Catalytic asymmetric formation of secondary allylic amines by aza-Claisen rearrangement of trifluoroacetimidates

Article abstract of DOI:10.1055/s-2008-1077792

A catalytic asymmetric synthesis of unprotected secondary allylic amines based on the aza-Claisen rearrangement of N-ar-yl- and N-alkyl-substituted trifluoroacetimidates has been developed, which provides the targeted products with excellent enantioselectivity.

Full text of DOI:10.1055/s-2008-1077792

LETTER
1495
Catalytic Asymmetric Formation of Secondary Allylic Amines by Aza-Claisen
Rearrangement of Trifluoroacetimidates
Catalytic
Asym
h
metric Synth
u
e
sis of Secon
o
dary
A
llylic
-
A
minesqun Xin, Daniel F. Fischer, René Peters*
Department of Chemistry and Applied Biosciences, Laboratory of Organic Chemistry, ETH Zürich, Hönggerberg HCI E 111, Wolfgang-
Pauli-Str. 10, , 8093 Zürich, Switzerland
Fax +41(44)6331226; E-mail: peters@org.chem.ethz.ch
Received 23 February 2008
OH
NH2
Abstract: A catalytic asymmetric synthesis of unprotected second-
ary allylic amines based on the aza-Claisen rearrangement of N-ar-
yl- and N-alkyl-substituted trifluoroacetimidates has been
developed, which provides the targeted products with excellent
enantioselectivity.
R
R
*
1
4
R' = H, PMP
X = Cl, F
depro-
tection
Key words: allylic amines, aza-Claisen rearrangement, ferrocene,
imidazolines, palladacycles
CX3
CX3
O
R'
R'
Pd(II) cat.
N
O
N
*
The catalytic asymmetric aza-Claisen rearrangement1 of
allylic trichloro- (X = Cl)2 and trifluoroacetimidates 2
(X = F)3 constitutes a very attractive platform for the re-
gioselective formation of branched chiral protected allylic
amines 3 starting from readily available achiral allylic al-
cohols 1 (Scheme 1). The trihaloacetamide protecting
groups can be readily removed4 from the initial rearrange-
ment products 3 and the overall transformation hence
leads to free primary allylic amines 4.
R
R
2
3
Scheme 1 The aza-Claisen rearrangement of allylic imidates
Ph
Ph
2
O
Ts
Ts
N
N
N
Ph
OTs
N
Pd O
CF3
Pd
Pd
N
Ph
Me
Me
N
Recently, we have reported the first highly active chiral
catalysts (Figure 1) for the rearrangement of N-p-methox-
yphenyl trifluoroacetimidates providing allylic trifluoro-
acetamides 3 with almost perfect enantiocontrol.3e–h
While the planar chiral ferrocenium imidazoline5 pallada-
cycle complex 5 gave excellent results with E-configured
olefins 2,3e the C2-symmetric bispalladacycle 6 was supe-
rior for Z-isomers.3f,h
Fe
Ts
Fe
Ph
Ph
Ph
Ph
Ph
N
OTs
N
Ph
FBIP (6)
Ph
FIP (5)
Figure 1 The first highly active catalysts for the aza-Claisen rear-
rangement of trifluoroacetimidates
The exceptional catalytic activity (precatalyst loadings
are usually at 0.05–0.2 mol%) can be attributed to various
factors, for example, the robustness of the active catalysts
and the low electron density of the bisimidazoline-substi-
tuted ferrocene or the pentaphenylferrocenium core which
is translated into an enhanced Lewis acidity of the Pd(II)
centers.6 This allowed us to generate even N-substituted
quaternary stereocenters enantioselectively using 3,3-di-
substituted allylic substrates.3g
cleavage of the trifluoroacetamide group, for example, by
cerium(IV) ammonium nitrate (CAN), to furnish the free
primary allylic amines 4.
A variation of the imidate N-substituent R¢ would allow
for the direct formation of chiral secondary allylic amines
without the need for a protecting group and a subsequent
alkylation step. To our knowledge, the catalytic asymmet-
ric formation of secondary allylic amines via the aza-
Claisen rearrangement of trihaloacetimidates has hitherto
not been reported and the substituent R¢ was always con-
sidered to be a protecting group. Moreover, even in the
case of the more reactive benzimidate substrates (aryl in-
stead of CX3 in 2) providing the synthetically less useful
benzoylamides, only a small number of examples have
been described. In those cases the N-substituent R¢ was re-
stricted to either a Cbz group (no enantioselectivity)3c or
to a phenyl group (also substituted ones).7 For the applica-
tion of N-alkyl substituents R¢ there was previously no ex-
ample in literature for unknown reasons.8
So far all of our approaches were limited though to sub-
strates in which the imidate N-atom is protected by a p-
methoxyphenyl (PMP) moiety R¢. This group can be oxi-
datively removed from the rearrangement product after
SYNLETT 2008, No. 10, pp 1495–1499
x
x
.x
x
.2
0
0
8
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1077792; Art ID: G03508ST
© Georg Thieme Verlag Stuttgart · New York

1496
Z.-q. Xin et al.
