Lewis Acid Catalyzed Annulation of Cyclopropane Carbaldehydes and Aryl Hydrazines: Construction of Tetrahydropyridazines and Application Toward a One-Pot Synthesis of Hexahydropyrrolo[1,2- b]pyridazines

Article abstract of DOI:10.1021/acs.joc.8b00332

In this report, a facile synthesis of tetrahydropyridazines via a Lewis acid catalyzed annulation reaction of cyclopropane carbaldehydes and aryl hydrazines has been demonstrated. Moreover, the generated tetrahydropyridazine further participated in a cycloaddition reaction with donor-acceptor cyclopropanes to furnish hexahydropyrrolo[1,2-b]pyridazines. We also performed these two steps in one pot in a consecutive manner. In addition, a monodecarboxylation reaction of hexahydropyrrolo[1,2-b]pyridazine was achieved with a good yield.

Full text of DOI:10.1021/acs.joc.8b00332

Subscriber access provided by Kaohsiung Medical University
Lewis acid Catalyzed Annulation of Cyclopropane Carbaldehydes and
Aryl Hydrazines: Construction of Tetrahydropyridazines and Application
Towards One-pot Synthesis of Hexahydropyrrolo[1,2-b]pyridazines
Raghunath Dey, Pankaj Kumar, and Prabal Banerjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00332 • Publication Date (Web): 25 Apr 2018
Downloaded from http://pubs.acs.org on April 25, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Lewis acid Catalyzed Annulation of Cyclopropane Carbaldehydes and Aryl
Hydrazines: Construction of Tetrahydropyridazines and Application Towards
One-pot Synthesis of Hexahydropyrrolo[1,2-b]pyridazines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Raghunath Dey, Pankaj Kumar and Prabal Banerjee*
Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road,
Rupnagar, Punjabꢀ140001, India.
Abstract
In this report, a facile synthesis of tetrahydropyridazines via Lewis acid catalyzed
annulation reaction of cyclopropane carbaldehydes and aryl hydrazines has been
demonstrated. Moreover, the generated tetrahydropyridazine further participated in
cycloaddition
hexahydropyrrolo[1,2ꢀb]pyridazines. We also performed these two steps in one pot in a
consecutive manner. In addition, monodecarboxylation reaction of
reaction
with
donorꢀacceptor
cyclopropanes
to
furnish
a
hexahydropyrrolo[1,2ꢀb]pyridazine was achieved with a good yield.
Introduction.
Nitrogenꢀcontaining heterocycles are coveted structural frameworks, present in
numerous molecules of biological importance.1 In this regard, tetrahydropyridazines and
hydropyrrolo[1,2ꢀb]pyridazines are of particular interest. Bemoradan acts as a
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 46
1
2
3
4
5
6
7
8
9
cardiotonic agent and RWJ25333 shows affinity towards PR binding of human bone
cell, are the representative examples of the molecule carrying tetrahydropyridazine as a
core cyclic structural motif (Figure 1).2 Tetrahydropyrrolo[1,2ꢀb]pyridazine, having
antimicrobial activity is the example of molecule which poses hydropyrrolo[1,2ꢀ
b]pyridazine moiety.3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Tetrahydropyridazine and hydropyrrolo[1,2ꢀb]pyridazine present in bioꢀactive
molecules.
Consequently, the development of an efficient route to synthesize these structural
motifs using readily accessible starting materials is of greater interest.
In this regard, due to convenient preparation, easy handling, and inevitable reactivity,
cyclopropanes have extensively been used as versatile building blocks in organic
syntheses for construction of diverse carbocycles, heterocycles, and functionalized
openꢀchain compounds.4 Among various cyclopropane derivatives, Lewis acid
catalyzed reactions of donorꢀacceptor cyclopropanes (DAC) have been studied widely.5
Whereas, cyclopropane carbaldehydes have been used for organocatalyzed ring
opening reactions.6 But the Lewis acid catalyzed reaction of cyclopropane
carbaldehydes are scared. The annulation of cyclopropane carbaldehyde and phenyl
2
ACS Paragon Plus Environment

Page 3 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
hydrazine hydrochloride was studied firstly by Kawaken Fine Chemicals Co. in 1984
(Scheme 1 A)7 and tryptamines were formed as the sole product.
7
8
9
Scheme 1. Reactivity of cyclopropyl ketone/cyclopropane carbaldehyde with phenyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
hydrazine
In 1987, Robinson et al. documented that, in the presence of dry HCl in refluxing
methanol, cyclopropyl ketone and phenyl hydrazine react to afford a mixture of 1,3ꢀ
diphenylꢀ1,4,5,6ꢀtetrahydropyridazine (26% yield) and 2ꢀphenylꢀ3ꢀ(2ꢀchloroethyl) indole
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 46
1
2
3
4
5
6
7
8
9
(17% yield).8 Following these reports, Tomilov et al. demonstrated two complementary
reaction conditions, in refluxing acetonitrile, cyclopropyl ketone and phenyl hydrazine
hydrochloride react to produce tryptamines as the major product along with the
formation of trace amount tetrahydropyridazine.9 Whereas, in the presence of NH4I at
reflux in acetonitrile, cyclopropyl ketone and phenyl hydrazine hydrochloride react to
furnish a mixture of tetrahydropyridazine and tryptamine.10 In the second case, product
ratio varies from substrate to substrate, in some cases, tetrahydropyridazine became
the major product and in some instances tryptamines produced as the primary product.
In all of these reports, reaction proceeds through ring opening of cyclopropyl hydrazone
by halide ion, following the ring closing and Fischer rearrangement of the ringꢀopened
intermediate, tetrahydropyridazine and tryptamines were formed respectively. To the
best of our knowledge, there is no report about the formation of tetrahydropyridazine as
the exclusive product. Keeping these reactivities in mind, we anticipated that through
imine activation by Lewis acid, cyclopropyl hydrazone would undergo selectively ring
opening by αꢀNitrogen to deliver tetrahydropyridazine as the sole product rather than
ring opening by halide ion and Fischer rearrangement towards the formation of a
mixture of tetrahydropyridazine and tryptamine.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Herein, we report a Lewis acid catalyzed annulation of cyclopropane carbaldehydes and
aryl hydrazines to furnish tetrahydropyridazines as the exclusive product along with a
broad substrate scope. The produced tetrahydropyridazines undergo Lewis acid
catalyzed [3+2]ꢀcycloaddition reaction with DACs to delivered hexahydropyrrolo[1,2ꢀ
b]pyridazines, a biologically important structural frameworks (Scheme 1 B).
4
ACS Paragon Plus Environment

