Stereochemically probing the photo-favorskii rearrangement: A mechanistic investigation

Article abstract of DOI:10.1021/jo301640q

Using model (R)-2-acetyl-2-phenyl acetate esters of (S)- or (R)-α-substituted-p-hydroxybutyrophenones (S,R)-12a and (R,R)-12b, we have shown that a highly efficient photo-Favorskii rearrangement proceeds through a series of intermediates to form racemic rearrangement products. The stereogenic methine on the photoproduct, rac-2-(p-hydroxyphenyl)propanoic acid (rac-9), is formed by closure of a phenoxy-allyloxy intermediate 17 collapsing to a cyclopropanone, the Favorskii intermediate 18. These results quantify the intermediacy of a racemized triplet biradical ³16 on the major rearrangement pathway elusively to the intermediate 18. Thus, intersystem crossing from the triplet biradical surface to the ground state generates a planar zwitterion prior to formation of a Favorskii cyclopropanone that retains no memory of its stereochemical origin. These results parallel the mechanism of Dewar and Bordwell for the ground state formation of cyclopropanone 3 that proceeds through an oxyallyl zwitterionic intermediate. The results are not consistent with the stereospecific S_N2 ground state Favorskii mechanism observed by Stork, House, and Bernetti. Interconversion of the diastereomeric starting esters of (S,R)-12a and (R,R)-12b during photolysis did not occur, thus ruling out leaving group return prior to rearrangement.

Full text of DOI:10.1021/jo301640q

Article
pubs.acs.org/joc
Stereochemically Probing the Photo-Favorskii Rearrangement:
A Mechanistic Investigation
Richard S. Givens,* Marina Rubina, and Kenneth F. Stensrud
Department of Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, 5010 Malott Hall, Lawrence, Kansas 66045,
United States
S
* Supporting Information
ABSTRACT: Using model (R)-2-acetyl-2-phenyl acetate esters of (S)- or (R)-α-substituted-p-
hydroxybutyrophenones (S,R)-12a and (R,R)-12b, we have shown that a highly efficient
photo-Favorskii rearrangement proceeds through a series of intermediates to form racemic
rearrangement products. The stereogenic methine on the photoproduct, rac-2-(p-hydroxyphenyl)-
propanoic acid (rac-9), is formed by closure of a phenoxy-allyloxy intermediate 17 collapsing
to a cyclopropanone, the “Favorskii” intermediate 18. These results quantify the intermediacy
3
of a racemized triplet biradical 16 on the major rearrangement pathway elusively to the
intermediate 18. Thus, intersystem crossing from the triplet biradical surface to the ground
state generates a planar zwitterion prior to formation of a Favorskii cyclopropanone that retains
no memory of its stereochemical origin. These results parallel the mechanism of Dewar and
Bordwell for the ground state formation of cyclopropanone 3 that proceeds through an oxyallyl
zwitterionic intermediate. The results are not consistent with the stereospecific SN2 ground
state Favorskii mechanism observed by Stork, House, and Bernetti. Interconversion of the
diastereomeric starting esters of (S,R)-12a and (R,R)-12b during photolysis did not occur, thus ruling out leaving group return
prior to rearrangement.
Nevertheless, 3 serves as the necessary bridge between the
structure of the pHP chromophore in 1 and its photoproducts,
p-hydroxyphenylacetic acid (4) and p-hydroxybenzyl alcohol
(6). Phenylacetic acid 4 is formed from hydrolysis of 3, whereas
decarbonylation forms 5 (a p-methylenequinone) that hydro-
lyzes to p-hydroxybenzyl alcohol 6.5b,7 However, evidence for
intermediate 2 and its subsequent conversion to 3 is incomplete
and circumstantial, leading others to propose alternative mecha-
INTRODUCTION
■
The p-hydroxyphenacyl (pHP) chromophore has been
established as a clean, efficient photoremovable protecting
group (PPG) for nucleofuges such as phosphates, sulfonates,
carboxylates, and certain thiols and phenols.1,2 The chromo-
phore imparts good hydrophilicity, excellent biological compat-
ibility, and relatively easy installation of the protected moiety. In
aqueous media, the photorelease is accompanied by rearrange-
ment of the chromophore, originally described as a photo-
Favorskii rearrangement by Reese and Anderson,3 that results in
a dramatic hypsochromic shift in its absorption spectrum. The
release of the leaving groups occurs rapidly (kr = 108−109 s−1) in
quantitative chemical yield, and the quantum yields approach
1.0. Together, these properties have encouraged us and others
to investigate further applications2 including the new chemical
transformations such as ring contraction reactions.4 In turn,
there has been a renewed interest in the mechanism of the
photo-Favorskii rearrangement itself.1,5,6
5c,6a−g
3
nisms that either bypassed the biradical 2 intermediate
or, in at least one report,6h completely disregarded the Favorskii
cyclopropanone 3 altogether.
