Synthesis of an isoindoline-annulated, tricyclic sultam library via microwave-assisted, continuous-flow organic synthesis (MACOS)

Article abstract of DOI:10.1055/s-0031-1289791

A microwave-assisted, continuous-flow organic synthesis (MACOS) protocol for the synthesis of an isoindoline-annulated, tricyclic sultam library, utilizing a Heck-aza-Michael (HaM) strategy, is reported. This sequence involves a Heck reaction on vinylsulfonamides with batch microwave heating followed by a one-pot, sequential intramolecular aza-Michael cyclization/Boc-deprotection using MACOS. Subsequent cyclization with either 1,1-carbonyldiimidazole or chloromethyl pivalate using MACOS provided an array of tricyclic sultams. This efficient three-step protocol requires only a few hours to produce the target sultams starting from simple starting materials. Using this strategy, a 38-member library of isoindoline-annulated sultams was generated in good to excellent overall yields (53-87%). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289791

SPECIAL TOPIC
▌2547
special topic
Synthesis of an Isoindoline-Annulated, Tricyclic Sultam Library via
Microwave-Assisted, Continuous-Flow Organic Synthesis (MACOS)
MACOS Synthesis of a Tricyclic Sultam Library
Farman Ullah,a,c Qin Zang,b,c Salim Javed,b,c Patrick Porubsky,c Benjamin Neuenswander,c Gerald H. Lushington,b,c
Paul R. Hanson,*b,c Michael G. Organ*a,c
a
Department of Chemistry, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
Fax +1(416)7365936; E-mail: organ@yorku.ca
b
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
c
The University of Kansas Center for Chemical Methodologies and Library Development (KU-CMLD), Del Shankel Structural Biology Center,
2034 Becker Drive, Lawrence, KS 66047-3761, USA
Fax +1(785)8645396; E-mail: phanson@ku.edu
Received: 17.04.2012; Accepted: 11.05.2012
examples of biologically active sultams include benz-
Abstract: A microwave-assisted, continuous-flow organic synthe-
oxathiazepine 1,1-dioxides10 as glucokinase activators
sis (MACOS) protocol for the synthesis of an isoindoline-annulat-
(type II diabetes), novel benzodithiazine dioxides11 with
ed, tricyclic sultam library, utilizing a Heck–aza-Michael (HaM)
strategy, is reported. This sequence involves a Heck reaction on vi-
both antiviral and anticancer activities, brinzolamide12 for
nylsulfonamides with batch microwave heating followed by a one- the treatment of glaucoma, the COX-2 inhibitors
ampiroxicam13 and S-2474,14 selective inhibitors of cal-
pot, sequential intramolecular aza-Michael cyclization/Boc-deprot-
ection using MACOS. Subsequent cyclization with either 1,1′-car-
bonyldiimidazole or chloromethyl pivalate using MACOS provided
of benzodithiazine dioxides11 displaying anti-HIV-1 ac-
an array of tricyclic sultams. This efficient three-step protocol re-
quires only a few hours to produce the target sultams starting from
simple starting materials. Using this strategy, a 38-member library
of isoindoline-annulated sultams was generated in good to excellent
overall yields (53–87%).
pain I,15 the antiepileptic agent sulthiame,16 and a number
tivity. This heightened activity profile has guided the
present study.
Diversity-oriented synthesis (DOS) has emerged as an ef-
fective strategy to synthesize large libraries of biological-
ly relevant small heterocycles for high throughput
screening.17 The need for new diverse heterocyclic probe
collections has prompted the development of a variety of
methodologies and protocols for the generation of diverse
sultam collections. These efforts include recently reported
protocols such as ‘Click, Cyclize’ to diversify benzoxathi-
azepine 1,1-dioxides,7c,f,18 ‘Click, Click, Cyclize’,7a,19
complementary ambiphile pairing (CAP),19 reagent-based
DOS,20 and ‘Click, Click, Cy-Click’.7b,21 The MACOS
platform was utilized in these strategies for the multigram
synthesis of building blocks that were further diversified
by alkylation and substitution reactions to generate skele-
tal and stereochemically diversified sultam libraries
(Scheme 1).7 Building on these reports, we herein report
the utilization of a MACOS platform for development of
a Heck–aza-Michael (HaM) strategy for the efficient syn-
thesis of a 38-member isoindoline sultam library.
