Asymmetric, catalytic phenyl transfer to imines: Highly enantioselective synthesis of diarylmethylamines

Article abstract of DOI:10.1002/1521-3773(20021004)41:19<3692::AID-ANIE3692>3.0.CO;2-N

Both planar and central chirality are not necessary in [2.2]paracyclophane-based N,O-ligands to achieve high enantioselectivity: diarylmethylamines are obtained in excellent yields and enantioselectivities up to 97% ee in the enantioselective transfer of a phenyl group from organozinc reagents to imines in the presence of catalytic amounts of ketimine L* (see scheme).

Full text of DOI:10.1002/1521-3773(20021004)41:19<3692::AID-ANIE3692>3.0.CO;2-N

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enantioselective addition of phenylzinc to imines and gives
rise to optically active diarylmethylamines in very high
enantiomeric excesses.
At the outset of our study we examined the use of different
N,O-ligands (Scheme 1) in the phenylation of N-[p-tolylmeth-
yl-(toluene-4-sulfonyl)]formamide (7a, Table 1).This class of
N-acylimine precursors is readily available in a one-pot
Asymmetric, Catalytic Phenyl Transfer to
Imines: Highly Enantioselective Synthesis of
Diarylmethylamines**
Nina Hermanns, Stefan Dahmen, Carsten Bolm, and
Stefan Br‰se*
Enantiomerically pure diarylmethylamines are important
intermediates in the synthesis of biologically active com-
pounds.[1] Cetirizine hydrochloride (1) stands out from several
drug candidates as a commercially important nonsedating
antihistamine agent.Binding studies indicate that the
R
enantiomer displays better
a
OH
pharmacological profile than the
racemate.[2] Despite the impor-
tance of enantiopure diarylme-
thylamines, synthetic accesses
and especially asymmetric (cata-
lytic) processes for their synthesis
are rather limited.[3] While there
are several synthetic routes to, for
example, enantiopure cetirizine
O
N
N
O
• 2 HCl
Cl
1
that utilize resolution techniques,[4] stoichiometric amounts
of chromium complexes,[5] or diastereoselective approaches
with chiral auxiliaries,[6] to the best of our knowledge there is
only a single report on an asymmetric catalytic addition of an
organometallic arylation agent to an imine derivative.Hay-
ashi and Ishigedani described a highly enantioselective
rhodium-catalyzed process for the arylation of N-sulfonyl-
imines with aryl stannanes (up to 96% ee).[7]
For quite some time we have been engaged in the
asymmetric transfer of a phenyl group from organozinc
reagents and have developed a protocol for the highly
enantioselective transfer of a phenyl group to aldehydes
using ferrocene (Rp,S)-2 and cyrhetrene (Rp,S)-3.[8] However,
a major difficulty in the development of asymmetric processes
for the transfer of a phenyl group remains the much higher
reactivity of diphenylzinc relative to dialkylzinc and the
concomitant rapid uncatalyzed background reaction.
Scheme 1.N,O-Ligands employed in the asymmetric transfer of a phenyl
group to imines.
