Pd-catalyzed amination as an alternative to nucleophilic aromatic substitution for the synthesis of N-alkyltacrines and analogs

Article abstract of DOI:10.1016/j.tetlet.2010.12.073

A reliable Pd-catalyzed amination protocol is described for the synthesis of N-alkyltacrines and analogs. The Josiphos ligand CyPFtBu was found to provide optimum yields: 16 examples are given. Compared to the typical high-temperature nucleophilic aromatic substitution (NAS) routes, Pd-catalyzed aminations proceed at significantly lower reaction temperatures, and enable the synthesis of otherwise inaccessible products.

Full text of DOI:10.1016/j.tetlet.2010.12.073

Tetrahedron Letters 52 (2011) 916–919
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed amination as an alternative to nucleophilic aromatic
substitution for the synthesis of N-alkyltacrines and analogs
⇑
Ming Ma, Jimit Mehta, Larry D. Williams, Paul R. Carlier
Department of Chemistry, Virginia Tech, Blacksburg, VA, 24060, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A reliable Pd-catalyzed amination protocol is described for the synthesis of N-alkyltacrines and analogs
The Josiphos ligand CyPFtBu was found to provide optimum yields: 16 examples are given. Compared
to the typical high-temperature nucleophilic aromatic substitution (NAS) routes, Pd-catalyzed amina-
tions proceed at significantly lower reaction temperatures, and enable the synthesis of otherwise inacces-
sible products.
Received 11 November 2010
Revised 10 December 2010
Accepted 15 December 2010
Available online 23 December 2010
Ó 2011 Elsevier Ltd. All rights reserved.
Intriguingly, acetylcholinesterase (AChE) inhibitors have found
use both as memory-enhancing therapeutic drugs for Alzheimer’s
disease, and as insecticides.1 Tacrine 1 was the first drug approved
by the FDA to treat Alzheimers’ memory loss, and since the initial
report of enhanced AChE inhibition potency and selectivity of ta-
crine dimer 4a,2 a variety of tacrine and tacrine analog dimers have
been synthesized in search of further improvements.3,4 Although
bis(7)-tacrine 4a and its longer tether homologs bis(8)- to
bis(10)-tacrine were first prepared by alkylation of the exocyclic
amine of tacrine 1,2 this method proved unsatisfactory for the syn-
thesis of short-tether homologs, due to the intervention of cycliza-
tion and elimination pathways.3a A high-temperature nucleophilic
aromatic substitution route was thus devised by reacting 2 with
diamines (e.g., 3a) in refluxing 1-pentanol (bp 138 °C).3a
Scheme 1. Synthesis of 4a by nucleophilic aromatic substitution.
This amination protocol afforded the complete series of bis(2)-
to bis(10)-tacrine in good yields, and in the last 10 years has been
widely used to prepare tacrine heterodimers, as well as homo- and
heterodimers of tacrine analogs.3,4 Until now it has not been nec-
essary to explore other possible amination protocols.
However, in our search for inhibitors with high selectivity for
AChE of the malaria mosquito (Anopheles gambiae),5 we found that
the standard protocol could not dimerize 12-chloro-2-methyl-
6,7,8,9,10,11-hexahydrocycloocta[b]quinoline 5, even when the
1-pentanol solvent was replaced by the even higher boiling (bp
195 °C) 1-octanol (Scheme 2). The use of excess amine to afford
monomer 7a was also unsuccessful.
Given the widespread success of Buchwald–Hartwig protocols
to effect amination of aryl halides,6 our attention turned to Pd-
catalysis. Although Pd-catalyzed amination has been applied to
several different classes of heteroaryl chlorides,7 including 4-halo-
quinolines,7d to our knowledge there is only one published account
of its application to the synthesis of an N-alkyltacrine and or ana-
⇑
Corresponding author. Tel.: +1 540 231 9219; fax: +1 540 231 3255.
E-mail address: pcarlier@vt.edu (P.R. Carlier).
Scheme 2. Attempted conversion of 12-chloro-2-methyl-6,7,8,9,10,11-hexahydro-
cycloocta[b]quinoline 5 to 6a (x = 0.5) or 7a (x = 3).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.073

