Directed C-H Functionalization Reactions with a Picolinamide Directing Group: Ni-Catalyzed Cleavage and Byproduct Recycling

Article abstract of DOI:10.1021/acs.joc.9b02299

An efficient strategy for the cleavage of the picolinamide directing group (DG) and recycling of the byproduct generated has been developed. In this protocol, picolinamides were first Boc activated into tertiary N-Boc-N-substituted picolinamides. These were then cleaved via a Ni-catalyzed esterification reaction with EtOH to give valuable N-Boc protected amines. Ni(cod)₂ was used as a catalyst without any ligands or base additives. The byproduct, ethyl 2-picolinate can be used to install the picolinamide DG in a direct or indirect manner on amines. The protocol exhibits a broad functional group tolerance and high yields. To demonstrate the utility of this approach, it was applied on many selected examples from the recent C-H functionalization literature featuring 2-picolinamide as a DG.

Full text of DOI:10.1021/acs.joc.9b02299

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Article
Directed C-H Functionalization Reactions with a Picolinamide
Directing Group: Ni-Catalyzed Cleavage and By-Product Recycling
Sovan Biswas, Narendraprasad Reddy Bheemireddy, Mathias Bal, Ben F. Van Steijvoort, and Bert U. W. Maes
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02299 • Publication Date (Web): 16 Sep 2019
Downloaded from pubs.acs.org on September 16, 2019
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Directed C–H Functionalization Reactions with a Picolinamide Directing Group: Ni-
Catalyzed Cleavage and By-Product Recycling
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Sovan Biswas, Narendraprasad Reddy Bheemireddy, Mathias Bal, Ben F. Van Steijvoort, Bert U.
W. Maes*
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Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-
2020, Antwerp, Belgium
ABSTRACT: An efficient strategy for the cleavage of the picolinamide directing group (DG) and
recycling of the by-product generated has been developed. In this protocol, picolinamides were
first Boc activated into tertiary N-Boc-N-substituted picolinamides. These were then cleaved via a
Ni-catalyzed esterification reaction with EtOH to give valuable N-Boc protected amines. Ni(cod)2
was used as a catalyst without any ligands or base additives. The by-product, ethyl 2-picolinate
can be used to install the picolinamide DG in a direct or indirect manner on amines. The protocol
exhibits a broad functional group tolerance and high yields. To demonstrate the utility of this
approach, it was applied on a number of selected examples from the recent C−H functionalization
literature featuring 2-picolinamide as a DG.
Introduction
The use of a directing group (DG) in transition metal (TM)-catalyzed C–H bond functionalization
reactions provides a versatile approach for the efficient selective (regio, stereo) and step
economical synthesis of organic materials, agrochemicals, pharmaceuticals and complex natural
products.1,2 Various amide based mono- and bidentate DGs have been developed which are derived
from either carboxylic acid or amine substrates (Figure 1).3–6 Among those N,N-bidentate directing
groups, picolinamide (PA), introduced by Daugulis,3 has widely been used for regioselective C–
H bond functionalization of amines (alkylation,7 alkenylation,8 alkynylation,9 arylation,10
amination/amidation,11 acyloxylation,12 borylation,13 cyanation,14 trifluoromethylation,15 and
sulfonylation16 reactions). The picolinoyl moiety can be easily introduced on an amine substrate
by reaction with 2-picolinic acid in the presence of an activator (HATU, TBTU, EDCI, HOBt,
EtCO2Cl).7d,10d,11a,12a,16,17 After C–H bond functionalization, the PA auxiliary needs to be removed
to unlock the free amine functionality as the DG is usually not a desired functionality in the
reaction product. Unfortunately, the cleavage of this secondary amide is difficult due to the
inherent stability of the amide due to the conjugation between the carbonyl group and the nitrogen
atom.18
A) RCOOH derived:
O
B) RNH2 derived:
R2 R2
O
O
O O
S
R
R
N
R1
N
H
N
R
N
H
H
H
N
N
N
N
Carretero (2011)
Fernández Ibáñez
Daugulis (2005)
Daugulis (2005)
R2 = H: Chatani (2011)
R2 = Me: Shi (2013)
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Figure 1. Common N,N-bidentate (sulfon)amide based DGs for transition metal-catalyzed C–H
bond functionalization: Carboxylic acid derived (A) and amine derived (B).
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7
8
9
Over the past few years, several approaches have been developed for the removal of the PA
auxiliary. Known methodologies for the cleavage of this DG are shown in Figure 2A. Some of
these strategies have, besides on secondary, also been used for tertiary picolinamides. The most
common approach is the hydrolysis under basic condition (e.g. using NaOH in EtOH at 70
°C).7a,10b,10g,11b–f,19 Chen’s group introduced a modified picolinamide where a silylated
hydroxymethyl group is attached at the ortho position of the PA to facilitate its removal under
acidic condition. When the modified PA was treated with aq. HCl in MeOH at 80 °C, a furo[3,4-
b]pyridin-7(5H)-one is obtained upon amide cleavage allowing to recycle the auxiliary in moderate
yield.7b,10a,10c A number of examples are reported using acidic hydrolysis lacking this ortho
substituent.7d,15,20 However, then harsh conditions are required and therefore often lead to
functional group incompatibilities. The group of You and co-workers reported the deprotection of
the picolinamide group by treatment with boron trifluoride-diethyl etherate (BF3·Et2O), but the
harsh Lewis acidic nature of BF3 also limited its application.21 Other Lewis acid catalysts such as
AlCl3 were used as well.9 A reductive acidic cleavage (Zn, HCl) was disclosed by Maulide,10h
Carretero,8b and Spring22 but only limitedly studied. Daugulis treated a tertiary picolinoylamide
with LiEt3BH for PA removal.11a In one example, Shi’s group used PCl5/2,4-lutidine in the
presence of MeOH to obtain the corresponding imino ether via the formation of imidoyl chloride
intermediate, and subsequent aqueous work-up resulted in the free amine.23 Unfortunately, all
these methods have their own limitations with respect to functional group compatibility and can’t
be applied as a general approach for the cleavage of the PA moiety. Moreover, not all approaches
allow (easy) recycling of the picoline by-product derivative. Clearly a new mild (neutral
conditions) and generally applicable method would be desirable.
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In 2015 Garg reported the first oxidative addition of the C–N bond of an activated tertiary amide
to a transition metal complex.24,25a A Ni(cod)2/SIPr precatalytic system was applied for the
esterification of N-methyl-N-phenylarenecarboxamides. Subsequently, in 2016 the same group
disclosed that tertiary N-alkyl-N-Boc-alkanecarboxamides could also be used when using
Ni(cod)2/terpyridine.25b This extended the applicability significantly as both secondary N-
alkylalkane- and N-alkylarenecarboxamides can be activated for TM catalysis by simple
Bocylation.
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A) Known methods for PA DG removal:
acidic or basic hydrolysis
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BF3.Et2O (10.0 equiv), EtOH, 140 °C, 32 h
AlCl3 (1.0 equiv), nBuNH2 (excess), toluene, 90 °C, 24 h
Zn (15.0 equiv), HCl, Zn(OTf)2 (1.0 equiv), H2O/THF, rt, 1.5-16 h
LiEt3BH (4.0 equiv), THF, 0 °C-rt, 1 h
O
R
O
R1
H
R1
N
N
R3
+
R2
R2
N
N
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(i) PCl5 (2.0 equiv), 2,4-lutidine (3.0 equiv), CH2Cl2, 70 °C, 6 h
(ii) MeOH, 0-30 °C, overnight
R = H, CH2OTBS
O
(iii) H2O, rt, 1 h
O
N
when
R = CH2OTBS
B) This work: PA removal via Boc-activation and Ni-catalyzed esterification
H
R
O
R
H
O
O
O
C-H
R
H
R
N
R
R
HATU
Boc2O, DMAP
Et3N
functionalization
N
H
HO
N
H
N
H
+
Boc N
N
N
N
DIPEA
2
1
7
3
4
H
Ni(cod)2
EtOH
1. NaOH in THF
2. HCl, pH 2-3
La(OTf)3
R
H
N
O
R
1
H
EtO
R
H
+
N
N
Boc
6
5
9 examples
(yield
up to 87%)
9 examples
(yield
up to 96%)
Figure 2. Known picolinamide (PA) cleavage methods (A) and our approach (B).
We wondered whether such an approach could be used to cleave the picolinamide directing group
(Figure 2B). Secondary PA featuring a N–H (2/3) does not undergo C–N bond cleavage with
transition metal catalysts when unactivated and is therefore expected to be fully orthogonal with
the C–H functionalization reaction. After C–H functionalization, PA can be activated by a simple
Bocylation and subsequently be removed as ethyl 2-picolinate by a Ni-catalyzed esterification
reaction on tertiary N-Boc-N-substituted picolinamides (4) using EtOH. Ni-catalyzed reactions on
tertiary N-Boc-N-substituted amides are typically performed aiming to obtain carboxylic acid
derivatives and not N-Boc protected amines like in our case. Boc deprotection into target amines
can be easily obtained with strong acid or under thermal treatment.26a-b In addition, the carbamate
can also be directly transformed into another functional group.26c-f The by-product, ethyl 2-
picolinate (6) can be directly used as a precursor for DG installation by amidation under Lewis
acid catalysis. Alternatively, hydrolysis to picolinic acid (7) which is then coupled with amine
substrate making use of a (super)stoichiometric coupling agent can be opted.17
Ni-catalyzed esterification has only been used to cleave unactivated N-quinolin-8-yl amides by
employing NiII(tmhd)2, interestingly acting both as Lewis acid and Bronsted base, in methanol or
in a one-pot process with follow-up transesterification of crude methyl ester with another alcohol
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using a [(salen)FeIII]2O catalyst when other esters are required.27 Activated N-quinolin-8-yl-N-Boc
tertiary amides have been used in transamidations providing immediate access to a variety of N-
substituted amides and do not require Ni catalysis.28 Ni-catalyzed esterification on N-alkyl/aryl-N-
Boc picolinamides have to the best of our knowledge not been reported. Transamidations on these
substrates are not interesting when aiming by-product recycling. After all, though they can release
product amine, the picolinamide by-product generated will be very unreactive to use as a reactant
to install the PA DG, either directly via transamidation or indirectly via amide hydrolysis.
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Results and Discussion
In our previous work on diastereoselective remote directed C(sp3)–H arylation of 3-
aminopiperidines we have used a picolinamide as DG and demonstrated a basic hydrolysis (NaOH,
iPrOH, 82 °C) for the cleavage of the picolinamide in the tert-butyl cis-3-[pyridine-2-
carbonyl)amino]-5-arylpiperidine-1-carboxylate
reaction
products
(3a).10d
Though
chemoselective amide hydrolysis versus the carbamate protective group was obtained, these
reaction conditions are not compatible with a variety of functional groups present in the aryl group.
The feasibility of the proposed alternative two-step N-Bocylation and Ni-catalyzed esterification
protocol was therefore evaluated on model substrate 3a. Accordingly, we commenced this work
by optimizing the Boc activation reaction (Table 1). Our first attempt of Boc introduction on the
picolinoylamide nitrogen of 3a, following classical reaction conditions using Boc2O (1.5 eq.) and
a catalytic amount of 4-dimethylaminopyridine (DMAP) in acetonitrile at room temperature, was
not successful (Table 1 entry 1).29 We noticed that the substrate was not dissolved completely in
acetonitrile and the solution remained turbid even after 24 h of stirring leading to almost no
reaction. Changing the solvent to DCM resolved the solubility problem, but unfortunately did not
improve the overall yield (Table 1 entry 2). Interestingly, even when the reaction was performed
at reflux, the desired product 4a was only obtained in 7% yield (Table 1 entry 3). Use of other
solvents such as dimethyl carbonate (DMC) and tert-butanol did not deliver any desired product
(Table 1 entries 4–5). Use of an additional base (Et3N) and excess of Boc2O (4.0–9.0 equiv) was
not successful either (Table 1 entry 6–7).30 Eventually, using 9.0 equivalent of Boc2O, 1.1
equivalent Et3N and 0.2 eq. of DMAP at 50 °C in THF successfully yielded the desired product 4a
in 96% yield (Table 1 entry 8, Table 2 entry 1). Next, we applied the Ni-catalyzed esterification
reaction developed by Garg’s group [Ni(cod)2 (10 mol%), SIPr (10 mol%) and ethanol (2.0 equiv)
in toluene at 80 °C]25a on our model substrate 4a. To our satisfaction, the reaction gave quantitative
conversion of 4a to tert-butyl cis-3-[(tert-butoxycarbonyl)amino]-5-phenylpiperidine-1-
carboxylate (5a) (Table S1 entry 1). Surprisingly, when the reaction was performed without SIPr,
also full conversion of 4a was obtained to give 5a in 90% isolated yield (Table S1 entry 2, Table
2 entry 1). Gratifyingly, the by-product ethyl 2-picolinate (6) was obtained in 73% yield.
