Bronsted acid or solid acid catalyzed Aza-Diels-Alder reactions of methylenecyclopropanes with ethyl (arylimino)acetates

Article abstract of DOI:10.1002/ejoc.200900050

Bronsted acid (TfOH) or solid acid (montmorillonite K-10) catalyzed aza-Diels-Alder reactions of methylenecyclopro- panes with ethyl (arylimino)acetates were shown for the construction of the tetrahydroquinoline skeleton with the untouched cyclopropyl gro

Full text of DOI:10.1002/ejoc.200900050

FULL PAPER
DOI: 10.1002/ejoc.200900050
Brønsted Acid or Solid Acid Catalyzed Aza-Diels–Alder Reactions of
Methylenecyclopropanes with Ethyl (Arylimino)acetates
Zhi-Bin Zhu,[a] Li-Xiong Shao,*[b] and Min Shi*[a,c]
Keywords: Small ring systems / Nitrogen heterocycles / Cycloaddition
Brønsted acid (TfOH) or solid acid (montmorillonite K-10)
catalyzed aza-Diels–Alder reactions of methylenecyclopro-
panes with ethyl (arylimino)acetates were shown for the con-
struction of the tetrahydroquinoline skeleton with the un-
touched cyclopropyl group in the 3,3Ј-position.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
of the three-membered ring renders this group an appealing
structural unit for the preparation of molecules with a de-
fined orientation of the pendant functional groups.[14]
Methylenecyclopropanes (MCPs) are highly strained but
readily accessible molecules that have served as useful build-
ing blocks in organic synthesis.[15,16] Previously, we reported
facile routes for the formation of tetrahydroquinoline deriv-
atives with a cyclopropyl group in the 3,3Ј-position by
Lewis acid catalyzed aza-Diels–Alder reactions of MCPs
with N-aryl imines[17] or by solid acid montmorillonite KSF
(mont. KSF) catalyzed one-pot, three-component, aza-
Diels–Alder reactions of MCPs with aryl aldehydes and
arylamines (Scheme 1).[18] These results promoted us to fur-
ther investigate the cycloaddition reactions of MCPs with
other types of imines. In this article, we will report our re-
cent results on the Brønsted acid trifluoromethanesulfonic
acid (TfOH) or solid acid montmorillonite K-10 (mont. K-
10) catalyzed aza-Diels–Alder reactions of MCPs 1 with
(arylimino)acetates 2 for the formation of tetrahydroquin-
oline skeletons.
Introduction
N-Heterocyclic compounds have attracted considerable
attention from organic chemists owing to their functionality
in pharmaceutical chemistry, material chemistry, synthetic
organic chemistry, and dyes.[1] Among them, the greatest
interest in 1,2,3,4-tetrahydroquinolines is due to their bio-
logical activities. Numerous tetrahydroquinolines bearing
various simple or complex substituents have interesting bio-
chemical activities; some of them are potential pharmaceu-
tical agents.[2] With regard to the synthesis of a quinoline
ring, various methods have been reported to date, such as
the Skraup synthesis,[3] the Friedländer synthesis,[4] the
Pfitzinger synthesis,[5] and so on.[6] However, to the best of
our knowledge, less attention has been focused on the [4+2]
cycloaddition reaction for the synthesis of a quinoline ring,
although the reactions of o-quinone methide imines with
olefins have recently appeared.[7,8] Chemical modification of
natural compounds has become a commonly used approach
for the formation of novel biologically active molecules with
different pharmacological characteristics. Although the cy-
clopropane ring is a highly strained entity, it is nonetheless
found in a wide variety of naturally occurring compounds[9]
including terpenes,[10] pheromones,[11] fatty acid metabo-
lites,[12] and unusual amino acids.[13] In addition, the rigidity
[a] Lab for Advanced Materials and Institute of Fine Chemicals,
East China University of Science & Technology,
130 Meilong Road, Shanghai 200237, P. R. China
[b] College of Chemistry and Materials Engineering, Wenzhou
University,
Scheme 1. Lewis acid or solid acid catalyzed reactions of MCPs 1
with N-aryl imines.
