Synthesis of new N-norbornylimide substituted amide derivatives, their reductive Heck and domino Heck reactions

Article abstract of DOI:10.24820/ark.5550190.p010.304

Palladium-catalyzed, regioselective hydroarylation reactions of N-norbornenylimide substituted amides were studied to synthesize pentanamide derivatives containing exo-aryl-substituted norbornyl imide groups in excellent yields. All newly synthesized derivatives have been characterized by FTIR, ¹H, ¹³C NMR, GC/MS and TOF/Qtof analyses.

Full text of DOI:10.24820/ark.5550190.p010.304

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for Organic Chemistry
Paper
Archive for
Arkivoc 2017, part v, 244-256
Organic Chemistry
Synthesis of new N-norbornylimide substituted amide derivatives, their
reductive Heck and domino Heck reactions
a
b
b
b
c
Fatma Albayrak, Omer Tahir Gunkara,* Elif Basak Ersoy, Nuket Ocal,* and Dieter E. Kaufmann
a
Department of Chemistry, Faculty of Science, Gebze Technical University, TR 41400, Gebze, Kocaeli, Turkey
Chemistry Department, Faculty of Science and Arts, Yildiz Technical University, Davutpasa Campus, 34220,
Esenler, Istanbul, Turkey
b
c
Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstr. 6, D-38678 Clausthal-Zellerfeld,
Germany
Email: gunkara@yildiz.edu.tr, nocal@yildiz.edu.tr
Received 07-17-2017
Accepted 10-29-2017
Published on line 11-17-2017
Abstract
Palladium-catalyzed, regioselective hydroarylation reactions of N-norbornenylimide substituted amides were
studied to synthesize pentanamide derivatives containing exo-aryl-substituted norbornyl imide groups in
1
13
excellent yields. All newly synthesized derivatives have been characterized by FTIR, H, C NMR, GC/MS and
TOF/Qtof analyses.
Keywords: Amides, hydrazides, microbiological activity, palladium catalyst, reductive Heck and domino Heck reactions,
regioselectivity
DOI: https://doi.org/10.24820/ark.5550190.p010.304
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Introduction
Carboxamide functions are widely found in various molecules such as drugs, polymers, pharmaceutical agents,
1
peptides, natural molecules, proteins, alkaloids, etc. Compounds containing an amide bond play an important
role in biological processes such as enzymatic catalysis, transportation and immune protection. Amide bonds
have been a main topic of scientific interest to medicinal and organic chemists for a long period due to their
2
biological properties of amides.
Functional groups, especially carboxamides, are important for the activity and pharmacokinetic properties
of a drug. There are many drugs containing amide groups and they are still widely used today, e.g. Penicilins 1,
Paracetamol 2 and Oxicams 3 (Scheme 1). Penicilin was the first broadspectrum antibiotic to be used against
3
4
many bacterial infections , Paracetamol is a widely used pharmaceutical to treat fever and pain , and Oxicams
5
are anti-inflammatory drugs. All of these important drugs contain an amide group and have a large share in
the worldwide pharmaceutical market.
Scheme 1. Some drugs including an amide group.
Additionally, anti-cancer agents containing amides have become a focus in the improvement of new
treatments of cancer. An increasing number of amide antitumor agents is now becoming effective; for
6
example, Fidarestat 4 (Scheme 2) and Sorbinil 5 are anti-cancer and anti-diabetic agents , and Leflunomide 6 is
7
also a well-known anti-cancer agent.
Scheme 2. Some anti-cancer drugs containing an amide group.
The carbon-carbon bond formation is a crucial transformation in synthetic organic chemistry. Among the
palladium-catalyzed transformations, the Heck and domino-Heck reactions are significant synthetic methods
8-10
to obtain biologically active compounds in the pharmaceutical industry.
N-Substituted tricyclic imides are
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reported for their biological effects such as antitumor, anti-inflammatory, and antimicrobial activities.1
1-12
13
Likewise, bi- and tricyclic imides are widely used in biomedical applications due to their biological properties.
Reductive Heck and domino-Heck reactions of unsaturated N-substituted tricyclic imides having feasible
14-20
biological activities, were reported previously.
There are many additional examples of Heck reactions
being used worldwide in industrial syntheses. As an example, in 2011 an Idebenone 7 total synthesis was
based on a Heck reaction. This compound was initially designed for the treatment of Alzheimer’s and
21
Parkinson’s diseases. Another example of an application of the Heck reaction is the synthesis of Axitinib 8.
Recently, Pfizer researchers designed this compound for vascular endothelial growth factor (VEGF)
2
2
inhibition. Naratriptan 9 (Scheme 3), a 5-HT
1
agonist for treatment of migraine headaches from
23
GlaxoSmithKline, was synthesized utilizing the Heck arylation.
Scheme 3. Application of the Heck reaction on some drugs’ total synthesis.
The Kaufmann reductive Heck procedure could allow the palladium-catalyzed, stereoselective
transformation of N-substituted tricyclic imides thus providing a new access to exo-aryl(hetaryl)-substituted
24-26
tricyclic imides in the presence of triphenylarsine as a ligand.
Having this information in mind, we focused on the synthesis of a new class of compounds including exo-
aryl(hetaryl)-substituted norbornylimide derivatives of N-4-azabicyclo[2.2.1]hept-8-ene-3-endo,5-endo-
dicarboximide-4-yl-2-(4-azabicyclo[2.2.1]hept-8-ene-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanamide
(5).
Results and Discussion
Initially, we prepared the endocyclic anhydride 1 using freshly distilled cyclopentadiene and maleic anhydride
27
in ethyl acetate at 0 °C using a known procedure. Thereafter, compound 2 was obtained from the reaction of
28
hydrazonium chloride and compound 1 in toluene at room temperature. We continued to prepare the
29
optically active norbornenylimide substituted acid 3 from 1 using Amos’ procedure. As the last step of this
part, we synthesized a new norbornenylimide acyl chloride derivative 4 from 3 in an excellent yield. (Scheme
4).
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Scheme 4. Preparation of compunds 1 – 4.
As the second step of our starting material preparation, we synthesized the new amide 5 from 2 and 4 in
dry dichloromethane at room temperature in a good yield (Scheme 5).
Scheme 5. Synthesis of compound 5.
Compound 5 was then reacted with various aryl iodides (Table 1) under reductive Heck reaction conditions
to afford newly synthesized amide derivatives (6a – e, 7a and 8) in good yields (Scheme 6). Table 1 shows the
angles of specific rotation for all new products we obtained.
