One-pot thiourea formation-palladium-catalyzed cyclization sequence to 3,4-dihydro-2H-1,3-benzothiazine-2-imines from 2-halo N-methylbenzylamine - Scope and limitations

Article abstract of DOI:10.1055/s-0032-1317381

A practical synthesis of 3,4-dihydro-3-methyl-2H-1,3-benzothiazine-2-imine via intramolecular palladium-catalyzed C-S bond formation is presented and exemplified for both alkyl- and arylisothiocyanates. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317381

LETTER
▌2639
letter
One-Pot Thiourea Formation–Palladium-Catalyzed Cyclization Sequence to
3,4-Dihydro-2H-1,3-benzothiazine-2-imines from 2-Halo N-Methylbenzyl-
amine – Scope and Limitations
3,4-Dihydro-2H-1,3-benzothiazine-2-imines
Franck Lach*
AstraZeneca, Parc Industriel Pompelle, Chemin de Vrilly, BP 1050-51698 Reims, Cedex 2, France
Fax +33(3)26616842; E-mail: franck.lach@astrazeneca.com; E-mail: franck_lach@hotmail.com
Received: 09.08.2012; Accepted after revision: 17.09.2012
(2) compared to the less readily available 2-iodo analogue
Abstract: A practical synthesis of 3,4-dihydro-3-methyl-2H-1,3-
would permit extension of scope to further variations on
benzothiazine-2-imine via intramolecular palladium-catalyzed C–S
the core structure. Only two examples of related intra-
bond formation is presented and exemplified for both alkyl- and
molecular palladium-mediated thiourea cyclization from
bromoarenes have been reported, with variable yield.6,7 In
this letter, we present a concise route that is amenable to
the introduction of both alkyl- and arylisothiocyanates as
highly variable substrates (Scheme 1, equation 5). Opti-
arylisothiocyanates.
Key words: palladium, heterocycles, sulfur, ring closure, catalysis
In the course of a recent research program, a direct synthe-
sis of a series of 3,4-dihydro-3-methyl-2H-1,3-benzo-
thiazine-2-imines, that would be amenable to parallel
synthesis, was required. According to the literature, the
3,4-dihydro-2H-1,3-benzothiazine-2-imine motif can be
accessed via photocyclization of an anionic thiocarbonyl
sulfur species with a proximate chloroarene moiety
(Scheme 1, equation 1),1 or by tandem pyrolysis of 2H-
benzo[b]thiet 12 and [8π + 2π] hetero Diels–Alder cyclo-
addition with N,N′-dialkyl or diarylcarbodiimide di-
polarophiles (Scheme 1, equation 2).3 However, neither of
those approaches conveniently introduces diversity at the
C2 imine position. A broader variation on the 3,4-di-
hydro-2H-1,3-benzothiazine-2-imine core was described
by Ohno with a one-pot thiourea formation and key intra-
molecular SNAr on a bromoarene scaffold to set up the
carbon–sulfur bond (Scheme 1, equation 3).4 Noticeably,
the reported SNAr proved to be effective only with an ac-
tivated bromoarene having a σ- or π-acceptor substituent
in the ortho position, which is in turn a clear limitation.5
In a recent alternative, Orain et al. published a two-step
synthesis of 3,4-dihydro-2H-1,3-benzothiazine-2-imines
from 2-iodo N-methyl benzylamine derivatives and sub-
stituted phenylisothiocyanates. In this process, limited to