276 Middle Xueyuan Road, Wenzhou, Zhejiang Province
325027, P. R. China
E-mail: shaolix_sioc@yahoo.com.cn
Results and Discussion
[c] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. China
Fax: +86-21-64166128
Firstly, the reactions of MCP 1a (R1 = R2 = C6H5) and
(arylimino)acetate 2a (R3 = 4-Br) were carried out in 1,2-
dichloroethane (DCE) in the presence of various Lewis
acids (10 mol-%) or Brønsted acid (10 mol-%) at 5 °C. We
E-mail: mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Brønsted Acid or Solid Acid-Catalyzed aza-Diels–Alder Reactions
found that the reactions proceeded smoothly to give the isomers of products 3f and 3g could be isolated by careful
aza-Diels–Alder reaction product, the corresponding tetra- flash column chromatography (Table 2, Entries 5 and 6).[19]
hydroquinoline derivative 3a, in good yields for all the cata- In the case of MCP 1j, no such cycloaddition reaction could
lysts screened (Table 1, Entries 2–11). However, no reaction take place under the same conditions, presumably as a re-
occurred in the absence of any catalyst (Table 1, Entry 1). sult of the steric hindrance of the substituent on the MCP
It was found that the TfOH Brønsted acid gave the best (Table 2, Entry 9). The use of 4-nitrophenyl MCP 1k as the
result and the corresponding cycloaddition product was ob- substrate did not produce the desired aza-Diels–Alder reac-
tained in 82% yield within 0.5 h (Table 1, Entry 4). As for tion product (Table 2, Entry 10).
the solvents examined, DCE, compared with tetra-
hydrofuran (THF), toluene, and CH3CN, DCE gave the
best result for the TfOH-catalyzed aza-Diels–Alder reaction
Table 2. Aza-Diels–Alder reactions of MCPs 1 with (arylimino)ace-
tate 2a catalyzed by TfOH.
of MCP 1a with (arylimino)acetate 2a (Table 1, Entries 4
and 12–14).
Table 1. Optimization for the Lewis acid or Brønsted acid catalyzed
reactions of MCP 1a with (arylimino)acetate 2a.
[a] All reactions were carried out by using 1 (0.3 mmol) and 2a
(0.3 mmol) catalyzed by TfOH (10 mol-%) in DCE for 0.5 h.
[b] Isolated yields. [c] Ratio of the isomers determined by 1H NMR
spectroscopy (see Supporting Information for details). [d] The iso-
mers can be isolated by silica-gel column chromatography.
By using MCP 1d as the substrate, we also examined its
reactions with various (arylimino)acetates 2 under identical
reaction conditions. All reactions took place smoothly to
give products 3 in good to high yields within 10–30 min
(Table 3). Substituents on the phenyl ring of (arylimino)ace-
[a] Unless otherwise specified, all reactions were carried out by
tates 2 have some effects on the reaction outcome. For ex-
using 1a (0.3 mmol), 2a (0.3 mmol) in DCE (1 mL) at 5 °C for the
ample, (arylimino)acetate 2b containing a strongly electron-
donating group (R3 = 4-MeO) afforded the corresponding
adduct in almost quantitative yield, and the reaction was
listed catalyst (10 mol-%) and time. [b] Isolated yields. [c] THF as
the solvent. [d] Toluene as the solvent. [e] CH3CN as the solvent.
Then, we investigated the generality of the aza-Diels– complete within 10 min (Table 3, Entry 1). The reaction rate
Alder reactions of MCPs 1 with (arylimino)acetate 2a un- was slightly retarded when an ortho-electron-withdrawing
der the optimized conditions. In most cases, the corre- group on the phenyl ring was present, as (arylimino)acetate
sponding cycloaddition products were obtained in good to 2f afforded 3l in a somewhat lower yield (Table 3, Entry 5).