Key words: MACOS, continuous flow, sultams, Heck reaction,
aza-Michael addition, isoindolines
Microwave-assisted organic synthesis (MAOS) has had a
significant impact on organic and medicinal chemistry by
reducing reaction times dramatically, producing cleaner
product mixtures, and making high-energy transforma-
tions routine that might otherwise be avoided.1 Recently,
microwave technology has also been applied to flowed
reactions2,3 to gain the full advantage of working in flow;
that is, reactions should proceed to a high degree of com-
pletion during the time that any plug of flowing reactants
resides in the reaction tube. The merging of these two
technologies, which is called microwave-assisted contin-
uous-flow organic synthesis, or MACOS, offers many ad-
vantages in synthetic chemistry. Most prominently,
successes in cross-coupling reactions,4 natural product
synthesis,5 in situ generations of reactive intermediates,6
scale-out production, and library synthesis have elevated
this powerful technology, aiding in early stage drug dis-
covery.7
The batch HaM strategy developed previously to prepare
the target scaffold required several days to carry out.21 To
further optimize this method, we combined microwave
heating and flow. Initial investigation focused on the de-
velopment and optimization of the corresponding Heck
and aza-Michael elements of this strategy. The electro-
philes 1 for the Heck coupling were prepared readily from
commercially available 2-chloroethanesulfonyl chloride
with a variety of alkyl and aryl amines.21 Similarly, the
nucleophilic partners 2 were generated from commercial-
ly available (2-bromophenyl)methanamine derivatives or
by reduction of the corresponding cyanides.22 The prima-
Sulfonamides, which have rich chemical and biological
profiles, are of interest in drug discovery.8 In particular,
attention has been directed toward cyclic sulfonamides,
also known as sultams, that, while not found in nature, ex-
hibit a wide spectrum of activity.9 The most well-known
SYNTHESIS 2012, 44, 2547–2554
Advanced online publication: 04.07.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1289791; Art ID: SS-2012-C0292-ST
© Georg Thieme Verlag Stuttgart · New York

2548
F. Ullah et al.
SPECIAL TOPIC
MACOS
R1
O
R3
O
O
O
O
O
R4
S
N
S
R2
OH
S
NH
(i) alkylation
N
R1
R1
H
F
F
(ii) substitution
F
O
O
R2
R2
multigram scale-out
R3
MACOS
O
(i)
(5 equiv)
(ii) SiO2
NH
R1
O
O
O
O
R1
R2
O
R3
S
N
S
F
R1
S
O
N
N
N
H
+
R2
O
F
F
O
R2
multigram quantities
of building blocks
all stereoisomers
MACOS
O
O
O
O
O
O
Ar
S
N
S
S
Ar
COOMe
N
Ar
COOMe
double aza-Michael
N
COOMe
TBSO
NH2
N
R
R
Scheme 1 Scale-out production of sultams via MACOS
ry amine was protected with Boc anhydride23 to avoid po-
lymerization with the vinylsulfonamide during Heck
coupling of 1 with 2 in the next step (see Tables 1 and 2).
Table 1 Optimization of the Microwave-Assisted, Heck Reaction
Conditions
O
O
S
PMB
Initially, we intended to telescope the synthesis of 6 and 7
by combining all steps together and avoiding the isolation
of intermediates. For this, we used the batch microwave to
determine the optimal concentration, temperature, and re-
action time. With some optimization, it was determined
that secondary sulfonamide 3a could be generated in 72%
yield (100% conversion based on 1a) utilizing 10 mol%
Pd(OAc)2 with triphenylphosphane as a catalyst, using 3
equivalents of triethylamine at 180 °C for 5 minutes, and
employing a minimum concentration of 0.5 M (Table 1,
entry 10). Utilizing this optimized protocol we synthe-
sized an array of secondary sulfonamides 3a–w in 54–
79% yield (Table 2).
O
O
N
H
S
PMB
Br
1a
N
H
NHBoc
3a
NHBoc
catalyst, Et3N
DMF, heat
2a
catalyst A: PdCl2(PPh3)2
catalyst B: Pd(OAc)2/Ph3P (1:2)
Entry
Catalyst
(mol%)
Temp
(°C)
Time
(min)
Concn
(M)
Conv.
