Gold-catalyzed [4+1]-annulation reactions between anthranils and 4-methoxy-1,2-dienyl-5-ynes involving a 1,2-allene shift

Article abstract of DOI:10.1039/c8cc09082c

Gold-catalyzed [4+1]-annulations of 4-methoxy-1,2-dienyl-5-ynes with anthranils are described. The mechanism of these annulations involves nitrene formation of α-imino gold carbenes that undergo a 1,2-allene shift to form (pyrrol-2-yl) methylgold intermediates. With allenyl ester substrates, these gold intermediates become enolate species to enable intramolecular aldol reactions to form useful pyrrolo[1,2-a]quinoline derivatives.

Full text of DOI:10.1039/c8cc09082c

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DOI: 10.1039/C8CC09082C
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Gold-catalyzed [4+1]-Annulation Reactions between Anthranils
and 4-Methoxy-1,2-dienyl-5-ynes Involving a 1,2-Allene Shift
Hsiang-Chu Hsieh,+ Kuo-Chen Tan,+ Antony Sekar Kulandai Raj and Rai-Shung Liu*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Gold-catalyzed [4+1]-annulations of 4-methoxy-1,2-dienyl-5-ynes subsequent 1,2-allene migration to form interesting (pyrrol-2-
with anthranils are described. The mechanism of these yl)methylgold intermediates In-4. A subsequent aldol reaction
annulations involves nitrene formation of -imino gold carbenes of these gold enolates delivers useful pyrrolo[1,2-a]quinoline
that undergo a 1,2-allene shift to form (pyrrol-2-yl)methylgold derivatives when allenyl esters were used (R’ = CO2Et). In
intermediates. With allenyl ester substrates, these gold mechanistic aspect, we are aware of no examples for a 1,2-
intermediates become enolate species to enable intramolecular allene migration into metal carbene moieties. The significance
aldol reactions to form useful pyrrolo[1,2-a]quinoline derivatives.
of this work is to provide an easy access to pyrrolo[1,2-
a]quinoline frameworks7 that are commonly found in many
bioactive molecules; the representatives I-IV are shown in
Interest in the N,O-functionalizations of alkynes with
isoxazoles and anthranils is rapidly increasing in gold catalysis
because of their efficient generations of versatile -imino gold
Figure 1. Among them, compounds
I and II are found to be
highly active in human-breast cancer cells T47D8 and
compound III exhibits bacteriostatic or fungistatic activity.9
Species IV can decrease the sensitivity to the toxicity of
anthrax.10
carbenes under ambient conditions.1 The current work focuses
intensively on activated alkynes such as ynamides and
propiolate derivatives.2-3 The N,O-functionalizations of
unactivated alkynes with these aromatic nitroxy species are
highly desirable. The high reactivity of 1,4-diyn-3-ols toward
gold-catalyzed nucleophilic attack is notable.4 We believe that
these 1,4-diyn-3-ols possess two adjacent alkynes toward gold
catalysts, thus increasing their electrophilic reactions. Hashmi
reported4a gold-catalyzed oxidations of 1,4-diyn-3-ols with
pyridine-based oxides to generate
-oxo gold carbenes In-1
that underwent a subsequent 1,2-alkyne shift to give 3-
formylfuran derivatives. We reported4b catalytic [4+1]-
annulations of 1,4-diyn-3-ols with isoxazoles or anthranils to
generate -imino gold carbenes In-2, resulting in a 1,2-alkyne
shift before proceeding to N-enonyl 3-formylpyrrole products
(eq 2). Apart from 1,4-diyn-3-ols, the present work reports
regioselective N,O-funtionalizations of 4-methoxy-1,2-dienyl-5-
ynes (
of allenes and alkynes with a gold complex are of comparable
affinity.6 Herein, anthranils attack initially at a
-acid activated
alkyne to form -imino gold carbenes In-3, which undergo a
1
)5 with anthranils; we postulate that the binding ability


