Palladium-Catalyzed H/D Exchange Reaction with 8-Aminoquinoline as the Directing Group: Access to ortho-Selective Deuterated Aromatic Acids and β-Selective Deuterated Aliphatic Acids

Article abstract of DOI:10.1021/acs.joc.8b00734

We develop a palladium-catalyzed H/D exchange reaction with 8-aminoquinoline as the directing group as well as D₂O as the source of deuterium atom and solvent. This reaction achieves selectively H/D exchange at the ortho-C-H of aromatic amides and the β-C-H of aliphatic amide. Ortho-deuterated aromatic acids and β-deuterated aliphatic acids are obtained by removal of the directing group. And a possible mechanism is also proposed.

Full text of DOI:10.1021/acs.joc.8b00734

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Article
Palladium-Catalyzed H/D Exchange Reaction with 8-Aminoquinoline
as the Directing Group: Access to ortho-Selective Deuterated
Aromatic Acids and beta-Selective Deuterated Aliphatic Acids
Donghong Zhao, Haofan Luo, Binhui Chen, Wenteng Chen, Guolin Zhang, and Yongping Yu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 04 Jul 2018
Downloaded from http://pubs.acs.org on July 4, 2018
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PalladiumꢀCatalyzed H/D Exchange Reaction with 8ꢀ
Aminoquinoline as the Directing Group: Access to orthoꢀSelective
Deuterated Aromatic Acids and betaꢀSelective Deuterated Aliphatic
Acids
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Donghong Zhao#, Haofan Luo#, Binhui Chen, Wenteng Chen, Guolin Zhang*, Yongping Yu*
Zhejiang Province Key Laboratory of AntiꢀCancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University,
Hangzhou 310058, P. R. China
Supporting Information Placeholder
ABSTRACT: We develop a palladiumꢀcatalyzed H/D exchange reaction with 8ꢀaminoquinoline as the directing group as well as
D2O as the source of deuterium atom and solvent. This reaction achieves selectively H/D exchange at the ortho CꢀH of aromatic
amides and the beta CꢀH of aliphatic amide. Ortho-deuterated aromatic acids and betaꢀdeuterated aliphatic acids are obtained by
removal of the directing group. And a possible mechanism is also proposed.
only [D4] acetic acidcan be the source of deuterium atom (deuꢀ
teriumꢀcontaining solvent D2O was also tested, but no deuterꢀ
ated product was observed.) and base is essential.7Sawama and
Sajiki obtained multiꢀdeuterated saturated fatty acids including
valproic acidꢀd15 by Pt/Cꢀcatalyzed multiꢀdeuteration method
in a mixed solvent of isopropylalcohol and deuterium oxꢀ
ide.8Also, the utilization of directing groups to achieve CꢀH
bond functionalization has been widely reported. Daugulis
reported they achieved that pyridineꢀcontaining auxiliary in
the molecule to be activated could result in selective arylation
of a variety of classes of organic compounds. Later, they reꢀ
ported palladiumꢀcatalyzed arylation and alkylation of CꢀH in
amine derivatives with pyridine or 8ꢀaminoquinoline as a diꢀ
recting group.9 Chen accomplished the total synthesis of celoꢀ
getin C using 8ꢀaminoquinoline as an auxiliary group. A
method of total synthesis of piperborenined with 8ꢀ
aminoquinoline directing the CꢀH activation was reported by
Baran.10Here, we developed a novel, practical and selective
deuteration of carboxylic acids. The approach proceeded using
D2O as the source of deuterium atom and solvent, commercialꢀ
ly available 8ꢀaminoquinoline as the directing group and palꢀ
ladiumacetateas the catalyst. The selective H/D exchange at
the ortho CꢀH of aromatic amides and the beta-CꢀH of aliphatꢀ
ic amide was achieved in this work (Scheme 1).Orthoꢀ
deuterated aromatic acids and βꢀdeuterated aliphatic acids
INTRODUCTION
Metalꢀcatalysed hydrogen isotope exchange labeling has
been playing a significant role in the preparation of stable isoꢀ
topically labeled compounds.1The deuterium labeled organic
compounds are widely used as internal standards in quantitaꢀ
tive LCꢀMS/MS analysis,2 mechanistic probes in chemical and
biological processes, as well as biologically active compoundꢀ
sand pharmaceuticals.3Therefore, the synthesis of deuterium
labeled organic compounds is an increased interest subject.
The previous synthetic methods are mainly divided into the
following two categories, including the conventional method
starting from commercially available, stable deuteriumꢀlabeled
synthons and the H/D exchange reactions via the direct exꢀ
change of hydrogen atom with deuterium atom under the cataꢀ
lytic condition, such as acid, base and metal catalyst (Pd, Pt,
Rh, Ru, Ni, Ir).2a, 4 Though the H/D exchange reaction is highꢀ
ly effective and accessible, the ortho-selective H/D exchange
reactions are mainly limited to the aromatic compound as subꢀ
strates and organoiridium as catalysts.5Fels investigated the
scope and limitation of an iridiumꢀcatalysed H/D exchange
reaction, and showed that the ortho-of benzoic acids was deuꢀ
6
terated, but phenylacetic acids was not. Yu achieved theꢀ
orthoꢀselective CꢀH deuteration of phenylacetic acid via pallaꢀ
diumꢀcatalyzed orthoꢀselective deuteration and treatment with
NaOH for reprotonation of the αꢀposition. And in Yu’ works,
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including valproic acidꢀd4 were also obtained by the hydrolysis
of deuterated amides.
