Photoredox-Catalyzed Site-Selective α-C(sp3)?H Alkylation of Primary Amine Derivatives

Article abstract of DOI:10.1002/anie.201812227

The synthetic utility of tertiary amines to oxidatively generate α-amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site-selective α-functionalization of primary amine derivatives through the generation of α-amino radical intermediates. Employing visible-light photoredox catalysis, primary sulfonamides are coupled with electron-deficient alkenes to efficiently and mildly construct C?C bonds. Interestingly, a divergence between intermolecular hydrogen-atom transfer (HAT) catalysis and intramolecular [1,5] HAT was observed through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site-selectivity.

Full text of DOI:10.1002/anie.201812227

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201812227
German Edition: DOI: 10.1002/ange.201812227
Photochemistry
3
À
Photoredox-Catalyzed Site-Selective a-C(sp ) H Alkylation of
Primary Amine Derivatives
Melissa A. Ashley+, Chiaki Yamauchi+, John C. K. Chu, Shinya Otsuka, Hideki Yorimitsu, and
Tomislav Rovis*
Abstract: The synthetic utility of tertiary amines to oxidatively
generate a-amino radicals is well established, however, pri-
mary amines remain challenging because of competitive side
reactions. This report describes the site-selective a-functional-
ization of primary amine derivatives through the generation of
a-amino radical intermediates. Employing visible-light photo-
redox catalysis, primary sulfonamides are coupled with
electron-deficient alkenes to efficiently and mildly construct
À
C C bonds. Interestingly, a divergence between intermolecular
hydrogen-atom transfer (HAT) catalysis and intramolecular
[1,5] HAT was observed through precise manipulation of the
protecting group. This dichotomy was leveraged to achieve
excellent a/d site-selectivity.
T
he formation of a-amino radicals using visible-light photo-
redox catalysis has garnered significant attention as a mild
[1]
À
method to construct C C bonds. Electron-rich tertiary
amines can be oxidized to generate nitrogen radical cations,
allowing facile access to a-amino radicals after deprotonation
[2]
À
of the a-C H bond. Competitive N-alkylation events for
primary and secondary amines can hinder the formation of a-
amino radicals (Figure 1a).[3] A cleavable functionality at the
a-position may be pre-installed to circumvent undesired
reactivity by accessing a-amino radicals (Figure 1b).[4] Hydro-
gen-atom transfer (HAT) catalysts have been successfully
Figure 1. Photoredox functionalization: a) Tertiary versus secondary
amines. b) Installation of cleavable functionality to direct a-amino
radical formation. c) Acidity-controlled site-selectivity.
À
implemented to achieve a-C H functionalization of acylated
secondary amine derivatives devoid of a-pre-functionaliza-
tion.[5] Our group has recently reported the selective a-
functionalization of primary aliphatic amines to afford g-
lactams under dual photoredox and HAT catalysis utilizing
CO2 as an activating group, wherein we identified an
acceleration of the HAT event by an electrostatic interaction
between the quinuclidinium cation and carbamate anion.[6]
We recognized, however, that ring closure is not always
desired and manipulation of primary amines themselves can
be challenging in multistep synthetic planning. For this
reason, we further explored the impact of either different
common activating or protecting groups searching for
a broadly applicable a-alkylation of primary amine deriva-
tives.
À
We sought to develop a protocol for amine C H
functionalization in which the site-selectivity can be achieved
through the judicious choice of the directing group on
[*] M. A. Ashley,[+] Dr. C. Yamauchi,[+] S. Otsuka, Prof. Dr. T. Rovis
Department of Chemistry, Columbia University
New York, NY 10027 (USA)
nitrogen. Independently, our group and the group of Knowles
3
À
demonstrated the robustness of d-C(sp ) H alkylation
E-mail: tr2504@columbia.edu
through [1,5] HAT.[7] Utilizing trifluoroacetamides, amidyl
radicals are formed under oxidative conditions to remotely
Dr. J. C. K. Chu, Prof. Dr. T. Rovis
Department of Chemistry, Colorado State University
Fort Collins, CO 80523 (USA)
À
activate the d-C H bond (Figure 1c), an undesirable pathway
for a-derivatization. We reasoned that using a more acidifying
S. Otsuka, Prof. Dr. H. Yorimitsu
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo-ku, Kyoto 606-8502 (Japan)
functionality could pivot reactivity towards the activation of
3
À
a-C(sp ) H bonds by leveraging the following consequences:
[+] These authors contributed equally to this work.
a change in the nature of the protecting group results in
a change in the bond strength and the pKa value of the NH.[8]
After surveying a variety of amine protecting groups, we
gratifyingly observed promising reactivity and selectivity
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201812227.
