Indium-mediated asymmetric barbier-type allylation of aldimines in alcoholic solvents: Synthesis of optically active homoallylic amines

Article abstract of DOI:10.1021/jo0477244

(Chemical Equation Presented) Chiral aldimines derived from phenylglycinol were diastereoselectively allylated with indium powder/allyl bromide in alcoholic solvents. Both aliphatic and aromatic aldimines provided good yield of the desired products with h

Full text of DOI:10.1021/jo0477244

Indium-Mediated Asymmetric Barbier-Type Allylation of
Aldimines in Alcoholic Solvents: Synthesis of Optically Active
Homoallylic Amines
Tirayut Vilaivan,*,† Chutima Winotapan,† Vorawit Banphavichit,† Tetsuro Shinada,‡ and
Yasufumi Ohfune‡
Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science,
Chulalongkorn University, Phayathai Road, Patumwan, Bangkok 10330, Thailand,
and Department of Material Sciences, Graduate School of Science, Osaka City University,
Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
vtirayut@chula.ac.th
Received December 30, 2004
Chiral aldimines derived from phenylglycinol were diastereoselectively allylated with indium
powder/allyl bromide in alcoholic solvents. Both aliphatic and aromatic aldimines provided good
yield of the desired products with high diastereoselectivity. A racemization-free protocol for removal
of the phenylglycinol auxiliary was also developed. The stereochemical assignment of the homoallylic
amine was made by NMR spectroscopy and a transition state model was proposed to explain the
selectivity.
Carbon-carbon bond formation by nucleophilic addi-
tion of carbon nucleophiles to imines is an important tool
in organic synthesis.1 Allylation of imines provides ho-
moallyic amines, which are important intermediates
for a wide range of pharmaceutical substances and
biologically active compounds.2 Extensive efforts have
been made toward development of an effective chiral
auxiliary or an asymmetric catalyst to induce high
enantio- and diastereoselectivities. Although a number
of excellent chiral reagents-based3 and chiral catalysts-
based4 methods for allylation of imines have recently
been developed, the range of substrates is still quite
limited. At present, very few of such methods are ap-
plicable to enolizable aldimines derived from aliphatic
aldehydes. On the other hand, auxiliary-based methods
generally display better substrate tolerance and often
provide better stereoselectivity.5-7 Most of the synthetic
* To whom correspondence should be addressed. Phone: +66-2-
2187627. Fax: +66-2-2187598.
(3) (a) Itsuno, S.; Watanabe, K.; El-Shehawy, A. A. Adv. Synth.
Catal. 2001, 343, 89-94. (b) Chen, G.-M.; Ramachandran, V.; Brown,
H. C. Angew. Chem., Int. Ed. Engl. 1999, 38, 825-826.
† Chulalongkorn University.
‡ Osaka City University.
(1) Recent reviews: (a) Enders, D.; Reinhold: U. Tetrahedron:
Asymmetry 1997, 8, 1895-1946. (b) Bloch, R. Chem. Rev. 1998, 98,
1407-1438. (c) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-
1094.
(4) (a) Fernandes, R. A.; Stimac, A.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 14133-14139. (b) Fernandes, R. A.; Yamamoto, Y. J.
Org. Chem. 2004, 69, 735-738. (c) Sugiura, M.; Robvieus, F.; Koba-
yashi, S. Synlett 2003, 1749-1751. (d) Gastner, R.; Ishitani, H.;
Akiyama, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2001, 40, 1896-
1898. (e) Fang, X.; Johannsen, M.; Yao, S.; Gethergood, N.; Hazell, R.
G.; Jørgensen, K. A. J. Org. Chem. 1999, 64, 4844-4849.
(5) (a) Wu, M.-J.; Pridgen, L. N. Synlett 1990, 636-637. (b) Wu, M.-
J.; Pridgen, L. N. J. Org. Chem. 1991, 56, 1340-1344. (c) Allin, S. M.;
Button, M. A. C.; Baird, R. D. Synlett 1998, 1117-1119. (d) Yanada,
R.; Negoro, N.; Okaniwa, M.; Ibuka, T. Tetrahedron 1999, 55, 13947-
13956. (e) Agami, C.; Couty, F.; Evano, G. Tetrahedron: Asymmetry
2000, 11, 4639-4643. (f) Yanada, R.; Kaieda, A.; Takemoto, Y. J. Org.
Chem. 2001, 66, 7516-7518. (g) Yanada, R.; Okaniwa, M.; Kaieda, A.;
Ibuka, T.; Takemoto, Y. J. Org. Chem. 2001, 66, 1283-1286.
(6) van der Sluis, M.; Dalmolen, J.; de Lange, B.; Kaptein, B.;
Kellogg, R. M.; Broxterman, Q. B. Org. Lett. 2001, 3, 3943-3946.
(2) (a) Laschat, S.; Kunz, H. J. Org. Chem. 1991, 56, 5883-5889.
(b) Ohfune, Y.; Hori, K.; Sakitani, M. Tetrahedron Lett. 1986, 27, 6079-
6082. (c) Franciotti, M.; Mann, A.; Mordini, A.; Taddei, M. Tetrahedron
Lett. 1993, 34, 1355-1358. (d) Deloisy, S.; Tietgen, H.; Kunz, H. Collect.
Czech. Chem. Commun. 2000, 65, 816-828. (e) Pannecoucke, X.;
Outurquin, F.; Paulmier, C. Eur. J. Org. Chem. 2002, 995-1006. (f)
Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1988, 1527-1528. (g) Jones, A. D.; Knight, D. W. J. Chem.
Soc., Chem. Commun. 1996, 915-916. (h) Graziani, L.; Porzi, G.;
Sandri, S. Tetrahedron: Asymmetry 1996, 7, 1341-1346. (i) Jones, A.
D.; Knight, D. W.; Hibbs, D. E. J. Chem. Soc., Perkin Trans. 1 2001,
1182-1203. (j) Jo, E.; Na, Y.; Chang, S. Tetrahedron Lett. 1999, 40,
5581-5582.
10.1021/jo0477244 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/02/2005
3464
J. Org. Chem. 2005, 70, 3464-3471

Synthesis of Optically Active Homoallylic Amines
TABLE 1. Addition of Allyl Indium Reagent to Chiral
Aldimines
SCHEME 1
methods along this line commenced with imines bearing
an electron-withdrawing group or an aryl group to
stabilize the resulting amide anion to accelerate the reac-
tion. These features extremely limit the applicability of
the chiral auxiliary to be used for asymmetric allylation
of imines. To overcome the limitation, we have recently
developed a Barbier-type allylation of N-alkylimines
using allyl bromide-indium in alcoholic solvents.8-10 In
this paper we wish to further investigate the scope of the
reaction with emphasis on diastereoselective allylation
of aldimines bearing a chiral auxiliary and subsequent
removal of the chiral auxiliary to produce optically active
homoallylic amines (Scheme 1).
(S)-Valine methyl ester has generally been used as a
chiral auxiliary for asymmetric alkylation of aldimines.
Recently Loh has reported a highly diastereoselective
allylation and Mannich-type reaction of imines derived
from (S)-valine methyl ester.11 Unfortunately, cleavage
of this auxiliary requires a multistep treatment.12 Chiral
1,2-amino alcohols and their derivatives have also been
successfully employed as chiral auxiliaries.13 Recent
works revealed that (S)-valinol and (S)-phenylglycinol are
very effective chiral auxiliaries for allylation of aldimines
in aprotic solvents.5 Our preliminary results suggested
that these amino alcohols similarly perform well as chiral
auxiliaries in alcoholic solvents.
