Asymmetric aza-friedel-crafts reaction of 2-naphthol with tosylimines catalyzed by a dinuclear zinc complex

Article abstract of DOI:10.1055/s-0029-1219390

The first asymmetric aza-Friedel-Crafts reaction of 2-naphthol with tosylimines was developed via a dinuclear zinc catalyst (up to 98% ee). It provided a new method for the asymmetric synthesis of Betti base derivatives.

Full text of DOI:10.1055/s-0029-1219390

LETTER
765
Asymmetric Aza-Friedel–Crafts Reaction of 2-Naphthol with Tosylimines
Catalyzed by a Dinuclear Zinc Complex
Asymmetric
A
z
i
a-Fried
a
el–Crafts
R
n
eaction of
2
g
-
Naphthol
w
-
F
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. of China
Fax +86(931)8915557; E-mail: xphui2003@yahoo.com.cn; E-mail: huixp@lzu.edu.cn
Received 20 October 2009
been expanded successfully to electron-rich benzenes9a–d
and five-membered aromatic heterocycles.9e–j In contrast,
the applications of the naphthols in asymmetric Friedel–
Crafts reaction have rarely been explored.10 The first ex-
ample of enantioselective Friedel–Crafts reaction involv-
ing 1-naphthols was reported by Erker and van der
Zeijden10a using a zirconium trichloride Lewis acid con-
taining a ‘dibornacyclopentadienyl’ ligand. Recently, Jør-
gensen,10b,c Chen10d and Wang10e presented the
organocatalytic asymmetric Friedel–Crafts reaction of 2-
naphthol with azodicarboxylates, nitroolefins, and a,b-
unsaturated aldehydes, respectively. However, the enanti-
oselective aza-Friedel–Crafts reaction of 2-naphthol with
electron-deficient imines has not been reported up till
now.
Abstract: The first asymmetric aza-Friedel–Crafts reaction of 2-
naphthol with tosylimines was developed via a dinuclear zinc cata-
lyst (up to 98% ee). It provided a new method for the asymmetric
synthesis of Betti base derivatives.
Key words: 2-naphthol, asymmetric synthesis, Betti base, Friedel–
Crafts reaction, tosylimine
Friedel–Crafts reaction of aromatic substrates to alde-
hydes, ketones, activated olefines, and imines is a key re-
action in synthetic organic chemistry for the formation of
carbon–carbon bonds.1 The stereoselective addition of sp2
C–H bonds to an imine, an aza-Friedel–Crafts reaction, is
particularly attractive both because the nucleophiles re-
quire no preactivation and because the products are chiral
benzylic amines, the substructure exists in many natural
products and medicinal chemistry programs.2 The com-
pounds, especially bearing 1,3-amino-oxygenated func-
tional motifs, are ubiquitous to a variety of potent drugs,
including a number of nucleoside antibiotics and HIV pro-
tease inhibitors, such as ritonavir and lipinavir.3 Since
these compounds have multiple centers for chelation with
metal ions, they are likely to be potent inhibitors of metal-
loenzymes containing Fe, Cu, Zn, Co, etc. ions as cofac-
tors.4 In addition, chiral aminophenols have been reported
as excellent chelating agents in metal-catalyzed asymmet-
ric induction in a variety of reactions5 and as precursors in
chiral boranate complexes.6 Chiral Betti base was proved
to be an excellent chiral auxiliary for total syntheses of
enantiopure alkaloidal natural products.7
Since racemic Betti base was achieved, numerous modifi-
cations of this reaction surfaced and optically pure Betti
base analogues were prepared either by resolution11 or by
induction of chirality using optically active amines or al-
dehydes.5,12 The development of new methods for their as-
sembly is therefore of considerable synthetic importance.
Herein, we wish to report first asymmetric aza-Friedel–
Crafts reaction of 2-naphthol with electron-deficient im-
ines in excellent enantioselectivity, which provided a
method for asymmetric synthesis of new Betti base deriv-
atives.
