Synthesis of novel bis(β-lactam)-1,3-diynes by copper-promoted homo- or cross-coupling of alkynyl-2-azetidinones

Article abstract of DOI:10.1002/ejoc.200701083

Cu(OAc)₂ in combination with K₂CO₃ (a solid base instead of an amine) was proven to be an extremely effective system for promoting the homocoupling of various (β-lactam)acetylenes to afford C₂-symmetrical bis(β-lactam)-1,3-diynes, whereas these 2-azetidinone-tethered alkynes underwent the Cadiot-Chodkiewicz cross-coupling reaction with different 2-azetidinone bromoalkynes to form a variety of unsymmetrical bis(β-lactam)diynes in good yields. In addition to their potential biological activity, the resulting enantiopure bis(β-lactam)-1,3- diynes can be converted into bis(β-amino ester)-1,3-diynes, which may find use as macrocyclic cavities, as well as chiral ligands. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701083

FULL PAPER
DOI: 10.1002/ejoc.200701083
Synthesis of Novel Bis(β-lactam)-1,3-diynes by Copper-Promoted Homo- or
Cross-Coupling of Alkynyl-2-azetidinones
Benito Alcaide,*[a] Pedro Almendros,*[b] Rocío Carrascosa,[a] and
Raquel Rodríguez-Acebes[a]
Keywords: Alkynes / Copper / C–C coupling / Lactams / Synthetic methods
Cu(OAc)2 in combination with K2CO3 (a solid base instead
of an amine) was proven to be an extremely effective system
symmetrical bis(β-lactam)diynes in good yields. In addition
to their potential biological activity, the resulting enantiopure
for promoting the homocoupling of various (β-lactam)acetyl- bis(β-lactam)-1,3-diynes can be converted into bis(β-amino
enes to afford C2-symmetrical bis(β-lactam)-1,3-diynes,
whereas these 2-azetidinone-tethered alkynes underwent
the Cadiot–Chodkiewicz cross-coupling reaction with dif-
ferent 2-azetidinone bromoalkynes to form a variety of un-
ester)-1,3-diynes, which may find use as macrocyclic cavities,
as well as chiral ligands.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
stitute a new class of compounds not explored as of yet. In
view of our interest in the application of metals for the syn-
thesis of β-lactams and other nitrogenated compounds of
biological interest,[10] efforts were directed towards explor-
ing the metal-mediated homo- and heterocoupling of alk-
ynyl-2-azetidinones to access novel racemic and enantio-
pure C2-symmetrical and unsymmetrical bis(β-lactam)-1,3-
diynes.
Introduction
Besides the utility of β-lactams as biologically active
agents,[1] they are used as building blocks for α- and β-
amino acids, alkaloids, heterocycles, taxoids, and other
types of compounds of biological and medicinal interest.[2]
As a small ring, 2-azetidinone provides a structural scaffold
of unique bond angles and well-defined configurations of
the substituents. Consequently, the development of new ap-
proaches to the stereocontrolled synthesis of β-lactam sys-
tems is a subject of great interest. On the other hand, diynes
are useful building blocks in organic synthesis and a recur-
ring functional group in many natural products and bioac-
tive compounds.[3] In particular, 1,3-diynes have been uti-
lized as equivalents to various functional groups, as well as
valuable intermediates for natural products and pharma-
ceuticals, and they have been recently recognized as a core
functional group in organic molecular materials such as
molecular wires and molecular architecture on the nanome-
ter scale.[4] Glaser oxidative acetylenic coupling,[5] modified
protocols such as the Eglinton[6] and Hay[7] variants for
homocoupling, and the Cadiot–Chodkiewicz[8] variant for
cross-coupling provide powerful methodologies for 1,3-di-
ynic compounds.[9] However, bis(β-lactam)-1,3-diynes con-
Results and Discussion
Our initial goal was to evaluate the effect of metals,
bases, and co-oxidants on the metal-promoted homocoup-
ling of alkynyl β-lactams. Starting substrates, isomerically
pure alkynyl-β-lactams 1a–j, were prepared by using our
previously described methodologies.[11] Alkyne (+)-1a was
chosen as the model compound for the present study
(Scheme 1, Table 1). The copper-mediated homocoupling
reactions of alkyne (+)-1a afforded quantitative yields of
bis(β-lactam)-1,3-diyne (+)-2a (Table 1, Entries 1–6),[12]
whereas low yields where obtained when homocoupling of
alkyne (+)-1a was attempted under palladium-catalyzed re-
action conditions (Table 1, Entries 7–10). The results in
Table 1 indicate that oxidative reagents have no fundamen-
tal influence on the reaction. Without any oxidative reagent
[a] Instituto de Química Orgánica General, Consejo Superior de
Investigaciones Científicas, CSIC,
28040 Madrid, Spain
Fax: +34-91-3944103
E-mail: alcaideb@quim.ucm.es
[b] Instituto de Química Orgánica General, Consejo Superior de
Investigaciones Científicas, CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34-91-5644853
E-mail: Palmendros@iqog.csic.es
Scheme 1. Homocoupling reaction of N-alkynyl-2-azetidinone (+)-
1a.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 1575–1581
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1575

B. Alcaide, P. Almendros, R. Carrascosa, R. Rodríguez-Acebes
FULL PAPER
(Table 1, Entries 2, 4, and 5), the yield of (+)-2a did not absence of base, while maintaining an excellent isolated
decrease. The use of either Et3N or K2CO3 as the base gave yield (Table 1, Entry 6). Optimization of solvent revealed
good results. The reaction proceeded more slowly in the that acetonitrile was superior to other solvents (THF and
DMF, see Table 1, Entry 9).
Amines have characteristic foul smells and pungent flav-
Table 1. Homocoupling reaction of N-alkynyl-2-azetidinone (+)-1a
ors. For these reasons, the development of an effective pro-
cedure for homocoupling of alkynes under amine-free con-
ditions would be desirable. Thus, we chose to use K2CO3
(instead of amines as the base) in our copper-promoted
homocoupling study of different functionalized 2-azetidi-
none-tethered alkynes.[13] Under the optimized reaction
conditions, the homocoupling reactions of various other
alkynyl-β-lactams 1b–k were carried out smoothly to afford
the corresponding bis(2-azetidinone)-1,3-diynes 2b–k in ex-
cellent-to-quantitative yields, and the results are summa-
rized in Scheme 2. The results show that the copper-medi-
ated homocoupling reaction tolerated a variety of func-
tional groups on the β-lactam ring, such as alkenyl, alkoxy,
aryl, bromoaryl, carboxyalkyl, dioxolanyl, hydroxy, and vi-
under different conditions.
Entry Metal source[a]
Base
Solvent Gas
t
[h]
Yield[b]
[%]
1
2
3
4
5
6
7
8
9
10
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2/Pd(OAc)2 K2CO3
Cu(OAc)2/Pd(OAc)2 K2CO3
Cu(OAc)2/Pd(OAc)2 K2CO3
Et3N
Et3N
K2CO3
K2CO3
K2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
O2
Ar
O2
Ar
2
2
4
4
4
28
5
4
16
0.5
100
98
100
98
100
98
Ar
O2
Ar
O2
27[c]
26[c]
15[c]
8[c]
CuI/PdCl2
Et3N[d]
MeCN
[a] Reactions were conducted by using a metal salt/alkyne molar
ratio of 2.1:1. [b] Yield of pure, isolated product (+)-2a with correct
analytical and spectroscopic data. [c] Disappearance of starting
(+)-1a was observed in all cases. Unidentified decomposition prod- nyl bromide moieties. It is noteworthy that the dimerization
ucts were also detected. [d] This experiment was carried out in the
additional presence of PPh3. PMP = 4-MeOC6H4.
reaction of 2-azetidinones bearing the alkyne tether at any
N1, C3, or C4 position occurred with similar efficiency.
