2-Diazo-1-(4-hydroxyphenyl)ethanone: A versatile photochemical and synthetic reagent

Article abstract of DOI:10.1039/c3pp50305d

α-Diazo arylketones are well-known substrates for Wolff rearrangement to phenylacetic acids through a ketene intermediate by either thermal or photochemical activation. Likewise, α-substituted p-hydroxyphenacyl (pHP) esters are substrates for photo-Favorskii rearrangements to phenylacetic acids by a different pathway that purportedly involves a cyclopropanone intermediate. In this paper, we show that the photolysis of a series of α-diazo-p- hydroxyacetophenones and p-hydroxyphenacyl (pHP) α-esters both generate the identical rearranged phenylacetates as major products. Since α-diazo-p-hydroxyacetophenone (1a, pHP N₂) contains all the necessary functionalities for either Wolff or Favorskii rearrangement, we were prompted to probe this intriguing mechanistic dichotomy under conditions favorable to the photo-Favorskii rearrangement, i.e., photolysis in hydroxylic media. An investigation of the mechanism for conversion of 1a to p-hydroxyphenyl acetic acid (4a) using time-resolved infrared (TRIR) spectroscopy clearly demonstrates the formation of a ketene intermediate that is subsequently trapped by solvent or nucleophiles. The photoreaction of 1a is quenched by oxygen and sensitized by triplet sensitizers and the quantum yields for 1a-c range from 0.19 to a robust 0.25. The lifetime of the triplet, determined by Stern-Volmer quenching, is 31 ns with a rate for appearance of 4a of k = 7.1 × 10 ⁶ s^-1 in aq. acetonitrile (1:1 v:v). These studies establish that the primary rearrangement pathway for 1a involves ketene formation in accordance with the photo-Wolff rearrangement. Furthermore we have also demonstrated the synthetic utility of 1a as an esterification and etherification reagent with a variety of substituted α-diazo-p- hydroxyacetophenones, using them as synthons for efficiently coupling it to acids and phenols to produce pHP protect substrates. The Royal Society of Chemistry and Owner Societies.

Full text of DOI:10.1039/c3pp50305d

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2-Diazo-1-(4-hydroxyphenyl)ethanone: a versatile
photochemical and synthetic reagent†‡
Cite this: DOI: 10.1039/c3pp50305d
Sanjeewa N. Senadheera,a Anthony S. Evans,b John P. Toscanob and
Richard S. Givens*a
α-Diazo arylketones are well-known substrates for Wolff rearrangement to phenylacetic acids through a
ketene intermediate by either thermal or photochemical activation. Likewise, α-substituted p-hydroxy-
phenacyl (pHP) esters are substrates for photo-Favorskii rearrangements to phenylacetic acids by a
different pathway that purportedly involves a cyclopropanone intermediate. In this paper, we show that
the photolysis of a series of α-diazo-p-hydroxyacetophenones and p-hydroxyphenacyl (pHP) α-esters
both generate the identical rearranged phenylacetates as major products. Since α-diazo-p-hydroxyaceto-
phenone (1a, pHP N2) contains all the necessary functionalities for either Wolff or Favorskii rearrangement,
we were prompted to probe this intriguing mechanistic dichotomy under conditions favorable to the
photo-Favorskii rearrangement, i.e., photolysis in hydroxylic media. An investigation of the mechanism for
conversion of 1a to p-hydroxyphenyl acetic acid (4a) using time-resolved infrared (TRIR) spectroscopy
clearly demonstrates the formation of a ketene intermediate that is subsequently trapped by solvent or
nucleophiles. The photoreaction of 1a is quenched by oxygen and sensitized by triplet sensitizers and the
quantum yields for 1a–c range from 0.19 to a robust 0.25. The lifetime of the triplet, determined by Stern–
Volmer quenching, is 31 ns with a rate for appearance of 4a of k = 7.1 × 106 s−1 in aq. acetonitrile (1 : 1 v : v).
These studies establish that the primary rearrangement pathway for 1a involves ketene formation in accord-
ance with the photo-Wolff rearrangement. Furthermore we have also demonstrated the synthetic utility of 1a
as an esterification and etherification reagent with a variety of substituted α-diazo-p-hydroxyacetophenones,
using them as synthons for efficiently coupling it to acids and phenols to produce pHP protect substrates.
Received 3rd September 2013,
Accepted 20th November 2013
DOI: 10.1039/c3pp50305d
www.rsc.org/pps
the pFR is due, in part, to its emergence in the mechanistic
studies of the p-hydroxyphenacyl (pHP) group as a photoremo-
Introduction
Two well-known and closely related ground state rearrange- vable protecting group (PPG) for several key functional groups
ments, the Wolff (WR) and Favorskii (FR) rearrangements, that are important in chemical and biological studies.5,6 Fur-
have a common signature for their reorganizational behavior.1 thermore, recent applications of pFR for ring-contraction reac-
Both proceed by elimination reactions coupled with a 1,2- tions by photolysis of 4-hydroxybenzocycloalkanone esters
carbon migration before reacting with a nucleophilic trapping have been demonstrated.7 Similar photoinduced ring contrac-
reagent that, overall, converts an α-substituted ketone to a car- tion reactions have been hallmarks of FR, WR, and pWR reac-
boxylic acid. Photochemical versions of these rearrangements, tions, particularly α-diazocycloalkanones.8 These similarities
the photo-Wolff (pWR)2 and photo-Favorskii (pFR)3 rearrange- plus recent mechanism studies of the photo-Favorskii reac-
ments, are well-known variations of these rearrangements tion3c,7b,9,10 have added significantly to our understanding of
(Scheme 1). Of these two, the photo-Favorskii rearrangement is the rearrangement reaction, inviting a more in depth compari-
the more recent3,4 and less well-studied. Increased interest in son between the pFR and the more well-established pWR.2,11
Based on literature precedence, the pWR and pFR
rearrangements follow two completely different pathways, yet
arrive at one common major product, carboxylic acid 4. One
aDepartment of Chemistry, University of Kansas, Lawrence, Kansas 66045, USA.
E-mail: givensr@ku.edu
bDepartment of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218,
common feature of both the pWR12 and pFR1–3,13 for aryl
ketones is that they commence by heterolytic departure of a
leaving group from an excited state of the α-substituted phena-
cyl ketone (e.g., 1) followed by 1,2-aryl migration. For the pFR,
a required p-hydroxyphenacyl group assists the leaving group
heterolysis in aqueous solvents through concomitant loss of
USA
†This article is dedicated to the memory of Professor Nicholas J. Turro
(1938–2012), one of the giants of physical-organic photochemistry upon whose
shoulders many of us stood.
‡Electronic supplementary information (ESI) available. See DOI:
10.1039/c3pp50305d
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Scheme 1 General rearrangement pathways for the photo-Wolff (pWR) and photo-Favorskii (pFR) reactions.
the phenolic proton, whereas the pWR should not be limited
by nor require any special assistance from the aryl substi-
Results
tuent.2c,d,14 However, since the p-hydroxy group has not been The potential synthetic utility of 1a is based on the well-esta-
among the substituents that have been reported for pWR blished applications of diazomethane and its derivatives16 as
rearrangements of aryl ketones, its role and the effect of esterification reagents. This methodology is especially appeal-
aqueous solvents on the pWR are not known. 2-Diazo-1- ing because of the rapid, clean installation of a phenacyl pro-
(4-hydroxyphenyl)ethanones (α-diazo-p-hydroxyphenacyl analogs, tecting group on acidic functional groups which should
1a–e (LG = N2) represent potential cross-over substrates that require fewer steps and expand pHP protection to other func-
may be employed to probe for either (or both) the photo-Wolff tional groups.17 In exploring these purposes, we chose a series
carbene–ketene or the photo-Favorskii diradical-cyclopropa- of α-diazo-p-hydroxyacetophenones as models that would serve
none sequences as depicted in Scheme 2.
as common reagents for the photo-Wolff rearrangement
To test for this dichotomous behavior, we have explored the studies and that could be compared with our previous studies
photochemistry of 1a and several other α-diazo-p-acetophe- using pHP analogs.9a,b,18
nones, tracking the mechanistic questions raised here, while
The diazo ketones were synthesized from the acylated
also exploiting the synthetic utility of these α-diazoketones substituted 4-hydroxybenzoic acids 6 by treatment with SOCl2
as synthons for general routes to direct installation of the to give the acid chlorides (Scheme 3). Conversion to acetyl-
p-hydroxyphenacyl (pHP) protecting group for important acidic protected diazo-p-hydroxyacetophenones 7 in 65–69% yield
functional groups in chemistry and biology.6a,15
occurred with addition of excess diazomethane.17,19,20
Scheme 2 The divergent pathways available to 2-diazo-1-(4-hydroxyphenyl) ethanone (α-diazo-p-hydroxyacetophenone, 1a).
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of dibenzyl phosphate,10b,21 three examples of sulfonates
esters,17,21 two phenol ethers,21 and several carboxylate
esters9,17 including the pHP protected, neuro active agents
glutamate9,18a and GABA.9 Previous syntheses of these pHP
derivatives employed SN2 strategies using protected bromo-
acetophenones (pHP Br), a more cumbersome route.
Properties of 2-diazo-4-hydroxyphenylethanones
The X-ray crystallographic data is provided in the ESI in
Table SI1 and Fig. SI1 and SI2.‡ The pKa’s and UV-vis spectra
of 1a–d in aqueous CH3CN (unbuffered) and buffered media
are given in Table 1 and in Fig. SI3 and SI4.‡
UV-vis spectra for 1a in H2O–CH3CN (Fig. SI3 and SI4‡) and
in buffer solutions show absorption maxima at λmax = 306 nm
at pH 4 to 7 giving no hint of the presence of its conjugate
base. This indicates that the absorption spectra at pH 4–7 are
Scheme 3 Synthesis of substituted 2-diazo-1-(4-hydroxyphenyl)-
ethanones (1a–d). Reagents and conditions; (a) SOCl2, reflux, 8 h,
95–99%; (b) CH2N2, Et2O, 0 °C to rt, overnight, 38–69%; (c) NH4OAc,
H2O–MeOH, 1 : 4, 50 °C, 8 h, 90–98%.
