Electrophilic cyclization of aryldiacetylenes in the synthesis of functionalized enediynes fused to a heterocyclic core

Article abstract of DOI:10.1021/jo501396s

An efficient strategy for the synthesis of asymmetrically substituted enediynes fused to benzothiophene, benzofuran, and indole was developed. The proposed approach is based on the electrophilic cyclization of diacetylenes and Sonogashira coupling. Thus, iodocyclization of readily available ortho-functionalized (buta-1,3-diynyl)arenes was used as a direct way for the synthesis of 2-ethynyl-3-iodoheteroindenes. These substrates and their modified derivatives were easily converted by Sonogashira coupling with acetylenes to a variety of asymmetrically substituted acyclic enediynes fused to heterocycles. The tolerance of the developed methodology to a variety of functional groups is a great advantage in the synthesis of macrocyclic enediyne systems fused to a heterocyclic core. Synthesis of indole-fused 12-membered macrocyclic dienediyne was achieved using ring-closing metathesis as a key step.

Full text of DOI:10.1021/jo501396s

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Article
Electrophilic Cyclization of Aryldiacetylenes in the Synthesis
of Functionalized Enediynes Fused to a Heterocyclic Core
Natalia A. Danilkina, Aleksandra E. Kulyashova, Alexander F. Khlebnikov, Stefan Bräse, and Irina A Balova
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501396s • Publication Date (Web): 27 Aug 2014
Downloaded from http://pubs.acs.org on August 29, 2014
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Electrophilic Cyclization of Aryldiacetylenes in the Synthesis of Functionalized Enediynes
Fused to a Heterocyclic Core
†
†
†
‡
†
N. A. Danilkina , A. E. Kulyashova , A. F. Khlebnikov , S. Bräse *, I. A. Balova *
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†
Saint Petersburg State University, Institute of Chemistry, Universitetskiy pr. 26, 198504, Saint
Petersburg, Russia
balova.irina@chem.spbu.ru
‡
Karlsruhe Institute of Technology, Campus South, Institute of Organic Chemistry, FritzꢀHaberꢀ
Weg 6, 76131 Karlsruhe, Germany
stefan.braese@kit.edu
Table of Content/Abstract Graphic
ABSTRACT: An efficient strategy for the synthesis of asymmetrically substituted enediynes fused
to benzothiophene, benzofuran and indole was developed. The proposed approach is based on the
electrophilic cyclization of diacetylenes and Sonogashira coupling. Thus iodocyclization of readily
available orthoꢀfunctionalized (butaꢀ1,3ꢀdiynyl)arenes was used as a direct way for the synthesis of
2ꢀethynylꢀ3ꢀiodoheteroindenes. These substrates and their modified derivatives were easily
converted by Sonogashira coupling with acetylenes to a variety of asymmetrically substituted
acyclic enediynes fused to heterocycles. The tolerance of the developed methodology to a variety of
functional groups is a great advantage in the synthesis of macrocyclic enediyne systems fused to a
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heterocyclic core. Synthesis of indoleꢀfused 12ꢀmembered macrocyclic dienediyne was achieved
using ringꢀclosing metathesis as a key step.
INTRODUCTION
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Nowadays the development of new, efficient anticancer drugs is one of the most important
challenges for scientists around the world. A great variety of different classes of organic compounds
1
with antitumor properties have been isolated from natural products. Acetylene derivatives make a
2
considerable contribution to this type of natural products. Enediyne antibiotics which firstly were
isolated from different kinds of Actinomyces in the 1960’s represent an important family of
3
naturallyꢀoccurring acetylenic anticancer molecules.
The key features of the enediynes structure are (Z)ꢀhexꢀ3ꢀenꢀ1,5ꢀdiyne or masked enyneallene
4
a
4b,c
moieties which are able to undergo Bergman or MyersꢀSaito type cyclizations
respectively,
with the formation of highly reactive biradicals. These species abstract H atoms from the
3
a,4dꢀf
carbohydrate moiety in the DNA backbone that leads to the DNA damage and cell death.
Naturallyꢀoccurring enediynes display amongst the strongest antitumor activity of the known
2
,3a
antineoplastic agents.
Nevertheless, despite the fact that many enediynes has been evaluated
through phases I and II of clinical trials nowadays only one drug based on neocarcinostatin
3
a
(SMANCS) is approved for patients with liver cancer in Japan. The second one named Mylotarg
5
was taken off the pharmaceutical market in 2010. This is due to problems associated with the high
instability, short halfꢀlives, high toxicity, allergenicity and therefore narrow therapeutic windows of
naturallyꢀoccurring enediynes. However, the remarkable potency of enediynes as anticancer agents
provides a strong motivation for the discovering of the next generation of these compounds. For this
reason, the development of simple synthetic analogues of naturallyꢀoccurring enediynes is very
important and attractive challenge for chemists and biologists.
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During the last several decades a large number of results in this field have been reported. The main
3
b,fꢀk
trends of these investigations are summarized in several excellent reviews.
From these data, two
important trends can be identified. The first of these is the investigation of structureꢀactivity
relationships among different enediyne systems (Scheme 1, aꢀd).
SCHEME 1. Relationships between structure of enediynes and their activity in Bergman
cyclization
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It was found that in order the Bergman cyclization (BC) proceeds at ambient temperature (≤ 37 °C)
the cd distance should lie within 2.9–3.4 Å and activation energy for the formation of biradical
3g,6
species should not exceed 22–24 kcal/mol.
The majority of naturallyꢀoccurring enediynes with
an enediyne scaffold incorporated into a nineꢀ or 10ꢀmembered ring match these conditions
Scheme 1, a). In these cases macrocyclic systems on the one hand are synthetically accessible and
(
on the other are strained enough to undergo the cycloaromatization at ambient temperatures.
However there is no predictive linear relationship between the cd distance and a value of activation
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energy for BC, because the change of the strain energy in the transition and the ground states was
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found to be the most important parameter.
In addition, the nature of a substituents upon the enediyne scaffold influences the cyclization ability
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of the enediyne moieties: electronꢀwithdrawing groups are favorable for the cyclization (Scheme
1
, b); halogen atoms and other electron withdrawing groups being attached at a vinyl position
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g,9
stabilizes the enediyne system against cyclization,
while OH and C=O groups neighboring to a
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triple bond carbon atom facilitate Bergman cyclization (Scheme 1, c). Incorporation of oxygen
1
1b,c
and nitrogen atoms
into enediyne macrocyclic system promotes the cyclization, whereas
1
2
thiaenediynes are less active (Scheme 1, d).
The second trend noted is the elaboration of highly reactive enediynes from their nonꢀactive
precursors or from molecules with masked enediyne moiety (Scheme 1, eꢀh). The triggering process
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for such enediynes was achieved by light (Scheme 1, e),
redox processes, complexation with
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k,15
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transition metal ions (Scheme 1, g),
ring contraction under chemical and photochemical
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conditions
(Scheme 1, f) and by the reduction of strain energy in the transition state by cleavage
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of fourꢀmembered lactam cycle fused to enediyne scaffold (Scheme 1, h).
