The Divergent Cascade Reactions of Arylalkynols with Homopropargylic Amines or Electron-Deficient Olefins: Access to the Spiro-Isobenzofuran- b-pyrroloquinolines or Bridged-Isobenzofuran Polycycles

Article abstract of DOI:10.1021/acs.joc.8b00691

Two divergent cascade reactions of arylalkynols with homopropargylic amines or electron-deficient olefins were developed to synthesize the spiro-isobenzofuran-b-pyrroloquinolines or bridged-isobenzofuran heterocycles in good yields, respectively. One reaction actually involved intramolecular 5-endo-dig hydroamination cyclization-protonation of homopropargylic amines to give cycloiminium ions and intramolecular 5-exo-dig hydroalkoxylation cyclization of arylalkynols to generate isobenzofuran with exocyclic double bond, followed by the nontypical Povarov-type reaction in the presence of PtCl₂/FeCl₃ cocatalysts. The other underwent intramolecular hydroalkoxylation cycloisomerization of alkynols with the subsequent normal [4 + 2] cycoaddition with dienophiles. Herein, the arylalkynols acted as both "masked" electron-rich olefins and "masked" electron-rich dienes.

Full text of DOI:10.1021/acs.joc.8b00691

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Article
The Divergent Cascade Reactions of Arylalkynols with Homopropargylic
Amines or Electron-deficient Olefins: Access to the Spiro-
isobenzofuran-b-pyrroloquinolines or Brigded-isobenzofuran Polycycles
Lun Wang, Lingyan Liu, Weixing Chang, and Jing Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00691 • Publication Date (Web): 06 Jun 2018
Downloaded from http://pubs.acs.org on June 6, 2018
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The Divergent Cascade Reactions of Arylalkynols with
Homopropargylic Amines or Electron-deficient Olefins:
Access to the Spiro-isobenzofuran-b-pyrroloquinolines or
Brigded-isobenzofuran Polycycles
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Lun Wang , Lingyan Liu* , Weixing Chang , Jing Li*
1
the State Key Laboratory and Institute of Elemento-Organic Chemistry, the College of Chemistry, Nankai
University, Tianjin, 300071 (China)
2
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Weijin Road 94#,
Nankai District, Tianjin 300071 (China)
E-mail: lijing@nankai.edu.cn; liulingyan@nankai.edu.cn
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ABSTRACT
Two divergent cascade reactions of arylalkynols with homopropargylic amines or
electron-deficient olefins were developed to synthesize the spiro-isobenzofuran-
b-pyrroloquinolines or bridged-isobenzofuran heterocycles in good yields, respectively.
One reaction actually involved intramolecular 5-endo-dig hydroamination
cyclization-protonation of homopropargylic amines to give cycloiminium ions and
intramolecular 5-exo-dig hydroalkoxylation cyclization of arylalkynols to generate
isobenzofuran with exocyclic double bond, followed by the nontypical Povarov-type
reaction in the presence of PtCl2/FeCl3 cocatalysts, the other underwent intramolecular
hydroalkoxylation cycloisomerization of alkynols with the subsequent normal [4+2]
cycoaddition with dienophiles. Herein, the arylalkynols acted as both “masked”
electron-rich olefins and “masked” electron-rich dienes.
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INTRODUCTION
The development of novel cascade reactions, possessing high efficiency, atom
economy, low cost and operational simplicity, has always been one of hot topic research
in the organic synthetic chemistry fields and become the focus of the chemists for ever.
And the new complex potential bioactive molecules can be constructed via several
consecutive steps to form multiple new bonds from simple and easily available substrates
in fast and efficient one pot cascade reaction. Obviously, the key points are the design
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and combination of applicable reactants for the cascade reactions. For instance, the
alkynols- or alkynlamines-based cascade reactions have attracted increasing attention in
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chemical synthesis in recent years. These cascade reactions afford the complex oxygen-
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and nitrogen-containing spiro or bridged fused heterocycles, as well as polycyclic
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structural units, which may have some certain bioactivities. For the arylalkynols 1,
previous reports mainly focus on the simple intramolecular 5-exo-dig and 6-endo-dig
hydroalkoxylation cyclizations to generate the isobenzofurans 2 (exo-cyclic enol ethers)
3
and isobenzopyrans 3 (endo-cyclic enol) (Figure 1).
Figure 1. The two possible Intramolecular hydroalkoxylation cyclization of arylalkynols
More recently, the less stable isobenzofurans and isobenzopyrans formed in situ have
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been developed as electron-rich olefins to undergo further diverse cycloadditions. Liu’s
research group reported many successful cascade reactions on the internal alkynols,
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which gave the isobenzopyrans, and followed by treating with other reactants.
Barluenga’s group also developed prosperous cascade reactions of alkynols to synthesize
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spiro-isobenzofuran polycyclic compounds 5. A typical example was the
multicomponents reaction of alkynols, aldehydes and amines in one pot through
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intramolecular hydroalkoxylation of alkynols and subsequent Povarov reaction (Scheme
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Scheme 1. The divergent reactions of alkynols and homopropargylic amines
On the other hand, alkynyl amines, especially for the β-aminoalkynes, can generate the
cycloenamines or cycloiminium ions intermediates through the intramolecular
hydroamination cyclization or further protonation. These two intermediates can further
perform various transformations. Ye’s group had made significant achievements in the
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field of hydroamination cyclization cascade reactions of N-protected β-aminoalkynes.
