Application of a double aza-Michael reaction in a click, click, cy-click strategy: From bench to flow

Article abstract of DOI:10.1055/s-0030-1260112

The development of a click, click, cy-click process utilizing a double aza-Michael reaction to generate functionalized 1,2,5-thiadiazepane 1,1-dioxides is reported. Optimization in flow, followed by scale out of the inter-/intramolecular double aza-Michael addition has also been realized using a microwave-assisted, continuous flow organic synthesis platform (MACOS). In addition, a facile one-pot, sequential strategy employing in situ Huisgen cycloaddition post-double aza-Michael has been accomplished, and is applicable to library synthesis. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260112

NIH Public Access
Author Manuscript
Synthesis (Stuttg). Author manuscript; available in PMC 2012 September 1.
Published in final edited form as:
Synthesis (Stuttg). 2011 September 1; 2011(17): 2743–2750. doi:10.1055/s-0030-1260112.
Application of a Double Aza-Michael Reaction in a ‘Click, Click,
Cy-Click’ Strategy: From Bench to Flow
a
a
b
a
a
Qin Zang , Salim Javed , Farman Ullah , Aihua Zhou , Christopher A. Knudtson , Danse
a
c
*,b
*,a
Bi , Fatima Z. Basha , Michael G. Organ , and Paul R. Hanson
aDepartment of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS
66045-7582 and the Center for Chemical Methodologies and Library Development at the
University of Kansas (KU-CMLD), 2034 Becker Drive, Delbert M. Shankel Structural Biology
Center, Lawrence, KS 66047-3761, USA
bDepartment of Chemistry, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
cH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological
Sciences University of Karachi, Pakistan
Abstract
The development of a ‘click, click, cy-click’ process utilizing a double aza-Michael reaction to
generate functionalized 1,2,5-thiadiazepane 1,1-dioxides is reported. Optimization in flow,
followed by scale out of the inter-/intramolecular double aza-Michael addition has also been
realized using a microwave-assisted, continuous flow organic synthesis platform (MACOS). In
addition, a facile one-pot, sequential strategy employing in situ Huisgen cycloaddition post-double
aza-Michael has been accomplished, and is applicable to library synthesis.
Keywords
double-aza-Michael; click; MACOS; flow; 1,2,5-thiadiazepane 1,1-dioxides
The development of facile, step-efficient methods to access new heterocycles is a key
component in the drug-discovery process. Hetero-Michael reactions are efficient pathways
that, historically, have been broadly used in synthesis, including several intramolecular
1
examples to access a variety of heterocycles, namely, dioxolanes en route to 1,3-diols,
2
3
4
5
azacycles, oxacycles, thiacycles, and bis-heterocycles. Recently, double aza-Michael
reactions have been utilized as efficient means to install two N–C bonds in a single
operation. Herein, we report a new approach termed ‘click, click, cy-click’ that utilizes two
6
7
click reactions and a double aza-Michael reaction for the facile synthesis of 1,2,5-
thiadiazepane 1,1-dioxides. Optimization using a microwave-assisted continuous flow
synthetic (MACOS) platform, has transformed the non-click cyclization step into a facile
one-minute (resident flow time) cyclization event (cy-click) that has also been scaled out.
Although not found in nature, sultams have emerged as privileged structures due to their
8,9
extensive chemical and biological profiles. Recently, a number of reports of sultams have
appeared demonstrating broad-spectrum bioactivity. Such reports include anti-HIV
10
11
12
activity, antidepressant activity, and as inhibitors of RSV, selective tumor necrosis
13
14
factor, and metalloproteinase.
Fax +1(785)8645396; phanson@ku.edu. Fax +1(416)7365936; organ@yorku.ca.
Supporting Information for this article is available online at http://www.thieme-connect.com/ejournals/toc/synthesis.

Zang et al.
Page 2
Previously, the inherent reactivity of vinyl sulfonamides was utilized in a ‘click, click,
cyclize’ strategy for the facile construction of diverse sultam scaffolds via intramolecular
3i,15
oxa- and intermolecular aza-Michael reactions (Scheme 1, pathway a).
At the heart of
this approach is the facile production of precursor tertiary vinyl sulfonamides by the use of
7
two click reactions, namely, sulfonylation of in situ generated vinyl sulfonyl chloride,
followed by alkylation of the resulting 2° sulfonamide and subsequent cyclization.
In this new report outlined in Scheme 1 (pathways b and c), an inter-/intramolecular double
aza-Michael pathway serves as the cyclization step in a ‘click, click, cy-click’ sequence, and
utilizes a TBS-protected serinol methyl ester in the initial sulfonylation step. Subsequent
alkylation, followed by a one-pot, β-elimination/double aza-Michael reaction yields
functionalized 1,2,5-thiadiazepane 1,1-dioxide scaffolds.
Overall, this facile approach utilizes the β-elimination of the alcohol in the serine-moiety
present in 2 to generate a second Michael acceptor armed for the titled protocol. This later
sequence has its roots in the biosynthesis of tryptophan, which utilizes tryptophan synthase,
a pyridoxal phosphate-containing bifunctional enzyme (PLP), to catalyze an elimination/
16
indole addition pathway on serine. Taken collectively, the route employs two click
reactions and a double aza-Michael cyclization step that is optimized using a MACOS
17
platform (cy-click).
