Beyond a Protecting Reagent: DMAP-Catalyzed Cyclization of Boc-Anhydride with 2-Alkenylanilines

Article abstract of DOI:10.1021/acs.joc.6b00519

A novel rapid synthesis of quinolines from 2-alkenylanilines has been described; the reaction involves an unexpected DMAP-catalyzed cyclization of 2-alkenylanilines with di-tert-butyl dicarbonate (Boc₂O, 2.0 equiv), and a series of tert-butyl quinolin-2-yl carbonate with various functional groups have been synthesized in good yields under mild conditions. Furthermore, the tert-butyl quinolin-2-yl carbonate can be easily converted into corresponding quinolinones and 2-(pseudo)haloquinolines.

Full text of DOI:10.1021/acs.joc.6b00519

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Article
Beyond a Protecting Reagent: DMAP-catalyzed
Cyclization of Boc-anhydride with 2-Alkenylanilines
Ya-Nan Huang, Yin-Long Li, Jian Li, and JUN DENG
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00519 • Publication Date (Web): 10 May 2016
Downloaded from http://pubs.acs.org on May 11, 2016
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Beyond a Protecting Reagent: DMAP-catalyzed
Cyclization of Boc-anhydride with 2-Alkenylanilines
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YaꢀNan Huang, YinꢀLong Li, Jian Li, Jun Deng*
School of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug
Delivery & HighꢀEfficiency, Tianjin University, Tianjin, 300072 P. R. China
Eꢀmail: jdeng@tju.edu.cn
ABSTRACT:
A novel rapid synthesis of quinolines from 2ꢀalkenylanilines has been described, the
reaction involves an unexpected DMAPꢀcatalyzed cyclization of 2ꢀalkenylanilines
with diꢀtertꢀbutyl dicarbonate (Boc2O, 2.0 equiv), and a series of tertꢀbutyl
quinolinꢀ2ꢀyl carbonate with various functional groups have been synthesized in good
yields under mild conditions. Furthermore, the tertꢀbutyl quinolinꢀ2ꢀyl carbonate can
be easily converted into corresponding quinolinones and 2ꢀ(pseudo)haloquinolines.
INTRODUCTION
Quinolines and their derivatives are present in a wide range of pharmaceuticals and
natural products with unique biological activities, and have received considerable
attention from the organic and medicinal chemistry community (Figure 1).1 Although
many strategies for the construction of the quinoline ring have been developed,2
including several classic name reactions such as Combes, Skraup, DöbnerꢀVon Miller,
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ConradꢀLimpach, Pfitzinger, Friedländer and Povarov reactions, etc.3 Given the
importance of quinolines and quinolinones as the pharmacologically active substances,
the development of more practical and effective process for the synthesis is still in
great demand.
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Figure 1. Representative Bioactive Quinolines and 2-Quinolinones
As an extremely efficient protecting reagent, diꢀtertꢀbutyl dicarbonate
(Bocꢀanhydride) has been extensively applied for the protection of amine, alcohol and
thiol functional groups due to its easily introduced and removed, especially in peptide
synthesis.4 In some cases, it has also been used for the conversion of amines to
corresponding isocyanates,5 carbamates6 and urea derivatives.7 Our laboratory is
engaged in developing transitionꢀmetalꢀfree methods for the synthesis of heterocycles,
especially through new C–N, C–O bond formation.8 Herein, we wish to report our
discovery that the reaction of substituted 2ꢀvinylanilines with diꢀtertꢀbutyl dicarbonate
in the presence of a catalytic amount of 4ꢀdimethylaminopyridine (DMAP) at room
temperature leads to tertꢀbutyl quinolinꢀ2ꢀyl carbonates. Although various approaches
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to quinolines and their derivatives starting from 2ꢀalkenylanilines have already been
reported,9 however, to the best of our knowledge, diꢀtertꢀbutyl dicarbonate as the
carbon source for the synthesis of these heterocyclic compounds is rarely reported.
More importantly, the tertꢀbutyl quinolinꢀ2ꢀyl carbonates can be easily converted into
quinolinones which possess interesting pharmacological, biological activities,10 and
have provided a huge driving force for chemists to develop efficient methods for their
synthesis.11 On the other hand, tertꢀbutyl quinolinꢀ2ꢀyl carbonates also serve as
valuable synthetic intermediates in organic synthesis by simply transformed into
2ꢀ(pseudo)haloquinolines (e.g., 2ꢀCl), which can readily undergo a broad variety of
functionalizations such as nucleophilic aromatic substitutions and coupling
reactions.12
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RESULTS AND DISCUSSION
Table 1. Optimization of Reaction Conditionsa
entry
catalyst loading (mol%)
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
yield (%)b
1
2
3
4
20
10
5
81
79
81
76
1
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0
CH2Cl2
DMSO
0
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5
55
65
80
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65
35
79
7
CH3CN
dichloroethane
THF
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Et2O
DMF
toluene
1,4ꢀdioxane
EtOAc
14
15 c
16d
17e
18f
5
5
5
5
5
21
69
56
84
80
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
aReaction conditions: 1a (0.20 mmol), Boc2O (2.0 equiv), solvent (2.0 mL), 1.0 h at
b
c
d
o
rt; Isolated yield; 1.5 equiv Boc2O was used; reaction was run at 0 C for 12 h;
ereaction was run at reflux for 1 h; freaction time was 12 h.
We commenced our studies by using 2ꢀ(1ꢀphenylvinyl)aniline 1a as the model
substrate to search for the optimal reaction conditions (Table 1). Treatment of 1a with
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2 equiv of Boc2O in the presence of 20 mol% of DMAP catalyst resulted in tertꢀbutyl
quinolinꢀ2ꢀyl carbonate as a major product in 81% yield after 1.0 h (entry 1) and the
structure of compound 2a was further confirmed by Xꢀray crystallography (Figure 2).
While decreasing the catalyst loading from 20 mol% to 5 mol% can give the desired
products with similar yields (entries 2 to 3), a further decrease of the catalyst loading
to 1 mol%, the reaction still took place smoothly to provide the desired product with
slightly lower yield (76%, entry 4). However, the reaction cannot occur in the absence
of catalyst and only the starting material was recovered (entry 5). On the other hand,
alteration of key operating parameters (e.g., extending reaction time, elevating or
lowering temperatures) was also examined, but there were no significant impact on
the yields (entries 16 to 18). Solvents other than CH2Cl2, dichloroethane and
1,4ꢀdioxane were less effective in delivering the desired tertꢀbutyl quinolinꢀ2ꢀyl
carbonates (entries 6 to 14) although the starting materials were completely converted,
thus implying that the selectivity becomes poor upon these variations. It was
interesting to observe that when reduced the loading of Boc2O to 1.5 equiv, the
reaction successfully gave the product with reasonable yield along with a small
amount of quinolinone 7 (entry 15).
