Chemistry of Tertiary Carbon Center in the Formation of Congested C?O Ether Bonds

Article abstract of DOI:10.1002/anie.202010697

Nucleophilic substitutions, including S_N1 and S_N2, are classical and reliable reactions, but a serious drawback is their intolerance for both bulky nucleophiles and chiral tertiary alkyl electrophiles for the synthesis of a chiral quaternary carbon center. An S_RN1 reaction via a radical species is another conventional method used to carry out substitution reactions of bulky nucleophiles and alkyl halides, but chiral tertiary alkyl electrophiles cannot be used. Therefore, a stereospecific nucleophilic substitution reaction using chiral tertiary alkyl electrophiles and bulky nucleophiles has not yet been well studied. In this paper, we describe the reaction of tertiary alkyl alcohols and non-chiral or chiral α-bromocarboxamides as a tertiary alkyl source for the formation of congested ether compounds possessing two different tertiary alkyl groups on the oxygen atom with stereoretention.

Full text of DOI:10.1002/anie.202010697

Angewandte
Research Articles
Chemie
How to cite:
International Edition: doi.org/10.1002/anie.202010697
Stereochemistry
Hot Paper
German Edition:
doi.org/10.1002/ange.202010697
À
Chemistry of Tertiary Carbon Center in the Formation of Congested C
O Ether Bonds
Goki Hirata, Kentarou Takeuchi, Yusuke Shimoharai, Michinori Sumimoto, Hazuki Kaizawa,
Toshiki Nokami,* Takashi Koike,* Manabu Abe,* Eiji Shirakawa,* and Takashi Nishikata*
In memory of Professor Jun-ichi Yoshida on his outstanding contribution to synthetic organic chemistry
Abstract: Nucleophilic substitutions, including SN1 and SN2,
are classical and reliable reactions, but a serious drawback is
their intolerance for both bulky nucleophiles and chiral tertiary
alkyl electrophiles for the synthesis of a chiral quaternary
carbon center. An SRN1 reaction via a radical species is another
conventional method used to carry out substitution reactions of
bulky nucleophiles and alkyl halides, but chiral tertiary alkyl
electrophiles cannot be used. Therefore, a stereospecific nucle-
ophilic substitution reaction using chiral tertiary alkyl electro-
philes and bulky nucleophiles has not yet been well studied. In
this paper, we describe the reaction of tertiary alkyl alcohols
and non-chiral or chiral a-bromocarboxamides as a tertiary
alkyl source for the formation of congested ether compounds
possessing two different tertiary alkyl groups on the oxygen
atom with stereoretention.
carbon center would complement current nucleophilic sub-
stitution chemistry.
Recent related progress in this area includes stereospe-
cific substitutions using chiral tertiary alkyl electrophiles and
small nucleophiles such as azide, isocyanide, carboxylate, and
other carbon nucleophiles (Scheme 1A).[4,5] Hayashi and
Introduction
Nucleophilic substitutions of alkyl electrophiles, including
SN1 and SN2 reactions, are well-established organic reactions
and extremely useful for installing an alkyl fragment in
a predictable manner. The reaction process is clear, but there
are some problems: 1) tertiary alkyl electrophiles and large
nucleophiles are less reactive, and 2) stereoselective substi-
tution with chiral tertiary alkyl electrophiles is difficult.[1]
Unimolecular radical nucleophilic substitution (SRN1) via an
electron-transfer process[2,3] is insensitive to steric hindrance
and thus suitable for tertiary alkylation, but is not stereose-
lective because an alkyl radical is a key intermediate. In this
context, we expect that a nucleophilic substitution of a chiral
tertiary alkyl electrophile that produced a chiral quaternary
Scheme 1. The reaction modes for nucleophilic substitutions.
