The Effect of Base and Nucleophile on the Nucleophilic Substitution of Methoxytropone Derivatives: An Easy Access to 4- And 5-Substituted Multifunctional Azulenes

Article abstract of DOI:10.1021/acs.joc.0c00951

The nucleophilic substitution on 3-substituted 2-methoxytropones to form azulenes is dependent on the nucleophile and base employed. With bulkier nucleophiles (ethyl/methyl cyanoacetate), the reaction proceeds with the abnormal nucleophilic substitution i

Full text of DOI:10.1021/acs.joc.0c00951

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Article
The Effect of Base and Nucleophile on the Nucleophilic
Substitution of Methoxytropone Derivatives: An Easy
Access to 4- and 5-Substituted Multifunctional Azulenes
NEHA KUMAR, Abhijeet R. Agrawal, Aditya Choudhury, and Sanjio S. Zade
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00951 • Publication Date (Web): 03 Jun 2020
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The Effect of Base and Nucleophile on the Nucleophilic Substitution of
Methoxytropone Derivatives: An Easy Access to 4- and 5-Substituted
Multifunctional Azulenes
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Neha R. Kumar, Abhijeet R. Agrawal, Aditya Choudhury and Sanjio S. Zade*
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Kolkata,
Mohanpur 741246, Nadia, West Bengal, India
ABSTRACT: The nucleophilic substitution on 3-substituted 2-methoxytropones to form azulenes is
dependent on the nucleophile and the base employed. With bulkier nucleophiles (ethyl/methyl
cyanoacetate), the reaction proceeds with the abnormal nucleophilic substitution irrespective of the
base and with smaller nucleophiles (malononitrile), the reaction follows base dependent normal and
abnormal nucleophilic substitution. Thus, the methodologies are developed to selectively obtain 4- and
5-substituted azulenes based on the nature of bases and nucleophile employed.
INTRODUCTION
Azulene, an isomer of naphthalene and a non-alternant aromatic hydrocarbon has unique
physicochemical characteristics attributed to its large dipole moment, a small gap between the highest
occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) and its anti-
Kasha’s rule emission.1 The design and synthesis of new organic functional materials with improved
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performance in devices has always been the quest. There have been several reports in the literature on
organic functional materials incorporating azulene unit and such materials have shown remarkable
applications in organic electronics.2,3
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In 1939, Plattner and Pfau4 reported the first azulene synthesis involving cumbersome
dehydrogenation step followed by the Ziegler and Hafner’s azulene synthesis, that provided ease for
introducing substituents on the seven-membered ring.5 Nozoe et al. employed troponoids and active
methylene compounds for the synthesis of multifunctional azulene in a single step (Scheme 1A).6
Machiguchi et al. provided a detailed theoretical and experimental insight into the mechanism involved
in Nozoe’s azulene synthesis.7,8
Ito and coworkers have contributed significantly to developing azulene derivatives.9 Other methods
of azulene synthesis include (i) Au-catalyzed10 dimerization of diarylalkynes,11 (ii) Pt-catalyzed ring
expanding cycloisomerization,12 (iii) Rh-catalyzed ring expansion–annulation of β’-bromo-α-diazo
ketones,13 (iv) [6+4] cycloaddition reactions,14 and (v) Synthesizing 1,1-dicyanoazulenes and subsequent
functionalization to give the bromo-cyano substituted azulene.15
Synthesis of functionalized/substituted azulenes has been difficult due to the lack of the
appropriate methods for the generation of azulenes from prefunctionalised precursors, and the
common strategy towards substituted azulenes has been the post functionalization of the azulene
skeleton. In our previous work, we developed a simple steric based strategy for the regioselective
synthesis of 5-substituted multifunctional azulenes from 3-substituted 2-methoxytropones which
undergo an abnormal nucleophilic attack by the cyanoacetate-enolate at C-7 to form 5-substituted
azulene rather than the expected normal attack at C-2 to form 4-substituted azulene (Scheme 1B).16 In
this work, we explore the influence of nucleophiles and bases of varying steric bulk and strength on the
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Scheme 1. Synthesis of multifunctional azulenes from 2-methoxytropone
nucleophilic substitution on 3- and 7-substituted 2-methoxytropones (Scheme 1C). This study has paved
paths for the efficient regioselective synthesis of both 4- and 5-substituted multifunctional azulenes.
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RESULTS AND DISCUSSION
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We chose propyl substituted tropolone17 1a (Scheme 2A) as the model substrate and converted it
to its methoxy derivative using K2CO3 and (CH3)2SO4, to give the tautomers 3-propyl-2-methoxytropone
(1b) and 7-propyl-2-methoxytropone (1c). We chose nucleophiles of varying steric bulk as methyl
cyanoacetate (MCA), ethyl cyanoacetate (ECA) and malononitrile (MLN) (Scheme 2B). Their steric bulk
varies in the order MLN<MCA<ECA, and the enolate stability follows the reverse order. Sodium
methoxide (NaOMe), 1,4-diazabicyclo[2.2.2]octane (DABCO), diisopropylethylamine (DIPEA),
triethylamine (Et3N), tributylamine (Bu3N), tert-butylamine (t-BuNH2), diisopropylamine (DIPA) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) were chosen as bases for screening (Scheme 2C). The strength of
the amine bases follows the following trend DBU>DIPA>t-BuNH2>Bu3N>Et3N>DIPEA>DABCO. We
attempted azulene synthesis reaction with model substrate 1b using each of MLN/MCA/ECA with the
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Scheme 2. (A) Synthesis of propyl substituted 2-methoxytropones (B) Nucleophiles of varying steric
bulk (C) Bases of varying steric bulk and strength
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bases NaOMe/DBU/DIPA/t-BuNH2/Bu3N/Et3N/DIPEA/DABCO following the general reaction conditions
as reported earlier.7,16
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As discussed by Machiguchi7 et al., the attack of the nucleophile at C-2 center and C-7 center of
2-methoxytropone are defined as the normal and abnormal nucleophilic attacks, respectively.
Theoretical and experimental evidence proved that the attack of nucleophile for 2-methoxytropone
takes place at C-2 center. To explore the effect of different nucleophiles and bases, 1b was subjected to
azulene formation reaction. We found that when MCA/ECA were used as nucleophiles, 2a/2b (62-
92%/66-90%) were always formed as the product irrespective of the nature of the base (Scheme 3A).
However, no product was formed when DIPEA and DABCO were used as a base (Scheme 3B, entry iii).
