Synthesis of Colchicinoids and Allocolchicinoids through Rh(I)-Catalyzed [2+2+2+1] and [2+2+2] Cycloadditions of o-Phenylenetriynes with and without CO

Article abstract of DOI:10.1021/acs.joc.8b01608

The nonbenzenoid aromatics, tropones and tropolones, are found in various natural products such as colchicine and hinokitol, which possess significant biological activities. The traditional methods to construct the tropone skeletons include oxidation of cycloheptatriene and [4+3] cycloadditions. In addition, the total synthesis of colchicine and its analogues requires laborious organic transformations in the formations of 6-7-7 fused-ring systems. Transition metal-catalyzed carbocyclization and cycloaddition reactions have proven to be among the most efficient methods for constructing complex polycyclic systems. On the basis of our recent discovery of the Rh-catalyzed carbonylative [2+2+2+1] cycloaddition of triynes to the formation of a fused tropone system, we report here the application of this methodology to the one-step formation of the 6-7-7-5 fused tetracyclic scaffold of colchicinoids based on the [2+2+2+1] cycloaddition of o-phenylenetriynes with CO. In addition, the one-step formation of allocolchicinoids bearing the 6-7-6-5 fused tetracyclic system through the Rh-catalyzed [2+2+2] cycloaddition of o-phenylenetriynes is also described.

Full text of DOI:10.1021/acs.joc.8b01608

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Article
Synthesis of Colchicinoids and Allocolchicinoids
through Rh(I)-catalyzed [2+2+2+1] and [2+2+2]
Cycloadditions of o-Phenylenetriynes with and without CO
Chih-Wei Chien, Yu-Han Gary Teng, Tadashi Honda, and Iwao Ojima
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01608 • Publication Date (Web): 21 Aug 2018
Downloaded from http://pubs.acs.org on August 21, 2018
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Synthesis of Colchicinoids and Allocolchicinoids through
Rh(I)-catalyzed [2+2+2+1] and [2+2+2] Cycloadditions of o-
Phenylenetriynes with and without CO
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†
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,†,‡
Chih-Wei Chien, Yu-Han Gary Teng, Tadashi Honda, and Iwao Ojima*
†Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400,
‡Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New
York 11794-3400
Email: iwao.ojima@stonybrook.edu
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ABSTRACT
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The non-benzenoid aromatics, tropones and tropolones, are found in various natural products such
as colchicine and hinokitol, which possess significant biological activities. The traditional methods
to construct the tropone skeletons include oxidation of cycloheptatriene and [4+3]
cycloadditions. In addition, the total synthesis of colchicine and its analogues requires laborious
organic transformations in the formations of 6-7-7 fused rings systems. Transition metal-catalyzed
carbocyclization and cycloaddition reactions have proven to be among the most efficient methods
for constructing complex polycyclic systems. On the basis of our recent discovery of the Rh-
catalyzed carbonylative [2+2+2+1] cycloaddition of triynes to the formation of fused tropone
system, we report here the application of this methodology to the one-step formation of the 6-7-7-
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fused-tetracyclic scaffold of colchicinoids based on the [2+2+2+1] cycloaddition of o-
phenylenetriynes with CO. In addition, the one-step formation of allocolchicinoids bearing the 6-
-6-5 fused tetracyclic system through the Rh-catalyzed [2+2+2] cycloaddition of o-
phenylenetriynes is also described.
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
INTRODUCTION
Colchicine, a cytotoxic natural product and secondary metabolite of autumn crocus, is
originally extracted from the poisonous plant meadow saffron (Colchicum autumnale L.). Owing
to the capability in suppressing inflammation, colchicine is one of the oldest known drugs and has
been used for treatment of rheumatic complaints and especially gout for thousands of years. In
addition to gout, colchicine has also been used for treatment of familial Mediterranean fever,
pericarditis, and Behçet's disease, due to its anti-inflammatory effect. In recent years, colchicine
and its analogues have received considerable interest for cancer chemotherapy. After the structural
confirmation in 1952, a number of synthetic approaches have been elaborated following
fundamentally different strategies towards colchicine.1, 2 In spite of all available modern
methodologies, the development of a synthetic method with satisfactory efficiency towards
colchicine and its derivatives is still challenging. The difficulties inherent to the target structure lie
in the regioselective construction of the highly oxidized ring C with an unusual 6,7,7 fused ring
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system, which appears to have hindered the discovery of more active colchicine analogues.
Therefore, in order to further explore the pharmaceutical potential and study the structure-activity
relationships, it is of great importance to develop a synthetic method which enables an efficient
construction of colchicine derivatives and analogs.
To rapidly implement molecular complexity from readily available simple starting
materials, transition metal-catalyzed carbocyclization and cycloaddition reactions are recognized
as synthetically very important processes.4-7 Considerable advances have been made recently in
the development of higher order cycloaddition reactions such as [2+2+2+1],8-11 [3+3+1],12
[
2+2+2+2],13-15 [4+2+2],16-18 [5+2+1],19-24 and [5+1+2+1]25 processes. Various polycyclization
reactions have been employed for the construction of natural and unnatural fused-ring systems that
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can be further elaborated into specific targets. Recently, we discovered the Rh-catalyzed [2+2+2+1]
cycloaddition of linear 1,6,11-, 1,6,12- and 1,6,13-triynes with CO, forming the corresponding
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fused tricyclic tropone systems. [Note: After the submission of this article, a related [2+2+2+1]
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carbonylative cycloaddition of triyens was published, which followed up the Ph.D. dissertation
works26, 28 of the two authors (C.-W.C. and Y,-H.G.T.) of this article.] Conceptually, the tropone
moiety of colchicine can be constructed through the [2+2+2+1] cycloaddition of a tethered diyne,
methoxyethyne and CO (Scheme 1). However, this three-component higher cycloaddition is
obviously very challenging, partly due to regioselectivity control in addition to energetics.
