Dihydropyridazine derivatives with cyclopenta-, benzo-, furo-, thiopyrano-and pyrido-annulation

Article abstract of DOI:10.1002/ejoc.201201158

Regioisomeric [c]annulated pyridazines were prepared from arylhydrazines and carbocyclic or heterocyclic β-oxo esters with an α-phenacetyl moiety. With AcOH/EtOH, the hydrazones were preferentially formed at the endocyclic ketone, which are further cycliz

Full text of DOI:10.1002/ejoc.201201158

FULL PAPER
DOI: 10.1002/ejoc.201201158
Dihydropyridazine Derivatives with Cyclopenta-, Benzo-, Furo-, Thiopyrano-
and Pyrido-Annulation
Miriam Penning[a] and Jens Christoffers*[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Ketones / Hydrazones / Amines
Regioisomeric [c]annulated pyridazines were prepared from
arylhydrazines and carbocyclic or heterocyclic β-oxo esters
led hydrazones at the exocyclic benzoyl group, which re-
acted further to give 1,4-dihydro-4aH-pyridazines. In this in-
with an α-phenacetyl moiety. With AcOH/EtOH, the hydraz- vestigation, examples of the rare or unknown heterocyclic
ones were preferentially formed at the endocyclic ketone,
which are further cyclized with trifluoroacetic acid (TFA)/
CH2Cl2 to give 2,4a-dihydropyridazines. Use of TFA/CH2Cl2
systems furo[3,4-c]-, thiopyrano[4,3-c]- and pyrido[4,3-c]pyr-
idazine were prepared.
aliphatic partially saturated pyridazines have been rarely re-
ported in the literature,[8] despite their simple retrosynthetic
breakdown into hydrazines and 1,4-dicarbonyl compounds.
Moreover, the aromatic or partially-hydrogenated pyrid-
azine moiety could be regarded of a privileged structural
motif in medicinal chemistry.[9] Therefore we would like to
report the scope and limitations, as well as the envisioned
regiochemistry problems, of dihydropyridazine formation
from various 1,4-diketones of general formula 1 and a
number of different hydrazines 5.
Introduction
Following on from our discovery that 1,4-dicarbonyl
compounds 1 (X = CH2) react in a bismuth-catalyzed ring
expansion reaction with primary amines to furnish eight-
membered ring lactams 2 (Scheme 1),[1] we have used this
reaction for the preparation of a model library of hexahy-
droazocinones 4 (X = CH2). The interconversion of the
five-membered ring in starting materials 1 to an eight-mem-
bered ring in products 2 is assumed to proceed through in-
termediate 3 with a bicyclo[3.3.0] skeleton. Apart from RA
originating from the amine RA-NH2 and RB introduced by
1,4-diketone 1, a third point of diversity RC was installed by
saponification and amidation of the carboxylate function
(Scheme 1).[2] Furthermore, we have been able to convert
tetrahydrothiophenes 1 (X = S) and pyrrolidines (X = N-
PG) to respective thiazocinones 4 (X = S)[3] and diazoci-
nones (X = N-RD),[4] the latter having a fourth point of
diversity RD, which was introduced after deprotection of
secondary amine N-PG. Attempts for the preparation of
benzoannulated congeners were however of limited suc-
cess.[5] In the course of our ongoing search for heterocyclic
scaffolds suitable for the development of combinatorial li-
braries,[6] we envisioned cyclic 1,4-diketones 1 could also be
converted with hydrazines 5 to give annulated dihydropyrid-
azines. Because hydrazines as unsymmetrical 1,2-dinucleo-
philes could preferentially attack one of the two carbonyl
groups of 1,4-dielectrophiles 1, we were expecting to face a Scheme 1. Synthesis of eight-membered-ring lactam libraries 4
from 1,4-diketones 1 and amines.
regioselectivity problem during this transformation. In con-
trast to fully-unsaturated aromatic cogeners,[7] annulated
[a] Institut für Chemie, Carl von Ossietzky-Universität Oldenburg,
26111 Oldenburg, Germany
Results and Discussion
Fax: +49-441-798-3873
E-mail: jens.christoffers@uni-oldenburg.de
In preliminary studies we had prepared cyclopenta-annu-
lated 2,5-dihydropyridazine 8a in two steps from oxo ester
1a, which was first converted under acidic conditions in po-
Homepage: www.christoffers.chemie.uni-oldenburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201158.
Eur. J. Org. Chem. 2013, 389–400
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389

M. Penning, J. Christoffers
FULL PAPER
lar protic solvent to give hydrazone 6a in 94% yield after replaced by an imine resonance at δ = 143 ppm (NMR spec-
crystallization (Scheme 2).[1] In contrast to our proposed troscopic data of 1a, 6a and 8a are known but are listed in
mechanism of azocanone formation through intermediate 3 the experimental section for reference). This actually proved
(see Scheme 1), hydrazine 5a preferentially reacted with the the regiochemistry of hydrazone formation at the alicyclic
1
endocyclic carbonyl group of compound 1a. Subsequent ketone. Furthermore, H NMR spectra of compounds 1a
treatment of hydrazone 6a in strongly-acidic polar aprotic and 6a showed an AX-system for the diastereotopic methyl-
medium gave annulation product 8a in 54% yield.[1] Our ene protons next to the benzoyl moiety (δA = 3.5, 3.2 ppm,
attempts to transfer that earlier result to hydrazone 6b, δX = 3.8, 4.1 ppm, JAX = 18.5, 18.1 Hz for 1a and 6a,
which was obtained from cyclohexanone derivative 1b in respectively). Compound 7a showed the same signals
74% yield, led to indole annulation product 9b instead of a shifted to higher field: δA = 2.5 ppm, δX = 3.8 ppm, JAX
=
pyridazine. This was not surprising, because the reaction 16.8 Hz. An additional sp2-CH resonance was detected in
conditions were typical for a Fischer indolization.[10] Be- the 1H NMR spectrum of compound 7a (δ = 2.5 ppm) with
cause we were aiming to avoid the latter process, we started coupling (t, 2.5 Hz) to the adjacent CH2 group, as estab-
to look for alternative conditions. Finally, the conversion of lished by a 1H,1H-COSY experiment. In contrast, com-
oxo ester 1b with hydrazine 5a under acidic conditions in pound 8a had a CH2–CH2–CH2 unit (established by
polar aprotic solvent and without isolation of any hydraz- HMBC, HMQC and 1H,1H-COSY) with complex J(1H,1H)
one gave 1,4-dihydro-5H-pyridazine derivative 7b in excel- coupling patterns and an olefinic singlet at δ = 4.8 ppm with
2
lent yield. The formation of compound 7b was the result of a J(1H,13C)-correlation (by HMBC) to the quaternary ali-
a first attack of hydrazine 5a to the benzoyl group of com- phatic signal indicating the depicted constitution. The diag-
pound 1b. Because the reaction time was prolonged relative nostic spectroscopic features of compounds 7a and 8a ap-
to the preparation of hydrazone 6b, which crystallized from peared in all compounds 7 (a characteristic AX-system with
the reaction mixture, we assumed several equilibrating spe- JAX = 17 Hz at δA = 2.4–2.8 and δX = 3.4–3.8 ppm) as well
cies within the reaction mixture and formation of com- as compounds 8 (singlet at 4.4–4.7 ppm) confirming the as-
pound 7b as the thermodynamic product. Conversion of signment of the respective regioisomers.
cyclopentanone derivative 1a under similar reaction condi-
We aimed to transfer the formation of dihydropyrid-
tions led to the formation of regioisomer 7a, the isolated azines 7 with PhNHNH2 (5a) to other 1,4-diketones 1
yield of this compound was however rather low and could (Scheme 3, Table 1). Starting with variations of the ring size
not be increased by varying the reaction conditions.
and introduction of heteroatoms, two out of several investi-
gated reaction conditions turned out to be privileged, be-
cause most of the optimal results were obtained with them
[(a) and (b) as specified in Table 1]. Results with starting
materials 1a and 1b are given in Table 1, Entries 1 and 2.
With seven-membered ring congener 1c, no unique product
was isolated (Table 1, Entry 3). Introduction of heteroatoms
in the five-membered ring gave only for tetrahydrofuran de-
rivative 1d a respective product 7d in poor yield (15%) and
containing small amounts of regioisomer 8d (2%; Table 1,
Entry 4). Furo[3,4-c]pyridazine derivatives, like compound
7d, are rarely reported in the literature.[12] Starting with
tetrahydrothiophene 1e and pyrrolidines 1f and 1g, no
unique products were isolated (Table 1, Entries 5–7). We
then investigated oxa-, thia-, and azacyclohexanone deriva-
tives 1h–1k. For tetrahydropyran 1h, no unique product was
isolated (Table 1, Entry 8). Tetrahydrothiopyran 1i gave
product 7i together with its regioisomer 8i, both in moder-
ate yields (35% and 20%, respectively; Table 1, Entry 9).
Compounds 7i and 8i were not separable by column
chromatography. The thiopyrano[4,3-c]pyridazine ring sys-
tem, as in compounds 7i and 8i, was not reported in the
Scheme 2. Preliminary studies towards dihydropyridazine forma-
tion. Conditions for 7a: (a) 1.5 equiv. 5a, 0.5 equiv. AcOH, CH2Cl2,
23 °C, 3 h; then + 0.5 equiv. TFA, 23 °C, 2.5 h. For 7b:
(b) 1.1 equiv. 5a, 0.6 equiv. TFA, CH2Cl2, 23 °C, 3 h.
Regioisomers 7 and 8 could be clearly distinguished by literature before, but with another pyrido[3Ј,2Ј:5,6]-annu-
1H NMR spectroscopy. Elucidation of their constitution lation.[13] Piperidine derivatives with either a Boc or Cbz-
was also accomplished by NMR spectroscopy, as outlined protective group at nitrogen gave both pyridopyridazines 7j
for compounds 6a, 7a, and 8a. For compound 1a, the 13C- and 7k (Table 1, Entries 10 and 11). As expected, the yield
NMR signals of both ketones could be assigned by com- for Cbz-protected compound 7k was higher (43%) than for
parison to literature values:[11] 197 ppm for the benzoyl Boc-protected product 7j (15%), because the latter protect-
group and 215 ppm for the alicyclic C=O. Upon formation ing group was expected to be labile under the reaction con-
of hydrazone 6a, the arylketone moiety was retained (δ = ditions. Pyrido[4,3-c]pyridazine derivatives, like compounds
198 ppm), whereas the signal previously at δ = 215 ppm was 7j and 7k, are rarely reported in the literature.[14]
390
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Dihydropyridazine Derivatives and Annulation
Table 1. Formation of regioisomeric annulated 1,4-dihydropyridazines 7 and 8. Residues X, R and Ar, conditions and yields.
Entry Starting material
X
R
Ar
Conditions[a]
Products (yield)[b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
CH2
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(a)
(b)
7a (40%)
7b (96%)
CH2CH2
CH2CH2CH2
O
[c]
Me
Me
Me
Me
Me
Et
Me
Me
Me
Et
(a) or (b)
(a)
(a) or (b)
(a) or (b)
(a) or (b)
(a) or (b)
(b)
(b)
(b)
(b)
(b)
–
7d (15%), 8d (2%)[d]
[c]
S
–
–
–
–
[c]
N(Boc)
N(Cbz)
CH2O
[c]
[c]
9
CH2S
Ph
Ph
Ph
7i (35%), 8i (20%)[d]
7j (15%)
10
11
12
13
14
15
CH2N(Boc)
CH2N(Cbz)
CH2CH2
CH2CH2
CH2CH2
CH2CH2
7k (43%)
7l (78%)
4-MeOC6H4
4-BrC6H4
4-NO2C6H4
2,4-(MeO)2C6H3
Et
Et
Et
7m (48%), 8m (15%)[d]
7n (46%), 8n (10%)[d]
8o (45%)
(b)
(b)
[a] Conditions: (a) 1.5 equiv. 5a, 0.5 equiv. AcOH, CH2Cl2, 23 °C, 3 h; then + 0.5 equiv. TFA, 23 °C, 2.5 h; (b) 1.1 equiv. 5a, 0.6 equiv.
TFA, CH2Cl2, 23 °C, 3 h. [b] Yields of isolated products. [c] No unique product isolated. [d] Regioisomers 7 and 8 were not separated.
significant negative influence on the yield (Table 2, En-
tries 2–4), an ortho-methyl group gave a low yield of prod-
uct 7t (18%; Table 2, Entry 6). This effect was not clearly
understood, because para-methoxy and -methyl groups
(Table 2, Entries 5 and 7) had opposite effects. para-Iodo-
phenyl derivative 7v (77% yield; Table 2, Entry 8) was ready
for further diversifying transformations through cross-cou-
Scheme 3. Conversion of 1,4-diketones 1a–1o with phenylhydrazine
pling reactions. In contrast to hydrazines 5a–5h, 2,3-dinitro
congener 5i led to no isolable materials under standard con-
ditions (a), but after heating in THF as solvent, hydrazone
6w was obtained from the reaction mixture (72%; Table 2,
Entry 9).
(5a).
We then continued by varying the aromatic residue Ar of
the 1,4-diketone motif by introducing electron accepting
and donating substituents (for the synthesis of starting ma-
terials 1 vide infra). For this purpose we chose X =
CH2CH2, because cyclohexanone derivative 1b was the
compound with be best result so far (96% yield of pyrid-
azine 7b; Table 1, Entry 2). A para-methoxy substituent in
starting material 1l did not significantly influence the out-
come of the reaction (78% yield of product 7l; Table 1, En-
try 12). In contrast, para-bromo and -nitro groups (starting
materials 1m and 1n) shifted the regioselectivity slightly
towards formation of byproducts 8m (15%) and 8n (10%;
Table 1, Entries 13 and 14), which was actually hardly
understood from an electronic point of view, because pref-
erential initial attack of hydrazine 5a at the benzoyl moiety
would be assumed with an electron withdrawing aromatic
system Ar. With two donor substituents (starting material
1o; Table 1, Entry 15), one of them even sterically congest-
ing, attack of hydrazine 5a at the benzoyl group seems to
be completely blocked, thus, no regioisomer 7o was ob-
served, only product 8o was isolated.
