Cobalt-Catalyzed, Directed C-H Functionalization/Annulation of Phenylglycinol Derivatives with Alkynes

Article abstract of DOI:10.1021/acs.joc.0c00207

A new method for cobalt-catalyzed C(sp²)-H functionalization of phenylglycinol derivatives with terminal and internal alkynes directed by picolinamide auxiliary has been developed. This method offers an efficient and highly regioselective route for the synthesis of 1-hydroxymethyltetrahydroisoquinolines. The reaction employs commercially available Co(II) catalyst in the presence of Mn(III) cooxidant and oxygen as a terminal oxidant and proceeds with full preservation of original stereochemistry.

Full text of DOI:10.1021/acs.joc.0c00207

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Article
Cobalt-catalyzed, directed C-H functionalization/
annulation of phenylglycinol derivatives with alkynes
Jekaterina Bolsakova, Lukass Lukasevics, and Liene Grigorjeva
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00207 • Publication Date (Web): 02 Mar 2020
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Cobalt-catalyzed, directed C-H functionalization/annulation of phenyl-
glycinol derivatives with alkynes
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Jekaterina Bolsakova, Lukass Lukasevics, and Liene Grigorjeva*
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia
E-mail: liene_grigorjeva@osi.lv
Supporting Information Placeholder
2
ABSTRACT: A new method for cobalt catalyzed C(sp )-H functionalization of phenylglycinol derivatives with terminal and internal
alkynes directed by picolinamide auxiliary has been developed. This method offers an efficient and highly regioselective route for
the synthesis of 1-hydroxymethyltetrahydroisoquinolines. The reaction employs commercially available Co(II) catalyst in the pres-
ence of Mn(III) cooxidant and oxygen as a terminal oxidant, and proceeds with full preservation of original stereochemistry.
5b
INTRODUCTION
directing group (Scheme 1, C). Despite the significant
progress made in picolinamide directed benzylamide
alkynylation and annulation, the methodology developed so far
unfortunately lack the substituent diversity at benzylamine
Transition metal catalyzed C-H bond functionalization
during the past decades has become an important tool that
allows simplification of synthetic schemes and allows the use
of less complex starting materials. In the past few years, C-H
functionalization using 3d-transition metals has emerged as an
attractive alternative to noble metals. Due to its earth-
abundance, lower toxicity and unique catalytic activity cobalt
has stood out as one of the promising alternatives. In 2014
Daugulis group demonstrated that simple Co(II) salts in
combination with bidentate directing group assistance can be
efficiently exploited for C-H functionalization as high-valent
6
1
benzylic position (Scheme 1). Typically only methyl
substituted or non-substituted benzylamine derivatives were
exploited that may limit the use of developed methodology in
total synthesis or synthesis of pharmaceutically relevant targets.
2
a
2
Scheme 1. Cobalt(II) catalyzed C-H functionalization with
alkynes
3
cobalt(III) precursors. Since the discovery a large number of
other C-H functionalization reactions based on this approach
have been reported showing the potential of this methodology
starting from readily available Co(II) salts and co-oxidants (e.g.
4
a-c
4d-f
4g-h
C-H functionalization with alkynes,
isonitriles, carbonylation, etc.).
alkenes, allenes,
4
i
4j-l
4
There is no literature precedent for the Co-catalyzed C-H
functionalization of phenylglycinol derivatives. Although,
several reports has been devoted to benzylamine derivatives. In
2
014 Daugulis group demonstrated the first example of
cobalt(II) catalyzed 1-methylbenzylamine derived
picolinamide reaction with 2-butyne yielding cyclized product
3
in moderate yield (Scheme 1, A). In 2017 Carretero group
published an extended study and improved methodology for
cobalt
catalyzed,
picolinamide-directed
C-H
functionalization/alkyne annulation of benzylamine derivatives
5
a
(
Scheme 1, B). The same year Cui group demonstrated the
1-Substituted tetrahydroisoquinoline is
a
structural
cobalt-catalyzed annulation of benzylamides with alkynes to
synthesize isoquinolines by using picolinamide as a traceless
backbone of a large number of alkaloids that commonly possess
a broad range of biological activity. 1-Substituted 1,2-
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dihydroisoquinoline derivatives are especially valuable as
With the optimized conditions in hand, we next examined
intermediates in the synthesis of alkaloid natural products, that
the substrate scope with respect to picolinamides 1 (Scheme 2).
We found that O-unprotected phenylglycinol picolinamide 1b
completely decomposed under the reaction conditions, and
product 2ba did not form. TBS, PMB and MOM protected
phenylglycinol derivatives gave corresponding products (2aa,
2ca, 2da, respectively) in very good yields (70 – 83%) as single
regioisomers (regiochemistry of products was confirmed by
2D-NOESY experiments, see SI for details). We were pleased
to find that under optimized reaction conditions benzamide
derivatives gave products in excellent yields (2ea and 2fa) as
well.
8
has led to increasing interest for their synthesis. Herein we
report an efficient method for the synthesis of 1-
hydroxymethyl-1,2-dihydroisoquinolines via cobalt catalyzed
C-H annulation of phenylglycinol derivatives using terminal
and internal alkynes.
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RESULTS AND DISCUSSION
For optimization studies model reaction between
phenylglycinol derivative 1a and 3,3-dimethyl-1-butyne was
chosen. During the optimization studies, a range of cobalt
catalysts, oxidants, base additives and reaction solvents were
evaluated. Treatment of 1a with 3,3-dimethyl-1-butyne in the
Subsequently, the scope of phenylglycinol derivatives 1
with diverse functional groups was examined under the
optimized conditions (Scheme 3). As shown in Scheme 3, we
found that reactions were successful on phenylglycinol
derivatives 1 with para-, meta- and ortho-substitution patterns.
Using meta-substituted substrates (2ia, 2ja), we observed that
reaction favors less hindered C-H bonds, yielding products in
excellent regioselectivity that is consistent with literature
2
presence of Co(OAc) catalyst, NaOPiv base and AgOAc
oxidant in MeOH at 80 °C led to regioselective formation of
9
2
aa in 5% yield (Table 1, entry 1). Screening of alternative
oxidants showed, that product 2aa yield can be slightly
improved by using of Mn(OAc) ·2 H O in combination with
3
2
oxygen (entries 2-5). Reducing the amount of NaOPiv
enhanced the product 2aa yield to 28% (entry 7). The results in
entries 8 and 9 indicated that MeOH is the solvent of choice.
Studies using alternative Co(II) and Co(III) salts identified
3
,5a
examples.
a
Scheme 2. Reaction scope with respect to picolinamides 1
Co(dpm)
yielding the product 2aa in 84% yield as single regioisomer
entries 9-13). Control experiments excluding catalyst (entry
4) and oxidant (entry 6) showed no product 2aa formation.
2
catalyst as the crucial factor for successful reaction,
(
1
a
Table 1. Optimization of reaction conditions
entry
catalyst
oxidant
AgOAc
yield, %[b]
1
2
3
4
5
6
7c
Co(OAc)
Co(OAc)
Co(OAc)
Co(OAc)
Co(OAc)
Co(OAc)
Co(OAc)
Co(OAc)
Co(OAc)
2
5
2
MnO
2
4
2
2
2
2
2
2
2
Mn(OAc)
Mn(OAc)
Mn(OAc)
-
2
3
3
·4H
·2H
·2H
2
2
2
O
5
O
12
16
-
O/O
2
a
Reaction conditions: 1 (0.5 mmol), 3,3-dimethyl-1-butyne (1.5
mmol, 3 equiv), catalyst (0.1 mmol, 20 mol%), NaOPiv (0.6 mmol,
Mn(OAc)
Mn(OAc)
Mn(OAc)
Mn(OAc)
Mn(OAc)
Mn(OAc)
Mn(OAc)
Mn(OAc)
3
3
3
3
3
3
3
3
·2H
·2H
·2H
·2H
·2H
·2H
·2H
·2H
2
2
2
2
2
2
2
2
O/O
O/O
O/O
O/O
O/O
O/O
O/O
O/O
2
2
2
2
2
2
2
2
28
1
1
O
.2 equiv), Mn(OAc)
, 80 °C; Isolated yields are given. Decomposition of substrate
1b.
3 2
·2H O (1.0 mmol, 2 equiv), MeOH (5 mL),
8c,d
9c,e
b
2
13
-
1
1
1
1
0c
1c
2c
CoCl
2
Different functional groups on phenylglycinol derivatives 1
were tolerated, including electron-donating groups, such as
alkyl (2ia, 2ka), methoxy (2ga, 2la), methoxymethyl ether
(2ma), as well as electron-withdrawing groups, such as
trifluoromethyl (2ja) and trifluoromethoxy group (2na). Fluoro
and bromo functionalities are compatible with reaction
conditions (2ha, 2oa, 2pa). -Phenylalaninol derivative 1r was
also competent substrate and gave corresponding product 2ra
in very good yield. Moreover, the reaction worked not only with
benzyl amides but also with thiophene amino alcohol derivative
Co(acac)
Co(dpm)
Co(dpm)
-
2
30
82
84
-
2
2
3c,f
14
a
Reaction conditions: 1a (0.1 mmol), 3,3-dimethyl-1-butyne
(
0.3 mmol, 3 equiv), catalyst (0.02 mmol, 20 mol%), NaOPiv (0.2
mmol, 2 equiv), Mn(OAc) ·2H O (0.2 mmol, 2 equiv), MeOH (1
mL), 80 °C. NMR yield using triphenylmethane as an internal
3
2
b
1
q and gave product 2qa in very good yield. Unfortunately,
c
d
standard. NaOPiv (0.12 mmol, 1.2 equiv). Solvent: EtOH (1
using substrate 1q C-H functionalization with 3,3-dimethyl-1-
e
3 2
CH
OH (1 mL). f Time: 24h. Pic – picolinyl.
mL). Solvent: CF
Co(dpm) – bis(2,2,6,6-tetramethyl-3,5-heptanedionato)cobalt(II),
CAS: 13986-53-3.
nd
butyne was not selective and both regioisomers (thiophene 2
vs 4 position) were obtained as 2.5/1 mixture.
2
th
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Scheme 3. Reaction scope with respect to phenylglycinol de-
rivatives 1
Scheme 4. Reaction scope with respect to alkynes
a
tBu (3 equiv)
Co(dpm)2 (20 mol%)
NaOPiv (1.2 equiv)
R
n
OTBS
R
NPic
n OTBS
NHPic
Mn(OAc)3. 2H2O (2 equiv)
tBu
MeOH, 80 oC, O2
Me
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CF3
OMe
F
OTBS
OTBS
OTBS
OTBS
NPic
NPic
NPic
NPic
tBu
ga, 55%c
tBu
2ha, 74%b
tBu
tBu
2ja, 65%c
2
2ia, 78%d
Me
MeO
OTBS
MOMO
OTBS
F3CO
OTBS
OTBS
NPic
NPic
NPic
NPic
tBu
2ka, 90%b
tBu
tBu
tBu
2la, 75%b
2ma, 84%b
2na, 75%c
F
Br
S
OTBS
OTBS
OTBS
OTBS
NPic
NPic
tBu
NPic
NPic
tBu
oa, 66%d
tBu
2qa, 84%c,f
tBu
2pa, 70%b
2ra, 71%e
2
a
Reaction conditions: 1 (0.5 mmol), 3,3-dimethyl-1-butyne (1.5
mmol, 3 equiv), catalyst (0.1 mmol, 20 mol%), NaOPiv (0.6 mmol,
1.2 equiv), Mn(OAc) ·2H O (1.0 mmol, 2 equiv), MeOH (5 mL),
, 80 °C; Isolated yields are given; All products were isolated as
3
2
O
2
b
c
single regioisomers unless stated. Time: 16 -17 h. Time: 20 h.
d
e
f
Time: 24 h. Time: 40 h. Isolated as 2.5:1 mixture of thiophene
regioisomers, major product shown.
Thereafter, we investigated the reaction scope with respect
to alkynes (Scheme 4). Both internal and terminal alkynes were
a
Reaction conditions: 1a (0.5 mmol), alkyne (0.75 - 1.5 mmol,
competent
reagents
for
C-H
functionalization.
1
1
.5 - 3 equiv), catalyst (0.1 mmol, 20 mol%), NaOPiv (0.6 mmol,
.2 equiv), Mn(OAc)
Cyclopropylacetylene was compatible with reaction conditions
and afforded product 2ab as single regioisomer in 73% yield.
Dialkyl-substituted alkynes reacted smoothly and gave
corresponding products in high yields (70 – 80%; 2ac, 2ad,
2ae). Terminal alkynes with either aromatic or heteroaromatic
substituent gave products as single regioisomers (2af-2aj).
Interestingly, 4-nitrophenylacetylene afforded mono C-H
alkenylation/cyclization product 2ah (50%) and bisalkenylation
product 2ah’ (16%). In the case of p-diethynylbenzene, product
ai was isolated in 54% yield. 3-Ethynylthiophene and
trimethylsilylacetylene were competent substrates and
selectively formed products 2aj and 2an, as well as 1-phenyl-
-propyne – 2am. Diarylacetylenes displayed excellent
reactivity under the reaction conditions (2ak, 2al). The
synthetic application of the developed methodology was
demonstrated through gram-scale synthesis of annulation
product 2an which was obtained in excellent yield – 80%.
To find out whether stereochemical integrity for -position
of phenylglycinol derivative 1 is preserved during the reaction,
enantiopure (S)-phenylglycinol derivative (S)-1a was tested
under the optimized reaction conditions (Scheme 5). Aliphatic
and aromatic terminal and internal alkynes were tested (2aa,
2ac, 2af, 2ak, 2an). We were pleased to find that stereocenter
was preserved completely and no loss of enantiopurity was
detected exploiting either terminal or internal alkynes.
.
3 2
2H O (1.0 mmol, 2 equiv), MeOH (5 mL),
b
c
O
2
, 80 °C; Isolated yields are given; Time: 16 -17 h. Time: 20 h.
d
e
Isolated as single regioisomer; Gram-scale synthesis, starting
from 1 g picolinamide 1a.
Scheme 5. Preservation of stereochemistry
2
1
The application of developed methodology was shown by
accessing valuable tetrahydroisoquinoline derivative (S,S)-4an
Scheme 6). Reduction of enantiopure (S)-2an using Na/NH
3
(
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proceeded in highly diastereoselective manner (>20/1) and gave
tetrahydroisoquinoline (S,S)-3an. Subsequent directing group
removal using LiAlH gave corresponding
tetrahydroisoquinoline (S,S)-4an in good yield and without the
loss of enantiopurity.
cooxidant. Major advantages of the methodology are
substituent diversity at benzylamine benzylic position,
excellent regioselectivity and full preservation of original
stereochemistry.
4
EXPERIMENTAL SECTION
Scheme 6. Synthesis of tetrahydroisoquinoline (S,S)-4an
General Comments. Reactions were performed using
standard glassware or were run in 4 mL vials with PTFE/Liner
screw caps and 30 mL vials using w/polyseal screw caps.
Reactions were heated using Chemglass aluminium reaction
blocks. Column chromatography was performed using
Kieselgel silicagel (35 - 70 and 60 - 200 m). Thin layer
chromatography (TLC) was performed on silica gel using
Merck TLC Silica gel 60 F254 Aluminum sheets and was
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Based on literature data
and experimental
observations, possible reaction mechanism was proposed
Scheme 7).
4
visualized by UV lamp, staining with KMnO . H, C, F and
9
2D-NMR spectra were recorded on 400 MHz Bruker
spectrometer using residual solvent peak as a reference.
Compounds for HRMS were analyzed by positive mode
electrospray ionization (ESI) using Waters Synapt G2-Si mass
spectrometer. HPLC data were obtained using Waters Alliance
2695 HPLC system with a Phenomenex Lux Amylose-1 (4.6 x
150 mm) or Chiralpac IC-1 (4.6 x 250 mm) column (conditions
specified on attached HPLC chromatograms). IR spectra were
obtained using a Shimadzu IR Prestige-21 FT-IR spectrometer.
Optical rotations were measured at 20 °C on a Rudolph
Research Analytical Autopol VI Polarimeter, cell lenght 50
mm, using solvent and concentration stated, at 589 nm. All
procedures were performed under ambient air unless otherwise
noted. Reagents and starting materials were obtained from
commercial sources and used without further purification
unless otherwise noted.
(
Scheme 7. Mechanistical considerations
Substrate synthesis. Amide substrates 1a-c,g-q,s were
synthesized through methyl-2-aryl-2-(picolinamido)acetates
(
(
5a,g-q,s).
Corresponding
methyl-2-aryl-2-
picolinamido)acetates were synthesized in two steps from
commercially available amino acids.
Methyl 2-phenyl-2-(picolinamido)acetate (5a). Procedure
A. Step 1: 2-Amino-2-phenylacetic acid (6.00 g, 39.69 mmol,
1 equiv) was suspended in MeOH (48 mL) under an argon
atmosphere. The solution was cooled to 0 °C and oxalyl
chloride (6.9 mL, 79.38 mmol, 2 equiv) was slowly added
dropwise. The reaction mixture was stirred overnight at room
temperature. Solvent was evaporated under vacuum to obtain
crude product as a pale solid. Crude product was used in the
next step without further purification. Step 2: Under an argon
atmosphere methyl 2-amino-2-phenylacetate hydrogen chloride
(39.69 mmol, 1 equiv), picolinic acid (5.12 g, 41.58 mmol, 1.05
Accordingly, oxidation of Co(II) catalyst in presence of
5
a
substrate 1 would generate Co(III) species I-1. C-H bond
activation would form intermediate I-2. Coordination, followed
by insertion of alkyne into Co-Ar bond would result in
formation of I-3. Subsequent reductive elimination would form
dihydroisoquinoline 2 and Co(I) species which is reoxidized to
Co(II) and returned to catalytic cycle. Protodemetallation
pathway from I-3 was excluded as no cyclization product 2af
formation was observed under standard reaction conditions
equiv)
and
N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-
9
(Scheme 8).
yl)uronium hexafluorophosphate (30.03 g, 79.38 mmol, 2
equiv) were dissolved in DMF (48 mL). Pyridine (9.6 mL,
Scheme 8. Possible cyclization of picolinamide 1s
1
19.07 mmol, 3 equiv) was added to the solution directly.
Reaction mixture was stirred at room temperature overnight.
Then reaction mixture was diluted with EtOAc (60 mL) and
H
2
O (40 mL), filtered. Organic phase was separated and
aqueous phase was extracted with EtOAc (50 mL), combined
organic phase was washed with dist. H O (20 mL), brine (20
mL) and dried over Na SO , filtered. Solvent was evaporated
2
2
4
under reduced pressure to afford the crude product, which was
further purified by flash chromatography on silica gel using
petroleum ether/EtOAc (3/1) as an eluent to give corresponding
product 8.07 g (75%) as a white solid. This compound is
In conclusion, we have developed a general method for
cobalt catalyzed C-H functionalization of phenylglycinol
derivatives with terminal and internal alkynes, directed by
picolinamide auxiliary. The reactions proceed in the presence
of commercially available cobalt(II) tetramethylheptanedionate
11
1
known. H-NMR (400 MHz, CDCl
3
) δ 8.98 (d, J = 8.4 Hz,
1
H), 8.56 (d, J = 4.1 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.81 (td,
2 3 2
catalyst, NaOPiv base, O oxidant, and Mn(OAc) ·2 H O
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J = 7.7, 1.7 Hz, 1H), 7.48 – 7.35 (m, 2H), 7.35 – 7.27 (m, 1H),
7.05 – 6.81 (m, 2H), 6.00 (d, J = 8.6 Hz, 1H), 3.89 (s, 3H), 3.73
procedure A. Step 1: 2-(3-Trifluoromethylphenyl)glycine (1.21
g, 5.50 mmol, 1 equiv), C Cl (0.95 mL, 11.00 mmol, 2
equiv), MeOH (12 mL). Step 2: Crude reaction mixture from
Step 1, picolinic acid (679 mg, 5.50 mmol, 1 equiv), N,N,N′,N′-
tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate (4.18 g, 11.00 mmol, 2 equiv), DMF (15
mL), pyridine (1.34 mL, 16.50 mmol, 3 equiv). After column
chromatography (gradient hexanes/EtOAc from 3:1 to 2:1) 1.12
O
2 2
2
(
s, 3H).
Methyl 2-(2-methoxyphenyl)-2-(picolinamido)acetate
5g). Synthesized according to procedure A. Step 1: (2-
Cl
1.2 mL, 14.20 mmol, 2 equiv), MeOH (12 mL). Step 2: Crude
(
Methoxyphenyl)glycine (1.28 g, 7.10 mmol, 1 equiv), C
(
2
O
2
2
reaction mixture from Step 1, picolinic acid (873 mg, 7.10
mmol, 1 equiv), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-
yl)uronium hexafluorophosphate (5.38 g, 14.20 mmol, 2 equiv),
DMF (15 mL), pyridine (1.7 mL, 21.30 mmol, 3 equiv). After
column chromatography (gradient hexanes/EtOAc from 3:1 to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
g (59%) of product was obtained as a colorless oil. R
(petroleum ether/EtOAc 3:1). H-NMR (400 MHz, CDCl
f
= 0.22
1
3
,
ppm) δ 9.07 (d, J = 7.0 Hz, 1H), 8.62 (ddd, J = 4.8, 1.6, 0.9 Hz,
1H), 8.15 (d, J = 7.8, 1.0 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H),
7.73 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H),
7.54 – 7.43 (m, 2H), 5.84 (d, J = 7.4 Hz, 1H), 3.80 (s, 3H).