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Figure 2. X-ray Crystallography of Compound 2a
Table 2. Scope of 2-Alkenylanilinesa
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entry
1
substrate
1a
R2
Ph
time (h)
product
2a
2b
2c
yield (%)b
81
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1
1
2
2ꢀMeO
3ꢀMeO
4ꢀMeO
ꢀ
ꢀ
ꢀ
C6H4
C6H4
C6H4
80
1b
1c
3
3
55
4
2.5
5
82
1d
1e
2d
2e
5
2ꢀMe
3ꢀMe
4ꢀMe
ꢀ
ꢀ
ꢀ
C6H4
C6H4
C6H4
71
6
3
76
1f
2f
7
3
68
1g
2g
2h
2i
8
3ꢀF
ꢀ
ꢀ
C6H4
C6H4
5
64
1h
1i
9
4ꢀF
3
76
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3ꢀCl
4ꢀCl
ꢀ
C6H4
C6H4
7
53
1j
2j
ꢀ
3
74
1k
1l
2k
2l
3ꢀCF3
ꢀ
C6H4
5
58
1ꢀnaphthyl
2ꢀnaphthyl
2ꢀthienyl
Me
5
71
1m
1n
1o
2m
2n
2o
2p
2q
2r
4
73
1.5
0.5
2
81
50
1p
1q
1r
nꢀBu
92
4ꢀNO2ꢀC6H4
30
27
aReaction conditions: 1 (0.20 mmol), Boc2O (2.0 equiv), DMAP (5 mol%), CH2Cl2
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(2.0 mL), rt; bisolated yield.
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With the optimal conditions in hand [5 mol% DMAP, 2.0 equiv of Boc2O,
CH2Cl2, rt], the scope of 2ꢀalkenylanilines bearing substituents at each position was
studied (Table 2). Firstly, the substrates with various ortho, meta and para substituted
on the phenyl ring at the alkene moiety were tested. The results revealed that there
was no major effect on the substitution pattern or steric hindrance of the substituent
on the phenyl ring of substrates, both the electronꢀdonating and electronꢀwithdrawing
groups at different positions furnished the corresponding products in moderate to
good yields. For examples, all of three substrates 1b-d with a methoxyl group which
is a strong electronꢀdonating group on the phenyl ring provided the desired products
2b-d in 55ꢀ82% yields. Furthermore, electronꢀrich hetero cyclic substrate 1o afforded
the desired tertꢀbutyl quinolinꢀ2ꢀyl carbonate 2o with 81% yield in 1.5 h. In addition,
using 2ꢀ and 3ꢀnaphthyl substituted 2ꢀalkenylanilines 1m-n as the substrates, products
2m and 2n can be obtained in good yields (71% and 73%). To our delight, the
aliphatic substituted substrates 1p and 1q also can provide the desired products 2p
and 2q with 50% and 92% yields, respectively. The substrate 1r with NO2 substituent
on the phenyl ring showed adverse effect and delivered the desired product with 27%
yield even when the reaction was run for 30 h.
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Table 3. Scope of 2-Alkenylanilinesa
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entry
substrate
3a
R1
4ꢀMeO
5ꢀMeO
6ꢀMeO
4ꢀF
time (h)
product
4a
yield (%)b
1
2
3
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5
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9
1.5
1
82
65
65
74
82
78
46
82
0
3b
4b
4c
22
5
3c
3d
4d
4e
5ꢀF
1
3e
6ꢀF
3.5
7
3f
4f
3g
4ꢀCl
4g
4ꢀMe
4ꢀNO2
1
3h
4h
--
24
3i
aReaction conditions: 3 (0.20 mmol), Boc2O (2.0 equiv), DMAP ((5 mol%), CH2Cl2
(2.0 mL), rt. bisolated yield.
The substrate scope of this process was further examined using a variety of the
substitution pattern of aniline (Table 3). The reaction exhibited good tolerance to
various substituents on the aromatic ring no matter is the electronꢀdonating or slight
electronꢀwithdrawing group, and took place smoothly to provide the desired
quinolines in 46ꢀ82% yields. Moreover, the reaction was not affected by the position
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of the substituents on the aromatic ring of anilines, for examples, the substrates 3a-c
with various electronꢀdonating ortho, meta and para substitutent, the reactions gave
the products 4a-4c with 65%ꢀ82% yields. The fluoro and chloro group could be
tolerated in the reaction conditions to generate the quinolines 4d-g in good to
moderate yields. Unfortunately, the substrate containing the most strong
electronꢀwithdrawing group (e.g., ꢀNO2) appeared to have completely retarded the
reaction only provided the Bocꢀprotected product.
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Scheme 1. Control experiments
To gain more insight about the mechanism of this reaction, several control
experiments were conducted. First, PPY* was selected as a chiral DMAP type catalyst
for achieving the asymmetric transformation,13 but the reaction provided racemic
product with 85% yield at room temperature in CH2Cl2. Subsequently, the model
substrate 1a reacted with 1.0 equiv of Boc2O in the presence of 5 mol% DMAP, the
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reaction delivered the product 2a in 23% yield along with 43% yield of quinolinone
product 7. Furthermore, the quinolinone 7 can be converted into the tertꢀbutyl
quinolinꢀ2ꢀyl carbonate product 2a in quantitative yield under the standard conditions,
which implies the quinolinone or 2ꢀhydroxyquinoline is a possible intermediate in this
transformation (Scheme 1).
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Scheme 2. A Proposed Mechanistic Pathway
Based on these findings and the literature reports,5,14 a plausible mechanism for
the DMAPꢀcatalyzed cyclization of Bocꢀanhydride with 2ꢀalkenylaniline toward
tertꢀbutyl quinolinꢀ2ꢀyl carbonates is illustrated in Scheme 2. Initially, the
Bocꢀanhydride reacts with the substrate in the presence of DMAP to afford the
intermediate I, which is already well investigated by Knölker.5 Afterwards, a 6ꢀπ
electrocyclization of oꢀisocyanatostyrene to afford II, followed by a rapid proton shift
to form 2ꢀhydroxyquinoline III or its tautomer IV. The 2ꢀhydroxyquinoline III reacts
with Boc2O by the catalysis of DMAP to provide the final product 2a.
Scheme 3. Demonstration of Synthetic Utility
a) Gram-scale reaction
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b) The synthetic transformations
To explore the potential synthetic utility of this new method, a gramꢀscale
reaction of 1a was carried out. The tertꢀbutyl quinolinꢀ2ꢀyl carbonate product 2a was
obtained with 92% yield (Scheme 3a). This method also is useful in medicinal
chemistry, the HBV inhibitor 8 can be synthesized with 98% yield through simple
transformation. In addition, the tertꢀbutyl quinolinꢀ2ꢀyl carbonate is a versatile
intermediate in organic synthesis. For example, the product 2a was easily converted
into 2ꢀ(pseudo)haloquinoline in 95% yield (Scheme 3b).
CONCLUSION
In conclusion, a new metalꢀfree, simple operation protocol for the rapid synthesis of
quinoline derivatives has been described, this process involves an unexpected
DMAPꢀcatalyzed cyclization of Bocꢀanhydride with 2ꢀalkenylaniline. The utility of
the methodology is also highlighted by the products can be easily transformed into
corresponding quinolinones and 2ꢀ(pseudo)haloquinolines (e.g., 2ꢀCl) for further
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functionalizations. This method could be used by the researchers in the areas of
organic and medicinal chemistry.
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EXPERIMENTAL SECTION
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Unless otherwise mentioned, all reactions were performed in flameꢀdried glassware
under N2. Solvents were distilled prior to use. Reagents were used as purchased
without further purification. Chromatographic separations were performed using silica
1
gel 200−300 mesh. H and 13C NMR spectra were obtained on 400, 600 MHz (100,
13
150 MHz for C NMR) spectrometers using CDCl3 with TMS or residual solvent as
standard unless otherwise noted. Chemicalꢀshift values are given in ppm and
referenced to the internal standard, TMS (tetramethylsilane). The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; dd,
doublet of doublets, and br s, broad singlet. The coupling constants (J) are reported in
Hertz (Hz). Melting points were determined using a micromelting point apparatus
without corrections. TLC analysis was performed using glassꢀbacked plates (60 Å,
250 ꢁm) and visualized using UV and Iodine stains. Lowꢀresolution mass spectra
were obtained using LS/MSD. Highꢀresolution mass spectrometry (HRMS) was
obtained on a QꢀTOF microspectrometer.