Page 5 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Result and Discussion: At the outset of our investigation, pꢀmethoxyꢀsubstituted
phenyl ring containing cyclopropane carbaldehyde (1a) and phenyl hydrazine (2a) were
taken as model substrates to identify the optimal conditions for this annulation reaction
(Table 1). Table 1. Lewis acid catalyzed annulation of cyclopropane carbaldehyde and
aryl hydrazine: optimization of reaction conditionsa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
Lewis
acid
LA
[mol%]
-
yield time
[%]b (h)
n.p.c 48
1
2
-
MgI2
20
20
20
20
20
20
20
20
20
59
47
69
74
73
56
55
63
74
10
06
4.5
05
05
08
08
07
05
3
Bi(OTf)3
Yb(OTf)3
BF3.OEt2
TiCl4
4
5
6
7
Cu(OTf)2
Sc(OTf)3
Sn(OTf)2
InCl3
8
9
10
aReactions were carried out with 1 equiv of 1a and 1
equiv of 2a in the presence molecular sieves (4 Å) in
dichloromethane solvent. bIsolated yield. cn.p. = no
product formation.
Consistent knowledge gained from the success of our previous study on the reactivity of
cyclopropanes and other strained rings,11 drive us to start this optimization survey in
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 46
1
2
3
4
5
6
7
8
9
dichloromethane solvent. Extensive screening of commercially available Lewis acids
(Table 1) elucidated that most of them could able to catalyze this annulation reaction.
To our satisfaction, 20 mol% InCl3 or BF3.OEt2 as a catalyst furnished the desired
product in 74% yield. Among them, for easy handling, InCl3 was picked as the catalyst
of choice. It is important to note that absence of a Lewis acid inhibited the formation of
the desired product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With the optimized conditions in hand, we probed the scope and limitation of this
annulation reaction with various cyclopropane carbaldehydes and aryl hydrazines, and
the obtained results are summarized in Table 2. Cyclopropane carbaldehyde bearing 4ꢀ
methoxyphenyl, phenyl and 4ꢀfluorophenyl ring in it’s vicinal position (1a, 1c, and 1d)
provided the good yield. Whereas cyclopropane carbaldehyde carrying 3,4ꢀdimethoxyꢀ
substituted phenyl ring (1b) leads to lowering the yield as well as the reaction time,
perhaps this is due to the high electron donating capability of two methoxy substituents
which making the cyclopropane carbaldehyde more active, thus susceptible to
decomposition. A naphthylꢀsubstituted and a heterocycle incorporated cyclopropane
carbaldehyde (1e, 1f) were also efficiently transformed into the expected product. To
explore the scope of aryl hydrazines in the mentioned annulation reaction, we employed
a series of aryl hydrazines bearing differently substituted phenyl ring. To our delight,
hydrazine derivative bearing electron donatingꢀsubstituted phenyl ring like tolyl and 4ꢀ
isopropyl phenyl hydrazine (2f, 2g) gave higher yield. Whereas, 4ꢀmethoxy phenyl
hydrazine (2h) furnished the desired product with a poor yield. This may be due to the
high electron donating capability of methoxy substituent; activated phenyl ring
undergoes in diverse reaction towards formation of some undesired product. Hydrazine
6
ACS Paragon Plus Environment

Page 7 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
derivative bearing electron withdrawing substituted phenyl ring like 4ꢀchloro, 4ꢀbromo
and 4ꢀcyano phenylhydrazine (2c, 2d, 2e) render the corresponding annulated product
with reduced yield along with a longer reaction time. The reason may be the electron
withdrawing ability of those substituent (choro, bromo, and cyano) making
corresponding aryl hydrazine less reactive. A benzyl containing hydrazine derivative (2i)
was also efficiently converted into
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Lewis acid catalyzed annulation of cyclopropane carbaldehyde and aryl
hydrazine: substrate scopea
entry
Ar1
Ar2
time yield
(h)
1
2
[%] b
74
4-methoxy phenyl
3,4-dimethoxy phenyl
phenyl
phenyl
phenyl
05
3aa 1a
3ba 1b
3ca 1c
3da 1d
3ea 1e
3fa 1f
3ab 1a
3ac 1a
3ad 1a
3ae 1a
3af 1a
3ag 1a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
04
05
05
05
4.5
05
06
06
08
4.5
4.5
57
75
71
57
68
70
64
62
56
75
75
phenyl
4-fluoro phenyl
1-napthyl
phenyl
phenyl
2-furyl
phenyl
4-methoxy phenyl
4-methoxy phenyl
4-methoxy phenyl
4-methoxy phenyl
4-methoxy phenyl
4-methoxy phenyl
4-fluoro phenyl
4-chloro phenyl
4-bromo phenyl
4-cyano phenyl
tolyl
4-isopropyl phenyl
2g
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 46
1
2
3
4
5
6
4-methoxy phenyl
4-methoxy phenyl
4-methoxy phenyl
benzyl
11
06
42
67
3ah 1a
3ai 1a
2h
2i
7
8
9
aUnless otherwise specified, all reactions were carried out in DCM at rt with 1 equiv of 1 and
1 equiv of 2 in presence of InCl3 (20 mol %) and 4 Å molecular sieves (200 weight %).
Isolated yields are reported.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
the desired product. In order to emphasize the generous applicability of the protocol,
we synthesize annulated product 3aa in gramꢀscale (starting with 1.50 g of 1a, 3aa was
obtained in 68% yield) under the same optimize conditions. To elucidate whether both
isomers (cis and trans) of cyclopropane carbaldehyde can be utilized as the efficient
substrates, we did the control experiment with cis 2ꢀphenylcyclopropanecarbaldehyde
(1c’) (scheme 2), which in turn gave the desired product 3ca in a lower yield and with
longer reaction time than that of in trans 2ꢀphenylcyclopropanecarbaldehyde (1c) (Table
2, entry 3ca). Therefore, from this control experiment we conclude that in the mentioned
annulation reaction trans isomer of cyclopropane carbaldehyde is more efficient
substrate than the cis one.
Scheme 2. Control experiment with cis cyclopropane carbaldehyde
We next utilized the annulated product tetrahydropyridazine 3aa in [3+2]ꢀcycloaddition
reaction with DAC. Initially, to optimize the reaction conditions, we employed
tetrahydropyridazine 3aa and DAC 4a as model substrate (Table 3). In the beginning,
10 mol% Yb(OTf)3 was used as a catalyst, and the expected product was formed in
50% yield with 52:48 diastereomeric ratio (Table 3). Consequently, this result prompted
us to raise the loading of Yb(OTf)3 up to 20 mol%, which delivered the desired product
8
ACS Paragon Plus Environment