LETTER
precatalyst 11 (Y mol%),
AgO2CCF3 (3.8 Y mol%),
PS (3 Y mol%), CH2Cl2, ∆
CCl4, PPh3,
Et3N
CF3
CF3
NR'
O
CF3
Cl
R'
R' NH2
+
N
O
72–93%
R'''
O
F3C
OH
R'N
42–98%
ee = 94–99%
R'''
R''
R''
7
9
10
A: NaH, THF,
0 °C to r.t. or
B: LHMDS,
precatalyst:
2
CF3
NR'
Ph
THF, –30 °C
CF3
Cl
R'''
OH
Pd
Cl
+
N
R'''
O
78–96%
R'N
R''
Ph
N
R''
Ts
8
9
Fe
Ph
7
Ph
Ph
Ph
Ph
FIP-Cl (11)
Scheme 2 Synthesis of allylic imidates 9
In this letter we report the first catalytic asymmetric prep-
aration of unprotected secondary allylic amines by aza-
Claisen rearrangement of N-aryl- or N-alkyl-substituted
trifluoroacetimidates.9
Scheme 3 Enantioselective rearrangement of allylic trifluoroacet-
imidates 9
CF3
NaBH4, EtOH,
R'
0 °C to r.t.
R'
NH
The imidate substrates 9 were prepared in good yield by
condensation of iminochlorides 7 with geometrically pure
allylic alcohols 8 after deprotonation of the hydroxy group
with NaH or LHMDS in THF (Scheme 2, Table 1). The
iminochlorides 7 were readily available by a modified lit-
erature procedure.10
N
O
R'''
R''
75–89%
R'''
R''
10
12
Scheme 4 Formation of the free secondary allylic amines 12
In order to find the lowest catalyst loadings which still
provide high yields for most of the rearrangement prod-
ucts 10 within a reaction time of 3 days (Scheme 3), vari-
ous substrates were investigated at 50 °C and 70 °C using
0.05, 0.1, 0.2, 0.5, 1.0, 2.0, or 5.0 mol% of precatalyst 11.
Those data with the minimum catalyst amounts are pre-
sented in Table 1.
achieved in high yield with NaBH4 (Scheme 4, Table 1).
This reductive cleavage has the general advantage of
shorter reaction times as compared to hydrolytic proce-
dures (4 h vs. 1–2 d). For 10a though, the iodo atom was
partially removed under reductive conditions and there-
fore basic hydrolysis [K2CO3, MeOH–H2O (10:1)] was
preferred for this example.
E-Configured imidates 9a–c carrying electron-deficient
or unsubstituted N-aryl residues, such as 4-F-C6H4, 4-I-
C6H4, or naphthyl, require similar precatalyst loadings
(0.05–0.2 mol%, entries 1–3) as substrates bearing the
electron-rich N-PMP moiety. Gratifyingly, also N-alkyl-
substituted imidates undergo the aza-Claisen rearrange-
ment with excellent enantioselectivity and in most cases
with high yield. The required catalyst loadings depend
largely upon the steric bulk of the alkyl substituent R¢:
while only 0.2 mol% precatalyst were required in the case
of unbranched alkyl residues as in n-hexyl (entry 6), with
branched or functionalized N-alkyl groups precatalyst
loadings of 1.0–2.0 mol% were needed. Nevertheless,
also in those cases the products were formed in high yield
and with almost perfect stereocontrol (entries 4, 7–9). A
moderate yield was obtained for the combination of an
alkyl residue R¢ with an a-branched residue R¢¢ (entry 5).
No product was formed employing a-branched alkyl sub-
stituents R¢. For Z-configured allylic imidates, bispallada-
cycle 6 is again the catalyst of choice (entry 10).
The absolute configuration was determined by chemical
correlation. R-Configured compounds 12f and 12k were
independently prepared by aza-Claisen rearrangement of
the corresponding PMP-substituted allylic trifluoroacet-
imidates [R¢ = PMP, R¢¢ = (CH2)2Ph, R¢¢¢ = H or Me], full
deprotection to yield the free primary amine and subse-
quent reductive monoalkylation with hexanal and NaBH4.
