Catalytic sp3 C-H oxidation of peptides and their analogues by radical cation salts: From glycine amides to quinolines

Article abstract of DOI:10.1021/jo401018v

A catalytic α-sp³ C-H oxidation of peptides and glycine amides was achieved under radical cation salt catalysis in the presence of O₂, producing a series of substituted quinolines. The scope of this reaction shows good functional group tolerance and high efficiency of the oxidative functionalization.

Full text of DOI:10.1021/jo401018v

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Note
Catalytic sp3 C-H Oxidation of Peptides and Their Analogues
by Radical Cation Salts: from Glycine Amides to Quinolines
Xiaodong Jia, Yaxin Wang, Fangfang Peng, Congde Huo, Liangliang Yu, Jing Liu, and Xicun Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401018v • Publication Date (Web): 16 Aug 2013
Downloaded from http://pubs.acs.org on August 17, 2013
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Catalytic sp3 C-H Oxidation of Peptides and Their Analogues by Radical Cation
Salts: from Glycine Amides to Quinolines
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a
Xiaodong Jia,a,* Yaxin Wang,a Fangfang Peng, a Congde Huo, a Liangliang Yu, a Jing Liu, Xicun
Wang a
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China.
Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, China
E-mail: jiaxd1975@163.com
Table of Contents Graphic
Abstract: A catalytic α-sp3 C-H oxidation of peptides and glycine amides was achieved under
radical cation salt catalysis in the presence of O2, producing a series of substituted quinolines. The
scope of this reaction shows good functional group tolerance and high efficiency of the oxidative
functionalization.
With the study of the properties and functions of natural and non-natural amino acids, great efforts
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have been devoted to synthesis and modification of amino acids. [1] Since natural amino acids are
relatively cheap and accessible, the development of a method for the direct modification of natural
amino acids would provide a convenient way to access diverse new amino acids and peptides,
which have potentially biological activities. Besides classical methods of functionalization of
amino acid derivatives, such as α-functionalization with a strong base, [2] α-bromination by NBS,
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[3]
[4]
[5]
Claisen rearrangements,
and UV photolysis,
Li and other groups recently developed a
direct α-C-H functionalization of amino acids and peptides, which provided a more convenient
way to synthesize amino acid derivatives. [6] Furthermore, Mancheño and Hu provided an efficient
route to quinolines using glycine derivatives via tandem cross dehydrogenative coupling (CDC)
[7]
reaction. However, in these elegant transformations, excess quantities of the oxidants (such as
DDQ, TEMPO oxoammonium and peroxides) are needed, which increases the amount of organic
or inorganic byproducts and causes the environmental impact as a result.
[8]
Over one century ago, the famous Wurster’s Red and Blue salts were prepared in 1879. Since
[9]
then a great variety of persistent and isolable radical cation salts have been prepared. Among
them, aminium radical cation salts, tris(2,4-dibromophenyl)aminium hexachloroantimonate
(TDBPAꢀQ) and the commercially available tris(4-bromophenyl)aminium hexachloroantimonate
(TBPAꢀQ), have been widely used to achieve selective and highly efficient transformations, such as
[10]
Diels-Alder reactions, rearrangements, couplings, etc.
In these transformations, radical cation
salts were used as single electron oxidants to obtain one electron from electron-rich substrate,
producing a radical cation intermediate which undergoes further transformations (See Figure 1, A).
[10, 11]
However, no report involving their ability to initiate aerobic oxidation of C-H bond was
established.
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Figure 1. Different reaction patterns induced by radical cation salts
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Recently, we reported, for the first time a catalytic α-C-H oxidation of glycine esters using
triarylaminium radical cation salts as an efficient initiator to prompt aerobic oxidation of α-sp3
[12]
C-H bond.
In this reaction, triarylaminium radical cation salts can react with O2 to generate a
distonic peroxide radical cation, followed by H-abstraction reaction from substrates to achieve
α-sp3 C-H bond activation (See Figure 1B). So we wondered whether our catalytic system could
be applied to more general substrates and whether this catalytic α-C-H bond activation could be
further extended to peptides and their analogues. Li et al. have reported that glycine esters, unlike
glycine amides, did not undergo the CDC reaction with alkynes and arylboronic acids, [6b] which
suggested that substituent effect significantly affects the CDC reaction. Herein, we wish to report
a novel method for modifying glycine amides and peptides through direct reaction at α-C-H bonds,
to provide an access to the quinoline skeleton in a catalytic CDC process.
Table 1. Optimization of Reaction Conditions in the Transformation of 1a into 3a.
Yield
(%)b
64
Entry
1
InCl3.H2O (mol %)
10 mol %
TBPA+. (mol %)
10 mol %
T (oC)
65
O2 or air
air
Solvent
CH3CN
Time (h)a
3
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2
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10 mol %
none
10 mol %
10 mol %
10 mol %
none
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65
65
65
r. t.
