A scalable, chromatography-free synthesis of benzotetramisole

Article abstract of DOI:10.1055/s-0034-1378931

The scalable, chromatography-free synthesis of the chiral isothiourea benzotetramisole (BTM) in two steps from commercially available materials is presented. A detailed procedure for the synthesis of both enantiomers and the racemate on ca. 10 gram scale

Full text of DOI:10.1055/s-0034-1378931

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 34–41
psp
34
D. S. B. Daniels et al.
PSP
Synthesis
A Scalable, Chromatography-Free Synthesis of Benzotetramisole
N
David S. B. Danielsa
Cl
Siobhan R. Smitha
Tomas Lebla
Peter Shaplandb
Andrew D. Smith*a
S
S
2 steps
N
+
N
Ph
Ph
OH
(R)-, (S)- and ( )-BTM
ca. 60% yield
10 g scale
chromatography-free
H2N
a School of Chemistry, University of St Andrews, North Haugh,
(R), (S) and ( )
St Andrews, Fife KY16 9ST, UK
ads10@st-andrews.ac.uk
b GSK, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY,
UK
+
4
4
1
(
3
3
4
4
)
6
3
8
0
8
Received: 22.08.2014
Accepted after revision: 17.10.2014
Published online: 21.11.2014
substitution pattern, have led to a series of powerful dihy-
dropyrimido[2,1-b]benzothiazole-based catalysts that have
been applied to a range of transformations (Figure 1).4
DOI: 10.1055/s-0034-1378931; Art ID: ss-2014-t0523-psp
Abstract The scalable, chromatography-free synthesis of the chiral
isothiourea benzotetramisole (BTM) in two steps from commercially
available materials is presented. A detailed procedure for the synthesis
of both enantiomers and the racemate on ca. 10 gram scale is dis-
closed.
S
N
S
N
S
N
N
N
N
Ph
Ph
Ph
(S)-tetramisole
(R)-benzotetramisole
(S)-homobenzotetramisole
Key words isothiourea, Lewis base catalysis, asymmetric catalysis, ki-
netic resolution, rearrangement, benzotetramisole
(HBTM)
(BTM)
S
N
S
S
N
Introduction
N
N
N
N
Ph
Ph
Isothioureas are an important class of Lewis base that
are becoming increasingly used within a range of organo-
catalytic procedures.1 This molecular class came to promi-
nence in organocatalysis with the seminal report by Birman
and Li in 20062 that demonstrated their power as acyl
transfer catalysts in the kinetic resolution of secondary al-
cohols. The most potent and selective catalyst in this study
was benzotetramisole (BTM), the benzannulated derivative
of the antihelminthic pharmaceutical tetramisole3 that it-
self is a competent catalyst for this transformation. Based
upon the isothiourea catalyst motif, further derivatisations
of the heterocyclic core, including changes to ring size and
i-Pr
Me
(S)-4-Mes-DHPB
(S,R)-HBTM-2.1
(S,R)-HBTM-2
Figure 1 A selection of isothiourea catalysts
The power of BTM (4) as a highly enantioselective acyl
transfer catalyst has been further demonstrated by
Birman,5 Shiina,6 and others7 in a range of kinetic resolution
processes. Similarly, BTM has found use in an asymmetric
Steglich rearrangement8 and the kinetic resolution of sec-
ondary alcohols by silylation.9 The reports by Romo and co-
workers on the nucleophile-catalysed aldol-lactonisation
S
N
MsCl (1.3 equiv), Et3N (4.0 equiv)
S
NH
CH2Cl2 (0.1 M), 0 °C to r.t.
i-Pr2NEt (2.5 equiv)
N
S
Ph
N
+
Ph
Cl
OH
N
then excess i-PrOH
Δ, 16 h
H2N
1,2-Cl2C6H4 (2.0 M)
195 °C, 24 h
Ph
OH
(R)-, (S)- or ( )-3
13.91–14.81 g, 74–79%
1
(R)-, (S)- or ( )-2
(1.05 equiv)
(R)-, (S)- or ( )-4 (BTM)
8.90–11.37 g, 73–84%
(1.0 equiv)
Scheme 1 A practical, multigram synthesis of benzotetramisole (BTM; 4)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 34–41