(%)
1
2
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
A (10)
B (10)
125
150
180
180
200
180
180
180
180
180
20
10
5
0.1
0.1
0.1
0.1
0.1
0.25
0.4
0.5
0.5
0.5
15
60
3
84
After preparing secondary sulfonamides 3a–w (Table 2)
by Heck coupling, we focused on screening different re-
action conditions (Table 3) for the aza-Michael cycliza-
tion and Boc-deprotection to occur in one pot in order to
find reaction conditions suitable for the MACOS plat-
form. Many attempts were made to deprotect the Boc
group by using a variety of bases reported in the
literature24 in order to facilitate the cascade reaction to get
the isoindoline product 5 in a single step without addition-
al reagents; however, all attempts led to aza-Michael cy-
clization product 4 containing the Boc-protected tertiary
amine. Surprisingly, the use of DBU as base in tetrahydro-
furan at room temperature for 24 hours gave no reaction
and only starting material 3a was observed (Table 3, entry
9). The same reaction mixture was further heated at 70 °C
for 7 hours, yet still no progress was observed (Table 3,
entry 10). Further studies revealed that DBU in N,N-di-
methylformamide gave the desired product in excellent
yield (Table 3, entry 8).
4
10
5
86
5
60
6
5
93
7
5
97
8
5
100
100
100 (72a)
9
5
10
5
a Isolated yield after flash chromatography on silica gel.
With the optimized aza-Michael reaction conditions in
hand, we next turned to the Boc-deprotection step. Use of
trifluoroacetic acid, the most commonly used reagent for
Boc-deprotection,25 in N,N-dimethylformamide at 180 °C
for 1 minute, yielded only starting material (Table 3, entry
11). Attempted deprotection with hydrochloric acid (1.0
Synthesis 2012, 44, 2547–2554
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
MACOS Synthesis of a Tricyclic Sultam Library
2549
Table 2 Preparation of Sulfonamides 3 by the Heck Reactiona
O
O
S
R3
O
O
R1
R2
S
R3
R1
R2
Br
N
H
1
N
H
NHBoc
NHBoc
Pd(OAc)2, Ph3P
Et3N, DMF
180 °C, 5 min
2
3a–w
Product R1 and R2
R3
Yield
Product R1 and R2
R3
Yield
(%)
(%)
3a
3b
3c
3d
3e
3f
R1 = R2 = H
PMB
PCB
72
62
76
67
65
3l
R1 = Me, R2 = H CH(Me)Ph
60
54
69
67
59
R1 = R2 = H
3m
3n
3o
3p
3q
3r
3t
R1 = H, R2 = F
R1 = H, R2 = F
R1 = H, R2 = F
R1 = H, R2 = F
R1 = H, R2 = F
R1 = H,R2 = F
PCB
R1 = R2 = H
Cy
Cy
R1 = R2 = H
CH2Cy
n-C10H21
CH2Cy
n-C10H21
R1 = R2 = H
R1 = R2 = H
3,4-(MeO)2C6H3CH2CH2 78
3,4-(MeO)2C6H3CH2CH2 65
3g
3h
3i
R1 = R2 = H
CH(Me)Ph
PCB
65
55
56
62
CH(Me)Ph
57
65
54
R1 = Me, R2 = H
R1 = Me, R2 = H
R1 = Me, R2 = H
R1 = Me, R2 = H
R1–R2 = OCH2O n-C10H21
Cy
3u
3w
R1–R2 = OCH2O Cy
3j
n-C10H21
R1–R2 = OCH2O 3,4-(MeO)2C6H3CH2CH2 70
3k
3,4-(MeO)2C6H3CH2CH2 79
a Reaction conditions: 1 (1.0 equiv), 2 (1.2 equiv), Pd(OAc)2 (10 mol%), Ph3P (20 mol%), Et3N (3 equiv), DMF (0.5 M), 180 °C, 5 min, mi-
crowave heating.
M) led to a complicated mixture (Table 3, entry 12). The employed at 140 °C (Table 3, entry 13) and full conver-
desired target 5 was produced in 72% conversion when sion was achieved when the temperature was increased to
1.0 equivalent of p-toluenesulfonic acid (p-TsOH) was 180 °C (Table 3, entry 15). When the reaction was carried
O
O
MACOS
MW/batch
S
PMB
O
N
O
O
O
H
S
S
PMB
1a
PMB
N
H
N
H
Br
NHBoc
NBoc
NHBoc
3a
Pd(OAc)2/Ph3P
Et3N, DMF
5 min
DBU, DMF, 110 °C
150 W, flow rate: 70 μL·min–1
80–92%
4
2a
54–79%
p-TsOH, DMF, 135 °C
230 W, flow rate: 30 μL·min–1
MACOS
75–85%
O
O
O
S
MACOS
O
O
N
PMB
N
N
S
N
N
N
PMB
N
H
O
6 60%
NH
O
O
O
5
S
O
Cl
DBU, DMF, 100 °C
80 W, flow rate: 70 μL·min–1
N
PMB
N
7 85%
Scheme 2 Synthesis of the tricyclic isoindoline sultam library via MACOS
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2547–2554

2550
F. Ullah et al.
SPECIAL TOPIC
out with 3.0 equivalents of p-TsOH at 140 °C, there was Initially, both reactions (aza-Michael cyclization and
full conversion with 83% isolated yield (Table 3, entry Boc-deprotection) were run using a single capillary flow
17).
