Stereospecific copper(II)-catalyzed tandem ring opening/oxidative alkylation of donor-acceptor cyclopropanes with hydrazones: Synthesis of tetrahydropyridazines

Article abstract of DOI:10.1021/acs.joc.9b01506

Aerobic copper(II)-catalyzed tandem ring opening and oxidative C-H alkylation of donor-acceptor cyclopropanes with bisaryl hydrazones is accomplished to produce tetrahydropyridazines, in which copper(II) plays dual role as a Lewis acid as well as redox catalyst. The reaction is stereospecific, and optically active cyclopropanes can be reacted with high optical purities (89-98% enantiomeric excess). The substrate scope, functional group tolerance, dual role of the copper(II) catalyst, and the use of air as an oxidant are the important practical features. A product bearing a 3-bromoaryl group can be subjected to Pd-catalyzed Suzuki coupling with boronic acid in high yield.

Full text of DOI:10.1021/acs.joc.9b01506

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Article
Stereospecific Copper(II)-Catalyzed Tandem Ring Opening/
Oxidative Alkylation of Donor-Acceptor Cyclopropanes
with Hydrazones: Synthesis of Tetrahydropyridazines
Manmath Mishra, Pinaki Bhusan De, Sourav Pradhan, and Tharmalingam Punniyamurthy
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 06 Aug 2019
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Stereospecific Copper(II)-Catalyzed Tandem Ring Opening/Oxidative Alkylation of Donor-
Acceptor Cyclopropanes with Hydrazones: Synthesis of Tetrahydropyridazines
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Manmath Mishra, Pinaki Bhusan De, Sourav Pradhan and Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
*E-mail: tpunni@iitg.ac.in
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RO2C
Ar
CO2R
Ar
CO2R
RO2C

+
Cu
air
N

N
NH
Ar
N
Ar'
Ar'
Ar
32 examples and
7 examples with
89-98% ee
ABSTRACT: Aerobic copper(II)-catalyzed tandem ring opening and oxidative C-H alkylation of
donor-acceptor cyclopropanes with bisaryl hydrazones is accomplished to produce
tetrahydropyridazines, in which copper(II) plays dual role as a Lewis acid as well as redox catalyst.
The reaction is stereospecific and optically active cyclopropanes can be reacted with high optical
purities (89-98% ee). The substrate scope, functional group tolerance, dual role of the copper(II)
catalyst and the use of air as an oxidant are the important practical features. A product bearing a
3-bromoaryl group can be subjected to Pd-catalyzed Suzuki-coupling with boronic acid in high
yield.
INTRODUCTION
Donor-acceptor (D-A) cyclopropanes are the versatile building blocks in organic synthesis.1 Ring
strain (27.5 kcal mol-1)2 and vicinal substitution pattern of donor and acceptor groups make them
to have a propensity to undergo ring-opening, rearrangement and cycloaddition reactions.3,4 To
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date, [3+n] (n = 2, 3, 4) cycloaddition of D-A cyclopropanes with [1,n]-dipolarophiles have been
extensively investigated to construct carbo- and heterocycles.5 Thereby, harnessing the reactivity
of D-A cyclopropanes as the 1,3-zwitterion equivalents in the synthesis of heterocycles is
emerging as a valuable asset in synthetic chemistry. Tetrahydropyridazines and their synthetic
analogues represent an imperative class of aza-heterocycles as they display unique biological
properties (Fig. 1).6 Significant synthetic contribution has thus been made for the construction of
tetrahydropyridazine scaffolds. Of the strategies developed, base promoted [4+2]-cycloaddition of
in situ generated 1,2-diaza-1,3-butadienes with alkenes is studied thoroughly to assemble
tetrahydropyridazines.7 Recently, Werz and co-workers reported a [3+3]-cycloaddition of in-situ
generated nitrile imines with D-A cyclopropanes using TiCl4 to give tetrahydropyridazines at
moderate temperature (Scheme 1a).8 Soon after, they have also shown the nucleophilic ring
opening of D-A cyclopropanes with naphthoquinones using SnCl2, which acts as both a Lewis
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NH2
Ph
Ph
H2N
N
CO2H
Et
N
N
N
N
N
S
O
AcHN
N
O
O
O
NO2
Et
I
Neuro-transmitter
inhibitor
Influenza neuraminidase
inhibitor
Nonsteroidal progesterone
receptor regulator
O
Me
O
Cl
Cl
N
N
N
CO2
N
Me
O
H2N
NH3
Me
HO
O
Me
Me
OH
Me
Azamerone
Pyridazomycin
Cl
Figure 1. Some examples of biologically important tetrahydropyridazine scaffolds
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acid as well as a redox catalyst.3e This strategy provides an effective synthetic tool for the
construction of tetrahydropyridazine scaffolds with readily accessible cyclopropanes.
Development of a stereospecific strategy for tetrahydropyridazine structural frameworks using the
optically active D-A cyclopropanes4a,4g-h,5e would thus be valuable. Further, the use of C–H
functionalization to assemble molecules has witnessed a dramatic advancement in recent years.9
Herein, we present an aerobic10 stereospecific copper(II)-catalyzed tandem11a nucleophilic ring
(SN2) opening and intramolecular oxidative C(sp2)-H alkylation11b of D-A cyclopropanes with
bisaryl hydrazones to afford tetrahydropyridazines (Scheme 1b). Optically active D-A
cyclopropanes can be coupled in high optical purities (89-98% ee). The reaction is atom
economical and generates water as the by-product.
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Scheme 1. Synthesis of Tetrahydropyridazines using D-A Cyclopropanes
a. Previous study: [3+3]-cycloaddition with nitrile imines
CO2Et
CO2Et
EtO2C CO2Et
Ar
Cl
Ar'
Ar
base
-HCl
Ar N N
Ar
N
N
H
N
Ar'
TiCl4 (20 mol%)
[3+3]
N
Ar
Ar
b. This study: tandem ring-opening/oxidative C-H alkylation using Cu as Lewis acid and redox catalyst
Stereospecific
RO2C CO2R
Ar
Ar
H
Aerobic
Cu(OTf)2 (10 mol%)
50 oC, air
CO2R
CO2R
N
H +
*
N
*
N
Atom economy
Ar'
N
Ar'
Ar
Ar
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RESULTS AND DISCUSSION
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Table 1. Optimization of the Reaction Conditionsa
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MeO2C CO2Me
Ph
MeO2C CO2Me
Ph
MeO2C CO2Me
catalyst
Ph
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N
+
+
N
N
NH
Ph
N
Ph
N
Ph
Ph
solvent, temp
Ph
4
Ph
3a
1a
2a
entry
catalyst
solvent
yieldb (%)
(10 mol%)
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Sc(OTf)3
Zn(OTf)2
Yb(OTf)3
AgOTf
3a
4
1
toluene
41
30
63
10
19
5
47
56
2
CH2Cl2
(CH2Cl)2
THF
3
27
17
24
81
4
5
PhCl
6
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
7
n.d.
36
n.d.
82
70
n.d.
trace
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23
10c
11d
12
Cu(OTf)2
Cu(OTf)2
-
trace
trace
n.d.
aReaction conditions: 1a (0.2 mmol), 2a (0.22 mmol), catalyst (10
b
c
o
mol%), solvent (1.5 mL), rt, 16 h. Isolated yield. Reaction at 50 C.
dReaction at 80 oC. n.d. = not detected.
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Our optimization studies commenced with (E)-1-benzylidene-2-phenylhydrazine 1a and D-A
cyclopropane 2a as the test substrates, utilizing a series of Lewis acids and solvents (Table 1).
Gratifyingly, tetrahydropyridazine 3a was produced in 41% yield along with 47% uncyclized 4,
when the reaction was carried out employing 10 mol % Cu(OTf)2 for 16 h in toluene at room
temperature (entry 1). Subsequent screening of solvents led to enhance the yield to 63% utilizing
(CH2Cl)2, whereas CH2Cl2, THF and chlorobenzene produced inferior results (entries 2-5). In a
set of Lewis acid catalysts screened, Cu(OTf)2, Sc(OTf)3, Zn(OTf)2, Yb(OTf)3 and AgOTf, the
former yielded superior results (entries 3 and 6-9). Gladly, increasing of reaction temperature to
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o
50 C improved the yield to 82% with a trace amount of 4 (entry 10). Further increment of
temperature (80 oC), however, led to drop the yield to 70%, which might be due to the low stability
of the imine C=N bond (entry 11).12 A control experiment confirmed that 3a was not formed in
the absence of the catalyst (entry 12).
