Site-Selective Copper-Catalyzed Azidation of Benzylic C-H Bonds

Article abstract of DOI:10.1021/jacs.0c05362

Site selectivity represents a key challenge for non-directed C-H functionalization, even when the C-H bond is intrinsically reactive. Here, we report a copper-catalyzed method for benzylic C-H azidation of diverse molecules. Experimental and density functional theory studies suggest the benzyl radical reacts with a CuII-azide species via a radical-polar crossover pathway. Comparison of this method with other C-H azidation methods highlights its unique site selectivity, and conversions of the benzyl azide products into amine, triazole, tetrazole, and pyrrole functional groups highlight the broad utility of this method for target molecule synthesis and medicinal chemistry.

Full text of DOI:10.1021/jacs.0c05362

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Communication
Site-Selective Copper-Catalyzed Azidation of Benzylic C–H Bonds
Sung-Eun Suh, Si-Jie Chen, Mukunda Mandal, Ilia A. Guzei, Christopher J. Cramer, and Shannon S. Stahl
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 15 Jun 2020
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Site-Selective Copper-Catalyzed Azidation of Benzylic C–H Bonds
Sung-Eun Suh,† Si-Jie Chen,† Mukunda Mandal,‡ Ilia A. Guzei,† Christopher J. Cramer,‡ and Shannon
S. Stahl*,†
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†Department of Chemistry, University of Wisconsin−Madison, 1101 University Avenue, Madison, Wisconsin 53706, United
States
‡Department of Chemistry, Chemical Theory Center and Supercomputing Institute, University of Minnesota, Minneapolis,
Minnesota 55455, United States
Supporting Information Placeholder
ABSTRACT: Site selectivity represents a key challenge for non-
directed C–H functionalization, even when the C–H bond is
intrinsically reactive. Here, we report a copper-catalyzed method
for benzylic C–H azidation of diverse molecules. Experimental
and density functional theory studies suggest the benzyl radical
reacts with a CuII-azide species via a radical-polar crossover
pathway. Comparison of this method with other C–H azidation
methods highlights the unique site-selectivity of this method, and
conversions of the benzyl azide products into amine, triazole,
tetrazole, and pyrrole functional groups highlight the broad utility
of this method for target molecule synthesis and medicinal
chemistry.
C–H functionalization methods improve the efficiency of
target molecule syntheses1–3 and expand the scope of accessible
structures.4 The large number of C–H bonds within individual
molecules, however, introduces site-selectivity challenges.1,5 ,6
Organic azides are versatile synthetic intermediates. 7 - 9 They
represent effective ammonia surrogates,10 are readily converted
11 , 12
into N-heterocycles,
and provide access to important
bioactive molecules. (Figures 1A and 1B).13-15 Recent efforts
have demonstrated C(sp3)–H azidation,16 including iron-17,18 and
manganese-catalyzed19 and photochemical20,21 methods that are
compatible with diverse C–H substrates as the limiting reagent.
These methods proceed via radical intermediates that show high
selectivity for tertiary over primary and secondary aliphatic C–H
bonds, but selectivity for benzylic over aliphatic positions is
relatively low20 or has not been investigated. Benzylic and
heterobenzylic C–H bonds are ubiquitous in bioactive molecules,
and site-selective functionalization of such positions could have
broad impact. We22 , 23 and others24 - 27 have reported copper
catalysts with N-fluorobenzenesulfonimide (NFSI) that enable
selective functionalization of benzylic C–H bonds.28-30 Here, we
describe a similar approach for C–H azidation that exhibits
unique benzylic site-selectivity relative to other azidation
methods (Figure 1C). Complementary studies provide
mechanistic insights into the reaction and showcase the synthetic
utility in the preparation of important target molecules.
Initial reaction optimization efforts used 1-ethylnaphthalene
3a and TMSN3 as coupling partners. An initial attempt with
previous benzylic C–H cyanation conditions22 led to the desired
product, but with low conversion and yield (6%, entry1, Table 1).
