Synthesis of 3D-Rich Heterocycles: Hexahydropyrazolo[1,5-A]pyridin-2(1H)-ones and Octahydro-2H-2a,2a1-diazacyclopenta[cd]inden-2-ones

Article abstract of DOI:10.1021/acs.joc.6b01608

Two cyclic azomethine imines, 7-methyl- and 7-phenyl-2-oxo-Δ⁷-hexahydropyrazolo[1,5-A]pyridin-8-ium-1-ide, were prepared in seven steps from the respective commercially available δ-keto acids. The addition of Grignard reagents followed by N-Alkylation at position 1 afforded the 1,7,7-trisubstituted hexahydropyrazolo[1,5-A]pyridin-2(1H)-ones, whereas 1,3-dipolar cycloadditions of these dipoles to typical acetylenic and olefinic dipolarophiles gave 4a-substituted 2a,2a¹-diazacyclopenta[cd]indene derivatives as the first representatives of a novel heterocyclic system. Regio- and stereoselectivity as well as the mechanism of these [3 + 2]-cycloadditions were evaluated using computational and experimental methods. The data obtained were in agreement with the polar concerted cycloaddition mechanism via the energetically favorable syn/endo-transition states.

Full text of DOI:10.1021/acs.joc.6b01608

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Article
Synthesis of 3D-rich heterocycles: Hexahydropyrazolo[1,5-a]pyridin-2(1H)-
ones and octahydro-2H-2a,2a1-diazacyclopenta[cd]inden-2-ones.
Eva Pušavec Kirar, Miha Drev, Jona Mirnik, Uroš Grošelj, Amalija Golobi#,
Georg Dahmann, Franc Požgan, Bogdan Štefane, and Jurij Svete
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01608 • Publication Date (Web): 14 Sep 2016
Downloaded from http://pubs.acs.org on September 16, 2016
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Synthesis of 3Dꢀrich heterocycles: Hexahydropyrazolo[1,5ꢀa]pyridinꢀ2(1H)ꢀ
1
ones and octahydroꢀ2Hꢀ2a,2a ꢀdiazacyclopenta[cd]indenꢀ2ꢀones.
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a
a
a
a
a
Eva Pušavec Kirar , Miha Drev , Jona Mirnik , Uroš Grošelj* , Amalija Golobič , Georg
b
a
a
a1
Dahmann , Franc Požgan , Bogdan Štefane , and Jurij Svete*
a) Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SIꢀ
1000 Ljubljana, Slovenia
b) Medicinal Chemistry, BoehringerꢀIngelheim Pharma GmbH&Co. KG, 88397 Biberach,
Germany
Eꢀmail: jurij.svete@fkkt.uniꢀlj.si; uros.groselj@fkkt.uniꢀlj.si
7
Abstract
—
Two cyclic azomethine imines, 7ꢀmethylꢀ and 7ꢀphenylꢀ2ꢀoxoꢀꢁ ꢀ
hexahydropyrazolo[1,5ꢀa]pyridinꢀ8ꢀiumꢀ1ꢀide were prepared in seven steps from the respective
commercially available δꢀketo acids. The addition of Grignard reagents followed by Nꢀalkylation
at position 1 afforded the 1,7,7ꢀtrisubstituted hexahydropyrazolo[1,5ꢀa]pyridinꢀ2(1H)ꢀones,
whereas 1,3ꢀdipolar cycloadditions of these dipoles to typical acetylenic and olefinic
1
dipolarophiles gave 4aꢀsubstituted 2a,2a ꢀdiazacyclopenta[cd]indene derivatives, as the first
representatives of a novel heterocyclic system. Regioꢀ and stereoselectivity as well as the
mechanism of these [3+2]ꢀcycloadditions were evaluated using computational and experimental
1
Corresponding author. Tel.: +386 1 4798 562; Fax: +386 1 2419 144; eꢀmail:
jurij.svete@fkkt.uniꢀlj.si
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methods. The data obtained were in agreement with the polar concerted cycloaddition mechanism
via the energetically favorable syn/endoꢀtransition states.
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Keywords: pyrazolo[1,5ꢀa]pyridine; 2a,2a ꢀdiazacyclopenta[cd]indene; azomethine imines;
[3+2]ꢀcycloadditions; Grignard reagents; saturated heterocycles.
1. Introduction
Heterocyclic systems are common building blocks for the synthesis of various biologically
important and naturally occurring compounds. Consequently, heterocycles are commonly used
1
building blocks for applications in medicinal chemistry, catalysis, and material science. In this
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context, pyrazolo[1,5ꢀa]pyridine (1) belongs to a group of wellꢀexplored systems with over
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1
00,000 hits and over 2,500 references according to a SciFinder® substructure search.
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Derivatives of 1 exhibit different biological activities, such as antiviral, inhibition of reverse
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transcriptase, dopamine D3 and D4 antagonist, dopamine D3 agonist, diuretic adenosine A1
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antagonist, and intercalating activity. A phosphodiesterase inhibitor, Ibudilast (2), is an
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0
approved antiꢀinflammatory drug. In contrast to thousands of known derivatives of
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pyrazolo[1,5ꢀa]pyridine (1), only ~120 fully saturated derivatives of 3 are known to date,
1
whereas the tricyclic analogues 4 (2a,2a ꢀdiazacyclopenta[cd]indenes) are unknown to the best of
our knowledge. Note that two related examples can be found in the literature. The first example is
1
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a theoretical report on 4 as a part of a heterofullerene system, while in the second example 4
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was a part of a cage compound (Figure 1).
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Figure 1. Pyrazolo[1,5ꢀa]pyridine (1), Ibudilast (2), less explored saturated analogues 3, the
unknown saturated tricyclic system 4, and the target structures 5 and 6.
In the context of our ongoing work on the synthesis of 3ꢀpyrazolidinones and pyrazole
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analogues of histamine, we recently reported two syntheses of tetrahydropyrazolo[1,5ꢀ
c]pyrimidineꢀ2,7(1H,3H)ꢀdiones as the first representatives of a novel saturated heterocyclic
1
4,15
system.
Subsequently, a library of related tetrahydropyrazolo[1,5ꢀc]pyrimidineꢀ3ꢀ
carboxamides as novel conformationally constrained pyrazole analogues of histamine was also
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synthesized. In continuation, we focused on 1,7,7ꢀtrisubstituted hexahydropyrazolo[1,5ꢀ
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a]pyridinꢀ2(1H)ꢀones 5 and their tricyclic analogues (3,4,4aꢀtrisubstituted octahydroꢀ2Hꢀ2a,2a ꢀ
diazacyclopenta[cd]indenꢀ2ꢀone) 6 (Figure 1). A literature search revealed that scaffolds 5 and 6
were unknown, which prompted us to focus our attention on their synthesis since the availability
of this type of template would enable the preparation of compound libraries, suitable for
screening for various activities or applications. The results of this study are reported herein.