Having identified the optimized reaction conditions, the scope of the procedure was assessed
engaging the substituted 2-aryl cyclopropane-1,1-dicarboxylates 2b-l with hydrazone 1a as a
representative example (Scheme 2). Cyclopropane 2b with 2-methyl substituent at the aryl ring
furnished tetrahydropyridazine 3b in 63% yield. Similarly, 3-bromo 2c and 3-trifluoromethyl 2d
substituted cyclopropanes in the aryl ring provided 3c and 3d in 73 and 69% yields, respectively.
Reactions of the cyclopropanes bearing 4-chloro 2e, 4-fluoro 2f, 4-methyl 2g and 4-phenyl 2h
functionalities at the aryl ring afforded the target products 3e-h in 71-80% yields, while the 2-
thienyl containing cyclopropane 2i was incompatible and produced a trace amount of 3i.
Interestingly, 1,1-diester variants of D-A cyclopropanes, such as 2j-l successfully participated in
the reaction to provide aza-heterocycles 3j-l in 76-79% yields. Under these conditions, vinyl
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cyclopropane 2m was an unsuccessful substrate, which may be due to the less electrophilic nature
of the C2 carbon compared to that of 2-aryl substituted cyclopropanes 2a-l.
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Scheme 2. Substrate Scope with Respect to D-A Cyclopropanesa-c
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RO2C CO2R
Ph
CO2Me
CO2Me
Ph
Cu(OTf)2 (10 mol%)
(CH2Cl)2, 50 oC
CO2R
CO2R
N
N
NH
Ph
+
Ar
N
Ar
unsucessful
substrate
Ph
3b-l
1a
2m
2b-l
MeO C
CO2Me
2
MeO C
MeO2C CO2Me
Ph
CO2Me
Me
2
Ph
Ph
N
N
N
X
N
N
N
Ph
Ph
Ph
X
3c
3e
3f
X = Br, , 73%, 18 h
X = Cl, , 80%, 16 h
3b
, 63%, 18 h
3d
X = CF3, , 69%, 18 h
X = F, , 77%, 16 h
MeO2C CO2Me
Ph
MeO C
MeO2C CO2Me
Ph
CO2Me
2
Ph
N
N
N
S
N
N
N
Ph
Ph
Ph
Ph
Me
3i
, trace, 17 h
3h
, 71%, 24 h
3g
, 79%, 17 h
variation in 1,1-dicarboxylate
iPrO C
EtO C
i
CO2Et
Ph
2
BnO2C CO2Bn
Ph
CO2 Pr
2
Ph
Ph
N
N
N
N
N
Ph
N
Ph
Ph
Ph
Ph
3j
, 77%, 18 h
3k
, 79%, 18 h
3l
, 76%, 18 h
aReaction conditions: 1a (0.2 mmol), 2b-l (0.22 mmol), Cu(OTf)2 (10 mol%), (CH2Cl)2 (1.5 mL),
50 oC. bIsolated yield. Bn = benzyl. cAccompanied ~5% of uncyclized products.
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Scheme 3. Substrate Scope with Respect to Hydrazonesa-c
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CO2Me
CO2Me
Ar
Ar
Cu(OTf)2 (10 mol%)
CO2Me
N
+
N
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NH
N
Ph
Ph
(CH2Cl)2, 50 oC
CO2Me
R
R
2a
1b-u
3m-af
X
X
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Br
N
N
N
Ph
N
N
Ph
N
Ph
Ph
Ph
Ph
3m
, 64%, 16 h
3n
X = Br, ,74%, 17 h
X = CH3,
X = CF3, , 70%, 18 h
3q
X = OAc, , 63%, 22 h
3r
X = Br, , 75%, 16 h
3s
X = Cl, ,81%, 17 h
3t
X = CN, , 69%, 22 h
3u
X = F, , 80%, 16 h
3v
X = Me, , 81%, 17 h
3o,
3p
80%, 16 h
CO2Me
CO2Me
CO2Me
CO2Me
S
3w
X = Ph,
, 73%, 16 h
3x
N
N
X = NO2, , 61%, 22 h
N
Ph
N
Ph
Ph
Ph
,74%, 21 h
3y
, 69%, 20 h
3z
OMe
Br
MeO
MeO
Br
N
MeO
MeO
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
F
N
N
N
Ph
N
Ph
N
Ph
Ph
Ph
Ph
3ac
, 73%, 24 h
3ab
, 77%, 22 h
3aa
, 66%, 24 h
CO2Me
CO2Me
CO2Me
Ph
CO2Me
Ph
Ph
CO2Me
CO2Me
N
N
Ph
N
Ph
N
N
N
Ph
Ph
F
Cl
3af
, 73%, 24 h
3ad
3ae
, 62%, 24 h
,76%, 24 h
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aReaction conditions: 1b-u (0.2 mmol), 2a (0.22 mmol), Cu(OTf)2 (10 mol%), (CH2Cl)2 (1.5 mL),
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50 oC. bIsolated yield. cAccompanied ~5% of uncyclized products.
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Next, the scope of the procedure was extended for the synthesis of functionalized
tetrahydropyridazines with a series of hydrazones 1b-u using D-A cyclopropane 2a as the
representative example (Scheme 3). N-Phenyl substituted hydrazones bearing both the electron-
donating and -withdrawing groups in the aryl rings can be readily cross-coupled. To mention, the
2-bromo derivative 1b resulted in 3m with 64% yield. The substrates having 3-bromo 1c, 3-methyl
1d and 3-trifluoromethyl 1e groups afforded the heterocycles 3n-p in 70-80% yields. Similar
results were observed for hydrazones containing 4-substituents with acetoxy 1f, bromo 1g, chloro
1h, cyano 1i, fluoro 1j, methyl 1k, phenyl 1l and nitro 1m functionalities, delivering the target
products 3q-x in 61-81% yields. Notably, 2-naphthyl 1n and 2-thienyl 1o substrates conveyed 3y
and 3z in 69 and 74% yields, respectively. To our delight, di- and tri-substituted hydrazones 1p-r
were found to be compatible, furnishing the heterocycles 3aa-ac in 66-77% yields. In addition, C-
styryl substituted hydrazone 1s participated in the reaction to give 3ad in 62% yield. Moreover, 4-
chloro 1t and 4-fluoro 1u substitution on the N-phenyl ring of hydrazones underwent reaction to
afford 3ae and 3af in 76 and 73% yields, respectively.
To reveal the stereoselectivity, the coupling of a series of hydrazones was investigated with
optically active D-A cyclopropanes (R)-2a′ and (S)-2a′ as the representative examples (Scheme
4). Hydrazone 1a underwent reaction with (R)-2a′ to give 3a′ in 91% ee, while hydrazones
containing 4-cyano 1i, 4-methyl 1k and 4-fluoro 1j substituents in the aryl ring produced
tetrahydropyridazines 3t′-u′ in 95-98% ee. Similarly, cyclopropane (S)-2e´ having a 4-chloro
group in the aryl ring on reaction with hydrazone 1a conveyed 3e´in 89% ee. Parallel results were
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Scheme 4. Enantiospecific Synthesis of Tetrahydropyridazinesa,b
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MeO2C CO2Me
Ar
Ar
CO2Me
CO2Me
Cu(OTf)2 (10 mol%)
(CH2Cl)2, rt, 18 h

N
+

NH
Ph
1
Ar'
N
9
N
Ar'
2a'
(R)- , 99% ee
10
11
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Ph
3'
-2a'
(S)
, 99% ee
2e'
(S)- , 90% ee
from (R)-cyclopropane
Me
NC
CO2Me
CO2Me
CO2Me
CO2Me
MeO2C CO2Me
Ph
N
N
N
N
Ph
N
Ph
N
Ph
Ph
Ph
Ph
3a'
3t'
3v'
, 78%, 98% ee
, 68%, 91% ee
, 64%, 95% ee
F
CO2Me
CO2Me
N
N
Ph
[X-ray]
Ph
3u'
, 76%, 98% ee
from (S)-cyclopropane
MeO
MeO
Br
CO2Me
MeO2C CO2Me
Ph
CO2Me
CO2Me
CO2Me
S
N
N
N
N
N
Ph
N
Ph
Ph
Ph
Ph
Cl
3e'
3z'
3ac'
, 67%, 92% ee
, 74%, 89% ee
, 70%, 94% ee
aReaction conditions: 1 (0.2 mmol), 2´ (0.22 mmol), Cu(OTf)2 (10 mol%), (CH2Cl)2 (1.5 mL), rt,
18 h. bIsolated yield.
