Stereoselective synthesis of diazabicyclic β-lactams through intramolecular amination of unactivated C(sp3)-H bonds of carboxamides by palladium catalysis

Article abstract of DOI:10.1021/acs.joc.5b02532

An efficient C(sp³)-H bond activation and intramolecular amination reaction via palladium catalysis at the β-position of carboxyamides to make β-lactams was described. The investigation of the substrate scope showed that the current reaction conditions favored activation of the β-methylene group. Short sequences were developed for preparation of various diazabicyclic β-lactam compounds with this method as the key step from chiral proline and piperidine derivatives.

Full text of DOI:10.1021/acs.joc.5b02532

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Article
Stereoselective Synthesis of Diazabicyclic beta-Lactams
through Intramolecular Amination of Unactivated C(sp3)-
H Bonds of Carboxamides by Palladium Catalysis
Shi-Jin Zhang, Wen-Wu Sun, Pei Cao, Xiao-Ping Dong, Ji-Kai Liu, and Bin Wu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Jan 2016
Downloaded from http://pubs.acs.org on January 8, 2016
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Stereoselective Synthesis of Diazabicyclic
β
ꢀLactams through Intramolecular
Amination of Unactivated C(sp3)ꢀH Bonds of Carboxamides by Palladium Catalysis
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ShiꢀJin Zhang,†,‡,⊥ WenꢀWu Sun,‡,ǀ,⊥ Pei Cao,∗,‡ XiaoꢀPing Dong,∗,† JiꢀKai Liu,§ Bin
Wu∗,‡,§
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†Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu
611137, China
‡State Key Laboratory of Phytochemistry and Plant Resources in West China,
Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
ǀUniversity of Chinese Academy of Sciences, Beijing 100049, China
§School of Pharmaceutical Sciences, SouthꢀCentral University for Nationalities,
Wuhan 430074, China
ABSTRACT: An efficient C(sp3)ꢀH bonds activation and intramolecular amination reaction via
Palladium catalysis at the βꢀposition of carboxyamides to make βꢀlactams was described. The
investigation of the substrate scope showed that the current reaction conditions favored to activate
the βꢀmethylene group. Short sequences were developed for preparation of various diazabicyclic
βꢀlactam compounds with this method as key step from chiral proline and piperidine derivatives.
INTRODUCTION
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The searching for new kinds of βꢀlactamase inhibitors is one of effective solutions to
βꢀlactamaseꢀmediated resistance problem in modern medicine and pharmaceutical area.1 The
unnatural diazabicyclic βꢀlactam skeletons 1 and 2 in Figure 1 are important structure motifs
existing in some important bioactive molecules such as compounds 3 to 7, which have been found
to be potent inhibitors of class C βꢀlactamase.2 For example, based on structure of R048ꢀ1256,
MKꢀ8712 was made and screened to be best for enzymatic inhibition against pseudomonal class C
βꢀlactamase AmpC in combination with imipenem.3 BAL29880 (5) was one of important
components of BAL30376, which overcomes a variety of Gramꢀnegative bacteria.4 Moreover,
compound 8 was the key intermediate for the synthesis of the tetrahydroisoquinoline family of
alkaloids such as saframycins and bioxalomycins, which are antitumor antibiotics, and
ecteinascidineꢀ743, which is a highly potent antitumor agent currently in phase II/III human
clinical trials.5
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Figure 1. Biologically active compounds with diazabicyclic βꢀlactam skeletons.
To achieve the above mentioned diazabicyclic βꢀlactam skeletons, Mitsunobu reaction and
intramolecular or intermolecular Staudinge keteneꢀimine cycloaddition reactions were used to
form the second ring based on the highly strained monocyclic βꢀlactams.6 However, these kinds of
typical procedures suffered from some limitations such as expensive starting materials, long steps,
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some toxic reagents and the removal of phosphine oxide and hydrazinodicarboxylate as
byꢀproducts.
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Transitionꢀmetalꢀcatalyzed intramolecular amination reaction of the CꢀH bonds is an effective
approach for the construction of Nꢀheterocyclic compounds, and has attracted much attention from
synthetic chemists in the past decade.7 Several approaches for the synthesis of various lactams
including βꢀlactams via Pd,8aꢀd Ni,8e Cu8fꢀg and Co8h catalysis have been reported. After the
successful construction of simple βꢀlactams in initial studies utilizing the 8ꢀaminoꢀquinoline (AQ)
as the directing group,9 we want to extend our previous methodology on the construction of
various diazabicyclic βꢀlactam compounds. It may provide good opportunity for the study of
structureꢀactivity relationship of βꢀlactamase inhibitors.
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RESULTS AND DISCUSSION
We began this project initially during our study at oxidative phosphonation at βꢀC(sp3)ꢀH of
substrate 9a with diphenylphosphine oxide in the presence of 10 mol% Pd(OAc)2 and 1 equiv of
o
AgOAc in toluene at 130 C for 24 h. Actually, we did not get the desired compound. Only very
small amount of γꢀlactam compound 11a was formed. The use of 4’ꢀiodoacetophenone instead of
diphenylphosphine oxide in the same reaction condition led to the formation of crossꢀcoupling
product 12 and βꢀlactam compound 10a (entry 1, Table 1). The structure of 10a was further
confirmed by the Xꢀray singleꢀcrystal analysis.10 Compared with the research work in Daugulis’
group,11 the major difference came from the use of phenyl iodides bearing different substituents.
In his paper, aryl iodides bearing electronꢀdonating group were used in most cases, and the major
products were crossꢀcoupling compounds. We screened
a set of aryl iodides with
electronꢀwithdrawing group and found this reaction led to a mixture with three kinds of products
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10aꢀ12 in the presence of Ac, CF3, NO2ꢀsubstituted aryl iodides. pꢀNO2C6H4I gave the better 64%
yield favoring the βꢀlactam product 10a (entries 1ꢀ7, Table 1). Pentafluoroiodobenzene was
usually employed as special fluorinated substrate in various crossꢀcoupling reaction and worked as
building blocks in material science.12 To our delight, when pentafluoroiodobenzene was used, the
reaction proceeded with high regioselectivity to afford 10a in moderate yield, and 11a was not
detected (entry 9, Table 1). Increasing temperature led to high yield of product 10a. And heating
by means of microwave is an efficient way for this reaction (entries 10ꢀ12, Table 1). Controlled
experiments showed the reaction did not occur without either Pd(OAc)2 or AgOAc. In addition to
AgOAc, Ag2CO3, AgF and AgF2 were also found to be effective in this reaction to give βꢀlactam
product 10a in 82%, 73% and 45% yield, respectively. Other silver salts such as Ag2O and
AgCO2CF3 failed to afford the typical product 10a. Finally, a combination of Pd(OAc)2 (5 mol%),
AgOAc (1.2 equiv), and pentafluoroiodobenzene (5.5 equiv) under microwave at 160 oC for 1.5 h
was the best system for palladiumꢀcatalyzed intramolecular amination reaction of 9 to afford
βꢀlactam compounds.
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Table 1. Optimization of the reaction conditions.
O
O
O
X
Pd(OAc)2 (2 mol %)
AgOAc (1.2 equiv)
N
NH
N
H
+
+
N
R
N
solvent free
temp, time
N
9a
4 equiv
11a
10a
O
N
H
+
N
R
12
Entry
RꢀC6H4X
Temp (oC), Time
120 oC, 20 min
120 oC, 24 h
Yield a (%) of 10a/11a/12
1
2
pꢀAcC6H4I
28 / ꢀ / 58 b
b, e
oꢀCF3 C6H4I
4 / 4 / ꢀ
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b, e
b, e
3
pꢀCF3 C6H4I
120 oC, 19 h
120 oC, 19 h
THF, 120 oC, 24 h
toluene, 120 oC, 24 h
170 oC, 15 h
120 oC, 24 h
130 oC, 24 h
130 oC, 2 h
24 / 6 / ꢀ
25 / 3 / 1
4
oꢀNO2 C6H4I
pꢀNO2 C6H4I
pꢀNO2 C6H4I
pꢀNO2 C6H4I
pꢀNO2 C6H4Br
C6F5I
5
64 / 5 / 20 b
53 / 8 / 26 b
65 / ꢀ / 15 b
6
7
b, e
8
ꢀ / 5 / ꢀ
49 / ꢀ / ꢀ
49 / ꢀ / ꢀ
83 / ꢀ / ꢀ
93 / ꢀ / ꢀ
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b, d, f
c, d, f
c, g
9
10
11
C6F5I
C6F5I
160 oC, 1 h
c,d
12
a
C6F5I
160 oC, 1.5 h
b
c
Isolated yield. The reaction was conducted in seal tube. The reaction was conducted with
microwave machine and C6F5I (5.5 equiv) was used. d Pd(OAc)2 (5 mol%) was used. e Most of 9a
was recovered. f 40% of 9a was recovered. g Pd(OAc)2 (2.5 mol%) was used, and 13% of 9a was
recovered.
