A highly efficient and selective AuI-catalyzed tandem synthesis of diversely substituted pyrrolo[1,2-a]quinolines in aqueous media

Article abstract of DOI:10.1002/anie.200800160

(Chemical Equation Presented) Bicycles built in water: The Au ^I-catalyzed tandem cyclization of 1-amino-4-alkynes with alkynes in water offers a simple and efficient method for the synthesis of diversely substituted pyrrolo[1,2-a]quinolines with good to excellent product yields and excellent regio- and chemoselectivities (see scheme).

Full text of DOI:10.1002/anie.200800160

Angewandte
Chemie
DOI: 10.1002/anie.200800160
Gold Catalysis
A Highly Efficient and Selective AuI-Catalyzed Tandem Synthesis of
Diversely Substituted Pyrrolo[1,2-a]quinolines in Aqueous Media**
Xin-Yuan Liu and Chi-Ming Che*
Transition-metal-catalyzed tandem carbon–carbon and
carbon–heteroatom bond-forming reactions are powerful
tools for the construction of multiring organic compounds
because of the intriguing selectivity and high atom economy.[1]
Among the numerous methods for this endeavor gold-
catalyzed transformations are receiving much attention,[2,3]
but examples of such reactions conducted in aqueous media
are sparse.[3k,l,u] Water often exhibits an unprecedented effect
on the rate and selectivity of organic reactions through
hydrophobic interactions and the enrichment of organic
substrates in the local hydrophobic environment.[4,5] We
have recently described a AuI-catalyzed tandem hydroami-
nation/hydroarylation reaction of aromatic amines and
alkynes in acetonitrile or nitromethane.[6] During the course
of the study, we observed a gold(I)-catalyzed tandem
cyclization of 1,4-aminoalkynes with alkynes in water to
expediently afford diversely substituted pyrrolo[1,2-a]quino-
lines; the reaction features the formation of two new carbon–
carbon bonds and one new carbon–nitrogen bond to make
two rings in a one-pot reaction with high yields in aqueous
solution (Scheme 1). Such reactions are particularly challeng-
their oxidized or reduced forms are widespread among
natural products and biologically active pharmaceuticals.[7]
To identify optimal reaction conditions for the gold-
catalyzed tandem synthesis of pyrrolo[1,2-a]quinolines, a
number of AuI, AgI, and AuIII catalysts and different organic
solvents at 60–758C were attempted for the reaction of 4-
methoxy-N-(pent-4-ynyl)aniline (1A) with phenylacetylene
(2a). In all cases, pyrrolo[1,2-a]quinoline derivative 3Aa was
obtained in low yields and poor regio- and chemoselectivities
(Table 1, entries 1–4, and see the Supporting Information,
Table 1: Optimization of the reaction conditions and the scope of the
reaction with respect to the alkyne.[a]
Entry
R2
Solvent
t [h]
Product
Yield [%][b]
1
2
3
4
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
4-CH3Ph (2b)
4-CH3OPh (2c)
3-CH3OPh (2d)
2-CH3OPh (2e)
4-PhPh (2 f)
4-CF3Ph (2g)
4-FPh (2h)
2i[k]
CH3NO2
dioxane
CH3CN
toluene
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
47
47
47
47
26
26
26
26
36
40
26
18
26
26
36
30
26
23
30
30
45
56
108[n]
3Aa
3Aa
3Aa
3Aa
3Aa
3Aa
3Aa
3Aa
3Aa
3Aa
3Aa
3Aa
3Ab
3Ac
3Ad
3Ae
3Af
42
10
18
59
87
85
74
66
86
48
73
85
À
ing because the regio- and chemoselectivity of alkyne C H
activation must be well-controlled to avoid formation of
intractable mixtures of regioisomeric homo- and heterocou-
pled compounds. Substituted pyrrolo[1,2-a]quinolines and
5
6[c]
7[d]
8[e]
9[f]
10[g]
11[h]
12[i]
13
14
15
16
17
18
19
20
21[l]
22[m]
23[n]
91(85[j])
90(86[j])
91
82
Scheme 1. Synthesis of diversely substituted pyrrolo[1,2-a]quinolines.