the use of arylisothiocyanates, the key C–S bond was set
up through a regioselective intramolecular palladium-
mediated cyclization between the thiourea moiety and the
iodoarene (Scheme 1, equation 4).6 Although this route is
suitable for a late-stage incorporation of a C2 imine sub-
stituent, we felt there was still significant room for im-
provement: firstly to achieve a more practical one-pot
process; whereby the intermediate thiourea would not be
isolated. Secondly, from a methodological viewpoint, the
use of the less expensive 2-bromo N-methylbenzylamine
S
Ar
hν, N2
HN
N
N
2 M NaOH, MeCN
N
N
N
(1)
41–45% yield
Ar
Cl
S
Ramakrishnan's work
RN=C=NR
R
N
N
R
S
S
toluene, 110 °C
S
(2)
24–72% yield
1
Meier's work
R = Alk, Ar
t-BuNCS, NaH, DMF
49% yield
N
N
N
N
NH
t-Bu
(3)
S
Br
Ohno's work
H
Me
R
N
N
N
R
i. ArNCS, dioxane, Et3N
ii. Pd0, Et3N, dioxane, Δ
Ar
(4)
Me
S
I
63–83% yield
(over 2 steps)
R = H, Et
2 examples
Orain's work
Me
N
H
N
RNCS , L, Pd2(dba)3,
Cs2CO3, toluene, Δ
N
R
Me
Br
S
(5)
47–100% yield
(one pot)
R = Alk, Ar
2
10 examples
This work
Scheme 1 Various synthetic approaches towards the 3,4-dihydro-3-
methyl-2H-1,3-benzothiazine-2-imine motif
SYNLETT 2012, 23, 2639–2642
Advanced online publication: 12.10.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317381; Art ID: ST-2012-D0677-L
© Georg Thieme Verlag Stuttgart · New York

2640
F. Lach
LETTER
Table 1 Synthesis of 3,4-Dihydro-3-methyl-2H-1,3-benzothiazine-
2-imine (continued)
mization of our novel one-pot two-step process was initi-
ated by reacting 2 with cyclohexyl isothiocyanate as a
model substrate (Table 1, entry 1). Initial assessment of
the two previously reported conditions for intramolecular
thiourea C–S bond formation with bromoarenes resulted
in disappointing outcomes.
Me
H
N
N
N
RNCS, L, Pd,
R
Me
base, solvent, Δ
S
Br
Table 1 Synthesis of 3,4-Dihydro-3-methyl-2H-1,3-benzothiazine-
2-imine
3a–j
2
Entry RNCS
Product
Yield
(%)a
Me
H
N
N
N
RNCS, L, Pd,
base, solvent, Δ
R
Me
Me
N
S
Br
N
OMe
77b
S
MeO
NCS
7
3a–j
2
Entry RNCS
Product
Yield
(%)a
3g
3h
Me
N
Me
N
N
N
N
N
100b
NCS
c
S
NCS
8
9
82b
–
S
S
S
1
(26)d
(57)e
3a
3b
3c
Me
N
Me
N
N
O
34b
66f
O
NCS
S
O
NCS
2
78b
O
3i
3j
Me
N
Me
N
O
N
NCS
b
O
–
S
10
57f
3
95b
NCS
a Isolated yields.
Me
N
b Unless otherwise noted all the reactions were performed in a sealed
vessel with 2 (0.7 mmol), RNCS (1.1 equiv), Cs2CO3 (2.2 equiv),
Pd2(dba)3 (0.05 equiv), and Xantphos (0.1 equiv) in dry degassed tol-
uene (1.4–1.5 mL) at 100–105 °C for 8–16 h.
N
N
N
S
S
S
NCS
4
47b
c Control reaction: same conditions as b) but without any ligand and
palladium source.
d Conversion by HPLC at λ = 254 nm for the following reaction con-
ditions: 2 (0.7 mmol), RNCS (1.1 equiv), Et3N (2.0 equiv), Pd[PPh3]4
(0.10 equiv), Ph3P (0.10 equiv) in dry degassed dioxane (1.2–1.3 mL)
at 100 °C for 16 h.
3d
3e
3f
Me
N
e Conversion by HPLC at λ = 254 nm for the following reaction con-
ditions: 2 (0.7 mmol), RNCS (1.1 equiv), Cs2CO3 (2.2 equiv), Pd[P(t-
Bu)3]2 (0.10 equiv) in dry degassed dioxane (1.2–1.3 mL) at 95–
100 °C for 16 h.