Application of the Co-catalyzed esterification reported by Gosmini and Danoun with
stoichiometric Mn as reductant in DMF/Pyridine gave complete conversion of 4a with ethanol but
only 33% isolated yield of 5a. Moreover only a trace amount of ethyl 2-picolinate (6) was isolated
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(Scheme S1).31 Ligandless Ni-catalyzed esterification with ethanol was therefore retained as
optimal for DG removal.
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Table 1. Optimization of the N-Bocylation of Picolinamide 3aa
8
9
H
N
Boc
N
O
O
Boc2O
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base
solvent
temp, time
N
N
N
N
Boc
Boc
3a
4a
Boc2O
(equiv)
Temp.
(°C)
Time
(h)
Isolated
yield 4a (%)
Entry
Base (equiv)
DMAP (0.1)
DMAP (0.2)
DMAP (0.2)
DMAP (0.2)
DMAP (0.2)
Solvent
1
2
3
4
5
6
7
8
1.5
2.0
2.0
2.0
2.0
4.0
9.0
9.0
CH3CN
DCM
rt
rt
24
21
17
17
17
17
24
24
trace
trace
DCM
40
85
40
rt
7b
DMC
no reaction
no reaction
trace
tert-BuOH
DCM
DMAP (0.2 eq.)
& Et3N (3.0 eq.)
DMAP (0.2 eq.)
& Et3N (1.1 eq.)
THF
rt
trace
DMAP (0.2 eq.)
& Et3N (1.1 eq.)
THF
50
96
a Conditions: 3a (0.2 mmol, 1.0 equiv), Boc2O, base, solvent (0.2 M), T, t. b 66% 3a was recovered.
We then selected two other cis-3-[(pyridine-2-carbonyl)amino]-5-arylpiperidines featuring
sensitive functional groups not compatible with the previously used basic hydrolysis (NaOH,
iPrOH, 82 °C).10d Benzyl cis-3-[(pyridine-2-carbonyl)amino]-5-[4-(ethoxycarbonyl)phenyl]-
piperidine-1-carboxylate (3b) and tert-butyl cis-3-[(pyridine-2-carbonyl)amino]-5-[1-
(benzenesulfonyl)-1H-indol-3-yl]piperidine-1-carboxylate (3c) respectively contain a hydrolysis
sensitive ester (PhCO2Et) and sulfonamide [PhSO2Nindole]. Gratifyingly, application of the two step
protocol delivered 3-[(tert-butyloxycarbonyl)amino]-5-arylpiperidines 5b and 5c in 92% and 83%
overall yield starting from 3b and 3c respectively (Table 2, entries 2 and 3). Interestingly to
specifically mention is that the use of a Cbz group on the piperidine nitrogen in 3b provides two
orthogonal protecting groups on the primary (Boc) and secondary amino (Cbz) group in the
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reaction product 5b, which is very useful for molecular library synthesis.32 The by-product 6 was
also in these cases easily recovered.
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In order to demonstrate the applicability of the protocol, we applied the optimized reaction
condition on a variety of other substrates beyond the 3-aminopiperidine core. The picolinamide
substrates 3d–i were synthesized by transition metal-catalyzed C(sp3/sp2)–H functionalization
reactions from 2 following literature protocols (see Supporting Information for details). These
functionalization involved directed arylation10d–e (Table 2 entries 1–3, 6), alkylation7b,7d (Table 2
entries 4–5), acetoxylation12a (Table 2 entry 7), arenesulfonylation16 (Table 2 entry 8) and
amidation11a (Table 2 entry 9). These substrates contain aliphatic esters (RCO2Me, RCO2Et,
BnOAc), ether (OtBu), silyl ethers (ArOTBS), ketones (ArCOMe), sulphonyl (PhSO2Napht),
halogens (chloro), and heteroarene (thiophene) functional groups. These are sensitive to common
acidic and/or basic hydrolysis reaction conditions, preventing classical PA cleavage, or pose
specific challenges for transition metal catalysis (chloro, benzyl acetate, thiophene). N-Bocylation
of substrates 3f–h gave the desired N-Boc tertiary amide products 4f–h with high to near-
quantitative yields (86–96%) under standard reaction condition (50 °C, 0.2 equiv DMAP and 1.1
equiv Et3N) (Table 2 entries 6–8). Both picolinamides derived from aliphatic and aromatic amines
could be used. Only the sterically hindered amino acid derivatives (3d–e) required a higher
reaction temperature (80 °C) and increased amount of Et3N (3.0–4.0 equiv) and DMAP (0.4 equiv),
giving 63% and 96% isolated yields of the desired products 4d and 4e respectively (Table 2 entries
4-5). All these activated picolinamide substrates could be esterified with ethanol under the standard
esterification conditions [Ni(cod)2 (10 mol%) and ethanol (2.0 equiv), toluene, 80 °C, 15 h].
Substrate 4d containing CO2Et, CO2Me, and a bulky O-tBu functional group, obtained via directed
Pd-catalyzed alkylation of methyl O-(tert-butyl)-N-picolinoyl-L-threoninate (2d) with ethyl
iodoacetate followed by N-Bocylation, gave the corresponding N-Boc-amine 5d in 94% and ethyl
picolinate (6) in 81% yield (Table 2 entry 4). No epimerization occurred at the α-position of the
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amino acid derivative 5d since only one set of peaks were observed in H and C NMR (see
spectra in the SI). Interestingly, the bis methylated tyrosine derived picolinamide 4e containing the
acid/base labile OTBS functional group was also well tolerated and gave N-Boc-amine 5e in 82%
yield and 6 in 72% yield (Table 2 entry 5). tert-Butyl {[3-(4-acetylphenyl)thiophen-2-
yl]methyl}(picolinoyl)carbamate (3f) gave 5f in 69% overall yield without affecting the keto
group, and the thiophene moiety did not hamper Ni catalysis (Table 2 entry 6). Ethyl picolinate (6)
was recovered in 72% yield. Furthermore, substrates 4g–h derived from aromatic amines (aniline
and 1-naphthylamine) featuring acetate ester, chloro and SO2Ph groups also proved to be viable
substrates (Table 2 entries 7–8).
Tertiary amide substrate (3-phenyl-2,3-dihydro-1H-indol-1-yl)(pyridin-2-yl)methanone (3i)
obtained via directed Pd-catalyzed amidation of N-(2,2-diphenylethyl)picolinamide (2i) cannot be
activated via Bocylation. However, N-methyl-N-phenylarenecarboxamides are also known to be
reactive towards oxidative addition.25a When we applied our standard reaction condition (without
SIPr), only 30% conversion of 3i was obtained (Table S2 entry 1). The cleavage of N-
benzoylindoline with methanol by the Garg group gave indoline in 58% yield using the
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Ni(cod)2/SIPr system.25a Further optimization (Table S2) revealed that a ligand was beneficial in
this case. With Ni(cod)2 (15 mol%), terpyridine (15 mol%),25b EtOH (30.0 equiv) at 100 °C for 20
h, an optimal yield of 5i was obtained (80%) with 63% by-product 6 (Table S2 entry 10, Table 2
entry 9).
9
Table 2. Scope of the Boc activation and subsequent Ni-catalyzed cleavage of N-Boc
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Picolinamides (4) with EtOH.
DMAP (0.2 equiv)
Boc2O (9.0 equiv)
Et3N (1.1 equiv)
R
R
R
O
O
O
Ni(cod)2 (10 mol%)
EtOH (2.0 equiv)
R
R
R
H
N
H
N
N
EtO
+
N
Boc N
Boc
N
THF, 50 °C, 24 h
toluene, 80 °C, 15 h
5
3
4
6
Yield
of 4
Yield
of 5
(%)c
Yield
of 6
Entry
1
3
N-Boc picolinamides (4)a
N-Boc amines (5)
(%)b
(%)
Boc
N
N
Boc
N
H
3a
96
96
90
96
73
87
O
N
N
4a
5a
Boc
Boc
EtO2C
EtO2C
Boc
N
N
Boc
N
H
2
3b
O
N
N
5b
4b
Cbz
Cbz
PhO2S
PhO2S
N
N
Boc
N
N
Boc
N
H
3
4
5
3c
3d
3e
97
63d
96e
86
94
82
74
81
72
O
N
N
5c
4c
Boc
Boc
O
CO2Me
CO2Me
CO2Et
H
N
CO2Et
5d
N
N
Boc O
Boc O
4d
Boc
Boc
N
MeO2C
N
O
N
MeO2C
H
Si
Si
5e
O
O
4e
H
N
O
N
Boc
N
S
6
3f
86
80
72
Boc
O
S
O
5f
4f
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O
O
Boc
N
N
Boc
N
O
O
H
7
8
3g
3h
96
91
91
75
70
O
5g
4g
Cl
Boc
Cl
N
O
Boc
O
H
O
N
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N
92
S
O
S
O
5h
4h
Ph
Ph
9f
3i
-
80g
63g
N
N
5i
O
H
3i
N
a
b
The wavy bond in 4 represents where the C–H functionalization has been performed.
Conditions: 3a–h (2.25–14.71 mmol, 1.0 equiv), DMAP (0.2 equiv), Boc2O (9.0 equiv), Et3N (1.1
equiv), THF (0.2 M), 50 °C, 24 h. c Conditions: 4a–h (0.15–1.20 mmol, 1.0 equiv), Ni(cod)2 (10
mol%), EtOH (2.0 equiv), toluene (1.0 M), 80 °C, 15 h. d DMAP (0.4 equiv), Et3N (3.0 equiv), 80
°C. 31% of 3d was recovered. e DMAP (0.4 equiv), Et3N (4.0 equiv), 80 °C. f Reaction product is
a tertiary amide, so N-Bocylation was not required. g Conditions: 3i (0.2 mmol, 1.0 equiv), Ni(cod)2
(15 mol%), terpyridine (15 mol%), EtOH (30.0 equiv), toluene (0.2 mL), 100 °C, 20 h; 8% 3i was
recovered.
Finally, we explored whether the recovered ethyl picolinate (6) could immediately be used as a
precursor for the DG introduction by reacting it with amines 1 in the presence of La(OTf)3 catalyst
without solvent based on a protocol disclosed by Oshima.33 This gives immediately access to the
substrates 2 for transition metal-catalyzed C(sp3/sp2)–H functionalization. The reaction was
optimized on tert-butyl 3-aminopiperidine-1-carboxylate (1a) which is the precursor for substrate
3a and 3c (see supporting information Table S3). The reaction temperature was kept above the
melting point of the desired product 2a, to avoid solidification upon product formation. The
reaction of 1a (1.0 equiv) with ethyl picolinate 6 (1.0 equiv) at 100 °C under neat condition gave
70% isolated yield of 2a (Table 3 entry 1). Similarly, the reaction of 1b with 6 yielded 2b in 71%
yield (Table 3 entry 2), this time requiring at 130 °C due to the higher melting point of 2b. With
these gratifying results, we applied the reaction condition on some other amines including aromatic
and aliphatic primary amines 1. On H-Thr(tBu)-OMe (1d) the required reaction temperature to
obtain a liquid is unfortunately too high to avoid epimerization (Table 3 entry 3). Moreover a low
yield of target compound was obtained. 5-Chloro-2-methylaniline (1g) provided a low yield under
the standard conditions (Table 3 entry 4). An additional base (DBU) was therefore used to increase
the nucleophilicity of the aromatic amine substrate 1g and a slight excess of 6 was also required to
get full conversion (Table 3 entries 5–6). Eventually, the product 2g was obtained in 77% isolated
yield using 1.2 equiv of 6 and 2.0 equiv of DBU after 22 h (Table 3 entry 6).