The dinuclear zinc complexes 1–3 were prepared as pre-
viously method13 by treating the bis-ProPhenol with 2
equivalents of diethylzinc in toluene at room temperature
(Scheme 1). Aza-Friedel–Crafts reaction of 2-naphthol
with
(E)-N-benzylidene-4-methylbenzenesulfonamide
During the past decades, indole and its derivatives have
been demonstrated to be good substrates for the asymmet-
ric Friedel–Crafts reaction.8 Recently, the substrates have
was first examined,14 which is a useful way to prepare
Betti base derivatives. The desired product could not be
Ar
Ar
Ar
Ar
Ar
Ar
OH
Et
O
Ar
Ar
HO
N
O
N
Zn
Zn
N
OH
Et2Zn (2 equiv)
N
O
Ar = Bn (1)
Ar = Ph (2)
Ar = 3,5-(CF3)2C6H3 (3)
Me
Me
Scheme 1 Preparation of complexes 1–3
SYNLETT 2010, No. 5, pp 0765–0768
1
6.
3
.2
0
1
0
Advanced online publication: 10.02.2010
DOI: 10.1055/s-0029-1219390; Art ID: W16709ST
© Georg Thieme Verlag Stuttgart · New York

766
L.-F. Niu et al.
LETTER
obtained in the absence of complex 2 (Table 1, entry 1). of 82–95% and good to excellent enantioselectivities of
On the other hand, combining 2-naphthol with (E)-N-ben- 74–98% ee of R-configuration for arylimines (entries 1–
zylidene-4-methylbenzenesulfonamide in the presence of 11). For the less sterically hindered 4-substituted
0.1 equivalents of complex 2 yielded Betti base derivative arylimines, the products were obtained in higher enanti-
in 37% yield and 10% ee (entry 2). Increasing the catalyst oselectivities ranging from 90–98% ee (entries 3, 5, 8, 10,
to 0.3 and 0.5 equivalents could improve the yields and and 11). On the other hand, the 2-substituted arylimines
enantioselectivities (entries 3 and 4). The enantioselectiv- gave lower enantioselectivities (entries 2, 4, and 6). Aza-
ities of the reaction were strongly affected by the reaction Friedel–Crafts reaction to aliphatic aldimine such as (E)-
conditions. The reaction proceeded at a faster rate and N-tosylbutan-1-imine was also examined, and the reaction
with slightly lower enantiomeric excess at 50 °C (entry 5). gave the product in high enantioselectivity of 91% (entry
In order to obtain a satisfactory result, 1 equivalent of the 12). For N-Boc imine, the alkylation reaction also pro-
complex 2 was used and 1-[(R)-phenyl(tosylamino)meth- ceeded smoothly and tert-butyl (2-hydroxynaphthalen-1-
yl]naphthalen-2-ol (4a) was afforded in 90% yield and yl)(phenyl)methylcarbamate was obtained in 88% yield
96% ee (entry 6). The results showed that dinuclear zinc and 91% ee.
complexes 1 and 3 gave lower enantioselectivities than
complex 2 (entries 7 and 8). Further optimization studies
were then carried out using complex 2. Solvents such as
1,4-dioxane, xylene, CH2Cl2, and THF were also exam-
ined and toluene was found to be the best choice (entries
9–12). Thus, entry 4 in Table 1 was identified as the opti-
mized reaction procedure.
Table 1 Screening of the Reaction Conditions
Ts
Ph
NH
OH
OH
complex
solvent
Ts
+
Ph
N
Entry Complex
(equiv)
Temp
(°C)
Solvent
Yield
(%)b
ee
Figure 1 X-ray crystallography structure of 4k
(%)c
n.d.
10
1
2
–
30
30
30
30
50
30
30
30
30
30
30
30
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
xylene
CH2Cl2
THF
n.r.
37
The absolute configuration of the product was confirmed
by X-ray crystal structure analysis of Betti base derivative
4k (Figure 1). On the basis of this structure, compound 4k
possessed an R-configuration at the newly formed chiral
center.16 In addition, the absolute configuration of product
4a was also determined by comparison of the optical rota-
tion of (S)-4a17 and (R)-4a. In order to obtain Betti base
5a, which was an excellent chiral auxiliary for total syn-
theses of enantiopure alkaloidal natural products, sodium/
naphthalene in dry THF was used to deprotect the Ts
group and the (R)-Betti base 5a could be obtained suc-
cessfully (Scheme 2).18
2 (0.1)
2 (0.3)
2 (0.5)
2 (0.3)
2 (1)
1 (1)
3 (1)
2 (1)
2 (1)
2 (1)
2 (1)
3
73
55
4
82
87
5
78
38
6
90
96 (R)
85
7
81
8
95
54
9
trace
83
–
Ts
10
11
12
86
NH
Ph
NH2
OH
89
92
OH
Na, naphthalene
THF
20
24
a Reaction conditions: 2-naphthol/tosylimine = 1:3 (molar ratio); re-
action time: 48 h.