reactor in sequential one pot under the same reaction con-
ditions (50 μL/min, 120 °C, 160 W), but mixtures of com-
pounds 4 and 5 were always observed. In order to
circumvent this issue, reinvestigation of the individual
steps was carried out to deduce which reaction needed a
longer residence time, which could be simply accom-
plished by lowering the flow rate. During these attempts,
it was observed that the first aza-Michael-cyclization step
can be processed successfully with a flow rate of 70
μL/min at 110 °C using 150 watts of power. In addition,
the concentration was found to be less important in this
step as this reaction can be run successfully with any con-
centration from 0.1 M to 1.0 M, with the entire range of
conditions providing a similar isolated yield. However,
the Boc-deprotection step was found to be the slower step
in the sequential one-pot synthesis, and thus required a
slower flow rate (30 μL/min) and slightly higher temper-
ature (135 °C) in order to achieve full conversion of 4 into
5. With this optimization in hand, the reaction sequence
Upon successful optimization of the first two steps in this
sequence, we worked to combine them into a one-pot, se-
quential reaction pathway. This sequence was carried out
using 1 equivalent of DBU, with heating at 120 °C for 1
minute, and subsequent addition of 3 equivalents of p-
TsOH, with heating at 140 °C for 1 minute, to provide 5
with favorable yield and efficiency (Table 3, entry 17). It
should be noted that product 5 produced by this method
could be used in further steps without additional purifica-
tion. The cyclization step using 1,1′-carbonyldiimidazole
(CDI) or chloromethyl pivalate worked smoothly afford-
ing 6 and 7, respectively, in good yields (Scheme 2).
A variety of reactor parameters were next investigated
taking the aforementioned preliminary conditions devel-
oped on the batch microwave into the MACOS platform
(e.g., flow rate, temperature, and power) in order to find a
suitable flow protocol (Scheme 2).
Table 3 Optimization of the Microwave-Assisted, Intramolecular Aza-Michael Cyclization and Boc-Deprotection Reaction Conditions
O
O
O
O
O
O
S
S
PMB
PMB
solvent
S
PMB
N
H
N
H
N
+
H
acid/base
heat
NBoc
NH
NHBoc
3a
4
5
Entry
Reaction conditions
Conversion (%)
4
5
1
2
TBAF, DMF, 180 °C, 1 min
K2PO4, MeOH, 120 °C, 2 min
100
–
–
–
3
Cs2CO3 (10 mol%), DMF–MeOH (5:1), 180 °C, 2 min
DMF, 180 °C, 1 min
100
–
4
–
–
5
Na2CO3, DMF, H2O, 180 °C, 1 min
DBU, DMF, 180 °C, 1 min
100
–
6
100
–
7
DBU, DMF, 140 °C, 1 min
100
–
8
DBU, DMF, 120 °C, 1 min
100 (92a)
–
9
DBU, THF, r.t., 24 h
–
–
–
–
–
–
–
–
–
–
10
11
12
13
14
15
16
17
DBU, THF, 70 °C, 7 h
–
TFA, DMF, 180 °C, 1 min
–
1 M HCl, DMF, 180 °C, 1 min
p-TsOH (1 equiv), DMF, 140 °C, 1 min
p-TsOH (1 equiv), DMF, 160 °C, 1 min
p-TsOH (1 equiv), DMF, 180 °C, 1 min
p-TsOH (3 equiv), DMF, r.t., 72 h
p-TsOH (3 equiv), DMF, 140 °C, 1 min
mixture
72
90
100
–
100 (83a)
a Isolated yield after flash chromatography on silica gel.
