Photochemical cleavage and release of para-substituted phenols from α-keto amides

Article abstract of DOI:10.1021/jo060338x

In aqueous media α-keto amides 4-YC₆H₄OCH ₂COCON(R)CH(R′)CH₃ (5a, R = Et, R′ = H; 5b, R = ⁱPr, R′ = Me) with para-substituted phenolic substituents (Y = CN, CF₃, H) undergo photocleavage and release of 4-YC ₆H₄OH with formation of 5-methyleneoxazolidin-4-ones 7a,b. For both 5a,b quantum yields range from 0.2 to 0.3. The proposed mechanism involves transfer of hydrogen from an N-alkyl group to the keto oxygen to produce zwitterionic intermediates 8a-c that eliminate the para-substituted phenolate leaving groups. The resultant imminium ions H₂C=C(OH) CON⁺(R)=C(R′)CH₃ 9a,b cyclize intramolecularly to give 7a,b. The quantum yields for photoelimination decrease in CH₃CN, CH₂Cl₂, or C₆H₆ due to competing cyclization of 5a,b to give oxazolidin-4-one products which retain the leaving group 4-YC₆H₄O^- (Y = H, CN). A greater tendency to undergo cyclization in nonaqueous media is observed for the N,N-diethyl amides 5a than the N,N-diisopropyl amides 5b. With para electron releasing groups Y = CH₃ and OCH₃ quantum yields for photoelimination significantly decrease and 1,3-photorearrangment of the phenolic group is observed. The 1,3-rearrangement involves excited state ArO-C bond homolysis to give para-substituted phenoxyl radicals, which can be observed directly in laser flash photolysis experiments.

Full text of DOI:10.1021/jo060338x

Photochemical Cleavage and Release of Para-Substituted Phenols
from r-Keto Amides
Chicheng Ma, Yugang Chen, and Mark G. Steinmetz*
Department of Chemistry, Marquette UniVersity, Milwaukee, Wisconsin 53201-1881
mark.steinmetz@marquette.edu
ReceiVed February 17, 2006
In aqueous media R-keto amides 4-YC6H4OCH2COCON(R)CH(R′)CH3 (5a, R ) Et, R′ ) H; 5b, R )
iPr, R′ ) Me) with para-substituted phenolic substituents (Y ) CN, CF3, H) undergo photocleavage and
release of 4-YC6H4OH with formation of 5-methyleneoxazolidin-4-ones 7a,b. For both 5a,b quantum
yields range from 0.2 to 0.3. The proposed mechanism involves transfer of hydrogen from an N-alkyl
group to the keto oxygen to produce zwitterionic intermediates 8a-c that eliminate the para-substituted
phenolate leaving groups. The resultant imminium ions H2CdC(OH)CON+(R)dC(R′)CH3 9a,b cyclize
intramolecularly to give 7a,b. The quantum yields for photoelimination decrease in CH3CN, CH2Cl2, or
C6H6 due to competing cyclization of 8a,b to give oxazolidin-4-one products which retain the leaving
group 4-YC6H4O- (Y ) H, CN). A greater tendency to undergo cyclization in nonaqueous media is
observed for the N,N-diethyl amides 5a than the N,N-diisopropyl amides 5b. With para electron releasing
groups Y ) CH3 and OCH3 quantum yields for photoelimination significantly decrease and 1,3-
photorearrangment of the phenolic group is observed. The 1,3-rearrangement involves excited state ArO-C
bond homolysis to give para-substituted phenoxyl radicals, which can be observed directly in laser flash
photolysis experiments.
Introduction
involved in a number of photochemical reactions. One such pho-
toreaction has been the photocyclization of R-keto amides 1 to
give oxazolidinones 2 and â-lactams 3 as products (Scheme
1), which can be considered to involve zwitterionic intermediates
Photochemical cleavage reactions have found widespread use
in biological applications that require intracellular photochemical
release of biologically active substrates1 or as photoremovable
protecting groups and photolinkers for the synthesis of biooli-
gomers.2 A number of photocleavage reactions have been
developed in recent years which release carboxylate and phos-
phate leaving groups for use in such applications.3-6 Neverthe-
less, photochemical elimination reactions that expel leaving
group anions remain quite uncommon. Zwitterionic intermedi-
ates possess a basic site that, in principle, can be utilized to
effect the elimination of leaving groups. Furthermore, intermedi-
ates with significant zwitterionic character are thought to be
(2) (a) Greenberg, M. M.; Venkatesan, H. J. Org. Chem. 1996, 61, 525-
529. (b) Greenberg, M. M.; Gilmore, J. L. J. Org. Chem. 1994, 59, 746-
753. (c) Pirrung, M. C.; Bradley, J.-C. J. Org. Chem. 1995, 60, 6270-
6276. (d) McGall, G. H.; Barone, A. D.; Diggelmann, M.; Fodor, S. P. A.;
Gentalen, E.; Ngo, N. J. Am. Chem. Soc. 1997, 119, 5081-5090. (e) Pease,
A. C.; Solas, D.; Sullivan, E. J.; Cronin, M. T.; Holmes, C. P.; Fodor, S. P.
A. Proc. Nat. Acad. Sci. U.S.A. 1994, 91, 5022-5026. (f) Fodor, S. P. A.;
Read, J. L.; Pirrung, M. C.; Stryer, L.; Lu, A. T.; Solas, D. Science 1991,
251, 767-773. (g) Amit, B.; Hazum, E.; Fridkin, M.; Patchornik, A. Int. J.
Peptide Protein Res. 1977, 9, 91-96. (h) Lloyd-Williams, P.; Albericio,
F.; Giralt, E. Tetrahedron 1993, 49, 11065-11133.
(3) (a) Il’ichev, Y. V.; Schworer, M. A.; Wirz, J. J. Am. Chem. Soc.
2004, 126, 4581-4595. (b) Walker, J. W.; Reid, G. P.; McCray, J. A.;
Trentham, D. R. J. Am. Chem. Soc. 1988, 110, 7170-7177.
(4) Park, C.-H.; Givens, R. S. J. Am. Chem. Soc. 1997, 119, 2453-2463.
(5) Rajesh, C. S.; Givens, R. S.; Wirz, J. J. Am. Chem. Soc. 2000, 122,
611-618.
(1) (a) Marriott, G., Ed. Methods in Enzymology; Academic Press: San
Diego, CA, 1998. (b) Givens, R. S.; Weber, J. F. W.; Conrad, P. G., II;
Orosz, G.; Donahue, S. L.; Thayer, S. A. J. Am. Chem. Soc. 2000, 122,
2687-2697. (c) Barth, A.; Corrie, J. E. T. Biophys. J. 2002, 83, 2864-
2871. (d) Kaplan, J. H.; Forbush, B., III; Hoffman, J. F. Biochemistry 1978,
17, 1929-1935. (e) Canepari, M.; Nelson, L.; Papageorgiou, G.; Corrie, J.
E. T.; Ogden, D. J. Neurosci. Methods 2001, 112, 29-42.
(6) (a) Morrison, J.; Wan, P.; Corrie, J. E. T.; Papageorgiou, G.
Photochem. Photobiol. Sci. 2002, 1, 960-969.
10.1021/jo060338x CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/05/2006
4206
J. Org. Chem. 2006, 71, 4206-4215

CleaVage and Release of Para-Substituted Phenols
for a wide variety of carboxylate leaving groups (Scheme 2).10
In these studies the formation of cyclization products analogous
to 2 or 3, which would have retained the carboxylate leaving
groups, were never observed.
SCHEME 1
In a preliminary communication we reported results which
extended the photochemical elimination reaction of R-keto
amides to effect the release of a variety of para-substituted
phenolate leaving groups (eq 1).11 The results of our studies on
SCHEME 2
4-YC6H4O- eliminations can be discussed within the context
of our previously proposed10a,b mechanism for carboxylate group
eliminations (Scheme 3). The obvious difference is that a
substantially more basic leaving group is being expelled in the
elimination of phenolates 4-YC6H4O- from 8a,b. However, the
expected slower rates of elimination are not manifested by
significantly reduced quantum yields for 4-YC6H4OH formation
for Y ) H, CF3, or CN under aqueous conditions. On the other
hand, changing to nonaqueous solvents (CH3CN, CH2Cl2, or
C6H6) sufficiently slows elimination so that a significant frac-
tion of 8a,b undergoes cyclization to give oxazolidinones 13a,b
(eq 2).