(R)-4a
(R)-5a
b Isolated yield.
c Determined by HPLC analysis using Chiralcel OD-H column.
Scheme 2 Formation of Betti base
A proposed reaction mechanism is shown in Scheme 3. 2-
Naphthol is deprotonized by complex 2 accompanied by
the formation of one equivalent of ethane. After this, the
tosylimine coordinates to this catalyst to form intermedi-
To extend substrate scope, a variety of different imine
substrates was further explored under the optimal reaction
conditions. As the results summarized in Table 2, the ex-
pected products could be obtained in good isolated yields
Synlett 2010, No. 5, 765–768 © Thieme Stuttgart · New York

LETTER
Asymmetric Aza-Friedel–Crafts Reaction of 2-Naphthol with Tosylimines
767
Table 2 Asymmetric Aza-Friedel–Crafts Reaction of 2-Naphthol
with Tosyliminesa
C2H6 (1 equiv)
OH
PG
complex 2
R
NH
OH
OH
complex 2
PG
+
R
N
toluene, 30 °C
Ph
4
OH HN
Ph
Ph
O
Entry
R
PG
Product Yield ee (%)c Config.
(%)b
Ts
Ph
Ph
O
O
N
Zn
Zn
HO
N
O
N
Ph
1
2
Ph
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Boc
4a
4b
4c
4d
4e
4f
90
92
88
83
87
92
90
89
91
82
95
76
88
96
82
93
83
90
80
74
98
89
90
92
91
91
(–)-(R)
(–)
Ts
2-FC6H4
4-FC6H4
3
(–)
Me
Ph
4
2-MeC6H4
4-MeC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
(–)
5
(–)
Ph
Ph
O
N
Ph
Ts
Zn
Ph
Ph
O
O
N
6
(–)
Zn
Ph
Ph
O
N
Ts
Zn
N
O
Ph
Ph
O
O
7
4g
4h
4i
(–)
Zn
8
(–)
N
O
N
aza-Friedel–Crafts
reaction
II
9
2-MeOC6H4
4-MeOC6H4
4-BrC6H4
Pr
(–)
Me
10
11
12
13
4j
(–)
I
Me
4k
4l
(–)-(R)
(–)
Scheme 3 Proposed reaction mechanism
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Ph
4m
(+)
a Reaction conditions: 2-naphthol/tosylimines/complex 2 = 1:3:1
(molar ratio); reaction time: 48 h.
b Isolated yield.
Acknowledgment
c Determined by HPLC analysis using Chiralcel OD-H, OJ-H or
AD-H column.15
We are grateful for the financial support of the National Natural Sci-
ence Foundation of China (No. 20702022, J0730425) and Izujbky-
2009-79.
ate I, which is followed by aza-Friedel–Crafts alkylation
reaction to generate intermediate II. The product is then
released, and the active catalyst is reformed by a proton
exchange between intermediate II and an incoming 2-
naphthol.
References and Notes
(1) For reviews on enantioselective Friedel–Crafts reactions,
see: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew.
Chem. Int. Ed. 2004, 43, 550. (b) Jørgensen, K. A. Synthesis
2003, 1117. (c) Bandini, M.; Melloni, A.; Tommasi, S.;
Umani-Ronchi, A. Synlett 2005, 1199. (d) Poulsen, T. B.;
Jørgensen, K. A. Chem. Rev. 2008, 108, 2903.
In summary, we have discovered the first highly asym-
metric aza-Friedel–Crafts reaction of 2-naphthol with to-
sylimines for the synthesis of optically active Betti base
derivatives. A wide variety of aryl aldimine substrates
possessing either electron-withdrawing or electron-donat-
ing groups and aliphatic aldimine could be employed suc-
cessfully. Currently, we are further expanding the
application of the Betti base derivatives to catalyze new
asymmetric reactions.
(2) Shirakawa, S.; Berger, R.; Leighton, J. L. J. Am. Chem. Soc.
2005, 127, 2858.
(3) (a) Seebach, D.; Matthews, J. L. J. Chem. Soc., Chem.