Our research group also exploited some hydroamination cyclization cycloaddition
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cascade reactions of N-arylhomopropargylic amines. Among them, we had ever used
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electron-rich olefins 7, such as the dihydrofuran, dihydropyran or dihydropyrrole, to react
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c
with homopropargylic amines 6 (Scheme 1b). In this reaction, the electron-olefins were
only limited to the cyclic olefins. Based on the previous literatures and as a continuous
work of our group, we herein designed to employ the arylalkynols 9 as “masked”
electron-olefins to react with the N-arylhomopropargylic amines 6 to deliver the complex
spiro-isobenzofuran-b-quinolines heterocycles. As a result, the reaction of alkynols and
homopropargylic amines was expectedly occurred, providing the complex polycyclic
compounds 10 in good yields (Scheme 1c). This interesting reaction actually involved an
intramolecular hydroamination cyclization-protonation of homopropargylic amines to
generate the cycloiminium ions and an intramolecular hydroalkoxylation of arylalkynols
to produce the isobenzofurans with exocyclic double bonds, followed by an
intermolecular nontypical Povarov reaction. Additionally, the isobenzofuran with
9
exocyclic double bond can isomerize to 1-methylisobenzofuran, which can be easily
captured by other electron-deficient dienes to perform the Diels-Alder reactions, and thus
giving the bridged polycycles 11 (Scheme 1c). The divergent cascade reactions of
alkynols would provide new strategies for the construction of complex nitrogen- and
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oxygen-containing polycycles, as may further lay a solid foundation for synthesizing
natural products or developing new bioactive molecules.
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RESULTS AND DISCUSSION
In our initial effort, we selected 4-chloro-N-(1-phenylbut-3-yn-1-yl)aniline 6c and
(2-ethynylphenyl)methanol 9a as model substrates using 10 mol% Cu(OTf)2 as catalyst
in CH3OH solvent. As a result, a spiro-isobenzofuran-b-pyrroloquinoline 10ca was
obtained in moderate yield (Table 1, entry 1). Changing the methanol solvent to toluene,
the yield of target molecule was slightly decreased (entry 2). Further screening the other
copper salts, such as CuCl2 and CuBr2, no improved results were obtained (entries 3-4).
Using FeCl3 catalyst, no target compound was observed and the phenylalkynol 9a
remained nearly untouched with small amount of homopropargylic amine 6c performing
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a formal self-dimerization (27% yield) (entry 5). Based on the literatures, we employed
PtCl2 as catalyst, the expected spiro-isobenzofuran-b-quinoline 10ca could be obtained in
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4% yield but with the self-dimerized side product of 6c in 51% yield (entry 6).
Considering for promoting the transformation of cycloenamine formed in situ to
cycloiminium ion, the cocatalysts were preferred to be used. For example, the reaction
could give the 10ca in improved yields in the presence of PtCl2/CuCl2 or PtCl2/CuBr2
cocatalysts (entries 7 and 8). Interestingly, the yield of spiro-isobenzofuran-b-
pyrroloquinoline 10ca was high up to 83% or 89% when employing the PtCl2/Fe(OTf)3
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or PtCl2/FeCl3 as cocatalysts, respectively (entries 9 and 10). Decreasing the amount of
homopropargylic amine 6c or the reaction temperature to room temperature, the reaction
gave a slightly decreased yield of product 10ca in the presence of PtCl2/FeCl3 cocatalysts
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(entries 11 and 12). Introducing the acidic Al2O3 as an additive, the yield remained hardly
changed yet (entry 13). In the case of PtCl2/AgOAc, the reaction could proceed but with
moderate yield of 10ca under dark conditions (entry 14). The reactions catalyzed by the
PtCl2/FeCl3 afforded no obvious improved results in other common used organic solvents,
such as CH3OH, n-PrOH, THF and CHCl3 (entries 15-18). And no reaction occurred in
CH3CN even with prolonging reaction time (entry 19). Under N2 atmosphere, similar
o
yield of 10ca was obtained (entry 20). Increasing the reaction temperature to 80 or 100 C,
the reaction gave the decreased yields of target molecules in toluene on the contrary
(Table 1, entries 21 and 22) in the presence of 5 mol% PtCl2 / 5 mol% FeCl . It should be
3
noteworthy that the corresponding products 10ca were obtained with nearly 7:2:1
diastereoselectivity in all cases. In the cases of low or moderate yields of target
compounds, the self-dimerization compound of homopropargylic amine 6c was observed
1
by the H NMR of crude products. Summarily, the optimal reaction conditions were 5
mol% PtCl2 / 5 mol% FeCl3, 1.5 equiv. homopropargylic amines, 1.0 equiv. arylalkynols,
o
0
.2 M (toluene), 50 C for 12 h in the air.