2
:1) 900 mg (42%) of product was obtained as a colorless oil.
11 1
This compound is known. H-NMR (400 MHz, CDCl
d, J = 8.4 Hz, 1H), 8.56 (d, J = 4.1 Hz, 1H), 8.16 (d, J = 7.8
Hz, 1H), 7.81 (td, J = 7.7, 1.7 Hz, 1H), 7.48 – 7.35 (m, 2H),
.35 – 7.27 (m, 1H), 7.05 – 6.81 (m, 2H), 6.00 (d, J = 8.6 Hz,
3
) δ 8.98
1
3
(
3
C{1H}NMR (100 MHz, CDCl , ppm) δ 170.6, 164.0, 149.2,
148.5, 137.9, 137.5, 131.5 (q, JC-F = 32.4 Hz), 130.9 (q, JC-F
1.2 Hz), 129.6, 126.8, 125.6 (q, JC-F = 3.6 Hz), 124.3 (q, JC-F
=
=
7
1
9
1H), 3.89 (s, 3H), 3.73 (s, 3H).
3.7 Hz), 124.0 (q, JC-F = 272.5 Hz), 122.5, 56.4, 53.3. F-NMR
(376 MHz, CDCl , ppm) δ -62.60. HR-MS (ESI-TOF) m/z:
Methyl 2-(2-fluorophenyl)-2-(picolinamido)acetate (5h).
Synthesized according to procedure A. Step 1: (2-
Fluorophenyl)glycine hydrochloride (1.84 g, 9.00 mmol, 1
3
+
Calcd. for [M+H] : C16
H
14
N
2
O
3
F
3
339.0957; found: 339.0957.
FT-IR (thin film, cm ) υ 2957, 1748, 1684, 1330, 1168, 1127.
Methyl 2-(4-methylphenyl)-2-(picolinamido)acetate
-1
equiv), C
mL). Step 2: Crude reaction mixture from Step 1, picolinic acid
1.16 g, 9.50 mmol, 1.04 equiv), N,N,N′,N′-tetramethyl-O-(1H-
2 2 2
O Cl (1.6 mL, 18.00 mmol, 2 equiv), MeOH (10
(5k). Synthesized according to procedure A. Step 1: (4-
Methylphenyl)glycine hydrochloride (1.4 g, 7.0 mmol, 1
equiv), C O Cl (1.2 mL, 14.0 mmol, 2 equiv), MeOH (8 mL).
2 2 2
Step 2: Crude reaction mixture from Step 1, picolinic acid (903
mg, 7.3 mmol, 1.04 equiv), N,N,N′,N′-tetramethyl-O-(1H-
benzotriazol-1-yl)uronium hexafluoro-phosphate (5.30 g, 14.0
mmol, 2 equiv), DMF (14 mL), pyridine (1.7 mL, 21.0 mmol, 3
(
benzotriazol-1-yl)uronium hexafluorophosphate (6.80 g, 18.00
mmol, 2 equiv), DMF (18 mL), pyridine (2.2 mL, 27.00 mmol,
3
equiv). After column chromatography (gradient
hexanes/EtOAc from 3:1 to 2:1) 1.50 g (58%) of product was
obtained as a colorless oil. R = 0.36 (petroleum ether/EtOAc
:1). H-NMR (400 MHz, CDCl , ppm) δ 8.98 (d, J = 7.4 Hz,
H), 8.58 (d, J = 4.7 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.82 (td,
f
1
2
1
3
equiv).
hexanes/EtOAc from 3:1 to 2:1) 750 mg (38%) of product was
obtained as a colorless oil. R = 0.40 (petroleum ether/EtOAc
2:1). H-NMR (400 MHz, CDCl , ppm) δ 8.90 (d, J = 6.8 Hz,
After
column
chromatography
(gradient
J = 7.7, 1.6 Hz, 1H), 7.52 – 7.38 (m, 2H), 7.39 – 7.27 (m, 1H),
.20 – 7.05 (m, 2H), 6.02 (d, J = 7.9 Hz, 1H), 3.78 (s, 3H).
f
1
7
3
13
C{1H}NMR (100 MHz, CDCl
3
, ppm) δ 170.6, 163.9, 160.7
1H), 8.62 – 8.45 (m, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.82 (td, J =
7.7, 1.7 Hz, 1H), 7.50 – 7.37 (m, 1H), 7.36 (d, J = 8.1 Hz, 2H),
7.18 (d, J = 7.9 Hz, 2H), 5.73 (d, J = 7.5 Hz, 1H), 3.76 (s, 3H),
(d, JC-F = 248.5 Hz), 149.3, 148.5, 137.4, 130.5 (d, JC-F = 8.3
Hz), 129.9 (d, JC-F = 3.5 Hz), 126.6, 124.7 (d, JC-F = 3.6 Hz),
124.4 (d, JC-F = 14.3 Hz), 122.5, 116.1 (d, JC-F = 21.3 Hz), 53.1,
1
3
3
2.34 (s, 3H). C{1H}NMR (100 MHz, CDCl , ppm) δ 171.4,
1
9
5
1
1.5 (d, JC-F = 2.6 Hz). F-NMR (376 MHz, CDCl
3
, ppm) δ -
163.9, 149.5, 148.4, 138.6, 137.4, 133.7, 129.8, 127.4, 126.5,
122.5, 56.5, 52.9, 21.3. HR-MS (ESI-TOF) m/z: Calcd. for
+
17.06. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
F 289.0988; found: 289.0999. FT-IR (thin film, cm
υ 3387, 2955, 1750, 1683, 1510, 1233.
-
+
C
15
H
14
N
2
O
3
[M+H] : C16
H
17
N
2
O
3
285.1239; found: 285.1243. FT-IR (thin
1
-1
)
film, cm ) υ 3388, 2951, 1743, 1684, 1507, 1437, 1180.
Methyl 2-(4-hydroxyphenyl)-2-(picolinamido)acetate
(5lm). Synthesized according to procedure A. Step 1: 4-
Hydroxyphenylglycine (1.50 g, 9.0 mmol, 1 equiv), C Cl
Methyl 2-(3-methylphenyl)-2-(picolinamido)acetate (5i).
Synthesized from commercially available methyl amino(3-
methylphenyl)acetate hydrochloride using procedure A, Step 2:
Amino(3-methylphenyl)acetate hydrochloride (1.0 g, 4.6
mmol), picolinic acid (599 mg, 4.8 mmol, 1.05 equiv),
N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate (3.52 g, 9.20 mmol, 2 equiv), DMF (10
mL), pyridine (1.1 mL, 13.80 mmol, 3 equiv). After column
chromatography (gradient hexanes/EtOAc from 3:1 to 2:1) 1.00
2
O
2
2
(1.6 mL, 18.0 mmol, 2 equiv), MeOH (10 mL). Step 2: Crude
reaction mixture from Step 1, picolinic acid (1.16 g, 9.45 mmol,
1.05 equiv), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-
yl)uronium hexafluoro-phosphate (6.80 g, 18.0 mmol, 2 equiv),
DMF (18 mL), pyridine (2.2 mL, 27.0 mmol, 3 equiv). After
column chromatography (gradient hexanes/EtOAc from 3:1 to
g (76%) of product was obtained as a colorless oil. R
f
= 0.59
2:1) 1.2 g (47%) of product was obtained as a colorless oil. This
1
12 1
(petroleum ether/EtOAc 1:1). H-NMR (400 MHz, CDCl
3
,
3
compound is known. H-NMR (400 MHz, CDCl , ppm) δ 8.97
ppm) δ 8.93 (d, J = 7.0 Hz, 1H), 8.60 (ddd, J = 4.8, 1.7, 0.9 Hz,
1H), 8.18 (dt, J = 7.8, 1.0 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz,
1H), 7.45 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.32 – 7.23 (m, 3H),
(d, J = 7.2 Hz, 1H), 8.59 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.16
(dt, J = 7.8, 1.0 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H), 7.45
(ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.30 – 7.21 (m, 2H), 6.79 – 6.67
(m, 2H), 5.67 (d, J = 7.3 Hz, 1H), 3.76 (s, 3H).
Methyl 2-(4-methoxyphenyl)-2-(picolinamido)acetate
(5l). To a solution of methyl 2-(4-hydroxy-phenyl)-2-
(picolinamido)acetate (5lm) (500 mg, 1.75 mmol) in DMF
(8 mL), NaH (60% dispersion in mineral oil, 105 mg,
2.62 mmol, 1.5 equiv ) was added at 0 °C. The reaction was
stirred at the same temperature for 5 min and then MeI (142 µL,
2.27 mmol 1.3 equiv) was added and further stirred for
7
.20 – 7.11 (m, 1H), 5.75 (d, J = 7.5 Hz, 1H), 3.79 (s, 3H), 2.38
13
(s, 3H). C{1H}NMR (100 MHz, CDCl
3
, ppm) δ 171.3, 163.9,
49.4, 148.4, 138.9, 137.4, 136.5, 129.5, 129.0, 128.2, 126.5,
24.6, 122.5, 56.7, 52.9, 21.5. HR-MS (ESI-TOF) m/z: Calcd.
1
1
+
for [M+H] : C16
H
17
2
N O
3
285.1239; found: 285.1250. FT-IR
thin film, cm ) υ 3388, 2953, 1744, 1685, 1512, 1437, 1202.
Methyl 2-(3-trifluoromethylphenyl)-2-
(picolinamido)acetate (5j). Synthesized according to
-1
(
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30 min at the same temperature. The reaction mixture was
quenched with ice water and then extracted with ethyl acetate
FT-IR (thin film, cm ) υ 3384, 2957, 1743, 1675, 1505, 1436,
1261, 1221, 1162.
(
3 x 20 mL). The combined organic phase was washed with dist.
O (20 mL), brine (20 mL) and then dried over anhydrous
Na SO , filtered and evaporated under reduced pressure. After
column chromatography (gradient hexanes/EtOAc from 3:1 to
:1) 270 mg (52%) of product was obtained as a colorless oil.
Methyl 2-(4-fluorophenyl)-2-(picolinamido)acetate (5o).
Synthesized according to procedure A. Step 1: 2-(4-
Fluorophenyl)glycine (1.0 g, 5.9 mmol, 1 equiv), C O Cl (1.5
2 2 2
mL, 17.7 mmol, 3 equiv), MeOH (9 mL). Step 2: Crude
reaction mixture from Step 1, picolinic acid (762 mg, 6.2 mmol,
1.05 equiv), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-
yl)uronium hexa-fluorophosphate (4.48 g, 11.8 mmol, 2 equiv),
DMF (12 mL), pyridine (1.4 mL, 17.7 mmol, 3 equiv). After
column chromatography (gradient hexanes/EtOAc from 3:1 to
2:1) 1.3 g (76%) of product was obtained as a colorless oil. R
f
= 0.37 (eluent petroleum ether/EtOAc = 2/1). H-NMR (400
MHz, CDCl , ppm) δ 8.96 (d, J = 6.8 Hz, 1H), 8.65 – 8.54 (m,
1H), 8.15 (d, J = 7.8 Hz, 1H), 7.89 – 7.76 (m, 1H), 7.50 – 7.40
(m, 3H), 7.12 – 7.00 (m, 2H), 5.75 (d, J = 7.4 Hz, 1H), 3.77 (s,
3H). C{1H}NMR (100 MHz, CDCl , ppm) δ 171.1, 163.9,
3
162.9 (d, JC-F = 247.4 Hz), 149.3, 148.5, 137.5, 132.6 (d, JC-F
3.3 Hz), 129.3 (d, JC-F = 8.4 Hz), 126.7, 122.5, 116.1 (d, JC-F
21.8 Hz), 56.0, 53.1. F-NMR (376 MHz, CDCl
113.28. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
289.0988; found: 289.1002. FT-IR (thin film, cm
) υ 3386, 2955, 1744, 1683, 1507, 1437, 1225, 1161.
Methyl 2-(4-bromophenyl)-2-(picolinamido)acetate
(5p). Synthesized according to procedure A. Step 1: 2-(4-
Bromophenyl)glycine (1.59 g, 6.0 mmol, 1 equiv), C Cl (1.6
mL, 18.0 mmol, 3 equiv), MeOH (10 mL). Step 2: Crude
reaction mixture from Step 1, picolinic acid (775 mg, 6.3 mmol,
1.05 equiv), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-
yl)uronium hexa-fluorophosphate (4.55 g, 12.0 mmol, 2 equiv),
DMF (12 mL), pyridine (1.5 mL, 18.0 mmol, 3 equiv). After
column chromatography (gradient hexanes/EtOAc from 3:1 to
2:1) 700 mg (33%) of product was obtained as a colorless oil.
= 0.40 (eluent petroleum ether/EtOAc = 2/1). H-NMR (400
MHz, CDCl , ppm) δ 8.99 (d, J = 7.0 Hz, 1H), 8.60 (ddd, J =
3
4.8, 1.7, 0.9 Hz, 1H), 8.14 (dt, J = 7.8, 1.1 Hz, 1H), 7.84 (td, J
= 7.7, 1.7 Hz, 1H), 7.53 – 7.47 (m, 2H), 7.45 (ddd, J = 7.6, 4.8,
1.2 Hz, 1H), 7.38 – 7.33 (m, 2H), 5.73 (d, J = 7.4 Hz, 1H), 3.77
(s, 3H). C{1H}NMR (100 MHz, CDCl , ppm) δ 170.8, 163.9,
3
149.2, 148.4, 137.5, 135.8, 132.3, 129.2, 126.7, 122.8, 122.5,
56.2, 53.1. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
N O 349.0188; found: 349.0190. FT-IR (thin film,
2 3
cm ) υ 3378, 2954, 1748, 1680, 1507, 1173.
Methyl 2-(picolinamido)-2-(thiophen-3-yl)acetate (5q).
Synthesized according to procedure A. Step 1: 2-Amino-2-
(thiophen-3-yl)acetic acid hydrochloride (1.23 g, 7.8 mmol, 1
H
2
2
4
2
R
C
1
f
= 0.25 (petroleum ether/EtOAc 2:1). H-NMR (400 MHz,
Cl , ppm) δ 8.86 (d, J = 7.4 Hz, 1H), 8.61 (d, J = 4.1 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
D
2
4
1H), 8.12 (d, J = 7.8 Hz, 1H), 7.87 (td, J = 7.7, 1.7 Hz, 1H),
7.48 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.45 – 7.32 (m, 2H), 6.96 –
6
3
1
5
.89 (m, 2H), 5.68 (d, J = 7.4 Hz, 1H), 3.81 (s, 3H), 3.78 (s,
1
3
1
H). C{1H}NMR (100 MHz, CDCl
3
, ppm) δ 171.5, 163.9,
59.9, 149.5, 148.4, 137.4, 128.8, 128.7, 126.5, 122.5, 114.5,
3
+
6.2, 55.5, 52.9. HR-MS (ESI-TOF) m/z: Calcd. for [M+Na] :
C
16
-1
H
16
N
2
O
4
Na 323.1002; found: 323.1015. FT-IR (thin film,
cm ) υ 3385, 3007, 2954, 1745, 1682, 1513, 1259, 1179.
Methyl 2-(4-(methoxymethoxy)phenyl)-2-
(picolinamido)acetate (5m). To a solution of methyl 2-(4-
hydroxy-phenyl)-2-(picolinamido)acetate (5lm) (1.0 g,
.49 mmol) in DMF (15 mL), NaH (60% dispersion in mineral
13
=
=
1
9
3
, ppm) δ -
+
3
-
oil, 210 mg, 5.24 mmol, 1.5 equiv ) was added at 0 °C. The
reaction was stirred at the same temperature for 5 min and then
MOMCl (0.35 mL, 4.54 mmol 1.3 equiv) was added and further
stirred for 30 min at the same temperature. The reaction mixture
was quenched with ice water and then extracted with ethyl
acetate (3 x 20 mL). The combined organic phase was washed
C
15FH14
N
2
O
3
1
2
O
2
2
with dist. H
anhydrous Na
pressure. After
hexanes/EtOAc from 3:1 to 2:1) 550 mg (48%) of product was
obtained as a colorless oil. R = 0.33 (petroleum ether/EtOAc
:1). H-NMR (400 MHz, CDCl , ppm) δ 8.88 (d, J = 7.1 Hz,
H), 8.58 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.15 (dt, J = 7.8, 1.1
2
O (20 mL), brine (20 mL) and then dried over
SO , filtered and evaporated under reduced
column chromatography (gradient
2
4
f
1
2
1
3
1
R
f
Hz, 1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.45 – 7.37 (m, 3H),
7.06 – 7.01 (m, 2H), 5.71 (d, J = 7.4 Hz, 1H), 5.16 (s, 2H), 3.77
1
3
(s, 3H), 3.46 (s, 3H). C{1H}NMR (100 MHz, CDCl
1
1
3
, ppm) δ
71.4, 163.9, 157.5, 149.4, 148.4, 137.4, 129.9, 128.8, 126.6,
22.5, 116.8, 94.5, 56.2, 56.1, 52.9. HR-MS (ESI-TOF) m/z:
1
3
+
Calcd. for [M+Na] :
53.1117. FT-IR (thin film, cm ) υ 3386, 2954, 1751, 1683,
C
17
H
18
N
2
O
5
Na 353.1113; found:
-1
+
3
1
508, 1236, 1153.
C
15BrH14
-1
Methyl
2-(4-trifluoromethoxyphenyl)-2-
(
picolinamido)acetate (5n). Synthesized according to
procedure A. Step 1: (4-Trifluoromethoxyphenyl)glycine (1.0
g, 4.3 mmol, 1 equiv), C Cl (0.74 mL, 8.6 mmol, 2 equiv),
2
O
2
2
MeOH (5 mL). Step 2: Crude reaction mixture from Step 1,
picolinic acid (550 mg, 4.5 mmol, 1.05 equiv), N,N,N′,N′-
2 2 2
equiv), C O Cl (1.36 mL, 15.6 mmol, 2 equiv), MeOH (15
mL). Step 2: Crude reaction mixture from Step 1, picolinic acid
(965 mg, 7.8 mmol, 1.0 equiv), N,N,N′,N′-tetramethyl-O-(1H-
benzotriazol-1-yl)uronium hexa-fluorophosphate (5.95 g, 15.6
mmol, 2 equiv), DMF (24 mL), pyridine (1.89 mL, 23.4 mmol,
tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexa-
fluorophosphate (3.23 g, 8.6 mmol, 2 equiv), DMF (8 mL),
pyridine (1.0 mL, 12.9 mmol, 3 equiv). After column
chromatography (gradient hexanes/EtOAc from 3:1 to 2:1) 1.3
3
equiv). After column chromatography (gradient
hexanes/EtOAc from 3:1 to 2:1) 280 mg (13%) of product was
obtained as a colorless oil. R = 0.51 (eluent petroleum
ether/EtOAc = 1/1). H-NMR (400 MHz, CDCl , ppm) δ 8.84
g (82%) of product was obtained as a colorless oil. R
f
= 0.42
(petroleum ether/EtOAc 2:1). H-NMR (400 MHz, CDCl
ppm) δ 9.01 (d, J = 7.2 Hz, 1H), 8.60 (ddd, J = 4.8, 1.6, 0.9 Hz,
1
3
,
f
1
3
1
1
7
H), 8.14 (dt, J = 7.8, 1.0 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz,
H), 7.55 – 7.47 (m, 2H), 7.45 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H),
.25 – 7.17 (m, 2H), 5.79 (d, J = 7.5 Hz, 1H), 3.79 (s, 3H).
(d, J = 7.2 Hz, 1H), 8.58 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.17
(dt, J = 7.8, 1.1 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.44
(ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.41 – 7.36 (m, 1H), 7.33 (dd, J
= 5.0, 3.0 Hz, 1H), 7.17 (dd, J = 5.0, 1.3 Hz, 1H), 5.92 (d, J =
3
7.9 Hz, 1H), 3.80 (s, 3H). C{1H}NMR (100 MHz, CDCl ,
13
C{1H}NMR (100 MHz, CDCl
q, JC-F = 1.6 Hz), 149.2, 148.5, 137.5, 135.4, 129.0, 126.7,
3
, ppm) δ 170.8, 164.0, 149.4
13
(
19
1
22.5, 121.5, 120.5 (q, JC-F = 257.6 Hz), 56.0, 53.2. F-NMR
ppm) δ 170.9, 164.0, 149.4, 148.4, 137.4, 136.6, 126.9, 126.6,
126.5, 123.5, 122.5, 53.0, 52.5. HR-MS (ESI-TOF) m/z: Calcd.
(376 MHz, CDCl , ppm) δ -57.84. HR-MS (ESI-TOF) m/z:
3
+
+
Calcd. for [M+H] : C16
H
14
N
O
2 4
F
3
355.0906; found: 355.0906.
for [M+H] : C13
H
13
N
2
O
3
S 277.0647; found: 277.0655. FT-IR
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(thin film, cm ) υ 3387, 3098, 2954, 1752, 1679, 1514, 1212,
1164.
