Improved procedure for the bimolecular oxidative amidation of phenols

Article abstract of DOI:10.1021/jo800267q

(Chemical Equation Presented) Trifluoroacetic acid (TFA) is an effective promoter of the bimolecular Ritter-like oxidative amidation of 4-substituted phenols induced by PhI(OAc)₂ in MeCN. This suppresses the need for fluoroalcohol cosolvents, i

Full text of DOI:10.1021/jo800267q

SCHEME 1. Bimolecular Oxidative Amidation of Phenols
SCHEME 2. Possible Oxidative Amidation Mechanism
Improved Procedure for the Bimolecular
Oxidative Amidation of Phenols
Huan Liang and Marco A. Ciufolini*
Department of Chemistry, The UniVersity of British Columbia,
2036 Main Mall, VancouVer, BC V6T 1Z1, Canada
ciufi@chem.ubc.ca
ReceiVed February 1, 2008
Trifluoroacetic acid (TFA) is an effective promoter of the
bimolecular Ritter-like oxidative amidation of 4-substituted
phenols induced by PhI(OAc)2 in MeCN. This suppresses
the need for fluoroalcohol cosolvents, increases the yields,
and facilitates isolation/purification procedures.
showed that solvolysis of (presumed) species 8 can be avoided
by operating poorly nucleophilic fluoroalcohol media. This
enables capture with various nucleophiles, both in an intra- and
in an intermolecular mode.6 Fluoroalcohol solvents have since
become a standard feature of many such reactions.
In accord with Wood,7 we observed that the use of the more
reactive PhI(OCOCF3)2 (PIFA) in lieu of DIB eliminates the
need for HFIP. However, the formation of polymeric materials
remains a serious problem; furthermore, PIFA is expensive.8
We thus sought a method to induce DIB to react in the absence
of HFIP and in such a manner as to minimize polymer
formation. A solution emerged as detailed herein.
Protic solvents are likely to favor heterolysis of hypervalent
iodine complexes, either by hydrogen bonding (cf. 3, 6) or by
reversible protonation, thereby behaving as acidic promoters.
Indeed, other acidic adjuvants capable of favoring dissociation
of hypervalent iodine species, such as heteropolyacids or TMS-
Br,9 do induce DIB oxidations in nonprotic media. This
suggested that HFIP might be replaceable with a suitable Lewis
or Brønsted acid. On the other hand, polymeric byproducts are
The oxidative amidation of phenols offers interesting op-
portunities in the synthesis of nitrogenous substances.1 This
appears to be especially true of the bimolecular variant of the
process, which converts 4-substituted phenols 1 into dienones
2 (Scheme 1).2 In its original form, the reaction entails attack
of the phenol with PhI(OAc)2 (DIB) in a mixture of MeCN
and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Products 2 emerge
in 40-70% yield, at least on a small scale.
Research focusing on the application of this reaction to current
synthetic problems has required substantial scaling-up of the
original procedure. Reactions run on larger scales afford
products contaminated with much polymeric matter, imposing
the need for impractical, costly chromatographic purifications.
Also, the cost of HFIP3 becomes a significant issue during scale-
up. The need for this cosolvent derives from the fact that the
reaction of phenolic substrates with DIB proceeds poorly in an
aprotic milieu such as plain MeCN,4 whereas nucleophilic protic
solvents such as alcohols or water (S-H in Scheme 2) promote
clean conversion to products 9 (Z ) OMe, OH, etc.), possibly
by the mechanism of Scheme 2. Pioneering work by Kita5
(6) Oxygen nucleophiles; cf. ref 5 as well as (a) Rodr´ıguez, S.; Wipf, P.
Synthesis 2004, 2767. (b) Wipf, P.; Jung, J.-K. Chem. ReV. 1999, 99, 1469. (c)
Li, C.; Danishefsky, S. J. Tetrahedron Lett. 2006, 47, 385. Nitrogen nucleophiles:
cf. refs 1, 2 as well as (d) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem.,
Int. Ed. 2000, 39, 4593. (e) Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T.
Tetrahedron Lett. 2002, 43, 2411. (f) Braun, N. A.; Ousmer, M.; Bray, J. D.;
Bouchu, D.; Peters, K.; Peters, E.-M.; Ciufolini, M. A. J. Org. Chem. 2000, 65,
4397. (g) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A.