The stereochemical integrity of the migrating methylene
group should serve as a quantitative measure by the degree of
racemization resulting from formation of a racemic intermediate
such as biradical 2. Indeed, stereochemistry has often been
employed in mechanistic investigations for both ground state
and photochemical rearrangements as documented, for example,
in the earlier work of Zimmerman’s studies of the Type A
photorearrangements of dienones.8 Rrelevant examples are
studies of the stereochemistry of the ground state Favorskii
rearrangement extensively examined by House,9 Sorenson,10
Bernetti,11 and Bordwell.12 The seminal studies by Loftfield13 on
the 1,2-carbon migration later challenged by Dewar’s theoretical
treatment14 now serve as the two limiting mechanisms for the
base-promoted Favorskii rearrangement. Loftfield’s one-step
Controversy surrounds the extent to which two transient
intermediates, the triplet biradical 2 and the spirodienone 3,
play a role in the photo-Favorskii rearrangement. The chrono-
logical sequence that we embraced for the photo-Favorskii
rearrangement (Scheme 1) includes 2 and 5, two detectable
3
3
transients using time-resolved (TR) transient absorption
spectroscopy.5b The earliest transient (λmax 445 and 455 nm)
has been assigned the structure of the triplet allyloxy-phenoxy
Special Issue: Howard Zimmerman Memorial Issue
biradical (32), which is formed from 1. It decays with a rate
3
constant of kbirad = 1.5 × 109 s−1 to form cyclopropanone 3, the
“Favorskii” intermediate,3 which has eluded detection thus far.
Received: August 16, 2012
Published: October 11, 2012
© 2012 American Chemical Society
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Scheme 1. General Mechanism for the Photo-Favorskii Rearrangement
Scheme 2. Loftfield and Dewar Limiting Mechanisms as Applied to Photolysis of pHP Homologues
concerted SN2 process contrasts with Dewar‘s two-step
preformation of an oxyallyl zwitterion intermediate prior to
cyclization by disrotatory closure15 to generate the Favorskii
cyclopropanone intermediate. While both mechanisms involve
the intermediacy of a cyclopropanone, the stereochemical con-
sequences of a migrating stereogenic carbon are clearly
distinguishable, and both limiting mechanisms have experimental
support.8−11,16−18
Synthesis and Assignment of Stereochemistry.
Enantiomerically pure (R)-2-acetoxyphenylacetic acid ((R)-11)
was reacted with α-bromo-p-hydroxybutyrophenone (rac-10)
through a SN2 displacement of bromide to provide the pair of
diastereomeric esters 12a,b as a 1:1 mixture (Scheme 3).21,22
Scheme 3. Synthethesis of Diastereomeric Isomers 12a and
12b
With this abundance of precedent of the limiting ground
state mechanisms, we were persuaded to pursue the stereo-
chemistry of the photochemically driven Favorskii rearrange-
ment. Our model employs a p-hydroxybutyrophenone equipped
with a chiral leaving group, thus providing us with a pair of
diastereomeric esters to test the stereochemical changes at the
migrating carbon.
Choice of the leaving group 11 served the dual purpose of
creating a pair of separable diastereomeric esters as well as
a direct, internal diagnostic for assigning the configuration of
the butyrophenone stereogenic center. The assignment of the
absolute configuration of each diastereomer23 was based on
the shielding effects of the (R)-11 aryl ring on identifiable
elements on the butyrophenone fragment. Using chemical
shift correlations analogous to those described by Trost for an
O-methylmandelate model24 (Figure 1), the configurations of
(S)-1-(4-hydroxyphenyl)-1-oxobutan-2-yl (R)-2-acetoxy-2-
phenylacetate for 12a and (R)-1-(4-hydroxyphenyl)-1-oxobutan-
2-yl (R)-2-acetoxy-2-phenylacetate for 12b were assigned.
