Buchwald-Hartwig amination approach for the synthesis of functionalized 1,2,3,4-tetrahydroacridine derivatives

Article abstract of DOI:10.1002/ejoc.201402122

Electrophilic 1,2,3,4-tetrahydroacridin-9-yl trifluoromethanesulfonates have been prepared and applied for the first time in the synthesis of functionalized tacrines with high efficacy by using the Buchwald-Hartwig amination reaction. Remarkably, secondar

Full text of DOI:10.1002/ejoc.201402122

Job/Unit: O42122
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FULL PAPER
DOI: 10.1002/ejoc.201402122
Buchwald–Hartwig Amination Approach for the Synthesis of Functionalized
1,2,3,4-Tetrahydroacridine Derivatives
Julien de Sousa,[a,b] Richard C. D. Brown,[b] and Rachid Baati*[a]
Keywords: Synthetic methods / Cross-coupling / Amination / Nitrogen heterocycles / Medicinal chemistry / Tacrines
Electrophilic 1,2,3,4-tetrahydroacridin-9-yl trifluoromethane-
sulfonates have been prepared and applied for the first time
in the synthesis of functionalized tacrines with high efficacy
versatility and convenience of these highly reactive deriva-
tives is illustrated through their application in other valuable
C–C (Sonogashira, Suzuki, and cyanation cross-coupling), C–
by using the Buchwald–Hartwig amination reaction. Re- S, and C–O bond-forming reactions under palladium cataly-
markably, secondary, poor nucleophilic, and functionalized
amines also reacted efficiently by using our conditions. The
sis.
co-drugs have been designed and synthesized with the aim
of enlarging and improving its pharmacological profile be-
yond its ability to serve as an AChE or BuChE inhibitor.[6]
In this context, the development of the multi-target-directed
ligand strategy requires reliable and selective synthetic
methods possessing broad substrate scope to assemble tac-
rines, and 1,2,3,4-tetrahydroacridines.[7] Traditional strate-
gies based on direct acylation or alkylation of poorly
nucleophilic 9-aminotacrine with appropriate electrophiles
usually suffer from restricted substrate scope and require
harsh and hazardous experimental conditions.[8,9] Alterna-
tively, functionalization of the 9-position can be effected
either by nucleophilic aromatic substitution (SNAr),[10] or
Buchwald–Hartwig amination (BHA)[11] of 9-chloro-
Introduction
Nitrogen-containing heterocycles are key functional
components of many drugs and other biologically active
molecules. Tacrines, such as 1,2,3,4-tetrahydroacridine-9-
amine (tacrine: THA, 1), is arguably a key structural motif
in bioorganic chemistry, medicinal chemistry and drug dis-
covery (Figure 1).[1] However, THA (1) is not naturally oc-
curring and has therefore attracted interest as a target for
synthesis and further modifications.[2]
1,2,3,4-tetrahydroacridine (2, Figure 1).
A significant
breakthrough has been recently disclosed by Renard and
co-workers, and by Carlier et al.[12] in the development of a
Pd-catalyzed amination reaction of 9-chloro-tetrahydro-
acridine (2) and 6,9-dichloro-1,2,3,4-tetrahydroacridine (3)
for the preparation of N-alkyltacrines (Figure 1, Scheme 1).
Figure 1. Structure of Tacrine (1), 9-chloro-1,2,3,4-tetrahydro-
acridine (2), and 6,9-dichloro-1,2,3,4-tetrahydroacridine (3).
Tacrine (Cognex®) was the first approved cholinesterase
inhibitor by the Food and Drug Administration agency in
1993 for the palliative treatment of Alzheimer diseases, re-
lated loss of memory and cognitive functions.[3] Owing to
its potent inhibition of acetylcholine esterase (AChE) and
butylcholinesterase (BuChE),[4] the chemical modification
of tacrine is of great interest for the development of
multipotent drugs prepared by conjugation of the THA
scaffold with other medicinally relevant groups.[5] Recently,
numerous multifunctional tacrine homo- and heterodimer
[a] Université de Strasbourg, Faculté de Pharmacie, UMR/CNRS
7199,
Scheme 1. Buchwald–Hartwig amination reactions of tetrahydro-
acridine derivatives 4–7.
74, route du Rhin, 67401 Illkirch, France
E-mail: rachid.baati@unistra.fr
Notwithstanding the efficiency of these recent accounts
for the cross-coupling of 2 and 3, a broadly applicable
method enabling the use of aromatic, heteroaromatic, sec-
ondary, non-nucleophilic nitrogen coupling partners, as well
http://www.camb.cnrs.fr/spip.php?article1
[b] School of Chemistry, University of Southampton,
Highfield, SO17 1BJ, Southampton, UK
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402122.