We initially screened a variety of amino acid-derived
chiral amines as an auxiliary for asymmetric allylation
of benzaldimines (Table 1). Allylation of the chiral
aldimines (1a-f) derived from benzaldehyde and an
appropriate chiral amine was chosen as a model reaction.
The allylation reaction was carried out in the presence
of 2 equiv of indium powder and 3 equiv of allyl bromide
in absolute methanol as a solvent at room temperature.14
(R)-Methylbenzylamine as well as (S)-phenylalanine
methyl ester and (S)-phenylalaninol gave poor diaste-
reoselectivity (entries 1-3). In contrast, (S)-valinol, with
its more bulky substituent together with a chelating
group, appeared to be a better auxiliary (entry 4). Among
all chiral amines investigated, (S)- and (R)-phenylglyci-
nols were found to give the most impressive results
a Ratio of major and minor isomers as determined by 1H NMR
(400 or 600 MHz). b [R]23D +43.0 (c 1.01, CHCl3). c [R]23D -42.0 (c
1.05, CHCl3) [lit. [R]29 for 2f -42.3 (c 4.00, CHCl3)] (ref 5g).
D
whereby the desired allylation products were isolated in
90% and 92% yield, respectively (entries 5 and 6). The
1
diastereomeric ratios as determined by H NMR spec-
troscopy on a 600 MHz spectrometer were over 15:1. By
comparison of the specific rotation with a literature value,
the (R,R)-homoallylic amine 2f was found to be the major
product derived from the (R)-phenylglycinol auxiliary.
The homoallylic amine derived from (S)-phenylglycinol
possesses the opposite specific rotation value; the struc-
ture of the major isomer was therefore assigned to be 3e
with (S)-configuration at the new stereogenic center.
Having established the most suitable chiral auxiliary,
we next investigated the allylation reaction of a variety
of chiral aldimines derived from (R)-phenylglycinol (Table
2). We were pleased to find that the reaction is applicable
to a wide range of substrates including those bearing a
hydroxy group or heterocycles to give the products in good
yields and excellent diastereoselectivity.
It is also interesting to observe that imines derived
from aromatic aldehydes bearing ortho substituents
(entries 2, 5, 7, and 12) consistently gave lower selectivity.
It should be noted that indium-mediated allylation of
imines derived from 5-formyluracil and chiral â-amino
alcohols was reported to give high diastereoselectivity
while the corresponding 2,4-dimethoxypyrimidine deriva-
tives gave very poor diastereoselectivity.15 The authors
invoked the mutual chelation between the uracil CdO,
CdN, and OH group to explain the difference and
concluded that an additional coordinating element on the
substrate is essential to give high diastereoselectivity.
Under our conditions, however, it appeared that the
presence of an additional chelating group is not required.
Good yield and excellent diastereoselectivity were ob-
served in reactions with imines derived from aliphatic
aldehydes as well (Table 3). The successful allylation of
(7) Cook, G. R.; Maity, B. C.; Kargbo, R. Org. Lett. 2004, 6, 1741-
1743.
(8) Vilaivan, T.; Winotapan, C.; Shinada, T.; Ohfune, Y. Tetrahedron
Lett. 2001, 42, 9073-9076.
(9) For a review of indium in organic synthesis, see: Cintas, P.
Synlett 1995, 1087-1095.
(10) Indium was shown to facilitate nucleophilic addition to the Cd
N bond as compared to the CdO bond: Loh, T.-P.; Liung, S. B. K. W.;
Tan, K.-L.; Wei, L.-L. Tetrahedron 2000, 56, 3227-3237.
(11) (a) Loh, T.-P.; Ho, D. S.-C.; Xu, K.-C.; Sim, K.-Y. Tetrahedron
Lett. 1997, 38, 865-868. (b) Loh, T.-P.; Chen, S.-L. Org. Lett. 2002, 4,
3647-3650.
t
(12) Ozone and BuOCl have been used successfully to oxidatively
cleave amino acid auxiliaries. See: Namba, K.; Kawasaki, M.; Takada,
I.; Iwama, S.; Izumida, M.; Shinada, T.; Ohfune, Y. Tetrahedron Lett.
2001, 42, 3733-3736.
(13) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835-875.
(14) Decreasing the amounts of indium and/or allyl bromides
resulted in poorer yield. Ethanol and 2-propanol were successfully used
as solvents but the reaction rates were considerably slower than
methanol while the diastereoselectivities were similar.
(15) Kumar, S.; Kumar, V.; Singh, S.; Chimni, S. S. Tetrahedron
Lett. 2001, 42, 5073-5075.
J. Org. Chem, Vol. 70, No. 9, 2005 3465

Vilaivan et al.
TABLE 2. Addition of Allyl Indium Reagent to Chiral Aldimines Derived from Aromatic Aldehydes and
(R)-Phenylglycinol
entry
substrate
product
R
yield (%)
dra
[R]24D, CHCl3
1
2
1g
1h
1i
2g
2h
2i
4-MeC6H4-
2-MeOC6H4-
3-MeOC6H4-
4-MeOC6H4-
2-HOC6H4-
3-HOC6H4-
2-ClC6H4-
3-ClC6H4-
4-ClC6H4-
2-pyridyl-
2-furyl-
94
82
84
93
49
88
83
87
95
91
90
81
93:7
87:13
91:9
-28.5 (c 1.02)
-45.2 (c 1.04)
-39.6 (c 1.11)
-24.4 (c 1.20)
-63.6 (c 0.89)
-36.1 (c 0.97)
-36.2 (c 1.02)
-22.1 (c 1.13)
-18.3 (c 1.04)
-15.2 (c 0.99)
-5.7 (c 1.05)
-75.0 (c 1.00)
3
4
1j
2j
92:8
5
1k
1l
2k
2l
89:11
92:8
6
7
1m
1n
1o
1p
1q
1r
2m
2n
2o
2p
2q
2r
89:11
97:3
8
9
98:2
10
11
12
94:6
>98:2b
81:19
1-naphthyl
a Determined by 1H NMR (400 MHz) integration. b Only one set of 1H and 13C signals was observed.
TABLE 3. Addition of Allyl Indium Reagent to Chiral Aldimines Derived from Aliphatic Aldehydes and
(R)-Phenylglycinol
entry
substrate
product
R
yield (%)
dra
[R]24D, CHCl3
1
2
4
5
6
7
8
9
1s
2s
iPr-
tBu-
Cy-
96
84
78
80
78
73
90
59
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
96:4
-122.9 (c 0.98)
-135.7 (c 0.98)
-78.9 (c 1.07)
-91.4 (c 1.51)
-73.8 (c 0.66)
-61.6 (c 0.93)
+28.7 (c 1.03)
-45.6 (c 1.02)
1t
2t
1u
1v
1w
1x
1y
1z
2u
2v
2w
2x
2y
2z
nPr-
nBu-
nHex-
cinnamyl-
PhCH2CH2-
>98:2
a Determined by 1H NMR (400 MHz) integration. With the exception of 2y, only one set of 1H and 13C signals was observed for each
compound.
N/O atoms of the substrate.17 A similar model has been
previously proposed for indium-mediated allylation of
imines bearing an L-valinol auxiliary.5f The high level of
stereoselectivity and very fast reaction rate observed in
protic solvents such as methanol are remarkable. It is
possible that methanol is also able to coordinate to the
indium metal center in the transition state besides the
internal hydroxymethyl group itself. It can also im-
mediately protonate the metal amide initially formed
from allylation therefore preventing further side reac-
tions. These features may play an important role in the
stereochemical outcomes and rate acceleration of the
present addition reaction.18 The involvement of a discrete
SCHEME 2
aliphatic imines bearing one or two R-hydrogens reflects
the advantage of low basicity of organoindium reagents
compared to other traditional organometallic reagents.
