Transient Directing Group Enabled Pd-Catalyzed γ-C(sp3)-H Oxygenation of Alkyl Amines

Article abstract of DOI:10.1021/acscatal.0c01310

We report a general protocol for γ-C(sp³)-H acyloxylation and alkoxylation of free amines using 2-hydroxynicotinaldehyde as the transient directing group. In the presence of an electrophilic fluorinating bystanding oxidant and acetic acid, a wide range of aliphatic amines could be oxygenated selectively at the γ-methyl positions. A vast variety of aryl, heteroaryl, and aliphatic acids could also be successfully coupled under this C-O bond formation reaction to afford amine-containing esters. Switching the nucleophile from acids to alcohols enables alkoxylation of free amines. Importantly, natural products and drug molecules such as ibuprofen, isoxepac, fenbufen, and lithocholic acid are all compatible coupling partners. Notably, synthesis of these monoprotected amino alcohols from free amino alcohols using conventional selective protection are not always feasible.

Full text of DOI:10.1021/acscatal.0c01310

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Letter
Transient Directing Group Enabled Pd-catalyzed
#-C(sp3)–H Oxygenation of Alkyl Amines
Yan-Qiao Chen, Yongwei Wu, Zhen Wang, Jennifer X Qiao, and Jin-Quan Yu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01310 • Publication Date (Web): 24 Apr 2020
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ACS Catalysis
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Transient Directing Group Enabled Pd-catalyzed -C(sp3)–H
Oxygenation of Alkyl Amines
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Yan-Qiao Chen†, Yongwei Wu†, Zhen Wang†, Jennifer X. Qiao§, Jin-Quan Yu*,†
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037.
§Discovery Chemistry, Bristol-Myers Squibb, PO Box 4000, Princeton, New Jersey 08543.
ABSTRACT: We report a general protocol for -C(sp3)–H acyloxylation and alkoxylation of free amines using 2-
hydroxynicotinaldehyde as the transient directing group. In the presence of an electrophilic fluorinating bystanding oxidant and acetic
acid, a wide range of aliphatic amines could be oxygenated selectively at the -methyl positions. A vast variety of aryl, heteroaryl,
and aliphatic acids could also be successfully coupled under this C–O bond formation reaction to afford amine containing esters.
Switching the nucleophile from acids to alcohols enables alkoxylation of free amines. Importantly, natural products and drug
molecules such as ibuprofen, isozepac, fenbufen, and lithocholic acid are all compatible coupling partners. Notably, synthesis of these
mono-protected amino alcohols from free amino alcohols using conventional selective protection are not always feasible.
KEYWORDS: Transient Directing Group, C(sp3)–H Activation, Palladium, C(sp3)–H Oxygenation, Bystanding Oxidant, Amine
One of the major challenges in directed C−H activation is
to enable the use of native substrates without covalently
installing external directing groups. While the combination of
weak coordination from substrates and ligand acceleration has
been successful in enabling a wide range of C−H activation
reactions of free carboxylic acids and Weinreb amides,1 the
development of catalytic transient directing groups (TDGs) for
aliphatic aldehydes, ketones, and free amines has emerged as a
complementary approach.2-5 While most of these reactions are
limited to (hetero)arylations,3-5 efforts to develop other C−X,
and C−O bond forming reactions have recently afforded new
advances.6 Using an electrophilic [F+] reagent as either the
bystanding oxidant or the fluorinating agent, we have recently
developed selective C−O and C−F bond formation reactions of
2-alkylbenzaldehydes via a novel amino amide transient
directing group (Scheme 1).6a Inspired by this development, we
have subsequently developed the first example of TDG enabled
-C(sp3)–H fluorination of free amines using similar [F+]
reagents (Scheme 2).6b Based on this particular investigation
and our previous studies of using [F+] as bystanding oxidant for
making C–C, C–N or C–O bonds,7 we decided to explore the
possibility of -oxidation of free amines using transient
directing groups.