Each approach obviously has its own advantages and limitations. Nevertheless the ideal enediyne
1
8
system has not yet been synthesized and investigations in this area are still active. From this point
of view it can be noted that a heterocycle fused to enediyne system may influence the properties of
the whole molecule significantly. Moreover, it is known that such small, flat molecules as
1
9
heterocycles impart intercalation ability to larger molecules. This property is very promising in the
case of enediyne systems because binding of enediyne molecules to DNA is necessary for the DNA
damaging and this binding can be achieved either by interaction with DNA minor groove or by
3a, 20
intercalation.
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However, among hundreds of publications devoted to enediyne systems there are only a few
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a, 21
manuscripts describing acyclic enediyne systems fused to a heterocyclic core.
As a result, only
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21d,e
14a
four examples of macrocyclic enediyne annelated with pyrimidine, imidazole,
furan and
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8b
cinnoline were reported. This fact can be explained by the lack of efficient synthetic approaches
toward heterocycleꢀfused enediyne systems. Known routes include double Sonogashira coupling of
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a,21a,b,d,e,g−i,22
21c,k
terminal acetylenes with dihaloꢀ or halogenꢀtriflate heterocycles,
rearrangement of
bisvinylidenecarbene heterocycles to corresponding acetylene derivatives , Seyferth‐Gilbert
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1b,k
21l
homologation
or even Negishi coupling. Undoubtedly, these approaches are not convenient
for the synthesis of asymmetrically substituted enediyne systems, which are more useful substrates
for generation of the corresponding macrocyclic enediynes.
2
3
The Richterꢀtype cyclization of orthoꢀ(alkaꢀ1,3ꢀdiynyl)arenediazonium salt was reported by us as
a synthetic approach that allowed the constructing of a cinnoline ring and introducing of an ethynyl
moiety and a bromine atom to neighboring carbon atoms of the heterocycle formed in one step.
Subsequent displacement of the halide by a second acetylene fragment gave asymmetrically
substituted enediynes. This approach was used as a key step in the synthesis of 10ꢀmembered
8
b
enediyne fused to a cinnoline ring and remains distinct from all methods described above. The
limitation of this approach is its applicability to only one type of heterocycle, i.e. cinnoline.
Searching for a more general approach, we focused on the electrophilic cyclization of
2
4
functionalized acetylenes which was widely studied by Larock’s group and others as a general
24a
method for the construction of wide diversity of heterocycles as well as heterocycles with
2
4
halogen moiety.
Switching to the iodocyclization of functionalized diynes without affecting one of the triple bonds
opens access to the variety of heterocyclic systems containing both halogen and ethynyl moieties at
neighboring carbon atoms. Recently we reported briefly that electrophilic cyclization of
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diacetylenic derivatives of thioanisole, anisole and N,Nꢀdimethylaniline can be used in the synthesis
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of iodoethynylheteroindenes and as a key step in the preparation of macrocyclic dienediyne
2
5b
system fused to benzothiophene ring.
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Herein we report the full investigation of the scope and limitations of the approach proposed.
Synthesis of orthoꢀfunctionalized aryldiacetylenes by Sonogashira coupling followed by their
electrophilic cyclization and second Sonogashira reaction of the corresponding
iodoethynylheterocycles with monoacetylenes are discussed in detail. In this report particular
attention was given to the synthesis of heterocycleꢀfused enediyne systems with different functional
groups at both ethynyl moieties. These functional groups are of crucial importance for further
synthesis of macrocyclic enediynes which can be obtained by different varieties of macrocyclization
techniques.
RESULTS AND DISCUSSION
Synthesis of starting materials. Functionalized orthoꢀ(butaꢀ1,3ꢀdiynyl)arenes 4ꢀ7 – starting
compounds for the electrophilic cyclization – were synthesized in several ways. The most efficient
26a,b
synthetic route to such type of compounds is the Sonogashira coupling
of orthoꢀfunctionalized
iodoarenes 3aꢀg with terminal diacetylenes (Table 1). Terminal diacetylenes with alkyl (2a) and
hydroxyalkyl substituents (2bꢀd) were easily obtained by treatment of corresponding internal
diacetylene compounds 1aꢀd with lithium 2ꢀaminoethylamide (LAETA) («diacetylene zipper
2
7a,b
reaction»)
(Table 1, Method A) and used without purification in Cu/Pdꢀcatalyzed crossꢀ
coupling. This route was employed in the synthesis of the corresponding thioanisoles 4aꢀd (Table 1,
entries 1–4), anilines 5a, 6aꢀc (Table 1, entries 9, 11–13) and Oꢀalkylated phenols 7a,c (Table 1,
entries 14, 16).
TABLE 1. Synthesis of orthoꢀfunctionalized (butaꢀ1,3ꢀdiynyl)arenes 4–7
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A-D
E,F
R1 ( )2 R2
a-f
R3 ( )2 H
R3
X
Y
)
2
1
2a-f
(
3
a
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G
R3 ( )2 TMS
4-7
1g,h
a
b
entry internal diyne, method
terminal diyne,
iodoarene, method
Product 4–7
1
2
3
(isolated yield, %)
Bu
(
)2 Bu
H
(
(
(
)
C H
Me
Me
1
2
3
4
5
6
7
8
A
A
A
A
B
C
ꢀ
8
17
S
D
E
E
E
D
D
F
S
C H
8 17
2
1
a
2a
2b
2
I
I
3a
4a (80%)
Pr
(
)2 CH OH
2
H
)2 (CH ) OH
Me
Me
Me
Me
Me
Me
2 4
S
S
2 4
(CH ) OH
)
1
b
2
(
3a
4b (85%)
(
(
)2 CH OH
2
H
H
)2 (CH
)
OH
Me
Me
Me
Me
Bu
Bu
2
5
S
S
(CH ) OH
2 5
1
c
2c
2
I
I
I
I
3a
4c (89%)
)
)2 C(Me) OH
2
)2 (CH ) C(Me) OH
2 4 2
S
S
(CH ) C(Me) OH
2
4
2
1
d
2d
2
3a
4d
(46%)
Ph
(
)2 C(Me) OH
2
H
H
(
)2 Ph
S
S
Ph
)
1
e
2e
2f
2
(
3a
4e (68%)
TMS
TMS
TMS
(
(
)
TMS
(
)2 TMS
S
S
TMS
2
)
1
f
2
(
3a
4f (77%)
)2 (CH ) OH
Me
Me
Me
Me
2
2
ꢀ
S
S
(CH ) OH
2
2
)
)
1
g
I
I
(
2
3a
4g (94%)
(
)2 (CH ) OH
2 3
ꢀ
ꢀ
S
F
S
(CH ) OH
2 3
1
h
2
(
3a
4h (86%)
Bu
Ph
(
(
)
Bu
H
(
(
)
8
C H
NH
2
NH
2
8 17
C H
2
9
1
2
A
B
17
D
D
2
1
a
2a
2e
I
I
3b
5a (87%)
NH Ph
)2 C(Me) OH
H
)2 Ph
NH2
2
0
2
2
1
e
3b
5b (94%)
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Pr
Pr
(
)2 CH
2
OH
H
H
(
(
)2 (CH ) OH
Me
Me
Me
Me
Me
Me
Me
1
1
1
2
A
A
2 4
N
E
E
N
2 4
(CH ) OH
1
b
2b
2b
2
I
3c
6
a (79%)
Me
(
)2 CH OH
)2 (CH ) OH
2
2 4
N
N
(CH ) OH
2 4
)
1b
2
I
(
0
1
2
3
4
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0
1
2
3
4
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0
1
2
3
4
5
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9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
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7
8
9
0
O
OMe
O
OMe
3
d
6
b (82%)
Me
Me
I
Me
Me
Pr
(
)2 CH OH
H
(
)2 (CH ) OH
2
2 4
N
N
(CH ) OH
1
3
A
E
2 4
)
1
b
2b
2
(
O
OEt
O
OEt
3e
6c (79%)
Bu
Ph
Bu
(
(
(
(
)
Bu
H
H
(
(
)
8
C H
Me
Me
1
1
4
5
2
A
B
A
B
17
O
D
D
D
D
O
8 17
C H
2
2
1a
2a
2e
I
3
f
7a (86%)
Me
Bn
)2 C(Me) OH
)2 Ph
Me
Bn
Bn
2
O
Ph
2
O
1e
I
I
I
3
f
7b (58%)
)
Bu
H
H
(
(
)
C H
8 17
2
16
2
O
O
C
8 17
H
1a
2a
2e
2
3
g
7c (79%)
)2 C(Me) OH
)2 Ph
Bn
Ph
17
2
O
O
Ph
1e
2
3
g
7d
(95%)
a
Conditions for the synthesis of terminal diacetylenes: A – LAETA, ethylenediamine/THF, 15–20
C, 10 min; B – NaOH, toluene, 70 °C, 50 min; C – MeLi/LiBr, Et O; Conditions for the
Sonogashira coupling: D – Pd(PPh ) /CuI, Et N; E – Pd(PPh ) Cl /CuI, diisopropanolamine
DIPA), DMF; F – Pd(PPh ) /CuI, K CO , MeOH, DMF.