Having obtained C2-symmetrical bis(β-lactam)-1,3-
diynes, the next stage was set to carry out selective hetero-
coupling conditions for the achievement of unsymmetrical
bis(β-lactam)-1,3-diynes.[14] We envisioned that the target
unsymmetrical diynes could come from the copper-cata-
lyzed Cadiot–Chodkiewicz cross-coupling reaction of a
bromoalkynyl-β-lactam with a terminal alkynyl-β-lactam.
Heterocoupling precursors, bromoalkynes 3, were smoothly
prepared from alkynes 1 in excellent yield by reaction with
NBS and AgOAc (or AgNO3) in acetone (Scheme 3).[15]
Scheme 2. Copper-promoted preparation of C2-symmetrical bis(β-
lactam)-1,3-diynes 2b–k. Reagents and conditions: (i) Cu(OAc)2,
K2CO3, MeCN, room temp.; 2b: 5 h; 2c: 22 h; 2d: 6 h; 2e: 2 h; 2f:
168 h; 2g: 6 h; 2h: 20 h; 2i: 16 h; 2j: 18 h; 2k: 24 h.
Scheme 3. Preparation of bromoalkynyl-β-lactams 3. Reagents and
conditions: (i) NBS, AgOAc (or AgNO3), acetone, room temp.,
darkness; 3a: 3 h; 3b: 2.5 h; 3c: 21 h; 3d: 4 h.
1576
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1575–1581

Copper-Promoted Synthesis of Novel Bis(β-lactam)-1,3-diynes
Cross-coupling by the Cadiot–Chodkiewicz reaction be-
A tentative mechanistic proposal for the copper-pro-
tween bromoalkynyl-β-lactams 3 and alkynyl-β-lactams 1 moted homodimerization of alkynyl-β-lactams is depicted
catalyzed by CuCl and NH2OH·HCl in a 70% ethylamine in Scheme 6. It may involve the formation of copper(I) ace-
in water solvent, produced the corresponding unsymmetri- tylides, which are rapidly oxidized by the transfer of a single
cal bis(β-lactam)-1,3-diynes 4 in good yields (Scheme 4). electron to copper(II) through an acetate ligand bridge. De-
The corresponding palladium-catalyzed heterocoupling composition of the resultant copper(II) acetylide and re-
procedure did afford poor yields of heterodimers 4.
combination of the free radicals would give the homocou-
pled products.
Scheme 6. Mechanistic explanation for the Cu-promoted homo-
coupling of alkynyl-β-lactams by using Cu(OAc)2 and K2CO3 in
the absence of O2.
The structure (by DEPT, HMQC, HMBC, and COSY)
and the stereochemistry (by vicinal proton couplings and
qualitative homonuclear NOE difference spectra) of bis(β-
lactam)-1,3-diynes 2 and 4 were assigned by one- and two-
dimensional NMR experiments. The cis stereochemistry of
the four-membered ring was set during the cyclization step
to form the 2-azetidinone ring, and it was transferred unal-
tered during the further synthetic steps.[16]
Scheme 4. Copper-promoted preparation of unsymmetrical bis(β-
lactam)-1,3-diynes 4a–d. Reagents and conditions: (i) MeOH/
CH2Cl2, CuCl, NH2OH·HCl, EtNH2, 0 °C; 4a: 3 h; 4b: 3 h; 4c: 4 h;
4d: 2 h.
The application of the alkynyl-β-lactam homo- or cross-
coupling strategy followed by selective 2-azetidinone ring
opening could afford bis(β-amino ester)s bearing a rigid
Conclusions
Cu(OAc)2 in combination with a solid base (K2CO3) was
spacer. Indeed, the sodium methoxide promoted N1–C2 proven to be an extremely effective system for promoting
amide bond cleavage in 1,3-diynes (+)-2a and (–)-2k gave the homocoupling of 2-azetidinone-tethered alkynes,
the corresponding bis(β-amino ester)-1,3-diynes (+)-3a and whereas the cross-coupling of bromoalkynyl-β-lactams with
(+)-3b (Scheme 5).
terminal alkynyl-β-lactams can be easily achieved by a cop-
Scheme 5. Preparation of bis(β-amino ester)-1,3-diynes 5. Reagents and conditions: (i) MeONa, MeOH, sealed tube, 65 °C; 5a: 1 h; 5b:
8 h.
Eur. J. Org. Chem. 2008, 1575–1581
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1577

B. Alcaide, P. Almendros, R. Carrascosa, R. Rodríguez-Acebes
FULL PAPER
= 5.85 (m, 2 H), 5.18 (m, 4 H), 4.48 (d, J = 4.9 Hz, 2 H), 4.47 (d,
J = 17.6 Hz, 2 H), 3.99 (d, J = 17.8 Hz, 2 H), 3.92 (m, 2 H), 3.81
(t, J = 5.0 Hz, 2 H), 3.59 (s, 6 H), 2.51 (br. s, 2 H), 2.33 (m, 4 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.8, 133.7, 118.5, 83.5,
per-catalyzed Cadiot–Chodkiewicz reaction. These method-
ologies offer a convenient way for the preparation of both
racemic and enantiopure C2-symmetrical and unsymmetri-
cal bis(β-lactam)-1,3-diyne hybrids, which in addition to
their potential biological activity may find use as macro-
cyclic cavities, as well as chiral ligands.
72.0, 69.8, 68.3, 59.9, 59.4, 38.7, 31.5 ppm. IR (KBr): ν = 3424,
˜
1739 cm–1. MS (ES): m/z (%) = 417 (100) [M + H]+, 416 (11)
[M]+. C22H28N2O6 (416.5): calcd. C 63.45, H 6.78, N 6.73; found
C 63.69, H 6.85, N 6.79.
Bis(β-lactam)-1,3-diyne (+)-2d: From alkynyl-2-azetidinone (+)-1d
(44 mg, 0.15 mmol), compound (+)-2d (44 mg, 100%) was obtained
as a colorless oil. [α]D = +30.8 (c = 0.5, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 5.78 (s, 2 H), 5.59 (d, J = 1.5 Hz, 2
H), 4.52 (d, J = 5.1 Hz, 2 H), 4.47 (d, J = 17.8 Hz, 2 H), 4.23 (m,
2 H), 4.00 (d, J = 17.8 Hz, 2 H), 3.85 (t, J = 5.0 Hz, 2 H), 3.62 (s,
6 H), 2.68 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.9,
129.3, 120.5, 83.7, 72.3, 68.6, 68.5, 59.8, 59.7, 46.0, 31.7 ppm. IR
Experimental Section
1
General Methods: H NMR and 13C NMR spectra were recorded
with a Bruker Avance-300, Varian VRX-300S, or Bruker AC-200
instrument. NMR spectra were recorded in CDCl3 solutions, unless
otherwise stated. Chemical shifts are given in ppm relative to TMS
(1H, 0.0 ppm), or CDCl3 (13C, 76.9 ppm). Low- and high-resolu-
tion mass spectra were obtained with a HP5989A spectrometer by
using the electronic impact (EI) or electrospray modes (ES), unless
otherwise stated. Specific rotation [α]D is given in 10–1 °cm2 g–1 at
20 °C, and the concentration (c) is expressed in g per 100 mL. All
commercially available compounds were used without further puri-
fication.
