Photochemical electrocyclization of α,β-unsaturated anilides to give zwitterionic intermediates which eliminate carboxylate and phenolate leaving groups

Article abstract of DOI:10.1016/j.tetlet.2008.05.079

α,β-Unsaturated anilides bearing allylic leaving groups undergo photochemical electrocyclic ring closure to produce zwitterionic intermediates which eliminate carboxylate and phenolate leaving groups.

Full text of DOI:10.1016/j.tetlet.2008.05.079

Tetrahedron Letters 49 (2008) 4621–4623
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Photochemical electrocyclization of ,b-unsaturated anilides to give
a
zwitterionic intermediates which eliminate carboxylate and phenolate
leaving groups
*
Jinli Jia, Mark G. Steinmetz , Ruchi Shukla, Rajendra Rathore
Department of Chemistry, Marquette University, Milwaukee, WI 53201-1881, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
a
,b-Unsaturated anilides bearing allylic leaving groups undergo photochemical electrocyclic ring closure
Received 13 May 2008
Accepted 16 May 2008
Available online 22 May 2008
to produce zwitterionic intermediates which eliminate carboxylate and phenolate leaving groups.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Photochemical
Electrocyclic
Anilide
Elimination
Caged
Phototrigger
Photolysis of the
a,b-unsaturated anilide 1a produces the six-
As shown in Scheme 2, an analogous elimination reaction can
membered ring lactam 3a (Scheme 1).1,2 The mechanism is
thought to involve a photochemically allowed conrotatory ring clo-
sure to afford a zwitterionic intermediate1–4 which rearranges to
the lactam photoproduct via a 1,5-H shift and/or a series of proton
transfer steps via an enol (Scheme 1).5 The potential intermediacy
of a zwitterionic species makes this reaction of interest, because
recent studies have shown that similar zwitterionic intermediates,
be envisioned from the zwitterionic intermediate 5, which would
be generated via excited state electrocyclization of a,b-unsaturated
anilides 4 which incorporate leaving groups (LGꢀ) at the allylic
position of the methacrylamide group. The elimination of LGꢀ from
5 may compete with either 1,5-H shift or protonation of the
enolate moiety by protic solvent. If the elimination is the major
process, anilides similar to 4 would offer the potential advantage
of having a modular, modifiable aniline group as the chromophore.
It is noteworthy that the aniline group is a common structural
motif in highly absorbing organic dyes. Incorporating such
chromophores into cage compounds similar to 4 could thus
generated photochemically from a-keto amides, eliminate carbox-
ylate and phenolate leaving groups attached to the position
a to
the keto group in the reactants.6,7
CH3
N
CH3
N
O
CH3
N
CH3
N
O
1,5-H
hν
CH3
O
O
or H+
Y
-LG-
-H+
Y
CH3
LG
H
CH3
N
Y
Y
Y
1a (Y = H)
2a,b
O
b (Y = PhCO)
6
CH3
hν
N
O
LG
Y
CH3
N
CH3
N
H
5
1,5-H
or H+
O
Y
CH3
H
O
3a,b
LG
LG
4 (Y = COPh)
LG- = PhCH2CO2 , PhO-
Y
H
Scheme 1.
7
-
* Corresponding author. Tel.: +1 414 288 3535; fax: +1 414 288 7066.
E-mail address: mark.steinmetz@marquette.edu (M. G. Steinmetz).
Scheme 2.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.079

4622
J. Jia et al. / Tetrahedron Letters 49 (2008) 4621–4623
provide a strategy for the photorelease of biologically active leav-
ing groups using long wavelength light. Photoactive cage com-
pounds are important, because they provide the most practical
means for rapidly activating biomolecules for triggering biological
processes for studies under physiological conditions.8,9 Photo-
chemically removable protecting groups are also used in the syn-
thesis of biopolymers, in photolithography, and in the fabrication
of oligonucleotide arrays.9,10
713 which retained the leaving group (Scheme 2). During the
photolysis the yield of 6 became progressively less than the
yield of the released carboxylic acid, evidently due to secondary
photolysis (Fig. 1).