87(84[j])
81(79[j])
80(76[j])
84
H2O
H2O
H2O
H2O
H2O
H2O
3Ag
3Ah
3Ai
3Aj
3Aa
3Aa
[*] X.-Y. Liu, Prof. Dr. C.-M. Che
nBu (2j)
Ph (2a)
Ph (2a)
67
91
85
Department of Chemistry and
Open Laboratory of Chemical Biology
Institute of Molecular Technology for Drug Discovery and Synthesis
The University of Hong Kong
[a] 1A (0.1 mmol), 2a (0.4 mmol), [Au{P(tBu)2(o-biphenyl)}]Cl/AgSbF6
(0.005 mmol), 758C. AuI catalyst=[Au{P(tBu)2(o-biphenyl)}]Cl/AgSbF6.
[b] Yield of isolated products based on 1A. [c] 1A/2a/catalyst=1:3:0.05.
[d] 1A/2a/catalyst=1:2:0.05. [e] 1A/2a/catalyst=1:1.5:0.05. [f] 1A/2a/
catalyst=1:4:0.02. [g] 1A/2a/catalyst=1:4:0.01. [h] Reaction performed
in the presence of air. [i] PEG 4000 (25 mg) was used as an additive.
[j] 1A/2/catalyst=1:3:0.05. [k] 2i=1-ethynylcyclohexene. [l] 1A/2j/cata-
lyst=1:5:0.05, 658C. [m] 1A (5 mmol), 2a (20 mmol), 5 mol% catalyst
loading, H2O (2 mL). [n] 1A (22 mmol), 2a (66 mmol), 2.5 mol%
catalyst added in two portions (48 h + 60 h), H2O (8 mL), 758C.
Pokfulam Road, Hong Kong (P.R. China)
Fax: (+852)2857-1586
E-mail: cmche@hku.hk
[**] This study was supported by The University of Hong Kong
(University Development Fund), the Hong Kong Research Grants
Council, and the University Grants Committee of the Hong Kong
SAR of China (Area of Excellence Scheme, AoE/P-10/01)
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 3805 –3810
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Table S1). Subsequently, we found that heating 1A in the
different steric and electronic properties (Table 2, entries 1–
13); however, a relatively longer reaction time was needed in
the cases of o-OMe- and p-Cl-substituted 1,4-aminoalkynes
(Table 2, entries 7 and 10–12). When PEG 4000 was used as
an additive the reaction times were shortened from 36–
42 hours to 24–27 hours with complete substrate conversion
(Table 2, entries 8–11). This tandem cyclization allows rapid
synthesis of tetracyclic pyrrolo[1,2-a]quinolines. Treatment of
N-(pent-4-ynyl)naphthalene-1-amine (1G) with alkynes in
water in the presence of Au[P(tBu)2(o-biphenyl)]Cl/AgSbF6
presence of 5 mol% of [Au{P(tBu)2(o-biphenyl)}]Cl/AgSbF6
(mol ratio = 1:1) in CH3CN at 808C for 36 hours gave 4, the
product of the homocoupling of 1A (Scheme 2). When 1A
furnished
1,2,3,3a-tetrahydrobenzo[h]pyrrolo[1,2-a]quino-
lines in 79–91% yields (Table 2, entries 14 and 15). The 1,4-
aminoalkynes containing a cyclohexyl group underwent AuI-
catalyzed tandem cyclization to furnish spirocyclic pyrrolo-
[1,2-a]quinolines in 87–96% yields (Table 2, entries 16–19).
We next extended the substrate scope to other amino-
alkynes. Treatment of 1,5-aminoalkyne 1J with alkynes under
the conditions described above did not give the corresponding
tricyclic product. However, when AuCl alone was used as the
catalyst in water, propargylamines 5Ja, 5Jc, and 5Jh were
exclusively afforded in 66–83% yields by using different
alkynes (see the Supporting Information, Scheme S1). Sub-
sequent reaction of 5Ja in the presence of Au[P(tBu)2(o-
biphenyl)]Cl/AgSbF6 did not yield any tricyclic product,
possibly attributed to the large steric hindrance during the
course of intramolecular hydroarylation. Similarly, treatment
of N-benzylpent-4-yn-1-amine (1K) with alkynes led to
corresponding propargylamines 5Ka, 5Kc, and 5Kh in 92–
97% yields when 5 mol% of the AuCl catalyst was used in
water (see the Supporting Information, Scheme S1).