Both MCA and ECA are bulkier nucleophiles, and the presence of substituent at C-3 of 1b (i.e. propyl
group) blocks the attack of the nucleophile at C-2 and the attack occurs at C-7 i.e. the abnormal
nucleophilic attack to form anionic intermediate 7 (Scheme 3B, right). The next step involves C-H bond
formation at C-2, followed by abstraction of H-atom at C-7 to form an anionic intermediate. The final
step involves the loss of MeOH molecule to form 8 (Scheme S4, ESI). The intermediate 8 then undergoes
a series of transformations in the presence of the second molecule of the nucleophile to form 5-
substituted azulene (2a/2b) as per the mechanism proposed by Machiguchi et al.7 The inactivity of the
substrate 1b when DIPEA and DABCO are used as a base may originate from the weakness of the
nucleophile-base (ion) pair as well as the inactivity of the C-7 position for nucleophilic substitution for
the particular DIPEA-MCA/ECA or DABCO-MCA/ECA ion pair.
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When 1b was subjected to azulene formation reaction with MLN, in the presence of bases
NaOMe, DABCO, DIPEA, t-BuNH2, DIPA, or DBU, azulene 3 (64-93%) was formed as the product (Scheme
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3A). The structure of compound 3 was first confirmed by H NMR spectra by the deshielded nature of
the -CH2 protons of propyl chain and then unambiguously by single-crystal X-ray diffraction (SCXRD,
Figure S57, ESI) analysis. Malononitrile (MLN) is comparatively less bulky than MCA
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Scheme 3. (A) Effect of nucleophile and base towards nucleophilic substitution on 3-propyl-2-
methoxytropones (B) Normal vs. abnormal nucleophilic substitution
and ECA, and the attack of the enolate of MLN is at C-2 of 1b, unaffected by the propyl group and
independent of the sterics of the base employed. When NaOMe/DABCO/DIPEA/t-BuNH2/DIPA or DBU
was used as a base, the MLN enolate attack the C-2 centre of 1b (normal nucleophilic attack) to form
intermediate 6 via anion 5 (Scheme3B, left). The intermediate 6 then undergoes a series of
transformations to form compound 3. However, when Et3N and Bu3N were employed as the base, the
enolate of MLN ensued a competitive nucleophilic attack at C-2 and C-7 i.e. normal and abnormal
nucleophilic attack to form a mixture of products 3 and 4 (Scheme 3B, entry ii). In both cases, the
normal substituted product was formed in a major amount (for Et3N, 65:35 (percentage of normal and
abnormal product) and for Bu3N, 70:30 (percentage of normal and abnormal product), and these
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products were easily distinguishable by H NMR spectra. For compound 3, the signal for -CH2 proton
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attached to the aromatic center was comparatively deshielded 3.37-3.41 ppm than the compound 4 for
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which the -CH2 proton was at 2.85 ppm.
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The introduction of a functional group on the five-membered ring of azulene is very well
documented in the literature.18 However, such functionalisation and modification on the 7-membered
ring of azulene are dearth owing to the subtle reactivity differences in the positions of the seven-
membered ring. There is no report for the regioselective synthesis of 4-substituted multifunctional
azulenes from prefunctionalised precursor.
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Scheme 4. Synthesis of 3- and 7- substituted 2-methoxytropones.
To check the substrate scope of the methodology we synthesized several 2-methoxytropone
derivatives with varied substituents at C-3 position. The substituents were varied from alkyl to aryl to
heteroaryl (Scheme 4).19 As observed for the propyl isomer, the allyl, phenyl, naphthyl, and 3-thienyl
substituted 2-methoxytropones (9b-12b) when treated with MCA/ECA in the presence of a base
(NaOMe/Amine base) gave 5-substituted azulenes (13a/b-16a/b, Scheme 5A), which was independent
of the nature of the base. When the compounds 9b-12b was treated with malononitrile, as observed for
the 3-propyl-2-methoxytropone (1b), both normal and abnormal nucleophilic substitution products
were formed depending on the base employed. When isomer 9b-12b were treated with enolate of
malononitrile in the presence of base t-BuNH2/DIPA/DIPEA/DABCO/DBU or NaOMe, normal nucleophilic
substitution occurred leading to 4-substituted azulene i.e., 17, 19, 21 and 23 (Scheme 5A). Structure of
compound 21 was also confirmed by SCXRD analysis (Figure S58, ESI). The practical utility of the
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Scheme 5. (A) Scope of the nucleophile and base dependent azulene synthesis (B) Isomerisation of
double bond in allyl substituted cyano azulenes.
nucleophile and base dependent azulene synthesis was demonstrated by scaling up the reaction to
furnish the products 13b and 19 in 68% and 79% yields, respectively (0.62 g i.e. 68% 13b obtained from
0.5 g of 9b using ECA and t-BuNH2; 1.18 g i.e. 79% 19 obtained from 1.2 g of 10b using MLN and DIPA).
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When Et3N/Bu3N was used as a base with malononitrile, then both normal and abnormal
nucleophilic substitution occurred, leading to a mixture of 4- and 5-substituted multifunctional azulenes
i.e., 17/18, 19/20, 21/22 and 23/24 (Scheme 5A) for allyl, phenyl, naphthyl, and 3-thienyl 2-
methoxytropones, respectively. On using Et3N as base the ratio of the percentage of isomers as
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calculated from H NMR were found to be 19:20~65:35, 21:22~67.3:32.6, 23:24~52.1:47.9 and on using
Bu3N as base the ratios were 19:20~50:50, 21:22~72.4:27.5, and 23:24~50.5:49.4. However, 4 and 5-
substituted allyl azulene (17/18) and 4- and 5- substituted substituted naphthyl azulenes (21/22) were
obtained as an inseparable mixture.
Interesting results were obtained for the allyl substituted azulenes when malononitrile was used
as the nucleophile. When an excess of base i.e., >5 equivalent (DIPA/DIPEA/DABCO/DBU/t-
BuNH2/NaOMe), was used with malononitrile and the reaction time prolonged, the allyl bond in 17
rearranged to an internal olefin 25. When 2.3-4.3 equivalent of Et3N/Bu3N was used as a base, then in
addition to compounds 17 (26-28%) and 18 (30%), compound 26 (41-43%) was formed, obtained by the
rearrangement of allyl bond in 18 (Scheme 5B). When an excess of Et3N/Bu3N was used, then formation
of compounds 25 (55%), 18 (13-15%), and 26 (29-31%) was observed (Scheme 5B). The isomers
obtained in each set of the condition were inseparable by column chromatography and were identified
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by their characteristic signal in H NMR spectra (17: -CH2 protons at 4.15 ppm, 18: -CH2 protons at 3.59
ppm, 25: -CH3 protons at 1.74-1.76 ppm and 26: -CH3 protons at 2.06-2.08 ppm). Such base-catalyzed
isomerization is documented in literature20 and is from a thermodynamically less stable olefin into a
more stable one, which means that a terminal olefin affords the internal isomer, a non-conjugated diene
the 1,3-diene and a non-conjugated aryl-substituted olefin the corresponding styrene.
