Expeditious routes to polycyclic molecular frameworks via one-pot, two-step Ugi ring-closing sequences

Article abstract of DOI:10.1055/s-0033-1340219

A very general and robust multicomponent-reaction protocol involving an Ugi condensation between ethyl glyoxylate, isonitriles, N-Boc-α-amino acids, and mono-N-Boc-protected diamines followed by a series of acid-promoted cyclization steps in a one-pot fashion is reported. This process allows for the assembly of complex polycyclic structures by means of just two simple synthetic operations and a single chromatographic purification in high overall yields. Of note, the first scaffolds derived from a highly A?selective sequence of ring-closing events involving three internal amino nucleophiles is reported. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340219

LETTER
▌225
letter
Expeditious Routes to Polycyclic Molecular Frameworks via One-Pot, Two-
Step Ugi Ring-Closing Sequences
Synthesis of Polycyclic Molecular Frameworks
Zhigang Xu,a Fabio De Moliner,a Alexandra P. Cappelli,a Muhammed Ayaz,a Christopher Hulme*a,b
a
Department of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd.,
Oro Valley, AZ 85737, USA
Fax +1(520)6260794; E-mail: hulme@pharmacy.arizona.edu
b
Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
Received: 27.09.2013; Accepted: 13.10.2013
(U-4CR)5 coupled with nucleophilic post-condensation
Abstract: A very general and robust multicomponent-reaction pro-
modifications6 to develop a strategy that enabled one-pot,
tocol involving an Ugi condensation between ethyl glyoxylate, iso-
expeditious, and facile assembly of polycyclic frame-
works.
nitriles, N-Boc-α-amino acids, and mono-N-Boc-protected
diamines followed by a series of acid-promoted cyclization steps in
a one-pot fashion is reported. This process allows for the assembly
of complex polycyclic structures by means of just two simple syn-
thetic operations and a single chromatographic purification in high
overall yields. Of note, the first scaffolds derived from a highly
selective sequence of ring-closing events involving three internal
amino nucleophiles is reported.
Embedding an additional nucleophile and a suitable elec-
trophilic counterpart into the reagents employed in the
Ugi reaction is the simplest way to enable a facile ring-
closing event after the Ugi condensation, which has been
exploited by in the group7 and by others.8 In particular,
carbonyl functionalities and Boc-protected amines pave
the way to annulation sequences that take place concomi-
tantly via one synthetic operation. Thus, it was envisioned
utilizing two masked amino nucleophiles on the carboxyl-
ic acid 3 and the amine input 4 which, after deprotection,
would ring close onto the ester moiety derived from ethyl
glyoxylate 5 and the secondary amide generated during
the U-4CR, affording fused nitrogen-containing hetero-
cycles of generic structure 1 (Scheme 1).
Key words: multicomponent reaction, nucleophilic attack, hetero-
cycles, isonitriles, one-pot process
Protocols enabling the one-pot construction of multiple
heterocyclic cores have recently grown extremely popu-
lar, in large due to the clear advantages offered by rapid
assembly of complex molecular architecture from struc-
turally simple reactants.1 Indeed, pathways involving syn-
chronous manifold cyclizations, cascades, tandem and
domino processes have gained increasing importance be-
ing beneficial in terms of reducing the cost, time, and ef-
fort of synthesis and recently described as a form of ‘art in
science’ comparable to a symphony or choreography.2
Unsurprisingly, introduction of the aforementioned ap-
proaches into the multicomponent-reaction (MCR) arena
has led to the production of elegant structures in concep-
tually exquisite and sophisticated yet operationally facile
ways.3 Prompted by our recent studies,4 it was decided to
exploit long-term expertise in the use of the Ugi reaction
Feasibility studies were thus conducted employing N-
Boc-glycine and tert-butyl[2-(aminomethyl) phenyl]car-
bamate 4 (n = 1) as reagents containing masked amino nu-
cleophiles. Ethyl glyoxalate and 4 (n = 1) were dissolved
in trifluoroethanol (TFE), followed by addition of n-butyl-
isonitrile and N-Boc-glycine after ten minutes. The reac-
tion proceeded smoothly upon stirring overnight at room
temperature.9 Employing TFE was particularly beneficial
with its low nucleophilicity rendering it less prone to in-
tercept the Schiff base intermediate than its more com-
COOH
NHBoc
3
R
NHBoc
NHBoc
NHBoc
HN
O
NH2
n
N
O
O
O
n
N
n = 0, 1
4
O
O
NH
N
O
HN
R
OHC
O
1
5
2
R
NC
6
Scheme 1 Retrosynthetic plan
SYNLETT 2014, 25, 0225–0228
Advanced online publication: 13.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340219; Art ID: ST-2013-D0922-L
© Georg Thieme Verlag Stuttgart · New York