Scheme 4. Conversion of 1,4-diketone 1b with various arylhydraz-
ines 5a–5i.
Table 2. Formation of annulated 1,4-dihydropyridazines 7 from 1,4-
diketone 1b. Residues Ar, conditions and yields.
Entry Hydrazine Ar
Conditions[a] Products (yield)[b]
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
2-ClC6H4
(a)
(a)
(a)
(a)
(a)
(a)
(a)
(a)
(b)
7b (96%)
7p (75%)
3,4-Cl2C6H3
2-MeOC6H4
4-MeOC6H4
2-MeC6H4
4-MeC6H4
4-IC6H4
7q (78%), 8q (3%)[c]
7r (53%)
7s (35%)
7t (18%)
7u (66%)
7v (77%), 8v (4%)[c]
6w (72%)
In addition, conversion of cyclohexanone derivative 1b
with several phenylhydrazine derivatives 5b–5i was investi-
gated (Scheme 4, Table 2; for the synthesis of starting mate-
rials 5 vide infra). For comparison, formation of product
7b is listed as Table 2, Entry 1. In all cases (except Table 2,
Entry 9) only the formation of regioisomer 7 was observed,
2,4-(NO2)2C6H3
[a] Conditions: (a) 1.1 equiv. 5, 0.6 equiv. TFA, CH2Cl2, 23 °C, 3 h;
(b) 1.0 equiv. 5, 0.6 equiv. TFA, THF, 67 °C, 3 h. [b] Yields of iso-
lated products. [c] Regioisomers 7 and 8 were not separated.
The synthesis of starting materials 1 was achieved by alk-
although products 7q and 7v contained small amounts of ylation of respective β-oxo esters 10 with α-bromoaceto-
regioisomers 8q and 8v (3% and 4%, respectively). Whereas phenones 11 as shown in Scheme 5. Compounds 1a–1c,[15]
ortho-chloro and -methoxy substituents seemed to have no 1d, 1e,[3] and 1f[4] were known from the literature and pre-
Eur. J. Org. Chem. 2013, 389–400
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391

M. Penning, J. Christoffers
FULL PAPER
Table 3. Conditions and yields for the α-alkylation of β-oxo esters 10 with α-bromo ketones 11.
Entry
Oxo ester[a]
X
R
Bromo ketone [equiv.] Ar
Conditions[b]
Product [yield]
1
2
3
4
5
6
7
8
9
10g
10h
10i
N(Cbz)
CH2O
CH2S
CH2N(Boc)
CH2N(Cbz)
CH2CH2
CH2CH2
CH2CH2
CH2CH2
Me
Et
Me
Me
Me
Et
Et
Et
Et
11a (1.1)
11a (1.1)
11a (1.1)
11a (1.1)
11a (1.1)
11l (2.0)
11m (1.2)
11n (1.2)
11o (1.1)
Ph
Ph
Ph
Ph
(a)
(a)
(a)
(a)
(a)
(a)
(b)
(a)
(a)
1g (44%)
1h (72%)
1i (49%)
1j (74%)
1k (70%)
1l (54%)
1m (44%)
1n (13%)
1o (47%)
10j
10k
10b
10b
10b
10b
Ph
4-MeOC6H4
4-BrC6H4
4-NO2C6H4
2,4-(MeO)2C6H3
[a] 1.0 equiv. was used. [b] Conditions: (a) K2CO3, acetone, 40 °C, 19 h; (b) NaH, THF, 60 °C, 17 h; K2CO3 or NaH were used in equi-
molar amounts relative to respective bromo ketone 11.
pared accordingly. Results and reaction conditions for
products 1g–1o are collected in Table 3. In general, K2CO3
in acetone was used, except for product 1m (Table 3, En-
try 7) were we used NaH in THF. Yields ranged from 45–
75%, except for para-nitro substituted product 1n, were it
was lower (13%; Table 3, Entry 8).
Scheme 7. Synthesis of tetrahydropyranonecarboxylate 10h from
diacid 13. Reagents, conditions and yields: (a) cat. H2SO4, EtOH,
CHCl3, Dean–Stark trap, 95 °C, 20 h, 50 %; (b) 2.2 equiv. LDA,
THF, –78 °C, 15 min, 18%.
α-Bromo ketones 11l,[23] 11m[24] and 11n[25] were known
Scheme 5. Synthesis of 1,4-diketones 1 by α-alkylation of β-oxo
from the literature and are commercially available. During
esters 10 with α-bromoacetophenones 11. For conditions and yields
the bromination of 2,4-dimethoxyacetophenone, bromina-
see Table 3.
tion of the aromatic ring cannot be avoided,[26] thus, bromo
ketone 11o was prepared by Friedel–Crafts acylation of 1,3-
Oxo esters 10i,[16] 10j,[17] and 10k[18] were literature
known and were prepared accordingly. Compound 10g had
not been reported before, thus, we prepared it by conjugate
dimethoxybenzene with bromoacetyl bromide.[27]
Hydrazines 5a and 5i were commercially available. Hy-
drazines 5b,[28] 5c,[29] 5d,[30] 5e,[31] 5f,[32] 5g[33] and 5h[34] were
addition of N-Cbz methyl gycinate (12)[19] to methyl acry-
reported in the literature. We prepared compounds 5b, 5d,
late followed by Dieckmann condensation as reported for
5e, 5f and 5g according to a reported procedure[35] and
the N-Boc-protected congener.[4] The conversion was per-
compounds 5c and 5h following a slightly different pro-
formed as a two-step-, one-flask-protocol and product 10g
was isolated in 68% yield after chromatographic purifica-
tion (Scheme 6).
cedure.[36]
Conclusions
The reaction of cyclic β-oxo esters 1 bearing an α-phena-
cetyl moiety with arylhydrazines 5 could lead to two re-
gioisomeric hydrazones. With AcOH in EtOH, hydrazone
formation at the endocyclic carbonyl group (products 6)
was observed. In two cases, hydrazones 6 could be further
transformed with TFA/CH2Cl2 to a [c]annulated 2,4a-dihy-
dropyridazine 8a or an indole derivative 9b. With TFA/
CH2Cl2 or AcOH/CH2Cl2, hydrazones at the exocyclic ben-
zoyl group were formed as intermediate products, which
Scheme 6. Synthesis of oxo ester 10g by conjugate addition of N-
Cbz-GlyOMe (12) to methyl acrylate followed by Dieckmann con-
densation.
Compound 10h was known in the literature,[20] reported cannot be isolated, but further cyclize under reaction condi-
protocols for acylation of tetrahydropyranone were how- tions to furnish [c]annulated 1,4-dihydro-4aH-pyridazines
ever not reproducible. We therefore prepared oxo ester 10h 7. We have investigated conversion of 15 different carbocy-
by Dieckmann condensation of diethyl ester 14 in analogy clic and heterocyclic 1,4-diketones 1 with nine different ar-
to
(Scheme 7).[21] Diethyl ester 14 was obtained by esterifica- isolated in 16 cases. Among them were rare furo[3,4-c]- (7d)
tion from diacid 13.[22]
and pyrido[4,3-c]pyridazines (7j and 7k) or even unknown
a
procedure reported for the dipropyl ester ylhydrazines 5. New 1,4-dihydro-4aH-pyridazines 7 were
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Dihydropyridazine Derivatives and Annulation
132.76 (CH), 137.39 (C), 145.23 (C), 146.61 (C), 174.75 (C), 197.30
ring systems like thiopyrano[4,3-c]pyridazine 7i. The yields
ranged between 15 and 96%, with the majority between 40
and 80%. In four cases regioisomeric 2,4a-dihydropyrid-
azines 8 were obtained as byproducts (10–20%) or even the
only product (8o, 45%). Five of starting materials 1 gave
no useful results.
(C) ppm. IR (ATR): ν = 3339 (m), 3063 (w), 2974 (w), 2955 (w),
˜
2933 (w), 1715 (s), 1687 (m), 1600 (m), 1446 (m), 1236 (m), 1219
(m), 1195 (m), 1141 (m), 1124 (m), 1034 (m), 744 (vs), 689
(vs) cm–1. HRMS (ESI): calcd. for C23H26N2NaO3 [M + Na+]
401.1841; found 401.1848.
Ethyl
2,3-Diphenyl-2,5,6,7-tetrahydrocyclopenta[c]pyridazine-4a-
carboxylate (8a): 1H NMR (CDCl3, 500 MHz): δ = 1.14 (t, J =
7.1 Hz, 3 H), 1.78–1.86 (m, 1 H), 1.93–2.06 (m, 2 H), 2.64–2.71 (m,
2 H), 2.89 (ddd, J = 6.5, J = 9.0, J = 16.8 Hz, 1 H), 4.05–4.12 (m,
2 H), 4.79 (s, 1 H), 6.85–6.89 (m, 1 H), 7.03–7.05 (m, 2 H), 7.07–
7.11 (m, 2 H), 7.18–7.23 (m, 5 H) ppm. 13C{1H} NMR (CDCl3,
125 MHz): δ = 14.05 (CH3), 22.50 (CH2), 30.17 (CH2), 37.06
(CH2), 51.05 (C), 61.17 (CH2), 101.22 (CH), 121.16 (2 CH), 122.55
(CH), 127.99 (3 CH), 128.20 (2 CH), 128.69 (2 CH), 135.51 (C),
140.38 (C), 143.52 (C), 153.38 (C), 172.89 (C) ppm.
Experimental Section
General: Preparative column chromatography was carried out with
Merck SiO2 (0.035–0.070 mm, type 60 A) with hexane, toluene and
tert-butyl methyl ether (MTBE) as eluents. TLC was performed
with Merck SiO2 F254 plates on aluminum sheets. 1H- and 13C-
NMR spectra were recorded with a Bruker Avance DRX 500. Mul-
tiplicities of carbon signals were determined with DEPT experi-
ments. MS and HRMS spectra were obtained with a Finnigan
MAT 95 (CI) and a Waters Q-TOF Premier (ESI) spectrometer. IR
spectra were recorded with a Bruker Tensor 27 spectrometer
equipped with a “GoldenGate” diamond ATR unit. Elemental
analyses were measured with a Euro EA-CHNS from HEKAtech.
Preparation and spectroscopic data of compounds 1a,[37] 6a[1] and
8a[1] were reported by us earlier. NMR spectroscopic data for these
three compounds are however listed below for comparison.
Ethyl 1-(2-Oxo-2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-
carboxylate (9b): TFA (47 mg, 0.40 mmol) was added to a solution
of hydrazone 6b (98 mg, 0.26 mmol) in CH2Cl2 (5 mL) and the
solution was stirred for 4 h at 23 °C. After removal of all volatile
materials in vacuo, the residue was purified by using chromatog-
raphy (SiO2, hexane/MTBE = 2:1, Rf = 0.37), to yield indole 9b
(65 mg, 0.18 mmol, 69%) as a colorless solid. M.p. 125 °C. 1H
NMR (500 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 3 H), 1.89–1.94
(m, 1 H), 1.98–2.07 (m, 2 H), 2.35–2.39 (m, 1 H), 2.71–2.82 (m, 2
H), 3.59 (d, J = 18.2 Hz, 1 H), 3.89 (d, J = 18.2 Hz, 1 H), 4.14–
4.24 (m, 2 H), 7.05 (t, J = 7.4 Hz, 1 H), 7.13 (t, J = 7.6 Hz, 1 H),
7.30 (d, J = 8.1 Hz, 1 H), 7.40–7.50 (m, 3 H), 7.56 (t, J = 7.4 Hz,
1 H), 7.95 (d, J = 7.6 Hz, 2 H), 8.76 (s, 1 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 14.36 (CH3), 20.58 (CH2), 21.26 (CH2),
35.42 (CH2), 44.90 (C), 49.43 (CH2), 61.53 (CH2), 111.24 (CH),
111.77 (C), 118.53 (CH), 119.16 (CH), 122.09 (CH), 127.03 (C),
128.33 (2 CH), 128.89 (2 CH), 133.47 (C), 133.83 (CH), 135.94
Ethyl 1-(Benzoylmethyl)cyclopentane-1-carboxylate (1a): 1H NMR
(CDCl3, 500 MHz): δ = 1.24 (t, J = 7.1 Hz, 3 H), 2.03–2.17 (m, 3
H), 2.53–2.69 (m, 3 H), 3.48 (d, J = 18.6 Hz, 1 H), 3.86 (d, J =
18.6 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 7.43–7.49 (m, 2 H), 7.55–
7.60 (m, 1 H), 7.93–7.97 (m, 2 H) ppm. 13C{1H} NMR (CDCl3,
125 MHz): δ = 14.00 (CH3), 19.86 (CH2), 33.40 (CH2), 37.76
(CH2), 43.48 (CH2), 57.47 (C), 61.66 (CH2), 128.11 (2 CH), 133.47
(2 CH), 136.31 (C), 170.71 (C), 196.74 (C), 215.11 (C) ppm.