Increasing the temperature to 50 °C and using nitromethane as the
solvent significantly increased the yield of 4a (entries 2 and 3,
Table 1; see Tables S1-S9 in the Supporting Information for full
screening data). CuI and CuII acetate salts were the most effective
Figure 1. Azides are important intermediates in organic syntheses (A)
and medicinal chemistry (B) and are ideally prepared by direct azidation
of sp3 C–H bonds (C). NFSI, N-fluorobenzenesulfonimide. Mes-Acr, 9-
mesityl-10-alkylacridinium catalyst.
catalyst precursors (entries 3 and 6). Cu(OAc)2 was selected
because it led to higher yields, and its air-stability facilitated
handing. Testing the reaction without L1 highlighted the
importance of an ancillary ligand (entry 7). Screening other
ligands (entries 8-10 and Table S4) showed that improved yields
could be obtained with 2,2'-bioxazoline (BiOx) ligands (e.g., 85%
yield with L4, entry 10). Further screening led to the optimized
conditions in entry 11, affording 93% yield of azide 4a. The lack
of enantioselectivity, even with a single enantiomer of the ligand,
prompted several efforts to probe the reaction mechanism.
CuI-mediated reductive activation of NFSI will generate an
imidyl radical that promotes hydrogen-atom transfer (HAT) from
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Table 1. Reaction Optimizationa
A. Synthesis of [(BPhen)CuII(N3)(µ-N3)]2
1
2
PhCl (0.02 M)
N2, 25 °C, 24h
+
+
TMS-N3
1/2 [(BPhen)CuII(N3)(µ-N3)]2
(BPhen)CuOAc
0.06 mmol
NFSI
0.03 mmol 0.6 mmol
3
4
5
6
7
8
9
N
N
N
N8
N7
N6
N
Cu1
yieldb
(%)
N2
N1
NFSI
(equiv.)
TMS-N3
(equiv.)
N
N
N
Cu
entry
catalyst (mol%), ligand (mol%)
N
N
N
N
CuOAc (10), L1 (10)
Cu
N3
N
1
2
1.5
1.5
3.0
3.0
6
(room temp., solv = benzene)22
N4
N
N5
N
CuOAc (10), L1 (10)
(solv = benzene)
N
51
N
3
CuOAc (10), L1 (10)
CuI (10), L1 (10)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.6
55
31
42
62
15
37
69
85
93c
[(BPhen)CuII(N3)(µ-N3)]2
X-ray structure
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B. Reaction of [(BPhen)CuII(N3)(µ-N3)]2 with Gomberg's dimer
5
Cu(acac)2 (10), L1 (10)
Cu(OAc)2 (10), L1 (10)
Cu(OAc)2 (10) (no ligand)
Cu(OAc)2 (10), L2 (10)
Cu(OAc)2 (10), L3 (10)
Cu(OAc)2 (10), L4 (10)
Cu(OAc)2 (2.0), L4 (4.0)
MeNO2 (0.2 M)
Gomberg's
dimer
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[(BPhen)CuII(N3)(µ-N3)]2
+
Ph
Ph
Ph
N2, 30 °C, 16 h
7
0.015 mmol
H
0.03 mmol
0.015 mmol
91%
8
N3
Cu(OAc)2/BPhen, TMS-N3, NFSI,
9
Ph
Ph
Ph
Ph
Ph
MeNO2 (0.2 M), N2, 50 °C, 16 h
Ph
10
11
66%
triphenylmethane
0.4 mmol
trityl azide
Figure 2. (A) Synthesis and crystal structure of [(BPhen)CuII(N3)(µ-N3)]2
(hydrogen atoms and chlorobenzene molecule omitted for clarity). (B)
Reaction of [(BPhen)CuII(N3)(µ-N3)]2 with Gomberg’s dimer (6 mol%
Cu(OAc)2/BPhen, 3.6 equiv. TMSN3, 2.5 equiv. NFSI).
a 0.4 mmol 3a. bNMR yield, ext. std. = mesitylene. cIsolated yield.