SCHEME 3
4.7-9 We recently reported evidence that analogous zwitterionic
intermediates 8, photogenerated from R-keto amides 5 (Schemes2
and 3), undergo elimination of carboxylate anions on the
microsecond time scale in aqueous solution.10a,b The chemical
yields of the carboxylic acids and for the formation of the cor-
responding cleavage coproducts 6 or 7 were essentially quantita-
tive, and quantum yields for the photoeliminations were gen-
erally 0.2-0.4 for N,N-diethyl- or N,N-diisopropyl amides 5a,b
Another difference between the phenolate versus carboxylate
anion eliminations in photolyses of 5a,b concerns the partition-
ing of imminium ion 9 between intermolecular versus intramo-
lecular pathways a and b that form products 6 and 7 under
aqueous conditions (Scheme 3). In the case of carboxylate elimi-
nations, path a and product 6a are favored by N,N-diethylamides
5a, whereas product 7b is exclusively formed via path b in the
case of N,N-diisopropylamides 5b. In contrast, with phenolate
leaving groups product 7a,b is strongly preferred, regardless
of whether 5a or 5b is the reactant. The preference for
intramolecular cyclization of 9a to give 7a in the phenolate
elimination reactions is explicable in terms of deprotonation of
9a by the basic phenolate anion in the ion pair initially produced
(7) (a) Aoyama, H.; Sakamoto, M.; Kuwabara, K.; Yoshida, K.; Omote,
Y. J. Am. Chem. Soc. 1983, 105, 1958-1964. (b) Aoyama, H.; Sakamoto,
M.; Omote, Y. J. Chem. Soc., Perkin Trans. 1 1981, 1357-1359. (c)
Aoyama, H.; Hasegawa, T.; Omote, Y. J. Am. Chem. Soc. 1979, 101, 5343-
5347. (d) Aoyama, H.; Hasegawa, T.; Watabe, M.; Shiraishi, H.; Omote,
Y. J. Org. Chem. 1978, 43, 419-422.
(8) Chesta, C. A.; Whitten, D. G. J. Am. Chem. Soc. 1992, 114, 2188-
2197.
(9) Wang R.; Chen C.; Duesler E.; Mariano P. S.; Yoon, U. C. J. Org.
Chem. 2004, 69, 1215-1220.
(10) (a) Ma, C.; Steinmetz, M. G.; Kopatz, E. J.; Rathore, R. J. Org.
Chem. 2005, 70, 4431-4442. (b) Ma, C.; Steinmetz, M. G.; Kopatz, E. J.;
Rathore, R. Tetrahedron Lett. 2005, 46, 1045-1048. (c) Ma, C.; Steinmetz,
M. G.; Cheng, Q.; Jayaraman, V. Org. Lett. 2003, 5, 71-74.
(11) Ma, C.; Steinmetz, M. G. Org. Lett. 2004, 6, 629-32.
J. Org. Chem, Vol. 71, No. 11, 2006 4207

Ma et al.
TABLE 1. Chemical Yields for Photolyses of N,N-Diethyl r-Keto
Amides 5a (LG- ) 4-YC6H4O-) in 33% D2O in CD3CNa
upon elimination in 8a. A similar phenolate assisted intramo-
lecular cyclization of 9a to give 7a persists in the hydrogen-
bonded ion pair formed in phenolate eliminations conducted
under nonaqueous conditions in CH3CN, CH2Cl2, or C6H6,
whereas carboxylate anions produced upon photoelimination
from 5a in CH3CN instead add to the imminium ion carbon of
9a to give aminal adduct 14a (eq 3).
ArOH,
pKa
ArOH,
%
unreacted
5a, %
5a, Y )
7a, %
6a, %
12a, %
4-CN
4-CF3
H
4-CH3
4-CH3O
7.95
8.51
9.95
10.26
10.20
98
30
47
24
43
14
<5
31
8
<5
0
0
0
<5
19
64
0
69
41
50
22
52
16b
<5
0
a Yields determined by 1H NMR spectroscopy with DMSO as standard.
b Yield determined by HPLC analyses, using an internal standard and 254
nm UV detection.
TABLE 2. Chemical Yields for Photolyses of N,N-Diisopropyl
r-Keto Amides 5b (LG- ) 4-YC6H4O-) in 33% D2O in CD3CNa
unreacted
5b, Y )
ArOH, %
7b, %
12, %
1, %
With para electron releasing groups Y ) CH3 and OCH3,
the R-keto amides 5a,b (LG- ) 4-YC6H4O-) show marked
reductions in the efficiencies for release of 4-YC6H4OH under
aqueous conditions, and 1,3-photorearrangement of the phenolic
group to give 12a,b (eq 1) becomes increasingly important or
even predominant as a photoprocess. This 1,3-photorearrange-
ment of the phenolic group in 5a,b likely involves C-O bond
homolysis and recombination of the radical pair. The corre-
sponding long-lived para-substituted phenoxyl radicals (Y )
CH3, OCH3) of cage escape were readily observed by laser flash
photolysis. Since these radicals were produced rapidly within
the duration of the laser pulse, the C-O bond homolysis was
thought to occur directly in the excited state as a process that
competes with the excited-state transfer of hydrogen from the
carboxamide alkyl group to the keto group.
4-CN
H
4-CH3
4-CH3O
76
59
79
60
49
0
0
<5
8
17
40
46
22
48b
<5
74
a Yields determined by 1H NMR spectroscopy with DMSO as standard.
b Yields determined by HPLC analysis, using an internal standard and 254
nm UV detection.
cleavage coproducts, oxazolidinones 7a,b (eq 1), whereas the
diastereomeric hemiacetal 6a was only observed as a minor
product. Cleavage coproducts 6a and 7a,b were identified by
comparison to H, 13C NMR spectra of the authentic samples,
1
which had been isolated and characterized previously.10 The
yields of these cleavage coproducts were similar to the yields
of 4-YC6H4OH produced in the photolyses (Tables1 and 2).
Substitution of 5a,b by para electron donating groups,
Y ) CH3 or OCH3, led to progressively lower yields of
4-YC6H4OH, 6a, and 7a,b, and the formation of 1,3-photore-
Results
Photochemical Reactants. The series of N,N-dialkyl R-keto
amides 5a,b were prepared by reaction of dilithio dianions of
para-substituted phenoxyacetic acids 15 with ethyl N,N-diethyl-
oxamate or ethyl N,N-diisopropyloxamate in THF according to
the literature method12 (eq 4).
1
arrangement products 12a,b was observed by H NMR spec-
troscopy. Photoproducts 12a (Y ) CH3, OCH3) and 12b (Y )
OCH3) were isolated chromatographically from larger scale
photolyses and identified by 1H, 13C NMR spectroscopy,
whereas the yields of 12b (Y ) CH3) were insufficient for
complete characterization. The salient feature of 12a,b was an
1
R-CH2 group ca. δ 3.9 in the H NMR spectra (CDCl3). The
isolated compounds also showed only three aromatic protons
and an exchangeable hydroxyl group. In 13C NMR spectra
(CDCl3) the R-CH2 group appeared at ca. δ 42, and there were
six peaks corresponding to the nonequivalent carbons of the
trisubstituted aryl groups.
In solution the photorearranged N,N-diethylamide 12a (Y )
CH3, OCH3) slowly air-oxidized to form the keto cyclic
hemiacetals 16a (Y ) CH3, OCH3) (eq 5). The N,N-diisopropyl
The absorption spectra of 5a showed a maximum below 300
nm that progressively shifted to longer wavelengths by substitu-
tion of p-Y substituents with increasing electron donating
abilities, e.g., Y ) CN, λ ) 246 nm (ꢀ 2050), Y ) H, λ ) 269
nm (ꢀ 2270), and Y ) OCH3, λ ) 288 nm (ꢀ 3510). Very similar
absorption maxima were observed for the N,N-diisopropyl
R-keto amides 5b bearing para-substituted phenolic groups. The
absorption spectra of 5a,b tailed out to longer wavelengths such
that photolyses could readily be conducted above 300 nm and
laser flash photolysis studies could be performed at 355 nm.
Photolyses in Aqueous Acetonitrile. Photolyses of R-keto
amides 5a,b (Y ) H, CF3, CN) in 33% aqueous CH3CN with
Pyrex-filtered light at 25 °C produced 4-YC6H4OH and the
amide 12b (Y ) OCH3) showed no evidence of undergoing
this reaction. The oxidation of 12a (Y ) CH3, OCH3) to 16a
1
(CH3, OCH3) was readily observed by H NMR spectroscopy
(CDCl3) by the disappearance of the δ 3.9 peak of 12a (Y )
CH3, OCH3) and by an accompanying downfield shift of two
out of three aromatic protons (from δ <7.0 to 7.3-7.4).
Conversion was essentially complete after 24 h at 25 °C. In the
(12) Koft, E. R.; Dorf, P.; Kullnig, R. J. Org. Chem. 1989, 54, 2936-
40.
4208 J. Org. Chem., Vol. 71, No. 11, 2006

CleaVage and Release of Para-Substituted Phenols
13C NMR spectra (CDCl3) the characteristic feature of products
16a was a quaternary carbon at δ 98, which was very similar
to quaternary carbon chemical shifts reported for model
compounds 1713 and 1814 (vide infra). The structures proposed
for 16a (Y ) CH3, OCH3) were also consistent with elemental
analyses.
TABLE 3. Chemical Yields for Photolyses of N,N-Diethyl r-Keto
Amides 5a (LG- ) 4-YC6H4O-) under Nonaqueous Conditions
(CD3CN or C6D6)a
reactant
unreacted
5a, Y )
solvent
ArOH, %
7a, %
13a, %
5a, %
H
CN
CN
CD3CN
CD3CN
C6D6
0
54
40
0
54
42
44
trace
42
53
38
12
a Yields determined by 1H NMR spectroscopy with DMSO as standard.
