Organic Letters
Letter
a
yields of 1,2-dibromoethane product were successfully attained
in the transformation (Table S5). This finding suggests that
not only the stability of radicals but also the interaction
between the arylethane and solvent molecules may represent
significant a reaction factor.
Table 1. Optimization of Reaction Conditions
To reveal the type of interactions of phenylethane and 1,2-
diphenylethane with the solvent (CCl4, DCM, DCE, and
TCE), a series of quantum chemical calculations were
performed, accounting for several possible interaction geo-
metries (Scheme 1b; details in Table S11). The average values
of the Gibbs free energy of interaction between phenylethane
and a solvent molecule decrease in the following order: DCM
(∼0 kJ/mol) > DCE (−0.2 kJ/mol) > TCE (−6.3 kJ/mol) >
CCl4 (−13.2 kJ/mol). In the latter two environments, the
phenylethane molecules are therefore less available for the 1,2-
dibromination reaction because of strong interactions with the
solvation shell. A similar thing happens to 1,2-diphenylethane,
whose average ΔG values of interaction are −3.2 kJ/mol
(DCM), −5.1 kJ/mol (DCE), −6.7 kJ/mol (TCE), and −15.8
kJ/mol (CCl4); this may be why the introduction of an
external initiator is necessary in the 1,2-dibromination process
of 1,2-diphenylethane in CCl4. The computed values of
substrate−solvent interaction are consistent with the exper-
imentally determined reaction yields. The strength of the
intermolecular noncovalent interactions (NCIs) established
between the reactant and the solvent is also depicted in Figure
S9, where in the case of CCl4 strongly attractive NCIs are
shown between the Cl atoms of the solvent and the C atoms of
the reactant molecule. TCE also shows extended positive NCI
regions but less strongly attractive ones. In the case of DCM
and DCE, the NCIs are weakly attractive or even repulsive in
nature.
To further establish an available synthesis method for the
dibromination of vicinal sp3 C−H bonds, a new radical
initiator free 1,2-dibromination transformation of 1-arylethane
derivatives with NBS as the bromine source has been
developed, affording various 1,2-dibromo products with
efficiencies ranging from moderate to high. In this dibromi-
nation reaction, chloroalkanes other than CCl4 were used as
the solvent, and the reactivity was obviously enhanced under
thermal conditions. The high-value-added compounds (e.g.,
azides, alcohols, ketones, and epoxides) were readily
synthesized from 1,2-dibromophenylethane. A preliminary
mechanistic study was attempted, involving a set of possible
reactions, explored by means of quantum chemical calcu-
lations, and revealed feasible radical chain pathways with
hydrogen atom abstraction (HAA).
b
entry
solvent
yield and dr
1
2
3
4
5
6
7
8
CCl4
DCE
trace
78%, dr = 69:31
81%, dr = 74:26
82%, dr = 75:25
CHCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
c
62%, dr = 80:20
d
e
82% (79%), dr = 75:25
df
,
trace
d,g
76%, dr = 75:25
77%, dr = 75:25
67%, dr = 75:25
82%, dr = 75:25
d,h
9
10
11
d,i
d,j
a
Reaction conditions: 1a (0.5 mmol, 1 equiv), NBS (1.75 mmol, 3.5
equiv), solvent (2.0 mL), 100 °C, 6 h, N2. Yield and dr value
determined by H NMR using the crude reaction. NBS (1.0 mmol,
b
c
1
d
e
f
2.0 equiv). NBS (1.25 mmol, 2.5 equiv). Isolated yield. At 60 °C.
g
h
i
j
At 80 °C. At 120 °C. For 3 h. For 12 h.
2u (Table 2). Benzenes with long chain alkyls 1a−1f readily
reacted with NBS to yield vicinal dibromoethanes 2a−2f with
high efficiencies. Interestingly, 1,2,3-tribromination product 2g
instead of a dibrominated or monobrominated compound10
was isolated via conversion of cyclopropylbenzene 1g.
Dibrominated compounds 2h−2j were easily obtained with
excellent diastereoselectivities by using 1-ester-2-phenylethanes
as the substrate. In particular, trans-2i was isolated and
characterized by X-ray single-crystal diffractometry, which
uncontroversially revealed the position of the two bromine
atoms lying almost on the same plane (Figure S8). Product 2k
was obtained in 54% yield by decreasing the reaction
temperature to 80 °C without any additive. 1l was successfully
transformed into the corresponding product 2l in modest yield
and high diastereoselectivity. For products 2a−2j and 2l, the
trans structure is primarily synthesized due to the higher
stability with respect to the other isomers, as shown by
quantum chemical calculations. The optimal reaction con-
ditions of 1,2-dibromination of phenylethane 1m were also
identified, with synthesis of 2m in 85% yield (Tables S5−S8).
The effects due to the presence of electron-withdrawing groups
in the aryl ring of phenylethanes were also inspected; upon 1,2-
dibromination, the desired products 2m−2r were effortlessly
obtained in 34−81% yields. The treatment of 4-methylphenyl-
ethane 1r with NBS provided 1,2-dibromo product 2r under
the standard reaction conditions.
With an increase in the amount of NBS to 3.5 equiv,
tribromination compound 2s could be isolated in moderate
yield. In addition to the methyl group, 2-methoxy and 2-
acetoxy groups in the aromatic ring were also compatible with
the investigated reaction, straightforwardly forming products 2t
and 2u, respectively.
To show the broadness of the synthetic applicability of 1,2-
dibromoethane derivatives, various compounds were formed
when 2m was used as a reactant (Scheme 2a). 1,2-
Dibromophenylethane 2m facilely reacted with NaN3 to
provide azides 4 and 5 in DMSO and DMF, respectively.4
1,2-Dihydroxyphenylethane 6 was produced from 2m under
basic conditions. When 2m was heated in acetone and H2O,
To refine the dibromination reaction, the treatment of
hexylbenzene 1a with NBS was performed at 100 °C for 6 h
(Table 1). CCl4 was initially employed as the solvent, and a
trace of dibromination product 2a was detected (entry 1). On
the contrary, when CCl4 was replaced with DCE, chloroform
(CHCl3), or dichloromethane (DCM), 2a was effortlessly
formed (entries 2−4). Solvent screening demonstrated that
DCM is the optimum, producing the highest yield (82%, entry
4). When the amount of NBS was decreased from 3.5 to 2.5
equiv, the conversion efficiency did not vary significantly
(entries 5 and 6). To further increase the yield, temperature
and time effects were also investigated, finally confirming 100
°C and 6 h as the optimized conditions (entries 7−11).
Exploiting the optimal reaction conditions to broaden the
scope of the investigated reaction, we tested a variety of
substrates, allowing the synthesis of arylethane derivatives 2a−
2400
Org. Lett. 2021, 23, 2399−2404