Table 1. Optimization studies of the cascade reaction of homopropargylic amine 6c and
a
phenylalkynol 9a
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b
Entry
Catalyst (mol%)
Cu(OTf)2 (10)
Solvent
CH3OH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Yield (%)
1
2
49
36
Cu(OTf)2 (10)
3
CuCl2 (10)
42
4
CuBr2(10)
39
5
FeCl3 (5)
0(27)
c
6
PtCl2 (5)
44 (51)
7
PtCl2 (5) / CuCl2 (10)
PtCl2 (5) / CuBr2 (10)
PtCl2 (5) / Fe(OTf)3 (5)
PtCl2 (5) / FeCl3 (5)
PtCl2 (5) / FeCl3 (5)
PtCl2 (5) / FeCl3 (5)
PtCl2 (5) / FeCl3 (5)
67
58
83
89
70
72
86
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d
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g
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PtCl2 (5) / AgOAc (5)
PtCl2 (5) / FeCl3 (5)
PtCl2 (5) / FeCl3 (5)
PtCl2 (5) / FeCl3 (5)
PtCl2 (5) / FeCl3 (5)
PtCl2 (5) / FeCl3 (5)
PtCl2 (5) / FeCl3 (5)
PtCl2 (5) / FeCl3 (5)
PtCl2 (5) / FeCl3 (5)
PhMe
MeOH
n-PrOH
THF
48
77
1
5
1
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53
1
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55
h
1
8
CHCl3
MeCN
PhMe
PhMe
PhMe
61
h
1
9
N.R.
88
i
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2
1
63
k
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2
47
a
Standard procedure: The homopropargylic amine 6c (76.7 mg, 0.3 mmol, 1.5 equiv.) and
(
2-ethynylphenyl)methanol 9a (26.4 mg, 0.2 mmol), catalyst and solvent (1 mL) were sequentially added
o
b
c
into the reaction tube. The reaction mixture was stirred at 50 C for 12 h in the air; Isolated yield; The
d
e
bracket was the yield of self-dimerized side product (counted by the loading of 6c); 1.2 equiv. 6c; The
f
g
h
reaction temperature was r.t.; 2.0 equiv. acidic Al2O3 was added; Under dark condition; The reaction
i
j
o
k
time was 24 h; under N atmosphere; The reaction temperature was 80 C; The reaction temperature
2
o
was 100 C.
The scope of the nontypical Povarov-type cascade reaction was evaluated on the
various homopropargylic amines 6 and alkynols 9. As shown in Table 2, all reactions
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could smoothly proceed and afford the corresponding spiro-isobenzofuran-
b-pyrroloquinolines in good to high yields. Moreover, the homopropargylic amines
bearing with electron-withdrawing substituted aryls on N atom or C atom generally
rendered better yields of corresponding products than that of electron-donating
substituted aryls compounds (10ba-10da, 10ha-10ja, 10la vs 10ea-10ga, 10ka). Even for
the nitro-substituted aryl substrate 3l, the reaction could also produce the 10la in 72%
total yields with 9:1 dr value. In the cases of homopropargylic amines with steric
hindrance naphthyl group (6m) and heteroatomic thiophenyl (6n) as well as hydrogen
atom (6o), the reactions gave the corresponding spiro-isobenzofuran-b-pyrroloquinolines
in above moderate yields (10ma-10oa). Similarly, for the arylalkynols 9, whether bearing
with electron-donating substituents or electron-withdrawing groups, the reaction afforded
the target molecules in good yields (10pb, 10jc and 10jd). Notably, the small amount of
self-dimerization compounds were concomitantly obtained besides the moderate yields of
spiro-isobenzofuran-b-pyrroloquinolines were produced (10aa, 10fa, 10ga, 10ka, 10ma
and 10oa). The diastereoselectivities of most target products were good with > 9:1 dr
values. And three diastereoisomers were generated at least and could not be isolated by
simple silica gel column chromatography. Therefore, the single crystal could not be
obtained, thus the absolute configuration of the major isomer remained unclear at present.
Nevertheless, the DEPT and 2D NMR analyses of product 10aa (HMBC and HMQC)
were determined and the structure was unambiguously confirmed (Figure S1-S4).
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Table 2. The hydroamination cyclization-protonation / hydroalkoxylation nontypical Povarov-type
a,b
cascade reactions of various homopropargylic amines 6 and arylalkynols 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
Various homopropargylic amines 6 and phenylalkynols 9a:
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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
Other arylalkynols 9b-9d:
a
Standard procedure: The homopropargylic amines 6 (0.3 mmol, 1.5 equiv.) and alkynols 9 (0.2
mmol), PtCl
2
(2.7 mg, 0.01 mmol, 5 mol%) and FeCl
3
(1.6 mg, 0.01mmol, 5 mol%) as well as toluene
o
(2 mL) were sequentially added into the reaction tube. The reaction mixture was stirred at 50 C for 12
b
1
c
h in the air; Isolated yield and the diastereoisomers ratios were determined by the H NMR; The
product was self-dimerization of homopropargylic amine and the yield was counted according to the
amount of homopropargylic amine.