4
RESULTS AND DISCUSSION
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We initiated our studies by using 2ꢀmethylꢀNꢀ(quinolinꢀ8ꢀ
yl)benzamide and testing different Pd(II) as the catalyst(Table
1, entry 1ꢀ3). To our delight, the orthoꢀselective deuteration of
aromatic amides was achieved and the deuterium incorporaꢀ
tion was up to 81% when Pd(OAc)2 was used as the cataꢀ
lyst(Table 1, entry 3). Then, a cheaper catalyst Cu(OAc)2 was
used instead of Pd(OAc)2, but the deuterium incorporation was
much lower(Table 1, entry 4). The ortho CꢀH of aromatic amꢀ
ides was deuterated in different degrees, which can easily be
seen by the frame area in the Table 1.
Entry
Catalyst(eq.)
Pd(dppf)2Cl2(0.2)
Pd(pph3)4(0.2)
Pd(OAc)2(0.2)
Cu(OAc)2(0.2)
T(°C) Time (h) Dincorporationb (%)
1
2
3
4
120
120
120
120
48
48
48
48
78
48
81
35
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aInitial conditions: 1b(1.0 equiv., 0.2 mmol), catalyst (0.2 equiv., 0.04
mmol), D2O (99.8% D content, 1 mL), in a sealed tube, 120 °C, 48h. b D
incorporation was determined by 1H NMR.
And then, in order to confirming the necessity of 8ꢀ
aminoquinoline as a directing group, we also test the free aroꢀ
matic acids and changing the directing group to 2ꢀ
methylpyridine. As shown in table 2, the deuteration of aroꢀ
matic nucleus can’t be abtained removing 8ꢀaminoquinoline.
Table 2.Deuteration of 2ꢀMethylꢀNꢀ(quinolinꢀ8ꢀyl) benꢀ
zamide (1b) Under the Conditionsa
Scheme 1. H/D Exchange Reactions
previous works
O
O
ref. 6
Ir
CO2H
n
CO2H
n
Ir catalyst
R
R
Solvent, D2O,90oC
D
n=0, Deuteration incorporation:45%-99%
n=1, Deuteration incorporation:0%
ref. 7
R
D
Entry
Directing group
T(°C) Time (h) Dincorporationb (%)
1) Pd(OAc)2 (10mol%)
Na2CO3 (1.5 equiv)
[D4]acetic acid,120oC,12h
CO2H
CO2H
ꢀ
1
2
140
140
24
48
0
0
R
H
2) NaOH (20 equiv)
H2O/CH2Cl2,120oC,12h
D
2ꢀmethylpyridine
aReaction conditions: 3b’/2x (1.0 eq., 0.2 mmol), Pd(OAc)2 (0.2 eq., 0.04
mmol), D2O (99.8% D content, 1 mL), in a sealed tube.b D incorporation
was determined by1H NMR.
ref. 8
Condition A
COOH
84
10%Pt/C (15mol%)
i-PrOH/D2O(0.5/3mL)
120oC,24h,sealed tube
Condition B
84
COOH
95
86
98
86
84
84
(0.25mmol)
COOH
Table 3.Optimization of the Reaction Conditions with
Pd(OAc)2 as the Catalysta
96
96
96
10%Pt/C (15mol%)
i-PrOD-d8/D2O(0.5/2mL)
120oC,24h,sealed tube
97
96 98
Q
this work
HN
O
R1=aryl group
D
ortho C-H/D exchange
Q
Q
HN
O
Pd(OAc)2, D2O
R1=alkenyl group
C-H/D exchange
HN
O
D
H,Ph,Alkyl
Entry Catalyst(eq.)
T(°C) Time (h)D incorporationc (%)
R1
Q= 8-quinolinyl
Sealed tube,
140oC,48h
H,Ph,Alkyl
Pd(OAc)2(0.2)
Pd(OAc)2(0.2)
Pd(OAc)2(0.2)
Pd(OAc)2(0.2)
Pd(OAc)2(0.1)
Pd(OAc)2(0.3)
Pd(OAc)2(0.2)
Pd(OAc)2(0.2)
_
81
98
96
96
91
93
85
94
0
1
2
120
140
160
reflux
140
140
140
140
140
48
48
48
48
48
48
24
72
48
Q
HN
O
R1=alkyl group
D
C-H/D exchange
H,Ph,Alkyl
3
4b
H,Ph,Alkyl
5
Table 1.Deuteration of 2ꢀMethylꢀNꢀ(quinolinꢀ8ꢀyl) benꢀ
zamide (1b) Under the Initial Conditionsa
6
7
8
9
aReaction conditions: 1b (1.0 equiv., 0.2 mmol), Pd(OAc)2, D2O (99.8% D
b
content, 1 mL), in a sealed tube. The reaction was performed in normal
c
pressure reactor with D2O refluxing. D incorporation was determined by
1H NMR.
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According to the above results, we selected Pd(OAc)2 as the
catalyst and other reaction factors were further examined (Taꢀ
ble 3). Firstly, the reaction temperature was investigated and
140oC was found to be the best (entry 2). The replacement of
sealed tube with normal pressure reactor with D2O refluxing
resulted in a slightly lower deuterium incorporation (entry 4).
Then, the equivalent of Pd(OAc)2 and reaction time were
screened. Compared with entry 2, there was no increase in the
deuterium incorporation(entry 5ꢀ8). Furthermore, control exꢀ
periments revealed that no reaction occurred in the absence of
Pd(OAc)2 (entry 9 vs entry 2). Accordingly, we obtained the
optimized reaction conditions: treatment of the substrate(1.0
eq.) with Pd(OAc)2 (0.2 eq.) in D2O at 140oC for 48h (entry 2).