Accordingly, we came up with a rational design of using tethered o-phenylenetriynes as the
substrates for the [2+2+2+1] cycloaddition with CO (Scheme 2).28 We envisioned that the
colchicine scaffold should be constructed in a single step using this methodology (Scheme 2). We
report here the Rh-catalyzed carbonylative [2+2+2+1] cycloaddition approach to the rapid
synthesis of novel colchicinoids. Besides colchicine, allocolchicine bearing
a
bisbenzocycloheptane 6-7-6 ring system is also known as a tubulin-interacting agent, exhibiting
apoptosis-inducing activity,29 and several synthetic routes to allocolchicine variants and their
biological activities have been reported.29-34 Accordingly, in the present work, we also examined
the formation of novel allocolchicinoid via [2+2+2] cycloaddition of o-phenylenetriynes (Scheme
2
).
Scheme 1. Retrosynthetic analysis of colchicine based on [2+2+2+1] cycloaddition approach
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Scheme 2. Colchicinoid and allocolchicinoid formations via higher cycloadditions of o-
phenylenetriynes
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
RESULTS AND DISCUSSION
Synthesis of o-phenylenetriynes. In order to prove our hypothesis on the possible
rapid construction of colchicinoide skeleton based on the Rh-catalyzed [2+2+2+1] cycloaddition
of designed triynes with CO, o-phenylenetriynes, 1a–d, 1f, 1h, 1l, 1m, and 1v, were synthesized
according to the sequence shown in Scheme 3. Diynealdehydes 5a–5c were obtained in good yield
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by Sonogashira coupling of iodobenzaldehydes 4a–4c with diethyl 2-(but-2-ynyl)-2-(prop-2-
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ynyl)malonate (12a). The diynealdehydes 5a–5c were then reduced with NaBH in MeOH to
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give diynealcohol 6a–6c, and subsequent alkylation with 1-bromobut-2-yne (13a) in the presence
of LiHMDS in THF afforded the desired triynes 1a–1c. o-Phenylenetriyne 1d was prepared
through alkylation of 6c with1-bromo-4,4-dimethylpent-2-yne (13b).
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Scheme 3. Synthesis of o-phenylenetriynes 1
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Diynealdehydes 5f, 5h, and 5m were prepared by Sonogashira coupling of 4c with diethyl
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,2-di(prop-2-yn-1-yl)malonate (12b), (diethyl 2-(prop-2-yn-1-yl)-2-(3-(trimethylsilyl)prop-2-
yn-1-yl)malonate (12c),36 and 1-(prop-2-yn-1-yloxy)but-2-yne (12d),38 respectively.
Diynealdehyde 5l was obtained from 4a using 12d. After reduction of the aldehydes to the
corresponding alcohols, o-phenylenetriynes 1f, 1h, 1l, and 1m were prepared by alkylation of
alcohols 6f, 6h, 6l, and 6m with 13a, respectively. It is noteworthy that during the synthesis of 1h,
a product without the TMS group, o-phenylenetriyne 1f was also isolated in 38% yield. Alkylation
of 6c with 3-bromoprop-1-yne (13c) gave 1v.
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o-Phenylenetriyne 1q was synthesized by the sequence shown in Scheme 4. Sonogashira
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coupling of iodinated benzyl alcohol 7 with THP-protected propagyl alcohol gave 8. Diyne 9
was obtained by etherification of 8, followed by deprotection. The Steglich esterification of 9 with
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o-Phenylenetriyne 1r was synthesized by Sonogashira coupling of 1040, 41 with 12a,
followed by substitution of the N,O-dimethylhydroxylamino moiety with a trimethylsilylacetylene
group (Scheme 5).
Scheme 4. Synthesis of o-phenylenetriyne 1q
Scheme 5. Synthesis of o-phenylenetriyne 1r
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Treatment of lithium acetylide of 1v with acetone gave 1w. The hydroxyl group of 1w was
protected with TESCl to afford 1e (Scheme 6).
Scheme 6. Synthesis of o-phenylenetriynes 1w and 1e
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Sonogashira coupling of 1f with phenyl iodide gave o-phenylenetriyne 1g. Lithium
acetylide of 1f with dimethylphenylsilylchloride (DMPSCl), dimethyl disulfide, and methyl
chroloformate gave 1i, 1j, and 1k, respectively (Scheme 7).
Scheme 7. Synthesis of o-phenylenetriynes 1g, 1i, 1j, and 1k
o-Phenylenetriynes 1n‒p bearing N-tosyl groups on both side chains were synthesized by
the sequence shown in Scheme 8. Diyne-benzylalcohols 6n–6p were prepared by Sonogashira
coupling of 4a–4c with 12e, followed by reduction with NaBH
N-tosylbut-2-yn-1-amine gave 1n‒p in good yields.
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. Mitsunobu reaction of 6n‒p with
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Scheme 8. Synthesis of o-phenylenetriynes 1n–1p
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o-Phenylenetriynes 1s‒u bearing a nitrogen atom on the side chain were synthesized as
shown in Scheme 9. Reductive amination of diyne-aldehyde 5a with propargylamine and
subsequent reduction with NaBH gave 1s. The secondary amine moiety of 1s was protected with
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a t-Boc group using di-tert-butyl dicarbonate to afford 1t. Lithium acetylide of 1t was reacted
with TMSCl to yield 1u.
Scheme 9. Synthesis of o-phenylenetriynea 1s, 1t, and 1u
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Optimization of the Rh-catalyzed carbonylative [2+2+2+1] cycloaddition
reaction conditions. o-Phenylenetriyne 1a was employed to optimize the reaction conditions
and the results are summarized in Table 1. The reaction of 1a in the presence of [Rh(CO)
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Cl] (10
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mol%) in eight different solvents (entries 1–8) was completed at 50 °C under ambient pressure of
CO for 48 h to give 2a as the predominant product accompanied by a small amount of 3a. The
products 2a and 3a are the products of [2+2+2+1] and [2+2+2] cycloaddition processes,
respectively. The attempted reactions in DMF (entry 9) and EtOH (entry 10) did not proceed at
all. The reaction in a mixed solvent, i.e., dichloroethane (DCE) and 2,2,2-trifluoroethanol (TFE)
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1:1), gave a high conversion, the product selectivity was low (2a/3a, 86:14, entry 8). Among the
solvents examined, the highest product selectivity (96:4) was observed in decane (entry 1), toluene
entry 3), and 1,4-dioxane (entry 7), wherein toluene gave the highest conversion (64%).