General procedure for the synthesis of 1 and 3.
1ꢀ(2ꢀaminophenyl)ꢀ1ꢀarylethanols S2 were prepared by the reaction of arylmagnesium
bromides with corresponding oꢀaminoacetophenone S1.15,16
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The 2ꢀalkenylanilines 1 and 3 were prepared following the general procedure
unless otherwise noted.
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To a stirred solution of S2 (1.0 equiv) in CH2Cl2 (4 M) was added
pꢀtoluenesulfonic acid monohydrate (pꢀTsOH) (1.1 equiv). After the mixture was
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o
stirred for 30 min at 0 C, a drop of H2SO4 was added. The mixture was stirred for
another 30 min, and then the saturated NaHCO3 solution was added. The organic
layer was separated. The aqueous layer was extracted with CH2Cl2 (10 mL×2). The
combined extracts were washed with saturated NaCl solution, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was purified
by column chromatography on SiO2 to give the corresponding phenylvinylanilines 1.
2-(1-Phenylvinyl)aniline (1a):16a white solid, 730 mg, 94% yield from S1 (4.0 mmol)
o
o
1
; mp 74 C (Lit. 80ꢀ81 C); Rf = 0.74 (20% EtOAc/Petroleum Ether); H NMR (600
MHz, CCl3) δ 3.53 (brs, 2H), 5.35 (s, 1H), 5.79 (s, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.78
(t, J = 7.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.30 (dd, J = 6.6,
14.4 Hz, 3H), 7.37 (d, J = 7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 115.7, 116.1,
118.4, 126.7, 127.4, 128.1, 128.6, 128.8, 130.8, 139.7, 143.9, 147.2. Mass spectrum
(m/z, ESI): 196.8; HRMS (ESI): m/z calculated for C14H13N (M+H)+: 196.1126, found:
196.1130.
2-(1-(2-Methoxyphenyl)vinyl)aniline (1b): yellow solid, 332 mg, 37% yield from S1
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(4.0 mmol); mp: 41ꢀ42 C; Rf = 0.36 (20% EtOAc/Petroleum Ether); H NMR (600
MHz, CDCl3) δ 3.43 (brs, 2H), 3.72 (s, 3H), 5.54 (s, 1H), 5.72 (s, 1H), 6.68 (d, J = 7.8
Hz, 1H), 6.72 (t, J = 7.2 Hz, 1H), 6.91 (dd, J = 7.8, 13.8 Hz, 2H), 7.09ꢀ7.05 (m, 2H),
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7.19 (d, J = 7.2 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ
55.6, 111.4, 115.6, 118.2, 119.6, 120.7, 128.0, 128.9, 129.0, 129.8, 130.2, 130.4,
143.4, 144.2, 157.0. Mass spectrum (m/z, ESI): 226.8; HRMS (ESI): m/z calculated
for C15H15NO (M+H)+: 226.1232, found: 226.1229.
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2-(1-(3-Methoxyphenyl)vinyl)aniline (1c):16b white solid, 612 mg, 68% yield from
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S1 (4.0 mmol); mp: 63ꢀ64 C (Lit. 60ꢀ62 C); Rf = 0.52 (20% EtOAc/Petroleum
Ether); 1H NMR (400 MHz, CDCl3) δ 3.53 (brs, 2H), 3.76 (s, 3H), 5.34 (d, J = 7.2 Hz,
1H), 5.77 (d, J = 1.2 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.77 (td, J = 1.2, 7.6 Hz, 1H),
6.83 (dd, J = 2.0, 8.0 Hz, 1H), 6.95ꢀ6.92 (m, 2H), 7.16ꢀ7.09 (m, 2H), 7.21 (t, J = 8.0
Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 55.2, 112.5, 113.4, 115.7, 116.4, 116.7,
118.4, 119.3, 127.3, 128.8, 129.6, 130.8, 141.3, 147.1, 159.8. Mass spectrum (m/z,
ESI): 226.1; HRMS (ESI): m/z calculated for C15H15NO (M+H)+: 226.1232, found:
226.1236.
2-(1-(4-Methoxyphenyl)vinyl)aniline (1d):17 grey solid, 710 mg, 79% yield from S1
(4.0 mmol); mp: 45ꢀ46 oC (Lit. 50.5 oC); Rf = 0.42 (20% EtOAc/Petroleum Ether); 1H
NMR (400 MHz, CDCl3) δ 3.54 (brs, 2H), 3.80 (s, 3H), 5.24 (s, 1H), 5.70 (s, 1H),
6.71 (d, J =8.0 Hz, 1H), 6.80 (t, J =8.0 Hz, 1H), 6.84 (d, J =8.6 Hz, 2H), 7.11 (d, J =
7.6 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H); 13C NMR (150 MHz,
CDCl3) δ 55.3, 113.9, 114.2, 115.6, 118.4, 127.6, 127.9, 128.7, 130.8, 132.1, 143.9,
146.6, 159.6. Mass spectrum (m/z, ESI): 226.1; HRMS (ESI): m/z calculated for
C15H15NO (M+H)+: 226.1232, found: 226.1237.
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2-(1-(o-Tolyl)vinyl)aniline (1e): brown solid, 535 mg, 64% yield from S1 (4.0
mmol); mp: 50ꢀ51 oC; Rf = 0.63 (20% EtOAc/Petroleum Ether); 1H NMR (400 MHz,
CDCl3) δ 2.11 (s, 3H), 3.88 (brs, 2H), 5.46 (d, J = 1.8 Hz, 1H), 5.61 (d, J = 1.8 Hz,
1H), 6.70 (dd, J = 8.0, 20.4 Hz, 2H), 7.01 (dd, J = 1.2 Hz, 1H), 7.08 (td, J = 1.5, 8.0
Hz, 1H), 7.16ꢀ7.14 (m, 1H), 7.21 (td, J = 1.6, 8.0 Hz, 2H), 7.31( dd, J = 1.2, 6.8 Hz,
1H); 13C NMR (150 MHz, CDCl3) δ 20.4, 116.0, 118.5, 118.7, 126.0, 127.4, 127.8,
128.5, 129.6, 130.2, 130.6, 135.9, 141.9, 143.5, 148.1. Mass spectrum (m/z, ESI):
210.0; HRMS (ESI): m/z calculated for C15H15N (M+H)+: 210.1283, found: 210.1287.
2-(1-(m-Tolyl)vinyl)aniline (1f): paleꢀyellow oil, 686 mg, 82% yield from S1 (4.0
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mmol); Rf = 0.56 (20% EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ 2.32
(s, 3H), 5.35 (s, 1H), 5.78 (s, 1H), 6.87ꢀ6.88(m, 2H), 7.10 (d, J = 7.2 Hz, 1H), 7.14 (t,
J = 7.2 Hz, 2H), 7.17 (s, 1H), 7.20 (d, J = 5.4 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ
21.5, 115.6, 116.1, 118.3, 123.9, 127.2, 127.5, 128.5, 128.7, 128.9, 130.8, 138.2,
139.7, 143.9, 147.3. Mass spectrum (m/z, ESI): 210.0; HRMS (ESI): m/z calculated
for C15H15N (M+H)+: 210.1283, found: 210.1287.
