Regio- And chemoselective multiple functionalization of chloropyrazine derivatives. Application to the synthesis of coelenterazine

Article abstract of DOI:10.1021/ol901275n

Successive regio- and chemoselective metalations of chloropyrazines using TMPMgCl-LiCl and TMPZnCIIiCI furnish, after trapping with electrophiles, highly functionalized pyrazines in high yields. Application to a synthesis of coelenterazine, a bioluminescent natural product in jellyfish Aequorea victoria, in nine steps (9% overall yield) is reported.

Full text of DOI:10.1021/ol901275n

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3406-3409
Regio- and Chemoselective Multiple
Functionalization of Chloropyrazine
Derivatives. Application to the Synthesis
of Coelenterazine
Marc Mosrin, Tomke Bresser, and Paul Knochel*
Department Chemie & Biochemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse
5-13, 81377, Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received June 8, 2009
ABSTRACT
Successive regio- and chemoselective metalations of chloropyrazines using TMPMgCl·LiCl and TMPZnCl·LiCl furnish, after trapping with
electrophiles, highly functionalized pyrazines in high yields. Application to a synthesis of coelenterazine, a bioluminescent natural product in
jellyfish Aequorea victoria, in nine steps (9% overall yield) is reported.
Pyrazines are important biologically active metabolites. They
are widely distributed in flavorings, formed either thermally
like alkylpyrazines present in coffee, meat, and potatoes or
biosynthetically like 2-alkyl-3-methoxy-pyrazines present in
wines such as Cabernet-Sauvignon. Some pyrazine natural
products such as coelenterazine (1), a natural occurring
bioluminescent imidazopyrazine of marine origin isolated
from the jellyfish Aequorea Victoria, bear a trisubstituted
pyrazine unit. Coelenterazine is used in new optical tech-
nologies for studying the complexity, diversity, and in vivo
behavior of cancers (Figure 1).1 The direct functionalization
of these heterocycles by lithiation is difficult due to the
electrophilic character of the ring, which readily undergoes
Figure 1. Natural products containing a pyrazine scaffold.
addition of various organometallics.2 The electrophilicity of
these heterocycles requires low temperatures for their meta-
lation.3
Recently, we and others have reported a range of new
powerful bases.4-6 Thus, TMPMgCl·LiCl5 (2a; TMP )
2,2,6,6-tetramethylpiperidyl) allows the direct magnesiation
(1) (a) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. ComprehensiVe
Heterocyclic Chemistry II; Pergamon: Oxford, 1996. (b) Gribble, G.; Joule,
J. Progress in Heterocyclic Chemistry, 18; Elsevier: Oxford, 2007. (c)
Weissleder, R.; Pittet, M. J. Nature 2008, 452, 580. (d) Vance, E. Nature
2008, 455, 726.
(3) (a) Zhang, C. Y.; Tour, J. M. J. Am. Chem. Soc. 1999, 121, 8783.
(b) Liu, W.; Wise, D. S.; Townsend, L. B. J. Org. Chem. 2001, 66, 4783.
(c) Buron, F.; Ple´, N.; Turck, A.; Que´guiner, G. J. Org. Chem. 2004, 70,
(2) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of Hetero-
cycles; Wiley: Weinheim, 2003.
2616. (d) Chevallier, F.; Mongin, F. Chem. Soc. ReV. 2008, 37, 595
.
10.1021/ol901275n CCC: $40.75
Published on Web 07/06/2009
 2009 American Chemical Society