(
Accordingly, toluene was selected for further optimization. The reactions were carried out under
different CO pressures (entries 11−14). Interestingly, CO pressure did not affect the product
selectivity but affected the conversion, wherein higher CO pressure was found to slow down the
reaction. Thus, best conversion (100%) was achieved under an ambient pressure of CO in 36 h
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entry 13). The reaction in a microwave reactor for 3 h gave 70% conversion and 96:4 product
selectivity (entry 14). Although some acceleration might have happened, there was no dramatic
effect of microwave irradiation.
Table 1. Effects of solvent and CO pressure on the conversion and product selectivity in the
reaction of 1a
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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
1,4-dioxane
DCE/TFE (1/1)
DMF
10
11
12
EtOH
0
toluene
toluene
toluene
toluene
77
100
100
70
96 : 4
96 : 4
96 : 4
1
3
c
14
aA mixture of 1a (0.15 mmol) and [Rh(CO)
2
2
Cl] (10 mol%) in a solvent (3 mL, 0.05M concentration) was used for
each entry.
b
Conversion and product selectivity were determined by HPLC. Since the reactions appeared to be clean, the
selectivity shown would represent HPLC yields or conversion yields when the reaction did not complete.
c
The reaction was carried out using a microwave reactor.
Next, we examined other reaction variables in toluene under ambient pressure of CO.
Results are summarized in Table 2. As entries 1−3 of Table 2 show, the increase in reaction
temperature lowered the product selectivity. However, lowering temperature below 50 °C did not
show any benefit. At 35° C, product selectivity was not improved, but reaction was slowed as
expected (entry 4) and at 20 °C even the product selectivity became worse (entry 5). Therefore, 50
oC was selected as the optimal reaction temperature. Next, the effect of substrate concentration on
the reaction was examined (entries 6 and 7). When the reaction of 1a was performed at higher
concentration, the product selectivity was slightly increased (entry 6 vs. entries 3 and 7). Lowering
the catalyst amount slowed down the reaction but did not give significant change in the product
selectivity (entries 8−10).
At 5 mol% of [Rh(CO)
2
Cl
2
] and 0.1-0.2 M concentration of 1a (entries 11−14), the
2
increase in the reaction temperature by 10 °C to 60 °C accelerated the reaction considerably
without sacrificing the product selectivity (entry 13). Bubbling CO did not show appreciable effect
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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
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5
5
5
5
5
5
5
5
5
5
6
(
entry 12). Addition of 1,3-bis(diphenylphosphono)propane (DPPP) (10 mol%) was detrimental
to the reaction (entry 14). In this case, it is likely that DPPP blocks the proper coordination of
triyne 1a. Another Rh-catalyst, [Rh(COD)Cl] gave similar product selectivity but with lower
conversion (entry 15 vs. entry 6). We also examined several catalyst systems for this reaction,
including Rh(acac)(CO) Rh(PPh (CO)Cl, Rh(PPh Cl, Rh Rh Co
Rh(COD) ]SbF , [Co(CO) , Ru (CO)12, and Ir(PPh (CO)Cl. However, none of them showed
2
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
,
3
)
2
3
)
3
4
(CO)12
,
2
2
(CO)12,
[
2
6
4
]
2
3
)
3 2
ability to catalyze the [2+2+2+1] and [2+2+2] cycloaddition reactions.
Table 2. Effects of the temperature, substrate concentration and catalyst concentration on the
conversion and product selectivity in the reaction of 1a under CO
b
b
Temp.
( C)
Conc.
(M)
0.05
0.05
0.05
0.05
0.05
0.1
0.025
0.1
0.1
0.1
0.2
[Rh(CO)
2
Cl
2
]
2
Time
(h)
6
Conversion
(%)
100
100
100
62
Product selectivity
2a : 3a
71 : 29
93 : 7
a
Entry
o
(mol%)
10
10
10
10
10
10
10
7.5
5
1
2
3
4
5
6
7
8
9
110
80
50
35
20
50
50
50
50
50
50
50
60
16
36
72
120
24
72
48
48
48
24
48
48
96 : 4
96 : 4
91 : 9
97 : 3
96 : 4
97 : 3
97 : 3
96 : 4
58
100
96
82
50
26
31
49
94
1
1
0
1
2.5
5
5
96 : 4
97 : 3
96 : 4
c
12
0.1
0.1
d
13
5
5
1
4
50
50
0.1
0.1
48
24
0
nd
(10 mol% DPPP)
10
([Rh(COD)Cl] )
15
46
96 : 4
2
a
b
0
.15 mmol of 1a was used for each entry.
Conversion and product selectivity were determined by HPLC. Since the reactions appeared to be clean, the
selectivity shown would represent HPLC yields or conversion yields when the reaction did not complete.
c
The reaction was carried out by bubbling CO.
Isolated yield of 2a was 80%.
d
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Scheme 10. Reactions of o-phenylenetriynes 1b and 1c under CO
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
Based on these optimization studies, we selected the reaction conditions of entry 13 in
Table 2 as the standard for the subsequent investigation on the synthesis of a variety of
colchicinoids 2 and allocolchicinoids 3. Thus, o-phenylenetriynes 1b and 1c were subjected to the
standard conditions but with longer reaction time (Scheme 10). The reactions of 1b and 1c were
considerably slower than that of 1a. The product selectivity for the reaction of 1b was excellent
(2b:3b = 98:2) and pure 2b was isolated in 84% yield. In contrast, the reaction of 1c was sluggish
and resulted in only moderate product selectivity (2c:3c = 68:32).
