Switching regioselectivity in the allylation of imines by N-side chain tuning

Article abstract of DOI:10.1021/ol301026w

A spectacular inversion of α- to γ-regioselectivity in the allylzincation of imines can be achieved by fine-tuning of the N-side chain. This approach allows easy preparation of regioisomeric amines, in racemic as well as enantiopure forms. The usefulness of the method is illustrated by the parallel asymmetric syntheses of 2,3- and 2,5-diphenylpyrrolidines.

Full text of DOI:10.1021/ol301026w

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3004–3007
Switching Regioselectivity in the
Allylation of Imines by N-Side
Chain Tuning
Pierre-Olivier Delaye, Jean-Luc Vasse,* and Jan Szymoniak*
ꢀ
Institut de Chimie Moleculaire de Reims, CNRS (UMR 7312) and Universite de Reims,
51687 Reims Cedex 2, France
ꢀ
jean-luc.vasse@univ-reims.fr; jan.szymoniak@univ-reims.fr
Received April 20, 2012
ABSTRACT
A spectacular inversion of α- to γ-regioselectivity in the allylzincation of imines can be achieved by fine-tuning of the N-side chain. This approach
allows easy preparation of regioisomeric amines, in racemic as well as enantiopure forms. The usefulness of the method is illustrated by the
parallel asymmetric syntheses of 2,3- and 2,5-diphenylpyrrolidines.
Owing to the fundamental role of the nitrogen atom in
an abundance of biologically active molecules,1 the devel-
opment of regio- and stereoselective methods aimed at
preparing amines is of constant interest.
In this context, the regiocontrolled addition (α- vs
γ-selectivity) of substituted allylmetals to imines2 is a major
issue. Despite the extensive literature dealing with imine
allylmetalation, only a few examples involving substituted
allylic organometallics have been reported.3 In particular,
allylzincs bearing an electron-donating fragment are not
common, due to the instability of the corresponding halide
precursors. In this typical case, an alternative procedure
involving allylzirconocenes, generated from allylic ethers,4
followed by the transmetalation to zinc can be carried out.5
Moreover, the branched γ-adduct product, which is
derived from a ZimmermanÀTraxler-like transition state,2,6
is generally observed. Therefore, synthetic methods selec-
tively affording the α-regoisomer would be useful.
In this paper, we wish to report that nitrogen side chain
tuning can induce a reversal of regioselectivity in the
addition of aromatic allylzincs to imines.
The TaguchiÀHanzawa protocol4bÀd was first applied
to a series of allylic silyl ethers 1 to generate the corre-
sponding zirconocenes. In a typical experiment, n-BuLi
(1) (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon Press:
New York, 1999; Vol. 13, pp 1À161. (b) Pu, X.; Ma, D. J. Org. Chem.
2003, 68, 4400–4405. (c) Vazzana, I.; Budriesi, R.; Terranova, E.; Ioan,
P.; Ugenti, M. P.; Tasso, B.; Chiarini, A.; Sparatore, F. J. Med. Chem.
2007, 50, 334–343. (d) Lawrence, S. A. Amines: Synthesis, Properties and
Applications; Cambridge University Press: Cambridge, U.K., 2004.
(2) (a) Ding, H.; Friestad, G. K. Synthesis 2005, 2815–2829.
(b) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207–2293.
(c) Ramadhar, T. R.; Robert A. Batey, R. A. Synthesis 2011, 1321–
1346. (d) Miginiac, L.; Courtois, G. J. Organomet. Chem. 1989, 376, 235.
(e) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 1996,
118, 8489–8490. (f) Jones, P.; Knochel, P. J. Org. Chem. 1999, 64, 186–
195. (g) Petrini, M.; Profeta, R.; Righi, P. J. Org. Chem. 2002, 67, 4530–
4535. (h) Dalmolen, J.; Van der Sluis, M.; Nieuwenhuijzen, J. W.;
Meetsma, A.; De Lange, B.; Kaptein, B.; Kellogg, R. M.; Broxterman,
Q. B. Eur. J. Org. Chem. 2004, 1544–1557.
(4) (a) Rousset, C. J.; Swanson, D. R.; Lamaty, F.; Negishi, E.
Tetrahedron Lett. 1989, 30, 5105–5108. (b) Ito, H.; Taguchi, T.;
Hanzawa, Y. Tetrahedron Lett. 1992, 33, 1295–1298. (c) Ito, H.;
Nakamura, T.; Taguchi, T.; Hanzawa, Y. Tetrahedron 1995, 51, 4507–
4518. (d) Sato, A.; Hisanaka, I.; Okada, M.; Nakamura, Y.; Taguchi, T.
Tetrahedron Lett. 2005, 46, 8381–8383.
(5) Delaye, P.-O.; Vasse, J.-L.; Szymoniak, J. Org. Biomol. Chem.
2010, 8, 3635–3637.
(3) (a) Kadouri-Puchot, C.; Bertin, B.; Comesse, S. Tetrahedron Lett.
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2004, 45, 3807–3809. (b) Dobbs, A. P.; Guesne, S. J. J.; Martinovic, S.;
Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880–7883. (c)
Rutjes, F. P. J. T.; Veerman, J. J. N.; Meester, W. J. N.; Hiemstra, H.;
Schoemaker, H. E. Eur. J. Org. Chem. 1999, 1127–1135.
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D.; Umani-Ronchi, A. J. Org. Chem. 1994, 59, 7766–7773.
r
10.1021/ol301026w
Published on Web 06/05/2012
2012 American Chemical Society

