Photochemical cyclization with release of carboxylic acids and phenol from pyrrolidino-substituted 1,4-benzoquinones using visible light

Article abstract of DOI:10.1021/ol051362k

(Chemical Equation Presented) Visible light irradiation of 5-acyloxymethyl- and 5-phenoxymethyl-2-pyrrolidino-1,4-benzoquinones effects photoisomerization to labile oxazolidines, which undergo elimination of carboxylate or phenolate leaving groups in high

Full text of DOI:10.1021/ol051362k

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3729-3732
Photochemical Cyclization with Release
of Carboxylic Acids and Phenol from
Pyrrolidino-Substituted
1,4-Benzoquinones Using Visible Light
Yugang Chen and Mark G. Steinmetz*
Department of Chemistry, Marquette UniVersity, Milwaukee, Wisconsin 53201-1881
mark.steinmetz@marquette.edu
Received June 10, 2005
ABSTRACT
Visible light irradiation of 5-acyloxymethyl- and 5-phenoxymethyl-2-pyrrolidino-1,4-benzoquinones effects photoisomerization to labile oxazolidines,
which undergo elimination of carboxylate or phenolate leaving groups in high yields to generate trappable o-quinone methide intermediates.
Early studies have shown that the photochemical cyclization
of 2-amino-1,4-benzoquinones to oxazolidines can be ef-
Scheme 2
fected with sunlight.1 This photocyclization is exemplified
by 2-pyrrolidino-1,4-benzoquinone 1, which gives oxazoli-
dine 2 as a photoproduct (Scheme 1).2 In the case of the
Scheme 1
respect to “dark” elimination of a leaving group (LG), such
as a carboxylate group or a phenolate group. Thus, visible
light would serve to activate a photoremovable protecting
group for release or unmasking of functionality in a
(2) (a) Oxazolidine 2 could be isolated in excellent yield after silica gel
structurally related 2-pyrrolidino-1,4-benzoquinone 3 (Scheme
2), the photocyclization product 4 should be unstable with
column chromatography, eluting with EtOAc in hexane. The high-field
spectral data were as follows: 1H NMR (CDCl3) δ 1.87 (m, 2 H), 2.07 (s,
3 H), 2.14 (s, 3 H), 2.21 (m, 2 H), 2.97 (m, 1 H), 3.35 (m, 1 H), 5.15 (br
s, 1 H), 5.81 (t, J ) 3.3 Hz, 1 H), 6.61 (s, 1 H); 13C NMR (CDCl3) δ 10.8,
15.3, 24.2, 32.8, 55.8, 102.8, 110.8, 111.1, 115.2, 140.5, 145.0, 148.3. (b)
Falci, K. J.; Franck, R. W.; Smith, G. P. J. Org. Chem. 1977, 42, 3317-
3319.
(1) (a) Cameron, D. W.; Giles, R. G. F. Chem. Commun. 1965, 573-
574. (b) Cameron, D. W.; Giles, R. G. F. J. Chem. Soc. C 1968, 1461-
1464. (c) Giles, R. G. F.; Mitchell, P. R. K.; Roos, G. H. P.; Baxter, I. J.
Chem. Soc., Perkin Trans. 1 1973, 493-496.
10.1021/ol051362k CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/27/2005