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perceived utilizing hydrazones 1o and 1r on reaction with (S)-2a´, affording 3z′ and 3ac´ in 94
and 92% ee, respectively. The absolute configuration of 3u´ was determined using a single-crystal
X-ray analysis (see the Supporting Information). These results suggest that the reaction may
proceed through a SN2 ring opening of D-A cyclopropanes and the construction of functionalized
tetrahydropyridazines can be achieved with high optical purities.
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Scheme 5. Preliminary Mechanistic Investigations
MeO2C CO2Me
MeO2C CO2Me
Ph
Ph
TfOH (10 mol%)
Cu(OTf)2 (10 mol%)
(CH2Cl)2, 50 oC, 7 h
Ph
N
N
Ph
N
3a
a.
b.
c.
, n.d.
Ph
N
(CH2Cl)2, 50 oC, 7 h
Ph
Ph
4
3a
, 95%
MeO2C CO2Me
Ph
CO2Me
CO2Me
Cu(OTf)2 (10 mol%)
N
H
+
N
Ph
Ph
N
(CH2Cl)2, 50 oC
N2 atm, 24 h
N
Ph
Ph
Ph
1a
2a
3a
32%,
MeO2C CO2Me
Ph
Ph
CO2Me
CO2Me
Cu(OTf)2 (10 mol%)
(CH2Cl)2, 50 oC, 16 h
N
H
+
N
N
N
Ph
3a
Ph
1a
Ph
2a
3a
radical scavenger
yield of
75%
70%
TEMPO
BHT
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Scheme 6. Proposed Reaction Pathway
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MeO
MeO
O
O
MeO
O
MeO
O
Cu(OTf)2
Ar
Cu(OTf)2
2e- oxidation
Cu(OTf)2
Ar
Ph
O
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O
Ar
2
..
N
NH
N
OMe
Ph
N
OMe
Ph
SN2
N
N
Ar'
Ar'
Ar'
A
1
B
1/2 O2
Cu(OTf)2 + 1/2 H2O
Cu(OTf) + TfOH
MeO2C CO2Me
Ar
N
N
Ph
Ar'
3
To gain insight into the reaction pathway, the reaction of 4 was performed employing 10 mol %
Cu(OTf)2 in (CH2Cl)2 and the tetrahydropyridazine 3a was obtained in 95% yield (Scheme 5a).
Hence, the reaction likely to proceed via a ring opening of D-A cyclopropane. In addition, the
cyclization of 4 was ineffective with TfOH, which implies that the cyclization may not occur via
Bronsted acid catalysis. Consequently, the standard reaction of 1a and 2a under N2 atmosphere
resulted in diminished yield of 3a (32%), bolstered the involvement of an aerobic oxidative
pathway (Scheme 5b).11b Further, the radical scavenger experiments independently in presence of
1 equiv 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 1 equiv of 2,6-di-tert-butyl-4-
methylphenol (BHT) do not impede the product formation, which invalidates a radical pathway
(Scheme 5c). Thus, Cu(OTf)2-catalyzed SN2 ring opening of D-A cyclopropanes 2 with
hydrazones 1 can deliver A with inverted configuration. The Cu(OTf)2-catalyzed 2e‾ oxidation11c
of A can produce an N-amino nitrilium ion11a B (Scheme 6). The Lewis acid catalyzed
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intramolecular cyclization of B can lead to the formation of the target heterocycle 3. Aerobic
oxidation of Cu(OTf) with TfOH can regenerate Cu(OTf)2 to complete the catalytic cycle. The
proposed catalytic cycle explains the dual role of Cu(OTf)2 as a redox catalyst for the oxidation of
imine to nitrile as well as Lewis acid catalyst for the nucleophilic ring opening and addition of the
enolate to nitrile to produce the target heterocycle 3.
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Scheme 7. Synthetic Applications
MeO2C CO2Me
Ph
Ph
CO2Me
CO2Me
Cu(OTf)2 (10 mol%)
N
H
+
a.
N
Ph
N
(CH2Cl)2, 50 oC
air, 18 h
N
Ph
Ph
Ph
1a
2a
scale up:
3a
(78%, 1 g)
3 mmol scale
Br
CO2Me
CO2Me
Pd(PPh3)4 (3 mol%)
pyrene-1-boronic acid
CO2Me
b.
CO2Me
N
N
Ph
Ph
N
N
Ph
3n
Ph
5,
78%
To display the synthetic utility, the scale-up synthesis was conducted on a 3 mmol scale and 3a
was obtained in 78% yield (Scheme 7a). In addition, a bromo bearing tetrahydropyridazine 3n was
transformed to 5 in 78% yield via Suzuki coupling using pyrene-1-boronic acid (Scheme 7b).
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CONCLUSIONS
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In summary, an aerobic copper-catalyzed tandem reaction of the readily accessible hydrazones
with D-A cyclopropanes have been demonstrated for the construction of tetrahydropyridazine
structural frameworks via a sequential nucleophilic ring opening (SN2) and aerobic oxidative C-C
bond formation. The method offers a potential route to access optically pure tetrahydropyridazines.
The substrate scope, air as the oxidant and functional group compatibility are the importance
practical features.
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EXPERIMENTAL SECTION
General Information. Cu(OTf)2 (98%), Sc(OTf)3 (99%), Zn(OTf)2 (98%), Yb(OTf)3 (99.99%)
and AgOTf (≥98.0%) were purchased from Aldrich and used as received. Merck silica gel G/GF
254 plates were utilized for analytical TLC. Rankem silica gel (60-120 mesh) was employed for
column chromatography. Bruker Avance III 600 and 400 MHz spectrometers were used for
recording NMR (1H and 13C) spectra utilizing CDCl3 as the solvent and TMS (Me4Si) as an internal
standard. Chemical shifts (δ) and spin-spin coupling constant (J) are reported in ppm and in Hz,
respectively, and other data are reported as follows: s = singlet, d = doublet, t = triplet, m =
multiplet, q = quartet and br s = broad singlet. Melting points were determined using a Büchi B-
540 apparatus and are uncorrected. Optical rotations were determined by using a PerkinElmer-343
Polarimeter with a 50 mm path length cell at 589 nm at 25 °C. HPLC analysis was carried out
using Waters-2489 with Daicel Chiralcel AD-H and Chiralpak IC column using 2-propanol and n-
hexane as an eluent. IR spectra were collected on Perkin Elmer FT-IR spectrometer. Q-Tof ESI-
MS instrument (model HAB 273) was used for mass spectra. Single crystal X-ray data were
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collected on a Bruker SMART APEX II equipped with a CCD area detector using Mo/Kα radiation
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and the structure was solved by direct method using SHELXL-16 (Göttingen, Germany).
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General Procedure for the Preparation of Bisaryl Hydrazones.13 To a stirred solution of aryl
hydrazine (2 mmol) in EtOH (5 mL) was added aldehyde (1.6 mmol) slowly. The mixture was
stirred at 60 oC in an oil bath for 30 min. The precipitated bisaryl hydrazone was filtered, washed
with EtOH (5 mL), dried and used without further purification. Bisaryl hydrazones (1a-b, 1g, 1i,
1o, 1s),13c (1c, 1k, 1n, 1t-u),13e (1d, 1m),13d 1f,13b (1h, 1j)13f and 1q13a are known compounds.
While the hydrazones 1e, 1l, 1p and 1r are new compounds whose characterization data are
presented.
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(E)-1-Phenyl-2-(3-(trifluoromethyl)benzylidene)hydrazine 1e. Synthesized according to the
given procedure in 81% yield (342.1 mg). 1H NMR (600 MHz, CDCl3) δ 7.91 (s, 1H), 7.84 (d, J
= 7.8 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.34-
13
7.31 (m, 2H), 7.16-7.15 (m, 2H), 6.93 (t, J = 7.2 Hz, 1H); C{1H} NMR (150 MHz, CDCl3) δ
144.2, 136.2, 135.26, 135.22, 131.4 (q, JC-F = 31.95 Hz), 129.3, 129.0, 126.3 (q, JC-F = 201.75 Hz),
124.7 (q, JC-F = 3.45 Hz), 122.7 (q, JC-F = 3.6 Hz), 120.6, 112.9; HRMS (ESI) m/z [M+H]+ calcd
for C14H12F3N2: 265.0947, found 265.0953.