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Table 3. Amidation of ethyl 2-picolinate (6) and 2-picolinic acid (7) with amines (1)
5
6
7
8
La-catalyzed amidation
of ester 6
Amidation of 7
with coupling agents
H
O
H
O
H
O
La(OTf)3 (5 mol%)
(base)
HATU (1.1 equiv)
DIPEA (2.0 equiv)
R
R
H
R
H
EtO
HO
N
H
+
+
9
N
H
N
H
neat
temp, time
N
N
DCM, rt, 18 h
N
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1
6
2
1
7
(1.0 equiv)
(1.0 equiv)
(1.0 equiv)
(1.1 equiv)
Classical
reaction
Yield of 2
(%)b
La-catalyzed amidation reaction
Entry
Amines 1
Yield of 2
Temp (° C)
100
Time (h)
Base
(%)a
H
N
H
1
24
No
70
96
N
1a
Boc
H
N
H
2
3
4
5
6
130
130
120
120
120
24
18
18
18
22
No
No
No
71
30
94
82c
88
88
88
N
1b
Cbz
CO2Me
H
N
H
O
1d
CH3
H
N
H
H
H
27
1g
Cl
CH3
H
N
DBU
(1.0 equiv)
49d
77d
1g
Cl
CH3
H
N
DBU
(2.0 equiv)
1g
Cl
a
Isolated yields. Conditions: 1 (1.0 mmol, 1.0 equiv), 6 (1.0 equiv), with or without DBU,
La(OTf)3 (5 mol%). Conditions: 1 (1.0 equiv), 7 (1.1 equiv), HATU (1.1 equiv), DIPEA (2.0
b
equiv), DCM, rt, 18 h. c 1d·HCl was used. d 1.2 equiv of 6 was used.
Although the direct La-catalyzed amidation reaction of ethyl 2-picolinote (6) with amines 1 is
inherently very attractive, it required a reaction temperature above the melting point of product 2
due to the absence of solvent sometimes avoiding applicability. We therefore also looked into the
hydrolysis of 6 into 2-picolinic acid (7) (Scheme 1).34 As 2-picolinic acid (7) has been used to
prepare all PA substrates 2 via coupling with the corresponding amines 1 (see supporting
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information and Table 3), it provided an indirect DG recycling strategy. In principle use of water
instead of EtOH to cleave 4, providing immediate access to 7, would also be interesting.
Unfortunately, a reaction starting from model substrate 3a proved this approach does not work and
only substrate was identified, which is not surprising based on the known sensitivity of Ni(cod)2.35
9
Scheme 1. Hydrolysis of ethyl 2-picolinate (6) and recycling of 2-picolinic acid (7)
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See Table 3
H
1. NaOH (6.6 M, 5.0 equiv)
THF (6.0 mL)
HATU (1.1 equiv)
DIPEA (2.0 equiv)
DCM, rt, 18 h
O
O
O
R
0 °C-rt, 15 h
HO
EtO
N
H
N
N
N
H
2. HCl (1 M), pH 2-3
96%
6
R
H
7
2
N
H
1
Conclusion
In conclusion, an efficient two-step protocol for the cleavage of the picolinamide directing group
has been developed. The protocol consists of activation via Bocylation followed by Ni-catalyzed
esterification of N-Boc-picolinamide with ethanol under neutral reaction conditions. N-Boc
protected amines were isolated in good to excellent yields. A broad range of sensitive functional
groups were well tolerated under these reaction conditions. Additionally, the by-product ethyl 2-
picolinate formed upon DG cleavage was recovered in good yields and a direct and indirect
recycling strategy has been disclosed. It can be expected that the newly developed picolinamide
DG cleavage procedure can be applied on other well-known amide based directing groups.
EXPERIMENTAL SECTION
General Considerations
All chemicals and solvents were used as obtained by their respective suppliers, unless otherwise
noted. In particular, acetone (99.5+%), dichloromethane (99.8+%), ethyl acetate (99.8+%), ethanol
(99.8%), toluene (99.85%, extra dry over molecular sieve) and commercial heptanes (extra pure,
used as an eluent in chromatographic purification) were purchased from a commercial source. The
latter was distilled prior to use. Ethanol was dried over activated molecular sieve for at least two
days prior to use. Water was deionized using a EUROTEC L4 reverse osmosis system. The used
water had a conductivity of max. 0.5 μS/cm.
Chromatographic purification was performed using an automated flash chromatography Biotage
system utilizing commercially available Silica Flash Cartridges (12, 40 or 80 g) at a flow rate of
20–30 mL/min. TLC analysis was performed using pre-coated TLC aluminium sheets
ALUGRAM® SIL G/UV254 (layer: 0.20 mm silica gel with fluorescent indicator UV254). The spots
were detected with UV light at 254 nm. Melting points were measured on a Melting Point B-545
apparatus and are uncorrected.
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Nuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker Avance 400 Fourier
Transform NMR spectrometer in CDCl3 at 303 K (unless stated otherwise). Samples were prepared
using ca. 10–30 mg of compound dissolved in 1.0 mL of deuterated solvents (CDCl3 or DMSO-
d6). All spectra were referenced either to the TMS reference peak (δ = 0.00 ppm for both 1H and
13C in CDCl3) or solvent residual peak (δ = 2.51 and 40.02 ppm for H and C respectively in
DMSO-d6). Chemical shifts (δ) are reported in ppm; coupling constants (J) are reported in Hz;
splitting patterns are assigned as s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet,
quin = quintet, or combinations thereof.
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High resolution mass spectrometry (HRMS) samples were prepared by dissolving 0.1–5.0 mg of
the compound in methanol and further diluting to a concentration of 10-5–10-6 M with 50%
methanol/50% H2O/0.1% formic acid. The samples were injected in the MS using a CapLC system
and a nanoelectrospray source operated in positive ion mode at a potential of 1.5 or 1.7 kV. The
eluent used was 30% A (0.1% formic acid in H2O) and 70% B (0.1% formic acid in CH3CN/H2O-
95/5) at a flow rate of 6.0 mL/min. Samples were injected with an interval of 3 min. Before
analysis, 2.0 mL of a 0.025% H3PO4 solution (MeOH/H2O-50/50) or 10.0 mL of 10-6M
deoxyadenosine solution (MeOH/H2O-50/50) was injected as a lock mass. Positive ion mode
accurate mass spectra were acquired using a Q-TOF instrument.
Synthetic Procedures and Characterization Data
General Procedure A (Boc activation of picolinamide)
A roundbottom flask was charged with Boc2O (9.0 equiv), 2-picolinamide substrate 3a-h (1.0
equiv), DMAP (0.2–0.4 equiv), anhydrous THF (5.0 mL/1.0 mmol) and Et3N (1.1–4.0 equiv). The
flask was attached to a reflux condensor and stirred at 50–80 °C (oil bath) for 24 h under argon
(balloon). Upon completion, volatiles were removed under reduced pressure. The crude was
diluted with DCM (1x20.0 mL/mmol) and washed with brine (1x20.0 mL/mmol). The organic
layer was separated, dried over MgSO4, filtered, evaporated to dryness and purified by automated
flash chromatography using heptane/EtOAc as eluent.
General Procedure B (Ni-catalyzed picolinamide esterification)
An oven dried 10 mL pressure vial containing N-Boc-picolinamide substrate 4a-h (1.0 equiv) was
charged with Ni(cod)2 (10 mol%) in a glovebox. The vial was sealed with an aluminium crimp cap
and removed from the glovebox. Then, toluene (1.0 mL/1.0 mmol) and ethanol (2.0 equiv) were
added into the sealed vial under argon (balloon). The closed reaction vial was inserted into an oil
bath, preheated at 80 °C, and stirred for 15 h. After cooling to room temperature, the reaction
mixture was diluted with DCM (5.0 mL), stirred for 10 min, filtered through a celite bed and
washed thoroughly with DCM (30.0 mL). The filtrate was evaporated to dryness under reduced
pressure to obtain the crude, which was purified by automated flash chromatography using
heptane/EtOAc as eluent.
General Procedure C (La-catalyzed DG introduction via amidation of ethyl 2-picolinate)
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The reaction was performed based on a literature procedure.33 To a Schlenk flask equipped with a
stir bar was added La(OTf)3 (5 mol%) and the flask was then flame-dried under vacuum. After
cooling to room temperature, the flask was backfilled with argon. Subsequently ethyl 2-picolinate
6 (1.0 equiv) and an amine substrate 1 (1.0 equiv) were added in air, then the flask was flushed
with argon and closed. The mixture was stirred at the required temperature for 18–24 h (Table 3).
After completion of the reaction time the reaction was allowed to cool to room temperature. The
crude was diluted with DCM (20.0 mL/mmol) and washed with brine (20.0 mL/mmol). The
organic layer was separated, dried over MgSO4, filtered, evaporated to dryness and purified by
automated flash chromatography using heptane/EtOAc as eluent.
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Compounds 2a,10d 2b,10d 2d,11b 2e,7d 2f,10e 2g,12a 2h,7c 2i,11a 3a,10d 3c,10d 3d,7b 3e,7d 3f,10e 3h,16 3i11a
were synthesized following the respective literature procedures (see SI for schemes, yields and
NMR spectra).
Benzyl
cis-3-[4-(methoxycarbonyl)phenyl]-5-[(pyridine-2-carbonyl)amino]piperidine-1-
carboxylate (3b) (SBI-079)
A pressure vial (10 mL) equipped with a magnetic stirring bar was charged with phenyl 3-
[(pyridine-2-carbonyl)amino]piperidine-1-carboxylate 2b (0.14 g, 0.40 mmol, 1.0 equiv), Ag2CO3
(0.11 g, 0.40 mmol, 1.0 equiv), 2,6-dimethylbenzoicacid (15.0 mg, 0.10 mmol, 0.25 equiv),
Pd(OAc)2 (9.0 mg, 0.04 mmol, 10 mol%), methyl 4-iodobenzoate (0.63 g, 2.40 mmol, 6.0 equiv).
All manipulations were performed in air. The vessel was flushed with argon, sealed with an
aluminum crimp cap and a securing metal clamp, and was placed in an oil bath preheated to 120
°C and stirred for 24 h. Additionally, the oil bath was covered with aluminum foil to avoid contact
with light. After the reaction time, the reaction vessel was removed from the oil bath, cooled to
room temperature, diluted with DCM (5.0 mL), stirred for 15 min, and filtered through a pad of
Celite, which was additionally rinsed with DCM till the washings became transparent (approx.
50.0 mL). The filtrate was concentrated under reduced pressure. The resulting crude residue was
purified by automated flash chromatography (SiO2, 80 g cartridge, 100% heptane isocratic over 5
min followed by 100% heptane to 50% heptane/50% EtOAc over 90 min followed by 50%
heptane/50% EtOAc isocratic over 10 min, 25 mL/min) to give the title compound 3b as a white
solid (0.15 g, 78%). No spectroscopic data available in literature.
mp 125–127 °C. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.5 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H),
8.01–7.98 (m, 3H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.44–7.30 (m, 8H), 5.23-5.14 (m, 2H), 4.58 (d,
J = 10.8 Hz, 1H), 4.38 (br s, 1H), 4.28–4.18 (m, 1H), 3.90 (s, 3H), 2.99 (t, J = 11.5 Hz, 1H), 2.78
13
(t, J = 11.9 Hz, 2H), 2.44–2.38 (m, 1H), 1.75 (q, J = 12.1 Hz, 1H) ppm. C NMR (101 MHz,
CDCl3) δ 166.8 (C), 163.8 (C), 155.1 (C), 149.6 (C), 148.0 (CH), 146.7 (C), 137.4 (CH), 136.6
(C), 130.0 (CH), 129.0 (C), 128.5 (CH), 128.1 (CH), 128.0 (CH), 127.1 (CH), 126.4 (CH), 122.3
(CH), 67.5 (CH2), 52.1 (CH3), 49.6 (CH2), 48.3 (CH2), 46.0 (CH), 41.4 (CH), 38.0 (CH2) ppm.
HRMS (ESI) for C27H28N3O5 [M+H]+ calcd. 474.2023, found 474.2035.