It was expected that during the reaction a mixture of diastereomers would be formed as 5 has two alkene
subunits (Scheme 6). In each case an excess of the arylating agent was used. From the results presented in
Scheme 6 it is apparent that the more reactive alkene is the one in the norbornene system proximal to the
N,N-succinoylhydrazide functionality since the product composition 6a and 7a indicates that the bis-arylation
succeeds the mono-arylation at the more reactive double bond. At this time, and without computational work,
it would be speculative to assess the relative reactivities at the two double bonds. However, the origin is most
likely an electronic one, i.e., it would not be unreasonable to argue that the norbornene system carrying the
N,N-succinoylhydrazide moiety is somewhat more electron-rich than the other nornbornene double bond.
Computational modeling studies are under way to address this interesting aspect of regioselectivity. The
structure of the N-N-cleavage product 8, which was obtained during the course of the attempted
hydroarylation reaction of 5 with difluoroiodobenzene, helped us to determine where the first aryl group was
located (Scheme 6). A structural proof by X-ray crystallography was not yet possible due to a missing single
crystal.
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Table 1. Bistricyclic amide derivatives 4, 5 and 6a – 9b produced via hydroarylation reaction
Compound
Aryl iodide
-
Yield % Specific Optical Rotation Appearance
22
[
α]
-7.5° (c: 0.013 g/mL)
+12.2° (c: 0.009 g/mL) creamy solid
D
(CH
2
Cl
2
)
4
5
94
creamy solid
-
80
85
75
85
85
70
85
80
75
75
6
6
a
b
1-iodobenzene
+13.8° (c: 0.010 g/mL)
+25.0° (c: 0.026 g/mL)
+15.0° (c: 0.010 g/mL)
+11.0° (c: 0.010 g/mL)
+11.4° (c: 0.010 g/mL)
+14.6° (c: 0.012 g/mL)
+4.0° (c: 0.010 g/mL)
+25.0° (c: 0.003 g/mL)
+23.0° (c: 0.010 g/mL)
colorless oil
white oil
4-chloro-1-iodobenzene
4-morpholino-1-iodobenzene
2-iodothiophene
3-bromomethyl-1-iodobenzene
1-iodobenzene
3,4-difluoro-1-iodobenzene
1-iodobenzene
4-chloro-1-iodobenzene
6c
white solid
brown oil
colorless oil
colorless oil
yellow oil
yellow oil
yellow oil
6d
6e
7a
8
9
9
a
b
Scheme 6. Synthesis of compounds 6a-e, 7a and 8.
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Scheme 7. Numbering of title compounds.
1
The exo-stereochemistry for each hydroarylation product was inferred from the H NMR spectra including
diagnostic spin-spin interactions. The exo-position of the C-8 substituent was confirmed by the fact that H8n
showed no significant interaction with H . The geminal protons on C-9 were identified by vicinal coupling to
1
1
1
H
1
. Additionally, H– H-COSY spectra showed cross peaks between H
2
and H
6
and between H
8
and H ,
9
1
respectively. The presence of alkenic hydrogens in the H NMR spectrum of compound 7a shows that it
13
undergoes hydroarylation on one side. In addition to the C NMR and FTIR spectral data which were in
agreement with the proposed structures, LC-MSMS (Qtof) results of all new compounds showed the expected
accurate mass with hydrogen additions.
Domino-Heck arylation conditions were also successfully applied to the reaction of 5 with 1-iodobenzene
and 4-chloro-1-iodobenzene together with phenylacetylene to give the new exo-alkynylated norbornyl
substituted amide derivatives (9a and 9b) in good yields, respectively (Scheme 8). The reactions were
repeated many times, obtaining the same results. It was determined that during the determination of
structures of these products, the arylation reagents were attached from the single alkenic side as compound
7a. The absence of H9x hydrogens in the proton NMR spectrum of the compounds indicates that phenyl
acetylene is also bound from the exo-position. In addition, the structures are confirmed with the observation
of alkyne carbons in the carbon NMR spectrum at the expected site.
Scheme 8. Synthesis of compounds 9a, b.
Conclusions
New bistricyclic amide derivatives (5, 6a – e, 7a) and acyl chloride derivative 4 have been synthesized and
1
13
extensively characterized by the use of spectroscopic studies such as FTIR, H NMR, C NMR, GC-MS and LC-
MSMS/QTOF analyses. Regioselective (Domino) Heck reactions of compound 5 were also studied, leading to
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the two new alkyne substituted derivatives 9a and 9b. These compounds should have the potential to show
various microbiological activities due to their substructures aryl groups, the leucine chain, amide and imide
groups.
Experimental Section
General. The solvents were dried by standard procedures. Reactions were monitored using TLC. Visualizations
of the chromatograms were performed with UV light, KMnO
4
or Vanillin stain. All melting points are
uncorrected and were determined on a Gallenkamp digital thermometer. IR spectra were obtained with a
–
1
1
13
Perkin Elmer FT-IR system and are reported in terms of the frequency of absorption (cm ). H and C NMR
spectra were recorded on a Bruker Avance III-500 MHz NMR spectrometer relative to tetramethylsilane, with
coupling constant (J) values in Hertz (Hz). Peak multiplicities are designated by the following abbreviations: s,
singlet; d, doublet; dd, double doublet; t, triplet; dt, double triplet; m, multiplet; br, broad; p, pentet; and
hept, heptet. Mass spectra were measured on an Agilent 6890N/5973 GC/IMSD system. High-resolution mass
spectra were acquired in the positive ion mode using an Agilent G6530B TOF/Qtof Mass spectrometer. Optical
rotations were measured with Bellingham Stanley ADP-410 Polarimeter. All crude compound mixtures were
purified with Teledyne Isco CombiFlash Rf 200 system and RediSep Rf Gold Silica columns (4 g).