Photochemistry. The 1:1 diastereomer mixture of 12a,b
(30 mmol in 0.6 mL of 4:1 CD3CN/D2O) was irradiated in an
NMR tube for 49 min to nearly complete conversion using a
Rayonet reactor equipped with two 15 W 300-nm lamps. Two
major products were detected by 1H NMR analysis of the crude
RESULTS AND DISCUSSION
■
A convenient framework for testing the two limiting Favorskii
rearrangement pathways is depicted in Scheme 2 using
p-hydroxybutyrophenone 7. The stereochemical integrity of
the migrating α-carbon (marked as ∗) was monitored by HPLC
1
(chiral stationary phase) and by H NMR.
Extension of the pHP aliphatic chain to p-hydroxybutyr-
ophenone raises the possibility of photochemical competition by
a Norrish Type II fragmentation instead of the photo-Favorskii
rearrangement.19 However, when the normally efficient Type II
reaction was pitted against the photo-Favorskii rearrangement
with a series of o-methyl pHP analogues, the Type II reaction
could be completely quenched by photolysis in solutions
containing >5% H2O, which gave exclusively photo-Favorskii
products. Solvents with less than 10% H2O yielded only Type II
products.20
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Figure 1. Fragments of 1H NMR chart of a diastereomeric mixture 12a and 12b. The intervening carboxyl groups on structures A and B are omitted
in order to emphasize the phenyl-aryl and phenyl-ethyl shielding interactions for the most stable rotamers of (S,R)-12a and (R,R)-12b, the major
contributors to the shielding effects for the chemical shift differences. The more shielded component (highlighted in blue) of each diastereomer is
shown to be eclipsed by the phenyl ring of 11 (shown in red).
Figure 2. 1H NMR spectra during photolysis of 12a. The arrows point to the stereogenic methine protons for the two minor (13 and 14) and the
major (9) products. See Figure 6 (Experimental Section) for the assignments.
reaction mixture, the chiral leaving group (R)-11 (100%) and
the rearranged 2-(4-hydroxyphenyl)butanoic acid25 (9, 82%).
Two minor products, 4-(1-hydroxypropyl)phenol (13, 7%)26
and 2-hydroxy-1-(4-hydroxyphenyl)butan-1-one (14, 3%), were
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Scheme 4. Photochemistry of (S)-1-(4-Hydroxyphenyl)-1-oxobutan-2-yl (R)-2-Acetoxy-2-phenylacetate ((S,R)-12a)
also detected and identified (Figure 2 and Figure 7, Experimental
Section). Hydroxy acid 14 is apparently formed by photo-
hydrolysis, whereas the benzyl alcohol 13, a ubiquitous minor
product in our studies, is formed from the photo-Favorskii
cyclopropanone 18. Decarbonylation of 18 gave 4-propoylide-
necyclohexa-2,5-dien-1-one (19), an analogue of p-methylene-
quinone (5, Scheme 2), which hydrolyzes to 13. No evidence for
competing Type II photoreaction of the butyrophenone was
observed as anticipated when H2O solvents are employed.19,20
The stereochemical consequences of the rearrangement
were assessed by irradiation of the individual diastereomers.
Photolysis of (S,R)-12a produced racemic α-arylbutanoic acid
(rac-9, see Supporting Information). Complete racemization
was confirmed for the reaction when diastereomeric (R,R)-12b
also gave only racemic products (Scheme 4).
Scheme 5. Photochemical Integrity of the Butyrophenone
Stereogenic Center of (S,R)-12a and (R,R)-12b.
1
In a control reaction monitored by H NMR, 12a was not
converted to its diastereomer 12b during photolysis, ruling out a
recombination reaction that would generate the diastereomeric
mixture of the esters (Figure 3), thus assuring the integrity of
Remaining fundamental questions are the nature of the ring
closure to cyclopropanone 3, which is not defined in Scheme 1,
and the origin of the hydroxyketone 14, which does not appear
in most treatments of the photo-Favorskii reaction mechanism.
