Organic Letters
Letter
a
laphotoredox reaction utilizing α-silyl amines as radical
precursors; however, electron-deficient amines were not
suitable substrates in this transformation.9 To our knowledge,
a metallaphotoredox reaction has not been used to synthesize
benzyl amines by placing an acid directly on an amine
nucleophile.9b Herein, we disclose the scope of this method to
afford diverse benzyl amine products from electron-poor amine
acids and aryl bromides.
Scheme 2. Aryl Bromide Scope
Initially, to test this proposed metallaphotoredox reaction,
the electron-deficient N-linked acid 1a was subjected to the
reaction conditions noted in Table 1.10 Based on similarities
a
Table 1. Initial Screening
a
Conditions: 1 mol % Ir catalyst, 10 mol % Ni catalyst, 1.0 equiv of
b
b
entry
change
ArBr
yield (%)
ArBr, 1.5 equiv of 1a, 1.5 equiv of DBU, 0.1 M in DMA, 5−10 h. 5%
Ni catalyst used. Reactions in Scheme 2 were conducted in a
PennOC/Merck photoreactor with 450 nm light.
1
2
3
4
5
6
7
none
Ru(bpy)3(PF6)2
4-CzIPN
Ir[dF(Me)ppy]2(dtbbpy)PF6
Cs2CO3
none
A
A
A
A
A
B
B
80, 2a
0, 2a
32, 2a
54, 2a
77, 2a
50, 2b
24, 2b
further interest, the reaction works well in the presence of an
unprotected alcohol (2f), which would be difficult to react
selectively when using a benzyl halide. More complex aryl
bromides worked in this reaction as well, and the desired
products 2g and 2h were afforded in good yield when
subjected to the conditions noted in Scheme 2.
To further test the utility of this transformation, a variety of
electron-deficient N-linked acids were subjected to the reaction
conditions. As noted in Scheme 3, aryl amide substrates like 1a
performed well in this reaction. For instance, N-linked acids
bearing other heteroatoms in the ring such as oxygen and
sulfur worked well under the reaction conditions to afford
products 2i and 2j in good yields. A more complex aryl amide
N-linked acid also worked, albeit in modest yield,13 to afford
compound 2k. Expanding the scope to nonaryl amide and urea
Cs2CO3
a
Conditions: 1 mol % Ir catalyst, 10 mol % Ni catalyst, 1.0 equiv of
ArBr, 1.5 equiv of 1a, 1.5 equiv of base, 0.1 M in DMA, 10 h.
Reactions in Table 1 were conducted in a hepatochem duo
photoreactor. Yields were based on H NMR with phenanthrene
b
1
as an internal standard.
between substrate 1a and acids recently reported to undergo
decarboxylative alkynylation, we envisioned that iridium
catalyst I (Table 1) would react with acid 1a.11a Utilizing I
as the photocatalyst in this reaction afforded 2a in 80% yield
(entry 1). The less oxidizing Ru(bpy)3(PF6)2 photocatalyst
(E1/2[*RuII/RuI] = +0.77 vs E1/2[*IrIII/IrII] = +1.21 for I),
which was used for a related transformation with electron-rich
substrates,9 was not viable in this reaction, and no desired
product was afforded under these conditions (entry 2).6,9a
Changing to the slightly more oxidizing metal free photo-
catalyst 4-CzIPN (E1/2[*P/P−] = +1.35), which has been used
in other decarboxylative arylations, gave a lower yield of 2a
(entry 3).11b Other iridium photocatalysts (entry 4) afforded
lower yields of 2a when compared to photocatalyst I. Initially,
Cs2CO3 was utilized as the base for these reactions, as it had
been employed for related transformations.6,11b However, we
found that DBU afforded higher and more consistent yields for
a variety of acids and aryl halides when compared to the
Cs2CO3 conditions (entries 1 and 6 vs entries 5 and 7).11c
With these optimal conditions in hand, further screening on
the aryl halide and acid scope was initiated.
a
Scheme 3. Electron-Deficient N-Linked Acid Scope
To exemplify some of the novel SAR this reaction can
deliver, aryl halides that had no commercially and/or readily
available benzyl halide equivalents were employed as coupling
partners in Scheme 2.12 As noted below, this reaction affords a
variety of benzyl amine products in moderate to good yields
with an array of aryl bromides. For example, the reaction
tolerates electron-poor aryl halides as noted in examples 2b
and 2c, but it also works well for electron-rich aryl halides such
as the methyl cyclopropyl substituted arene in example 2d. Of
a
Conditions: 1 mol % Ir catalyst, 10 mol % Ni catalyst, 1.0 equiv of
ArBr, 1.5 equiv of 1a, 1.5 equiv of DBU, 0.1 M in DMA, 5−10 h.
Reactions in Scheme 3 were conducted in a hepatochem duo
photoreactor. Reaction used 2 mol % Ir, 5 mol % Ni, and was
conducted in a PennOC/Merck photoreactor.
b
B
Org. Lett. XXXX, XXX, XXX−XXX