Davis-Beirut reaction: Route to thiazolo-, thiazino-, and thiazepino-2 h -indazoles

Article abstract of DOI:10.1021/jo501014e

Methods for the construction of thiazolo-, thiazino-, and thiazepino-2H-indazoles from o-nitrobenzaldehydes or o-nitrobenzyl bromides and S-trityl-protected 1°-aminothioalkanes are reported. The process consists of formation of the requisite N-(2-nitroben

Full text of DOI:10.1021/jo501014e

Article
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Open Access on 07/14/2015
Davis−Beirut Reaction: Route to Thiazolo‑, Thiazino‑, and
Thiazepino‑2H‑indazoles
Kelli M. Farber,† Makhluf J. Haddadin,‡ and Mark J. Kurth*,†
†Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
‡Department of Chemistry, American University of Beirut, Beirut, 1107 2020 Lebanon
S
* Supporting Information
ABSTRACT: Methods for the construction of thiazolo-,
thiazino-, and thiazepino-2H-indazoles from o-nitrobenzalde-
hydes or o-nitrobenzyl bromides and S-trityl-protected 1°-
aminothioalkanes are reported. The process consists of
formation of the requisite N-(2-nitrobenzyl)(tritylthio)-
alkylamine, subsequent deprotection of the trityl moiety with
TFA, and immediate treatment with aq. KOH in methanol under Davis−Beirut reaction conditions to deliver the target thiazolo-,
thiazino-, or thiazepino-2H-indazole in good overall yield. Subsequent S-oxidation gives the corresponding sulfone.
attempts to employ RSH in the base-mediated Davis−Beirut
reaction failed, we have found that a thiol tethered to the 1°-
aminoalkane7,21 used in the reductive amination step to
construct the o-nitrobenzylamine intermediate (in turn,
prepared from the appropriate o-nitrobenzaldehyde or o-
nitrobenzyl bromide precursor) can deliver C3 S-substituted
2H-indazoles. We report here the details of this investigation.
INTRODUCTION
■
2H-Indazoles are of considerable interest due to their medicinal
chemistry applications, which include anticancer,1,2 imidazoline
I2 receptor,3 and antiangiogenic4 activities (Figure 1a).
RESULTS AND DISCUSSION
■
Sulfur-containing molecules are quite relevant in medicine and
in human biology.22−25 Thioethers also offer an intriguing point
of diversification through easy access to higher oxidation states
at sulfur. The potential of sulfur-containing 2H-indazoles
piqued the interest of Corsi and Palazzo, leading them to
develop a limited and somewhat circuitous route to
thiazoloindazole 1a that proceeds by pyrolysis of 1-benzyl-3-
((2-chloroethyl)thio)-1H-indazole (Scheme 1; 40% yield).26
Attempts to employ external thiols under a variety of Davis−
i
Beirut reaction conditions (generically PrOH + EtSH + aq.
KOH) failed to deliver the thioether-containing 2H-indazole
(e.g., the 2H-indazole in Figure 1b where the −OEt moiety
would be replaced with the sought after −SEt). These reaction
attempts resulted primarily in nitroaryl reduction27 to the
Scheme 1. Thiazolo-2H-indazole 1a by Pyrolysis of 1-Benzyl-
3-((2-chloroethyl)thio)-1H-indazole
Figure 1. (a) Bioactive 2H-indazoles. (b) A typical Davis−Beirut
reaction proceeding through the proposed nitrosoimine intermediate.6
Addressing this need, we recently developed the Davis−Beirut
reaction,5−16 which is characterized by a noteworthy N,N-bond
forming heterocyclization step, for the construction of a wide
variety of 2H-indazoles and indazolones (Figure 1b).
In connection with ongoing research activities addressing
cystic fibrosis (CF),17,18 our interest in the development of
myeloperoxidase inhibitors19,20 led us to explore introduction
of a thioether moiety at C3 of the 2H-indazole scaffold. While
Received: May 9, 2014
© XXXX American Chemical Society
A
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corresponding aniline with only trace formation of the thia-
containing 2H-indazole.
With this setback as a backdrop, we decided to explore the
formation of 2,3-dihydrothiazolo[3,2-b]indazole (1a; Scheme
2) from 2-nitrobenzaldehyde and cysteamine before abandon-
and then the resulting crude thiol was immediately (to
minimize disulfide formation) subjected to the Davis−Beirut
reactiontreatment with KOH in methanol plus 10% water at
90 °Cto deliver 1a in 77% overall yield from 2-nitro-
benzaldehyde.
It is interesting to note that Davis−Beirut reaction on the
alcohol analogue of 5 (−SH replaced with −OH, 5a) leads
transiently to 2,3-dihydrooxazolo[3,2-b]indazole (6), but base-
mediated opening of the dihydrooxazolo ring under the
reaction conditions produces 1H-indazol-3(2H)-one 7.12
While this ring-opening of 6 can be avoided by increasing
steric hindrance at the electrophilic −CH2− through placement
of alkyl substituents at the C2 and/or C3 positions of 6 and by
conducting the heterocyclization at 60 °C,12 these modifica-
tions are not required in the formation of thiazoloindazole 1a.
With the gratifying result of 4 leading to stable 1a in hand,
we next set out to prepare homologues (Scheme 4a) of 1a with
Scheme 2. Unwanted Aminal Formation using 2-
Aminoethanethiol
ing the thia-based Davis−Beirut reaction. Condensation of
these two commercially available reagents in methanol provided
the requisite imine 2, but LCMS analysis of the reaction
mixture indicated the formation of a second product that was
determined to be thioaminal 3. Varied reaction times, reaction
Scheme 4. (a) Thiazino and Thiazepino Analogues of 1a. (b)
Oxazepino Analogue of 1c
i
conditions, and solvents (MeOH and PrOH) all resulted in 3
being the major product. Also, attempts at reduction of this
crude mixture of 2 and 3 (NaCNBH3 in MeOH), followed
immediately by the Davis−Beirut reaction, resulted in a
complex mixture of products (TLC).
