A general access to 1,1-cyclopropane aminoketones and their conversion into 2-benzoyl quinolines

Article abstract of DOI:10.1039/c2cc35235d

1,1-Cyclopropane aminoketones were efficiently synthesized in high yields by the tandem reaction of α-amino aryl ketones with vinyl sulfonium salts using DBU as the base in CH₂Cl₂. This methodology was utilized to synthesize 2-benzoyl quinolines. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc35235d

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 9927–9929
www.rsc.org/chemcomm
COMMUNICATION
A general access to 1,1-cyclopropane aminoketones and their conversion
into 2-benzoyl quinolinesw
Zhenjun Mao, Haijun Qu, Yanyan Zhao and Xufeng Lin*
Received 20th July 2012, Accepted 18th August 2012
DOI: 10.1039/c2cc35235d
1,1-Cyclopropane aminoketones were efficiently synthesized in
high yields by the tandem reaction of a-amino aryl ketones with
vinyl sulfonium salts using DBU as the base in CH2Cl2. This
methodology was utilized to synthesize 2-benzoyl quinolines.
Table 1 Optimization of the reaction conditionsa
Entry
Solvent
Base
T/1C
Yieldb (%)
Cyclopropanes, which play an important role in organic chemistry,
occur widely as key structural units in many biologically active
natural products as well as in drugs, such as ciprofloxacin.1 In
addition, they are frequently employed as versatile building blocks
in organic synthesis.2 Consequently, synthesis of cyclopropane
derivatives has received much attention and general methods for
cyclopropanation have been reviewed, including Simmons–Smith
cyclopropanation, Michael-initiated ring closure, and the cyclo-
propanation of olefins with halomethyl metal reagents.3
Although the literature on cyclopropane synthesis enjoys a rich
history of versatile methodologies, new direct approaches
remain highly valuable due to the continued importance of the
cyclopropane derivatives in both biological and chemical fields.
As a consequence of their unique chemical and biological
properties, 1,1-cyclopropane aminoketones have attracted
wide interest for use in pharmaceutical products.4 Despite
their remarkable biological importance, the direct synthesis of this
type of compounds remains a challenge. Inspired by the diverse
reactivity of vinyl sulfonium salts which have been identified as
valuable intermediates,5 and in continuation of our current studies
on tandem synthesis of cyclic compounds,6 we herein report a
simple and efficient access to 1,1-cyclopropane aminoketones with
the tandem reaction of a-amino aryl ketones and vinyl sulfonium
salts, and also their conversion into 2-benzoyl quinolines.
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
DBU
DBU
None
TEA
NaH
DBU
DBU
DBU
25
0
0 or 25
0
0
0
0
0
76
89
0
Trace
31
75
62
32
CH3CN
Toluene
a
All the reactions were carried out using 1a (1 mmol), 2a (1.2 mmol),
b
base (2.0 mmol) in 7 mL of solvent. Isolated yields.
The reaction did not take place in the absence of base (Table 1,
entry 3), and when the reaction was conducted in the presence of
Et3N, only trace amounts of 3a could be detected while most of
the 1a remained (Table 1, entry 4). Low yield was observed
when the reaction was conducted in the presence of NaH
(Table 1, entry 5). Then, we moved on to screen the reaction
solvent. It was found that methylene chloride was the most
suitable solvent for this transformation among others, such as
THF, acetonitrile and toluene (Table 1, entries 6–8). Thus, the
most suitable reaction conditions for the formation of 3a were
established (Table 1, entry 2).
Under the optimized reaction conditions, the scope of the
a-amino aryl ketones was explored. As shown in Table 2,
the protocol with a variety of a-amino aryl ketones 1 gave the
corresponding 1,1-cyclopropane aminoketones in good to excellent
yields. Electron-donating as well as electron-withdrawing groups
on aromatic rings were tolerated. Moreover, substrate 1h with an
N-(1-naphthyl) substituent showed excellent reaction activity in this
tandem process, and afforded the corresponding product 3h in
96% yield (Table 2, entry 8). Furthermore, the tertiary amine
substrates (1k–1m) also reacted well in this cyclization, and
smoothly afforded the desired 1,1-cyclopropane aminoketone
products in 70–88% yields (Table 2, entries 11–13).
Firstly we examined the reaction between 1-phenyl-2-(phenyl-
amino)ethanone (1a) and diphenyl vinyl sulfonium triflate (2a),
which led to the formation of 1,1-cyclopropane aminoketone (3a)
with a yield of 76% in the presence of DBU in methylene
chloride solution at 25 1C for 1 h. Results of optimization are
listed in Table 1. By lowering the temperature of the reaction to
0 1C, the yield of 3a increased up to 89% (Table 1, entry 2).
The choice of base played a key role in this transformation.
Encouraged by these results, we extended our reaction to
diphenyl styryl sulfonium triflate (2b) as the substrate. As shown
in Table 3, the substrate (2b) could successfully participate in the
tandem reaction to afford the desired products 4 in moderate
yields under the same optimized conditions. Significantly, in each
Department of Chemistry, Zhejiang University, Hangzhou 310027,
China. E-mail: lxfok@zju.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedure, 1H and 13C NMR spectra for all compounds. CCDC
885176. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc35235d
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9927–9929 9927

