Radical-Cation-Induced Crossed [2+2] Cycloaddition of Electron-Deficient Anetholes Initiated by Iron(III) Salt

Article abstract of DOI:10.1002/adsc.201901337

Radical cation-induced crossed [2+2] cycloaddition of electron-deficient anetholes was developed with the use of Fe(OTf)₃ as an initiator. Various 1,2-diarylcyclobutanes can be synthesized in high yields with high diastereoselectivity from electron-deficient anetholes, which have been less explored using conventional methods. This practical reaction system can be used for a decagram-scale reaction (12 gram), in which the resulting product can be transformed to 1,2-dicarbonyl compounds.

Full text of DOI:10.1002/adsc.201901337

Title: Radical Cation-induced Crossed [2 + 2] Cycloaddition of
Electron-deficient Anetholes Initiated by Iron(III) Salt
Authors: Takahiro Horibe, Kei Katagiri, and Kazuaki Ishihara
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Advanced Synthesis & Catalysis
10.1002/adsc.201901337
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Radical-Cation-Induced Crossed [2 + 2] Cycloaddition of
Electron-Deficient Anetholes Initiated by Iron(III) Salt
Takahiro Horibe, Kei Katagiri and Kazuaki Ishihara*
Graduate School of Engineering, Nagoya University, B2-3(611), Furo-cho, Chikusa, Nagoya 464-8603, Japan
ishihara@cc.nagoya-u.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Radical cation-induced crossed [2
cycloaddition of electron-deficient anetholes was crossed [2 + 2] cycloaddition. Besides, pairs of
developed with the use of Fe(OTf) as an initiator. Various electron-deficient anetholes can be also used.
,2-diarylcyclobutanes can be synthesized in high yields However, the substrate scope has been still limited to
+
2] mediator, electron-rich anetholes can be used for
3
1
with high diastereoselectivity from electron-deficient -unsaturated ketones and esters. To expand the
anetholes, which have been less explored using
conventional methods. This practical reaction system can
be used for a decagram-scale reaction (12 gram), in which
the resulting product can be transformed to 1,2-dicarbonyl
compounds.
scope of electron-deficient anetholes, we were
intrigued by optimizing the iron(III) salt initiator and
the reaction conditions. We anticipated that cationic
iron(III) salt, having a less-coordinating counter
anion, would improve its oxidation potential. If the
proper iron(III) salt oxidizing electron-deficient
Keywords: Radical cation; Iron(III) salt; [2 + 2]
Cycloaddition; Electron-deficient anethole; Styrene
•+
anetholes is used, generation of the key 1 and
subsequent cycloaddition should be possible.
Therefore, we began to explore iron(III) salts that
could oxidize a variety of electron-deficient anetholes.
Because cyclobutane derivatives are present in
[
1]
various natural products and pharmaceuticals,
tremendous effort has been devoted to their
synthesis.[
2–4]
Among them, radical cation-induced
crossed [2 + 2] cycloaddition of anetholes with
styrenes is of particular interest because it is one of
the most straightforward methods to synthesize 1,2-
diarylcyclobutanes 3 (Scheme 1a).[5] Thus far,
various one-electron oxidants have been developed as
initiators for the crossed [2 + 2] cycloaddition of
anetholes. In general, an initiator oxidizes anethole 1
•
+ [6,7]
•+
to give a key radical cation 1 .
The resulting 1
•+
reacts with styrenes 2 to give 3 . The final step is
reduction of 3 by 1 as chain propagation. Regarding
•+
•+
generation of the key intermediate 1 of crossed [2 +
] cycloaddition, great progress has been made using
2
[8]
[9]
aminium radical cation, photoredox catalysis,
hypervalent iodine[ and iron(III) initiators.
10]
[11,12]
Whereas electron-rich anetholes can be used for these
conventional methods, electron-deficient anetholes
has been less explored for crossed [2 + 2]
[
12,13]
cycloaddition (Scheme 1b).