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. Results and Discussion
Initially, we attempted to access the title compounds via 7ꢀsubstituted 2ꢀoxoꢀ2,3,3a,4,5,6ꢀ
hexahydropyrazolo[1,5ꢀa]pyridinꢀ8ꢀiumꢀ1ꢀides 12 as keyꢀintermediates available by microwaveꢀ
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assisted cyclization of pentꢀ4ꢀenꢀ1ꢀyl NꢀBocꢀhydrazones 11 following the procedure described
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recently by Beauchemin and coꢀworkers. First, hexꢀ5ꢀenꢀ2ꢀone (9a) was prepared by Cu(I)ꢀ
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catalyzed treatment of acetyl chloride (7a) with pentꢀ4ꢀenꢀ1ꢀylmagnesium bromide (8a). The
crude ketone 9a was, without purification, transformed further with Bocꢀcarbazate (10) into the
corresponding hydrazone 11a, which was isolated in 56% yield over two steps. Subsequent
cyclization of hydrazone 11a was performed in trifluoromethylbenzene under microwave
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8
irradiation at 150 °C to afford the desired azomethine imine 12a in 60% yield. Finally,
stereoselective reduction of dipole 12a with excess PhMgBr at 0–20 °C followed by workup
using column chromatography furnished the (3aS*,7S*)ꢀisomer 13'a in 31% yield (Scheme 1).
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Scheme 1. Fourꢀstep synthesis of compound 13'a.
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Reaction conditions: (i) pentꢀ4ꢀenꢀ1ꢀylmagnesium bromide (8a), THF, CuI (4 mol%), r.t. (Ref.
9); (ii) BocNHNH (10), MeOH, AcOH, r.t. (Ref. 18); (iii) µꢀwaves, 300 W, C H CF , 150 °C,
1
2
6
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3 h (Ref. 18); and (iv) excess PhMgBr (8b), THF, 0→20 °C, followed by column
chromatography.
The successful preparation of 13'a confirmed the viability and simplicity of the original
synthetic approach. However, the microwaveꢀassisted cyclization of 11a into 12a was the
bottleneck of this synthetic sequence because in our hands the reaction was reproducible only on
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a ~0.3 mmol scale, i.e. on a similar scale as that reported previously (0.2 mmol). In addition, the
incomplete conversion and the formation of byꢀproducts required a tedious chromatographic
workup to obtain pure 12a. Thus, despite its simplicity, the original synthetic approach was not
suitable to provide sufficient amounts of the keyꢀintermediates 12 for further transformations.
Consequently, a sevenꢀstep synthesis of 12 was developed based on a synthetic method applied
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previously for the preparation of related pyrazolidinones. The synthesis commenced with an
almost quantitative oneꢀpot transformation of commercially available γꢀacetylꢀ (14a) and γꢀ
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benzoylbutyric acid (14b) into the δꢀketo acid ketals 16a and 16b; these steps were composed
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of ketalization and esterification with ethylene glycol and trimethyl orthoformate (TMOF) and
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were followed by hydrolysis of the intermediate ketalꢀesters 15a,b.
MasamuneꢀClaisen
condensation of the acids 16 afforded the corresponding βꢀketo esters 17a,b in quantitative
yields. Then, reduction of ketones 17, followed by Oꢀmesylation of alcohols 18, and cyclization
of Oꢀmesylates 19 with hydrazine hydrate furnished the pyrazolidinones 20a and 20b in good
yields over three steps. Finally, acidolytic removal of the ketal protecting group and concomitant
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cyclization furnished the desired keyꢀintermediates 12a and 12b in 80% and 60% yield,
respectively (Scheme 2).
Scheme 2. Sevenꢀstep synthesis of azomethine imines 12a and 12b.
Yield (%)
Compound
R
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97
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14→12
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1
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2a, 14a–20a
2b, 14b–20b
Me
Ph
43
Reaction conditions: (i) ethylene glycol, TMOF, H SO (cat.), r.t. (Ref. 22); (ii) 2
M
aq. NaOH,
2
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H O–MeOH, r.t. (Ref. 22); (iii) CDI, THF, r.t., then MeO CCH CO K, MgCl , r.t.; (iv) NaBH ,
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MeOH, 0 °C; (v) MsCl, pyridine, 0 °C; (vi) N H ·H O, MeOH, 50 °C; and (vii) EtOH, TFA (cat.),
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reflux.
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Next, the addition of Grignard reagents to dipoles 12a and 12b was studied. First, we
attempted to add excess PhMgBr (8b) to the dipole 12a at a lower temperature; however, at –78
°C, no reaction occurred after several hours. When the reaction was performed at –20 °C for 1 h
followed by treatment at room temperature for 12 h, pure (3aS*,7S*)ꢀisomer 13'a was isolated in
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54% yield. The other epimer could not be detected in the reaction mixture. As expected, the
epimer 13a was exclusively obtained in 69% yield upon treatment of the 7ꢀphenyl analogue 12b
with excess MeMgBr (8c) under the same reaction conditions. However, the addition of MeMgBr
(8c) to 12a gave compound 13b in 31% yield. NꢀAlkylation of 13a, 13'a, and 13b with methyl
iodide or benzyl bromide in DMF in the presence of K CO furnished the title compounds 5a,
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5'a, 5'b, and 5c in good yields. The stereoselectivity of the addition reaction is explainable by the
preferential attack of the Grignard reagent 8 to the less hindered face of the dipole 12 to give the
major isomer with synꢀoriented R' and H–3a (Scheme 3).
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Scheme 3. Synthesis of title bicyclic compounds 5, 5', 13, and 13' and the proposed
stereochemistry of the addition to the C=N bond.
Ph
Ph
R
H
N
N
N
i
N
H
ii
N
H
N
5'a (68%, R = Me)
5'b (55%, R = Bn)
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O
O
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4%
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(
3aS*,7S*)ꢀisomer 13'a
5'a,b
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Ph
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Ph
Me
N
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3aS*,7R*)ꢀisomer 13a
Bn
H
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hindered
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HN1
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Compound 12
H
7
R'
R
H
syn
less hindered
R'MgBr
Major isomer 13 or 13'
Reaction conditions: (i) excess PhMgBr (8b) or MeMgBr (8c), THF, –20 °C→ r.t.; (ii) MeI or BnBr,
K CO , DMF, r.t.
2
3
The 1,3ꢀdipolar characteristic of azomethine imines 12a and 12b was tested in [3+2]ꢀ
cycloadditions to acetylenicꢀ (21a–d) and olefinic dipolarophiles 22a–c. Most cycloadditions
were highly regioꢀ and stereoselective and gave the corresponding cycloadducts 23–26 as single
isomers upon workup using flash chromatography. Cycloadditions of 12a,b to dimethyl
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acetylenedicarboxylate (DMAD) (21a) and terminal ynones 21b–d proceeded at room
temperature to give the major (4aS*,7aS*)ꢀisomers 23a,b and 24a–f in 42–73% yields.
