Microwave-promoted synthesis of bicyclic azocine-β-lactams from Bis(allenes)

Article abstract of DOI:10.1021/jo501231q

A metal-free preparation of structurally novel bicyclic azocine-β-lactams has been developed. The first examples accounting for the preparation of eight-membered rings from bis(allenes) in the absence of metals have been achieved by the thermolysis of nonconjugated 2-azetidinone-tethered bis(allenes) on application of microwave irradiation. This selective carbocyclization reaction has been studied experimentally, and additionally, its mechanism has been investigated by a DFT study.

Full text of DOI:10.1021/jo501231q

Subscriber access provided by UNIV LAVAL
Article
Microwave-Promoted Synthesis of Bicyclic
Azocine-beta-Lactams from Bis(allene)s
Benito Alcaide, Pedro Almendros, Cristina Aragoncillo, Israel Fernandez, and Gonzalo Gómez-Campillos
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501231q • Publication Date (Web): 10 Jul 2014
Downloaded from http://pubs.acs.org on July 14, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 30
The Journal of Organic Chemistry
1
1
2
3
4
5
6
7
8
9
MicrowaveꢀPromoted Synthesis of Bicyclic
AzocineꢀβꢀLactams from Bis(allene)s
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benito Alcaide,*,† Pedro Almendros,*,‡ Cristina Aragoncillo,† Israel Fernández,§ and
Gonzalo GómezꢀCampillos†
†Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Orgánica I, Unidad
Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid, 28040ꢀMadrid,
Spain
‡Instituto de Química Orgánica General, IQOGꢀCSIC, Juan de la Cierva 3, 28006ꢀMadrid, Spain
§Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense de Madrid,
28040ꢀMadrid, Spain
Eꢀmail: alcaideb@quim.ucm.es; Palmendros@iqog.csic.es
O
OR3
R2
R2
OR3
H H
H H
N
H H
R1O
R1O
R1O
ꢀ
•
ꢀ
Toluene,
Toluene,
R2
microwave
N
microwave
R3 = H
N
•
O
O
O
R3 = Me, Ac
ABSTRACT: A metalꢀfree preparation of structurally novel bicyclic azocineꢀβꢀlactams has been
developed. The first examples accounting for the preparation of eightꢀmembered rings from
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 30
2
1
2
3
4
5
6
7
8
9
bis(allene)s in the absence of metals have been achieved by the thermolysis of nonꢀconjugated 2ꢀ
azetidinoneꢀtethered bis(allene)s applying microwave irradiation. This selective carbocyclization
reaction has been studied experimentally and additionally, its mechanism has been investigated by a
DFT study.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
INTRODUCTION
The βꢀlactam (2ꢀazetidinone) motif has been identified as an attractive synthetic target because of
its prevalence in many naturally occurring products and due to their medicinally interesting
activities.1 Apart from their biological interest, the use of βꢀlactams as intermediates in organic
synthesis for the preparation of compounds of biological relevance, such as amino acids, alkaloids,
heterocycles, and taxoids, is now well established.2 In accordance, efforts devoted to the synthesis
of this molecular framework remain highly desirable.
On the other hand, fused nitrogen containing eight membered ring systems, azocines, are
-
found in a range of bioactive natural products such as the alkaloids apparicine, nakadomarin A,
manzamine A, and magallanesine.3 Additionally, synthetic derivatives I–IV (Figure 1) exhibited
central nervous system activities (I and II) and antihypertensive activities (III and IV).4
Figure 1. Representative examples of bioactive azocine derivatives
CO2H
NH
NH
HN
N
N
(CH2)2NHCNH2
X
O
HO2C
I :
II :
X = O
X = S
III
IV
In the last two decades the chemistry of allenes has been extensively studied and many
reviews on their preparation and reactivities have appeared.5 Allenes have shown an interesting
reactivity and selectivity affording complex structures in a limited number of steps. While the
ACS Paragon Plus Environment

Page 3 of 30
The Journal of Organic Chemistry
3
1
2
3
4
5
6
7
8
9
chemistry of allenes is still developing and many reports appear every year, the study of the
reactivity of bis(allene)s is in its infancy.6 Taking into account that there is only one report available
on the thermal cyclization of nonꢀconjugated bis(allene)s,7 we decided to study the reactivity of 2ꢀ
azetidinoneꢀtethered bis(allene)s under thermal conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RESULTS AND DISCUSSION
Starting materials, new βꢀlactam bis(allene)s 4a–h and 5a–k were obtained in optically pure form
from 2ꢀazetidinoneꢀtethered alkynyl dioxolanes 1a–c.8 Terminal alkynes 1 were conveniently
converted into allenes 2 by treatment with paraformaldehyde in the presence of diisopropylamine
and copper(
) bromide (Crabbé reaction).9 2ꢀAzetidinoneꢀtethered allenals 3a–c were prepared from
I
allenyl dioxolanes 2a–c through BiCl3ꢀcatalyzed acetonide deprotection followed by oxidative diol
cleavage (Scheme 1).10 The allenic diol formation was not feasible using a Brønsted acid such as
PTSA, because the allene moiety did not survive under these conditions. The indiumꢀmediated
Barbierꢀtype carbonyl–allenylation reaction of allenic aldehydes 3a–c in aqueous media yielded
bis(allene)s 4a–h with total allenic/propargylic regioselectivity and reasonable syn/anti
diastereoselectivity (de 60–100%, by integration of wellꢀresolved signals in the 1H NMR spectra of
the crude reaction mixtures before purification). Fortunately, in the cases of absence of total
diasteroeselectivity (4a, 4c, and 4d) the diastereomeric bis(allene)s synꢀ4 and antiꢀ4 could be easily
separated by flash chromatography (Scheme 1). The hydroxy functionality of allenols synꢀ4a–h was
either acetylated or protected in the form of methyl ether under phase transfer conditions to afford
βꢀlactam bis(allene)s 5a–k (Scheme 1).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 30
4
1
2
3
4
5
6
7
Scheme 1. Preparation of enantiopure βꢀlactam bis(allene)s 4a–h and 5a–k. Reagents and
conditionsa
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
H H
N
H H
H H
N
R1O
R1O
R1O
CHO
O
O
i)
ii)
N
•
•
O
O
O
1
(+)ꢀ1a
(+)ꢀ2a
(+)ꢀ3a
(quantitative yield)
R = Me
(73%)
(+)ꢀ1b R1 = Bn
(+)ꢀ1c R1 = Ph
(+)ꢀ2b (71%)
(+)ꢀ2c (72%)
(+)ꢀ3b (quantitative yield)
(+)ꢀ3c (quantitative yield)
R2
iii)
Br
OR3
OH
OH
H H
H H
N
H H
R1O
R1O
R1O
•
•
•
iv) or v)
+
R2
R2
R2
N
N
•
•
•
O
O
O
(+)ꢀ5a R1 = Me, R2 = Me, R3 = Me (72%)
(+)ꢀsynꢀ4a (80%)
(+)ꢀsynꢀ4b (68%)
(+)ꢀantiꢀ4a (8%)
R = Me, R = Ph, R3 = Me (61%)
(+)ꢀ5c R1 = Me, R2 = PMP, R3 = Me (63%)
(+)ꢀ5d R1 = Ph, R2 = Me, R3 = Me (66%)
R = Ph, R = Ph, R3 = Me (59%)
(+)ꢀ5f R1 = Ph, R2 = PMP, R3 = Me (64%)
(–)ꢀ5g R1 = Bn, R2 = Me, R3 = Me (80%)
R = Bn, R = Ph, R3 = Me (54%)
(+)ꢀ5i R1 = Me, R2 = Me, R3 = Ac (64%)
(+)ꢀ5j R1 = Me, R2 = Ph, R3 = Ac (74%)
1
2
(+)ꢀ5b
(+)ꢀsynꢀ4c
(+)ꢀantiꢀ4c
(42%)
(16%)
(+)ꢀsynꢀ4d (42%)
(+)ꢀsynꢀ4e (57%)
(+)ꢀantiꢀ4d (15%)
1
2
(+)ꢀ5e
(+)ꢀsynꢀ4f
(48%)
(–)ꢀsynꢀ4g (72%)
(+)ꢀsynꢀ4h (56%)
(+)ꢀantiꢀ4g (15%)
1
2
(+)ꢀ5h
(+)ꢀsynꢀ4a
(+)ꢀantiꢀ4a
(80%)
(8%)
(+)ꢀsynꢀ4b (68%)
(+)ꢀsynꢀ4c (42%)
1
2
3
(+)ꢀ5k
(+)ꢀantiꢀ4c (16%)
R = Me, R = PMP, R = Ac (68%)
aConditions: i) (CH2O)n, iPr2NH, CuBr, dioxane, reflux, 2 h. ii) (a) 50 mol% BiCl3, MeCN–H2O, rt, 24 h; (b) NaIO4,
NaHCO3 (aq. sat.), CH2Cl2, rt, 24 h. iii) In, THF/NH4Cl (aq. sat.) (1:5), rt, 24 h. iv) Me2SO4, TBAI, CH2Cl2, NaOH (aq
50%) (1:1), rt, 8 h. v) Ac2O, Et3N, DMAP (cat), CH2Cl2, 0 oC, 2 h. PMP = 4ꢀMeOC6H4. DMAP = 4ꢀ
(Dimethylamino)pyridine.
To explore the reactivity of bis(allene)s 4 and 5 under thermal conditions, 2ꢀazetidinoneꢀ
tethered bis(allene) 4a was selected as a model substrate. Attempts to generate a polycyclic
o
structure from 4a either in refluxing toluene or at 250 C in a sealed tube failed. When the
thermolysis was carried out in a microwave by heating a solution of bis(allene) 4a in toluene at 200
ACS Paragon Plus Environment