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J. de Sousa, R. C. D. Brown, R. Baati
FULL PAPER
as functionalized amine-containing substrates, is still lack- ridin-9-yl trifluoromethanesulfonate (7, Scheme 1). To this
ing. Given the importance of the tacrine pharmacophore in end, 5 was obtained in modest unoptimized yield (23%) by
medicinal chemistry,[1–6] and in the framework of our syn- P(O)Br3-mediated cyclodehydration reaction of 5-chloro-
thetic efforts towards medicinally relevant tacrine-hybrids anthranilic acid with cyclohexanone.[14] With the aim of an-
for the reactivation of phosphylated AChE,[13] we recog- alyzing the reactivity of 9-halo-tetrahydroacridines deriva-
nized the need for tetrahydroacridine derivatives with en- tives in BHA reactions, the synthesis of 9-iodo-7-chloro-
hanced electrophilicity for application in BHA. More highly 1,2,3,4-tetrahydroacridine was initially considered. How-
activated derivatives such as 9-bromo-, and 9-OTf-1,2,3,4- ever, owing to the inefficiency of the reported procedure in
tetrahydroacridines 5–7 could fulfill this requirement, re- our hands,[15] our attention moved to the preparation of
sulting in increased efficiency of the BHA reactions with a acridin-9-yl trifluoromethanesulfonates. Accordingly, tetra-
wider scope of application (Scheme 1). Our specific interest hydroacridines 6 and 7 were prepared on a gram-scale in
in the development of more reactive tetrahydroacridines 5– 78% and 87% isolated yields, respectively, as stable white
7 for use in BHA is driven by the failure of 7,9-dichloro- crystalline solids from commercially available 1,2,3,4-tetra-
tetrahydroacridine (4) to react selectively and efficiently hydroacridin-9(10H)-one and 7-chloro-1,2,3,4-tetrahydro-
with certain functionalized amines of interest during the acridin-9(10H)-one (8), respectively.[16] With substrate 4[14]
synthesis of tacrine hybrids by using the reported proto- and new electrophiles 5–7 in hand we next evaluated their
cols.[12] Herein we report the synthesis of 9-bromo-7-chloro- reactivity in the BHA reaction.
1,2,3,4-tetrahydroacridine (5) and 1,2,3,4-tetrahydroacridin-
In an initial experiment the direct reactions of unprotec-
9-yl trifluoromethanesulfonates 6–7, and their use in the mi- ted 1-amino-3-butyne, a bifunctional linker, and 1,2,3,4-
crowave-assisted Buchwald–Hartwig amination reaction tetrahydroacridines 4–7 were explored. Four electrophiles
with various amines.
4–7 were reacted by using a modified BHA procedure, un-
der microwave irradiation in dioxane in the presence of a
tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] and
Results and Discussion
2,2Ј-bis(diphenylphosphino)-1,1Ј-binaphthalene
[(Ϯ)-
Prior to embarking on BHA reactions, our initial efforts BINAP] catalyst system, with Cs2CO3 as the base.[12] After
focused on the synthesis of 9-bromo-7-chloro-1,2,3,4-tetra- 1.5 h of reaction at 130 °C, the conversion of starting elec-
hydroacridine (5), 1,2,3,4-tetrahydroacridin-9-yl trifluoro- trophiles 4–7 was determined by analyzing the crude reac-
1
methanesulfonate (6) and 7-chloro-1,2,3,4-tetrahydroac- tion mixtures by H NMR spectroscopy. Although the use
Scheme 2. Substrate scope for the microwave-assisted Buchwald–Hartwig Amination reaction with 6 and 7 (isolated yields after column
1
chromatography are given, and conversion of starting triflates are given in brackets and were determined by H NMR spectroscopy).
2
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Synthesis of Functionalized 1,2,3,4-Tetrahydroacridine Derivatives
of chloride 4 resulted in moderate conversion (40–60%), we ports that used chloro derivative 4, in which cyclic second-
were pleased to observe that bromide 5 and the analogous ary amines were inferior cross-coupling partners.[12a]
triflate 7 underwent complete conversion (Ͼ99%) forming Attempts to further expand the scope of BHA to include
the desired adduct 9 in excellent isolated yield (92% and allylamine and propargylamine were fruitful and expected
85%, respectively) after column chromatography on silica adducts 19 and 20 were isolated in acceptable chemical
gel (Supporting Information and Scheme 2). In view of yields (64 and 76%, respectively). Notably, the use of a het-
these promising preliminary results, demonstrating the high eroaromatic nucleophile, such as 3-aminopyridine, also led
reactivity of triflate 7 combined with its ease of preparation, to cross-coupled product 21 in excellent isolated yield
the scope of the amination reaction was evaluated by using (81%). Other nitrogen nucleophiles, such as tert-butylsulfin-
additional selected amines. A brief survey of temperature amide, benzamide and diethyl phosphoramidate, also suc-
and reaction conditions, revealed that smooth arylation of cessfully engaged in BHA reactions under our optimized
benzylamine in 1,4-dioxane with either 6 or 7 occurred at conditions. To our delight, the reactions displayed, unex-
100–130 °C after 1 h, to furnish benzylated tacrines 10 and pectedly, not only total conversion of reagent 7 but also a
11 in quantitative yield (Scheme 2). Gratifyingly, exposure high chemical efficiency; the sulfinylated, acylated and
of primary amines, such as n-butylamine, aniline, and bulky phosphorylated tacrines were obtained in good to excellent
1-aminopyrene, resulted in the formation of expected isolated yields (67, 76 and 87% for 22, 23 and 24, respec-
alkylated tacrines 12–14 in excellent isolated yields tively). Amine substrates containing additional functional
(Scheme 2), which constituted a substantial improvement groups, such as 2-(2-aminothoxy)ethanol and glycine ethyl
relative to previous reports that used chloride 4.[12]
ester, were also subjected to the Pd-catalyzed BHA reaction
Significantly, the method is compatible with both elec- with triflate 7 to give aminated adducts 25 and 26 in excel-
tron-rich and electron-poor anilines bearing a variety of lent yields (96 and 92%, respectively).