J. Am. Chem. Soc. 2001, 123, 7534. (h) Canesi, S.; Bouchu, D.; Ciufolini, M. A.
Angew. Chem., Int. Ed. 2004, 43, 4336. Carbon nucleophiles: leading reviews
of the massive volume of literature in this area: (i) Arisawa, M.; Toma, H.;
Kita, Y. Yakugaku Zasshi 2000, 120, 1061. (j) Tohma, H.; Kita, Y. Top. Curr.
Chem. 2003, 224. Recent developments: (k) Berard, D.; Jean, A.; Canesi, S.
Tetrahedron Lett. 2007, 48, 8238. (l) Jean, A.; Cantat, J.; Berard, D.; Bouchu,
D.; Canesi, S. Org. Lett. 2007, 9, 2553.
(1) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai,
D. Synthesis 2007, 3759.
(2) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175.
(3) About $1000 for 500 g (Sigma-Aldrich).
(4) This is true also for other polar, aprotic solvents such as MeNO2, CH2Cl2,
etc. See ref 1 and literature cited therein.
(5) (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52,
3927. (b) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J. Org.
Chem. 1991, 56, 435. (c) Kita, Y.; Takada, T.; Tohma, H. Pure Appl. Chem.
1996, 68, 627. (d) Dohi, T.; Ito, M.; Morimoto, K.; Minamitsuji, Y.; Takenaga,
N.; Kita, Y. Chem. Commun. 2007, 4152.
(7) Drutu, I.; Njardarson, J. T.; Wood, J. L. Org. Lett. 2002, 4, 493.
(8) Gram per gram, PIFA is about 3 times as costly as DIB, and more than
4 times as expensive on a molar basis.
10.1021/jo800267q CCC: $40.75
Published on Web 05/01/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4299–4301 4299

TABLE 1. Effect of TFA on the Yield of Desired Producta
of 3a to 4a. In each case, a MeCN solution of substrate was
added over 10 min (syringe pump) to a MeCN solution of DIB
and TFA. The final concentration was equivalent to 8 mmol/L
of substrate. At least 1 equiv of TFA relative to DIB is required
for efficient conversion. Excess acid complicates isolation
procedures and diminishes the yields. Best results are obtained
when a MeCN solution of the phenol (1 equiv) is slowly added
to a MeCN solution of DIB (1.2 equiv vs substrate) and TFA
(1.3 equiv vs DIB for small scales, 1.5 equiv vs DIB for large-
scale work).
mol ratio TFA:DIB
50 25 10
5
2.5 1.3 1.0 0.5
0
0
isolated yield (%) of 4a 75 75 79 85 86 86 80 36
a Slow addition of a MeCN solution of 3a to a MeCN solution of 1.2
equiv of DIB and 1.3 equiv of TFA versus DIB, at rt. Final con-
centration ) 8 mM.
Reactions run under these conditions require no aqueous
workup.14 Small-scale reactions may be neutralized with solid
NaHCO3 then filtered and concentrated as a prelude to chro-
matographic recovery of the product. However, and especially
for large-scale operations, it is more expedient to concentrate
the reaction mixture15 and isolate the product by rapid filtration
through a pad of silica gel, followed by crystallization in the
case of solid materials.
The effect of temperature on the above transformation was
examined in the range of -30 to +70 °C.16 Chemical yields
remained constant in this interval. Not unexpectedly, the rate
of the reaction increases greatly as the temperature rises from
-30 to +20 °C, at which point the conversion of 3a to 4a is
virtually instantaneous. The reaction is thus most conveniently
carried out at room temperature.
The new and previous oxidation procedures are compared in
Table 2. All reactions were conducted by adding a solution of
4 mmol of substrate to a total volume of 500 mL of solvent,
giving a final concentration of 8 mmol/L. This diminished
polymer formation and improved the yields, sometimes by a
factor of 2 or more. Efforts to further reduce the amount of
polymeric byproducts centered on the oxidation of silyl ether
derivatives of phenols 3. This method proved to be inferior to
the oxidation of unprotected substrates. The TBS ether of 3a
resisted the action of DIB, but it underwent oxidation in poor
yield when TBAF was added to the reaction medium. The DIB/
TFA system did convert TES and TMS ethers of 3a to the
expected 4a in the absence of fluoride ion, but in only 33 and
81% yield, respectively. Silylation of the phenol thus offers no
advantage.