high yields within 0.5 h (Table 2, Entries 1–8). Electron-do-
At the same time, we also examined the solvent effect on
nating or electron-withdrawing substituents (R1 and R2) on the reaction of MCP 1a with (arylimino)acetate 2a in the
the phenyl ring of MCPs 1 did not significantly affect these presence of solid acid mont. K-10. The aza-Diels–Alder re-
reaction outcomes (Table 2, Entries 1–8). As for the reac- action using DCE as the solvent at room temperature pro-
tions involving unsymmetrical MCPs 1 such as 1e, 1f, 1g, vided 88% yield of tetrahydroquinoline derivative 3a within
and 1i, products 3e, 3f, 3g, and 3n were obtained as mix- 3 h (Table 4, Entry 1).By using THF as the solvent, the re-
tures of cis/trans isomers (Table 2, Entries 4–6 and 8). As action became disordered and no desired product was ob-
for products 3e and 3n, the two isomers could not be iso- tained (Table 4, Entry 2), which may be due to the fact that
lated by silica-gel column chromatography and their ratios the oxygen atom in THF can coordinate to the active site
1
were determined by H NMR spectroscopy (Table 2, En- in mont. K-10 clay and subsequently impair its catalytic
tries 4 and 8) (see Supporting Information for details). The ability in the reaction. Only some lower yields were found
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Z.-B. Zhu, L.-X. Shao, M. Shi
FULL PAPER
Table 3. TfOH-catalyzed aza-Diels–Alder reactions of MCP 1d ogy. All reactions were complete within 3 h at room tem-
with various (arylimino)acetates 2.
perature to give cycloaddition products 3 in excellent yields
(Table 5). To our delight, the yields were generally higher
than those catalyzed by the TfOH Brønsted acid (Table 2
and Table 5).
Table 5. Mont. K-10 catalyzed reactions of MCPs 1 with (arylim-
ino)acetate 2a.
[a] All reactions were carried out with 1d (0.3 mmol) and 2
(0.3 mmol) catalyzed by TfOH (10 mol-%) in DCE (1 mL) at 5 °C
for the listed time. [b] Isolated yields.
if toluene and CH3CN were used as the solvent (Table 4,
Entries 3 and 4). The recovered solid acid catalyst (mont.
K-10) can be reused to give similar results (Table 4, En-
tries 5 and 6). Other solid acids such as mont. KSF only
gave 70% yield of the product for the same reaction and
zeolite and silica gel showed no catalytic activities in this
reaction (Table 4, Entries 7–9).
Table 4. Optimization of the mont. K-10 catalyzed reactions of
MCP 1a with (arylimino)acetate 2a.
[a] All reactions were carried out with 1 (0.3 mmol) and 2a
(0.3 mmol) catalyzed by mont. K-10 (50 mg) in DCE (1.0 mL) at
room temperature for 3 h. [b] Isolated yields. [c] Ratio of the iso-
1
mers determined by H NMR spectroscopy (see Supporting Infor-
mation for details). [d] The isomers can be isolated by silica-gel
column chromatography.
The reactions of MCP 1d with various (arylimino)ace-
tates 2 were also investigated to further examine the gener-
ality of the reaction under identical reaction conditions. Al-
though a reaction time of 3 h was required, the yields of
the corresponding aza-Diels–Alder reactions catalyzed by
mont. K-10 were higher than those catalyzed by TfOH in
most cases (Table 3 and Table 6).
It should be mentioned that for bis(alkyl)-substituted
MCPs 1 (R1, R2 = alkyl group) or (alkylimino)acetates 2
derived from aliphatic amines, neither Brønsted acid nor
solid acid showed catalytic activity for the corresponding
aza-Diels–Alder reactions. This is because the stepwise aza-
Diels–Alder reaction of (bis)alkyl-substituted MCPs with
imines under the same conditions cannot stabilize a cationic
intermediate, which should be generated during the reac-
tion.[17]
The ester group of the aza-Diels–Alder reaction products
can be converted into other functional groups by simple
reported operations. For example, product 3a can be easily
converted into corresponding imidazoline derivative 4 in
[a] Unless otherwise specified, all reactions were carried out by
using 1a (0.3 mmol), 2a (0.3 mmol) catalyzed by mont. K-10
(50 mg) in the presence of the listed solvent (1 mL) at room tem-
perature. [b] Isolated yields. [c] The recovered mont. K-10 was used
for a second round. [d] The recovered mont. K-10 was used for a
third round. [e] Mont. KSF was used as the catalyst. [f] Zeolite was
used as the catalyst. [g] SiO2 was used as the catalyst.
