Application of a sequential multicomponent assembly process/Huisgen cycloaddition strategy to the preparation of libraries of 1,2,3-triazole-fused 1,4-benzodiazepines

Article abstract of DOI:10.1021/co2002087

A strategy featuring a multicomponent assembly process followed by an intramolecular azide-alkyne dipolar (Huisgen) cycloaddition was implemented for the facile synthesis of three different 1,2,3-triazolo-1,4-benzodiazepine scaffolds. A diverse library of

Full text of DOI:10.1021/co2002087

Research Article
pubs.acs.org/acscombsci
Application of a Sequential Multicomponent Assembly Process/
Huisgen Cycloaddition Strategy to the Preparation of Libraries of
1,2,3-Triazole-Fused 1,4-Benzodiazepines
James R. Donald, Rebekah R. Wood, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The Texas Institute for Drug and Diagnostic Development, The University of Texas,
Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: A strategy featuring a multicomponent assem-
bly process followed by an intramolecular azide−alkyne
dipolar (Huisgen) cycloaddition was implemented for the
facile synthesis of three different 1,2,3-triazolo-1,4-benzodiaz-
epine scaffolds. A diverse library of 170 compounds derived
from these scaffolds was then created through N-functionaliza-
tions, palladium-catalyzed cross-coupling reactions, and several
applications of α-aminonitrile chemistry.
KEYWORDS: triazole, dipolar cycloaddition, azide−alkyne, benzodiazepine, multicomponent reaction, α-aminonitrile,
diversity oriented synthesis
he identification of biologically active small molecules
through high-throughput screening (HTS) is a common
T
strategy in campaigns to discover both novel drug leads and
molecular probes that may be used to study aberrant biological
pathways leading to disease.1 Because of their high hit rates in
HTS and “drug-like” pharmacological profiles, derivatives of
privileged structures are uniquely well-suited as molecular
scaffolds in drug discovery.2 Straightforward variation of the
substituents on privileged scaffolds often leads to potent and
selective binders for multiple biological targets from a single
library.
More than 20 years ago, Evans identified the benzodiazepine
ring system as the archetypal privileged structure, thereby
introducing the term into medicinal chemistry.3,4 Compounds
derived from the 1,4-benzodiazepine ring system bind to a
multitude of targets, including G protein-coupled receptors
(GPCRs), ligand-gated ion channels, and enzymes.2a The
propensity of compounds derived from the benzodiazepine
nucleus to bind to GPCRs has been suggested to arise from
the ability of the scaffold to act as a structural mimic of peptide
β-turns5 and α-helices.6 Such secondary structural elements
orient substituents in a manner that enhances protein binding.
Indeed, virtually all GPCR-binding ligands adopt α-, β- or γ-
turns.7 It is therefore unsurprising that the 1,4-benzodiazepine
substructure is a common structural subunit in numerous
pharmaceutical agents, biological probes, and bioactive natural
products, such as diazepam (1),8 devazepide (2),9 and
anthramycin (3),10 respectively (Figure 1).
Figure 1. Derivatives of the 1,4-benzodiazepine ring system.
A key consideration inherent in designing and preparing
novel compound libraries for HTS is the efficient synthesis of
core scaffolds that bear functionality to enable facile
diversification. In this context, we have recently developed a
Mannich-type multicomponent assembly process (MCAP) to
construct aryl aminomethyl adducts that are suitably function-
alized for use in subsequent cyclizations to afford a variety of
nitrogen-containing heterocyclic structures.11 This sequential
MCAP/cyclization strategy has been successfully utilized to
rapidly access natural products11,12,13 and unnatural hetero-
a
cyclic frameworks.13,14 We also applied this approach to the
Received: December 15, 2011
Revised: January 19, 2012
Published: January 24, 2012
© 2012 American Chemical Society
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Research Article
syntheses of diverse, medicinally relevant scaffolds based upon the
Scheme 3. Cross-Coupling Reactions with Scaffold 7
1,2,3-triazolo-1,4-benzodiazepine core 6 (Scheme 1),15,16 2-aryl
Scheme 1. Synthesis of Scaffolds 6 and 7
a
Scheme 2. Nitrogen Functionalization of Scaffolds 6 and 7
Scheme 4. Two-Dimensional Library Derived from Scaffold
a
7
a
Reaction conditions: (a) 20, Et3N, CH2Cl2; (b) 21, Et3N, CH2Cl2;
(c) 22, CH2Cl2; (d) 23, CH2Cl2; (e) 24, Et3N, CH2Cl2; (f) 25,
NaB(OAc)3H, AcOH, DCE; (g) 26{1−5}, Pd(OAc)2 (5 mol%),
(
)-BINAP (7.5 mol %), NaOt-Bu, toluene, 80 °C; (h) 26{6},
Pd2(dba)3 (4 mol %), dppp (8 mol%), NaOt-Bu, toluene, 70 °C.
