Synthesis of 2,6-disubstituted-7,8-dihydro-6H-pyrano[2,3-6]pyrazines

Article abstract of DOI:10.1016/j.tetlet.2011.12.018

A straightforward synthesis of a 2,6-disubstituted-7,8-dihydro-6H-pyrano[2, 3-6]pyrazine is described. The synthesis relies on a versatile dichloropyrazine-aldehyde intermediate and an olefination partner.

Full text of DOI:10.1016/j.tetlet.2011.12.018

Tetrahedron Letters 53 (2012) 852–853
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Tetrahedron Letters
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Synthesis of 2,6-disubstituted-7,8-dihydro-6H-pyrano[2,3-6]pyrazines
Jian-Cheng Li a, Michael Munchhof b, Joseph S. Warmus c, Paul D. Bonin c, Kim F. McClure c,
⇑
a 154 Overbrook Road, Madison, CT 06443, USA
b 266 West Road, Salem, CT 06420, USA
c Pfizer Inc., 620 Memorial Drive, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward synthesis of a 2,6-disubstituted-7,8-dihydro-6H-pyrano[2,3-6]pyrazine is described.
The synthesis relies on a versatile dichloropyrazine–aldehyde intermediate and an olefination partner.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 16 November 2011
Revised 5 December 2011
Accepted 5 December 2011
Available online 9 December 2011
Keywords:
Pyrazine
Dichloropyrazine
Formylation
Pyran
In our pursuit of superior agonists of the G-protein coupled
receptor 119 (GPR119) we were interested in constrained analogs
of compound 1 (Fig. 1).1,2 To achieve this conformational goal
while incorporating superior physicochemical properties (lower
ClogP), we envisioned the use of a dihydro-6H-pyrano[2,3-6]pyra-
zine ring system as exemplified by compound 2.
While this ring system has precedent in the literature,3,4 it is
only sparsely described and no substitution is reported on the pyr-
an ring. Herein we describe a more versatile synthesis wherein the
ring system is rapidly assembled from dichloropyrazine using a
formylation–Wittig-etherification sequence, allowing substitution
at both ends of the molecule.
Key to our synthesis is the novel and versatile pyrazine-alde-
hyde 4 shown in Scheme 1. Formylation of 2,5-dichloropyrazine
3 was accomplished in a 21% yield in a fashion similar to the pub-
lished work on 2-chloropyrazine5 using commercially available
2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chlo-
ride complex and 4-formylmorpholine.6
Figure 1. Pyridyl-ether versus dihydro-6H-pyrano[2,3-6]pyrazine.
The Wittig partner for aldehyde 4 was prepared as shown in
Scheme 2. Starting with the known acetyl piperidine 5,7 selective
silylenol ether formation and reaction with bromine provided 6
in a good yield. The more straight-forward reaction of 5 with bro-
mine in methanol provided only a 20% yield of the desired bromo
acetate 6. Generation of the Wittig reagent 7 was achieved by
phosphonium salt formation followed by treatment with hydrox-
ide. In principle, a b-ketophosphonate analogous to 7 could have
been prepared from a N-Boc-piperidine-4-carboxylate as reported
Scheme 1. Synthesis of 3,6-dichloropyrazine-2-carbaldehyde. Reagents and con-
ditions: (a) 2,2,6,6-tetramethylpiperidinylmagnesium chloride,ÁLiCl, THF/toluene,
À78 °C, 1 h; (b) 4-formylmorpholine, À78 °C, 2 h (one pot, 21%).
⇑
Corresponding author. Tel.: +1 6175513516; fax: +1 6175513082.
E-mail address: kim.f.mcclure@pfizer.com (K.F. McClure).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.018

J.-C. Li et al. / Tetrahedron Letters 53 (2012) 852–853
853
Scheme 2. Assembly of the dihydro-6H-pyrano[2,3-6]pyrazine ring system. Reagents and conditions: (a) LiN(TMS)2, TMSCl, THF, À78 °C to 0 °C; (b) Br2, À78 °C to 22 °C, 1 h
(one pot, 88%); (c) Ph3P, toluene, 22 °C, 16 h, then NaOH (77%); (d) 4, CH2Cl2, 22 °C, 16 h (78%); (e) NaBH4, EtOH, 22 °C, 3 h (96%); (f) NaH, THF, reflux, 4 h (30%).
provided 10 in a high yield. Trifluoroacetic acid removal of the
Boc group and acylation with isopropyl chloroformate gave the de-
sired comparator compound 11. Unfortunately, 11 has only modest
human GPR119 agonist pharmacology (63% response at 10 lM;
N = 3) in our previously described recombinant cAMP functional
assay.9
In summary, we have developed a straightforward approach to
2,6-disubstituted-7,8-dihydro-6H-pyrano[2,3-6]pyrazines. The syn-
thesis relies on the versatile aldehyde intermediate 4 and an olefin-
ation partner, enabling variation at both ends of the ring system.
Acknowledgments
Scheme 3. Synthesis of dihydro-6H-pyrano[2,3-6]pyrazine GPR119 analog.
Reagents and conditions: (a) 4-(methanesulfonyl)phenylboronic acid, dioxane,
water, Pd(PPh3)4, K2CO3, 100 °C, 3 h (90%); (b) (1:1) TFA/CH2Cl2, 22 °C, 1 h (100%);
(c) isopropyl chloroformate, Et3N, CH2Cl2, toluene, 22 °C, 2 h (46%).
The authors would like to thank Etzer Darout and Elnaz
Menhaji-Klotz for their review of the Letter.
References and notes
by Maloney.8 This alternative was not tried. Nevertheless, reaction
of ylide 7 with aldehyde 4 smoothly provides the a,b-unsaturated
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From 9 the desired target was constructed as shown in Scheme
3. Suzuki coupling with commercial 4-(methanesulfonyl)phenyl-
boronic acid and 9 in a sealed tube under an argon atmosphere