Synthesis of enantiopure benzyl homoallylamines by indium-mediated barbier-type allylation combined with enzymatic kinetic resolution: Towards the chemoenzymatic synthesis of N-containing heterocycles

Article abstract of DOI:10.1002/ejoc.200901216

Barbier-type indium-mediated allylations of different N, N(dimethylsulfamoyl)-protected aldimines with a number of allyl bromides followed by high-yielding deprotection afforded allylic amines in good to excellent yields, The racemic amines were then subj

Full text of DOI:10.1002/ejoc.200901216

FULL PAPER
DOI: 10.1002/ejoc.200901216
Synthesis of Enantiopure Benzyl Homoallylamines by Indium-Mediated
Barbier-Type Allylation Combined with Enzymatic Kinetic Resolution: Towards
the Chemoenzymatic Synthesis of N-Containing Heterocycles
Ari Hietanen,[a][‡] Tiina Saloranta,[b][‡] Sara Rosenberg,[b] Evelina Laitinen,[b] Reko Leino,*[b]
and Liisa T. Kanerva*[a]
Keywords: Amines / Allylation / Enzyme catalysis / Kinetic resolution / Ring-closing metathesis
Barbier-type indium-mediated allylations of different N,N-
(dimethylsulfamoyl)-protected aldimines with a number of
allyl bromides followed by high-yielding deprotection af-
forded allylic amines in good to excellent yields. The racemic
amines were then subjected to enzymatic kinetic resolution
in order to obtain the corresponding (S)-amines and (R)-
amides. When acyl donors with a terminal double bond were
applied in the enzymatic kinetic resolution, the product
amide could be converted into unsaturated lactams in a
straightforward manner by utilizing ring-closing metathesis.
Furthermore, the enantiopure (S)-1-phenylbut-3-enylamine
was converted into the corresponding diallylamine, which
was subjected to ring-closing metathesis to yield a substi-
tuted dehydropiperidine mimicking a number of natural
products.
Introduction
Chiral benzylamines are important intermediates in the
synthesis of biologically and pharmaceutically relevant tar-
gets. Thus, the development of synthetic strategies towards
such moieties is of considerable academic as well as indus-
trial importance in both fine chemical and pharmaceutical
industries. In particular, chiral benzylamines have emerged
as fragments in some neuroactive pharmaceutical ingredi-
ents. For example, the parasympathomimetic (S)-rivastig-
mine has been adopted in the clinical treatment of dementia
associated with Alzheimer’s disease.[1] Moreover, the syn-
thesis of N-containing heterocycles such as piperidines,[2]
lactams[3] and derivatives thereof is of topical interest due
to the frequent occurrence of such moieties in biologically
active small molecules, whether of natural or synthetic ori-
gin, and peptidomimetics. Figure 1 illustrates representative
examples of each of these compound classes.[4]
Figure 1. Examples of bioactive chiral benzylamines, piperidines
and lactams.
ylsulfamoyl-protected aldimine followed by subsequent de-
protection by transamination.[5] A series of N,N-dimeth-
ylsulfamoyl-protected aldimines have also been utilized in
Pd-catalyzed allylations to produce various protected
amines in good to excellent yields.[6] In the present work,
we further examine the Barbier-type allylation of the N,N-
Recently, we briefly described an efficient and high-yield-
ing procedure for the synthesis of racemic homoallylamines
by utilization of Barbier-type allylation of an N,N-dimeth-
[a] Institute of Biomedicine/Department of Pharmacology, Drug
Development and Therapeutics/Laboratory of Synthetic Drug dimethylsulfamoyl-protected aldimines and extend the
Chemistry,
product scope to amines with different electronic and steric
properties (Figure 2).
University of Turku, 20014 Turku, Finland
Fax: +358-2-333-7955
E-mail: lkanerva@utu.fi
Similar homoallylic amines have been synthesized pre-
viously in an enantioselective manner by utilizing chiral in-
duction from the protective group,[7a] enantiodifferentiation
by addition of cinchona alkaloids,[7b] or in the presence of
a chiral ligand in catalytic allylations.[7c] Herein, we report
a methodology to produce the enantiomers of bifunctional
[b] Laboratory of Organic Chemistry
Åbo Akademi Univeristy, 20500 Åbo, Finland
Fax: +358-2-215-4866
E-mail: reko.leino@abo.fi
[‡] A. Hietanen and T. Saloranta contributed equally to this work
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901216.
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R. Leino, L. T. Kanerva et al.
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precursor aldimine was briefly explored.[5] In the present
work, the substrate scope of this reaction was successfully
extended to cover also substituted benzaldimines with elec-
tron-withdrawing (1b) and electron-donating (1c) para-sub-
stituents to prepare the racemic amines 3b and 3c (Figure 3,
Table 1). In addition, sterically demanding allylating agents
methallyl bromide and prenyl bromide were utilized to syn-
thesize the products 3d and 3e, respectively. The indium-
mediated allylations of aldimines 1a–c were performed in
anhydrous THF giving full conversions in all cases except
with the bulkier prenyl bromide reagent as allylating agent
(Table 1, Entry 5, step 1).
Figure 2. General structure of homoallylamines prepared in present
work with variations in electronic and steric properties.
homoallylbenzylamines rac-3a–e (Figure 3) using the lipase-
catalyzed N-acylation of the more reactive (R)-amines in
racemates. Racemic 1-phenylbut-3-en-1-amine (rac-3a) was
selected as a model substrate for the enzymatic studies
throughout the work.
Table 1. Synthesis of homoallylic amine series.[a]
Figure 3. Homoallylbenzylamines prepared in the present work for
enzymatic kinetic resolution.
Finally, we have also explored the utilization of the
enantiopure homoallylic amines for the synthesis of N-con-
taining heterocycles by olefin metathesis. The approach is
schematically illustrated in Scheme 1. By utilization of acyl
donors with a terminal double bond, the enzymatically pro-
duced (R)-amides can be converted into the corresponding
unsaturated lactams by ring-closing metathesis, a strategy
previously used in the synthesis of lactones.[8] Therefore,
this approach directly utilizes the enhanced molecular func-
tionality and increases the attractiveness of the kinetic reso-
lution method. Furthermore, conversion of the enzymati-
cally less reactive (S)-amines into the corresponding dial-
lylic compounds provides precursors for ring-closing me-
tathesis to yield substituted dehydropiperidines.