0
O2
air
O2
air
O2
O2
O2
O2
O2
O2
O2
O2
O2
-
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
40 min
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41
3
4
none
3
24
42
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
NR
NR
12
5
none
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7
10 mol %
10 mol %
10 mol %
1 mol %
5 mol %
10 mol %
10 mol %
10 mol %
10 mol %
40 min
40 min
40 min
1
8
CHCl3
36
9
ClCH2CH2Cl
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
46
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15c
trace
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3
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80 min
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trace
a Monitored by TLC; b Detected by crude 1H NMR based on 1a. c Under argon atmosphere.
We started our study with the radical cation salts initiated CDC reaction of
N-methyl-2-(p-tolylamino)acetamide (1a) with styrene (2a) in the presence of 10 mol % of
TBPAꢀQ and 10 mol % InCl3·4H2O under open air. The reaction gave a moderate yield of the
desired product 3a (Table 1, entry 1). [13] If the reaction solution was performed under O2 (1 atm),
only after 40 minutes, a 65% yield was reached (entry 2). In the absence of InCl3·4H2O, the
starting materials could also be completely consumed, but only poor yields were obtained under
air or O2, respectively, together with some unidentified oxidation products (entries 3 and 4).
However, no product was detected in the absence of TBPAꢀQ, which implied that Lewis acid could
only accelerate the reaction between glycine amide and styrene instead of initiating it (entries 5
and 6). Solvent optimization efforts showed that acetonitrile was a better solvent, probably due to
that InCl3·4H2O has a higher solubility in acetonitrile (entries 7 to 9 compared to entry 2).
Reducing the catalyst loading to 5 mol % and 1 mol % led to decrease in the yields (entries 10 and
11). Lower reaction temperature decreased the reaction rate and the yield (entries 12 to 13). Below
o
40 C, the best result was obtained using acetonitrile as a solvent (entry 14). We also tried the
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model reaction in the absence of O2 (entry 15), and only trace of the desired product was
generated, which implied that O2 is crucial to the C-H bond oxidation.
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Scheme 1. Transformation of N-phenylglycine amides into quinoline-2-carboxamides
a Below 40oC; b 20 mol % TBPAꢀQ added; c 15 mol % TBPA+. added; d Under refluxing.
Under the best reaction conditions established, the generality of this catalytic CDC reaction was
investigated. We used styrene as a nucleophile to test the substituent effect on glycine amides, and
the results were compiled in Scheme 1. Glycine amides with electron-donating groups afforded
the quinoline products in good yields (3a and 3b). When glycine amides with
electron-withdrawing groups were employed, higher catalyst loading was needed and good to
excellent yields were obtained after prolonged reaction time (3c and 3d). Electron-donating
groups make the substrate easier to be oxidized and some non-identified oxidation products were
1
observed by crude H NMR. Interestingly, phenolic hydroxyl group could also be tolerated,
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producing the desired product in good yield, which suggested good functional group tolerance of
the standard oxidation conditions (3e). In the absence of a para-substituent at the aniline, the
quinoline products 3f-i were isolated in lower yields together with some unidentified products.
Most likely coupling at the p-position of the aniline moiety of the starting N-phenylglycine amide
would provide undesired byproducts. [14]
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Other N-(4-bromophenyl)glycine amides were then tested. The corresponding N-phenyl amide
gave the desired product 3j in medium yield, and N-benzylamide with another active benzyl sp3
C-H bond could also be tolerated, producing the 3k product in 80% yield, which suggested that
site-specific activation of glycine amides and peptides could be achieved via the current methods.
Steric hindrance has a deleterious effect on reaction efficiency, as bulky amide reacted to form the
desired product 3l in 42% yield. We also found that a primary amide group does not affect the
efficiency of the reaction, giving a medium yield of 3m. According to Li’s report, the CDC
reaction does not work when glycine amides without hydrogen on the amide nitrogen are
[6b]
employed.
The current method could also be applied to these kinds of amides, showing good
functional group tolerance.
Scheme 2. Reaction of N-(4-bromophenyl)glycine amides with styrenes
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To further extend the scope of our protocol, we next turned our attention to various alkenes other
than styrene (Scheme 2). Styrene derivatives with electron-donating groups gave better results
than electron-withdrawing groups (3o, 3p, 3q vs. 3s), but the acetoxy group decreased the yield
due to its decomposition under oxidation conditions (3r).
Scheme 3. Reactions of N-(4-bromophenyl)glycine amides with cyclic 1,3-dienes
Next, other aliphatic olefins were employed in this reaction. When cyclopentadiene was used, a
mixture of two polycyclic quinolines (Scheme 3, 4a and 4a’) was isolated in medium yields (ratio
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= 1.6:1), one of the components of which (4a’) was identified by single crystal X-ray structure
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[15]
analysis.
