Highly Stereoselective Synthesis of Fused Tetrahydropyrans via Lewis-Acid-Promoted Double C(sp3)-H Bond Functionalization

Article abstract of DOI:10.1021/acs.orglett.0c01867

We have achieved a sequential hydride-shift-triggered double C(sp3)-H bond functionalization at a position adjacent to an oxygen atom and a benzylic/aliphatic position through the employment of substrates with a dialkyl group in the alkyl chain, which enabled the highly diastereoselective synthesis of fused tetrahydropyrans.

Full text of DOI:10.1021/acs.orglett.0c01867

pubs.acs.org/OrgLett
Letter
Highly Stereoselective Synthesis of Fused Tetrahydropyrans via
Lewis-Acid-Promoted Double C(sp3)−H Bond Functionalization
Kazuma Yokoo, Dan Sakai, and Keiji Mori*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01867
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We have achieved a sequential hydride-shift-triggered
double C(sp3)−H bond functionalization at a position adjacent to an
oxygen atom and a benzylic/aliphatic position through the employment
of substrates with a dialkyl group in the alkyl chain, which enabled the
highly diastereoselective synthesis of fused tetrahydropyrans.
he direct transformation of a C−H bond is a powerful
T
methodology for the construction of organic molecules.
Because of its utility from the perspective of atom economy1
and step economy, much effort has been devoted to the
development of new strategies.2 In recent years, a more
challenging transformation, namely, the double C−H bond
functionalization, was developed.3,4 Most of the methods
reported so far deal with the functionalization of C(sp2)−H/
C(sp2)−H bonds3 and C(sp2)−H/C(sp3)−H bonds.4 Exam-
ples of corresponding double functionalization of the strongest
C(sp3)−H bond are scarce,5 and the development of new
methods has been pursued.
Our continuous efforts for the development of new synthetic
methods based on hydride-shift-triggered C(sp3)−H bond
functionalization (internal redox process)6−11 have revealed
that double C(sp3)−H bond functionalization is achievable by
the sequential utilization of the internal redox process (Figure
1).8 In addition to the accomplishment of this challenging
transformation, this method offers rapid access to multi-
functionalized polyheterocycles. To make this sequential
system a more useful and attractive synthetic tool, the
achievement of analogous double C(sp3)−H functionalization
at a position adjacent to a heteroatom and a benzylic/aliphatic
position (without an adjacent heteroatom) is highly desirable.
The challenge of the planned reaction lies in the restricted
conformation in the first hydride shift step. Previous studies by
us and other groups have suggested that efficient overlapping
between the lone pair of the heteroatom (X) and the σ* orbital
of a C−H bond is important to promote the hydride shift.6,7,10
In the previous method, a desired conformation like A is easy
to take because the heteroatom is located outside the cyclic
transition state structure (high conformational freedom). In
sharp contrast, the required orbital overlapping would be
insufficient in the planned reaction because the conformation
of the heteroatom is restricted.
Figure 1. Double C(sp3)−H bond functionalization developed by our
group and challenge for the new sequential system.
oxygen atom and a benzylic/aliphatic position (Scheme 1).
When dialkyl ether derivatives with a dialkyl group in the alkyl
chain were treated with a catalytic amount of BF3·OEt2, the
expected [1,5]-[1,5]-hydride shift proceeded to afford fused
tetrahydropyrans in good chemical yields with excellent
diastereoselectivities (up to d.r. = >20:1).
