Palladium-catalyzed regioselective [3 + 2] annulation of internal alkynes and iodo-pyranoquinolines with concomitant ring opening

Article abstract of DOI:10.1021/ol3022935

A regioselective tandem synthesis of highly functionalized pyrrolo[1,2-a]quinolines has been developed through a novel strategy by palladium-catalyzed [3 + 2] annulation of iodo-pyranoquinolines and internal alkynes with subsequent ring opening. Pyranoquinoline with n-alkyl substitution at the 3-position leads to the formation of pyrrolo-acridones via [3 + 2] annulations/ring opening and successive intramolecular cross-aldol condensation.

Full text of DOI:10.1021/ol3022935

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5184–5187
Palladium-Catalyzed Regioselective
[3 þ 2] Annulation of Internal Alkynes and
Iodo-pyranoquinolines with Concomitant
Ring Opening
Trapti Aggarwal,† Rajeev R. Jha,† Rakesh K. Tiwari,†,‡ Sonu Kumar,†
Siva K. Reddy Kotla,† Sushil Kumar,† and Akhilesh K. Verma*,†
Department of Chemistry, University of Delhi, Delhi, 110007, India, and Department of
Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston,
Rhode Island 02881, United States
averma@acbr.du.ac.in
Received August 17, 2012
ABSTRACT
A regioselective tandem synthesis of highly functionalized pyrrolo[1,2-a]quinolines has been developed through a novel strategy by palladium-
catalyzed [3 þ 2] annulation of iodo-pyranoquinolines and internal alkynes with subsequent ring opening. Pyranoquinoline with n-alkyl substitution at the
3-position leads to the formation of pyrrolo-acridones via [3 þ 2] annulations/ring opening and successive intramolecular cross-aldol condensation.
Nitrogen-containing heterocycles are an important class
of compounds due to their presence in numerous natural
products and potent biological activity.1 Among various
N-heterocycles, reduced and oxidized forms of pyrrolo-
[1,2-a]quinolines occur widely among natural products2a,b
and exhibit a wide array of biological activities.2c Despite
various synthetic protocols available for the synthesis of
pyrrolo[1,2-a]quinoline,3 a need for novel and versatile
methods for their efficient synthesis attracts the interest of
synthetic chemists.
The annulation reactions catalyzed by transition metals
are among the most demanding synthetic processes for
constructing a wide variety of heterocyclic/carbocyclic
frameworks.4,5 Among various annulations, the [3 þ 2]
annulation represents a breakthrough in the field of
† University of Delhi.
‡ University of Rhode Island.
(1) (a) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008,
108, 264. (b) Bailly, C. Anti-Cancer Agents 2004, 4, 363. (c) Yao, B.;
Prinsep, M. R.; Nicholson, B. K.; Gordon, D. P. J. Nat. Prod. 2003, 66,
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Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892. (c) Martin, S. F. In The
Alkaloids; Brossi, A., Ed.; Academic Press Inc.: London, 1987; Vol. 30, p
251. (d) Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503. (e) Larock, R. C.
Top. Organomet. Chem. 2005, 14, 147. (f) Zeni, G.; Larock, R. C. Chem.
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104, 2127.
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Santarem, M.; Vanucci-Bacque, C.; Lhommet, G. J. Org. Chem. 2008,
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7915.
r
10.1021/ol3022935
Published on Web 09/28/2012
2012 American Chemical Society