Ethyl
1-(Benzoylmethyl)-2-phenylhydrazonocyclopentane-1-carb-
oxylate (6a): 1H NMR (CDCl3, 500 MHz): δ = 1.20 (t, J = 7.1 Hz,
3 H), 1.83 (ddd, J = 7.7, J = 9.8, J = 13.1 Hz, 1 H), 1.94–2.00 (m,
1 H), 2.16–2.25 (m, 1 H), 2.35–2.42 (m, 1 H), 2.48 (ddd, J = 3.9, J
= 9.4, J = 17.2 Hz, 1 H), 2.77 (ddd, J = 3.4, J = 7.3, J = 13.0 Hz,
1 H), 3.23 (d, J = 18.1 Hz, 1 H), 4.11 (d, J = 18.1 Hz, 1 H), 4.16
(q, J = 7.0 Hz, 2 H), 6.80–6.83 (m, 1 H), 6.98–7.01 (m, 2 H), 7.17–
7.21 (m, 2 H), 7.36 (s, 1 H), 7.44–7.48 (m, 2 H), 7.54–7.57 (m, 1
H), 7.98–8.00 (m, 2 H) ppm. 13C{1H} NMR (CDCl3, 125 MHz): δ
= 14.08 (CH3), 22.46 (CH2), 26.25 (CH2), 35.60 (CH2), 45.69
(CH2), 54.44 (C), 61.00 (CH2), 112.90 (2 CH), 119.92 (CH), 128.06
(2 CH), 128.54 (2 CH), 129.11 (2 CH), 133.03 (CH), 137.09 (C),
145.36 (C), 153.46 (C), 173.27 (C), 197.97 (C) ppm.
(CH), 136.68 (CH), 175.28 (C), 199.80 (C) ppm. IR (ATR): ν =
˜
3066 (w), 1661 (s), 1596 (m), 1578 (m), 1447 (m), 1329 (m), 1304
(m), 1218 (s), 1178 (m), 1065 (m), 1040 (s), 1015 (s), 799 (m), 714
(s), 689 (m), 644 (m) cm–1. HRMS (ESI): calcd. for C23H23NNaO3
[M + Na+] 384.1576; found 384.1583.
Ethyl 1,3-Diphenyl-4,4a,5,6-tetrahydro-1H-cyclopenta[c]pyridazine-
4a-carboxylate (7a): Phenylhydrazine (5a; 177 mg, 1.64 mmol) and
AcOH (33 mg, 0.55 mmol) were added to a solution of 1,4-diketone
1a (300 mg, 1.09 mmol) in CH2Cl2 (3.3 mL) and the reaction mix-
ture was stirred for 3 h at 23 °C. Then TFA (63 mg, 0.55 mmol)
was added and stirring was continued for 2.5 h. After removal of
all volatile materials in vacuo, the residue was purified by using
Ethyl 1-(2-Oxo-2-phenylethyl)-2-(2-phenylhydrazono)cyclohexane- chromatography (SiO2, hexane/MTBE = 20:1, Rf = 0.22) to yield
carboxylate (6b): Phenylhydrazine (5a; 111 mg, 1.03 mmol) and
AcOH (72 mg, 1.2 mmol) were added to a solution of 1,4-diketone
1b (298 mg, 1.03 mmol) in EtOH (2 mL) and the reaction mixture
was stirred for 90 min at 23 °C. The precipitated solid was filtered
off and dried to furnish hydrazone 6b (290 mg, 766 μmol, 74%) as
a colorless solid. M.p. 153 °C. 1H NMR (500 MHz, CDCl3): δ =
1.32 (t, J = 6.5 Hz, 3 H), 1.45–1.50 (m, 1 H), 1.64–1.69 (m, 1 H),
1.72–1.81 (m, 2 H), 1.96–1.98 (m, 1 H), 2.45 (d, J = 12.3 Hz, 1 H),
pyridazine 7a (150 mg, 430 μmol, 40%) as a yellowish oil. 1H NMR
(500 MHz, CDCl3): δ = 1.17 (t, J = 7.1 Hz, 3 H), 1.93 (td, J = 8.9,
J = 12.9 Hz, 1 H), 2.41 (ddd, J = 2.2, J = 8.9, J = 15.2 Hz, 1 H),
2.47 (d, J = 16.8 Hz, 1 H), 2.65 (dd, J = 8.3, J = 13.1 Hz, 1 H),
2.70–2.79 (m 1 H), 3.78 (d, J = 16.8 Hz, 1 H), 4.11 (q, J = 7.2 Hz,
2 H), 5.37 (t, J = 2.5 Hz, 1 H), 7.08 (t, J = 7.3 Hz, 1 H), 7.30 (t, J
= 7.3 Hz, 1 H), 7.33–7.39 (m, 4 H), 7.55–7.57 (m, 2 H), 7.78 (d, J
= 7.5 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 14.15
2.50–2.56 (m, 1 H), 2.78 (d, J = 14.6 Hz, 1 H), 3.33 (d, J = 16.6 Hz, (CH3), 28.26 (CH2), 35.42 (CH2), 36.95 (CH2), 50.62 (C), 61.23
1 H), 3.90 (d, J = 16.6 Hz, 1 H), 4.29–4.32 (m, 2 H), 6.58 (d, J = (CH2), 106.02 (CH), 120.66 (2 CH), 123.35 (CH), 125.27 (2 CH),
7.5 Hz, 2 H), 6.68 (t, J = 6.7 Hz, 1 H), 6.92 (t, J = 7.0 Hz, 2 H),
127.96 (CH), 128.26 (2 CH), 128.67 (2 CH), 136.82 (C), 137.92 (C),
7.20 (br. s, 1 H), 7.52 (t, J = 7.0 Hz, 2 H), 7.63 (t, J = 6.8 Hz, 1 141.32 (C), 145.59 (C), 174.02 (C) ppm. IR (ATR): ν = 2960 (w),
˜
H), 8.06 (d, J = 7.1 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz,
2929 (w), 2326 (w), 2194 (w), 1982 (w), 1761 (m), 1726 (s), 1687
CDCl3): δ = 14.15 (CH3), 22.16 (CH2), 23.44 (CH2), 25.60 (CH2), (m), 1595 (m), 1493 (s), 1446 (m), 1369 (m), 1300 (s), 1190 (s), 1095
37.81 (CH2), 45.41 (CH2), 53.31 (CH2), 60.98 (CH2), 112.73 (2 (s), 1015 (s), 913 (m), 756 (s), 691 (s) cm–1. HRMS (ESI): calcd. for
CH), 119.34 (CH), 128.23 (2 CH), 128.49 (2 CH), 128.70 (2 CH), C22H23N2O2 [M + H+] 347.1760; found 347.1750.
Eur. J. Org. Chem. 2013, 389–400
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
393

M. Penning, J. Christoffers
FULL PAPER
Ethyl
1,3-Diphenyl-1,4,4a,5,6,7-hexahydrobenzo[c]pyridazine-4a-
2 H), 7.07–7.10 (m, 2 H), 7.13–7.18 (m, 3 H), 7.26 (d, J = 7.1 Hz,
2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3), major regioisomer
7i: δ = 26.27 (CH2), 33.49 (CH2), 35.92 (CH2), 42.70 (C), 52.91
(CH3), 105.06 (CH), 122.90 (2 CH), 124.64 (2 CH), 127.90 (CH),
128.07 (CH), 128.24 (2 CH), 128.77 (2 CH), 137.22 (C), 137.54 (C),
138.09 (C), 146.13 (C), 173.18 (C) ppm; minor regioisomer 8i: δ =
28.94 (CH2), 34.46 (CH2), 37.67 (CH2), 48.79 (C), 52.73 (CH3),
101.35 (CH), 123.25 (2 CH), 123.83 (CH), 123.89 (CH), 127.95 (2
carboxylate (7b): Phenylhydrazine (5a; 121 mg, 1.14 mmol) and
TFA (74 mg, 0.62 mmol) were added to a solution of 1,4-diketone
1b (300 mg, 1.04 mmol) in CH2Cl2 (3.5 mL) and the reaction mix-
ture was stirred for 3 h at 23 °C. After removal of all volatile mate-
rials in vacuo, the residue was purified by using chromatography
(SiO2, hexane/MTBE = 10:1, Rf = 0.34) to yield pyridazine 7b
1
(359 mg, 1.00 mmol, 96%) as a yellowish oil. H NMR (500 MHz,
CDCl3): δ = 1.09 (t, J = 7.1 Hz, 3 H), 1.54–1.59 (m, 1 H), 1.63– CH), 127.98 (2 CH), 128.12 (2 CH), 135.53 (C), 140.32 (C), 143.41
1.75 (m, 2 H), 2.06–2.13 (m, 1 H), 2.23–2.32 (m, 2 H), 2.45 (d, J (C), 143.62 (C), 171.77 (C) ppm. IR (ATR): ν = 3056 (w), 2950
˜
= 17.1 Hz, 1 H), 3.50 (d, J = 17.1 Hz, 1 H), 4.05 (q, J = 7.1 Hz, 2 (w), 2906 (w), 1730 (s), 1593 (m), 1491 (s), 1297 (m), 1262 (m),
H), 5.40 (t, J = 3.6 Hz, 1 H), 6.96 (t, J = 7.3 Hz, 1 H), 7.16–7.19 1194 (s), 1156 (m), 1136 (m), 1029 (w), 758 (s), 691 (s) cm–1. HRMS
(m, 1 H), 7.22–7.27 (m, 4 H), 7.47 (d, J = 8.1 Hz, 2 H), 7.65 (d, J
= 7.9 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 14.23
(CH3), 19.31 (CH2), 24.78 (CH2), 35.05 (2 CH2), 41.95 (C), 61.43
(CH2), 108.59 (CH), 122.05 (2 CH), 123.07 (CH), 124.84 (2 CH),
127.65 (CH), 128.22 (2 CH), 128.58 (2 CH), 135.69 (C), 138.01 (C),
(ESI): calcd. for C21H20N2NaO2S [M + Na+] 387.1143; found
387.1137.
6-tert-Butyl 4a-Methyl 1,3-Diphenyl-1,4,4a,5,6,7-hexahydropyr-
ido[4,3-c]pyridazine-4a,6-dicarboxylate (7j): Following the pro-
cedure given for compound 7b, 1,4-diketone 1j (640 mg,
1.70 mmol), phenylhydrazine (5a; 257 mg, 2.38 mmol) and TFA
(116 mg, 1.02 mmol) were reacted in CH2Cl2 (5.8 mL). Chromatog-
raphy (SiO2, hexane/MTBE = 10:1, Rf = 0.29) gave pyridazine 7j
(133 mg, 250 μmol, 15%) as a yellowish oil. A double signal set is
observed due to E/Z-isomers (ratio 1.0:0.73) at the carbamate C–
138.92 (C), 146.41 (C), 174.30 (C) ppm. IR (ATR): ν = 3059 (w),
˜
2979 (w), 2934 (w), 2865 (w), 1723 (s), 1590 (m), 1491 (s), 1445
(m), 1267 (m), 1186 (s), 1024 (m), 758 (s), 693 (s), 633 (s) cm–1.
HRMS (ESI): calcd. for C23H25N2O2 [M + H+] 361.1916; found
361.1921.
1
Methyl
1,3-Diphenyl-1,4,4a,5-tetrahydrofuro[3,4-c]pyridazine-4a-
N bond. H NMR (500 MHz, CDCl3), major conformer: δ = 1.49
carboxylate (7d) and Methyl 2,3-Diphenyl-4a,5,6,7-tetrahydrofuro-
[c]pyridazine-4a-carboxylate (8d): Following the procedure reported
for compound 7a, 1,4-diketone 1d (100 mg, 380 μmol), phenylhy-
drazine (5a; 62 mg, 0.57 mmol), AcOH (11 mg, 0.19 mmol) and
TFA (22 mg, 0.19 mmol) were reacted in CH2Cl2 (1.2 mL).
Chromatography (SiO2, hexane/MTBE = 2:1, Rf = 0.15) gave a
mixture of regioisomers 7d (19 mg, 57 μmol, 15%) and 8d (3 mg,
9 μmol, 2%) as a yellowish oil. 1H NMR (500 MHz, CDCl3), major
regioisomer 7d: δ = 2.66 (d, J = 16.9 Hz, 1 H), 3.59 (d, J = 16.9 Hz,
1 H), 3.62 (s, 3 H), 4.22 (d, J = 9.6 Hz, 1 H), 4.94 (d, J = 9.6 Hz,
1 H), 6.52 (s, 1 H), 6.93 (t, J = 7.3 Hz, 1 H), 7.24–7.32 (m, 5 H),
7.45 (d, J = 8.2 Hz, 2 H), 7.69 (d, J = 7.8 Hz, 2 H) ppm; minor
regioisomer 8d: δ = 3.64 (s, 3 H), 3.85 (d, J = 8.8 Hz, 1 H), 4.44
(d, J = 14.0 Hz, 1 H), 4.70 (s, 1 H), 4.74 (d, J = 14.0 Hz, 1 H),
(s, 9 H), 2.31 (d, J = 17.1 Hz, 1 H), 2.88–2.96 (m, 2 H), 3.37 (d, J
= 16.5 Hz, 2 H), 3.69 (s, 3 H), 4.58–4.65 (m, 2 H), 5.26 (br. s, 1 H),
7.09–7.14 (m, 2 H), 7.33–7.38 (m, 3 H), 7.52 (d, J = 7.3 Hz, 2 H),
7.71 (d, J = 7.3 Hz, 2 H) ppm; minor conformer: δ = 1.48 (s, 9 H),
2.31 (d, J = 17.1 Hz, 1 H), 2.88–2.96 (m, 1 H), 2.96–3.04 (m, 1 H),
3.74 (s, 3 H), 4.41–4.45 (m, 1 H), 4.58–4.65 (m, 2 H), 4.76 (d, J =
16.0 Hz, 1 H), 5.18 (br. s, 1 H), 7.01 (d, J = 7.3 Hz, 1 H), 7.09–
7.14 (m, 2 H), 7.33–7.38 (m, 2 H), 7.52 (d, J = 7.3 Hz, 2 H), 7.71 (d,
J = 7.3 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3), major
conformer: δ = 28.34 (3 CH3), 30.03 (CH2), 42.16 (C), 42.65 (CH2),
50.73 (CH2), 52.96 (CH3), 80.20 (C), 102.54 (CH), 123.59 (CH),
124.40 (CH), 124.79 (2 CH), 127.98 (2 CH), 128.29 (2 CH), 128.84
(2 CH), 137.33 (C), 138.02 (C), 143.51 (C), 145.90 (C), 153.81 (C),
172.61 (C) ppm; minor conformer: δ = 28.29 (3 CH3), 29.67 (CH2),
6.85 (t, J = 7.2 Hz, 1 H), 7.05 (t, J = 7.8 Hz, 2 H) ppm. 13C{1H} 41.97 (C), 43.44 (CH2), 49.43 (CH2), 52.67 (CH3), 80.09 (C), 102.49
NMR (125 MHz, CDCl3), major regioisomer 7d: δ = 34.89 (CH2), (CH), 122.77 (CH), 123.37 (2 CH), 124.79 (2 CH), 128.17 (CH),
49.91 (CH3), 53.54 (C), 80.12 (CH2), 117.77 (2 CH), 117.91 (C), 128.29 (2 CH), 128.84 (2 CH), 135.47 (C), 138.02 (C), 143.51 (C),
122.76 (CH), 125.54 (2 CH), 128.61 (CH), 128.82 (2 CH), 129.49 145.90 (C), 153.81 (C), 172.57 (C) ppm. IR (ATR): ν = 2975 (w),
˜
(2 CH), 131.63 (CH), 138.19 (C), 140.01 (C), 145.58 (C), 173.51 2952 (w), 2930 (w), 1734 (m), 1696 (s), 1597 (m), 1493 (m), 1423
(C) ppm. IR (ATR): ν = 3060 (w), 3033 (w), 2912 (w), 1732 (s), (m), 1365 (m), 1236 (m), 1198 (s), 1163 (s), 1153 (s), 1124 (s), 754
˜
1598 (m), 1495 (s), 1290 (m), 1212 (s), 1172 (m), 1127 (m), 1096 (s), 691 (s) cm–1. HRMS (ESI): calcd. for C26H30N3O4 [M + H+]
(s), 765 (s), 694 (s), 636 (m) cm–1. HRMS (ESI): calcd. for 448.2236; found 448.2231.