Deacetylative deprotection of the phenol with NH4OAc in for the neutral form of 1a as expected from its pKa of 9.1.
aqueous methanol occurred in the workup step and gave quan- Although the conjugate base is not present in this pH range, it
titative yields of 1a–d. The acetyl analog 1d21 was synthesized is prominent at pH 10 as evidenced by the 40 nm red-shifted
by first converting p-acetoxybenzoic acid 6a to 3-acetyl-4-hydro- λmax at 346 nm (Fig. SI4‡). The solution’s color changes from a
xybenzoic acid through a Fries rearrangement followed by re- light yellow at pH 7 to a bright yellow at pH 10. In general, all
acetylation of the phenolic group to give 6d.22 Conversion to of the maxima of 1a–d are red shifted relative to their p-hydro-
the acid chloride and addition of diazomethane gave 3-acetyl xyacetophenones (pHA) and pHP esters due to the extended
derivative 7d in low yield (38%), however.
cross-conjugation of the α-diazo group.
The α-diazoketones 1a–d were converted to their diethyl
The pKa’s for p-hydroxyacetophenone and pHP esters are
phosphate esters 9a–d in 75–79% yield by treatment with generally an order of magnitude lower than 1a–d. For example,
diethyl phosphoric acid.21 The ortho methoxy substituted 1a (pKa 9.1) is much less acidic than 4-hydroxyacetophenone
analog 2-diazo-1-(4-hydroxy-2-methoxyphenyl)ethan-1-one (1e) (pHA, pKa 7.9)21,24 or any of the pHP esters (pKa range from
could not be synthesized by this route due to instability of 1e 3.9 to 8.2).21 The complex acid–base equilibria for 1a are pro-
to the reaction conditions. However, treatment of 6e with filed in Scheme 6. UV-vis spectra confirm that structure 1a pre-
SOCl2 and then excess diazomethane gave 2-methoxy diazo- dominates at pH 4–7 and that the conjugate base 1a−
ketone 7e in good yield (69%). Exposure of 7e to silica gel, acids, predominates at pH 10. There is no UV, transient UV, or transi-
aqueous bases, or unbuffered H2O resulted in the formation of ent IR (vide infra) evidence for either the quinone methide
6-hydroxybenzofuran-3(2H)-one (8e). A similar neighboring enol alcohol (QEA) or the diazoquinone methide enolate zwit-
group cyclization had been reported by Gefflaut and Périé23 for terion (QEZ) that have been reported for p-hydroxyacetophe-
o-benzyloxy α-diazoacetophenone upon treatment with diben- none.5 Likewise, the complete absence of any hydrogen–
zyl phosphoric acid (Scheme 4). Therefore, acetate 7e was used deuterium exchange of the α-proton of 1a for samples dis-
as its protected phenol for photochemical studies. Likewise, solved and then photolyzed in D2O (1H NMR). This precludes
the instability of 7e to acid precluded its conversion to any equilibrium between 1a and the quinone enolate form
2-methoxy-pHP diethyl phosphate which, instead, was obtained (QEZ). Therefore, structures like 1a′H+, 1a″H+, and QEZ
by the SN2 bromide displacement from α-bromo-2-methoxy-4- (Scheme 6) are not contributing to the equilibria of 1a within
hydroxyacetophenone, the method previously reported for the pH range of 4–7.
most pHP phosphates.10b
The X-ray crystallographic structure of 1a (Fig. SI1 and SI2,
To further demonstrate the utility of 1a, it was employed as Table SI1‡) confirm that the molecule is indeed nearly planar,
a synthon to cage several other functional groups (Scheme 5), only slightly twisted by approximately 12–14° out of the aryl
i.e., as a general entrée for the synthesis of pHP esters plane, with the diazo functional group anti-periplanar to the
Scheme 4 Cyclization reactions of 2-diazo-1-(2-methoxyphenyl)ethanones (7e, f) to furanones 8e, f. Reagents and conditions; (a) NH4OAc,
H2O–MeOH, 1 : 4, 50 °C, 8 h or H+ or H2O or OH−, rt, 100%.
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Scheme 5 Substituted 2-diazo-4-hydroxyphenylethanones as synthons for pHP caging. Reagents and conditions; (a) HOP(O)(OEt)2, benzene,
60 °C, 24 h, 75–79%, (b) HOP(O)(OPh)2, benzene, 60 °C, 24 h, 92%, (c) PhCO2H, benzene, 70 °C, 42 h, 97%; (d) CH3COOH, H2O–CH3CN, 1 : 1, 16 h,
rt, 98%; (e) CF3COOH, benzene, 0 °C – rt, 1 h, 94%; (f) Boc-Glu(OtBu)-OH, cat. Cu(acac)2, toluene, 60 °C, 2 h, followed by TFA–CH2Cl2, 1 : 1, 15 min,
rt, 71% overall yield (g) Boc-GABA, cat. Cu(acac)2, toluene, 60 °C, 2 h followed by TFA–CH2Cl2, 1 : 1, 15 min, rt, 75% overall yield, (h) p-TsOH·H2O,
CH3CN, 0 °C – rt, 1 h, 71%; (i) CF3SO3H, benzene, 0 °C – rt, 30 min, 91% (crude); ( j) MsOH, benzene, 0 °C – rt, 1.5 h, 98%, (k) as the acetate 7a,
p-CH3OC6H4OH, 50 °C, 8 h, then NH4OAc, H2O–MeOH, (1 : 4), 50 °C, 8 h, 56–68% overall yield (l) as the acetate 7a, p-CF3C6H4OH, 50 °C, 8 h, then
NH4OAc, H2O–MeOH (1 : 4), 50 °C, 8 h, 56–68% overall yield.
Table 1 pKa’s and UV-vis maxima and extinction coefficients for 1a–d
aryl ring. The C1–C2 ethanone bond is shortened to 1.43 Å
from 1.46 Å for other diazo acetophenones,25 suggesting a
Substituted α-diazo
acetophenones
pKa
pH/buffer
λmax (log εmax)
small degree of conjugation between the diazo group and the
carbonyl.
4.0a
7.0b
10.0c
H2O
H2O
H2O
306 (4.23)
306 (4.15)
346 (4.13)
315 (4.15)
318 (4.27)
295 (3.90)
1H NMR of 1a displays one singlet at δ 6.30 (D2O–CD3CN,
1H, s) for the α-methine proton consistent with a single s-Z
configuration deduced from the crystallographic data (SI1‡)
and consistent with several other diazoacetophenones25–31
and semi empirical (AM1) and ab initio (HF/6-31G(d))
determinations.32,33
1a
9.1
1b, 3-OMe
1c, 3,5-(OMe)2
1d, 3-COCH3
8.9
9.0
7.7
a Sodium acetate/acetic acid buffer (0.1 M). b Ammonium acetate/
ammonia (0.1 M). c Ammonium acetate/ammonia (0.1 M).
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Scheme 6 Single proton acid–base equilibria of 2-diazo-1-(4-hydroxyphenyl)ethanone 1a.
Photochemistry
to room temperature. Some effervescence due to unreacted 1a
was noted. H NMR indicated two products, methyl p-hydroxy-
1
Irradiation of 1a at 300 or 350 nm in Pyrex vessels under
ambient conditions either in unbuffered or buffered (pH 4, 7,
or 10) aqueous acetonitrile (D2O–CD3CN, 1 : 1) produced nitro-
gen effervescence. Disappearance of 1a and appearance of
4-hydroxyphenylacetic acid (4a) were determined by the changes
phenylacetate and 2-methoxy-1-(4-hydroxyphenyl)ethanone,
the latter from the workup (Scheme 7). A control run without
irradiation indicated no exchange of the α-H for D in 1a and
no indication exchange in this product.
Quantum yields for the disappearance of diazo pHP 1a and
appearance of 4a were determined by RP-HPLC in unbuffered
aqueous acetonitrile (1 : 1) at 300 nm. The disappearance
quantum yield for 1a and the three substituted derivatives
1b–d are comparable to other diazo 4-substituted acetophenones
photolyzed at 300 nm as indicated in Table 2.35
1
in their H NMR signals at 6.23 and 3.49 ppm, respectively or
by reverse-phase HPLC (RP-HPLC) analysis. The total areas of
the 3.49 and 6.23 ppm signals remained constant while the
ratio of the two areas changed throughout the reaction indicat-
ing that there was no exchange with D2O before, during, or
after the rearrangement.
Quantum yield measurements and the photorearrangement
products for 1b–d and 7b,e were determined (Scheme 8). The
acetyl protected 3-methoxy diazo pHP 7b produced rearranged
acid 4b in good yield, whereas the acetyl-protected 2-methoxy
diazo pHP 7e gave a 1 : 1 mixture of 3-oxo-2,3-dihydrobenzo-
furan-6-yl acetate (8g) and rearranged acid 4e. The formation
of 4e follows the same rearrangement pathway as the un-
substituted and meta substituted diazo pHP derivatives
1a–d and is also responsible for the formation of 4b indepen-
dent of the added acetyl protecting group. In contrast, for-
mation of acetate 8g must arise by another pathway, possibly
Several unidentified minor products were detected by NMR,
HPLC and LC-MS. Attempts were made to probe the reaction
mixture for other photoproducts analogous to those expected
1
in either the pWR or pFR reactions including H NMR and co-
injection of the photolyzate mixtures of 1a with authentic
samples, 4-hydroxyacetophenone (by photoreduction), 4-(1-
hydroxyethyl)phenol (by photohydrolysis),10c,34 or 4-hydroxy-
benzyl alcohol (the ubiquitous byproduct of pFR photorearran-
gement)3c and analyzed by RP-HPLC and GC/MS. None of
these compounds were present. Similarly, photolysis in
aqueous CH3CN at pH 10 and in dry CH3CN gave only complex
mixtures of photoproducts, none of which were the expected
rearrangement or hydrolysis photoproducts. These results are
in contrast with photolysis in >5% H2O–CH3CN at a pH of
4.0–7.0 where 4a was the product.
involving
a carbene, but does not involve the pWR
rearrangement.
Sensitization and quenching studies
Photolysis of 1a in the presence of Lewis acid (HBF4) in 1 : 1
CD3OD–CD3CN and in H2O–CH3CN at −10 °C, conditions The singlet and triplet energies of the diazo pHP 1a are esti-
similar to those for ground state esterification reactions were mated to be ES = 85 kcal mol−1 (λfluor 338 nm) and ET 69 = kcal
performed. At this temperature, 1a is stable and no N2 efferves- mol−1 (λphos 410 nm), respectively. Two sensitizers were chosen
cence is observed. After photolysis for 1 h with 16 × 300 nm based on their ET values and their hydrophilicity: benzophe-
lamps in HBF4 (1 : 1 CD3OD–CD3CN), the sample was warmed none-4,4′-dicarboxylic acid (20, ET = 69 kcal mol−1 31,36–40
and
)
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Scheme 7 The photorearrangements of 1a in neutral and acidic aqueous acetonitrile.
mangiferin (21, a xanthone derivative, ET = 71–74 kcal mol−1
Table 2 Substituent and solvent effects on the photorearrangement of
4-substituted α-diazo acetophenones 1 to arylacetates 4 at 300 nm
(ethanol–ether).41–44 The results demonstrate that there
is a significant triplet contribution to the rearrangement
(Table 3).
a
Substituted α-diazo
acetophenones
λmax
nm
/
b
b
Φdis
Φapp
Ref.
