Facile synthesis of optically pure 1,2-diaryl (and 1-alkyl-2-aryl) ethyl and propylamines

Article abstract of DOI:10.1021/ol027464h

(Figure presented) A concise high-yielding route to synthetically useful 1,2-diaryl (and 1-alkyl-2-aryl) ethyl and propylamines in high enantiomeric purity is described. The key step of this route is the completely stereoselective addition of lithium (R)-ortho-(p-toluenesulfinyl)benzylic carbanions to (S).N.p-toluenesulfinylimines, which takes place in very high or quantitative yields. N-Desulfinyiation and C-desulfinylation of the resulting adducts can be achieved with no loss of optical purity employing conventional methods (TFA and Raney-Ni, respectively).

Full text of DOI:10.1021/ol027464h

ORGANIC
LETTERS
2003
Vol. 5, No. 5
677-680
Facile Synthesis of Optically Pure
1,2-Diaryl (and 1-Alkyl-2-aryl) Ethyl and
Propylamines
Jose´ L. Garc´ıa Ruano,* Jose´ Alema´n, and Jose´ F. Soriano
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid, Cantoblanco,
28049-Madrid, Spain
joseluis.garcia.ruano@uam.es
Received December 13, 2002
ABSTRACT
A concise high-yielding route to synthetically useful 1,2-diaryl (and 1-alkyl-2-aryl) ethyl and propylamines in high enantiomeric purity is described.
The key step of this route is the completely stereoselective addition of lithium (R)-ortho-(p-toluenesulfinyl)benzylic carbanions to (S)-N-p-
toluenesulfinylimines, which takes place in very high or quantitative yields. N-Desulfinylation and C-desulfinylation of the resulting adducts
can be achieved with no loss of optical purity employing conventional methods (TFA and Raney-Ni, respectively).
Enantiomerically pure 2-arylethyl and propylamines are
relevant structural subunits because of their frequent occur-
rence in natural products and their importance as valuable
synthetic intermediates.1 The nucleophilic addition of organo-
metallic reagents to iminic CdN double bonds2 is a syntheti-
cally attractive route to chiral amine derivatives. Moderate
reactivity and stereoselectivity, usually observed when using
imines, can be substantially improved by using enantiopure
N-sulfinylimines.3 The diastereoselectivity of these reactions
is usually high, as has shown by several authors, the most
significant contributions being those from Davis’4 and
Ellman’s groups.5 Despite the success of these approaches,
the benzylation of N-sulfinylimines, which affords 2-aryl-
ethylamines, remains elusive because it usually proceeds with
only moderate stereoselectivity. The first systematic study
of these reactions was performed in 1997 by Moreau,6 who
reported the reaction of BnMgCl with different N-p-tolyl-
sulfinyl aromatic aldimines. These reactions evolved with
60-74% des. Davis and co-workers7 observed better dia-
stereoselectivities (up to 88% de) by using N-t-butanesulfi-
nylimines derived from glyoxylic esters.8 Some of the results
recently reported by Davis’ group could suggest that the use
(4) (a) Davis, F. A.; Zhou, P.; Chen, B. C. Chem. Soc. ReV. 1998, 27,
13 and references therein. (b) Recent references; Davis, F. A.; Prasad, K.
R.; Carroll, P. J. J. Org. Chem. 2002, 67, 7802. (c) Davis, F. A.; Deng, J.;
Zhang, Y.; Haltiwanger, R. C. Tetrahedron 2002, 58, 7135. (d) Davis, F.
A.; Chao, B.; Andemichael, Y. W.; Mohanty, P. K.; Fang, T.; Burns, D.
M.; Rao, A.; Szewczyk, J. M. Heteroat. Chem. 2002, 13, 486.
(5) (a) Liu, G.; Cogan, D. A.: Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278. (b) Cogan, D. A.; Liu, G.; Kim, K.: Backes,
B. J.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 8011. (c) Cogan, D. A.;
Liu. G.; Ellman, J. A. Tetrahedron 1999, 55, 8883. (d) Tang, T. P.; Ellman,
J. A. J. Org. Chem. 1999, 64, 12. (e) Cogan, D. A.; Ellman, J. A. J. Am.
Chem. Soc. 1999, 121, 268. (f) Ellman, J. A.; Owens, T. D.; Tang, T. P.
Acc. Chem. Res. 2002, 35, 984.