Several transition state models based on metal chela-
tion have been proposed to explain the stereochemical
outcome of the addition of imines derived from phenyl-
glycinol.16 It is well-known that the starting imines exist
as an equilibrium mixture between the imine and ox-
azolidine forms. The effect of the equilibrium, which is
dependent on several parameters including the solvent
and the nature of the R group, on the stereoselectivity
has not been well clarified. A simple transition model that
is consistent with the results observed is shown in
Scheme 2 whereby the imine assumes E-configuration
and addition of the allyl group takes place from the
opposite side of the phenyl group, which is the Re face
for chiral imines derived from (R)-phenylglycinol. The
high diastereoselectivity could be explained by formation
of the rigid chelated transition state between indium and
1
allylindium species was suggested by H NMR experi-
ments, although the radical pathway cannot be totally
ruled out as a possibility. When a suspension of indium
powder in CD3OD was treated with allyl bromide (1.5
equiv), the indium was dissolved with some gas evolution.
The 1H NMR spectrum of the reaction mixture revealed
two new allylic CH2 signals at 1.92 and 1.68 ppm at a
(17) Investigating a CPK model of the transition state suggested
that the rotating phenyl group carrying ortho substituents can hinder
the approach of the allyl group from the Re-face in Scheme 2 to some
extent, hence might be the cause of low diastereoselectivity.
(18) Rate enhancement of allylation of CdO and CdN in the
presence of proton sources has previously been observed: (a) Cokley,
T. M.; Harvey, P. J.; Marshall, R. L.; McCluskey, A.; Young, D. J. J.
Org. Chem. 1997, 62, 1961-1964. (b) Yasuda, M.; Fujibayashi, T.;
Baba, A. J. Org. Chem. 1998, 63, 6401-6404. (c) Tussa, L.; Lebreton,
C.; Mosset, P. Chem. Eur. J. 1997, 3, 1064-1070.
(16) Alvaro, G.; Savoia, D. Synlett 2002, 651-673.
3466 J. Org. Chem., Vol. 70, No. 9, 2005

Synthesis of Optically Active Homoallylic Amines
SCHEME 3
of optical purity. The partial racemization observed in
this experiment suggested that the diastereofacial dis-
crimination during the rearrangement was incomplete.
Possible causes for this include geometrical equilibrium
of aldimines (E/Z), unfavorable transition states includ-
ing an axial substituent in the chair transition states,
or involvement of boat transition states.
To overcome the problem of the aza-Cope rearrange-
ment leading to both poor yield and racemization, the
standard cleavage protocol was modified with the aim
to avoid exposure of the intermediate Schiff base to high
temperature, and to keep the lifetime of this intermediate
the shortest. After several experiments, we were pleased
to find that hydroxylamine hydrochloride is the reagent
of choice to assist cleavage of the Schiff base at low
tempearture.6 According to the new protocol, the homoal-
lylic amines 2 bearing the (R)-phenylglycinol auxiliary
were treated with a slight excess of Pb(OAc)4 in 1:1 CH2-
Cl2/MeOH at 0 °C for 30 min. An excess of a methanolic
solution of hydroxylamine hydrochloride (10 equiv) was
then added at 0 °C without isolation of the intermediate
imine from the lead salts. After the solution was stirred
for another 30 min, the organic solvents were removed
in vacuo and the products were isolated as their N-Boc
derivatives 4. In this way, starting from 0.5 mmol of the
imines 1f and 1s prepared in situ, the N-Boc homoallylic
amines 4f and 4s were obtained in 75% and 55% overall
yield, respectively, with only single chromatographic
purification at the end of the reaction sequences. Fur-
thermore, the chiral integrity of the products was almost
completely preserved as the amides derived from coupling
of N-Boc-deprotected 4f and 4s with (R)- and (S)-BPG22
showed only one set of the 1H NMR spectrum without a
detectable level of the other diastereomer. A more
quantitative analysis of enantiomeric ratio was per-
formed by 1H NMR and HPLC analysis of the corre-
sponding (R)- and (S)-MTPA derivatives, which also
showed no significant level of racemization. This auxil-
iary clevage condition therefore offered a significant
improvement compared to the standard condition,5a,21
which provided 4f and 4s in low optical purities (er )
70:30 and 80:20, respectively). The new cleavage method
was tested with all remaining compounds 2. In most
cases, fair to good overall yield and enantiomeric purity
of the N-Boc homoallylic amines 4 were obtained (Table
4). The only exceptions were hydroxyphenyl derivatives
(2k and 2l), which gave complex mixtures containing
none of the desired product after Pb(OAc)4 cleavage.
ratio of about 5:1. Addition of N-benzylidenebenzylamine
to this solution caused rapid disappearance of the signal
at 1.92 ppm while a new signal due to allylic CH2 of the
homoallylic amine appeared at 2.80 and 2.95 ppm. The
allylic species being responsible for the signal at 1.92 ppm
is probably the same as allylindium(I) proposed by Chan
as a possible intermediate in indium-mediated Barbier-
type allylation of aldehydes in water.19
The chiral auxiliary was removed to give the free homo-
allylic amines. Among cleavage conditions tried, oxidative
cleavage of the auxiliary by Pb(OAc)4 was found to be
the best condition.20 It was disappointing, however, that
the standard cleavage protocol involving Pb(OAc)4 treat-
ment followed by acid hydrolysis at room temperature5a,21
gave a rather poor yield, and led to an unacceptable level
of byproducts. When the amine 2s (R ) iPr) was subjected
to the above condition, 2-isopropyl-3-butenamine (5) and
2-phenyl-3-butenamine (6) were isolated (as their N-Boc
derivatives) in 59% and 30% yield, respectively. To
determine the optical purity, 5 and 6 were transformed
into the corresponding Boc-(R)- and Boc-(S)-phenylglycine
amide (BPG) derivatives that were analyzed by 1H
NMR.22 Both 5 and 6 were found to have low optical
purities. Interestingly, the major enantiomer of 6 was
found to possess (S)-configuration, which is opposite to
that of the major enantiomer of 5 and the starting amine
2s.
The above results include two aspects on the genera-
tion of 6 and racemization of both 5 and 6. A proposed
reaction mechanism giving the byproduct 6 that involves
a 2-aza-Cope rearrangement is illustrated in Scheme 3.23
Cleavage of the chiral auxiliary from 2s gave benzaldi-
mine A that is in equilibrium with another imine B via
the aza-Cope rearrangement. Hydrolysis of A and B
would afford 5 and 6, respectively. According to the
product ratio 5:6 of ca. 2:1, the equilibrium would
preferentially shift to A. When the rearrangement pro-
The absolute configurations of the N-Boc homoallylic
1
amines 4f, 4p, 4s, 4u, and 4y were determined by H
NMR analysis of their BPG derivatives22 to be (R). The
absolute configuration of the N-Boc homoallylic amine
4e derived from the (S)-phenylglycinol auxiliary was
similarly determined, and was shown to be (S). The
results indicated that the type of R group (aliphatic,
aromatic) and substituents on the aromatic ring have
virtually no effect on the selectivity of the reaction.
i
ceeds in a stable chair transition state whereby the Pr
and Ph groups occupy equatorial positions, the chirality
transfer between the two should take place without loss
(19) Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228-3229.
(20) Cleavage conditons attempted: H5IO6/MeNH2, hydrogenolysis,
O-tosylation or N-bromination followed by base-catalyzed elimination.
In all cases the reactions were incomplete and several byproducts were
formed.
The present method offers significant advantages
compared to the previously reported methods including
the use of an inexpensive chiral auxiliary, fast reaction
rates, simple reaction and workup conditions, good and
predictable diastereoselectivity for a range of substrates,
and the ease of removal of the auxiliary.
