Concise one-pot preparation of unique bis-pyrrolidinone tetrazoles

Article abstract of DOI:10.1021/co200209a

A one-pot, two-step synthesis of bis-pyrrolidinone tetrazoles has been established via the Ugi-Azide reaction using methyl levulinate, primary amines, isocyanides and azidotrimethylsilane with subsequent acid treatment to catalyze the lactam formation. The efficiency of the protocol was established followed by a successful transition to library production in four 24-well plates.

Full text of DOI:10.1021/co200209a

Letter
pubs.acs.org/acscombsci
Concise One-Pot Preparation of Unique Bis-Pyrrolidinone Tetrazoles
Steven Gunawan,† Joachim Petit,‡ and Christopher Hulme*,†
†BIO5 Oro Valley, The University of Arizona, 1580 East Hanley Boulevard, Oro Valley, Arizona 85737, United States
‡CADD Laboratory, TGen, 445 North Fifth Street, Suite 600, Phoenix, Arizona 85004, United States
S
* Supporting Information
ABSTRACT: A one-pot, two-step synthesis of bis-pyrrolidinone tetrazoles has
been established via the Ugi−Azide reaction using methyl levulinate, primary
amines, isocyanides and azidotrimethylsilane with subsequent acid treatment to
catalyze the lactam formation. The efficiency of the protocol was established
followed by a successful transition to library production in four 24-well plates.
KEYWORDS: 1,5-disubstituted tetrazoles, Ugi reaction
The pilot reaction during optimization of the sequence
utilized methyl levulinate 2, 2-thiophenemethylamine 4, 2,6-
dimethylphenyl isocyanide 5 and TMSN3 to generate 5-(1-(2,6-
dimethylphenyl)-1H-tetrazol-5-yl)-5-methyl-1-(thiophen-2-
ylmethyl)pyrrolidin-2-one 7 (Scheme 3). After allowing the
mixture to stir overnight at room temperature, the Ugi
condensation product 6 was typically observed in high yield
(LC-MS > 90% A% purity as judged by UV214 and ELS)
(Scheme 3). Subsequent microwave irradiation (100 °C,
erivatization of isocyanide based MCR products such as
those from the Ugi reaction, followed by a postcon-
D
densation modification have received massive attention in
medicinal chemistry for the pursuit of generating collections of
small molecules with high molecular diversity.1−6 Interestingly,
substitution of the carboxylic acid in the generic Ugi MCR with
azidotrimethylsilane (TMSN3) makes it possible to afford 1,5-
disubstituted tetrazoles, 1 (Scheme 1),7,8 an effective conforma-
tional mimic for the cis-amide bond conformation.9,10
Scheme 1. General Ugi−Azide Reaction
Scheme 3. Synthesis of 5-(1-(2,6-Dimethylphenyl)-1H-
tetrazol-5-yl)-5-methyl-1-(thiophen-2-ylmethyl)pyrrolidin-
2-one 7
Exploration of the Ugi−Azide MCR using a variety of diverse
reagents have led to the creation of unique scaffolds as exemplified
by ketopiperazine−tetrazoles,8 azepine−tetrazoles,11,12 benzodia-
zepine−tetrazoles,13 and quinoxaline−tetrazoles.14 This letter
reports the establishment of unique methodology which utilizes
keto-esters (methyl levulinate 2), along with primary amines,
isocyanides, and TMSN3 to afford novel peptidomimetic-like bis-
pyrrolidinone tetrazoles 3 (Scheme 2).
5 min) failed to deliver the desired bis-heterocyclic product 7
(Table 1, entry 2). However, very encouragingly simple
addition of a 10% solution of trifluoroacetic acid (TFA) in
1,2-dichloroethane (DCE) into the ongoing Ugi reaction
afforded γ-lactam formation in good to moderate yield
Scheme 2. General Synthetic Route to Access Bis-
pyrrolidinone Tetrazole 3
Received: December 17, 2011
Revised: February 8, 2012
Published: February 13, 2012
© 2012 American Chemical Society
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Letter
Table 1. Optimization for the Pilot Synthesis of 7
Scheme 4. Synthesis of Bis-pyrrolidinone Tetrazoles 18
yield
of 7
(%)
2
4
5
TMSN3
entry
conditions
25 °C, 24 h
μwave 100 °C,
10 min
(equiv) (equiv) (equiv) (equiv)
1
2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3
4
10% TFA in DCE,
μwave 100 °C,
10 min
1.0
1.5
1.0
1.0
1.0
2.0
1.0
1.0
40
56
final products were purified by in-house mass-triggered
purification platforms, successfully yielding 84 products 18
from the 96 reactions.
10% TFA in DCE,
μwave 100 °C,
10 min
5
6
7
8
10% TFA in DCE,
25 °C, 24 h
15% TFA in DCE,
25 °C, 24 h
20% TFA in DCE,
25 °C, 24 h
10% TFA in DCE,
25 °C, 24 h
1.5
1.5
1.5
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
1.0
1.0
1.0
1.0
2.0
58
59
61
39
The reaction seemed robust for a wide range of primary
amines and isocyanides, Figure 2. Table 2 presents both
isolated yields and purities of final target mole-
cules demonstrating the generality of the protocol. Notably,
2,6-dichlorobenzylamine 16{2}, which performed well in
the Ugi reaction, did not undergo any cyclization upon
addition of TFA, possibly due to strong steric and elec-
tronic effects. In addition, two amines, 4-morpholinoaniline
16{11} and 1-benzylpiperidin-4-amine 16{22} produced
Ugi congeners which underwent ring formation in only
