Chemoselective cascade synthesis of N-fused heterocycles via silver(I) triflate-catalyzed friedel-crafts/N-C bond formation sequence

Article abstract of DOI:10.1002/adsc.201000525

An efficient cascade methodology toward chemoselective synthesis of N-fused heterocycles including 9H-pyrrolo[1,2-a]indole, 3H-pyrrolo[1,2-a]indole and 1H-pyrrolo[1,2-a]indole derivatives has been developed. This transformation proceeds via a silver(I) triflate-catalyzed consecutive Friedel-Crafts reaction/N-C bond formation sequence between readily available propargyl alcohols and 3-substituted 1H-indoles. Not only is excellent chemoselectivity observed according to the substitution patterns of propargyl alcohols, but also the Lewis acid-catalyzed N-C bond formation process can be carried out under base- and ligand-free conditions. Copyright

Full text of DOI:10.1002/adsc.201000525

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DOI: 10.1002/adsc.201000525
Chemoselective Cascade Synthesis of N-Fused Heterocycles via
Silver(I) Triflate-Catalyzed Friedel–Crafts/N-C Bond Formation
Sequence
Lu Hao,a Yingming Pan,a Tao Wang,a Min Lin,a Li Chen,a and Zhuang-ping Zhana,*
a
Department of Chemistry, College of Chemistry and Chemical Engineering, and State Key Laboratory for Physical
Chemistry of Solid Surfaces, Xiamen University, Xiamen 361005, Fujian, Peopleꢀs Republic of China
Fax : (+86)-592-218-0318; phone: (+86)-592-218-0318; e-mail: zpzhan@xmu.edu.cn
Received: July 5, 2010; Revised: September 6, 2010; Published online: December 5, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000525.
Abstract: An efficient cascade methodology toward
chemoselective synthesis of N-fused heterocycles in-
cluding 9H-pyrrolo
N
ACHTUNGTNER[NUNG 1,2-
a]indole and 1H-pyrroloAHCTNUGTRENNNUG
has been developed. This transformation proceeds
via a silver(I) triflate-catalyzed consecutive Friedel–
À
Crafts reaction/N C bond formation sequence be-
tween readily available propargyl alcohols and 3-
substituted 1H-indoles. Not only is excellent chemo-
selectivity observed according to the substitution
patterns of propargyl alcohols, but also the Lewis
À
acid-catalyzed N C bond formation process can be
carried out under base- and ligand-free conditions.
Figure 1. Several key N-fused heterocyclic skeletons.
Keywords: cascade reaction; Friedel-Crafts reac-
tion; indoles; N-fused heterocycles; propargyl alco-
hol; silver
tive assembly of different N-fused heterocyclic skele-
tons with diverse substitution patterns catalyzed by
single catalyst are in high demand.
Over the past several years, our group has devel-
oped effective methods for the construction of O- and
N-containing heterocycles via consecutive propargyl
Nitrogen-containing heterocyclic scaffolds are preva- substitution and cycloisomerization, both of which
lent in naturally occurring and pharmaceutically were catalyzed by the same metallic catalyst.[5] It
active molecules, and therefore play a key role in me- seemed plausible that this strategy could be extended
dicinal chemistry and organic synthesis. Molecules to prepare the above-mentioned N-fused heterocycles
containing bicyclic 9H-pyrrolo
ACHTUNGTRENNUNG
pyrrol[1,2-a]indoles (II), 3H-pyrroloACTHUNGTRENNUNG
G
À
(III) and other closely related cores such as reduced N C bond-formation pathway for the synthesis of 4
analogues (IV) have increasingly been of paramount or 5 (Scheme 1). Overall, this atom-economical trans-
interest in recent years due to their latent biological formation would provide a new avenue to access N-
activity[1] (Figure 1). For instance, it was shown that fused heterocyclic cores through consecutive forma-
these molecules exhibited strong anti-tumor,[2] anti- tion of C C and N C bonds using a single catalyst
À
À
S1P1-associated disorder[3] and anti-diabetes[1b,4h] ac- from simple substrates.
