Enantioselective friedel-crafts aminoalkylation catalyzed by chiral ammonium 1,1-binaphthyl-2,2-disulfonates

Article abstract of DOI:10.1055/s-0030-1260538

A catalytic enantioselective Friedel-Crafts aminoalkylation between aromatic aldimines and N-benzylpyrrole with the use of a homogeneous chiral ammonium salt, (R)-BINSA-N,N-dimethylbutylamine, as a dynamic Br?nsted acid-Br?nsted base catalyst, is reported. Unlike the results with conventional catalysts, remarkably high reactivity was established at -78 C within 30 minutes, and the corresponding aryl(1H-pyrrol-2-yl)methanamines were obtained with good to high enantioselectivities. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260538

CLUSTER
1247
Enantioselective Friedel–Crafts Aminoalkylation Catalyzed by Chiral
Ammonium 1,1¢-Binaphthyl-2,2¢-disulfonates
E
nantioselective Frie
d
a
A
n
minoalkylati
a
on bu Hatano,a Yoshihiro Sugiura,a Matsujiro Akakura,b,c Kazuaki Ishihara*a,c
a
b
c
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Department of Chemistry, Aichi University of Education, Igaya-cho, Kariya 448-8542, Japan
Japan Science and Technology Agency (JST), CREST, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Fax +81(52)7893222; E-mail: ishihara@cc.nagoya-u.ac.jp
Received 1 February 2011
benzyl benzylidenecarbamate (1a) and N-benzylpyrrole
(2a) in dichloromethane at –78 °C for 30 minutes in the
presence of MgSO4 as a drying agent (Table 1).8 The pre-
vious homogeneous catalyst, which was optimized for the
Abstract: A catalytic enantioselective Friedel–Crafts aminoalkyla-
tion between aromatic aldimines and N-benzylpyrrole with the use
of a homogeneous chiral ammonium salt, (R)-BINSA–N,N-dimeth-
ylbutylamine, as a dynamic Brønsted acid–Brønsted base catalyst,
is reported. Unlike the results with conventional catalysts, remark- direct Mannich-type reaction and prepared in situ from
(R)-BINSA and 2,6-diphenylpyridine (4a),5c promoted
the reaction but showed only a moderate enantioselectivi-
ty of (S)-3a (45% ee, Table 1, entry 1). While a secondary
ably high reactivity was established at –78 °C within 30 minutes,
and the corresponding aryl(1H-pyrrol-2-yl)methanamines were ob-
tained with good to high enantioselectivities.
Key words: ammonium salt, Friedel–Crafts reaction, 1,1¢-binaph-
thyl-2,2¢-disulfonic acid (BINSA), chiral Brønsted acid, organocat-
alyst
amine such as diethylamine (4b) was less suitable
(Table 1, entry 2), a tertiary aniline 4c and tertiary aliphat-
ic amines 4d–n gave better enantioselectivities (Table 1,
entries 3–16). In particular, the less sterically hindered
N,N-dimethylalkylamines were effective, and the desired
products were obtained in >70% yields and with >70% ee.
Chirality (see 4g–i) and the length of the N-alkyl chain
(see 4j,k,m,n) did not significantly affect the enantiose-
lectivities (entries 7–10, 12, 15, and 16), although sterical-
ly demanding N-butyl-N-methylbutylamine (4l) was less
favored (Table 1, entry 14). Next we optimized the molar
amount of N,N-dimethylbutylamine (4k), and a 1:1 molar
ratio of (R)-BINSA and 4k was the most effective
(Table 1, entries 11–13). Interestingly, a 1:2 molar ratio of
(R)-BINSA and 4k significantly decreased the catalytic
activity, probably due to neutralization of the two SO3H
moieties (Table 1, entry 13). Moreover, diamines such as
N,N,N¢,N¢-tetramethylethylenediamine (TMEDA, 4o) and
1,4-diazabicyclo[2.2.2]octane (DABCO, 4p) were less ef-
fective than monoamines due to the lower solubility of the
catalysts prepared in situ (Table 1, entries 17 and 18).
