Synthetic and mechanistic investigations on the rearrangement of 2,3-unsaturated 1,4-bis(alkylidene)carbenes to enediynes

Article abstract of DOI:10.1002/ejoc.200601137

The synthesis of 3,4-ene-1,5-diynes, the key structural moiety present in several naturally occurring antitumor antibiotics, from 1,2-enedialdehydes under two different experimental conditions is reported. One method involves the dibromomethylenation of dialdehydes under Corey-Fuchs conditions (CBr ₄, Ph₃P, and Zn) and treatment of the resulting tetrabromides with nBuLi or LDA to afford enediynes. The second method involves a base-mediated reaction of enedialdehydes with diethyl (1-diazo-2-oxopropyl) phosphonate (Bestmann-Ohira reagent) and subsequent transformation of the bis(diazo) compounds generated in situ to enediynes. While the transformation of bis(diazo) compounds to enediynes could take place exclusively through alkylidene-carbenes, generated in situ by geminal elimination of N₂, an alternative pathway, involving the vicinal elimination of HBr to afford an intermediate bromoalkyne and its subsequent metal-halogen exchange and protonation during workup, exists for the bis(dibromoalkylidenes). However, our deuterium-labeling experiments with a model substrate, deuterated p-methoxybenzylidene dibromide, established the predominance of the alkylidenecarbenes, generated in situ by metal-halogen exchange and elimination, for this substrate and, by analogy, for the tetrabromides as well. The scope of this novel methodology was extended to the synthesis of various heteroatom-based (S, Se, and P) enediynes by quenching the acetylides with suitable electrophiles. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200601137

FULL PAPER
DOI: 10.1002/ejoc.200601137
Synthetic and Mechanistic Investigations on the Rearrangement of
2,3-Unsaturated 1,4-Bis(alkylidene)carbenes to Enediynes
Bichismita Sahu,[a] Rajendran Muruganantham,[a] and Irishi N. N. Namboothiri*[a]
Dedicated to Professor Jayaraman Chandrasekhar on the occasion of his 55th birthday
Keywords: Vinylidenecarbene / Enediyne / Corey–Fuchs reaction / Bestmann–Ohira reagent / Enynes / Rearrangement
The synthesis of 3,4-ene-1,5-diynes, the key structural moi-
ety present in several naturally occurring antitumor anti-
biotics, from 1,2-enedialdehydes under two different experi-
mental conditions is reported. One method involves the di-
bromomethylenation of dialdehydes under Corey–Fuchs con-
ditions (CBr4, Ph3P, and Zn) and treatment of the resulting
tetrabromides with nBuLi or LDA to afford enediynes. The
second method involves a base-mediated reaction of enedial-
dehydes with diethyl (1-diazo-2-oxopropyl)phosphonate
(Bestmann–Ohira reagent) and subsequent transformation of
the bis(diazo) compounds generated in situ to enediynes.
While the transformation of bis(diazo) compounds to ene-
diynes could take place exclusively through alkylidene-
carbenes, generated in situ by geminal elimination of N2, an
alternative pathway, involving the vicinal elimination of HBr
to afford an intermediate bromoalkyne and its subsequent
metal-halogen exchange and protonation during workup, ex-
ists for the bis(dibromoalkylidenes). However, our deute-
rium-labeling experiments with a model substrate, deuter-
ated p-methoxybenzylidene dibromide, established the pre-
dominance of the alkylidenecarbenes, generated in situ by
metal-halogen exchange and elimination, for this substrate
and, by analogy, for the tetrabromides as well. The scope of
this novel methodology was extended to the synthesis of
various heteroatom-based (S, Se, and P) enediynes by
quenching the acetylides with suitable electrophiles.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
hydroarene diradicals 3, and (d) abstraction of hydrogen
from DNA by the 1,4-dehydroarene diradicals 3, thereby
inflicting permanent damage on the genetic material
(Scheme 1). The high potency shown by the structurally
complex, natural, enediyne antibiotics motivated numerous
groups to design and synthesize simpler functional analogs
of these enediyne antibiotics.[5]
Introduction
The irreversible cleavage of duplex DNA in tumor cells
is central to combating cancer.[1] Although several natural[2]
and synthetic[3] organic compounds exhibit DNA-cleavage
activity, the application of many such compounds is se-
verely limited by their scarcity, complexities associated with
constructing their molecular structures, or generating the
reactive species under biological conditions.[4] However, five
different classes of natural products possessing a (Z)-3-
hexen-1,5-diyne moiety, such as calicheamicin, esperamicin,
dynemicin, kedarcidin, and C-1027 have attracted enor-
mous attention due to their excellent DNA-cleaving abil-
ity.[5] These natural products operate through a four-stage
mechanism, which involves (a) the recognition of and bind-
ing to DNA by a specific structural feature covalently
bonded or complexed to the enediyne, (b) activation of the
enediyne 1 towards Bergman cyclization[6] by a unique trig-
gering mechanism, (c) Bergman cyclization to give 1,4-de-
Scheme 1.
[a] Department of Chemistry, Indian Institute of Technology,
Bombay,
Construction of Z-enediyne subunits, in both linear and
cyclic form, has been extensively carried out by various
metal-mediated methods.[7–17] These include the Pd-cata-
lyzed alkynylation[7] of 1,2-dihalides[7,8] or 1,2-ditri-
Mumbai 400 076, India
Fax: +91-22-2576-7152
E-mail: irishi@iitb.ac.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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B. Sahu, R. Muruganantham, I. N. N. Namboothiri
FULL PAPER
flates[9,10] and the coupling of vinyl/alkynyl stannanes,[11] alkylidenecarbene from 8d by metal-halogen exchange and
boranes,[12] cuprates,[13] Li/Mg[14] and Zn[15] compounds, elimination[23] appeared to be the most convenient method,
tellurides,[16] and carbenoids.[17] However, these procedures as 8d was easily accessible by the one-carbon elongation of
are often complicated by the cost and scarcity of 1,2-diha- corresponding aldehydes[32–34] or ketones[35] with the well-
lides, the formation of complex mixtures in the case of tri- known Corey–Fuchs method of dihalomethylenation.[32]
flates,[9] and the requirement of multistep reaction se-
quences and highly sensitive and often toxic organometallic
reagents. Alternative strategies for the synthesis of en-
ediynes, though limited in scope, focused on the generation
of a double bond between and in conjugation with a 1,5-
diyne.[18–20] Thermal (Diels–Alder),[18] photochemical (Nor-
rish type II)[19] and various elimination[20] methods belong
to this category.
We sought a methodology that is conceptually novel and
operationally simple for the synthesis of functional analogs
of the enediyne antibiotics. Our approach, which is based
on the Fritsch–Buttenberg–Wiechell (FBW) rearrange-
ment[21] of a vinylidenecarbene to its corresponding acetyl-
Scheme 3.
At first, we used commercially available o-phthalal-
dehyde 11a as the model substrate and subjected it to dibro-
momethylenation under the Corey–Fuchs conditions with
CBr4 and PPh3 (Table 1). The desired product 12a was iso-
lated in low yield (42%) when stoichiometric amounts of
CBr4 were used in conjunction with 4 equiv. each of Ph3P
and Zn (Table 1, Entry 1). Although marginal improvement
in the yield (56%) was noticed when the amounts of CBr4,
PPh3, and Zn were increased 1.5-fold (Table 1, Entry 2),
doubling the amounts of all the three reagents had a dra-
matic effect, providing the desired tetrabromide 12a in 94%
yield (Table 1, Entry 3). Entries 4 and 5 (Table 1) show that
decreasing the amount of Zn or excluding it completely has
a detrimental effect on the yield.
ene, does not require complex organometallic reagents and
[22]
difficult reaction conditions. Although acetylenes
have
been synthesized by the FBW rearrangement,[21,23–25] the
synthesis of enediynes 1 from 1,2-enedialdehydes 5 by the
2,3-unsaturated bis(vinylidene)carbene 7 (Scheme 2)[26] re-
mained an unexplored strategy until we recently reported
our preliminary results.[27] This is despite the application of
the FBW rearrangement to numerous systems in which the
migrating group is an alkyl, aryl, or heteroaryl group.[28,29]
Table 1. Optimization of the reaction conditions for the dibro-
momethylenation of o-phthalaldehyde 11a.
Entry
CBr4
(equiv.)
PPh3
(equiv.)
Zn
(equiv.)
Yield
(%)[a]
1
2
3
4
5
2
3
4
4
4
4
6
8
8
8
4
6
8
7
0
42
56
94
89
68
Scheme 2.
[a] Isolated yield after purification by silica gel column chromatog-
raphy.
Under the optimized conditions described above, we sub-
jected a variety of 2,3-unsaturated 1,4-dicarbonyl com-
Results and Discussion
Since our approach relies on the rearrangement by a 1,2- pounds, namely 1,2-enedialdehydes 11b–h, to the dibro-
shift of bis(vinylidene)carbene 7 to enediyne 1, we needed momethylenation conditions (Table 2). The desired tetra-
efficient geminal elimination methods. Various such meth- bromides 12b–h were isolated in good to excellent yields
ods available in the literature for the generation of alkyl- (Table 2, Entries 2–8).
idenecarbene 9 (Scheme 3)[23–24] include deprotonation–
The transformation of tetrabromides 12a–h to enediynes
elimination from 8a, desilylation–elimination from 8b, 13a–h was performed under two different conditions, nBuLi
metal-halogen exchange followed by elimination from 8c[30] or LDA. At first, the experimental conditions for the
or 8d,[23] extrusion of N2 from 8e,[31] and cycloelimination nBuLi-mediated reaction were optimized with tetrabromide
by pyrolysis from 8f. Among these, the generation of an 12a as the model substrate (Table 3). The yields were 14%
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Enediynes from 2,3-Unsaturated 1,4-Bis(alkylidene)carbenes
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Table 2. Conversion of various 1,2-enedialdehydes 11 to tetrabro-
mides 12.
Table 3. Optimization of the reaction conditions for the nBuLi-me-
diated transformation of tetrabromide 12a to enediyne 13a.
Entry
nBuLi (equiv.)
Solvent
Yield (%)[a] of 13a
1
2
3
4
5
6
7
2
4
5
6
5
5
5
n-hexane
n-hexane
n-hexane
n-hexane
THF
14
55
96[b]
93
23
78
57
toluene
benzene/toluene
[a] Isolated yield after purification by silica gel column chromatog-
raphy. [b] 5 equiv. of nBuLi were required to obtain the best yields
even upon scale up of the reaction (from 1 mmol to 5 mmol).
were subsequently isolated as their bis(trimethylsilyl) deriv-
atives 13g and 13h (R = TMS) by quenching the reaction
mixtures with TMSCl (Table 4, Entries 7–8).
In a parallel strategy, tetrabromides 12a–h were treated
with LDA. Optimization of the LDA-mediated transforma-
tion of tetrabromide 12a to enediyne 13a was carried out
by screening different solvents and by varying the amount
of LDA (Table 5). Although stoichiometric amounts of
LDA were insufficient to obtain the desired enediyne in a
considerable amount (Table 5, Entry 1), increasing the
amount of LDA in toluene led to a gradual increase in the
yield of 13a (Table 5, Entries 2–5). The best yield of 13a
(88%) was obtained when excess (6 equiv.) LDA in toluene
was used (Table 5, Entry 4). When the same amount of
LDA was used in other solvents such as THF, n-hexane, or
toluene, the yields were only moderate (Table 5, Entries 6–
8).
[a] The dialdehydes 11a and 11h were commercially available. All
other dialdehydes (11b–g) were prepared in the laboratory follow-
ing published procedures; see ref.[36]. [b] Isolated yield after purifi-
cation by silica gel column chromatography. [c] 12a, reported in
ref.,[37] was prepared by a procedure similar to the one we recently
reported; see ref.[27] [d] Ar = 4-OMe-Ph.