Page 9 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
with the best yield. Further increment of catalyst facilitated the dimerization and
decomposition of DAC, thus leads to decrease the yield of the desired cycloadduct.
However, a superficial increment of diastereomeric ratio was observed with MgI2 and
InCl3, but in both cases the yield was not satisfactory. Weak Lewis acid like Cu(OTf)2
could not catalyze the reaction, whereas strong Lewis acid like Bi(OTf)3, BF3.OEt2 and
TiCl4 provided an unidentified Table 3. Lewis acid catalyzed [3+2]ꢀcycloadditions of
tetrahydropyridazine and DAC: optimization of reaction conditionsa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
Lewis
acid
LA
[mol%]
-
solvent yield time
dre
(h) (cis:trans)
(%)b
n.r.c
1
2
-
DCM
DCM
48
06
-
MgI2
20
20
20
20
20
20
10
20
40
30
60:40
3
BF3.OEt2
TiCl4
DCM c.m.d 04
DCM c.m.d 04
-
-
4
5
Cu(OTf)2
Bi(OTf)3
InCl3
DCM
n.r.c
08
-
6
DCM c.m.d 06
-
7
DCM
DCM
DCM
DCM
40
50
65
56
07
08
05
04
60:40
52:48
52:48
52:48
8
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
9
10
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 46
1
2
3
4
5
6
aReactions were carried out with 1 equiv of 3aa and 1 equiv of 4a in presence
b
of molecular sieves (4 Å). Isolated yields. cn.r. = no reaction. dc.m. = complex
mixture. DCM = dichloromethane. edr = diastereomeric ratio was determined by
1H NMR analysis of the reaction mixture.
7
8
9
complex mixture. It is crucial to note that no reaction was taking place in the absence of
Lewis acid. The geometry of both diastereomers (cis and trans) was determined by
NOE experiment, and the geometry of the major diastereomer was further supported by
single crystal Xꢀray structure (Figure 2).13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Having developed the optimized reaction conditions, we then evaluated the substrate
scope and limitation with various DACs, and the outcomes are depicted in Table 4. DAC
(4a) bearing 3,4ꢀdimethoxyꢀsubstituted phenyl ring in it’s vicinal position delivered the
Table 4. Lewis acid catalyzed [3+2]ꢀcycloaddition of tetrahydropyridazine and DAC:
substrate scopea
entry
5a 3aa 4a
Ar
CO2R time yield
(h) [%] b (cis:trans)
drc
3
4
3,4-dimethoxy phenyl CO2Et
3,4-dimethoxy phenyl CO2Me
3,4-dimethoxy phenyl CO2Bn
05
05
05
05
08
08
10
65
63
64
65
73
68
69
52:48
-
5b
5c
5d
5e
5f
3aa 4b
3aa 4c
3aa 4d
3aa 4e
3aa 4f
3aa 4g
60:40
65:35
55:45
57:43
53:47
4-methoxy phenyl
tolyl
CO2Et
CO2Et
CO2Et
CO2Et
2- tolyl
phenyl
5g
10
ACS Paragon Plus Environment

Page 11 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
4-fluoro phenyl
2-furyl
CO2Et
CO2Et
CO2Et
12
4.5
4.5
65
62
63
50:50
67:33
70:30
5h
5i
3aa 4h
3aa 4i
3aa 4j
2-thiophenyl
5j
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aUnless otherwise specified, all reactions were carried out in DCM at rt with 1 equiv of 3
and 1 equiv of 4 in presence of Yb(OTf)3 (20 mol %) and 4 Å molecular sieves (200 weight
%). Isolated yields are reported. dr (cis:trans) was determined by H NMR analysis of
reaction mixture.
b
c
1
the cycloadduct 5a in a moderate yield along with a poor diastereomeric ratio. However,
a substantial improvement of diastereomeric ratio was observed in the case of the DAC
bearing 4ꢀmethoxyphenyl ring (4d). The DAC bearing tolyl ring (4e) gave the highest
yield. Relatively less activated DAC, like phenyl and 4ꢀfluoro phenylꢀcontaining DAC
(4g, 4h) delivered the cycloadduct with longer reaction time. oꢀTolylꢀcontaining DAC (4f)
was employed to examine the effect of orthoꢀsubstituted phenyl ring on the
cycloaddition reaction, convenient conversion into the corresponding cycloadduct (5f)
indicating the broad substrate tolerance of this methodology. To check the effect of the
size of the ester functionality in the mentioned transformation, we exposed a series of
DAC bearing different ester group (4a, 4b, 4c), but no such profound consequence was
noticed.
Scheme 3. One pot synthesis of hexahydropyrrolo[1,2ꢀb]pyridazine
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 46
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Having a series of cycloadduct in hand, we conducted these two reactions in one pot via
in situ formation of tetrahydropyridazine (3aa) and it’s cycloaddition with DAC (4e).
Notably, the desired cycloadduct (5e) was obtained in moderate yield (Scheme 3).
Moreover, to exhibit the potentiality of the developed methodology, we carried out a
Scheme 4. Monodecarboxylation of 5a
12
ACS Paragon Plus Environment

Page 13 of 46
The Journal of Organic Chemistry
1
2
3
4
monodecarboxylation reaction of 5a (Scheme 4). Upon reflux with alcoholic KOH, 5a
5
6
easily converted into corresponding monoacid 6a in good yield.12 The geometry of 6a
7
8
9
was
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Xꢀray structure of 3ba and 5a (Hydrogen atoms are omitted for the sake of
clarity).
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 46
1
2
3
4
Scheme 5. Plausible mechanism for annulation and cycloaddition reaction
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
unambiguously determined by NOE experiment. In order to clarify the observed
14
ACS Paragon Plus Environment

Page 15 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
diastereomer formation, on the basis of other literature reports and our experimental
outcomes, a plausible mechanism for both the annulation and cycloaddition reaction
has been sketched in scheme 5. Initially, cyclopropane carbaldehyde (1) and aryl
hydrazine (2) underwent a condensation reaction to form a transient cyclopropyl
hydrazone (B) (Scheme 5 A). Upon imine activation by Lewis acid, cyclopropyl
hydrazone form an activated intermediate (C), which undergoes an intramolecular
cyclization reaction via cyclopropane ring opening by αꢀNitrogen atom to give
intermediate D. Following the enamineꢀimine tautomerization into more stable imine
form, intermediate D gave desired tetrahydropyridazine 3. For cycloaddition reaction,
initially Lewis acid activates the DAC (4) to form an activated Lewis acidꢀDAC complex
E (Scheme 5 B) which undergoes a nucleophilic ring opening by imine nitrogen of
tetrahydropyridazine 3 to afford an open chain intermediate F. Upon cyclization,
intermediate F gave hexahydropyrrolo[1,2ꢀb]pyridazine (5) as the desired cycloadduct.
Cyclization can happen either through equatorial approach or axial approach. In
equatorial approach, the reaction proceeds through a more chair like TS, which is more
favored TS, thus leads to the cis isomer as a major diastereomer, whereas, in axial
approach, the reaction proceeds through a less chair like TS (disfavored TS) and leads
to the trans isomer as a minor diastereomer.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conclusion: In summary, we have developed a convenient route for the synthesis of
hexahydropyrrolo[1,2ꢀb]pyridazines via Lewis acid catalyzed annulation reactions of
cyclopropane carbaldehydes and aryl hydrazines, followed by [3+2]ꢀcycloaddition
reactions with DACs. Finally, we displayed a oneꢀstep version of the protocol by
employing annulation and cycloaddition reaction in one pot. Additionally a
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 46
1
2
3
4
5
6
7
8
9
monodecraboxylation of hexahydropyrrolo[1,2ꢀb]pyridazine has also been performed.
We believe that the developed protocol would serve as a tool for the rapid synthesis of
tetrahydropyridazine and hexahydropyrrolo[1,2ꢀb]pyridazine motifs.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental section
General information
All reactions were carried out under an inert atmosphere with ovenꢀdried glassware. All
solvents and reagents were obtained from commercial sources and were purified
following the standard procedure prior to use. Powdered molecular sieves 4 Å (MS 4 Å)
was dried at 200 °C under vacuum prior to use. The developed chromatogram was
analyzed by UV lamp (254 nm) or pꢀanisaldehyde solution. Products were purified by
flash chromatography on silica gel (mesh size 230–400). Unless otherwise specified, all
1
13
1
the H NMR and C NMR spectra were recorded in CDCl3 . Chemical shifts of H and
13C NMR spectra are expressed in parts per million (ppm). All coupling constants are
absolute values and are expressed in Hertz. The description of the signals includes the
following: s = singlet, d = doublet, dd = doublet of doublet, t = triplet, dt = doublet of
triplet, q = quartet, br = broad, and m = multiplet.
General procedure for preparation of trans-2-arylcyclopropanecarbaldehydes (for
the reaction schemes, see scheme S1 in supporting information)14
1) To a mixture of triethyl phosphonoacetate (1.1 equiv.), DBU (0.035 equiv.), and finely
ground K2CO3 (2 equiv.) was added ArCHO (1 equiv.) and the resulting mixture was
stirred using a magnetic stirrer for 4 h at room temperature under argon atmosphere.
Ethyl acetate was added to the crude mixture and the solid was filtered off. The solid
16
ACS Paragon Plus Environment