226
Z. Xu et al.
LETTER
NHBoc
NHBoc
NHBoc
O
COOH
NHBoc
NH2
n
N
O
O
TFE, r.t.
n
4
3
O
n = 0, 1
R
NC
6
O
HN
OHC
O
R
5
2
TFA
MW
R
H2N
O
O
O
HN
O
O
O
N
n
N
H2N
NH
R
NH
N
1
7
Scheme 2 Synthetic procedure toward compounds 1
monly used counterpart solvent methanol.10 After TFE way involving an ordered reaction between the primary
removal in vacuo the relatively clean crude product 2 was amine derived from the α-amino acid on the ester moiety
used without further purification and dissolved in a 10% and the anilinic nitrogen from the phenylenediamine input
TFA solution in DCE to remove Boc protecting groups on the carboxylic acid derived amide (a cyclodehydration
and trigger the double ring-closing sequence (Scheme 2). step) being highly favored.
However, unlike the Ugi reaction, ring formation proved
Having optimized the second step of the sequence, differ-
unfeasible at room temperature, with only Boc cleavage –
ent reagents were evaluated to explore the scope of the
affording 7 – observed.
protocol. A key feature of this diversity-enabling route
Microwave irradiation was thus employed to drive the two proved to be the accessibility of multiple heterocyclic sys-
amines to react with their complementary carbonyl moi- tems through the same operationally friendly MCR-
eties depicted in 7. Using ten-minute irradiation cycles, based/ring-closing sequences. Thus, altering the amine
different temperatures were evaluated. Encouragingly, input afforded three enticing nitrogen-containing cores
heating at 100 °C initiated the desired transformation, exemplified by the seven examples 1a–g (Figure 2), con-
whereas irradiating at 60 °C and 80 °C proved ineffective taining fused benzimidazole12 and piperazine13 moieties,
(Figure 1). Conversely, increasing irradiation temperature which represent two valuable, privileged scaffolds in me-
to 120 °C proved optimal, while more elevated tempera- dicinal chemistry.14
tures resulted in a reduction of yield.
Five amines and three isonitriles were employed in scope
evaluation, whilst the α-amino acid pool was limited to
glycine and isoaminobutyric acid to avoid the formation
of diastereoisomers. It is interesting to note that the meth-
odology proceeded in a smooth manner in a consistently
high-yielding fashion (35–76% over two steps). Subse-
quently, seeking to further enhance molecular complexity
whilst still employing the same reaction conditions, stud-
ies were initiated to generate an additional benzimidazole
ring system in the target molecules, to afford molecules of
generic structure 11 (Scheme 3).
Key to the success of this endeavor was ortho-N-Boc-
Figure 1 Optimization of the two ring-closing events toward 1a:
phenylisonitrile (8) previously shown to afford benz-
imidazoles from multicomponent-derived adducts via
postcondensation modifications.15 Thus, the Ugi reaction
was conducted at room temperature in TFE, and the sec-
ond step was initiated via microwave irradiation with
120 °C again proving optimal after treatment with TFA.