amino alcohol derivative synthesis which requires protection
and deprotection of the amino group, our protocol features a
one-step coupling between a wide range of aliphatic amines and
a vast variety of acids and alcohols via selective CO bond
formation at the unactivated  positions.
via:
t-Bu
O
O
F
NEt2
O
cat. Pd(OAc)2
TDG
F3C
F3C
N
Pd
F3C
[F+]
OAc
H
OAc
Me
Me
RCO2H
Me
Scheme 1. TDG Enabled Acetoxylation of 2-
Alkylbenzaldehydes
R
via:
1F
R2
O
cat. Pd(OAc)2
TDG & Ligand
[F+];
Bz Protection
H
NH2
R1
F
NHBz
R1
N
O
Pd
R
N
R2
R2


3
N
R4
Scheme 2. Pyridone Assisted -C(sp3)–H Fluorination of
Free Amines
cat. Pd(OAc)2
PhI(OAc)2
Limited to amines
containing -quaternary
H
NH2
R1
R2
OAc NH2
R1
HOAc
centers


R2
Considering the synthetic utility, we began to develop -
acyloxylation with carboxylic acids and -etherification with
alcohols which could afford of mono-protected amino alcohols
that are not trivial to make. Although -C(sp3)–H acetoxylation
of amines have been reported before, most of these reactions
Scheme 3. Free Amine Directed -C(sp3)–H Acetoxylation
R
1F
via:
cat. Pd(OAc)2
TDG
H
NH2
R1
OR NH2
R1
N
O
require the installation of exogenous directing groups.8-9
A
Pd
[F+]


OAc
single example of free amine directed -C(sp3)–H acetoxylation
is limited to amines containing -quaternary centers (Scheme
3).10 Herein, we report a transient directing group strategy for -
C(sp3)–H oxygenation of broad range of free amines using N-
fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as the
bystanding oxidant (Scheme 4). Advantageous to traditional -
RCO2H or ROH
N
Scheme 4. This Work: TDG Enabled -C(sp3)–H
Acylocylation and Alkoxylation of Free Amines
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Table 1. Initial Studies and Reaction Optimization of -C(sp3)–H Acetoxylation of Aminesa,b
10 mol% Pd(OAc)2
NEt3
MeONH2 HCl;
TDG
X mol%
O
NHBz
NH2
H
X eq. oxidants
N
TDG
OH
R
OAc
5
6
HFIP:AcOH
70 oC, 12h
BzCl
R
1a
2a
7
Entry
Oxidants
Yield (%)
Reaction Conditions
8
9
1
2
1.50 eq. N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate
1.50 eq. N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate
1.50 eq. PhI(OAc)2
20 mol% TDG, HFIP:AcOH (19:1)
No TDG, HFIP:AcOH (19:1)
68 (63c)
<10
17
10
11
12
13
14
15
16
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18
19
20
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24
25
26
27
28
29
30
31
32
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
20 mol% TDG, HFIP:AcOH (19:1)
20 mol% TDG, HFIP:AcOH (19:1)
20 mol% TDG, HFIP:AcOH (19:1)
20 mol% TDG, HFIP:AcOH (19:1)
20 mol% TDG, HFIP:AcOH (19:1)
50 mol% TDG, HFIP:AcOH (19:1)
30 mol% TDG, HFIP:AcOH (2:1)
30 mol% TDG, HFIP:AcOH (19:1)
30 mol% TDG, HFIP:AcOH (2:1)
50 mol% TDG, HFIP:AcOH (19:1)
4
1.50 eq. H2O2
15
5
1.50 eq. AcOOtBu
21
6
1.50 eq. TBHP (5M in decane)
53
7
1.50 eq. K2S2O8
36
68 (67)c
8
2.0 eq. TBHP (5M in decane)
9
2.0 eq. K2S2O8 + 10 mol% (nBu)4NOAc
2.0 eq. N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate
2.0 eq. N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate
2.0 eq. N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate
66
10
11
12
89
89
94 (91)c
aExperiments were performed with substrate 1a (0.10 mmol), Pd(OAc)2 (0.01 mmol), TDG, oxidants, HFIP:AcOH (0.5 mL), 70 °C, 12 h. Yields were
b
determined by 1H NMR analysis of the crude product using 1,1,2,2-tetrachloroethane as the internal standard. cIsolated yields.