TABLE 4. Chemical Yields for Photolyses of N,N-Diisopropyl
r-Keto Amides 5b (LG- ) 4-YC6H4O-) under Nonaqueous
Conditions (CD3CN, CD2Cl2, or C6D6)a
reactant
unreacted
5b, Y )
solvent
ArOH, %
7b, %
13b, %
5b, %
H
CD3CN
CD3CN
CD2Cl2
C6D6
30
44
45
39
31
45
47
39
24
0
24
31
43
52
27
26
CN
CN
CN
a Yields determined by 1H NMR spectroscopy with DMSO as standard.
The photochemistry of N,N-diethyl R-keto amide 19 was
studied for comparison to the phenoxy-substituted R-keto amides
5a,b (eq 6). The photolyses of 0.05 M 19 in 30% aqueous
TABLE 5. Quantum Yields for Photolyses of 5a,b (LG-
4-YC6H4O-) in 33% Aqueous CH3CN for Various Para
Substituents, Ya
)
Φ
Φ
reactant
5a, Y )
reactant
5b, Y
ArOH
12ab
ArOH
0.30
12bb
CN
CF3
H
CH3
OCH3
0.30
0.30
0.26
0.16
0.07
0
0
0
0.13
0.26
CN
0
H
CH3
OCH3
0.23
0.15
0.07
0
0.10
0.19
a HPLC analyses with internal standard used to quantify 5a,b and 4-Y-
C6H4OH. b Taken as Φdis - Φphenol where Φdis is the disappearance quantum
yield and ΦArOH is the quantum yield for 4-Y-C6H4OH (ArOH).
CH3CN with Pyrex-filtered light gave oxazolidinone 20 as the
sole photoproduct in 84% yield at high conversions, according
1
to H NMR spectroscopic analyses of the photolyzates. There
was no sign of other products, including those analogous to
7b, which might arise from elimination of the leaving group.
Oxazolidinone 20 was isolated chromatographically. Its 1H
NMR spectrum (CDCl3) showed the presence of the benzyloxy
group and a pair of doublet of doublets at δ 3.69 and 3.77 due
to diastereotopic CH2 protons. In addition, there was a corre-
sponding doublet of doublets at δ 4.39 that was assigned to the
lone methine proton in 20. In the 13C NMR spectrum (CDCl3)
the methine carbon appeared at δ 95.2, and the only carbonyl
group present was that ascribable to an amide.
Photolyses in Nonaqueous Solvents.. With a sufficiently
poor leaving group, such as a strongly basic alkoxide, cyclization
to form oxazolidinones such as 20 becomes the predominant
photoprocess (eq 6). Although this type of photoreactivity is
not observed under aqueous conditions in photolyses of R-keto
amides 5a,b with phenolate leaving groups, such photocycliza-
tions could become important if the phenolate photoeliminations
are slowed by changing to nonaqueous media. Under these latter
conditions, photolyses of 5a,b (Y ) H, CN) performed in neat
CH3CN and CH2Cl2 show that photocyclization to 13a,b can
become an important or even the predominant photoreaction
(eq 2, Tables 3 and 4).
that was observed was that of photocyclization to form oxazoli-
dinone 13a (Y ) H) (Table 3). With the less basic p-cyano-
phenolate leaving group, however, photoelimination almost
completely prevailed over photocyclization, and 4-CNC6H4OH
plus 7a were the principal photoproducts in CH3CN. Unlike
the N,N-diethylamide 5a (Y ) H), the N,N-diisopropylamide
5b (Y ) H) underwent both photoelimination and photocy-
clization to give phenol, 7a, and 13b (Y ) H) in both CH3CN
and benzene (Table 4). In the case of 5b (Y ) CN) photo-
elimination was exclusively observed in CH3CN, but was
retarded by photolyzing in CH2Cl2 or benzene, such that the
photocyclized product 13b (Y ) CN) was obtained in addition
to 4-CNC6H4OH and 7b.
Control experiments were performed to determine whether
13a (Y ) H) and 13b (Y ) H, CN) undergo elimination of
4-YC6H4OH to produce 6a or 7a,b in 33% aqueous CD3CN.
The above solutions were monitored by 1H NMR spectroscopy
for periods of 2 weeks. Only unreacted 13a,b were observed
and no trace of any other compound was detected in the
solutions.
Quantum Yields. The quantum yields for photolyses of 0.01
M 5a,b at 310 nm in 33% aqueous CH3CN showed that the
elimination of the para-substituted phenols 4-YC6H4OH is
efficient for electron withdrawing groups Y ) CN or CF3 and
for Y ) H (Table 5). However, the quantum efficiencies strongly
decreased for electron donating groups Y ) CH3 and OCH3,
and there was a corresponding increase in the quantum yields
for formation of the 1,3-photorearrangement products 12a,b.
In the case of 5a (Y ) H) photolysis in dry CH3CN produced
no phenol or cleavage coproduct 7a, and the only photoproduct
(13) Frimer, A. A.; Marks, V.; Gilinsky-Sharon, P.; Aljadeff, L.; Gottlieb,
H. E. J. Org. Chem. 1995, 60, 4510-20.
(14) Krishnamachari, V.; Levine, L. H.; Pare´, P. W. J. Agric. Food Chem.
2002, 50, 4357-63.
J. Org. Chem, Vol. 71, No. 11, 2006 4209

Ma et al.
FIGURE 1. (A) Spectrum of p-methylphenoxyl radical, λmax ) ca. 400 nm, produced from LFP of R-keto amide 5a (Y ) CH3). (B) Spectrum of
p-methoxyphenoxyl radical, λmax ) ca. 410 nm, produced from LFP of R-keto amide 5b (Y ) OCH3). Insets are kinetic plots of the intermediates,
monitored at 390 and 410 nm, respectively.
For the photoeliminations the quantum yields, ΦArOH, were
determined by measuring the yields of the para-substituted
phenol photoproducts by direct phase HPLC, using the internal
standard method. We also measured the quantum yields of
disappearance, Φdis, of the reactants 5a,b by the same method.
The quantum yields for 12a,b were then obtained by subtracting
ΦArOH from Φdis (Table 5).
intermediates through laser flash photolysis of 0.01 M ben-
zophenone in the presence of ca. 0.007 M of the corresponding
para-substituted phenols under identical conditions to the above
experiments with 5a (Y ) CH3) and 5b (Y ) OCH3). In addition
to the para-substituted phenoxyl radicals, accompanying absorp-
tion was observed due to benzophenone ketyl radicals in the
550 nm region. Absorption due to the triplet excited state of
the benzophenone, which is usually observed in this region, was
largely quenched under the above conditions. Quenching of the
triplet excited state of benzophenone by phenol also was used
to generate unsubstituted phenoxyl radicals, which were readily
observed at 400 nm. However, transient absorption attributable
to such phenoxyl radicals was not observed upon laser flash
photolysis of 5a (Y ) H).
Quantum yield measurements were also made for photolyses
of 5a (Y ) H) in CH3CN and for 5b (Y ) H) in CH3CN and
5b (Y ) CN) in C6H6. In these cases the products were
1
quantified by H NMR spectroscopy with use of DMSO as a
standard. The quantum yield for formation of the cyclic product
13a (Y ) H) in CH3CN was Φ ) 0.20, which is similar to the
value (Φ ) 0.26) for photoelimination to produce phenol in
33% aqueous CH3CN as the solvent. In the case of 5b (Y ) H)
in CH3CN the quantum yield for photoelimination of phenol
was lowered due to competition by photocyclization to form
13b, such that Φ ) 0.12 for elimination of C6H5OH to form
7b and Φ ) 0.11 for photocyclization to form 13b. No solvent
effect on the total quantum yield (Φ ) 0.23) in CH3CN was
observed as compared to 33% aqueous CH3CN. For photolyses
of 5b (Y ) CN) in C6H6, the quantum yield for photoelimination
of 4-CNC6H4OH to form 7b was Φ ) 0.081, whereas Φ )
0.073 for cyclization to form 13b, and the total quantum yield
for formation of products was Φ ) 0.15, which is lower than
the total quantum in aqueous CH3CN (Table 5).
Laser Flash Photolyses. Considering the likelihood that the
1,3-photorearrangement products 12a,b were formed via re-
combination of radicals produced upon photochemical ArO-C
bond homolysis of 5a,b (Y ) CH3, OCH3), we performed 355
nm nanosecond laser flash photolysis experiments with argon
flushed solutions of 0.05 and 0.08 M reactants 5a (Y ) CH3)
and 5b (Y ) OCH3) in 33% aqeuous CD3CN in efforts to detect
long-lived para-substituted phenoxyl radicals. The flash pho-
tolyses produced transient absorptions at 400 (Y ) CH3) and
410 nm (Y ) OCH3) (Figure 1A,B). These absorptions did not
decay within the microsecond time scale used for these experi-
ments. The kinetics of formation of the transients were moni-
tored at 390 and 410 nm, respectively, and showed that the
transients were produced within the duration of the laser pulse
(ca. 10 ns).