Page 17 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
was rinsed with ethyl acetate and the combined filtrate was concentrated. The resulting
oil was distilled under reduced pressure using a bulbꢀtoꢀbulb apparatus (10 mm Hg/240
°C) to give corresponding alkene (yield 84%) (E:Z = 99:1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2) A suspension of TMSOI (1.2 equiv.) and NaH (1.5 equiv.) in anhydrous DMSO (15
mL) was stirred for 1 h. A DMSO solution (14 mL) of alkene (14 mmol, 1 equiv) was
added at 0 °C. The reaction mixture was stirred at 55 °C for 24 h. Another suspension of
TMSOI (0.3 equiv.) and NaH (0.3 equiv.) in DMSO (10 mL) was added to the reaction
mixture and reaction was stirred at 65 °C for 84 h. The solution was poured into a brine
solution and extracted with ethyl acetate. Combined organic layer was washed with
water and dried over MgSO4, concentrated and purified by silica gel column to afford
corresponding cyclopropane derivative as a white solid (60ꢀ80% yield).
3) To a stirred solution of LAH (1.5 equiv.) in 7 mL diethyl ether was added dropwise a
solution of cyclopropane ester (0.90 mmol, 1equiv.) in 3 mL diethyl ether under N2
atmosphere. After addition was completed the reaction mixture was refluxed for another
6 h. The reaction mixture was then cooled to rt, and the excess LAH was destroyed by
water. 15 mL of 10% H2SO4 and 8 mL of ether was added and the aqueous layer was
extracted several times with diethyl ether. The combined organic layer was washed with
water and 5% NaHCO3, dried over MgSO4 and concentrated in a rotary evaporator (90ꢀ
95% yield). Without any further purification, the crude material (a colorless oil) was used
for next step.
4) To a solution of cyclopropane alcohol (6.8 mmol, 1 equiv.) in dry DCM (14 mL), PCC
(2 equiv.) was added in a portionꢀwise manner through a solid addition tube under N2
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 46
1
2
3
4
5
6
7
8
9
atmosphere. After 3 h reaction mixture was filtered through a small plug of celite and
concentrated in vacuo. The crude mixture was purified by silica gel column
chromatography using ethyl acetate in hexane as an eluent. Starting from aryl aldehyde
the 2ꢀarylcyclopropanecarbaldehydes was obtained in 40ꢀ50% overall yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
trans-2-(4-methoxyphenyl)cyclopropanecarbaldehyde (1a)14(e)
4ꢀmethoxybenzaldehyde (1.0 g, 7.35 mmol), 1a (0.62 g, 3.53 mmol), overall yield: 48%,
colorless crystal, in final step 1a was purified by silica gel column chromatography with
1
ethyl acetate/hexane (1:9) as eluent. H NMR (400 MHz): δ 9.30 (d, J = 4.99 Hz, 1H),
7.05 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H) 2.63ꢀ2.57 (m, 1H), 2.13ꢀ
2.07 (m, 1H), 1.73ꢀ1.67 (m, 1H), 1.51ꢀ1.46 (m, 1H).
trans-2-(3,4-dimethoxyphenyl)cyclopropanecarbaldehyde (1b)
3,4ꢀdimethoxybenzaldehyde (1.0 g, 6.02 mmol), 1b (0.53 g, 2.59 mmol), overall yield:
43%, white solid, in final step 1b was purified by silica gel column chromatography with
1
ethyl acetate/hexane (2:8) as eluent. H NMR (400 MHz): δ 9.28 (d, J = 4.5 Hz, 1H),
6.77 (d, J = 8.3 Hz, 1H), 6.65 (d, J = 8.2 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.62ꢀ2.55
13
(m, 1H), 2.13ꢀ2.06 (m, 1H), 1.71ꢀ1.65 (m, 1H), 1.51ꢀ1.46 (m, 1H). C-NMR (100 MHz):
δ 199.9, 149.1, 148.1, 131.4, 118.4, 111.3, 110.1, 56.0, 33.7, 26.6, 16.2. IR (neat):
2956, 2835, 2733, 1697, 1589, 1516, 1463, 1253, 1232, 1139, 1024, 972, 852, 761
cm˗1. HRMS (ESI, QꢀTOF) m/z: [M + H]+ Calculated for C12H15O3 207.1021, found
207.1003.
trans-2-phenylcyclopropanecarbaldehyde (1c)14(g)
18
ACS Paragon Plus Environment