(CHCl ): ν = 3429, 1743 cm–1. MS (ES): m/z (%) = 577 (44) [M +
˜
3
4 + H]+, 575 (100) [M + 2 + H]+, 573 (48) [M + H]+.
C22H26Br2N2O6 (574.3): calcd. C 46.01, H 4.56, N 4.88; found C
46.25, H 4.62, N 4.81.
Bis(β-lactam)-1,3-diyne (+)-2e: From alkynyl-2-azetidinone (+)-1e
(50 mg, 0.15 mmol), compound (+)-2e (49 mg, 99%) was obtained
as a colorless oil after purification by flash chromatography (hex-
anes/ethyl acetate, 1:3). [α]D = +21.3 (c = 0.6, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 5.76 (s, 2 H), 5.60 (d, J = 1.7 Hz, 2
H), 4.55 (d, J = 5.1 Hz, 2 H), 4.21 (m, 2 H), 3.83 (t, J = 5.4 Hz, 2
H), 3.68 (m, 2 H), 3.62 (s, 6 H), 3.35 (m, 2 H), 2.67 (m, 10 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 167.5, 129.1, 120.1, 82.9, 74.5,
Copper(II) Acetate Promoted Homocoupling Reaction of 2-Azetid-
inone-Tethered Alkynes 1 in a Medium Containing K2CO3. General
Procedure for the Synthesis of C2-Symmetrical Bis(β-lactam)-1,3-
diynes 2: Copper(II) acetate (1.05 mmol) and potassium carbonate
(0.6 mmol) were sequentially added to a well-stirred solution of
the appropriate alkynyl 2-azetidinone 1 (0.5 mmol) in acetonitrile
(12 mL). The resulting suspension was stirred at room temperature
until disappearance (TLC) of the starting material. The organic
extract was washed with brine, dried (MgSO4), and concentrated
under reduced pressure to give analytically pure C2-symmetrical
bis(β-lactam)-1,3-diynes. Spectroscopic and analytical data for
some representative forms of bis(β-lactam)-1,3-diynes 2 follow.
68.8, 66.6, 60.47, 59.3, 45.6, 40.0, 18.6 ppm. IR (CHCl ): ν = 3431,
˜
3
1745 cm–1. MS (ES): m/z (%) = 605 (48) [M + 4 + H]+, 603 (100)
[M + 2 + H]+, 601 (52) [M + H]+. C24H30Br2N2O6 (602.3): calcd.
C 47.86, H 5.02, N 4.65; found C 47.64, H 5.09, N 4.71.
Bis(β-lactam)-1,3-diyne (–)-2f: From alkynyl-2-azetidinone (+)-1f
(47 mg, 0.17 mmol), compound (–)-2f (47 mg, 100%) was obtained
as a colorless oil. [α]D = –72.0 (c = 1.3, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.44 (d, J = 9.0 Hz, 4 H), 6.88 (d,
J = 9.0 Hz, 4 H), 4.67 (d, J = 5.4 Hz, 2 H), 4.55 (dd, J = 5.2,
3.5 Hz, 2 H), 4.18 (td, J = 7.0, 3.3 Hz, 2 H), 3.69 (s, 6 H), 3.79 (s,
6 H), 2.68 (dd, J = 17.2, 6.5 Hz, 2 H), 2.50 (dd, J = 17.0, 7.7 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.6, 156.8, 130.4,
120.1, 114.2, 82.6, 73.7, 69.1, 67.5, 59.7, 58.7, 55.3, 24.7 ppm. IR
Bis(β-lactam)-1,3-diyne (+)-2a: From alkynyl-2-azetidinone (+)-1a
(54 mg, 0.23 mmol), compound (+)-2a (54 mg, 100%) was obtained
as a colorless oil. [α]D = +26.1 (c = 1.3, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 4.46 (d, J = 5.1 Hz, 2 H), 4.43 (d,
J = 16.6 Hz, 2 H), 4.29 (ddd, J = 9.1, 6.5, 4.9 Hz, 2 H), 4.11 (dd,
J = 8.9, 6.6 Hz, 2 H), 3.97 (d, J = 17.3 Hz, 2 H), 3.78 (dd, J = 9.0,
5.1 Hz, 2 H), 3.69 (dd, J = 8.8, 5.1 Hz, 2 H), 3.53 (s, 6 H), 1.48
and 1.35 (s, each 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.5, 109.6, 83.1, 76.5, 71.8, 67.9, 66.5, 59.4, 59.1, 31.0, 26.8,
(CHCl ): ν = 3425, 1748 cm–1. MS (EI): m/z (%) = 549 (8) [M +
˜
3
25.0 ppm. IR (CHCl ): ν = 1740 cm–1. HRMS (FAB): calcd. for
˜
H]+, 548 (24) [M]+, 149 (100). C30H32N2O8 (548.6): calcd. C 65.68,
3
C24H33N2O8 [M + H]+ 477.2237; found 477.2259. C24H32N2O8
(477.2): calcd. C 60.49, H 6.77, N 5.88; found C 60.70, H 6.71, N
5.93.
H 5.88, N 5.11; found C 65.94, H 5.73, N 5.18.
Bis(β-lactam)-1,3-diyne (+)-2g: From alkynyl-2-azetidinone (+)-1g
(48 mg, 0.17 mmol), compound (+)-2g (47 mg, 98%) was obtained
as a colorless oil after purification by flash chromatography (hex-
anes/ethyl acetate, 1:2). [α]D = +28.1 (c = 0.7, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 5.90 (t, J = 1.0 Hz, 2 H), 5.67 (dd,
J = 2.2, 0.5 Hz, 2 H), 4.58 (d, J = 5.1 Hz, 2 H), 4.41 (d, J = 15.6 Hz,
2 H), 4.04 (d, J = 15.6 Hz, 2 H), 4.03 (m, 2 H), 3.90 (t, J = 5.4 Hz,
Bis(β-lactam)-1,3-diyne (–)-2b: From alkynyl-2-azetidinone (–)-1b
(112 mg, 0.42 mmol), compound (–)-2b (112 mg, 100%) was ob-
tained as a colorless oil. [α]D = –26.7 (c = 1.0, CHCl3). H NMR
(300 MHz, CDCl3, 25 °C): δ = 5.79 (d, J = 4.9 Hz, 2 H), 4.49 (d,
J = 17.1 Hz, 2 H), 4.24 (ddd, J = 8.8, 6.5, 5.2 Hz, 2 H), 4.02 (d, J
1
= 17.6 Hz, 2 H), 3.97 (dd, J = 8.9, 6.5 Hz, 2 H), 3.92 (dd, J = 8.8, 2 H), 3.62 (s, 6 H), 2.59 (d, J = 6.1 Hz, 6 H) ppm. 13C NMR
4.9 Hz, 2 H), 3.66 (dd, J = 8.8, 5.1 Hz, 2 H), 2.13 (s, 6 H), 1.47 (75 MHz, CDCl3): δ = 167.6, 126.9, 120.5, 83.1, 73.4, 69.3, 67.8,
and 1.35 (s, each 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
59.6, 59.5, 49.7, 25.0 ppm. IR (CHCl ): ν = 3427, 1747 cm–1. MS
˜
3
169.1, 163.6, 110.1, 75.8, 74.4, 71.5, 68.3, 66.3, 59.4, 31.6, 26.7,
(ES): m/z (%) = 577 (51) [M + 4 + H]+, 575 (100) [M + 2 + H]+,
25.1, 20.3 ppm. IR (CHCl ): ν = 1740, 1728 cm–1. MS (ES): m/z
573 (54) [M + H]+. C22H26Br2N2O6 (574.3): calcd. C 46.01, H 4.56,
˜
3
(%) = 533 (100) [M + H]+, 532 (16) [M]+. C26H32N2O10 (532.5): N 4.88; found C 46.27, H 4.48, N 4.80.
calcd. C 58.64, H 6.06, N 5.26; found C 58.90, H 5.99, N 5.32.
