Bifunctional building blocks in the Ugi-azide condensation reaction: A general strategy toward exploration of new molecular diversity

Article abstract of DOI:10.1039/c3ob40900g

1,5-Disubstituted tetrazoles are an important drug-like scaffold known for their ability to mimic the cis-amide bond conformation. The scaffold is readily accessible via substitution of the carboxylic acid component of the Ugi multi-component reaction (MCR) with TMSN₃ in what is herein denoted the Ugi-azide reaction. This full paper presents a concise, novel, general strategy to access a plethora of new heterocylic scaffolds utilizing tethered aldo/keto-acids/esters in the Ugi-azide reaction followed by a ring closing event that generates novel highly complex bis-heterocyclic lactam-tetrazoles. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob40900g

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Bifunctional building blocks in the Ugi-azide
condensation reaction: a general strategy toward
Cite this: Org. Biomol. Chem., 2013, 11,
6036
exploration of new molecular diversity†
Steven Gunawan and Christopher Hulme*
1,5-Disubstituted tetrazoles are an important drug-like scaffold known for their ability to mimic the cis-
amide bond conformation. The scaffold is readily accessible via substitution of the carboxylic acid com-
ponent of the Ugi multi-component reaction (MCR) with TMSN3 in what is herein denoted the Ugi-azide
reaction. This full paper presents a concise, novel, general strategy to access a plethora of new heterocylic
scaffolds utilizing tethered aldo/keto-acids/esters in the Ugi-azide reaction followed by a ring closing
event that generates novel highly complex bis-heterocyclic lactam-tetrazoles.
Received 30th April 2013,
Accepted 25th June 2013
DOI: 10.1039/c3ob40900g
www.rsc.org/obc
isocyanide based MCR, and subsequent chemical manipulation
of the flexible product has received immense interest in the
Introduction
The design of peptidomimetics to circumvent small molecule medicinal chemistry community providing access to arrays of
biological stability issues, thus delivering improved pharmaco- highly diverse small molecules.9 Moreover, an offspring of the
kinetic profiles, has gained massive interest over the last Ugi reaction, denoted the Ugi-azide reaction, offers a concise
twenty years.1 In particular, cis-amide bonds have been shown chemical route to 1,5-disubstituted tetrazoles which is initiated
to play key roles in protein secondary structures involved in with simple replacement of the carboxylic acid with TMSN3, deli-
several important biological systems.2 In studies to determine vering 1,5-disubstituted tetrazoles B (Scheme 1).10 Through use
effective mimics of the cis-amide bond, the tetrazole ring and of a variety of assorted reagents and systematically exploring
more specifically the 1,5-disubstituted tetrazole, has proven to different ring closing possibilities of the Ugi-azide product B,
be a valuable bioisostere, extensively reported on by Marshall unique scaffolds such as ketopiperazine-tetrazoles,11 azepine-
et al.3 The biological significance of related ring systems has tetrazoles,12 benzodiazepine-tetrazoles13 and quinoxaline-tetra-
grown in recent years with a number of tetrazole analogs zoles14 have been successfully generated.
reported to exhibit biological activity toward the cannabinoid-1
Recently, we reported on the use of methyl levulinate 1, a
receptor (CB1),4 fatty acid amide hydrolase,5 melanin-concen- tethered keto-ester, in the Ugi-azide MCR followed by sub-
trating hormone receptor 1,6 polo-like kinase 1,7 and to act as sequent rigidification.15 This full paper details the versatility
orally effective human growth hormone secretagogues.8 and generality of the methodology with greatly enhanced
Clearly, development of concise routes to novel 1,5-disubsti- scope in tether diversity between the aldehyde and electro-
tuted tetrazole chemical space has the potential to deliver philic acid or ester appendage (Scheme 2), enabling access to
small molecule partners or probes for new or established multiple collections of bis-heterocyclic lactam-tetrazoles
protein receptors, enabling studies on protein function or even
initiation of translational campaigns.
The classical Ugi MCR is comprised of four components,
an aldehyde, amine, isocyanide and carboxylic acid, which on
mixing generate the peptidic-like structure A containing 4 points
of diversification (Scheme 1). As such, it is probably the premiere
Scheme 1 Ugi and Ugi-azide MCR.
BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ
85737, USA. E-mail: hulme@pharmacy.arizona.edu; Tel: +1 (520) 626-5322
†Electronic supplementary information (ESI) available: General procedure, 1H
and 13C NMR spectra for aldo/keto-esters (8b, 19b, 19 and 30). 1H and 13C NMR
spectra for all new synthesized compounds (10, 10b–j, 20a–e, 22a–f, 24a–e, 29a–e
and 31a–f). CCDC 936637. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c3ob40900g
Scheme 2 General strategy to lactam-tetrazoles.
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recently submitted to the United States Molecular Libraries
Small Molecule Repository (MLSMR).
Table 1 Tetrazolyl-pyrrolidinones series
Results and discussion
Syntheses of tetrazolyl-pyrrolidinones and -indolinones
Initial studies concentrated on exploring the suitability of com-
mercially available methyl levulinate 1 to provide the tetr-
azolyl-lactam 5a with supporting reagents thiophen-2-ylamine
2 and 2-isocyano-1,3-dimethylbenzene 3 (Scheme 3).15 After
formation of the Ugi product 4, direct addition of a solution of
10% TFA in DCE [Note: without removal of MeOH] facilitated
lactam formation to give 5a in 56% yield over two steps
(Scheme 3). Interestingly, when methanol was removed prior
to addition and dissolution of 4 in 10% TFA/DCE, 5a was only
observed in negligible amounts. The Ugi product was thus iso-
lated and subjected to basic conditions (Scheme 3, 2. KOH,
MeOH, THF, H2O). Gratifyingly, 2a was attained in comparable
yields (59% over 2 steps), presumably through cyclization of
the secondary amine directly onto a newly formed carboxylic
acid from the methyl ester moiety. With two complementary
routes in hand the more operationally friendly acid mediated
protocol was employed to establish the reactivity domain
through preparation of a further eight tetrazolyl-pyrrolidinones
2 (Table 1). Furthermore, the methodology was importantly
shown to be compatible with plate based production, deliver-
ing 96 congeners in rapid fashion.16
R1
R2
Product
Yield (%)
78
5b
5c
5d
5e
54
69
59
5f
52
5g
5h
64
40
5i
48
Encouraged by this operationally friendly protocol, we
embarked upon additional studies of new tether diversity
exploring the production of tetrazolyl-indolinones 10. Prelimi-
nary attempts focused on the use of methyl 2-acetylbenzoate
8a, n-pentyl isocyanide 7a and furfurylamine 6a in the Ugi-
azide MCR (Scheme 4). Unexpectedly, the condensation per-
formed poorly for the acetophenone 8a, whereas the aldehyde
congener, methyl 2-formylbenzoate 8b, performed in exemp-
lary fashion and 10b was formed directly without the need for
addition of acid (85% isolated yield, 2 steps).
Eight analogs were thus prepared using an assortment of
primary amines and isocyanides (Table 2) and the chemistry
was progressed to plate based production delivering 96
additional analogs of indolinone-tetrazoles 8.17,18
Syntheses of tetrazolyl-piperidinones, -ketopiperazines, and
-thiomorpholinones
Scheme 4 Synthesis of 2-(furan-2-ylmethyl)-isoindolin-1-one 10b.
Using the same diversity reagents 6a and 7a, the feasibility of
expanding the generality of this methodology to afford
6 membered rings was subsequently investigated with bifunc-
tional reagents methyl ester 11a and free carboxylic acid 11b.
Thus, after Ugi-azide reaction of 6a, 7a and 11a, TFA was
added to the methanolic reaction medium of 12a and contrary
to observations with its 5-membered ring congener no cycliza-
tion to desired product 13a was observed.
From prior experience with 4 (Scheme 3) possessing both
ester and amine functionalities akin to 12a, lactamization was
attempted via two additional steps i.e. ester cleavage to the free
acid and amide bond formation to afford the lactam. Thus,
reaction of methyl 5-oxohexanoate 11a in the azide modified
Scheme 3 Access to tetrazolyl-pyrrolidinone 5a.
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Table 2 Indolinone tetrazole series
R1
R2
Product
Yield (%)
51
10c
10d
10e
58
66
Scheme 6 Ugi-azide condensation to afford 17.