isobutylamine and even propylamine were also compatible
substrates for this reaction, affording the corresponding
products in 3070% yields (2g-i). Acetoxylation of trans-2-
methyl-cyclohexylamine could afford the product in 22% yield,
whereas the cis isomer was completely unreactive (2j). Since
AcOH was a good oxygen source for this protocol, we
wondered whether other acids could also be coupled similarly
for this reaction. We were pleased to find that -C(sp3)–H
oxygenation of 1a with a vast variety of aryl acids proceeded
smoothly with good to excellent yields (Table 3). Notably, no
acetoxylation product was observed in the presence of a
different carboxylic acid without AcOH in pure HFIP. Various
benzoic acids containing para and meta substituents, including
methyl, methoxy, trifluoromethyl, nitro, cyano, and halogens,
were well tolerated regardless of their electronic properties (2a1-
9). Ortho-substituted benzoic acids containing iodo or phenyl
groups provided the corresponding products in good to
excellent yields (2a10-12). Sterically demand-
We began our experimental efforts by testing -
acetoxylation of sec-butylamine (Table 1). Under similar
reaction conditions as our previous -methyl fluorination
conditions in a 19:1 mixture HFIP and AcOH,6b we were
pleased to find the desired acetoxylated product in 68% NMR
yield
when
N-fluoro-2,4,6-
trimethylpyridinium
tetrafluoroborate was used as the [F+] bystanding oxidant and
2-hydroxylnicotinaldehyde as the TDG (Table 1, entry 1). Only
less than 10% of the product was detected in the absence of
TDG, thus demonstrating the importance of TDG in this
acetoxylation reaction. (entry 2). Since we had already
established moderate reactivity with pyridinium salt, we
wondered whether other cheaper and more accessible oxidants
could also promote this reaction. When we changed the oxidant
to PhI(OAc)2 the yield lowered to only 17% (entry 3). Upon
evaluation of various peroxide-based oxidants, we discovered
that although H2O2 and AcOOtBu gave inferior yields of the
product in 15% and 21% respectively (entry 4-5), TBHP was an
effective oxidant for this reaction, providing the product in 53%
yield (entry 6). K2S2O8 was also identified as another potentially
effective oxidant for this reaction (entry 7). Unfortunately,
despite extensive reaction optimization, the reaction could only
be improved to around 70% yield using TBHP or K2S2O8 as the
oxidant (entry 8-9). Gratifyingly, the reaction could be further
optimized to above 90% isolated yield by increasing the loading
of the TDG with 2.0 eq. of N-fluoro-2,4,6-trimethylpyridinium
tetrafluoroborate (entry 10-12).
Table 2. Scope of Alkyl Amines for -C(sp3)–H
Acetoxylationa,b
Me
10 mol% Pd(OAc)2
NEt3
NHBz
BF4
Me
NH2
H
TDG
50 mol%
MeONH2 HCl;
R
OAc
OAc
OAc
HFIP:AcOH (19:1)
70 oC, 12h
BzCl
Me
N
F
R
1a-g
2a-g
NHBz
NHBz
NHBz
H3C
OAc
Me
OAc
AcO
c
c
2a
, 91%
2b
2c
, 42%
, 44%
With the optimized conditions in hand, we next
investigated the amine scope of this acetoxylation reaction
(Table 2). For ease of analysis and separation, the acetoxylated
products were isolated in the form of the Bz-protected amines.