tivities. Although several synthetic routes to those N-
Although this cascade sequence could have consid-
fused heterocycles have existed in recent years,[4] erable utility, to achieve our desired transformation,
these methods have some limitations such as multi- we would need to overcome a significant obstacle:
À
step procedures, harsh conditions and poor selectivity. the initial C C bond-formatin process, which could be
Accordingly, new approaches allowing for the selec- achieved by a Friedel–Crafts reaction and was gener-
Adv. Synth. Catal. 2010, 352, 3215 – 3222
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Scheme 1. Proposed cascade reaction for the synthesis of N-fused heterocycles.
ally catalyzed by Brønsted or Lewis acids,[6,7] whereas was observed, generating the three different skeletons
the addition of 1H-indole-NH to an alkyne moiety I, II and III according to the substitution pattern of
was always performed under basic conditions.[8] the substrates.
Therefore, it was necessary to search for a catalyst
which must not only favor the Friedel–Crafts reaction tion. On the basis of our previous success in FeACHTUNGTRENNUNG
Our investigation began with the catalyst optimiza-
(III)-
but also facilitate the nucleophilic attack of 1H- catalyzed propargyl substitution reactions,[13,14] we ini-
indole-NH on alkyne-C. On the other hand, a chal- tially treated propargyl alcohol 1a with 3-methyl-1H-
lenge was posed for us: 3-substituted 1H-indoles pos- indole 2a in toluene at 808C using 5 mol% FeCl3 as
sess two nucleophilic centers,[9] and similarly, proparg- the catalyst. Unfortunately, only a small amount of
yl alcohols have two electrophilic sites,[10] which make desired product 3aa was formed under these reaction
both the mechanism and final products complicated conditions (Table 1, entry 1). We reasoned that the
(Scheme 2). Also, in the case of R2 =H, the two poor yield of 3aa was probably due to the weak abili-
double bonds in the bicyclic skeleton are probably ty of FeCl3 to activate the alkyne moiety. Thus, Lewis
prone to isomerization by virtue of relative thermody- acids such as BiCl3, InCl3, Sc
ACHUTNGTRNENUG(OTf)3, BiACHTUNGTRENNUNG(OTf)3,
namic stability of the products, making the reaction Cu(OTf)2 and AgOTf, which are generally considered
AHCTUNGTRENNUNG
result much more uncertain. With these in mind and to possess both strong Lewis acidity and good alkyno-
after exhaustive exploration, we were pleased to dis- philicity, were adopted as the catalysts (Table 2, en-
cover that the novel cascade reaction could be suc- tries 2–7). To our delight, it was found that, in the
cessfully carried out in the presence of 5 mol% presence of 5 mol% AgOTf, the reaction result was
AgOTf.[11,12] Importantly, excellent chemoselectivity drastically improved and the target product 3aa was
Scheme 2. Plausible routes of formation and products in the synthesis of N-fused heterocycles.
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Chemoselective Cascade Synthesis of N-Fused Heterocycles
Table 1. Optimization of catalysts and solvents.[a]
required and lower yields were given (Table 2, en-
tries 13 and 14). In the case of AgOAc and AgNO3,
no or only a trace of product was produced accompa-
nied by the recovery of the starting materials
(Table 2, entries 15 and 16). Such results showed that
the nature of the counterions markedly affected the
catalytic activity of silver(I) salts: the trifluorometha-
nesulfonate anion may be the best counterion to facil-
itate this cascade reaction. Next, solvent screening
demonstrated that toluene was still the preferential
solvent (Table 1, entries 17–22).
This preliminary study confirmed the efficacy of
5 mol% AgOTf in toluene to catalyze both the Frie-
del–Crafts reaction and the nucleophilic addition of
the 1H-indole-NH to alkyne-C. Importantly, the latter
process was for the first time accomplished under
Lewis acid-catalyzed, and base- and ligand-free condi-
tions. It was noteworthy that in this case (R1, R3 =
phenyl, R2 =H), the N-fused heterocyclic skeleton I
(Figure 1) was chemoselectively constructed.