Bis(β-lactam)-1,3-diyne (+)-2h: From alkynyl-2-azetidinone (+)-1h
Bis(β-lactam)-1,3-diyne (+)-2c: From alkynyl-2-azetidinone (+)-1c
(54 mg, 0.26 mmol), compound (+)-2c (54 mg, 100%) was obtained
as a colorless solid. M.p. 117–118 °C (hexanes/ethyl acetate). [α]D
(47 mg, 0.14 mmol), compound (+)-2h (47 mg, 100%) was obtained
as a colorless oil. [α]D = +34.4 (c = 0.7, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.55 (dd, J = 7.9, 1.0 Hz, 2 H), 7.38
(dd, J = 7.6, 2.0 Hz, 2 H), 7.32 (dd, J = 7.1, 1.2 Hz, 2 H), 7.16
1
= +14.1 (c = 0.7, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ
1578
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1575–1581

Copper-Promoted Synthesis of Novel Bis(β-lactam)-1,3-diynes
(ddd, J = 7.8, 7.1, 1.9 Hz, 2 H), 4.79 (d, J = 15.4 Hz, 2 H), 4.52
(d, J = 5.1 Hz, 2 H), 4.46 (d, J = 15.6 Hz, 2 H), 4.00 (td, J = 6.2,
5.4 Hz, 2 H), 3.75 (t, J = 5.2 Hz, 2 H), 3.62 (s, 6 H), 2.47 (d, J =
6.3 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.7, 134.5,
133.0, 130.6, 129.4, 127.7, 123.3, 83.0, 73.4, 69.3, 67.6, 59.7, 59.5,
cally pure bromoalkynyl-β-lactams 3. Spectroscopic and analytical
data for some representative forms of compounds 3 follow.
Bromoalkynyl-β-lactam (+)-3a: From alkynyl-2-azetidinone (+)-1a
(100 mg, 0.42 mmol), compound (+)-3a (108 mg, 81%) was ob-
tained as a pale yellow oil after purification by flash chromatog-
raphy (hexanes/ethyl acetate, 3:1). [α]D = +28.2 (c = 0.4, CHCl3).
1H NMR (300 MHz, CDCl3, 25 °C): δ = 4.46 (d, J = 5.1 Hz, 2 H),
4.38 and 3.92 (d, J = 17.3 Hz, each 1 H), 4.30 (m, 1 H), 4.11 (dd,
J = 8.8, 6.5 Hz, 1 H), 3.80 and 3.70 (dd, J = 9.0, 5.0 Hz, each 1
H), 3.53 (s, 3 H), 1.48 and 1.35 (s, each 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.7, 109.7, 83.1, 76.6, 73.3, 66.7, 59.5,
46.0, 24.9 ppm. IR (CHCl ): ν = 3427, 1745 cm–1. MS (ES): m/z
˜
3
(%) = 677 (55) [M + 4 + H]+, 675 (100) [M + 2 + H]+, 673 (50)
[M + H]+. C30H30Br2N2O6 (674.4): calcd. C 53.43, H 4.48, N 4.15;
found C 53.64, H 4.40, N 4.08.
Bis(β-lactam)-1,3-diyne (+)-2i: From alkynyl-2-azetidinone (+)-1i
(53 mg, 0.14 mmol), compound (+)-2i (53 mg, 100%) was obtained
as a colorless oil after purification by flash chromatography (hex-
anes/ethyl acetate, 1:1). [α]D = +87.9 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.37 (d, J = 9.0 Hz, 4 H), 6.88 (d,
J = 9.0 Hz, 4 H), 5.65 (d, J = 1.7 Hz, 2 H), 5.57 (d, J = 1.7 Hz, 2
H), 5.06 (m, 2 H), 4.99 (d, J = 5.1 Hz, 1 H), 4.47 (m, 4 H), 4.36
(dd, J = 5.1, 3.2 Hz, 1 H), 3.80 (s, 6 H), 2.70 (m, 4 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.9, 157.0, 130.5, 129.1, 120.7,
120.5, 114.4, 77.0, 75.8, 68.8, 68.6, 60.5, 60.4, 55.5, 46.5 ppm. IR
59.2, 43.7, 31.5, 26.9, 25.1 ppm. IR (CHCl ): ν = 1742 cm–1. MS
˜
3
(EI): m/z (%) = 319 (100) [M + 2]+, 317 (98) [M]+. C12H16BrNO4
(318.2): calcd. C 45.30, H 5.07, N 4.40; found C 45.42, H 5.05, N
4.43.
Bromoalkynyl-β-lactam (–)-3b: From alkynyl-2-azetidinone (+)-1f
(100 mg, 0.42 mmol), compound (–)-3b (25 mg, 63%) was obtained
as a colorless oil after purification by flash chromatography (hex-
anes/ethyl acetate, 2:1). [α]D = –9.0 (c = 0.3, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.44 and 6.88 (d, J = 9.0 Hz, each
2 H), 4.66 (d, J = 5.1 Hz, 1 H), 4.54 (dd, J = 5.1, 3.7 Hz, 1 H),
4.16 (m, 1 H), 3.80 (s, 3 H), 3.69 (s, 3 H), 2.81 (d, J = 3.9 Hz, 1
H), 2.61 (dd, J = 17.0, 6.5 Hz, 1 H), 2.44 (dd, J = 17.0, 8.0 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.8, 156.9, 130.6,
120.3, 114.3, 82.7, 76.1, 69.1, 59.8, 58.8, 55.5, 41.2, 25.2 ppm. IR
(CHCl ): ν = 3427, 1749 cm–1. MS (ES): m/z (%) = 761 (50) [M +
˜
3
4 + H]+, 759 (100) [M + 2 + H]+, 757 (52) [M + H]+.
C34H34Br2N2O8 (758.5): calcd. C 53.84, H 4.52, N 3.69; found C
53.62, H 4.61, N 3.60.