C20H18N2NaO3 [M + Na+] 357.1215; found 357.1223.
6-Benzyl 4a-Methyl 1,3-Diphenyl-1,4,4a,5,6,7-hexahydropyrido-
Methyl 1,3-Diphenyl-1,4,4a,5,6,7-hexahydrothiopyrano[4,3-c]pyrid-
[4,3-c]pyridazine-4a,6-dicarboxylate (7k): Following the procedure
azine-4a-carboxylate (7i) and Methyl 2,3-Diphenyl-2,4a,5,6,7,8- given for compound 7b, 1,4-diketone 1k (145 mg, 350 μmol), phen-
hexahydrothiopyrano[4,3-c]pyridazine-4a-carboxylate (8i): Follow-
ing the procedure given for compound 7b, 1,4-diketone 1i (480 mg,
1.64 mmol), phenylhydrazine (5a; 195 mg, 1.80 mmol) and TFA
ylhydrazine (5a; 42 mg, 0.39 mmol) and TFA (24 mg, 0.21 mmol)
were reacted in CH2Cl2 (1.2 mL). Twofold chromatography (SiO2,
toluene/MTBE = 10:1, Rf = 0.34, then hexane/MTBE = 3:1, Rf =
(112 mg, 0.980 mmol) were reacted in CH2Cl2 (5.6 mL). 0.20) gave pyridazine 7k (70 mg, 0.15 mmol, 43%) as a yellowish
Chromatography (SiO2, hexane/MTBE = 10:1, Rf = 0.27) gave a
mixture of regioisomers 7i (211 mg, 580 μmol, 35%) and 8i
oil. A double signal set is observed due to E/Z-isomers (ratio ≈ 1:1)
at the carbamate C–N bond. 1H NMR (500 MHz, CDCl3): δ =
(118 mg, 320 μmol, 20%) as a yellowish solid. 1H NMR (500 MHz, 2.32 (t, J = 16.6 Hz, 2 H), 2.88–2.94 (m, 2 H), 3.41 (s, 3 H), 3.45–
CDCl3), major regioisomer 7i: δ = 2.69–2.73 (m, 1 H), 2.78 (d, J
3.53 (m, 5 H), 3.66–3.78 (m, 2 H), 4.44–4.57 (m, 2 H), 4.60–4.75
= 13.7 Hz, 1 H), 2.94–2.97 (m, 1 H), 3.19–3.22 (m, 1 H), 3.38 (d, (m, 2 H), 5.04–5.16 (m, 6 H), 7.00–7.11 (m, 4 H), 7.17–7.20 (m, 2
J = 13.4 Hz, 1 H), 3.46 (d, J = 17.2 Hz, 1 H), 3.71 (s, 3 H), 5.53 H), 7.24–7.30 (m, 16 H), 7.41 (d, J = 7.9 Hz, 4 H), 7.60–7.63 (m,
(s, 1 H), 7.07–7.10 (m, 2 H), 7.31–7.35 (m, 4 H), 7.52 (d, J = 7.7 Hz, 4 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 29.85 (CH2),
2 H), 7.68 (d, J = 7.7 Hz, 2 H) ppm; minor regioisomer 8i: δ =
2.69–2.73 (m, 1 H), 2.88–2.89 (m, 1 H), 2.94–2.97 (m, 1 H), 3.25–
3.26 (m, 1 H), 3.38 (d, J = 13.4 Hz, 1 H), 3.42–3.43 (m, 1 H), 3.80
29.97 (CH2), 41.99 (C), 42.18 (C), 43.35 (2 CH2), 50.08 (CH2),
50.36 (CH2), 52.78 (CH3), 52.95 (CH2), 67.39 (2 CH2), 101.22
(CH), 101.97 (CH), 122.85 (2 CH), 123.44 (2 CH), 123.62 (2 CH),
(s, 3 H), 4.55 (s, 1 H), 6.92 (t, J = 7.3 Hz, 1 H), 6.97 (d, J = 7.8 Hz, 123.70 (2 CH), 124.51 (2 CH), 124.82 (2 CH), 127.92 (2 CH),
394
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 389–400

Dihydropyridazine Derivatives and Annulation
128.00 (2 CH), 128.04 (2 CH), 128.18 (2 CH), 128.30 (4 CH), 751 (m), 732 (m), 695 (m), 632 (s) cm–1. HRMS (ESI): calcd. for
128.52 (2 CH), 128.87 (4 CH), 133.80 (C), 134.26 (C), 136.41 (C), C23H24BrN2O2 [M + H+] 439.1021; found 439.1030.
136.55 (C), 137.31 (2 C), 138.21 (C), 138.60 (C), 145.85 (2 C),
Ethyl 3-(4-Nitrophenyl)-1-phenyl-1,4,4a,5,6,7-hexahydrobenzo[c]pyr-
154.62 (C), 154.88 (C), 172.09 (C), 172.34 (C) ppm. IR (ATR): ν =
˜
idazine-4a-carboxylate (7n) and Ethyl 3-(4-Nitrophenyl)-2-phenyl-
2,4a,5,6,7,8-hexahydrobenzo[c]pyridazine-4a-caboxylate (8n): Fol-
lowing the procedure given for compound 7b, 1,4-diketone 1n
(75 mg, 0.22 mmol), phenylhydrazine (5a; 26 mg, 0.24 mmol) and
TFA (15 mg, 0.13 mmol) were reacted in CH2Cl2 (0.8 mL).
Chromatography (SiO2, hexane/MTBE = 5:1, Rf = 0.31) gave a
mixture of regioisomers 7n (41 mg, 0.10 mmol, 46%) and 8n (9 mg,
3062 (w), 3033 (w), 2951 (w), 2924 (w), 2849 (w), 1732 (m), 1702
(s), 1594 (m), 1493 (m), 1445 (m), 1430 (m), 1336 (m), 1294 (m),
1262 (m), 1227 (s), 1197 (s), 1121 (m), 759 (m), 732 (m), 693
(s) cm–1. HRMS (ESI): calcd. for C29H27N3NaO4 [M + Na+]
504.1899; found 504.1909.
Ethyl 3-(4-Methoxyphenyl)-1-phenyl-1,4,4a,5,6,7-hexahydrobenzo-
[c]pyridazine-4a-carboxylate (7l): Following the procedure given for
compound 7b, 1,4-diketone 1l (1.00 g, 3.14 mmol), phenylhydrazine
(5a; 373 mg, 3.45 mmol) and TFA (214 mg, 1.88 mmol) were re-
acted in CH2Cl2 (11 mL). Chromatography (SiO2, hexane/MTBE
= 10:1, Rf = 0.24) gave pyridazine 7l (955 mg, 2.45 mmol, 78%) as
1
0.02 mmol, 10%) as a yellowish oil. H NMR (500 MHz, CDCl3),
major isomer 7n: δ = 1.15 (t, J = 7.1 Hz, 3 H), 1.61–1.66 (m, 1 H),
1.71–1.81 (m, 2 H), 2.13–2.21 (m, 1 H), 2.32 (ddd, J = 4.5 Hz, J =
8.9 Hz, J = 17.9 Hz, 1 H), 2.38–2.40 (m, 1 H), 2.52 (d, J = 17.0 Hz,
1 H), 3.55 (d, J = 17.0 Hz, 1 H), 4.07–4.15 (m, 2 H), 5.51 (dd, J =
3.5 Hz, J = 5.0 Hz, 1 H), 7.10 (t, J = 7.1 Hz, 1 H), 7.34 (t, J =
7.9 Hz, 2 H), 7.50 (d, J = 7.6 Hz, 2 H), 7.81 (d, J = 9.0 Hz, 2 H),
8.15 (d, J = 9.0 Hz, 2 H) ppm; minor isomer 8n: δ = 1.21 (t, J =
7.1 Hz, 3 H), 1.55–1.60 (m, 2 H), 1.61–1.66 (m, 1 H), 1.71–1.81 (m,
2 H), 1.91–1.94 (m, 1 H), 2.55–2.56 (m, 1 H), 2.65–2.69 (m, 1 H),
4.16–4.26 (m, 2 H), 4.71 (s, 1 H), 6.92 (t, J = 7.4 Hz, 1 H), 6.96 (d,
J = 7.6 Hz, 2 H), 7.10 (t, J = 7.1 Hz, 2 H), 7.30 (d, J = 8.7 Hz, 2
H), 8.01 (d, J = 8.8 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz,
CDCl3), major isomer 7n: δ = 14.66 (CH3), 19.60 (CH2), 25.16
(CH2), 34.84 (CH2), 35.28 (CH2), 42.03 (C), 62.09 (CH2), 110.79
(CH), 122.99 (2 CH), 124.12 (2 CH), 124.64 (CH), 125.22 (2 CH),
129.21 (2 CH), 135.73 (C), 136.35 (C), 144.45 (C), 146.23 (C),
146.98 (C), 174.37 (C) ppm; minor isomer 8n: δ = 14.61 (CH3),
23.19 (CH2), 30.12 (CH2), 32.72 (CH2), 37.76 (CH2), 47.64 (C),
61.91 (CH2), 107.16 (CH), 122.87 (2 CH), 123.79 (2 CH), 124.23
(CH), 128.75 (2 CH), 128.99 (2 CH), 137.98 (C), 143.33 (C), 143.83
1
a yellowish solid. M.p. 113 °C. H NMR (500 MHz, CDCl3): δ =
1.16 (t, J = 7.1 Hz, 3 H), 1.62 (t, J = 12.0 Hz, 1 H), 1.69–1.82 (m,
2 H), 2.13–2.17 (m, 1 H), 2.29–2.37 (m, 2 H), 2.49 (d, J = 17.1 Hz,
1 H), 3.54 (d, J = 17.1 Hz, 1 H), 3.80 (s, 3 H), 4.11 (q, J = 7.1 Hz,
2 H), 5.46 (br. s, 1 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.01 (t, J = 7.2 Hz,
1 H), 7.30 (t, J = 7.7 Hz, 2 H), 7.53 (d, J = 8.2 Hz, 2 H), 7.66 (d,
J = 8.6 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ =
14.19 (CH3), 19.26 (CH2), 24.73 (CH2), 35.00 (CH2), 35.10 (CH2),
42.00 (C), 55.25 (CH3), 61.34 (CH2), 108.22 (CH), 113.63 (2 CH),
121.79 (2 CH), 122.73 (CH), 126.12 (2 CH), 128.50 (2 CH), 130.81
(C), 135.69 (C), 138.97 (C), 146.45 (C), 159.46 (C), 174.30 (C) ppm.
IR (ATR): ν = 3002 (w), 2957 (w), 2935 (w), 2858 (w), 2837 (w),
˜
1723 (s), 1598 (m), 1511 (m), 1494 (s), 1453 (m), 1297 (m), 1240
(m), 1214 (m), 1183 (s), 1157 (m), 1084 (m), 1037 (m), 1025 (m),
836 (s), 764 (s), 698 (s) cm–1. HRMS (ESI): calcd. for C24H27N2O3
[M + H+] 391.2022; found 391.2029.
(C), 147.61 (C), 147.89 (C), 172.46 (C) ppm. IR (ATR): ν = 2980
˜
(w), 2935 (w), 2864 (w), 2837 (w), 1725 (m), 1594 (m), 1553 (m),
1511 (m), 1491 (m), 1338 (vs), 1191 (s), 1109 (m), 854 (m), 753
(m), 695 (m) cm–1. HRMS (ESI): calcd. for C23H24N3O4 [M + H+]
406.1767; found 406.1763.
Ethyl 3-(4-Bromophenyl)-1-phenyl-1,4,4a,5,6,7-hexahydrobenzo[c]-
pyridazine-4a-carboxylate (7m) and Ethyl 3-(4-Bromophenyl)-2-
phenyl-2,4a,5,6,7,8-hexahydrobenzo[c]pyridazine-4a-caboxylate (8m):
Following the procedure given for compound 7b, 1,4-diketone 1m
(181 mg, 491 μmol), phenylhydrazine (5a; 58 mg, 0.54 mmol) and
TFA (33 mg, 0.29 mmol) were reacted in CH2Cl2 (1.7 mL).