These difficulties led us to pursue an alternate route wherein
the sulfur moiety was initially protected. While there are a
number of effective thiol-protecting groups, trityl protection
was selected for all of the aminothiols employed in this study
for three reasons (i) the S-trityl group is easy to deprotect; (ii)
the S-trityl group is stable to reductive amination conditions;
and (iii) the UV activity of the S-trityl protected aminothiols, as
well as their markedly different solubility characteristics, makes
them easier to isolate and manipulate than their unprotected
analogues. In the event (Scheme 3), 2-nitrobenzaldehyde in
methanol reacted quickly with 2-(tritylthio)ethanamine (syn-
thesized from cysteamine·HCl and trityl chloride in DMF)28 to
give an imine intermediate (not isolated) and subsequent
addition of sodium cyanoborohydride delivered 4. This crude o-
nitrobenzylamine was treated with TFA and triethylsilane29 in
methylene chloride to cleave the trityl protecting group (→ 5),
six- (thiazino; 1b) and seven-membered (thiazepino; 1c)
sulfur-containing heterocycles. Applying Scheme 3 sequence
of reactions to 3-(tritylthio)propan-1-amine delivered thiazi-
noindazole 1b in 82% overall yield, whereas 4-(tritylthio)butan-
1-amine delivered 1c in 71% overall yield. This last result led us
to prepare the unknown oxygen analogue of 1c for comparison
(e.g., 8; Scheme 4b), which we obtained from 4-aminobutan-1-
ol (→ 8) in 44% overall yield. Indeed, we observe that the O-
analogues of 1a, 1b, and 1c are obtained in lower yield than the
corresponding S-analogues: O-analogues of 1a−c in 24% (see 6
in Scheme 3), 84%, and 44% yields (respectively) vs S-
analogues 1a−c in 77%, 82%, and 71% yields (respectively).12
Next, the scope of the sulfur-based Davis−Beirut reaction
was expanded to include substituents on the carbocyclic ring of
these 2H-indazoles. These thia-based Davis−Beirut reactions
proceed well with both electron-withdrawing (−COOH → 9,
−Br → 10, −Cl → 11, and pyridyl → 14a,b; Scheme 5a) and
electron-donating (−OCH2O− → 15a−c and 8,9 di-OMe →
16; Scheme 5b) substituents as well as with both o-
nitrobenzaldehyde and o-nitrobenzyl bromide precursors
(Scheme 5a−c). Also, substitution ortho to the aldehyde does
not dramatically affect the reaction (ortho-Cl → 11). o-
Nitrobenzaldehydes can also be replaced with heteroaryl
nitroaldehydes (e.g., 12 and 13) to give interesting sulfur-
Scheme 3. Davis−Beirut Route to Thiazolo-2H-indazole 1a
B
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Scheme 5. Versatility of the Thia-Based Davis−Beirut
Reaction
Scheme 6. (a) Route to S-Trityl Aminoalkanes (Exemplified
with 22). (b) Synthesis of an Alkyl-Substituted
Thiazoloindazole 23
aminoalkane. DL-1-(Tritylthio)propan-2-amine (22) was sub-
sequently employed in the Davis−Beirut sequence with o-
nitrobenzaldehye (imine formation and reduction, trityl
cleavage, and then aq. KOH in MeOH) to deliver 23the
C3 methyl analogue of 1ain 66% yield (Scheme 6b).
Having successfully introduced a thia moiety into the 2H-
indazole scaffold, a contrast between these thia- (cf., 1a) and
oxo-bridged (cf., 6) systems in terms of Davis−Beirut reaction
yields is informative. In fact, whereas some 2,3-dihydrooxazolo-
[3,2-b]indazoles (cf., 6) and 3,4-dihydro-2H-[1,3]oxazino[3,2-
b]indazoles (e.g., oxa analogues of 1b) exhibit base and light
sensitivity, the thia-2H-indazoles reported here are quite stable.
Also, while the oxo analogues can generally undergo further
reaction with the alcohol solvent to form indazolones (cf., 6 →
7 in Scheme 3), the sulfur analogues reported here do not
even at higher reaction temperatures and extended reaction
times.
It is also noteworthy that oxo-2H-indazole functionalization
is generally limited to conversion to the corresponding
indazolone, whereas thia-2H-indazoles present new diversifica-
tion pathways via, for example, S-oxidation to the correspond-
ing sulfone. Indeed, as summarized in Figure 2, oxidation33 of
the thioether moiety in these thiazolo-, thiazino-, and
thiazepino-2H-indazoles with Na2WO4·2H2O/30% aq. H2O2/
EtOAc leads cleanly and in high yield to the corresponding
sulfones (24−29).
containing heteroaryl analogues (14a,b and 15a−c) in good
yields. Benzo-fused analogue 17 was synthesized via trityl-
protected 2-aminothiophenol (Scheme 5c).30 In earlier
unpublished work, we found that the oxygen analogue of 17
(e.g., where “S” is replaced with “O”) was not similarly
accessible with 2-aminophenol; 2-(3-methoxy-2H-indazol-2-
yl)phenol was formed instead.