b
°
2
3
4
3
3 2
2
(
3 4 2 3
Phenylꢀ (2e) and TMSꢀsubstituted (2f) butaꢀ1,3ꢀdiynes were synthesized according to known
2
8a,b
procedures (Table 1, Methods B, C)
without purification, providing the corresponding aryldiacetylenes 4e,f, 5b, 7b,d in good yields
Table 1, entries 5, 6, 10, 15, 17).
In the case of compounds 4g,h ((СH ) , n ≤ 3) the diacetylene zipper reaction of the corresponding
and were used subsequently in Sonogashira reactions
(
2
n
internal diacetylenic alcohols is not easy to perform, because it demands handling of gaseous
acetylenes (propyne, 1ꢀbutyne) as starting materials for the preparation of corresponding internal
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8
9
diynes. Therefore a special procedure for the synthesis of compounds 4g,h based on oneꢀpot TMS
group removal and Sonogashira coupling starting from TMSꢀprotected diacetylenes 1g,h and oꢀ
iodothioanisole 3a was developed (Table 1, entries 7, 8). In this case K CO /MeOH system was
2
3
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
used as both a TMSꢀdeprotection source and a base in the Sonogashira coupling. This route which
I
0
29
was used earlier with Ag /Pd system turned out to be very efficient in the synthesis of alcohols
I
0
4
g,h applying Cu /Pd catalysts (Table 1, entries 7, 8), moreover it did not require an excess of
TMSꢀprotected diacetylene commonly used which is an important advantage of the developed
procedure.
It was surprising that common conditions for the Sonogashira coupling (Pd/Cu, Et N, Table 1,
3
Method D) that were efficient in the synthesis of compounds 4a,e,f, 7aꢀd (Table 1, entries 1, 5, 6,
14–17) including orthoꢀ(butaꢀ1,3ꢀdiynyl)anilines 5a,b (Table 1, entries 9, 10) as well as for the
30
preparation of orthoꢀethynylꢀN,Nꢀdimethylanilines did not work for the Sonogashira coupling of
orthoꢀiodoꢀN,Nꢀdimethylanilines with terminal diacetylenes. Using DIPA as a base and DMF as a
solvent was successful for the Sonogashira coupling of orthoꢀiodoꢀN,Nꢀdimethylanilines with
terminal diacetylenes and gave orthoꢀ(butaꢀ1,3ꢀdiynyl)ꢀN,Nꢀdimethylanilines 6aꢀc in good yields
(Table 1, entries 11–13), whereas compounds 6d,e were obtained by reductive methylation of
31
corresponding anilines 5a,b (Scheme 2).
SCHEME 2. Synthesis of butadiynylꢀN,Nꢀdimethylanilines 6a,d,e via alternative methods
Me
Me
I
(CH ) OH Me
Me
NH2
R3
2
N
R3
2
2 4
N
H
)
(
CH O) , NaCNBH
2 n 3
)
9
(
(
MeCN, AcOH
CuI, piperidine
5a,b
6a (73%)
d (69%)
e (78%)
8
6
6
3
R = C H (5a, 6d), Ph (5b, 6e), (CH ) OH (6a)
8
17
2 4
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4
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4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
Optimized conditions for the coupling (Pd/Cu, DIPA, DMF, Table 1, Method E) were also the best
for the synthesis of hydroxyalkylthioanisole derivatives (Table 1, entries 2–4).
An alternative route to asymmetrically substituted butaꢀ1,3ꢀdiynes is the Cadiot–Chodkiewicz
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
32
30
coupling. Taking into account that 2ꢀethynylꢀN,Nꢀdimethylaniline (8) can be easily synthesized
we tested this widely used reaction in the synthesis of oꢀ(butaꢀ1,3ꢀdiynyl)ꢀN,Nꢀdimethylaniline 6a
Scheme 2). Nevertheless, a lower overall yield and more expensive starting compounds in
(
comparison with the approaches discussed above prompted us to reject this route in favour of the
Sonogashira reaction of diacetylenes.
Thus the Sonogashira coupling of terminal diacetylenes and their TMSꢀderivatives with orthoꢀ
iodothioanisole, anisole and N,Nꢀdimethylanilines proved to be an efficient and convenient
synthetic path to the corresponding orthoꢀS,N,Oꢀfunctionalized aryldiacetylenes, which on the next
step were used as substrates for the electrophilic cyclization.
Electrophilic cyclization. During the last decade an increasing number of Sꢀ, Nꢀ, Oꢀ, Seꢀ, Siꢀ
cyclizations of acetylene derivatives in the presence of electrophiles were reported as a general
synthetic approach for the preparation of different heterocycles (heteroindenes, coumarins,
chromones, quinolines, isoquinolines, oxazoles, thiazines, etc.) under relatively mild reaction
24b,c
conditions.
The generally accepted mechanism of the electrophilic cyclization includes activation of the triple
bond by external electrophile followed by intramolecular nucleophilic attack of a heteroatom upon
the activated triple bond. The reaction ends with the elimination of a leaving group via SN2
2
4b
substitution reaction and the formation of the haloheterocycle (Scheme 3).
