Efficient synthesis of pyrimido[1,2-c] [1,3]benzothiazin-6-imines and related tricyclic heterocycles by SNAr-type C-S, C-N, or C-O bond formation with heterocumulenes

Article abstract of DOI:10.1021/jo902327n

(Chemical Equation Presented) A simple and practical synthetic method of pyrimido[1,2-c]-[1,3]benzothiazin-6-imines and related tricyclic heterocycles has been developed. Treatment of 2-(2-haloaryl)-tetrahydropyrimidines with NaH and a heterocumulene such as carbon disulfide, isothiocyanates, and isocyanates in DMF provides the desired cyclization products through a regioselective S _NAr-type reaction. This method provides direct access to PD 404182 and related compounds.

Full text of DOI:10.1021/jo902327n

pubs.acs.org/joc
(SAR) of PD 404182 has not been carried out, presumably due to
Efficient Synthesis of Pyrimido[1,2-c]
[1,3]benzothiazin-6-imines and Related Tricyclic
Heterocycles by SNAr-Type C-S, C-N, or C-O
Bond Formation with Heterocumulenes
the lack of an efficient synthetic method suitable for lead optimiza-
tion, as well as the cost of commercially available PD 404182.3
To develop a reliable, short-step synthetic method of
tricyclic heterocycles related to PD 404182, we planned a
novel strategy based on carbon (sp2)-heteroatom bond
formation using 2-(2-haloaryl)tetrahydropyrimidine deriva-
tives. The carbon-heteroatom bond formation reaction is
becoming a powerful methodology for construction of var-
ious heterocycles, providing several biologically active com-
pounds.4 The nucleophilic aromatic substitution (SNAr)
reaction is a well-established transition metal-free5,6 car-
bon-heteroatom bond formation reaction.7,8 In general,
the SNAr reaction requires harsh conditions (>100 °C)
and/or sufficiently activated aromatic rings by powerful
electron-withdrawing group(s) (e.g., nitro). We describe a
direct synthesis of tricyclic heterocycles related to PD 404182
by a regioselective SNAr-type reaction of tetrahydropyrimi-
dine-substituted haloarenes with heterocumulene in the
absence of additional electron-withdrawing groups.9 The
efficient short-step synthesis of PD 404182 is also presented.
Tsukasa Mizuhara, Shinya Oishi, Nobutaka Fujii,* and
Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto
University, Sakyo-ku, Kyoto 606-8501, Japan
nfujii@pharm.kyoto-u.ac.jp; hohno@pharm.kyoto-u.ac.jp
Received October 30, 2009
(3) $76.20/2 mg, Sigma-Aldrich.
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formation, see: (a) Hartwig, J. F. Synlett 1997, 329–340. (b) Baranano, G.
M.; Hartwig, J. F. Curr. Org. Chem. 1997, 1, 287–305. (c) Hartwig, J. F.
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Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
A simple and practical synthetic method of pyrimido[1,2-c]-
[1,3]benzothiazin-6-imines and related tricyclic hetero-
cycles has been developed. Treatment of 2-(2-haloaryl)-
tetrahydropyrimidines with NaH and a heterocumulene
such as carbon disulfide, isothiocyanates, and isocyanates
in DMF provides the desired cyclization products through a
regioselective SNAr-type reaction. This method provides
direct access to PD 404182 and related compounds.
(5) Separation of the transition metal catalyst sometimes can be proble-
matic during the synthesis of pharmaceuticals and fine chemicals because of
their residual toxicity. For recent examples on transition metal-free car-
bon-heteroatom bond formation via benzyne intermediate, see: (a) Shi, L.;
Wang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Org. Lett. 2003, 5, 3515–
3517. (b) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673–4675. (c) Narayan,
S.; Seelhammer, T.; Gawley, R. E. Tetrahedron Lett. 2004, 45, 757–759. (d)
Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99–102. (e) Liu, Z.; Larock, R. J.
Org. Chem. 2006, 71, 3198–3209. (f) Bolliger, J. L.; Frech, C. M. Tetrahedron
2009, 65, 1180–1187.
The pyrimidobenzothiazine derivative PD 404182 (1) was
recently discovered to be an antibiotic agent (Figure 1).1,2
(6) (a) Carroll, M. A.; Wood, R. A. Tetrahedron 2007, 63, 11349–11354.
(b) Rey, V.; Soria-Castro, S. M.; Arguello, J. E.; Penenory, A. B. Tetrahedron
Lett. 2009, 50, 4720–4723.
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Bunnet, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273–412. (b) Buncel, E.;
Dust, J. M.; Terrier, F. Chem. Rev. 1995, 95, 2261-2280 and references cited
therein.
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see: (a) Annulli, A.; Mencarelli, P.; Stegel, F. J. Org. Chem. 1984, 49, 4065–
4067. (b) Gorvin, J. H. J. Chem. Soc., Perkin Trans. 1 1988, 1331–1335. (c)
Raeppel, S.; Raeppel, F.; Suffert, J. Synlett 1998, 794–796. (d) Ratz, A. M.;
Weigel, L. O. Tetrahedron Lett. 1999, 40, 2239–2242. (e) Rogers, J. F.; Green,
D. M. Tetrahedron Lett. 2002, 43, 3585–3587. (f) Grecian, S. A.; Hadida, S.;
Warren, S. D. Tetrahedron Lett. 2005, 46, 4683–4685. (g) Barbero, N.;
FIGURE 1. Structure of PD 404182.
This compound inhibits 3-deoxy-D-manno-octulosonic acid
8-phosphate (KDO 8-P) synthase, which catalyzes the condensa-
tion of phosphoenolpyruvate and arabinose 5-phosphate in the first
committed step in the synthesis of KDO (an integral part of the
lipopolysaccharide layer in Gram-negative bacteria). PD 404182 is
considered to be an important lead in the development of struc-
turally novel antibiotics effective against multidrug-resistant
bacteria.2b Extensive study of the structure-activity relationship
SanMartin, R.; Domınguez, E. Tetrahedron 2009, 65, 5729–5732.
´
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Org. Chem. 1976, 41, 3564–3568. (b) Leymarie-Beljean, M.; Pays, M.; Richer,
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Liepa, A. J. Aust. J. Chem. 1987, 40, 1179–1190. (d) Easmon, J.; Heinisch, G.;
€
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DOI: 10.1021/jo902327n
r
Published on Web 12/08/2009
J. Org. Chem. 2010, 75, 265–268 265
2009 American Chemical Society