Chromatography (SiO2, hexane/MTBE = 10:1, Rf = 0.36) gave a
mixture of regioisomers 7m (104 mg, 240 μmol, 48%) and 8m
(41 mg, 90 μmol, 15%) as a yellowish oil. 1H NMR (500 MHz,
CDCl3), major regioisomer 7m: δ = 1.15 (t, J = 7.1 Hz, 3 H), 1.49–
1.64 (m, 2 H), 1.69–1.78 (m, 2 H), 2.11–2.18 (m, 1 H), 2.32–2.36
(m, 1 H), 2.48 (d, J = 17.1 Hz, 1 H), 3.49 (d, J = 17.0 Hz, 1 H),
4.07–4.14 (m, 2 H), 5.46–5.47 (m, 1 H), 7.04 (t, J = 7.3 Hz, 1 H),
7.30 (t, J = 7.9 Hz, 2 H), 7.42 (d, J = 8.5 Hz, 2 H), 7.50 (d, J =
8.1 Hz, 2 H), 7.57 (d, J = 6.6 Hz, 2 H) ppm; minor regioisomer
8m: δ = 1.20 (t, J = 7.1 Hz, 3 H), 1.69–1.78 (m, 2 H), 1.89–1.91
(m, 1 H), 2.27–2.30 (m, 2 H), 2.51–2.54 (m, 2 H), 2.64–2.67 (m, 1
H), 4.14–4.25 (m, 2 H), 4.57 (s, 1 H), 6.91 (t, J = 7.3 Hz, 1 H), 6.97
(d, J = 8.0 Hz, 2 H), 7.00 (d, J = 8.4 Hz, 2 H), 7.10 (t, J = 7.8 Hz,
2 H), 7.27–7.29 (m, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3),
major regioisomer 7m: δ = 14.21 (CH3), 19.21 (CH2), 24.71 (CH2),
34.67 (CH2), 34.90 (CH2), 41.74 (C), 61.49 (CH2), 109.00 (CH),
121.52 (C), 122.08 (2 CH), 123.32 (CH), 126.24 (2 CH), 128.62 (2
CH), 131.36 (2 CH), 135.41 (C), 136.84 (C), 137.60 (C), 146.15
(C), 174.17 (C) ppm; minor regioisomer 8m: δ = 14.17 (CH3), 22.82
(CH2), 24.71 (CH2), 32.35 (CH2), 37.31 (CH2), 47.11 (C), 61.25
(CH2), 104.54 (CH), 121.91 (C), 122.57 (2 CH), 123.32 (CH),
128.31 (2 CH), 129.54 (2 CH), 131.17 (2 CH), 135.09 (C), 138.25
Ethyl
3-(2,4-Dimethoxyphenyl)-2-phenyl-2,4a,5,6,7,8-hexahydro-
benzo[c]pyridazine-4a-carboxylate (8o): Following the procedure
given for compound 7b, 1,4-diketone 1o (100 mg, 290 μmol), phen-
ylhydrazine (5a; 35 mg, 0.32 mmol) and TFA (15 mg, 0.13 mmol)
were reacted in CH2Cl2 (1.0 mL). Chromatography (SiO2, hexane/
MTBE = 2:1, Rf = 0.49) gave pyridazine 8o (54 mg, 13 μmol, 45%)
as an orange oil. 1H NMR (500 MHz, CDCl3): δ = 1.24 (t, J =
7.1 Hz, 3 H), 1.49 (dt, J = 12.8, J = 3.0 Hz, 1 H), 1.57 (dt, J =
12.9, J = 3.6 Hz, 1 H), 1.67 (td, J = 13.2, J = 3.4 Hz, 1 H), 1.86–
1.89 (m, 1 H), 2.46–2.49 (m, 1 H), 2.55 (dd, J = 5.2, J = 13.3 Hz,
1 H), 2.64–2.67 (m, 1 H), 3.27 (s, 3 H), 3.73 (s, 3 H), 3.79 (d, J =
11.7 Hz, 1 H), 4.11–4.26 (m, 2 H), 4.39 (s, 1 H), 6.09 (d, J = 2.1 Hz,
1 H), 6.38 (dd, J = 2.3, J = 8.4 Hz, 1 H), 6.83 (t, J = 7.1 Hz, 1 H),
6.96–7.01 (m, 4 H), 7.12 (d, J = 8.3 Hz, 1 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 14.27 (CH3), 22.91 (CH2), 25.45 (CH2),
32.39 (CH2), 37.14 (CH2), 46.85 (C), 55.02 (CH3), 55.26 (CH3),
60.92 (CH2), 98.30 (CH), 102.07 (CH), 104.17 (CH), 118.02 (C),
122.33 (2 CH), 122.88 (CH), 127.30 (2 CH), 131.84 (CH), 137.36
(C), 144.40 (C), 144.74 (C), 157.34 (C), 161.33 (C), 173.09 (C) ppm.
IR (ATR): ν = 2933 (w), 2859 (w), 2838 (w), 1725 (s), 1608 (m),
˜
1598 (m), 1504 (m), 1496 (m), 1464 (m), 1308 (m), 1283 (m), 1209
(s), 1033 (w) cm–1. HRMS (ESI): calcd. for C25H28N2NaO4 [M +
Na+] 443.1947; found 443.1959.
(C), 143.69 (C), 147.03 (C), 172.36 (C) ppm. IR (ATR): ν = 2979
(w), 2935 (w), 2865 (w), 2836 (w), 1724 (s), 1594 (m), 1577 (w),
Ethyl 1-(2-Chlorophenyl)-3-phenyl-1,4,4a,5,6,7-hexahydrobenzo[c]-
pyridazine-4a-carboxylate (7p): Following the procedure given for
˜
1310 (m), 1295 (m), 1267 (m), 1189 (s), 1072 (m), 909 (m), 825 (m), compound 7b, 1,4-diketone 1b (150 mg, 520 μmol), 2-chlorophenyl-
Eur. J. Org. Chem. 2013, 389–400
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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395

M. Penning, J. Christoffers
FULL PAPER
hydrazine (5b; 81 mg, 0.57 mmol) and TFA (15 mg, 0.13 mmol)
(w), 2975 (w), 2933 (w), 2835 (w), 1721 (m), 1584 (m), 1498 (m),
1460 (m), 1444 (m), 1293 (m), 1271 (m), 1243 (m), 1194 (s), 1159
were reacted in CH2Cl2 (1.8 mL). Chromatography (SiO2, hexane/
MTBE = 10:1, Rf = 0.33) gave pyridazine 7p (155 mg, 390 μmol, (s), 1123 (m), 1024 (s), 752 (s), 693 (m) cm–1. HRMS (ESI): calcd.
1
75%) as a yellowish oil. H NMR (500 MHz, CDCl3): δ = 1.24 (t,
J = 7.1 Hz, 3 H), 1.65 (dd, J = 3.4, J = 13.0 Hz, 1 H), 1.75–1.84
(m, 2 H), 2.18–2.28 (m, 2 H), 2.42 (dt, J = 13.3, J = 3.7 Hz, 1 H),
2.48 (d, J = 16.7 Hz, 1 H), 3.58 (d, J = 16.7 Hz, 1 H), 4.15–4.26
(m, 2 H), 4.73 (t, J = 4.3 Hz, 1 H), 7.23 (t, J = 7.7 Hz, 1 H), 7.25–
7.28 (m, 2 H), 7.32–7.37 (m, 2 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.60
(d, J = 7.9 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 2 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 14.23 (CH3), 19.48 (CH2), 24.48 (CH2),
33.96 (CH2), 34.49 (CH2), 42.04 (C), 61.40 (CH2), 103.90 (CH),
125.04 (2 CH), 127.41 (CH), 127.58 (CH), 127.77 (CH), 128.24 (2
CH), 129.47 (CH), 130.40 (CH), 132.42 (C), 136.08 (C), 137.81 (C),
for C24H27N2O3 [M + H+] 391.2022; found 391.2021.
Ethyl 1-(4-Methoxyphenyl)-3-phenyl-1,4,4a,5,6,7-hexahydrobenzo-
[c]pyridazine-4a-carboxylate (7s): Following the procedure given for
compound 7b, 1,4-diketone 1b (150 mg, 520 μmol), 4-methoxy-
phenylhydrazine (5e; 79 mg, 0.57 mmol) and TFA (15 mg,
0.13 mmol) were reacted in CH2Cl2 (1.8 mL). Chromatography
(SiO2, hexane/MTBE = 10:1, Rf = 0.32) gave pyridazine 7s (69 mg,
1
0.18 mmol, 35%) as a yellowish oil. H NMR (500 MHz, CDCl3):
δ = 1.16 (t, J = 7.1 Hz, 3 H), 1.59–1.61 (m, 1 H), 1.70–1.76 (m, 2
H), 2.11–2.18 (m, 1 H), 2.24–2.27 (m, 1 H), 2.35 (dt, J = 13.2, J =
4.0 Hz, 1 H), 2.46 (d, J = 16.7 Hz, 1 H), 3.53 (d, J = 17.0 Hz, 1
H), 3.79 (s, 3 H), 4.11 (q, J = 7.1 Hz, 2 H), 5.20 (br. s, 1 H), 6.87
(d, J = 8.5 Hz, 2 H), 7.20–7.23 (m, 1 H), 7.30 (t, J = 7.6 Hz, 2 H),
7.41 (d, J = 8.5 Hz, 2 H), 7.67 (d, J = 8.0 Hz, 2 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 14.23 (CH3), 19.40 (CH2), 24.68
(CH2), 34.40 (CH2), 34.90 (CH2), 41.97 (C), 55.50 (CH3), 61.38
(CH2), 106.16 (CH), 113.95 (2 CH), 124.67 (2 CH), 124.71 (2 CH),
127.42 (CH), 128.17 (2 CH), 136.38 (C), 137.95 (C), 138.04 (C),
140.11 (C), 143.14 (C), 173.88 (C) ppm. IR (ATR): ν = 3061 (w),
˜
2978 (w), 2932 (w), 2869 (w), 2837 (w), 1722 (s), 1585 (w), 1479
(m), 1444 (m), 1292 (m), 1194 (vs), 1113 (m), 1024 (m), 759 (m),
693 (m), 632 (m), 600 (m), 536 (m) cm–1. HRMS (ESI): calcd. for
C23H23ClN2NaO2 [M + Na+] 417.1346; found 417.1336.
Ethyl 1-(3,4-Dichlorophenyl)-3-phenyl-1,4,4a,5,6,7-hexahydrobenzo-
[c]pyridazine-4a-carboxylate (7q) and Ethyl 2-(3,4-Dichlorophenyl)-
3-phenyl-2,4a,5,6,7,8-hexahydrobenzo[c]pyridazine-4a-carboxylate
(8q): Following the procedure given for compound 7b, 1,4-diketone
1b (150 mg, 520 μmol), 3,4-dichlorophenylhydrazine (5c; 100 mg,
570 μmol) and TFA (15 mg, 0.13 mmol) were reacted in CH2Cl2
(1.8 mL). Chromatography (SiO2, hexane/MTBE = 10:1, Rf = 0.35)
gave a mixture of regioisomers 7q (174 mg, 410 μmol, 78%) and
139.78 (C), 156.27 (C), 174.25 (C) ppm. IR (ATR): ν = 3062 (w),
˜
2978 (w), 2933 (w), 2868 (w), 2835 (w), 1723 (m), 1506 (s), 1444
(m), 1293 (m), 1241 (s), 1178 (s), 1111 (m), 1028 (m), 830 (m), 759
(m), 692 (m) cm–1. HRMS (ESI): calcd. for C24H26N2NaO3 [M +
Na+] 413.1841; found 413.1837.