[*] Dr. G. Hirata, K. Takeuchi, Y. Shimoharai, Prof. Dr. M. Sumimoto,
Prof. Dr. T. Nishikata
E-mail: koike.t.ad@m.titech.ac.jp
Prof. Dr. M. Abe
Graduate School of Science and Engineering, Yamaguchi University
2-16-1 Tokiwadai, Ube, Yamaguchi, 755-8611 (Japan)
E-mail: nisikata@yamaguchi-u.ac.jp
Department of Chemistry, Graduate School of Science, Hiroshima
University
Higashi-Hiroshima, Hiroshima 739-8526 (Japan)
E-mail: mabe@hiroshima-u.ac.jp
H. Kaizawa, Prof. Dr. T. Nokami
Department of Chemistry and Biotechnology, Graduate School of
Engineering (Center for Research on Green Sustainable Chemistry,
Faculty of Engineering), Tottori University
4-101 Koyamachominami, Tottori city, Tottori, 680-8552 (Japan)
E-mail: tnokami@tottori-u.ac.jp
Prof. Dr. E. Shirakawa
Department of Applied Chemistry for Environment, School of
Science and Technology, Kwansei Gakuin University
Sanda, Hyogo 669-1337 (Japan)
E-mail: eshirakawa@kwansei.ac.jp
Prof. Dr. T. Koike
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202010697.
Laboratory for Chemistry and Life Science, Institute of Innovative
Research, Tokyo Institute of Technology, R1-27
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226–8503
(Japan)
&&&&
ꢀ 2020 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2020, 59, 2 – 8
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Mukaiyama reported the stereospecific substitution of chiral
a nucleophile generates the corresponding product with
tertiary alkyl alcohols with 2-sulfanylbenzothiazoles in the
presence of a phosphorus compound and an azide to produce
inversion products.[6,7] Mascal reported the SN2 reaction of
a tertiary alkyl oxonium salt (1,4,7-trimethyloxatriquinane)
with azide.[8] Shibatomi and Iwasa reported the stereoselec-
tive SN2 reaction of chiral halo malonates as tertiary alkyl
electrophiles[9a] which took place with inversion of stereo-
chemistry. Later, Parkꢀs group extended this reaction.[9b]
Shenviꢀs group found that an SN1-like reaction of a chiral
tertiary alkyl trifluoroacetate results in an inversion product
via ion pairs.[10] Baik and Cookꢀs group and Samecꢀs group
reported that an intramolecular SN2 reaction using an iron
retention, in which double SN2 reactions occur. Quast,[39]
Maran,[40] and D’Angeli[41] reported stereospecificity of this
reactive intermediate but only aziridinones possessing chiral
secondary alkyl groups were able to be used as an electro-
phile. On the other hand, stereospecific reactions at a tertiary
carbon atom have not yet been studied in aziridinone and
related chemistry.
Herein, we report our work on the inherent reactivity and
stereoselectivity of a tertiary carbon atom in a nucleophilic
substitution reaction using a-bromocarboxamides.
Lewis acid-activated chiral tertiary alkyl alcohol proceeds Results and Discussion
with stereoinversion.[11,12]
It is very difficult to construct a congested ether bond by
using Williamson ether synthesis[13–15] or other SN2[5a] or SN1[5b]
reactions. Related progress in this area includes hydroalkox-
ylation,[16–19] dehydration of alcohols[20–26] and, metal-cata-
lyzed alkoxylations.[27,28] Very recently Kꢁrti reported copper
catalyzed alkoxylation of non-chiral a-bromocarboxamides as
a tertiary alkyl source.[29] However, tertiary alkyl substitution
reactions with stereoretention is still challenging. To accom-
plish substitution reactions with retention, chiral rigid multi-
cyclic electrophiles are sometimes employed.[30] Despite
significant research on nucleophilic substitution reactions
for the synthesis of ethers, a reaction with inherent reactivity
and stereoselectivity (especially retention) of tertiary carbon
atoms has not yet been established[31–34] (Scheme 1B).
Reactions with non-chiral substrates: We examined the
reactivities of a-bromocarboxamides (1) possessing sec- or
tert-amides, an ester, or ketone in the presence of cesium
carbonate at room temperature (Figure 1). The reaction of N-
In the course of our research on a-bromocarbonyl
compounds in the presence of a copper salt,[35,36] we found
that a-bromocarboxamide (1) reacts with tertiary alkyl
alcohol (2) as a tertiary alkyl source in the absence of copper
salts to produce a highly congested ether bond (Scheme 2).