Received: June 3, 2020
Herein, we describe the realization of a highly diaster-
eoselective synthesis of fused tetrahydropyrans by double
C(sp3)−H bond functionalization at a position adjacent to an
https://dx.doi.org/10.1021/acs.orglett.0c01867
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. Double C(sp3)−H Bond Functionalization at the
Position Adjacent to the Oxygen Atom and the Benzylic/
Aliphatic Position
Table 1. Examination of Reaction Conditions
b
yield (%)
d.r.
entry
catalyst
X
5a
4a
Our study commenced with the reaction of dialky ether-type
cinnamylidene malonate 1, which is expected to be confoma-
tionally more flexible, enabling the desired orbirtal interaction
compared to a phenol-type substrate (Scheme 2). When a
1
2
3
4
5
6
7
8
Sc(OTf)3
Yb(OTf)3
Gd(OTf)3
Mg(OTf)2
Bi(OTf)3
Zn(OTf)2
TfOH
Tf2NH
TiCl4
SnCl4
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
B(C6F5)3
BBr3
30
30
30
30
30
0
0
0
0
0
0
0
0
0
15
61
68
trace
55
0
−
−
−
−
−
−
−
−
98
95
98
98
98
98
97
98
94
0
0
0
0
0
94
90
Scheme 2. Initial Trial for the Planned Reaction
30
100
100
100
100
100
30
20
30
30
30
9
−
10
11
12
13
>20:1
>20:1
>20:1
−
>20:1
−
solution of 1 in 1,2-dichloroethane was treated with 30 mol %
of Sc(OTf)3, 1 was almost completely consumed after 14 h.
The resulting product was not desired fused pyran 2 but
alcohol 3, which was produced by the E2 elimination from 1
through the acid activation of ether oxygen. Other metal
triflates, such as Yb(OTf)3 and Gd(OTf)3, were also
ineffective, and substantial amounts of 3 were obtained in
both cases (40−55%).
c
14
15
16
0
−
a
Unless otherwise noted, all reactions were conducted with 0.10
mmol of 4a in the presence of an acid catalyst (X mol %) in
ClCH2CH2Cl (1.0 mL) at refluxing temperature. Isolated yield.
2.66 mmol scale.
b
c
To suppress this unwanted reaction, we planned to use
substrate 4 with a dialkyl group β to the oxygen atom (Figure
2). This structural modification was expected to be effective
OEt2 turned out to be the most effective, and both good
chemical yield and excellent diastereoselectivity were realized
(61%, d.r. = >20:1, entry 11). Gratifyingly, the catalyst loading
of BF3·OEt2 could be reduced to 30 mol % without sacrificing
chemical yield and diastereoselectivity (68%, d.r. = >20:1,
entry 12). A scale-up reaction was also acceptable (2.66 mmol,
entry 14). Catalyst screening focusing on the boron Lewis
acids suggested that BF3·OEt2 was an effective catalyst. Both
B(C6F5)3 and BBr3 resulted in the recovery of 4a (entries 15
and 16). Employment of the malonate moiety was essential to
realize the target reaction; subjection of cinnamylidene
barbiturate 6 under optimized reaction conditions (30 mol %
of BF·OEt2, ClCH2CH2Cl, reflux, 24 h) resulted in complete
recovery of starting material.12
The relative stereochemistry of the major diastereomer was
determined as described in 5a by X-ray crystallographic
analysis of the compound 8a, which was synthesized from 5a
by a two-step sequence (reduction of two-ester moieties
followed by acetal formation, Scheme 3),13 and those of others
shown in Figure 3 were surmised by analogy.
The substrate scope of this reaction is illustrated in Figure 3.
Changing the ester portion of the malonate moiety from
methyl to ethyl resulted in almost the same result (5b: 61%,
d.r. = >20:1). The dialkyl moiety was not limited to the methyl
group. Substrates with not only the diethyl group but also the
cyclic groups, such as cyclopentyl and cyclohexyl moieties,
participated in the reaction, and good chemical yields and
excellent diastereoselectivities were realized (5c−f: 65−73%,
d.r. = >20:1). In contrast to the wide acceptability of the
dialkyl moiety, the para-methoxyphenyl (PMP) group was
indispensable to achieving the catalytic and excellent
Figure 2. Reasons for using substrate 4 with a dialkyl moiety.
because it would not only suppress the elimination of the
alcohol moiety due to the absence of β-hydrogens but also
enhance the reactivity as a result of the Thorpe−Ingold effect.