M. Ma et al. / Tetrahedron Letters 52 (2011) 916–919
917
Thus these optimized conditions were used to explore the gen-
erality of this Pd-catalyzed amination of 2 with various primary
amines 3a–j (Table 2).8 In general, moderate to good yields were
obtained. Using 0.5 equiv of diamine 3a, bis-(7)-tacrine 4a can be
obtained in 72% yield in 24 h, at lower temperature than the NAS
procedure (cf. Table 2, entry 1 and Scheme 1). Reaction of 2 with
5.0 equiv of diamine 3a gave a mixture of the intended amino-
terminated tacrine monomer 8a (78%) and tacrine dimer 4a (17%,
Table 2, entry 2). Thus the Pd-catalyzed amination route to 8a af-
fords a yield comparable to that of the published NAS route
(71%).3d Reactions with Butini’s substrate 1,4-diaminobutane 3b
were also investigated. Using 1.05 equiv of 3b, the desired product
8b was obtained in 58% yield, and the dimer 4b was isolated in 12%
yield (Table 2 entry 3). Thus higher yields are again obtained with
the CyPFtBu ligand relative to BINAP, at lower Pd loading (c.f. Table
2, entry 3 and Scheme 3). Furthermore, increasing the amount of
3b to 5 equiv gave the desired product 8b in 76% yield (Table 2
entry 4). For mono-1° amines, use of 1.05 equiv of amine was
Scheme 3. Synthesis of 8b by Pd-catalyzed amination.
log. Butini et al. reported the use of 2 mol % Pd(OAc)2 and 2 mol %
BINAP to couple 2 and 1,4-diaminobutane, affording 8b in 40%
yield (Scheme 3).7j Herein we report optimized conditions for the
synthesis of N-alkyltacrines and analogs via Pd-catalyzed
amination.
The reaction of 9-chloro-1,2,3,4-tetrahydroacridine 2 and n-
heptylamine 3c was initially used to screen for suitable reaction
conditions. We selected DPEPhos,7d R-BINAP,7d,j and CyPFtBu7b,f
as ligands since they had been previously used in Pd-catalyzed
amination of heteroaryl chlorides (Table 1). DPEphos was reported
to be an effective ligand for the cross-coupling of 4-chloroquinoline
generally successful, including 1° amines that are
a-branched
with a
-branched 1° amines,7d and we successfully repeated several
(Table 2, entries 6–7), and those containing polar functional groups
(Table 2, entries 6, 10, and 11). Interestingly, in some of these cases
(Table 2, entries 6, 9, and 10) a significant amount of tetrahydroac-
ridine 9 was isolated; we believe this byproduct likely originates
from b-hydride elimination.9,10 In particular, the low yield of 8g
relative to 8h thus appears to be due to significant incursion of
the b-hydride elimination pathway (Table 2, cf entries 9 and 10).
It is not clear whether coordination of the proximal pendant hy-
droxyl group in 3g contributes towards this side reaction, but we
note that it is less problematic in the methyl ether analog 3i (Table
2, cf. entries 9 and 11). Note that no byproduct 9 was observed
when the amine substrate did not have a b-hydrogen, such as
m-methyl aniline 3e (Table 2, entry 7). Reaction with the function-
of the published aminations of this heteroaryl chloride (data not
shown). However we found that this ligand is not very effective
for Pd(OAc)2-catalyzed coupling of 2 and heptylamine 3c (Table
1, entries 1and 2), Interestingly, when KOtBu was used as base, a
95% yield of reduced product 9 was obtained (Table 1, entry 1).
When NaOtBu was used as base, the desired product 8c was ob-
tained in 41% yield, albeit at high catalyst/ligand loading (Table
1, entry 2). Use of R-BINAP as ligand (Table 1, entry 3) allowed low-
er catalyst loadings (1% Pd, 2% ligand) but provided 8c in only 47%
yield; note this yield is similar to that obtained by Butini et al. for
8b (Scheme 3).7j The best results were obtained with the Josiphos
ligand CyPFtBu (87%, Table 1, entry 4). Hartwig and co-workers
have shown that CyPFtBu functions well in Pd-catalyzed couplings
of 1° amines with pyridin-2-yl, pyridin-4-yl, and quinolin-2-yl ha-
lides.7b,f Reduction of Pd/ligand loadings below 1%/2% gave poor
conversions even at a longer reaction time (Table 1, cf. entries 4–
6). In addition, a brief survey of toluene and dioxane suggested that
DME is the best solvent for the CyPFtBu/NaOtBu system (Table 1,
cf. entries 4, 7, and 8).
alized a,x-diamine 3j was most challenging, but with higher cata-
lyst/ligand loading (4% Pd, 8% CyPFtBu) the desired dimer 4j was
obtained in 46% yield, significantly higher than the published
two-step NAS route (11% overall).4b Finally, we did explore the
use of R-BINAP as ligand in cases where yields with CyPFtBu as li-
gand were lower than 50% (3g,j); however, even at higher catalyst
loading, R-BINAP did not afford higher yields (data not shown).
Table 1
Optimization of Pd-catalyzed amination of 9-chloro-1,2,3,4-tetrahydroacridine 2 by n-heptylamine 3c
Entry
Ligand
x
y
Base
Solvent
T (°C)
t (h)
Yielda (%)
1
2
3
4
5
6
7
8
DPEphos
DPEphos
R-BINAP
CyPFtBu
CyPFtBu
CyPFtBu
CyPFtBu
CyPFtBu
4
4
1
1
0.5
0.1
1
8
8
2
2
1
0.2
2
KOtBu
1,4-Dioxane
1,4-Dioxane
DME
DME
DME
DME
Toluene
1,4-Dioxane
85
85
24
12
24
4
20
40
20
20
<5% (95% 9)
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
41
47
87
51
20
40
25
100
100
100
100
100
100
1
2
a
Yield of isolated 8c after chromatography.