2
-(4-Azabicyclo[2.2.1]hept-8-ene-3-endo,5-endo-dicarboximide-4-yl)-3-methyl pentanoyl chloride (4). A
solution of oxalyl chloride (507 mg, 4.00 mmol) in dry CH Cl (10 mL) was added dropwise 2-(4-
azabicyclo[2.2.1]hept-8-ene-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanoic acid (3) (454 mg, 2.00
mmol) in dry CH Cl (5 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred
at room temperature overnight. The organic phase was concentrated and washed with diethyl ether. The
2
2
2
2
22
compound 4 was obtained as a crème solid, yield 472.8 mg (94%), mp 50-52 °C, [α]
D
-7.5° (c 0.013, CH
2
Cl ),
2
R
f
: 0.17 (ethyl acetate/n-hexane 4:1), FTIR (ATR) ν 2967, 2936, 2876, 1747 (C=O), 1674 (C=O), 1463, 1384,
1
1
0
2
=
4
336, 1185, 1120, 1048; H NMR (CDCl3, 500 MHz) δ 0.76 (t, J 7.25 Hz, 3H, CH
.94 (d, J 6.62 Hz, 3H, CH
.19-2.23 (m, 1H, CH), 3.27 (brs, 2H, H
CH); C NMR (CDCl
4.9 (CH), 51.5 (CH
3
), 0.88 (p, J 7.25 Hz, 1H, CH
), 1.50 (d, J 8.51 Hz, 1H, H10a), 1.69 (d, J 8.82 Hz, 1H, H10s),
), 3.35 (brs, 2H, H , H ), 4.33 (d, J 7.88 Hz, 1H, CH), 6.06 (brs, 2H,
), 15.5 (CH ), 24.6 (CH ), 32.8 (CH), 44.0 (CH), 44.2 (CH), 44.8 (CH),
), 56.3 (CH), 133.4 (=CH), 133.9 (=CH), 171.8 (C=O), 176.3 (C=O), 176.4 (C=O); GC-MS (EI, 70
2
),
3
), 1.32-1.37 (m, 1H, CH
, H
, 125 MHz) δ 9.8 (CH
2
1
7
2
6
13
3
3
3
2
2
+
+
+
eV) calculated for [C15
1 (C ), 66 (C ), 54 (C
N-4-Azabicyclo[2.2.1]hept-8-ene-3-endo,5-endo-dicarboximide-4-yl-2-(4-azabicyclo[2.2.1]hept-8-ene-3-
endo,5-endo-dicarboximide-4-yl)-3-methylpentanamide (5). A solution of N-aminobicyclo[2.2.1]hept-8-ene-2-
endo, 6-endo-carboxiimide (2) (356 mg, 2.00 mmol) in dry CH Cl (10 mL) was added dropwise to 2-(4-
azabicyclo[2.2.1]hept-8-ene-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanoyl chloride (4) (591 mg, 2.00
mmol) in dry CH Cl (10 mL) under nitrogen atmosphere. The resulting mixture was stirred at room
temperature overnight. The organic phase was concentrated and the oily residue was washed with diethyl
H18ClNO
3
] m/z 295.5 (M) , found 295 (M) , 261 (M -Cl), 245 (C14
H15NO
3 9
), 203 (C11H NO
3
),
9
7
H
8
5
H
6
4
6
H ).
2
2
2
2
22
ether. The compound 5 was obtained as a crème yellow solid, yield 699.2 mg (80%), mp 193-195 °C, [α]
D
+
12.2° (c 0.009, CH
2
Cl
2
), R
f
: 0.42 (ethyl acetate/n-hexane 5:1), FTIR (ATR) ν 3328 (NH), 2972, 2950, 1765, 1716
1
(C=O), 1686 (C=O), 1401, 1384, 1336, 1196; H NMR (CDCl3, 500 MHz) δ 0.82 (t, J 7.25 Hz, 3H, CH
3
), 0.97 (p, J
), 1.55 (d, J 7.88 Hz, 2H, H10a), 1.77 (d, J
and H ), 3.42 (s, 4H, H and H ), 4.34 (d, J
7
8
2
.25 Hz, 1H, CH ), 1.07 (d, J 6.93 Hz, 3H, CH
3
), 1.27-1.31 (m, 1H, CH
2
.82 Hz, 2H, H10s), 2.53-2.60 (m, 1H, CH), 3.34 (d, J 12.9 Hz, 4H, H
2
6
1
7
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1
1.98 Hz, 1H, CH), 6.17 (dd, J 2.20;5.67 Hz, 1H, =CH), 6.19 (s, 2H, =CH), 6.34 (dd, J 2.20;5.67 Hz, 1H, =CH), 8.87
13
(
(
1
s, 1H, NH); C NMR (CDCl
2×CH), 45.2 (CH), 45.4 (CH), 45.6 (CH), 45.7 (CH), 51.8 (CH
34.8 (=CH), 135.2 (=CH), 166.4 (C=O), 173.4 (2×C=O), 177.8 (C=O), 179.0 (C=O); HRMS (ESI): calcd for
3
, 125 MHz) δ 9.8 (CH
3
), 15.1 (CH
3
), 25.1 (CH
), 52.2 (CH
2
), 32.0 (CH), 44.2 (CH), 44.3 (CH), 44.9
), 60.8 (CH), 134.4 (=CH), 134.7 (=CH),
2
2
+
+
[
C
24
H
27
N
3
O
5
] ([M] ): m/z 437.4883, found 438.2022 [M+H] .
General procedure for the synthesis of compounds 6a-e, 7a and 8. A solution of Pd(OAc)
mmol) and Ph As (67.5 mg, 0.22 mmol) in dry DMF (3 mL) was stirred in a Schlenk flask under nitrogen
atmosphere at 65 °C for 15 min to form the catalyst complex. Then, aryl iodide (3.00 mmol), compound 5 (437
mg, 1.00 mmol), Et N (708 mg, 7.00 mmol), and HCOOH (0.226 mL, 6.00 mmol) were added. The mixture was
heated to 65 °C for 24–48 h. After cooling to room temperature, brine (50 mL) was added, and the mixture
2
(11.2 mg, 0.05
3
3
was extracted with AcOEt. The aqueous layer was dried over MgSO
was purified by column chromatography or flash chromatography.