35
D. S. B. Daniels et al.
PSP
Synthesis
N
Cl
S
S
N
1
NH
MsCl (1.5 equiv)
Et3N (3.0 equiv)
i-Pr2NEt
(1.5 equiv)
S
N
(1.0 equiv)
Ph
N
+
Ph
CH2Cl2
0 °C, 1 h
then excess MeOH
excess Et3N
Δ, 16 h
135 °C, 19 h
sealed tube
OH
Ph
(R)-3
OH
(R)-4 (BTM)
97% after
chromatography
H2N
83% after
chromatography
(R)-2
(1.03 equiv)
Scheme 2 Birman’s original procedure for the synthesis of (R)-41
(NCAL) reaction using ammonium enolates, generated ini-
tially from cinchona alkaloids10 and later using iso-
thioureas,11 stimulated our group to further demonstrate
that isothioureas serve as excellent Lewis base organocata-
lysts for these processes.12 BTM (4) in particular has en-
abled the catalytic enantioselective synthesis of
dihydropyridones12c and β-lactams,12j as well as promoting
the asymmetric [2,3]-rearrangement of allylic ammonium
ylides.13 Romo and co-workers have also reported the use of
BTM (4) in the asymmetric synthesis of bicyclic lactones.14
While tetramisole is commercially available at reason-
able cost and a scalable route to HBTM-2.1 has been report-
ed,12d in our hands, Birman’s original procedure (detailed in
Scheme 2) was suitable for the synthesis of (R)-BTM on ca.
1 g scale.2 Although this sequence was reproduceable, in
practice we found this sequence to be limited by the use of
a sealed tube in the first step, chromatographic purifica-
tions to obtain both (R)-3 and noncrystalline (R)-4, and
multiple recrystallisations to obtain pure material.
Scope and Limitations
First, the neat reaction between 2-chlorobenzothiazole
(1), 2-phenylglycinol (2) and ethyldiisopropylamine to form
3 was optimised. The use of a high-boiling co-solvent (chlo-
robenzene at reflux) whilst maintaining high concentra-
tions of 1 (ca. 2.0 M) allowed the reaction to be performed
in standard glassware under air without the need for sealed
tubes or an inert atmosphere. However, extended reaction
times (>48 h) at reflux (ca. 140 °C) were required for high
conversions of 1 as measured by GC analysis. Switching to
1,2-dichlorobenzene and increasing the reflux temperature
(ca. 195 °C) led consistently and reproducibly to >95% con-
version of 1 after 24 hours (Scheme 3, a). Reducing the tem-
perature, equivalents of ethyldiisopropylamine, or diluting
the reaction further led to lower conversions and extended
reaction times.
Chen7a,b and Nagano7e observed precipitation of product
3 in the separatory funnel during aqueous workup of the
reaction. Seeking to exploit this to improve the workup pro-
cedure, the reaction mixture was diluted with water result-
ing in the formation of a thick paste. Upon addition of an
organic solvent (e.g., hexanes or dichloromethane), large
amounts of a fine solid precipitate of 3 were formed. This
could be collected by filtration, followed by washing with
further portions of organic solvent to leave crude 3 as a tan
solid. In our hands, recrystallisation from hot chloroform as
detailed by Chen7a returned the chloroform adduct of 3,
from which residual chloroform could not be removed even
after extended periods under reduced pressure. Multiple
cycles of re-slurrying the solid with dichloromethane fol-
lowed by evaporation of the solvent allowed the isolation of
solid 3 that was pure by 1H and 13C{1H} NMR analysis
(Scheme 3, b).
This material contained variable amounts of water as
evidenced by droplets present during recrystallisation and
slurrying. This water was not purged by filtration and had a
detrimental effect on the subsequent step. The azeotropic
removal of water from 3 was achieved through heating a
suspension of 3 at reflux in toluene using a Dean–Stark ap-
paratus. However, 3 was observed to dissolve in toluene at
reflux, so direct recrystallisation of crude 3 from toluene in
a Dean–Stark apparatus was considered as a possible sim-
Further syntheses of BTM have been reported,7a–c,15
based upon this original procedure.2 Incremental improve-
ments have been made by Chen and co-workers, finding
firstly that intermediate 3 can be purified by recrystallisa-
tion from chloroform,7a and secondly that the two reactions
could be performed sequentially in ‘one-pot’ without isola-
tion of 3.15 However, chromatography and recrystallisation
were still required to furnish pure BTM and the final yield
of crystalline material was not disclosed. Recently, Okamoto
and co-workers reported a conceptually different four-step
synthesis of BTM starting from o-bromoaniline.16
Although (R)- and (S)-4 are now commercially available
(ca. £ 90/1 g),17 the need for multi-gram quantities of race-
mic and enantiopure BTM (4) to support our investigations
into its use in catalysis motivated the development of a
scalable, operationally simple synthesis. Herein we report
the multi-gram synthesis of (R)-, (S)- and (±)-4 from com-
mercially available 2-chlorobenzothiazole (1) and 2-
phenylglycinol (2) without recourse to chromatographic
purifications (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 34–41