{4-Chloro-2-[(pyridine-2-carbonyl)amino]phenyl}methyl acetate (3g) (NPR-238)
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A mixture of N-(5-chloro-2-methylphenyl)picolinamide 2g (0.60 g, 2.43 mmol, 1.0 equiv),
Pd(OAc)2 (55.0 mg, 0.24 mmol, 0.1 equiv), and PhI(OAc)2 (1.96 g, 6.08 mmol, 2.5 equiv) in
anhydrous toluene (16.0 mL) was mixed in a 50 mL pressure tube (purged with argon, sealed with
screw cap) and heated at 110 °C for 20 hours. The reaction mixture was allowed to cool to room
temperature, and was diluted with DCM (40.0 mL). After filtration through celite, the filtrate was
concentrated in vacuum and subsequently purified by automated flash chromatography (SiO2, 40
g cartridge, 90% heptane/10% EtOAc isocratic over 20 min followed by 90% heptane/10% EtOAc
to 85% heptane/15% EtOAc over 20 min, followed by 85% heptane/15% EtOAc to 50%
heptane/50% EtOAc over 15 min, 30 mL/min) to give the title compound 3g as a white solid (0.40
g, 62%).
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mp 107–109 °C (No data in the literature); 1H NMR (400 MHz, CDCl3) δ 10.64 (br s, 1H), 8.62–
8.60 (m, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.93 (td, J = 7.7, 1.7 Hz, 1H), 7.50
(ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.13 (dd, J = 8.2, 2.1 Hz, 1H), 5.17 (s
13
2H), 2.19 (s, 3H) ppm; C NMR (101 MHz, CDCl3) δ 170.6 (C), 162.3 (C), 149.6 (C), 148.2
(CH), 138.0 (C), 137.8 (CH), 135.5 (C), 131.3 (CH), 126.7 (CH), 124.5 (CH), 124.0 (C), 122.7
(CH), 122.2 (CH), 63.8 (CH2), 20.8 (CH3) ppm; HRMS (ESI) for C15H14ClN2O3 [M+H]+calcd.
305.0687, found 305.0698.
tert-Butyl cis-3-[(tert-butoxycarbonyl)(pyridine-2-carbonyl)amino]-5-phenylpiperidine-1-
carboxylate (4a) (SBI-065)
The title compound was synthesized using Boc2O (1.18 g, 5.40 mmol, 9.0 equiv), amide 3a (0.23
g, 0.60 mmol, 1.0 equiv), DMAP (15.0 mg, 0.12 mmol, 0.2 equiv), Et3N (92 μL, 0.66 mmol, 1.1
equiv) and THF (3.0 mL) at 50 °C following the general procedure A. The resulting crude residue
was purified by automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic
over 5 min followed by 100% heptane to 60% heptane/40% EtOAc over 45 min, 25 mL/min) to
give the title compound 4a as a white solid (0.28 g, 96%). No spectroscopic data available in
literature.
mp 140-141 °C. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 4.4 Hz, 1H), 7.80 (td, J = 7.6, 1.7 Hz,
1H), 7.74 (d, J = 7.7 Hz, 1H), 7.38 (ddd, J = 7.4, 4.8, 1.4 Hz, 1H), 7.32–7.20 (m, 5H), 4.59 (tt, J =
11.8, 4.1 Hz, 1H), 4.26 (s, 2H), 3.52 (t, J = 11.0 Hz, 1H), 2.92–2.86 (m, 1H), 2.77 (s, 1H), 2.49 (q,
J = 12.2 Hz, 1H), 2.17 (d, J = 12.3 Hz, 1H), 1.48 (s, 9H), 1.16 (s, 9H) ppm. 13C NMR (101 MHz,
CDCl3) δ 171.5 (C), 154.7 (C), 154.4 (C), 153.1 (C), 148.3 (CH), 142.1 (C), 136.9 (CH), 128.6
(CH), 127.2 (CH), 126.8 (CH), 125.6 (CH), 123.1 (CH), 83.3 (C), 80.0 (C), 53.5 (CH), 49.8 (CH2),
46.2 (CH2), 42.8 (CH), 34.9 (CH2), 28.5 (CH3), 27.4 (CH3) ppm. HRMS (ESI) for C27H36N3O5
[M+H]+ calcd. 482.2649, found 482.2661.
Benzyl
cis-3-[(tert-butoxycarbonyl)(pyridine-2-carbonyl)amino]-5-[4-
(methoxycarbonyl)phenyl]piperidine-1-carboxylate (4b) (SBI-081)
The title compound was synthesized using Boc2O (1.18 g, 5.40 mmol, 9.0 equiv), amide 3b (0.28
g, 0.60 mmol, 1.0 equiv), DMAP (15.0 mg, 0.12 mmol, 0.2 equiv), Et3N (92 μL, 0.66 mmol, 1.1
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equiv) and THF (3.0 mL) at 50 °C following the general procedure A. The resulting crude residue
was purified by automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic
over 5 min followed by 100% heptane to 50% heptane/50% EtOAc over 40 min followed by 50%
heptane/50% EtOAc isocratic over 15 min, 25 mL/min) to give the title compound 4b as a white
solid (0.33 g, 96%). No spectroscopic data available in literature.
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mp 63-64 °C. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 7.9 Hz, 2H),
7.80 (t, J = 7.2 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.41–7.31 (m, 8H), 5.17 (s, 2H), 4.63 (t, J = 10.9
Hz, 1H), 4.37 (s, 2H), 3.89 (s, 3H), 3.63 (s, 1H), 2.98–2.87 (m, 2H), 2.62–2.51 (m, 1H), 2.19 (d, J
= 11.9 Hz, 1H), 1.14 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 171.6 (C), 166.8 (C), 155.2 (C),
154.3 (C), 152.9 (C), 148.3 (CH), 146.9 (C), 136.9 (CH), 136.7 (C), 130.0 (CH), 128.9 (C), 128.5
(CH), 128.0 (CH), 127.9 (CH), 127.3 (CH), 125.7 (CH), 123.2 (CH), 83.5 (C), 67.4 (CH2), 53.2
(CH), 52.0 (CH3), 49.6 (CH2), 46.2 (CH2), 42.6 (CH), 34.5 (CH2), 27.3 (CH3) ppm. HRMS (ESI)
for C32H36N3O7 [M+H]+ calcd. 574.2548, found 574.2542.
tert-Butyl cis-3-[(tert-butoxycarbonyl)(pyridine-2-carbonyl)amino]-5-[1-(benzenesulfonyl)-
1H-indol-3-yl]piperidine-1-carboxylate (4c) (SBI-194)
The title compound was synthesized using Boc2O (0.49 g, 2.25 mmol, 9.0 equiv), amide 3c (0.14
g, 0.25 mmol, 1.0 equiv), DMAP (6.10 mg, 0.05 mmol, 0.2 equiv), Et3N (38 μL, 0.28 mmol, 1.1
equiv) and THF (1.25 mL) at 50 °C following the general procedure A. The resulting crude residue
was purified by automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic
over 5 min followed by 100% heptane to 50% heptane/50% EtOAc over 60 min, 25 mL/min) to
give the title compound 4c as a white solid (0.16 g, 97%). No spectroscopic data available in
literature.
mp 91–94 °C. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 4.5 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H),
7.85 (d, J = 7.7 Hz, 2H), 7.81 (dd, J = 7.6, 1.4 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 5.4
Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.44–7.40 (m, 3H), 7.36 (s, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.27–
7.23 (m, 1H), 4.62 (tt, J = 11.7, 4.0 Hz, 1H), 4.44 (s, 1H), 4.27 (s, 1H), 3.55 (s, 1H), 3.10 (t, J =
11.0 Hz, 1H), 2.67 (t, J = 12.2 Hz, 1H), 2.56 (q, J = 12.2 Hz, 1H), 2.31 (d, J = 12.3 Hz, 1H), 1.50
(s, 9H), 1.17 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 171.6 (C), 154.7 (C), 154.4 (C), 153.0
(C), 148.3 (CH), 138.2 (C), 137.0 (CH), 135.3 (C), 133.8 (CH), 130.0 (C), 129.3 (CH), 126.7 (CH),
125.6 (CH), 125.0 (CH), 123.6 (C), 123.3 (CH), 123.2 (CH), 121.9 (CH), 119.9 (CH), 113.8 (CH),
83.5 (C), 80.2 (C), 53.3 (CH), 48.8 (CH2), 46.9 (CH2), 34.1 (CH), 33.4 (CH2), 28.5 (CH3), 27.4
(CH3) ppm. HRMS (ESI) for C35H41N4O7S [M+H]+ calcd. 661.2690, found 661.2682.
6-Ethyl
1-methyl
(2S,3R)-3-tert-butoxy-2-[(tert-butoxycarbonyl)(pyridine-2-
carbonyl)amino]hexanedioate (4d) (SBI-205)
The title compound was synthesized using Boc2O (1.81 g, 8.28 mmol, 9.0 equiv), amide 3d (0.35
g, 0.92 mmol, 1.0 equiv), DMAP (45.0 mg, 0.37 mmol, 0.4 equiv), Et3N (0.39 mL, 2.76 mmol,
3.0 equiv) and THF (4.6 mL) at 80 °C following the general procedure A. The resulting crude
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residue was purified by automated flash chromatography (SiO2, 80 g cartridge, 100% heptane
isocratic over 5 min followed by 100% heptane to 70% heptane/30% EtOAc over 80 min followed
by 70% heptane/30% EtOAc isocratic over 20 min, 30 mL/min) to give the title compound 4d as
a pale yellow oil (0.28 g, 63%). Additionally, 31% (0.11 g, 0.29 mmol) of the starting material 3d
was recovered. No spectroscopic data available in literature.
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1H NMR (400 MHz, CDCl3) δ 8.62–8.60 (m, 1H), 7.78 (td, J = 7.7, 1.7 Hz, 1H), 7.61 (dt, J = 7.8,
1.0 Hz, 1H), 7.38 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 4.97 (d, J = 9.0 Hz, 1H), 4.54 (ddd, J = 8.9, 4.8,
2.4 Hz, 1H), 4.13 (qd, J = 7.1, 1.5 Hz, 2H), 3.70 (s, 3H), 2.56 (ddd, J = 16.0, 9.4, 6.6 Hz, 1H), 2.42
(ddd, J = 16.0, 9.8, 6.1 Hz, 1H), 2.27–2.15 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.24 (s, 9H), 1.17 (s,
9H) ppm. 13C NMR (101 MHz, CDCl3) δ 174.2 (C), 170.9 (C), 169.2 (C), 154.3 (C), 152.8 (C),
148.4 (CH), 136.7 (CH), 125.2 (CH), 122.8 (CH), 83.5 (C), 75.0 (C), 67.9 (CH), 60.3 (CH2), 59.5
(CH), 52.3 (CH3), 29.2 (CH2), 28.5 (CH3), 28.0 (CH2), 27.5 (CH3), 14.2 (CH3) ppm. HRMS (ESI)
for C24H37N2O8 [M+H]+ calcd. 481.2544, found 481.2526.
Methyl N-(tert-butoxycarbonyl)-O-[tert-butyl(dimethyl)silyl]-2,6-dimethyl-N-(pyridine-2-
carbonyl)-L-tyrosinate (4e) (NPR-243)
The title compound was synthesized using Boc2O (2.22 g, 10.17 mmol, 9.0 equiv), amide 3e (0.50
g, 1.13 mmol, 1.0 equiv), DMAP (55.0 mg, 0.45 mmol, 0.4 equiv), Et3N (0.64 mL, 4.52 mmol,
4.0 equiv) and THF (5.7 mL) at 80 °C following the general procedure A. The resulting crude
residue was purified by automated flash chromatography (SiO2, 80 g cartridge, 90% heptane/10%
EtOAc isocratic over 30 min followed by 90% heptane/10% EtOAc to 50% heptane/50% EtOAc
over 30 min followed by 50% heptane/50% EtOAc isocratic over 10 min, 30 mL/min) to give the
title compound 4e as a pale yellow oil (0.59 g, 96%). No spectroscopic data available in literature.