synthesis from benzaldehyde, amide, and p-tolylsulfinic
acid.[11] The addition to the imine then proceeds by deproto-
nation of amide 7a, followed by elimination of the sulfinate to
form N-formylimine 8a.Addition of the zinc reagent gives
rise to the N-formylamine 9a.We started out by employing
the reaction conditions developed for the enantioselective
transfer of a phenyl group to aldehydes using a mixed zinc
reagent formed in situ from diphenylzinc and diethylzinc.This
reagent selectively transfers only the phenyl moiety to the
substrate to afford N-formylamine 9a in very high yield
without formation of the corresponding ethylation product.[12]
The ligand screening (Table 1) showed that ferrocene
(Rp,S)-2 and cyrhetrene 3, which represent the best ligands
for the enantioselective transfer of a phenyl group to
aldehydes (up to 99% ee) so far, gave only moderate
enantioselectivities in the addition to imine 8a (entries 1
and 3).The catalysis with diastereomeric ferrocene ( Sp,S)-2
did not lead to any improvement (entry 2).In contrast, the use
of [2.2]paracyclophane-based ketimines 4 6[13] gave rise to N-
formyldiarylmethylamines in good to excellent enantioselec-
tivities (up to 97% ee, entry 11).Ketimine ( Rp,S)-6 showed
the best results in the ligand screening and was chosen for
further optimization studies.Interestingly, ( Sp)-5 bearing only
the element of planar chirality, also gave rise to the product
amine in very high enantioselectivity (entry 6).Within our
ongoing study of [2.2]paracyclophane-based N,O-ligands, this
Recently, we developed a catalytic procedure for the
enantioselective addition of diethylzinc to masked N-formyl-
imines by employing catalytic amounts of [2.2]paracyclo-
phane-based ketimines.[9,10] We now report on the combina-
tion of both methods, which leads to the first highly
[*] Prof.Dr.S.Br‰se
Kekulÿ-Institut f¸r Organische Chemie und Biochemie der Rheini-
schen Friedrich-Wilhelms-Universit‰t Bonn
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
Fax : (þ 49)228-739608
E-mail: braese@uni-bonn.de
Dipl.-Chem.N.Hermanns, Dipl.-Chem.S.Dahmen, Prof.Dr.C.Bolm
Institut f¸r Organische Chemie der Rheinisch-Westf‰lischen Techni-
schen Hochschule Aachen
Professor-Pirlet-Strasse 1, 52074 Aachen (Germany)
[**] We are grateful to the Fonds der Chemischen Industrie and to the
Deutsche Forschungsgemeinschaft (DFG) within the SFB 380 ™Asym-
metric Synthesis by Chemical and Biological Methods∫ for financial
support.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
3692
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0044-8249/02/4119-3692 $ 20.00+.50/0
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[a]
Table 1.Ligand screening for the transfer of a phenyl group to imines.
observation can be explained by a faster and,
therefore, more competitive uncatalyzed back-
ground reaction of diphenylzinc occurring relative
to when the modified reagent formed from diphen-
ylzinc and diethylzinc was used.
O
O
O
ZnEt2,
ZnPh2
cat. 2-6
HN
H
ZnEt2
ZnPh2
HN
H
N
H
SO2Tol
H
The reaction temperature had a significant
impact on the stereochemical outcome of the
process as well.With 7a as the substrate, the
highest ee value of 97% was obtained at À208C.At
À408C not only did the ee value drop significantly,
but the yield was also diminished (entry 14).
9a
Entry Ligand (10 mol%) T [8C] ZnPh2/ZnEt2 [equiv] Yield [%][b] ee [%][c]
7a
8a
1
2
3
4
5
6
7
8
(Rp,S)-2
(Sp,S)-2
(Rp,S)-3[d]
(Rp,S)-4
(Sp,S)-4
(Sp)-5
(Sp,S)-6
(Rp,S)-6
(Rp,S)-6
(Rp,S)-6
(Rp,S)-6
(Rp,S)-6
(Rp,S)-6
(Rp,S)-6
0
0
2/2
2/2
2/2
2/2
2/2
2/2
2/2
2/2
98
99
98
99
97
94
98
99
99
96
98
85
99
51
54 (À)
48 (À)
41 (À)
89 (þ)
72 (À)
91 (À)
71 (À)
93 (þ)
95 (þ)
92 (þ)
97 (þ)
87 (þ)
92 (þ)
67 (þ)
À20
A wider range of substrates was applied in the
title reaction to demonstrate the broad applicabil-
ity of the method (Table 2).The results reveal that
aromatic imine precursors with different electronic
properties as well as different substitution patterns
are equally well tolerated.The substrates can be
electron rich or electron poor, and even sterically
hindered imines with a double ortho substitution
gave excellent results (95% ee, entry 8).Only a
meta-substituted starting material gave a product
with a slightly lower ee value (89% ee, entry 7).
Interestingly, the same effect was observed in the
addition of diethylzinc to imines using (Rp,S)-4 and
(Rp,S)-6.[9] A decrease in the catalyst loading
resulted in the formation of products with slightly
0
0
0
0
0
À10
À10
À20
À20
À20
À40
9
2/2
10
11
12
13
14
1.2/1.2
1.5/1.5
1.2/1.2
2.5/
2/2
[a] Reactions were carried out in toluene for 12 h with 0.25 mmol of imine precursor 7a.