Synthesis 2012, 44, 2547–2554
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
MACOS Synthesis of a Tricyclic Sultam Library
2551
was carried out in a one-pot, sequential synthesis. After and 7 in good yield. Overall, the three-step protocol, in-
running the aza-Michael reaction at 110 °C with a flow cluding the Heck coupling, was run successfully in a few
rate of 70 μL/min, 3 equivalents of p-TsOH were added, hours. With these conditions in hand, we produced a 38-
and the conditions were switched for the Boc-deprotec- member library of tricyclic isoindoline sultams in yields
tion (30 μL/min, 135 °C, 230 W), which provided com- ranging from 53% to 87% (Figure 1).
pound 5 in good yield compatible with the results
obtained on the bench. The product 5 was isolated as a
In conclusion, we have developed a one-pot, sequential
HaM strategy in flow for a small library of isoindoline-
brown solid, pure enough to be used in next step after
annulated, tricyclic sultams using a multi-capillary flow
workup with aqueous sodium bicarbonate solution.
reactor that significantly reduces the reaction time, is step-
After successful runs using a single capillary in the flow efficient, and minimizes chromatography. Overall this
reactor, it was equipped with two capillaries in order to three-step protocol, one on the bench and two using
double throughput. Using this double-capillary flow reac- MACOS, efficiently generates the tricyclic sultams 6 and
tor, we moved on to the cyclization step by reaction of 7 in a few hours. These compounds will be evaluated by
isoindoline 5 with 1,1′-carbonyldiimidazole or chloro- our collaborators for biological activity in a variety of bi-
methyl pivalate using a flow rate of 70 μL/min at 100 °C. ological screens, the results of which will be reported in
These two reactions were run in parallel under the same due course.
reaction conditions, which provided the desired sultams 6
O
O
O
O
O
O
O
O
S
S
S
S
N
N
N
N
9
2
N
N
X
N
N
X
X
X
Me
OMe
6a, X = CO, 84%
7a, X = CH2, 70%
6b, X = CO, 56%
7b, X = CH2, 58%
6c, X = CO, 60%
7c, X = CH2, 64%
6d, X = CO, 54%
OMe
O
O
O
O
S
O
O
O
O
S
S
S
N
N
N
N
9
Me
F
N
F
N
N
N
X
2
X
X
X
OMe
6e, X = CO, 70%
7d, X = CH2, 57%
6f, X = CO, 70%
7e, X = CH2, 57%
6g, X = CO, 59%
7f, X = CH2, 60%
6h, X = CO, 63%
7g, X = CH2, 87%
Cl
OMe
O
O
O
O
O
O
O
S
O
S
S
S
N
N
N
F
N
F
F
F
N
N
X
N
X
N
X
X
6i, X = CO, 60%
7h, X = CH2, 56%
6k, X = CO, 79%
7i, X = CH2, 65%
6l, X = CO, 62%
7j, X = CH2, 76%
6j, X = CO, 62%
Cl
O
O
O
O
O
O
O
S
S
S
O
S
N
N
N
9
N
N
N
X
2
X
N
X
Me
N
X
OMe
6o, X = CO, 74%
7m, X = CH2, 57%
6p, X = CO, 61%
7n, X = CH2, 80%
6m, X = CO, 55%
7k, X = CH2, 53%
6n, X = CO, 85%
7l, X = CH2, 58%
OMe
O
Cl
O
O
S
O
O
O
O
O
O
S
O
O
O
S
S
N
N
2
N
N
N
9
N
X
X
O
O
N
N
X
X
Me
6r, X = CO, 67%
7o, X = CH2, 87%
6s, X = CO, 65%
7p, X = CH2, 67%
OMe
7q, X = CH2, 59%
6q, X = CO, 59%
OMe
Figure 1 Tricyclic isoindoline scaffolds (the reported yields are isolated yields after flash column chromatography on silica gel)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2547–2554

2552
F. Ullah et al.
SPECIAL TOPIC
Isoindoline-Annulated Sultams 6 and 7 Using MACOS; Gener-
al Procedure
All microwave irradiation (MACOS) experiments were performed
in 1700 μm (i.d.) borosilicate capillaries, using a single-mode
Biotage Initiator unit operating at a frequency of 2.45 GHz with ir-
radiation power from 0 to 350 W. The capillary was fed reactants
from Hamilton gastight syringes attached to a Harvard 22 syringe
pump preset to the desired flow rate. The system was connected to
a sealed collection vial, where a pressurized airline (75 psi) was at-
tached to create backpressure. The temperatures reported were mea-
sured off the surface of the capillaries by an IR sensor built into the
microwave chamber. All reagents and solvents were purchased
from commercial sources and used without additional purification.