synthetically valuable functional groups (Scheme 2). In-
It is noteworthy that total conversion of triflates 6 and 7
deed, 4-bromoaniline is suitable and cross-coupling product was observed for the majority of the reactions, with signifi-
15 was obtained selectively in excellent yield (91%), high- cantly reduced reaction times and lower temperature.
lighting the high reactivity of triflate 7 in BHA reactions. Furthermore, lower quantities of reduced byproducts were
Electron-rich anilines, such as p-anisidine, exhibited good formed under BHA conditions by using the triflates; this is
reactivity and gave 16 in 65% yield. Secondary cyclic a significant drawback of the existing BHA protocols which
amines, such as pyrrolidine and piperidine, also underwent use less reactive substrates, such as 2–4.[12] Besides these
coupling (87 and 54% for 17 and 18, respectively) under features, a wide range of functionality was tolerated, includ-
otherwise identical reaction conditions. These results sug- ing unprotected alkynes, free alcohols, olefins, bromo- and
gest that the cross-coupling of 7 with secondary amines is chloroarenes, ethers and ester groups. Additionally, in the
less sensitive to steric hindrance in contrast to previous re- cross-coupling reactions, complete chemoselectivity of the
Scheme 3. Versatility of triflate 7 in C–C, C–S and C–O bond-forming reactions; THF = tetrahydrofuran.
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0.137 mmol), Pd2(dba)3 (8 mg, 6 mol-%), (Ϯ)-BINAP (11 mg,
12 mol-%) and Cs2CO3 (2.5 equiv., 0.343 mmol). The vessel was se-
aled with a microwave septum and purged with argon. Degased
1,4-dioxane (1.7 mL) and amine (1–1.5 equiv.) were introduced
through the septum. The resulting mixture was heated by using a
Biotage® Initiator Microwave Synthesizer Apparatus to 130 °C for
1 h. After cooling, the reaction mixture was concentrated and puri-
fied by column chromatography.
triflate group versus the chloro substituent was always ob-
served. Consequently, this method provides efficient access
to new tacrine derivatives containing functionality suitable
for further potential ligation to a variety of other valuable
building blocks through Pd cross-coupling (9, 15, 19, 20),
click chemistry (9, 20), metathesis (19), thiol-ene reaction
(9, 19, 20), and ester- and amide-bond formation (25, 26).
To extend the scope of the cross-coupling methodology
to other 1,2,3,4-tetrahydroacridines, the application of tri-
flate 7 in other synthetically useful Pd-catalyzed C–C bond
forming reactions, such as Sonogashira, Suzuki, and cyan-
ation cross-couplings, was investigated (Scheme 3).
N-(But-3-yn-1-yl)-7-chloro-1,2,3,4-tetrahydroacridin-9-amine
(9):
Following general procedure A, 1-amino-3-butyne (17 μL,
0.205 mmol) gave 9 as a yellow oil (31 mg, 80%). Rf (petroleum
ether/EtOAc/MeOH, 6:4:0.02) = 0.33. IR (neat): ν = 3301, 2934,
˜
2861, 1581, 1555, 1487, 1433, 1349, 1338, 1126 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.95 (d, J = 2.33 Hz, 1 H), 7.83 (d, J =
8.96 Hz, 1 H), 7.48 (dd, J = 2.24, 8.85 Hz, 1 H), 4.22 (t, J =
6.87 Hz, 1 H), 3.57 (q, J = 6.37 Hz, 2 H), 3.04 (t, J = 5.96 Hz, 2
H), 2.79 (t, J = 6.41 Hz, 2 H), 2.46 (dt, J = 2.68, 6.20 Hz, 2 H),
Sonogashira reaction of 7 with phenyl acetylene afforded
desired product 27 in excellent isolated yield (98%).[2a]
Furthermore, it was also possible to access 9-phenyltetra-
hydroacridine derivative 28 in 71% yield under Suzuki
cross-coupling conditions, along with a minor bisarylated 2.14 (t, J = 2.61 Hz, 1 H), 1.96–1.90 (m, 4 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 159.30, 149.21, 145.97, 130.67, 129.76,
129.25, 121.95, 121.72, 118.90, 81.63, 71.15, 47.53, 34.17, 24.84,
23.02, 22.82, 21.01 ppm. HRMS (ESI): calcd. for C17H17ClN2 [M
+ H]+ 285.1153; found 285.1159.
product (28%) which resulted from secondary arylation of
the 7-chloro group. Synthetically valuable 9-CN-tetra-
hydroacridine derivative 29 was obtained in 75% yield
through cyanation of triflate 7 by using Zn(CN)2 under Pd-
catalysis in dry dimethylformamide (DMF), along with a
minor amount of biscyanated product (25%). Finally, we
N-Benzyl-1,2,3,4-tetrahydroacridin-9-amine (10): Following general
procedure A, 1,2,3,4-tetrahydroacridin-9(10H)-one (50 mg,
explored C–S and C–O bond-formation by using thio- 0.151 mmol) and benzylamine (25 μL, 0.227 mmol) gave 10 as a
yellow oil (42 mg, 96%). Rf (petroleum ether/EtOAc/MeOH,
phenol and benzyl alcohol, respectively. Gratifyingly, mer-
captotetrahydroacridine and benzyloxytetrahydroacridine
derivatives 30 and 31 were formed after 1 h under our opti-
mized microwave conditions in 83 and 60% yields, respec-
tively.