4
, filtered, and concentrated. The residue
N-[8-Phenyl-4-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl] 2-(8-phenyl-4-azabicyclo[2.2.1]-
heptane-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanamide (6a). Colorless oil, yield 504 mg (85%),
2
2
[
α]
D
+13.8° (c 0.010, CH
2
Cl
2
), R
f
: 0.32 (ethyl acetate/n-hexane 1:1), FTIR (ATR) ν 3283 (NH), 3003, 2968, 2966,
1
2
3
2
2
H
1
950, 1728 (C=O), 1704 (C=O), 1494, 1454, 1381, 1136 1076; H NMR (CDCl
3
, 500 MHz) δ 0.83 (t, J 7.25 Hz,
), 1.28-1.35 (m, 1H, CH ), 1.56 (d, J 10.08 Hz,
), 1.87 (d, J 10.08 Hz, 2H, H10s), 2.08-2.19 (m, 1H, CH ), 2.67-2.73 (m, 1H, CH ),
), 2.86 (brs, 3H, H and H ), 2.92-2.95 (m, 2H, H8n), 3.08-3.12 (m, 1H, CH), 3.16-3.19 (m, 3H,
), 3.24-3.28 (m, 1H, H ), 4.54 (d, J 11.98 Hz, 1H, CH), 7.09-7.14 (m, 5H, Har), 7.17-7.22 (m, 5H, Har), 9.08 (brs,
, 125 MHz) δ 9.0 (CH ), 14.3 (CH ), 24.4 (CH ), 28.7 (CH ), 31.0 (CH), 31.2 (CH), 31.8
), 38.3 (CH ), 38.8 (CH), 39.1 (CH), 40.7 (CH), 44.2 (CH), 45.3 (CH), 46.0 (CH), 47.0 (CH), 47.2
CH), 47.6 (CH), 60.1 (CH), 124.8 (Car), 125.0 (Car), 125.8 (Car), 125.9 (Car), 126.0 (Car), 126.1 (2×Car), 127.4 (Car),
H, CH
H, H10a), 1.69-1.78 (m, 2H, CH
.82 (brs, 1H, H
3
), 1.03 (p, J 7.25 Hz, 1H, CH
2
), 1.10 (d, J 6.62 Hz, 3H, CH
3
2
2
2
2
1
1
7
2
6
13
H, NH); C NMR (CDCl
3
3
3
2
2
(
(
CH ), 32.6 (CH
2
2
2
1
27.4 (Car), 127.5 (Car), 143.5 (C
q
), 143.7 (C
q
), 165.8 (C=O), 165.9 (C=O), 166.1 (C=O), 172.9 (C=O), 173.0 (C=O);
+
+
HRMS (ESI): calcd for [C36
39
H N
3
O
5
] ([M] ): m/z 593.7120, found 594.2964 [M+H] .
N-[8-(4-Chlorophenyl)-4-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl]-2-(8-(4-chlorophenyl-
4
4
3
0
-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanamide (6b). White oil, yield
2
2
96.5 mg (75%), [α]
D
+25.0° (c 0.026, CH
2
Cl
2
), R
f
: 0.42 (ethyl acetate/n-hexane 3:1), FTIR (ATR) ν 3328 (NH),
1
003 , 2971, 2879, 1730, 1705 (C=O), 1694 (C=O), 1493, 1402, 1337, 1190, 1135; H NMR (CDCl3, 500 MHz) δ
.79 (t, J 7.25 Hz, 3H, CH
3
), 0.94 (p, J 7.25 Hz, 1H, CH
), 1.78 (d, J 10.08 Hz, 2H, H10s), 1.97-2.12 (m, 1H, CH
), 2.77 (brs, 3H, H , H ), 2.84-2.92 (m, 2H, H8n), 2.98-3.04 (m, 1H, CH), 3.06-
), 3.22-3.24 (m, 1H, H ), 4.47 (d, J 11.98 Hz, 1H, CH), 6.95-7.05 (m, 4H, Har), 7.09-7.15 (m, 4H,
ar), 9.05 (brs, 1H, NH); C NMR (CDCl3, 125 MHz) δ 10.0 (CH ), 15.3 (CH ), 25.3 (CH ), 32.1 (CH), 33.5 (CH ),
9.2 (CH ), 39.4 (CH ), 39.8 (CH), 39.9 (CH ), 40.1 (CH), 41.1 (CH), 44.9 (CH), 45.4 (CH), 46.3 (CH), 46.9 (CH),
7.8 (CH), 48.1 (CH), 48.4 (CH), 61.0 (CH), 128.2 (Car), 128.3 (Car), 128.4 (2×Car), 128.5 (2×Car), 128.6 (2×Car),
2
), 1.08 (d, J 6.62 Hz, 3H, CH
3
), 1.24-1.30 (m, 1H, CH
2
), 1.46
(d, J = 10.08 Hz, 2H, H10a), 1.61-1.70 (m, 2H, CH
2
2
), 2.61-
2
3
.67 (m, 1H, CH
.16 (m, 3H, H
2
), 2.68 (brs, 1H, H
1
1
7
2
6
1
3
H
3
3
2
2
3
4
1
2
2
2
31.7 (2×C
q
), 143.2 (2×C
q
+
), 166.9 (C=O), 167.0 (C=O), 173.7 (C=O), 173.8 (C=O), 174.0 (C=O); HRMS (ESI): calcd
+
for [C36
H
37Cl
2
N
3
O
5
] ([M] ): m/z 662.6021, found 662.2189 [M+H] .
N-[8-Morpholino-4-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl]-2-(8-morpholino-4-aza-
bicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanamide (6c). White solid, yield
2
2
6
48.5 mg (85%), mp 191-193 °C, [α]
D
+15.0° (c 0.010, CH
2
Cl
2
), R
f
: 0.49 (ethyl acetate/n-hexane 6:1), FTIR (ATR)
1
ν 3200 (NH), 3010, 2967, 2880, 1727 (C=O), 1699 (C=O), 1494, 1470, 1439, 1381, 1182, 1137; H NMR (CDCl
3
,
5
00 MHz) δ 0.91 (t, J 7.25 Hz, 3H, CH
3
), 1.08-1.14 (p, J 7.25 Hz, 1H, CH
2
), 1.18 (d, J 6.62 Hz, 3H, CH ), 1.37-1.43
3
2
(m, 1H, CH ), 1.54 (d, J 9.14 Hz, 1H, H10a), 1.61 (d, J 10.08 Hz, 1H, H10a), 1.76- 1.86 (m, 2H, CH
2
), 1.90-1.97 (m,
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Albayrak, F. et al.
2
3
4
1
3
6
H, H10s), 2.12-2.30 (m, 2H, CH
.13 (brd, J 4.72 Hz, 8H, CH ), 3.22-3.26 (m, 3H, H
.60 (d, J 11.98 Hz, 1H, CH), 6.83-6.86 (m, 4H, Har), 7.10-7.15 (m, 4H, Har), 9.29 (brs, 1H, NH); C NMR (CDCl
25 MHz) δ 10.1 (CH ), 15.3 (CH ), 25.4 (CH ), 32.0 (CH), 32.3 (CH), 33.1 (CH ), 33.4 (CH ), 39.5 (CH ), 39.8 (CH),
9.9 (CH ), 40.6 (CH), 41.0 (CH), 45.4 (CH), 46.5 (CH), 47.0 (CH), 48.1 (CH), 48.2 (CH), 48.7 (CH), 49.6 (4×CH ),
1.2 (CH), 66.9 (4×CH ), 115.7 (4×Car), 127.8 (4×Car), 136.4 (2×C ), 149.4 (2×C ), 166.9 (C=O), 167.0 (C=O), 167.1
2
), 2.75-2.79 (m, 1H, CH), 2.80-2.84 (m, 1H, H8n), 2.89-2.98 (m, 5H, H
, H ), 3.31-,3.34 (m, 1H, H ), 3.87 (brd, J 4.09 Hz, 8H, CH ),
1
, H , H8n),
7
2
2
6
6
2
13
3
,
3
3
2
2
2
2
2
2
2
q
q
+
(C=O), 174.0 (C=O), 174.1 (C=O); HRMS (ESI): calcd for [C44
H
53
N
5
O ] ([M] ): m/z 763.9209, found 764.4006
7
+
[M+H] .