The substrate scope was subsequently investigated (Table 2). A variety of methylene CꢀH bonds at
the βꢀposition of carboxamides can be efficiently activated and aminated to make the βꢀlactam
compounds. Aromatic rings with electronꢀdonating or ꢀwithdrawing groups were compatible.
Many function groups on the phenyl rings, such as ethers (10cꢀ10f), halides (10gꢀ10l), nitroarenes
(10m), esters (10n) remained untouched. Moreover, substrates with alkyl groups at the βꢀposition
of carboxamides underwent reactions to afford the corresponding βꢀlactam products (10oꢀ10v)
with good to excellent yields, including the sterically demanding cyclohexyl, cyclopentyl moieties
and alkyl bromide, which theoretically provides potent way to make the bicyclic fused βꢀlactam
compound via SN2ꢀtype reaction at the αꢀposition of monocyclic βꢀlactam compound 10t.
Table 2. Substrate scope.
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a
Typical reaction conditions: substrate (0.10 mmol), Pd(OAc)2 (0.005 mmol, 5 mol%), AgOAc
(0.12 mmol, 1.2 equiv), C5F5I (0.55 mmol, 5.5 equiv), microwave, 160 oC, 1.5h. Isolated yields. b
Pd(OAc)2 (7 mol%) was used. c Pd(OAc)2 (10 mol%) was used. Reaction time was 5h.
Further investigation demonstrated the limitation of this reaction. Under the current reaction
conditions, βꢀC(sp2)ꢀH, βꢀtertiary C(sp3)ꢀH bonds of carboxamides 13 and 17ꢀ21 (Table 3) could
not be activated. It showed that the position of CꢀC double bonds played an important effect on the
reaction. In case of substrate 9v (Table 2), which has a CꢀC double bond far away from the
reaction center, the βꢀlactam product 10v was obtained in 82% yield successfully. In contrast,
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substrates 23ꢀ25 (Table 3), which have CꢀC double bonds close to reaction center probably acting
as a ligand to coordinate to metal to inhibit the reaction.13 Due to the high ring strain, cyclopropyl,
cyclobutyl substrates 14ꢀ16 and 26 (Table 3) did not produce bicyclic fused βꢀlactam products. No
reaction occurred when the auxiliary groups were changed to substrates 27 and 28. The primary
methyl CꢀH bonds of 29 can be activated and crossꢀcoupled with C6F5I to afford 30 and 31 in 30%
and 37% yield, respectively (eq 1).
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Table 3. Typical unreactive substrates:
The reaction proceeded well with different
example, to ꢀdisubstitued substrates 41g, the reaction gave 6/4 fused
with the angular methyl group intact (entry7, Table 4). To ꢀmonosubstitued substrates 32 and 35,
the reactions gave two diastereoisomers favoring transꢀ34 and transꢀ37, respectively (eq 2 and 3).
1,10ꢀDecanediamide 38 underwent double cyclization to afford diꢀ ꢀlactam 39 in 86% yield,
αꢀsubstituted aminoquinoline carboxamides. For
α
β
ꢀlactam product cisꢀ42g
α
β
accompanied with monoꢀ
β
ꢀlactam 40 in 8% yield (eq 4). A controlled reaction with substrate 9e
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and 9l in one pot was carried out to give
β
ꢀlactam products 10e and 10l in 27% and 85% yield,
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along with 52% yield of recovered substrate 9e. It indicated that the reaction rate with
electronꢀwithdrawing group on the phenyl ring was 3 times than that of electronꢀdonating group
(eq 5).
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Pd(OAc)2 (5 mol%)
AgOAc (1.2 equiv)
O
O
F
O
F
F
AcO
H
N
N
H
N
H
(1)
+
H
C6F5I (5.5 equiv)
neat, MW, 160 oC, 1.5 h
F
N
N
N
F
29
31, 37%
30, 30%
H
O
O
Pd(OAc)2 (5 mol%)
AgOAc (1.2 equiv)
n-C3H7
n-C3H7
Et
O
N
N
N
H
+
H
Et
(2)
H
C6F5I (5.5 equiv)
neat, MW, 160 oC, 1.5 h
N
N
N
32
cis-33, 29%
trans-34, 51%
Pd(OAc)2 (5 mol%)
AgOAc (1.2 equiv)
O
H
O
H
O
N
Ph
Ph
H
Ph
N
+
H
N
H
C6F5I (5.5 equiv)
neat, MW, 160 oC, 1.5 h
Me
(3)
Me
N
N
N
35
cis-36, 18%
trans-37, 61%
O
O
O
Pd(OAc)2 (10 mol%)
AgOAc (2.4 equiv)
N
O
O
N
H
N
N
4
N
H
N
C6F5I (12 equiv)
neat, MW, 160 oC, 1.5 h
N
N
(4)
38
39
, 86%
+
HN
O
N
N
N
40, 8%
O
O
O
Q
O
Q
Pd(OAc)2 (5 mol%)
AgOAc (1.2 equiv)
N
N
N
H
+
9e
N
H
+
+
N
N
C6F5I (5.5 equiv)
neat, MW, 160 oC, 1.5 h
Q = 8-quinolinyl
(5)
Br
MeO
MeO
Br
9l
9e
0.1 mmol
10l
85%
10e
27%
0.1 mmol
52%
The skeletons of bicyclic or polycyclic fused βꢀlactams are widespread in pharmaceutical such as
various βꢀlactam antibiotics.1 It is much more challenge to make these kinds of skeletons based on
aliphatic CꢀH bonds activation. Inspired by our experiments, we next screened the carboxamides
with differentꢀsized aliphatic rings. We found that the substrates with five, six, seven,
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eightꢀmembered and bridged ring fragments were suitable for this conversion to finish the relative
cisꢀfused βꢀlactam products with good to excellent yields. The results are summarized in Table 4.
It showed that the configuration of the substrates played a key effect on the efficiency of the
reaction. For example, the endoꢀ41i and exoꢀ41j gave the corresponding relative cisꢀfused
products cisꢀendoꢀ42i and cisꢀexoꢀ42j in 87% and 82% yield, respectively. Because of different
orientation of CꢀC double bonds and carboxamides group in substrates exoꢀ41k and endoꢀ41l, the
reaction of the exoꢀ41k afforded the product cisꢀexoꢀ42k in 48% yield, while the endoꢀ41l did not
work at all, probably due to the CꢀC double bond acting as a ligand coordinating to the metal to
inhibit the reaction.13 Interestingly, Cbz protected NH group did not affect the outcome of product
cisꢀ42h (entry 8, Table 4).
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Table 4. Production of cisꢀfused βꢀlactamsa
Entry
1
Substrate
Product
Yield (%)
93
2
3
93
88
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N
H
83
98
73b
85
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N
41d
H
H
O
Q
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N
Me
cis-42e
9
87
10
11
82
48
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H
O
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12
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ꢀ
ꢀc
HN
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endo-41l
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a Typical reaction condition. b Pd(OAc)2 (10 mol%) was used. c No reaction.
Application of the methodology on the preparation of various diazabicyclic β-lactam
compounds14
As we mentioned earlier, the core structures of Ro48ꢀ1256, MKꢀ8712 and their derivatives are
diazabicyclic βꢀlactams. MKꢀ8712, developed by Merk company, provided an important
therapeutic option for the treatment of carbapenem resistance in Pseudomonas. We want to apply
our reaction conditions to make the key intermediates for the synthesis of MKꢀ8712 and their
derivatives. Compound (ꢀ)ꢀ43 was easily obtained through protection with benzyl chloroformate,
and coupling with 5ꢀmethoxyquinolinꢀ8ꢀamine under the reagents of EDCI and DMAP from the
commercial available Lꢀproline. The intramolecular amination reaction of (ꢀ)ꢀ43 was performed
under the standard conditions by combining Pd(OAc)2, AgOAc, together with
pentafluoroiodobenzene, and gave the desired product (ꢀ)ꢀ44 in 86% yield. The 5ꢀMeOꢀquinoline
(MQ) group of (ꢀ)ꢀ44 was readily removed upon treatment with ceric ammonium nitrate (CAN),
and removal of Cbz group by hydrogenation reaction provided the cisꢀfused compound (ꢀ)ꢀ46,
which is the key intermediate for the synthesis of MKꢀ8712 (Scheme 1).
