N-H insertion reactions of Boc-amino acid amides: Solution- and solid-phase synthesis of pyrazinones and pyrazines

Article abstract of DOI:10.1021/ol047933a

(Chemical equation presented) A series of α-diazo-β-ketoesters were reacted with Boc amino acid amides in the presence of rhodium octanoate catalyst. The resulting N-H insertion products were treated with acid, providing the 1,4-azine intermediates, which

Full text of DOI:10.1021/ol047933a

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4627-4629
N−H Insertion Reactions of Boc-Amino
Acid Amides: Solution- and Solid-Phase
Synthesis of Pyrazinones and Pyrazines
Hana Matsushita,† Sang-Hyeup Lee,† Kazuhiro Yoshida,† Bruce Clapham,*,†
Guido Koch,‡ Jurg Zimmermann,‡ and Kim D. Janda*,†
1
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
NoVartis Pharma AG, NIBR Basel, Combinatorial Chemistry, WSJ-507.704,
CH-4002 Basel, Switzerland
bclapham@scripps.edu; kdjanda@scripps.edu
Received October 7, 2004
ABSTRACT
A series of
r-diazo-â-ketoesters were reacted with Boc amino acid amides in the presence of rhodium octanoate catalyst. The resulting N−H
insertion products were treated with acid, providing the 1,4-azine intermediates, which were oxidized by air to form the corresponding pyrazine-
6-one products. The pyrazine-6-ones were further derivatized by N-alkylation or by conversion to the arylpyrazines using sequential bromination
and Suzuki coupling reactions.
The synthesis of collections of small “druglike” compounds
is of great importance to meet the need for high throughput
screening programs in the search for new medicines.1
Accordingly, simple methodologies that employ common
reagents and reaction strategies, yet can yield a multitude of
chemically and structurally diverse scaffolds are in high
demand.2 In addition, solid-phase strategies that enable the
automated synthesis of chemical arrays are of great impor-
tance.3 To these ends, research in our own laboratory has
centered upon the utility of polymer-bound R-diazo-â-
ketoesters4 as modular building blocks for the synthesis of
a plethora of different heterocycles. By utilizing the high
synthetic utility of diazocarbonyl-functionalized molecules,5
rhodium carbenoid N-H insertion reactions with primary
amides, N-alkylanilines, and primary ureas have been
employed to synthesize arrays of oxazoles,6 indoles7 and
imidazolones,8 respectively.
For the synthesis of imidazolones, a series of primary ureas
were reacted with the polymer-bound R-diazo-â-ketoesters,
and the five-membered ring was formed using an acid-
catalyzed imine formation reaction. The efficiency of this
methodology led us to speculate as to whether an imine-
† The Scripps Research Institute.
‡ Novartis Pharma AG.
(4) Clapham, B.; Lee, S.-H.; Koch, G.; Zimmermann, J.; Janda, K. D.
Tetrahedron Lett. 2002, 43, 5407. For a recent review in this area see:
Clapham B. Curr. Opin. Drug. DiscoVery DeV. In press.
(5) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; John Wiley & Sons Ltd.: New York, 1997.
(6) Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3, 2173.
(7) Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.; Janda, K. D. J.
Comb. Chem. 2003, 5, 188.
(1) (a) Bunin, B. A. The Combinatorial Index; Academic Press Ltd.:
London, 1998. (b) Obrecht, D.; Villalgordo, J. M. Solid-Supported Com-
binatorial and Parallel Synthesis of Small-Molecular-Weight Compound
Libraries; Elsevier Science Ltd.: New York, 1998. (c) Combinatorial
Chemistry: Synthesis, Analysis, Screening; Jung, G., Ed., Wiley-VCH:
Weinheim, 1999. (d) Combinatorial Chemistry and Molecular DiVersity in
Drug DiscoVery; Gordon, E. M., Kerwin, J. F., Jr., Eds., John Wiley &
Sons Ltd.: New York, 1998.
(2) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46.
(3) (a) Solid Phase Organic Synthesis; Czarnik, A. W., Ed., John Wiley
& Sons Ltd.: New York, 2001. (b) Solid Phase Organic Synthesis; Burgess,
K., Ed., John Wiley & Sons Ltd.: New York, 2000.
(8) (a) Lee, S.-H.; Yoshida, K.; Matsushita, H.; Clapham, B.; Koch, B.;
Zimmermann, J.; Janda, K. D. J. Org. Chem. Accepted for publication. (b)
Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.; Janda, K. D. Org.
Lett. 2003, 5, 511.
10.1021/ol047933a CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/04/2004

