Highly selective domino multicyclizations for forming polycyclic fused acridines and azaheterocyclic skeletons

Article abstract of DOI:10.1021/ol400322v

Highly selective four-component domino multicyclizations for the synthesis of new fused acridines and azaheterocyclic skeletons have been established by mixing common reactants in isobutyric acid under microwave irradiation. The reactions proceeded at fast rates and were conducted to completion within 20-30 min. Up to seven new chemical bonds, four rings, and four stereocenters were assembled in a convenient one-pot operation. The resulting hexacyclic and pentacyclic fused acridines and their stereochemistry have been fully characterized and determined by X-ray structural analysis.

Full text of DOI:10.1021/ol400322v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Selective Domino Multicyclizations
for Forming Polycyclic Fused Acridines
and Azaheterocyclic Skeletons
Bo Jiang,†, Xue Wang,†, Hai-Wei Xu,† Man-Su Tu,† Shu-Jiang Tu,*,† and Guigen Li*,‡,§
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou,
221116, Jiangsu, P. R. China, Institute of Chemistry & BioMedical Sciences (ICBMS),
Nanjing University, Nanjing 210093, P. R. China, and Department of Chemistry and
Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
laotu@jsnu.edu.cn; guigen.li@ttu.edu
Received February 3, 2013
ABSTRACT
Highly selective four-component domino multicyclizations for the synthesis of new fused acridines and azaheterocyclic skeletons have been
established by mixing common reactants in isobutyric acid under microwave irradiation. The reactions proceeded at fast rates and were
conducted to completion within 20ꢀ30 min. Up to seven new chemical bonds, four rings, and four stereocenters were assembled in a convenient
one-pot operation. The resulting hexacyclic and pentacyclic fused acridines and their stereochemistry have been fully characterized and
determined by X-ray structural analysis.
The assembly of complex polycyclic skeletons of chemi-
cal and biomedical importance has become a challenging
and hot topic in modern organic chemistry.1,2 Among
these skeletons, a unique pyrrolo-fused acridine parent
ring system commonly exists in natural alkaloids and has
been represented by Stellettamine,3 Cyclodercitin,3,4 and
Plakinidines5 (Figure 1); it shows a broad range of bio-
logical activities. These complex architectures have inspired
our interest on creating new synthetic strategies for total
synthesis and methodologies.6
Highly efficient syntheses usually reflect the sum of
enormous efforts aimed at atom-economic and environ-
mental elements and remarkable chemo-, stereo-, and
regioselective control of multiring construction.7 Domino
multicyclizations (DMCs) have been successfully applied
to the total synthesis of natural and natural-like products
† Jiangsu Normal University.
These authors contributed equally.
‡ Nanjing University.
§ Texas Tech University.
(1) (a) Melhado, A. D.; Brenzovitch, W. E.; Lackner, A. D.; Toste,
F. D. J. Am. Chem. Soc. 2010, 132, 8885–8887. (b) Adams, G. L.;
Carroll, P. J.; Smith, A. B., III. J. Am. Chem. Soc. 2013, 135, 519–528.
(c) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L.
J. Am. Chem. Soc. 2009, 131, 1753.
(2) (a) Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105, 4730–
4756. (b) Sutherland, J. K. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Elmsford, NY, 1991; Vol. 1, pp 341ꢀ377.
(3) (a) Gunawardana, G. P.; Koehn, F. E.; Lee, A. Y.; Clardy, J.; He,
H. Y.; Faulkner, D. J. J. Org. Chem. 1992, 57, 1523–1526. (b) Agrawal,
M. S.; Bowden, B. F. Nat. Prod. Res. 2007, 21, 782–786.
(4) Le Bozec, L.; Moody, C. J. Aust. J. Chem. 2009, 62, 639–647.
(5) (a) Inman, W. D.; O’Neill-Johnson, M.; Crews, P. J. Am. Chem.
Soc. 1990, 112, 1–4. (b) West, R. R.; Mayne, C. L.; Ireland, C. M.;
Brinen, L. S.; Clardy, J. Tetrahedron Lett. 1990, 31, 3271–3274.
(6) (a) Wang, H.; Li, L.; Lin, W.; Xu, P.; Huang, Z.; Shi, D. Org. Lett.
2012, 14, 4598–4601. (b) Jiang, B.; Wang, X.; Li, M.-Y.; Wu, Q.; Ye, Q.;
Xu, H.-W.; Tu, S.-J. Org. Biomol. Chem. 2012, 10, 8533–8538.
(c) Kefayati, H.; Narchin, F.; Rad-Moghadam, K. Tetrahedron
Lett. 2012, 53, 4573–4575. (d) Gellerman, G.; Rudi, A.; Kashman, Y.
Tetrahedron 1994, 50, 12959.