10f
43
51
were prepared using an assortment of primary amines and
isocyanides reported previously.16 Mechanistically, this was
intriguing and a postulated sequence of events is depicted in
Scheme 6.19 Thus, condensation of an aldo-acid and a primary
amine forms imine 15. Upon imine protonation, isocyanide
addition forms the intermediate nitrilium ion 16. The classical
intramolecular Ugi MCR (Path a) would typically afford lactam
18 after Mumm rearrangement. However, the small and highly
nucleophilic azide ion intercepts 16 (Path b) in preference to
intramolecular ring closure with the free carboxylic acid,
affording 17 which is ready for CDI mediated ring closure.
Further efforts were devoted to enrich molecular diversity
through the assembly of more elaborated heterocyclic cores
and three additional libraries incorporating unique molecular
features and six membered rings found in medicinally valu-
able compounds were thus evaluated for route feasibility.
Thus, integration of a sulphur atom into the 6-membered ring
to generate thiomorpholinone derivatives 20 was attempted.
This peculiar moiety has been the subject of intense study due
to its pharmacological properties depicted as a 1,4-benzothi-
azine framework in the calcium antagonist Semotiadil.20
When keto-acid 19a (R = H) was mixed with 2,5-dimethoxy-
benzylamine and cyclopentyl isocyanide, competition between
path a and b, illustrated in Scheme 6 gave two products, i.e. 17
and 18 derivatives. Subsequently, the crude mixture was
10g
10h
10i
10j
58
29
36
Scheme 5 Optimization of the preparation of piperidine-tetrazole 13.
Ugi reaction with 6a and 7a (Scheme 5) gave the Ugi amino- treated with CDI to give 20a in only 21% yield. Due to this low
ester 12a (83% yield). Basic hydrolysis of 12a and subsequent yield, we turned our attention to methyl 2-((2-oxopropyl)thio)-
1-ethyl-3-(3-dimethyllaminopropyl)-carbodiimide (EDC) or acetate 19b (R = Me), prepared from methyl thioglycolate and
SOCl2 mediated intramolecular amide coupling provided 13a chloroacetone, which delivered 20a in 69% yield in two steps.
in 75% and 83% yield respectively over the final two steps. Accordingly, a variety of primary amines, isocyanides and 19b
Looking to improve the route to 13, we investigated utilizing were evaluated to establish a preliminary reactivity domain
the tethered keto-acid 11b in the Ugi-Azide MCR and, to our and furnish an array of five unique thiomorpholinones 20a–e
delight, the Ugi product 12b as opposed to 18 was formed, (Table 3).
Scheme 6. Without purification of 12b, coupling agent 1,1′-carb-
Another enticing moiety that drew our attention was the
onyldiimidazole (CDI) was able to catalyze lactam formation to 4-sulfonyl-2-piperazinone skeleton embedded in 22. This con-
provide tetrazolyl-piperidinone 13b in 37% overall yield for formationally restricted motif represents an essential struc-
the combined two steps (Scheme 5). With a general one-pot, tural feature of human factor Xa and gene transcription
two-step optimized procedure in hand, five other examples inhibitors.21,22 Indeed, sulfonamide keto-acids have previously
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Table 3 Array of thiomorpholinone-tetrazole derivatives 20
Table 4 Array of 4-sulfonyl-2-piperazinone-tetrazole derivatives 22
R1
R2
Product
Ugi (%)
16
Final stepsa (%)
78
R1
R2
Product
Ugi (%)
78
Final stepsa (%)
88
22a
20a
22b
27
93
20b
20c
61
42
66
22
22c
22d
59
55
82
86
20d
20e
86
61
73
96
22e
22f
74
64
58
64
a Basic hydrolysis and SOCl2 activation.
a Basic hydrolysis and SOCl2 activation.
been reported as highly compatible bifunctional reagents in
intramolecular Ugi three component condensations affording
5-carbamoyl-5-methyl-4-sulfonyl-2-piperazinones in a single
step.23 The sulfonamide keto-ester 21 was thus synthesized
from glycine methyl ester in two steps consisting of sequential
sulfonylation and alkylation using 18-crown-6 as a phase-trans-
fer catalyst and a relatively mild base (K2CO3). A series of six
4-sulfonyl-2-piperazinones 22 were generated to confirm the
utility of 21 in producing novel tetrazolo-fused analogs,
thereby further expanding the generality of the lactam-tetra-
zole forming methodology depicted in Scheme 2 (Table 4).
Additional attempts to further diversify the portfolio of
scaffolds derived from this methodology were carried out by
fusing heteroaromatic rings onto the bifunctional input.
In particular, derivatives of 4,5,6,7-tetrahydropyrazolo[1,5-a]-
pyrazine-4-one represent an uncultivated set of pharmaceuti-
cally relevant compounds where the scaffold is currently found
in both fibrinogen and vitronectin receptor antagonists.24,25
Intrigued by the potential new biological applications of this
rare bifunctional substituted-pyrazole methyl ester,26 it was
thus employed with supporting reagents 6 and 7 in the devel-
opment of new synthetic route to scaffold 24. Alkylation of
methyl 1H-pyrazole-3-carboxylate with chloroacetone under
phase transfer conditions in the presence of K2CO3 and
18-crown-6 provided 23 in a single step. In analogous fashion
to prior methods reported herein, 23 was mixed with a variety
of primary amines and isocyanides in the Ugi-Azide MCR. Sub-
sequent basic hydrolysis and SOCl2-mediated ring closure
Table 5 Array of 4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrazine-4-one tetrazole
derivatives 24
R1
R2
Product
Ugi (%)
74
Final stepsa (%)
51
24a
24b
73
57
24c
24d
67
51
78
72
24e
42
55
a Basic hydrolysis and SOCl2 activation.
Syntheses of tetrazolyl-azepanones, -thiazepanones, and
-benzoxazepinones
furnished a compilation of five 4,5,6,7-tetrahydropyrazolo- With five diverse scaffolds in hand, we subsequently expanded
[1,5-a]-pyrazine-4-one derivatives 24a–e depicted in Table 5 the generality to variations of seven-membered ring lactams.
with moderate to good isolated yields.
Initial efforts were devoted to preparations of 1-(furan-2-
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Table 6 Array of [1,4]thiazepanone derivatives 29
R1
R2
Product
Ugi (%)
68
Final stepsa (%)
57
Scheme 7 Optimization of azepinone-tetrazoles 27.
29a
ylmethyl)-7-methyl-7-(1-pentyl-1H-tetrazol-5-yl)azepan-2-one 27
analogs (Scheme 7). In similar fashion with attempts to
prepare tetrazolyl-piperidines 13, TFA failed to deliver 27 after
direct addition of TFA/DCE to a methanolic solution of the on-
going Ugi-azide reaction with 25a (R = Me) and supporting
reagents 6a and 7a. However, unlike 13 which was accessible
via CDI or EDC-mediated amide coupling, 27 was not obtained
after similar coupling methods were employed with crude 26b
(R = H). Azepine-tetrazole 27 was ultimately generated in 48%
yield through SOCl2 triggered in situ acyl chloride formation
on partially purified 26b (Scheme 7). Due to its high polarity,
complete isolation of 26b did prove difficult and hence atten-
tion was turned to the Ugi amino-ester 26a, synthesized from
methyl 6-oxoheptanoate 25a (82% yield). Yield improvement to
62% was observed when 27 was produced from 26a (R = H) in
two steps comprising consecutive basic hydrolysis and in situ
acyl chloride formation (Scheme 7). This method was exempli-
fied by the assembly of four analogs and has been previously
reported.16
29b
70
66
29c
29d
70
61
54
45
29e
75
51
a Basic hydrolysis and SOCl2 activation.
Table 7 Array of benzo[1,4]oxazepinone derivatives 31
Thiazepanone derivatives 29 were successfully prepared in
similar fashion to the thiomorpholinones 20. The key reagent
in production of this derivative, namely methyl 2-((3-oxobutyl)-
thio)acetate 28, was prepared from methyl thioglycolate and
4-chlorobutan-2-one in one step. Upon completion of the Ugi-
azide condensation, MCR intermediates were subjected to the
optimized two-step protocol to ultimately afford five examples
29a–e in good overall yields for the 3 step process (Table 6).