Column chromatographic purifications were carried out using the
flash technique on silica gel 60 (200–400 mesh). 1H and 13C NMR
spectroscopy was run using a Bruker Avance 300 (300 MHz and 75
A stock solution containing an isoindoline 5 (1.0 equiv, 0.3–0.8
mmol), CDI (2.0 equiv) or chloromethyl pivalate (2.0 equiv), and
DBU (2.0 equiv) in DMF (0.1–0.2 M) was prepared and loaded into
a Hamilton gastight syringe (10 mL). One syringe was loaded with
the reagents containing isoindoline 5, DBU, and CDI, and the sec-
ond was loaded with the reagents containing isoindoline 5, DBU,
and chloromethyl pivalate, to deliver 70 μL/min. These reaction
mixtures were irradiated parallel under the same reaction conditions
(flow rate, power, temperature) and collected in separate sealed vi-
als. After completion of the reaction, the internal pressure of the
system was released by piercing the septum with the needle, and the
septum was removed and the product was analyzed directly by 1H
NMR spectroscopy. The product was extracted with EtOAc (150
mL), and the organic layer was washed with brine (100 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude
products were purified by flash column chromatography (EtOAc–
n-pentane, 2:8) to afford products 6 and 7 in 53–87% yield.
1
MHz, respectively) spectrometer. All H NMR spectra were cali-
brated to the signal from the residual proton of the CDCl3 solvent
(7.26 ppm) while 13C NMR spectra were calibrated to the middle
carbon signal of the triplet for CDCl3 (77.00 ppm). All compounds
in this study have been isolated by silica gel or aluminum oxide
chromatography for the purpose of spectroscopic identification.
Characterization Data for Representative Compounds 6 and 7
Sulfonamides 3 by the Microwave-Assisted Heck Coupling of
Vinylsulfonamides 1 with tert-Butyl 2-Bromobenzylcarbamates
2; General Procedure
3-Decyl-6,10b-dihydro-1H-[1,2,4]thiadiazino[5,4-a]isoindol-
4(3H)-one 2,2-Dioxide (6a)
Yield: 170 mg (84%); colorless crystalline solid; mp 65 °C.
Into a 10-mL standard microwave vial (Biotage) was added the tert-
butyl 2-bromobenzylcarbamate 2 (1.2 equiv), the vinylsulfonamide
1 (1.0 equiv, 0.3–0.8 mmol), anhyd DMF (0.5 M), Pd(OAc)2 (10
mol%), Ph3P (20 mol%), and Et3N (3 equiv). No special precautions
to exclude atmospheric oxygen were taken. The reaction vessel was
capped, and heated at 180 °C for 5 min using a single-mode Biotage
Initiator Synthesizer with an irradiation power up to 350 W. The re-
action mixture was cooled to r.t., diluted with EtOAc (150 mL), and
washed with H2O (50 mL). The layers were separated and the or-
ganic layer was concentrated under reduced pressure. The resulting
crude product was purified by flash chromatography (EtOAc–
n-pentane, 3:7) to afford the sulfonamide 3a–w in 54–79% yield.
FTIR (thin film): 2923, 2856, 1672, 1405, 1316, 1152, 747 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.36 (m, 3 H), 7.26 (d,
J = 6.9 Hz, 1 H), 5.44 (d, J = 12.3 Hz, 1 H), 5.02 (d, J = 15.0 Hz, 1
H), 4.73 (d, J = 15.0 Hz, 1 H), 3.99 (dd, J = 12.9, 3.0 Hz, 1 H), 3.90–
3.83 (m, 1 H), 3.80–3.66 (m, 1 H), 3.24 (t, J = 12.8 Hz, 1 H), 1.74
(t, J = 7.2 Hz, 2 H), 1.26 (s, 14 H), 0.90 (t, J = 6.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 149.7, 135.9, 135.8, 129.2, 128.2,
123.3, 121.8, 56.4, 52.7, 51.8, 41.5, 31.8, 29.6, 29.5, 29.2, 29.1,
26.7, 22.6, 14.1.
HRMS (ESI): m/z calcd for C20H30N2O3S: 378.1977; found:
378.19776.
Isoindolines 5 by Aza-Michael Cyclization and Boc Deprotec-
tion Using MACOS; General Procedure
3-(4-Chlorobenzyl)-6,10b-dihydro-1H-[1,2,4]thiadiazino[5,4-
a]isoindol-4(3H)-one 2,2-Dioxide (6e)
Yield: 113 mg (70%); colorless solid; mp 158 °C.