Entry
Catalyst
Solvent[b]
Time [h]
Yield[c] [%]
1
2
3
4
5
6
7
8
FeCl3
BiCl3
InCl3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
1,2-DCE
CH3NO2
CH2Cl2
THF
24
24
24
0.5
8
24
0.5
12
24
24
3
0.5
3
3
12
12
24
1
10
26
13
63
16
49
82
31
0
Sc
Bi
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Cu
A
ACHTUNGTRENNUNG
9
ZnCl2
p-TSA
TfOH
10
11
12[d]
13
14
15
16
17
18
19
20
21
22
0
25
84
59
35
0
traces
16
61
55
0
AgOTf
AgBF4
AgSbF6
AgOAc
AgNO3
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
Next, the scope of this reaction was investigated
under the optimized conditions (Table 2). We were
pleased to find that aryl-substituted secondary prop-
argyl alcohols (R1 =aryl, R2 =H) proceeded very well
in this transformation, offering an easy access to N-
fused heterocyclic skeleton I with various substitution
patterns. A wide range of functionalities such as
chloro, bromo, methoxy and methoxycarbonyl could
be well tolerated, leading to the products in moderate
to good yields (Table 2). An electron-donating sub-
stituent (R1 =p-MeOC6H4; Table 2, entry 2) increased
the rate of this reaction and gave a good yield, where-
as an electron-withdrawing substituent (R1 =Br;
Table 2, entry 3) slowed the transformation down and
provided a moderate yield. In particular, the presence
1
24
24
24
8
11
Acetone
[a]
All reactions were performed with 1a (0.5 mmol,
1.0 equiv.) and 2a (0.55 mmol, 1.1 equiv.) in toluene
(2 mL) at 808C for an appropriate time.
1,2-DCE=1,2-dichloroethane; THF=tetrahydrofuran.
Isolated yields based on propargyl alcohol 1a.
10 mol% AgOTf.
[b]
[c]
[d]
of
a
strong
electron-withdrawing
(R1 =p-
MeOOCC6H4) group on the propargyl alcohol had an
furnished in 82% yield (Table 1, entry 7). In contrast, apparent adverse impact on the conversion (Table 2,
the reactions catalyzed by other Lewis acids proceed- entry 4, 48% yield). This result could be attributed to
ed with either more sluggish conversion or lower the instability of the propargyl cation intermediate. In
yields (Table 1, entries 2–6, 8 and 9), among which Sc- addition, the presence of a-thiophenyl group did not
ACHTUNGTRENNUNG(OTf)3 displayed an acceptable catalytic efficacy retard this reaction leading to a moderate yield
albeit inferior to that of AgOTf (Table 1, entry 4, (Table 2, entry 6). We also tested the reactivity of
63% yield). The catalytic efficacy of Brønsted acids alkyl-substituted secondary propargyl alcohol (R1 =
was also explored. p-TSA gave no product (Table 1, pentyl, R2 =H), but we found that no expected prod-
entry 10), while TfOH afforded the product in 25% uct was obtained (Table 2, entry 7).
yield (Table 1, entry 11). Increasing the catalyst load-
Encouraged by these results, we next examined the
ing of AgOTf from 5% to 10% made an unremarka- reactivity of aryl-substituted secondary propargyl al-
ble influence on the reaction, in which the expected cohols bearing trimethylsilyl and alkyl groups on the
product was formed in 84% yield (Table 1, entry 12). alkyne moiety (Scheme 3). Interestingly, products 4ga
Plainly, 5 mol% AgOTf was adequate for complete and 4ha with the skeleton pattern II were exclusively
conversion of the substrates into the final products. generated in 46% and 61% yields, respectively.
Subsequently, the effect of counterions of silver salts
To further define the generality of the present pro-
on this cascade transformation was investigated cedure, attention was turned to the reactions of terti-
(Table 1, entries 13–16). It was found when adopting ary propargyl alcohols. Intriguingly, it was found not
AgBF4 and AgSbF6 as the catalysts the desired prod- only were the N-fused heterocyclic skeletons III ex-
uct could be obtained, but longer reaction time was clusively obtained but also the substitution patterns
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Scheme 3. Cascade reactions of TMS- and alkyl-substituted propargyl alcohols with 3-methyl-1H-indole.