Scheme 1. Synthesis of diazabicyclic β-lactam (-)-46 from L-proline.
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We next examined the more challenge substrate octahydroꢀ1Hꢀindole, which has three chiral
centers. Compound (ꢀ)ꢀ47 was prepared according the general procedure involving protection and
amidation reactions from (2S, 3aS, 7aS)ꢀoctahydroindoleꢀ2ꢀcarboxylic acid. Then (ꢀ)ꢀ47 was
subjected to the standard reaction conditions to afford the product (ꢀ)ꢀ48 in 88% yield. After two
deprotection steps, (ꢀ)ꢀ50, which has four contiguous chiral centers, was successfully obtained in
high yield (Scheme 2).
Scheme 2. Synthesis of diazabicyclic β-lactam (-)-50.
Piperidines bearing substituents at C3 positions are important structural motifs widely existing in
natural products and pharmaceuticals with various biological activities. We envisioned to
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functionalize at C3 of piperidine derivatives under the current reaction conditions to make the key
building blocks for the synthesis of 6 and 7 (Figure 1). Compound (ꢀ)ꢀ55 was easily prepared, and
then subjected to standard conditions to form the diazabicyclic βꢀlactam (ꢀ)ꢀ56 with a gram scale
in 78% yield, which was readily undergone deprotection step and hydrogenation reaction to get
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50
51
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53
54
55
56
57
58
59
60
compound (ꢀ)ꢀ58. Compound (ꢀ)ꢀ57 was right intermediate for preparation of 6 and 7 (Scheme 3).
Scheme 3. Synthesis of diazabicyclic β-lactam (-)-58.
To our delight, compound (ꢀ)ꢀ59, prepared from (S)ꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ3ꢀcarboxylic
acid, was smoothly cyclized under our reaction conditions to form (ꢀ)ꢀ60. After two deprotection
steps, (+)ꢀ62 was obtained in high yield, whose structure was confirmed by Xꢀray single crystal
analysis (Scheme 4).15
Scheme 4. Synthesis of diazabicyclic β-lactam (+)-62.
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9
O
O
EDCI (1.5 equiv)
DMAP (0.1 equiv)
CbzCl, NaOH, H2O
OH
Cbz
OH
N
5-MeO-8-NH2-quinoline
DCM, rt, 12h
72%
rt, 4h, 80%
NH
(S)-1,2,3,4-tetrahydroisoquinoline
-3-carboxylic acid
MeO
OMe
O
H
N
AgOAc (1.5 equiv)
O
Pd(OAc)2 (15 mol%)
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11
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17
18
19
20
21
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48
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50
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53
54
55
56
57
58
59
60
CAN (3.0 equiv)
N
H
N
N
N
N
C6F5I
MeCN/H2O, 0 o
57%
C
O
N
Cbz
MW, 150 oC, 4 h
66%
Cbz
(-)-59
(+)-61
N
Cbz
60
(-)-
H
N
O
Pd/C, H2
EtOAc, 60 oC, 24h
80%
N
H
(+)-62
Encouraged by the success with the above substrates, it was thought worthwhile to investigate the
cyclization reaction of some different types of substrates. Compound 63, prepared from
(±)ꢀindolineꢀ2ꢀcarboxylic acid, was selected as substrate for this reaction. Unfortunately, the
reaction failed to produce diazatricyclic βꢀlactam compound, but to give 64 in 15% yield (Scheme
5).
transꢀ4ꢀHydroxyꢀLꢀproline is a very useful chiral resource for organic synthesis. We next tested
this kind of substrates. Three different amide substrates 65ꢀ67 bearing free hydroxyl, ester and
ether group at C4 position of Lꢀproline were made. Disappointingly, none of these three substrates
led to form the corresponding diazabicyclic βꢀlactams under the standard conditions (Scheme 5).
Scheme 5. Unsuccessful examples.
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O
HO
O
HO
CbzCl, NaHCO3, THF
rt, 24 h, 75%
OH
OH
N
Cbz
N
H
trans-4-hydroxy
7
-L-proline
O
O
8
9
O
HO
8-NH2-quinoline
N-methyl morpholine
Isobutyl chloroformate
THF, 0 oC-rt, 24 h
O
HO
Acetyl Chloride,
DCM, Et3N
N
O
N
N
Cbz
H
OH
N
Cbz
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
Cbz
N
0 oC-rt, 12 h
75%
N
66
65
Standard
conditions
79%
Standard
conditions
NaH,MeI,THF
sealed tube, 70 oC, 34%
0%
0%
OH
H
O
O
O
O
H
N
H
OH
N
N
N
N
Cbz
N
O
Cbz
Cbz
N
H
O
69
68
8-NH2-quinoline
EDCI, DMAP, DCM
40 oC, 24 h, 71%
Standard conditions:
Pd(OAc)2 (10 mol%)
AgOAc (2 equiv)
O
O
N
O
H
N
N
N
H
N
C6F5I (10 equiv)
Cbz
N
microwave, 130 oC, 4 h
H
Cbz
O
67
70
0%
CONCLUSION
In conclusion, an efficient Pdꢀcatalyzed C(sp3)ꢀH bonds activation and intramolecular amination
reaction at the βꢀposition of carboxyamides to make various βꢀlactams was described. The
substrate scope of the reaction was fully investigated, which indicated that the current reaction
conditions favored to activate the methylene group over methyl and tertiary CH group at the
βꢀposition of carboxamides. This method is especially very useful for making βꢀlactams with 5/4,
6/4, 7/4, 8/4 cisꢀfused ring system, which would otherwise require lengthy synthetic sequences. In
consideration of important biological activities of diazabicyclic βꢀlactam compounds, short
sequences were developed for preparation of various diazabicyclic βꢀlactam compounds with this
method as key step from chiral proline and piperidine derivatives.
EXPERIMENTAL SECTION
General Techniques. All melting points are uncorrected. Microwave irradiation reactions were
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carried out in a CEM Discover SP system with a floor mounted infrared temperature sensor.
Reactions were performed in glass vessels (capacity 10 mL or 30 mL) sealed with a septum.
Preparative chromatographic separations were performed on silica gel (300ꢀ400 mesh). Reactions
were followed by TLC analysis using silica plates with a fluorescent indicator (254 nm) and
visualized with a UV lamp, KMnO4 or phosphomolybdic acid. Optical rotations were measured on
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1
a digital polarimeter. H and 13C NMR spectra were recorded in Fourier transform mode at the
field strength specified on a 400, 500, or 600 MHz spectrometer. Spectra were obtained on CDCl3
or C5D5N solutions in 5 mm diameter tubes, and chemical shifts in ppm (part per million) are
quoted relative to the residual signals of chloroform (δH 7.26 ppm, or δC 77.16 ppm) and pyridine
(δH 7.20 ppm, or δC 135.43 ppm). J values are given in hertz. IR spectra were measured for
samples as KBr pellets in a FTꢀIR spectrophotometer. High resolution mass spectra (HRMS) were
measured at 70 eV using a double focusing magnetic sector mass analyzer with an EI source.
Crystallographic data were collected using graphite monochromated Mo Kα radiation (λ =
0.71073 Å) for the compounds 10a, 10e and 10h, and graphite monochromated Cu Kα radiation (λ
= 1.54178 Å) for the compound (+)-62 in the
φ and ω scans mode.
General Procedure for the Preparation of aminoquinoline carboxamides 13-28: To a solution
of acid (1.0 mmol), 8ꢀaminoquinoline (173.0 mg, 1.2 mmol) in anhydrous CH2Cl2 (5 mL) were
added EDCI (230.0 mg, 1.2 mmol) and DMAP (11 mg, 0.2 mmol). The reaction mixture was
stirred at room temperature for 24 h, then diluted with CH2Cl2 (30 mL), washed with aq. HCl (1 M,
2 x 30mL) and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification
by flash chromatography (Silica gel, CH2Cl2 as eluent) gave the corresponding aminoquinoline
carboxamide compound.