Entry Product R1
R2
R3
R4
Conv.
[%][b]
Yield
[%][c]
1
2
3
4
5
rac-3a
rac-3b
rac-3c
rac-3d
rac-3e
H
F
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
100/100 71/91
100/100 68/68
100/100 68/90
100/100 65/76
75/100 27/83
Me
Me
[a] Allylations were performed at room temp. on 4–11-mmol scale
with 3 equiv. of indium and allylating agent, respectively. [b] Con-
version as determined by 1H NMR spectroscopy (step 1/step 2). [c]
Isolated yields (step 1/step 2).
In our previous work,[5] it was shown that the N,N-di-
methylsulfamoyl group is smoothly removed by transami-
nation with 1,3-diaminopropane under conventional reflux
conditions. Here, the same protocol was utilized to depro-
tect all modified substrates 2b–e. The method proved its
feasibility and the desired allylic amines 3a–e were obtained
in good to excellent yields (Table 1, step 2).
Enzymatic Kinetic Resolution of Homoallylic Amines
Enzymatic kinetic resolution of racemic amines is typi-
cally based on reactions between a primary or, less fre-
quently, a secondary amine and a suitable acyl donor in
organic solvents.[9,10] Lipases (E.C. 3.1.1.3) in general, and
Burkholderia cepacia lipase (as a lipase PS-D preparation
on Celite) and Candida antarctica lipases A (as adsorbed
on Celite in the presence of sucrose[11]) and B (CAL-B as a
Novozym 435 preparation) in particular, are useful biocata-
Scheme 1. Synthesis of enantiopure N-containing heterocycles via
a chemoenzymatic pathway.
Results and Discussion
Synthesis of Homoallylic Amines
In our previous work, the synthesis of racemic homo- lysts for the enantioselective N-acylation of amino groups
allylbenzylamine rac-3a via Barbier-type allylation of the since they only rarely can split an amide bond other than
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Synthesis of Enantiopure Benzyl Homoallylamines
that in β-lactams, and accordingly cause the transformation propyl acetate content enantioselectivity increased (Entries
of the amide back into the amine.[12,13] It has been sug- 4–7). When ethyl methoxyacetate content was increased, con-
gested that the resonance stabilization of normal amide version after 3 d was enhanced at the expense of enantio-
functionalities makes amides stable toward lipases.[13c] An- selectivity (Entries 13, 19 and 22). Accordingly, working at
other issue related to amide stability is the intrinsic reactiv- low ethyl methoxyacetate content or in neat isopropyl acetate
ity of the acyl donor. High enough reactivity is pivotal to was shown to be favorable. Attempts to neutralize the poss-
enable reasonable reaction rates while too high reactivity ibly formed methoxyacetic (Entries 14 and 20) or acetic acid
can lead to chemical N-acylation parallel with the enzy- (Entry 8) by performing the reaction in the presence of tri-
matic one. Moreover, irreversible acyl donors, vinyl and iso- ethylamine affected the outcome only at high ethyl meth-
propenyl esters (common with alcoholic substrates), are in- oxyacetate contents. Attempts to keep the system dry by add-
appropriate with amine substrates due to possible imine for- ing molecular sieves into the reaction mixture were more
mation with acetaldehyde and acetone, tautomerization productive, and excellent E values could be calculated when
products from the liberated vinyl and isopropenyl alcohols, the reaction proceeded in neat isopropyl acetate (water con-
respectively.
tent 60 ppm) or with ethyl methoxyacetate (6 vol.-%, equals
For developing a procedure for the enzymatic kinetic res- to 5 equiv.) in toluene (water content 40 ppm) (Entries 9 and
olution, rac-3a (0.1 ) was first subjected to lipase screening 15). In addition, considerable reactivity enhancement was
(see the lipases in the Exp. Section) using commercial lipase gained. In order to further increase reactivity, the enzyme
preparations (25 mgmL–1) and ethyl methoxyacetate content was increased from 25 mgmL–1 to 50 mgmL–1 (En-
(5 equiv. corresponding to 6 vol.-% of the acyl donor) in tries 11 and 17). Larger amounts of the enzyme did not
tert-butyl methyl ether (TBME) dried with molecular sieves boost reactivity higher. Increasing the temperature above
(4 Å). The potential of Subtilisin Carlsberg (a serine prote- room temperature negatively affected enantioselectivity with
ase) and acylase I to acylate rac-3a was also tested. Acyl isopropyl acetate (Entries 16–18).
activated ethyl methoxyacetate was chosen as it was re-
ported to work well in the CAL-B-catalyzed acylation of
Table 2. Screening of acyl donors (0.5 ) for the acylation of rac-
amines.[14] The activation is mainly due to a weak hydrogen
3a (0.1 ) with lipase PS-D (25 mgmL–1) in toluene at room tem-
bond between the β-oxygen atom of the methoxyacetate
moiety of the acyl-enzyme intermediate and the amine hy-
drogen of the reactive amine counterpart on the mechan-
istic pathway of serine hydrolases.[15] CAL-A was by far the
most reactive but virtually a non-enantioselective catalyst
while lipase PS-D [ee(R)-amide = 95% at 30% conversion] and
CAL-B [ee(R)-amide = 92% at 35% conversion] both showed
reactivity with relatively good enantioselectivity. Other en-
zymes in the test set were completely inefficient. A possible
chemical background reaction was excluded by performing
the reaction under the same conditions except in the ab-
sence of an enzyme. However, the ammonium salt between
the substrate and methoxyacetic acid (hydrolysis product of
the acyl donor) precipitated and lowered the rate and selec-
tivity of the resolution. Changing the solvent from ethers
(TBME or diisopropyl ether) to toluene (dried on molecu-
lar sieves) more than halved the water content (from more
than 90 ppm to about 40 ppm), and precipitation was not
visually detectable any more with lipase PS-D. This effect
is in accordance with our earlier experience of lipase PS-D
causing less hydrolysis of hydrolyzable compounds than
CAL-B (Novozym 435) when used in organic solvents,[16]
and might explain the better selectivity of lipase PS-D vs.