(6) Moreau, P.; Essiz, M.; Merour, J.-Y.; Bouzard, D. Tetrahedron:
Asymmetry 1997, 8, 591.
(7) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396.
(8) However, N-t-butanesulfinylimines with alkoxy groups at C-R
afforded poorer stereoselectivity in the attack of benzylic anions (0-55%
de); see: Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.;
Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051.
(1) Scott, J. W. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1985; Vol. 5, pp 27-29.
(2) (a) Volkmann, R. A. In ComprehensiVe Organic Synthesis; Schreiber,
S. L., Ed.; Pergamon Press: Oxford, 1991; Vol. 1, Chapter 1.12, p 355. (b)
Risch, N.; Arend, M. In Methods of Organic Chemistry (Houben-Weyl):
StereoselectiVe Synthesis; Helmechen, G., Hoffmann, R. W., Mulzer, J.,
Schauman, E., Eds.; Georg Thieme Verlag: Stutgart, 1995, E21b; D.1.4, p
1833. (c) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(d) Pridgen, L. N. AdV. Asymm. Synth. 1997, 2, 55.
(3) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J. J. Org. Chem. 1997, 62, 2555.
10.1021/ol027464h CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/08/2003

of ortho-substituted benzyl carbanions would improve the
stereoselectivity. Thus, one diastereomer was almost exclu-
sively formed in reactions of ortho-carboxamide9,11 and
ortho-cyano10 benzyl carbanions with N-sulfinylalkylaldi-
mines. Nevertheless, the lower de (76-80%) observed for
the addition of ortho-cyano benzyl carbanion to N-p-tolyl-
sulfinylarylaldimines pointed out that this tendency was not
general.11 Bearing in mind these antecedents, the develop-
ment of a new general procedure for the highly stereoselec-
tive benzylation of imines remained a synthetic challenge.
The fact that optically pure substituted 2-arylethylamines
have been widely used in the synthesis of tetrahydroiso-
quinolines, as well as other more elaborated structures
containing such a skeleton,11,12 increases the interest of the
development of new methods for the preparation of 2-aryl-
ethylamines. Additionally, to the best of our knowledge there
are no reported highly stereoselective approaches to 2-aryl
propylamines containing chiral centers at both C-1 and C-2.
Scheme 1
mide17 (for alkyl aldehydes). Aryl imines were isolated by
crystallization18 and alkyl imines by chromatography. The
configurational assignment of compounds 1b and 1d, which
had not been previously described, was based on the
generally accepted reaction pathway involved in their
preparation.
To determine whether the sulfinyl group at the nucleophile
played any role in the stereochemical course of the addition
reaction and to identify, in such a case, the matched pair,
we first studied the reactions of (S)-ortho-2-p-tolylsulfinyl
toluene19 (2) with (R)-1a, (S)-1a, and their corresponding
sulfone 1′a. In this context, the reaction of sulfone 2′ with
(S)-1a (Table 1) was also investigated.
We have recently reported that R-sulfinyl carbanions
derived from ethyl p-tolyl sulfoxides react with N-p-
tolylsulfinylimines derived from aromatic aldehydes with
complete control of the stereoselectivity at the two newly
created chiral centers.13 Since some problems associated with
the use of benzyl R-sulfinyl carbanions as nucleophiles were
to be expected,14 we decided to investigate the behavior of
benzyl carbanions bearing the sulfinyl group at the ortho
position, which had already been successfully used in
reactions with carbonyl compounds.15 We reasoned that the
stereoselectivity of the benzylation of N-sulfinylimines could
be sharply increased by using ortho-sulfinyl benzyl carban-
ions, as a consequence of a double asymmetric induction
process. Additionally, the use of methyl benzyl carbanions
would allow the exploration of the scope of these reactions
in the simultaneous control of two chiral centers. In this
paper, we report the results obtained in the completely
stereoselective reactions of different N-p-tolylsulfinylimines
(1a-i), derived from aromatic and aliphatic aldehydes, with
2-p-tolylsulfinyl toluene (2) and 2-p-tolylsulfinyl ethylben-
zene (4). Application of this method to the preparation of
1,2-diaryl (and 1-alkyl-2-aryl) ethyl and propylamines through
a facile desulfinilation protocol is also described.