Diverse aminothiols are not readily available, and the
literature provides few examples of diverse S-trityl amino-
alkanes. Therefore, the method devised to prepare the S-trityl
aminoalkanes employed in this study is presented in Scheme 6a
(exemplified with the preparation of 22; note that 2-
(tritylthio)ethanamine,28 3-(tritylthio)propan-1-amine,31 and
4-(tritylthio)butan-1-amine31 were prepared as reported in
the literature). Since the protecting group used for the amine
̀
must be orthogonally removed vis-a-vis the S-trityl protecting
group, phthalimide protection was selected as both its
introduction [amine + phthalic anhydride (PAN) in refluxing
xylenes] and its deprotection (phthalimide + hydrazine
monohydrate) are well established S-trityl-compatible proto-
cols. From the requisite amino alcohol, amine protection (18
→ 19; 80%), alcohol-to-iodide conversion (19 → 20; 76%),32
S-alkylation with triphenylmethanethiol (20 → 21; 55%), and
hydrazinolysis (21 → 22; 44%) delivers the targeted S-trityl
Figure 2. Sulfones obtained by oxidation of the corresponding thia-
2H-indazoles.
C
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50% EtOAc in hexanes) provided 1b as an amorphous tan solid in 82%
yield (94 mg). 1H NMR (600 MHz, CDCl3) δ 7.58 (m, 1H), 7.49 (m,
1H), 7.27 (m, 1H), 6.99 (m, 1H), 4.55 (app. t, J = 6.4 Hz, 2H), 3.23
(app. t, J = 6.4 Hz, 2H), 2.54 (app p, J = 6.4 Hz, 2H); 13C NMR (150
MHz, CDCl3) δ 147.8, 127.0, 120.2, 119.8, 119.2, 117.0, 105.2, 48.8,
25.2, 24.8. HRMS (ESI) m/z: [M + H]+ calcd for C10H10N2SH
191.0643; Found 191.0648.
CONCLUSION
■
In summary, we have shown that the Davis−Beirut reaction
affords thiazolo-, thiazino-, and thiazepino-2H-indazoles from o-
nitrobenzaldehyde and S-trityl-protected 1°-aminoalkanes in
good yields. The process consists of reductive amination of the
o-nitrobenzaldehyde-derived imine, S-trityl deprotection, and
immediate refluxing with aqueous base in methanol. The
resulting thia-2H-indazoles are generally more stable than the
corresponding oxo-2H-indazoles, and they can also be oxidized
to the corresponding sulfones.
2,3,4,5-Tetrahydro-[1,3]thiazepino[3,2-b]indazole (1c). Pre-
pared from 199 mg (0.57 mmol) of 4-(tritylthio)butan-1-amine using
General Procedure A. Purification by silica gel chromatography (20 →
50% EtOAc in hexanes) provided 1c as an amorphous solid in 71%
1
yield (83 mg). H NMR (600 MHz, CDCl3) δ 7.68 (dt, J = 8.8, 1.0
Hz, 1H), 7.65 (dt, J = 8.5, 1.1 Hz, 1H) 7.33 (ddt, J = 8.8, 6.8, 1.1 Hz,
1H), 7.14 (ddt, J = 8.5, 6.8, 1.0 Hz, 1H), 4.84 (m, 2H), 2.78 (m, 2H),
2.25 (m, 2H), 1.90 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 144.6,
128.5, 126.5, 124.0, 123.1, 120.4, 116.2, 53.7, 34.1, 32.2, 26.7. HRMS
(ESI) m/z: [M + H]+ calcd for C11H12N2SH 205.0778; Found
205.0772.
EXPERIMENTAL SECTION
■
General Experimental. All solvents and reagents were purchased
from commercial suppliers and used without further purification.
Analytical thin-layer chromatography was carried out on precoated
plates (Silica gel 60 F254, 0.50 mm thickness) and visualized with UV
light. Flash chromatography was performed with 60 Å, 35−70 mm
silica gel. Concentration refers to rotary evaporation under reduced
pressure.
2,3,4,5-Tetrahydro-[1,3]oxazepino[3,2-b]indazole (8). 4-
Amino-1-butanol (160 mg, 1.8 mmol) and 2-nitrobenzaldehyde (250
i
mg, 1.65 mmol) were dissolved in PrOH (5 mL) and stirred until
1H NMR spectra were recorded at 600 MHz at ambient
temperature with DMSO-d6, MeOD-d4, or CDCl3 as solvents. 13C
NMR spectra were recorded at 150 MHz at ambient temperature with
TLC showed consumption of the starting material. NaCNBH3 (310
mg, 4.94 mmol) was added portionwise, and the mixture was stirred
for 20 min, at which time TLC showed consumption of the imine.
Isopropanol (10 mL) was added to the solution. KOH (1.40 g, 25
mmol) was dissolved in a portion of water (2 mL) and added to the
iPrOH solution, which changed to a dark orange color. This solution
was heated at 60 °C for 8 h. The organic layer was washed twice with
water and once with brine, dried over Na2SO4, filtered, and
concentrated. Purification by silica gel chromatography (50% EtOAc
in hexanes) provided 8 as a tan amorphous solid in 44% yield (142
1
DMSO-d6, MeOD-d4 or CDCl3 as solvents. Data for H NMR are
recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; quint, quintet; m, multiplet), coupling
constant (Hz), integration. Chemical shifts are reported in parts per
million relative to DMSO-d6 (1H, δ 2.50; 13C, δ 39.52), MeOD-d4
(1H, δ 3.31; 13C, δ 49.99), or CDCl3 (1H, δ 7.26; 13C, δ 77.16).
Infrared spectra were recorded on an ATI-FTIR spectrometer. High-
resolution mass spectra were acquired on an LTQ Orbitrap XL mass
spectrometer equipped with an electrospray ionization source
operating in the positive ion mode. Samples were introduced into
the source via loop injection at a flow rate of 200 ul/min, in a solvent
system of 1:1 acetonitrile:water with 0.1% formic acid.