The optimized conditions described above (6 equiv. of
LDA in toluene at –78 °C) were employed for the conver-
sion of tetrabromides 12b–h to enediynes 13b–h (Table 6).
and 55% when 2 equiv. and 4 equiv. of nBuLi in n-hexane, As in the case of the nBuLi-mediated reactions of 12g and
respectively, were used (Table 3, Entries 1 and 2). However, 12h (Table 4, Entries 7–8), the parent enediynes were trans-
with 5 equiv. and 6 equiv. of nBuLi in n-hexane, tetrabro- formed in situ into their TMS derivatives for convenient
mide 12a afforded the desired enediyne 13a in excellent isolation and characterization (Table 6, Entries 7–8).
yield (96% and 93%, respectively, Table 3, Entries 3 and 4).
The strategy developed for the synthesis of enediynes 13
The yields were much lower when the reaction was carried from enedialdehydes 11 through bis(alkylidene dibromides)
out with the same amount of nBuLi (5 equiv.) in other sol- 12 involved two steps requiring isolation and purification
vents such as THF, toluene, or a benzene/toluene mixture of the intermediate 12. Furthermore, the transformation of
(Table 3, Entries 5–7).
12 to enediynes 13 required strong bases such as nBuLi or
Under the optimized conditions described above LDA. Therefore, we embarked on the idea of developing
(5 equiv. of nBuLi in n-hexane at –78 °C), tetrabromides another strategy, which involved a one-pot transformation
12b–h were subsequently subjected to the nBuLi-mediated of enedialdehydes 11 to enediynes 13 through bis(diazo)
transformation to enediynes 13b–h (Table 4, Entries 2–8). compounds. Although dialkyl (diazomethyl)phosphonate
Although tetrabromides 12b–f provided their corresponding (14, Seyferth–Colvin–Gilbert reagent, DAMP) has been re-
enediynes 13b–f in very high yields (Table 4, Entries 2–6), acted with ketones,[31] and its synthetic equivalent dialkyl
complex mixtures were isolated in the cases of tetrabro- (1-diazo-2-oxopropyl)phosphonate (15, Bestmann–Ohira
mides 12g and 12h due to poor stability of the parent ene- reagent, BOR) has been reacted with aldehydes[44] for the
diynes under these experimental conditions. The enediynes synthesis of acetylenes,[45] the synthesis of enediynes 13
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Table 4. nBuLi-mediated transformation of tetrabromides 12 to
enediynes 13.
Table 5. Optimization of the reaction conditions for the LDA-me-
diated transformation of tetrabromide 12a to enediyne 13a.
Entry
LDA
(equiv.)
Solvent
Yield (%)[a] of 13a
1
2
3
4
5
6
7
8
2
4
5
6
7
6
6
6
toluene
toluene
toluene
toluene
toluene
Ͻ5
41
79
88
84
60
66
61
THF
n-hexane
benzene/toluene (1:1)
[a] Isolated yield after purification by silica gel column chromatog-
raphy.
Table 6. LDA-mediated transformation of tetrabromide 12 to ene-
diyne 13.
Entry
Tetrabromide 12 Enediyne 13
Yield (%)[a]
1
2
3
4
5
6
7
8
12a
12b
12c[b]
12d
12e
12f
13a
13b
13c
13d
13e
13f
13g
13h
88
68
84
44
87
61
12g
12h
26[c]
31[c]
[a] Isolated yield after purification by silica gel column chromatog-
raphy. [b] Heated at 70 °C for 4 h. [c] The parent enediyne, due to
its instability under these experimental conditions, was isolated as
its bis(trimethylsilyl) derivative (R = TMS).
[a] Isolated yield after purification by silica gel column chromatog-
raphy; 13a–e and 13h are known compounds; see ref.[38–43] [b] Ar
= 4-OMe-Ph. [c] The parent enediyne (R = H), due to its instability
under these experimental conditions, was isolated as its bis(tri-
methylsilyl) derivative (R = TMS).
from enedialdehydes 11 with either of these reagents re-
mains unreported heretofore.
Initially, the efficacy of DAMP (14) was investigated for
the transformation of enedialdehydes 11 to enediynes 13 from commercially available diethyl (2-oxopropyl)phos-
with phthalaldehyde 11a as the model substrate. However, phonate and stored without any appreciable decomposition.
the desired enediyne 13a was isolated only in low yield More importantly, only mild conditions are required for the
(15%) even with an excess (6 equiv.) of DAMP (14) in the key step.
presence of tBuOK as the base at low temperature (–78 °C)
The reaction of naphthalene-1,2-dicarbaldehyde (11d)
for 12 h. The problems associated with the multi-step prep- with BOR (15, 3 equiv.) mediated by K2CO3 (4 equiv.) at
aration of the reagent, its poor storability, the requirement room temperature provided the desired enediyne 13d in
of a strong base such as tBuOK, and prolonged mainte- 38% yield (Table 7, Entry 1). Increasing the amount of the
nance of low temperature (for 12 h) prompted us to employ reagent (to 4 equiv.) improved the yield considerably
an alternative reagent such as BOR (15),[44,45] which can be (Table 7, Entry 2). However, a strong improvement in the
prepared conveniently on a multi-gram scale in a single step yield of 13d (84%) was noticed when the reaction mixture
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Enediynes from 2,3-Unsaturated 1,4-Bis(alkylidene)carbenes
FULL PAPER
was maintained at 0 °C initially for a period of 30 min halogen; R1 or R2 = H, Scheme 3), a β-elimination and sub-
(Table 7, Entry 3). A further increase in the amount of rea- sequent metal-halogen exchange of a haloacetylene (10, R1
gents had only a marginal effect (Table 7, Entry 4).
or R2 = halogen, Scheme 3) is assumed to be the mechan-
istic pathway.[47] While the carbene/carbenoid pathway, ap-
parently the only pathway available, has been widely ac-
cepted for the former,[23] the β-elimination pathway for the
latter remained speculative. This ambiguity exists for the
transformation of 1-haloalkenes possessing a β-hydrogen
(e.g. 8, X = halogen, Y = H; R1 or R2 = H, Scheme 3) to
the corresponding acetylenes (10, R1 or R2 = H, Scheme 3)
as well. For instance, an alkylidenecarbene was suggested
as an intermediate in the formation of phenylacetylene from
β-styryl bromide in the presence of PhLi.[48] From stereo-
chemical study and low-temperature experiments, a car-
benoid was found to be the intermediate in the conversion
of 1-halo-2-arylpropene to the corresponding acetylene.[49]
However, Schlosser and coworkers ruled out the involve-
ment of any alkylidenecarbene in the reaction of β-chloro-
styrene with organolithium, which produced the corre-
sponding acetylene.[50] Based on their labeling experiments,
an alternate mechanism (E2CB) was proposed.
In view of the above, we considered two alternative
mechanistic pathways for the formation of enediynes 13,
i.e. the carbene pathway and the β-elimination pathway and
proposed to establish the pathway that is operative by tak-
ing 2-aryl 1,1-dibromoethylene 16 as the model substrate
(Scheme 4). In dibromide 16, the more sterically hindered
bromine[51] is likely to undergo metal-halogen exchange to
provide carbenoid 17. Carbenoid 17 or its α-elimination
product vinylidenecarbene 18 (path A) would undergo a
1,2-shift (FBW rearrangement) to afford acetylene 19.[52]
Alternatively, carbenoid 17 could isomerize to give 20,[53]
which is poised to undergo HBr elimination rather than α-
elimination since Br and the β-H are trans to each other,
affording the acetylide 21, which would furnish acetylene
19 upon aqueous workup.
Table 7. Optimization of the reaction conditions for the transfor-
mation of dialdehyde 11d to enediyne 13d with BOR (15).
Entry
15
K2CO3
Temp [°C]
Time [h] Yield (%)[a]
(equiv.) (equiv.)
of 13d
1
2
3
4
3
4
4
5
4
5
5
6
room temp.
room temp.
0 °C to room temp. 0.5–11
0 °C to room temp. 0.5–11
8
7
38
53
84
82
[a] Isolated yield after purification by silica gel column chromatog-
raphy.
Under the optimized conditions described above, we
transformed a variety of 1,2-dialdehydes 11a–b, d–f, and g–
h to their corresponding enediynes in good yields (Table 8).
Table 8. Conversion of dialdehydes 11 to enediynes 13 with BOR.
Entry
Aldehyde
Enediyne
Time
[h]
Yield (%)[a]
11
13
of 13
1
2
3
4
5
6
7
11a
11b
11d
11e
11f
11g
11h
13a
13b
11.5
7.5
11
15.5
6.5
15
72
79
84
76
13d
13e
13f
64
13g[b]
13h[b]
[c]
In order to ascertain the mechanism which is operative
in the conversion of alkylidene dibromide 16 to acetylene
19 (and by analogy tetrabromide 12 to enediyne 13), we
performed a preliminary experiment as shown in Scheme 5.
Thus, alkylidene dibromide 22 was prepared from p-meth-
oxybenzaldehyde in 64% yield.[54] Dibromide 22 was then
treated with nBuLi (2 equiv.) under conditions similar to
those employed for the desired transformation of tetrabro-
8
45
[a] Isolated yield after purification by silica gel column chromatog-
raphy. [b] R = H. [c] Decomposition on silica gel.
Mechanistic Studies
It is well documented in the literature that 1,1-dihaloalk- mides 12 to enediynes 13.[55] The reaction mixture was
enes (e.g. 8, X, Y = halogen, Scheme 3), on treatment with quenched with excess TMSCl (3 equiv.) in anticipation that
a strong base such as nBuLi or LDA, produce acetylenes if the carbene mechanism were operative (Scheme 4, path
(vide supra). In the case of 2,2-disubstituted 1,1-dihaloalk- A), the product would be 25, which is expected to form by
enes (8, X = Y = halogen; R1 and R2 ϶ H, Scheme 3), metal-halogen exchange to form the vinylidenecarbene 23,
metal-halogen exchange followed by a geminal elimination followed by an intramolecular 1,2-shift. No incorporation
to generate alkylidenecarbenes/carbenoids 9, which are con- of an external electrophile is expected. On the other hand,
verted to acetylenes 10 by a 1,2-shift of one of the β-substit- path B, which involves a deprotonation step, would provide
1
uents (FBW rearrangement), are the mechanistic steps.[23,28] TMS-acetylene 26. Analysis of the product by H NMR
For instance, the transformation of 1,1-dihalo-2,2-diaryl- revealed that only alkyne 25 was formed (72%).[56] There
ethylenes (8, X = Y = halogen; R1 = R2 = Ar, Scheme 3) was no evidence for the formation of TMS-acetylene 26.
to diarylacetylenes (10, R1 = R2 = Ar, Scheme 3) involves
Encouraged by the above observation, though inconclus-
a carbenoid as an intermediate.[46] However, in the case of ive, we desired to gather more corroborative evidence by
1,1-dihaloalkenes possessing a β-hydrogen (8, X = Y = a deuterium-labeling experiment (Scheme 6). To this end,
Eur. J. Org. Chem. 2007, 2477–2489
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B. Sahu, R. Muruganantham, I. N. N. Namboothiri
FULL PAPER
Scheme 4. Proposed mechanistic pathways for the conversion of tetrabromides 12 to enediynes 13 with 16 as the model substrate.
Scheme 6. Mechanistic evaluation of the base-mediated transfor-
mation of alkylidene dibromide 28 into the acetylene 29 by a deute-
rium-labeling experiment.
Scheme 5) over β-elimination (path B). However, a substan-
tial amount of non-deuterated acetylene 25 (45.5%) is
formed by the β-elimination pathway (path B, Scheme 4)
and, by analogy, in enediyne 13.[59]
One-Pot Synthesis of Heteroatom-Based Enediynes
The critical c,d distance (distance between the two acetyl-
ene moieties) in enediynes is an important parameter in the
Scheme 5. Treatment of dibromide 22 with nBuLi and quenching
the reaction mixture with TMSCl.