Page 19 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
Benzaldehyde (1.0 g, 9.43 mmol), 1c (0.69 g, 4.72 mmol), overall yield: 50%, white
solid, in final step 1c was purified by silica gel column chromatography with ethyl
7
8
9
1
acetate/hexane (1:9) as eluent. H NMR (400 MHz): δ 9.32 (d, J = 4.5 Hz, 1H), 7.33ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7.20 (m, 3H), 7.12(d, J = 8.3 Hz, 2H), 2.66ꢀ2.60 (m, 1H), 2.21ꢀ2.15 (m, 1H), 1.77ꢀ1.71
(m, 1H), 1.51ꢀ1.46 (m, 1H).
trans-2-(4-fluorophenyl)cyclopropanecarbaldehyde (1d)6a
4ꢀfluorobenzaldehyde (1.0 g, 8.06 mmol), 1d (0.66 g, 4.03 mmol), overall yield: 50%,
white solid, in final step 1d was purified by silica gel column chromatography with ethyl
1
acetate/hexane (1:9) as eluent. H NMR (400 MHz): δ 9.32 (d, J = 4.5 Hz, 1H), 7.09ꢀ
7.05 (m, 2H), 6.98 (t, J = 8.7 Hz, 2H), 2.64ꢀ2.58 (m, 1H), 2.15ꢀ2.09 (m, 1H), 1.74ꢀ1.69
(m, 1H), 1.51ꢀ1.45 (m, 1H).
trans-2-(naphthalen-1-yl)cyclopropanecarbaldehyde (1e)
1ꢀnaphthaldehyde (1.0 g, 6.41 mmol), 1e (0.53 g, 2.69 mmol), overall yield: 42%, pale
yellow oil, in final step 1e was purified by silica gel column chromatography with ethyl
acetate/hexane (1:9) as eluent. 1H NMR (400 MHz): δ 9.54 (d, J = 8.6 Hz, 1H), 8.14 (d,
J = 8.6 Hz, 1H), 7.88 (d, J = 7.1 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.60ꢀ7.50 (m, 2H),
7.41 (t, J = 7.1 Hz, 1H), 7.29 (t, J = 7.1 Hz, 1H), 2.22ꢀ2.16 (m, 1H), 1.88ꢀ1.82 (m, 1H),
1.72ꢀ1.67 (m, 2H). 13C-NMR (100 MHz): δ 200.5, 128.7, 128.0, 126.5, 126.1, 123.7,
31.9, 24.5, 15.2. IR (neat): 3045, 2825, 2725, 1697, 1595, 1508, 1394, 1168, 1031,
1014, 933, 860, 796, 775 cm˗1. HRMS (ESI, QꢀTOF) m/z: [M + H]+ Calculated for
C14H13O 197.0966, found 197.0949.
trans-2-(furan-2-yl)cyclopropanecarbaldehyde (1f)14(e)
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 46
1
2
3
4
5
6
furanꢀ2ꢀcarbaldehyde (1.0 g, 10.41 mmol), 1f (0.64 g, 4.69 mmol), overall yield: 45%,
pale yellow oil, in final step 1f was purified by silica gel column chromatography with
7
8
9
1
ethyl acetate/hexane (1:9) as eluent. H NMR (400 MHz): δ 9.36 (d, J = 4.3 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7.27ꢀ7.25 (m, 1H), 6.30ꢀ6.28 (m, 1H), 6.10 (d, J = 3.3 Hz, 1H), 2.65ꢀ2.59 (m, 1H), 2.32ꢀ
2.26 (m, 1H), 1.69ꢀ1.64 (m, 1H), 1.62ꢀ1.56 (m, 1H).
General procedure for preparation of cis-2-phenylcyclopropanecarbaldehyde 1c’
(for the reaction scheme, see scheme S2 in supporting information)14(f), 14(g)
To a suspension of styrene (3.0 g, 28.8 mmol) and Rh2(OAc)4 (40 mg, 0.09 mmol) in
CH2Cl2 at room temperature was added ethyl diazoacetate (3.28 g, 28.8 mmol) via
syringe pump and over the course of 12 hours. Once the addition was complete, the
green mixture was stirred for another 12 hours, and then filtered through a short pad of
silica gel to afford the desired cyclopropane derivative as a mixture of diastereoisomers
(trans:cis = 60:40) in 88% yield. The mixture was separated by flash chromatography
(typical eluent, diethyl ether/pentane 2:8). The desired cis ethyl 2ꢀ phenylcyclopropane
carboxylate was obtained as a clear oil (32% yield).
The reduction of cis ethyl 2ꢀphenylcyclopropanecarboxylate to cis 2ꢀ
phenylcyclopropylmethanol, and the oxidation of cis 2ꢀphenylcyclopropylmethanol to cis
2ꢀphenylcyclopropanecarbaldehyde was carried out following the general procedure
described in the preparation of trans cyclopropanecarbaldehydes.
Styrene (1.0 g, 9.61 mmol), 1C’ (0.34 g, 2.34 mmol), overall yield: 24%, colorless oil, in
final step 1C’ was purified by silica gel column chromatography with ethyl
1
acetate/hexane (1:9) as eluent. H NMR (400 MHz): δ 8.66 (d, J = 6.6 Hz, 1H), 7.33ꢀ
20
ACS Paragon Plus Environment

Page 21 of 46
The Journal of Organic Chemistry
1
2
3
4
7.20 (m, 5H), 2.82 (q, J = 8.3, 15.9 Hz, 1H), 2.16ꢀ2.09 (m, 1H), 1.90ꢀ1.85 (m, 1H), 1.61ꢀ
5
6
1.55 (m, 1H).
7
8
9
General procedure for preparation of aryl hydrazine free bases (for the reaction
scheme, see scheme S3 in supporting information)15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Phenylhydrazine (2a) was commercially available as their free base. The other aryl
hydrazine free bases (2b-2i) were prepared by neutralization of the corresponding
commercially available hydrochloride salts according to the following procedure.
To a solution of arylhydrazine hydrochloride in water (0.5 M), K2CO3 (1.5 equiv) was
added and the mixture was stirred for 15 min at room temperature. The aqueous layer
was extracted with dichloromethane and the organic layer was dried over MgSO4 and
concentrated under reduced pressure to afford arylhydrazine as a white solid (around
90% yield).
General procedure for preparation of aryl cyclopropane-1,1-dicarboxylate
derivatives (for the reaction scheme, see scheme S4 in supporting information)16
Sodium hydride (2.5 equiv) was taken in a twoꢀneck, roundꢀbottom flask and washed
three to four times with dry hexane. Trimethylsulfoxonium iodide (2.5 equiv) was added
and the mixture suspended in anhydrous DMSO under a nitrogen atmosphere. The
mixture was cooled to 0 °C and stirred for 30 min. A solution of the appropriate
benzylidene malonate (1 equiv) in anhydrous DMSO was added, and the reaction
mixture was allowed to stir at room temperature. Upon completion of the reaction (as
determined by TLC analysis), the solution was poured into ice and extracted with diethyl
ether. The combined organic layers were washed once with brine, dried over sodium
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 46
1
2
3
4
5
6
7
8
9
sulfate, filtered and concentrated in vacuo to give the crude product, which was purified
by silica gel column chromatography with ethyl acetate/hexane as eluent. Aryl
cyclopropaneꢀ1,1ꢀdicarboxylate derivatives was obtained in 70ꢀ80% yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Diethyl 2-(3,4-dimethoxyphenyl)cyclopropane-1,1-dicarboxylate (4a)11a
Reaction time: 5 h, diethyl 2ꢀ(3,4ꢀdimethoxybenzylidene)malonate (1.0 g, 3.24 mmol),
4a (0.76 g, 2.36 mmol), yield: 73%, colorless oil, purified by silica gel column
chromatography with ethyl acetate/hexane (2:8) as eluent. 1H NMR (400 MHz): δ 6.76ꢀ
6.72 (m, 3H), 4.23 (q, J = 7.1 Hz, 2H), 3.89 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.84 (s,
3H), 3.17 (t, J = 8.5 Hz, 1H), 2.12 (dd, J = 8.3, 5.1 Hz, 1H), 1.68 (dd, J = 8.1, 5.3 Hz,
1H), 1.29 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H).
Dimethyl 2-(3,4-dimethoxyphenyl)cyclopropane-1,1-dicarboxylate (4b) 11a
Reaction time = 5 h, dimethyl 2ꢀ(3,4ꢀdimethoxybenzylidene)malonate (1.0 g, 3.56
mmol), 4b, (0.79 g, 2.68 mmol), yield: 75%, colorless solid, purified by silica gel column
chromatography with ethyl acetate/hexane (3:7) as eluent. 1H NMR (400 MHz): δ 6.77ꢀ
6.71 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.78 (s, 3H), 3.40 (s, 3H), 3.18 (t, J = 8.5 Hz,
1H), 2.15 (dd, J = 8.2, 5.0 Hz, 1H), 1.72(dd, J = 9.2, 5.0 Hz, 1H).
Dibenzyl 2-(3,4-dimethoxyphenyl)cyclopropane-1,1-dicarboxylate (4c) 11a
Reaction time = 5 h, dibenzyl 2ꢀ(3,4ꢀdimethoxybenzylidene)malonate (1.0 g, 2.31
mmol), 4c, (0.77 g, 1.73 mmol), yield: 75%, white solid, purified by silica gel column
1
chromatography with ethyl acetate/hexane (2:8) as eluent. H NMR (400 MHz): δ 7.37ꢀ
7.26 (m, 6H), 7.25ꢀ7.18 (m, 3H), 6.93 (d, J = 7.6 Hz, 1H), 6.69 (s, 3H), 5.27ꢀ5.17 (m,
22
ACS Paragon Plus Environment

