Enantiopure N-protected α-amino glyoxals 1. Synthesis from α-amino acids and some condensation reactions with amines

Article abstract of DOI:10.1039/a907948c

A series of N-protected α-ammo diazoketones has been prepared from L-amino acids and dipeptides and used as precursors in the synthesis of novel N-protected α-amino glyoxals via oxidation with distilled dimethyldioxirane (DMD) in acetone. The glyoxals have been converted, without purification, into enantiopure imines, pyrazines, quinoxalines, and pyrido[2,3-b]pyrazines via condensation with the appropriate amine or diamine. The molecular structure of the pyrido[2,3-b]pyrazine derived from N-Cbz-L-phenylalanine has been determined by X-ray analysis.

Full text of DOI:10.1039/a907948c

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Enantiopure N-protected ꢀ-amino glyoxals 1. Synthesis from
ꢀ-amino acids and some condensation reactions with amines
Paul Darkins, Michelle Groarke, M. Anthony McKervey,* Hazel M. Moncrieff,
Noreen McCarthy and Mark Nieuwenhuyzen
1
School of Chemistry, The Queen’s University, Belfast BT9 5AG, UK
Received (in Cambridge, UK) 4th October 1999, Accepted 1st November 1999
A series of N-protected α-amino diazoketones has been prepared from -amino acids and dipeptides and used as
precursors in the synthesis of novel N-protected α-amino glyoxals via oxidation with distilled dimethyldioxirane
(DMD) in acetone. The glyoxals have been converted, without purification, into enantiopure imines, pyrazines,
quinoxalines, and pyrido[2,3-b]pyrazines via condensation with the appropriate amine or diamine. The molecular
structure of the pyrido[2,3-b]pyrazine derived from N-Cbz--phenylalanine has been determined by X-ray analysis.
When the research described below was initiated N-protected
α-amino glyoxals of type 3 were unknown.1 Without N-protec-
tion, α-amino glyoxals would be prone to spontaneous self-
condensation. With N-protection, they should be much more
stable yet amenable to a wide range of useful transformations
through one or both carbonyl groups. Such transformations
could provide access to numerous novel amino acid and peptide
derivatives including potential protease inhibitors. We have
developed a convenient synthesis of N-protected α-amino
glyoxals from α-amino acids and dipeptides and have explored
their conversion into ketomethylene amino pseudopeptides.2
We have also tested their efficacy as inhibitors towards typical
members of the serine and cysteine protease families.3,4 Else-
where, we will describe the elaboration of these glyoxals into
polyfunctional amino acid and peptide derivatives via Wittig
reactions.5
documented route known to be free of racemization.6,7 The
transformation of diazoketone into glyoxal was accomplished
using distilled dimethyldioxirane (DMD) in acetone as the
oxidant.8 Glyoxals 3a–x were thus prepared: 3a, 3b, from
-alanine, 3c from -arginine, 3d from -aspartic acid, 3e, 3f
from -isoleucine, 3g from ,-isoleucine, 3h, 3i, 3j from
-leucine, 3k from -leucine, 3l, 3m, 3n from -phenylalanine,
3o from -proline, 3p from -serine, 3q, 3r, 3s from -valine, 3t
from -Ala--Leu, 3u from -Ala--Phe, 3v from -Phe--Ala,
3w from -Val--Phe, 3x from -Pro--Ala, and 3y from -Pro-
-Phe, respectively. These glyoxals were predominately, if not
exclusively, in the hydrated form 4, presumably from reaction
with adventitious moisture present in the DMD solution.
Although the glyoxal hydrate 3m derived from Cbz--phenyl-
alanine could be fully characterized, routinely the oxidation
products were not scrutinised closely other than by TLC (to
1
The synthesis, summarised in Scheme 1, is applicable to any
monitor the disappearance of the diazoketone) and H NMR
analysis which confirmed that product purity was >95% in each
case. The 1H NMR spectrum of 3m exhibited, in addition to the
normal Cbz-phenylalanine signals, a multiplet at δ 5.35 for the
methine hydrogen atom of the CH(OH)2 group and a doublet at
δ 5.82 corresponding to the two hydroxylic protons.
To further characterize these glyoxals and explore their effi-
cacy as in situ intermediates for amino acid and peptide elabor-
ation, a number of reactions involving condensation with
amines were examined. All of these reactions were conducted as
one-pot procedures: the diazoketone was oxidized with DMD,
acetone was removed at reduced pressure and replaced by
another solvent, usually dichloromethane or ethanol, and the
appropriate reagent was then added. These glyoxals condensed
with simple 1,2-diamines to form dihydropyrazines (Scheme 2)
which could be dehydrogenated to yield pyrazines on treatment
with manganese dioxide in the presence of potassium hydrox-
ide.9 Representative examples of pyrazines formed in this way
are 5f and 5q (Table 2) derived from 1,2-diaminoethane and
glyoxals 3f and 3q. 1,2-Diaminopropane and glyoxal 3b fur-
nished pyrazine 6 as a 3:2 inseparable mixture of regioisomers.
Reaction of 1,2-diaminoethane carboxylic acid methyl ester
with glyoxal 3b furnished a 1:1 mixture of pyrazines 7 and 8,
but these isomers could be separated by flash chromatography
and the individual isomers could be distinguished by analysis of
their HMBC and HMQC NMR spectra.
Scheme 1
amino acid or peptide with a free carboxylic acid function
and the reaction conditions tolerate most common forms of
N-protection. We have successfully employed phthaloyl, benzyl-
oxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), ethoxy-
carbonyl and 1-adamantyloxycarbonyl (Adoc) protecting
groups. The two-step sequence involved conversion of the
N-protected amino acids and peptides 1a–x (all known com-
pounds) into diazoketones 2a–x (Table 1) which were then con-
verted into the glyoxal by oxidation. Diazoketone formation
was accomplished by the action of ethereal diazomethane on
the acyl chloride or mixed anhydride of the amino acid, a well-
Reaction with freshly purified 1,2-diaminobenzene (Scheme
3) furnished a series of novel, optically active quinoxalines 9
(91–96% yield of microanalytically pure products) (Table 3)
with the chiral aminoalkyl residue of an amino acid or peptide
as a side chain. The quinoxalines, with the exception of the
J. Chem. Soc., Perkin Trans. 1, 2000, 381–389
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Table 1 Preparation of glyoxals from N-protected amino acids and dipeptides
product derived from -proline, which was an oil, were obtained
as crystalline solids. All the spectral data were in agreement
with the structural assignments, which were confirmed by H–H
COSY, and H–C COSY NMR experiments. Confirmation of
the enantiomeric purity of the quinoxalines was obtained by
comparison of the 13C NMR spectrum of the product derived
382
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Scheme
diamines.
2
Condensation of N-protected amino glyoxals with
Table 2 Derivatization of N-protected amino glyoxals as pyrazines
Fig. 1 A view of (1ЈS)-3-(2Ј-phenyl-1Ј-N-benzyloxycarbonylamino-
ethyl)pyrido[2,3-b]pyrazine 10m showing the atom-labelling scheme for
all non-hydrogen atoms. Thermal ellipsoids at 50% level.
3-amino group of the pyridine, we concluded that the pyrido-
[2,3-b]pyrazines should have the regiochemistry depicted in
structure 10 (Scheme 3). Crystallization of the pyrido[2,3-b]-
pyrazine derivative of N-Cbz--phenylalanine (10m) enabled
us to confirm by X-ray diffraction analysis10 that the molecule
does indeed possess structure 10 (Fig. 1).
In conclusion, we have demonstrated that N-protected
α-amino glyoxals, which are readily available from α-amino
acids and peptides, can be used to construct a range of mono-
cyclic and bicyclic heteroaromatic products bearing chiral
aminoalkyl residues as side chains.
Experimental
General procedures
All the diazoketones used in this study were prepared from
known N-protected amino acids and dipeptides by one of two
well-established procedures both known not to cause racemiz-
ation. For diazoketones with ethoxycarbonyl or phthaloyl pro-
tection, the amino acid was activated via the acyl chloride prior
to exposure to ethereal diazomethane.11 For all other forms of
N-protection (Cbz, Boc, Adoc) the amino acid was activated via
in situ mixed anhydride formation with isobutyl chloroform-
ate.6,7 The crude products from both routes were purified by
flash chromatography over silica. Purity levels were ≥97% by 1H
NMR analysis.
The following diazoketones were thus prepared: (N-tert-
butoxycarbonyl--alanyl)diazomethane, 2a;6 (N-benzyloxy-
carbonyl--alanyl)diazomethane, 2b;12 [(3S,4S)-N-tert-butoxy-
carbonylisoleucyl]diazomethane, 1e;7 [(3S,4S)-N-benzyloxy-
carbonylisoleucyl]diazomethane, 1f;12 [( )-N-tert-butoxycarb-
Scheme 3 Formation of quinoxalines and pyrido[2,3-b]pyrazines from
N-protected amino glyoxals.
from -isoleucine 3e with that derived from ,-isoleucine 3g.
Whereas the latter displayed two sets of signals, attributable
to the presence of two diastereoisomers, the spectrum of the
former indicated the presence of a single diastereoisomer, a
distinction from which we could conclude that the two trans-
formations leading from diazoketone to quinoxaline in the iso-
leucine series were free of racemization. We inferred, on the
basis of these observations, that all the quinoxalines (and other
amine condensation products) were produced in an enantiopure
form.