Bergman cyclization.[60] Structural perturbations of en-
ediynes can affect the critical c,d distance and allow the
enediyne to cyclize even at room temperature.[61] The effect
deuterated p-methoxybenzaldehyde 27 was prepared follow- of substituents[62,63] or metal-ion complexation[64,65] on
ing literature procedure.[57] Aldehyde 27 was then converted Bergman cyclization kinetics has been investigated. How-
to the corresponding dibromide 28 (60% yield, 92.3% D, ever, existing methods for the synthesis of structurally
1H NMR). Dibromide 28 was subsequently treated with modified enediynes involve multistep protocols.[5] More im-
nBuLi (2 equiv.) as in the case of 22. The reaction mixture portantly, the direct insertion of heteroatoms such as S, Se,
1
was analyzed by H NMR after an aqueous workup. The and P, which are capable of chelating with metal ions, on
1H NMR analysis indicated that the product acetylene the terminal acetylenic moieties of enediyne appears to be
29[58] contained 50.3% of D (70% yield, see also the Sup- an attractive objective for facilitating the Bergman cycliza-
porting Information).
tion and exploring the biological properties of heteroatom-
The formation of acetylene 29 possessing 50.3% D from based enediynes.[66]
dibromide 28 possessing 92.3% D suggested an overall re-
Our methodology, especially the one involving the bis(di-
tention of 54.5% D by a 1,2-shift (FBW rearrangement). bromoalkylidene) compound 12, appeared suitable for the
This confirms that the carbene pathway (path A, Scheme 4 synthesis of heteroatom-based enediynes. Since conversion
and Scheme 5) is the predominant pathway because of the of dibromide 12 to the corresponding enediyne 13 in high
preference for α-elimination (path A, Scheme 4 and yield required excess base (5 equiv. of nBuLi or 6 equiv. of
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Enediynes from 2,3-Unsaturated 1,4-Bis(alkylidene)carbenes
FULL PAPER
LDA, Table 4, Table 6), we envisioned that the diacetylide turned our attention to the introduction of heteroatoms
30 should be amenable for trapping in situ with different such as S, Se, and P. Thus, representative examples of het-
electrophiles (Scheme 7).[67] Therefore, such an approach eroatom-substituted enediynes 31b–f were prepared in mod-
would provide a convenient entry into substituted enediynes erate to good yield with tetrabromides and commercially
in general and heteroatom-substituted enediynes in particu- available electrophiles such as Me2S2, Ph2S2, PhSeBr, and
lar.
P(O)(OEt)2Cl (Table 9, Entries 2–6).
Conclusion
Two simple and efficient methodologies for the synthesis
of enediyne analogs from 1,2-enedialdehydes have been de-
veloped. While one methodology involves the synthesis of
bis(alkylidene dibromides) from 1,2-enedialdehydes under
Corey–Fuchs conditions and subsequent treatment of the
tetrabromides with nBuLi or LDA, the second one involves
a one-pot transformation of 1,2-enedialdehydes into en-
ediynes with diethyl (1-diazo-2-oxopropyl)phosphonate
(BOR) in the presence of K2CO3. The intermediacy of a
bis(alkylidene)carbene in the conversion bis(alkylidene di-
bromides) to enediynes has been confirmed by deuterium-
labeling experiments. The scope of our methodology has
been expanded by trapping the bis(acetylides) with different
electrophiles, which provides a simple yet novel class of het-
eroatom-substituted enediynes.
Scheme 7.
To test the viability of the proposed methodology, we
converted the tetrabromide 12a to its corresponding en-
ediyne 13a under the conditions of Method A (5 equiv. of
nBuLi, n-hexane, Table 3 and Table 4) and quenched the re-
action mixture with MeI. This provided a complex mixture
from which the substituted enediyne 31a could not be iso-
lated. However, we have succeeded in synthesizing 31a in
one pot in 62% yield by employing Method B (LDA, tolu-
ene, Table 5 and Table 6) for the generation of enediyne 13a
and the trapping of its corresponding bis(acetylide) with
MeI (Table 9, Entry 1). Encouraged by this result, we
Table 9. Generation of diacetylides 30 from tetrabromides 12 with
LDA and their trapping with different electrophiles.
Experimental Section
General Procedure for Dibromomethylenation of Dialdehydes 11: To
a stirred suspension of activated Zn dust (0.520 g, 8 mmol) in dry
CH2Cl2 (20 mL) under N2 was added triphenylphosphane (2.09 g,
8 mmol). The reaction mixture was cooled to 0 °C, and carbon tet-
rabromide (1.342 g, 4 mmol) dissolved in dry CH2Cl2 (5 mL) was
added over 15 min, which resulted in an intense yellow color. At the
same temperature, 1,2-dialdehyde 11 (1 mmol) dissolved in CH2Cl2
(10 mL) was added dropwise to the reaction mixture, and the reac-
tion mixture was brought to room temp. It was allowed to stir
until the completion of the reaction, which was confirmed by TLC
analysis (ca. 3 h). The reaction mixture was diluted with water
(30 mL), the layers were separated, and the aqueous layer was fur-
ther extracted with CH2Cl2 (2ϫ20 mL). The combined organic lay-
ers were dried (anhydrous Na2SO4) and concentrated in vacuo. The
crude residue was purified by silica gel column chromatography (n-
hexane or n-hexane/ethyl acetate mixture, gradient elution) to af-
ford pure alkylidenetetrabromide 12.
1,2-Bis(2,2-dibromovinyl)benzene (12a):[37] Yellow liquid. Yield 94%
(0.415 g). IR (neat): ν = 3061 (m), 3013 (m), 2924 (m), 1596 (s),
˜
1459 (m), 1263 (m), 861 (s), 811 (m), 749 (s) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.41 (s, 2 H), 7.34–7.39 & 7.49–7.54
(AAЈBBЈ, J = 5.9, 3.3 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 93.2 (s), 128.4 (d), 128.8 (d), 134.5 (s), 135.3 (d) ppm. MS
(DCI, CH4): m/z (%) = 448, (4) [M + 6]+, 446, (6) [M + 4]+, 444
(4) [M + 2]+, 367 (25), 365 (25), 288 (45), 286 (100), 284 (54), 195
(11), 193 (11), 126 (29). HRMS (DCI, CH4): calcd. for
C10H679Br381Br [M + 2]+ 443.7182; found 443.7175. These data are
in agreement with literature data.[37]
1,2-Bis(2,2-dibromovinyl)4,5-dimethylbenzene (12b): Colorless solid.
[a] Attempted trapping of the diacetylides with ethylene 1,2-dibro-
mide provided only a complex mixture. [b] Isolated yield after puri-
fication by silica gel column chromatography. [c] 31a is a known
compound, see ref.[68]
Yield 62% (0.290 g). M.p. 95 °C. IR (CH Cl ): ν = 2922 (m), 1595
˜
2
2
(m), 1447 (m), 1265 (s), 895 (m), 741 (s) cm–1. 1H NMR (300 MHz,
CDCl3): δ = 2.26 (s, 6 H), 7.28 (s, 2 H), 7.35 (s, 2 H) ppm. 13C
Eur. J. Org. Chem. 2007, 2477–2489
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2483

B. Sahu, R. Muruganantham, I. N. N. Namboothiri
FULL PAPER
NMR (75 MHz, CDCl3): δ = 19.8 (q), 92.3 (s), 129.8 (d), 132.0 (s), 137 (10). HRMS (DCI, CH4): calcd. for C12H6O79Br81Br3
135.5 (d), 137.2 (s) ppm. MS (DCI, CH4): m/z (%) = 476 (10) [M [M + 6]+ 487.7091; found 487.7102.
+ 6]+, 474 (13) [M + 4]+, 472 (9) [M + 2]+, 395 (21), 393 (21), 316
2,3-Bis(2,2-dibromovinyl)thiophene (12h): Yellow liquid. Yield 95%
(52), 314 (100), 312 (53), 235 (12), 233 (11), 153 (14). HRMS (DCI,
(0.424 g). IR (KBr): ν = 2955 (m), 2924 (s), 2853 (m), 1682 (w),
˜
CH4): calcd. for C12H1079Br281Br2 [M + 4]+ 473.7475; found
473.7471.
1
1459 (w), 1270 (m), 1091 (w), 840 (m), 808 (s), 751 (m) cm–1. H
NMR (300 MHz, CDCl3): δ = 7.37 (ABq, J = 2.6 Hz, 2 H), 7.54
(s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 89.6 (s), 92.9 (s),
126.2 (d), 126.7 (d), 128.8 (d), 130.6 (d), 135.4 (s), 136.4 (s) ppm.
MS (DCI, CH4): m/z (%) = 456 (11) [M + 8]+, 454 (37) [M + 6]+,
452 (54) [M + 4]+, 450 (40) [M + 2]+, 448 (10) [M]+, 447 (11), 446
(35), 294 (53), 292 (100), 290 (55), 211 (12), 132 (34), 97 (19), 85
(25), 83 (19), 71 (22), 69 (15). HRMS (DCI, CH4): calcd. for
C8H4S79Br281Br2 [M + 4]+ 451.6726; found 451.6748.
1,2-Bis(2,2-dibromovinyl)4,5-dimethoxybenzene (12c): White solid.
Yield; 46% (0.230 g). M.p. 128–129 °C. IR (CH Cl ): ν = 2960 (s),
˜
2
2
2931 (s), 1599 (m), 1502 (s), 1459 (s), 1293 (s), 1210 (s), 1101 (s),
1
875 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 3.90 (s, 6 H), 7.07
(s, 2 H), 7.38 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 56.2
(q), 92.2 (s), 111.4 (d), 127.5 (s), 135.2 (d), 148.8 (s) ppm. MS (DCI,
CH4): m/z (%) = 510 (6) [M + 8]+, 508 (17) [M + 6]+, 506 (23) [M
+ 4]+, 504 (22) [M + 2]+, 502 (5) [M]+, 348 (46), 346 (100), 344
(58), 149 (100). HRMS (DCI, CH4): calcd. for C12H10O279Br381Br
[M + 2]+ 503.7394; found 503.7368.
General Procedures for the Conversion of Dialdehydes 11 to Ene-
diynes 13
Reaction of Bis(dibromoalkylidene) Compounds 12 with nBuLi.
Method A: To a stirred solution of tetrabromide 12 (0.95 mmol) in
dry n-hexane (30 mL) at –78 °C under N2 was added dropwise
nBuLi (1.9 mL, 4.75 mmol, 5 equiv., 2.5  solution in hexanes) over
20 min. Stirring was continued at the same temperature for another
3 h. The reaction mixture was then brought to room temp. over
1 h. After confirming the completion of the reaction (by TLC), the
reaction mixture was poured into cold saturated aqueous NH4Cl
(10 mL). The layers were separated, and the organic layer was
washed with water (2ϫ10 mL) and brine (10 mL), dried (anhy-
drous Na2SO4), and concentrated in vacuo. The crude residue was
purified by silica gel column chromatography (n-hexane or n-hex-
ane/ethyl acetate mixture, gradient elution) to afford pure enediyne
13. See also Tables 3 and 4.
2,3-Bis(2,2-dibromovinyl)naphthalene (12d): Light yellow solid.
Yield 88% (0.432 g). M.p. 135–137 °C. IR (CH Cl ): ν = 3068 (m),
˜
2
2
3005 (m), 1588 (s), 1276 (m), 904 (s), 843 (m), 788 (m), 679 (w),
608 (w) cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.53 (m, 4 H), 7.84
(m, 2 H), 7.99 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
93.1 (s), 127.1 (d), 128.0 (d), 128.5 (d), 132.1 (s), 132.5 (s), 135.3
(d) ppm. MS (DCI, CH4): m/z (%) = 498 (13) [M + 6]+, 496 (19)
[M + 4]+, 494 (13) [M + 2]+, 492 (3) [M]+, 338 (48), 336 (100), 334
(50), 245 (36), 243 (38), 176 (51). HRMS (DCI, CH4): calcd. for
C14H879Br281Br2 [M + 4]+ 495.7319; found 495.7320.