2-(1-(p-Tolyl)vinyl)aniline (1g): light brown oil, 334 mg, 40% yield from S1 (4.0
1
mmol); Rf = 0.59 (20% EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ 2.34
(s, 3H), 3.49 (brs, 2H), 5.30 (s, 1H), 5.76 (s, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.79 (t, J =
6.0 Hz, 1H), 7.12 (m, 3H), 7.16 (t, J = 9.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.2, 115.3, 115.7, 118.5, 126.6, 127.7, 128.7, 129.3, 130.8,
136.8, 138.0, 143.7, 146.3. Mass spectrum (m/z, ESI): 210.0; HRMS (ESI): m/z
calculated for C15H15N (M+H)+: 210.1283, found: 210.1287.
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2-(1-(3-Fluorophenyl)vinyl)aniline (1h): brown solid, 596 mg, 70% yield from S1
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(4.0 mmol); mp: 40ꢀ41 C; Rf = 0.72 (20% EtOAc/Petroleum Ether); H NMR (400
MHz, CDCl3) δ 3.63 (brs, 2H), 5.40 (s, 1H), 5.83 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H),
6.80 (t, J = 7.6 Hz, 1H), 6.98 (td, J = 2.4, 4.4Hz, 1H), 7.08 (m, 2 H), 7.16 (dd, J = 7.6,
11.2 Hz, 2H), 7.27ꢀ7.30 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 113.5 (d, JCꢀF = 22.0
Hz), 114.9 (d, JCꢀF = 21.2 Hz), 115.7, 117.2, 118.5, 118.5, 122.4, 126.7, 129.0, 130.1
(d, JCꢀF = 8.0 Hz), 130.8, 142.1(d, JCꢀF = 7.2 Hz), 143.9, 146.2, 162.5 (d, JCꢀF = 244.2
Hz). Mass spectrum (m/z, ESI): 214.0; HRMS (ESI): m/z calculated for C14H12FN
(M+H)+: 214.1032, found: 214.1036.
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2-(1-(4-Fluorophenyl)vinyl)aniline (1i): white solid, 716 mg, 84% yield from S1
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(4.0 mmol); mp: 50ꢀ51 C; Rf = 0.52 (20% EtOAc/Petroleum Ether); H NMR (600
MHz, CDCl3) δ 4.04 (brs, 2H), 5.34 (s, 1H), 5.74 (s, 1H), 6.78ꢀ6.74 (m, 1H), 6.83 (dd,
J = 7.2 Hz, 1H), 7.00ꢀ6.97 (m, 2H), 7.10 (d, J = 6.6 Hz, 1H), 7.19ꢀ7.17 (m, 1H), 7.33
(d, J = 6.0 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 115.4, 115.5, 115.7, 115.9, 118.5,
127.1, 128.4 (d, JCꢀF = 7.8 Hz), 128.9, 130.8, 135.8 (d, JCꢀF = 3.2 Hz), 143.8, 146.1,
162.7 (d, J
= 246.0 Hz). Mass spectrum (m/z, ESI): 213.9; HRMS (ESI): m/z
CꢀF
calculated for C14H12FN (M+H)+: 214.1032, found: 214.1037.
2-(1-(3-Chlorophenyl)vinyl)aniline (1j): brown oil, 311 mg, 34% yield from S1 (4.0
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mmol); Rf = 0.52 (20% EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ 4.24
(brs, 2H), 5.41 (s, 1H), 5.81 (s, 1H), 6.78 (d, J = 7.8 Hz, 1H), 6.84 (t, J = 7.8 Hz, 1H),
7.09 (d, J = 7.2 Hz, 1H), 7.19 (t, J = 8.4 Hz, 1H), 7.22ꢀ7.26 (m, 4H), 7.36 (s, 1H); 13C
NMR (150 MHz, CDCl3) δ 115.7, 117.4, 118.5, 125.0, 126.5, 126.7, 128.1, 129.1,
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129.8, 130.8, 134.6, 141.7, 143.9, 146.0. Mass spectrum (m/z, ESI): 229.9; HRMS
(ESI): m/z calculated for C14H12ClN (M+H)+: 230.0737, found: 230.0743.
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2-(1-(4-Chlorophenyl)vinyl)aniline (1k): grey solid, 641 mg, 70% yield from S1
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(4.0 mmol); mp: 45ꢀ46 C; Rf = 0.64 (20% EtOAc/Petroleum Ether); H NMR (600
MHz, CDCl3) δ 3.74 (brs, 2H), 5.37 (s, 1H), 5.79 (s, 1H), 6.72 (d, J = 7.8 Hz, 1H),
6.80 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.27ꢀ7.30
(m, 4H); 13C NMR (150 MHz, CDCl3) δ 115.7, 116.6, 118.5, 126.8, 128.0, 128.7,
129.0, 130.8, 134.0, 138.1, 143.8, 146.1. Mass spectrum (m/z, ESI): 230.0. HRMS
(ESI): m/z calculated for C14H12ClN (M+H)+: 230.0737, found: 230.0726.
2-(1-(3-(Trifluoromethyl)phenyl)vinyl)aniline (1l): light brown oil, 841 mg, 80%
1
yield from S1 (4.0 mmol); Rf = 0.44 (20% EtOAc/Petroleum Ether); H NMR (600
MHz, CDCl3) δ 3.52 (brs, 2H), 5.43 (s, 1H), 5.84 (s, 1H), 6.68 (d, J = 7.8 Hz, 1H),
6.78 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 7.38 (t, J =
7.8 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H); 13C NMR
(150 MHz, CDCl3) δ 115.8, 117.7, 118.5, 123.2 (q, JCꢀF = 3.8 Hz), 124.2 (q, JCꢀF
=
271.0 Hz), 124.8 (q, JCꢀF = 3.8 Hz), 126.3, 129.1, 129.2, 130.2, 130.8, 131.11 (q, JCꢀF
= 31.8 Hz), 140.7, 143.9, 146.1. Mass spectrum (m/z, ESI): 264.9; HRMS (ESI): m/z
calculated for C15H12F3N (M+H)+: 264.1000, found: 264.1004.
2-(1-(Naphthalen-1-yl)vinyl)aniline (1m): white solid, 823 mg, 84% yield from S1
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(4.0 mmol); mp: 86ꢀ87 C; Rf = 0.56 (20% EtOAc/Petroleum Ether); H NMR (600
MHz, CDCl3) δ 3.68 (brs, 2H), 5.59 (s, 1H), 5.77 (s, 1H), 6.57 (d, J = 7.8 Hz, 1H),
6.66 (t, J = 7.2 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 7.3ꢀ7.43 (m,
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4H), 7.78 (dd, J = 7.8, 11.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 1H); C NMR (100 MHz,
CDCl3) δ 116.2, 118.5, 120.1, 125.5, 125.8, 126.0, 126.3, 126.9, 128.2, 128.4, 128.6,
128.8, 130.3, 131.4, 134.1, 140.3, 143.8, 146.9. Mass spectrum (m/z, ESI): 246.1;
HRMS (ESI): m/z calculated for C18H15N (M+H)+: 246.1283, found: 246.1289.