In an extension of this approach to novel chiral nitrogen
heterocycles we examined the condensation of several N-
protected amino glyoxals with 2,3-diaminopyridine (Scheme 3)
as a route to pyrido[2,3-b]pyrazines. Since the two amino func-
tions are no longer equivalent, cyclization with the pyridine
reagent could lead to regioisomeric products. In the event,
condensation of glyoxals 3b, 3i, 3m, 3o, and 3q (Table 3) with
2,3-diaminopyridine produced a single pyrido[2,3-b]pyrazine
in each case, to which we assigned structures 10b, 10i, 10m, 10o,
and 10q, respectively, on mechanistic grounds. Arguing that the
first condensation step should involve the more reactive alde-
hydic carbonyl group of the glyoxal and the more reactive
onylisoleucyl]diazomethane,
1g;7
(N-phthaloyl--leucyl)-
diazomethane, 2h;14 (N-benzyloxycarbonyl--leucyl)diazo-
methane, 2i;13 (N-tert-butoxycarbonyl--leucyl)diazomethane,
2j;14 (N-tert-butoxycarbonyl--leucyl)diazomethane, 2k;13
(N-tert-butoxycarbonyl--phenylalanyl)diazomethane, 2l;7 (N-
benzyloxycarbonyl--phenylalanyl)diazomethane, 2m;12 (N-
phthaloyl--phenylalanyl)diazomethane,
2n;14
(N-ethoxy-
carbonyl--prolyl)diazomethane, 1o;7 (N-benzyloxycarbonyl--
valyl)diazomethane, 1q;14 (N-ethoxycarbonyl--valyl)diazo-
methane, 1r.7
Nꢀ-Benzyloxycarbonyl-Nꢁ,Nꢂ-bis(1-adamantyloxycarbonyl)-L-
arginyldiazomethane, 2c
The title compound was prepared from the N-protected acid 1c
(15.0 g, 22.6 mmol) via the literature procedure. The crude
J. Chem. Soc., Perkin Trans. 1, 2000, 381–389
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Table 3 Derivatization of N-protected amino glyoxals as quinoxalines and azaquinoxalines
product was purified by recrystallization from dichloro-
methane–hexane to afford the pure α-diazoketone 2c (9.3 g,
62%) as a pale yellow, crystalline solid, mp 80–82 ЊC (Found:
C, 64.2; H, 7.3; N, 11.7. C37H48N6O7 requires: C, 64.5; H, 7.0; N,
12.2%); [α]2D0 = 4.1 (c, 0.8 in CH2Cl2); νmax (KBr)/cmϪ1 3377
(NH), 2105 (CHN2), 1712, 1640, 1607 (COs); δH (300 MHz,
CDCl3) 1.53–1.67 (20H, m, Adam-H and (CH2)2CH), 2.02–2.19
(14H, m, Adam-H), 3.84 (2H, m, CH2(N)CO), 4.35 (1H, m,
(CH2)2CH), 5.12 (2H, s, OCH2Ph), 5.98 (1H, s, CHN2), 6.46
(1H, d, J = 8.1 Hz, NH), 7.33 (5H, m, Ar-H), 9.25 (1H, br s,
66.65, 82.21 ((CH3)3C), 127.80, 127.89, 128.27, 136.12, 155.83
(CO of carbamate), 169.56 (CO of ester), 191.43 (CO of
diazoketone).
(N-Butoxycarbonyl-N,O-isopropylidene-L-seryl)diazomethane,
2p
This compound was prepared from the diprotected acid 1p (9.0
g, 37 mmol) via the literature procedure. The crude product was
purified by flash chromatography on silica (20% ethyl acetate–
80% hexane) to afford 2p (6.1 g, 62%) as a pale yellow solid,
mp 55–56 ЊC (Found: C, 53.7; H, 7.1; N, 15.7. C12H19N3O4
requires: C, 53.5; H, 7.1; N, 15.6%); [α]D20 Ϫ145.8 (c, 1.1 in
CH2Cl2); νmax (KBr)/cmϪ1 2115 (CN2), 1703 (NCO2), 1625
(COCHN2); δH (300 MHz, CDCl3) 1.45, 1.52 (12H, 2 × s,
C(CH3)3 and CH3CCH3), 1.65 and 1.71 (3H, 2 × s, CH3CCH3),
4.11 (2H, m, OCH2CH), 4.29, 4.40 (1H, 2 × m, CH(N)CO),
5.52 (1H, s, CHN2).
HN᎐CNH), 9.41 (1H, br s, HN᎐CNH).
᎐
᎐
(S)-2-Benzyloxycarbonylamino-5-diazo-4-oxopentanoic acid
tert-butyl ester, 2d
This compound was prepared from the diprotected acid 1d (5.9
g, 18 mmol) according to the literature procedure. The crude
product was purified by flash chromatography on silica (20%
ethyl acetate–80% hexane) to afford pure α-diazoketone 2d
(3.8 g, 61%) as a yellow oil (Found: C, 58.5; H, 6.2; N, 11.8.
C17H21N3O5 requires: C, 58.8; H, 6.1; N, 12.1%); [α]D20 37.1
(c, 3.64 in CH2Cl2); νmax (film)/cmϪ1 2100 (CN2), 1720 (NCO2
and CO2), 1630 (COCHN2); δH (300 MHz, CDCl3) 1.44 (9H,
s, (CH3)3C), 2.83 (1H, m, CH2CHNH), 2.98 (1H, m, CH2-
CHNH), 4.46 (1H, m, CH2CHNH), 5.10 (2H, s, OCH2Ph),
5.26 (1H, br s, CHN2), 5.84 (1H, br d), 7.34 (5H, br s, Ar-H);
δC (75 MHz, CDCl3) 27.63 ((CH3)3C), 41.86, 50.91, 54.94,
(N-Benzyloxycarbonyl-L-alanyl-L-leucyl)diazomethane, 2t
The dipeptide acid 1t (2.68 g, 7.96 mmol) was treated according
to the literature procedure to give the title compound 2t (1.87 g,
65%) as a yellow solid. The crude product was recrystallised
from ethyl acetate–hexane–THF to give the pure α-diazo-
ketone, mp 93–94 ЊC (Found: C, 60.2; H, 7.1; N, 15.3. C18H24-
N4O4 requires: C, 60.0; H, 6.7; N, 15.6%); [α]D20 Ϫ57.5 (c, 0.6
in CH2Cl2); νmax (KBr)/cmϪ1 3326 (NH), 2109 (CN2), 1715
384
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(NCO2), 1645 (CONH), 1634 (COCHN2); δH (300 MHz,
CDCl3) 0.90 (6H, m, (CH3)2CH2), 1.37 (3H, d, J = 8.1 Hz,
CH3CH), 1.25–1.63 (3H, br m, CH2CH(CH3)2), 4.31 (1H, br
m, CH(N)CO), 4.94 (1H, br m, CH(N)CO), 5.10 (2H, s,
OCH2Ph), 5.50 (1H, s, CHN2), 5.59 (1H, br d, J = 6.9 Hz, NH),
6.87 (1H, br d, J = 7.4 Hz, NH), 7.34 (5H, s, Ar-H); δC (75
MHz, CDCl3) 18.44 (CH3), 21.69 (CH3), 22.85 (CH3), 24.63,
40.84, 50.40, 53.95, 54.43, 66.89, 127.85, 128.07, 128.38,
135.94, 155.83 (CO of carbamate), 172.14 (CO of amide),
193.65 (CO of diazoketone); m/z 332 (Mϩ Ϫ N2, 34%), 91
(PhCH2ϩ, 100).
128.48, 129.09, 135.90, 156.24 (CO of carbamate), 170.87 (CO
of amide), 192.24 (CO of diazoketone); m/z 394 (Mϩ Ϫ N2,
16%), 352 (41), 91 (PhCH2ϩ, 100).
(N-Benzyloxycarbonyl-L-prolyl-L-alanyl)diazomethane, 2x
The dipeptide acid 1x (3.00 g, 9.36 mmol) was treated according
to the literature procedure to give the title compound 2x (2.37 g,
74%) as a yellow solid. The crude product was purified by
recrystallization from ethyl acetate–hexane–THF to give the
pure α-diazoketone, mp 59–61.5 ЊC (Found: C, 59.5; H, 6.0;
N, 15.9. C17H20N4O4 requires: C, 59.3; H, 5.9; N, 16.3%); [α]D20
Ϫ105.9 (c, 0.56 in CH2Cl2); νmax (KBr)/cmϪ1 3311 (NH), 2128
(CN2), 1694 (CO of carbamate), 1666 (CO of amide), 1626 (CO
of diazoketone); δH (300 MHz, CDCl3) 1.24 (3H, br d, J = 10.6
Hz, CH3), 1.88–2.12 (4H, br m, CH2CH2), 3.48–3.55 (2H, br m,
CH2N), 4.33 (1H, br d, CH(N)CO), 4.43 (1H, br s, CH-
(N)CO), 5.14 (2H, s, OCH2Ph), 5.37, 5.69 (1H, 2 × br s, CHN2),
7.18 (1H, br s, NH), 7.30 (5H, br s, Ar-H); δC (50 ЊC, 125 MHz,
CDCl3) 16.93 (CH3), 23.78 (br), 28.80, 30.64 (2 × br s), 46.70,
51.62, 52.64, 60.12, 66.65, 127.14, 127.45, 127.91, 135.98,
155.09 (br) (CO of carbamate), 171.44 (CO of amide), 193.61
(br) (CO of diazoketone); m/z 316 (Mϩ Ϫ N2, 24%), 275
(Mϩ Ϫ C2N2OH, 25), 91 (PhCH2ϩ, 100).