We expected that the reactivity of the electrophiles would
depend on the size of the three substituents on the halo-
substituted carbon atom (or the size of nucleophiles), but the
corresponding product (3) was smoothly obtained with the aid
of a carboxamide moiety (neighboring effect or formation of
aziridinone). Moreover, after careful experiments, we found
that the reaction occurred with retention, in which a nucleo-
phile formally attacks at the front side of a leaving group.
a-Bromocarboxamides (1) have been employed as syn-
thetic intermediates.[37] Among them, the formation of
aziridinone (a-lactam) from 1 in the presence of a strong
base is well-known chemistry, which is summarized by
Sheehan and Lengyel in 1968.[37a] For example, t-BuOK and
related alcohols reacted with aziridinone to give the corre-
sponding ether.[38] Fundamental reactivities of aziridinones
have been studied deeply, whereas stereospecific reactions
are still challenging. Generally, the reaction of chiral 1 and
Figure 1. Basic reactivities of 1.
phenyl and benzyl substituted 1a or 1b and t-BuOH (2a),
which is a neutral and bulky nucleophile, gave 3a and 3b in
82% and 65% (72 h), respectively, but similar sec-amides (1c,
1d) were not effective at all. The reactivity of 1b possessing
N-alkyl moiety was slower than that of substrate possessing
aryl group. Cs2CO3 was better than K3PO4 and K2CO3. We
were concerned that 1 could undergo E2 elimination to
produce methacryl amide under basic conditions, but such
a side product was not obtained. The NH acidity could play an
À
important role to activate the C Br bond through electron
transfer from an amide anion. Although the NH of imide 1d
has strong acidity compared with other amides, 3d was not
obtained and the starting material was recovered. The
substrates possessing tert-amides (1e, 1 f), an ester (1g), and
ketone (1h) were also not reactive, probably due to the
absence of an electron donor (amide anion). Primary-amide
possessing NH2 moiety did not give any product. We also
examined the effect of additional electron donors, such as N-
phenylbenzamide as a super electron donor, to promote the
reaction[42–44] but the reaction of 1 f (or 1g, 1h) and 2a in the
presence of N-phenylbenzamide did not give 3 f. When the
reaction of the corresponding chloride (1a-Cl) was carried
out, 3a was obtained after prolonged reaction time.
The reactivities of various bromocarboxamides (1) and
alcohols (2) were examined under the optimized reaction
Scheme 2. Congested ether formation.
Angew. Chem. Int. Ed. 2020, 59, 2 – 8
ꢀ 2020 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Table 1: Substrate Scope of a-Alkylation.[a]
Figure 2. Synthetic applications 1.
reactions of various diols (4) were carried out, the selectivities
were apparently dependent on the steric hindrance (Fig-
ure 2B). We also carried out the reaction with an enol as an
alcohol. The reaction of 1a and 6 as an enol precursor
produced the corresponding ether product 7 with the yield of
56% (Figure 2C). The structure of 7 was determined by X-ray
analysis (See SI). a-Bromocarboxamides possessing substi-
tuted arenes (1i–1m) were examined (Table 1). Both elec-
tron-donating and -withdrawing groups can be applied to this
reaction and the yields ranged from 52%-82% (3q–3u).
Compound 1m possessing a cinnamyl moiety gave 52% yield
of 3u but no side products were observed. We also checked
the reactivities of substrate 1 possessing various degrees of
steric bulkiness at the carbonyl a-position (1n–1t). As a result,
various lengths of alkyl chains showed good reactivities (3v–
3bb). Finally, we examined various substrate combinations
and obtained highly congested and functionalized ether
compounds in moderate to good yields (3cc–3hh). Overall
functional group compatibilities were very nice. For example,
the ethers possessing epoxide (3x, 3dd), a primary alkyl-Br
bond (3v), heteroarene moiety (3z, 3gg), or terminal alkyne
(3ee) can be synthesized from the corresponding substrates.
The results of 3v and 3x indicated that this reaction does
not include a simple ionic substitution reaction because no
[a] Conditions: 1 (0.5 mmol), 2 (1.5 mmol), Cs2CO3 (2.0 equiv), MeCN
(0.25 mL) at rt for 18 h. Yields of isolated products were shown.