Commun. 1997, 2015. (b) Wang, Y.-F.; Izawa, T.;
Kobayashi, S.; Ohno, M. J. Am. Chem. Soc. 1982, 104,
6465. (c) Knapp, S. Chem. Rev. 1995, 95, 1859. (d)Juaristi,
E. In Enantioselective Synthesis of b-Amino Acids; John
Wiley and Sons: New York, 1997.
(4) Jha, A.; Paul, N. K.; Trikha, S.; Cameron, T. S. Can. J.
Chem. 2006, 84, 843.
Synlett 2010, No. 5, 765–768 © Thieme Stuttgart · New York

768
L.-F. Niu et al.
LETTER
(5) For a review, see: (a) Kocovsky, P.; Vyskocil, S.; Smrcina,
M. Chem. Rev. 2003, 103, 3213. For some selected
examples, see: (b) Cimarelli, C.; Palmieri, G.; Volpini, E.
Tetrahedron: Asymmetry 2002, 13, 2417. (c) Lu, J.; Xu, X.;
Wang, S.; Wang, C.; Hu, Y.; Hu, H. J. Chem. Soc., Perkin
Trans. 1 2002, 2900. (d) Ji, J.-X.; Qui, L.-Q.; Yip, C. W.;
Chan, A. S. C. J. Org. Chem. 2003, 68, 1589. (e) Ji, J.-X.;
Wu, J.; Au-Yeung, T. T.-L.; Yip, C.-W.; Haynes, R. K.;
Chan, A. S. C. J. Org. Chem. 2005, 70, 1093.
(6) Kaiser, P. F.; White, J. M.; Hutton, C. A. J. Am. Chem. Soc.
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(8) For some recent examples, see: (a) Esquivias, J.; Arrayás,
R. G.; Carretero, J. C. Angew. Chem. Int. Ed. 2006, 45, 629.
(b) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem.
Soc. 2005, 127, 8942. (c) Evans, D. A.; Fandrick, K. R.;
Song, H.-J.; Scheidt, K. A.; Xu, R. S. J. Am. Chem. Soc.
2007, 129, 10029. (d) Takenaka, N.; Abell, J. P.;
(4 mL) in a Schlenk tube was added dropwisely a solution of
diethylzinc (0.68 mL, 0.6 mmol) under a nitrogen atmo-
sphere. The solution was continued to stir for 1 h to give a
solution of complex 2 (0.75 M in toluene). 2-Naphthol (43
mg, 0.3 mmol) and tosylimine (0.9 mmol) were added, and
the reaction was stirred for 48 h at 30 °C. After the reaction
was completed, the mixture was quenched with sat. NH4Cl
solution (5 mL) and EtOAc (5 mL). The organic layer was
separated, and the aqueous phase was extracted with EtOAc
(3 × 5 mL). The combined organic layers were dried over
Na2SO4. The solvent was removed under reduced pressure
using a rotary evaporator. The residue was purified by
column chromatography using CH2Cl2–PE–EtOAc =
10:10:1 to give the desired product.
N-[(2-Hydroxynaphthalen-1-yl)(phenyl)methyl]-4-
methylbenzenesulfonamide (4a)
Yield 90%; light yellow solid; [a]D20 –55 (c 1.0, CHCl3); mp
142–144 °C. 1H NMR (400 MHz, CDCl3): d = 7.72 (d,
J = 7.2 Hz, 1 H), 7.70 (d, J = 4.4 Hz, 1 H), 7.65–7.50 (m, 1
H), 7.40–7.37 (m, 1 H), 7.33–7.30 (m, 5 H), 7.25–7.20 (m, 3
H), 6.87–6.83 (m, 1 H), 6.64 (d, J = 8.0 Hz, 3 H), 6.48 (s, 1
H), 6.39 (d, J = 8.4 Hz, 1 H), 2.09 (s, 3 H). 13C NMR (75
MHz, CDCl3): d = 151.1, 142.8, 139.9, 135.9, 132.3, 129.6,
128.8, 128.7, 128.3, 127.2, 127.1, 126.7, 126.5, 123.3,
121.8, 118.1, 117.3, 54.4, 21.1. ESI-HRMS: m/z calcd for
C24H21NO3S + Na: 426.1140; found: 426.1134. HPLC: ee
96% [Chiralcel OD-H, n-hexane–i-PrOH (95:5), flow rate:
1.0 mL/min]: tR(minor) = 20.36 min; tR(major) = 25.71 min.