CAL-B.
perature; reaction time 3 d.
Entry Acyl donor/[vol.-%]
Conv. [%] ee(R)-amide [%] ee(S)-3 [%]
(E)[g]
1
2
3
ethyl acetate/6
ethyl propanoate/6
ethyl butanoate/6
11
1
6
10
43
2
1
Ͻ1
Ͻ1
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
isopropyl acetate/6
3
5
78
87
95
95
95
99
98
99
96
95
96
99
99
99
97
91
94
75
76
2
5
23
42
isopropyl acetate/20
isopropyl acetate/50
isopropyl acetate/100
isopropyl acetate/100[a]
isopropyl acetate/100[b]
isopropyl acetate/100[c,d]
isopropyl acetate/100[c]
isopropyl acetate/100[c,e]
ethyl methoxyacetate/6
ethyl methoxyacetate/6[a]
ethyl methoxyacetate/6[b]
ethyl methoxyacetate/6[c,d]
ethyl methoxyacetate/6[c]
19
31
32
31
38
45
48
14
17
44
42
45
44
45 (200)
59 (200)
82 (200)
87 (100)
16
20
76 (200)
73 (200)
82 (200)
97 (200)
37
58
99
39
ethyl methoxyacetate/6[c,e,f] 50
At this point, attention was paid to the nature of the acyl
donor and to the reaction conditions in order to increase
reactivity and enantioselectivity. The commonly used alkyl-
activated acyl donors, 2,2,2-trifluoroethyl acetate and but-
anoate, resulted in fast but completely non-selective acylation
of rac-3a (0.1 ) with lipase PS-D (25 mgmL–1) in toluene.
The ability of normal esters (6 vol.-%, Entries 1–4) to enan-
tioselectively acylate rac-3a indicated isopropyl acetate to
ethyl methoxyacetate/20
ethyl methoxyacetate/20[a]
ethyl methoxyacetate/20[b]
ethyl methoxyacetate/50
29
38
57
34
[a] Et3N (0.1 ) was added. [b] Molecular sieves (4 Å) were added.
[c] 50 mgmL–1 of lipase PS-D in the presence of molecular sieves
(4 Å). [d] Reaction temperature 4 °C. [e] Reaction temperature
48 °C. [f] Reaction time 2 d. [g] E given only with clearly excellent
have some potential (Entry 4) (Table 2). With increasing iso- enantioselectivity.
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With this data available, the preparative-scale kinetic res-
According to the Kazlauskas rule, the (R)-enantio-prefer-
olution of rac-3a was performed with ethyl methoxyacetate ence was expected for the lipase PS-D in the present N-acyla-
(6 vol.-%) in toluene in the presence of lipase PS-D tions.[17] This was confirmed when (S)-3a and (S)-3c were at
(50 mgmL–1) and molecular sieves (4 Å) at 48 °C (Entry 1, our hands after the kinetic resolution allowing the sign of
Table 3) to afford (R)-4a and (S)-3a. The outcome was the [α]D values to be compared to those given for the (S)-
slightly less satisfactory with E = 98 than what was expected enantiomers in literature.[7c] In order to further support this
on the basis of a small-scale reaction (Entry 18, Table 2). suggestion, both enantiomers of 3a were derivatized with (S)-
For that reason, the kinetic resolutions of rac-3a–c were (+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride [(S)-
next performed in isopropyl acetate in the presence of lipase MTPA-Cl] giving a pair of diastereomeric amides that were
1
PS-D (50 mgmL–1) and molecular sieves (4 Å) at room tem- characterized by H NMR spectroscopy. The comparison of
perature (Entries 2–4, Table 3). While the kinetic resolution the ∆δ values further corroborates the reacting stereoisomer
of rac-3c gave the resolution products (S)-3c and (R)-5c of the amine to have the (R)-configuration.[18]
with excellent enantiopurities after 4 d at 49% conversion,
To extend the scope of the resolution, we then used ethyl
the reactions with substrates 3a and 3b slowed down be- and isopropyl acrylates and isopropyl 3-butenoate as func-
yond about 30–40% of conversion. For instance, the resolu- tionalized acyl donors in the kinetic resolution of rac-3a in
tion of rac-3a was at 46% conversion after 3 d, but 6 more toluene (Table 4). We envisioned that the amides (R)-6 and
days were required to reach 49% conversion. Lipase PS-D, (R)-7 could yield the corresponding enantiopure six- and
CAL-B and CAL-A were all unable to acylate rac-3d and seven-membered unsaturated lactams when used as sub-
rac-3e in neat isopropyl acetate. On the other hand, when strates for ring-closing metathesis. The resolution with iso-
the acyl donor was changed to ethyl methoxyacetate propyl acrylate was completely non-enantioselective (En-
(20 vol.-% was required) in toluene, acylation of 3d slowly tries 4–6) while excellent enantioselectivities were observed
proceeded in the presence of CAL-B, and after 7 d (R)-4d with ethyl acrylate (Entries 1–3) and with isopropyl 3-but-
was obtained enantiopure (ee Ͼ 99%) at 31% conversion enoate (Entries 7–9). The reactions with acrylate esters re-
(Entry 5). Rac-3e stayed unreacted. The enantiomerically mained very slow, and it was not possible to affect reactivity
enriched unreacted (S)-3a (ee = 84%), (S)-3b (ee = 48%) by increasing the content of the acyl donor from 5 to
and (S)-3d (ee = 44%) were further purified by subjecting 20 vol.-% (Entries 1–6). Finally, preparative-scale kinetic
them under the kinetic resolution conditions, yielding 99%, resolution produced (R)-6 with 65% isolated yield (calcu-
95% and 72% ee, respectively. In general, the isolated yields lated from conversion) when 19% of the racemate had re-
for the unreacted (S)-amines stayed somewhat low and the acted (Scheme 3). The lipase-catalyzed Michael addition
need to further enantiomerically purify the products by re- started to compete seriously with the N-acylation at this
peating the enzymatic acylation lowered the yields. Our ef- point.[19] Lacking Michael acceptor properties, isopropyl 3-
forts to hydrolyze (R)-4a and (R)-5a gave also low yields for butenoate (10 vol.-%) successfully afforded the amide (R)-7
(R)-3a due to by-product formation (see Exp. Sect.).
at 47% conversion with 85% isolated yield and ee Ͼ 99%.