Here we draw upon the Zimmerman paradigm developed in his
early work on the photorearrangement of 2,5-cyclohexadien-1-
one to bicycle[3.1.0]hexenone. He suggested that photochemical
reactions might be viewed as four common steps: (1) excitation,
(2) adiabatic bond alteration and (3) demotion or relaxation to
the ground state energy surface where (4) further bond alteration
is proceeding along a classical ground state surface to the final
photoproducts.8,27 Steps 2 and 4 are classical electron pushing
approaches toward defining a mechanism. We have applied the
approach to the photorearrangement of 12a,b and to our recent
study on photo-Favorskii ring contraction reaction of cyclic
analogue 20 shown together in Scheme 6.
Formation of cyclopropanone 18 (or 24) is a prohibitively
high energy process on the triplet excited state surface5b and is
spin forbidden; therefore, it must occur from a relaxed singlet
oxyallyl biradical (open shell) or closed shell counterpart, the
ground state Dewar zwitterion (Scheme 2). In ground state
Favorskii rearrangements where the Dewar mechanism obtains,
the reaction leads to complete loss of the stereochemical
integrity of the α-carbon. For our photo-Favorskii study, the
α-carbon is completely racemized at the final productstage, e.g.,
rac-9, thus quantifying the extent of involvement of the oxyallyl
biradical 16 intermediate. In our previous study, the transient
nature of the oxyallyl biradical limited our assessment of its
relative significance as an intermediate in the formation of the
phenylacetic acid.5b
1
Figure 3. Portions of H NMR spectra of 12b at t = 14 min (top) at
40% conversion and at t = 0 min for 12b (middle) and at t = 0 min
(lower) for 12a. The broadening and added complexity of the H
NMR signals at t = 14 min surrounding the terminal CH3 group at
0.8 ppm arise from the contributions from the terminal CH3 groups
of products 9, 13, and 14 (see Experimental Section for further
details).
1
starting esters (S,R)-12a and (R,R)-12b throughout the
photolysis and demonstrating that rac-9 was not the result of
an a priori equilibration of the stereogenic center (Scheme 5).
Quantum yields are also consistent with irreversible release of
the acid (Φdis = 0.54 ( 0.05) for 12a and b) and are among the
most efficient pHP arboxylates.
The two minor products from the photo-Favorskii rear-
rangement, hydroxyphenol 13 and hydroxyketone 14, provide
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Scheme 6. Contrasting and Comparing the Cyclic (20) and Acyclic (12a) p-Hydroxybutyrophenone Pathways
additional insight. The hydroxyphenol 13, always seen as a
minor product, is formed by decarbonylation of the cyclo-
propanone 18 followed by hydrolysis4,5b,6 yielding racemic
p-hydroxyphenyl propanol (( )-13; Scheme 6). We previously
denoted this product as a signature of the intermediacy of the
Favorskii cyclopropanone 18.5,6
the same two products are formed by competition between
solvolysis and rearrangement.4,28 These results support a
mechanism where the rearrangements emanate from a ground
state zwitterion 17, i.e., step 4 in the Zimmerman paradigm.8,27
CONCLUSIONS
■
The origin of the hydroxyketone 14 is less apparent and less
frequently encountered. Corri and Wan5c first reported this
minor photohydrolysis product, which we have subsequently
confirmed.4,5a,b,d Most recent, cycloalkanone 20 (Scheme 6),
which may be viewed as having the terminal carbon of the butyl
group on butyrophenone bonded directly to the aryl ring, yields
a hydroxyketone, e.g., 23, as the major photoproduct (57% vs
3% for 14) upon photolysis.4 In solvent containing 18O-labeled
water, the hydroxyl group contained the 18O-label. The
mechanism that incorporates the previous findings with this
stereochemical study suggests that the hydrolysis reaction also
results from divergence of the closure pathway for the zwitterion
21 toward reaction with the solvent. The very minor proportion
of the bifurcation from Favorskii toward hydrolysis in this
reaction is the lack of steric or strain interfering with ring closure
for 17 vis-a-vis 22. The previous study demonstrated that ring
strain was a major factor in the partitioning of the two pathways:
smaller cycloalkanone rings favored formation of the hydroxy-
ketone while larger rings and acyclic ketones gave predom-
inantly the rearranged acids.4 The low yield of 14 from 12
accords well with the increase in ring strain of 24. The results
further suggest that the butyryl group does not cause sufficient
steric congestion to divert zwitterion 17 away from the Favorskii
pathway. It is noteworthy that the quantum efficiencies are not
diminished, supporting the conclusion that the changes in
product ratios are independent of the photorelease of the
leaving group but are subject to the partitioning of a common
intermediates, e.g., the zwitterions 17 and 22. Similar results are
found for the ground state, ZnCl2-catalyzed Favorskii rearrange-
ments of the corresponding bromides where the formation of
The most attractive sequence that accomplishes both the
rearrangement and complete equilibration of the stereogenic
center to form rac-9 begins with the irreversible heterolysis of
the leaving group from the chromophore from the chiral triplet,
312a or 312b, forming an achiral and planar triplet biradical 316.