A final example highlighting the generality of this methodo-
logy enabled access to the tetrazolo-benzoxazepinones 31. Akin
to the [1,4]thiazepanone 29, the benzo[1,4]oxazepinone frag-
ment may also be viewed as a relatively under-developed
scaffold in the pharmaceutical sector, although, a handful of
articles do describe some utility with the chemotype observed
embedded in ACE/neutral endopeptidase (NEP)27 and HIV-128
inhibitors. Methyl esterification of 2-(2-formylphenoxy)acetic
acid generated methyl 2-(2-formylphenoxy)acetate 30, that was
used as the tethered bifunctional component (Table 7). Six
analogs 31a–31f were synthesized and the structure of 31c was
confirmed by X-ray crystallography (Fig. 1).29
R1
R2
Product
Ugi (%)
80
Final stepsa (%)
29
31a
31b
31c
63
74
31
84
31d
31e
31f
78
77
66
70
35
62
a Basic hydrolysis and SOCl2 activation.
context, tethered aldo-esters/keto-acids/keto-esters were key
bifunctional precursors that in combination with supporting
isonitrile and amine reagents typically afforded the Ugi-azide
adduct in good yield. Not surprisingly during the optimization
of the post-condensation ring closing methodology, it was
apparent that stronger activating reagents were required as the
Conclusions
A straightforward, robust and extremely versatile strategy coup-
ling the Ugi-Azide MCR with amidative post-condensation
modifications enabling ring-closure to a variety of pharmaco-
logically relevant scaffolds has been established. In this
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were dissolved in MeOH (1.0 ml) in a 10 ml vial. The reaction
was allowed to run at room temperature for 24 h. The crude
mixture was concentrated in vacuo and purified by flash chromato-
graphy (hexane–EtOAc) to afford the indolinone tetrazoles.
2-(Furan-2-ylmethyl)-3-(1-pentyl-1H-tetrazol-5-yl)isoindo-lin-1-
one (10b). White solid (m.p. 95–97 °C); 85% yield (one step);
1H NMR (400 MHz, CDCl3) δ ppm 8.02–7.97 (m, 1H), 7.65–7.56
(m, 2H), 7.28–7.22 (m, 2H), 6.26–6.21 (m, 2H), 6.19–6.15 (m,
1H), 4.78 (d, J = 15.6 Hz, 1H), 4.57 (d, J = 15.6 Hz, 1H), 3.57
(ddd, J = 14.8, 8.8, 6.3 Hz, 1H), 3.43 (ddd, J = 14.8, 8.8, 6.3 Hz,
1H), 1.38–1.24 (m, 1H), 1.19–1.08 (m, 1H), 1.08–0.95 (m, 2H),
0.89–0.78 (m, 2H), 0.71 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ ppm 167.7, 150.2, 148.6, 142.9, 140.3, 133.0, 131.2,
130.1, 124.7, 123.1, 110.7, 109.6, 55.1, 55.0, 47.6, 38.1, 28.4,
28.2, 21.7, 13.6; [M + H]+ = 352.4; HRMS (ESI): m/z calcd for
(C19H22N5O2): 352.1768; found: 352.1772.
Fig. 1 X-Ray crystal structure of 31c.
3-(1-Cyclopentyl-1H-tetrazol-5-yl)-2-(2,5-dimethoxybenzyl) iso-
indolin-1-one (10c). Yellow solid (m.p. 118–119 °C); 51% yield
(one step); 1H NMR (400 MHz, CDCl3) δ ppm 8.01–7.94 (m,
1H), 7.62–7.50 (m, 2H), 7.21–7.15 (m, 1H), 6.96–6.91 (m, 1H),
6.77 (ddd, J = 8.9, 3.0, 1.6 Hz, 2H), 6.71 (dd, J = 8.9, 1.3 Hz,
2H), 6.20 (s, 1H), 4.96 (d, J = 14.5 Hz, 1H), 4.41 (d, J = 14.4 Hz,
1H), 3.99–3.88 (m, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 2.01–1.75 (m,
3H), 1.74–1.59 (m, 1H), 1.59–1.47 (m, 1H), 1.41–1.28 (m, 1H),
1.19–1.07 (m, 1H), 1.06–0.92 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ ppm 168.4, 153.5, 151.4, 150.3, 140.8, 132.8, 131.3,
129.8, 124.4, 124.3, 123.1, 116.7, 114.4, 111.3, 59.3, 55.74,
55.68, 55.4, 39.9, 33.4, 32.6, 24.7, 24.6; [M + H]+ = 420.3; HRMS
(ESI): m/z calcd for (C23H26N5O3): 420.20302; found:
420.20308.
desired lactam ring size increased, yet all of the 5 to 7-exo-trig
processes remained, as expected, ultimately feasible.30 By
means of this general route, nine bis-heterocyclic tetrazolo-
scaffolds and related congener sets were prepared incorporating
a wide array of bifunctional input linker diversity (Scheme 2, x =
linker) and additional diversity elements from supporting
reagents 6 and 7. Coupled with the cis-amide bond surrogacy
possessed by the 1,5-disubstituted tetrazole nucleus, these new
bis-heterocylic scaffolds represent potential innovative new
molecular probes to interrogate peptidergic biological systems.
3-(1-Benzyl-1H-tetrazol-5-yl)-2-(thiophen-2-ylmethyl)iso-indolin-
1-one (10d). Yellow solid (m.p. 134–136 °C); 58% yield (one
step); 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (d, J = 7.6 Hz,
1H), 7.53 (t, J = 7.6 Hz, 1H), 7.38 (td, J = 7.6, 1.3 Hz, 1H),
7.24–7.18 (m, 2H), 7.16 (td, J = 7.3, 1.4 Hz, 2H), 6.97–6.93 (m,
1H), 6.90 (ddd, J = 5.1, 3.5, 1.7 Hz, 1H), 6.83–6.79 (m, 1H), 6.68
(d, J = 7.9 Hz, 2H), 6.15 (s, 1H), 4.89 (dd, J = 15.4, 4.5 Hz, 2H),
4.62 (d, J = 15.3 Hz, 1H), 4.12 (d, J = 15.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ ppm 167.5, 150.4, 139.7, 137.3, 132.9,
132.3, 131.2, 130.0, 128.8, 128.7, 127.8, 127.2, 127.1, 126.5,
124.6, 123.1, 54.0, 51.2, 39.3; [M + H]+ = 388.3; HRMS (ESI):
m/z calcd for (C21H18N5OS): 388.12266; found: 388.12239.
2-(2,5-Dimethoxybenzyl)-3-(1-(2,6-dimethylphenyl)-1H-tetra-
zol-5-yl)isoindolin-1-one (10e). White solid (m.p. 167–169 °C);
66% yield (one step); 1H NMR (400 MHz, CDCl3) δ ppm
7.61–7.57 (m, 1H), 7.46–7.41 (m, 1H), 7.41–7.36 (m, 1H),
7.30–7.26 (m, 2H), 7.19–7.12 (m, 2H), 6.80–6.73 (m, 4H), 6.09
(s, 1H), 4.95 (d, J = 15.0 Hz, 1H), 4.10 (d, J = 15.0 Hz, 1H), 3.78
(s, 3H), 3.69 (s, 3H), 2.04 (s, 3H), 1.22 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ ppm 167.6, 153.6, 152.4, 151.5, 139.7,
135.3, 135.0, 131.7, 131.5, 131.2, 130.7, 129.5, 128.7, 128.3,
124.8, 123.9, 123.2, 116.1, 113.8, 111.4, 55.8, 55.7, 54.4, 39.8,
17.6, 17.0; [M + H]+ = 456.3; HRMS (ESI): m/z calcd for
(C26H26N5O3): 456.20302; found: 456.20242.
Experimental
General remarks
All reagents were purchased from Acros Organics, Alfa Aesar,
Sigma Aldrich and TCI America. Microwave assisted reactions
were conducted in a 10-ml vial on a CEM microwave initiator.
The flash column chromatography was carried out on Teledyne
Isco CombiFlash Rf 200. 1H and 13C NMR spectra were
recorded in CDCl3 or DMSOd6 on a Varian 400 MHz spectro-
meter. Chemical shifts in 1H NMR spectra are reported in
parts per million (ppm, d) downfield from the internal stan-
dard Me4Si (TMS). Chemical shifts in 13C NMR spectra are
reported relative to the central line of the chloroform signal
(d = 77.70 ppm) or the DMSO signal (d = 40.0 ppm). Low-
resolution mass spectra were obtained with a Shimadzu Promi-
nence UFLCXR/LCMS-2020/ELSD-LTII instrument. High-
resolution mass spectra were obtained with 9.4 Tesla Bruker
FT/ICR-MS instrument.
General procedure for aldo/keto-esters (8b, 19b, 28 and 30)
All can be found in the ESI.†
General experimental procedure for synthesis of indolinone
tetrazoles (10b–10j)
Methyl 2-formylbenzoate 8b (0.250 mmol), R1NH2
6
2-(2-(1H-Indol-3-yl)ethyl)-3-(1-(tert-butyl)-1H-tetrazol-5-yl)-
(0.250 mmol), TMSN3 (0.250 mmol) and R2NC 7 (0.250 mmol) isoindolin-1-one (10f). White solid (m.p. 108–110 °C); 43%
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yield (one step); H NMR (400 MHz, DMSOd6) δ ppm 10.83 (s, 124.0, 122.8, 121.7, 55.8, 24.2, 6.6, 5.1; [M + H]+ = 368.3; HRMS
1H), 7.88–7.80 (m, 1H), 7.63–7.56 (m, 2H), 7.37–7.27 (m, 3H), (ESI): m/z calcd for (C22H18N5O): 368.1506; found: 368.1513.