(7) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115–136. (b) Tietze, L. F.;
Brasche, G.; Gerike, K. Domino Reactions in Organic Chemistry; Wiley-
VCH: Weinheim, 2006. (b) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072–
3081. (c) Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res. 2009, 42,
367–378. (e) Ganem, B. Acc. Chem. Res. 2009, 42, 463–472.
r
10.1021/ol400322v
XXXX American Chemical Society

Scheme 1. Two Novel Domino Multicyclization Reactions
Figure 1. Several representative natural products.
(IV)) were readily formed in domino fashion that involved
novel sequential [3 þ 2]/[4 þ 2]/[2 þ 2 þ 1]/[2 þ 2]
cyclizations in a one-pot operation. The four newly formed
stereocenters including two quaternary centers were also
well controlled in a one-pot operation. Very interestingly,
by changing the terminal groups of alkynes, the reaction
can be controlled toward formation of tricyclic 5ꢀ6ꢀ7
skeletons including pyrrole (V), pyridine (VI), and azepine
(VII) via another novel sequential [3 þ 2]/[4 þ 2]/[2 þ 2 þ
2 þ 1] cyclization mechanism. In addition, the direct
conversion of allylic CꢀH bonds into CꢀC bonds was
achieved in this domino system without the use of any
metal catalysts. To the best of our knowledge, the synthetic
strategy and mechanistic sequences described in this com-
munication have not been reported so far.
We began our investigation on the multicyclization
reaction of unsubstituted indoline-2,3-dione 1a, N-(4-
chlorophenyl) enaminones 2a, and symmetrical diethyl
but-2-ynedioate 3a. When these components were mixed
in a ratio of 1:1:2.2 and subjected to microwave irradiation
in acetic acid (HOAc) at 110 °C, an intermolecular hex-
acyclic product, cyclobuta[4,5]pyrrolo [3,2,1-de]pyrrolo-
[4,3,2-mn]acridines 4a, was obtained in 45% yield. Its
structure was unambiguously determined by X-ray dif-
fraction analysis (see Supporting Information (SI)). This
unprecedented observation prompted us to further optimize
the reaction conditions. Various acidic solvents, such as
formic acid (HCOOH), trifluoroacetic acid (TFA), propa-
noic acid (EtCOOH), n-butyric acid (CH3(CH2)2COOH),
and isobutyric acid ((CH3)2CHCOOH), were thus em-
ployed as microwave irradiation media. Among these
by controlling multiring-junction frameworks.8 These re-
actions not only enable the construction of complex struc-
tures in a single operation but also avoid tedious isolation
and purification workup.9 Among these methodologies,
various DMCs toward the formation of polycyclic fused
azaheterocycles have been extensively studied.10 However,
more efficient methodologies for the total synthesis of
azaheterocyclic products from readily available reactants
remain extremely challenging.
In the past several years, we and others have developed a
series of domino reactions for the construction of multiple
functional ring structures of chemical and pharmaceutical
importance.11,12 During our continuous effort on this
domino project, we now discovered novel domino multi-
cyclization reactions of enaminones with isatin and elec-
tron-deficient alkynes divergently leading to the formation
of polyfunctionalized hexacyclic and pentacyclic fused
acridines 4 and 5 in good yields and excellent stereoselec-
tivity (Scheme 1). The resulting polyfunctionalized multi-
cyclic fused acridines are important scaffolds for drug
design and discovery and can serve in pharmaceutical
research.1
The attractive aspects of these domino reactions are
demonstrated by the fact that up to seven new chemical
bonds and four new rings (tetracyclic 5ꢀ6ꢀ5ꢀ4 skeleton
including pyrrole (I and III), pyridine (II), and cyclobutane
(8) (a) Turner, C. I.; Williamson, R. M.; Tumer, P.; Sherburn, M. S.
Chem. Commun. 2003, 1610–1611. (b) Padwa, A.; Brodney, M. B.;
Lynch, S. M.; Rashatasakhon, P.; Wang, Q.; Zhang, H. J. Org. Chem.
2004, 69, 3735–3745.
(9) (a) Stearman, C. J.; Wilson, M.; Padwa, A. J. Org. Chem. 2009,
74, 3491–3499. (b) France, S.; Boonsombat, J.; Leverett, C. A.; Padwa,
A. J. Org. Chem. 2008, 73, 8120–8123. (c) Topczewski, J. J.; Callahan,
M. P.; Neighbors, J. D.; Wiemer, D. F. J. Am. Chem. Soc. 2009, 131,
14630–14631.
(10) (a) Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115, 12491–
12509. (b) Huang, A. X.; Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 9999–10003.
(11) (a) Jiang, B.; Li, C.; Shi, F.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G.