It is well-known that cyclopentadiene could undergo the Diels-Alder
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[10a]
cyclodimerization to yield [4+2] adduct under SET oxidation conditions,
which further
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reacted with glycine amides, generating the tandem DA / imino DA / aromatization products. But
when cyclohexadiene was used instead of cyclopentadiene, no such polycyclic adduct was found
(Scheme 3). Besides the normal quinoline product 5 was isolated in 27% yield, a phenanthridine
derivative 6 (formed through aromatization of 5) was obtained. This reaction might open a new
potential way to synthesize phenanthridine derivatives, and further investigations and applications
were still under way in this laboratory.
Scheme 4. Catalytic transformations of dipeptide esters
Having succeeded in the catalytic functionalization of glycine amides, we decided to apply this
methodology to more challenging substrates. Because of the diverse existence of peptides in
nature, we focused on the catalytic functionalization of dipeptides. To our delight, glycine
derived dipeptides reacted smoothly with styrene, affording the quinolines in good yield (Scheme
4, 7a and 7b). It is worth mentioning that the functionalization occurred exclusively at the N
terminus of the dipeptides without any scrambling on other amino acid moieties.
Scheme 5. Plausible rationale for the α-sp3 C-H activation of N-phenylglycine amides and their
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transformation into 4-phenylquinoline-2-carboxamides
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On the basis of the results that we obtained, a plausible pathway was presented (Scheme 5).
Glycine amide was oxidized by TBPAꢀQ in the presence of O2, yielding a glycine imine
[16]
intermediate, which readily reacted with alkenes catalyzed by InCl3·4H2O (Povarov reaction).
The corresponding tetrahydroquinoline intermediate was further oxidized and aromatized to
quinolines. More details of the mechanism are currently under investigation in this laboratory.
In summary, we demonstrated an efficient radical cation salt prompted sp3 C-H oxidaiton of
glycine amides and peptides. Different from reported CDC reactions, only catalytic amounts of
triarylaminium radical cation salts can efficiently induce this reaction, avoiding addition of excess
oxidants. This method might potentially open a new way to achieve CDC reactions and also make
a contribution to research in radical cation chemistry. The mild reaction conditions, good
functional group tolerance and the high efficiency of the oxidative functionalization make the
present transformation attractive for future applications.
Experimental Section
Typical Procedure for TBPA+. Induced Reaction of Glycine amides and Styrenes
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A solution of 1 (0.5 mmol), 2 (1.25 mmol) and InCl3·4H2O (10 mol %) in CH3CN (5 ml) was
mixed fully and then flushed with O2 (keep flushing until the reaction has been completed),
followed by addition of TBPAꢀQ (10 mol % based on 1) under certain temperature. After
completion has been monitored by TLC, the reaction was quenched with sodium carbonate /
methanol solution. The mixture was poured into a separatory funnel with the addition of excess
DCM, and then the crude organic solution was extracted three times with water to remove
inorganic salts. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and
the solvent was removed under reduced pressure. The products were separated by silica gel
column chromatography using petroleum ether/acetone (v/v 10:1) to afford the products.
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N,6-Dimethyl-4-phenylquinoline-2-carboxamide (3a)
Compound 3a was isolated in 65% yield (89.7 mg, colorless crystal); mp 168.0−170.0 °C;1H
NMR (400 MHz, CDCl3): δ 8.20 (s, NH, 1H), 8.15 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H),
7.51 (d, J = 8.5 Hz, 1H), 7.45 (s, 5H), 3.04 (d, J = 5.1 Hz, 3H), 2.41 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 165.3, 149.1, 148.5, 145.7, 138.1, 137.9, 132.2, 129.6, 129.6, 128.6, 128.5, 127.7, 124.6,
119.1, 26.2, 22.0; EI-MS m/z (relative intensity, %): 276 (20.6%), 247 (5.4%), 219 (100%), 204
(14.0%); HRMS (ESI, ion trap): Calc’d for C18H16N2O+H+, 277.1341; found, 277.1351.
6-Methoxy-N-methyl-4-phenylquinoline-2-carboxamide (3b) 7b
1
Compound 3b was isolated in 70% yield (102.2 mg, colorless crystal); mp 171.0−174.0 °C; H
NMR (400 MHz, CDCl3) δ 8.30 – 8.19 (m, 2H), 8.02 (dd, J = 9.2, 3.0 Hz, 1H), 7.59 – 7.44 (m, 4H),
7.43 – 7.36 (m, 1H), 7.28 – 7.20 (m, 2H), 3.79 (s, 3H), 3.10 (d, J = 4.8 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 165.4, 158.9, 148.3, 147.2, 143.1, 138.0, 131.4, 129.3, 128.9, 128.7, 128.5, 122.6, 119.4,
103.5, 55.5, 26.2; EI-MS m/z (relative intensity, %): 292 (22.0%), 263 (6.2%), 235 (100%), 191
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(18.3%); HRMS (ESI, ion trap): Calc’d for C18H16N2O2+H+, 293.1290; found, 293.1289.
