Asymmetric synthesis of allyl- and α-allenylamines from chiral imines and alkynes via (η2-imine)Ti(O-i-Pr)2 complexes

Article abstract of DOI:10.1021/ol034599u

(Matrix presented) The reaction of a divalent titanium reagent Ti(O-i-Pr)₄/2i-PrMgX with optically active arylaldimines derived from arylaldehydes and O-methylphenylglycinol provided, in a highly diastereoselective manner, chiral (η²-imine)Ti(O-i-Pr) ₂ complexes, which in turn reacted with 1-alkynes or propargyl compounds to give optically active allyl- and α-allenylamines, respectively.

Full text of DOI:10.1021/ol034599u

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2145-2148
Asymmetric Synthesis of Allyl- and
r-Allenylamines from Chiral Imines and
Alkynes via (η2-Imine)Ti(O-i-Pr)2
Complexes
Kohki Fukuhara, Sentaro Okamoto,† and Fumie Sato*
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
fsato@bio.titech.ac.jp
Received April 6, 2003
ABSTRACT
The reaction of a divalent titanium reagent Ti(O-i-Pr)4/2i-PrMgX with optically active arylaldimines derived from arylaldehydes and
O-methylphenylglycinol provided, in a highly diastereoselective manner, chiral (η2-imine)Ti(O-i-Pr)2 complexes, which in turn reacted with
1-alkynes or propargyl compounds to give optically active allyl- and r-allenylamines, respectively.
The synthesis of unsaturated amines such as allylamines1
and R-allenylamines (2,3-alkadienylamines)2 has attracted
much interest, because they are important compounds in
organic synthesis. Although a variety of synthetically useful
methods to access optically active allylamines has been
developed,3 asymmetric synthesis of R-allenylamines has
scarcely been reported.2b,c
We recently reported that a divalent titanium reagent Ti(O-
i-Pr)4/2 i-PrMgX (1) reacts with arylaldimines to provide
the corresponding azatitanacyclopropanes (η2-imine)Ti(O-
i-Pr)2 that, in turn, react with 1-alkynes to provide allylamines
after hydrolysis of the resulting azatitanacyclopentene com-
plexes as exemplified in path a in Scheme 1.4-6 With these
results, we envisioned that the reaction of the azatitanacy-
clopropane complexes with propargyl halides might afford
R-allenylamines through the â-elimination reaction of the
resulting azatitanacyclopentene intermediate and found that
this expectation was realized as exemplified by the reaction
shown in path b in Scheme 1. With these findings in hand,
we were interested in carrying out these reactions in an
asymmetric way starting with optically active imines, and
reported herein is the successful result.
First, we investigated the reaction of 1 with several chiral
imines 2a-5a prepared from the corresponding R-substituted
(3) For recent leading references, see: (a) Ohmura, T.; Hartwig, J. F. J.
Am. Chem. Soc. 2002, 124, 15164. (b) Chen, Y. K.; Lurain, A. E.; Walsh,
P. J. J. Am. Chem. Soc. 2002, 124, 12225. (c) Konno, T.; Nagata, K.;
Ishihara, T.; Yamanaka, H. J. Org. Chem. 2002, 67, 1768. (d) Mart´ın, R.;
Alco´n. M.; Perica`s, M. A.; Riera, A. J. Org. Chem. 2002, 67, 6896. (e)
Wipf, P.; Nunes, R. L.; Ribe, S. HelV. Chim. Acta 2002, 85, 3478. (f) Evans,
P. A.; Robinson, J. E.; Moffett, K. K. Org. Lett. 2001, 3, 3269. (g) Lo¨ber,
O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366. (h)
Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3, 2847. (i)
Yadav, J. S.; Bandyopadhyay, A.; Reddy, B. V. S. Tetrahedron Lett. 2001,
42, 6385. (j) Chao, B.; Dittmer, D. C. Tetrahedron Lett. 2001, 42, 5789.
(k) Yadav, J. S.; Bandyopadhyay, A.; Reddy, B. V. S. Synlett 2001, 1608.
(4) Gao, Y.; Yoshida, Y.; Sato, F. Synlett 1997, 1353.
† Current address: Department of Applied Chemistry, Kanagawa Uni-
versity, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama, 221-8686, Japan.
E-mail: okamos10@kanagawa-u.ac.jp.
(1) For a review on methods for synthesis of allylamines, see: Johannsen,
M.; Jørgensen, K. A. Chem. ReV. 1998, 98, 1689. See also ref 3.
(2) For recent leading references, see: (a) Billet, M.; Schoenfelder, A.;
Klotz, P.; Mann, A. Tetrahedron Lett. 2002, 43, 1453. (b) Dieter, R. K.;
Yu, H. Org. Lett. 2001, 3, 3855. (c) Ohno, H.; Anzai, M.; Toda, A.; Ohishi,
S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66,
4904.
10.1021/ol034599u CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/21/2003

