Journal of the American Chemical Society
Communication
a
have shown redox-neutral addition of ketyl radicals to alkynes
afford Z-vinyl iodides,36 we reasoned a suitable, terminal H-
donor may now also afford reductive reactivity, in the form of
an aza-pinacol coupling.
Table 1. Reaction Optimization
To test our hypothesis (Figure 2), pentanal 1 and imine 2a
were irradiated with visible light in the presence of a
entry
R
light
reductant
base
yield 3
3:4
1
2
3
4
5
6
7
8
Ph
Ts
blue LED
blue LED
blue LED
blue LED
blue LED
white CFL
white CFL
white CFL
white CFL
white CFL
Hantzsch
Hantzsch
Hantzsch
none
Zn
Zn
Zn
Zn
Zn
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
KOAc
Cy2NMe
Cy2NMe
Cy2NMe
28%
50%
56%
10%
40%
70%
29%
90%
99%
70%
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
b
9
10
c
Zn
a
Conditions: 0.2 mmol imine, pentanal (3 equiv), AcI (2.6 equiv), 5%
Mn2(CO)10, reductant (2 equiv), base (5 equiv), CH2Cl2 (1 mL), 24
b
c
h. 15% Mn2(CO)10, 2 h. Aldehyde (1 equiv).
The scope and generality of this mild, cross-selective aza-
pinacol coupling was then explored using a wide variety of
imines and aldehydes (Table 2). For example, several ortho-,
meta-, and para-substituted aryl aldimines were shown to be
effective imine partners (5−14). Notably, an exceptionally
broad range of electronically diverse substituents were
tolerated, spanning Hammett constants (σp) of −0.3 (OMe)
to +0.5 (CF3) as well as a wide redox window,9 including
imines that may otherwise afford homodimerization via an
SET manifold. Steric variation similarly does not inhibit
efficiency, although ortho substituents strongly influence
diastereoselectivity with o-Me groups affording β-amino
alcohols in up to 9:1 dr (11, 15). Bis-substitution is well-
tolerated for both sterically (15) and electronically exaggerated
cases, such as bis-CF3 arene (16) and bis-F pyridine (17),
again without dimerization. Lastly, a pair of mechanistic probes
were investigated, containing weak, benzylic C−H bonds that
may facilitate H atom transfer (HAT) to the N-radical
intermediate.42,43 However, since no remote functionalization
products were observed (by either inter- or intramolecular
HAT), including on the strong H atom donor, fluorene, (18
and 19), we conclude N-radical termination occurs more
rapidly.
To critically probe the chemoselectivity of this cross-
selective coupling, we designed a series of experiments
examining imines with acid-labile or easily reducible groups
that would not be tolerated under typical SmI2, photocatalytic,
or other highly reducing conditions. In each of these cases, aza-
pinacol coupling was the exclusive product observed. For
example, benzofuran (20), acetal (21), aryl nitrile (22), and
aryl iodides (23−25) all remain intact. Most notably,
benzophenone (26; −1.3 V)44 is unperturbed despite its less
negative potential than the imine (−1.5 V), or the aldehyde
(−2.9 V) that is chemoselectively converted to a ketyl radical.
Next, a range of aliphatic aldehydes were investigated to
determine the generality of β-amino alcohols accessible by this
ketyl coupling. Steric effects appear minimal as both smaller
acetaldehyde (27 and 28) and larger isobutyraldehyde (29)
provide similar efficiency, with the imine partner having a
stronger stereoselectivity influence (28; 10:1 dr with o-tolyl
imine). As further chemoselectivity probes, reductively prone
Figure 2. Development of cross-selective aza-pinacol coupling.
photocatalyst (1% Ir(ppy)2(dtbbpy)PF6) and terminal reduc-
tant (3 equiv nBu3N). As expected from previous reports,13
this SET strategy does not provide aza-pinacol adduct 3, but
instead affords only imine-derived homodimer 4a (68%).
Conversely, to probe our atom transfer strategy, AcI and
pentanal 1 were first combined in CH2Cl2 at 0 °C for 15 min.
The in situ generated α-oxy iodide 1a was then subjected to
imine 2b and photocatalytic conditions. To our delight, a
complete switch in reactivity is observed, wherein cross-selective
aza-pinacol adduct 3 is now obtained exclusively (76%),
without homodimer 4 (0%). Desiring an imine with a more
easily removed protecting group, we replaced N-aryl imines
2a,b with sulfonimine 2c (R = Ms). However, this more easily
reduced imine (Ms: −1.5 V vs Ph: −1.9 V)9−11 falls within the
redox window of the Ir photocatalyst (−1.5 V)37,38 and thus
yields exclusive dimerization (64% 4c). To solve this problem,
we pivoted from an SET reduction mechanism to atom
transfer activation by a Mn2(CO)10 catalyst.39−41 In this case,
iodide 1a and sulfonimine 2c selectively afford cross-coupled
adduct 3c (56%) without any dimer 4 (0%).
To further improve this atom transfer-enabled, aza-pinacol
coupling, several reaction parameters were examined (Table
1). First, including a coreductant (e.g., Hantzsch ester) affords
cross-coupled adduct 3 in >20:1 chemoselectivity over dimer
4, for three classes of imines (R = Ph, Ts, Ms, entries 1−3).
Although excluding the Hantzsch reductant diminishes
efficiency (10% vs 56%, entries 3−4), replacing with Zn
recovers reactivity (40%, entry 5) and affords a simpler
purification (separation of Zn salts versus coeluting Hantzsch
pyridine). A switch from irradiation by blue LED to a broader
spectrum white CFL further improves reactivity (70%, entry
6). And the hindered base, Cy2NMe, proves superior to either
iPr2NEt or KOAc (90%, entries 6−8), suggesting its likely role
as H atom donor to the transient N-radical. Finally, increased
catalyst loading (15% vs 5%) affords >99% yield within 2 h
(entry 9), and 1:1 stoichiometry (i.e., without excess aldehyde)
also provides efficient cross-selective reactivity (entry 10).
5623
J. Am. Chem. Soc. 2021, 143, 5622−5628