[b] Determined by 1H NMR spectroscopy.[c] Determined by HPLC on a chiral
stationary phase (see Supporting Information).[d] 9 mol% of ( Rp,S)-3 was used.
is the first example of a ligand in which the combination of
both planar and central chirality is not required to achieve
high enantioselectivity.
Toluene proved to be the solvent of choice; in hexane only
moderate yields were obtained.The amount and ratio of zinc
reagents was varied and found to be optimal with respect to
yield and enantioselecitity when 1.5 equivalents of both
ZnPh2 and ZnEt2 were used (entries 9 12).If diphenylzinc
was used alone, the ee value was slightly lower relative to that
obtained with the mixed reagent (entries 11 and 13).This
or significantly lower enantiomeric excesses depending on the
substrate (entries 2, 4, and 5).
The deprotection of N-formylamines 9 to the free amines
can easily be achieved by acidic methanolysis (Scheme 2).The
deprotection of N-formylamine 9b proceeds quantitatively
and without racemization.The absolute configuration of 9b
was assigned to be R by comparison of the specific optical
rotation of free amine (À)-10b with the literature value.[14,15]
This configuration is consistent with the asymmetric induction
observed in the addition of diethylzinc to imines in the
presence of (Rp,S)-4 and (Rp,S)-6.[9] The ee value of C-(4-
chloro-phenyl)-C-phenylmethylamine 10b was determined by
HPLC analysis of N-[(4-chlorophenyl)phenylmethyl]acet-
amide (11b) obtained by treatment of 10b with acetic
anhydride and triethylamine.[16]
[a]
Table 2.Substrate spectrum for the transfer of a phenyl group to imines.
ZnEt2
O
O
O
ZnPh2
ZnEt2
ZnPh2
cat. (Rp,S)-6
HN
H
HN
H
N
H
In summary, we have presented the first catalytic and highly
enantioselective process for the asymmetric addition of a
phenylzinc reagent to imines that gives rise to diarylmethyl-
R
R
SO2Tol
R
H
7a-g
Entry R
9a-g
Product (Rp,S)-6 [mol%] Yield [%][b] ee [%][c]
8a-g
O
1
2
3
4
5
6
7
8
9
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
3-MeC6H4
2,6-Cl2C6H4
4-tBuC6H4
9a
9a
9b
9b
9b
9c
9d
9e
9 f
10
5
10
5
99 (85)
99
99 (82)
99
98
99 (75)
98
99 (89)
98 (81)
99 (80)
97 (þ)
NH2
10b
NH
NH
H
94 (þ)
HCl, MeOH,
50 °C, 4 h
94 (þ)-(R)
81 (þ)-(R)
69 (þ)-(R)
97 (þ)
>99%
Cl
Cl
1
9b (94% ee)
10
10
10
10
10
89 (þ)
95 (þ)
O
96 (þ)
Ac2O, NEt3
toluene, RT
10
4-COOMeC6H4 9g
95 (À)
[a] Reactions were carried out in toluene at À208C for 12 h, 1.5 equiv
ZnPh2, 1.5 equiv ZnEt2, with 0.25 mmol of imine precursor 7a g.[b] De-
termined by 1H NMR spectroscopy.Yields in parenthesis refer to yields
after column chromatography.[c] Determined by HPLC on a chiral
stationary phase (see Supporting Information).
96%
Cl
11b (94% ee)
Scheme 2.Deprotection of N-formylamine 9b.
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3693

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amines in excellent yields and enantioselectivities.Further
optimizations and applications of this methodology as well as
a detailed mechanistic study are in progress.
[(PPh3)Ag(HCB11Me11)]: A Complex with
Intermolecular Ag¥¥¥H3C Interactions**
Michael J.Ingleson, Mary F.Mahon,
Nathan J.Patmore, Giuseppe D.Ruggiero, and
Andrew S.Weller*
Dedicated to Professor Thomas P. Fehlner
on the occasion of his 65th birthday
Received: June 4, 2002 [Z19442]
[1] For examples, see a) M.J.Bishop, R.W.McNutt, Bioorg. Med. Chem.