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using trifluoromethanesulfonamides. We were delighted to
observe a-functionalization of 1a in 50% yield with benzyl
acrylate in the presence of a carbonate base, the photocatalyst
A, and blue light (Table 1, entry 1). A superior yield was
Table 1: Reaction optimization.
Entry
PG
Photocatalyst
R
Base
Yield [%][b]
1
2
3
4
5
6
7
8
9
Tf
Tf
Tf
Tf
Tf
Tf
COCF3
Ts
Ac
A
A
A
B
A
B
B
B
B
Bn
Bn
Bn
Bn
tBu
tBu
tBu
tBu
tBu
Cs2CO3
K2CO3
K3PO4
K3PO4
quinuclidine
quinuclidine
quinuclidine
quinuclidine
quinuclidine
50
54
58
65
71
77[c]
0
0
0
[a] 1a (0.1 mmol), alkene (0.15 or 0.3 mmol), base (0.2 mmol), photo-
catalyst (2.0 mol%), DMF (0.2m), 34 W blue LED, ca. 408C, 16 h.
[b] Yields determined by 1H NMR spectroscopy using trimethoxyben-
zene as an internal standard. [c] Yield of isolated product. Ac=acetyl,
Bn=benzyl, DMF=N,N-dimethylformamide, Et=ethyl, Me=methyl,
PG=protecting group, tBu=tert-butyl, Tf=triflyl, Ts=tosyl.
obtained when using [Ir(dF-CH3-ppy)2(dtbbpy)PF6] (B)[9] as
the photocatalyst, and subjecting quinuclidine to the reaction
conditions (entry 6). Control experiments confirmed photo-
catalyst, base, and light were all essential for successful a-
alkylation of 1a (see the Supporting Information for details).
Desired product formation was not obtained with weaker
electron-withdrawing groups on nitrogen (entries 7–9).
With optimized reaction conditions in hand, we sought to
investigate the scope with respect to the alkene with 1a as the
substrate (Scheme 1). Both acrylates devoid of a-substituents
(3aa–ad), as well as methyl-methacrylate (3ae), give products
in acceptable yields. Acrylates containing b-substituents (3af)
lead to a moderate drop in reactivity (33%) except in the case
of highly activated dimethyl fumarate (3 f), which proceeds in
moderate yield (53%). In addition to acrylates, enones
provide the desired a-functionalization (3ah–ai). Additional
Michael acceptors, including vinyl sulfones (3aj), vinyl
phosphonates (3ak), and acrylonitrile (3al–am) are well
tolerated. Dimethylacrylamide (3an) is incorporated with
a slightly compromised yield (38%). Of note is the successful
use of electron-deficient styrene derivatives as coupling
partners (3ao–aq) as well as a heteroarene-substituted
olefin (3ar).[10]
Scheme 1. Olefin scope. [a] 1a (0.1 mmol), alkene (0.15 or 0.3 mmol),
quinuclidine (0.2 mmol), [Ir(dF-CH3-ppy)2(dtbbpy)PF6] (2.0 mol%),
DMF (0.2m), 34 W blue LED, ca. 408C, 16 h. [b] Yield of the isolated
products. [c] The d.r. value was determined by H NMR analysis of the
isolated product. [d] Used 1.2 equiv of 3-buten-2-one. [e] 0.3 mmol
1
scale. EWG=electron-withdrawing group.