Although the production of alcohol 3 was completely
suppressed when substrate 4a was subjected to the same
reaction conditions as those in Scheme 2, desired fused pyran
5a was not obtained. Instead, 4a was completely recovered
(entry 1, Table 1). Motivated by the suppression of the side
reaction, extensive screening for the reaction conditions was
conducted (Table 1). Various metal triflates, such as
Yb(OTf)3, Gd(OTf)3, and Zn(OTf)2, also resulted in the
complete recovery of 4a (entries 2−6). The same situation
occurred when strong Brønsted acids, such as TfOH and
Tf2NH, were used (entries 7 and 8). Further screening for
catalyst revealed that commonly used strong Lewis acids gave
satisfactory results. Whereas TiCl4 resulted in the recovery of
4a (94%, entry 9), SnCl4 gave fused pyran 5a in 15% chemical
yield (entry 10). Only two diastereomers were observed in this
reaction even though 5a had three stereogenic centers, and
fortunately, one diastereomer was majored (d.r. = >20:1). BF3·
B
https://dx.doi.org/10.1021/acs.orglett.0c01867
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
substrate was essential to achieve the sequential reaction:
subjection of substrate 4l with a linear alkyl chain to the
modified optimized reaction conditions (150 mol % of BF3·
OEt2, CH2CH2Cl, reflux, 24 h) resulted in exclusive formation
of a single hydride shift adduct 9 (83%). The results in 5j and
5k offered us important information: the two diastereomers in
5h were considered to be α- and β-isomers at C-7 (adjacent to
the R2/R3 group).
Scheme 3. Determination of the Relative Stereochemistry of
5a
Our previous report on the highly diastereoselective
synthesis of 1,3-disubstituted tetralins suggested that an acid-
catalyzed interconversion between the α- and β-isomers
derived from the benzylic position easily took place via the
strong electron-donating ability of the PMP group.7d Taking
this result and the stereochemical information on 5j and 5k
(vide supra) into account, the low diastereoselectivity of 5h
with a phenyl group could be well rationalized (Figure 4). In
Figure 4. Rationalization for high diastereoselectivity.
contrast to PMP, p-Tol, and ortho-methoxyphenyl groups
(strong electron-donating groups), the simple phenyl group
could not induce the key interconversion between the two
diastereomers, as shown in the upper part of Figure 4, and as a
result, the diastereomeric ratio of 5h remained at a low level.
This assumption, i.e., thermodynamic control, was further
supported by the comparison of the relative energies of the two
diastereomers by DFT calculations (B3LYP/6-31G*), in
which the major diastereomer (α-isomer) was more stable
than the minor one (β-isomer) due to the direction of the
aromatic ring (equatorial vs axial).
Figure 3. Substrate scope.
diastereoselective reaction. In the case of substrates 5g and 5h
having a para-tolyl (p-Tol) group and a simple phenyl group,
100 mol % of BF3·OEt2 was required for the completion of the
reaction. Although excellent diastereoselectivity was observed
for p-tolyl product 5g (d.r. = >20:1), the diastereoselectivity
was low (d.r. = 1.1:1) when phenyl-substituted substrate 4h
was employed. The substituent position was also important,
and a substoichiometric amount of catalyst (50 mol %) was
essential to achieve a good result (66%, d.r. = >20:1) in the
case of substrate 4i with an ortho-methoxyphenyl group.