As shown in the Table 3, the ortho CꢀH of aromatic amides of
substrate (1b) and products (2b, Table 3) was framed.
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Scheme 2. Scope of the Aromatic Amides a
aReaction conditions:1 (0.4 mmol, 1.0 equiv.), Pd(OAc)2(0.08 mmol, 0.2
equiv.), D2O (99.8% D content, 2 mL), in a sealed tube, 140 °C, 48h. bD
incorporation was determined by 1H NMR. cIsolated yields = (Mass of
product 2/Mass of substrate 1)×100%, as shown in parentheses.
With the optimized reaction conditions in hand, the deuterꢀ
ation of a number of aromatic amides was investigated. The
results were shown in the Scheme 2, which indicated that the
applicability of this reaction was related to the electron effect
of the aromatic ring. Electronꢀrich aromatic rings achieved the
orthoꢀselective deuteration with good deuterium incorporation,
while electronꢀdeficient aromatic rings had no reactions (2aꢀ
2d, 2ivs2gꢀ2h, 2fvs2e). Besides, there is no distinct difference
of incorporation between the hindered 2ꢀH and the less hinꢀ
dered 5ꢀH in 2i.
Furthermore, to explore the scope of this method, a subꢀ
strate scope study on aliphatic amides was then performed. As
shown in Scheme 3, βꢀCꢀH selective deuteration of α, βꢀ satuꢀ
rated aliphatic amides (2jꢀ2l) and α, βꢀunsaturated aliphatꢀ
icamides (2nꢀ2o) were achieved with excellent deuterium inꢀ
corporation except 2m. The aliphatic amide (2m) with three
methyl groups at the beta position, achieved 33.3% deuterium
incorporation of all three methyl groups. Unexpected and reaꢀ
sonable, βꢀselective deuteration at the propenyl group and
orthoꢀselective deuteration at the 2ꢀphenyl group of 2p was
obtained, and orthoꢀselective deuteration at the phenyl group
of 2q was achieved. The amides 2o and 2p further demonꢀ
strated that this method can achieve selective deuteration at
the ortho CꢀH of aromatic amides and the βꢀCꢀH of aliphatic
amides.
aReaction conditions:1 (0.4 mmol, 1.0 equiv.), Pd(OAc)2(0.08 mmol, 0.2
equiv.), D2O (99.8% D content, 2 mL), in a sealed tube, 140 °C, 48h.bD
1
c
incorporation was determined by H NMR. Isolated yields = (Mass of
product 2/Mass of substrate 1)×100%, as shown in parentheses.
Scheme 3.Scope of the Aliphatic and OlefinicAmidesa
On the basis of the above and to further broaden the appliꢀ
cation of this synthetic methodology, the 8ꢀquinolylamino
directing group was removed11 and some orthoꢀdeuterated
benzoic acids were obtained (Scheme 4).
Scheme 4. Removal of the Directing Group by Hydrolysis a
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N
N
N
PdII
-HD2O
D2O
D2O
HN
O
N
O
N
O
4
PdII
AcO
5
6
7
AcO
-HOAc
C-H activation
Pd(OAc)2
A
1b
B
D2O
8
HOAc
H/D exchange
9
AcO
PdII
N
10
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DN
O
OD
D
2b
aHydrolysis conditions:2 (0.45mmol) and 40% H2SO4aqueous solution (2
mL), 120 °C, 12h. bD incorporation was determined by 1H NMR. cisolated
yields = (Real mass of 3/Theoretical mass of 3according to the 100% D
incorporation)×100%,as shown in parentheses.
CONCLUSION
In summary, we have developed an approach resulting inselecꢀ
tive H/D exchange reaction. The reaction proceeded using
D2O as the source of deuterium atom and solvent, as well as 8ꢀ
aminoquinoline as the directing group and palladium acetate
as the catalyst. Some orthoꢀdeuterated benzoic acids and βꢀ
deuterated valproic acid were obtained by the removal of the
directing group. A possible reaction mechanism was proposed
involving formation of palladium amide, cyclometalation, and
deuteration steps.
Valproic acid is a widely used antiepileptic drug. Abbott
reported that Valproic acid is mainly metabolized by hydroxꢀ
ylated at betaꢀposition. 12Using βꢀdeuterated Valproic acid as
a probe can indicate whether Valproic acid is βꢀmetabolized
in a human body by detecting the existent ofβꢀD. In this way,
selectiveβꢀdeuterated Valproic acid can be used in the study
of drug metabolism field. The βꢀdeuterated valproic acid was
obtained in gramꢀscale by this catalytic H/D exchange reaction
following with the removal of the directing group (Scheme 5).
The activity evaluation of βꢀdeuterated valproic acidis also
undergoing.
EXPERIMENTAL SECTION
General Information.1H NMR were recorded in CDCl3 or
DMSOꢀd6 at 500 MHz. Tetramethylsilane (TMS) served as
internal standard (δ=0) and data are reported as follows: chemꢀ
ical shift, integration, multiplicity (s=singlet, d=doublet, t=
triplet, q=quartet, m=multiplet), and coupling constant(s) in
Hertz. LCꢀHRMS data was obtained using Agilent Technoloꢀ
gies 6224 TOF LC/MS.
On the basis of the results above, the possible mechanism
was proposed and shown in Scheme 6. 2ꢀmethylꢀNꢀ(quinolinꢀ
8ꢀyl)benzamide (1b)was reacted with palladium acetate to
afford the intermediate A. Then palladium amide A transꢀ
formed to B by achieving the CꢀH activation with a rapid cyꢀ
clometalation of phenyl group. Complex B was deuterated
leading to 2b. 13
Unless otherwise noted, all reagents were obtained from
commercial suppliers and used without further purification.
