Ag-containing all-carbon 1,3-dipoles: Generation and formal cycloaddition for furo[3,2-b]-β/γ-lactams

Article abstract of DOI:10.1039/b917856b

A new strategy for highly diastereoselective synthesis of furo[3,2-b]-β-lactams and furo[3,2-b]-γ-lactams via a novel Ag(i)-mediated intramolecular 1,3-dipolar cycloaddition of oxo-N- propargylamides, is developed and the possible mechanism of these trans

Full text of DOI:10.1039/b917856b

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Ag-containing all-carbon 1,3-dipoles: generation and formal cycloaddition
for furo[3,2-b]-b/c-lactamsw
Zhiguo Zhang, Qian Zhang,* Zhikun Ni and Qun Liu*
Received (in Cambridge, UK) 1st September 2009, Accepted 15th December 2009
First published as an Advance Article on the web 16th January 2010
DOI: 10.1039/b917856b
A new strategy for highly diastereoselective synthesis of
furo[3,2-b]-b-lactams and furo[3,2-b]-c-lactams via a novel
Ag(I)-mediated intramolecular 1,3-dipolar cycloaddition of
oxo-N-propargylamides, is developed and the possible mechanism
of these transformation is proposed.
Table 1 The synthesis of furo[3,2-b]-g-lactam 2a from 1aa
Yield of
2ab (%)
Yield of
3a (%)
Intramolecular 1,3-dipolar cycloadditions are powerful tools
for the efficient synthesis of various cyclic molecules.1
Although various C3 1,3-dipolar reagents or their synthetic
equivalents have been developed, the generation of all carbon
1,3-dipoles in an efficient approach is a much more challenging
task.2,3 In this communication, we describe a facile generation
of the first Ag-containing all-carbon 1,3-dipoles A from oxo-
N-propargylamides 1 and their applications in the synthesis of
furo[3,2-b]-b/g-lactams (Scheme 1).
Entry
Base (equiv.)
Ag salt (equiv.)
1
2
3
4
5
6
7
8
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
NaOH (1.0)
DBU (1.0)
ButOK (1.0)
KOH (0.2)
KOH (1.0)
KOH (1.0)
KOH (1.0)
Ag2O (0.5)
AgNO3 (1.0)
AgOAc (1.0)
AgSbF6 (1.0)
Ag2O (0.5)
Ag2O (0.5)
Ag2O (0.5)
Ag2O (0.5)
Ag2O (0.1)
Ag2O (0.5)
Ag2O (0.5)
75
55
9
13
16
0
0
0
55
72
28
68
9
18
15
10
17
0
9
10
11
0
53
Tracec
8d
In
a recent report, Zhang et al. demonstrated that
Au-containing all-carbon 1,3-dipoles can be generated through
the elaboration of propargyl alcohols by the introduction of an
electron withdrawing group and a ketal structure.3a In the
research on carbocyclization of aldehydes and alkynes under
the co-catalysis of gold(I) and amine bases, Kirsch et al.
proved that, in a single case, a tricyclic cis-fused dihydrofuran
compound could be constructed via a formal [3 + 2] cyclo-
addition starting from b-propargylmethyl cyclohexanone in a
sealed vial in xylenes at 150 1C.3i Recently, N-propargylamides
have proven to be valuable substrates for alkyne-activated
cycloisomerization4a–d and alkyne-carbonyl coupling reactions.4e
However, to our knowledge, no cycloaddition reaction
with the propargyl moiety of N-propargylamide as a potential
1,3-dipoles has ever been reported.
a
Reactions were carried out with 1a (1.0 mmol) in CH3CN (4 mL) at
b
room temperature for 24 h unless specially mentioned. Isolated
c
d
yield. The reaction was carried out at 0 1C. The reaction was
carried out at 82 1C and some unidentified by-products were detected.
starting from N-propargylamides, all-carbon 1,3-dipoles A
(Scheme 1) could be generated in the presence of suitable
transition-metal ions under basic conditions. In the present
research, the intramolecular cycloaddition of b-oxo-N-
propargylamides 16 was initially evaluated with the aim of
creating a one-step synthesis of furo[3,2-b]-g-lactams 2, the key
structural feature of several bioactive natural products,7 usually
prepared by several steps starting from acyclic precursor.8 To
our delight, a screening of reaction conditions (Table 1)
showed that furo[3,2-b]-g-lactam 2a can be obtained in 75%
yield along with cyclopropanecarboxamide 3a (13%) by
treating oxo-N-propargylamide 1a (1.0 mmol) with Ag2O
(0.5 mmol) and KOH (1.0 equiv.) in acetonitrile (4 mL) at
room temperature for 24 h (entry 1).zy Other silver salts, such
as AgNO3, AgOAc and AgSbF6 were less (entries 2 and 3) or
not effective (entry 4). The reaction was base dependent.
