An efficient route to quinolines and other compounds by iron-catalysed cross-dehydrogenative coupling reactions of glycine derivatives

Article abstract of DOI:10.1002/ejoc.201101656

A simple method has been developed for functionalizing glycine derivatives by iron-catalysed cross-dehydrogenative coupling (CDC) reactions. In particular, N-arylglycine derivatives reacted with alkynes by oxidative C-H/C-H coupling reactions to provide a

Full text of DOI:10.1002/ejoc.201101656

FULL PAPER
DOI: 10.1002/ejoc.201101656
An Efficient Route to Quinolines and Other Compounds by Iron-Catalysed
Cross-Dehydrogenative Coupling Reactions of Glycine Derivatives
Peng Liu,[a] Zhiming Wang,[a] Jue Lin,[a] and Xianming Hu*[a]
Keywords: Natural products / Amino acids / Nitrogen heterocycles / Iron / Cross-coupling / Oxidation
A simple method has been developed for functionalizing gly-
cine derivatives by iron-catalysed cross-dehydrogenative
reactions to provide a series of substituted quinolines starting
from commercially inexpensive materials. Moreover, N-aryl-
coupling (CDC) reactions. In particular, N-arylglycine deriv- glycine esters can be oxidatively coupled to ketones by using
atives reacted with alkynes by oxidative C–H/C–H coupling
FeCl3 in the presence of DDQ.
We have developed an efficient process in which oxidative
coupling is carried out with an acetylene. The iron salts in
a tandem process subsequently catalyse in situ the cycliza-
tion and dehydrogenation to form interesting quinoline de-
rivatives. Two oxidative processes are involved, as shown in
Scheme 1: i. the formation of an iminium ion intermediate,
which will undergo the CDC reaction in the presence of an
alkyne as nucleophile and ii. the final oxidative aromatiza-
tion of the dihydroquinoline intermediate to form the quin-
oline unit. We note that quinolines and their derivatives oc-
cur in a large number of biologically active natural prod-
ucts, and they are also important starting materials for the
chemical and pharmaceutical industry.[10] Although many
approaches providing efficient access to quinolines have
been developed,[11] this method provides an environmen-
tally friendly and atom-economic synthesis of quinolines
from glycine derivatives.
Introduction
There is considerable interest in methods for the func-
tionalization of amino acids to provide molecules that are
prevalent in bioactive natural products and therapeutic
drug molecules.[1] Generally applicable and relatively cheap
methods for the rapid modification of amino acids are
highly sought after. Traditionally, the α-functionalization of
amino acid derivatives has been accomplished by deproton-
ation with a strong base,[2] Claisen rearrangements[3] and
UV photolysis.[4]
The direct cross-dehydrogenative coupling (CDC) of C–
H bonds in C–C bond-forming reactions is more atom
economic and environmentally friendly than these meth-
ods,[5] although selective oxidative functionalization of α-
amino acid derivatives is still relatively rare.[6] As far as we
know, the only two examples are those of Li and co-
workers, who have developed CDC reactions of N-acetyl-
glycine esters and N-arylglycine amides with malonates and
alkynes in the presence of Cu(OAc)2 (2.0 equiv.) catalysed
by CuBr,[7] and Xie and Huang, who reported the coupling
of N-arylglycine esters with ketones by cooperative catalysis
by Cu(OAc)2 and pyrrolidine in the presence of TBHP or
DDQ as oxidant.[8]
Because of the low price, ready availability, non-toxicity
and environmentally benign character, considerable effort
has recently been directed towards developing these redox
processes by using iron catalysts.[9] Herein, we report a
method for functionalizing phenylglycine derivatives by di-
rect CDC reactions using iron catalysis.
Scheme 1. Synthesis of quninolines in a one-pot reaction.
[a] State Key Laboratory of Virology, Ministry of Education Key
Laboratory of Combinatorial Biosynthesis and Drug Discovery,
Wuhan University, School of Pharmaceutical Sciences, Wuhan
University,
Results and Discussion
To initiate our study, we studied the reaction of phenyl-
glycine derivative 1a (1.0 equiv.) with phenylacetylene (2a,
1.2 equiv.) catalysed by various iron salts (10 mol-%) with
di-tert-butyl peroxide (2.0 equiv.) as the oxidant in 1,2-
dichloroethane (DCE) at 80 °C in a Schlenk tube. A Frie-
Wuhan 430071, China
Fax: +86-27-6875-9850
E-mail: xmhu@whu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101656.