The dilute conditions of the above experiments do reduce
the extent of polymer formation, but they are problematic for
process work, even though the MeCN utilized in such reactions
may be recycled without purification and with no adverse effect
on yields.17 The effect of concentration on the efficiency of the
reaction was therefore examined with 3a and para-cresol, 3j,
as representative substrates (Table 3). Yields diminish with
increasing concentration; however, good results are obtained
by operating in the 0.1 M range, always with slow addition of
substrate to the oxidant. It is worthy of note that the DIB-TFA
system is more efficient than PIFA for the oxidation of 3a at a
final concentration of 110 mM (66 vs 53%). Preparative runs
TABLE 2. Comparison of the New versus the Old Procedure
entry
R
X
Y
yield %a
a
b
c
d
e
f
g
h
i
CH2CO2Me
Et
n-Pr
i-Pr
Me
CH2CN
(CH2)2CN
(CH2)2NHTs
(CH2)2Br
Me
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
Me
H
H
H
H
86 (58b, 35c)
87
82 (54b)
40d (62b)
41
71 (31b)
81 (67b)
59 (53b)
57 (<10b)
89 (56b)
41 (24b)
65
j
k
l
H
Br
H
Me
CH2COOBn
a Slow addition of 4 mmol of substrate to 1.2 equiv of DIB and 1.3
equiv of TFA versus DIB, at rt, in a total of 500 mL of MeCN. b Yields
in parentheses refer to the old procedure (ref 2). c Yield of reactions run
on a 0.6 mmol scale as per ref 2. d Yield of reactions run as per ref 2,
but on scales greater than 2-3 mmol. e The product of dienone-phenol
rearrangement of 4d, i.e., 3-isopropyl-4-acetamidophenol, was also iso-
lated in 30% chromatographed yield.
likely to arise upon nucleophilic capture of an electrophile such
as 8 by an intact molecule of substrate. If so, polymer formation
could be contained by keeping the instant concentration of
phenol low (operation in dilute solutions, slow addition, or both).
Indeed, PIFA oxidation of 3a10 (cf. Table 1) in MeCN, run at
a final substrate concentration of 500 mM, provided 4a in 30%
yield.11 The yield improved to 53% at a final concentration of
110 mM and to 83% at 8 mM.
The search for an alternative to HFIP in DIB oxidations
centered on the conversion of 3a to 4a (Tables 1 and 2) in a
dilute MeCN solution. Lewis (BF3•OEt2, TiCl4) and Brønsted
(HCl,12 98% H2SO4, TsOH•H2O, 85% H3PO4, 70% HNO3, or
AcOH) acids did promote the reaction, but they induced
formation of mixtures of products. By contrast, clean, efficient
oxidative amidation occurred in the presence of a slight molar
excess of trifluoroacetic acid (TFA), which, as an added bonus,
also greatly increased the solubility of DIB in MeCN: while
the reagent is poorly soluble in acetonitrile, addition of TFA to
a MeCN suspension of DIB results in rapid dissolution.13 Table
1 summarizes the effect of TFA on the DIB-mediated oxidation
(14) Many compounds of the type 2 are water-soluble, a property that
complicates aqueous workups.
(15) While most dienones 2 are sensitive to prolonged exposure to excess
TFA (ref 1), the small amounts of TFA that accumulate in the solution during
concentration of these reaction mixtures have little adverse effect on compounds
2 if R is a group possessing poor migratory aptitude in the dienone-phenol
rearrangement, e.g., a primary (cf. 4b,c,e,j) or an electronically deactivated (4a)
alkyl substituent. Dienones incorporating secondary (cf. 4d) or tertiary C-4 alkyls
(cf. Scheme 3) are progressively more prone to undergo dienone-phenol
rearrangement.
(9) (a) Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett. 2006, 8,
2007. (b) Hata, K.; Hamamoto, H.; Shiozaki, Y.; Kita, Y. Chem. Commun. 2005,
2465.
