Chiral 5-(diphenylphosphanyl)-1,2,3,4-tetrahydroacridines: New N,P-ligands for asymmetric catalysis

Article abstract of DOI:10.1016/j.tetlet.2005.03.113

Three chiral 5-(diphenylphosphanyl)-1,2,3,4-tetrahydroacridines, as first representative examples of a new class of chiral N,P-ligands were prepared from (+)-nopinone, (+)-camphor and 5α-androst-2-en-17-one. These ligands have been assessed in the enantioselective palladium-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. Enantioselectivity up to 74% has been obtained.

Full text of DOI:10.1016/j.tetlet.2005.03.113

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3493–3496
Chiral 5-(diphenylphosphanyl)-1,2,3,4-tetrahydroacridines:
new N,P-ligands for asymmetric catalysis
Giorgio Chelucci* and Gianmauro Orru`
`
Dipartimento di Chimica, Universita di Sassari, via Vienna 2, I-07100 Sassari, Italy
Received 22 February 2005; revised 15 March 2005; accepted 16 March 2005
Available online 5 April 2005
Abstract—Three chiral 5-(diphenylphosphanyl)-1,2,3,4-tetrahydroacridines, as first representative examples of a new class of chiral
N,P-ligands were prepared from (+)-nopinone, (+)-camphor and 5a-androst-2-en-17-one. These ligands have been assessed in the
enantioselective palladium-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. Enantioselecti-
vity up to 74% has been obtained.
Ó 2005 Elsevier Ltd. All rights reserved.
Since the design of chiral ligands plays a key role in the
development of metal-catalysed asymmetric reactions,
many recent studies have addressed the development
of novel chiral ligands.1
Recently, Kocovsky and co-workers4 and the present
authors5 have reported the synthesis of the chiral 2-(2-
diphenylphosphinophenyl)-5,6,7,8-tetrahydroquinolines
1 (Fig. 1) and their application in several type of cata-
lytic asymmetric processes. In this class of ligands the
2-diphenylphosphinophenyl group is bonded to the 2-
position of a chiral 5,6,7,8-tetrahydroquinoline ring.
Pursuing our research in this field, we have now directed
our interest to chiral 5-(diphenylphosphanyl)-1,2,3,4-tet-
rahydroacridines of type 2 (Fig. 1), in which the phenyl
group of the 2-diphenylphosphinophenyl substituent is
now annulated to the pyridine ring of chiral 5,6,7,8-tet-
rahydroquinoline framework. This structural modifica-
tion makes the two nitrogen and phosphorus donor
To date, a large number of chiral ligands having hetero-
donor atoms with nitrogen and phosphorus functional
moieties (N,P-ligands) has been prepared and their use-
fulness for asymmetric reactions has been investigated.2
In the context of N,P-ligands, those with pyridine N-
donors are receiving a great deal of attention and an
increasing number of reports on their synthesis and
use in various catalytic processes are appearing in the
literature.3
R*
R*
N
N
PPh2
PPh2
1
2
N
N
N
PPh2
PPh2
PPh2
3
5
4
Figure 1.
Keywords: Phosphinopyridine ligands; Chiral acridines; Palladium catalysts; Enantioselective allylic substitutions.
*
Corresponding author. Tel.: +39 079 229539; fax: +39 079 229559; e-mail: chelucci@ssmain.uniss.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.113

