Photoinduced Cyclization of (o-Alkylbenzoyl)phosphonates to Benzocyclobutenols

Article abstract of DOI:10.1002/asia.201700766

(o-Alkylbenzoyl)phosphonates readily cyclize to highly strained benzocyclobutenols simply upon irradiation with UV light. The remarkable efficiency is ascribed to the electron-accepting character of the phosphonate substituent, which facilitates thermal ring closing of the o-quinodimethane intermediate and suppresses reversion to the starting carbonyl compound.

Full text of DOI:10.1002/asia.201700766

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Accepted Article
Title: Photo-Induced Cyclization of (o-Alkylbenzoyl)phosphonates to
Benzocyclobutenols
Authors: Naoki Ishida, Takaaki Yano, Tatsuya Yuhki, and Masahiro
Murakami
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Photo-Induced Cyclization of (o-Alkylbenzoyl)phosphonates to
Benzocyclobutenols
Naoki Ishida, Takaaki Yano, Tatsuya Yuhki, and Masahiro Murakami*[a]
OH
Abstract: (o-Alkylbenzoyl)phosphonates readily cyclize to highly
strained benzocyclobutenols simply upon irradiation with UV light.
The remarkable efficiency is ascribed to the electron-accepting
character of the phosphonate substituent, which facilitates thermal
ring closing of the o-quinodimethane intermediate and suppresses
reversion to the starting carbonyl compound.
O
hν
R
R
CH2
CH3
2
1
A benzocyclobutene skeleton is a highly strained structural motif
that has found a variety of applications in organic synthesis and
material sciences.[1] Synthetic approaches to such a strained
structure require highly energetic reactants like n-butyllithium
OH
R
R
OH
and/or harsh reaction conditions in general.[1]
A different
3a
3b
approach is available with o-alkylphenyl ketones, which undergo
photocyclization. This approach offers a straightforward and
atom-economical access to benzocyclobutenols starting from
readily available substrates in an endergonic manner.[2] However,
successful and reproducible examples are considerably limited.
‡
OH
1,5-proton
transfer
thermal
ring closing
R
O
H
R
bimolecular
proton transfer
OH
R
1
Herein,
we
report
that
an
extraordinarily efficient
with (o-
photocyclization
reaction
takes
place
alkylbenzoyl)phosphonates, which are easily prepared from acyl
chlorides. Since the photoreaction is operationally simple and
tolerant to various functional groups, the present approach
would come into use for further derivatization of synthetic
purposes.
4
Scheme 1. Photocyclization of o-Alkylphenyl Ketones.
The mechanism of the photocyclization of o-alkylphenyl
ketones has been studied intensively (Scheme 1).[3] Upon
excitation, intramolecular hydrogen transfer (C(sp3)–H to O–H)
occurs with 1 to generate biradical 2. It isomerizes into o-
quinodimethane 3,[4,5] which has a closed shell configuration but
lacks aromaticity. There are two stereoisomers 3a and 3b
possibly generated from 2. Two pathways are subsequently
available for the dienes 3a and 3b. One is a proton transfer
pathway reverting to 1[6] and the other is a 4p-electrocyclic ring-
closing pathway to benzocyclobutenol 4. In the case of 3a, an
intramolecular 1,5-proton transfer reaction is so much faster
than a ring-closing reaction that it readily reverts to the starting 1.
