A synthesis of dihydroimidazo[5,1-a]isoquinolines using a sequential Ugi-Bischler-Napieralski reaction sequence

Article abstract of DOI:10.1016/j.tetlet.2011.12.050

A flexible route to analogues of dihydroimidazo[5,1-a]isoquinolines is described. The synthesis hinges on a sequential Ugi coupling, followed by a Bischler-Napieralski reaction to form the imidazole isoquinoline core. This route facilitates the introduction of a range of substitutions throughout the carbon framework.

Full text of DOI:10.1016/j.tetlet.2011.12.050

Tetrahedron Letters 53 (2012) 903–905
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A synthesis of dihydroimidazo[5,1-a]isoquinolines using a sequential
Ugi–Bischler–Napieralski reaction sequence
⇑
W. Michael Seganish , Ana Bercovici, Ginny D. Ho, Hubert J.J. Loozen, Cornelis M. Timmers,
Deen Tulshian
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A flexible route to analogues of dihydroimidazo[5,1-a]isoquinolines is described. The synthesis hinges on
a sequential Ugi coupling, followed by a Bischler–Napieralski reaction to form the imidazole isoquinoline
core. This route facilitates the introduction of a range of substitutions throughout the carbon framework.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 October 2011
Revised 8 December 2011
Accepted 12 December 2011
Available online 19 December 2011
Keywords:
Isoquinoline
Ugi coupling
Bischler–Napieralski
Cribrostatin 6 (1) is the first known naturally occurring example
of an imidazole isoquinoline containing compound. In the course of
several of our medicinal chemistry programs, we were interested
in pursuing structures similar to compound 2. The compounds con-
tained a very similar carbon framework to cribrostatin 6 (blue).
There have been several synthetic approaches to the imidazole
isoquinoline core, including those that have led to the total synthe-
sis of cribrostatin itself.1 These synthetic approaches, although
elegant, do not allow for the rapid introduction of different
functional groups onto the core structure.
followed by a Bischler–Napieralski3 reaction to form the desired
imidazole isoquinoline ring system (Scheme 1). It has been previ-
ously reported that the imidiazole isoquinoline ring system can
be assembled via a Bischler–Napieralski reaction in low yield
(11%).4 We thought that we could improve the yield and efficiency
of this reaction. Additionally, with careful selection of aldehyde 6,
acid 7, and isonitrile 5 components for the Ugi coupling, we could
assemble a large degree of chemical diversity in this tandem reac-
tion sequence.
The desired isonitrile substrate for the Ugi coupling was rou-
tinely synthesized from the corresponding amine (Scheme 2).
The amine was heated in neat ethyl formate to provide formamide
9. The formamide was then cleanly converted to the desired
In our approach to the imidazole isoquinoline core, a key
requirement would be the ability to rapidly create novel analogues
for testing in biological assays. We were most interested in modi-
fications to the imidazole ring, but also wanted a route that would
still be amenable to modifications of the isoquinoline ring as well.
We envisioned an Ugi multicomponent coupling2 that would allow
for the assembly of the different R group-containing fragments,
Scheme 1. Ugi–Bischler–Napieralski approach.
⇑
Corresponding author. Tel.: +1 908 740 2896; fax: +1 908 740 7152.
E-mail address: william.seganish@merck.com (W.M. Seganish).
Scheme 2. Synthesis route for isonitriles.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.050

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W. M. Seganish et al. / Tetrahedron Letters 53 (2012) 903–905
Table 1
Synthesis of dihydroimidazolisoquinones5
Entry
Isonitrile
Ugi coupling product
Yielda (%)
Bischler–Napieralski coupling product
Yielda (%)
1
52
74
2
3
50
58
77
46
4
5
99
62
48
56
6
82
43
7
8
84
58
45
62
9
64
65
46
68
64
40
10
11
a
Isolated yield.
isonitrile 5 using POCl3. With the isonitrile in hand, we could at-
tempt the desired Ugi–Bischler–Napieralski sequence (Table 1).
Methanol was an acceptable solvent for the Ugi coupling; how-
ever, optimal results were obtained by pre-forming the imine in