(N-Benzyloxycarbonyl-L-alanyl-L-phenylalanyl)diazomethane,
2u
The dipeptide acid 1u (3.88 g, 10.48 mmol) was treated accord-
ing to the literature procedure to give the title compound 2u
(3.01 g, 73%) as a yellow solid. The crude product was recrystal-
lized from ethyl acetate–hexane–THF to give the pure α-diazo-
ketone, mp 113–115 ЊC (Found: C, 64.1; H, 5.5; N, 13.9.
C21H22N4O4 requires: C, 64.0; H, 5.6; N, 14.2%); [α]D20 Ϫ28.2 (c,
0.55 in CH2Cl2); νmax (KBr)/cmϪ1 3309 (NH), 2105 (CN2), 1689
(CO of carbamate), 1654 (CO of amide), 1625 (CO of diazo-
ketone); δH (300 MHz, CDCl3) 1.29 (3H, d, J = 7.0 Hz, CH3),
3.02 (2H, br m, PhCH2), 4.21 (1H, br m, CH(N)CO), 4.69 (1H,
br m, CH(N)CO), 5.09 (2H, d, J = 3.4 Hz, OCH2Ph), 5.29 (1H,
s, CHN2), 5.31 (1H, br s, NH), 6.78 (1H, br m, NH), 7.14–7.38
(10H, m, Ar-H); δC (75 MHz, CDCl3) 18.17 (CH3), 37.89, 50.54,
54.62, 56.89, 67.01, 126.93, 127.93, 128.15, 128.43, 128.48,
129.13, 135.88, 155.78 (CO of carbamate), 171.81 (CO of
amide), 192.23 (CO of diazoketone); m/z 366 (Mϩ Ϫ N2, 66%),
91 (PhCH2ϩ, 100).
(N-Benzyloxycarbonyl-L-prolyl-L-phenylalanyl)diazomethane,
2y
The dipeptide acid 1y (6.94 g, 17.5 mmol) was treated according
to the literature procedure to give the title compound 2y as a
yellow solid. The crude product was purified by flash chrom-
atography using 60% ethyl acetate–40% hexane as eluant, to
give the pure α-diazoketone (4.92 g, 67%), mp 85–86.5 ЊC
(Found: C, 65.5; H, 5.8; N, 12.7. C23H24N4O4 requires: C, 65.7;
H, 5.8; N, 13.3%); [α]D20 Ϫ97.0 (c, 0.76 in CH2Cl2); νmax (KBr)/
cmϪ1 3349 (NH), 2105 (CN2), 1732 (CO of carbamate), 1661
(CO of amide), 1649 (CO of diazoketone); δH (500 MHz,
CDCl3) 1.35–1.48 (4H, br m, CH2CH2), 2.89–3.50 (4H, br m,
CH2N and PhCH2), 4.31 (1H, br m, CH(N)CO), 4.60–4.80
(1H, br m, CH(N)CO), 5.13 (2H, s, PhCH2O), 4.95, 5.51 (1H,
2 × s, CHN2), 6.40, 6.81 (1H, 2 × br s, NH), 7.10–7.37 (10H, m,
Ar-H); δC (50 ЊC, 125 MHz, CDCl3) 24.16 (br), 28.61 (br),
37.58, 47.12, 53.97, 56.87, 60.87, 67.51, 126.94, 127.93, 128.23,
128.56, 129.15, 136.43, 156.00 (br) (CO of carbamate), 171.49
(CO of amide), 192.50 (br) (CO of diazoketone).
(N-Benzyloxycarbonyl-L-phenylalanyl-L-alanyl)diazomethane,
2v
The dipeptide acid 1v (1.70 g, 4.59 mmol) was treated according
to the literature procedure to give the title compound 2v (1.52 g,
84%) as an orange solid. The crude product was recrystal-
lized from ethyl acetate–hexane–THF to give the pure α-
diazoketone, mp 117–118.5 ЊC (Found: C, 64.1; H, 5.9; N, 14.1.
C21H22N4O4 requires: C, 64.0; H, 5.6; N, 14.2%); [α]D20 Ϫ13.2
(c, 0.58 in CH2Cl2); νmax (KBr/cmϪ1) 3304 (NH), 2113 (CN2),
1692 (CO of carbamate), 1651 (CO of amide), 1629 (CO of
diazoketone); δH (300 MHz, CDCl3) 1.23 (3H, d, J = 7.0 Hz,
CH3), 3.07 (2H, d, J = 6.8 Hz, PhCH2), 4.42–4.50 (2H, br m,
CH(N)CO and CH(N)CO), 5.06 (2H, s, OCH2Ph), 5.10 (1H, s,
CHN2), 5.50 (1H, d, J = 7.8 Hz, NH), 6.73 (1H, br d, J = 5.2
Hz, NH), 7.17–7.32 (10H, m, Ar-H); δC (75 MHz, CDCl3) 17.73
(CH3), 38.30, 51.85, 53.23, 55.98, 67.04, 126.96, 127.85, 128.10,
128.39, 128.55, 129.23, 135.93, 155.83 (CO of carbamate),
170.40 (CO of amide), 193.11 (CO of diazoketone); m/z 366
(Mϩ Ϫ N2, 75%), 91 (PhCH2ϩ, 100).
Oxidation of N-protected ꢀ-amino acid and dipeptide derived
diazoketones using dimethyldioxirane: general procedure
The N-protected diazoketone (1 eq.) was dissolved in the mini-
mum amount of dry, distilled acetone and 1.5 eq. of freshly
dried (using anhydrous Na2SO4) DMD in acetone solution was
added at room temp. and the reaction stirred. Evolution of
nitrogen was observed. The reaction was followed by TLC and
generally took approximately 10 min. The acetone was then
removed under reduced pressure to yield the crude glyoxal and
water. The crude glyoxal was dissolved in dry CH2Cl2, dried
over Na2SO4 and the solvent removed by evaporation to give
the glyoxal in quantitative yield.
(N-Benzyloxycarbonyl-L-valyl-L-phenylalanyl)diazomethane, 2w
The dipeptide acid 1w (0.61 g, 1.53 mmol) was treated accord-
ing to the literature procedure to give the title compound 2w
(0.46 g, 72%) as a yellow solid. The crude product was recrystal-
lized from ethyl acetate–hexane–THF to give the pure α-diazo-
ketone, mp 191–195 ЊC (Found: C, 65.5; H, 6.4; N, 13.0. C23H26-
N4O4 requires: C, 65.4; H, 6.2; N, 13.3%); [α]D20 Ϫ9.4 (c, 0.51
in CH2Cl2); νmax (KBr)/cmϪ1 3317 (NH), 2111 (CN2), 1695
(NCO2), 1650 (CONH), 1630 (COCHN2); δH (300 MHz,
CDCl3) 0.81 (3H, d, J = 6.5 Hz, (CH3)2CH), 0.90 (3H, d, J = 6.6
Hz, (CH3)2CH), 2.10 (1H, m, (CH3)2CH), 3.03 (2H, m, PhCH2),
4.05 (1H, br m, CH(N)CO), 4.74 (1H, br m, CH(N)CO), 5.10
(2H, s, OCH2Ph), 5.26 (1H, s, CHN2), 5.42 (1H, br d, J = 8.3
Hz, NH), 6.87 (1H, br d, NH), 7.15–7.34 (10H, m, Ar-H); δC
(75 MHz, CDCl3) 17.41 (CH3), 19.05 (CH3), 30.67, 38.06,
54.68, 56.86, 60.27, 66.97, 126.90, 127.87, 128.08, 128.40,
(S)-1-(Benzyl-3,3-dihydroxy-2-oxopropyl)carbamic acid benz-
yl ester, 4m. Treatment of (N-benzyloxycarbonyl--phenyl-
alanyl)diazomethane 2m (311.2 mg, 0.96 mmol) in acetone
(10 ml) with one equivalent of DMD (15 ml of a 0.065 M
solution in acetone, 0.98 mmol) according to general procedure
described above, after 10 min (TLC CH2Cl2) afforded the
title compound 4m (311.7 mg, 98%) as a pale yellow solid, mp
71–73 ЊC (Found: C, 65.8; H, 5.4; N, 4.2. C18H19NO5 requires:
C, 65.6; H, 5.8; N, 4.3%); [α]D20 Ϫ10.8 (c, 0.7 in CH2Cl2); νmax
(KBr)/cmϪ1 3390, 3315 (OH and NH), 2949, 2925 (aldehydic
C-H), 1736 (CO of carbamate), 1691 (COs of ketoaldehyde);
J. Chem. Soc., Perkin Trans. 1, 2000, 381–389
385

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δH (300 MHz, CD3COCD3) 2.92 (1H, dd, J1 = 14.0 Hz, J2 = 9.7
Hz, PhCH2), 3.32 (1H, dd, J1 = 14.1 Hz, J2 = 4.2 Hz, PhCH2),
4.94 (1H, m, CH(N)CO), 5.00 (2H, s, OCH2Ph), 5.36 (1H, m,
CH(OH)2), 5.82 (2H, d, J = 7.9 Hz, CH(OH)2), 6.66 (1H, d,
J = 7.9 Hz, NH), 7.18–7.30 (10H, m, Ar-H).