1,2-Bis(2,2-dibromovinyl)-4-methoxybenzene (12e): Light yellow li-
quid. Yield 66% (0.310 g). IR (neat): ν = 3006 (m), 2931 (m), 2835
˜
(m), 1601 (s), 1563 (s), 1289 (s), 1240 (s), 1036 (s), 868 (s), 754 (s)
Reaction of Bis(dibromoalkylidene) Compounds 12 with LDA.
Method B: To a stirred solution of dry diisopropylamine (0.8 mL,
5.82 mmol) in dry toluene (10 mL) at 0 °C under N2 was added
dropwise nBuLi (2.24 mL, 5.6 mmol, 2.5  solution in hexanes)
over 20 min. Stirring was continued at the same temperature for
another 2.5 h. The reaction mixture was then diluted with dry tolu-
ene (25 mL) and cooled to –78 °C. To the cooled solution was
added tetrabromide 12 (0.95 mmol) in toluene (5 mL), during
which time the solution turned yellow. The resulting solution was
stirred at the same temperature for another 3 h and gradually
brought to room temperature while being stirred overnight. The
reaction mixture was then poured into ice-cold dilute HCl (2%,
10 mL). The layers were separated, and the aqueous layer was fur-
ther extracted with toluene (2ϫ20 mL). The combined organic lay-
ers were washed with water (2ϫ10 mL) and brine (10 mL), dried
(anhydrous Na2SO4), and concentrated in vacuo. The crude residue
was purified by silica gel column chromatography (n-hexane or n-
hexane/ethyl acetate mixture, gradient elution) to afford pure en-
ediyne 13. See also Tables 5 and 6.
1
cm–1. H NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H), 6.89 (dd, J
= 8.7, 2.6 Hz, 1 H), 7.03 (d, J = 2.6 Hz, 1 H), 7.34 (s, 1 H), 7.39
(s, 1 H), 7.49 (d, J = 8.7 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 55.6 (q), 91.8 (s), 93.3 (s), 113.9 (d), 114.1 (d), 126.9
(s), 130.0 (d), 134.8 (d), 135.2 (d), 135.9 (s), 159.1 (s) ppm. MS
(DCI, CH4): m/z (%) = 480 (4) [M + 8]+, 478 (16) [M + 6]+, 476
(26) [M + 4]+, 474 (19) [M + 2]+, 472 (5) [M]+, 446 (29), 317 (65),
316 (100), 314 (65), 272 (40), 225 (44), 223 (44), 113 (52). HRMS
(DCI, CH4): calcd. for C11H8O79Br281Br2 [M + 4]+ 475.7268; found
475.7255.
2,3-Bis(2,2-dibromovinyl)-4,5-bis(4-methoxyphenyl)furan (12f): Yel-
low solid. Yield 80% (0.514 g). M.p. 119–121 °C. IR (CH Cl ): ν =
˜
2
2
2963 (w), 2840 (w), 1606 (m), 1519 (m), 1492 (w), 1265 (s), 1178
(m), 1032 (w), 761 (s) cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.78
(s, 3 H), 3.86 (s, 3 H), 6.79 (d, J = 9.1 Hz, 2 H), 6.90 (s, 1 H), 6.94
(d, J = 8.8 Hz, 2 H), 7.19 (d, J = 9.1 Hz, 2 H), 7.26 (s, 1 H), 7.45
(d, J = 8.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.2
(2ϫq), 87.1 (s), 94.9 (s), 114.0 (d), 114.4 (d), 120.9 (s), 122.8 (s),
124.1 (s), 124.4 (d), 125.3 (d), 127.2 (d), 129.2 (s), 130.9 (d), 143.2
(s), 149.6 (s), 159.3 (s), 159.5 (s) ppm. MS (MALDI): m/z (%) =
651 (2) [(M – H) + 8], 649 (6) [(M – H) + 6], 647 (9) [(M – H) +
4], 645 (6) [(M – H) + 2], 643 (2) [M – H], 379 (30), 190 (100).
Reaction with 15. Method C: To a stirred solution of 1,2-dialdehyde
11 (1 mmol) and K2CO3 (828 mg, 6 mmol) in dry MeOH (5 mL)
was added reagent 15 (880 mg, 4 mmol) at 0 °C. The reaction mix-
ture was maintained at 0 °C for 30 min and was gradually brought
to room temp. and stirred until the reaction was complete (moni-
tored by TLC, see Table 8). The reaction mixture was diluted with
water (15 mL), neutralized with dilute HCl (5%, 5 mL), and ex-
tracted with dichloromethane (3ϫ15 mL). The combined organic
layers were then washed with brine (2ϫ10 mL), dried (anhydrous
Na2SO4), and then concentrated in vacuo. The crude residue was
purified by column chromatography (silica gel, n-hexane) to afford
pure enediynes 13. See also Tables 7 and 8.
2,3-Bis(2,2-dibromovinyl)benzofuran (12g): Colorless solid. Yield
73% (0.351 g). M.p. 136–138 °C. IR (KBr): ν = 2922 (m), 2856 (w),
˜
1608 (w), 1517 (w), 1444 (w), 1345 (w), 1256 (m), 1185 (m), 1123
1
(m), 1005 (w), 929 (w), 801 (s), 745 (s) cm–1. H NMR (300 MHz,
CDCl3): δ = 7.20–7.57 (m, 4 H), 7.36 (s, 1 H), 7.37 (s, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 91.9 (s), 95.6 (s), 111.7 (d), 117.6
(s), 121.0 (d), 123.5 (d), 124.8 (d), 125.8 (s), 126.2 (d), 127.7 (d),
147.4 (s), 154.2 (s) ppm. MS (DCI, CH4): m/z (%) = 490 (3) [M +
8]+, 488 (15) [M
+
6]+, 486 (24) [M
+
4]+, 484 (17) 1,2-Diethynylbenzene (13a):[38] Yellow liquid. Yield 96% (0.114 g)
(Method A), 88% (0.105 g) (Method B), 72% (0.090 g) (Method
[M + 2]+, 446 (65), 328 (47), 326 (100), 324 (45), 166 (18), 138 (15),
2484
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2477–2489

Enediynes from 2,3-Unsaturated 1,4-Bis(alkylidene)carbenes
FULL PAPER
C). IR (neat): ν = 3291 (s), 3063 (w), 2925 (m), 2854 (w), 2109
138.1 (s), 149.7 (s), 159.2 (s), 159.6 (s) ppm. MS (ESI, Ar): m/z (%)
˜
1
(w), 1476 (m), 1439 (m), 1258 (m), 761 (s), 649 (s) cm–1. H NMR = 329 (100) [M + H]+, 214 (4), 158 (9). HRMS (ESI, Ar): calcd.
(300 MHz, CDCl3): δ = 3.34 (s, 2 H), 7.27–7.35 & 7.48–7.56 for C22H17O3 [M + H]+ 329.1178; found 329.1188.
(AAЈBBЈ, J = 5.9, 3.3 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3):
2,3-Bis[2-(trimethylsilyl)ethynyl]benzofuran (13g, R = TMS): Yellow
δ = 81.2 (d), 81.9 (s), 125.1 (s), 128.6 (d), 132.7 (d) ppm. MS (EI):
liquid. Yield 33% (0.097 g) (Method A), 26% (0.076 g) (Method
m/z (%) = 126 (100) [M]+, 98 (9), 74 (20), 63 (30). These data are
B). IR (neat): ν = 2961 (s), 2160 (s), 1449 (m), 1368 (w), 1252 (s),
˜
in agreement with literature data.[38a,38e]
1,2-Diethynyl-4,5-dimethylbenzene (13b):[39] Light yellow viscous li-
1183 (m), 1125 (s), 845 (s), 751 (s) cm–1. 1H NMR (300 MHz,
CDCl3): δ = 0.30 (s, 9 H), 0.31 (s, 9 H), 7.26–7.42 (m, 3 H), 7.62
(dt, J = 8.0, 0.7 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
–0.3 (q), 0.1 (q), 93.1 (s), 94.2 (s), 103.5 (s), 106.8 (s), 111.5 (d),
120.9 (d), 123.8 (d), 126.7 (d), 127.5 (2ϫs), 142.0 (s), 153.9 (s) ppm.
MS (DCI, CH4): m/z (%) = 310 (100) [M]+, 296 (10), 295 (16), 280
(5), 267 (7), 73 (22). HRMS (DCI, CH4): calcd. for C18H22OSi2
[M]+ 310.1209; found 310.1220.
quid. Yield 84% (0.122 g) (Method A), 68% (0.099 g) (Method B),
79% (0.121 g) (Method C). IR (CHCl ): ν = 3302 (s), 3026 (m),
˜
3
2927 (m), 2868 (w), 2111 (w), 1611 (w), 1452 (m), 1218 (s), 1025
1
(m), 907 (m), 769 (s), 670 (m), 620 (m) cm–1. H NMR (300 MHz,
CDCl3): δ = 2.20 (s, 6 H), 3.27 (s, 2 H), 7.29 (s, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 19.7 (q), 80.2 (d), 82.3 (s), 122.4 (s),
133.8 (d), 137.9 (s) ppm. MS (DCI, CH4): m/z (%) = 310 (100) [2
(M + H)]+, 154 (10) [M]+, 141 (29), 115 (19), 91 (33). HRMS (DCI,
CH4): calcd. for C24H22 [2 (M + H)]+ 310.1723; found 310.1836.
No experimental data were available in the literature.
2,3-Diethynylthiophene (13h, R = TMS):[43] Yellow liquid. Yield
43% (0.112 g) (Method A), 31% (0.081 g) (Method B). IR (neat):
ν = 3291 (w), 3109 (w), 2960 (s), 2162 (s), 2152 (s), 1250 (s), 970
˜
1
(m), 842 (s), 759 (m) cm–1. H NMR (300 MHz, CDCl3): δ = 0.25
1,2-Diethynyl-4,5-dimethoxybenzene (13c):[40] Colorless solid. Yield
71% (0.125 g) (Method A), 84% (0.148 g) (Method B). M.p. 120–
(s, 9 H), 0.26 (s, 9 H), 6.97 (d, J = 5.3 Hz, 1 H), 7.10 (d, J = 5.3 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = –0.2 (q), –0.4 (q),
96.2 (s), 98.7 (s), 98.8 (s), 103.5 (s), 125.7 (d), 127.2 (s), 127.5 (s),
129.3 (d) ppm. MS (EI): m/z (%) = 277 (25) [M + H]+, 237 (100),
164 (19). HRMS (ESI, Ar): calcd. for C14H21SSi2 [M + H]+
277.0903, found 277.0902. No experimental data were available in
the literature.
122 °C. IR (KBr): ν = 3302 (s), 2927 (m), 2868 (w), 2104 (w), 1604
˜
(w), 1506 (m), 1466 (w), 1262 (m), 1229 (m), 1104 (w), 911 (s), 737
1
(s) cm–1. H NMR (300 MHz, CDCl3): δ = 3.28 (s, 2 H), 3.89 (s, 6
H), 6.97 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 56.1 (q),
79.8 (d), 82.1 (s), 114.7 (d), 118.1 (s), 149.4 (s) ppm. MS (DCI,
CH4): m/z (%) = 186 (100) [M]+, 143 (8), 115 (10), 84 (16). HRMS
(DCI, CH4): calcd. for C12H10O2 [M]+ 186.0681; found 186.0660.
These data are in agreement with literature data.[40c]
2,3-Diethynylthiophene (13h, R = H):[43] Light yellow viscous liquid.