1H NMR (400 MHz, CDCl3)  8.55 (d, J = 4.2 Hz, 1H), 7.71 (td, J = 7.7, 1.6 Hz, 1H), 7.48 (d, J =
7.8 Hz, 1H), 7.33 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 6.42 (s, 2H) 5.43 (dd, J = 11.0, 4.0 Hz, 1H), 3.76
(s, 3H), 3.64 (dd, J = 14.9, 11.1 Hz, 1H), 3.48 (dd, J = 14.9, 4.0 Hz, 1H), 2.33 (s, 6H), 1.04 (s,
9H), 0.91 (s, 9H), 0.08 (s, 6H) ppm. 13C NMR (101 MHz, CDCl3)  170.9 (C), 170.5 (C), 154.0
(C), 153.7 (C), 152.6 (C), 148.3 (CH), 139.0 (C), 136.5 (CH), 126.7 (C), 125.1 (CH), 122.6 (CH),
119.6 (CH), 83.4 (C), 57.6 (CH), 52.5 (CH3), 29.5 (CH2), 27.1 (CH3), 25.7 (CH3), 20.3 (CH3), 18.1
(C), -4.5 (CH3) ppm. HRMS (ESI) for C29H43N2O6Si [M+H]+ calcd. 543.2885, found 543.2880.
tert-Butyl {[3-(4-acetylphenyl)thiophen-2-yl]methyl}(pyridine-2-carbonyl)carbamate (4f)
(SBI-211)
The title compound was synthesized using Boc2O (1.64 g, 7.49 mmol, 9.0 equiv), amide 3f (0.28
g, 0.83 mmol, 1.0 equiv), DMAP (20.0 mg, 0.17 mmol, 0.2 equiv), Et3N (0.13 mL, 0.92 mmol,
1.1 equiv) and THF (4.2 mL) at 50 °C following the general procedure A. The resulting crude
residue was purified by automated flash chromatography (SiO2, 80 g cartridge, 100% heptane
isocratic over 5 min followed by 100% heptane to 50% heptane/50% EtOAc over 60 min followed
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by 50% heptane/50% EtOAc isocratic over 20 min, 30 mL/min) to give the title compound 4f as a
pale yellow oil (0.31 g, 86%). No spectroscopic data available in literature.
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1H NMR (400 MHz, CDCl3) δ 8.57–8.55 (m, 1H), 8.03 (dt, J = 8.4, 1.8 Hz, 2H), 7.78 (td, J = 7.7,
1.7 Hz, 1H), 7.66 (dt, J = 7.8, 1.0 Hz, 1H), 7.59 (dt, J = 8.4, 1.8 Hz, 2H), 7.37 (ddd, J = 7.6, 4.8,
1.2 Hz, 1H), 7.27 (d, J = 5.1 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 5.27 (s, 2H), 2.63 (s, 3H), 1.12 (s,
9H) ppm. 13C NMR (101 MHz, CDCl3) δ 197.7 (C), 171.1 (C), 154.2 (C), 152.6 (C), 148.3 (CH),
141.2 (C), 139.1 (C), 137.0 (C), 136.7 (CH), 135.8 (C), 129.2 (CH), 128.7 (CH), 128.6 (CH), 125.3
(CH), 124.3 (CH), 122.9 (CH), 83.5 (C), 43.1 (CH2), 27.3 (CH3), 26.6 (CH3) ppm. HRMS (ESI)
for C24H25N2O4S [M+H]+ calcd. 437.1530, found 437.1527.
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{2-[(tert-Butoxycarbonyl)(pyridine-2-carbonyl)amino]-4-chlorophenyl}methyl acetate (4g)
(SBI-204)
The title compound was synthesized using Boc2O (3.16 g, 14.47 mmol, 9.0 equiv), amide 3g (0.49
g, 1.61 mmol, 1.0 equiv), DMAP (39.0 mg, 0.32 mmol, 0.2 equiv), Et3N (0.25 mL, 1.77 mmol,
1.1 equiv) and THF (8.0 mL) at 50 °C following the general procedure A. The resulting crude
residue was purified by automated flash chromatography (SiO2, 80 g cartridge, 100% heptane
isocratic over 5 min followed by 100% heptane to 75% heptane/25% EtOAc over 60 min followed
by 75% heptane/25% EtOAc isocratic over 10 min followed by 75% heptane/25% EtOAc to 50%
heptane/50% EtOAc over 15 min, 30 mL/min) to give the title compound 4g as a white solid (0.62
g, 96%). No spectroscopic data available in literature.
mp 95–97 °C. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 4.5 Hz, 1H), 7.85 (td, J = 7.6, 1.6 Hz,
1H), 7.80 (dt, J = 7.6, 1.2 Hz, 1H), 7.47–7.43 (m, 2H), 7.40–7.38 (m, 2H), 5.24 (d, J = 12.3 Hz,
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1H), 5.14 (d, J = 12.3 Hz, 1H), 1.93 (s, 3H), 1.20 (s, 9H) ppm. C NMR (101 MHz, CDCl3) δ
170.8 (C), 170.6 (C), 153.5 (C), 152.2 (C), 148.5 (CH), 138.2 (C), 136.9 (CH), 134.6, (C) 133.3
(C), 131.1 (CH), 130.0 (CH), 129.2 (CH), 125.9 (CH), 123.4 (CH), 83.9 (C), 62.3 (CH2), 27.4
(CH3), 20.7 (CH3) ppm. HRMS (ESI) for C20H22ClN2O5 [M+H]+, calcd 405.1212, found 405.1213.
tert-Butyl [4-benzenesulfonyl)naphthalen-1-yl](pyridine-2-carbonyl)carbamate (4h) (SBI-
212)
The title compound was synthesized using Boc2O (3.21 g, 14.71 mmol, 9.0 equiv), amide 3h (0.64
g, 1.64 mmol, 1.0 equiv), DMAP (40.0 mg, 0.33 mmol, 0.2 equiv), Et3N (0.25 mL, 1.80 mmol,
1.1 equiv) and THF (8.2 mL) at 50 °C following the general procedure A. The resulting crude
residue was purified by automated flash chromatography (SiO2, 80 g cartridge, 100% heptane
isocratic over 5 min followed by 100% heptane to 40% heptane/60% EtOAc over 60 min followed
by 40% heptane/60% EtOAc isocratic over 30 min, 30 mL/min) to give the title compound 4h as
a white solid (0.73 g, 92%). No spectroscopic data available in literature.
mp 189–190 °C. 1H NMR (400 MHz, CDCl3) δ 8.72–8.68 (m, 2H), 8.59 (d, J = 7.8 Hz, 1H), 8.33–
8.29 (m, 1H), 8.01–7.98 (m, 2H), 7.89–7.82 (m, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.61–7.56 (m, 2H),
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7.55–7.51 (m, 1H), 7.50–7.45 (m, 3H), 1.18 (s, 9H) ppm. C NMR (101 MHz, CDCl3) δ 171.2
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(C), 153.3 (C), 152.5 (C), 148.5 (CH), 141.5 (C), 141.3 (C), 137.1 (CH), 136.5 (C), 133.2 (CH),
131.9 (C), 129.8 (CH), 129.7 (C), 129.2 (CH), 128.6 (CH), 128.0 (CH), 127.5 (CH), 126.1 (CH),
125.5 (CH), 124.8 (CH), 123.8 (CH), 123.6 (CH), 84.2 (C), 27.3 (CH3) ppm. HRMS (ESI) for
C27H25N2O5S [M+H]+ calcd. 489.1479, found 489.1495.
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tert-Butyl cis-3-[(tert-butoxycarbonyl)amino]-5-phenylpiperidine-1-carboxylate (5a) (SBI-
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223)
The title compound was synthesized using N-Boc-picolinamide 4a (96.0 mg, 0.20 mmol, 1.0
equiv), Ni(cod)2 (5.5 mg, 0.02 mmol, 10 mol%), EtOH (23.0 μL, 0.40 mmol, 2.0 equiv) and
toluene (0.2 mL) following the general procedure B. The resulting crude residue was purified by
automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic over 5 min
followed by 100% heptane to 70% heptane/30% EtOAc over 60 min followed by 70%
heptane/30% EtOAc isocratic over 10 min followed by 70% heptane/30% EtOAc to 50%
heptane/50% EtOAc over 10 min, 25 mL/min) to give the title compound 5a as a white solid (68.0
mg, 90%). Additionally, ethyl 2-picolinate 6 was obtained as a by-product in 73% yield (22.0 mg).
No spectroscopic data available in literature.
mp 137-139 °C. 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.3 Hz, 2H), 7.25–7.19 (m, 3H), 4.43–
4.38 (m, 2H), 4.24 (s, 1H), 3.65 (s, 1H), 2.79 (tt, J = 11.8, 3.7 Hz, 1H), 2.62 (t, J = 11.8 Hz, 1H),
2.42 (t, J = 11.8 Hz, 1H), 2.30 (d, J = 12.5 Hz, 1H), 1.47 (s, 9H), 1.45 (s, 9H), 1.44 (q, J = 12.0
Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 155.0 (C), 154.5 (C), 142.0 (C), 128.6 (CH), 127.0
(CH), 126.9 (CH), 80.0 (C), 79.6 (C), 49.7 (CH2), 48.8 (CH2), 47.4 (CH), 41.5 (CH), 38.9 (CH2),
28.42 (CH3), 28.37 (CH3) ppm. HRMS (ESI) for C21H33N2O4 [M+H]+ calcd. 377.2435, found
377.2451.
Benzyl
carboxylate (5b) (SBI-235)
cis-3-[(tert-butoxycarbonyl)amino]-5-[4-(methoxycarbonyl)phenyl]piperidine-1-
The title compound was synthesized using N-Boc-picolinamide 4b (0.143 g, 0.25 mmol, 1.0
equiv), Ni(cod)2 (6.88 mg, 0.025 mmol, 10 mol%), EtOH (29.0 μL, 0.50 mmol, 2.0 equiv) and
toluene (0.25 mL) following the general procedure B. The resulting crude residue was purified by
automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic over 5 min
followed by 100% heptane to 70% heptane/30% EtOAc over 60 min followed by 70%
heptane/30% EtOAc isocratic over 10 min followed by 70% heptane/30% EtOAc to 50%
heptane/50% EtOAc over 10 min, 25 mL/min) to give the title compound 5b as a white solid (0.112
g, 96%). Additionally, ethyl 2-picolinate 6 was obtained as a by-product in 87% yield (33.0 mg).
No spectroscopic data available in literature.
mp 124-125 °C. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 2H), 7.36–7.30 (m, 5H), 7.26
(d, J = 7.4 Hz, 2H), 5.15 (t, J = 11.0 Hz, 2H), 4.60 (d, J = 7.4 Hz, 1H), 4.49 (d, J = 11.0 Hz, 1H),
4.32 (s, 1H), 3.90 (s, 3H), 3.69 (s, 1H), 2.87 (t, J = 12.2 Hz, 1H), 2.71 (s, 1H), 2.54 (t, J = 12.2 Hz,
1H), 2.30 (d, J = 12.2 Hz, 1H), 1.51 (q, J = 12.2 Hz, 1H), 1.43 (s, 9H) ppm. 13C NMR (101 MHz,
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CDCl3) δ 166.8 (C), 155.1 (C), 155.0 (C), 146.8 (C), 136.6 (C), 130.0 (CH), 128.9 (C), 128.5 (CH),
128.1 (CH), 127.9 (CH), 127.1 (CH), 79.7 (C), 67.4 (CH2), 52.1 (CH3), 49.5 (CH2), 48.7 (CH2),
47.2 (CH), 41.5 (CH), 38.4 (CH2), 28.3 (CH3) ppm. HRMS (ESI) for C26H33N2O6 [M+H]+ calcd.
469.2333, found 469.2328.
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tert-Butyl
cis-3-[(tert-butoxycarbonyl)amino]-5-[1-(benzenesulfonyl)-1H-indol-3-
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yl]piperidine-1-carboxylate (5c) (SBI-233)
The title compound was synthesized using N-Boc-picolinamide 4c (0.100 g, 0.151 mmol, 1.0
equiv), Ni(cod)2 (4.16 mg, 0.015 mmol, 10 mol%), EtOH (18.0 μL, 0.303 mmol, 2.0 equiv) and
toluene (0.15 mL) following the general procedure B. The resulting crude residue was purified by
automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic over 5 min
followed by 100% heptane to 70% heptane/30% EtOAc over 60 min followed by 70%
heptane/30% ethyl acetate isocratic over 10 min followed by 70% heptane/30% ethyl acetate to
50% heptane/50% ethyl acetate over 10 min, 25 mL/min) to give the title compound 5c as a white
solid (72.0 mg, 86%). Additionally, ethyl 2-picolinate 6 was obtained as a by-product in 74% yield
(17.0 mg). No spectroscopic data available in literature.
mp 106–109 °C. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H),
7.59 (d, J = 7.6 Hz, 1H), 7.54–7.51 (m, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.33–7.30 (m, 2H), 7.26–
7.22 (m, 1H), 4.45–4.39 (m, 3H), 3.70 (br, s, 1H), 3.02–2.96 (m, 1H), 2.60–2.43 (m, 3H), 1.50–
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1.45 (m, 19H) ppm. C NMR (101 MHz, CDCl3) δ 155.0 (C), 154.5 (C), 138.2 (C), 135.3 (C),
133.8 (CH), 129.9 (C), 129.3 (CH), 126.7 (CH), 125.1 (CH), 123.8 (C), 123.3 (CH), 121.7 (CH),
119.7 (CH), 113.8 (CH), 80.3 (C), 79.7 (C), 49.0 (2 x CH2), 47.1 (CH), 37.6 (CH2), 32.9 (CH),
28.43 (CH3), 28.39 (CH3) ppm. HRMS (ESI) for C29H38N3O6S [M+H]+ calcd. 556.2476, found
556.2477.
