Application of carbenoid N-H insertion in the synthesis of the tricyclic 1,4-dihydropyrazines

Article abstract of DOI:10.1016/j.tetlet.2006.06.053

The N-H insertion of the substituted anilines with 2-diazo-1,3-cyclohexanedione or 2-diazo-1,3-cyclopentanedione and subsequent cyclization enabled an efficient synthesis of a novel series of tricyclic 1,4-dihydropyrazines.

Full text of DOI:10.1016/j.tetlet.2006.06.053

Tetrahedron Letters 47 (2006) 5953–5955
Application of carbenoid N–H insertion in the synthesis
of the tricyclic 1,4-dihydropyrazines
Xuqing Zhang* and Zhihua Sui
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LLC, 665 Stockton Drive, Exton, PA 19341, USA
Received 28 March 2006; revised 2 June 2006; accepted 8 June 2006
Available online 30 June 2006
Abstract—The N–H insertion of the substituted anilines with 2-diazo-1,3-cyclohexanedione or 2-diazo-1,3-cyclopentanedione and
subsequent cyclization enabled an efficient synthesis of a novel series of tricyclic 1,4-dihydropyrazines.
Ó 2006 Elsevier Ltd. All rights reserved.
In the course of our medicinal chemistry effort on
KATP channel openers (KCOs), we were interested in
developing analogues to mimic ZD-0947 and ABT-
598 structures—two leading KCOs with dihydopyridine
scaffold under development by AstraZeneca and Ab-
bott Laboratory (Fig. 1).1 We envisaged that displace-
ment of dihydropyridine with dihydropyrazine core
would lead to a novel series of KCOs without the
chiral center in ZD-0947 or ABT-598 structure. There
is not much precedence on using dihydropyrazine as a
surrogate of dihydropyridine in the study of biologically
active compounds, probably due to the difficulty in effi-
cient preparation of dihydropyrazine skeleton.2 While
some 1,4-dihydropyrazines are known in the literature,3
to the best of our knowledge, the tricyclic dihydropyr-
azine scaffold (I) has not been disclosed. A search of
the literatures for possible synthetic methods to 1,4-
dihydropyrazine structures resulted in very few returns.
One procedure drew our attention by utilization of a
double carbenoid N–H insertion reaction between 2-di-
azo acetoacetate and anilines. This procedure was found
to be very practical for the preparation of 2,6-disubsti-
tuted 1,4-dihydropyrazine system. Therefore, we applied
this methodology by using either 2-diazo-1,3-cyclohex-
anedione or 2-diazo-1,3-cyclopentanedione (1) as the
diazo sources for the synthesis of structures I. Herein,
we report our preliminary study on the preparation of
tricyclic 1,4-dihydropyrazines as KCOs.
Comparing with 2-diazo acetoacetate, 2-diazo-1,
3-cyclohexanedione, and 2-diazo-1,3-cyclopentanedione
(1) are much more reactive carbenoids that side-reactions
between them and the solvents are unavoidable.4 Formal
insertion of 1 into a C-halogen or C–H bond was a major
drawback to compete with the desired N–H insertion in
many cases. Usually this reaction was conducted in neat
condition, with one of the substrates in excess acting as
solvent.5 However, the utility of substrate as a solvent
for the type of N–H insertion is not general due to the
limitation on melting point, reaction temperature, and
chemical stability of the substrate. To focus on obtaining
the target tricyclic 1,4-dihydropyrazines, we chose benz-
ene as the reaction solvent in our studies.
F
NC
O
Br
R
O
O
S
O
O
O
N
We first evaluated the carbenoid N–H reaction between
2-diazo-1,3-cyclohexanedione and 3-cyano-aniline cata-
lyzed by rhodium acetate dimer (Scheme 1 and entries
1 and 2 in Table 1).6 Generally the reaction afforded
the mono-insertion adduct 4a and the bis-insertion
adduct 5a through the rhodium species 2, along with
some minor side-products generated from aromatic
C–H insertion between two substrates. The possible
side-product from the reaction of benzene (solvent) with
N
H
CF3
n
N
H
N
H
n
I
ZD-0947
ABT-598
Figure 1.
*
Corresponding author. Tel.: +1 610 458 4137; fax: +1 610 458
8249; e-mail: xzhang5@prdus.jnj.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.053