Page 5 of 30
The Journal of Organic Chemistry
5
1
2
3
4
5
6
7
8
9
oC, bicyclic azocinoneꢀβꢀlactam 6a was obtained, albeit in a low 18% yield.11 It should be noted
that traditional ringꢀclosure strategies are problematic for eightꢀmembered rings owing to
unfavorable enthalpic and entropic contributions.12,13 Applying microwave irradiation in toluene at
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
250 C and using deactivated silica gel during purification resulted in an increased 25% yield for
adduct 6a, without harming the sensitive βꢀlactam ring (Scheme 2). Remarkably, this rare
carbocyclization reaction was the only operative cyclization mode. When substrate 4d was used as
bis(allene) precursor, low yield of the corresponding bicyclic azocinoneꢀβꢀlactam 6d was also
o
obtained; but the reaction best proceeds after long exposure of microwave irradiation at 185 C
(Scheme 2). Bicycles 6a and 6d were obtained as single regioꢀ and diastereomers. Probably, the
ketone funtionality in adducts 6 arises from a keto–enol isomerization. Any efforts to improve the
efficiency of this transformation were in vain. Thus, in order to prevent the isomerization involving
the allenol group, methyl ethers 5a–h and acetates 5i–k were identified as cyclization precursors.
Scheme 2. Preparation of azocinoneꢀβꢀlactams 6a and 6d. PMP = 4ꢀMeOC6H4
O
H H
Me
OH
H H
N
MeO
MeO
•
XToluene
Toluene
(+)ꢀ6a
250 oC, 1h
microwave
N
250 oC, 24h
sealed tube
Me
•
O
O
(+)ꢀ4a
(+)ꢀ6a
(25%)
Toluene, 200 oC, 1.5 h
microwave
(+)ꢀ6a
(18%)
OH
O
H H
Me
H H
N
PhO
PhO
•
Toluene
N
Me
185 oC, 26h
microwave
•
O
O
(+)ꢀ4d
(+)ꢀ6d (23%)
Our next effort focused on the application of microwave irradiation to the selective
construction of fused azocines starting from bis(allene)s 5 bearing a βꢀlactam moiety. The use of
the above thermal conditions on 2ꢀazetidinoneꢀtethered bis(allene) 5a retains the reactivity pattern,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 30
6
1
2
3
4
5
6
7
8
9
but suppresses the keto–enol isomerization while maintaining the same regioselectivity of the
cyclization step. Thus, in the case of bis(allene) 5a we observed exclusive formation of the bicyclic
enol ether 7a in a reasonable 60% yield (Scheme 3). HMQC experiments of derivative 7a
satisfactorily established information about the presence of a new eightꢀmembered azocinone ring.
Similarly, adducts 7b–k were obtained in fair yields in a totally selective fashion using the thermal
protocol (Scheme 3), through cyclization by attack of the central allene carbon of one moiety to the
central carbon of the other cumulene. Applying standard microwave irradiation conditions to nonꢀβꢀ
lactam bis(allene)s A–C resulted in complex reaction mixtures (Scheme S1; see the Supporting
Information), which lead to the exclusion of bis(allene)s A–C as efficient substrates. Consequently,
it can be inferred that the 2ꢀazetidinone nucleus plays a key template role in the cyclization
processes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Preparation of azocineꢀβꢀlactams 7a–k
OR3
H H
R2
OR3
H H
R1O
R1O
Toluene, T oC
microwave
•
R2
N
N
•
O
O
1
2
R = Me, R = Me, R3 = Me
(60%, 250 C, 0.5 h)
(50%, 200 oC, 1 h)
o
(+)ꢀ5a
(–)ꢀ7a
(–)ꢀ7b
(+)ꢀ5b R1 = Me, R2 = Ph, R3 = Me
1
2
3
(+)ꢀ5c
R = Me, R = PMP, R = Me
(+)ꢀ7c (45%, 200 oC, 1 h)
1
2
R = Ph, R = Me, R3 = Me
(50%, 225 C, 1 h)
o
(+)ꢀ5d
(–)ꢀ7d
o
(+)ꢀ5e R1 = Ph, R2 = Ph, R3 = Me
(–)ꢀ7e
(61%, 200 C, 1 h)
R1 = Ph, R2 = PMP, R3 = Me
R = Bn, R = Me, R3 = Me
(–)ꢀ7f (47%, 175 oC, 1 h)
(+)ꢀ5f
1
2
o
(–)ꢀ5g
(–)ꢀ7g
(54%, 225 C, 1 h)
o
(+)ꢀ5h R1 = Bn, R2 = Ph, R3 = Me
(–)ꢀ7h
(52%, 185 C, 3 h)
R1 = Me, R2 = Me, R3 = Ac
(–)ꢀ7i (58%, 200 oC, 2 h)
(+)ꢀ5i
R1 = Me, R2 = Ph, R3 = Ac
(48%, 200 C, 1.5 h)
o
(+)ꢀ5j
(–)ꢀ7j
o
(+)ꢀ5k R1 = Me, R2 = PMP, R3 = Ac
(–)ꢀ7k
(42%, 200 C, 1 h)
A conceivable mechanism for the formation of bicycles 7 from bis(allene)s 5 may initially
involve the formation of diradical intermediates. When a catalytic amount of hydroquinone was
added, the reaction rate was considerably reduced and the product yield fell dramatically. This fact
ACS Paragon Plus Environment

Page 7 of 30
The Journal of Organic Chemistry
7
1
2
3
4
5
6
7
8
9
is consistent with involvement of a radical mechanism. The formation of azocineꢀβꢀlactams 7 can
be rationalized by a mechanism that includes exocyclic diallylic diradical intermediates 8 through
initial carbon–carbon bond formation, involving the central allene carbon atoms of both cumulenic
moieties. Species 8 may suffer a ringꢀclosure to produce intermediate tricyclic cyclobutanes 9,14
which finally give bicycles 7 through a rearrangement process (path A, Scheme 4). An alternative
explanation for the thermal cyclization, which leads to bicycles 7 is proposed in path B (Scheme 4).
This pathway involves the isomerization of species 8 to allylic diradical 10, which is a resonance
form of the final product 7.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Rationalization for the thermal carbocyclization of bis(allene)s 5
R3O
H H
R3O
H H
R2
R2
OR3
H H
N
R1O
R1O
R1O
•
250 oC
CH2
CH2
CH2
CH2
isomerization
path B
R2
N
N
C–C bond
formation
•
O
O
O
5
8
10
C–C bond
formation
path A
R3O
R3O
H H
R3O
H H
R2
R2
R2
H H
R1O
R1O
R1O
rearrangement
process
N
N
N
O
O
O
7
7
9
Density functional theory (DFT) calculations have been carried out to gain more insight into
the reaction mechanism of the above discussed microwaveꢀinduced azocine formation. The reaction
profile involving 5a is depicted in Figure 2, which shows the corresponding relative energies (zeroꢀ
point vibrational energy corrections included) computed in toluene solution at the PCM(toluene)ꢀ
M06ꢀ2X/6ꢀ311+G*//B3LYP/6ꢀ31+G* level.15
As stated above, and similar to related transformations involving allenes,16 the process begins
with a stepwise [2+2]ꢀcycloaddition reaction which initially produces the diallylic diradical
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 30
8
1
2
3
4
5
intermediate INT1 in a slightly exothermic reaction (ꢀER = −2.0 kcal/mol). This species is formed
6
7
8
9
through the transition state TS1, which is associated with the C−C bond formation involving both
central allene carbon atoms with a computed activation barrier of 33.5 kcal/mol. This relatively
high barrier is similar to those computed for related processes16 and agrees with the harsh reaction
conditions used for the synthesis of the bicyclic azocineꢀβꢀlactams (see above). The diallylic
diradical nature of INT1 is confirmed by the computed spin densities, which clearly reflect the
delocalization of both unpaired electrons on the distal and proximal carbon atoms of the former
allene moieties (see the inset in Figure 2). Subsequent diradical ringꢀclosure renders tricyclic
intermediate INT2 in a highly exothermic process (ꢀER = −30.2 kcal/mol) via TS2, a saddle point
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
associated with the formation of the new C−C bond of the cyclobutane moiety (computed activation
barrier of 16.1 kcal/mol). Once INT2 is formed, a 1,5ꢀhydrogen atom migration occurs thus
forming species INT3, which is 2.4 kcal/mol more stable than its isomer INT2. This migration
occurs via TS3 with a considerably high computed barrier of 40.1 kcal/mol. Finally, a ringꢀopening
step of the cyclobutane moiety affords the reaction product 7a through the transition state TS4
(computed activation barrier of 35.2 kcal/mol).
ACS Paragon Plus Environment

Page 9 of 30
The Journal of Organic Chemistry
9
1
2
3
4
5
Figure 2. Computed reaction profile for the transformation of 5a into bicyclic azocineꢀβꢀ
6
7
lactam 7aa
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aRelative energies (zeroꢀpoint vibrational energies included) and bond distances are given in kcal/mol and angstroms,
respectively. Inset: computed spin densities on INT1. All data have been computed at the PCM(toluene)M06ꢀ2X/6ꢀ
311+G*//B3LYP/6ꢀ31+G* level.
In view of the relatively high activation barriers computed for the steps involving TS3 and
TS4 (40.1 and 35.2 kcal/mol, respectively), we hypothesized that an alternative reaction pathway
may be competitive in the transformation of 5a into 7a. Indeed, we were able to locate a transition
state (TS5) on the potential energy surface, which directly connects the initially formed diradical
intermediate INT1 with the final reaction product 7a. This saddle point is associated with an
analogous 1,5ꢀhydrogen atom migration to that described above (involving TS3) but occurring with
a much lower computed activation barrier (ꢀE‡ = 26.8 kcal/mol). Therefore, the conversion of
bis(allene) 5 into bicyclic azocineꢀβꢀlactams 7 proceeds through the formation of an initial diallylic
diradical intermediate which evolves to the final product via a multiꢀstep process, or alternatively,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 30
10
1
2
3
4
5
6
7
via a direct 1,5ꢀH migration. Under the harsh reaction conditions used experimentally, both reaction
pathways seems to be feasible and competitive.
8
9
CONCLUSION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, we developed a preparation of structurally novel bicyclic azocineꢀβꢀlactams in the
absence of metals. The first examples accounting for the metalꢀfree preparation of eightꢀmembered
rings from bis(allene)s have been achieved by the thermolysis of nonꢀconjugated 2ꢀazetidinoneꢀ
tethered bis(allene)s applying microwave irradiation. This selective carbocyclization reaction has
been studied experimentally and additionally, its mechanism has been investigated by a DFT study,
which suggests the involvement of an initial diallylic diradical intermediate.
Experimental Section
o
1
General methods: NMR spectra were recorded at 25 C on a 300 MHz instrument: H
13
NMR (300 MHz) and C NMR (75 MHz). Chemical shifts are given in ppm relative to TMS (1H,
0.0 ppm), or CDCl3 (13C, 76.9 ppm). Low and high resolution mass spectra were taken on a QTOF
LC/MS spectrometer using the electronic impact (EI) or electrospray modes (ES). Specific rotation
[α]D is given in 10–1 deg cm2 g–1 at 20 °C, and the concentration (c) is expressed in g per 100 mL.
Microwave irradiation was carried out in a Monowave 300 from Anton Paar GmbH. The reaction
temperatures during microwave heating were measured with an internal infrared sensor.
General Procedure for the Preparation of Allenic Dioxolanes 2. A well stirred solution
of (CH2O)n (0.5 mmol), CuI (0.1 mmol), alkynic dioxolane 1 (0.2 mmol), and N,Nꢀ
diisopropylethylamine (Hüning's base) (0.36 mmol) in dioxane (1 mL) was refluxed under argon
atmosphere. When the reaction was complete as monitored by TLC, it was cooled to RT. Water (5
mL) was added before being extracted with ethyl acetate (3 x 15 mL). The organic phase was
washed with water (2 x 5 mL), dried (MgSO4) and concentrated under reduced pressure.
ACS Paragon Plus Environment