Table 3. Preparative-scale kinetic resolution of rac-3a–e (0.1 ) in isopropyl acetate (neat) at room temperature or with ethyl methoxyace-
tate in toluene in the presence of molecular sieves (4 Å).
Entry
Substrate
Time [d] Conv. [%]
(R)-Amide
(S)-Amine
Yield [%][a] ee [%]
Yield [%][a] ee [%]
1
2
3
4
5
6
3a[b]
3a
4
3
4
4
7
–
48
46
33
49
31
–
83
92
75
65
quant.
–
94
99
Ͼ99
Ͼ99
Ͼ99
–
58
66
75
93
35
–
87
84/99[e]
48/95[e]
94
3b
3c
3d
[c]
44/72[e]
–
[d]
3e
[a] Isolated yields based on conversion. [b] Ethyl methoxyacetate (6 vol.-%) in toluene at 48 °C. [c] CAL-B (50 mgmL–1) in the place of
lipase PS-D and ethyl methoxyacetate (20 vol.-%) in toluene at room temp. [d] No reaction with any applied method. [e] ee after enantio-
meric enrichments.
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Synthesis of Enantiopure Benzyl Homoallylamines
Table 4. Kinetic resolution of rac-3a (0.1 ) with ethyl and isopropyl acrylate and isopropyl 3-butenoate (toluene was used as cosolvent)
in the presence of lipase PS-D (50 mgmL–1) and molecular sieves (4 Å) at room temperature; reaction time 3 d.
Entry
R
n
Acyl donor [vol.-%]
Conv. [%]
ee(R)-amide [%]
ee(S)-3a [%]
E
1
2
3
4
5
6
7
8
9
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
0
0
0
0
0
0
1
1
1
5
17
16
18
7
1
2
40
45
48
98
98
98
3
23
13
Ͼ99
Ͼ99
Ͼ99
21
19
21
Ͻ1
Ͻ1
Ͻ1
67
83
91
Ͼ100
Ͼ100
Ͼ100
1
2
1
Ͼ200
Ͼ200
Ͼ200
10
20
5
10
20
5
10
20
Synthesis of N-Containing Heterocycles
based on a longer synthetic route for preparation of the
enantiopure diallyl precursors, has been described by Fior-
elli and Savoia.[21] In their work, a number of substituted
diallylic amides were successfully ring-closed to yield the
corresponding α,β-unsaturated δ-lactams in good to excel-
lent yields. In accordance with this published procedure,[21]
the δ-lactam (R)-10 was synthesized from (R)-6 in 83% iso-
lated yield (Scheme 3). In our hands, however, the corre-
sponding seven-membered lactam (R)-11 was formed in low
yield only (22%) when starting from the diallylic amide (R)-
9.
In our previous work, the protected crotylated amine was
converted into the corresponding diallylic sulfamide that
was then ring-closed using Grubbs’ 2nd generation catalyst
to yield a substituted dehydropiperidine in excellent overall
yield.[5] Unfortunately, the removal of the N,N-dimethylsulf-
amoyl protective group from this tertiary amine proved un-
successful. In the present work, having the enantiopure
amine at hand, we were encouraged to redesign the synthe-
sis strategy in order to prepare enantiopure dehydropiper-
idines in a similar fashion. Accordingly, the unprotected
amine (S)-3a was converted into the corresponding diallylic
amine (S)-8 by deprotonation with KOH and subsequent
reaction with one equivalent of allyl bromide in 67% yield.
The diallylic amine obtained was then subjected to ring-
closing metathesis. As known from the literature, free
amines are detrimental to the Grubbs-type ruthenium cata-
lysts.[20] When, however, the diallylic amine was converted
into the corresponding salt by adding one equivalent of p-
toluenesulfonic acid (pTsA) the ring-closure proceeded
smoothly affording the enantiopure dehydropiperidine (S)-
9 in 70% isolated yield (Scheme 2).
Scheme 3. Kinetic resolution of 3a to yield amide (R)-6 and the
synthesis of the lactam (R)-10.
Nevertheless, this work has shown that a number of bio-
logically relevant N-containing heterocycles could be pro-
duced by combining the elegancy of enzymatic and metal-
catalyzed reactions. Currently, we are investigating the pos-
sibilities to extend the scope of this protocol to synthesis of
some natural products and analogues.
Scheme 2. Synthesis of cyclic secondary amine (S)-9. i) allyl bro-
mide (1 equiv.), KOH (3 equiv.), DMF. ii) Grubbs’ 2nd generation
cat. (10 mol-%), pTsA (1 equiv.), CH2Cl2, 40 °C.
Conclusions
Finally, the diallylic resolution products (R)-6 and (R)-7
were subjected to ring-closing metathesis using Grubbs’ 2nd
We have shown that the indium-mediated allylation of
generation catalyst. A similar type of approach, although N,N-dimethylsulfamoyl-protected aldimines and the subse-
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R. Leino, L. T. Kanerva et al.
FULL PAPER
using silica gel (60 Å, Merck, 230–400 mesh, enriched with 0.1%
Ca).
quent deprotection by transamination is a reliable pro-
cedure for production of homoallylic amines with different
electronic and steric properties. Moreover, our study has
shown that the enzymatic kinetic resolution of the sterically
more demanding benzyl homoallylamines (allyl as the me-
dium-sized group) is possible by carefully adjusting the
most critical reaction parameters. As the steric crowding
is transferred closer to the reaction center, the resolution
becomes more challenging. Furthermore, by utilizing acyl
donors with a terminal double bond, the N-acylation has
been used as a synthetic step, as the resolution product can
be directly subjected to ring-closing metathesis yielding un-
saturated lactam products as exemplified by the straightfor-
ward synthesis of an enantiopure α,β-unsaturated δ-lactam.
Finally, an enantiopure amine has been transferred into its
diallylic counterpart, which has been subjected to ring-clos-
ing metathesis to afford a substituted enantiopure dehy-
dropiperidine product. The obtained N-containing hetero-
cycles represent an attractive class of moieties found in a
number of biologically and pharmaceutically relevant tar-
gets.