General Procedure A: Preparation of Thiazolo-, Thiazino-,
and Thiazepino-2H-indazoles. 2-Nitrobenzaldehyde (1.1 equiv)
was dissolved in MeOH (0.4 M). The requisite S-trityl-protected
aminothioalkane (1.0 equiv) was added, and the solution was stirred
until TLC showed consumption of the starting amine. NaCNBH3 (2.0
equiv) was added portionwise, and the solution was stirred until
consumption of the imine was observed. The solution was evaporated,
and the resulting residue was redissolved in methylene chloride. The
organic layer was washed twice with 1 M HCl, dried over Na2SO4,
filtered, and concentrated to ∼10 mL. An equal volume of TFA was
added, followed by addition of triethylsilane (3.0 equiv). This solution
was left to stir for 30 min and then concentrated (care was taken to
vent the rotary evaporator to nitrogen to prevent disulfide formation).
To the remaining residue was added MeOH (0.1 M), KOH (15
equiv), and 10% v/v H2O. The solution was heated at reflux in a 90 °C
oil bath for 3−6 h. Upon reaction completion, the MeOH was
evaporated and the remaining aqueous mixture was partitioned with
EtOAc. The aqueous layer was extracted with EtOAc twice, and the
resulting organic extracts were combined, washed with brine, dried
over Na2SO4, filtered, and concentrated. Purification with silica gel
chromatography provided the desired indazole.
1
mg). H NMR (600 MHz, CDCl3) δ 7.54 (dt, J = 8.5, 1.2 Hz, 1H),
7.49 (dt, J = 8.8, 1.0 Hz, 1H), 7.22 (ddd, J = 8.8, 6.6, 1.2 Hz, 1H), 6.97
(ddd, J = 8.5, 6.6, 1.0 Hz, 1H), 4.51 (m, 2H), 4.20 (m, 2H), 2.16 (m,
2H), 1.96 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 148.4, 146.8,
126.5, 120.3, 118.9, 117.1, 110.0, 74.6, 52.8, 31.7, 26.1; HRMS (ESI)
m/z: [M + H]+ calcd for C11H12N2OH 189.1028; Found 189.1027.
3,4-Dihydro-2H-[1,3]thiazino[3,2-b]indazole-8-carboxylic
acid (9). 4-(Bromomethyl)-3-nitrobenzoic acid (150 mg, 0.54 mmol
1.0 equiv) and DIPEA (0.250 mL, 1.40 mmol, 2.5 equiv) were
dissolved in MeOH. 3-(Tritylthio)propan-1-amine (480 mg, 1.40
mmol, 2.5 equiv) was dissolved in MeOH and added dropwise over 6
h to the stirring benzyl bromide solution. After addition was complete,
the solution was left to stir overnight. The solvent was evaporated, and
the remaining residue was redissolved in 10 mL of methylene chloride.
To this solution was added 10 mL of TFA, followed quickly by
addition of triethylsilane (0.225 mL, 1.40 mmol, 2.5 equiv). The
solution was left to stir for 30 min. The solvent was evaporated, and
the residue was redissolved in MeOH. KOH (484 mg, 8.63 mmol, 15
equiv) was dissolved in 10% v/v water and added to the MeOH
solution. This mixture was heated at reflux in a 90 °C bath for 4 h.
After the solution cooled, the MeOH was evaporated and EtOAc was
added to the remaining aqueous residue. The aqueous layer was
extracted once with EtOAc and then acidified. The aqueous layer was
then extracted twice more with EtOAc (these extracts were not
combined with the first). The organic layer was then washed with
brine, dried over Na2SO4, filtered, and concentrated. Purification by
silica gel chromatography (AcOH in 99% EtOAc → 1% AcOH, 10%
EtOH in 89% EtOAc) provided 9 as an amorphous pale yellow solid in
2,3-Dihydrothiazolo[3,2-b]indazole (1a). Prepared from 216
mg (0.68 mmol) of 2-(tritylthio)ethan-1-amine using General
Procedure A. Purification by silica gel chromatography (20 → 50%
EtOAc in hexanes) provided 1a as a white amorphous solid in 77%
1
73% yield (98 mg). IR (neat) νmax 3250, 1740 cm−1; H NMR (600
MHz, DMSO) δ 12.04 (s, 1H), 8.17 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H),
7.47 (d, J = 8.7 Hz, 1H), 4.53 (app. t, J = 5.9 Hz, 2H), 3.33 (app. t, J =
5.5, 5.5 Hz, 2H), 2.57 (app. p, J = 6.3 Hz, 2H); 13C NMR (150 MHz,
DMSO) δ 167.7, 146.0, 128.9, 124.6, 120.8, 119.7, 119.2, 48.8, 24.3,
23.9; HRMS (ESI) m/z: [M + H]+ calcd for C11H10N2O2SH
235.0541; Found 235.0540.
9-Bromo-3,4-dihydro-2H-[1,3]thiazino[3,2-b]indazole (10).
Prepared from 132 mg (0.40 mmol) of 3-(tritylthio)propan-1-amine
using General Procedure A. Purification by silica gel chromatography
(50% EtOAc in hexanes) provided 10 as a yellow amorphous solid in
1
yield (92 mg); H NMR (600 MHz, CDCl3) δ 7.60 (dt, J = 8.9, 1.0
Hz, 1H), 7.47 (dt, J = 8.4, 0.9 Hz, 1H), 7.25 (ddd, J = 8.4, 6.6, 1.0 Hz,
1H), 7.00 (ddd, J = 8.4, 6.6, 0.9 Hz, 1H), 4.67 (t, J = 7.6 Hz, 2H), 3.97
(t, J = 7.6 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 154.0, 133.1,
126.6, 120.8, 120.0, 118.0, 116.1, 50.4, 34.4. HRMS (ESI) m/z: [M +
H]+ calcd for C9H8N2SH 177.0486; Found 177.0482.