Initial efforts focused on the preparation of vinyl sulfonamide 3, obtained in a simple three-
step sequence from serine methyl ester (Scheme 2). Racemic serine methyl ester was
18
protected as a TBS-ether, to which 2-chloroethanesulfonyl chloride was added, providing
2, which was subsequently benzylated under mild conditions to provide 3. A facile pathway
19,20
to 5 was next envisioned to proceed via elimination of the TBS-ether moiety
to generate
4, followed by a double aza-Michael reaction of an amine. Towards this goal, treatment of 3
with TBAF in tetrahydrofuran, in the absence of nucleophile, resulted in the production of
elimination product 4 in 30% yield. Use of cesium carbonate in acetonitrile further promoted
the elimination pathway to yield 4 in 91%. Addition of cyclopentylamine to 4 in acetonitrile
gave 5 in moderate yield (Scheme 2).
Further studies showed that while 4 can be isolated, a one-pot operation consisting of adding
base and cyclopentylamine to a stirring solution of 3, directly afforded the double aza-
Michael product 5a (Table 1). Optimization of various parameters, including solvent,
temperature and base (equiv), revealed that cesium carbonate in acetonitrile at 40 °C gave
nice conversion (Table 1, entries 1–6). However, use of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) as base (Table 1, entries 7–10) improved the yield significantly, with optimized
conditions established using 0.1 equivalent of DBU in methanol at 40 °C for one hour (entry
10).
With the optimized conditions in hand, a demonstration set of 1,2,5-thiadiazepane 1,1-
dioxides were synthesized using linear (Table 2, entries 1, 2, 5, and 6) as well as
benzylamines (Table 2, entries 3, 4, and 7). Within the aliphatic amines, several linear
amines worked well. Not surprisingly, more sterically encumbered tert-butylamine failed to
undergo the double aza-Michael reaction, but instead simple Michael addition of methanol
was obtained in roughly 40% yield.
In efforts to utilize the double aza-Michael strategy in library synthesis, it was deemed
imperative that the scaffold be synthesized efficiently and quickly on a larger scale. This
seemed achievable by combining microwave heating and flow chemistry using the MACOS
(microwave-assisted, continuous-flow organic synthesis) platform. Using this synthetic
technique, one set of optimization experiments is all that is necessary to obtain, and in
theory, any amount of desired product can be generated by scaling the synthesis out, rather
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Zang et al.
Page 3
than scaling it up, which involves extensive reaction reoptimization at each growing scale in
the process.
The optimal bench conditions in Table 1 (entry 10) were initially employed in MACOS,
resulting in a mixture with the mono aza-Michael product as the major component. A more
complex product mixture was obtained when additional heat was applied in order to push
the reaction in methanol. Use of higher-boiling n-butanol did provide the double aza-
Michael product, but transesterification was also observed (5–15%). This problem was
circumvented by the use of propan-2-ol leading to products 5a and 5c in 60% (0.5 g) and
71% (0.7 g), respectively (Table 2, entries 8 and 9). These proof-of-concept experiments
illustrate that we can obtain any amount of product we require for library elaboration using
scale-out in MACOS.
Successes with the double aza-Michael reaction led us to explore a sequential, one-pot
process employing an additional in situ Huisgen 1,3-dipolar cycloaddition click reaction, to
21
terminate the route. The propargyl-substituted sulfonamide was synthesized in 79% yield
(over three steps) using potassium carbonate in the presence of sodium iodide in N,N-
dimethylformamide. The double aza-Michael reaction was performed using the optimal
bench conditions (Table 1, entry 10), and the resultant mixture was concentrated in the
reaction vial and reconstituted in dichloromethane, after which the azide and copper(I)
iodide were added, and stirred at room temperature for 16 hours. Efforts aimed at
simplifying the procedure by using same solvent for both double aza-Michael and Huisgen
cycloaddition reactions, either gave a lower yield (in CH Cl ) or multiple products (in
2
2
MeOH). While additional efforts continue toward this goal, a set of reactions was carried out
using a sequential, one-pot procedure to afford the desired products in good yields (Table 3).
In conclusion, we have developed a double aza-Michael procedure using MACOS to
synthesize 1,2,5-thiadiazepane 1,1-dioxides that involves minimal chromatography and is
step-efficient. Application of flow chemistry for optimization and scale-out sets the stage for
library synthesis. Further investigations have led to a sequential, one-pot elimination, double
aza-Michael and Huisgen cycloaddition for the synthesis of triazolated 1,2,5-thiadiazepane
1,1-dioxides. Subsequent research will be focused on library synthesis using this protocol.
All compounds synthesized have been submitted to the NIH Molecular Library Small
Molecule Repository (MLSMR) for distribution within the MLSCN, which will allow for
extensive biological screening.
All reactions were carried out without inert atmosphere. Stirring was achieved with oven-
dried magnetic stir bars. Solvents were either purchased through Sigma-Aldrich or purified
22
by passage through the Solv-Tek purification system employing activated Al O . Et N
2
3
3
was purified by passage over basic Al O or distilled over CaH and stored over KOH.
2
3
2
Flash column chromatography was performed with Sorbent Technologies (30930M-25,
Silica Gel 60A, 40–63 µm). TLC was performed on silica gel 60F254 plates (EM-5717,
1
13
Merck). Deuterated solvents were purchased from Cambridge Isotope laboratories. H,
C
NMR spectra were recorded on a Bruker DRX-400 spectrometer operating at 400 MHz, 100
MHz, respectively, as well as a Bruker DRX-500 spectrometer operating at 500 MHz, 125
MHz, respectively, and a Avance AV-III 500 with a dual carbon/proton (CPDUL) cryoprobe
operating at 500 MHz, 125 MHz, respectively. High-resolution mass spectrometry (HRMS)
measurements were obtained on a VG Instrument ZAB double-focusing mass spectrometer.
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Zang et al.