(E)-1-([1,1'-Biphenyl]-4-ylmethylene)-2-phenylhydrazine 1l. Synthesized according to the
given procedure in 85% yield (369.9 mg). 1H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 3H),
7.64-7.58 (m, 5H), 7.44 (t, J = 7.8 Hz, 2H), 7.36-7.34 (m, 1H), 7.28 (t, J = 8.4 Hz, 2H), 7.13 (d, J
= 7.8 Hz, 2H), 6.88 (t, J = 7.2 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 144.6, 141.0, 140.6,
136.8, 134.3, 129.3, 128.8, 127.4, 127.3, 126.9, 126.6, 120.1, 112.7; HRMS (ESI) m/z [M+H]+
calcd for C19H17N2: 273.1386, found 273.1390.
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(E)-1-(2-Bromo-5-fluorobenzylidene)-2-phenylhydrazine 1p. Synthesized according to the
given procedure in 87% yield (406.4 mg). 1H NMR (600 MHz, CDCl3) δ 7.96-7.94 (m, 2H), 7.76-
7.75 (m, 1H), 7.48-7.46 (m, 1H), 7.31-7.28(m, 2H), 7.13-7.11 (m, 2H), 6.93-6.90 (m, 1H), 6.87-
6.84 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 162.8 (JC-F = 244.5 Hz), 143.9, 134.57, 134.56,
134.1 (JC-F =7.95 Hz), 129.4, 120.8, 116.7, 116.5, 113.3 (JC-F =24.3 Hz), 113.0; HRMS (ESI) m/z
[M+H]+ calcd for C13H11BrFN2: 293.0084, found 293.0088.
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(E)-1-(2-Bromo-4,5-dimethoxybenzylidene)-2-phenylhydrazine 1r. Synthesized according to
the given procedure in 84% yield (448.8 mg). 1H NMR (600 MHz, CDCl3) δ 7.96 (s, 1H), 7.77 (s,
1H), 7.55 (s, 1H), 7.28 (t, J = 7.8 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 6.96 (s, 1H), 6.88 (t, J = 7.2
Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 149.9, 148.6, 144.5, 136.2,
129.3, 126.6, 120.2, 115.0, 113.6, 112.7, 108.5, 56.1, 56.0. HRMS (ESI) m/z [M+H]+ calcd for
C15H16BrN2O2: 335.0390, found 335.0389.
General Procedure for the Preparation of D-A Cyclopropanes.14 To a stirred solution of the
aldehyde (5 mmol) in benzene (10 mL), dimethyl malonate (5 mmol, 660 mg), piperidine (0.5
mmol, 50 µL) and acetic acid (0.5 mmol, 28 µL) were added. The flask was equipped with a Dean-
Stark trap and condenser, and the solution was heated to reflux in an oil bath. After completion,
evaporation of the solvent gave a residue that was purified by silica gel column chromatography
using ethyl acetate and hexane.
Sodium hydride (4 mmol, 60% dispersion in mineral oil, 96 mg) was suspended in anhydrous
DMF (10 mL) under nitrogen. Trimethylsulfoxonium iodide (3.85 mmol, 847 mg) was added and
the solution was stirred for 1 h at room temperature. A solution of the appropriate benzylidene
malonate (3.5 mmol) in anhydrous DMF (1 mL) was added, and the reaction mixture was allowed
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to stir over night at room temperature. After completion, the solution was poured onto a mixture
of ice and 2 M HCl (5 mL) and extracted with diethyl ether (25 mL). Drying (Na2SO4) and
evaporation of the solvent gave a residue that was purified on a silica gel column chromatography
using n-hexane and ethyl acetate as an eluent to give cyclopropanes. All the synthesized
cyclopropanes 2a,14f 2b,14a 2c,14c 2d,14g 2e-g,14f 2h,14b 2i-j,14f and 2k-l14e are known compounds.
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General Procedure for the Preparation of Enantio-enriched Cyclopropanes 2aʹ and 2e4b,14h
To a stirred solution of chiral 1-phenylethane-1,2-diol (2.2 mmol, 304 mg) in CH2Cl2 (5 mL) at 0
°C, was added NEt3 (6.5 mmol, 1 mL). After 10 minutes, a solution of MsCl (5.4 mmol, 618 mg)
in CH2Cl2 (1 mL) was added for 1 h dropwise. The resultant mixture was warmed to room
temperature, and the stirring was continued for an additional 4 h. The reaction mixture was then
poured into 1M HCl (5 mL) and extracted using CH2Cl2 (3 x 10 mL). The combined organic layer
was washed successively with 1M HCl (5 mL), saturated NaHCO3 (5 mL) and water (5 mL).
Drying (Na2SO4) and evaporation of the solvent gave a residue, which was used in the next step.
To a suspension of NaH (60% in mineral oil, 0.9 mmol, 22 mg) in THF (5 mL) was added a
solution of dimethylmalonate (0.6 mmol, 79 mg) in THF (0.5 mL) for 20 min at 0 °C. The resultant
mixture was treated with a solution of the above prepared bismesylate (0.3 mmol, 88 mg) in THF
(0.5 mL) dropwise (0 °C). The reaction mixture was then stirred under reflux for 24 h in an oil
bath, poured into water (2 mL) and extracted with EtOAc (3 x 5 mL). Drying (Na2SO4) and
evaporation of the solvent gave a residue that was purified on silica gel column chromatography
using ethyl acetate and hexane as an eluent to afford the known enantio-enriched cyclopropanes
2aʹ and 2eʹ.4b, 14h
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General Procedure for the Synthesis of Tetrahydropyridazines. Bisaryl hydrazone 1 (0.2
mmol), cyclopropane 2 (0.22 mmol) and Cu(OTf)2 (0.02 mmol, 7.23 mg) were stirred in (CH2Cl)2
(1.5 mL) at 50 C using CaCl2 guard tube in an oil bath. Progress of the reaction was monitored
using TLC with ethyl acetate and n-hexane as an eluent. After completion, the reaction mixture
was cooled to room temperature and diluted with CH2Cl2 (10 mL), and washed with water (5 mL).
Drying (Na2SO4) and evaporation of the solvent gave a residue that was purified on a silica gel
column chromatography using n-hexane and ethyl acetate as an eluent to give
tetrahydropyridazines 3.
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Procedure for the Enantiospecific Tetrahydropyridazine Synthesis. Bisaryl hydrazone 1 (0.2
mmol), optically active cyclopropanes (0.22 mmol) and Cu(OTf)2 (0.02 mmol, 7.23 mg) were
stirred at room temperature for 18 h. The work-up was carried out as above described general
procedure for the synthesis of tetrahydropyridazines. The ee was determined using chiral HPLC
analysis.
Gram-scale Synthesis of 3a. Hydrazone 1a (3 mmol, 588 mg), cyclopropane 2a (3.3 mmol, 772

mg) and Cu(OTf)2 (10 mol %, 108 mg) were stirred in (CH2Cl)2 (10 mL) at 50 C using CaCl2
guard tube in an oil bath. Progress of the reaction was monitored using TLC with ethyl acetate and
n-hexane as an eluent. After completion, the reaction mixture was cooled to room temperature and
diluted with CH2Cl2 (3 x 10 mL), and washed with water (10 mL). Drying (Na2SO4) and
evaporation of the solvent gave a residue that was purified on a silica gel column chromatography
using n-hexane and ethyl acetate as the eluent to give 3a in 78% yield (1 gm).
Dimethyl 1,3,6-triphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate 3a. Analytical TLC
on silica gel, 1:9 ethyl acetate/hexane Rf = 0.43; colorless solid; mp 160-161 C; yield 68% (58
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mg); 1H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.33-7.31
(m, 5H), 7.29-7.25 (m, 3H), 7.20 (d, J = 7.2 Hz, 2H), 6.94 (t, J = 7.2 Hz, 1H), 5.34-5.33 (m, 1H),
3.54 (s, 3H), 3.27 (dd, J = 13.8, 3.0 Hz, 1H), 3.13 (s, 3H), 2.93 (dd, J = 13.2, 6.0 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 170.7, 168.6, 145.9, 138.2, 138.2, 133.7, 129.1, 128.8, 128.1, 127.8,
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127.7, 127.2, 126.9, 120.9, 114.5, 53.9, 53.4, 53.2, 52.5, 33.9; IR (KBr) 2948, 2928, 1753, 1743,
25
1726, 1594, 1556, 1489, 1449, 1434, 1367, 1348, 1241, 1217, 1172, 1068 cm-1; 3aʹ: [α]D
=
+17.95 (c= 0.08, CHCl3); HPLC analysis: 91% ee [Daicel CHIRALCEL AD-H column,
hexane/iPrOH = 97:3, flow rate: 1 mL /min, λ = 254 nm, tR = 14.44 min (minor), 16.40 min
(major)]; HRMS (ESI) m/z [M+H]+ calcd for C26H25N2O4: 429.1809, found 429.1810.