A. Three plausible reaction pathways
the benzylic C–H bond.23 The resulting benzyl radical can react
with a CuII-azide species to afford the benzyl azide. Under
simulated catalytic conditions lacking the benzylic substrate,
CuIOAc, L2, NFSI, and TMSN3 generate a dimeric CuII-azide
complex, characterized by X-ray crystallography (Figure 2A).
Addition of Gomberg's dimer,31 which readily dissociates into
two trityl radicals, to a solution of this complex generated trityl
azide in 91% yield (Figure 2B).32,33 This stoichiometric reaction
was complemented by a catalytic reaction with triphenylmethane,
which afforded the benzyl azide in 66% yield.
L*CuIII(N3)2
Path I
TS1
TS2
1-Naph
Me
– L*CuII(N3)2
*
Int-1
N3
N3
N3
CuIIL*
(S)
Path II
N3
L*CuII
N3
1-Naph
1-Naph
3a
(R)
[L*CuII(N3)2]2
1-Naph
L* = L4
L*CuI(N3)
[L*CuII/I(N3)2]2
Int-3
Path III
L*CuII(N3)2
1-Naph
SET
Seminal studies by Kochi suggest several possible pathways
for C–N bond formation (Figure 3A).34-39 In Path I, the benzyl
radical adds to CuII to generate a benzyl-CuIII species that can
undergo C–N reductive elimination.22,34 Path II includes multiple
pathways involving radical attack at a terminal or bridging azide
ligand, either at the proximal or distal N-atom of the azide.35-37
Finally, Path III involves one-electron oxidation of the benzyl
radical by CuII to generate a cation, which can react readily with
an azide nucleophile.23,38,39 Density functional theory calculations
were performed to assess relevant structures and the energies of
these pathways (M06-L/basis-II/SMD(MeNO2); B3LYP-
D3(BJ)/basis-I level of theory: Basis-I = 6–31G(d,p) for non-
metals; SDD basis and pseudopotential for Cu. Basis-II = def2-
TZVP for non-metals, def2-TZVP basis and SDD
pseudopotential for Cu; see Section 9 in Supporting Information).
The energy diagrams in Figure 3B highlight the most favorable
energies identified for Paths I–III involving reaction of the benzyl
radical of 1-ethylnaphthalene and L4-ligated CuII-dimer. The
results show that radical addition to CuII, followed by C–N
reductive elimination from Int-1 has the highest energy among
the different mechanisms (Figure 3B). Radical addition to an
azide ligand proceeds with much lower barrier. The pro-R face
favors addition to a bridging azide while the pro-S favors addition
to a terminal azide: DG‡ = 2.6 and 2.4 kcal/mol for RTS2 and
STS2, respectively. In both cases, radical addition is favored at
the distal N-atom of the azide ligand. Computational analysis of
the electron-transfer pathway leveraged the experimental redox
B. Calculated energies for reaction pathways
20
15
10
5
RTS-1
L*CuII(N3)
(15.8)
Path I
RInt-1
(11.6)
N
N
N
Path II
Path III
STS-1
(14.7)
1-Naph
Me
SInt-1
(8.0)
R/STS1
R
(2.6)
TS2
N3
N3
CuIIL*
N3
S
L*CuII
(2.4)
TS2
1-Naph
0
N
N
N
(0)
N
(-0.8)
Int-3
3a
N
1-Naph
L*CuI(N3)
N
-5
[L*CuII(N3)2]2
(S)
L*CuII(N3)2
(R)
-10
-15
1-Naph
R/STS2
L* = L4
(-10.4)
Reaction Coordinate
Figure 3. Three proposed pathways for azidation of the benzyl radical
(A), and simplified energy diagrams comparing the three pathways (B)
(see text and Supporting Information for details).
potential measured for [(BPhen)CuII(N3)(µ-N3)]2 (–0.16 V vs.