À
nucleophilic attack of t-BuOH occurs at primary alkyl Br
bond or epoxide moiety. Interestingly, a-bromocarboxamide
possessing a phenol moiety on the amide nitrogen atom
underwent an intramolecular etherification reaction to pro-
duce 3ii in 42% yield. A combination of the classical SN2
À
conditions (Table 1). Alcohols possessing a C C double bond,
À
C Br bond, cyclic structure, or silanol group smoothly
reacted with 1a to produce congested ethers in good yields
(3j–3p), but adamantanol 2b gave the low yield of 3i. In this
reaction, primary-, secondary-, and tertiary-alkyl alcohols
(MeOH, i-PrOH, t-BuOH) can be employed as a substrate.
The reaction rates were in the order of primary > secondary
> tertiary (Figure 2A). Sterically hindered alcohols can be
employed in this reaction, but the reaction of a sterically less
hindered primary-alcohol is the fastest. Indeed, when the
reaction and the current reaction of 8, which possesses both
3
À
primary and tertiary Csp Br bonds, gave an interesting
double etherificated product 10 in good yield (Figure 3A). In
this reaction, t-BuOH (2a) reacted selectively with the
3
3
À
À
tertiary Csp Br bond and the primary Csp Br bond
remained intact. Further advantage can also be taken of the
reaction conditions associated with these etherifications to
allow for cyclizations (Figure 3B). We expected that the
&&&&
www.angewandte.org
ꢀ 2020 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2020, 59, 2 – 8
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Table 2: Reaction with diastereo-enriched alkyl bromides.[a]
Figure 3. Synthetic applications 2.
reaction of 11 would produce an oligomerized ether, but C-H
cyclized product 12 was obtained in 64% yield. 12 might be
generated via radical or related electron transfer process.[45] In
the case of the reaction of propargylic alcohol (13), ether-
ification followed by hydroamidation occurred to produce
a six-membered ring 14 in 53% yield (Figure 3C).
Reactions with chiral substrates: We next carried out the
stereospecific substitution of diastereo-enriched alkyl bro-
mides (1 or 15) with alcohols (2) (Table 2A,B).
When using bromides possessing (R)-phenethyl alcohol
fragments (15a–15c), both diastereomers reacted smoothly
with 2c with high diastereospecificities (ds), although the
diastereospecificities from 15 and 15’ (which have opposite
diastereoisomers) were slightly different (Runs 1–6). This
could be attributed to (R)-phenethyl alcohol fragment which
may act as chiral auxiliaries. However, in the case of the
reaction of 1q (96:4 dr), which possesses an (l)-menthyl
fragment at a distal position with respect to the alpha-carbon,
gave 3y with 91% ds (using AcOEt instead of MeCN was
effective for increasing the yield) (Runs 7 and 8). This result
indicated that a chiral auxiliary is not needed to carry out the
stereospecific substitutions of diastereo-enriched a-bromo-
carbonyl compounds (1 or 15). a-Chlorocarbonyl compounds
(15d, 15’d, and 15’’d) also reacted with various alcohols (2) to
produce the corresponding products (16d-16h) in good yields
with high ds (Runs 9–19). The corresponding a-aryl substi-
tuted bromides were too unstable to carry out the reactions.
When the reaction was carried out with 15d and 15’d (which
have opposite diastereoisomers), both diastereospecificities
were very high (Runs 17 and 18), indicating that the (R)-
phenethyl fragment does not affect stereospecific substitu-
tions.
[a] Conditions: 1 or 15 (0.5 mmol), 2 (1.5 mmol), Cs2CO3 (2.0 equiv),
MeCN (0.25 mL) at rt for 72 h. Yields of isolated products were shown.
Diastereomeric ratios were determined by 1H NMR analysis of the crude
reaction mixture.
gave better results than reactions at room temperature. Alkyl
bromides possessing an aryl group on the nitrogen atom (15e
and 15g) gave ethers (16j, 16k, and 16n) in good yields with
moderate es (28, 68 and 52% es, respectively) at 08C (Runs 1–
4) but bromides possessing Bn group (15 f) gave ethers (16l
and 16m) in good yields with high es (98 or 97% es) at 08C
(Runs 5–8). We expected that the moderate es might be
attributed to fast racemization of 15e, 15’e, and 15g during
the reaction. When the reaction of 15e (98:2) was stopped at
0.5 h, the enantiomeric ratio of recovered 15e was 86:14. This
suggests that a racemization process of starting alkyl bromide
via an aza-oxyallylic cation[46] could be involved in this
reaction. On the other hand, alkyl substituted substrate 15g
gave moderate results even at 08C (Runs 9 and 10).