Mizuhara et al.
JOCNote
a
TABLE 1. Optimization of Reaction Conditions with CS2
TABLE 2. Reaction of Substituted 2-(2-Halophenyl)-1,4,5,6-tetrahy-
dropyrimidinesa
entry
X
base (equiv)
solvent
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
Br
Br
Br
Br
Br
Br
Br
Br
F
NaH (5)
NaH (5)
NaH (5)
NaH (2)
none
Et3N (2)
KH (2)
NaOt-Bu (2)
NaH (2)
MeCN
THF
4
4
6
12
12
12
6
6
12
trace
trace
75
88
12
trace
trace
27
DMF
DMF
DMF
DMF
DMF
DMF
DMF
86
aAll reactions were carried out at 80 °C with 2 or 5 equiv of CS2
(corresponding to the base loading). bIsolated yields.
Initial experiments were carried out with bromoarene 2aa,
which can be readily obtained by oxidative amidination10 of 2-
bromobenzaldehyde with propanediamine, and carbon disul-
fide as a heterocumulene (Table 1). Exposure of 2aa with
sodium hydride (5.0 equiv) and carbon disulfide (5.0 equiv) in
acetonitrile or THF afforded only a trace amount of desired
compound 3a (entries 1 and 2). The desired reaction was effi-
ciently promoted in DMF to give 3a in 75% yield (entry 3). A
decreasing amount of sodium hydride and carbon disulfide
(2.0 equiv) slightly improved the yield of 3a (88%) under the
reaction for 12 h (entry 4).11 The reaction in the absence of
sodium hydride provided a yield of 3a of only 12%. We next
screened several bases such as triethylamine, potassium
hydride12 and sodium tert-butoxide (entries 6-8): sodium
hydride was the most effective (entry 4). The fluoride 2ab gave
a comparable result with the bromide 2aa to afford 3a in 86%
yield under optimized conditions (entry 9).
aUnless otherwise stated, reactions were carried out with CS2 (2.0
equiv) and NaH (2.0 equiv) in DMF at 80 °C for 12 h. bIsolated yields. cA
complex mixture formed. dYields in parentheses indicate those of the
reactions at rt.
With knowledge of the optimized conditions, we examined
the reaction of several substituted substrates (Table 2).
Substrates 2b-d having a methoxy, methyl, or fluoro group
at the 4-position provided the corresponding cyclized pro-
ducts 3b-d in good-to-excellent yields (76-95%, entries
1-3). Whereas the reaction of 2e bearing the 4-nitro group
at 80 °C resulted in formation of a complex mixture, the
reaction at room temperature gave the cyclization product 3e
in 73% yield (entry 4). A methoxy group on the 5-position
considerably diminished the reactivity, affording 3f in only
17% yield (entry 5). This was presumably due to increased
electron density at the carbon substituted by a bromine
atom. In the case of 2g bearing a 5-nitro group, the corre-
sponding product 3g was obtained by the reaction at room
temperature (entry 6), similarly to 2e (entry 4). Pyridine
derivatives 4 and 6 showed different reactivity depend-
ing on the position of the nitrogen atom: the 2-bromo-
pyridine derivative 6 gave a better result (71%, entry 8)
than the 3-bromopyridine derivative 4 (18%, entry 7). The
naphthalene derivative 8 afforded the tetracyclic compound 9
in quantitative yield (entry 9).
To further expand our methodology for construction of
other heterocyclic frameworks, we investigated the reaction
using isothiocyanates or isocyanates13,14 as heterocumulene
(Table 3). When benzylisothiocyanate was employed, the
reaction of 2aa or 2ab efficiently proceeded to give the
corresponding N-arylated product 10 in 82% and 97%
yields, respectively (entries 1 and 2). The reaction with tert-
butylisothiocyanate exclusively furnished an S-arylated pro-
duct 11 as a single isomer (entry 3). These results indicate
(13) For related reactions of electron-deficient (haloaryl)isothiocyanates,
see: (a) Muthusamy, S.; Paramasivam, R.; Ramakrishnan, V. T. J. Hetero-
cycl. Chem. 1991, 28, 759–763. (b) Zambounis, J. S.; Christen, E.; Pfeiffer, J.;
Ribs, G. J. Am. Chem. Soc. 1994, 116, 925–931. (c) Huang, S.; Connolly, P. J.
Tetrahedron Lett. 2004, 45, 9373–9375.
(14) For related transition metal-catalyzed reactions, see: (a) Ferraccioli,
R.; Carenzi, D. Synthesis 2003, 1383–1386. (b) Benedı, C.; Bravo, F.; Uriz, P.;
´
ꢀ
ꢀ
Fernandez, E.; Claver, C.; Castillon, S. Tetrahedron Lett. 2003, 44, 6073–
6077. (c) Yang, D.; Liu, H.; Yang, H.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y.
Adv. Synth. Catal. 2009, 351, 1999–2004. (d) Murru, S.; Mondal, P.; Yella,
R.; Patel, B. K. Eur. J. Org. Chem. 2009, 5406–5413. (e) Qiu, J.-W.; Zhang,
X.-G.; Tang, R.-Y.; Zhong, P.; Li, J.-H. Adv. Synth. Catal. 2009, 351, 2319–
2323. (f ) Shen, G.; Lv, X.; Bao, W. Eur. J. Org. Chem. 2009, 5897–5901.
(10) Ishihara, M.; Togo, H. Tetrahedron 2007, 63, 1474–1480.
(11) Larger amounts of unidentified byproduct were formed when using 5
equiv of NaH than in the reaction with 2 equiv of NaH (entry 4).
(12) A reason for the significant countercation effect (NaH vs. KH) on the
reactivity is unclear.
266 J. Org. Chem. Vol. 75, No. 1, 2010