Because electron-
Scheme 1. Radical cation-induced crossed [2 + 2]
cycloaddition.
deficient anetholes are less-reducing substrates, the
generation of anethole radical cation 1 is less
•+
likely.[
14]
In our previous study, we developed FeCl
crossed [2 + 2] cycloaddition of various electron-rich
3
-initiated
To identify a highly active initiator, our initial
attempt was focused on the screening of iron(III) salts
anetholes.[
12]
When FeCl
initiator is used in the
3
for crossed [2
+
2] cycloaddition of 4-
presence of 2,5-dimethyl-2,4-hexadiene as a redox
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201901337
methoxychalcone 1a with styrene 2a (Table 1).
amount of Fe(OTf)
3
could be reduced to 2 mol%
When 10 mol% of iron(III) salt [Fe(acac)
Fe(OCOCF or Fe(OTs)
the corresponding product 3a was not obtained
entries 1–4). When FeCl was used, the
corresponding product 3a was obtained in 53% yield
entry 5). In contrast, iron(III) salts having less-
3
, Fe(OAc)
3
,
without decreasing the yield of the corresponding 3a.
Moreover, carboxylic acid 1f and sulfonyl acetamides
1g and 1h, which have an acidic proton, were also
suitable carbonyl groups, although 10 mol% of
3
)
3
3
] was used as an initiator,
(
3
Fe(OTf) was required. Notably, relatively labile
3
(
thioester 1i was tolerated under the reaction
conditions to afford the corresponding product,
although the yield was moderate.
coordinating anion were efficient. For example, the
corresponding product was obtained quantitatively
when Fe(ClO
7
4
)
3
or Fe(OTf) was used (entries 6 and
3
). Notably, the corresponding product was obtained
Table 2. Scope of trans-Anetholes.[a]
with high diastereoselectivity [dr > 95:5] in contrast
to those with relatively low diastereoselectivity in
MeO
Cl
MeO
Cl
[13]
triplet-sensitized crossed [2 + 2] cycloadditions.
The amount of initiator [Fe(ClO or Fe(OTf) ] could
be reduced to 5 mol% without decreasing the yield
entries 8 and 9). The best result was obtained when
Fe(OTf)3 (5 mol%)
MeCN, 0 ℃, 6–48 h
4
)
3
3
+
R1
R1
1
O
2a
equiv
(
5
2
O
3
6
mol% of Fe(OTf)
3
was used as an initiator (entry 9).
which efficiently
Scope of trans-Anetholes
Cl MeO Cl MeO
,5-Dimethyl-2,4-hexadiene,
MeO
Cl
suppressed the degradation of electron-rich trans-
anethole in our previous study,[12] did not improve the
yield (entry 10). Presumably, electron-deficient
trans-anethole 1a is more stable than electron-rich
trans-anethole. The degradation and dimerization of
X
Ph
EtO
O
O
O
3a
X = Br 3b 90% (24 h)
3d
9
1%[b] (6 h)
dr > 95:5
dr > 95:5
Cl 3c 86% (24 h)
dr > 95:5
91% (24 h)
dr > 95:5
1
a are less likely in comparison with electron-rich
trans-anethole (see Scheme S1 in Supporting
Information for details). Therefore, 2,5-dimethyl-2,4-
hexadiene was not required as a redox mediator for
crossed [2 + 2] cycloaddition of electron-deficient
anetholes.
MeO
Cl MeO
Cl
MeO
Cl
Me
N
HO
TfHN
MeO
O
O
O
3e
3f
3g
Table 1. Screening of Iron(III) Salt.[a]
87% (48 h)
dr > 95:5
81%[c,d] (24 h)
dr > 95:5
70%[c,d] (24 h)
dr > 95:5
MeO
Cl
MeO
Cl
TsHN
EtS
O
O
3
h
3i
c]
51%[c,d] (48 h)
dr > 95:5
8
1%[ (24 h)
dr > 95:5
X-ray
[
b]
entry
FeX
Fe(acac)
Fe(OAc)
Fe(OCOCF
Fe(OTs)
FeCl 10
Fe(ClO
Fe(OTf)
Fe(ClO
Fe(OTf)
Fe(OTf)
3
[mol%]
Yield [%]
dr
–
–
–
–
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
[a]The reaction was carried out with Fe(OTf)
0.00925 mmol), 1 (1.0 equiv, 0.185 mmol) and 2 (6.0 equiv,
1
2
3
4
5
6
7
8
9
3
10
10
0
0
0
3
(5.0 mol%,
3
)
3
10
[b]
3
1
3
.11 mmol) in MeCN at 0 ºC. Fe(OTf) (2.0 mol%, 0.00370
3
10
0
[c]
[d]
mmol).