A stock solution containing a sulfonamide 3 (1.0 equiv, 0.3–0.8
mmol) and DBU (1.0 equiv) in DMF (0.1–0.2 M) was prepared and
loaded into a Hamilton gastight syringe (10 mL). The tubing was
primed with DMF and the syringe was connected to the reactor sys-
tem with the aid of Microtight™ fittings. The system was connected
to a sealed collection vial, where a pressurized airline (75 psi) was
attached to create backpressure. The syringe was placed in a Har-
vard 22 syringe pump that was set to deliver 70 μL/min. The single-
mode microwave was programmed to heat constantly; the power
level was controlled manually so as to keep the temperature con-
stant at the specified levels (see Scheme 2). The effluent from the
reactor was collected into a sealed vial. After completion of the re-
action, the internal pressure of the system was released by piercing
the septum with the needle, and the septum was removed and the
FTIR (thin film): 2932, 1681, 1432, 1396, 1321, 1158, 1085, 729
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.47–7.37 (m, 5 H), 7.32–7.23 (m,
3 H), 5.47 (d, J = 12.3 Hz, 1 H), 5.08–4.83 (m, 3 H), 4.75 (d,
J = 15.0 Hz, 1 H), 4.03 (dd, J = 13.2, 2.7 Hz, 1 H), 3.36 (t, J = 12.9
Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 149.6, 135.8, 135.4, 135.2, 133.6,
130.2, 129.4, 128.6, 128.3, 123.4, 121.7, 56.5, 52.7, 51.9, 43.5.
HRMS (ESI): m/z [M – H]+ calcd for C17H14ClN2O3S: 361.0414;
found: 361.0426.
1
product was analyzed directly by H NMR spectroscopy. For the
3-Cyclohexyl-8-fluoro-6,10b-dihydro-1H-[1,2,4]thiadiazi-
no[5,4-a]isoindol-4(3H)-one 2,2-Dioxide (6j)
Yield: 90 mg (62%); colorless crystalline solid; mp 219 °C.
Boc-deprotection step, p-TsOH (3 equiv) was added to the crude re-
action mixture and it was again loaded into a Hamilton gastight sy-
ringe (10 mL). The syringe pump was set to deliver 30 μL/min (see
Scheme 2 for specific conditions). After collection of the product
mixture from the reactor, it was diluted with EtOAc (150 mL) and
basified with sat. NaHCO3 soln until it reached pH 8–9. The solu-
tion was extracted with EtOAc (150 mL), and the organic layer was
washed with brine (100 mL), and dried (Na2SO4). The mixture was
filtered through a small pad of silica gel and the solvent was re-
moved under reduced pressure. The crude, pink-colored product 5
was purified by flash column chromatography (EtOAc–n-pentane,
9:1). Alternatively, the crude product was clean enough to be used
in the next step without any further purification.
FTIR (thin film): 2923, 2851, 1654, 1490, 1445, 1392, 1241, 1169,
1134, 987, 738 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.28–7.18 (m, 1 H), 7.11–7.06 (m,
2 H), 5.41 (d, J = 12.3 Hz, 1 H), 5.01 (d, J = 15.6 Hz, 1 H), 4.71 (d,
J = 15.6 Hz, 1 H), 4.29–4.21 (m, 1 H), 3.89 (dd, J = 12.9, 3.0 Hz, 1
H), 3.35 (t, J = 12.6 Hz, 1 H), 2.34–2.22 (m, 2 H), 2.00 (d, J = 12.0
Hz, 1 H), 1.88 (d, J = 9.3 Hz, 3 H), 1.67 (d, J = 12.3 Hz, 1 H), 1.41–
1.18 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 165.1 (d, JC–F = 246.8 Hz), 149.5,
138.2 (d, JC–F = 9.0 Hz), 131.4 (d, JC–F = 3.0 Hz), 123.4 (d, JC–F
=
9.0 Hz), 115.8 (d, JC–F = 22.5 Hz), 110.9 (d, JC–F = 24.0 Hz), 56.6,
55.8, 52.9, 52.5, 31.1, 30.7, 26.7, 26.5, 25.1.
Synthesis 2012, 44, 2547–2554
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
MACOS Synthesis of a Tricyclic Sultam Library
2553
HRMS (ESI): m/z calcd for C16H19FN2O3S: 338.1100; found:
338.1107.
13C NMR (75 MHz, CDCl3): δ = 141.6, 137.0, 136.1, 128.6, 122.8,
121.8, 62.8, 60.8, 54.1, 53.7, 52.3, 32.1, 31.6, 26.0, 25.8, 25.3, 21.3.
HRMS (ESI): m/z calcd for C17H24N2O2S: 320.1558; found:
320.1552.
3-Cyclohexyl-9-methyl-6,10b-dihydro-1H-[1,2,4]thiadiazi-
no[5,4-a]isoindol-4(3H)-one 2,2-Dioxide (6o)
Yield: 176 mg (74%); greenish crystalline solid; mp 192 °C.
