Ruthenium-catalysed C-alkylation of 1,3-dicarbonyl compounds with primary alcohols and synthesis of 3-keto-quinolines

Article abstract of DOI:10.1039/c6ra03585j

The mono-alkylation of 1,3-diketones using alcohols is possible in the presence of catalytic amounts of Ru(CO)(PPh₃)₃HCl and 10% mol of the Hantzsch ester. The borrowing hydrogen process between the catalyst and the dihydropyridine/p

Full text of DOI:10.1039/c6ra03585j

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DOI: 10.1039/C6RA03585J
ARTICLE
Ruthenium-catalysed C-alkylation of 1,3-dicarbonyl
compounds with primary alcohols and synthesis of 3-
keto-quinolines
Cite this: DOI: 10.1039/x0xx00000x
Elena Cini, Elena Petricci, Giuseppina I. Truglio, Marialaura Vecchio and Maurizio
Taddei*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
The mono-alkylation of 1,3-diketones using alcohols is possible in the presence of catalytic
amounts of Ru(CO)(PPh3)3HCl and 10% mol of the Hantzsch ester. The borrowing hydrogen
process between the catalyst and the dihydropyridine/pyridine couple prevents the common
double alkylation of the Knoevenagel adduct without the need of stoichiometric reducing agents
or sacrificial nucleophiles. The reaction was applied to the synthesis of a lactone intermediate
for the preparation of the anti-obesity drug Orlistat. Moreover, under the same Ru catalysis, a
Friedländer reaction occurred with o-amino benzyl alcohols giving access to different 3-keto-
substituted quinolines.
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Introduction
The functionalization of activated methylene compounds,
including 1,3-diketones, is one of the most important synthetic
techniques for carbon-carbon bond formation. The standard
procedure for alkylation is the reaction of the anion, derived from
the 1,3-dicarbonyl compound, with alkyl halides (Scheme 1, path
a). Alternatively,
a Knoevenagel-Doebner reaction with
aldehydes followed by carbon-carbon double bond reduction is
possible (Scheme 1, path b). Nowadays, these two
methodologies require to be replaced by more efficient
processes. Alkylation works under highly basic conditions and
employs toxic and mutagenic alkyl halides. On the other hand,
depending on the substrate nature, the Knoevenagel-Doebner
process leads to poor yield. The intermediate conjugated alkene
D
is indeed a good Michael acceptor capable of engaging the
unreacted dicarbonyl reagent in a kinetically rapid 1,4-
addition to give the bis-adduct E.1 To avoid this side reactions
two possible strategies are: i) slow addition of the -diketone to
a mixture of the aldehyde and a reducing agent (stoichiometric
amount) in order to keep low the concentration of so that the
A
Scheme 1 Possible pathways to prepare 2-alkylated 1,3-diketones
β
Recent demonstrations of Lewis and Brønsted acid catalysed
alkylation of 1,3-dicarbonyl compounds with benzyl-, allyl- and
propargyl- alcohols have been reported.4 However, these
procedures often suffer from low versatility being the alcohol
scope limited to the very reactive substrates previously
mentioned. A valuable alternative is the metal catalysed
alkylation with alcohols through the red-ox ‘borrowing
hydrogen’5–7 strategy that has been already successfully applied
to ketonitriles,8,9 and cyanoacetates.10
D
Michael addition will occur more slowly in comparison with the
reduction of the Knoevenagel alkene;2 ii) use of stoichiometric
amount of strong nucleophiles (i.e. thiols, NaSO2Ph, primary
amines) to intercept
case, a further step of reduction to remove the sacrificial
nucleophile is required.
Unquestionably, the alkylation of β-dicarbonyl compounds with
an alcohol would provide an attractive salt-free, environmentally
friendly and atom-economic alternative to known protocols
(Scheme 1, path c).
D . In this
before forming the bis-adduct E 1,3
Engaged in
a total synthesis of Orlistat, a powerful
gastrointestinal lipase inhibitor contained in anti-obesity drugs,
we were interested in a suitable protocol for the preparation of
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key intermediate lactone
2
(Scheme 2).11,12 Unfortunately, direct
produced a mixture of compound
. Attempts to react hexanal with
gave almost exclusively the bis-adduct . Consequently, the
investigation of possible alkylation of 1,3-dicarbonyl
Table 1 Optimization of reaction conditions
base mediated alkylation of
and O-alkylated enol ether
1
3
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DOI: 10.1039/C6RA03585J
2
1
5
a
compounds with primary alcohols in the presence of
homogeneous Ru catalysts was investigated (Scheme 1, path c).