1:1:0.02) = 0.15. IR (neat): ν = 3317, 3060, 2932, 2859, 1581, 1561,
˜
1495, 1452, 1418, 1349, 1123, 1028 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.96 (q, J = 8.64 Hz, 2 H), 7.57 (t, J = 7.58 Hz, 1 H),
7.39–7.30 (m, 6 H), 4.61 (s, 2 H), 4.15 (br. s, 1 H), 3.07 (t, J =
6.27 Hz, 2 H), 2.64 (t, J = 6.31 Hz, 2 H), 1.94–1.82 (m, 4 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 159.93, 150.51, 147.77, 139.92,
129.09, 129.00 (2 C), 128.47, 127.86, 127.76 (2 C), 124.09, 122.88,
120.59, 117.12, 53.78, 34.29, 24.94, 23.14, 22.93 ppm. HRMS
(ESI): calcd. for C20H20N2 [M + H]+ 289.1699; found 289.1696.
Conclusions
In summary, we have demonstrated 1,2,3,4-tetrahydro-
acridin-9-yl trifluoromethanesulfonates 6 and 7 to be supe-
rior substrates in Buchwald–Hartwig amination reactions,
which display broader substrate scope and applicability rel-
ative to previously employed 9-chloro derivatives. A variety
of amines (alkylamines, anilines, heteroarylamines) were
shown to react smoothly under microwave conditions to
give corresponding N-substituted tacrines in reasonable to
excellent yields. Even secondary and poorly nucleophilic
amines, such as tert-butylsulfinamide, benzamide and di-
ethyl phosphoramidate, were shown to react efficiently, and
functional groups, including terminal alkynes, alcohols,
bromo- and chloro-arenes, ethers, esters, and olefins, were
tolerated. Investigation of other Pd-catalyzed C–C, C–O
and C–S bond-forming reactions also show promise for the
development of practical routes to 9-substituted 1,2,3,4-
tetrahydroacridines, which extends the application of this
heterocycle in drug design.
N-Benzyl-7-chloro-1,2,3,4-tetrahydroacridin-9-amine (11): Follow-
ing general procedure A, benzylamine (22 μL, 0.205 mmol) gave 11
as a yellow wax (44 mg, quant.). Rf (petroleum ether/EtOAc, 1:1)
= 0.23. IR (neat): ν = 3065, 3028, 2930, 2859, 1580, 1554, 1484,
˜
1452, 1427, 1346, 1118, 1078 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.97 (d, J = 2.33 Hz, 1 H), 7.87 (d, J = 9.01 Hz, 1 H), 7.50 (dd,
J = 2.31, 9.01 Hz, 1 H), 7.39–7.28 (m, 5 H), 4.58 (s, 2 H), 4.11 (br.
s, 1 H), 3.04 (t, J = 6.37 Hz, 2 H), 2.59 (t, J = 6.31 Hz, 2 H),
1.92–1.81 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 159.18,
149.83, 146.04, 139.56, 130.62, 129.73, 129.36, 129.08 (2 C), 128.04,
127.81 (2 C), 122.18, 121.28, 117.99, 53.84, 34.12, 24.83, 22.98,
22.77 ppm. HRMS (ESI): calcd. for C20H19ClN2 [M + H]+
323.1310; found 323.1313.
N-Butyl-7-chloro-1,2,3,4-tetrahydroacridin-9-amine (12): Following
general procedure A, n-butylamine (20 μL, 0.205 mmol) gave 12 as
a yellow oil (28 mg, 71%). Rf (petroleum ether/EtOAc, 1:1) = 0.24.
IR (neat): ν = 3339, 2927, 2860, 1578, 1556, 1487, 1431, 1359, 1263,
˜
1115, 1081 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J =
2.32 Hz, 1 H), 7.82 (d, J = 9.03 Hz, 1 H), 7.47 (dd, J = 2.33,
9.01 Hz, 1 H), 3.87 (br. s, 1 H), 3.46 (t, J = 7.13 Hz, 2 H), 3.05–
3.01 (m, 2 H), 2.70–2.66 (m, 2 H), 1.93–1.89 (m, 4 H), 1.65 (quint,
J = 7.28 Hz, 2 H), 1.43 (sext, J = 7.39 Hz, 2 H), 0.96 (t, J =
7.32 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 158.96,
150.21, 146.11, 130.59, 129.22, 129.15, 122.25, 121.09, 116.84,
49.39, 34.17, 34.02, 24.84, 23.10, 22.84, 20.24, 13.99 ppm. HRMS
(ESI): calcd. for C17H21ClN [M + H]+ 289.1466; found 289.1462.
Experimental Section
General Procedure A for the Palladium-Catalyzed Amination Reac-
tion under Microwave Irradiation: A microwave tube (0.5–2 mL)
containing a magnetic stirrer bar was charged with 1,2,3,4-tetra-
hydroacridine trifluoromethanesulfonate derivative (1 equiv.,
4
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Synthesis of Functionalized 1,2,3,4-Tetrahydroacridine Derivatives
N-Phenyl-7-chloro-1,2,3,4-tetrahydroacridin-9-amine (13): Follow-
ing general procedure A, aniline (19 μL, 0.205 mmol) gave 13 as a
yellow solid (34 mg, 80%). Rf (petroleum ether/EtOAc, 7:3) = 0.39.