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P. Liu, Z. Wang, J. Lin, X. Hu
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del–Crafts reaction to provide the final product 3a was as- Table 2. Functionalization of 1 by CDC reactions with alkynes 2.[a]
sumed to occur after the coupling reaction. As seen in
Table 1, Fe(OTf)3 and FeCl3 (entries 1 and 2, Table 1) were
found to be the best catalysts with di-tert-butyl peroxide as
oxidant. As seen from entries 3–5, FeCl2·4H2O,
FeCl3·6H2O and Fe(ClO4)3 are less effective as catalysts.
Clearly a catalyst is necessary, as seen from entry 6. Iron
complex [Fe(dmf)6(ClO4)3] was disappointing as catalyst
(entry 7). The use of highly anhydrous FeCl3 (entry 8) did
not lead to significant improvement over laboratory-grade
FeCl3 (97% FeCl3). We thus chose laboratory-grade FeCl3
as the best catalyst owing to its cheapness and ready avail-
ability.
Table 1. Optimization of the conditions for the CDC reaction of
phenylglycine 1a and acetylene 2a.[a]
Entry Catalyst
Solvent
T [°C] Oxidant Yield [%][b]
1
2
3
4
5
6
7
8
Fe(OTf)3
FeCl3
FeCl2·4H2O
FeCl3·6H2O
Fe(ClO4)3
no cat.
[Fe(dmf)6(ClO4)3] DCE
FeCl3 (Ͼ99.9%)
FeCl3
FeCl3
Cu2O
CF3SO3H
FeCl3
FeCl3
DCE
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
80
80
80
60
40
80
80
60
60
50
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
TBHP
92
78
23
62
70
n.r.[c]
23
DCE
DCE
DCE
DCE
81
59
Ͻ5
n.r.[c]
39
36
31
59
23
9
10
11
12
13
14
15
16
17
18
19
H2O2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
DCE
CHCl3
CH2Cl2
CH3CN
toluene
THF
FeCl3
FeCl3
FeCl3
FeCl3
31
6
18
MeOH
acetone
FeCl3
[a] Reagents and conditions: 1a/2a/oxidant/cat. = 1:1.2:2:0.1, 12 h.
[b] Isolated yield. [c] n.r.: no reaction (no quinoline product de-
tected).
The effect of varying the oxidant was also examined.
Both TBHP and H2O2 were found to lead to lower or no
yields (entries 9 and 10). It has been reported that traces of
metal impurities or contaminants can affect the catalytic
activity (typically copper oxide in iron salts).[12] Note that
when Cu2O (10 mol-%) was employed as the catalyst, no
quinoline product was detected (entry 11). This establishes
that iron plays a crucial role in this reaction. Brønsted acid
CF3SO3H was relatively ineffective as the catalyst (en-
try 12).
Different solvents were also screened and 1,2-dichloro-
ethane (DCE) was found to be the best for this reaction
(entries 13–19).
The scope of this method for the synthesis of quinoline
derivatives was explored and the results are summarized in
Table 2. Various phenylglycine derivatives and a range of
substituted acetylenes were examined. Glycine derivative 1a
[a] Reagents and conditions: 1 (0.2 mmol), 2 (0.24 mmol), (tBuO)2
(0.4 mmol), FeCl3 (0.02 mmol), ClCH2CH2Cl, 80 °C, 12 h. [b] Iso-
lated yield. [c] n.r.: no reaction (no quinoline product detected). [d]
CHCl3, 60 °C, 1 h.
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Quinolines by Cross-Dehydrogenative Coupling Reactions
readily reacted with various substituted alkynes, including
2b with a bulky substituent at the phenyl 4-position, to give
excellent yields (74–88%; entries 2–6). However, with elec-
tron-deficient alkyne 2g, no quinoline product was detected
(entry 7). Unsubstituted phenylglycine 1b reacted with 2a
to give the desired product 3g in 62% yield (entry 8), al-
though the yield is somewhat lower than with the more re-
active 1a. Excellent product yields were also obtained with
R1 = Cl (entries 9–11). With R2 an aromatic amine, the cor-
responding quinolines were obtained in 79 and 83% yields
(entries 12 and 13).