In our previous article,16 we had observed that the 7-substituted 2-methoxytropones were inert
to the reaction condition when treated with ECA and t-BuNH2 and was attributed to the reversibility of
the nucleophilic attack at the C-2 position or at other free conjugate position. Here we further explored
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the effect of nucleophile and base on the nucleophilic substitution of 7-substituted-2-methoxytropones
(1c and 9c-12c, Scheme 4). All the compounds were inert to the nucleophilic substitution by MCA/ECA
enolate when NaOMe/DABCO/DIPEA/Et3N/Bu3N/t-BuNH2/DIPA was used as a base. Surprisingly the
isomers bearing aromatic substituents (phenyl, naphthyl, and 3-thienyl) i.e., 10c, 11c, and 12c, lead to 4-
substituted azulenes i.e., 27a/b-29a/b with MCA/ECA enolate and DBU as a base (Scheme 6, left). This
anomalous reactivity is attributed to the synergistic role of DBU-MCA/ECA (ion) pair, and the aromatic
substituent (phenyl, naphthyl, and 3-thienyl) as DBU is one of the strongest amine base (leading to
strong ion-pair) and can assist in stabilizing the negative charge (carbanion) generated during the
reaction course. We also observed that the 7-substituted isomer reacts with malononitrile irrespective
of the nature of the base to give compounds 3, 17, 19, 21, and 23 in moderate yields. The products
obtained in this case also assisted us in the assignment of the products formed on reaction of MLN with
compounds 1b and 9b-12b. The enolate of MLN is more stable than that of MCA/ECA and hence are
their corresponding ion pair with bases that help in driving the azulene formation reaction for
compounds 1c and 9c-12c in the forward direction.
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Scheme 6. Effect of nucleophile and base towards nucleophilic substitution on 7-substituted 2-
methoxytropones
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CONCLUSION
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In summary, systematic investigation of azulene formation from tropolone derivative in the
presence of nucleophiles and bases of varying steric bulk and strength led us to develop new selective
synthetic strategies for 4- and 5-substituted multifunctional azulenes. The regioselective modification of
the seven-membered ring of azulene is difficult due to the subtle reactivity difference among the various
positions, and the base and nucleophile dependent azulene synthesis provides easy access to the
otherwise difficult to synthesize multifunctional azulenes. The possibility to tune the properties by
variation of the substitution on the seven-membered ring and the possibility of functional group
modifications on the five-membered ring renders the described regioselective synthesis of 4-and 5-
substituted multifunctional azulenes highly interesting in the field of organic synthesis and
optoelectronics.
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EXPERIMENTAL SECTION
Materials and Instrumentation
All reagents were obtained from commercial sources (Sigma Aldrich, Spectrochem, Merck and
Alfa Aesar) and used as received without further purification, unless otherwise specified. Toluene,
tetrahydrofuran (THF) and diethyether (Et2O) were dried over sodium/benzophenone before use.
Methanol and ethanol were dried using magnesium turning and iodine. Dry reactions were conducted in
oven-dried glassware using a standard Schlenk line under an inert atmosphere of dry nitrogen.
Tropolone was obtained from Sigma Aldrich.
1H and 13C{1H} NMR spectra were recorded at room temperature on a Jeol JNM-ECS 400
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spectrometer (400 MHz H, 100 MHz 13C) and Bruker Avance 500 (500 MHz H, 125 MHz 13C)
spectrometer with tetramethylsilane as the internal reference; chemical shifts (δ) are given in parts per
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million (ppm). Spectra were processed using Mest ReNova v5 and referenced to residual protonated
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solvent signals (CDCl3: H: 7.26 ppm, 13C{1H}: 77.16 ppm). Mass spectra were recorded on Bruker
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micrOTOF-Q II spectrometer. FT-IR spectra were recorded by Perkin–Elmer FT–IR Spectrometer. The
single crystals of compound 3 and 21 suitable for X-ray diffraction were obtained by slow evaporation of
saturated acetone solutions. The measurements on the suitable crystals were done on Agilent
SuperNova (Dual, Cu/Mo at zero, Eos) diffractometer. The structure was solved using Olex221 and
refined with the ShelXL22 refinement package using Least Squares minimization.
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Preparation of methyl ethers of substituted tropolones
Methyl Ethers of propyl, allyl, phenyl, naphthyl and 3-thienyl substituted tropolone (1b/1c, 9b/9c,
10b/10c, 11b/11c, and 12b/12c, respectively) were synthesized using the procedures reported in
literature.16,17,19 1H NMR data of all the tropolone derivatives matched with those reported earlier.
General procedure for cyclisation of methyl ethers of substituted tropolones
For reaction with amine bases:
To methoxytropone (1 mmol) dissolved in dry EtOH (10 ml), active methylene compound (2.3
mmol) was added, followed by the slow addition of amine base (2.3 mmol) under ice cooling. The
reaction mixture was stirred overnight while the temperature was allowed to rise to room temperature.
After completion of the reaction as monitored by thin layer chromatography, the solvent was
evaporated and residue extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated
and the residue was further purified by column chromatography.
For Sodium methoxide as base:
In a typical case, to a suspension of the sodium salt of Methyl cyanoacetate/Ethyl cyanoacetate
[prepared from (2 mmol) of metallic sodium and 2 mmol of the active methylene compound] in 5 mL of
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methanol was added dropwise a solution of 1 mmol of substituted 2-methoxytropone in 2 mL of
methanol at 0 °C. The reaction mixture was stirred at room temperature overnight. After completion of
the reaction as monitored by thin layer chromatography, the solvent was evaporated and residue
extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated and the residue was
further purified by column chromatography.