1
Ethyl 1-(2-Methylphenyl)-3-phenyl-1,4,4a,5,6,7-hexahydrobenzo-
[c]pyridazine-4a-carboxylate (7t): Following the procedure given for
compound 7b, 1,4-diketone 1b (150 mg, 520 μmol), 2-methylphen-
ylhydrazine (5f; 70 mg, 0.57 mmol) and TFA (15 mg, 0.13 mmol)
were reacted in CH2Cl2 (1.8 mL). Chromatography (SiO2, hexane/
MTBE = 10:1, Rf = 0.38) gave pyridazine 7t (35 mg, 90 μmol, 18%)
8q (7.0 mg, 16 μmol, 3%) as a yellowish oil. H NMR (500 MHz,
CDCl3), major isomer 7q: δ = 1.14 (t, J = 7.1 Hz, 3 H), 1.61–1.66
(m, 1 H), 1.70–1.81 (m, 2 H), 2.14–2.21 (m, 1 H), 2.31–2.39 (m, 2
H), 2.53 (d, J = 17.3 Hz, 1 H), 3.57 (d, J = 17.3 Hz, 1 H), 4.09 (q,
J = 7.1 Hz, 2 H), 5.58 (t, J = 4.2 Hz, 1 H), 7.27–7.36 (m, 4 H),
7.41 (dd, J = 2.4, J = 8.8 Hz, 1 H), 7.65 (d, J = 2.3 Hz, 1 H), 7.70
(d, J = 7.6 Hz, 2 H) ppm; minor isomer 8q: 1.20 (t, J = 7.1 Hz, 3
H), 4.14–4.25 (m, 2 H), 4.66 (s, 1 H), 6.62 (dd, J = 2.4, J = 8.8 Hz,
1 H), 7.04 (d, J = 8.8 Hz, 1 H) 7.11–7.13 (m, 2 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3), major isomer 7q: δ = 14.17 (CH3), 19.08
(CH2), 24.70 (CH2), 34.83 (CH2), 35.32 (CH2), 41.81 (C), 61.57
(CH2), 111.02 (CH), 120.00 (CH), 122.18 (CH), 124.95 (2 CH),
125.04 (C), 128.20 (CH), 128.31 (2 CH), 129.99 (C), 132.19 (C),
134.85 (C), 137.36 (C), 140.68 (C), 145.75 (C), 174.03 (C) ppm. IR
1
as a yellowish oil. H NMR (500 MHz, CDCl3): δ = 1.18 (t, J =
7.1 Hz, 3 H), 1.49–1.60 (m, 1 H), 1.72–1.78 (m, 2 H), 2.10–2.20 (m,
2 H), 2.26 (s, 3 H), 2.34 (dt, J = 13.1, J = 3.1 Hz, 1 H), 2.42 (d, J
= 14.8 Hz, 1 H), 3.53 (d, J = 16.6 Hz, 1 H), 4.08–4.20 (m, 2 H),
4.56 (br. s, 1 H), 7.14–7.17 (m, 1 H), 7.20–7.23 (m, 3 H), 7.28 (t, J
= 7.6 Hz, 2 H), 7.35–7.37 (m, 1 H), 7.66 (d, J = 7.7 Hz, 2 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 14.20 (CH3), 18.04 (CH3),
19.47 (CH2), 24.49 (CH2), 33.79 (CH2), 34.74 (CH2), 42.24 (C),
61.36 (CH2), 102.82 (CH), 124.75 (2 CH), 126.53 (CH), 126.69
(CH), 127.49 (CH), 127.70 (CH), 128.20 (2 CH), 130.85 (CH),
135.79 (C), 136.25 (C), 137.92 (C), 138.90 (C), 144.29 (C), 173.99
(ATR): ν = 2980 (w), 2937 (w), 2866 (w), 2837 (w), 1725 (m), 1585
˜
(m), 1471 (s), 1445 (m), 1266 (m), 1180 (m), 1126 (m), 1112 (m),
1023 (m), 760 (m), 737 (m), 693 (m), 631 (m) cm–1. HRMS (ESI):
calcd. for C23H22Cl2N2NaO2 [M + Na+] 451.0956; found 451.0943.
(C) ppm. IR (ATR): ν = 3059 (w), 3025 (w), 2981 (w), 2934 (w),
˜
2870 (w), 2837 (w), 1724 (s), 1585 (m), 1493 (m), 1447 (m), 1294
(m), 1270 (m), 1190 (s), 1126 (m), 1068 (m), 1025 (m), 761 (m), 695
(m), 633 (s) cm–1. HRMS (ESI): calcd. for C24H27N2O2 [M + H+]
375.2073; found 375.2070.
Ethyl 1-(2-Methoxyphenyl)-3-phenyl-1,4,4a,5,6,7-hexahydrobenzo-
[c]pyridazine-4a-carboxylate (7r): Following the procedure given for
compound 7b, 1,4-diketone 1b (150 mg, 520 μmol), 2-methoxy-
phenylhydrazine (5d; 79 mg, 0.57 mmol) and TFA (15 mg,
0.13 mmol) were reacted in CH2Cl2 (1.8 mL). Chromatography
(SiO2, hexane/MTBE = 10:1, Rf = 0.32) gave pyridazine 7r (107 mg,
270 μmol, 53%) as a yellowish oil. 1H NMR (500 MHz, CDCl3): δ
= 1.12 (t, J = 7.1 Hz, 3 H), 1.47–1.54 (m, 1 H), 1.62–1.68 (m, 2
H), 2.09–2.14 (m, 2 H), 2.28 (dt, J = 12.8, J = 3.2 Hz, 1 H), 2.38
(d, J = 16.3 Hz, 1 H), 3.42 (d, J = 16.5 Hz, 1 H), 3.76 (s, 3 H),
4.03–4.13 (m, 2 H), 4.62 (br. s, 1 H), 6.92 (t, J = 8.9 Hz, 2 H),
Ethyl 1-(4-Methylphenyl)-3-phenyl-1,4,4a,5,6,7-hexahydrobenzo-
[c]pyridazine-4a-carboxylate (7u): Following the procedure given for
compound 7b, 1,4-diketone 1b (150 mg, 520 μmol), 4-methylphen-
ylhydrazine (5g; 70 mg, 0.57 mmol) and TFA (15 mg, 0.13 mmol)
were reacted in CH2Cl2 (1.8 mL). Chromatography (SiO2, hexane/
MTBE = 10:1, Rf = 0.37) gave pyridazine 7u (128 mg, 340 μmol,
1
66%) as a yellowish oil. H NMR (500 MHz, CDCl3): δ = 1.15 (t,
7.13–7.18 (m, 2 H), 7.22 (t, J = 7.6 Hz, 2 H), 7.37 (t, J = 6.8 Hz, J = 7.1 Hz, 3 H), 1.55–1.63 (m, 1 H), 1.69–1.76 (m, 2 H), 2.11–2.18
1 H), 7.58 (d, J = 7.7 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz,
(m, 1 H), 2.26–2.37 (m, 2 H), 2.31 (s, 3 H), 2.48 (d, J = 17.1 Hz, 1
CDCl3): δ = 14.67 (CH3), 20.05 (CH2), 24.95 (CH2), 34.18 (CH2), H), 3.54 (d, J = 17.1 Hz, 1 H), 4.10 (q, J = 7.1 Hz, 2 H), 5.35 (br.
34.94 (CH2), 42.51 (C), 56.54 (CH3), 61.71 (CH2), 103.13 (CH), s, 1 H), 7.11 (d, J = 8.1 Hz, 2 H), 7.21–7.24 (m, 1 H), 7.30 (t, J =
113.34 (CH), 121.69 (CH), 125.35 (2 CH), 127.76 (CH), 128.04 7.6 Hz, 2 H), 7.40 (d, J = 8.1 Hz, 2 H), 7.69 (d, J = 7.8 Hz, 2
(CH), 128.57 (2 CH), 129.42 (CH), 135.51 (C), 137.13 (C), 138.65
(C), 139.08 (C), 156.22 (C), 174.53 (C) ppm. IR (ATR): ν = 3058
H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 14.45 (CH3),
19.56 (CH2), 21.08 (CH3), 24.94 (CH2), 34.95 (CH2), 35.21 (CH2),
˜
396
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Eur. J. Org. Chem. 2013, 389–400

Dihydropyridazine Derivatives and Annulation
42.12 (C), 61.62 (CH2), 107.72 (CH), 122.76 (2 CH), 124.94 (2 CH), was stirred for 19 h at 40 °C. Then water (10 mL) was added and
127.71 (CH), 128.40 (2 CH), 129.41 (2 CH), 133.12 (C), 136.10 (C),
the aqueous phase was extracted with MTBE (3 ϫ10 mL). The
138.22 (C), 138.50 (C), 144.17 (C), 175.54 (C) ppm. IR (ATR): ν = combined organic extracts were dried (MgSO4), filtered and the
˜
3029 (w), 2975 (w), 2934 (w), 2864 (w), 2835 (w), 1725 (m), 1509 solvent was evaporated to yield 1,4-diketone 1g (83 mg, 0.21 mmol,
(m), 1445 (w), 1267 (w), 1191 (m), 760 (w), 694 (w), 632 (s) cm–1.
HRMS (ESI): calcd. for C24H26N2NaO2 [M + Na+] 397.1892;
found 397.1866.
44%) after chromatography (SiO2, hexane/MTBE = 2:1, Rf = 0.13)
as a colorless oil. A double signal set is observed due to E/Z-iso-
mers (ratio 1.0:0.95) at the carbamate C–N bond. 1H NMR
(500 MHz, CDCl3): δ = 3.65–3.74 (m, 4 H), 3.71 (s, 6 H), 3.85 (s,
2 H), 4.16–4.28 (m, 4 H), 4.39–4.46 (m, 2 H), 5.19 (s, 4 H), 7.32–
7.38 (m, 10 H), 7.46 (t, J = 7.5 Hz, 4 H), 7.58 (t, J = 7.5 Hz, 2 H),
7.92 (d, J = 7.8 Hz, 4 H) ppm. 13C{1H} NMR (125 MHz, CDCl3):
δ = 42.83 (CH2), 43.04 (CH2), 52.54 (CH2), 52.70 (CH2), 52.95
(CH2), 53.07 (CH2), 53.59 (2 CH3), 56.70 (C), 57.68 (C), 67.62 (2
CH2), 128.21 (4 CH), 128.38 (2 CH), 128.40 (4 CH), 128.74 (4 CH),
129.00 (4 CH), 134.20 (2 CH), 135.72 (2 C), 136.56 (2 C), 154.86
(C), 155.03 (C), 169.35 (C), 169.62 (C), 196.31 (C), 196.37 (C),
Ethyl 1-(4-Iodophenyl)-3-phenyl-1,4,4a,5,6,7-hexahydrobenzo[c]pyr-
idazine-4a-carboxylate (7v) and Ethyl 2-(4-Iodophenyl)-3-phenyl-
2,4a,5,6,7,8-hexahydrobenzo[c]pyridazine-4a-carboxylate (8v): Fol-
lowing the procedure given for compound 7b, 1,4-diketone 1b
(150 mg, 520 μmol), 4-iodophenylhydrazine (5h; 133 mg, 570 μmol)
and TFA (15 mg, 0.13 mmol) were reacted in CH2Cl2 (1.8 mL).
Chromatography (SiO2, hexane/MTBE = 10:1, Rf = 0.27) gave a
mixture of regioisomers 7v (194 mg, 400 μmol, 77 %) and 8v
(10 mg, 21 μmol, 4 %) as a red solid. M.p. 44 °C. 1H NMR
(500 MHz, CDCl3), major isomer 7v: δ = 1.07 (t, J = 7.1 Hz, 3 H),
1.53–1.59 (m, 1 H), 1.63–1.71 (m, 2 H), 2.08–2.11 (m, 1 H), 2.23–
2.31 (m, 2 H), 2.45 (d, J = 17.3 Hz, 1 H), 3.50 (d, J = 17.2 Hz, 1
H), 4.03 (q, J = 7.1 Hz, 2 H), 5.47 (t, J = 4.2 Hz, 1 H), 7.18–7.21
(m, 1 H), 7.25–7.28 (m, 4 H), 7.51 (d, J = 8.6 Hz, 2 H), 7.63 (d, J
= 7.7 Hz, 2 H) ppm; minor isomer 8v: δ = 1.13 (t, J = 7.2 Hz, 3
H), 2.60 (d, J = 14.8 Hz, 1 H), 4.07–4.18 (m, 2 H), 4.56 (s, 1 H),
6.68 (d, J = 8.5 Hz, 2 H), 7.06 (d, J = 6.3 Hz, 2 H), 7.13 (d, J =
7.0 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3), major iso-
mer 7v: δ = 14.67 (CH3), 19.61 (CH2), 25.18 (CH2), 35.36 (CH2),
35.60 (CH2), 42.26 (C), 61.95 (CH2), 85.84 (C), 110.39 (CH), 123.72
(2 CH), 125.30 (2 CH), 128.40 (CH), 128.72 (2 CH), 135.51 (C),
137.90 (2 CH), 138.07 (C), 140.28 (C), 146.56 (C), 174.58 (C) ppm.
205.94 (C), 206.57 (C) ppm. IR (ATR): ν = 3063 (w), 3032 (w),
˜
2955 (w), 2920 (w), 1769 (m), 1704 (s), 1681 (s), 1449 (m), 1418
(m), 1352 (m), 1270 (m), 1211 (m), 1180 (m), 1120 (m), 911 (m),
754 (m), 730 (s), 689 (s) cm– 1 . HRMS (ESI): calcd. for
C22H21NNaO6 [M + Na+] 418.1267; found 418.1274.
Ethyl 4-Oxo-3-(2-oxo-2-phenylethyl)tetrahydro-2H-pyran-3-carb-
oxylate (1h): Following the procedure given for compound 1g, oxo
ester 10h (413 mg, 2.40 mmol), phenacyl bromide (11a; 525 mg,
2.64 mmol) and K2CO3 (365 mg, 2.64 mmol) were reacted in ace-
tone (4.8 mL). Chromatography (SiO2, hexane/MTBE = 1:1, Rf =
0.38) gave 1,4-diketone 1h (502 mg, 1.73 mmol, 72%) as a colorless
solid. M.p. 90 °C. 1H NMR (500 MHz, CDCl3): δ = 1.26 (t, J =
7.1 Hz, 3 H), 2.53–2.57 (m, 1 H), 3.05 (ddd, J = 7.3, J = 11.0, J =
15.4 Hz, 1 H), 3.38 (d, J = 17.7 Hz, 1 H), 3.51 (d, J = 17.7 Hz, 1
H), 3.89–3.95 (m, 2 H), 4.22–4.28 (m, 3 H), 4.43 (d, J = 11.4 Hz,
1 H), 7.44 (t, J = 7.7 Hz, 2 H), 7.56 (t, J = 7.4 Hz, 1 H), 7.91 (d,
J = 7.6 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ =
13.97 (CH3), 39.53 (CH2), 40.79 (CH2), 60.04 (C), 62.00 (CH2),
68.26 (CH2), 73.97 (CH2), 128.09 (2 CH), 128.64 (2 CH), 133.42
(CH), 136.50 (C), 170.73 (C), 196.00 (C), 202.88 (C) ppm. IR
IR (ATR): ν = 3059 (w), 2978 (w), 2934 (w), 2865 (w), 2835 (w),
˜
1723 (s), 1579 (m), 1481 (vs), 1444 (m), 1301 (m), 1266 (m), 1184
(s), 1170 (s), 1110 (m), 1022 (m), 818 (m), 758 (s), 691 (s) cm–1.
HRMS (ESI): calcd. for C23H24IN2O2 [M + H+] 487.0882; found
487.0891.