N-[8-(2-Thienyl)-4-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl]-2-(8-(2-thienyl)-4-aza-
bicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanamide (6d). Brown oil, yield 514.8
2
2
mg (85%), [α]
D
+11.0° (c 0.010, CH
2
Cl
2
), R
f
: 0.43 (ethyl acetate/n-hexane 1:1), FTIR (ATR) ν 3282 (N-H), 3010,
1
2
7
8
967, 2880, 1727 (C=O), 1699 (C=O), 1494, 1470, 1430, 1381, 1182, 1137; H NMR (CDCl
3
, 500 MHz) δ 0.91 (t, J
), 1.35-1.41 (m, 1H, CH ), 1.60 (d, J
), 1.98-2.05 (m, 2H, CH ), 2.06-2.09 (m, 1H,
), 2.75-2.80 (m, 1H, CH), 2.91-2.99 (m, 4H, H and H ), 3.06-3.10 (m, 1H, H8n), 3.18-3.19
m, 1H, H8n), 3.21-3.28 (m, 3H, H and H ), 3.30-3.34 (m, 1H, H ), 4.58 (d, J 11.98 Hz, 1H, CH), 6.77-6.81 (m, 1H,
ar), 6.84-6.86 (m, 1H, Har), 6.89-6.93 (m, 2H, Har), 7.11-7.15 (m, 2H, Har), 9.23 (brs, 1H, NH); C NMR (CDCl
.25 Hz, 3H, CH
.82 Hz, 1H, H ), 1.67 (d, J 10.4 Hz, 1H, H
), 2.18-2.26 (m, 1H, H
3
), 1.10 (p, J 7.25 Hz, 1H, CH
2
), 1.18 ( d, J 6.93 Hz, 3H, CH
3
2
a
a
), 1.82-1.91 (m, 2H, CH
2
2
H
s
s
1
7
(
H
2
6
6
13
3
,
1
3
1
25 MHz) δ 9.9 (CH
3
), 15.3 (CH
), 39.8 (CH), 40.3 (CH
3
), 20.7 (CH), 25.4 (CH
), 46.2 (CH), 46.6 (CH), 46.9 (CH), 47.9 (CH), 48.3 (CH), 60.9 (CH),
2
), 32.1 (CH), 34.9 (CH
2
), 35.5 (CH ), 37.7 (CH), 38.1 (CH),
2
9.5 (CH), 39.6 (CH
2
2
23.1 (Car), 123.2 (Car), 123.6 (Car), 123.7 (Car), 126.7 (Car), 126.8 (Car), 149.3 (C
q
), 149.5 (C
q
), 166.9 (C=O), 167.0
+
(C=O), 173.7 (C=O), 173.9 (C=O), 176.3 (C=O); HRMS (ESI): calcd for [C32
35
H N
3
O
5
S
2
] ([M] ): m/z 605.7674, found
+
606.2095 [M+H] .
N-[8-(3-Bromomethylphenyl)-4-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl] 2-(8-(3-bromo-
methylphenyl)-4-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanamide (6e).
2
2
Colorless oil, yield 545.3 mg (70%), [α]
(
D
+11.4° (c 0.010, CH
2
Cl
2
), R
f
: 0.70 (ethyl acetate/n-hexane 1:1), FTIR
1
ATR) ν 3270 (NH), 3056, 2964, 2878, 1704 (C=O), 1607, 1588, 1514, 1455, 1438, 1379, 1182, 1042; H NMR
(
CDCl
3
, 500 MHz) δ 0.83 (t, J 7.25 Hz, 3H, CH
.35 (m, 1H, CH ), 1.48-1.57 (m, 2H, H10a), 1.69-1.75 (m, 2H, H10s), 1.80-1.91 (m, 3H, H
.66-2.74 (m, 1H, CH), 2.77-2.82 (m, 1H, H8n), 2.86 (brs, 2H, H ), 2.91-2.94 (m, 2H, H ), 3.08-3.11 (m, 1H, H8n),
.14-3.18 (m, 2H, H ), 3.23-3.27 (m, 2H, H ), 4.51 (d, J 11.98 Hz, 1H, CH), 5.09 (d, J 7.25 Hz, 4H, CH ), 7.09-7.11
, 125 MHz) δ
), 40.1 (CH), 41.2 (CH),
1.4 (CH), 44.9 (CH), 45.2 (CH), 46.3 (CH), 46.9 (CH), 47.0 (CH), 48.1 (CH), 48.6 (CH), 61.0 (CH), 65.7 (CH ), 65.8
), 124.7 (Car), 126.0 (Car), 126.8 (Car), 127.0 (Car), 127.1 (Car), 127.3 (Car), 128.7 (Car), 128.8 (Car), 135.2 (C ),
3
), 1.00 (p, J 7.25 Hz, 1H, CH
2
), 1.18 (d, J 7.25 Hz, 3H, CH
3
), 1.29-
1
2
3
2
9
), 2.09-2.18 (m, 1H, H
9
),
1
7
2
6
2
13
(m, 4H, Har), 7.16-7.19 (m, 2H, Har), 8.04 (d, J 4.04 Hz, 2H, Har), 9.12 (brs, 1H, NH); C NMR (CDCl
3
1
4
0.0 (CH
3
), 15.3 (CH
3
), 25.4 (CH
2
), 32.0 (CH), 32.9 (CH), 39.4 (CH
2
), 39.8 (CH), 40.0 (CH
2
2
(CH
2
q
1
45.3 (C
q
), 145.4 (C
q
), 160.7 (C
q
), 166.9 (C=O), 167.0 (C=O), 173.8 (C=O), 173.9 (C=O), 174.1 (C=O); HRMS (ESI):
+
+
calcd for [C38
H41Br
2
N
3
O
5
] ([M] ): m/z 779.1319, 780.1599 found [M+H] .