2-(1-(Naphthalen-2-yl)vinyl)aniline (1n): white solid, 141 mg, 38% yield from S1
(4.0 mmol); mp: 107ꢀ108 oC; Rf = 0.68 (20% EtOAc/Petroleum Ether); 1H NMR (600
MHz, CDCl3) δ 3.40 (brs, 2H), 5.45 (s, 1H), 5.93 (s, 1H), 6.73 (d, J = 7.2 Hz, 1H),
6.83 (t, J = 7.8 Hz, 1H), 7.18 (dd, J = 7.2, 16.8 Hz, 2H), 7.44 (d, J = 3.6 Hz, 2H), 7.59
(d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.75 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H);
13C NMR (150 MHz, CDCl3) δ 115.7, 116.7, 118.5, 124.5, 120.6, 126.2, 126.3, 127.4,
127.6, 128.3, 128.4, 128.9, 131.0, 133.2, 133.4, 137.0, 143.9, 147.1. Mass spectrum
(m/z, ESI): 246.0; HRMS (ESI): m/z calculated for C18H15N (M+H)+: 246.1283, found:
246.1285.
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0.59 (5% EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ 2.36 (s, 3H), 5.51
(s, 1H), 6.08 (s, 1H), 6.59 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.82 (d, J = 7.2
Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.42ꢀ7.41 (m, 2H), 7.73 (d,
J = 8.4 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ 20.6, 116.3, 118.4, 119.8, 124.9, 125.8, 126.3, 126.4, 127.3, 128.0,
128.3, 128.9, 129.7, 132.2, 132.5, 133.1, 138.9, 143.6, 144.5. Mass spectrum (m/z,
ESI): 259.9; HRMS (ESI): m/z calculated for C19H17N (M+H)+: 260.1439, found:
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2-(1-(Thiophen-2-yl)vinyl)aniline (1o):18 To a solution of thiophene (1.0 mL, 13.2
mmol) in THF (20 mL) was added nꢀBuLi (5.5 mL, 2.4 M in hexanes, 13.5 mmol) by
dropwise at ꢀ78 oC, and the mixture was stirred at ꢀ78 °C for 20 min and at 0 oC for 2
h. Then the mixture was cooled to ꢀ78 °C and 1ꢀ(2ꢀaminophenyl)ethanone (0.36 mL,
3.0 mmol) in THF (4 mL) was added dropwise. After 15 min, the cooling bath was
removed and the mixture was stirred overnight. Subsequently, saturated NH4Cl
solution was added and the aqueous layer was extracted with EtOAc (2×10 mL). The
combined extracts were washed with saturated NaCl solution, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was purified by
column chromatography on SiO2 to give 1ꢀ(2ꢀaminophenyl)ꢀ1ꢀ(thiophenꢀ2ꢀyl)ethanol.
1o was prepared following the general procedure. Brown oil, 223 mg, 37% yield; Rf =
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0.36 (20% EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ 3.64 (brs, 2H),
5.18 (s, 1H), 5.79 (s, 1H), 6.73 (d, J = 7.9 Hz, 1H), 6.81ꢀ6.77 (m, 2H), 6.93 (t, J = 3.8
Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.17 ( t, J = 7.7 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H);
13C NMR (150 MHz, CDCl3) δ 114.6, 115.7, 118.3, 125.4, 126.2, 126.8, 127.6, 129.0,
130.3, 140.6, 143.7, 144.2. Mass spectrum (m/z, ESI): 202.0; HRMS (ESI): m/z
calculated for C12H11NS (M+H)+: 202.0690, found: 202.0693.
2-(Prop-1-en-2-yl)aniline (1p):19 To a solution of Ph3PMeBr (3.93 g, 11 mmol, 1.5
equiv) in THF (20 mL) was added tꢀBuOK (1.23 g, 1.5 equiv) in portions under N2 at
room temperature. After the mixture was stirred at room temperature for 0.5 h, a
solution of 1ꢀ(2ꢀaminophenyl)ethanone (676 mg, 5 mmol, 1 equiv) in THF (10 mL)
was added dropwise. The reaction mixture was stirred at room temperature under N2
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overnight and then quenched with H2O and extracted twice with EtOAc. The
combined organic layers were washed with saturated NaHCO3 and NaCl solution,
dried over Na2SO4, filtered and concentrated, and the residue was purified by column
chromatography on silica gel to obtain the compound 1p. Brown oil, 88mg, 13%
yield; Rf = 0.50 (10% EtOAc/Petroleum Ether); 1H NMR (400 MHz, CDCl3) δ 2.07 (s,
3H), 3.83 (brs, 2H), 5.06 (dd, J = 0.8, 2.0 Hz,1H), 5.28 (m, 1H), 6.70ꢀ6.68 (m, 1H),
6.73 (td, J = 0.8, 7.6 Hz, 1H), 7.02ꢀ7.07 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 23.9,
115.3, 115.6, 118.2, 127.9, 128.2, 129.3, 142.8, 143.5.
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2-(hex-1-en-2-yl)aniline (1q): following the procedure for synthesis of 1p using
1ꢀ(2ꢀaminophenyl)pentanꢀ1ꢀone (700 mg, 3.95 mmol) as the starting material. Yellow
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oil, 277 mg, 40% yield; Rf = 0.68 (20% EtOAc/Petroleum Ether); H NMR (600
MHz, CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.3 (m, 2H), 1.39 (m, 2H), 2.37 (t, J = 7.2 Hz,
2H), .4.03 (brs, 2H), 5.05 (s, 1H), 5.27 (s, 1H), 6.74 (dd, J = 7.2, 13.8 Hz, 2H), 6.99
(d, J = 7.2 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 14.0,
22.5, 30.2, 37.2, 114.5, 115.8, 118.6, 127.8, 128.6, 129.3, 142.4, 147.9. Mass
spectrum (m/z, ESI): 176.8; HRMS (ESI): m/z calculated for C12H18N (M+H)+:
176.1439; found: 176.1433.
2-(1-(4-nitrophenyl)vinyl)aniline (1r): following the procedure for synthesis of 1p
using (2ꢀaminophenyl)(4ꢀnitrophenyl)methanone (242 mg) as the starting material.
o
Yellow solid, 110 mg, 46% yield, mp: 99ꢀ101 C; Rf = 0.52 (20% EtOAc/Petroleum
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Ether); H NMR (600 MHz, CDCl3) δ 3.58 (brs, 2H), 5.57 (s, 1H), 5.97 (s, 1H), 6.73
(d, J = 7.8 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 7.19 (t, J = 7.2
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Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H); 13C NMR (150 MHz,
CDCl3) δ 115.8, 118.6, 119.9, 123.9, 125.8, 127.5, 129.4, 130.7, 143.8, 145.5, 146.2,
147.4. Mass spectrum (m/z, ESI): 241.6; HRMS (ESI): m/z calculated for C14H12N2O2
(M+H)+: 241.0977; found: 241.0978.
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4-Methoxy-2-(1-phenylvinyl)aniline (3a): brown oil; Rf
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0.56 (20%
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EtOAc/Petroleum Ether); H NMR (400 MHz, CDCl3) δ 3.15 (brs, 2H), 3.76 (s, 3H),
5.36 (s, 1H), 5.81 (s, 1H), 6.68 (d, J = 9.6 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 6.78 (dd,
J = 3.2, 8.8 Hz, 1H), 7.34ꢀ7.29 (m, 3H), 7.37 (d, J = 6.8 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 55.8, 114.6, 116.1, 116.3, 117.1, 126.6, 128.2, 128.6, 128.8, 137.2,
139.4, 147.0, 152.6. Mass spectrum (m/z, ESI): 226.1; HRMS (ESI): m/z calculated
for C15H15NO (M+H)+: 226.1232, found: 226.1236.