Among the bases tested, NaOH, DBU and ButOK gave 2a
in relatively lower yields (entries 5–7). Other solvents, such as
dichloromethane, ethanol and DMSO were not as effective as
acetonitrile, provided 2a in 60%, 60% and 42% yields,
respectively. A catalytic amount of KOH was proved effective
but with a little lower product yield (entry 8) while a catalytic
amount of Ag2O gave poor product yield (entry 9).
Combined with our recent research for the direct synthesis
of fused heterocyclic compounds from acyclic precursors,5
especially acetoacetanilide derivatives,5b–e we speculated that,
Scheme 1 Generation of all-carbon 1,3-dipoles from N-propargylamides.
Department of Chemistry, Northeast Normal University, Changchun,
130024, P. R. China.
E-mail: zhangq651@nenu.edu.cn, liuqun@nenu.edu.cn;
Fax: 86-431-85099759; Tel: 86-431-85099759
w Electronic supplementary information (ESI) available: Experimental
procedures, full characterization data, copies of 1H and 13C NMR
spectra for all the new compounds. CCDC 740390 (2j) and 740389
(6c). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b917856b
To gain insight into the mechanism of this reaction, a
controlled experiment was conducted. Under otherwise iden-
tical conditions in Table 1, entry 1, but quenching the reaction
with aqueous NH4Cl after reacting for 9 h, an inseparable
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Table 2 The synthesis of furo[3,2-b]-g-lactams 2a
Substrate
Yield of
R1
R2
R3R3
Entry
2 (3)b (%)
1
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
Et
3-MeOC6H4-
CHQCH
4-MeOC6H4
Me
C6H5
4-MeC6H4
(CH2)2
(CH2)2
4-MeOC6H4 (CH2)2
75 (13)
67 (9)
74 (10)
68 (10)
74 (12)
76 (9)
Scheme 2 Proposed mechanism for the formation of 2a.
3-MeC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
(CH2)2
(CH2)2
(CH2)4
mixture of cis-(hydroxy cis to ethynyl group) and trans-4a was
obtained in 19% yield (Scheme 1, trans : cis E 10 : 1 based on
1H NMR spectra, for details, see ESIw) together with 2a and
3a in 56% and 11% yields, respectively. On the basis of the
above results, a stepwise 1,3-dipolar cycloaddition reaction
pathway for the Ag(I)-mediated transformation from 1a to 2a
is depicted in Scheme 2. In the presence of KOH and Ag2O,
the in situ generated 1,3-dipole A from 1a attacks the Ag(I)-
activated carbonyl carbon to give a mixture of Ag-containing
cis- and trans-4a in equilibrium. Then, Ag(I)-mediated
cyclization of Ag-containing cis-4a lead to 2a.8d,9 On the other
hand, by-product 3a is formed by cleavage of the allenamide
intermediate10 D, probably formed from the hydrolysis of
intermediate C. As shown in Scheme 2, the coordination of
Ag(I) to both carbonyl and alkynyl groups9 may play a critical
role for the efficient transformation from 1a to 2a.
1g
1h
Me, Me 68 (13)
51 (19)
(CH2)2
9
1i
4-ClC6H4
(CH2)2
81 (18)
10
11
12
13
1j
1k
1l
4-MeC6H4
2-MeC6H4
2-ClC6H4
Me
(CH2)2
(CH2)2
(CH2)2
(CH2)2
66 (30)c
45 (7)
42 (7)
Me
1m 4-MeOC6H4
35 (29)
14
1n
0 (0)
a
Reactions were carried out with 1a (1.0 mmol), Ag2O (0.5 mmol),
KOH (1.0 equiv.) in CH3CN (4 mL) at room temperature for
b
c
24 h unless specially mentioned. Isolated yield. The reaction was
performed for 48 h.
Under optimal conditions (Table 1, entry 1), the above
1,3-dipolar cycloaddition showed broad scope for various
N-propargylamides (Table 2). N-Propargylamides 1b–e, with
either electron-rich or electron-deficient N-aryl groups,
afforded the desired cis-fused bicyclic products 2b–e in high
yields (entries 2–5). Amides 1f and 1g with a cyclopentane ring
and gem-dimethyl groups underwent cycloaddition to give 2f
and 2g in 76% and 68% yields, respectively (entries 6 and 7).