6-Ethyl 1-methyl (2S,3R)-3-tert-butoxy-2-[(tert-butoxycarbonyl)amino]hexanedioate (5d)
(SBI-237)
The title compound was synthesized using N-Boc-picolinamide 4d (0.15 g, 0.312 mmol, 1.0
equiv), Ni(cod)2 (8.59 mg, 0.031 mmol, 10 mol%), EtOH (36.0 μL, 0.624 mmol, 2.0 equiv) and
toluene (0.31 mL) following the general procedure B. The resulting crude residue was purified by
automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic over 5 min
followed by 100% heptane to 70% heptane/30% EtOAc over 60 min followed by 70%
heptane/30% EtOAc isocratic over 10 min followed by 70% heptane/30% EtOAc to 50%
heptane/50% EtOAc over 10 min, 25 mL/min) to give the title compound 5d as a colorless oil
(0.11 g, 94%). Additionally, ethyl 2-picolinate 6 was obtained as a by-product in 81% yield (38.0
mg). No spectroscopic data available in literature.
1H NMR (400 MHz, CDCl3) δ 5.28 (d, J = 9.6 Hz, 1H), 4.31 (d, J = 9.8 Hz, 1H), 4.14 (q, J = 6.9
Hz, 2H), 4.06 (t, J = 6.7 Hz, 1H), 3.71 (s, 3H), 2.45–2.30 (m, 2H), 1.86 (dd, J = 14.2, 7.0 Hz, 2H),
1.45 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H), 1.12 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 173.1 (C),
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172.0 (C), 156.1 (C), 79.9 (C), 74.5 (C), 70.6 (CH), 60.4 (CH2), 56.2 (CH), 52.1 (CH3), 30.3 (CH2),
29.1 (CH2), 28.4 (CH3), 28.3 (CH3), 14.2 (CH3) ppm. HRMS (ESI) for C18H34NO7 [M+H]+ calcd.
377.2330, found 377.2335.
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Methyl N-(tert-butoxycarbonyl)-O-[tert-butyl(dimethyl)silyl]-2,6-dimethyl-L-tyrosinate (5e)
(SBI-227)
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The title compound was synthesized using N-Boc-picolinamide 4e (0.13 g, 0.24 mmol, 1.0 equiv),
Ni(cod)2 (6.59 mg, 0.024 mmol, 10 mol%), EtOH (28.0 μL, 0.479 mmol, 2.0 equiv) and toluene
(0.24 mL) following the general procedure B. The resulting crude residue was purified by
automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic over 5 min
followed by 100% heptane to 70% heptane/30% EtOAc over 60 min followed by 70%
heptane/30% EtOAc isocratic over 10 min followed by 70% heptane/30% EtOAc to 50%
heptane/50% EtOAc over 10 min, 25 mL/min) to give the title compound 5e as a colorless oil (86.0
mg, 82%). Additionally, ethyl 2-picolinate 6 was obtained as a by-product in 72% yield (26.0 mg).
No spectroscopic data available in literature.
1H NMR (400 MHz, CDCl3) δ 6.50 (s, 2H), 5.05 (d, J = 7.4 Hz, 1H), 4.48 (q, J = 8.0 Hz, 1H), 3.61
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(s, 3H), 2.99 (d, J = 7.4 Hz, 2H), 2.27 (s, 6H), 1.38 (s, 9H), 0.97 (s, 9H), 0.17 (s, 6H) ppm. C
NMR (101 MHz, CDCl3) δ 173.4 (C), 154.9 (C), 153.9 (C), 138.3 (C), 126.1 (C), 119.7 (CH), 79.8
(C), 53.1 (CH), 52.1 (CH3), 32.8 (CH2), 28.3 (CH3), 25.7 (CH3), 20.3 (CH3), 18.2 (C), -4.4 (CH3)
ppm. HRMS (ESI) for C23H40NO5Si [M+H]+ calcd. 438.2670, found 438.2675.
tert-Butyl {[3-(4-acetylphenyl)thiophen-2-yl]methyl}carbamate (5f) (SBI-248)
The title compound was synthesized using N-Boc-picolinamide 4f (0.14 g, 0.32 mmol, 1.0 equiv),
Ni(cod)2 (8.82 mg, 0.032 mmol, 10 mol%), EtOH (37.0 μL, 0.64 mmol, 2.0 equiv) and toluene
(0.32 mL) following the general procedure B. The resulting crude residue was purified by
automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic over 5 min
followed by 100% heptane to 70% heptane/30% ethyl acetate over 60 min followed by 70%
heptane/30% EtOAc isocratic for 10 min followed by 70% heptane/30% EtOAc to 50%
heptane/50% EtOAc over 10 min, 25 mL/min) to give the title compound 5f as a colorless oil (85.0
mg, 80%). Additionally, ethyl 2-picolinate 6 was obtained as a by-product in 72% yield (35.0 mg).
No spectroscopic data available in literature.
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 5.3
Hz, 1H), 7.06 (d, J = 5.2 Hz, 1H), 4.91 (br, s, 1H), 4.53 (d, J = 4.6 Hz, 2H), 2.62 (s, 3H), 1.45 (s,
9H) ppm. 13C NMR (101 MHz, CDCl3) δ 197.6 (C), 155.4 (C), 140.8 (C), 138.5 (C), 138.2 (C),
135.8 (C), 129.0 (CH), 128.8 (CH), 128.7 (CH), 124.2 (CH), 79.9 (C), 38.4 (CH2), 28.4 (CH3),
26.6 (CH3) ppm. HRMS (ESI) for C18H22NO3S [M+H]+ calcd. 332.1315, found 332.1321.
{2-[(tert-Butoxycarbonyl)amino]-4-chlorophenyl}methyl acetate (5g) (SBI-232)
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The title compound was synthesized using N-Boc-picolinamide 4g (0.24 g, 0.59 mmol, 1.0 equiv),
Ni(cod)2 (16.0 mg, 0.059 mmol, 10 mol%), EtOH (69.0 µL, 1.18 mmol, 2.0 equiv) and toluene
(0.59 mL) following the general procedure B. The resulting crude residue was purified by
automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic over 5 min
followed by 100% heptane to 70% heptane/30% EtOAc over 60 min followed by 70%
heptane/30% EtOAc isocratic over 10 min followed by 70% heptane/30% EtOAc to 50%
heptane/50% EtOAc over 10 min, 25 mL/min) to give the title compound 5g as a white solid (0.16
g, 91%). Additionally, ethyl 2-picolinate 6 was obtained as a by-product in 75% yield (67.0 mg).
No spectroscopic data available in literature.
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mp 83–85 °C. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 1.1 Hz, 1H), 7.52 (br, s, 1H), 7.22 (d, J
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= 8.2 Hz, 1H), 7.03 (dd, J = 8.2, 2.1 Hz, 1H), 5.05 (s, 2H), 2.09 (s, 3H), 1.54 (s, 9H) ppm. C
NMR (101 MHz, CDCl3) δ 171.4 (C), 152.9 (C), 138.6 (C), 135.7 (C), 132.1 (CH), 123.5 (CH),
123.2 (C), 121.8 (CH), 81.0 (C), 63.1 (CH2), 28.3 (CH3), 20.9 (CH3) ppm. HRMS (ESI) for
C14H19ClNO4 [M+H]+ calcd. 300.0997, found 300.0983.
tert-Butyl [4-benzenesulfonyl)naphthalen-1-yl]carbamate (5h) (SBI-225)
The title compound was synthesized using N-Boc-picolinamide 4h (98.0 mg, 0.20 mmol, 1.0
equiv), Ni(cod)2 (5.5 mg, 0.02 mmol, 10 mol%), EtOH (23.0 μL, 0.40 mmol, 2.0 equiv) and
toluene (0.20 mL) following the general procedure B. The resulting crude residue was purified by
automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic over 5 min
followed by 100% heptane to 70% heptane/30% EtOAc over 60 min followed by 70%
heptane/30% EtOAc isocratic over 10 min followed by 70% heptane/30% EtOAc to 50%
heptane/50% EtOAc over 10 min, 25 mL/min) to give the title compound 5h as a white solid (70.0
mg, 91%). Additionally, ethyl 2-picolinate 6 was obtained as a by-product in 70% yield (21.0 mg).
No spectroscopic data available in literature.
mp 190–191 °C. 1H NMR (400 MHz, CDCl3) δ 8.67–8.62 (m, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.24
(d, J = 8.4 Hz, 1H), 7.93–7.90 (m, 2H), 7.87–7.84 (m, 1H), 7.56–7.40 (m, 5H), 7.26 (br, s, 1H),
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1.57 (s, 9H) ppm. C NMR (101 MHz, CDCl3) δ 152.5 (C), 142.2 (C), 139.4 (C), 132.8 (CH),
131.2 (CH), 129.9 (C), 129.4 (C), 129.0 (CH), 128.2 (CH), 127.2 (CH), 126.8 (CH), 125.3 (C),
125.2 (CH), 120.6 (CH), 114.2 (CH), 81.9 (C), 28.3 (CH3) ppm. HRMS (ESI) for C21H22NO4S
[M+H]+ calcd. 384.1264, found 384.1289.
3-Phenyl-2,3-dihydro-1H-indole (5i) (SBI-242)
An oven dried 10 mL pressure vial containing tertiary amide 3i (60.0 mg, 0.20 mmol, 1.0 equiv)
and terpyridine (7.0 mg, 15 mol%) was charged with Ni(cod)2 (15 mol%) in a glovebox. The vial
was sealed with an aluminium crimp cap and removed from the glovebox. Then, toluene (0.2 mL)
and ethanol (0.35 mL, 6.0 mmol, 30.0 equiv) were added into the sealed vial under argon (balloon).
The reaction vial was inserted into an oil bath, preheated at 100 °C, and stirred for 20 h. After
cooling to room temperature, the reaction mixture was diluted with DCM (5.0 mL), stirred for 10
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min, filtered through a celite bed and washed thoroughly with DCM (30.0 mL). The filtrate was
evaporated to dryness under reduced pressure. The resulting crude residue was purified by
automated flash chromatography (SiO2, 40 g cartridge, 100% heptane isocratic over 5 min
followed by 100% heptane to 70% heptane/30% ethyl acetate over 60 min followed by 70%
heptane/30% EtOAc isocratic for 10 min followed by 70% heptane/30% EtOAc to 50%
heptane/50% EtOAc over 10 min, 25 mL/min) to give the title compound 5i as a pale yellow oil
(31.0 mg, 80%). Additionally, ethyl 2-picolinate 6 was obtained as a by-product in 63% yield (19.0
mg) and unreacted starting material 3i was recovered in 8% yield (5.0 mg). Spectroscopic data are
in accordance with the literature.11a
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1H NMR (400 MHz, CDCl3) δ 7.32–7.20 (m, 5H), 7.06 (tt, J = 7.5, 0.9 Hz, 1H), 6.90 (dt, J = 7.7,
1.0 Hz, 1H), 6.71–6.68 (m, 2H), 4.47 (t, J = 9.0 Hz, 1H), 3.91 (t, J = 9.1 Hz, 1H), 3.75–3.63 (m,
1H), 3.48 (t, J = 8.9 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 151.6 (C), 143.6 (C), 132.3 (C),
128.6 (CH), 128.1 (CH), 127.7 (CH), 126.7 (CH), 125.0 (CH), 119.0 (CH), 109.7 (CH), 56.6
(CH2), 48.7 (CH) ppm. HRMS (ESI) for C14H14N [M+H]+ calcd. 196.1121, found 196.1123.
