Reactivity of quinoline- and isoquinoline-based heteroaromatic substrates in palladium(0)-catalyzed benzylic nucleophilic substitution

Article abstract of DOI:10.1021/ol991274y

(Formula presented) Quinolylmethyl, 1-(isoquinolyl)ethyl, and 1-(quinolyl)ethyl acetates reacted with dimethylmalonate anion in the presence of a Pd(0) catalyst to give products of nucleophilic substitution and/or byproducts, depending upon the substitution pattern. The observed side reactions were reduction in the case of primary acetates and elimination or elimination/Michael-type addition sequence for secondary substrates.

Full text of DOI:10.1021/ol991274y

ORGANIC
LETTERS
2
000
Vol. 2, No. 4
33-436
Reactivity of Quinoline- and
4
Isoquinoline-Based Heteroaromatic
Substrates in Palladium(0)-Catalyzed
Benzylic Nucleophilic Substitution
Jean-Yves Legros,* Ga e1 lle Primault, Martial Toffano, Marie-Alix Rivi e` re, and
,†
Jean-Claude Fiaud*
Laboratoire de Catalyse Mol e´ culaire associ e´ au C.N.R.S., UPRESA 8075,
Institut de Chimie Mol e´ culaire d’Orsay, B aˆ timent 420, UniVersit e´ de Paris-Sud,
F91405 Orsay, France
jylegros@icmo.u-psud.fr
Received November 23, 1999
ABSTRACT
Quinolylmethyl, 1-(isoquinolyl)ethyl, and 1-(quinolyl)ethyl acetates reacted with dimethylmalonate anion in the presence of a Pd(0) catalyst to
give products of nucleophilic substitution and/or byproducts, depending upon the substitution pattern. The observed side reactions were
reduction in the case of primary acetates and elimination or elimination/Michael-type addition sequence for secondary substrates.
We described in recent years the formation of a benzylic
carbon-carbon bond by the palladium(0)-catalyzed nucleo-
philic substitution of naphthylmethyl and 1-(1- or 2-naph-
thyl)ethyl acetates and carbonates by sodium dimethyl
1
malonate (Scheme 1). This method has been extended to
Scheme 1
Figure 1. Structure of compounds 1-5.
the formation of a carbon-nitrogen bond by using amines
as nucleophiles.2
We report in this communication the substitution of
quinoline and isoquinoline. We recently described the
N-heteroaromatic substrates 1-3 (Figure 1) derived from
reactivity of 4-quinolylmethyl acetate 1c and other 4-quinolyl-
methyl esters in the palladium-catalyzed substitution by
†
formate anion (formation of a carbon-hydrogen bond).3
E-mail: fiaud@icmo.u-psud.fr.
1
0.1021/ol991274y CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/21/2000