(21) Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1997, 62, 5537-
5541.
(22) Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem. 1999, 64,
4669-4675.
(23) The aza-Cope rearrangement of similar substrates has been
briefly mentioned in ref 6.
J. Org. Chem, Vol. 70, No. 9, 2005 3467

Vilaivan et al.
TABLE 4. Removal of the Auxiliary from the Homoallylic Amines
entry
substrate
product
R
yield (%)a
erb
[R]24D, CHCl3
1
2
2f
4f
Ph-
75
71
68
63
71
70
69
72
54
67
60
55
52
63
58
51
60
68
51
98:2
94:6
88:12
91:9
93:7
91:9
93:7
94:6
95:5
N.D.c
82:18
96:4
97:3
>99:1
96:4
>99:1
95:5
96:4
99:1
+45.0 (c 1.00)
+60.0 (c 1.00)
+63.0 (c 1.00)
+41.3 (c 0.80)
+76.0 (c 1.00)
+49.0 (c 1.00)
+56.0 (c 1.00)
+58.0 (c 1.00)
+15.3 (c 0.72)
+93.0 (c 1.00)
+38.6 (c 0.70)
-15.6 (c 0.90)
-21.4 (c 0.70)
-16.0 (c 1.00)
-18.9 (c 0.90)
-22.1 (c 0.68)
-12.2 (c 0.90)
+43.0 (c 1.00)
-17.1 (c 0.70)
2g
2h
2i
4g
4h
4i
4-MeC6H4-
2-MeOC6H4-
3-MeOC6H4-
4-MeOC6H4-
2-ClC6H4-
3-ClC6H4-
4-ClC6H4-
2-pyridyl-
2-furyl-
3
4
5
2j
4j
6
2m
2n
2o
2p
2q
2r
2s
2t
4m
4n
4o
4p
4q
4r
4s
4t
7
8
9
10
11
12
13
14
15
16
17
18
19
1-naphthyl
iPr-
tBu-
2u
2v
2w
2x
2y
2z
4u
4v
4w
4x
4y
4z
Cy-
nPr-
nBu-
nHex-
cinnamyl-
PhCH2CH2-
a Yield refers to isolated overall yield (5 steps) starting from aldehydes and (R)-phenylglycinol b Ratio of major:minor enantiomers as
determined by HPLC or 1H NMR (400 MHz) analyses of the crude products obtained from 4, after removal of N-Boc group by TFA and
derivatization with (R)- and (S)-MTPA. c The homoallylic amine 4q decomposed on treatment with TFA before derivatization with MTPA.
(m, 1H), 5.82 (m, 1H), 6.80 (d, J ) 7 Hz, 1H), 6.96 (t, J ) 7
Hz, 1H), 7.28 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 39.9, 55.0,
56.6, 61.7, 65.2, 110.5, 116.7, 120.4, 127.2, 127.3, 128.0, 128.3,
131.1, 136.0, 141.8, 157.1; MS (ESI+) m/z 298.1 (100). Anal.
Calcd for C19H23NO2: C, 76.73; H, 7.80; N, 4.71. Found: C,
76.67; H, 7.65; N, 4.72.
(2R)-2-Phenyl-2-[(1′R)-1′-(3′′-methoxyphenyl)but-3′-enyl-
amino]ethanol (2i). Yellow oil (dr 91:9); 1H NMR (400 MHz,
CDCl3) δ 2.58 (m, 2H), 3.62 (dd, J ) 11.7, 4.0 Hz, 1H), 3.79 (t,
J ) 7 Hz, 1H), 3.81 (s, 3H), 3.90 (dd, J ) 7.0, 2.1 Hz, 2H),
5.15 (m, 1H), 5.78 (m, 1H), 6.82 (m, 3H), 7.32 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 41.3, 55.2, 60.0, 61.2, 65.7, 112.5, 112.8,
117.5, 119.6, 127.3, 127.5, 128.5, 129.4, 135.0, 141.3, 145.4,
159.6; HRMS(FAB+) Calcd for C19H23NO2‚H+ 298.1807, found
298.1800.
(2R)-2-Phenyl-2-[(1′R)-1′-(4′′-methoxyphenyl)but-3′-enyl-
amino]ethanol (2j). Colorless solid (dr 92:8); mp 44-45 °C;
1H NMR (400 MHz, CDCl3) δ 2.58 (m, 1H), 2.62 (m, 1H), 2.76
(br s, 1H), 3.62 (dd, J ) 10.7, 7.1 Hz, 1H), 3.78 (dd, J ) 10.8,
4.6 Hz, 2H), 3.82 (s, 3H), 3.94 (dd, J ) 6.8, 4.4 Hz, 2H), 5.15
(m, 2H), 5.78 (m, 1H), 6.84 (d, J ) 7.0 Hz, 2H), 7.21-7.40 (m,
7H); 13C NMR (100 MHz, CDCl3) δ 41.2, 55.1, 59.0, 61.2, 65.5,
113.6, 117.1, 127.3, 127.5, 128.3, 128.6, 135.0, 135.6, 141.2,
158.5; HRMS(CI+) calcd for C19H23NO2‚H+ 298.1807, found
298.1817. Anal. Calcd for C19H23NO2: C, 76.74; H, 7.80; N,
4.71. Found: C, 76.62; H, 7.82; N, 4.71.
In conclusion, we have demonstrated a highly diaste-
reoselective allylation of chiral aldimines derived from
optically active phenylglycinol mediated by indium metal
in alcoholic solvents. We have also developed a racem-
ization-free protocol for removal of the chiral auxiliary.
The simplicity and compatibility to a variety of functional
groups of the stereoselective indium-mediated allylation
described herein should provide a convenient access to
optically active homoallylic amines.
Experimental Section
General Procedure for the Allylation of Aldimines. To
a mixture of the imine (1.0 mmol) and indium powder (288
mg, 2.0 mmol) in absolute methanol (5 mL) was added allyl
bromide (3.0 mmol). The reaction was stirred vigorously at
room temperature until all the metal had dissolved (30 min
to 2 h), at which time TLC indicated complete reaction. The
reaction mixture was diluted with 10% aqueous NaHCO3 and
extracted with ethyl acetate. The product was purified by flash
column chromatography on silica gel, using hexanes-ethyl
acetate as eluent.
(2R)-2-Phenyl-2-[(1′R)-1′-(4′′-methylphenyl)but-3′-enyl-
amino]ethanol (2g). White solid (dr 93:7); mp 66-68 °C; 1H
NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 2.57 (m, 2H), 3.62 (dd,
J ) 10.6, 6.9 Hz, 1H), 3.82 (m, 2H), 3.95 (m, 1H), 5.12 (m,
2H), 5.76 (m, 1H), 7.30 (m, 4H), 7.38 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 21.1, 41.3, 59.3, 61.2, 65.5, 117.3, 127.0, 127.2,
127.4, 128.6, 129.1, 135.1, 136.7, 140.6, 141.3; MS (ESI+) m/z
282.2 (100). Anal. Calcd for C19H23NO: C, 81.10; H, 8.24; N,
4.98. Found: C, 80.90; H, 8.41; N, 5.10.
(2R)-2-Phenyl-2-[(1′R)-1′-(2′′-hydroxyphenyl)but-3′-enyl-
1
amino]ethanol (2k). Colorless oil (dr 89:11); H NMR (400
MHz, CDCl3) δ 2.62 (m, 2H), 3.81-4.00 (m, 4H), 5.24 (m, 2H),
5.82 (m, 1H), 6.78 (m, 2H), 6.96 (d, J ) 7.5 Hz, 1H), 7.16 (t, J
) 7 Hz, 1H), 7.26 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 40.1,
60.4, 61.2, 64.2, 116.9, 119.0, 125.5, 127.3, 127.7, 128.0, 128.4,
128.6, 128.9, 134.4, 139.3, 157.2; HRMS (ESI+) calcd for
C18H21NO2‚H+ 284.1651, found 284.1638. Anal. Calcd for
C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C, 76.08; H,
7.45; N, 4.97.