Reaction
Entry
Ru Catalyst
8b(%)
Conditionsa
Toluene, 160 °C
Toluene, 160 °C
Toluene, 160 °C
Toluene, 160 °C
Toluene, 160 °C
Toluene, reflux 24
h
1c
2
Ru3(CO)12
Ru3(CO)12
[Ru(p-Cymene) Cl2]2
[Ru (CO)(PPh3)3HCl]
[Ru (CO)(PPh3)3HCl]
21
-
18
20
23
<5
3c
4c
5
6
[Ru (CO)(PPh3)3HCl]
Scheme 2 Attempts to prepare a key intermediate for the total synthesis of
Orlistat.
7d
8e
9
10
12
[Ru (CO)(PPh3)3HCl]
[Ru (CO)(PPh3)3HCl]
[Ru (CO)(PPh3)3HCl]
[Ru (CO)(PPh3)3HCl]
[Ru (CO)(PPh3)3HCl]
Toluene, 160 °C
Toluene, 160 °C
Dioxane 160 °C
THF 160 °C
TAA, 160 °C
Toluene, MW
160 °C, 1 h
Toluene, t-BuOK
(1 eq), 160 °C
Toluene, 160 °C,
9 (1 eq)
Toluene, 160 °C,
9 (0.5 eq)
25
22
22
15
19
<5
Results and discussion
Initially, in order to find the best reaction conditions, 1,3
13
14
15
16
17
[Ru (CO)(PPh3)3HCl]
[Ru (CO)(PPh3)3HCl]
[Ru (CO)(PPh3)3HCl]
[Ru (CO)(PPh3)3HCl]
[Ru (CO)(PPh3)3HCl]
indandione
valuable lactone
6
was chosen as a model substrate for the more
, while 3-phenyl-1-propanol was selected as
15
1
7
a UV visible non-benzylic alcohol. These starting materials were
heated under different conditions in the presence of ruthenium-
based catalytic species obtained by mixing different ruthenium
precursors, sometimes using Xantphos as the ligand (Table 1).
Mixing the two starting materials dissolved in toluene in the
presence of Ru3(CO)12 or [Ru(p-Cymene) Cl2]2 with or without
58
57
58
Toluene, 160 °C,
9 (0.1 eq)
[a] Reaction conditions: 6 (0.5 mmol), 7 (0.5 mmol), catalyst (4 mol%) in
solvent (1 mL) under nitrogen, sealed vial at 160 °C for 16 h. b) Yields of
pure product isolated by flash chromatography [c] Xantphos (6 mol%). [d] 3
eq of 6 [e] 3 eq of 7.
Xantphos, the expected compound
8 was formed in low yields,
most of the starting material remaining unchanged (Table 1,
entry 1-3). [Ru(CO)(PPh3)3HCl] turned out to be the best catalyst
providing product 8 in moderate yields even without the addition
As in principle the Hantzsch ester could be regenerated during
the overall process, we explored the reaction in the presence of
catalytic amounts of 9, founding that 10% molar was enough to
carry out the transformation without affecting isolated yields of
8 (Table 1, entries 16-17).
of Xantphos as the ligand (Table 1, entries 4-5). High
temperature (160 °C) was always required for the
transformation, as only traces of product were observed in
refluxing toluene (Table 1, entry 6). No improvements were
achieved by using different amounts of
6 or 7 (Table 1, entries
The scope and generality of the overall process was further
examined by treating different 1,3-dicarbonyl compounds with
several primary alcohols carrying different functional groups
under the previously optimized reaction conditions. A series of
alkylated 1,3-dicarbonyl compounds was obtained in moderate
to good yields as shown in Scheme 3. In any case, in the crude
reaction mixture we observed different amounts of the starting
1,3-diketones and, with compounds 11 and 12, small amounts of
the O-alkylated products (< 5%). The mono-alkylation products
7-8), changing solvents (Table 1, entries 9-12), under microwave
dielectric heating (Table 1, entry 13) or by using 1 eq of base
(Table 1, entry 14, other bases different from t-BuOK that gave
no trace of product
8 are not quoted in the Table). In any of the
attempted reactions, the main by-product was the bis-adduct 8b
suggesting that the hydrogen extracted by the ruthenium catalyst
reduced the Knoevenagel alkene 8a too slowly respect to the
kinetic of the Michael addition. The addition of Hantzsch ester
(9
) in order to increase the efficiency of the reductive step13–15
obtained from 1,3 indandione
6 are formed in higher yield with
was then investigated observing a substantial increase of the
yields and the disappearance of the dimer (Table 1, entry 15).
