Regioselective, Photocatalytic α-Functionalization of Amines

Article abstract of DOI:10.1021/jacs.0c03758

Photocatalytic α-functionalization of amines provides a mild and atom-economical means to synthesize α-branched amines. Prior examples featured symmetrical or electronically biased substrates. Here we report a controllable α-functionalization of amines in which regioselectivity can be tuned with minor changes to the reaction conditions.

Full text of DOI:10.1021/jacs.0c03758

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Regioselective, Photocatalytic #-Functionalization of Amines
Lingying Leng, yue fu, Peng Liu, and Joseph M. Ready
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03758 • Publication Date (Web): 23 Jun 2020
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Regioselective, Photocatalytic -Functionalization of Amines
Lingying Leng, Yue Fu, Peng Liu,* and Joseph M. Ready*
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UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9038, United States and Department of
Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
Supporting Information Placeholder
lation.3 Such methods control the regioselectivity of radi-
ABSTRACT: Photocatalytic -functionalization of
cal formation but require pre-functionalized reagents.
Atom economical approaches to radical generation rely
on abstraction of hydrogen atoms. In this setting, selec-
tivity cleaving one of many C-H bonds presents a formi-
dable challenge. Substrate tethering, as in the Hofmann-
Löffler-Freytag reaction leverages the propensity of N-
centered radicals to participate in 1,5-H atom transfer re-
actions.4 Alternatively, the photocatalytic fluorination of
benzylic positions provides a representative example of
abstracting the weakest C-H bond.5 In another approach,
polarity matching enables electron deficient aminium
radicals to abstract the most electron rich hydrogen atom.6
Notably, these conditions are not generally controllable –
i.e., it is not possible to change the site of radical genera-
tion by altering reaction conditions, catalysts or reagents.
amines provides a mild and atom economical means to
synthesize -branched amines. Prior examples featured
symmetrical or electronically biased substrates. Here we
report a controllable -functionalization of amines in
which regioselectivity can be tuned with minor changes
to the reaction conditions.
Carbon-centered radicals react with olefins, halogenat-
ing reagents, (hetero)arenes, other radicals, and transition
metals. 1 Addition reactions involving carbon-centered
radicals are often rapid and highly exothermic and there-
fore of high synthetic value.2 However, controlling the
site of radical generation can lack atom economy or flex-
ibility. Here we describe a photocatalytic -amino func-
tionalization reaction that features precise control of regi-
ochemistry and product distribution through subtle
changes to the reaction conditions.
Table 1. Functionalization of N-Benzyl-N-methyl Aniline.
PF6
O
Ph
Ph
N
tBu
N
Ir
N
Ph
N
O
Ph
N
N
tBu
8
7
CH3
Ph
PC3
(5 mol%)
Ph
Ph
Ph
N
Ph
N
Ph
N
CH3
MVK
6
O
O
O
O
conditions
450 nm, rt, 24 h
OH
10
9
(±)-
#
equiv
MVK
solv.
add.
isolated yield (%)
7
8
9
10
1
2
3
4
5
6
3
3
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
--
--
74
49
70
84
3
TFA
1.1
3
DBU
DBU
76 <5
<5 70
3
CH3CN K3PO4
Traditional approaches to generate radicals require ho-
molysis of C-halide or C-O bonds or involve decarboxy-
Photocatalytic strategies provide mild methods to form
and functionalize carbon-centered radicals.7 For example,
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the Pandey and Reiser groups8 and the Yoon group9 inde-
pendently described the formation of -amino radicals 2
derived from tetrahydroisoquinolines in the presence of a
methyl vinyl ketone (MVK) were irradiated in the pres-
ence of several photocatalysts under a variety of reaction
conditions. Key findings are highlighted in Table 1, while
a more detailed summary is provided in the SI. As ex-
pected, the benzyl-functionalized product 7 was obtained
cleanly in the presence of iridium photocatalyst PC3. Sur-
prisingly, however, changing the solvent to acetonitrile
resulted in a complete switch to the methyl-functionalized
product 8 (entry 2). Trifluoroacetic acid switched the se-
lectivity back to the benzylic position (entry 3), whereas
DBU promoted functionalization of the methyl group and
improved the yield, perhaps due to increased catalyst life-
time (entry 4).14 Addition of excess MVK under the DBU
conditions provided the double-alkylated product 9 in
high selectivity (entry 5). Finally, use of a stronger base,
K3PO4, yielded the cyclized aldol product 10 as a single
observable diastereomer.