Fe(OTf)
3
1
(10 mol%, 0.0185 mmol).
was determined by H NMR analysis using 1,3-dinitrobenzene
as an internal standard.
The yield
3
53
96
98
4
)
3
3
10
10
[c]
)
4 3
5
90
[
c,d]
3
5
94
[e]
1
0
3
5
72
Regarding styrene, a variety of electron-donating
and -withdrawing substituents of the aromatic group
could be used (Table 3). For example, ortho-, meta-
and para-substituents of the aromatic group of
styrene (2j–2p) did not decrease the yield. Styrene
[
a]
The reaction was carried out with FeX
3
(5.0 mol%,
0
.00925 mmol), diene (0–15 mol %, 0–0.0278 mmol), 1a (1.0
equiv, 0.185 mmol) and 2 (6.0 equiv, 1.11 mmol) in MeCN at
ºC. The yield was determined by H NMR analysis using
,3-dinitrobenzene as an internal standard. 1.5 h. Isolated
[
b]
1
0
1
[
c]
[d]
[
e]
2q having
corresponding product in high yield in the presence
of 10 mol% of Fe(OTf) Moreover, -methyl-
a
carboxylic acid provided the
yield. 15 mol% of 2,5-dimethyl-2,4-hexadiene was used.
3
.
substituted styrene provided the corresponding 3r,
although the yield was somewhat moderate. In short,
various electron-deficient anetholes and styrenes can
be used in iron(III) salt-initiated crossed [2 + 2]
cycloaddition in comparison with conventional
With the optimized conditions in hand, we
examined the scope of substrate
(Table 2).
Regarding -unsaturated carbonyl compounds,
various carbonyl compounds were well-tolerated.
Simple carbonyl groups, such as ketones, ester and
amide were suitable functional groups under the
reaction conditions (see 3a–3e). In the case of 1a, the
[12]
methods.
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201901337
Table 3. Scope of styrene.[a]
group of 3a afforded 1,4-dicarbonyl compound 4a.[16]
After esterification under acidic conditions, 1,4-
ketoester 5a was obtained in 66% yield.
Cyclobutanes with a 1,4-dicarbonyl moiety are
[17]
present in potential pharmaceuticals.
Construction
of the cyclobutane by crossed [2 + 2] cycloaddition of
electron-deficient anetholes can be used to synthesize
these compounds.
Scheme 3. Transformation of the product 3a.
In summary, Fe(OTf) has been developed as an
3
initiator for the crossed [2 + 2] cycloaddition of
electron-deficient anetholes. A cationic iron(III) salt
has strong oxidation potential, which is sufficient for
oxidizing less-reducing anetholes. With the optimal
iron(III) salt identified, a wide substrate scope of
electron-deficient anetholes and styrenes has been
achieved. As a simple yet efficient one-electron
[a]The reaction was carried out with Fe(OTf)
(5 mol%,
3
0
1
.00925 mmol), 1 (1.0 equiv, 0.185 mmol) and 2 (6.0 equiv,
[
b]
3
.11 mmol) in MeCN at 0 ºC. Fe(OTf) (10 mol%, 0.0185
[
c]
1
mmol). The yield was determined by H NMR analysis
using 1,3-dinitrobenzene as an internal standard.
oxidant, Fe(OTf)
3
is a suitable initiator even for
We
decagram-scale reactions (12 gram-scale).
believe that this study provides a powerful method
for the synthesis of 1,2-diaryl cyclobutanes, and also
provides further insight into the oxidation properties
of iron(III) salts for other relevant one-electron
oxidation reactions.
To test the synthetic potential of our approach, a
large-scale reaction was conducted (Scheme 2).