View Article Online
Table 2 Tandem reactions for the synthesis of 1,1-cyclopropane
aminoketones 3a
Table 3 The tandem reaction of a-amino aryl ketones and styryl
sulfonium saltsa
Yieldb (%)
63
Entry
Substrate
Product
Yieldb (%)
Entry
1
Substrate
Product
1
2
89
83
2
61
79
3
4
5
6
7
8
87
98
85
90
96
96
3
a
1a (1 mmol), 2b (1.2 mmol), DBU (2.0 mmol) in 7 mL of DCM.
Isolated yields of the Z-isomer.
b
Scheme 1 Proposed mechanism.
9
88
gave fused heterocyclic epoxides and morpholines, respectively,
possibly due to the different deprotonation properties of these
substrates.
10
11
78
73
The intensive synthetic utility is shown in Scheme 2. 1,1-
Cyclopropane aminoketone 3a was first reduced with NaBH4
in MeOH to form the corresponding 1,1-cyclopropane amino
alcohol 3aa in 95% yield. Treatment of 3aa with vinyl
sulfonium salt 2a in the presence of NaH generated 7-oxa-4-
azaspiro[2.5]octane 6 as a mixture of two isomers (19 : 6) in
84% yield. The 7-oxa-4-azaspiro[2.5]octane core belongs to an
underutilized class of heterocycles whose biological properties
have been explored.7
12
13
a
70
88
All the reactions were carried out using 1 (1 mmol), 2a (1.2 mmol)
b
and DBU (2.0 mmol) in 7 mL of DCM. Isolated yields.
Finally, to extend the synthetic value of our protocol,
1,1-cyclopropane aminoketones have been converted into 2-benzoyl
quinolines. Quinolines and their derivatives have many important
applications, not only as key structural units in many natural
products and important pharmaceuticals but also as useful
intermediates for various biologically active molecules and
functional materials.8 We have found that 2-benzoyl quinolines can
be obtained from the prepared 1,1-cyclopropane aminoketones
with diethyl azodicarboxylate (DEAD, 2.0 equiv.) in toluene
at 80 1C for 8 h by oxidation, ring-opening and cyclization
(Scheme 3). As shown in Table 4, we explored the protocol
with a variety of the prepared 1,1-cyclopropane aminoketones
case, the ratio of Z : E stereomers of 4 was determined to be
higher than 97 : 3 by 1H NMR. The structure of compound 4a
(Table 3, entry 1) was unambiguously confirmed by single-
crystal X-ray analysis, and the configuration of the product
was determined to have a cis relationship of the aryl amino
and the phenyl group.
A possible mechanism for this annulation reaction is pos-
tulated in Scheme 1. Nucleophilic addition of enolate I to the
vinyl sulfonium salt gives the ylide intermediate II, which
forms enolate III after proton transfer. IV as shown by its
Newman projection is the most stable conformation of
intermediate III, where the less sterically hindered NHPh is
cis to the phenyl group. Then, an intramolecular nucleophilic
substitution forms the 1,1-cyclopropane aminoketone 4a. As
previously reported,5b–d the use of N-tosyl amino ketones or
N-phenyl amino alcohols instead of N-aryl a-amino aryl ketones
Scheme 2 Synthesis of 7-oxa-4-azaspiro[2.5]octane.
c
9928 Chem. Commun., 2012, 48, 9927–9929
This journal is The Royal Society of Chemistry 2012