Page 4
Generation of 1,2,5-Thiadiazepane 1,1-Dioxides 5 via Double Aza-Michael
on Bench; General Procedure
To the tertiary sulfonamide 3 (0.2 mmol, 1 equiv) was added MeOH (0.1 M), amine (0.22
mmol, 1.1 equiv), and DBU (0.04 mmol, 0.2 equiv). The solution was stirred at 40 °C for 1
h, the solvent was evaporated and the crude product was purified by flash column
chromatography on silica gel (hexane–EtOAc, 3:1).
Methyl 5-Cyclopentyl-2-(4-methylbenzyl)-1,2,5-thiadiazepane-3-carboxylate
1,1-Dioxide (5a)
Yield: 57 mg (75%); colorless oil.
−1
FTIR (thin film): 2951, 2866, 1734, 1329, 1142 cm
.
1
H NMR (500 MHz, CDCl ): δ = 7.29 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 7.8 Hz, 2 H), 4.79
3
(d, J = 15.0 Hz, 1 H), 4.31 (d, J = 15.0 Hz, 1 H), 3.94–3.86 (m, 1 H), 3.60 (s, 3 H), 3.45 (s, 1
H), 3.43 (d, J = 3.3 Hz, 1 H), 3.23 (d, J = 4.3 Hz, 1 H), 3.22 (d, J = 4.1 Hz, 1 H), 3.11 (ddd,
J = 14.8, 4.1, 4.1 Hz, 1 H), 3.01 (ddd, J = 14.7, 6.7, 6.7 Hz, 1 H), 2.76–2.67 (m, 1 H), 2.35
(s, 3 H), 1.67 (m, 4 H), 1.48–1.38 (m, 2 H), 1.35–1.20 (m, 2 H).
13
C NMR (126 MHz, CDCl ): δ = 170.6, 137.8, 132.8, 129.2, 129.0, 63.3, 57.0, 55.0, 54.6,
3
53.6, 52.3, 48.7, 30.8, 30.2, 23.6, 23.5, 21.1.
+
HRMS (TOF MS ES+): m/z calcd for C H N O S (M + H) : 381.1848; found: 381.1851.
19 29
2 4
Methyl 2-(4-Methoxybenzyl)-5-octyl-1,2,5-thiadiazepane-3-carboxylate 1,1-
Dioxide (5b)
Yield: 57 mg (65%); colorless oil.
−1
FTIR (thin film): 2951, 2928, 2854, 1736, 1514, 1329, 1248, 1142 cm
.
1
H NMR (500 MHz, CDCl ): δ = 7.34–7.29 (m, 2 H), 6.90–6.84 (m, 2 H), 4.67 (d, J = 14.9
3
Hz, 1 H), 4.34 (d, J = 14.9 Hz, 1 H), 3.90 (dd, J = 10.5, 6.5 Hz, 1 H), 3.81 (s, 3 H), 3.57 (s, 3
H), 3.47 (dd, J = 14.7, 10.6 Hz, 1 H), 3.36 (dd, J = 14.7, 6.5 Hz, 1 H), 3.26–3.22 (m, 2 H),
3.02 (dd, J = 7.8, 3.9 Hz, 2 H), 2.46–2.40 (m, 2 H), 1.41–1.17 (m, 12 H), 0.90 (t, J = 7.0 Hz,
3 H).
13
C NMR (126 MHz, CDCl ): δ = 170.5, 159.4, 130.4, 127.8, 113.8, 57.1, 55.8, 55.3, 55.3,
3
54.8, 53.3, 52.3, 50.0, 31.8, 29.4, 29.3, 27.7, 27.1, 22.7, 14.1.
+
HRMS (TOF MS ES+): m/z calcd for C H N O S (M + H) : 441.2423; found: 441.2419.
22 37
2 5
Methyl 2-Benzyl-5-butyl-1,2,5-thiadiazepane-3-carboxylate 1,1-Dioxide (5c)
Yield: 53 mg (74%); light yellow solid; mp 58 °C.
−1
FTIR (thin film): 2954, 2931, 2869, 1737, 1454, 1330, 1143, 1072, 744, 703 cm
.
1
H NMR (300 MHz, CDCl ): δ = 7.38–7.36 (m, 2 H), 7.32–7.27 (m, 3 H), 4.72 (d, J = 15.3
3
Hz, 1 H), 4.32 (d, J = 15.0 Hz, 1 H), 3.93 (m, 1 H), 3.49 (s, 3 H), 3.43–3.27 (m, 2 H), 3.22–
3.20 (m, 2 H), 2.99 (m, 2 H), 2.44 (t, J = 7.2 Hz, 2 H), 1.37–1.32 (m, 2 H), 1.26–1.21 (m, 2
H), 0.89 (t, J = 7.2 Hz, 3 H).
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Zang et al.
Page 5
13
C NMR (75 MHz, CDCl ): δ = 170.3, 135.9, 128.9, 128.4, 127.9, 57.4, 55.8, 55.2, 54.7,
3
53.7, 52.1, 49.3, 29.8, 20.1, 13.9.
+
HRMS (TOF MS ES+): m/z calcd for C H N O S (M) : 354.1613; found: 354.1606.
17 26
2 4
Methyl 2-Benzyl-5-(4-fluorobenzyl)-1,2,5-thiadiazepane-3-carboxylate 1,1-
Dioxide (5d)
Yield: 56 mg (69%); yellow oil.
−1
FTIR (thin film): 2951, 2843, 1732, 1508, 1329, 1219, 1142, 771, 743, 704 cm
.