Discussion
Both the N,N-diethyl and N,N-diisopropyl amides 5a and 5b
with para electron accepting substituents Y ) H, CF3, or CN
on the phenolic ring exclusively undergo excited state hydrogen
transfer and subsequent expulsion of the corresponding pheno-
late leaving groups to form primarily 7a,b as the cleavage
coproducts in aqueous CH3CN. The phenolate eliminations do
not appear to be occurring directly in the excited state, but in a
ground-state intermediate thought to be the zwitterionic species
8a,b (Scheme 4). Quantum yields are essentially the same for
photoelimination of carboxylate and 4-YC6H4O- (Y ) H, CF3,
CN) groups in aqueous CH3CN. In dry CH3CN the expulsions
of 4-YC6H4O- (Y ) H, CF3, CN) are sufficiently slow such
that intermediates 8a,b undergo competitive cyclization to
give 13a,b. The cyclization of 8a,b to give 13a,b increases in
proportion to elimination when the solvent is changed from
CH3CN to CH2Cl2 or benzene. Such cyclizations in CH3CN
are not observed when the leaving group is a carboxylate
group.10 In dry CH3CN elimination of acetate anion occurs in
the case of 5a (LG- ) CH3CO2-) to give the aminal recombi-
nation product 14a in the ion pair (eq 3), whereas 5b (LG-
)
CH3CO2-) gives only 7b and acetic acid.10a Aside from the
ability of the phenolate substituted intermediates 8a,b to undergo
competitive cyclization under nonaqueous conditions, the mech-
anism for elimination of 4-YC6H4O- (Y ) H, CF3, CN) groups
is considered to be similar to that proposed previously10a,b for
expulsion of carboxylate groups from 5a,b (Scheme 3). Impor-
The assignment of the transients 4-YC6H4O radicals was
made on the basis of independent generation of the radical
4210 J. Org. Chem., Vol. 71, No. 11, 2006

CleaVage and Release of Para-Substituted Phenols
SCHEME 4
SCHEME 6
group always becomes monodeuterated, consistent with the
tautomerization step in its mechanism for formation (Scheme
5). Such a tautomerization step does not occur prior to the
formation of 7a,b, and these products do not come from 6a or
unobserved 6b.
SCHEME 5
The photoelimination quantum yields rather abruptly decrease,
and 1,3-photorearrangement of the phenolic group to give 12a,b
becomes an important, even dominant photoprocess (Table 5)
when the remote para substituent Y on the phenolic ring of 5a,b
is varied from Y ) H to Y ) CH3 to OCH3. The mechanism
for 1,3-photorearrangement likely involves scission of the
ArO-C bond of 5a,b to give a para-substituted phenoxyl radical
and an R-keto amide radical as a caged radical pair. Recombina-
tion at the ortho position of the phenoxyl radicals followed by
tautomerization would give 12a,b (Scheme 6).
The formation of para-substituted phenoxyl radicals has
previously been observed upon photolysis of R-(p-methoxyphe-
noxy)acetophenone15 and R-(p-methoxyphenoxy)acetone.16 These
radical cleavages are known to occur in the excited states of
tantly, control experiments show that the phenolate eliminations
do not occur in a dark reaction of the cyclized products 13a,b.
These products are stable for weeks in 33% aqueous CH3CN.
Although the photoeliminations to give 4-YC6H4OH and 7a,b
become less efficient due to competing cyclization of 8a,b in
CD3CN, CD2Cl2, or C6D6, appreciable yields of these products
are observed under such nonaqueous conditions (Tables 3 and
4). These photoeliminations are thought to proceed via initial
formation of a hydrogen bonded ion pair involving the phenolate
anion and the enolic imminium ion 9a,b. A related issue is the
formation of 7a as the major cleavage coproduct from N,N-
diethyl amides 5a in aqueous CH3CN. Under aqueous conditions
we invariably observe hemiacetal 6a rather than methyleneox-
azolidinone 7a as the major product when the leaving group is
carboxylate rather than phenolate.10a The basic phenolate anion
evidently promotes formation of 7a by enhancing the nucleo-
philicity of the enolic oxygen in 9a (Scheme 5). Proton transfer
from 9a to phenolate is envisioned to favor the intramolecular
cyclization (path b) leading to 7a over the intermolecular
addition of water (path a), which would give the hemiacetal
6a. On the other hand, for the N,N-diisopropyl amides 5b the
only cleavage coproduct observed under aqueous or nonaqueous
conditions is 7b, regardless of whether the leaving group is a
phenolate or carboxylate group.
these R-substituted ketones with rate constants of 107-109 s-1
.
In the cases of 5a,b the para-substituted phenoxyl radicals
(4-YC6H4O, Y ) CH3, OCH3) are detected in laser flash pho-
tolysis experiments and exhibit long-lived transient absorption
in the 390-410 nm region. These absorption maxima are iden-
tical with those observed upon independent generation of these
radicals by photolysis of benzophenone in the presence of
various concentrations of 4-YC6H4OH. We also find from
analysis of the rise times of the transient absorptions of the
substituted phenoxyl radicals that they are produced within the
duration of the laser pulse, suggesting that the radical cleavages
occur directly in the excited state of 5a,b (Y ) CH3, OCH3).
The rate constants for ArO-C cleavage of R-(4-YC6H4O)-
substituted acetophenones have been found to correlate to σ+
constants of the Y para substituents.15a The photochemical
homolyses observed for 5a,b (Y ) CH3, OCH3) are consistent
with the known ArO-C bond17 weakening by para electron
donors. Phenoxyl radicals are not detected in flash photolyses
of 5a (Y ) H), and no 1,3-photorearrangement products are
observed for 5a,b (Y ) H, CF3, CN), which would be consistent
with the known substantial ArO-C bond strengthening effect
of para electron withdrawing groups (EWG). In these latter cases
the predominant excited state reaction is hydrogen transfer to
give elimination products of 8a,b in aqueous CH3CN.
In the foregoing discussion, paths a and b in Schemes 3 and
5 are mechanistically distinct pathways, each leading to its
respective product 6a or 7a,b. From previously reported con-
trol experiments it is known that compounds 6a and 7a do
not interconvert under aqueous conditions at pH as low as 2.10a
In addition, deuterium labeling studies with D2O in CD3CN
show that no deuterium is incorporated into the terminal position
of the double bond of 7a,b.10 For 6a the corresponding CH3
(15) (a) Netto-Ferreira, J. C.; Avellar, I. G. J.; Scaiano, J. C. J. Org.
Chem. 1990, 55, 89-92. (b) Palm, W.-U.; Dreeskamp, H.; Bouas-Laurent,
H.; Castellan, A. Ber. Bunsen-Ges. Phys. Chem. 1992, 96, 50-61.
(16) Grimme, S.; Dreeskamp, H. J. Photochem. Photobiol., A 1992, 65,
371-382.
(17) (a) Pratt, D. A.; de Heer, M. I.; Mulder, P.; Ingold, K. U. J. Am.
Chem. Soc. 2001, 123, 5518-5526. (b) Suryan, M. M.; Kafafi, S. A.; Stein,
S. E. J. Am. Chem. Soc. 1989, 111, 4594-4600.
J. Org. Chem, Vol. 71, No. 11, 2006 4211

Ma et al.
SCHEME 7
the phenolate leaving group for para EWG or H. 1,3-Photore-
arrangement of the phenolic group occurs for para EDG. In both
cases, the photoreactions are efficient under aqueous conditions,
with total quantum yields of 0.2-0.3. The zwitterionic inter-
mediates 8a,b are postulated as the key intermediates in the
photoelimination of the phenolate anions. Direct cyclization
of these intermediates to give oxazolidinones which retain the
leaving group is observed in nonaqueous media such as
CH3CN, CH2Cl2, or benzene. For those para-substituted phe-
nolate groups with electron releasing substituents (Y ) CH3,
OCH3), 1,3-photorearrangement at the phenolic substituent
becomes an important even predominant photoprocess. Laser
flash photolyses show that the mechanism likely involves excited
state homolysis to radicals which recombine. The homolytic
cleavage could occur directly in the excited state or via a
photoinduced electron-transfer mechanism with those para-
substituted phenols that are good electron donors.
When ArO-C homolysis competes with hydrogen transfer
in the excited state, the disappearance quantum yields, Φdis, of
5a,b will not necessarily increase in going from Y ) EWG to
Y ) EDG. The Φdis remain nearly constant as the Y substituent
is varied (Table 5), likely because homolysis to generate the
radical pair results in recombination to give ground-state reactant
in addition to giving 1,3-rearrangement product 12a,b. If the
probability that recombination gives 1,3-rearrangement product
is some fraction P, then Φdis ) ΦHOP + ΦH, where ΦHO and
ΦH are the quantum yields for homolysis and hydrogen transfer.