Table 1. Reaction of 2 and 4 with N-Thioderivative Imines
from Benzaldehyde
de (%)
sulfoxide
imine
(configuration
of C-1)
entry reagents configuration configuration
1
2
3
4
5
6
2′ + (S)-1a
2 + 1′a
2 + (R)-1a
2 + (S)-1a
4 + (S)-1a
4 + (R)-1a
S
64 (S)
38 (S)
56 (R)
>98 (S)
>98 (S)
4 (S)
S
S
S
S
S
R
S
S
R
Enantiopure sulfinylimines 1 were prepared in good yields
according to Davis' procedures (Scheme 1) starting from (S)-
menthyl sulfinate16 (for aryl aldehydes) or p-toluenesulfina-
The sulfonyl group at the ortho position of the benzyl
carbanion (generated by treatment of 2′ with LDA) has scarce
influence on the stereoselectivity of its addition to (S)-1a
(64% de, entry 1), which is identical to that observed for
reaction of (S)-1a with BnMgCl.5 On the other hand, we
focused our attention on finding whether there is any
significant influence of the sulfinyl group at the nucleophile
on the stereoselectivity of the addition to the CdN bond. In
(9) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W.
Org. Lett. 2000, 2, 3902.
(10) Davis, F. A.; Andemichael, Y. W. Tetrahedron Lett. 1999, 49, 3099.
(11) In this work, the use of the sterically more demanding N-
naphalenesulfinyl arylimine was required to increase the de up to 96%.
See: Davis, F. A.; Pradyudmna, K. M. J. Org. Chem. 2002, 67, 1290.
(12) Recent references: (a) Cutter, P. S.; Miller, R. B.; Schore, N. E.
Tetrahedron 2002, 58, 1471. (b) Laumer, J. M.; Kim, D. D.; Beak, P. J.
Org. Chem. 2002, 67, 6797. (c) Katritzky, A. R.; Suzuki, K.; He, H.-Y. J.
Org. Chem. 2002, 67, 8224.
(13) Garc´ıa Ruano, J. L.; Alcudia, A.; Prado, M.; Barros, D.; Maestro,
M. C.; Fernandez, I. J. Org. Chem. 2000, 65, 2856.
(14) Moderate configurational stability of benzyl sulfoxides due to the
sulfoxide-sulfenate rearrangement and, mainly, low thermal stability of
the amines resulting from their reactions with N-sulfinylimines, prone to
desulfinylation, should be expected.
(16) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Portonovo, P. S.,
Tetrahedron Lett. 1993, 34, 6229.
(17) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
(18) This allowed for the rapid preparation of these compounds on a
multigram scale, with no chromatographic separation being needed.
(19) See Supporting Information for experimental details concerning the
synthesis of this compound.
(15) Garc´ıa Ruano, J. L.; Aranda, M.; Carren˜o, M. C.; Toledo, M. A.;
Angew. Chem., Int. Ed. 2000, 39, 2736.
678
Org. Lett., Vol. 5, No. 5, 2003

this sense, the reaction of (S)-2 with achiral sulfonamide 1′a
evolved with a 38% de (entry 2), the (1S)-amine being
favored.20 On the basis of this influence, the results we
obtained in reactions of the sulfoxide 2 with the imines 1a
were not unexpected. The reaction with (R)-1a (entry 3)
afforded a mixture of amines with 56% de ((1R)-isomer being
predominant), lower than that observed in reactions with
benzyl Grignard.5 However, to our delight, the exclusive
formation of the disulfinylated 1,2-diphenyl ethylamine 3a
Scheme 2a
1
a Reaction conditions: (a) TFA, MeOH (>90%). (b) Raney-Ni,
THF (72-78%).
(>98% de, measured by H NMR) in almost quantitative
yield was observed when (S)-2 reacted with (S)-1a (entry 4)
under the same conditions (LDA; THF at -78 °C for 10
min).21 These results indicated that reagents with identical
configurations at the sulfur atoms conform with the matched
pair.
proposed the configuration depicted in Table 2 for com-
pounds 3a-i by assuming identical stereochemical evolution
for all the imines.
With these results in hand, the reactions of (S)-2 with a
variety of imines 1b-i, all of them with the (S)-configuration,
To investigate the possibilities of these reactions to achieve
the simultaneous control of the configurations at C-1 and
C-2 when both are chiral centers, we studied the reactions
of (S)-2-p-toluenesulfinyl ethylbenzene (4) with (R)-1a and
(S)-1a. Once again, the mismatched pair is that formed by
(S)-4 and (R)-1a, yielding an almost equimolecular mixture
of two isomers (4% de, entry 6) that exhibit the same
configuration at the benzyl carbon. This indicates that both
sulfinyl groups generate a similar level but an opposite sense
of asymmetric induction at C-1, whereas that at C-2 is
exclusively controlled by the sulfinyl group at the nucleo-
phile. Complete control of the stereoselectivity at both chiral
centers is also observed in reaction of (S)-4 and (S)-1a, which
represent the consonant pair, only yielding one diastereomer
(>98% de, entry 5, Table 1).