Fc0/+; see Figure S8) and reported potentials for the benzyl
+
•
radicals of ethylbenzene and isopropylbenzene (E°R
= –0.01
|R
and –0.22 V vs. Fc0/+).40 Using these values as benchmarks,
calculated redox potentials for [(L4)CuII(N3)(µ-N3)]2 and the
benzyl radical of 3a reveal that oxidation of the radical by the
CuII-dimer is thermodynamically favorable (ΔG ° = –0.8
kcal/mol). The small calculated energy difference between Paths
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II and III, and the absence of an electron-transfer rate constant,
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prevent clear distinction between these two paths on the basis of
computational studies; however, both are predicted to afford little
or no enantioselectivity.41 Experimental data providing some
support for Path III was obtained from catalytic azidation of 4-
Ph-cumene. Benzylic azidation was observed in 2:1 ratio with a
vicinal diazide byproduct. Control experiments suggest
diazidation arises from an a-methylstyrene intermediate (see
Figures S3 and S4). These results are most consistent with a
radical-polar crossover mechanism, in which the benzyl cation is
trapped by an azide nucleophile or loses a proton to generate an
alkene, which can undergo subsequent 1,2-diazidation.
Efforts were then made to explore the site-selectivity of this
method (Figure 4). Three substrates incorporating both secondary
benzylic and tertiary aliphatic C–H bonds were selected:
isobutylbenzene 3b, isopentylbenzene 3c, and ibuprofen methyl
ester 3d. Use of the Cu/NFSI catalytic conditions at 30 °C led to
azidation yields of 48%, 71%, and 62%, respectively, with
benzylic:tertiary (B:T) selectivity ranging from 11:1–30:1. No
azidation was observed at the tertiary benzylic position adjacent
to the ester in 3d. This result probably reflects both steric
inhibition and a polarity mismatch in reaction with the
sulfonimidyl radical. These results were compared to analogous
data from three other C–H azidation methods, including
photochemical,20 Mn-catalyzed,19 and Fe-catalyzed17-18 reactions
(II–IV, Figure 4). The reported site-selectivity for 3b and 3d with
method II exhibit a B:T ratio of ~ 1:1.20 Independent testing of 3c
revealed tertiary C–H azidation. Mn(salen)Cl with PhIO (method
III)19 also exhibits good selectivity for benzylic azidation: B:T =
4.6:1, 4.6:1, and 14:1, respectively, for 3b, 3c, and 3d, although
these reactions were operationally more challenging and led to
lower yields (28–48%) than Cu/NFSI. The Fe(OAc)2/IIII-azide
system (method IV)17-18 showed relatively low B:T selectivity
with 3b–3d (1:1–2.5:1). Collectively, the data in Figure 4 show
that Cu/NFSI exhibits unique benzylic site-selectivity.
Expanding on the results obtained with substrates 3a–3d, we
evaluated the azidation of other benzylic C–H substrates (Table
2). Reactions of various para-substituted ethylbenzenes (4-Ph, -
Br, -OAc, and -OMe) resulted in moderate-to-good yields (45-
81%, 4e–4h). An exception was the electron-deficient 4-CN
derivative 4j (25%), while an aliphatic nitrile was better tolerated
(4k, 51%). The common pharmacophore chroman42 underwent
azidation in 60% yield (4l), and tetralin and benzosuberan,
containing 6- and 7-membered rings, afforded good yields of 4m
(90%) or 4n (85%). In contrast, indane led to only 12% yield of
the azide, together with various byproducts (see Table S13 for a
summary of this and other unsuccessful substrates). Bibenzyl
underwent selective mono-azidation (72%, 4o), and a series of
diarylmethane derivatives, which are common pharmaceutical
core structures, accessed moderate-to-good azide product yields
(4p–4s).43 Substrate 3t underwent azidation at two sites: adjacent
to the carbonyls of the ketoester and at the benzylic position
(4t/4u). Increasing the temperature to 60 °C led to exclusive
azidation at the α-C–H of the ketoester. Heterobenzylic substrates
with pyridine and pyrazole units afforded the desired azides 4v–
4x in moderate yield (30-65%), demonstrating tolerance to
pharmaceutically relevant heterocycles.