3.09 (t, J = 6.63 Hz, 2 H), 2.81 (t, J = 6.32 Hz, 2 H), 2.15–2.08
(m, 4 H), 1.98–1.91 (m, 2 H), 1.87–1.81 (m, 2 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 160.77, 150.30, 146.29, 130.67, 130.59,
129.95, 129.08, 127.36, 123.02, 51.28 (2 C), 34.05, 26.62 (2 C),
26.57, 22.99 (2 C) ppm. HRMS (ESI): calcd. for C17H19ClN2 [M
IR (neat): ν = 3247, 3041, 2948, 2869, 1669, 1579, 1558, 1496, 1435,
˜
1404, 1374, 1199, 1131 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.92 (d, J = 9.03 Hz, 1 H), 7.76 (d, J = 2.32 Hz, 1 H), 7.52 (dd, J + H]+ 287.1310; found 287.1310.
= 2.35, 9.01 Hz, 1 H), 7.24–7.19 (m, 2 H), 6.92 (t, J = 7.39 Hz, 1
7-Chloro-9-(piperidin-1-yl)-1,2,3,4-tetrahydroacridine (18): Follow-
ing general procedure A, piperidine (16 μL, 0.164 mmol) gave 18
as a colorless oil (22 mg, 54%). Rf (petroleum ether/EtOAc/MeOH,
H), 6.67 (d, J = 8.13 Hz, 2 H), 5.83 (br. s, 1 H), 3.13 (t, J = 6.51 Hz,
2 H), 2.72 (t, J = 6.42 Hz, 2 H), 2.00–1.80 (m, 4 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 160.50, 145.89, 144.30, 142.55, 130.99,
130.60, 129.70, 129.52 (2 C), 124.82, 124.24, 122.25, 121.05, 116.56
(2 C), 34.15, 25.61, 22.87, 22.70 ppm. HRMS (ESI): calcd. for
C19H17ClN2 [M + H]+ 309.1153; found 309.1151.
9:1:0.02) = 0.32. IR (neat): ν = 2932, 2854, 1567, 1479, 1450, 1428,
˜
1388, 1099 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J =
2.36 Hz, 1 H), 7.86 (d, J = 8.89 Hz, 1 H), 7.49 (dd, J = 2.36,
8.92 Hz, 1 H), 3.23 (t, J = 5.02 Hz, 4 H), 3.09 (t, J = 6.69 Hz, 2
H), 2.90 (t, J = 6.37 Hz, 2 H), 1.96–1.89 (m, 2 H), 1.88–1.74 (m, 8
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 160.80, 153.62, 146.26,
130.61, 130.40, 129.15, 128.23, 127.00, 123.29, 52.08 (2 C), 34.16,
27.11 (2 C), 27.07, 24.70, 23.11, 22.91 ppm. HRMS (ESI): calcd.
for C18H21ClN2 [M + H]+ 301.1466; found 301.1472.
N-(Pyren-2-yl)-7-chloro-1,2,3,4-tetrahydroacridin-9-amine (14): Fol-
lowing general procedure A, 1-aminopyrene (45 mg, 0.206 mmol)
gave 14 as a green solid (57 mg, 96%). Rf (petroleum ether/EtOAc,
8:2) = 0.14. IR (neat): ν = 3361, 3037, 2920, 2853, 1601, 1551, 1512,
˜
1482, 1466, 1370, 1333, 1272, 1089 cm–1. 1H NMR (500 MHz,
DMSO): δ = 8.86 (br. s, 1 H), 8.68 (d, J = 9.29 Hz, 1 H), 8.22–8.18
(m, 3 H), 8.09 (d, J = 2.27 Hz, 1 H), 8.04–7.99 (m, 3 H), 7.96–7.94
(m, 2 H), 7.66 (dd, J = 2.27, 9.13 Hz, 1 H), 6.96 (d, J = 8.60 Hz,
1 H), 3.08–3.04 (m, 2 H), 2.72–2.67 (m, 1 H), 2.35–2.31 (m, 1 H),
1.91–1.59 (m, 4 H) ppm. 13C NMR (125 MHz, DMSO): δ = 160.51,
145.60, 143.54, 139.59, 131.54, 131.21, 130.71, 129.40, 129.11,
127.44, 126.41, 126.06, 125.91, 125.33, 124.86, 124.77, 124.48,
124.45 (2 C), 124.30, 123.94, 122.40, 122.35, 119.56, 115.16, 33.46,
25.59, 22.31, 21.99 ppm. HRMS (ESI): calcd. for C29H21ClN2 [M
+ H]+ 433.1466; found 433.1475.