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2-Methyl-N-(quinolin-8-yl)cyclopropane carboxamide (15): Yellow oil; H NMR (400 MHz,
CDCl3) δ 9.96 (s, 1H), 8.87–8.62 (m, 2H), 8.14 (dd, J = 8.2 and 1.3 Hz, 1H), 7.55–7.37 (m, 3H),
1.55–1.49 (m, 1H), 1.37–1.30 (m, 1H), 1.26 (d, J = 6.0 Hz, 1H), 1.18 (d, J = 5.6 Hz, 3H), 0.79–
0.67 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 172.2, 148.1, 138.3, 136.5, 134.9, 128.1, 127.6,
121.6, 121.2, 116.4, 25.1, 18.1, 17.0, 16.7; HRMS(EI) Calcd for C14H14N2O [M+]: 226.1106,
Found 226.1109; IR (KBr) V(cmꢀ1) : 1679, 1528, 1486, 1426, 1384, 1329, 1164.
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60
2-Cyclopropyl-N-(quinolin-8-yl)acetamide (17): White solid; mp 32ꢀ34℃; 1H NMR (400 MHz,
CDCl3) δ 10.29 (brs, 1H), 8.87–8.72 (m, 2H), 8.25–7.97 (m, 1H), 7.61–7.34 (m, 3H), 2.53–2.42
(m, 2H), 1.31–1.14 (m, 1H), 0.84–0.70 (m, 2H), 0.36 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
171.4, 148.3, 138.7, 136.4, 134.8, 128.1, 127.5, 121.7, 121.5, 116.5, 43.3, 7.5, 5.0; HRMS(EI)
Calcd for C14H14N2O [M+]: 226.1106, Found 226.1108; IR (KBr) V(cmꢀ1) : 1684, 1529, 1486,
1425, 1385, 1328, 827, 792.
2-Cyclopentyl-N-(quinolin-8-yl)acetamide (18): White solid; mp 40ꢀ42℃; 1H NMR (400 MHz,
CDCl3) δ 9.80 (brs, 1H), 8.90–8.70 (m, 2H), 8.21–8.05 (m, 1H), 7.61–7.36 (m, 3H), 2.61–2.52 (m,
2H), 2.50–2.36 (m, 1H), 2.04–1.86 (m, 2H), 1.76–1.51 (m, 4H), 1.38–1.21 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 171.7, 148.2, 138.5, 136.5, 134.8, 128.1, 127.6, 121.7, 121.4, 116.5, 44.6,
37.4, 32.8, 25.2; HRMS(EI) Calcd for C16H18N2O [M+]: 254.1419, Found 254.1424; IR (KBr)
V(cmꢀ1) : 1686, 1526, 1485, 1425, 1386, 1326, 827, 792.
2-Cyclohexenyl-N-(quinolin-8-yl)acetamide (19): White solid; mp 65ꢀ67℃; 1H NMR (400 MHz,
CDCl3) δ 10.22 (brs, 1H), 8.88–8.59 (m, 2H), 8.20–8.06 (m, 1H), 7.60–7.35 (m, 3H), 5.86 (s, 1H),
3.19 (s, 2H), 2.25–2.15 (m, 2H), 2.15–2.05 (m, 2H), 1.80–1.60 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 170.1, 148.4, 138.8, 136.4, 134.7, 132.6, 128.14, 128.06, 127.5, 121.7, 121.5, 116.3,
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48.0, 28.8, 25.8, 23.0, 22.1; HRMS(EI) Calcd for C17H18N2O [M+]: 266.1419, Found 266.1423; IR
(KBr) V(cmꢀ1) : 1684, 1525, 1485, 1425, 1385, 1327, 827, 792.
7
8
9
1
3-Methyl-N-(quinolin-8-yl)butanamide (20): White solid; mp 53ꢀ55℃; H NMR (400 MHz,
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16
17
18
19
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47
48
49
50
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53
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56
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58
59
60
CDCl3) δ 9.78 (brs, 1H), 8.90–8.70 (m, 2H), 8.14 (d, J = 7.3 Hz, 1H), 7.60–7.36 (m, 3H), 2.43 (d,
J = 7.1 Hz, 2H), 2.38–2.23 (m, 1H), 1.07 (d, J = 6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
171.4, 148.2, 138.5, 136.5, 134.7, 128.0, 127.5, 121.7, 121.5, 116.5, 47.7, 26.4, 22.7; HRMS(EI)
Calcd for C14H16N2O [M+]: 228.1263, Found 228.1266; IR (KBr) V(cmꢀ1) : 1687, 1527, 1485,
1385, 793.
2-Cycloheptyl-N-(quinolin-8-yl)acetamide (21): White solid; mp 71ꢀ72℃; 1H NMR (400 MHz,
CDCl3) δ 9.78 (brs, 1H), 8.85–8.75 (m, 2H), 8.20–8.05 (m, 1H), 7.58–7.36 (m, 3H), 2.52–2.42 (m,
2H), 2.28–2.14 (m, 1H), 1.92–1.79 (m, 2H), 1.74–1.58 (m, 4H), 1.58–1.42 (m, 4H), 1.40–1.27 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 171.5, 148.2, 138.5, 136.5, 134.7, 128.1, 127.6, 121.7, 121.4,
116.5, 47.0, 37.2, 34.8, 28.4, 26.4; HRMS(EI) Calcd for C18H22N2O [M+]: 282.1732, Found
282.1738; IR (KBr) V(cmꢀ1) : 1681, 1525, 1485, 1385, 831.
1
N-(Quinolin-8-yl)cyclohex-3-ene carboxamide (23): White solid; mp 95ꢀ96℃; H NMR (400
MHz, CDCl3) δ 9.95 (brs, 1H), 8.85–8.75 (m, 2H), 8.19–8.06 (m, 1H), 7.57–7.37 (m, 3H), 5.84–
5.68 (m, 2H), 2.84–2.65 (m, 1H), 2.55–2.33 (m, 2H), 2.27–2.08 (m, 3H), 1.99–1.81 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 174.6, 148.2, 138.6, 136.5, 134.7, 128.1, 127.5, 126.9, 125.5, 121.7,
121.5, 116.6, 42.9, 28.4, 26.0, 24.9; HRMS(EI) Calcd for C16H16N2O [M+]: 252.1263, Found
252.1259; IR (KBr) V(cmꢀ1) : 1679, 1527, 1485, 1423, 1379, 792.
N-(Quinolin-8-yl)hex-5-enamide (25): Yellow oil; 1H NMR (400 MHz, CDCl3) δ 9.78 (brs, 1H),
8.85–8.70 (m, 2H), 8.10 (dd, J = 8.1 and 1.7 Hz, 1H), 7.55–7.35 (m, 3H), 5.92–5.72 (m, 1H),
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5.15–4.95 (m, 2H), 2.55 (t, J = 7.4 Hz, 2H), 2.19 (q, J = 6.9 Hz, 2H), 1.97–1.85 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 171.6, 148.1, 138.3, 137.9, 136.4, 134.6, 127.9, 127.4, 121.6, 121.4,
116.4, 115.5, 37.4, 33.2, 24.7; HRMS(EI) Calcd for C15H16N2O [M+]: 240.1263, Found 240.1263;
IR (KBr) V(cmꢀ1) : 1688, 1527, 1485, 1425, 1386, 1326, 792.
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N-(Quinolin-8-yl)-3,5-dimethyladamantane-1-carboxamide (26): White solid; mp 65ꢀ66℃; 1H
NMR (400 MHz, CDCl3) δ 10.21 (brs, 1H), 8.90–8.75 (m, 2H), 8.15 (d, J = 8.2 Hz, 1H), 7.60–
7.37 (m, 3H), 2.28–2.20 (m, 1H), 1.95 (d, J = 2.2 Hz, 2H), 1.78–1.66 (m, 4H), 1.52–1.36 (m, 4H),
1.25 (s, 2H), 0.93 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 176.6, 148.4, 139.0, 136.5, 134.8, 128.1,
127.6, 121.6, 121.3, 116.5, 50.9, 45.7, 44.4, 43.0, 38.2, 31.4, 30.6, 29.6； HRMS(EI) Calcd for
C22H26N2O [M+]: 334.2045, Found 334.2037; IR (KBr) V(cmꢀ1) : 1673, 1527, 1486, 1326, 792.