While sec-butylamine could be acetoxylated in 91% isolated
yield (2a), the yield lowered to 44% when 3-aminohexane was
employed as the substrate (2b). For 3-aminopentane, the di-
acetoxylated product was obtained as the sole product in 42%
yield (2c). Various oxygen containing substrates could also be
acetoxylated in moderate yields (2d-f). Simple aliphatic amines
without -alkyl substituents such as 2-methylbutylamine,
NHBz
NHBz
NHBz
, 70%
MeO
BnO
OAc
OAc
OAc
MeO
2d
2e
2f
, 66%
, 72%
Me
AcO
BzHN
2g
BzHN
2i
, 30%
OAc
BzHN
Me
2h
, 70%
, 61%
NHBz
OAc
c
2j
, 22%
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ACS Catalysis
aExperiments were performed with substrate 1a (0.10 mmol), Pd(OAc)2
(0.01 mmol), TDG (0.05 mmol), N-fluoro 2,4,6-methylpyridinium
tetrafluoroborate (0.20 mmol), HFIP:AcOH (19:1) (0.5 mL), 70 °C, 16 h.
bIsolated yields. cReaction performed with 0.75 eq of TDG.
1
2
Table 3. Scope of Aromatic Acids for -C(sp3)–H Acyloxylation of Free Aminesa,b
3
4
5
6
10 mol% Pd(OAc)2
Me
TDG
50 mol%
NEt3
MeONH2 HCl;
O
NHBz
O
RCO H
NH2
H
1.5 eq
BF4
Me
2
N
TDG
OH
R
O
2a1-25
R
HFIP
BzCl
Me
N
F
R
70 oC, 12h
1a
7
8
9
ArCO2H
NHBz
NHBz
Me
O
NHBz
O
O
NHBz
O
NHBz
O
OMe
O
Me
O
Me
O
Me
O
Me
O
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
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46
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CF3
NO2
CN
Me
OMe
Cl
2a
2a
2a
2a
2a
1, 84%
2, 76%
3, 70%
4, 91%
O
5, 66%
NHBz
O
O
NHBz
O
O
NHBz
O
O
NHBz
NHBz
O
I
F
I
Me
Me
Me
Me
Me
O
Me
O
2a
2a
2a
2a
2a
10, 78%
6, 85%
7, 81%
8, 66%
9, 77%
Me
NHBz
O
O
OMe
NHBz
O
Br
NHBz
O
O
iPr
NHBz
O
Ph
Me
O
Me
Me
O
NHBz
O
O
MeO
13, 73%
Me
iPr
iPr
Me
O
2a
2a
2a
2a
2a
11, 86%
12, 70%
14, 93%
15, 74%
HetArCO2H
NHBz
NHBz
O
O
NHBz
O
O
F
O
O
NHBz
O
O
NHBz
O
CF3
N
N
CF3
F
Me
Me
N
Me
N
Me
Me
Me
Me
O
N
CF3
tBu
F
16, 55%c
17, 50%c
18, 70%c
1, 66%c
20, 82%c
2a
2a
2a
2a
2a
NHBz
Ph
O
O
S
NHBz
O
NHBz
O
Me
O
NHBz
O
NHBz
O
O
S
O
Me
O
Me
Me
O
Me
O
N
N
O
Me
21, 75%
22, 48%c
23, 73%
24, 80%
2a
2a
2a
2a
2a
25, 83%
aExperiments were performed with substrate 1a (0.10 mmol), Pd(OAc)2 (0.01 mmol), TDG (0.05 mmol), N-fluoro 2,4,6-methylpyridinium tetrafluoroborate
(0.20 mmol), HFIP (0.5 mL), 70 °C, 16 h. bIsolated yields. cReaction performed with 0.75 eq of TDG.
Table 4. Scope of Aliphatic Acids for -C(sp3)–H
Acyloxylation of Free Aminesa,b
Table 5. Scope of Aliphatic Alcohols for -C(sp3)–H
Alkoxylation of Free Aminesa,b
10 mol% Pd(OAc)2
Me
TDG
75 mol%
RCO H
NEt3
NHBz
O
NH2
H
1.5 eq.