(0.035 ml, 0.52 mmol) in CH2Cl2 (20 ml) yielded the crude
dihydropyrazine as a yellow oil. The dihydropyrazine was
dehydrogenated according to the general procedure in the pres-
ence of MnO2 (0.135 g, 1.56 mmol) and KOH (0.032 g, 0.57
mmol) to yield the crude pyrazine as a brown oil. Purification
by flash chromatography on silica using EtOAc–hexane (40:60)
gave the title compound 5f as a pale yellow waxy solid (70 mg,
45%) (Found: C, 68.3; H, 7.2; N, 13.8%. C17H21N3O2 requires:
C, 68.2; H, 7.0; N, 14.0%); [α]D20 Ϫ51.3 (c, 1.92 in CHCl3); νmax
(KBr)/cmϪ1 3357, 1689; δH (500 MHz, CDCl3) 0.77 (3H, d,
J = 6.75 Hz, CH3CH), 0.91 (3H, t, J = 7.4 Hz, CH3CH2-
CH), 1.16 (1H, m, CH3CHHCH), 1.55 (1H, m, CH3CHHCH),
1.91 (1H, m, CH3CH2CHCH), 4.77 (1H, m, CHNH), 5.07, 5.11
(2H, 2 × d, J = 12.3 Hz, PhCH2OCO), 5.84 (1H, br d, J = 8.6
Assignment was also facilitated by H–H COSY, H–C COSY
and decoupling experiments.
Oxidation of N-protected amino acid diazoketones and
derivatization as pyrazines: general procedure
The diazoketone (1 eq.) was dissolved in acetone and stirred at
0 ЊC, under nitrogen. 1.5 equivalents of the acetone DMD
solution were added in a single portion. Reactions were moni-
tored by TLC. Upon completion (<10 min), the solvent was
removed under reduced pressure. The crude glyoxal was then
dissolved in dichloromethane (15 ml) and dried over anhydrous
Na2SO4. 1 equivalent of the diamine and some MgSO4 were
added. The reaction mixture was allowed to stir for 2 hours at
room temperature. The solid was then filtered and solvent
evaporated to give the crude dihydropyrazine. Oxidation of the
dihydropyrazine was achieved by dissolving the crude dihydro-
pyrazine in EtOH and stirring at reflux for 6 hours in the
presence of three equivalents of MnO2 and 1.1 equivalents of
KOH. The MnO2 was filtered through a pad of Celite and the
solvent evaporated. The crude reaction product was dissolved
in EtOAc and washed with brine, dried over anhydrous Na2SO4
and the solvent evaporated under reduced pressure to yield
the crude pyrazine which was generally purified by flash
chromatography on silica using EtOAc–hexane as eluant.
Hz, NH), 7.31 (5H, m, ArH), 8.46 (1H, s, N᎐CHC), 8.51 (2H,
᎐
m, NCH᎐CHN); δ (125 MHz, CDCl3) 11.37, 14.57, 15.36,
᎐
C
25.13, 40.07, 57.91, 66.89, 128.12, 128.14, 128.38, 128.52,
136.42, 142.38, 143.47, 144.04, 155.34, 156.06; m/z 299 (Mϩ), 91
(PhCH2, 100%).
(1ЈS)-2-(1Ј-N-Benzyloxycarbonylaminoethyl)-5-methyl-
pyrazine and (1ЈS)-2-(1Ј-N-benzyloxycarbonylaminoethyl)-6-
methylpyrazine, 6. Treatment of (N-benzyloxycarbonyl--
alanyl)diazomethane 2b (0.2 g, 0.81 mmol) in acetone (15 ml)
with DMD (17 ml, 0.07 M, 1.5 eq.) according to the general
procedure and subsequent condensation with 1,2-diamino-
propane (0.07 ml, 0.52 mmol) in CH2Cl2 (20 ml) for 4 hours
yielded the crude dihydropyrazine as a pale yellow oil. The
dihydropyrazine was dehydrogenated according to the general
procedure in the presence of MnO2 (0.21 g, 2.4 mmol) and
KOH (0.05 g, 0.89 mmol) to yield the crude pyrazines as
a brown oil. Purification by flash chromatography on silica
using EtOAc–hexane (40:60) gave the title compounds as an
inseparable mixture of regioisomers (3:2) as a colourless oil 6
(0.12 g, 55%) (Found: Mϩ 271.1326. C15H17N3O2 requires: Mϩ
271.1321); δH (500 MHz, CDCl3) 1.48 (2 × 3H, d, CH3CH-
(NH)), 2.52, 2.54 (2 × 3H, s, Het-CH3), 4.97 (2 × 1H, CH3CH-
(NH)), 5.10 (2 × 2H, m, PhCH2OCO), 5.83, 5.94 (2 × 1H, br s,
NH), 7.31 (2 × 5H, m, Ph-H), 8.34, 8.36, 8.46 (2 × 2H, s,
Het-H).
(1ЈS)-2-(2Ј-Methyl-1Ј-N-benzyloxycarbonylaminopropyl)-
pyrazine, 5q. Oxidation of (N-benzyloxycarbonyl--valyl)-
diazomethane 2q (0.2 g, 0.73 mmol) in acetone (15 ml) with
DMD (16 ml, 0.07 M, 1.5 eq.) according to the general pro-
cedure and subsequent condensation with diaminoethane (0.05
ml, 0.73 mmol) in CH2Cl2 (20 ml) yielded the crude dihydro-
pyrazine as a yellow oil (Found: Mϩ, 287.1624. C16H21N3O2
requires: Mϩ, 287.1634); νmax (KBr)/cmϪ1 1710 (CO); δH (300
MHz, CDCl3) 0.84 (3H, d, J = 6.9 Hz, (CH3)2CH), 1.00 (3H, d,
J = 6.7 Hz, (CH3)2CH), 2.06 (1H, m, (CH3)2CH), 3.35 (2H, d,
J = 12.9 Hz, NCH2CH2N), 3.57 (2H, d, J = 12.3 Hz, NCH2-
CH2N), 4.45 (1H, m, CH(N)CO), 5.10 (2H, s, OCH2Ph),
5.79 (1H, d, J = 8.1 Hz, NH), 7.35 (5H, s, Ar-H), 7.78 (1H,
(1ЈS)-2-(1Ј-N-Benzyloxycarbonylaminoethyl)-5-methoxycarb-
onylpyrazine, 7, and (1ЈS)-2-(1Ј-N-benzyloxycarbonylamino-
ethyl)-6-methoxycarbonylpyrazine 8. Treatment of (N-benzyl-
oxycarbonyl--alanyl)diazomethane 2b (0.2 g, 0.81 mmol) in
acetone (15 ml) with DMD (17 ml, 0.07 M, 1.5 eq.) according
to the general procedure and subsequent condensation with
2,3-diaminopropionic acid methyl ester dihydrochloride (0.15 g,
0.81 mmol) in the presence of NEt3 (0.23 ml, 1.6 mmol) in
MeOH (20 ml) overnight, yielded the crude pyrazine as a mix-
ture of regioisomers which was purified by flash chromato-
graphy on silica using EtOAc–hexane (50:50) as eluant to give
regioisomer 7 as a colourless oil (65 mg, 25%), [α]D20 Ϫ48.6 (c,
1.68 in CHCl3); νmax (film)/cmϪ1 3330, 1723; δH (500 MHz,
CDCl3) 1.46 (3H, d, J = 6.9 Hz, CH3CHNH), 3.95 (3H, s,
CO2CH3), 4.69 (1H, m, CH3CHNH), 5.07 (2H, s, PhCH2OCO),
5.72 (1H, br d, J = 4.35 Hz, NH), 7.27 (5H, m, Ar-H), 8.69 (1H,
s, Het-H), 9.11 (1H, s, Het-H); δC (125 MHz, CDCl3) 22.07,
47.87, 51.13, 65.10, 126.26, 126.35, 126.55, 126.67, 126.85,
134.35, 142.79, 144.00, 163.50. Further elution of the column
gave regioisomer 8 as a colourless oil (72 mg, 28%), [α]D20 Ϫ57.4
(c, 0.86 in CHCl3); νmax (film)/cmϪ1 3336, 1724; δH (500 MHz,
CDCl3), 1.44 (3H, d, J = 6.9 Hz, CH3CHNH), 3.97 (3H, s,
CO2CH3), 5.03 (3H, m, PhCH2OCO ϩ CH3CHNH), 5.62 (1H,
br s, NH), 7.29 (5H, Ar-H), 8.63 (1H, s, Het-H), 9.15 (1H, s,
Het-H); δC (125 MHz, CDCl3), 20.98, 48.78, 52.09, 66.03,
127.14, 127.24, 127.55, 140.95, 141.50, 144.34, 163.29 (Found:
C, 60.6; H, 5.4; N, 12.9. C16H17N3O4 requires: C, 60.9; H, 5.4; N,
13.3%). Regioisomers assigned by HMBC and HMQC NMR
spectra.
s, CH᎐N); δ (75 MHz, CDCl3) 16.87, 19.24, 31.18, 43.54,
᎐
C
44.61, 58.45, 66.65, 127.89, 128.28, 136.24, 152.57, 156.21,
159.08. The dihydropyrazine was then dehydrogenated
according to the general procedure in the presence of MnO2
(0.19 g, 2.2 mmol) and KOH (0.045 g, 0.8 mmol) to yield the
crude pyrazine as a brown oil. Purification by flash chrom-
atography on silica using EtOAc–hexane (40:60) gave the title
compound 5q as a pale yellow oil (0.11 g, 53%) (Found: Mϩ
285.1477. C16H19N3O2 requires: Mϩ 285.1476); [α]D20 Ϫ54.4 (c,
1.9 in CHCl3); νmax (film)/cmϪ1 3329, 1716, 1608; δH (500
MHz, CDCl3) 0.8 (3H, d, J = 6.8 Hz, (CH3)CH3CHCH), 0.95
(3H, d, J = 6.8 Hz, (CH3)CH3CHCH), 2.14 (1H, m, (CH3)2-
CHCH), 4.72 (1H, m, (CH3)2CHCH), 5.07 (1H, d, J = 12.3 Hz,
PhCHHOCO), 5.12 (1H, d, J = 12.1 Hz, PhCHHOCO), 5.81
(1H, br d, J = 8.6 Hz, NH), 7.31 (5H, m, ArH), 8.47 (1H, s,
N᎐CHC), 8.51 (2H, m, NCH᎐CHN); δ (125 MHz, CDCl3)
᎐
᎐
C
18.24, 19.15, 33.79, 58.92, 66.91, 128.12, 128.15, 128.53, 136.42,
143.47, 144.07, 155.38, 156.19; m/z 285 (Mϩ), 91 (PhCH2,
100%).