(-)-(2S,3aS,7aS)-Benzyl 2-(5-methoxyquinolin-8-ylcarbamoyl)octahydro-1H- indole-1-
Carboxylate (47): To a 25 ml of roundꢀbottom flask equipped with magnetic stirrer were added
NꢀCarbobenzyloxyꢀLꢀoctahydroindoleꢀ2ꢀcarboxylic
acid
(274
mg,
0.9
mmol),
5ꢀmethoxyquinolinꢀ8ꢀamine (131 mg, 0.75 mmol), EDCI (188 mg, 1.0 mmol), DMAP (9.2 mg,
0.08 mmol) and anhydrous CH2Cl2(10 mL). The mixture was stirred at room temperature for 12 h,
then diluted with CH2Cl2(50 mL), and washed with aq. HCl (1 M, 2 x 50 mL) and brine, dried
over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography
(Silica gel, CH2Cl2 as eluent) gave the product (ꢀ)ꢀ47 (407 mg, 72 % yield) as a white solid: mp
156ꢀ157 oC; [α]22D ꢀ41.8 (c 1.10, CHCl3); 1H NMR (400 MHz, C5D5N, 70°C) δ 10.54 (s, 1H), 9.09
(d, J = 8.5 Hz, 1H), 8.80 (s, 1H), 8.59 (d, J = 8.2 Hz, 1H), 7.40 (s, 3H), 7.13 (s, 3H), 6.90 (d, J =
8.6 Hz, 1H), 5.32 (s, 2H), 4.81 (t, J = 8.1 Hz, 1H), 4.16 (s, 1H), 3.85 (s, 3H), 2.42–2.21 (m, 4H),
2.18–1.80 (m, 1H), 1.75–1.48 (m, 3H), 1.46–0.98 (m, 3H); 13C NMR (100 MHz, C5D5N, 70°C) δ
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171.0, 155.6, 150.9, 149.3, 140.1, 137.8, 131.4, 129.1, 128.7, 128.0, 121.2, 121.1, 117.2, 105.4,
67.2, 63.2, 59.0, 56.1, 37.4, 33.4, 29.0, 26.3, 24.0, 21.1; HRMS(EI) Calcd for C27H29N3O4 [M+]:
459.2158, Found 459.2155; IR (KBr) V(cmꢀ1): 3348, 1717, 1695, 1531, 1419, 1092.
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(-)-(2aS,3aS,7aR,7bR)-Benzyl 1-(5-methoxyquinolin-8-yl)-2-oxooctahydro-1H- azeto[3,2-b]
indole-3(7bH)-carboxylate (48): In a 10 mL of glass tube were placed substrate (ꢀ)ꢀ47 (116 mg,
0.25 mmol), Pd(OAc)2 (5.7 mg, 0.025 mmol), AgOAc (84.5 mg, 0.51 mmol), and
iodoperfluorobenzene (735 mg 2.5 mmol). After the reaction mixture was mixed well with stirring
at room temperature for about 5 min, the glass tube was placed into the CEM microwave reactor
and sealed with a pressure lock. Use stepꢀbyꢀstep program to increase the reaction temperature as
o
following: first, increase the temperature from room temperature to 50 C with 20 W irradiation
o
o
o
and keep it at 50 C for 1 min; then increase the temperature from 50 C to 120 C with 50 W
irradiation and keep it at 120 oC for 3 min; after that, increase the temperature from 120 oC to 160
o
oC with 100 W irradiation; finally, start the reaction with stirring at 160 C for 5 h. After the
reaction mixture was cooled down below 50 °C, the pressure lock was opened. Purification by
flash chromatography (Silica gel, petroleum ether : ethyl acetate = 2 : 1 as eluent) gave the product
o
1
(ꢀ)ꢀ48 (99.9 mg, 88 % yield) as a brown solid: mp 73ꢀ74 C; [α]22 ꢀ131.7 (c 1.10, CHCl3); H
D
NMR (400 MHz, C5D5N, 70°C) δ 8.95 (dd, J = 4.1 and 1.8 Hz, 1H), 8.59 (dd, J = 8.5 and 1.8 Hz,
1H), 8.36 (d, J = 8.4 Hz, 1H), 7.57 (s, 2H), 7.44–7.25 (m, 4H), 6.91 (d, J = 8.5 Hz, 1H), 6.20 (t, J
= 5.2 Hz, 1H), 5.60 (s, 1H), 5.40 (s, 2H), 4.37–4.22 (m, 1H), 3.86 (s, 3H), 2.48–2.27 (m, 2H), 1.86
(d, J = 14.4 Hz, 1H), 1.75–1.60 (m, 1H), 1.54–1.36 (m, 2H), 1.10–0.85 (m, 2H), 0.79–0.60 (m,
1H); 13C NMR (100 MHz, C5D5N, 70°C) δ166.5, 154.1, 152.7, 149.8, 142.3, 137.9, 131.2, 128.9,
128.5, 128.24, 128.16, 122.7, 121.6, 121.1, 105.1, 69.3, 67.2, 66.3, 59.3, 56.1, 39.4, 30.0 23.5,
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23.3, 22.2; HRMS(EI) Calcd for C27H27N3O4 [M+]: 457.2002, Found 457.2008; IR (KBr) V(cmꢀ1):
1748, 1703, 1593, 1411, 1093.
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(-)-(2aS,3aS,7aS,7bR)-Benzyl 2-oxooctahydro-1H-azeto[3,2-b]indole-3(7bH)-carboxylate (49):
To a solution of (ꢀ)ꢀ48 (71 mg, 0.16 mmol) in CH3CN (5 mL) was added ceric ammonium nitrate
(256 mg, 0.48 mmol) in H2O (2 mL) at room temperature. The mixture was stirred at room
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temperature for 5 h. Then purification by preparative TLC plate (CHCl3 : MeOH = 10 : 1 as eluent)
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gave the product (ꢀ)ꢀ49 (29.2 mg, 62%) as a brown oil. [α]21 ꢀ129.1 (c 0.50, CHCl3); H NMR
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(400 MHz, C5D5N, 70°C) δ 8.89 (s, 1H), 7.59–7.22 (m, 5H), 5.43–5.22 (m, 3H), 4.41–4.16 (m,
2H), 2.44–2.12 (m, 1H), 2.10–1.85 (m, 2H), 1.80–1.30 (m, 5H), 1.20–1.0 (m, 1H); 13C NMR (100
MHz, C5D5N, 70°C) δ 167.7, 137.9, 128.9, 128.2, 128.1, 70.0, 67.1, 61.3, 58.9, 37.6, 26.2, 24.2,
23.4, 22.3; HRMS(EI) Calcd for C17H20N2O3 [M+]: 300.1474, Found 300.1468; IR (KBr) V(cmꢀ1):
1759,1726,1422,1294,1098.
(-)-(2aS,3aS,7aR,7bR)-Octahydro-1H-azeto[3,2-b]indol-2(7bH)-one (50): To a solution of
(ꢀ)ꢀ49 (15 mg, 0.05 mmol ) in MeOH (2 mL) was added (10%) Pd/C (3 mg). The reaction mixture
was stirred at room temperature for 24 hours under H2 (balloon). The reaction mixture was filtered
through celite and then washed with MeOH. The solution was condensed under vacuum.
Purification by preparative TLC plate (CHCl3 : MeOH = 10 : 1 as eluent) gave the product (ꢀ)ꢀ50
(8 mg, 96%) as a brown solid: mp 150ꢀ151 oC; [α]16D ꢀ54.2 (c 0.20, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 6.04 (s, 1H), 4.46 (t, J = 3.2 Hz, 1H), 4.17 (t, J = 4.7 Hz, 1H), 3.46–3.38 (m, 1H), 2.07–
1.99 (m, 2H), 1.80–1.72 (m, 2H), 1.60–1.48 (m, 2H), 1.37–1.14 (m, 4H). 13C NMR (150 MHz,
CDCl3) δ 171.3, 72.0, 60.0, 59.5, 38.0, 31.7, 24.1, 24.0, 23.2. HRMS(EI) Calcd for C9H14N2O
[M+]: 166.1106, Found 166.1108;IR (KBr) V(cmꢀ1): 2932,1743,1639,1418,582.