SCHEME 3. Proposed mechanism of the electrophilic cyclization of orthoꢀfunctionalized
arylacetylenes
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43
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53
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55
56
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58
59
60
Despite the fact that this reaction is wellꢀstudied among monoacetylenes, its mechanism has not
been investigated in details, thus the rateꢀdetermining step is still unknown. It was shown that
nucleophilicity of functional groups as well as electronic effects of substituents in aryl rings can
33
either favour the cyclization or can be unfavorable for the formation of the heterocyclic product. It
was also noted that solubility of the ‘onium’ salt intermediate in different solvents influences the
3
4
reaction. Nevertheless, there are no doubts that all transition states and intermediates in this
process are partly or fully charged and so polarity and solvation ability of the solvent employed will
dramatically influence the reaction rate and yields. Based on this knowledge and our previous
results two solvents with different polarity (MeCN and DCM) were compared in order to choose
optimal conditions for the synthesis of ethynyliodoheterocycle containing targets (Table 2).
TABLE 2. Electrophilic cyclization of orthoꢀfunctionalized (butaꢀ1,3ꢀdiynyl)arenes 4ꢀ7
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1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
5
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5
5
6
Me
X
Y
R
2
I
I
I
)
E
(
Y
Y
R
solvent
R
or
X
X
Cl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
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8
9
0
1
2
3
4
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6
7
8
9
0
4-7
10-12
13
E = I , ICl, IPy BF ; solvent = MeCN, DCM
2
2
4
a
entry
1
substrate
conditions
product
isolated
yield, %
83
Me
S
I
Ph
2
MeCN / rt / 3 h
DCM / rt / 1.5 h
)
(
Ph
S
95
10a
4
e
Me
I
I
2
3
4
5
6
7
S
TMS
MeCN / rt / 3 h
DCM / rt / 1.5 h
61:13
86:9
)
(
2
TMS
+
H
S
S
10b
10c
4
f
Me
Me
Me
Me
I
S
(CH ) OH
MeCN / rt / 3 h
DCM / rt / 1.5 h
67
94
2
2
)
2
(
(
(
2 2
CH ) OH
S
10d
4
g
I
S
(CH ) OH
MeCN / rt / 5 h
DCM / rt / 1.5 h
85
97
)
2 3
2
(
2 3
CH ) OH
S
10e
4
h
I
S
(CH ) OH
DCM / 40 °С / 0.5 h
93
93
83
2
4
)
2
(
(
(
CH ) OH
2 4
S
10f
4
b
I
S
(CH ) OH
2 5
DCM / 40 °С / 0.5 h
)
2
(CH ) OH
2
5
S
1
0g
0h
4
c
Me
I
S
(CH ) C(Me) OH DCM / 40 °С / 0.5 h
2
4
2
)
2
(
(
CH ) C(Me) OH
2 4 2
S
1
4
d
Me
Me
I
8
9
N
C
2
8
H
17
MeCN / 40 °С / 5 h
DCM / 40 °С / 0.5 h
89
55
)
(
C
8
H
17
N
Me
6
d
1
1a
Me
Me
Me
Me
I
N
Ph
2
MeCN / 40 °С / 5 h
DCM / 40 °С / 0.5 h
75
65
)
(
Ph
N
Me
6
e
11b
I
1
0
N
(CH ) OH
MeCN / 40 °С / 20 h
DCM / 40 °С / 0.5 h
72
75
2
4
)
2
(
(
CH ) OH
2 4
N
Me
6
a
11c
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Me
Me
Me
I
1
1
1
N
(CH
(CH
2
)
4
OH
DCM /40 °С / 0.5 h
77
51
)
2
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
(
CH ) OTBDMS
2 4
N
Me
6ab
Me
1
1d
O
N
)
OH
DCM / 40 °С / 0.5 h
I
2
3
2
4
2
EtO
2 4
(CH ) OH
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
O
OEt
Me
1
1e
6
c
Me
O
I
1
1
N
(CH
2
)
4
OTBDMS DCM / 40 °С / 0.5 h
76
89
16
2
EtO
(
CH ) OTBDMS
2
4
N
Me
O
OEt
Me
11f
6g
Me
O
I
4
N
(CH ) OTBDMS DCM / 40 °С / 0.5 h
2
4
2
MeO
2 4
(CH ) OTBDMS
N
Me
11g
O
OMe
6h
Me
I
1
1
1
1
1
2
5
6
7
8
9
0
O
Ph
MeCN / 40 °С /
overnight
)
2
(
Ph
O
1
2a
7b
Bn
Me
Me
Me
Me
I
O
Ph
ICl (1.5 equiv.) /
MeCN / rt /
overnight
49
)
2
(
Ph
Ph
O
12a
7d
I
I
I
c
O
Ph
ICl (1 equiv.) / DCM
)
)
Ph
2
(
+
/
rt / overnight
O
O
Cl
12a
13a
7b
I
I
O
Ph
ICl (2 equiv.) / DCM
rt / overnight
59
38
15
Ph
2
(
/
O
Cl
Cl
1
3ad
7b
I
I
O
C H
ICl (1.5 equiv.) /
MeCN / rt /
overnight
8
17
17
)
)
8 17
C H
2
(
(
O
13bd
7a
I
O
C H
Py IBF (1.1 equiv.),
2
4
8
2
C8H17
HBF ·Et O (1.1
4
2
O
equiv.) / DCM / rt to
0 °C / > 24 h
I2 (1.0 equiv.) was used as the electrophile (entries 1–15).
Alcohol 6a was converted to the corresponding TBDMS ether prior to the cyclization.
The mixture of 12a and 13a was detected by GCMS monitoring.
12b
7a
3
a
b
c
d
The position of iodine and chlorine atoms in compounds 13a,b was estimated by HMBC NMR
experiments.
3
5
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6
Electrophilic cyclization of phenylꢀ (4e) (Table 2, entry 1), trimethylsilylꢀ (4f) (Table 2, entry 2)
and hydroxyalkyl substituted thioanisoles 4g,h (Table 2, entries 3,4) was faster in DCM than in
MeCN, moreover using DCM as a solvent allowed us to obtain iodobenzothiophenes 10a,b,d,e in
almost quantitative yields (Table 2, entries 1–4). Increasing the reaction temperature to 40 °C
notably decreased the reaction time that was used in the scaleꢀup syntheses (5–15 mmol) of
benzothiophene derivatives 10fꢀh (Table 2, entries 5–7).
0
1
2
3
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9
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1
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3
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0
1
2
3
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8
9
0
Iodocyclization of N,Nꢀdimethylaniline derivatives 6a,e,d in MeCN (Table 2, entries 8–10)
proceeded slower than Sꢀcyclization due to the decreased nucleophilicity of the nitrogen than sulfur
atom. These substrates demanded heating at 40 °C in MeCN over 5–20 h, whereas in DCM the
same reaction accomplished within half an hour with the formation of indole derivatives 11aꢀg in
satisfactory and good yields (Table 2, entries 8–14). Even electronꢀwithdrawing groups in the arene
ring did not hamper the formation of desired iodoethynylindoles 11eꢀg in high yields (Table 2,
entries 12–14). It was found that in the case of dimethylaniline derivatives with hydroxyalkyl
substituents 6aꢀc protection of the OHꢀgroup with bulky silyl ethers was essential for the
achievement of high yields of iodoindoles 11d,f,g and to scalingꢀup the reaction up to 5–15 mmol
(Table 2, entries 11, 13, 14). The reaction with unprotected substrates 6a,c ran only in microscale
range and was accompanied with the formation of byproducts with iodinated triple bond. Although
we were able to isolate unprotected indoles 11c,e in rather good yields (Table 2, entries 10, 12), fine
chromatographic separation of desired products from byproducts was time and resources
consuming.