Scheme 2. Mechanistic probe for the CDC reaction of 1e and alk-
yne with (tBuO)2.
When N-arylglycine esters 1e and 1f were used as sub-
strates, no quinoline products were detected. However,
when 1,2-dichloroethane was replaced with chloroform as
solvent, quinoline products 3m–p were obtained in good
yields at 60 °C (entries 14–17). A detailed explanation of
this unusual effect will require further investigation, which
we hope will be carried out in the future.
To establish the practicality of the method, the reaction
was scaled up to 0.1 mol. As an example, 1a (19.4 g,
0.1 mol) readily reacted with 2a (0.12 mol) under the condi-
tions described and provided 3a in 71% isolated yield.
A radical mechanism for the oxidative dehydrogenation
seems probable. This idea is supported by the observation
that addition of a radical inhibitor, 2,6-di-tert-butyl-4-meth-
ylphenol (BHT, 1.0 equiv.), to the reaction of 1a with 2a led
to a reduction in the yield of 3a from 78 to 25%. To gain
further mechanistic insights, the reaction of 1e with
(tBuO)2 in CHCl3 was examined (reactions with 1a failed
to lead to identifiable products). Reaction for 1 h in the
absence of alkyne led to the isolation of imine 6 in 32%
yield. Imine 6 reacted with acetylene 2a in the presence of
a catalytic amount of FeCl3 to give the desired product 3m
in 82% yield (Scheme 2). Based on these experimental re-
We also examined the CDC reactions of ketones with
glycine derivatives. The results are shown in Table 3. When
cyclohexanone (8a) was employed instead of an alkyne in
the reaction with 1a with the combination of FeCl3 and
di-tert-butyl peroxide or DDQ, no reaction was detected
(entries 1 and 2). The reaction between N-(4-meth-
oxyphenyl)glycine ester 1e and 8a (15.0 equiv.) catalysed by
FeCl3 (10 mol-%) with di-tert-butyl peroxide (2.0 equiv.) as
oxidant in 1,2-dichloroethane also failed (entry 3). How-
ever, when di-tert-butyl peroxide was replaced with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the oxi-
dant, the coupling product 9a was obtained in 10% yield
Table 3. Optimization of the conditions for the reaction of phenyl-
glycine with ketone 8a.[a]
sults, the tentative mechanism shown in Scheme 3 has been Entry
R
Solvent
T [°C] Oxidant Yield [%][b]
proposed. A tert-butoxyl radical, generated by the iron-cat-
alysed decomposition of (tBuO)2, abstracts a hydrogen
atom from 1e to form radical 4. Single electron transfer
(SET) from 4 leads to iminium ion 5, which deprotonates
to give imine 6. Subsequent nucleophilic attack of the al-
kyne on 6 generates 7, which then undergoes an intramolec-
ular Friedel–Crafts reaction and oxidation catalysed by
FeCl3 to give the quinoline product 3m. Excess (tBuO)2 en-
1
2
3
4
5
6
NHMe ClCH2CH2Cl
NHMe ClCH2CH2Cl
80
80
80
80
60
40
(tBuO)2
DDQ
(tBuO)2
DDQ
DDQ
DDQ
n.r.[c]
n.r.[c]
OEt
OEt
OEt
OEt
ClCH2CH2Cl
ClCH2CH2Cl
CHCl3
n.r.[c]
10 (4:1)[d]
51 (6:1)[d]
n.r.[c]
CH2Cl2
[a] Reagents and conditions: 1a or 1e (0.2 mmol), 8a (15.0 equiv.),
oxidant (0.24 mmol), FeCl3 (0.02 mmol), solvent (1 mL), 12 h. [b]
Isolated yield. [c] n.r.: no reaction (no product detected). [d] Dia-
stereomeric ratio: anti/syn.
sures that Fe2+ is reoxidized to Fe3+
.
Scheme 3. Proposed mechanism for the CDC reaction of 1e and alkyne with (tBuO)2 and FeCl3.
Eur. J. Org. Chem. 2012, 1583–1589
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(entry 4). Different solvents were screened and chloroform
Co-catalysis using a secondary amine as organic catalyst
was found to be the best, giving a yield of 51% after 12 h and a metal has been reported; the intermediate enamines
reaction time and a diastereoselectivity of 6:1 (entry 5).
are more reactive than the ketones.[8] Pyrrolidine (30 mol-
%) was added to increase the reactivity of cyclohexanone.