All subsequent products must be racemic. Subsequent relaxation
3
1
of the triplet biradical 16 to its open shell singlet 16 then to
the closed shell Dewar intermediate 1729 followed by ring
closure of the oxyallyl-phenoxy intermediate provides a route to
the racemic products (Scheme 6). Furthermore, the triplet
3
biradical 2 observed in our earlier TR laser flash absorption
studies5b accounts for the complete racemization.
The results do not accord with a stereospecific, SN2-like
pathways analogous to those observed for several ground state
Favorskii rearrangements, e.g., the work of Stork,16a House,9
Bernetti,11 and Sorenson.10 Instead, the complete racemization of
pHP analogues involves an oxyallyl-phenoxy intermediate
paralleling the ground state mechanism of Dewar14 and
documented by Bordwell.12,17 Alternative routes, e.g., equilibration
of the starting esters or a concerted formation of p-hydroxybenzyl
acylium intermediates,6h do not occur.
EXPERIMENTAL SECTION
■
General Information. NMR spectra were recorded on a 400 MHz
instrument, equipped with a quadruple-band gradient probe (H/C/P/F
QNP) or a 500 MHz with a dual carbon/proton cryoprobe (CPDUL).
13C NMR spectra were recorded with broad-band decoupling. Chiral
HPLC was performed using Chiralcel OD-H column (250 mm × 4.6 mm,
10% IPA in hexanes) using a UV−vis detector tuned to 254 nm.
Photolysis studies were carried out in a rotating merry-go-round
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butan-1-one, 2.99 g of CuBr2 (13.4 mmol), and 30 mL of 1:1 EtOAc/
CHCl3. The heterogeneous solution was brought to reflux and, with
vigorous stirring, preceded for 12 h. After this time, the solution was
cooled to room temperature, and supervening filtration through a plug
of silica afforded, after inspissation, 1.50 g of a white, crystalline
material that through 1H NMR analysis (CDCl3) adduced 2-bromo-1-
(4-hydroxyphenyl)butan-1-one (9) as the primary product with trace
amounts of the starting material and the dibrominated analogue.
Isolation of 10 was not essential for the next reaction step but could
be achieved by flash chromatography with EtOAc/Hex (1:2) as the
eluent.
Figure 4. Chemical shift correlation model for assigning the absolute
configurations of (S,R)-pHP (R)-APAc 12a,b.
apparatus fitted into a Rayonet reactor equipped with two 15 W
300-nm lamps.
Synthesis of 1-(4-Hydroxyphenyl)-1-oxobutan-2-yl (R)-2-Acetoxy-
2-phenylacetate (12a,b). A flame-dried 50 mL RBF was charged with
1.00 g (5.15 mmol) of (R)-2-acetoxy-2-phenylacetic acid 11, and
20 mL of dry DMF. The corresponding solution was cooled to −10 °C
Anhydrous acetonitrile was obtained by passing degassed HPLC-
grade consecutively through two columns filled with activated alumina.
Anhydrous DMF was obtained by distillation of ACS-grade DMF over
calcium hydride under a nitrogen atmosphere. α-Bromo-p-hydrox-
ybutyrophenone 10,30 4-(1-hydroxypropyl) phenol (13),26 and
racemic 2-(4-hydroxyphenyl)butanoic acid (9)25 have been described
previously. (R)-(−)-O-Acetylmandelic acid ((R)-11) is commercially
available.
Synthesis of α-Bromo-p-hydroxybutyrophenone (10). A 50 mL
RBF was charged with 1.00 g (6.09 mmol) of 1-(4-hydroxyphenyl)-
Figure 5. Fragments of 1H NMR charts used for assigning of the absolute configuration of 12a,b: (A) 63:37 mixture of 12a and 12b; (B) pure 12a;
(C) pure 12b.