36
D. S. B. Daniels et al.
PSP
Synthesis
S
N
a)
b)
NH
i-Pr2NEt (2.5 equiv)
N
S
Ph
+
Ph
Cl
OH
H2N
1,2-Cl2C6H4 (2.0 M)
195 °C, 24 h
then H2O + hexane,
CH2Cl2 or toluene
OH
1
2
3
(1.0 equiv)
(1.05 equiv)
(crude)
S
N
S
hot CHCl3
CH2Cl2
NH
NH
N
3•xH2O
Ph
Ph
recrystallisation
trituration
•CHCl3
OH
OH
3
3•CHCl3
(crude)
c)
S
N
S
N
from 10.00 g 2:
hot toluene
NH
NH
(R)-3 14.81 g, 79%
(S)-3 13.91 g, 74%
( )-3 14.52 g, 77%
Ph
Ph
recrystallisation
Dean–Stark
OH
OH
3
3
(crude)
(pure)
Scheme 3 Optimisation of the first step
TsCl (1.5 equiv)
Et3N (3.0 equiv)
CH2Cl2, r.t. to Δ
S
N
plification to access analytically pure, anhydrous 3. Using
this process and starting from 10.00 grams of (R)-, (S)-, or
(±)-2,18 this procedure gave analytically pure, fluffy white
crystals of 3 consistently in 74–79% yield after one or two
recrystallisations from hot toluene in a Dean–Stark appara-
tus (Scheme 3, c).19
With large quantities of 3 easily accessible, the transfor-
mation of the alcohol functionality and cyclisation into
BTM 4 was examined. Employing Birman’s conditions of
methanesulfonyl chloride and triethylamine (Scheme 2)
followed by aqueous workup yields a yellow gum which, al-
though relatively pure by 1H NMR analysis, proved difficult
to transform into high yields of crystalline BTM by tritura-
tion or recrystallisation without recourse to chromatogra-
phy. This tentatively suggested the presence of polymeric
impurities that were largely silent by 1H NMR analysis.
Therefore, alternative activation methods for the alcohol
cyclisation were examined.
S
N
NH
N
Ph
Ph
or
Ph
SOCl2 (2.0 equiv)
toluene, Δ
OH
(R)-3
(R)-4 (BTM)
S
S
N
N
NH
DIAD (1.05 equiv)
Ph3P (1.1 equiv)
N
Ph
CH2Cl2, 0 ºC
OH
(R)-3
5
major product
Scheme 4 Alternative activating agents for the cyclisation of 3
ride were required for complete consumption of 3, even
with freshly distilled methanesulfonyl chloride under
strictly anhydrous conditions. TLC and H NMR analysis of
1
Both tosyl chloride and thionyl chloride gave unsatisfac-
tory results, with the former giving a complex mixture of
products and the latter incomplete conversion of 3 (Scheme
4). Interestingly, the reaction of 3 under Mitsonobu condi-
tions resulted in skeletal rearrangement to give isomeric
isothiourea 5 as the major species. The structure was in-
the reaction mixture indicated the formation of two prod-
ucts. Attempted chromatographic isolation of the two spe-
cies failed to allow isolation of purported O-mesylate 6
owing to its instability on silica gel. However, a second N,O-
bis-mesylate species 7 was isolated and characterised
(Scheme 5). Treating 3 with >2 equivalents of methanesul-
fonyl chloride allowed 7 to be produced exclusively without
any of the alternative isomeric N,O-bis-mesylate being ob-
served.20 Interestingly, heating a dichloromethane solution
of 7 at reflux in the presence of triethylamine and methanol
overnight gave BTM 4 as the sole product in excellent yield
after chromatography. This observation suggests that under
Birman’s original conditions a mixture of mono- and bis-
mesylate 6 and 7 forms with complete consumption of
1
ferred by comparison of the crude H NMR spectra to that
reported by Okamoto and co-workers.4 This unexpected re-
activity was not pursued further, and the fidelity of stereo-
chemical transfer was not determined.
As alternative activating agents were ultimately unsuc-
cessful, efforts were focused upon understanding and im-
proving the reaction of 3 with methanesulfonyl chloride. It
was found that >1.25 equivalents of methanesulfonyl chlo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 34–41

37
D. S. B. Daniels et al.
PSP
Synthesis
MsCl (1.25 equiv)
Et3N (2.0 equiv)
S
S
N
NH
N
+
(R)-3
N
Ph
Ph
OMs
CH2Cl2 (0.1 M)
0 °C
Ms
OMs
15 min
(R)-6
(R)-7
not isolated
MsCl
(2.5 equiv)
Et3N
Et3N
(3.0 equiv)
excess MeOH
S
N
S
N
N
(4.0 equiv)
N
Ph
OMs
(R)-3
CH2Cl2 (0.1 M)
0 °C, 15 min
CH2Cl2 (0.1 M)
Ms
Ph
Δ, 16 h
(R)-7 84%
(R)-4 (BTM) 89%
after chromatography
Scheme 5 Synthesis and cyclisation of N,O-bis-mesylate 7
methanesulfonyl chloride. Both components of this mixture
cyclise upon heating with base to give 4 exclusively, with
the sulfene eliminated from the cyclisation of bis-mesylate
7 quenched by methanol.21 Indeed, if a nucleophilic co-sol-
vent is absent the reaction turns black and the isolable yield
of BTM 4 is significantly reduced.
cluded a toluene azeotrope during the solvent switch to re-
move the remaining triethylamine, and treatment of the
final organic solution of 4 with charcoal to decolourise it.