Comparison of HPLC data revealed that this material had
the same configuration as the material reported in Table 1,
entries 6 and 11, respectively. Since it is known from our
previous work, that the aza-Claisen rearrangement of al-
lylic trifluoroacetimidates is a stereospecific reaction and
a uniform reaction mechanism can be assumed, the con-
figuration has been assigned to all allylic amines 12a–k.
In conclusion, we have reported the first examples for the
catalytic asymmetric formation of unprotected secondary
allylic amines by aza-Claisen rearrangement of N-aryl-
and N-alkyl-substituted trifluoroacetimidates and subse-
quent reductive or hydrolytic removal of the trifluoroacet-
amide protecting group.11,12 The reaction outcome in
terms of yield and required catalyst amount depends most-
ly on the steric bulk of the substituents R¢ and R¢¢, while
the enantioselectivities are in general very high.
In contrast to catalytic allylic substitutions, secondary al-
lylic amines with quaternary N-substituted stereocenters
can also be generated highly enantioselectively, albeit in
moderate yield (entry 11, ee = 98%).
Reductive removal of the trifluoroacetamide protecting
group releasing the free secondary allylic amines was
Synlett 2008, No. 10, 1495–1499 © Thieme Stuttgart · New York

LETTER
Catalytic Asymmetric Synthesis of Secondary Allylic Amines
1497
Table 1 Synthesis of Imidates 9, Enantioenriched Trifluoroacetamides 10, and the Free Secondary Allylic Amines 12
Entry
R¢
R¢¢
R¢¢¢
9
Yield (%)a 10
Temp
(°C)
Y
Yield
ee (%) 12
Yield
(mol%)b (%)c
(%)c
90
82
86
77
75
89
84
78
80
87
76
1
4-I-C6H4
n-Pr
H
9a 63 (A)
9b 68 (A)
9c 85 (A)
9d 80 (A)
9e 83 (A)
9f 74 (A)
9g 77 (A)
9h 67 (A)
9i 58 (B)
9j 88 (A)
9k 70 (A)
10a
10b
10c
10d
10e
10f
70
50
70
50
70
50
50
70
70
50
70
0.2
0.1
0.05
2.0
2.0
0.2
1.0
1.0
1.0
1.0
2.0
85
91
90
98
51
91
99
92
84
98
42
96e
96e
97e
94d
97d
99e
98e
98d
99d
98d
98d
12a
2
4-F-C6H4
1-Naphthyl
(CH2)2Ph
(CH2)2Ph
n-Hex
n-Pr
H
12b
12c
12d
12e
12f
12g
12h
12i
3
n-Pr
H
4
Me
H
5
i-Pr
H
6
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
H
H
7
(CH2)2i-Pr
(CH2)2OTIPS
(CH2)2CO2Et
(CH2)2Ph
n-Hex
H
10g
10h
10i
8
H
9
H
10
11
CH2OTBS
Me
10jf
12j
(CH2)2Ph
10k
12k
a Isolated yield over two steps from the primary amine R¢NH2. The method that was used is given in parentheses (see Scheme 2).
b Precatalyst loading (see Scheme 3).
c Isolated yield.
d Enantiomeric excess determined by HPLC on a chiral stationary phase (Daicel OD-H or AD-H).
e Enantiomeric excess determined by HPLC on a chiral stationary phase (Daicel OD-H or AD-H) after hydrolysis of 10 to 12.
f Catalyst 6 was used (prepared from the corresponding Cl-bridged dimeric precatalyst by activation with AgOTs.3f,h
(5) For the first preparation of chiral ferrocenyl imidazolines,
see: (a) For further preparations and/or applications see ref.
3d–g and: Peters, R.; Fischer, D. F. Org. Lett. 2005, 7, 4137.
(b) Ma, J.; Cui, X.; Gao, L.; Wu, Y. Inorg. Chem. Commun.
2007, 10, 762. (c) Ma, J.; Cui, X.-L.; Zhang, B.; Song, M.-
P.; Wu, Y.-J. Tetrahedron 2007, 63, 5529.
Acknowledgment
This work was financially supported by ETH research grants TH-
30/04-2, TH-01/07-1, and F. Hoffmann-La Roche. We thank Nico
Santschi and Lukas Dialer for skilful experimental contributions
during their internships in our laboratory.
