Identification of a highly effective asymmetric phase-transfer catalyst derived from α-methylnaphthylamine

Article abstract of DOI:10.1016/S0040-4039(03)01352-2

A library of quaternary ammonium salts has been generated via reaction of simple chiral amines with a series of conformationally dynamic biphenyl units. Screening of this library against the alkylation of a glycine imine has led to the identification of a highly effective asymmetric phase-transfer catalyst derived from α-methylnaphthylamine.

Full text of DOI:10.1016/S0040-4039(03)01352-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5629–5632
Identification of a highly effective asymmetric phase-transfer
catalyst derived from a-methylnaphthylamine
Barry Lygo,a,* Bryan Allbutta and S. Russell Jamesb
aSchool of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
bAstraZeneca, Process R&D, Silk Road Business Park, Charter Way, Macclesfield, Cheshire SK10 2NA, UK
Received 9 May 2003; accepted 30 May 2003
Abstract—A library of quaternary ammonium salts has been generated via reaction of simple chiral amines with a series of
conformationally dynamic biphenyl units. Screening of this library against the alkylation of a glycine imine has led to the
identification of a highly effective asymmetric phase-transfer catalyst derived from a-methylnaphthylamine.
© 2003 Elsevier Ltd. All rights reserved.
Induced atropisomerism is increasingly being recog-
nised as a useful strategy for amplifying the effect of
simple chiral elements in asymmetric catalysis. In par-
ticular, the replacement of atropisomerically stable
binaphthyl components with their conformationally
dynamic biphenyl analogues has received significant
attention in recent years.1 Biphenyls offer the advantage
that they are generally less expensive to prepare (no
resolution required) and allow for a wider variety of
substitution around the initial aryl ring. In addition,
their conformationally dynamic nature means there are
no matched/mismatched issues when they are incorpo-
rated into structures containing other chiral elements.
pounds of this type would be straightforward to pre-
pare from inexpensive commercially-available
materials, and that variation of the substituents X, Y
and R% would allow for large libraries of structures to
be generated. In this paper we describe preliminary
results of a study in which we examined if it would be
possible to generate effective asymmetric phase-transfer
catalysts 2 via combination of biphenyls 1 with simple
commercially-available chiral secondary amines.
The biphenyl core utilised in this study was conve-
niently prepared as outlined in Scheme 1. Thus o-brom-
ination of commercially-available phenol 3,3 followed
by oxidative coupling4 and O-methylation gave the key
dibromide 4 in good overall yield.
We have recently developed a simple automated
approach for the generation and screening of quater-
nary ammonium salt libraries, and demonstrated that
this can be applied to the optimisation of cinchona
Recently it has been shown that a binaphthyl-derived
C2-symmetric quaternary ammonium salt incorporating
a conformationally flexible biphenyl group can act as a
highly effective catalyst for the asymmetric alkylation
of glycine imines.2 Within this context we have become
interested in the potential utility of biphenyls of type 1
(X=C or O, Y=C or O). We envisaged that com-
Scheme 1. Reagents and conditions: (i) NBS, CCl4, rt (60%);
(ii) CuCl, TMEDA, MeOH, rt (88%); (iii) K2CO3, MeI,
DMF, rt (98%).
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01352-2

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B. Lygo et al. / Tetrahedron Letters 44 (2003) 5629–5632
Scheme 3.
The enantioselectivities observed ranged from −30 to
91% e.e.7 (Fig. 1), with the majority of salts tested
favouring formation of the (R)-isomer of 8. From these
results a number of general observations can be made.
Firstly, this study did indeed result in the identification
of catalysts that were capable of high levels of asym-
metric induction. Moreover, it appears that C2-symmet-
rical systems are not necessarily required. Indeed in this
study the most effective catalysts found were those
derived from the simplest chiral amines; (R)-a-methyl-
benzylamine and (R)-a-methylnaphthylamine. Sec-
ondly, it appears that both the chiral amine and the
conformationally flexible biphenyl unit play important
roles in determining the overall selectivity of the alkyla-
tion process. All the salts derived from biphenyl 6 gave
low levels of induction (−2 to 6% e.e.), suggesting that,
at least for the amines investigated here, further substi-
tution in the biphenyl unit is essential. It also appears
that the substituent R% has a significant influence on the
stereoselectivity.8 For example, the salt generated from
(R)-N-methyl-a-methyl naphthylamine and biphenyl 5a
(R%=Br) gave similar but opposite levels of enantio-
selectivity compared with the salt generated from the
same amine and biphenyl 5b (R%=Ph).
Scheme 2. Reagents and conditions: (i) R%-B(OH)2, Pd(PPh3)4,
K2CO3, THF, 70°C; (ii) NBS, hw, AIBN, CCl4.
alkaloid derived catalysts.5 Applying a similar approach
here we next generated a library of quaternary ammo-
nium salts 2 from compound 4 via (where appropriate)
Suzuki coupling followed by radical bromination6 and
salt formation (Scheme 2). For comparison a series of
quaternary ammonium salts derived from the unsubsti-
tuted bis-bromomethylbiphenyl unit
prepared.
6 were also
The most effective catalyst identified in this study was
9, and in order to further probe its potential as an
asymmetric phase-transfer catalyst we briefly examined
the effect of catalyst loading, base and reaction temper-
ature (Table 1).
In total 40 quaternary ammonium salts were generated
in this study and these were then tested on the alkyla-
tion of glycine imine 7 (Scheme 3).
Figure 1. Screening of biphenyl PTC’s in the alkylation of imine 5 (Scheme 3)