Indeed, 9a was obtained in increased yield (83%) at 60 °C
(entry 1, Table 4). When the temperature was lowered to
room temperature, 9a was obtained in 80% yield, but the
diastereoselectivity decreased to 5:2 (entry 2, Table 4).
The substrate scope of the iron-catalysed CDC reactions
of ketones with the C–H bond of glycine derivatives was
examined. In these experiments, 1e readily underwent CDC
reaction with different cyclic ketones to give the desired
coupling products 9b and 9c in satisfactory yields (69 and
78%) and diastereoselectivities (2:3 and 7:2; entries 3 and
4). If the substituent on ester 1e was changed from ethyl to
methyl (1f), isopropyl (1g) or tert-butyl (1h), the reaction
proceeded readily to give coupling products 9d–9i in good
yields (63–79%) with up to 7:1 diastereoselectivity (en-
tries 5–10). Unfortunately, linear ketones such as acetone
and acetophenone failed to react.
Table 4. Functionalization of 1 by CDC reaction with cyclic
ketones 8.[a]
To gain an insight into the mechanism, the reaction of
1e with enamine 11 derived from cyclohexanone and pyr-
rolidine was examined. The coupling product 9a was ob-
tained in 85% yield (Scheme 4). The imine intermediate 6
derived from 1e was obtained in 46% yield under the cata-
lytic conditions without cyclohexanone (Scheme 4). The
radical inhibitor BHT was also added to the reaction sys-
tem with cyclohexanone, pyrrolidine and DDQ. The yield
Scheme 4. Mechanistic probe for the CDC reactions with DDQ.
[a] Reagents and conditions: 1 (0.2 mmol), 8 (15.0 equiv.), DDQ
(0.24 mmol), pyrrolidine (0.06 mmol), FeCl3 (0.02 mmol), CHCl3,
60 °C, 12 h. [b] Isolated yield. [c] Diastereomeric ratio: anti/syn. [d]
Room temperature.
Scheme 5. Proposed mechanism for the reactions with DDQ.
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Quinolines by Cross-Dehydrogenative Coupling Reactions
[M]+. HRMS (EI): calcd. for C22H24N2O2 348.1832; found
348.1833.
of the coupling product 9a then decreased from 83 to 19%.
Based on the experimental results above, the reaction likely
proceeds by a radical pathway analogous to that described
in Scheme 3: iminium 5 deprotonates to give 6 as shown in
Scheme 5. Nucleophilic attack by the enamine derived from
cyclohexanone and pyrrolidine followed by hydrolysis leads
to the final product 9a and regenerates the pyrrolidine.
1
3c: H NMR (CDCl3, 400 MHz): δ = 8.21 (br. s, 1 H), 8.18 (s, 1
H), 8.04 (d, J = 8.8 Hz, 1 H), 7.52 (d, J = 8.6 Hz, 2 H), 7.48 (d, J
= 8.6 Hz, 2 H), 7.42 (dd, J = 8.8, 2.4 Hz, 1 H), 7.16 (d, J = 2.4 Hz,
1 H), 3.82 (s, 3 H), 3.11 (d, J = 4.8 Hz, 3 H) ppm. 13C NMR
(CDCl3, 101 MHz): δ = 165.44, 159.28, 147.31, 147.11, 143.32,
136.64, 134.87, 131.73, 130.80, 129.15, 128.86, 122.98, 119.53,
103.32, 55.70, 26.36 ppm. MS (EI): m/z = 326 [M]+. HRMS (EI):
calcd. for C18H15ClN2O2 326.0817; found 326.0821.
