Sequential asymmetric homoallenylation of primary amines with a palladium catalyst

Article abstract of DOI:10.1016/j.tetlet.2008.05.144

Optically active bis(homoallenyl)amines bearing two chiral axes with the same sense of axial chirality were prepared by a one-pot, palladium-catalyzed sequential homoallenylation of primary amines with 2,3-allenyl phosphates.

Full text of DOI:10.1016/j.tetlet.2008.05.144

Tetrahedron Letters 49 (2008) 4915–4917
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sequential asymmetric homoallenylation of primary amines
with a palladium catalyst
*
*
Yasushi Imada , Masayuki Nishida, Takeshi Naota
Department of Chemistry, Graduate School of Engineering Science, Osaka University Machikaneyama, Toyonaka, Osaka 560-8531, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically active bis(homoallenyl)amines bearing two chiral axes with the same sense of axial chirality
were prepared by a one-pot, palladium-catalyzed sequential homoallenylation of primary amines with
2,3-allenyl phosphates.
Received 3 April 2008
Revised 23 May 2008
Accepted 30 May 2008
Available online 4 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalyst
Asymmetric reaction
Optically active allenes
Bishomoallenylamines
Sequential asymmetric induction has attracted much attention
toward the ultimate goal of developing one-pot sequential syn-
thetic reactions.1 One-pot asymmetric reactions of molecules bear-
ing multiple and remote functionalities (Eq. 1) have been studied
extensively for sequential asymmetric inductions in many types
of organic reactions including oxidation of sulfides,2 epoxida-
tion of trienes,3 phosphination of dibromides,4 hydrogenation of
diketones,5 alkylation of dialdehydes with diethyl zinc,6 and cyana-
tion–aldol reactions.7 In contrast, asymmetric inductions per-
formed via successive enantiomeric differentiations on the same
reaction point (Eq. 2) are not as frequently reported despite their
potential importance in various fields of organic synthesis such
as catalytic allylation8 and 1,4-conjugate additions.9 The difficul-
ties in this mode of asymmetric induction are probably due to
the fatal conflict of enantiomeric differentiation which commonly
arises from the inevitable generation of the adjacent diastereoface
by the first asymmetric induction.
During the course of our systematic studies on catalytic cou-
pling reactions via
p
-allyl palladium intermediates,10 we found
that catalytic homoallenylation of primary amines11a is a rare
and suitable platform for the above sequential asymmetric induc-
tion (Eq. 2). This is due to the specific axial chirality of
a-methy-
lene-p
-allyl intermediates,11,12 which would prevent the above
conflict of facial differentiation. In this Letter, we describe a practi-
cal method for one-pot asymmetric bishomoallenylation of pri-
mary amines with 2,3-allenyl phosphates in the presence of
palladium complex catalysts (Eq. 3). Since bishomoallenylamino
compounds have been used as starting materials in a variety of car-
bocyclizations such as [2+2] cycloadditions13 and stannylative
cyclizations,14,15 the reaction provides a facile and convenient
method for synthesizing a wide variety of optically active nitro-
gen-containing carbon skeletons.
O
H
Pd-L*n cat.
OP(OEt)2
R2
R1NH2
+
∗
∗
A
A
chiral cat.
A
A
B
B
ð1Þ
ð2Þ
+
H
2 B
2 B
1
ð3Þ
H
R1
N
H
R2
R2
B
B
chiral cat.
∗
∗
+
A
A
H
H
(R*,R*)-3
The sequential asymmetric homoallenylation was examined
using the reaction of diethyl 5,5-dimethyl-2,3-hexadienyl phos-
phate (1a) with benzylamine in the presence of Pd2(dba)3ꢀCHCl3
(0.025 equiv) and (R)-SEGPHOS [(R)-4]16 (0.05 equiv) in THF at
20 °C (Scheme 1). 1H NMR analysis of the time-dependent change
* Corresponding authors. Tel.: +81 6 6850 6221; fax: +81 6 6850 6222 (Y.I);
tel.: +81 6 6850 6220; fax: +81 6 6850 6222 (T.N.).