of a number of arenes and heteroarenes even bearing esters
or ketones. TMPZnCl·LiCl6 (2b) permits a direct zincation
of much more sensitive aromatics and heteroaromatics and
tolerates aldehydes and nitro groups. Herein, we report a
procedure allowing the selectiVe functionalization of all
positions of the pyrazine ring starting from simple com-
pounds such as dichloropyrazines by performing successive
metalations using TMPMgCl·LiCl (2a) or TMPZnCl·LiCl
(2b).
Table 1. Products Obtained by Regio- and Chemoselective
Metalation of Chloropyrazines with TMPMgCl·LiCl (2a) or
TMPZnCl·LiCl (2b) and Quenching with Electrophiles
Thus, the treatment of 2,3-dichloropyrazine (3) with
TMPMgCl·LiCl (2a; 1.1 equiv, 25 °C, 15 min) leads to the
5-magnesiated pyrazine (4), which is trapped by electrophiles
such as MeSO2SMe and 3-bromocyclohexene (after trans-
metalation with ZnCl2 and addition of a catalytic amount of
CuCN·2LiCl), leading to the expected pyrazines of type 5a
and 5b in 67% and 72% yield (Scheme 1 and entries 1 and
Scheme 1. Magnesiation of 2,3-Dichloropyrazine (3) at
Positions 5 and 6 Using TMPMgCl·LiCl (2a; 1.1 equiv) and
Trapping with Electrophiles
2 of Table 1). The formation of a new carbon-carbon bond
is readily performed by a Negishi cross-coupling7 or a
Sonogashira reaction8 of in situ generated 2,3-dichloro-5-
iodopyrazine providing the 5-substituted heterocycles 5c and
5d in 78% and 77% yield (entries 3 and 4).
A further magnesiation was achieved at the last position
by the addition of TMPMgCl·LiCl (2a; 1.1 equiv). Thus, 2,3-
dichloro-5-(methylthio)pyrazine9 5a is converted within 30
(4) For an excellent review, see: (a) Mulvey, R. E.; Mongin, F.;
Uchiyama, M.; Kondo, Y. Angew. Chem., Int. Ed. 2007, 46, 3802. (b)
L’Helgoual’ch, J.-M.; Bentabed-Ababsa, G.; Chevallier, F.; Yonehara, M.;
Uchiyama, M.; Derdour, A.; Mongin, F. Chem. Commun. 2008, 5375. (c)
Seggio, A.; Chevallier, F.; Vaultier, M.; Mongin, F. J. Org. Chem. 2007,
72, 6602.
(5) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.; Knochel, P. Org. Lett.
2006, 8, 5673. (c) Mosrin, M.; Knochel, P. Org. Lett. 2008, 10, 2497. (d)
Mosrin, M.; Knochel, P. Chem.sEur. J. 2009, 15, 1468. (e) Piller, F.;
Knochel, P. Org. Lett. 2009, 11, 445. (f) Clososki, G. C.; Rohbogner, C. J.;
Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7681. (g) Rohbogner, C. J.;
Clososki, G. C.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 1503. (h)
Garcia-Alvarez, P.; Graham, D. V.; Hevia, E.; Kennedy, A. R.; Klett, J.;
Mulvey, R. E.; O’Hara, C. T.; Weatherstone, S. Angew. Chem., Int. Ed.
2008, 47, 8079.
a Isolated, analytically pure product. b Catalyzed by 5 mol % of
CuCN·2LiCl. c Obtained by Pd-catalyzed cross-coupling using Pd(dba)2 (3
mol %) and (o-furyl)3P (6 mol %). d Obtained by Pd-catalyzed cross-
coupling using Pd(dba)2 (3 mol %), (o-furyl)3P (6 mol %), CuI (4 mol %),
and NEt3. e Transmetalation performed with 1.1 equiv of CuCN·2LiCl.
(6) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837.
(7) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Negishi, E.; Kobayashi, M. J. Org. Chem. 1980, 45,
5223. (c) Negishi, E. Acc. Chem. Res. 1982, 15, 340.
(8) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467. (b) Sonogashira, K. ComprehensiVe Organic Synthesis; Pergamon
Press: New York, 1991; Vol. 3.
Org. Lett., Vol. 11, No. 15, 2009
3407