(10) This phenol is of special interest in an ongoing synthetic venture.
(11) Slow addition of 3a to 1.3 equiv of PIFA in MeCN at rt.
(12) Commercial 4 N HCl in dioxane.
(16) A series of reactions were run at 15-20° C intervals within this range.
(17) The solvent may be recovered from the rotary evaporator and directly
reused.
(13) Mixed iodonium carboxylates such as PhI(OAc)(OCOCF3) may form
under these conditions.
4300 J. Org. Chem. Vol. 73, No. 11, 2008

TABLE 3. Effect of Substrate Concentration on the Yield of
Desired Product
is now available. Synthetic applications of this reaction will be
reported in due course.
Experimental Section19
General Procedure for Oxidative Amidation of Phenols under
Dilute Conditions. A MeCN (20 mL) solution of 3a (53 mg, 0.32
mmol, 1 equiv) was added over 10 min (syringe pump) to a solution
of DIB (123 mg, 0.38 mmol, 1.2 equiv) and TFA (47 mg, 0.4 mmol,
1.3 equiv vs DIB) in MeCN (20 mL) at rt 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) yielded 61
mg (86% yield) of 4a, off-white solid, mp 100-102 °C.
General Procedure for Preparative Scale Oxidative Amida-
tion of Phenols. A MeCN (20 mL) solution of 3a (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. The
final concentration was equal to 110 mmol of substrate/L. 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 concentrated, and the residue was taken up with toluene (10
mL). The suspension was concentrated, 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 PhI) and then 300 mL of Et2O/
CH3CN (2.5:1, elution of the product). Concentration afforded a
brown solid, which was refiltered 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 4a.
Concentration of the mother liquor afforded an additional crop of
crystalline material. A total of 8.13 g (66% yield) of 4a was
obtained. A recrystallized sample (2:1 EtOAc/hexanes) had mp
100-102 °C.
NMR yieldc
chemical yieldd
[substrate]b
mmol/L
R ) Me R ) CH2CO2Me R ) Me R ) CH2CO2Me
8
16
32
64
125
250
500
94
87
82
73
63
51
42
91
84
80
74
70
54
40
89
80
71
59
48
38
25
86
80
73
69
62
49
35
a Slow addition of 4 mmol of substrate to 1.2 equiv of DIB and 1.3
equiv of TFA versus DIB, in a total of 500 mL of MeCN. b Apparent
final concentration. c NMR yields were determined by using 1,4-dioxane
as an internal standard. d Yields of chromatographed products.
SCHEME 3. Poor Substrates for Oxidative Amidation
of this reaction carried out with 10-30 g batches of 3a
consistently gave yields in the 65-70% range.
The phenols shown in Scheme 3 are poor substrates for the
reaction. The behavior of 3m,n (Pht ) phthalimido) is consistent
with the tendency of suitably positioned carbonyl groups to
intercept the electrophilic species (cf. 8) produced upon DIB
activation of the phenol.18 Steric effects may complicate the
reaction of BHT, 3r. Phenol 3o decomposes on standing at room
temperature, and dissolution in MeCN may exacerbate this
instability. The initial products of oxidative amidation of 3p,q
appear to undergo dienone-phenol rearrangement and quinon-
imine formation, respectively.
Acknowledgment. Financial support by the University of
British Columbia, the Canada Research Chair Program, CFI,
NSERC, CIHR, and MerckFrosst Canada, Ltd., is gratefully
acknowledged.
Supporting Information Available: Experimental protocols,
characterization data, and spectra of all compounds described
herein. This material is available free of charge via the Internet
at http://pubs.acs.org.
In summary, an improved procedure for the bimolecular
oxidative amidation of phenols on preparatively useful scales
JO800267Q
(18) (a) Wong, Y.-S. Chem. Commun. 2002, 686. (b) Peuchmaur, M.; Wong,
Y.-S. J. Org. Chem. 2007, 72, 5374. (c) Chang, J.; Chan, B.; Ciufolini, M. A.
Tetrahedron Lett. 2006, 47, 3599 and refs cited therein.
(19) Experimental protocols are provided as Supporting Information.
J. Org. Chem. Vol. 73, No. 11, 2008 4301