1
H NMR (500 MHz, CDCl ): δ = 7.44–7.35 (m, 5 H), 7.10–7.05 (m, 2 H), 7.02–6.94 (m, 2
3
H), 4.94 (d, J = 15.1 Hz, 1 H), 4.32 (d, J = 15.1 Hz, 1 H), 3.86 (dd, J = 10.5, 6.6 Hz, 1 H),
3.59–3.55 (m, 1 H), 3.57 (s, 3 H), 3.52–3.46 (m, 2 H), 3.34 (dd, J = 14.7, 6.6 Hz, 1 H), 3.25–
3.22 (m, 2 H), 3.04–2.96 (m, 2 H).
13
1
4
C NMR (126 MHz, CDCl ): δ = 170.2, 162.1 (d, J = 245.9 Hz), 135.9, 133.7 (d, J
C,F
3
C,F
3
2
= 3.1 Hz), 129.9 (d, J = 8.0 Hz), 129.3, 128.7, 128.2, 115.4 (d, J = 21.3 Hz), 59.1,
C,F
C,F
57.1, 55.7, 55.1, 53.6, 52.3, 49.7.
+
HRMS (TOF MS ES+): m/z calcd for C H FN O S (M + H) : 407.1441; found:
20 24
2 4
407.1438.
Methyl 2-(4-Chlorobenzyl)-5-(4-methoxybenzyl)-1,2,5-thiadiazepane-3-
carboxylate 1,1-Dioxide (5e)
Yield: 74 mg (82%); yellow oil.
FTIR (thin film): 2951, 2932, 2837, 1736, 1610, 1512, 1329, 1246, 1144, 1078, 1014, 837,
−1
741 cm
.
1
H NMR (500 MHz, CDCl ): δ = 7.36 (s, 4 H), 7.10 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.7
3
Hz, 2 H), 4.77 (d, J = 15.3 Hz, 1 H), 4.36 (d, J = 15.3 Hz, 1 H), 3.88 (dd, J = 10.4, 6.7 Hz, 1
H), 3.82 (s, 3 H), 3.66 (d, J = 12.4 Hz, 1 H), 3.58 (d, J = 13.0 Hz, 1 H), 3.53 (s, 3 H), 3.45
(dd, J = 14.4, 10.5 Hz, 1 H), 3.32 (dd, J = 14.5, 6.6 Hz, 1 H), 3.25–3.14 (m, 2 H), 3.03–2.90
(m, 2 H).
13
C NMR (126 MHz, CDCl ): δ = 170.0, 159.0, 134.6, 133.9, 130.4, 130.0, 129.7, 128.7,
3
113.9, 60.6, 57.7, 55.9, 55.3, 54.8, 52.9, 52.3, 49.5.
+
HRMS (TOF MS ES+): m/z calcd for C H ClN O S (M + H) : 453.1251; found:
21 26
2 5
453.1242.
Methyl 2-(4-Chlorobenzyl)-5-phenethyl-1,2,5-thiadiazepane-3-carboxylate
1,1-Dioxide (5f)
Yield: 67 mg (77%); yellow oil.
FTIR (thin film): 2951, 2930, 2847, 1738, 1491, 1331, 1142, 1082, 1014, 752, 739, 700
−1
cm
.
1
H NMR (500 MHz, CDCl ): δ = 7.36–7.30 (m, 2 H), 7.30–7.22 (m, 5 H), 7.19–7.14 (m, 2
3
H), 4.31 (d, J = 15.4 Hz, 1 H), 4.23 (d, J = 15.4 Hz, 1 H), 3.91 (dd, J = 10.5, 6.7 Hz, 1 H),
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Zang et al.
Page 6
3.51 (s, 3 H), 3.48 (dd, J = 14.5, 10.6 Hz, 1 H), 3.39 (dd, J = 14.5, 6.7 Hz, 1 H), 3.24–3.19
(m, 2 H), 3.12–2.99 (m, 2 H), 2.95–2.83 (m, 2 H), 2.81– 2.73 (m, 2 H).
13
C NMR (126 MHz, CDCl ): δ = 170.0, 139.4, 134.5, 133.7, 130.2, 128.6, 128.6, 128.5,
3
126.4, 58.2, 57.9, 56.2, 54.3, 52.9, 52.3, 49.9, 34.4.
+
HRMS (TOF MS ES+): m/z calcd for C H ClN O S (M + H) : 437.1302; found:
21 26
2 4
437.1281.
Methyl 2-(4-Fluorobenzyl)-5-isobutyl-1,2,5-thiadiazepane-3-carboxylate 1,1-
Dioxide (5g)
Yield: 48 mg (65%); colorless oil.
−1
FTIR (thin film): 2955, 2870, 1738, 1510, 1329, 1221, 1146, 1078, 754 cm
.
1
H NMR (500 MHz, CDCl ): δ = 7.62–7.32 (m, 2 H), 7.19–6.91 (m, 2 H), 4.69 (d, J = 15.1
3
Hz, 1 H), 4.38 (d, J = 15.1 Hz, 1 H), 3.92 (dd, J = 10.6, 6.5 Hz, 1 H), 3.55 (s, 3 H), 3.48 (dd,
J = 14.7, 10.7 Hz, 1 H), 3.33 (dd, J = 14.7, 6.5 Hz, 1 H), 3.28–3.22 (m, 2 H), 3.04–2.99 (m,
2 H), 2.28–2.18 (m, 2 H), 1.68–1.62 (m, 1 H), 0.86 (d, J = 6.6 Hz, 6 H).
13
1
4
C NMR (126 MHz, CDCl ): δ = 170.2, 162.5 (d, J = 246.7 Hz), 131.8 (d, J = 3.2
3
C,F
C,F
3
2
Hz), 130.7 (d, J = 8.2 Hz), 115.4 (d, J = 21.5 Hz), 63.9, 57.4, 56.5, 54.9, 53.0, 52.3,
C,F
C,F
50.4, 26.8, 20.5, 20.5.
