Halonium-initiated C - O bond formation via umpolung of α-carbon to the carbonyl: Efficient access to 5-amino-3(2 H)-furanones

Article abstract of DOI:10.1021/ol203183k

Highly efficient C - O bond formation has been developed via carboxylic acid catalyzed reaction of 1-acetylcyclopropanecarboxamides with N-halosuccinimide (NXS), which provides strategically novel and atom-economic access to biologically important 5-amino

Full text of DOI:10.1021/ol203183k

ORGANIC
LETTERS
2012
Vol. 14, No. 3
712–715
Halonium-Initiated CꢀO Bond Formation
via Umpolung of r-Carbon to the
Carbonyl: Efficient Access to 5-Amino-
3(2H)-furanones
Ying Wei, Shaoxia Lin, Hongxun Xue, Fushun Liang,* and Baozhong Zhao
Department of Chemistry, Northeast Normal University, Changchun 130024, China
liangfs112@nenu.edu.cn
Received November 29, 2011
ABSTRACT
Highly efficient CꢀO bond formation has been developed via carboxylic acid catalyzed reaction of 1-acetylcyclopropanecarboxamides with N-
halosuccinimide (NXS), which provides strategically novel and atom-economic access to biologically important 5-amino-3(2H)-furanones. The
mechanism of halonium-initiated tandem oxa-cyclization and ring opening of cyclopropane was proposed. A variety of nucleophiles were found to
open the cyclopropane.
The 3(2H)-furanone is a core structural unit in a number
of natural products such as bullatenon,1 jatrophone,2
pseurotin A,3 and eremantholide A.4 They have a wide
range of applications in medicine and biology, including
antitumor, antiulcer, and antiallergic activities.5 Various
methods have been developed for the construction of this
five-membered ring system.6 However, most of the current
approaches suffer from (i) limited substrate scope or the lack
of readily available precursors, and (ii) tedious synthetic
procedures. Therefore, further development of efficient meth-
ods that allow the facile assembly of highly functionalized
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r
10.1021/ol203183k
Published on Web 01/24/2012
2012 American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Umpolung Strategy via Bromonium Ion Intermedi-
ate Generated in Situ
catalyst
(equiv)
temp
time
(h)
yield
(%)b
entry
solvent
(°C)
1
2
3
4
5
6
7
8
9
;
DMF
80
12
12
12
12
12
8
n.r.
32
30
34
65
96
94
89c
93
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuBr
DMF
80
DCE
80
3(2H)-furanones from readily available and simple starting
materials is still required.
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
reflux
reflux
reflux
reflux
reflux
reflux
TsOH
The R-carbon to the carbonyl group is generally re-
garded as a nucleophilic center. The reversal of this prime
reactivity (umpolung7), that is, making the R-carbon of the
carbonyl electrophilic, would be of significant synthetic
utility and provide a complementary strategy to access
derivatives that are otherwise difficult to prepare conven-
tionally. In our research on the synthetic potential of β-
ketoamides toward various carbo- and heterocycles,8 we
have developed a convenient and economic route for
intramolecular CꢀO coupling of 1-acetylcyclopropane-
carboxamides via an umpolung strategy. The reactivity
of the R-carbon to the carbonyl group is converted from
originally nucelophilic to electrophilic via an in situ formed
halonium ion intermediate (Scheme 1).9 The sequential
TFA
8
HCO2H
PhCO2H
8
8
a Reactions were carried out with 1a (1.0 mmol), NBS (1.2 mmol),
and catalyst (5% loading amount for Lewis acid; 0.2 equiv for Brønsted
acid) in solvent (2.0 mL). b Isolated yield. c With trace amount of 2i (5%).
Table 2. Halonium-Induced Intramolecular CꢀO Bond For-
mation of 1-Acetylcyclopropanecarboxamides 2a
(8) (a) Cheng, X.; Liang, F.; Shi, F.; Zhang, L.; Liu, Q. Org. Lett.
2009, 11, 93. (b) Liang, F.; Cheng, X.; Liu, J.; Liu, Q. Chem. Commun.
2009, 45, 3636. (c) Wei, Y.; Lin, S. X.; Liu, J.; Ding, H.; Liang, F.; Zhao,
B. Org. Lett. 2010, 12, 4220. (d) Liu, J.; Lin, S.; Ding, H.; Wei, Y.; Liang,
F. Tetrahedron Lett. 2010, 51, 6349. (e) Wei, Y.; Lin, S.; Zhang, J.; Niu,
Z.; Fu, Q.; Liang, F. Chem. Commun. 2011, 47, 12394. (f) Liang, F.; Lin,
S.; Wei, Y. J. Am. Chem. Soc. 2011, 133, 1781.