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G. Chelucci, G. Orru / Tetrahedron Letters 46 (2005) 3493–3496
3494
atoms to be arranged in rigid backbone in such a way as
to provide a more rigid array of the ligand around the
metal centre. Last but not least, the ligands 1 form a
six-membered metal chelate while the new ligands 2
form a five-membered chelate ring.
To overcome this drawback a different method, which
avoids the isolation of the o-amino benzaldehyde was
followed9 (Scheme 1). Accordingly, the N-Boc aldehyde
10 and the ketone 13 were stirred in dioxane containing
potassium tert-butoxide at room temperature for 2 h
and then a 3 N hydrochloric acid solution was added.
Heating the resulting mixture under reflux for 2 h led
to 12 in good overall yield (88%). Finally, treatment of
12 with LiPPh2 (THF, 0 °C, 0.5 h, then 60 °C, 2 h) affor-
ded the desired diphenylphosphinoacridine 310 in good
yield (82%).
Herein, we report the synthesis of the chiral 5-(diphenyl-
phosphanyl)-1,2,3,4-tetrahydroacridines 3–5 (Fig. 1), as
first representative examples of N,P-ligands of the type 2
and the preliminary results obtained with these ligands
in the enantioselective palladium-catalysed allylic
substitution.
However, the extention of this procedure to the N,P-
ligand 4 derived from (+)-camphor (14) failed (Scheme
2). In fact, no compound was obtained by reaction of
10 with 14 in the presence of t-BuOK as the base. The
condensation product 15 was instead obtained, although
in low yield (21%), when the preformed lithium enolate
anion of 14 (LDA, THF, ꢀ40 °C, 2 h) was treated with
the aldehyde 10. Moreover, no azaannulation product
was obtained when 15 was headed under reflux in a
dioxane solution for several hours. This outcomes
account for the steric hindrance of camphor carbonyl
group that reduces the ability of 14 to undergo both
condensation and azaannulation steps.11 Mostgraitfy-
ingly, high yield (85%) of the fluoroacridine 16 was ob-
tained when the cyclisation reaction of 15 was carried
out under rather drastic conditions (carbitol, HCl, re-
flux, 1 h). Atlas,t compound 16 was converted in the
usual way into the desired diphenylphosphinoacridine
412 in satisfactory yield (75%).
For the synthesis of ligands of the type 2, we envisaged
that a convenient approach could involve the introduc-
ing of the diphenylphosphanyl group by nucleophilic
substitution with lithium diphenylphosphide (LiPPh2)
of an electrophilic aryl fluoride on the C5 of the tetrahy-
droacridine 6.6 This could be in turn obtained by the
Friedla¨nder condensation7 between the 3-substituted
2-aminobenzaldehyde
(Fig. 2).
7 and the chiral ketone 8
For this purpose, the 2-amino-3-fluorobenzaldehyde (7)8
obtained by hydrolysis of the N-Boc aldehyde 10,9 was
submitted to Friedla¨nder condensation with the (+)-
nopinone (13) (ethanol or carbitol, saturated KOH in
MeOH) to afford the 5-fluorotetrahydroacridine 12 in
only 9% yield (Scheme 1). The low yield is due to the rela-
tive instability of the o-amino aryl aldehyde, which can
readily undergo self-condensation reactions.
CHO
R*
R*
R*
+
NH2
N
N
O
F
F
PPh2
2
6
7
8
Figure 2.
CHO
CHO
NH2
a
b
NHBoc
NHBoc
F
F
F
10
7
d
9
c
f
e
F
N
N
NHBoc
O
F
PPh2
12
3
11
O
13
Scheme 1. Reagents and conditions: (a) t-BuLi, ꢀ78 to ꢀ50 °C, 3 h, then DMF, ꢀ78 °C to slowly rt, 71%; (b) HCl (3 N), dioxane, 60 °C, 1 h, 55%;
(c) 13, carbitol, saturated KOH in MeOH, 9%; (d) 13, t-BuOK, 1,4-dioxane, rt, 2 h, then 3 N HCl, reflux, 2 h, 88%; (e) LiPPh2, THF, ꢀ10 °C, 0.5 h,
then 60 °C, 2 h, 82%.