were opposite to those of secondary propargyl alco- The reaction of triaryl-substituted propargyl alcohols
hols (Table 3). On the basis of literature reports and (R1, R2, R3 =aryl) proceeded very well affording the
our previous observations, we reasoned these N-fused desired products in 84–96% yields (Table 3, entries 1,
À
products may be afforded via a C2-allenation/N C 5–14). On the other hand, the substrate with a substi-
cyclization route[15] as shown in Scheme 2. The sub- tution pattern of R1 =aryl, R2 =methyl and R3 =aryl
strate investgation revealed that substrates possessing was also smoothly converted into the N-fused hetero-
a variety of functionalities exhibited very good reac- cycle in good yield (Table 3, entry 2). However, in the
tivity and moderate to excellent yields were obtained. case of R3 =alkyl or TMS, only moderate yields were
Table 2. Cascade synthesis of N-fused heterocycles (skeleton I) from secondary propargyl alcohols.[a]
Entry 1: R1, R3
2: R4, R5
Product
Time Yield[b] Entry 1: R1, R3
Product
Time Yield[b]
[h]
[%]
2: R4, R5
[h]
[%]
1e: 1-naph-
thyl; Ph
1a: Ph; Ph
83
2a: Me; H
2a: Me; H
1
3aa
3ba
0.5
82
5
3ea
0.5
1b: p-
MeOC6H4; Ph
2a: Me; H
1f: 2-thie-
nyl; Ph
2c:
CH2COOEt;
H
68
0
2
0.4
85
6
7
3fc
2
1c: p-BrC6H4; Ph
2b: Ph; Cl
1g: n-pent; Ph
2a: Me; H
3
4
3cb
3da
0.7
3
79
48
3ga
12
1d: p-
MeOOCC6H4; Ph
2a: Me; H
[a]
[b]
All reactions were performed with propargyl alcohols 1 (0.5 mmol, 1.0 equiv.), 3-substituted indoles 2 (0.55 mmol, 1.1 equiv.)
and 5 mol% AgOTf (0.025 mmol) in toluene (2 mL) at 808C for an appropriate time.
Isolated yields based on propargyl alcohols 1.
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Chemoselective Cascade Synthesis of N-Fused Heterocycles
Table 3. Cascade synthesis of N-fused heterocycles (skeleton III) from tertiary propargyl alcohols.[a]
Entry 1: R1; R2; R3
2: R4; R5
Product
Time Yield[b] Entry 1: R1; R2; R3
Product
Time Yield[b]
[h]
[%]
2: R4; R5
[h]
[%]
1i: Ph; Ph;
Ph
2a: Me; H
1q: 1-naph-
thyl; Ph; Ph
2a: Me; H
5ia
94
1
0.4
92
9
5qa
0.4
1j: Ph; Me;
Ph
2a: Me; H
1i: Ph; Ph;
Ph
2c:
CH2COOEt;
H
1p: 2-thien-
yl; Ph; Ph
2c:
5ja
90
84
2
3
0.4
0.8
89
65
10
11
5ic
0.7
0.7
1k: Ph; Me;
TMS
2a: Me; H
5ka
5pc
CH2COOEt;
H
1o: p-
MeC6H4;
Ph; Ph
2d: Et; Me
1l: Ph; Ph;
n-Bu
5la
93
91
95
4
5
6
7
0.7
0.3
0.4
0.4
71
96
90
93
12
5od
5ib
5ie
5ra
0.4
0.4
0.3
12
2a: Me; H
1m: p-
MeOC6H4;
Ph; Ph
2a: Me; H
1i: Ph; Ph;
Ph
5ma
13
2b: Ph; Cl
1n: p-
ClC6H4; Ph; 5na
Ph
1i: Ph; Ph;
Ph
14
2a: Me; H
2e: Ph;
MeO
1o: p-
MeC6H4; Ph; 5oa
Ph
2a: Me; H
1r: Me; Me;
Ph
35
32
15[c]
2a: Me; H
1p: 2-thienyl;
5pa
1s: -(CH2)5-;
Ph
Ph; Ph
2a: Me; H
2a: Me; H
8
0.4
88
16[c]
5sa
12
[a]
All reactions were performed with propargyl alcohols 1 (0.5 mmol, 1.0 equiv.), 3-substituted indoles 2 (0.55 mmol,
1.1 equiv.) and 5 mol% AgOTf (0.025 mmol) in toluene (2 mL) at 808C for an appropriate time.