1, H–C6H4–COCHN2
1a, 4-OH
294c
306
315
318
295
0.46c, 0.40c
0.25
0.21
35
0.23
0.19
0.18
nd
This work
This work
This work
This work
35
1b, 4-OH, 3-OMe
1c, 4-OH, 3,5-(OMe)2
1d, 4-OH, 3-COCH3
0.19
0.10
1f, 4-CH3O–C6H4–COCHN2 304c
0.34c
0.18c
1g, 4-NO2–C6H4–COCHN2
307c
35
a H2O–CH3CN (1 : 1). b D2O–CD3CN (1 : 1). c Methanol.
Time-resolved infrared studies
Likewise, oxygen quenched the reaction, decreasing the
quantum yields by 30% to 55%. When samples were purged Nanosecond time-resolved infrared (TRIR) experiments49–51
were performed using a 266 nm (5 ns, 1.5 mJ) laser for the
for 30 min either with argon or with 100% O2 before photo-
lysis, the Stern–Volmer dependence on the quencher concen- photolysis of 1a in argon-saturated 5% aqueous acetonitrile
tration was used to determine the triplet lifetime (τ = 31 × (v : v) and monitored in the spectral region 2200–2000 cm−1
10−9 s) and the rate of appearance of 4a of 7.1 × 106 s−1 using (Fig. 1). The strong band observed at 2110 cm−1 is assigned
an estimated rate constant for O2 diffusion of kdiff = 1.37 × to ketene 3a in good agreement with previous studies on
1010 M−1 s−1 in 50% aqueous acetonitrile (Table 4 and α-diazo ketones52–55 such as α-diazo-p-methoxyacetophenone
Fig. SI5‡).24,45–48
(2115 cm−1) and α-diazoacetophenone (2118 cm−1).52
Scheme 8 Photochemistry of 1a–d, 7b and 7e.
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1685 cm−1. This intermediate is assigned to either zwitterion
23 or its tautomer, enol 22, the addition product of DEA to 3a,
which collapses to amide 24 as indicated by the growth of the
Table 3 Sensitization and quenching quantum yields for 1a
Excitation
wavelength (nm)
Conditionsa
Φdis.
Φapp.
b
b
band at 1640 cm−1
.
Direct irradiationc
Sensitization with 21d
Sensitization with 20e
Purged with 100% O2
Purged with Ar
300
300
300
300
300
0.25
0.13
0.19
0.17
0.28
0.22
0.11
0.13
0.12
0.24
Measurements of the rate of decay of the 2110 cm−1 ketene
signal and the rate of growth of the 1685 cm−1 signal with
varying concentrations of DEA were used to obtain the second-
order rate constant for the addition of DEA to ketene 3a,
kDEA = 6 × 106 M−1 s−1. The observed rate of the relevant inter-
mediate decay or formation (kobs) as a function of added DEA
is given by kobs = k0 + kDEA[DEA], where k0 is the observed first-
order decay rate constant in the absence of DEA and kDEA is
the second-order rate constant for reaction with DEA (see
Fig. SI6‡). This derived rate constant is approximately two
orders of magnitude slower than other closely related DEA-
ketene addition rates.52 The sluggishness of the reaction may
be attributed to the lower electrophilicity of the ketene caused
by the p-hydroxyphenyl group or its conjugate base. Protona-
tion of DEA by the phenol may further influence the rate by
diminishing its concentration.
a Solvents were 1 : 1 H2O–CH3CN. Each sample was irradiated for 8 min
using the conditions given in Table 3 with 2–300 nm lamps. b Analysis
of the samples was by RP-HPLC, error limits were 0.01. c Not
degassed. d Sensitization with 21 using 16–350 nm lamps, concentration
of 21 was 4.76 × 10−3 M. e Concentration of 20 was 3.70 × 10−3 M.
Table 4 O2 quenching of 1a in 1 : 1 H2O–CH3CN
Experimental
condition
[O2], M
Φdis Φapp (Φ0/Φ)dis (Φ0/Φ)app
Purged with Ara
2.7 × 10−6 0.28 0.24 1.00
1.00
1.09
Ambient conditions, 2.7 × 10−4 0.25 0.22 1.12
not purged
Attempts to detect the cyclopropanone CvO stretch the IR
region of 1950–1800 cm−1, which would be characteristic of
the spirodienedione intermediate 2, the intermediate expected
from the pFR reaction, were unsuccessful. No transient signals
were observed in this region.
Purged with O2
2.0 × 10−3 0.17 0.12 1.65
1.83
a The oxygen concentration was reduced to approximately 10−6 M by
degassing the photolysis solution with Ar.38
Discussion
To confirm our assignment of the 2110 cm−1 signal to
ketene 3a, we examined its reactivity with diethylamine (DEA)
The TRIR evidence clearly demonstrates that the major if not
exclusive pathway for α-diazo-p-hydroxyacetophenone photo-
chemistry is through a ketene intermediate. At room tempera-
ture when performed at a pH less than 4 (HBF4–CD3OD), 1a is
unstable and spontaneously expels N2 to form α-methoxy-p-
hydroxyacetophenone, the solvolysis product. At −10 °C with
to
form
N,N-diethyl-p-hydroxyphenyl
acetamide
(24,
Scheme 9). TRIR data observed following photolysis of 1a in
argon-saturated acetonitrile with 2 mM added DEA are shown
in Fig. 2. Under these conditions the 2110 cm−1 ketene signal
is quenched and a transient intermediate is observed at
Fig. 1 TRIR difference spectra averaged over the timescales indicated following 266 nm laser photolysis of a solution of 1a prepared in argon-
saturated 5% aqueous acetonitrile with an O.D. of 0.99 at 266 nm (0.5 mm path length). The inset shows the corresponding kinetic trace observed
at 2110 cm−1
.
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Scheme 9 The photochemistry of 1a in acetonitrile with added diethylamine to form N,N-diethyl amide 24.
Fig. 2 (a) TRIR difference spectra averaged over the timescales indicated following 266 nm laser photolysis of a solution of 1a with 2 mM diethyl-
amine prepared in argon-saturated acetonitrile with an O.D. of 0.99 at 266 nm (0.5 mm path length). The corresponding kinetic traces observed
at 1685 cm−1 and 1640 cm−1 are shown in (b) and (c), respectively. The red curves are experimental data; the black curves are best fits to a single-
exponential function.
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HBF4 (in 1 : 1 CD3OD–CD3CN), a temperature low enough that specifically absent was the benzyl alcohol 5a, the ubiquitous
N2 is not released thermally, photolysis of 1a gives Wolff side product of the photo Favorskii reaction (Scheme 1).
rearrangement product, i.e., p-hydroxyphenylacetate methyl
Nonetheless, these results are perplexing when one con-
ester (d5), through its ketene precursor (and the corresponding siders the ground state reactions and chemistry of 1a and its
solvolysis product from workup). Neither p-hydroxybenzyl analogs. For example, the most common ground state reac-
1
alcohol (5) nor its methyl ether was detected. Furthermore, H tions of 1a in the absence of light or catalysts but in the pres-
NMR of the photoreaction mixture gave no evidence for ence of mild to strong acids in hydroxylic solvents, such as
exchange of the original α-proton on 1a in the deuterated sol- H2O or CH3OH, is either esterification or etherification without
vents, i.e., the α-proton remaining intact throughout the con- skeletal rearrangement, a very advantageous feature for our
version to the rearrangement and photosolvolysis products. general synthetic methodology for the synthesis of pHP pro-
These results along with the studies of buffered D2O–CD3CN tected derivatives.
(1 : 1) solutions from pH 4–7 rule out any reversible protona-
General consideration of the mechanistic pathway for these
tion or deuteration of 1a at the α-carbon expected form inter- synthetically valuable esterification reactions for 1a and its
mediate species such as 1a′H+, 1a″H+ or the quinone methide derivatives with diazo alkanes begins with protonation of the
QEZ (Scheme 6) which may be crucial for onset of a pFR diazo derivative by acid followed by nucleophilic displacement
56
pathway.
of N2 (Scheme 10). For diazomethane, the protonation at
The photochemistry at pH 10, on the other hand, produces carbon has been shown to be reversible using deuterium
only a complex mixture of unidentified product and none of exchange conditions.16 However, in our case for 1a, exchange
the signature products from either the pFR or pWR pathways. does not occur, suggesting that alternative mechanistic path-
While this is not an exhaustive, all-inclusive investigation of ways or irreversible protonation are occurring. It is also appar-
possible variables that might divert the pathway of 1a away ent that intermolecular nucleophilic pathways prevail over any
from the Wolf rearrangement, the dominance of the pWR intramolecular participation of the electron rich phenol ring,
pathway is clearly evident under conditions examined here.
TRIR spectroscopy provides the spectral evidence, demon-
which, of course, would lead to Favorskii products.
Since pHP has become an important photoremovable pro-
strating ketene 3a as the exclusive intermediate. No evidence tecting group (PPG) for biological studies6 by providing rapid
for a cyclopropanone carbonyl stretch in the region of rates (fs to ns) for heterolysis with little or no byproduct
1800–1850 cm−1 as anticipated for 2a was found.
damage or deleterious biological interference to proteins and
Quantum yield studies demonstrate that the p-hydroxy by very efficiently releasing many functional groups (Φ =
group does not impact the overall efficiency of the photo-Wolff 0.1–1.0), a general synthetic entrée to pHP and its congeners is
rearrangement reaction when compared with other substituted now possible by employing substituted α-diazo-p-hydroxyaceto-
phenacyl derivatives (Table 2). However, the TRIR studies do phenones (1a–d) to afford pHP photoprotection. Synthesizing
reveal that nucleophilic addition by diethylamine to the inter- a range of substituted 2-diazo-1-(4-hydroxyphenyl)ethanones
mediate ketene 3a proceeds much more slowly, i.e., by over has value in its utility for protecting important acid and
two orders of magnitude, than reported for DEA additions to phenol functionalities under very mild conditions in quantitat-
similarly substituted phenylketenes (kDEA = 6 × 106 M−1 s−1 for ive yield.
p-OH vs. kDEA = 3.30 × 108 M−1 s−1 for p-OCH3).52 The greater
electron-donating character of the p-hydroxy substituent or
possibly its conjugate base reduces the ketene’s nucleophilicity
thus slowing the rate of attack at the carbonyl carbon
Conclusions
(Scheme 9, Fig. 2).