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I
II III IV
I
II III IV
I
II III IV
Figure 4. Azidation site selectivity with different catalytic methods (see
Section 5 in the Supporting Information for details). Standard condition
for method I; substrate (0.4 mmol), Cu(OAc)2 (2.0 mol%), BiOx (4.0
mol%), TMSN3 (3.6 equiv.), NFSI (2.5 equiv.), 0.2 M MeNO2, 30 °C, 24
h for 3b, 48 h for 3c and 3d.
abietylamine derivative 3ae features three potential sites for
functionalization, a tertiary aliphatic and secondary and tertiary
benzylic C–H bonds. Only the secondary benzyl azide (–)-4ae
was observed (62% yield, 0.5 g). Finally, azidation of
celestolide49 proceeded in excellent yield to 4af (92%, 1.25 g).
The appeal of the benzylic C–H azidation reactions in Table
2 is amplified by opportunities for further elaboration of the azide
unit. For example, azides are highly effective ammonia
surrogates. A Staudinger reduction of the azide in (‒)-4ae
proceeded efficiently to (‒)-5 in 91% yield with a phosphine resin
that facilitates product isolation (Figure 5A). This route to (‒)-5
is an appealing alternative to a recently reported route involving
Mn-catalyzed C–H amidation of 3ae with a sulfamate ester,
followed by reductive deprotection of the sulfamate to afford (‒
)-5 in 43% overall yield.29 Azides are also versatile precursors to
pharmaceutically important heterocycles. The formal synthesis of
Lipitor, 2, a lipid-lowering drug,50 was achieved via conversion
of azido compound 4t into the pyrrole precursor to Lipitor (6,
Figure 5B; cf. Figure 1).14,15 The anti-tuberculosis agent 7, used
against mycobacterium tuberculosis strain H37RV,
was
synthesized via copper-catalyzed alkyne-azide cycloaddition of
4n with m-methoxyphenylacetylene (Figure 5C).51 The related
[3+2]-cycloaddition of 4af with ethyl cyanoformate gave two
regioisomeric celestolide analogues (8 and 9) in quantitative yield
(Figure 5D).
The results described herein demonstrate that a copper-based
catalyst system composed entirely of commercially available
components enables selective benzylic C–H azidation with broad
scope. The reaction is initiated by hydrogen-atom transfer,
followed by reaction of the benzylic radical with a CuII-azide
intermediate. Experimental and computational data support a
radical-polar crossover pathway involving a benzylic cation. The
unique combination of good yields, diverse functional group
compatibility, and high benzylic site-selectivity make this
method well-suited for the incorporation of primary amines and
azide-derived heterocycles (pyrroles, triazoles, and tetrazoles)
into pharmaceutical and agrochemical building blocks,
intermediates, and existing bioactive molecules.
The azidation reaction was also used in late-stage
functionalization of drug molecules and derivatives. Examples
include azidation of precursors to sildenafil44 with a nitrogen
45
heterocycle (4y); dronedarone
with a benzofuran (4z);
canagliflozin46 with a thiophene (4aa), and the natural product
desoxyanisoin (4ab). 47 The tetrahydroquinoline of a GnRH
antagonist precursor led to reaction at the benzylic position (4ac),
with no byproduct observed from reaction adjacent to nitrogen.