Table 5. Gas chromatographic analysis of the resolved compounds.
Amine Amide derivative
Oven temp. [°C] tr[(S)/(R)] [min]
3a[a]
3a[a]
3a
acetamide
acetamide
butanamide
130
130
130
37.7/39.3
43.1/45.5
85.3/87.3
57.0/58.5
27.2/28.3
36.4/37.2
53.0/54.4
147.1/147.4
54.1/56.3
84.6/89.7
3a
methoxyacetamide 130
3a
acrylamide
3-butenamide
acetamide
acetamide
acetamide
160, then 130
160, then 130
130
130
130
3a
3b
3c
3d
3d
methoxyacetamide 130
[a] The acetamides were analyzed with two columns, the retention
times depending on the column specifics.
Synthesis of N,N-(Dimethylsulfamoyl)benzaldimines 1a–c: Com-
pounds 1a–c were synthesized according to a literature pro-
cedure.[25] The corresponding benzaldehyde (20 mmol) and N,N-
dimethylsulfamide (2.54 g, 20.5 mmol) were dissolved in toluene
(80 mL) and water was azeotropically distilled for 16 h using a
Dean–Stark apparatus. After removal of the solvent under reduced
pressure, the residue was dissolved in CH2Cl2 and filtered. Solvents
were evaporated under reduced pressure and the crude product was
used as such in the allylation step.
Experimental Section
Materials and Methods: The allylation and ring-closing reactions
were performed under dry argon using anhydrous solvents. THF
was distilled from Na/benzophenone and CH2Cl2 was distilled
from CaH2. The anhydrous solvents were then stored under argon.
N,N-dimethylsulfamide was readily prepared from commercial di-
methylsulfamoyl chloride and 30% aqueous ammonia. All other
reagents were purchased and used as received. Solvents and acyl
donors for enzymatic reactions were obtained from commercial
sources and stored over molecular sieves unless stated otherwise.
Isopropyl acrylate and isopropyl 3-butenoate were prepared ac-
cording to literature procedures.[22] Burcholderia cepacia lipase (li-
pase PS-D) was acquired from Amano Europe, Candida antarctica
lipase B (CAL-B, Novozym 435), Thermomyces lanuginosus lipase
(Lipozyme TL IM) and Rhizopus miehei lipase (lipase RM IM)
were purchased from Novozymes, Candida antarctica lipase A
(CAL-A, immobilized) was from Biocatalytics, Candida rugosa li-
pase (CRL) and Protease (Subtilisin Carlsberg) were from Sigma
and Acylase I (on Eupergit C) was from Fluka. Enantiomeric ex-
cesses of the amines 3a–e as the corresponding acet-, propan- or
butanamides (amines derivatized with the corresponding anhy-
Standard Procedure for the Synthesis of Homoallylic Amines
(Table 1): In a Schlenk tube flushed with argon, substrate 1a–c was
dissolved in anhydrous THF (0.10–0.18  solution). Indium
(3 equiv.) and allylating agent (3 equiv.) were added and the re-
sulting mixture was stirred overnight at room temperature. The re-
action was quenched by adding 1  HCl until pH ≈ 3 and extracted
with diethyl ether. The combined organic phase was washed with
saturated NaHCO3 solution and brine, and dried with anhydrous
Na2SO4. After evaporation of ether, the crude product was sub-
jected to analysis and purified by flash chromatography (eluent:
hexane/EtOAc, 4:1) affording 2a–e as a white solid. Compound 2a–
e was then dissolved in 1,3-diaminopropane (24-fold molar excess),
the mixture was heated to 140 °C and refluxed for 2 h. After cool-
ing to room temperature, the mixture was diluted with CH2Cl2 and
washed with water. The organic phase was dried with anhydrous
Na2SO4 and concentrated to yield 3a–e.
1-Phenylbut-3-en-1-amine (3a): Step 1: starting from 1a (1.95 g,
9.18 mmol) to yield 2a (1.67 g, 6.56 mmol, 71%). Step 2: starting
from 2a (2.14 g, 8.41 mmol) to yield 3a (1.13 g, 7.68 mmol, 91%)
as light yellow oil. 1H NMR (600.13 MHz, CDCl3, 25 °C): δ =
7.38–7.33 (m, 4 H, arom. H), 7.28–7.23 (m, 1 H, arom. H), 5.75
(dddd, JCH=,CH2a = 6.3, JCH=,CH2b = 8.0, JCH=,CH2cis = 10.2,
dride) were determined with
a HP1090 gas chromatograph
equipped with a Varian CP Chirasil-Dex CP chiral column. For
retention times and temperature programs, see Table 5. NMR spec-
tra were recorded with Bruker Avance 500 MHz or 600 MHz spec-
trometers. 1H NMR spectra were analyzed by PERCH software
with spin simulation/iteration techniques.[23] HRMS were measured
in ESI+ mode with Bruker micrOTOF-Q quadrupole-TOF or Fi-
sons ZABSpec-oaTOF spectrometers. Melting points were re-
corded with a Gallenkamp apparatus and are uncorrected. Optical
rotations were determined with a PerkinElmer 241 or 341 polarime-
ter, and [α]D values are given in units of 10–1 degcm2 g–1. Enzymatic
reactions were performed at room temperature (23–24 °C) unless
indicated otherwise. The determination of E was based on equation
E = ln[(1 – c)(1 – eeS)]/ln[(1 – c)(1 + eeS)] with c = eeS/(eeS + eeP)
using linear regression (E as the slope of the line ln[(1 – c)(1 – eeS)]
vs. ln[(1 – c)(1 + eeS)]).[24] Flash chromatography was performed
JCH=,CH2trans
= 17.1 Hz, 1 H, CH2-CH=CH2), 5.12 (dddd,
JCH2trans,CH2b = –1.2, JCH2trans,CH2a = –1.6, JCH2trans,CH2cis = –2.0,
JCH2trans,CH = 17.1 Hz, 1 H, CH2-CH=CH2trans), 5.08 (dddd,
JCH2cis,CH2b = –0.8, JCH2cis,CH2a = –1.2, JCH2cis,CH2trans = –2.0,
JCHcis,CH = 10.2 Hz, 1 H, CH2-CH=CH2cis), 3.99 (dd, JCH,CH2a
5.2, JCH,CH2b = 8.2 Hz, 1 H, CHNH2), 2.46 (ddddd, JCH2a,CH2cis
=
=
–1.2, JCH2a,CH2trans = –1.6, JCH2a,CH = 5.2, JCH2a,CH = 6.2,
JCH2a,CH2b –13.8 Hz, H, CH2a-CH=CH2), 2.36 (ddddd,
=
1
JCH2b,CH2cis = –0.8, JCH2b,CH2trans = –1.2, JCH2b,CH = 8.0, JCH2b,CH
= 8.2, JCH2b,CH2a = –13.8 Hz, 1 H, CH2b-CH=CH2), 1.53 (br. s., 2
H, NH2) ppm. 13C NMR (150.9 MHz, CDCl3, 25 °C): δ = 145.9
(arom. C), 135.5 (CH=CH2), 128.4 (2 arom. C), 126.9 (arom. C),
126.4 (2 arom. C), 117.6 (CH=CH2), 55.4 (CHNH2), 44.1 (CH2-
914
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 909–919

Synthesis of Enantiopure Benzyl Homoallylamines
CH=CH2) ppm. HRMS: calcd. for C10H13N [M]+ 147.1071; found
147.1048.