Dimethyl
1,3-diphenyl-6-(o-tolyl)-5,6-dihydropyridazine-4,4(1H)-dicar-boxylate
3b.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.42; yellow solid; mp 141-142 C;
yield 63% (55.6 mg); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.2 Hz, 2H), 7.27 (t, J = 7.2 Hz,
2H), 7.22-7.20 (m, 1H), 7.16-7.10 (m, 5H), 7.05 (t, J = 8.0 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 6.82-
6.77 (m, 2H), 5.29-5.27 (m, 1H), 3.46 (s, 3H), 3.13 (dd, J = 13.2, 3.2 Hz, 1H), 3.06 (s, 3H), 2.71
(dd, J = 13.6, 6.0 Hz, 1H), 2.44 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 171.0, 168.6, 145.7,
138.2, 135.7, 134.8, 133.0, 131.1, 129.1, 128.1, 127.8, 127.7, 127.1, 127.0, 126.4, 120.9, 114.4,
53.5, 53.3, 52.6, 51.9, 31.4, 19.2; IR (KBr) 2949, 2853, 1742, 1597, 1562, 1491, 1459, 1444, 1462,
1329, 1268, 1249, 1181, 1172, 1070 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C27H27N2O4:
443.1965, found 443.1965.
Dimethyl 6-(3-bromophenyl)-1,3-diphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate 3c.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.38; yellow solid; mp 159-162 C;
yield 73% (73.8 mg); 1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 7.8 Hz, 2H), 7.37-7.33 (m, 4H),
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7.30-7.27 (m, 1H) 7.26-7.23 (m, 4H), 7.15 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.93-6.90
(m, 1H), 5.25-5.24 (m, 1H), 3.50 (s, 3H), 3.22 (s, 3H), 3.18 (dd, J = 13.2, 2.4 Hz, 1H), 2.87 (dd, J
=13.8, 6.0 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.5, 168.5, 145.6, 140.9, 137.9, 133.9,
131.0, 130.5, 129.7, 129.2, 128.2, 128.0, 127.1, 125.6, 122.8, 121.2, 114.4, 53.4, 53.2, 52.7, 33.6;
IR (KBr) 3057, 2947, 1752, 1745, 1595, 1496, 1425, 1366, 1216, 1068 cm-1; HRMS (ESI) m/z
[M+H]+ calcd for C26H24BrN2O4: 507.0914, found 507.0913.
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Dimethyl
1,3-diphenyl-6-(3-(trifluoromethyl)phenyl)-5,6-dihydropyri-dazine-4,4(1H)-
dicarboxy-late 3d. Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.25; colorless
solid; mp 80-82 C; yield 69% (68.4 mg); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.2 Hz, 2H),
7.54-7.52 (m, 2H), 7.42-7.35 (m, 3H), 7.32-7.24 (m, 6H), 6.95-6.92 (m, 1H), 5.37-5.35 (m, 1H),
3.53 (s, 3H), 3.24 (dd, J = 13.6, 2.8Hz, 1H), 3.12 (s, 3H), 2.95 (dd, J = 13.6, 6.0 Hz, 1H); 13C{1H}
NMR (150 MHz, CDCl3) δ 170.4, 168.5, 145.6, 139.6, 137.9, 134.1, 131.3 (q, JC-F = 31.9 Hz),
130.5, 129.4, 129.2, 128.2, 128.0, 127.2, 126.7 (q, JC-F = 270.4 Hz), 124.7 (q, JC-F = 3.3 Hz), 123.7
(q, JC-F = 3.7 Hz), 121.3, 114.4, 53.5, 53.4, 53.2, 52.6, 33.5; IR (KBr) 2953, 2924, 2852, 1734,
1597, 1559, 1496, 1444, 1434, 1367, 1328, 1265, 1243, 1166, 1069 cm-1; HRMS (ESI) m/z [M+H]+
calcd for C27H24F3N2O4: 497.1683, found 497.1688.
Dimethyl 6-(4-chlorophenyl)-1,3-diphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate 3e.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.43; brown solid; mp 190-192 C;
yield 74% (68.4 mg); 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 6.8 Hz,
2H), 7.33-7.25 (m, 7H), 7.13 (d, J = 8.4 Hz, 2H), 6.95-6.91 (m, 1H), 5.29-5.27 (m, 1H), 3.53 (s,
3H), 3.22-3.18 (m, 4H), 2.91 (dd, J = 13.6, 5.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.5,
168.6, 145.6, 138.0, 136.8, 134.0, 133.5, 129.1, 128.9, 128.4, 128.1, 127.9, 127.2, 121.1, 114.4,
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53.38, 53.35, 53.32, 52.6, 33.7; IR (KBr) 2950, 1746, 1760, 1596, 1577, 1494, 1457, 1443, 1365,
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1266, 1241, 1216, 1067 cm-1; 3eʹ: [α]D = +10.39 (c= 0.08, CHCl3); HPLC analysis: 89% ee
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[Daicel CHIRALCEL AD-H column, hexane/iPrOH = 97:3, flow rate: 1 mL /min, λ = 254 nm, tR
= 18.01 min (major), 23.57 min (minor)]; HRMS (ESI) m/z [M+H]+ calcd for C26H24ClN2O4:
463.1419, found 463.1440.
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Dimethyl 6-(4-fluorophenyl)-1,3-diphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate 3f.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.42; brown solid; mp 168-169 C;
yield 77% (68.6 mg); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz,
2H), 7.28 (d, 7.2 Hz, 1H), 7.23-7.22 (m, 4H),7.13-7.09 (m, 2H), 6.95 (t, J = 8.8 Hz, 2H), 6.91-6.87
(m, 1H), 5.26-5.24 (m, 1H), 3.49 (s, 3H), 3.18-3.15 (m, 4H), 2.86 (dd, J = 13.6, 6.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.5, 168.6, 163.4 (JC-F = 244.9 Hz), 145.7, 138.0, 133.94,
133.90, 129.1, 128.7 (JC-F = 8.1 Hz), 128.1, 127.9, 127.2, 121.1, 115.8 (JC-F = 21.5 Hz), 114.4,
53.36, 53.30, 53.2, 52.5, 33.9; IR (KBr) 2949, 1741, 1596, 1560, 1456, 1489, 1345, 1260, 1218,
1155, 1091, 1066 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C26H24FN2O4: 447.1715, found
447.1731.
Dimethyl
1,3-diphenyl-6-(p-tolyl)-5,6-dihydropyridazine-4,4(1H)-dicarboxylate
3g.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.41; colorless solid; mp 167-168 C;
yield 79% (69.8 mg); 1H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.8 Hz,
2H), 7.32-7.29 (m, 3H),7.28-7.25 (m, 2H), 7.12 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 6.92
(t, J = 7.2 Hz, 1H), 5.30-5.28 (m, 1H), 3.53 (s, 3H), 3.23 (dd, J = 13.8, 3.0 Hz, 1H), 3.14 (s, 3H),
2.89 (dd, J = 13.2, 5.4 Hz, 1H), 2.32 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.8, 168.6,
145.8, 138.2, 137.3, 134.9, 133.4, 129.4, 129.0, 128.1, 127.7, 127.1, 126.8, 120.8, 114.4, 53.5,
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6-([1,1'-biphenyl]-4-yl)-1,3-diphenyl-5,6-dihydropyrid-azine-4,4(1H)-
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dicarboxylate 3h. Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.33; colorless solid;
mp 86-87 C; yield 71% (71.5 mg); 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 2H), 7.58-
7.54 (m, 4H), 7.45 (t, J = 7.2 Hz, 2H), 7.40-7.25 (m, 10H), 6.94 (t, J = 6.8 Hz, 1H), 5.39-5.36 (m,
1H), 3.54 (s, 3H), 3.29 (dd, J = 13.6, 2.8 Hz, 1H), 3.13 (s, 3H), 2.95 (dd, J = 13.6, 5.6 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 168.6, 145.9, 140.6, 140.5, 138.2, 137.2, 133.7, 129.1,
129.0, 128.1, 127.8, 127.6, 127.45, 127.42, 127.2, 127.1, 121.0, 114.5, 53.6, 53.4, 53.3, 52.5, 33.8;
IR (KBr) 2950, 2924, 2852, 1734, 1598, 1557, 1493, 1443, 1366, 1263, 1242, 1225, 1206, 1112,
1068 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C32H29N2O4: 505.2122, found 505.2126.