The tetraacetate derivative of dapagliflozin 48 reacted at the
benzhydryl position, rather than the benzyl ether (4ad). Dehydro-
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Table 2. Scope of Alkylarene Benzylic C–H Azidationa,b
1
2.0 mol% Cu(OAc)2
4.0 mol% L4
3.6 equiv. TMS-N3
2.5 equiv. NFSI
2
3
4
5
H
N3
O
N
O
N
R
R
Bn
Bn
L4
0.2 M MeNO2
N2, 30 °C, 24 h
3
4
6
7
8
9
N3
(B)
N3
(T)
(B)
(B)
N3
N3
N3
N3
N3
N3
N3
H
H
(T)
MeO2C
H
(T)
Br
AcO
MeO
4h, 81%e
OMe
Me
4d, 62%d, (30:1)h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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43
44
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46
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49
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59
60
4a, 93%c
4b, 48%, (11:1)h
4e, 45%
4g, 56%
4c, 71%d, (25:1)h
4f, 61%d
4i, 57%e
N3
N3
N3
N3
N3
N3
N3
N3
N3
CN
Br
NC
O
F
F
4j, 25%c
4k, 51%c
4l, 60%
4m, 90%
4n, 85%
4o, 72%e
4p, 48%e
4q, 81% (1.7 g)
4r, 60%d
N3
F3C
N3
N3
N3
N3 CO2Et
CO2Et
O
O
EtO
N
N
N3
N
H
N3
HN
O
MeO
MeO
N
Br
N
Br
F
F
N
N
O
4s, 51%e
4t, 52% (1:1)f,h, d.r. (1:1)h
4u, 82%g,h
4v, 30%
4w, 30%c
4x, 65%e
Me
4y, 30%e
N3
N3
Br
N3 Cl
S
N3-precursor of sildenafil
F
(3° B)
N3
(2° B)
Me
MeO
Me
H
N
S
O
N3
O
(T)
Me
4aa, 36%d
O
O
EtO
N3
OAc
OAc
H
Me
NHTFA
N3-precursor of canagliflozin
OMe
O
AcO
O
N3
O2N
O2N
OAc
Cl
(–)-4ae, 62% (0.53 g)
(only 2° B), d.r. (6:1)h
N3-TFA-protected-
O
4z, 55%c
4ac, 42%d
4ad, 34%d,h, d.r. (1.4:1)
N3-dapagliflozin
tetraacetate
MeO
4af, 92% (1.25 g)
N3-precursor of
Dronedarone
4ab, 62%
N3-precursor of desoxyanisoin
N3-precursor of
N3-celestolide
GnRH antagonists
(–)-dehydroabietylamine
aSubstrate (0.4 mmol). bIsolated yield. cStandard condition at 50 °C for 16 h. dStandard condition for 48 h. eSubstrate (0.2 mmol), Cu(OAc)2 (6.0 mol%),
BiOx (12 mol%). fSubstrate (0.2 mmol), Cu(OAc)2 (1.0 mol%), BiOx (2.0 mol%), 24 °C. g60 °C for 48 h. h 1H NMR analysis.
Figure 5. Derivatization of azides to access primary amine in (‒)-dehydroabietylamine (A), pyrrole in Lipitor precursor (B), triazole in anti-
tuberculosis agent (C), and tetrazoles in celestolide analogues (D).
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Notes
ASSOCIATED CONTENT
Supporting Information.
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxxx
This work was supported by funding from the NIH (R01
GM126832 and R35 GM134929). Spectroscopic instrumentation
was supported by a gift from Paul. J. Bender, the NSF (CHE-
1048642), and the NIH (1S10 OD020022-1). Mukunda Mandal
acknowledges a doctoral dissertation fellowship from the
University of Minnesota. The authors thank Dr. Joshua A. Buss
for providing a sample of Gomberg’s dimer and Amelia M.
Wheaton for X-ray crystallographic assistance.
Experimental details with screening results, characterization
data, and NMR spectra (PDF), X-ray crystal structure data for
[(BPhen)CuII(N3)(µ-N3)]2 (CIF), and DFT computational
results, including xyz coordinates for computed structures.
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AUTHOR INFORMATION
Corresponding Author
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