(2R)-2-Phenyl-2-[(1′R)-1′-(2′′-methoxyphenyl)but-3′-enyl-
amino]ethanol (2h). Yellow oil (dr 87:13); 1H NMR (400 MHz,
CDCl3) δ 2.61 (m, 2H), 2.90 (br s, 1H), 3.62 (dd, J ) 10.4, 6.4
Hz, 1H), 3.74 (s, 3H), 3.82 (m, 2H), 4.18 (t, J ) 7 Hz, 1H), 5.16
3468 J. Org. Chem., Vol. 70, No. 9, 2005

Synthesis of Optically Active Homoallylic Amines
(2R)-2-Phenyl-2-[(1′R)-1′-(3′′-hydroxyphenyl)but-3′-enyl-
amino]ethanol (2l). Colorless oil (dr 92:8); 1H NMR (400
MHz, CDCl3) δ 2.56 (m, 2H), 3.65 (m, 2H), 3.80 (m, 1H), 3.98
(m, 1H), 4.60 (br s, 1H), 5.06 (m, 2H), 5.66 (m, 1H), 6.78 (m,
3H), 7.17-7.38 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 40.7,
59.6, 61.2, 65.4, 114.3, 114.6, 117.6, 119.2, 127.3, 127.7, 128.6,
129.6, 134.8, 140.4, 144.9, 156.4; HRMS (ESI+) calcd for
C18H21NO2‚H+ m/z 284.1651, found 284.1661.
(2R)-2-Phenyl-2-[(1′R)-1′-(2′′-chlorophenyl)but-3′-enyl-
amino]ethanol (2m). White solid (dr 89:11); mp 67-68 °C;
1H NMR (400 MHz, CDCl3) δ 2.58 (m, 2H), 2.74 (br s, 1H),
3.62 (dd, J ) 10.4, 6.1 Hz, 1H), 3.83 (m, 2H), 4.42 (t, J ) 6.4
Hz, 1H), 5.16 (m, 2H), 5.82 (m, 1H), 7.16-7.42 (m, 9H); 13C
NMR (100 MHz, CDCl3) δ 40.5, 56.3, 62.0, 65.5, 117.9, 126.9,
127.3, 127.4, 128.4, 129.7, 133.2, 134.5, 140.9, 141.3; HRMS
(ESI+) calcd for C18H20ClNO‚H+ 302.1312, found 302.1311.
Anal. Calcd for C18H20ClNO: C, 71.63; H, 6.68; N, 4.64.
Found: C, 71.46; H, 6.88; N, 4.64.
(2R)-2-Phenyl-2-[(1′R)-1′-(3′′-chlorophenyl)but-3′-enyl-
amino]ethanol (2n). White solid (dr 97:3); mp 67-68 °C; 1H
NMR (400 MHz, CDCl3) δ 2.52 (m, 2H), 3.62 (dd, J ) 11.0, 7.1
Hz, 1H), 3.76 (m, 2H), 3.88 (dd, J ) 2.4, 7.0 Hz, 1H), 5.09 (m,
2H), 5.71 (m, 1H), 7.10-7.40 (m, 9H); 13C NMR (100 MHz,
CDCl3) δ 41.2, 59.8, 62.1, 65.9, 118.0, 127.2, 127.6, 128.5, 128.6,
132.7, 134.4, 140.9, 145.9. Anal. Calcd for C18H20ClNO: C,
71.63; H, 6.68; N, 4.64. Found: C, 70.68; H, 6.54; N, 4.66.
(2R)-2-Phenyl-2-[(1′R)-1′-(4′′-chlorophenyl)but-3′-enyl-
amino]ethanol (2o). White solid (dr 98:2); mp 68-70 °C; 1H
NMR (400 MHz, CDCl3) δ 2.56 (m, 2H), 3.60 (dd, J ) 10.4, 6.8
Hz, 1H), 3.78 (m, 2H), 3.90 (m, 1H), 5.11 (m, 2H), 5.71 (m,
1H), 7.08-7.38 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 41.4,
59.4, 61.6, 65.8, 117.8, 127.1, 127.5, 128.4, 128.6, 132.7, 134.5,
140.9, 142.2; MS (ESI+) m/z 302.1 (100). Anal. Calcd for
C18H20ClNO: C, 71.63; H, 6.68; N, 4.64. Found: C, 71.61; H,
6.70; N, 4.65.
(2R)-2-Phenyl-2-[(1′R)-1-(2′′-pyridyl)but-3′-enylamino]-
ethanol (2p). Yellow oil (dr 94:6); 1H NMR (400 MHz, CDCl3)
δ 2.53 (m, 2H), 3.22 (br s, 1H), 3.54 (dd, J ) 10.6, 7.6 Hz, 1H),
3.62 (m, 1H), 3.78 (m, 2H), 4.95 (m, 2H), 5.60 (m, 1H), 6.90-
7.10 (m, 7H), 7.40 (t, J ) 7.9 Hz, 1H), 8.37 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 40.5, 61.3, 62.8, 66.1, 117.6, 121.8, 122.3,
127.2, 127.4, 128.3, 134.8, 136.1, 141.0, 149.0, 162.4; HRMS
(ESI+) calcd for C17H20N2O‚H+ 269.1654, found 269.1649.
Anal. Calcd for C17H20N2O: C, 76.09; H, 7.51; N, 10.44.
Found: C, 74.83; H, 7.75; N, 10.36.
(2R)-2-Phenyl-2-[(1′R)-1′-(2′′-furyl)but-3′-enylamino]-
ethanol (2q). Yellow oil (dr > 98:2); 1H NMR (400 MHz,
CDCl3) δ 2.42 (m, 2H), 2.58 (br s, 1H), 3.43 (dd, J ) 10.8, 7.4
Hz, 1H), 3.62 (dd, J ) 10.8, 4.5 Hz, 1H), 3.76 (m, 2H), 4.98
(m, 2H), 5.58 (m, 1H), 5.98 (d, J ) 3.1 Hz, 1H), 6.15 (m, 1H),
7.10-7.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 38.3, 53.7,
61.8, 66.0, 106.5, 109.9, 110.0, 117.7, 127.2, 127.5, 128.5, 134.5,
140.8, 141.5, 155.9; MS (ESI+) m/z 258.1 (100). Anal. Calcd
for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.72;
H, 7.43; N, 5.45.
35.9, 62.4, 62.6, 66.9, 115.8, 127.7, 128.6, 129.7, 138.4, 141.0;
HRMS (CI+) calcd for C16H25NO‚H+ 248.2014, found 248.1999.
(2R)-2-Phenyl-2-[(1′R)-1′-cyclohexylbut-3′-enylamino]-
ethanol (2u). Colorless oil (dr > 98:2 determined by 1H NMR);
1H NMR (400 MHz, CDCl3) δ 0.90-1.84 (m, 11H), 2.23 (m,
2H), 2.38 (m, 1H), 3.54 (dd, J ) 10.5, 8.5 Hz, 1H), 3.66 (dd, J
) 10.5, 4.5 Hz, 1H), 3.92 (dd, J ) 8.5, 4.5 Hz, 1H), 5.14 (m,
2H), 5.82 (m, 1H), 7.23-7.38 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 26.4, 28.8, 29.2, 34.8, 40.8, 58.7, 61.8, 66.8, 116.7,
127.4, 128.4, 136.0, 141.3; HRMS (CI+) calcd for C18H27NO‚
H+ 274.2171, found 274.2192.