Finally, trituration of the crude with hot diethyl ether pro-
vided analytically pure BTM (4) in consistently high yield
for both enantiomers and the racemate of 73–84% from 3
(Scheme 6).
With this information in hand, optimised conditions for
the cyclisation were established (Scheme 6). A suspension
of 3 and excess triethylamine (4.0 equiv) in anhydrous di-
chloromethane (0.1 M) was cooled in an ice/water bath. A
slight excess of methanesulfonyl chloride (1.3 equiv) was
added, sufficient to completely consume 3. The resulting
solution was treated with isopropanol,22 heated to reflux
overnight, and checked for completion by 1H NMR analysis.
These conditions consistently led to full conversion of 3 into
crude 4. An improved workup procedure was sought to
avoid chromatography, with the Brønsted basic nature of 4
considered an exploitable property through acid/base ex-
tractions. Hence, the reaction was quenched with aqueous
1 M sodium hydroxide to remove acidic impurities (MsOH,
etc.) and the dichloromethane layer extracted multiple
times with aqueous 1 M hydrochloric acid to leave an aque-
ous solution of BTM·HCl (4·HCl). Basification (aq 2 M NaOH,
pH >14) of the combined aqueous layers, extraction with an
organic solvent (EtOAc, Et2O, etc.), and concentration af-
forded solid 4 that was reasonably pure in ca. 50% yield.
This material could be triturated or recrystallised from di-
ethyl ether–hexanes to give analytically pure 4, demon-
strating that a chromatography-free route was plausible.
However, the loss of material was concerning until it was
discovered that BTM·HCl is highly soluble in dichlorometh-
ane, with multiple extractions with aqueous 1 M hydro-
chloric acid failing to completely remove it from the organic
layer. A solvent switch from dichloromethane to diethyl
ether (in which BTM·HCl is only sparingly soluble) was per-
formed after the aqueous 1 M sodium hydroxide wash and
this greatly increased the mass recovery of crude 4 after the
acid/base extractions. Final modifications to the workup in-
MsCl (1.3 equiv)
Et3N (4.0 equiv)
CH2Cl2 (0.1 M)
S
S
NH
0 °C to r.t.
N
N
Ph
N
then excess i-PrOH
Δ, 16 h
Ph
OH
(R)-3 12.42 g
(S)-3 13.15 g
( )-3 14.51 g
(R)-4 (BTM) 8.90 g, 77% (>99% ee)
(S)-4 (BTM) 8.96 g, 73% (>99% ee)
( )-4 (BTM) 11.37 g, 84%
Scheme 6 Optimised conditions of the synthesis of BTM (4)
In conclusion, the scalable, chromatography-free, and
operationally simple synthesis of the isothiourea organo-
catalyst BTM has been demonstrated. The transformation of
intermediate 3 with methanesulfonyl chloride has also
been investigated, showing that both mono- and bis-
mesylates 6 and 7 will cyclise to form BTM under the reac-
tion conditions.
Reactions were performed in oven-dried glassware, using DrySyn®
blocks for heated reactions. Anhydrous CH2Cl2 was obtained from an
MBraun SPS-800 system. 2-Chlorobenzothiazole was fractionally dis-
tilled under reduced pressure prior to use, i-Pr2NEt and Et3N were
stored over KOH pellets, and MsCl was distilled under reduced pres-
sure from P2O5 prior to use and stored in a fridge under N2.23 All other
solvents and commercial reagents were used as received without fur-
ther purification. Petroleum ether (PE) used refers to the fraction
boiling in the 40–60 °C range. Analytical TLC was performed on pre-
coated aluminum plates (Kieselgel 60 F254 silica). Plates were visual-
ised under UV light (254 nm) or by staining with KMnO4 followed by
heating. Flash column chromatography was performed on Kieselgel
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 34–41

38
D. S. B. Daniels et al.
PSP
Synthesis
60 silica in the solvent system stated. Melting points were recorded
on an Electrothermal 9100 melting point apparatus. Optical rotations
were measured on a PerkinElmer Precisely/Model-341 polarimeter
operating at the sodium D line with a 100 mm path cell at 20 °C. HPLC
analyses were obtained on a Shimadzu HPLC using a Chiralpak AD-H
column. GC analyses were obtained on a Shimadzu GC-2025, with He
as the carrier gas in split injection mode at constant linear velocity.