(picolinamido)acetate (1.50 g, 5.55 mmol, 1 equiv) was
dissolved in THF (20 mL) under an argon atmosphere. The
solution was cooled in water/ice bath to 0 °C and lithium
borohydride (4 M in THF, 1.8 mL, 7.21 mmol, 1.3 equiv) was
added slowly dropwise, then reaction mixture was stirred at
room temperature for 3 h. The reaction was monitored by TLC
to achieve full conversion, then cooled in water/ice bath and
quenched by 15% citric acid solution in water. Organic solvent
was evaporated in vacuum and water phase was extracted by
DCM (2 x 30 mL). Combined organic phase was dried over
Methyl (E)-2-(picolinamido)-2-(2-styrylphenyl)acetate
(
5s). Step 1: To a stirred solution of ammonium chloride (0.58
g, 10.87 mmol, 1.3 equiv) in 25 mL of ammonium hydroxide
solution (25% NH in water), sodium cyanide (0.52 g, 10.45
mmol, 1.25 equiv) carefully was added, followed by dropwise
3
11
(
over 30 min) addition of (E)-2-styrylbenzaldehyde (1.74 g,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
.36 mmol, 1 equiv) solution in iPrOH (10 mL). The mixture
was stirred at room temperature overnight. The solvent was
removed under reduced pressure and the crude mixture was
diluted with water (pH > 10) and extracted with DCM (3 x 30
mL). The combined organic layers were washed with brine (1 x
2 4
Na SO , filtered and evaporated under reduced pressure to
afford the crude product, which was used in next step without
further purification. Step 2: To the solution of N-(2-hydroxy-1-
phenylethyl)picolinamide (5.55 mmol, 1 equiv) in DMF (18
mL) under an argon atmosphere imidazole (1.10 g, 7.21 mmol,
1.3 equiv) and tert-butyldimethylsilyl chloride (491 mg, 7.21
mmol, 1.3 equiv) were added. The reaction mixture was stirred
at room temperature to achieve full conversion, then was diluted
3
2 4
0 mL), dried over Na SO , filtered and evaporated under
reduced pressure to afford the crude product, which was used in
next step without further purification. Step 2: To a stirred
solution of crude product from Step 1 in 1,4-dioxane (5 mL),
concentrated hydrochloric acid (37%, 5.2 mL, 167.23 mmol, 20
equiv) was added dropwise and resulting mixture was refluxed
for 5 h. The solvent was removed under reduced pressure to
afford the crude product, which was used in next step without
further purification. Step 3: The crude product from Step 2 was
suspended in MeOH (24 mL) under an argon atmosphere. The
solution was cooled to 0 °C and oxalyl chloride (1.5 mL, 16.72
mmol, 2 equiv) was slowly added dropwise. The reaction
mixture was stirred overnight at room temperature. Solvent was
evaporated under vacuum, the residue was dissolved in dist.
with EtOAc (30 mL) and H
separated and water phase was extracted with EtOAc (20 mL),
combined organic phase was washed with dist. H O (20 mL)
and brine (20 mL). Combined organic phase was dried over
Na SO , filtered and evaporated under reduced pressure to
2
O (20 mL). Organic phase was
2
2
4
afford the crude product, which was further purified by flash
chromatography on silica gel using petroleum ether/EtOAc
(6/1) as an eluent to give corresponding product 1.6 g (81%) as
1
colorless oil. R
f
= 0.34 (petroleum ether/EtOAc 4:1). H-NMR
H
2
O (50 mL), extracted with EtOAc (50 mL). Using 1M NaOH
(400 MHz, CDCl
3
, ppm) δ 8.86 (d, J = 7.7 Hz, 1H), 8.58 (ddd,
the pH of aqueous phase was adjusted to ~8. Aqueous phase
was extracted with EtOAc (3 x 50 mL). Combined organic
phase was dried over Na SO , filtered. Solvent was evaporated
2 4
under reduced pressure to afford the crude product as a
yellowish oil. Crude product was used in the next step without
further purification. Step 4: Under argon atmosphere crude
product from Step 3, picolinic acid (1.08 g, 8.78 mmol, 1.05
J = 4.8, 1.6, 0.9 Hz, 1H), 8.18 (dt, J = 7.8, 1.0 Hz, 1H), 7.83 (td,
J = 7.7, 1.7 Hz, 1H), 7.45 – 7.38 (m, 3H), 7.36 – 7.29 (m, 2H),
7.28 – 7.22 (m, 1H), 5.22 (dt, J = 8.7, 4.6 Hz, 1H), 4.01 (dd, J
= 10.2, 4.6 Hz, 1H), 3.94 (dd, J = 10.2, 4.6 Hz, 1H), 0.87 (s,
13
9H), -0.01 (s, 3H), -0.05 (s, 3H). C{1H}NMR (100 MHz,
CDCl
3
, ppm) δ 163.9, 150.1, 148.2, 140.3, 137.4, 128.5, 127.5,
127.2, 126.3, 122.4, 66.4, 54.9, 25.9, 18.4, -5.4, -5.5. HR-MS
+
equiv)
and
N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-
29 2 2
(ESI-TOF) m/z: Calcd. for [M+H] : C20H N O Si 357.1998;
-1
yl)uronium hexafluorophosphate (6.34 g, 16.72 mmol, 2 equiv)
were dissolved in DMF (10 mL). Pyridine (1.4 mL, 16.72
mmol, 2 equiv) was added to the solution directly. Reaction
mixture was stirred at room temperature overnight. Then
found: 357.2007. FT-IR (thin film, cm ) υ 3386, 2954, 2927,
2856, 1681, 1517, 1254, 1107.
N-(2-Hydroxy-1-phenylethyl)picolinamide
(1b).
Synthesized according to procedure B. Step 1: Methyl 2-
phenyl-2-(picolinamido)acetate (1.10 g, 4.07 mmol, 1 equiv),
LiBH4 (4 M in THF 1.32 mL, 5.29 mmol, 1.3 equiv), THF (15
mL). After column chromatography (gradient hexanes/EtOAc
from 1:1 to EtOAc) 880 mg (89%) of product was obtained as
2
reaction mixture was diluted with EtOAc (50 mL) and H O (40
mL), filtered. Organic phase was separated and aqueous phase
was extracted with EtOAc (50 mL), combined organic phase
was washed with dist. H2O (20 mL), brine (20 mL) and dried
1
3 1
over Na
2
SO
4
, filtered. Solvent was evaporated under reduced
a colorless oil. This compound is known. H-NMR (400 MHz,
CDCl , ppm) δ 8.70 (d, J = 6.5 Hz, 1H), 8.63 – 8.48 (m, 1H),
pressure to afford the crude product, which was further purified
by flash chromatography on silica gel using petroleum
ether/EtOAc (3/1) as an eluent to give corresponding product
3
8.23 – 8.09 (m, 1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.51 – 7.22
(m, 6H), 5.32 – 5.18 (m, 1H), 4.11 – 3.89 (m, 2H), 3.07 (s, 1H).
N-(2-((4-Methoxybenzyl)oxy)-1-
1
(
.04 g (34% over 4 steps) as a yellowish oil. R
f
= 0.28
petroleum ether/EtOAc 3:1). H-NMR (400 MHz, CDCl
ppm) δ 8.92 (d, J = 7.5 Hz, 1H), 8.52 (ddd, J = 4.8, 1.7, 0.9 Hz,
H), 8.17 (dt, J = 7.8, 1.1 Hz, 1H), 7.82 (td, J = 7.7, 1.7 Hz,
1
3
,
phenylethyl)picolinamide (1c). To a solution of N-(2-
hydroxy-1-phenylethyl)picolinamide (300 mg, 1.24 mmol) in
DMF (4 mL), NaH (60% dispersion in mineral oil, 74 mg,
1.86 mmol, 1.5 equiv) was added at 0 °C. The reaction was
stirred at the same temperature for 5 min and then PMBCl (0.22
mL, 1.61 mmol 1.3 equiv) was added and further stirred for
30 min at the same temperature. The reaction mixture was
quenched with ice water and then extracted with ethyl acetate
(3 x 10 mL). The combined organic phase was washed with dist.
1
1H), 7.71 – 7.64 (m, 2H), 7.61 – 7.54 (m, 2H), 7.44 – 7.35 (m,
5H), 7.33 – 7.26 (m, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.16 (d, J
1
3
= 7.7 Hz, 1H), 3.76 (s, 3H). C{1H}NMR (100 MHz, CDCl
3
,
ppm) δ 171.6, 163.9, 149.4, 148.4, 137.4, 137.3, 134.2, 132.7,
1
1
29.0, 128.8, 128.4, 128.0, 127.9, 127.1, 127.0, 126.6, 125.4,
+
22.5, 53.9, 53.0. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
-
C
23
H
21
N
2
O
3
373.1552; found: 373.1561. FT-IR (thin film, cm
H
2
O (10 mL), brine (10 mL) and then dried over anhydrous
1
)
υ 3389, 1743, 1680, 1507, 1220.
Na SO , filtered and evaporated under reduced pressure. After
2
4
Synthesis and characterization of picolinamides 1.
N-(2-((Tert-butyldimethylsilyl)oxy)-1-phenylethyl)pico-
linamide (1a). Procedure B. Step 1: Methyl 2-phenyl-2-
column chromatography (gradient hexanes/EtOAc from 5:1 to
3:1) 380 mg (85%) of product was obtained as a colorless oil.
1
R
f
= 0.10 (petroleum ether/EtOAc 4:1). H-NMR (400 MHz,
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CDCl
3
, ppm) δ 8.75 (d, J = 8.0 Hz, 1H), 8.58 (ddd, J = 4.8, 1.7,
equiv) was added to the solution directly. Reaction mixture was
stirred at room temperature overnight. Reaction was monitored
by TLC to achieve full conversion, and then was diluted with
0.9 Hz, 1H), 8.18 (dt, J = 7.8, 1.0 Hz, 1H), 7.83 (td, J = 7.7, 1.7
Hz, 1H), 7.46 – 7.38 (m, 3H), 7.38 – 7.30 (m, 2H), 7.31 – 7.23
(m, 1H), 7.24 – 7.18 (m, 2H), 6.87 – 6.81 (m, 2H), 5.39 (dt, J =
EtOAc (30 mL) and H
separated and aqueous phase was extracted with EtOAc (30
mL), combined organic phase was washed with dist. H O (20
mL), brine (20 mL) and dried over Na SO , filtered. Solvent
2
O (30 mL), filtered. Organic phase was
8
3
1
1
.2, 5.2 Hz, 1H), 4.59 – 4.46 (m, 2H), 3.83 (d, J = 5.3 Hz, 2H),
.79 (s, 3H). C{1H}NMR (100 MHz, CDCl
59.3, 150.0, 148.2, 139.9, 137.4, 130.1, 129.4, 128.6, 127.5,
27.1, 126.3, 122.4, 113.9, 72.8, 72.3, 53.3, 53.1. HR-MS (ESI-
1
3
3
, ppm) δ 164.0,
2
2
4
was evaporated under reduced pressure to afford the crude
product, which was further purified by flash chromatography on
silica gel using petroleum ether/EtOAc (3/1) as an eluent to give
corresponding product 931 mg (85%) as white powder. This
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TOF) m/z: Calcd. for [M+Na] : C22
found: 385.1530. FT-IR (thin film, cm ) υ 3393, 2862, 1683,
1512, 1250, 1096.
H
22
N
O
2 3
Na 385.1528;
-
1
14 1
N-(2-(Methoxymethoxy)-1-phenylethyl)picolinamide
3
compound is known. H-NMR (400 MHz, CDCl , ppm) δ 8.75
(
1d).
phenylethyl)picolinamide (300 mg, 1.24 mmol) in DMF
4 mL), NaH (60% dispersion in mineral oil, 74 mg, 1.86 mmol,
.5 equiv) was added at 0 °C. The reaction was stirred at the
To
a
solution
of
N-(2-hydroxy-1-
(d, J = 8.1 Hz, 1H), 8.57 (ddd, J = 4.8, 1.6, 0.9 Hz, 1H), 8.24
(dt, J = 7.8, 1.0 Hz, 1H), 7.87 (td, J = 7.7, 1.7 Hz, 1H), 7.45
(ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.40 – 7.20 (m, 10H), 6.47 (d, J
= 8.6 Hz, 1H).
(
1
same temperature for 5 min and then MOMCl (0.12 mL,
1.61 mmol 1.3 equiv) was added and further stirred for
30 min at the same temperature. The reaction mixture was
quenched with ice water and then extracted with ethyl acetate
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(2-
methoxyphenyl) ethyl)picolinamide (1g). Synthesized
according to procedure B. Step 1: Methyl 2-(2-
methoxyphenyl)-2-(picolinamido)-acetate (0.90 g, 2.99 mmol,
(
H
3 x 10 mL). The combined organic phase was washed with dist.
O (10 mL), brine (10 mL) and then dried over anhydrous
Na SO , filtered and evaporated under reduced pressure. After
column chromatography (gradient hexanes/EtOAc from 2:1 to
:1) 185 mg (52%) of product was obtained as a colorless oil.
4
1 equiv), LiBH (4 M in THF 0.97 mL, 3.89 mmol, 1.3 equiv),
2
THF (24 mL). Step 2: Crude reaction mixture from Step 1,
imidazole (265 mg, 3.89 mmol, 1.3 equiv), TBSCl (587 mg,
3.89 mmol, 1.3 equiv), DMF (12 mL). After column
chromatography (hexanes/EtOAc 6:1) 627 mg (54%) of
2
4
1
1
R
f
= 0.29 (petroleum ether/EtOAc 1:1). H-NMR (400 MHz,
CDCl , ppm) δ 8.71 (d, J = 8.0 Hz, 1H), 8.53 – 8.42 (m, 1H),
8.11 (d, J = 7.8 Hz, 1H), 7.79 – 7.67 (m, 1H), 7.43 – 7.30 (m,
product was obtained as a colorless oil. R
ether/EtOAc 3:1). H-NMR (400 MHz, CDCl , ppm) δ 9.02 (d,
f
= 0.38 (petroleum
1
3
3
J = 8.6 Hz, 1H), 8.59 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.18 (dt, J
= 7.8, 1.1 Hz, 1H), 7.82 (td, J = 7.7, 1.7 Hz, 1H), 7.41 (ddd, J =
7.6, 4.8, 1.2 Hz, 1H), 7.33 – 7.27 (m, 1H), 7.22 (td, J = 7.9, 1.7
Hz, 1H), 6.94 – 6.85 (m, 2H), 5.53 (dt, J = 9.0, 5.1 Hz, 1H),
3.98 (dd, J = 10.0, 5.2 Hz, 1H), 3.94 – 3.86 (m, 4H), 0.83 (s,
3
5
3
1
7
H), 7.32 – 7.22 (m, 2H), 7.23 – 7.14 (m, 1H), 5.34 (dt, J = 8.5,
.1 Hz, 1H), 4.63 – 4.52 (m, 2H), 3.92 – 3.82 (m, 2H), 3.20 (s,
1
3
3
H). C{1H}NMR (100 MHz, CDCl , ppm) δ 163.9, 149.8,
48.1, 139.7, 137.3, 128.6, 127.5, 126.9, 126.3, 122.3, 96.5,
0.4, 55.4, 53.0. HR-MS (ESI-TOF) m/z: Calcd. for [M+Na] :
+
13
9H), -0.06 (s, 3H), -0.10 (s, 3H). C{1H}NMR (100 MHz,
C H
16
-1
18
N
2
O
3
Na 309.1215; found: 309.1217. FT-IR (thin film,
3
CDCl , ppm) δ 163.7, 157.1, 150.5, 148.3, 137.3, 128.8, 128.5,
cm ) υ 3390, 2932, 2887, 1680, 1518, 1151, 1041.
127.9, 126.1, 122.4, 120.6, 110.7, 64.9, 55.6, 51.4, 25.9, 18.4, -
+
N-(1-Phenylethyl)picolinamide (1e). Under an argon
atmosphere phenylethylamine (1.50 g, 12.38 mmol, 1 equiv),
picolinic acid (1.60 g, 13.00 mmol, 1.05 equiv) and N,N,N′,N′-
tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate (9.39 g, 24.76 mmol, 2 equiv) were
dissolved in DMF (24 mL). Pyridine (3.0 mL, 37.14 mmol, 3
equiv) was added to the solution directly. Reaction mixture was
stirred at room temperature overnight. Reaction was monitored
by TLC to achieve full conversion, and then was diluted with
EtOAc (50 mL) and H
separated and aqueous phase was extracted with EtOAc (50
mL), combined organic phase was washed with dist. H O (20
mL), brine (20 mL) and dried over Na SO , filtered. Solvent
was evaporated under reduced pressure to afford the crude
product, which was further purified by flash chromatography on
silica gel using petroleum ether/EtOAc (2/1) as an eluent to give
corresponding product 2.05 g (73%) as colorless oil. This
5.47, -5.48. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
21 31 2 3
C H N O Si 387.2104; found: 387.2108. FT-IR (thin film,
-1
cm ) υ 3394, 2930, 2856, 1694, 1508, 1256, 1110.
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(2-fluorophenyl)
ethyl)picolinamide (1h). Synthesized according to procedure
B. Step 1: Methyl 2-(2-fluorophenyl)-2-(picolinamido)acetate
4
(1.40 g, 4.86 mmol, 1 equiv), LiBH (4 M in THF 1.58 mL, 6.32
mmol, 1.3 equiv), THF (24 mL). Step 2: Crude reaction mixture
from Step 1, imidazole (430 mg, 6.32 mmol, 1.3 equiv), TBSCl
(952 mg, 6.32 mmol, 1.3 equiv), DMF (10 mL). After column
chromatography (hexanes/EtOAc 6:1) 1.30 g (71%) of product
2
O (50 mL), filtered. Organic phase was
2
was obtained as a colorless oil. R
ether/EtOAc 4:1). H-NMR (400 MHz, CDCl , ppm) δ 8.91 (d,
f
= 0.38 (petroleum
1
2
4
3
J = 8.2 Hz, 1H), 8.59 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.17 (dt, J
= 7.8, 1.0 Hz, 1H), 7.83 (td, J = 7.6, 1.7 Hz, 1H), 7.42 (ddd, J =
7.6, 4.8, 1.2 Hz, 1H), 7.37 (td, J = 7.6, 1.7 Hz, 1H), 7.26 – 7.18
(m, 1H), 7.11 – 7.01 (m, 2H), 5.52 (dt, J = 8.9, 4.8 Hz, 1H), 4.01
(dd, J = 10.1, 4.8 Hz, 1H), 3.95 (dd, J = 10.1, 4.8 Hz, 1H), 0.84
3
1
3
compound is known. H-NMR (400 MHz, CDCl , ppm) δ 8.53
(ddd, J = 4.8, 1.6, 0.9 Hz, 1H), 8.34 (d, J = 6.6 Hz, 1H), 8.20
(d, J = 7.8 Hz, 1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.45 – 7.38
1
3
(s, 9H), -0.03 (s, 3H), -0.09 (s, 3H). C{1H}NMR (100 MHz,
CDCl , ppm) δ 163.9, 160.7 (d, JC-F = 245.5 Hz), 150.0, 148.3,
3
(m, 3H), 7.38 – 7.33 (m, 2H), 7.26 (tt, J = 6.9, 1.3 Hz, 1H), 5.38
137.4, 129.1 (d, JC-F = 4.5 Hz), 129.0 (d, JC-F = 8.3 Hz), 127.1
(d, JC-F = 13.4 Hz), 126.3, 124.0 (d, JC-F = 3.4 Hz), 122.4, 115.5
(d, JC-F = 21.8 Hz), 65.2 (d, JC-F = 1.2 Hz), 50.0 (d, JC-F = 1.4
–
5.28 (m, 1H), 1.63 (d, J = 6.9 Hz, 3H).
N-Benzhydrylpicolinamide (1f). Under an argon
1
9
atmosphere diphenylmethanamine (0.66 mL, 3.82 mmol, 1
equiv), picolinic acid (470 mg, 3.82 mmol, 1 equiv) and
N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate (2.90 g, 7.64 mmol, 2 equiv) were
dissolved in DMF (15 mL). Pyridine (0.62 mL, 7.64 mmol, 2
Hz), 25.9, 18.3, -5.5, -5.6. F-NMR (376 MHz, CDCl
-118.54. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
SiF 375.1904; found: 375.1916. FT-IR (thin film,
cm ) υ 3388, 2955, 2928, 1685, 1514, 1107.
3
, ppm) δ
+
20 28 2 2
C H N O
-1
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1
2
3
+
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(3-methylphenyl)
ethyl)picolinamide (1i). Synthesized according to procedure B.
Step 1: Methyl 2-(3-methylphenyl)-2-(picolinamido)acetate
1.00 g, 3.52 mmol, 1 equiv), LiBH (4 M in THF 1.07 mL, 4.26
HR-MS
(ESI-TOF)
m/z:
Calcd.
for
[M+H] :
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
C H N O Si 371.2155; found: 371.2164. FT-IR (thin film,
21 31 2 2
-1
cm ) υ 3389, 2952, 2859, 1679, 1518, 1257, 1115.
(
4
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(4-
mmol, 1.2 equiv), THF (17 mL). Step 2: Crude reaction mixture
from Step 1, imidazole (312 mg, 4.58 mmol, 1.3 equiv), TBSCl
methoxphenyl)-ethyl)picolinamide
according to procedure B. Step 1: Methyl 2-(4-
methoxyphenyl)-2-(picolinamido)acetate (260 mg, 0.87 mmol,
4
1 equiv), LiBH (4 M in THF 0.28 mL, 1.12 mmol, 1.3 equiv),
THF (5 mL). Step 2: Crude reaction mixture from Step 1,
imidazole (77 mg, 1.12 mmol, 1.3 equiv), TBSCl (170 mg, 1.12
mmol, 1.3 equiv), DMF (4 mL). After column chromatography
(1l).