Scheme 2. Synthesis of 4 by homocoupling of 1A. AuI catalyst=[Au{P-
(tBu)2(o-biphenyl)}]Cl/AgSbF6.
was treated with 4 equivalents of 2a in the presence of
5 mol% of [Au{P(tBu)2(o-biphenyl)}]Cl/AgSbF6 in water at
758C for 26 hours, product 3Aa was obtained exclusively in
87% yield (Table 1, entry 5). As depicted in Table 1, this
reaction did not require a large excess of either reagent or
careful control of reagent addition; and derivative 4 was not
observed even when the amount of 2a was reduced from 4 to
1.5 equivalents (Table 1, entries 5–8). The yield of 3Aa
remained almost the same upon decreasing the catalyst
loading from 5 to 2mol% (Table 1, entries 5 and 9). It is
evident that water is instrumental to this gold-catalyzed
tandem cyclization. The yield of 3Aa was not significantly
affected by the presence of air (Table 1, entry 11) and when
poly(ethylene glycol) (PEG) 4000 (25 mg) was used as an
additive the reaction time was shortened from 26 hours to
18 hours (Table 1, entry 12). In all cases, the excess phenyl-
acetylene (2a) was converted into acetophenone after the
tandem reaction and notably, CF3SO3H did not catalyze this
reaction (see the Supporting Information, Table S1).
To gain insight into the mechanism of the AuI-catalyzed
transformations, we examined the reaction of 1A with 2a in
the presence of [Au{P(tBu)2(o-biphenyl)}]Cl/AgSbF6 at room
temperature in water for 24 hours. This reaction gave
propargylamine 6 in 74% yield. Subsequent treatment of 6
with [Au{P(tBu)2(o-biphenyl)}]Cl/AgSbF6 in water at 608C
for 8 hours afforded compound 3Aa in 96% yield
(Scheme 3). On the basis of these observations, a reaction
mechanism is proposed (Scheme 4). Reaction of 1 catalyzed
by cationic phosphinegold(I) could generate enamine II. Two
plausible pathways for the formation of enamine II can be
envisioned: one proceeding by an intramolecular hydroami-
nation[8] and the other involving the hydration of 1 to generate
Under the optimized reaction conditions, we examined
the substrate scope of this AuI-catalyzed tandem cyclization in
water. A variety of aromatic alkynes (4 or 3 equiv) were
similarly treated with 1A in water and the corresponding
pyrrolo[1,2-a]quinolines 3Aa–Ah were obtained in good to
excellent yields (80–91%) (Table 1, entries 5, and 13–19).
Compounds 3Ai and 3Aj were obtained in 84 and 67% yield,
respectively, when 1-ethynylcyclohexene (2i) and 1-hexyne
(2j) were used as the substrates (Table 1, entries 20 and 21).
This protocol can be scaled up to the gram-scale synthesis of
pyrrolo[1,2-a]quinolines. A one-pot reaction of 1A (5 or
22 mmol) with 2a (20 or 66 mmol) in the presence of 5 or
2.5 mol% of [Au{P(tBu)2(o-biphenyl)}]Cl/AgSbF6 afforded
3Aa (1.3 or 5.5 g) in 91 or 85% yield, respectively, and the
product was purified by simple vacuum distillation or flash
chromatography (Table 1, entries 22 and 23). The [Au{P-
(tBu)2(o-biphenyl)}]Cl/AgSbF6 catalyst is remarkably stable
and does not show appreciable decomposition after being
heated in water at 758C for approximately 60 hours (as
1
revealed by H NMR spectroscopy).
A wide range of 1,4-aminoalkynes were similarly reacted
with alkynes in water to furnish diversely substituted pyrrolo-
[1,2-a]quinolines (Table 2). Generally, the reaction worked
well for a range of 1,4-aminoalkynes with substituents having
Scheme 3. Propargylamine formation and cyclization.