respect to the products derived from the simple 1-3-
cyclohexandione 10 or 1,3-cyclopentandione 11, suggesting
probably a (stereo)electronic effect of the aromatic ring. The
remarkable effect of the cyclic 1-3 dicarbonyl compound on the
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reaction was confirmed by the observation that no reaction Probably the result observed on this substrate can be related to a
occurred with acyclic 1,3-diketones as acetylacetone or 1- coordinative effect of the carbamate on the ruthenium catalyst.
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phenyl-1,3-butandione.
To investigate the synthetic potential of thDeOnIe: 1w0.1C0b39z/dCe6rRiAv0a3t5iv8e5Js
synthesized, the removal of Cbz was attempted. Treating 16 with
H2 and Pd/C in AcOH a domino deprotection reductive
amination occurred to form the tricycic 3,4,4a,9b-tetrahydro H-
indeno[1,2-b]pyridine-5-one 29 (Scheme 4). This new product,16
obtained as a 9:1 diastereomeric mixture after 16 h of reaction,
was isolated as a single diastereomer in 47% yield after
purification by flash chromatography. Finally, using secondary
alcohols (e.g. 2-propanol or cyclopentanol), very low yield of the
alkylated product was obtained.
For this Ru catalysed mono-alkylation of 1,3-diketones mediated
by catalytic amount of the Hantzsch ester, a possible mechanism
was hypothesized (Scheme 5). The alcohol
Ru catalyst17 to the corresponding aldehyde 7a that reacts with
the -diketone to give the Knoevenagel product 8a. The
conjugated alkene is then reduced to the monolakylated 1,3-
dicarbonyl compound
by the Hantzsch ester,14 while the
contemporary formed pyridine 29 is reduced again by the
Ru[H2], regenerating the Hantzsch ester and the Ru catalyst.
7 is oxidized by the
β
6
8
9
Thus, through this double borrowing hydrogen process between
the alcohol and the couple dihydropyridine/pyridine, a catalytic
alkylation of β-diketones with alcohol is possible.
Scheme 3. Alkylation of 1,3-dicarbonyl compounds with alcohols: reaction scope.
10 = 1,3-cyclohexandione; 11= 1,3-cycopentandione.
Carbamates are well tolerated by this transformation giving
previously unreported Cbz protected amino diketones 16-17 in
satisfactory yields. Also lactone
yields giving the amino derivative 23 and also the Orlistat
intermediate was obtained in 50% isolated yields (Scheme 3).
However, using acyclic -keto esters such as ethyl acetoacetate
1 was alkylated in acceptable
2
β
or even t-butyl acetoacetate, the product coming from a
transesterification reaction between the alcohol and the ester was
formed in large amounts. Only using the N-Cbz-3-amino-1-
propanol 25 a moderate amount of the alkylated product 27 was
obtained, although the transesterification derivative 26 was again
the major product (Scheme 4).
Scheme 5. Possible mechanism.
The potential use of o-amino-benzyl alcohol 30 with 1,3-
diketones (as 10
)
was investigated in order to explore the
possibility of a ruthenium catalysed Friedländer cyclisation
(Table 2). Although modified quinoline synthesis via ruthenium-
catalysed coupling of 2-aminobenzyl alcohols and 2-nitrobenzyl
alcohols with alcohols or ketones has been previously
reported,18–25 to our knowledge, the only example of 3-carbonyl-
quinolines synthesis involves the reaction of β-keto esters with
formation of α-carbocation intermediate generated by the red-ox
catalytic couple FeCl3 / SnCl2.26
In the reaction conditions explored so far, condensation of 10
with 30 gave the 3,4-dihydro 1(2H)-acridone 31 in 70% yield
(Table 2, entry 1). In order to increase the yield of the pursued
approach, different reaction conditions were explored. First of
all, the influence of the temperature was investigated. Lowering
the reaction temperature to 120 °C, the yield dropped down to
Scheme 4. Reaction with acyclic
intramolecular reductive amination.