LC–MS conversion (as judged by A% under curve at UV220) vs. re-
action temperature
Considering intermediate 7 in principle contains three car-
bonyl partners, it was encouraging to observe only the
polycyclic molecule 1a formed11 with the expected path-
Synlett 2014, 25, 225–228
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Polycyclic Molecular Frameworks
227
Intriguingly, employment of the designer isonitrile 8 af-
fords generic structure 9 which contains three masked in-
ternal nucleophiles and an ester, in an unprecedented
scenario where all four components of the Ugi reaction
contain an additional reactive functionality positioned to
participate in a sequence of three ring-closing events de-
picted in 10. Five analogues 11a–e were prepared to ex-
emplify the reaction scope (Figure 3).
N
N
N
O
H
N
O
N
HN
HN
HN
O
O
1a, 53%
1b, 76%
N
N
H
N
N
O
N
O
N
N
HN
O
N
N
N
N
O
HN
HN
O
O
N
H
1c, 54%
1d, 52%
N
H
HN
HN
O
O
O
O
11b, 80%
11a, 57%
HN
O
HN
O
N
HN
N
HN
N
N
N
N
N
N
N
N
OMe
1f, 41%
N
H
N
H
HN
HN
1e, 48%
O
O
11c, 73%
11d, 60%
N
N
N
N
H
N
N
N
H
HN
HN
O
O
O
11e, 45%
1g, 35%
Figure 3 Compounds 11a–e assembled via an Ugi and triple ring-
closing sequence
Figure 2 Structures 1 assembled via the Ugi double-cyclization
pathway
NHBoc
COOH
O
N
O
O
O
NH2
NHBoc
n
BocHN
BocHN
TFE, r.t.
3
4
n = 0, 1
NHBoc
n
NH
NHBoc
O
OHC
O
NC
5
8
9
TFA
MW
H2N
O
N
O
O
N
N
NH
NH
NH2
n
O
O
n
H2N
NH
N
10
11
Scheme 3 Synthetic procedure toward compounds 11
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 225–228

228
Z. Xu et al.
LETTER
Hulme, C. Tetrahedron Lett. 2012, 53, 1998. (d) Shaw, A.
Y.; McLaren, J. A.; Nichol, G. S.; Hulme, C. Tetrahedron
Lett. 2012, 53, 2592. (e) Ayaz, M.; Dietrich, J.; Hulme, C.
Tetrahedron Lett. 2011, 52, 4821. (f) Shaw, A. Y.; Medda,
F.; Hulme, C. Tetrahedron Lett. 2012, 53, 1313.
Specifically, two isonitriles, two diamines, and two α-
amino acids were employed with final products obtained
in high overall yields (45–80%). Surprisingly, N-Boc 1,2-
phenylenediamine was found to readily participate in the
Ugi reaction, yet failed to garner the fully constrained tri-
cyclic 11.
(8) For a review, see: Banfi, L.; Riva, R.; Basso, A. Synlett 2010,
23.
(9) Marcaccini, S.; Torroba, T. Nat. Protoc. 2007, 2, 632.
(10) (a) Wang, W.; Dömling, A. J. Comb. Chem. 2009, 11, 403.
(b) Westermann, B.; Neuhaus, C. Angew. Chem. Int. Ed.
2005, 44, 4077.
Conversely, tert-butyl[2-(aminomethyl)phenyl]carbamate
4 (n = 1) readily afforded the 4,6-dihydropyrazinoquinaz-
olinone scaffold 11a–c, in analogy to observations seen
for formation of 1a and 1d, and N-Boc-ethylenediamine
was successfully employed to give 11d and 11e. In sum-
mary, we have herein reported several one-pot, two-step
routes to four scaffolds derived from an Ugi condensation,
followed by either two of three ring-closing events. The
initial Ugi condensation takes place under mild condi-
tions, and subsequent acid-triggered cyclizations afford
the arrays of nitrogen-containing polycyclic frameworks
presented herein. Due to the facile nature of the method-
ology, it is expected to be a useful tool amenable to paral-
lel synthesis and could become a method of choice for the
preparation of the polycyclic moieties described herein.