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G. Chelucci, G. Orru / Tetrahedron Letters 46 (2005) 3493–3496
3495
CHO
a
b
+
N
NHBoc
F
O
O
F
F
NHBoc
14
16
10
15
c
N
PPh2
4
Scheme 2. Reagents and conditions: (a) 14, LDA, THF, ꢀ40 °C, 2 h, then 10, 15 min then slowly rt, 21%; (b) carbitol, catalytic HCl, reflux, 1 h, 85%;
(c) LiPPh2, THF, ꢀ10 °C, 0.5 h, then 60 °C, 2 h, 75%.
Finally, following the protocol established for 4, t he
N,P-ligand 513 was obtained in 51% overall yield start-
ing from 5a-androst-2-en-17-one 1714 (Scheme 3).
analogue ligands 1 bearing the same chiral tetrahydro-
quinoline unit. Thus, ligand 3a induced in 2 h the
formation of (S)-21 with 74% ee, whereas 1a [(6R,8R)-(+)-
5,6,7,8-tetrahydro-7,7-dimethyl-2-(2-diphenylphosphino-
phenyl)-6,8-methanoquinoline] required 70 h to give
(S)-21 with 70% ee.5 More evidentis hte difference
between ligands 4 and 1b [(5S,8R)-(ꢀ)-5,6,7,8-tetrahydro-
8,9,9-trimethyl-2-(2-diphenylphosphinophenyl)-7,8-meth-
anoquinoline]. In fact, ligand 4 led in less than 3 h to
the reaction product with 69% ee, whilst 1b needed
12 h to afford (S)-21 with 50% ee.5 Both ligands 3,4
and 1a,b afforded the product with the same prevailing
(S)-configuration indicating that the reactive transition
state, which determines the stereochemical outcome is
likely the same.
As a model for the evaluation of the ability of the new
P–N ligands to provide asymmetric induction in cata-
lytic processes we selected the palladium-catalysed
allylic substitutions and in particular the alkylation of
1,3-diphenylprop-2-enyl acetate (20) with dimethyl malo-
nate, which serves as a model substrate to compare the
outcome of different ligands.15 Allylic substitutions were
carried outemploying [Pd( g3-C3H5)Cl]2 as procatalyst
and a mixture of dimethyl malonate, N,O-bis(trimethyl-
silyl)acetamide (BSA) and potassium acetate in methyl-
ene chloride.16
[Pd(η3-C3H5)Cl]2 / Ligand
OCOCH3
CH(COOCH3)2
C6H5
C6H5
C6H5
C6H5
CH2(COOCH3)2, BSA,
CH2Cl2, KOAc
20
21
Ligands 3–5 were able to provide effective palladium
catalysts to give the dimethyl 1,3-diphenylprop-2-enyl
malonate (21) in good yields (90–95%) within
3 h. In all cases the (S)-enantiomer of the product
in moderate enantiomeric excess (69–74%) was
obtained.
In summary, we have prepared a new class of chelating
ligands of the type N–P from naturally occurring natu-
ral compounds. The preliminary results obtained in
enantioselective palladium-catalysed allylic substitutions
indicate that they are worthy of attention for their appli-
cations in the field of asymmetric catalysis. Further
studies aimed at the modification to the ligand design
and the application to other catalytic asymmetric reac-
tions are in progress.
In this process ligands 3–5 showed a general better cata-
lytic activity and stereodifferentiating ability than the
CHO
F
a
+
NHBoc
BocHN
O
F
O
10
17
18
b
c
N
N
F
PPh2
19
5
Scheme 3. Reagents and conditions: (a) 17, LDA, THF, ꢀ40 °C, 2 h, then 10, 15 min, then slowly rt, 74%; (b) carbitol, catalytic HCl, reflux, 1 h,
69%; (c) LiPPh2, THF, ꢀ10 °C, 0.5 h, then 60 °C, 2 h, 50%.