+
HRMS (TOF MS ES+): m/z calcd for C H FN O S (M + H) : 373.1597; found:
17 26
2 4
373.1595.
Methyl 5-Benzyl-2-[4-(trifluoromethyl)benzyl]-1,2,5-thiadiazepane-3-
carboxylate 1,1-Dioxide (5h)
Yield: 72 mg (79%); yellow oil.
−1
FTIR (thin film): 2953, 2930, 2843, 1740, 1325, 1163, 1144, 1122, 1067, 735, 700 cm
.
1
H NMR (500 MHz, CDCl ): δ = 7.64 (d, J = 8.1 Hz, 2 H), 7.56 (d, J = 8.1 Hz, 2 H), 7.36–
3
7.28 (m, 3 H), 7.25–7.21 (m, 2 H), 4.85 (d, J = 15.6 Hz, 1 H), 4.47 (d, J = 15.6 Hz, 1 H),
3.95 (dd, J = 10.4, 6.6 Hz, 1 H), 3.77 (d, J = 13.2 Hz, 1 H), 3.69 (d, J = 13.2 Hz, 1 H), 3.50
(s, 3 H), 3.49 (dd, J = 14.4, 10.5 Hz, 1 H), 3.35 (dd, J = 14.4, 6.6 Hz, 1 H), 3.29–3.19 (m, 2
H), 3.08–2.94 (m, 2 H).
13
2
C NMR (126 MHz, CDCl ): δ = 169.8, 140.3, 138.0, 130.2 (q, J = 32.5 Hz), 129.1,
3
C,F
1
3
128.6, 128.5, 127.8, 126.2 (q, J = 272.1 Hz), 125.4 (q, J = 3.7 Hz), 61.6, 58.0, 56.1,
C,F
C,F
54.7, 52.9, 52.3, 49.7.
+
HRMS (TOF MS ES+): m/z calcd for C H F N O S (M + H) : 457.1409; found:
21 24 3
2 4
457.1406.
Scale-Out Synthesis of 1,2,5-Thiadiazepane 1,1-Dioxides 5a and 5c Utilizing
MACOS Flow Platform; General Procedure
A stock solution containing the respective sulfonamide 3a, 3c (2.4 or 2.8 mmol, 1.0 equiv),
DBU (2.4 or 2.8 mmol, 1.0 equiv), and amine (2.8 or 3.3 mmol, 1.2 equiv) in i-PrOH (0.3
M) was prepared and loaded into Hamilton gas-tight syringe (10 mL). The tubing was
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Zang et al.
Page 7
primed with i-PrOH and the syringe was connected to the reactor system with the aid of
Microtight™ fittings. A sealed collection vial was connected to the system, where a
pressurized airline (75 psi) was attached to create backpressure. A Harvard 22 syringe pump
was set to deliver the reaction solution at a rate of 75 µL/min. The single mode microwave
was programmed to heat constantly with the power level controlled manually so as to keep
the temperature constant at the specified levels (130 W, ~100 °C). The effluent from the
1
reactor was fed into a sealed vial and analyzed directly by H NMR spectroscopy
immediately after the reaction. The crude reaction mixture was collected and the product
was purified by flash chromatography (EtOAc–n-pentane, 2:8) to afford the desired sultam
5a (534 mg, 60%, greenish oil) and 5c (700 mg, 71%, light yellow solid).
Triazolated 1,2,5-Thiadiazepane 1,1-Dioxides 7; General Procedure
To the tertiary sulfonamide 6 (0.2 mmol, 1 equiv) was added MeOH (0.1 M), amine (0.24
mmol, 1.2 equiv), and DBU (0.04 mmol, 0.2 equiv). The solution was stirred at 40 °C for 1
h. The solvent was removed under a Techne sample concentrator. The residue was further
dried under high vacuum pump for 2 h. To the residue was added CH Cl (0.1 M), azide
2
2
(0.4 mmol, 2 equiv), CuI (0.04 mmol, 0.2 equiv) and stirred overnight. The solvent was
removed under a Techne sample concentrator and the crude product was purified by flash
column chromatography on silica gel (hexane–EtOAc, 2:1).
Methyl 5-Butyl-2-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]methyl}-1,2,5-
thiadiazepane-3-carboxylate 1,1-Dioxide (7a)
Yield: 45 mg (61%); yellow oil.
−1
FTIR (thin film): 2953, 2930, 1747, 1329, 1144, 779, 758 cm
.
1
H NMR (400 MHz, CDCl ): δ = 7.61 (s, 1 H), 7.18 (s, 4 H), 5.47 (s, 2 H), 4.74 (d, J = 15.9
3
Hz, 1 H), 4.50 (d, J = 15.9 Hz, 1 H), 4.08 (t, J = 8.5 Hz, 1 H), 3.54 (s, 3 H), 3.43 (d, J = 8.6
Hz, 2 H), 3.24–3.13 (m, 2 H), 3.07–2.93 (m, 2 H), 2.52–2.39 (m, 2 H), 2.35 (s, 3 H), 1.43–
1.33 (m, 2 H), 1.33–1.20 (m, 2 H), 0.91 (t, J = 7.2 Hz, 3 H).
13
C NMR (126 MHz, CDCl ): δ = 170.3, 144.2, 138.7, 131.5, 129.8, 128.1, 123.2, 58.2,
3
55.8, 54.7, 54.4, 54.0, 52.2, 49.8, 45.7, 29.8, 21.1, 20.2, 13.9.