5954
X. Zhang, Z. Sui / Tetrahedron Letters 47 (2006) 5953–5955
improved, with less than 5% of 4a isolated. We realized
X
O
O
that this procedure should generate synthetic utility for
practical preparation of the target structure I via the
key intermediate 5. Analogous synthesis on various
anilines 3 with either 2-diazo-1,3-cyclohexanedione or
2-diazo-1,3-cyclopentanedione (1) afforded the desired
bis-insertion adducts 5b–5e in acceptable yields, along
with a small amount of mono-insertion adducts 4b–4e
as side products. It was interesting that mono-insertion
adducts 4 were isolated as only or major products when
benzamides or sulfonamides were applied as substrates
for N–H insertion, as shown in entries 7–10. Adjustment
of the ratio of two substrates did not drive the reaction
to the bis-insertion pathway (entry 7). This result indi-
cated that the reactivity of the N–H bond greatly affect
the reaction outcome. In the cases of benzamides or
sulfonamides, the N–H bond is not as reactive as that
of primary anilines. Thus, the sequential N–H insertion
cascade stopped at the mono-insertion stage to afford
mainly 4 as products. The attempted Rh-catalyzed
N–H insertion of 2-diazo-1,3-cyclohexanedione and
4-chlorobenzylamine (entry 11) failed to give either
mono-insertion adduct 4 or bis-insertion adduct 5. It is
not surprising for this result since benzylamine is highly
reactive toward carbonyl group in substrate 1.
R
H2N
Rh2(OAc)4
N2
O
RhLm
O
3
n
n
1
2
R
O
R
X
O
X
O
N
NH
+
n
n
OH
n
OH OH
4
5
Scheme 1.
Table 1. N–H insertion of 3 with 1a
Entry
n
X
R
1:3b 4c Yield (%) 5 Yield (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
1
2
2
2
2
2
nsd
ns
ns
ns
ns
ns
3-CN
3-CN
3-I
1:1
2:1
2:1
4a (32)
4a (5)
4b (5)
5a (35)
5a (55)
5b (51)
5c (62)
5d (48)
5e (45)
5f (5)
nde
3.4-Di-F 2:1
3-Br–4-F 2:1
4c (11)
4d (12)
4e (15)
4f (41)
4f (55)
4h (52)
4i (45)
3-CN
2:1
2:1
1:1
1:1
1:1
1:1
C(O) 4-Cl
C(O) 4-Cl
C(O) 4-OMe
The bis-insertion adducts 5 were then treated with
ammonium acetate in t-BuOH at 70 °C for 4–10 h to give
the corresponding 6 in reasonable yields (Scheme 2).
Conversion of 6 to the final tricyclic dihydropyrazines
7 was accomplished by treatment with NaNH2 in reflux-
ing THF for 6–8 h. Interestingly, direct reaction of 6 with
NaNH2 did not result in the cyclized adducts 7.7
9
10
11
nd
5g (8)
—
SO2
4-Me
f
CH2 4-Cl
—
a Reaction temperature: 50–70 °C; reaction time: 0.5–4 h; catalysis
load: ꢀ0.5 mmol %.
b Ratio of reactants 1 and 3.
c Isolated yields.
In summary, the carbenoid N–H insertion of anilines 3
with corresponding diazo species 1, followed by intra-
molecular cyclization, provided an efficient route to a
novel series of tricyclic dihydropyrazines. The biological
activities will be reported elsewhere.
d ns = no substitution.
e nd = not detected.
f — = no desired product.
species 2 was not detected, presumably due to the high
reactivity of the primary aniline 3. The ratio of two
substrates (1 vs. 3) utilized significantly dictated the
outcome of products 4a and 5a. It was found to be
infeasible for obtaining 4a as a single product after effort
on optimization with the ratio of 1 and 3, catalyst load-
ing, temperature and time. However, when applying 2:1
ratio of 2-diazo-1,3-cyclohexanedione and the aniline,
the yield of the bis-insertion adduct 5a was greatly
References and notes
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O
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NaNH2
N
N
N
t
THF
n
n
n
n
n
N
H
n
OH OH
NH2 OH
45-70%
7a, R = 3-CN, n = 2
7b, R = 3-I, n = 2
7c, R = 3,4-di-F, n = 2
7d, R = 3-Br-4-F, n = 2
7e, R = 3-CN, n = 1
5a, R = 3-CN, n = 2
5b, R = 3-I, n = 2
5c, R = 3,4-di-F, n = 2
5d, R = 3-Br-4-F, n = 2
5e, R = 3-CN, n = 1
6a-6e
Scheme 2.

X. Zhang, Z. Sui / Tetrahedron Letters 47 (2006) 5953–5955
5955
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6. Typical procedure of N–H insertion reaction, synthesis
of 4a and 5a: 2-Diazo-cyclohexane-1,3-dione (470 mg,
3.40 mmol), 3-cyano-aniline (200 mg, 1.70 mmol) and rho-
dium acetate dimer (5 mg, 0.011 mmol) in benzene (4 mL)
were heated at 70 °C for 2 h. The solid was filtered off and
the filtrate was concentrated to give a yellow oil, which was
purified by silica gel column chromatography to afford 4a
1
(19 mg, 5%) and 5a (316 mg, 55%) as white solids. 4a: H
NMR (300 MHz, CDCl3) d 8.95 (s, 1H), 8.02 (s, 1H), 7.68
(d, J = 6.5 Hz, 1H), 7.41 (m, 2H), 3.17 (t, J = 8.0 Hz, 1H),
2.45 (m, 3H), 2.15 (m, 1H), 1.90 (m, 1H). CIMS, m/z (%):
229 ([M+1]+, 100). Compound 5a: 1H NMR (300 MHz,
CDCl3) d 12.8 (br s, 2H), 7.25 (d, J = 7.5 Hz, 1H), 7.05 (d,
J = 7.5 Hz, 1H), 6.76 (m, 2H), 2.75 (m, 4H), 2.55 (m, 4H),
2.11 (m, 4H). CIMS, m/z (%): 339 ([M+1]+, 100). Anal.
calcd for C19H18N2O4: C, 67.44; H, 5.36; N, 8.28. Found:
C, 67.35; H, 5.30; N, 8.42.
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J = 8.5 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.75 (d,
J = 7.0 Hz, 1H), 6.70 (s, 1H), 2.62 (m, 4H), 2.48 (m, 4H),
2.01 (m, 4 H). CIMS, m/z (%): 320 ([M+1+], 100). Anal.
calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found:
C, 71.48; H, 5.42; N, 13.25.
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