Control experiments showed no indication of a ‘dark’ solvolytic
release of carboxylic acid from 4 or 7 ðLGꢀ ¼ Ph2CO ꢀ) in 50% D2O
2
in CD3CN containing 0.1 M phosphate buffer at pD 7 at room tem-
perature for over a period of a week.
In this Letter, we demonstrate that the release of leaving groups
is the predominate photoreaction of para-benzoyl substituted ani-
lides 4 (Y = PhCO) (Scheme 2).11 Moreover, the para-benzoyl group
in anilide 4 has the advantage of substantially shifting light absorp-
tion to relatively long wavelengths such that the photolyses can be
Changing the leaving group to phenolate in 4 (LGꢀ = PhOꢀ) led
to mainly photolytic elimination to give 45% of 6, 20% of lactam
7 (LGꢀ = PhOꢀ), and 36% unreacted starting material in 50% D2O
in CD3CN containing 0.1 M phosphate buffer at pD 7 (Scheme 2).
Interestingly, however, in the nonpolar solvent C6D6 the photoeli-
routinely performed at 365 nm (
e
120 L molꢀ1 cmꢀ1), which makes
mination product 6 was not observed and instead, lactam 7 (LGꢀ
=
this cage system potentially useful for practical biological applica-
PhOꢀ)14 was formed as the sole product in 85% yield, together with
10% unreacted starting material. These results with LGꢀ = PhOꢀ are
consistent with the involvement of a ground state intermediate,
such as 5, which can partition between products 6 and 7, depend-
ing upon the solvent polarity.
tions. The details of these findings are described herein.
Photolysis (>300 nm) of 4 ðLGꢀ ¼ PhCH2CO ꢀ) in an air-satu-
2
rated solution of 50% D2O in CD3CN containing 0.1 M phosphate
buffer at pD 7 resulted in the release of phenylacetic acid in 71%
yield and the formation of the
a
-methylene lactam 612 in 53% yield
Such behavior of 5 (LGꢀ = PhOꢀ) has been observed previously
at 94% conversion according to 1H NMR analyses of the photoly-
sate. These products were accompanied by a 25% yield of lactam
in the case of a
-keto amides bearing phenolic leaving groups,7b
for which the zwitterionic intermediate predominantly eliminates
the phenolate leaving group in polar or aqueous solvents, but
cyclizes to give significant amounts of product retaining the
phenolic group in nonpolar solvents.
100
90
80
70
60
50
40
30
20
10
0
The zwitterionic intermediate 5 is thought to be formed via
photochemical electrocyclic ring closure in the excited state. The
quantum efficiency for this ring closure step would not be
expected to be affected significantly by the basicity of the remote
leaving group attached to the methacrylamide group. This is evi-
denced by the similarity in total quantum yields for products
6 + 7 determined for 4 ðLGꢀ ¼ PhCH2CO ꢀ), 4 (LGꢀ = PhOꢀ), and
2
for comparison, 1b (Y = PhCO), which has no leaving group (Table
1) and gives only 3b upon photolysis. These quantum yields argue
against expulsion of the leaving group directly in a short-lived
excited state, since the quantum yields would then be expected
to decrease with increasing leaving group basicity. For the
same reason, the quantum yields would not be consistent with a
reversible ring closure step.
The reactive excited state responsible for the photochemistry of
1b and 4 is the singlet excited state, according to the following
quenching studies. The involvement of the triplet excited state,
produced via rapid intersystem crossing, would be expected on
0
10
20
time, min
30
40
50
the basis of the very weak fluorescence (
U < 0.01) for 1b, as has
been reported for other aminobenzophenone derivatives.15 How-
ever, the quantum yields for products are unaffected by the pres-
Figure 1. Plot of yield versus time for photolysis of 4 in 50% D2O containing buffer
in CD3CN at pD
from 1H NMR analyses. Symbols correspond to unreacted
(j), and lactam
ence of 10ꢀ2
M 2-naphthalene sulfonate (an efficient triplet
7
4
(s), released PhCH2CO2H (d), elimination coproduct
6
quencher) in 50% buffer in CH3CN (Table 1). In the case of 1b we
find that comparable concentrations of the 2-naphthalene sulfo-
7 (LGꢀ ¼ PhCH2CO ꢀ), N).