type formation reaction could also be used to prepare
heterocyles from N-H insertion products with different ring
sizes, as depicted in Figure 1. We were especially interested
carboxylic acid ester (pyrazine-6-ones) 5. We believe that
the intermediate product from this reaction was the cyclic
imine 4, which then is oxidized by atmospheric oxygen to
form the stable product 5.
With these results in hand, methodology to convert the
pyrazine-6-ones into the fully aromatized pyrazines was
investigated. Accordingly, treatment of pyrazine-6-ones 5
with phosphorus oxybromide in 1,2-dichloroethane gave the
corresponding 6-bromopyrazines 6 in excellent yield, Scheme
2. Next, the 6-bromopyrazines 6 were subjected to Suzuki11
Scheme 2
Figure 1. Intramolecular imine formation of N-H insertion
products.
as to whether this chemistry could be used for the synthesis
of pyrazines since this class of heterocylcle exhibits a wide
range of biological functions, including the drug pyrazina-
mide that is used to treat tuberculosis.9
coupling conditions; biphenyl boronic acid in the presence
of cesium carbonate base and Pd(dppf)Cl2 catalyst gave the
6-arylpyrazines 7 in excellent yields.
With a successful solution-phase strategy for the synthesis
of pyrazine-6-ones and pyrazines developed, attention was
turned to the synthesis of these scaffolds using a solid-phase
approach, Scheme 3, Table 1. In this approach, the JandaJel12
polymer-bound R-diazo-â-ketoesters4 8 were employed as
the key building blocks.
Scheme 1
Scheme 3a
To test this hypothesis, N-H insertion reactions of primary
amino acid amides were explored.10 More specifically, a
series of R-diazo-â-ketoesters 1 were reacted with Boc-valine
amide 2 in the presence of rhodium octanoate catalyst to
give the corresponding N-H insertion product, R-acylamino-
â-ketoester 3. This set the stage to investigate the conversion
of insertion product 3 into the corresponding cyclic products.
Treatment of 3 with trifluoroacetic acid swiftly removed the
Boc group as estimated by thin-layer chromatography (TLC).
After this reaction was warmed, two new spots were observed
by TLC; however, after continued heating, the lower Rf
product was completely consumed. After isolation of the
products from these reactions, the spectroscopic data obtained
were consistent with the 6-oxo-1,6-dihydro-pyrazine-2-
a Reagents and conditions: (a) (i) 9 (3 equiv), Rh2Oct4 (2 mol
%), ClCH2CH2Cl, 80 °C, 1 h; (ii) TFA (10 equiv), ClCH2CH2Cl,
3 h, then wash; (iii) AcOH (∼20 equiv), ClCH2CH2Cl, 100 °C, 3
h. (b) LiOtBu (5 equiv), R3Br or R3I (10 equiv), DMF/THF 1:1, rt,
24 h. (c) (i) POBr3 (7 equiv), ClCH2CH2Cl 100 °C, 4 h; (ii)
ArB(OH)2 (7 equiv) Cs2CO3 (7 equiv), Pd(dppf)Cl2 (3 mol %),
toluene, rt, 24 h. (d) NaOMe (2.5 equiv), MeOH/THF 1:5, 60 °C,
2 h. (e) R,4R5NH (5 equiv), AlMe3 (2.5 equiv) toluene, 80 °C, 17 h.
(9) Mitchison, D. A Nat. Med. 1996, 6, 635.
(10) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J.; Slawin, A.
M. Z. Synlett 1996, 825.
4628
Org. Lett., Vol. 6, No. 24, 2004