Since the reaction conditions for 1c, in particular, were clearly not optimal, we examined
the reaction variables and effect of additives on the conversion and product selectivity. The results
are summarized in Table 3. The increase in reaction temperature to 80 °C exhibited substantial
enhancement in the reaction rate, while the product selectivity was only slightly affected. Thus,
1
00% conversion in 64 h was achieved with a 2c:3c ratio of 66:34 (entry 1). Next, we examined
the effect of additives on the reaction in toluene. In the presence of 4Å molecular sieves, a slightly
longer reaction time but similar product selectivity was observed (entry 2). While the addition of
Brønsted and Lewis acids drastically shortened the reaction time and afforded 100% conversion
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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
after 24 h, these acids did not improve the product selectivity (entries 3–7). Nevertheless, the
addition of a solid Lewis acid, montmorillonite K10 (K10), provided slightly better product
selectivity than those of other additives, and more importantly achieved 100% conversion in 32 h
at 60 °C with a 2c:3c ratio of 70:30 (entries 8 and 9), wherein 2c was isolated in 52% yield.
Consequently, we used K10 as the additive in the subsequent reactions of various o-
phenylenetriynes 1d-1r.
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
Table 3. Effect of additives on the reaction of 1c under CO
b
b
Temp.
Time
(h)
Conversion
(%)
Product selectivity
a
Entry
Additive
—
(
°C)
2c : 3c
Scheme
60
120
60
68 : 32
10
1
—
4Å MS
CSA
HOAc
TFE
LiClO
80
80
80
80
80
80
80
80
60
60
72
24
24
24
24
24
24
32
100
100
100
100
100
100
100
100
100
66 : 34
65 : 35
66 : 34
68 : 32
68 : 32
65 : 35
61 : 39
69 : 31
70 : 30
2
3
4
5
6
7
8
c
c
c
c
4
c
BF
3
·OEt
2
K10
K10
d
9
a
b
0
.15 mmol of 1c was used for each entry.
Conversion and product selectivity were determined by HPLC. Since the reactions appeared to be clean, the
selectivity shown would represent HPLC yields or conversion yields when the reaction did not complete.
c
0
.2 equiv. of additive was used.
d
Isolated yield of 2c was 52%.
Effects of the substituents at the - and -terminal ethyne units on the
carbonylative [2+2+2+1] cycloaddition. We have examined the effects of substituents (Y and
Z) at the two terminal ethyne moieties of ten o-phenylenetriynes 1d-k on the product selectivity
and yield of the [2+2+2+1] cycloaddition with CO. Results are summarized in Table 4.
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First, we fixed the Z terminus to a methyl group and introduced a bulky group to the Y
terminus. The reaction of 1d, bearing a t-Bu group as Y, gave 2d almost exclusively (99% by
o
HPLC; isolated yield of 2d was 83%) in 72 h at 60 C (entry 1). However, the same reaction
o
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
completed in 24 h at 80 C without any change in the product selectivity (entry 2). Thus, the
subsequent reactions were all carried out at 80 °C. The reaction of 1e, bearing a 2-
triethylsiloxyisopropyl group that is bulkier than a t-Bu group as Y at 80 °C, afforded 2e
exclusively (isolated yield of 2e was 87%), i.e., the formation of 3e was not detected at all (entry
3
). Accordingly, it is clearly shown that a bulky substituent at the Y terminal strongly favors the
tropone formation. Next, we fixed the Y terminus to a methyl group and introduced different
groups to the Z terminus. The reaction of 1f, bearing an unsubstituted enyne at the Z terminus (Z
=
H), gave 2f with only 56% selectivity although the reaction completed in 24 h (entry 4). The
reaction of 1g, bearing a phenyl group as Z, afforded 2g with 84% selectivity (entry 5). Since the
reaction of 1c, bearing a methyl group as Z, gave 2c with 69% selectivity, the introduction of a
bulkier substituent as Z appears to favor the tropone formation in a manner similar to the case of
Y. Thus, we introduced TMS and dimethylphenylsilyl (DMPS) groups as Z next. These reactions,
however, disclosed totally unexpected results.
The reaction of 1h, bearing a TMS group as Z, gave [2+2+2+1] cycloaddition products
with 96% combined yield (HPLC), accompanied by 3h (4%) (entry 6). However, surprisingly, no
anticipated product 2h was detected, and 2f (90%) and 2c (6%) were formed instead. The structures
of these products were unambiguously identified (see the Experimental Section). The formation
of 2f in this reaction can be accommodated rather easily by assuming the desilylation of 2h under
the reaction conditions. In contrast, the formation of 2c requires to hypothesize an unprecedented
methyl migration from the TMS group to the Z terminal ethyne carbon, involving C-Si activation.
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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
The reaction of 1h in the absence of K10 under otherwise the same conditions as those for entry 6
afforded the same products 2f (81%), 2c (13%) and 3c (6%) with slightly different ratio at 94%
conversion in 120 h (entry 7). Thus, it appears that K10 accelerates the reaction and rather
suppresses the methyl migration, but is not responsible for the desilylation process. It is worth
mentioning that the desilylation did not occur in the starting 1h to give 1f, since the product
selectivity and the reaction rate are markedly different between the reactions of 1f (entry 4) 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
1
h (entry 6). Thus, the desilylation should have occurred after the [2+2+2+1] cycloaddition was
completed or the carbonylated key intermediate (B or B’ in Scheme 11) leading to the formation
of the [2+2+2+1] cycloaddition product 2 was formed. It is also noteworthy that no desilylation
took place in the [2+2+2] cycloaddition process, forming 3h.
In a manner similar to entry 3 and entry 6, the reaction of 1i, bearing a bulky DMPS) group
as Z, yielded the [2+2+2+1] cycloaddition products 2 exclusively without any trace of the [2+2+2]
cycloaddition product 3i, wherein the product 2 was not 2i, but a mixture of 2g (79%) and 2g (21%)
(entry 8). Thus, in the same manner as the entry 6, the desilylation and the phenyl migration took
place in this reaction. To the best of our knowledge, this type of the methyl or phenyl group
migration from the TMS or DMPS group has not been reported in the literature. Therefore, this
novel methyl/phenyl migration reaction involving C-Si activation warrants further investigation.