subsequent step. The use of visible light for unmasking of
functionality is of fundamental importance for the develop-
ment of selective methods for photodeprotection of poly-
functional molecules,3 where selectivity in the deprotection
would depend on the color of the incident light. Progress in
this area has been hindered by the dearth of photocleavable
protecting groups that can be removed with visible light.
With few exceptions,4,5 the usable wavelength region for
photoremoval of protecting groups typically lies below about
400 nm.
Scheme 3
2-Amino-1,4-benzoquinones generally absorb light in the
450-650 nm wavelength region.6 Although the available
energy in this wavelength region (44-63 kcal mol-1) is
insufficient to directly cleave relatively strong bonds, it is
capable of effecting the photocyclization of 1. In the case
of 3, the release of the leaving group is expected to occur
after such a photocyclization, in a dark elimination step that
would be expected to be pH dependent. Nevertheless, one
concern is that no quantum yield has been reported for the
photocyclization of a 2-amino-1,4-benzoquinone. We thus
conducted a preliminary investigation with 1 and found that
upon irradiation at 458 nm the photocyclization occurs in
100% chemical yield with a quantum efficiency of 0.091 in
CH2Cl2 as the solvent.7
The intermediacy of o-quinone methide 5 was probed by
photolyzing the benzoate derivative of 3 (LG ) PhCO2 )
-
with 0.1 M 3-(dimethylamino)cyclohexen-1-one 7 as a
trapping reagent (Scheme 3). In addition to 92% yield of
benzoic acid, a cycloadduct was obtained in 87% yield,
which was identified as 8 after chromatographic isolation.9
The photocyclizations with release of carboxylic acids
from 3 were initially investigated with a benzoate leaving
-
group (LG ) PhCO2 ). Irradiation of 0.02 M solutions in
30% D2O in CD3CN with a 120 W sunlamp produced
benzoic acid in 58% yield at 100% conversion. An additional
product was isolated as a ca. 1:1 mixture of diastereomers
in 36% yield by column chromatography. Its structure, which
-
With other carboxylate leaving groups (LG ) PhCH2CO2
-
or LG ) 4-CNC6H4CO2 ), the cycloadduct 8 was obtained
in 79% and 82% yields, along with 92% and 89% yields of
the corresponding carboxylic acids. Evidently, the presence
of the electron-releasing pyrrolidino and the dimethyl groups
in 5 reduces its reactivity compared to other o-quinone
methides,10 since attempts to trap 5 with various electron-
rich alkenes (ethyl vinyl ether, vinylene carbonate, methyl
trimethylsilyldimethylketene acetal) failed to produce the
corresponding cycloadducts.
-
was assigned as 6 (LG ) PhCO2 ),8 suggested that it was
produced via cycloaddition of an o-quinone methide inter-
mediate 5 with unreacted starting material (Scheme 3), which
would account for the low yields of photoreleased benzoic
acid. Similar results were obtained upon photolysis of 3 (LG
-
) PhCO2 ) at 542 nm with light passed through a mono-
chromator.
The intermediacy of o-quinone methide 5 could account
for new absorption bands that were observed at 339 and 455
nm after 30 min of photolysis of 5 × 10-4 M aminoquinone
(3) (a) Bochet, C. G. Tetrahedron Lett. 2000, 41, 6341-6346. (b) Bochet,
C. G. Angew. Chem., Int. Ed. 2001, 40, 2071-2073.
-
3 (LG ) PhCO2 ) at 2 °C in 30% aq CH3CN with a sunlamp
(4) Furuta, T.; Wang, S. S.-H.; Dantzker, J. L.; Dore, T. M.; Bybee, W.
J.; Callaway, E. M.; Denk, W.; Tsien, R. Y. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 1193-1200.
(Figure 1) or at 542 nm. Upon warming to 20 °C, the new
absorptions disappeared, and the rate of disappearance was
strongly accelerated by adding 8 × 10-3 M dimethylamino-
cyclohexenone 7.11a In 30% phosphate buffer in CH3CN at
(5) Banerjee, A.; Grewer, C.; Ramakrishnan, L.; Jager, J.; Gameiro, A.;
Breitinger, H.-G. A.; Gee, K. R.; Carpenter, B. K.; Hess, G. P. J. Org.
Chem. 2003, 68, 8361-8367.
(6) Herre, W.; Wunderer, H. Tetrahedron 1972, 28, 5433-5443.
(7) (a) Quantum yield determinations were performed at 458 nm. The
ferrioxalate actinometer concentration was increased to ensure that all of
the long-wavelength light was absorbed, as prescribed in ref 7b. (b) Murov,
S. L.; Carmichael, I.; Hug, G. L. Handbook of Photochemistry, 2nd ed.;
Marcel Dekker: New York, 1993; pp 301, 303.
(9) Compound 8, mp 194-196 °C. The spectral data were as follows:
1H NMR (CDCl3) δ 1.08 (s, 3 H) 1.09 (s, 3 H) 1.86 (m, 2 H) 2.05 (s, 3 H)
2.16 (s, 3 H) 2.21 (m, 2 H) 2.29 (s, 2 H) 2.39 (s, 2 H) 2.93 (m, 1 H) 3.24
(m, 2 H) 3.34 (m, 1 H) 5.79 (m, 1 H); 13C NMR (CDCl3) δ 10.8, 11.7,
20.1, 24.1, 28.6, 32.4, 32.7, 41.6, 50.9, 56.0, 102.9, 107.7, 111.5, 113.9,
114.4, 138.8. Anal. Calcd for C21H25NO3: C, 74.31; H, 7.42; N, 4.13.
Found: C, 74.28; H, 7.56; N, 4.20.
(8) The spectral data for the ca. 1:1 diastereomeric mixture of 6 (LG )
PhCO2-) were as follows (minor diastereomer carbons are in parentheses):
1H NMR (CDCl3) δ 1.40 (s, 3 H), 1.44 (s, 3 H), 1.68 (m, 8 H), 1.86 (s, 6
H), 1.85 (m, 4 H), 2.13 (s, 3 H), 2.15 (s, 3 H), 2.17 (m, 4 H), 2.19 (s, 3 H),
2.20 (s, 3 H), 2.45 (m, 2 H), 2.73 (m, 6 H), 2.88 (m, 4 H), 2.99 (m, 2 H),
3.34 (m, 2 H), 5.23 (d, J ) 12 Hz, 2 H), 5.32 (d, J ) 12 Hz, 2 H), 5.76 (m,
2 H), 7.41 (t, J ) 7.8 Hz, 4 H), 7.54 (t, J ) 7.8 Hz, 2 H), 7.95 (d, J ) 7.8
Hz, 4 H); 13C NMR (CDCl3) δ 10.7 (10.6), 11.6, 13.2 (13.1), 17.9 (17.8),
24.1, 25.0 (24.9), 32.61 (32.58), 36.6, 48.0 (47.9), 52.3 (52.0), 55.9 (55.8),
58.6, 94.94 (94.92), 102.6, 110.9 (110.8), 112.0 (111.8), 112.5, 128.7, 129.8,
133.5, 138.98 (138.96), 139.3, 145.0 (144.8), 145.6 (145.5), 146.9 (146.7),
166.2, 193.8 (193.4), 199.1. Anal. Calcd for C33H36N2O6: C, 71.15; H,
6.52; N, 5.03. Found: C, 70.76; H, 6.58; N, 4.99.
(10) Wan, P.; Barker, B.; Diao, L.; Fischer, M.; Shi, Y.; Yang, C. Can.
J. Chem. 1996, 74, 465-475.
(11) (a) The 550 nm band in Figure 1 is due to unreacted starting material.
At low concentrations (<5 × 10-4 M) of reactant 3 (LG ) PhCO2-) present,
trapping of the o-quinone methide is not significant. (b) The pseudo-first-
order decay kinetics observed under buffered conditions is consistent with
hydration of the o-quinone methide. Hydration of o-quinone methide can
be uncatalyzed and can be catalyzed by hydrogen ion and hydroxide ion.11c
(c) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2001, 123, 8089-
8094.
3730
Org. Lett., Vol. 7, No. 17, 2005