8
Acetates 1 were prepared by reduction/acetylation of the
(entries 5 and 6). It is worth noting that under the same
commercialy available quinolinecarboxaldehydes. Acetates
reaction conditions reduction products (i.e., 1- and 2-methyl-
naphthalenes) were never detected from naphthylmethyl
acetates.
The substitution of secondary acetates 2 and 3 were next
examined (Table 2). These substrates did not give reduction
2
and 3 were obtained similarly from the corresponding
1
a
arylmethyl ketones 4 and 5. We recently developed a new
preparation of compounds 4 and 5 from quinolyl and
isoquinolyl derivatives (chlorides, bromides, or triflates) via
4
palladium-catalyzed Stille and Heck coupling reactions. The
5
6
secondary acetates 2 and 3 were also prepared in lower
yields by literature methods.
Table 2. Substitution of Secondary Acetates 2 and 3a
We first studied the reactivity of primary acetates 1 (Table
1). The nucleophile was preformed by mixing dimethyl-
Table 1. Substitution of Primary Acetates 1a
substitution
product (%)
elimination
product (%)
entry
substrate
M
t (h)
1
2
3
2b
2b
2b
2c
2d
3b
3c
3c
3c
Na
K
10
8
8
24
24
24
24
24
24
8b (61)
8b (59)
8b (54)
8c (74)
8d (14)
9b (13)b
9c (78)
9c (44)
9c (60)
10b (3)
10b (7)b
entry
substrate
solvent
product 6 (%)
product 7 (%)
Cs
Na
Na
Na
Na
K
10b (7)
10c (<5)b
10d (29)
11b (21)b
11c (11)
11c (12)
11c (20)
1
2
3
4b
5
6
1a
1b
1c
1c
1b
1c
DMF
DMF
DMF
DMF
THF
THF
4
6b (23)
6c (55)
6c (49)
6b (80)
6c (66)
7b (74)
7c (24)
7c (21)
5c
6d
7
8
9
Cs
a
Isolated yields. b NaCH(CO2CH3)2 (from NaH and dimethylmalonate)
a
Isolated yields. b Proportion of product from H NMR spectrum. 52%
1
c
as nucleophile.
isolated 2d recovered. d 66% (from 1H NMR) 3b recovered.
malonate and potassium tert-butoxide. Substrate 1a was
totally unreactive under the conditions described below (entry
products, ethylquinolines and ethylisoquinolines, respectively.
In addition to the expected substitution products 8 and 9 a
competitive elimination pathway leading to vinylquinolines
1). At higher (100 °C) temperature, a slow degradation was
observed but the expected substitution product 6a was never
obtained.
In contrast, acetates 1b and 1c displayed good reactivity
with total consumption of the substrate in less than 4 h. The
10 and vinylisoquinolines 11 was observed. This side reaction
was also previously observed in the substitution of 1-naph-
1b,c
thylethyl acetates.
The extent of elimination was dependent upon the coun-
terion of the nucleophile. This effect was studied in the case
of the two substrates 2b and 3c (entries 1-3 and 7-9). These
compounds were the most reactive, being consumed in 8-10
h for the former and 24 h for the latter. The cesium salt
1- and 2-naphthylmethyl acetates achieved 100% conversion
in more than 5 h. However, in addition to the expected
7
substitution products 6b and 6c, 3- and 4-methylquinolines
7b and 7c, resulting from a formal reduction process, were
obtained (entries 2 and 3). Sodium dimethylmalonate gave
essentially the same result (entry 4), but the solvent was the
source of this side reaction. Switching from DMF to THF
allowed for a selective and high-yielding substitution reaction
(from dimethylmalonate and cesium carbonate) gave the
larger amount of 10b (13%) and 11c (33%). In contrast, use
of sodium dimethylmalonate (from sodium hydride and
dimethylmalonate) minimized the elimination process and
led to better isolated yields of 8b (61%) and 9c (78%).
Under these optimized conditions, 1-(4-quinolyl)ethyl
acetate 2c reacted cleanly to give 8c in 74% isolated yield
(
1) (a) Legros, J. Y.; Fiaud, J. C. Tetrahedron Lett. 1992, 33, 2509-
2
3
510. (b) Legros, J. Y.; Toffano, M.; Fiaud, J. C. Tetrahedron 1995, 51,
235-3246. (c) Legros, J. Y.; Toffano, M.; Fiaud, J. C. Tetrahedron:
Asymmetry 1995, 6, 1899-1902.
1
with less than 5% 4-vinylquinoline 10c detected by H NMR
(2) Toffano, M.; Legros, J. Y.; Fiaud, J. C. Tetrahedron Lett. 1997, 38,
7
7-80.
analysis of the crude reaction mixture (entry 4).
(
3) (a) Boutros, A.; Legros, J. Y., Fiaud, J. C. Tetrahedron Lett. 1999,
The other acetates were less reactive compounds; 2d and
3b only gave a partial conversion after 24 h, leading
predominantly to the elimination products 10d and 11b,
4
0, 7329-7332. (b) Boutros, A.; Legros, J. Y., Fiaud, J. C. Tetrahedron,
accepted for publication.
(
(
(
4) Legros, J. Y., Primault, G., Fiaud, J. C., unpublished work.
5) Taylor, R. J. Chem. Soc. B 1971, 2382-2387.
6) Glyde, E., Taylor, R. J. Chem. Soc., Perkin Trans. 2 1975, 1783-
1
791.
(8) To investigate the nature of the reducing agent, we performed the
same reaction as above on acetate 1b in DMF-d7; no reduction product
was detected in these conditions.
(
7) All new compounds were characterized by proton and carbon-13
NMR, IR, and either HRMS or elemental analysis.
434
Org. Lett., Vol. 2, No. 4, 2000