The reaction of 1j, bearing a methylsulfanyl group as Z, gave a 1:1 mixture of 2j and 3j
(entry 9). Thus, it has been shown that the sulfide group does not interfere with this Rh-catalyzed
reaction, but it does not favor the tropone formation, either. The introduction of an electron-
withdrawing ester group to 1 as Z appears to be unfavorable to the [2+2+2+1] cycloaddition. Thus,
the reaction of 1k, bearing a methoxycarbonyl group as Z, yielded the [2+2+2] cycloaddition
product 3k as the major product (entry 10).
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Those results clearly indicate that the introduction of a bulky substituent to either ethyne
terminus as Y or Z strongly favor the carbonylative [2+2+2+1] cycloaddition process. Also, it is
disclosed that a bulky silyl group used as Z can be eliminated via a desilylation under the reaction
conditions. This finding can be further exploited for the design and synthesis of various
colchicinoids for structure-activity relationship studies.
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
Table 4. Substituent effects on the reaction of o-phenylenetriynes 1d–k under CO
b
b
Time
(h)
Conversion
(%)
Product selectivity
a
Entry
o-Phenylenetriyne
2 : 3
c
1d
1
72
24
100
100
100
100
100
100
94
99 : 1
99 : 1
Y = t-Bu, Z = Me
d
1d
2
Y = t-Bu, Z = Me
1
e
e
3
72
100 : 0
56 : 44
84 : 16
Y = CMe OTES, Z = Me
2
1f
4
16
Y = Me, Z = H
1
g
f
5
36
Y = Me, Z = Ph
1
h
6
96
90 (2f) : 6 (2c) : 4 (3h)
81 (2f) : 13 (2c) : 6 (3h)
79 (2f) : 21 (2g)
50 : 50
Y = Me, Z = TMS
g
1h
7
120
96
Y = Me, Z = TMS
1i
8
9
100
100
100
Y = Me, Z = DMPS
1j
Y = Me, Z = SMe
1k
120
20
1
0
34 : 66
Y = Me, Z = CO Me
2
a
b
0
.15 mmol of starting material was used for each entry.
Conversion and product selectivity were determined by HPLC. Since the reactions appeared to be clean, the
selectivity shown would represent HPLC yields or conversion yields when the reaction did not complete.
c
d
e
o
Reaction was carried out at 60 C.
Isolated yield of 2d was 83%.
Isolated yield of 2e was 87%.
Isolated yield of 2g was 66%.
f
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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
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
g
Reaction was carried out without K10 additive.
Effects of the tether groups on the carbonylative [2+2+2+1] cycloaddition.
Next, we investigated the effects of the tether groups connecting two ethyne groups as well as the
o-phenylene and ethyne groups on the product selectivity and yield of the [2+2+2+1] cycloaddition
process. Results are summarized in Table 5. The reactions of 1l and 1m, wherein the malonate
moiety of 1a and 1c were replaced with an ether group, gave the corresponding 2l and 2m with
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
9
8% and 70% selectivity (entries 1 and 2). Replacement of the ether tether and the malonate tether
of 1a, 1b and 1c with tosylamino groups gave nitrogen-containing o-phenylenetriynes 1n, 1o and
p, respectively. The reactions of 1n-p afforded the corresponding mixtures of 2n-p and 3n-p with
1
considerably lower product selectivity than that for 2a-c (entries 3-5).
The reaction of 1q, wherein the malonate moiety of 1c was replaced with an ester linkage,
yielded the corresponding [2+2+2] cycloaddition product 3q as the predominant product (87%
HPLC yield) (entry 6). Thus, the ester linkage at this tether position appears to be detrimental to
the tropone formation. The replacement of the but-2-ynyloxy moiety of 1c with a
trimethylsilylethynylcarbonylmethyl group gave 1r. The reaction of 1r afforded the corresponding
2
r’ (58%) and 3r (42%), wherein the originally expected product 2r was not yielded, but its
desilylated product 2r’ was obtained. The formation of 2r’ can be explained in the same manner
as that for the cases of the reactions of 1h and 1i discussed above (Table 4), but no methyl migration
was observed in this reaction.
Table 5. Reaction of o-phenylenetriynes 1l–ra
c
c
Temp. Time Conversion
( C)
Product selectivity
b
Entry
o-Phenylenetriyne
o
(h)
(%)
2 : 3
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d
1
60
80
48
48
100
100
98
:
2
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
2
70
:
30
e
3
60
30
100
81
:
19
4
70
80
80
80
24
48
100
100
96
6
4
1
6
5
3
:
:
:
:
34
55
87
42
5
f
6
120
24
7
100
58
a
b
c
The same conditions as shown in Table 4 were used.
.15 mmol of starting material was used for each entry.
Conversion and product selectivity were determined by HPLC. Since the reactions appeared to be clean, the
selectivity shown would represent HPLC yields or conversion yields when the reaction did not complete.
Isolated yield of 2l was 80%.
0
d
e
Isolated yield of 2n was 62%.
q was identified based on HRMS due to minute quantity.
f
2
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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
Proposed mechanism for the Rh-catalyzed [2+2+2+1] and [2+2+2]
cycloaddition reactions of 1. The proposed mechanism of the [2+2+2+1] and [2+2+2]
cycloaddition reactions of ortho-phenylenetriynes 1 is illustrated in Scheme 11. The carbonylative
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+2+2+1] cycloaddition reaction proceeds through (i) selective coordination of the diyne side
chain of 1 to the active Rh-catalyst species to give rhodacycle A or A’ ([2+2+M]); (ii) migratory
insertion of CO into the Rh‒C bond to form rhodacyclohexadienone B or B’; (iii) insertion of the
alkyne side chain of B or B’ into the Rh‒C bond to generate 6-7-8-5 fused-tetracyclic
rhodacyclooctatrienone C or C’; and (iv) reductive elimination to give [2+2+2+1] cycloaddition
product 2 and regenerate the active Rh-catalyst species.