(9) For recent application of halonium-producing reagent in organic
synthesis, see: (a) Sasaki, M.; Yudin, A. K. J. Am. Chem. Soc. 2003, 125,
14242. (b) Yeung, Y.-Y.; Gao, X.; Corey, E. J. J. Am. Chem. Soc. 2006,
128, 9644. (c) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445,
900. (d) Tanuwidjaja, J.; Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc.
2009, 131, 12084. (e) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed.
2009, 48, 7899. (f) Zhou, L.; Tan, C. K.; Zhou, J.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2010, 132, 10245. (g) Zhou, L.; Tan, C. K.; Jiang, X.; Chen,
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X.; Hui, Y.; Jiang, J.; Wang, W.; Chen, W.; Lin, L.; Feng, X. Angew.
Chem., Int. Ed. 2010, 49, 6160.
yield
entry
1
R1
R2
2
(%)b
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Bn
H
2a
2b
2c
2d
2e
2f
93
90
94
92
0
2-Cl-C6H4CH2
4-MeC6H4CH2
BnCH2
H
H
H
Ph
H
Bn
Me
90
a Reactions were carried out with 1 (1.0 mmol), NBS (1.2 mmol), and
PhCO2H (0.2 mmol) in MeCN (2.0 mL). b Isolated yield.
(10) Examples of oxa-cyclization from amide oxygen atom: (a)
Reddy, D. N.; Prabhakaran, E. N. J. Org. Chem. 2011, 76, 680. (b)
Saito, T.; Ogawa, S.; Takei, N.; Kutsumura, N.; Otani, T. Org. Lett.
2011, 13, 1098. (c) Couto, I.; Tellitu, I.; Domınguez, E. J. Org. Chem.
2010, 75, 7954. (d) Jaganathan, A.; Garzan, A.; Whitehead, D. C.;
Staples, R. J.; Borhan, B. Angew. Chem., Int. Ed. 2011, 50, 2593.
(11) Reviews on cyclopropane chemistry: (a) Danishefsky, S. Acc.
Chem. Res. 1979, 12, 66. (b) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.;
Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165. (c) Reissig,
H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151. (d) Yu, M.; Pagenkopf,
B. L. Tetrahedron 2005, 61, 321. (e) Rubin, M.; Rubina, M.; Gevorgyan,
V. Chem. Rev. 2007, 107, 3117. (f) Carson, C. A.; Kerr, M. A. Chem. Soc.
Rev. 2009, 38, 3051. (g) De Simone, F.; Waser, J. Synthesis 2009, 3353.
(h) Shi, M.; Shao, L.-X.; Lu, J.-M.; Wei, Y.; Mizuno, K.; Maeda, H.
Chem. Rev. 2010, 110, 5883. For recent papers, see: (i) Xing, S.; Li, Y.;
Li, Z.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2011, 50, 12605.
(j) Sathishkannan, G.; Srinivasan, K. Org. Lett. 2011, 13, 6002. (k)
Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130,
1814. (l) Sparr, C.; Gilmour, R. Angew. Chem., Int. Ed. 2011, 50, 8391.
(m) Chung, S. W.; Plummer, M. S.; McAllister, L. A.; Oliver, R. M., III;
Abramite, J. A.; Shen, Y.; Sun, J.; Uccello, D. P.; Arcari, J. T.; Price,
L. M.; Montgomery, J. I. Org. Lett. 2011, 13, 5338.
amide oxa-cyclization10 and ring opening of cyclopropane11
represents a new strategy toward substituted 5-amino-
3(2H)-furanones.
Initially, the model reaction of 1-acetyl-N-benzylcyclopro-
panecarboxamide (1a) with NBS was examined under acidic
conditions (Table 1). No reaction occurred in the absence of
an acid catalyst (entry 1). The reaction with Lewis acid
catalysts like Cu(OAc)2 and CuBr (5% loading amount) at
80 °C gave an amide oxa-cyclized and cyclopropane ring-
opened product, 5-(benzylamino)-4-(2-bromoethyl)furan-
3(2H)-one (2a) in 32ꢀ65% yields (entries 2ꢀ5). The reaction
with Brønsted acids such as TsOH or TFA as the catalyst
exhibited higher efficiency, giving 2a in 94ꢀ96% yields
(entries 6 and 7). When formic acid was introduced as the
catalyst, product 2a was obtained in 89% yield, along with
Org. Lett., Vol. 14, No. 3, 2012
713

the separation of side product 2i in 5% yield (entry 8).