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8
9
Since the isobenzofuran with exocyclic double bond generated from arylalkynol 9 can
isomerize to 1-methylisobenzofuran, which may act as diene, we attempted to introduce
dienophiles. The N-phenylmaleimide sa was first selected to react with the
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
1
-(2-ethynylphenyl)ethan-1-ol 9f. As shown in Table 3, the reaction of 9f and sa (1.2
o
equiv.) was complicated in toluene at 50 C with the prolonging reaction time for 4 h in
the presence of 5 mol% PtI2 (Table 3, entry 1). To our delight, the expected
o
bridged-isobenzofuran-polycycle was obtained with 55 % yield at elevating 80 C (entry
o
2
). Further increasing the reaction temperature to 110 C, slightly improved yield of
o
target molecule was generated (entry 3). Nevertheless, the reaction was messy at 130 C
o
in anisole (entry 4). Other solvents were then examined at 110 C with PtI2 catalyst, no
obvious improved results were obtained (entries 5-10). Adjusting the amount of the sa
from 1.2 equiv. to 1.5 equiv., the product 11fa was given in increased yield of 79% (entry
1
1). Changing the PtI to PtCl , the reaction could also smoothly proceed with slightly
2 2
decreased yield of 11fa (entry 12). The common used AuCl3 and AuCl catalysts were
also investigated and the reaction was complicated with no target compound. Notably, the
endo-11fa was generated as a major prodcuct in all above cases. Therefore, the optimal
reaction conditions were as follows: arylalkynols 9 1.0 equiv., dienophiles 1.5 equiv., 5
o
mol% PtI2, toluene (0.4 M), 110 C for about 2 h.
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2
3
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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
Table 3. The experimental parameters screening on the hydroalkoxylation cascade reactions of
a
1
-(2-ethynylphenyl)ethan-1-ol 9f and N-phenylmaleimide sa
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
o
1
[b]
Entry sa (equiv.) T( C)
Solv.
toluene
toluene
toluene
anisole
anisole
DMF
H NMR Yield (%)
1
2
3
4
5
6
7
8
9
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
50
complicated
80
55
110
130
110
110
110
110
110
110
61
complicated
48
37
44
51
47
56
1,4-dioxane
THF
MeCN
DCM
1
0
11
1.5
110
toluene
79
[
c]
1
2
1.5
110
toluene
72
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6
7
8
9
a
Standard procedure: The 1-(2-ethynylphenyl)ethan-1-ol 9f (29 mg, 0.2 mmol) and
2
N-phenylmaleimide (given amount), PtI (2.7 mg, 0.01 mmol, 5 mol%) and solvent (0.5 mL) were
sequentially added into the reaction tube. The reaction mixture was stirred under given conditions for
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 1
c
2
h in the air; H NMR yield of crude product using benzylbromide as an internal standard sample.
The catalyst was PtCl (5 mol%).
2
With the optimized reaction conditions in hand, we examined the scope of this cascade
reaction with various arylalkynols and dienophiles. The results were shown in Table 4.
Both electron withdrawing and electron donating substituents on the alkynols bearing
aromatic ring proceeded smoothly under the standard reaction conditions and afforded
the correspongding products in 72-81% yields (11aa-11da). Moreover, the large steric
hindrance naphthylalkynol was also competent with N-phenylmaleimide in this reaction
(
11ea). Additionally, in the cases of 1-(2-ethynylphenyl)ethan-1-ol 9f, various N-alkyl- or
aryl- substituted maleimides delivered the bridged heteropolycycles in 55-79% yields
(11fa-11fd). Employing other dienophiles, such as quinone, benzoquinone, maleic
anhydride and diethyl but-2-ynedioate, these reactions could also afford the polycycles in
good yields with excellent diastereoselectivities (11fe-11fh). For the 11ga, the allenyl
group of the allenylalkynol remained untouched in this hydroalkoxylation
cyclization-[4+2]-cycloaddition cascade reaction. The absolute configuration was
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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
unambiguously determined by the single-crystal X-ray diffraction of endo-11ga (Figure
1
0
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
Table 4. The hydroalkoxylation cascade reactions of various arylalkynols
9
and
a,b
electron-deficient olefins
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The Journal of Organic Chemistry
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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
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
2
Standard procedure: The arylalkynols 9 (0.4 mmol) and dienophiles (0.6 mmol, 1.5 equiv.), PtI (2.7
mg, 0.01 mmol, 5 mol%) and toluene (1 mL) were sequentially added into the reaction tube. The
b
reaction mixture was stirred under given conditions for 2 h in the air; Isolated yield.
Figure 2. The ORTEP drawing (30% thermal ellipsoids) of endo-11ga
The gram scale of these two divergent cascade reactions between the aryalkynols and
homopropargylic amines or dienophiles were then investigated. As shown in Scheme 2,
the spiro-cyclic compound 10da and the bridge-cyclic mixture of 11fa and 11fa’ could
be obtained in 61% and 72% yield, respectively.
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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
Scheme 2. The gram scale of these two divergent cascade reactions
In addition, the bridged polycyclic compounds 11 could be easily transformed to the
multi-susbtituted naphthene derivatives 12 with high yields (86-91%) in the presence of
Cu(OTf)2 (Table 5).