6-Chloro-N-methyl-4-phenylquinoline-2-carboxamide (3c) 7b
9
1
Compound 3c was isolated in 98% yield (145.0 mg, colorless crystal); mp 206.0−208.0 °C; H
NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.16 (s, NH, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 2.2 Hz,
1H), 7.62 (dd, J = 9.0, 2.3 Hz, 1H), 7.51 – 7.41 (m, 5H), 3.04 (d, J = 5.0 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 164.8, 149.6, 149.3, 145.5, 137.0, 134.0, 131.6, 130.8, 129.4, 128.9, 128.4, 124.8, 124.7,
119.8, 26.2; EI-MS m/z (relative intensity, %): 298 (8.7%), 296 (28.6%), 269 (3.4%), 267 (9.1%), 241
(34.0%), 239 (100%), 204 (31.3%), 203 (32.3%); HRMS (ESI, ion trap): Calc’d for C17H13ClN2O+H+,
297.0795; found, 297.0808.
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6-Bromo-N-methyl-4-phenylquinoline-2-carboxamide (3d)
1
Compound 3d was isolated in 79% yield (134.3 mg, colorless crystal); mp 231.0−235.0 °C; H
NMR (400 MHz, CDCl3) δ 8.28 (d, J = 1.6 Hz, 1H), 8.23 (s, NH, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.05 –
7.99 (m, 1H), 7.84 (dt, J = 9.0, 2.0 Hz, 1H), 7.60 – 7.48 (m, 5H), 3.12 (d, J = 5.3 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 164.8, 149.7, 149.2, 145.7, 137.0, 133.5, 133.4, 131.6, 129.6, 128.9, 128.8, 128.2,
122.3, 119.8, 26.2; EI-MS m/z (relative intensity, %): 342 (22.2%), 340 (22.1%), 313 (6.3%), 311
(7.2%), 285 (98.9%), 283 (100%), 204 (39.9%), 203 (48.9%); HRMS (ESI, ion trap): Calc’d for
C17H13BrN2O+H+, 341.0290; found, 341.0299.
6-Hydroxy-N-methyl-4-phenylquinoline-2-carboxamide (3e)
1
Compound 3e was isolated in 79% yield (109.8 mg, colorless crystal); mp 238.0−240.0 °C; H
NMR (400 MHz, DMSO) δ 10.27 (s, OH, 1H), 8.82 (d, NH, J = 4.8 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H),
7.89 (d, J = 1.9 Hz, 1H), 7.67 – 7.49 (m, 5H), 7.42 (dd, J = 9.1, 2.5 Hz, 1H), 7.21 – 7.15 (m, 1H), 2.89
(dd, J = 4.8, 1.6 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 164.9, 157.3, 146.9, 146.8, 141.9, 137.7,
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131.6, 129.2, 128.9, 128.7, 128.5, 123.0, 118.6, 106.2, 26.1; EI-MS m/z (relative intensity, %): 278
(31.0%), 249 (10.5%), 235 (9.0%), 221 (100%), 190 (12.1%), 165 (9.1%); HRMS (ESI, ion trap):
Calc’d for C17H14N2O2+H+, 279.1134; found, 279.1145.
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N-Methyl-4-phenylquinoline-2-carboxamide (3f) 7b
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Compound 3f was isolated in 22% yield (28.8 mg, colorless ail); H NMR (400 MHz, CDCl3) δ
8.32 (s, NH, 1H), 8.29 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.81 – 7.73 (m, 1H),
7.62 – 7.47 (m, 6H), 3.13 (d, J = 5.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.2, 150.0, 149.4,
147.1, 137.7, 130.0, 129.9, 129.6, 128.6, 127.8, 127.7, 126.0, 119.0, 26.3, one 13C signal lost for
overlap; EI-MS m/z (relative intensity, %): 262 (34.0%), 231 (18.4%), 205 (100%), 190 (20.8%), 176
(13.5%), 105 (15.6%); HRMS (ESI, ion trap): Calc’d for C17H14N2O+H+, 263.1184; found, 263.1180.
N,8-Dimethyl-4-phenylquinoline-2-carboxamide (3g)
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Compound 3g was isolated in 15% yield (20.7 mg, colorless oil); H NMR (400 MHz, CDCl3) δ
8.32 (s, NH, 1H), 8.28 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.58 – 7.42 (m, 4H),
7.38 – 7.34 (m, 1H), 6.94 – 6.91 (m, 1H), 3.16 (d, J = 5.1 Hz, 3H), 2.89 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 165.5, 150.2, 147.9, 146.1, 138.2, 137.6, 132.5, 130.0, 129.6, 128.5, 127.5, 125.6, 124.0,
118.8, 26.3, 18.4; EI-MS m/z (relative intensity, %): 276 (28.1%), 247 (8.7%), 219 (100%), 189
(16.2%); HRMS (ESI, ion trap): Calc’d for C18H16N2O+H+, 277.1341; found, 277.1355.