Diethyl 1,3,6-triphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate 3j. Analytical TLC on
silica gel, 1:9 ethyl acetate/hexane Rf = 0.68; brown solid; mp 125-126 C; yield 77% (70.2 mg);
1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H), 7.24 (t, J = 7.2 Hz, 2H), 7.20-7.11 (m,
8H), 7.07 (d, J = 7.2 Hz, 2H), 6.79 (t, J = 6.8 Hz, 1H), 5.20-5.18 (m, 1H), 3.97-3.89 (m, 1H), 3.87-
3.79 (m, 1H), 3.51-3.43 (m, 1H), 3.32-3.24 (m, 1H), 3.11 (dd, J = 13.6, 2.8 Hz, 1H), 2.79 (dd, J =
13
13.2, 5.6 Hz, 1H), 0.92 (t, J = 6.8 Hz, 3H), 0.83 (t, J = 7.2 Hz, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 170.1, 168.2, 145.9, 138.5, 138.3, 134.3, 129.0, 128.7, 127.9, 127.79, 127.72, 127.6,
126.9, 120.8, 114.5, 62.4, 61.8, 54.0, 53.7, 33.8, 13.7, 13.6; IR (KBr) 2925, 1749, 1721, 1594,
1561, 1444, 1490, 1364, 1329, 1266, 1226, 1176, 1068 cm-1; HRMS (ESI) m/z [M+H]+ calcd for
C28H29N2O4: 457.2122, found 457.2131.
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Dibenzyl 1,3,6-triphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate 3k. Analytical TLC on
silica gel, 1:9 ethyl acetate/hexane Rf = 0.65; yellow solid; mp 80-81 C; yield 79% (91.6 mg); 1H
NMR (400 MHz, CDCl3) δ 7.67-7.64 (m, 2H), 7.21-7.11 (m, 16H), 7.09-7.07 (m, 2H), 6.98-6.96
(m, 2H), 6.90 (d, J = 6.8 Hz, 2H), 6.81-6.77 (m, 1H), 5.18-5.16 (m, 1H), 4.85-4.77 (m, 2H), 4.49
(d, J = 12.4 Hz, 1H), 4.14 (d, J = 12.4 Hz, 1H), 3.15 (dd, J = 13.2, 3.2 Hz, 1H), 2.83 (dd, J = 13.6,
6.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.9, 168.1, 145.8, 138.4, 138.1, 135.0, 134.6,
133.8, 129.0, 128.8, 128.6, 128.55, 128.53, 128.3, 128.1, 127.8, 127.7, 127.4, 127.0, 120.9, 114.6,
68.2, 67.5, 54.0, 53.9, 53.7, 34.1; IR (KBr) 2923, 2858, 1732, 1638, 1597, 1492, 1454, 1171, 1116,
1064 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C38H33N2O4: 581.2435, found 581.2447.
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Diisopropyl 1,3,6-triphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate 3l. Analytical TLC
on silica gel, 1:4 ethyl acetate/hexane Rf = 0.66; yellow solid; mp 112-113 C; yield 76% (73.5
mg); 1H NMR (400 MHz, CDCl3) δ 7.86-7.83 (m, 2H), 7.38-7.36 (m, 2H), 7.32-7.25 (m, 7H),
7.23-7.20 (m, 3H), 6.89 (t, J = 6.8 Hz, 1H), 5.27-5.25 (m, 1H), 4.89 (m, 1H), 4.27 (m, 1H), 3.15
(dd, J = 13.6, 3.6 Hz, 1H), 2.92 (dd, J = 13.2, 5.6 Hz, 1H), 1.12 (d, J = 6.0 Hz, 3H), 1.09 (d, J =
6.4 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 168.5, 166.9, 144.9, 138.0, 137.4, 133.9, 127.9, 127.7, 127.0, 126.8, 126.77, 126.72, 125.9,
119.7, 113.7, 69.2, 69.1, 53.3, 53.1, 33.1, 20.48, 20.41, 20.2, 20.0; IR (KBr) 2981, 1734, 1637,
1497, 1455, 1372, 1341, 1266, 1238, 1226, 1204, 1175, 1106, 1060 cm-1; HRMS (ESI) m/z [M+H]+
calcd for C30H33N2O4: 485.2435, found 485.2447.
Dimethyl-3-(2-bromophenyl)-1,6-diphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate
3m. Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.38; brown solid; mp 108-109
C; yield 64% (64.7 mg); 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 8.0, 2.0 Hz, 1H), 7.54 (dd,
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J = 8.0, 1.2 Hz, 1H), 7.27-7.21 (m, 3H), 7.20-7.15 (m, 3H), 7.13-7.08 (m, 5H), 6.81-6.77 (m, 1H),
5.22-5.20 (m, 1H), 3.33 (s, 3H), 3.03-3.02 (m, 2H), 2.97 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 168.8, 168.6, 146.1, 138.64, 138.61, 133.0, 132.3, 132.0, 129.5, 129.0, 128.7, 127.7, 127.1,
126.8, 124.8, 121.1, 114.8, 54.94, 54.91, 53.1, 52.5, 32.4; IR (KBr) 2951, 2924, 2853, 1735, 1597,
1573, 1496, 1450, 1432, 1367, 1330, 1264, 1238, 1171, 1066 cm-1; HRMS (ESI) m/z [M+H]+ calcd
for C26H24BrN2O4: 507.0914, found 507.0915.
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Dimethyl-3-(3-bromophenyl)-1,6-diphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate
3n. Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.39; colorless solid; mp 141-142
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C; yield 74% (74.8 mg); H NMR (600 MHz, CDCl3) δ 7.99 (s, 1H), 7.66 (d, J = 9.0 Hz, 1H),
7.43 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 7.8 Hz, 2H), 7.28-7.23 (m, 5H), 7.21 (t, J = 8.4 Hz, 1H), 7.16
(d, J = 7.2 Hz, 2H), 6.96-6.93 (m, 1H), 5.33-5.32 (m, 1H), 3.58 (s, 3H), 3.25 (dd, J = 13.8, 3.0 Hz,
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1H), 3.12 (s, 3H), 2.89 (dd, J = 13.8, 6.0 Hz, 1H); C{1H} NMR (150 MHz, CDCl3) δ 170.5,
168.4, 145.6, 140.1, 137.8, 131.9, 130.6, 130.0, 129.6, 129.2, 128.8, 127.8, 126.8, 125.6, 122.3,
121.3, 114.6, 53.9, 53.5, 53.1, 52.6, 33.7; IR (KBr) 2950, 2924, 1741, 1734, 1595, 1497, 1328,
1262, 1218, 1060 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C26H24BrN2O4: 507.0914, found
507.0915.
Dimethyl
1,6-diphenyl-3-(m-tolyl)-5,6-dihydropyridazine-4,4(1H)-dicarboxylate
3o.
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.41; yellow solid; mp 98-99 C; yield
80% (70.7 mg); 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.22-7.12
(m, 8H), 7.09 (d, J = 7.6 Hz, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.83-6.79 (m, 1H), 5.22-5.20 (m, 1H),
3.44 (s, 3H), 3.13 (dd, J = 13.6, 3.2 Hz, 1H), 3.02 (s, 3H), 2.81 (dd, J = 13.6, 5.6 Hz, 1H), 2.30 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.8, 168.7, 145.9, 138.2, 138.1, 137.6, 133.8, 129.1,
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128.8, 128.6, 128.0, 127.8, 127.7, 126.9, 124.3, 120.8, 114.4, 53.8, 53.35, 53.32, 52.5, 33.9, 21.9;
IR (KBr) 2952, 2924, 2853, 1736, 1687, 1596, 1559, 1496, 1433, 1265, 1226, 1068 cm-1; HRMS
(ESI) m/z [M+H]+ calcd for C27H27N2O4: 443.1965, found 443.1973.
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Dimethyl
1,6-diphenyl-3-(3-(trifluoromethyl)phenyl)-5,6-dihydro-pyridazine-4,4(1H)-
dicarboxy-late 3p. Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.25; colorless
solid; mp 98-99 C; yield 70% (69.4 mg); 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 8.00 (d, J
= 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.33-7.23 (m, 7H), 7.17 (d, J =
7.2 Hz, 2H), 6.98-6.91 (m, 1H), 5.36-5.34 (m, 1H), 3.56 (s, 3H), 3.27 (dd, J = 13.2, 2.8 Hz, 1H),
3.13 (s, 3H), 2.91 (dd, J = 13.6, 5.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.5, 168.4,
145.6, 138.9, 137.9, 132.0, 130.6, 130.4, 130.3, 129.2, 128.8, 128.6, 127.9, 126.8, 124.2 (q, JC-F
=3.6 Hz), 123.9 (q, JC-F =3.6 Hz), 121.5, 114.6, 54.0, 53.4, 53.2, 52.6, 33.8; IR (KBr) 2955, 2923,
1761, 1727, 1592, 1565, 1497, 1488, 1369, 1339, 1266, 1219, 1168, 1070 cm-1; HRMS (ESI) m/z
[M+H]+ calcd for C27H24F3N2O4: 497.1683, found: 497.1689.