low yield (8−23%, eight examples). Likewise, sterically
hindered cyclohexylamine 16{23} produced no final
cyclized product. Taken as a whole, 84 compounds were
obtained with overall yields ranging from 2 to 84% with 82
compounds having purity greater than 95% [as judged by
UV absorbance at 214 nm, 254 nm, and evaporative light
scattering (ELS)].
Virtual libraries derived from reagents used in both the
initial pilot and plate based library (7, Figure 1 and 2) were
also enumerated to establish their uniqueness relative to a
collection of over 400 000 chemically diverse small
molecules in the NIH molecular libraries small molecule
repository (MLSMR).15 As such, principle component
analysis (PCA)16 demonstrates the unique spatial occu-
pancy of the bis-pyrrolidinone tetrazole scaffold when
compared to 942 nearest MLSMR neighbors described
herein Figure 3, with no substructure match in the MLSMR
(Table 1, entry 3). Indeed, to the best of the authors’
knowledge, we believe this is the first example of TFA-mediated
γ-lactam formation. The yield was also further improved
with the use of excess keto-ester and isocyanide (Table 1,
entry 4).
With these encouraging results from the pilot study in-hand,
a small library comprised of eight compounds (Figure 1)
was synthesized to further validate this one-pot, two-step
synthetic protocol by varying the primary amine and isocyanide
inputs. Predictably, given their poor nucleophilicity, use
of anilines as the amine component resulted in lower yields
(14 and 15).
Although microwave irradiation expedites the process, it
is worth mentioning that each step can be performed at
room temperature (Table 1, entry 5). Stoichiometry studies
performed at room temperature (entries 6, 7, and 8) failed
to significantly increase yields of final product. The
procedure was thus progressed to 4 24-well plate produc-
tion (Scheme 4) with an assortment of primary amines
16{1−24} and isocyanides 17{1−4} where subsequently,
Figure 1. Example analogs (x% = overall yield).
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ACS Combinatorial Science
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Figure 2. Diversity reagents 16{1−24} and 17{1−4}.
a
Table 2. Yield and Purity (%) of the 96-Well Plate Production of 18{1−24,1−4}
R2NC (17)
R2NC (17)
1
2
3
4
1
2
3
4
R1NH2 (16)
Y
P
Y
P
Y
P
Y
P
R1NH2 (16)
Y
P
Y
P
Y
P
Y
P
1
nr
nr
nr
nr
69
49
50
57
57
56
23
47
46
un
45
45
42
36
39
42
42
41
16
34
100
57
un
45
50
53
38
50
50
55
51
8
100
53
un
66
65
64
55
54
62
49
60
13
53
98
13
14
15
16
17
18
19
20
21
22
23
24
46
49
38
45
56
51
26
55
59
7
100
100
100
100*
100
100
100
100
100
93*
41
nr
100
48
38
43
27
58
39
29
61
64
6
100
100
100
100
100
100
100
100
100
100*
63
59
47
8
100
100
100
100*
100
100
100
95
2
3
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
98
27
47
44
39
23
51
44
22
un
24
100
100
100
100
100
100
100
100*
4
5
97
61
61
33
83
72
2
6
100
100
100
100
98
100
100
100
100
100
100
100
7
8
9
100
100*
10
11
12
70
un
28
un
18
un
55
100
50
96
100
100
100
a
Y = Yield (%); P = Purity (%) based on UV 214 nm; nr = not recovered/lost during purification; un = no cyclization to 18 observed; * purity based
on ELS
and only minor overlap in similarity space with its nearest
neighbors.
In summary, a one-pot, two-step protocol for large scale
production of libraries of bis-pyrrolidinone tetrazoles has been
successfully developed using the tethered keto-ester methyl
levulinate 2, primary amines, isocyanides and azidotrimeth-
ylsilane through the use of the Ugi-Azide reaction followed
by subsequent lactam formation under acidic conditions.
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Figure 3. Similarity space occupied by the bis-pyrrolidinone tetrazoles
library (blue dots) relative to the 942 nearest neighbors in MLSMR
(red dots).
Because of the robustness of the described methodology, future
studies will continue to expand readily available molecular
diversity delivering scaffolds of interest, in particular to
chemists involved in file enhancement programs.
ASSOCIATED CONTENT
■
(15) Visit http://mli.nih.gov/mli/compound-repository/ for over-
view of molecular libraries program.
S
* Supporting Information
Detailed experimental procedures, H and 13C NMR, low and
1
(16) Details of how PCA was conducted can be found in Supporting
Information.
high resolution MS data for the nine analogs (7−15) from
small library, and virtual library generation. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Corresponding Author. E-mail: hulme@pharmacy.arizona.edu.
■
Funding Sources
This work was supported by the National Institutes of Health
(P41GM086190).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thanked Kristen Keck for compound purification,
Alex Laetsch for compound management, and Nicole Schechter
for proof-reading.
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