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Purification procedure and characterization
dimethyl 2-amino-5-propylazulene-1,3-dicarboxylate (2a)
Purification: Column chromatography using silica gel (60-120 mesh), 10% EtOAc/Hexane, orange viscous
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oil which solidifies in few hours. H NMR (400 MHz, CDCl3): δ 1.15 (t, 3H, J = 5 Hz), 1.42-1.68 (m, 2H),
2.84 (t, 2H, J = 8 Hz), 3.98 (s, 3H), 3.99 (s, 3H), 7.33-7.46 (m, 4H), 8.94-8.97 (m, 1H), 9.15 (d, 1H, J = 5 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 13.9, 29.8, 43.9, 50.8, 98.7, 125.2, 132.2, 133.3, 135.4, 139.9, 146.1,
148.9, 162.6, 166.9, 167.1. HRMS (ESI) m/z: [M+Na]+ Calcd for C17H19NO4Na 324.1212; Found: 324.1209.
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Melting point: 121-123 C, IR (ATR): 푣: 3434, 3301, 2919, 2890, 2826, 1704, 1647, 1565, 1496, 1429,
1360, 1246, 1211, 1167, 1116, 1075, 1009, 841, 784, 686, 626 cm-1.
Product yield: 50 mg of 1b was used as starting material, amount of 2a obtained from different bases:
1) NaOMe: 52 mg, 62% 2) DBU: 77 mg, 92% 3) DIPA: 72 mg, 85% 4) t-BuNH2: 76 mg, 90% 5) Bu3N:
62 mg, 74% 6) Et3N: 68 mg, 81% 7) DIPEA: No product obtained and starting material was
recovered 8) DABCO: No product obtained and starting material was recovered.
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diethyl 2-amino-5-propylazulene-1,3-dicarboxylate (2b)
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Purification: Column chromatography using silica gel (60-120 mesh), 15% EtOAc/Hexane, orange viscous
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oil which solidifies in few hours. H NMR (400 MHz, CDCl3): δ 1.00 (t, 3H, J = 8 Hz), 1.45-1.48 (m, 6H),
1.76-1.80 (m, 2H), 2.82 (t, 2H, J = 8 Hz), 4.43-4.47 (m, 4H), 7.31 (d, 1H, J = 8 Hz), 7.43 (t, 1H, J = 8 Hz),
7.75 (s, 2H), 8.98 (d, 1H, J = 8 Hz), 9.17 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 13.8, 14.7, 14.8, 25.6,
43.9, 59.7, 59.8, 98.8, 99.0, 130.1, 132.1, 133.1, 134.2, 145.8, 146.2, 148.4, 162.7, 166.6, 166.7. HRMS
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(ESI) m/z: [M+Na]+ Calcd for C19H23NO4Na 352.1525; Found: 352.1521. Melting point: 96-98 C, IR (ATR):
푣: 3401, 3288, 2918, 2891, 2825, 1640, 1556, 1491, 1441, 1407, 1352, 1318, 121, 1147, 1107, 1066, 862,
754, 679, 586 cm-1.
Product yield: 50 mg of 1b was used as starting material, amount of 2b obtained from different bases:
1) NaOMe: 61 mg, 66% 2) DBU: 79 mg, 86% 3) DIPA: 83 mg, 90% 4) t-BuNH2: 81 mg, 88% 5) Bu3N:
69 mg, 75% 6) Et3N: 77 mg, 84% 7) DIPEA: No product obtained and starting material was
recovered 8) DABCO: No product obtained and starting material was recovered.
2-amino-4-propylazulene-1,3-dicarbonitrile (3)
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Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid.
1H NMR (400 MHz,CDCl3): δ 1.13 (t, 3H, J = 10 Hz), 1.82-1.90 (m, 2H), 3.37-3.41 (2H, m), 5.56 (bs, 2H),
7.51-7.52 (m, 3H), 8.18-8.26 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 13.5, 25.4, 40.8, 81.4, 83.4, 115.2,
117.2, 130.9, 132.2, 134.8, 136.3, 141.5, 145.8, 149.3, 160.2. HRMS (ESI) m/z: [M+Na]+ Calcd for
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C15H13N3Na 258.1007; Found: 258.1003. Melting point: 227-229 C, IR (ATR): 푣: 3285, 3175, 2907, 2830,
2158, 1626, 1498, 1370, 1294, 1170, 971, 885, 719, 685, 562 cm-1.
Product yield:
When 50 mg of 1b was used as starting material, amount of 3 obtained from different bases:
1) NaOMe: 43 mg, 65% 2) DBU: 61 mg, 93% 3) DIPA: 57 mg, 87% 4) t-BuNH2: 58 mg, 89% 5) DIPEA:
47 mg, 71% 6) DABCO: 42 mg, 64%
When 100 mg of 1c was used as starting material, amount of 3 obtained from different bases:
1) NaOMe: 13 mg, 10% 2) DBU: 46 mg, 35% 3) DIPA: 48 mg, 37% 4) t-BuNH2: 41 mg, 31% 5) Bu3N:
35 mg, 27% 6) Et3N: 26 mg, 20% 7) DIPEA: 31 mg, 24% 8) DABCO: 11 mg, 8%
2-amino-5-propylazulene-1,3-dicarbonitrile (4)
Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid.
1H NMR (400 MHz, CDCl3): δ 1.01 (t, 3H, J = 10 Hz), 1.73-1.82 (m, 2H), 2.85 (t, 2H, J = 10 Hz), 5.55 (bs,
2H), 7.52-7.54 (m, 2H), 8.05-8.08 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 13.8, 25.8, 43.5, 81.8, 81.9,
115.2, 115.3, 129.9, 131.8, 132.9, 136.4, 145.4, 145.8, 148.9, 159.6. HRMS (ESI) m/z: [M+Na]+ Calcd for
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C15H13N3Na 258.1007; Found: 258.1002. Melting point: 182-184 C, IR (ATR): 푣: 3301, 3152, 2923, 2885,
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2819, 2176, 1643, 1515, 1407, 1294, 1191, 1075, 857, 775, 598 cm-1.
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Product yield: When 100 mg of 1b was used as starting material, amount of 4 obtained on using Et3N
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and Bu3N as bases:
1) Et3N: 42 mg, 32% 2) Bu3N: 39 mg, 30%
2-amino-4-propylazulene-1,3-dicarbonitrile and 2-amino-5-propylazulene-1,3-dicarbonitrile (3+4)
Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid,
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mixture of 3 and 4. Characteristic peak: H NMR (400 MHz, CDCl3): δ 2.84 (t, 1H, J = 8 Hz) from
compound 3 and 3.36-3.40 (m, 2H) from compound 4.