N-[8-Phenyl-4-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl]-2-(4-azabicyclo[2.2.1]hept-8-
ene-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanamide (7a). Colorless oil, yield 438.26 mg (85%),
2
2
[
1
(
1
(
H
α]
D
+14.6° (c 0.012, CH
2
Cl
2
), R
f
: 0.30 (ethyl acetate/n-hexane 1:1), FTIR (ATR) ν 3283 (N-H), 3010, 2968, 2810,
1
727 (C=O), 1703 (C=O), 1494, 1383, 1184, 1136; H NMR (CDCl
3
, 500 MHz) δ 0.76 (t, J 7.25 Hz, 3H, CH
), 1.49 ( d, J 8.82 Hz, 2H, H10a), 1.57-
), 1.85 ( d, J 10.4 Hz, 1H, H10s), 2.51-2.57
), 3.08-3.10 (m, 1H, H ), 3.14-3.16 (m, 1H,
), 3.35-3.37 (m, 2H, H ), 4.32 (d, J 11.98 Hz, 1H, CH), 6.13 (dd, J
3
), 0.90
p, J 6.62 Hz, 1H, CH
2
), 1.03 (d, J 6.62 Hz, 3H, CH
), 1.69 ( d, J 8.82 Hz, 1H, H10s), 1.74-1.75 (m, 1H, CH
), 2.88 (brd, J 5.67 Hz, 1H, H
), 3.21-3.24 (m, 1H, H8n), 3.29- 3.30 (m, 2H, H
3
), 1.21-1.27 (m, 1H, CH
2
.64 (m, 1H, CH
2
2
m, 1H, CH), 2.84 (brd, J 4.41 Hz, 1H, H
1
1
7
7
2
6
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Albayrak, F. et al.
2
.83; 5.67 Hz, 1H, =CH), 6.30 (brs, 1H, =CH), 7.07-7.13 (m, 2H, Har), 7.27-7.30 (m, 3H, Har), 9.01 (brs, 1H, NH);
13
C NMR (CDCl
3
, 125 MHz) δ 9.8 (CH
3
), 15.2 (CH
3
), 25.2 (CH
2
), 32.2 (CH), 33.2 (CH
2
), 39.4 (CH
), 60.9 (CH), 125.9
2
), 39.9 (CH), 41.3
(
(
CH), 45.2 (CH), 45.4 (CH), 45.6 (CH), 45.8 (CH), 46.5 (CH), 47.0 (CH), 47.1 (CH), 52.3 (CH
C
2
ar), 127.0 (2×Car), 128.4 (2×Car), 134.5 (=CH), 135.3 (=CH), 144.7 (C
q
), 166.9 (C=O), 174.2 (C=O), 174.3 (C=O),
+
+
177.9 (C=O), 179.1 (C=O); HRMS (ESI): calcd for [C30
33
H N
3
O
5
] ([M] ): m/z 515.6000, found 516.2484 [M+H] .
8
-(3,4-Difluorophenyl)-4-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide (8). Yellow oil, yield 220.8
2
2
mg (80%), [α]
D
+4.0° (c 0.010, CH
2
Cl
2
), R
f
: 0.36 (ethyl acetate/n-hexane 5:1), FTIR (ATR) ν 3305 (N-H), 2972,
1
1
1
5
1
704 (C=O), 1665 (C=O), 1609, 1519, 1477, 1179, 1125 (C-N); H NMR (CDCl
3
, 500 MHz) δ 1.53 (d, J 9.14 Hz,
H, H10a), 1.69-1.72 (m, 2H, H9n and H9
.04, 1H, H ), 2.86 (brs, 1H, H ), 3.09 (dd, J 1.87; 5.04 Hz, 1H, H
H, NH), 6.79-6.82 (m, 1H, Har), 6.90 (ddt, J 2.20; 7.56; 9.77 Hz, 1H, Har), 6.99 (dd, J 8.19; 10.08 Hz, 1H, Har); C
, 125 MHz) δ 32.9 (CH ), 39.1 (CH ), 39.4 (CH), 41.1 (CH), 45.3 (CH), 46.5 (CH), 47.1 (CH), 115.9 (Car),
17.2 (Car), 122.9 (Car), 141.3 (C ), 147.7 (C
x
), 1.76 (d, J 10.4 Hz, 1H, H10s), 2.65 (dt, J 6.93 Hz, 1H, H8n), 2.79 (d, J
1
7
2
), 3.14 (dd, J 5.35; 9.45 Hz, 1H, H ), 4.19 (brs,
6
1
3
NMR (CDCl
1
3
2
2
q
q
), 149.7 (C
] m/z 276 (M) , found 276 (M ), 206 (C13
q
), 174.8 (C=O), 174.9 (C=O); GC-MS (EI, 70 eV) calculated
+
+
+
for [C15
13
H F
2
NO
2
14
H F
2
), 164 (M -C
6
H
4
F
2
), 114 (C
6
H
4
F ).
2
General procedure for the synthesis of compound 9a and 9b. A solution of Pd(OAc)
and Ph As (67.5 mg, 0.22 mmol) in dry DMF (3 mL) was stirred in a Schlenk flask under nitrogen atmosphere at
5 °C for 15 min to form the catalyst complex. Then, aryl iodide (3.00 mmol), compound 5 (437 mg, 1.00
2
(11.2 mg, 0.05 mmol)
3
6
mmol), phenylacetylene (612 mg, 6.00 mmol), and Et
heated to 65 C for 24–48 h. After cooling to room temperature, brine (50 mL) was added, and the mixture
3
N (708 mg, 7.00 mmol) were added. The mixture was
o
was extracted with AcOEt. The aqueous layer was dried over MgSO
was purified by column chromatography or flash chromatography.