yield presumably due to the larger steric bulkiness of OSit-
BuMe2 than that of the OMe group, and 5a gave a complex
mixture.
Scheme 1
With the finding that 3a afforded a good result, we carried
out the reaction of the azatitanacyclopropane derived from
it with trimethylsilylacetylene. Thus, the titanium complex
prepared by adding 2 equiv of i-PrMgCl to a mixture of 3a
and Ti(O-i-Pr)4 was treated with trimethylsilylacetylene (1.5
equiv) at -35 °C to afford, after hydrolysis or iodinolysis,
the corresponding allylamine 6a and 7a in 81 and 74% yields,
respectively.7 The diastereomeric ratio of 6a thus obtained
was found to be >97:3 by 1H NMR analysis, and the absolute
structure of the major product was confirmed as depicted in
eq 1 (vide infra).
benzylamine and benzaldehyde and saw the diastereofacial
selectivity of the formation of azatitanacyclopropane com-
plexes by their deuteriolysis product. As shown in Scheme
2, the titanium complexes derived from 2a and 3a provided
The results of the reaction with other representative
1-alkynes are summarized in Table 1. It can be seen that the
Table 1
Scheme 2
1
b
a By H NMR. Not determined.
the corresponding amine with quantitative deuterium incor-
poration in excellent yield. While 2a provided two possible
diastereomers in a ratio of 64:36, to our satisfaction, 3a,
which has a 2-methoxy-1-phenylethyl group as the N-
substituent, afforded one diastereomer with excellent selec-
tivity of >97:3, indicating the highly diastereoselective
formation of the azatitanacyclopropane from 3a, though its
absolute stereochemistry was not determined. Meanwhile,
4a furnished the corresponding azatitanacyclopropane in low
a Determined by 1H and 13C NMR analyses. No regioisomer was detected.
b isolated yield.
reaction is reasonably general. An alkyl- and phenylacetylene
reacted with excellent selectivity as shown in entries 2 and
3. Ethyl propiolate could be used equally well to give the
desired allylamine 6d. Sulfonylacetylene also provided the
expected allylamine 6e, albeit in low yield. The present
reaction appears to allow preparation of optically active
(5) We also reported that the (η2-alkyne)Ti(O-i-Pr)2 complexes derived
from 1 and internal alkynes react with imines to provide the corresponding
â,γ-disubstituted allylamines: Gao, Y.; Harada, K.; Sato, F. Tetrahedron
Lett. 1995, 36, 5913.
2146
Org. Lett., Vol. 5, No. 12, 2003