Table 1. Solid-Phase Synthesis of Pyrazine-6-ones 13 and 14 and Pyrazines 15 and 16
entry
R1
R2
R3
R4
R5
R6
product
purity (%)a
yield (%)b
1
2
3
4
5
6
7
8
Me
Me
Ph
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
iPr
iPr
iPr
Bn
Bn
iPr
iPr
iPr
Ph
Ph
Ph
Ph
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
H
H
H
H
13
14
14
14
14
13
13
13
14
14
14
14
15
16
16
16
16d
15
16
16
16
c
63
88
58
48
c
c
c
c
c
93
24
49
32
26
36
25
13
28
59
36
53
60
29
23
29
16
43
9
Bu
H
Bu
Bu
Bn
H
H
H
H
Me
Bn
Me
Me
Bn
9
Bu
Ph
Bu
Bn
H
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
4-ClBn
4-MeOBn
c
c
4-Ph-C6H4
4-Ph-C6H4
4-MeO-C6H4
Ph
87
34
26
45
c
61
25
26
57
-(CH2)5
Bn
Bu
H
H
Ph
benzothaizole
4-Ph-C6H4
4-Ph-C6H4
4-Ph-C6H4
4-MeO-C6H4
Et
Bn
Et
H
15
8
morpholine
a Purity of crude product assessed using HPLC (254 nm). b Yield of pure product after isolation by preparative TLC. c Not determined. d Benzothiazole
cleavage product prepared according to ref 14c.
Treatment of 8 with a series of Boc amino acid amides13
9 in the presence of rhodium catalyst gave the corresponding
insertion products that were converted into the pyrazine-6-
ones 10. To devise milder conditions that are more amenable
to the use of building blocks that contain diverse functional
or protecting groups, the cyclization procedure was modified.
After brief treatment with TFA to remove the Boc group,
the intermediate was isolated by filtration and the excess TFA
was washed away with solvent. Acetic acid was then added
to effect the imine/pyrazine-6-one formation reaction to give
the polymer-bound products 10. Pyrazine-6-ones 10 were
then subjected to further diversification before cleavage from
the resin. N-Alkylation was performed by treating 10 with a
mixture of lithium tert-butoxide base and either alkyl
bromides or iodides in a DMF/THF solvent mixture.
Alternatively, polymer-bound pyazine-6-ones 10 were treated
with POBr3 to provide the corresponding 6-bromopyrazines,
which were reacted with a series of aryl boronic acids under
solid-phase Suzuki coupling reactions to give the corre-
sponding 6-arylpyrazines 12. Finally, both the pyrazine-6-
one 11 and 6-arylpyrazine 12 scaffolds were cleaved from
the resin either by using transesterification with sodium
methoxide or by a diversity-building amide formation/resin-
cleavage reaction14 to give the products 13, 14, 15, and 16.
in Table 1. Given the number of steps in the library synthesis,
in most cases the purified products were isolated in modest
to good yields based upon the loading of starting resin 8,
(8-93%, av 34%) and the purity of the crude products was
25-88% (av 52%) as estimated by HPLC.
In summary, new methodology for the efficient synthesis
of pyrazin-6-ones and pyrazines utilizing a rhodium-catalyzed
N-H insertion reaction between Boc amino acid amides and
R-diazo-â-ketoesters as the key step has been developed.
These N-H insertion products are easily converted into the
corresponding pyrazin-6-ones by acid-promoted cyclodehy-
dration and can be further decorated by N-alkylation with
alkyl halides. Alternatively, the pyrazin-6-ones are converted
readily into the corresponding 6-bromopyrazines that can be
further elaborated using Suzuki cross coupling reaction with
aryl boronic acids. Finally, we have shown that this
methodology is amenable to the synthesis of libraries using
solid-phase procedures.
Acknowledgment. We gratefully acknowledge financial
support from The Scripps Research Institute, The Skaggs
Institute for Chemical Biology, and Novartis Pharma AG.
Supporting Information Available: Representative pro-
cedures, characterization of all products, and 1H NMR spectra
of compounds 3-16. This material is available free of charge
via the Internet at http://pubs.acs.org.
The results from this study for the preparation of a small
library of pyrazine-6-ones and 6-arylpyrazines are outlined
OL047933A
(11) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(12) JandaJel resins are available from Aldrich Chemical Co. (a) Toy,
P. H.; Reger, T. S.; Garibay, P.; Garno, J. C.; Malikayil, J. A.; Liu, G.;
Janda, K. D. J. Comb. Chem. 2001, 3, 117. For recent applications, see:
(b) Brummer, O.; Clapham, B.; Janda, K. D. Tetrahedron Lett. 2001, 42,
2257. (c) Clapham, B.; Cho, C.-W.; Janda, K. D. J. Org. Chem. 2001, 66,
868. (d) Moss, J. A.; Dickerson, T. J.; Janda, K. D. Tetrahedron Lett. 2002,
43, 37.
(14) (a) Barn, D. R.; Morphy, J. R.; Rees, D. C. Tetrahedron Lett. 1996,
37, 3213. (b) Ley, S. V.; Mynett, D. M.; Koot, W.-J. Synlett 1995, 1017.
For the application of this chemistry in the preparation of benzimidazoles,
benzothiazoles, and ureas see: (c) Matsushita, H.; Lee, S.-H.; Joung, M.;
Clapham, B.; Janda, K. D. Tetrahedron Lett. 2004, 45, 313. (d) Lee, S.-H.;
Matsushita, H.; Clapham, B.; Janda, K. D. Tetrahedron 2004, 60, 3439.
(e) Lee, S.-H.; Matsushita, H, Koch, G.; Zimmermann, J.; Clapham, B.;
Janda, K. D. J. Comb. Chem. 2004, 6, 822.
(13) Xia, Z.; Smith, C. D. J. Org. Chem. 2001, 66, 3459.
Org. Lett., Vol. 6, No. 24, 2004
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