Product yield: When 100 mg of 1b was used as starting material, amount of 3 and 4 obtained on using
Et3N and Bu3N as bases:
1) Et3N; 3: 84 mg, 64%, 4: 42 mg, 32% 2) Bu3N; 3: 88 mg, 67%, 4: 39 mg, 30%
dimethyl 5-allyl-2-aminoazulene-1,3-dicarboxylate (13a)
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Purification: Column chromatography using silica gel (60-120 mesh), 15% EtOAc/Hexane, orange viscous
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oil which solidifies in few hours. H NMR (400 MHz, CDCl3): δ 3.98 (s, 6H), 5.16-5.21 (m, 2H), 5.99-6.11
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(m, 1H), 7.35-7.51 (m, 2H), 7.72 (bs, 1H), 7.79 (bs, 1H), 8.98 (d, 1H, J = 8 Hz), 9.14 (s, 1H). 13C{1H} NMR
(100 MHz, CDCl3): δ 46.0, 50.2, 90.1, 99.3, 116.9, 130.2, 132.1, 133.0, 134.0, 134.4, 137.1, 137.6, 145.3,
146.1, 162.8, 166.8, 167.3. HRMS (ESI) m/z: [M+Na]+ Calcd for C17H17NO4Na 322.1055; Found: 322.1051.
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Melting point: 92-95 C, IR (ATR): 푣: 3418, 3300, 3039, 2910, 2881, 2817, 1708, 1650, 1555, 1487, 1422,
1366, 1165, 1106, 1011, 907, 781, 686 cm-1
Product yield: 50 mg of 9b was used as starting material, amount of 13a obtained from different bases:
1) NaOMe: 40 mg, 48% 2) DBU: 66 mg, 78% 3) DIPA: 63 mg, 75% 4) t-BuNH2: 68 mg, 81% 5) Bu3N:
52 mg, 62% 6) Et3N: 62 mg, 74% 7) DIPEA: No product obtained and starting material was
recovered 8) DABCO: No product obtained and starting material was recovered.
diethyl 5-allyl-2-aminoazulene-1,3-dicarboxylate (13b)
Purification: Column chromatography using silica gel (60-120 mesh), 5% EtOAc/Hexane, orange solid. 1H
NMR (400 MHz, CDCl3): δ 1.46-1.50 (m, 6H), 3.63 (d, 2H. J = 8 Hz), 4.41-4.47 (m, 4H), 5.15-5.21 (m, 2H),
6.01-6.10 (m, 1H), 7.34 (d, 1H, J = 8 Hz), 7.44 (t, 1H, J = 8 Hz), 7.79 (bs, 2H), 9.01 (d, 1H, J = 8 Hz), 9.16 (d,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 14.6, 14.7, 45.7, 59.8, 99.1, 99.2, 116.9, 130.1, 132.0, 133.9,
133.0, 137.0, 145.3, 145.4, 146.0, 162.7, 166.6. HRMS (ESI) m/z: [M+Na]+ Calcd for C19H21NO4Na
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350.3698; Found: 350.3695. Melting point: 68-70 C, IR (ATR): 푣: 3441, 3304, 2944, 2877, 1725, 1642,
1568, 1481, 1403, 1250, 1203, 1140, 1100, 1077, 1014, 904, 783, 692, 645 cm-1.
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Product yield: 50 mg of 9b was used as starting material, amount of 13b obtained from different bases:
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1) NaOMe: 42 mg, 45% 2) DBU: 65 mg, 70% 3) DIPA: 63 mg, 68% 4) t-BuNH2: 69 mg, 75% 5) Bu3N:
60 mg, 65% 6) Et3N: 64 mg, 69% 7) DIPEA: No product obtained and starting material was
recovered 8) DABCO: No product obtained and starting material was recovered.
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Half-gram scale synthesis: To 0.5 g (2.83 mmol) 9b dissolved in dry EtOH (25 ml), ethylcyano acetate
(735 mg, 6.5 mmol) was added, followed by the slow addition of t-BuNH2 (476 mg, 6.5 mmol) under ice
cooling. The reaction mixture was stirred overnight while the temperature was allowed to rise to room
temperature. After completion of the reaction as monitored by thin layer chromatography, the solvent
was evaporated and residue extracted with ethyl acetate and dried with Na2SO4. The solvent was
evaporated and the residue was further purified by column chromatography to give 13b as orange solid
(0.62 g, 68% yield).
dimethyl 2-amino-5-phenylazulene-1,3-dicarboxylate (14a)
Purification: Column chromatography using silica gel (60-120 mesh), 15% EtOAc/Hexane, orange solid.
1H NMR (500 MHz, CDCl3): δ 3.97 (s, 3H), 4.00 (s, 3H), 7.41-7.70 (m, 9H), 9.05 (d, 1H, J = 10 Hz), 9.51 (s,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 51.1, 99.7, 100.2, 125.1, 128.0, 128.6, 129.0, 130.5, 132.3, 132.4,
144.7, 145.5, 146.0, 146.3, 167.0, 167.1. HRMS (ESI) m/z: [M+Na]+ Calcd for C20H17NO4Na 358.1055;
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Found: 358.1052. Melting point: 128-129 C, IR (ATR): 푣: 3425, 3304, 2911, 2884, 2816, 1645, 1559,
1470, 1419, 1362, 1260, 1152, 1095, 996, 831, 780, 736, 678 cm-1.
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Product yield: 50 mg of 10b was used as starting material, amount of 14a obtained from different bases:
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1) NaOMe: 49 mg, 62% 2) DBU: 71 mg, 90% 3) DIPA: 66 mg, 84% 4) t-BuNH2: 68 mg, 87% 5) Bu3N:
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62 mg, 79% 6) Et3N: 64 mg, 81% 7) DIPEA: 9 mg, 12% 8) DABCO: 8 mg, 10%.
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diethyl 2-amino-5-phenylazulene-1,3-dicarboxylate (14b)
Purification: Column chromatography using silica gel (60-120 mesh), 15% EtOAc/Hexane, orange solid.
1H NMR (400 MHz, CDCl3): δ 1.44-1.50 (m, 6H), 4.41-1.50 (m, 6H), 7.40-7.43 (m, 1H), 7.49 (t, 2H, J = 10
Hz), 7.58 (t, 1H, J = 10 Hz), 7.69-7.70 (m, 3H), 7.83 (bs, 2H), 9.06 (d, 1H, J = 12 Hz), 9.53 (s, 1H, J = 1.6 Hz).
