Angewandte
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Chemie
intermediates 3 are then easily desulfonylated to reach the
target products.
In implementing the a-alkylation of aldehydes with a-
iodosulfones (2), we were inspired by our recent studies on
the direct photoexcitation of enamines and their potential for
generating radicals under mild reaction conditions.[13] We
demonstrated that I, upon light absorption, can reach an
excited state (I*) to become a strong reductant, as implied by
its reduction potential, which was estimated as about ꢀ2.0 V
(vs. Ag/Ag+ in CH3CN).[13a] Thus, I* could trigger the
formation of radicals through SET reduction of easily
red
reducible bromomalonates (Ep diethyl bromomalonate =
ꢀ1.69 V vs. Ag/Ag+ in CH3CN). We surmised that a similar
photochemical mechanism could generate (phenylsulfony-
l)alkyl radicals (II) from 2. A critical design element was the
phenylsulfonyl moiety, which would act as a redox auxiliary
group[14] to facilitate the reductive cleavage of the C I bond
ꢀ
by an SET mechanism (Figure 1b). In consonance with this
scenario, we measured, by cyclic voltammetry, a reduction
potential for the iodomethyl phenyl sulfone (2a; Y= H in
Figure 1b) as low as ꢀ1.49 V (Ep vs. Ag/Ag+ in CH3CN).
red
This experiment suggested 2a as a viable precursor of
phenylsulfonyl methyl radicals.[15]
To test the feasibility of our design plan, we focused on the
reaction between butanal (1a) and 2a (Table 1). The experi-
Figure 2. a) Optical absorption spectra acquired in toluene in 1 cm
path quartz cuvettes: [1a]=1.5m; [2a]=0.5m; (S)-A=0.1 M. b) Evalu-
ating the photostability of 2a: (i) aspect of a 0.25m solution of 2a in
degassed toluene; (ii) the same solution after black LED irradiation at
l=365 nm for 16 hours; (iii) the same solution after the addition of
water, starch, and NaI; (iv) final view of the solution after the addition
of Na2S2O3.
Table 1: Optimization studies.[a]
chemical alkylation, which reached a standstill at about 40%
of conversion and could not evolve further.
Entry Solvent
Additives and
Conditions
Yield ee
A useful insight into tackling this reactivity issue came
from the optical absorption spectra of the reaction compo-
nents, and confirmed our expectation that I, generated upon
condensation of the catalyst Awith 1a, could absorb up to the
visible region (blue line in Figure 2a; absorption band up to
l = 415 nm). In addition, we noticed that 2a could also absorb
light up to l = 390 nm (red line). This observation prompted
us to investigate the photochemical stability of 2a under the
reaction conditions by irradiating a toluene solution of 2a at
l = 365 nm over 16 hours. The colorless solution developed
a yellow color over time (Figures 2bi and ii). Although we
recovered 95% of 2a, the color change suggested the
[%][b]
[%][c]
1
2
3
4
toluene
toluene
toluene
–
43
13
50
99
80
80
80
82
I2 (10 mol%)
Na2S2O3 (10 mol%)
toluene/hexanes/H2O Na2S2O3 (50 mol%)
(1:1:2 ratio)
(76)[d] (80)
5
6
7
toluene/hexanes/H2O Na2S2O3 (50 mol%),
<5
<5
92
–
(1:1:2 ratio)
toluene/hexanes/H2O Na2S2O3 (50 mol%),
(1:1:2 ratio) O2 or TEMPO (1 equiv)
toluene/hexanes/H2O Na2S2O3 (50 mol%),
(1:1:2 ratio) band pass @ 400 nm
in the dark
–
82
ꢀ
[a] Reactions performed over 16 h on a 0.1 mmol scale using 3 equiv of
1a and a single black LED (lmax =365 nm) to illuminate the reaction
vessel. [b] Yield determined by NMR spectroscopy using 1,1,2-trichlor-
oethene as the internal standard. [c] Enantiomeric excess determined by
HPLC analysis on the corresponding alcohol after in situ NaBH4
reduction of 3a. [d] Yield and ee of the isolated aldehyde 3a are shown
within parentheses. TMS=trimethylsilyl.
possibility of a photoinduced homolytic cleavage of the C I
bond within 2a, a minor pathway which could generate small
amounts of intensely colored molecular iodine (2IC!I2).
Diiodine, even in traces, is a well-known inhibitor of radical-
chain reactions,[17] as it can trap carbon-centered radicals at
very high rates (rate constants of about 109 mꢀ1 sꢀ1).[17b] In
addition, the intense light absorption of molecular iodine may
also interfere with other photochemical steps by an inner
filter effect. A positive standard iodine detection test
confirmed the generation of I2 from 2a under the reaction
conditions:[18] adding a starch solution, sodium iodide, and
water to the photolyzed yellow solution of 2a, depicted in
Figure 2bii, produced the characteristic dark-blue color
(Figure 2biii). Finally, the solution switched back to achro-
matic (Figure 2biv) when adding solid sodium thiosulfate
ments were conducted at 58C in toluene and under irradiation
by a single black-light-emitting diode (black LED, lmax
=
365 nm). When adding the chiral secondary amine catalyst
A[16] (20 mol%), the desired (phenylsulfonyl)methylated
aldehyde 3a was formed in good enantioselectivity but with
moderate chemical yield (entry 1). Despite extensive exper-
imentation, we could not increase the yield of the photo-
2
ꢀ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!