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G. Chelucci, G. Orru / Tetrahedron Letters 46 (2005) 3493–3496
3496
8. The 2-amino-3-fluorobenzaldehyde has been obtained in
Acknowledgements
55% yield by hydrolysis of tert-butyl N-(2-formyl-6-fluo-
rophenyl)carbamate (1,4-dioxane, 3 N HCl, 60 °C, 3 h).
9. Chelucci, G.; Manca, I.; Pinna, G. A. Tetrahedron Lett.
2005, 46, 767.
Financial supportfrom MIUR (PRIN 2003033857-Chi-
ral ligands with nitrogen donors in asymmetric catalysis
by transition metal complexes. Novel tools for the syn-
thesis of fine chemicals) and from the University of Sas-
sari is gratefully acknowledged by G.C.
10. (2R,4R)-5-(Diphenylphosphino)-2,4-methano-3,3-dimeth-
25
D
yl-1,2,3,4-tetrahydroacridine (3): mp 160–161 °C; ½aŠ
1
ꢀ31.3 (c 3.77, CHCl3); H NMR d 7.79 (s, 1H), 7.66 (d,
1H, J = 8.1 Hz), 7.40–7.20 (m, 11H), 7.02–6.93 (m, 1H),
3.07 (s, 2H), 3.02 (t, 1H, J = 5.7 Hz), 2.70–2.63 (m, 1H),
1.34 (s, 3H), 1.27 (d, 1H, J = 9.6 Hz), 0.53 (s, 3H). 13C
NMR d 166.5, 146.9, 138.1, 137.9, 137.8, 134.3, 134.1,
134.0, 133.8, 133.5, 132.6, 129.3, 128.2, 128.1, 128.0, 127.9,
127.8, 127.7, 127.1, 127.0, 125.2, 50.8, 39.7, 39.2, 31.1, 30.5,
25.8, 21.1. 31P NMR d ꢀ13.08. Anal. Calcd for C28H26NP:
C, 82.53; H, 6.43; N, 3.44. Found: C, 82.98; H, 6.66; N, 3.23.
11. (1S,4R)-5-(Diphenylphosphino)-1,4-methano-4,11,11-tri-
References and notes
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methyl-1,2,3,4-tetrahydroacridine (4): mp 173–174 °C;
D
25
½aŠ ꢀ71.93 (c 1.48, CHCl3); 1H NMR d 7.63 (d, 1H,
J = 8.1 Hz), 7.45–7.17 (m, 11H), 7.0–6.95 (m, 2H), 2.87 (d,
1H, J = 3.9 Hz), 2.2–2.0 (m, 2H), 1.85–1.7 (m, 2H), 1.00 (s,
3H), 0.94 (s, 3H), 0.37 (s, 3H). 13C NMR d 170.5, 139.9,
138.2, 138.0, 137.9, 134.5, 134.2, 134.1, 133.8, 133.7, 131.2,
128.1, 128.0, 127.9, 127.8, 127.8, 127.8, 127.7, 127.0, 125.5,
124.9, 55.2, 53.9, 51.1, 31.3, 26.2, 19.9, 18.7, 9.7. 31P NMR
d ꢀ10.23. Anal. Calcd for C29H28NP: C, 82.63; H, 6.70; N,
3.32. Found: C, 82.33; H, 6.85; N, 3.37.
12. 50a-20-Androstadieno-[170,160-b]-5-(diphenylphosphino)-
25
quinoline (5): mp 174–175 °C; ½aŠ +110.78 (c 1.38,
D
CHCl3); 1H NMR d 7.80 (s, 1H), 7.66 (d, 2H, J = 8.1
Hz), 7.87–7.40 (m, 10H), 6.99 (dd, 1H, J = 4.0, 7.0 Hz),
5.59 (s, 2H), 2.83 (dd, 1H, J = 6.0, 14.0 Hz), 2.54 (t, 1H,
J = 12.0 Hz), 2.08–0.90 (m, 16H), 0.80 (s, 3H), 0.74 (s,
3H). 13C NMR d 173.20, 138.42, 138.31, 138.02, 137.88,
137.08, 135.16, 137.51, 134.38, 134.24, 134.12, 131.94,
130.48, 128.13, 128.09, 128.05, 128.03, 127.95, 126.85,
125.86, 125.73, 125.18, 88.23, 55.25, 54.48, 45.61, 41.56,
39.56, 34.88, 34.66, 33.21, 31.44, 30.27, 30.15, 28.54,
20.41, 17.29, 11.65. 31P NMR d ꢀ10.78. Anal. Calcd for
C38H40NP: C, 84.25; H, 7.44; N, 2.59. Found: C, 84.50; H,
7.64; N, 2.39.
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