With the array of substituted diazoketones 1a–d, we have
Sensitization and quenching studies indicate that there is a explored the concept of dual mechanisms for the photo-Wolff
prominent triplet component to the rearrangement. Both and photo-Favorskii rearrangements. Although two excited
hydrophilic triplet sensitizers, benzophenone (20) and 9H- state pathways for α-diazo-p-hydroxyacetophenone (1a) might
xanthen-9-one (21), promote the rearrangement with sensiti- include a traditional photo-Wolff ketene mechanism57 or a
zation quantum yields by 20 occurring at very nearly the same photo-Favorskii cyclopropanone pathway (or both), 1a and its
efficiencies as found for direct excitation of 1a. Likewise, congeners exclusively follow the photo Wolff pathway. These
oxygen quenching decreases the quantum efficiency by >40%. reactions were shown to be triplet processes through sensiti-
The concentration dependence of the oxygen quenching pro- zation and quenching studies. Subtle changes in the excited
vides a Stern–Volmer estimate of quenching rate of kq
=
state pKa’s, substituents on the chromophore, solvent, or the
3
1.37 × 1010 M−1 s−1 and a lifetime for 1a of τ3 = 31 × 10−9 s, pH of the solvent do not alter or divert the reaction pathway of
sufficiently long that proton transfer is possible on the excited 1 from ketene formation, i.e., from the Wolff rearrangement
state surface. However, there is no evidence for changes in the pathway.
product distribution or the isotopic integrity of the reactant or
It is both significant and utilitarian that α-diazo-p-hydroxy-
product that would be expected if a Favorskii pathway inter- acetophenones (1a–d) function as excellent synthons for pHP
vened. The byproduct characteristic of the pFR pathway protection reactions. Synthetic yields of pHP protected
was not detected under direct or sensitization conditions; functional groups using α-diazo-p-hydroxyacetophenones give
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Scheme 10 Mechanism for irreversible protonation yielding esterification of acids.
better yields and avoid the necessity for masking the phenolic pieces for 1 h at 0 °C. Then a solution of the acid chloride
group of pHP during installation of the protecting group.
(200 mg, 1.00 mmol) in dry ether (10 mL) was added to the dis-
tillate with vigorous stirring at −5 °C. The reaction mixture was
allowed to come to 0 °C and stirred for 4 h. The solvent was
evaporated, and the yellow colored crude residue was purified
by flash chromatography using a gradient solvent system:
EtOAc–hexane (1 : 4), EtOAc–hexane (1 : 3), and EtOAc–hexane
(1 : 2) to afford α-diazo-p-acetoxyacetophenone (7a) as yellow
Experimental
General methods
All compounds were prepared by literature procedures unless
indicated otherwise. All reagents were purchased from com-
mercial sources and used without further purification unless
otherwise noted. Nitrobenzene and dichloromethane (DCM)
were distilled prior to use. 1H NMR spectra were recorded on a
Bruker 400 MHz instrument unless otherwise noted. IR
spectra were recorded on a Shimadzu FTIR-8400S spectropho-
tometer; results are reported in cm−1. UV/vis spectra were
recorded on a Cary 100 spectrophotometer. HPLC analyses
were performed with a C18 Econosphere 250 × 4.6 mm analyti-
cal column connected to a dual pump system for preliminary
studies. Mass spectrometry was performed on a Sciex API-1
Plus quadrupole mass spectrometer with an electrospray
ionization (ESI) source. pH values of solutions were measured
using a pH 510 meter calibrated with certified buffer solutions
of pH 4, 7, and 10. A freeze drier was used for lyophilization
(at −52 °C and 0.04 mbar). Thin layer and column chromato-
graphy were performed on precoated silica gel plates and stan-
dard grade (32–63 μm) silica gel, respectively. Melting points
are uncorrected.
The following compounds were synthesized as described
previously: 2-hydroxy-1-(4-hydroxyphenyl)ethan-1-one,58 4-
acetoxy-3-methoxybenzoic acid (6b),59 4-acetoxy-3,5-dimethoxy-
benzoic acid (6c),60 4-acetoxy-3-acetylbenzoic acid (6d),21 1-(3-
acetyl-4-hydroxyphenyl)-2-diazoethanone (1d),21 diethyl 2-(3-
acetyl-4-hydroxyphenyl)-2-oxoethyl phosphate (7d),21 2-(4-
hydroxyphenyl)-2-oxoethyl 2,2,2-trifluoroacetate (12),21 2-(4-
hydroxyphenyl)-2-oxoethyl 4-methylbenzenesulfonate (15),17
2-(4-hydroxyphenyl)-2-oxoethyl methanesulfonate (17).17
4-(2-Diazoacetyl)-3-methoxyphenyl acetate, 7a (α-diazo-p-
acetoxyacetophenone). The general methods of Arndt61 and
Beames and Mander62 were applied with modifications.
(General method A) To a solution of KOH (678 mg, 12.1 mmol)
in 2-methoxyethanol (5 mL) and water (5 mL), diazold (1.17 g,
5.4 mmol) in diethylether (50 mL) was added carefully. The
resulting mixture was gently heated to reflux temperatures
(40–50 °C). The ether layer was distilled into a collection flask
that was kept in an ice bath at 0 °C. The ether distillate was
sequentially dried over KOH pellets for 1 h at 0 °C and with Na
1
needles (112 mg, 0.55 mmol, 55% yield): mp 105–107 °C; H
NMR (CDCl3) δ ppm 7.81–7.79 (1H, dd, J = 6.8 Hz, 1.8 Hz),
7.20–7.18 (1H, dd, J = 6.8 Hz, 1.8 Hz), 5.88 (1H, s), 2.33 (3H, s);
13C NMR (100 MHz, CDCl3) δ (ppm) 185.3, 169.1, 154.2, 134.4,
128.4, 122.1, 54.4, 21.4; IR (KBr, cm−1) 3067, 2114, 1757, 1609,
1574, 1417, 1392, 1369, 1103, 1167, 916, 860; MS (ESI (+)) m/z
calcd for (C10H8N2O3 + H)+ 205.0613, found 205.0624.
4-(2-Diazoacetyl)-2-methoxyphenyl acetate (7b). The general
methods of Adams and Binder63 and Arndt61 were followed
with modifications. A flame dried 50 mL round bottomed
flask was charged with 4-acetoxy-3-methoxybenzoic acid (6b,
0.840 g, 2.8 mmol) and freshly distilled SOCl2 (20 mL) was
added under Ar. The resulting mixture was refluxed at 80 °C
for 8 h and concentrated under reduced pressure to afford
4-acetoxy-3-methoxy-benzoyl chloride as colorless oil. This acid
chloride was used in the next step without any purification.
A solution of acid chloride (910 mg, 3.9 mmol) in dry ether
(10 mL) was added dropwise to the dried ether distillate con-
taining the diazomethane with vigorous stirring at −5 °C. The
reaction mixture was allowed to come to 0 °C and stirred over-
night. The solvent was evaporated, and the yellow residue was
purified by flash chromatography with a gradient solvent
system. [EtOAc–hexane (1 : 4), EtOAc–hexane (1 : 3), and EtOAc–
hexane (1 : 2)] to afford 4-(2-diazoacetyl)-2-methoxyphenyl
acetate (7b) as a yellow crystalline solid (645 mg, 69% yield):
mp = 96–99 °C; 1H NMR (500 MHz, CD3COCD3) δ ppm 7.56
(1H, d, J = 2 Hz), 7.47–7.45 (1H, d, J = 8.2 Hz), 7.18–7.16 (1H, d,
J = 8.2 Hz), 6.63 (1H, s), 3.90 (3H, s), 2.26 (3H, s); 13C NMR
(125 MHz, CDCl3) δ ppm 185.6, 168.8, 152.6, 144.5, 136.5, 124,
120.4, 111.6, 56.5, 54.4, 20.5; IR (KBr, cm−1) 3078, 2112, 1765,
1582, 1508, 1420, 1367, 1192, 904, 785; MS (ESI (−)) calcd for
(C11H9N2O4 − H)− 233.0562, found 233.0553.
2-Diazo-1-(4-hydroxyphenyl)ethan-1-one,
1a
(α-diazo-p-
hydroxyacetophenone). The general method of Das et al.64 was
followed with modifications. To a stirred solution of α-diazo-p-
acetoxyacetophenone (7a, 60 mg, 0.29 mmol) in aqueous
MeOH (H2O–MeOH, 1 : 4, 10 mL), NH4OAc (181 mg, 2.4 mmol)
was added. The resulting mixture was warmed to 50 °C and
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the progress of the reaction was monitored by TLC. After 4 h, reaction was monitored by TLC. After 8 h, the reaction mixture
the reaction mixture was concentrated and the residue was was concentrated and the residue was extracted with acetone
extracted with EtOAc (10 mL × 5). Combined organic layers (10 mL × 5). The combined organic layers were dried over
were dried over anhydrous MgSO4 and the solvent was evapor- anhydrous MgSO4 and the solvent was evaporated to afford
ated to afford α-diazo-p-hydroxyacetophenone (1a) as a yellow- 2-diazo-1-(4-hydroxy-3,5-dimethoxyphenyl)ethanone (7c) as a
ish orange colored crystalline solid that was further purified yellow-brown oil which was further purified on silica gel
on silica gel (hexane–EtOAc, 1 : 1) to generate the pure com- (hexane–EtOAc, 1 : 1) to generate the pure compound as a
pound as yellow colored crystals (48 mg, 0.30 mmol, 100% thick yellow oil (545 mg, 94% yield): 1H NMR (400 MHz,
yield), mp = 144–150 °C (dec.): 1H NMR (CD3COCD3) δ ppm CD3COCD3) δ ppm 8.03 (1H, s), 7.20 (2H, s), 3.88 (6H, s); 13C
9.20 (1H, s), 7.77–7.75 (2H, d, J = 8.8 Hz), 6.92–6.90 (2H, d, J = NMR (125 MHz, CD3COCD3) δ (ppm) 185.5, 148.6, 128.6,
8.8 Hz), 6.47 (1H, s); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 105.5, 56.8, 53.3; IR (KBr, cm−1) 3313, 2115, 1601, 1564, 1518,
185.4, 162.7, 129.9, 129.7, 116.2, 53.2; IR (KBr, cm−1) 3263, 1456, 1371, 1194, 1114, 762, 733, 669; MS (ESI (−)) m/z calcd
2170, 2123, 1605, 1560, 1508, 1261, 1230, 1173, 1099, 1028, for (C10H10N2O4 − H)− 221.0562, found 221.0558.
