Convenient access to novel functionalized pyrazino[1,2-b]isoquinolin-6-one and diazepino[1,2-b]isoquinolin-7-one scaffolds via the Cushman multicomponent reaction followed by post-condensation

Article abstract of DOI:10.1016/j.tetlet.2014.02.099

Post-multicomponent reaction modifications of Cushman reaction-derived 1,2,3,4-tetrahydroisoquinolin-4-carboxylic acids turned out to be a surprisingly underdeveloped strategy in scaffold-oriented synthesis. In this Letter, we describe a concise synthesis of hitherto unreported pyrazino- and diazepino-fused isoquinolones in two chemical operations. The synthesis involves the use, for the first time, of aryl glyoxals as carbonyl components for the Cushman multicomponent reaction.

Full text of DOI:10.1016/j.tetlet.2014.02.099

Tetrahedron Letters 55 (2014) 2299–2303
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient access to novel functionalized pyrazino[1,2-b]
isoquinolin-6-one and diazepino[1,2-b]isoquinolin-7-one
scaffolds via the Cushman multicomponent reaction
followed by post-condensation
⇑
Pakornwit Sarnpitak, Mikhail Krasavin
Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Post-multicomponent reaction modifications of Cushman reaction-derived 1,2,3,4-tetrahydroisoquino-
lin-4-carboxylic acids turned out to be a surprisingly underdeveloped strategy in scaffold-oriented syn-
thesis. In this Letter, we describe a concise synthesis of hitherto unreported pyrazino- and diazepino-
fused isoquinolones in two chemical operations. The synthesis involves the use, for the first time, of aryl
glyoxals as carbonyl components for the Cushman multicomponent reaction.
Received 30 December 2013
Revised 5 February 2014
Accepted 25 February 2014
Available online 4 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Cushman reaction
Post-MCR modifications
Aryl glyoxals
Deprotection–cyclization
Enamines
Scaffold-oriented synthesis
Coupling a multicomponent reaction (MCR) with a premedi-
tated post-MCR event, in a sequence, has proven itself as a rich
and operationally simple source of new and diverse heterocyclic
scaffolds. The power of this approach has been explored in detail,
in particular, for isocyanide-based MCRs, such as the Ugi reaction.1
The condensation of Schiff bases with various cyclic anhydrides
was initially discovered by Castagnoli and Cushman,2 and subse-
quently extended to homophthalic anhydride at the start of Cush-
man’s independent career (with a coincidental independent report
from a Bulgarian group3). The latter reaction (which we would like
to term the Cushman reaction) is essentially a three-component
condensation of an amine and a carbonyl (most often, an alde-
hyde4) component with a homophthalic anhydride (1). It received
particular prominence as a tool to generate various biologically ac-
tive compounds based on the resulting 1,2,3,4-tetrahydro-1-oxo-
isoquinolin-4-carboxylic acid (2) scaffold (Fig. 1).5 The latter
contains two stereogenic centers and can be obtained diastereose-
lectively as pure cis- or trans-isomer—or as a mixture of both—
depending on the conditions of the condensation step.6
On reviewing the literature on the Cushman reaction, we were
surprised at the scarcity of examples of post-MCR modifications
coupled to this powerful and atom-efficient7 three-component
process. Not intending to undertake an exhaustive review of the
literature, we would like to note the following examples (Fig. 2):
(a) the unexpected formation of 5-benzo[d]naphtha[2,3-b]pyran
3 via a base-triggered rearrangement of cyanomethyl derivative
4;8 (b) elaboration of the natural ( )-corynoline core 5 via manip-
ulation of judiciously crafted precursor 6;9 (c) formation of inden-
oisoquinolone 8 via Friedel–Crafts cyclization of 7 in PPA10—a
transformation that ultimately led to the discovery of potent topo-
isomerase inhibitors11 and retinoid X receptor (RXR) agonists
(termed rexinoids);12 (d) an intriguing oxidative conversion of
indenoisoquinoline 8 into isoquinoline-3-spiro-30-phthalide 9;13
(e) reductive manipulation of the carboxylic function of Cushman
adduct 10 leading to the formation of cyclopropane-fused core
11 related to the duocarmycins;14 (f) similar ester reduction with
subsequent straightforward conversion of the resulting alcohols
into amino-substituted compounds 12;15 (g) formation of the fused
lactones 13 and 14 via intramolecular SN2-type lactonization16 or
phenol acylation,17 respectively.