Although an accurate mechanism is not yet available, this
reaction is not a simple nucleophilic substitution reaction and
might include a double inversion (SN2) process via an
aziridinone[37,47] or an SN2 front-like mechanism via single-
electron transfer. We failed to detect an aziridinone or related
electrophilic intermediate. Instead we found that an electro-
We then employed (S,R)-15b to check whether retention
or inversion occurred in this reaction, and the reaction was
observed to proceed in a stereoretentive manner (Table 2C,
Run 20). The absolute configuration was determined by X-ray
analysis of 16i after purification of the major isomer (See SI).
We also checked the reactivity of enantio-enriched alkyl
chlorides or bromide (15e–15g) (Table 3). Reactions at 08C
Angew. Chem. Int. Ed. 2020, 59, 2 – 8
ꢀ 2020 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Table 3: Reaction with enantio-enriched alkyl bromides.[a]
Acknowledgements
We thank JST CREST (Grant Number JPMJCR18R4), JSPS
KAKENHI for Grant Number 18K19182 in Challenging
Research (Exploratory), (T.N.), Tokuyama Science Founda-
tion (T. N.), the Naito Foundation (T. N.) and Yamaguchi
University (T. N.) for financial support. We also thank Ms.
Saaya Teranishi (YU) for preparing chiral substrates.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkylation · amide · etherification · substitution
[1] J. E. McMurray, Organic Chemistry, 8th ed., KY: Cengage
Learning, Independence, 2011.
[2] N. Kornblum, R. E. Michel, R. C. Kerber, J. Am. Chem. Soc.
1966, 88, 5662 – 5663.
[3] G. A. Russell, W. C. Danen, J. Am. Chem. Soc. 1966, 88, 5663 –
5665.
[a] Conditions: 15 (0.5 mmol), 2 (1.5 mmol), Cs2CO3 (2.0 equiv), MeCN
(0.25 mL) at rt for 18 h. Yields of isolated products were shown.
Enantiomeric ratios were determined by chiral HPLC. [b] Reaction was
carried out at 08C.
[4] T. Mukaiyama, T. Shintou, K. A. Fukumoto, J. Am. Chem. Soc.
2003, 125, 10538 – 10539.
chemical reaction was effective for carrying out the current
stereospecific etherifications. For example, 16h, 16’k, and
16m (up to 98% ds and 98% es) were obtained under
electrochemical conditions (0.5 FmolÀ1, 4 mA, electrode: Pt.
See Supporting Figure 25 in SI) without any bases. Our
proposed mechanisms and some control experiments, includ-
ing NMR studies, ESR analysis, DFT calculations, and
reactions under electrochemical conditions, are available in
the supporting information. Considering all mechanistic
scenarios shown in SI, current reaction could occur via
aziridinone (a) (Scheme 3).
[5] a) T. Shintou, T. Mukaiyama, J. Am. Chem. Soc. 2004, 126, 7359 –
7367; b) J. Xiang, M. Shang, Y. Kawamata, H. Lundberg, S.
Reisberg, M. Chen, P. Mykhailiuk, G. Beutner, M. Collins, A.
Davies, M. Del Bel, G. Gallego, J. Spangler, J. T. Starr, S. Yang,
D. Blackmond, P. S. Baran, Nature 2019, 573, 398 – 402.
[6] K. Kuroda, Y. Maruyama, Y. Hayashi, T. Mukaiyama, Chem.
Lett. 2008, 37, 836 – 837.
[7] T. Mukaiyama, K. Kuroda, Y. Maruyama, Y. Hayashi, Chem.
Lett. 2008, 37, 1072 – 1073.
[8] M. Mascal, N. Hafezi, M. D. Toney, J. Am. Chem. Soc. 2010, 132,
10662 – 10664.