(6) For recent reviews about palladacycles, see: (a) Herrmann,
W. A.; Bohm, V. P. W.; Reisinger, C. P. J. Organomet.
Chem. 1999, 576, 23. (b) Albrecht, M.; van Koten, G.
Angew. Chem. Int. Ed. 2001, 40, 3750; Angew. Chem. 2001,
40, 3866. (c) Dupont, J.; Pfeffer, M.; Spencer, J. Eur. J.
Inorg. Chem. 2001, 1917. (d) Bedford, R. B. Chem.
Commun. 2003, 1787. (e) van der Boom, M. E.; Milstein, D.
Chem. Rev. 2003, 103, 1759. (f) Singleton, J. T.
References and Notes
(1) Reviews: (a) Hollis, T. K.; Overman, L. E. J. Organomet.
Chem. 1999, 576, 290. (b) Overman, L. E.; Carpenter, N. E.
Org. React. 2005, 66, 1.
(2) (a) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003,
125, 12412. (b) Kirsch, S. F.; Overman, L. E.; Watson, M. P.
J. Org. Chem. 2004, 69, 8101. (c) Nomura, H.; Richards, C.
J. Chem. Eur. J. 2007, 13, 10216.
(3) (a) Overman, L. E.; Owen, C. E.; Pavan, M. M.; Richards, C.
J. Org. Lett. 2003, 5, 1809. (b) Prasad, R. S.; Anderson, C.
E.; Richards, C. J.; Overman, L. E. Organometallics 2005,
24, 77. (c) Anderson, C. E.; Donde, Y.; Douglas, C. J.;
Overman, L. E. J. Org. Chem. 2005, 70, 648. (d) Peters, R.;
Xin, Z.-q.; Fischer, D. F.; Schweizer, W. B. Organometallics
2006, 25, 2917. (e) Weiss, M. E.; Fischer, D. F.; Xin, Z.-q.;
Jautze, S.; Schweizer, W. B.; Peters, R. Angew. Chem. Int.
Ed. 2006, 45, 5694; Angew. Chem. 2006, 118, 5823.
(f) Jautze, S.; Seiler, P.; Peters, R. Angew. Chem. Int. Ed.
2007, 46, 1260; Angew. Chem. 2007, 119, 1282.
(g) Fischer, D. F.; Xin, Z.-q.; Peters, R. Angew. Chem. Int.
Ed. 2007, 46, 7704; Angew. Chem. 2007, 117, 7848.
(h) Jautze, S.; Seiler, P.; Peters, R. Chem. Eur. J. 2008, 14,
1430.
Tetrahedron 2003, 59, 1837. (g) Bellina, F.; Carpita, A.;
Rossi, R. Synthesis 2004, 2419. (h) Bedford, R. B.; Cazin,
C. S. J.; Holder, D. Coord. Chem. Rev. 2004, 248, 2283.
(i) Omae, I. Coord. Chem. Rev. 2004, 248, 995.
(j) Beletskaya, I. P.; Cheprakov, A. V. J. Organomet. Chem.
2004, 689, 4055. (k) Dunina, V. V.; Gorunova, O. N. Russ.
Chem. Rev. 2004, 73, 309. (l) Dupont, J.; Consorti, C. S.;
Spencer, J. Chem. Rev. 2005, 105, 2527.
(7) See ref. 3c and: (a) Nonenantioselective: Metz, P.; Mues,
C.; Schoop, A. Tetrahedron 1992, 48, 1071. (b) Calter, M.;
Hollis, T. K.; Overman, L. E.; Ziller, J.; Zipp, G. G. J. Org.
Chem. 1997, 62, 1449. (c) Hollis, T. K.; Overman, L. E.
Tetrahedron Lett. 1997, 38, 8837. (d) Uozumi, Y.; Kato, K.;
Hayashi, T. Tetrahedron: Asymmetry 1998, 9, 1065.
(e) Jiang, Y.; Longmire, J. M.; Zhang, X. Tetrahedron Lett.
1999, 40, 1449. (f) Donde, Y.; Overman, L. E. J. Am. Chem.
Soc. 1999, 121, 2933. (g) Use of formimidates: Leung, P.-
H.; Ng, K.-H.; Li, Y.; White, A. J. P.; Williams, D. J. Chem.
Commun. 1999, 2435. (h) Moyano, A.; Rosol, M.; Moreno,
R. M.; López, C.; Maestro, M. A. Angew. Chem. Int. Ed.
2005, 44, 1865; Angew. Chem. 2005, 117, 1899.