Isolated yields based on propargyl alcohols 1.
[b]
[c]
The reactions were performed in nitromethane (CH3NO2) instead of toluene.
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obtained (Table 3, entries 3 and 4). In addition, 3-sub- triple bond delivered intermediate A, which under-
stituted 1H-indoles with either electron-withdrawing went elimination to give the alkynyl cation species B
groups (R4 =CH2COOEt or R5 =Cl) or electron-do- and its allenic resonance form C.[10] The following
nating groups (R5 =Me or OMe) on the 3- or 5- posi- Friedel–Crafts reaction occurred by C2-nucleophilic
tion all showed excellent reactivity, generating the attack of 3-substituted 1H-indoles on B and C, lead-
products in 84–95% yields (Table 3, entries 10–14). It ing to the substitution products D and E, respectively.
was noteworthy that in contrast with secondary prop- Through Ag(I)-mediated p-activation, D would expe-
argyl alcohols, the electronic effect of R1 did not have rience a 5-endo-dig cyclizaiton to generate two differ-
any obvious influence on the reactivity of the tertiary ent N-fused skeletons I (F) and II (G) according to
propargyl alcohols. The reactions of tertiary propargyl the R3 substitution pattern, whereas E would undergo
alcohols with electron-withdrawing and electron-do- a 5-endo-trig cyclization to furnish the skeleton III
nating groups both provided the desired products in (H). Finally, the released Ag(I) catalyst entered into
good yields (Table 3, entries 5–7). We also carried out the next catalytic cycle. Notably, excellent chemose-
this transformation using dialkyl-substituted tertiary lectivity was obtained between skeleton I and skele-
propargyl alcohols as the substrates. Unforturnately, ton II, which was presumably due to the relative sta-
we found that no desired products were obtained. We bility of the two types of N-fused heterocycles. When
replaced toluene with nitromethane as the solvent.[16] the R1 and R3 were both aryl groups, the total conju-
To our delight, the corresponding N-fused heterocy- gation effect of R1 and R3 with the pyrrole ring of the
cles were formed albeit with prolonged reaction times N-fused heterocycle made skeleton I more stable than
and in low yields (Table 3, entries 15 and 16). The ex- skeleton II. Hence, skeleton I would be formed pref-
ample of entry 16 offered a new access to N-contain- erentially through double bond isomerization. When
ing spirocyclic compounds, which may possess poten- the R1 =aryl and R3 =alkyl or TMS, such a conjuga-
tial biological activity.
tion effect of R3 disappeared, resulting in the skeleton
To validate the formation mechanism of the three II which was more stable than skeleton I in this case
different N-fused heterocyclic skeletons I, II and III, as well as being the initial product of the cyclization
attempts were made to capture the possible corre- process of compound D.
sponding intermediates. Thus, three reactions were
In summary, we have developed an efficient cas-
À
performed at room temperature to 508C, and three cade Friedel–Crafts reaction/N C bond formation
key intermediates 6, 7 and 8 were successfully isolated protocol for the chemoselective assembly of N-fused
1
and fully characterized by H and 13C NMR methods heterocyclic compounds starting from readily avail-
and high resolution mass spectroscopic (HR-MS) data able propargyl alcohols and 3-substituted 1H-indoles.
(Figure 2).[17] It was further discovered that without Three useful N-fused heterocyclic cores can be easily
isolation and after being heated to 808C for an appro- obtained in the presence of 5 mol% AgOTf under
priate time, the three intermediates 6, 7 and 8 mild conditions and a broad range of functional
smoothly converted into the corresponding heterocy- groups are well tolerated. Importantly, this is the first
clic products 3aa, 4ha and 5ja.
example of a single metallic Lewis acid-catalyzed nu-
The above work demonstrated that the formation cleophilic addition of 1H-indole-NH to alkyne-C and
of the three N-fused heterocyclic skeletons proceeded allene-C under base- and ligand-free conditions.