Page 11 of 30
The Journal of Organic Chemistry
11
1
2
3
4
5
Chromatography of the residue eluting with hexanes/ethyl acetate mixtures gave analytically pure
6
7
compounds 2.
8
9
Allenic Dioxolane (+)ꢀ2a. From 400 mg (1.66 mmol) of alkynic dioxolane (+)ꢀ1a, and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as eluent gave compound (+)ꢀ2a
(307 mg, 73%) as a colorless oil; [α]D = +12.4 (c 0.7, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 oC)
δ 1.34 (s, 3H), 1.44 (s, 3H), 3,53 (s, 3H) 3.64 (dd, 1H, J = 8.8, 5.6 Hz), 3.74 (m, 2H), 4.12 (m, 2H),
4.29 (m, 1H), 4.43 (d, 1H, J = 5.1 Hz), 4.81 (ddd, 1H, J = 6.5, 3.3, 2.5 Hz), 5.14 (qd, 1H, J = 6.8,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
5.7 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 209.1, 167.3, 109.5, 85.7, 82.8, 76.9, 76.9, 66.7,
59.8, 59.1, 39.3, 26.9, 25.1; IR (CHCl3) ν 1958, 1759; HRMS (ES): calcd for C13H19NO4[M]+
253.1314, found 253.1317.
Allenic Dioxolane (+)ꢀ2b. From 700 mg (2.22 mmol) of alkynic dioxolane (+)ꢀ1b, and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as eluent gave compound (+)ꢀ2b
(519 mg, 71%) as a colorless oil; [α]D = +14.9 (c 0.3, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 oC)
δ 1.33 (s, 3H), 1.43 (s, 3H), 3.65 (dd, 1H, J = 8.8, 5.6 Hz), 3.77 (m, 2H), 4.14 (m, 2H), 4.35 (dt,
1H, J = 9.1, 6.1 Hz), 4.63 (m, 2H), 4.81 (m, 2H), 4.91 (d, 1H, J = 11.8 Hz), 5.14 (m, 1H), 7.32 (m,
o
5H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 209.0, 167.3, 136.9, 128.4, 128.0, 127.7, 109.5, 85.6,
80.4, 77.0, 76.8, 72.8, 66.7, 59.8, 39.4, 26.8, 25.1; IR (CHCl3) ν 1945, 1744; HRMS (ES): calcd for
C19H23NO4[M]+ 329.1627, found 329.1632.
Allenic Dioxolane (+)ꢀ2c. From 700 mg (2.32 mmol) of alkynic dioxolane (+)ꢀ1c, and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as eluent gave compound (+)ꢀ2c
(527 mg, 72%) as a colorless oil; [α]D = +93.1 (c 0.6, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 oC)
δ 1.64 (s, 3H), 1.73 (s, 3H), 3.97 (dd, 1H, J = 8.9, 5.7 Hz), 4.11 (ddt, 1H, J = 15.1, 7.0, 2.4 Hz),
4.20 (dd, 1H, J = 9.1, 5.1 Hz), 4.46 (m, 2H), 4.73 (dt, 1H, J = 9.1, 6.1 Hz), 5.12 (m, 2H), 5.47 (m,
13
2H), 7.31 (m, 3H), 7.57 (m, 2H); CꢀNMR (75 MHz, CDCl3, 25 oC) δ 209.2, 165.6, 157.3, 129.6,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 30
12
1
2
3
4
5
6
7
122.5, 115.6, 109.7, 85.6, 79.9, 77.0, 77.0, 66.8, 59.8, 39.7, 26.8, 25.1; IR (CHCl3) ν 1958, 1762;
HRMS (ES) calcd for C18H21NO4[M]+ 315.1471, found 315.1477.
8
9
General procedure for the preparation of 2ꢀazetidinoneꢀtethered allenals 3. The
corresponding allenic dioxolane 2 (1.00 mmol) was dissolved in acetonitrile/water (10 mL; 95:5)
and the solution was cooled to 0 °C. BiCl3 (0.05 mmol) was added, the ice bath was removed and
the mixture was stirred at RT for 24 h (monitoring by TLC). The reaction mixture was poured into
a satd. aq. solution of NaHCO3. The aqueous layer was extracted with ethyl acetate (3 x 20 mL),
and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford
(3R,4S)ꢀ1ꢀ(butaꢀ2,3ꢀdienyl)ꢀ4ꢀ[(S)ꢀ2,2ꢀdimethylꢀ1,3ꢀdioxolanꢀ4ꢀyl]ꢀ3ꢀalkoxyazetidinꢀ2ꢀones.
Further purification was not necessary.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Saturated aqueous sodium hydrogen carbonate (100 ꢁL) was added to a solution of the
corresponding diol (1.0 mmol) in dichloromethane (3.3 mL), maintaining the temperature below 25
oC. Solid sodium periodate (2.0 mmol) was added over a 10 min period with vigorous stirring and
o
the reaction was allowed to proceed for 24 h, while the temperature was maintained below 25 C.
The solid was removed by filtration, the filtrate was dried (MgSO4) and the solvent was removed
under reduced pressure. The crude product was used for next step without any further purification.
Spectroscopic and analytical data for some representative forms of 4ꢀoxoazetidineꢀ2ꢀcarbaldehydes
3 follow.
Allenal (+)ꢀ3a. From 400 mg (1.88 mmol) of allenic dioxolane (+)ꢀ2a, compound (+)ꢀ3a
1
(370 mg, quantitative yield) was obtained as a pale brown oil; [α]D = +52.1 (c 0.7, CHCl3); Hꢀ
o
NMR (300 MHz, CDCl3, 25 C) δ 3,49 (s, 3H) 3.94 (m, 2H), 4.22 (dd, 1H, J = 4.9, 3.1 Hz), 4.77
(d, 1H, J = 5.0 Hz), 4.82 (dd, 2H, J = 6.1, 2.9 Hz), 5.09 (m, 1H), 9.69 (d, 1H, J = 3.0 Hz); 13Cꢀ
NMR (75 MHz, CDCl3, 25 oC) δ 209.6, 198.9, 165.9, 85.8, 84.9, 77.5, 63.5, 59.2, 40.1; IR (CHCl3)
ν 1957, 1760; HRMS (ES) calcd for C9H11NO3[M]+ 181.0739; found: 181.0737.
ACS Paragon Plus Environment

Page 13 of 30
The Journal of Organic Chemistry
13
1
2
3
4
5
6
7
Allenal (+)ꢀ3b. From 432 mg (1.49 mmol) of allenic dioxolane (+)ꢀ2b, compound (+)ꢀ3b
1
(383 mg, quantitative yield) was obtained as a pale yellow oil; [α]D = +40.9 (c 0.2, CHCl3); Hꢀ
8
9
NMR (300 MHz, CDCl3, 25 oC) δ 3.91 (m, 1H), 4.01 (m, 1H), 4.19 (dd, 1H, J = 5.0, 3.1 Hz), 4.63
(d, 1H, J = 11.7 Hz), 4.77 (d, 1H, J = 11.7 Hz), 4.83 (m, 2H), 4.93 (d, 1H, J = 5.1 Hz), 5.09 (m, 1H,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
J = 6.6 Hz), 7.33 (m, 5H), 9.61 (d, 1H, J = 3.1 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 209.6,
198.8, 166.0, 135.9, 128.5, 128.4, 128.2 (2C), 84.9, 83.4, 77.4, 73.3, 63.6, 40.1; IR (CHCl3) ν
1957, 1742; HRMS (ES) calcd for C15H15NO3[M]+ 257.1052; found: 257.1046.
Allenal (+)ꢀ3c. From 661 mg (2.40 mmol) of allenic dioxolane (+)ꢀ2c, compound (+)ꢀ3c (584
1
mg, quantitative yield) was obtained as a pale brown oil; [α]D = +16.8 (c 0.9, CHCl3); HꢀNMR
o
(300 MHz, CDCl3, 25 C) δ 3.95 (m, 1H), 4.08 (m, 1H), 4.45 (dd, 1H, J = 5.1, 2.8 Hz), 4.86 (m,
2H), 5.13 (m, 1H), 5.46 (d, 1H, J = 5.1 Hz), 7.03 (m, 3H), 7.31 (m, 2H), 9.72 (d, 1H, J = 2.8 Hz);
13CꢀNMR (75 MHz, CDCl3, 25 C) δ 209.6, 197.4, 164.5, 156.8, 129.7 (2C), 122.9, 115.5 (2C),
o
84.8, 82.1, 77.6, 63.4, 40.3; IR (CHCl3) ν 1957, 1748; HRMS (ES) calcd for C14H13NO3[M]+
243.0895; found: 243.0899.
Indiumꢀpromoted reaction between 3ꢀsubstituted propꢀ2ꢀynyl bromides and allenals 3.
General procedure for the synthesis of bis(allene)s 5a. 1ꢀBromobutꢀ2ꢀyne, (3ꢀbromopropꢀ1ꢀ
ynyl)benzene or 1ꢀ(3ꢀbromopropꢀ1ꢀynyl)ꢀ4ꢀmethoxybenzene (3.0 mmol) was added to a well stirred
suspension of the appropriate allenal (1.0 mmol) and indium powder (6.0 mmol) in THF/NH4Cl
o
(aq. sat.) (1:5, 5 mL) at 0 C. After disappearance of the starting material (TLC) the mixture was
extracted with ethyl acetate (3 x 5 mL). The organic extract was washed with brine, dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the residue using ethyl
acetate/hexanes or dichloromethane/ethyl acetate mixtures gave analytically pure compounds.
Spectroscopic and analytical data for pure forms of 5 follow.
Preparation of (+)ꢀsynꢀ4a and (+)ꢀantiꢀ4a. From 300 mg (1.65 mmol) of allenal (+)ꢀ3a, and
after chromatography of the residue using hexanes/ethyl acetate (1:1) as eluent, 234 mg (80%) of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 30
14
1
2
3
4
5
the less polar compound (+)ꢀsynꢀ4a and 36 mg (8%) of the more polar compound (+)ꢀantiꢀ4a were
6
7
obtained.
8
9
1
Bis(allene) (+)ꢀsynꢀ4a. Colorless oil; [α]D = +26.0 (c 0.4, CHCl3); HꢀNMR (300 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
CDCl3, 25 C) δ 1.79 (t, 3H, J = 3.2 Hz), 3.57 (s, 3H), 3.70 (ddt, 1H, J = 15.3, 6.9, 2.5 Hz), 4.02
(dd, 1H, J = 4.8, 4.2 Hz), 4.15 (ddt, 1H, J = 15.3, 5.5, 3.5 Hz), 4.25 (dd, 1H, J = 6.5, 3.1 Hz), 4.47
(d, 1H, J = 4.9 Hz), 4.82 (m, 4H, =CH2), 5.12 (qd, 1H, J = 6.9, 5.6 Hz); 13CꢀNMR (75 MHz,
o
CDCl3, 25 C) δ 208.8, 205.4, 167.4, 99.7, 86.1, 83.6, 77.4, 76.9, 70.1, 59.6, 59.1, 39.7, 16.0; IR
(CHCl3) ν 3392, 1958, 1742; HRMS (ES) calcd for C13H17NO3[M]+ 235.1208; found: 235.1208.
1
Bis(allene) (+)ꢀantiꢀ4a. Colorless oil; [α]D = +61.2 (c 0.8, CHCl3); HꢀNMR (300 MHz,
CDCl3, 25 oC) δ 1.83 (t, 3H, J = 3.0 Hz), 3.63 (s, 3H), 3.97 (dd, 1H, J = 5.9, 4.9 Hz), 4.09 (m, 2H),
4.32 (d, 1H, J = 5.6 Hz), 4.58 (d, 1H, J = 4.8 Hz), 4.78 (m, 2H), 4.83(m, 2H), 5.09 (m, 1H); 13Cꢀ
NMR (75 MHz, CDCl3, 25 oC) δ 209.0, 206.0, 167.2, 98.8, 85.7, 84.4, 77.3, 76.2, 71.0, 59.6, 58.1,
38.5, 15.2; IR (CHCl3): ν 3393, 1960, 1747; HRMS (ES) calcd for C13H17NO3[M]+ 235.1208;
found: 235.1211.
Bis(allene) (+)ꢀsynꢀ4b. From 302 mg (1.66 mmol) of allenal (+)ꢀ3a, and after
chromatography of the residue using hexanes/ethyl acetate (1:1) as eluent gave compound (+)ꢀsynꢀ
4b (336 mg, 68%) as a colorless oil; [α]D = +28.0 (c 0.5, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25
oC) δ 3.57 (s, 3H), 3.77 (ddt, 1H, J = 15.3, 6.5, 2.6 Hz), 4.10 (t, 1H, J = 5.1 Hz), 4.17 (m, 1H), 4.45
(d, 1H, J = 4.8 Hz), 4.74 (m, 2H), 4.93 (m, 1H), 5.09 (dt, 1H, J = 12.4, 6.2 Hz), 5.26 (qd, 1H, J =
12.3, 2.5 Hz), 7.34 (m, 5H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ 208.8, 207.6, 167.5, 133.9, 128.6
(2C), 127.3, 126.7 (2C), 107.0, 86.0, 83.5, 80.6, 77.1, 68.4, 59.6, 59.6, 39.7; IR (CHCl3) ν 3391,
1956, 1743; HRMS (ES) calcd for C18H19NO3[M]+ 297.1365; found: 297.1365.
Preparation of (+)ꢀsynꢀ4c and (+)ꢀantiꢀ4c. From 473 mg (2.60 mmol) of allenal (+)ꢀ3a, and
after chromatography of the residue using dichloromethane/ethyl acetate (9:1) as eluent, 357 mg
ACS Paragon Plus Environment