a
Reaction conditions: (a) 20, Et3N, CH2Cl2; (b) 21, Et3N, CH2Cl2;
piperidines,15,17 tetrahydroisoquinolines,15,18 as well as isoindoli-
nones, norbenzomorphans, benzazocines, and benzoxacines.15,19
We now report the application of this general approach for
diversity oriented synthesis (DOS) to the preparation of libraries
of 1,2,3-triazolo-1,4-benzodiazepines, a subclass of the benzodiaz-
epine privileged structure whose biological properties have not
been widely explored.20
As described previously, the parent 1,2,3-triazolo-1,4-benzodiaz-
epine 6 and brominated analog 7 were readily prepared on
multigram scale by a reductive amination and azide−alkyne dipolar
(Huisgen) cycloaddition sequence (Scheme 1).15 This approach
afforded scaffolds 6 and 7 in high purity after recrystallization and
represents a considerably more expedient access to compound 6
than previously reported.21
(c) 22, CH2Cl2; (d) 23{3}, CH2Cl2; (e) 25, RCHO, NaB(OAc)3H,
AcOH, DCE; (f) 26{1}, Pd(OAc)2 (5 mol%), ( )-BINAP (7.5 mol%),
NaOt-Bu, toluene, 80 °C.
The two heterocycles 6 and 7 were then subjected to various
tactics for N-functionalization to diversify the scaffolds into
libraries of amides 8 and 9, sulfonamides 10 and 11, ureas 12 and
13, thioureas 14 and 15, carbamate 16, and amine derivatives
17−19 (Scheme 2, Figure 2, Table 1). Reagents were typically
used in excess to mitigate for variations in the purity of reagents,
which were used without purification, and reaction efficiency.
Functionalizing agents were selected to contain a mixture of
aliphatic and aromatic groups. Different aliphatic substituents
were chosen to vary the nonpolar surface area, whereas aromatic
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Scheme 5. Synthesis of Nitrile-Substituted Scaffold 44
Figure 2. Nitrogen-functionalizing agents used to derivatize scaffolds 6 and 7.
groups were varied by selecting substituents that would modulate
the electrostatic properties of the aromatic ring. In this manner,
it would be possible to acquire preliminary structure activity
relationship (SAR) data from a small set of compounds.
N-Arylation procedures to access chemset 19 were explored for the
formation of p-toluidine derivative 19{2}. We discovered that
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Table 1. Nitrogen Functionalization of Scaffolds 6 and 7
entry
scaffold
functionalizing agent
product
yield (%)
entry
scaffold
functionalizing agent
product
yield (%)
1
6
6
6
6
6
6
6
6
6
6
6
7
7
6
6
6
6
6
6
6
6
6
6
7
7
7
6
6
6
6
6
6
6
6
6
7
20{1}
20{2}
20{3}
20{4}
20{5}
20{6}
20{7}
20{8}
20{9}
20{10}
20{11}
20{9}
20{12}
21{1}
21{2}
21{3}
21{4}
21{5}
21{6}
21{7}
21{8}
21{9}
21{10}
21{1}
21{4}
21{6}
22{1}
22{2}
22{3}
22{4}
22{5}
22{6}
22{7}
22{8}
22{9}
22{2}
8{1}
95
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
7
7
6
6
6
6
6
6
6
7
7
7
6
6
6
6
6
6
6
6
6
6
6
6
6
6
7
7
7
6
6
6
6
6
6
22{3}
22{4}
23{1}
23{2}
23{3}
23{4}
23{5}
23{6}
23{7}
23{1}
23{3}
23{7}
24{1}
24{2}
24{3}
25{1}
25{2}
25{3}
25{4}
25{5}
25{6}
25{7}
25{8}
25{9}
25{10}
25{11}
25{5}
25{12}
25{13}
26{1}
26{2}
26{3}
26{4}
26{5}
26{6}
13{3}
13{4}
14{1}
14{2}
14{3}
14{4}
14{5}
14{6}
14{7}
15{1}
15{3}
15{7}
16{1}
16{2}
16{3}
17{1}
17{2}
17{3}
17{4}
17{5}
17{6}
17{7}
17{8}
17{9}
55
2
8{2}
96
quant.