Table 5. The transformation of bridged polycycles
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The Journal of Organic Chemistry
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9
3
-6
Based on the previous literatures about the arylalkynols and combined with our
8
developed methodologies about the homopropargylic amines , the possible mechanisms
of these two reactions were proposed (Scheme 3). Herein, the PtCl2 mainly catalyzed the
intramolecular hydroalkoxylation cyclization of the arylalkynol 9a to render the
isobenzofuran intermediate III (red), and the FeCl3 preferred to catalyze the
intramolecular hydroamination cyclization of homopropargylic amine 6a and followed by
the protonation in the presence of trace protonic acid to give the cycloiminium ion
intermediate VII. The intermediate III (red) attacked the intermediate VII to give the
final product 10aa via two steps of nucleophilic addition (VII-VIII) and proton
elimination processes (VIII-IX). On the other hand, the intermediate III could easily
isomerize to intermediate X (blue) through the 1,5-hydrogen shift, which was followed
by the normal [4+2]-cycloaddition reaction in the presence of the high reactive dienophile
sa to afford the bridge-cyclic compounds 11aa and 11aa’.
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
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Page 20 of 55
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2
3
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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
Scheme 3. The possible mechanisms of these two cascade reactions
CONCLUSION
In conclusion, the divergent cascade reactions of arylalkynols and homopropargylic
amines or dienophiles were developed in the presence of PtCl2/FeCl3 cocatalysts or PtI2.
The arylalkynols performed the intramolecular hydroalkoxylation cyclization to deliver
the isobenzofurans with exocyclic double bond, which could undergo nontypical Povarov
reactions with the homopropargylic amines. And the isobenzofurans can isomerize to the
1-methylisobenzofurans to act as electron-rich dienes to further react with dienophiles via
normal Diels-Alder cycloaddition process. In the former, the cascade reaction actually
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The Journal of Organic Chemistry
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8
9
involves intramolecualr hydroalkoxylation cyclization of arylalkynols and intramolecular
hydroamination cyclization-protonation of homopropargylic amines as well as
subsequent Povarov-type reaction. These four steps were highly efficiently achieved in
one pot and four new bonds were formed, concomitant with two new stereocenters. Thus
the complex spiro-isobenzofuran-pyrrolo-b-quinolines fused heteropolycycles were
facilely constructed. Whereas in the latter, the intramolecular hydroalkoxylation
cycloisomerization of arylalkynols and [4+2]-cycloaddition processes were involved, and
consequently a bridged isobenzofuran polycycles were produced with four new bonds
and three new stereocenters formed in one pot. These two methodologies provide simple
and highly efficient strategy for the construction of complex heteropolycyclic compounds.
Further research on the synthesis of the bioactive natural products or pharmaceutical
intermediates is our ongoing work.
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
EXPERIMENTAL SECTION
1
. General Information
1
13
The H NMR, C NMR and DEPT (Distortionless Enhancement by Polarization
Transfer) as well as HMQC (Heteronuclear Multiple Quantum Correlation) and HMBC
(Heteronuclear Multiple Bond Correlation) spectra were recorded at Bruker AV 400
1
13
MHz or 600 MHz. H and C NMR Chemical shifts were calibrated to tetramethylsilane
as an internal reference. Chemical shifts are given in (ppm) and coupling constants (J) in
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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
Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet:
t, triplet; q, quartet; m, multiplet; Infrared spectra were recorded on an Bruker Fourier
transform spectrometer (FT-IR) and are reported in wave numbers. High resolution mass
spectrometric (HRMS) analyses spectrum was determined on the Varian 7.0T FTMS
instrument (Fourier transform ion cyclotron resonance, FTICR).
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
. Synthesis and characterization
1) Synthesis and characterization of the Imines
A dried round-bottom flask was charged with aromatic aldehydes (20 mmol), the
8d,8f
(
appropriate anilines (20 mmol), 4Å molecular sieves (1g/1.0mmol aldehyde) and
dichloromethane. The reaction mixture was stirred at room temperature and traced by
TLC until the reaction finished. Then the mixture was filtered and the filtrate was
concentrated underreduced pressure, gave the pure imines without additional purification.
(E)-N-(2-bromo-4-fluorobenzylidene)-4-methylaniline: Yellow solid; 5.8 g, yield 99%;
1
H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.18 (dd, J = 8.8, 6.3 Hz, 1H), 7.23
dd, J = 8.1, 2.6 Hz, 1H), 7.17 – 7.09 (m, 4H), 7.01 (td, J = 8.3, 2.6 Hz, 1H), 2.32 (s, 3H);
(
1
3
C NMR (101 MHz, CDCl3) δ 165.2, 162.6, 156.7, 148.9, 136.4, 131.29, 131.26, 130.6,
1
30.5, 129.9, 126.3, 126.18, 121.19, 120.4, 120.1, 115.5, 115.2, 21.1.
8d,8f
(2) Synthesis and characterization of homopropargylic amines (6a-6p)
The homopropargylic amines (6a-6p) were prepared according to the known
procedures. Among them, the 6g and 6h were unknown compounds.