Page 15 of 30
The Journal of Organic Chemistry
15
1
2
3
4
5
6
7
(42%) of the less polar compound (+)ꢀsynꢀ4c and 137 mg (16%) of the more polar compound (+)ꢀ
antiꢀ4c were obtained.
8
9
1
Bis(allene) (+)ꢀsynꢀ4c. Colorless oil; [α]D = +41.7 (c 1.2, CHCl3); HꢀNMR (300 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CDCl3, 25 oC) δ 2.61 (brs, 1H), 3.54 (s, 3H), 3.76 (ddd, 1H, J = 6.7, 5.6, 2.6 Hz), 3.81 (s, 3H), 4.10
(t, 1H, J = 5.0 Hz), 4.19 (ddt, 1H, J = 15.3, 5.7, 3.5 Hz), 4.47 (d, 1H, J = 4.8 Hz), 4.76 (td, 2H, J =
6.4, 3.2 Hz) , 4.90 (m, 1H), 5.11 (m, 1H), 5.25 (qd, 2H, J = 12.1, 2.8 Hz), 6.90 (d, 2H, J = 8.8 Hz),
o
7.36 (d, 2H, J = 8.8 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 208.8, 207.2, 167.4, 159.0, 127.9
(2C), 125.9, 114.3 (2C), 106.5, 86.0, 83.6, 80.6, 77.2, 68.5, 59.6, 59.6, 55.3, 39.7; IR (CHCl3) ν
3398, 1956, 1737; HRMS (ES) calcd for C19H21NO4[M]+ 327.1473; found 327.1471.
1
Bis(allene) (+)ꢀantiꢀ4c. Colorless oil; [α]D = +28.8 (c 1.5, CHCl3); HꢀNMR (300 MHz,
CDCl3, 25 oC) δ 3.61 (m, 1H), 3.65 (s, 3H), 3.81 (s, 3H), 4.04 (m, 1H), 4.09 (m, 1H), 4.61 (d, 1H, J
= 4.8 Hz), 4.77 (dt, 2H, J = 6.3, 3.0 Hz) , 4.87 (m, 1H), 5.06 (m, 1H), 5.25 (m, 2H), 6.89 (d, 2H, J
o
= 8.8 Hz), 7.44 (d, 2H, J = 8.8 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 208.8, 208.1, 167.2,
158.9, 127.8 (2C), 126.1, 114.0 (2C), 105.8, 85.8, 84.5, 80.6, 77.3, 68.8, 59.6, 58.8, 55.3, 38.5; IR
(CHCl3) ν 3422, 1956, 1744; HRMS (ES) calcd for C19H21NO4[M]+ 327.1473; found 327.1471.
Preparation of (+)ꢀsynꢀ4d and (+)ꢀantiꢀ4d. From 335 mg (1.38 mmol) of allenal (+)ꢀ3c, and
after chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent, 61 mg (15%) of the
less polar compound (+)ꢀantiꢀ4d and 172 mg (42%) of the more polar compound (+)ꢀsynꢀ4d were
obtained.
1
Bis(allene) (+)ꢀsynꢀ4d. Colorless oil; [α]D = +70.0 (c 1.2, CHCl3); HꢀNMR (300 MHz,
CDCl3, 25 oC) δ 1.81 (t, 3H, J = 3.1 Hz), 3.84 (ddt, 1H, J = 15.3, 6.8, 2.6 Hz), 4.19 (m, 2H), 4.39
(dd, 1H, J = 5.1, 2.5 Hz), 4.74 (dd, 2H, J = 6.5, 3.2 Hz), 4.86 (m, 2H), 5.19 (m, 2H, H3), 7.05 (m,
o
3H), 7.30 (m, 2H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 209.0, 205.6, 166.2, 157.6, 129.5 (2C),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 30
16
1
2
3
4
5
6
7
122.5, 115.9 (2C), 99.5, 86.0, 80.5, 77.4, 77.2, 70.9, 59.5, 40.1, 15.9; IR (CHCl3) ν 3420, 1957,
1736; HRMS (ES) calcd for C18H19NO3[M]+ 297.1365; found 297.1372.
8
9
1
Bis(allene) (+)ꢀantiꢀ4d. Colorless solid; mp 91–93 ºC; [α]D = +120.4 (c 1.6, CHCl3); Hꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (300 MHz, CDCl3, 25 oC) δ 1.88 (t, 3H, J = 3.1 Hz), 2.73 (brs, 1H), 3.68 (ddt, 1H, J = 15.4,
7.0, 2.5 Hz), 4.18 (m, 2H, H4), 4.47 (d, 1H, J = 5.6 Hz), 4.71 (dd, 2H, J = 5.3, 2.4 Hz), 4.88 (m,
2H), 5.15 (m, 1H), 5.32 (d, 1H, J = 4.9 Hz), 7.06 (t, 1H, J = 7.3 Hz), 7.14 (m, 2H), 7.32 (m, 2H);
o
13CꢀNMR (75 MHz, CDCl3, 25 C) δ 209.1, 206.2, 165.9, 157.4, 129.6 (2C), 122.9, 116.2 (2C),
98.4, 85.6, 82.0, 77.4, 76.4, 70.8, 58.4, 38.8, 15.2; IR (CHCl3) ν 3421, 1957, 1743; HRMS (ES)
calcd for C18H19NO3[M]+ 297.1365; found: 297.1372.
Bis(allene) (+)ꢀsynꢀ4e. From 223 mg (0.92 mmol) of allenal (+)ꢀ3c, and after chromatography
of the residue using hexanes/ethyl acetate (3:1) as eluent gave compound (+)ꢀsynꢀ4e (188 mg, 57%)
as a colorless oil; [α]D = +85.6 (c 0.8, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ 3.94 (ddt, 1H,
J = 15.3, 6.7, 2.6 Hz), 4.28 (m, 2H), 4.85 (m, 2H), 5.09 (m, 1H), 5.17 (m, 2H), 5.23 (m, 2H), 7.00
o
(m, 2H), 7.36 (m, 8H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 209.0, 207.8, 166.4, 157.6, 134.0,
129.4 (2C), 128.7 (2C), 127.4, 126.7 (2C), 122.4, 115.9 (2C), 106.9, 85.9, 80.6, 80.4, 77.2, 69.7,
60.0, 40.2; IR (CHCl3) ν 3452, 1959, 1752; HRMS (ES) calcd for C23H21NO3[M]+ 359.1521; found
359.1519.
Bis(allene) (+)ꢀsynꢀ4f. From 256 mg (1.05 mmol) of allenal (+)ꢀ3c, and after chromatography
of the residue using hexanes/ethyl acetate (3:1) as eluent gave compound (+)ꢀsynꢀ4f (196 mg, 48%)
as a colorless oil; [α]D = +76.0 (c 0.4, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ 3.87 (s, 3H),
3.99 (m, 1H), 4.30 (m, 2H), 4.88 (m, 2H), 5.06 (m, 1H), 5.12 (d, 1H, J = 2.0 Hz), 5.18 (d, 1H, J =
1.6 Hz), 5.25 (m, 2H), 6.95 (d, 2H, J = 8.9 Hz), 7.03 (m, 3H), 7.31 (dd, 2H, J = 7.4, 1.1 Hz), 7.41
(d, 2H, J = 8.8 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ 208.9, 207.5, 166.3, 159.0, 157.6, 129.4
(2C), 127.9 (2C), 126.0, 122.3, 116.0 (2C), 114.2 (2C), 106.4, 85.9, 80.5, 80.4, 77.2, 69.8, 60.0,
ACS Paragon Plus Environment