Figure 2. Change in mmole versus photolysis time of 3 (LG )
C6H5O-).
appear in the spectrum, suggestive of formation of a high
molecular weight material which could not be readily
identified.
Quantum yields for disappearance of 10-3 M 3 (LG )
C6H5O-) at 458 nm were 0.10 in CH2Cl2 but were lower in
the more polar solvent, CH3CN (Φ ) 0.04). Under aqueous
conditions (30% H2O in CH3CN), quantum yields for
Figure 1. Absorption spectrum of 3 (LG ) C6H5CO2-) before
photolysis in 30% aq CH3CN (- - -) at 2 °C and after photolysis
(s) at 20 °C with a sunlamp. Bands at 339 and 455 nm are
attributed to 5. Scans after photolysis also show decay of the
intermediate at 10 min time intervals and increases in product at
295 nm.
-
disappearance of aminoquinones 3 (LG ) PhCO2 ,
-
-
PhCH2CO2 , and 4-CNC6H4CO2 ) were only ca. 0.005-
0.006. These latter values were determined in the presence
of 0.1 M dimethylaminocyclohexenone trapping agent 7 to
prevent trapping of 5 by unreacted 3. For the phenolate
derivative, the quantum yields correspond to photocyclization
to 4 (LG ) C6H5O-). For the carboxylate derivatives of 3,
the quantum yields likely correspond to the efficiencies for
the photocyclization step in the photochemical mechanism,
which is thought to occur prior to the expulsion of the
carboxylate leaving groups.
pH 6.95 the decay of 5 followed pseudo-first-order kinetics
and had a half-life of 3.5 h at 20 °C.11b The new absorption
bands are similar to those of other long-lived o-quinone
methide intermediates that have been reported previously.12
-
In the above photolyses with 3 (LG ) PhCO2 , PhCH2-
-
-
CO2 , 4-CNC6H4CO2 ), the corresponding photocyclization
products 4 were never observed. However, with a less labile
phenolate leaving group, product 4 (LG ) C6H5O-) was
readily obtained in quantitative yields upon irradiation of
0.014 M aminoquinone 3 (LG ) C6H5O-) in CD2Cl2, neat
CD3CN, or 30% phosphate buffer in CD3CN at pD 5.6 at
25 °C. Compound 4 (LG ) C6H5O-) eliminated phenol at
neutral or basic pH, and the elimination could also be effected
under nonaqueous conditions by adding Et3N to solutions
of 4 (LG ) C6H5O-) in CD2Cl2 or CD3CN. In 30%
phosphate buffer in CD3CN (pD 7) at 17 °C, the elimination
displayed first-order kinetics with a half-life of 9.1 h. Under
identical buffered conditions photolysis of 3 (LG ) C6H5O-)
produced 4 (LG ) C6H5O-) in 73% yield along with 2.7%
of 6 (LG ) C6H5O-) and 8% phenol at 86% conversion
(Figure 2), and the phenol produced by this photolysis could
be accounted for by “dark” elimination from 4 (LG )
C6H5O-). While monitoring the elimination of phenol from
Although the initial photochemical step in the photo-
cyclization of 3 could involve an excited-state hydrogen atom
transfer from the pyrrolidino group to the 1,4-benzoquinone
(Scheme 4), the decreased efficiencies for photocyclization
and leaving group release in going to polar solvents suggests
the existence of a photoinduced electron-transfer step (labeled
as et in Scheme 4) that would be subject to back-electron
transfer (bet) to regenerate the ground state of the reactant.
Electron transfer13 from the pyrrolidino group to the 1,4-
benzoquinone moiety in the lowest triplet excited state14
would generate an intramolecular charge-transfer excited
state, e.g., 9, which could undergo proton transfer followed
by cyclization of intermediate 10 to give 4. The bet would
be competing with proton transfer in 9 and is expected to
be promoted by stabilization of this intramolecular charge-
transfer excited state in polar solvent.
1
(13) An analogous electron transfer occurs from triethylamine to the
benzophenone triplet excited state: Peters, K. S.; Shaefer, C. G. J. Am.
Chem. Soc. 1980, 102, 7566-7567.
(14) Hubig, S. M.; Bockman, T. M.; Kochi, J. K. J. Am. Chem. Soc.
1997, 119, 2926-2935.
4 by H NMR spectroscopy, broad peaks were observed to
(12) Diao, L.; Yang, C.; Wan, P. J. Am. Chem. Soc. 1995, 117, 5369-
5370.
Org. Lett., Vol. 7, No. 17, 2005
3731