2+
Ru(bpy)3 photocatalyst (Scheme 1A). Similarly, Nice-
wicz showed that symmetrical carbamates could be alkyl-
ated with electron poor olefins10 in the presence of an or-
ganic photocatalyst (Scheme 2B).11 Both of these trans-
formations proceed in good yields and with complete se-
lectivity for functionalization adjacent to nitrogen. None-
theless, existing technology only provides access to sin-
gle regioisomeric products; the benzylic radical 2 is
highly favored relative to the non-benzylic position while
the Nicewicz substrates (4) were symmetrical.
In connection with our recent study on photocatalytic
functionalization of indolines,12 we questioned whether it
would be possible to control the regioselectivity of -
functionalization of non-symmetrical amines. 13 To ad-
dress this question, N-benzyl-N-methyl aniline (6) and
Slight modification of the reaction conditions could
controllably give four distinct products in good yield and
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selectivity. To explore the generality of these addition re-
By iteratively alkylating under different conditions, tri-
functionalized products could be obtained. For example,
substrate 6 could be alkylated at the methyl position with
ethyl acrylate, followed by benzyl functionalization with
MVK and a final addition of a vinyl sulfone in CH3CN to
form the adduct 57 in good overall yield (eq 1). We also
returned to tetrahydroisoquinoline 1 and found that Con-
ditions A fully substituted the benzylic position to give
58. By contrast, Conditions B again switched the selec-
tivity to favor addition at the non-stabilized position (59,
1
2
3
4
5
6
7
8
actions, we evaluated combinations of several amines and
electron-deficient olefins (Table 2). Under Conditions A,
which favor benzylic functionalization, dimethyl maleate,
chromone and cyclohexanone reacted cleanly (11-13).
Additionally, 4-vinyl pyridine added with complete selec-
tivity (14). By contrast, a methylidene malonate and sev-
eral mono-activated olefins provided the cyclized prod-
ucts 15-18 in modest yield. We attempted to intercept the
intermediate radicals with a hydrogen atom donor, but
surprisingly, t-BuSH actually increased the yield of cy-
clized products 15 and 16.
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eq
2).
Functionalization of the N-methyl group proved to be
rather general (Conditions B). The N-methyl group added
to olefins activated with a nitrile, ester or sulfone in high
yield (19-21). Similarly, dimethyl maleate, cyclic olefins,
vinyl pyridine, and a 1,1-diactivated olefins were excel-
lent substrates (22-26). Conditions C were identified to
provide difunctionalized products. Rather than forming
symmetrical products, the N-methyl group was first
mono-functionalized with 1.1 equiv MVK, then irradi-
ated in the presence of 2.0 equiv of a second olefin. In this
way, nitrile, ester, sulfone, amide and phosphonate prod-
ucts were formed in good yield (27-31). Addition to cy-
clic olefins provided adducts 32-35 as mixtures of dia-
stereomers. Under these conditions, additions to vinyl
(hetero)arenes formed the cyclic adducts 36 and 37 in
moderate to good diastereoselectivity.
To develop an asymmetric version of the addition reac-
tion, oxazolidinone 60 was irradiated under conditions
that favor N-methyl functionalization (eq 3). Remarkably,
the [3+3] adduct 61 was isolated in good yield. While the
Conditions D provided an opportunity to evaluate the
impact of substitution on the N-benzyl and N-phenyl
rings. The addition/cyclization was generally insensitive
to substitution on the benzyl ring. Mono-substitution at
all positions was tolerated, as was di-substitution (38-46).
Electron-withdrawing groups and mildly electron-releas-
ing groups provided the cyclized products in similar
yields as single observed diastereomers. A more strongly
electron-donating methoxy group altered the regioselec-
tivity of the reaction such that both the benzylic and me-
thyl positions were functionalized (53). Substitution on
the N-phenyl ring favored electron-withdrawing groups,
as products 47–52 were formed in good yield. A substrate
derived from p-anisidine only provided mono-functional-
ization. However, heterocycles could be introduced at ei-
ther position, as illustrated by pyridines 54-56. For each
set of conditions (A – D), similar yields were observed on
a
20
mg
and
500
mg
scale.