This is also expressed by eq 7 , where kho and kH are the
Experimental Section
Preparation of N,N-Diethyl-3-(4-methylphenoxy)-2-oxopro-
panamide 5a (LG- ) 4-CH3C6H4O-). To 80 mL of freshly
distilled THF in a 250 mL three-neck round-bottom flask cooled
in dry ice-acetone bath under nitrogen was added 60.0 mL (120
mmol) of 2 M LDA in THF via a long-needle syringe. To the stirred
LDA at -72 °C was added 10.0 g (60.0 mmol) of 4-methylphe-
noxyacetic acid in 60 mL of THF during 15 min. After 40 min of
reaction, 10.0 g (58.0 mmol) of ethyl N,N-diethyloxamate, dissolved
in the 40 mL of THF, was added dropwise to the mixture over 2
min. After 30 min, the ice bath was removed. The reaction was
allowed to warm to room temperature, 50 mL of 2 N HCl was
added to the solution to adjust the pH to 1, and then 50 mL of
concentrated HCl was added. After the reaction was stirred for 30
min, 80 mL of ether was added, and the aqueous phase, which
was separated, was extracted by 80 mL of ether. The combined
ether extracts were washed twice by 40 mL of water, twice by 40
mL of 2 N NaOH, and once by saturated NaCl, then dried over
Na2SO4. After concentration in vacuo, the residue was purified by
medium-pressure liquid chromatography on 230-400 mesh silica
gel (MPLC), eluting with 10% EtOAc in hexane to give 9.3 g (62%
yield) of product as colorless oil. The spectral data were as
follows: 1H NMR (CDCl3) δ 1.21(t, J ) 7.2 Hz, 3H), 1.22 (t, J )
7.2 Hz, 3H), 2.30 (s, 3H), 3.35 (q, J ) 7.2 Hz, 2H), 3.44 (q, J )
7.2 Hz, 2H), 5.03 (s, 2H), 6.81(d, J ) 9.0 Hz, 2H), 7.07(d, J )
9.0 Hz, 2H); 13C NMR (CDCl3) δ 13.3, 15.2, 21.2, 40.3, 42.6,
71.2, 114.2, 129.7, 130.8, 154.9, 163.9, 195.0. Anal. Calcd for
C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.18; H, 7.96;
N, 5.34.
Preparation of N,N-Diethyl-2-oxo-3-phenoxypropanamide 5a
(LG- ) C6H5O-). The same method as that used for the synthesis
of N,N-diethyl-3-(4-methylphenoxy)-2-oxopropanamide 5a (LG-
) 4-CH3C6H4O-) was used to prepare 3.0 g (47% yield) of N,N-
diethyl-2-oxo-3-phenoxypropanamide 5a (LG- ) C6H5O-) from
4.7 g (27.1 mmol) of ethyl N,N-diethyloxamate and 5.0 g (32.0
mmol) of phenoxyacetic acid. The spectral data were as follows:
1H NMR (CDCl3) δ 1.17 (t, J ) 7.2 Hz, 3 H), 1.21 (t, J ) 7.2 Hz,
3 H), 3.33 (q, J ) 7.2 Hz, 2H), 3.43 (q, J ) 7.2 Hz, 2H), 5.05 (s,
2H), 6.91 (d, J ) 8.2 Hz, 1 H), 6.99 (t, J ) 8.0, 2.7 Hz, 1H), 7.28
(t, J ) 8.2 Hz, 1H); 13C NMR (CDCl3) δ 12.9, 14.8, 40.3, 42.5,
67.5, 128.7, 130.1, 133.7, 164.1, 166.2, 193.2. Anal. Calcd for
C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.09; H, 7.07;
N, 6.02.
khoP
kH
Φdis
)
+
(7)
kho + kH + kd kho + kH + kd
respective rate constants and kd is the rate constant for
radiationless decay of the reactive excited state. If P ≈ ΦH,
then Φdis will remain essentially constant even when homolysis
occurs at a very much faster rate than hydrogen transfer. From
Table 5 the ΦH values for 5a,b are ca. 0.3. For P ) 0.3, Φdis
will be essentially constant at 0.3, whereas for P much larger
than 0.3, Φdis will increase as kho increases relative to kH and
kd, and for P much less that 0.3, Φdis will decrease as kho
increases.
It is possible that ArO-C homolysis involves an intramo-
lecular electron transfer from the easily oxidized para-substituted
phenoxy groups (Y ) CH3 and OCH3), which would produce
an anion radical/cation radical intermediate (Scheme 7). The
electron transfer from the phenolic group would be energetically
feasible. This step could be exergonic by 10-14 kcal mol-1
for 5a,b (Y ) CH3, OCH3) in CH3CN, based on our measured
reduction potential of N,N-diethyl-2-oxopropanamide of -1.85
V in CH3CN (SCE) and the oxidation potentials of 1,4-
CH3C6H4OCH3 (1.52 V, SCE18a) and 1,4-CH3OC6H4OCH3 (1.34
V vs SCE18b) as model compounds. The estimate uses an excited
state energy of 79 kcal mol-1, which would be the 1n,π* excited
state of pyruvamide.19 The multiplicity of the reactive excited
state in R-keto amide photochemistry is not known for certain.9
If the lowest 3n,π* (pyruvamide, ET ) ca. 67-69 kcal mol-1 19
)
is instead involved, then ∆G° ) -2 to 0 or -2 to -4 kcal
mol-1 for Y ) CH3 and OCH3, respectively.
Conclusion
Photolyses of 5a,b with a variety of phenolic leaving groups,
4-YC6H4O-, in aqueous CH3CN results in photoelimination of
Preparation of N,N-Diethyl-3-(4-methoxyphenoxy)-2-oxopro-
panamide 5a (LG- ) 4-CH3OC6H4O-). The same method as that
used for the synthesis of N,N-diethyl-3-(4-methylphenoxy)-2-
oxopropanamide 5a (LG- ) 4-CH3C6H4O-) was used to prepare
5.0 g (56% yield) of R-keto amide 5a (LG- ) 4-CH3OC6H4O-)
(18) (a) Dileesh, S.; Gopidas, K. R. J. Photochem. Photobiol., A 2004,
162, 115-120. (b) Rathore, R.; Kochi, J. K. AdV. Phys. Org. Chem. 2000,
35, 193-317.
(19) Larson, Donald B.; Arnett, J. F.; Seliskar, C. J.; McGlynn, S. P. J.
Am. Chem. Soc. 1974, 96, 3370-3380.
4212 J. Org. Chem., Vol. 71, No. 11, 2006

CleaVage and Release of Para-Substituted Phenols
from 6.5 g (37.5 mmol) of ethyl N,N-diethyloxamate and 8.0 g
(43.9 mmol) of p-methoxyphenoxyacetic acid. The product was a
colorless oil. The spectral data were as follows: 1H NMR (CDCl3)
δ 1.21 (t, J ) 7.2 Hz, 3H), 1.23 (t, J ) 7.2 Hz, 3H), 3.34 (q, J )
7.2 Hz, 2H), 3.45 (q, J ) 7.2 Hz, 2H), 3.77 (s, 3H), 5.01 (s, 2H),
6.84 (m, 4H); 13C NMR (CDCl3) δ 13.4, 15.2, 40.4, 42.7, 56.1,
72.0, 114.5, 115.6, 151.3, 154.0, 164.0, 195.2. Anal. Calcd for
C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.36; H, 7.53;
N, 5.10.
Preparation of N,N-Diethyl-3-(4-cyanophenoxy)-2-oxopro-
panamide 5a (LG- ) 4-CNC6H4O-). The same method as that
used for the synthesis of N,N-diethyl-3-(4-methylphenoxy)-2-
oxopropanamide 5a (LG- ) 4-CH3C6H4O-) was used to prepare
6.6 g (56% yield) of R-keto amide 5a (LG- ) 4-CNC6H4O-) from
7.8 g (45.1 mmol) of ethyl N,N-diethyloxamate and 9.8 g (55.0
mmol) of p-cyanophenoxyacetic acid.20 The product was obtained
as a colorless solid, mp 77-79 °C after MPLC, eluting with 50%
EtOAc in hexane. The spectral data were as follows: 1H NMR
(CDCl3) δ 1.21 (t, J ) 7.2 Hz, 3H), 1.23 (t, J ) 7.2 Hz, 3H), 3.39
(q, J ) 7.2 Hz, 2H), 3.46 (q, J ) 7.2 Hz, 2H), 5.18 (s, 2H), 6.98
(d, J ) 8.7 Hz, 2H), 7.61 (d, J ) 8.7 Hz, 2H); 13C NMR (CDCl3)
δ 12.9, 14.9, 40.6, 42.6, 70.9, 105.4, 115.4, 119.0, 134.3, 160.9,
163.7, 193.7. Anal. Calcd for C14H16N2O4: C, 64.60; H, 6.19; N,
10.76. Found: C, 64.39; H, 6.23; N, 10.59.
Preparation of N,N-Diethyl-3-(4-trifluoromethylphenoxy)-2-
oxapropanamide 5a (LG- ) 4-CF3C6H4O-). The same method
as that used for the synthesis of N,N-diethyl-3-(4-methylphenoxy)-
2-oxopropanamide 5a (LG- ) 4-CH3C6H4O-) was used to prepare
4.5 g (80% yield) of R-keto amide 5a (LG- ) 4-CF3C6H4O-) from
3.9 g (22.5 mmol) of ethyl N,N-diethyloxamate and 5.0 g (29.4
mmol) of p-trifluoromethylphenoxyacetic acid.21 The product was
a colorless oil, after MPLC, eluting with 50% EtOAc in hexane.