3,4-Dihydro-2H-[1,3]thiazino[3,2-b]indazole (1b). Prepared
from 200 mg (0.60 mmol) of 3-(tritylthio)propan-1-amine using
General Procedure A. Purification by silica gel chromatography (20 →
D
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66% yield (70 mg). 1H NMR (600 MHz, CDCl3) δ 7.79 (s, 1H), 7.55
(d, J = 9.3 Hz, 1H), 7.32 (d, J = 9.3 Hz, 1H), 4.44 (dd, J = 8.3, 7.1 Hz,
2H), 3.66 (app. t, J = 6.2 Hz, 2H), 2.10 (app. p, J = 7.1 Hz, 2H); 13C
NMR (150 MHz, CDCl3) δ 147.1, 129.5, 122.9, 122.3, 122.2, 119.0,
115.1, 62.0, 29.4, 27.1; HRMS (ESI) m/z: [M + H]+ calcd for
C10H9BrN2SH 268.9748; Found 268.9739.
stirring benzyl bromide solution. After addition was complete, the
solution was left to stir overnight. The solvent was evaporated, and the
remaining residue was redissolved in 10 mL of methylene chloride. To
this solution was added 10 mL of TFA, followed quickly by addition of
triethylsilane (0.470 mL, 3 mmol, 3.0 equiv). The solution was left to
stir for 30 min. The solvent was evaporated, and the residue was
redissolved in MeOH. KOH (841 mg, 15 mmol 15 equiv) was
dissolved in 10% v/v water and added to this MeOH solution. The
mixture was heated at reflux in a 90 °C bath for 4 h. After the solution
cooled, MeOH was evaporated and EtOAc was added to the remaining
aqueous residue. The aqueous layer was extracted once with EtOAc
and then acidified. The aqueous layer was then extracted twice more
with EtOAc (these extracts were not combined with the first). The
organic layer was then washed with brine, dried over Na2SO4, filtered,
and concentrated. Purification by silica gel chromatography (10%
EtOH in EtOAc) provided 16 as an amorphous yellow solid in 75%
yield (188 mg). 1H NMR (600 MHz, MeOD) δ 6.84 (s, 1H), 6.73 (s,
1H), 4.40 (app. t, J = 5.9 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.25 (dd,
J = 8.0, 3.2 Hz, 2H), 2.49 (m, 2H); 13C NMR (150 MHz, MeOD) δ
153.6, 148.1, 145.0, 125.6, 119.3, 117.3, 114.7, 98.1, 96.0, 56.6, 56.4,
25.8; HRMS (ESI) m/z: [M + H]+ calcd for C12H14N2O2SH
251.0854; Found 251.0848.
10-Chloro-3,4-dihydro-2H-[1,3]thiazino[3,2-b]indazole (11).
Prepared from 200 mg (0.60 mmol) of 3-(tritylthio)propan-1-amine
using General Procedure A. Purification by silica gel chromatography
(50% EtOAc in hexanes) provided 11 as a tan amorphous solid in 60%
1
yield (81 mg). H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 8.7 Hz,
1H), 7.12 (dd, J = 8.7, 7.2 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 4.51
(app. t, J = 6.1 Hz, 2H), 3.18 (m, 2H), 2.49 (m, 2H); 13C NMR (150
MHz, CDCl3) δ 148.7, 127.1, 126.0, 125.7, 120.0, 118.5, 115.6, 49.2,
25.2, 24.0; HRMS (ESI) m/z: [M + H]+ calcd for C10H9ClN2SH
225.0253; Found 225.0253.
2,3-Dihydrothiazolo[3′,2′:1,5]pyrazolo[4,3-b]pyridine (14a).
Prepared from 198 mg (0.62 mmol) of 2-(tritylthio)ethan-1-amine
using General Procedure A. Purification by silica gel chromatography
(50 → 70% EtOAc in hexanes) provided 14a as an orange amorphous
solid in 80% yield (88 mg). 1H NMR (600 MHz, CDCl3) δ 8.47 (dt, J
= 4.1, 1.2 Hz, 1H), 7.95 (dt, J = 8.8, 1.2 Hz, 1H), 7.19 (ddd, J = 8.8,
4.1, 1.2 Hz, 1H), 4.72 (app. t, J = 7.7 Hz, 2H), 4.00 (app. t, J = 7.7 Hz,
2H); 13C NMR (150 MHz, CDCl3) δ 146.8, 134.6, 133.2, 126.4,
121.8, 105.2, 51.1, 34.4; HRMS (ESI) m/z: [M + H]+ calcd for
C8H7N3SH 178.0439; Found 178.0444.
Benzo[4,5]thiazolo[3,2-b]indazole (17). Prepared from 178 mg
(0.49 mmol) of 2-(tritylthio)aniline using General Procedure A.