E-mail addresses: imada@chem.es.osaka-u.ac.jp (Y. Imada), naota@chem.es.
osaka-u.ac.jp (T. Naota).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.144

4916
Y. Imada et al. / Tetrahedron Letters 49 (2008) 4915–4917
Pd2(dba)3•CHCl3 (2.5 mol%)
ligand (5.0 mol%)
H
O
H
Bn H
N
H
Bn H
N
H
H
N
OP(OEt)2
+
BnNH2
R
R
R
R
R
R
Bn
+
+
THF, 20 °C
H
H
H
H
H
H
(R∗,R∗)-3
(R∗,S∗)-3
1a: R = t-Bu
1b: R = Me
2
O
1c: R = n-C5H11
O
O
PAr2
PAr2
(R)-4: (R)-SEGPHOS; Ar = Ph
(R)-5: (R)-DTBM-SEGPHOS; Ar = 4-MeO-3,5-t-Bu2C6H2
O
Scheme 1. Palladium-catalyzed homoallenylation of benzylamine.
in product distribution showed that the process occurs via the ini-
tial formation of N-benzyl-5,5-dimethyl-2,3-hexadienylamine (2a),
which undergoes subsequent catalytic homoallenylation to afford
the chiral (R*,R*) form of N,N-bis(5,5-dimethyl-2,3-hexadienyl)ben-
zylamine (3a) along with achiral (R*,S*)-3a with a diastereoselectiv-
ity of 81/19. HPLC analysis using a chiral stationary phase column
showed that moderately high enantioselectivity was observed for
the product (R*,R*)-3a (88% ee). Compounds 2a and 3a exhibited
(ꢁ) specific rotations,17 from which their absolute configurations
were assigned to be (R) and (R,R), respectively, from the estab-
lished molecular structure of (R)-(ꢁ)- and (S)-(+)-N-benzyl-N-
methyl-2,3-pentadienylamine.18
Sequential asymmetric homoallenylations of primary amines
can be performed with 2,3-allenyl phosphates. Representative
results for the reactions with benzylamine are shown in Table 1.
Moderate to high enantio- and diastereoselectivities were
observed in the reactions with 2,3-allenyl phosphates 1a–c bearing
substituents at C4 position, when (R)-SEGPHOS [(R)-4] or (R)-
DTBM-SEGPHOS [(R)-5] was used as the chiral ligand (entries 1,
3, and 5). Other chiral ligands such as BINAP showed moderate
enantioselectivity. The use of the (S)-ligands afforded (S,S)-prod-
ucts with nearly identical diastereo- and enantioselectivities
(entries 2 and 4).
X
R
H
BnNH2
major
PdL∗
(R)-7
(R)-2
(S)-2
X
PdL∗
R
H
PdL∗
1
6
R
H
X
BnNH2
minor
PdL∗
(S)-7
Scheme 2. Asymmetric induction of chiral axes by palladium-catalyzed homoall-
enylation of benzylamine.
to afford the (R,R)- or (S,S)-form of the bishomoallenylamines 3
with high enantioselectivity.
Similar treatment of 1a with benzylamine (0.7 equiv) in the
presence of achiral catalyst, Pd2(dba)3ꢀCHCl3 (0.025 equiv) and
dppp (0.05 equiv), afforded a mixture of (R*,R*)- and (R*,S*)-3a in
a 50:50 ratio (total yield 71%). This result indicates that nucleo-
philic attack of (R)-2a to a-methylene-p-allylpalladium intermedi-
The present asymmetric induction can be rationalized by the
mechanism shown in Scheme 2,11 where oxidative addition of
the chiral palladium species to the 2,3-allenyl phosphate 1 gives
ate (R)-7 proceeds at the same rate as that of (S)-2. Thus, we can be
fairly certain that the system is substantially protected from the
common diastereomeric conflict, which is encountered in sequen-
tial aldol and Michael reactions. This can be ascribed to the mole-
cular structure of the homoallenylamines, whose asymmetric
carbon (C4) is located in a sufficiently remote position from the
reactive nitrogen atom.
r
-1,3-alkadienylpalladium 611b and the equilibrated chiral isomers
of the a-methylene-p-allylpalladium intermediates (R)- and (S)-7.