Me
BF4
Me
MeONH2 HCl;
2
10 mol% Pd(OAc)2
100 mol%
NEt3
MeONH2 HCl;
R
O
2a26-36
R
HFIP
BzCl
NHBz
Me
N
F
R
NH2
H
BF4
Me
TDG
70 oC, 12h
1a
ROH
HFIP:
(19:1)
R
OR
BzCl
Me
N
F
R
70 oC, 16h
2a37-50
1a
Me
O
O
Me
BzHN
2a
O
NHBz
O
Primary Alcohols
BzHN
O
Me
O
NHBz
NHBz
NHBz
O
O
c
2a26
,
2a
28, 51%
67%
27, 70%
Me
OMe
37, 65%c
NHBz
Me
2a
OEt
38, 60%d
Me
O
2a
2a
39, 47%
NHBz
O
NHBz
O
Me
O
Ph
Me
Me
NHBz
NHBz
Me
O
Me
O
BzHN
O
Me
Me
O
Me
O
Me
2a
OBn
42, 52%
30, 60%d
2a
2a
31, 68%
29, 60%
2a
41, 37%c
2a
40, 41%
2a
Me
Me
Me
Secondary Alcohols
NHBz
O
O
Me
O
Me
NHBz
NHBz
NHBz
Me
Me
Me
O
Me
2a
OiPr
43, 45%
Me
O
Me
O
O
O
BzHN
O
BzHN
2a
2a
2a
45, 55%
O
44, 47%
O
32, 60%d
33, 51%e
34, 81%
2a
2a
NHBz
NHBz
NHBz
NHBz
O
NHBz
O
Cbz
N
O
Me
O
Me
O
Me
46, 55%e
48, 40%e
Me
O
2a
47, 45%
2a
2a
Me
O
N
Tertiary Alcohols
Fmoc
2a
36, 74%
NHBz
NHBz
2a
35, 58%
O
Me
Me
2a
OtBu
49, 23%e
aExperiments were performed with substrate 1a (0.10 mmol), Pd(OAc)2
(0.01 mmol), TDG (0.075 mmol), N-fluoro 2,4,6-methylpyridinium
tetrafluoroborate (0.20 mmol), HFIP (0.5 mL), 70 °C, 16 h. bIsolated yields.
cReaction performed with 0.5 eq of TDG. dReaction performed with 2.0 eq
of acid. eReaction performed with 1.0 eq of TDG.
50, 18%e
2a
aExperiments were performed with substrate 1a (0.10 mmol), Pd(OAc)
(0.01 mmol), TDG (0.1 mmol), N-fluoro 2,4,6-methylpyridinium
tetrafluoroborate (0.20 mmol), HFIP:ROH (19:1) (0.5 mL), 70 °C, 16 h.
bIsolated yields. cReaction performed with 0.75 eq TDG (0.075 mmol) and
0.5 eq of 5-chloro-3-nitropyridin-2-ol as the pyridone ligand. dReaction
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performed with 0.5 eq of TDG. eReaction performed with 1.0 eq TDG (0.1
mmol) and 0.5 eq of 5-chloro-3-nitropyridin-2-ol as the pyridone ligand.
2 mol% Pd(OAc)2
TDG
20 mol%
RCO H
NHBz
O
NEt3
MeONH2 HCl;
1.5 eq
1
2
R
R
O
HFIP
BzCl
70 oC, 72h
2
2a ,
4
82%
Me
NO2
NH2
H
BF4
Me
ing substrates such as 2,6-dimethoxy, 2-bromo-6-methyl, and
even2,4,6-triisopropyl benzoic acids were also well tolerated
(2a13-15). Importantly, heteroaryl acids containing pyridines
with different substitutions such as fluoro- and trifluoromethyl
groups are all compatible coupling partners, providing 5082%
yields (2a16-20). Coupling with other heteroaryl acids containing
thiophene, furan, chromene, and even pyrazole groups were
successfully accomplished with this protocol (2a21-25). Notably,
higher TDG loadings are used for certain heteroaryl acids
presumably to prevent catalyst poisoning by the heteroaryl
acids.