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(-)-(S)-Benzyl 2-(quinolin-8-ylcarbamoyl)piperidine-1-carboxylate (51): To a 25 ml of
roundꢀbottom flask equipped with magnetic stirrer were added NꢀCarbobenzyloxyꢀLꢀPipecolic
acid (1.1g, 4.19 mmol), 8ꢀamine ꢀquinoline (725 mg, 5 mmol), EDCI (1.2 g, 6.3 mmol), DMAP
(51 mg, 0.4 mmol) and anhydrous CH2Cl2 (50 mL). The mixture was stirred at room temperature
for 12 h, then diluted with CH2Cl2 (50 mL), and washed with aq. HCl (1 M, 2 x 100 mL) and brine,
dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash
chromatography (Silica gel, CH2Cl2 as eluent) gave the product (ꢀ)ꢀ51 (1.4 g, 87 % yield) as a
yellow oil. [α]24D ꢀ107.7 (c 0.78, CHCl3); 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.78 (dd, J
= 7.0 and 1.8 Hz, 1H), 8.71 (brs, 1H), 8.13 (dd, J = 8.2 and 1.2 Hz, 1H), 7.59–7.12 (m, 8H), 5.45–
5.02 (m, 3H), 4.30 (brs, 1H), 3.16 (brs, 1H), 2.51 (d, J = 11.6 Hz, 1H), 1.81–1.44 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 169.4, 148.5, 138.7, 136.6, 136.2, 134.2, 128.5, 128.1, 128.0, 127.9,
127.3, 121.8, 121.7, 116.4, 67.7, 56.2, 42.5, 26.0, 25.0, 20.6; HRMS(EI) Calcd for C23H23N3O3
[M+]: 389.1739, Found 389.1735; IR (KBr) V(cmꢀ1): 2942, 1693, 1528, 1422, 1258.
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(-)-(1S,6R)-Benzyl 8-oxo-7-(quinolin-8-yl)-2,7-diazabicyclo[4.2.0]octane-2- carboxylate (52):
In a 10 mL of glass tube were placed substrate (ꢀ)ꢀ51 (113mg, 0.29 mmol), Pd(OAc)2 (6.5 mg,
0.029 mmol), AgOAc (97 mg, 0.58 mmol), iodoperfluorobenzene (852 mg, 2.9 mmol) and
ClCH2CH2Cl (1 ml). After the reaction mixture was mixed well with stirring at room temperature
for about 5 min, the glass tube was placed into the CEM microwave reactor and sealed with a
pressure lock. Use stepꢀbyꢀstep program to increase the reaction temperature as following: first,
increase the temperature from room temperature to 50 oC with 20 W irradiation and keep it at 50
oC for 1 min; then increase the temperature from 50 oC to 120 oC with 50 W irradiation and keep it
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at 120 C for 3 min; after that, increase the temperature from 120 C to 130 C with 100 W
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irradiation; finally, start the reaction with stirring at 130 oC for 4 h. After the reaction mixture was
cooled down below 50 °C, the pressure lock was opened. Purification by flash chromatography
(Silica gel, petroleum ether : ethyl acetate = 4 : 1 as eluent) gave the product (ꢀ)ꢀ52 (82.3 mg, 73 %
yield) as a brown solid: mp 56ꢀ58 oC; [α]24D ꢀ186.3 (c 0.26, CHCl3); 1H NMR (400 MHz, CDCl3)
two rotamers δ 8.88–8.79 (m, 1H), 8.52 (d, J = 7.5 Hz, 0.48H), 8.47 (d, J = 7.4 Hz, 0.52H), 8.13
(d, J = 8.2 Hz, 1H), 7.62–7.56 (m, 1H), 7.52 (td, J = 7.8 and 2.4 Hz, 1H), 7.47–7.27 (m, 6H),
5.76–5.64 (m, 1.51H), 5.55 (d, J = 6.2 Hz, 0.49H), 5.31–5.12 (m, 2H), 3.76–3.61 (m, 1H), 3.59–
3.46 (m, 1H), 2.18–2.03 (m, 1H), 1.87–1.73 (m, 2H), 1.72–1.53 (m, 1H); 13C NMR (100 MHz,
CDCl3) two rotamers δ 168. 6, 168.1, 156.3, 155.5, 149.10, 149.08, 140.2, 140.1, 136.53, 136.51,
136.23, 136.21, 134.1, 133.8, 129.1, 128.6, 128.2, 128.14, 128.11, 128.05, 126.93, 126.91, 124.4,
124.2, 121.53, 121.50, 121.4, 121.2, 67.7, 67.6, 60.0, 57.7, 57.5, 43.2, 24.63, 24.58, 16.7, 16.4;
HRMS(EI) Calcd for C23H21N3O3 [M+]: 387.1583, Found 387.1579; IR (KBr) V(cmꢀ1): 1749,
1702, 1503, 1474, 1406, 1307, 1117.
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(-)-(1S,6R)-2-Methyl-7-(1,2,3,4-tetrahydroquinolin-8-yl)-2,7-diazabicyclo[4.2.0]octan-8-one
(53): To a solution of (ꢀ)ꢀ52 (120 mg, 0.31 mmol ) in 20 mL of EtOAc/MeOH (1:1, v/v) was
added (10%) Pd/C (12 mg). The reaction mixture was stirred at room temperature for 120 hours
under H2 (balloon). The reaction mixture was filtered through celite and washed with MeOH. The
solution was condensed under vacuum. Purification by preparative TLC plate (CHCl3 : MeOH =
30 : 1 as eluent) gave the product (ꢀ)ꢀ53 (21 mg, 25%) and the product (ꢀ)ꢀ54 (29 mg, 37%). Data
of (ꢀ)ꢀ53: white solid, mp 134ꢀ135 oC; [α]23D ꢀ301.4 (c 0.21, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 6.81 (d, J = 7.3 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 6.52 (t, J = 7.6 Hz, 1H), 5.57 (s, 1H), 4.43–
4.37 (m, 1H), 3.93 (d, J = 5.8 Hz, 1H), 3.47–3.26 (m, 2H), 2.88–2.67 (m, 4H), 2.59 (s, 3H), 1.94–
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1.84 (m, 4H), 1.79–1.64 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.7, 139.2, 127.4, 123.8, 123.0,
118.5, 115.7, 66.8, 52.9, 48.3, 44.0, 42.0, 27.9, 21.6, 20.2, 16.7; HRMS(EI) Calcd for C16H21N3O
[M+]: 271.1685, Found 271.1684;IR (KBr) V(cmꢀ1): 2933, 1714, 1632, 1604, 1462, 1386, 732.
(-)-(1S,6R)-7-(1,2,3,4-Tetrahydroquinolin-8-yl)-2,7-diazabicyclo[4.2.0]octan-8-one (54): Data
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of (ꢀ)ꢀ54 (29 mg, 37%): yellow solid, mp 82ꢀ83 oC; [α]23 ꢀ212.9 (c 0.36, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 6.82 (d, J = 7.3 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.52 (t, J = 7.6 Hz, 1H), 5.63
(brs, 1H), 4.43–4.31 (m, 1H), 4.23 (d, J = 5.7 Hz, 1H), 3.45–3.28 (m, 2H), 3.19–3.06 (m, 1H),
3.03–2.89 (m, 1H), 2.88–2.67 (m, 2H), 2.07 (brs, 1H), 2.00–1.80 (m, 4H), 1.75–1.52 (m, 2H);13C
NMR (100 MHz, CDCl3) δ 167. 7, 139.1, 127. 5, 123.8, 123.0, 118. 6, 115.7, 60.4, 52.5, 42.0,
39.5, 27. 9, 21.5, 21.3, 17.0; HRMS(EI) Calcd for C15H19N3O [M+]: 257.1528, Found 257.1535;IR
(KBr) V(cmꢀ1): 2941, 2926, 1714, 1606, 1463, 1385, 1304, 1191, 731.