(11) General Procedure for the Preparation of Compounds
1a–g and 11a–e, Exemplified by Compound 1c
tert-Butyl (2-aminophenyl)carbamate (1 equiv, 1.0 mmol,
208 mg) and ethyl glyoxylate (1.5 equiv, 1.5 mmol, 361 μL
of a 50% solution in toluene) were dissolved in TFE (5 mL).
After 10 min, N-Boc-glycine (1 equiv, 1.0 mmol, 175 mg)
and 6-isocyano-2,3-dihydrobenzo[b][1,4]dioxane (1 equiv,
1.0 mmol, 161 mg) were added to the reaction mixture,
which was stirred overnight at r.t. The reaction was
monitored by LC–MS and TLC. Upon completion, the
solvent was removed in vacuo and the crude material
dissolved in 10% TFA–DCE (3.0 mL), with subsequent
irradiation at 120 °C for 10 min. After the vial was cooled to
r.t., the mixture was diluted with EtOAc (50 mL), and the
organic layer was washed with sat. NaHCO3 (20 × 2 mL) and
brine. The organic phase was dried over MgSO4, evaporated
in vacuo, and the crude material was purified by flash
chromatography (MeOH–EtOAc 0–10%) using an ISCO
purification system to afford N-{2,3-dihydrobenzo-
[b][1,4]dioxan-6-yl}-3-oxo-1,2,3,4-tetrahydrobenzo-
[4,5]imidazo[1,2-a]pyrazine-4-carboxamide (1c) as a white
solid (197 mg, 54% yield). 1H NMR (400 MHz, DMSO-d6):
δ = 10.89 (s, 1 H), 8.94–8.78 (m, 1 H), 7.68–7.58 (m, 1 H),
7.40 (dd, J = 6.2, 2.9 Hz, 1 H), 7.30–7.15 (m, 3 H), 7.01 (dd,
J = 8.7, 2.3 Hz, 1 H), 6.81 (d, J = 8.7 Hz, 1 H), 5.74 (s, 1 H),
4.88–4.59 (m, 2 H), 4.19 (s, 4 H). 13C NMR (100 MHz,
DMSO-d6): δ = 163.1, 162.5, 146.0, 143.2, 143.0, 140.1,
132.8, 131.5, 122.6, 122.3, 118.9, 117.0, 112.6, 109.5,
108.4, 64.1, 63.9, 60.6. MS: m/z = 365 [M + H]+. ESI-
HRMS: m/z calcd for C19H17N4O4 [M + H]+: 365.1244;
found: 365.1242.
(12) For examples of the biological profiles displayed by the
benzimidazole core, see: (a) Zarrinmayeh, H.; Nunes, A. M.;
Ornstein, P. L.; Zimmerman, D. M.; Arnold, M. B.; Schober,
D. A.; Gackenheimer, S. L.; Bruns, R. F.; Hipskind, P. A.;
Britton, T. C.; Cantrell, B. E.; Gehlert, D. R. J. Med. Chem.
1998, 41, 2709. (b) He, Y.; Yang, J.; Wu, B.; Risen, L.;
Swayze, E. E. Bioorg. Med. Chem. Lett. 2004, 14, 1217.
(c) Horn, J. Clin. Therap. 2000, 22, 266. (d) Prichard, M. N.;
Frederick, S. L.; Daily, S.; Borysko, K. Z.; Townsend, L. B.;
Drach, J. C.; Kern, E. R. Antimicrob. Agents Chemother.
2011, 55, 2442. (e) Li, Y.; Tan, C.; Gao, C.; Zhang, C.;
Luan, X.; Chen, X.; Liu, H.; Chen, Y.; Jiang, Y. Bioorg.
Med. Chem. 2011, 19, 4529.
Acknowledgment
Financial support from the National Institutes of Health (Grant
P41GM086190) is gratefully acknowledged. We also thank Dr.
Federico Medda and Dr. David Bishop for proofreading and copy-
editing.