4
, filtered, and concentrated. The residue
N-[9-Phenylethynl-8-phenyl-4-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl]-2-(4-azabicyclo-
2.2.1]hept-8-ene-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanamide (9a). Yellow oil, yield 461.7 mg
[
22
(75%), [α]
D
+25.0° (c 0.003, CH
2
Cl
2
), R
f
: 0.28 (ethyl acetate/n-hexane 1:1), FTIR (ATR) ν 3200 (NH), 3010, 2968,
1
2
0
1
5
900, 2861, 1726 (C=O), 1700 (C=O), 1512 (C=C), 1470, 1440, 1381, 1183, 1137; H NMR (CDCl
3
, 500 MHz) δ
), 1.23-1.27 (m, 1H, CH ),
), 2.52-2.58 (m, 1H, CH), 2.99 (d, J
), 3.36-3.40 (m, 2H, H , H ), 4.38 (d, J 11.98
.77 (t, J 7.25 Hz, 3H, CH
.48-1.53 (m, 2H, H10a), 1.68-1.72 (m, 2H, H10s), 2.45 (d, J 10.71 Hz, 1H, H
.67 Hz, 1H, H ), 3.11-3.19 (m, 4H, H , H ), 3.29-3.31 (m, 2H, H , H
3
), 0.92 (p, J 7.25 Hz, 1H, CH
2
), 1.04 (d, J 6.62 Hz, 3H, CH
3
2
8
9
1
7
2
6
2
6
Hz, 1H, CH), 6.12 (dd, J 3.15;5.67 Hz, 1H, =CH), 6.29-6.32 (m, 1H, =CH), 6.72 (d, J 6.62 Hz, 2H, Har), 7.02-7.07 (m,
13
3
H, Har), 7.12 (t, J 6.93 Hz, 1H, Har), 7.16-7.18 (m, 2H, Har), 7.21 (d, J 7.25 Hz, 2H, Har), 9.07 (brs, 1H, NH); C
NMR (CDCl , 125 MHz) δ 9.8 (CH ), 15.2 (CH ), 25.2 (CH ), 32.2 (CH), 38.1 (CH), 40.2 (CH ), 43.5 (CH), 45.2 (CH),
5.4 (CH), 45.6 (CH), 45.7 (CH), 45.8 (CH), 46.4 (CH), 47.3 (CH), 47.4 (CH), 52.3 (CH ), 60.8 (CH), 85.4 (C≡C), 89.7
3
3
3
2
2
4
2
(
1
6
C≡C), 126.1 (Car), 127.4 (Car), 127.9 (4×Car), 128.3 (2×Car), 131.3 (2×Car), 134.5 (=CH), 135.3 (=CH), 140.9 (C
q
),
+
41.1 (C
q
), 167.0 (2×C=O), 167.1 (2×C=O), 173.6 (C=O); HRMS (ESI): calcd for [C38
37
H N
3
O
5
] ([M] ): m/z
+
15.7175, found 616.2804 [M+H] .
N-[9-Phenylethynl-8-(4-chlorophenyl)-4-azabicyclo[2.2.1]heptane-3-endo,5-endo-dicarboximide-4-yl]-2-(4-
azabicyclo[2.2.1]hept-8-ene-3-endo,5-endo-dicarboximide-4-yl)-3-methylpentanamide (9b). Yellow oil, yield
2
2
4
3
86.9 mg (75%), [α]
D
+23.0° (c 0.010, CH
2
Cl
2
), R
f
: 0.31 (ethyl acetate/n-hexane 1:1), FTIR (ATR) ν 3275 (NH),
1
010, 2967, 2880, 1727 (C=O), 1699 (C=O), 1494 (C=C), 1470, 1439, 1381, 1183 (C-O), 1043 (C-N); H NMR
(
1
CDCl
3
, 500 MHz) δ 0.76 (t, J 7.56 Hz, 3H, CH
.14 (m, 1H, CH ), 1.47-1.50 (m, 1H, H10a), 1.67-1.70 (m, 2H, H10a, H10s), 1.74-1.79 (m, 1H, H10s), 2.42 (d, J 10.71
), 3.24-3.27 (m, 2H, H ), 3.28-
), 4.36 (d, J 11.98 Hz, 1H, CH), 6.10-6.13 (m, 1H, =CH), 6.29-6.31 (m, 1H,
3
), 0.86 (p, J 7.56 Hz, 1H, CH
2
), 1.04 (d, J 6.93 Hz, 3H, CH ), 1.10-
3
2
Hz, 1H, H9n), 2.97-3.01 (m, 1H, CH), 3.10-3.12 (m, 1H, H8n), 3.16-3.19 (m, 2H, H
.31 (m, 2H, H ), 3.35-3.37 (m, 2H, H
7
1
3
2
6
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1
3
CH), 6.71 (d, J 6.62 Hz, 2H, Har), 7.02-7.07 (m, 3H, Har), 7.16-7.23 (m, 4H, Har), 9.07 (brs, 1H, NH); C NMR
(
(
(
CDCl
CH), 44.2 (CH), 44.9 (CH), 45.2 (CH), 45.6 (CH), 46.3 (CH), 47.1 (CH), 53.2 (CH
C≡C), 123.2 (C ), 127.6 (Car), 127.9 (Car), 128.0 (Car), 129.6 (Car), 129.7 (Car), 131.2 (Car), 131.3 (Car), 132.0 (C
34.4 (Car), 134.5 (Car), 134.8 (Car), 135.2 (Car), 139.5 (C ), 167.1 (C=O), 173.4 (C=O), 173.5 (2xC=O), 175.4
3
, 125 MHz) δ 9.7 (CH
3
), 15.2 (CH
3
), 20.6 (CH), 25.1 (CH
2
), 32.1 (CH), 36.6 (CH), 38.0 (CH), 40.0 (CH
), 60.7 (CH), 85.7 (C≡C), 89.0
),
2
), 43.4
2
q
q
1
q
+
+
(C=O); HRMS (ESI): calcd for [C38
H36ClN
3
5
O ] ([M] ): m/z 649.2343, found 650.2632 [M+H] .
Acknowledgements
We gratefully acknowledge financial support of this work by the Yildiz Technical University Scientific Research
Projects Coordination Department (2015-01-02-GEP02) and Yildiz Technical University Technology Transfer
Office. We thank Prof. Dr. Ihsan Erden (San Francisco State University) for helpful discussion.
Supplementary Material
1
13
H NMR, C NMR, IR, and MS data of all new compounds are available with the article through the journal
Web site
References
1. Stryer, L. Biochemistry, 4th Ed. W H Freeman & Co: New York, 1995.
2. Boonen, J.; Bronselaer, A.; Nielandt, J.; Veryser, L.; De Tre, G.; De Spiegeleer, B. J. Ethnopharmacol 2012,
142 (3), 563-590.
https://doi.org/10.1016/j.jep.2012.05.038
3
. Collins, R.; Reith, C.; Emberson, J.; Armitage, J.; Baigent, C.; Blackwell, L.; Blumenthal, R.; Danesh, J.; Smith,
G. D.; DeMets, D.; Evans, S.; Law, M.; MacMahon, S.; Martin, S.; Neal, B.; Poulter, N.; Preiss, D.; Ridker, P.;
Roberts, I.; Rodgers, A.; Sandercock, P.; Schulz, K.; Sever, P.; Simes, J.; Smeeth, L.; Wald, N.; Yusuf, S.; Peto,
R. Lancet 2016, 388 (10059), 2532-2561.
https://doi.org/10.1016/S0140-6736(16)31357-5
4
5
. Jeffrey Tobias, D. H., Cancer and its Management, 7th Edition. Wiley-Blackwell: New York, 2014.