Ethyl pyridine-2-carboxylate (or ethyl 2-picolinate) (6) (SBI-072-2)
The title compound was obtained as a by-product during the Ni-catalyzed N-Boc-picolinamide
esterification reactions following the general procedure B. Spectroscopic data are in accordance
with the literature.31
1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.3 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.85 (td, J = 7.7,
1.5 Hz, 1H), 7.48 (dd, J = 7.0, 5.0 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H) ppm.
13C NMR (101 MHz, CDCl3) δ 165.3 (C), 149.9 (CH), 148.4 (C), 137.0 (CH), 126.8 (CH), 125.1
(CH), 61.9 (CH2), 14.4 (CH3) ppm. HRMS (ESI) for C8H10NO2 [M+H]+ calcd. 152.0706, found
152.0713.
Pyridine-2-carboxylic acid (or 2-picolinic acid) (7) (NPR-256)
The title compound was synthesised following a literature procedure.34 Ethyl pyridine-2-
carboxylate 6 (0.50 g, 6.62 mmol, 1.0 equiv) was dissolved in 6.0 mL THF (0.55 M) at 0 °C in a
100 mL round-bottom flask. To the resulting solution aq. NaOH solution (2.5 mL, 6.6 M, 5.0
equiv) was added dropwise and stirred for 15 h under air at room temperature. After starting
materials were consumed (checked by TLC), water (20.0 mL) was added. The reaction mixture
was washed with ethyl acetate (1x20.0 mL). The aqueous solution was acidified (pH 2 to 3) with
1 M HCl (aq). The resulting suspension was concentrated under vacuum to remove water and
evaporated to dryness to give a white solid. Ethanol (1x40.0 mL) and pentane (1x40.0 mL) were
added to the resulting solid, and the resulting suspension was sonificated and subsequently filtered
through filter paper to remove inorganic salts. The filtrate was evaporated to dryness to give title
compound 7 as white solid (0.39 g, 96% yield with >95% NMR purity). The spectral data are in
accordance with the literature.36
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mp 129–131 °C (lit.34 130–134 C). H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 4.2 Hz, 1H),
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8.05 (d, J = 7.7 Hz, 1H), 7.98 (td, J = 7.7, 1.6 Hz, 1H) 7.64–7.61 (m, 1H) ppm. C NMR (101
6
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MHz, DMSO-d6) δ 166.7 (C), 149.8 (CH), 149.1(C), 138.0 (CH), 127.4 (CH), 125.0 (CH), ppm.
HRMS (ESI) for C6H6NO2 [M+H]+ calcd. 124.0399, found 124.0389.
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ASSOCIATED CONTENT
Supporting Information.
Optimization tables, reaction schemes, H, 13C NMR and 2D spectra of all compounds are shown
in the supporting information. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
AUTHOR INFORMATION
Corresponding author
Email: bert.maes@uantwerpen.be
Author Contributions
All authors have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work has been supported by the European Union’s Horizon 2020 research and innovation
programme under the Marie Skłodowska-Curie Actions Grant n°837718, COST action CA15106
(CHAOS – C–H Activation in Organic Synthesis), the Research Foundation-Flanders (FWO)
(BioFact Excellence of Science project Grant n°30902231), the Francqui and the Hercules
Foundation.
REFERENCES
1. For comprehensive reviews on directed C-H functionalizations, see: (a) Chen, Z.; Wang, B.;
Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Transition Metal-Catalyzed C–H Bond Functionalizations
by the Use of Diverse Directing Groups. Org. Chem. Front. 2015, 2, 1107–1295. (b) Sambiagio,
C.; Schonbauer, D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M.
F.; Wencel-Delord, J.; Besset, T.; Maes, B. U. W.; Schnurch, M. A Comprehensive Overview of
Directing Groups Applied in Metal-Catalysed C–H Functionalisation Chemistry. Chem. Soc. Rev.
2018, 47, 6603–6743.
2. For reviews on distal C-H functionalization including the use of directing groups, see: (a)
Dey, A.; Agasti, S.; Maiti, D. Palladium catalysed meta-C–H functionalization reactions. Org. Biomol.
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2
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5
6
7
8
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Chem., 2016, 14, 5440-5453. (b) Leitch, J.A.; Frost, C.G. Ruthenium-catalysed -activation for
remote meta-selective C–H functionalization. Chem. Soc. Rev. 2017, 46, 7145-7153. (c) Khan,
F.F.; Sinha, S.K.; Lahiri, G.K.; Maiti, D. Ruthenium-Mediated Distal C-H Activation. Chem.
Asian J. 2018, 13, 2243–2256. (d) Mihai, M.T.; Genov, G.R.; Phipps, R.J. Access to the meta
position of arenes through transition metal catalysed C–H bond functionalisation: a focus on metals
other than palladium. Chem. Soc. Rev. 2018, 47, 149–171.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
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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. Zaitsev, V. G.; Shabashov, D.; Daugulis, O. Highly Regioselective Arylation of sp3 C−H Bonds
Catalyzed by Palladium Acetate. J. Am. Chem. Soc. 2005, 127, 13154–13155.
4. Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N. Highly Regioselective
Carbonylation of Unactivated C(sp3)–H Bonds by Ruthenium Carbonyl. J. Am. Chem. Soc. 2011,
133, 8070–8073.
5. Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.-J.; Shi, B.-F. Stereoselective Synthesis of
Chiral
α-Amino-β-Lactams
through
Palladium(II)-Catalyzed
Sequential
Monoarylation/Amidation of C(sp3)–H Bonds. Angew. Chem. Int. Ed. 2013, 52, 13588–13592.
6. (a) Garcia-Rubia, A.; Gomez Arrayas, R.; Carretero, J. C. Palladium(II)-Catalyzed
Regioselective Direct C2 Alkenylation of Indoles and Pyrroles Assisted by the N-(2-
Pyridyl)sulfonyl Protecting Group. Angew. Chem. Int. Ed. 2009, 48, 6511–6515. (b) Rodríguez,
N.; Romero-Revilla, J. A.; Fernández-Ibáñez, M. Á.; Carretero, J. C. Palladium-Catalyzed N-(2-
pyridyl)sulfonyl-directed C(sp3)–H γ-Arylation of Amino Acid Derivatives. Chem. Sci. 2013, 4,
175–179.
7. Alkylation: (a) Zhao, Y.; Chen, G. Palladium-Catalyzed Alkylation of ortho-C(sp2)-H Bonds of
Benzylamide Substrates with Alkyl Halides. Org. Lett. 2011, 13, 4850–4853. (b) Zhang, S. Y.;
He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. Palladium-Catalyzed Picolinamide-Directed
Alkylation of Unactivated C(sp3)−H Bonds with Alkyl Iodides. J. Am. Chem. Soc. 2013, 135,
2124–2127. (c) Shang, R.; Ilies, L.; Nakamura, E. Iron-Catalyzed Directed C(sp2)–H and C(sp3)–
H Functionalization with Trimethylaluminum. J. Am. Chem. Soc. 2015, 137, 7660–7663. (d)
Wang, X.; Niu, S.; Xu, L.; Zhang, C.; Meng, L.; Zhang, X.; Ma, D. Pd-Catalyzed Dimethylation
of Tyrosine-Derived Picolinamide for Synthesis of (S)-N-Boc-2,6-dimethyltyrosine and Its
Analogues. Org. Lett. 2017, 19, 246–249.
8. Alkenylation: (a) Martinez, A. M.; Echavarren, J.; Alonso, I.; Rodriguez, N.; Gomez Arrayas,
R.; Carretero, J. C. RhI/RhIII Catalyst-Controlled Divergent Aryl/Heteroaryl C–H Bond
Functionalization of Picolinamides with Alkynes. Chem. Sci. 2015, 6, 5802–5814. (b) Martinez,
A. M.; Rodriguez, N.; Gomez-Arrayas, R.; Carretero, J. C. Cobalt-Catalyzed ortho-C–H
Functionalization/Alkyne
Annulation
of
Benzylamine
Derivatives:
Access
to
Dihydroisoquinolines. Chem. Eur. J. 2017, 23, 11669–11676.
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5
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9. Alkynylation: Landge, V. G.; Midya, S. P.; Rana, J.; Shinde, D. R.; Balaraman, E. Expedient
Cobalt-Catalyzed C–H Alkynylation of (Enantiopure) Benzylamines. Org. Lett. 2016, 18, 5252–
5255.
7
8
9
10. Arylation: (a) He, G.; Chen, G. A Practical Strategy for the Structural Diversification of
Aliphatic Scaffolds through the Palladium-Catalyzed Picolinamide-Directed Remote
Functionalization of Unactivated C(sp3)-H Bonds. Angew. Chem. Int. Ed. 2011, 50, 5192–5196.
(b) Roman, D. S.; Charette, A. B. C–H Functionalization of Cyclopropanes: A Practical Approach
Employing a Picolinamide Auxiliary. Org. Lett. 2013, 15, 4394–4397. (c) Cui, W.; Chen, S.; Wu,
J. Q.; Zhao, X.; Hu, W.; Wang, H. Palladium-Catalyzed Remote C(sp3)−H Arylation of
3‑Pinanamine. Org. Lett. 2014, 16, 4288–4291. (d) Van Steijvoort, B. F.; Kaval, N.; Kulago, A.
A.; Maes, B. U. W. Remote Functionalization: Palladium-Catalyzed C5(sp3)-H Arylation of 1-
Boc-3-aminopiperidine through the Use of a Bidentate Directing Group. ACS Catal. 2016, 6,
4486–4490. (e) Rajkumar, V.; Naveen; Babu, S. A. Palladium(II)-Promoted Directing Group-
Enabled Regioselective C–H Arylation of The C-3 Position of 2- or 3-(Aminoalkyl)-Thiophene
and Furfurylamine Derivatives. ChemistrySelect 2016, 1, 1207–1219. (f) Parella, R.; Babu, S. A.
Pd(II)-Catalyzed, Picolinamide-Assisted, Z-Selective γ-Arylation of Allylamines to Construct Z-
Cinnamylamines. J. Org. Chem. 2017, 82, 6550–6567. (g) Zang, Z. L.; Karnakanti, S.; Zhao, S.;
Hu, P.; Wang, Z.; Shao, P. L.; He, Y. Synthesis of Spiro-dihydroquinoline and
Octahydrophenanthrene Derivatives via Palladium-Catalyzed Intramolecular Oxidative Arylation.
Org. Lett. 2017, 19, 1354–1357. (h) DH, O. D.; Aillard, P.; Berger, M.; de la Torre, A.; Petkova,
D.; Knittl-Frank, C.; Geerdink, D.; Kaiser, M.; Maulide, N. C–H Activation Enables a Concise
Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity. Angew. Chem.
Int. Ed. 2018, 57, 10737–10741. (i) Guin, S.; Dolui, P.; Zhang, X.; Paul, S.; Kumar Singh, V.;
Pradhan, S.; Chandrashekar, H.B.; Anjana, S.S.; Paton, R.S.; Maiti, D. Iterative Arylation of
Amino Acids and Aliphatic Amines via -C(sp3)-H Activation: Experimental and Computational
Exploration. Angew. Chem. Int. Ed. 2019, 58, 5633–5638.
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11. Amination/Amidation: (a) Nadres, E. T.; Daugulis, O. Heterocycle Synthesis via Direct C–
H/N–H Coupling. J. Am. Chem. Soc. 2012, 134, 7–10. (b) He, G.; Zhao, Y.; Zhang, S.; Lu, C.;
Chen, G. Highly Efficient Syntheses of Azetidines, Pyrrolidines, and Indolines via Palladium
Catalyzed Intramolecular Amination of C(sp3)-H and C(sp2)-H bonds at γ and δ Positions. J. Am.
Chem. Soc. 2012, 134, 3–6. (c) He, G.; Lu, C.; Zhao, Y.; Nack, W. A.; Chen, G. Improved Protocol
for Indoline Synthesis via Palladium-Catalyzed Intramolecular C(sp2)-H Amination. Org. Lett.
2012, 14, 2944–2947. (d) Li, Q.; Zhang, S. Y.; He, G.; Ai, Z.; Nack, W. A.; Chen, G. Copper-
Catalyzed Carboxamide-Directed Ortho Amination of Anilines with Alkylamines at Room
Temperature. Org. Lett. 2014, 16, 1764–1767. (e) Li, Z.; Sun, S.; Qiao, H.; Yang, F.; Zhu, Y.;
Kang, J.; Wu, Y.; Wu, Y. Palladium-Catalyzed Regioselective C8-H Amination of 1-
Naphthylamine Derivatives with Aliphatic Amines. Org. Lett. 2016, 18, 4594–4597. (f) Pradhan,
S.; De, P. B.; Punniyamurthy, T. Copper(II)-Mediated Chelation-Assisted Regioselective N-
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Naphthylation of Indoles, Pyrazoles and Pyrrole through Dehydrogenative Cross-Coupling. J.