View Article Online
Scheme 3 Concise synthesis of 2-benzoyl quinolines.
Table 4 Synthesis of 2-benzoyl quinolines 5a
Scheme 4 Proposed mechanism for the synthesis of 2-benzoyl
Entry Substrate
Product
Yieldb (%)
quinolines.
Finally, the target product 5a is obtained by dehydrogenation of D.
This cascade approach to 2-benzoyl quinolines is concise and
efficient, and the products are potentially useful scaffolds for
the synthesis of biologically active compounds.
1
2
3
78
77
65
In conclusion, we have developed a novel direct synthesis of
1,1-cyclopropane aminoketones from a wide range of a-amino
aryl ketones and vinyl sulfonium salts. Notably, the utility of
this protocol has been demonstrated in the rapid access to
7-oxa-4-azaspiro[2.5]octanes and 2-benzoyl quinolines.
We thank the National Natural Science Foundation of
China (21272202) and the Fundamental Research Funds for
the Central Universities for financial support.
4
67
5c
60
Notes and references
1 (a) H.-W. Liu and C. T. Walsh, The Chemistry of the
Cyclopropyl Group, ed. Z. Rappoport, John Wiley & Sons Ltd.,
New York, 1987; (b) L. A. Wessjohann and W. Brandt, Chem. Rev.,
2003, 103, 1625.
2 (a) H. U. Reissig and R. Zimmer, Chem. Rev., 2003, 103, 1151;
(b) F. Gnad and O. Reiser, Chem. Rev., 2003, 103, 1603.
3 (a) H. Lebel, J. F. Marcoux, C. Molinaro and A. B. Charette, Chem.
Rev., 2003, 103, 977; (b) W. A. Donaldson, Tetrahedron, 2001,
57, 8589.
4 (a) J. Nurbo, S. D. Peterson, G. Dahl, U. H. Danielson, A. Karlena
and A. Sandstrom, Bioorg. Med. Chem., 2008, 16, 5590;
(b) K. Mitsuru, S. Hirosada, M. Iwao, K. Kiyohisa, K. Seiji,
N. Shunsaku and S. Yasushi, Chem. Pharm. Bull., 1981, 29, 1912.
6d
50
47
7
8
5 (a) J. Gosselck, L. Beress and H. Schenk, Angew. Chem., Int. Ed. Engl.,
´
1966, 5, 596; (b) M. G. Unthank, N. Hussain and V. K. Aggarwal,
Angew. Chem., Int. Ed., 2006, 45, 7066; (c) M. G. Unthank,
B. Tavassoli and V. K. Aggarwal, Org. Lett., 2008, 10, 1501;
(d) M. Yar, E. McGarrigle and V. K. Aggarwal, Org. Lett., 2009,
11, 257; (e) M. Yar, E. McGarrigle and V. K. Aggarwal, Angew.
Chem., Int. Ed., 2008, 47, 3784; (f) C. S. Xie, D. Y. Han, J. H. Liu and
T. Xie, Tetrahedron Lett., 2010, 51, 5238; (g) H. Yamanaka and
T. Muaiyama, Chem. Lett., 2003, 32, 1192; (h) H. Yamanaka,
J. I. Matsuo, A. Kawana and T. Muaiyama, Chem. Lett., 2003,
32, 626; (i) J. I. Matsuo, H. Yamanaka, A. Kawana and
T. Muaiyama, Chem. Lett., 2003, 32, 392; (j) H. Yamanaka,
J. I. Matsuo, A. Kawana and T. Muaiyama, ARKIVOC, 2004, 42;
(k) S. P. Fritz, J. F. Moya, M. G. Unthank, E. M. McGarrigle and
V. K. Aggarwal, Synthesis, 2012, 1584; (l) J. Gosselck, H. Ahlbrecht,
F. Dost, H. Schenk and G. Schmidt, Tetrahedron Lett., 1968, 9, 995;
(m) J. Gosselck and G. Schmidt, Angew. Chem., Int. Ed. Engl., 1968,
7, 456; (n) J. Gosselck, G. Schmidt, L. Beress and H. Schenk, Tetra-
hedron Lett., 1968, 9, 331; (o) J. Gosselck and G. Schmidt, Tetrahedron
Lett., 1969, 10, 2615.
75
84
9
a
3 (0.5 mmol) and DEAD (1 mmol) in 2 mL of toluene at 80 1C for
b
c
d
8 h. Isolated yields. 5e/5e0 = 3 : 2. 5f/5f0 = 7 : 3.
3 to provide the 2-benzoyl quinoline products in moderate to
good yields. Electron-donating as well as electron-withdrawing
groups on aromatic rings were tolerated. In the case of meta-
substituted substrates (3f and 3g), the corresponding products
were observed as a mixture of two isomers which could be
separated by flash chromatography on silica gel (Table 4,
entries 5 and 6).
6 X. F. Lin, Z. J. Mao, X. Dai, P. Lu and Y. G. Wang, Chem.
Commun., 2011, 47, 6620.
The reaction is proposed to proceed via a cascade procedure
(Scheme 4). 1,1-Cyclopropane aminoketone 3a is first oxidized
with DEAD to give cyclopropene intermediate B. Then, ring-
opening of B gives N-aza-diene intermediate C, which undergoes
an intramolecular [4+2] reaction to yield the dihydroquinoline D.
7 D. J. Blythin, S. Kuo, H. Shue, A. Mcphail, R. Chapman,
W. Kreutner, C. Rizzo, H. She and R. West, Bioorg. Med. Chem.
Lett., 1996, 6, 1529.
8 (a) J. P. Michael, Nat. Prod. Rep., 1997, 14, 605; (b) M. Movassaghi
and M. D. Hill, J. Am. Chem. Soc., 2006, 128, 4592; (c) O. Tsuge
and H. Watanabe, Heterocycles, 1976, 4, 1905.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9927–9929 9929