[9] a) K. Shibatomi, Y. Soga, A. Narayama, I. Fujisawa, S. Iwasa, J.
Am. Chem. Soc. 2012, 134, 9836 – 9839; See other related work
by Park: b) D. Kim, M. W. Ha, S. Hong, C. Park, B. Kim, J. Yang,
H.-g. Park, J. Org. Chem. 2017, 82, 4936 – 4943.
[10] S. V. Pronin, C. A. Reiher, R. A. Shenvi, Nature 2013, 501, 195 –
199.
[11] P. T. Marcyk, L. R. Jefferies, D. I. AbuSalim, M. Pink, M.-H.
Baik, S. P. Cook, Angew. Chem. Int. Ed. 2019, 58, 1727 – 1731;
Angew. Chem. 2019, 131, 1741 – 1745.
Scheme 3. Proposed mechanism.
[12] R. A. Watile, A. Bunrit, J. Margalef, S. Akkarasamiyo, R. Ayub,
E. Lagerspets, S. Biswas, T. Repo, J. S. M. Samec, Nat. Commun.
2019, 10, 3826.
Conclusion
[13] A. I. Williamson, Justus Liebigs Ann. Chem. 1851, 77, 37 – 49.
[14] H. Masada, H. Gotoh, M. Ohkubo, Chem. Lett. 1991, 20, 1739 –
1742.
[15] A. J. Fry, S.-S. Hong, J. Org. Chem. 1981, 46, 1962 – 1964.
[16] H. Shigehisa, T. Aoki, S. Yamaguchi, N. Shimizu, K. Hiroya, J.
Am. Chem. Soc. 2013, 135, 10306 – 10309.
Here we have developed room temperature stereospecific
nucleophilic substitutions between tert-alkyl alcohols and a-
bromocarboxamides possessing a tert-alkyl group to form
À
congested C O bonds possessing two different tert-alkyl
groups on the oxygen atom. When chiral a-bromocarbox-
amides reacted with alcohols, the reactions occurred with
retention. Although mechanistic studies did not give clear
proof of a mechanism, these stereospecific reactions are
expected to occur with the aid of a carboxamide group. Our
findings could begin a renaissance of nucleophilic substitution
chemistry and open up next-generation reaction systems to
overcome current problems with steric hindrance in organic
chemistry.
[17] M. C. Haibach, C. Guan, D. Y. Wang, B. Li, N. Lease, A. M.
Steffens, J. Am. Chem. Soc. 2013, 135, 15062 – 15070.
[18] N. Sakai, T. Moriya, T. Konakahara, J. Org. Chem. 2007, 72,
5920 – 5922.
[19] K. M. Gligorich, M. J. Schultz, M. S. Sigman, J. Am. Chem. Soc.
2006, 128, 2794 – 2795.
[20] G. Bartoli, M. Bosco, A. Carlone, R. Dalpozzo, M. Locatelli, P.
Melchiorre, L. Sambri, J. Org. Chem. 2006, 71, 9580 – 9588.
[21] P. K. Sahoo, S. S. Gawali, C. Gunanathan, ACS Omega 2018, 3,
124 – 136.
&&&&
www.angewandte.org
ꢀ 2020 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2020, 59, 2 – 8
These are not the final page numbers!

Angewandte
Research Articles
Chemie
[22] J. Kim, D.-H. Lee, N. Kalutharage, C. S. Yi, ACS Catal. 2014, 4,
[37] a) I. Lengyel, J. C. Sheehan, Angew. Chem. Int. Ed. Engl. 1968, 7,
3881 – 3885.
25 – 36; Angew. Chem. 1968, 80, 27 – 37; b) A. Fantinati, V.
Zanirato, P. Marchetti, C. Trapella, ChemistryOpen 2020, 9, 100 –
170.
[23] T. Mitsudome, T. Matsuno, S. Sueoka, T. Mizugaki, K. Jitsukaw,
K. Kaneda, Green Chem. 2012, 14, 610 – 613.
[24] S. Y. Seo, X. Yu, T. J. Marks, J. Am. Chem. Soc. 2009, 131, 263 –
276.
[38] J. C. Sheehan, I. Lengyel, J. Am. Chem. Soc. 1964, 86, 1356 –
1359.