The spectral data were as follows: 1H NMR (CDCl3) δ 1.20(t, J
) 6.9 Hz, 3H), 1.22 (t, J ) 7.2 Hz, 3H), 3.37 (q, J ) 6.9 Hz, 2H),
3.45 (q, J ) 7.2 Hz, 2H), 5.14 (s, 2H), 6.98 (d, J ) 9.0 Hz, 2H),
7.54 (d, J ) 9.0 Hz, 2H); 13C NMR (CDCl3) δ 12.8, 14.8, 40.4,
42.5, 70.9, 115.0, 124.1 (q, J ) 32.7 Hz, 1C), 124.3 (q, J ) 269.1
Hz, 1C), 127.2 (q, J ) 3.8 Hz, 1C), 160.0, 164.0, 194.4. Anal.
Calcd for C14H16F3NO3: C, 55.45; H, 5.32; N, 4.62. Found: C,
55.40; H, 5.39; N, 4.45.
Preparation of N,N-Diisopropyl-2-oxo-3-phenoxypropana-
mide 5b (LG- ) C6H5O-).12 The same method as that used for
the synthesis of N,N-diethyl-3-(4-methylphenoxy)-2-oxopropana-
mide 5a (LG- ) 4-CH3C6H4O-) was used to prepare 1.4 g (yield
30%) of N,N-diisopropyl-3-phenoxy-2-oxopropanamide 5b (LG-
) C6H5O-) from 3.6 g (18 mmol) of N,N-diisopropyloxamate and
3.0 g (20 mmol) of phenoxyacetic acid. The product was obtained
as a colorless oil after MPLC, eluting with 10% EtOAc in hexane.
The spectral data were as follows: 1H NMR (CDCl3) δ 1.18 (d, J
) 7.2 Hz, 6H), 1.50 (d, J ) 7.2 Hz, 6H), 3.50 (septet, J ) 7.2 Hz,
1H), 3.78 (septet J ) 7.2 Hz, 1H), 4.96 (s, 2H), 6.92 (d, J ) 8.5
Hz, 1H), 6.98 (t, J ) 8.0 Hz, 1H), 7.30 (t, J ) 8.2 Hz, 1H); 13C
NMR (CDCl3) δ 20.4, 20.9, 46.4, 50.3, 70.7, 114.6, 122.0, 129.8,
157.6, 165.7, 196.4. Anal. Calcd for C15H21NO3: C, 68.41; H, 8.04;
N, 5.32. Found: C, 68.48; H, 8.15; N, 5.10.
1H NMR (CDCl3) δ 1.19(d, J ) 7.2 Hz, 6H), 1.45 (d, J ) 7.2 Hz,
6H), 3.53 (septet, J ) 7.2 Hz, 1H), 3.76 (s, 3H), 3.79 (septet J )
7.2 Hz, 1H), 4.87 (s, 2H), 6.84 (m, 4H); 13C NMR (CDCl3) δ 20.4,
21.0, 49.4, 50.3, 55.9, 71.6, 114.9, 115.7, 151.9, 154.6, 165.9, 196.8.
Anal. Calcd for C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found:
C, 65.76; H, 8.21; N, 4.52.
Preparation of N,N-Diisopropyl-3-(4-methylphenoxy)-2-oxo-
propanamide 5b (LG- ) 4-CH3C6H4O-). The same method as
that used for the synthesis of N,N-diethyl-3-(4-methylphenoxy)-2-
oxopropanamide 5a (LG- ) 4-CH3C6H4O-) was used to prepare
6.1 g (73% yield) of R-keto amide 5b (LG- ) 4-CH3C6H4O-) from
6.0 g (30.0 mmol) of ethyl N,N-diisopropyloxamate and 5.8 g (35.0
mmol) of p-methylphenoxyacetic acid. The product was obtained
as a colorless solid, mp 80-82 °C, after MPLC, eluting with 10%
EtOAc in hexane. The spectral data were as follows: 1H NMR
(CDCl3) δ 1.18 (d, J ) 7.2 Hz, 6H), 1.46 (d, J ) 7.2 Hz, 6H),
2.28 (s, 3H), 3.52 (septet, J ) 7.2 Hz, 1H), 3.79 (septet J )
7.2 Hz, 1H), 4.89 (s, 2H), 6.81 (d, J ) 8.4 Hz, 2H), 7.08 (d,
J ) 8.4 Hz, 2H); 13C NMR (CDCl3) δ 20.4, 20.8, 20.9, 46.4, 50.3,
71.0, 114.5, 130.2, 131.3, 155.6, 165.8, 196.7. Anal. Calcd for
C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.55; H, 8.43;
N, 4.95.
Preparation of N,N-Diisopropyl-3-(4-cyanophenoxy)-2-oxo-
propanamide 5b (LG- ) 4-CNC6H4O-). The same method as
that used for the synthesis of N,N-diethyl-3-(4-methylphenoxy)-2-
oxopropanamide 5a (LG- ) 4-CH3C6H4O-) was used to prepare
4.6 g (76% yield) of R-keto amide 5b (LG- ) 4-CNC6H4O-) from
4.2 g (21.0 mmol) of ethyl N,N-diisopropyloxamate and 4.2 g (24.0
mmol) of p-cyanophenoxyacetic acid.20 The product was obtained
as a colorless solid, mp 79-82 °C, after MPLC, eluting with 50%
EtOAc in hexane. The spectral data were as follows: 1H NMR
(CDCl3) δ 1.21 (d, J ) 7.2 Hz, 6H), 1.44 (d, J ) 7.2 Hz, 6H),
3.55 (septet, J ) 7.2 Hz, 1H), 3.83 (septet, J ) 7.2 Hz, 1H), 5.03
(s, 2H), 6.98 (d, J ) 8.4 Hz, 2H), 7.60 (d, J ) 8.4 Hz, 2H); 13C
NMR (CDCl3) δ 20.4, 21.0, 47.2, 50.3, 70.7, 105.5, 115.4, 119.0,
134.3, 160.8, 165.2, 194.4. Anal. Calcd for C16H22N2O3: C, 66.18;
H, 7.63; N, 9.65. Found: C, 66.40; H, 7.36; N, 9.59.
Preparation of N,N-Diisopropyl-3-benzyloxy-2-oxopropana-
mide 19. The same method as that used for the synthesis of 5a
(LG- ) 4-CH3C6H4O-) was used to prepare 4.7 g (74% yield) of
R-keto amide 19 from 3.9 g (19.0 mmol) of N,N-diisopropyloxamate
and 3.8 g (23.0 mmol) of benzyloxyacetic acid.22 The product was
a colorless oil. The spectral data were as follows: 1H NMR (CDCl3)
δ 1.17 (d, J ) 6.6 Hz, 6H), 1.43 (d, J ) 6.9 Hz, 6H), 3.49 (septet,
J ) 7.2 Hz, 1H), 3.72 (septet, J ) 7.2 Hz, 1H), 4.39 (s, 2H), 4.64
(s, 2H), 7.33 (m, 5H); 13C NMR (CDCl3) δ 20.3, 20.9, 46.2, 50.1,
73.0, 74.1, 128.0, 128.1, 128.5, 137.0, 166.5, 198.5. Anal. Calcd
for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.20; H,
8.44; N, 4.83.
Preparative Photolyses of r-Keto Amides 5a (LG- ) C6H5O-,
4-CNC6H4O-, 4-F3CC6H4O-) in Aqueous CH3CN. A solution
of 0.86 g (3.6 mmol) of 5a (LG- ) C6H5O-) in 25 mL of 33%
aqueous acetonitrile in a quartz tube was irradiated through a Pyrex
filter with a Hanovia 450 W medium-pressure mercury lamp for 2
h at room temperature. NMR analysis of an aliquot showed over
70-90% conversion. The photolyzate was extracted three times
with ethyl acetate. After concentration in vacuo the oxazolidinone
7a, diastereomeric hemiacetals 6a, and the phenol were isolated
by MPLC, eluting with 10% EtOAc in hexane (Table 1). A similar
procedure was used for the photolyses of 5a (LG- ) 4-CNC6H4O-,
4-CF3C6H4O-).