The enantiomer differentiating reaction of primary amines with 7
affords optically active monohomoallenylamine (R)- or (S)-2,
which in turn acts as a nucleophile in this asymmetric reaction
As shown in Scheme 3, a minor product, meso-3, is formed both
by the major reaction with the minor intermediate, (S)-2, and the
minor reaction with the major intermediate, (R)-2. Thus, it is note-
worthy that the present sequential process can substantially
achieve high enantioselectivity of the product, since most of the
minor intermediate is transformed into the removable meso com-
pound in the second step.19 Principally, 95% ee of (R,R)-3 can be
obtained by enantioselectivities of 86:14 both in the first and in
Table 1
Palladium-catalyzed sequential asymmetric homoallenylation of benzylaminea
Entry Phosphate Ligand Product Yieldb
(%)
(R*,R*)/
(R*,S*)c
ee of (R*,R*)-3d
(%)
1
2
3
4
5
1a
1a
1a
1b
1c
(R)-4
(S)-4
(R)-5
(S)-4
(R)-4
3a
3a
3a
3b
3c
75
78
52
68
72
81:19
82:18
85:15
73:27e
73:27
88 (R,R)
87 (S,S)
95 (R,R)
75 (S,S)
75 (R,R)
(R,R)-3
(R)-2
a
All reactions were conducted in THF (0.075 M) at room temperature for 20–
24 h. The ratio of 1/benzylamine/Pd2(dba)3ꢀCHCl3/ligand was 100/70/2.5/5.0.
b
Isolated yield based on phosphate 1.
1
meso-3
(R*,R*)/(R*,S*) was determined by HPLC analysis with a chiral stationary phase
c
column using calibration curves.
(S)-2
d
Enantiomeric excess was determined by HPLC analysis using a chiral stationary
phase column, and the absolute configurations of the major enantiomer are shown
in parentheses.
(S,S)-3
e
Determined by GLC analysis using a chiral stationary phase column.
Scheme 3. Statistical enantiomeric amplification by sequential homoallenylation.

Y. Imada et al. / Tetrahedron Letters 49 (2008) 4915–4917
4917
11. (a) Imada, Y.; Nishida, M.; Kutsuwa, K.; Murahashi, S.-I.; Naota, T. Org. Lett.
2005, 7, 5837–5839; (b) Imada, Y.; Ueno, K.; Kutsuwa, K.; Murahashi, S.-I.
Chem. Lett. 2002, 31, 140–141.
the second homoallenylation steps. Further studies are currently
underway.
12. (a) Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001, 123,
2089–2090; (b) Trost, B. M.; Fandrick, D. R.; Dinh, D. C. J. Am. Chem. Soc. 2005,
127, 14186–14187.
Acknowledgments
13. Jiang, X.; Cheng, X.; Ma, S. Angew. Chem., Int. Ed. 2006, 45, 8009–8013.
14. Kang, S.-K.; Baik, T.-G.; Kulak, A. N.; Ha, Y.-H.; Lim, Y.; Park, J. J. Am. Chem. Soc.
2000, 122, 11529–11530.
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan. We thank Takasago International Co., Japan for a generous
gift of chiral ligands.
15. Hong, Y.-T.; Yoon, S.-K.; Kang, S.-K.; Yu, C.-M. Eur. J. Org. Chem. 2004, 4628–
4635.