One of possible ways for the modification of OH group is the substitution by halogen atoms. The
36a
substitution is usually carried out under Appel reaction conditions (halogen source, PPh ). Thus
3
36b,c
by using iodine, PPh and imidazole different alcohols can be easily converted to iodoalkanes.
3
As iodine is a suitable electrophile for the cyclization of oꢀfunctionalized aryldiacetylenes we
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decided to combine these reactions in a oneꢀpot synthesis in order to synthesize 3ꢀiodoꢀ2ꢀ
iodoalkylethynylheteroindenes. It was found that the corresponding iodoethynylindole 11h and ꢀ
benzothiophene 10i could be obtained in high yields (Scheme 4).
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
SCHEME 4. Oneꢀpot synthesis of diiodoheteroindenes
Moreover, substitution of the OHꢀgroup in the starting hydroxyalkyl aniline 6b with iodine worked
in the same way as the OꢀTBDMS protection and afforded the formation of the corresponding
iodoalkylethynyl indole 11h without any byproducts.
In contrast to the results described above, the cyclization of diacetylenic derivatives of anisole
proceeded with notable complications. Thus iodocyclization of orthoꢀ(4ꢀphenylbutaꢀ1,3ꢀ
diynyl)anisole 7b with 1 equiv. of iodine in MeCN at 40 °C gave the desired product 12a in
unsatisfied yield due to poor conversion of the starting material (35%) (Table 2, entry 15). It was
found that the use of iodine monochloride in MeCN is favorable for selective cyclization of Oꢀ
benzylated derivative 7d. In this case 2ꢀethynylbenzofurane 12a was isolated in 49% yield (Table 2,
entry 16). The reaction of anisole 7b with equimolar amount of ICl in DCM led to the formation of
a mixture of ethynylbenzofuran 12a and byproduct 13a with iodochlorinated triple bond (Table 2,
entry 17). Switching to twoꢀfold excess of ICl accomplished the formation of benzofuran 13a with
an iodochlorinated triple bond (Table 2, entry 18) as a single reaction product.
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Electrophilic cyclization of orthoꢀdodecaꢀ1,3ꢀdiynylanisole 7a mediated by iodine in MeCN as well
as in DCM led to mixtures of reaction products 12b, 13b along with remaining starting material 7a
and starting compound 7a with one iodinated triple bond. The attempt to use ICl in MeCN for the
cyclization of anisole 7a finished with the formation of 3ꢀiodoꢀ2ꢀdecynylbenzofurane with
iodochlorinated triple bond 13b (Table 2, entry 19). Only the use of bis(pyridine)iodonium
tetrafluoroborate allowed to isolate the desired compound 12b but the yield was low (Table 2, entry
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
0).
The low reactivity of alkaꢀ1,3ꢀdiynylanisole was expected, because the similar results were
observed in the case of electrophilic cyclization of oꢀ(alkꢀ1ꢀynyl)anisoles earlier. Thus using of
iodine was absolutely ineffective in the synthesis of 2ꢀalkylꢀ3ꢀiodobenzofurane by electrophilic
3
7
cyclization and led only to the iodination of the triple bond in starting oꢀethynylanisoles.
Evidently it comes from the lower nucleophilicity of alkoxy group in comparison with other
nucleophilic groups and the higher reactivity of alkyl substituted triple bond towards electrophiles.
The empirical rank of reactivity of activated single triple bond towards different nucleophile
functions is known to be depended on electronic (relative nucleophilicity of the functional groups:
SMe > COOMe > NMe > > OMe > OBn; polarization of the carbonꢀcarbon triple bond, and the
2
cationic nature of the intermediate) and steric factors (hindrance and geometrical alignment of the
33
functional groups). The reactivity of diacetylene derivatives under electrophilic cyclization
conditions observed herein is mostly in a good accordance with the data established for
monoacetylenes.
Moreover, the obtained data revealed that the use of less polar DCM for the electrophilic cyclization
of oꢀmethylsulfanylꢀ and oꢀdimethylaminoaryldiacetylenes is more efficient than carrying out these
reactions in more polar acetonitrile. This observation could be explained by assumption that the last
SN2 «dealkylation» step is the limiting step of the overall process. The ‘onium’ salt, which is the
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starting compound at this step, is more charged than the transition state and the reaction product
Scheme 4), and therefore solvent with less polarity and solvation ability (DCM) would favour the
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
reaction.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis and properties of enediynes. For the construction of enediyne fragment fused to a
heterocyclic core on the next step the second ethynyl moiety was introduced into the position 3 of
the heterocycles obtained. At this stage different types of substituents can be brought into enediyne
systems easily along with the acetylene moiety: aryl and alkyl substituents and at least three
different functional groups (OHꢀ(CH ) , TMS, terminal double bond) which are essential if
2
n
macrocyclic enediyne systems are supposed to be target structures. These groups by themselves or
after one or two steps might allow applying a lot of macrocyclization strategies which have been
8
b, 13b, 17, 22, 38a
widely employed in the synthesis of enediynes (NozakiꢀHiyamaꢀKishi,
pinacol
38b
38c
12, 13a, 16a, 21d,e, 38c,d,
coupling,
McMurry reaction,
intramolecular alkylation,
Mitsunobu
1
1c
25b
reaction, ringꢀclosing metathesis and others).
Hydroxyalkyl groups can also be modified before the next Sonogashira coupling. Thus in the case
of hydroxyalkyl benzothiophene 10e a cyclopropyl moiety was easily introduced in two steps: the
hydroxy group in 10e was substituted by iodine affording the diiodobenzothiophene 10j. The last
one was involved in the synthesis of cyclopropyl derivative 14 (Scheme 5).
SCHEME 5. Functional group modification in (hydroxyalkylethynyl)benzothiophenes
The iodoethynylheterocycles 10a,dꢀh, 11aꢀc,eꢀg, 12a, 14 were used as starting materials for a
second Sonogashira reaction within the proposed approach (Table 3). Depending on the nature of
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
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5
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5
5
5
5
5
5
5
6
the substituent at position 2 and nature of the acetylene used in Sonogashira coupling different
reaction conditions were applied (Table 3).