All solvents were purified and dried according to standard
methods prior to use. Products were purified by flash column
chromatography on 200ꢀ300 mesh silicagel, SiO2.
Typical procedure for the preparation of carboxamides
1.All amides 1 were synthesized from the corresponding carꢀ
boxylic acids or acid chlorides and 8ꢀaminoquinoline referring
to literature procedures.14
Scheme 5.GramꢀScale Synthesis and Synthetic Applicaꢀ
tions
Synthesis of amides (1a, 1i, 1j, 1l, 1m, 1p) from acid chlo-
rides.1a-d
8ꢀAminoquinoline (1.0 equiv.) was dissolved in anhydrous
CH2Cl2 (20 mL) and Et3N (1.2 equiv.) was added under nitroꢀ
gen atmosphere. The solution was cooled to 0 °C and then acid
chloride (1.2 equiv.) was added dropwise. The reaction mixꢀ
ture was stirred over night at room temperature. The reaction
mixture was quenched with saturated aqueous solution of soꢀ
dium bicarbonate and extracted with dichloromethane three
times. The combined organic phase was washed with water,
brine and dried with Na2SO4 and concentrated in vacuum. The
crude mixture was purified by silica gel column chromatogꢀ
raphy to give the carboxamide.
Scheme 6.Possible Mechanism
Synthesis of amides (1b, 1c, 1d, 1e, 1f, 1g, 1h, 1k, 1n, 1o) from
carboxylic acids.1e-j
To a solution of acid (1.0 equiv.) and catalytic amount DMF
(2 drops) anhydrous CH2Cl2 under nitrogen atmosphere, oxꢀ
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alyl chloride (1.2 equiv.) was added dropwise at 0 °C. After
acidified with 2M HCl to pH=2 and extracted with ether (3×30
mL). The combined ether phase was washed with saturated
salt water (45 mL) and dried with Na2SO4 and filtered. The
filtrate was concentrated under reduced pressure to give the βꢀ
deuterated valproic acid 3e(1.71g, 96%).
stirring for 3 h at room temperature, the solvent was evapoꢀ
rated under reduced pressure and the resulting acid chloride
was used immediately without further purification.
8ꢀAminoquinoline (1.0 equiv.) was dissolved in anhydrous
CH2Cl2 (20 mL) and Et3N (1.2 equiv.) was added under nitroꢀ
gen atmosphere. The solution was cooled to 0 °C and then the
above obtained acid chloride (1.2 equiv.) was added dropwise.
The reaction mixture was stirred over night at room temperaꢀ
ture. The reaction mixture was quenched with saturated aqueꢀ
ous solution of sodium bicarbonate and extracted with diꢀ
chloromethane three times. The combined organic phase was
washed with water, brine and dried with Na2SO4 and concenꢀ
trated in vacuum. The crude mixture was purified by silica gel
column chromatography to give the carboxamide.
1H NMR Spectral Dataof Substrates and Products.
1
N-(quinolin-8-yl)benzamide(1a). White solid; H NMR (500
MHz, CDCl3) δ 10.75 (s, 1H), 8.95 (dd, J = 7.6, 1.5 Hz, 1H),
8.85 (dd, J = 4.2, 1.7Hz, 1H), 8.19 (dd, J = 8.3, 1.7 Hz, 1H),
8.13 – 8.07 (m, 2H), 7.62 – 7.53 (m, 5H), 7.48 (dd, J = 8.2Hz,
4.2Hz, 1H).
2-methyl- N-(quinolin-8-yl)benzamide(1b).White solid; 1H
NMR (500 MHz, CDCl3) δ 10.22 (s, 1H), 8.95 (d, J = 7.3 Hz,
1H), 8.78 (dd, J = 4.2, 1.7 Hz, 1H), 8.19 (dd, J = 8.3, 1.6 Hz,
1H), 7.69 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.56
(dd, J = 8.3, 1.4 Hz, 1H), 7.46 (dd, J = 8.2, 4.2 Hz, 1H), 7.43 –
7.39 ( m, 1H), 7.33 (t, J = 8.1 Hz, 2H), 2.61 (s, 3H).
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General Experimental Procedure for the Synthesis of Deuꢀ
terated Amides 2. In a sealed tube, amides1(0.4mmol, 1.0
equiv.), Pd(OAc)2 (0.08mmol, 0.2 equiv.) and D2O (99.8% D
content, 2 mL) were added. The reaction was stirred at 140 °C
for 48 hours. Then, the reaction mixture was cooled to room
temperature and extracted with water (15 mL)ꢀethyl acetate
(3×20 mL). The combined organic phase was washed with
saturated salt water and dried with Na2SO4 and concentrated
under reduced pressure. The crude mixture was purified by
silica gel column chromatography (Petroleum ether/ethyl aceꢀ
tate=15/1) to give the deuterated amides 2.
4-methyl- N-(quinolin-8-yl)benzamide(1c). White solid; 1H
NMR (500 MHz, CDCl3) δ 10.72 (d, J = 7.8 Hz, 1H), 8.94
(dd, J = 7.6, 1.4 Hz, 1H), 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.18
(dd, J = 8.3, 1.7 Hz, 1H), 8.01 – 7.97 (m, 2H), 7.59 (t, J = 7.9
Hz, 1H), 7.53 (dd, J = 8.3, 1.4 Hz, 1H), 7.47 (dd, J = 8.3, 4.2
Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 2.45 (s, 3H).