Substrates 1h–j with various R1 substituents could also lead to
the formation of 2h–j in good to high yields (entries 8–10). The
structure of 2 was further confirmed by the X-ray diffraction
analysis of 2j (Fig. 1).11 The reactions of 1k and 1l having
N-(o-methyl)/(o-chloro) phenyl groups also gave the desired
2k and 2l in 45% and 42% yield, respectively (entries 11 and
12). The relatively lower yields of 2k and 2l may due to the
steric hindrance of the ortho-substituent (comparing the
results from substrate 1b and 1e). In addition, starting from
N-methyl amide 1m with ButOK as base, the desired 2m was
obtained in 35% yield with a reaction time of 2.5 h (entry 13).
In the case of 1n with an N-(3-phenylprop-2-ynyl) group, no
desired 2n was obtained, and 1n was recovered in 83% yield
(entry 14).
Scheme 3
The above 1,3-dipolar cycloaddition provides ready access
to furo[3,2-b]-g-lactams from simple acyclic precursors in an
atom-economical manner.8 Moreover, this method was found
to be powerful for the direct synthesis of furo[3,2-b]-b-lactams.
Under optimal conditions (Table 1, entry 1) but with DBU as
base and reacted for 4 h, furo[3,2-b]-b-lactams 6a and 6b were
synthesized from 2-oxo-N-propargyl-N-arylamides 5a and 5b,6
in 61% and 41% yields, respectively (Scheme 3).12 In addition,
6c11 was obtained in 48% yield with ButOK (0.5 equiv.) as
base for 7 h from 5c. It should be noted that, although
considerable synthetic progress has been made in the area
of mono- and bicyclic b-lactam antibiotics,13 to date, the
construction of furan-fused b-lactams are still based on the
preformed b-lactam rings.14
In conclusion, the first Ag(I)-mediated 1,3-dipolar cyclo-
addition reaction of N-propargylamides with propargyl as
potential 1,3-dipoles has been developed. As a synthetic
application, furo[3,2-b]-b-lactams 6/2, the key structural
features of several bioactive natural products, were constructed
efficiently in a single step and a regiospecific and highly
diastereoselective and atom-economic manner from the readily
available acyclic precursors. Further studies are in progress.
Fig. 1 ORTEP drawing of 2j.
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Financial supports of this research by the NCET-08-0756,
NNSFC (20772015), NENU-STC07006, JLSDP (20080547
and 20082212) are greatly acknowledged.
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Notes and references
z General procedure for the preparation of 2 (with 2a as an example):
A mixture of 1-acetyl-N-phenyl-N-(prop-2-ynyl)cyclopropanecarbox-
amide 1a (0.24 g, 1.0 mmol), Ag2O (0.116 g, 0.5 mmol) and KOH
(0.112 g, 1.0 mmol) was well stirred for 24 h at room temperature in
CH3CN (4 mL), then to the mixture was added water (10 mL) and
NH4Cl (0.1 g, 2.0 mmol), and extracted with CH2Cl2 (6 mL ꢁ 4). The
solvent was removed under reduced pressure, and the residue was
purified by a short flash silica gel column chromatography to give
compound 2a (0.18 g, 75%) as a yellow solid (eluent: diethyl ether–
petroleum ether = 1 : 14) and 3a (0.026 mg, 13%) (eluent: diethyl
ether–petroleum ether = 1 : 9).
y Selected data for 2a: 1H NMR (500 MHz, CDCl3): d 1.10–1.13
(m, 1H), 1.17–1.25 (m, 2H), 1.33–1.38 (m, 4H), 4.98 (s, 1H), 5.19
(t, J = 2.5 Hz, 1H), 6.46 (d, J = 2.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H),
7.34–7.38 (m, 2H), 7.59–7.60 (m, 2H); 13C NMR (125 MHz, CDCl3): d
12.01, 13.43, 22.01, 32.19, 70.24, 86.70, 98.37, 120.91, 124.75, 128.94,
138.04, 150.03, 173.75; MS: calc. m/z 241.1, found 242.1 [M + 1]+; IR
(KBr, neat), n/cmꢂ1: 3381, 3007, 2969, 2926, 1696, 1604, 1496,
1384, 1318, 1179, 1100, 1059, 974, 815 cmꢂ1; Anal. (%). calc.
for C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.50; H,
6.14; N, 5.98.
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