J. Org. Chem. 2010, 75, 2962–2965. (b) Jiang, B.; Tu, S.-J.; Kaur, P.;
Wever, W.; Li, G. J. Am. Chem. Soc. 2009, 131, 11660–11661. (c) Jiang,
B.; Wang, X.; Shi, F.; Tu, S.-J.; Ai, T.; Ballew, A.; Li, G. J. Org. Chem.
2009, 74, 9486–9489. (d) Jiang, B.; Li, Q.-Y.; Zhang, H.; Tu, S.-J.; Pindi,
S.; Li, G. Org. Lett. 2012, 14, 700–703.
(12) (a) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.;
Zografos, A. L. J. Am. Chem. Soc. 2009, 131, 1753–1765. (b) Yang,
J. W.; Fonseca, M. T. H.; List, B. J. Am. Chem. Soc. 2005, 127, 15036–
15037.
Table 1. Optimization for the Synthesis of 4a under MW
temp
time
entry
solvent
acetic acid
(°C)
(min)
yielda%
1
2
3
4
5
6
100
120
120
100
100
100
20
25
25
20
20
20
45
formic acid
trace
trace
47
trifluoroacetic acid
propanoic acid
n-butyric acid
isobutyric acid
51
59
a Isolated yield.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Domino Synthesis of Fused Acridines 4 and 5
a Conditions: the synthesis of products 4, (CH3)2CHCOOH (1.5 mL), 90ꢀ100 °C, microwave heating; the synthesis of products 5, (CH3)2CHCOOH
(1.5 mL), 130ꢀ140 °C, microwave heating. b Isolated yield.
solvents, the first two acids (HCOOH and TFA) led to poor
yields of product 4a even at an enhanced temperature of
120 °C. Instead, only intermediate D (Table 1, entries 2ꢀ3
and Scheme 2) was observed. The other two solvents,
propanoic acid and n-butyric acid, resulted in product 4a
in 47% and 51% isolated yield, respectively. The best yield
of 59% was achieved when the reaction was performed in
isobutyric acid. In an attempt to enhance the yield further,
metal triflates such as Sc(OTf)3, Cu(OTf)2, and Zn(OTf)2
were then employed to promote the reaction.14 Unfortu-
nately, complex mixtures were formed, making purification
very difficult. It was found that acetic acid can serve not
only as a suitable media but also as an adequate Brønsted
acid promoter for the present multicyclizations shown in
Scheme 1. It should be noted that, for four-component
reactions, this yield would be interpreted as a very good one.
With this optimization in hand, we next examined the
substrate scope of this reaction by using various readily
available starting materials. As revealed in Table 2, various
starting materials can be employed for this reaction and
result in highly functionalized fused acridine derivatives
that offer flexibility for structural modifications. For
enaminone substrates, a variety of N-substituents bearing
electron-withdrawing or -donating groups can all tolerate
the reaction conditions. Meanwhile, various substituted
isatins, such as 5-F (1b) 5-Me (1c), and 5-Cl (1d), can
also be utilized and result in corresponding hexacyclic
fused acridines 4bꢀ4q smoothly. With the importance
of N-substituted amino acids considered,15 the preformed
N-carboxymethyl enaminone 2f was subjected to the reac-
tion with 1a and 3b, providing the corresponding poly-
cyclic substituted amino acid derivative 4k. As shown in
Table 2, the present intermolecular domino multiple cycli-
laztions showed a broad substrate scope to give hexacyclic
products in excellent stereoselectivity. Essentially, only
1
a single diastereomer was detected by H and 13C NMR
spectroscopic analysis.
During our investigation on alkyne substrates, we found
when unsymmetrical electron-deficient alkynes, propargyl
esters 3cꢀd, were subjected to the reaction with indoline-
2,3-diones1andN-substitutedenaminones2aꢀ2hinacetic
acid at 130ꢀ140 °C, propargyl esters were consumed
(13) (a) Groundwaater, P. W.; Munawar, M. A. Adv. Heterocycl.
Chem. 1998, 70, 88–161. (b) Cookson, J. C.; Heald, R. A.; Stevens,
M. F. G. J. Med. Chem. 2005, 48, 7198–7207. (c) Antonini, I.; Polucci, P.;
Magnano, A.; Sparapani, S.; Martelli, S. J. Med. Chem. 2004, 47, 5244–
5250.
(14) (a) Kobayashi, S.; Hachiya, I.; Araki, M.; Ishitani, H. Tetrahedron
Lett. 1993, 34, 3755–3758. (b) Kobayashi, S.; Nagayama, S.; Busujima, T.
J. Am. Chem. Soc. 1998, 120, 8287–8288. (c) Nishina, Y.; Kida, T.;
Ureshino, T. Org. Lett. 2011, 13, 3960–3963.
(15) (a) Paquette, L. A. J. Org. Chem. 1964, 29, 3447–3449. (b)
Paquette, L. A.; Broadhurst, M. J. J. Org. Chem. 1973, 38, 1886–1893.