5-Methoxy-2-(1-phenylvinyl)aniline (3b): yellow solid, 3.51 g, 52% yield from
3ꢀmethoxyaniline (30 mmol); mp: 70ꢀ71 oC; Rf = 0.56 (20% EtOAc/Petroleum Ether);
1H NMR (600 MHz, CDCl3) δ 3.66 ( s, 3H), 5.33 (s, 1H), 6.04 (s, 1H), 6.40 (d, J =
7.8 Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.28 (t, J = 7.2 Hz,
3H), 7.37 (d, J = 7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 55.8, 101.4, 108.8,
116.4, 116.8, 125.9, 157.9, 127.8, 128.4, 128.8, 139.3, 142.3, 144.6. Mass spectrum
(m/z, ESI): 226.0; HRMS (ESI): m/z calculated for C15H15NO (M+H)+: 226.1232,
found: 226.1237.
2-Methoxy-6-(1-phenylvinyl)aniline (3c): light yellow gum, 4.05 g, 60% yield from
2ꢀmethoxyaniline (30 mmol); Rf = 0.45 (20% EtOAc/Petroleum Ether); 1H NMR (600
MHz, CDCl3) δ 3.50 (brs, 2H), 3.87 (s, 3H), 5.37 (s, 1H), 5.80 (s, 1H), 6.75 (d, J = 7.2
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Hz, 2H), 6.80 (d, J = 7.2 Hz, 1H), 7.32ꢀ7.28 (m, 3H), 7.37 (d, J = 7.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 55.6, 109.5, 116.0, 117.3, 122.9, 127.2, 126.7, 128.0,
128.0, 128.5, 133.9, 139.7, 146.9, 147.1. Mass spectrum (m/z, ESI): 226.0; HRMS
(ESI): m/z calculated for C15H15NO (M+H)+: 226.1232, found: 226.1236.
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4-Fluoro-2-(1-phenylvinyl)aniline (3d): brown oil; Rf
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0.53 (20%
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EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ 3.34 (brs, 2H), 5.36 (s, 1H),
5.81 (s, 1H), 6.64ꢀ6.62 (m, 1H), 6.87 (dd, J = 9.0, 13.8 Hz, 2H), 7.35ꢀ7.32 (m, 5H);
13C NMR (150 MHz, CDCl3) δ 115.2 (d, J
= 22.5 Hz), 116.5 (d, J
= 7.5 Hz),
CꢀF
CꢀF
116.7, 117.1 (d, J CꢀF = 22.5 Hz), 126.6, 128.3, 128.4 (d, J CꢀF = 13.5 Hz), 128.7, 139.0,
140.0 (d, J CꢀF = 6.6 Hz), 146.3, 156.1 (d, J CꢀF = 234.9 Hz). Mass spectrum (m/z, ESI):
214.4; HRMS (ESI): m/z calculated for C14H12FN (M+H)+: 214.1032, found:
214.1036.
5-Fluoro-2-(1-phenylvinyl)aniline (3e): white solid, 1.98 g, 31% yield from
o
3ꢀfluoroaniline (30 mmol); mp: 80ꢀ82 C; Rf = 0.68 (20% EtOAc/Petroleum Ether);
1H NMR (600 MHz, CDCl3) δ 3.28 (brs, 2H), 5.34 (s, 1H), 5.79 (s, 1H), 6.44 (d, J =
9.6 Hz, 1H), 6.51 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H ), 7.33ꢀ7.29 (m, 3H),
7.35 (d, J = 7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 102.0 (d, J
= 24.6 Hz),
CꢀF
104.8 (d, J CꢀF = 21.3 Hz), 116.5, 123.2, 126.6, 128.3, 128.6, 132.0 (d, J CꢀF = 9.7 Hz),
139.5, 145.5 (d, J = 10.8 Hz), 146.3, 162.6, 163.4 (d, J = 163.4 Hz). Mass
CꢀF
CꢀF
spectrum (m/z, ESI): 214.0; HRMS (ESI): m/z calculated for C14H12FN (M+H)+:
214.1032, found: 214.1036.
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2-Fluoro-6-(1-phenylvinyl)aniline (3f): brown oil, 2.36 g, 37% yield from
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2ꢀfluoroaniline (30 mmol); Rf = 0.71 (10% EtOAc/Petroleum Ether); H NMR (600
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MHz, CDCl3) δ 3.59 (brs, 2H), 5.35 (s, 1H), 5.79 (s, 1H), 6.66 (dd, J = 7.2, 13.8 Hz,
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1H), 6.88 (d, J = 7.8 Hz, 1H), 6.96 (t, J = 9.6 Hz, 1H), 7.30ꢀ7.28 (m, 3H), 7.33 (d, J =
13
7.2 Hz, 2H); C NMR (150 MHz, CDCl3) δ 114.4 (d, J
= 18.9 Hz), 116.6, 117.5
CꢀF
(d, J CꢀF = 7.6 Hz), 126.0 (d, J CꢀF = 3.0 Hz), 126.7, 128.4, 128.7, 129.2 (d, J CꢀF = 3.3
Hz), 132.7 (d, J CꢀF = 12.3 Hz), 139.3, 146.2 (d, J CꢀF = 2.6 Hz), 151.8 (d, J CꢀF = 237.2
Hz). Mass spectrum (m/z, ESI): 214.0; HRMS (ESI): m/z calculated for C14H12FN
(M+H)+: 214.1032, found: 214.1035.
4-Chloro-2-(1-phenylvinyl)aniline (3g): brown oil; Rf
=
0.51 (20%
1
EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ 3.48 (brs, 2H), 5.36 (s, 1H),
5.81 (s, 1H), 6.62 (d, J= 8.4 Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 7.35ꢀ7.32 (m, 5H); 13C
NMR (150 MHz, CDCl3) δ 116.8, 116.9, 126.6, 128.4, 128.6, 128.7, 130.0, 130.3,
138.9, 142.4, 146.1. Mass spectrum (m/z, ESI): 229.9; HRMS (ESI): m/z calculated
for C14H12ClN (M+H)+: 230.0737, found: 230.0736.
4-Methyl-2-(1-phenylvinyl)aniline (3h): yellow oil, 1.39 g, 74% yield from
pꢀtoluidine (30 mmol); Rf = 0.85 (20% EtOAc/Petroleum Ether); 1H NMR (600 MHz,
CDCl3) δ 2.27 (s, 3H), 5.35 (s, 1H), 5.79 (s, 1H), 6.67 (d, J = 6.0 Hz, 1H), 6.95 (s,
1H), 7.00 (d, J = 6.0 Hz, 1H), 7.30 (dd, J = 6.6, 14.4 Hz, 3H), 7.35 (d, J = 7.2 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 20.5, 116.2, 116.3, 126.7, 128.1, 128.6, 129.3, 131.3,
139.7, 147.0. Mass spectrum (m/z, ESI): 210.9; HRMS (ESI): m/z calculated for
C15H15N (M+H)+: 210.1283, found: 210.1278.