Yield 45% (0.059 g) (Method C). IR (neat): ν = 3303 (s), 2926 (m),
˜
2855 (w), 2112 (m), 1654 (m), 1461 (m), 1378 (m), 1091 (m), 910
2,3-Diethynylnaphthalene (13d):[41] Yellow crystalline solid. Yield
67% (0.112 g) (Method A), 44% (0.073 g) (Method B), 84%
1
(s), 736 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 3.32 (s, 1 H),
3.61 (s, 1 H), 7.03 (d, J = 5.1 Hz, 1 H), 7.17 (d, J = 5.1 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 75.7 (s), 77.6 (s), 81.3 (d),
85.5 (d), 126.4 (s), 126.6 (d), 126.7 (s), 130.0 (d) ppm. MS (ESI,
Ar): m/z (%) = 133 (3) [M + H]+, 102 (11), 77 (11), 73 (76). HRMS
(ESI, Ar): calcd. for C8H5S [M + H]+ 133.0112; found 133.0014.
No experimental data were available in the literature.
(0.147 g) (Method C). M.p. 119–120 °C. IR (KBr): ν = 3306 (s),
˜
3284 (s), 3059 (m), 2922 (m), 2849 (m), 2116 (w), 1584 (m), 1488
(m), 1244 (m), 956 (m), 902 (s), 801 (m), 750 (s) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 3.35 (s, 2 H), 7.48–7.56 & 7.74–7.82
(AAЈBBЈ, J = 6.2, 3.3 Hz, 4 H), 8.10 (s, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 80.7 (d), 82.1 (s), 121.2 (s), 127.7 (2ϫd),
132.5 (s), 133.1 (d) ppm. MS (DCI, CH4): m/z (%) = 176 (77)
[M]+, 150 (10), 131 (25), 119 (23), 84 (16), 69 (100). HRMS (DCI,
CH4): calcd. for C14H8 [M]+ 176.0626; found 176.0587. These data
are in agreement with literature data.[41b]
[D]1-(2,2-Dibromovinyl)-4-methoxybenzene (28): To a stirred sus-
pension of activated Zn dust (0.260 g, 4 mmol) in dry CH2Cl2
(15 mL) under N2 was added triphenylphosphane (1.04 g, 4 mmol).
The reaction mixture was cooled to 0 °C, and carbon tetrabromide
(0.670 g, 2 mmol) dissolved in dry CH2Cl2 (2 mL) was added over
15 min, which resulted in an intense yellow color. At the same tem-
perature, [D]4-methoxybenzaldehyde 27 (0.137 g, 1 mmol, 95.6% D
by 1H NMR, average of 3 integrations) dissolved in CH2Cl2 (2 mL)
was added dropwise to the reaction mixture, and the reaction mix-
ture was brought to room temp. over a period of 4 h. The reaction
mixture was then diluted with CH2Cl2 (10 mL), washed with water
(20 mL), dried (anhydrous Na2SO4), and concentrated in vacuo.
The crude residue was purified by silica gel column chromatog-
raphy (n-hexane as the eluent) to afford pure dibromide 28. Yellow
1,2-Diethynyl-4-methoxybenzene (13e):[42] Yellow liquid. Yield 91%
(0.135 g) (Method A), 87% (0.129 g) (Method B), 76% (0.118 g)
(Method C). IR (neat): ν = 3287 (s), 2945 (m), 2844 (m), 2110 (s),
˜
1606 (s), 1565 (s), 1489 (s), 1316 (s), 1255 (s), 1041 (s), 832 (m),
1
639 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 3.25 (s, 1 H), 3.33
(s, 1 H), 3.82 (s, 3 H), 6.86 (dd, J = 8.7, 2.7 Hz, 1 H), 7.02 (d, J =
2.7 Hz, 1 H), 7.43 (d, J = 8.7 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 55.4 (q), 79.6 (d), 80.9 (d), 81.8 (2ϫs), 115.5 (d),
117.32 (d), 117.44 (s), 126.3 (s), 134.0 (d), 159.4 (s) ppm. MS (EI):
m/z (%) = 156 (100) [M]+, 141 (29), 113 (60), 63 (25). HRMS (DCI,
CH4): calcd. for C11H8O [M]+ 156.0575; found 156.0549. These
data are in agreement with literature data.[42b]
solid. Yield 60% (0.175 g). M.p. 48–50 °C. IR (CHCl ): ν = 2960
˜
3
(m), 1602 (m), 1505 (m), 1450 (m), 1258 (s), 1176 (m), 1029 (s), 834
1
(s), 803 (s) cm–1. H NMR (300 MHz, CDCl3): δ = 3.81 (s, 3 H),
2,3-Diethynyl-4,5-bis(4-methoxyphenyl)furan (13f): Dark brown vis-
cous liquid. Yield 70% (0.218 g) (Method A), 61% (0.190 g)
6.88 (d, J = 8.8 Hz, 2 H), 7.50 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 55.2 (q), 87.1 (s), 113.8 (d), 127.7 (s), 129.8
(d), 136.2 (t, JC-D = 23.7 Hz), 159.7 (s) ppm. MS (DCI, CH4): m/z
(%) = 295 (70) [M + 4]+, 293 (100) [M + 2]+, 291 (58) [M]+, 278
(Method B), 64% (0.209 g) (Method C). IR (neat): ν = 3300 (s),
˜
2928 (s), 2852 (m), 2305 (w), 1613 (s), 1520 (m), 1265 (s), 1177 (s),
1
761 (s), 741 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 3.12 (s, 1 (25), 213 (10), 171 (13), 133 (50). HRMS (ESI, Ar): calcd. for
H), 3.75 (s, 1 H), 3.78 (s, 3 H), 3.84 (s, 3 H), 6.80 (d, J = 8.7 Hz,
2 H), 6.93 (d, J = 8.9 Hz, 2 H), 7.35 (d, J = 8.7 Hz, 2 H), 7.41 (d,
J = 8.9 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.18
(q), 55.21 (q), 74.1 (d), 74.3 (d), 84.3 (s), 86.0 (s), 113.0 (d), 114.0
C9H981Br2O [M + 4]+ 294.8979; found 294.8974. Deuterium incor-
1
poration in 28 was determined to be 92.3% by H NMR (average
of 3 integrations, a singlet at δ = 7.40 ppm with an integration value
of Ͻ 0.1 H corresponds to the olefinic proton of the minor non-
(d), 115.6 (s), 122.0 (s), 122.3 (s), 123.6 (s), 127.8 (d), 130.7 (d), deuterated compound, see the Supporting Information).
Eur. J. Org. Chem. 2007, 2477–2489
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2485

B. Sahu, R. Muruganantham, I. N. N. Namboothiri
FULL PAPER
Procedure for the nBuLi-Mediated Transformation of Dibromide 28
to Acetylene 29. D-Labeling Experiment: To a stirred solution of
dibromide 28 (310 mg, 1.05 mmol, 92.3% D) in n-hexane (6 mL)
was added nBuLi (1.3 mL, 2.1 mmol, 2.0 equiv., 1.6  solution in
hexanes) dropwise at –78 °C over a period of 20 min. Stirring was
continued at the same temperature for another 3 h. The reaction
mixture was then brought to room temp. over 1 h and was poured
into cold saturated aqueous NH4Cl (10 mL). The layers were sepa-
rated, and the organic layer was washed with water (2ϫ10 mL)
and brine (10 mL), dried (anhydrous Na2SO4), and concentrated in
vacuo. The crude residue was passed through a plug of silica gel
and eluted with hexanes to afford acetylene 29. Light yellow liquid.
(400 MHz, CDCl3): δ = 7.07–7.20 (m, 2 H), 7.25–7.35 (m, 6 H),
7.45–7.55 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 80.0
(s), 96.8 (s), 125.0 (s), 126.0 (d), 126.4 (d), 128.1 (d), 129.4 (d),
131.7 (d), 132.4 (s) ppm. MS (ESI, Ar): m/z (%) = 343 (100) [M]+,
306 (50), 264 (48), 234 (32), 224 (14), 158 (12), 141 (10). HRMS
(ESI, Ar): calcd. for C22H15S2 [M]+ 343.0615; found 343.0618.
1,2-Bis[2-(phenylselanyl)ethynyl]benzene (31d): Brown viscous li-
quid. Yield 54% (0.182 g). IR (neat): ν = 3056 (m), 2921 (m), 2155
˜
(m), 1577 (m), 1477 (s), 1439 (m), 1021 (m), 734 (s) cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.18–7.31 (m, 8 H), 7.48 (dd, J = 5.8,
3.5 Hz, 2 H), 7.55–7.60 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 74.0 (s), 101.8 (s), 125.4 (s), 127.0 (d), 128.0 (d), 128.7
(s), 128.8 (d), 129.6 (d), 131.9 (d) ppm. 77Se NMR (57 MHz,
CDCl3): δ = 273.9 ppm. MS (ESI): m/z (%) = 439 (10) [M + H]+,
413 (100), 374 (12), 338 (15), 322 (30), 258 (13), 189 (35), 149 (50),
129 (17). HRMS (ESI, Ar): calcd. for C22H15Se2 [M + H]+,
438.9504; found 438.9485.
Yield 70% (0.097 g). IR (neat): ν = 3290 (s), 2957 (m), 2931 (m),
˜
2582 (s), 2106 (w), 1607 (s), 1507 (s), 1291 (m), 1251 (s), 1171 (m),
1
1032 (s), 833 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 3.79 (s, 3
H), 6.83 (d, J = 8.8 Hz, 2 H), 7.42 (d, J = 8.8 Hz, 2 H) ppm. D
incorporation in 29 is 50.3% (average of 3 integrations, a singlet at
δ = 3.0 ppm with an integration value of about 0.5 H corresponds
to the acetylenic proton of the minor non-deuterated compound,
see the Supporting Information).[56,58]
2,3-Bis[2-(phenylselanyl)ethynyl]naphthalene (31e): Brown solid.
Yield 53% (0.199 g). M.p. 110–111 °C. IR (CHCl ): ν = 3054 (m),
˜
3
3020 (m), 2985 (m), 2305 (m), 1422 (m), 1266 (s), 1217 (s), 1063
(m), 896 (m), 741 (s) cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.20–
7.31 (m, 6 H), 7.48 (shielded half of AAЈXXЈ, J = 6.2, 3.1 Hz, 2
H), 7.62–7.64 (m, 4 H), 7.75 (deshielded half of AAЈXXЈ, J = 6.0,
3.3 Hz, 2 H), 8.00 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 73.4 (s), 101.9 (s), 122.0 (s), 127.0 (d), 127.4 (d), 127.6 (d), 128.8
(s), 128.9 (d), 129.6 (d), 132.0 (d), 132.3 (s) ppm. 77Se NMR
(57 MHz, CDCl3): δ = 274.4 ppm. MS (ESI): m/z (%) = 527 (2) [M
+ K]+, 525 (10), 342 (18), 298 (7), 255 (8), 212 (25). HRMS (ESI,
Ar): calcd. for C26H16KSe2 [M + K]+, 526.9219; found 526.9257.
General Procedure for the Quenching of Acetylide 30 with Different
Electrophiles: To
a stirred solution of dry diisopropylamine
(0.62 mL, 5.0 mmol) in dry toluene (10 mL) at 0 °C under N2 was
added dropwise nBuLi (2.8 mL, 4.6 mmol, 1.6  solution in hex-
anes) over 20 min. Stirring was continued at the same temperature
for another 2.5 h. The reaction mixture was then diluted with dry
toluene (25 mL) and cooled to –78 °C. At the same temperature,
tetrabromide 12 (0.77 mmol) in toluene (4 mL) was added dropwise
over a period of 15 min. Low temperature was maintained for 3 h,
and then the reaction mixture was gradually warmed to –40 °C.
At this temperature, the reaction mixture was quenched with the
electrophile (1.7 mmol, 2.2 equiv., see Table 9) in toluene or THF
(2 mL). The resulting brown mixture was stirred overnight and sub-
sequently quenched with saturated aqueous NH4Cl (5 mL). The
layers were separated, and the aqueous layer was further extracted
with diethyl ether (2ϫ20 mL). The combined organic layers were
washed with water (2ϫ10 mL) and brine (10 mL), dried (anhy-
drous Na2SO4), and concentrated in vacuo. The crude residue was
purified by silica gel column chromatography (n-hexane or n-hex-
ane/ethyl acetate mixture, gradient elution) to afford pure substi-
tuted enediynes 31.