organic synthesis.6 In 1998, Larock et al. reported an
elegant approach for the synthesis of indoles by [3 þ 2]
annulations7 and other polycyclic compoundsthrough CH
activation.8 Recently, Cramer and Tran reported the
synthesis of substituted indenes by [3 þ 2] annulations of
aromatic ketimines with internal alkynes using a Rh(I)-
catalyst along with chiral ligands.9 As a part of our ongoing
efforts in the synthesis of heterocycles using alkyne chem-
istry,10 for the first time herein we report the Pd-catalyzed
intermolecular [3 þ 2] annulation of internal alkynes and
iodo-pyranoquinolines with subsequent ring opening for
the synthesis of pyrrolo[1,2-a]quinolines 3 (Scheme 1). The
developed chemistry was successfully extended for the syn-
thesis of pharmaceutically important pyrrolo acridinones11
4 from easily accessible iodo-pyrano quinolines12 (R2 =
n-alkyl) via [3 þ 2] annulations/ring opening and successive
intramolecular cross-aldol condensation.
Based on the previous studies by Larock13 and our
group,14 we hypothesized and envisioned the formation
of polyheterocycle 5 by [4 þ 2] annulation via palladacycle
X (Scheme 1, route a). We also anticipated the possible
formation of product 3a by [3 þ 2] alkyne annulation
(using pyridyl nitrogen) and successive pyran ring opening
via generation of vinylpalladium intermediate IV and
adduct V (Scheme 1, route b). A preliminary study showed
that the reaction failed to afford the polyheterocycle 5
under Pd-catalyzed conditions (Scheme 1, route a). How-
ever, an interesting product 3 was detected and isolated,
which was characterized by spectroscopic analysis and
further confirmed by X-ray crystallographic studies of
compound 3k.15
Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Design of Polyheterocycles via [4 þ 2]/[3 þ 2] Alkyne
Annulation
entry
solvent
base
catalyst
mol %
yieldb
1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
KOAc
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
5
5
3
5
5
5
5
5
5
5
5
5
5
5
5
5
5
30c
80
55
60d
78
75
0
2
3
4
5
6
Pd(PPh3)2Cl2
CuI
7
8
Cu(OTf)2
Cu(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0
9
0
0e
10
11
12
13
14
15
16
17
(6) (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215 and
references cited therein. (b) Hanhan, N. V.; Ball-Jones, N. R.; Tran,
N. T.; Franz, A. K. Angew. Chem., Int. Ed. 2012, 51, 989. (c) Wang,
Z.-Q.; Lei, Y.; Zhou, M.-B.; Chen, G.-X.; Song, R.-J.; Xie, Y.-X.; Li,
J.-H. Org. Lett. 2011, 13, 14. (d) Lian, Y.; Davies, H. M. L. J. Am. Chem.
Soc. 2010, 132, 440. (e) Kim, H.; Lee, K.; Kim, S.; Lee, P. H. Chem.
Commun. 2010, 46, 6341. (f) Yang, M.; Zhang, X.; Lu, X. Org. Lett.
2007, 9, 5131. (g) Mizumura, M.; Shinokubo, H.; Osuka, A. Angew.
Chem., Int. Ed. 2008, 47, 5378.
65
20
30
77
50f
78g
60h
K2CO3
Na2CO3
NaOAc
NaOAc
NaOAc
NaOAc
(7) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
(8) (a) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem. 1999, 64,
8770. (b) Larock, R. C.; Doty, M. J.; Tian, Q.; Zenner, J. M. J. Org.
Chem. 1997, 62, 7536.
a Reactions were performed using 0.25 mmol of 1a, 1.2 equiv of 2a,
2.0 equiv of base, 3.0 equiv of LiCl in 2.0 mL of solvent at 140 °C for 36 h
unless otherwise noted. b Isolated yield. c For 24 h. d 1.0 equiv of NaOAc
and 1.5 equiv of LiCl used. e Absence of LiCl. f At 120 °C for 40 h. g Using
microwave irradiation at 120 °C for 20 min. h Using microwave irradia-
tion at 120 °C for 15 min.
(9) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 11098.
(10) (a) Joshi, M.; Tiwari, R. K.; Verma, A. K. Org. Lett. 2012, 14,
1106. (b) Rustagi, V.; Aggarwal, T.; Verma, A. K. Green Chem. 2011, 13,
1640. (c) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock,
R. C. Angew. Chem., Int. Ed. 2009, 48, 1138.
(11) (a) Ralifo, P.; Sanchez, L.; Gassner, N. C.; Tenney, K.; Lokey,
R. S.; Holman, T. R.; Valeriote, F. A.; Crews, P. J. Nat. Prod. 2007, 70,
95. (b) West, R. R.; Mayne, C. L.; Ireland, C. M.; Brinen, L. S.; Clardy, J.
Tetrahedron Lett. 1990, 31, 3271. (c) Smith, C. J.; Venables, D. A.;
Hopmann, C.; Salomon, C. E.; Jompa, J.; Tahir, A.; Faulkner, D. J.;
Ireland, C. M. J. Nat. Prod. 1997, 60, 1048. (d) Thale, Z.; Johnson, T.;
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Pietraszkiewicz, H.; Valeriote, F. A.; Crews, P. J. Org. Chem. 2002,
67, 9384.
To test our hypothesis, we began an investigation from
the reaction of 4-iodo-1-methoxy-3-phenyl-1H-pyrano-
[4,3-b] quinoline (1a) and diphenylacetylene (2a) using
NaOAc and LiCl with different Pd(II) catalysts in DMF
at 140 °C. When 5 mol % of Pd(OAc)2 was used, only a
30% yield of product 3a was observed after 24 h, while an
80% yield of the product was obtained after 36 h (Table 1,
entries 1 and 2). Further lowering of the catalyst loading
decreases the yield to 55% (entry 3). No significant effect
onthe yield was observedby decreasing the amountof base
(12) (a) Aggarwal, T.; Imam, M.; Kaushik, N. K.; Chauhan, V. S.;
Verma, A. K. ACS Comb. Sci. 2011, 13, 530. (b) Verma, A. K.; Rustagi,
V.; Aggarwal, T.; Singh, A. P. J. Org. Chem. 2010, 75, 7691. (c) Verma,
A. K.; Aggarwal, T.; Rustagi, V.; Larock, R. C. Chem. Commun. 2010,
46, 4064.
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2011, 76, 5670.
(15) See Supporting Information.
(13) (a) Liu, Z.; Larock, R. C. J. Org. Chem. 2007, 72, 223. (b) Yue,
D.; Ca, N. D.; Larock, R. C. J. Org. Chem. 2006, 71, 3381. (c) Yao, T.;
Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511.
Org. Lett., Vol. 14, No. 20, 2012
5185