Ethyl 2-[2-(2,4-Dinitrophenyl)hydrazono]-1-(2-oxo-2-phenylethyl)-
cyclohexanecarboxylate (6w): 2,4-Dinitrophenylhydrazine 5i
(151 mg, 690 μmol) and TFA (47 mg, 0.41 mmol) were added to a
solution of 1,4-diketone 1b (200 mg, 690 μmol) in THF (2.4 mL)
and the resulting reaction mixture was stirred for 3 h under reflux.
After removal of all volatile materials in vacuo, the residue was
purified by using chromatography (SiO2, hexane/MTBE = 3:1, Rf
= 0.22) to yield hydrazone 6w (233 mg, 500 μmol, 72 %) as an
orange solid. M.p. 75 °C. 1H NMR (500 MHz, CDCl3): δ = 1.30
(t, J = 7.1 Hz, 3 H), 1.47–1.56 (m, 1 H), 1.58–1.66 (m, 1 H), 1.78–
1.84 (m, 2 H), 2.05–2.08 (m, 1 H), 2.44–2.47 (m, 1 H), 2.74–2.86
(m, 2 H), 3.35 (d, J = 16.7 Hz, 1 H), 3.80 (d, J = 16.7 Hz, 1 H),
4.23–4.36 (m, 2 H), 6.86 (d, J = 9.6 Hz, 1 H), 7.52–7.55 (m, 3 H),
7.68 (t, J = 7.4 Hz, 1 H), 8.03 (d, J = 7.5 Hz, 2 H), 8.98 (d, J =
2.5 Hz, 1 H), 11.20 (s, 1 H) ppm. 13C{1H} NMR (125 MHz,
CDCl3): δ = 14.58 (CH3), 22.37 (CH2), 26.09 (CH2), 26.32 (CH2),
38.57 (CH2), 45.71 (CH2), 54.50 (C), 62.02 (CH2), 116.45 (CH),
123.73 (CH), 128.64 (2 CH), 129.36 (2 CH), 129.59 (C), 129.75
(CH), 133.98 (CH), 137.26 (C), 138.09 (C), 145.34 (C), 158.95 (C),
(ATR): ν = 2979 (w), 2931 (w), 2865 (w), 1733 (s), 1714 (s), 1710
˜
(s), 1451 (m), 1385 (m), 1364 (m), 1300 (m), 1252 (m), 1220 (s),
1197 (m), 1106 (m), 1003 (m), 746 (m), 693 (m), 632 (s) cm–1
.
HRMS (CI, isobutane): calcd. for C16H18O5 [M + H+] 291.1232;
found 291.1227. C16H19O5 (290.31): calcd. C 66.19, H 6.25; found
C 66.19, H 6.39.
Methyl 4-Oxo-3-(2-oxo-2-phenylethyl)tetrahydro-2H-thiopyran-3-
carboxylate (1i): Following the procedure given for compound 1g,
oxo ester 10i (300 mg, 1.72 mmol), phenacyl bromide (11a; 376 mg,
1.89 mmol) and K2CO3 (261 mg, 1.89 mmol) were reacted in ace-
tone (3.5 mL). Chromatography (SiO2, hexane/MTBE = 1:1, Rf =
0.38) gave 1,4-diketone 1i (248 mg, 0.850 mmol, 49%) as a yellow-
1
ish solid. M.p. 86 °C. H NMR (500 MHz, CDCl3): δ = 2.80–2.88
(m, 2 H), 2.97–3.09 (m, 2 H), 3.26 (s, 2 H), 3.50 (A-part of an AB-
system, J = 17.3 Hz 1 H), 3.61 (B-part of an AB-system, J =
17.3 Hz, 1 H), 3.75 (s, 3 H), 7.40 (t, J = 7.7 Hz, 2 H), 7.51 (t, J =
7.3 Hz, 1 H), 7.88 (d, J = 7.8 Hz, 2 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 29.78 (CH2), 37.62 (CH2), 41.96 (CH2),
42.64 (CH2), 52.71 (CH3), 60.68 (C), 127.89 (2 CH), 128.47 (2 CH),
133.24 (CH), 136.26 (C), 171.31 (C), 196.06 (C), 204.25 (C) ppm.
174.11 (C), 197.06 (C) ppm. IR (ATR): ν = 3323 (w), 2941 (w),
˜
2865 (w), 1727 (m), 1688 (m), 1618 (s), 1591 (m), 1517 (m), 1504
(m), 1334 (s), 1312 (m), 1221 (m), 1198 (m), 1137 (m), 763 (m), 744
(m), 630 (s) cm–1. HRMS (ESI): calcd. for C23H24N4NaO7 [M +
Na+] 491.1543; found 491.1542.
IR (ATR): ν = 3002 (w), 2968 (w), 2951 (w), 2931 (w), 1734 (s),
˜
1706 (s), 1596 (m), 1448 (m), 1430 (m), 1418 (m), 1364 (m), 1317
(m), 1291 (m), 1208 (s), 1136 (m), 1130 (m), 1004 (m), 968 (m),
779 (m), 754 (m), 691 (m) cm–1. HRMS (CI, isobutane): calcd. for
C15H17O4S [M + H+] 293.0848; found 293.0840.
1-Benzyl 3-Methyl 4-Oxo-3-(2-oxo-2-phenylethyl)pyrrolidine-1,3-di-
carboxylate (1g): Phenacyl bromide (105 mg, 530 μmol) and K2CO3
(73 mg, 0.53 mmol) were added to a solution of β-oxo ester 10g
(134 mg, 480 μmol) in acetone (1 mL) and the resulting mixture
1-tert-Butyl 3-Methyl 4-Oxo-3-(2-oxo-2-phenylethyl)piperidine-1,3-
dicarboxylate (1j): Following the procedure given for compound 1g,
Eur. J. Org. Chem. 2013, 389–400
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
397

M. Penning, J. Christoffers
FULL PAPER
oxo ester 10j (1.15 g, 4.47 mmol), phenacyl bromide (11a; 979 mg,
4.92 mmol) and K2CO3 (680 mg, 4.92 mmol) were reacted in acet-
one (14 mL). Chromatography (SiO2, hexane/MTBE = 2:1, Rf =
0.14) gave 1,4-diketone 1j (1.24 g, 3.31 mmol, 74%) as a colorless
Ethyl 1-[2-(4-Bromophenyl)-2-oxoethyl]-2-oxocyclohexanecarboxyl-
ate (1m): NaH (60% in mineral oil, 57 mg, 1.4 mmol) and 4-bromo-
phenacyl bromide (11m; 395 mg, 1.42 mmol) were added at 60 °C
to a solution of oxo ester 10b (200 mg, 1.18 mmol) in THF
(1.2 mL) and the reaction mixture was stirred at this temperature
for 17 h. Then water (5 mL) and brine (5 mL) were added and the
mixture was extracted with MTBE (3ϫ10 mL). The combined or-
ganic extracts were dried (MgSO4), filtered and the solvent was
1
solid. M.p. 45 °C. H NMR (500 MHz, CDCl3): δ = 1.40 (s, 9 H),
2.60 (d, J = 14.9 Hz, 1 H), 2.84–2.97 (m, 1 H), 3.44–3.79 (m, 4 H),
3.72 (s, 3 H), 4.15 (s, 1 H), 4.34–4.50 (m, 1 H), 7.44 (t, J = 7.1 Hz,
2 H), 7.56 (t, J = 7.0 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 2 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 28.47 (3 CH3), 39.51 removed in vacuo. Chromatography (SiO2, hexane/MTBE = 5:1, Rf
(CH2), 41.12 (CH2), 42.69 (CH2), 50.02 (CH2), 53.08 (CH3), 58.56 = 0.23) yielded 1,4-diketone 1m (191 mg, 520 μmol, 44%) as a yel-
(C), 80.72 (C), 128.32 (2 CH), 128.88 (2 CH), 133.77 (CH), 136.44
(C), 154.46 (C), 171.03 (C), 196.22 (C), 204.60 (C) ppm. IR (ATR): H), 1.71–1.83 (m, 4 H), 2.04–2.08 (m, 1 H), 2.42–2.45 (m, 1 H),
low oil. 1H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 3
ν = 2977 (w), 2954 (w), 2932 (w), 1737 (m), 1686 (s), 1424 (m), 2.47–2.52 (m, 1 H), 2.80–2.87 (m, 1 H), 3.29 (d, J = 17.3 Hz, 1 H),
˜
1366 (m), 1295 (m), 1249 (m), 1220 (m), 1157 (s), 1132 (m), 1000 3.47 (d, J = 17.3 Hz, 1 H), 4.17–4.27 (m, 2 H), 7.57 (d, J = 8.6 Hz,
(m), 756 (m), 739 (m), 690 (m) cm–1. HRMS (ESI): calcd. for
C20H25NNaO6 [M + Na+] 398.1580; found 398.1570.
2 H), 7.79 (d, J = 8.6 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz,
CDCl3): δ = 14.03 (CH3), 21.98 (CH2), 26.84 (CH2), 36.90 (CH2),
40.52 (CH2), 43.87 (CH2), 59.06 (C), 61.60 (CH2), 128.25 (C),
129.59 (2 CH), 131.83 (2 CH), 135.56 (C), 171.94 (C), 196.04 (C),
1-Benzyl 3-Methyl 4-Oxo3-(2-oxo-phenylethyl)piperidine-1,3-dicarb-
oxylate (1k): Following the procedure given for compound 1g, oxo
ester 10k (524 mg, 1.80 mmol), phenacyl bromide (11a; 384 mg,
1.98 mmol) and K2CO3 (274 mg, 1.98 mmol) were reacted in ace-
tone (3.6 mL). Chromatography (SiO2, hexane/MTBE = 1:1, Rf =
0.25) gave 1,4-diketone 1k (517 mg, 1.26 mmol, 70%) as a colorless
oil. A double set of broad signals is observed due to E/Z-isomers
207.30 (C) ppm. IR (ATR): ν = 2939 (w), 2865 (w), 1728 (m), 1708
˜
(s), 1687 (s), 1585 (m), 1397 (m), 1215 (s), 1193 (s), 1133 (m), 1071
(s), 1006 (m), 626 (m) cm–1. HRMS (CI, isobutane): calcd. for
C17H20BrO4 [M + H+] 367.0545; found 367.0540.
Ethyl 1-[2-(4-Nitrophenyl)-2-oxoethyl]-2-oxocyclohexanecarboxylate
(1n): Following the procedure given for compound 1g, oxo ester
10b (500 mg, 2.94 mmol), 4-nitrophenacyl bromide (11n; 1.43 g,
1
(ratio 1.0:0.62) at the carbamate C–N bond. H NMR (500 MHz,
CDCl3): δ = 2.64 (d, J = 15.6 Hz, 2 H), 2.89–2.99 (m, 2 H), 3.44–
3.48 (m, 3 H), 3.54–3.58 (m, 8 H), 3.64–3.72 (m, 2 H), 3.81 (d, J 5.88 mmol) and K2CO3 (813 mg, 5.88 mmol) were reacted in ace-
= 17.8 Hz, 1 H), 4.29–4.33 (m, 2 H), 4.46–4.57 (m, 2 H), 5.05–5.19 tone (6 mL). Chromatography (SiO2, hexane/MTBE = 3:1, Rf =
(m, 4 H), 7.31–7.35 (m, 10 H), 7.44 (t, J = 7.6 Hz, 4 H), 7.57 (t, J
0.16) gave 1,4-diketone 1n (122 mg, 370 μmol, 13%) as a yellowish
= 7.3 Hz, 2 H), 7.86–7.90 (m, 4 H) ppm. 13C{1H} NMR (125 MHz, oil. 1H NMR (500 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H),
CDCl3), major conformer: δ = 38.91 (CH2), 40.96 (CH2), 42.85 1.69–1.83 (m, 4 H), 2.07–2.13 (m, 1 H), 2.43–2.51 (m, 2 H), 2.85–
(CH2), 49.53 (CH2), 52.67 (CH3), 57.77 (C), 67.49 (CH2), 127.62 2.93 (m, 1 H), 3.29 (d, J = 17.2 Hz, 1 H), 3.49 (d, J = 17.2 Hz, 1
(2 CH), 127.91 (CH), 128.08 (2 CH), 128.43 (2 CH), 128.57 (2 CH), H), 4.22–4.28 (m, 2 H), 8.07 (d, J = 8.7 Hz, 2 H), 8.28 (d, J =
133.53 (CH), 135.92 (C), 136.04 (C), 154.85 (C), 170.58 (C), 196.00 8.7 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 14.48
(C), 203.67 (C) ppm; minor conformer: δ = 39.13 (CH2), 41.27 (CH3), 22.37 (CH2), 27.40 (CH2), 37.70 (CH2), 40.95 (CH2), 44.69
(CH2), 42.85 (CH2), 49.87 (CH2), 52.79 (CH3), 57.43 (C), 67.49 (CH2), 60.05 (C), 62.21 (CH2), 124.22 (2 CH), 129.51 (2 CH),
(CH2), 127.62 (2 CH), 127.91 (CH), 128.08 (2 CH), 128.43 (2 CH), 141.89 (C), 150.70 (C), 172.24 (C), 196.20 (C), 207.73 (C) ppm. IR
128.57 (2 CH), 133.53 (CH), 135.92 (C), 136.37 (C), 155.08 (C), (ATR): ν = 2941 (w), 2868 (w), 1730 (m), 1697 (s), 1605 (w), 1526
˜
170.74 (C), 196.27 (C), 203.87 (C) ppm. IR (ATR): ν = 3065 (w),
3031 (w), 2953 (w), 1737 (m), 1695 (s), 1473 (w), 1447 (m), 1430
(s), 1347 (s), 1318 (m), 1214 (m), 1197 (m), 1013 (m), 856 (m), 633
˜
(m) cm–1. HRMS (CI, isobutane): calcd. for C17H20NO6 [M + H+]
(m), 1355 (w), 1293 (m), 1277 (m), 1248 (m), 1217 (s), 1127 (m), 334.1291; found 334.1294.