+
HRMS (TOF MS ES+): m/z calcd for C H N O S (M + H) : 450.2175; found: 450.2160.
21 32
5 4
Methyl 5-Butyl-2-{[1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-1,2,5-
thiadiazepane-3-carboxylate 1,1-Dioxide (7b)
Yield: 51 mg (65%); colorless oil.
−1
FTIR (thin film): 2953, 2860, 1745, 1327, 1143, 775 cm
.
1
H NMR (400 MHz, CDCl ): δ = 7.70 (s, 1 H), 7.37–7.29 (m, 2 H), 7.25 (s, 1 H), 7.18–7.15
3
(m, 1 H), 5.50 (s, 2 H), 4.73 (d, J = 15.9 Hz, 1 H), 4.54 (d, J = 15.9 Hz, 1 H), 4.11 (t, J = 8.5
Hz, 1 H), 3.57 (s, 3 H), 3.46–3.40 (m, 2 H), 3.19 (t, J = 5.2 Hz, 2 H), 3.05–2.96 (m, 2 H),
2.56–2.43 (m, 2 H), 1.46–1.35 (m, 2 H), 1.34–1.22 (m, 2 H), 0.92 (t, J = 7.3 Hz, 3 H).
13
C NMR (126 MHz, CDCl ): δ = 170.2, 144.7, 136.6, 135.0, 130.4, 129.0, 128.0, 126.0,
3
123.5, 58.5, 55.8, 54.9, 54.4, 53.5, 52.3, 49.8, 45.8, 29.8, 20.2, 14.0.
Synthesis (Stuttg). Author manuscript; available in PMC 2012 September 1.

Zang et al.
Page 8
+
HRMS (TOF MS ES+): m/z calcd for C H ClN O S (M + H) : 470.1629; found:
20 29
5 4
470.1630.
Methyl 2-{[1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-5-butyl-1,2,5-
thiadiazepane-3-carboxylate 1,1-Dioxide (7c)
Yield: 63 mg (73%); yellow oil.
−1
FTIR (thin film): 2953, 2930, 2860, 1747, 1329, 1144, 756 cm
.
1
H NMR (400 MHz, CDCl ): δ = 7.73 (s, 1 H), 7.62 (dd, J = 7.9, 1.1 Hz, 1 H), 7.32 (td, J =
3
7.5, 1.2 Hz, 1 H), 7.24 (td, J = 7.8, 1.8 Hz, 1 H), 7.18 (dd, J = 7.6, 1.5 Hz, 1 H), 5.66 (s, 2
H), 4.78 (d, J = 15.9 Hz, 1 H), 4.52 (d, J = 15.9 Hz, 1 H), 4.11 (t, J = 8.5 Hz, 1 H), 3.59 (s, 3
H), 3.44 (d, J = 8.6 Hz, 2 H), 3.26–3.14 (m, 2 H), 3.00 (dt, J = 9.1, 3.3 Hz, 2 H), 2.53–2.36
(m, 2 H), 1.43–1.33 (m, 2 H), 1.30–1.20 (m, 2 H), 0.90 (t, J = 7.3 Hz, 3 H).
13
C NMR (126 MHz, CDCl ): δ = 170.3, 144.1, 134.0, 133.3, 130.5, 130.4, 128.3, 123.7,
3
123.5, 58.3, 55.8, 54.7, 54.5, 53.9, 52.4, 49.9, 45.6, 29.8, 20.2, 14.0.
+
HRMS (TOF MS ES+): m/z calcd for C H BrN O S (M + H) : 514.1124; found:
20 29
5 4
514.1134.
Methyl 5-Benzyl-2-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]methyl}-1,2,5-
thiadiazepane-3-carboxylate 1,1-Dioxide (7d)
Yield: 67 mg (83%); yellow oil.
−1
FTIR (thin film): 2951, 2924, 1745, 1329, 1142, 735 cm
.
1
H NMR (400 MHz, CDCl ): δ = 7.61 (s, 1H), 7.36–7.28 (m, 3H), 7.23 (d, J = 7.0 Hz, 2H),
3
7.20–7.12 (m, 4H), 5.50 (s, 2H), 4.89 (d, J = 15.9 Hz, 1H), 4.49 (d, J = 15.9 Hz, 1H), 4.08
(dd, J = 10.1, 6.9 Hz, 1H), 3.67 (d, J = 13.4 Hz, 1H), 3.59 (d, J = 13.4 Hz, 1H), 3.54 (s, 3H),
3.50 (dd, J = 14.7, 10.1 Hz, 1H), 3.44 (dd, J = 14.7, 6.9 Hz, 1H), 3.24–3.09 (m, 2H), 3.05–
2.90 (m, 2H), 2.34 (s, 3H).
13
C NMR (126 MHz, CDCl ): δ = 170.2, 144.1, 138.8, 138.0, 131.5, 129.8, 128.6, 128.5,
3
128.1, 127.6, 123.2, 59.2, 58.1, 55.9, 54.5, 54.1, 52.3, 49.1, 45.5, 21.1.
+
HRMS (TOF MS ES+): m/z calcd for C H N O S + Na (M + Na) : 506.1838; found:
24 29
5 4
506.1838.
Methyl 5-Benzyl-2-{[1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-1,2,5-
thiadiazepane-3-carboxylate 1,1-Dioxide (7e)
Yield: 55 mg (65%); colorless oil.
−1
FTIR (thin film): 2951, 2833, 1747, 1327, 1142, 737 cm
.