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9
An aluminum amalgam was prepared from aluminum powder (0.5 g, 18.0 mmol) and a
catalytic amount of mercuric chloride (10 mg) in 7.5 mL anhydrous THF by vigorously
stirring at room temperature for 1 h under a N2 atmosphere. A solution of propargylic
bromide (18.0 mmol) in 12.5 mL of anhydrous THF was then slowly added to the
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
o
suspension at such a rate as to maintain the temperature between 30-40 C. After the
addition, the reaction mixture was continued to stir until a dark grey solution formed. The
generated propargylic aluminum sesqui-bromide solution was added to a solution of
o
imine (6.0 mmol) in 20.0 mL of anhydrous THF at 0 C under N2 atmosphere. The
o
reaction mixture was stirred at 0 C for about 1 h, then warmed to room temperature and
continued to stir for additional 3-4 h (monitored by TLC). The mixture was quenched by
adding saturated NH4Cl aqueous solution, and extracted with EtOAc (3 × 20 mL). The
combined organic extracts were washed with brine and dried over MgSO4, and then
filtered, the filtration was concentrated in vacuo to give the residue. The residue was
purified by flash chromatography over silica gel (gradient elution of EtOAc/petroleum
ether, PE : EA = 50 : 1).
1
4-methyl-N-(1-(m-tolyl)but-3-yn-1-yl)aniline (6g): Yellow oil; 1.03 g, yield 69%; H
NMR (400 MHz, Chloroform-d) δ 7.11 (s, 3H), 6.98 (d, J = 6.1 Hz, 1H), 6.84 (d, J = 8.2
Hz, 2H), 6.40 (d, J = 8.2 Hz, 2H), 4.37 (t, J = 6.2 Hz, 1H), 4.18 (s, 1H), 2.71 – 2.48 (m,
1
3
2H), 2.25 (s, 3H), 2.11 (s, 3H), 1.96 (t, J = 2.2 Hz, 1H). C NMR (101 MHz, CDCl3) δ
1
45.1, 142.6, 138.4, 129.8, 128.7, 128.46, 127.23, 127.17, 123.6, 114.1, 80.8, 71.4, 57.0,
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8.3, 21.8, 20.6. HRMS (ESI-FT-ICR) m/z: [M + H] Calcd for C18H20N 250.1596;
found 250.1601.
N-(1-(2-bromo-4-fluorophenyl)but-3-yn-1-yl)-4-methylaniline (6h): Yellow solid;
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.44 g, yield 72%; m.p. 52-54 C; H NMR (400 MHz, Chloroform-d) δ 7.45 (dd, J = 8.7,
6.1 Hz, 1H), 7.31 (dd, J = 8.1, 2.6 Hz, 1H), 6.96 (dd, J = 8.3, 2.5 Hz, 1H), 6.94 – 6.89 (m,
2
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H), 6.37 (d, J = 8.4 Hz, 2H), 4.85 (s, 1H), 4.44 (s, 1H), 2.85 (ddd, J = 17.0, 4.5, 2.7 Hz,
13
H), 2.60 (ddd, J = 17.0, 6.6, 2.6 Hz, 1H), 2.19 (s, 3H), 2.08 (t, J = 2.6 Hz, 1H);
C
NMR (101 MHz, CDCl3) δ 163.0, 160.6, 144.1, 136.4, 136.3, 130.0, 129.43, 129.35,
127.6, 122.9, 122.8, 120.5, 120.2, 115.2, 115.0, 113.9, 79.7, 72.2, 54.7, 26.1, 20.6.
+
HRMS (ESI-FT-ICR) m/z: [M + H] Calcd for C17H16BrFN 332.0450; found 332.0442.
11
(
3) Synthesis and characterization of homopropargylic amines (6o)
The N-(but-3-yn-1-yl)aniline 6o were prepared according to the known procedures. To
a solution of but-3-yn-1-ol (10 mmol, 700 mg) in DCM (30 mL) at 0 ºC was added Et N
3
(
20 mmol, 2. 8mL) and TsCl (13 mmol, 2.478 g). The solution was slowly warmed to
room temperature and stirred for overnight. Then saturated NaHCO3 aqueous solution
was added and extracted several times with DCM. The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure. Purification by flash
chromatography (10:1 hexanes/EtOAc) provided a colorless oil but-3-yn-1-yl
4-methylbenzenesulfonate (1.90 g, 90%).
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To a solution of anilines (12.0 mmol), p-toluenesulfonate derivatives (8.0 mmol) and
KI (132 mg, 0.8 mmol) in DMF (20 mL) was added K2CO3 (3.3 g, 24.0 mmol). The
mixture was heated to 90 °C. After complete consumption of the p-toluenesulfonate
derivatives, the reaction mixture was cooled to room temperature and quenched with a
saturated solution of NH4Cl. EtOAc was used to extract the product from the aqueous
layer (3 × 60 mL). The combined organic layer was washed with water (3 × 50 mL),
dried over Na2SO4, filtered and concentrated to afford the crude product, which was
purified by flash column chromatography to afford the product in moderate yield as
yellow oil 6o (765 mg, 66%).
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(
4) Synthesis and characterization of the arylalkynols (9a-9f)
To a solution of 2-bromobenzaldehyde or its derivatives (20 mmol, 1 equiv.),
PdCl2(PPh3)2 (702.0 mg, 5 mol%), and CuI (76.0 mg, 2 mol%) in NEt3 (40.0 mL) was
added under N atmosphere. After being stirred for 10 min at room temperature, terminal
2
acetylene (1.5 equiv.) was added to the mixture. The resulting mixture was heated under
N2 atmosphere at 50 °C for 6-18 hours. After the reaction was completed, the reaction
mixture was quenched with distilled water and extracted with CH2Cl2 (three times). The
combined organic layer was washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by column chromatography on silica gel to afford the
desired product 2-((trimethylsilyl)ethynyl)benzaldehyde derivatives S1.