Conclusions
1
3e: H NMR (400 MHz, CDCl3): δ = 8.26 (s, 1 H), 8.24 (br. s, 1
We have developed a facile and economic method for the H), 8.06 (d, J = 9.2 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 2 H), 7.71 (d, J
= 7.4 Hz, 2 H), 7.64 (d, J = 8.0 Hz, 2 H), 7.50 (t, J = 7.6 Hz, 2 H),
7.43 (m, 2 H), 7.32 (d, J = 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.12 (d, J =
5.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 165.46,
159.01, 147.93, 147.24, 143.24, 141.37, 140.35, 137.00, 131.54,
129.87, 128.96, 128.91, 127.73, 127.41, 127.16, 122.73, 119.46,
103.56, 55.60, 26.25 ppm. MS (EI): m/z = 368 [M]+. HRMS (EI):
calcd. for C24H20N2O2 368.1525; found 368.1601.
functionalization of glycine derivatives. A series of substi-
tuted quinolines have been synthesized from commercially
inexpensive starting materials by using an inexpensive, read-
ily available catalyst. N-Arylglycine esters can also be func-
tionalized with ketones by FeCl3 in the presence of DDQ
under mild conditions. This reaction could be applicable to
other amino acids. The effectiveness of iron salts as cata-
lysts makes these processes especially interesting. Further
studies on the CDC reactions of secondary amines with
other C–H bonds by iron catalysis and the synthetic appli-
cations are in progress.
3f: 1H NMR (400 MHz, CDCl3): δ = 8.30 (s, 1 H), 8.25 (br. s, 1
H), 8.05 (d, J = 9.2 Hz, 1 H), 7.97 (s, 1 H), 7.89 (d, J = 8.4 Hz, 1
H), 7.82 (d, J = 9.6 Hz, 1 H), 7.63 (dd, J = 8.4, 1.7 Hz, 1 H), 7.42
(dd, J = 9.2, 2.8 Hz, 1 H), 7.31 (d, J = 2.7 Hz, 1 H), 7.26–7.21 (m,
2 H), 3.98 (s, 3 H), 3.77 (s, 3 H), 3.12 (d, J = 5.1 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 165.55, 158.96, 158.39, 148.39,
147.21, 143.26, 134.39, 133.27, 131.51, 129.82, 129.11, 128.87,
128.61, 127.58, 127.11, 122.72, 119.67, 119.60, 105.69, 103.60,
55.52, 55.43, 26.25 ppm. MS (EI): m/z = 372 [M]+. HRMS (EI):
calcd. for C23H20N2O3 372.1474; found 372.1553.
Experimental Section
General: Reagents were obtained commercially and used without
further purification unless indicated otherwise. Solvent was re-
moved under reduced pressure and the residue obtained was puri-
fied by chromatography on a silica gel column (300–400 mesh)
using a gradient solvent system (EtOAc/petroleum ether as eluent
unless specified otherwise). 1H and 13C NMR spectra were mea-
sured with a Bruker DPX-400 spectrometer. Chemical shifts [ppm]
were determined with tetramethylsilane (TMS) as internal refer-
ence. Mass spectra were determined with a Finnigan MAT 95 mass
spectrometer.
1
3g: H NMR (CDCl3, 400 MHz): δ = 8.31 (br. s, 1 H), 8.27 (s, 1
H), 8.15 (d, J = 9.2 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 1 H), 7.77 (t, J
= 8.6 Hz, 1 H), 7.57 (t, J = 8.8 Hz, 1 H), 7.54 (m, 5 H), 3.12 (d, J
= 5.1 Hz, 3 H) ppm. 13C NMR (CDCl3, 101 MHz): δ = 165.40,
150.21, 149.53, 147.29, 137.89, 130.17, 130.03, 129.76, 128.77,
128.76, 128.00, 127.91, 126.14, 119.19, 26.43 ppm. MS (EI): m/z
= 262 [M]+. HRMS (EI): calcd. for C17H14N2O 262.1101; found
262.1098.
1
3h: H NMR (CDCl3, 400 MHz): δ = 8.28 (s, 1 H), 8.24 (br. s, 1
General Procedure for the Synthesis of 3a–l: Compounds 1a–d
(0.20 mmol), FeCl3 (0.02 mmol), phenylacetylene (0.24 mmol) and
(tBuO)2 (0.40 mmol) were successively added to DCE (1 mL) in a
Schlenk tube. The mixture was stirred for 12 h at 80 °C, filtered
through a small pad of silica gel and concentrated in vacuo. Flash
chromatography on silica gel using ethyl acetate/petroleum ether
(1:3) furnished the final product. The spectroscopic data for 3d are
consistent with the literature.[11e]
H), 8.07 (d, J = 9.6 Hz, 1 H), 7.94 (d, J = 2.0 Hz, 1 H), 7.69 (dd,
J = 9.6, 2.0 Hz, 1 H), 7.53 (m, 5 H), 3.12 (d, J = 4.8 Hz, 3 H) ppm.