2
Table 1
Quantum yields for 1b, 4 ðLGꢀ ¼ PhCH2CO ꢀ), and 4 (LGꢀ = PhOꢀ
)
2
Reactant
Solvent
Additive
Ua b
,
6
7
4 ðLGꢀ ¼ PhCH2CO2
4 (LGꢀ = PhOꢀ)
1b
)
Bufferc
None
0.069
0.075
0.061
0
0.018
0.021
0.016
0.10
ꢀ
Bufferc
0.011 M 2-NPSd
None
Bufferc
C6H6
None
None
Bufferc
nae
0.077 (3b)e
0.070 (3b)e
0.10 (3b)e
Bufferc
0.012 M 2-NPSd
0.15 M trans-piperylene
nae
20% aq CH3CN
nae
a
Determined at 365 nm as an average of two or more independent determinations using ferrioxalate as the actinometer.
Products quantified by HPLC analyses using an internal standard.
Solvent was 50% water containing 0.10 M phosphate buffer in CH3CN.
Sodium 2-naphthalenesulfonate.
b
c
d
e
Only product 3b is observed without a leaving group.

J. Jia et al. / Tetrahedron Letters 49 (2008) 4621–4623
4623
0.020
0.015
0.010
0.005
0.000
tion of
6
andꢀ
7 = 4
(LGꢀ PhOꢀ), and NMR spectra for
(LGꢀ ¼ PhCH2CO2 , PhOꢀ), 6, and 7 (LGꢀ ¼ PhCH2COꢀ2 , PhOꢀ). Sup-
plementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2008.05.079.
0.020
0.015
0.010
0.005
0.000
References and notes
2000 4000 6000 8000 10000
time (ns)
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Figure 2. Transient triplet absorption spectrum produced upon laser flash photol-
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showed identical decay lifetimes (s = 335 ns).
nate strongly quench a transient absorption (Fig. 2) attributable to
the triplet excited state.16 Such quenching, which likely involves
energy transfer, occurs at close to diffusion controlled rate, with
a bimolecular rate constant of kq = 3.77 ꢁ 109 Mꢀ1 sꢀ1, according
to the linear Stern–Volmer plot. We therefore conclude that the
photochemistry of 1b and 4 derives from the singlet excited state.
Although the triplet excited state is observed in the laser flash
photolyses, its triplet yield is not especially high, as energy transfer
to effect trans-cis isomerization of 0.15 M trans-piperylene17 gives
Uisc = 0.20 in benzene and 0.15 in 10% aq CH3CN, while the reaction
of 1b is unquenched by the piperylene such that
In conclusion, methacrylanilides with allylic leaving groups
photolytically release phenylacetic acid and phenol to form an
methylene lactam in aqueous buffer with a quantum yield of ca.
0.06–0.07. The minor product is a lactam which retains the leaving
group, and the elimination from the postulated intermediate, zwit-
terion 5, effectively competes with the formation of the minor lac-
tam. The overall quantum yield for the reaction is governed by the
efficiency for the singlet excited state electrocyclic ring closure
step.
11. (a) According to a previous report,11b para-substituted derivatives 1b are
capable of overcoming
a strongly adverse polar solvent effect on the
photochemistry to give high yields of lactams as photoproducts, whereas
1a,1 which lacks the para-benzoyl group, was photochemically unreactive in
polar or protic solvents such as CH3CN or alcohols.; (b) Nishio, T.; Tabata, M.;
Koyama, H.; Sakamoto, M. Helv. Chim. Acta 2005, 88, 78–86.