Figure 1. Representative bioactive molecules
Frontier Research Centers on Fundamental and Applied Science of Matters,
Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan,
Republic of China.
E-mail: rsliu@mx.nthu.edu.tw
† H.-C. Hsieh and K.-C. Tan contributed equally.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Table 1 shows optimizations of conditions between 4-
methoxy-1,2-dienyl-5-ynes 1a with anthranil 2a
tests employed IPrAuCl/AgNTf2 (10 mol %) to catalyze the
reactions of 1,2-dienyl-5-yne 1a with anthranil 2a in
. Our initial
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Table 2. Reactions with 4-Methoxy-1,2-dienyl-5-yneVsiew Article Online
dichloroethane (DCE, 70 °C, 18 h), affording pyrrole 3a in 12%
yield (entry 1). Under this condition, a high loading (4.0 equiv.)
of anthranil 2a gave 3a in a slightly increased yield, ca. 19%; an
alcohol derivative 4a was isolated in 13% yield (entry 2). A
switch of catalyst to LAuCl/AgNTf2 (10 mol %, L = P(t-Bu)2(o-
biphenyl), rendered the desired product 3a in only 10% yield
(entry 3). We observed no reactivity with PPh3AuCl/AgNTf2
(entry 4). Among other silver salts (AgX, X = OTf, SbF6 and
CO2CF3), only AgCO2CF3 gave an increased yield of compound
3a with 27% (entries 5–7). Notably, we employed a high
loading (15 mol %) of IPrAuCl/AgCO2CF3 to increase compound
3a to 30% yield (entry 8); an increased amount of AgCO2CF3
(50 mol %) gave compound 3a up to 65% yield (entry 9). In the
presence of CF3CO2Li (35 mol %) additive, this 15 % IPrAuCl
/AgCO2CF3 system became much less active (entry 10). The
use of IPrAuCl(15 mol %)/AgNTf2(50 mol %) gave the desired
products 3a and 4a in small proportions (< 5%) (entry 11).
AgCO2CF3 (50%) alone was catalytically inactive (entry 12). The
performance of IPrAuCl/AgCO2CF3 in a 15/50 molar ratio was
also examined in toluene, 1,4-dioxane, and DMF; only toluene
showed a moderate efficiency to deliver desired 3a in 48%
yield (entries 13-15). The molecular structures of compound 3a
and 4a were characterized with X-ray diffraction study.11
DOI: 10.1039/C8CC09082C
1 (0.14 M, 1.0 equiv.) a Product yields are obtained after purification
from a silica column. b IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene.
desired 3b–3f in 54-66% yields (entries 1–5). To our delight,
these annulations were applicable also to various alkyl-
substituted 1,2-dienyl-5-ynes (1g-i; R = isopropyl, cyclopropyl
and n-butyl), further affording the desired products 3g-3i in
61-75% yields (entries 6-8). For 2-thienyl-substituted 1,2-
dienyl-5-yne 1j, its corresponding product 3j was obtained in
41% yield (entry 9). We tested the reaction on 3-allenyl-5-yne
1k, but yielding a complicated mixture of product (entry 10).
We assess the scope of these [4+1]-annulation reactions
with various 4-methoxy-1,2-dienyl-5-ynes
1 and anthranil 2a
using IPrAuCl (15 mol %)/AgCO2CF3 (50 mol %) in DCE; the
results are summarized in Table 2. For 1,2-dien-5-ynes bearing
4-substituted phenylalkynyl species (1b-f; R = 4-XC6H4, X = Cl,
Br, OMe, Me, t-Bu), their gold-catalyzed reactions yielded
We also prepared various anthranils 2b-2l to test their
efficiencies with these gold catalyzed reactions. For species 2b-
2f bearing various 5-substituted anthranils (X = Cl, Br, Me,
OMe and OAc), their gold catalyzed reactions rendered the
desired products 3b’-3f’ in 59-74% yields (Table 3, entries 1-5).
Table 1. Catalytic reactions with various metal catalysts
In the case of 6-substituted anthranils 2g-2j (X = Cl, Br, Me, and
OMe), their resulting products 3g’-3j’ were obtained in 62-71%
yields (entries 6-9). Under the standard conditions, dioxolo-
substituted anthranil 2k delivered compound 3k’ in
Table 3. Catalytic Reactions with various anthranils
1a (0.14 M, 1.0 equiv.) a Product yields are obtained after purification from
a silica column, b IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene, c L = P(t-
Bu)2(o-biphenyl), Tf = trifluoromethanesulfonyl. d LiCF3CO2 (35 mol %) was
added
1a (0.14 M, 1.0 equiv.) a Product yields are obtained after purification from
a silica column. b IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene.
2 | J. Name., 2012, 00, 1-3
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Table 4. One-pot synthesis of pyrrolo[1,2-a]quinolVinieewsArticle Online
68% yield (entry 10). We examined the reaction on 3-
methylanthranil 2l, yielding compound 3l’ in 76% yield (entry
11).
DOI: 10.1039/C8CC09082C
The presence of the minor byproduct 4a in Table 1 (entry 2)
inspires us to prepare an allenyl ester derivative 1a’ to
facilitate a possible aldol reaction. Among different silver salts
(X = NTf2, SbF6 and CO2CF3), IPrAuCl/AgNTf2 (15 mol %) was the
most productive, delivering an aldol product 4b in 78% yield
with dr = 1.6:1. In the presence of DBU (1 equiv.), this aldol
product was efficiently converted to pyrrolo[1,2-a]quinoline 5a