13C NMR (CDCl3, 101 MHz): δ = 164.99, 149.71, 149.44, 145.63,
137.18, 134.12, 131.69, 131.04, 129.60, 129.06, 128.97, 128.53,
124.93, 119.97, 26.43 ppm. MS (EI): m/z = 296 [M]+. HRMS (EI):
calcd. for C17H13ClN2O 296.0711; found 296.0711.
3i: 1H NMR (CDCl3, 400 MHz): δ = 8.26 (s, 1 H), 8.22 (br. s, 1
H), 8.15 (d, J = 9.2 Hz, 1 H), 7.88 (d, J = 2.0 Hz, 1 H), 7.71 (dd,
J = 9.2, 2.0 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 2 H), 7.45 (d, J = 8.8 Hz,
2 H), 3.12 (d, J = 4.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 101 MHz):
δ = 164.85, 149.75, 148.12, 145.65, 135.57, 135.42, 134.43, 131.81,
131.23, 130.91, 129.31, 128.30, 124.60, 119.92, 26.45 ppm. MS (EI):
m/z = 330 [M]+. HRMS (EI): calcd. for C17H12Cl2N2O 330.0321;
found 330.0318.
1
3a: H NMR (CDCl3, 400 MHz): δ = 8.23 (br. s, 1 H), 8.21 (s, 1
H), 8.04 (d, J = 9.2 Hz, 1 H), 7.54 (m, 4 H), 7.52 (m, 1 H), 7.41
(dd, J = 9.2, 2.8 Hz, 1 H), 7.24 (d, J = 2.8 Hz, 1 H), 3.81 (s, 3 H),
3.11 (d, J = 5.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 101 MHz): δ =
165.58, 159.08, 148.46, 147.35, 143.32, 138.22, 131.60, 129.51,
129.08, 128.85, 128.68, 122.82, 119.61, 103.68, 55.65, 26.36 ppm.
MS (EI): m/z = 292 [M]+. HRMS (EI): calcd. for C18H16N2O2
292.1206; found 292.1205.
3j: 1H NMR (CDCl3, 400 MHz): δ = 8.26 (s, 1 H), 8.24 (br. s, 1
3b: H NMR (CDCl3, 400 MHz): δ = 8.23 (br. s, 1 H), 8.21 (s, 1 H), 8.07 (d, J = 8.8 Hz, 1 H), 7.99 (d, J = 2.4 Hz, 1 H), 7.68 (dd,
1
H), 8.03 (d, J = 9.6 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.50 (d, J
= 8.4 Hz, 2 H), 7.41 (dd, J = 9.6, 2.4 Hz, 1 H), 7.33 (d, J = 2.4 Hz,
1 H), 3.84 (s, 3 H), 3.11 (d, J = 6.0 Hz, 3 H), 1.41 (s, 9 H) ppm.
13C NMR (CDCl3, 101 MHz): δ = 165.63, 158.99, 151.78, 148.46,
147.36, 143.35, 135.23, 131.58, 129.24, 129.11, 125.79, 122.57,
119.63, 104.01, 55.74, 34.91, 31.50, 26.34 ppm. MS (EI): m/z = 348
J = 8.8, 2.4 Hz, 1 H), 7.46 (d, J = 8.6 Hz, 2 H), 7.08 (d, J = 8.6 Hz,
2 H), 3.92 (s, 3 H), 3.12 (d, J = 5.2 Hz, 3 H) ppm. 13C NMR
(CDCl3, 101 MHz): δ = 165.13, 160.40, 149.69, 149.23, 145.75,
133.98, 131.70, 130.96, 130.85, 129.47, 128.71, 125.04, 119.83,
114.55, 55.58, 26.43 ppm. MS (EI): m/z = 326 [M]+. HRMS (EI):
calcd. for C18H15ClN2O2 326.0817; found 326.0817.
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1
3k: H NMR (CDCl3, 400 MHz): δ = 10.09 (br. s, 1 H), 8.36 (s, 1 raphy by using ethyl acetate/petroleum ether (1:5) furnished the
H), 8.18 (d, J = 9.2 Hz, 1 H), 7.98 (d, J = 2.2 Hz, 1 H), 7.74 (dd, final product 6 in 32% yield.