3
4
+
R
10 mol% Pd(OAc)2
Me
N
F
1a
TDG
50 mol%
RCO H
NEt3
MeONH2 HCl
NH2
O
1.5 eq
2
5
6
O
HFIP
70 oC, 12h
2a '
4 , 78%
NO2
Scheme 5. Catalyst Loading and Synthetic Applications
Table 6. Scope of Drug Derivativesa,b
7
8
9
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
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10 mol% Pd(OAc)2
Me
TDG1
75 mol%
NEt3
The scope of various aliphatic acids was investigated next
(Table 4). Primary aliphatic acid such as 2-norbornaneacetic
acid afforded the corresponding ester product in 67% isolated
yield (2a26). Secondary aliphatic acids containing oxygenated
functionalities and unsaturation were also tolerated in moderate
yields (2a27-29). Sterically demanding tertiary acids containing
tert-butyl, phenyl, and adamantyl groups were all coupled
successfully in 6068% islolated yields (2a30-32). Aliphatic
acids from natural products such as ketopinic acid and
camphanic acid afforded the corresponding products in 51%
and 81% respectively (2a33-34). Lastly, N-protected amino acids
could also be coupled under this protocol in good efficiencies
(2a35-36).
NHBz
O
RCO H
NH2
H
1.5 eq.
BF4
Me
MeONH2 HCl;
2
R
O
R
HFIP
BzCl
Me
N
F
R
70 oC, 12h
2a51-54
1a
O
Me
NHBz
O
NHBz
O
Me
Me
O
Me
O
Me
51, 73% (Ibuprofen)
O
2a
2a
52, 64% (Isozepac)
O
NHBz
Me
O
Me
NHBz
H
Me
Me
O
H
Me
O
H
H
O
2a
2a
54, 53% (lithocholic acid)
53, 65% (Fenbufen)
H
OH
Since the reaction was compatible with a vast range of
different carboxylic acids, we next wondered whether other
oxygen containing nucleophiles such as alcohols could also
serve as effective coupling partners for this reaction. We were
pleased to find that -C(sp3)–H oxygenation of 1a with a range
of aliphatic alcohols could also be accomplished, albeit in lower
efficiencies (Table 5). Primary alcohols such as methanol,
aExperiments were performed with substrate 1a (0.10 mmol), Pd(OAc)2
(0.01 mmol), TDG (0.075 mmol), N-fluoro 2,4,6-methylpyridinium
tetrafluoroborate (0.20 mmol), HFIP (0.5 mL), 70 °C, 16 h. bIsolated yields.
To demonstrate the synthetic utility of this -C(sp3)–H
oxygenation reaction, we were pleased to find that the catalyst
and TDG loading could be lowered to 2 mol% and 20 mol%
respectively, thus rendering our protocol highly efficient
(Scheme 5). In addition, the C–H oxygenated free amine
product could also be isolated in 78% yield. More importantly,
natural products and drug molecules such as ibuprofen,
isozepac, fenbufen, and lithocholic acid were all well tolerated
(Table 6), thus demonstrating this protocol’s potential to
perform late-stage functionalization and provide facile access
to amine containing drug analogs.
ethanol,
cyclobutylmethanol,
cyclopentylmethanol,
cyclohexylmethanol, and benzyl alcohol all underwent the
desired alkoxylation reaction in 3765% yields (2a37-42).
Secondary alcohols such as isopropanol, cyclobutanol,
cyclopentanol, cyclohexanol, cycloheptanol, and even 2-
adamantanol were also effective nucleophiles, affording the
hindered ethers in 4055% isolated yields (2a43-48). Remarkably,
even tertiary alcohols such as tBuOH, and 1-adamantanol were
competent nucleophiles to afford the highly hindered ethers in
23% and 18% isolated yields respectively with the aid of an
electron-deficient pyridone ligand (2a49-50). The ability to
perform C–H oxygenation with secondary and tertiary alcohols
provides a straight-forward method for the synthesis of
hindered aminoethers, which is difficult to achieve via
conventional approaches. Furthermore, we have also evaluated
other less reactive amines (1c-d, 1g-h, 1i) with methanol as the
coupling partner. The NMR yields of 1c and 1d were similar to
that of the model substrate 1a. Roughly 40% NMR yield of the
alkoxylated product was detected for 1g and 1h. Simple
propylamine (1i) with methanol only gave 10-15% NMR yields.