[CH2-C(CH3)=CH2], 22.2 (CH3) ppm. HRMS: calcd. for C11H15N
[M]+ 161.1205; found 161.1223.
2,2-Dimethyl-1-phenylbut-3-en-1-amine (3e): Step 1: starting from
1a (2.12 g, 9.99 mmol) to yield 2e (0.76 g, 2.69 mmol, 27%) after
repeated purification by column chromatography. Step 2: starting
from 2e (1.25 g, 4.42 mmol) to yield 3e (0.64 g, 3.67 mmol, 83%)
as yellow oil. 1H NMR (600.13 MHz, CDCl3, 25 °C): δ = 7.30–
7.27 (m, 4 H, arom. H), 7.25–7.22 (m, 1 H arom. H), 5.87 (dd,
JCH=,CH2cis = 10.8, JCH=,CH2trans = 17.5 Hz, 1 H, CH=CH2), 5.09
(dd, JCH2cis,CH2trans = –1.4, JCHcis,CH= = 10.8 Hz, 1 H, CH=CH2cis),
5.03 (dd, JCH2trans,CH2cis = –1.4, JCH2trans,CH = 17.5 Hz, 1 H,
CH=CH2trans), 3.75 (s, 1 H, CHNH2), 1.43 (br. s, 2 H, NH2), 0.99
(s, 3 H, CH3), 0.95 (s, 3 H, CH3) ppm. 13C NMR (150.9 MHz,
CDCl3, 25 °C): δ = 145.8 (CH=CH2), 142.9 (arom. C), 128.5 (2
arom. C), 127.5 (2 arom. C), 126.9 (arom. C), 113.0 (CH=CH2),
64.1 (CHNH2), 41.5 [C(CH3)2], 25.5 (CH3), 21.7 (CH3) ppm.
HRMS: calcd. for C12H17N [M]+ 175.1361; found 175.1311.
1-(4-Fluorophenyl)but-3-en-1-amine (3b): Step 1: starting from 1b
(1.59 g, 6.91 mmol) to yield 2b (1.28 g, 4.69 mmol, 68%). Step 2:
starting from 2b (1.28 g, 4.69 mmol) to yield 3b (0.53 g, 3.21 mmol,
68%) as yellow oil. 1H NMR (600.13 MHz, CDCl3, 25 °C): δ =
7.33–7.29 (m, 2 H, arom. H), 7.04–6.99 (m, 2 H, arom. H), 5.73
(dddd, JCH=,CH2a = 6.2, JCH=,CH2b = 8.0, JCH=,CH2cis = 10.1,
JCH=,CH2trans
= 17.1 Hz, 1 H, CH2-CH=CH2), 5.11 (dddd,
JCH2trans,CH2b = –1.2, JCH2trans,CH2a = –1.6, JCH2trans,CH2cis = –2.0,
JCH2trans,CH = 17.1 Hz, 1 H, CH2-CH=CH2trans), 5.08 (dddd,
JCH2cis,CH2b = –0.9, JCH2cis,CH2a = –1.2, JCH2cis,CH2trans = –2.0,
JCHcis,CH2 = 10.1 Hz, 1 H, CH2-CH=CH2cis), 3.99 (dd, JCH,CH2a
5.3, JCH,CH2b = 8.1 Hz, 1 H, CHNH2), 2.42 (ddddd, JCH2a,CH2cis
=
=
–1.2, JCH2a,CH2trans = –1.6, JCH2a,CH = 5.3, JCH2a,CH = 6.2,
JCH2a,CH2b –13.8 Hz, H, CH2a-CH=CH2), 2.33 (ddddd,
=
1
JCH2b,CH2cis = –0.9, JCH2b,CH2trans = –1.2, JCH2b,CH = 8.0, JCH2b,CH
= 8.1, JCH2b,CH2a = –13.8 Hz, 1 H, CH2b-CH=CH2), 1.47 (br. s, 2
H NH2) ppm. 13C NMR (150.9 MHz, CDCl3, 25 °C): δ = 161.8 (d,
Standard Procedure for the Small-Scale Enzymatic Kinetic Resolu-
tion: Lipase PS-D and molecular sieves (4 Å) were weighed in a
reaction vial before rac-3a (0.1 , 1.0 mL) in dry isopropyl acetate
(or an acyl donor in an organic solvent) was added. Reactions pro-
ceeded under shaking at 170 rpm. The progress was followed by
taking samples (100 µL) at intervals, filtering off the enzyme and
analyzing the samples (diluted with hexane after derivatization of
the amine with an appropriate acid anhydride) by GC.
4
1JC,F = 244.7 Hz, arom. C-F), 141.5 (d, JC,F = 3.3 Hz, arom. C),
3
135.2 (CH=CH2), 127.8 (d, JC,F = 7.7 Hz, 2 arom. C), 117.8
2
(CH=CH2), 115.1 (d, Jc,F = 20.9 Hz, 2 arom. C), 54.7 (CHNH2),
44.3 (CH2-CH=CH2) ppm. HRMS: calcd. for C10H12NF [M]+
165.0954; found 165.0929.