N-Allyl-7-chloro-1,2,3,4-tetrahydroacridin-9-amine (19): Following
general procedure A, allylamine (16 μL, 0.205 mmol) gave 19 as a
white powder (24 mg, 64%). Rf (petroleum ether/EtOAc, 1:1) =
0.16. IR (neat): ν = 3290, 3089, 2945, 2871, 1669, 1584, 1519, 1417,
˜
1349, 1325, 1199, 1176, 1131 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.91 (d, J = 2.26 Hz, 1 H), 7.85 (d, J = 9.13 Hz, 1 H), 7.48 (dd,
J = 2.49, 8.92 Hz, 1 H), 6.05–5.95 (m, 1 H), 5.38 (dd, J = 1.51,
17.03 Hz, 1 H), 5.24 (dd, J = 1.30, 10.26 Hz, 1 H), 4.05 (d, J =
5.43 Hz, 2 H), 3.97 (br. s, 1 H), 3.06–3.03 (m, 2 H), 2.74–2.70 (m,
2 H), 1.95–1.89 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
159.03, 149.89, 145.92, 135.62, 130.53, 129.66, 129.36, 122.11,
121.22, 117.71, 117.36, 51.90, 34.09, 24.86, 23.04, 22.80 ppm.
HRMS (ESI): calcd. for C16H17ClN2 [M + H]+ 273.1153; found
273.1146.
N-(4-Bromophenyl)-7-chloro-1,2,3,4-tetrahydroacridin-9-amine (15):
Following general procedure A, 4-bromoaniline (24 mg,
0.137 mmol) was introduced before sealing the vessel and gave 15
as a bright yellow solid (48 mg, 91%). Rf (petroleum ether/EtOAc,
75:25) = 0.29. IR (neat): ν = 3244, 3108, 2927, 2855, 1669, 1577,
˜
N-(Prop-2-yn-1-yl)-7-chloro-1,2,3,4-tetrahydroacridin-9-amine (20):
Following general procedure A, propargylamine (10 μL,
0.151 mmol) gave 20 as a white solid (28 mg, 76%). Rf (petroleum
1506, 1487, 1404, 1200, 1181, 1132 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.48 (br. s, 1 H), 8.12 (d, J = 9.14 Hz, 1 H), 7.89 (d,
J = 4 Hz, 1 H), 7.52–7.49 (m, 3 H), 6.93 (d, J = 8.55 Hz, 2 H),
3.26 (t, J = 6.23 Hz, 2 H), 3.39 (t, J = 6.31 Hz, 2 H), 1.93–1.81 (m, 4
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 155.33, 150.93, 139.53,
136.38, 133.24, 132.67, 132.60, 129.18, 128.37, 125.44, 123.84,
122.16, 119.92, 118.82, 117.80, 28.67, 26.30, 21.72, 20.60 ppm.
HRMS (ESI): calcd. for C19H16BrClN2 [M + H]+ 387.0257; found
387.0258.
ether/EtOAc, 1:1) = 0.19. IR (neat): ν = 3292, 3112, 2943, 2874,
˜
1669, 1583, 1567, 1517, 1417, 1338, 1199, 1177, 1130 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 2.11 Hz, 1 H), 8.14 (d,
J = 9.18 Hz, 1 H), 7.61 (dd, J = 2.18, 9.02 Hz, 1 H), 6.61 (br. s, 1
H), 4.58–4.56 (m, 2 H), 3.19 (t, J = 6.20 Hz, 2 H), 2.76 (t, J =
5.57 Hz, 2 H), 2.55 (t, J = 2.45 Hz, 1 H), 1.94–1.87 (m, 4 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 154.23, 153.58, 137.09, 133.33,
132.08, 123.05, 122.60, 117.25, 113.19, 78.62, 75.22, 37.58, 28.48,
24.07, 21.90, 20.63 ppm. HRMS (ESI): calcd. for C16H15ClN2 [M
+ H]+ 271.0996; found 271.0991.
N-(4-Methoxyphenyl)-7-chloro-1,2,3,4-tetrahydroacridin-9-amine
(16): Following general procedure A, p-anisidine (25 mg,
0.205 mmol) was introduced before sealing the vessel and gave 16
as a yellow solid (30 mg, 65%). Rf (petroleum ether/EtOAc, 75:25)
N-(Pyridin-3-yl)-7-chloro-1,2,3,4-tetrahydroacridin-9-amine
(21):
= 0.18. IR (neat): ν = 3271, 3108, 2947, 2840, 1779, 1667, 1581,
˜
Following general procedure A, 3-aminopyridine (19 mg,
1559, 1507, 1436, 1404, 1245, 1198, 1170, 1134 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 8.46 (br. s, 1 H), 7.95 (d, J = 9.03 Hz, 1
H), 7.69 (d, J = 2.12 Hz, 1 H), 7.49 (dd, J = 2.16, 8.93 Hz, 1 H),
6.97 (dd, J = 8.72, 69.25 Hz, 4 H), 3.82 (s, 3 H), 3.11 (t, J =
5.92 Hz, 2 H), 2.48 (t, J = 5.92 Hz, 2 H), 1.88–1.81 (m, 4 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 159.09, 153.65, 152.26, 136.99,
133.57, 132.25, 131.74, 126.03 (2 C), 123.93, 122.19, 117.42, 115.30
(2 C), 114.59, 55.81, 28.50, 24.37, 21.73, 20.63 ppm. HRMS (ESI):
calcd. for C20H19ClN2O [M + H]+ 339.1259; found 339.1260.