7-(3,4-Dimethoxyphenethyl)-4b,7,8,10-tetrahydro-5H-[1,3]di-
oxolo[4,5-f][1,2,4]thiadiazino[5,4-a]isoindole 6,6-Dioxide (7q)
Yield: 182 mg (59%); colorless solid; mp 155 °C.
FTIR (thin film): 2927, 2847, 1677, 1383, 1316, 1160, 1138, 987,
729 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.25–7.18 (dd, J = 7.8, 7.8 Hz, 2
H), 7.02 (s, 1 H), 5.38 (d, J = 12.3 Hz, 1 H), 4.95 (d, J = 14.7 Hz, 1
H), 4.67 (d, J = 14.7 Hz, 1 H), 4.27–4.19 (m, 1 H), 3.90 (dd,
J = 12.9, 3.0 Hz, 1 H), 3.31 (t, J = 12.9 Hz, 1 H), 2.39 (s, 3 H), 2.34–
2.21 (m, 2 H), 1.99 (d, J = 12.0 Hz, 1 H), 1.84 (br d, J = 10.8 Hz, 3
H), 1.65 (d, J = 12.3 Hz, 1 H), 1.38–1.35 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 149.6, 138.2, 135.9, 132.8, 130.1,
123.0, 122.3, 56.4, 56.1, 52.9, 52.5, 31.2, 30.7, 26.8, 26.5, 25.1,
21.3.
FTIR (thin film): 2927, 1512, 1467, 1245, 1227, 1160, 1022, 916,
733 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.79 (m, 3 H), 6.70 (s, 1 H), 6.59
(s, 1 H), 5.94 (s, 2 H), 4.61 (d, J = 12.9 Hz, 1 H), 4.50 (d, J = 9.9 Hz,
1 H), 4.12 (d, J = 11.4 Hz, 1 H), 3.99 (d, J = 12.9 Hz, 1 H), 3.87 (s,
3 H), 3.85 (s, 3 H), 3.81 (s, 1 H), 3.54 (m, 2 H), 3.34 (dd, J = 12.9,
3.0 Hz, 1 H), 2.91–2.81 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 148.9, 147.7, 147.6, 147.1, 133.6,
131.9, 131.0, 120.7, 112.0, 111.3, 103.9, 102.0, 101.4, 66.8, 63.1,
55.9, 53.6, 51.2, 49.9, 35.9.
HRMS (ESI): m/z calcd for C17H22N2O3S: 334.1351; found:
334.1382.
HRMS (ESI): m/z calcd for C21H24N2O6S: 432.1355; found:
432.1354.
3-(3,4-Dimethoxyphenethyl)-3,4,6,10b-tetrahydro-1H-
[1,2,4]thiadiazino[5,4-a]isoindole 2,2-Dioxide (7c)
Yield: 182 mg (64%); brown solid; mp 90 °C.
Acknowledgment
FTIR (thin film): 2923, 2820, 1512, 1456, 1341, 1226, 1153, 1023,
755 cm–1.
This work was supported by the National Institute of General Me-
dical Science (Center for Chemical Methodologies and Library De-
velopment at the University of Kansas, KU-CMLD; NIH P50-
GM069663 and NIH P41-GM076302), the Ontario Centres of Ex-
cellence, and NSERC (Canada).
1H NMR (300 MHz, CDCl3): δ = 7.27 (m, 3 H), 7.15 (m, 1 H), 6.83–
6.78 (m, 3 H), 4.64 (d, J = 12.9 Hz, 1 H), 4.58 (d, J = 10.8 Hz, 1 H),
4.19 (d, J = 12.3 Hz, 1 H), 4.05 (d, J = 12.3 Hz, 1 H), 3.92 (d, J =
12.9 Hz, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.60–3.39 (m, 3 H), 2.95
(m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 148.9, 147.6, 140.1, 139.0, 131.0,
128.0, 127.3, 122.9, 120.9, 120.8, 112.1, 111.3, 66.8, 63.2, 55.9,
53.7, 51.1, 50.0, 35.9.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
HRMS (ESI): m/z calcd for C20H24N2O4S: 388.1457; found:
388.1448.
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1H NMR (300 MHz, CDCl3): δ = 7.13–7.09 (m, 1 H), 7.01–6.93 (m,
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338.1453.
3-Cyclohexyl-9-methyl-3,4,6,10b-tetrahydro-1H-[1,2,4]thiadi-
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Synthesis 2012, 44, 2547–2554
© Georg Thieme Verlag Stuttgart · New York