When 10 g of 1a was used in the presence of 5 mol%
of Fe(OTf)
3
prepared from FeCl and AgOTf, the
3
crude product was obtained quantitatively in 12 hours
using a flask open to air. Concentration and
distillation to remove the solvent and 2a under
reduced pressure gave a crude mixture, which was
purified by flash chromatography to provide pure 3a
Experimental Section
General procedure for crossed [2 + 2] cycloaddition: A
one dram vial equipped with a magnetic stir bar was
charged with Fe(OTf) (0.05 equiv, 0.00925 mmol) and
3
in 81% yield (12.8 g). Since Fe(OTf)
3
is one of the
[15]
simplest and strongest inorganic iron(III) oxidants,
MeCN (600 μL) at ambient conditions. After being stirred
for 5 min at 0 ºC, styrene (6.0 equiv, 1.11 mmol) and -
unsaturated carbonyl compound (1.0 equiv, 0.185 mmol)
were added to the mixture. The resulting mixture was
stirred at 0 ºC and monitored periodically by TLC. Upon
consumption of -unsaturated carbonyl compound, the
reaction mixture was directly subjected to silica gel
chromatography (hexane/ethyl acetate) to give the desired
product.
a decagram-scale reaction in standard glassware (300
mL Erlenmeyer flask) could be successfully
conducted.
CCDC-1952076
contains
the
supplementary
crystallographic data for 3h. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac. uk/data_request/cif.
Scheme 2. Decagram-scale reaction.
Acknowledgements
Finally, we performed a transformation of 3a to
Financial support was provided in part by JSPS KAKENHI
(Grant Numbers 15H05755, 15H05810 and 19K15560), Fujifilm
demonstrate the utility of the [2 + 2] cycloadduct
(
Scheme 3). Oxidative cleavage of the 4-(MeO)C
6
H
4
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201901337
Corporation Award in Synthetic Organic Chemistry, Japan, and
MEXT, Japan.
M. P. Shores, E. M. Ferreira, Angew. Chem. Int. Ed. 2015,
5
4, 6506–6510; f) R. F. Higgins, S. M. Fatur, S. G.
Shepard, S. M. Stevenson, D. J. Boston, E. M. Ferreira, N.
H. Damrauer, A. K. Rappé, M. P. Shores, J. Am. Chem.
Soc. 2016, 138, 5451–5464; g) Y. Zhao, M. Antonietti,
Angew. Chem. Int. Ed. 2017, 56, 9336–9340; h) P. D.
Morse, T. M. Nguyen, C. L. Cruz, D. A. Nicewicz,
Tetrahedron 2018, 74, 3266–3272; i) Y. Okada, Y.
Yamaguchi, A. Ozaki, K. Chiba, Chem. Sci. 2016, 7, 6387–
References
[
1] a) T. V. Hansen, Y. Stenstrøm, Naturally Occurring
Cyclobutanes, in Organic Synthesis: Theory and
Applications, ed. Hudlicky, T., Elsevier, Oxford, UK, 2001,
vol. 5, pp. 1–38; b) V. M. Dembitsky, J. Nat. Med., 2008,
6
395.
6
2, 1–33; c) A. Sergeiko, V. V. Proikov, L. O. Hanus, V. M.
Dembitsky, Open Med. Chem. J. 2008, 2, 26–37.
2] a) E. Lee-Ruff, G. Mladenova, Chem. Rev. 2003,
03, 1449–1483; b) E. Lee-Ruff, Synthesis of
[
8] a) N. L. Bauld, R. Pabon, J. Am. Chem. Soc. 1983,
1
5
05, 633–634; b) N. L. Bauld, Tetrahedron 1989, 45,
307–5367.
[
1
[
9] a) M. A. Ischay, M. S. Ament, T. P. Yoon, Chem. Sci.
Cyclobutanes, in The Chemistry of Cyclobutanes, (Eds.: Z.
Rappoport, J. F. Liebman), Wiley, 2005, pp. 281–355; c) S.
Poplata, A. Trꢀster, Y.-Q. Zou, T. Bach, Chem. Rev. 2016,
2
012, 3, 2807–2811; b) R. Li, B. C. Ma, W. Huang, L.
Wang, D. Wang, H. Lu, K. Landfester, K. A. I. Zhang, ACS
Catal. 2017, 7, 3097–3101.
1
16, 9748−9815.
3] For selected reviews of photochemical [2 + 2]
cycloadditions, see: a) M. T. Crimmins, Chem. Rev. 1988,
[
10] a) I. Colomer, R. C. Barcelos, T. J. Donohoe,
[
Angew. Chem. Int. Ed. 2016, 55, 4748–4752; b) I.
Colomer, C. Batchelor-McAuley, B. Odell, T. J. Donohoe,
R. G. Compton, J. Am. Chem. Soc. 2016, 138, 8855–8861.
8
1
8, 1453–1473; b) M. Demuth, G. Mikhail, Synthesis
989, 145–162; c) D. I. Schuster, G. Lem, N. A.