Surprisingly, methyl propiolate (21e) did not react at room temperature, and heating at 80 °C was
required to obtain cycloadducts 24g and 24h. In the reaction of 12b with 21e, the minor isomer
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24'h was also isolated. The CuIꢀcatalyzed reactions of 12a,b with 21e occurred at room
temperature to give inseparable 85:15 mixtures of cycloadducts 24g,h and methyl (E)ꢀ3ꢀ
24
[
ethyl(isopropyl)amino]acrylate (29). The reactions of dipoles 12 with olefinic dipolarophiles
22a–c required heating at 80 °C to achieve satisfactory conversion into the products. Treatment
of 12a with methyl acrylate (22a) produced a mixture of products; upon chromatographic
separation, the endoꢀcycloadduct 25a and the regioisomeric exoꢀadduct 25'a were isolated in 11%
and 16% yield, respectively. The reactions of the 7ꢀphenyl analogue 12b with methyl (22a) and
tertꢀbutyl acrylate (22b) were highly regioꢀ and stereoselective and afforded the major endoꢀ
isomers 25b and 25c as single products. Cycloadditions of 12a and 12b to Nꢀphenylmaleimide
(22c) followed by chromatographic separation furnished the major exoꢀisomers 26a and 26b in
1
3% and 40% yield, respectively. To evaluate the further diversification of the core scaffold, the
acidolytic deprotection of the carboxy function of cycloadduct 25c gave the carboxylic acid 27 in
8% yield. Amidation of 27 using bis(pentafluorophenyl) carbonate (BPC) as the activating
reagent furnished carboxamides 28a–c in 70–79% yields (Scheme 4, Table 1).
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a
Scheme 4. Synthesis of the title tricyclic compounds 23–28.
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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 conditions: (i) DMAD (21a), toluene or CH Cl , r.t.; (ii) ynone 21b–d or methyl
2
2
propiolate (21e), CH Cl , r.t. or 80 °C (pressure vessel); (iii) methyl propiolate (21e), CuI (20
2
2
mol%), DIPEA (20 mol%), CH Cl , r.t.; (iv) methyl acrylate (22a) or tꢀbutyl acrylate (22b),
2
2
toluene or CH Cl (pressure vessel), 80 °C; (v) Nꢀphenylmaleimide (22c), toluene, 80 °C
2
2
followed by column chromatography; (vi) CH Cl –TFA (2:1), r.t.; and (vii) BPC, Et N, DMF,
2
2
3
r.t., 1 h followed by RR'NH, Et N, r.t., 24 h.
3
a
24
)
In the CuIꢀcatalyzed reactions (see iii), byꢀproduct 29 was also formed.
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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Table 1. Experimental data on tricyclic compounds 23–28.
1
2
3
a
Compound
R
R
ꢀ
R
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
D.r.
Yield (%)
2
3a
3b
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Ph
Me
Me
Ph
Ph
Me
Ph
Ph
ꢀ
94:6
60
56
73
69
67
71
42
50
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
ꢀ
100:0
93:7
24a
Me
Me
Ph
2
2
4b
4c
91:9
90:10
100:0
93:7
24d
Ph
2
4e
4f
CH
CH
2
2
NHBoc
NHBoc
2
89:11
b
b
24g
OMe
OMe
OMe
Me
Me
Me
tꢀBu
ꢀ
93:7 (100:0 )
56 (47 )
b
b
2
2
2
2
4h
85:15 (100:0 ) 60 (59 )
c
d
4'h
5a
100:0
11
16
11
44
77
13
40
48
79
76
70
d
100:0
d,e
5'a
e
25b
e,f
2
5c
6a
100:0
2
78:22
26b
ꢀ
90:10
2
2
2
7
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
8a
8b
8c
H
Bn
(CH
ꢀ
H
) OH
2 3
2
ꢀ
piperidinꢀ1ꢀyl
a
1
b
c
d
) Determined using H NMR. ) CuIꢀcatalyzed reaction. ) Minor epimer. ) Upon separation by
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e
column chromatography. ) The isomer ratio could not be determined due to overlapped signals
1
f
in the H NMR spectrum of the crude product. ) Upon purification using flash column
chromatography.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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35
36
37
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41
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45
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47
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49
50
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53
54
55
56
57
58
59
60
The regioselectivity of the cycloadditions to terminal ynones 21b–d and alkyl acrylates 22 was
1
3,25,26
in agreement with the regioselectivity of closely related thermal
and Cuꢀcatalyzed
13,26,27
reactions.
The preferential formation of the regioisomers 24 and 25 is in line with the
electrostatically controlled approach of the polarized dipolarophile 21 or 22 to the mesomeric
structure 12 via the proposed transition states TS1 and TS2 (Scheme 5). Facial selectivity of
cycloadditions to 12a,b is explainable by the preferential attack of the dipolarophile 21 or 22
from the less hindered face of the dipole 12 via the proposed transition states TS1–TS3.
Accordingly, the endoꢀattack of the acrylate 22 via TS2 should lead to the major diastereomer 25,
whereas the exoꢀapproach of maleimide 22c via TS3 should give the major exoꢀisomers 26
(Scheme 5).
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 5. Regioꢀ and stereoselectivity of cycloadditions to chiral dipoles 12a and 12b.
R
7
N 1
6
N
O
2
5
3
4
Ph
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2a,b
+
O
O
R'OC
R''
R'O C
2
+
2
1a–e
2
2a,b
22c
hindered
O
‡
hindered
O
‡
hindered
O
‡
H
H
H
H
H
H
H
H
H
H
H
H
N
N
N
N
N
N
H
H
H
R
O
R
+
R
+
R''
N
Ph
CO R'
2
COR'
H
O
exoꢀapproach
endoꢀapproach
TS1
TS2
TS3
O
O
O
R
N
R
R
N
N
N
N
N
O
H
O
H
R''
N
Ph
H
H
H
H
COR'
CO R'
2
Major isomers 23 and 24 (R'' = H)
Major isomers 25
Major isomers 26
3. Structure determination.
The structures of novel compounds 5a,c, 5'a,b, 13a,b, 13'a, 17a,b, 18a,b, 19a,b, 20a,b, 23a,b,
1
24a–h, 24'h, 25a–c, 25'a, 27, and 28a–c were determined using spectroscopic methods (IR, H
13
and C NMR, COSY, HSQC, HMBC and NOESY spectroscopy, and MS). The structure and
purity of compounds 12b, 5'a, and 5'b were additionally determined via elemental analyses for
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C, H, and N. Crude intermediates 16a,b, 17a,b, 18a,b, 19a,b, and 20a,b were used in the
following transformation without any purification.