A catalytic enantioselective Friedel–Crafts aminoalkyla-
tion (aza-Friedel–Crafts reaction) between aldimines and
pyrroles is highly useful for synthesizing the chiral build-
ing blocks of biologically and pharmaceutically active ar-
yl(1H-pyrrol-2-yl)methanamines.1,2 Over the past several
years, much attention has been devoted to methods for the
catalytic enantioselective Friedel–Crafts aminoalkylation
using chiral metal catalysts3 or organocatalysts.4 In partic-
ular, chiral BINOL (1,1¢-bi-2-naphthol) derived phospho-
ric acids have been widely used as effective chiral
Brønsted acid catalysts for this reaction.4a,c–j,l In sharp
contrast, BINSA (1,1¢-binaphthyl-2,2¢-disulfonic acid)
and its derivatives have not yet been applied to the
Friedel–Crafts aminoalkylation, although they have been
recognized as attractive chiral Brønsted acid catalysts for
some asymmetric catalyses.5,6 In our initial study of
BINSA-derived catalysts, we developed pyridinium 1,1¢-
binaphthyl-2,2¢-disulfonates as effective Brønsted acid–
Brønsted base catalysts7 for the direct Mannich-type reac-
tion of aromatic aldimines with 1,3-dicarbonyl com-
pounds (Scheme 1).5c In general, acid–base combined
salts have several advantages over single-molecule cata-
lysts, with regard to flexibility in the design of their dy-
namic complexes. Based on the relevance of the
ammonium salts of BINSA, we report here a catalytic
enantioselective Friedel–Crafts aminoalkylation between
aromatic aldimines and N-benzylpyrrole.
R1
NH
*
O
R1
H
(R)-BINSA (1 mol%)
2,6-Ar22-pyridine (2 mol%)
O
O
N
Ar1
R3
+
*
MgSO4
CH2Cl2, 0 °C
R2
R3
R
Ar1
O
R2
R
N
H
R
N
H
R
R
R
+ NR3
– NR3
SO3
SO3
SO3
First, we optimized ammonium salts by tuning the achiral
amines for (R)-BINSA (5 mol%) in the reaction between
SO3H
H
N
R
SYNLETT 2011, No. 9, pp 1247–1250
Advanced online publication: 20.04.2011
x
x.
x
x.
2
0
1
1
R
R
tuning acidity, bulkiness, and flexibility in situ
DOI: 10.1055/s-0030-1260538; Art ID: Y03511ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Direct Mannich-type reaction catalyzed by (R)-BINSA
pyridinium salts

1248
M. Hatano et al.
CLUSTER
In the probe reaction between 1a and 2a in Table 1, we of- 3a would occur (Scheme 2). As a result, enantioenriched
ten obtained overreaction compound 5 in yields of 0– (S)-3a was recovered in 40% yield with 67% ee in addi-
10%, which was the result of the aminoalkylation product tion to inseparable diastereomeric mixture 5 (39% yield,
3a. Therefore, we reacted 1a (0.5 equiv) and racemic 3a dl/meso = ca. 1:1) and other complex mixtures (<20%).
(1 equiv) in the presence of 5 mol% each of (R)-BINSA This result strongly suggested that most of the enantioen-
and 4k to examine whether or not a kinetic resolution of riched (S)-3a would be provided by the Friedel–Crafts
aminoalkylation of 1a with 2a, and the enantioselectivity
Table 1 Screening of Catalystsa
of (S)-3a would be slightly increased by the subsequent
Friedel–Crafts aminoalkylation of (R)-3a with 1a prior to
(S)-3a.