Scheme 3a
Table 2
a (i) n-Bu4NF, DMF. (ii) H2, Pd(OH)2/C, MeOH. (iii) BBr3,
CH2Cl2. (iv) H5IO6, MeNH2,MeOH-H2O.
optically active allylamine has been reported previously.8,9
However, the scope of the reaction was not explored.
We next carried out the reaction of the azatitanacyclo-
propanes derived from 3 with propargyl compounds 8 and
found that the reaction afforded the expected optically active
R-allenylamines highly selectively. Thus, the titanium com-
plex prepared from 1 and 3a was treated with propargyl
bromide (8a) (1.5 equiv) at -35 °C to afford R-allenylamine
9aa in 74% isolated yield. The diastereomeric ratio of 9aa
thus obtained was found to be >98:2 by 1H NMR analysis,
while the absolute configuration of the major isomer was
determined as depicted in the equation shown in Table 2
(vide infra).
This highly diastereoselective formation of R-aryl-R-
allenylamines from chiral imines of type 3 and propargyl
compounds appears to be reasonably general, and additional
results are collected in Table 2. Optically active R-allen-
ylamines having 1- and 2-naphthyl groups (entries 3 and 4),
a 4-siloxy-phenyl group (entry 5), or a mesityl group (entry
6) as an R-aryl moiety can be prepared starting with the
corresponding 3. As mentioned above (see entry 6 in Table
1), an aromatic iodide survives these reductive conditions
so that 2-iodophenyl imine 3b gave the desired 9ba without
any complication (entry 2). As can be seen from entries
7-10, propargyl phosphates (8b,c) and acetates (8d,e) in
addition to the halides can be used as a propargylic substrate.
The results shown in these entries also indicate that the
propargyl substrate having a substituent at the 1- or 3-position
proceeded with similar excellent diastereoselectivity to afford
allenylamines having an allenyl substituent, though in the
case where the product has an axial allenyl chirality such as
9ad and 9ae, two diastereomers regarding the allenyl portion
were produced.
a Stereochemistry was determined for 9aa. That of other compounds was
assigned from analogy with 9aa. b Determined by 1H and 13C NMR
analyses. c Isolated yield. No regioisomer was detected. d Ratio of diaste-
1
reomer regarding the allenyl moiety determined by H NMR.
allylamines having other aromatic substituents than phenyl
at the R-position as exemplified by the preparation of 6f
(entry 6, see also Table 2). Thus, in conclusion, a new
attractive entry to an optically active R-arylallylamines has
been developed. It should be noted that the preparation of
an optically active Cp2Zr(η2-imine) complex from Cp2Zr-
(η2-butene) and 3a and its highly diastereoselective reaction
with trimethylsilylacetylene providing the corresponding
(6) Recent reviews for synthetic reactions mediated by a Ti(O-i-Pr)4/2
i-PrMgCl: Sato, F.; Urabe, H. In Titanium and Zirconium in Organic
Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 319-
354. Sato, F.; Okamoto, S. AdV. Synth. Catal. 2001, 343, 759. Sato, F.;
Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835.
The stereochemistry of 7a and 9aa thus obtained was
determined by converting to the known compounds 1110 and
13,11 respectively, as shown in Scheme 3. The stereochem-
(7) No regioisomer was detected.4
Org. Lett., Vol. 5, No. 12, 2003
2147

titanium and two aryl groups (Ar and Ph) are situated at the
equatorial position.12
Scheme 4
In summary, we have developed a one-pot method for
synthesizing optically active allyl- and R-allenylamines from
arylaldimines 3 and 1-alkynes or propargyl compounds via
the chiral azatitanacyclopropanes. Although the present
method is restricted to preparation of allyl- and R-allen-
ylamines having an R-aryl group, the method might find wide
utility because of the ready availability of all reagents used
and the operational simplicity of the reaction.
Acknowledgment. K.F. is thankful for the Grant of the
21st Century COE Program, Ministry of Education, Culture,
Sports, Science and Technology, Japan, for financial support.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for 6, 7a, and 9-13. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL034599U
(8) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33, 4469.
(9) Enantioselective synthesis of allylamines by the reaction of optically
active azazirconacyclopropanes derived from (ansa-bistetrahydroindenyl)-
ZrMe2 and amines with alkynes was reported: Grossman, R. B.; Davis,
W. M.; Buchwald, S. L. J. Am. Chem. Soc. 1991, 113, 2321.
(10) Kawakami, T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada, Y.;
Murahashi, S. Bull. Chem. Soc. Jpn. 2000, 73, 2423.
(11) Yamamoto, Y.; Shimoda, H.; Oda, J.; Inoue, Y. Bull. Chem. Soc.
Jpn. 1976, 49, 3247.
(12) Insertion of an alkyne is expected to proceed with retention of
configuration at the imine carbon atom similarly to that proposed for the
zirconocene system.8,9
istry of other products shown in Tables 1 and 2 was assigned
from analogy with 7a or 9aa, respectively.
The stereochemical outcome of the reaction shown in
Tables 1 and 2 can be explained by assuming that the reaction
proceeds through the azatitanacyclopropane complex shown
in Scheme 4, which has the six-membered chair-like titana-
cyclic structure A in which the oxygen is coordinated to the
2148
Org. Lett., Vol. 5, No. 12, 2003