Dimethyl 3-(4-acetoxyphenyl)-1,6-diphenyl-5,6-dihydropyri-dazine-4,4(1H)-dicarboxylate
3q. Analytical TLC on silica gel, 1:9 ethyl acetate/hexane, Rf = 0.29; colorless solid; mp 168-169
C; yield 63% (61.2 mg); 1H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 9.0 Hz, 2H), 7.31-7.23 (m,
7H), 7.16 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 6.93-6.90 (m, 1H), 5.32-5.31 (m, 1H), 3.54
(s, 3H), 3.24 (dd, J = 13.8, 3.0 Hz, 1H), 3.11 (s, 3H), 2.90 (dd, J = 13.2, 5.4 Hz, 1H), 2.32 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 170.7, 169.5, 168.6, 150.3, 145.7, 138.0, 135.9, 132.7, 129.1,
128.8, 128.2, 127.7, 126.8, 121.1, 121.0, 114.4, 53.7, 53.4, 53.3, 52.6, 33.7, 21.4; IR (KBr) 2924,
2850, 1750, 1686, 1597, 1497, 1435, 1369, 1197 cm-1; HRMS (ESI) m/z [M+H]+ calcd for
C28H27N2O6: 487.1864, found 487.1860.
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Dimethyl 3-(4-bromophenyl)-1,6-diphenyl-5,6-dihydropyriazine-4,4(1H)-dicarboxylate 3r.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.39; yellow solid; mp 187-188 C;
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2H), 7.21-7.11 (m, 7H), 7.05 (d, J = 7.2 Hz, 2H), 6.85-6.80 (m, 1H), 5.22- 5.20 (m, 1H), 3.45 (s,
3H), 3.13 (dd, J = 13.6, 2.8 Hz, 1H), 3.00 (s, 3H), 2.77 (dd, J = 13.2, 6.0 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 170.4, 168.3, 145.5, 137.7, 137.0, 132.2, 131.0, 128.9, 128.6, 128.5, 127.6,
126.6, 121.7, 121.0, 114.3, 53.7, 53.2, 53.0, 52.4, 33.5; IR (KBr) 2951, 2924, 2853, 1734, 1636,
1597, 1549, 1497, 1489, 1332, 1266, 1244, 1226, 1173, 1068 cm-1; HRMS (ESI) m/z [M+H]+ calcd
for C26H24BrN2O4: 507.0914, found 507.0910.
Dimethyl 3-(4-chlorophenyl)-1,6-diphenyl-5,6-dihydropyri-dazine-4,4(1H)-dicarboxylate 3s.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.41; brown solid; mp 151-152 C;
yield 81% (74.8 mg); 1H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 2H), 7.33-7.29 (m, 4H),
7.28-7.23 (m, 5H), 7.16 (d, J = 7.8 Hz, 2H), 6.94-6.92 (m, 1H), 5.33-5.31 (m, 1H), 3.56 (s, 3H),
3.25 (dd, J = 13.8, 3.0 Hz, 1H), 3.11 (s, 3H), 2.89 (dd, J = 13.8, 6.0 Hz, 1H); 13C{1H} NMR (150
MHz, CDCl3) δ 170.6, 168.5, 145.6, 137.9, 136.7, 133.6, 132.3, 129.1, 128.8, 128.4, 128.2, 127.8,
126.8, 121.2, 114.4, 53.8, 53.4, 53.1, 52.6, 33.7; IR (KBr) 2952, 1755, 1726, 1598, 1549, 1498,
1489, 1451, 1399, 1373, 1337, 1212, 1173, 1068 cm-1; HRMS (ESI) m/z [M+H]+ calcd for
C26H24ClN2O4: 463.1419, found: 463.1429.
Dimethyl 3-(4-cyanophenyl)-1,6-diphenyl-5,6-dihydropyri-dazine-4,4(1H)-dicarboxylate 3t.
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.21; yellow solid; mp 178-179 °C;
yield 64% (58 mg); 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 9.0 Hz,
2H), 7.32-7.24 (m, 7H), 7.14 (d, J = 7.8 Hz, 2H), 7.00-6.95(m, 1H), 5.37-5.36 (m, 1H), 3.58 (s,
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3H), 3.29 (dd, J = 13.8, 3.0 Hz, 1H), 3.11 (s, 3H), 2.87 (dd, J = 13.8, 5.4 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 170.5, 168.2, 145.4, 142.5, 137.5, 131.9, 131.4, 129.2, 128.9, 128.0, 127.2,
126.7, 121.9, 119.3, 114.9, 110.6, 54.1, 53.5, 52.8, 52.7, 33.8; IR (KBr) 2949, 1734, 1597, 1563,
1494, 1450, 1368, 1329, 1260, 1185, 1108, 1034 cm-1; 3tʹ: [α]D25 = +24 (c= 0.1, CHCl3); HPLC
analysis: 95% ee [Daicel CHIRALCEL AD-H column, hexane/iPrOH = 97:3, flow rate: 1 mL
/min, λ = 215 nm, tR = 38.32 min (minor), 48.39 min (major)]; HRMS (ESI) m/z [M+H]+ calcd for
C27H24N3O4: 454.1761, found 454.1770.
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Dimethyl 3-(4-fluorophenyl)-1,6-diphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate 3u.
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane, Rf = 0.42; colorless solid; mp 175-176 C;
yield 76% (67.7 mg); 1H NMR (600 MHz, CDCl3) δ 7.78-7.75 (m, 2H), 7.31 (t, J = 7.2 Hz, 2H),
7.28-7.23 (m, 5H), 7.17 (d, J = 7.2 Hz, 2H), 7.05 (t, J = 8.4 Hz, 2H), 6.93-6.90 (m, 1H), 5.32-5.31
(m, 1H), 3.53 (s, 3H), 3.24 (dd, J = 13.8, 3.0 Hz, 1H), 3.11 (s, 3H), 2.89 (dd, J = 13.2, 5.4 Hz, 1H);
13C{1H} NMR (150 MHz, CDCl3) δ 170.6, 168.6, 163.4 (JC-F = 245.7 Hz), 145.7, 138.0, 134.4
(JC-F = 3.3 Hz), 132.6, 129.1, 129.1 (JC-F = 7.8 Hz), 128.8, 127.8, 126.8, 121.0, 115.1 (JC-F = 21.3
Hz), 114.4, 53.7, 53.4, 53.4, 52.6, 33.6; IR (KBr) 2947, 1750, 1738, 1600, 1554, 1508, 1496, 1453,
1328, 1240, 1216, 1174, 1160, 1067 cm-1; 3uʹ: [α]D25 = +32 (c=0.1, CHCl3); HPLC analysis: 98%
ee [Daicel CHIRALPAK IC column, hexane/iPrOH = 97:3, flow rate: 1 mL /min, λ = 254 nm, tR
= 8.40 min (major), 9.80 min (minor)]; HRMS (ESI) m/z [M+H]+ calcd for C26H24FN2O4:
447.1715, found 447.1718.
Dimethyl
1,6-diphenyl-3-(p-tolyl)-5,6-dihydropyridazine-4,4(1H)-dicarboxylate
3v.
Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.41; yellow solid; mp 141-142 C;
yield 78% (69 mg); 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 7.8 Hz, 2H), 7.31-7.28 (m, 4H),
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7.25 (t, J = 7.2 Hz, 3H), 7.18-7.16 (m, 4H), 6.91 (t, J = 7.2 Hz, 1H), 5.31-5.30 (m, 1H), 3.55 (s,
3H), 3.24 (dd, J = 13.8, 3.0 Hz, 1H), 3.11 (s, 3H), 2.91 (dd, J = 13.8, 6.0 Hz, 1H), 2.37 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 170.8, 168.6, 145.9, 138.2, 137.6, 135.4, 133.7, 129.0, 128.8,
128.7, 127.6, 127.0, 126.8, 120.7, 114.3, 53.6, 53.3, 53.2, 52.5, 33.8, 21.3; IR (KBr) 2949, 1759,
1727, 1595, 1575, 1493, 1449, 1430, 1367, 1327, 1272, 1184, 1071 cm-1; 3vʹ: [α]D25 = +29.33
(c=0.15, CHCl3); HPLC analysis: 98% ee [Daicel CHIRALPAK IC column, hexane/iPrOH = 97:3,
flow rate: 1 mL /min, λ = 254 nm, tR = 12.41 min (major), 14.45 min (minor)]; HRMS (ESI) m/z
[M+H]+ calcd for C27H27N2O4: 443.1965, found 443.1964.