Page 23 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
2H), 4.81ꢀ4.78 (m. 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.23 (t, J = 8.9 Hz, 1H), 2.19 (dd, J =
8.0, 5.0 Hz, 1H), 1.73 (dd, J = 8.9, 5.0 Hz, 1H).
7
8
9
Diethyl 2-(4-methoxyphenyl)cyclopropane-1,1-dicarboxylate (4d) 11a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reaction time = 5 h, diethyl 2ꢀ(4ꢀmethoxybenzylidene)malonate (1.0 g, 3.59 mmol), 4d,
(0.77 g, 2.64 mmol), yield: 74%, colorless oil, purified by silica gel column
1
chromatography with ethyl acetate/hexane (1:9) as eluent. H NMR (400 MHz): δ 7.12
(d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.84 (q, J = 7.1
Hz, 2H), 3.75 (s, 3H), 3.75 (s, 3H), 3.15 (t, J = 8.8 Hz, 1H), 2.19ꢀ2.11 (m, 1H), 1.68ꢀ1.65
(m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H).
Diethyl 2-(p-tolyl)cyclopropane-1,1-dicarboxylate (4e) 11a
Reaction time = 5 h, diethyl 2ꢀ(pꢀmethylbenzylidene)malonate (1.0 g, 3.81 mmol), 4e
(0.78 g, 2.82 mmol), yield: 74%, colorless oil, purified by silica gel column
1
chromatography with ethyl acetate/hexane (1:9) as eluent. H NMR (400 MHz): δ 7.10ꢀ
7.06 (m, 4H), 4.25ꢀ4.20 (m, 2H), 3.86 (q, J = 7.1 Hz, 2H), 3.17 (t, J = 8.2 Hz, 1H), 2.29
(s, 3H), 2.15ꢀ2.13 (m, 1H), 1.69ꢀ1.67 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.1
Hz, 3H).
Diethyl 2-(o-tolyl)cyclopropane-1,1-dicarboxylate (4f) 11a
Reaction time = 6 h, diethyl 2ꢀ(oꢀmethylbenzylidene)malonate (1.0 g, 3.81 mmol), 4f,
(0.73 g, 2.64 mmol), yield: 70%, colorless oil, purified by silica gel column
1
chromatography with ethyl acetate/hexane (1:9) as eluent. H-NMR (400 MHz): δ 7.16ꢀ
6.91 (m, 4H), 4.15ꢀ4.10 (m, 2H), 3.66ꢀ3.62 (m, 2H), 3.03 (t, J = 8.7 Hz, 1H), 2.24 (s,
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 46
1
2
3
4
5
6
3H), 2.16 (dd, J = 8.1, 5.0 Hz, 1H), 1.56 (dd, J = 5.0, 9.1 Hz, 1H), 1.17 (t, J = 7.1 Hz,
3H), 0.66 (t, J = 7.1 Hz, 3H).
7
8
9
Diethyl 2-phenylcyclopropane-1,1-dicarboxylate (4g) 11a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reaction time = 6 h, diethyl 2ꢀbenzylidenemalonate (1.0 g, 4.03 mmol), 4g, (0.71 g, 2.71
mmol), yield: 67%, colorless oil, purified by silica gel column chromatography with ethyl
1
acetate/hexane (1:9) as eluent. H-NMR (400 MHz): δ 7.27ꢀ7.17 (m, 5H), 4.30ꢀ4.15 (m,
2H), 3.81 (q, J = 14.3, 7.1 Hz, 2H), 3.20 (t, J = 8.7 Hz, 1H), 2.17 (dd, J = 7.8, 5.0 Hz,
1H), 1.69 (dd, J = 9.2, 5.1 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.84 (t, J = 7.3 Hz, 3H).
Diethyl 2-(4-fluorophenyl)cyclopropane-1,1-dicarboxylate (4h) 16d
Reaction time = 6 h, diethyl 2ꢀ(4ꢀfluorobenzylidene)malonate (1.0 g, 3.75 mmol), 4h,
(0.73 g, 2.60 mmol), yield: 69%, colorless oil, purified by silica gel column
1
1
chromatography with ethyl acetate/hexane (1:9) as eluent. H-NMR (400 MHz): δ Hꢀ
NMR (400 MHz): δ 7.17ꢀ7.16 (m, 2H), 6.93 (t, J = 8.6 Hz, 2H), 4.24ꢀ4.19 (m, 2H), 3.86ꢀ
3.83 (m, 2H), 3.16 (t, J = 7.9 Hz, 1H), 2.11 (dd, J = 7.7, 5.1 Hz, 1H), 1.68 (dd, J = 9.1,
8.4 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H).
Diethyl 2-(furan-2-yl)cyclopropane-1,1-dicarboxylate (4i) 11a
Reaction time = 4 h, diethyl 2ꢀ(furanꢀ2ꢀylmethylene)malonate (1.0 g, 4.20 mmol), 4i
(0.75 g, 2.98 mmol), yield: 71%, colorless oil, purified by silica gel column
1
chromatography with ethyl acetate/hexane (2:8) as eluent. H-NMR (400 MHz): δ 7.29
(br, 1H), 6.27 (dd, J = 3.2, 1.9 Hz, 1H), 6.12 (d, J = 3.2 Hz, 1H), 4.24ꢀ4.19 (m, 2H), 4.02
24
ACS Paragon Plus Environment