1-(4-Methoxyphenyl)but-3-en-1-amine (3c): Step 1: starting from 1c
(0.93 g, 4.42 mmol) to yield 2c (0.85 g, 3.00 mmol, 68%). Step 2:
starting from 2c (0.85 g, 3.00 mmol) to yield 3c (0.48 g, 2.70 mmol,
Procedures for the Preparative-Scale Enzymatic Kinetic Resolutions
1-Phenylbut-3-en-1-amine (3a) with Ethyl Methoxyacetate: Lipase
PS-D (0.93 g, 50 mgmL–1) and molecular sieves (4 Å, 0.93 g) were
weighed in the reaction vessel before rac-3a (273 mg, 1.85 mmol)
in toluene (17 mL) containing ethyl methoxyacetate [6% (v/v)] was
added. After 4 d at +48 °C the reaction was stopped at 48% conver-
sion. The enzyme was filtered, washed with CH2Cl2 and the com-
bined organic phases were concentrated in vacuo. The crude prod-
uct was purified by silica gel chromatography (5% Et3N in EtOAc)
to yield (S)-3a as a pale yellow oil [82 mg, 0.56 mmol, 58%, ee =
87%, [α]2D5 = –30 (c = 1.0, CHCl3)] and (R)-4a as a white solid
[162 mg, 0.74 mmol, 83%, ee = 94%, [α]2D5 = +43 (c = 1.0, CHCl3),
1
90%) as colorless oil. H NMR (600.13 MHz, CDCl3, 25 °C): δ =
7.28–7.24 (m, 2 H, arom. H), 6.89–6.85 (m, 2 H, arom. H), 5.75
(dddd, JCH=,CH2a = 6.2, JCH=,CH2b = 8.0, JCH=,CH2cis = 10.2,
JCH=,CH2trans
= 17.1 Hz, 1 H, CH2-CH=CH2), 5.11 (dddd,
JCH2trans,CH2b = –1.3, JCH2trans,CH2a = –1.6, JCH2trans,CH2cis = –2.1,
JCH2trans,CH = 17.1 Hz, 1 H, CH2-CH=CH2trans), 5.07 (dddd,
JCH2cis,CH2b = –0.9, JCH2cis,CH2a = –1.1, JCH2cis,CH2trans = –2.1,
JCH2cis,CH2 = 10.2 Hz, 1 H, CH2-CH=CH2cis), 3.95 (dd, JCH,CH2a
=
5.3, JCH,CH2b = 8.1 Hz, 1 H, CHNH2), 3.80 (s, 3 H, OCH3), 2.43
(ddddd, JCH2a,CH2cis = –1.1, JCH2a,CH2trans = –1.6, JCH2a,CH = 5.3,
JCH2a,CH = 6.2, JCH2a,CH2b = –13.8 Hz, 1 H, CH2a-CH=CH2), 2.34
(ddddd, JCH2b,CH2cis = –0.9, JCH2b,CH2trans = –1.2, JCH2b,CH = 8.0,
JCH2b,CH = 8.1, JCH2b,CH2a = –13.8 Hz, 1 H, CH2b-CH=CH2), 1.46
(br. s, 2 H NH2) ppm. 13C NMR (150.9 MHz, CDCl3, 25 °C): δ =
158.5 (arom. C), 138.0 (arom. C), 135.6 (CH=CH2), 127.3 (2 arom.
C), 117.5 (CH=CH2), 113.7 (2 arom. C), 55.3 (OCH3), 54.8
(CHNH2), 44.3 (CH2-CH=CH2) ppm. HRMS: calcd. for
C11H15NO [M]+ 177.1154; found 177.1112.
1
m.p. 60Ϯ1 °C]. (R)-4a: H NMR (CDCl3, 600.13 MHz, 25 °C): δ
= 7.36–7.23 (m, 5 H, arom. H), 6.85 (d, JNH,CH = 8.6 Hz, 1 H,
NH), 5.70 (dddd, JCH=,CH2a = 7.0, JCH=,CH2b = 7.0, JCH=,CH2cis
= 10.2, JCH=,CH2trans = 17.1 Hz, 1 H, CH2-CH=CH2), 5.13 (ddd,
JCH,CH2a = 5.8, JCH,CH2b = 8.0, JCH,NH = 8.6 Hz, 1 H, CHNH),
5.12 (dddd, JCH2trans,CHa
=
–1.4, JCH2trans,CH2b
=
–1.5,
JCH2trans,CH2cis –1.9, JCH2trans,CH
=
=
17.1 Hz,
1 H, CH2-
CH=CH2trans), 5.08 (dddd, JCH2cis,CHa = –1.0, JCH2cis,CH2b = –1.1,
JCH2cis,CH2trans = –1.9, JCH2cis,CH = 10.2 Hz, 1 H, CH2-CH=CH2cis),
3.91 (d, JCH2c,CH2d = –15.1 Hz, 1 H, CH2cOCH3), 3.88 (d,
JCH2d,CH2c = –15.1 Hz, 1 H, CH2dOCH3), 3.41 (s, 3 H, CH2OCH3),
2-Methyl-1-phenylbut-3-en-1-amine (3d): Step 1: starting from 1a
(2.42 g, 11.4 mmol) to yield 2d (1.92 g, 7.15 mmol, 65%). Step 2:
starting from 2d (1.60 g, 5.86 mmol) to yield 3d (0.72 g, 4.44 mmol,
2.59 (ddddd, JCH2a,CH2cis = –1.0, JCH2a,CH2trans = –1.4, JCH2a,CH
5.8, JCH2a,CH = 7.0, JCH2a,CH2b = –14.0 Hz, 1 H, CH2a-CH=CH2),
2.59 (ddddd, JCH2b,CH2cis = –1.1, JCH2b,CH2trans = –1.5, JCH2b,CH
=
1
76%) as light yellow oil. H NMR (600.13 MHz, CDCl3, 25 °C): δ
= 7.38–7.35 (m, 2 H, arom. H), 7.35–7.31 (m, 2 H, arom. H), 7.26–
7.22 (m, 1 H, arom. H), 4.85 [ddq, JCHtrans,CHa = –0.5, JCH2trans,CH3
= 1.5, JCHtrans,CHcis = –2.2 Hz, 1 H, CH2-C(CH3)=CH2trans], 4.80
[dddq, JCH2cis,CH3 = 0.9, JCHcis,CHb = –0.9, JCHcis,CHa = –1.4,
JCHcis,CHtrans = –2.2 Hz, 1 H, CH2-C(CH3)=CH2cis], 4.10 (dd,
JCH,CH2a = 4.5, JCH,CH2b = 9.5 Hz, 1 H, CHNH2), 2.36 (dddd,
JCH2a,CH2trans = –0.5, JCH2a,CH2cis = –1.4, JH2a,CH = 4.5, JCH2a,CH2b
= –13.6 Hz, 1 H, CH2a-CH=CH2), 2.31 (ddd, JCH2b,CH2cis = –0.9,
=
7.0, JCH2b,CH = 8.0,, JCH2b,CH2a = –14.0 Hz, 1 H, CH2b-CH=CH2)
ppm. 13C NMR (CDCl3,150.9 MHz, 25 °C): δ = 168.8 (CO), 141.4
(arom. C), 133.8 (CH=CH2), 128.6 (2 arom. C), 127.4 (arom. C),
126.5 (2 arom. C), 118.3 (CH=CH2), 72.0 (CH2OCH3), 59.2
(CH2OCH3), 51.8 (CHNH), 40.6 (CH2-CH=CH2) ppm. HRMS:
calcd. for C13H17NO2Na [M + Na]+ 242.1152; found 242.1171.