Bis(β-lactam)-1,3-diyne (؎)-2j: From of alkynyl-2-azetidinone (Ϯ)-
1j (55 mg, 0.14 mmol), compound (Ϯ)-2j (54 mg, 99%) was ob-
tained as a colorless oil after purification by flash chromatography
(hexanes/ethyl acetate, 1:1). 1H NMR (300 MHz, CDCl3, 25 °C): δ
= 7.36 (d, J = 9.0 Hz, 4 H), 6.88 (d, J = 9.0 Hz, 4 H), 5.69 (s, 2
H), 5.59 (d, J = 1.7 Hz, 2 H), 4.50 (td, J = 8.7, 4.5 Hz, 2 H), 4.30
(dd, J = 5.5, 4.5 Hz, 2 H), 3.79 (s, 6 H), 3.58 (dt, J = 9.5, 5.6 Hz,
2 H), 2.97 (m, 4 H), 2.79 (dd, J = 14.5, 3.5 Hz, 2 H), 2.64 (dd, J =
14.5, 9.2 Hz, 2 H), 1.96 (d, J = 4.6 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.7, 157.0, 130.6, 129.0, 121.2, 120.7,
114.3, 74.8, 68.4, 67.0, 58.0, 55.5, 49.9, 47.7, 15.5 ppm. IR (CHCl3):
(CHCl ): ν = 3310, 1744 cm–1. MS (EI): m/z (%) = 353 (100) [M +
˜
3
2]+, 355 (98) [M]+. C15H16BrNO4 (354.2): calcd. C 50.86, H 4.55,
N 3.95; found C 50.99, H 4.51, N 3.98.
Bromoalkynyl-β-lactam (؎)-3c: From alkynyl-2-azetidinone (Ϯ)-1l
(90 mg, 0.28 mmol), compound (Ϯ)-3c (112 mg, 100%) was ob-
tained as a colorless oil after purification by flash chromatography
(hexanes/ethyl acetate, 4:1). 1H NMR (300 MHz, CDCl3, 25 °C): δ
= 7.26 and 6.77 (d, J = 9.0 Hz, each 2 H), 7.22 (m, 4 H), 5.16 (s,
2 H), 4.14 and 3.91 (d, J = 15.8 Hz, each 1 H), 3.73 (s, 3 H), 2.35
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.2, 156.3, 138.5,
130.5, 130.0, 129.3, 128.0, 118.8, 114.3, 81.5, 74.9, 61.6, 58.5, 55.4,
ν = 3428, 1750 cm–1. MS (ES): m/z (%) = 729 (49) [M + 4 + H]+,
˜
727 (100) [M + 2 + H]+, 725 (52) [M + H]+. C34H34Br2N2O6
(726.5): calcd. C 56.21, H 4.72, N 3.86; found C 53.36, H 4.76, N
3.83.
47.7, 21.2 ppm. IR (CHCl ): ν = 1742 cm–1. MS (EI): m/z (%) =
˜
3
401 (100) [M + 2]+, 399 (98) [M]+. C20H18BrNO3 (399.1): calcd. C
60.01, H 4.53, N 3.50; found C 60.15, H 4.49, N 3.54.
Bis(β-lactam)-1,3-diyne (–)-2k: From alkynyl-2-azetidinone (–)-1k
(32 mg, 0.12 mmol), compound (–)-2k (26 mg, 81%) was obtained
as a colorless oil after purification by flash chromatography (hex-
anes/ethyl acetate, 1:1). [α]D = –31.4 (c = 0.7, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 5.87 (ddt, J = 17.3, 9.8, 7.3 Hz, 2
H), 5.25 (m, 4 H), 4.49 (d, J = 17.6 Hz, 2 H), 4.36 (td, J = 6.5,
4.5 Hz, 2 H), 4.17 (dd, J = 8.9, 7.0 Hz, 2 H), 3.94 (d, J = 17.6 Hz,
2 H), 3.83 (dd, J = 9.2, 4.5 Hz, 2 H), 3.64 (d, J = 6.1 Hz, 2 H),
2.62 (dd, J = 13.9, 7.1 Hz, 2 H), 2.49 (dd, J = 13.9, 7.6 Hz, 2 H),
1.46 and 1.35 (s, each 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.0, 131.1, 120.3, 110.1, 84.7, 75.3, 71.7, 68.2, 66.5, 64.1, 39.3,
Bromoalkynyl-β-lactam (؎)-3d: From alkynyl-2-azetidinone (Ϯ)-1m
(88 mg, 0.26 mmol) compound (Ϯ)-3d (63 mg, 58%) was obtained
as a pale yellow oil after purification by flash chromatography (hex-
anes/ethyl acetate, 3:1). 1H NMR (300 MHz, CDCl3, 25 °C): δ =
7.28 and 6.80 (d, J = 9.0 Hz, each 2 H), 7.23 (s, 4 H), 5.18 (s, 1
H), 3.75 (s, 3 H), 3.07 (br. s, 1 H), 2.91 (d, J = 1.5 Hz, 2 H), 2.36
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.6, 156.5, 138.9,
130.2, 130.0, 129.9, 127.3, 119.1, 114.4, 84.0, 74.2, 66.6, 55.4, 42.2,
26.7, 21.2 ppm. IR (CHCl ): ν = 3322, 1743 cm–1. MS (EI): m/z
˜
3
(%) = 401 (100) [M + 2]+, 399 (98) [M]+. C20H18BrNO3 (399.1):
30.9, 26.5, 24.9 ppm. IR (CHCl ): ν = 3430, 1747 cm–1. MS (ES):
˜
calcd. C 60.01, H 4.53, N 3.50; found C 59.89, H 4.50, N 3.53.
3
m/z (%) = 529 (100) [M + H]+, 528 (23) [M]+. C28H36N2O8 (528.6):
Copper(I) Chloride Promoted Heterocoupling Reaction between 2-
Azetidinone-Tethered Alkynes 1 and Bromoalkynyl-β-lactams 3.
General Procedure for the Synthesis of Unsymmetrical Bis(β-lac-
tam)-1,3-diynes 4: Few crystals of hydroxylamine hydrochloride,
EtNH2 (70% in water, 2.5 mL), and CuCl (0.06 mmol, 0.02 equiv.)
were sequentially added at room temperature to a solution of the
calcd. C 63.62, H 6.86, N 5.30; found C 63.79, H 6.96, N 5.37.
General Procedure for the Synthesis of Bromoalkynyl-β-lactams 3:
To
a solution of the appropriate alkynyl-2-azetidinone 1
(0.37 mmol) in acetone (2.5 mL) was added NBS (0.094 g,
0.46 mmol) and silver acetate (0.019 g, 0.11 mmol). The reaction
mixture was stirred at room temperature in the dark until disap-
pearance (TLC) of the starting material. The solids were removed
by filtration through a Celite pad (washing with ethyl acetate). The
combined organic filtrate was washed with water and brine, dried
(Na2SO4), concentrated under reduced pressure, and then purified
by column chromatography (ethyl acetate/hexanes) to give analyti-
appropriate alkynyl-2-azetidinone
1 (3.6 mmol) in methanol
(18 mL). Then, the corresponding bromoalkynyl-β-lactam
3
(3.6 mmol) in CH2Cl2 (50 mL) was added to the above acetylide
suspension cooled to 0 °C. More crystals of hydroxylamine hydro-
chloride were added throughout the reaction as necessary to pre-
vent the solution from turning blue or green. The reaction mixture
Eur. J. Org. Chem. 2008, 1575–1581
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1579

B. Alcaide, P. Almendros, R. Carrascosa, R. Rodríguez-Acebes
FULL PAPER
was stirred until disappearance (TLC) of the starting materials. The
products were extracted with ethyl acetate (3ϫ20 mL), dried with
MgSO4, and concentrated under reduced pressure. Purification by
column chromatography (ethyl acetate/hexanes) gave analytically
pure unsymmetrical bis(β-lactam)-1,3-diynes. Spectroscopic and
analytical data for some representative forms of bis(β-lactam)-1,3-
diynes 4 follow.