1
4-methoxyl- N-(quinolin-8-yl)benzamide(1d). White solid; H
NMR (500 MHz, CDCl3) δ 10.68 (s, 1H), 8.92 (dd, J = 4.2,
1.7 Hz, 1H), 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.18 (dd, J = 8.2,
1.6 Hz, 1H), 8.08 – 8.04 (m, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.52
(dd, J = 8.3, 1.2 Hz, 1H), 7.47 (dd, J = 8.2, 4.2 Hz, 1H), 7.07 –
7.02 (m, 2H), 3.89 (s, 3H).
N-(quinolin-8-yl)isonicotinamide (1e).Pale yellow solid; 1H
NMR (500 MHz, CDCl3) δ 10.82 (s, 1H), 8.91 (dd, J = 6.4,
2.5 Hz, 1H), 8.88 – 8.85 (m, 3H), 8.21 (dd, J = 8.3, 1.6 Hz,
1H), 7.92 – 7.90 (m, 2H), 7.63 – 7.59 (m, 2H), 7.51 (dd, J =
8.3, 4.2 Hz, 1H).
Hydrolysis of deuterated benzoic amides (2a, 2b, 2c,
2d).15The deuterated benzoic amide (2a, 2b, 2c, 2d) (0.3
mmol) was dissolved in 2mL aq. H2SO4 (40%) and stirred at
120 °C for 12h (The reaction is complete by TLC detection).
The reaction mixture was cooled to room temperature and
extracted with water (10 mL) ꢀ ether (3×20 mL). The comꢀ
bined organic phase was washed with saturated salt water and
dried with Na2SO4 and filtered. The filtrate was concentrated
under reduced pressure to give the corresponding ortho deuꢀ
terated benzoic acid (3a, 3b, 3c, 3d).
N-(quinolin-8-yl)thiophene-2-carboxamide (1f).White solid;
1H NMR (500 MHz, CDCl3) δ 10.60 (s, 1H), 8.87 – 8.82 (m,
2H), 8.19 (dd, J = 8.3, 1.6 Hz, 1H), 7.84 (dd, J = 3.7, 1.1 Hz,
1H), 7.61 – 7.56(m, 2H), 7.54 (dd, J = 8.3, 1.4 Hz, 1H), 7.48
(dd, J = 8.3, 4.2 Hz, 1H), 7.19 (dd, J = 5.0, 3.7 Hz, 1H).
Gramꢀscale Synthesis of βꢀdeuterated valproic acid. In
Synthesis
of
deuterated
2-propyl-N-(quinolin-8-
yl)pentanamide 2k.
In a sealed tube, 2ꢀpropylꢀNꢀ(quinolinꢀ8ꢀyl)pentanamide 1k
(4.13g, 15.26 mmol, 1.0 equiv.), Pd(OAc)2 (0.68g, 3.05 mmol,
0.2 equiv.) and D2O (99.8% D content, 8.3 mL) were added.
The reaction was stirred at 140 °C for 48 hours. Then, the reꢀ
action mixture was cooled to room temperature and extracted
with water (20 mL)ꢀethyl acetate (3×30 mL). The combined
organic phase was washed with saturated salt water and dried
with Na2SO4 and concentrated under reduced pressure. The
crude mixture was purified by silica gel column chromatogꢀ
raphy (Petroleum ether/ethyl acetate=15/1) to give the deuterꢀ
ated 2ꢀpropylꢀNꢀ(quinolinꢀ8ꢀyl)pentanamide 2k (3.97g, 95%).
3-methoxyl- N-(quinolin-8-yl)benzamide (1i).White solid;1H
NMR(500 MHz, CDCl3)δ 10.76 (s, 1H), 8.95 (dd, J = 7.5, 0.8
Hz, 1H), 8.90 – 8.84 (m, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.67 (d,
J = 3.4 Hz, 1H), 7.66 (s, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.57 (d,
J = 8.2 Hz, 1H), 7.49 (dt, J = 10.2, 5.8 Hz, 2H), 7.17 – 7.12 (m,
1H), 3.94 (s, 3H).
N-(quinolin-8-yl)propionamide (1j). Pale yellow liquid; 1H
NMR (500 MHz, CDCl3) δ 9.82 (s, 1H), 8.83 – 8.75 (m, 2H),
8.16 (dd, J = 8.3, 1.6 Hz, 1H), 7.56 – 7.52 (m, 1H), 7.49 (dd, J
= 8.3, 1.4 Hz, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 2.61 (q, J =
7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H).
Hydrolysis
of
deuterated
2-propyl-N-(quinolin-8-
N-(quinolin-8-yl)tetradecanamide (1k). White solid; 1H NMR
(500 MHz, CDCl3) δ 9.81 (s, 1H), 8.83 – 8.76 (m, 2H), 8.16
(dd, J = 8.3, 1.6 Hz, 1H), 7.56 – 7.51 (m, 1H), 7.49 (dd, J =
8.3, 1.4 Hz, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 2.58 – 2.54
(m, 2H), 1.86 –1.79 (m, 2H), 1.46 – 1.40 (m, 2H), 1.39 – 1.34
(m, 2H), 1.32 – 1.23 (m, 17H), 0.88 (t, J = 7.0 Hz, 3H).