(1ЈS,2ЈS)-2-(2Ј-Methyl-1Ј-N-benzyloxycarbonylaminobutyl)-
pyrazine, 5f. Treatment of (N-benzyloxycarbonyl--isoleucyl)-
diazomethane 2f (0.15 g, 0.52 mmol) in acetone (15 ml) with
DMD (11 ml, 0.07 M, 1.5 eq.) according to the general pro-
cedure and subsequent condensation with diaminoethane
386
J. Chem. Soc., Perkin Trans. 1, 2000, 381–389

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Oxidation of N-protected amino acid diazoketones and
derivatization as quinoxalines and pyrido[2,3-b]pyrazines:
general procedure
0.34 mmol) yielded the crude product as a brown solid. Purifi-
cation by PLC on silica, using 25% ethyl acetate–75% hexane as
eluant, yielded the pure product 9f (102.8 mg, 91%) as a yellow
solid, mp 116–118 ЊC (Found: C, 71.7; H, 6.9; N, 11.8.
C21H23N3O2 requires: C, 72.2; H, 6.6; N, 12.0%); [α]D20 Ϫ117.2
(c, 2 in CH2Cl2); νmax (KBr)/cmϪ1 3210 (NH), 1700 (CO of carb-
amate); δH (300 MHz, CDCl3) 0.87 (3H, d, J = 6.7 Hz, CH3CH),
0.92 (3H, t, J = 7.4 Hz, CH3CH2), 1.17–1.28 (1H, br m,
CH3CH2), 1.54–1.61 (1H, br m, CH3CH2), 2.03–2.07 (1H, br m,
CH3CH), 5.05 (1H, overlapping dd, J = 8.1 Hz, CH(N)CO),
5.12 (2H, d, J = 2.5 Hz, OCH2Ph), 6.18 (1H, d, J = 8.4 Hz,
NH), 7.26–7.35 (5H, m, Ar-H), 7.71–7.77 (2H, m, Ar-H), 8.03–
The diazoketone (1 eq.) was dissolved in acetone and stirred at
0 ЊC, under an atmosphere of nitrogen. One equivalent of
dimethyldioxirane was added in a single portion. Reactions
were monitored by TLC and if more DMD was required it was
added. The crude glyoxal was then dissolved in ethanol and
stirred at room temperature. 1.05 equivalents of freshly reduced
o-phenylenediamine† or 2,3-diaminopyridine‡ was added and
the solution stirred overnight at room temperature. The solvent
was then removed under reduced pressure and the crude
material purified by flash chromatography or PLC on silica.
8.13 (2H, m, Ar-H), 8.80 (1H, s, CH᎐N); δ (75 MHz, CDCl )
᎐
C
3
11.33 (CH3CH2), 15.31 (CH3CH), 24.87 (CH2), 40.38
(CHCH3), 58.23 (CH(N)CO), 66.76 (OCH2), 127.97, 128.34,
128.90, 129.12, 129.43, 129.97, 136.22 (Ar-CCH2O), 141.60
(1ЈS)-2-(1Ј-N-Benzyloxycarbonylaminoethyl)quinoxaline, 9b.
Treatment of (N-benzyloxycarbonyl--alanyl)diazomethane 2b
(61.9 mg, 0.25 mmol) in acetone (40 ml) with 1 equivalent
DMD (3.0 ml of a 0.089 M solution in acetone, 0.27 mmol)
according to the general procedure and subsequent conden-
sation with o-phenylenediamine (27.9 mg, 0.26 mmol) yielded
the crude product as a brown oil (81.3 mg). The crude material
was purified by PLC on silica, using 50% ethyl acetate–hexane
as eluant, to give the pure quinoxaline 9b (71.6 mg, 93%) as a
white solid, mp 124–125 ЊC (Found: C, 70.2; H, 5.7; N, 13.7.
C18H17N3O2 requires: C, 70.3; H, 5.6; N, 13.7%); [α]D20 Ϫ111.2
(c, 2.2 in CH2Cl2); νmax (KBr)/cmϪ1 3324 (NH), 1684 (CO of
carbamate); δH (500 MHz, CDCl3) 1.61 (3H, d, J = 6.6 Hz,
CH3CH), 5.14 (2H, dd, J1 = 17.2 Hz, J2 = 12.1 Hz, OCH2Ph),
5.22 (1H, m, CH(N)CO), 6.30 (1H, d, J = 7.0 Hz, NH), 7.31–
7.38 (5H, m, Ar-H), 7.74 (2H, m, Ar-H), 8.07 (2H, m, Ar-H),
(Ar-C-N), 141.69 (Ar-C-N), 144.62 (HC᎐N), 154.76, 156.00
᎐
(CO of carbamate and CC᎐N).
᎐
( )-2-(2Ј-Methyl-1Ј-N-tert-butoxycarbonylaminobutyl)quin-
oxaline, 9g. Treatment of ( )-(N-tert-butoxycarbonylisoleucyl)-
diazomethane 2g (85.9 mg, 0.34 mmol) in acetone (50 ml) with
1 equivalent DMD (3.7 ml of a 0.093 M solution in acetone,
0.34 mmol) according to the general procedure and subsequent
condensation with o-phenylenediamine (42 mg, 0.39 mmol)
yielded the crude product as a brown oil. Purification by PLC
on silica, using 25% ethyl acetate–75% hexane as eluant, yielded
the pure product 9g (97.5 mg, 92%) as a white solid; δH (300
MHz, CDCl3) 0.87 (3H, m, CH3CH2), 0.97 (3H, m, CH3CH),
1.14–1.25 (1H, br m, CH3CH2), 1.45 (9H, s, (CH3)3C), 1.40–
1.57 (1H, br m, CH3CH2), 1.98–2.04 (1H, br m, CH3CH), 4.96,
5.07 (1H, 2 × br m, CH(N)CO), 5.77 (1H, br m, NH), 7.74
8.84 (1H, s, CH᎐N).
᎐
(2H, m, Ar-H), 8.09 (2H, m, Ar-H), 8.78 (1H, s, CH᎐N);
᎐
(1ЈS,2ЈS)-2-(1Ј-N-tert-Butoxycarbonylamino-2Ј-methylbutyl)-
quinoxaline, 9e. Treatment of [(3S,4S)-N-tert-butoxy-
carbonylisoleucyl]diazomethane 2e (109.7 mg, 0.43 mmol) in
acetone (50 ml) with 1 equivalent DMD (4.6 ml of a 0.093 M
solution in acetone, 0.43 mmol) according to the general pro-
cedure and subsequent condensation with o-phenylenediamine
(54 mg, 0.50 mmol) yielded the crude product as a brown oil.
Purification by PLC on silica, using 25% ethyl acetate–75%
hexane as eluant, yielded the pure product 9e (128.9 mg, 95%)
as a white solid, mp 131–133 ЊC (Found: C, 68.4; H, 8.2; N,
13.4. C18H25N3O2 requires: C, 68.5; H, 8.0; N, 13.3%); [α]D20
Ϫ96.4 (c, 2.7 in CH2Cl2); νmax (KBr)/cmϪ1 3255 (NH), 1713 (CO
of carbamate); δH (300 MHz, CDCl3) 0.86 (3H, d, J = 6.8 Hz,
CH3CH), 0.93 (3H, t, J = 7.3 Hz, CH3CH), 1.19–1.26 (1H,
br m, CH3CH2), 1.45 (9H, s, (CH3)3C), 1.50–1.60 (1H, br m,
CH3CH2), 2.03 (1H, br m, CH3CH2), 4.97 (1H, br t, CH-
(N)CO), 5.82 (1H, br d, NH), 7.75 (2H, m, Ar-H), 8.10 (2H,
δC (75 MHz, CDCl3) 11.41, 11.64 (CH3CH2), 13.95, 15.39
(CH3CH), 24.88, 26.36 (CH3CH2), 28.24 ((CH3)3C), 40.39,
40.59 (CH3CH), 57.12, 57.40 (CH(N)CO), 79.41 ((CH3)3C),
128.96, 129.10, 129.30, 129.33, 129.89, 141.57, 141.64, 141.70
(Ar-C-N), 144.52, 144.55 (HC᎐N), 155.33, 155.69 (CO of
᎐
carbamate and CC᎐N).