99
3
8{3}
quant.
93
4
8{4}
98
5
8{5}
98
98
6
8{6}
96
83
7
8{7}
98
94
8
8{8}
98
95
9
8{9}
98
90
a,b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
8{10}
8{11}
9{9}
82
95
90
67
97
64
91
98
98
89
94
88
81
84
85
53
55
99
79
96
99
99
86
91
79
83
quant.
88
9{12}
10{1}
10{2}
10{3}
10{4}
10{5}
10{6}
10{7}
10{8}
10{9}
10{10}
11{1}
11{4}
11{6}
12{1}
12{2}
12{3}
12{4}
12{5}
12{6}
12{7}
12{8}
12{9}
13{2}
77
98
71
quant.
98
83
quant.
82
65
60
96
17{10}
17{11}
18{5}
18{12}
18{13}
19{1}
19{2}
19{3}
19{4}
19{5}
19{6}
96
56
98
55
70
96
83
73
48
0
c
quant.
quant.
58
c
85
Table 1. continued
a
b
c
An additional 3.0 equiv of Et3N were employed. Isolated as the free-base. No AcOH added.
Figure 4. Nitrogen-functionalizing agents used in the two-dimensional
library derived from scaffold 7.
conditions reported by Buchwald utilizing Pd(OAc)2, ( )-BINAP,
and NaOt-Bu were superior to alternative protocols in which
Pd2(dba)3 was employed as the Pd source.22 Use of this method
Figure 3. Cross-coupling partners employed with scaffold 7.
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allowed the introduction of aryl halides onto the parent scaffold
(19{1} and 19{3}) without the intervention of observable side
reactions involving secondary cross-couplings. The 2-amino
pyridine derivative 19{6} was also prepared using a procedure
described by Buchwald, but a catalyst loading of 4 mol % Pd2dba3
was necessary for complete conversion.23
The aryl bromide functionality present within scaffold 7 was
exploited as a handle for diversification through several
palladium-catalyzed cross-couplings (Scheme 3, Figure 3,
Table 2). To avoid homocoupling of 7 during Buchwald−
Table 3. Two-Dimensional Library Derived from Scaffold 7
entry
amine input
functionalizing agent
product
yield (%)
1
27{1}
27{1}
27{1}
27{1}
27{1}
27{1}
27{1}
27{1}
27{1}
27{1}
27{2}
27{2}
27{2}
27{2}
27{2}
27{2}
27{2}
27{2}
27{2}
27{2}
28{1}
28{1}
28{1}
28{1}
28{1}
28{1}
28{1}
28{1}
28{1}
28{1}
28{2}
28{2}
28{2}
28{2}
28{2}
28{2}
28{2}
28{2}
28{2}
28{2}
28{5}
28{5}
28{5}
28{5}
28{5}
28{5}
28{5}
28{5}
28{5}
28{5}
20{4}
20{13}
21{5}
21{11}
22{2}
22{3}
23{3}
25{2}
25{14}
26{1}
20{4}
20{13}
21{5}
21{11}
22{2}
22{3}
23{3}
25{2}
25{14}
26{1}
20{4}
20{13}
21{5}
21{11}
22{2}
22{3}
23{3}
25{2}
25{14}
26{1}
20{4}
20{13}
21{5}
21{11}
22{2}
22{3}
23{3}
25{2}
25{14}
26{1}
20{4}
20{13}
21{5}
21{11}
22{2}
22{3}
23{3}
25{2}
25{14}
26{1}
31{1,4}
31{1,13}
33{1,5}
33{1,11}
35{1,2}
35{1,3}
37{1,3}
39{1,2}
39{1,14}
41{1,1}
31{2,4}
31{2,13}
33{2,5}
33{2,11}
35{2,2}
35{2,3}
37{2,3}
39{2,2}
39{2,14}
41{2,1}
32{1,4}
32{1,13}
34{1,5}
34{1,11}
36{1,2}
36{1,3}
38{1,3}
40{1,2}
40{1,14}
42{1,1}
32{2,4}
32{2,13}
34{2,5}
34{2,11}
36{2,2}
36{2,3}
38{2,3}
40{2,2}
40{2,14}
42{2,1}
32{5,4}
32{5,13}
34{5,5}
34{5,11}
36{5,2}
36{5,3}
38{5,3}
40{5,2}
40{5,14}
42{5,1}
quant.