(c) Sato, E.; Ikeda, Y.; Kanaoka, Y. Liebigs Ann. Chem. 1989, 8, 781–
788.
Org. Lett., Vol. XX, No. XX, XXXX
C

reaction, the latter also resulted in multiple rings and
chemical bonds rapidly in a one-pot operation. Besides
the characteristic of a high reaction rate, these two reac-
tions can be both worked out conveniently, in which water
is a major byproduct and the products can precipitate out
after cold water was poured into the reaction mixture,
which makes workup very convenient simply by filtration/
washing.
Scheme 2. Domino Synthesis of Pentacyclic Fused Acridines 5
The mechanism for these two domino cyclizations are
proposed and shown in Scheme 3. The former involves
the ring closure cascade reactions that consist of initial
nucleophilic addition (2 to A), intramolecular cyclization
(A to B), and ring-opening of indoline-2,3-dione 1 (B to C),
recyclization and dehydration (C to D), and second inter-
molecular double nucleophilic additions and third double
cyclizations (D to 4). Similar to the former, the latter
underwent the same sequent processes to give intermediate
D, which is followed by a subsequent intermolecular
nucleophilic addition with one molecular propargyl ester
leading to the formation of N-vinylethenamines E. The
[5 þ 2] cycloaddition between N-vinylethenamines E and
propargyl ester occurred to yield thermodynamically
stable pentacyclic products 5. This mechanism has been
partially supported by an experiment in which the isolated
intermediate D was subjected to the reaction with 3a in
isobutyric acid; the hexacyclic product 4a was generated in
58% yield.
Scheme 3. Mechanism Hypothesis for Forming 4 and 5
In summary, novel four-component domino [3 þ 2]/
[4 þ 2]/[2 þ 2 þ 1]/[2 þ 2] and [3 þ 2]/[4 þ 2]/[2 þ 2 þ 2 þ 1]
multicyclizations have been discovered for selectively
diverse constructions of hexa- and pentacyclic fused acri-
dines and polycyclic fused azaheterocyclic skeletons. The
ready accessibility of starting materials and the broad
compatibility of N-substituted enaminones make these
reactions highlyvaluablefororganicand biomedical fields.
Other attractive features of these reactions include mild
conditions, convenient one-pot operation, short reaction
times of 20ꢀ30 min, and excellent regio- and stereoselec-
tivity. The continuing work on this project will be focused
on the development of asymmetric versions of these reac-
tions and applications of the resulting highly conjugate
systems.
within 20ꢀ30 min. Surprisingly, the reaction occurred
toward another direction to give multifunctionalized pen-
tacyclic fused acridines 5 that belong to another family
of important scaffolds for organic and pharmaceutical
sciences (Scheme 2).16 Two molecules of unsymmetrical
electron-deficient alkynes 3cꢀd were introduced into the
final pentacyclic fused acridine products (Scheme 2). The
structural elucidation and attribution of stereoselectivity
were unequivocally determined by NMR spectroscopic
analysis and X-ray diffraction of single crystals that were
obtainedby slow evaporation of the solvents (4a and 5i; see
SI). The results are summarized in Table 2. Both electron-
deficient and -rich aromatic groups on the N-substituted
enaminones gave very good chemical yields (5aꢀ5m) for
this reaction. Furthermore, halogen functional groups
(Cl and Br) were tolerated well under the current condi-
tions and can provide opportunities for further functional
manipulations via cross-couplings.17 Similar to the former
Acknowledgment. We are grateful to the NSFC (Nos.
20928001, 21072163, 21232004, and 21102124), PAPD of
Jiangsu Higher Education Institutions, Jiangsu Sci & Tech
Support Program (No. BE2011045), NIH (R21DA031860-
01, G.L.), and Robert A. Welch Foundation (D-1361,
G.L.) for their generous support.
(16) (a) Gowan, S. M.; Heald, R.; Stevens, M. F. G.; Kelland, L. R.
Mol. Pharmcol. 2001, 60, 981–988. (b) Stanslas, J.; Hagan, D. J.; Ellis,
M. J.; Turner, C.; Carmichael, J.; Ward, W.; Hammonds, T. R.; Stevens,
M. F. G. J. Med. Chem. 2000, 43, 1563–1572.
(17) (a) Rummelt, S. M.; Ranocchiari, M.; van Bokhoven, J. A. Org.
Lett. 2012, 14, 2188–2190. (b) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41,
1450–1460. (c) Fagnoni, M.; Albini, A. Acc. Chem. Res. 2005, 38, 713–
721. (d) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith,
M. R., III. Science 2002, 295, 305–308. (e) Lipshutz, B. H.; Butler, T.;
Swift, E. Org. Lett. 2008, 10, 697–700.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX