Towards molecular diversity: Dealkylation of tert-butyl amine in Ugi-type multicomponent reaction product establishes tert-butyl isocyanide as a useful convertible isonitrile

Article abstract of DOI:10.1039/c0ob00022a

With the development of a novel microwave-assisted one-pot tandem de-tert-butylation of tert-butyl amine in an Ugi-type multicomponent reaction product, tert-butyl isocyanide as a useful convertible isonitrile has been explored for the first time affordin

Full text of DOI:10.1039/c0ob00022a

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Towards molecular diversity: dealkylation of tert-butyl amine in Ugi-type
multicomponent reaction product establishes tert-butyl isocyanide as a useful
convertible isonitrile†
Sankar K. Guchhait* and Chetna Madaan
Received 20th April 2010, Accepted 9th June 2010
First published as an Advance Article on the web 24th June 2010
DOI: 10.1039/c0ob00022a
With the development of a novel microwave-assisted one-pot
tandem de-tert-butylation of tert-butyl amine in an Ugi-type
multicomponent reaction product, tert-butyl isocyanide as a
useful convertible isonitrile has been explored for the first time
affording access to molecular diversity of pharmaceutically-
important polycyclic N-fused imidazo-heterocycles.
MCR product was found to be ineffective in methods mediated
by various Brønsted acids such as HCl, AcOH, conc. HCl and
H2SO4. The reaction under reflux in neat TFA is complicated
by uncontrollable over-trifluoroacetylation of primary amine, and
thus requires stringent alkaline hydrolysis in the subsequent step.
Furthermore, the reaction sequence is not suitable for the in situ
generation of molecular diversity. The over-trifluoroacetylation of
the derived amine in de-tert-butylation can be avoided only by its
internal trapping with tethered electrophile.9 To the best of our
knowledge, there is no report of de-tert-butylation which does not
require internal trapping, is one-step and amenable to access to
molecular diversity. We present herein the development of a novel
tandem one-step dealkylation of derived tert-butyl amine in an
Ugi-type MCR product (Scheme 1). This has established first time
tert-butyl isocyanide as a useful convertible isonitrile affording
one-pot preparation of therapeutically-relevant diverse polycyclic
N-fused heterocycles including N-fused imidazole-amines (A) and
tetracyclic heterocycles (B). The diversity of compounds A has
been found to be extendable via various post-modifications at the
primary amino group into their derivatives (C).
The preparation of chemical libraries is an essential prerequi-
site for lead discovery, lead optimization, and targeted drug
design. The class of multicomponent reactions (MCRs),1 espe-
cially isocyanide-based, is an excellent tool for the generation
of chemical libraries. However, the diversity of products from
iscocyanide-based MCRs is restricted by the limited availability
and synthetic-troublesomeness of isocyanides. The use of convert-
ible isocyanides,2 an excellent concept introduced by Armstrong,
and its combination with UDC (Ugi/De-BOC/Cyclize) strategy3
affords rapid access via the Ugi product to a large library
with scaffold- and functionality-diversities. This approach has
thus gained immense importance in the generation of molecu-
lar diversity and therapeutic agents.4 The problematic removal
of alkyl amine (or aryl amine) derived from the isocyanide
component in the Ugi-MCR product, which is crucial for in
situ cyclization or functionality-interconversion, has led to the
development of several convertible isonitriles.2c–h Recently, an
Ugi-type multicomponent reaction (also referred to as Groebke–
Blackburn or Groebke–Blackburn–Bienayme´ reaction) has exhib-
ited its potential in the preparation of therapeutically-relevant
N-fused imidazoles.5,6 To offer a convertible isocyanide in this
Ugi-type MCR, the dealkylation of the derived alkyl amine in the
MCR product was found to be critical. It requires a particular
alkyl group in the isonitrile component, which in post-MCR
protonolytic dealkylation can generate a highly stable carbocation
such as isooctyl in the case of 1,1,3,3-tetramethylbutyl isocyanide
(Walborsky reagent). It is also necessary to use the dealkylat-
ing agent in a large excess or as solvent.5g,7 Besides, 1,1,3,3-
tetramethylbutyl isocyanide is expensive and thus not applicable
to bulk- and solid-phase library-synthesis. The use of tert-butyl
isocyanide, which is economical, commercially available, stable
and storable, as a convertible isonitrile has been attempted.7a,8
But, the de-tert-butylation of the tert-butyl amine-containing
Scheme 1 Development of tandem de-tert-butylation in MCR product
affording tert-butyl isocyanide as a useful converting isonitrile towards the
preparation of diverse N-fused imidazoles (A, B and C).
Recently, we have developed efficient methods of Groebke–
Blackburn MCR catalyzed by ZrCl4 for the synthesis of N-fused
imidazoles.5d,e Our initial investigations centered on developing a
tandem one-step dealkylation of the derived tert-butyl amine in the
MCR product formed by this reaction using tert-butyl isocyanide.
We envisioned that for Brønsted acid-mediated protonolytic
elimination of imidazole-amine, controlling parameters might be
the pKa of acid (HX), size of anion (X-), using a solvent capable
of transient stabilizing ion pair [tBu+ X-], and the availability
of sufficient activation energy. With this thought, a systematic
screening of acids, solvents and reaction conditions was carried
out. The results are summarized in Table 1. HBF4 in microwave
irradiation was found to be the most effective dealkylating
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), S. A. S. Nagar (Mohali) - 160062,
Punjab, India. E-mail: skguchhait@niper.ac.in; Fax: +91 (0)172 2214692;
Tel: +91 (0)172 2214683
† Electronic supplementary information (ESI) available: General exper-
imental procedure and characterization data for products. See DOI:
10.1039/c0ob00022a
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 3631–3634 | 3631
©

View Online
Table 1 Screening of protic acids, solvents and conditionsa
Table 2 One-pot MCR-tandem de-tert-butylation: synthesis of N-fused
imidazole-aminesa
Yield (%)b
Entry Acid
pKa (in H2O) Solvent
Conventional mW
Aldehyde
Entry Amidine
1
(R2CHO)
Product
Yield b(%)
90
1
2
3
4
TFA
-0.25
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
PEG-400
DMSO
0
0
CH3SO3H -2.6
HBF4
HCl
21
35
28
26
—
—
—
—
—
60
90
81
76
78
72
89
74
33
-0.4
-8.0
-9.0
5
6
7
HBr
HBF4
HBF4
HBF4
HBF4
HBF4
2
92
8c
9c
10c
n-BuOH
PEG-400
DMSO
3
4
89
94
a Reactants and reagents: azine (1 mmol), aldehyde (1 mmol), tert-BuNC
(1 mmol), ZrCl4 (10 mol%), n-BuOH (1 mL) and Brønsted acid (1 mmol).
Conditions in conventional heating: 1.a. 50 ◦C, 2 h; 1.b. 110 ◦C, 15 h. mW
conditions: 1.a. 140 ◦C, 7 min; 1.b. 160 ◦C, 20 min. b Isolated yields.
c 4-Bromobenzaldehyde was used in place of 4-chlorobenzaldehyde.
agent, although HCl exhibited a similar dealkylation activity.
The correlation of dealkylation activity of acids with their acidity
(pKa in water) reveals that there must be parameter(s) other than
acidity responsible for dealkylation efficiency, and they may be
the size and shape of counter anions. Inorganic acids are better
dealkylating agents than organic acids. While n-BuOH, PEG-
400 and DMSO as solvents showed similar results for the mul-
ticomponent reaction, n-BuOH was found to be superior to other
solvents for the de-tert-butylation affording a cleaner reaction,
easier isolation and higher yield of final products. This observation
was also evident in a different reaction of 2-aminopyridine with
4-bromobenzaldehyde and tert-butyl isocyanide (Entries 8–10,
Table 1). In conventional heating, the MCR proceeded well, but
the de-tert-butylation suffered from very slow and incomplete
reaction. In contrast, the microwave irradiation promoted the
de-tert-butylation with much enhanced reaction rate and higher
yield of product. The variation in equivalence of HBF4 revealed
that one equivalent was optimal for its best dealkylation activity.
The MCR–de-tert-butylation performed in a domino10 fashion
resulted in decreased activities of both ZrCl4 and HBF4. The
mutually exchanged use of ZrCl4 and HBF4 in this tandem
protocol caused little progress of the multicomponent reaction
and the de-tert-butylation. This implies that ZrCl4 and HBF4 are
efficient catalyst and promoter for their respective use. The de-
tert-butylation was also found to undergo non-significantly, while
catalyzed by Lewis acids (20 mol%) such as BF3·OEt2, Sc(OTf)3
and CeCl3·7H2O. The effectiveness of the HBF4-promoted de-
tert-butylation procedure was also tested in a single step. N-
tert-Butyl-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-amine, pre-
pared by our earlier developed procedure,5e in these de-alkylation
reaction conditions provided the product in 88% yield, which
reflected an almost identical result to Table 1, entry 3. The
actual reason for HBF4 in optimized conditions being the most
efficient de-tert-butylating protocol is not clear at the present
stage. However, the overall results of screening (Table 1) indicate
that plausible favorable factors are the enhanced acidity and
5
6
7
80
88
95
8
9
70
82
a Reactants and reagents: azine (1 mmol), aldehyde (1 mmol), tert-BuNC
(1 mmol), ZrCl4 (10 mol%), n-BuOH (1 mL) and 40% aqueous HBF4
(1 mmol). b Isolated yields.
reactivity in microwave irradiation, and the increased transition
state-stabilization of the ion pair (tBu+X-) by like-size of counter
anion and by solvation with n-BuOH via hydrogen bond and
electrostatic interaction.
With the optimized tandem MCR–de-tert-butylation method
in hand, we next set out to explore its scope. To our delight, var-
ious heterocyclic-2-amidines and aldehydes in this methodology
produced diverse N-fused imidazole–primary amines in good to
high yields (Table 2). The experimental procedure is simple and
straightforward.11 The sensitive functionalities such as halogens
(Cl, Br), methoxy and cyano remained tolerated.
We were then interested in in situ cyclization of primary amine
functionality generated by de-tert-butylation in MCR products
with tethered internal functional group. For this, we chose
3632 | Org. Biomol. Chem., 2010, 8, 3631–3634
This journal is
The Royal Society of Chemistry 2010
©

View Online
Table 3 One-pot MCR–de-tert-butylation–cyclization: synthesis of N-
preparation of isoquinolinone-imidazole-heterocycles. This novel
protocol has led to the establishment of tert-butyl isocyanide
as a useful convertible isonitrile. It is remarkable that among
commercially available isonitriles tert-butyl isocyanide is econom-
ical, according to the Sigma-Aldrich price. Thus, the method is
amenable for bulk-scale and solid phase syntheses towards the easy
generation of scaffold- and substitution/functionality-diversities.
fused isoquinolinone-imidazole-heterocyclesa
Entry Amidine
1
Aldehyde
Product
Yield b(%)
85
Conclusion
In conclusion, we have developed a novel microwave-assisted
tandem protocol of de-tert-butylation of derived tert-butyl amine
in an Ugi-type MCR product, which has afforded to the successful
implementation of tert-butyl isocyanide as a useful convertible
isonitrile. The method provides access to a diverse array of
medicinally-relevant N-fused heterocycles. This new finding can
be extended to many multicomponent reactions using tert-butyl
isocyanide as a convertible isonitrile for generating molecular
diversity, which is under our current investigation.
2
3
4
5
72
89
87
80
Acknowledgements
We gratefully acknowledge financial support from DST, New
Delhi for this investigation.
Notes and references
1 (a) J. Zhu and H. Bienayme´, ed., Multicomponent Reactions, Wiley-
VCH, Weinheim, 2005; (b) A. Do¨mling, Chem. Rev., 2006, 106, 17–89.
2 (a) T. A. Keating and R. W. Armstrong, J. Am. Chem. Soc., 1995, 117,
7842–7843; (b) T. A. Keating and R. W. Armstrong, J. Am. Chem.
Soc., 1996, 118, 2574–2583; (c) M. C. Pirrung and S. Ghorai, J. Am.
Chem. Soc., 2006, 128, 11772–11773; (d) C. B. Gilley and Y. Kobayashi,
J. Org. Chem., 2008, 73, 4198–4204; (e) C. B. Gilley, M. J. Buller and
Y. Kobayashi, Org. Lett., 2007, 9, 3631–3634; (f) A. L. Kennedy, A. M.
Fryer and J. A. Josey, Org. Lett., 2002, 4, 1167–1170; (g) C. Hulme,
S. Chappeta and J. Dietrich, Tetrahedron Lett., 2009, 50, 4054–4057;
(h) M. Nikulnikov, S. Tsirulnikov, V. Kysil, A. Ivachtchenko and M.
Krasavin, Synlett, 2009, 260–262.