86
2
3
86
4
87
5
92
6
7
7
91
8
78
9
88
Table 2. Cross-Coupling Reactions with Scaffold 7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
83
94
entry
coupling partner
product
yield (%)
73
1
2
3
4
5
6
7
8
9
29{1}
29{2}
30{1}
30{2}
30{3}
30{4}
30{5}
30{6}
30{7}
27{1}
27{2}
28{1}
28{2}
28{3}
28{4}
28{5}
28{6}
28{7}
75
69
84
73
74
78
78
76
92
87
88
76
90
94
88
79
90
quant.
88
Hartwig aminations, it was necessary to employ a 10-fold excess
of amines 29 to afford the aniline derivatives 27 (Figure 3).22
Suzuki cross-couplings of 7 with boronic acids 30 afforded
biaryl products 28 bearing substituents having a broad range of
electronic properties. The use of heteroaromatic boronic acid
derivatives is exemplified by the synthesis of 28{7}.
Five cross-coupled products (27{1−2}, 28{1−2}, and
28{5}) were subjected to ten independent N-functionalizations
to afford a “two-dimensionally” functionalized collection of 50
compounds (chemsets 31−42) in generally high yields
(Scheme 4, Figure 4, and Table 3).
91
quant.
86
97
98
85
39
94
quant.
73
quant.
quant.
90
Because compounds bearing the α-aminonitrile functionality
are synthetically versatile intermediates, we envisioned that a
scaffold containing this subunit might facilitate diversification
through a number of strategies.24 The Strecker MCAP
employing benzaldehyde 4 and propargylamine furnished the
α-aminonitrile 43 in 78% yield (Scheme 5). Upon mild heating,
43 underwent facile Huisgen cycloaddition to deliver the cyano-
substituted scaffold 44 in 88% yield. It was necessary to perform
this reaction under dilute conditions and at a temperature not
exceeding 60 °C to avoid elimination of HCN from the product 44.
Interestingly, when 43 wasN-acylated, the intermediate amide
underwent facile cycloaddition at ambient temperature to yield the
amide derivative of the scaffold 45{1}. This observation led to the
development of a convenient, 4-component process to afford 45{1}
directly from benzaldehyde 4 in 49% yield (Scheme 5). This
MCAP approach is an expedient method to access amide
derivatives of 44. However, N-functionalization of this scaffold is
a better strategy for the library synthesis outlined in Scheme 6,
because this approach allows the use of a number of parallel
diversification reactions to give products that may be easily purified.
N-Acylations and N-sulfonylations of scaffold 44 to produce
chemsets 45 and 46 were conducted using pyridine as the
base; when triethylamine was employed, elimination of HCN
was a significant side-reaction (Scheme 6, Figure 5, Table 4).
Reductive amination of 44, which was achieved under the
same conditions as those described for the preparation of 17
and 18 (Scheme 2), generally proceeded in good yields.
However, the reaction of 44 with the electron poor aldehyde
quant.
quant.
94
35
96
quant.
85
97
quant.
94
98
99
94
40
99
25{5} required the presence of trifluoroacetic acid and
additional quantities of NaBH(OAc)3 to consume the starting
material 44 (Table 4, entry 19).
The acidic nature of the proton α to the cyano group in
amide derivatives 45 was exploited to facilitate further
elaboration of the scaffold (Scheme 7, Figure 6, Table 5). In the
event, deprotonation of 45 with NaH, followed by trapping the
intermediate carbanion with alkylating agents 50 delivered a
small library of compounds bearing fully substituted carbon
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Table 4. Nitrogen Functionalization of Scaffold 44
Scheme 7. Anion Derived Diversification of Amides 45
entry
functionalizing agent
product
yield (%)
1
20{1}
20{4}
20{7}
20{10}
20{12}
20{13}
20{14}
20{15}
20{16}
20{17}
21{1}
21{3}
21{5}
21{6}
21{7}
21{9}
21{11}
25{1}
25{5}
25{12}
25{14}
45{1}
92
92
93
2
45{4}
3
45{7}
a
4
45{10}
45{12}
45{13}
45{14}
45{15}
45{16}
45{17}
46{1}
92
b
5
49
6
95
98
7
c
8
66
9
quant.
quant.