(4) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups
in Organic Synthesis, 4th ed.; J. Wiley and Sons: Hoboken,
New Jersey, 2007.
Synlett 2008, No. 10, 1495–1499 © Thieme Stuttgart · New York

1498
Z.-q. Xin et al.
LETTER
(8) An alternative approach to chiral secondary allylic amines is,
for example, the Ir-catalyzed enantioselective allylic
amination. For an overview, see: Helmchen, G.; Dahnz, A.;
Dübon, P.; Schelwies, M.; Weihofen, R. Chem. Commun.
2007, 675.
Compound 12b: 1H NMR (300 MHz, CDCl3): d = 0.96 (t,
J = 7.2 Hz, 3 H), 1.38–1.61 (m, 4 H), 3.51 (br, 1 H), 3.74 (q,
J = 6.3 Hz, 2 H), 5.12 (dt, J1 = 1.2 Hz, J2 = 10.2 Hz, 1 H),
5.19 (dt, J1 = 1.5 Hz, J2 = 17.1 Hz, 1 H), 5.71 (ddd, J1 = 6.0
Hz, J2 = 10.2 Hz, J3 = 17.1 Hz, 1 H), 6.51–6.55 (m, 2 H),
6.84–6.89 (m, 1 H). 13C NMR (75 MHz, CDCl3): d = 14.1,
19.2, 38.1, 56.5, 113.9, 114.1, 115.0, 115.2, 115.5, 140.0,
143.8, 153.8, 156.9. MS (EI): m/z (%) = 150 (100), 193 (15)
[M+]. HRMS (EI): m/z calcd for C12H16FN [M]+: 193.1261;
found: 193.1262. [a]D28.4 –4.4 (c 0.120, CHCl3); ee
determination: Chiralcel AD-H, n-hexane–i-PrOH
(99.5:0.5), 0.8 mL/min, 250 nm, tR = 9.0 min (R), 9.8 min
(S).
(9) For other applications of imidazolines in asymmetric
catalysis, see ref. 3d–h and, for example: (a) Menges, F.;
Neuburger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713.
(b) Busacca, C. A.; Grossbach, D.; So, R. C.; O’Brien, E. M.;
Spinelli, E. M. Org. Lett. 2003, 5, 595. (c) Bhor, S.;
Anilkumar, G.; Tse, M. K.; Klawonn, M.; Dobler, C.;
Bitterlich, B.; Grotevendt, A.; Beller, M. Org. Lett. 2005, 7,
3393. (d) Ma, K.; You, J. Chem. Eur. J. 2006, 13, 1863.
(e) Arai, T.; Mizukami, T.; Yanagisawa, A. Org. Lett. 2007,
9, 1145. (f) Enthaler, S.; Hagemann, B.; Bhor, S.;
Anilkumar, G.; Tse, M. K.; Bitterlich, B.; Junge, K.; Erre,
G.; Beller, M. Adv. Synth. Catal. 2007, 349, 853. (g) Arai,
T.; Yokoyama, N.; Yanagisawa, A. Chem. Eur. J. 2008, 14,
2052.
Compound 12c: 1H NMR (300 MHz, CDCl3): d = 0.97 (t,
J = 7.2 Hz, 3 H), 1.45–1.56 (m, 2 H), 1.73 (dt, J1 = 6.8 Hz,
J2 = 14.4 Hz, 2 H), 4.01 (dt, J1 = 6.4 Hz, J2 = 6.4 Hz, 1 H),
4.38 (br, 1 H), 5.15–5.35 (m, 2 H), 5.83 (ddd, J1 = 6.0 Hz,
J2 = 10.0 Hz, J3 = 17.2 Hz, 1 H), 6.63 (d, J = 6.4 Hz, 1 H),
7.20–7.24 (m, 1 H), 7.31 (dd, J1 = 7.6 Hz, J2 = 8.0 Hz, 1 H),
7.41–7.46 (m, 2 H), 7.76–7.84 (m, 2 H). HRMS (EI): m/z
(10) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J. Org. Chem. 1993, 58, 32.
(11) Catalyst Activation
calcd for C16H19N [M]+: 225.1512; found: 225.1512. [a]D
27.9
–5.6 (c 0.242, CHCl3). Additional data are consistent with
those reported in the literature for a racemic sample, see ref.
13; ee determination: Chiralcel OD-H, n-hexane–i-PrOH
(98.0:2.0), 0.8 mL/min, 250 nm, tR = 11.4 min (S), 14.3 min
(R).