999 (m), 909 (m), 755 (m), 737 (m), 691 (m), 643 (m), 609 (m) cm–1.
HRMS (CI, isobutane): calcd. for C23H24NO6 [M + H+] 410.1604;
found 410.1593.
Ethyl 1-[2-(2,4-Dimethoxyphenyl)-2-oxoethyl]-2-oxocyclohexane-
carboxylate (1o): Following the procedure given for compound 1g,
oxo ester 10b (90 mg, 0.53 mmol), 2,4-dimethoxyphenacyl bromide
(11o; 150 mg, 580 μmol) and K2CO3 (80 mg, 0.58 mmol) were re-
acted in acetone (1.1 mL). Chromatography (SiO2, hexane/MTBE
= 2:1, Rf = 0.20) gave 1,4-diketone 1o (86 mg, 0.25 mmol, 47%) as
a colorless solid. M.p. 83 °C. 1H NMR (500 MHz, CDCl3): δ =
1.23 (t, J = 7.1 Hz, 3 H), 1.71–1.83 (m, 4 H), 2.00–2.05 (m, 1 H),
2.37–2.41 (m, 1 H), 2.47–2.50 (m, 1 H), 2.76–2.83 (m, 1 H), 3.39
(A-part of an AB-system, J = 18.2 Hz, 1 H), 3.50 (B-part of an
AB-system, J = 18.2 Hz, 1 H), 3.82 (s, 3 H), 3.86 (s, 3 H), 4.14–
Ethyl 1-[2-(4-Methoxyphenyl)-2-oxoethyl]-2-oxocyclohexanecarbox-
ylate (1l): Following the procedure given for compound 1g, oxo
ester 10b (1.00 g, 5.88 mmol), 4-methoxyphenacyl bromide (11l;
1.62 g, 7.06 mmol) and K2CO3 (976 mg, 7.06 mmol) were reacted
in acetone (12 mL). Chromatography (SiO2, hexane/MTBE = 2:1,
Rf = 0.23) gave 1,4-diketone 1l (1.01 g, 3.16 mmol, 54%) as a yel-
1
lowish oil. H NMR (500 MHz, CDCl3): δ = 1.24 (t, J = 7.1 Hz, 3
H), 1.74–1.83 (m, 4 H), 2.04–2.06 (m, 1 H), 2.41–2.45 (m, 1 H),
2.50–2.53 (m, 1 H), 2.75–2.82 (m, 1 H), 3.35 (d, J = 17.3 Hz, 1 H), 4.25 (m, 2 H), 6.41 (d, J = 1.4 Hz, 1 H), 6.49 (dd, J = 1.7, J =
3.50 (d, J = 17.3 Hz, 1 H), 3.84 (s, 3 H), 4.16–4.25 (m, 2 H), 6.90
8.8 Hz, 1 H), 7.78 (d, J = 8.7 Hz, 1 H) ppm. 13C{1H} NMR
(d, J = 8.6 Hz, 2 H), 7.91 (d, J = 8.6 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 14.49 (CH3), 22.44 (CH2), 27.22 (CH2),
(125 MHz, CDCl3): δ = 14.01 (CH3), 22.00 (CH2), 26.71 (CH2), 37.04 (CH2), 41.00 (CH2), 49.58 (CH2), 55.89 (CH3), 55.94 (CH3),
36.58 (CH2), 40.51 (CH2), 43.68 (CH2), 55.43 (CH3), 58.75 (C),
61.44 (CH2), 113.62 (2 CH), 129.86 (C), 130.30 (2 CH), 163.48 (C),
59.50 (C), 61.65 (CH2), 98.68 (CH), 105.55 (CH), 121.20 (C),
133.28 (CH), 161.23 (C), 164.92 (C), 172.95 (C), 196.90 (C), 208.13
172.08 (C), 195.42 (C), 207.40 (C) ppm. IR (ATR): ν = 2938 (w),
(C) ppm. IR (ATR): ν = 2977 (w), 2955 (w), 2932 (w), 2863 (w),
˜
˜
2865 (w), 2842 (w), 1728 (m), 1710 (s), 1679 (m), 1600 (s), 1510
1730 (m), 1702 (m), 1666 (m), 1311 (m), 1298 (m), 1257 (m), 1221
(m), 1312 (m), 1260 (m), 1223 (s), 1170 (s), 1027 (m), 631 (s) cm–1. (m), 1210 (m), 1177 (s), 1136 (s), 1127 (s), 1074 (m), 1025 (m), 842
HRMS (CI, isobutane): calcd. for C18H23O5 [M + H+] 319.1545;
found 319.1538.
(m) cm–1. HRMS (CI, isobutane): calcd. for C19H25O6 [M + H+]
349.1651; found 349.1649.
398
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 389–400

Dihydropyridazine Derivatives and Annulation
1-Benzyl 3-Methyl 4-Oxopyrrolidine-1,3-dicarboxylate (10g): Meth-
ylacrylate (193 mg, 2.24 mmol) and KOtBu (276 mg, 2.46 mmol)
were added at 0 °C to a solution of carbamate 12 (500 mg,
2.24 mmol) in THF (4 mL) and the mixture was stirred at 23 °C
for 3 d. Afterwards the solvent was removed in vacuo, the residue
was dissolved in CH2Cl2 (15 mL) and the pH-value was adjusted
to 1 with hydrochloric acid (1 mol/L). The phases were separated
and the aqueous phase was extracted with CH2Cl2 (2ϫ15 mL).
The combined organic layers were dried (MgSO4), filtered and the
solvent was evaporated to yield pyrrolidine 10g (424 mg,
1.53 mmol, 68 %) after chromatography (SiO2, hexane/MTBE =
1:2, Rf = 0.16) as a colorless oil. A double signal set is observed
due to keto-enol-tautomers (ratio 1.0:0.50). 1H NMR (500 MHz,
CDCl3); ketone: δ = 3.76 (s, 3 H), 3.88–3.98 (m, 2 H), 4.07–4.11
(m, 1 H), 4.27 (s, 2 H), 5.11–5.17 (m, 2 H), 7.32–7.36 (m, 5 H) ppm;
enol: δ = 3.78 (s, 3 H), 3.88–3.98 (m, 1 H), 4.07–4.11 (m, 2 H), 4.27
(s, 1 H), 5.11–5.17 (m, 2 H), 7.32–7.36 (m, 5 H), 10.01 (s, 1 H) ppm.
13C{1H} NMR (125 MHz, CDCl3), ketone: δ = 48.54 (CH2), 50.94
(CH2), 51.45 (CH), 52.85 (CH2), 67.44 (CH2), 127.86 (CH), 128.00
(2 CH), 128.41 (2 CH), 135.98 (C), 154.38 (C), 167.64 (C), 203.45
(C) ppm; enol: δ = 48.79 (CH2), 51.28 (CH2), 51.38 (CH3), 67.07
(CH2), 96.87 (C), 128.00 (2 CH), 128.20 (CH), 127.47 (2 CH),
H), 11.82 (s, 1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3), ketone:
δ = 14.09 (CH3), 42.05 (CH2), 57.87 (CH), 61.56 (CH2), 68.22
(CH2), 69.70 (CH2), 167.80 (C), 201.43 (C) ppm; enol: δ = 14.24
(CH3), 28.76 (CH2), 60.35 (CH2), 63.05 (CH2), 63.97 (CH2), 97.43
(C), 168.84 (C), 170.15 (C) ppm. IR (ATR): ν = 2980 (w), 2938
˜
(w), 2915 (w), 2856 (w), 1739 (w), 1719 (m), 1661 (s), 1628 (m),
1403 (w), 1368 (w), 1306 (s), 1285 (m), 1240 (m), 1218 (s), 1193
(m), 1100 (m), 1052 (m), 722 (w), 630 (m) cm–1. HRMS (CI, isobut-
ane): calcd. for C8H13O4 [M + H+] 173.0814; found 173.0811.
2-Bromo-1-(2,4-dimethoxyphenyl)ethanone (11o): Anhydrous AlCl3
(995 mg, 7.46 mmol) was added to a solution of 1,3-dimethoxyben-
zene (1.03 g, 7.46 mmol) in bromoacetyl bromide (1.51 g,
7.46 mmol) and the mixture was stirred for 1 h at 23 °C. Water
(20 mL) was carefully added and the aqueous phase was extracted
with EtOAc (3 ϫ 15 mL). The combined organic extracts were
washed with hydrochloric acid (40 mL, 1 mol/L), then dried
(MgSO4), filtered and the solvent was evaporated. Chromatography
[hexane/MTBE = 10:1, then 3:1, Rf(hexane/MTBE = 10:1) = 0.11]
gave phenacyl bromide 11o (666 mg, 2.57 mmol, 34%) as a color-
1
less solid. M.p. 103 °C. H NMR (500 MHz, CDCl3): δ = 3.85 (s,
3 H), 3.91 (s, 3 H), 4.55 (s, 2 H), 6.44 (d, J = 2.2 Hz, 1 H), 6.55
(dd, J = 2.2, J = 8.8 Hz, 1 H), 7.89 (d, J = 8.8 Hz, 1 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 37.97 (CH2), 55.62 (CH3),
55.70 (CH3), 98.23 (CH), 105.85 (CH), 117.84 (C), 133.82 (CH),
136.34 (C), 154.29 (C), 166.80 (C), 167.50 (C) ppm. IR (ATR): ν =
˜
3274 (m, br.), 2956 (w), 2934 (w), 2891 (w), 2869 (w), 1699 (s), 1682
(s), 1641 (m), 1456 (m), 1425 (m), 1365 (m), 1329 (m), 1224 (m),
1217 (m), 1121 (s), 1045 (m), 767 (m), 730 (s), 690 (m) cm–1. HRMS
(CI, isobutane): calcd. for C14H16NO5 [M + H+] 278.1028; found
278.1022.
160.88 (C), 165.37 (C), 190.16 (C) ppm. IR (ATR): ν = 3013 (w),
˜
2979 (w), 2948 (w), 1661 (s), 1596 (m), 1574 (m), 1453 (m), 1334
(m), 1275 (s), 1212 (m), 1182 (s), 1112 (m), 1020 (s), 992 (m), 828
(m), 633 (m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 258 (5) [M+],
165 (100), 137 (4), 121 (8), 106 (9), 77 (12).
Diethyl 3,3Ј-Oxydipropanoate (14): EtOH (1.49 g, 32.4 mmol) and
conc. H2SO4 (128 mg, 1.30 mmol) were added to a solution of acid
13 (1.05 g, 6.48 mmol) in CHCl3 (30 mL) and the mixture was
stirred for 20 h in an inverse Dean–Stark trap under reflux. The
organic phase was washed with water (20 mL) and brine (20 mL)
and then dried (MgSO4), filtered and evaporated to yield ester 14
(705 mg, 3.23 mmol, 50 %) after chromatography (SiO2, hexane/
MTBE = 2:1, Rf = 0.35) as a colorless oil. 1H NMR (500 MHz,
CDCl3): δ = 1.23 (t, J = 7.1 Hz, 6 H), 2.53 (t, J = 6.4 Hz, 4 H),
3.69 (t, J = 6.4 Hz, 4 H), 4.11 (q, J = 7.1 Hz, 4 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 14.15 (2 CH3), 35.01 (2 CH2), 60.46
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C{1H} NMR spectra of all products.
Acknowledgments
The authors are grateful to B. Sc. Alexandra Schischko for prelimi-
nary experiments and Dr. Herbert Frey for helpful discussions.
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(2 CH ), 66.33 (2 CH ), 171.48 (2 C) ppm. IR (ATR): ν = 2982
˜
2
2
(w), 2935 (w), 2905 (w), 2876 (w), 1731 (s), 1373 (m), 1258 (m),
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Ethyl 4-Oxotetrahydro-2H-pyran-3-carboxylate (10h): nBuLi
(1.6 mol/L hexane, 16.5 mL, 26.4 mmol) was added at –78 °C under
an inert atmosphere (N2) to a solution of anhydrous iPr2NH
(2.67 g, 26.4 mmol) in absolute THF (24 mL) and afterwards the
mixture was stirred at 0 °C for 15 min. This solution was then
added at –78 °C to a solution of diester 14 (2.95 g, 13.5 mmol) in
absolute THF (36 mL) and stirring was continued for 15 min. After
warming to ambient temperature, water (40 mL), hydrochloric acid
(100 mL, 1 mol/L) and hexane (40 mL) were added and the layers
were separated. The aqueous phase was extracted with EtOAc
(3 ϫ 50 mL) and the combined organic extracts were dried
(MgSO4), filtered and the solvent was evaporated to yield β-oxo
ester 10h (422 mg, 2.45 mmol, 18%) after chromatography (SiO2,
hexane/MTBE = 5:1, Rf = 0.38) as a colorless liquid. A double
signal set is observed owing to keto-enol-tautomers (ratio 0.30:1.0).
1H NMR (500 MHz, CDCl3), ketone: δ = 1.27 (t, J = 7.1 Hz, 3 H),
2.50–2.55 (m, 1 H), 2.63–2.68 (m, 1 H), 3.44 (t, J = 5.9 Hz, 1 H),
3.93–4.01 (m, 2 H), 4.07 (dd, J = 11.6 Hz, J = 4.9 Hz, 1 H) 4.18–
4.22 (m, 3 H) ppm; enol: δ = 1.27 (t, J = 7.1 Hz, 3 H), 2.35–2.37
(m, 2 H), 3.82 (t, J = 5.5 Hz, 2 H), 4.18–4.22 (m, 2 H), 4.25 (s, 2
Eur. J. Org. Chem. 2013, 389–400
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
399

M. Penning, J. Christoffers
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Received: August 27, 2012
Published Online: November 26, 2012
400
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Eur. J. Org. Chem. 2013, 389–400