0.206 mmol) gave 21 as a yellow solid (34 mg, 81%). Rf (petroleum
ether/EtOAc, 6:4) = 0.30. IR (neat): ν = 3229, 3088, 2935, 2863,
˜
1586, 1557, 1480, 1374, 1286, 1240, 1111, 1092 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 8.18–8.15 (m, 2 H), 7.93 (d, J = 9.08 Hz,
1 H), 7.73 (d, J = 2.30 Hz, 1 H), 7.54 (dd, J = 2.19, 8.95 Hz, 1 H),
7.12–7.08 (m, 1 H), 6.81–6.78 (m, 1 H), 6.02 (br. s, 1 H), 3.13 (t, J
= 6.49 Hz, 2 H), 2.71 (t, J = 6.43 Hz, 2 H), 1.99–1.92 (m, 2 H),
1.87–1.81 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 160.72,
145.93, 141.90, 141.19, 140.90, 138.64, 131.56, 130.84, 129.96,
125.84, 124.30, 123.92, 121.99, 121.81, 34.13, 25.75, 22.80,
22.60 ppm. HRMS (ESI): calcd. for C18H16ClN3 [M + H]+
310.1105; found 310.1101.
7-Chloro-9-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroacridine (17): Follow-
ing general procedure A, pyrrolidine (57 μL, 0.206 mmol) gave 17
as a pale yellow wax (34 mg, 87%). Rf (petroleum ether/EtOAc,
9:1) = 0.20. IR (neat): ν = 2929, 2858, 1667, 1476, 1450, 1427, 1380,
N-(7-Chloro-1,2,3,4-tetrahydroacridin-9-yl)-2-methylpropane-2-sulf-
inamide (22): Following general procedure A, 2-methyl-2-propane-
sulfinamide (25 mg, 0.206 mmol) gave 22 as a pale yellow solid
˜
1
1150, 1101 cm–1. H NMR (400 MHz, CDCl3): δ = 7.89–7.87 (m,
2 H), 7.48 (dd, J = 2.33, 9.00 Hz, 1 H), 3.38 (t, J = 6.46 Hz, 4 H),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Pages: 8
J. de Sousa, R. C. D. Brown, R. Baati
(31 mg, 67 %). Rf (petroleum ether/EtOAc/MeOH, 75:25:0.02) = 120.82, 117.77, 62.01, 50.34, 34.11, 24.63, 22.95, 22.76, 14.26 ppm.
FULL PAPER
0.10. IR (neat): ν = 3353, 3242, 2932, 2864, 2004, 1650, 1573, 1491,
HRMS (ESI): calcd. for C17H19ClN2O2 [M + H]+ 319.1208; found
˜
1
1445, 1375, 1031 cm–1. H NMR (400 MHz, CDCl3): δ = 7.83 (d, 319.1210.
J = 9.15 Hz, 1 H), 7.68 (d, J = 2.36 Hz, 1 H), 7.49 (dd, J = 2.17,
Supporting Information (see footnote on the first page of this arti-
8.94 Hz, 1 H), 4.68 (br. s, 1 H), 3.01 (t, J = 5.93 Hz, 2 H), 2.61 (t,
J = 6.05 Hz, 2 H), 1.99–1.90 (m, 4 H), 1.23 (s, 9 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 158.64, 146.36, 144.46, 130.01, 129.60,
129.53, 119.41, 117.81, 111.20, 55.53, 34.74, 23.81, 22.74, 22.71,
22.26 (3 C) ppm. HRMS (ESI): calcd. for C17H21ClN2OS [M +
H]+ 337.1136; found 337.1136.
cle): Procedures for the synthesis of original compounds are given.
1H and 13C NMR spectra are also reported.
Acknowledgments
The authors gratefully acknowledge the Direction Générale de
l’Armement (DGA), France and the Centre National de la Recher-
che Scientifique (CNRS) for a research grant (to J. D. S.). We also
thank warmly the Commissariat à l’Energie Atomique et aux Ener-
gies Alternatives (CEA) for financial support to R. B through the
Programme Risques Nucléaires, Radiologiques, Biologiques et Chi-
miques (Grant NRBC no. I8.3). The University of Strasbourg, the
Defense Science and Technology Laboratory (DSTL), UK and the
University of Southampton are also acknowledged for their sup-
port. Cyril Antheaume, Dr Patrick Wehrung and Pascale Buisine
(SCA, Service Commun d’Analyses) are acknowledged for NMR
spectroscopic and HRMS measurements.
N-(7-Chloro-1,2,3,4-tetrahydroacridin-9-yl)benzamide (23): Follow-
ing general procedure A, benzamide (25 mg, 0.206 mmol) gave 23
as a white solid (35 mg, 76%). Rf (petroleum ether/EtOAc/MeOH,
6:4:0.02) = 0.38. IR (neat): ν = 3248, 2934, 2862, 1649, 1590, 1511,
˜
1
1482, 1282, 1082 cm–1. H NMR (400 MHz, CDCl3): δ = 8.01 (d,
J = 7.57 Hz, 2 H), 7.94 (d, J = 9.06 Hz, 2 H), 7.77 (d, J = 2.40 Hz,
1 H), 7.67–7.61 (m, 1 H), 7.58–7.52 (m, 3 H), 3.14 (t, J = 6.55 Hz,
2 H), 2.87 (t, J = 6.54 Hz, 2 H), 2.01–1.95 (m, 2 H), 1.90–1.83 (m, 2
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 165.94, 160.47, 145.40,
137.77, 133.44, 132.72, 132.11, 130.11, 129.95, 129.13 (2 C), 128.98,
127.69 (2 C), 124.97, 121.31, 34.07, 25.79, 22.73, 22.43 ppm.