Having established the optimized reaction conditions in- 60% yield by triethylaluminum (TEA) and ethane-1,2-di-
volving the use of solid acid mont. K-10 as the catalyst, amine (EDA) in toluene under reflux for 45 min, which is
various MCPs 1 and (arylimino)acetate 2a were subjected structurally analogous to some compounds with potential
to the reaction to examine the feasibility of the methodol- pharmaceutical activities (Scheme 2).[20]
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Brønsted Acid or Solid Acid-Catalyzed aza-Diels–Alder Reactions
Compound 3a: White solid, m.p. 176–177 °C. IR (CH Cl ): ν =
˜
Table 6. Mont. K-10 catalyzed reactions of MCP 1d with (aryl-
imino)acetates 2.
2
2
3397, 3054, 2979, 2899, 1732, 1711, 1595, 1489, 1442, 1365, 1291,
1203, 1123, 1082, 1030, 873, 807, 754, 702 cm–1. 1H NMR
(300 MHz, CDCl3, TMS): δ = 0.45–0.56 (m, 3 H), 1.04–1.07 (m, 1
H), 1.25 (t, J = 6.9 Hz, 3 H, CH3), 4.06–4.12 (m, 2 H), 4.36 (s, 1
H), 4.51 (s, 1 H, NH), 6.55 (d, J = 8.4 Hz, 1 H, Ar), 6.99–7.04 (m,
3 H, Ar), 7.16–7.27 (m, 5 H, Ar), 7.32–7.37 (m, 2 H, Ar), 7.53 (d,
J = 8.4 Hz, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, TMS): δ
= 4.5, 8.9, 14.1, 23.4, 56.0, 58.1, 61.4, 108.1, 117.3, 126.6, 126.77,
126.81, 128.8, 129.7, 130.4, 131.3, 134.6, 141.9, 142.2, 143.0, 145.2,
171.7 ppm. MS (EI): m/z (%) = 463 (43), 462 (13), 461 [M]+ (44),
390 (94), 389 (25), 388 (100), 310 (24), 309 (41), 210 (58), 208 (61).
C26H24BrNO2 (461.10): calcd. C 67.54, H 5.23, N 3.03; found C
67.26, H 5.08, N 2.91.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and spectroscopic data.
[a] All reactions were carried out with 1d (0.3 mmol) and 2
(0.3 mmol) catalyzed by mont. K-10 (50 mg) in DCE (1 mL) at
room temperature for 3 h. [b] Isolated yields.
Acknowledgments
Financial support from the Shanghai Municipal Committee of Sci-
ence and Technology (06XD14005 and 08dj1400100-2), the
National Basic Research Program of China (973-2009CB825300),
and the National Natural Science Foundation of China (20872162,
20672127, 20732008, 20821002, and 20702013) is greatly acknowl-
edged.
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Conclusions
In conclusion, we have disclosed two facile routes for the
formation of the tetrahydroquinoline skeleton with a cy-
clopropyl group in the 3,3Ј-position. As a result of the po-
tential pharmaceutical applications of this tetrahydroquino-
line skeleton containing a highly strained cyclopropyl-ring
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Experimental Section
General Procedure for the TfOH-Catalyzed Reactions of MCPs 1
with Ethyl (Arylimino)acetates 2: Under an argon atmosphere, 2a
(76.8 mg, 0.3 mmol), 1a (61.8 mg, 0.3 mmol), TfOH (3 µL,
0.03 mmol, 10 mol-%), and DCE (1.0 mL) were added into a
Schlenk reaction tube. The mixture was stirred at 5 °C for 0.5 h,
then quenched by the addition of solid sodium hydrogen carbonate.
The solvent was removed under reduced pressure, and the residue
was purified by flash column chromatography (SiO2) to give 3a in
82% yield (113 mg).
General Procedure for the Mont. K-10 Catalyzed Reactions of
MCPs 1 with Ethyl (Arylimino)acetates 2: Under an argon atmo-
sphere, 2a (76.8 mg, 0.3 mmol), 1a (61.8 mg, 0.3 mmol), mont. K-
10 (50 mg), and DCE (1.0 mL) were added into a Schlenk reaction
tube. The mixture was stirred at room temperature for 3 h. The
solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography (SiO2) to give 3a in 82%
yield (122 mg).
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Z.-B. Zhu, L.-X. Shao, M. Shi
FULL PAPER
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[17]
[18]
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Received: January 19, 2009
Published Online: April 8, 2009
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