Synthesized
(
690 mg, 4.58 mmol, 1.3 equiv), DMF (15 mL). After column
chromatography (petroleum ether/EtOAc 6:1) 441 mg (34%) of
product was obtained as a colorless oil. R = 0.37 (petroleum
ether/EtOAc 5:1). H-NMR (400 MHz, CDCl , ppm) δ 8.82 (d,
J = 7.7 Hz, 1H), 8.58 (ddd, J = 4.7, 1.5, 0.8 Hz, 1H), 8.18 (d, J
7.8 Hz, 1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.42 (ddd, J = 7.6,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
1
3
=
(hexanes/EtOAc 6:1) 180 mg (54%) of product was obtained as
1
4
–
1
.8, 1.2 Hz, 1H), 7.24 – 7.16 (m, 3H), 7.10 – 7.01 (m, 1H), 5.22
5.10 (m, 1H), 3.99 (dd, J = 10.2, 4.6 Hz, 1H), 3.92 (dd, J =
a colorless oil. R
f
= 0.33 (petroleum ether/EtOAc 4:1). H-NMR
(400 MHz, CDCl
3
, ppm) δ 8.79 (d, J = 7.8 Hz, 1H), 8.56 (d, J
0.2, 4.6 Hz, 1H), 2.33 (s, 3H), 0.88 (s, 9H), 0.00 (s, 3H), -0.04
= 4.1 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.82 (td, J = 7.7, 1.6
Hz, 1H), 7.45 – 7.37 (m, 1H), 7.37 – 7.29 (m, 2H), 6.94 – 6.80
(m, 2H), 5.16 (dt, J = 8.7, 4.6 Hz, 1H), 3.98 (dd, J = 10.2, 4.7
Hz, 1H), 3.91 (dd, J = 10.2, 4.7 Hz, 1H), 3.78 (s, 3H), 0.88 (s,
13
3
(s, 3H). C{1H}NMR (100 MHz, CDCl , ppm) δ 164.0, 150.2,
1
48.3, 140.3, 138.0, 137.3, 128.4, 128.2, 128.0, 126.2, 124.2,
122.3, 66.4, 54.9, 25.9, 21.6, 18.4, -5.4. HR-MS (ESI-TOF)
+
13
m/z: Calcd. for [M+H] : C21
H
N
31 2
O
2
Si 371.2155; found:
9H), 0.01 (s, 3H), -0.02 (s, 3H). C{1H}NMR (100 MHz,
-
1
371.2159. FT-IR (thin film, cm ) υ 3397, 2954, 2927, 2857,
CDCl
3
, ppm) δ 163.9, 159.0, 150.1, 148.2, 137.4, 132.6, 128.3,
1
684, 1512, 1101.
126.2, 122.3, 113.9, 66.4, 55.4, 54.3, 25.9, 18.3, -5.4. HR-MS
(ESI-TOF) m/z: Calcd. for [M+Na] : C H N O NaSi
21 30 2 3
409.1923; found: 409.1926. FT-IR (thin film, cm ) υ 3389,
3058, 2952, 2929, 2857, 1688, 1505, 1249, 1109.
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(4-
methoxymethoxyphenyl)ethyl)picolinamide
Synthesized according to procedure B. Step 1: Methyl 2-(4-
methoxymethoxyphenyl)-2-(picolinamido)-acetate (514 mg,
1.56 mmol, 1 equiv), LiBH (4 M in THF 0.51 mL, 2.02 mmol,
4
1.3 equiv), THF (10 mL). Step 2: Crude reaction mixture from
Step 1, imidazole (138 mg, 2.02 mmol, 1.3 equiv), TBSCl (305
mg, 2.02 mmol, 1.3 equiv), DMF (5 mL). After column
chromatography (hexanes/EtOAc 6:1) 370 mg (57%) of
+
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(3-
-1
trifluoromethyl-phenyl)ethyl)picolinamide (1j). Synthesized
according to procedure B. Step 1: Methyl 2-(3-
trifluoromethylphenyl)-2-(picolinamido)acetate (1.12 g, 3.30
mmol, 1 equiv), LiBH
4
(4 M in THF 1.07 mL, 4.29 mmol, 1.3
(1m).
equiv), THF (30 mL). Step 2: Crude reaction mixture from Step
1, imidazole (292 mg, 4.29 mmol, 1.3 equiv), TBSCl (647 mg,
4
.29 mmol, 1.3 equiv), DMF (12 mL). After column
chromatography (hexanes/EtOAc 6:1) 1.40 g (60%) of product
was obtained as a colorless oil. R = 0.37 (petroleum
ether/EtOAc 3:1). H-NMR (400 MHz, CDCl , ppm) δ 8.94 (d,
J = 7.9 Hz, 1H), 8.59 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.17 (dt, J
7.8, 1.0 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.69 (s, 1H),
.60 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.49 – 7.32
f
1
3
=
7
product was obtained as a colorless oil. R
f
= 0.20 (petroleum
1
ether/EtOAc 4:1). H-NMR (400 MHz, CDCl , ppm) δ 8.78 (d,
3
(m, 2H), 5.26 (dt, J = 8.2, 4.1 Hz, 1H), 4.04 (dd, J = 10.2, 4.4
Hz, 1H), 3.94 (dd, J = 10.2, 3.8 Hz, 1H), 0.88 (s, 9H), 0.01 (s,
J = 7.9 Hz, 1H), 8.56 (ddd, J = 4.8, 1.6, 0.9 Hz, 1H), 8.17 (dt, J
= 7.8, 1.0 Hz, 1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.41 (ddd, J =
7.6, 4.8, 1.2 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.03 – 6.95 (m, 2H),
5.23 – 5.08 (m, 3H), 3.98 (dd, J = 10.2, 4.7 Hz, 1H), 3.91 (dd,
J = 10.2, 4.7 Hz, 1H), 3.46 (s, 3H), 0.88 (s, 9H), 0.01 (s, 3H), -
1
3
3
1
H), -0.05 (s, 3H). C{1H}NMR (100 MHz, CDCl
3
, ppm) δ
64.1, 149.8, 148.4, 141.7, 138.5, 130.8, 130.8 (q, JC-F = 32.1
Hz), 128.9, 126.4, 124.4 (q, JC-F = 3.8 Hz), 124.1 (q, JC-F = 3.8
1
3
Hz), 124.3 (q, JC-F = 272.4 Hz), 122.4, 66.2, 54.4, 25.8, 18.3, -
3
0.02 (s, 3H). C{1H}NMR (100 MHz, CDCl , ppm) δ 163.9,
19
5
(
.5, -5.6. F-NMR (376 MHz, CDCl
3
, ppm) δ -62.54. HR-MS
SiF 425.1872;
156.3, 150.2, 148.3, 137.4, 133.9, 128.4, 126.2, 122.3, 116.3,
+
ESI-TOF) m/z: Calcd. for [M+H] : C21
found: 425.1881. FT-IR (thin film, cm ) υ 3386, 2955, 2930,
2859, 1683, 1508, 1329, 1126.
H
28
N
2
O
2
3
94.6, 66.4, 56.1, 54.3, 25.9, 18.4, -5.37, -5.41. HR-MS (ESI-
-
1
+
TOF) m/z: Calcd. for [M+H] : C22
H
33
N
2
O
4
Si 417.2210; found:
-1
417.2206. FT-IR (thin film, cm ) υ 3388, 2930, 1512, 1153,
1108, 1080, 1006.
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(4-methylphenyl)-
ethyl)picolinamide (1k). Synthesized according to procedure
B. Step 1: Methyl 2-(4-methylphenyl)-2-(picolinamido)acetate
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(4-
trifluoromethoxyphenyl)ethyl)picolinamide
Synthesized according to procedure B. Step 1: Methyl 2-(4-
trifluoromethoxyphenyl)-2-(picolinamido)-acetate (1.16 g,
(1n).
(668 mg, 2.35 mmol, 1 equiv), LiBH
4
(4 M in THF 0.76 mL,
3
.05 mmol, 1.3 equiv), THF (15 mL). Step 2: Crude reaction
mixture from Step 1, imidazole (208 mg, 3.05 mmol, 1.3 equiv),
TBSCl (460 mg, 3.05 mmol, 1.3 equiv), DMF (8 mL). After
column chromatography (hexanes/EtOAc 6:1) 514 mg (59%) of
4
3.27 mmol, 1 equiv), LiBH (4 M in THF 1.06 mL, 4.26 mmol,
1.3 equiv), THF (24 mL). Step 2: Crude reaction mixture from
Step 1, imidazole (290 mg, 4.26 mmol, 1.3 equiv), TBSCl (642
mg, 4.26 mmol, 1.3 equiv), DMF (10 mL). After column
chromatography (hexanes/EtOAc 6:1) 1.00 g (69%) of product
product was obtained as a colorless oil. R
f
= 0.46 (petroleum
ether/EtOAc 4:1). H-NMR (400 MHz, CDCl , ppm) δ 8.79 (d,
J = 7.8 Hz, 1H), 8.56 (ddd, J = 4.8, 1.6, 0.9 Hz, 1H), 8.17 (dt, J
7.8, 1.0 Hz, 1H), 7.82 (td, J = 7.7, 1.7 Hz, 1H), 7.41 (ddd, J =
.6, 4.8, 1.2 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 7.9
1
3
was obtained as a colorless oil. R
f
= 0.34 (petroleum
1
=
7
ether/EtOAc 4:1). H-NMR (400 MHz, CDCl , ppm) δ 8.88 (d,
3
J = 7.9 Hz, 1H), 8.58 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.17 (dt, J
= 7.8, 1.1 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.48 – 7.40
(m, 3H), 7.21 – 7.12 (m, 2H), 5.21 (dt, J = 8.3, 4.3 Hz, 1H), 4.01
(dd, J = 10.2, 4.5 Hz, 1H), 3.92 (dd, J = 10.2, 4.2 Hz, 1H), 0.87
Hz, 2H), 5.17 (dt, J = 8.7, 4.7 Hz, 1H), 3.99 (dd, J = 10.2, 4.7
Hz, 1H), 3.92 (dd, J = 10.2, 4.9 Hz, 1H), 2.32 (s, 3H), 0.88 (s,
13
9
H), 0.01 (s, 3H), -0.02 (s, 3H). C{1H}NMR (100 MHz,
1
3
CDCl
3
, ppm) δ 163.9, 150.2, 148.2, 137.4, 137.3, 137.0, 129.2,
(s, 9H), 0.01 (s, 3H), -0.05 (s, 3H). C{1H}NMR (100 MHz,
CDCl , ppm) δ 164.1, 149.9, 148.6 (q, JC-F = 1.8 Hz), 148.3,
127.1, 126.2, 122.3, 66.4, 54.7, 25.9, 21.2, 18.4, -5.38, -5.42.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 19
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2
2
2
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3
3
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3
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3
3
3
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5
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139.3, 137.5, 128.6, 126.4, 122.4, 121.0, 120.6 (q, JC-F = 256.8
4.07 – 3.93 (m, 2H), 0.89 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H).
C{1H}NMR (100 MHz, CDCl , ppm) δ 163.8, 150.1, 148.3,
3
19
13
Hz), 66.3, 54.2, 25.9, 18.3, -5.47, -5.48. F-NMR (376 MHz,
CDCl , ppm) δ -57.19. HR-MS (ESI-TOF) m/z: Calcd. for
3
141.3, 137.4, 127.1, 126.3, 125.7, 122.4, 122.0, 65.8, 50.7, 25.9,
+
+
[
(
M+H] : C21
H
28
1
N
2
O
3
SiF
3
441.1821; found: 441.1828. FT-IR
18.4, -5.4. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
-
thin film, cm ) υ 3386, 2955, 2931, 2858, 1686, 1507, 1260,
18 27 2 2
C H N O SiS 363.1563; found: 363.1573. FT-IR (thin film,
-1
1
224, 1165, 1109.
cm ) υ 2954, 2928, 1676, 1513, 1510, 1255, 1114.
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(4-
fluorophenyl)ethyl)picolinamide (1o). Synthesized according
to procedure B. Step 1: Methyl 2-(4-fluorophenyl)-2-
N-(3-((Tert-butyldimethylsilyl)oxy)-1-
phenylpropyl)picolinamide (1r). Procedure C. Step 1: Under
an argon atmosphere 3-amino-3-phenylpropan-1-ol (700 mg,
4.62 mmol, 1 equiv), picolinic acid (570 mg, 4.62 mmol, 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(picolinamido)-acetate (742 mg, 2.57 mmol, 1 equiv), LiBH
4
(4 M in THF 0.84 mL, 3.34 mmol, 1.3 equiv), THF (20 mL).
Step 2: Crude reaction mixture from Step 1, imidazole (228 mg,
equiv)
and
N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-
yl)uronium hexafluorophosphate (3.51 g, 9.24 mmol, 2 equiv)
were dissolved in DMF (15 mL). Pyridine (0.75 mL, 9.24
mmol, 2 equiv) was added to the solution directly. Reaction
mixture was stirred at room temperature overnight. Reaction
was monitored by TLC to achieve full conversion, and then was
diluted with EtOAc (30 mL) and H O (30 mL), filtered. Organic
2
phase was separated and aqueous phase was extracted with
EtOAc (30 mL), combined organic phase was washed with dist.
3
.34 mmol, 1.3 equiv), TBSCl (504 mg, 3.34 mmol, 1.3 equiv),
DMF (10 mL). After column chromatography (petroleum
ether/EtOAc 6:1) 590 g (61%) of product was obtained as a
1
colorless oil. R
f
= 0.32 (petroleum ether/EtOAc 5:1). H-NMR
(
400 MHz, CDCl
3
, ppm) δ 8.85 (d, J = 7.7 Hz, 1H), 8.57 (ddd,
J = 4.8, 1.6, 0.9 Hz, 1H), 8.17 (dt, J = 7.8, 0.9 Hz, 1H), 7.83 (td,
J = 7.7, 1.7 Hz, 1H), 7.46 – 7.33 (m, 3H), 7.05 – 6.94 (m, 2H),
5.18 (dt, J = 8.4, 4.4 Hz, 1H), 3.99 (dd, J = 10.1, 4.6 Hz, 1H),
2 2 4
H O (20 mL), brine (20 mL) and dried over Na SO , filtered.
3
.91 (dd, J = 10.1, 4.3 Hz, 1H), 0.88 (s, 9H), 0.01 (s, 3H), -0.04
Solvent was evaporated under reduced pressure to afford the
crude product, which was used in next step without further
purification. Step 2: To the solution of crude reaction mixture
from previous step in DMF (12 mL) under an argon atmosphere
imidazole (471 mg, 6.93 mmol, 1.5 equiv) and tert-
butyldimethylsilyl chloride (1.04 g, 6.93 mmol, 1.5 equiv) were
added. The reaction mixture was stirred at room temperature to
achieve full conversion, then was diluted with EtOAc (30 mL)
13
(s, 3H). C{1H}NMR (100 MHz, CDCl
3
, ppm) δ 164.0, 162.2
(d, JC-F = 245.0 Hz), 150.0, 148.3, 137.4, 136.3 (d, JC-F = 3.1
Hz), 128.8 (d, JC-F = 8.1 Hz), 126.3, 122.4, 115.3 (d, JC-F = 21.4
19
Hz), 66.3, 54.2, 25.9, 18.4, -5.4, -5.5. F-NMR (376 MHz,
3
CDCl , ppm) δ -115.67. HR-MS (ESI-TOF) m/z: Calcd. for
+
[M+H] : C20FH28
2
N O
2
Si 375.1904; found: 375.1910. FT-IR
-1
(thin film, cm ) υ 3388, 2954, 2929, 2858, 1687, 1514, 1258,
1
223, 1103.
and H
was extracted with EtOAc (20 mL), combined organic phase
was washed with dist. H O (20 mL) and brine (20 mL).
Combined organic phase was dried over Na SO , filtered and
2
O (20 mL). Organic phase was separated and water phase
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(4-
bromophenyl)ethyl)picolinamide
according to procedure B. Step 1: Methyl 2-(4-bromophenyl)-
-(picolinamido)-acetate (335 mg, 0.96 mmol, 1 equiv), LiBH
4 M in THF 0.31 mL, 1.24 mmol, 1.3 equiv), THF (20 mL).
(1p).
Synthesized
2
2
4
2
4
evaporated under reduced pressure to afford the crude product,
which was further purified by flash chromatography on silica
gel using petroleum ether/EtOAc (5/1) as an eluent to give
(
Step 2: Crude reaction mixture from Step 1, imidazole (85 mg,
1.24 mmol, 1.3 equiv), TBSCl (188 mg, 1.24 mmol, 1.3 equiv),
DMF (10 mL). After column chromatography (hexanes/EtOAc
corresponding product 776 mg (68%) as colorless oil. R
(petroleum ether/EtOAc 3:1). H-NMR (400 MHz, CDCl
f
= 0.40
1
3
,
6
=
:1) 222 g (53%) of product was obtained as a colorless oil. R
0.33 (petroleum ether/EtOAc 5:1). H-NMR (400 MHz,
f
ppm) δ 8.90 (d, J = 7.6 Hz, 1H), 8.56 – 8.42 (m, 1H), 8.10 (d, J
= 7.8 Hz, 1H), 7.76 (td, J = 7.7, 1.7 Hz, 1H), 7.35 (ddd, J = 7.6,
4.8, 1.2 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.30 – 7.21 (m, 2H), 7.20
– 7.14 (m, 1H), 5.37 – 5.25 (m, 1H), 3.67 – 3.52 (m, 2H), 2.23
1
3
CDCl , ppm) δ 8.85 (d, J = 7.7 Hz, 1H), 8.61 – 8.49 (m, 1H),
8
7
3
0
.16 (d, J = 7.8 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.51 –
.40 (m, 3H), 7.33 – 7.27 (m, 2H), 5.15 (dt, J = 8.3, 4.3 Hz, 1H),
.99 (dd, J = 10.2, 4.5 Hz, 1H), 3.90 (dd, J = 10.2, 4.2 Hz, 1H),
– 2.07 (m, 1H), 2.10 – 1.96 (m, 1H), 0.86 (s, 9H), -0.00 (s, 3H),
13
3
-0.01 (s, 3H). C{1H}NMR (100 MHz, CDCl , ppm) δ 163.8,
1
3
.88 (s, 9H), 0.01 (s, 3H), -0.03 (s, 3H). C{1H}NMR (100
, ppm) δ 164.0, 150.0, 148.3, 136.6, 137.4, 131.5,
129.0, 126.4, 122.4, 121.3, 66.1, 54.3, 25.9, 18.4, -5.4, -5.5.
150.3, 148.1, 142.1, 137.3, 128.6, 127.2, 126.7, 126.1, 122.4,
MHz, CDCl
3
60.4, 51.9, 38.6, 26.1, 18.5, -5.30, -5.32. HR-MS (ESI-TOF)
+
m/z: Calcd. for [M+H] : C21
H
31
N
2
O
2
Si 371.2155; found:
+
-1
HR-MS
(ESI-TOF)
Si 435.1103; found: 435.1102. FT-IR (thin film,
cm ) υ 2954, 2928, 2856, 1684, 1515, 1255, 1107.
m/z:
Calcd.
for
[M+H] :
371.2155. FT-IR (thin film, cm ) υ 3379, 2952, 2928, 2856,
1682, 1519, 1257, 1093.
C
2 2
20BrH28N O
-1
(S)-N-(2-((Tert-butyldimethylsilyl)oxy)-1-
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(thiophen-3-
yl)ethyl)picolinamide (1q). Synthesized according to
procedure B. Step 1: Methyl 2-(picolinamido)-2-(thiophen-3-
phenylethyl)picolinamide (S-1a). Synthesized according to
procedure C. Step 1: (S)-2-Amino-2-phenylethanol (1.00 g,
7.29 mmol, 1 equiv), picolinic acid (942 mg, 7.65 mmol, 1.05
yl)acetate (280 mg, 1.01 mmol, 1 equiv), LiBH
4
(4 M in THF
equiv),
N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-
0.33 mL, 1.31 mmol, 1.3 equiv), THF (10 mL). Step 2: Crude
reaction mixture from Step 1, imidazole (89 mg, 1.31 mmol, 1.3
equiv), TBSCl (197 mg, 1.31 mmol, 1.3 equiv), DMF (5 mL).
After column chromatography (petroleum ether/EtOAc 6:1)
yl)uronium hexafluoro-phosphate (5.53 g, 14.58 mmol, 2
equiv), DMF (20 mL), pyridine (1.18 mL, 14.58 mmol, 2
equiv). Reaction mixture was filtered through short silicagel
column. Step 2: Reaction mixture from previous step,
imidazole (645 mg, 9.48 mmol, 1.3 equiv), TBSCl (1.43 g, 9.48
mmol, 1.3 equiv), DMF (25 mL). After column
chromatography (petroleum ether/EtOAc 6:1) 1.87 g (72%) of
2
0
f
33 g (64%) of product was obtained as a colorless oil. R =
.36 (petroleum ether/EtOAc 5:1). H-NMR (400 MHz, CDCl ,
3
1
ppm) δ 8.72 (d, J = 8.4 Hz, 1H), 8.55 (ddd, J = 4.8, 1.7, 0.9 Hz,
H), 8.20 (dt, J = 7.8, 1.0 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz,
1
product was obtained as a colorless oil. R
f
= 0.34 (petroleum
1H), 7.42 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.32 – 7.23 (m, 2H),
7.16 (dd, J = 4.9, 1.4 Hz, 1H), 5.36 (dt, J = 8.5, 4.2 Hz, 1H),
ether/EtOAc 4:1). ee = 99.9% (see attached HPLC data). The
ACS Paragon Plus Environment

Page 11 of 19
The Journal of Organic Chemistry
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NMR data matched to racemate. []
CHCl ).