A solution of FIP-Cl (11, 1 equiv) in dry CH2Cl2 (0.33 mL/
mmol) is added into a dry pear-shaped flask equipped with a
magnetic stirring bar and containing AgO2CCF3 (3.8 equiv).
The flask is sealed, shielded from light, and the suspension
is stirred at r.t. for 24 h. The resulting wine-red suspension is
filtrated through Celite and CaH2 (ca. 1:1) under N2
atmosphere and the filter cake is washed with dry CH2Cl2.
Proton-sponge solution (1 M in CH2Cl2, 3 equiv) is added to
the filtrate.
Compound 12d: 1H NMR (300 MHz, CD2Cl2): d = 1.04 (br,
1 H), 1.10 (d, J = 6.6 Hz, 3 H), 2.72–2.89 (m, 4 H), 3.13–
3.22 (m, 1 H), 4.98–5.10 (m, 2 H), 5.59–5.71 (m, 1 H), 7.16–
7.31 (m, 5 H). 13C NMR (75 MHz, CD2Cl2): d = 21.9, 37.0,
49.1, 56.9, 114.1, 126.4, 128.7, 129.1, 141.1, 143.6. MS
(EI): m/z (%) = 84 (100), 175 (1) [M+]. HRMS (EI): m/z
Catalysis
27.8
The required amount of the solution of the activated catalyst
is transferred into a dry flask equipped with a magnetic
stirring bar containing the corresponding imidate 9. A stream
of N2 is passed through the flask until the solvent is almost
removed. The septum is replaced by a plastic stopper and the
mixture stirred at the indicated temperature for 72 h. Then
the highly viscous residue is dissolved in CH2Cl2 (1.0 mL for
100 mg of product) and the resulting solution is suspended
in pentane–EtOAc (9:1, 10 mL for 100 mg of product) and
filtrated through a short plug of SiO2 [eluent: pentane–
EtOAc (9:1), ca. 50 mL for 100 mg of product], followed by
removal of the solvent in vacuo. Further purification is
performed by column chromatography [pentane–EtOAc
(9:1)].
calcd for C12H17N [M]+: 175.1356; found: 175.1356. [a]D
–21.1 (c 0.085, CHCl3); ee determination (on the stage of
10d): Chiralcel OD-H, n-hexane–i-PrOH (99.5:0.5), 0.8 mL/
min, 210 nm, tR = 12.1 min (R), 13.0 min (S).
Compound 12e: 1H NMR (300 MHz, CD2Cl2): d = 0.83 (d,
J = 6.9 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3 H), 1.03 (br, 1 H),
1.56–1.65 (m, 1 H), 2.65–2.78 (m, 4 H), 2.83–2.90 (m, 1 H),
5.01–5.12 (m, 2 H), 5.56 (ddd, J1 = 8.4 Hz, J2 = 10.2 Hz,
J3 = 17.1 Hz, 1 H), 7.16–7.31 (m, 5 H). 13C NMR (75 MHz,
CD2Cl2): d = 18.5, 19.6, 32.7, 36.9, 49.3, 68.0, 116.3, 126.3,
128.7, 129.2, 140.0, 141.2. MS (EI): m/z (%) = 160 (100),
188 (1) [M – CH3]+. HRMS (EI): m/z calcd for C13H18N [M
– CH3]+: 188.1434; found: 188.1432. [a]D26.9 –13.5 (c 0.075,
CHCl3); ee determination (on the stage of 10e): Chiralcel
AD-H, n-hexane–i-PrOH (99.5:0.5), 0.8 mL/min, 210 nm,
tR = 7.5 min (R), 9.4 min (S).
Removal of the TFA Protecting Group
Sodium tetrahydridoborate (4 equiv) is added in one portion
to a solution of allylic amide 10 in EtOH (12.5 mmol/mL) at
0 °C. The reaction mixture is then allowed to warm to r.t. and
stirred for additional 4 h. Water is subsequently added and
the mixture extracted three times with MTBE. The combined
organic phases are dried over MgSO4 and the solvent is
removed in vacuo to provide the pure allylic amine 12.