An Agilent DB-5 analytical column was used for analyses (30 m, 0.25
mm ID, 0.5 μm film thickness). IR spectra were recorded on a Shimad-
zu IRAffinity-1 Fourier transform IR spectrophotometer using a Pike
MIRacle ATR accessory. 1H and 13C{1H} NMR spectra were acquired on
Bruker 500 or 400 MHz spectrometers. Chemical shifts (δ) are quoted
in parts per million (ppm) and are referenced to the residual solvent
peak (1H: CDCl3 7.26 ppm, MeOH-d4 3.31 ppm; 13C: CDCl3 77.16 ppm,
MeOH-d4 49.00 ppm). Coupling constants (J) are quoted to the nearest
0.1 Hz. Mass spectrometry (HRMS) data were acquired by electro-
spray ionisation (ESI) at the EPSRC UK National Mass Spectrometry
Facility at Swansea University. Elemental analysis (CHN) was per-
formed by Mr. Stephen Boyer at London Metropolitan University.
GC [Agilent DB-5, 40 cm/s (He), inj. temp 250 °C, FID temp 325 °C;
temp profile: initial 120 °C (2 min), then ramp to 320 °C (20 °C/min,
hold 5 min), total run = 17 min]: tR i-Pr2NEt, 1.87 min; o-dichloroben-
zene, 3.20 min; 2-phenylglycinol (2), 5.34 min; 2-chlorobenzothi-
azole (1), 5.74 min; 3, 12.56 min.
HPLC (Chiralcel AD-H, 10% i-PrOH–hexane, 1.5 mL/min, 40 °C, 254
nm): tR 13.75 min (100%), >99% ee.
1H NMR (500 MHz, MeOH-d4): δ = 3.80 [1 H, dd, J = 11.4, 7.4 Hz,
C(1)HAHB], 3.85 [1 H, dd, J 11.4, 5.0 Hz, C(1)HAHB], 5.00 [1 H, dd, J = 7.4,
5.0 Hz, C(2)H], 7.03 (1 H, td, J = 7.5, 1.1 Hz, ArH), 7.22 (1 H, td, J = 7.5,
1.2 Hz, ArH), 7.26 (1 H, t, J = 7.4 Hz, p-PhH), 7.34 (2 H, t, J = 7.4 Hz, m-
PhH), 7.38 (1 H, d, J = 8.1 Hz, ArH), 7.44 (2 H, d, J = 7.4 Hz, o-PhH), 7.55
(1 H, d, J = 7.8 Hz, ArH).
13C{1H} NMR (126 MHz, MeOH-d4): δ = 62.2, 66.9, 119.0, 121.7, 122.7,
126.8, 128.1, 128.6, 129.5, 131.3, 141.1, 153.0, 169.0.
Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36. Found: C,
66.57; H, 5.31; N, 10.33.
1H and 13C NMR data were consistent with literature values.1
(R)-(–)-2-(Benzo[d]thiazol-2-ylamino)-2-phenylethanol [(R)-3]
(S)-(+)-2-(Benzo[d]thiazol-2-ylamino)-2-phenylethanol [(S)-3]
A 250 mL round-bottomed flask containing a stirrer bar was charged
with (R)-2-phenylglycinol [(R)-2; 10.00 g, 72.80 mmol, 1.05 equiv), o-
dichlorobenzene (34.5 mL, 2.0 M), i-Pr2NEt (31.0 mL, 173.6 mmol, 2.5
equiv), and 2-chlorobenzothiazole (1; 8.60 mL, 69.43 mmol, 1.0
equiv). The resulting yellow suspension was stirred vigorously and
heated to reflux at 195 °C (DrySyn® temperature), at which point the
suspended solid had dissolved to leave a yellow solution. After 24 h at
reflux,24 the orange reaction mixture was allowed to cool to r.t. Once
cooled, the mixture was diluted with distilled H2O (100 mL) and tolu-
ene (75 mL) with vigorous stirring. A precipitate formed over the next
15 min and stirring was maintained for a further 1 h. The reaction
mixture was filtered through a 1.0 L sintered glass filter funnel (po-
rosity 3) under vacuum to leave the solid precipitate. The solid was
washed with toluene (2 × 100 mL) and dried on the sinter under vacu-
um for 30 min until a free-flowing powder was obtained. The crude
product (typically 22–24 g) was transferred to a 500 mL round-bot-
tomed flask containing a stirrer bar, followed by toluene (100 mL). A
10 mL Dean–Stark trap filled with toluene and a reflux condenser
were fitted to the flask, and the suspension heated to reflux (180 °C
DrySyn® temperature). Once at reflux, further 10 mL portions of tolu-
ene were added down the condenser, waiting ~5 min between por-
tions, until a clear solution was obtained (4–6 portions were typically
needed). The reflux was maintained until no further H2O was ob-
served condensing into the trap (typically 30 min were sufficient).
The flask was removed from the heating block and allowed to cool
slowly to r.t., over which time a precipitate formed. Once cooled, the
flask was further cooled to –10 °C in a NaCl/ice/water bath for 30 min.