Org. Chem. 2017, 82, 4883–4890.
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7
8
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12. Acyloxylation: (a) Li, Q.; Zhang, S.-Y.; He, G.; Nack, W. A.; Chen, G. Palladium-Catalyzed
Picolinamide-Directed Acetoxylation of Unactivated γ-C(sp3)–H Bonds of Alkylamines. Adv.
Synth. Catal. 2014, 356, 1544–1548. (b) Naveen; Rajkumar, V.; Babu, S. A.; Gopalakrishnan, B.
Pd(II)-Catalyzed Bidentate Directing Group-Aided Chemoselective Acetoxylation of Remote ε-
C(sp2)–H Bonds in Heteroaryl-Aryl-Based Biaryl Systems. J. Org. Chem. 2016, 81, 12197–12211.
(c) Lan, J.; Xie, H.; Lu, X.; Deng, Y.; Jiang, H.; Zeng, W. Co(II)-Catalyzed Regioselective Cross-
Dehydrogenative Coupling of Aryl C–H Bonds with Carboxylic Acids. Org. Lett. 2017, 19, 4279–
4282.
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13. Borylation: Zhang, L. S.; Chen, G.; Wang, X.; Guo, Q. Y.; Zhang, X. S.; Pan, F.; Chen, K.;
Shi, Z. J. Direct Borylation of Primary C–H Bonds in Functionalized Molecules by Palladium
Catalysis. Angew. Chem. Int. Ed. 2014, 53, 3899–3903.
14. Cyanation: Song, H.; Liu, X.; Wang, C.; Qiao, J.; Chu, W.; Sun, Z. Cu(TFA)2-Catalyzed
Picolinamido-Directed C(sp2)−H Cyanation of Naphthalenes by Using Benzoyl Cyanide as a
Cyano Source. Asian J. Org. Chem. 2017, 6, 1693–1698.
15. Trifluoromethylation: Xu, J.; Qiao, L.; Shen, J.; Chai, K.; Shen, C.; Zhang, P. Nickel(II)-
Catalyzed Site-Selective C–H Bond Trifluoromethylation of Arylamine in Water through a
Coordinating Activation Strategy. Org. Lett. 2017, 19, 5661–5664.
16. Sulfonylation: Li, J.-M.; Wang, Y.-H.; Yu, Y.; Wu, R.-B.; Weng, J.; Lu, G. Copper-Catalyzed
Remote C–H Functionalizations of Naphthylamides through a Coordinating Activation Strategy
and Single-Electron-Transfer (SET) Mechanism. ACS Catal. 2017, 7, 2661–2667.
17. For reviews on amide coupling reagents, see: (a) Dunetz, J. R.; Magano, J.; Weisenburger, G.
A. Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals.
Org. Process Res. Dev. 2016, 20, 140–177. (b) Hollanders, K.; Maes, B. U. W.; Ballet, S. A New
Wave of Amide Bond Formations for Peptide Synthesis. Synthesis 2019, 51, 2261–2277.
18. Liu, C.; Szostak, M. Twisted Amides: From Obscurity to Broadly Useful Transition-Metal-
Catalyzed Reactions by N−C Amide Bond Activation. Chem. Eur. J. 2017, 23, 7157–7173.
19. For basic hydrolysis of picolinamides, see: (a) Xie, Y.; Yang, Y.; Huang, L.; Zhang, X.; Zhang,
Y. Pd-Catalyzed Arylation/Oxidation of Benzylic C–H Bond. Org. Lett. 2012, 14, 1238–1241. (b)
Odani, R.; Hirano, K.; Satoh, T.; Miura, M. Copper-Mediated Dehydrogenative Biaryl Coupling
of Naphthylamines and 1,3-Azoles. J. Org. Chem. 2013, 78, 11045–11052. (c) Seki, A.;
Takahashi, Y.; Miyake, T. Synthesis of cis-3-Arylated Cycloalkylamines through Palladium-
Catalyzed Methylene sp3 Carbon–Hydrogen Bond Activation. Tetrahedron Lett. 2014, 55, 2838–
2841. (d) Wang, P. L.; Li, Y.; Wu, Y.; Li, C.; Lan, Q.; Wang, X. S. Pd-Catalyzed C(sp3)–H
Carbonylation of Alkylamines: A Powerful Route to γ‑Lactams and γ‑Amino Acids. Org. Lett.
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2015, 17, 3698–3701. (e) Yu, X.; Yang, F.; Wu, Y.; Wu, Y. Palladium-Catalyzed C8–H Acylation
of 1-Naphthylamines with Acyl Chlorides. Org. Lett. 2019, 21, 1726–1729.
6
7
8
9
20. S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. Efficient Alkyl Ether Synthesis
via Palladium-Catalyzed, Picolinamide-Directed Alkoxylation of Unactivated C(sp3)–H and
C(sp2)–H Bonds at Remote Positions. J. Am. Chem. Soc. 2012, 134, 7313–7316.
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53
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21. Li, K.; Wu, Q.; Lan, J.; You, J. Coordinating Activation Strategy for C(sp3)–H/C(sp3)–H Cross-
Coupling to Access β-Aromatic α-Amino Acids. Nature Communications 2015, 6, 8404.
22. O’ Donovan, D. H.; De Fusco, C.; Spring, D. R. The Reductive Cleavage of Picolinic Amides.
Tetrahedron Lett. 2016, 57, 2962-2964.
23. Xu, J.-W.; Zhang, Z.-Z.; Rao, W.-H.; Shi, B.-F. Site-Selective Alkenylation of δ-C(sp3)–H
Bonds with Alkynes via a Six-Membered Palladacycle. J. Am. Chem. Soc. 2016, 138, 10750–
10753.
24. For recent reviews, accounts and perspectives on transition metal-catalyzed reactions with N-
activated secondary amides: (a) Meng, G.; Shi, S.; Szostak, M. Cross-Coupling of Amides by N–
C Bond Activation. Synlett 2016, 27, 2530–2540. (b) Dander, J. E.; Garg, N. K. Breaking Amides
using Nickel Catalysis. ACS Catal. 2017, 7, 1413–1423. (c) Takise, R.; Muto, K.; Yamaguchi, J.
Cross-Coupling of Aromatic Esters and Amides. Chem. Soc. Rev. 2017, 46, 5864–5888. (d) Kaiser,
D.; Bauer, A.; Lemmerer, M.; Maulide, N. Amide Activation: An Emerging Tool for
Chemoselective Synthesis. Chem. Soc. Rev. 2018, 47, 7899–7925. (e) Chaudhari, M. B.;
Gnanaprakasam, B. Recent Advances in the Metal-Catalyzed Activation of Amide Bonds. Chem.
Asian J. 2019, 14, 76–93. (f) Buchspies, J.; Szostak, M. Recent Advances in Acyl Suzuki Cross-
Coupling. Catalysts 2019, 9, 53. (g) Bourne-Branchu, Y.; Gosmini, C.; Danoun, G. N-Boc-Amides
in Cross-Coupling Reactions. Chem. Eur. J. 2019, 25, 2663–2674.
25. (a) Hie, L.; Fine Nathel, N. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang, Y. F.; Liu, P.; Houk,
K. N.; Garg, N. K. Conversion of Amides to Esters by the Nickel-Catalysed Activation of Amide
C-N bonds. Nature 2015, 524, 79–83. (b) Hie, L.; Baker, E. L.; Anthony, S. M.; Desrosiers, J. N.;
Senanayake, C.; Garg, N. K. Nickel-Catalyzed Esterification of Aliphatic Amides. Angew. Chem.
Int. Ed. 2016, 55, 15129–15132.
26. (a) Li, B.; Berliner, R.; Buzon, R.; Chiu, C. K.-F.; Colgan, S. T.; Kaneko, T.; Keene, N.; Kissel,
W.; Le, T.; Leeman, K. R.; Marquez, B.; Morris, R.; Newell, L.; Wunderwald, S.; Witt, M.;
Weaver, J.; Zhang, Z.; Zhang, Z. Aqueous Phosphoric Acid as a Mild Reagent for Deprotection
for tert-Butyl Carbamates, Esters, and Ethers. J. Org. Chem. 2006, 71, 9045–9050. (b) Stahl, G.
L.; Walter, R.; Smith, C. W. General Procedure for the Synthesis of Mono-N-acylated 1,6-
Diaminohexanes. J. Org. Chem. 1978, 43, 3396–2286. (c) Spyropoulos, C.; Kokotos, C. G. One-
Pot Synthesis of Ureas from Boc-Protected Amines. J. Org. Chem. 2014, 79, 4477–4483. (d) Lee,
S.-H.; Matsushita, H.; Clapham, B.; Janda, K. D. The direct conversion of carbamates to ureas
using aluminium amides. Tetrahedron 2004, 60, 3439–3443. (e) Nazih, A.; Heissler, D. One-pot
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Conversion of t-Butyl Carbamates to Amides with Acyl Halide-Methanol Mixtures. Synthesis
2002, 203–206. (f) Lim, D. S. W.; Lew, T. T. S.; Zhang, Y. Direct Amidation of N-Boc- and N-
Cbz-Protected Amines via Rhodium-Catalyzed Coupling of Arylboroxines and Carbamates. Org.
Lett. 2015, 17, 6054–6057.
9
27. Deguchi, T.; Xin, H.-L.; Morimoto, H.; Ohshima, T. Direct Catalytic Alcoholysis of
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Unactivated 8-Aminoquinoline Amides. ACS Catal. 2017, 7, 3157–3161.
28. Verho, O.; Pourghasemi Lati, M.; Oschmann, M. A Two-Step Procedure for the Overall
Transamidation of 8-Aminoquinoline Amides Proceeding via the Intermediate N-Acyl-Boc-
Carbamates. J. Org. Chem. 2018, 83, 4464–4476.
29. Grehn, L.; Ragnarsson, U. Exhaustive tert-Butoxycarbonylation of Peptide Nitrogens. Angew.
Chem. Int. Ed. 1985, 24, 510–511.
30. Monaco, M. R.; Poladura, B.; Diaz de Los Bernardos, M.; Leutzsch, M.; Goddard, R.; List,
B. Activation of Carboxylic Acids in Asymmetric Organocatalysis. Angew. Chem. Int. Ed. 2014,
53, 7063–7067.
31. Bourne-Branchu, Y.; Gosminni, C; Danoun, G. Cobalt‐Catalyzed Esterification of Amides.
Chem. Eur. J. 2017, 23, 10043–10047.
32. Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood,
A. Organic Synthesis Provides Opportunities to Transform Drug Discovery. Nat. Chem. 2018, 10,
383–394.
33. Morimoto, H.; Fujiwara, R.; Shimizu, Y.; Morisaki, K.; Ohshima, T. Lanthanum(III) triflate
Catalyzed Direct Amidation of Esters. Org. Lett. 2014, 16, 2018–2021.
34. Tung, T. T.; Jakobsen, T. H.; Dao, T. T.; Fuglsang, A. T.; Givskov, M.; Christensen, S. B.;
Nielsen, J. Fusaric Acid and Analogues as Gram-Negative Bacterial Quorum Sensing Inhibitors.
Eur. J. Med. Chem. 2017, 126, 1011–1020.
35. Wender, P. A.; Smith, T. E.; Duong, H. A.; Louie, J.; Standley, E. A.; Tasker, S. Z.
Bis(1,5‐cyclooctadiene)nickel(0). In Encyclopedia of Reagents for Organic Synthesis. 2015
(doi:10.1002/047084289X.rb118.pub3).
36. Lian, X.; Fu, S.; Ma, T.; Li, S.; Zeng, W. An Efficient FeCl3-Promoted O-Alkyl Cleavage of
Esters to Carboxylic Acids. Appl. Organometal. Chem. 2011, 25, 443–447.
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R
R
O
DG cleavage
[Ni], EtOH
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R
R
H
N
N
Boc
N
Boc
O
yield up to 96%
H
X
Boc
activation
N
R
H
N
H
X = OEt (up to 87%)
X = OH (96%)
DG
introduction
R
O
H
O
C-H functionalization
R
N
R
N
H
N
H
N
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