7.11 (s, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H),
General experimental procedure for synthesis of tetrazolyl-
6.68 (s, 1H), 3.94–3.83 (m, 1H), 3.15–2.93 (m, 2H), 2.82–2.71
thiomorpholinones (20a–e), tetrazolyl ketopiperazines (22a–f
(m, 1H), 1.81 (s, 9H); 13C NMR (100 MHz, DMSOd6) δ ppm
and 24a–e), tetrazolyl-thiazepanones (29a–e), and tetrazolyl-
167.71, 153.00, 143.32, 136.63, 132.83, 131.69, 129.76, 127.31,
123.80, 123.29, 123.25, 121.51, 118.80, 118.22, 111.94, 111.26,
benzoxazepinones (31a–f)
62.67, 55.24, 42.53, 40.60, 40.39, 40.18, 39.97, 39.76, 39.56, Bifunctional reagents (20, 22, 24, 29 or 31, 0.250 mmol),
39.35, 30.27, 24.28; [M + H]+ = 401.4; HRMS (ESI): m/z calcd for R1NH2 (0.250 mmol), TMSN3 (0.250 mmol) and R2NC
(C23H25N6O): 401.20844; found: 401.20824.
(0.250 mmol) were dissolved in MeOH (1.0 ml) in a 10 ml vial.
3-(1-Cyclohexyl-1H-tetrazol-5-yl)-2-(4-hydroxyphenethyl) iso- The reaction was allowed to run at room temperature for 24 h.
indolin-1-one (10g). White solid (m.p. 162–164 °C); 51% yield The crude mixture was concentrated in vacuo and purified by
(one step); 1H NMR (400 MHz, CDCl3) δ ppm 8.04–7.94 (m, flash chromatography (hexane–EtOAc) to afford the Ugi-tetra-
1H), 7.66–7.55 (m, 2H), 7.26–7.22 (m, 1H), 7.06–7.00 (m, 2H), zoles. Subsequently, MeOH (1.5 ml), THF (0.75 ml), and H2O
6.84–6.75 (m, 2H), 6.52–6.40 (m, 1H), 6.09 (s, 1H), 4.22–4.11 (0.5 ml) were added, followed by 0.03 ml of a 1 g/1 ml solution
(m, 1H), 3.13 (tt, J = 11.6, 3.7 Hz, 1H), 3.05–2.90 (m, 2H), of KOH in H2O and the reaction mixture was irradiated in a
2.80–2.69 (m, 1H), 2.00–1.49 (m, 8H), 1.15–1.03 (m, 2H), 0.92 microwave initiator at 100 °C for 5 min. Upon acidification
(dd, J = 16.4, 11.1 Hz, 1H), 0.68–0.54 (m, 1H); 13C NMR with 1 M HCl solution to pH 2, the hydrolyzed product was
(100 MHz, CDCl3) δ ppm 168.0, 155.1, 149.5, 140.2, 132.9, then extracted with EtOAc (3 × 2 ml) and the organic layer was
131.6, 130.2, 129.7, 128.9, 124.4, 123.0, 115.7, 58.9, 54.9, 42.7, dried over Na2SO4 and concentrated in vacuo. The residue was
33.3, 32.7, 32.6, 25.2, 25.1, 24.4; [M + H]+ = 404.4; HRMS (ESI): dissolved in DCE (2 ml) followed by addition of SOCl2 (1.5 eq.)
m/z calcd for (C23H26N5O2): 404.20810; found: 404.20828.
3-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1H-tetrazol-5-yl)- (0.5 ml) was added and the mixture was stirred for 2 h before
2-isobutylisoindolin-1-one (10h). Yellow solid (m. being purified by flash chromatography (hexane–EtOAc) on
p. 66–67 °C); 58% yield (one step); H NMR (400 MHz, CDCl3) silica gel to afford final products.
and the reaction was refluxed at 85 °C. When completed, TEA
1
δ ppm 7.70–7.64 (m, 1H), 7.58–7.45 (m, 2H), 7.29 (d, J = 7.4 Hz,
5-(1-Cyclopentyl-1H-tetrazol-5-yl)-4-(2,5-dimethoxybenzyl)-
1H), 6.68–6.64 (m, 1H), 6.23 (s, 1H), 6.17–6.14 (m, 1H), 5-methylthiomorpholin-3-one (20a). Viscous liquid; 69%
4.32–4.11 (m, 5H), 3.66 (dd, J = 13.9, 9.5 Hz, 1H), 2.48 (dd, J = (three steps); 1H NMR (400 MHz, CDCl3) δ ppm 6.76–6.66
13.9, 5.7 Hz, 1H), 2.09–1.96 (m, 1H), 0.94 (d, J = 6.6 Hz, 3H), (m, 3H), 4.98 (d, J = 16.5 Hz, 1H), 4.88–4.77 (m, 1H), 3.80–3.70
0.86 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ ppm (m, 4H), 3.67 (s, 3H), 3.63 (d, J = 17.2 Hz, 1H), 3.53 (d, J =
167.6, 151.7, 145.5, 143.5, 140.2, 132.2, 132.0, 129.6, 125.1, 17.2 Hz, 1H), 3.20 (d, J = 14.4 Hz, 1H), 3.08 (d, J = 14.3 Hz, 1H),
124.0, 122.8, 118.3, 117.6, 114.6, 64.3, 64.1, 54.6, 48.0, 27.5, 2.31–2.20 (m, 1H), 2.20–2.02 (m, 5H), 1.98 (s, 3H), 1.83–1.66
20.3, 19.7; [M + H]+ = 392.3; HRMS (ESI): m/z calcd for (m, 2H); 13C NMR (100 MHz, CDCl3) δ ppm 166.5, 155.8, 153.5,
(C21H22N5O3): 392.17172; found: 392.17184.
150.2, 125.9, 114.4, 111.5, 110.6, 63.1, 60.6, 55.6, 55.5, 43.6,
2-(1-Benzylpiperidin-4-yl)-3-(1-(4-methoxyphenyl)-1H-tetrazol- 40.0, 35.2, 34.4, 32.7, 27.1, 25.2, 25.1; [M + H]+ = 418.2; HRMS
5-yl)isoindolin-1-one (10i). Light tangerine solid (m.p. (ESI): m/z calcd for (C20H28N5O3S): 418.19074; found:
83–84 °C); 29% yield (one step); 1H NMR (400 MHz, CDCl3) 418.19068.
δ ppm 7.62 (d, J = 7.4 Hz, 1H), 7.52 (td, J = 7.5, 1.3 Hz, 1H),
5-(1-Cyclohexyl-1H-tetrazol-5-yl)-4-(4-hydroxyphenethyl)-
7.45 (t, J = 7.4 Hz, 1H), 7.35–7.22 (m, 7H), 6.70–6.64 (m, 2H), 5-methylthiomorpholin-3-one (20b). Viscous liquid; 40%
1
6.63–6.57 (m, 2H), 6.29 (s, 1H), 4.15–4.03 (m, 1H), 3.77 (s, 3H), (three steps); H NMR (400 MHz, CDCl3) δ ppm 7.00 (dd, J =
3.47 (s, 2H), 2.97–2.89 (m, 1H), 2.88–2.80 (m, 1H), 2.08–1.99 8.3, 1.6 Hz, 2H), 6.78 (dd, J = 8.3, 1.6 Hz, 2H), 4.51 (tt, J = 11.7,
(m, 3H), 1.69 (d, J = 9.4 Hz, 1H), 1.72–1.64 (m, 1H), 1.48–1.39 3.8 Hz, 1H), 4.19–4.06 (m, 1H), 3.81 (td, J = 11.9, 4.3 Hz, 1H),
(m, 2H); 13C NMR (100 MHz, CDCl3) δ ppm 168.2, 160.9, 153.2, 3.55 (d, J = 17.3 Hz, 1H), 3.45 (d, J = 17.3 Hz, 1H), 3.18–2.98
141.1, 138.3, 132.4, 132.1, 129.7, 128.9, 128.2, 127.0, 126.7, (m, 2H), 2.65 (td, J = 12.0, 5.2 Hz, 1H), 2.42 (td, J = 11.8,
125.3, 124.0, 122.7, 114.3, 62.6, 55.6, 52.8, 52.7, 51.6, 30.1, 5.0 Hz, 1H), 2.27 (d, J = 11.4 Hz, 1H), 2.19 (s, 3H), 2.14–1.67
29.9; [M
+
H]+
=
481.3; HRMS (ESI): m/z calcd for (m, 4H), 1.57–1.42 (m, 1H), 1.40–1.21 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ ppm 165.9, 155.2, 155.0, 140.5, 129.8,
(C28H29N6O2): 481.23465; found: 481.23441.