yl)pentanamide 2k.16
The deuterated 2ꢀpropylꢀNꢀ(quinolinꢀ8ꢀyl)pentanamide 2k
(3.30g, 12 mmol, 1.0 equiv.) was dissolved in MeOH (17mL)
and NaOH (4.80g, 120 mmol, 10.0 equiv.) was added. The
reaction mixture was refluxed with stirring for 36h (The reacꢀ
tion is complete by TLC detection). The reaction mixture was
cooled to room temperature and extracted with ethyl acetate
(30 mL) ꢀ water (2×30 mL). The combined aqueous phase was
2-propyl-N-(quinolin-8-yl)pentanamide (1l). Pale yellow liqꢀ
1
uid; H NMR (500 MHz, CDCl3) δ 9.85 (s, 1H), 8.88 – 8.78
(m, 2H), 8.16 (dd, J = 8.3, 1.4 Hz, 1H), 7.54 (t, J = 7.9 Hz,
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1H), 7.51 – 7.47 (m, 1H), 7.45 (dd, J = 8.2, 4.2 Hz, 1H), 2.53
– 2.47 (m, 1H), 1.83 – 1.75 (m, 2H), 1.59 – 1.52 (m, 2H), 1.47
– 1.38 (m, 4H), 0.94 (t, J = 7.3 Hz, 6H).
8.21 (dd, J = 8.3, 1.6 Hz, 1H), 7.92 – 7.90 (m, 1.94H), 7.63 –
7.58 (m, 2H), 7.51 (dd, J = 8.2, 4.2 Hz, 1H).
N-(quinolin-8-yl)thiophene-3-d1-2-carboxamide
(2f).White
N-(quinolin-8-yl)pivalamide (1m). Pale yellow liquid; 1H
NMR (500 MHz, CDCl3) δ 10.28 (s, 1H), 8.85 – 8.76 (m, 2H),
8.15 (dd, J = 8.3, 1.6 Hz, 1H), 7.56 – 7.51 (m, 1H), 7.49 (dd, J
= 8.3, 1.4 Hz, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 1.43 (s, 9H).
N-(quinolin-8-yl)acrylamide (1n). Yellow liquid; 1H NMR
(500 MHz, CDCl3) δ 9.96 (s, 1H), 8.86 (dd, J = 7.4, 1.5 Hz,
1H), 8.81 (dd, J = 4.2, 1.6 Hz, 1H), 8.16 (dd, J = 8.3, 1.6 Hz,
1H), 7.57 – 7.54 (m, 1H), 7.52 (dd, J = 8.2, 1.5 Hz, 1H), 7.46
(dd, J = 8.3, 4.2 Hz, 1H), 6.53 – 6.48 (m, 2H), 5.83 (dd, J =
8.1, 3.4 Hz, 1H).
solid; 96.6 mg, yield: 95%;1H NMR (500 MHz, CDCl3) δ
10.59 (s, 1H), 8.87 – 8.82 (m, 2H), 8.19 ꢀ8.16(m, 1H), 7.84 (d,
J = 3.5, 0.06H), 7.60ꢀ7.55 (m, 1.66H), 7.53 (d, J = 8.0, 1H),
7.47 (dd, J = 8.2, 4.2 Hz, 1H), 7.18 (d, J = 3.6 Hz, 1H).
3-methoxyl- N-(quinolin-8-yl)benzamide (2i).White solid;
yield: 104.7 mg, 94%;1H NMR (500 MHz, CDCl3) δ 10.76 (s,
0.92H), 8.96 (dd, J = 7.5, 1.3 Hz, 0.92H), 8.87 (dd, J = 4.2, 1.6
Hz, 1H), 8.21 (dd, J = 8.3, 1.6 Hz, 1H), 7.68 (s, 0.01H), 7.66
(d, J = 2.4 Hz, 0.03H), 7.62 (t, J = 7.9 Hz, 1H), 7.57 (dd, J =
8.3, 1.3 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.15 (d, J = 8.3 Hz, 1H),
3.94 (s, 3H).
N-(quinolin-8-yl)propanamide-3,3,3-d3(2j).Pale yellow liquid;
yield: 76.1 mg, 95%; 1H NMR (500 MHz, CDCl3) δ 9.82 (s,
1H), 8.82 – 8.76 (m, 1.43H), 8.15 (dd, J = 8.3, 1.6 Hz, 1H),
7.56 – 7.52 (m, 1H), 7.49 (d, J = 8.3, 1H), 7.44 (dd, J = 8.3,
4.2 Hz, 1H), 2.58 (s, 2H).
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N-(quinolin-8-yl)cinnamamide (1o). Pale yellow solid; 1H
NMR (500 MHz, CDCl3) δ 10.02 (s, 1H), 8.92 (dd, J = 7.5,
1.2 Hz, 1H), 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.19 (dd, J = 8.3,
1.6 Hz, 1H), 7.83 (d, J = 15.6 Hz, 1H), 7.63 (dd, J = 7.7, 1.4
Hz, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.54 (dd, J = 8.2, 1.3 Hz,
1H), 7.48 (dd, J = 8.2, 4.2 Hz, 1H), 7.44 – 7.37 (m, 3H), 6.82
(d, J = 15.5 Hz, 1H).
N-(quinolin-8-yl)tetradecanamide-3,3-d2(2k).White
solꢀ
id;yield: 134.7 mg, 95%; 1H NMR (500 MHz, CDCl3) δ 9.81
(s, 0.96H), 8.82 – 8.76 (m, 1H), 8.16 (dd, J = 8.3, 1.6 Hz, 1H),
7.56 – 7.51 (m, 1H), 7.49 (dd, J = 8.3, 1.4 Hz, 0.97H), 7.45
(dd, J = 8.3, 4.2 Hz, 0.82H), 2.58 – 2.54 (m, 2H), 1.46 – 1.40
(m, 2H), 1.39 – 1.34 (m, 2H), 1.32 – 1.23 (m, 17H), 0.88 (t, J
= 7.0 Hz, 3H).