97
10
11
12
13
14
15
16
17
18
19
20
21
22
46{3}
91
46{5}
86
46{6}
90
Scheme 8. Diversification of Aminonitriles 47 using the
Bruylants Reaction
46{7}
91
46{9}
85
46{11}
47{1}
80
63
d
47{5}
41
47{12}
47{14}
47{15}
84
74
87
25{15}
a
b
Isolated as the free-base. Yield after recrystallization from toluene
c
(following chromatography). Yield after the product was washed with
hexanes (3 × 5 mL) following chromatography. The addition of TFA
d
(1.0 equiv) and extra NaBH(OAc)3 (4.0 equiv) was required to fully
consume 44.
Scheme 6. Nitrogen Functionalization of Scaffold 44
Table 5. Libraries Derived from Amides 45
entry
amide
electrophile
product
yield (%)
1
45{1}
50{1}
50{2}
50{1}
50{2}
51
48{1,1}
48{1,2}
48{15,1}
48{15,2}
49{1}
80
86
80
76
72
66
2
45{1}
3
45{15}
45{15}
45{1}
4
5
6
45{13}
45{4}
51
49{13}
49{4}
a
7
51
trace
8
45{15}
45{16}
45{7}
51
49{15}
49{16}
49{7}
95
85
44
91
0
9
51
10
11
12
51
45{10}
45{17}
51
49{10}
49{17}
51
a
Trace formation of the pyrrole product 49{4} was observed in the 1H
NMR spectrum of the crude reaction mixture.
Table 6. Amines Derived from the Bruylants Reaction
entry
aminonitrile
organo-zinc precursor
product
yield (%)
centers (chemset 48). Following literature precedent, vinyl-
triphenylphosphonium bromide (Schweizer’s reagent) (51) was
utilized as an electrophile to prepare a novel collection of pyrrole-
fused structures (chemset 49) through an addition/intramolecular
Wittig reaction/elimination sequence.25 Notably, the Wittig reaction
and aromatization steps were complete within 90 min at
ambient temperature. With the sole exception of the pivalamide
45{4}, N-alkyl substituted amides were good substrates for this
sequence of reactions. Aryl-substituted amides such as 45{15},
1
2
3
4
5
6
7
8
9
47{1}
54{1}
54{2}
54{1}
54{2}
54{1}
54{2}
55
52{1,1}
52{1,2}
52{12,1}
52{12,2}
52{14,1}
52{14,2}
53{1}
73
86
75
73
80
81
74
77
75
47{1}
47{12}
47{12}
47{14}
47{14}
47{1}
47{12}
47{14}
55
53{12}
55
53{14}
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Figure 5. Nitrogen functionalizing agents used with scaffold 44.
Figure 6. Electrophiles employed to trap anions derived from amides
45.
Figure 7. Precursors to organo-zinc reagents used in the Bruylants
reaction.
45{16}, and 45{7} also participated in this transformation, as
did the nicotinamide 45{10}, which represents the first example
of the use of a heteroaryl-substituted amide in this reaction. On
the other hand, treating the anion of 5-nitro-furanyl amide
45{17} with the vinyl phosphonium salt 51 formed a complex
mixture of products; no pyrrole was observed. It should be
noted that the bromo-substituted benzaldehyde 5 might be
used as a starting material to prepare the corresponding bromo
derivatives of 44, 45, 48, and 49. These compounds could then
be further derivatized by palladium-catalyzed cross-coupling
reactions to introduce aryl and amine substituents onto the
benzodiazepine rings of 44, 45, 48, and 49.