. Olkkola, K. T.; Brunetto, A. V.; Mattila, M. J. Clin. Pharmacokinet 1994, 26 (2), 107-120.
https://doi.org/10.2165/00003088-199426020-00004
6. El-Kabbani, O.; Carbone, V.; Darmanin, C.; Oka, M.; Mitschler, A.; Podjarny, A.; Schulze-Briese, C.; Chung,
R. P. T. J. Med. Chem. 2005, 48 (17), 5536-5542.
https://doi.org/10.1021/jm050412o
7. Thacher, S. M.; Vasudevan, J.; Tsang, K. Y.; Nagpal, S.; Chandraratna, R. A. S. J. Med. Chem. 2001, 44 (3),
281-297.
https://doi.org/10.1021/jm0000214
8. Negishi, E.-i., Handbook of organopalladium chemistry for organic synthesis. Wiley: New York, 2002.
9. Beletskaya,
I. P.; Cheprakov, A. V.,
Chem.
Rev. 2000, 100 (8),
3009-3066.
https://doi.org/10.1021/cr9903048
Page 254
©ARKAT USA, Inc

Arkivoc 2017, v, 244-256
Albayrak, F. et al.
10. Wei, Z. L.; George, C.; Kozikowski, A. P., Tetrahedron Lett. 2003, 44 (19), 3847-3850.
https://doi.org/10.1016/S0040-4039(03)00737-8
11. Ferri, N.; Beccalli, E. M.; Contini, A.; Corsini, A.; Antonino, M.; Radice, T.; Pratesi, G.; Tinelli, S.; Zunino, F.;
Gelmi, M. L. Bioorgan. Med. Chem. 2008, 16 (4), 1691-1701.
https://doi.org/10.1016/j.bmc.2007.11.024
1
2. Ferri, N.; Radice, T.; Antonino, M.; Beccalli, E. M.; Tinelli, S.; Zunino, F.; Corsini, A.; Pratesi, G.; Ragg, E. M.;
Gelmi, M. L.; Contini, A. Bioorgan. Med. Chem. 2011, 19 (18), 5291-5299.
https://doi.org/10.1016/j.bmc.2011.08.016
13. Sondhi, S. M.; Rani, R.; Roy, P.; Agrawal, S. K.; Saxena, A. K. Bioorg. Med. Chem. Lett. 2009, 19 (5), 1534-
1538.
https://doi.org/10.1016/j.bmcl.2008.07.048
14. Yolacan, C.; Bagdatli, E.; Ocal, N.; Kaufmann, D. E. Molecules 2006, 11 (8), 603-614.
https://doi.org/10.1016/j.bmcl.2008.07.048
15. Storsberg, J.; Yao, M. L.; Ocal, N.; de Meijere, A.; Adam, A. E. W.; Kaufmann, D. E. Chem. Commun. 2005,
(45), 5665-5666.
https://doi.org/10.1039/b507732j
16. Goksu, G.; Gul, M.; Ocal, N.; Kaufmann, D. E. Tetrahedron Lett. 2008, 49 (17), 2685-2688.
https://doi.org/10.1016/j.tetlet.2008.02.171
17. Namyslo, J. C.; Storsberg, J.; Klinge, J.; Gartner, C.; Yao, M. L.; Ocal, N.; Kaufmann, D. E. Molecules 2010, 15
(5), 3402-3410.
https://doi.org/10.3390/molecules15053402
18. Gunkara, O. T.; Kulu, I.; Ocal, N.; Kaufmann, D. E. Monatsh. Chem. 2010, 141 (11), 1237-1243.
https://doi.org/10.1007/s00706-010-0384-3
19. Gunkara, O. T.; Sucu, B. O.; Ocal, N.; Kaufmann, D. E. Chem. Pap. 2013, 67 (6), 643-649.
https://doi.org/10.2478/s11696-013-0338-4
2
2
0. Gul, M.; Kulu, I.; Gunkara, O. T.; Ocal, N. Acta Chim Slov 2013, 60 (1), 87-94.
1. Biajoli, A. F. P.; Schwalm, C. S.; Limberger, J.; Claudino, T. S.; Monteiro, A. L. J. Brazil. Chem. Soc. 2014, 25
(12), 2186-2214.
https://doi.org/10.5935/0103-5053.20140255
2
2. Chekal, B. P.; Guinness, S. M.; Lillie, B. M.; McLaughlin, R. W.; Palmer, C. W.; Post, R. J.; Sieser, J. E.; Singer,
R. A.; Sluggett, G. W.; Vaidyanathan, R.; Withbroe, G. J., Org. Process Res. Dev. 2014, 18 (1), 266-274.
https://doi.org/10.1021/op400088k
2
2
3. Larsen, R.; Abdel-Magid, A. F. Organometallics in Process Chemistry. Springer: New York, 2004.
4. Namyslo, J. C.; Kaufmann, D. E. Synlett 1999, (6), 804-806.
https://doi.org/10.1055/s-1999-2719
2
2
2
5. Stuhlmann, F.; Kaufmann, D. E. J. Prak. Chem-Chem. Ztg. 1999, 341 (5), 455-460.
https://doi.org/10.1002/(SICI)1521-3897(199907)341:5<455::AID-PRAC455>3.0.CO;2-2
6. Namyslo, J. C.; Kaufmann, D. E.
https://doi.org/10.1002/cber.19971300924
Chem Ber-Recl 1997, 130 (9), 1327-1331.
7. Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.; Maruyama, K. J. Org. Chem. 1982, 47 (1), 119-126.
https://doi.org/10.1021/jo00340a026
Page 255
©ARKAT USA, Inc

Arkivoc 2017, v, 244-256
Albayrak, F. et al.
28. Kas'yan, L. I.; Tarabara, I. N.; Bondarenko, Y. S.; Shishkina, S. V.; Shishkin, O. V.; Musatov, V. I. Russ. J. Org.
Chem.+ 2005, 41 (8), 1122-1131.
https://doi.org/10.1007/s11178-005-0305-9
29. Amos, S. E.; Nielsen, K. E.; Wicki, M. A. U.S. Patent 5,922,793; Chem. Abstr. 1999.
Page 256
©ARKAT USA, Inc