Preparation of N,N-Diisopropyl-3-(4-methoxyphenoxy)-2-
oxopropanamide 5b (LG- ) 4-CH3OC6H4O-). The same method
as that used for the synthesis of N,N-diethyl-3-(4-methylphenoxy)-
2-oxopropanamide 5a (LG- ) 4-CH3C6H4O-) was used to prepare
5.7 g (78% yield) of R-keto amide 5b (LG- ) 4-CH3OC6H4O-)
from 5.0 g (25.0 mmol) of ethyl N,N-diisopropyloxamate and 5.2
g (28.6 mmol) of p-methoxyphenoxyacetic acid. The product was
a obtained as a colorless solid, mp 56-57 °C, by MPLC, eluting
with 10% EtOAc in hexanes. The spectral data were as follows:
Preparative Photolyses of r-Keto Amides 5a (LG-
)
4-CH3OC6H4O-, 4-CH3C6H4O-) in Aqueous CH3CN. A solution
of 4.0 mmol of 5a (LG- ) 4-CH3OC6H4O- or 4-CH3C6H4O-) in
25 mL of 33% aqueous acetonitrile in a quartz tube was irradiated
through a Pyrex filter with a Hanovia 450 W medium-pressure
mercury lamp for 3 h at room temperature. The photolyzate was
(20) Hayes, N. V.; Branch, G. E. K. J. Am. Chem. Soc. 1943, 65, 1555-
1564.
(21) Hansch, C.; Muir, R. M.; Fujita, T.; Maloney, P. P.; Geiger, F.;
Streich, M. J. Am. Chem. Soc. 1963, 85, 2817-2824.
(22) Benington, F.; Morin, R. D. J. Org. Chem. 1961, 26, 194-197.
J. Org. Chem, Vol. 71, No. 11, 2006 4213

Ma et al.
extracted three times with ethyl acetate and concentrated in vacuo.
Only a trace amount of oxazolidinone 7a and the para-substituted
phenol were isolated by MPLC, eluting with 10% EtOAc in hexane.
The major products isolated were 1,3-rearrangement products 12a
(Y ) CH3O, CH3), which were colorless oils that readily underwent
further oxidation to 16a (Y ) CH3O, CH3). The spectral data of
12a (Y ) CH3O) were as follows: 1H NMR (CDCl3) δ 1.08 (t, J
) 7.2 Hz, 3H), 1.11 (t, J ) 7.2 Hz, 3H), 3.27 (q, J ) 7.2 Hz, 2H),
3.36 (q, J ) 7.2 Hz, 2H), 3.74 (s, 3H), 3.95 (s, 2H), 6.68 (d, J )
3.0 Hz, 1H), 6.74 (dd, J ) 3.0, 8.7 Hz, 1H), 6.88 (d, J ) 8.7 Hz,
1H), 7.46 (br, 1H); 13C NMR (CDCl3) δ 12.7, 14.8, 41.1, 42.7,
42.9, 56.1, 115.1, 116.3, 119.5, 120.5, 148.9, 154.0, 166.3, 196.4.
The spectral data of 12a (Y ) CH3) were as follows: 1H NMR
(CDCl3) δ 1.10 (t, J ) 7.2 Hz, 3H), 1.11 (t, J ) 7.2 Hz, 3H), 2.25
(s, 3H), 3.27 (q, J ) 7.2 Hz, 2H), 3.37 (q, J ) 7.2 Hz, 2H), 3.94
(s, 2H), 6.82 (d, J ) 8.1 Hz, 1H), 6.95 (s, 1H), 6.98 (d, J ) 8.1
Hz, 1H), 7.62 (br, 1H); 13C NMR (CDCl3) δ 12.6, 14.6, 40.8, 42.3,
42.8, 117.9, 119.2, 130.1, 130.4, 132.0, 152.6, 166.4, 196.8.
In solution, compound 12a (Y ) CH3) was slowly oxidized in
air to form 16a (Y ) CH3), which was obtained as a colorless
solid, mp 140-143 °C, after MPLC, eluting with 50% EtOAc in
hexanes. The spectral data of 16a (Y ) CH3) were as follows: 1H
NMR (CDCl3) δ 0.99 (t, J ) 7.2 Hz, 3H), 1.20 (t, J ) 7.2 Hz,
3H), 2.38 (s, 3H), 2.84 (q, J ) 7.2 Hz, 1H), 2.91 (q, J ) 7.2 Hz,
1H), 3.43 (dq, J ) 14.0, 7.2 Hz, 1H), 3.49 (dq, J ) 14.0, 7.2 Hz,
2H), 7.03 (s, OH), 7.04 (dd, J ) 0.9, 8.1 Hz, 1H), 7.49 (dd, J )
8.1, 0.9 Hz, 1H), 7.51(s, 1H); 13C NMR (CDCl3) δ 12.7, 13.5, 21.0,
42.8, 42.3, 98.2, 113.5, 118.9, 124.9, 133.9, 140.4, 164.7, 168.9,
195.4. MS (m/z) 263 (0.44), 235 (1.5), 163 (4.5), 135 (16.5), 100
(100), 72 (73.1), 78 (12.1), 44 (21.1). Anal. Calcd for C14H17NO4:
C, 63.86, H, 6.51; N, 5.32. Found: C, 63.62; H, 6.59; N, 5.14.
In solution, compound 12a (Y ) CH3O) was slowly oxidized in
air to form 16a (Y ) CH3O), which was obtained as a colorless
solid, mp 120-122 °C, after MPLC, eluting with 50% EtOAc in
hexane. The spectral data of 16a (Y ) CH3O) were as follows:
1H NMR (CDCl3) δ 1.00 (t, J ) 7.2 Hz, 3H), 1.20 (t, J ) 7.2 Hz,
3H), 2.85 (q, J ) 7.2 Hz, 1H), 2.92 (q, J ) 7.2 Hz, 1H), 3.43 (dq,
J ) 14.0, 7.2 Hz, 1H), 3.49 (dq, J ) 14.0, 7.2 Hz, 1H), 3.83 (s,
3H), 7.04 (s, OH), 7.06 (d, J ) 8.7 Hz, 1H), 7.12 (d, J ) 3.0 Hz,
1H), 7.30 (dd, J ) 3.0, 8.7 Hz, 1H); 13C NMR (CDCl3) δ 12.7,
13.5, 42.3, 42.8, 56.2, 98.7, 105.5, 114.8, 118.9, 128.7, 155.8, 164.4,
165.7, 195.6. MS (m/z) 279, 251, 179, 151, 108, 100 (100), 79, 72.
Anal. Calcd for C14H17NO5: C, 60.21, H, 6.13; N, 5.01. Found:
C, 60.35; H, 6.16; N, 5.14.
mL of 33% aqueous acetonitrile in a quartz tube was irradiated
through a Pyrex filter with a Hanovia 450 W medium-pressure
mercury lamp for 2 h at room temperature. The photolyzate was
extracted three times with EtOAc. After concentration in vacuo,
the oxazolidinone 20 was isolated as a colorless oil by MPLC,
eluting with 10% EtOAc in hexane. The spectral data were as
follows: 1H NMR (CDCl3) δ 1.42 (d, J ) 7.2 Hz, 3 H), 1.44 (s, 3
H), 1.45 (d, J ) 7.2 Hz, 3 H), 1.49 (s, 3 H), 3.36 (septet, J ) 7.2
Hz, 1 H), 3.69 (dd, J ) 5.1, 10.5 Hz, 1 H), 3.77 (dd, J ) 2.4, 10.5
Hz, 1 H), 4.39 (dd, J ) 2.4, 5.1 Hz, 1 H), 4.55 (d, J ) 12.3 Hz, 1
H), 4.63 (d, J ) 12.3 Hz, 1 H), 7.31 (m, 5 H); 13C NMR (CDCl3)
δ 20.2, 20.5, 27.1, 27.5, 49.1, 70.3, 70.6, 76.8, 95.2, 127.6, 127.6,
128.3, 138.1, 168.2. Anal. Calcd for C16H23NO3: C, 69.29; H, 8.36;
N, 5.05. Found: C, 68.90; H, 8.08; N, 5.05.
Preparative Photolysis of r-Keto Amide 5a (LG- ) C6H5O-)
in CH3CN. A solution of 1.0 g (4.25 mmol) of 5a (LG- ) C6H5O-)
in 30 mL of CH3CN in a quartz tube mounted beside a water-
jacketed Hanovia 450 W medium-pressure mercury lamp was
irradiated through a Pyrex filter for several hours at room
temperature until no starting material remained. The photolyzate
was concentrated in vacuo. MPLC of the residue, eluting with 10%
EtOAc in hexane, gave a major diastereomer of a photoproduct
containing a minor diastereomer, which eluted in the leading edge
of the peak. The major diastereomer was rechromatographed five
times, cutting the leading edge of the peak each time, to obtain
0.26 g (26% yield) of pure major diastereomer of the cyclization
product 13a (LG- ) C6H5O-) as colorless crystals, mp 63.0-64.5
°C. The minor diastereomer was rechromatographed six times,
cutting the trailing edge of the peak each time, to obtain 60 mg
(6.0% yield) of NMR pure minor diastereomer of the cyclization
product as an oil.