Lett. 1995, 5, 1311; b) C.M.Spencer, D.Foulds, D.H.Peters,
Drugs
1993, 46, 1055; c) S.Sakurai, N.Ogawa, T.Suzuki, K.Kato, T.Ohashi,
S.Yasuda, H.Kato, Y.Ito, Chem. Pharm. Bull. 1996, 44, 765.
[2] M.Gillard, C.van der Perren, N.Moguilevsky, R.Massingham, P.
Chatelain, Mol. Pharmacol. 2002, 61, 391.
The ™least-coordinating∫ peralkylated monoanionic carbor-
anes based around [1-closo-CB11R12]À (R ¼ alkyl)[1,2] are of
significant technological interest.They can form stable,
lipophilic, free radicals that are also strong oxidants,[3] novel
electrolytes,[2] act as partners with lithium ions as catalysts for
pericyclic rearrangements,[4] or can be used to isolate reactive
cations such as [nBu3Sn]þ[5] or Meþ.[6] They constitute some of
weakest nucleophiles within the family of icosahedral mono-
carborane anions,[7] and also have the attractive properties of
being relatively chemically robust[8] and available in gram
quantities.Given that much of the interest in least-coordinat-
ing anions, such as the perfluorinated tetraaryl borates, is
based around the generation of cationic Lewis acidic metal
centers that show enhanced catalytic properties,[9] analogous
complexes partnered with peralkylated carborane anions are
of significant interest.The fact that peralkylated anions such
as 1 can be considered as being negatively charged ™alkane
¼
[3] For reviews on auxiliary controlled additions to C N, see a) D.
Enders, U.Reinhold, Tetrahedron: Asymmetry 1997, 8, 1895; b) R.
Bloch, Chem. Rev. 1998, 98, 1407; c) G.Alvaro, D.Savoia, Synlett
2002, 651; for reviews on corresponding catalytic processes, see d) S.
Kobayashi, H.Ishitani, Chem. Rev. 1999, 99, 1069; e) S.E.Denmark,
O.J-.C.Nicaise in Comprehensive Asymmetric Catalysis (Eds.: E. N.
Jacobsen, A.Pfaltz, H.Yamamoto), Springer, Berlin, 1999, p.924.
[4] a) C.J.Opalka, T.E. D©Ambra, J.J.Faccone, G.Bodson, E. Cosse-
ment, Synthesis 1995, 766; b) E.Cossement, G.Motte, G.Bodson, J.
Gobert, UK Patent Appl.2225321 1990 [Chem. Abstr. 1990, 113,
191396]; c) for a large-scale preparative HPLC (on a chiral stationary
phase) approach, see D.A. Pflum, H.S. Wilkinson, G.J. Tanoury,
DW. .Kessler, HB. .Kraus, CH. .Senanayake, SA. .Wald,
Process Res. Dev. 2001, 5, 110.
Org.
[5] E.J.Corey, C.J.Helal, Tetrahedron Lett. 1996, 37, 4837.
[6] a) DA. .Pflum, D.Krishnamurthy, Z.Han, S.A Wald, CH. .
Senanayake, Tetrahedron Lett. 2002, 43, 923; b) N.Plobeck, D.Powell,
Tetrahedron: Asymmetry 2002, 13, 303.
[7] T.Hayashi, M.Ishigedani, J. Am. Chem. Soc. 2000, 122, 976.This
method gives rise to diarylmethylamines in very high enantioselectiv-
ities but requires the use of five equivalents of the stannane to obtain
the products in high yields.
[8] a) C.Bolm, N.Hermanns, J.P.Hildebrand, K.MuÊiz,
2000, 112, 3607; Angew. Chem. Int. Ed. 2000, 39, 3465; b) C.Bolm, M.
Kesselgruber, N.Hermanns, JP..Hildebrand, G.Raabe, Angew.
Angew. Chem.
Chem. 2001, 113, 1536; Angew. Chem. Int. Ed. 2001, 40, 1488; c) C.