Page 17 of 30
The Journal of Organic Chemistry
17
1
2
3
4
5
55.3, 40.2; IR (CHCl3) ν 3447, 1956, 1753; HRMS (ES) calcd for C24H23NO4[M]+ 389.1627; found
6
7
389.1622.
8
9
Preparation of (–)ꢀsynꢀ4g and (+)ꢀantiꢀ4g. From 200 mg (0.78 mmol) of allenal (+)ꢀ3b, and
after chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent, 36 mg (15%) of the
less polar compound (+)ꢀantiꢀ4g and 175 mg (72%) of the more polar compound (–)ꢀsynꢀ4g were
obtained.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Bis(allene) (–)ꢀsynꢀ4g. Colorless oil; [α]D = –163.0 (c 0.5, CHCl3); HꢀNMR (300 MHz,
CDCl3, 25 oC) δ 1.78 (t, 3H, J = 3.1 Hz), 3.72 (ddt, 1H, J = 15.3, 7.0, 2.5 Hz), 4.02 (m, 1H), 4.19
(m, 2H, OCH), 4.69 (dd, 2H, J = 8.2, 3.3 Hz), 4.82 (m, 4H, =CH2), 4.93 (d, 1H, J = 11.6 Hz) 5.11
(m, 1H), 7.35 (s, 5H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ 208.9, 205.4, 167.4, 136.6, 128.6 (2C),
128.2, 128.0 (2C), 99.6, 86.1, 81.2, 77.4, 77.1, 73.4, 70.1, 58.9, 39.8, 16.1; IR (CHCl3) ν 3385,
1958, 1741; HRMS (ES) calcd for C19H21NO3[M]+ 311.1521; found 311.1527.
1
Bis(allene) (+)ꢀantiꢀ4g. Colorless oil; [α]D = +75.2 (c 1.8, CHCl3); HꢀNMR (300 MHz,
CDCl3, 25 oC) δ 1.82 (t, 3H, J = 3.1 Hz), 3.01 (brs, 1H), 3.62 (ddt, 1H, J = 15.4, 6.9, 2.4 Hz), 3.98
(m, 1H), 4.11 (m, 1H), 4.36 ( d, 1H, J = 5.9 Hz), 4.75 (m, 4H), 4.84 (m, 2H), 4.97 (d, 1H, J = 11.5
o
Hz), 5.10 (m, 1H), 7.36 (s, 5H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 209.0, 206.0, 167.1, 136.4,
128.6 (2C), 128.2, 128.0 (2C), 98.8, 85.7, 82.0, 77.2, 76.3, 73.4, 70.9, 58.0, 38.6, 15.1; IR (CHCl3)
ν 3420, 1957, 1738; HRMS (ES) calcd for C19H21NO3[M]+ 311.1521; found 311.1529.
Bis(allene) (+)ꢀsynꢀ4h. From 248 mg (0.96 mmol) of allenal (+)ꢀ3b, and after
chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent gave compound (+)ꢀsynꢀ
4h (200 mg, 56%) as a colorless oil; [α]D = +174.7 (c 0.2, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25
oC) δ 3.77 (ddt, 1H, J = 15.3, 6.8, 2.6 Hz), 4.05 (t, 1H, J = 5.1 Hz) 4.18 (ddt, 1H, J = 15.3, 5.6, 3.5
13
Hz), 4.62 (m, 2H), 4.71 (m, 2H), 4.88 (m, 2H), 5.16 (m, 3H), 7.30 (m, 10H); CꢀNMR (75 MHz,
o
CDCl3, 25 C) δ 208.8, 207.6, 167.6, 136.7, 133.9, 128.6 (2C), 128.5 (2C), 128.1, 128.0 (2C),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 30
18
1
2
3
4
5
6
7
127.4, 126.7 (2C), 107.0, 86.0, 81.1, 80.7, 77.1, 73.4, 68.6, 59.6, 39.8; IR (CHCl3) ν 3455, 1958,
1742; HRMS (ES) calcd for C24H23NO3[M]+ 373.1678; found 373.1678.
8
9
General procedure for the preparation of bis(allenyl) methyl ethers 5a–h. Tetrabutyl
ammonium iodide (cat), 50% aqueous sodium hydroxide (18 mL) and dimethyl sulfate (0.60 mmol)
were sequentially added at room temperature to a solution of the corresponding bis(allenyl) alcohol
4 (0.92 mmol) in dichloromethane (18 mL). The reaction was stirred until disappearance of the
starting material (TLC). Then aqueous ammonia (30%) was added (2.5 mL), before being
partitioned between dichloromethane and water. The aqueous phase was extracted with
dichloromethane (3 x 15 mL), the combined organic extracts were dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using ethyl acetate/hexanes mixtures gave
analytically pure compounds. Spectroscopic and analytical data for some representative pure forms
of compounds 5a–h follow.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bis(allenyl) methyl ether (+)ꢀ5a. From 150 mg (0.64 mmol) of bis(allenyl) alcohol (+)ꢀsynꢀ
4a, and after chromatography of the residue using hexanes/ethyl acetate (1:1) as eluent gave
1
compound (+)ꢀ5a (115 mg, 72%) as a colorless oil; [α]D = +10.4 (c 0.7, CHCl3); HꢀNMR (300
o
MHz, CDCl3, 25 C) δ 1.72 (t, 3H, J = 3.2 Hz), 3.30 (s, 3H) 3.48 (s, 3H), 3.77 (ddt, 1H, J = 15.3,
6.9, 2.5 Hz), 3.90 (m, 2H), 4.08 (ddt, 1H, J = 15.1, 5.8, 3.4 Hz), 4.42 (dd, 1H, J = 3.0, 1.3 Hz), 4.74
(q, 2H, J = 3.2 Hz), 4.81 (m, 2H), 5.12 (qd, 1H, J = 6.9, 5.6 Hz); 13CꢀNMR (75 MHz, CDCl3, 25
oC) δ 208.8, 207.9, 167.6, 95.3, 86.1, 83.5, 82.2, 76.9, 75.1, 59.5, 58.9, 55.6, 39.8, 14.6; IR
(CHCl3) ν 1960, 1747; HRMS (ES) calcd for C14H19NO3[M]+ 249.1365; found 249.1360.
Bis(allenyl) methyl ether (+)ꢀ5b. From 150 mg (0.64 mmol) of bis(allenyl) alcohol (+)ꢀsynꢀ
4b, and after chromatography of the residue using hexanes/ethyl acetate (1:1) as eluent gave
1
compound (+)ꢀ5b (98 mg, 61%) as a colorless oil; [α]D = +11.8 (c 1.6, CHCl3); HꢀNMR (300
o
MHz, CDCl3, 25 C) δ 3.26 (s, 3H), 3.31 (s, 3H), 3.75 (ddt, 1H, J = 15.1, 6.8, 2.6 Hz), 4.08 (m,
2H), 4.30 (d, 1H, J = 4.8 Hz), 4.43 (d, 1H, J = 9.3 Hz), 4.74 (m, 2H), 5.10 (m, 3H), 7.23 (m, 3H),
ACS Paragon Plus Environment

Page 19 of 30
The Journal of Organic Chemistry
19
1
2
3
4
5
6
7
8
9
7.46 (m, 2H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ 210.0, 209.9, 167.6, 134.6, 128.5 (2C), 127.2,
126.9 (2C), 103.1, 86.1, 83.6, 80.5, 78.5, 76.9, 59.6, 59.4, 55.4, 39.9; IR (CHCl3) ν 1956, 1744;
HRMS (ES) calcd for C19H21NO3[M]+ 311.1521; found 311.1508.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bis(allenyl) methyl ether (+)ꢀ5c. From 140 mg (0.43 mmol) of bis(allenyl) alcohol (+)ꢀsynꢀ
4c, and after chromatography of the residue using hexanes/ethyl acetate (1:1) as eluent gave
1
compound (+)ꢀ5c (92 mg, 63%) as a colorless oil; [α]D = +12.4 (c 1.5, CHCl3); HꢀNMR (300
MHz, CDCl3, 25 oC) δ 3.32 (s, 3H), 3.39 (s, 3H), 3.84 (m, 4H), 3.81 (s, 3H), 4.14 (m, 2H), 4.37 (d,
1H, J = 4.7 Hz), 4.47 (d, 1H, J = 9.3 Hz) , 4.82 (m, 2H), 5.16 (m, 3H), 6.89 (d, 2H, J = 8.8 Hz),
o
7.45 (d, 2H, J = 8.8 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 209.9, 209.2, 167.8, 159.1, 128.4
(2C), 127.0, 114.3 (2C), 102.9, 86.4, 83.9, 80.9, 78.7, 77.2, 60.0, 59.3, 55.6, 55.5, 40.2; IR (CHCl3)
ν 1957, 1753; HRMS (ES) calcd for C20H23NO4[M]+ 341.1627; found 341.1616.
Bis(allenyl) methyl ether (+)ꢀ5d. From 68 mg (0.23 mmol) of bis(allenyl) alcohol (+)ꢀsynꢀ
4d, and after chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent gave
1
compound (+)ꢀ5d (47 mg, 66%) as a colorless oil; [α]D = +20.0 (c 0.1, CHCl3); HꢀNMR (300
MHz, CDCl3, 25 oC) δ 1.69 (t, 3H, J = 3.2 Hz), 3.32 (s, 3H), 3.85 (m, 1H), 4.06 (m, 2H), 4.15 (m,
1H), 4.37 (m, 1H), 4.60 (m, 1H), 4.84 (m, 2H), 5.19 (m, 2H), 7.00 (m, 3H), 7.27 (m, 2H); 13Cꢀ
o
NMR (75 MHz, CDCl3, 25 C) δ 210.0, 208.3, 166.1, 157.9, 129.3 (2C), 122.0, 115.6 (2C), 94.6,
86.0, 82.3, 79.9, 77.0, 75.0, 58.4, 55.6, 40.2, 14.2; IR (CHCl3) ν 1958, 1762; HRMS (ES) calcd for
C19H21NO3[M]+ 311.1521; found 311.1522.
Bis(allenyl) methyl ether (+)ꢀ5e. From 77 mg (0.21 mmol) of bis(allenyl) alcohol (+)ꢀsynꢀ
4e, and after chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent gave
1
compound (+)ꢀ5e (46 mg, 59%) as a colorless oil; [α]D = +44.4 (c 0.2, CHCl3); HꢀNMR (300
o
MHz, CDCl3, 25 C) δ 3.41 (s, 3H), 3.92 (m, 1H), 4.24 (m, 1H), 4.31 (dd, 1H, J = 9.2, 4.9 Hz),
4.62 (d, 1H, J = 9.1 Hz), 4.78 (d, 1H, J = 12.4 Hz), 4.85 (m, 2H), 4.99 (d, 1H, J = 12.5 Hz), 5.14 (d,
13
1H, J = 4.9 Hz), 5.21 (m, 1H), 6.81 (m, 2H), 6.99 (m, 2H), 7.29 (m, 4H), 7.48 (m, 2H); CꢀNMR
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 30
20
1
2
3
4
o
(75 MHz, CDCl3, 25 C) δ 210.5, 209.2, 166.2, 157.8, 134.4, 129.2 (2C), 128.5 (2C), 127.2 (3C),
121.9, 115.6 (2C), 102.3, 85.9, 81.2, 79.8, 78.1, 77.2, 58.7, 55.5, 40.4); IR (CHCl3) ν 1959, 1760;
HRMS (ES) calcd for C24H23NO3[M]+ 373.1678; found 373.1690.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bis(allenyl) methyl ether (+)ꢀ5f. From 54 mg (0.14 mmol) of bis(allenyl) alcohol (+)ꢀsynꢀ4f,
and after chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent gave compound
1
(+)ꢀ5f (36 mg, 64%) as a colorless oil; [α]D = +26.0 (c 0.2, CHCl3); HꢀNMR (300 MHz, CDCl3,
25 oC) δ 3.40 (s, 3H), 3.83 (s, 3H), 3.92 (m, 1H), 4.24 (m, 1H), 4.30 (dd, 1H, J = 9.2, 4.9 Hz), 4.57
(d, 1H, J = 9.2 Hz), 4.71 (d, 1H, J = 12.2 Hz), 4.86 (m, 2H), 4.95 (d, 1H, J = 12.2 Hz), 5.13 (d, 1H,
J = 4.8 Hz), 5.21 (m, 1H), 6.86 (m, 4H), 6.98 (t, 1H, J = 7.4 Hz), 7.24 (m, 2H), 7.40 (d, 2H, J = 8.8
o
Hz); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 210.2, 209.2, 166.1, 158.9, 157.9, 129.2 (2C), 128.4
(2C), 126.4, 121.9, 115.7 (2C), 114.0 (2C), 101.6, 85.9, 81.5, 79.8, 77.9, 77.2, 58.6, 55.4, 55.3,
40.3; IR (CHCl3) ν 1957, 1759; HRMS (ES) calcd for C25H25NO4[M]+ 403.1784; found 403.1781.
Bis(allenyl) methyl ether (–)ꢀ5g. From 71 mg (0.23 mmol) of bis(allenyl) alcohol (–)ꢀsynꢀ
4g, and after chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent gave
compound (–)ꢀ5g (60 mg, 80%) as a colorless oil; [α]D = –5.5 (c 1.0, CHCl3); 1HꢀNMR (300 MHz,
o
CDCl3, 25 C) δ 1.71 (t, 3H, J = 3.2 Hz), 3.31 (s, 3H), 3.79 (ddt, 1H, J = 15.1, 6.6, 2.6 Hz), 3.94
(m, 2H), 4.11 (m, 1H), 4.61 (m, 4H), 4.82 (m, 3H), 5.15 (m, 4H), 7.32 (m, 5H); 13CꢀNMR (75
o
MHz, CDCl3, 25 C) δ 208.9, 207.9, 167.8, 137.3, 128.3 (2C), 127.7, 127.6 (2C), 95.2, 86.1, 82.3,
81.0, 76.9, 75.2, 72.9, 58.5, 55.5, 39.9, 14.7; IR (CHCl3) ν 1957, 1752; HRMS (ES) calcd for
C20H23NO3[M]+ 325.1678; found 325.1681.
Bis(allenyl) methyl ether (+)ꢀ5h. From 75 mg (0.20 mmol) of bis(allenyl) alcohol (+)ꢀsynꢀ
4h, and after chromatography of the residue using hexanes/ethyl acetate (3:1) as eluent gave
1
compound (+)ꢀ5h (44 mg, 54%) as a colorless oil; [α]D = +17.0 (c 0.1, CHCl3); HꢀNMR (300
o
MHz, CDCl3, 25 C) δ 3.35 (s, 3H), 3.84 (ddt, 1H, J = 15.0, 6.8, 2.6 Hz), 4.16 (m, 2H), 4.57 (m,
3H), 4.75 (d, 1H, J = 11.9 Hz), 4.81 (m, 2H), 5.03 (q, 2H, J = 12.5 Hz), 5.16 (td, 1H, J = 12.5, 6.7
ACS Paragon Plus Environment