W. M. Seganish et al. / Tetrahedron Letters 53 (2012) 903–905
905
trifluroethanol, then adding the isonitrile.6 A variety of modifica-
tions were tolerated on the phenyl ring (entries 1–6). Electron-
withdrawing (entry 1) and electron-donating (entries 3–6) groups
were well tolerated. Trisubstitution on the aryl ring (entry 2) did
not hinder the reaction. It was interesting to note that in the case
of entry 5, the Bischler–Napieralski cyclization gave only the less
sterically hindered product. The coupling-cyclization sequence
also tolerated a variety of aromatic and heteroaromatic aldehydes
(6) including thiophene (entries 1–3), pyridine (entries 4, 5 and
7–9), phenyl (entry 6), imidiazole (entry 10), and thiazole (entry
11). Additionally, the reaction sequence was tolerant of modifica-
tions of the acid coupling partner (7) with Me (entries 4, 5, 8 and
10) and phenyl (entry 7) being well tolerated.
In summary, we have optimized a new two step Ugi–Bischler–
Napieralski sequence for the synthesis of biologically active dihy-
droimidiazoleisoquinolines. These conditions have been applied
on a large scale to provide gram quantities of the desired products.
Future efforts will focus on expanding the scope of the reaction to
new substrate classes.
3. For a review, see: Rozwadowska, M. D. Heterocycles 1994, 39, 903.
4. Nagarajan, K.; Rodrigues, P. J. J. Chem. Res. 1993, 336.
5. Representative procedure (entry 8): 3-Pyridine carboxaldehyde (1.00 mL,
10.6 mmol) was dissolved in trifluroethanol (18 mL). Ammonium acetate
(1.63 g, 21.2 mmol) was added in one portion and the solution was heated to
60 °C for 30 min. Isonitrile 10 (2.23 g, 11.7 mmol) was added in one portion
at 60 °C and the resulting solution was stirred for a further 4 h at 60 °C. The
reaction mixture was cooled to room temperature and concentrated. The
residue was purified via column chromatography on silica gel (0–10% MeOH/
DCM) to provide 2.17 g (58%) of the desired product as a white solid. TLC
Rf = 0.33 (5% MeOH/DCM); mp = 151–152 °C; 1H NMR 400 MHz (CDCl3) d 8.54
(m, 1H), 8.49 (m, 1H), 7.62 (m, 1H), 7.23 (m, 1H), 7.09 (m, 2H), 6.72
(d, J = 8 Hz, 1H), 6.65 (m, 1H), 6.60 (m, 1H), 6.52 (d, J = 8 Hz, 1H), 5.45 (d,
J = 7.2 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.56 (m, 1H), 3.47 (s, 3H), 3.41 (m,
1H), 2.68 (m, 2H), 1.99 (s, 3H); 13C NMR 100 MHz (CDCl3) d 170.2, 169.4,
148.9, 148.8, 148.6, 147.5, 134.8, 134.3, 131.0, 123.8, 120.6, 111.7, 111.2, 55.8,
54.5, 50.4, 41.1, 34.9, 22.9; LC–MS (ESI+) 97.6% [M+H] = 358. P2O5 (4.31 g,
30.4 mmol) was added to methanesulfonic acid and heated to 75 °C for
30 min, at which time all of the P2O5 had dissolved. The Ugi coupling product
(2.17 g, 6.07 mmol) was added in one portion at 75 °C and the reaction was
stirred for 4 h to consume all of the starting material (TLC). The reaction was
cooled to room temperature and poured slowly into solid NaHCO3. Ice water
was slowly added and the resulting mixture was extracted with EtOAc. The
combined organic extracts were dried (MgSO4), filtered, and concentrated to a
yellow oil that was purified via column chromatography on silica gel (0–5%
MeOH/DCM/NH3) to provide 1.18 g (62%) the desired product as
a white
solid. TLC Rf = 0.40 (5% MeOH/DCM3/NH); mp = 170–171 °C 1H NMR 400 MHz
(CDCl3) d 8.95 (m, 1H), 5.52 (m, 1H), 8.01 (m, 1H), 7.32 (m, 1H), 6.96 (s, 1H),
6.75 (s, 1H). 3.98 (m, 2H), 3.88 (s, 3H), 3.57 (s, 3H), 3.05 (m, 2H), 2.46 (s, 3H);
References and notes
13C NMR (CDCl3)
d 149.6, 148.1, 148.0, 144.5, 143.5, 135.6, 131.8, 131.7,
1. (a) Knueppel, D.; Martin, S. F. Angew. Chem., Int. Ed. 2009, 48, 2569; (b) Markey,
M. D.; Kelly, T. R. J. Org. Chem. 2008, 73, 7441; (c) Nakahara, S.; Kubo, A.; Mikami,
Y.; Ito, J. Heterocycles 2006, 68, 515; (d) Nakahara, S.; Kubo, A. Heterocycles 2004,
63, 2355.
2. For a review, see: Zhu, J. Eur. J. Org. Chem. 2003, 1133; For additional applications
of multicomponent reactions see: Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10,
51; Domling, A. Chem Rev. 2006, 106, 17.
125.0, 124.1, 123.1, 120.3, 111.3, 106.7, 56.0, 55.7, 41.2, 29.3, 13.0. LC–MS
(ESI+) 99.9% [M+H] = 322.
6. Isaacson, J.; Gilley, C. B.; Kobayashi, Y. J. Org. Chem. 2007, 72, 3913.