min at -40 °C to the 6-magnesiated species 6 which is
iodinated by reaction with I2 leading to the iodopyrazine 7a
in 80% yield (entry 5). Reaction with 4-fluorobenzoyl
chloride (after transmetalation with CuCN·2LiCl)10 furnishes
the ketopyrazine 7b in 72% yield (entry 6). Trapping with
TMSCN leads to the fully substituted pyrazine 7c in 88%
yield (entry 7).
entry 14). Negishi cross-coupling7 with ethyl 4-iodobenzoate
provides the substituted heterocycle 15b in 80% yield.
Subsequent metalation of the ester derivative 15b using
TMPZnCl·LiCl (2b; 1.1 equiv, 25 °C, 30 min) gives the zinc
species 16, which was benzoylated (after transmetalation with
CuCN·2LiCl)10 giving the ketopyrazine 17a in 90% yield.
An allylation with 3-bromocyclohexene (in the presence of
CuCN·2LiCl (5 mol %)) or a Negishi7 cross-coupling is
furnishing the fully substituted pyrazines 17b and 17c in 85%
and 78% yield (entries 17 and 18).
As an application, we have carried out the total synthesis
of coelenterazine (1)1a,13 in nine steps and 9% overall yield.
Thus, a Negishi cross-coupling7 using 2,5-dichloropyrazine
(13) as an electrophile provides the arylpyrazine 18 in 64%
yield. A magnesiation using TMPMgCl·LiCl (2a; 1.1 equiv,
-45 °C, 1 h) gives after transmetalation with ZnCl2 and
acylation14 with benzoyl chloride the ketopyrazine 19 in 71%
yield. The chlorine substitution is then achieved using NH3
in BuOH15 furnishing the aminopyrazine 20 in 94% yield.
Cleavage of the methyl ether with sodium thioethanolate in
DMF16 yields the corresponding alcohol 21 in 76% yield.
The reduction of the ketone is finally carried out using a
Wolff-Kishner17 reduction affording coelenteramine (22)
in 93% yield (Scheme 4).
Other dichloropyrazines are metalated as well under mild
conditions. Thus, 2,6-dichloropyrazine (8) is zincated quan-
titatively with TMPZnCl·LiCl (2b; 1.1 equiv, 25 °C, 30 min)
giving the zinc species 9, which undergoes a Negishi cross-
coupling7 providing the 3-substituted heterocycles 10a and
10b in 86% and 83% (Scheme 2 and entries 8 and 9).
Scheme 2. Metalation of 2,6-Dichloropyrazine (8) at Positions 3
and 5 Using TMPMgCl·LiCl (2a; 1.1 equiv) and TMPZnCl·LiCl
(2b; 1.1 equiv) and Trapping with Electrophiles
Scheme 4. Synthesis of Coelenteramine (22)
Subsequent metalation of the arylpyrazine 10a using
TMPMgCl·LiCl (2a; 1.1 equiv, -40 °C, 60 min) provides
the magnesium reagent 11, which affords after transmeta-
lation with CuCN·2LiCl,10 and trapping with furoyl chloride,
the ketopyrazine 12a in 84% yield (entry 10).
Quenching with 3-bromocyclohexene or ethyl 2-(bromom-
ethyl)acrylate11 gives fully substituted pyrazines 12b and 12c
in 93% and 74% yield, respectively (entries 11 and 12).
Negishi cross-coupling7 using ethyl 4-iodobenzoate provides
the substituted heterocycle 12d in 94% (entry 13).
Similarly, 2,5-dichloropyrazine12 (13) undergoes smooth
zincation using TMPZnCl·LiCl (2b; 1.1 equiv, 25 °C, 30
min), affording the zinc reagent 14. An iodolysis leads to
the 2,5-dichloro-3-iodopyrazine 15a in 76% (Scheme 3 and
The preparation of the diazine ring in coelenterazine (1)
requires a condensation of coelenteramine (22) with the
ketoaldehyde 26 (Scheme 5). The addition of 4-(chlorom-
ethyl)phenyl acetate (23) to commercial Zn dust (2.5 equiv)
in the presence of LiCl (2.5 equiv) at 25 °C is complete
within 24 h.18 Trapping with bromoacetyl chloride after
transmetalation with CuCN·2LiCl10 furnishes the acylated
derivative 24 in 61% yield. Addition of silver nitrate at 25
°C gives after 18 h the nitrate ester 25 in 98% yield.19
Subsequent reaction of 25 with NaOAc·3H2O in DMSO at
Scheme 3. Zincation of 2,5-Dichloropyrazine (13) at Positions 3
and 6 Using TMPZnCl·LiCl (2b; 1.1 equiv) and Trapping with
Electrophiles
(9) The thiomethyl group can serve as a leaving group in cross-coupling
reactions: (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979. (b)
Prokopcova´, H.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48, 2276.
(10) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(11) Villie´ras, J.; Rambaud, M. Org. Synth. 1988, 66, 220.
(12) Preparation of 2,5-dichloropyrazine, see: Klein, B.; Hetman, N. E.;
O’Donnell, M. E. J. Org. Chem. 1963, 28, 1682.
3408
Org. Lett., Vol. 11, No. 15, 2009