The spectral data of the major diastereomer of the cyclization
product 13a (LG- ) C6H5O-) were as follows: 1H NMR (CDCl3)
δ 1.18 (t, J ) 7.2 Hz, 3 H), 1.48 (d, J ) 5.4 Hz, 3 H), 3.20 (m, 1
H), 3.58 (m, 1 H), 4.24 (m, 1H), 4.58 (m, 1H), 5.31 (m, 1H), 6.91
(d, J ) 9.0 Hz, 2H), 6.93 (t, J ) 9.0 Hz, 1H), 7.25 (t, J ) 9.0 Hz,
2H); 13C NMR (CDCl3) δ 13.4, 21.4, 35.0, 67.9, 77.4, 87.0, 114.8,
121.2, 129.5, 158.5, 168.1. Anal. Calcd for C13H17 NO3: C, 66.36;
H, 7.28; N, 5.95. Found: C, 66.23 H, 7.28; N, 5.98.
The spectral data of the minor diastereomer of the cyclization
product 13a (LG- ) C6H5O-) were as follows: 1H NMR (CDCl3)
δ 1.19 (t, J ) 7.2 Hz, 3 H), 1.44 (d, J ) 5.4 Hz, 3 H), 3.11(m, 1
H), 3.67 (m, 1 H), 4.27 (d, J ) 3.0 Hz, 2 H), 4.66(q, J ) 3.0 Hz,
1H), 5.43 (m, 1H), 6.86 (d, J ) 9.0 Hz, 2H), 6.93 (t, J ) 9.0 Hz,
1H), 7.25 (t, J ) 9.0 Hz, 2H); 13C NMR (CDCl3) δ 13.1, 21.2,
35.0, 68.5, 77.0, 87.6, 114.7, 121.3, 129.5, 158.4, 168.7.
Preparative Photolysis of r-Keto Amide 5b (LG-
)
4-CH3OC6H4O-, 4-CH3C6H4O-) in Aqueous CH3CN. A solution
of 3.0 mmol of 5b (LG- ) 4-CH3OC6H4O-, 4-CH3C6H4O-) in 25
mL of 33% aqueous acetonitrile in a quartz tube was irradiated
through a Pyrex filter with a Hanovia 450 W medium-pressure
mercury lamp for 3 h at room temperature. For 5b (4-CH3C6H4O-),
the photolyzate was extracted three times with ethyl acetate and
concentrated in vacuo. The major product, oxazolidinone 7b, and
4-CH3C6H4OH were isolated by MPLC. A small amount of 12b
(Y ) CH3) was obtained, which could not be further purified by
MPLC. For 5b (LG- ) 4-CH3OC6H4O-) the major product was
the 1,3-rearrangement product 12b (Y ) CH3O), which was
obtained as a colorless oil by MPLC, eluting with 10% ethyl acetate
in hexane. The spectral data of 12b (Y ) CH3O) were as follows:
1H NMR (CDCl3) δ 0.99 (d, J ) 6.9 Hz, 6H), 1.32 (d, J ) 6.9 Hz,
6H), 3.38 (septet, J ) 6.9 Hz, 1H), 3.74 (s, 3H), 3.76 (septet J )
6.9 Hz, 1H), 3.91 (s, 2H), 6.66 (d, J ) 3.0 Hz, 1H), 6.76 (dd,
J ) 3.0, 8.7 Hz, 1H), 6.91 (d, J ) 8.7 Hz, 1H), 7.02 (br s,
1 H); 13C NMR (CDCl3) δ 20.1, 20.7, 42.5, 46.7, 50.5, 56.0, 115.2,
116.2, 120.0, 120.5, 148.7, 154.2, 168.2, 196.5. Anal. Calcd for
C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C, 65.15; H, 7.72;
N, 4.78.
Preparative Photolysis of r-Keto Amide 5b (LG- ) C6H5O-)
in CH3CN. A solution of 1.2 g (4.56 mmol) of 5b (LG- ) C6H4O-)
in 30 mL of CH3CN in a quartz tube mounted beside a water-
jacketed Hanovia 450 W medium-pressure mercury lamp was
irradiated through a Pyrex filter for several hours at room
temperature. The photolyzate was concentrated in vacuo. MPLC
of the residue eluting with 20% EtOAc in hexane gave unreacted
5b (LG- ) C6H5O-) together with methyleneoxazolidinone 7b,
followed by 0.27 g (23% yield) of NMR pure cyclization product
13b (LG- ) C6H5O-) as an oil.
The spectral data of cyclization product 13b (LG- ) C6H5O-)
were as follows: 1H NMR (CDCl3) δ 1.62 (s, 3 H), 1.64 (s, 3 H),
1.73 (s, 3 H), 1.84 (s, 3 H), 3.92 (m, 1H), 4.54 (s, 2 H, in CD3CN,
m), 7.16 (d, J ) 7.2 Hz, 2H), 7.24 (d, J ) 7.2 Hz, 1H), 7.63 (t, J
) 7.2 Hz, 2H); 13C NMR (CDCl3) δ 21.9, 22.1, 23.3, 44.2, 66.2,
67.8, 85.0, 114.7, 121.5, 129.6, 158.4, 167.6.
Preparative Photolysis of r-Keto Amide 5a (LG-
)
4-CNC6H5O-) in C6H6. A solution of 0.30 g (1.2 mmol) of 5a
(LG- ) 4-CN C6H5O-) in 20 mL of C6H6 in a quartz tube mounted
beside a water-jacketed Hanovia 450 W medium-pressure mercury
lamp was irradiated through a Pyrex filter for several hours at room
temperature until no starting material remained. The photolyzate
was concentrated in vacuo. MPLC of the residue, eluting with 50%
Preparative Photolysis of N,N-Diisopropyl-3-benzyloxy-2-
oxopropanamide 19 (LG- ) C6H5CH2O-) in Aqueous CH3CN.
A solution of 0.5 g (3.6 mmol) of 19 (LG- ) C6H5CH2O-) in 25
4214 J. Org. Chem., Vol. 71, No. 11, 2006

CleaVage and Release of Para-Substituted Phenols
EtOAc in hexane, gave 0.10 g (33% yield) of pure cyclization
6.9 Hz, 3 H), 1.46 (d, J ) 6.9 Hz, 3 H), 1.47 (s, 3 H), 1.50 (s, 3
H), 3.43 (m, 2H), 4.54 (m, 1 H), 6.91 (d, J ) 9.0 Hz, 2H), 7.50 (d,
J ) 9.0 Hz, 2H); 13C NMR (CDCl3) δ 20.1, 20.5, 27.2, 27.5, 46.4,
68.4, 75.8, 95.8, 104.6, 115.6, 119.3, 134.2, 162.0, 167.3.
product 13a (LG- ) 4-CNC6H5O-) as colorless liquid.
The spectral data of the cyclization product 13a (LG-
)
4-CNC6H5O-) were as follows: 1H NMR (CDCl3) δ 1.19 (t, J )
7.2 Hz, 3 H), 1.46 (d, J ) 5.1 Hz, 3 H), 3.21 (m, 1 H), 3.58 (m,
1 H), 4.29 (m, 1H), 4.59(m, 1H), 5.32 (m, 1H), 6.97 (d, J ) 9.0
Hz, 2H), 7.57 (d, J ) 9.0 Hz, 2 H); 13C NMR (CDCl3) δ 13.2,
21.3, 35.1, 68.0, 77.1, 87.0, 104.8, 115.6, 119.2, 134.2, 161.9, 167.8.
Acknowledgment. We thank Ms. Erica Kopatz and Prof.
Rajendra Rathore for assistance with the nanosecond laser
flash photolysis experiments and determination of reduction
potential of N,N-diethyl 2-oxopropanamide. Acknowledgment
is made to the donors of the Petroleum Research Fund,
administered by the American Chemical Society, for support
of this research.
Preparative Photolysis of r-Keto Amide 5b (LG-
)
4-CNC6H4O-) in CH2Cl2. A solution of 0.80 g (2.77 mmol) of
5b (LG- ) 4-CNC6H4O-) in 20 mL of CH2Cl2 in a quartz tube
mounted beside a water-jacketed Hanovia 450 W medium-pressure
mercury lamp was irradiated through a Pyrex filter for several hours
at room temperature. The photolyzate was concentrated in vacuo.
MPLC of the residue eluting with 60% EtOAc in hexane gave, in
order of elution, unreacted starting material 5b (LG- ) 4-CNC6H4O-)
together with methyleneoxazolidinone 7b, followed by 0.16 mg
Supporting Information Available: 1H, 13C NMR spectral data
for major and minor diastereomers of 13a (LG- ) C6H5O-), 13b
(LG- ) C6H5O-) in CD3CN and CDCl3, and 13a,b (LG-
)
4-CNC6H4O-). This material is available free of charge via the
Internet at http://pubs.acs.org.
(20% yield) of NMR pure cyclization product 13b (LG-
4-CNC6H4O-) as an oil.
)
The spectral data of the cyclization product 13b (LG-
)
4-CNC6H4O-) were as follows: 1H NMR (CDCl3) δ 1.44 (d, J )
JO060338X
J. Org. Chem, Vol. 71, No. 11, 2006 4215