in 85% yield (eq 4). The molecular structure of compound 5a
was characterized by X-ray diffraction.11
We assess the scope of the pyrrolo[1,2-a]quinoline synthesis
with various aryl- substituted allenyl esters 1b’-1k’ via one-pot
two-step operations; the results were summarized in Table 4.
Treatment of 4-methoxy-1,2-dienyl-5-ynes 1’ with anthranil 2a
(4 equiv.) and IPrAuCl/AgNTf2 (15 mol %) in hot DCE (70 °C, 42-
45 h) afforded the intermediate
pyrrolo[1,2-a]quinolines with DBU (1.0 equiv.) in DCE at 25 °C.
We prepared 4-substituted phenyl derivatives 1b’ 1d’ (X =
OMe, Me and Cl) that afforded the desired products 5b 5d in
52-80% yields (entries 1-3); as we expected, electron-rich
arylalkyne derivatives (X = OMe and Me) were efficient with
these annulations. We tested the reactions also on 3- and 2-
4 that was converted to
-
-
a
1’ (0.10 M, 1.0 equiv.) Product yields are obtained after purification from a
silica column.
b
IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene. Tf =
trifluoromethanesulfonyl.
phenyl analogues 1e’
(entries 5-8), their resulting products 5e
-
1h’ bearing OMe and Cl substituents
5h were obtained in
cyclized product 4a was completely absent (eq 7). This
information indicated that (pyrrol-2-yl)methylgold species In-
Au likely formed cyclized product 4a, although species In-Au
was more active toward hydrodeauration to form 3-
formylpyrrole product 3a. We also prepared species 1a with
13C-enriched at the C(4)- carbon; the gold-catalyzed reaction
gave pyrrolyl product 3a with the 13C-enrichment at the formyl
carbon.
We postulate a mechanism in Scheme 2 involving gold-
containing intermediates In-Au that are inferred by our data in
Scheme 1. The nitrogen of anthranil is generally more
nucleophilic than its adjacent oxygen atom; this N-attack
occurs preferably at the alkynyl rather than at the allene
-
high yields (> 74%) except compound 5f that was obtained in
47% (entry 6). For 2-thienyl substituted analogue 1i’, its
corresponding product 5i was produced in 34% yield (entry 9).
We tested the reactions on alkyl substituted analogues 1j’ and
1k’ that afforded compounds 5j and 5k in 76% and 60% yields
respectively (entries 10-11). Such pyrrolo[1,2-a]quinoline
synthesis was also operable with 5-substituted anthranils (R2 =
Cl, OCO2Me; R3 = H), affording the desired compounds 5b’ and
5c’ in 58% and 27% yields respectively (entries 12-13). For 6-
substituted anthranils (R2 = H; R3 = Cl and Me), their
corresponding products 5d’ and 5e’ were produced in 41% and
73% yields respectively (entries 14-15). 5,6-Disubstituted
anthranils (R2 = R3 = OMe or R2,R3 = -OCH2O-) led to formation
of pyrrolo[1,2-a]quinoline 5f’ and 5g’ species in high yields (70-
89% entries 16-17).
moiety. After a nitrene transfer, the resulting -imino gold-
As shown in Scheme 1, we found that 15% IPrAuCL/30%
AgNTf2 gave cyclic alcohol 4a in a notable 18% yield (eq 5). But
this condition failed to convert pyrrole 3a to the alcohol
derivative 4a at all (eq 6). We also tested a running condition
in Table 4. With a mixture of allenyl ester 1j’ (1 equiv.),
anthranil 2a (4 equiv.) and pyrrolyl species 3a, we obtained
only pyrrolo[1,2-a]quinoline 5j in 71% yield whereas another
Scheme 1. Mechanistic Elucidations
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(a) T. Wang, S. Shi, M. M. Hansmann, E. Rettenmeier, M.
3715; (b) Y.-C. Hsu, S.-A. Hsieh, P.-H.DLOi Ia: 1n0d.10R3.-9S/C. 8LCiuC,0C9h0e8m2C.
Commun. 2018, 54, 2114; (c) R. D. Kardile, B. S. Kale, P.
Sharma and R.-S. Liu, Org. Lett. 2018, 20, 3806.
4
Rudolph and A. S. K. Hashmi, Angew. Chem. Int.VEiedw.A2rt0ic1le4O,n5lin3e
,
5
6
Although there is no reports for the synthesis of 4-methoxy-
1,2-dienyl-5-ynes, their synthetic procedures are short and
efficient. See supporting information.
For gold-catalyzed reactions on allenes, see reviews: (a) N.
Krause and C. Winter, Chem. Rev. 2011, 111, 1994; (b) W.
Yang and A. S. K. Hashmi, Chem. Soc. Rev. 2014, 43, 2941; (c)
D. J. Gorin, B. D. Sherry and F. D. Toste, Chem. Rev. 2008,
108, 3351; (d) R. A. Widenhoefer and X. Han, Eur. J. Org.
Chem. 2006, 4555.
Scheme 2. A plausible mechanism
7
For the synthesis of pyrrolo[1,2-a]quinoline derivatives, see
(a) C.-L. Ma, J.-H. Zhao, Y. Yang, M.-K. Zhang, C. Shen, R.
Sheng, X.-W. Dong and Y.-Z. Hu, Sci. Rep. 2017, 7, 16640; (b)
carbenes undergoes a 1,2-allene shift rather than a 1,2-
F.-S. Wu, H.-Y. Zhao, Y.-L. Xu, K. Hu, Y.-M. Pan and X.-L. Ma, J.
Org. Chem. 2017, 82, 4289; (c) D. G. Hulcoop and M. Lautens,
hydrogen shift, subsequently yielding Au-
we postulate that this allene migration is probably due to an
efficient overlap through space between the -orbitals of the
C(3) and C(5) carbons in species . An intramolecular
cyclization of intermediate generates gold-containing pyrrole
species in which the oxonium moiety is attacked by water to
-allene species D;
Org. Lett. 2007, 9, 1761; (d) D. I. Chai and M. Lautens, J. Org.