Mizuhara et al.
JOCNote
TABLE 3. Reaction with Isothiocyanates or Isocyanatesa
SCHEME 1. Proposed Reaction Mechanisms
SCHEME 2. Synthesis of PD 404182
the heterocumulene may be involved in the reaction to form
the intermediate C in which the amidine moiety can be a
more powerful electron-withdrawing group suitable for the
SNAr-type reaction. The regioselectivity in the nucleophilic
attack on the aromatic ring (Y vs. Z) is controlled by a subtle
balance of inherent nucleophilicity and steric hindrance of
these functionalities.
We finally focused on the synthesis of PD 404182 (1)
(Scheme 2). Hydrolysis of the carbamodithioate derivative
3a followed by treatment with cyanogen bromide15 readily
afforded the desired compound 1. The same compound was
also obtained in a single step by heating compound 11 in
trifluoroacetic acid in the presence of molecular sieves.
In conclusion, we developed a simple and practical syn-
thetic method for tricyclic heteroarenes related to PD
404182. This reaction provides divergent access to several
related heterocycles under mild conditions without a power-
ful activating group. Further investigations including SAR
study of these derivatives are currently underway.
aUnless otherwise stated, reactions were carried out with R-NCX (2.0
b
equiv) and NaH (2.0 equiv) in DMF at rt for 2-3 h. Isolated yields.
cThese reactions were carried out at 80 °C. dA trace amount of
regioisomeric N-arylation product was also formed. eIsolated as a single
isomer.
that the regioselectivity of the reaction can be perfectly
switched by changing a substituent on the nitrogen atom.
As expected, the reaction of 2ab with benzylisocyanate
provided an N-arylated product 12 in quantitative yield
(entry 4) as in the case with isothiocyanate (entries 1 and 2).
Interestingly, tert-butylisocyanate showed moderate selec-
tivity to mainly afford an N-arylation product 13 (54%),
formed by the arylation at the more bulky position, as well
as an O-arylation product 14 (18%, entry 5). Phenylisocya-
nate also provided an N-arylated product 15 (entry 6). The
2-phenylimidazoline derivative 16 (a 5-membered-ring ami-
dine congener) also provided the corresponding S-arylated
product 17 in a slightly decreased yield (49%, entry 7).
This reaction would proceed via nucleophilic addition of
the amidine moiety to heterocumulene followed by an in-
tramolecular SNAr reaction of the resulting adducts such as
B (Scheme 1). Nonactivated aromatic rings efficiently re-
acted under relatively mild conditions, so two molecules of
Experimental Section
General Procedure for Synthesis of 3,4-Dihydro-2H-pyrimido-
[1,2-c][1,3]benzothiazine-6-thione (3a) (Table 1, Entry 4). To a
mixture of 2aa (59.8 mg, 0.25 mmol) and NaH (20.0 mg, 0.50
mmol; 60% oil suspension) in DMF (0.83 mL) was added
carbon disulfide (30.5 μL, 0.50 mmol) under an Ar atmosphere.
After being stirred at 80 °C for 12 h, the mixture was concen-
trated in vacuo. The residue was purified by flash chromatog-
raphy over silica gel with n-hexane-EtOAc (9:1) to give
compound 3a as a pale-yellow solid (51.4 mg, 88%): mp
139-141 °C (from CHCl3-n-hexane); IR (neat) (cm-1) 1624
(CdN); 1H NMR (400 MHz, CDCl3) δ 2.01-2.07 (m, 2H,
(15) Peter, S.; Gerhard, S. Ger. Offen. DE2811131, 1979.
J. Org. Chem. Vol. 75, No. 1, 2010 267