-27.2 (c = 0.993,
obtained using Mn(OAc)
Organics and self-made Mn(OAc)
(3-(Tert-butyl)-1-(((tert-
butyldimethylsilyl)oxy)methyl)isoquinolin-2(1H)-
yl)(pyridin-2-yl)me-thanone (2aa). N-(2-((Tert-
3
·2 H
2
O purchased from Acros
·2 H O.
D
3
3
2
(E)-N-(2-((Tert-butyldimethylsilyl)oxy)-1-(2-
styrylphenyl)ethyl)picolinamide (1s). Step 1: Methyl (E)-2-
picolinamido)-2-(2-styrylphenyl)acetate (918 mg, 2.47 mmol,
equiv) was dissolved in THF (20 mL) under an argon
atmosphere. The solution was cooled in water/ice bath to 0 °C
and lithium borohydride (4 M in THF, 0.8 mL, 3.21 mmol, 1.3
equiv.) was added slowly dropwise, then reaction mixture was
stirred at room temperature for 3 h. The reaction was monitored
by TLC to achieve full conversion, then cooled in water/ice bath
and quenched by 15% citric acid solution in water. Organic
solvent was evaporated in vacuum and water phase was
extracted by 2 x DCM (30 mL). Combined organic phase was
(
1
butyldimethylsilyl)oxy)-1-phenylethyl)picolinamide (178 mg,
0.5 mmol), 3,3-dimethyl-1-butyne (185 µL, 1.5 mmol, 3 equiv),
Co(dpm)
mmol, 1.2 equiv), Mn(OAc)
equiv), and MeOH (5 mL), 16 h, 80 °C, O
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 183 mg (84%) of a yellowish oil was obtained. R
2
(42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
·2 H O (268 mg, 1.0 mmol, 2
atmosphere. After
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
2
f
=
0.45 (petroleum ether/EtOAc 4:1). Isolated as single
regioisomer. Structure confirmed by 2D-NMR (COSY,
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl
1
dried over Na
2
SO
4
, filtered and evaporated under reduced
3
,
pressure to afford the crude product, which was used in next
step without further purification. Step 2: To the solution of
crude product from Step 1 in DMF (7 mL) under an argon
atmosphere imidazole (218 mg, 3.21 mmol, 1.3 equiv) and tert-
butyldimethylsilyl chloride (483 mg, 3.21 mmol, 1.3 equiv)
were added. The reaction mixture was stirred at room
temperature to achieve full conversion, then was diluted with
ppm) δ 8.71 (d, J = 4.7 Hz, 1H), 7.86 – 7.72 (m, 2H), 7.43 –
7.36 (m, 1H), 7.23 – 7.17 (m, 1H), 7.13 (d, J = 6.6 Hz, 1H), 7.05
(td, J = 7.4, 1.3 Hz, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.57 (s, 1H),
5.01 (t, J = 6.3 Hz, 1H), 3.97 (dd, J = 9.8, 7.3 Hz, 1H), 3.62 (dd,
J = 9.8, 7.7 Hz, 1H), 1.38 (s, 9H), 0.85 (s, 9H), -0.08 (s, 3H), -
1
3
3
0.09 (s, 3H). C{1H}NMR (100 MHz, CDCl , ppm) δ 171.3,
153.7, 149.5, 149.3, 136.9, 132.7, 131.7, 128.0, 126.7, 126.5,
125.7, 125.3, 124.8, 118.1, 62.3, 60.7, 36.7, 31.0, 26.0, 18.4, -
5.4, -5.6. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
EtOAc (30 mL) and H
and water phase was extracted with EtOAc (20 mL), combined
organic phase was washed with dist. H O (20 mL) and brine (20
mL). Combined organic phase was dried over Na SO , filtered
2
O (20 mL). Organic phase was separated
+
C
26
-1
H
37
N
2
O
2
Si 437.2624; found: 437.2624. FT-IR (thin film,
2
cm ) υ 2955, 2930, 2858, 1653, 1117.
2
4
and evaporated under reduced pressure to afford the crude
product, which was further purified by flash chromatography on
silica gel using petroleum ether/EtOAc (6/1) as an eluent to give
(S)-(3-(Tert-butyl)-1-(((tert-
butyldimethylsilyl)oxy)methyl)isoquinolin-2(1H)-
yl)(pyridin-2-yl) methanone ((S)-2aa). (S)-N-(2-((Tert-
butyldimethylsilyl)oxy)-1-phenylethyl)picolinamide (178 mg,
0.5 mmol), 3,3-dimethyl-1-butyne (185 µL, 1.5 mmol, 3 equiv),
corresponding product 520 mg (46%) as colorless oil. R
f
= 0.37
petroleum ether/EtOAc 5:1). H-NMR (400 MHz, CDCl
ppm) δ 8.93 (d, J = 7.8 Hz, 1H), 8.60 (ddd, J = 4.8, 1.6, 0.9 Hz,
1
(
3
,
Co(dpm)
mmol, 1.2 equiv), Mn(OAc)
equiv), and MeOH (5 mL), 16 h, 80 °C, O
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 167 mg (77%) of a yellowish oil was obtained. R
2
(42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
·2 H O (268 mg, 1.0 mmol, 2
atmosphere. After
1
1
(
H), 8.22 (dt, J = 7.8, 1.0 Hz, 1H), 7.86 (td, J = 7.7, 1.7 Hz,
H), 7.68 (d, J = 16.0 Hz, 1H), 7.65 – 7.56 (m, 3H), 7.52 – 7.38
m, 4H), 7.37 – 7.25 (m, 3H), 7.02 (d, J = 16.0 Hz, 1H), 5.70
(dt, J = 8.3, 4.7 Hz, 1H), 4.05 (dd, J = 10.3, 4.7 Hz, 1H), 3.95
(dd, J = 10.3, 4.9 Hz, 1H), 0.89 (s, 9H), 0.00 (s, 3H), -0.05 (s,
3
2
2
f
=
0.45 (petroleum ether/EtOAc 4:1). Isolated as single
regioisomer. ee = > 99% (see attached HPLC data). The NMR
1
3
3H). C{1H}NMR (100 MHz, CDCl
3
, ppm) δ 163.9, 150.1,
48.3, 137.7, 137.6, 137.4, 136.4, 131.7, 128.8, 127.8, 127.7,
2
0
1
1
2
data matched to racemate. []
(3-(Tert-butyl)-1-(((4-
methoxybenzyl)oxy)methyl)isoquinolin-2(1H)-yl)(pyridin-
2-yl)metha-none (2ca). N-(2-((4-Methoxybenzyl)oxy)-1-
phenylethyl)picolinamide (181 mg, 0.5 mmol), 3,3-dimethyl-1-
D
3
-225.0 (c = 0.970, CHCl ).
27.6, 126.9, 126.8, 126.7, 126.23, 126.21, 122.3, 65.6, 51.4,
+
5.9, 18.3, -5.5. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
C
28
H
-1
35
N
2
O
2
Si 459.2468; found: 459.2476. FT-IR (thin film,
cm ) υ 3390, 2953, 2928, 2856, 1682, 1519, 1254, 1105.
Synthesis and characterization of reaction products 2.
butyne (185 µL, 1.5 mmol, 3 equiv), Co(dpm)
mmol, 20 mol%), NaOPiv (75 mg, 0.6 mmol, 1.2 equiv),
Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2 equiv), and MeOH (5
mL), 16 h, 80 °C, atmosphere. After column
2
(42.5 mg, 0.1
2
General procedure for cobalt-catalyzed sp C-H
alkenylation/cyclization. A 30 mL vial equipped with a
magnetic stir bar was charged with picolinamide (0.5 mmol),
3
2
O
2
Co(dpm)
.6 mmol, 1.2 equiv), Mn(OAc)
equiv), and MeOH (5 mL). The reaction mixture was purged
with O for 30 sec and then alkyne (0.75 – 1.50 mmol, 1.5 – 3
2
(42.5 mg, 0.10 mmol, 20 mol%), NaOPiv (74.5 mg,
chromatography (gradient petroleum ether/EtOAc from 6:1 to
4:1, then 2:1), 166 mg (75%) of a yellowish oil was obtained.
0
3
·2 H O (268 mg, 1.0 mmol, 2
2
R
f
= 0.16 (petroleum ether/EtOAc 4:1). Isolated as single
2
regioisomer. Structure confirmed by 2D-NMR (COSY,
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl ,
3
ppm) δ 8.68 (dt, J = 4.8, 1.3 Hz, 1H), 7.80 – 7.67 (m, 2H), 7.41
– 7.35 (m, 1H), 7.29 – 7.16 (m, 3H), 7.14 (d, J = 6.7 Hz, 1H),
7.07 (t, J = 8.0 Hz, 1H), 6.91 – 6.81 (m, 3H), 6.57 (s, 1H), 5.33
– 5.13 (m, 1H), 4.44 (s, 2H), 3.88 – 3.74 (m, 4H), 3.44 (dd, J =
9.8, 6.7 Hz, 1H), 1.35 (s, 9H). C{1H}NMR (100 MHz, CDCl ,
3
ppm) δ 171.2, 159.3, 153.7, 149.5, 149.4, 136.9, 132.8, 131.8,
130.4, 129.4, 128.1, 126.8, 126.0, 125.9, 125.3, 124.8, 118.2,
1
equiv) was added and mixture was heated at 80 °C for for
indicated time (16 h – 24 h). Reaction was monitored by TLC
after 16 h, 20 h and 24 h to determine the completion time. The
reaction mixture was cooled to room temperature and solvent
was evaporated. To the residue potassium sodium tartrate (10
mL of 1M aqueous solution) was added and mixture was
extracted with EtOAc (3 x 15 mL). Combined organic phase
1
3
2 4
was dried over Na SO , filtered, and solvent was evaporated.
Product was purified by column chromatography on silica gel
using appropriate eluent. After purification product was dried
under reduced pressure. Note! It was observed that the reaction
113.9, 72.9, 69.2, 58.6, 55.4, 36.8, 31.0. HR-MS (ESI-TOF)
+
m/z: Calcd. for [M+H] :
28 31 2 3
C H N O 443.2335; found:
-1
443.2341. FT-IR (thin film, cm ) υ 2959, 2864, 1658, 1607,
1512, 1255, 1169.
3 2
is sensitive to Mn(OAc) ·2 H O. Reproducible results were
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1
1
1
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1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
5
5
6
+
(3-(Tert-butyl)-1-
((methoxymethoxy)methyl)isoquinolin-2(1H)-yl)(pyridin-2-
[M+H] : C25
H
25
N
2
O 369.1967; found: 369.1973. FT-IR (thin
-1
film, cm ) υ 2967, 2905, 1653, 1648, 1375, 1364, 1334.
(3-(Tert-butyl)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
8-methoxyisoquinolin-2(1H)-yl)(pyri-din-2-yl)methanone
yl)methanone
phenylethyl)picolinamide (143 mg, 0.5 mmol), 3,3-dimethyl-1-
butyne (185 µL, 1.5 mmol, 3 equiv), Co(dpm) (42.5 mg, 0.1
mmol, 20 mol%), NaOPiv (75 mg, 0.6 mmol, 1.2 equiv),
Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2 equiv), and MeOH (5
mL), 24 h, 80 °C, atmosphere. After column
chromatography (gradient petroleum ether/EtOAc from 2:1 to
1:1), 128 mg (70%) of a yellowish oil was obtained. R = 0.40
(2da).
N-(2-(Methoxymethoxy)-1-
2
(2ga).
methoxyphenyl)ethyl)picolinamide (193 mg, 0.5 mmol), 3,3-
dimethyl-1-butyne (185 µL, 1.5 mmol, equiv),
Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2
equiv), and MeOH (5 mL), 20 h, 80 °C, O atmosphere. After
column chromatography (gradient petroleum ether/EtOAc from
8:1 to 6:1, then 4:1), 127 mg (55%) of a yellowish oil was
obtained. R
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(2-
3
2
3
O
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
f
2
(petroleum ether/EtOAc 2:1). Isolated as single regioisomer.
Structure confirmed by 2D-NMR (COSY, NOESY, see
1
attached NMR data). H-NMR (400 MHz, CDCl
3
, ppm) δ 8.69
f
= 0.48 (petroleum ether/EtOAc 3:1). Isolated as
(
ddd, J = 4.8, 1.6, 1.0 Hz, 1H), 7.81 – 7.67 (m, 2H), 7.39 (ddd,
single regioisomer. Structure confirmed by 2D-NMR (COSY,
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl ,
3
1
J = 7.4, 4.8, 1.4 Hz, 1H), 7.20 (td, J = 7.5, 1.2 Hz, 1H), 7.14 (d,
J = 6.5 Hz, 1H), 7.06 (td, J = 7.4, 1.4 Hz, 1H), 6.88 (d, J = 7.4
Hz, 1H), 6.58 (s, 1H), 5.34 – 5.06 (m, 1H), 4.63 – 4.54 (m, 2H),
3.91 (dd, J = 9.8, 7.0 Hz, 1H), 3.59 (dd, J = 9.8, 7.6 Hz, 1H),
3.24 (s, 3H), 1.37 (s, 9H). C{1H}NMR (100 MHz, CDCl
ppm) δ 171.0, 153.6, 149.5, 149.0, 137.0, 132.8, 131.6, 128.0,
ppm) δ 8.72 – 8.64 (m, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.74 (td,
J = 7.7, 1.7 Hz, 1H), 7.36 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 7.15
(t, J = 7.9 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 8.1 Hz,
1H), 6.54 (s, 1H), 5.53 – 5.33 (m, 1H), 3.70 (dd, J = 10.5, 9.2
Hz, 1H), 3.63 (s, 3H), 3.52 (dd, J = 10.6, 4.7 Hz, 1H), 1.38 (s,
9H), 0.91 (s, 9H), 0.01 (s, 3H), -0.01 (s, 3H). C{1H}NMR
(100 MHz, CDCl , ppm) δ 171.6, 154.8, 154.0, 149.9, 149.7,
136.3, 133.5, 128.5, 124.8, 124.5, 120.7, 118.5, 118.1, 109.5,
61.1, 55.5, 55.2, 36.8, 30.9, 26.1, 18.5, -5.39, -5.40. HR-MS
(ESI-TOF) m/z: Calcd. for [M+H] : C27
found: 467.2747. FT-IR (thin film, cm ) υ 2952, 2858, 1674,
1474, 1259, 1104.
(3-(Tert-butyl)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
8-fluoroisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
(2ha).
fluorophenyl)ethyl)picolinamide (187 mg, 0.5 mmol), 3,3-
dimethyl-1-butyne (185 µL, 1.5 mmol, equiv),
Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2
equiv), and MeOH (5 mL), 24 h, 80 °C, O atmosphere. After
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 169 mg (74%) of a yellowish oil was obtained. R
13
3
,
1
3
1
3
26.7, 126.1, 125.8, 125.4, 124.8, 118.1, 96.3, 66.7, 58.5, 55.3,
6.7, 31.0. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
+
3
-
C
22
H
27
N
2
O
3
367.2022; found: 367.2033. FT-IR (thin film, cm
υ 2956, 1662, 1653, 1365, 1149, 1116, 1038.
3-(Tert-butyl)-1-methylisoquinolin-2(1H)-yl)(pyridin-
-yl)methanone (2ea). N-(1-Phenylethyl)picolinamide (113
mg, 0.5 mmol), 3,3-dimethyl-1-butyne (185 µL, 1.5 mmol, 3
equiv), Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75
mg, 0.6 mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0
mmol, 2 equiv), and MeOH (5 mL), 16 h, 80 °C, O atmosphere.
1
)
+
(
H
39
N
2
O
3
Si 467.2730;
-1
2
2
3
2
2
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(2-
After column chromatography (gradient petroleum
ether/EtOAc from 6:1 to 4:1), 126 mg (82%) of a yellowish oil
3
was obtained. R
f
= 0.33 (petroleum ether/EtOAc 4:1). Isolated
2
as single regioisomer. Structure confirmed by 2D-NMR
3
2
1
(
COSY, NOESY, see attached NMR data). H-NMR (400
MHz, CDCl , ppm) δ 8.72 (d, J = 5.4 Hz, 1H), 7.78 (td, J = 7.7,
1.7 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.45 – 7.38 (m, 1H), 7.20
7.11 (m, 2H), 7.05 (td, J = 7.2, 1.8 Hz, 1H), 6.78 (d, J = 7.4
Hz, 1H), 6.61 (s, 1H), 5.23 – 5.03 (m, 1H), 1.43 (d, J = 6.8 Hz,
2
3
f
=
–
0.52 (petroleum ether/EtOAc 4:1). Isolated as single
regioisomer. Structure confirmed by 2D-NMR (COSY,
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl
ppm) δ 8.79 – 8.60 (m, 1H), 7.86 – 7.73 (m, 2H), 7.40 (ddd, J =
7.4, 4.8, 1.4 Hz, 1H), 7.16 (td, J = 8.0, 5.6 Hz, 1H), 6.93 (d, J =
7.5 Hz, 1H), 6.79 (t, J = 9.1 Hz, 1H), 6.59 (d, J = 1.7 Hz, 1H),
5.47 (t, J = 7.2 Hz, 1H), 3.92 (dd, J = 10.0, 7.7 Hz, 1H), 3.65
(dd, J = 10.1, 6.8 Hz, 1H), 1.38 (s, 9H), 0.85 (s, 9H), -0.04 (s,
1
3
1
3
1
1
H), 1.38 (s, 9H). C{1H}NMR (100 MHz, CDCl
3
, ppm) δ
3
,
71.0, 154.2, 148.9, 148.7, 137.21, 137.19, 131.1, 127.5, 127.0,
26.0, 125.4, 124.8, 124.1, 118.2, 55.7, 36.6, 30.9, 19.6. HR-
MS (ESI-TOF) m/z: Calcd. for [M+H] : C20
found: 307.1823. FT-IR (thin film, cm ) υ 2966, 1653, 1395,
1341, 1164.
(3-(Tert-butyl)-1-phenylisoquinolin-2(1H)-yl)(pyridin-
-yl)methanone (2fa). N-Benzhydrylpicolinamide (144 mg,
.5 mmol), 3,3-dimethyl-1-butyne (185 µL, 1.5 mmol, 3
+
H
23
N
2
O 307.1810;
-
1
1
3
3
3H), -0.06 (s, 3H). C{1H}NMR (100 MHz, CDCl , ppm) δ
2
0
171.4, 158.4 (d, JC-F = 245.8 Hz), 153.4, 150.9, 149.5, 136.8,
134.2, (d, JC-F = 4.9 Hz), 129.0 (d, JC-F = 8.4 Hz), 125.4, 124.7,
121.4 (d, JC-F = 2.9 Hz), 119.5 (d, JC-F = 17.5 Hz), 117.6 (d, JC-
equiv), Co(dpm)
mg, 0.6 mmol, 1.2 equiv), Mn(OAc)
mmol, 2 equiv), and MeOH (5 mL), 16 h, 80 °C, O
2
(42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75
·2 H O (268 mg, 1.0
atmosphere.
3
2
F
= 3.4 Hz), 113.8 (d, JC-F = 21.9 Hz), 61.5, 54.5, 36.9, 30.9,
19
2
26.0, 18.4, -5.49, -5.52. F-NMR (376 MHz, CDCl
121.12. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
SiF 455.2530; found: 455.2543. FT-IR (thin film,
3
, ppm) δ -
+
After column chromatography (gradient petroleum
ether/EtOAc from 6:1 to 4:1), 162 mg (88%) of a yellowish oil
26 36 2 2
C H N O
-1
was obtained. R
f
= 0.40 (petroleum ether/EtOAc 4:1). Isolated
cm ) υ 2957, 2930, 2858, 1653, 1465, 1250, 1111, 1082.