Cbz
Bn
N
Bn
N
(R)-BINSA (5 mol%)
amine 4 (5 mol%)
NH
Cbz
H
N
+
Ph
MgSO4
CH2Cl2, –78 °C, 30 min
With the optimized reaction conditions in hand, we next
examined the scope of aldimines 1 and pyrroles 2
(Table 2). Unfortunately, unprotected pyrrole 2b, N-Boc-
Ph
1a
2a
(1 equiv)
3a
(1.5 equiv)
Cbz
Ph
N
Ph
N
Bn
N
NH
N
4e
Ph
Cbz
H
N
Et2NH
Et3N
N
Ph
4a
4b
4c
4d
4f
Ph
(S)-3a
1a
(R)-BINSA (5 mol%)
40%, 67% ee
(0.5 equiv)
4k (5 mol%)
Et
n-Bu
n-Bu
n-Bu
N
Ph
N
N
N
Ph
N
Ph
N
+
+
MgSO4
CH2Cl2, –78 °C, 30 min
Cbz
Cbz
Ph
Cbz
Ph
Bn
Bn
HN
4g
4h
4i
4j
4k
4l
NH
NH
N
N
Ph
N
n-C6H13
n-C10H21
N
N
N
N
N
5
rac-3a
(1 equiv)
39% (dl/meso = ca. 1:1)
4m
4n
4o
4p
Scheme 2 Kinetic resolution of product 3a
Entry
1
Amine (mol%)
4a (10)
4b (5)
Yield (%)
84
ee (%)
45
37
62
60
70
71
77
70
77
72
77
89
0
Table 2 Catalytic Enantioselective Friedel–Crafts Aminoalkylation
with a BINSA–4k Salt Prepared in situa
2
22
R1
R2
N
R2
N
(R)-BINSA (5 mol%)
R1
H
NH
3
4c (5)
46
4k (5 mol%)
N
+
Ar
4
4d (5)
30
MgSO4
CH2Cl2, –78 °C, 30 min
Ar
1
2
3
5
4e (5)
58
(1.5 equiv)
(1 equiv)
6
4f (5)
29
Entry 1 Ar, R1
2 R2
3
Yield ee
(%)
75
69
44
84
59
79
82
72
92
85
(%)
7
4g (5)
79
1
2
1b Ph, Boc
2a Bn
2b H
3b
3c
3d
3a
3e
3f
44
6
8
4h (5)
77
1a Ph, Cbz
1a Ph, Cbz
1a Ph, Cbz
9
4i (5)
79
3
2c Boc
2a Bn
22
10
11
12
13
14
15
16
17
18
4j (5)
79
4
89 (98)b
81 (96)b
67 (96)b
84 (89)b
92 (>99)b
70
4k (2.5)
4k (5)
69
5
1c 4-MeOC6H4, Cbz 2a Bn
84
6
1d 4-FC6H4, Cbz
1e 4-ClC6H4, Cbz
1f 4-BrC6H4, Cbz
1g 3-BrC6H4, Cbz
2a Bn
2a Bn
2a Bn
2a Bn
4k (10)
4l (5)
20
7
3g
3h
3i
10
3
8
4m (5)
4n (5)
73
72
79
62
44
9
81
10
1h 1-naphthyl, Cbz 2a Bn
3j
71
4o (2.5)
4p (2.5)
82
a The reaction of 1 (0.30 mmol) with 2 (0.20 mmol) was conducted in
the presence of (R)-BINSA (0.01 mmol), 4k (0.01 mmol), and MgSO4
(40 mg) in CH2Cl2 (2 mL) at –78 °C for 30 min unless otherwise not-
ed.
77
a The reaction of 1a (0.30 mmol) with 2a (0.20 mmol) was conducted
in the presence of (R)-BINSA (0.01 mmol), amine (0.005–0.02
mmol), and MgSO4 (40 mg) in CH2Cl2 (2 mL) at –78 °C for 30 min.
b Enantioselectivity after a single recrystallization.