Page 21 of 30
The Journal of Organic Chemistry
21
1
2
3
4
5
6
7
8
9
13
Hz), 7.29 (m, 8H), 7.51 (m, 2H); CꢀNMR (75 MHz, CDCl3, 25 oC) δ 210.1, 209.0, 167.9, 137.2,
134.7, 128.5 (2C), 128.2 (2C), 127.7, 127.7 (2C), 127.2, 127.0 (2C), 103.0, 86.1, 81.0, 80.5, 78.5,
76.9, 73.1, 58.7, 55.3, 40.0; IR (CHCl3) ν 1959, 1758; HRMS (ES) calcd for C25H25NO3[M]+
387.1834; found 387.1830.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the preparation of bis(allenyl) acetates 5i–k. Triethylamine (0.94
mmol) and acetic anhydride (0.47 mmol) were sequentially added dropwise via syringe to a
solution of the corresponding bis(allenyl) alcohol 4 (0.39 mmol) and DMAP (cat) in
o
dichloromethane (4 mL) at 0 C under argon. The resulting mixture was allowed to warm to room
temperature and stirred for 2 h. The crude mixture was diluted with CH2Cl2 (10 mL) and washed
with saturated aqueous ammonium chloride (3 x 5 mL) and brine (3 x 5 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue using
ethyl acetate/hexanes mixtures gave analytically pure compounds. Spectroscopic and analytical data
for some representative pure forms of compounds 5i–k follow.
Bis(allenyl) acetate (+)ꢀ5i. From 75 mg (0.32 mmol) of bis(allenyl) alcohol (+)ꢀsynꢀ4a, and
after chromatography of the residue using hexanes/ethyl acetate (1:1) as eluent gave compound (+)ꢀ
5i (57 mg, 64%) as a colorless oil; [α]D = +27.1 (c 0.4, CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 oC)
δ 1.76 (t, 3H, J = 3.2 Hz), 2.08 (s, 3H) 3.51 (s, 3H), 3.56 (m, 1H), 4.10 (m, 2H), 4.46 (d, 1H, J =
4.9 Hz), 4.84 (m, 4H), 5.08 (td, 1H, J = 12.4, 6.8 Hz), 5.39 (m, 1H); 13CꢀNMR (75 MHz, CDCl3,
25 oC) δ 208.9, 206.9, 169.9, 167.6, 97.7, 85.7, 83.5, 77.4, 77.3, 72.6, 59.5, 58.3, 39.6, 21.1, 16.4;
IR (CHCl3) ν 1958 (C=C=C), 1748 (C=O); HRMS (ES) calcd for C15H19NO4[M]+ 277.1314;
found: 277.1315.
Bis(allenyl) acetate (+)ꢀ5j. From 50 mg (0.17 mmol) of bis(allenyl) alcohol (+)ꢀsynꢀ4b, and
after chromatography of the residue using hexanes/ethyl acetate (1:1) as eluent gave compound (+)ꢀ
1
5j (43 mg, 74%) as a colorless oil; [α]D = +37.1 (c 0.8, CHCl3); HꢀNMR (300 MHz, CDCl3, 25
oC) δ 2.06 (s, 3H), 3.39 (s, 3H), 3.57 (m, 1H), 4.24 (m, 2H), 4.46 (d, 1H, J = 4.8 Hz), 4.81 (m, 2H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 30
22
1
2
3
4
5
6
7
8
9
5.08 (m, 1H), 5.28 (m, 2H), 6.09 (dt, 1H, J = 7.1, 1.8 Hz) 7.35 (m, 3H), 7.46 (m, 2H); 13CꢀNMR
(75 MHz, CDCl3, 25 oC) δ 209.1, 209.0, 169.9, 169.6, 128.6 (2C), 127.5, 126.8 (2C), 106.6, 105.5,
85.6, 83.6, 80.6, 77.3, 70.2, 59.6, 58.6, 39.7, 21.1; IR (CHCl3) ν 1957, 1753; HRMS (ES) calcd for
C20H21NO4[M]+ 339.1471; found 339.1460.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bis(allenyl) acetate (+)ꢀ5k. From 160 mg (0.49 mmol) of bis(allenyl) alcohol (+)ꢀsynꢀ4c, and
after chromatography of the residue using hexanes/ethyl acetate (1:1) as eluent gave compound (+)ꢀ
1
5k (123 mg, 68%) as a colorless oil; [α]D = +9.8 (c 1.7, CHCl3); HꢀNMR (300 MHz, CDCl3, 25
oC) δ 2.05 (s, 3H), 3.38 (s, 3H), 3.53 (m, 1H), 3.80 (s, 3H), 4.19 (m, 2H), 4.45 (d, 1H, J = 4.9 Hz),
4.82 (m, 2H) , 5.07 (qd, 1H, J = 6.9, 5.5 Hz), 5.24 (dd, 2H, J = 3.6, 1.8 Hz), 6.05 (dt, 1H, J = 7.2,
o
1.8 Hz), 6.87 (d, 2H, J = 8.9 Hz), 7.37 (d, 2H, J = 8.9 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ
209.0, 208.7, 169.7, 167.6, 159.0, 127.9 (2C), 125.3, 114.0 (2C), 104.9, 85.5, 83.5, 80.6, 77.3, 70.2,
59.6, 58.6, 55.2, 39.6, 21.1; IR (CHCl3) ν 1957, 1753; HRMS (ES) calcd for C21H23NO5[M]+
369.1576; found 369.1584.
General procedure for the microwaveꢀpromoted reaction of βꢀlactam bis(allene)s 4.
Preparation of azocinoneꢀβꢀlactams 6. A stirred solution of the corresponding bis(allene) 4 (0.1
mmol) in toluene (2.0 mL) was heated at the appropriate temperature under microwave irradiation
until disappearance of the starting material (TLC). The reaction was allowed to cool to room
temperature, concentrated under vacuum, and purified by flash column chromatography eluting
with ethyl acetate/dichloromethane mixtures. Spectroscopic and analytical data for pure forms of
compounds 6 follow.
o
Azocinoneꢀβꢀlactam (+)ꢀ6a. Microwave heating (toluene, 250 C, 1h). From 40 mg (0.16
mmol) of bis(allene) (+)ꢀ4a, and after chromatography of the residue using dichloromethane/ethyl
acetate (9:1) as eluent gave compound (+)ꢀ6a (10 mg, 25%) as a colorless oil; [α]D = +156.0 (c 0.7,
CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ 5.22 (d, 1H, 0.6 Hz), 5.12 (d, 1H, J = 1.7 Hz), 4.91
(t, 1H, J = 1.1 Hz), 4.89 (m, 1H), 4.68 (dd, 1H, J = 4.8, 0.7 Hz), 4.13 (m, 2H), 3.92 (dq, 1H, J =
ACS Paragon Plus Environment