coupling partner (Scheme 2). Substrates containing secon-
3
À
dary a-C(sp ) H bonds (3ba–da) provide product in good
yields, whereas tertiary (3ea–fa) a-positions show lower
levels of reactivity. Interestingly, methyl-triflamide (3ga) as
substrate leads to a 34% yield of the dialkylated product as
nearly the sole product. Altering the ratio of triflamide and
olefin coupling partner did not suppress dialkylation. We
reasoned the second alkylation event occurs by a faster rate
because of the resulting radical stability from the first
(primary carbon radical) versus second hydrogen-atom
abstraction event (secondary carbon radical). Nearby elec-
tron-withdrawing groups create a more difficult alkylation
event (3hb, 34%) presumably because of the decreased
À
hydridicity of the triflamide a-C H bond. Absence of over-
We examined the scope with respect to the amine using
either tert-butyl acrylate (2a) or ethyl acrylate (2b) as the
alkylation in the formation of the products 3ba and 3ca can
be attributed to this mode of deactivation in conjunction with
2
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Scheme 2. Triflamide scope. [a] 1a (0.1 mmol), alkene (0.15 or 0.3 mmol), quinuclidine (0.2 mmol), [Ir(dF-CF3-ppy)2(dtbbpy)PF6] (2.0 mol%), DMF
1
(0.2m), 34 W blue LED, ca. 408C, 16 h. [b] Yield of isolated products are reported. [c] The d.r. value was determined by H NMR analysis of
isolated product. [d] 0.3 mmol scale. Boc=tert-butyloxycarbonyl.
a sterically demanding environment. Furthermore, the for-
mation of the fully branched 3ea and 3 fa proceeds in lower
yield. This methodology also proved tolerant of heterocyclic
derivatives (3ia–ja).
To demonstrate the robustness of our site-selective a-
alkylation, we sought to functionalize sulfonamides bearing
Several mechanistic experiments proved enlightening.
Stern–Volmer quenching studies (Scheme 3b) reveal
a strong kinetic preference for the single-electron oxidation
of quinuclidine (E1/2red = 1.1 V vs. SCE in DMF) over the
triflamide anion (E1/2red = 1.2 V vs. SCE in DMF) by the
excited state of B. A deuterium-labelling experiment reveals
a lack of appreciable deuteration at the position a to the ester,
suggesting that a chain-transfer mechanism by direct HAT
from another molecule of substrate to the enoyl radical is
a minor pathway at best. Taken together, we propose the
following mechanism to explain these observations. Under
quinuclidine conditions, a dual HAT/photoredox catalytic
cycle is proposed (Scheme 3a).[11] The highly electrophilic
quinuclidinium radical cation (VI) abstracts an activated
hydridic a-hydrogen atom of the triflamide anion (I) to
deliver an a-amino radical anion (II).[12] Subsequent radical
trapping by an electron-deficient olefin coupling partner will
furnish a carbon-centered radical (III). Single-electron reduc-
tion of III by the reduced iridium photocatalyst (E1/2red = IrIII/
IrII = À1.42 V vs. SCE) and a final protonation event affords
the desired product VIII, closing the catalytic cycle.
additional potential sites of activation. A glucose derivative
3
À
containing multiple abstractable tertiary C(sp ) H bonds
affords the desired a-functionalization selectively to form
3kb in 68% yield (Scheme 2). The inclusion of primary (3la)
and secondary Boc-protected amines (3ma) provide a com-
petitive site for a-functionalization. Previous work from the
group of MacMillan demonstrates a quinuclidine radical
cation can abstract a hydrogen atom from these sites.[5]
Gratifyingly, alkylation occurs site-selectively at the a-C-
3
À
(sp ) H triflamide site. A lysine-derived triflamide also
participates, delivering 3na as a single constitutional isomer
in 58% yield. Preference for the selective formation of a-
amino radicals over [1,5] HAT pathways is further demon-
strated with the products 3oa–qa. This selectivity is quite
remarkable considering our previous work with trifluoroace-
À
tamide directing groups which activate the d-C H bond by
[1,5] HAT.
More significant, perhaps, is the question of mechanism in
the presence of phosphate as a base (entry 3 in Table 1).
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Scheme 3. Mechanistic interrogation. [a] No deuterium/hydrogen scrambling was observed a to the nitrogen center. Deuterium incorporation was
measured in the product. Reaction was repeated under phosphate conditions in which about 1% incorporation was observed. [b] Phosphate
conditions. [c] Reaction conditions: trifluoroacetamide (0.1 mmol), alkene (0.15 or 0.3 mmol), K3PO4 (0.2 mmol), [Ir(dF-CF3-ppy)2(dtbbpy)PF6]
(2.0 mol%), PhCF3 (0.4m), blue LED. [c] KSV =Stervn–Volmer quenching constant.
While phosphate has been implicated as a potential HAT
catalyst, [13] we believe its dominant role is to deprotonate the
acidic triflamide forming the anion in high concentration. A
control experiment revealed that the potassium salt of the
triflamide undergoes the a-alkylation reaction in the absence
of added phosphate or quinuclidine in similar yield
(Scheme 3d). As mentioned above, Stern–Volmer studies
support triflamide oxidation by the excited state of the
photocatalyst. Thus, we suggest the N-centered triflamidyl
radical undergoes intermolecular HAT from another mole-
cule of triflamide anion, delivering the C-centered radical.
By subjecting isohexylamine derivatives to the photo-
that from a triflamide.[8] Under phosphate conditions, tri-
À
fluoroacetamides lie toward heavily protonated, thus, a-C H
bond activation is minimized when compared to their
triflamide counter partners. The trifluoroacetamide nitro-
gen-centered radical will experience a larger driving force for
intramolecular [1,5] HAT due to nitrogen radical instability
À
and the absence of activated a-C H bonds in solution
(trifluoroacetamides in solution lie in the protonated state).
The more stable nitrogen-centered radical present on trifla-
mide acts as an intermolecular hydrogen-atom abstractor to
deprotonated triflamides in solution, which possess highly
À
activated a-C H bonds due to the anionic character. This
À
redox catalyzed C H activation reaction (Scheme 3e) we find
pivot in reactivity allows selective functionalization of both a-
À
that trifluoroacetamides site-selectively functionalize at the d-
position (4aa), whereas triflamides conserve a-activation
(3qa). This divergence in reactivity can be attributed to the
resulting nitrogen radical stability and extent of deprotona-
and d-C H bonds depending on the installed nitrogen
protecting group.
In summary, we have developed a site-selective, visible-
light-driven photocatalyzed a-functionalization of primary
amines. Key to success is the use of a trifluoromethanesulfonyl
À
tion of the N H bond. Computational studies suggest the
À
nitrogen radical from a trifluoroacetamide is less stable than
group on nitrogen as it allows full deprotonation of the N H
4
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À
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Acknowledgements
We thank NIGMS (GM125206) for support. J.C.K.C. thanks
the Croucher Foundation for financial support.
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Conflict of interest
The authors declare no conflict of interest.
ˇ
´
[8] For nitrogen-radical stability, see: D. Sakic, H. Zipse, Adv. Synth.
Catal. 2016, 358, 3983 – 3991; For discussions pertaining to the
Keywords: amines · photochemistry · radicals ·
reaction mechanisms · synthetic methods
À
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optimization was a 1:2 adduct resulting from oligomerization of
acrylate off the enoyl radical formed from the initial addition. B
may allow a more facile reduction of this resulting carbon-
centered radical and minimize undesired reactivity.
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desired product formation.
[11] The reaction proceeds with catalytic amounts of quinuclidine.
However, byproducts that are observed include those arising
from acrylate oligomerization (from III). Increasing the equiv-
alents of quinuclidine ensures high reaction efficiency. As seen in
Table 1, K3PO4 gives comparable yields.
[12] We cannot discount an electrostatic attraction between VI and
the triflamide anion, analogous to what we observe with CO2-
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Manuscript received: October 24, 2018
Revised manuscript received: January 4, 2019
Version of record online: && &&, &&&&
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M. A. Ashley, C. Yamauchi, J. C. K. Chu,
S. Otsuka, H. Yorimitsu,
T. Rovis*
&&&& — &&&&
Photoredox-Catalyzed Site-Selective a-
3
À
C(sp ) H Alkylation of Primary Amine
Derivatives
By choice: Judicious choice in nitrogen
protecting group allows the site-selective
functionalization a to a primary amine.
Under photoredox catalysis conditions,
a variety of alkene acceptors participate,
leading to good yields and excellent
selectivities. Tf=trifluoromethanesul-
fonyl.
6
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