Deaminative Reductive Arylation Enabled by Nickel/Photoredox Dual Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b01097

Described is a cross-electrophilic, deaminative coupling strategy harnessing Katritzky salts as a new species of electrophile in Ni/photoredox dual catalytic reductive cross-coupling reactions. Distinguishing features of this arylation protocol include its mild reaction conditions, high chemoselectivity, and adaptability to a variety of complex substrates [i.e., pyridinium salts derived from amines and partners derived from (hetero)aryl bromides].

Full text of DOI:10.1021/acs.orglett.9b01097

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Deaminative Reductive Arylation Enabled by Nickel/Photoredox
Dual Catalysis
Jun Yi,†,‡,§ Shorouk O. Badir,†,§ Lisa Marie Kammer,† María Ribagorda,† and Gary A. Molander*,†
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
‡Jiangsu Laboratory of Advanced Functional Materials, School of Chemistry and Materials Engineering, Changshu Institute of
Technology, Changshu 215500, China
S
* Supporting Information
ABSTRACT: Described is a cross-electrophilic, deaminative
coupling strategy harnessing Katritzky salts as a new species of
electrophile in Ni/photoredox dual catalytic reductive cross-
coupling reactions. Distinguishing features of this arylation
protocol include its mild reaction conditions, high chemo-
selectivity, and adaptability to a variety of complex substrates
[i.e., pyridinium salts derived from amines and partners
derived from (hetero)aryl bromides].
liphatic primary amines are a privileged class of
Acompounds prevalent in natural products, valued
synthetic intermediates, and pharmaceutical drugs such as
Tamiflu, Linagliptin, Amlodipine, and Sitagliptin.1 In an
elegant report, the Watson group recently demonstrated the
use of Katritzky salts, formed via a simple condensation of the
corresponding amines with a bench-stable, commercially
available pyrylium salt, as alkyl radical precursors in cross-
couplings with arylboronic acids.2,3 Subsequently, Glorius,
Aggarwal, Shi, Gryko, and Liu further demonstrated the utility
of these redox-active amines in C−H arylation,4 borylation,5
alkynylation,6 allylation,7 and dicarbofunctionalization, respec-
tively.8 More recently, Watson and co-workers disclosed a
deaminative alkyl−alkyl Negishi cross-coupling with alkylzinc
halides.9 The growing interest in this area highlights the
challenges associated with C−N bond activation and presents
new opportunities to address these limitations, in particular
with regard to the development of cross-electrophilic,
deaminative strategies to forge C(sp3)-hybridized centers.
In recent years, nickel/photoredox dual catalysis has
emerged as a powerful tool to construct C−C bonds via a
single-electron transmetalation pathway.10 In this context, the
unique characteristics of this reaction manifold favor the
formation of tetrahedral carbon centers without the need for
harsh nucleophilic organometallic reagents or elevated temper-
ature.11 Given our and other groups’12 longstanding interest in
reductive nickel transformations and our deep understanding
of photoredox catalysis,13 we envisioned the application of
Katritzky salts as a new species of alkyl radical precursors in a
reductive, cross-electrophilic coupling with (hetero)aryl
bromides, representing one of the few synthetic methods employing
a net reductive photoredox/Ni dual catalytic transformation
(Scheme 1).14
Scheme 1. Aliphatic Amines as Radical Precursors in Cross-
Coupling
Given the accessible redox potential of Katritzky salts (E1/2
=
−0.93 V vs SCE),7 the organic dye 4CzIPN (reduced
photocatalyst E1/2 = −1.21 V vs SCE) was examined and
proved effective at delivering the desired coupled product
(Table 1). Other photocatalysts were also tested (entries 2 and
3 in Table 1). Not surprisingly, [Ir(dtbbpy)(ppy)2]PF6
Received: March 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01097
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
position (14 and 18) was explored, whereby efficient cross-
coupling events took place. Moreover, electron-deficient
difluoroaryl bromide 18 and several heteroaryl systems (19−
30 and 36) were successfully employed. Because of their
notoriously unstable nature as the corresponding boronic acids
(owing to protodeboronation under strongly basic condi-
tions),16 the analogous substructural partners had provided
sluggish reactivity in previous reports.2
Table 1. Optimization of the Reaction Conditions
Given their importance in pharmaceutical settings,17
a
variety of nitrogen-containing heteroaryl bromides, including
pyrimidine (20 and 26), quinoline (23, 27, and 28),
isoquinoline 24, pyridine (25 and 29), and indole (30)
electrophiles were effectively incorporated under this reaction
manifold. It is worth highlighting that heteroaromatics (23 and
24), previously well-behaved under photoinduced deamina-
tion/C−H arylation conditions,3 reacted in a chemoselective
manner. This highlights the complementary advantages of this
protocol to existing Minisci transformations.4,18
Next, attention was turned to the scope of the alkylpyr-
idinium salts, where a wide array of functional groups were
tolerated. Katritzky salts bearing a free hydroxyl group (39 and
40) did not inhibit the reaction, presenting orthogonal
reactivity to C−O bond formation previously reported by
MacMillan.19 Other pyridinium salts bearing an ester handle
(41) and nitrogen heterocyclic structural motifs (33 and 34)
afforded the desired products in excellent yields. It is worth
noting that both cyclic (31−36, 39−42) and acyclic (37, 38,
43, and 44) alkylpyridinium salts reacted efficiently under the
reaction conditions.