3 (a) UDC strategy was indroduced by Hulme et al.: C. Hulme, M. M.
Morrissette, F. A. Volz and C. J. Burns, Tetrahedron Lett., 1998, 39,
1113–1116; (b) C. Hulme, J. Peng, S.-Y. Tang, C. J. Burns, I. Morize
and R. Labaudiniere, J. Org. Chem., 1998, 63, 8021–8023; (c) C. Hulme
and V. Gore, Curr. Med. Chem., 2003, 10, 51–80; (d) T. A. Keating and
R. W. Armstrong, J. Org. Chem., 1996, 61, 8935–8939.
4 (a) H. Habashita, M. Kokubo, S. Hamano, N. Hamanaka, M. Tada,
S. Shibayama, H. Tada, K. Sagawa, D. Fukushima, K. Maeda and
H. Mitsuya, J. Med. Chem., 2006, 49, 4140–4152; (b) K. Maeda, H.
Nakata, Y. Koh, T. Miyakawa, H. Ogata, Y. Takaoka, S. Shibayama,
K. Sagawa, D. Fukushima, J. Moravek, Y. Koyanagi and H. Mitsuya,
J. Virol., 2004, 78, 8654–8662; (c) S. R. Pulley, Chemikine Bilo., 2007, 2,
145–163; (d) A. D. Borthwick, D. E. Davies, A. M. Exall, R. J. D. Hatley,
J. A. Hughes, W. R. Irving, D. G. Livermore, S. L. Sollis, F. Nerozzi,
K. L. Valko, M. J. Allen, M. Perren, S. S. Shabbir, P. M. Woollard and
M. A. Price, J. Med. Chem., 2006, 49, 4159–4170.
5 Ugi-type MCRs were first reported in 1998 by three independent
research groups Groebke, Blackburn and Bienayme: (a) K. Groebke,
L. Weber and F. Mehlin, Synlett, 1998, 661–663; (b) C. Blackburn, B.
Guan, P. Fleming, K. Shiosaki and S. Tsai, Tetrahedron Lett., 1998, 39,
3635–3638; (c) H. Bienayme and K. Bouzid, Angew. Chem., Int. Ed.,
1998, 37, 2234–2237; (d) S. K. Guchhait and C. Madaan, Synlett, 2009,
628–632and references cited therein; (e) S. K. Guchhait, C. Madaan and
B. S. Thakkar, Synthesis, 2009, 3293–3300; (f) T. Kercher, C. Rao, J. R.
Bencsik and J. A. Josey, J. Comb. Chem., 2007, 9, 1177–1187; (g) E. F.
DiMauro and J. M. Kennedy, J. Org. Chem., 2007, 72, 1013–1016.
6 For a few selected patents related to this Ugi-type reaction, see:
(a) M. Klein, R. Gericke, N. Beier, B. Cezanne, C. Tsaklakidis and
W. Mederski, DE Pat., 102006048728, 2008; (b) M. Thormann, DE
a Reactants and reagents: azine (1 mmol), aldehyde (1 mmol), tert-BuNC
(1 mmol), ZrCl4 (10 mol%), n-BuOH (1 mL) and 40% aqueous HBF4
(1 mmol). b Isolated yields.
phthalaldehydic esters as the aldehyde component. Their Ugi-type
multicomponent reaction with heterocyclic-2-amidines and tert-
butyl isocyanide and the tandem dealkylation by the developed
protocol formed the in situ cyclized products isoquinolinone-
imidazole-heterocycles in good to high yields (Table 3). This
novel one-pot process of MCR-tandem dealkylation-in situ cy-
clization, which involves six-centered-three component reactions,
is much amenable for rapid and economical preparation of large
arrays of isoquinolinono-tetracycles in parallel format. The post-
modification of Ugi-type MCR products at their secondary amino
group (NH-tert-butyl or NH-isooctyl) without dealkylation was
found difficult,7 as revealed also in our attempted investigations.
The present protocol of one-pot MCR-de-tert-butylation is useful
in generation of further molecular diversity via various post-
modifications at primary amino group of products (Table 2).