Puzzled by this unfilled void in synthetic organic chemistry, and
excited about the vast scaffold-oriented research opportunity, we
proceeded to investigate the feasibility of various post-Cushman
⇑
Corresponding author. Tel.: +61 (0)73735 6009; fax: +61 (0)73735 6001.
E-mail address: m.krasavin@hotmail.com (M. Krasavin).
http://dx.doi.org/10.1016/j.tetlet.2014.02.099
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2300
P. Sarnpitak, M. Krasavin / Tetrahedron Letters 55 (2014) 2299–2303
O
O
X
O
*
R2
R1
R2
R2
O
1
N
R1 NH2
+
X
N
*
R1
with or without
a catalyst
O
2
COOH
Figure 1. The Cushman reaction.
CN
OMe O
NaH
O
O
O
O
MeO
N
MeO
MeO
(a)
O
O
HOOC
4
3
CN
O
O
O
O
O
O
O
O
O
TFA
O
O
N
N
H
N
(b)
O
O
O
O
O
O
HOOC
O
N+
5
6
-N
O
N
MeO
MeO
PPA
N
MeO
(c)
(d)
(e)
H
O
O
H
MeO
O
HOOC
O
8
O
7
O
O
O
OsO4 - NMO
O
N
MeO
MeO
O
O
9
OMs
COOH
NaH
N
N
N
O
HO
BnO
11
10
O
R3
N
O
O
OTs
R1
R4
R1
COOMe
R1
HNR3R4
(f)
N
R2
N
R2
N
R2
O
12
O
O
Et3N+
SOCl2
-OOC
O
O
O
H
O
DMAP
N
N
(g)
Ph
Ph
H
N
H
OH
N
O
HOOC
Cl
O
O
O
13
14
Figure 2. Examples of post-Cushman transformations described in the literature.
events as a means to build molecular complexity in a practically
simple, expeditious manner. Herein, we report on our first findings
in this area.
We reasoned that incorporating a masked amino functionality
in one of the reagents for the Cushman reaction, and a relatively
unreactive carbonyl functionality in the other would create an
opportunity for a ring-forming process in the Cushman adduct
once the amino function is unmasked. While there are a number
of commercially available monoprotected diamines (such as N-
Boc ethylenediamine or 1,3-diaminopropane), identifying an
appropriate dicarbonyl input that would unequivocally react in
the Cushman step, proved more challenging. After considering sev-
eral possibilities (including monoprotected dicarbonyl variants),
we focused on aryl glyoxals, which we expected to react

P. Sarnpitak, M. Krasavin / Tetrahedron Letters 55 (2014) 2299–2303
2301
O
O
O
O
Ar
15
O
NHBoc
O
O
N
O
n
Ar
NH2
n
N
n
BocHN
BocHN
Ar
MgSO4
CH2Cl2, r. t., 3 h
MeCN, r. t.
overnight
16
O
RO
MeI, K2CO3
17, R = H
18, R = Me
acetone
r. t., overnight
Scheme 1. The Cushman reaction of aryl glyoxals 15.
O
it turned out later, the relative stereochemistry of compounds 18,
designed as precursors for post-Cushman transformations, was
unimportant as one of the stereocenters was destroyed in the next
step (vide infra).
NHBoc
N
Hb
O
nOe
MeOOC
Ha
For the deprotection–cyclization step that was central to this
study, we screened a number of conditions using the model ester
18a. Attempts to obtain the cyclized product 19a in glacial acetic
acid (similar to our earlier work19), as well as on basifying the
TFA salts of the deprotected amines under aqueous conditions
failed. To our delight, in situ basification with triethylamine in
the presence of molecular sieves as a water scavenger20 led to
the desired product 19a, which was isolated in 75% yield (Table 1).