60.3, 58.5, 55.4, 53.2, 29.7, 26.3, 21.2 ppm. IR (CHCl ): ν = 3348,
˜
3
1744 cm–1. MS (EI): m/z (%) = 524 (40) [M]+, 226 (100).
C31H28N2O6 (524.6): calcd. C 70.98, H 5.38, N 5.34; found C 70.85,
H 5.34, N 5.29.
Sodium Methoxide Promoted Reaction of Bis(β-lactam)-1,3-
diynes 2. General Procedure for the Preparation of Bis(β-amino
ester)-1,3-Diynes 5: Sodium methoxide (10.8 mg, 0.2 mmol) was
added in portions to a solution of the appropriate bis(β-lactam)-
1,3-diyne 2 (0.2 mmol) in methanol (2 mL). The reaction mixture
was heated in a sealed tube at 65 °C until disappearance of the
starting material (TLC). The mixture was cooled to room tempera-
ture, and the solvent was removed under reduced pressure. Then,
water was added (1 mL), and the aqueous residue was extracted
with ethyl acetate (4ϫ3 mL). The organic extract was washed with
brine, dried with MgSO4, and the solvent was removed under re-
duced pressure. Chromatography of the residue (ethyl acetate/hex-
anes) gave analytically pure compounds 5. Spectroscopic and ana-
lytical data for some representative forms of bis(β-amino ester)-1,3-
diynes 3 follow.
Bis(β-lactam)-1,3-diyne (–)-4a: From bromoalkynyl-2-azetidinone
(+)-3a (40 mg, 0.13 mmol), compound (–)-4a (58 mg, 87%) was ob-
tained as a pale yellow oil. [α]D = –27.3 (c = 1.4, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.42 and 6.87 (d, J = 9.0 Hz, each
2 H), 4.64 (d, J = 5.1 Hz, 1 H), 4.51 (dd, J = 5.1, 3.7 Hz, 1 H),
4.45 (d, J = 5.1 Hz, 1 H), 4.43 and 3.96 (d, J = 18.0 Hz, each H),
4.30 (m, 1 H), 4.10 (dd, J = 8.8, 6.6 Hz, 2 H), 3.73 (m, 2 H), 3.79
(s, 3 H), 3.67 (s, 3 H), 3.52 (s, 3 H), 2.91 (br. s, 1 H), 2.66 (dd, J =
17.3, 6.3 Hz, 1 H), 2.66 (dd, J = 17.3, 7.7 Hz, 1 H), 1.49 and 1.34
(s, each 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.7, 164.7,
156.9, 130.5, 120.2, 114.3, 109.7, 83.1, 82.6, 76.6, 75.6, 70.1, 69.1,
68.4, 67.1, 66.5, 60.3, 59.7, 59.5, 58.9, 55.4, 31.1, 26.9, 25.1,
24.8 ppm. IR (CHCl ): ν = 3345, 1742 cm–1. MS (ES): m/z (%) =
˜
3
513 (100) [M + H]+, 512 (15) [M]+. C27H32N2O8 (512.6): calcd. C
Bis(β-amino ester)-1,3-diyne (+)-5a: From bis(β-lactam)-1,3-diyne
(+)-2a (41 mg, 0.08 mmol), compound (+)-5a (21 mg, 45%) was
obtained as a pale brown oil after purification by flash chromatog-
raphy (hexanes/ethyl acetate, 1:1). [α]D = +31.2 (c = 1.2, CHCl3).
1H NMR (300 MHz, CDCl3, 25 °C): δ = 4.16 (m, 2 H), 4.04 (dd,
J = 8.3, 6.5 Hz, 2 H), 3.91 (d, J = 3.6 Hz, 2 H), 3.90 (dd, J = 8.3,
6.7 Hz, 2 H), 3.79 (s, 6 H), 3.67 (d, J = 9.1 Hz, 4 H), 3.42 (s, 6 H),
3.21 (dd, J = 6.2, 3.6 Hz, 2 H), 1.43 and 1.34 (s, each 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 171.3, 109.2, 79.6, 76.1, 75.8,
63.27, H 6.29, N 5.47; found C 63.40, H 6.23, N 5.52.
Bis(β-lactam)-1,3-diyne (+)-4b: From bromoalkynyl-2-azetidinone
(–)-3b (49 mg, 0.14 mmol), compound (+)-4b (61 mg, 72%) was ob-
1
tained as a colorless oil. [α]D = +59.4 (c = 1.6, CHCl3). H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.57 and 6.86 (d, J = 9.0 Hz, each
2 H), 7.38 and 6.82 (d, J = 9.0 Hz, each 2 H), 5.07 (br. s, 1 H),
4.63 (d, J = 5.1 Hz, 1 H), 4.45 (m, 2 H), 4.31 (dd, J = 9.0, 6.8 Hz,
1 H), 4.22 (d, J = 7.1 Hz, 1 H), 4.09 (m, 1 H), 3.92 (dd, J = 9.0,
6.5 Hz, 2 H), 3.78 (s, 3 H), 3.72 (s, 3 H), 3.67 (s, 3 H), 2.95 (d, J =
3.7 Hz, 1 H), 2.60 (dd, J = 17.3, 6.3 Hz, 1 H), 2.41 (dd, J = 17.3,
8.0 Hz, 1 H), 1.48 and 1.35 (s, each 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.1, 164.9, 156.9, 156.8, 130.5, 130.2, 120.3, 114.3,
68.1, 66.7, 59.7, 58.7, 52.1, 37.6, 26.5, 25.2 ppm. IR (CHCl ): ν
˜
3
= 3420, 1720 cm–1. MS (EI): m/z (%) = 540 (11) [M]+, 43 (100).
C26H40N2O10 (540.6): calcd. C 57.76, H 7.46, N 5.18; found C
57.60, H 7.37, N 5.10.
114.0, 109.9, 82.6, 74.3, 71.5, 70.1, 69.2, 68.2, 67.4, 66.7, 66.1, 59.7, Bis(β-amino ester)-1,3-diyne (+)-5b: From bis(β-lactam)-1,3-diyne
58.8, 55.4, 55.3, 26.6, 26.5, 25.0, 24.7 ppm. IR (CHCl ): ν = 3340,
(–)-2j (26 mg, 0.05 mmol), compound (+)-5b (12 mg, 42%) was ob-
˜
3
1744 cm–1. MS (ES): m/z (%) = 605 (100) [M + H]+, 604 (14) tained as a colorless oil after purification by flash chromatography
[M]+. C33H36N2O9 (604.7): calcd. C 65.55, H 6.00, N 4.63; found
C 65.43, H 6.07, N 4.60.