5
6
97b
NCS
f Reaction conditions: 2 (0.7 mmol), RNCS (1.1 equiv), Cs2CO3 (2.7
equiv), Pd2(dba)3 (0.12–0.15 equiv) and DPPF (0.25–0.30 equiv) in
dry degassed toluene (1.5 mL) at 125–130 °C for 24–32 h.
Me
N
NEt2
87b
Et2N
NCS
Thus, a combination of monodendate ligand Ph3P with
Et3N in refluxing dioxane led to a sluggish reaction and
modest conversion. Alternatively, a mixture of strongly
basic and hindered Fu’s phosphine [P(t-Bu)3] and Cs2CO3
Synlett 2012, 23, 2639–2642
© Georg Thieme Verlag Stuttgart · New York

LETTER
3,4-Dihydro-2H-1,3-benzothiazine-2-imines
2641
electron donating than Xantphos and thus tends to disfa-
vor reductive elimination.11,12 A control experiment was
next conducted in order to probe whether intramolecularity
plays a role in the key C–S bond formation. Thus, a mix-
ture of bromobenzene, diethylamine, and cyclohexyl iso-
thiocyanate was reacted under standard conditions to
NMe
S
NMe
R
N
L = ligand
S
NR
Pd
Pd
L
L
L
4
5
Figure 1 Putative κ2-‘isothioamidate’complex 4 and κ1-‘isothioami- deliver the arylated isothiourea 6 in quantitative yield
date’complex 5
(Scheme 2). Apparently, intramolecularity is not a key
driver for the coupling. We believe that the wide-bite-
in dioxane afforded better conversions (still less than two
angle bidendate chelating ligand imposes a great steric
thirds), but the reaction did not proceed to completion at
100 °C. By analogy with the known reluctance of aryl-
strain on the seven-membered ring isothioamidate com-
plex 5, promoting fast reductive elimination of palladium-
bound substituents. The associated cost in energy could
somehow compensate for favorable six-membered ring
amidate complexes to undergo fast reductive elimination
from palladiumII due to κ2-amidate coordination,8 we hy-
pothesized that a putative κ2-‘isothioamidate-type’ com-
formation.
plex 4 may arise in the catalytic cycle (Figure 1), thus
Et2N
N
inhibiting reductive elimination and therefore catalytic
turnover. It has also been shown that the use of large-bite-
angle bidendate ligands prevents κ2-binding modes.9
Et2NH
NCS
Br
S
+
Xantphos, Pd2(dba)3,
Cs2CO3, toluene, 120 °C
Gratifyingly, we found that a system of Xantphos,
Pd2(dba)3, and Cs2CO3 in toluene afforded 3a in quantita-
tive yield. To rule out a possible thiourea cyclization driv-
en by SNAr, a control experiment was carried out under
similar conditions, omitting the catalytic system and, as
expected, no trace of 3a was found. Our protocol was next
exemplified with a range of alkyl isothiocyanates (Table
1, entries 2–8), providing the corresponding 3,4-dihydro-
2H-1,3-benzothiazine-2-imines 3b–h in moderate to ex-
cellent yields.10 Notably, esters and basic groups were tol-
erated in the reaction. Unfortunately, phenyl- and to a
lesser extent benzyl isothiocyanates reacted poorly under
those conditions (Table 1, entries 9 and 10). This trend
was assigned to both a lower nucleophilicity of the inter-
mediate thiourea and an increased ionic character of the
PdII ‘isothioamidate’ complex leading to a stronger Pd–S
bond.9 The reductive elimination was therefore slower
and occurred in very low yield. Eventually, we were able
to achieve reasonable conversion rates and deliver prod-
ucts 3i–j in acceptable yields by increasing temperature,
reaction time, catalyst loading, and using DPPF as an al-
ternative ligand. Although we cannot provide a clear ex-
planation for this ligand effect, we suggest that the
chelating bidendate ligand maintains a fast rate of reduc-
tive elimination for steric reasons – in other words, by en-
forcement of cis geometry and angle minimization
between the two metal-bound substituents. Electronic fac-
tors in this case cannot be invoked since DPPF is more
6
100% yield
Scheme 2 Intermolecular palladium-catalyzed isothiourea coupling
with bromobenzene
In order to expand the scope of the reaction to commer-
cially available chloroarene 7, several attempts using
monodendate ligands were performed but all met with
failure (Scheme 3). More specifically, reactions conduct-
ed in the presence of commercially available bipyrazole
BippyPhos (Figure 2),13 or Buchwald’s XPhos, ligands,
known to promote, respectively, smooth intermolecular
coupling of chloroarenes with phenylureas, and intermo-
lecular o-chloroanilines urea cyclizations afforded 3a
only in trace amounts.14,15 It is recognized that both steri-
cally demanding ligands facilitate dissociation to mono-
phosphine–palladium adducts to which the chloroarene
rapidly oxidatively adds as a result of the phosphine elec-
tron density.16,17 In addition, coordination of the isothio-
urea with the monophosphine LPd(Ar)Cl complex should
also be faster relative to the coordinatively saturated
L2Pd(Ar)Cl complex.8 Therefore, the poor results ob-
served in this C–S bond formation may again stem from
problematic reductive elimination.
