Organic Letters
Letter
Scheme 1. Prominent Examples of C−X (X = O, S, N)
Bond-Forming Methods Building on Tertiary Alkyl
Substrates
Table 1. Optimization of the Reaction of Tertiary Alkyl
a
Bromide 1 with Primary Alcohol 2
b
entry
X:1
variation of standard conditions
none
Zn(OTf)2 (39 mol %), w/o Zn
20% of Zn used
10% of Zn used
50% of Zn used
w/o Zn
w/o molecular sieve
none
10% of Zn used
30% of Zn used
yield%
c
1
2
3
4
5
6
7
8
1.6:1
1.6:1
1.6:1
1.6:1
1.6:1
1.6:1
1.6:1
1.4:1
1.2:1
1.2:1
1.6:1
1.6:1
1.6:1
1.6:1
84
73
72
71
81
61
31
78
73
77
76
nd
77
nd
9
10
11
12
13
14
Cu(OTf)2 instead of Zn(OTf)2
Ni(OTf)2 instead of Zn(OTf)2
Sc(OTf)2 instead of Zn(OTf)2, 25 °C
BF3OEt instead of Zn(OTf)2, 25 °C
a
Standard reaction conditions: 1 (1.6 equiv), 2 (0.3 mmol, 1 equiv),
Zn(OTf)2 (9 mol %), Zn (30 mol %), 4 Å molecular sieves (150 mg),
b
toluene (1 mL), 12 h. Yield was referred to an NMR yield using 2,5-
c
dimethyl furan as a standard. Isolated yield.
potential competing Friedel−Crafts alkylation of the benzene
moiety did not occur.
derived oxalates, that has not been used for amination and
thiolation.
The scope of tertiary alkyl bromides was surveyed next. A
benzoyl-attached gem-dimethyl substrate afforded the ether
products 5a and 5b in 60% and 50% yields. The decreased
efficiency with respect to that of 1 was likely due to the
inductive effect invoked by the benzoyl moiety, which
destabilizes the putative carbocation intermediate. An increase
in the sizes of tertiary alkyl moieties proved to be influential on
the reaction yields. Replacement of one gem-methyl with an
ethyl group led to a decrease in yields, as evident in products 6
and 7a−c. The coupling of the sterically more demanding 3-
bromo-3-ethylpentane to primary and secondary alcohols and
4-methoxyphenol was moderately effective, generating 8a−c
respectively. The tertiary alkyl bromides within cyclic scaffolds
also afforded the products, as evident in the examples of 9−11.
In 11 and the secondary benzyl ether 12, the β-bromides were
intact and could be used for further functionalization. No
reaction took place for the unactivated secondary alkyl
bromide.
The etherification protocol is suitable for the amination and
thiolation of tertiary alkyl bromides containing a gem-dimethyl
with primary amides and thiols, in which a molecular sieve or a
base additive was not needed.18 Whereas Cbz-protected amine,
tosyl, and thiophenylsulfonyl amides delivered the tertiary alkyl
amine and amides 13−15 in good yields,19 the thiolation
process was competent with a set of primary and secondary
alkyl thiols and aryl thiols that delivered the thioethers 16a−d
in good to excellent yields.
We set out to investigate the reaction of (3-bromo-3-
methylbutyl)benzene 1 with 3-phenyl-1-propanol 2. After an
extensive survey of the reaction conditions, we identified that a
combination of 9 mol % of Zn(OTf)2 and 30 mol % Zn
powder along with 4 Å molecular sieves in toluene at ambient
temperature furnished the ether product 3a in a highest 84%
isolated yield (Table 1, entry 1). By comparison, the use of 39
mol % Zn(OTf)2 generated 3a in 73% yield (entry 2),
indicating that the use of Zn powder as an additive is more
effective than an increase in the loading of Zn(OTf)2, likely
due to the neutralization of in situ generated HBr. The amount
of Zn was briefly screened but did not provide better results
(entries 3−5), wherein without Zn, the reaction afforded 3 in
61% yield (entry 6). The use of 1.2 equiv of 1 and 10 mol % of
Zn led to 3a in a synthetically useful 73% yield (entry 9),
which was boosted to 77% in the presence of 30 mol % of Zn
(entry 10). The examination of other Lewis acids did not result
The optimized etherification method A, as in Table 1, entry
1, was compatible with a wide array of alcohols (Figure 1). The
primary and secondary alcohols, as exemplified in 3b−j and
4a−h, were effective to couple to tertiary butyl bromide and
(3-bromo-3-methylbutyl)benzene 1. The functionalized phe-
nols also delivered the aryl alky ethers 4i−m in moderate to
good yields. The compatible functional groups on the primary
alcohols included 1-bromo, terminal alkyne, ester, thiophenyl,
and benzophenone. The secondary alcohols derived from Bn-
protected 1-glucose (4d) and amino acids (4a, 4e, and 4g)
afforded the products in good yields, manifesting that the
scope of the alcohols was broad. The substituents on the
phenols include 4-iodo, MeO, Bpin, and CHO. Remarkable
chemoselectivity for 4-methoxyphenol was observed, where a
The Zn(OTf)2-mediated carbon−heteroatom bond-forming
conditions via tertiary C(sp3)−Br bond breakage (method A)
proved to be effective for the thiolation and amination of more
accessible tertiary alkyl oxalates (Scheme 2). By slightly
altering the reaction conditions using 1,2-dichloroethane as the
solvent without external additives, the coupling of di-t-
1006
Org. Lett. 2021, 23, 1005−1010