1
2-phenyl-N-(quinolin-8-yl)acrylamide (1p). Brown liquid; H
NMR (500 MHz, CDCl3) δ 10.26 (s, 1H), 8.90 (dd, J = 7.5,
1.4 Hz, 1H), 8.64 (dd, J = 4.2, 1.7 Hz, 1H), 8.13 (dd, J = 8.3,
1.6 Hz, 1H), 7.60 – 7.54 (m, 3H), 7.53 – 7.51 (m, 1H), 7.47 –
7.43 (m, 3H), 7.40 (dd, J = 8.3, 4.2 Hz, 1H), 6.33 (d, J = 0.9
Hz, 1H), 5.84 (d, J = 0.9 Hz, 1H).
2-(propyl-1,1-d2)-N-(quinolin-8-yl)pentanamide-3,3-d2(2l).
2-phenyl-N-(quinolin-8-yl)acetamide (1q). Pale yellow solid;
1H NMR (500 MHz, CDCl3) δ 9.91 (s, 1H), 8.77 (dd, J = 7.4,
1.5 Hz, 1H), 8.73 – 8.66 (m, 1H), 8.12 (dd, J = 8.3, 1.6 Hz,
1H), 7.53 – 7.50 (m, 1H), 7.48 (dd, J = 8.3, 1.5 Hz, 1H), 7.45
(d, J = 7.0 Hz, 2H), 7.43 – 7.39 (m, 3H), 7.36 – 7.32 (m, 1H),
3.90 (s, 2H).
1
Pale yellow liquid; yield: 103.8 mg, 96%; H (500 MHz,
CDCl3) δ 9.84 (s, 1H), 8.85 – 8.80 (m, 1H), 8.19 – 8.14 (m,
1H), 7.54 (m, 1H), 7.51 – 7.47 (m, 1H), 7.48 – 7.43 (m,
0.69H), 2.47 (d, J = 5.4 Hz, 1H), 1.80 – 1.74 (m, 0.20H), 1.55
– 1.52 (m, 0.26H), 1.41 (q, J = 7.4, 7.0 Hz, 4H), 0.94 (t, J =
7.3 Hz, 6H).
N-(quinolin-8-yl)benzamide-2,6-d2(2a). White solid; yield:
94.4 mg, 95%;1H NMR (500 MHz, CDCl3) δ 10.75 (s, 0.95H),
8.95 (dd, J = 7.6 Hz, 1.5Hz, 1H), 8.85 (dd, J = 4.2, 1.5 Hz,
1H), 8.19 (dd, J = 8.2, 1.5 Hz, 1H), 8.09 (d, J = 7.6 Hz,
0.14H), 7.55–7.61 (m, 5H), 7.48 (dd, J = 8.2, 4.2 Hz, 1H).
2,2-bis(methyl-d3)-N-(quinolin-8-yl)propanamide-3,3,3-
1
d3(2m). Pale yellow liquid; yield: 86.8 mg, 95%; H (500
MHz, CDCl3) δ 10.28 (s, 1H), 8.82 – 8.79 (m, 2H), 8.15 (dd, J
= 8.2, 1.4 Hz, 1H), 7.55 – 7.51 (m, 1H), 7.48 (d, J = 8.2 Hz,
1H), 7.45 (dd, J = 8.2, 4.2 Hz, 1H), 1.43 (s, 6H).
2-methyl-N-(quinolin-8-yl)benzamide-6-d1(2b).White
solid;
yield: 99.7 mg, 95%; 1H NMR (500 MHz, CDCl3) δ 10.22 (s,
0.94H), 8.96 (d, J = 7.6 Hz, 0.43H), 8.78 (dd, J = 4.2, 1.6 Hz,
1H), 8.18 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.6 Hz, 0.02H), 7.59
– 7.62 (m, 1H), 7.56 (d, J = 8.3 Hz, 0.66H), 7.46 (dd, J = 8.3,
4.2 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.35 – 7.31 (m, 2H), 2.62
(s, 3H).
N-(quinolin-8-yl)acrylamide-3,3-d2(2n). Yellow liquid; yield:
75.3 mg, 95%; 1H NMR (500 MHz, CDCl3) δ 9.96 (s, 1H),
8.86 (dd, J = 7.4, 1.5 Hz, 1H), 8.81 (dd, J = 4.2, 1.7 Hz, 1H),
8.17 – 8.15 (m, 1H), 7.57 – 7.54 (m, 1H), 7.52 (dd, J = 8.3, 1.5
Hz, 1H), 7.47 – 7.45 (m, 1H), 6.48 (s, 1H), 5.81 (d, J = 10.3
Hz, 0.02H).
N-(quinolin-8-yl)cinnamamide-3-d1(2o). Pale yellow solid;
yield: 103.1 mg, 94%; 1H NMR (500 MHz, CDCl3) δ 10.02 (s,
1H), 8.92 (dd, J = 7.5, 1.1 Hz, 1H), 8.84 (dd, J = 4.2, 1.6 Hz,
1H), 8.18 (dd, J = 8.2, 1.5 Hz, 1H), 7.83 (d, J = 15.5 Hz,
0.02H), 7.64 – 7.60 (m, 2H), 7.58 (dd, J = 7.6, 2.9 Hz, 1H),
7.53 (dd, J = 8.2, 1.2 Hz, 1H), 7.48 (dd, J = 8.2, 4.2 Hz, 1H),
7.44 – 7.39 (m, 3H), 6.82 (d, J = 1.9 Hz, 1H).