TABLE 3. Synthesis of enediyne systems
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Entry 3ꢀiodoheteroindene
acetylene
conditions product (isolated yield, %)
A
I
H
C H
C H
6 13
6
13
1
15a
15b
15c
15c
Ph
S
0a
1
Ph
S
16a (70%)
I
H
H
(CH ) OH
2 3
(CH ) OH
2 3
2
3
4
5
6
7
A
A
A
A
B
B
Ph
S
1
0a
Ph
Ph
S
1
6b (72%)
I
TMS
TMS
Ph
S
10a
S
1
6c (83%)
I
H
H
TMS
TMS
TMS
TMS
(
CH ) OH
2 2
S
10d
(
2 2
CH ) OH
S
16d (63%)
I
15c
2 3
(CH ) OH
S
10e
(
2 3
CH ) OH
S
16e (85%)
I
H
H
TMS
TMS
TMS
TMS
15c
(
CH ) OH
2 4
S
1
1
0f
(
2 4
CH ) OH
S
16f (83%)
I
15c
(
2 5
CH ) OH
S
0g
(
CH ) OH
2 5
S
16g (80%)
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I
H
H
H
(CH ) OTHP
(CH ) OH
2 2
2
2
8
A
A
A
C
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
15d
(
(
CH ) OH
2 2
S
1
0d
(CH ) OH
2 2
S
16h (71%)b
I
(CH ) OTHP
(CH ) OH
2 3
2 3
9
1
1
5e
5e
CH ) OH
2
2
S
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10d
(
2 2
CH ) OH
S
1
6i (66%)b
2 3
(CH ) OH
I
(CH ) OTHP
2
3
10
(CH ) OH
2
3
S
10e
(CH ) OH
2 3
S
1
6j (83%)
I
11
TMS
Ph
S
15f
10a
Ph
S
1
6k (85%)
I
12
13
18
D
C
B
TMS
TMS
S
15f
14
S
16l (85%)
I
(
CH
2
)
3
OH
15g
S
1
0e
(
CH ) OH
2 3
S
1
6m (92%)
I
H
CH OH
OH
2
1
5h
(
CH ) OH
2 4
S
10f
10f
(
CH ) OH
2 4
S
1
6n (78%)
I
H
H
(CH ) OTBDMS
2 2
(CH ) OTBDMS
2 2
1
9
0
B
B
1
5i
(
(
CH ) OH
2 4
S
(
CH
2
)
4
OH
S
1
6o (81%)
I
(CH ) OTBDMS
2 2
(CH ) OTBDMS
2
2
2
15i
CH ) C(Me) OH
2
4
2
S
1
0h
(CH ) C(Me) OH
2 4
2
S
1
6p (81%)
I
H
Ph
Ph
21
A
15j
C H
8
17
N
Me
C H
8 17
1
1a
N
CH3
7a (74%)
1
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
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5
5
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5
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6
I
H
H
H
TMS
TMS
TMS
TMS
2
2
A
B
B
A
B
15c
C H
8
17
N
Me
C H
8 17
1
1a
N
CH
3
1
7b (70%)
O
TMS
I
23
15c
EtO
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 4
(CH ) OTBDMS
N
EtO
Me
(CH ) OTBDMS
2 4
11f
N
Me
1
7c (80%)
O
TMS
I
24
15c
EtO
O
(
2 4
CH ) OH
N
EtO
Me
(CH ) OH
2 4
N
1
1e
Me
1
7d (61%)
I
H
CH
2
OH
2
CH OH
25
15h
(CH ) OTBDMS
2
4
N
Me
(CH ) OTBDMS
2 4
1
1d
N
Me
1
7e (40%)
O
H
(CH ) OH
(CH ) OH
2 4
I
2 4
2
6
7
15k
MeO
O
(
2 4
CH ) OTBDMS
N
MeO
Me
(CH ) OTBDMS
2 4
1
1g
N
Me
17f (86%)
C H
6 13
I
H
H
C H
6
13
2
A
A
15a
Ph
O
Ph
Ph
1
2a
O
1
8a (47%)
I
TMS
TMS
28
15c
Ph
O
1
2a
O
1
8b (69%)
a
Conditions: A – Pd(PPh ) , CuI, PPh , DIPA, DMF, 40–70 °C; B – Pd(PPh ) Cl , CuI, PPh ,
DIPA, DMF, 40–70 °C; C – Pd(PPh ) , CuI, K CO , MeOH, DMF, 40–50 °C; D – Pd(PPh ) , CuI,
3 4
3
3 2
2
3
3
4
2
3
3 4
KF, MeOH, DIPA, DMF, 40 °C.
b
Overall yields are given for two steps: Sonogashira coupling and deprotection of the OTHPgroup
using Amberlyst 15 in MeOH at 45 °C over 3.5 h.
In the case of TMSꢀacetylene the highest yields of enediynes 16cꢀg, 17bꢀe were achieved by
carrying out reactions at 50 °C (Table 3, entries 3–7, 22, 23–25, 28) in 0.1
M concentration range of
iodoheterocycle. To reach the full conversion for the Sonogashira coupling of hydroxyalkynyl
derivatives 10d,e with THPꢀprotected acetylenic alcohols 16d,e, higher temperature (up to 70 °C)
and longer reaction time (36 h) (Table 3, entries 8–10) were required. In these cases corresponding
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diols 16hꢀj obtained after deprotection of the THPO group by amberlystꢀ15 in methanol were
isolated in good overall yields.
4
5
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Despite the fact that the Sonogashira reaction is a commonly employed synthetic methodology and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
26b
has been tested for a large number of different substrates, introduction of enyne fragments via
Sonogashira coupling with one pot deprotection of TMSꢀenynes is still unknown. Nevertheless in
our hands this type of Sonogashira coupling of 3ꢀiodoꢀ2ꢀsubstituted benzothiophene derivatives
1
0a,e, 14 with TMSꢀprotected enynes 15e,f enabled us to introduce hexꢀ5ꢀenꢀ1ꢀynꢀ1ꢀyl and pentꢀ4ꢀ
enꢀ1ꢀynꢀ1ꢀyl fragments into position 3 of benzothiophene ring (Table 3, entries 11–13). It should be
pointed out that using of K CO as a deprotection source and a base in the case of enyne 15f
2
3
afforded an inseparable mixture of products. The major product contained a double bond isomerized
from the terminal to internal position. To avoid the double bond isomerization, KF was used as a
TMSꢀdeprotecting agent instead of K CO . This reaction which can be defined as a type of silaꢀ
2
3
3
9
Sonogashira coupling, allowed isolating the desired enediyne 16m with terminal double bond in
high yield (Table 3, entry13).
In order to illustrate some possibilities of functional group modification within synthesized
enediynes some additional reactions were carried out. Thus the conjugated enyne system at position
3
of the benzothiophene ring was successfully constructed by a oneꢀpot TMSꢀdeprotection and
Sonogashira coupling of the TMSꢀprotected enediyne 16e with vinylbromide (Scheme 6)
employing K CO as a deprotecting agent and a base. Dienediyne alcohols 16q,m obtained were
2
3
oxidized to corresponding aldehyde 19a,b by DessꢀMartin periodinane (DMP) in good yields
Scheme 6).
(
SCHEME 6. Modification of benzothiophene fused enediynes.
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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5
5
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5
5
6
Br
TMS
Pd(PPh ) CuI,
3 4,
K CO MeOH
2
3,
DMF, 0 C to rt
(CH ) OH
2
3
(
CH ) OH
2 3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
S
S
16q (90%)
1
6e
(
CH2)n
(
CH2)n
O
DMP
DCM, 0 C to rt
OH
S
S
19a, n = 0 (68%)
19b, n = 1 (76%)
1
1
6q, n = 0
6m, n = 1
OH
O
O
OH DMP (2.5 equiv)
DCM, rt
S
S
16n
20 (70%)
Double oxidation of an enediyne 16j bearing two OHꢀgroups with DMP, which was recently used
2
5b
in the synthesis of symmetric enediyne dialdehyde, was also convenient for the synthesis of not
symmetrical dialdehyde 20 from the corresponding diol 16n (Scheme 6).