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4-Nitro-2-(1-phenylvinyl)aniline (3i): Sodium hydride (120 mg, 5 mmol) was
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suspended in dimethyl sulfoxide (20 mL) and heated at 70 C under nitrogen until
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evolution of hydrogen gas ceased (approximately 30 min). To this suspension was
added a solution of (methyl)triphenyl phosphonium bromide (1.78 g, 5 mmol) in
dimethyl sulfoxide (20 mL) at room temperature. The mixture was stirred at room
temperature for 15 min, 2ꢀaminoꢀ5ꢀnitrobenzophenone (605 mg, 2.5 mmol) was
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added to this solution. The resulting dark red solution was heated at 90 C for 18 h
under nitrogen. The reaction mixture was cooled and quenched with water (500 mL).
The pH was adjusted to 7.0 by the addition of 3N HCl. This solution was extracted
with EtOAc. The combined organic extracts were washed with water, dried over
Na2SO4 and concentrated under reduced pressure. The resulting dark oil was purified
by flash column chromatography over silica gel to provide the product 199 mg, 33%
o
1
yield, yellow solid, mp: 82 C; Rf = 0.26 (10% EtOAc/Petroleum Ether); H NMR
(600 MHz, CDCl3) δ 5.44 (s, 1H), 7.35 (s, 5H), 8.08(s, 2H), 8.08 (s, 2H); 13C NMR
(150 MHz, CDCl3) δ 114.0, 117.9 125.5, 126.0, 126.5, 127.3, 128.8, 128.9, 138.1,
138.9, 150.1, 150.2. Mass spectrum (m/z, ESI): 263.3; HRMS (ESI): m/z calculatd for
C14H12N2O2 (M+Na)+: 263.0796, found: 263.0803.
General procedure for the synthesis of 2a-2p, 4a-4h and 6.
To a solution of phenylvinylaniline (0.2 mmol) in CH2Cl2 (2 mL) was added Boc2O
(87.3 mg, 0.4 mmol) and DMAP (5 mol%, 1.2 mg). The solution was stirred at room
temperature for the indicated time, then the reaction was quenched with H2O and
extracted with CH2Cl2 (2×4 mL), the combined organic layer was washed with
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saturated NaCl solution, dried over Na2SO4, concentrated in vacuo and the crude
residue was purified by flash column chromatography eluting with EtOAc and
petroleum ether to give the title compounds.
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tert-Butyl (4-phenylquinolin-2-yl) carbonate (2a): 1 h, white solid, 52 mg, 81%
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yield; mp: 140ꢀ142 C; Rf = 0.28 (5% EtOAc/Petroleum Ether); H NMR (600 MHz,
CDCl3) δ 1.59 (s, 9H), 7.21 (s, 1H), 7.52ꢀ7.46 (m, 6H), 7.72 (t, J = 7.2 Hz, 1H), 7.90
(d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 27.7,
84.1, 115.1, 125.8, 126.5, 128.6, 128.8, 129.1, 129.5, 130.1, 137.3, 147.1, 151.1,
152.8, 155.8. Mass spectrum (m/z, ESI): 344.1; HRMS (ESI): m/z calculated for
C20H19NO3 (M+Na)+: 344.1263, found: 344.1267.
tert-Butyl (4-(2-methoxyphenyl)quinolin-2-yl) carbonate (2b): 1 h, white solid, 56
o
mg, 80% yield; mp: 65ꢀ67 C; Rf = 0.18 (3% EtOAc/Petroleum Ether); 1H NMR (600
MHz, CDCl3) δ 1.58 (s, 9H), 3.71 (s, 3H), 7.06 (d, J = 8.3 Hz, 1H), 7.10 (t, J = 7.4
Hz, 1H), 7.20 (s, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.48 (t, J =
7.8 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 8.05 (d, J = 8.3 Hz,
1H); 13C NMR (150 MHz, CDCl3) δ 27.3, 55.5, 84.0, 111.1, 116.0, 120.7, 126.10,
126.12, 126.3, 126.5, 129.0, 129.8, 130.3, 131,2, 146.6, 150.2, 151.1, 155.8, 156.7.
Mass spectrum (m/z, ESI): 374.2; HRMS (ESI): m/z calculated for C21H21NO4
(M+Na)+: 374.1368, found: 374.1363.
tert-Butyl (4-(3-methoxyphenyl)quinolin-2-yl) carbonate (2c): 3 h, light yellow
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solid, 39 mg, 55% yield; mp: 95ꢀ96 C; Rf = 0.56 (20% EtOAc/Petroleum Ether); H
NMR (400 MHz, CDCl3) δ 1.59 (s, 9H), 3.86 (s, 3H), 7.04 (d, J = 6.7 Hz, 2H), 7.09
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(d, J = 7.5 Hz, 1H), 7.21 (s, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.41ꢀ7.51 (t, J = 7.2 Hz,
1H), 7.72 (t, J = 7.3 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H); 13C
NMR (150 MHz, CDCl3) δ 27.7, 55.4, 84.2, 114.3, 115.0, 115.1, 122.0, 126.0, 126.5,
129.1, 129.7, 130.1, 138.7, 147.0, 151.1, 152.7, 155.8, 159.7. Mass spectrum (m/z,
ESI): 374.1; HRMS (ESI): m/z calculated for C21H21NO4 (M+Na)+: 374.1368, found:
374.1376.
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tert-Butyl (4-(4-methoxyphenyl)quinolin-2-yl) carbonate (2d): 2.5 h, grey solid, 58
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mg, 82% yield; mp: 45ꢀ46 C; Rf = 0.67 (20% EtOAc/Petroleum Ether); H NMR
(600 MHz, CDCl3) δ 1.59 (s, 9H), 3.91 (s, 3H), 7.07 (d, J = 7.9 Hz, 2H), 7.19 (s, 1H),
7.48 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.95 (d, J =
8.4 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 27.7, 55.4, 84.3,
114.1, 114.9, 125.9, 126.0, 126.5, 129.0, 129.6, 130.1, 130.8, 146.9, 151.0, 152.8,
155.8, 160.2. Mass spectrum (m/z, ESI): 374.1; HRMS (ESI): m/z calculated for
C21H21NO4 (M+Na)+: 374.1368, found: 374.1372.
tert-Butyl (4-(o-tolyl)quinolin-2-yl) carbonate (2e): 5 h, light yellow gum, 48 mg,
1
71% yield; Rf = 0.59 (5% EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ
1.58 (s, 9H), 2.06 (s, 3H), 7.14 (s, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.31ꢀ7.48 (m, 5H),
7.71 (t, J = 7.2 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.0,
27.7, 84.2, 115.4, 125.8, 125.9, 126.4, 126.5, 128.7, 129.1, 129.5, 130.1, 130.3, 136.0,
136.8, 146.7, 151.0, 152.8, 155.9. Mass spectrum (m/z, ESI): 358.1; HRMS (ESI): m/z
calculated for C21H21NO3 (M+Na)+: 358.1419, found: 358.1421.
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tert-Butyl (4-(m-tolyl)quinolin-2-yl) carbonate (2f): 3 h, white solid, 51 mg, 76%
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yield; mp: 88 C; Rf = 0.7 (20% EtOAc/Petroleum Ether); H NMR (600 MHz,
CDCl3) δ 1.59 (s, 9H), 2.46 (s, 3H), 7.19 (s, 1H), 7.32 (d, J = 9.0 Hz, 3H), 7.42 (t, J =
7.2 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H),
8.07 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.2, 27.2, 84.2, 115.0, 125.9,
126.0, 126.4, 126.6, 128.5, 129.1, 129.5, 130.0, 130.1, 137.3, 138.4, 147.0, 151.1,
153.1, 155.8. Mass spectrum (m/z, ESI): 358.2; HRMS (ESI): m/z calculated for
C21H21NO3 (M+Na)+: 358.1419, found: 358.1427.