The [2+2+2] cycloaddition reaction also involves rhodacyclopentadine A or A’. In this
reaction pathway, however, the alkyne side chain of A or A’ inserts into the Rh‒C bond, instead
of CO migratory insertion, leading to the formation of 6-7-7-5 fused-tetracyclic
rhodacycloheptatriene D, which undergoes reductive elimination to afford [2+2+2] cycloaddition
product 3. The [2+2+2] cycloaddition or cyclotrimerization of triynes and its applications is well
precedented.42
The proposed mechanism can nicely accommodate the observed remarkable effect of bulky
substituents at either terminal ethyne moiety (Y or Z), favoring the formation of the carbonylative
[
2+2+2+1] cycloaddion product 2. The bulky terminal groups, i.e., t-Bu, TMS, and DMPS, would
interfere with the approach of the alkyne side chain to the Rh metal of A or A’ and block or slow
down the alkyne insertion, which allows the CO migratory insertion to occur predominantly or
exclusively, pushing the catalytic cycle to produce the carbonylative [2+2+2+1] cycloaddition
product 2.
As described above, no desilylation took place in the [2+2+2] cycloaddition process,
2
0
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forming 3. Accordingly, it is strongly suggested that the rhodacyclooctatrienone C’ intermediate
would be responsible for the desilylation and the methyl/phenyl migration observed in this reaction.
Scheme 11. Proposed mechanism for the Rh-catalyzed [2+2+2+1] and [2+2+2] cycloaddition
reactions of triyne 1
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
Comparison of the results obtained for the reactions of 1a‒c and other o-phenylenetriynes,
it is obvious that the introduction of additional methoxy group to the C4-position of the o-
phenylene moiety significantly affects the formation of the fused tropone products. The electronic
effect of the methoxy group can be ruled out for this phenomenon since there is no apparent
difference in product selectivity between non-substituted o-phenylenetriynes such as 1a and
2
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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
dimethoxy-o-phenylenetriynes such as 1b. The unfavorable effect of the 4-methoxyl group in 1
on the carbonylative [2+2+2+1] cycloaddition would be explained as follows: (i) The 4-methoxy
group of the o-phenylene moiety restricts the free rotation of the rhodacyclopentadiene moiety of
A or A’; (ii) The lack of the free rotation places the alkyne side chain at a very good position to
coordinate to the Rh metal; (iii) The coordination of the alkyne moiety to the Rh metal facilitates
the alkyne insertion over CO migratory insertion to generate the rhodacycle D, leading to the
formation of the [2+2+2] cycloaddition product 3.
0
1
2
3
4
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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
Rh-catalyzed [2+2+2] cycloaddition. In addition to the Rh-catalyzed carbonylative
[
2+2+2+1] cycloaddition to synthesize colchicinoids, we also investigated the Rh-catalyzed
[2+2+2] cycloaddition of o-phenylenetriynes 1 as an efficient approach to allocolchicinoids. We
examined reaction variables in the reaction of 1a to optimize this process, as shown in Table 6. As
described above, under the carbonylative [2+2+2+1] cycloaddition conditions, only [Rh(CO)
and [Rh(COD)Cl] showed catalytic activity and the addition of 2,2,2-trifluoroethanol (TFE) as a
co-solvent appears to have favored the formation of [2+2+2] cycloaddition product 3a (Table 1,
2
Cl]
2
2
entry 8). Accordingly, a combination of [Rh(COD)Cl]
conditions for optimization.
2
and TFE was chosen as the initial reaction
2
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Table 6. Optimization of the [2+2+2] cycloaddition of 1a
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
b
[Rh(COD)Cl]
(mol%)
2
Temp.
( C)
Time
(h)
Conversion
(%)
Isolated Yield
(%)
a
Entry
Ligand
none
o
1
5
80
48
62
51
DPPP
10 mol%)
DPPP
10 mol%)
DPPP
2
3
4
5
5
80
16
1
100
100
100
100
86
92
94
92
(
(
5
80 (μw)
80 (μw)
100 (μw)
2.5
2.5
2
(
5 mol%)
DPPP
0.5
(5 mol%)
a
b
0
.15 mmol of 1a was used for each entry.
Conversion was determined by HPLC.
When the reaction of 1a was carried out in the presence of [Rh(COD)Cl]
2
(5 mol%) in TFE
o
at 80 C for 48 h, only 62% of the starting material 1a was consumed to afford the desired
cycloadduct 3a in 51% isolated yield (entry 1). Addition of 1,3-bis(diphenylphosphino)propane
(DPPP) (10 mol%) drastically accelerated the reaction to complete in 16 h, giving 3a in 86%
isolated yield (entry 2). Next, we carried out the reaction using a microwave reactor. The reaction
of 1a in the presence of [Rh(COD)Cl] (5 mol%) and DPPP (10 mol%) in TFE under microwave
2
o
irradiation at 80 C for 1 h, 3a was obtained in 92% isolated yield (entry 3). When the amounts of
the catalyst and the ligand were reduced to 2.5 and 5 mol%, respectively, the reaction needed 2 h
to complete, but gave 3a in 94% isolated yield (entry 4). The reaction of 1a under the same
conditions, except for the elevated temperature at 100 °C, completed in 30 min, giving 3a in 92%
isolated yield (entry 5).
Consequently, we selected the reaction variables under microwave irradiation in the entry
2
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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
5
as the standard conditions for the subsequent investigation of the scope and limitations of this
reaction process using a variety of o-phenylenetriynes 1. As Table 7 shows, various functional
groups and heteroatoms are well tolerated under the microwave irradiation conditions to give the
corresponding fused 6-7-6-5 tetracyclic allocolchicinoids 3 in moderate to excellent isolated yields.