The relative configurations of bicyclic (5, 5', 13, and 13') and tricyclic compounds 23–26
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
28
were determined by H NMR and NOESY spectroscopy. The structures of structurally
representative compounds 5'b, 13'a, 23b, 24b, 26b, and 28a were unambiguously determined
2
8
using Xꢀray diffraction. The crystal structure of cycloadduct 24b is depicted in Figure 2.
Figure 2. ORTEP drawing of the 24b molecule showing the atom labelling. The displacement
ellipsoids are drawn with a 30% probability level and the hydrogen atoms are shown as small
spheres of arbitrary radii.
4. Computational determination of the mechanism and selectivity of [3+2]ꢀcycloadditions
2
7
In contrast to highly regioselective catalyzed reactions, thermal cycloadditions of
2
5,26
azomethine imines to terminal acetylenes usually furnish mixtures of regioisomers.
Intrigued
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
by the high regioselectivity of thermal cycloadditions of dipoles 12 (cf. Scheme 4), we attempted
29
to find a plausible mechanistic explanation using computational methods. Dipoles 12a,b, 3ꢀ
butynꢀ2ꢀone (21b), methyl propiolate (21e), and methyl acrylate (22a) were chosen as model
reactants.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
30
All computations were performed using the Gaussian 09 program suite. Geometry
optimization of all stationary points was performed using DFT methods at the B3LYP/6ꢀ
31
3
11+G(d,p) level of theory. First, the ideal gas approximation under the standard conditions
was assumed and then the polarizable continuum model (PCM) for solvation by toluene was used
for the computations. The DFT study started with an evaluation of the energetic and structural
aspects of possible regioꢀ and stereoisomeric transition states. The syn/antiꢀapproach refers to facial
selectivity with respect to the angular proton H–3a, while for the acetylenic dipolarophiles 21b and
28
21e, the endoꢀorientation refers to the orientation of the C=O function in the transition state.
3
2
The calculated activation and distortion/interaction parameters as well as asynchronicity
3
2g,h
parameter (ꢁdTS/P
)
are reported in Table 2. In all reactions, the synꢀtransition states were
found to be energetically favourable. The differences of the Gibbs energy of activation values
–1
between the syn and the anti forms in the range of 2.7–4.0 kcal mol demonstrate that the
reaction channel prefers the synꢀapproach to the dipole 12. The typical asynchronicity measure
value, ꢁdTS/P ~ 0.3, suggests that reactions are concerted, although asynchronous. The computed
‡
free energy of activation values in toluene as the reaction medium are significantly smaller (ꢁꢁ
G
–
1
≈
8 kcal mol ) for the ynoneꢀderived cycloadducts 24 compared to the acrylateꢀderived
cycloadducts 25. In the reactions with acrylate 22a, the 7ꢀphenyl dipole 12b has a lower energy
and more asynchronous transition state than its 7ꢀmethyl analogue 12a. Transition states leading
to the minor regioisomers 25' are higher in energy than those for the major isomers 25. Finally,
‡
the energy difference between the 4aꢀmethyl regioisomers 25a and 25'a (ꢁꢁG = 2.8 kcal/mol) is
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smaller than that for the 4aꢀphenyl analogs 25b and 25'b (ꢁꢁG = 6.1 kcal/mol). The calculated
parameters given in Table 2 are in agreement with the experimental results in terms of reactivity
2
8
and selectivity (cf. Scheme 4, Table 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
‡
Table 2. B3LYP/6ꢀ311+G(d,p) calculated activation energies, distortion energies (
ꢁ
E ),
d
‡
interaction energies (
ꢁ
E ), and asynchronicity degrees for transition states.
i
‡
TS
B3LYP/6ꢀ331+G(d,p)
‡
a
‡b
‡c
‡d
‡d
e
ꢁG
ꢁG
ꢁE
ꢁEd
ꢁEi
ꢁdTS/P
12
21/22 Total
1
2
3
4
5
6
7
8
9
24aꢀanti/exo
28.9
26.6
29.3
26.5
29.4
28.8
26.2
26.1
36.8
36.2
33.6
32.5
38,3
38,8
32.0
31.8
28.8
27.9
31.5
31.0
27.4
27.4
40.0
39.3
36.6
35.3
–
16.2
16.0
13.6
13.7
16.2
12.3
12.3
13.5
23.3
22.3
19.7
18.6
24,6
25,1
10.6
11.0
8.2
14.0
13.9
14.2
13.8
18.1
14.3
20.4
14.2
14.1
14.7
14.2
14.6
–
24.6
24.9
22.4
23.0
27.3
25.0
31.8
23.5
31.2
31.2
29.8
29.3
–
–8.4
–8.8
–8.8
–9.3
0.30
0.28
0.40
0.33
24aꢀanti/endo
24aꢀsyn/exo
24aꢀsyn/endo
24gꢀanti/exo
24gꢀanti/endo
24gꢀsyn/exo
24gꢀsyn/endo
25aꢀanti/exo
25aꢀanti/endo
25aꢀsyn/exo
9.2
9.2
–11.2 0.53
–12.7 0.53
–19.5 0.57
–10.0 0.70
10.7
11.4
9.2
17.1
16.6
15.5
14.7
–
–7.9
–8.9
0.18
0.27
1
0
1
1
–10.1 0.19
12 25aꢀsyn/endo
–10.7 0.24
1
3
4
25'aꢀanti/exo
–
–
0.30
0.37
1
25'aꢀanti/endo
–
–
–
–
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
5
6
25'aꢀsyn/exo
35,3
35,3
36.0
34.1
34.3
31.2
40,0
39,4
38,0
37,3
–
21,5
21,6
22.4
20.3
20.1
17.6
26,3
25,4
24,0
–
–
–
–
0.36
0.37
0.30
0.38
0.30
0.33
0.20
0.24
0.22
0.24
25'aꢀsyn/endo
–
–
–
–
–
17 25bꢀanti/exo
37.2
35.1
35.2
32.4
–
13.5
10.4
13.1
12.1
–
15.4
17.0
15.7
15.3
–
28.9
27.4
28.8
27.4
–
–6.5
–7.2
–8.7
–9.8
–
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
18
19
20
21
25bꢀanti/endo
25bꢀsyn/exo
25bꢀsyn/endo
25'bꢀanti/exo
22 25'bꢀanti/endo
–
–
–
–
–
2
3
4
25'bꢀsyn/exo
–
–
–
–
–
2
25'bꢀsyn/endo
–
23,4
–
–
–
–
a
‡
b
‡
c
ꢁG =G –Gdipole–Gdipolarophile at 298 K in gas.
ꢁG at 298 K in toluene as a solvent. Zeroꢀpoint
TS
d
‡
‡
‡
energy corrected values (EZPE) of B3LYP/6ꢀ311+G(d,p).