2-Cyclopropyl-3-(1-(naphthalen-2-yl)-1H-tetrazol-5-yl)iso-indolin- 115.6, 62.4, 60.2, 58.9, 49.0, 39.7, 34.0, 33.8, 33.0, 27.3, 25.7,
1-one (10j). Light tangerine solid (m.p. 88–89 °C); 36% yield 25.4, 24.8, 24.6; [M + H]+ = 402.2; HRMS (ESI): m/z calcd for
(one step); 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (d, J = (C20H28N5O2S): 402.1958; found: 402.1957.
8.0 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.59–7.51 (m, 4H), 7.46 (d,
J = 7.5 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 7.6, H), 7.10 tetrazol-5-yl)-5-methylthiomorpholin-3-one
4-(3-(1H-Imidazol-1-yl)propyl)-5-(1-(2,6-dimethylphenyl)-1H-
(20c). Viscous
(d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.7, 2.2 Hz, 1H), 6.17 (s, 1H), liquid; 9% (three steps); 1H NMR (400 MHz, CDCl3) δ ppm
2.47–2.39 (m, 1H), 0.95–0.88 (m, 1H), 0.81–0.72 (m, 3H); 13C 7.46–7.38 (m, 2H), 7.24 (d, J = 7.6 Hz, 2H), 7.03 (s, 1H), 6.87 (s,
NMR (100 MHz, CDCl3) δ ppm 168.4, 152.3, 140.4, 133.5, 1H), 4.08–3.96 (m, 1H), 3.96–3.83 (m, 1H), 3.55–3.44 (m, 1H),
132.5, 132.2, 129.8, 129.8, 128.3, 128.2, 128.0, 127.7, 124.7, 3.37 (d, J = 17.0 Hz, 1H), 3.12 (d, J = 15.7 Hz, 1H), 3.05 (d, J =
6042 | Org. Biomol. Chem., 2013, 11, 6036–6046
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15.7 Hz, 1H), 2.85 (d, J = 14.1 Hz, 1H), 2.73–2.58 (m, 1H),
1-(Furan-2-ylmethyl)-6-methyl-4-(methylsulfonyl)-6-(1-pentyl-
2.39–2.23 (m, 1H), 1.87 (s, 3H), 1.86 (s, 3H), 1.56 (s, 3H), 1.26 1H-tetrazol-5-yl)piperazin-2-one (22c). Viscous liquid; 48%
1
(s, 2H); 13C NMR (100 MHz, CDCl3) δ ppm 165.7, 157.4, 137.0, (three steps); H NMR (400 MHz, CDCl3) δ ppm 7.25–7.21 (m,
136.1, 135.8, 132.8, 131.3, 129.7, 129.24, 129.21, 118.6, 62.5, 1H), 6.30–6.25 (m, 1H), 6.19 (d, J = 3.2 Hz, 1H), 4.60 (d, J =
45.0, 44.0, 38.4, 32.0, 30.4, 24.9, 17.8, 17.5; [M + H]+ = 412.1; 15.7 Hz, 1H), 4.36 (d, J = 15.7 Hz, 1H), 4.17 (d, J = 16.7 Hz, 1H),
HRMS (ESI): m/z calcd for (C20H26N7OS): 412.1914; found: 4.13–4.07 (m, 1H), 4.01 (d, J = 16.7 Hz, 1H), 3.96–3.85 (m, 1H),
412.1916.
3.81 (d, J = 12.9 Hz, 1H), 3.50 (d, J = 13.0 Hz, 1H), 2.80 (s, 3H),
4-(Furan-2-ylmethyl)-5-methyl-5-(1-pentyl-1H-tetrazol-5-yl)- 2.07 (s, 3H), 2.04–1.92 (m, 2H), 1.45–1.29 (m, 4H), 0.92 (t, J =
thiomorpholin-3-one (20d). White solid (m.p. 134–135 °C); 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 164.3, 154.3,
63% yield (three steps); 1H NMR (400 MHz, CDCl3) δ ppm 149.1, 142.1, 110.8, 110.0, 59.4, 53.5, 49.2, 49.0, 39.8, 36.1,
7.25–7.21 (m, 1H), 6.32–6.22 (m, 1H), 6.16–6.11 (m, 1H), 4.39 29.2, 28.8, 24.4, 22.1, 13.8; [M + H]+ = 410.9; HRMS (ESI): m/z
(d, J = 15.4 Hz, 1H), 4.28 (d, J = 15.4 Hz, 1H), 4.18–4.04 (m, calcd for (C17H27N6O4S): 411.1809; found: 411.1803.
1H), 3.86–3.73 (m, 1H), 3.50 (q, J = 17.2 Hz, 2H), 3.22 (d, J =
14.3 Hz, 1H), 2.95 (d, J = 14.3 Hz, 1H), 2.20 (s, 3H), 2.06–1.91 6-methyl-4-(methylsulfonyl)piperazin-2-one
6-(1-(2,6-Dimethylphenyl)-1H-tetrazol-5-yl)-1-(4-fluoro-benzyl)-
(22d). Viscous
(m, 2H), 1.44–1.28 (m, 4H), 0.93 (t, J = 6.7 Hz, 3H); 13C NMR liquid; 47% (three steps); 1H NMR (400 MHz, CDCl3) δ ppm
(100 MHz, CDCl3) δ ppm 165.5, 155.4, 149.7, 141.7, 110.8, 7.43 (td, J = 7.7, 2.5 Hz, 1H), 7.34–7.20 (m, 2H), 7.12–7.05 (m,
109.7, 61.8, 48.8, 41.3, 39.0, 32.5, 29.2, 28.9, 2637, 22.1, 13.8; 2H), 6.96 (td, J = 8.7, 2.7 Hz, 2H), 4.99 (d, J = 16.1 Hz, 1H),
[M + H]+ = 350.2; HRMS (ESI): m/z calcd for (C16H24N5O2S): 4.23–4.08 (m, 2H), 4.05 (d, J = 13.0 Hz, 1H), 3.58 (d, J =
350.16452; found: 350.1645.
16.2 Hz, 1H), 3.37 (d, J = 13.0 Hz, 1H), 2.81 (s, 3H), 2.04
4-Cyclopropyl-5-methyl-5-(1-(naphthalen-2-yl)-1H-tetrazol-5-yl)- (s, 3H), 1.96 (s, 3H), 1.31 (s, 3H); 13C NMR (100 MHz, CDCl3)
thiomorpholin-3-one (20e). Light tangerine solid (m.p. δ ppm 165.6, 160.7, 156.4, 135.6, 135.5, 133.1, 132.9, 131.4,
164–165 °C); 59% (three steps); 1H NMR (400 MHz, CDCl3) 129.3, 129.1, 128.5, 128.4, 115.7, 115.5, 60.2, 53.9, 48.4, 47.3,
δ ppm 8.06 (d, J = 8.7 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.93 (d, 37.9, 22.8, 17.7, 17.6; [M + H]+ = 472.8; HRMS (ESI): m/z calcd
J = 9.6 Hz, 2H), 7.76–7.61 (m, 2H), 7.44 (dd, J = 8.7, 1.6 Hz, for (C22H26FN6O3S): 473.1766; found: 473.1761.
1H), 3.22 (d, J = 16.2 Hz, 1H), 2.94 (dd, J = 15.0, 5.9 Hz, 2H),
2.84 (d, J = 14.0 Hz, 1H), 2.44–2.32 (m, 1H), 2.07 (s, 3H), 1-(3-(trifluoromethyl)benzyl)piperazin-2-one
6-(1-Isopropyl-1H-tetrazol-5-yl)-6-methyl-4-(methylsulfonyl)-
(22e). Viscous
1.03–0.87 (m, 2H), 0.80–0.68 (m, 1H), 0.67–0.54 (m, 1H); 13C liquid; 43% (three steps); 1H NMR (400 MHz, CDCl3) δ ppm
NMR (100 MHz, CDCl3) δ ppm 167.5, 158.0, 133.8, 132.5, 7.53 (d, J = 7.6 Hz, 1H), 7.48–7.41 (m, 2H), 7.38 (d, J = 7.7 Hz,
131.6, 130.2, 128.6, 128.5, 128.2, 128.1, 126.4, 123.3, 63.0, 38.4, 1H), 5.40 (d, J = 16.1 Hz, 1H), 4.69–4.58 (m, 1H), 4.30 (d, J =
31.4, 28.5, 26.2, 9.0, 7.7; [M + H]+ = 366.1; HRMS (ESI): m/z 16.9 Hz, 1H), 4.12–3.94 (m, 2H), 3.82 (d, J = 16.1 Hz, 1H), 3.48
calcd for (C19H20N5OS): 366.1383; found: 366.1383.