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tert-Butyl (4-(p-tolyl)quinolin-2-yl) carbonate (2g): 3 h, white solid, 46 mg, 68%
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yield; mp: 77ꢀ78 C; Rf = 0.4 (70% CH2Cl2/Petroleum Ether); H NMR (400 MHz,
CDCl3) δ 1.58 (s, 9H), 2.45 (s, 3H), 7.18 (s, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.40 (d, J =
7.9 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.91 (d, J = 4.4 Hz,
1H), 8.07 (d, J = 8.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 21.3, 27.7, 84.2, 115.0,
125.9, 126.0, 126.4, 129.1, 129.3, 129.4, 130.0, 134.4, 138.8, 147.1, 151.1, 153.0,
155.8. Mass spectrum (m/z, ESI): 358.1; HRMS (ESI): m/z calculated for C21H21NO3
(M+Na)+: 358.1419, found: 358.1423.
tert-Butyl (4-(3-fluorophenyl)quinolin-2-yl) carbonate (2h): 5 h, white solid, 43
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mg, 64% yield; mp: 97ꢀ98 C; Rf = 0.62 (CH2Cl2/Petroleum Ether = 4:1); H NMR
(600 MHz, CDCl3) δ 1.59 (s, 9H), 7.21ꢀ7.25 (m, 3H), 7.30 (d, J = 7.4 Hz, 1H),
7.49ꢀ7.53 (m, 2H), 7.75 (t, J = 7.2 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.3
Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 27.7, 84.4, 115.1, 115.8 (d, JCꢀF = 22.3 Hz),
116.6 (d, JCꢀF = 22.3 Hz), 125.3 (d, JCꢀF = 2.8 Hz), 125.5 (d, JCꢀF = 8.4 Hz), 126.8,
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129.2, 130.3 (d, JCꢀF = 3.0 Hz), 130.4, 139.4 (d, JCꢀF = 7.6 Hz), 147.0, 151.0, 151.3,
155.7, 162.7 (d, JCꢀF = 246.0 Hz). Mass spectrum (m/z, ESI): 362.1; HRMS (ESI): m/z
calculated for C20H18FNO3 (M+Na)+: 362.1168, found: 362.1179.
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tert-Butyl (4-(4-fluorophenyl)quinolin-2-yl) carbonate (2i): 3 h, white solid, 52 mg,
76% yield; mp: 105ꢀ106 oC; Rf = 0.63 (CH2Cl2/Petroleum Ether = 4:1); 1H NMR (600
MHz, CDCl3) δ 1.59 (s, 9H), 7.18 (s, 1H), 7.22 (t, J = 7.7 Hz, 2H), 7.49 (s, 3H), 7.72
(t, J = 6.8 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ 27.7, 84.3, 115.2, 115.7 (d, JCꢀF = 21.5 Hz), 125.5, `125.8, 126.7,
129.2, 130.2, 131.2 (d, JCꢀF = 8.4 Hz), 133.3, (d, JCꢀF = 3.2 Hz), 147.0, 151.1, 151.7,
155.7, 163.1 (d, JCꢀF = 247.4 Hz). Mass spectrum (m/z, ESI): 362.1; HRMS (ESI): m/z
calculated for C20H18FNO3 (M+Na)+: 362.1168, found: 362.1179.
tert-Butyl (4-(3-chlorophenyl)quinolin-2-yl) carbonate (2j): 7 h, white solid, 38
o
1
mg, 53% yield; mp: 103ꢀ104 C; Rf = 0.5 (CH2Cl2/Petroleum Ether = 4:1); H NMR
(600 MHz, CDCl3) δ 1.59 (s, 9H), 7.20 (s, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.46 (d, J =
7.0 Hz, 2H), 7.52 (t, J = 11.6 Hz, 2H), 7.75 (t, J = 7.5 Hz, 1H), 7.84 (d, J = 8.4 Hz,
1H), 8.09 (d, J = 8.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 27.7, 84.3, 115.1, 125.4,
125.5, 126.8, 127.7, 128.9, 129.2, 129.4, 129.9, 130.3, 134.7, 139.1, 147.0, 151.0,
151.1, 155.7. Mass spectrum (m/z, ESI): 378.0; HRMS (ESI): m/z calculated for
C20H18ClNO3 (M+Na)+: 378.0873, found: 378.0881.
tert-Butyl (4-(4-chlorophenyl)quinolin-2-yl) carbonate (2k): 3 h, white solid, 53
mg, 74% yield; mp: 115ꢀ116 oC; Rf = 0.47 (CH2Cl2/Petroleum Ether = 4:1); 1H NMR
(400 MHz, CDCl3) δ 1.59 (s, 9H), 7.19 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.51 (m,
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3H), 7.75 (t, J =8.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H); 13C
NMR (150 MHz, CDCl3) δ 27.8, 84.3, 115.1, 125.4, 125.6, 126.8, 129.0, 129.2, 130.2,
130.8, 135.1, 135.7, 147.0, 151.0, 151.5, 155.7. Mass spectrum (m/z, ESI): 378.1;
HRMS (ESI): m/z calculated for C20H18ClNO3 (M+Na)+: 378.0873, found: 378.0863.
tert-Butyl (4-(3-(trifluoromethyl)phenyl)quinolin-2-yl) carbonate (2l): 5 h, white
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solid, 45 mg, 58% yield; mp: 40 C; Rf = 0.67 (20% EtOAc/Petroleum Ether); H
NMR (600 MHz, CDCl3) δ 1.60 (s, 9H), 7.23 (s, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.68 (t,
J = 7.8 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 9.0 Hz,
3H), 8.10 (d, J = 8.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 27.7, 84.4, 115.3, 123.9
(q, JCꢀF = 271.0 Hz), 125.2, 125.5, 125.6 (q, JCꢀF = 3.4 Hz), 126.2 (d, JCꢀF = 3.6 Hz),
127.0, 129.28, 129.32, 130.4, 131.2 (q, JCꢀF = 32.6 Hz), 132.8, 138.1, 147.0, 151.0,
155.7. Mass spectrum (m/z, ESI): 412.1; HRMS (ESI): m/z calculated for
C21H18F3NO3 (M+Na)+: 412.1136, found: 412.1146.
tert-Butyl (4-(naphthalen-1-yl)quinolin-2-yl) carbonate (2m): 5 h, white solid, 53
o
1
mg, 71% yield; mp: 135ꢀ136 C; Rf = 0.20 (20% EtOAc/Petroleum Ether); H NMR
(600 MHz, CDCl3) δ 1.59 (s, 9H), 7.31 (s, 1H), 7.35 (t, J = 7.1 Hz, 2H), 7.43ꢀ7.40 (m,
2H), 7.52ꢀ7.50 (m, 2H), 7.60 (t, J = 7.9 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.95 (d, J =
8.2 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ 27.7, 84.2, 116.4, 125.8, 126.28, 126.29, 126.5, 126.7, 127.1, 127.5, 128.3,
129.0, 129.1, 130.2, 131.7, 133.5, 134.9, 146.7, 151.0, 151.7, 155.9. Mass spectrum
(m/z, ESI): 394.2; HRMS (ESI): m/z calculated for C24H21NO3 (M+Na)+: 394.1419,
found: 394.1428.
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