Bolm, N.Hermanns, M.Kesselgruber, J.P.Hildebrand, J. Organomet.
Chem. 2001, 624, 157; d) C.Bolm, M.Kesselgruber, A.Grenz, N.
Hermanns, J.P.Hildebrand, New J. Chem. 2001, 25, 13; e) for a recent
review on catalyzed asymmetric arylations, see C.Bolm, JP..
Hildebrand, K.MuÊiz, N.Hermanns, Angew. Chem. 2001, 113, 3382;
Angew. Chem. Int. Ed. 2001, 40, 3284.
[9] S.Dahmen, S.Br‰se, J. Am. Chem. Soc. 2002, 124, 5940.
[10] For other recent examples for the enantioselective addition of
balls∫ is of particular relevance as there is considerable
interest in the isolation and structure of metal alkane
complexes.[10] The structures of simple alkali-metal salts of
[1-closo-CB11Me12]À have been reported,[11] while the main-
group-metal complex [nBu3Sn][1-closo-CB11Me12] is a closely
associated ion-pair in the solid state, a structure that is thought
to be retained in solution.[5] However, no analogous tran-
sition-metal complexes have been described.We have a
current interest in the chemistry of metal ligand complexes
partnered with monoanionic carborane anions[12] and report
here the first example of a d-block-metal complex containing
diethylzinc to imines, see a) H.Fujihara, K.Nagai, K.Tomioka,
J.
Am. Chem. Soc. 2000, 122, 12055; b) J.R.Porter, J.F.Traverse, A.H.
Hoveyda, M.L.Snapper, J. Am. Chem. Soc. 2001, 123, 984; c) J.R.
Porter, J.F.Traverse, A.H.Hoveyda, M.L.Snapper,
Soc. 2001, 123, 10409.
J. Am. Chem.
[11] J.Sisko, M.Mellinger, P.W.Sheldrake, N.H.Baine,
1996, 37, 8113.
Tetrahedron Lett.
[12] For reports on mixed alkyl- and alkenylzinc species, see a) H.Nehl,
W.R. Scheidt, J. Organomet. Chem. 1985, 289, 1; b) W.Oppolzer,
R.N.Radinov, Helv. Chim. Acta 1992, 75, 170; c) S.Berger, F.Langer,
C.Lutz, P.Knochel, T.A.Mobley, C.K.Reddy,
Angew. Chem. 1997,
109, 1603; Angew. Chem. Int. Ed. 1997, 36, 1454; d) C.Lutz, P.
Knochel, J. Org. Chem. 1997, 62, 7895.
[*] Dr.A.S.Weller, M.J.Ingleson, Dr.M.F.Mahon, N.J.Patmore,
Dr.G.D.Ruggiero
[13] The [2.2]paracyclophane-based N,O-ligands have previously been
employed in the dialkylzinc and the alkenylzinc addition to aldehydes:
a) S.Dahmen, S.Br‰se, Chem. Commun. 2002, 26; b) S.Dahmen, S.
Br‰se, Org. Lett. 2001, 3, 4119; c) for the synthesis of compounds 4 and
6, see V.Rozenberg, T.Danilova, E.Sergeeva, E.Vorontsov, Z.
Starikova, K.Lysenko, Y.Belokon, Eur. J. Org. Chem. 2000, 3295.
[14] For (S)-10b: [a]2D0 ¼ þ 10.8 (c ¼ 2.18, ethanol), see G. R. Clemo, C.
Gardner, R.Raper, J. Chem. Soc. 1939, 1958.
Department of Chemistry
University of Bath
Bath, BA2 7AY (UK)
Fax : (þ 44)1225-386-231
E-mail: a.s.weller@bath.ac.uk
[**] This work was supported by the Royal Society (A.S.W.), the EPSRC
(GR/R36824), and the University of Bath.Dr.M.A.Fox (University
of Durham) is thanked for his help and useful discussions.
[15] The absolute configurations of all other products should be R as well if
an analogous stereochemical reaction pathway is assumed.
[16] Attempts to determine the enantiomeric excess of amine 10b itself by
means of HPLC on a chiral stationary phase were unsuccessful.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
3694
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4119-3694 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 19