(d, J = 13.1 Hz, 1H), 2.77 (s, 3H), 1.78 (s, 3H), 1.68 (d, J =
6-(1-Cyclopentyl-1H-tetrazol-5-yl)-1-(2,5-dimethoxybenzyl)- 6.4 Hz, 3H), 1.62 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz,
6-methyl-4-(methylsulfonyl)piperazin-2-one (22a). Viscous CDCl3) δ ppm 165.4, 153.8, 138.5, 130.5, 129.3, 124.5, 123.7,
liquid; 12% (three steps); 1H NMR (400 MHz, CDCl3) δ ppm 60.6, 53.5, 53.3, 48.8, 47.9, 35.9, 24.8, 23.8, 23.0; [M + H]+
=
6.83 (s, 1H), 6.80–6.66 (m, 2H), 4.98 (d, J = 16.3 Hz, 1H), 461.2; HRMS (ESI): m/z calcd for (C18H24F3N6O3S): 461.1577;
4.77–4.67 (m, 1H), 4.26 (d, J = 16.8 Hz, 1H), 4.10–3.95 (m, 2H), found: 461.1582.
3.89 (d, J = 12.9 Hz, 1H), 3.75 (s, 3H), 3.65 (s, 3H), 3.47 (d, J =
6-(1-Cyclohexyl-1H-tetrazol-5-yl)-1-(4-methoxybenzyl)-6-methyl-
12.9 Hz, 1H), 2.77 (s, 3H), 2.31–2.17 (m, 1H), 2.14–1.96 (m, 4-(methylsulfonyl)piperazin-2-one (22f). Viscous liquid; 41%
5H), 1.85 (s, 3H), 1.78–1.65 (m, 2H); 13C NMR (100 MHz, (three steps); 1H NMR (400 MHz, CDCl3) δ ppm 7.11 (d, J =
CDCl3) δ ppm 165.2, 154.4, 153.6, 150.3, 126.0, 115.4, 112.1, 8.1 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 5.26 (d, J = 15.4 Hz, 1H),
110.8, 60.8, 60.4, 55.7, 55.6, 54.0, 49.0, 42.0, 35.9, 35.2, 34.2, 4.28 (d, J = 16.7 Hz, 1H), 4.22–4.11 (m, 1H), 4.01 (d, J =
25.2, 25.1, 24.4; [M + H]+ = 479.2; HRMS (ESI): m/z calcd for 16.7 Hz, 1H), 3.89 (d, J = 12.9 Hz, 1H), 3.78 (s, 3H), 3.59 (d, J =
(C21H31N6O5S): 479.2071; found: 479.2066.
15.4 Hz, 1H), 3.41 (d, J = 12.9 Hz, 1H), 2.78 (s, 3H), 2.17–1.88
6-(1-Benzyl-1H-tetrazol-5-yl)-6-methyl-4-(methylsulfonyl)-1- (m, 4H), 1.81 (s, 3H), 1.48–1.20 (m, 4H), 0.95–0.78 (m, 2H);
(thiophen-2-ylmethyl)piperazin-2-one (22b). Viscous liquid; 13C NMR (100 MHz, CDCl3) δ ppm 164.9, 159.0, 154.0, 129.4,
1
25% (three steps); H NMR (400 MHz, CDCl3) δ ppm 7.42–7.32 128.6, 114.1, 60.6, 60.5, 55.3, 54.0, 49.3, 47.6, 35.4, 34.0, 33.5,
(m, 3H), 7.28–7.22 (m, 1H), 7.07 (d, J = 7.4 Hz, 2H), 6.88–6.80 29.7, 25.7, 25.5, 24.6; [M + H]+ = 463.2; HRMS (ESI): m/z calcd
(m, 1H), 6.43–6.36 (m, 1H), 5.30 (d, J = 16.1 Hz, 1H), 4.96 for (C21H31N6O4S): 463.2122; found: 463.2118.
(d, J = 16.2 Hz, 1H), 4.51 (d, J = 15.3 Hz, 1H), 4.41 (d, J = 15.3
6-(1-Cyclopentyl-1H-tetrazol-5-yl)-5-(2,5-dimethoxybenzyl)-
Hz, 1H), 4.18 (d, J = 16.7 Hz, 1H), 3.75 (d, J = 16.7 Hz, 1H), 6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (24a). Light
3.34 (d, J = 12.7 Hz, 1H), 3.11 (d, J = 12.7 Hz, 1H), 2.52 (s, 3H), brown solid (m.p. 171–172 °C); 38% (three steps); 1H NMR
2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 164.5, (400 MHz, CDCl3) δ ppm 7.61–7.58 (m, 1H), 7.03 (d, J = 2.6 Hz,
154.0, 138.4, 133.5, 129.5, 129.2, 127.6, 127.5, 127.2, 127.1, 1H), 7.01–6.98 (m, 1H), 6.75 (dd, J = 9.0, 2.9 Hz, 1H), 6.69 (d,
126.4, 59.5, 52.0, 51.7, 49.0, 43.1, 35.1, 24.0; [M + H]+ = 447.0; J = 8.9 Hz, 1H), 5.04 (d, J = 15.8 Hz, 1H), 4.76 (d, J = 13.3 Hz,
HRMS (ESI): m/z calcd for (C19H23N6O3S2): 447.1268; found: 1H), 4.76–4.67 (m, 1H), 4.43 (d, J = 13.3 Hz, 1H), 4.38 (d, J =
447.1265.
15.8 Hz, 1H), 3.73 (s, 3H), 3.58 (s, 3H), 2.09–1.92 (m, 4H), 1.89
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(s, 3H), 1.86–1.76 (m, 2H), 1.72–1.58 (m, 2H); 13C NMR (three steps); 1H NMR (400 MHz, CDCl3) δ ppm 7.23 (d, J =
(100 MHz, CDCl3) δ ppm 158.9, 153.7, 153.5, 150.6, 140.5, 2.6 Hz, 1H), 6.86–6.76 (m, 2H), 5.39 (d, J = 16.4 Hz, 1H),
133.0, 126.0, 116.0, 113.2, 111.0, 109.2, 60.8, 59.9, 55.8, 55.7, 4.84–4.72 (m, 1H), 4.54 (d, J = 16.3 Hz, 1H), 4.06–3.93 (m, 1H),
55.6, 55.5, 40.2, 35.1, 33.5, 24.9, 24.1; [M + H]+ = 438.3; HRMS 3.81 (s, 3H), 3.80 (s, 3H), 3.15 (d, J = 15.0 Hz, 1H), 2.82–2.61
(ESI): m/z calcd for (C22H28N7O3): 438.2248; found: 438.2242.
(m, 3H), 2.32–1.89 (m, 7H), 1.83–1.66 (m, 2H), 1.70 (s, 3H); 13
C
6-(1-(2,6-Dimethylphenyl)-1H-tetrazol-5-yl)-5-(4-fluoro-benzyl)- NMR (100 MHz, CDCl3) δ ppm 174.3, 157.7, 153.8, 145.0,
6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (24b). White 126.5, 114.0, 111.8, 60.1, 58.9, 56.0, 55.9, 41.4, 39.6, 34.6, 34.3,
solid (m.p. 163–164 °C); 42% (three steps); 1H NMR (400 MHz, 30.1, 27.3, 25.1, 25.1; [M + H]+ = 432.2; HRMS (ESI): m/z calcd
CDCl3) δ ppm 7.51–7.48 (m, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.31 for (C21H30N5O3S): 432.20639; found: 432.2064.