[25] B. D. Sherry, A. T. Radosevich, F. D. Toste, J. Am. Chem. Soc.
2003, 125, 6076 – 6077.
[26] K. Manabe, S. Iimura, X.-M. Sun, S. Kobayashi, J. Am. Chem.
Soc. 2002, 124, 11971 – 11978.
[27] M. Palucki, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1996,
118, 10333 – 10334.
[28] G. Mann, J. F. Hartwig, J. Am. Chem. Soc. 1996, 118, 13109 –
13110.
[29] Z. Zhou, N. E. Behnke, L. Kꢁrti, Org. Lett. 2018, 20, 5452 – 5456.
[30] J. Kim, M. Movassaghi, J. Am. Chem. Soc. 2011, 133, 14940 –
14943.
[31] P. G. Stevens, N. L. McNiven, J. Am. Chem. Soc. 1939, 61, 1295 –
1296.
[32] C. A. Bunton, E. D. Hughes, C. K. Ingold, D. F. Meigh, Nature
1950, 166, 680.
[33] W. von E. Doering, H. H. Zeiss, J. Am. Chem. Soc. 1953, 75,
4733 – 4738.
[39] a) H. Quast, H. Leybach, Chem. Ber. 1991, 124, 2105 – 2112;
b) H. Quast, H. Leybach, E.-U. Wꢁrthwein, Chem. Ber. 1992,
125, 1249 – 1262.
[40] F. Maran, J. Am. Chem. Soc. 1993, 115, 6557 – 6563.
[41] a) F. D’Angeli, P. Marchetti, V. Bertolasi, J. Org. Chem. 1995, 60,
4013 – 4016; b) P. Marchetti, F. D’Angeli, V. Bertolasi, Tetrahe-
dron: Asymmetry 1997, 8, 3837 – 3842.
[42] E. Doni, J. Murphy, Chem. Commun. 2014, 50, 6073 – 6087.
[43] J. A. Murphy, J. Org. Chem. 2014, 79, 3731 – 3746.
[44] S. Zhou, E. Doni, G. M. Anderson, R. G. Kane, S. W. MacDou-
gall, V. M. Ironmonger, T. Tuttle, J. A. Murphy, J. Am. Chem.
Soc. 2014, 136, 17818 – 17826.
[45] This reaction occured under electrochemical conditions without
any bases. Therefore, we speculated that current reaction might
include an electron transfer process (See also Figure 25 in SI).
[46] C. S. Jeffrey, K. L. Barnes, J. A. Eickhoff, C. R. Carson, J. Am.
Chem. Soc. 2011, 133, 7688 – 7691.
[34] P. Mꢁller, J.-C. Rossier, J. Chem. Soc. Perkin Trans. 2 2000, 2232 –
2237.
[47] D. J. Tantillo, K. N. Houk, V. Robert, J. Org. Chem. 1999, 64,
3830 – 3837.
[35] T. Nishikata, Y. Noda, R. Fujimoto, T. Sakashita, J. Am. Chem.
Soc. 2013, 135, 16372 – 16375.
[36] S. Ishida, K. Takeuchi, N. Taniyama, Y. Sunada, T. Nishikata,
Angew. Chem. Int. Ed. 2017, 56, 11610 – 11614; Angew. Chem.
2017, 129, 11768 – 11772.
Manuscript received: August 4, 2020
Revised manuscript received: October 9, 2020
Version of record online: && &&
,
&&&&
Angew. Chem. Int. Ed. 2020, 59, 2 – 8
ꢀ 2020 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Research Articles
Stereochemistry
G. Hirata, K. Takeuchi, Y. Shimoharai,
M. Sumimoto, H. Kaizawa, T. Nokami,*
T. Koike,* M. Abe,* E. Shirakawa,*
T. Nishikata*
&&&& — &&&&
Chemistry of Tertiary Carbon Center in the
Cs2CO3 reaction system enables stereo-
specific reaction of functionalized tertiary
alkyl bromides and bulky alcohols. The
reaction occurred with retention of con-
figuration.
À
Formation of Congested C O Ether
Bonds
&&&&
www.angewandte.org
ꢀ 2020 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2020, 59, 2 – 8
These are not the final page numbers!