8-Methoxy-N-methyl-4-phenylquinoline-2-carboxamide (3h)
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Compound 3h was isolated in 50% yield (73.0 mg, colorless crystal); mp 152.0-155.0 °C; H
NMR (400 MHz, CDCl3) δ 8.24 (s, NH, 1H), 8.22 (s, 1H), 7.51 – 7.37 (m, 7H), 7.04 (d, J = 7.6 Hz,
1H), 4.04 (s, 3H), 3.04 (d, J = 5.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.3, 155.6, 150.0, 148.3,
139.1, 138.0, 129.6, 129.0, 128.6, 128.5, 128.0, 119.8, 117.8, 108.0, 56.2, 26.2; EI-MS m/z (relative
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intensity, %): 292 (18.9%), 291 (18.3%), 235 (60.7%), 233 (100%), 204 (27.1%), 203 (24.5%); HRMS
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(ESI, ion trap): Calc’d for C18H16N2O2+H+, 293.1290; found, 293.1301.
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8-Chloro-N-methyl-4-phenylquinoline-2-carboxamide (3i)
Compound 3i was isolated in 62% yield (91.8 mg, colorless crystal); mp 178.0−180.0 °C; 1H NMR
(400 MHz, CDCl3) δ 8.39 (s, NH, 1H), 8.34 (s, 1H), 7.90 (t, J = 7.2 Hz, 2H), 7.60 – 7.44 (m, 6H), 3.15
(d, J = 5.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 164.8, 150.8, 149.5, 143.3, 137.4, 134.3, 129.0,
129.6, 129.2, 128.9, 128.7, 127.5, 125.1, 119.9, 26.4; EI-MS m/z (relative intensity, %): 298 (6.0%),
296 (19.9%), 269 (3.2%), 267 (11.9%), 241 (32.0%), 239 (100%), 204 (31.4%); HRMS (ESI, ion trap):
Calc’d for C17H13ClN2O+H+, 297.0795; found, 297.0805.
6-Bromo-N,4-diphenylquinoline-2-carboxamide (3j)
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Compound 3j was isolated in 54% yield (108.5 mg, colorless crystal); mp 225.0−227.0 °C; H
NMR (400 MHz, CDCl3) δ 10.20 (s, NH, 1H), 8.39 (s, 1H), 8.19 – 8.09 (m, 2H), 7.88 (t, J = 8.2 Hz,
3H), 7.57 (q, J = 7.7 Hz, 5H), 7.44 (t, J = 7.9 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δ 161.8, 149.7, 145.5, 137.7, 136.9, 133.7, 131.7, 129.6, 129.5, 129.1, 129.1, 129.0, 128.9,
128.2, 124.5, 122.7, 119.8, one 13C signal lost for overlap; EI-MS m/z (relative intensity, %): 404
(78.8%), 402 (80.7%), 285 (90.1%), 283 (100%), 203 (70.9%), 176 (21.6%); HRMS (ESI, ion trap):
Calc’d for C22H15BrN2O+H+, 403.0446; found, 403.0455.
N-Benzyl-6-bromo-4-phenylquinoline-2-carboxamide (3k)
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Compound 3k was isolated in 80% yield (172.0 mg, colorless crystal); mp 256.0-257.0 °C; H
NMR (400 MHz, CDCl3) δ 8.59 (t, NH, J = 5.5 Hz, 1H), 8.34 (s, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.01 (d,
J = 9.0 Hz, 1H), 7.83 (dd, J = 9.0, 2.1 Hz, 1H), 7.62 – 7.49 (m, 5H), 7.44 (d, J = 7.1 Hz, 2H), 7.39 (t, J
= 7.4 Hz, 2H), 7.33 (dd, J = 8.3, 6.0 Hz, 1H), 4.77 (d, J = 6.1 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ
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164.1, 149.5, 149.3, 145.7, 138.2, 137.0, 133.5, 131.7, 129.5, 129.0, 128.9, 128.9, 128.8, 128.1, 127.9,
127.6, 122.4, 120.0, 43.7; EI-MS m/z (relative intensity, %): 418 (22.2%), 416 (19.7%), 375 (22.9%),
373 (24.2%), 285 (41.5%), 283 (47.4%), 204 (22.4%), 203 (31.9%), 106 (100%); HRMS (ESI, ion
trap): Calc’d for C23H17BrN2O+Na+, 439.0422; found, 439.0429.
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6-Bromo-N-(tert-butyl)-4-phenylquinoline-2-carboxamide (3l)
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Compound 3l was isolated in 42% yield (80.2 mg, colorless crystal); mp 216-220.0 °C; H NMR
(400 MHz, CDCl3) δ 8.29 (s, 1H), 8.20 (s, NH, 1H), 8.12 (s, 1H), 8.05 (d, J = 9.0 Hz, 1H), 7.84 (dd, J =
9.0, 2.0 Hz, 1H), 7.53 (dd, J = 17.9, 7.6 Hz, 5H), 1.57 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 163.3,
150.6, 149.2, 145.6, 137.1, 133.3, 131.6, 129.4, 128.9, 128.8, 128.7, 128.1, 122.2, 119.6, 51.1, 28.8;
EI-MS m/z (relative intensity, %): 384 (38.4%), 382 (40.9%), 369 (93.8%), 367 (93.8%), 284 (89.2%),
282 (100%), 203 (76.2%); HRMS (ESI, ion trap): Calc’d for C20H19BrN2O+H+, 383.0759; found,
383.0759.