ꢁE
d dipole,
ꢁ
E
, and ꢁE
d total
d dipolarophile
‡
are the distortion energies of the dipole, dipolarophile, and total distortion energy.
ꢁ
E indicates
i
e
the interaction energy between distorted fragments.
ꢁdTS/P = |(C–C) /(C–C) –(C–N) /(C–N) |.
TS P TS P
Transition states leading to regioisomers 25a and 25'a are shown in Figure 3. In the transition
state for the major isomer, TS25aꢀsyn/endo, the C–N bond is shorter than the C–C bond, while
these values are inversed in TS25'aꢀsyn/endo. This result suggests that the C–C bond formation is
more advanced in TS25'a,bꢀsyn/endo, while the formation of the C–N bond is more advanced in
28
TS25aꢀsyn/endo.
1
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.38
2.38
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
1.97
1
.86
1.86
2
.45
TS25aꢀsyn/endo
TS25'a ꢀsyn/endo
Figure 3. Most favourable transition states for cycloaddition, 12a + 22a → 25a + 25'a, in the gas
phase, calculated at the 6ꢀ311+G(d,p) level.
3
3
The electrophilicity ω and nucleophilicity N values for the dipoles 12a,b and dipolarophiles
2
1b, 21e, and 22a are displayed in Table 3. All dipolarophiles, 21b, 21e, and 22a, have high
electrophilicity indices, 1.93, 1.97, and 2.20 eV, respectively, and are classified as strong
34
electrophiles on the electrophilicity scale. However, the dipoles 12a and 12b present moderate
to strong respective electrophilicity indices of 1.39 and 2.13 eV, respectively, while both are
classified as a strong nucleophiles due to their high nucleophilicity index, N > 3 eV.
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1
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1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Electrophilicity ω and nucleophilicity N of dipoles 12a,b and dipolarophiles.
Entry Compound
η
ꢂ
ω (eV)
1.39
2.13
2.20
1.97
1.93
N (eV)
3.04
3.10
1.27
0.85
1.03
1
2
3
4
5
7ꢀMeꢀdipole 12a
4.87
3.92
5.71
6.47
6.33
–3.67
–4.09
–5.01
–5.05
–4.94
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7ꢀPhꢀdipole 12b
3ꢀButynꢀ2ꢀone (21b)
Methyl propiolate (21e)
Methyl acrylate (22a)
The frontier molecular orbital (FMO) analysis for the cycloadditions studied show that the
main interactions occur between the HOMOdipole of dipoles 12a,b and the LUMOdipolarophile of the
electronꢀpoor dipolarophiles 21b,e and 22a due to the very different energy gaps, ꢁE' – ꢁE > 1.5
29
eV (Figure 4). In terms of favourable FMO interactions, similar HOMO orbital coefficients at
2
8
N(1) and C(7) in 12a and larger coefficients at N(1) in the phenyl analogue 12b indicate a
greater regioselectivity for the phenyl analogue 12b, which was also observed experimentally.
Figure 4. FMO diagram of HOMOꢀLUMO orbitals calculated by NBO6/6ꢀ311+G(d,p) using
PCM: toluene.
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The high asynchronicity of the cycloaddition of dipole 12a to 3ꢀbutynꢀ2ꢀone (21b) that was
determined theoretically (cf. Table 2, entry 8) suggested the possibility of a stepwise
10
11
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49
50
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54
55
56
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59
60
29
mechanism. To check this possibility experimentally, the kinetics of this cycloaddition was
1
investigated. The reaction progress was followed using H NMR in CDCl , CD CN, and DMSOꢀ
3
3
d6 by monitoring the disappearance of the dipole 12a. The finding of no significant solvent effect
on the reaction kinetics was clearly in agreement with the concerted 1,3ꢀdipolar reaction
mechanism (Figure 5).
Figure 5. The kinetics of the reaction 12a + 21b → 24a in CDCl , CD CN, and DMSOꢀd .
3
3
6
Next, the reaction kinetics was measured in CD CN at different temperatures (302, 312, 322,
3
28
and 332 K) as a pseudoꢀfirst order reaction with respect to butynone 21b. Acetonitrile was
selected as the solvent of choice due to the appropriate solubility of all reactants within the
3
5
temperature range needed to construct the Eyring plot (Figure 6). The corresponding
‡
‡
experimental activation parameters were determined as ꢁH = 13.8 ± 0.1 kcal/mol, ꢁS = –27.2 ±
‡
0
.2 cal/mol K, and ꢁG = 21.9 ± 0.1 kcal/mol. The experimental results are in fairly good
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agreement with the computed values (cf. Table 2, entry 8); however, the strong negative entropy
value suggests a highly ordered rateꢀdetermining transition state, as expected for a polar
2
9
concerted cycloaddition.
0
1
2
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4
5
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8
9
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2
3
4
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9
0
Figure 6. Eyring plot for the cycloaddition between dipole 12a and butynone 21b.
5. Conclusion
7
A sevenꢀstep synthesis of C,N,Nꢀcyclic azomethine imines, 7ꢀsubstituted 2ꢀoxoꢀꢁ ꢀ
hexahydropyrazolo[1,5ꢀa]pyridinꢀ8ꢀiumꢀ1ꢀides 12, from δꢀacyl butyric acids 14 was developed as
an alternative to the previously described threeꢀstep process starting with acid chlorides 7 and
1
8
pentꢀ4ꢀenꢀ1ꢀylmagnesium bromide (8). Though requiring a longer synthesis time, the present
method allows largeꢀscale preparation of cyclic dipoles 12, while the shorter and more elegant
1
8
threeꢀstep synthesis has a scale limitation (< 0.5 mmol). The stereoselective addition of
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Grignard reagents to cyclic azomethine imines 12 gave 7,7ꢀdisubstituted hexahydropyrazolo[1,5ꢀ
a]pyridinꢀ2(1H)ꢀones 13 or 13', which were further Nꢀalkylated into the title 1,7,7ꢀtrisubstituted
compounds 5 and 5'. [3+2]ꢀCycloadditions of 12 were highly stereoselective particularly in
reactions with acetylenes 21 (one regioisomer, d.r. ≥ 89:11), whereas with olefins 22, the
stereoselectivity was lower (d.r. ≥ 78:22). Interestingly, thermal cycloadditions to terminal
acetylenes 21b–e were as regioselective as CuIꢀcatalyzed reactions with methyl propiolate (21e).
Moreover, the nonꢀcatalyzed reactions were even cleaner because they did not lead to the byꢀ
product enaminone 29, which was difficult to separate. Acidolytic deprotection of the carboxy
function gave the carboxylic acid 27, which was amidated into carboxamides 28a–c. Both
reactions, the addition and [3+2]ꢀcycloaddition exhibit the same stereocontrol leading to the
major isomers in which R–C(7) and H–C(3a) from the parent dipole become antiꢀoriented.