᎐
(1ЈS)-2-(1Ј-N-tert-Butoxycarbonylamino-2Ј-phenylethyl)quin-
oxaline, 9l. Treatment of (N-tert-butoxycarbonyl--phenyl-
alanyl)diazomethane 2l (78.8 mg, 0.27 mmol) in acetone (40 ml)
with 1 equivalent DMD (3.2 ml of a 0.089 M solution in acet-
one, 0.28 mmol) according to the general procedure and sub-
sequent condensation with o-phenylenediamine (30.5 mg, 0.28
mmol) yielded the crude product as a brown oil. Purification by
PLC on silica, using 50% ethyl acetate–50% hexane as eluant,
yielded the pure product 9l (95.2 mg, 93%) as a white solid,
mp 108–110 ЊC (Found: C, 71.8; H, 6.8; N, 11.8. C21H23N3O2
requires: C, 72.2; H, 6.6; N, 12.0%); [α]D20 ϩ16.1 (c, 4.8 in
CH2Cl2); νmax (KBr)/cmϪ1 3201 (NH), 1700 (CO of carbamate);
δH (500 MHz, CDCl3) 1.45 (9H, s, (CH3)3C), 3.16 (1H, dd,
J1 = 12.9 Hz, J2 = 8.1 Hz, PhCH2), 3.37 (1H, dd, J1 = 13.3 Hz,
J2 = 5.6 Hz, PhCH2), 5.15, 5.30 (1H, br s and m, CH(N)CO),
5.70, 5.94 (1H, br s and d, J = 7.3 Hz, NH), 7.02 (2H, s, Ar-H),
7.19 (3H, s, Ar-H), 7.75 (2H, m, Ar-H), 8.07 (2H, dd, J1 = 7.3
m, Ar-H), 8.80 (1H, s, CH᎐N); δ (75 MHz, CDCl3) 11.40
᎐
C
(CH3CH2), 15.39 (CH3CH), 24.88 (CH2), 28.24 ((CH3)3C),
40.39 (CHCH3), 57.84 (CH(N)CO), 79.41 ((CH3)3C), 128.96,
129.11, 129.34, 129.90, 141.64 (Ar-C-N), 141.70 (Ar-C-N),
144.74 (HC᎐N), 155.32, 155.47 (CO of carbamate and CC᎐N).
᎐
᎐
(1ЈS,2ЈS)-2-(2Ј-Methyl-1Ј-N-benzyloxycarbonylaminobutyl)-
quinoxaline, 9f. Treatment of [(3S,4S)-N-benzyloxycarb-
onylisoleucyl]diazomethane 2f (93.8 mg, 0.32 mmol) in acetone
(50 ml) with 1 equivalent DMD (4.0 ml of a 0.086 M solution in
acetone, 0.34 mmol) according to the general procedure and
subsequent condensation with o-phenylenediamine (37 mg,
Hz, J = 1.3 Hz, Ar-H), 8.40 (1H, s, CH᎐N).
᎐
2
(1ЈS)-2-(1Ј-N-Benzyloxycarbonylamino-2Ј-phenylethyl)quin-
oxaline, 9m. Treatment of (N-benzyloxycarbonyl--phenyl-
alanyl)diazomethane 2m (79.5 mg, 0.24 mmol) in acetone (20
ml) with 1 equivalent DMD (3.7 ml of a 0.065 M solution in
acetone, 0.24 mmol) according to the general procedure and
subsequent condensation with o-phenylenediamine (31 mg,
0.28 mmol) yielded the crude product as a brown oil. The crude
material was purified by PLC on silica, following multiple elu-
tion, using 70% ether–30% hexane as eluant. The resulting
product was then recrystallized from methanol to give the pure
quinoxaline 9m (86.7 mg, 92%) as a pale yellow solid, mp 110–
† The crude o-phenylenediamine (25 g) was dissolved in hot water (90
ml) containing sodium hydrosulfite (2 g), clarified with decolorizing
charcoal. After cooling, the crystals were filtered and stored in a
vacuum desiccator. L. F. Fieser and M. Fieser, Reagents for Organic
Synthesis, Wiley, New York, 1967, vol. 1, p. 835.
‡ The crude 2,3-diaminopyridine was purified by dissolution in boiling
benzene and clarifying with decolorizing charcoal followed by crystal-
lization from benzene to give purple needle-like crystals.
J. Chem. Soc., Perkin Trans. 1, 2000, 381–389
387

View Article Online
111.5 ЊC (Found: C, 75.2; H, 5.6; N, 10.7. C24H21N3O2 requires:
C, 75.2; H, 5.5; N, 11.0%); [α]D20 ϩ 18.9 (c, 0.8 in CH2Cl2); νmax
(KBr)/cmϪ1 3329 (NH), 1717 (CO of carbamate); δH (500 MHz,
CDCl3) 3.16 (1H, dd, J1 = 13.4 Hz, J2 = 8.0 Hz, PhCH2), 3.40
(1H, dd, J1 = 13.6 Hz, J2 = 5.7 Hz, PhCH2), 5.13 (2H, dd,
J1 = 18.6 Hz, J2 = 12.3 Hz, OCH2Ph), 5.35 (1H, dd, J1 = 14.0
Hz, J2 = 7.8 Hz, CH(N)CO), 6.21 (1H, d, J = 7.8 Hz, NH), 6.98
(2H, m, Ar-H), 7.19 (4H, m, Ar-H), 7.36 (4H, d, J = 4.1 Hz,
Ar-H), 7.76 (2H, m, Ar-H), 8.06 (2H, dd, J1 = 18.1 Hz, J2 = 7.4
8.08 (1H, dd, J1 = 7.7 Hz, J2 = 1.8 Hz, Ar-H), 8.77 (1H, s,
Ar-H).
(S)-2-(1Ј-N-Phthaloylamino-2Ј-methylpropyl)quinoxaline, 9s.
Treatment of (N-phthaloyl--valyl)diazomethane 2s (74.0 mg,
0.27 mmol) in acetone (40 ml) with 1 equivalent DMD (3.5
ml of a 0.089 M solution in acetone, 0.31 mmol) according
to the general procedure and subsequent condensation with
o-phenylenediamine (31.0 mg, 0.29 mmol) yielded the crude
product as a brown oil. Purification by PLC on silica, using 50%
ethyl acetate–50% hexane as eluant, yielded the pure product
9s as a white solid, mp 101–103 ЊC (Found: C, 72.1; H, 5.1; N,
12.4. C20H17N3O2 requires: C, 72.5; H, 5.2; N, 12.7%); [α]D20
Ϫ90.0 (c, 0.12 in CH2Cl2); νmax (KBr)/cmϪ1 1715 (carbonyls);
δH (500 MHz, CDCl3) 1.03 (3H, d, J = 6.7 Hz, (CH3)2CH), 1.09
(3H, d, J = 6.7 Hz, (CH3)2CH), 3.47 (1H, m, (CH3)2CH), 5.32
(1H, d, J = 11.2 Hz, CH(N)CO), 7.70–7.76 (4H, m, Ar-H), 7.84
(2H, dd, J1 = 5.4 Hz, J2 = 3.2 Hz, Ar-H), 8.09 (2H, m, Ar-H),
Hz, Ar-H), 8.38 (1H, s, CH᎐N); δ (125 MHz, CDCl3) 42.57
᎐
C
(PhCH2), 55.58 (CH(N)CO), 66.96 (OCH2Ph), 126.95, 128.18,
128.21, 128.57, 129.00, 129.35, 129.46, 129.74, 130.22, 136.23
(Ar-C), 136.37 (Ar-C), 141.70 (Ar-C-N), 141.91 (Ar-C-N),
144.47 (CH᎐N), 154.42, 155.74 (CO of carbamate and CC᎐N).
᎐
᎐
Structural assignment was facilitated by H–H COSY and
H–C COSY experiments.
(S)-2-(N-Ethoxycarbonylpyrrolidin-2-yl)quinoxaline,
9o.
Treatment of (N-ethoxycarbonyl--prolyl)diazomethane 2o
(100.9 mg, 0.48 mmol) in acetone (40 ml) with 1 equivalent
DMD (6 ml of a 0.089 M solution in acetone, 0.53 mmol)
according to the general procedure and subsequent condens-
ation with o-phenylenediamine (52.0 mg, 0.48 mmol) yielded
the crude product as a brown oil. Purification by PLC on silica,
using 50% ethyl acetate–50% hexane as eluant, yielded the pure
product 9o (116.5 mg, 90%) as an oil (Found: C, 66.2; H, 6.5;
N, 15.3. C15H17N3O2 requires: C, 66.4; H, 6.3; N, 15.5%); [α]D20
Ϫ140.4 (c, 0.9 in CH2Cl2); νmax (KBr)/cmϪ1 1695 (CO of carb-
amate); δH (500 MHz, CDCl3) 0.88, 1.23 (3H, 2 × t, J = 7.0 Hz,
CH2CH3), 1.93–2.47 (4H, br m, CH2CH2), 3.62–3.78 (2H, br m,
CH2N), 3.94, 4.09 (2H, q, J = 7.0 Hz and m, OCH2CH3), 5.11,
5.19 (1H, dd, J1 = 8.1 Hz, J2 = 4.4 Hz and dd, J1 = 7.7 Hz,
J2 = 4.0 Hz, CH(N)CO), 7.65–7.74 (2H, m, Ar-H), 8.00–8.07
9.23 (1H, s, CH᎐N).