6-Bromo-4-phenylquinoline-2-carboxamide (3m)
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Compound 3m was isolated in 54% yield (88.0 mg, colorless crystal); mp 240.0-242.0 °C; H
NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.15 (d, J = 2.1 Hz, 1H), 8.05-8.07 (m, 3H), 7.86 (dd, J = 9.0,
2.2 Hz, 1H), 7.62 – 7.49 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 166.7, 149.0, 145.8, 136.9, 133.6,
132.5, 131.8, 129.5, 129.0, 128.9, 128.1, 125.6, 122.7, 119.9; EI-MS m/z (relative intensity, %): 328
(4.1%), 326 (4.7%), 306 (25.1%), 304 (28.1%), 201 (18.9%), 199 (19.3%), 186 (96.2%), 184 (100%),
173 (20.0%), 171 (22.2%); HRMS (ESI, ion trap): Calc’d for C16H11BrN2O+Na+, 348.9953; found,
348.9955.
6-Bromo-N,N-dimethyl-4-phenylquinoline-2-carboxamide (3n)
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Compound 3n was isolated in 95% yield (168.1 mg, colorless crystal); mp 207.0-209.0 °C; H
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NMR (400 MHz, CDCl3) δ 8.07 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.81 (dd, J = 9.0, 2.2 Hz,
1H), 7.66 (s, 1H), 7.54 – 7.47 (m, 5H), 3.19 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 168.6, 154.0, 148.8,
145.6, 136.7, 133.3, 131.6, 129.3, 128.9, 128.8, 127.8, 127.6, 121.8, 121.4, 39.0; EI-MS m/z (relative
intensity, %): 356 (43.9%), 354 (43.1%), 299 (20.0%), 297 (20.6%), 285 (96.1%), 283 (100%), 204
(32.6%), 203 (44.9%); HRMS (ESI, ion trap): Calc’d for C18H15BrN2O+H+, 355.0446; found,
355.0459.
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6-Bromo-N,3-dimethyl-4-phenylquinoline-2-carboxamide (3o)
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Compound 3o was isolated in 80% yield (141.6 mg, colorless crystal); mp 195.0-198.0 °C; H
NMR (400 MHz, CDCl3) δ 8.27 (s, NH, 1H), 8.22 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.82 (dd, J = 9.0,
2.1 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.46 – 7.31 (m, 3H), 7.20 (d, J = 7.3 Hz, 1H), 3.13 (d, J = 5.1 Hz,
3H), 2.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.9, 149.7, 149.3, 145.4, 136.4, 135.8, 133.6,
131.6, 130.5, 129.5, 128.9, 128.2, 126.0, 122.4, 26.3, 20.0; EI-MS m/z (relative intensity, %): 356
(39.8%), 354 (40.8%), 299 (100%), 297 (97.2%), 217 (37.1%), 203 (12.6%); HRMS (ESI, ion trap):
Calc’d for C18H15BrN2O+H+, 355.0446; found, 355.0440.
6-Bromo-N-methyl-4-(p-tolyl)quinoline-2-carboxamide (3p)
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Compound 3p was isolated in 71% yield (125.7 mg, colorless crystal); mp 197.0-200.0 °C; H
NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.25 (s, NH, 1H), 8.16 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 9.0 Hz,
1H), 7.82 (dd, J = 9.0, 2.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 3.13 (d, J = 5.1
Hz, 3H), 2.49 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.9, 149.7, 149.3, 145.7, 139.0, 134.1, 133.4,
131.6, 129.6, 129.4, 128.9, 128.2, 122.2, 119.8, 26.3, 21.3; EI-MS m/z (relative intensity, %): 356
(40.8%), 354 (40.7%), 299 (96.3%), 297 (100%), 217 (27.3%), 203 (20.0%); HRMS (ESI, ion trap):
Calc’d for C18H15BrN2O+H+, 355.0446; found, 355.0447.
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6-Bromo-4-(4-methoxyphenyl)-N-methylquinoline-2-carboxamide (3q)
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Compound 3q was isolated in 76% yield (140.6 mg, colorless crystal); mp 185.0-188.0 °C; H
NMR (400 MHz, CDCl3) δ 8.26-8.24 (m, 2H), 8.17 (s, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 9.0
Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H), 3.12 (d, J = 5.1 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 164.8, 160.2, 149.6, 148.9, 145.7, 133.3, 131.5, 130.8, 129.2, 128.9, 128.1,
122.1, 119.6, 114.3, 55.4, 26.2; EI-MS m/z (relative intensity, %): 372 (33.4%), 370 (32.6%), 315
(100%), 313 (98.7%), 203 (13.5%); HRMS (ESI, ion trap): Calc’d for C18H15BrN2O2+H+, 371.0395;
found, 371.0400.