In summary, we have developed a general method for -
C(sp3)–H oxygenation of free aliphatic amines using 2-
hydroxynicotinaldehyde as the transient directing group and N-
fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as the [F+]
bystanding oxidant. This reaction features a wide amine scope
with good functional group tolerance. A vast range of aryl,
heteroaryl, and aliphatic acids, as well as primary, secondary,
and even tertiary alcohols are all compatible nucleophiles in this
-C(sp3)–H oxygenation reaction. Compared to traditional -
amino alcohol derivative synthesis which require protection and
deprotection of the amino group, our reaction provides facile
access to these compounds and even hindered ethers in a single
step. More importantly, natural products and drug molecules are
also competent coupling partners, thus demonstrating this
protocol’s potential for late-stage functionalization to access
amine containing drug analogs. Efforts in designing new TDG
and ligands to enable coupling of other nucleophiles are
currently underway in light of these developments.
AUTHOR INFORMATION
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Page 5 of 6
ACS Catalysis
Catalyzed C-H Functionalization. ChemSusChem. 2019, 12,
2955−2969.
Corresponding Author
1
2
3
4
5
6
7
8
* Email: yu200@scripps.edu
(3) For examples on TDG enabled C(sp3)–H (hetero)arylations on
Aldehydes: a) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-
Q. Functionalization of C(sp3)–H bonds using a transient directing
group. Science. 2016, 351, 252−256. b) Yang, K.; Li, Q.; Liu, Y.;
Li, G.; Ge, H. Catalytic C–H Arylation of Aliphatic Aldehydes
Enabled by a Transient Ligand. J. Am. Chem. Soc. 2016, 138,
12775−12778. c) Ma, F.; Lei, M.; Hu, L. Acetohydrazone: A
Transient Directing Group for Arylation of Unactivated C(sp3)–H
Bonds. Org. Lett. 2016, 18, 2708−2711. d) St, J.-C. S.; White, A.
J. P.; Bull, J. A. Single operation palladium catalysed C(sp3)–H
functionalisation of tertiary aldehydes: investigations into
transient imine directing groups. Chem. Sci. 2017, 8, 4840−4847.
e) Gou, B.; Liu, H.; Chen, J.; Zhou, L. Palladium-Catalyzed Site-
Selective C(sp3)–H Arylation of Phenylacetaldehydes. Org. Lett.
2019, 21, 7084−7088. f) Li, B.; Lawrence, B.; Li, G.; Ge, H.
Ligand-Controlled Direct -C-H Arylation of Aldehydes. Angew.
Chem. Int. Ed. 2020, 59, 30783082. g) Wen, F.; Li, Z.
Semicarbazideꢀ: A Transient Directing Group for C(sp3)H
Arylation of 2-Methylbenzaldehydes. Adv. Synth. Catal. 2020,
362, 133−138.
Supporting Information. Experimental procedures and
spectral data for all new compounds and full computational
data (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
ACKNOWLEDGMENT We gratefully acknowledge The
Scripps Research Institute, the NIH (NIGMS 5R01
GM084019), and Bristol-Myers Squibb for financial
support. Y-Q. C. thanks the NSF Graduate Research
Fellowships for financial support. Dr. Jason Chen, Emily
Strugell and Brittany Sanchez from the Scripps
Automated Synthesis Center are acknowledged for
guidance on analytical methods and DoE screening.