(2R)-2-Phenyl-2-[(1′S)-1′-propylbut-3′-enylamino]-
1
ethanol (2v). Colorless oil (dr > 98:2); H NMR (400 MHz,
CDCl3) δ 0.84 (m, 3H), 1.22-1.38 (m, 4H), 2.22 (m, 2H), 2.57
(m, 1H), 3.56 (m, 1H), 3.67 (dd, J ) 10.5, 4.5, 1H), 3.93 (dd, J
) 8.6, 4.5 Hz, 1H), 5.15 (m, 2H), 5.82 (m, 1H), 7.30-7.40 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 14.1, 19.0, 37.0, 37.8, 53.5,
61.6, 65.8, 117.2, 127.2, 127.5, 128.6, 135.2, 141.3; MS (ESI+)
m/z 234.2 (100). Anal. Calcd for C15H23NO: C, 77.21; H, 9.93;
N, 6.00. Found: C, 77.51; H, 10.26; N, 5.71.
(2R)-2-Phenyl-2-[(1′S)-1′-butylbut-3′-enylamino]-
1
ethanol (2w). Colorless oil (dr > 98:2); H NMR (400 MHz,
CDCl3) δ 0.84 (m, 3H), 1.18-1.42 (m, 6H), 2.23 (m, 2H), 2.58
(m, 1H), 3.58 (m, 1H), 3.71 (dd, J ) 10.6, 4.6, 1H), 3.92 (dd, J
) 8.6, 4.5 Hz, 1H), 5.18 (m, 2H), 5.82 (m, 1H), 7.23-7.38 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.7, 28.0, 34.4, 37.7,
53.7, 61.7, 66.8, 117.2, 127.2, 127.5, 128.6, 135.2, 141.2; MS
(ESI+) m/z 248.2 (100). Anal. Calcd for C16H25NO: C, 77.68;
H, 10.19; N, 5.66. Found: C, 77.51; H, 10.26; N, 5.72.
(2R)-2-Phenyl-2-[(1′S)-1′-hexylbut-3′-enylamino]-
1
ethanol (2x). Colorless oil (dr > 98:2); H NMR (400 MHz,
CDCl3) δ 0.77 (t, J ) 7 Hz, 3H), 1.08-1.42 (m, 10H), 2.22 (m,
2H), 2.38 (br s, 1H), 2.58 (m, 1H), 3.58 (dd, J ) 10.7, 8.8 Hz,
1H), 3.74 (dd, J ) 10.8, 4.6 Hz, 1H), 3.92 (dd, J ) 8.6, 4.4 Hz,
1H), 5.15 (m, 2H), 5.82 (m, 1H), 7.28 and 7.38 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 14.0, 22.5, 25.7, 29.2, 31.7, 34.7,
37.8, 53.6, 61.6, 66.8, 117.1, 127.2, 127.4, 128.5, 135.2, 141.3;
HRMS (CI+) calcd for C18H29NO‚H+ 276.2328, found 276.2323.
(2R)-2-Phenyl-2-[(1′S)-1′-(2′′-phenylethyl)but-3′-enyl-
amino]ethanol (2z). Yellow oil (dr > 98:2); 1H NMR (400
MHz, CDCl3) δ 1.75 (m, 2H), 2.38 (m, 2H), 2.56 (m, 1H), 2.66
(m, 2H), 3.58 (dd, J ) 9.8, 8.5 Hz, 1H), 3.76 (dd, J ) 10.5, 4.4
Hz, 1H), 3.96 (dd, J ) 8.8, 4.6 Hz, 1H), 5.16 (m, 2H), 5.82 (m,
1H), 7.05-7.40 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 32.1,
36.7, 37.8, 53.6, 61.8, 66.9, 117.4, 125.7, 127.3, 127.7, 128.4,
128.6, 134.9, 141.2, 142.2; HRMS (CI+) calcd for C20H25NO‚
H+ 296.2014, found 296.2007.
General Procedure for the Oxidative Cleavage of the
Auxiliary and Boc-Protection.To a solution of the amino
alcohol in CH2Cl2/MeOH (1:1) at 0 °C was added, in one
portion, 1.2 equiv of lead tetraacetate [Pb(OAc)4]. The reaction
mixture was stirred for 30 min, at which time TLC indicated
complete reaction. Then 10 equiv of hydroxylamine hydrochlo-
ride (NH2OH.HCl) was added and the mixture was stirred for
another 30 min. The residue remained after removal of the
solvents was washed with hexanes and suspended in CH2Cl2
followed by filtration of the lead precipitates. To the CH2Cl2
solution of the amine salt was added Et3N (2.0 equiv) and
Boc2O (1.2 equiv). The reaction was stirred for 2 h and then
3-morpholinopropylamine (1 equiv) was added as a scavenger
for the excess Boc2O and the stirring was continued for another
1 h. The solution was diluted with ethyl acetate and extracted
with 5% HCl. The organic layer was dried with anhydrous
Na2SO4 and evaporated. The crude product was purified by
flash column chromatography on silica gel with hexanes-ethyl
acetate as eluent.
(2R)-2-Phenyl-2-[(1′R)-1′-(1′′-naphthyl)but-3′-enyl-
1
amino]ethanol (2r). Colorless oil (dr 81:19); H NMR (400
MHz, CDCl3) δ 2.58 (br s, 1H), 2.80 (m, 2H), 3.62 (m, 1H), 3.86
(m, 1H), 4.02 (m, 1H), 4.77 (t, 1H), 5.16 (m, 2H), 5.82 (m, 1H),
7.25-8.08 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 40.6, 54.6,
61.5, 65.8, 117.6, 123.0, 124.0, 125.4, 125.5, 126.0, 127.3, 127.6,
127.8, 128.6, 129.1, 131.2, 134.0, 135.0, 139.2, 141.1; HRMS
(CI+) calcd for C22H23NO‚H+ 317.1780, found 317.1795. Anal.
Calcd for C22H23NO: C, 83.24; H, 7.80; N, 4.41. Found: C,
82.90; H, 7.85; N, 4.72.
(2R)-2-Phenyl-2-[(1′R)-1′-tert-butylbut-3′-enylamino]-
ethanol (2t). Colorless oil (dr > 98:2); 1H NMR (400 MHz,
CDCl3) δ 0.77 (s, 9H), 2.18 (m, 2H), 2.38 (m, 1H), 2.60 (br s,
1H), 3.60-3.65 (m, 2H), 3.98 (dd, J ) 8.3, 4.6 Hz, 1H), 5.00
(d, J ) 9.1 Hz, 1H), 5.02 (d, J ) 16.0 Hz, 1H), 5.82 (m, 1H),
7.20-7.25 (5H, m); 13C NMR (100 MHz, CDCl3) δ 27.0, 35.1,
General Procedure for Determination of Enantio-
meric Purities of 4. Trifluoroacetic acid (0.2 mL) was added
to the solution of the Boc-protected homoallylamine (4) in CH2-
Cl2 (5.0 mg in 0.2 mL). After standing at room temperature
for 15 min, the solvents were removed by a gentle stream of
nitrogen. The residual amine salt was dissolved in CH2Cl2 (1.0
J. Org. Chem, Vol. 70, No. 9, 2005 3469

Vilaivan et al.
mL) and then treated with Et3N (10 µL) and (R)- or (S)-
Mosher’s acid chloride (5 µL). TLC indicated complete reaction
after 30 min at room temperature. The crude product was
purified by acid-base extraction and the (R)- and (S)-MTPA
amides analyzed by normal phase HPLC (150 × 4.6 mm2 silica
gel column, 3 µm particle size) with hexanes-iPrOH as eluants
and UV detection at 254 nm. When the HPLC peaks were not
well separated, the enantiomeric ratio was estimated by
integration of 1H NMR signals of the diastereomeric MTPA
amides at 400 MHz.