Based on its 1H NMR spectrum (in which the signal corresponding
to the Hb proton of the Cushman precursor was no longer present),
it was shown to exist in the enamine (rather than Schiff base) form
(Scheme 2). Thus, one of the stereocenters generated in the Cush-
man step was destroyed (thereby also removing any potential
ambiguity about the diastereochemical outcome of the latter).
Using the newly identified conditions for the post-Cushman
cyclization step, we transformed esters 18a–o into a set of nine
pyrazino[1,2-b]isoquinolin-6-ones (19a–i) and six diazepino[1,2-
b]isoquinolin-7-ones (19j–o) that were obtained in moderate to
excellent yields (Scheme 3).21 The yields of the cyclization were
markedly lower for the diazepino-fused compounds (Table 2).
Compounds 19a–o are based on novel scaffolds; they contain phe-
nyl substitutents and the newly formed six- or seven-membered
ring as diversity elements. Further product diversity can be poten-
tially achieved via the use of substituted homophthalic anhydrides
Figure 3. NOESY correlations observed in 18a confirming the cis stereochemistry of
the Cushman adducts.
chemoselectively at the aldehyde function leaving the aromatic ke-
tone functionality available for subsequent interaction with the
amino group, when the latter is unmasked.
There were no examples of using glyoxals as carbonyl compo-
nents for the Cushman reaction in the literature.18 However, we
found a range of substituted phenyl glyoxals 15 that reacted very
efficiently—first with the amines 16 and then with homophthalic
anhydride to give a single diastereomer of the acids 17a–o (as
established by the presence of only one set of product signals in
the 1H NMR spectrum of the crude reaction mixtures). For the sake
of easier chromatographic purification, the crude carboxylic acids
17a–o were esterified and the resulting methyl esters 18a–o were
isolated in good to excellent yields (from homophthalic anhydride)
by column chromatography, and were fully characterized
(Scheme 1, see also the Supporting information). The relative ste-
reochemistry of the sole Cushman reaction-derived esters 18 was
established as cis, according to the presence of a through-space
interaction of the vicinal methine protons Ha and Hb (Fig. 3). As
Table 1
Screening of the conditions for the 18a ? 19a cyclization
Acid
Solvent
Temp (°C)
Reaction time
Neutralization–cyclization conditions
Result
Glacial AcOH
Glacial AcOH
TsOH
TFA
TFA
Neat
Neat
Toluene
CH2Cl2
Neat
100
200 (MW)
110
rt
4 h
1 h
Overnight
10 min
—
—
—
K2CO3
30% aq NaOH
Et3N, 4 Å MS
No reaction
No reaction
Complex mixture
Complex mixture
Complex mixture
75% yield of 19a
rt
3 h
TFA
CH2Cl2
0 °C ? rt
10 min (TFA) then overnight (Et3N, 4 Å MS)
O
O
N
O
N
NHBoc
Ph
Conditions
(see Table 1)
N
O
NH
Ph
NH
Ph
*
O
MeO
MeO
O
MeO
O
18a
the enamine form
19a
Scheme 2. Model system 18a to identify workable cyclization conditions.

2302
P. Sarnpitak, M. Krasavin / Tetrahedron Letters 55 (2014) 2299–2303
O
Supplementary data
O
1) TFA, CH2Cl2
r. t., 30 min
NHBoc
N
O
n
N
O
n
Supplementary data (NMR spectra of Cushman reaction-derived
esters 18a–o, as well as the products of their cyclization (19a–o))
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.02.099.
Ar
NH
2) Et3N, 4 Å MS
O
Ar
oC--> r. t.
MeO
MeO
0
overnight
18a-o
19a-o
References and notes
Scheme 3. Cyclization of Cushman reaction derived esters 18a–o.
1. Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125–147.