For example, the derivatives that we have prepared using normal
procedures are acylamide (Ugi reaction), urea (carbamoylation),
N-arylalkyl (nucleophilic substitution), imine, and N-aryl (Pd-
catalysed N-arylation). In reported studies of developing a
convertible isocyanide in the Groebke–Blackburn MCR, the
dealkylation was either complicated or specific. Whereas, our
developed protocol of dealkylation of tert-butyl amine uses only
one equiv. HBF4 (which is less corrosive) and n-butanol as solvent
(which is greener), and is a one-step reaction, compatible with
MCR conditions in tandem-mode and well matched to one-pot
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 3631–3634 | 3633
©

View Online
Pat., 102005019181, 2006; (c) W. Mederski, N. Beier, B. Cezanne, R.
Gericke, M. Klein and C. Tsaklakidis, WO PCT Int. Appl., 2007147478
A1, 2007.
7 (a) C. Blackburn and B. Guan, Tetrahedron Lett., 2000, 41, 1495–
1500; (b) Y. Sandulenko, A. Komarov, K. Rufanov and M. Krasavin,
Tetrahedron Lett., 2008, 49, 5990–5993.
8 M. Krasavin, S. Tsirulnikov, M. Nikulnikov, Y. Sandulenko and K.
Bukhryakov, Tetrahedron Lett., 2008, 49, 7318–7321.
9 C. Che, J. Xiang, G.-X. Wang, R. Fathi, J.-M. Quan and Z. Yang,
J. Comb. Chem., 2007, 9, 982–989.
mixture was then extracted with EtOAc (60 mL) and the solution
was washed with H2O (3 ¥ 10 mL). The organic layer was dried
(anhy. Na2SO4), filtered, and concentrated under reduced pressure.
The column chromatographic purification of the crude product over
silica gel (mesh size: 60–120) with EtOAc–hexane as eluent afforded
2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-amine in 90% yield as yel-
low solid; mp = 146–148 ◦C; IR (KBr) nmax = 3310, 2932, 1646, 1492,
1270, 1091, 767 cm-1; 1H NMR (400 MHz, DMSO-d6): 5.22 (br s,
NH2), 6.85 (t, J = 6.7 Hz, 1H), 7.08 (dd, J = 7.2, 8.3 Hz, 1H), 7.41
(d, J = 9.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz,
2H), 8.25 (d, J = 6.9 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
111.5, 116.9, 122.9, 123.0, 126.6, 127.2, 128.1 (2CH), 128.7 (2CH),
130.7, 134.3, 139.3; MS (APCI) m/z: 244 (MH+). Anal. found: C, 63.8;
H, 4.05; N, 17.4. Calcd. for C13H10ClN3: C, 64.1; H, 4.1; N, 17.2%.
This experimental procedure was followed for all compounds (Table 2).
General procedure for synthesis of compounds (Table 3): The resultant
mixture obtained after reaction following the above procedure was
made basic (pH = 8) with addition of aqueous ammonia solution
(10%). The precipitated solids were then filtered and washed with water
and EtOAc. The pure products were obtained by crystallization from
EtOH–EtOAc. The structures of the products were identified by 1H and
13C NMR, mass and IR spectroscopies, and confirmed by elemental
analysis or HRMS. The compounds, which were reported in literature,
showed identical spectroscopic data.
10 (a) L. F. Tietze, G. Brasche and K. M. Gerickle, ed, Domino Reactions
in Organic Synthesis, Wiley-VCH, Weinheim, 2006; (b) L. F. Tietze,
Chem. Rev., 1996, 96, 115–136.
11 Representative experimental procedure (Table 2, entry 1): To a mixture of
2-aminopyridine (0.09 g, 1 mmol) and 4-chlorobenzaldehyde (0.14 g,
1 mmol) in n-BuOH (1 mL) taken in a microwave vial were added
tert-butyl isocyanide (0.08 g, 0.11 mL, 1 mmol) and ZrCl4 (0.023 g,
10 mol%). The vessel was sealed with a cap and the mixture was then
irradiated in a monomode microwave synthesizer (Biotage InitiatorTM
EXP) at 140 ◦C for 7 min. After cooling to r.t. in the microwave
cavity, the vial cap was removed and to the reaction mixture was
added 40% aqueous HBF4 (0.2 mL, 1 mmol). The vial was resealed
and then irradiated at 160 ◦C for 20 min. To the resultant mixture
was added aqueous ammonia solution (10%) to basify (pH = 8). The
3634 | Org. Biomol. Chem., 2010, 8, 3631–3634
This journal is
The Royal Society of Chemistry 2010
©