À
in two ways: one was the C2-propargylation/N C cyc- Through the isolation and characterization of key in-
lization (5-endo-dig) route, and the other was the C2- termediates, we confirmed two distinct routes to the
À
allenation/N C cyclization (5-endo-trig) route. Thus, three skeletons: C2-propargylation/N-C 5-endo-dig-
we proposed the following mechanism for this substi- cyclization and C2-allenation/N-C 5-endo-trig-cycliza-
tution/cyclization sequence (Scheme 4). First, the acti- tion. Further study to expand the scope of synthetic
vation of propargyl alcohol through coordination of utilities of this novel reaction is in progress in our lab-
the metal catalyst with the hydroxy group and the oratory.
Experimental Section
Typical Procedure
To a dry 10-mL flask equipped with a magnetic bar, prop-
argyl alcohol 1 (0.5 mmol, 1.0 equiv.), 3-substituted indole 2
(0.55 mmol, 1.1 equiv.), toluene (2 mL) and 5 mol% AgOTf
(0.025 mmol) were successively added. The reaction mixture
was stirred at 808C and monitored periodically by thin layer
Figure 2. Isolated intermediates formed by Friedel–Crafts
reaction of propargyl alcohols and 3-methyl-1H-indole.
chromatography (TLC). Upon completion, the solvent was
removed under reduced pressure, and the residue was puri-
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Chemoselective Cascade Synthesis of N-Fused Heterocycles
Scheme 4. Proposed mechanism for the formation of the three N-fused heterocycles.
fied by column chromatography on silica gel to afford the
N-fused heterocyclic compounds.
[3] R. M. Jones, D. J. Buzard, A. M. Kawasaki, H. S. Kim,
L. Thoresen, J. Lehmann, X. Zhu, WO Patent 027431,
2010.
[4] For recent reviews and selected examples, see: a) A. R.
Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K.
Taylor, in: Comprehensive Heterocyclic Chemistry III,
Vol. 11, (Ed.: J. Cossy), Elsevier, Oxford, 2008, pp 1–
40; b) D. M. Schultz, J. P. Wolfe, Org. Lett. 2010, 12,
1028–1031; c) W. He, K. Yip, N. Zhu, D. Yang, Org.
Lett. 2009, 11, 5626–5628; d) X. Huang, S. Zhu, R.
Shen, Adv. Synth. Catal. 2009, 351, 3118–3122; e) K. S.
Feldman, D. K. Hester, M. R. Iyer, P. J. Munson, C. S.
Lopez, O. N. Faza, J. Org. Chem. 2009, 74, 4958–4974;
f) C. S. Bryan, M. Lautens, Org. Lett. 2008, 10, 4633–
4636; g) K. S. Feldman, D. K. Hester, C. S. Lopez, O. N.
Faza, Org. Lett. 2008, 10, 1665–1668; h) M. Tanaka, M.
Ubukata, T. Matsuo, K. Yasue, K. Matsumoto, Y. Kaji-
moto, T. Ogo, T. Inaba, Org. Lett. 2007, 9, 3331–3334;
i) K. S. Feldman, M. R. Iyer, D. K. Hester, Org. Lett.
2006, 8, 3113–3116; j) W. H. Pearson, W. Fang, J. Org.
Chem. 2000, 65, 7158–7174; k) N. Matsumura, Y.
Yagyu, M. Ito, T. Adachi, K. Mizuno, J. Org. Chem.
2000, 65, 3341–3345; l) A. R. Katritzky, C. N. Fali, J. Li,
J. Org. Chem. 1997, 62, 4148–4154.
Acknowledgements
We gratefully acknowledge the financial support of the Na-
tional Natural Science Foundation of China (Nos. 20772098
and 21072159).
References
[1] For studies on the biological activity and reactivity of
these N-fused heterocycles, see: a) R. Kakadiya, H.
Dong, P. Lee, N. Kapuriya, X. Zhang, T. Chou, T. Lee,
K. Kapuriya, A. Shan, T. Su, Bioorg. Med. Chem. 2009,
17, 5614–5626; b) M. Tanaka, S. Sagawa, J. Hoshi, F.