(3-(Tert-butyl)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
7-methylisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
(2ia).
methylphenyl)ethyl)picolinamide (185 mg, 0.5 mmol), 3,3-
dimethyl-1-butyne (185 µL, 1.5 mmol, equiv),
Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2
equiv), and MeOH (5 mL), 24 h, 80 °C, O atmosphere. After
column chromatography (gradient petroleum ether/EtOAc from
as single regioisomer. Structure confirmed by 2D-NMR
1
(
COSY, NOESY, see attached NMR data). H-NMR (400
MHz, CDCl , ppm) δ 8.77 (d, J = 4.3 Hz, 1H), 7.81 (t, J = 7.2
Hz, 1H), 7.70 (d, J = 6.9 Hz, 1H), 7.55 – 7.34 (m, 3H), 7.32 –
3
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(3-
7
–
.24 (m, 5H), 7.14 (t, J = 6.7 Hz, 1H), 6.99 – 6.77 (m, 1H), 6.69
6.24 (m, 2H), 1.02 (s, 9H). C{1H}NMR (100 MHz, CDCl
ppm) δ 170.5, 153.9, 150.1, 148.6, 139.3, 137.3, 133.4, 132.9,
128.9, 128.1, 127.8, 127.7, 127.0, 126.1, 125.8, 125.5, 125.1,
119.1, 60.7, 36.3, 30.6. HR-MS (ESI-TOF) m/z: Calcd. for
3
13
3
,
2
3
2
2
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The Journal of Organic Chemistry
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1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6:1 to 3:1), 176 mg (78%) of a yellowish oil was obtained. R
0.71 (petroleum ether/EtOAc 3:1). Isolated as single
f
=
(3-(Tert-butyl)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
6-methoxyisoquinolin-2(1H)-yl)(pyri-din-2-yl)methanone
regioisomer. Structure confirmed by 2D-NMR (COSY,
(2la).
methoxyphenyl)ethyl)picolinamide (161 mg, 0.41 mmol), 3,3-
dimethyl-1-butyne (150 µL, 1.23 mmol, equiv),
Co(dpm) (34 mg, 0.08 mmol, 20 mol%), NaOPiv (62 mg, 0.5
mmol, 1.2 equiv), Mn(OAc) ·2 H O (220 mg, 0.82 mmol, 2
equiv), and MeOH (4 mL), 16 h, 80 °C, O atmosphere. After
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 143 mg (75%) of a yellowish oil was obtained. R
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(4-
1
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl
3
,
ppm) δ 8.70 (dt, J = 4.8, 1.3 Hz, 1H), 7.84 – 7.71 (m, 2H), 7.42
3
–
5
7.34 (m, 1H), 7.07 – 6.97 (m, 2H), 6.68 (s, 1H), 6.53 (s, 1H),
.08 – 4.82 (m, 1H), 3.95 (dd, J = 9.8, 7.4 Hz, 1H), 3.59 (dd, J
2
3
2
=
9.8, 7.6 Hz, 1H), 2.23 (s, 3H), 1.37 (s, 9H), 0.85 (s, 9H), -0.08
2
13
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
(s, 3H), -0.09 (s, 3H). C{1H}NMR (100 MHz, CDCl , ppm)
δ 171.2, 153.9, 149.4, 148.4, 136.8, 136.3, 132.7, 129.0, 128.6,
127.4, 125.6, 125.2, 124.7, 118.0, 62.3, 60.8, 36.6, 31.0, 25.9,
f
=
0.33 (petroleum ether/EtOAc 4:1). Isolated as single
2
1.3, 18.4, -5.48, -5.53. HR-MS (ESI-TOF) m/z: Calcd. for
regioisomer. Structure confirmed by 2D-NMR (COSY,
+
1
[M+H] : C27
H
39
2
N O
2
Si 451.2781; found: 451.2794. FT-IR (thin
film, cm ) υ 2956, 2928, 2858, 1660, 1388, 1364, 1258, 1113.
3-(Tert-butyl)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
-trifluoromethylisoquinolin-2(1H)-yl) (pyridin-2-
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl
3
,
-1
ppm) δ 8.74 – 8.65 (m, 1H), 7.82 – 7.72 (m, 2H), 7.42 – 7.37
(m, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.61
(dd, J = 8.3, 2.6 Hz, 1H), 6.53 (s, 1H), 4.95 (t, J = 6.9 Hz, 1H),
3.94 (dd, J = 9.8, 7.3 Hz, 1H), 3.77 (s, 3H), 3.57 (dd, J = 9.8,
7.6 Hz, 1H), 1.37 (s, 9H), 0.85 (s, 9H), -0.07 (s, 3H), -0.08 (s,
(
7
yl)methanone (2ja). N-(2-((Tert-butyldimethylsilyl)oxy)-1-(3-
trifluoromethylphenyl)ethyl)picolinamide (212 mg, 0.5 mmol),
1
3
3,3-dimethyl-1-butyne
Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2
equiv), and MeOH (5 mL), 24 h, 80 °C, O atmosphere. After
column chromatography (gradient petroleum ether/EtOAc from
(185 µL, 1.5 mmol, 3 equiv),
3
3H). C{1H}NMR (100 MHz, CDCl , ppm) δ 171.3, 159.4,
2
153.8, 150.1, 149.4, 136.8, 132.9, 127.6, 125.3, 125.2, 124.8,
118.2, 112.4, 110.7, 62.5, 60.3, 55.5, 36.8, 31.0, 26.0, 18.4, -
3
2
+
2
5.4, -5.5. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
27 39 2 3
C H N O Si 467.2730; found: 467.2736. FT-IR (thin film,
-
1
6
0
:1 to 4:1), 165 mg (65%) of a yellowish oil was obtained. R
.77 (petroleum ether/EtOAc 3:1). Isolated as single
f
=
cm ) υ 2955, 2930, 2858, 1653, 1246, 1154, 1110.
(3-(Tert-butyl)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
6-(methoxymethoxy)isoquinolin-2(1H)-yl)(pyridin-2-
yl)methanone (2ma). N-(2-((Tert-butyldimethylsilyl)oxy)-1-
(4-methoxymethoxyphenyl)ethyl)pico-linamide (208 mg, 0.5
mmol), 3,3-dimethyl-1-butyne (185 µL, 1.5 mmol, 3 equiv),
regioisomer. Structure confirmed by 2D-NMR (COSY,
1
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl
3
,
ppm) δ 8.71 (dt, J = 4.8, 1.3 Hz, 1H), 7.87 – 7.74 (m, 2H), 7.51
–
1
1
3
1
3
7.38 (m, 2H), 7.22 (d, J = 7.9 Hz, 1H), 7.13 (s, 1H), 6.60 (s,
H), 5.11 (dd, J = 8.6, 6.5 Hz, 1H), 4.08 (dd, J = 9.4, 6.4 Hz,
H), 3.69 – 3.58 (m, 1H), 1.37 (s, 9H), 0.82 (s, 9H), -0.10 (s,
Co(dpm)
mmol, 1.2 equiv), Mn(OAc)
equiv), and MeOH (5 mL), 20 h, 80 °C, O
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 209 mg (84%) of a yellowish oil was obtained. R
2
(42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
·2 H O (268 mg, 1.0 mmol, 2
atmosphere. After
3
2
13
H), -0.12 (s, 3H). C{1H}NMR (100 MHz, CDCl
71.2, 153.1, 152.6, 149.2, 137.2, 134.8, 133.3, 128.2 (q, JC-F
2.4 Hz), 125.8, 125.7, 125.2, 124.9 (q, JC-F = 3.8 Hz), 124.3 (q,
C-F = 272.0 Hz), 124.0 (q, JC-F = 3.7 Hz), 117.1, 61.9, 60.3,
3
, ppm) δ
2
=
f
=
J
0.31 (petroleum ether/EtOAc 4:1). Isolated as single
1
9
37.1, 31.0, 25.9, 18.3, -5.5, -5.6. F-NMR (376 MHz, CDCl
3
+
,
regioisomer. Structure confirmed by 2D-NMR (COSY,
1
ppm) δ -62.29. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
SiF 505.2498; found: 505.2511. FT-IR (thin film,
cm ) υ 2958, 2930, 2859, 1661, 1331, 1164, 1131, 1125, 1070.
3-(Tert-butyl)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
-methylisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
2ka). N-(2-((Tert-butyldimethylsilyl)oxy)-1-(4-
methylphenyl)ethyl)picolinamide (185 mg, 0.5 mmol), 3,3-
dimethyl-1-butyne (185 µL, 1.5 mmol, equiv),
Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2
equiv), and MeOH (5 mL), 16 h, 80 °C, O atmosphere. After
column chromatography (gradient petroleum ether/EtOAc from
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl
3
,
C
27
-
H
36
N
2
O
2
3
ppm) δ 8.73 – 8.64 (m, 1H), 7.85 – 7.63 (m, 2H), 7.43 – 7.35
(m, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.81 – 6.69 (m, 2H), 6.53 (s,
1H), 5.17 – 5.09 (m, 2H), 4.96 (t, J = 6.8 Hz, 1H), 3.93 (dd, J =
9.8, 7.3 Hz, 1H), 3.57 (dd, J = 9.8, 7.5 Hz, 1H), 3.45 (s, 3H),
1.36 (s, 9H), 0.86 (s, 9H), -0.06 (s, 3H), -0.07 (s, 3H).
3
C{1H}NMR (100 MHz, CDCl , ppm) δ 171.3, 157.0, 153.8,
1
(
6
(
13
3
150.1, 149.4, 136.8, 132.9, 127.5, 126.5, 125.3, 124.8, 118.2,
114.6, 113.3, 94.6, 62.4, 60.3, 56.0, 36.8, 31.0, 26.0, 18.4, -5.4,
2
+
3
2
-5.5. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
2
28 41 2 4
C H N O Si 497.2836; found: 497.2840. FT-IR (thin film,
-
1
cm ) υ 2955, 2929, 2857, 1653, 1241, 1152, 1112.
6
0
:1 to 4:1), 202 mg (90%) of a yellowish oil was obtained. R
.44 (petroleum ether/EtOAc 4:1). Isolated as single
f
=
(3-(Tert-butyl)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
6-trifluoromethoxyisoquinolin-2(1H)-yl)(pyridin-2-
yl)methanone (2na). N-(2-((Tert-butyldimethylsilyl)oxy)-1-
(4-trifluoromethoxyphenyl)ethyl)picolin-amide (260 mg, 0.5
mmol), 3,3-dimethyl-1-butyne (185 µL, 1.5 mmol, 3 equiv),
regioisomer. Structure confirmed by 2D-NMR (COSY,
1
3
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl ,
ppm) δ 8.69 (dd, J = 5.4, 1.9 Hz, 1H), 7.84 – 7.70 (m, 2H), 7.42
– 7.35 (m, 1H), 6.96 (s, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.75 (d,
J = 7.6 Hz, 1H), 6.52 (s, 1H), 5.09 – 4.87 (m, 1H), 3.93 (dd, J =
Co(dpm)
mmol, 1.2 equiv), Mn(OAc)
equiv), and MeOH (5 mL), 17 h, 80 °C, O
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 194 mg (75%) of a yellowish oil was obtained. R
2
(42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
·2 H O (268 mg, 1.0 mmol, 2
atmosphere. After
3
2
9
1
.8, 7.4 Hz, 1H), 3.57 (dd, J = 9.8, 7.4 Hz, 1H), 2.29 (s, 3H),
2
.36 (s, 9H), 0.86 (s, 9H), -0.06 (s, 3H), -0.07 (s, 3H).
1
3
C{1H}NMR (100 MHz, CDCl
3
, ppm) δ 171.3, 153.9, 149.5,
f
=
1
1
49.4, 137.6, 136.7, 131.6, 130.0, 127.2, 126.5, 126.4, 125.2,
0.52 (petroleum ether/EtOAc 4:1). Isolated as single
24.7, 118.2, 62.5, 60.6, 36.7, 31.0, 26.0, 21.3, 18.5, -5.4, -5.5.
regioisomer. Structure confirmed by 2D-NMR (COSY,
+
1
HR-MS (ESI-TOF) m/z: Calcd. for [M+H] : C27
451.2781; found: 451.2786. FT-IR (thin film, cm ) υ 2956,
2928, 2858, 1661, 1653, 1364, 1111.
H
39
N
2
O
2
Si
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl
3
,
-
1
ppm) δ 8.70 (dd, J = 3.7, 2.4 Hz, 1H), 7.88 – 7.74 (m, 2H), 7.47
– 7.37 (m, 1H), 7.00 (s, 1H), 6.94 – 6.84 (m, 2H), 6.54 (s, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5.06 (t, J = 7.4 Hz, 1H), 4.01 (dd, J = 9.6, 6.8 Hz, 1H), 3.62 (dd,
J = 9.6, 8.3 Hz, 1H), 1.37 (s, 9H), 0.83 (s, 9H), -0.09 (s, 3H), -
butyldimethylsilyl)oxy)-1-(thiophen-3-yl)ethyl)picolinamide
(181 mg, 0.5 mmol), 3,3-dimethyl-1-butyne (185 µL, 1.5 mmol,
3 equiv), Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv
(75 mg, 0.6 mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0
mmol, 2 equiv), and MeOH (5 mL), 16 h, 80 °C, O atmosphere.
1
3
0
1
1
1
.10 (s, 3H). C{1H}NMR (100 MHz, CDCl
53.3, 151.6, 149.3, 149.0 (q, JC-F = 1.8 Hz), 137.1, 133.4,
31.3, 128.2, 125.6, 125.0, 120.6 (q, JC-F = 257.0 Hz), 118.8,
3
, ppm) δ 171.3,
2
3
2
2
1
9
18.0, 117.2, 62.0, 60.1, 36.9, 31.0, 25.9, 18.4, -5.47, -5.54. F-
, ppm) δ -57.84. HR-MS (ESI-TOF)
After column chromatography (gradient petroleum
ether/EtOAc from 6:1 to 4:1), 185 mg (84%) of a yellowish oil
NMR (376 MHz, CDCl
3
+
m/z: Calcd. for [M+H] : C27
H
36
N
2
O
3
F
3
Si 521.2447; found:
21.2458. FT-IR (thin film, cm ) υ 2957, 2930, 2859, 1662,
1260, 1168, 1118.
was obtained.Unseperable mixture of regioisomers (3.1:1). R
f
=
-1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
0.54 (petroleum ether/EtOAc 3:1). Note! In NMR signals for
1
3
major regioisomer are given. H-NMR (400 MHz, CDCl ,
(3-(Tert-butyl)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
ppm) δ 8.74 – 8.67 (m, 1H), 7.84 – 7.73 (m, 2H), 7.42 – 7.38
(m, 1H), 7.02 (d, J = 5.0 Hz, 1H), 6.65 (d, J = 5.0 Hz, 1H), 6.58
(s, 1H), 5.19 – 5.06 (m, 1H), 3.93 (dd, J = 9.6, 7.0 Hz, 1H), 3.61
(dd, J = 9.6, 7.9 Hz, 1H), 1.34 (s, 9H), 0.86 (s, 9H), -0.05 (s,
6
-fluoroisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
(
2oa).
fluorophenyl)ethyl)picolinamide (187 mg, 0.5 mmol), 3,3-
dimethyl-1-butyne (185 µL, 1.5 mmol, equiv),
Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2
equiv), and MeOH (5 mL), 24 h, 80 °C, O atmosphere. After
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 151 mg (66%) of a yellowish oil was obtained. R
.76 (petroleum ether/EtOAc 2:1). Isolated as single
regioisomer. Structure confirmed by 2D-NMR (COSY,
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(4-
1
3
3
3
3H), -0.07 (s, 3H). C{1H}NMR (100 MHz, CDCl , ppm) δ
2
171.8, 153.6, 149.4, 147.1, 136.9, 133.8, 133.6, 125.8, 125.4,
3
2
125.0, 123.0, 112.6, 62.0, 58.1, 36.9, 31.1, 26.0, 18.4, -5.4, -5.6.
+
2
HR-MS (ESI-TOF) m/z: Calcd. for [M+H] : C24
H
35
1
N
2
O
2
SSi
-
443.2189; found: 443.2199. FT-IR (thin film, cm ) υ 2956,
2928, 2858, 1655, 1364, 1257, 1113.
f
=
0
(3-(Tert-butyl)-1-(2-((tert-
butyldimethylsilyl)oxy)ethyl)isoquinolin-2(1H)-yl)(pyridin-
2-yl) methanone (2ra). N-(3-((Tert-butyldimethylsilyl)oxy)-1-
phenylpropyl)picolinamide (185 mg, 0.5 mmol), 3,3-dimethyl-
1-butyne (185 µL, 1.5 mmol, 3 equiv; additional 93 µL, 0.75
1
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl
3
,
ppm) δ 8.70 (dt, J = 4.8, 1.3 Hz, 1H), 7.83 – 7.74 (m, 2H), 7.44
–
1
7.37 (m, 1H), 6.87 – 6.78 (m, 2H), 6.75 (td, J = 8.5, 2.5 Hz,
H), 6.51 (s, 1H), 5.02 (t, J = 7.3 Hz, 1H), 3.98 (dd, J = 9.6, 6.9
mmol, 1.5 equiv after 16 h), Co(dpm)
mol%), NaOPiv (75 mg, 0.6 mmol, 1.2 equiv),
Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2 equiv), and MeOH (5
mL), 40 h, 80 °C, atmosphere. After column
chromatography (gradient petroleum ether/EtOAc from 6:1 to
4:1), 160 mg (71%) of a yellowish oil was obtained. R = 0.51
2
(42.5 mg, 0.1 mmol, 20
Hz, 1H), 3.59 (dd, J = 9.6, 8.1 Hz, 1H), 1.36 (s, 9H), 0.84 (s,
1
3
9H), -0.08 (s, 3H), -0.09 (s, 3H). C{1H}NMR (100 MHz,
CDCl , ppm) δ 171.3, 162.6 (d, JC-F = 244.7 Hz), 153.5, 151.1,
49.3, 137.0, 133.5 (d, JC-F = 8.6 Hz), 128.6 (d, JC-F = 2.8 Hz),
3
2
3
O
2
1
1
1
3
28.2 (d, JC-F = 8.5 Hz), 125.5, 124.9, 117.5 (d, JC-F = 2.3 Hz),
f
13.0 (d, JC-F = 21.9 Hz), 112.2 (d, JC-F = 22.3 Hz), 62.2, 60.1,
(petroleum ether/EtOAc 4:1). Isolated as single regioisomer.
19
6.9, 31.0, 26.0, 18.4, -5.4, -5.5. F-NMR (376 MHz, CDCl
3
+
,
Structure confirmed by 2D-NMR (COSY, NOESY, see
1
ppm) δ -114.98. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
SiF 455.2530; found: 455.2540. FT-IR (thin film,
attached NMR data). H-NMR (400 MHz, CDCl
3
, ppm) δ 8.69
C
26
-
H
36
N
2
O
2
(dd, J = 6.0, 1.2 Hz, 1H), 7.75 (td, J = 7.7, 1.7 Hz, 1H), 7.57 (d,
J = 7.8 Hz, 1H), 7.37 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.21 – 7.11
(m, 2H), 7.05 (td, J = 7.3, 1.6 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H),
6.59 (s, 1H), 5.20 – 5.02 (m, 1H), 3.66 (ddd, J = 10.3, 6.3, 3.8
Hz, 1H), 3.40 (dd, J = 20.2, 4.9 Hz, 1H), 2.28 – 2.18 (m, 1H),
1.80 – 1.72 (m, 1H), 1.39 (s, 9H), 0.84 (s, 9H), 0.02 (s, 3H), -
1
cm ) υ 2956, 2929, 2858, 1662, 1652, 1365, 1240, 1146, 1109.
(3-(Tert-butyl)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
6
-bromoisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
2pa). N-(2-((Tert-butyldimethylsilyl)oxy)-1-(4-
bromophenyl)ethyl)picolinamide (202 mg, 0.46 mmol), 3,3-
dimethyl-1-butyne (170 µL, 1.38 mmol, equiv),
Co(dpm) (39 mg, 0.092 mmol, 20 mol%), NaOPiv (69 mg,
.55 mmol, 1.2 equiv), Mn(OAc) ·2 H O (247 mg, 0.92 mmol,
equiv), and MeOH (5 mL), 16 h, 80 °C, O atmosphere. After
(
1
3
3
3
0.00 (s, 3H). C{1H}NMR (100 MHz, CDCl , ppm) δ 171.5,
2
154.2, 149.6, 149.0, 137.0, 134.6, 131.3, 127.6, 126.5, 126.0,
125.4, 125.1, 124.2, 118.2, 59.5, 56.5, 36.6, 35.1, 31.0, 26.1,
0
2
3
2
+
2
18.3, -5.2, -5.3. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 165 mg (70%) of a yellowish oil was obtained. R
.50 (petroleum ether/EtOAc 4:1). Isolated as single
regioisomer. Structure confirmed by 2D-NMR (COSY,
27 39 2 2
C H N O Si 451.2781; found: 451.2786. FT-IR (thin film,
-1
f
=
cm ) υ 2955, 2857, 1653, 1098.
0
(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-
cyclopropylisoquinolin-2(1H)-yl)(pyridin-2-yl) methanone
1
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl
ppm) δ 8.76 – 8.61 (m, 1H), 7.83 – 7.71 (m, 2H), 7.45 – 7.35
m, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.18 (dd, J = 8.0, 1.9 Hz, 1H),
.74 (d, J = 8.0 Hz, 1H), 6.50 (s, 1H), 5.01 (t, J = 7.1 Hz, 1H),
3.98 (dd, J = 9.6, 6.8 Hz, 1H), 3.62 – 3.56 (m, 1H), 1.35 (s, 9H),
3
,
(2ab).
phenylethyl)picolinamide
cyclopropylacetylene (127 µL, 1.5 mmol,
Co(dpm)
mmol, 1.2 equiv), Mn(OAc)
equiv), and MeOH (5 mL), 20 h, 80 °C, O
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 154 mg (73%) of a yellowish oil was obtained. R
N-(2-((Tert-butyldimethylsilyl)oxy)-1-
(178
mg,
0.5
mmol),
3 equiv),
(
6
2
(42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
·2 H O (268 mg, 1.0 mmol, 2
atmosphere. After
3
2
13
0.83 (s, 9H), -0.07 (s, 3H), -0.08 (s, 3H). C{1H}NMR (100
MHz, CDCl , ppm) δ 171.2, 153.3, 151.3, 149.2, 137.0, 133.6,
31.6, 129.2, 128.4, 128.3, 125.5, 124.9, 121.6, 117.0, 62.0,
0.2, 36.9, 30.9, 26.0, 18.4, -5.4, -5.5. HR-MS (ESI-TOF) m/z:
2
3
1
6
f
=
0.40 (petroleum ether/EtOAc 3:1). Isolated as single
+
Calcd. for [M+H] :
5
1
C
26
H
36
N
2
1
O
2
BrSi 515.1729; found:
15.1742. FT-IR (thin film, cm ) υ 2957, 2929, 2858, 1662,
653, 1365, 1111.