to 1.0 equiv and LiCl to 1.5 equiv (entry 4). Also, 5 mol %
of PdCl2 and Pd(PPh3)2Cl2 were found to be effective
(entries 5 and 6). The Cu(I) salts such as CuI, Cu(OTf)2,
and Cu(OAc)2 were found to be ineffective (entries 7ꢀ9).
No product formation was observed in the absence of LiCl
(entry 10). Use of KOAc afforded the product 3a in lower
yield (entry 11). Inferior results were observed when
K2CO3 and Na2CO3 were used as a base (entries 12 and
13). Using DMSO as a solvent, the desired product was
obtained in 77% yield (entry 14). Lowering the reaction
temperature to 120 °C leads to the incomplete conversion
of the substrate (entry 15).
within 20 min, affording a 78% yield of product 3a
(entry 16), whereas, in 15 min, only a 60% yield was
obtained (entry 17).
After optimizing the reaction conditions, we examined
the scope of the reaction by utilizing a variety of pyrano-
[4,3-b]quinolines 1 and internal alkynes 2. The substrate
4-iodo-pyrano[4,3-b]quinolines 1aꢀf were readily pre-
pared by electrophilic iodocyclization using the reported
procedure.12 Phenyl substituted pyranoquinoline reacted
well with symmetrical internal alkynes and afforded the
desired product 3aꢀd in 80ꢀ85% yields under the optimized
reaction conditions (Scheme 2). Electron-donating substitu-
ents at R2 had no considerable effect on the reaction and
afforded the desired product 3dꢀj, 3l in good to excellent
yields. The aryl substituted symmetrical internal alkynes also
afforded the products in good yield, while a comparatively
lower yield of product 3h was obtained with 1,2-di(thiophen-
3-yl)ethyne (2f). The aliphatic internal alkynes reacted slowly
and afforded the desired product 3dꢀe in 68 and 65% yield,
respectively. With 3-tert-butyl-iodo-pyrano[4,3-b]quinoline
1f, the product 3k was obtained in 72% yield. When a
methoxy group was substituted at R1, the reaction proceeded
smoothly in 30 h and afforded the product 3l in 85% yield.
Scheme 2. Substrate Scope of the Palladium-Catalyzed [3 þ 2]
Alkyne Annulationa,b
Scheme 3. A Plausible Mechanism
With the above results, a plausible mechanism was
proposed on the basis of the reported mechanism7
(Scheme 3). The reaction proceeds via reduction of the
Pd(OAc)2 toPd(0), and thenLiCl donates Clꢀ to Pd(0) asa
ligand and forms [PdCl]ꢀ. The oxidative addition of the
aryl iodide to Pd(0) (I) and coordination of the alkyne to
the Pd-atom resulted in palladium alkyne intermediate II.
The regioselective insertion of alkyne into the aryl palla-
dium bond leads to the formation of intermediate III. The
attack of the nitrogen lone pair on the vinylpalladium
intermediate forms a palladacyclic complex (IV)16 which
upon reductive elimination forms the [3 þ 2] annulated
a Unless otherwise specified, reactions were performed using
0.25 mmol of 1, 1.2 equiv of 2, 5 mol % Pd(OAc)2, 2.0 equiv of NaOAc,
3.0 equiv of LiCl in 2.0 mL of DMF at 140 °C for 36 h. bIsolated yield.
c For 40ꢀ44 h. d Using microwave irradiation at 120 °C for 20 min.
From the above studies, the optimal conditions consist
of 2.0 equiv of NaOAc and 3.0 equiv of LiCl with 5 mol %
of Pd(OAc)2 in DMF for 36ꢀ44 h to carry out this
transformation in good yields. Interestingly, under mi-
crowave irradiation at 120 °C the reaction is complete
5186
Org. Lett., Vol. 14, No. 20, 2012