12. The spectral data for 6 were as follows: 1H NMR (CDCl3) d 3.44 (s, 3H), 3.78 (s,
2H), 5.53 (s, 1H), 6.19(s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.58
(t, J = 8.0 Hz 1H), 7.68–7.76 (m, 4H); 13C NMR (CDCl3) 30.3, 34.2, 114.1, 124.0,
124.3, 128.5, 129.5, 129.9, 130.6, 132.0, 132.4, 135.2, 137.9, 143.5, 165.1, 195.6.
When stored as a solid, compound 6 slowly reacts in the dark to give unknown
products which show broad peaks in the 1H NMR spectrum. The ‘dark’ reaction
substantially slows when 6 is stored as a dilute solution in 50% buffer in
CH3CN.
U (3b) = 0.10.
a
-
13. Pure lactam 7 ðLGꢀ ¼ PhCH2CO2ꢀÞ, mp 77–79 °C, was obtained by acylating
lactam 7 (LGꢀ = HOꢀ), produced upon photolysis of 4 (LGꢀ = HOꢀ) in benzene,
followed by chromatographic separation from
unreacted starting material. The spectral data for
a
small amount of
7
6 and
(LGꢀ = HOꢀ) were as
follows: 1H NMR (CDCl3) d 2.68–2.85 (m, 3H), 3.33 (s, 3H), 3.55 (s, 2H), 4.28
(dd, J = 5.20, 8.40 Hz, 1H), 4.50 (dd, J = 3.33, 8.40 Hz, 1H), 6.96 (d, J = 6.33 Hz,
1H), 7.12–7.24 (m, 5H), 7.43 (t, J = 5.52 Hz, 2H), 7.54 (t, J = 5.56 Hz, 2H), 7.69
(m, 2H); 13C NMR (CDCl3) 28.3, 30.1, 40.0, 41.4, 63.5, 114.4, 124.9, 127.4, 128.6,
128.8, 129.5, 130.0, 130.2, 130.8, 132.3, 132.5, 134.0, 138.0, 143.8, 169.7, 171.6,
195.6.
14. Chromatography of the photolysate on silica gel eluting with 10% ethyl acetate
in hexane gave NMR pure 7 (LGꢀ = PhOꢀ) as a colorless oil. The spectral data
were as follows: 1H NMR (CDCl3) d 2.99–3.12 (m, 2H), 3.26 (dd, J = 11.6,
21.3 Hz, 1H ), 3.44 (s, 3H), 4.19 (dd, J = 7.6, 9.6 Hz, 1H ), 4.50 (dd, J = 3.7, 9.6 Hz,
1H), 6.95 (m, 3H), 7.07 (d,J = 8.2 Hz, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.50 (t,
J = 8.0 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.75–7.79 (m, 4H); 13C NMR (CDCl3) 28.8,
30.2, 40.6, 66.8, 114.3, 114.8, 121.3, 125.4, 128.5, 129.7, 130.0, 130.3, 130.7,
132.3, 132.5, 138.0, 144.0, 158.8, 170.2, 195.7.
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(c) Barnabas, M. V.; Liu, A.; Trifunac, A. D.; Krongauz, V. V.; Chang, C. T. J. Phys.
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Acknowledgments
We thank Ms. Ja Eun Lee and Dr. Yugang Chen for technical
assistance. Acknowledgment is made to the donors of the Petro-
leum Research Fund, administered by the American Chemical Soci-
ety (M.G.S.) and to the National Science Foundation for a Career
Award (R.R.) for support of this research.
Supplementary data
17. (a) Lamola, A. A.; Hammond, G. S. J. Chem. Phys. 1965, 43, 2129–2135; (b)
Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of Photochemistry, 2nd ed.;
Marcel Dekker: New York, 1993; pp 310–312.
Detailed experimental procedures for ꢀthe synthesis of
4
(LGꢀ ¼ PhCH2CO2ꢀ, PhOꢀ), synthesis of 7 ðLG ¼ PhCH2COꢀ2 Þ, isola-