᎐
(1ЈS,2ЉS)-2-[1Ј-(2Љ-N-Benzyloxycarbonylamino-3Љ-phenyl-
propanoylamino)ethyl]quinoxaline, 9v. Treatment of (N-benzyl-
oxycarbonyl--phenylalanyl--alanyl)diazomethane 2v (267.0
mg, 0.68 mmol) in acetone (30 ml) with 1 equivalent DMD
(15.0 ml of a 0.045 M solution in acetone, 0.68 mmol) accord-
ing to the general procedure and subsequent condensation with
o-phenylenediamine (73.2 mg, 0.68 mmol) yielded the crude
product as a yellow solid. Purification by flash chromatography
on silica yielded the pure product 9v (279.5 mg, 91%) as a
white solid. A microanalytically pure sample was obtained by
recrystallization from ethyl acetate–hexane (Found: C, 71.2; H,
5.6; N, 12.5. C27H26N4O3 requires: C, 71.3; H, 5.8; N, 12.3%);
[α]D20 Ϫ106.2 (c, 1.2 in CH2Cl2); νmax (KBr)/cmϪ1 3264 (NH),
1687 (CO of carbamate), 1647 (CO of amide); δH (500 MHz,
CDCl3) 1.51 (3H, d, J = 6.6 Hz, CH3CH), 2.97 (1H, m, PhCH2),
3.16 (1H, dd, J1 = 13.7 Hz, J2 = 5.7 Hz, PhCH2), 4.50 (1H, m,
CH(N)CO), 5.12 (2H, s, OCH2Ph), 5.30 (1H, quintet, J = 7.0
Hz, CH(N)CO), 5.52 (1H, br d, J = 7.3 Hz, NH), 6.70 (1H, br
m, NH), 6.99 (3H, br d, Ar-H), 7.10 (3H, d, J = 7.3 Hz, Ar-H),
7.35 (4H, s, Ar-H), 7.77 (2H, dd, J2 = 6.4 Hz, J2 = 3.5 Hz,
Ar-H), 7.91 (1H, dd, J1 = 6.2 Hz, J2 = 3.3 Hz, Ar-H), 8.12 (1H,
(2H, m, Ar-H), 8.75, 8.81 (1H, 2 × s, CH᎐N).
᎐
(S)-2-(1Ј-N-Benzyloxycarbonylamino- 2Ј-methylpropyl)quin-
oxaline, 9q. Treatment of (N-benzyloxycarbonyl--valyl)-
diazomethane 2q (2.29 g, 8.32 mmol) in acetone (60 ml) with
1 equivalent DMD (100 ml of a 0.084 M solution in acetone,
8.4 mmol) according to the general procedure and subsequent
condensation with o-phenylenediamine (0.91 g, 8.42 mmol)
yielded the crude product as a yellow solid. Flash chrom-
atography on silica using 20% ethyl acetate–80% hexane as
eluant yielded the pure product 9q (2.67 g, 96%) as a white
solid, mp 99–100.5 ЊC (Found: C, 71.5; H, 6.2; N, 12.5. C20H21-
N3O2 requires: C, 71.6; H, 6.3; N, 12.5%); [α]D20 Ϫ129.6 (c, 3.5 in
CH2Cl2); νmax (KBr)/cmϪ1 3287 (NH), 1688 (CO of carbamate);
δH (500 MHz, CDCl3) 1.06 (6H, overlapping d, J = 7.2 Hz,
(CH3)2CH), 2.38 (1H, m, (CH3)2CH), 5.10 (1H, dd, J1 = 8.6 Hz,
J2 = 6.0 Hz, CH(N)CO), 5.23 (2H, dd, J1 = 21.8 Hz, J2 = 12.3
Hz, OCH2Ph), 7.42–7.49 (5H, m, Ar-H), 7.85–7.89 (2H, m,
dd, J = 6.0 Hz, J = 3.8 Hz, Ar-H), 8.73 (1H, s, CH᎐N); δ (125
᎐
1
2
C
MHz, CDCl3) 21.92 (CH3), 39.12 (PhCH2), 48.23 (CHNCO),
56.50 (CH(N)CO), 67.04 (OCH2Ph), 128.48, 128.51, 128.99,
129.09, 129.24, 129.73, 130.23, 136.11 (Ar-C), 141.93 (Ar-C-N),
143.93 (HC᎐N), 155.13, 155.80 (CO of carbamate and CC᎐N),
᎐
᎐
170.11 (CO of amide).
(S)-3-(1Ј-N-Benzyloxycarbonylaminoethyl)pyrido[2,3-b]-
pyrazine, 10b. Oxidation of (N-Cbz--alanyl)diazomethane 2b
(0.15 g, 0.61 mmol) in acetone (10 ml) with DMD (13 ml, 0.07
M, 1.5 eq.) according to the general procedure and subsequent
condensation with 2,3-diaminopyridine (66 mg, 0.61 mmol) in
EtOH (15 ml) yielded the crude product as a brown oil which
was purified by flash chromatography on silica using EtOAc as
eluant to give the title compound as a pale yellow oil 10b (0.172
g, 92% yield) (Found: Mϩ, 308.1273. C17H16N4O2 requires: M,
308.1273); [α]D20 Ϫ73.3 (c, 0.93, CHCl3); νmax (film)/cmϪ1 3313,
1716, 1602; δH (500 MHz, CDCl3) 1.67 (3H, d, J = 6.9 Hz,
CH3CH), 5.12 (2H, dd, J1 = 18.6 Hz, J2 = 12.4 Hz, OCH2Ph),
5.32 (1H, m, CH3CH), 6.49 (1H, d, J = 6.9 Hz, N-H), 7.28–7.33
(5H, m, Ar-H), 7.68 (1H, m, Ar-H), 8.47 (1H, m, Ar-H), 9.03
Ar-H), 8.18 (2H, m, Ar-H), 8.90 (1H, s, CH᎐N).
᎐
(S)-2-(1Ј-N-Ethoxycarbonylamino-2Ј-methylpropyl)quin-
oxaline, 9r. Treatment of (N-ethoxycarbonyl--valyl)diazo-
methane 2r (81.9 mg, 0.38 mmol) in acetone (40 ml) with
1 equivalent DMD (4.5 ml of a 0.089 M solution in acetone,
0.40 mmol) according to the general procedure and subsequent
condensation with o-phenylenediamine (43.0 mg, 0.40 mmol)
yielded the crude product as a brown oil. Purification by PLC
on silica, using 50% ethyl acetate–50% hexane as eluant, yielded
the pure product 9r as a white solid, mp 62–65 ЊC (Found: C,
65.5; H, 7.2; N, 15.1. C15H19N3O2 requires: C, 65.9; H, 7.0; N,
15.4%); [α]D20 Ϫ163.5 (c, 2.9 in CH2Cl2); νmax (KBr)/cmϪ1 3323
(NH), 1681 (CO of carbamate); δH (500 MHz, CDCl3) 0.91
(3H, d, J = 6.6 Hz, (CH3)2CH), 0.93 (3H, d, J = 7.0 Hz,
(CH3)2CH), 1.22 (3H, t, J = 7.0 Hz, CH3CH2), 2.24 (1H, m,
(CH3)2CH), 4.10 (2H, m, CH2CH3), 4.94 (1H, dd, J1 = 8.6 Hz,
J2 = 6.6 Hz, CH(N)CO), 6.03 (1H, d, J = 8.4 Hz, NH), 7.72
(2H, m, Ar-H), 8.03 (1H, dd, J1 = 8.3 Hz, J2 = 1.2 Hz, Ar-H),
(1H, s, CH᎐N), 9.14 (1H, m, Ar-H); δ (75 MHz, CDCl3)
᎐
C
22.74, 51.06, 67.72, 126.00, 128.85, 128.94, 129.35, 137.25,
137.99, 139.36, 146.50, 151.07, 155.14, 156.78, 160.95; m/z 308
(Mϩ), 159 (Mϩ Ϫ Cbz, 100%).
(S)-3-(3Ј-Methyl-1Ј-N-benzyloxycarbonylaminobutyl)pyrido-
[2,3-b]pyrazine, 10i. Oxidation of (N-Cbz--leucyl)diazo-
methane 2i (50 mg, 0.17 mmol) in acetone (5 ml) with DMD
388
J. Chem. Soc., Perkin Trans. 1, 2000, 381–389

View Article Online
(4 ml, 0.07 M, 1.5 eq.) according to the general procedure and
subsequent condensation with 2,3-diaminopyridine (20 mg,
0.17 mmol) in EtOH (10 ml) yielded the crude product as a
brown oil which was purified by flash chromatography on silica
using EtOAc–hexane (60:40) as eluant to give the title com-
pound as a yellow oil 10i (64 mg, 90%) (Found: C, 68.3; H, 6.2;
N, 15.9. C20H22N4O2 requires: C, 68.5; H, 6.3; N, 16.0); [α]D20
Ϫ133 (c, 1.0 in CHCl3); νmax (film)/cmϪ1 3440, 1716; δH (500
MHz, CDCl3) 0.97 (3H, d, J = 6.6 Hz, CH3CH(CH3)), 1.01
(3H, d, J = 6.4 Hz, CH3CH(CH3)), 1.17 (1H, m, (CH3)2CH),
1.81 (2H, m, (CH3)2CHCH2), 5.00 (2H, dd, J1 = 20.3 Hz,
J2 = 12.4 Hz, OCH2Ph), 5.28 (1H, m, (CH3)2CHCH2CH), 6.07
(IH, d, J = 8.6 Hz, N-H), 7.17–7.35 (5H, m, Ar-H), 7.70 (1H, m,
on silica using EtOAc as eluant to give the title compound as a
yellow oil 10q (0.17 g, 94%) (Found: C, 67.9; H, 6.1; N, 16.8.
