketals see: (c) Breuning, M.; Corey, E. J. Org.
Lett. 2001, 3, 1559; (d) Yu, M.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130,
2783; (e) Hayden, A. E.; DeChancie, J.; George, A. H.; Dai, M.; Yu, M.; Dani-
shefsky, S. J.; Houk, K. N. J. Org. Chem. 2009, 74, 6770; (f) Dory, Y. L.; Roy, A.-L.;
Soucy, P.; Deslongchamps, P. Org. Lett. 2009, 11, 1197.
(266 m
mol, 71%) of 126, colorless crystals, mp 162e163 ꢁC. 1H (ac-
etone-d6): 7.84 (br s, 1H), 6.41 (dd, J¼10.3, 2.0, 1H), 6.15 (dd, J¼10.3,
0.5, 1H), 4.72 (dd, J¼9.7, 0.5, 1H), 4.28 (ddd, J¼9.7, 2.0, 1.6, 1H), 2.69
(m, 1H), 2.64 (m, 2H), 2.37 (m, 1H), 1.84 (s, 1H). 13C (acetone-d6):
191.1, 170.4, 169.3, 146.5, 132.7, 79.8, 63.6, 53.5, 42.2, 42.1, 23.1, 19.3.
ESI-MS: 243.3 [MþNa]þ. HRMS calcd for C11H12N2O3Na [MþNa]þ
243.0746; found 243.0752.
Acknowledgements
We thank the University of British Columbia, the Canada Research
Chair Program, NSERC, CIHR, CFI, BCKDF, and MerckFrosst Canada for
support of our research. Portions of this work were carried out at the
Ecole Supérieure de Chimie, Physique, Electronique de Lyon and the
Université ClaudeBernard Lyon1, France, with supportfromthe CNRS
and the MRT. H.L. is the recipient of a Laird Graduate Fellowship.
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