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4-(6-Bromo-2-(methylcarbamoyl)quinolin-4-yl)phenyl acetate (3r)
Compound 3r was isolated in 50% yield (99.5 mg, colorless crystal); mp 171.0-173.0 °C; 1H NMR
(400 MHz, CDCl3) δ 8.27 (s, 1H), 8.23 (s, NH, 1H), 8.13 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H),
7.84 (dd, J = 9.0, 2.1 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 3.12 (d, J = 5.1 Hz,
3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.2, 164.7, 151.1, 149.5, 148.1, 145.6, 134.4,
133.5, 131.6, 130.6, 128.6, 127.8, 122.5, 122.1, 119.8, 26.3, 21.2; EI-MS m/z (relative intensity, %):
400 (20.2%), 398 (20.5%), 358 (43.6%), 356 (45.8%), 301 (99.6%), 299 (100%), 219 (15.8%), 190
(23.8%); HRMS (ESI, ion trap): Calc’d for C19H15BrN2O3+H+, 399.0344; found, 399.0354.
6-Bromo-4-(4-bromophenyl)-N-methylquinoline-2-carboxamide (3s)
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Compound 3s was isolated in 59% yield (123.3 mg, colorless crystal); mp 256.0-258.0 °C; H
NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.21 (s, NH, 1H), 8.05 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 9.0 Hz,
1H), 7.85 (dd, J = 9.0, 2.0 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 3.13 (d, J = 5.1
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 164.6, 149.6, 147.8, 145.6, 135.8, 133.6, 132.1, 131.7, 131.0,
128.4, 127.7, 123.4, 122.6, 119.7, 26.3; EI-MS m/z (relative intensity, %): 422 (11.4%), 420 (22.5%),
418 (11.0%), 365 (52.0%), 363 (100%), 361 (52.3%), 203 (27.9%); HRMS (ESI, ion trap): Calc’d for
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C17H12Br2N2O+H+, 418.9395; found, 418.9406.
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2-Bromo-N-methyl-7a,10,10a,11-tetrahydro-7H-7,11-methanocyclopenta
[j]phenanthridine-6-carboxamide (4a and 4a’)
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Compound 4a and 4a’ was isolated in 41% yield as a mixture of two isomers (75.4 mg, colorless
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crystal, ratio: 1 :1.6); 4a’: mp 176.0-178.0 °C; Major product, H NMR (400 MHz, CDCl3) δ
8.21 (s, NH, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 7.70 (d, J = 1.9 Hz, 1H), 5.38 (dd, J = 5.4,
2.2 Hz, 1H), 4.81 (dd, J = 5.5, 1.7 Hz, 1H), 4.73 (d, J = 3.8 Hz, 1H), 3.90 (d, J = 4.0 Hz, 1H), 3.77
– 3.70 (m, 1H), 3.28 – 3.15 (m, 1H), 3.06 (d, J = 5.2 Hz, 3H), 2.26 – 2.08 (m, 1H), 2.02 – 1.89 (m,
2H), 1.38 – 1.22 (m, 1H); Minor product, 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.99 (d, J
= 2.0 Hz, 1H), 7.89 (s, 1H), 7.68 (d, J = 1.9 Hz, 1H), 5.13 (dd, J = 5.4, 2.2 Hz, 1H), 4.85 (dd, J =
5.5, 1.8 Hz, 1H), 4.68 (d, J = 4.0 Hz, 1H), 3.93 (d, J = 3.8 Hz, 1H), 3.81 – 3.65 (m, 1H), 3.29 –
3.14 (m, 1H), 3.07 (d, J = 5.2 Hz, 3H), 2.26 – 2.08 (m, 1H), 2.03 – 1.89 (m, 2H), 1.80 – 1.61 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 165.8, 165.7, 156.5, 153.0, 144.7, 144.4, 143.5, 140.2, 137.5,
132.3, 132.3, 132.1, 131.8, 131.7, 130.9, 130.2, 127.5, 126.8, 126.1, 126.0, 121.5, 121.4, 54.1,
53.9, 51.4, 51.3, 47.3, 46.7, 45.8, 45.3, 41.2, 41.1, 34.0, 33.8, 25.9, 25.8, one 13C signal lost for
overlap; EI-MS m/z (relative intensity, %): 370 (41.1%), 368 (41.8%), 304 (34.2%), 302 (35.4%), 247
(74.3%), 245 (100%), 166 (26.2%), 164 (26.2%); HRMS (ESI, ion trap): Calc’d for C19H17BrN2O+H+,
369.0603; found, 369.0593.