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Figure 6. Photolysis of 12a at complete conversion to products. See Discussion and Figure 2 for more detail.
with an ice/saturated, aqueous NaCl bath, and with vigorous stirring,
206 mg of NaH (60% w/w in mineral oil, 5.15 mmol) was added. The
suspension brought to room temperature with further stirring for
30 min before 1.04 g (4.29 mmol) of 9 (2-bromo-1-(4-hydroxyphenyl)-
butan-1-one, racemic) was added. The reaction proceeded overnight,
after which the solution was diluted with EtOAc and washed profusely
with H2O. Flash column chromatography (1:1 EtOAc/Hex) afforded
1.71 g of 12a ((R)-1-(4-hydroxyphenyl)-1-oxobutan-2-yl (R)-2-acetoxy-
2-phenylacetate (R)-pHP (R)-APAc)) and 12b ((S)-1-(4-hydroxyphenyl)-
1-oxobutan-2-yl (R)-2-acetoxy-2-phenylacetate (S)-pHP (R)-APAc))
as a ∼1:1 mixture, in 93% yield, as a white crystalline solid.
750, 698, 685, 623, 513; HRMS (TOF ESI) calculated for M + Li =
C20H20O6Li 363.1420; found 363.1423.
(R,R)-12b: mp 166−167 °C. H NMR (500.13 MHz, CD3CN) δ
1
7.76 (d, J = 8.8 Hz, 2H), 7.79 (br. s., 1H), 7.49 (dd, J = 6.5 Hz, 3.0 Hz,
2H), 7.45−7.40 (m, 3H), 6.82 (d, J = 8.8 Hz, 2H), 6.01 (s, 1H), 5.80
(dd, J = 8.0 Hz, 4.3 Hz, 1H), 2.11 (s, 3H), 1.98−1.88 (m, 1H), 1.82−
1.72 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (125.76 MHz,
CD3CN) δ 194.7, 171.2, 169.4, 162.9, 134.7, 131.9 (2C), 130.3, 129.7
(2C), 129.0 (2C), 127.6, 116.4 (2C), 78.3, 75.2, 25.7, 20.9, 9.9; FT-IR
(KBr, cm−1): 3364, 2984, 1747, 1730, 1688, 1599, 1585, 1512, 1441,
1375, 1350, 1281, 1265, 1231, 1213, 1173, 1097, 1057, 935, 901, 856,
843, 750, 696, 685, 669, 660, 615, 532, 513, 401. HRMS (TOF ESI)
calculated for M + H = C20H21O6 357.1338, found 357.1339.
Resolution of the diastereomeric mixture was accomplished as follows:
A 1:1 mixture of diastereomers 12a,b was dissolved in minimum amount
of hot ether and dichloromethane (∼3:1) and refluxed until all solid was
dissolved. Cyclohexane was added gradually, until crystals began to form.
The mixture was then cooled in a refrigerator overnight. Crystals were
collected by vacuum filtration to give (R,R)-12b with 90% dr. The
mother liquor was concentrated to give (S,R)-12a with 85% dr.
Additional recrystallization of the diastereomers from ethyl acetate
Synthesis of 2-Hydroxy-1-(4-hydroxyphenyl)butan-1-one (14).
2-Hydroxy-1-(4-hydroxyphenyl)butan-1-one was obtained from bromide
1
provided (R,R)-12b and (S,R)-12a with >98% dr as determined by H
NMR analysis. The absolute configurations of the resolved esters were
1
established by H NMR using chemical shift correlations analogous to
Trost’s model developed for O-methylmandelates (Figure 4).24 The
extended Newman projections A and B with omitted intervening ester
linkage represent the most stable conformations, which contribute the
most to the observed chemical shifts of diastereomers (S,R)-12a and
(R,R)-12b. The substituents shown in blue, eclipsing the mandelate
phenyl rings (shown in red) are expected to be shifted upfield as a result
of anisotropic shielding interaction. Accordingly, the absolute config-
uration (S,R) was assigned to diastereomer 12a based on the observed
upfield shift of a triplet component of the A3X2 system corresponding to
the ethyl group (0.75 ppm). Analogously, shielding of both doublet
components (6.79 and 7.78 ppm) of the AA′XX′ system corresponding
to the para-substituted aromatic ring allowed for assigning the (R,R)-
configuration to diastereomer 12b (Figure 5).