Regioꢀ and stereoselectivity as well as mechanism of these [3+2]ꢀcycloadditions were evaluated
by computational and experimental methods supporting a polar concerted cycloaddition
mechanism with the most favorable energetically syn/endoꢀtransition states (ꢁꢁG ~ 3 kcal/mol).
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
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41
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43
44
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46
47
48
49
50
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52
53
54
55
56
57
58
59
60
To the best of our knowledge, the title compounds, 23–28, are the first known representatives of
1
2
a,2a ꢀdiazacyclopenta[cd]indene, which is an unexplored saturated heterocyclic system. In
summary, we developed a viable synthetic protocol for the preparation of cyclic azomethine
imines 12 as useful intermediates in the synthesis of 3Dꢀrich saturated heterocycles, which may
serve as a starting point in the search for novel lead compounds in medicinal chemistry, chemical
biology, and material science.
6. Experimental
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6
.1. General methods. Melting points were determined on a Kofler micro hot stage and on
an automated melting point system. The NMR spectra were recorded in CDCl and DMSOꢀd6
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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9
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2
3
4
5
6
7
8
9
0
using TMS as the internal standard on a 300 MHz or 500 MHz instrument at 300 and 500 MHz
1
13
for H and at 75.5 and 126 MHz for C nucleus, respectively. Mass spectra were recorded on
timeꢀofꢀflight (TOF) mass spectrometer equipped with a double orthogonal electrospray source at
athmospheric pressure ionization (ESI) coupled to an HPLC instrument. IR spectra were recorded
on a FTIR ATR spectrophotometer. Microanalyses were performed by combustion analysis on a
CHN analyzer. Microwaveꢀassisted reactions were performed in a single mode microwave
instrument in pressure reaction vessels. Reaction times refer to hold times at the temperature
indicated not the total irradiation times. The temperature was measured using IR temperature
sensor of the instrument. Column chromatography and flash column chromatography were
performed on silica gel (particle size 35–70 ꢂm). Acetyl chloride (7a), Grignard reagents 8a–c,
tertꢀbutyl carbazate (10), γꢀacetylꢀ (14a) and γꢀbenzoyl butyric acid (14b), 1,1'ꢀ
carbonyldiimidazole, bis(pentafluorophenyl) carbonate, potassium monomethyl malonate,
benzylamine, 3ꢀaminoꢀ1ꢀpropanol, piperidine, and dipolarophiles 21a–e and 22a–c are
1
9
commercially available. Hexꢀ5ꢀenꢀ2ꢀone (9a) and tertꢀbutyl 2ꢀ(heptꢀ6ꢀenꢀ2ꢀylidene)hydrazineꢀ
18
1
ꢀcarboxylate (11a) were prepared according to the literature procedures.
6.2. Synthesis of 7ꢀmethylꢀ2ꢀoxoꢀ2,3,3a,4,5,6ꢀhexahydropyrazolo[1,5ꢀa]pyridinꢀ8ꢀiumꢀ1ꢀ
ide (12a) by microwaveꢀassisted cyclization of hydrazone 11a. Compound 12a was prepared
1
8
following slightly modified literature procedure. A 5 mL Pyrex reaction vessel was charged
with hydrazone 9a (57 mg, 0.25 mmol) and trifluoromethylbenzene (2 mL) and the mixture was
heated under microwave irradiation (P = 300 W) at 150 °C for 3 h. Volatile components were
evaporated in vacuo, the residue was dissolved in a mixture of MeOH and CH Cl (1:5, 10 mL),
2
2
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silica gel (500 mg), and the suspension was carefully evaporated in vacuo. The so formed silica
gel with adsorbed reaction product(s) was poured into a stabilized chromatographic column
(silica gel, 1.5×5 cm, EtOAc). First, the nonꢀreacted hydrazine 11a was eluted with EtOAc,
followed by elution of the product 12a with CH Cl ꢀMeOH (10:1). Fractions containing the
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
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43
44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
2
product were combined and evaporated in vacuo to give 12a. Yield: 22 g (60%) of a beige solid;
1
mp 125–126 °C (decomp.). H NMR (500 MHz, CDCl ): δ 1.67–1.84 (2H, m); 2.00–2.07 (1H,
3
m); 2.30 (3H, br t, J = 0.8 Hz); 2.33–2.39 (1H, m); 2.57 (1H, dd, J = 15.6, 10.4 Hz); 2.55–2.65
(1H, m); 2.72 (1H, dd, J = 20.5, 6.8 Hz); 2.81 (1H, dd, J = 15.6, 8.4 Hz); 4.17 (1H, br q, J = 10.2
1
3
Hz). C NMR (126 MHz, DMSOꢀd ): δ 18.3, 20.8, 27.3, 30.1, 37.5, 64.5, 148.8, 180.4. m/z (ESI)
6
+
+
=
153 (MH ). m/z (HRMS) Found: 153.1021 (MH ). C H N O requires: m/z = 153.1022. ν
8
13
2
max
–
1
(
ATR) 3382, 2936, 1674, 1584, 1373, 1337, 1082, 765, 667 cm . Physical and spectral data of
18
compound 12a were in agreement with the literature data.
6.3. A sevenꢀstep synthesis of 7ꢀsubstitutedꢀ2ꢀoxoꢀ2,3,3a,4,5,6ꢀhexahydropyrazolo[1,5ꢀ
a]pyridinꢀ8ꢀiumꢀ1ꢀides 12a and 12b from γꢀacyl butyric acids 14a and 14b.
6
.3.1.
Synthesis of 4ꢀ(2ꢀsubstitutedꢀ1,3ꢀdioxolanꢀ2ꢀyl)butanoic acids 16a and 16b.
Compounds 16a and 16b were prepared following literature procedure for the synthesis of related
22
compounds. A mixture of carboxylic acid 14 (5 mmol), anh. CH Cl (10 mL), ethylene glycol
2
2
(
1.4 mL, 25 mmol), TMOF (1.6 mL, 15 mmol), and H SO (96%, 25 µL) was stirred at r.t. for 6
2 4
h. Then, NaHCO (250 mg) was added and the mixture was stirred at r.t. for 10 min. Volatile
3
components were evaporated in vacuo (2 mbar, 40 °C), MeOH (7 mL) and 2
M aq. NaOH (5 mL)
were added, and the mixture was stirred at r.t. for 12 h. The mixture was concentrated to a half of
the initial volume by evaporation in vacuo (2 mbar, 40 °C) and aqueous residue was acidified
with citric acid to pH ~2. The product was extracted with EtOAc (3×20 mL), the combined
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6
organic phases were dried over anh. sodium sulfate, filtered, the filtrate was evaporated in vacuo
to give 16.