(5 mmol) was added to Cp2ZrCl2 (2.5 mmol) at À78 °C.
Compound 1 (2.5 mmol) was next added, and the reaction
mixture slowly warmed to 0 °C. Subsequent ZrfZn
transmetalation using Zn(OTf)2 (2.5 mmol)7 provided
the allylzinc, which was allowed to react with an imine
(1 mmol) derived from ethanolamine (Table 1).
This method allowed the addition of allyl fragments
bearing different electron-donating moieties (Table 1, en-
tries 2, 3, and 6) but could also be applied to other groups,
such as phenyl (Table 1, entry 1), alkenyl (Table 1, entry 5),
and alkyl (Table 1, entries 4 and 7) ones. This approach
appears to be quite general, leading to the expected
compounds 2aÀg in good yield. The syn/anti selectivity is
typically moderate but could be improved with an imine
derived from a chiral aminoalcohol.2b,8
This regioselectivity reversal reflects an alternative
mechanistic pathway and may be considered as a case
of group tuning involving the O-ZrCp2Cl moiety. It was
thus thought that the formation of the linear product
could be favored by protecting the hydroxy group by a
noncovalent-Zn-bonding function. This α-reactivity has
been described in the literature with Cr9 and allylsilane10
but is rare with allylzincs.11 This aspect was thus fur-
ther studied using imines derived from 2-methoxyethy-
lamine (Table 2). The experimental procedure, Barbier
(Method A) or TaguchiÀHanzawa (Method B), was
chosen according to the structure of the initial allylzinc
derivatives.
A series of homoallylic amines were obtained in moder-
ate to good yields. In the case of allylzincs bearing an aro-
matic (Table 2, entries 1À6) or a heteroaromatic (Table 2,
entries 7À12) substituent, the nearly exclusive formation of
the linear isomer was observed, irrespective of the method
used. In the typical case of a dienylzinc reagent (Table 2,
entry 13), the linear adduct remained the major product;
however, the branched regioisomer was also observed. In
contrast, variations were observed with alkyl-substituted
allylzincs (Table 2, entries 14À16). Whereas the branched
product was the major isomer (Table 2, entry 15), or
even the unique reaction product (Table 2, entry 16)
with primaryR1 alkylgroups, itwasminor when R1 = i-Pr
(Table 2, entry 14).
Table 1. Allylation of Ethanolamine-Derived Imines
entry
R1
R2
2 (yield)
dr
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
2a (83%)
2b (84%)
2c (87%)
2d (72%)
2e (70%)a
2f (69%)
2g (64%)
4.2:1
3.6:1
4:1
3-furyl
The double bond in compounds 3 are almost all
E-configurated, except when substituted with a heteroaro-
matic fragment. In most cases, the two isomers can be
separated by simple column chromatography.