In the case of the other stereo-isomer 3b, the hydrogen of the
hydroxy group is located too remote to transfer intramolecularly
onto the terminal carbon of the diene moiety. Although
bimolecular proton transfer is an alternative pathway, it is much
slower than the intramolecular 1,5-proton transfer occurring with
3a. As a result, 3b has a much longer lifetime so that a thermal
4p-electrocyclic ring-closing pathway becomes feasible. The
The substituent effect on thermal 4p-electrocyclic reactions
has been a topic of interest from viewpoints of synthetic as well
as theoretical chemistries.[7-11] A substituent of an electron-
accepting nature at the 3-position of cyclobutene accelerates a
ring opening reaction of cyclobutenes and prefers inward
rotation.[7] When an electron-accepting substituent such as
formyl and boryl groups rotates inward, its energetically low-lying
unoccupied orbitals accept electron density from the HOMO of
the cyclobutene backbone. This electron delocalization lowers
the activation barrier. A related accelerating effect of electron-
accepting substituents has been identified with a ring closing
reaction of vinylallenes.[8] We recently found that a phosphonate
substituent (-P(O)(OR')2) also accelerates a thermal ring opening
reaction of cyclobutenes and exhibits a preference for inward
rotation over outward one.[11] This finding led us to examine a
photocyclization reaction of phosphonate-substituted carbonyl
compounds, i.e., (o-alkylbenzoyl)phosphonates. A phosphonate
substituent may facilitate a 4p-electrocyclic ring-closing process
of a photochemically generated o-quinodimethane by way of a
similar orbital interaction, and thus, the 4p-electrocyclic pathway
may become dominant over the proton transfer pathway
reverting to an acylphosphonate fruitlessly. Firstly, the model
compound, o-toluoylphosphonate 5a was prepared by the
Michaelis-Arbuzov reaction[12] of o-toluoyl chloride with trimethyl
phosphite, and the reactivities of 5a and o-tolyl methyl ketone 8
were compared (Scheme 2). Their benzene solution (1.0 mmol,
0.05 M) in a Pyrex® tube was irradiated with UV light[13] under a
nitrogen atmosphere for 12 h. The phosphonate 5a readily
ring-closing
pathway
leads
to
the
formation
of
benzocyclobutenol 4.
[a]
Dr. N. Ishida, T. Yano, T. Yuhki, Prof. Dr. M. Murakami*
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University
Katsura, Kyoto 615-8510, Japan
E-mail: murakami@sbchem.kyoto-u.ac.jp
Homepage: http://www.sbchem.kyoto-u.ac.jp/murakami-lab/
underwent
a
photocyclization
reaction
to
afford
Supporting information for this article is given via a link at the end of
the document.
benzocyclobutenol 7a almost quantitatively (93% isolated yield).
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a)
a)
Proton transfer
Ring closing
O
OH
O
OMe
OMe
O
OMe
OMe
UV light
‡
P
P
OH
OH
Me
benzene
12 h
23.3
16.8
CH3
5a
Me
6
thermal
ring closing
OH
9
O
P
OMe
0
OMe
OH
7a 93%
-9.2
Me
‡
OH
Me
b)
O
10
proton
transfer
O
OH
Me
H
O
UV light
Me
-41.4
Me
8
Me
benzene
12 h
CH3
CH3
9
8
8
b)
Scheme 2. Photocyclization of 5a.
‡
OH
P
OH
24.1
O
P
O
H
In sharp contrast, no reaction occurred with 8 (94% recovery),
although the o-quinodimethane intermediate 9 was generated.[14]
Thus, the phosphonate substituent brought in dramatic
acceleration.
P OMe
OMe
P = -P(O)(OMe)2
18.3
6
0
The photocyclization of 5a would proceed through the
mechanistic pathway shown in Scheme 1. The remarkable
efficiency can be explained by assuming that the phosphonate
substituent as R exerts the following two influences upon the o-
quinodimethane intermediate; (i) at the transition state of the 4p-
electrocyclic ring-closing process, the phosphonate substituent
accepts electron density of the HOMO, thereby accelerating the
ring closing, (ii) the electron-withdrawing nature of the
phosphonate substituent makes the diene moiety less basic,
thereby suppressing a proton transfer reaction reverting to 5a.