Page 25 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
(q, J = 14.2, 7.1 Hz, 2H), 3.08 (t, J = 8.6 Hz, 1H), 2.05 (dd, J = 7.7, 5.0 Hz, 1H), 1.77
(dd, J = 9.5, 5.0 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H).
7
8
9
Diethyl 2-(thiophen-2-yl)cyclopropane-1,1-dicarboxylate (4j)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reaction time = 5 h, diethyl 2ꢀ(thiophenꢀ2ꢀylmethylene)malonate (1.0 g, 3.93 mmol), 4j
(0.73 g, 2.72 mmol), yield: 70%, light yellow oil, purified by silica gel column
1
chromatography with ethyl acetate/hexane (2:8) as eluent. H-NMR (400 MHz): δ 7.13
(d, J = 5.1 Hz, 1H), 6.87 (dd, J = 5.2, 3.5 Hz, 1H), 6.82ꢀ6.80 (m, 1H), 4.29ꢀ4.16 (m, 2H),
3.97ꢀ3.89 (m, 2H), 3.25 (t, J = 8.5 Hz, 1H), 2.10 (dd, J = 7.8, 5.0 Hz, 1H), 1.77 (dd, J =
9.1, 5.0 Hz, 1H), 1.27 (t, J = 7.3 Hz, 3H), 0.96 (t, J = 7.0 Hz, 3H). 13C-NMR (100 MHz):
δ 169.5, 166.4, 138.3, 126.7, 126.1, 124.9, 61.9, 61.4, 38.1, 26.9, 20.7, 14.1, 13.8. IR
(neat): 2980, 1718, 1444, 1369, 1319, 1273, 1201, 1126, 1022, 848, 698 cm˗1. HRMS
(ESI, QꢀTOF) m/z: [M + H]+ Calculated for C13H17O4S 269.0848, found 269.0836.
Representative procedure for Lewis acid catalyzed annulation reaction between
cyclopropane carbaldehydes (1) and aryl hydrazines (2)
To a roundꢀbottom flask equipped with a magnetic stir bar was charged with 4 Å MS
(200 wt%), and InCl3 (0.2 equiv) under nitrogen atmosphere. A DCM solution of
cyclopropane carbaldehyde (1 equiv) and aryl hydrazine (1 equiv) was added and
stirred at room temperature until completion of the reaction (as monitored by TLC). The
reaction mixture was passed through a small pad of celite, and solvent was evaporated
on a rotary evaporator. The crude mixture was further purified by column
chromatography on silica gel with ethyl acetate/hexane as eluent.
6-(4-methoxyphenyl)-1-phenyl-1,4,5,6-tetrahydropyridazine (3aa)
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 46
1
2
3
4
Reaction time: 5 h, 1a (0.05 g, 0.28 mmol), 2a (0.03 g, 0.28 mmol), 3aa (0.05g, 0.21
5
6
mmol), yield: 74%, reddish yellow viscous liquid, Rf = 0.56 (ethyl acetate/hexane 1:9).
7
8
9
1H-NMR (400 MHz): δ 7.21 (t, J = 8.5 Hz, 2H), 7.10 (dd, J = 8.1, 15.3 Hz, 4H), 6.85 (d, J
= 8.6 Hz, 2H), 6.81 (d, J = 7.3 Hz, 2H), 5.17 (br, 1H), 3.78 (s, 3H), 2.25ꢀ1.99 (m, 3H),
1.95ꢀ1.82 (m, 1H). 13C-NMR (100 MHz): δ 158.7, 146.9, 135.5, 133.0, 129.0, 127.2,
119.5, 114.2, 113.3, 55.7, 55.3, 24.4, 18.9. IR (neat): 2924, 2848, 1595, 1510, 1498,
1263, 1176, 1132, 1024, 941, 840, 810, 756 cm˗1. HRMS (ESI, QꢀTOF) m/z: [M + H]+
Calculated for C17H19N2O 267.1497, found 267.1481.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-(3,4-dimethoxyphenyl)-1-phenyl-1,4,5,6-tetrahydropyridazine (3ba)
Reaction time: 4 h, 1b (0.06 g, 0.28 mmol), 2a (0.03 g, 0.28 mmol), 3ba (0.05 g, 0.16
mmol), yield: 57%, pale yellow needle like crystal, melting point: 98 °C, Rf = 0.57 (ethyl
acetate/hexane 2:8).
1H-NMR (400 MHz): δ 7.21 (t, J = 8.7 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.85ꢀ6.75 (m,
3H), 6.70ꢀ6.65 (m, 2H), 5.14 (br, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 2.24ꢀ2.01 (m, 3H), 1.97ꢀ
13
1.85 (m, 1H). C-NMR (100 MHz): δ 149.2, 148.0, 146.9, 135.5, 133.6, 128.9, 119.59,
118.3, 113.4, 111.3, 109.0, 56.1, 55.9, 24.4, 19.0. IR (neat): 2922, 2835, 1595, 1516,
1502, 1413, 1249, 1234, 1182, 1085, 1024, 748, 717, 692 cm˗1. HRMS (ESI,
quadrupole) m/z: [M + H]+ Calculated for C18H21N2O2 297.1603, found 297.1594
1,6-diphenyl-1,4,5,6-tetrahydropyridazine (3ca)
Reaction time: 5 h, 1c (0.04 g, 0.28 mmol), 2a (0.03 g, 0.28 mmol), 3ca (0.05 g, 0.21
mmol), yield: 75%, pale yellow viscous liquid, Rf = 0.72 (ethyl acetate/hexane 1:9).
26
ACS Paragon Plus Environment