13C{1H} NMR (100 MHz, CDCl3): δ 14.6, 14.8, 59.9, 99.7, 100.2, 128.0, 128.5, 128.9, 130.4, 132.1, 132.3,
132.9, 144.4, 145.2, 145.9, 146.0, 162.9, 166.6, 166.7. HRMS (ESI) m/z: [M+Na]+ Calcd for C22H21NO4Na
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386.1368; Found: 386.1343. Melting point: 104-106 C, IR (ATR): 푣: 3454, 3307, 2938, 2888, 2822, 1640,
1573, 1479, 1416, 1268, 1141, 1094, 1014, 927, 870, 840, 776, 746, 686 cm-1.
Product yield: 50 mg of 10b was used as starting material, amount of 14b obtained from different bases:
1) NaOMe: 54 mg, 64% 2) DBU: 77 mg, 91% 3) DIPA: 71 mg, 84% 4) t-BuNH2: 76 mg, 89% 5) Bu3N:
66 mg, 78% 6) Et3N: 70 mg, 82% 7) DIPEA: 7 mg, 8% 8) DABCO: 8 mg, 10%.
dimethyl 2-amino-5-(naphthalen-1-yl)azulene-1,3-dicarboxylate (15a)
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Purification: Column chromatography using silica gel (60-120 mesh), 15% EtOAc/Hexane, orange solid.
1H NMR (500 MHz, CDCl3): δ 3.8 (s, 3H), 4.04 (s, 3H), 7.44-7.65 (m, 6H), 7.83-7.95 (m, 5H), 9.15 (t, 1H, J =
10 Hz), 9.36 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 51.0, 51.1, 100.2, 125.1, 125.3, 125.9, 126.1, 126.5,
127.5, 128.4, 128.5, 130.8, 131.5, 131.8, 134.2, 135.3, 135.8, 142.9, 144.8, 145.4, 146.1, 162.8, 166.8.
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HRMS (ESI) m/z: [M+Na]+ Calcd for C24H19NO4Na 408.1212; Found: 408.1209. Melting point: 157-159 C,
IR (ATR): 푣: 3437, 3310, 3011, 2912, 2879, 2814, 1672, 1638, 1549, 1480, 1422, 1360, 1244, 1165, 1107,
1042, 1008, 946, 839, 785, 757, 651 cm-1.
Product yield: 50 mg of 11b was used as starting material, amount of 15a obtained from different bases:
1) NaOMe: 43 mg, 59% 2) DBU: 66 mg, 91% 3) DIPA: 61 mg, 84% 4) t-BuNH2: 64 mg, 88% 5) Bu3N:
55 mg, 75% 6) Et3N: 58 mg, 80% 7) DIPEA: 5 mg, 7% 8) DABCO: 7 mg, 9%.
diethyl 2-amino-5-(naphthalen-1-yl)azulene-1,3-dicarboxylate (15b)
Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid.
1H NMR (400 MHz, CDCl3): δ 1.16 (t, 3H, J = 8 Hz), 1.52 (t, 3H, J = 8 Hz), 4.26-4.53 (m, 4H), 7.43-7.60 (m,
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6H), 7.85-7.92 (m, 5H), 9.16-9.19 (m, 1H), 9.44 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 14.2, 14.7, 59.7,
59.9, 125.3, 125.9, 126.0, 127.4, 128.3, 128.4, 130.7, 131.4, 131.7, 133.9, 134.4, 135.3, 142.8, 144.8,
145.3, 146.0, 162.9, 166.6. HRMS (ESI) m/z: [M+Na]+ Calcd for C26H23NO4Na 436.1525; Found: 436.1521.
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Melting point: 102-105 C, IR (ATR): 푣: 3444, 3294, 3015, 2935, 2881, 2820, 1643, 1569, 1479, 1407,
1359, 1147, 1093, 1006, 928, 860, 764, 689, 638, 551 cm-1.
Product yield: 50 mg of 11b was used as starting material, amount of 15b obtained from different bases:
1) NaOMe: 47 mg, 60% 2) DBU: 71 mg, 91% 3) DIPA: 69 mg, 88% 4) t-BuNH2: 70 mg, 90% 5) Bu3N:
63 mg, 81% 6) Et3N: 67 mg, 85% 7) DIPEA: 9 mg, 12% 8) DABCO: 7 mg, 9%.
dimethyl 2-amino-5-(thiophen-3-yl)azulene-1,3-dicarboxylate (16a)
Purification: Column chromatography using silica gel (60-120 mesh), 15% EtOAc/Hexane, orange solid.
1H NMR (400 MHz, CDCl3): δ 4.00 (s, 3H), 4.00 (s, 3H), 7.45-7.58 (m, 4H), 7.63-7.74 (m, 1H), 7.65-7.78 (m,
3H), 8.98 (d, 1H, J = 1H), 9.615 (d, 1H, J = 4 Hz) 13C{1H} NMR (100 MHz, CDCl3): δ 51.1, 51.3, 99.7, 100.1,
123.2, 127.4, 130.3, 131.2, 132.0, 132.3, 140.4, 145.6, 146.1, 162.5, 166.6, 167.2. HRMS (ESI) m/z:
[M+Na]+ Calcd for C18H15NO4SNa 364.0619; Found: 364.0613. Melting point: 152-153 C, IR (ATR): 푣:
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3389, 3272, 3064, 2883, 2819, 1254, 1574, 1540, 1483, 1423, 1356, 1319, 1212, 1155, 1075, 1041, 964,
914, 840, 773, 716, 676, 555, 512 cm-1
Product yield: 50 mg of 12b was used as starting material, amount of 16a obtained from different
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Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid.
1H NMR (400 MHz, CDCl3): δ 1.47-1.52(m, 6H), 4.43-4.49 (m, 4H), 7.41-7.61 (m, 4H), 7.72 (d, 1H, J = 8
Hz), 7.81 (bs, 2H), 8.99 (d, 1H, J = 12 Hz), 9.61 (d, 1H, J = 4 Hz). 13C{1H} NMR (100 MHz, CDCl3): δ 14.8,
59.8, 99.8, 100.0, 123.0, 126.8, 127.4, 130.2, 131.1, 131.7, 132.1, 140.1, 145.4, 145.6, 146.0, 162.9,
166.6, 166.7 HRMS (ESI) m/z: [M+Na]+ Calcd for C20H19NO4SNa 392.0932; Found: 392.0925. Melting
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point: 101-104 C, IR (ATR): 푣: 3445, 3301, 3060, 2883, 2822, 1725, 1637, 1553, 1480, 1421, 1359, 1271,
1139, 1088, 1019, 916, 843, 773, 678, 586, 531 cm-1.