(15) The ee of compounds 4a–l were determined by HPLC using
Chiralcel column, see Supporting Information for full
details.
Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 742. (e)Yang,
H.; Hong, Y.-T.; Kim, S. Org. Lett. 2007, 9, 2281.
(f) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H. M.; Deng, L.
J. Am. Chem. Soc. 2006, 128, 8156. (g) Terada, M.;
Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292. (h) Kang,
Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129,
1484.
(9) For some recent examples, see: (a) Gathergood, N.;
Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2000, 122,
12517. (b) Shirakawa, S.; Berger, R.; Leighton, J. L. J. Am.
Chem. Soc. 2005, 127, 2858. (c) Yuan, Y.; Wang, X.; Li, X.;
Ding, K. J. Org. Chem. 2004, 69, 146. (d) Zhao, J.-L.; Liu,
L.; Sui, Y.; Liu, Y.-L.; Wang, D.; Chen, Y.-J. Org. Lett.
2006, 8, 6127. (e) Paras, N. A.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2001, 123, 4370. (f) Palomo, C.; Oiarbide, M.;
Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc.
2005, 127, 4154. (g) Li, G. L.; Rowland, G. B.; Rowland, E.
B.; Antilla, C. Org. Lett. 2007, 9, 4065. (h) Uraguchi, D.;
Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126,
11804. (i) Liu, H.; Xu, J.; Du, D.-M. Org. Lett. 2007, 9,
4725. (j) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am.
Chem. Soc. 2005, 127, 8942.
(16) The molecular structure of product 4k was determined
by X-ray crystallography. CCDC 751078 contains the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallo-graphic data centre via www.ccdc.cam.ac.uk/
data_request/cif or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax:
+44 (1223)336033.
(17) The preparative procedure of compound (S)-4a, see
Supporting Information for full details.
(10) (a) Erker, G.; van der Zeijden, A. A. H. Angew. Chem., Int.
Ed. Engl. 1990, 29, 512. (b) Brandes, S.; Bella, M.;
Kjoersgaard, A.; Jørgensen, K. A. Angew. Chem. Int. Ed.
2006, 45, 1147. (c) Brandes, S.; Niess, B.; Prieto, A.;
Overgaard, J.; Jørgensen, K. A. Chem. Eur. J. 2006, 12,
6039. (d) Liu, T.-Y.; Cui, H.-L.; Chai, Q.; Long, J.; Li, B.-J.;
Wu, Y.; Ding, L.-S.; Chen, Y.-C. Chem. Commun. 2007,
2228. (e) Hong, L.; Wang, L.; Sun, W.; Wong, K.; Wang, R.
J. Org. Chem. 2009, 74, 6881.
(18) Synthesis of Compound (R)-5a
To dry degassed THF (2.5 mL) taken in a round-bottomed
flask under nitrogen was added Na metal (69 mg, 3 mmol)
following naphthalene (40 mg, 2.9 mmol). The mixture was
stirred for 1 h at r.t. To this solution was added a concen-
trated solution of (R)-4a (58 mg, 0.14 mmol) in dry THF (3
mL). The reaction was stirred at r.t. overnight. The mixture
was quenched by addition of a small amount of H2O care-
fully, the solution dried over anhydrous MgSO4 and filtered.
The crude mass was purified by column chromatography to
give (R)-5a (21.6 mg, 62%). 1H NMR (300 MHz, CDCl3):
d = 7.74–7.69 (m, 3 H), 7.49–7.35 (m, 2 H), 7.37–7.15 (m, 6
H), 6.16 (s. 1 H). HPLC: ee 94% [Chiralcel OJ, n-hexane–
i-PrOH (70:30), flow rate: 1.0 mL/min]: tR(minor) = 22.35
min; tR(major) = 51.87 min.
(11) Dong, Y.; Li, R.; Lu, J.; Xu, X.; Wang, X.; Hu, Y. J. Org.
Chem. 2005, 70, 8617.
(12) Cappannini, L.; Cimarelli, C.; Giuli, S.; Palmieri, G.; Petrini,
M. Tetrahedron: Asymmetry 2007, 18, 1022.
(13) The preparative procedure of the dinuclear zinc complex, see
Supporting Information for full details.
(14) General Procedure for Aza-Friedel–Crafts Reaction
To a solution of ligand 2 (r.t., 192 mg, 0.3 mmol) in toluene
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