B. Lygo et al. / Tetrahedron Letters 44 (2003) 5629–5632
5631
Table 1.
In conclusion, we have demonstrated that a conforma-
tionally flexible biphenyl unit of type 1 can be utilised
as a key component in the construction of asymmetric
phase-transfer catalysts. This has led to the identifica-
tion of a new quaternary ammonium salt 9 which gives
high levels of enantioselectivity in the alkylation of
glycine imine 7. Further studies into the utility of
catalysts of this type are underway and will be reported
in due course.
Acknowledgements
We thank the EPSRC for funding and AstraZeneca for
a studentship (to B.A.) and Dr. D. Levin for helpful
discussions.
Mol% (9)
Base
Temp. (°C)
% E.e.7
References
1.0
1.0
1.0
1.0
1.0
1.0
3.0
5.0
9 M aq. KOH
9 M aq. KOH
9 M aq. KOH
12.5 M aq. KOH
12.5 M aq. NaOH
15 M aq. KOH
9 M aq. KOH
9 M aq. KOH
30
20
10
20
20
0
91
94
94
94
94
97
96
97
1. For recent reviews that cover aspects of this topic, see:
Mikami, K.; Aikawa, K.; Yusa, Y.; Jodry, J. J.;
Yamanaka, M. Synlett 2002, 1561–1578; Alexakis, A.;
Benhaim, C. Eur. J. Org. Chem. 2002, 3221–3236.
2. Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K. Angew.
Chem., Int. Ed. 2002, 41, 1551–1554.
20
20
3. Carreno, M. C. Synlett 1997, 1241–1242.
4. Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto,
S.-I.; Noji, M.; Koga, K. J. Org. Chem. 1999, 64, 2264–
2271.
5. Lygo, B.; Andrews, B. I.; Crosby, J.; Peterson, J. A.
Tetrahedron Lett. 2002, 43, 8015–8018.
6. Carter, S. D.; Wallace, T. W. Synthesis 1983, 1000–1002.
7. Enantiomeric excess was determined by HPLC (Chiralcel
OD-R, 60% acetonitrile/40% water, 0.5 ml/min) using
racemic 8 (generated using n-Bu4NBr as the PTC) as a
control. Retention times observed were 45.0 min (R)-iso-
mer and 49.2 min (S)-isomer.
From these results it would appear that high levels of
enantioselectivity can be obtained using 1 mol% cata-
lyst, in conjunction with 9–15 M aq. KOH. These
conditions are similar to those that we have previously
found to be effective with cinchona alkaloid-derived
phase-transfer catalysts9 and are also similar to those
commonly used with binaphthyl-derived quaternary
ammonium salts.2,10
In order to test the utility of catalyst 9 further, the
alkylation of imine 7 with a series of electrophiles was
also examined (Table 2). High enantioselectivities were
obtained and in all cases the reactions favoured the
(R)-isomer.12,13 The levels of selectivity observed are
uniformly high and reaction times are short, which
would seem to suggest that catalyst 9 may have con-
siderable utility in the synthesis of a-amino acid
derivatives.11
8. Similar observations have been made with binaphthyl-
derived catalysts.2
9. (a) Lygo, B.; Humphreys, L. D. Tetrahedron Lett. 2002,
43, 6677–6679; (b) Lygo, B.; Crosby, J.; Peterson, J. A.
Tetrahedron 2001, 57, 6447–6453; (c) Lygo, B.; Crosby,
J.; Lowdon, T. R.; Peterson, J. A.; Wainwright, P. G.
Tetrahedron 2001, 57, 2403–2409; (d) Lygo, B.; Crosby,
J.; Lowdon, T. R.; Wainwright, P. G. Tetrahedron 2001,
57, 2391–2402; (e) Lygo, B. Tetrahedron Lett. 1999, 40,
1389–1392; (f) Lygo, B.; Crosby, J.; Peterson, J. A.
Tetrahedron Lett. 1999, 40, 1385–1388; (g) Lygo, B.;
Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595–8598.
10. (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 5139–5157; (b) Ooi, T.; Tayama, E.;
Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 579–582;
(c) Ooi, T.; Uematsu, Y.; Maruoka, K. Adv. Synth. Catal.
2002, 344, 288–291; (d) Ooi, T.; Taniguchi, M.; Kameda,
M.; Maruoka, K. Angew. Chem., Int. Ed. 2002, 41,
4542–4544; (e) Ooi, M.; Takeuchi, M.; Maruoka, K.
Synthesis 2001, 1716–1718; (f) Ooi, T.; Kameda, M.;
Tannai, H.; Maruoka, K. Tetrahdedron Lett. 2000, 41,
8339–8342; (g) Ooi, T.; Kameda, M.; Maruoka, K. J.
Am. Chem. Soc. 1999, 121, 6519–6520.
Table 2.
R-Br
Time (h)
% E.e.12
% Yield
PhCH2Br
1.5
2
1
2
1
97
94
95
93
96
89
89
83
100
77
97
71
CH2CHCH2Br
CH2CMeCH2Br
CH2CBrCH2Br
2-NaphthylCH2Br
CHCCH2Br
1

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B. Lygo et al. / Tetrahedron Letters 44 (2003) 5629–5632
13. Absolute stereochemistry was determined by comparison
with previously prepared materials.9 Preliminary experi-
ments have shown that the (S)-amino acid derivatives can
be prepared with similar levels of enantioselectivity by
using the enantiomer of salt (9).
11. For a comprehensive review of glycine imine chemistry
covering the literature up to 2001, see: O’Donnell, M. J.
Aldrichimica Acta 2001, 34, 3–15.
12. E.e.’s were measured via HPLC using previously reported
methods.9