Product yield: 50 mg of 12b was used as starting material, amount of 16b obtained from different bases:
1) NaOMe: 45 mg, 54% 2) DBU: 66 mg, 78% 3) DIPA: 68 mg, 81% 4) t-BuNH2: 67 mg, 79% 5) Bu3N:
57 mg, 68% 6) Et3N: 60 mg, 72% 7) DIPEA: 11 mg, 13% 8) DABCO: 7 mg, 8%.
4-allyl-2-aminoazulene-1,3-dicarbonitrile (17)
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Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid.
1H NMR (400 MHz, CDCl3): δ 4.22 (d, 2H, J = 8 Hz), 5.10-5.22 (m, 2H), 5.57 (bs, 2H), 6.11-6.17 (m, 1H),
7.51-7.56 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 41.8, 81.7, 83.5, 115.2, 117.3, 117.8, 131.3, 132.1,
134.7, 135.2, 136.2, 141.6, 145.6, 146.0, 160.7. HRMS (ESI) m/z: [M+Na]+ Calcd for C15H11N3Na
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256.0851; Found: 256.0848. Melting point: 178-180 C, IR (ATR): 푣: 3287, 3181, 2884, 2815, 2169, 1625,
1504, 1443, 1385, 1301, 1178, 1104, 981, 904, 725, 571 cm-1.
Product yield:
When 50 mg of 9b was used as starting material, amount of 17 obtained from different bases:
1) NaOMe: 34 mg, 52% 2) DBU: 57 mg, 87% 3) DIPA: 55 mg, 84% 4) t-BuNH2: 59 mg, 89% 5) DIPEA:
47, 71% 6) DABCO: 43, 65%
When 100 mg of 9c was used as starting material, amount of 17 obtained from different bases:
1) NaOMe: 16 mg, 12% 2) DBU: 47 mg, 36% 3) DIPA: 50 mg, 38% 4) t-BuNH2: 53 mg, 40% 5) Bu3N:
33 mg, 25% 6) Et3N: 27 mg, 21% 7) DIPEA: 39 mg, 30% 8) DABCO: 20 mg, 15%
5-allyl-2-aminoazulene-1,3-dicarbonitrile (18)
Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid.
1H NMR (400 MHz,CDCl3) The compound was obtained as mixture with 17 and 26 and could not be
separated using column chromatography. Characteristic peak for compound 18 is a doublet at 3.64 ppm
from the allylic -CH2 connected to the aromatic centre.
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Product yield: Estimated from 1H NMR as the product was inseparable from the mixture
1) Et3N: 30% 2) Bu3N: 31% On using excess base: 1) Et3N: 13% 2) Bu3N: 15%
(E)-2-amino-4-(prop-1-en-1-yl)azulene-1,3-dicarbonitrile (25)
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Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid.
1H NMR (400 MHz, CDCl3): δ 1.75 (dd, 3H, J = 12 Hz), 5.62 (bs, 2H), 6.19-6.25 (m, 1H), 7.18 (dd, 1H, J = 8
Hz), 7.45-7.55 (m, 3H), 8.18-8.21 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 21.2, 60.5, 83.0, 115.2, 116.8,
129.9, 131.2, 131.8, 132.4, 134.0, 135.4, 141.0, 145.8, 160.4. HRMS (ESI) m/z: [M+Na]+ Calcd for
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C15H11N3Na 256.0851; Found: 256.0843. Melting point: 276-278 C, IR (ATR): 푣: 3328, 3280, 3180, 2880,
2816, 2162, 1622, 1502, 1382, 1298, 1178, 1128, 998, 945, 728, 598 cm-1.
Product yield: When 50 mg of 9b was used as starting material, amount of 25 obtained from different
bases:
1) NaOMe: 38 mg, 58% 2) DBU: 55 mg, 84% 3) DIPA: 59 mg, 89% 4) t-BuNH2: 53 mg, 81% 5) DIPEA:
51 mg, 78% 6) DABCO: 41 mg, 62%
4-allyl-2-aminoazulene-1,3-dicarbonitrile (17) + 5-allyl-2-aminoazulene-1,3-dicarbonitrile (18) + (E)-2-
amino-5-(prop-1-en-1-yl)azulene-1,3-dicarbonitrile (26)
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Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid
(The compounds were inseparable by column chromatography and were identified by their
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characteristic peak in H NMR) H NMR (400 MHz, CDCl3): δ 17: -CH2 protons at 4.15 ppm, 18: -CH2
protons at 3.59 ppm, 26: -CH3 protons at 2.06-2.08 ppm. IR (ATR) of the mixture (17+18+26): 푣: 3287,
3178, 2880, 2820, 2165, 1629, 1504, 1396, 1297, 1182, 1140, 993, 958, 904, 786, 757, 728, 581 cm-1.
Product yield: Estimated from 1H NMR as the mixture was inseparable.
1) Et3N, 17: 28%, 18: 30%, 26: 41% 2) Bu3N, 17: 26%, 18: 31%, 26: 43%
(E)-2-amino-4-(prop-1-en-1-yl)azulene-1,3-dicarbonitrile
(25)
+
5-allyl-2-aminoazulene-1,3-
dicarbonitrile (18) + (E)-2-amino-5-(prop-1-en-1-yl)azulene-1,3-dicarbonitrile (26)
Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid
(The compounds were inseparable by column chromatography and were identified by their
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characteristic peak in 1H NMR) H NMR (400 MHz, CDCl3): δ 25: -CH3 protons at 1.74-1.76 ppm 18: -CH2
protons at 3.59 ppm, 26: -CH3 protons at 2.06-2.08 ppm. IR (ATR) of the mixture (25+18+26): 푣: 3295,
3174, 2883, 2815, 2167, 1629, 1507, 1397, 1297, 1188, 1139, 943, 899, 759, 715, 571 cm-1.
Product yield: Estimated from 1H NMR as the mixture was inseparable.
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1) Et3N, 25: 55%, 26: 31%, 18: 13% 2) Bu3N, 25: 55%, 26: 29%, 18: 15%
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2-amino-4-phenylazulene-1,3-dicarbonitrile (19)
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Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid.
1H NMR (400 MHz, CDCl3): δ 5.53 (bs, 2H), 7.39-7.41 (m, 2H), 7.50-7.59 (m, 6H), 8.28-8.30 (m, 1H).
