LiAlH4). Hydroamination is an excellent
alternative to these traditional amination
tools, as two easily accessible starting materials are coupled with 100% atom efficiency
(all atoms from both starting materials are
incorporated into the product) (2).
Much of the challenge involved in accomplishing such catalysis resides in the
innate thermodynamic barrier of transforming relatively stable amine and olefin
reaction components into what are often
less stable amine products. An effective
solution to correcting such unfavorable
energetics has been realized in the use of
prefunctionalized electrophilic amines
as the nitrogen source. This elegant approach to the formal hydroamination of
simple, unactivated alkenes uses a copper
hydride catalyst to couple alkenes with
nucleophilic silanes (R3Si–H) and activated electrophilic amines (R2N–OR) (5).
In these reactions, the Cu–H species adds
across the alkene to form the more stable, terminal C–Cu bond, which is subsequently aminated to generate the product
with a terminal C–N bond. This approach
has proved to be a powerful and general
method for the synthesis of C–N bonds.
The efficiency of this strategy, however, is
less than ideal because an equivalent of
R3Si–OR is generated as a stoichiometric
by-product, and it requires the synthesis of
the electrophilic amine component.
The anti-Markovnikov hydroamination
developed by Musacchio et al. circumvents
this energetic impasse by leveraging the
highly reactive nature of ARCs. Formed
by one-electron oxidation of secondary
amines by a photoexcited iridium catalyst
(see the middle panel of the figure), this
strategy transforms stable, unfunctional-ized feedstock materials into viable building blocks for the robust construction of
C–N bonds. Importantly, this method is
entirely atom economical because the
2,4,6-triisopropylbenzenethiol catalyst can
enable both C–H bond formation in a hydrogen atom transfer (HAT) event and
generation of an oxidizing thiyl radical
that permits the necessary reoxidation of
the reduced iridium photocatalyst.
The cooperative action of ARC olefin
addition and HAT is a testament to the
power of this method to modulate com-
plex reactivity. Although the highly reac-
tive ARCs may directly oxidize aryl thiols
to the corresponding sulfur-centered radi-
cals or competitively oxidize the reduced
photocatalyst, such deleterious pathways
have been avoided. Indeed, this mechanis-
tic manifold effectively modulates and ex-
ploits the productive reactivity of nitrogen-,
carbon-, and sulfur-centered radical spe-
cies in a single chemical operation.
Alkene hydroamination typically yields
the Markovnikov isomer, forming the C–N
bond at the terminal carbon of the alkene
(2). The method developed by Musacchio
et al. is transformative in that the anti-
Markovnikov product is formed exclusively.
Recent successful efforts to control the re-giochemical outcome of more traditional
transition metal–catalyzed olefin hydroamination have exploited substrate-controlled
reactivity to stabilize high-energy organometallic intermediates (6, 7). Such methods
produce a high degree of selectivity for the
anti-Markovnikov product, but they are
inherently limited to substrates bearing
the requisite stabilizing group. The present solution, however, exploits the native
stability of radical intermediates—
addition of the ARC to the alkene produces a
secondary carbon-centered radical at the
internal position of the new C–C single
bond with exquisite selectivity (8). The use
of the latent radical reactivity of reaction
intermediates enabled by the action of a
photoredox catalyst is illustrative of the orthogonality of this approach to traditional
The catalytic hydroamination methodology by Musacchio et al. has the power
to transform the paradigm of amine synthesis. They successfully aminated a representative of every olefin type, including
cyclic, terminal and internal acyclic, sty-renyl, 1,1-disubstituted, trisubstituted, and
even tetrasubstituted olefins (see the bottom panel of the figure). The reaction proceeds both inter- and intramoleculary, and
despite the involvement of highly reactive
intermediates, it exhibits noteworthy functional group tolerance, permitting the presence of amides, silyl groups, free amines,
and free hydroxyl groups. j
1. E.Vitaku,D. T.Smith,J. T.Njardarson, J. Med. Chem.57,
2. T. E. Muller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada,
Chem. Rev. 108, 3795 (2008).
3. A. J. Musacchio et al ., Science 355, 727 (2017).
4. S. D. Roughley, A. M. Jordan, J. Med. Chem.54, 3451 (2011).
5. M. T.Pirnot, Y.-M. Wang,S.L.Buchwald, Ange w. Chem. Int.
Ed. 55, 48 (2015).
6. M. Beller et al ., Chem. Eur. J .5, 1306 (1999).
7 . S. C. Ensign etal. ,
J.Am.Chem.Soc.137, 13748 (2015).
8. J. Kemper, A. Studer, Angew . Chem. Int. Ed .44, 4914
Reaction coordinate Reaction coordinate
Representative products (yield in %)
60% 40% 65% 83% 92%
H3CH3C CH3 CH3
H3CH3C CH3 CH3
N ∆G >> 0
∆G << 0
Markovnikov (easy) Anti-Markovnikov (hard) Two ways to add
Two types of products are
possible, depending on
where the nitrogen adds
to the alkene.
C4H10 N N N H OO N H
Light gives amination a boost
Hydroamination adds an amine to an alkene, but adding the H atom onto the carbon with the alkyl (R) group
is hard. Musacchio et al. used a light-driven iridium (Ir) catalyst to lower the barrier to such products.