802; UV/Vis (CH3CN–H2O), λmax (ε L mol−1 cm−1) 306 (14 165);
4-(2-Diazoacetyl)-3-methoxyphenyl acetate (7e). A flame
MS (ESI (+)) m/z calcd for (C8H6N2O2 + H)+ 163.0507, found dried 50 mL round bottomed flask was charged with 4-acetoxy-
163.1299; m/z calcd for (C8H6N2O2 + Na)+ 185.1118, found 2-methoxybenzoic acid (6e, 840 mg, 4.0 mmol) and freshly dis-
185.1129.
tilled SOCl2 (20 mL) was added under Ar. The resulting
2-Diazo-1-(4-hydroxy-3-methoxyphenyl)ethanone (1b). The mixture was refluxed at 80 °C for 8 h and concentrated under
general method of Das et al.64 was applied with modifications. reduced pressure to afford 4-acetoxy-2-methoxybenzoyl chlor-
To a stirred solution of 4-(2-diazoacetyl)-2-methoxyphenyl ide as colorless oil. This acid chloride was used in the next
acetate (7b, 600 mg, 2.56 mmol) in aqueous MeOH (H2O– step without further purification. General method A was used
MeOH, 1 : 4, 20 mL), was added NH4OAc (1.578 g, to generate diazomethane in excess by distillation in dry ether.
20.49 mmol). The resulting mixture was warmed at 50 °C and Then a solution of acid chloride (913 mg, 4.0 mmol) in dry
the progress of the reaction was monitored by TLC. After 8 h, ether (10 mL) was added dropwise to the distillate containing
the reaction mixture was concentrated and the residue was the diazomethane in ether with vigorous stirring at −5 °C. The
extracted with acetone (10 mL × 5). The combined organic reaction mixture was allowed to come to 0 °C and stirred over-
layers were dried over anhydrous MgSO4 and the solvent was night. The solvent was evaporated, and the yellow solid was
evaporated to afford 2-diazo-1-(4-hydroxy-3-methoxyphenyl)- purified by flash chromatography on triethylamine saturated
ethanone (1b) as a yellow-orange oil which was further purified silica gel with a gradient solvent system [EtOAc–hexane (1 : 4),
on silica gel (hexane–EtOAc, 1 : 1) to generate the pure com- EtOAc–hexane (1 : 3), and EtOAc–hexane (1 : 2)] to afford 4-(2-
1
pound as a yellow oil (473 mg, 96% yield): H NMR (500 MHz, diazoacetyl)-3-methoxyphenyl acetate (7e) as a yellow solid
CD3COCD3) δ ppm 8.45 (1H, s), 7.40–7.38 (1H, d, J = 2.1 Hz), (645 mg, 69% yield): mp 87–90 °C; 1H NMR (500 MHz,
6.88–6.86 (2H, d, J = 8.4 Hz), 6.53 (1H, s), 3.90 (3H, s); 13C NMR CD3COCD3) δ ppm 7.90–7.88 (1H, d, J = 7.8 Hz), 6.94 (1H, d,
(125 MHz, CD3COCD3) δ (ppm) 185.4, 152.1, 148.5, 130, 122, J = 2 Hz), 6.84–6.82 (1H, d, J = 8.5), 6.63 (1H, s), 3.95 (3H, s),
115.6, 110.8, 56.4, 53.3; IR (Teflon film, cm−1) 3279, 3008–2839, 2.27 (3H, s); 13C NMR (125 MHz, CD3COCD3) δ (ppm) 169.3,
2106, 1688, 1591, 1516, 1356, 1277, 1200, 1028, 777; MS (ESI 156.1, 131.8, 115, 107.1, 58.1, 56.6, 21.1; IR (KBr, cm−1
(−)) calcd for (C9H8N2O3 − H)− 191.0457, found 191.0438.
3126–3032, 2102, 1765, 1618, 1601, 1418, 1358, 1261, 1207,
)
2-Diazo-1-(4-hydroxy-3,5-dimethoxyphenyl)ethanone (7c). A 1016, 962, 906, 690; MS (ESI (+)) m/z calcd for (C11H10N2O4 +
flame dried 50 mL round bottomed flask was charged with H)+ 235.0719, found 235.0728.
4-acetoxy-3,5-dimethoxybenzoic acid (6c, 1.085 g, 4.5 mmol) and
Conversion of 2-diazo-1-(4-hydroxyphenyl)ethanones 1a–d to
the corresponding pHP phosphate and carboxylate esters
freshly distilled SOCl2 (20 mL) was added under Ar. The result-
ing mixture was refluxed at 80 °C for 8 h and concentrated
under reduced pressure to afford 3,5-dimethoxy-4-acetoxyben-
Diethyl 2-(4-hydroxyphenyl)-2-oxoethyl phosphate (9a). To a
zoyl chloride as a colorless oil. This acid chloride was used in stirred solution of α-diazo-p-hydroxyacetophenone (1a, 100 mg,
the next step without any further purification. General method 0.62 mmol) in benzene (5 mL), diethyl phosphate (190 mg,
A was used to generate diazomethane in excess by distillation 1.23 mmol) in benzene (5 mL) was added dropwise. The result-
in dry ether. Then a solution of acid chloride (1.165 g, ing mixture was stirred at 60 °C and the progress of the reac-
4.5 mmol) in dry ether (10 mL) was added dropwise to the dis- tion was monitored by TLC. After 24 h the benzene layer was
tillate (diazomethane) with vigorous stirring at −5 °C. The washed sequentially with saturated NaHCO3 (20 mL) and water
reaction mixture was allowed to come to 0 °C and stirred over- (20 mL) and dried over anhydrous MgSO4. The solvent was
night. The solvent was evaporated, and the dark yellow colored evaporated to afford diethyl 2-(4-hydroxyphenyl)-2-oxoethyl
residue was used in the next step without purification. To a phosphate (9a) as yellowish white solid that was chromato-
stirred solution of crude 4-(2-diazoacetyl)-2,6-dimethoxyphenyl graphed on silica gel (hexane–EtOAC, 1 : 1) to produce the pure
acetate (690 mg, 2.61 mmol) in aqueous MeOH (H2O–MeOH, compound as a white solid (149 mg, 84% yield). The spectro-
1 : 4, 20 mL), NH4OAc (1.61 g, 20.89 mmol) was added. The scopic data agree with literature values.4 Likewise, diethyl phos-
resulting mixture was warmed at 50 °C and the progress of the phate esters of 9a′–d were synthesized by the same procedure.
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Diethyl 2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl phosphate (30 mg, 0.147 mmol) in aqueous MeOH (1 : 4, 10 mL), NH4OAc
(9b). A dark yellow crude product of 9b was further purified (92 mg, 1.19 mmol) was added. The resulting mixture was
on silica gel using a gradient solvent system [EtOAc–hexane warmed at 50 °C and the progress of the reaction was moni-
(3 : 1), and EtOAc–MeOH (19 : 1)] to isolate the pure compound tored by TLC. After 4 h, the reaction mixture was concentrated
as a white crystalline solid (340 mg, 92% yield): mp 95–98 °C: and the residue was extracted with EtOAc (10 mL × 5). The
1H NMR (400 MHz, CD3COCD3) δ ppm 9.40 (1H, s) 7.83–7.7.81 combined organic layers were dried over anhydrous MgSO4
(2H, d, J = 8.8 Hz), 6.56 (2H, m, including a doublet), 5.12–5.09 and the solvent was evaporated to afford the crude benzoate
(2H, d, J = 11.2 Hz); 4.20–4.13 (4H, m), 3.94 (3H, s), 1.33–1.29 ester as a yellowish orange colored crystalline solid. The crude
(6H, m); 31P NMR (162 MHz, CD3COCD3) δ ppm −0.37; 13C compound was further purified on silica gel (EtOAc–hexane
NMR (125 MHz, CD3COCD3) δ (ppm) 191.5, 164.97, 162.9, 1 : 1) to give pure 2-(4-hydroxyphenyl)-2-oxoethyl benzoate (10)
133.4, 117.3, 109.4, 99.7, 73.1–73.0, 64.4, 56.1, 16.5; IR (KBr, as a white solid (25 mg, 0.098 mmol, 97% yield), 1H NMR
cm−1) 3134, 1672, 1602, 1473, 1383, 1337, 1231, 1032, 984, (CD3COCD3) δ ppm 9.33 (1H, s), 8.12–8.09 (2H, m), 7.98–7.95
849; UV/vis [H2O–CH3CN (1 : 1)], λmax (ε M−1 cm−1) 307 (8498), (2H, m), 7.70–7.66 (1H, m), 7.57–7.53 (2H, m), 7.00–6.97 (2H,
278 (9465); MS (ESI (+)) m/z calcd for (C13H19O7P − H)− m), 5.65 (2H, s); 13C NMR (125 MHz, CD3COCD3) δ (ppm)
317.0790, found 317.0795.