2. (a) Castagnoli, N. J. Org. Chem. 1969, 34, 3187–3189; (b) Cushman, M.;
Castagnoli, N. J. Org. Chem. 1971, 36, 3404–3406; (c) Cushman, M.; Castagnoli,
N. J. Org. Chem. 1972, 37, 1268–1271; (d) Cushman, M.; Castagnoli, N. J. Org.
Chem. 1973, 38, 440–448; (e) Cushman, M.; Castagnoli, N. J. Org. Chem. 1974, 39,
1546–1550.
Table 2
Compounds 18a–o and 19a–o prepared in this work
Compound
Ar
n
Yield of 18 (%)
Yield of 19 (%)
3. (a) Cushman, M.; Gentry, J.; Dekow, F. W. J. Org. Chem. 1977, 42, 286–288; (b)
Haimova, M. A.; Mollow, N. M.; Ivanova, S. C.; Dimitrova, A. I.; Ognyanov, V. I.
Tetrahedron 1977, 33, 331–336.
18a/19a
18b/19b
18c/19c
18d/19d
18e/19e
18f/19f
Ph
4-FC6H4
3-FC6H4
3,4-DiFC6H3
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3,4-Di(MeO)2C6H4
1
1
1
1
1
1
1
1
47
68
60
56
42
69
69
56
75
91
66
78
78
65
44
88
4. There are a few isolated examples of using ketones in the Cushman reaction,
see: (a) Adams, C.; Papillon, J.; Ksander, G. M. PCT Int. Appl. WO 2007117982;
Chem. Abstr. 2007, 147, 448779.; (b) Xiao, X.; Morrell, A.; Fanwick, P. E.;
Cushman, M. Tetrahedron 2006, 62, 9705–9712; (c) Georgieva, A.; Stanoeva, E.;
Spassov, S.; Macicek, J.; Angelova, O.; Haimova, M.; De Kimpe, N. Tetrahedron
1991, 47, 3375–3388; (d) Stoyanova, M. P.; Angelova, S. E.; Petrov, P. Y.;
Nikolova, R. P.; Shivachev, B. L. ARKIVOC 2010, ii, 303–314; (e) Fodor, L.; Szabo,
J.; Bernath, G.; Sohar, P.; MacLean, D. B.; Smith, R. W.; Ninomiya, I.; Naito, T. J.
Heterocycl. Chem. 1989, 26, 333–337; (f) Gangloff, A. R.; Litvak, J.;
Pararajasingham, K.; Sperandio, D. PCT Int. Appl. WO 2004004727; Chem.
Abstr. 2004, 140, 105251.
5. For representative reports on biologically active Cushman reaction derived
compounds, see: (a) Karimi, A. R.; Momeni, H. R.; Pashazadeh, R. Tetrahedron
Lett. 2012, 53, 3440–3443 (neuroprotective); (b) Christiansen, E.; Urban, C.;
Grundmann, M.; Due-Hansen, M. E.; Hagesaether, E.; Schmidt, J.; Pardo, L.;
Ullrich, S.; Kostenis, E.; Kassack, M.; Ulven, T. J. Med. Chem. 2011, 54, 6691–
6703 (antidiabetic); (c) Rothweiler, U.; Czarna, A.; Krajewski, M.; Ciombor, J.;
Kalinski, C.; Khazak, V.; Ross, G.; Skobeleva, N.; Weber, L.; Holak, T. A.
ChemMedChem 2008, 3, 1118–1128 (apoptosis inducers).
18g/19g
18h/19h
O
18i/19i
1
39
54
O
*
18j/19j
18k/19k
18l/19l
3-F3CC6H4
Ph
4-FC6H4
1
2
2
79
83
68
90
45
34
O
O
18m/19m
2
92
43
*
18n/19n
18o/19o
3,4-Di(MeO)2C6H4
3,4-DiFC6H3
2
2
87
66
46
51
6. Vara, Y.; Bello, T.; Aldaba, E.; Arrieta, A.; Pizarro, J. L.; Arriortua, M. I.; Lopez, X.;
Cossio, F. P. Org. Lett. 2008, 10, 4759–4762. and references cited therein.
7. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–281.
8. Cushman, M.; Dikshit, D. K. J. Org. Chem. 1980, 45, 5064–5067.
9. (a) Cushman, M.; Gupta, Y. P. Heterocycles 1982, 19, 1431–1433; (b) Cushman,
M.; Abbaspour, A.; Gupta, Y. P. Heterocycles 1982, 19, 1587–1590; (c) Cushman,
M.; Abbaspour, A.; Gupta, Y. P. J. Am. Chem. Soc. 1983, 105, 2873–2879; (d)
Cushman, M.; Chen, J.-K. J. Org. Chem. 1987, 52, 1517–1521.
10. Cushman, M.; Mohan, P.; Smith, E. C. R. J. Med. Chem. 1984, 27, 544–547.
11. (a) Morrell, A.; Placzek, M.; Parmley, S.; Antony, S.; Dexheimer, T. S.; Pommier,
Y.; Cushman, M. J. Med. Chem. 2007, 50, 4419–4430; (b) Conda-Sheridan, M.;
Reddy, P. V. N.; Morrell, A.; Cobb, B. T.; Marchand, C.; Agama, K.; Chergui, A.;
Renaud, A.; Stephen, A. G.; Bindu, L. K.; Pommier, Y.; Cushman, M. J. Med. Chem.
2013, 56, 182–200.
O
N
O
N
O
N
MeO
NH
H2NOC
21
20
12. Conda-Sheridan, M.; Park, E.-J.; Beck, D. E.; Reddy, P. V. N.; Nguyen, T. X.; Hu,
B.; Chen, L.; White, J. J.; van Breemen, R. B.; Pezzuto, J. M.; Cushman, M. J. Med.
Chem. 2013, 56, 2581–2605.
Figure 4. Examples of known biologically active compounds related to compounds
19a–o.
13. Jayaraman, M.; Fanwick, P. E.; Cushman, M. J. Org. Chem. 1998, 63, 5736–5737.
14. Venkatram, A.; Colley, T.; Smith, F. J. Heterocycl. Chem. 2005, 42, 297–301.
15. (a) Christov, P. P.; Kozekov, I. D.; Palamareva, M. D. J. Heterocycl. Chem. 2006, 43,
1015–1019; (b) Kandinska, M. I.; Kozekov, I. D.; Palamareva, M. D. Molecules
2006, 11, 403–414.
16. Georgieva, A.; Stanoeva, E.; Spassov, S.; Macicek, J.; Angelova, O.; Naimova, M.;
De Kimpe, N. Tetrahedron 1991, 47, 3375–3388.
17. Georgieva, A.; Stanoeva, E.; Karamfilova, K.; Spassov, S.; Angelova, O.; Haimova,
M.; De Kimpe, N.; Boelens, M. Tetrahedron 1994, 50, 9399–9410.
in the Cushman step, as well as by manipulation of the ester and
enamine functionalities.
In summary, we have reported a convenient synthesis of novel
scaffolds that is based on the Cushman MCR (wherein aryl glyoxals
were used as the carbonyl component for the first time), followed
by post-MCR cyclization. With this route to a new chemistry space
available to us, we will focus on studying further opportunities for
modifying these scaffolds as well as identifying their utility as tools
for modulating various biological targets (at this point, it should be
noted that compounds 19a–i are related to Merck’s potassium
channel blockers represented by structure 20,22 while compounds
19j–o resemble the cytotoxic alkaloid, auranomide C (21), isolated
in China from the marine-derived fungus, Penicillium auratiogrise-
um,23 Fig. 4). The results of these efforts will be reported in due
course.
18. A report on ethyl glyoxylate being used as a Cushman reaction input has
appeared in the literature, see: Hammad, S. F.; Smith, F. T. J. Heterocycl. Chem.
2013, 50, 114–119.