Synlett 2011, No. 9, 1247–1250 © Thieme Stuttgart · New York

CLUSTER
Enantioselective Friedel–Crafts Aminoalkylation
1249
protected pyrrole 2c, and N-Boc-protected aldimine 1b
gave the corresponding products in low enantioselectivi-
ties (Table 2, entries 1–3). In contrast, with optimal N-
benzylpyrrole (2a), the reaction of aromatic aldimines
with an electron-donating or electron-withdrawing sub-
stituent proceeded smoothly, and the desired products
were obtained with good to high enantioselectivities
(Table 2, entries 4–10). Fortunately, one recrystallization
of the products from n-hexane–Et2O–CH2Cl2 increased
the values of enantioselectivity (89 to >99% ee) without
any serious loss of yield (Table 2, entries 4–8).
To determine the absolute stereochemistry of the prod-
ucts, X-ray analysis of a single crystal of 3h was conduct-
ed, and its S-configuration revealed that the reaction
would proceed via predominant attack on the re-face side
of 1f (Figure 1).
Finally, ESI-MS analysis of the catalyst, which was pre-
pared in situ from (R)-BINSA (1 equiv) and 4k (1 equiv)
in MeCN, was performed. Interestingly, monomeric am-
monium salts of BINSA [i.e., Ar*(SO3H)2], such as
[Ar*(SO3H)(SO3Na) + 4k]+ at m/z = 537,9 [Ar*(SO3H)2 +
2(4k) + H]+ at m/z = 617, and [Ar*(SO3H)2+3(4k) + H]+
at m/z = 718, were observed, and these species strongly
support the assumed dynamic acid–base structures as il-
lustrated in Scheme 1.10 Although a further investigation
of the actual catalysts is required to fully understand the
reaction mechanism, the postulated structures of the cata-
lyst and the substrate were considered based on theoretical
Figure 2 M05-2X/6-31G* optimized geometry of (R)-BINSA–4k–
1a and a proposed transition state; hydrogen atoms are partially omit-
ted for clarity.
calculations for
a
monomeric (R)-BINSA–4k–1a
complex11 as a working model.10 As shown in Figure 2,
4k is protonated by a bridged proton between the two
SO3 moieties and oriented outward. Moreover, 1a is pro-
In summary, we have developed a catalytic enantioselec-
tive Friedel–Crafts aminoalkylation between aromatic al-
dimines and N-benzylpyrrole with the use of (R)-BINSA–
N,N-dimethylbutylamine as a dynamic Brønsted acid–
Brønsted base combined salt catalyst. Unlike convention-
al catalysts, remarkably high reactivity was achieved even
at –78 °C within 30 minutes, and the corresponding ar-
yl(1H-pyrrol-2-yl)methanamines were obtained in high
yields with good to high enantioselectivities. Further ap-
plications of chiral ammonium salts of BINSA to other
catalytic enantioselective reactions are now under way.
–
tonated and thus activated by the other proton of the dis-
ulfonic acid. In this calculated complex, an attractive p–p
interaction is observed between the electronically positive
protonated 1a and the electronically negative naphthyl–
–
SO3 moiety. Therefore, in the possible transition state, 2a
would predominantly attack the re-face side of aldimines.
In this preliminary stage, however, we cannot perfectly
explain why 4k, unlike other N,N-dimethylalkylamines
4g–j,m,n or N-methyl cyclic amines 4e,f, was critical for
inducing high enantioselectivity.
Figure 1 X-ray crystal structure analysis of the Friedel–Crafts aminoalkylation product 3h
Synlett 2011, No. 9, 1247–1250 © Thieme Stuttgart · New York

1250
M. Hatano et al.
CLUSTER
General Procedure for Enantioselective Friedel–Crafts Ami-
noalkylation
(4) (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 11804. (b) Wang, Y.-Q.; Song, J.; Hong, R.;
Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156.
(c) Kang, Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc.