Mizuhara et al.
JOCNote
CH2), 3.76 (t, J = 5.6 Hz, 2H, CH2), 4.45 (t, J = 6.2 Hz, 2H,
CH2), 7.03 (dd, J = 7.8, 1.5 Hz, 1H, Ar), 7.28-7.33 (m, 1H, Ar),
7.41 (ddd, J = 8.0, 7.6, 1.5 Hz, 1H, Ar), 8.20 (dd, J = 8.0, 1.2 Hz,
1H, Ar); 13C NMR (125 MHz, CDCl3) δ 21.6, 45.5, 48.6, 121.6,
126.5, 127.5, 128.9, 131.1, 131.8, 144.2, 189.8. Anal. Calcd for
C11H10N2S2: C, 56.38; H, 4.30; N, 11.95. Found: C, 56.23; H,
4.44; N, 11.85.
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, the Program for Promotion of Funda-
mental Studies in Health Sciences of the National Institute of
Biomedical Innovation (NIBIO), and Targeted Proteins
Research Program.
Supporting Information Available: Experimental proce-
1
dures, full characterization, and H and 13C NMR charts of
Acknowledgment. This work was supported by a Grant-
in-Aid for Encouragement of Young Scientists (A) (H.O.)
substrates and cyclization products. This material is available
free of charge via the Internet at http://pubs.acs.org.
268 J. Org. Chem. Vol. 75, No. 1, 2010