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(4) For examples on TDG enabled C(sp3)–H (hetero)arylations on
Ketones: a) Hong, K.; Park, H.; Yu, J.-Q. Methylene C(sp3)–H
Arylation of Aliphatic Ketones Using a Transient Directing
Group. ACS Catal. 2017, 7, 6938−6941. b) Wang, J.; Dong, C.;
Wu, L.; Xu, M.; Lin, J.; Wei, K. Palladium-Catalyzed β-C−H
Arylation of Ketones Using Amino Amide as a Transient
Directing Group: Applications to Synthesis of Phenanthridinone
Alkaloids. Adv. Synth. Catal. 2018, 360, 3709−3715. c) Dong, C.;
Wu, L.; Yao, J.; Wei, K. Palladium-Catalyzed β-C–H Arylation
of Aliphatic Aldehydes and Ketones Using Amino Amide as a
Transient Directing Group. Org. Lett. 2019, 21, 2085−2089.
(5) For examples on TDG enabled C(sp3)–H (hetero)arylations on
Amines: a) Wu, Y.; Chen, Y.-Q.; Liu, T.; Eastgate, M. D.; Yu, J.-
Q. Pd-Catalyzed γ-C(sp3)–H Arylation of Free Amines Using a
Transient Directing Group. J. Am. Chem. Soc. 2016, 138,
14554−14557. b) -C(sp3)−H arylation of 2-tert-butylaniline was
demonstrated: Xu, Y.; Young, M. C.; Wang, C.; Magness, D. M.;
Dong, G. Catalytic C(sp3)−H Arylation of Free Primary Amines
with an exo Directing Group Generated InꢁSitu. Angew. Chem. Int.
Ed. 2016, 55, 9084−9087. c) Liu, Y.; Ge, H. Site-selective C–H
arylation of primary aliphatic amines enabled by a catalytic
transient directing group. Nat. Chem. 2017, 9, 26−32. d) Yada, A.;
Liao, W.; Sato, Y.; Murakami, M. Buttressing Salicylaldehydes:
A Multipurpose Directing Group for C(sp3)−H Bond Activation.
Angew. Chem. Int. Ed. 2017, 56, 1073−1076. e) St John-Campbell,
S.; Ou, A. K.; Bull, J. A. Palladium-Catalyzed C(sp3)−H
Arylation of Primary Amines Using a Catalytic Alkyl Acetal to
Form a Transient Directing Group. Chem. Eur. J. 2018, 24,
17838−17843. f) Lin, H.; Wang, C.; Bannister, T. D.; Kamenecka,
T. M. Site-Selective γ-C(sp3)−H and γ-C(sp2)−H Arylation of
Free Amino Esters Promoted by a Catalytic Transient Directing
Group. Chem. Eur. J. 2018, 24, 9535−9541. g) Kapoor, M.; Liu,
D.; Young, M. C. Carbon Dioxide-Mediated C(sp3)-H Arylation
of Amine Substrates. J. Am. Chem. Soc. 2018, 140, 6818−6822.
(6) a) Park, H.; Verma, P.; Hong, K.; Yu, J.-Q. Controlling Pd(IV)
Reductive Elimination Pathways Enables Pd(II)-Catalysed
Enantioselective C(sp3)-H Fluorination. Nat. Chem. 2018, 10,
755−762. b) Chen, Y-Q.; Singh, S.; Wu, Y.; Wang, Z.; Qiao, J.;
Sunoj, R.; Yu, J-Q. Pd-catalyzed -C(sp3)–H Fluorination of Free
Amines. J. Am. Chem. Soc. 2020, under revision.
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Table of Contents
2 mol% Pd(II)
TDG
[F+]
CO2R or ROH
protection
H
NH2
R1
OR NH2
R1
OH NH2
R1
and
deprotection
sequence


65 examples
Up to 91% yield
R
via:
NHBz
O
1F
R2
N
NHBz
Me
Me
O
Pd
O
OAc
N
O
N
Fmoc
O
NHBz
O
NHBz
O
Me
O
tBu
Me
O
N
N
(Isozepac)
Me
O
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