Page 23 of 30
The Journal of Organic Chemistry
23
1
2
3
4
5
6
7
8
9
6.5, 0.7 Hz), 3.46 (s, 3H), 2.83 (m, 1H), 2.58 (m, 1H), 2.45 (ddd, 1H, J = 14.9, 5.1, 2.8 Hz), 1.23
(d, 3H, J = 6.7 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ: 208.9, 166.6, 148.4, 148.2, 115.7, 114.6,
86.5, 67.0, 59.4, 45.4, 43.3, 33.8, 13.4; IR (CHCl3) ν 1755, 1719; HRMS (ES) calcd for
C13H17NO3[M]+ 235.1208; found 235.1215.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
Azocinoneꢀβꢀlactam (+)ꢀ6d. Microwave heating (toluene, 185 C, 26h). From 40 mg (0.13
mmol) of bis(allene) (+)ꢀ4d, and after chromatography of the residue using dichloromethane/ethyl
acetate (9:1) as eluent gave compound (+)ꢀ6d (9 mg, 23%) as a colorless oil; [α]D = +111.8 (c 0.5,
1
o
CHCl3); HꢀNMR (300 MHz, CDCl3, 25 C) δ 7.30 (m, 2H), 7.04 (m, 3H), 5.39 (d, 1H, J = 5.2
Hz), 5.23 (s, 1H), 5.15 (d, 1H, J = 1.5 Hz), 4.94 (d, 2H, J = 1.0 Hz), 4.35 (d, 1H, J = 5.2 Hz), 4.18
(ddd, 1H, J = 13.9, 5.8, 3.2 Hz), 3.98 (q, 1H, J = 6.6 Hz), 2.93 (m, 1H), 2.60 (m, 1H), 2.47 (m,
1H),1.24 (d, 3H, J = 6.7 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ 208.0, 165.4, 157.1, 148.2 (2C),
129.6 (2C), 122.9, 116.0, 115.9 (2C), 114.7, 83.2, 66.7, 45.9, 43.5, 33.7, 13.7; IR (CHCl3) ν 1768,
1722; HRMS (ES) calcd for C18H19NO3[M]+ 297.1365; found 297.1355.
General procedure for the microwaveꢀpromoted reaction of βꢀlactam bis(allene)s 5.
Preparation of azocineꢀβꢀlactams 7. A stirred solution of the corresponding bis(allene) 5 (0.1
mmol) in toluene (2.0 mL) was heated at the appropriate temperature under microwave irradiation
until disappearance of the starting material (TLC). The reaction was allowed to cool to room
temperature, concentrated under vacuum, and purified by flash column chromatography eluting
with hexanes/ethyl acetate or ethyl acetate/dichloromethane mixtures. Spectroscopic and analytical
data for pure forms of compounds 7 follow.
o
Azocineꢀβꢀlactam (–)ꢀ7a. Microwave heating (toluene, 250 C, 0.5h). From 50 mg (0.2
mmol) of bis(allene) (+)ꢀ5a, and after chromatography of the residue using dichloromethane/ethyl
acetate (9:1) as eluent gave compound (–)ꢀ7a (30 mg, 60%) as a colorless oil; [α]D = –106.0 (c 0.6,
CHCl3); 1HꢀNMR (300 MHz, CDCl3, 25 oC) δ 5.29 (d, 1H, J = 2.0 Hz), 5.13 (d, 1H, J = 1.3), 4.83
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 30
24
1
2
3
4
5
6
7
(t, 1H, J = 1.8 Hz), 4.70 (d, 1H, J = 2.0 H), 4.52 (dd, 1H, J = 4.6, 1.2 Hz), 4.22 (d, 1H, J = 4.5),
3.71 (td, 1H, J = 13.7, 4.0 Hz), 3.60 (s, 3H), 3.51 (s, 3H), 3.03 (m, 1H), 2.66 (m, 1H), 2.18 (ddd,
8
9
o
1H, J = 14.3, 3.8, 2.1 Hz),1.79 (d, 3H, J = 0.8 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 167.1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
148.4, 148.3, 144.8, 123.9, 113.9, 112.7, 85.1, 59.2, 58.7, 58.4, 41.1, 32.0, 18.2; IR (CHCl3) ν
1753; HRMS (ES) calcd for C14H19NO3[M]+ 249.1365; found 249.1365.
o
Azocineꢀβꢀlactam (–)ꢀ7b. Microwave heating (toluene, 200 C, 1h). From 40 mg (0.13
mmol) of bis(allene) (+)ꢀ5b, and after chromatography of the residue using hexanes/ethyl acetate
(2:1) as eluent gave compound (–)ꢀ7b (21 mg, 50%) as a colorless oil; [α]D = –34.0 (c 0.4, CHCl3);
1HꢀNMR (300 MHz, CDCl3, 25 oC) δ 7.31 (m, 5H), 5.48 (d, 1H, J = 2.0 Hz), 5.10 (s, 1H), 4.86 (m,
2H), 4.63 (d, 1H, J = 4.6), 4.35 (d, 1H, J = 4.6), 3.78 (td, 1H, J = 13.7, 4.0 Hz), 3.56 (s, 3H), 3.38
(s, 3H), 3.11 (dd, 1H, J = 13.6, 4.8 Hz), 2.82 (m, 1H), 2.24 (m, 1H); 13CꢀNMR (75 MHz, CDCl3,
o
25 C) δ 167.0, 148.8, 147.0, 146.9, 138.3, 128.5 (2C), 128.0 (2C), 126.9, 125.2, 117.1, 113.2,
85.6, 61.0, 59.0, 58.9, 41.2, 32.0; IR (CHCl3) ν 1759; HRMS (ES) calcd for C19H21NO3[M]+
311.1521; found 311.1516.
o
Azocineꢀβꢀlactam (+)ꢀ7c. Microwave heating (toluene, 200 C, 1h). From 40 mg (0.12
mmol) of bis(allene) (+)ꢀ5c, and after chromatography of the residue using hexanes/ethyl acetate
(1:1) as eluent gave compound (+)ꢀ7c (18 mg, 45%) as a colorless oil; [α]D = +42.7 (c 0.4, CHCl3);
o
1HꢀNMR (300 MHz, CDCl3, 25 C) δ 7.38 (d, 2H, J = 8.9 Hz), 6.84 (d, 2H, J = 8.9 Hz), 5.48 (d,
1H, J = 2.0 Hz), 5.10 (d, 1H, J = 1.6 Hz), 4.84 (m, 2H), 4.61 (d, 1H, J = 4.6 Hz), 4.34 (d, 1H, J =
4.6 Hz), 3.80 (m, 4H), 3.55 (s, 3H), 3.39 (s, 3H), 3.10 (dd, 1H, J = 13.3, 5.3 Hz), 2.78 (m, 1H), 2.21
(m, 1H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ 167.1, 158.4, 148.0, 147.2, 147.1, 130.4, 129.7 (2C),
124.8, 116.9, 113.4 (2C), 113.1, 85.6, 61.1, 58.8, 58.8, 55.2, 41.2, 32.0; IR (CHCl3) ν 1756; HRMS
(ES) calcd for C20H23NO4[M]+ 341.1627; found: 341.1625.
ACS Paragon Plus Environment

Page 25 of 30
The Journal of Organic Chemistry
25
1
2
3
4
5
6
7
8
9
o
Azocineꢀβꢀlactam (–)ꢀ7d. Microwave heating (toluene, 225 C, 1h). From 40 mg (0.13
mmol) of bis(allene) (+)ꢀ5d, and after chromatography of the residue using hexanes/ethyl acetate
(1:1) as eluent gave compound (–)ꢀ7d (21 mg, 50%) as a colorless oil; [α]D = –49.5 (c 0.6, CHCl3);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1HꢀNMR (300 MHz, CDCl3, 25 oC) δ 7.31 (dd, 1H, J = 7.0, 1.7 Hz), 7.09 (dd, 2H, J = 8.7, 1.0 Hz),
7.01 (m, 2H), 5.29 (d, 1H, J = 1.9 Hz), 5.25 (dd, 1H, J = 4.7, 1.1 Hz), 5.17 (d, 1H, J = 1.4 Hz), 4.87
(t, 1H, J = 1.7 Hz), 4.72 (d, 1H, J = 1.9 H), 4.41 (d, 1H, J = 4.7 Hz), 3.80 (td, 1H, J = 13.8, 4.2 Hz),
3.56 (s, 3H), 3.10 (dd, 1H, J = 13.7, 5.0 Hz), 2.70 (td, 1H, J = 14.1, 5.0 Hz), 2.21 (ddd, 1H, J =
o
14.2, 4.0, 1.9 Hz), 1.80 (d, 3H, J = 0.8 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 165.9, 157.6,
148.5, 146.0, 144.8, 129.5 (2C) 124.2, 122.1, 115.9 (2C) 114.0, 113.0, 81.8, 60.2, 58.4, 41.3, 32.0,
18.1; IR (CHCl3) ν 1760; HRMS (ES) calcd for C19H21NO3[M]+ 311.1521; found 311.1518.
o
Azocineꢀβꢀlactam (–)ꢀ7e. Microwave heating (toluene, 200 C, 1h). From 40 mg (0.11
mmol) of bis(allene) (+)ꢀ5e, and after chromatography of the residue using hexanes/ethyl acetate
(2:1) as eluent gave compound (–)ꢀ7e (24 mg, 61%) as a colorless oil; [α]D = –109.4 (c 0.2,
1
o
CHCl3); HꢀNMR (300 MHz, CDCl3, 25 C) δ 7.34 (m, 5H), 7.21 (d, 1H, J = 7.2 Hz), 7.04 (m,
4H), 5.53 (d, 1H, J = 2.0 Hz), 5.37 (dd, 1H, J = 4.7, 0.9 Hz), 5.09 (d, 1H, J = 1.4 Hz), 4.97 (d, 1H,
J = 1.9 Hz), 4.83 (m, 1H), 4.58 (d, 1H, J = 4.7 Hz), 3.87 (td, 1H, J = 13.7, 4.3 Hz), 3.20 (m, 1H),
3.13 (s, 3H), 2.83 (m, 1H), 2.22 (m, 1H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ 165.7, 157.3, 151.2,
151.0, 146.4, 138.2, 137.4, 129.5 (2C), 128.6 (2C), 128.1 (2C), 127.1, 122.2, 117.1, 115.5 (2C),
113.5, 81.8, 62.1, 59.5, 41.4, 32.1; IR (CHCl3) ν 1763; HRMS (ES) calcd for C24H23NO3[M]+
373.1678; found: 373.1692.
Azocineꢀβꢀlactam (–)ꢀ7f. Microwave heating (toluene, 175 oC, 1h). From 50 mg (0.12 mmol)
of bis(allene) (+)ꢀ5f, and after chromatography of the residue using hexanes/ethyl acetate (2:1) as
1
eluent gave compound (–)ꢀ7f (24 mg, 47%) as a colorless oil; [α]D = –30.0 (c 0.4, CHCl3); Hꢀ
o
NMR (300 MHz, CDCl3, 25 C) δ 7.31 (m, 4H, Ph), 7.08 (m, 3H), 6.83 (d, 2H, J = 8.9 Hz), 5.53
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 30
26
1
2
3
4
5
6
7
8
9
(d, 1H, J = 2.0 Hz), 5.36 (dd, 1H, J = 4.7, 0.8 Hz), 5.10 (d, 1H, J = 2.0 Hz), 4.94 (d, 1H, J = 2.0
Hz), 4.83 (m, 1H), 4.57 (d, 1H, J = 4.7 Hz), 3.80 (m, 4H), 3.19 (m, 1H), 3.15 (s, 3H), 2.79 (m, 1H),
2.21 (m, 1H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ 167.0, 157.4, 151.8, 146.9, 138.2, 136.6, 129.8
(2C), 129.5 (2C), 126.5, 126.2, 125.2, 115.5 (2C), 113.6, 113.5 (2C), 113.5, 78.9, 63.5, 55.0, 53.10,
41.4, 30.1; IR (CHCl3) ν 1764; HRMS (ES) calcd for C25H25NO4[M]+ 403.1784; found 403.1782.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
Azocineꢀβꢀlactam (–)ꢀ7g. Microwave heating (toluene, 225 C, 1h). From 50 mg (0.15
mmol) of bis(allene) (–)ꢀ5g, and after chromatography of the residue using hexanes/ethyl acetate
(1:1) as eluent gave compound (–)ꢀ7g (27 mg, 54%) as a colorless oil; [α]D = –65.9 (c 0.5, CHCl3);
1HꢀNMR (300 MHz, CDCl3, 25 oC) δ 7.35 (m, 5H), 5.28 (d, 1H, J = 1.9 Hz), 5.14 (d, 1H, J = 1.6
Hz), 4.83 (s, 1H), 4.70 (m, 4H), 4.24 (d, 1H, J = 4.4 Hz), 3.73 (td, 1H, J = 13.8, 3.9 Hz), 3.61 (s,
3H), 3.04 (dd, 1H, J = 13.6, 4.6 Hz), 2.68 (td, 1H, J = 14.1, 4.9 Hz), 2.19 (ddd, 1H, J = 14.4, 3.7,
2.0 Hz), 1.80 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 oC) δ 167.0, 148.8, 146.4, 144.9, 137.4, 128.3
(2C), 127.9 (2C), 127.7, 124.0, 114.0, 112.7, 82.9, 72.2, 59.4, 58.5, 41.2, 32.0, 18.2; IR (CHCl3) ν
1757; HRMS (ES) calcd for C20H23NO3[M]+ 325.1678; found 325.1693.
o
Azocineꢀβꢀlactam (–)ꢀ7h. Microwave heating (toluene, 185 C, 3h). From 40 mg (0.10
mmol) of bis(allene) (+)ꢀ5h, and after chromatography of the residue using hexanes/ethyl acetate
(2:1) as eluent gave compound (–)ꢀ7h (21 mg, 52%) as a colorless oil; [α]D = –29.7 (c 0.4, CHCl3);
1HꢀNMR (300 MHz, CDCl3, 25 oC) δ: 7.28 (m, 10H), 5.48 (d, 1H, J = 2.0 Hz), 5.10 (d, 1H, J = 1.8
Hz), 4.83 (m, 5H), 4.38 (d, 1H, J = 4.7 Hz), 3.79 (m, 1H), 3.39 (s, 3H), 3.12 (dd, 1H, J = 13.4, 4.5
o
Hz), 2.83 (m, 1H), 2.25 (ddd, 1H, J = 14.1, 3.9, 1.7 Hz); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ:
167.5, 159.9, 148.8, 147.1, 146.9, 141.2, 130.3, 128.4 (3C), 128.4 (2C), 128.0 (2C), 127.7, 127.6
(2C), 115.3, 113.2, 83.3, 72.5, 59.0, 53.4, 41.2, 32.2; IR (CHCl3) ν 1758; HRMS (ES) calcd for
C25H25NO3[M]+ 387.1834; found 387.1828.
ACS Paragon Plus Environment