2-Bromo-N-methyl-7,8-dihydrophenanthridine-6-carboxamide
2-Bromo-N-methylphenan- thridine-6-carboxamide (6)
(5)
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Compound 5 and 6 was isolated as a mixture (77.2 mg); 5: mp 169.0-171.0 °C; Mixture of two
products; 1H NMR (400 MHz, CDCl3) δ 9.52 (d, J = 8.4 Hz, 1H), 8.61 (d, J = 1.9 Hz, 1H), 8.45 (d,
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J = 8.3 Hz, 1H), 8.10 (t, J = 14.6 Hz, 3H), 7.91 (d, J = 8.7 Hz, 1H), 7.88 – 7.80 (m, 1H), 7.80 –
7.70 (m, 3H), 7.67 (dd, J = 9.0, 1.9 Hz, 1H), 7.07 (d, J = 9.9 Hz, 1H), 6.62 – 6.52 (m, 1H), 3.53 (t,
J = 8.6 Hz, 2H), 3.12 (d, J = 5.1 Hz, 3H), 3.05 (d, J = 5.1 Hz, 3H), 2.37 (ddt, J = 10.9, 8.0, 4.0 Hz,
2H); 13C NMR (101 MHz, CDCl3) δ 166.8, 166.3, 149.8, 148.3, 143.7, 140.3, 138.2, 136.6, 132.4,
132.3, 132.1, 131.7, 131.4, 131.2, 129.0, 128.5, 128.1, 126.6, 125.7, 124.9, 124.2, 122.7, 121.7,
121.6, 121.2, 26.4, 26.2, 22.6, 22.5, one 13C signal lost for overlap; EI-MS m/z (relative
intensity, %): 5: 318 (22.9%), 316 (23.0%), 259 (95.8%), 257 (100%); 6: 316 (17.8%), 314 (16.5%),
259 (97.6%), 257 (100%); HRMS (ESI, ion trap): Calc’d for 5 (C15H13BrN2O+H+), 317.0290; found,
317.0282; 6 (C15H11BrN2O+H+), 315.0133; found, 315.0138.
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Ethyl N-[(6-methoxy-4-phenylquinolin-2-yl)carbonyl] aminoacetate (7a)
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Compound 7a was isolated in 81% yield (147.4 mg, colorless crystal); mp 226.0-229.0 °C; H
NMR (400 MHz, CDCl3) δ 8.69 (t, J = 5.5 Hz, NH, 1H), 8.19 (s, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.60 –
7.46 (m, 5H), 7.42 (dd, J = 9.2, 2.7 Hz, 1H), 7.24 (d, J = 2.6 Hz, 1H), 4.34 (d, J = 5.7 Hz, 2H), 4.28 (q,
J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.9, 165.0,
159.0, 148.2, 146.4, 143.2, 138.0, 131.7, 129.3, 129.0, 128.7, 128.5, 122.7, 119.4, 103.4, 61.5, 55.5,
41.5, 14.2; EI-MS m/z (relative intensity, %): 364 (29.0%), 318 (18.3%), 291 (25.4%), 235 (100%),
234 (81.1%), 191 (22.8%), 190 (13.2%); HRMS (ESI, ion trap): Calc’d for C21H20N2O4+Na+, 387.1321;
found, 387.1310.
N-[(6-Methoxy-4-phenylquinolin-2-yl)carbonyl]-2-aminopropionate (7b)
1
Compound 7b was isolated in 78% yield (147.4 mg, colorless crystal); mp 211.0-213.0 °C; H
NMR (400 MHz, CDCl3) δ 8.71 (d, J = 7.9 Hz, NH, 1H), 8.19 (s, 1H), 8.12 (t, J = 7.5 Hz, 1H), 7.62 –
7.47 (m, 5H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 7.23 (d, J = 2.7 Hz, 1H), 4.86 (p, J = 7.2 Hz, 1H), 4.27 (q,
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J = 7.1 Hz, 2H), 3.81 (s, 2H), 1.61 (d, J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 172.9, 164.3, 159.0, 148.2, 146.5, 143.2, 138.0, 131.7, 129.3, 129.0, 128.7, 128.5, 122.6,
119.4, 103.4, 61.5, 55.5, 48.2, 18.6, 14.2; EI-MS m/z (relative intensity, %): 378 (22.1%), 335 (8.8%),
305 (59.9%), 262 (15.2%), 235 (75.6%), 234 (100%), 191 (22.8%), 190 (12.4%); HRMS (ESI, ion
trap): Calc’d for C22H22N2O4+Na+, 401.1477; found, 401.1463.
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Acknowledgments
We thank NSFC (21002079) for the financial support.
1
Supporting Information. Copies of all H NMR and 13C NMR spectra of all compounds.
Crystallographic data of products 4a and 5. This material is available free of charge via the
Internet at http://pubs.acs.org.
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standard conditions.
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[14] See Supporting Information of reference 7a.
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