[
11] a) Y. Yu, Y. Fu, F. Zhong, Green Chem. 2018, 20,
743–1747; b) J. H. Shin, E. Y. Seong, H. J. Mun, Y. J.
Jang, E. J. Kang, Org. Lett. 2018, 20, 5872–5876.
12] T. Horibe, S. Ohmura, K. Ishihara, J. Am. Chem.
Soc. 2019, 141, 1877–1881.
13] Triplet-sensitized crossed [2 + 2] cycloadditions of
-unsaturated carbonyls were recently reported.
Kaprinidis, Chem. Rev. 1993, 93, 3–22; d) J. Iriondo-
Alberdi, M. F. Greaney, Eur. J. Org. Chem. 2007, 4801–
1
4
5
815; e) T. Bach, J. P. Hehn, Angew. Chem. Int. Ed. 2011,
0, 1000–1045.
[
[
4] For selected electrochemical methods for [2 + 2]
[
cycloaddition, see: a) Y. Okada, R. Akaba, K. Chiba, Org.
Lett. 2009, 11, 1033–1035; b) Y. Okada, A. Nishimoto, R.
Akaba, K. Chiba, J. Org. Chem. 2011, 76, 3470–3476.

A
variety of -unsaturated carbonyls can be used despite
the low diastereoselectivity of the product. a) Z. D. Miller,
B. J. Lee, T. P. Yoon, Angew. Chem. Int. Ed. 2017, 56,
[
5] For selected homo [2 + 2] cycloaddition of anetholes,
see: a) F. A. Bell, R. A. Crellin, H. Fujii, A. Ledwith, J.
Chem. Soc. D. 1969, 1969, 251–252; b) A. Ledwith, Acc.
Chem. Res. 1972, 5, 133–139; c) H. Ohara, T. Itoh, M.
Nakamura, E. Nakamura, Chem. Lett. 2001, 30, 624–625;
d) C. A. Marquez, H. Wang, F. Fabbretti, J. O. Metzger, J.
Am. Chem. Soc. 2008, 130, 17208–17209. e) M. Riener,
D. A. Nicewicz, Chem. Sci. 2013, 4, 2625–2629.
11891–11895; b) T. Lei, C. Zhou, M.-Y. Huang, L.-M.
Zhao, B. Yang, C. Ye, H. Xiao, Q.-Y. Meng, V.
Ramamurthy, C.-H. Tung, L.-Z. Wu, Angew. Chem. Int.
Ed. 2017, 56, 15407–15410.
[
14] For the generation of electron-deficient anethole
radical cation for [4 + 2] cycloaddition, see: S. M.
Stevenson, R. F. Higgins, M. P. Shores, E. M. Ferreira,
Chem. Sci. 2017, 8, 654–660.
[
6] Y. Okada, K. Chiba, Chem. Rev. 2018, 118, 4592–
630.
7] For related cyclizations leveraging the generation of
4
[
15] J. R. Cabrero-Antonino, A. Leyva-Pérez, A. Corma,
Chem. Eur. J. 2013, 19, 8627–8633.
16] P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B.
Sharpless, J. Org. Chem. 1981, 46, 3936-3938.
17] K. Raha, K. M. Merz, J. Med. Chem. 2005, 48,
558-4575.
[
trans-anethole radical cation, see: a) D. J. Bellville, N. L.
Bauld, R. Pabon, S. A. Gardner, J. Am. Chem. Soc. 1983,
[
1
05, 3584–3588; b) R. A. Pabon, D. J. Bellville, N. L.
[
Bauld, J. Am. Chem. Soc. 1983, 105, 5158–5159; c) D. W.
Reynolds, N. L. Bauld, Tetrahedron 1986, 42, 6189–6194;
d) S. Lin, M. A. Ischay, C. G. Fry, T. P. Yoon, J. Am.
Chem. Soc. 2011, 133, 19350–19353; e) S. M. Stevenson,
4
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201901337
UPDATE
Radical Cation-induced Crossed [2 + 2]
Cycloaddition of Electron-deficient Anetholes
Initiated by Iron(III) Salt
Adv. Synth. Catal. Year, Volume, Page – Page
Takahiro Horibe, Kei Katagiri and Kazuaki
Ishihara*
5
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