The solid precipitate was recovered by vacuum filtration on a 1.0 L
sintered glass filter funnel (porosity 3), and washed with further por-
tions of toluene (2 × 100 mL). The solid was dried on the sinter under
vacuum for 30 min, then transferred to a 250 mL round-bottomed
flask and dried in vacuo to constant weight. This gave title compound
(R)-3 as fluffy white crystals; yield: 14.81 g (54.78 mmol, 79%). A sec-
ond recrystallisation from toluene at reflux may be required if a pow-
der is obtained from the first attempt. Typical mass loss on second
recrystallisation was <500 mg on this scale; mp 158–159 °C (toluene)
[Lit.7b 159–160 °C (CHCl3)]; [α]D20 –102.7 (c 1.04, MeOH) {Lit.7b [α]D
–103 (c 1.17, MeOH)}.
An identical procedure to that outlined for (R)-3 using (S)-2-phenyl-
glycinol [(S)-2; 10.00 g, 72.80 mmol] gave the title compound (S)-3 as
fluffy white crystals after a second recrystallisation; yield: 13.91 g
(51.45 mmol, 74%); mp 158–159 °C (toluene); [α]D +101.7 (c 1.01,
MeOH).
20
HPLC (Chiralcel AD-H, 10% i-PrOH–hexane, 1.5 mL/min, 40 °C, 254
nm): tR 18.06 min (100%), >99% ee.
Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36. Found: C,
66.43; H, 5.36; N, 10.33.
All spectroscopic data were identical to those of (R)-3.
(±)-2-(Benzo[d]thiazol-2-ylamino)-2-phenylethanol [(±)-3]
An identical procedure to that outlined for (R)-3 using a mixture of
(R)-2-phenylglycinol [(R)-2; 5.00 g, 36.40 mmol] and (S)-2-phenylgly-
cinol [(S)-2; 5.00 g, 36.40 mmol] gave the title compound (±)-3 as
fluffy white crystals; yield: 14.52 g (53.71 mmol, 77%); mp 163–
164 °C (toluene).
HPLC (Chiralcel AD-H, 10% i-PrOH–hexane, 1.5 mL/min, 40 °C, 254
nm): tR 13.74 min (50%), 17.33 min (50%).
Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36. Found: C,
66.49; H, 5.35; N, 10.44.
All spectroscopic data were identical to those of (R)-3.
(R)-(+)-2-Phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole [(R)-
(+)-BTM; (R)-(+)-4]
A 1.0 L round-bottomed flask containing a stirrer bar was charged
with anhydrous CH2Cl2 (460 mL, 0.1 M) followed by (R)-3 (12.42 g,
45.94 mmol, 1.0 equiv) with stirring and fitted with a suba seal and
exit needle (19 gauge). Et3N (25.6 mL, 183.8 mmol, 4.0 equiv) was
added via syringe and the suspension cooled in an ice/water bath. Af-
ter 10 min, MsCl (4.62 mL, 59.72 mmol, 1.3 equiv) was added drop-
wise over ca. 5 min, during which time the suspension dissolved to
give a pale yellow solution. The ice/water bath was removed and the
reaction mixture stirred for 15 min. The reaction was checked by TLC
[CH2Cl2–Et2O 1:1, UV254/KMnO4, Rf (R)-3 = ~0.28; 6 = 0.61; 7 = 0.81]
and a further portion of MsCl (0.36 mL, 4.6 mmol, 0.1 equiv) added if
(R)-3 remained (stir 15 min, re-check TLC, and repeat if necessary). It
is crucial that all (R)-3 was consumed. Once complete consumption of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 34–41

39
D. S. B. Daniels et al.
PSP
Synthesis
(R)-3 was observed, i-PrOH (9.0 mL) was added and the suba seal re-
placed by a reflux condenser. The reaction mixture was heated to re-
flux (50 °C DrySyn® temperature) overnight (ca. 18 h) and checked for
completion by 1H NMR analysis. The reaction was quenched with aq 1
M NaOH (200 mL) and the biphasic mixture stirred vigorously for 30
min. The layers were separated and the aqueous layer extracted with
CH2Cl2 (100 mL). The combined organics were washed with brine
(100 mL), dried (MgSO4), filtered, and concentrated in vacuo. The
crude residue was azeotroped with toluene (3 × 50 mL) to remove
most of the residual Et3N. The residue was triturated with Et2O (200
mL) with sonication and the liquid collected by decantation through a
plug of cotton wool. This was repeated with two further portions of
Et2O (100 mL), filtering the final portion through the cotton wool. The
filter cake was rinsed with a further portion of Et2O (50 mL). The
combined ethereal washings were extracted with aq 1 M HCl (5 × 50
mL) and the combined aqueous layers basified with aq 2 M NaOH (pH
>14) at which point a cloudy white precipitate formed. The aqueous
layer was extracted with Et2O (3 × 100 mL) and the combined organ-
ics washed with brine (100 mL). The organic layer was treated with
activated charcoal (~5 g) and dried (MgSO4). The suspension was fil-
tered through a pad of Celite, rinsing with further portions of Et2O
(2 × 100 mL). The solvent was removed in vacuo to leave the crude
product as a white to pale yellow solid (9.81 g). This solid was sus-
pended in Et2O (50 mL, ~5 mL/g crude), scraping any residues from
the side of the flask, and heated to reflux for 30 min (the solid did not
completely dissolve). An equal volume of PE (50 mL) was added and
the flask allowed to cool to r.t. with stirring. Once cooled, the solid
was collected by vacuum filtration on a 100 mL sintered glass filter
funnel (porosity 3), washing with further portions of PE (3 × 50 mL).