OH
O
P OMe
OMe
‡
OH
-12.3
-36.4
O
P OMe
OMe
7a
O
O
P OMe
OMe
CH3
5a
c)
In order to support this assumption, we carried out a
theoretical study upon the o-quinodimethanes 9 and 6 using
DFT calculation (Figure 1).[15] The activation energy for the
bimolecular proton transfer pathway of 9 is 16.8 kcal/mol, lower
than that for the 4p-electrocyclization (23.3 kcal/mol) by 6.5
kcal/mol. The energy profile of the reactions of 6 is reverse. The
activation energy for the bimolecular proton transfer is as high
as 24.1 kcal/mol, and that for the ring-closure is lower (18.3
kcal/mol). Thus, the phosphonate substituent favors ring closing
and disfavors protonation. Natural bond orbital (NBO) analysis of
the transition state for ring closing of 6 indicates that electrons of
the developing s-bond orbital which is still distorted (originally p-
electrons of the diene moiety of 6) delocalize into the low-lying
s*-orbitals of the P–O bonds, as is the case with the ring
opening of 3-phosphorylcyclobutenes.[11] This electron
delocalization stabilizes the transition state, lowering the
activation energy.
σC-C
O
H
σ*P-O
P
O
O
Me
O
Me
Figure 1. (a) Energy Profiles of Reactions of 9, (b) Energy Profiles of
Reactions of 6, (c) Donor-Acceptor Interaction between Forming C–C s-Orbital
and P–O s*-Orbital in TS for Ring Closure of 6. All the calculations were
carried out with the B3LYP/6-31+G(d) level of theory in benzene (PCM) at
25 °C. Shown are Gibbs' energies (kcal/mol).
can be reasonably explained. There are four possible
stereoisomers for the o-quinodimethane intermediate 11.
Isomers 11c and 11d having an inward-oriented methyl group
suffer from steric congestion, and the sterically less-congested
isomers 11a and 11b having an outward-oriented methyl group
would be preferentially formed. The isomer 11a undergoes
intramolecular 1,5-proton transfer to readily revert to the starting
ketone. On the other hand, the isomer 11b undergoes a thermal
4p-electron ring-closing reaction. The substituents at the diene
terminals rotate in a conrotatory fashion in accordance with the
Woodward-Hoffmann rule,[17] furnishing the cis-isomer 7b
When a benzoylphosphonate possesses an ethyl group
instead of a methyl group as the o-substituent (5b, Scheme 3),
two diastereomeric benzocyclobutenols would potentially arise.
Nonetheless, only the cis-isomer 7b was stereoselectively
produced upon photoirradiation of 5b and no trans-isomer was
observed.[16] The stereoselective formation of the cis-isomer 7b
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OH
O
O
3
4
O
P
OPh
P
OPh
P
OPh
OPh
Me
OH
7e 97%
OH
5e
5b
O
1,5-proton
transfer
O
O
P
Me
11a
O
P O
O
O
Me
Me
OH
Me
Me
Me
OH
5f
P
P
7f 87%
thermal
ring closing
O
OH
O
Me
O
5
6
7
8
9
O
OMe
OMe
P
OMe
OMe
Me
11b
7b 78%
dr > 95:5
P
UV light
P
MeO
F3C
H
benzene
12 h
MeO
F3C
Me
7g 89%
P
5g
Me
5b
P = -P(O)(OMe)2
O
OH
O
P
OMe
OH
Me
O
OMe
OMe
✕
✕
OMe
P
11c
OH
Me
7h 81%
5h
O
OH
O
P
O
OMe
OMe
P
OMe
P
Me
OMe
Br
11d
Br
Me
7i 77%
OH
Scheme 3. Photocyclization of 5b.
5i
O
O
OMe
OMe
stereoselectively.
O
P
Experimentally examined next was the effect of various alkyl
and aryl phosphonates (Table 1). Ethyl, i-propyl, and phenyl
phosphonates efficiently underwent a photocyclization reaction
to furnish the corresponding benzocyclobutenols in good yield
(entries 1-3). Cyclic ester 5f also afforded the benzocyclobutenol
7f (87%, entry 4). Various functional groups like methoxy,
trifluoromethyl, bromo, and carbamate groups were allowed on
the aromatic ring to give the benzocyclobutenols 7g-j in yields
ranging from 74 to 89% (entries 5-8). A reaction of 5k having a
3-methoxypropyl substituent at the o-position gave the cis-
isomer 7k exclusively (entry 9). The photoreaction of o-i-propyl
substituted benzoylphosphonate 5l necessitates addition of
benzophenone (1.0 equiv) as the photosensitizer (entry 10). A
sterically congested fully-substituted C–C linkage is created to
afford a,a-dimethyl benzocyclobutenol 7l in 88% yield.