2007, 129, 1484. (d) Rowland, G. B.; Rowland, E. B.;
Liang, Y.; Perman, J. A.; Antilla, J. C. Org. Lett. 2007, 9,
2609. (e) Terada, M.; Yokoyama, S.; Sorimachi, K.;
Uraguchi, D. Adv. Synth. Catal. 2007, 349, 1863. (f) Li, G.;
Rowland, G. B.; Rowland, E. B.; Antilla, J. C. Org. Lett.
2007, 9, 4065. (g) Kang, Q.; Zheng, X.-J.; You, S.-L. Chem.
Eur. J. 2008, 14, 3539. (h) Zhang, G.-W.; Wang, L.; Nie, J.;
Ma, J. A. Adv. Synth. Catal. 2008, 350, 1457. (i) Kang, Q.;
Zhao, Z.-A.; You, S.-L. Tetrahedron 2009, 65, 1603.
(j) Nakamura, S.; Sakurai, Y.; Nakashima, H.; Shibata, N.;
Toru, T. Synlett 2009, 1639. (k) Qian, Y.; Ma, G.; Lv, A.;
Zhu, H.-L.; Zhao, J.; Rawal, V. H. Chem. Commun. 2010,
46, 3004. (l) Enders, D.; Seppelt, M.; Beck, T. Adv. Synth.
Catal. 2010, 352, 1413.
A well-dried pyrex Schlenk tube was charged with (R)-BINSA (4.1
mg, 0.01 mmol) and N,N-dimethylbutylamine (4k, 1.4 mL, 0.01
mmol) under a nitrogen atmosphere. MeCN (2 mL) was added, and
the solution was stirred at r.t. for 30 min. The volatile solvent was
removed in vacuo at r.t. for 1 h, and then MgSO4 (40 mg, 0.33
mmol), CH2Cl2 (1.5 mL), and n-benzylpyrrole (2a, 30.8 mL 0.20
mmol) were added. The mixture was cooled to –78 °C and stirred
for 30 min. Aldimine 1 (0.30 mmol) in CH2Cl2 (0.5 mL) was added
via a cannula. The resultant mixture was then stirred at –78 °C for
30 min. A sat. NaHCO3 aq solution (1 mL) was poured into the re-
action mixture, and the product was extracted with EtOAc (2 × 15
mL). The combined extracts were washed with brine (10 mL) and
dried over MgSO4. The organic phase was concentrated under re-
duced pressure, and the crude product was purified by silica gel col-
umn chromatography (eluent: n-hexane–EtOAc = 3:1 to 1:1) to
give the desired products 3. The enantiomeric purity was deter-
mined by chiral HPLC analysis.
(5) Asymmetric catalysis by BINSA and its derivatives:
(a) Kampen, D.; Ladépêche, A.; Claßen, G.; List, B. Adv.
Synth. Catal. 2008, 350, 962. (b) Pan, S. C.; List, B. Chem.
Asian J. 2008, 3, 430. (c) Hatano, M.; Maki, T.; Moriyama,
K.; Arinobe, M.; Ishihara, K. J. Am. Chem. Soc. 2008, 130,
16858. (d) Hatano, M.; Hattori, Y.; Furuya, Y.; Ishihara, K.
Org. Lett. 2009, 11, 2321. (e) García-García, P.; Lay, F.;
García-García, P.; Rabalakos, C.; List, B. Angew. Chem. Int.
Ed. 2009, 48, 4363. (f) LaLonde, R. L.; Wang, Z. J.; Mba,
M.; Lackner, A. D.; Toste, F. D. Angew. Chem. Int. Ed.
2010, 49, 598. (g) Ban, S.; Du, D.-M.; Liu, H.; Yang, W.
Eur. J. Org. Chem. 2010, 5160. (h) Zhang, Y.; Lay, F.;
García-García, P.; List, B.; Chen, E. Y.-X. Chem. Eur. J.