AuI catalyst=[Au{P(tBu)2(o-biphenyl)}]Cl/AgSbF6.
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Table 2: Tandem synthesis of diversely substituted pyrrolo[1,2-a]quinolines catalyzed by [Au{P(tBu)2(o-biphenyl)}]Cl/AgSbF6 in water.[a]
Entry
Aminoalkyne
Alkyne
t [h]
Product
Yield [%][b]
97 (93[c])
1
2b
24 (32[c])
2
3
2c
2d
25 (32[c])
96 (98[c])
34
92
4
5
2e
2i
30
30
90
93
6[d]
2j
45
72
7
2c
2b
56
85
8
36 (24[e])
89 (86[e])
9
2c
2b
36 (26[e])
42 (27[e])
92 (89[e])
94 (92[e])
10
11
2c
2j
42 (24[e])
89 (91[e])
12[d]
45
51
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Table 2: (Continued)
Entry
Aminoalkyne
Alkyne
t [h]
Product
Yield [%][b]
82
13
2c
32
14
15
2b
2c
36
36
79
91
16
2b
32
92
17
18
19
2c
2b
2c
26
87
36 (40[c])
88 (87[c])
36 (40[c])
96 (92[c])
[a] 1 (0.1 mmol), 2 (0.4 mmol), Au[P(tBu)2(o-biphenyl)]Cl/AgSbF6 (0.005 mmol), H2O (0.5 mL), 758C. [b] Yield of isolated product based on 1.
[c] 1/2/catalyst=1:4:0.02. [d] 1/2/catalyst=1:5:0.05, 658C. [e] PEG 4000 (25 mg) was used as an additive.
ketone I[9,10] and intramolecular reaction of the ketone and
the amine. Attack of enamine II by alkyne 2 would generate a
propargylamine.[11] The propargylamine was cyclized intra-
molecularly in the presence of the gold(I) catalyst.[12] For all
these steps, the proton-catalyzed reactions (if present) should
not contribute significantly (see the Supporting Information,
Scheme S2) despite the acidity of aquo–gold complexes.[13]
Electrospray ionization mass spectrometry analysis of a
solution of 6 and [Au{P(tBu)2(o-biphenyl)}]SbF6 (20 mol%)
in CH3CN after stirring for 15 minutes at room temperature
showed a peak at m/z 786 that was attributed to the adduct
formed between [Au{P(tBu)2(o-biphenyl)}]+ and 6; this data
supports the intermediacy of III depicted in Scheme 4.
Labeling studies with deuterated starting materials or D2O
revealed that the vinyl hydrogen atom of 3Lk and 7 came
from D2O (Scheme 5).[3j,q] The formation of [D6]-7 directly
from D2O is also consistent with the literature, in that
hydrogen atoms in positions a to the enamine group can be
Scheme 4. Proposed mechanism.
exchanged with D2O (Scheme 5).[3p]
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Scheme 5. Labeling studies with deuterated starting materials or D2O.
AuI catalyst=[Au{P(tBu)2(o-biphenyl)}]Cl/AgSbF6.
In summary, we have developed a simple and highly
efficient method for the synthesis of diversely substituted
pyrrolo[1,2-a]quinolines with product yields up to 98% and
with excellent regio- and chemoselectivities in water. The
tandem sequence described here permits a straightforward
and efficient synthesis of novel tri- or tetracyclic amines in
which several carbon–carbon and carbon–nitrogen bonds can
be formed in a one-pot reaction from simple starting
materials. This method was applied in gram-scale synthesis
of substituted pyrrolo[1,2-a]quinolines (up to 5 g). Our
preliminary studies revealed that 3Bc exhibited a significantly
higher cytotoxicity against the HeLa (cervical epithelioid
carcinoma) cell line (IC50 = 34.7 mm) than against the normal
lung fibroblast (CCD-19 Lu) cell line (IC50 = 82.3 mm), sug-
gesting a potential application of this class of substituted
pyrrolo[1,2-a]quinolines in anticancer studies.
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Received: January 12, 2008
Revised: February 14, 0000
Published online: April 10, 2008
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Keywords: alkynes · gold · pyrrolo[1,2-a]quinolines ·
tandem reactions · water chemistry
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Communications
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