The opposite regioselectivity observed between conju-
gated and nonconjugated allylzinc derivatives might origi-
nate from the intrinsic reactivity of these two cases, which
is likely to differ (Figure 1).
N-Boc-3-indolyl
i-Pr
2.6:1
7:1
Styryl
N-Boc-3-indolyl
Ph-CH2
CH2OBn
Ph
4.9:1
2.2:1
a The regioisomer was also formed and isolated in 17% yield.
Additionally, since 2 equiv of the allylzinc reagent were
required for a complete reaction (one being consumed by
the hydroxy group), we next decided to test an imine which
was preliminarily deprotonated with a zirconocene hy-
dride. Surprisingly, the linear adduct was obtained as the
major compound in this case (Scheme 1).
However, theses differences only appear with imines
derived from an aminoether. In this case, the direct
1,2-addition at the α-position prevails leading to com-
pounds 3. This implies that the organometallic interacts
differently depending on the imine side chain (Figure 1).
The nonracemic version was initiated by using an
imine derived from phenylglycinol methyl ether. In this
case, the regioselectivity is not α-exclusive but is still in
favor of the linear product 3q (8:1), which is obtained as a
single diasteroisomer (Scheme 2).12 The formation of 3q is
consistent with a chelation-controlled cinnamyl addition,
with attack occurring at the more accessible re face
(Scheme 2).
Scheme 1
(9) Giammaruco, M.; Taddei, M.; Ulivi, P. Tetrahedron Lett. 1993,
34, 3635–3638.
(10) Wang, D.-K.; Zhou, Y.-G.; Tang, Y.; Hou, X.-L.; Dai, L.-X.
J. Org. Chem. 1999, 64, 4233–4237.
(11) (a) Bustos, F.; Gorgojo, J. M.; Suero, R.; Aurrecoechea, J. M.
(7) Several Zn(II) sources were tested, and the best results were
obtained with Zn(OTf)2.
ꢀ
Tetrahedron 2002, 58, 6837–6842. (b) Aurrecoechea, J. M.; Fernandez,
A.; Gorgojo, J. M.; Suero, R. Synth. Commun. 2003, 33, 693–702. (c)
Zhao, L.-M.; Zhang, S.-Q.; Jin, H.-S.; Wan, L.-J.; Dou, F. Org. Lett.
2012, 14, 886–889. (d) Wipf, P.; Pierce, J. G. Org. Lett. 2005, 7, 3537–
3540.
(12) The R configuration of the newly formed stereogenic center was
deduced by analogy with 7 (vide infra, Scheme 5) which was converted
into known compound 11 (vide infra, Scheme 6).
(8) For highly diastereoselective allylmetalation of an imine derived
from an aminoalcohol, see: (a) Roy, U. K.; Roy, S. Chem. Rev. 2010,
110, 2472–2535. (b) Jang, T. S.; Ku, I. W.; Jang, M. S.; Keum, G.; Kang,
S. B.; Chung, B. Y.; Kim, Y. Org. Lett. 2006, 8, 195–198. (c) Black, D. A;
Arndtsen, B. A. Org. Lett. 2006, 8, 1991–1993. (d) Babu, S. A.; Yasuda,
M.; Baba, A. Org. Lett. 2007, 9, 405–408. (e) Thirupathi, P.; Kim, S. S.
Tetrahedron 2010, 66, 8623–8628.
Org. Lett., Vol. 14, No. 12, 2012
3005