References and Notes
(1) For recent examples, see: (a) Lian, X.; Ma, S. Chem. Eur. J.
2010, 16, 7960. (b) Medley, J. W.; Movassaghi, M. Angew.
Chem. Int. Ed. 2012, 51, 4572. (c) Murata, T.; Murai, M.;
Ikeda, Y.; Miki, K.; Ohe, K. Org. Lett. 2012, 14, 2296.
(d) Chiou, W. H.; Lin, Y. H.; Chen, G. T.; Gao, Y. K.; Tseng,
Y. C.; Kao, C. L.; Tsai, J. C. Chem. Commun. 2011, 47,
3562. (e) Gembus, V.; Janvier, S.; Lecouvé, J. P.; Vaysse-
Ludot, L.; Brièrea, J. F.; Levacher, V. Org. Biomol. Chem.
2012, 10, 2003.
(2) For reviews, see: (a) Nicolaou, K. C.; Chen, J. S. Chem. Soc.
Rev. 2009, 38, 2993. (b) Malacria, M. Chem. Rev. 1996, 96,
289.
(3) (a) Santra, S.; Andreana, P. R. Angew. Chem. Int. Ed. 2011,
50, 9418. (b) Ribelin, T. P.; Judd, A. S.; Akritopoulou-
Zanze, I.; Henry, R. F.; Cross, J. L.; Whittern, D. N.; Djuric,
S. W. Org. Lett. 2007, 24, 5119. (c) Riva, R.; Banfi, L.;
Basso, A.; Cerulli, V.; Guanti, G.; Pani, M. J. Org. Chem.
2010, 75, 5134.
(4) (a) De Moliner, F.; Hulme, C. Org. Lett. 2012, 14, 1354.
(b) Xu, Z.; De Moliner, F.; Cappelli, A. P.; Hulme, C.
Angew. Chem. Int. Ed. 2012, 51, 8037.
(13) Dömling, A.; Huang, Y. Synthesis 2010, 2859; and
references cited therein.
(5) Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72, 267.
(6) (a) Nixey, T.; Kelly, M.; Hulme, C. Tetrahedron Lett. 2000,
41, 8729. (b) Nixey, T.; Kelly, M.; Semin, D.; Hulme, C.
Tetrahedron Lett. 2002, 43, 3681. (c) Hulme, C.; Bienaymé,
H.; Nixey, T.; Chenera, B.; Jones, W.; Tempest, P.; Smith,
A. Methods Enzymol. 2003, 369, 469. (d) Hulme, C.;
Chappeta, S.; Dietrich, J. Tetrahedron Lett. 2009, 50, 4054.
(7) (a) Dietrich, J.; Kaiser, C.; Meurice, N.; Hulme, C.
Tetrahedron Lett. 2010, 51, 3951. (b) Gunawan, S.; Ayaz,
M.; De Moliner, F.; Frett, B.; Kaiser, C.; Patrick, N.; Hulme,
C. Tetrahedron 2012, 68, 5606. (c) Shaw, A. Y.; Xu, Z.;
(14) Shiozaki, M.; Maeda, K.; Miura, T.; Kotoku, M.; Yamasaki,
T.; Matsuda, I.; Aoki, K.; Yasue, K.; Imai, H.; Ubukata, M.;
Suma, A.; Yokota, M.; Hotta, T.; Tanaka, M.; Hase, Y.;
Haas, J.; Fryer, A. M.; Laird, E. R.; Littmann, N. M.;
Andrews, S. W.; Josey, J. A.; Mimura, T.; Shinozaki, Y.;
Yoshiuchi, H.; Inaba, T. J. Med. Chem. 2011, 54, 2839.
(15) (a) Xu, Z.; Shaw, A. Y.; Nichol, G. S.; Cappelli, A. P.;
Hulme, C. Mol. Diversity 2012, 16, 607. (b) Xu, Z.; Ayaz,
M.; Cappelli, A. P.; Hulme, C. ACS Comb. Sci. 2012, 14,
460.
Synlett 2014, 25, 225–228
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