Benzoic acid, as an easily available, cheap, safe, and envi-
ronmentally benign organic carboxylic acid, was finally
examined. To our delight, the reaction afforded the desired
product 2a in 93% yield (entry 9).12
Then, a range of reactions were carried out with various
substrates 1 inthe presenceofNBS and PhCO2H (Table2).
The amide scope was examined first. All of the reactions
based on N-alkylamide substrates 1aꢀd, NBS (1.2 equiv),
and PhCO2H (0.2 equiv) in MeCN proceeded efficiently,
affording 5-amino-3(2H)-furanones 2aꢀd, in excellent
yields (entries 1ꢀ4). Nevertheless, no reaction occurred
with N-aryl counterpart 1e as the substrate (entry 5).13 For
1-acetylcyclopropanecarboxamide 1f bearing a methyl
group on the cyclopropane ring, the reaction proceeded
smoothly to furnish the corresponding 5-amino-3(2H)-
furanone 2f in 90% yield (entry 6).14
In the following work, we further examined the scope of
the reaction, mainly through the variation of NXS, car-
boxylic acids, and solvents (Table 3). Similar to NBS,
reactions with NCS orNIS gave5-amino-3(2H)-furanones
2g and 2h in excellent yields (entries 1ꢀ2). Aliphatic
carboxylic acids including HCO2H, CH3CO2H, and
CH3CH2CO2H proved to be suitable, affording 2iꢀk,
respectively, in high yields (entries 3ꢀ5). Alcoholic sol-
vents such as methanol and ethanol are also efficient in the
explored reactions, giving the corresponding products 2l
and 2mingood yields (entries 6ꢀ7). Interestingly, whenthe
reaction was conducted in DMF, product 2i was produced
in 85% yield (entry 8). In this case, DMF acts as an
external nucleophile to participate in the reaction.15 Ob-
viously, a variety of nucleophiles may be used to open the
cyclopropane.
Figure 1. Effect of R-substituent(s) on the substrates.
oxobutanamide (1i) gave desired product 2n in 88% yield,
while N-benzyl-2,2-dimethyl-3-oxobutanamide (1h) gave
no reaction and N-benzyl-3-oxobutanamide (1j) gave a
complex mixture. Surprisingly, 4,40-(phenylmethylene)
difuran-3(2H)-ones 4a and 4b were successfully ob-
tained in high yields from N-benzyl-2-benzylidene-3-
oxobutanamides 3a and 3b, respectively, via double
oxa-cyclization (Scheme 2). The structure of 4a was
confirmed unambiguously by X-ray single crystal dif-
fraction (Figure 2).16
Scheme 2. Reaction of Benzylidene-Substituted β-Ketoamides 3
Table 3. Exploration the Scope of Nua
yield
entry
X
R
solvent
Nu
Cl
2
(%)b
1
2
3
4
5
6
7
8
Cl
I
Ph
Ph
H
MeCN
MeCN
HCO2H
MeCO2H
EtCO2H
HOMe
HOEt
2g
2h
2i
93
94
92
87
85
73
79
85
I
Br
Br
Br
Br
Br
Br
O2CH
O2CMe
O2CEt
OMe
OEt
Me
Et
2j
2k
2l
Ph
Ph
Ph
2m
2i
DMF
O2CH
Figure 2. ORTEP drawing of 4a.
a Reactions were carried out with 1 (1.0 mmol), NXS (1.2 mmol),
RCO2H (0.2 mmol) in the solvent (2.0 mL). b Isolated yield.
To clarify the proposed halonium ion initiated CꢀO bond
formation involved in the reaction leading to 5-amino-3(2H)-
furanones (Tables 2 and 3), we performed a control reaction
In order to explore the effect of R-substituent(s) of
acetamides on the reactions, noncyclopropane substrates
1hꢀj and 3aꢀb were subjected to the reaction sequences
(Figure 1 and Scheme 2). As a result, N-benzyl-2-methyl-3-
(12) Different from formic acid (Table 1, entry 8 and Table 3, entries
3ꢀ5), benzoic acid is incapable of ring opening the cyclopropane, due to
the weak nucleophilicity.