CO2Et
PC3
PC3
PC3
Ph
N
, DBU
, DBU
Ph
CH3CN, h CH2Cl2, h CH3CN, h
Ph
(1)
SO2Ph
Ph
N
O
O
CH3
SO2Ph
OEt
81% yield
57
6
72% yield
65% yield
O
Py
N
N
(2)
Ph
N
N
N
PC3
CH2Cl2
Ph
Ph PC3
, DBU
1
CH3CN
58
59
Py
Py
67% yield
54% yield
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Scheme 2. Proposed reaction mechanism and computational studies
1
O
2
3
4
5
6
7
8
9
H H
Ph
H
N
Ph
H3C
H
O
MVK
PC3 + H+
CH3
TS1
DG‡(CH3CN) = 18.1
DG‡(CH2Cl2) = 18.4
Ph
Ph
N
7
Ph
CH3
pKa = 2.4
Ph
N
− H+
+ H+
PC3
•
6Bn
CH3
H
H
PC3*
Ph
Ph
DG(CH3CN) = 0.0
DG(CH2Cl2) = 0.0
Ph
N
Ph
N
O
CH3
CH3
10
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Ph
PC3
Ph
NH
H2C
TS2
pKa = 8.2
− H+
6
MVK
Ph
H
Ph
PC3 + H+
6•+
Ph
N
Ph
N
CH2
8
DG‡(CH3CN) = 11.2
DG‡(CH2Cl2) = 11.3
•
6Me
PC3
CH3
H
DG(CH3CN) = 7.7
DG(CH2Cl2) = 7.8
O
All energies are in kcal/mol. Gibbs free energies of TS1 and TS2 are with respect to 6Bn• and 6Me•, respectively.
diastereomeric and enantiomeric ratios are modest, the re-
sults provide proof-of-concept for asymmetric synthesis.
In this condensation, initial 1,4-addition is likely followed
by a [1,5]-hydrogen abstraction to form a benzylic radi-
cal. Reduction and cyclization with expulsion of the Ev-
ans auxiliary would account for the product.
product 8, as expected (eq 6). The majority of the deuter-
ium label remained at the benzylic position, while some
deuterium label was noted alpha to the ketone, likely a
consequence of 1,5-hydrogen atom transfer. In methylene
chloride solvent, the expected benzylic functionalization
was obtained without loss of deuterium at the benzylic
position (eq 7). Deuterium was not observed adjacent to
the ketone, which we attribute to exchange with adventi-
tious water (all reactions performed with solvents stored
on the benchtop). Critically, in neither case was deuterium
observed at the N-methyl position, ruling out equilibra-
tion between the benzylic and methyl radicals via intra-
or intermolecular H-atom transfer in either solvent.
The overall mechanism of -amino functionalization
likely follows the sequence outlined by Pandey, Reiser8
and Yoon9. Irradiation of the Ir catalyst generates an ex-
cited state complex that is capable of accepting an elec-
tron from the amine substrate to form an ammonium rad-
ical cation. Loss of a proton generates a neutral -amino
radical (see 2) that can participate in Giese-type additions
to activated olefins.10
Several insights were obtained from the substrate with
a deuterated N-methyl group (6-d3). In acetonitrile, selec-
tivity was erased, such that the benzyl functionalized
product 7-d3 and the methyl functionalized product 8-d2
were obtained in equal quantities (eq 8). The change in
selectivity is a reflection of a kinetic isotope effect in the
methyl-functionalization and indicates that formation of
a radical at this position could be rate-limiting. In meth-
ylene chloride, clean benzylic functionalization was ob-
served with no loss of the deuterium label (eq 9).
To gain more insight into the impact of solvent on regi-
oselectivity,15 we performed deuterium labeling studies
and initial computational evaluation. Addition of CD3OD
(10 equiv) to the reaction mixture did not affect yield or
selectivity but allowed us to monitor protonation events.
Thus, we ran the reaction to partial conversion in acetoni-
trile (eq 4). Functionalization occurred at the N-methyl
position, but the isolated product and recovered starting
material showed substantial deuterium incorporation at
the benzylic position. In methylene chloride, the recov-
ered starting material showed partial deuteration, while
little deuterium incorporation was observed at the ben-
zylic position in the isolated product (eq 5). Control ex-
periments revealed extensive deuterium incorporation in
the absence of MVK (see SI). In neither case was deuter-
ium observed at the methyl position. Taken together, the
isotope labeling experiments indicate that activation of
the benzylic site is reversible whereas activation of the
methyl site is irreversible. Related reactions with added
D2O revealed similar levels of deuteration, indicating that
the label is likely introduced as D+ rather than D radical.