that result from the elimination process. This reactivity was
9
already reported in the literature.
Scheme 2
To verify this hypothesis, compound 10a was prepared
from commercially available 2-chloroquinoline by a Stille
coupling reaction with tri(n-butyl)vinylstannane (Scheme
1
0
3
). Subjecting 10a to the substitution reaction conditions
in the presence or absence of the palladium catalyst produced
compound 12 in both cases at approximately the same rate;
evidently the palladium is not involved in this readdition
process.
These results can be rationalized according to Scheme 4,
which illustrates the different pathways in the case of acetates
Scheme 3
1
b and 2b. After oxidative addition of the substrate on a
1
-3
palladium(0) complex,
a nucleophilic attack of the di-
3
methylmalonate anion on the cationic η -benzylpalladium
intermediate 14 leads to the substitution product 6b or 8b
(path a). From 14a (R ) H) in DMF only, a hydride source
gives the neutral hydrido complex 15 and finally reduction
product 7b after reductive elimination (path b). The nature
of this hydride source is presently unknown, but the DMF
respectively (entries 5 and 6). Attempts to improve the
3
is involved in its formation. In the case of 14b (R ) CH ),
an E2-type base-promoted elimination gives 10b (path c).1
Finally, the acetates of cinchonidine 16 and of quinidine
17 (Figure 2) were prepared to extend this reaction to natural
product derivatives. However, the corresponding substitution
(or elimination) products were not detected after 7 days, at
80 °C in DMF or even at 140 °C in DMA. This inertness
may result from steric hindrance and/or the presence of the
basic nitrogen of the quinuclidine moiety.
1
reactivity were unsuccessful; at 100 °C, 8-vinylquinoline 10d
1
was obtained in 83% yield (calculated by H NMR) from
2d.
Substrates 2a and 3a showed a different behavior. Instead
of substitution (8a and 9a) and/or elimination (10a and 11a)
products, the linear isomers of the former products (12 and
1
3) were produced in low yields, the major products being
the unreacted acetates (Scheme 2). The formation of 12 and
3 could be explained by a Michael-type addition of the
1
In conclusion, the palladium-catalyzed nucleophilic sub-
stitution of heteroaromatic benzylic acetates was investigated.
nucleophile on electron-deficient vinylarenes 10a and 11a
Scheme 4
Org. Lett., Vol. 2, No. 4, 2000
435

and 4-substituted quinoline and the 4-substituted isoquinoline
substrates exhibit a higher reactivity than their analogues
derived from naphthalene. Concerning 1-(8-quinolyl)ethyl
acetate 2d, the lack of reactivity observed can probably be
attributed to the proximity of the neighboring nitrogen atom.12
OL991274Y
Figure 2. Acetates of cinchonine and quinidine.
(
11) An alternative mechanism for the formation of 10b is to consider a
1
â-elimination from an η -palladium intermediate analogous to 14b; because
of the electron-withdrawing properties of the pyridinic nitrogen atom, the
aromatic CdC double bond is very likely to be weakly interacting with
palladium. We thank one of the referees for this suggestion.
The relative positions of the nitrogen and of the acetoxy-
methyl or acetoxyethyl substituent are crucial for the course
of the reaction. In the case of 2-substituted quinoline and 1-
or 3-substituted isoquinoline substrates, no (in the case of
(
12) Representative Experimental Procedure (Table 2, entry 4). 1-(4-
Quinolyl)ethyl acetate 2c (215 mg, 1 mmol) in 1 mL of DMF was added
under argon to a mixture of Pd(dba)2 (11.5 mg, 0.02 mmol) and dppe (12
mg, 0.03 mmol) in 1 mL of DMF. After 0.25 h of stirring, this solution
was added to a suspension of sodium dimethylmalonate [from NaH (48
mg, 2 mmol) and CH2(CO2CH3)2 (0.23 mL, 2 mmol)]. The reaction mixture
was stirred at 80 °C for 24 h and then diluted with ether (20 mL), and the
organic phase washed with 2 × 10 mL of a solution of saturated NaHCO3.
The aqueous phases were extracted with ether (3 × 10 mL), and the
combined ethereal phases were dried (MgSO4) and concentrated. The crude
product was purified by flash chromatography (silica, heptane/ethyl acetate
70:30) to give dimethyl 2-(1-(4-quinolyl)ethyl)propanedioate 8c (212 mg,
0.74 mmol, 74%).
1a, 2a, and 3a) or little (for 3b) substitution occurs. The 3-
(9) (a) Oda, R.; Teramura, K.; Tanimoto, S.; Nomura, M.; Suda, H.;
Matsuda, K. Bull. Inst. Chem. Res. Kyoto UniV. 1955, 33, 117-125. (b)
Boekelheide, V.; Sieg, A. L. J. Org. Chem. 1954, 19, 587-592.
(
10) Compound 10a was already prepared by a Stille reaction on
2
4
-quinolyl triflate: Crisp, G. T.; Papadopoulos, S. Aust. J. Chem. 1989,
2, 279-285.
436
Org. Lett., Vol. 2, No. 4, 2000