13C{1H} NMR (125 MHz, CDCl3): δ 83.7, 114.0, 115.1, 128.6, 129.3, 129.4, 131.2, 132.0, 134.0, 135.6,
141.4, 146.5, 147.2, 152.2, 160.6, 163.7. HRMS (ESI) m/z: [M+Na]+ Calcd for C18H11N3Na 292.0851;
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Found: 292.0848. Melting point: 306-309 C, IR (ATR): 푣: 3294, 3168, 2889, 2850, 2167, 1630, 1507,
1388, 1172, 1061, 1009, 875, 737, 708, 686, 577 cm-1.
Product Yield:
When 50 mg of 10b was used as starting material, amount of 19 obtained from different bases:
1) NaOMe: 38 mg, 61% 2) DBU: 59 mg, 94% 3) DIPA: 54 mg, 85% 4) t-BuNH2: 58 mg, 92% 5) DIPEA:
50 mg, 79% 6) DABCO: 41 mg, 65%
When 100 mg of 10c was used as starting material, amount of 19 obtained from different bases:
2) NaOMe: 31 mg, 25% 2) DBU: 78 mg, 62% 3) DIPA: 72 mg, 57% 4) t-BuNH2: 68 mg, 54% 5) Bu3N:
57 mg, 45% 6) Et3N: 59 mg, 47% 7) DIPEA: 46 mg, 40% 8) DABCO: 36 mg, 31%
Gram scale synthesis: To 1.2 g (5.6 mmol) 10b dissolved in dry EtOH (40 ml), malononitrile (0.85 g, 12.8
mmol) was added, followed by the slow addition of DIPA (1.29 g, 1.8 mL, 12.8 mmol) under ice cooling.
The reaction mixture was stirred overnight while the temperature was allowed to rise to room
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temperature. After completion of the reaction as monitored by thin layer chromatography, the solvent
was evaporated and residue extracted with ethyl acetate and dried with Na2SO4. The solvent was
evaporated and the residue was further purified by column chromatography to give 19 as orange solid
(1.18 g, 79% yield).
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2-amino-5-phenylazulene-1,3-dicarbonitrile (20)
Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid.
1H NMR (400 MHz,CDCl3): δ 5.66 (bs, 2H), 7.48-7.53 (m, 3H), 7.63-7.70 (m, 3H), 7.845 (dd, 1H, J = 12 Hz),
8.14 (d, 1H, J = 8 Hz), 8.358 (d, 1H, J = 4 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 82.5, 83.4, 108.8, 109.1,
109.8, 115.1, 115.2, 128.6, 128.8, 129.3, 130.2, 131.9, 135.6, 143.0, 145.2, 145.8, 146.6, 159.8 HRMS
(ESI) m/z: [M+Na]+ Calcd for C18H11N3Na 292.0851; Found: 292.0849. Melting point: 192-194 C, IR (ATR):
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푣: 3309, 3180, 2890, 2827, 2176, 1642, 1521, 1408, 1362, 1291, 1189, 1068, 992, 864, 792, 743, 682,
550 cm-1.
Product yield: When 100 mg of 10b was used as starting material, amount of 20 obtained on using Et3N
and Bu3N as bases:
1) Et3N: 43 mg, 34% 2) Bu3N: 61 mg, 48%
2-amino-4-phenylazulene-1,3-dicarbonitrile and 2-amino-5-phenylazulene-1,3-dicarbonitrile (19+20)
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Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid,
mixture of 19 and 20. Characteristic peak: 1H NMR (400 MHz, CDCl3):
Reaction with Et3N: 5.54 (bs, 2H) for compound 19 and 5.64 (bs, 2H) for compound 20 Reaction with
Bu3N: 5.52 (bs, 2H) for compound 19 and 5.61 (bs, 1H) for compound 20
Product yield: When 100 mg of 10b was used as starting material, amount of 19 and 20 obtained on
using Et3N and Bu3N as bases:
1) Et3N; 19: 78 mg, 62%, 20: 43 mg, 34% 2) Bu3N; 19: 55 mg, 44%, 20: 61 mg, 48%
2-amino-4-(naphthalen-1-yl)azulene-1,3-dicarbonitrile (21)
Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid.
1H NMR (400 MHz, CDCl3): δ 5.44 (s, 2H), 7.22 (d, 1H, J = 8 Hz), 7.36 (t, 1H, J = 8 Hz), 7.47-7.67 (m, 6H),
7.99 (d, 1H, J = 8 Hz), 8.09 (d, 1H, J = 8 Hz), 8.35 (d, 1H, J = 8 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 83.7,
84.4, 113.6, 115.1, 124.9, 125.1, 126.4, 126.9, 127.5, 128.9, 130.0, 131.6, 132.0, 132.2, 133.5, 134.0,
138.5, 143.1, 145.2, 146.2, 160.5. HRMS (ESI) m/z: [M+Na]+ Calcd for C22H13N3Na 342.1007; Found:
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342.1003. Melting point: 274-276 C, IR (ATR): 푣: 3300, 3148, 3019, 2880, 2173, 1638, 1504, 1381, 1178,
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Product yield:
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When 50 mg of 11b was used as starting material, amount of 21 obtained from different bases:
1) NaOMe: 37 mg, 62% 2) DBU: 54 mg, 90% 3) DIPA: 55 mg, 91% 4) t-BuNH2: 53 mg, 88% 5) DIPEA:
49 mg, 81% 6) DABCO: 45 mg, 75%
When 100 mg of 11c was used as starting material, amount of 21 obtained from different bases:
1) NaOMe: 14 mg, 12% 2) DBU: 53 mg, 44% 3) DIPA: 55 mg, 45% 4) t-BuNH2: 47 mg, 39% 5) Bu3N:
37 mg, 31% 6) Et3N: 45 mg, 37% 7) DIPEA: 35 mg, 29% 8) DABCO: 18 mg, 15%
2-amino-4-(naphthalen-1-yl)azulene-1,3-dicarbonitrile and 2-amino-5-(naphthalen-1-yl)azulene-1,3-
dicarbonitrile (21+22)
Purification: Column chromatography using silica gel (60-120 mesh), 20% EtOAc/Hexane, orange solid,
mixture of 21 and 22. Characteristic peak: 1H NMR (400 MHz, CDCl3):
Reaction with Et3N: 5.48 (bs, 2H) for compound 21 and 5.67 (bs, 1H) for compound 22 Reaction with
Bu3N: 5.49 (bs, 2H) for compound 21 and 5.69 (bs, 0.76H) for compound 22. IR (ATR) of mixture
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