The solid was dried on the sinter under vacuum for 30 min, then
transferred to a 100 mL round-bottomed flask and dried in vacuo to
constant weight to leave pure (R)-(+)-BTM [(R)-(+)-4] (7.83 g) as
white to off-white crystals. A second crop (1.07 g) was obtained by
concentration of the filtrate in vacuo and repetition of the above trit-
uration procedure (5 mL/g Et2O, equal volume PE). Both crops gave
identical melting points and optical rotations, so were combined to
give (R)-(+)-BTM [(R)-(+)-4] as white crystals; total yield: 8.90 g
(35.27 mmol, 77%); mp 89–90 °C [Lit.2 mp 94.5–95 °C (Et2O–hex-
ane)]; [α]D20 +255.4 (c 1.05, MeOH) {Lit.2 [α]D +256.7 (c 1.00, MeOH)}.
HPLC (Chiralcel AD-H, 10% i-PrOH–hexane, 1.5 mL/min, 40 °C, 254
nm): tR 20.98 min (100%), >99% ee.
Anal. Calcd for C15H12N2S: C, 71.40; H, 4.79; N, 11.10. Found: C, 71.25;
H, 4.91; N, 10.95.
All other spectroscopic data were identical to those of (R)-(+)-BTM.
(±)-2-Phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole [(±)-
BTM; (±)-4]
An identical procedure to that outlined for (R)-(+)-BTM using (±)-3
(14.51 g, 53.67 mmol), MsCl (5.40 mL, 69.77 mmol), and Et3N (30.0
mL, 214.7 mmol) in anhydrous CH2Cl2 (540 mL) gave (±)-BTM [(±)-4]
in two crops as white crystals; yield: 11.37 g (45.06 mmol, 84%); mp
94–95 °C.
HPLC (Chiralcel AD-H, 10% i-PrOH–hexane, 1.5 mL/min, 40 °C, 254
nm): tR 13.42 min (50%), 20.95 min (50%).
Anal. Calcd for C15H12N2S: C, 71.40; H, 4.79; N, 11.10. Found: C, 71.28;
H, 4.91; N, 10.97.
All other spectroscopic data were identical to those of (R)-(+)-BTM.
(R)-2-[N-(Benzo[d]thiazol-2-yl)methylsulfonamido]-2-phenyleth-
yl Methanesulfonate [(R)-7]
A 100 mL round-bottomed flask containing a stirrer bar was charged
with (R)-3 (500 mg, 1.85 mmol, 1.0 equiv) and anhydrous CH2Cl2 (20
mL). Et3N (1.03 mL, 7.40 mmol, 4.0 equiv) was added, the suspension
cooled in an ice/water bath, and MsCl (0.36 mL, 4.63 mmol, 2.5 equiv)
added dropwise over 2 min. The reaction mixture was stirred for 10
min, checked by TLC (CH2Cl2–Et2O, 1:1) and quenched with sat. aq
NaHCO3 (20 mL). The layers were separated and the aqueous layer ex-
tracted with CH2Cl2 (20 mL). The combined organics were washed
with aq 0.1 M HCl (30 mL), dried (MgSO4), and filtered. The solvent
was removed in vacuo to leave the crude product, which was purified
by flash chromatography on silica gel (CH2Cl2) to leave (R)-7 as a co-
lourless foam; yield: 661 mg (1.55 mmol, 84%); [α]D20 +31.8 (c 1.0, CH-
Cl3).
IR (film): 3028, 2936, 1636, 1580, 1454, 1352, 1244, 1173, 1157,
1034, 961 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.97 (3 H, s, OSO2CH3), 3.67 (3 H, m,
NSO2CH3), 4.33–4.52 [2 H, m, C(2)H and C(1)HAHB], 4.55 [1 H, dd, J =
8.4, 7.2 Hz, C(1)HAHB], 7.12 (1 H, td, J = 7.6, 1.1 Hz, ArH), 7.20–7.27 (2
H, m, ArH), 7.30–7.40 (3 H, m, m- and p-PhH), 7.43–7.46 (2 H, m, o-
PhH), 7.98 (1 H, dd, J = 8.5, 0.7 Hz, ArH).
13C{1H} NMR (100 MHz, CDCl3): δ = 37.7, 42.7, 68.1, 73.8, 115.8, 122.3,
122.4, 124.6, 126.9, 127.8, 128.6, 129.0, 136.0, 137.2, 154.8.
HPLC (Chiralcel AD-H, 10% i-PrOH–hexane, 1.5 mL/min, 40 °C, 254
nm): tR 13.41 min (100%), >99% ee.