1,2-Bis[2-(diethoxyphosphoryl)ethynyl]benzene (31f): Colorless li-
quid. Yield 48% (0.147 g). IR (neat): ν = 3056 (m), 2986 (s), 2962
˜
(m), 2933 (m), 2190 (s), 1734 (s), 1444 (w), 1374 (m), 1266 (s), 1046
(s), 742 (s) cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.42 (t, J =
7.1 Hz, 12 H), 4.24–4.28 (m, 8 H), 7.48, 7.64 (AAЈXXЈ, J = 5.8,
3.3 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.1 (d, J =
6.8 Hz), 63.5 (d, J = 5.4 Hz), 83.0 (d, J = 292.9 Hz), 95.5 (d, J =
51.9 Hz), 123.1 (d, J = 2.3 Hz), 130.4 (d), 133.4 (d, J = 2.3 Hz)
ppm. 31P NMR (120 MHz, CDCl3): δ = –8.6 (s) ppm. MS (ESI,
Ar): m/z (%) = 421 (38) [(M – 1) + Na]+, 399 (100) [M]+, 243 (25),
177 (11), 124 (9). HRMS (ESI, Ar): calcd. for C18H25O6P2 [M]+
399.1126; found 399.1125.
1,2-Di(prop-1-ynyl)benzene (31a):[68] Colorless liquid. Yield 62%
Supporting Information (see also the footnote on the first page of
(0.073 g). IR (neat): ν = 3052 (s), 2982 (m), 2917 (s), 2851 (m), 2236
˜
1
this article): Copies of H and 13C NMR spectra for all new com-
(m), 1481 (m), 1441 (m), 1265 (s), 745 (s) cm–1. 1H NMR
(400 MHz, CDCl3): δ = 2.12 (s, 6 H), 7.18 (shielded half of
AAЈXXЈ, J = 9.1, 2.5 Hz, 2 H), 7.37 (deshielded half of AAЈXXЈ,
J = 9.3, 2.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 4.6
(q), 78.6 (s), 89.5 (s), 126.1 (s), 127.2 (d), 131.9 (d) ppm. MS (EI):
m/z (%) = 154 (100) [M]+, 152 (70), 128 (10), 115 (8), 76 (20). These
data are in agreement with literature data.[68b]
pounds and some of the known compounds for which experimental
data are not available in the literature and 31P and 79Se NMR spec-
tra, wherever applicable.
Acknowledgments
1,2-Bis[2-(methylthio)ethynyl]benzene (31b): Yellow liquid. Yield
The authors thank Department of Science and Technology (DST),
India for financial assistance, SIF, IISc, Bangalore and SAIF, IIT
Bombay for NMR spectroscopic data, Dr. Rachel Persky, Bar-Ilan
University, Israel, for selected mass spectrometric data, and Prof.
G. K. Lahiri, Department of Chemistry, IIT Bombay, for his gener-
ous gift of D2O. B. S. thanks CSIR, and R. M. thanks IIT Bombay
for a research fellowship.
65% (0.109 g). IR (neat): ν = 2929 (m), 2157 (s), 1472 (m), 1440
˜
1
(m), 1265 (s), 740 (s) cm–1. H NMR (300 MHz, CDCl3): δ = 2.51
(s, 6 H), 7.19 (shielded half of AAЈXXЈ, J = 5.5, 3.4 Hz, 2 H), 7.36
(deshielded half of AAЈXXЈ, J = 5.8, 3.3 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.6 (q), 85.4 (s), 90.8 (s), 125.4 (s), 127.4
(d), 130.9 (d) ppm. MS (ESI, Ar): m/z (%) = 219 (19) [M + H]+.
HRMS (ESI, Ar): calcd. for C12H11S2 [M + H]+ 219.0302; found
219.0307.
[1] a) U. Galm, M. H. Hager, S. G. Van Lanen, J. Ju, J. S. Thorson,
B. Shen, Chem. Rev. 2005, 105, 739–758; b) J. P. Cosgrove, P. C.
Dedon in Small Molecule DNA and RNA Binders (Eds: M. De-
meunynck, C. Bailly, W. D. Wilson), Wiley-VCH, Weinheim,
1,2-Bis[2-(phenylthio)ethynyl]benzene (31c): Yellow liquid. Yield
78% (0.205 g). IR (neat): ν = 3058 (w), 2925 (w), 2157 (m), 1582
˜
(s), 1478 (s), 1441 (s), 1024 (s), 757 (m), 736 (s) cm–1. 1H NMR
2486
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2477–2489

Enediynes from 2,3-Unsaturated 1,4-Bis(alkylidene)carbenes
FULL PAPER
Germany, 2003, vol. 2, p. 609; c) P. R. Hamann, J. Upeslacis,
D. B. Borders in Anticancer Agents from Natural Products (Eds:
G. M. Cragg, D. G. I. Kingston, D. J. Newman), CRC Press
LLC, Boca Raton, Florida, 2005, p. 451.
a) E. L. Baldwin, N. Osheroff, Curr. Med. Chem.: Anti-Cancer
Agents 2005, 5, 363–372; b) C. Escude, J.-S. Sun, Top. Curr.
Chem. 2005, 253, 109–148; c) A. S. Boutorine, P. B. Arimondo,
Nucleic Acids Mol. Biol. 2004, 13, 243–268; d) A. Kamal, M. V.
Rao, N. Laxman, G. Ramesh, G. S. K. Reddy, Curr. Med.
Chem.: Anti-Cancer Agents 2002, 2, 215–254; e) D. L. Boger,
H. Cai, Angew. Chem. Int. Ed. 1999, 38, 448–476.
a) F. Mancin, P. Scrimin, P. Tecilla, U. Tonellato, Chem. Com-
mun. 2005, 2540–2548; b) S. Samal, C. N. Murthy, K. E. Geck-
eler in Advanced Macromolecular and Supramolecular Materi-
als and Processes (Ed.: K. E. Geckeler), Kluwer Academic/Ple-
num Publishers, New York, N. Y., 2003, p. 291; c) T. Da Ros,
G. Spalluto, A. S. Boutorine, R. V. Bensasson, M. Prato, Curr.
Pharm. Design 2001, 7, 1781–1821; d) M. Binaschi, M. Bigioni,
A. Cipollone, C. Rossi, C. Goso, C. A. Maggi, G. Capranico,
F. Animati, Curr. Med. Chem.: Anti-Cancer Agents 2001, 1,
113–130.
a) L. F. Povirk, Current Opinion in Oncologic, Endocrine and
Metabolic Investigational Drugs 1999, 1, 370–379; b) J. Stubbe,
J. W. Kozarich, Chem. Rev. 1987, 87, 1107–1136; c) G. Pratviel,
J. Bernadou, B. Meunier, Angew. Chem. Int. Ed. Engl. 1995, 34,
746–769; d) A. P. Breen, J. A. Murphy, Free Radical Biol. Med.
1995, 18, 1033–1077.
Selected reviews: a) K. C. Nicolaou, W.-H. Dai, Angew. Chem.
Int. Ed. Engl. 1991, 30, 1387–1416; b) K. C. Nicolaou, A. L.
Smith, E. W. Yue, Proc. Natl. Acad. Sci. USA 1993, 90, 5881–
5888; c) K. C. Nicolaou, A. L. Smith in Modern Acetylene
Chemistry (Eds: P. J. Stang, F. Diederich), VCH, Weinheim,
1995; p. 203; d) H. H. Wenk, M. Winkler, W. Sander, Angew.
Chem. Int. Ed. 2003, 42, 502–528; e) A. Basak, S. Mandal, S. S.
Bag, Chem. Rev. 2003, 103, 4077–4094; f) J. W. Grissom, G. U.
Gunawardena, D. Klingberg, D. Huang, Tetrahedron 1996, 52,
6453–6518; g) K. C. Nicolaou, A. L. Smith, Acc. Chem. Res.
1992, 25, 497–503; h) N. Zein, D. R. Schroeder in Advances in
DNA Sequence Specific Agents (Ed.: G. B. Jones), Jai Press
Inc., Greenwich, CT, 1998, vol. 3; i) K. K. Wang, Chem. Rev.
1996, 96, 207–222; j) R. Gleiter, D. Kratz, Angew. Chem. Int.
Ed. Engl. 1993, 32, 842–845.
a) R. G. Bergman, Acc. Chem. Res. 1973, 6, 25–31; b) T. P.
Lockhart, R. G. Bergman, J. Am. Chem. Soc. 1981, 103, 4091–
4096; c) S. J. Blanksby, G. B. Ellison, Acc. Chem. Res. 2003, 36,
255–263; d) J. B. Biggins, K. Onwueme, J. S. Thorson, Science
2003, 301, 1537–1541; e) P. R. Schreiner, A. Navarro-Vazquez,
M. Prall, Acc. Chem. Res. 2005, 38, 29–37; f) R. J. McMahon,
R. J. Halter, R. L. Fimmen, R. J. Wilson, S. A. Peebles, R. L.
Kuczkowski, J. F. Stanton, J. Am. Chem. Soc. 2000, 122, 939–
949; g) M. Klein, T. Walenzyk, B. Koenig, Collect. Czech.
Chem. Commun. 2004, 69, 945–965; h) D. S. Rawat, J. M. Zale-
ski, Synlett 2004, 393–421; i) G. B. Jones, K. C. Russell in CRC
Handbook of Organic Photochemistry and Photobiology, 2nd ed.
(Eds: W. Horspool, F. Lenci), CRC Press LLC, Boca Raton,
Fla, 2004, vol. 29, p. 1.
a) S. Takahashi, Y. Kuroyama, K. Sonogashira, N. Hagihara,
Synthesis 1980, 627–630; b) K. Sonogashira in Handbook of
Organopalladium Chemistry for Organic Synthesis (Ed.: E. Neg-
ishi), John Wiley & Sons, Inc., N. J, Hoboken, 2002, vol. 1, p.
493; c) A. de Meijere, P. von Zezschwitz, S. Braese, Acc. Chem.
Res. 2005, 38, 413–422.
Selected recent articles: a) A. Basak, J. C. Shain, U. K. Kham-
rai, K. R. Rudra, J. Chem. Soc., Perkin Trans. 1 2000, 1955–
1964; b) D. S. Rawat, M. Zaleski, J. Am. Chem. Soc. 2001, 123,
9675–9676; c) B. J. Kraft, N. L. Coalter, M. Nath, A. E. Clark,
A. R. Siedle, J. C. Huffman, J. M. Zaleski, Inorg. Chem. 2003,
43, 1463–1471; d) I. V. Alabugin, M. Manoharan, S. V. Kova-
lenko, Org. Lett. 2002, 4, 1119–1122; e) O. S. Miljanic, K. P. C.
Vollhardt, G. D. Whitener, Synlett 2003, 29–30; f) B. König, W.
Pitsch, M. Klein, R. Vasold, M. Prall, P. R. Schreiner, J. Org.
Chem. 2001, 66, 1742–1746; g) A. J. Boydston, M. M. Haley,
R. V. Williams, J. R. Armantrout, J. Org. Chem. 2002, 67,
8812–8819; h) J. D. Spence, E. D. Cline, D. M. LLagostera,
P. S. O ’Toole, Chem. Commun. 2004, 180–181.
N. A. Powel, S. D. Rychnovsky, Tetrahedron Lett. 1996, 37,
7901–7904.
[2]
[3]
[9]
[10]
[11]
K. C. Nicolaou, W.-M. Dai, Y. P. Hong, S.-C. Tsay, K. K. Bald-
ridge, J. S. Siegel, J. Am. Chem. Soc. 1993, 115, 7944–7953.
a) P. A. Magriotis, M. E. Scott, K. D. Kim, Tetrahedron Lett.
1991, 32, 6085–6088; b) Z. Wang, K. K. Wang, J. Org. Chem.