Purification by silica gel chromatography (50% EtOAc in hexanes)
1
provided 17 as an amorphous solid in 65% yield (71 mg). H NMR
3,4-Dihydro-2H-pyrido[3′,2′:3,4]pyrazolo[5,1-b][1,3]thiazine
(14b). Prepared from 200 mg (0.60 mmol) of 3-(tritylthio)propan-1-
amine using General Procedure A. Purification by silica gel
chromatography (50 → 70% EtOAc in hexanes) provided 14b as an
(600 MHz, CDCl3) δ 8.35 (d, J = 8.2 Hz, 1H), 7,87 (m, 2H), 7.81 (d,
J = 8.4 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.46
(t, J = 7.6 Hz, 1H), 7.17 (t, J = 8.3 Hz, 1H) 13C NMR (150 MHz,
CDCl3) δ 162.4, 153.6, 149.0, 135.9, 132.4, 131.8, 131.0, 128.0, 126.6,
125.9, 124.5, 123.9, 121.6. HRMS (ESI) m/z: [M + H]+ calcd for
C13H8N2SH 225.0486; Found 225.0482.
2-(1-Hydroxypropan-2-yl)isoindoline-1,3-dione (19). DL-alani-
nol (1.00 g, 13.30 mmol, 1 equiv) and phthalic anhydride (2.37 g,
16.00 mmol, 1.2 equiv) were dissolved in xylenes and heated at 140 °C
for 3 h. The solution was concentrated, and the resulting solid was
purified by silica gel chromatography (20% EtOAc in hexanes) to give
the desired phthalimido alcohol. Isolated in 80% yield (2.18 g).
Spectral data were in accordance with literature values.34
1
amorphous yellow solid in 76% yield (87 mg). H NMR (600 MHz,
CDCl3) δ 8.45 (dt, J = 4.1, 0.5 Hz, 1H), 7.92 (dt, J = 8.8, 0.5 Hz, 1H),
7.19 (ddd, J = 8.8, 4.1, 0.5 Hz, 1H), 4.56 (app. t, J = 4.9 Hz, 2H), 3.27
(m, 2H), 2.57 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 146.1, 140.9,
136.5, 126.5, 125.1, 122.2, 49.3, 24.8, 24.5; HRMS (ESI) m/z: [M +
H]+ calcd for C9H9N3SH 192.0595; Found 192.0605.
7,8-Dihydro-[1,3]dioxolo[4,5-f]thiazolo[3,2-b]indazole (15a).
Prepared from 211 mg (0.66 mmol) of 2-(tritylthio)ethan-1-amine
using General Procedure A. Purification by silica gel chromatography
(20 → 50% EtOAc in hexanes) provided 15a as a tan solid in 84%
2-(1-Iodopropan-2-yl)isoindoline-1,3-dione (20). Triphenyl-
phosphine (2.55g, 9.70 mmol, 2 equiv) and imidazole (67 mg, 0.99
mmol, 0.2 equiv) were dissolved in dry methylene chloride. Iodine
(2.50g, 9.84 mmol, 2 equiv) was added, and the solution was left to stir
for 10 min. 19 (1.00 g, 4.87 mmol, 1 equiv) was dissolved in dry
methylene chloride and added dropwise over 20 min. After addition,
the solution was left to stir overnight. The solution was concentrated
and then redissolved in EtOAc. The organic layer was washed with
saturated sodium thiosulfate and brine, dried over Na2SO4, filtered,
and concentrated. Purification by column chromatography (5% EtOAc
in hexanes) provided the desired product. Isolated in 76% yield
(1.16g). Spectral data were in accordance with literature values.35
2-(1-(Tritylthio)propan-2-yl)isoindoline-1,3-dione (21). Trityl
mercaptan (965 mg, 3.50 mmol, 1.1 equiv) was dissolved in dry DMF
and cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil,
152 mg, 3.80 mmol, 1.2 equiv) was added, and the solution was stirred
for 20 min. 20 (1.00 g, 3.17 mmol, 1 equiv) was dissolved in dry DMF
and added dropwise to the stirring solution over 10 min. After
addition, the reaction was allowed to warm to room temperature and
tracked by TLC to completion. The solution was partitioned between
water and EtOAc. The organic layer was washed with water, dried over
Na2SO4, filtered, and concentrated. Purification by silica gel
chromatography (30% EtOAc in hexanes) provided 21 as a white
amorphous solid in 55% yield (809 mg). IR (neat) νmax 1711, 1600
1
yield (122 mg). mp decomposed at 250 °C; H NMR (600 MHz,
CDCl3) δ 6.87 (s, 1H), 6.66 (s, 1H), 5.93 (s, 2H), 4.55 (app. t, J = 7.6
Hz, 2H), 3.88 (app. t, J = 7.6 Hz, 2H); 13C NMR (150 MHz, CDCl3)
δ 151.3, 149.4, 144.8, 132.1, 111.1, 101.0, 95.0, 94.8, 50.2, 34.5 HRMS
(ESI) m/z: [M + H]+ calcd for C10H8N2O2SH 221.0384; Found
221.0384.
8,9-Dihydro-7H-[1,3]dioxolo[4,5-f ][1,3]thiazino[3,2-b]-
indazole (15b). Prepared from 201 mg (0.60 mmol) of 3-
(tritylthio)propan-1-amine using General Procedure A. Purification
by silica gel chromatography (20 → 50% EtOAc in hexanes) provided
1
15b as a tan amorphous solid in 80% yield (113 mg). H NMR (600
MHz, CDCl3) δ 7.03 (s, 1H), 6.77 (s, 1H), 6.06 (s, 2H), 4.75 (app. t, J
= 5.9 Hz, 2H) 3.27 (m, 2H), 2.55 (m, 2H); 13C NMR (150 MHz,
CDCl3) δ 154.0, 146.7, 137.7, 133.6, 114.0, 102.6, 95.4, 91, 47.6, 24.6,
22.9; HRMS (ESI) m/z: [M + H]+ calcd for C11H10N2O2SH
235.0541; Found 235.0523.