Table 2. Synthesis of Homoallylamines 3 vs 4a
entry
R1
R2
method
3/4
3 (yield)
E/Z
4 (yield)
dr
1
Ph
Ph
B
A
A
A
A
A
B
B
B
B
B
B
B
B
A
A
>20:1
16:1
3a (98%)b
3b (73%)b
3c (63%)b
3d (65%)b
3e (50%)b
3f (67%)b
3g (97%)b
3hb (82%)c
3i (95%)c
3j (84%)d
3k (83%)d
3l (82%)d
3m (63%)c
3n (42%)c
3o (8%)
97:3
2
Ph
3-pyridyl
3-furyl
i-Bu
96:4
3
Ph
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
9:1
98:2
4
Ph
95:5
5
Ph
n-C4H9
styryl
Ph
96:4
6
Ph
95:5
7
3-furyl
80:20
71:29
63:37
56/44
65:35
62:38
85:15
>95:5
ND
8
2-thiophenyl
benzothiophenyl
N-Boc-3-indolyl
N-Boc-3-indolyl
N-Boc-3-indolyl
Styryl
Ph
9
Ph
10
11
12
13
14
15
16
Ph
4-BrC6H4
4-MeOC6H4
Ph
i-Pr
Ph
3:1
4n (14%)b
4o (49%)b
4p (53%)b
9:1
1.5:1
2:1
CH2Ph
3-furyl
n-C2H5
1:6
n-C4H9
<20:1
a Reaction conditions: Method A: Imine (2 mmol), bromide (2.2 mmol) and Zn (2.2 mmol) in THF (5 mL) at rt for 6 h. Method B: Cp2ZrCl2
(1.5 mmol), n-BuLi (3 mmol), THF À78 °C, 1 h; add 1 (1.5 mmol), then warm to 0 °C, 3 h; add Zn(OTf)2 (1.5 mmol), 30 min, 0 °C; add Imine, rt, 10 h.
b Yields of the major isomer isolated in the pure isomeric form. c Combined yield of unseparable isomers. d Combined yield of separable isomers
Scheme 2. Stereoselective Cinnamylzinc Addition to Imine
Figure 1. Reactivities of allylzincs toward imines.
phenylglycinol 613 as chiral inducer. The imine, obtained by
In parallel, the analogous phenylglycinol-derived imine
was subjected to the same reaction conditions to give the
branched adduct 2h as the major isomer (Scheme 2).
To take advantage of the selectivity reversal, regioisomeric
primary homoallylic amines were prepared. First, amine 5
was obtained by adding Pb(OAc)4 to 2h (Scheme 3). This
could also be applied to the linear regioisomer. In this case
however, it was necessary to replace the OMe by a more labile
protecting group. We thus chose the more suitable PMB
condensing 6 with benzaldehyde, was subjected to allylation
and afforded 7 in good yield as well as regio- and diastereo-
selectivity. A simple acid treatment provided 8, the regioiso-
mer of 2h. Finally, theamine9was obtained under oxidative
conditions (Scheme 3).
Such regioisomeric amines have a significant potential in
the field of heterocyclic synthesis. For example, amines 5
and 9 were converted to pyrrolidines (Scheme 4). First,
(14) (a) Jones, A. D.; Knight, D. W.; Hibbs, D. E. J. Chem. Soc.,
Perkin Trans. 1 2001, 1182–1203. (b) Davis, F. A.; Song, M.; Augustine,
A. J. Org. Chem. 2006, 71, 2779–2786.
(13) For the preparation of 9 see Supporting Information.
3006
Org. Lett., Vol. 14, No. 12, 2012

Scheme 3. Preparation of Regioisomeric Primary Amines
Scheme 4. Synthesis of Disubstituted Pyrrolidines
phenylglycinol and its OPMB analogue makes this reaction
promising in terms of synthetic applications as illustrated
by the synthesis of pyrrolidines.
NTs-amine 10 underwent a iodoamination/deiodination
sequence14 to provide 1114b as a 94:6 mixture of diaste-
reomers. 2,3-Diphenylpyrrolidine 12 was then obtained
by applying a hydrozirconation/iodation sequence to the
temporarily trityl-protected amine 5.15
Acknowledgment. Financial support of this work by
CNRS and MENRT is gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures, characterization, and NMR spectra of all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
In summary, a simple tuning of the imine lateral side
chain combined with an easy removal of the N-side chain
provides a selective access to regioisomeric primary amines.
Moreover, the high stereoselectivity observed when using
(15) Delaye, P.-O.; Ahari, M.; Vasse, J.-L.; Szymoniak, J. Tetrahe-
dron: Asymmetry 2010, 21, 2505–2511.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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