(12) Analytical Data for the Secondary Amines
Compound 12a: 1H NMR (300 MHz, CDCl3): d = 0.94 (t,
J = 6.9 Hz, 3 H), 1.38–1.49 (m, 2 H), 1.53 (m, 2 H), 3.66 (br,
1 H), 3.75 (d, J = 6.0 Hz, 1 H), 5.09–5.20 (m, 2 H), 5.70
(ddd, J1 = 6.0 Hz, J2 = 10.2 Hz, J3 = 16.8 Hz, 1 H), 6.38 (dt,
J1 = 2.6 Hz, J2 = 5.7 Hz, 2 H), 7.38 (dt, J1 = 2.6 Hz, J2 = 5.7
Hz, 2 H). 13C NMR (75 MHz, C6D6): d = 14.1, 19.3, 37.9,
55.4, 77.7, 114.6, 115.7, 137.8, 139.5, 147.2. MS (EI): m/z
(%) = 258 (100), 301 (31) [M+]. HRMS (EI): m/z calcd for
C12H16IN [M]+: 301.0322; found: 301.0326. [a]D28.6 +8.1 (c
0.407, CHCl3); ee determination: Chiralcel AD-H, n-
hexane–i-PrOH (99.5:0.5), 0.8 mL/min, 250 nm, tR = 12.4
min (R), 13.8 min (S).
Compound 12f: 1H NMR (300 MHz, CDCl3): d = 0.88 (t,
J = 6.6 Hz, 3 H), 1.19–1.65 (m, 10 H), 1.65–1.89 (m, 2 H),
2.41–2.50 (m, 1 H), 2.45–2.73 (m, 2 H), 2.97–3.04 (m, 1 H),
5.08–5.17 (m, 2 H), 5.62 (ddd, J1 = 8.1 Hz, J2 = 10.2 Hz,
J3 = 17.1 Hz, 1 H), 7.15–7.30 (m, 5 H). 13C NMR (75 MHz,
CDCl3): d = 14.2, 22.7, 27.2, 30.3, 31.9, 32.3, 37.3, 47.4,
61.6, 116.0, 125.6, 128.2, 128.3, 141.3, 142.1. MS (EI): m/z
(%) = 140 (100), 245 (2) [M+]. HRMS (EI): m/z calcd for
C17H27N [M]+: 245.2138; found: 245.2137. [a]D27.9 –2.0 (c
0.322, CHCl3); ee determination: Chiralcel OD-H, n-
hexane–i-PrOH (99.5:0.5), 0.8 mL/min, 210 nm, tR = 9.8
min (S), 11.1 min (R).
Compound 12g: 1H NMR (300 MHz, CDCl3): d = 0.89 (d,
J = 6.3 Hz, 6 H), 1.29–1.39 (m, 2 H), 1.54–1.90 (m, 3 H),
2.43–2.51 (m, 1 H), 2.55–2.73 (m, 3 H), 2.98–3.05 (dt,
J1 = 5.4 Hz, J2 = 7.8 Hz, 1 H), 5.09–5.17 (m, 2 H), 5.63 (ddd,
J1 = 8.4 Hz, J2 = 10.2 Hz, J3 = 17.1 Hz, 1 H), 7.15–7.30 (m,
5 H). 13C NMR (75 MHz, CDCl3): d = 22.6, 22.7, 26.1, 32.2,
37.2, 39.3, 45.3, 61.6, 116.0, 125.6, 128.2, 128.3, 141.2,
Synlett 2008, No. 10, 1495–1499 © Thieme Stuttgart · New York

LETTER
Catalytic Asymmetric Synthesis of Secondary Allylic Amines
1499
142.2. MS (EI): m/z (%) = 126 (100), 231 (3) [M+]. HRMS
Compound 12j: 1H NMR (300 MHz, CDCl3): d = 0.002 (s, 3
H), 0.006 (s, 3 H), 0.83 (s, 9 H), 1.76 (br, 1 H), 2.70–2.98 (m,
4 H), 3.17 (dt, J1 = 3.9 Hz, J2 = 8.1 Hz, 1 H), 3.46 (dd,
J1 = 8.4 Hz, J2 = 9.9 Hz, 1 H), 3.57 (dd, J1 = 4.5 Hz, J2 = 9.9
Hz, 1 H), 5.12–5.24 (m, 2 H), 5.55–5.67 (m, 1 H), 7.16–7.31
(m, 5 H). 13C NMR (75 MHz, CDCl3): d = –5.5, –5.4, 18.3,
25.9, 36.4, 48.7, 63.6, 66.2, 117.5, 126.1, 128.5, 128.7,
138.1, 140.2. MS (EI): m/z (%) = 160 (100), 305 (1) [M+].
HRMS (EI): m/z calcd for C18H31NOSi [M]+: 305.2170;
found: 305.2173. [a]D25.7 –20.4 (c 0.31, CHCl3); ee
determination (on the stage of 10j): Chiralcel OD-H, n-
hexane–i-PrOH (99.5:0.5), 0.8 mL/min, 210 nm, tR = 6.2
min (R), 8.0 min (S).