According to our previous report on the examination of the
substituent effect on the benzylic hydride shift process, the low
electron-donating ability and the steric hindrance in the
aromatic ring considerably lowered the reactivity.7b These
situations would apply to this reaction as well, leading to the
requirement of an increased amount of catalyst in substrates
5g−i. It is worth noting that this sequential system was
applicable to the combination of hydride shifts at the position
adjacent to the oxygen atom and the aliphatic position, giving
5j and 5k in moderate chemical yields with excellent
diastereoselectivities (5j: 41%, d.r. = >20:1, 5k: 37%, d.r. =
>20:1, respectively). The employment of the branched
Deuterium labeling experiments were conducted to clarify
the reaction mechanism (Scheme 4). In contrast to the first
hydride shift process, the primary kinetic isotope effect was not
observed in the second hydride shift process (kH/kD = 1.3 vs
Scheme 4. Kinetic Studies
C
https://dx.doi.org/10.1021/acs.orglett.0c01867
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
kH/kD = 2.6 for the first hydride shift). These results suggested
that the first hydride shift process would be the rate-
determining step like the double C(sp3)−H bond functional-
ization at the position adjacent to the same heteroatom.8
In summary, we have achieved an expedient synthesis of
fused tetrahydropyrans via the double C(sp3)−H bond
functionalization at the position adjacent to an oxygen atom
and the benzylic/aliphatic position. The employment of a
substrate with a dialkyl group in the alkyl chain was the key to
achieving the reaction, and various types of products were
obtained in good chemical yields with excellent diastereose-
lectivities (up to d.r. = >20:1). Our previous studies and
additional experiments provided important information on the
reaction mechanism: (1) the first hydride shift process was the
rate-determining step and (2) diastereoselectivity could be
controlled thermodynamically. Multiple C−H bond function-
alizations triggered by a sequential hydride shift/cyclization
system are under way in our laboratory and will be reported in
due course.
REFERENCES
■
(1) Trost, B. M. Science 1991, 254, 1471.
(2) For recent reviews on C−H activation, see: (a) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Davies, H.
M. L.; Manning, J. R. Nature 2008, 451, 417. (c) Chen, X.; Engle, K.
M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.
(d) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(e) Davies, H. M. L.; Du Bois, J.; Yu, J.-Q. Chem. Soc. Rev. 2011, 40,
1855. (f) Bruckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem.
̈
Res. 2012, 45, 826. (g) Davies, H. M. L.; Morton, D. J. Org. Chem.
2016, 81, 343. See also highlights on visible-light photocatalysis:
(h) Hu, X.-Q.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2017,
56, 1960.
(3) For selected recent examples on dual functionalization of the
C(sp2)−H/C(sp2)−H bond, see: (a) Umeda, N.; Hirano, K.; Satoh,
T.; Shibata, N.; Sato, H.; Miura, M. J. Org. Chem. 2011, 76, 13.
(b) Peng, S.; Liu, S.; Zhang, S.; Cao, S.; Sun, J. Org. Lett. 2015, 17,
5032. (c) He, Z.; Huang, Y. ACS Catal. 2016, 6, 7814. (d) Minami,
Y.; Sakai, M.; Anami, T.; Hiyama, T. Angew. Chem., Int. Ed. 2016, 55,
8701. (e) Zhang, W.-B.; Yang, X.-T.; Ma, J. B.; Su, Z.-M.; Shi, S.-L. J.
Am. Chem. Soc. 2019, 141, 5628. (f) Yano, Y.; Mitoma, N.;
Matzushima, K.; Wang, F.; Matsui, Y.; Takakura, A.; Miyauchi, Y.;
Ito, H.; Itami, K. Nature 2019, 571, 387. (g) Yano, Y.; Wang, F.;
Mitoma, N.; Miyauchi, Y.; Ito, H.; Itami, K. J. Am. Chem. Soc. 2020,
142, 1686. (h) Wang, Y.-X.; Zhang, F.-P.; Luan, Y.-X.; Ye, M. Org.
Lett. 2020, 22, 2230. For review, see: (i) Minami, Y.; Hiyama, T.
Tetrahedron Lett. 2018, 59, 781.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01867.
(4) Selected examples on dual functionalization of the C(sp2)−H/
C(sp3)−H bond, see: (a) Nakao, Y.; Morita, E.; Idei, H.; Hiyama, T.