1
H NMR (400 MHz, CDCl ): δ = 7.70 (s, 1 H), 7.38–7.24 (m, 8 H), 7.16 (d, J = 7.1 Hz, 1
3
H), 5.52 (s, 2 H), 4.88 (d, J = 16.0 Hz, 1 H), 4.54 (d, J = 15.9 Hz, 1 H), 4.11 (dd, J = 10.1,
7.0 Hz, 1 H), 3.72 (d, J = 13.3 Hz, 1 H), 3.64 (d, J = 13.5 Hz, 1 H), 3.56 (s, 3 H), 3.51 (dd, J
= 14.9, 10.2 Hz, 1 H), 3.45 (dd, J = 14.7, 7.0 Hz, 1 H), 3.23–3.12 (m, 2 H), 3.05–2.94 (m, 2
H).
Synthesis (Stuttg). Author manuscript; available in PMC 2012 September 1.

Zang et al.
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13
C NMR (126 MHz, CDCl ): δ = 170.1, 144.6, 138.0, 136.5, 135.1, 130.4, 129.0, 128.6,
3
128.5, 128.0, 127.6, 126.0, 123.5, 59.5, 58.5, 56.0, 54.4, 53.5, 52.4, 49.2, 45.6.
+
HRMS (TOF MS ES+): m/z calcd for C H ClN O S + Na (M + Na) : 526.1292; found:
23 26
5 4
526.1281.
Methyl 5-Benzyl-2-{[1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-1,2,5-
thiadiazepane-3-carboxylate 1,1-Dioxide (7f)
Yield: 69 mg (74%); yellow oil.
−1
FTIR (thin film): 2951, 2841, 1744, 1329, 1142, 737 cm
.
1
H NMR (400 MHz, CDCl ): δ = 7.74 (s, 1 H), 7.62 (d, J = 7.8 Hz, 1 H), 7.32 (m, 4 H),
3
7.25–7.17 (m, 4 H), 5.69 (s, 2 H), 4.93 (d, J = 15.9 Hz, 1 H), 4.52 (d, J = 15.9 Hz, 1 H), 4.11
(dd, J = 10.1, 6.9 Hz, 1 H), 3.67 (d, J = 13.4 Hz, 1 H), 3.60 (d, J = 13.4 Hz, 1 H), 3.59 (s, 3
H), 3.52 (dd, J = 14.8, 10.2 Hz, 1 H), 3.46 (dd, J = 14.9, 7.1 Hz, 1 H), 3.26–3.11 (m, 2 H),
3.06–2.92 (m, 2 H).
13
C NMR (126 MHz, CDCl ): δ = 170.2, 144.0, 138.0, 133.9, 133.3, 130.5, 130.4, 128.6,
3
128.5, 128.2, 127.6, 123.7, 123.5, 59.1, 58.2, 55.9, 54.6, 54.0, 52.4, 49.2, 45.4.
+
HRMS (TOF MS ES+): m/z calcd for C H BrN O S + Na (M + Na) : 570.0787; found:
23 26
5 4
570.0790.
Methyl 5-(2-Hydroxyethyl)-2-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-
yl]methyl}-1,2,5-thiadiazepane-3-carboxylate 1,1-Dioxide (7g)
Yield: 58 mg (81%); yellow oil.
−1
FTIR (thin film): 3381, 2951, 2926, 1740, 1329, 1142, 779, 758 cm
.
1
H NMR (400 MHz, acetone-d ): δ = 8.00 (s, 1 H), 7.27 (d, J = 7.7 Hz, 2 H), 7.19 (d, J = 7.6
6
Hz, 2 H), 5.57 (s, 2 H), 4.85 (d, J = 15.9 Hz, 1 H), 4.44 (d, J = 16.0 Hz, 1 H), 4.17 (dd, J =
10.4, 6.9 Hz, 1 H), 3.53 (s, 3 H), 3.50–3.28 (m, 6 H), 3.19–3.04 (m, 2 H), 3.04–2.92 (m, 1
H), 2.52 (s, 2 H), 2.31 (s, 3 H).
13
C NMR (126 MHz, acetone-d ): δ = 171.2, 144.5, 138.8, 134.0, 130.2, 128.9, 124.6, 60.7,
6
58.1, 57.3, 57.1, 55.4, 54.0, 52.2, 51.2, 45.8, 21.0.
+
HRMS (TOF MS ES+): m/z calcd for C H N OS + Na (M + Na) : 460.1631; found:
19 27
5
460.1632.
Methyl 2-{[1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-
hydroxyethyl)-1,2,5-thiadiazepane-3-carboxylate 1,1-Dioxide (7h)
Yield: 66 mg (87%); yellow oil.
−1
FTIR (thin film): 3433, 2951, 2928, 1742, 1329, 1142, 777 cm
.
1
H NMR (400 MHz, acetone-d ): δ = 8.12 (s, 1 H), 7.45–7.30 (m, 4 H), 5.67 (s, 2 H), 4.86
6
(d, J = 16.0 Hz, 1 H), 4.47 (d, J = 16.0 Hz, 1 H), 4.20 (dd, J = 10.4, 7.0 Hz, 1 H), 3.56 (s, 3
H), 3.52–3.42 (m, 4 H), 3.40–3.32 (m, 1 H), 3.20–3.05 (m, 2 H), 3.03–2.94 (m, 1 H), 2.56 (t,
J = 4.8 Hz, 2 H), 2.09 (s, 1 H).
Synthesis (Stuttg). Author manuscript; available in PMC 2012 September 1.

Zang et al.
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13
C NMR (126 MHz, acetone-d ): δ = 171.2, 144.7, 139.3, 134.9, 131.4, 129.1, 128.8,
6
127.4, 125.0, 60.7, 58.3, 57.5, 57.1, 55.4, 53.4, 52.2, 51.2, 45.8.