We were also interested in exploiting the Bruylants reaction
to generate substituted benzylamine derivatives 52 by
displacing cyanide ion from α-aminonitriles 47 with organo-
metallic reagents (Scheme 8, Figure 7, Table 6).26 After
conducting a brief series of exploratory studies, we discovered
that transmetalation of Grignard reagents to their correspond-
ing organo-zinc species was necessary to avoid competitive
deprotonation of the acidic proton α to the cyano group.27
Displacement of cyanide ion under ‘Reformatsky-type’ con-
ditions with the enolate of ethyl acetate afforded chemset 53;
these compounds bear an ethyl ester group that might serve as
a further point of diversification.28
In summary, a diverse collection of 170 1,2,3-triazolo-1,
4-benzodiazepines was prepared. A sequential MCAP/Huisgen
cycloaddition strategy was instrumental for the rapid
construction of the parent scaffolds. N-Functionalization and
cross-coupling reactions were then applied to these scaffolds to
enable the rapid production of derivatives through a com-
binatorial style approach, whereas exploitation of α-aminonitrile
chemistry facilitated the introduction of significant structural
diversity via a DOS approach. A complete Lipinski analysis of a
representative selection of 80 compounds containing at least
two examples of each structural subtype and having a maximal
diversity of substituents was performed, and no compound was
found that violated the Lipinski rule of five.29 Hence, the library
members have physiochemical properties that are likely to be
associated with good solubility, membrane permeability, and
bioavailability. All compounds have been submitted to the
National Institutes of Health (NIH) Molecular Libraries Small
Molecule Repository (MLSMR) and are being distributed to
the Molecular Libraries Probe Production Centers Network
(MLPCN) for HTS in a wide range of biological assays. Selected
compounds have also been sent to the National Institute of
Mental Health, Psychoactive Drug Screening Program (NIMH
PDSP). The further development and application of our
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Research Article
cholecystokinin antagonist. Proc. Natl. Acad Sci. U.S.A. 1986, 83,
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anthramycin. J. Am. Chem. Soc. 1965, 87, 5793−5795.
(11) For the first exampleof this process, see: Martin, S. F.; Benage,
B.; Geraci, L. S.; Hunter, J. E.; Mortimore, M. Unified strategy for
synthesis of indole and 2-oxindole alkaloids. J. Am. Chem. Soc. 1991,
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(12) Cheng, B.; Sunderhaus, J. D.; Martin, S. F. Concise total
synthesis of pseudotabersonine via double ring-closing metathesis
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(13) (a) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F.
Applications of multicomponent reactions for the synthesis of diverse
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sequential MCAP/cyclization strategy to the synthesis of
medicinally relevant small molecules is ongoing and will be
reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, full characterization data for representa-
tive compounds, LCMS data for representative compounds, and
tabulated Lipinski’s rule parameters for representative compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sfmartin@mail.utexas.edu.
■
Notes
The authors declare no competing financial interest.
(14) For a review of relatedstrategies, see: Sunderhaus, J. D.; Martin,
S. F. Applications of multicomponent reactions to the synthesis of
diverse heterocyclic scaffolds. Chem.−Eur. J. 2009, 15, 1300−1308.
(15) Donald, J. R.; Martin, S. F. Synthesis and diversification of 1,2,3-
triazole-fused 1,4-benzodiazepine scaffolds. Org. Lett. 2011, 13, 852−
855.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM 86192) and
the Robert A. Welch Foundation (F-0652) for their generous
support of this work.
(16) Donald, J. R.; Granger, B. A.; Hardy, S.; Sahn, J. J.; Martin, S. F.
Applications of multicomponent assembly processes to the facile
syntheses of diversely functionalized nitrogen heterocycles. Heterocycles
2012, DOI: 10.3987/COM-11-S(P)92.
(17) Hardy, S.; Martin, S. F. Multicomponent assembly and
diversification of novel heterocyclic scaffolds derived from
2-arylpiperidines. Org. Lett. 2011, 13, 3102−3105.
(18) Granger, B. A.; Kaneda, K.; Martin, S. F. Multicomponent
assembly strategies for the synthesis of diverse tetrahydroisoquinoline
scaffolds. Org. Lett. 2011, 13, 4542−4545.
(19) (a) Sahn, J. J.; Su, J. Y.; Martin, S. F. Facile and unified approach
to skeletally diverse, privileged scaffolds. Org. Lett. 2011, 13, 2590−
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conformationally-constrained benzoxazocines and benzazocines via
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(20) For reports of the biological activity of 1,2,3-triazole fused
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Barili, P. L. 1,2,3-Triazolo[1,5-a][1,4]- and 1,2,3-triazolo[1,5-a]-
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