Chem. 2009, 74 ,3054; (e) V. Mamane, P. Hannen and A.
Fürstner, Chem. Eur. J. 2004, 10, 4556; (f) D. Wu, L. Chen, S.
Ma, H. Luo, J. Cao, R. Chen, Z. Duan and F. Mathey, Org. Lett.
2018, 20, 4103.
(a) S. Kumar, S. Bawa and H. Gupta, Mini. Rev. Med. Chem.
2009, 9, 1648; (b) W. Kemnitzer, J. Kuemmerle, S. Jiang, N.
B
D
E
8
9
yield a key intermediate In-Au. For unsubstituted 1,2-dienyl-5-
yne 1a (R = H), most of species In-Au is protonated to give the
observed product 3a. In the case of an ester derivative (1a’),
species In-Au bearing a stable enolate (R = CO2Et) undergoes
an aldol reaction to afford compounds 4b efficiently.
Catalytic N,O-functionalizations of alkynes with isoxazoles
and anthranils were studied intensively on activated alkynes.
In seeking unactivated alkynes, we report gold catalyzed [4+1]-
Sirisoma, S. Kasibhatla, C.-G. Candace, B. Tseng, J. Drewe
and S.-X. Cai, Bioorg. Med. Chem. Lett. 2009, 19, 3481.
A. Hazra, S. Mondal, A. Maity, S. Naskar, P. Saha, R. Paira, K.
B. Sahu, P. Paira, S. Ghosh, C. Sinha, A. Samanta, S. Banerjee
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10 L. H. Slater, E. C. Hett, K. Mark, N. M. Chumbler, D. Patel, D.
B. Lacy, R. J. Collier and D. T. Hung, ACS Chem. Biol. 2013, 8,
812.
11 Crystallographic data of compounds 3a, 4a and 5a were
annulations
anthranils.12,13 The mechanism of these annulations involves
initial formation of -imino gold carbenes that undergo a
subsequent 1,2-allene shift before forming (pyrrol-2-
yl)methylgold intermediates With these organogold
intermediates, we performed one-pot synthesis of pyrrolo[1,2-
of
4-methoxy-1,2-dienyl-5-ynes
with
deposited at Cambridge Crystallographic Data Center: 3a
(CCDC 1863731), 4a (CCDC 1863729) and 5a (CCDC
1863730).