J. Am. Chem. Soc. 2011, 133, 3264. (b) Reddy Chidipudi, S.; Khan, I.;
Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 12115. (c) Anand, M.;
Sunoj, R. B. Org. Lett. 2012, 14, 4584. (d) Aihara, Y.; Chatani, N. J.
Am. Chem. Soc. 2014, 136, 898. (e) Aihara, Y.; Tobisu, M.; Fukumoto,
Y.; Chatani, N. J. Am. Chem. Soc. 2014, 136, 15509. (f) Zhou, W.;
Zheng, S.; Schultz, J. W.; Rath, N. P. L.; Mirica, M. J. Am. Chem. Soc.
2016, 138, 5777. (g) Zhao, M.-N.; Yu, L.; Hui, R.-R.; Ren, Z.-H.;
Wang, Y.-Y.; Guan, Z.-H. ACS Catal. 2016, 6, 3473. (h) Feng, S.; Xie,
X.; Zhang, W.; Liu, L.; Zhong, Z.; Xu, D.; She, X. Org. Lett. 2016, 18,
3846. (i) Romanov-Michailidis, F.; Ravetz, B. D.; Paley, D. W.; Rovis,
T. J. Am. Chem. Soc. 2018, 140, 5370. For review, see: (j) Arun, V.;
Mahanty, K.; DeSarkar, S. ChemCatChem 2019, 11, 2243.
Experimental procedures, analytical and spectroscopic
data for new compounds, copies of NMR spectra,
computational details, and Cartesian coordinates (PDF)
Accession Codes
CCDC 1990657 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
(5) Selected examples on dual functionalization of the C(sp3)−H/
C(sp3)−H bond, see: (a) Stang, E. M.; White, M. C. J. Am. Chem. Soc.
2011, 133, 14892. (b) Zhou, L.; Xu, B.; Zhang, J. Angew. Chem., Int.
Ed. 2015, 54, 9092. (c) Xu, G.-Q.; Xu, J.-T.; Feng, Z.-T.; Liang, H.;
Wang, Z.-Y.; Qin, Y.; Xu, P.-F. Angew. Chem., Int. Ed. 2018, 57, 5110.
(6) For recent reviews on the internal redox process, see: (a) Tobisu,
M.; Chatani, N. Angew. Chem., Int. Ed. 2006, 45, 1683. (b) Wang, M.
ChemCatChem 2013, 5, 1291. (c) Peng, B.; Maulide, N. Chem. - Eur. J.
2013, 19, 13274. (d) Wang, L.; Xiao, J. Adv. Synth. Catal. 2014, 356,
1137. (e) Haibach, M. C.; Seidel, D. Angew. Chem., Int. Ed. 2014, 53,
5010. (f) Kwon, S. J.; Kim, D. Y. Chem. Rec. 2016, 16, 1191. (g) Xiao,
M.; Zhu, S.; Shen, Y.; Wang, L.; Xiao, J. Youji Huaxue 2018, 38, 328.
(7) For the internal redox reaction developed by our group, see:
(a) Mori, K.; Sueoka, S.; Akiyama, T. J. Am. Chem. Soc. 2011, 133,
2424. (b) Mori, K.; Sueoka, S.; Akiyama, T. Chem. Lett. 2011, 40,
1386. (c) Mori, K.; Ehara, K.; Kurihara, K.; Akiyama, T. J. Am. Chem.
Soc. 2011, 133, 6166. (d) Yoshida, T.; Mori, K. Chem. Commun. 2017,
53, 4319. (e) Yoshida, T.; Mori, K. Chem. Commun. 2018, 54, 12686.
(f) Tamura, R.; Kitamura, E.; Tsutsumi, R.; Yamanaka, M.; Akiyama,
T.; Mori, K. Org. Lett. 2019, 21, 2383. (g) Otawa, Y.; Mori, K. Chem.
Commun. 2019, 55, 13856. (h) Yokoo, K.; Mori, K. Org. Lett. 2020,
22, 244.