6.3.1.1. 4ꢀ(2ꢀMethylꢀ1,3ꢀdioxolanꢀ2ꢀyl)butanoic acid (16a). Prepared from 14a (596 µL, 5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
mmol). Yield: 800 mg (91%) of pale yellow oil. H NMR (500 MHz, CDCl ): δ 1.33 (3H, s);
3
1
3
1
.63–1.79 (4H, m); 2.39 (2H, t, J =7.1 Hz); 3.88–4.02 (4H, m); 10.42 (1H, br s). C NMR (126
MHz, CDCl ): δ 19.2, 23.8, 33.8, 38.2, 64.7, 109.7, 178.7. Physical and spectral data of 16a were
3
20
in agreement with the literature data.
6.3.1.2. 4ꢀ(2ꢀPhenylꢀ1,3ꢀdioxolanꢀ2ꢀyl)butanoic acid (16b). Prepared from 14b (960 mg, 5
1
mmol). Yield: 1.180 g (98%) of white solid; mp 68–71 °C. H NMR (500 MHz, CDCl ): δ 1.71
3
(1H, tt, J = 10.6, 6.3 Hz); 1.89–1.99 (2H, m); 2.35 (2H, t, J = 7.6 Hz); 3.73–3.81 (2H, m); 3.96–
13
4.07 (2H, m); 7.27–7.36 (3H, m), 7.43–7.46 (2H, m). C NMR (126 MHz, CDCl ): δ 18.9, 33.6,
3
39.5, 64.5, 110.1, 125.6, 127.9, 128.1, 142.3, 178.2. Physical and spectral data of 16b were in
2
1
agreement with the literature data.
6.4. Synthesis of methyl 3ꢀoxoꢀ6ꢀ(2ꢀsubstitutedꢀ1,3ꢀdioxolanꢀ2ꢀyl)hexanoates 17a and
17b. Under argon 1,1'ꢀcarbonyldiimidazole (815 mg, 5.2 mmol) was added to a solution of
carboxylic acid 16 (5 mmol) in anh. THF (15 mL) and the mixture was stirred at r.t. for 1 h.
Then, a solid well homogenized mixture of anh. MgCl (395 mg, 4.8 mmol), and potassium
2
monomethyl malonate (1.130 g, 7.5 mmol) was added, and the suspension was stirred at r.t. for
12 h. Volatile components were evaporated in vacuo, the residue was taken up in EtOAc (20
mL), and the suspension was washed with 1
M NaHSO (3×20 mL) and brine (3×10 mL). The
4
organic phase was dried over anh. sodium sulfate, filtered, and the filtrate was evaporated in
vacuo to give 17.
6
.4.1.
Methyl 6ꢀ(2ꢀmethylꢀ1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate (17a). Prepared from 16a
1
(
800 mg, 5 mmol). Yield: 977 mg (98%) of brownish oil. H NMR (500 MHz, CDCl ): δ 1.33
3
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(3H, s); 1.64–1.77 (4H, m); 2.60 (2H, t, J = 7.1); 3.47 (2H, s); 3.76 (3H, s); 3.90–4.00 (4H, m).
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
C NMR (126 MHz, CDCl ): δ 18.0, 23.7, 38.0, 42.8, 49.0, 52.4, 64.6, 64.6, 109.8, 167.7, 202.5.
3
+
+
m/z (ESI) = 231 (MH ). m/z (HRMS) Found: 231.1224 (MH ). C H O requires: m/z =
1
1
19
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–1
2
31.1227. νmax (ATR) 2954, 2883, 2078, 1737, 1713, 1055 cm .
6.4.2.
Methyl 6ꢀ(2ꢀphenylꢀ1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀoxohexanoate (17b). Prepared from 16b
1
(800 mg, 5 mmol). Yield: 1.100 g (99%) of yellow oil. H NMR (500 MHz, CDCl ): δ 1.64–1.70
3
(2H, m); 1.88–1.91 (2H, m); 2.54 (2H, t, J = 7.4 Hz); 3.41 (2H, s); 3.71 (3H, s); 3.73–3.78 (2H,
1
3
m); 3.98–4.03 (2H, m); 7.30–7.27 (1H, m); 7.31–7.35 (2H, m); 7.41–7.45 (2H, m). C NMR
(126 MHz, CDCl ): δ 17.7, 39.3, 42.8, 49.0, 52.3, 64.5, 64.5, 110.1, 125.7, 127.9, 128.2, 142.3,
3
+
+
1
67.7, 202.5. m/z (ESI) = 293 (MH ). HRMS (ESI): MH , found 293.1384. C H O requires
16 21 5
–
1
2
93.1384. νmax (ATR) 2953, 2889, 1966, 1154, 1075, 1039, 949 cm .
.5. Synthesis of methyl 3ꢀhydroxyꢀ6ꢀ(2ꢀ substitutedꢀ1,3ꢀdioxolanꢀ2ꢀyl)hexanoates 18a
and 18b. Finely ground NaBH (188 mg, 5 mmol) was added slowly in several portions to a cold
6
4
(0 °C, iceꢀbath) solution of βꢀketo ester 17 (5 mmol) in MeOH (10 mL) and the mixture was
stirred at 0 °C for 1.5 h. Then, brine (5 mL) was added, iceꢀbath was removed, the mixture was
stirred at r.t. for 5 min., and the product was extracted with CH Cl (3×20 mL). The combined
2
2
organic phases were dried over anh. sodium sulfate, filtered, and the filtrate was evaporated in
vacuo to give 18.
6
.5.1.
Methyl 3ꢀhydroxyꢀ6ꢀ(2ꢀmethylꢀ1,3ꢀdioxolanꢀ2ꢀyl)hexanoate (18a). Prepared from
1
7a (800 mg, 3.5 mmol) and NaBH (132 mg, 3.5 mmol) in MeOH (8 mL). Yield: 698 mg (85%)
4
1
of yellow oil. H NMR (500 MHz, CDCl ): δ 1.34 (3H, s); 1.43–1.53 (2H, m); 1.53–1.62 (2H,
3
m); 1.66–1.72 (2H, m); 2.45 (1H, dd, J = 16.5, 9.1 Hz); 2.54 (1H, dd, J = 16.4, 3.1 Hz); 2.94
13
(1H, d, J = 3.9 Hz); 3.72 (3H, s); 3.92–4.00 (4H, m); 4.04 (1H, ddd, J = 11.3, 7.7, 3.7 Hz). C
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2
2
2
2
2
2
2
3
3
3
3
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3
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3
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4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
NMR (126 MHz, CDCl ): δ 20.0, 23.8, 36.5, 38.9, 41.1, 51.8, 64.7, 64.7, 67.9, 110.0, 173.5. m/z
3
+
+
(
ESI) = 171 (MH ꢀ H O ꢀ C H O ). m/z (HRMS) Found: 171.1006 (MH ꢀ H O ꢀ C H O ).
2 2 4 2 2 4
–
1
C H O requires: m/z = 171.1021. ν (ATR) 3420, 2951, 1733, 1652, 1118, 1043 cm .