12 For gold-catalyzed [4+1]-annulations with alkynes, see ref
4(c) and selected examples: (a) J. Wang, X. Yao, T. Wang, J.
Han, J. Zhang, X. Zhang, P. Wang and Z. Zhang, Org. Lett.
2015, 17, 5124; (b) C. Zhu, G. Xu and J. Sun, Angew. Chem.
Int. Ed. 2016, 55, 11867; (c) Y.-H. Wang, M. E. Muratore, Z.-T.
.
a]quinoline products
5 using allenyl ester substrates; the key
step involves intramolecular aldol reactions.14
Rong and A. M. Echavarren, Angew. Chem. Int. Ed. 2014, 53
,
14022; (d) Z. Yu, H. Qiu, L. Liu and J. Zhang, Chem. Commun.
2016, 52, 2257; (e) C. Shu, Y.-H. Wang, C.-H. Shen, P.-P. Ruan,
X. Lu and L.-W. Ye, Org. Lett. 2016, 18, 3254; (f) R. B. Dateer,
K. Pati and R.-S. Liu, Chem. Commun. 2012, 48, 7200.
Conflicts of interest
There are no conflicts to declare.
13 For gold-catalyzed reactions of 1-allenyl-n-ynes, see selected
Notes and references
examples: (a) R. Kawade and R.-S. Liu, Org. Lett. 2013, 15
,
4094; (b) C.-Y. Yang, G.-Y. Lin and R.-S. Lin, J. Org. Chem.
2008, 73, 4907; (c) J. Zhao, C. O. Hughes and F. D. Toste, J.
Am. Chem. Soc. 2006, 128, 7436; (d) D. Leboeuf, A.
Simmonneau, C. Aubert, M. Malacria, V. Gandon and L.
Fensterbank, Angew. Chem. Int. Ed. 2011, 50, 6868; (e) A. S.
K. Raj, B. S. Kale, B. D. Mokar and R.-S. Liu, Org. Lett. 2017,
19, 5243.
1
See selected reviews: (a) L. Li, T. D. Tan, Y. Q. Zhang, X. Liua
and L. W. Ye, Org. Biomol. Chem. 2017, , 8483; (b) D. B.
Huple, S. Ghorpade and R.-S. Liu, Adv. Synth. Catal. 2016,
358, 1348.
(a) A.-H. Zhou, Q. He, C. Shu, Y.-F. Yu, S. Liu, T. Zhao, W.
Zhang, X. Lu and L.-W. Ye, Chem. Sci. 2015, 6, 1265; (b) X.-Y.
Xiao, A.-H. Zhou, C. Shu, F. Pan, T. Li and L.-W. Ye, Chem.
Asian J. 2015, 10, 1854; (c) W.-B. Shen, X.-Y. Xiao, Q. Sun, B.
Zhou, X.-Q. Zhu, J.-Z. Yan, X. Lu and L.-W. Ye, Angew. Chem.
Int. Ed. 2017, 56, 605; (d) H. Jin, L. Huang, J. Xie, M. Rudolph,
F. Rominger and A. S. K. Hashmi, Angew. Chem. Int. Ed. 2016,
55, 794; (e) H. Jin, B. Tian, X. Song, J. Xie, M. Rudolph, F.
Rominger and A. S. K. Hashmi, Angew. Chem. Int. Ed. 2016,
55, 12688.
5
2
14 The results in Table 1 (entries 9-12), indicated that both Ag+
-
and CF3CO2 play important roles for the annulations of non-
allenyl esters 1. Allenyl esters 1’ did not require extra AgNTf2
because the cyclization of intermediate
D proceeds through
a Michael-type reaction. For unactivated allenes
1, we
speculate that this process requires additional Ag+ to form
-
Ag(I)-

-allene to facilitate the cyclization. CF3CO2 possibly
stabilizes oxonium intermediates
depicted below.
E via a complexation as
3
(a) R. L. Sahani and R.-S. Liu, Angew. Chem. Int. Ed. 2017, 56,
1026; (b) R. L. Sahani and R.-S. Liu, Angew. Chem. Int. Ed.
2017, 56, 12736.
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DOI: 10.1039/C8CC09082C
Table of content (TOC)
O
O
OHC
R
H
LAu
R
O
R'

AuL
AuL
R

CO2Et
R'
C
CHR'
N
R
N
N
N
O
O
O
1,2-allene
shift
In-4
In-3
R ' = CO2Et
Gold catalyzed [4+1]-annulations of 4-methoxy-1,2-dien-5-ynes with anthranils are
described; the reaction mechanism involves initial formation of -imino gold
carbenes, followed by a subsequent 1,2-allene shift.