191.12, 166.47, 163.31, 134.20, 131.27, 131.07, 130.55, 129.54,
Diethyl 2-(4-hydroxy-3,5-dimethoxyphenyl)-2-oxoethyl phos- 127.66, 116.44, 116.36, 67.34; IR (KBr, cm−1) 3350, 1685, 1600,
phate (9c). A brown-yellow oil crude product was chromato- 1500, 840, 720, 690; MS (ESI (+)) m/z calcd for (C15H13O4 + H)+
graphed on silica gel with a gradient solvent system; EtOAc– 256.0798, found 256. 0814.
hexane (1 : 2), EtOAc–hexane (1 : 1), EtOAc–hexane (2 : 1), and
2-(4-Hydroxyphenyl)-2-oxoethyl acetate (11). To a stirred
EtOAc–hexane (3 : 1)) to produce the pure diethyl 2-(4-hydroxy- solution of α-diazo-p-hydroxyacetophenone (1a, 10 mg,
3-methoxyphenyl)-2-oxoethyl phosphate (9c) as a thick yellow 0.062 mmol) in acetonitrile and water (10 mL, 4 : 1), glacial
oil (588 mg, 75% yield): 1H NMR (400 MHz, CD3COCD3) δ ppm acetic acid (1 mL, 16 mmol) was added dropwise at rt. The
8.26 (1H, s) 7.32 (2H, s), 5.37–5.34 (2H, d, J = 10.8 Hz); resulting mixture was stirred at rt and the progress of the reac-
4.20–4.13 (2H, m), 3.91 (3H, s), 1.33–1.29 (6H, m); 31P NMR tion was monitored by TLC. After 16 h the reaction mixture
(162 MHz, CD3COCD3) δ ppm −0.12; 13C NMR (125 MHz, was concentrated and ethyl acetate (10 mL) was added. The
CD3COCD3) δ (ppm) 191.8–191.7, 148.7, 142.6, 106.6, 69.5, organic layer was washed sequentially with saturated NaHCO3
64.5–64.4, 56.8, 16.50; IR (Teflon film, cm−1) 3242, 2982–2848, (20 mL) and water (20 mL) and dried over anhydrous MgSO4.
1693, 1605, 1518, 1460, 1327, 1194, 1115, 1045, 802; UV/vis The solvent was evaporated to afford crude acetate ester as a
[H2O–CH3CN (1 : 1)], λmax (ε M−1 cm−1) 305 (1617); MS (ESI (−)) yellowish brown solid that was chromatographed on silica gel
m/z calcd for (C14H21O8P − H)− 347.0896, found 347.0889.
2-(4-Hydroxyphenyl)-2-oxoethyl diphenyl
(EtOAc–hexane 1 : 1) to give the pure 2-(4-hydroxyphenyl)-2-
phosphate oxoethyl acetate, 11, as a white solid (11.8 mg, 0.061 mmol,
(9a′). The general methods of Epstein and Garrossian65 and 98% yield). The spectroscopic data are in agreement with
Périé and Gefflaut23 were used with modifications. To a stirred reported data.21
2-Amino-5-(2-(4-hydroxyphenyl)-2-oxoethoxy)-5-oxopentanoic
acid (13). The general method of Shinada et al.66 was followed
with modifications. To a stirred solution of α-diazo-p-hydroxy-
acetophenone (20 mg, 0.12 mmol) in toluene (10 mL), 5-tert-
butoxy-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (Boc-
Glu(OtBu)-OH – 56 mg, 0.18 mmol) in toluene (2 mL) was
added dropwise at rt. A catalytic amount of copper acetoace-
tonate (3 mg, 0.012 mmol) was added. The resulting mixture
was stirred at 60 °C and the progress of the reaction was
monitored by TLC. After 2 h ethyl acetate (10 mL) was added.
The organic layer was washed sequentially with saturated
NaHCO3 (20 mL) and water (20 mL) and dried over anhy-
drous MgSO4. The solvent was evaporated to afford the crude
protected glutamate ester that was chromatographed on
silica gel (hexane–EtOAc, 1 : 1) to produce protected gluta-
mate ester as a yellowish brown solid that was then used in
the deprotection step. To a stirred solution of the above com-
pound in CH2Cl2 (1 mL), freshly distilled TFA (9 mL) was
added. The reaction mixture was allowed to stir for 15 min
and concentrated under reduced pressure. Then residue was
dissolved in water and CH2Cl2 (20 mL, 1 : 1). The water layer
was extracted, frozen, and then lyophilized to afford pHP-
glutamate, 13, as a white solid (35 mg, 71% overall yield).
solution of α-diazo-p-hydroxyacetophenone (1a, 11 mg,
0.068 mmol) in benzene (5 mL), diphenyl phosphate (34 mg,
0.14 mmol) in benzene (5 mL) was added dropwise. The result-
ing mixture was stirred at rt and the progress of the reaction
was monitored by TLC. After 30 min, the benzene layer was
washed sequentially with saturated NaHCO3 (20 mL) and water
(20 mL) and dried over anhydrous MgSO4. The solvent was
evaporated to afford 2-(4-hydroxyphenyl)-2-oxoethyl diphenyl
phosphate 9a′, as a yellowish white solid that was chromato-
graphed on silica gel (hexane–EtOAC, 1 : 1) to produce the pure
compound (24 mg, 92% yield). The spectroscopic data are in
agreement with reported data.10b
2-(4-Hydroxyphenyl)-2-oxoethyl benzoate (10). To a stirred
solution of α-diazo-p-acetoxyacetophenone (1a, 20 mg,
0.098 mmol) in benzene (5 mL), benzoic acid (24 mg,
0.20 mmol) in benzene (5 mL) was added dropwise. The result-
ing mixture was refluxed at 70 °C. The progress of the reaction
was monitored by TLC. After 42 h the benzene layer was
washed sequentially with saturated NaHCO3 (40 mL) and water
(40 mL) and dried over anhydrous MgSO4. The solvent was
evaporated to afford a mixture of acetoxy benzoate and unpro-
tected benzoate as a yellowish brown colored solid. (30 mg,
0.10 mmol, 100% yield). To a solution of the above mixture
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The spectroscopic data are in agreement with reported overnight under inert atmosphere. The reaction mixture was
data.67
concentrated and the yellow colored crude product was used
2-(4-Hydroxyphenyl)-2-oxoethyl 4-aminobutanoate (14). The for the deprotection step without further purification. To a
general method of Shinada et al.66 was followed with modifi- stirred solution of the crude acetate in aqueous MeOH (1 : 4,
cations. To a stirred solution of α-diazo-p-hydroxyacetophe- 10 mL), NH4OAc (60 mg, 0.78 mmol) was added. The resulting
none (1a, 50 mg, 0.31 mmol) in toluene (10 mL), 4-(tert- mixture was warmed at 50 °C and the progress of the reaction
butoxycarbonylamino) butanoic acid (Boc-GABA, 75 mg, was monitored by TLC. After 8 h, the reaction mixture was con-
37 mmol) in toluene (2 mL) was added dropwise at rt. A cataly- centrated and the residue was extracted with EtOAc (10 mL ×
tic amount of copper acetylacetonate (8 mg, 0.031 mmol) was 5). The combined organic layers were dried over anhydrous
added to the reaction mixture. The resulting mixture was MgSO4 and the solvent was evaporated to afford 2-(4-methoxy-
stirred at 60 °C and the progress of the reaction was monitored phenoxy)-4-hydroxyacetophenone, 18, as a brownish white
by TLC. After 2 h ethyl acetate (10 mL) was added. The organic solid which was further purified on silica gel (hexane–EtOAc,
layer was washed sequentially with saturated NaHCO3 (20 mL) 1 : 1) to generate the pure compound as a white solid (18 mg,
and water (20 mL) and dried over anhydrous MgSO4. The 56% overall yield). The spectroscopic data are in strong agree-
solvent was evaporated to afford crude Boc-GABA ester as a yel- ment with reported data.21
lowish brown solid which was chromatographed on silica gel
1-(4-Hydroxyphenyl)-2-(4-(trifluoromethyl)phenoxy)ethan-1-
(hexane–EtOAc, 1 : 1) to give the pHP Boc-GABA as a yellowish one (19). To a stirred solution of α-diazo-p-acetoxyacetophe-
brown solid. To a stirred solution of the above compound in none (1a, 40 mg, 0.20 mmol) in anhydrous toluene (10 mL),
CH2Cl2 (5 mL), freshly distilled TFA (5 mL) was added. The and p-trifluoromethyl phenol (64 mg, 0.39 mmol) in toluene
reaction mixture was allowed to stir for 15 min and concen- (2 mL) was added dropwise at rt. A catalytic amount of
trated under reduced pressure. The residue was dissolved in rhodium(II) acetate dimer (9 mg, 0.02 mmol) was added to the
water and CH2Cl2 (20 mL, 1 : 1). The water layer was extracted, reaction mixture. The resulting mixture was stirred at 60 °C
frozen, and then lyophilized to afford pHP GABA, 14, as a overnight under inert atmosphere. The reaction mixture was
white solid (81 mg, 75% overall yield). The spectroscopic data concentrated and the yellow colored crude product was used
are in strong agreement with literature.9b
for the deprotection step without any purification. To a stirred
2-(4-Hydroxyphenyl)-2-oxoethyl trifluoromethanesulfonate solution of the crude 1-(4-acetoxyphenyl)-2-(4-(trifluoromethyl)-
(16). To a stirred solution of α-diazo-p-hydroxyacetophenone phenoxy)ethanone in aqueous MeOH (1 : 4, 10 mL), NH4OAc
(1a, 10 mg, 0.062 mmol) in anhydrous benzene (6 mL), triflic (120 mg, 1.6 mmol) was added. The resulting mixture was
acid (10 mg, 0.068 mmol) in benzene (4 mL) was added drop- warmed to 50 °C and the progress of the reaction was moni-
wise at 0 °C under Ar. The reaction mixture was allowed to stir tored by TLC. After 8 h, the reaction mixture was concentrated
for 30 min at 0 °C, and then brought to room temperature. At and the residue was extracted with EtOAc (10 mL × 5). The
that point, ethyl acetate (10 mL) was added to the reaction combined organic layers were dried over anhydrous MgSO4
mixture and the organic phase was washed with saturated and the solvent was evaporated to afford the 1-(4-hydroxyphe-
NaHCO3 solution (15 mL × 3) and water (20 mL). The organic nyl)-2-(4-(trifluoromethyl)phenoxy)ethanone as
a brownish
layer was separated, dried over anhydrous MgSO4 and filtered. white solid which was further purified on silica gel (hexane–
The solvent was evaporated to afford 2-(4-hydroxyphenyl)-2- EtOAc, 1 : 1) to generate the pure 1-(4-hydroxyphenyl)-2-(4-(tri-
oxoethyl trifluoromethanesulfonate as a yellowish brown solid fluoromethyl)phenoxy)ethanone, 19, as a brownish white solid
which was run through a small pad of silica gel (hexane– (49 mg, 68% overall yield. The spectroscopic data are in strong
EtOAc, 1 : 1) to afford the 2-(4-hydroxyphenyl)-2-oxoethyl tri- agreement with reported data.21
fluoromethanesulfonate (16, R = CF3SO3) as a white solid
Physical and spectral properties of 2-diazo-1-(4-hydroxyphenyl)-
ethan-1-one
which decomposed with time at room temperature (16 mg,
0.056 mmol, 91% yield), 1H NMR (400 MHz, CD3COCD3) δ
ppm 9.48 (1H, s), 7.96–7.94 (2H, dd, J = 6.8 Hz, 2 Hz),
X-Ray crystallographic structure for the 2-diazo-1-(4-hydroxy-
7.00–6.98 (2H, dd, J = 6.8 Hz, 1.96 Hz), 5.81 (2H, s); 19F NMR phenyl)ethan-1-one (1a). The needle shaped light yellow color
(376 MHz, CD3COCD3) δ (ppm) −76.47 (3F, s). Product was crystals of diazo pHP 1a were produced from hexane–EtOAc
really unstable and decomposed slowly at room temperature. solvent system. Colorless rectangular parallelepiped-shaped
Thus, the other spectroscopic data was not obtained on the crystals of C8H6N2O2 are, at 100(2) K, orthorhombic, space
15
target compound.