β-keto esters and Cbz removal followed by
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57% (Table 2, entry 2). However, the reaction works beautifully prepared in acid or base-free conditions in good yields under
under microwave dielectric heating without the Hantzsch ester microwave dielectric heating. It is worthy to note that this
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(Table 2, entries 3-6). After 30 minutes at 120 °C compound 31 procedure constitutes an example of high atom efficiency
DOI: 10.1039/C6RA03585J
was isolated in 73 % yield (Table 2, entry 6).
reaction and, to our knowledge, it is the first example of a Ru
catalysed Friedländer quinoline synthesis heating under
microwaves.
Table 2 Optimisation of the Ru catalysed Friedländer reaction
Table 3 Scope of quinoline syntyhesis
Dicarbonyl
compound
Entry
1
Alcohol
Product (yield, %)
Entry
1
2
3
4
Conditionsa
160 °C, 16 h
Yield(%)
70
57
43
53
41
73
55
42
57
51
47
52
120 °C, 16 h
MW, 160 °C, 15 min
MW, 120 °C, 15 min
MW, 80 °C, 15 min
MW, 120 °C, 30 min
32
10
37 (70)
5
6b
7
2
Cyclohexene (10 eq.), MW, 120 °C, 30 min
Crotonitrile (10 eq.), MW, 120 °C, 30 min
MW, 120 °C, 30 min
MW, 120 °C, 30 min
KOH (1 eq.), MW, 120 °C, 30 min
t-BuOH (1 eq.), MW, 120 °C, 30 min
33
10
8
9
10
11
12
38 (62)
39 (49)
OH
NH2
3
4
30
11
[a] 10 (1 eq), 30 (1 eq), catalyst (4% mol), [bmim][BF4] (25µl), toluene (1
mL) [b] 2 eq. of ketone
OH
NH2
30
Unexpectedly, using the two different hydrogen acceptors
cyclohexene (Table 2, entry 7) and crotonitrile (Table 2, entry 8)
the yield did not improve while still traces of reduced by-
products were present. The reaction is supposed to follow the
standard Ru catalysed Friedländer mechanism including a last
oxidative step done by air.18 Once established the best reaction
conditions, different 1,3-dicarbonyl compound and 2-
aminobenzyl alcohols were examined to explore the generality
of the protocol (Table 3). It is possible to carry out the reaction
with o-substituted amino-benzyl alcohols or in the presence of
an aryl chloride (Table 3, entries 1-2). The reaction worked well
with 1,3-cyclopentandione (11), 1,3-cyclohexanediones 10 and
6
40 (61)
41 (67)
OH
NH2
5
30
34
OH
NH2
6
7
8
35
36
30
42 (58)
43 (52)
OH
NH2
30
OH
NH2
34, and indandione
6 (Table 3, entries 3-5). It was worth noting
that even linear diketones such as 35 and 36 gave the 3-
ketoquinolines in acceptable yields (Table 3, entries 6-7). In the
case of not symmetrical diketone 36, the quinolone 43 was the
only product isolated. The identity of 43 was established by
30
1
44 (44)
comparison with reported data.27 Analogously, keto lactone
1
Experimental
gave the quinolone lactone 44 in acceptable yield.
2-(3-Phenylpropyl)-1,3-indandione (8), general procedure
.
Conclusions
In a glass vial containing a magnetic stirring bar, 1,3-indandione
In summary, we have developed an hydrogen borrowing process
for a direct -alkylation of -dicarbonyl compounds using
6
(100 mg, 0.68 mmol) was dissolved in 1 mL of toluene under
α
β
nitrogen. 3-Phenyl-1-propanol (93 mg, 93 µL, 0.68 mmol),
7
alcohols instead of toxic alkyl or benzyl halides. The
contemporary use of ruthenium and Hantzsch ester catalysis
prevents the formation of the Michael addition by-product
without using stoichiometric amounts of reducing agents or
sacrificial nucleophiles. The yield of the final products strongly
depends on the ketones and the alcohols nature, obtaining
quinolines when aminobenzyl alcohols were used as alkylating
agents. In this way, different 3-keto quinolines can be shortly
Hantzsch ester (17 mg, 0,068 mmol) and [Ru(CO)(PPh3)3HCl]
(26 mg, 0,027 mmol) were added and the vial sealed. The
mixture was stirred in a sand bath heated at 160 °C for 16 h.