(t, J = 7.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.19 (dd, J = 7.4,
5-(1-Benzyl-1H-tetrazol-5-yl)-5-methyl-4-(thiophen-2-ylmethyl)-
5.5 Hz, 2H), 7.05–6.93 (m, 2H), 6.86 (d, J = 1.4 Hz, 1H), 5.41 (d, 1,4-thiazepan-3-one (29b). White solid (m.p. 192–193 °C); 46%
1
J = 16.4 Hz, 1H), 4.76 (d, J = 13.7 Hz, 1H), 4.29 (d, J = 13.7 Hz, (three steps); H NMR (400 MHz, CDCl3) δ ppm 7.43–7.31 (m,
1H), 3.87 (d, J = 16.4 Hz, 1H), 1.89 (s, 5H), 1.63 (s, 3H); 13C 3H), 7.26–7.22 (m, 1H), 7.13–7.01 (m, 2H), 6.93–6.87 (m, 1H),
NMR (100 MHz, CDCl3) δ ppm 163.2, 160.7, 158.7, 156.5, 6.80–6.74 (m, 1H), 5.42 (d, J = 15.8 Hz, 1H), 5.32–5.12 (m, 2H),
140.4, 136.1, 136.0, 134.1, 133.2, 132.3, 131.5, 129.3, 128.4, 4.39 (d, J = 15.6 Hz, 1H), 3.59–3.44 (m, 1H), 3.12 (d, J =
115.7, 115.5, 109.0, 105.5, 59.8, 55.7, 45.6, 23.7, 17.7, 17.5; 15.3 Hz, 1H), 2.76 (d, J = 15.3 Hz, 1H), 2.67–2.52 (m, 2H),
[M + H]+ = 432.2; HRMS (ESI): m/z calcd for (C23H23FN7O): 2.00–1.87 (m, 1H), 1.81 (s, 3H); 13C NMR (100 MHz, CDCl3)
432.19426; found: 432.19474.
δ ppm 172.9, 157.9, 139.5, 133.2, 129.2, 129.1, 127.1, 127.0,
5-(Furan-2-ylmethyl)-6-methyl-6-(1-pentyl-1H-tetrazol-5-yl)-6,7- 126.4, 126.3, 59.3, 51.8, 44.0, 39.0, 33.9, 28.2, 26.1; [M + H]+ =
dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (24c). Viscous liquid; 400.2; HRMS (ESI): m/z calcd for (C19H22N5OS2): 400.12603;
1
38% (three steps); H NMR (400 MHz, CDCl3) δ ppm 7.62–7.57 found: 400.12546.
(m, 1H), 7.28–7.25 (m, 1H), 7.00–6.97 (m, 1H), 6.34–6.24 (m,
4-(Furan-2-ylmethyl)-5-methyl-5-(1-pentyl-1H-tetrazol-5-yl)-
1H), 6.15–6.10 (m, 1H), 4.76–4.63 (m, 2H), 4.57–4.46 (m, 2H), 1,4-thiazepan-3-one (29c). Viscous liquid; 38% (three steps);
4.04–3.90 (m, 1H), 3.88–3.73 (m, 1H), 2.08 (s, 3H), 1.92–1.79 1H NMR (400 MHz, CDCl3) δ ppm 7.39–7.34 (m, 1H), 6.50–6.43
(m, 1H), 1.77–1.63 (m, 1H), 1.40–1.17 (m, 4H), 0.88 (t, J = (m, 1H), 6.40–6.37 (m, 1H), 5.08 (d, J = 15.8 Hz, 1H), 4.55 (d,
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 157.8, 153.8, J = 15.8 Hz, 1H), 4.02 (t, J = 7.7 Hz, 2H), 3.97–3.83 (m, 1H),
149.4, 142.2, 140.6, 132.8, 110.9, 109.7, 109.4, 59.1, 55.3, 48.8, 3.04 (d, J = 14.8 Hz, 1H), 2.87 (dt, J = 14.8, 3.9 Hz, 1H), 2.64 (dt,
39.1, 29.4, 28.6, 23.9, 22.0, 13.7; [M + H]+ = 370.1; HRMS (ESI): J = 14.6, 4.4 Hz, 1H), 2.56 (d, J = 14.8 Hz, 1H), 2.14 (ddd, J =
m/z calcd for (C19H22N5O2): 352.1768; found: 352.1772.
15.1, 11.2, 4.0 Hz, 1H), 1.93 (s, 3H), 1.98–1.77 (m, 2H),
6-(1-Isopropyl-1H-tetrazol-5-yl)-6-methyl-5-(3-(trifluoromethyl)- 1.41–1.18 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
benzyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (24d). White CDCl3) δ ppm 173.2, 157.7, 150.5, 141.6, 112.0, 110.0, 58.4,
solid (m.p. 187–188 °C); 37% (three steps); 1H NMR (400 MHz, 48.6, 40.8, 39.5, 34.4, 30.5, 29.1, 28.7, 27.0, 22.1, 13.8; [M + H]+
CDCl3) δ ppm 7.57 (t, J = 1.9 Hz, 1H), 7.56–7.49 (m, 2H), 7.44 = 364.2; HRMS (ESI): m/z calcd for (C17H26N5O2S): 364.18017;
(t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 6.98 (t, J = 2.0 Hz, found: 364.18077.
1H), 5.38 (d, J = 16.1 Hz, 1H), 4.83 (d, J = 13.6 Hz, 1H),
5-(1-(2,6-Dimethylphenyl)-1H-tetrazol-5-yl)-4-(4-methoxy-
4.61–4.52 (m, 2H), 4.25 (d, J = 16.1 Hz, 1H), 1.90 (s, 3H), 1.52 benzyl)-5-methyl-1,4-thiazepan-3-one (29d). White solid
(d, J = 6.5 Hz, 3H), 1.42 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, (m.p. 182–184 °C); 27% (three steps); 1H NMR (400 MHz,
CDCl3) δ ppm 159.0, 153.4, 140.7, 140.6, 138.9, 132.8, 130.7, CDCl3) δ ppm 7.45 (t, J = 7.6 Hz, 1H), 7.33–7.27 (m, 2H), 7.05 (d,
129.4, 124.6, 124.1, 124.1, 109.5, 60.1, 55.6, 53.1, 46.7, 24.4, J = 8.3 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.09 (d, J = 16.3 Hz, 1H),
23.6, 22.8; [M + H]+ = 420.2; HRMS (ESI): m/z calcd for 3.89–3.79 (m, 1H), 3.76 (s, 3H), 3.16–2.97 (m, 3H), 2.88 (dd, J =
(C19H21F3N7O): 420.1754; found: 420.1751.
15.0, 6.9 Hz, 1H), 2.76 (dd, J = 12.5, 5.7 Hz, 1H), 2.20–2.08 (m,
6-(1-(2,6-Dimethylphenyl)-1H-tetrazol-5-yl)-5-(4-methoxy- 1H), 1.94 (s, 3H), 1.93 (s, 3H), 1.61 (s, 3H); 13C NMR (100 MHz,
benzyl)-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (24e). CDCl3) δ ppm 173.2, 159.3, 158.5, 136.6, 135.9, 132.5, 131.2,
1
Viscous liquid; 23% (three steps); H NMR (400 MHz, CDCl3) 130.6, 129.3, 129.1, 127.7, 114.0, 58.7, 55.2, 47.1, 41.3, 36.6,
δ ppm 7.49 (d, J = 2.0 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.30 (d, 33.8, 28.6, 18.0, 17.9; [M + H]+ = 438.0; HRMS (ESI): m/z calcd
J = 7.6 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), for (C23H28N5O2S): 438.19582; found: 438.19671.
6.85 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 8.7 Hz, 2H), 5.35 (d, J =
5-(1-Isopropyl-1H-tetrazol-5-yl)-5-methyl-4-(3-(trifluoromethyl)-
16.2 Hz, 1H), 4.80 (d, J = 13.6 Hz, 1H), 4.28 (d, J = 13.6 Hz, 1H), benzyl)-1,4-thiazepan-3-one (29e). Viscous liquid; 38% (three
1
3.76 (s, 3H), 3.75 (d, J = 16.2 Hz, 1H), 1.89 (d, J = 12.0 Hz, 6H), steps); H NMR (400 MHz, CDCl3) δ ppm 7.74 (s, 1H), 7.67 (d,
1.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 158.8, 158.7, J = 7.6 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H),
156.7, 140.3, 136.2, 135.9, 133.3, 132.3, 131.5, 130.4, 129.3, 5.58 (d, J = 16.0 Hz, 1H), 4.63–4.49 (m, 1H), 4.39 (d, J =
128.1, 114.1, 108.9, 59.7, 55.9, 55.3, 45.6, 23.8, 17.7, 17.5; 15.9 Hz, 1H), 4.00 (ddd, J = 14.5, 11.2, 2.9 Hz, 1H), 3.17 (d, J =
[M + H]+ = 443.8; HRMS (ESI): m/z calcd for (C24H26N7O2): 15.0 Hz, 1H), 2.86–2.68 (m, 2H), 2.69 (d, J = 15.0 Hz, 1H),
444.21425; found: 444.215.