1
were studied. De values higher than 98% (measured by H
NMR) and almost quantitative isolated yields were obtained
in all cases, regardless of the aliphatic or aromatic nature of
the imine and the electronic effect of the substituent on the
aromatic ring (Table 2).
Table 2. Reactions of 2 with N-Sulfinylimines (S)-1a-i
Then we studied the reactions of compound 4 with imines
1b-i in the presence of LDA. The results are collected in
Table 3. As expected, the reactivity of 4 was slightly lower
entry
products
(R ) Ph) 3a
(R ) o-BrC6H4) 3b
(R ) p-MeOC6H4) 3c
(R ) p-CNC6H4) 3d
(R ) Naph) 3e
(R ) n-Bu) 3f
(R ) Ph-CH2) 3g
(R ) i-Pr) 3h
isolated yield (%)
de (%)
1
2
3
4
5
6
7
8
9
quantitative
91
quantitative
88
>98
>98
>98
>98
>98
>98
>98
>98
>98
Table 3. Reactions of 4 with N-Sulfinylimines (S)-1a-i
quantitative
95
93
94
91
(R ) t-Bu) 3i
entry
products
(R ) Ph) 5a
(R ) o-BrC6H4) 5b
(R ) p-MeOC6H4) 5c
(R ) p-CNC6H4) 5d
(R ) Naph) 5e
(R ) n-Bu) 5f
(R ) Ph-CH2) 5g
(R ) i-Pr) 5h
isolated yield (%)
de (%)
The absolute configuration of 3i was unequivocally
established by X-ray analysis (see Supporting Information),
whereas that of 3a was assigned by chemical correlation with
8a (see Scheme 2), whose enantiomer had been previously
reported.5 The configuration at C-1 of 8f, obtained from 3f
after N- and C-desulfinylation (Scheme 2), was established
as (R)22 by studying its corresponding Mo¨sher amides.23 We
1
2
3
4
5
6
7
8
9
82
87
84
60
75
85
88
88
89
>98
>98
>98
>98
78
>98
>98
>98
>98
(20) From the results obtained in reactions of 4 with other achiral N-aryl
aldimines, we have checked that the level of the asymmetric induction
depends on the group joined to the iminic nitrogen. De values become higher
than those achieved by benzylation of N-sulfinylimines in ref 5. These results
will be published in due course.
(21) Reactions of 2 and 4 with (S)-1a could be successfully performed
on a gram scale (see Supporting Information for experimental details).
(22) The (R) or (S) stereochemical notation assigned to C(1) in
compounds 3 and 5-9 depends on the nature of the R group.
(23) Kusumi, T.; Fukushima, T.; Ohtani, I.; Kakisawa, H. Tetrahedron
Lett. 1991, 32, 2939.
(R ) t-Bu) 5i
than that of 2,24 and the yields ranged between 60 and 89%.
The stereoselectivity remained complete in all cases (>98%
de) except for the reaction of 1e, affording a 89:11 mixture
of two propylamines, 5e and 5′e, presumably epimers at
C-1.25
Org. Lett., Vol. 5, No. 5, 2003
679

the latter being destabilized by the steric interactions (Tol/
H)1,3-diaxial and (Tol/SOTol) (adopting an almost 1,3-diaxial
arrangement) and dipolar repulsion between the CdN and
S-O dipoles (lower in AS with the sulfinyl oxygen in an
s-cis arrangement). This model would account for the
exclusive formation of compounds 3 (Table 2) in all these
reactions. According to the same model, a higher stereose-
lectivity could be expected from 4 (R ) Me, II would be
clearly favored with respect to I due to the allylic strain),
where BS would be additionally destabilized by the interac-
tion between the almost eclipsed Me and R′ groups.29 The
lower de observed in reactions of the mismatched pair, 2
and (R)-1a (entry 3, Table 1), can be explained with the same
stereochemical model. In this case, the stability differences
between AR and BR are not as large as in the matched pair
[CdN/S-O dipolar repulsion and steric (Tol/H)1,3-diaxial
interaction destabilize AR with respect to AS but stabilize
BR with respect to BS], which accounts for the decrease in
the de, as shown in Table 1. According to the experimental
results, AR is seemingly less stable than BR in the case of 2
(entry 3, Table 1) but slightly more stable in the case of 4
(entry 6, Table 1), where the interaction between the Me
group at the nucleophile and R′ at the imine would cause an
additional destabilization of BR.