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Dimethyl
3-([1,1'-biphenyl]-4-yl)-1,6-diphenyl-5,6-dihydropyri-dazine-4,4(1H)-
dicarboxylate 3w. Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.33; yellow solid;
mp 87-88 C; yield 73% (73.5 mg); 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.63-
7.57 (m, 4H), 7.44 (t, J = 7.2 Hz, 2H), 7.36-7.32 (m, 1H), 7.30-7.20 (m, 7H), 7.17 (d, J = 7.2 Hz,
2H), 6.90 (t, J = 6.8 Hz, 1H), 5.33-5.30 (m, 1H), 3.55 (s, 3H), 3.25 (dd, J = 13.6, 2.8 Hz, 1H), 3.11
(s, 3H), 2.90 (dd, J = 13.6, 5.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 168.6, 145.9,
140.9, 140.3, 138.1, 137.2, 133.3, 129.1, 128.9, 128.8, 127.7, 127.4, 127.1, 126.9, 126.7, 121.0,
114.5, 53.8, 53.4, 53.2, 52.5, 34.0; IR (KBr) 2949, 1758, 1597, 1562, 1541, 1495, 1432, 1450,
1328, 1216, 1172, 1065 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C32H29N2O4: 505.2122, found
505.2134.
Dimethyl 3-(4-nitrophenyl)-1,6-diphenyl-5,6-dihydropyridazine-4,4(1H)-dicarboxylate 3x.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.16; yellow solid; mp 182-183 C;
yield 61% (57.7 mg); 1H NMR (600 MHz, CDCl3) δ 8.22 (d, J = 9.6 Hz, 2H), 7.95 (d, J = 9.6 Hz,
2H), 7.33-7.30 (m, 5H), 7.28-7.25 (m, 2H) 7.15 (d, J = 6.6 Hz, 2H), 7.01-6.98 (m, 1H), 5.389-
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5.384 (m, 1H), 3.59 (s, 3H), 3.33 (dd, J = 13.2, 2.4 Hz, 1H), 3.12 (s, 3H), 2.89 (dd, J = 13.8, 6.0
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Hz, 1H); C{1H} NMR (150 MHz, CDCl3) δ 170.5, 168.2, 146.7, 145.3, 144.3, 137.4, 131.1,
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2956, 2924, 2852, 1733, 1596, 1543, 1512, 1491, 1451, 1435, 1378, 1366, 1263, 1213, 1105, 1069
cm-1; HRMS (ESI) m/z [M+H]+ calcd for C26H24N3O6: 474.1660, found 474.1659.
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Dimethyl 3-(naphthalen-2-yl)-1,6-diphenyl-5,6-dihydropyri-dazine-4,4(1H)-dicar-boxylate
3y. Analytical TLC on silica gel, 1:4 ethyl acetate/hexane Rf = 0.31; brown solid; mp 182-183 C;
yield 69% (65.9 mg); 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 8.8, 3.0 Hz, 1H), 7.96 (s, 1H),
7.75-7.71 (m, 3H), 7.38-7.33 (m, 2H), 7.24-7.14 (m, 7H), 7.12-7.08 (m, 2H), 6.83 (t, J = 7.2 Hz,
1H), 5.26-5.23 (m, 1H), 3.39 (s, 3H), 3.19 (dd, J = 13.6, 3.2 Hz, 1H), 3.03 (s, 3H), 2.84 (dd, J =
13.6, 6.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 168.7, 145.9, 138.2, 135.7, 133.6,
133.3, 133.0, 129.1, 128.8, 128.7, 127.7, 127.6, 127.6, 126.9, 126.1, 126.1, 126.0, 125.4, 121.1,
114.6, 53.9, 53.4, 53.3, 52.5, 34.0; IR (KBr) 2948, 1754, 1726, 1595, 1557, 1495, 1450, 1431,
1365, 1248, 1223, 1174, 1105, 1069 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C30H27N2O4:
479.1965, found 479.1971.
Dimethyl 1,6-diphenyl-3-(thiophen-2-yl)-5,6-dihydropyridazine-4,4(1H)-dicarboxylate 3z.
Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.32; brown solid; mp 185-186 C;
yield 70% (60.7 mg); 1H NMR (400 MHz, CDCl3) δ 7.20-7.13 (m, 7H), 7.11 (d, J = 4.8 Hz, 1H),
7.05 (d, J = 7.2 Hz, 2H), 6.90-6.89 (m, 1H), 6.85-6.79 (m, 2H), 5.23-5.20 (m, 1H), 3.55 (s, 3H),
3.17 (dd, J = 13.2, 2.4 Hz, 1H), 3.03 (s, 3H), 2.80 (dd, J = 13.6, 5.2 Hz, 1H); 13C{1H} NMR (150
MHz, CDCl3) δ 170.7, 167.9, 145.4, 143.9, 137.5, 129.8, 129.1, 128.8, 127.3, 126.7, 125.1, 124.4,
121.1, 114.4, 53.58, 53.56, 53.0, 52.6, 33.5; IR (KBr) 2949, 2840, 1747, 1733, 1595, 1558, 1497,
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1450, 1433, 1322, 1242, 1225, 1177, 1067 cm-1; 3zʹ: [α]D25 = +17.91 (c= 0.07, CHCl3); HPLC
analysis: 94% ee [Daicel CHIRALCEL AD-H column, hexane/iPrOH = 97:3, flow rate: 1 mL
/min, λ = 254 nm, tR = 19.79 min (minor), 21.03 min (major)]; HRMS (ESI) m/z [M+H]+ calcd for
C24H23N2O4S: 435.1373, found 435.1380.
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Dimethyl
3-(2-bromo-5-fluorophenyl)-1,6-diphenyl-5,6-dihydro-pyridazine-4,4(1H)-
dicarboxylate 3aa. Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.38; yellow solid;
mp 149-150 C; yield 66% (69.1 mg); 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 10.0, 3.2 Hz,
1H), 7.51-7.47 (m, 1H), 7.25 (t, J = 6.8 Hz, 2H), 7.19-7.08 (m, 7H), 6.86-6.78 (m, 2H), 5.22-5.20
(m, 1H), 3.35 (s, 3H), 3.07-2.98 (m, 2H), 2.97 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.6,
168.4, 162.6 (JC-F =245.5 Hz), 145.9, 140.3 (JC-F =8.6 Hz), 138.2, 134.0 (JC-F =8.1 Hz), 130.9 (JC-
F =2.2 Hz), 129.0, 128.7, 127.8, 127.0, 121.4, 119.6 (JC-F =23.6 Hz), 119.0 (JC-F =3.4 Hz), 116.8
(JC-F =22.2 Hz), 114.8, 54.8, 54.6, 53.2, 52.6, 32.2; IR (KBr) 3068, 2947, 1749, 1738, 1576, 1492,
1325, 1260, 1062 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C26H23BrFN2O4: 525.0820, found
525.0821.
Dimethyl
1,6-diphenyl-3-(3,4,5-trimethoxyphenyl)-5,6-dihydro-pyridazine-4,4(1H)-
dicarboxylate 3ab. Analytical TLC on silica gel, 1:9 ethyl acetate/hexane Rf = 0.11; yellow solid;
mp 101-102 C; yield 77% (79.7 mg); 1H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 3H), 7.26-7.22
(m, 4H), 7.17 (d, J = 7.2 Hz, 2H), 7.08 (s, 2H), 6.93-6.89 (m, 1H), 5.33-5.31 (m, 1H), 3.89 (s, 6H),
3.88 (s, 3H), 3.57 (s, 3H), 3.15 (dd, J = 13.2, 2.8 Hz, 1H), 3.12 (s, 3H), 2.89 (dd, J = 13.6, 6.0 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 168.4, 152.6, 145.5, 137.9, 133.6, 133.0, 128.9,
128.6, 127.6, 126.7, 120.8, 114.1, 104.5, 60.9, 56.0, 53.6, 53.4, 53.2, 52.3, 33.6; IR (KBr) 2951,
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