■
Corresponding Author
Keiji Mori − Department of Applied Chemistry, Graduate
School of Engineering, Tokyo University of Agriculture and
Technology, Koganei, Tokyo 184-8588, Japan; orcid.org/
0000-0002-9878-993X; Email: k_mori@cc.tuat.ac.jp
Authors
Kazuma Yokoo − Department of Applied Chemistry, Graduate
School of Engineering, Tokyo University of Agriculture and
Technology, Koganei, Tokyo 184-8588, Japan
Dan Sakai − Department of Applied Chemistry, Graduate School
of Engineering, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01867
Notes
The authors declare no competing financial interest.
(8) For the double C(sp3)−H bond functionalization by sequential
utilization of the internal redox reaction developed by our group, see:
(a) Mori, K.; Kurihara, K.; Yabe, S.; Yamanaka, M.; Akiyama, T. J.
Am. Chem. Soc. 2014, 136, 3744. See, also: (b) Wang, L.; Xiao, J. Org.
Chem. Front. 2016, 3, 635. (c) Mori, K.; Isogai, R.; Kamei, Y.;
Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2018, 140, 6203.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion
of Science and by grants from The Naito Foundation.
D
https://dx.doi.org/10.1021/acs.orglett.0c01867
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(d) Mori, K.; Umehara, N.; Akiyama, T. Chem. Sci. 2018, 9, 7327.
(e) Kataoka, M.; Otawa, Y.; Ido, N.; Mori, K. Org. Lett. 2019, 21,
9334.
(9) These types of reactions are classified as “tert-amino effect.” For
reviews, see: (a) Meth-Cohn, O.; Suschitzky, H. Adv. Heterocycl.
Chem. 1972, 14, 211. (b) Verboom, W.; Reinhoudt, D. N. Recl. Trav.
Chim. Pays-Bas 1990, 109, 311. (c) Meth-Cohn, O. Adv. Heterocycl.
́
́
́
́
Chem. 1996, 65, 1. (d) Matyus, P.; Elias, O.; Tapolcsanyi, P.;
́
́
́
Polonka-Balint, A.; Halasz-Dajka, B. Synthesis 2006, 2006, 2025−
2625.
(10) For selected recent examples of the internal redox reactions,
see: (a) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem. Soc.
2005, 127, 12180. (b) Pastine, S. J.; Sames, D. Org. Lett. 2005, 7,
5429. (c) Zhang, C.; Kanta De, C.; Mal, R.; Seidel, D. J. Am. Chem.
Soc. 2008, 130, 416. (d) McQuaid, K. M.; Sames, D. J. Am. Chem. Soc.
2009, 131, 402. (e) McQuaid, K. M.; Long, J. Z.; Sames, D. Org. Lett.
2009, 11, 2972. (f) Yang, S.; Li, Z.; Jian, X.; He, C. Angew. Chem., Int.
Ed. 2009, 48, 3999. (g) Vadola, P. A.; Sames, D. J. Am. Chem. Soc.
̈
2009, 131, 16525. (h) Jurberg, I. D.; Peng, B.; Wostefeld, E.;
Wasserloos, M.; Maulide, N. Angew. Chem., Int. Ed. 2012, 51, 1950.
(i) Chen, D.-F.; Han, Z.-Y.; He, Y.-P.; Yu, J.; Gong, L.-Z. Angew.
Chem., Int. Ed. 2012, 51, 12307. (j) Li, Y.-Z.; Zhao, M.-L.; Chang, W.-
F.; Wen, X.; Sun, H.; Xu, Q.-L. J. Org. Chem. 2015, 80, 9620.
(k) Ramakumar, K.; Maji, T.; Partridge, J. J.; Tunge, J. A. Org. Lett.
2017, 19, 4014. (l) Li, S.-S.; Zhou, L.; Wang, L.; Zhao, H.; Yu, L.;
Xiao, J. Org. Lett. 2018, 20, 138. (m) Gandamana, D. A.; Wang, B.;
Tejo, C.; Bolte, B.; Gagosz, F.; Chiba, S. Angew. Chem., Int. Ed. 2018,
57, 6181. (n) Wang, S.; An, X. D.; Li, S. S.; Liu, X.; Liu, Q.; Xiao, J.