1H NMR (500 MHz, CDCl3): δ = 3.72 [1 H, dd, J = 8.9, 8.1 Hz, C(3)HAHB],
4.28 [1 H, dd, J = 10.2, 8.9 Hz, C(3)HAHB], 5.67 [1 H, dd, J 10.2, 8.1 Hz,
C(2)H], 6.67 (1 H, dd, J = 8.0, 1.1 Hz, ArH), 6.97 (1 H, td, J = 7.7, 1.1 Hz,
ArH), 7.19 (1 H, td, J = 7.7, 1.2 Hz, ArH), 7.27–7.32 (1 H, m, p-PhH),
7.31 (1 H, dd, J = 7.7, 1.1 Hz, ArH), 7.35–7.40 (4 H, m, o-, and m-PhH).
13C{1H} NMR (126 MHz, CDCl3): δ = 52.6, 75.5, 108.6, 121.6, 123.3,
126.6, 126.7, 127.5, 127.7, 128.9, 137.2, 143.1, 166.8.
HRMS (ESI): m/z [M + H+] calcd for C17H19N2O5S3: 427.0451; found:
427.0441 (–2.5 ppm).
Anal. Calcd C15H12N2S: C, 71.40; H, 4.79; N, 11.10. Found: C, 71.28; H,
4.67; N, 11.07.
1H and 13C NMR data were consistent with literature values.2
Cyclisation of (R)-7 To Form (R)-BTM
A 50 mL round-bottomed flask containing a stirrer bar and fitted with
a reflux condenser was charged with (R)-7 (650 mg, 1.52 mmol, 1.0
equiv), Et3N (0.64 mL, 4.57 mmol, 3.0 equiv), anhydrous CH2Cl2 (15
mL), and MeOH (1.0 mL). The resulting solution was heated to reflux
overnight, allowed to cool, and quenched with aq 1 M NaOH (20 mL).
The layers were separated and the aqueous layer was extracted with
CH2Cl2 (20 mL). The combined organics were dried (MgSO4), filtered,
and the solvent removed in vacuo to leave the crude product, which
was purified by flash chromatography on silica gel (CH2Cl2 → 1:4
Et2O–CH2Cl2) to leave pure noncrystalline (R)-BTM [(R)-4] as a white
powder; yield: 341 mg (1.35 mmol, 89%). This material was not re-
crystallised.
(S)-(–)-2-Phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole [(S)-
(–)-BTM; (S)-(–)-4]
An identical procedure to that outlined for (R)-(+)-BTM 4 using (S)-3
(13.15 g, 48.64 mmol), MsCl (4.89 mL, 63.23 mmol), and Et3N (27.1
mL, 194.6 mmol) in anhydrous CH2Cl2 (490 mL) gave (S)-(–)-BTM [(S)-
(–)-4] in two crops as white crystals; yield: 8.96 g (35.51 mmol, 73%);
mp 89–90 °C; [α]D20 –256.5 (c 0.98, MeOH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 34–41

40
D. S. B. Daniels et al.
PSP
Synthesis
1H NMR spectrum was identical to that prepared by the optimised
route.
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Acknowledgment
We thank the Royal Society for a University Research Fellowship
(ADS), the EPSRC (EP/J018139/1, DSBD), and GSK (Case award to SRS)
for funding. We also thank the European Research Council under the
European Union’s Seventh Framework Programme (FP7/2007-2013)
ERC grant agreement number 279850 for additional funding, and the
EPSRC UK National Mass Spectrometry Service Centre at Swansea
University.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378931.
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D. S. B. Daniels et al.
PSP
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(19) See experimental for details.
(20) The site of N-mesylation was determined by 1H-15N HMBC spec-
troscopy, supported by DFT calculations for the 15N chemical
shifts. See Supporting Information for details.
(21) Birman states that the addition of MeOH serves to quench addi-
tional MsCl, see ref. 1.
(22) MeOH was replaced with i-PrOH as it was considered that the
by-product i-PrOMs from reaction with sulfene would be less
reactive as an alkylating agent than MeOMs, thereby reducing
polymeric impurities.
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(17) From TCI-UK Ltd.: (R)-BTM P/N: B3296, £ 94.20/1 g; (S)-BTM
P/N: B3549, £ 83.45/1 g (accessed 22/08/2014).
(18) Racemic 2-phenylglycinol is prohibitively expensive and was
obtained by mixing equal amounts of the commercially avail-
able (R)- and (S)-2-phenylglycinols.
(23) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chem-
icals, 6th ed.; Butterworth-Heinemann: Oxford, 2009.
(24) GC analysis indicated >95% conversion of 2-chlorobenzothiazole
against o-dichlorobenzene as the internal standard. Approxi-
mately 200 μL samples of the reaction mixture at t = 0 and 24 h
were taken and diluted to ~1.5 mL in CH2Cl2 for analysis.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 34–41