Scheme 4
Scheme 5
The photochemical mechanism (Scheme 4) offers the
possibility that the leaving group could be dispelled from
zwitterionic intermediate 10 prior to the formation of 4. This
alternate, zwitterionic elimination mechanism is similar to
that proposed by our studies of R-keto amides.15 Although
we are unable to rule it out in the case of carboxylate leaving
groups, it is clearly not a significant pathway when the
more labile carboxylate leaving groups undergo elimination
such that the unstable photoproduct is not observed. The
leaving group eliminations afford an o-quinone methide
intermediate, which is observable by absorption spectroscopy.
The intermediate is readily trapped by â-aminoalkenones or
unreacted starting material to give cycloadducts. Photo-
cyclization is efficient in intermediate polarity solvents but
becomes less efficient with increasing polarity of the solvent.
leaving group is phenolate (LG ) C6H5O-).
-
2-Pyrrolidino-1,4-benzoquinone
3
(LG
)
PhCO2 ,
-
-
PhCH2CO2 , 4-CNC6H4CO2 ) was obtained from acylation
of quinone 14 with the corresponding acid chlorides (Scheme
5). The addition of pyrrolidine to 13 likely involves air
oxidation of a hydroquinone intermediate to furnish 14. For
3 (LG ) PhO-), low yields were encountered in the
analogous reaction of 17, probably due to competing
elimination of phenolate.
Acknowledgment. We thank Mr. Adam Nothnagel for
technical assistance in the synthesis of 3 (LG ) PhO-).
Acknowledgment is made to the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, for support of this research.
In summary, 2-amino-1,4-benzoquinones 3 undergo pho-
tocyclization with visible light, which activates the system
toward elimination of a suitably placed carboxylate or
phenolate leaving group. With phenolate as the leaving
group, the cyclized photoproduct is isolable but undergoes
pH-dependent elimination of phenol in the dark, whereas
Supporting Information Available: Procedures for the
synthesis of 3 (LG ) PhCO2-, PhCH2CO2-, 4-CNC6H4CO2-,
1
PhO-). H and 13C NMR spectra of 2, 3 (LG ) PhO-), 4
-
1
(LG ) PhO-), 6 (LG ) PhCO2 ), and 8. H NMR spectra
of intermediates in the synthesis of 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) (a) Ma, C.; Steinmetz, M. G.; Cheng, Q.; Jayaraman, V. Org. Lett.
2003, 5, 71-74. (b) Ma, C.; Steinmetz, M. G. Org. Lett. 2004, 6, 629-
632. (c) Ma, C.; Steinmetz, M. G.; Kopatz, E. J.; Rathore, R. Tetrahedron
Lett. 2005, 46, 1045-1048. (d) Ma, C.; Steinmetz, M. G.; Kopatz, E. J.;
Rathore, R. J. Org. Chem. 2005, 70, 4431-4442.
OL051362K
3732
Org. Lett., Vol. 7, No. 17, 2005