4-methyl-N-(quinolin-8-yl)benzamide-2,6-d2(2c). White solid;
yield: 98.6 mg, 94%;1H NMR (500 MHz, CDCl3) δ 10.72 (s,
1H), 8.94 (d, J = 7.6 Hz, 1H), 8.86 (dd, J = 4.2, 1.5 Hz, 1H),
8.19 (dd, J = 8.2, 1.4 Hz, 1H), 7.99 (d, J = 8.2 Hz, 0.50H),
7.60 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.48 (m,
1H), 7.35 (s, 2H), 2.46 (s, 3H).
4-methoxy-N-(quinolin-8-yl)benzamide-2,6-d2(2d). White solꢀ
id; yield: 104.6 mg, 94%;1H NMR (500 MHz, CDCl3) δ 10.68
(s, 0.95H), 8.93 (d, J = 7.5 Hz, 0.70H), 8.86 (d, J = 2.8 Hz,
1H), 8.19 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.7 Hz, 0.04H), 7.63
– 7.57 (m, 1H), 7.53 (d, J = 8.1 Hz, 0.78H), 7.49 – 7.47 (m,
1H), 7.05 (s, 2H), 3.90 (s, 3H).
2-(phenyl-2,6-d2)-N-(quinolin-8-yl)acrylamide-3,3-
1
d2(2p).Brown liquid; yield: 87.8 mg, 80%; H (500 MHz,
CDCl3) δ 10.26 (s, 1H), 8.90 (dd, J = 7.5, 1.3 Hz, 1H), 8.65
(dd, J = 4.2, 1.7 Hz, 1H), 8.13 (dd, J = 8.3, 1.7 Hz, 1H), 7.59 –
7.55 (m, 1.30H), 7.52 (dd, J = 8.3, 1.4 Hz, 1H), 7.47 – 7.42
(m, 3H), 7.40 (dd, J = 8.3, 4.2 Hz, 1H), 6.33 (d, J = 0.9 Hz,
0.05H), 6.31 (s, 0.20H), 5.84 (d, J = 0.8 Hz, 0.05H), 5.82 (s,
0.35H).
N-(quinolin-8-yl)isonicotinamide-3,5-d2(2e).Pale yellow solid;
yield: 98.7 mg, 99%; 1H NMR (500 MHz, CDCl3) δ 10.82 (s,
0.95H), 8.91 (dd, J = 6.4, 2.5 Hz, 1H), 8.88 – 8.85 (m, 3H),
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(3) (a) Allen, P. H.; Hickey, M. J.; Kingston, L. P.; Wilkinson, D.
2-(phenyl-2,6-d2)-N-(quinolin-8-yl)acetamide-2,2-d2(2q).Pale
yellow solid; yield: 98.6 mg, 94%; 1H (500 MHz, CDCl3) δ
9.91 (s, 1H), 8.77 (dd, J = 7.4, 1.5 Hz, 0.03H), 8.73 – 8.66 (m,
1H), 8.12 (dd, J = 8.3, 1.6 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H),
7.48 (d, J = 8.3 Hz, 1H), 7.46 – 7.44 (m, 0.08H), 7.46 – 7.44
(m, 3H), 7.43 – 7.39 (m, 1H), 3.90 (s, 1.24H).
Benzoic acid-2,6-d2(3a). White solid; yield: 34.8mg, 95%;1H
NMR (500 MHz, CDCl3) δ 8.14 (dd, J = 8.0, 1.0 Hz, 0.14H),
7.65 – 7.61 (m, 1H), 7.50 (t, J = 5.6 Hz, 2H).
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Sawama, Y.; Park, K.; Yamada, T.; Sajiki, H. New Gateways to the
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2-methylbenzoic acid-6-d1(3b). White solid; yield: 38.8 mg,
95%;1H NMR (500 MHz, CDCl3) δ 12.51 (s, 1H), 8.09 (d,
0.02H), 7.49 – 7.45 (m, 1H), 7.32 – 7.28 (m, 2H), 2.68 (s, 3H).
4-methylbenzoic acid-2,6-d2 (3c). White solid; yield: 38.8 mg,
95%;1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 8.2 Hz, 0.5H),
7.28 (t, J = 6.6 Hz, 2H), 2.44 (s, 3H).
4-methoxylbenzoic acid-2,6-d2 (3d).White solid; yield: 43.4
mg, 95%;1H NMR (500 MHz, DMSOꢀd6) δ 7.87 (d, J = 8.8
Hz, 0.04H), 7.00 (s, 2H), 3.81 (s, 3H).
2-(propyl-1,1-d2)pentanoic acid-3,3-d2 (3e). Colorless liquid;
yield: 1.17 g, 96%; 1H NMR (500 MHz, CDCl3) δ 2.37 (d,
1H), 1.62 – 1.57 (m, 0.18H), 1.44ꢀ1.41 (m, 0.20H), 1.40 – 1.28
(m, J = 6.7 Hz, 4H), 0.91 (t, J = 7.3 Hz, 6H).
ASSOCIATED CONTENT
Supporting Information
1
Supplementary data (copies of H NMR and LCꢀHRMS Spectral
spectra for all products).
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail:guolinzhang@zju.edu.cn (G.Z.).
* Eꢀmail:yyu@zju.edu.cn (Y.Y.).
Notes
#They are coꢀfirst authors.
ACKNOWLEDGMENT
This project was supported from Zhejiang Provincial Natural
Science Foundation of China (LY16H300001) to G. Zhang, Naꢀ
tional Natural Science Foundation of China (No. 81673291 and
81473074)and Osteoporosis & Breast Cancer Research Center,
USA to Y. Yu, Zhejiang Provincial Natural Science Foundation of
China (LY18H300001) to W. Chen.
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