Page 27 of 30
The Journal of Organic Chemistry
27
1
2
3
4
5
6
Azocineꢀβꢀlactam (–)ꢀ7i. Microwave heating (toluene, 200 oC, 2h). From 40 mg (0.14 mmol)
of bis(allene) (+)ꢀ5i, and after chromatography of the residue using hexanes/ethyl acetate (1:2) as
7
8
9
1
eluent gave compound (–)ꢀ7i (23 mg, 58%) as a colorless oil; [α]D = –37.5 (c 0.8, CHCl3); Hꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (300 MHz, CDCl3, 25 oC) δ 5.35 (d, 1H, J = 1.7 Hz), 5.16 (d, 1H, J = 1.9 Hz), 4.86 (t, 1H, J
= 1.7 Hz), 4.76 (d, 1H, J = 1.7 Hz), 4.52 (dd, 1H, J = 4.3, 1.1 Hz), 4.08 (d, 1H, J = 4.2 Hz), 3.74
(m, 1H), 3.49 (s, 3H), 3.04 (m, 2H), 2.23 (s, 3H), 2.18 (m, 1H), 1.70 (d, 3H, J = 0.8 Hz); 13CꢀNMR
(75 MHz, CDCl3, 25 oC) δ 169.4, 166.6, 148.1, 146.0, 137.1, 128.3, 114.4, 113.2, 85.2, 60.0, 58.8,
41.4, 31.8, 20.6, 18.8; IR (CHCl3) ν 1755; HRMS (ES) calcd for C15H19NO4[M]+ 277.1314; found:
277.1315.
o
Azocineꢀβꢀlactam (–)ꢀ7j. Microwave heating (toluene, 200 C, 1.5h). From 50 mg (0.15
mmol) of bis(allene) (+)ꢀ5j, and after chromatography of the residue using hexanes/ethyl acetate
(1:1) as eluent gave compound (–)ꢀ7j (24 mg, 48%) as a colorless oil; [α]D = –25.3 (c 0.5, CHCl3);
1HꢀNMR (300 MHz, CDCl3, 25 oC) δ 7.26 (m, 5H), 5.48 (d, 1H, J = 1.5 Hz), 5.18 (d, 1H, J = 1.9
Hz), 4.95 (t, 1H, J = 1.7 Hz), 4.87 (d, 1H, J = 1.5 Hz), 4.64 (dd, 1H, J = 4.3, 1,1 Hz), 4.19 (d, 1H, J
= 4.3 Hz), 3.79 (td, 1H, J = 13.2, 3.8 Hz), 3.58 (s, 3H), 3.31 (m, 1H), 3.17 (m, 1H), 2.36 (ddd, 1H,
o
J = 13.9, 3.7, 1.6 Hz), 1.94 (s, 3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 169.4, 166.2, 147.0,
146.7, 139.2, 132.3, 128.1 (2C), 127.4 (2C), 127.4, 119.6, 117.0, 113.8, 85.8, 60.5, 58.9, 41.6, 31.8,
20.7; IR (CHCl3) ν 1759; HRMS (ES) calcd for C20H21NO4[M]+ 339.1471; found: 339.1469.
o
Azocineꢀβꢀlactam (–)ꢀ7k. Microwave heating (toluene, 200 C, 1h). From 50 mg (0.14
mmol) of bis(allene) (+)ꢀ5k, and after chromatography of the residue using hexanes/ethyl acetate
(1:1) as eluent gave compound (–)ꢀ7k (21 mg, 42%) as a colorless oil; [α]D = –5.1 (c 0.6, CHCl3);
o
1HꢀNMR (300 MHz, CDCl3, 25 C) δ 7.21 (d, 2H, J = 8.9 Hz), 6.82 (d, 2H, J = 8.9 Hz), 5.48 (d,
1H, J = 1.6 Hz), 5.19 (d, J = 1.8 Hz), 4.94 (s, 1H), 4.85 (d, 1H, J = 1.5 Hz), 4.62 (dd, 1H, J = 4.2,
0.9 Hz), 4.18 (d, 1H, J = 4.3 Hz), 3.76 (m, 4H), 3.56 (s, 3H), 3.23 (m, 2H), 2.34 (m, 1H), 1.99 (s,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 30
28
1
2
3
4
5
6
7
8
9
o
3H); 13CꢀNMR (75 MHz, CDCl3, 25 C) δ 169.5, 166.3, 158.7, 147.2, 147.0, 138.4, 131.7, 131.2,
128.8 (2C), 117.0, 113.6, 113.4 (2C), 85.7, 60.6, 58.8, 55.2, 41.5, 31.8, 20.8; IR (CHCl3) ν 1757;
HRMS (ES) calcd for C21H23NO5[M]+ 369.1576; found: 369.1571.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Acknowledgment. Support for this work by MINECO (Projects CTQ2012ꢀ33664ꢀC02ꢀ01,
CTQ2012ꢀ33664ꢀC02ꢀ02, and CTQ2010ꢀ20714ꢀC02ꢀ01) are gratefully acknowledged. G. G. C.
thanks the MEC for a predoctoral grant.
Supporting Information Available: Computational details, cartesian coordinates as well as
copies of the 1H NMR and 13C NMR spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) The βꢀlactam nucleus is the key structural motif in biologically relevant compounds such as
antibiotics, enzyme inhibitors, neurotherapeutics, antitumorals, and gene activators. For
selected references, see: (a) Page, M. G. P.; Dantier, C.; Desarbre, E. Antimicrob. Agents
Chemother. 2010, 54, 2291. (b) Banik, B. K.; Banik, E.; Becker, F. F. In Topics in
Heterocyclic Chemistry, vol. 22, pp. 349, Banik, B. K., Ed.; SpringerꢀVerlag: Berlinꢀ
Heidelberg, 2010. (c) Payne, D. J. Science 2008, 321, 1644. (d) Spencer, J.; Walsh, T. Angew.
Chem. Int. Ed. 2006, 45, 1022. (e) Fisher, J. F.; Meroueh, S. O.; Mobashery, S. Chem. Rev.
2005, 105, 395. (f) Miller, T. M.; Cleveland, D. W. Science 2005, 307, 361. (g) Veinberg, G.;
Vorona, M.; Shestakova, I.; Kanepe, I.; Lukevics, E. Curr. Med. Chem. 2003, 10, 1741.
ACS Paragon Plus Environment

Page 29 of 30
The Journal of Organic Chemistry
29
1
2
3
4
5
6
7
8
9
(2) For selected recent reviews, see: (a) Kamath, A.; Ojima, I. Tetrahedron 2012, 68, 10640. (b)
Alcaide, B.; Almendros, P. Chem. Rec. 2011, 11, 311. (c) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Rev. 2007, 107, 4437.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) For selected examples, see: (a) Kettle, J. G.; Roberts, D.; Joule, J. A. Heterocycles 2010, 82,
349. (b) Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465. (c) Winkler, J. D.;
Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425. (d) Valencia, E.; Fajardo, V.; Freyer, A. J.;
Shamma, M. Tetrahedron Lett. 1985, 26, 993.
(4) (a) Lien, E. J.; Lien, L. L.; Tong, G. L. J. Med. Chem. 1971, 14, 846. (b) Thorsett, E. D.;
Harris, E. E.; Aster, S. D.; Peterson, E. R.; Snyder, J. P.; Springer, J. P.; Hirshfield, J.;
Tristan, E. W.; Patchett, A. A.; Ulm, E. H.; Vassil, T. C. J. Med. Chem. 1986, 29, 251.
(5) For reviews on allene chemistry, see: (a) Progress in Allene Chemistry (issue 9, themed
collections), Chem. Soc. Rev. 2014, 43, 2879ꢀ3205; Alcaide, B.; Almendros, P., Eds. (b)
Lechel, T.; Pfrengle, F.; Reissig, H.ꢀU.; Zimmer, R. ChemCatChem 2013, 5, 2100. (c) Yu, S.;
Ma, S. Angew. Chem. Int. Ed. 2012, 51, 3074. (d) Krause, N.; Winter, C. Chem. Rev. 2011,
111, 1994.
(6) For reviews, see: (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Soc. Rev. 2014, 43,
3106. (b) Stamm, R.; Hopf, H. Beilstein J. Org. Chem. 2013, 9, 36. (c) Hopf, H.;
Markopoulus, G. Beilstein J. Org. Chem. 2012, 8, 1936.
(7) Treatment of 1,5ꢀbis(allenes) in xylene at reflux temperature afforded tailꢀtoꢀtail [2+2]
cycloadducts in moderate to good yields: Jiang, X.; Cheng, X.; Ma, S. Angew. Chem. Int. Ed.
2006, 45, 8009.
(8) Terminal alkynyldioxolanes
1
were prepared from imines of (R)ꢀ2,3ꢀOꢀ
isopropylideneglyceraldehyde as we previously described: (a) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Commun. 1999, 1913. (b) Alcaide, B.; Almendros, P.; Aragoncillo, C.;
Redondo, M. C. J. Org. Chem. 2007, 72, 1604.
ACS Paragon Plus Environment