(-)-(S)-Benzyl 2-(5-methoxyquinolin-8-yl carbamoyl)piperidine-1-carboxylate (55): To a 25
ml
of
roundꢀbottom
flask
equipped
with
magnetic
stirrer
were
added
NꢀCarbobenzyloxyꢀLꢀPipecolic acid (263 mg, 1 mmol), 5ꢀmethoxyquinolinꢀ8ꢀamine (209 mg,1.2
mmol), EDCI (287.6 mg, 1.5 mmol), DMAP (12.2 mg, 0.1 mmol) and anhydrous CH2Cl2 (10 mL).
The mixture was stirred at room temperature for 12 h, then diluted with CH2Cl2 (50 mL), and
washed with aq. HCl (1 M, 2 x 50 mL) and brine, dried over anhydrous Na2SO4, and concentrated
under vacuum. Purification by flash chromatography (Silica gel, CH2Cl2 as eluent) gave the
product (ꢀ)ꢀ55 (343mg, 82 % yield) as a yellow oil. [α]24 ꢀ138.0 (c 0.14, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 10.18 (s, 1H), 8.71 (s, 1H), 8.68 (d, J = 8.5 Hz, 1H), 8.55 (dd, J = 8.4 and 1.6 Hz,
1H), 7.52–7.12 (m, 6H), 6.83 (d, J = 8.5 Hz, 1H), 5.44–4.99 (m, 3H), 4.29 (brs, 1H), 3.98 (s, 3H),
3.17 (brs, 1H), 2.50 (d, J = 11.3 Hz, 1H), 1.80–1.44 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
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168.9, 150.5, 149.0, 139.4, 136.8, 131.2, 128.6, 128.1, 127.9, 127.7, 120.8, 120.5, 116.5, 104.3,
67.7, 56.3, 55.9, 42.5, 26.1, 25.0, 20.6; HRMS(EI) Calcd for C24H25N3O4 [M+]: 419.1845, Found
419.1849; IR (KBr) V(cmꢀ1): 2942, 1686, 1531, 1462, 1271.
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(-)-(1S,6R)-Benzyl 7-(5-methoxyquinolin-8-yl)-8-oxo-2,7-diazabicyclo[4.2.0]octane-2-
carboxylate (56): In a 10 mL of glass tube were placed substrate (ꢀ)ꢀ55 (197 mg, 0.47 mmol),
Pd(OAc)2 (10.8 mg, 0.048 mmol), AgOAc (160.4 mg, 0.95 mmol), iodoperfluorobenzene (705.6
mg, 2.4 mmol) and 1,1,2,2ꢀtetrachloroethane (2 ml). After the reaction mixture was mixed well
with stirring at room temperature for about 5 min, the glass tube was placed into the CEM
microwave reactor and sealed with a pressure lock. Use stepꢀbyꢀstep program to increase the
reaction temperature as following: first, increase the temperature from room temperature to 50 oC
with 20 W irradiation and keep it at 50 oC for 1 min; then increase the temperature from 50 oC to
o
120 oC with 50 W irradiation and keep it at 120 C for 3 min; after that, increase the temperature
from 120 oC to 130 oC with 100 W irradiation; finally, start the reaction with stirring at 130 oC for
4 h. After the reaction mixture was cooled down below 50 °C, the pressure lock was opened.
Purification by flash chromatography (Silica gel, petroleum ether : ethyl acetate = 4 : 1 as eluent)
gave the product (ꢀ)ꢀ56 (159.7 mg, 81 % yield) as a brown solid: mp 134ꢀ135 oC; [α]24D ꢀ156.6 (c
0.13, CHCl3); 1H NMR (400 MHz, CDCl3) two rotamers δ 8.88–8.79(m, 1H), 8.55 (d, J = 8.5 Hz,
1H), 8.32 (d, J = 8.4 Hz, 0.48H), 8.26 (d, J = 8.4 Hz, 0.52H), 7.48–7.28 (m, 6H), 6.84 (d, J = 8.4
Hz, 1H), 5.71 (d, J = 6.1 Hz, 0.48H), 5.61–5.50 (m, 1.54H), 5.30–5.12 (m, 2H), 3.98 (s, 3H),
3.75–3.63 (m, 1H), 3.57–3.44 (m, 1H), 2.07–1.95 (m, 1H), 1.93–1.52 (m, 3H); 13C NMR (100
MHz, CDCl3) two rotamers δ 168.2, 167.7, 156.3, 155.5, 152.7, 152.5, 149.69, 149.65, 141.6,
141.4, 136.57, 136.56, 131.0, 130.9, 128.60, 128.59, 128.2, 128.1, 128.0, 126.9, 126.5, 122.6,
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122.1, 121.1, 121.0, 120.69, 120.67, 104.33, 104.30, 67.7, 67.6, 59.8, 57.1, 56.9, 56.0, 43.2, 24.3,
16.6, 16.3; HRMS(EI) Calcd for C24H23N3O4 [M+]: 417.1689, Found 417.1696; IR (KBr) V(cmꢀ1):
1743, 1692, 1471, 1413, 1266, 1112.
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Compound (ꢀ)ꢀ56 was also characterized in C5D5N at 77 C. Data shown as following indicated
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(ꢀ)ꢀ56 was a pure chemical compound. H NMR (400 MHz, C5D5N, 77°C) δ 8.95–8.88(m, 1H),
8.58 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.60–7.47 (m, 2H), 7.45–7.25 (m 4H), 6.91 (d, J
= 8.4 Hz, 1H), 5.80 (brs, 1H), 5.57–5.50 (m, 1H), 5.43–5.27 (m, 2H), 3.90 (s, 3H), 3.78–3.67 (m,
1H), 3.67–3.51 (m, 1H), 2.06 (d, J = 14.4 Hz, 1H), 1.97–1.82 (m, 1H), 1.79–1.65 (m, 1H), 1.60–
1.45 (m, 1H); 13C NMR (100 MHz, C5D5N, 77°C) δ 168.0, 156.1, 153.0, 150.0, 142.1, 137.8,
131.1, 128.9, 128.32, 128.27, 127.8, 122.7, 121.6, 121.1, 105.3, 67.7, 60.7, 57.2, 56.2, 43.4, 24.8,
17.3.
(-)-(1S,6R)-Benzyl 8-oxo-2,7-diazabicyclo[4.2.0]octane-2-carboxylate (57): To a solution of
(ꢀ)ꢀ56 (100 mg, 0.24 mmol) in CH3CN (5 mL) was added ceric ammonium nitrate (394 mg, 0.72
mmol) in H2O (2 mL) at room temperature. The mixture was stirred at room temperature for 5 h,
then diluted with CH2Cl2 (15 mL), and washed with H2O (2 x 15 mL) and brine, dried over
anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica
gel, CHCl3: MeOH = 50 : 1 as eluent) gave the product (ꢀ)ꢀ57 (44.8 mg, 72%) as a brown oil.
[α]25D ꢀ75.3 (c 0.84, CHCl3); 1H NMR (400 MHz, CDCl3) two rotamers δ 7.45–7.25 (m, 5H), 6.39
(s, 1H), 5.36 (d, J = 5.7 Hz, 0.53H), 5.24–5.05 (m, 2.63H), 4.19–4.06 (m, 1H), 3.68–3.55 (m, 1H),
3.40 (td, J = 12.2 and 5.7 Hz, 1H), 2.03–1.87 (m, 2H), 1.78–1.58 (m, 2H); 13C NMR (100 MHz,
CDCl3) two rotamers δ 170.5, 170.0, 156.2, 155.4, 136.40, 136.36, 128.6, 128.20, 128.16, 128.1,
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67.7, 67.6, 59.8, 59.7, 49.1, 49.0, 43.10, 43.07, 26.0, 16.0, 15.7; HRMS(EI) Calcd for C14H16N2O3
[M+]: 260.1161, Found 260.1156; IR (KBr) V(cmꢀ1): 1754, 1700, 1417, 1312, 1112.