Finally, to demonstrate the applicability of this protocol to
the synthesis of bioactive molecules, we prepared the
corresponding alkylpyridinium salt from Mexiletine, a volt-
age-gated sodium channel blocker used as an antiarrhythmic.20
Utilizing two different aryl bromides, success was achieved at
delivering the cross-coupled products 43 and 44 in excellent
yields. Finally, a complex aryl bromide derived from
Loratadine,21 used in the treatment of allergies, was compatible
under the reaction conditions (45).
To highlight the benefits of employing 4CzIPN as an
inexpensive organic photocatalyst [∼$5 mmol−1], a trans-
formation was successfully performed on gram scale, whereby
the desired heteroaryl coupled product 27 was obtained in
90% yield (Scheme 3).
By taking further advantage of the inherent chemoselectivity
of this cross-coupling as described earlier, the quinoline
scaffold of 27 was further elaborated at the C2 position to
obtain 46 and 47 in good yields, utilizing Minisci-type
photoinduced deaminative and decarboxylative strategies
previously reported by Glorius and Dhar, respectively.4,18c
The ease with which a wide array of aryl and heteroaryl
systems can be fashioned showcases the significant potential of
deaminative-based C−C bond construction in industrial
settings.
a
1 (0.45 mmol), 2 (0.3 mmol), 4CzIPN (3 mol %), and
NiBr2(dtbbpy) (5 mol %) in dry, degassed solvent (3.0 mL, 0.1 M)
under blue LED irradiation for 24 h. GCMS yield using 1,3,5-
trimethoxybenzene as internal standard. Isolated yield in parentheses.
b
provided quantitative conversion to the desired product, likely
because of its strongly reductive nature (E1/2 = −1.51 V vs
SCE).4,10b Considering the low cost, ease of preparation, and
excellent reactivity of 4CzIPN,15 it was chosen as the
photocatalyst of choice. Although DMA provided equally
good results in this cross-coupling (entry 6 in Table 1), THF
was chosen because of its low boiling point. However, it should
be noted that the use of DMA for electron-rich substrates
proved effective at times (see Supporting Information). As
anticipated, control experiments proved that all components of
the reaction were necessary for the dual catalytic system to
proceed (entries 7−10). Finally, in an attempt to provide an
easier reaction setup, the optimization was carried out using
the precomplex NiBr2·dtbbpy.
With suitable reaction conditions in hand, the scope of this
deaminative cross-coupling was examined (Scheme 2). To this
end, a wide array of aryl bromides bearing electron-with-
drawing substituents at the para-position exhibited excellent
reactivity (3−10, 16). Electron-rich aryl bromides were also
compatible substrates (11 and 12). Importantly, aryl bromides
bearing an additional handle for further elaboration in Chan−
Lam and Suzuki couplings, such as pinacol boronic ester (17)
and aryl chlorides (6 and 13), reacted to afford the
corresponding products in good yields.
To probe the reaction pathway, we conducted a series of
mechanistic experiments. In the presence of the radical
scavenger TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxyl],
the arylation was completely inhibited, with full recovery of the
aryl bromide (Scheme 4A). This is suggestive of the
involvement of radical species under this metallaphotoredox
manifold. This hypothesis was further corroborated by
isolation of 48, a byproduct likely formed via a radical−radical
coupling of the persistent dihydropyridine radical intermediate
Given the mildly basic conditions of this protocol, a variety
of sensitive functional groups, including lactone 15 and
sulfonamide 16, were compatible structural motifs. Substitu-
tion at the meta-position (13, 15, 17, and 18) and ortho-
B
DOI: 10.1021/acs.orglett.9b01097
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 2. Scope of (Hetero)aryl Bromides and Alkylpyridinium Salts
a
b
As in Table 1 (entry 1), 0.5 mmol scale. Using DMA as a solvent, 48 h.
