Synthesis of fluorinated δ-lactams via cycloisomerization of gem-difluoropropargyl amides

Article abstract of DOI:10.3762/bjoc.6.48

Gem-Difluoro-1,7-enyne amides are suitable building blocks for the synthesis of difluorodihydropyridinones via a ring-closing metathesis reaction, and of 4,4-difluoro-3-oxoisoquinolines through a ring-closing metathesis-enyne metathesis tandem reaction. These products, in turn, undergo a Diels-Alder reaction to yield heterotricyclic systems in moderate to good yields.

Full text of DOI:10.3762/bjoc.6.48

Synthesis of fluorinated δ-lactams via
cycloisomerization of gem-difluoropropargyl amides
Satoru Arimitsu1 and Gerald B. Hammond*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, No. 48.
1Department of Chemistry, Kyoto University, Kyoto, Japan and
2Department of Chemistry, University of Louisville, Louisville,
Kentucky 40292, United States
doi:10.3762/bjoc.6.48
Received: 15 February 2010
Accepted: 14 April 2010
Published: 14 May 2010
Email:
Gerald B. Hammond* - gb.hammond@louisville.edu
Guest Editor: D. O’Hagan
* Corresponding author
© 2010 Arimitsu and Hammond; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
bicyclic lactams; cycloisomerization; difluoropropargyl; enyne;
ring-closing metathesis
Abstract
gem-Difluoro-1,7-enyne amides are suitable building blocks for the synthesis of difluorodihydropyridinones via a ring-closing
metathesis reaction, and of 4,4-difluoro-3-oxoisoquinolines through a ring-closing metathesis–enyne metathesis tandem reaction.
These products, in turn, undergo a Diels–Alder reaction to yield heterotricyclic systems in moderate to good yields.
Introduction
It has been estimated that as many as 25% of all synthetic structures. In their pioneering work on middle-range lactams
pharmaceutical drugs contain an amide bond [1]. Commonly, bearing fluorine(s), Fustero et al. developed a ring-closing
β- and γ-lactams are present in many natural products and metathesis of α,α-difluoro-1,n-dienyl amides to furnish the
pharmaceuticals, and the introduction of a gem-difluoro- corresponding α,α-difluorinated lactams [14]. The synthesis of
methylene moiety has been reported to improve their biological medium-size heterocycles by a metathesis reaction is quite
activities. For example, a gem-difluoro-γ-lactam can inhibit relevant, as demonstrated by its extensive application to multi-
γ-lactamase, which is responsible for bacterial resistance to fused heterocyclics [15-19]. We postulated that functionalized
γ-lactam antibiotics [2-4]. Additionally, α,α-difluoro lactams are fluorinated enyne amides could be used for the synthesis of a
precursors of some biologically active compounds [5-8]. Our chemically diverse suite of δ-lactams because enynes are
group’s entry in this arena started as a collaboration with suitable partners in ring-closing metathesis reactions or
Professor Fustero and resulted in the syntheses of fluorinated cycloisomerizations. An additional benefit of using enynes in
β- and γ-lactams [9-13]. This sparked our interest in the metathesis reactions is that the resulting diene product could be
synthesis of larger-ring lactams, with six to eight members, further elaborated using a Diels–Alder reaction to construct
because nitrogen-containing medium-size heterocyclics are bi- or tricyclic ring systems [20].
found in many natural products as part of fused cyclic
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Beilstein J. Org. Chem. 2010, 6, No. 48.