adduct (V) and regeneration of the Pd(0). The instability of
intermediate V subsequently leads to the opening of the
pyran ring to form intermediate VI, which upon loss of Me
provided the product 3.8a
group also afforded the single isomer 3q in 60% yield
(entry 5). The reason might be the substantial difference in
electron density at the two ends of the CꢀC triple bond.8a
In an effort to synthesize the fused heterocycle, we had
employed aliphatic substituted pyranoquinoline which con-
tained R-H. With this objective, 3-butyl-4-iodo-1-methoxy-1H-
pyrano[4,3-b]quinoline (1h) and 1i were treated with different
internal alkynes 2aꢀc under microwave conditions. Surpris-
ingly, the corresponding products 4aꢀd were obtained in good
yields by [3 þ 2] annulations/ring opening followed by intra-
molecular cross-aldol condensation (Scheme 5). The structure
Table 2. Synthesis of Pyrrolo[1,2-a]quinolines Using Unsym-
metrical Internal Alkynesa
1
of pyrrolo-acridones was confirmed by H, 13C NMR and
finally by X-ray crystallographic studies of compound 4c.
entry
1
substrate
internal alkyne
product
yield%b
1a
2h, R3 = Ph,
R4 = 4-MeOC6H4
2i, R3 = CH2OH,
R4 = 4-MeC6H4
2i
3m
70(70:30)
Scheme 5. Synthesis of Pyrroloacridones via Alkyne Annula-
tions Followed by Intramolecular Cross-Aldol Condensation
2
1a
3n
62
3
4
5
1b
1c
1c
3o
3p
3q
65
68c
2i
2j, R3 = COOEt,
R4 = Ph
60
a Unless otherwise specified, reactions were performed using
0.25 mmol of 1, 1.2 equiv of 2, 5 mol % Pd(OAc)2, 2.0 equiv of NaOAc,
3.0 equiv of LiCl in 2.0 mL of DMF at 140 °C for 36 h. b Isolated yields.
c At 120 °C for 20 min in microwave.
Scheme 4. Regioselectivity via Formation of Chelated Complex
In summary, we have demonstrated a Pd-catalyzed tan-
dem synthesis of pyrrolo[1,2-a]quinolines by [3 þ 2] annula-
tion of iodo-pyranoquinolines with successive ring opening
under mild reaction conditions. This chemistry was success-
fully extended to the synthesis of diverse pharmaceutically
important pyrrolo-acridinone via [3 þ 2] annulations/ring
opening and successive intramolecular cross-aldol condensa-
tion. It is noteworthy that unsymmetrical internal alkynes
containing a propargyl alcoholic group and ester group
selectively afforded a single isomer. Further investigation
of the scope and synthetic applications of the present strategy
are currently underway and will be reported in due course.
To examine the generality of this developed chemistry,
unsymmetrical internal alkynes were allowed to react with
the pyrano[4,3-b]quinoline under the optimized reaction
conditions (Table 2). With 1-methoxy-4-(phenylethynyl)-
benzene (2h), the product was obtained in 75% yield as a
mixture of regioisomers (70:30) (entry 1).
Interestingly, alcohol substituted internal alkyne 3-p-
tolylprop-2-yn-1-ol (2i) afforded the single isomers 3mꢀp
in 62ꢀ68% yields (entries 2ꢀ4). The effect of the adjacent
hydroxyl group on the regioselectivity of the alkyne was
due to coordination ofthe hydroxyl group tothe Pd.14 This
is due to the formation of a chelated complex with Pd
during the insertion step (III), leaving only one position
availableforthe formation ofthe CꢀC bond (IV), and thus
we obtained a single isomer (Scheme 4). Annulation with
internal alkyne 2j having an electron-withdrawing ester
Acknowledgment. The Research work was supported
by the Department of Science and Technology (SR/S1/
OC-66/2010). We are thankful to the University of Delhi
and USIC for instrumental facilities. T.A., R.R.J., S.K.,
S.K.R.K., and S.K. are thankful to CSIR for a fellowship.
Supporting Information Available. Experimental pro-
cedures and characterization of all new compounds (1H
NMR, 13C NMR, HRMS) and CIFs for compounds 3n
(CCDC no. 886428) and 4c (CCDC no. 886429). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Chernyak, D.; Skontos, C.; Gevorgyan, V. Org. Lett. 2010, 12,
3242.
The authors declare no competing financial interest.
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