The 2-((trimethylsilyl)ethynyl)benzaldehyde derivatives (1.0 equiv.) was dissolved in
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the mixture solution of MeOH, and treated with K2CO3 (2.0 equiv.). After stirring at
ambient temperature for 2 h, the mixture was diluted with Et2O, partitioned with H2O,
dried over Na2SO4 and concentrated in vacuo, purified by flash column chromatography
to give the arylalkynyl benzaldehyde derivatives product S2.
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The arylalkynyl benzaldehyde derivatives (1.0 equiv.) was added to round-bottomed
flask and dissolved by MeOH. At 0℃, NaBH4 (2.0 equiv.) was added to the flask in
batches. After 30 minutes, the mixture was quenched with saturated NH4Cl aqueous
solution, and then was washed three times with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column chromatography on silica gel
to afford the desired product 9.
(2-ethynylphenyl)methanol (9a) (purified by column chromatography over silica gel
treated with petroleum ether/EtOAc (5:1)): Yellowish solid;1.8 g, yield 68%; m.p. 64-66
o
1
C; H NMR (400 MHz, Chloroform-d) δ 7.48 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.7 Hz,
1
1
H), 7.35 (td, J = 7.6, 3.8 Hz, 1H), 7.28 – 7.19 (m, 1H), 4.80 (s, 2H), 3.32 (d, J = 1.6 Hz,
1
3
H), 2.46 (s, 1H); C NMR (101 MHz, CDCl3) δ 143.4, 133.0, 129.4, 127.6, 127.4,
+
120.3, 82.2, 81.5, 63.8; HRMS (ESI-FT-ICR) m/z: [M + H] Calcd for C9H9O 133.0653,
found 133.0659.
(2-ethynyl-4-methoxyphenyl)methanol (9b) (purified by column chromatography over
silica gel treated with petroleum ether/EtOAc (3:1)): Red solid; 2.4 g, yield 74%; m.p.
o
1
7
1-73 C; H NMR (400 MHz, Chloroform-d) δ 7.31 (dd, J = 8.5, 1.8 Hz, 1H), 7.01 (t, J =
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.3 Hz, 1H), 6.89 (dt, J = 8.6, 2.3 Hz, 1H), 4.73 (d, J = 1.9 Hz, 2H), 3.78 (d, J = 1.9 Hz,
1
3
3H), 3.31 (d, J = 1.8 Hz, 1H), 2.34 (s, 1H); C NMR (101 MHz, CDCl3) δ 135.8, 129.3,
+
1
17.8, 113.3, 110.2, 81.7, 81.5, 63.4, 55.6; HRMS (ESI-FT-ICR) m/z: [M + H] Calcd
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for C10H11O2 163.0759, found 163.0755.
(2-ethynyl-4-methylphenyl)methanol (9c) (purified by column chromatography over
silica gel treated with petroleum ether/EtOAc (5:1)): Yellow solid; 2 g, yield 68%; m.p.
o
1
6
1
0-62 C; H NMR (400 MHz, Chloroform-d) δ 7.35 – 7.28 (m, 2H), 7.16 (d, J = 8.0 Hz,
1
3
H), 4.77 (s, 2H), 3.29 (d, J = 2.0 Hz, 1H), 2.32 (s, 3H), 2.22 (s, 1H); C NMR (101
MHz, CDCl3) δ 140.5 , 133.6 , 130.3 , 127.7 , 120.34 , 81.71 , 81.66 , 63.8 , 21.1. HRMS
+
(ESI-FT-ICR) m/z: [M + H] Cacld for C10H11O 147.0810, found 147.0811.
(2-ethynyl-5-fluorophenyl)methanol (9d) (purified by column chromatography over
silica gel treated with petroleum ether/EtOAc (5:1)): Yellow solid; 2.3 g, yield 77%; m.p.
o
1
5
9-61 C; H NMR (400 MHz, Chloroform-d) δ 7.46 (dd, J = 8.4, 5.5 Hz, 1H), 7.20 (dd, J
=
9.4, 2.7 Hz, 1H), 6.93 (td, J = 8.4, 2.7 Hz, 1H), 4.81 (s, 2H), 3.30 (s, 1H), 2.36 (s, 1H);
1
3
C NMR (101 MHz, CDCl3) δ 164.5, 162.0, 146.5, 146.4, 134.9, 134.8, 115.92, 115.88,
114.7, 114.48, 114.46, 114.2, 82.02, 82.00, 80.4, 63.3, 29.9, 23.3; HRMS (ESI-FT-ICR)
+
m/z: [M + H] Cacld for C9H8FO 151.0559, found 151.0561.