C19H20N4O2 requires: C, 67.8; H, 5.9; N, 16.6); [α]D20 Ϫ125 (c, 1.48
in CHCl3); νmax (film)/cmϪ1 3317, 1716, 1602; δH (500 MHz,
CDCl3) 0.96 (3H, d, J = 6.9 Hz, CH3CH(CH3)), 1.00 (3H, d,
J = 6.8 Hz, CH3CH(CH3)), 2.35 (1H, m, (CH3)2CH), 5.06 (1H,
m, (CH3)2CHCH), 5.09 (2H, dd, J1 = 17.7 Hz, J2 = 12.4 Hz,
OCH2Ph), 6.30 (IH, d, J = 8.8 Hz, N-H), 7.27–7.33 (5H, m,
Ar-H), 7.71 (1H, m, Ar-H), 8.49 (1H, m, Ar-H), 8.96 (1H,
s, CH᎐N), 9.17 (1H, m, Ar-H); δ (75 MHz, CDCl3) 18.03,
᎐
C
19.46, 34.07, 59.30, 66.85, 125.09, 127.90, 127.99, 128.41,
136.33, 137.08, 138.52, 146.16, 150.33, 154.23, 156.38, 159.03;
m/z 336 (Mϩ).
Ar-H), 8.48 (1H, m, Ar-H), 9.00 (1H, s, CH᎐N), 9.15 (1H, m,
᎐
Ar-H); δC (75 MHz, CDCl3) 20.05, 21.62, 22.33, 24.35, 44.67,
45.75, 52.09, 59.75, 66.27, 67.51, 124.46, 126.19, 126.70, 127.32,
127.42, 127.83, 128.05, 135.68, 136.57, 137.94, 143.84, 144.49,
145.26, 149.83, 153.58, 154.68, 155.33, 155.50, 159.67; m/z 350
(Mϩ).
X-Ray crystal structure determination
Data were collected using a Siemens P3 four circle diffract-
ometer with graphite monochromated Cu-Kα radiation using
standard procedures at room temperature. The structure was
solved by direct methods all non-hydrogen atoms were refined
with anisotropic thermal parameters. Hydrogen atom positions
were added at idealized positions and a riding model with fixed
thermal parameters (Uij = 1.2 Uij (eq)) was used for subsequent
refinement. The absolute configuration of 10m was defined by
the use of pure (-phenylalanyl)glyoxal in the preparation of
10m. The SHELXTL PC15 and SHELXL-9316 packages were
used for structure solution and refinement. Additional material,
available from the Cambridge Crystallographic Data Centre
includes atomic coordinates, thermal parameters, remaining
bond lengths and angles, and structure factors.10
Crystal data for [C23H20O2N4] (10m): M = 384.43, mono-
clinic, space group P21, a = 5.119(1) Å, b = 9.171(2) Å, c =
21.063(4) Å, β = 92.94(3)Њ, U = 987.6(3) ÅϪ3, Z = 2, Dc = 1.293
Mg mϪ3, F(000) = 404, µ = 0.685 mmϪ1, crystal dimensions =
0.54 × 0.35 × 0.15 mm. A total of 1940 reflections were meas-
ured for 4 < 2θ < 110 and 1720 unique reflections were used in
the refinement. The final parameters were wR2 = 0.1196 and
R1 = 0.0483 [I > 2σ(I)].
(S)-3-(2Ј-Phenyl-1Ј-N-benzyloxycarbonylaminoethyl)pyrido-
[2,3-b]pyrazine, 10m. Oxidation of (N-Cbz--phenylalanyl)-
diazomethane 2m (0.15 g, 0.46 mmol) in acetone (10 ml) with
DMD (10 ml, 0.07 M, 1.5 eq.) according to the general pro-
cedure and subsequent condensation with 2,3-diaminopyridine
(50 mg, 0.46 mmol) in EtOH (15 ml) yielded the crude product
as a brown oil which was purified by flash chromatography on
silica using EtOAc–hexane (80:20) as eluant to give the title
compound as a pale brown solid 10m (0.16 g, 90% yield); mp
115–117 ЊC (Found: C, 71.8; H, 5.5; N, 14.8. C23H20N4O2
requires: C, 71.8; H, 5.2; N, 14.6); [α]D20 ϩ65.56 (c, 0.9, CHCl3);
νmax (KBr)/cmϪ1 3347, 1686; δH (500 MHz, CDCl3) 3.21 (1H,
dd, J1 = 13.4 Hz, J2 = 8.4 Hz, PhCH2CH), 3.44 (1H, dd,
J1 = 13.3 Hz, J2 = 6.1 Hz, PhCH2CH), 5.09 (2H, dd, J1 = 20.9
Hz, J2 = 12.4 Hz, OCH2Ph), 5.42 (1H, m, PhCH2CH(NH)),
6.30 (1H, br d, J = 7.65, N-H), 7.01–7.32 (5H, m, Ar-H), 7.71
(1H, m, Ar-H), 8.44 (1H, m, Ar-H), 8.49 (1H, s, CH᎐N), 9.16
᎐
(1H, m, Ar-H); δC (75 MHz, CDCl3) 41.46, 54.74, 65.90, 124.23,
126.09, 126.95, 127.09, 127.50, 127.71, 128.38, 135.17, 136.17,
137.63, 144.90, 149.35, 153.27, 154.87, 157.56; m/z 384 (Mϩ), 91
(PhCH2, 100%).
References
1 For a preliminary account of the synthesis of N-protected α-amino
glyoxals see, P. Darkins, N. McCarthy, M. A. McKervey and T. Ye,
J. Chem. Soc., Chem. Commun., 1993, 1222.
2 M. Groarke, B. Hartzoulakis, M. A. McKervey, B. Walker and
C. H. Williams, Bioorg. Med. Chem. Lett., 2000, in the press.
3 B. Walker, N. McCarthy, A. Healy, T. Ye and M. A. McKervey,
Biochem. J., 1993, 293, 321.
4 J. F. Lynas, P. Harriott, A. Healy, M. A. McKervey and B. Walker,
Bioorg. Med. Chem. Lett., 1998, 8, 373.
5 P. Darkins, N. McCarthy, M. A. McKervey and H. Moncrieff,
manuscript in preparation.
6 J. Podlech and D. Seebach, Liebigs Ann. Chem., 1995, 1217.
7 T. Ye and M. A. McKervey, Tetrahedron, 1992, 48, 8007.
8 Simple diazoketones have been oxidized by DMD, see H. Ihmels,
M. Maggini, M. Prato and G. Scorrano, Tetrahedron Lett., 1991, 32,
6215.
9 T. Akiyama, Y. Enomoto and T. Shibamoto, J. Agric. Food Chem.,
1978, 26, 1176.
(S)-3-(N-Ethoxycarbonylpyrrolidin-2-yl)pyrido[2,3-b]pyr-
azine, 10o. Oxidation of (N-ethoxycarbonyl--prolyl)diazo-
methane 2o (50 mg, 0.24 mmol) (5 ml) with DMD (5 ml, 0.07
M, 1.5 eq.) according to the general procedure and subsequent
condensation with 2,3-diaminopyridine (26 mg, 0.24 mmol) in
EtOH (10 ml) yielded the crude product as a brown oil which
was purified by flash chromatography on silica using EtOAc
as eluant to give the title compound as a brown oil 10o (60
mg, 92%) (Found: Mϩ, 272.1271; C14H16N4O2 requires: Mϩ,
272.1273); [α]D20 Ϫ102 (c, 3.2 in CHCl3); νmax (film)/cmϪ1 3475,
1694, 1601; δH (500 MHz, CDCl3) 0.94, 1.26 (3H, 2 × t, J = 6.8
Hz, CH3CH2), 2.01–2.35 (4H, br m, CH2CH2), 3.66–3.79 (2H,
br m, CH2CH2N), 3.99, 4.12 (2H, 2 × m, CO2CH2CH3), 5.24,
5.28 (1H, 2 × m, CH2CHN), 7.74 (1H, m, Ar-H), 8.50 (1H, m,
10 CCDC reference number 207/382. See http://www.rsc.org/suppdata/
p1/a9/a907948c/ for crystallographic files in .cif format.
11 L. T. Scott and C. A. Sumpter, Org. Synth., 1990, 69, 180.
12 K. Pulcinska and B. Liberek, Tetrahedron, 1987, 3509.
13 E. M. Gordon, J. D. Godfrey, N. G. Delaney, M. M. Asaad, D. von
Langan and D. W. Cushman, J. Med. Chem., 1988, 31, 2199.
14 B. Penke, J. Czombos, L. Balaspiri, J. Petres and K. Kovacs, Helv.
Chim. Acta, 1970, 53, 1057.
15 G. M. Sheldrick, SHELXTL, Siemens Analytical X-Ray Instru-
ments, Madison, WI, 1994.
16 G. M. Sheldrick, SHELXL93, Siemens Analytical X-Ray Instru-
ments, Madison, WI, 1993.
Ar-H), 8.91, 8.96 (1H, 2 × s, CH᎐N), 9.18 (1H, m, Ar-H); δ (75
᎐
C
MHz, CDCl3) 14.41, 14.62, 23.69, 24.48, 32.51, 34.02, 47.16,
47.66, 60.84, 61.10, 61.30, 104.55, 124.75, 124.86, 136.87,
138.31, 144.68, 144.75, 150.33, 153.87, 154.18, 160.98.
(S)-3-(2Ј-Methyl-1Ј-N-benzyloxycarbonylaminopropyl)-
pyrido[2,3-b]pyrazine, 6q. Oxidation of (N-Cbz--valyl)-
diazomethane 2q (0.15 g, 0.54 mmol) in acetone (10 ml) with
DMD (12 ml, 0.07 M, 1.5 eq.) according to the general pro-
cedure and subsequent condensation with 2,3-diaminopyridine
(59 mg, 0.54 mmol) in EtOH (15 ml) yielded the crude product
as a pale brown oil which was purified by flash chromatography
Paper a907948c
J. Chem. Soc., Perkin Trans. 1, 2000, 381–389
389