Except for the reactions of 1d and 1i which required 1 h and 1.5 h irradiation to reach full
conversion (entries 4 and 8), all other o-phenylenetriynes completed the reaction within 30 min. It
was found that a free secondary amino group was not tolerated. Thus, the reaction of 1s, bearing a
free secondary amino group, gave a messy mixture with no trace of 3s (entry 17). On the other
hand, N-protected secondary amino groups were well tolerated in this reaction. Thus, the reactions
of 1n–p and 1t–u, bearing sulfonamide and carbamate groups, respectively, gave the
corresponding allocolchicinoids, 3n–p and 3t–u, in high to excellent yields (entries 13–15 and 18–
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
9).
Table 7. [2+2+2] cycloaddition of o-phenylenetriynes 1a–u
Product (isolated
Product
(isolated yield)
a
a
Entry
o-Phenylenetriyne
Entry
o-Phenylenetriyne
yield)
1
11
2
12
2
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3
13
14
15
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17
18
19
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
b
4
5
6
7
NH
EtO2C
EtO2C
3s (—)
c
8
9
2
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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
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1
0
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
Reaction of 1 (0.15 mmol) was carried out in the presence of [Rh(COD)Cl]
TFE at 100 C under microwave irradiation (250 W) for 0.5 h.
h irradiation.
.5 h irradiation.
2
(3.75 μmol) and DPPP (7.5 μmol) in
o
b
c
1
1
 CONCLUSIONS
The [2+2+2+1] cycloaddition of o-phenylenetriynes with CO catalyzed by Rh complexes
was investigated as a new and efficient approach to the rapid construction of various colchicinoids.
Various o-phenylenetriynes 1 were designed and synthesized to examine the feasibility as well as
the scope and limitation of this novel reaction process. The novel carbonylative [2+2+2+1]
cycloaddition of 1 proceeded as designed with broad functional group tolerance to afford the
corresponding colchicinoids 2 in moderate to excellent yields, accompanied by [2+2+2]
cycloaddition by-products 3. It has been found that the introduction of bulky substituents to the
terminal ethyne moieties can markedly promote the carbonylation process to give colchicinoids 2
exclusively. When silyl groups were introduced to the terminal ethyne moieties, desilylation took
place along with the formation of 2 under the reaction conditions, and an unprecedented
methyl/phenyl migration via C-Si activation was observed as a minor process. Besides the
carbonylative [2+2+2+1] cycloaddition, Rh-catalyzed [2+2+2] cycloaddition of 1 was also
investigated, which provided a rapid access to a variety of allocolchicinoids. This process was
found to be effectively promoted by microwave irradiation.
These two processes have a high synthetic potential to provide efficient routes to various
polycyclic skeletons of biological interest. Further studies on the expansion of these catalytic
processes for the synthesis of colchicinoids and allocolchicinoids, as well as their biological
2
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evaluations are actively underway in our laboratory.
 EXPERIMENTAL SECTION
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
General Methods. Microwave-assisted reactions were carried out with CEM Discover
1
13
S series microwave reactor. H and C NMR spectra were measured on Bruker Avance III HD-
1
13
Nanobay 400 (400 MHz H; 100 MHz C) spectrometer in a deuterated solvent using residual
1
: H, 7.26 ppm; 13C, 77.00 ppm. CHDCl
: H, 5.32 ppm; 13C, 54.00 ppm.
1
protons (CHCl
3
2
: H, 2.05 ppm; 13C, 29.92 ppm) as the internal standard. Melting points were
1
CD
3
COCHD
2
measured on a Thomas Hoover Capillary melting point apparatus and are uncorrected. Optical
rotations were measured on a Perkin-Elmer Model 241 polarimeter. TLC was performed on Merck
DC-Alufolien Kieselgel 60F 254 and flash column chromatography was carried out on Silicyle
®
SiliaFlashP60 . Analytical HPLC was carried out with a Shimadzu LC-2010A HPLC system.
High resolution mass spectrometry analysis was carried out on an Agilent LC-UV-TOF (ESI/APCI)
mass spectrometer at the Institute of Chemical Biology and Drug Discovery, Stony Brook
University. The X-ray crystallographic structures were obtained on Oxford Gemini A
diffractometer. Unless otherwise noted, all reactions were carried out under nitrogen atmosphere
in oven-dried glassware using standard Schlenck technique.
Materials. All solvents used as reaction media were purified using the Solvent
Purification System 400-4 from Innovative Technology, Inc. or distilled under nitrogen
immediately before use. Ether and THF were distilled from Na/benzophenone ketyl. Toluene and
CH2Cl
2
were distilled from CaH . Solvents for extraction and chromatography were reagent grade
2
and used as received. All chemicals were purchased from Alfa Aesar, Aldrich, or Acros Chemical
Co., and were used without further purification unless otherwise noted. 2-Iodobenzaldehyde (4a)
2
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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
43
was commercially available. 2-Iodo-4,5-dimethoxybenzaldehyde (4b) , 2-iodo-3,4,5-
2
9
44
trimethoxybenzaldehyde (4c) 2-[3-(but-2-ynyloxy)prop-1-ynyl]benzaldehyde (5l) and N-(but-
2-yn-1-yl)-N-[3-(2-formylphenyl)prop-2-yn-1-yl]-4-methylbenzenesulfonamide (5n)44 were
prepared by the literature methods.