Having in hands the efficient synthetic approach for constructing of acyclic enediyne systems fused
to S,Nꢀheteroindenes with different functional groups at both ethynyl moieties we decided to
continue our previous investigation regarding application a ringꢀclosing metathesis (RCM) for the
25b
synthesis of 12ꢀmembered dienediyne macrocycle fused to benzothiophene. An indole containing
dienediyne was chosen as a target structure.
As we described recently synthesis of the benzothiopheneꢀfused macrocycle was carried out using
25b
double oxidation of diol 16j followed by double Wittig olefination and RCM. However the yield
at the olefination step was only 61% and required an excess of a strong base such as NaHMDS.
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For the synthesis of an indolе ringꢀcontaining analog we decided to use an alternative approach.
Therefore double elimination was chosen as the key step for the synthesis of terminal diolefin 22.
Thus diol 17g, generated after deprotection of corresponding OꢀTBDMS ether 17f, was easily
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
36b,c
converted to corresponding diiodide 21 using Appel iodination (Scheme 7).
a
SCHEME 7. Synthesis of terminal diolefin 22.
The elimination step was supposed to run under usual conditions: by treating of diiodide 21 with
4
0
tertꢀBuOK. However this reaction underwent with low conversion and the formation of
byproducts mixture. Looking for efficient conditions for HI elimination we paid attention to the
dehydrohalogenation methodology using TBAF hydrate as a base in aprotic solvent (DMSO)
4
1
reported earlier for the synthesis of terminal olefins. This technique was extremely efficient in our
case that allowed the oneꢀstep constructing of both terminal double bonds and isolating of terminal
diolefin 22 in high yield.
The RCM of terminal diolefin 22 was carried out under the same conditions as for the synthesis of
2
5b
1
2ꢀmembered benzothiopheneꢀfused dienediyne.
Thus the employment of Grubbs II catalyst
4
2
along with benzoquinone for the preventing of doubleꢀbond migration afforded the mixture of Eꢀ
and Zꢀisomers 23a,b (E/Z = 6:1) in 78% overall yield. A careful separation of this mixture by
column chromatography allowed the isolation of the major Eꢀisomer 23a in 34% yield (Scheme 8).
SCHEME 8. Synthesis of indoleꢀfused 12ꢀmembered dienediyne macrocycle.
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
The (E) configuration of the double bond formed in the major isomer 23a was elucidated by H
NMR spectroscopy with selective decoupling from hydrogen atoms of both CH groups next to the
2
double bond that allowed measuring the (H)C −(H)Csp2 spinꢀspin coupling constant. The value of
sp2
3
the constant J = 15 Hz fully corresponds to the (E) configuration of the double bond.
The structure of the major isomer 23a was also confirmed by Xꢀray analysis (Fig. 1).
FIGURE 1. Molecular structure of dienediyne macrocycle 23a.
Moreover Xꢀray studies revealed that dienediyne 23a as in the case of the benzothiopheneꢀfused
25b
dienediyne in solid state presents a mixture of two enantiomers due to restricted switching of the
double bond through the plane of the molecule. However this plane type of chirality like in
4
3a,b
43c
cyclooctene
and silacycloheptene
derivatives could not be fixed in a solution at room
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temperature due to fast inversion process, which was confirmed by magnetic equivalence of H
atoms of all methylene groups.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Thus RCM as a versatile synthetic method for a one step formation of the double bond and ringꢀ
closure was found to be an efficient technique for the synthesis of S,Nꢀheteroindeneꢀfused
dienediyne macrocycles.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Finally, the ability of some synthesized enediynes to undergo Bergman cyclization (BC) was
studied by Differential Scanning Calorimetry (DSC) which is known to be an efficient express
44
method for this purpose. Enediynes (16c,j,rꢀu, 17a, 18a,b) were picked up for DSC studies (Table
).
TABLE 4. Studying the reactivity of enediynes 16ꢀ18 in Bergman cyclization by DSC and
4
45
DFT calculations.
1
2
‡b
Entry №
X
R
R
tBC, angle angle Σ
cd, Å ꢁE
a
°
C
1, °
2, °
1+2
1
2
3
4
5
6
7
8
9
1
17а NMe C H
Ph
266 126.5 128.5 255.0 4.602 45.6
258 124.0 127.8 251.8 4.511 48.0
250 127.0 131.3 258.3 4.724 50.1
227 127.0 131.3 258.3 4.726 46.9
225 124.1 129.9 254.0 4.513 41.8
222 124.1 127.9 252.0 4.515 44.0
220 124.0 128.0 252.0 4.518 43.8
200 124.0 127.8 251.8 4.500 41.6
8
17
16с
18b
18a
S
O
O
S
S
S
S
S
S
S
Ph
Ph
Ph
TMS
TMS
C H
6
13
c
16j
16r
16sd
16t
(CH ) OH
2
3
(CH ) OH
2 3
d
C H
C H ꢀ4ꢀOMe
8
17
6
4
d
C H
Ph
8
17
(CH ) CHO
(CH ) CHO
2
2
2 2
d
16u
16v
16w
(CH ) CH=CH (CH ) CH=CH 203e 124.0 127.9 251.9 4.508 41.4
Me
H
2
2
2
2 2
2
0
Me
H
209 124.1 127.9 252.0 4.514 42.4
f
e
11
137 124.0 127.6 251.6 4.494 34.1
a
Onset temperatures are reported.
b
c
‡
ꢁ
E = (E+ZPE), kcal/mol.
Data obtained for compound 16j were not used in correlation.
d
e
25a,b
The synthesis of enediynes 16r,s and 16t,u was described earlier
.
tBC values were calculated in accordance with the linear equation y = –158.49+ 8.66x.
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f
21k
Synthesis of polyphenylene from enediyne 16w by thermolysis at 150 °C was reported.
Thus, exothermic peaks observed at thermograms at 200–266 °C (onset temperatures) obviously
illustrate that the BC of corresponding compounds (16c,j,rꢀu, 17a, 18a,b) took place. Additional
evidence suggesting that irreversible BC occurred is the fact that neither endothermic nor
exothermic features were observed during the scanning of the thermolyzed samples for the second
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46
time. DSC measurement revealed that both the nature of heterocycle and substituents at ethynyl
moieties influence the ability of enediynes to undergo BC.