714
Org. Lett., Vol. 14, No. 3, 2012

Scheme 3. Control Experiment
Scheme 5. Possible Mechanism for the Formation of
4,40-Methylene-3(2H)-furanones 4
Scheme 4. Possible Mechanism for the Formation of 3(2H)-
Furanones 2
opening of the cyclopropane takes place, furnishing the
5-amino-3(2H)-furanone product 2.19
The possible mechanism for the formation of 4 was
illustrated in Scheme 5, which involves the coupling of
carbocation VI and β-ketoamide VIII.20
In conclusion, we have developed a practical and efficient
protocol for the production of highly functionalized 5-amino-
3(2H)-furanones by the reactions of 1-acetylcyclopropane-
carboxamides with NXS. Through in situ generated halonium
ion intermediates, the reactivity of the R-carbon to the
carbonyl group was converted from originally nucleophilic
into electrophilic, leading to the formation of a CꢀO bond
with an amide oxygen atom.21 Further work on the synthetic
application of the reactivity umpolung is ongoing in our
laboratory.
of R-bromonated counterpart 5 in HCO2H at 80 °C
(Scheme 3). As a result, no reaction took place.17
Based on all the results described, a possible mechanism
for the efficient one-pot transformation into 5-amino-
3(2H)-furanones 2 was proposed, as depicted in Scheme 4.
First, acid-induced enolization of 1-cyclopropylethanone1
produces enolate I. Second, in the presence of NXS,
halonium ion II is supposed to generate in situ, which is
directly captured by the amide oxygen, giving the oxonium
intermediate III and its resonance structure, iminium ion
IV.18 Finally, triggered by an external nucleophile, ring
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Nos. 20972027 and
21172034) and the Fundamental Research Funds for the
Central Universities (11SSXT129) is gratefully acknowledged.
(13) An N-alkyl substituted amide oxygen atom has stronger nucleo-
philicity than an N-aryl counterpart, due to the greater electron-donating
ability of the alkylamino group vs the arylamino group.
(14) Reactions with β-ketoesters, such as ethyl 1-acetyl-cyclopropane-
carboxylate, and 1,3-diketones, such as 1,1-diacetylcyclopropane, as the
substrates were also examined but proved to be inefficient.
(15) With DMF as a nucleophile, see: (a) Dakanali, M.; Tsikalas,
G. K.; Krautscheid, H.; Katerinopoulos, H. E. Tetrahedron Lett. 2008,
49, 1648. (b) Muzart, J. Tetrahedron 2009, 65, 8313.
Supporting Information Available. Experimental de-
tails and characterization for all new compounds and
crystal structure data (CIF file). This material is available
free of charge via the Internet at http://pubs.acs.org. The
authors declare no competing financial interest.
(20) Intermediate VIII in Scheme 5 was presumably produced from 3.
In a separate reaction of substrate 3a and TsOH H2O, benzaldehyde
was observed clearly on a TLC plate.
(16) See the Supporting Information.
(17) No R-bromonated ketone 5 was observed during the transfor-
mation from 1 to 2 (Tables 1ꢀ3).
3
(21) For recent papers on R CꢀH functionalization of ketones, see:
(a) Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2011, 133, 1738. (b) Hesp, K. D.; Lundgren, R. J.;
Stradiotto, M. J. Am. Chem. Soc. 2011, 133, 5194. (c) Gandeepan, P.;
Parthasarathy, K.; Cheng, C.-H. J. Am. Chem. Soc. 2010, 132, 8569. (d)
He, C.; Guo, S.; Huang, L.; Lei, A. J. Am. Chem. Soc. 2010, 132, 8273. (e)
Xie, J.; Huang, Z.-Z. Angew. Chem., Int. Ed. 2010, 49, 10181.
(18) The efficient CꢀO bond formation may indicate that the for-
mation of 3(2H)-furanones 2 via oxa-cyclization is predominant com-
pared to the generally observed R-bromonation of ketones leading to 5.
(19) In this case, cyclopropanes appear to be highly sensitive to
external nucleophiles, which can be attributed to (i) inherent strain; (ii)
spiro structure; and (iii) activation by a strongly electron-withdrawing
oxonium or iminium ion. For recent examples of cyclopropyl iminium,
oxonium, or phosphonium activation, see: ref 11kꢀ11m.
The authors declare no competing financial interest.
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