Then, the mixture was cooled to room temperature, and the
reaction was checked by TLC (petroleum ether/EtOAc, 7:3). The
solvent was removed under vacuum and the crude reaction
mixture was loaded directly onto
a column for flash
chromatographic purification (eluent: from petroleum ether to
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petroleum ether/EtOAc, 7:3) which gave pure
8 (105 mg, 58%)
7
8
9
S. Werkmeister, J. Neumann, K. Junge, M. Beller, Chem. Eur. J., 2015,
1
as a yellowish waxy material. H-NMR (400 MHz, CDCl3): δ
8.02 – 7.88 (m, 2H), 7.84 – 7.75 (m, 2H), 7.22 (t, J = 7.0 Hz,
2H), 7.12 (d, J = 7.5 Hz, 3H), 3.00 (t, J = 6.0 Hz, 1H), 2.59 (d, J
= 7.7 Hz, 2H), 1.98 (d, J = 9.8 Hz, 2H), 1.71 (t, J = 7.9 Hz, 2H).
13C-NMR (100 MHz, CDCl3): δ 204.4, 146.0, 145.2, 131.9,
129.4, 126.7, 81.0, 80.7, 80.4, 56.9, 39.5, 31.8. GC/MS: Rt 22.86
min; m/z 264 (C18H16O2). HRMS (EI): Calcd for C18H16O2Na
[M+Na]+: 287.1048, found 287.1047
21, 12226–12250.
View Article Online
P. A. Slatford, M. K. Whittlesey, J. M. J. Williams, Tetrahedron Lett.,
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2006, 47, 6787–6789.
T. D. Nixon, P. A. Slatford, M. K. Whittlesey, J. M. J. Williams, Org.
Synth., 2009, 86, 28-35.
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4187.
3,4-Dihydro-2H-acridin-1-one (31), general procedure
A 10-mL vial for MW equipped with a magnetic stirring bar was
charged with 1,3-cyclohexanedione (100 mg, 0.89 mmol) under
nitrogen. Dry toluene (1 mL), 2-aminobenzyl alcohol (110 mg,
0.89 mmol), [Ru(CO)(PPH3)3HCl] (34 mg, 0.036 mmol) and 25
14 D. B. Ramachary, M. Kishor, Y. V. Reddy, Eur. J. Org. Chem., 2008,
975–993.
µ
L
of
ionic
liquid
1-butyl-3-methylimidazolium
tetrafluoroborate were added and the mixture was stirred under
MW dielectric heating for 30 min at 120ꢀ°C (max internal
pressure 180 psi). Then, the mixture was cooled to room
temperature, and the reaction was checked by TLC (petroleum
ether/EtOAc, 7:3). The solvent was removed under vacuum and
crude reaction mixture was loaded directly onto a column for
flash chromatographic eluted with a gradient of petroleum ether
to petroleum ether/EtOAc, 7:3. Pure 31 (127 mg, 73%) was a
yellowish solid. M.p. 108-109 °C (lit m.p. 109-110 °C)28 1H
NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H),
7.79 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.4
Hz, 1H), 3.20 (t, J = 6.1 Hz, 2H), 2.73 – 2.58 (m, 2H), 2.16 (p, J
= 6.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 197.3, 161.5,
149.2, 136.6, 131.8, 129.2, 128.1, 126.3, 126.2, 125.8, 38.6,
33.0, 21.3. HRMS (EI): Calcd for C13H12NO [M+H]+ 198.0919,
found 198.0921.
15 J. Che, Y. Lam, Adv. Synth. Catal., 2010, 352, 1752–1758.
16 C. R. Hurt, N. Filipescu, J. Am. Chem. Soc., 1972, 94, 3650–3651.
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Acknowledgements
The financial support of Chemessentia-Chemo (Novara, Italy) is
gratefully acknowledged.
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Notes and references
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DOI: 10.1039/C6RA03585J
Mono alkylation of 1,3-dicarbonyls is now possible with alcohols and
catalytic amount of Hantzsch ester under Ru catalysis.