(hexanes/ethyl acetate, 1:1). [α]D = +5.9 (c = 0.5, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 5.76 (m, 2 H), 5.16 (m, 4 H), 4.34
(m, 2 H), 4.14 (dd, J = 8.3, 6.6 Hz, 2 H), 3.88 (dd, J = 8.4, 7.0 Hz,
2 H), 3.81 (s, 6 H), 3.80 (m, 4 H), 3.18 (d, J = 4.6 Hz, 2 H), 2.52
Bis(β-lactam)-1,3-diyne (؎)-4c: From bromoalkynyl-2-azetidinone
(Ϯ)-3c (112 mg, 0.28 mmol), compound (؎)-4c (81 mg, 55%) was
(m, 4 H), 1.46 and 1.36 (s, each 6 H) ppm. IR (CHCl ): ν = 3430,
˜
3
1
obtained as a pale yellow oil. H NMR (300 MHz, CDCl3, 25 °C):
3420, 1722 cm–1. MS (ES): m/z (%) = 593 (100) [M + H]+, 592 (35)
[M]+. C30H44N2O10 (592.7): calcd. C 60.80, H 7.48, N 4.73; found
C 60.96, H 7.40, N 4.79.
δ = 7.55 (m, 1 H), 7.45 (t, J = 1.7 Hz, 1 H), 7.23 (m, 4 H), 7.22
and 6.76 (d, J = 9.0 Hz, each 2 H), 6.49 (m, 1 H), 5.17 (d, J =
4.9 Hz, 1 H), 5.13 (d, J = 4.9 Hz, 1 H), 4.84 (d, J = 4.6 Hz, 1 H),
4.70 (d, J = 4.6 Hz, 1 H), 4.36 and 3.67 (d, J = 19.3 Hz, each H),
4.18 and 3.92 (d, J = 16.8 Hz, each H), 3.72 (s, 3 H), 3.31 (s, 3 H),
2.34 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.8, 163.1,
156.3, 143.6, 142.3, 138.6, 130.4, 129.9, 129.3, 127.9, 118.8, 118.3,
114.3, 110.1, 85.5, 81.4, 73.4, 72.4, 71.4, 68.3, 61.5, 58.5, 57.9, 55.3,
Supporting Information (see also the footnote on the first page of
this article): Full spectroscopic and analytical data for previously
unreported compounds not included in the Experimental Section.
Compound characterization data and experimental procedures for
compounds 1c–e, 1g–j, and 1m; general procedures for the dimer-
ization reaction of N-alkynyl-2-azetidinones under different condi-
tions.
53.4, 29.7, 21.2 ppm. IR (CHCl ): ν = 1745 cm–1. MS (ES): m/z
˜
3
(%) = 525 (100) [M + H]+, 524 (17) [M]+. C31H28N2O6 (524.6):
calcd. C 70.98, H 5.38, N 5.34; found C 71.02, H 5.33, N 5.38.
Bis(β-lactam)-1,3-diyne (؎)-4d: From bromoalkynyl-2-azetidinone
(Ϯ)-3d (63 mg, 0.15 mmol), compound (؎)-4d (62 mg, 78%) was
obtained as a pale yellow solid. M.p. 71–73 °C (hexanes/ethyl ace-
Acknowledgments
1
tate). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.48 (m, 1 H), 7.42
(m, 1 H), 7.28 and 6.80 (d, J = 9.0 Hz, each 2 H), 7.22 (s, 4 H), Support for this work by the Dirección General de Investigación,
6.45 (m, 1 H), 5.16 (s, 1 H), 4.75 (m, 1 H), 4.66 (dd, J = 4.6, 3.1 Hz, Ministerio de Educación Ciencia (DGI-MEC) (Project
1 H), 4.32 and 3.59 (d, J = 18.3 Hz, each H), 3.74 (s, 3 H), 3.30 (s, CTQ2006-10292) and Comunidad Autónoma de Madrid-Uni-
3 H), 2.97 (s, 2 H), 2.36 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): versidad Complutense de Madrid (CAM-UCM) (Grant GR69/06)
y
δ = 166.0, 165.5, 156.5, 142.3, 143.6, 138.9, 130.1, 129.9, 127.3,
119.1, 118.3, 114.3, 110.1, 85.4, 84.0, 73.9, 69.4, 68.8, 67.4, 66.6,
are gratefully acknowledged. R. C. and R. R. A. thank the MEC
for predoctoral grants.
1580
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1575–1581

Copper-Promoted Synthesis of Novel Bis(β-lactam)-1,3-diynes
[10]
See, for instance: a) B. Alcaide, P. Almendros, T. Martí-
nez del Campo, Angew. Chem. Int. Ed. 2007, 46, 6684; Angew.
Chem. 2007, 119, 6804; b) B. Alcaide, P. Almendros, T. Martí-
nez del Campo, R. Rodríguez-Acebes, Adv. Synth. Catal. 2007,
349, 749; c) B. Alcaide, P. Almendros, T. Martínez del Campo,
Angew. Chem. Int. Ed. 2006, 45, 4501; Angew. Chem. 2006, 118,
4613; d) B. Alcaide, P. Almendros, A. Luna, M. R. Torres, J.
Org. Chem. 2006, 71, 4818; e) B. Alcaide, P. Almendros, J. M.
Alonso, Chem. Eur. J. 2006, 12, 2874; f) B. Alcaide, P. Al-
mendros, R. Rodríguez-Acebes, J. Org. Chem. 2006, 71, 2346;
g) B. Alcaide, P. Almendros, M. C. Redondo, Chem. Commun.
2006, 2616; h) B. Alcaide, P. Almendros, C. Aragoncillo, M. C.
Redondo, M. R. Torres, Chem. Eur. J. 2006, 12, 1539.
[1] For antibiotic uses, see: a) W. Cabri, R. Di Fabio, From Bench
to Market: The Evolution of Chemical Synthesis; Oxford Uni-
versity Press, Oxford, 2000; b) R. Southgate, C. Branch, S. Co-
ulton, E. Hunt in Recent Progress in the Chemical Synthesis of
Antibiotics and Related Microbial Products (Ed.: G. Lukacs),
Springer, Berlin, 1993, vol. 2, p. 621; c) M. I. Page (Ed.), The
Chemistry of β-Lactams, Chapman and Hall, London, 1992.
For nonantibiotic uses, see: d) J. D. Rothstein, S. Patel, M. R.
Regan, C. Haenggeli, Y. H. Huang, D. E. Bergles, L. Jin, M. D.
Hoberg, S. Vidensky, D. S. Chung, S. V. Toan, L. I. Bruijn, Z.-
z. Su, P. Gupta, P. B. Fisher, Nature 2005, 433, 73; e) P. C.
Hogan, E. J. Corey, J. Am. Chem. Soc. 2005, 127, 15386; f) L.
Kvaerno, T. Ritter, M. Werder, H. Hauser, E. M. Carreira, An-
gew. Chem. Int. Ed. 2004, 43, 4653; g) G. Veinberg, M. Vorona,
I. Shestakova, I. Kanepe, E. Lukevics, Curr. Med. Chem. 2003,
10, 1741.
[2] For selected reviews, see: a) B. Alcaide, P. Almendros, C. Ara-
goncillo, Chem. Rev. 2007, 107, 4437; b) B. Alcaide, P. Al-
mendros, Curr. Med. Chem. 2004, 11, 1921; c) A. R. A. S.