The data support a scenario in which both the benzylic
and methyl radicals are formed in acetonitrile, but the me-
thyl radical participates in the Giese addition more rap-
idly.16 Computation of the reaction energy profile at the
M06-2X/6-311++G(d,p), SMD(acetonitrile) // M06-
2X/6-31+G(d) level of theory partially supports this inter-
pretation (Scheme 2). The benzylic radical (6Bn ) is more
stable than the methyl radical (6Me ) by 7.7 kcal/mol.
However, the methyl radical has a lower barrier for addi-
tion to MVK than the benzylic radical by 6.9 kcal/mol
(11.2 vs 18.1 kcal/mol). The simplest mechanism for re-
versible activation of the benzylic position involves sim-
ple proton transfer (Scheme 2). Protonation of the C-cen-
⦁
⦁
Substrate 6-d2, which is labeled at the benzylic position,
reacted in acetonitrile to give the methyl-functionalized
⦁
tered radical 6Bn may appear counterintuitive, but it is
simply the microscope reverse of deprotonation of the
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amine radical cation 6⦁+. DFT calculations indicate that
the pKa of the N-benzyl and N-methyl C−H bonds in 6⦁+
are 2.4 and 8.2, respectively,17 implying that the more
acidic benzylic C−H is susceptible to reversible protona-
tion/deprotonation. This model suggests that in acetoni-
This material is available free of charge via the Internet at
1
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http://pubs.acs.org.” Complete experimental and computa-
tional methods. Characterization data for all new com-
pounds.
AUTHOR INFORMATION
⦁
trile, 1,4-addition of 6Me to electron-poor olefins is fast
relative to reversion to the amine radical cation. In this
context, the result in eq 5 provides a tantalizing clue re-
garding the different outcome in methylene chloride. We
observed approximately 20% D incorporation in the re-
covered starting material, but <5% deuteration at the ben-
zylic position in the product (7). This result indicates that
in methylene chloride, the relative energy barriers for 1,4-
addition of 6Bn⦁ to olefins vs. protonation back to 6⦁+ now
favor Giese addition. It is surmised that the more polar
acetonitrile facilitates proton transfer by stabilizing the
charged transition states, because the computed barriers
to Giese additions are not substantially different in the dif-
ferent solvents (Scheme 2).18 Ongoing work seeks to un-
derstand these effects more completely and probe their
generality. In the meantime, the protocols described
herein provide convenient and controllable means to ac-
cess four different product classes from the same starting
materials.
Corresponding Author
Peng Liu (pengliu@pitt.edu)
Joseph M. Ready (joseph.ready@utsouthwestern.edu)
9
Notes
The authors declare no competing financial interests. .
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ACKNOWLEDGMENT
Funding from the Welch Foundation (I-1612), NIH (R01
CA216863) and NSF (CHE-1654122, P.L.). DFT calcula-
tions were performed at the Center for Research Computing
at the University of Pittsburgh and the Extreme Science and
Engineering Discovery Environment (XSEDE) supported
by the National Science Foundation grant number ACI-
1548562.
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deactivation pathway in a fac-Ir(ppy)3-mediated radical addition.
Chem. Sci. 2015, 6, 537-541. (b) Föll, T.; Rehbein, J.; Reiser, O.:

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Ir(ppy)3-catalyzed, visible-light-mediated reaction of α-chloro cin-
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(16) The Yoon group showed that acids accelerate the 1,4-addition
step, which likely renders the C-H cleavage rate-determining (ref 9).
Consistent with this proposal, addition of TFA reversed the selectivity
in acetonitrile (see Table 1).
(17) pKa values were calculated using DFT-calculated energies of
6⦁+, 6Bn⦁, and 6Me⦁ in water using the SMD implicit solvation model and
the free energy of proton in aqueous solution (Gaq(H+) = −270.29
kcal/mol). See: Thapa, B.; Schlegel, H. B., Density Functional Theory
Calculation of pKa’s of Thiols in Aqueous Solution Using Explicit Wa-
ter Molecules and the Polarizable Continuum Model. J. Phys. Chem. A.
2016, 20, 5726-5735.
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(18) We attempted to calculate the activation barriers to protona-
tion/deprotonation in the different solvents. However, the computa-
tional results were not conclusive (see SI for details). This illustrates
the difficulty of capturing solvent effects on proton transfer rates com-
putationally.
R
N
R
N
Conditions
Conditions
R'
Ar
Ar
A
C
CH3
R'
R'
R"
[Ir], h
R
N
Ar
Ar
R"
R'
[Ir], h
CH3
R
R
N
Ar
N
O
Conditions
Conditions
OH
CH3
D
B
R'
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