J = 9.2, 2.2 Hz, 1 H), 7.56 (m, 6 H), 7.16 (dd, J = 8.4, 1.8 Hz, 1
Synthesis of Quinoline 3m from 6: Imine 6 (0.20 mmol), FeCl3
H), 6.84 (d, J = 8.4 Hz, 1 H), 6.00 (s, 2 H) ppm. 13C NMR (CDCl3,
(0.02 mmol) and 2a (0.24 mmol) were successively added to CHCl3
101 MHz): δ = 161.77, 149.91, 149.58, 148.12, 145.49, 144.54,
137.14, 134.50, 132.28, 131.72, 131.34, 129.65, 129.22, 129.07,
(1 mL) in a Schlenk tube. The mixture was stirred for 5 h at 60 °C,
filtered through a small pad of silica gel and concentrated in vacuo.
128.71, 125.08, 119.97, 113.10, 108.42, 102.51, 101.49 ppm. MS
Flash chromatography on silica gel using ethyl acetate/petroleum
(EI): m/z = 402 [M]+. HRMS (EI): calcd. for C23H15ClN2O3
ether (1:4) furnished the final product 3m in 82% yield.
402.0766; found 402.0763.
Synthesis of Cyclohexanone 9a from 1e with 11: N-(4-Meth-
1
3l: H NMR (CDCl3, 400 MHz): δ = 10.05 (br. s, 1 H), 8.33 (s, 1
oxyphenyl)glycine ester 1e (0.20 mmol), FeCl3 (0.02 mmol), 11
H), 8.18 (d, J = 9.6 Hz, 1 H), 7.90 (d, J = 1.6 Hz, 1 H), 7.75 (dd,
J = 9.6, 2.4 Hz, 1 H), 7.57 (m, 3 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.15
(0.22 mmol) and DDQ (0.24 mmol) were successively added to
CHCl3 (1 mL) in a Schlenk tube. The mixture was stirred for 12 h
at 60 °C, filtered through a small pad of silica gel and concentrated
in vacuo. Flash chromatography on silica gel using ethyl acetate/
(dd, J = 8.4, 2.4 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 6.00 (s, 2
H) ppm. 13C NMR (CDCl3, 101 MHz): δ = 161.62, 149.62, 148.57,
148.16, 145.49, 144.60, 135.58, 135.50, 134.79, 132.20, 131.85,
petroleum ether (1:4) furnished the final product 9a in 85% yield.
131.52, 130.94, 129.39, 128.48, 124.71, 119.92, 113.13, 108.41,
102.51, 101.52 ppm. MS (EI): m/z = 436 [M]+. HRMS (EI): calcd.
Synthesis of Imine 6 from 1e with DDQ: N-(4-Methoxyphenyl)-
glycine ester 1e (0.20 mmol), FeCl3 (0.02 mmol) and DDQ
(0.24 mmol) were successively added to CHCl3 (1 mL) in a Schlenk
tube. The mixture was stirred for 1 h at 60 °C, filtered through a
small pad of silica gel and concentrated in vacuo. Flash chromatog-
raphy using ethyl acetate/petroleum ether (1:5) furnished the final
product 6 in 46% yield.
for C23H14Cl2N2O3 436.0376; found 436.0365.
General Procedure for the Synthesis of 3m–p: Compound 1e or 1f
(0.20 mmol), FeCl3 (0.02 mmol), phenylacetylene (0.24 mmol) and
(tBuO)2 (0.40 mmol) were successively added to CHCl3 (1 mL) in
a Schlenk tube. The mixture was stirred for 1 h at 60 °C, filtered
through a small pad of silica gel and concentrated in vacuo. Flash
chromatography on silica gel by using ethyl acetate/petroleum ether
(1:3) furnished the final product. The spectroscopic data for 3m,[11e]
3n,[11e] 3o[13] and 3p[13] are consistent with the literature.