89-90 °C; 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 2.50 (m,
2H), 4.73 (br m, 1H), 4.95 (br d, J ) 6.8 Hz, 1H), 5.14 (m, 2H),
5.67 (m, 1H), 7.22 (d, J ) 8.4, Hz, 2H), 7.32 (d, J ) 8.4, Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 28.4, 41.1, 53.4, 79.7, 118.6,
127.6, 128.6, 132.7, 133.5, 141.1, 155.1; HRMS (FAB+) calcd
for C15H20O2NCl‚H+ m/z 282.1261, found 282.1258.
N-tert-Butoxycarbonyl-(R)-2-pyridylbut-3-enamine (4p).
Yellow oil (er 95:5 determined by 1H NMR); 1H NMR (400
MHz, CDCl3) δ 1.46 (s, 9H), 2.61 (m, 2H), 4.83 (br m, 1H), 5.06
(m, 2H), 5.68 (m, 1H), 7.18-7.25 (m, 2H), 7.66 (m, 1H), 8.58
(d, J ) 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 28.4, 40.8,
55.0, 79.3, 118.1, 121.9, 122.2, 133.8, 136.5, 149.2, 155.4, 160.1;
HRMS (FAB+) calcd for C14H20O2N2‚H+ m/z 249.1603, found
249.1604.
N-tert-Butoxycarbonyl-(R)-1-phenylbut-3-enamine (4f).
1
White solid (er 98:2 determined by HPLC); mp 76-77 °C; H
NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 2.55 (m, 2H), 4.79 (br
m, 1H), 5.10 (br m, 1H), 5.12 (dd, J ) 10.0, 17.2 Hz, 3H), 5.72
(m, 1H), 7.27-7.38 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 28.4,
41.3, 54.1, 79.4, 118.1, 126.3, 127.1, 128.5, 134.1, 142.4, 155.2;
HRMS (FAB+) calcd for C15H21O2N‚H+ m/z 248.1650, found
248.1649.
N-tert-Butoxycarbonyl-(R)-2-furylbut-3-enamine (4q).
Yellow oil; 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.58 (m,
2H), 4.87 (br m, 1H), 4.93 (br m, 1H), 5.10 (m, 2H), 5.71 (m,
1H), 6.17 (d, J ) 2.8 Hz, 1H), 6.31 (m, 1H), 7.35 (d, J ) 0.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 28.4, 38.6, 48.2, 79.6,
105.9, 110.1, 118.2, 133.6, 141.7, 154.5, 155.1; HRMS (FAB+)
calcd for C13H19O3N‚H+ m/z 238.1443, found 238.1437.
N-tert-Butoxycarbonyl-(R)-1-naphthylbut-3-enamine
(4r). White solid (er 82:18 determined by HPLC): mp 118-
N-tert-Butoxycarbonyl-(R)-1-(4′-methylphenyl)but-3-
enamine (4g). White solid (er 94:6 determined by HPLC); mp
1
93-95 °C; H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.37 (s,
3H), 2.54 (m, 2H), 4.74 (br m, 1H), 4.96 (br m, 1H), 5.12 (m,
2H), 5.71 (m, 1H), 7.17 (d, J ) 8.0 Hz, 2H), 7.20 (d, J ) 8.0
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.1, 28.4, 41.3, 53.8,
79.4, 118.1, 126.2, 129.2, 134.2, 136.7, 139.4, 155.2; HRMS
(FAB+) calcd for C16H23O2N‚H+ m/z 262.1807, found 262.1794.
1
120 °C; H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 2.65-2.86
(m, 2H), 5.07 (br m, 1H), 5.18 (2d, J ) 10.0 and 16.8 Hz, 2H),
5.66 (br m, 1H), 5.79 (m, 1H), 7.48-7.61 (m, 4H), 7.83 (m, 1H),
7.91 (d, J ) 7.6 Hz, 1H), 8.19 (d, J ) 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 28.4, 40.3, 49.8, 79.6, 118.1, 122.6, 123.1,
125.2, 125.7, 126.3, 128.0, 128.9, 130.9, 134.0, 134.2, 137.9,
155.2; HRMS (FAB+) calcd for C19H23O2N‚H+ m/z 298.1807,
found 298.1811.
N-tert-Butoxycarbonyl-(R)-1-(2′-methoxyphenyl)but-3-
enamine (4h). White solid (er 88:12 determined by HPLC);
mp 109-110 °C; 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H),
2.56 (m, 2H), 3.88 (s, 3H), 4.97 (br m, 1H), 4.98 (dd, J ) 10.8,
18.4 Hz, 2H), 5.42 (br d, J ) 8.0 Hz, 1H), 5.72 (m, 1H), 6.89-
6.96 (m, 2H), 7.20 (d, J ) 6.8 Hz, 1H), 7.27 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 28.5, 40.0, 51.9, 55.3, 79.1, 110.8, 117.3,
120.5, 128.1, 128.2, 129.9, 135.0, 155.2, 156.8; HRMS (FAB+)
calcd for C16H23O3N‚H+ m/z 278.1756, found 278.1768.
N-tert-Butoxycarbonyl-(R)-1-isopropylbut-3-enam-
ine (4s). Colorless oil (er 96:4 determined by HPLC); 1H NMR
(400 MHz, CDCl3) δ 0.90 (d, J ) 6.8 Hz, 3H), 0.92 (d, J ) 6.8
Hz, 3H), 1.44 (s, 9H), 1.74 (m, 1H), 2.12 (m, 1H), 2.26 (m, 1H),
3.52 (br m, 1H), 4.37 (br d, J ) 8.0 Hz, 1H), 5.07 (m, 2H), 5.78
(m, 1H); 13C NMR (100 MHz, CDCl3) 17.7, 19.3, 28.4, 31.4,
37.0, 55.1, 78.8, 117.1, 135.0, 155.9; HRMS (CI+) calcd for
C12H23O2N‚H+ m/z 214.1807, found 214.1795.
N-tert-Butoxycarbonyl-(R)-1-tert-butylbut-3-enam-
ine (4t). White solid (er 97:3 determined by HPLC); mp 66-
68 °C; 1H NMR (400 MHz, CDCl3) δ 0.93 (s, 9H), 1.44 (s, 9H),
1.85 (m, 1H), 2.42 (m, 1H), 3.45 (m, 1H), 4.28 (br d, J ) 10.0
Hz, 1H), 5.05 (m, 2H), 5.82 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 26.4, 28.4, 34.7, 35.3, 58.4, 78.8, 116.5, 136.1, 156.2;
HRMS (CI+) calcd for C9H18O2N (M - tBu + 2H) m/z 172.1337,
found 172.1343.
N-tert-Butoxycarbonyl-(R)-1-(3′-methoxyphenyl)but-3-
1
enamine (4i). White solid (er 91:9 determined by H NMR);
mp 87-89 °C; 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.54
(m, 2H), 3.83 (s, 3H), 4.75 (br m, 1H), 4.93 (br m, 1H), 5.12
(m, 2H), 5.71 (m, 1H), 6.80-6.90 (m, 3H), 7.28 (t, J ) 8.0 Hz
1H); 13C NMR (100 MHz, CDCl3) δ 28.4, 41.2, 54.0, 55.2, 79.5,
112.1, 112.3, 118.2, 118.5, 129.5, 134.0, 144.1, 155.2, 159.7;
HRMS (FAB+) calcd for C16H23O3N‚H+ m/z 278.1756, found
278.1772.