Shimoma, K. Yasue, M. Ubukata, T. Ikemoto, Y. Hase,
M. Takahashi, T. Sasase, N. Ueda, M. Matsushita, T.
Inaba, Bioorg. Med. Chem. 2006, 14, 5781–5794;
c) R. W. Franck, K. F. Bernady, J. Org. Chem. 1968, 33,
3050–3055.
[5] For our previous research on heterocyclic synthesis cat-
[2] T. Su, T. Chou, US Patent 0117125, 2009.
alyzed by a single catalyst via the consecutive propargyl
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COMMUNICATIONS
substitution and cycloisomerization strategy, see: a) X.
Liu, L. Huang, F. Zheng, Z. Zhan, Adv. Synth. Catal.
2008, 350, 2778–2788; b) Y. Pan, S. Zhao, W. Ji, Z.
Zhan, J. Comb. Chem. 2009, 11, 103–109.
[12] For selected examples of Ag(I)-catalyzed synthesis of
N-containing heterocycles, see: a) K. Ji, X. Shu, S.
Zhao, H. Zhu, Y. Niu, X. Liu, Y. Liang, Org. Lett.
2009, 11, 3206–3209; b) Y. Niu, Z. Yan, G. Gao, H.
Wang, X. Shu, K. Ji, Y. Liang, J. Org. Chem. 2009, 74,
2893–2896; c) I. V. Seregin, A. W. Schammel, V. Ge-
vorgyan, Org. Lett. 2007, 9, 3433–3436; d) J. T. Binder,
S. F. Kirsch, Org. Lett. 2006, 8, 2151–2153.
[6] For recent reviews of Friedel–Crafts reaction, see: a) S.
You, Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190–
2201; b) M. Rueping, B. J. Nachtsheim, Beilstein J. Org.
Chem. 2010, 6, No. 6; c) M. Badini, M. Tragni, Org.
Biomol. Chem. 2009, 7, 1501–1507.
[13] For other groupsꢀ and our research on FeACTHNUGRTENUNG(III)-catalyzed
[7] For selected examples of the Friedel–Crafts reaction of
propargyl alcohols, see: a) Y. Nishibayashi, M. Yoshika-
wa, Y. Inada, M. Hidai, S. Uemura, J. Am. Chem. Soc.
2002, 124, 11846–11847; b) Y. Nishibayashi, Y. Inada,
M. Yoshikawa, M. Hidai, S. Uemura, Angew. Chem.
2003, 115, 1533–1536; Angew. Chem. Int. Ed. 2003, 42,
1495–1498; c) Y. Inada, M. Yoshikawa, M. D. Milton,
Y. Nishibayashi, S. Uemura, Eur. J. Org. Chem. 2006,
881–890; d) H. Matsuzawa, Y. Miyake, Y. Nishibayashi,
Angew. Chem. 2007, 119, 6608–6611; Angew. Chem.
Int. Ed. 2007, 46, 6488–6491; e) H. Matsuzawa, K.
Kanao, Y. Miyake, Y. Nishibayashi, Org. Lett. 2007, 9,
5561–5564; f) M. Yoshimatsu, T. Otani, S. Matsuda, T.
Yamamoto, A. Sawa, Org. Lett. 2008, 10, 4251–4254;
g) C. Li, J. Wang, J. Org. Chem. 2007, 72, 7431–7434;
h) ref.[16a]
propargyl substitution, see: a) P. Li, Y. Zhang, L. Wang,
Chem. Eur. J. 2009, 15, 2045–2049; b) Z. Zhan, J. Yu,
H. Liu, Y. Cui, R. Yang, W. Yang, J. Li, J. Org. Chem.
2006, 71, 8298–8301; c) Z. Zhan, X. Cai, S. Wang, J.
Yu, H. Liu, Y. Cui, J. Org. Chem. 2007, 72, 9838–9841;
d) W. Ji, Y. Pan, S. Zhao, Z. Zhan, Synlett 2008, 3046–
3052.
[14] For recent reviews of the metal-catalyzed propargyl
substitution, see: a) N. Ljungdahl, N. Kann, Angew.
Chem. 2009, 121, 652–654; Angew. Chem. Int. Ed.
2009, 48, 642–644; b) R. J. Detz, H. Hiemstra, J. H.