Results and Discussion
to prevent isomerization [22], gave disappointing results (entry
Initially, we investigated the enyne metathesis reaction of fluor- 8, Table 1). When our optimized conditions were applied to
inated enyne 1a with commercially available ruthenium carbene other fluorinated 1,7-enynes we isolated the desired lactams
complexes, the Hoveyda–Grubbs second-generation catalyst (entries 1–3, Table 2). Higher temperatures were required with
being the most reactive (entries 1–3, Table 1). The reaction at internal alkynes (entries 2–5, Table 2), where isomerization
110 °C gave 2a-iso as the major compound, probably through occurs and the enyne ester 1d did not yield satisfactory results.
the isomerization of 2a (entry 3, Table 1) [14]. The latter (2a) Interestingly, although enyne ketone 1e gave a good 19F NMR
was isolated when the reaction was carried out at 70 °C in yield (97%) of the desired diene 2e, we could only isolate the
toluene (entry 4, Table 1). Other solvents did not give good ortho-fluorophenol 3 in good yield after silica gel chromatog-
yields or selectivities (entries 5 and 6, Table 1). From experi- raphy. This unexpected result could have positive synthetic
mentation, it became clear that ethylene gas was crucial for repercussions, as ortho-fluorophenol is a moiety that has
driving this reaction forward (compare entry 4 with 7, Table 1) attracted attention because it is present in some bioactive
[21]. 2,6-Dichloro-1,4-benzoquinone, which has been reported compounds [23-25].
Table 1: Screening reaction conditions for the enyne metathesis of 1a.
Entry
Solvent
Ru cat.
Gas
Temp. (°C)
Yield of products (%)a 1a/2a/2a-iso
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
1,2-DCEc
THF
G-I
C2H4
C2H4
C2H4
C2H4
C2H4
C2H4
Argon
C2H4d
110
110
110
70
53/0/0
G-II
0/34/0
HG-II
HG-II
HG-II
HG-II
HG-II
HG-II
0/6/66 (60)b
0/85 (70)/0
No rxn.
70
70
30/25/0
28/34/0
0/20/11
Toluene
Toluene
70
110
aYield was determined by 19F NMR and the value in parentheses is the isolated yield.
b2a-iso was isolated as an E/Z mixture (E/Z = 3/1).
c1,2-Dichloroethane.
d20 mol % of 2,6-dichloro-1,4-benzoquinone was used.
Table 2: Metathesis reaction of fluorinated 1,7-enyne carbonyl compounds.
Entry
X
R
Temp. (°C)
Yield of 2 (%)a
1
2
3
4
5
NBn
NBn
NBn
O
H (1a)
70
70 [85] (2a)
52 [78] (2b)
69 [95] (2c)
— [33]b (2d)
— [97]c (2e)
n-Hex (1b)
Ph (1c)
Ph (1d)
Ph (1e)
110
110
110
110
C
aThe yields in brackets were determined by 19F NMR.
bIsolation of 2d was unsuccessful due to the complex mixture that had been formed.
cCompound 3 was isolated in 84% after silica gel chromatography.
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Beilstein J. Org. Chem. 2010, 6, No. 48.
Scheme 1: Diels–Alder reaction of diene 2 with 4 and 6. aThe other isomers of 7a and 7b were isolated in 8% and 20% yield, respectively.
Dienes 2a and 2b were used in Diels–Alder reactions with 4 substituted gem-difluoroisoquinolinones through a subsequent
and 6 to produce 5 and 4,4-difluoroisoquinolin-3-one deriva- Diels–Alder reaction (eq 2, Scheme 2) [28].