1994, 59, 4738–4742.
a) K. K. Wang, Z. Wang, Y. G. Gu, Tetrahedron Lett. 1993, 34,
8391–8394; b) K. K. Wang, ACS Symp. Ser. 2001, 783, 52–64.
a) L. Feng, D. Kumar, S. M. Kerwin, J. Org. Chem. 2003, 68,
2234–2242; b) Y. Miki, A. Momotake, T. Arai, Org. Biomol.
Chem. 2003, 1, 2655–2660; c) P. J. Stang, T. Blume, V. V.
Zhdankin, Synthesis 1993, 35–36; d) M. F. Semmelhack, L.
Wu, R. A. Pascal, D. M. Ho, J. Am. Chem. Soc. 2003, 125,
10496–10497.
For Li compounds: a) G. B. Jones, G. Hynd, J. M. Wright, A.
Purohit, G. W. Plourde II, R. S. Huber, J. D. Mathews, A. Li,
M. W. Kilgore, G. J. Bubley, M. Yancisin, M. A. Brown, J. Org.
Chem. 2001, 66, 3688–3695; for Mg compounds: b) G. X.
Wang, S. Iguchi, M. Hirama, J. Org. Chem. 2001, 66, 2146–
2148.
N. P. Bowling, R. J. McMahon, J. Org. Chem. 2006, 71, 5841–
5847.
G. Zeni, A. L. Braga, H. A. Stefani, Acc. Chem. Res. 2003, 36,
731–738.
a) G. B. Jones, J. M. Wright, G. W. Plourde II, G. Hynd, R. S.
Huber, J. E. Mathews, J. Am. Chem. Soc. 2000, 122, 1937–1944;
b) C. P. Casey, S. Kraft, D. R. Powell, J. Am. Chem. Soc. 2002,
124, 2584–2594.
H. Hopf, M. Theurig, Angew. Chem. Int. Ed. Engl. 1994, 33,
1099–1100.
J. M. Nuss, M. M. Murphy, Tetrahedron Lett. 1994, 35, 37–40.
a) W. Pitsch, M. Klein, M. Zabel, B. König, J. Org. Chem.
2002, 67, 6805–6807; b) A. Orita, D. Hasegawa, T. Nakano, J.
Otera, Chem. Eur. J. 2002, 8, 2000–2004; c) X. Cao, Y. Yang,
X. J. Wang, J. Chem. Soc., Perkin Trans. 1 2002, 2485–2489; d)
S. Chaffins, M. Brettreich, F. Wudl, Synthesis 2002, 1191–1194;
e) H. Wandel, O. Wiest, J. Org. Chem. 2002, 67, 388–393; f)
G. W. Plourde II, P. M. Warner, D. A. Parrish, G. B. Jones, J.
Org. Chem. 2002, 67, 5369–5374.
a) P. Fritsch, Justus Liebigs Ann. Chem. 1894, 272, 319–324; b)
W. P. Buttenberg, Justus Liebigs Ann. Chem. 1894, 272, 324–
337; c) H. Wiechell, Justus Liebigs Ann. Chem. 1894, 272, 337–
344.
a) R. Gleiter, Angew. Chem. Int. Ed. Engl. 1992, 31, 27–44; b)
M. A. Bennett, H. P. Schwemlein, Angew. Chem. Int. Ed. Engl.
1989, 28, 1296–1320; c) N. E. Schore, Chem. Rev. 1988, 88,
1081–1119; d) K. P. C. Vollhardt, Angew. Chem. Int. Ed. Engl.
1984, 23, 539–556; e) D. A. Ben-Ephraim in The Chemistry of
the Carbon-Carbon Triple Bond, part 2 (Ed.: S. Patai), Wiley,
New York, 1978, p. 755; f) J. C. Craig, M. D. Bergenthal, I.
Fleming, J. Harley-Mason, Angew. Chem. Int. Ed. Engl. 1969,
8, 429–437; g) G. Köbrich, Angew. Chem. Int. Ed. Engl. 1965,
4, 49–68; h) N. P. Bowling, R. J. Halter, J. A. Hodges, R. A.
Seburg, P. S. Thomas, C. S. Simmons, J. F. Stanton, R. J.
McMahon, J. Am. Chem. Soc. 2006, 128, 3291–3302; i) A.
Auffrant, F. Diederich, C. Boudon, J.-P. Gisselbrecht, M.
Gross, Helv. Chim. Acta 2004, 87, 3085–3105; j) S. Sankarara-
man, S. Manivannan, Org. Biomol. Chem. 2003, 1, 2388–2392;
k) Y. Morisaki, T. Luu, R. R. Tykwinski, Org. Lett. 2006, 8,
689–692.
[12]
[13]
[14]
[4]
[5]
[15]
[16]
[17]
[18]
[19]
[20]
[6]
[21]
[22]
[7]
[8]
[23]
Reviews: a) R. Knorr, Chem. Rev. 2004, 104, 3795–3850; b) F.
Eymery, B. Iorga, P. Savignac, Synthesis 2000, 185–213; c) M.
Braun, Angew. Chem. Int. Ed. 1998, 37, 430–450; d) W. Kirmse,
Angew. Chem. Int. Ed. Engl. 1997, 36, 1164–1170; e) P. J. Stang,
Eur. J. Org. Chem. 2007, 2477–2489
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2487

B. Sahu, R. Muruganantham, I. N. N. Namboothiri
FULL PAPER
Chem. Rev. 1978, 78, 383–405; f) H. D. Hartzler in Carbenes
(Eds: R. A. Moss, M. Jones, Jr), Wiley and Sons, New York,
1983, vol. 2, p. 43.
1998, 3623–3628; d) A. P. Marchand, K. C. V. Ramanaiah,
S. G. Bott, J. C. Gilbert, S. Kirschner, Tetrahedron Lett. 1996,
37, 8101–8104; e) Ref.[24h]; f) R. T. Lewis, W. B. Motherwell,
Tetrahedron 1992, 48, 1465–1484.
E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769–3772.
For examples of, including those with modifications to, the Co-
rey–Fuchs dibromomethylenation of aldehydes, see: a) D.
Grandjean, P. Pale, J. Chuche, Tetrahedron Lett. 1994, 35,
3529–3530; b) P. Michel, D. Gennet, A. Rassat, Tetrahedron
Lett. 1999, 40, 8575–8578; c) F. Dolhem, C. Lievre, G. De-
mailly, Tetrahedron Lett. 2002, 43, 1847–1849; d) G. T. Hwang,
H. S. Son, J. K. Ku, B. H. Kim, J. Am. Chem. Soc. 2003, 125,
11241–11248.
For other dihaloolefination methods for aldehydes, see: a) V. N.
Korotchenko, A. V. Shastin, V. G. Nenajdenko, E. S. Balen-
kova, Org. Biomol. Chem. 2003, 1, 1906–1908; b) P. Savignac,
J. Petrova, M. Dreux, P. Coutrot, Synthesis 1975, 535–537; c)
J. Villieras, P. Perriot, J. F. Normant, Synthesis 1975, 458–461;
d) D. Seyferth, R. S. Marmor, J. Organomet. Chem. 1973, 59,
237–245.
[24]
Selected reports on experimental studies: a) A. P. Marchand,
I. N. N. Namboothiri, B. Ganguly, S. G. Bott, J. Am. Chem.
Soc. 1998, 120, 6871–6876; b) L. Xu, G. Lin, F. Tao, U. H.
Brinker, Acta Chem. Scand. 1992, 46, 650–653; c) L. Fitjer, S.
Modaressi, Tetrahedron Lett. 1983, 24, 5495–5498; d) K. L. Er-
ickson, J. Wolinsky, J. Am. Chem. Soc. 1965, 87, 1142–1143; e)
J. C. Gilbert, M. E. Baze, J. Am. Chem. Soc. 1984, 106, 1885–
1886; f) T. Harada, K. Iwazaki, T. Otani, A. Oku, J. Org.
Chem. 1998, 63, 9007–9012; g) G. J. Baxter, R. F. Brown, Austr.
J. Chem. 1978, 31, 327–339; h) A. P. Marchand, K. A. Kumar,
D. Rajagopal, R. Eckrich, S. G. Bott, Tetrahedron Lett. 1996,
37, 467–470; i) K.-D. Baumgart, G. Szeimies, Tetrahedron Lett.
1984, 25, 737–740; j) J. C. Gilbert, D.-R. Hou, Tetrahedron
2004, 60, 469–474; k) D. W. Laird, J. C. Gilbert, J. Am. Chem.
Soc. 2001, 123, 6704–6705; l) A. P. Marchand, S. Alihodzic,
S. G. Bott, W. H. Watson, S. G. Bodige, R. Gilardi, Tetrahedron
1998, 54, 13427–13434.
Selected reports on theoretical studies: a) J. C. Gilbert, S.
Kirschner, Tetrahedron 1996, 52, 2279–2290; b) R. P. Johnson,
K. J. Daoust, J. Am. Chem. Soc. 1995, 117, 362–367; c) J.
Tseng, M. L. McKee, P. B. Shevlin, J. Am. Chem. Soc. 1987,
109, 5474–5477; d) S. M. Bachrach, J. C. Gilbert, D. W. Laird,
J. Am. Chem. Soc. 2001, 123, 6706–6707; e) R. L. Hayes, E.
Fattal, N. Govind, E. A. Carter, J. Am. Chem. Soc. 2001, 123,
641–657.
[32]
[33]
[34]
[35]
[25]
[26]
a) V. N. Korotchenko, A. V. Shastin, V. G. Nenajdenko, E. S.
Balenkova, J. Chem. Soc., Perkin Trans. 1 2002, 883–887; b)
T. Takeda, Y. Endo, A. C. S. Reddy, R. Sasaki, T. Fujiwara,
Tetrahedron 1999, 55, 2475–2486; c) H. Rezaei, J. F. Normant,
Synthesis 2000, 109–112; d) G. Burton, J. S. Elder, S. C. M.
Fell, A. V. Stachulski, Tetrahedron Lett. 1988, 29, 3003–3006;
e) P. Savignac, P. Coutrot, Synthesis 1976, 197–199; f) Ref.[33b]
;
g) R. Neidlein, M. Winter, Synthesis 1998, 1362–1366; h) G. A.
Olah, A. Wu, Synthesis 1990, 885–886.
For a sequential (three-step) transformation of arene-1,2-dicar-
baldehyde monoacetal to arene-1,2-diyne by dibromomethylen-
ation and treatment with LDA: J. D. Tovar, N. Jux, T. Jarros-
son, S. I. Khan, Y. Rubin, J. Org. Chem. 1997, 62, 3432–3433.
B. Sahu, I. N. N. Namboothiri, R. Persky, Tetrahedron Lett.
2005, 46, 2593–2597.
[36]
11b: a) O. Farooq, Synthesis 1994, 1035–1036; 11c: b) D. Bhat-
tacharjee, F. D. Popp, J. Heterocycl. Chem. 1980, 17, 315–320;
c) M. A. A. Meziane, S. Royer, J. P. Bazureau, Tetrahedron Lett.
2001, 42, 1017–1020; 11d: d) A. Mallouli, Y. Lepage, Synthesis
1980, 689; 11e: e) Ref.[36b]; 11f: a new compound, prepared by
the procedure reported for its analogs: f) S. I. Pennanen, J. Het-
erocycl. Chem. 1977, 14, 745–748; 11g: g) A. Shafiee, J. Hetero-
cycl. Chem. 1975, 12, 177–179.
M. L. G. Borst, R. E. Bulo, C. W. Winkle, D. J. Gibney, A. W.
Ehlers, M. Schakel, M. Lutz, A. Spek, L. Anthony, K. Lam-
mertsma, J. Am. Chem. Soc. 2005, 127, 5800–5801.
13a: a) C. Huynh, G. Linstrumelle, Tetrahedron 1988, 44, 6337–
6344; b) A. J. Matzger, K. P. C. Vollhardt, Tetrahedron Lett.
1998, 39, 6791–6794; c) S. Torii, T. Hase, M. Kuroboshi, C.