6-(Tert-butyl)-4-(((tert-
butyldimethylsilyl)oxy)methyl)thieno[3,2-c]pyridin-5(4H)-
yl)(pyridin-2-yl)methanone (2qa). N-(2-((Tert-
regioisomer. Structure confirmed by 2D-NMR (COSY,
-
1
NOESY, see attached NMR data). H-NMR (400 MHz, CDCl
3
,
ppm) δ 8.61 (d, J = 4.3 Hz, 1H), 7.75 (td, J = 7.7, 1.7 Hz, 1H),
7.67 (d, J = 7.7 Hz, 1H), 7.33 (ddd, J = 7.4, 4.9, 1.1 Hz, 1H),
7.25 – 7.16 (m, 1H), 7.17 – 7.08 (m, 2H), 7.06 (d, J = 7.4 Hz,
1H), 5.98 (s, 1H), 5.85 – 5.35 (m, 1H), 3.85 – 3.67 (m, 1H), 3.61
(
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(dd, J = 9.8, 7.1 Hz, 1H), 0.92 – 0.79 (m, 10H), 0.65 – 0.48 (m,
(see comparison of H-NMR spectra at RT and 65 °C). Better
1
3
1
3H), 0.48 – 0.31 (m, 1H), -0.10 (s, 6H). C{1H}NMR (100
MHz, CDCl , ppm) δ 168.1, 155.3, 148.8, 140.7, 136.7, 132.0,
31.4, 127.9, 127.3, 126.5, 124.9, 124.8, 124.4, 112.7, 62.8,
7.7, 25.9, 18.3, 16.3, 10.3, 7.8, -5.5, -5.6. HR-MS (ESI-TOF)
quality H-NMR spectra was obtained at 65 °C temperature
(due to the hardware limitations 65 °C is the maximum
temperature). H-NMR (400 MHz, C
(d, J = 4.4 Hz, 1H), 7.78 (td, J = 7.7, 1.5 Hz, 1H), 7.66 (d, J =
7.5 Hz, 1H), 7.42 – 7.29 (m, 3H), 7.18 (t, J = 7.2 Hz, 1H), 7.15
– 6.87 (m, 1H), 5.55 – 4.77 (m, 1H), 4.03 – 3.79 (m, 1H), 3.66
(dd, J = 9.5, 7.9 Hz, 1H), 3.19 – 1.73 (m, 4H), 1.19 (t, J = 7.5
Hz, 3H), 1.17 – 1.04 (m, 3H), 0.87 (s, 9H), 0.02 – -0.28 (m, 6H).
3
1
1
5
2
D
2
Cl
4
, 65 °C, ppm) δ 8.65
+
m/z: Calcd. for [M+H] : C25
H
33
N
2
O
2
Si 421.2311; found:
21.2315. FT-IR (thin film, cm ) υ 2953, 2928, 2857, 1655,
251, 1108.
1-(((Tert-butyldimethylsilyl)oxy)methyl)-3,4-
dimethylisoquinolin-2(1H)-yl)(pyridin-2-yl) methanone
(2ac). N-(2-((Tert-butyldimethylsilyl)oxy)-1-
phenylethyl)picolinamide (178 mg, 0.5 mmol), 2-butyne (60
µL, 0.75 mmol, 1.5 equiv), Co(dpm) (42.5 mg, 0.1 mmol, 20
mol%), NaOPiv (75 mg, 0.6 mmol, 1.2 equiv),
Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2 equiv), and MeOH (5
mL), 16 h, 80 °C, atmosphere. After column
chromatography (gradient petroleum ether/EtOAc from 6:1 to
4:1), 142 mg (70%) of a yellowish oil was obtained. R = 0.25
-1
4
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1
3
2 2 4
C{1H}NMR (100 MHz, C D Cl , list of peaks given due to
the splitted carbon signals caused by rotamers, ppm) δ 168.5,
166.9, 153.7, 148.9, 136.6, 135.7, 134.8, 133.3, 131.6, 127.7,
127.3, 127.2, 126.9, 126.2, 124.8, 124.1, 123.6, 122.7, 62.1,
59.6, 55.9, 25.7, 22.1, 20.6, 18.1, 14.0, 13.1, -5.6, -5.8. HR-MS
(ESI-TOF) m/z: Calcd. for [M+H] : C26
found: 437.2629. FT-IR (thin film, cm ) υ 2959, 2928, 2856,
1649, 1391, 1112.
(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3,4-
dipropylisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
(2ae).
phenylethyl)picolinamide (178 mg, 0.5 mmol), oct-4-yne (110
µL, 1.5 mmol, 3 equiv), Co(dpm) (42.5 mg, 0.1 mmol, 20
mol%), NaOPiv (75 mg, 0.6 mmol, 1.2 equiv),
Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2 equiv), and MeOH (5
mL), 16 h, 80 °C, atmosphere. After column
chromatography (gradient petroleum ether/EtOAc from 6:1 to
4:1), 185 mg (80%) of a yellowish oil was obtained. R = 0.36
2
+
3
2
H
37
N
2
O
2
Si 437.2624;
-1
O
2
f
(petroleum ether/EtOAc 4:1). Note! Due to restricted rotation
1
about the amide bond, the signals observed in NMR are broad
N-(2-((Tert-butyldimethylsilyl)oxy)-1-
and coupling resolution is low, some proton signals are splitted
1
(
see comparison of H-NMR spectra at RT and 65 °C). Better
2
1
quality H-NMR spectra was obtained at 65 °C temperature
due to the hardware limitations 65 °C is the maximum
temperature). H-NMR (400 MHz, C
(
3
2
1
2
D
2
Cl
4
, 65 °C, ppm) δ 8.65
O
2
(d, J = 4.5 Hz, 1H), 7.80 (td, J = 7.7, 1.7 Hz, 1H), 7.68 (d, J =
7.7 Hz, 1H), 7.47 – 7.29 (m, 3H), 7.24 – 7.15 (m, 1H), 7.16 –
6.95 (m, 1H), 5.68 – 5.02 (m, 1H), 4.00 – 3.78 (m, 1H), 3.69
f
(petroleum ether/EtOAc 4:1). Note! Due to restricted rotation
about the amide bond, the signals observed in NMR are broad
1
(
dd, J = 9.7, 7.3 Hz, 1H), 2.12 (s, 3H), 1.96 (bs, 3H), 0.88 (s,
1
3
9
H), -0.04 (s, 3H), -0.05 (s, 3H). C{1H}NMR (100 MHz,
Cl , list of peaks given due to the splitted carbon signals
caused by rotamers, ppm) δ 168.1, 166.4, 154.2, 153.5, 148.8,
and coupling resolution is low, some proton signals are splitted
1
C
2
D
2
4
(see comparison of H-NMR spectra at RT and 65 °C). Better
1
quality H-NMR spectra was obtained at 65 °C temperature
(due to the hardware limitations 65 °C is the maximum
temperature). H-NMR (400 MHz, C
1
1
1
36.8, 132.9, 132.6, 130.2, 128.5, 127.7, 126.9, 126.3, 124.8,
24.0, 122.7, 121.6, 120.2, 118.2, 62.3, 59.9, 56.1, 25.7, 21.0,
1
2
D
2
Cl
4
, 65 °C, ppm) δ 8.65
8.1, 17.7, 13.8, -5.6, -5.8. HR-MS (ESI-TOF) m/z: Calcd. for
(d, J = 4.4 Hz, 1H), 7.78 (td, J = 7.7, 1.6 Hz, 1H), 7.64 (d, J =
7.4 Hz, 1H), 7.42 – 7.28 (m, 3H), 7.17 (t, J = 7.1 Hz, 1H), 7.14
– 6.88 (m, 1H), 5.46 – 4.85 (m, 1H), 4.04 – 3.85 (m, 1H), 3.70
– 3.57 (m, 1H), 2.68 –2.46 (m, 3H), 1.75 – 1.39 (m, 5H), 1.06
(t, J = 7.3 Hz, 3H), 1.00 – 0.91 (m, 3H), 0.87 (s, 9H), 0.11 – -
0.23 (m, 6H). C{1H}NMR (100 MHz, C D Cl , ppm) δ 168.5,
2 2 4
153.7, 148.9, 136.6, 135.1, 133.2, 131.9, 127.7, 127.2, 126.2,
124.9, 124.1, 123.4, 122.9, 62.1, 59.7, 56.0, 31.3, 29.6, 25.7,
+
[M+H] : C24
H
33
2
N O
2
Si 409.2311; found: 409.2315. FT-IR (thin
-1
film, cm ) υ 2952, 2929, 2857, 1653, 1394, 1250, 1112.
S)-(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3,4-
dimethylisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
(S)-2ac). (S)-N-(2-((Tert-butyldimethylsilyl)oxy)-1-
phenylethyl)picolinamide (178 mg, 0.5 mmol), 2-butyne (118
µL, 1.5 mmol, 3 equiv), Co(dpm) (42.5 mg, 0.1 mmol, 20
mol%), NaOPiv (75 mg, 0.6 mmol, 1.2 equiv),
Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2 equiv), and MeOH (5
mL), 16 h, 80 °C, atmosphere. After column
chromatography (gradient petroleum ether/EtOAc from 6:1 to
:1), 142 mg (70%) of a yellowish oil was obtained. R = 0.25
petroleum ether/EtOAc 4:1). ee = > 99% (see attached HPLC
(
1
3
(
2
22.6, 21.7, 18.1, 14.4, -5.7, -5.8. HR-MS (ESI-TOF) m/z:
+
3
2
Calcd. for [M+H] : C28
H
41
N
2
2
O Si 465.2937; found: 465.2946.
-
1
O
2
FT-IR (thin film, cm ) υ 2957, 2929, 2871, 1653, 1391, 1112.
(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-
4
f
phenylisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone (2af).
N-(2-((Tert-butyldimethylsilyl)oxy)-1-
phenylethyl)picolinamide (178 mg, 0.5 mmol), phenylacetylene
(
2
0
data). The NMR data matched to racemate. []
D
-429.2 (c =
0
.917, CHCl
1-(((Tert-butyldimethylsilyl)oxy)methyl)-3,4-
diethylisoquinolin-2(1H)-yl)(pyridin-2-yl)metha-none
2ad). N-(2-((Tert-butyldimethylsilyl)oxy)-1-
phenylethyl)picolinamide (178 mg, 0.5 mmol), hex-3-yne (169
µL, 1.5 mmol, 3 equiv), Co(dpm) (42.5 mg, 0.1 mmol, 20
mol%), NaOPiv (75 mg, 0.6 mmol, 1.2 equiv),
Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2 equiv), and MeOH (5
mL), 16 h, 80 °C, atmosphere. After column
chromatography (gradient petroleum ether/EtOAc from 6:1 to
:1), 167 mg (76%) of a yellowish oil was obtained. R = 0.33
petroleum ether/EtOAc 4:1). Note! Due to restricted rotation
3
).
(82 µL, 0.75 mmol, 1.5 equiv), Co(dpm)
20 mol%), NaOPiv (75 mg, 0.6 mmol, 1.2 equiv),
Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2 equiv), and MeOH (5
mL), 16 h, 80 °C, atmosphere. After column
chromatography (gradient petroleum ether/EtOAc from 6:1 to
4:1), 167 mg (73%) of a yellowish oil was obtained. R = 0.27
(petroleum ether/EtOAc 4:1). Isolated as single regioisomer.
Structure confirmed by 2D-NMR (COSY, NOESY, see
attached NMR data).Note! Due to restricted rotation about the
amide bond, the signals observed in NMR are broad and
coupling resolution is low, some proton signals are splitted (see
2D-NOESY NMR for crosspeaks). H-NMR spectra at 65 °C
temperature did not improve coupling resolution quality (due to
the hardware limitations 65 °C is the maximum temperature).
2
(42.5 mg, 0.1 mmol,
(
3
2
(
O
2
2
f
3
2
O
2
1
4
f
1
(
1
about the amide bond, the signals observed in NMR are broad
and coupling resolution is low, some proton signals are splitted
ACS Paragon Plus Environment

The Journal of Organic Chemistry
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6
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H-NMR (400 MHz, CDCl
3
, ppm) δ 8.39 – 8.16 (m, 1H), 7.46
f
R = 0.30 (petroleum ether/EtOAc 3:1). Isolated as single
regioisomer. Structure confirmed by 2D-NMR (COSY,
– 7.15 (m, 8H), 7.07 – 6.88 (m, 4H), 6.36 – 6.22 (m, 1H), 6.16
–
1
MHz, C
1
1
5.87 (m, 1H), 3.99 – 3.83 (m, 1H), 3.77 (dd, J = 10.1, 6.4 Hz,
NOESY, see attached NMR data). Note! Due to restricted
1
3
1
H), 0.89 (s, 9H), 0.08 – -0.10 (m, 6H). C{1H}NMR (100
Cl , ppm) δ 168.2, 154.3, 147.7, 138.9, 138.3, 136.0,
32.3, 131.3, 128.1, 127.9, 127.5, 127.3, 127.2, 126.8, 125.6,
24.2, 124.0, 114.5, 62.3, 56.7, 25.7, 18.0, -5.6, -5.7. HR-MS
rotation about the amide bond, the signals observed in NMR
2
D
2
4
are broad and coupling resolution is low, some proton signals
are splitted (see 2D-NOESY NMR for crosspeaks and
1
1
comparison of H-NMR spectra at RT and 65 °C). H-NMR
spectra at 65 °C temperature did not improve coupling
+
(
33 2 2
ESI-TOF) m/z: Calcd. for [M+H] : C28H N O Si 457.2311;
-1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
found: 457.2318. FT-IR (thin film, cm ) υ 2957, 2928, 2856,
1661, 1653, 1363, 1111.
(S)-(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-
phenylisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone ((S)-
resolution quality (due to the hardware limitations 65 °C is the
1
maximum temperature). H-NMR (400 MHz, C
2
D
2
Cl
4
, 65 °C,
ppm) δ 8.63 – 8.19 (m, 1H), 8.17 – 6.72 (m, 11H), 6.72 – 6.27
(m, 1H), 6.18 – 5.69 (m, 1H, overlapped with C Cl ), 4.24 –
3.86 (m, 1H), 3.89 – 3.72 (m, 1H), 0.92 (s, 9H), 0.25 – -0.25
2
D
2
4
2
af).
phenylethyl)picolinamide (178 mg, 0.5 mmol), phenylacetylene
82 µL, 0.75 mmol, 1.5 equiv), Co(dpm) (42.5 mg, 0.1 mmol,
mol%), NaOPiv (75 mg, 0.6 mmol, 1.2 equiv),
Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2 equiv), and MeOH (5
mL), 16 h, 80 °C, atmosphere. After column
chromatography (gradient petroleum ether/EtOAc from 6:1 to
4:1), 160 mg (70%) of a yellowish oil was obtained. R = 0.27
petroleum ether/EtOAc 4:1). Isolated as single regioisomer. ee
(S)-N-(2-((Tert-butyldimethylsilyl)oxy)-1-
1
3
2 2 4
(m, 6H). C{1H}NMR (100 MHz, C D Cl , ppm) δ 167.4,
(
2
2
153.6, 147.9, 146.1, 145.7, 136.5, 136.4, 132.5, 130.8, 129.3,
127.3, 127.0, 126.2, 126.1, 124.6, 123.8, 123.1, 117.5, 62.8,
0
3
2
56.7, 25.8, 18.0, -5.6, -5.7. HR-MS (ESI-TOF) m/z: Calcd. for
+
O
2
[M+H] : C28
32
H N
O
3 4
Si 502.2162; found: 502.2166. FT-IR (thin
-1
film, cm ) υ 2954, 2929, 2856, 1662, 1595, 1520, 1343, 1108.
(E)-(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-(4-
nitrophenyl)-8-(4-nitrostyryl)isoquinolin-2(1H)-
f
(
=
> 99% (see attached HPLC data). The NMR data matched to
yl)(pyridin-2-yl)methanone (2ah’). In addition to the major
product described above, 52 mg (16%) of a minor product as a
yellow oil was obtained. R = 0.20 (petroleum ether/EtOAc 3:1).
f
2
0
racemate. []
D
3
-264.6 (c = 0.923, CHCl ).
(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-(4-
methoxyphenyl)isoquinolin-2(1H)-yl)(pyridin-2-
Note! Due to restricted rotation about the amide bond, the
1
yl)methanone (2ag). N-(2-((Tert-butyldimethylsilyl)oxy)-1-
phenylethyl)picolinamide (178 mg, 0.5 mmol), 4-
methoxyphenylacetylene (97 µL, 0.75 mmol, 1.5 equiv),
signals observed in NMR are broad and coupling resolution is
low, some proton signals are splitted (see 2D-NOESY NMR for
1
crosspeaks). H-NMR (400 MHz, C
2
D
2
4
Cl , ppm) δ 8.32 – 8.22
Co(dpm)
mmol, 1.2 equiv), Mn(OAc)
equiv), and MeOH (5 mL), 17 h, 80 °C, O
column chromatography (gradient petroleum ether/EtOAc from
:1 to 4:1, then 2:1), 215 mg (88%) of a yellowish oil was
obtained. R = 0.66 (petroleum ether/EtOAc 1:1). Isolated as
2
(42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
·2 H O (268 mg, 1.0 mmol, 2
atmosphere. After
(m, 3H), 8.00 – 7.84 (m, 2H), 7.82 – 7.62 (m, 4H), 7.60 – 7.50
(m, 2H), 7.51 – 7.40 (m, 2H), 7.41 – 7.28 (m, 2H), 7.17 (d, J =
16.0 Hz, 1H), 7.11 – 6.99 (m, 1H), 6.58 (dd, J = 8.7, 5.1 Hz,
1H), 6.50 (s, 1H), 3.86 (t, J = 10.1 Hz, 1H), 3.74 (dd, J = 10.9,
3
2
2
13
6
4.9 Hz, 1H), 0.92 (s, 9H), 0.18 – -0.22 (m, 6H). C{1H}NMR
2 2 4
(100 MHz, C D Cl , ppm) δ 167.4, 153.5, 147.8, 146.8, 146.2,
145.5, 143.3, 142.0, 136.6, 133.9, 131.6, 130.7, 130.0, 128.7,
128.5, 127.4, 127.2, 126.8, 126.1, 124.8, 124.7, 124.1, 123.2,
f
single regioisomer. Structure confirmed by 2D-NMR (COSY,
NOESY, see attached NMR data). Note! Due to restricted
rotation about the amide bond, the signals observed in NMR
are broad and coupling resolution is low, some proton signals
are splitted (see see comparison of H-NMR spectra at RT and
6
at 65 °C temperature did not improve coupling resolution
quality (due to the hardware limitations 65 °C is the maximum
1
117.5, 61.2, 53.1, 25.7, 18.0, -5.4, -5.6. HR-MS (ESI-TOF) m/z:
+
Calcd. for [M+H] : C36
H
37
N
4
O
6
Si 649.2482; found: 649.2490.
1
-1
FT-IR (thin film, cm ) υ 2965, 2828, 2847, 1595, 1519, 1341,
1109.
1
5 °C and 2D-NOESY NMR for crosspeaks). H-NMR spectra
(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-(4-
ethynylphenyl)isoquinolin-2(1H)-yl)(pyridin-2-
yl)methanone (2ai). N-(2-((Tert-butyldimethylsilyl)oxy)-1-
phenylethyl)picolinamide (178 mg, 0.5 mmol), 1,4-
diethynylbenzene (95 mg, 0.75 mmol, 1.5 equiv),
1
temperature). H-NMR (400 MHz, C
m, 1H), 7.43 – 7.26 (m, 5H), 7.24 – 7.09 (m, 3H), 7.04 – 6.95
(m, 1H), 6.69 – 6.50 (m, 2H), 6.21 (s, 1H), 6.03 – 5.91 (m, 1H,
overlapped with C Cl ), 3.94 – 3.83 (m, 1H), 3.78 – 3.62 (m,
H), 0.92 (s, 9H), 0.03 (s, 3H), -0.03 (s, 3H). C{1H}NMR
100 MHz, C Cl , ppm) δ 168.3, 158.7, 154.5, 149.8, 137.9,
2 2 4
D Cl , ppm) δ 8.40 – 8.15
(
D
2
4
Co(dpm)
mmol, 1.2 equiv), Mn(OAc)
equiv), and MeOH (5 mL), 16 h, 80 °C, O
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 130 mg (54%) of a yellowish oil was obtained. R
2
(42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
·2 H O (268 mg, 1.0 mmol, 2
atmosphere. After
2
13
4
(
3
2
D
2 2
4
2
1
1
5
4
2
35.9, 135.5, 132.3, 131.8, 131.5, 130.6, 128.2, 128.0, 127.3,
26.9, 125.4, 123.9, 113.2, 62.2, 56.7, 55.3, 25.8, 18.0, -5.6, -
.7. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] : C29
87.2417; found: 487.2415. FT-IR (thin film, cm ) υ 2954,
929, 2856, 1653, 1507, 1249, 1180, 1111.
f
=
+
H
34
N
2
O
3
Si
0.40 (petroleum ether/EtOAc 3:1). Isolated as single
regioisomer. Structure confirmed by 2D-NMR (COSY,
NOESY, see attached NMR data). Note! Due to restricted
-1
1
(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-(4-
rotation about the amide bond, the signals observed in NMR
nitrophenyl)isoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
2ah). N-(2-((Tert-butyldimethylsilyl)oxy)-1-
are broad and coupling resolution is low, some proton signals
1
(
are splitted. H-NMR spectra at 65 °C temperature did not
phenylethyl)picolinamide (178 mg, 0.5 mmol), 4-
nitrophenylacetylene (110 mg, 0.75 mmol, 1.5 equiv),
Co(dpm)
mmol, 1.2 equiv), Mn(OAc)
equiv), and MeOH (5 mL), 16 h, 80 °C, O
improve coupling resolution quality (due to the hardware
1
limitations 65 °C is the maximum temperature). H-NMR (400
(42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
·2 H O (268 mg, 1.0 mmol, 2
atmosphere. After
MHz, C
(m, 11H), 6.70 – 6.22 (m, 1H), 6.17 – 5.67 (m, 1H, overlapped
with C Cl ), 4.25 – 3.85 (m, 1H), 3.79 (dd, J = 10.1, 6.2 Hz,
1H), 3.12 (s, 1H), 0.92 (s, 9H), 0.22 – -0.31 (m, 6H).