19. Nikulnikov, M.; Shumsky, A.; Krasavin, M. Synthesis 2010, 2527–2532.
20. Pardo, L. M.; Tellitu, I.; Dominguez, E. Synthesis 2010, 971–978.
21. Characterization data for representative compounds: 19a—waxy solid, 1H NMR
(500 MHz, CDCl3) d 7.98 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.44 (t,
J = 7.4 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 7.6 Hz,
1H), 5.37 (br s, 1H), 4.54 (dd, J = 13.5, 4.5 Hz, 1H), 4.12 (s, 1H), 3.98 (dd, J = 16.9,
3.4 Hz, 1H), 3.65 (ddd, J = 16.9, 11.8, 4.5 Hz, 1H), 3.41 (s, 3H), 2.95 (ddd, J = 13.5,
11.8, 3.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 168.5, 165.0, 162.9, 137.3, 132.8,
131.5, 129.8, 129.2, 129.1, 128.6, 128.2, 127.0, 80.3, 53.1, 52.2, 48.5, 33.6;
HRMS m/z calcd for C20H19N2O3 (M+H+) 335.3860, found 335.3799; 19j—grey
solid, mp = 86–88 °C; 1H NMR (500 MHz, CDCl3) d 8.11–8.07 (m, 2H), 7.91 (d,
J = 7.8 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz,
1H), 7.31 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 5.65 (br s, 1H), 4.58 (dd,
J = 13.3, 4.5 Hz, 1H), 4.06 (dd, J = 17.0, 3.3 Hz, 1H), 4.02 (s, 1H), 3.68 (ddd,
Acknowledgment
J = 16.8, 11.8, 4.7 Hz, 1H), 3.43 (s, 3H), 3.04 (ddd, J = 13.4, 11.8, 3.8 Hz, 1H); 13
C
Mikhail Krasavin acknowledges support from Griffith
University.
NMR (125 MHz, CDCl3) d 168.3, 164.2, 162.9, 137.9, 133.0, 132.4, 131.3, 130.6
(q, J = 32.5 Hz), 129.2, 128.8, 128.7, 127.8, 126.5 (q, J = 3.1 Hz), 126.3 (q,

P. Sarnpitak, M. Krasavin / Tetrahedron Letters 55 (2014) 2299–2303
2303
J = 4.0 Hz), 123.9 (q, J = 272.3 Hz), 80.4, 53.1, 52.3, 48.6, 33.7; HRMS m/z calcd
for C21H18F3N2O3 (M+H+) 403.3844, found 403.3873; 19m—viscous oil; 1H
NMR (500 MHz, CDCl3) d 8.09 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.3 Hz, 1H), 7.43 (t,
J = 7.6 Hz, 1H), 7.28–7.23 (m, 2H), 7.18 (d, J = 7.3 Hz, 1H), 6.84 (d, J = 8.0 Hz,
1H), 5.99 (s, 2H), 4.43 (dd, J = 14.3, 7.8 Hz, 1H), 4.29 (s, 1H), 3.95–3.81 (m, 2H),
3.65 (s, 3H), 3.20 (ddd, J = 14.3, 11.5, 6.9 Hz, 1H), 2.27–2.17 (m, 1H), 2.01–1.90
(m, 1H); 13C NMR (125 MHz, CDCl3) d 169.2, 166.2, 163.3, 148.2, 147.2, 133.3,
132.4, 131.6, 128.8, 128.5, 128.3, 128.1, 123.2, 109.8, 107.8, 101.2, 90.8, 54.4,
52.9, 46.3, 39.8, 24.9; HRMS m/z calcd for C22H21N2O5 (M+H+) 393.4231, found
393.4255.
22. Claremon, D. A.; McIntyre, C. J.; Liverton, N. J. PCT Int. Appl. WO2002024655A1;
Chem. Abstr. 2002, 136, 263104.
23. Song, F.; Ren, B.; Yu, K.; Chen, C.; Guo, H.; Yang, N.; Gao, H.; Liu, X.; Liu, M.;
Tong, Y.; Dai, H.; Bai, H.; Wang, J.; Zhang, L. Mar. Drugs 2012, 10, 1297–1306.