+
HRMS (TOF MS ES+): m/z calcd for C H ClN O S + Na (M + Na) : 480.1084; found:
18 24
5 5
480.1088.
Methyl 2-{[1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-
hydroxyethyl)-1,2,5-thiadiazepane-3-carboxylate 1,1-Dioxide (7i)
Yield: 62 mg (73%); yellow oil.
−1
FTIR (thin film): 3385, 2926, 2930, 1734, 1327, 1142, 760 cm
.
1
H NMR (400 MHz, acetone-d ): δ = 8.08 (s, 1 H), 7.68 (d, J = 8.5 Hz, 1 H), 7.41 (t, J = 7.4
6
Hz, 1 H), 7.32 (dd, J = 10.4, 4.7 Hz, 1 H), 7.22 (d, J = 7.5 Hz, 1 H), 5.74 (s, 2 H), 4.89 (d, J
= 16.0 Hz, 1 H), 4.48 (d, J = 15.9 Hz, 1 H), 4.26–4.15 (m, 1 H), 3.59 (s, 3 H), 3.56–3.35 (m,
6 H), 3.18–3.09 (m, 2 H), 3.03–2.96 (m, 1 H), 2.56 (s, 2 H).
13
C NMR (126 MHz, acetone-d ): δ = 171.2, 136.0, 133.9, 131.2, 131.2, 129.6, 129.1,
6
125.2, 123.8, 60.7, 58.2, 57.4, 57.1, 55.4, 54.1, 52.3, 51.2, 45.8.
+
HRMS (TOF MS ES+): m/z calcd for C H BrN O S + Na (M + Na) : 524.0579; found:
18 24
5 5
524.0587.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Financial support of this work was provided by the Institute of General Medical Sciences (P50-GM069663 and
P41-GM076302), NIH K-INBRE funds (D.B., P20 RR016475), and the University of Kansas for an Undergraduate
Research Award (D.B.), and is gratefully acknowledged.
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21. For the recent review on Cu-catalyzed azide-alkyne cycloaddition, see: Meldal M, Tornøe CW.
Chem. Rev. 2008; 108:2952. and references cited therein. [PubMed: 18698735]
22. Grubbs RH, Rosen RK, Timmers FJ. Organometallics. 1996; 15:1518.
Synthesis (Stuttg). Author manuscript; available in PMC 2012 September 1.

Zang et al.
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Scheme 1.
Hetero-Michael pathways using a ‘click, click, cyclize’ strategy
Synthesis (Stuttg). Author manuscript; available in PMC 2012 September 1.

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Page 14
Scheme 2.
The preparation of double aza-Michael precursors
Synthesis (Stuttg). Author manuscript; available in PMC 2012 September 1.

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Page 15
Table 1
Optimization of One-Pot Elimination and Double Aza-Michael Reactiona
Entry
Base
Temp, time
Solvent
b
Yield (%)
1
Cs2CO3 (1 equiv)
Cs2CO3 (1 equiv)
Cs2CO3 (1 equiv)
Cs2CO3 (1 equiv)
Cs2CO3 (2 equiv)
Cs2CO3 (1 equiv)
DBU (0.5 equiv)
DBU (0.1 equiv)
DBU (0.1 equiv)
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
60 °C, 12 h
60 °C, 12 h
40 °C, 12 h
r.t., 12 h
MeCN
CH2Cl2
MeOH
MeCN
MeCN
DMF
50
44
0
2
3
4
5
6
7
8
9
43
32
42
23
30
69
75
MeCN
DMF
40 °C, 1 h
r.t., 12 h
MeOH
MeOH
10 DBU (0.1 equiv)
40 °C, 1 h
a
A solution of compound 3a (1 equiv) and cyclopentylamine (1.1 equiv) in solvent (0.1 M) was added base and stirred at the indicated temperature
and time.
b
Isolated yields following silica gel chromatography.
Synthesis (Stuttg). Author manuscript; available in PMC 2012 September 1.

Zang et al.
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Table 2
Synthesis of 1,2,5-Thiadiazepane 1,1-Dioxides
R1
MeO
H
R2
Entry
Product
Yield (%)
1
2
3
4
5
6
7
n-C8H17
n-Bu
5b
5c
5d
5e
5f
65
74
69
82
77
65
79
H
4-FC6H4CH2
4-MeOC6H4CH2
PhCH2CH2
i-Bu
Cl
Cl
F
5g
5h
CF3
Me
Bn
a
c-C5H9
a
a
8
5a
60
71
a
H
n-Bu
a
a
9
5c
a
Performed using the following MACOS conditions: 3a/3c (1.0 equiv), DBU (1.0 equiv), amine (1.2 equiv), i-PrOH (0.3 M), 75 µL/min, 100 °C,
130 W.
Synthesis (Stuttg). Author manuscript; available in PMC 2012 September 1.

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Table 3
Sequential, One-Pot Elimination, Double Aza-Michael and Huisgen 1,3-Dipolar Cycloaddition
R1
R2
Entry
Product
7a
Yield (%)
1
2
3
4
5
6
7
8
9
n-Bu
4-MeC6H4CH2
3-ClC6H4CH2
2-BrC6H4CH2
4-MeC6H4CH2
3-ClC6H4CH2
2-BrC6H4CH2
4-MeC6H4CH2
3-ClC6H4CH2
2-BrC6H4CH2
61
65
73
83
65
74
81
87
73
n-Bu
7b
n-Bu
7c
Bn
7d
Bn
7e
Bn
7f
HOCH2CH2
HOCH2CH2
HOCH2CH2
7g
7h
7i
Synthesis (Stuttg). Author manuscript; available in PMC 2012 September 1.