A with a transient secondary alkyl radical during the course of
the reaction6 (Scheme 4B).
To gain further understanding of the role of the photo-
catalyst, fluorescence quenching studies were performed
(Figure 1). As anticipated, the Stern−Volmer relationship
confirmed that the photoexcited 4CzIPN was quenched by
both triethylamine and the Katritzky salt. Although these
results could support an operative single-electron-transfer
(SET) reduction of the alkylpyridinium salt by the photo-
catalyst, we cannot rule out the possibility of a direct SET
C
DOI: 10.1021/acs.orglett.9b01097
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Organic Letters
Letter
Scheme 3. Sequential Gram-Scale Deaminative Cross-
Coupling and Minisci C−H Arylation
Figure 1. Stern−Volmer Fluorescence Quenching Studies of 4CzIPN
(c = 2.0 M) in THF.
Scheme 5. Reductive Nickel/Photoredox Dual Catalysis:
Mechanistic Rationale
Scheme 4. Support for Involvement of Radical
Intermediates
a
b
As in Table 1 (entry 1), 0.3 mmol scale. NMR yield was calculated
Reduction of VIII by the ground state of the reduced
photocatalyst III (E1/2 = −1.21 V vs SCE) concurrently
completes both catalytic cycles.
based on the alkylpyridinium reagent (theoretical yield of 0.225
mmol).
The developed arylation protocol does exhibit a limitation
owing to the inherent stability of the dihydropyridine radical
intermediate A generated (Scheme 5). Thus, primary
alkylpyridinium salts preferentially undergo reoxidation to
deliver the corresponding pyridine byproduct.6 Considering
the sheer number of existing, complementary cross-coupling
approaches for primary alkyl radicals developed by our group
and others,22 we foresee the current work as an important,
complementary approach to the challenges associated with the
activation of inert C−N bonds in recently described systems
that appear restricted to aryl iodides and use excess metal
reductants at elevated temperatures.23
In conclusion, a cross-electrophilic, reductive deaminative
arylation protocol under photoredox conditions has been
developed, using triethylamine as the terminal reductant. By
eliminating the need for stoichiometric metal reductants,
elevated temperatures, and/or strong bases, an exceptional
array of functional groups and complex structural scaffolds can
event from a low-valent nickel intermediate as proposed by
Watson and Lei.2,14a
Based on these results and precedented literature reports
detailing the reductive cleavage of Katritzky salts,2−8
a
plausible mechanism is depicted in Scheme 5. First, visible-
light irradiation of 4CzIPN generates a potent excited-state
oxidant (E1/2 = +1.35 V vs SCE),22 which is sufficiently
quenched by triethylamine D (E1/2 = +1.0 V vs SCE),10b thus
forming the reduced state of the photocatalyst. Upon
generation of alkyl radical IV from the Katritzky salt (E1/2
=
−0.93 V vs SCE)7 via SET from the photoexcited 4CzIPN or a
low-valent nickel intermediate, the radical is intercepted by a
ligated Ni(0) complex V to afford a Ni(I) intermediate.
Subsequently, VI undergoes oxidative addition with the
(hetero)aryl bromide to afford the corresponding high-valent
Ni(III) complex VII. Reductive elimination would then occur
to yield the desired coupled product 3 and Ni−Br species VIII.
D
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This arylation protocol is scalable, operationally simple, and
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01097.
General procedures; fluorescence quenching studies;
NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
ORCID
María Ribagorda: 0000-0001-7185-4095
Gary A. Molander: 0000-0002-9114-5584
Author Contributions
§J.Y. and S.O.B. contributed equally to this work.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support provided by
the NSF (CHE-1664818) and the NIGMS (R01 GM 113878
to G.M.). J.Y. acknowledges funding from the National Natural
Science Foundation of China (Grant No. 21602017), the
Natural Science Foundation of Jiangsu Province (Grant No.
BK20160405), the University Science Research Project of
Jiangsu Province (16KJB150001), and China Scholarship
Council (201708320115). M.R. acknowledges support from
́
the Ministerio de Educacion, Cultura y Deporte, Subprograma
Estatal de Movilidad and Fulbright grant visiting scholar
program. We thank Mr. Shuai Zheng (UPenn) for stimulating
discussions. We thank Dr. Charles W. Ross, III (UPenn) for
his assistance in obtaining HRMS data. Kessil is acknowledged
for providing the lights used in this study.
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