Chem. Commun. 2018, 54, 13833. (o) Li, S.-S.; Zhu, S.; Chen, C.;
Duan, K.; Liu, Q.; Xiao, J. Org. Lett. 2019, 21, 1058. (p) Zhao, S.;
Wang, X.; Wang, P.; Wang, G.; Zhao, W.; Tang, X.; Guo, M. Org. Lett.
2019, 21, 3990. (q) Paul, A.; Seidel, D. J. Am. Chem. Soc. 2019, 141,
8778. (r) Zhou, L.; Shen, Y.-B.; An, X.-D.; Li, X.-J.; Li, S.-S.; Liu, Q.;
Xiao, J. Org. Lett. 2019, 21, 8543. (s) Wang, B.; Gandamana, D. A.;
Rayo, D. F. L.; Gagosz, F.; Chiba, S. Org. Lett. 2019, 21, 9179.
(t) Kaiser, D.; Tona, V.; Goncalves, C. R.; Shaaban, S.; Oppedisano,
A.; Maulide, N. Angew. Chem., Int. Ed. 2019, 58, 14639. (u) Zhou, L.;
An, X.-D.; Yang, S.; Li, X.-J.; Shao, C.-L.; Liu, Q.; Xiao, J. Org. Lett.
2020, 22, 776.
(11) For examples of the enantioselective internal redox reactions,
see: (a) Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem. Soc.
2009, 131, 13226. (b) Kang, Y. K.; Kim, S. M.; Kim, D. Y. J. Am.
Chem. Soc. 2010, 132, 11847. (c) Cao, W.; Liu, X.; Wang, W.; Lin, L.;
Feng, X. Org. Lett. 2011, 13, 600. (d) Zhou, G.; Liu, F.; Zhang, J.
Chem. - Eur. J. 2011, 17, 3101. (e) He, Y.-P.; Du, Y.-L.; Luo, S.-W.;
Gong, L. Z. Tetrahedron Lett. 2011, 52, 7064. (f) Chen, L.; Zhang, L.;
Lv, Z.; Cheng, J.-P.; Luo, S. Chem. - Eur. J. 2012, 18, 8891. (g) Jiao,
Z.-W.; Zhang, S.-Y.; He, C.; Tu, Y.-Q.; Wang, S.-H.; Zhang, F.-M.;
Zhang, Y.-Q.; Li, H. Angew. Chem., Int. Ed. 2012, 51, 8811. (h) Kang,
Y. K.; Kim, D. Y. Adv. Synth. Catal. 2013, 355, 3131. (i) Kang, Y. K.;
Kim, D. Y. Chem. Commun. 2014, 50, 222. (j) Suh, C. W.; Kim, D. Y.
Org. Lett. 2014, 16, 5374. (k) Cao, W.; Liu, X.; Guo, J.; Lin, L.; Feng,
X. Chem. - Eur. J. 2015, 21, 1632. (l) Li, J.; Preinfalk, A.; Maulide, N. J.
Am. Chem. Soc. 2019, 141, 143. See also, refs 7e and 8c
(12) The trial of the planned double C(sp3)−H bond functionaliza-
tion with cinnamylidene malonate having a phenol core failed.
Treatment of the phenol-type substrate with 100 mol % of BF3·OEt2
in refluxing ClCH2CH2Cl for 24 h resulted in almost complete
recovery of starting material (>90%). We consider that there are two
points of this disappointing result: (1) low conformational flexibility
and (2) low electron-donating ability of phenol oxygen compared to
ether oxygen.
(13) See Supporting Information for details.
E
https://dx.doi.org/10.1021/acs.orglett.0c01867
Org. Lett. XXXX, XXX, XXX−XXX