Amatore, A. Jutand, H. Kawafuchi, Tetrahedron Lett. 1997, 38,
7391–7394; d) Refs.[7a,8d,8f]; e) C.-F. Lin, Y.-H. Lo, M.-C. Hsieh,
Y.-H. Chen, J.-J. Wang, M.-J. Wu, Bioorg. Med. Chem. 2005,
13, 3565–3575.
[27]
[28]
Selected recent articles: a) H. Rezaei, S. Yamanoi, F. Chemla,
J. F. Normant, Org. Lett. 2000, 2, 419–421; b) W. G.
von der Schulenburg, H. Hopf, R. Walsh, Angew. Chem. Int.
Ed. 1999, 38, 1128–1130; c) W. Sander, C. Kötting, Chem. Eur.
J. 1999, 5, 24–28; d) I. Creton, H. Rezaei, I. Marek, J. F. Norm-
ant, Tetrahedron Lett. 1999, 40, 1899–1902; e) V. Mouriès, R.
Waschbusch, J. Carran, P. Savignac, Synthesis 1998, 271–274;
f) H. Sato, N. Isono, I. Miyoshi, M. Mori, Tetrahedron 1996,
52, 8143–8158; g) M. Kunishima, K. Hioki, T. Ohara, S. Tani,
J. Chem. Soc., Chem. Commun. 1992, 219–220; h) T. Gibtner,
F. Hampel, J.-P. Gisselbrecht, A. Hirsch, Chem. Eur. J. 2002,
8, 408–432; i) A. L. K. S. Shun, R. R. Tykwinski, J. Org. Chem.
2003, 68, 6810–6813; j) Y. Tobe, N. Iwasa, R. Umeda, M. Son-
oda, Tetrahedron Lett. 2001, 42, 5485–5488; k) T. Sato, K. Tak-
ano, H. Ota, H. Someya, K. Matsuda, M. Koyama, Tetrahe-
dron 1998, 54, 5557–5574; l) S. Eisler, N. Chahal, R. McDon-
ald, R. R. Tykwinski, Chem. Eur. J. 2003, 9, 2542–2550; m)
A. L. K. S. Shun, E. T. Chernick, S. Eisler, R. R. Tykwinski, J.
Org. Chem. 2003, 68, 1339–1347; n) N. Tsuboya, R. Hamasaki,
M. Ito, M. Mitsuishi, T. Miyashita, Y. Yamamoto, J. Mater.
Chem. 2003, 13, 511–513; o) H. Yanagisawa, K. Miura, M.
Kitamura, K. Narasaka, A. Kaori, Bull. Chem. Soc. Jpn. 2003,
76, 2009–2026; p) B. R. Kaafarani, B. Wex, F. Wang, O. Cat-
anescu, L. C. Chien, D. C. Neckers, J. Org. Chem. 2003, 68,
5377–5380.
The thermal rearrangement of acetylenes 10 to vinylidenecarb-
enes 9 under FVP conditions has also been described: a)
R. F. C. Brown, Recl. Trav. Chim. Pays-Bas 1988, 107, 655–661
and the references cited therein; b) J. Mabry, R. P. Johnson, J.
Am. Chem. Soc. 2002, 124, 6497–6501.
T. Satoh, T. Sakamoto, M. Watanabe, Tetrahedron Lett. 2002,
43, 2043–2046.
a) J. C. Gilbert, D. H. Giamalva, J. Org. Chem. 1992, 57, 4185–
4188; b) S. G. Bott, A. P. Marchand, K. A. Kumar, E. Z. Dong,
J. Chem. Crystallogr. 1999, 29, 15–18; c) T. Mori, M. Tanigu-
chi, F. Suzuki, H. Doi, A. Oku, J. Chem. Soc., Perkin Trans. 1
[37]
[38]
[39]
13b: a) J. W. Grissom, G. U. Gunawardena, Tetrahedron Lett.
1995, 36, 4951–4954; b) M. Chakraborty, D. B. McConville,
T. Saito, H. Meng, P. L. Rinaldi, C. A. Tessier, W. J. Youngs,
Tetrahedron Lett. 1998, 39, 8237–8240.
13c: a) Ref.[38a]; b) M. Lu, Y. Pan, Z. Peng, Tetrahedron Lett.
2002, 43, 7903–7906; c) C.-Y. Lo, M. P. Kumar, H. K. Chang,
S. F. Luz, R.-S. Liu, J. Org. Chem. 2005, 70, 10482–10487.
13d: a) T. Kaneko, M. Takahashi, M. Hirama, Tetrahedron
Lett. 1999, 40, 2015–2018; b) S. Taillemite, C. Aubert, D.
Fichou, M. Malacria, Tetrahedron Lett. 2005, 46, 8325–8328.
13e: a) Ref.[8d]; b) Ref.[40c]
[40]
[41]
[42]
[43]
13h: a) Y. Sugihara, R. Miyatake, T. Yagi, Chem. Lett. 1993,
933–936; b) Ref.[8g]
[29]
[44]
a) G. J. Roth, B. Liepold, S. G. Mueller, H. J. Bestmann, Syn-
thesis 2004, 59–62; b) P. Meffre, S. Hermann, P. Durand, G.
Reginato, A. Riu, Tetrahedron 2002, 58, 5159–5162; c) K. P.
Kaliappan, V. Ravikumar, S. A. Pujari, Tetrahedron Lett. 2006,
47, 981–984; d) A. G. M. Barrett, B. T. Hopkins, A. C. Love,
L. Tedeschi, Org. Lett. 2004, 6, 835–837; e) K. M. J. Brands,
UK Pat. Appl. 2001, GB 2355988; Chem. Abstr. 2001, 135,
152576; f) N. Murakami, T. Nakajima, M. Kobayashi, Tetrahe-
dron Lett. 2001, 42, 1941–1943; g) S. Mueller, B. Liepold, G. J.
Roth, H. J. Bestmann, Synlett 1996, 521–522.
[30]
[31]
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2477–2489

Enediynes from 2,3-Unsaturated 1,4-Bis(alkylidene)carbenes
FULL PAPER
[45] a) Ref.[23b] and the references cited therein; b) For a novel appli-
cation of BOR (15) in the synthesis of phosphonylpyrazoles:
R. Muruganantham, S. M. Mobin, I. N. N. Namboothiri, Org.
Lett. 2007, 9, 1125–1128.
in the unlikely event of 20 being generated in the medium, it
could, in principle, dedeuterate acetylene 29 (corresponding to
19) and then undergo β-elimination to afford deuterated acetyl-
ene 29 by path B. Although such scrambling of D between
products of the two mechanisms can be visualized, it should
be noted that such scrambling is feasible only after formation
of product 29 (19) by path A, and therefore, the primary path-
way is path A.
[46] G. Köbrich, H. R. Merkle, H. Trapp, Tetrahedron Lett. 1965,
6, 969–972.
[47] a) Ref.[33a]; b) J. J. Li, Name Reactions: A Collection of Detailed
Reaction Mechanisms, Springer-Verlag, New Delhi, 2003, p. 90.
[48] G. Wittig, H. Witt, Ber. Dtsch. Chem. Ges. 1941, 74, 1474– [60] a) Ref.[6f]; b) K. C. Nicolaou, G. Zuccarello, Y. Ogawa, E. J.
1491.
Schweiger, T. Kumazawa, J. Am. Chem. Soc. 1988, 110, 4866–
4868; c) Ref.[5b]; d) E. Krata, D. J. Cremer, J. Am. Chem. Soc.
1994, 116, 4929–4936.
[49] G. Köbrich, F. Ansari, Chem. Ber. 1967, 100, 2011–2020.
[50] M. Schlosser, V. Ladenberger, Tetrahedron Lett. 1964, 5, 1945–
1959.
[51] For an example: a) T. Harada, K. Takehashi, K. Hahari, A.
Oku, Tetrahedron 1994, 50, 7987–8002; For a recent theoretical
study: b) K. Ando, J. Org. Chem. 2006, 71, 1837–1850.
[52] For an example: D. Syferth, R. L. Lambert Jr, M. Massol, J.
Organomet. Chem. 1975, 88, 255–286.
[61] a) M. F. Semmelhack, T. Neu, F. Foubelo, Tetrahedron Lett.
1992, 33, 3277–3280; b) C.-S. Kim, K. C. Russel, J. Org. Chem.
1998, 63, 8229–8234; c) H. Wandel, O. Wiest, J. Org. Chem.
2002, 67, 388–393.
[62] G. B. Jones, P. M. Warner, J. Am. Chem. Soc. 2001, 123, 2134–
2145.
[53] For examples: a) A. A. Bothner-By, J. Am. Chem. Soc. 1955,
77, 3293–3296; b) G. Köbrich, G. Reitz, U. Schumacher, Chem.
Ber. 1972, 105, 1674–1682; c) D. Y. Curtin, E. W. Flynn, R. N.
Nystrom, J. Am. Chem. Soc. 1958, 80, 4599–4601.
[54] D. H. Hun, J. S. Jeong, H. B. Lee, H. Ryu, Y. G. Kim, Tetrahe-
dron 2002, 58, 9925–9932.
[63] a) N. Koga, K. Morokuma, J. Am. Chem. Soc. 1991, 113, 1907–
1911; b) J. M. Galbraith, P. R. Schreiner, N. Harris, W. Wei,
M. Shaik, Chem. Eur. J. 2000, 6, 1446–1454; c) M. Schmittel,
S. Kiau, Chem. Lett. 1995, 953–954.
[64] a) B. Konig, H. Rutters, Tetrahedron Lett. 1994, 35, 3501–3504;
b) B. Konig, E. Schofield, P. Bubenitschek, P. G. Jones, J. Org.
Chem. 1994, 59, 7142–7143.
[65] B. P. Warner, S. P. Miller, R. D. Broee, S. L. Buchwald, Science
1995, 269, 814–816.
[66] Interestingly, phenylselenoacetylenes inhibited mammalian and
plant δ-aminolivulinate dehydratase with IC50 values of about
250 µ and at least 400 µ, respectively. B. R. Cordeiro, F.
Vanderlei, F. Marcelo, Z. Gilson, N. C. Wayne, R. J. Teixeire,
E. Tatiana, Phamacology Toxicology 2002, 90, 214–219.
[55] The minimum amount of nBuLi required for the complete con-
version of 22 to 25 was found to be 2 equiv. from our optimiza-
tion experiments. Care was taken to ensure that there was no
excess nBuLi in the medium, which would generate acetylide
24 by deprotonating the product 25 from path A.
1
[56] For H and 13C NMR data of non-deuterated compound 25:
A. Elangovan, Y.-H. Wang, T.-I. Ho, J. Org. Chem. 2003, 5,
1841–1844.
[57] A. W. Burgstahler Jr, D. E. Walker, J. P. Kuebrich, R. L. [67] For trapping of acetylides arising from 1,1-dihaloalkenes with
Schowen, J. Org. Chem. 1972, 37, 1272–1273.
an electrophile, see ref.[32]
[58] For 1H NMR data of deuterated compound (29): Z. Rappo-
port, Y. Apeloig, J. Am. Chem. Soc. 1974, 96, 6428–6436.
[59] Since sufficient nBuLi was employed to ensure the complete
conversion of dibromide 28 to acetylene 29, the carbenoid 17
was expected to be configurationally stable. Therefore, any pos-
sibility of isomerization of (E)-carbenoid 17 to (Z)-carbenoid
20 by a reaction of 17 with unreacted 16 is ruled out. However,
[68] 31a: a) E. Müller, M. Sauerbier, D. Streichfuss, R. Thomas, W.
Winter, G. Zountsas, J. Heiss, Justus Liebigs Ann. Chem. 1971,
750, 63–75; b) W. Bleckmann, M. Hanack, Chem. Ber. 1984,
117, 3021–3033; c) O. S. Miljanic, K. P. C. Vollhardt, G. D.
Whitener, Synlett 2003, 29–34.
Received: December 30, 2006
Published Online: March 27, 2007
Eur. J. Org. Chem. 2007, 2477–2489
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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