In summary, we have reported the multiple functionaliza-
tion20 of the pyrazine scaffold using TMPMgCl·LiCl (2a)
and TMPZnCl·LiCl (2b) as effective bases and reported a
nine-step synthesis of the natural product coelenterazine (1).
Further extensions and applications of this method are
currently underway in our laboratories.
Scheme 5
.
Synthesis of 3-(4-Methoxyphenyl)-2-oxopropanal
(26) and Coelenterazine (1)
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the Deutsche Forschungsgemeinschaft (DFG), and
the European Research Council (ERC) for financial support.
We also thank Evonik GmbH, BASF AG, W.C. Heraeus
GmbH, and Chemetall GmbH for the generous gift of
chemicals.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
25 °C for 1 h affords the corresponding acetoxy R-keto
aldehyde 26 in 70% yield.19 Finally, the condensation of the
1,2-dicarbonyl derivative 26 with coelenteramine (22) pro-
vides the bioluminescent natural product coelenterazine (1)
in 64% yield.19
OL901275N
(17) Lehr, M. J. Med. Chem. 1997, 40, 3381.
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(19) Chen, F.-Q.; Zheng, J.-L.; Hirano, T.; Niwa, H.; Ohmiya, Y.;
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2747. (b) Inoue, S.; Sugiura, S.; Kakoi, H.; Hashizume, K.; Goto, T.; Iio,
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(20) Procedure for the synthesis of 3,5-dichloro-2-(4-methoxyphe-
nyl)pyrazine (10a): A dry and argon flushed 50 mL Schlenk flask, equipped
with a magnetic stirrer and a septum, was charged with 2,6-dichloropyrazine
(8) (1,49 g, 10.0 mmol) dissolved in THF (10 mL). A solution of
TMPZnCl·LiCl (2b) (1.4 M in THF, 7.9 mL, 11.1 mmol) at 25 °C was
then added, and the reaction mixture was stirred at this temperature for 30
min. Pd(dba)2 (113 mg, 2 mol %) and P(o-furyl)3 (93 mg, 4 mol %)
dissolved in THF (5 mL) and mixed with 4-iodoanisole (3.04 g, 13 mmol,
1.3 equiv) were then transferred via cannula to the reaction mixture. The
resulting mixture was stirred at 65 °C for 1 h, quenched with a sat. aq.
NH4Cl solution (100 mL), extracted with diethyl ether (3 × 100 mL), and
dried over anhydrous Na2SO4. After filtration, the solvent was evaporated
in vacuo. Purification by flash chromatography (CH2Cl2/pentane 1:3)
furnished the compound 10a (2.18 g, 86% yield) as a colourless solid.
(14) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F. T.; Miller, J. A.;
Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
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Org. Lett., Vol. 11, No. 15, 2009
3409