2.16–2.05 (m, 1H), 1.76 (s, 3H), 1.62–1.48 (m, 6H); 13C NMR
5-(1-Cyclopentyl-1H-tetrazol-5-yl)-4-(2,5-dimethoxybenzyl)- (100 MHz, CDCl3) δ ppm 174.2, 156.8, 138.9, 131.1, 131.0,
5-methyl-1,4-thiazepan-3-one (29a). Viscous liquid; 39% 129.4, 125.3, 124.5, 122.6, 59.1, 52.2, 47.6, 39.5, 34.5, 30.1,
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27.2, 23.2, 23.1; [M + H]+ = 302.1; HRMS (ESI): m/z calcd for White solid (m.p. 209–210 °C); 27% (three steps); 1H NMR
(C18H23N5OS): 414.15699; found: 414.15684. (400 MHz, CDCl3) δ ppm 7.31–7.22 (m, 1H), 7.00 (d, J = 8.0 Hz,
5-(1-Cyclopentyl-1H-tetrazol-5-yl)-4-(2,5-dimethoxybenzyl)- 1H), 6.89 (td, J = 7.5, 1.1 Hz, 1H), 6.82–6.75 (m, 2H), 6.50–6.35
4,5-dihydrobenzo[f][1,4]oxazepin-3(2H)-one (31a). Viscous (m, 2H), 5.37 (s, 1H), 4.86 (dd, J = 16.6, 1.0 Hz, 1H), 4.38–4.18
liquid; 23% (three steps); 1H NMR (400 MHz, CDCl3) δ ppm (m, 5H), 4.16–4.04 (m, 1H), 3.34–3.21 (m, 1H), 1.65–1.53 (m,
7.40 (tt, J = 8.0, 1.9 Hz, 1H), 7.21–7.05 (m, 3H), 6.87–6.77 (m, 1H), 1.53–1.43 (m, 2H), 0.92 (s, 3H), 0.91 (s, 3H); 13C NMR
3H), 5.62 (s, 1H), 5.39 (d, J = 15.1 Hz, 1H), 4.98 (d, J = 16.7 Hz, (100 MHz, CDCl3) δ ppm 169.2, 156.9, 155.5, 145.5, 143.7,
1H), 4.43 (d, J = 16.7 Hz, 2H), 4.15–4.03 (m, 1H), 3.74 (s, 3H), 131.5, 130.4, 128.9, 126.2, 124.5, 121.5, 118.9, 117.7, 115.3,
3.67 (s, 3H), 2.15–1.85 (m, 3H), 1.85–1.72 (m, 1H), 1.66–1.63 73.3, 64.4, 64.2, 56.7, 48.3, 36.7, 25.9, 22.6, 22.5; [M + H]+
=
(m, 1H), 1.50–1.32 (m, 1H), 1.30–1.22 (m, 1H), 1.18–1.05 (m, 436.3; HRMS (ESI): m/z calcd for (C23H26N5O4): 436.19793;
1H); 13C NMR (100 MHz, CDCl3) δ ppm 169.8, 157.6, 153.8, found: 436.19759.
153.5, 151.8, 132.0, 130.6, 128.7, 125.1, 122.1, 115.9, 114.3,
111.8, 110.0, 73.4, 59.6, 56.1, 55.7, 55.6, 47.1, 32.9, 32.8, 24.5, 4,5-dihydrobenzo[f][1,4]oxazepin-3(2H)-one
24.3; [M
H]+ 450.3; HRMS (ESI): m/z calcd for liquid; 41% (three steps); 1H NMR (400 MHz, CDCl3) δ ppm
(C24H28N5O4): 450.2136; found: 450.213. 7.48–7.40 (m, 1H), 7.22–7.09 (m, 2H), 7.02 (d, J = 7.5 Hz, 1H),
4-Cyclopropyl-5-(1-(naphthalen-2-yl)-1H-tetrazol-5-yl)-4,5- 6.77 (dd, J = 7.7, 2.0 Hz, 1H), 6.73–6.67 (m, 2H), 6.02–5.92 (m,
dihydrobenzo[f][1,4]oxazepin-3(2H)-one (31b). Viscous 2H), 5.70 (d, J = 15.0 Hz, 1H), 5.37 (s, 1H), 4.97 (dd, J = 16.8,
4-(Benzo[d][1,3]dioxol-5-ylmethyl)-5-(1-butyl-1H-tetrazol-5-yl)-
(31f). Viscous
+
=
liquid; 20% (three steps); 1H NMR (400 MHz, CDCl3) δ ppm 1.9 Hz, 1H), 4.46 (dd, J = 16.8, 2.2 Hz, 1H), 4.06 (d, J = 15.1 Hz,
7.88 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 1H), 3.82–3.59 (m, 2H), 1.52–1.36 (m, 1H), 1.19–0.94 (m, 3H),
7.6 Hz, 1H), 7.66–7.56 (m, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.10 0.74 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ ppm
(td, J = 7.6, 2.0 Hz, 1H), 7.00 (dd, J = 8.6, 2.1 Hz, 2H), 6.97 (d, 169.7, 157.7, 153.5, 148.2, 147.5, 132.3, 130.3, 129.5, 128.6,
J = 8.0 Hz, 2H), 6.60–6.45 (m, 2H), 5.63 (s, 1H), 4.92 (d, J = 125.4, 122.2, 121.9, 108.9, 108.3, 101.2, 73.5, 54.3, 51.2, 47.6,
16.5 Hz, 1H), 4.33 (d, J = 16.5 Hz, 1H), 3.08–2.97 (m, 1H), 30.9, 19.4, 13.3; [M + H]+ = 422.1; HRMS (ESI): m/z calcd for
1.05–0.76 (m, 5H); 13C NMR (100 MHz, CDCl3) δ ppm 171.25, (C22H24N5O4): 422.18228; found: 422.8213.
156.90, 156.02, 133.45, 132.38, 131.43, 130.51, 130.04, 129.75,
128.83, 128.18, 128.13, 127.89, 127.67, 125.42, 124.35, 122.42,
121.38, 77.31, 76.99, 76.68, 73.58, 58.71, 33.47, 8.77, 7.83;
Acknowledgements
[M + H]+ = 398.2; HRMS (ESI): m/z calcd for (C23H20N5O2):
398.16115; found: 398.16105.
The authors thanked the National Institutes of Health
5-(1-(2,6-Dimethylphenyl)-1H-tetrazol-5-yl)-4-(4-fluoro-benzyl)- (P41GM086190) for funding, Dr Sue Roberts for the X-Ray crys-
4,5-dihydrobenzo[f][1,4]oxazepin-3(2H)-one (31c). White solid tallography work, Kristen Keck for compound purification,
(m.p. 178–179 °C); 62% (three steps); 1H NMR (400 MHz, Alex Laetsch for compound management, and Dr Fabio De
CDCl3) δ ppm 7.26–7.14 (m, 4H), 7.08 (d, J = 7.6 Hz, 1H), Moliner for proof-reading.
7.04–6.96 (m, 3H), 6.76 (d, J = 7.6 Hz, 1H), 6.70–6.62 (m, 1H),
5.96 (d, J = 7.4 Hz, 1H), 5.62 (d, J = 15.3 Hz, 1H), 5.11 (dd, J =
16.8, 2.2 Hz, 1H), 5.03 (d, J = 2.2 Hz, 1H), 4.50 (dd, J = 16.8,
2.5 Hz, 1H), 4.25 (d, J = 15.3 Hz, 1H), 1.77 (s, 3H), 1.22 (s, 3H);
Notes and references
13C NMR (100 MHz, CDCl3) δ ppm 170.1, 163.7, 161.3, 157.1,
154.7, 136.9, 133.7, 131.7, 131.4, 131.3, 131.1, 130.7, 130.1,
130.0, 129.3, 128.8, 128.3, 124.8, 121.4, 115.9, 115.7, 73.3, 55.1,
50.9, 16.8, 16.4; [M + H]+ = 444.1; HRMS (ESI): m/z calcd for
(C25H23FN5O2): 444.18303; found: 444.18303.
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liquid; 55% (three steps); 1H NMR (400 MHz, CDCl3) δ ppm
7.63–7.56 (m, 1H), 7.52–7.42 (m, 4H), 7.24–7.17 (m, 1H), 7.15
(d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 5.83 (d, J = 16.0 Hz,
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5.6 Hz, 3H), 0.86 (d, J = 5.4 Hz, 3H); 13C NMR (100 MHz,
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129.4, 128.5, 125.6, 124.8, 124.5, 122.3, 73.5, 55.5, 51.5, 51.4,
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isopentyl-4,5-dihydrobenzo[f][1,4]oxazepin-3(2H)-one
(31e).
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