Maarseveen, Eur. J. Org. Chem. 2009, 6263–6276.
[15] For recent selected examples of C-allenation reactions
of propargyl compounds, see: a) R. Sanz, D. Miguel, A.
Martinez, J. M. Alvarez-Gutierrez, F. Rodriguez, Org.
Lett. 2007, 9, 727–730; b) ref.[16b]
[16] The work of Bach and Yoshimatsu directed us to the
use of CH3NO2 as the solvent, which was considered a
good medium to stabilize the propargyl cation inter-
mediate. For the successful use of nitromethane in
propargyl substitution reactions, see: a) P. Rubenbauer,
E. Herdtweck, T. Strassner, T. Bach, Angew. Chem.
2008, 120, 10260–10263; Angew. Chem. Int. Ed. 2008,
47, 10106–10109; b) M. Yoshimatsu, T. Yamamoto, A.
Sawa, T. Kato, G. Tanabe, O. Muraoka, Org. Lett. 2009,
11, 2952–2955; c) M. Yoshimatsu, T. Otani, S. Matsuda,
T. Yamamoto, A. Sawa, Org. Lett. 2008, 10, 4251–4254.
[17] The experiments on capturing the three key intermedi-
À
[8] To the best of our knowledge, the N C bond formation
between 1H-indole-NH and alkyne-C is exclusively
achieved in the presence of base or ligand, and the
single metallic Lewis acid-catalyzed addition has not
been reported previously. For a recent example of
Cu(I)-catalyzed tandem synthesis of N-fused heterocy-
cles in the presence of strong base and ligand, see:
A. K. Verma, T. Kesharwani, J. Singh, V. Tandon, R. C.
Larock, Angew. Chem. 2009, 121, 1158–1163; Angew.
Chem. Int. Ed. 2009, 48, 1138–1143.
[9] Although the normal electrophilic site of 3-substituted
1H-indoles is known to be at C2, two recent examples
À
revealed that direct transition metal-catalyzed N C for-
ates are performed with propargyl alcohols
(0.5 mmol, 1.0 equiv.), 3-substituted indoles
1
2
mation between the free N-H of 3-subsituted 1H-in-
doles and multi-bonds could occur, see: a) ref.[8]
;
(0.55 mmol,
1.1 equiv.)
and
5 mol%
AgOTf
b) M. R. Luzung, C. A. Lewis, P. S. Baran, Angew.
Chem. 2009, 121, 7159–7163; Angew. Chem. Int. Ed.
2009, 48, 7025–7029.
(0.025 mmol) in toluene (2 mL), which are shown
below. In the course of forming 6, 7 and 8, certain
amounts of the corresponding final N-fused heterocy-
cles (3aa, 4ha and 5ja) were also furnished. Without
isolation and after being heated for an appropriate
time, these intermediates would be converted com-
pletely into corresponding N-fused heterocyclic prod-
ucts.
[10] For research on the resonance of alkynyl cation and al-
lenic cation, see: a) J. Andres, R. Cardenas, E. Silla, O.
Tapia, J. Am. Chem. Soc. 1988, 110, 666–674; b) G. A.
Olah, R. J. Spear, P. W. Westerman, J. Denis, J. Am.
Chem. Soc. 1974, 96, 5855–5859; c) H. G. Richey, J. C.
Philips, L. E. Rennick, J. Am. Chem. Soc. 1965, 87,
1381–1382.
[11] For recent reviews of Ag(I)-catalyzed synthesis of het-
erocycles and related mechanistic rationale, see: a) M.
Alvarez-Corral, M. Munoz-Dorado, I. Rodriguez-
Garcia, Chem. Rev. 2008, 108, 3174–3198; b) J. Weibel,
A. Blanc, P. Pale, Chem. Rev. 2008, 108, 3149–3173;
c) N. T. Patil, Y. Yamamoto, Chem. Rev. 2008, 108,
3395–3442; d) Y. Yamamoto, Chem. Rev. 2008, 108,
3199–3222; e) M. Naodovic, H. Yamamoto, Chem. Rev.
2008. 108. 3132–3148.
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Adv. Synth. Catal. 2010, 352, 3215 – 3222