N-tert-Butoxycarbonyl-(R)-1-(4′-methoxyphenyl)but-3-
1
enamine (4j). White solid (er 93:7 determined by H NMR);
mp 105-107 °C; 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H),
2.53 (m, 2H), 3.82 (s, 3H), 4.71 (br m, 1H), 4.90 (br m, 1H),
5.10 (dd, J ) 10.0, 17.2 Hz, 2H), 5.70 (m, 1H), 6.88 (d, J ) 8.4
Hz, 2H), 7.21 (d, J ) 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 28.4, 41.2, 53.5, 55.2, 79.4, 113.8, 118.0, 127.4, 134.2, 155.2,
158.6; HRMS (FAB+) calcd for C16H23O3N‚H+ m/z 278.1756,
found 278.1754.
N-tert-Butoxycarbonyl-(R)-1-cyclohexylbut-3-enam-
ine (4u). White solid (er > 99:1 determined by HPLC); mp
1
87-89 °C; H NMR (400 MHz, CDCl3) δ 0.91-1.28 (m, 7H),
1.44 (s, 9H), 1.63-1.76 (m, 4H), 2.12 (m, 1H), 2.25 (m, 1H),
3.50 (br m, 1H), 4.36 (br d, J ) 8.4 Hz, 1H), 5.07 (m, 2H), 5.78
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 26.2, 26.3, 26.4, 28.3,
28.4, 29.7, 36.8, 41.5, 54.5, 78.9, 117.2, 135.1, 155.9; HRMS
(FAB+) calcd for C15H27O2N‚H+ m/z 254.2120, found 254.2116.
N-tert-Butoxycarbonyl-(S)-1-propylbut-3-enamine (4v).
Colorless oil (er 96:4 determined by HPLC); δ 0.93 (t, J ) 7.2
Hz, 3H), 1.24-1.36 (m, 4H), 1.44 (s, 9H), 2.22 (m, 2H), 3.66
(br m, 1H), 4.37 (br d, J ) 7.2 Hz, 1H), 5.09 (m, 2H), 5.80 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 19.2, 28.4, 36.9, 39.6,
49.8, 78.9, 117.5, 134.6, 155.6; HRMS (CI+) calcd for C12H23O2N‚
H+ m/z 214.1807, found 214.1822.
N-tert-Butoxycarbonyl-(R)-1-(2′-chlorophenyl)but-3-
enamine (4m). White solid (er 91:9 determined by HPLC);
mp 104-106 °C; 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H),
2.50 (m, 1H), 2.58 (m, 1H), 5.14 (m, 2H), 5.72 (m, 1H), 7.17-
7.37 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 28.4, 39.4, 51.4,
79.6, 118.5, 126.9, 127.2, 128.2, 129.9, 132.5, 133.7, 139.8,
155.0; HRMS (FAB+) calcd for C15H20O2NCl‚H+ m/z 282.1261,
found 282.1266.
N-tert-Butoxycarbonyl-(R)-1-(3′-chlorophenyl)but-3-
enamine (4n). White solid (er 93:7 determined by HPLC); mp
72-74 °C; 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 2.49 (m,
2H), 4.72 (br m, 1H), 4.94 (br m, 1H), 5.14 (m, 2H), 5.67 (m,
1H), 7.16 (d, J ) 7.6 Hz, 1H), 7.22-7.29 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 28.4, 41.1, 53.6, 79.8, 118.8, 124.5, 126.4,
127.3, 129.8, 133.4, 134.4, 144.7, 155.2; HRMS (FAB+) calcd
for C15H20O2NCl‚H+ m/z 282.1261, found 282.1268.
N-tert-Butoxycarbonyl-(S)-1-butylbut-3-enamine (4w).
1
Colorless oil (er > 99:1 determined by HPLC); H NMR (400
MHz, CDCl3) δ 0.91 (t, J ) 6.8 Hz, 3H), 1.33-1.40 (m, 6H),
1.46 (s, 9H), 2.14-2.30 (m, 2H), 3.63 (br m, 1H), 4.36 (br m,
1H), 5.10 (m, 2H), 5.80 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 14.1, 22.6, 28.1, 28.4, 34.4, 39.6, 50.1, 78.9, 117.6, 134.6,
155.6; HRMS (FAB+) calcd for C13H25O2N‚H+ m/z 228.1964,
found 228.1981.
N-tert-Butoxycarbonyl-(R)-1-(4′-chlorophenyl)but-3-
enamine (4o). White solid (er 94:6 determined by HPLC); mp
N-tert-Butoxycarbonyl-(S)-1-hexylbut-3-enamine (4x).
Colorless oil (er 95:5 determined by HPLC); 1H NMR (400
3470 J. Org. Chem., Vol. 70, No. 9, 2005

Synthesis of Optically Active Homoallylic Amines
MHz, CDCl3) δ 0.88 (t, J ) 6.8 Hz, 3H), 1.22-1.36 (m, 10H),
1.45 (s, 9H), 2.13-2.28 (m, 2H), 3.63 (br m, 1H), 4.34 (br m,
1H), 5.09 (m, 2H), 5.78 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 14.1, 22.6, 25.9, 28.4, 29.2, 31.8, 34.7, 39.6, 50.1, 78.9, 117.6,
134.6, 155.6; HRMS (FAB+) calcd for C15H29O2N‚H+ m/z
256.2277, found 256.2276.
N-tert-Butoxycarbonyl-(R)-1-(2′-phenylethenyl)but-3-
enamine (4y). Yellow solid (er 96:4 determined by HPLC);
mp 73-75 °C; 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 2.41
(m, 2H), 4.41 (br m, 1H), 4.66 (br m, 1H), 5.15 (m, 2H), 5.83
(m, 1H), 6.15 (dd, J ) 5.6, 16.0 Hz, 1H), 6.53 (d, J ) 16.0 Hz,
1H), 7.23-7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 28.4,
39.9, 51.7, 79.5, 118.3, 126.4, 127.5, 128.6, 129.9, 130.1, 133.8,
136.8, 155.3; HRMS (FAB+) calcd for C17H23O2N‚H+ m/z
274.1807, found 274.1815.
50.0, 79.1, 117.8, 125.9, 128.4, 128.5, 134.3, 142.0, 155.6;
HRMS (FAB+) calcd for C17H25O2N‚H+ m/z 276.1963, found
276.1978.
Acknowledgment. This work is supported by a
TJTTP-JBIC project (under the Center for Bioactive
Compounds, Chulalongkorn University). We also ac-
knowledge the financial support from the Department
of Chemistry and the Graduate School, Chulalongkorn
University and a Grant-in-Aid from the Japan Society
for the Promotion of Science (JSPS).
Supporting Information Available: Characterization
1
data for known compounds; H NMR spectra of (R)- and (S)-
BPG derivatives of 4e, 4f, and 4s, 1H NMR spectra of allyl
bromide-indium in CD3OD before and after addition of
N-tert-Butoxycarbonyl-(S)-1-(2′-phenylethyl)but-3-
enamine (4z). White solid (dr 99:1 determined by HPLC); mp
1
N-benzylidenebenzylamine, and H and 13C NMR spectra of
2e-z and 4e-z. This material is available free of charge via
1
56-58 °C; H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.62-
the Internet at http://pubs.acs.org.
1.92 (m, 2H), 2.22 (m, 2H), 2.70 (m, 2H), 3.76 (br m, 1H), 4.40
(br d, J ) 7.2 Hz, 1H), 5.13 (m, 2H), 5.81 (m, 1H), 7.21-7.34
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 28.4, 32.5, 36.7, 39.7,
JO0477244
J. Org. Chem, Vol. 70, No. 9, 2005 3471