7,8,9,10-Tetrahydro-[1,3]dioxolo[4,5-f ][1,3]thiazepino[3,2-
b]indazole (15c). Prepared from 180 mg (0.52 mmol) using General
Procedure A. Purification by silica gel chromatography (20 → 50%
EtOAc in hexanes) provided 15c as an amorphous solid in 73% yield
1
(94 mg). H NMR (600 MHz, CDCl3) δ 6.91 (s, 1H), 6.82 (s, 1H),
5.93 (s, 2H), 4.64, (m, 2H), 2.69 (m, 2H), 2.18 (m, 2H), 1.82 (m,
2H); 13C NMR (150 MHz, CDCl3) δ 149.1, 145.7, 144.5, 126.7,
120.3, 101.0, 95.3, 94.2, 53.6, 34.4, 32.5, 27.4; HRMS (ESI) m/z: [M +
H]+ calcd for C12H12N2O2SH 249.0697; Found 249.0698.
1
cm−1; H NMR (600 MHz, CDCl3) δ 7.79 (m, 2H), 7.69 (m, 2H),
7.38−7.20 (m, 15H), 4.08 (m, 1H), 3.12 (dd, J = 12.2, 9.8 Hz, 1H),
2.51 (dd, J = 12.2, 9.8 Hz, 1H), 1.30 (d, J = 6.9, 3H); 13C NMR (150
MHz, CDCl3) δ 168.1, 144.7, 134.0, 132.0, 129.7, 128.0, 126.8, 123.3,
67.1, 46.9, 35.4, 18.8. HRMS (ESI) m/z: [M + H]+ calcd for
C30H25NO2SH 464.1684; Found 464.1680.
8,9-Dimethoxy-3,4-dihydro-2H-[1,3]thiazino[3,2-b]indazole
(16). 1-(Bromomethyl)-4,5-dimethoxy-2-nitrobenzene (276 mg, 1
mmol, 1.0 equiv) and DIPEA (0.521 mL, 3 mmol, 3.0 equiv) were
dissolved in MeOH. 3-(Tritylthio)propan-1-amine (666 mg, 2 mmol,
2 equiv) was dissolved in MeOH and added dropwise over 6 h to the
E
dx.doi.org/10.1021/jo501014e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3-Methyl-1-(tritylthio)butan-2-amine (22). Isoindolinedione 21
(500 mg, 1.07 mmol, 1.0 equiv) was suspended in a 4:1 solution of
EtOH:BuOH. To this solution was added hydrazine monohydrate (6.0
equiv). The mixture was heated at reflux overnight. Upon cooling, a
white precipitate formed. The precipitate was filtered off, and the
filtrate was concentrated. The resulting residue was redissolved in
chloroform, and the solution was left to stir for 1 h. The resulting
precipitate was filtered off, and the filtrate was concentrated.
Purification of the residue by silica gel chromatography (10% EtOAc
in methylene chloride →10% MeOH in methylene chloride) provided
22 as a white crystalline solid in 44% yield (160 mg). mp 151−153 °C;
IR (neat) νmax 3379 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.32−7.28
(m, 15H), 2.60 (m, 1H), 2.21 (m, 1H), 2.08 (m, 1H), 0.89 (d, J = 6.4
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 144.9, 129.5, 128.5, 127.2,
66.4, 48.6, 46.6, 22.0. HRMS (ESI) m/z: [M-CPh3+H]+ calcd for
C3H9NSH 92.0534; Found 92.0524.
Procedure B. Sulfone 27 was isolated as a light tan amorphous solid in
1
91% yield (52 mg). IR (neat) νmax 1328 cm−1; H NMR (600 MHz,
DMSO-d6) δ 7.21 (s, 1H), 7.17 (s, 1H), 6.12 (s, 2H), 4.93 (td, J = 6.5,
1.0 Hz, 2H), 4.34 (td, J = 6.5, 1.0 Hz, 2H); 13C NMR (150 MHz,
DMSO-d6) δ 149.4, 149.2, 147.5, 130.7, 109.9, 101.8, 95.0, 93.3, 55.0,
46.2. HRMS (ESI) m/z: [M + H]+ calcd for C10H8N2O4SH 253.0283;
Found 253.0277.
8,9-Dihydro-7H-[1,3]dioxolo[4,5-f ][1,3]thiazino[3,2-b]-
indazole 10,10-Dioxide (28). Prepared from 15b (50 mg, 0.21
mmol) by General Procedure B. Sulfone 28 was isolated as a tan
amorphous solid in 90% yield (51 mg). IR (neat) νmax 1320 cm−1; 1H
NMR (600 MHz, CDCl3) δ 7.15 (s, 1H), 6.97 (s, 1H), 6.02 (s, 2H),
4.54 (app. t, J = 6.0 Hz, 2H), 3.52 (dd, J = 6.3, 5.5 Hz, 2H), 2.81 (app.
p, J = 6.0 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 150.3, 148.2,
145.0, 130.4, 115.7, 101.7, 95.5, 94.4, 51.2, 49.2, 21.4. HRMS (ESI) m/
z: [M + H]+ calcd for C11H10N2O4SH 267.0439; Found 267.0437.
7,8,9,10-Tetrahydro-[1,3]dioxolo[4,5-f ][1,3]thiazepino[3,2-
b]indazole 11,11-Dioxide (29). Prepared from 15c (50 mg, 0.20
mmol) by General Procedure B. Sulfone 29 was isolated as a yellow
amorphous solid in 90% yield (54 mg). IR (neat) νmax 1350 cm−1; 1H
NMR (600 MHz, CDCl3) δ 7.28 (s, 1H), 6.94 (s, 1H), 6.00 (s, 1H),
4.79 (dd, J = 5.6, 1.2 Hz, 2H), 3.34 (app. t, J = 6.3 Hz, 2H), 2.34 (m,
2H), 2.00 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 149.8, 148.5,
144.3, 130.0, 120.2, 101.6, 95.0, 94.3, 56.2, 54.3, 27.6, 24.2. HRMS
(ESI) m/z: [M + H]+ calcd for C12H12N2O4SH 281.0596; Found
281.0590.