group Pbca – D2h (no. 61)68 with a = 13.729(2) Å, b = 6.795(1)
1-(4-Hydroxyphenyl)-2-(4-methoxyphenoxy)ethan-1-one Å, c = 16.111(2) Å, V = 1503.1(3) Å3 and Z = 8 molecules [dcalcd
=
(18). The general method of Shinada et al.66 was followed with 1.433 g cm−3; μa(MoKα) = 0.106 mm−1]. A full hemisphere of
modifications. To a stirred solution of α-diazo-p-acetoxyaceto- diffracted intensities (1850 40-second frames with a ω scan
phenone (1a, 20 mg, 0.098 mmol) in anhydrous toluene width of 0.30°) was measured for a single-domain specimen
(10 mL), and 4-methoxyphenol (24 mg, 0.19 mmol) in toluene using graphite-monochromated MoKα radiation (λ
=
(2 mL) was added dropwise at rt. A catalytic amount of 0.71073 Å) on a Bruker SMART APEX CCD Single Crystal Dif-
rhodium(II) acetate dimer (4 mg, 0.01 mmol) was added to the fraction System.69 X-rays were provided by a fine-focus sealed
reaction mixture. The resulting mixture was stirred at 60 °C X-ray tube operated at 50 kV and 30 mA. Lattice constants were
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determined with the Bruker SAINT software package using and with 16–350 nm (RPR 3500 Å) or 2–300 nm (RPR 3000 Å)
peak centers for 5566 reflections. A total of 12 759 integrated lamps. The tubes were placed in a RPR merry-go-round appar-
reflection intensities having 2θ((MoKα) < 58.23° were produced atus and a counter was started at the onset of exposure to
using the Bruker program SAINT;70 1932 of these were unique record the time of irradiation. The samples were irradiated at
and gave Rint = 0.063 with a coverage which was 95.5% com- 40–45 °C in the presence or absence of oxygen as indicated in
plete. The data were corrected empirically for variable absorp- Tables 3 and 4. Exposure times were controlled by manual
tion effects using equivalent reflections; the relative removal of the sample from the reactor or alternately by
transmission factors ranged from 0.722 to 1.000. The Bruker turning the lamps on or off.
software package SHELXTL was used to solve the structure
For the NMR tubes, the reaction course was monitored by
using “direct methods” techniques. All stages of weighted full- 1H NMR. The NMR yields of the major products 4a–d, or 8g
matrix least-squares refinement were conducted using Fo2 data and the disappearance of the diazo pHP derivative (1a–d, 7b,
with the SHELXTL Version 6.10 software package.71
e) were monitored until the diazo pHP had disappeared. For
The final structural model incorporated anisotropic the Pyrex tubes, the crude mixture was concentrated and the
thermal parameters for all nonhydrogen atoms and isotropic main products were isolated by base extraction. The product
1
thermal parameters for all hydrogen atoms. All hydrogen identities were confirmed by comparison of their H and 13C
atoms were located in a difference Fourier and included in the NMR spectra with those of authentic samples available from
structural model as independent isotropic atoms whose para- earlier pHP photochemical studies. The presence or absence
meters were allowed to vary in least-squares refinement cycles. of minor side products were established by spiking the reac-
A total of 133 parameters were refined using no restraints, tion mixture with authentic samples and analysis by NMR
1932 data and weights of w = 1/[σ2(F2) + (0.0870P)2 + 0.7647P], or HPLC.
where P = [Fo2 + 2Fc ]/3. Final agreement factors at convergence
are: R1(unweighted, based on F) = 0.064 for 1835 independent
2
Quantum yield measurements
absorption-corrected “observed” reflections having 2θ(MoKα) <
By RP-HPLC. A stock solution was prepared by dissolving
58.23° and I > 2σ(I); R1(unweighted, based on F) = 0.067 and biphenyl (160 mg, 1.04 mmol, standard) in CH3CN (90 mL) in
wR2(weighted, based on F2) = 0.165 for all 1932 independent a 100 mL volumetric flask and diluting it to the mark with
absorption-corrected reflections having 2θ(MoKα) < 58.23°. H2O (10 mL). A quartz tube was charged with 2-diazo-1-
The largest shift/s.u. was 0.000 in the final refinement cycle. (4-hydroxyphenyl)ethan-1-one (1a, 10 mg, 0.062 mmol) CH3CN
The final difference map had maxima and minima of 0.42 and (1.0 mL) and H2O (1.0 mL) and 2.0 mL of the biphenyl internal
−0.35 e− Å−3, respectively.
standard solution (3.2 mg, 0.021 mmol) was added. The
UV/Vis study of 2-diazo-1-(4-hydroxyphenyl)ethan-1-one (1a) sample was irradiated at 300 or 350 nm with 2–300 or
at different pH values. A 10 mL volumetric flask was charged 16–350 nm lamps, aliquots (100 µL) were collected after 0, 2, 4,
with 2-diazo-1-(4-hydroxyphenyl)ethan-1-one (1a, 10 mg, 6, and 8 min and diluted with 950 µL of CH3CN–H2O (1 : 1),
0.062 mmol) and dissolved in CH3CN (5.0 mL) and H2O then analyzed by HPLC using a Waters XTerra MS-C18 analyti-
(5.0 mL). The pH was adjusted by changing the pH of H2O cal column. Average peak areas from three injections of each
(5.0 mL) before mixing it with CH3CN (5.0 mL). A buffer solu- aliquot corrected for the internal standard were used to obtain
tion of sodium acetate/acetic acid in water was used to obtain vs. irradiation time (in min) to obtain slope (m) for the best fit
pH 4. A buffer solution of ammonium acetate/ammonia was by linear regression analysis. The light output (L) in units of
used to achieve pH 7 and 10, respectively. The UV-Vis scans millieinsteins per minute of 300 and/or 350 nm irradiation.
were performed under ambient conditions with suitable The quantum yields (Φ) for the disappearance of 2-diazo-1-
dilutions at each pH value.
(4-hydroxyphenyl)ethan-1-one and appearance of PAA (4) are
given in Tables 2 and 3.
General procedure for pKa determination
Photolysis samples were also analyzed by RP-HPLC per-
A sample of the 2-diazo-1-(4-hydroxyphenyl)ethan-1-one 1a–d formed with a Waters XTerra MS-C18 analytical column
(∼10 mg, ∼0.05 mmol) was dissolved in H2O–CH3CN (20 mL) (column size: 2.1 × 150 mm, particle size: 5 μm) connected to
in a beaker and was titrated with 0.005 M NaOH solution (pre- a Waters Alliance HT 2795 or a Waters Aquity UPLC. The
pared in H2O–CH3CN) while stirring the contents vigorously solvent system was 99% CH3CN, 1% H2O, 0.06% formic acid
after each addition. pH measurements were taken for each and 99% H2O, 1% CH3CN, 0.08% formic acid. Detection was
0.4 mL addition of NaOH solution. Scatter plots were created at 250 nm and 280 nm. The flow rate was 0.2 mL min−1 and
by plotting pH vs. volume of NaOH solution for each com- the injection volume was 5 µL. Each sample was run three
pound. pKa for compounds 1a–d was determined at the half times. The light output for the determination of quantum
equivalence point using these plots.
General procedure for photolysis. A sample of the 2-diazo-1- method.72 The results are given in Tables 2 and 3.
(4-hydroxyphenyl)ethan-1-one 1a–d, 7b,e (∼6 mg. ∼0.05 mmol)
By 1H-NMR. A Pyrex NMR tube was charged with 1b–d
efficiencies was measured by using the potassium ferrioxalate
dissolved in 1.0 mL of CD3CN–D2O was placed in an NMR (∼6 mg, ∼0.05 mmol, 2 mg in the case of 1d) and dissolved in
tube (or Pyrex test tubes) and irradiated in a Rayonet RPR-100 CD3CN (400 μL) and D2O (400 μL). DMF (2 µL) was added as
photochemical reactor fitted with a merry-go-round apparatus an internal standard. The contents were mixed thoroughly.
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The resulting sample was photolyzed without degassing at experiment was repeated with a sensitizer concentration of
300 nm with 4–3000 Å lamps, and the 1H NMR spectra were 9.25 × 10−3 M. Results are in Table 3.
collected after 0, 2, 4, 6 and 8 min. The depletion of 1b–d and
Photolysis of 1a with a xanthone sensitizer, mangiferin, 21
appearance of 4b–c was determined by integration of the 1H (4.76 × 10−3 M and 1.19 × 10−2 M). A quartz tube charged with
NMR signals at δ ∼6.2 ppm and ∼3.50 ppm compared to the 1a (10 mg, 0.062 mmol) dissolved in CH3CN–H2O (1 : 1.
DMF peaks which gave the disappearance of starting material 1.0 mL) and biphenyl (2.0 mL from the internal standard stock
and appearance of the corresponding phenylacetic acid solution, and mangiferin, 21 (8 mg, 0.019 mmol, sensitizer)
respectively. Scatter plots were created by plotting the number were placed in a quartz test tube. After thorough mixing, the
of mmol of 1b–d or 4b–c vs. irradiation time. The slope (m) of sample was irradiated at 300 or 350 nm and aliquots (100 µL)
the best fit line from the linear regression analysis was deter- collected after 0, 2, 4, 6, and 8 min. Aliquots were diluted with
mined. The light output (L) of the 4–3000 Å lamps in the 950 µL of CH3CN–H2O, 1 : 1 and analyzed by HPLC. The experi-
photoreactor was determined separately using the potassium ment was repeated with the sensitizer concentration of 1.19 ×
ferrioxalate method in units of millieinsteins per min. The 10−2 M. The quantum yields for disappearance of 1a and
quantum yield (Φ) for the disappearance of 1b–d and the appearance of 4 in Table 3.
appearance of 4b–c was then calculated (Φ = |m|/L). The
results are given in Table 2.