(1-ethynylnaphthalen-2-yl)methanol (9e) (purified by column chromatography over
silica gel treated with petroleum ether/EtOAc (5:1)): Yellow solid; 2.5 g, yield 69%; m.p.
o
1
8
7-89 C; H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 8.3 Hz, 1H), 7.79 – 7.73 (m,
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H), 7.54 – 7.47 (m, 2H), 7.43 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 4.96 (s, 2H), 3.67 (s, 1H),
1
3
2.10 (s, 1H); C NMR (101 MHz, CDCl3) δ 142.6, 133.8, 132.7, 129.6, 128.4, 127.4,
+
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26.6, 126.2, 125.3, 117.4, 87.59, 79.5, 64.4; HRMS (ESI-FT-ICR) m/z: [M + H] Cacld
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for C13H11O 183.0810, found 183.0822.
1-(2-ethynylphenyl)ethanol (9f) (purified by column chromatography over silica gel
1
treated with petroleum ether/EtOAc (5:1)): Yellow liquid; 2.1 g, yield 72%; H NMR
(400 MHz, Chloroform-d) δ 7.46 (dd, J = 7.9, 1.3 Hz, 1H), 7.39 (dd, J = 7.6, 1.4 Hz, 1H),
7
.33 – 7.26 (m, 1H), 7.19 – 7.10 (m, 1H), 5.26 (q, J = 6.5 Hz, 1H), 3.25 (s, 1H), 1.44 (d, J
1
3
= 6.5 Hz, 3H); C NMR (101 MHz, CDCl3) δ 148.4, 133.0, 129.5, 127.1, 124.9, 119.3,
+
8
2.3, 81.6, 68.3, 24.2; HRMS (ESI-FT-ICR) m/z: [M + H] Cacld for C10H11O 147.0810,
found 147.0817.
1
3
(5) The synthesis of allenynol 9g
A saturated aqueous solution of ammonium chloride (10.5 mL) was added to a
methanolic (33 mL) solution of 1-bromo-2-butyne (2.593 g, 19.5 mmol, 1.3 equiv.) and
the 2-ethynylbenzaldehyde (1.952 g, 15 mmol, 1.0 equiv.), and the solution was cooled to
0 °C. Indium powder (100 mesh) (1.894 g, 16.5 mmol, 1.1 equiv.) was added in four
portions (over 20 min), and the mixture was stirred vigorously until completion of the
reaction (1 h) as evidenced by TLC. The mixture was diluted with an equal volume of
Et2O, and this was washed with brine. The brine was re-extracted with Et2O. The
combined extracts were dried with anhydrous MgSO4 and concentrated. Column
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chromatography (SiO2) of the residue was carried out with PE/EA (20:1) to afford the
disired allenynol 9g as a yellow oil, 1.6 g, yield 68%.
1
-(2-ethynylphenyl)-2-methylbuta-2,3-dien-1-ol (9g) (purified by column
1
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chromatography over silica gel treated with petroleum ether/EtOAc (5:1)): Yellow oil;
1
1.6 g, yield 68%; H NMR (400 MHz, Chloroform-d) δ 7.48 (ddd, J = 7.8, 4.4, 1.3 Hz,
2
4
H), 7.36 (td, J = 7.7, 1.4 Hz, 1H), 7.24 (td, J = 7.5, 1.3 Hz, 1H), 5.57 (t, J = 2.8 Hz, 1H),
13
.87 (dq, J = 5.1, 3.2 Hz, 2H), 3.31 (s, 1H), 2.46 (s, 1H), 1.62 (t, J = 3.2 Hz, 3H);
C
NMR (101 MHz, CDCl3) δ 205.3, 144.7, 133.2, 129.3, 127.7, 126.8, 120.8, 102.8, 82.4,
+
81.9, 78.4, 72.4, 15.3; HRMS (ESI-FT-ICR) m/z: [M + H] Cacld for C H O 185.0966,
1
3
13
found 185.0961.
6) The characterization of products 10
(
1'-phenyl-2',3',3a',4'-tetrahydro-1'H,3H-spiro[isobenzofuran-1,5'-pyrrolo[1,2-a]qui
noline] (10aa) (purified by column chromatography over silica gel treated with
petroleum ether/EtOAc (100:1)): Yellowish solid; 40.8 mg, yield 58%; dr = 10.4:1.6:1;
o
1
m.p. 85-87 C. H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.17 (m, 10.23H), 7.16 –
7.05 (m, 1.51H), 6.96 (t, J = 7.7 Hz, 1.13H), 6.86 – 6.71 (m, 1.18H), 6.49 (dd, J = 7.6, 1.5
Hz, 1.05H), 6.43 (d, J = 12.3 Hz, 0.17H), 6.31 (t, J = 7.3 Hz, 0.91H), 6.16 – 6.02 (m,
1
.17H), 5.30 – 5.21 (m, 0.59H), 5.20 – 5.06 (m, 1.96H), 4.76 (t, J = 7.4 Hz, 1.04H), 4.63
(s, 0.22H), 4.23 (dddd, J = 12.4, 9.0, 5.7, 3.6 Hz, 0.97H), 4.13 (ddt, J = 12.4, 9.5, 4.6 Hz,
0
.16H), 3.92 – 3.81 (m, 0.09H), 2.52 (dtd, J = 11.2, 7.6, 3.5 Hz, 1.16H), 2.24 – 2.13 (m,
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