Figure 1. Stereochemical model explaining the reactions of 2 and
4 with N-sulfinylimines 1.
Hydrolysis of the N-S bond of compounds 3 and 5 with
TFA/methanol followed by C-desulfinylation of the resulting
free amines 6 and 7 with Raney Ni in THF30 afforded a wide
variety of 1,2-diaryl (and 1-alkyl-2-aryl) ethyl and propy-
lamines. The reaction took place in high yields for com-
pounds 3a, 3f, 5a, and 5f with no loss of optical purity.31
In conclusion, the benzylation of N-p-toluenesulfinylimines
can be achieved under smooth conditions in a completely
stereoselective manner by introduction of a sulfinyl group
with the proper configuration at the ortho position of the
benzyl carbanion. The broad range of sulfinylimines compat-
ible with this method, along with a facile desulfinylation
protocol, provide an easy access to optically pure 1,2-diaryl
(and 1-alkyl-2-aryl) ethyl and propylamines.
The absolute configurations of 5h and 5i were assigned
by X-ray crystallography as (1R,2S) and (1S,2S),22 respec-
tively (see Supporting Information).26 The configuration at
C-1 of 9f, obtained from 5f by N and C-desulfinylation
(Scheme 2), was established as (R)22 by studying its Mo¨sher
amides.23 The amine 5a was chemically correlated with 9a
(Scheme 2), whose enantiomer had been previously re-
ported.27
The initial formation of a benzyllithium intermediate,
stabilized by the ortho-sulfinyl oxygen, allows us to explain
the stereochemical results. This species must exhibit the
p-tolyl group at the sulfur atom in a pseudo axial arrangement
(I and II in Figure 1) in the half-chair conformation of the
six-membered ring, thus avoiding any allylic strain with the
aromatic ortho proton.15 The approaches of the imine could
take place according to an almost concerted mechanism
through a four-membered cyclic transition state involving
the simultaneous formation of the C-C and Li-N bonds,
the first one being more developed (Figure 1).
Acknowledgment. We thank CAICYT (Grant PB2000-
246) for financial support. J.A. thanks Spanish Ministerio
de Ciencia y Tecnolog´ıa for a predoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1b, 1d, 2, 3,
and 5-9 and X-ray data for 3i, 5i, and 5h. This material is
available free of charge via the Internet at http://pubs.acs.org.
Each (R)- or (S)-imine may approach the benzyllithium
intermediate in two different ways28 (A and B, in Figure 1).
In reactions of 2 (R ) H, I and II are identical) with (S)-1,
AS must be strongly favored with respect to BS (Figure 1),
(24) Reactions of compound 4 required 30-40 min for completion,
whereas less than 20 min were required for the reactions of compound 2.
(25) Stereochemistry for 5′e has not been unequivocally established.
(26) Atomic coordinates for 5h, 5i, and 3i have been deposited with the
Cambridge Crystallographic Data Centre (deposition numbers CCDC
197 388, 197 389, and 197 390, respectively). The coordinates can be
obtained, upon request, from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge Cb2 1EZ, UK.
OL027464H
(29) AS approach will be relatively destabilized in the case of the reaction
of 4 with 1e because of the orientation of the naphthalene ring, which would
strongly interact with the methyl group at benzyl carbanion. This would
explain the lower de observed in the entry 5 of Table 3.
(30) Lower yields of some unidentified amine derivatives are obtained
by using EtOH as the solvent.
(27) Berova, N. D.; Kurtev, B. J. Tetrahedron 1969, 25, 2301.
(28) Favored conformations around the N-S bond in these approaches
are those displaying the lone electron pair at sulfur oriented towards the
anion, thus minimizing the interactions between both SOTol groups.
(31) De values higher than 98% were determined for 8f and 9f by using
the Mo¨sher amides protocol. The same conclusion could be deduced for
8a and 9a from their specific rotations (see Supporting Information).
680
Org. Lett., Vol. 5, No. 5, 2003