P
OMe
OMe
BocHN
BocHN
Me
7j 74%
5j
OH
O
O
O
P
OMe
P
OMe
OMe
OMe
OMe
OMe
7k 70% (>95:5)
5k
O
O
P
10[d]
HO
O
P
OMe
OMe
OMe
OMe
Me
i-Pr
Me
5l
7l 88%
a
Reaction conditions: aroylphosphonates 5 (1.0 mmol), benzene (20 mL), UV
light, 12 h. b Isolated yield. c 24 h. d Benzophenone (1.0 equiv) was added.
Table 1. Scope.[a]
In summary, we have found that an extraordinarily efficient
O
photocyclization
reaction
takes
place
with
(o-
O
OR3
OR3
OH
O
UV light
P
OR3
OR3
R2
P
alkylbenzoyl)phosphonates to furnish benzocyclobutenols in an
endergonic manner. Mechanistic studies suggest that the
electron-accepting character of the phosphonate substituent
leads to the remarkable efficiency in dual ways. Since highly
R1
benzene, rt
R1
R2
7
5
energetic molecules with
a variety of functionalities are
entry
1[c]
5
7[b]
OH
synthesized from readily available substances through an
operationally simple experimental procedure, the present photo-
induced reaction would offer a convenient synthetic maneuver.
O
O
OEt
OEt
O
P
P
OEt
OEt
Me
5c
O
7c 92%
OH
O
Experimental Section
2
O
Oi-Pr
Oi-Pr
P
Oi-Pr
Oi-Pr
P
Photo-induced cyclization of 5a: To a schlenk tube equipped with a
magnetic stir bar was charged with (o-toluoyl)phosphonate 5a (45.6 mg,
Me
7d 79%
5d
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0.20 mmol) and benzene (4.0 mL). The mixture was irradiated with UV
light for 12 h. The solvent was removed under reduced pressure, and the
residue was purified by preparative thin layer chromatography to give 7a
(42.4 mg, 0.186 mmol, 93%).
Chem. Soc. 1996, 118, 1881; c) C. Delas, H. Urabe, F. Sato, J. Am.
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Am. Chem. Soc. 2004, 126, 10838.
[9]
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W. Jefford, G. Bernardinelli, Y. Wang, D. C. Spellmeyer, A. Buda, K. N.
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Ed. 2010, 49, 3026.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
[10] For substituent effects on the ring opening of oxetenes and azetines: a)
S. M. Bachrach, M. Liu, J. Org. Chem. 1992, 57, 209; b) S.
Mangelinckx, V. Van Speybroeck, P. Vansteenkiste, M. Waroquier, N.
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Mikami, Chem. Sci. 2014, 5, 410.
15H05756,
15J07224,
and
JST
ACT-C
Grant
Number JPMJCR12Z9, Japan. T. Yano acknowledged a JSPS
fellowship for young scientists.
Keywords: cyclization • electrocyclic reactions • substituent
effects • phosphorus
[11] N. Ishida, T. Yano, M. Murakami, Asian J. Org. Chem. 2017, 6, 174.
[12] A. K. Nhattacharya, G. Thyagarajan, Chem. Rev. 1981, 81, 415.
[13] We employed the Rayonet photoreactor. See supporting information for
the spectrum of the UV light employed.
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[14] When a benzene solution containing 8 was irradiated with UV light in
the presence of dimethyl acetylenedicarboxylate, Diels-Alder adduct
was efficiently produced, proving the o-quinodimethane
9 was
generated. For the Diels-Alder reaction of o-quinodimethanes, see refs.
4 and 5.
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[8]
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Naoki Ishida, Takaaki Yano, Tatsuya
Yuhki, Masahiro Murakami*
Page No. – Page No.
Photo-Induced Cyclization of (o-
Alkylbenzoyl)phosphonates to
Benzocyclobutenols
(o-Alkylbenzoyl)phosphonates readily cyclize to highly strained benzocyclobutenols
simply upon irradiation with UV light.
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