HRMS (ESI): calcd. for C20H17ClN2O [M + H]+ 337.1102; found
337.1101.
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Diethyl (7-Chloro-1,2,3,4-tetrahydroacridin-9-yl)phosphoramide
(24): Following general procedure A, diethyl phosphoramidate
(32 mg, 0.206 mmol) gave 24 as a pale white solid (44 mg, 87%).
R (petroleum ether/EtOAc/MeOH, 1:1:0.02) = 0.31. IR (neat): ν =
˜
f
3083, 2979, 2931, 2861, 1584, 1549, 1501, 1482, 1389, 1362, 1235,
1203, 1165, 1091, 1033 cm–1. 1H NMR (400 MHz, CDCl3): δ =
8.24 (d, J = 2.08 Hz, 1 H), 7.87 (d, J = 8.91 Hz, 1 H), 7.54–7.51
(m, 1 H), 4.87 (br. s, 1 H), 4.20–4.10 (m, 4 H), 3.11–3.00 (m, 4 H),
1.98–1.86 (m, 4 H), 1.36–1.27 (m, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 160.36, 145.56, 131.40, 130.28, 129.74 (2 C), 127.32,
125.42, 122.58, 63.82, 63.76, 34.13, 25.69, 22.71 (2 C), 16.34,
16.27 ppm. 31P NMR (162 MHz, CDCl3): δ = 2.95 ppm. HRMS
(ESI): calcd. for C17H22ClN2O3P [M + H]+ 369.1129; found
369.1133.
2-{2-[(7-Chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]ethoxy}ethan-
1-ol (25): Following general procedure A, 2-(2-aminoethoxy)ethan-
1-ol (21 μL, 0.206 mmol) gave 25 as a pale white solid (42 mg,
96%). R (EtOAc/MeOH, 97:3) = 0.16. IR (neat): ν = 3346, 2931,
˜
f
2861, 1645, 1580, 1558, 1488, 1436, 1341, 1258, 1156, 1117, 1071,
1030 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 2.24 Hz,
1 H), 7.84 (d, J = 8.91 Hz, 1 H), 7.48 (dd, J = 2.20, 9.03 Hz, 1 H),
5.48 (br. s, 1 H), 4.63 (br. s, 1 H), 3.83–3.81 (m, 2 H), 3.63–3.60
(m, 6 H), 3.05–3.02 (m, 2 H), 2.76–2.73 (m, 2 H), 1.93–1.88 (m, 4
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 158.07, 150.68, 129.97
(2 C), 129.24, 122.22, 120.91, 117.72, 72.41, 70.31, 61.97, 48.65,
33.18, 24.58, 22.84, 22.52 ppm. HRMS (ESI): calcd. for
C17H21ClN2O2 [M + H]+ 321.1364; found 321.1361.
Ethyl (7-Chloro-1,2,3,4-tetrahydroacridin-9-yl)glycinate (26): Fol-
lowing general procedure A, glycine ethyl ester hydrochloride
(29 mg, 0.206 mmol) and triethylamine (29 μL, 0.206 mmol) gave
26 as a pale yellow oil (40 mg, 92%). Rf (petroleum ether/EtOAc/
MeOH, 6:4:0.02) = 0.29. IR (neat): ν = 3386, 2980, 2935, 2862,
˜
1736, 1582, 1557, 1487, 1435, 1373, 1339, 1210, 1161, 1023 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 2.35 Hz, 1 H), 7.83
(d, J = 8.87 Hz, 1 H), 7.47 (dd, J = 2.30, 9.09 Hz, 1 H), 4.86 (t, J
= 5.04 Hz, 1 H), 4.24 (q, J = 7.17 Hz, 2 H), 4.19 (d, J = 4.94 Hz,
2 H), 3.04–3.01 (m, 2 H), 2.86–2.83 (m, 2 H), 1.92–1.88 (m, 4 H),
1.28 (t, J = 7.15 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
171.58, 159.22, 149.42, 145.91, 130.66, 129.65, 129.26, 121.81,
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Synthesis of Functionalized 1,2,3,4-Tetrahydroacridine Derivatives
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Received: February 22, 2014
Published Online: ᭿
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Job/Unit: O42122
/KAP1
Date: 17-04-14 18:18:04
Pages: 8
J. de Sousa, R. C. D. Brown, R. Baati
FULL PAPER
Synthetic Methods
J. de Sousa, R. C. D. Brown,
R. Baati* .......................................... 1–8
Buchwald–Hartwig Amination Approach
for the Synthesis of Functionalized 1,2,3,4-
Tetrahydroacridine Derivatives
Electrophilic 1,2,3,4-tetrahydroacridin-9-yl
trifluoromethanesulfonates have been pre-
pared and applied for the first time in the
synthesis of functionalized tacrines with
high efficacy by using the Buchwald–Hart-
wig amination reaction. Secondary, poor
nucleophilic, and functionalized amines are
well tolerated.
Keywords: Synthetic methods / Cross-cou-
pling / Amination / Nitrogen heterocycles /
Medicinal chemistry / Tacrines
8
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