General Procedure for the Reaction with Radical Inhibitor BHT:
Compound 1a (0.20 mmol), FeCl3 (0.02 mmol), phenylacetylene
(0.24 mmol), (tBuO)2 (0.40 mmol) and BHT (0.20 mmol) were suc-
cessively added to DCE (1 mL) in a Schlenk tube. The mixture was
stirred for 12 h at 80 °C, filtered through a small pad of silica gel
and concentrated in vacuo. Flash chromatography on silica gel by
using ethyl acetate/petroleum ether (1:3) as eluent furnished the
final product 3a in 25% yield.
General Procedure for the Synthesis of 9a–i: Compounds 1e–h
(0.20 mmol), FeCl3 (0.02 mmol), cyclohexanone (3.0 mmol,
15.0 equiv.), pyrrolidine (0.06 mmol, 30 mol-%) and DDQ
(0.24 mmol) were successively added to CHCl3 (1 mL) in a Schlenk
tube. The mixture was stirred for 12 h at 60 °C, filtered through a
small pad of silica gel and concentrated in vacuo. Flash chromatog-
raphy on silica gel using ethyl acetate/petroleum ether (1:4) fur-
nished the final product. The spectroscopic data for 9a–d, 9g and
9i are consistent with the literature.[8]
Compound 1e (0.20 mmol), FeCl3 (0.02 mmol), cyclohexanone
(3.0 mmol, 15.0 equiv.), pyrrolidine (0.06 mmol, 30 mol-%), DDQ
(0.24 mmol) and BHT (0.20 mmol) were successively added to
CHCl3 (1 mL) in a Schlenk tube. The mixture was stirred for 12 h
at 60 °C, filtered through a small pad of silica gel and concentrated
in vacuo. Flash chromatography on silica gel by using ethyl acetate/
petroleum ether (1:4) as eluent furnished the final product 9a in
19% yield.
9e: dr (anti/syn) = 2:3. Mixture of two diastereomers: 1H NMR
(400 MHz, CDCl3): δ = 6.83–6.71 (m, 2 H), 6.67–6.65 (m, 2 H),
4.31–4.27 (m, 1 H), 3.74 (s, 3 H), 3.70 (s, 1.1 H), 3.68 (s, 1.8 H),
3.07 (m, 0.39 H), 2.94 (m, 0.59 H), 2.55–2.48 (m, 2 H), 2.06–1.82
(m, 4 H), 1.74–1.66 (m, 2 H), 1.63–1.52 (m, 2 H) ppm. MS (EI): m/z
= 305 [M]+. HRMS (EI): calcd. for C17H23NO4 305.1627; found
305.1702.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra.
Acknowledgments
9f: dr (anti/syn) = 2:1. Mixture of two diastereomers: 1H NMR
(400 MHz, CDCl3): δ = 6.81–6.74 (m, 2 H), 6.70 (d, J = 9.0 Hz,
0.65 H), 6.61 (d, J = 8.9 Hz, 1.27 H), 4.27–3.76 (m, 6 H), 3.73 (m,
3 H), 3.71 (s, 2 H), 3.69 (s, 1 H), 3.30–3.21 (m, 0.63 H), 2.95–2.91
(m, 0.34 H), 2.66–2.53 (m, 1.38 H), 2.46 (m, 0.66 H) ppm. MS (EI):
m/z = 293 [M]+. HRMS (EI): calcd. for C15H19NO5 293.1263;
found 293.1279.
This investigation was supported by the Important National Sci-
ence
& Technology Specific Projects, China (grant number
2009ZX09301-14-1), the National Natural Science Foundation of
China (NSFC) (grant number 21102107) and Chinese Postdoctoral
Science Foundation (grant number 20110491199).
9h: dr (anti/syn) = 7:2. Mixture of two diastereomers: 1H NMR
(400 MHz, CDCl3): δ = 6.82–6.71 (m, 2 H), 6.64 (m, 2 H), 5.05 (m,
1 H), 4.64–4.51 (m, 1 H), 4.25–3.86 (m, 4 H), 3.73 (s, 3 H), 3.30–
3.25 (m, 0.79 H), 3.12–3.08 (m, 0.23 H), 2.63–2.48 (m, 2 H), 1.26–
1.21 (m, 6 H) ppm. MS (EI): m/z = 321 [M]+. HRMS (EI): calcd.
for C17H23NO5 321.1576; found 321.1608.
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Received: November 17, 2011
Published Online: January 30, 2012
Eur. J. Org. Chem. 2012, 1583–1589
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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