(EI): m/z calcd for C16H25N [M]+: 231.1982; found:
231.1981. [a]D27.9 –2.7 (c 0.382, CHCl3); ee determination:
Chiralcel AD-H, n-hexane–i-PrOH (95.0:5.0), 0.8 mL/min,
210 nm, tR = 5.0 min (R), 5.3 min (S).
Compound 12h: 1H NMR (300 MHz, CDCl3): d = 1.06 (d,
J = 8.1 Hz, 21 H), 1.63 (br, 1 H), 1.68–1.90 (m, 2 H), 2.57–
2.81 (m, 4 H), 3.01–3.08 (m, 1 H), 3.74–3.84 (m, 2 H), 5.10–
5.17 (m, 2 H), 5.60–5.72 (m, 1 H), 7.15–7.30 (m, 5 H). 13
NMR (75 MHz, CDCl3): d = 12.0, 18.0, 32.2, 37.4, 49.4,
61.2, 62.6, 115.9, 125.5, 128.1, 128.2, 141.1, 142.0. MS
C
(EI): m/z (%) = 256 (100), 361 (6) [M+]. HRMS (EI): m/z
calcd for C22H39NOSi [M]+: 361.2795; found: 361.2796.
[a]D24.5 –2.6 (c 0.435, CHCl3); ee determination (on the stage
of 10h): Chiralcel OD-H, n-hexane–i-PrOH (99.5:0.5), 0.8
mL/min, 210 nm, tR = 7.5 min (S), 9.2 min (R).
Compound 12k: 1H NMR (300 MHz, CDCl3): d = 0.89 (t,
J = 6.6 Hz, 3 H), 1.06 (br, 1 H), 1.21 (s, 3 H), 1.26–1.35 (m,
6 H), 1.37–1.47 (m, 2 H), 1.75 (dt, J1 = 3.0 Hz, J2 = 8.7 Hz,
2 H), 2.48 (t, J = 7.2 Hz, 2 H), 2.58 (dd, J1 = 6.6 Hz,
J2 = 10.8 Hz, 2 H), 5.04–5.15 (m, 2 H), 5.77 (dd, J1 = 10.8
Hz, J2 = 17.4 Hz, 1 H), 7.15–7.31 (m, 5 H). 13C NMR (75
MHz, CDCl3): d = 14.1, 22.7, 23.6, 27.3, 30.4, 31.0, 31.9,
42.1, 42.5, 56.8, 112.9, 125.7, 128.3, 128.4, 142.9, 146.4.
MS (EI): m/z (%) = 154 (100), 244 (7) [M – CH3]+. HRMS
(EI): m/z calcd for C17H26N [M – CH3]+: 244.2060; found:
244.2059. [a]D26.5 –18.0 (c 0.125, CHCl3); ee determination
(on the stage of 10k): Chiralcel OD-H, n-hexane–i-PrOH
(99.5:0.5), 0.8 mL/min, 210 nm, tR = 7.5 min (S), 8.9 min
(R).
Compound 12i: 1H NMR (300 MHz, CDCl3): d = 1.26 (t,
J = 7.2 Hz, 3 H), 1.41 (br , 1 H), 1.65–1.87 (m, 2 H), 2.45–
2.50 (m, 2 H), 2.55–2.78 (m, 3 H), 2.86–2.95 (m, 1 H), 3.01
(q, J = 6.6 Hz, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 5.10–5.17 (m,
2 H), 5.62 (ddd, J1 = 8.1 Hz, J2 = 10.2 Hz, J3 = 17.1 Hz, 1
H), 7.17–7.30 (m, 5 H). 13C NMR (75 MHz, CDCl3):
d = 14.3, 32.2, 34.9, 37.3, 42.5, 60.4, 61.2, 116.3, 125.8,
128.4, 128.4, 141.0, 142.2, 172.9. MS (EI): m/z (%) = 156
(100), 261 (2) [M+]. HRMS (EI): m/z calcd for C16H23NO2
[M]+: 261.1723; found: 261.1725. [a]D27.2 –3.6 (c 0.250,
CHCl3); ee determination (on the stage of 10i): Chiralcel
OD-H, n-hexane–i-PrOH (95.0:5.0), 0.8 mL/min, 210 nm,
tR = 12.8 min (S), 15.6 min (R).
(13) Yang, S.-C.; Feng, W. H.; Gan, K. H. Tetrahedron 2006, 62,
3752.
Synlett 2008, No. 10, 1495–1499 © Thieme Stuttgart · New York

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