Photolysis of 1a under Ar. A quartz tube was charged with
1a (10 mg, 0.062 mmol) dissolved in CH3CN–H2O (1 : 1.
Photolysis of 1a under acidic conditions at −10 °C. General 1.0 mL) and biphenyl (2.0 mL from the internal standard stock
procedure for photolysis was performed on 1a as mentioned solution, and mangiferin (8 mg, 0.019 mmol, sensitizer) were
above under following specific conditions in an NMR tube. placed in a quartz test tube. The tube, fitted with a rubber
Dry ice in isopropanol was utilized to maintain the tempera- septum, was cooled in an ice bath, purged with Ar for 30 min
ture at −10 °C in a dewar during the photolysis. A Pyrex NMR and irradiated at 300 nm. Aliquots (100 µL) were collected
tube was charged with MeOH-d4 (380 µL) and HBF4 [48% (w/w) after 0, 2, 4, 6, and 8 min of photolysis. Aliquots were diluted
in H2O (20 µL)] was added to it. Small amount of anhydrous with 950 µL of CH3CN–H2O (1 : 1) and analyzed by HPLC. The
MgSO4 was used to dry MeOH-d4 and the content was cooled quantum yields of the disappearance of 1a and appearance
at −10 °C in a beaker. A separate scintillation vial was charged of 4 are given in Table 3.
with 1a (∼6 mg, ∼0.05 mmol) and dissolved in MeOH-d4
(400 μL) and transferred to the NMR tube after lowering the
Quenching experiments
temperature to −10 °C. The contents were mixed thoroughly at
Photolysis of 1a outgassed with oxygen. A quartz tube was
−10 °C. The resulting sample was photolyzed in the dewar at charged with 1a (10 mg, 0.062 mmol) dissolved in CH3CN–
−10 °C without degassing at 300 nm with 16–3000 Å lamps, H2O (1 : 1. 1.0 mL) and biphenyl (2.0 mL from the internal
and the 1H NMR spectrum was collected after 80 min. (the standard stock solution, and the contents mixed thoroughly.
content from the NMR tube was filtered through a fluted filter The tube was fitted with a rubber septum and sealed, cooled
paper followed by plug of cotton wool and sea sand to remove in an ice bath, and purged with pure oxygen for 30 min. The
MgSO4 before running the NMR). The same experiment was sample was irradiated at 300 nm, and aliquots (100 µL) col-
repeated at room temperature to compare the effect of temp- lected after 0, 2, 4, 6, and 8 min of photolysis. Aliquots were
erature on photolysis under very acidic conditions. The diluted with 950 µL of CH3CN–H2O, 1 : 1 and analyzed by
product identities were confirmed by comparison of their 1H HPLC. The same procedure was repeated three times. The
NMR spectra with those of authentic samples available from quantum yields of the disappearance of 1a and appearance of
earlier pHP photochemical studies. The presence or absence 4 are given in Table 3. Stern–Volmer quenching determined
of minor side products were established by spiking the reac- using the values from literature determinations of the oxygen
tion mixture with authentic samples and analysis by NMR.
concentrations for degassing with Argon, ambient air concen-
trations and purging with pure O2. The Stern–Volmer results
are given in Table 4.
Sensitization experiments
Photolysis of α-diazo-p-hydroxyacetophenone with benzo-
Time-resolved infrared experiments
phenone-4,4-dicarboxylic acid (3.70 × 10−3 M and 9.25 ×
10−3 M). A quartz tube charged with 1-diazo-2-(4-hydroxyphenyl)- Nanosecond time-resolved infrared (TRIR) experiments were
ethanone (1a, 10 mg, 0.062 mmol) dissolved in CH3CN–H2O conducted (with 16 cm−1 spectral resolution) following the
(1 : 1. 1.0 mL) and biphenyl (2.0 mL from the internal standard method of Hamaguchi49,50 and co-workers as has been
stock solution, (3.2 mg, 0.021 mmol) and benzophenone-4,4- described previously.51 Briefly, the broadband output of a
dicarboxylic acid (4 mg, 0.015 mmol, sensitizer) were placed in MoSi2 IR source (JASCO) is crossed with excitation pulses from
a quartz test tube. The resulting mixture was thoroughly mixed a Continuum Minilite II Nd:YAG laser (266 nm, 5 ns, 1.5 mJ)
to give a clear solution then irradiated at 300 or 350 nm and operating at 15 Hz. Changes in IR intensity are monitored
aliquots (100 µL) collected after 0, 2, 4, 6, and 8 min of pho- using an AC-coupled mercury/cadmium/tellurium (MCT)
tolysis. Each aliquot was diluted with 950 µL of CH3CN–H2O, photovoltaic IR detector (Kolmar Technologies, KMPV11-J1/
1 : 1 and analyzed by HPLC. The quantum yields of the dis- AC), amplified, digitized with a Tektronix TDS520A oscillo-
appearance of 1a and appearance of 4 were determined. The scope, and collected for data processing. The experiment is
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conducted in dispersive mode with a JASCO TRIR 1000 1209, 1146, 1016, 960, 899, 804; MS (ESI (+)) m/z calcd for
spectrometer.
(C11H12O5 + Na)+ 247.0583, found 247.0575.
Control experiments with the 2-diazo-1-(4-hydroxyphenyl)-
ethan-1-one (1a); dark reaction. An NMR tube was charged
with 2-diazo-1-(4-hydroxyphenyl)ethan-1-one (1a, 10 mg,
0.062 mmol) dissolved in CD3CN (1 mL) and D2O (1 mL). The
Acknowledgements
contents were mixed thoroughly and warmed in a water bath Support for this work was provided by NIH grant R01
at 40 °C in the dark for 2 h. 1H NMR spectra were recorded GM72910 (RSG) and NSF grant CHE-1213438 (JPT). We thank
before and after heating. There was no significant change Anuranga I. Bandara for assistance with the pKa determi-
before and after the heating. The sample was kept another nations and the quantum yield measurements for compounds
1
48 h in the dark and the H NMR spectrum was recorded. No 1a–d. We wish to thank Dr Victor Day of the University of
significant difference was observed.
Kansas X-ray Crystallography Laboratory for his efforts in
acquiring the X-ray crystallographic data of 1a.
Characterization of photoproducts
6-Hydroxybenzofuran-3(2H)-one (8e). 6-Hydroxybenzofuran-
3(2H)-one (8e) was a product of the deprotection of 4-(2-diazo-
acetyl)-3-methoxyphenyl acetate (7e, 280 mg, 1.47 mmol) with
NH4OAc (898 mg, 11.65 mmol) in H2O–MeOH, 1 : 4 (20 mL) at
50 °C for 8 h. The off-white compound was characterized by
NMR and mass spectroscopy as 6-hydroxybenzofuran-3(2H)-
one [8e, (218 mg, 100% yield)]. The spectroscopic data are in
agreement with reported data.73
3-Oxo-2,3-dihydrobenzofuran-6-yl acetate (8g). Method A:
the general method of Wuennemann was followed.74 Method
B: 3-Oxo-2,3-dihydrobenzofuran-6-yl acetate (8g) was also
formed in the photolysis of 4-(2-diazoacetyl)-3-methoxyphenyl
acetate (7e, 40.0 mg, 0.17 mmol) in CH3CN–H2O (1 : 1) using
2–300 nm lamps under ambient conditions. After 10 min, the
photolysis mixture was concentrated and the resulting residue
was chromatographed on silica gel (EtOAc–hexane (1 : 3),
EtOAc–hexane (1 : 2), and EtOAc–hexane (1 : 1)) to afford 3-oxo-
2,3-dihydrobenzofuran-6-yl acetate (8g) as white crystalline
solid (12 mg, 0.062 mmol, 36% yield), mp 122–124 °C: 1H
NMR (500 MHz, CD3COCD3) δ ppm 7.65–7.64 (1H, d, J = 8.3
Hz), 7.02 (1H, d, J = 1.8 Hz), 6.92–6.90 (1H, d, J = 8.3 Hz), 4.75
(2H, s), 2.30 (3H, s); 13C NMR (125 MHz, CD3COCD3) δ (ppm)
198.6, 175.4, 169.2, 159.5, 125.3, 119.9, 117.4, 108.1, 76.3, 21.1;
IR (KBr, cm−1) 3113–2943, 1759, 1707, 1618, 1454, 1194, 1015,
906, 829, 688; MS (ESI (−)) m/z calcd for (C10H8O4 − H)−
191.0344, found 191.0359.
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2-(4-Acetoxy-2-methoxyphenyl)acetic acid (4e). The 2-(4-
acetoxy-2-methoxyphenyl)acetic acid, 4e was obtained from
photolysis of 4-(2-diazoacetyl)-3-methoxyphenyl acetate (7e,
40.0 mg, 0.17 mmol) in CH3CN–H2O, 1 : 1 at 300 nm under
ambient conditions. After 10 min, the photolysis mixture was
concentrated and the resulting residue was chromatographed
on silica gel (EtOAc–hexane (1 : 3), EtOAc–hexane (1 : 2),
EtOAc–hexane (1 : 1), and EtOAc–hexane (2 : 1)) to afford 2-(4-
acetoxy-2-methoxyphenyl)acetic acid as a yellow solid (4e,
1
10 mg, 0.045 mmol, 26% yield): mp 94–104 °C (dec.); H NMR
8 L. Blancafort, A. Migani and Q. Li, J. Phys. Chem. Lett.,
2012, 3, 1056–1061.
9 (a) K. F. Stensrud, D. Heger, P. Sebej, J. Wirz and
R. S. Givens, Photochem. Photobiol. Sci., 2008, 7, 614–624;
(b) K. Stensrud, J. Noh, K. Kandler, J. Wirz, D. Heger and
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(500 MHz, CD3COCD3) δ ppm 7.22–7.20 (1H, d, J = 8 Hz), 6.70
(1H, s), 6.61–6.60 (1H, d, J = 7.2 Hz), 3.75 (3H, s), 3.54 (2H, s),
2.23 (3H, s); 13C NMR (125 MHz, CD3COCD3) δ (ppm) 169.7,
159.1, 151.8, 132, 117.7, 114.7, 114.1, 105.8, 56.2, 27.4, 21.1; IR
(KBr, cm−1) 3396–2554 (br), 1763, 1705, 1608, 1506, 1419,
Photochem. Photobiol. Sci.
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