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
Experimental Procedures. Diethyl 2-(but-2-ynyl)-2-[3-(2-formylphenyl)prop-2-
ynyl]malonate (5a). A solution of 2-iodobenzaldehyde (4a) (2.32 g, 10.0 mmol) and diethyl 2-
3
6
(
but-2-ynyl)-2-(prop-2-ynyl)malonate (12a) (3.75 g, 15.0 mmol) in THF (40 mL) was added to
a mixture of Pd(PPh Cl (0.14 g, 0.20 mmol), CuI (76 mg, 0.40 mmol), and K CO (4.15 g, 30.0
3
)
2
2
2
3
mmol) in THF (40 mL). After addition, the reaction mixture was refluxed for 24 h and then cooled
®
to room temperature. The reaction was filtered through Celite , and the filtrate was concentrated
in vacuo. The residue was purified by column chromatography on silica gel (hexanes:EtOAc = 9:1)
1
to give 5a (3.18 g, 90% yield) as a light yellow oil: H NMR (300 MHz, CDCl
3
) δ 10.45 (d, J =
0.9 Hz, 1H), 7.90–7.87 (m, 1H), 7.55–7.38 (m, 3H), 4.24 (q, J = 7.2 Hz, 4H), 3.27 (s, 2H), 2.97 (q,
1
3
J = 2.4 Hz, 2H), 1.77 (t, J = 2.4 Hz, 3H), 1.25 (t, J = 7.2 Hz, 6H); C NMR (100 MHz, CDCl
3
) δ
1
1
92.1, 169.2, 136.4, 133.9, 133.8, 128.6, 127.2, 127.1, 92.2, 79.6, 79.4, 73.1, 62.2, 57.1, 24.0, 23.6,
+
4.3, 3.7; HRMS (TOF) calcd for C21
In the same manner, 5b–c, 5f, 5h, 5m, 5o and 5p were synthesized using corresponding
diynes or alkyne.
Diethyl 2-(but-2-ynyl)-2-(3-(2-formyl-4,5-dimethoxyphenyl)prop-2-ynyl)malonate
H
23
O
5
[M + H] 355.1545, found 355.1545 (Δ = 0.0 ppm).
1
(5b). The titled compound 5b was obtained as a light yellow oil (1.28 g, 90% yield): H NMR
300 MHz, CDCl )  10.28 (s, 1H), 7.36 (s, 1H), 6.90 (s, 1H), 4.24 (q, J = 7.2 Hz, 4H), 3.94 (s,
H), 3.93 (s, 3H), 3.25 (s, 2H), 2.97 (q, J = 2.4 Hz, 2H), 1.77 (t, J = 2.4 Hz, 3H), 1.26 (t, J = 7.2
(
3
3
1
3
Hz, 6H); C NMR (125 MHz, CDCl )  191.1, 169.6, 149.5, 148.2, 131.5, 115.1, 113.9, 111.5,
3
2
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7.5, 81.5, 79.5, 73.2, 62.2, 57.2, 56.3, 56.1, 24.1, 23.5, 14.3, 3.7; HRMS (TOF) calcd for C23
H
27
O
7
+
[
M + H] 415.1757, found 415.1758 (Δ = +0.2 ppm).
Diethyl 2-(but-2-ynyl)-2-(3-(6-formyl-2,3,4-trimethoxyphenyl)prop-2-ynyl)malonate
1
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
(5c). The titled compound 5c was obtained as a light yellow oil (0.98 g, 71% yield): H NMR (300
MHz, CDCl ) δ 10.33 (s, 1H), 7.21 (s, 1H), 4.23 (q, J = 7.2 Hz, 4H), 3.95 (s, 3H), 3.93 (s, 3H),
3
3.91 (s, 3H), 3.30 (s, 2H), 2.99 (q, J = 2.4 Hz, 2H), 1.77 (t, J = 2.4 Hz, 3H), 1.26 (t, J = 7.2 Hz,
13
6
7
H); C NMR (125 MHz, CDCl
3
)  191.1, 169.2, 155.2, 154.0, 147.8, 132.5, 116.0, 105.2, 94.8,
9.5, 74.8, 73.2, 62.2, 61.6, 61.4, 57.0, 56.4, 24.3, 23.5, 14.3, 3.7; HRMS (TOF) calcd for C24
H
29
O
8
+
[M + H] 445.1862, found 445.1861 (Δ = ‒0.2 ppm).
Diethyl
2-[3-(6-formyl-2,3,4-trimethoxyphenyl)prop-2-ynyl]-2-(prop-2-
ynyl)malonate (5f). The titled compound 5f (1.30 g, 69% yield) was obtained as a pale yellow
o
1
solid: mp 95.0–96.5 C; H NMR (400 MHz, CDCl
3
) δ 10.31 (s, 1H), 7.20 (s, 1H), 4.28–4.19 (m,
4
H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.32 (s, 2H), 3.06 (d, J = 2.6 Hz, 2H), 2.05 (t, J = 2.6
13
Hz, 1H), 1.25 (t, J = 7.1 Hz, 6H); C NMR (100 MHz, CDCl
3
) δ 190.7, 168.6, 154.9, 153.8, 147.5,
1
32.2, 115.6, 104.50, 94.0, 78.4, 74.8, 71.8, 62.1, 61.4, 61.1, 56.4, 56.2, 24.0, 22.8, 14.0; HRMS
+
(TOF) calcd for C23
H
27
O
8
[M + H] 431.1706, found 431.1706 (Δ = 0.0 ppm).
Diethyl
2-[3-(6-formyl-2,3,4-trimethoxyphenyl)prop-2-ynyl]-2-[3-
(trimethylsilyl)prop-2-ynyl]malonate (5h). The titled compound 5h (1.84 g, 73% yield) was
1
obtained as an orange oil: H NMR (400 MHz, CDCl
3
) δ 10.29 (s, 1H), 7.18 (s, 1H), 4.26–4.16
(m, 4H), 3.91 (s, 3H), 3.90 (s, 3H), 3.87 (s, 3H), 3.28 (s, 2H), 3.05 (s, 2H), 1.24 (t, J = 7.1 Hz, 6H),
1
3
0
1
.10 (s, 9H); C NMR (100 MHz, CDCl ) δ 190.6, 168.6, 154.9, 153.7, 147.5, 132.1, 115.6, 104.9,
3
00.7, 94.2, 88.5, 74.7, 61.9, 61.3, 61.06, 56.6, 56.1, 24.2, 23.9, 14.0, –0.18; HRMS (TOF) calcd
+
for C26
H
35
O
8
Si [M + H] 503.2101, found 503.2100 (Δ = –0.2 ppm).
2
9
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