Deshmukh, B. M. Bhawal, D. Krishnaswamy, V. V. Govande,
B. A. Shinkre, A. Jayanthi, Curr. Med. Chem. 2004, 11, 1889;
d) B. Alcaide, P. Almendros, Synlett 2002, 381; e) C. Palomo,
J. M. Aizpurua, I. Ganboa, M. Oiarbide, Synlett 2001, 1813;
f) B. Alcaide, P. Almendros, Chem. Soc. Rev. 2001, 30, 226; g)
B. Alcaide, P. Almendros, Org. Prep. Proced. Int. 2001, 33, 315;
h) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Amino-
Acids 1999, 16, 321; i) M. S. Manhas, D. R. Wagle, J. Chiang,
A. K. Bose, Heterocycles 1988, 27, 1755.
[11]
[12]
a) B. Alcaide, P. Almendros, R. Rodríguez-Acebes, J. Org.
Chem. 2005, 70, 2713; b) B. Alcaide, P. Almendros, C. Aragon-
cillo, Chem. Eur. J. 2002, 8, 1719; c) B. Alcaide, P. Almendros,
C. Aragoncillo, R. Rodríguez-Acebes, J. Org. Chem. 2001, 66,
5208.
C2-Symmetrical compound (+)-2a can be considered as a hy-
brid scaffold as a combination of the naturally occurring β-
lactam and 1,3-diyne moieties. For a review on natural product
hybrids, see: a) L. F. Tietze, H. P. Bell, S. Chandrasekhar, An-
gew. Chem. Int. Ed. 2003, 42, 3996. For a review on C2-sym-
metrical natural products, see: b) M. Vrettou, A. A. Gray,
A. R. E. Brewer, A. G. M. Barrett, Tetrahedron 2007, 63, 1487.
[13]
[14]
In addition to being odorless, K2CO3 can be easily removed by
aqueous workup. To the best of our knowledge, this is the first
time that K2CO3 has been used for the dimerization of terminal
alkynes.
[3] a) A. L. K. Shi Shun, R. R. Tykwinski, Angew. Chem. Int. Ed.
2006, 45, 1034; b) F. Diederich, P. J. Stang, R. R. Tykwinski
(Eds.), Acetylene Chemistry: Chemistry, Biology and Materials
Science, Wiley-VCH, Weinheim, 2005; c) F. Bohlmann, F. T.
Burkhart, C. Zero in Naturally Occurring Acetylenes, Aca-
demic, London and New York, 1973.
[4] For reviews, see: a) P. Siemsen, R. C. Livingston, F. Diederich,
Angew. Chem. Int. Ed. 2000, 39, 2632; b) D. R. Kanis, M. A.
Ratner, T. J. Marks, Chem. Rev. 1994, 94, 195; c) A. Stüts, An-
gew. Chem. Int. Ed. Engl. 1987, 26, 320.
Unsymmetrical diynes play an important structural role in
many natural products and possess a wide range of potential
applications in material science. For selected natural products
references, see: a) S. López, F. Fernández-Trillo, P. Midón, L.
Castedo, C. Saá, J. Org. Chem. 2006, 71, 2802; b) G. Sabitha,
C. S. Reddy, J. S. Yadav, Tetrahedron Lett. 2006, 47, 4513; c)
B. W. Gung, R. M. Fox, R. Falconer, D. Shissler, Tetrahedron:
Asymmetry 2006, 17, 40; d) H. Yun, T.-C. Chou, H. Dong, Y.
Tian, Y.-M. Li, S. J. Danishefsky, J. Org. Chem. 2005, 70,
10375; e) D. Alves, C. W. Nogueira, G. Zeni, Tetrahedron Lett.
2005, 46, 8761. For selected material science references, see: f)
X. Nie, G. Wang, J. Org. Chem. 2006, 71, 4734; g) C. Klinger,
O. Vostrowsky, A. Hirsch, Eur. J. Org. Chem. 2006, 6, 1508; h)
N. Hayashi, T. Matsukihira, K. Miyabayashi, M. Miyake, H.
Higuchi, Tetrahedron Lett. 2006, 47, 5585; i) S. A. Vail, P. J.
Krawczuk, D. M. Guldi, A. Palkar, L. Echegoyen, J. P. Tome,
M. A. Fazio, D. I. Schuster, Chem. Eur. J. 2005, 11, 3375.
[5] C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422.
[6] G. Eglinton, A. R. Galbrait, Chem. Ind. (London) 1956, 737.
[7] A. S. Hay, J. Org. Chem. 1962, 27, 3320.
[8] a) W. Chodkiewicz, P. Cadiot, C. R. Hebd. Seances Acad. Sci.
1955, 241, 1055; b) W. Chodkiewicz, Ann. Chim. 1957, 2, 819.
[9] For recent selected examples for the homocoupling of alkynes,
see: a) B. J. Morgan, X. Xie, P.-W. Phuan, M. C. Kozlowski, J.
Org. Chem. 2007, 72, 6171; b) S. V. Damle, D. Seomoon, P. H.
Lee, J. Org. Chem. 2003, 68, 7085; c) I. J. S. Fairlamb, P. S.
Bäuerelein, L. R. Marrison, J. M. Dickinson, Chem. Commun.
2003, 632; d) Y. Liao, R. Fathi, Z. Yang, Org. Lett. 2003, 5,
909; e) J.-H. Li, Y. Liang, Y.-X. Xie, J. Org. Chem. 2005, 70,
4393; f) J.-H. Li, Y. Liang, X.-D. Zhang, Tetrahedron 2005, 61,
1903; g) A. S. Batsanov, J. C. Collings, I. J. S. Fairlamb, J. P.
Holland, J. A. K. Howard, Z. Lin, T. B. Marder, A. C. Parsons,
R. M. Ward, J. Zhu, J. Org. Chem. 2005, 70, 703; h) H.-F. Ji-
ang, J.-Y. Tang, A.-Z. Wang, G.-H. Deng, S.-R. Yang, Synthe-
sis 2006, 1155; i) M. Shi, H. X. Qian, Appl. Organomet. Chem.
2006, 20, 771; j) J. Yan, F. Lin, Z. Yang, Synthesis 2007, 1301.
For recent selected references on heterocoupling alkyne reac-
tions, see: k) J. P. Marino, H. N. Nguyen, J. Org. Chem. 2002,
67, 6841; l) L.-S. Li, Y.-L. Wu, Tetrahedron 2002, 58, 9049; m)
E. J. Cho, M. Kim, D. Lee, Eur. J. Org. Chem. 2006, 3074; n)
H.-F. Jiang, A.-Z. Wang, Synthesis 2007, 1649.
[15]
[16]
H. Hofmeister, K. Annen, H. Laurent, R. Wiechert, Angew.
Chem. Int. Ed. Engl. 1984, 23, 727.
No partial configuration inversion was involved in the transfor-
mation of monoalkynes 1 into 1,3-diynes 2 and 4. The assign-
ment of the cis stereochemistry to β-lactams 2a–k and 4a–d
was based on the observed coupling constants of about 5.0 Hz
for methine protons 3-H and 4-H, whereas trans stereochemis-
try is consistent with methine coupling constants of ca. 2.0 Hz
in their 1H NMR spectra. The assignment of relative stereo-
chemistry on the basis of the observed coupling constant for
methine protons 3-H and 4-H is a very well-established crite-
rion in β-lactam chemistry. See, for example: B. Alcaide, P. Al-
mendros, N. R. Salgado, A. Rodríguez-Vicente, J. Org. Chem.
2000, 65, 4453.
Received: November 15, 2007
Published Online: February 1, 2008
Eur. J. Org. Chem. 2008, 1575–1581
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1581