The first inference comes from the comparison of onset Bergman cyclization temperatures (t ) of
BC
indole (17a), furan (18a) and benzothiophene (16s) fused enediynes with similar substituents (Table
4
, entries 1, 4, 7). In this series of heteroindenes decrease of tBC and therefore increase of reactivity
in BC observed from indole to benzothiophene: N (266 °C), O (227 °C), S (220 °C). As we have
already discussed in the introduction the electron withdrawing properties of substituents as well as a
3
j,8
heterocycle fused to enediyne are known to facilitate the BC. Due to electronꢀdonating ability of
heteroindenes, which was found to change in following way: benzofuran > indole >
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benzothiophene, benzothiophene fused enediyne is expected to be the most reactive within this
rank. From another point of view the sulfur’s van der Waals atomic radius (1.85 Å), which is
48
significantly larger than the radii of nitrogen (1.50 Å) and oxygen (1.40 Å) evidently can reduce
the values of bond angles 1 and 2 (Table 4) and, therefore, lead to the decrease of cd distance for
4
1
benzothiophene fused enediyne 16s. In order to prove this assumption DFT calculations were
carried out. As expected calculated values of bond angles 1 and 2 as well as the cd distance are in
inverse proportion with van der Waals atomic radii of the heteroatoms. Thus cd distance decreases
in following order: benzothiophene 16s < indole 17a < benzofuran 18a that fully coincides with the
highest reactivity observed for the compound 16s. It is interesting to note that the calculated
‡
activation energy ꢁE for the BC changes in accordance with the electron properties of heterocycles
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and cd distance in enediynes 18a, 17a, 16s. However from the DSC data benzofuran 18a was found
to be more reactive than indole 17a.
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Regarding the nature of substituents, it is known that it also has an impact on the activity of
enediynes in the cyclization. Thus enediynes with bulky groups at ethynyl moieties (e.g. TMS) are
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7d, 21a, 49
less active in BC than unsubstituted ones.
This tendency is in a good accordance with high
tBC of TMSꢀsubstituted compounds 16c, 18b (258 °C and 250 °C) (Table 4, entries 2, 3). The same
conclusion came from the comparison of tBC within benzothiophene derivatives 16j,rꢀu (Table 4,
entries 5–9). Thus, introduction of terminal C=C or C=O double bonds into the substituents at both
ethynyl moieties lowered the tBC from the average value of 220 °C (16j,r,s) (Table 4, entries 5–7) to
~
200 °C (16t,u) (Table 4, entries 8, 9). However, all calculated values of cd distance (4.50–4.52 Å)
and bond angles (the sum of both angles ~ 252 °) were found to be almost the same within
benzothiophene series including TMSꢀsubstituted enediyne 16c and do not depend on the nature of
substituents. This fact could be attributed to less steric interaction between both substituents with
terminal double bonds in transition state in comparison with TMSꢀ, Arꢀ and Alk substituted
enediynes that might lead to the reduction of activation energy of BC for enediynes 16t,u.
It is known that the ability of enediynes to undergo Bergman cyclization correlates accurately with
7
‡
the values of activation energy barriers. We found that calculated activation barriers ꢁE and t
BC
obtained from DSC measurements are in good agreement. Moreover there is a quite good
‡
correlation (R = 0.992) between ꢁE and t within benzothiophene fused enediyne series that
BC
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could be used for the prediction of reactivity. For example, values of t for dimethylenediyne 16v
BC
and unsubstituted 2,3ꢀbisethynylbenzithiophene 16w are supposed to be 209 °C and 137 °C (Table
4).
However, for indole derivative 17a and benzothiopheneꢀfused enediyne with OH groups 16j
calculated values of activation energy do not match the observed t . This misfit could probably be
BC
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caused by the protonꢀacceptor and protonꢀdonor capability of compounds 17a and 16j, respectively
that can affect the mechanism of BC.
In order to illustrate the influence of a fused heterocycle to the reactivity of a macrocyclic enediyne
system in the cycloaromatization process the DSC measurements for indole containing dienediyne
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3a were carried out. It was found that the onset temperature of the exothermic peak observed upon
46
the first heating of the compound 23a is 239 °C which is significantly higher than the temperature
25b, 51
estimated earlier for the benzothiopheneꢀfused dienediyne (201 °C).
This difference is the
result of both electron properties of heteroindenes and atomic radii of heteroatoms discussed above
and fully corresponds with the structureꢀreactivity relationships for the series of acyclic enediynes.
From this point of view benzothiopheneꢀfused macrocyclic enediynes are supposed to be more
promising for the searching of bioactive molecules.
On the other hand it is obviously clear that even additional double bond being incorporated into the
enediyne system does not increase the reactivity of 12ꢀmembered enediynes in thermal induced
cycloaromatization. Therefore smaller macrocyclic enediynes fused to heterocycles are challenging
synthetic targets and the topic of the investigation in our research group which are goingꢀon.
CONCLUSION
A convenient and efficient approach towards enediyne systems fused to a heterocyclic core based
on electrophilic cyclization and Sonogashira coupling was elaborated. The innovation of this
synthetic route is the iodocyclization of readily available orthoꢀfunctionalized aryldiacetylenes that
allowed the construction of heterocycles bearing the ethynyl moiety along with iodine functionality
at neighbor positions in a single step. The effect of solvent polarity on the cyclization was revealed
and dichloromethane was found to be better than acetonitrile for the synthesis of benzothiophenes
and indoles. The lower nucleophilicity of alkoxy groups in comparison with Sꢀ, Nꢀcontaining
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groups required electrophilic reagents stronger than iodine for the cyclization to proceed, and led to
lower yields of 2ꢀethynylꢀ3ꢀiodobenzofurans. Subsequent Sonogashira coupling of the heterocycles
obtained with acetylenes afforded asymmetricallyꢀsubstituted enediyne systems fused to S,N,Oꢀ
heteroindenes with various functional groups at both ethynyl fragments. In this way, a diversity of
asymmetrically substituted acyclic enediyne systems fused to benzothiophene, benzofuran and
indole were synthesized with complete regiocontrol. Due to both the tolerance of this methodology
to the nature of functional groups attached to ethynyl moieties and opportunity of further functional
group transformation, the approach developed can be used in the synthesis of heterocycleꢀfused
macrocyclic enediyne systems. Ring closing metathesis was found to be an efficient technique for
the synthesis of S,Nꢀheteroindeneꢀfused macrocycles as the method for the one step formation of the
double bond and closing of 12ꢀmembered dienediene macrocycles. It was estimated that the nature
of the heteroatom does not influence the general structural properties of 12ꢀmembered dienediynes.
However the nature of the heterocycle fused to both cyclic and acyclic enediyne systems influence
their ability to undergo thermal induced cycloaromatization significantly. Other macrocyclization
approaches for the synthesis of macrocyclic enediynes within the methodology developed are under
investigation.
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EXPERIMENTAL SECTION
General Information and Methods. Solvents, reagents and chemicals (1f, 3a,b,f, 15aꢀc,h,j,k)
used for reactions were purchased from commercial suppliers. Catalysts Pd(PPh3)4 and
Pd(PPh ) Cl were purchased in SigmaꢀAldrich. Solvents were dried under standard conditions;
3 2
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52a
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52b
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52c
chemicals were used without further purification. Compounds 3c, 3d, 3e, 3g, 8, 9,
52d
52e
52f
25b
1
5d,e, 15g, 15i and enediynes 16t,u were synthesized by known procedures without any
modification. All reactions were carried out under Ar in flameꢀdried glassware. Evaporation of
solvents and concentration of reaction mixtures were performed in vacuo at 30−40 °C on a rotary
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