918
M. Ma et al. / Tetrahedron Letters 52 (2011) 916–919
Table 2
Table 3
Pd-catalyzed amination of 9-chloro-1,2,3,4-tetrahydroacridine 2 and amines 3a–j
Pd-catalyzed amination of 12-chloro-2-methyl-6,7,8,9,10,11-hexahydrocyclooc-
under the optimized conditions
ta[b]quinoline 5 and amines 3a,c,d under the optimized conditions
Entry Aminea
t (h) Product(s) Yieldb (%)
4a
8a
72d
11
3a H2N
3a H2N
NH2
NH2
1c
2e
3
24
24
24
4a
8a
17
78c
Entry Amine
t (h) Product Yielda,b (%)
3b
3b
H2N
H2N
4b
8b
12
58
6a
7a
62
16
H2N
NH2
NH2
NH2
NH2
3a
3a
1c
24
4b
8b
21
76
87d
4e
5
24
4
H2N
6a
7a
11
45
2d
3
24
4
3c H2N
8c
3c H2N
7c
95
8d
9
70
17
H2N
H2N
N
3d
6
7
18
1
N
N
3d
4
18
18
7d
18e
H2N
8e
8f
92f
5f
7d
50e
3d
3e
3f
NH2
a
b
c
d
e
f
NH2
OH
Yield of isolated product after chromatography.
Trace amounts of byproduct 10 was found on the TLC in all cases.
0.5 equiv of 3a was used.
The amount of diamine 3a used was 5.0 equiv.
Quantitative recovery of remaining starting material.
4% Pd, 8% ligand.
8
9
3.5
24
86d
8g
9
35
63
3g
H2N
OH
8h
9
68
26
60d
3h
10
11
24
5
H2N
3i
H2N
OMe
8i
3j
H2N
12c,g
40
4j
46
1 mol % Pd(OAc)2 as catalyst, unbranched,
a-branched, and func-
N
NH2
tionalized primary amines can be successfully coupled with steri-
cally encumbered heteroaryl chlorides 2 and 5 (a total of 16
examples). In some cases (highly functionalized amines 3d,j) high-
er catalyst loadings are required. However, compared to the classi-
cal high-temperature NAS route, the Pd-catalyzed amination
protocol offers milder reaction conditions (c.f. Schemes 1 and 2
and Table 1–3), and wider substrate scope.
a
b
c
d
e
f
1.05 equiv of amine unless otherwise specified.
Yield of isolated product after chromatography.
The amount of diamine used was 0.5 equiv.
A trace amount of byproduct 9 was detected by TLC.
The amount of diamine used was 5.0 equiv.
No byproduct 9 visible by TLC.
g
4% Pd, 8% ligand.
Acknowledgments
We then explored the reaction generality with regard to the
heteroaryl chloride partner by carrying out reactions with the
bulkier substrate 5 (Table 3). Although this substrate proved resis-
tant to traditional NAS conditions (Scheme 2), as hoped, reaction
with amines 3a,c,d under the optimized conditions was successful
(Table 3).
Important to note herein is that reaction of 5 with 0.5 equiv
diamine 3a gave the dimer product 6a in 62% yield after 24 h at
100 °C; under traditional NAS conditions no trace of this product
was found after refluxing in 1-octanol at 190 °C for three days
(cf. Table 3, entry 1 and Scheme 2). Reaction of 5 with 5 equiv of
diamine 3a gave the intended amino-terminated monomer 7a in
45% yield, and the unintended dimer 6a in 11% yield. Reaction with
unbranched 1° amine 3c gave the desired product in 95% yield
The project was generously supported by a grant from the
Foundation for the National Institutes of Health (1R01AI082581-
01).
Supplementary data
Supplementary data (tabulated analytical data for synthesized
compounds) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2010.12.073.
References and notes
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In conclusion, we have developed a mild and convenient
alternative to the synthesis of N-alkyltacrines and analogs via
Pd-catalyzed amination. By using 2 mol % CyPFtBu as ligand and

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919
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8. Representative procedure: Pd-catalyzed amination of 5 to N-alkyltacrines analog
7c: Pd(OAc)2 (0.86 mg, 0.0038 mmol) and CyPFtBu (4.26 mg, 0.0077 mmol)
were dissolved in anhydrous DME (0.5 mL). The solution was stirred at room
temperature under N2 for 10 min. To the solution were added substrate 5
(100 mg, 0.38 mmol), amine 3c (0.06 mL, 0.40 mmol), NaOtBu (93 mg,
0.95 mmol) and anhydrous DME (0.5 mL). The solution was stirred at 100 °C
for 4 h until substrate 5 was totally consumed as judged by TLC. The solution
was cooled to the room temperature and evaporated under the vacuum. The
crude product was purified by column chromatography to give pure 7c
(124 mg, 95%).
5. Manuscript in preparation.
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