2010, 16, 10462. (i) Ratjen, L.; García-García, P.; Lay, F.;
Beck, M. E.; List, B. Angew. Chem. Int. Ed. 2011, 50, 754.
(6) Synthesis of BINSA derivatives: (a) Treskow, M.;
Neudörfl, J.; Giernoth, R. Eur. J. Org. Chem. 2009, 3693.
(b) Hatano, M.; Sugiura, Y.; Ishihara, K. Tetrahedron:
Asymmetry 2010, 21, 1311. (c) He, H.; Chen, L.-Y.; Wong,
W.-Y.; Chan, W.-H.; Lee, A. W. M. Eur. J. Org. Chem.
2010, 4181. (d) Barbero, M.; Bazzi, S.; Cadamuro, S.;
Dughera, S.; Magistris, C.; Venturello, P. Synlett 2010,
1803. (e) Berkessel, A.; Christ, P.; Leconte, N.; Neudörfl,
J.-M.; Schäfer, M. Eur. J. Org. Chem. 2010, 5165.
(7) For reviews in acid–base chemistry: (a) Kanai, M.; Kato,
N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491.
(b) Ishihara, K.; Sakakura, A.; Hatano, M. Synlett 2007,
686. (c) Ishihara, K. Proc. Jpn. Acad., Ser. B 2009, 85, 290.
(8) With regard to other solvents, THF and propionitrile showed
low enantioselectivities, and the catalysts showed poor
solubility in Et2O, n-hexane, and toluene.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial support for this project was provided by JSPS. KAKENHI
(20245022), MEXT. KAKENHI (21750094, 21200033), and the
Global COE Program of MEXT. Calculations were performed at
the Research Faculties, National Institutes of Natural Science
(NINS).
References and Notes
(1) For reviews on catalytic enantioselective Friedel–Crafts
aminoalkyation: (a) Bandini, M.; Melloni, A.; Umani-
Ronchi, A. Angew. Chem. Int. Ed. 2004, 43, 550.
(b) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108,
2903. (c) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev.
2009, 38, 2190. (d) Terrasson, V.; de Figueiredo, R. M.;
Campagne, J. M. Eur. J. Org. Chem. 2010, 2635.
(2) (a) Gusman, A.; Yuste, F.; Toscano, R. A.; Young, J. M.
J. Med. Chem. 1986, 29, 589. (b) Kleemann, A.; Engel, J.;
Kutscher, B.; Reichert, D. Pharmaceutical Substances, 4th
ed.; Thieme: New York, 2001. (c) Katritzky, A. R.; Jain, R.;
Xu, Y.-J.; Stee, P. J. J. Org. Chem. 2002, 67, 8220.
(d) Roman, G. Mini-Rev. Org. Chem. 2006, 3, 167.
(3) (a) Johannsen, M. Chem. Commun. 1999, 2233. (b) Saaby,
S.; Fang, X.; Gathergood, N.; Jørgensen, K. A. Angew.
Chem. Int. Ed. 2000, 39, 4114. (c) Saaby, S.; Bayón, P.;
Aburel, P. S.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
4352. (d) Jia, Y.-X.; Xie, J.-H.; Duan, H.-F.; Wang, L.-X.;
Zhou, Q.-L. Org. Lett. 2006, 8, 1621. (e) Niu, L.-F.; Xin,
Y.-C.; Wang, R.-L.; Jiang, F.; Xu, P.-F.; Hui, X.-P. Synlett
2010, 765.
(9) Naturally abundant Na+ might be included during the
analysis.
(10) See the Supporting Information for details.
(11) The optimum ratio of 4k to (R)-BINSA (1:1), which was
examined in entries 11–13 in Table 1, suggests that a
monomeric (R)-BINSA–4k–1a complex is one of the most
likely structures.
Synlett 2011, No. 9, 1247–1250 © Thieme Stuttgart · New York