16. (R)-SEGPHOS: (R)-[4,40-Bi-(1,3-benzodioxole)-5,50-diyl]bis(diphenylphosphine);
(R)-DTBM-SEGPHOS: (R)-[4,40-Bi-(1,3-benzodioxole)-5,50-diyl]bis[bis[3,5- bis(1,1-
dimethylethyl)-4-methoxyphenyl]]-bis(diphenylphosphine): Saito, T.; Yokozawa,
T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumobayashi, H. Adv. Synth. Catal.
2001, 343, 264–267.
References and notes
1. For
a review, see: Metal Catalyzed Cascade Reactions; Müller, T. J. J., Ed.;
17. A typical procedure is exemplified by the preparation of 3a. A solution of 2,3-
allenyl phosphate 1a (0.30 mmol), benzylamine (0.21 mmol), Pd2(dba)3ꢀCHCl3
(7.50 ꢂ 10ꢁ3 mmol), and (R)-DTBM-SEGPHOS [(R)-5, 1.50 ꢂ 10ꢁ2 mmol] in
THF (4 mL) was stirred at 20 °C for 20 h. After the usual work-up,
bishomoallenylamine 3a was isolated by a simple column chromatographic
separation through silica gel (25 mg, 52%). HPLC analysis using ChiralpakÒ OD
(hexane–i-PrOH = 99:1) showed the diastereomeric ratio of 3a to be (R*,R*)/
(R*,S*) = 85:15 and enantiomeric excess of (R*R*)-3a to be 95% ee (R,R). (R,R)-3a:
Springer: Berlin, 2006.
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[
a
]
ꢁ81.88 (c 0.149, CHCl3); IR (neat) 3029, 2866, 1960 (C@C@C) cmꢁ1
;
1H
D
NMR (CDCl3, 270 MHz)
d 1.08 [s, 18H, (CH3)3C], 3.11–3.21 (m, 4H,
NCH2CH@C@CH), 3.61–3.72 (m, 2H, PhCH2N), 5.12–5.16 (m, 2H, t-
BuCH@C@CHCH2N), 5.21 (ddt, J = 2.5, 6.5, 7.5 Hz, 2H, t-BuCH@C@CHCH2N),
7.21–7.26 (m, 2H, ArH), 7.28–7.37 (m, 3H, ArH); 13C NMR (CDCl3, 125 MHz) d
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ꢁ54.0 (c 0.183, CHCl3); IR
(neat) 3320, 3028, 2960, 1960 (C@C@C) cmꢁ1 1H NMR (CDCl3, 270 MHz) d 1.04
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a
]
D
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Murahashi, S.-I.; Imada, Y.; Taniguchi, Y.; Higashiura, S. Tetrahedron Lett. 1988,
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Chem. 1993, 58, 1538–1545; Imada, Y.; Fujii, M.; Kubota, Y.; Murahashi, S.-I.
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I.; Imada, Y.; Taniguchi, Y.; Kodera, Y. Tetrahedron Lett. 1988, 29, 2973–2976;
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Chem. Commun. 1988, 1578–1579; Murahashi, S.-I.; Imada, Y.; Nishimura, K.
Tetrahedron 1994, 50, 453–464.
;
[s, 9H, (CH3)3C], 3.28 (dd, 2H, J = 3.0, 6.3 Hz, NCH2CH@C@C), 3.82 (d, 1H,
J = 14 Hz, PhCHHN), 3.87 (d, 1H, J = 14 Hz, PhCHHN), 5.22 (dt, 1H, J = 6.3, 3.0 Hz,
t-BuCH@CH@CH), 5.29 (dt, 1H, J = 6.3, 6.3 Hz, NCH2CH@C@CH), 7.24–7.36 (m,
5H, ArH).
18. Sahlberg, C.; Ross, S. B.; Fagervall, I.; Ask, A.-L.; Claesson, A. J. Med. Chem. 1983,
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19. Precedent examples of statistical enantiomeric amplification, see: Fleming, I.;
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