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(-)-(1S,6R)-2,7-Diazabicyclo[4.2.0]octan-8-one (58): To a solution of (ꢀ)ꢀ57 (81 mg, 0.31 mmol )
in MeOH (5 mL) was added (10%) Pd/C (8 mg). The reaction mixture was stirred at room
temperature for 24 hours under H2 (balloon). The reaction mixture was filtered through celite and
washed with MeOH. The solution was condensed under vacuum. Purification by flash
chromatography (Silica gel, CHCl3: MeOH = 50 : 1 as eluent) gave the product (ꢀ)ꢀ58 (25.5 mg,
65%) as a yellow solid: mp 143ꢀ145 oC; [α]23D ꢀ6.0 (c 1.1, CHCl3); 1H NMR (600 MHz, CDCl3) δ
6.46 (s, 1H), 4.15 (d, J = 5.1 Hz, 1H), 3.86 (dd, J = 7.7 and 4.7 Hz, 1H), 3.06–2.94 (m, 1H), 2.92–
2.84 (m, 1H), 2.14 (s, 1H), 2.00–1.90 (m, 1H), 1.86–1.79 (m, 1H), 1.73–1.64 (m, 1H), 1.61–1.52
(m, 1H). 13C NMR (150 MHz, CDCl3) δ 172.3, 64.0, 47.8, 39.7, 24.1, 16.8; HRMS(EI) Calcd for
C6H10N2O [M+]: 126.0793, Found 126.0797;IR (KBr) V(cmꢀ1): 2929, 1733, 1643, 1455, 592.
(-)-(S)-Benzyl 3-(5-methoxyquinolin-8-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1 H)-
carboxylate (59): To a 25 ml of roundꢀbottom flask equipped with magnetic stirrer were added
(S)ꢀ2ꢀ(benzyloxycarbonyl)ꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ3ꢀcarboxylic acid (600 mg, 1.9 mmol),
5ꢀmethoxyquinolinꢀ8ꢀamine (403 mg, 2.3 mmol), EDCI (665 mg, 3.5 mmol), DMAP (24.4 mg,
0.2 mmol) and anhydrous CH2Cl2(20 mL). The mixture was stirred at room temperature for 12 h,
then diluted with DCM (50 mL), and washed with aq. HCl (1 M, 2 x 50 mL) and brine, dried over
anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica
gel, CH2Cl2 as eluent) gave the product (ꢀ)ꢀ59 (649 mg, 72 % yield) as a yellow oil. [α]25D ꢀ5.0 (c
0.72, CHCl3); 1H NMR (400 MHz, CDCl3) two rotamers δ 10.17 (s, 0.45H), 10.01 (s, 0.55H), 8.71
(dd, J = 4.1 and 1.4 Hz, 1H), 8.61–8.46 (m, 2H), 7.54–6.95 (m, 10H), 6.79–6.71 (m, 1H), 5.46–
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4.99 (m, 3H), 4.96 (d, J = 16.0 Hz, 1H), 4.79 (d, J = 16.0 Hz, 1H), 3.99–3.89 (m, 3H), 3.55 (d, J =
15.3 Hz, 0.48H), 3.43 (dd, J = 15.1 and 3.5 Hz, 0.58H), 3.26 (d, J = 6.0 Hz, 0.64H), 3.22 (d, J =
6.0 Hz, 0.47H); 13C NMR (100 MHz, CDCl3) two rotamers δ 169.3, 168.7, 156.5, 155.9, 150. 6,
148.9, 139.32, 139.29, 136.6, 136.2, 133.5, 133.2, 132.9, 132.5, 131.13, 131.07, 128.7, 128.3,
128.1, 128.0, 127.9, 127.5, 127.4, 127.3, 127.0, 126.76, 126.75, 126.4, 126.18, 126.16, 120.7,
120.4, 116.6, 116.5, 104.2, 67.9, 56.9, 55.8, 55.7, 45.2, 45.0, 31. 8, 30.8; HRMS(EI) Calcd for
C28H25N3O4 [M+]: 467.1845, Found 467.1853; IR (KBr) V(cmꢀ1): 1704, 1532, 1495, 1402, 1270,
1091.
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(-)-(2aS,8bR)-Benzyl 1-(5-methoxyquinolin-8-yl)-2-oxo-1,2,2a,8b-tetrahydroazeto [3,2-c]
isoquinoline-3(4H)-carboxylate (60): In a 10 mL of glass tube were placed substrate (ꢀ)ꢀ59 (46.8
mg, 0.1 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), AgOAc (25 mg, 0.15 mmol), and
iodoperfluorobenzene (0.5 mL). After the reaction mixture was mixed well with stirring at room
temperature for about 5 min, the glass tube was placed into the CEM microwave reactor and
sealed with a pressure lock. Use stepꢀbyꢀstep program to increase the reaction temperature as
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following: first, increase the temperature from room temperature to 50 C with 20 W irradiation
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and keep it at 50 C for 1 min; then increase the temperature from 50 C to 120 C with 50 W
irradiation and keep it at 120 oC for 3 min; after that, increase the temperature from 120 oC to 150
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oC with 100 W irradiation; finally, start the reaction with stirring at 150 C for 4 h. After the
reaction mixture was cooled down below 50 °C, the pressure lock was opened. The crude H1 NMR
was checked directly. Purification by preparative TLC plate (petroleum ether : ethyl acetate = 2 : 1
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as eluent) gave the product (ꢀ)ꢀ60 (30.8 mg, 66 % yield) as a yellow solid: mp 66ꢀ67 C; [α]25
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ꢀ153.6 (c 1.07, CHCl3); H NMR (400 MHz, CDCl3) two rotamers δ 9.00 (brs, 1H), 8.55 (d, J =
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8.3 Hz, 1H), 7.76 (d, J = 8.2 Hz, 0.46H), 7.70 (d, J = 8.3 Hz, 0.60H), 7.50–7.11 (m, 9H), 7.04–
6.96 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 5.1 Hz, 0.48H), 6.31 (d, J = 5.3 Hz, 0.65H),
6.24 (d, J = 4.0 Hz, 0.42H), 6.10 (d, J = 4.6 Hz, 0.58H), 5.34–5.07 (m, 3H), 4.49 (d, J = 16.0 Hz,
0.46H), 4.41 (d, J = 15.9 Hz, 0.62H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) two rotamers δ
166.5, 166.3, 154.9, 154.7, 153.7, 153.6, 149.9, 142.8, 142.7, 136.3, 136.2, 134.9, 131.9, 131.5,
131.31, 131.30, 131.16, 131.0, 128.9, 128.6, 128.3, 128.1, 127.5, 127.2, 126.8, 125.1, 125.0, 124.7,
121.2, 120.9, 103.9, 68.1, 63.2, 63.0, 57.9, 55.9, 44.7, 44.1; HRMS(EI) Calcd for C28H23N3O4
[M+]: 465.1689, Found 465.1694; IR (KBr) V(cmꢀ1): 1750, 1706, 1591, 1480, 1427, 1271, 1211,
1092.
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(+)-(2aS,8bR)-Benzyl 2-oxo-1,2,2a,8b-tetrahydroazeto[3,2-c]isoquinoline-3(4H)-carboxylate
(61): To a solution of (ꢀ)ꢀ60 (75 mg, 0.16 mmol) in CH3CN (3 mL) was added ceric ammonium
nitrate (263 mg, 0.48 mmol) in H2O (0.5 mL) at room temperature. The mixture was stirred at
room temperature for 4 h, then diluted with CH2Cl2 (15 mL), and washed with H2O (2 x 15 mL)
and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash
chromatography (Silica gel, CHCl3: MeOH = 50 : 1 as eluent) gave the product (+)ꢀ61 (28.2 mg,
57%) as a brown solid: mp 55ꢀ56 oC; [α]25D +125.7 (c 0.25, CHCl3); 1H NMR (500 MHz, CDCl3)
two rotamers δ 7.42–7.27 (m, 9H), 6.24 (s, 0.46H), 6.21 (s, 0.54H), 5.96 (d, J = 4.4 Hz, 0.46H),
5.80 (d, J = 4.7 Hz, 0.54H), 5.26–5.01 (m, 3H), 4.85 (d, J = 5.1 Hz, 0.47H), 4.82 (d, J = 5.2 Hz,
0.56H), 4.26 (d, J = 16.0 Hz, 0.47H), 4.18 (d, J = 16.0 Hz, 0.55H); 13C NMR (100 MHz, CDCl3)
two rotamers 167.7, 167.4, 154.8, 154.5, 136.1, 136.0, 134.7, 134.6, 132.8, 132.5, 130.2, 130.0,
129.0, 128.7, 128.3, 128.1, 128.0, 127.6, 127.2, 68.2, 64.0, 63.8, 50.4, 50.2, 44.4, 43.8; HRMS(EI)
Calcd for C18H16N2O3 [M+]: 308.1161, Found 308.1159; IR (KBr) V(cmꢀ1): 1761, 1703, 1429,
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