9
15
3
max
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
.5.2.
Methyl 3ꢀhydroxyꢀ6ꢀ(2ꢀphenylꢀ1,3ꢀdioxolanꢀ2ꢀyl)hexanoate (18b). Prepared from
17b (800 mg, 2.5 mmol) and NaBH (94 mg, 3.5 mmol) in MeOH (5 mL). Yield: 600 mg (85%)
4
1
of pale yellow oil. H NMR (500 MHz, CDCl ): δ 1.35–1.46 (2H, m); 1.46–1.59 (2H, m); 1.87–
3
1.97 (2H, m); 2.38 (1H, dd, J = 16.4, 9.1 Hz); 2.47 (1H, dd, J = 16.4, 3.2 Hz); 2.87 (1H, br s);
3.69 (3H, s); 3.74–3.78 (2H, m); 3.94–3.99 (1H, m); 3.99–4.03 (2H, m); 7.26–7.31 (1H, m);
13
7
.31–7.36 (2H, m); 7.46–7.41 (2H, m), C (126 MHz, CDCl ) δ 19.6, 36.4, 40.2, 41.1, 51.8,
3
+
6
4.5, 64.5, 67.9, 110.3, 125.7, 127.8, 128.1, 142.5, 173.4. m/z (ESI) = 233 (MH ꢀ H O ꢀ C H O ).
2
2
4
+
m/z (HRMS) Found: 233.1176 (MH ꢀ H O ꢀ C H O ). C H O requires: m/z = 233.1178. ν
2
2
4
14 17
3
max
–
1
(
ATR) 3467, 3050, 1731, 1171, 1102, 1072, 1026 cm .
6.6. Synthesis of methyl 3ꢀ(methylsulfonyl)oxyꢀ6ꢀ(2ꢀsubstitutedꢀ1,3ꢀdioxolanꢀ2ꢀ
yl)hexanoates 19a and 19b. Mesyl chloride (450 µL, 5.8 mmol) was added to a cold (0 °C, iceꢀ
bath) solution of the ester 18 (5 mmol) in anh. pyridine (5 mL) and the mixture was stirred at 0
°
C for 3 h. The reaction mixture was diluted with toluene (30 mL) and washed with 1 M aq.
NaHSO until pH of aqueous phase was around 2. The organic phase was washed again with
4
brine (2×10 mL), dried over anh. sodium sulfate, filtered, and the filtrate was evaporated in vacuo
to give 19.
6
.6.1.
Methyl 6ꢀ(2ꢀmethylꢀ1,3ꢀdioxolanꢀ2ꢀyl)ꢀ3ꢀ((methylsulfonyl)oxy)hexanoate (19a).
Prepared from 18a (600 mg, 2.5 mmol) and mesyl chloride (225 µL, 2.9 mmol) in anh. pyridine
1
(
2.5 mL). Yield: 620 mg (80%) of orange oil. H NMR (500 MHz, CDCl ): δ 1.33 (3H, s); 1.48–
3
1.59 (2H, m); 1.65–1.76 (2H, m); 1.76–1.91 (2H, m); 2.68 (1H, dd, J = 16.4, 4.8 Hz); 2.81 (1H,
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1
2
3
4
5
13
dd, J = 16.4, 7.9 Hz); 3.06 (3H, s); 3.74 (3H, s); 3.91–4.02 (4H, m); 5.04–5.09 (1H, m). C NMR
(
126 MHz, CDCl ): δ 19.3, 23.9, 34.9, 38.4, 38.5, 39.2, 52.1, 64.7, 64.7, 79.0, 109.7, 170.4. m/z
3
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
(ESI) = 311 (MH ). m/z (HRMS) Found: 311.1154 (MH ). C H O S requires: m/z = 311.1159.
1
2
23
7
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–1
νmax (ATR) 3021, 2954, 1734, 1710, 1334, 1167, 968, 902 cm .
6.6.2.
Methyl
3ꢀ(methylsulfonyl)oxyꢀ6ꢀ(2ꢀphenylꢀ1,3ꢀdioxolanꢀ2ꢀyl)hexanoate
(19b).
1
Prepared from 18b (1.4 g, 5 mmol). Yield: 1.55 g (95%) of pale orange oil. H NMR (500 MHz,
CDCl ): δ 1.37–1.53 (2H, m); 1.69–1.85 (2H, m); 1.85–2.00 (2H, m); 2.61 (1H, dd, J = 16.4,
3
4.9); 2.75 (1H, dd, J = 16.4, 7.9 Hz); 2.97 (3H, s); 3.69 (3H, s); 3.73–3.81 (2H, m); 3.93–4.08
(
2H, m); 4.98 (1H, dtd, J = 7.9, 6.2, 4.8 Hz); 7.28–7.31 (1H, m); 7.31–7.36 (2H, m); 7.40–7.46
1
3
(
2H, m). C NMR (126 MHz, CDCl ): δ 19.0, 34.7, 38.3, 39.2, 39.7, 52.0, 64.5, 64.5, 79.1,
3
+
1
10.0, 125.7, 127.9, 128.2, 142.3, 170.4. m/z (ESI) = 373 (MH ). m/z (HRMS) Found: 373.1312
+
(
MH ). C H O S requires: m/z = 373.1316. ν
(ATR) 2951, 2915, 2884, 1736, 1441, 1355,
max
1
7
25
7
–
1
1337, 1156, 1111, 910, 887, 702 cm .
.7. Synthesis of 5ꢀ(3ꢀ(2ꢀsubstitutedꢀ1,3ꢀdioxolanꢀ2ꢀyl)propyl)pyrazolidinꢀ3ꢀone 20a and
0b. Hydrazine monohydrate (1.3 mL, 26 mmol) was added to a solution of ester 19 (5 mmol) in
6
2
MeOH (20 mL) and the mixture was stirred at 50 °C for 3 days. Volatile components were
evaporated in vacuo and the crude product was purified by column chromatography (silica gel,
EtOAc–MeOH, 10:1). Fractions containing the product were combined and evaporated in vacuo
to give 20.
4
.7.1.
5ꢀ(3ꢀ(2ꢀMethylꢀ1,3ꢀdioxolanꢀ2ꢀyl)propyl)pyrazolidinꢀ3ꢀone (20a). Prepared from 19a
(295 mg, 1 mmol) and hydrazine monohydrate (260 µL, 5 mmol) in MeOH (5 mL). Yield: 160
1
mg (74%) of yellow oil. H NMR (500 MHz, CDCl ): δ 1.82 (1H, dtd, J = 13.6, 11.6, 5.8 Hz);
3
1
.92–2.02 (1H, m); 2.02–2.10 (1H, m); 2.40 (1H, ddt, J = 13.4, 5.8, 3.7 Hz); 2.55 (1H, dd, J =
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