In conclusion, a simple procedure to rapidly access the
3,4-dihydro-2H-1,3-benzothiazine-2-imine motif in the
o-bromoarene series has been developed using Pd0 chem-
PPh2
P(Cy)2
N
i-Pr
i-Pr
Fe
N
(t-Bu)2P
O
N
N
PPh2
PPh2
PPh2
i-Pr
Xantphos
DPPF
XPhos
BippyPhos
Figure 2 Ligands used for Pd0-catalyzed isothiourea arylation
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2639–2642

2642
F. Lach
LETTER
Me
NH
Me
N
a. BippyPhos, Pd2(dba)3, DME (or toluene)
K3PO4, 100–110 °C
N
NCS
b. XPhos, Pd(OAc)2, t-BuOH (or i-PrOH),
Cl
S
K3PO4 (or K2CO3), 110–120 °C
X
+
3a
7
Scheme 3 Attempted palladium-mediated C–S bond formation from chloroarene 7
(5) For references on the thermal synthesis of 2-amino
benzothiazoles via base-promoted cyclization of
o-bromophenylthiourea and the rationale about factors
involved in such a SNAr activation, see: (a) Feng, E.; Huang,
H.; Zhou, Y.; Ye, D.; Jiang, H.; Liu, H. J. Comb. Chem.
2010, 12, 422. (b) Ding, Q.; Huang, X.; Wu, J. J. Comb.
Chem. 2009, 11, 1047.
istry and validated with both alkyl- and arylisothiocya-
nates. Utilization of wide-bite-angle bidendate ligands
was found to be crucial for successful outcomes. Applica-
tion of the current methodology to substituted o-bromo
N-alkyl benzylamine substrates is under way and will be
reported in due course.
(6) Orain, D.; Blumstein, A.; Tasdelen, E.; Haessig, S. Synlett
2008, 2433.
(7) Hardy, S.; Martin, S. F. Org. Lett. 2011, 13, 3102.
(8) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2007, 129, 13001.
(9) Fujita, K.; Yamashita, M.; Puschmann, F.; Alvarez-Falcon,
M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 9044.
Acknowledgment
The author would like to thank Richard Ducray and Gilles Ouvry
for revising the manuscript, Paul Davey for analytical support, and
Patrice Koza for RP-HPLC purifications.
(10) For a general procedure and spectroscopic data for final
compounds 3a–j, see the Supporting Information.
(11) Hammann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998,
120, 7369.
(12) Suparabhorn, S.; Lange, S.; Chen, W.; Xiao, J. J. Mol. Catal.
A 2003, 196, 125.
(13) Singer, R. A.; Dore, M.; Sieser, J. E.; Berliner, M. A.
Tetrahedron Lett. 2006, 47, 3727.
(14) Kotecki, B. J.; Fernando, D. P.; Haight, A. R.; Lukin, K. A.
Org. Lett. 2009, 11, 947.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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Synlett 2012, 23, 2639–2642
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