2 2 4
D Cl , 65 °C, ppm) δ 8.52 – 8.19 (m, 1H), 8.14 – 6.89
2
3
2
2
D
2
4
2
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1, then 2:1), 125 mg (50%) of a yellow oil was obtained.
1
3
2 2 4
C{1H}NMR (100 MHz, C D Cl , ppm) δ 167.9, 154.1, 147.8,
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
5
5
6
139.5, 137.5, 136.2, 132.4, 131.6, 131.2, 128.1, 127.5, 127.1,
126.6, 125.8, 124.3, 124.2, 120.7, 115.3, 83.5, 78.1, 62.5, 56.7,
5.7, 18.0, -5.6, -5.7. HR-MS (ESI-TOF) m/z: Calcd. for
equiv), and MeOH (5 mL), 16 h, 80 °C, O
column chromatography (gradient petroleum ether/EtOAc from
6:1 to 4:1), 177 mg (67%) of a yellowish oil was obtained. R
2
atmosphere. After
2
f
=
+
[
M+H] : C30
H
33
N
2
O
2
Si 481.2311; found: 481.2319. FT-IR (thin
film, cm ) υ 2955, 2930, 2857, 1653, 1363, 1111.
1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-(thiophen-
-yl)isoquinolin-2(1H)-yl)(pyridin-2-yl)methanone (2aj). N-
0.25 (petroleum ether/EtOAc 4:1). ee = > 99% (see attached
-1
20
HPLC data). The NMR data matched to racemate. []D -385.4
(
3
(c = 0.773, CHCl ).
(3,4-Bis(4-bromophenyl)-1-(((tert-
butyldimethylsilyl)oxy)methyl)isoquinolin-2(1H)-yl)(pyri-
3
(2-((Tert-butyldimethylsilyl)oxy)-1-phenylethyl)picolinamide
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(178 mg, 0.5 mmol), 3-ethynylthiophene (149 µL, 1.5 mmol, 3
din-2-yl)methanone
(2al).
N-(2-((Tert-
equiv), Co(dpm)
mg, 0.6 mmol, 1.2 equiv), Mn(OAc)
mmol, 2 equiv), and MeOH (5 mL), 16 h, 80 °C, O
2
(42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75
·2 H O (268 mg, 1.0
atmosphere.
butyldimethylsilyl)oxy)-1-phenylethyl)picolinamide (178 mg,
0.5 mmol), bis(4-bromophenyl)acetylene (252 mg, 0.75 mmol,
3
2
2
1.5 equiv), Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv
2
After column chromatography (gradient petroleum
ether/EtOAc from 6:1 to 4:1), 150 mg (65%) of a yellowish oil
(75 mg, 0.6 mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0
3
2
mmol, 2 equiv), and MeOH (5 mL), 16 h, 80 °C, O atmosphere.
2
was obtained. R
as single regioisomer. Structure confirmed by 2D-NMR
COSY, NOESY, see attached NMR data). Note! Due to
f
= 0.55 (petroleum ether/EtOAc 2:1). Isolated
After column chromatography (gradient petroleum
ether/EtOAc from 6:1 to 4:1), 261 mg (76%) of a white powder
(
was obtained. R = 0.33 (petroleum ether/EtOAc 3:1). Note!
f
3,5
restricted rotation about the amide bond, the signals observed
Due to restricted rotation about the amide bond, some of the
1
1
in NMR are broad and coupling resolution is low, some proton
signals observed in NMR are broad and coupling resolution is
1
1
signals are splitted. H-NMR spectra at 65 °C temperature did
low, some proton signals are splitted. H-NMR spectra at 65 °C
not improve coupling resolution quality (due to the hardware
temperature did not improved coupling resolution quality (due
to the hardware limitations 65 °C is the maximum temperature).
1
limitations 65 °C is the maximum temperature). H-NMR (400
1
MHz, C
2
D
2
Cl
4
, 65 °C, ppm) 8.55 – 8.26 (m, 1H), 7.62 – 7.49
H-NMR (400 MHz, C D Cl , ppm) δ δ 8.65 – 8.14 (m, 1H),
2
2
4
(
(
m, 1H), 7.45 – 7.22 (m, 5H), 7.23 – 6.84 (m, 4H), 6.54 – 6.25
7.50 – 7.19 (m, 7H), 7.12 – 7.00 (m, 3H), 6.95 – 6.87 (m, 2H),
6.76 – 6.70 (m, 1H), 6.11 – 5.94 (m, 1H, overlapped with
C D Cl ), 4.17 – 3.96 (m, 1H), 3.93 – 3.82 (m, 1H), 0.97 (s,
m, 1H), 6.05 – 5.62 (m, 1H, overlapped with C
2
D
2
Cl
4
), 4.06 –
3
.86 (m, 1H), 3.80 (dd, J = 10.0, 6.8 Hz, 1H), 0.91 (s, 9H), 0.19
2
2
4
1
3
13
– -0.18 (m, 6H). C{1H}NMR (100 MHz, C
2
D
2
Cl
4
, ppm) δ
9H), 0.17 (s, 3H), 0.10 (s, 3H). C{1H}NMR (100 MHz,
C D Cl , ppm) δ 168.6, 154.6, 147.6, 137.1, 136.3, 135.0,
168.0, 154.2, 147.9, 140.5, 136.0, 133.5, 132.5, 131.2, 128.0,
2
2
4
1
5
27.4, 127.1, 126.4, 125.5, 124.1, 123.8, 122.8, 113.4, 62.3,
133.5, 132.4, 132.1, 131.9, 131.5, 131.3, 130.1, 128.0, 127.7,
127.0, 125.4, 125.2, 124.1, 123.8, 121.1, 120.8, 62.9, 56.3, 25.8,
6.8, 25.8, 18.1, -5.6, -5.7. HR-MS (ESI-TOF) m/z: Calcd. for
+
+
[M+H] : C26
H
31
1
N
2
O
2
SiS 463.1876; found: 463.1877. FT-IR
18.1, -5.4, -5.6. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
-
(
thin film, cm ) υ 2957, 2927, 2856, 1653, 1507, 1111.
1-(((Tert-butyldimethylsilyl)oxy)methyl)-3,4-
diphenylisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
2ak). N-(2-((Tert-butyldimethylsilyl)oxy)-1-
phenylethyl)picolinamide (178 mg, 0.5 mmol),
diphenylacetylene (134 mg, 0.75 mmol, 1.5 equiv),
Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2
equiv), and MeOH (5 mL), 16 h, 80 °C, O atmosphere. After
column chromatography (gradient petroleum ether/EtOAc from
C H N O SiBr 689.0828; found: 689.0835. FT-IR (thin film,
3
4
35
2
2
2
-1
(
cm ) υ 2955, 2929, 2857, 1668, 1389, 1108.
(1-(((Tert-butyldimethylsilyl)oxy)methyl)-4-methyl-3-
phenylisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
(
(2am).
N-(2-((Tert-butyldimethylsilyl)oxy)-1-
phenylethyl)picolinamide (178 mg, 0.5 mmol), 1-phenyl-1-
2
propyne (94 µL, 0.75 mmol, 1.5 equiv), Co(dpm) (42.5 mg,
2
3
2
0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6 mmol, 1.2 equiv),
Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2 equiv), and MeOH (5
2
3
2
mL), 16 h, 80 °C, O2 atmosphere. After column
chromatography (gradient petroleum ether/EtOAc from 6:1 to
6
0
:1 to 4:1), 205 mg (77%) of a yellowish oil was obtained. R
f
=
.25 (petroleum ether/EtOAc 4:1). Note! Due to restricted
4:1), 171 mg (73%) of a yellowish oil was obtained. R = 0.22
f
(petroleum ether/EtOAc 4:1). Isolated as single regioisomer.
Structure confirmed by 2D-NMR (COSY, NOESY, see
attached NMR data). Note! Due to restricted rotation about the
3
,5
rotation about the amide bond, some of the signals observed
in NMR are broad and coupling resolution is low, some proton
signals are splitted (see 2D-NOESY NMR for crosspeaks). H-
1
1
3
,5
1
NMR (400 MHz, C
2
D
2
Cl
7.07 (m, 11H), 7.03 – 6.95 (m, 1H), 6.87 – 6.69 (m, 5H), 6.06
5.98 (m, 1H, overlapped with C Cl ), 4.23 – 4.05 (m, 1H),
.93 (dd, J = 10.2, 6.3 Hz, 1H), 0.98 (s, 9H), 0.13 (s, 3H), 0.08
4
, ppm) δ 8.34 (d, J = 4.0 Hz, 1H), 7.44
amide bond, some of the signals observed in NMR are broad
and coupling resolution is low, some proton signals are splitted
–
–
3
1
2
D
2
4
(see 2D-NOESY NMR for crosspeaks). H-NMR (400 MHz,
C D Cl , ppm) δ 8.30 (d, J = 4.4 Hz, 1H), 7.48 – 7.17 (m, 6H),
2
2
4
13
(s, 3H). C{1H}NMR (100 MHz, CDCl
3
, ppm) δ 163.3, 155.4,
7.08 – 6.98 (m, 5H), 6.81 (d, J = 7.7 Hz, 1H), 5.91 (t, J = 7.0
Hz, 1H), 4.01 – 3.89 (m, 1H), 3.81 (dd, J = 10.3, 6.1 Hz, 1H),
2.06 (s, 3H), 0.93 (s, 9H), 0.07 (s, 3H), 0.01 (s, 3H).
1
47.9, 138.8, 137.0, 136.1, 134.3, 133.2, 132.3, 131.2, 130.2,
128.2, 127.9, 127.3, 127.2, 127.0, 126.7, 126.6, 125.8, 123.9,
1
3
123.7, 63.2, 56.7, 26.1, 18.5, -5.2, -5.4. HR-MS (ESI-TOF) m/z:
2 2 4
C{1H}NMR (100 MHz, C D Cl , ppm) δ 168.7, 155.1, 147.5,
+
Calcd. for [M+H] : C34
37
H N
O
2 2
Si 533.2624; found: 533.2632.
138.4, 136.0, 133.8, 132.9, 132.6, 129.9, 128.0, 127.3, 127.2,
127.0, 126.8, 123.9, 123.6, 123.5, 118.7, 62.6, 56.0, 25.8, 18.0,
-1
FT-IR (thin film, cm ) υ 2957, 2930, 2857, 1663, 1112.
S)-(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3,4-
diphenylisoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
(S)-2ak). (S)-N-(2-((Tert-butyldimethylsilyl)oxy)-1-
phenylethyl)picolinamide (178 mg, 0.5 mmol),
diphenylacetylene (134 mg, 0.75 mmol, 1.5 equiv),
Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2
+
(
15.2, -5.6, -5.7. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
29 35 2 2
C H N O Si 471.2468; found: 471.2469. FT-IR (thin film,
-1
(
cm ) υ 3060, 2954, 2929, 2857, 1653, 1388, 1363, 1117.
(1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-
(trimethylsilyl)isoquinolin-2(1H)-yl)(pyridin-2-
yl)methanone (2an). N-(2-((Tert-butyldimethylsilyl)oxy)-1-
2
3
2
phenylethyl)picolinamide
(178
mg,
0.5
mmol),
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
trimethylsilylacetylene (213 µL, 1.5 mmol,
Co(dpm) (42.5 mg, 0.1 mmol, 20 mol%), NaOPiv (75 mg, 0.6
mmol, 1.2 equiv), Mn(OAc) ·2 H O (268 mg, 1.0 mmol, 2
equiv), and MeOH (5 mL), 16 h, 80 °C, O atmosphere. After
column chromatography (gradient petroleum ether/EtOAc from
3
equiv),
= 7.8, 1.0 Hz, 1H), 7.33 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 7.23 –
2
7.09 (m, 3H), 6.94 (d, J = 7.3 Hz, 1H), 5.04 (dd, J = 8.4, 6.1 Hz,
1H), 4.19 (dd, J = 9.5, 6.1 Hz, 1H), 3.96 (dd, J = 12.3, 7.2 Hz,
1H), 3.73 (dd, J = 9.4, 8.6 Hz, 1H), 3.08 (dd, J = 15.7, 12.4 Hz,
1H), 2.96 (dd, J = 15.9, 7.2 Hz, 1H), 0.75 (s, 9H), 0.20 (s, 9H),
3
2
2
1
3
6
0
:1 to 4:1), 160 mg (71%) of a yellowish oil was obtained. R
.80 (petroleum ether/EtOAc 2:1). Isolated as single
f
=
3
-0.14 (s, 3H), -0.18 (s, 3H). C{1H}NMR (100 MHz, CDCl ,
ppm) δ 169.3, 155.5, 148.5, 136.9, 135.8, 135.6, 128.2, 127.8,
127.3, 126.0, 124.3, 124.1, 65.4, 60.8, 43.4, 29.5, 26.0, 18.4, -
regioisomer. Structure confirmed by 2D-NMR (COSY,
NOESY, see attached NMR data).
Procedure for gram-scale synthesis: A 100 mL pressure
tube equipped with a magnetic stir bar was charged with N-(2-
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.4, -5.5. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
25 39 2 2 2
C H N O Si 455.2550; found: 455.2564. FT-IR (thin film,
-1
20
D
cm ) υ 2952, 2928, 2857, 1628, 1405, 1248, 1109. [] 66.5
(
(
(tert-butyldimethylsilyl)oxy)-1-phenylethyl)picolinamide
1.00 g, 2.79 mmol), Co(dpm) (238 mg, 0.56 mmol, 20 mol%),
·2 H
1.50 g, 5.58 mmol, 2 equiv), and MeOH (28 mL). The reaction
(c = 1.140, CHCl3).
2
(1S,3S)-1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-
(trimethylsilyl)-1,2,3,4-tetrahydroisoqui-noline (S,S)-4an.
((1S,3S)-1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-
(trimethylsilyl)-3,4-dihydro-isoquinolin-2(1H)-yl)(pyridin-2-
yl)methanone (147 mg, 0.32 mmol) was dissolved in THF (4
mL) under an argon atmosphere. The solution was cooled in
NaOPiv (415 mg, 3.35 mmol, 1.2 equiv), Mn(OAc)
(
3
2
O
mixture was purged with O2 for 30 sec and then
trimethylsilylacetylene (1.2 mL, 8.37 mmol, 3 equiv) was added
and mixture was heated at 80 °C for for 18 h. The reaction
mixture was cooled to room temperature and solvent was
evaporated. To the residue potassium sodium tartrate (50 mL of
water/ice bath to 0 °C temperature and LiAlH (18.4 mg, 0.48
4
mmol, 1.5 equiv.) was added, then reaction mixture was stirred
at 0 °C temperature for 10 min (until complete conversion by
TLC). The reaction was quenched with water (10 mL) and
extracted with EtOAc (3 x 10 mL). Combined organic phase
was dried over Na SO , filtered and evaporated under reduced
1
M aqueous solution) was added and mixture was extracted
with EtOAc (3 x 50 mL). Combined organic phase was dried
over Na2SO4, filtered, and solvent was evaporated. After
column chromatography (gradient petroleum ether/EtOAc from
2
4
1
6
:1 to 4:1), 1.00 g (80%) of a yellowish oil was obtained. H-
pressure to afford the crude product. After column
chromatography (petroleum ether/EtOAc 10:1), 96 mg (86%)
of a yellowish oil was obtained. Rf = 0.50 (petroleum
ether/EtOAc 10:1). ee = > 99% (see attached HPLC data; for ee
3
NMR (400 MHz, CDCl , ppm) δ 8.64 (ddd, J = 4.8, 1.7, 1.0 Hz,
1H), 7.84 – 7.71 (m, 2H), 7.42 – 7.33 (m, 1H), 7.25 (td, J = 7.5,
1.3 Hz, 1H), 7.20 – 7.12 (m, 2H), 7.00 (d, J = 7.3 Hz, 1H), 6.61
(s, 1H), 5.37 (t, J = 7.1 Hz, 1H), 3.89 (dd, J = 9.7, 7.9 Hz, 1H),
determination
compound
was
derivatized
to
N-
1
3
.47 (dd, J = 9.7, 6.6 Hz, 1H), 0.78 (s, 9H), 0.33 (s, 9H), -0.11
benzoylderivative and TBS group was cleaved). H-NMR (400
13
(s, 3H), -0.16 (s, 3H). C{1H}NMR (100 MHz, CDCl
3
, ppm)
MHz, CDCl , ppm) δ 7.19 – 7.01 (m, 4H), 4.18 (dd, J = 9.6, 3.6
3
δ 168.2, 154.2, 148.5, 142.0, 136.9, 132.2, 130.8, 128.2, 127.3,
Hz, 1H), 4.13 – 3.99 (m, 1H), 3.66 (dd, J = 9.4, 8.1 Hz, 1H),
2.86 – 2.76 (m, 1H), 2.62 (dd, J = 15.9, 2.8 Hz, 1H), 2.38 (dd,
J = 12.6, 3.0 Hz, 1H), 1.80 (bs, 1H, overlapped with water),
0.88 (s, 9H), 0.10 (s, 9H), 0.07 (s, 3H), 0.02 (s, 3H).
1
5
28.1, 125.9, 125.2, 125.0, 124.8, 62.8, 59.5, 26.0, 18.4, 0.9, -
.49, -5.50. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
+
25 37 2 2 2
C H N O Si 453.2394; found: 453.2397. FT-IR (thin film,
-1
13
cm ) υ 2952, 2929, 2857, 1647, 1405, 1246, 1118.
C{1H}NMR (100 MHz, CDCl , ppm) δ 137.5, 136.5, 129.1,
3
Synthesis of tetrahydroisoquinolines (S,S)-3an and
126.1, 125.6, 125.1, 67.5, 59.1, 43.6, 31.8, 26.0, 18.4, -3.8, -5.1,
+
(
(
S,S)-4an.
-5.2. HR-MS (ESI-TOF) m/z: Calcd. for [M+H] :
-
((1S,3S)-1-(((Tert-butyldimethylsilyl)oxy)methyl)-3-
19 2
C H36NOSi 350.2335; found: 350.2347. FT-IR (thin film, cm
1
20
trimethylsilyl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyridin-
) υ 2954, 2929, 2857, 1472, 1249, 1100. []D 58.3 (c = 1.080,
2
-yl)methanone (S,S)-3an. Approximately 15 - 20 mL of
CHCl3).
ammonia was condensed in 50 mL flask equipped with a
magnetic stirbar and cooled to -78 °C temperature using
acetone/dry ice bath. Under an argon atmosphere, at -78 °C
ASSOCIATED CONTENT
The Supporting Information is available free of charge at
http://pubs.acs.org.
Optimization studies along with copies of the NMR spectra and
HPLC chromatograms.
temperature
(trimethyl-silyl)isoquinolin-2(1H)-yl)(pyridin-2-yl)methanone
255 mg, 0.56 mmol) solution in THF (6 mL) was added
(1-(((tert-butyldimeth-ylsilyl)oxy)methyl)-3-
(
followed by sodium (61 mg, 2.52 mmol, 4.5 equiv). The
resulting mixture (dark blue) was stirred at -78 °C temperature
until complete conversion (TLC control). The resulting mixture
AUTHOR INFORMATION
2
was diluted with dist. H O (10 mL) and EtOAc (15 mL),
Corresponding Author
allowed to warm to room temperature and stirred with open cap
until all liquid ammonia evaporated. Organic phase was
separated, aqueous phase was extracted with EtOAc (2 x 15
*E-mail: liene_grigorjeva@osi.lv
mL), dried over Na
2
SO
4
, filtered, evaporated under reduced
ORCID ID:
Liene Grigorjeva: 0000-0003-3497-6776
pressure. After column chromatography (petroleum
ether/EtOAc 4:1), 175 mg (69%) of a yellowish oil was
1
Notes
obtained. R
f
= 0.50 (petroleum ether/EtOAc 4:1). Note! H-
The authors declare no competing financial interest.
NMR analysis of crude reaction mixture showed d.r. >20/1.
Only major diastereomer was collected. Structure of major
ACKNOWLEDGMENT
diastereomer was confirmed by 2D-NMR after directing group
1
removal. H-NMR (400 MHz, CDCl
3
, ppm) δ 8.61 (ddd, J =
4.8, 1.6, 0.9 Hz, 1H), 7.76 (td, J = 7.7, 1.8 Hz, 1H), 7.58 (dt, J
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This research was financially supported by ERDF project
Nr.1.1.1.5/17/A/004. We thank Prof. Aigars Jirgensons for scien-
tific discussions and LIOS analytical service.
with allenes g) Thrimurtulu, N.; Dey, A.; Maiti, D.; Volla, M. R. C.
2
Cobalt-Catalyzed
sp -C-H
Activation:
Intermolecular
Heterocyclization with Allenes at Room Temperature. Angew. Chem.
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