10 following the previously reported procedure.6d Sodium formate
(3.82 g, 112.2 mmol) was dissolved in ethanol (150 mL), and bromide
10 (2.124 g, 8.74 mmol) was added. The resulting mixture was stirred at
reflux (78 °C) for 1 day, after which time the mixture was filtered hot and
concentrated in vacuo. The crude residue was crystallized from ethyl
acetate:hexane to give 2-hydroxy-1-(4-hydroxyphenyl)butan-1-one (14)
(0.757 g, 4.2 mmol, 48%) as a white crystalline solid. Mp 123−124 °C.
1H NMR (500.13 MHz, CD3CN) δ 7.89 (d, J = 8.5 Hz, 2H), 6.93 (d, J =
8.5 Hz, 2H), 4.99 (br. s., 1H), 3.69 (d, J = 6.3 Hz, 1H), 2.34 (br. s., 1H),
1.87 (dtd, J = 14.4 Hz, 7.3 Hz, 3.9 Hz, 1H), 1.55 (dq, J = 14.3 Hz, 7.2
Hz, 1H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (125.76 MHz, CD3CN) δ
201.4, 163.0, 132.2 (2C), 127.3, 116.4 (2C), 74.4, 29.8, 9.4; FT-IR (KBr,
cm−1): 3223, 3072, 3026, 2968, 2935, 2912, 2876, 1663, 1603, 1591,
1516, 1445, 1439, 1406, 1313, 1279, 1256, 1238, 1167, 1128, 1113, 1092,
1059, 970, 960, 874, 852, 841, 829, 810, 771, 735, 712, 677, 613, 509,
494; HRMS (TOF ESI) calculated for M+ = C10H12O3 180.0786, found
180.0786.
1
(S,R)-12a: mp 154−155 °C. H NMR (500.13 MHz, CD3CN) δ
7.94−7.76 (m, 2H), 7.56 (dd, J = 6.6 Hz, 2.8 Hz, 2H), 7.49−7.43 (m,
3H), 6.90 (d, J = 8.8 Hz, 2H), 6.02 (s, 1H), 5.76 (dd, J = 8.7 Hz, 3.9
Hz, 1H), 2.15 (s, 3H), 1.93−1.83 (m, 1H), 1.86−1.71 (m, 1H), 0.84
(t, J = 7.4 Hz, 3H); 13C NMR (125.76 MHz, CD3CN) δ 195.1, 171.4,
169.8, 163.3, 135.4, 132.3 (2C), 130.7, 130.1 (2C), 129.2 (2C), 127.9,
116.8 (2C), 78.6, 75.7, 26.1, 21.2, 10.3; FT-IR (KBr, cm−1): 3202,
2980, 1757, 1742, 1726, 1686, 1659, 1603, 1570, 1518, 1458, 1441,
1373, 1267, 1227, 1215, 1173, 1097, 1055, 1041, 933, 901, 856, 843,
General Procedure for Photolysis. Ester 12a (11 mg, 0.03 mmol)
was placed in an NMR tube and dissolved in a 4:1 mixture
of CD3CN/D2O. The sample was irradiated in a Rayonet reactor
equipped with two 15 W RPR3000 lamps for 50 min. The reaction
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Figure 7. (A) Reaction mixture A obtained from photolysis of 12a stopped at ∼30% conversion (see Figures 2 and 6). (B) Mixture A spiked with an
authentic sample of 13. (C) Mixture A spiked with an authentic sample of 14.
course was monitored by 1H NMR (Figure 6). The NMR yields of the
released (R)-2-acetoxy-2-phenylacetic acid (11) and the rearranged
product 9 were found to be 100% and 82%, respectively. Upon
completion of the reaction, the crude mixture was concentrated, and
DEDICATION
■
This article is dedicated to the memory of Professor Howard E.
Zimmerman, University of Wisconsin, Madison ( July 5,
1926−February 11, 2012).
the main products were isolated by acid−base extraction. The
1
products identity was confirmed by comparison of their H and 13C
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■
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Support for this work was provided by NIH grant R01
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