Page 27 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1H-NMR (400 MHz): δ 7.29 (t, J = 7.7 Hz, 2H), 7.25ꢀ7.06 (m, 7H), 6.82ꢀ6.75 (m, 2H),
5.18 (br, 1H), 2.24ꢀ1.92 (m, 3H), 1.90ꢀ1.79 (m, 1H). 13C-NMR (100 MHz): δ 146.8,
141.1, 135.5, 129.0, 128.8, 127.1, 126.1, 119.5, 113.3, 56.2, 24.3, 18.9. IR (neat):
2924, 2852, 1608, 1496, 1448, 1369, 1319, 1300, 1238, 1076, 939, 755 cm˗1. HRMS
(ESI, QꢀTOF) m/z: [M + H]+ Calculated for C16H17N2 237.1392, found 237.1371.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-(4-fluorophenyl)-1-phenyl-1,4,5,6-tetrahydropyridazine (3da)
Reaction time: 5 h, 1d (0.04 g, 0.28 mmol), 2a (0.03 g, 0.28 mmol), 3da (0.05 g, 0.2
mmol), yield: 71%, reddish yellow viscous liquid, Rf = 0.75 (ethyl acetate/hexane 1:9).
1H-NMR (400 MHz): δ 7.12 (t, J = 8.8 Hz, 2H), 7.02 (t, J = 8.7 Hz, 4H) 6.91 (t, J = 8.6
Hz, 2H) 6.74 (q, J = 7.1, 14.0 Hz, 2H), 5.10 (br, 1H), 2.16ꢀ2.07 (m, 1H), 2.05ꢀ1.93 (m,
13
2H), 1.82ꢀ1.70 (m, 1H). C-NMR (100 MHz): δ 161.9 (d, JCF = 245.5 Hz), 146.6, 136.7
(d, JCF = 3.0 Hz), 135.6, 129.0, 127.7 (d, JCF = 7.8 Hz), 119.6, 115.7 (d, JCF = 21.9 Hz),
113.2, 55.6, 24.3, 18.7. 19F-NMR (376 MHz): δ ꢀ115.60 (s, 1F), IR (neat): 2926, 2852,
1506, 1496, 1220, 1014, 943, 690, 624, 580 cm˗1. HRMS (ESI, QꢀTOF) m/z: [M + H]+
Calculated for C16H16N2F 255.1298, found 255.1273.
6-(naphthalen-1-yl)-1-phenyl-1,4,5,6-tetrahydropyridazine (3ea)
Reaction time: 5 h, 1e (0.05 g, 0.28 mmol), 2a (0.03 g, 0.28 mmol), 3ea (0.04 g, 0.16
mmol), yield: 57%, reddish brown viscous liquid, Rf = 0.71 (ethyl acetate/hexane 1:9).
1H-NMR (400 MHz): δ 8.11 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H) 7.78 (d, J = 8.2
Hz, 1H) 7.63 (t, J = 6.8 Hz, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.17 (t,
J = 6.3 Hz, 3H), 7.11 (d, J = 9.2 Hz, 2H), 6.87 (d, J = 4.5 Hz, 1H), 6.80 (t, J = 6.8 Hz,
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 46
1
2
3
4
5
6
7
8
9
1H), 5.95 (br, 1H), 2.38ꢀ2.26 (m, 2H), 2.14ꢀ2.05 (m, 1H), 1.95ꢀ1.84 (m, 1H). 13C-NMR
(100 MHz): δ 146.6, 135.5, 134.6, 134.4, 129.5, 129.4, 128.9, 128.0, 126.5, 125.7,
125.6, 124.6, 122.4, 119.5, 113.2, 53.9, 22.5, 19.2. IR (neat): 3047, 2927, 1595, 1496,
1338, 1301, 1263, 1132, 1039, 937, 800, 742 cm˗1. HRMS (ESI, QꢀTOF) m/z: [M + H]+
Calculated for C20H19N2 287.1548, found 287.1525.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-(furan-2-yl)-1-phenyl-1,4,5,6-tetrahydropyridazine (3fa)
Reaction time: 4.5 h, 3f (0.045g, 0.28 mmol), 2a (0.03g, 0.28 mmol), 3fa (0.044g, 0.19
mmol), yield: 68%, yellow viscous liquid, Rf = 0.73 (ethyl acetate/hexane 1:9).
1H-NMR (400 MHz): δ 7.31 (s, 1H), 7.19 (t, J = 8.9 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H),
6.80 (t, J = 7.1 Hz, 1H), 6.73 (d, J = 4.2 Hz, 1H), 6.21 (dd, J = 1.9, 3.3 Hz, 1H), 5.97 (d,
J = 3.3 Hz, 1H) 5.20 (br, 1H), 2.35ꢀ2.29 (m, 1H), 2.10ꢀ1.89 (m, 3H). 13C-NMR (100
MHz): δ 152.4, 146.82, 142.0, 136.1, 129.0, 119.8, 113.4, 110.4, 107.7, 50.9,31.5, 30.3,
21.5, 19.7. IR (neat): 2931, 1597, 1576, 1346, 1292, 1278, 1170, 1132, 1072, 1006,
937, 745 cm˗1. HRMS (ESI, quadrupole) m/z: [M + H]+ Calculated for C14H15N2O
227.1184, found 227.1166
1-(4-fluorophenyl)-6-(4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine (3ab)
Reaction time: 5 h, 1a (0.05 g, 0.28 mmol), 2b (0.036 g, 0.28 mmol), 3ab (0.056 g, 0.19
mmol), yield: 70%, light reddish oil, Rf = 0.76 (ethyl acetate/hexane 1:9).
1H-NMR (400 MHz): δ 7.08ꢀ7.00 (m, 4H), 6.93ꢀ6.82 (m, 4H), 6.79ꢀ6.76 (m, 1H), 5.09 (br,
1H), 3.77 (s, 3H) 2.26ꢀ2.14 (m, 1H), 2.13ꢀ2.01 (m, 2H), 1.94ꢀ1.82 (m, 1H). 13C-NMR
(100 MHz): δ 158.7, 157.0 (d, JCꢀF = 237.6 Hz), 143.4, 135.4, 132.8, 127.2, 115.4 (d, JCꢀ
F = 22.1 Hz), 114.4 (d, JCꢀF = 7.0 Hz), 114.2, 56.0, 55.3, 24.5, 18.8. 19F-NMR (376 MHz):
28
ACS Paragon Plus Environment

Page 29 of 46
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
δ ꢀ126.05 (s, 1F) IR (neat): 2927, 2835, 1608, 1520, 1220, 1128, 1097, 1068, 1024,
941, 815, 692 cm˗1. HRMS (ESI, QꢀTOF) m/z: [M + H]+ Calculated for C17H18N2OF
285.1403, found 285.1375.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(4-chlorophenyl)-6-(4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine (3ac)
Reaction time: 6 h, 1a (0.05 g, 0.28 mmol), 2c (0.04 g, 0.28 mmol), 3ac (0.055 g, 0.18
mmol), yield: 64%, pale yellow viscous liquid, Rf = 0.75 (ethyl acetate/hexane 1:9).
1H-NMR (400 MHz): δ 7.13 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.2 Hz, 4H) 6.83 (t, J = 8.6
Hz, 3H), 5.11 (br, 1H), 3.77 (s, 3H), 2.24ꢀ2.01 (m, 3H), 1.94ꢀ1.82 (m, 1H). 13C-NMR
(100 MHz): δ 158.7, 145.4, 136.2, 132.4, 128.7, 127.1, 124.2, 114.3, 114.2, 55.7, 55.3,
24.4, 18.7. IR (neat): 2954, 2926, 1610, 1490, 1247, 1176, 1024, 943, 827, 810, 734
cm˗1. HRMS (ESI, QꢀTOF) m/z: [M + H]+ Calculated for C17H18N2OCl 301.1108, found
301.1095.
1-(4-bromophenyl)-6-(4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine (3ad)
Reaction time: 6 h, 1a (0.05 g, 0.28 mmol), 2d (0.053 g, 0.28 mmol), 3ad (0.06 g, 0.17
mmol), yield: 62%, reddish white oil, Rf = 0.74 (ethyl acetate/hexane 1:9).
1H-NMR (400 MHz): δ 7.18 (d, J = 9.2 Hz, 2H), 6.92 (dd, J = 8.7, 17.3 Hz, 4H) 6.79ꢀ6.71
(m, 3H), 5.02 (br, 1H), 3.69 (s, 3H), 2.15ꢀ1.93 (m, 3H), 1.85ꢀ1.74 (m, 1H). 13C-NMR (100
MHz): δ 158.8, 145.8, 136.3, 132.3, 131.6, 127.1, 114.8, 114.2, 111.6, 55.6, 55.3, 24.4,
18.7. IR (neat): 2953, 2854, 1614, 1587, 1510, 1487, 1369, 1249, 1176, 1132, 1022,
939, 827, 760, 509 cm˗1. HRMS (ESI, QꢀTOF) m/z: [M + H]+ Calculated for
C17H18N2OBr 345.0603, found 345.0558.
29
ACS Paragon Plus Environment