3-Methyl-2,3-dihydrothiazolo[3,2-b]indazole (23). Prepared
from 160 mg (0.47 mmol) of 22 using General Procedure A.
Purification by silica gel chromatography (20 → 50% EtOAc in
hexanes) provided 23 as an amorphous yellow solid in 66% yield (60
1
mg). H NMR (600 MHz, CDCl3) δ 7.46 (d, J = 9.0 Hz, 2H), 7.20
(m, 1H), 6.89 (m, 1H), 5.58 (m, 1H), 4.66 (ddd, J = 9.5, 8.3 1H), 4.17
(dd, J = 9.5, 8.0, 1H), 1.71 (d, J = 6.4 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 153.7, 151.4, 126.8, 119.4, 119.0, 117.6, 101, 85.4, 52.7, 20.9.
HRMS (ESI) m/z: [M + H]+ calcd for C10H10N2SH 191.0643; Found
191.0644.
General Procedure B: Preparation of Sulfones. The indazole
(1.0 equiv) was dissolved in EtOAc to 0.8 M. Na2WO4·2H2O (0.1
equiv) was dissolved in a small amount of water and added to the
EtOAc solution. A solution of 30% hydrogen peroxide (3.0 equiv) was
added dropwise. After addition, the mixture was stirred until starting
material was consumed (tracked by LCMS and TLC). The solution
was cooled to 0 °C, and saturated sodium bisulfite (2 mL) was added
dropwise. The solution was extracted with EtOAc, and then the
organic layer was dried over Na2SO4, filtered, and concentrated.
2,3-Dihydrothiazolo[3,2-b]indazole 1,1-Dioxide (24). Pre-
pared from 1a (50 mg, 0.28 mmol) by General Procedure B. Note
that the sulfone precipitated out of solution and was analyzed without
further purification. Sulfone 24 was isolated as a white amorphous
solid in 99% yield (58 mg). IR (neat) νmax 1305, 1124 cm−1; 1H NMR
(600 MHz, CDCl3) δ 7.83 (dd, J = 8.5, 0.9 Hz, 1H), 7.78 (d, J = 8.8
Hz, 1H), 7.83, 7.43 (ddd, J = 8.8, 6.8, 1.0 Hz, 1H) 7.33 (ddd, J = 8.5,
6.8, 0.8 Hz, 1H), 5.01 (dd, J = 7.3, 6.1 Hz, 2H), 4.15 (dd, J = 7.3, 6.1,
2H); 13C NMR (150 MHz, CDCl3) δ 153.2, 131.1, 127.8, 125.5,
118.7, 118.6, 115.6, 55.3, 46.3; HRMS (ESI) m/z: [M + H]+ calcd for
C9H8N2O2SH 209.0384; Found 209.0385.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mjkurth@ucdavis.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Tara K. Telford Fund for Cystic Fibrosis
Research at the University of California-Davis and the National
Institutes of Health (Grants DK72517 and GM089153) for
generous financial support of this work. We also thank Dr.
William Jewell (UC Davis Mass Spectrometry Facility) for
assistance with HRMS data collection.
3,4-Dihydro-2H-[1,3]thiazino[3,2-b]indazole 1,1-Dioxide
(25). Prepared from 1b (50 mg, 0.26 mmol) by General Procedure
B. Sulfone 25 was isolated as an off-white crystalline solid in 93% yield
1
(53 mg). mp decomposed at 250 °C; IR (neat) νmax 1342 cm−1; H
REFERENCES
■
NMR (600 MHz, CDCl3) δ 7.93 (dd, J = 8.5, 0.9 Hz, 1H), 7.72 (d, J =
8.8 Hz, 1H), 7.38 (ddd, J = 8.5, 6.8, 0.9 Hz, 1H), 7.29 (ddd, J = 7.5,
7.0, 0.9 Hz 1H), 4.64 (dd, J = 6.3, 5.6 Hz, 2H), 3.55 (dd, J = 6.3, 5.6
Hz, 2H), 2.83 (app. p, J = 5.9 Hz, 2H); 13C NMR (150 MHz, CDCl3)
δ 147.3, 130.7, 127.6, 125.3 119.3, 119.2, 117.9, 51.2, 49.6, 21.3;
HRMS (ESI) m/z: [M + H]+ calcd for C10H10N2O2SH 223.0541;
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2,3,4,5-Tetrahydro-[1,3]thiazepino[3,2-b]indazole 1,1-Diox-
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Procedure B. Sulfone 26 was isolated as an off-white amorphous solid
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MHz, CDCl3) δ 8.11 (dt, J = 8.6, 1.1 Hz, 1H), 7.75 (d, J = 8.6, 1.0 Hz,
1H), 7.38 (ddd, J = 8.7, 6.7, 1.1 Hz, 1H), 7.31 (ddd, J = 8.5, 6.7, 1.0
Hz, 1H), 4.96 (dd, J = 6.1, 5.8 Hz, 2H), 3.39 (dd, J = 6.1, 5.8 Hz, 2H),
2.35 (m, 2H), 1.50 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 147.1,
127.1, 125.8, 123.6, 119.8, 118.2, 105.2, 56.1, 54.8, 27.5 24.3. HRMS
(ESI) m/z: [M + H]+ calcd for C11H12N2O2SH 237.0697; Found
237.0681.
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