tives 7, respectively, in excellent yield and good stereose-
lectivity (Scheme 1). Phenyl-substituted diene 2c gave no reac- In this regard, we screened various ruthenium carbene
tion, even after a longer reaction time. The stereochemistry of complexes using 1,7-enyne amide 1a and styrene 8a as a model
7a and 7b was determined by COSY and NOESY experiments. reaction and found that the Hoveyda–Grubbs second-genera-
tion catalyst gave the best mass balance of products 2a and 9a
Recently, various tandem reactions with ruthenium complexes (entry 3, Table 3). We obtained better results when the reaction
have become popular in organic chemistry because Ru(II) was carried out in a sealed pressure reaction vessel (compare
complexes are capable of catalyzing additional reactions entries 3 and 4, Table 3). More interestingly, the choice of
[26,27]. Since our enyne metathesis reaction of fluorinated 1,7- solvent had a tremendous effect on the selectivity between 2a
enynes does not permit substitution at the 6-position of the (EYM product) and 9a (CM–EYM product) (entries 4–8,
resultant gem-difluoroisoquinolinone (eq 1, Scheme 2), we Table 3). Methylene chloride was found to be the best solvent
examined a potential cross metathesis–enyne metathesis (entry 5, Table 3). Other reaction factors were also examined
tandem-type reaction (CM–EYM reaction). In theory, if the carefully; higher concentrations reduced the yield and
terminal vinyl group of diene 2 can be modified by a tandem selectivity slightly (entries 9 and 10, Table 3). Lower reaction
metathesis reaction, this would permit the synthesis of multi- temperature (50 °C) resulted in no conversion (entry 11,
Scheme 2: Synthetic concept toward multi-substituted gem-difluoroisoquinolinones.
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Beilstein J. Org. Chem. 2010, 6, No. 48.
Table 3: Screening of CM–EYM tandem reaction.
Entry
Ru cat.
Solvent
Conc. (M)
Temp. (°C)
Timea (h)
Yield of products 2a/3a (%)b
1c
2c
3c
4
G-I
Toluene
Toluene
Toluene
Toluene
CH2Cl2
1,2-DCE
THF
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.05
0.1
110
110
110
110
110
110
110
110
110
110
50
1.5
1.5
3
Complex
23/17
G-II
HG-II
HG-II
HG-II
HG-II
HG-II
HG-II
HG-II
HG-II
HG-II
HG-II
34/46
3
33/37
5
24
24
24
24
24
24
24
24
0/68 (67)d
26/24
6
7
4/28
8
1,4-Dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9/32
9
0/56
10
11
12e
8/32
0.02
0.02
No reaction
18/30
110
aTime was determined by TLC and/or GC–MS.
bThe yield and ratio of products were determined by 19F NMR.
cThe reaction was carried out without a pressure vessel.
dThe value in parentheses is the isolated yield.
eThe reaction was carried out under argon.
Table 3), and the reaction produced a mixture of 2a and 9a in alkenes 8 decrease the efficiency of the tandem reaction; the
lower yield in the absence of ethylene gas (entry 12, Table 3). non-tandem product 2a being formed instead (entries 2 and 6,
Table 4). Allyl acetate 8f gave the desired product only when
These optimized reaction conditions were applied to other vinyl toluene was employed as solvent (entry 6, Table 4).
compounds 8 (Table 4). After 4-substituted aryl alkenes gave
the desired product 9 in moderate yields with excellent The stereochemistry of the terminal double bond of 9 was deter-
selectivity (E-major) (entries 3 and 4, Table 4), it then became mined by comparing coupling constants of vinyl protons of
clear that steric hindrance and the electronic deficiency of compound 2a. The coupling constants of trans-protons (Ha–Hc)
Table 4: CM–EYM tandem reaction with fluorinated 1,7-enyne 1a and alkene 8.
Entry
R
Time (h)a
Isolated yields of 9 [E/Z]b + 2a (%)
1
Ph (8a)
24
24
24
24
27
3
67 [1/0] (9a) + 0
2
3-MeO-C6H4 (8b)
4-MeO-C6H4 (8c)
4-Cl-C6H4 (8d)
4-F-C6H4 (8e)
CH2OAc (8f)
36 [1/0] (9b) + 15
33 [1/0] (9c) + trace
43 [1/0] (9d) + trace
33 [1/0] (9e) + 19
31 [1/0] (9f) + 31
3
4
5
6c
aTime was determined by TLC and/or GC–MS.
bThe ratio of products was determined by 1H and/or 19F NMR.
cToluene was used instead of CH2Cl2.
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