JH2b,CH = 9.5, JCH2a,CH2b = –13.7 Hz, 1 H, CH2b-CH=CH2), 1.76 1-Phenylbut-3-en-1-amine (3a) with Isopropyl Acetate: Lipase PS-D
(dd, JCH3,CH2cis = 0.9, JCH3,CH2trans = 1.5 Hz, 3 H, CH3), 1.48 (br. (1.00 g, 50 mgmL–1) and molecular sieves (4 Å, 1.00 g) were
s, 2 H NH2) ppm. 13C NMR (150.9 MHz, CDCl3, 25 °C): δ = 146.2 weighed in the reaction vessel before rac-3a (300 mg, 2.04 mmol)
(arom. C), 142.9 [C(CH3)=CH2], 128.4 (2 arom. C), 126.9 (arom.
in neat isopropyl acetate (20 mL) was added. After 3 d the reaction
C), 126.3 (2 arom. C), 113.3 [CH(CH3)=CH2], 53.4 (CHNH2), 48.6 was stopped at 46% conversion. The crude product was purified
Eur. J. Org. Chem. 2010, 909–919
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
915

R. Leino, L. T. Kanerva et al.
FULL PAPER
by silica gel chromatography (EtOAc) to yield (S)-3a as a colorless
oil (108 mg, 0.73 mmol, 66%, ee = 84%) and (R)-5a as white solid
[163 mg, 0.86 mmol, 92%, ee = 99%, [α]2D5 = +115 (c = 1.0, CHCl3),
m.p. 74Ϯ1 °C]. A fraction of the enantiomerically enriched (S)-3a
(86 mg, 0.59 mmol) was purified under kinetic resolution condi-
tions, yielding (S)-3a as a colorless oil [38 mg, 0.26 mmol, 44%, ee
= 99%, [α]2D5 = –51 (c = 1.0, CHCl3), [α]2D5 (lit.) = –50.0 (c = 1.13,
(10 mL) and the solution was acidified with 4  HCl (4 mL) and
extracted with EtOAc (3ϫ20 mL). Purification as above yielded
(R)-7 as a white solid [504 mg, 1.88 mmol, 85%, ee Ͼ 99%, [α]2D5
=
+63 (c = 1.0, CHCl3), m.p. 55Ϯ1 °C]. 1H NMR (CDCl3,
500.13 MHz, 25 °C): δ = 7.35–7.31 (m, 2 H, arom. H), 7.27–7.23
(m, 3 H, arom. H), 5.94 (dddd, JCH=Ј,CH2aЈ = 7.1, JCH=Ј,CH2bЈ
=
7.2, JCH=Ј,CH2cisЈ = 10.1, JCH=Ј,CH2transЈ = 17.1 Hz, 1 H, CO-CH2Ј-
CHCl3, ee = 96%)[7c]]. (R)-5a: 1H NMR (CDCl3, 500.13 MHz, CHЈ=CH2Ј), 5.92 (d, JNH,CH = 8.2 Hz, 1 H, NH), 5.67 (JCH=,CH2a
25 °C): δ = 7.39–7.23 (m, 5 H, arom. H), 5.99 (d, JNH,CH = 8.2 Hz, = 6.9, JCH=,CH2b = 7.3, JCH=,CH2cis = 10.1, JCH=,CH2trans = 17.1 Hz,
1 H, NH), 5.68 (dddd, JCH=,CH2b = 6.7, JCH=,CH2a = 7.3,
JCH=,CH2cis = 10.1, JCH=,CH2trans = 17.2 Hz, 1 H, CH2-CH=CH2), JCH2cisЈ,CH2aЈ
5.10 (dddd, JCH2trans,CHa –1.4, JCH2trans,CH2b –1.4, 10.1 Hz, 1 H, CO-CH2Ј-CHЈ=CH2cisЈ), 5.23 (dddd, JCH2transЈ,CH2bЈ
JCH2trans,CH2cis –1.9, JCH2trans,CH= 17.2 Hz, H, CH2- –1.4, JCH2transЈ,CH2aЈ –1.4, JCH2transЈ,CH2cisЈ –1.6,
CH=CH2trans), 5.07 (dddd, JCH2cis,CHa = –1.1, JCH2cis,CH2b = –1.1, JCH2transЈ,CH=Ј = 17.1 Hz, 1 H, CO-CH2Ј-CHЈ=CH2transЈ), 5.10
JCH2cis,CH2trans = –1.9, JCH2cis,CH = 10.1 Hz, 1 H, CH2-CH=CH2cis), (dddd, JCH2trans,CH2b = –1.4, JCH2trans,CH2a = –1.4, JCH2trans,CH2cis
5.07 (ddd, JCH,CH2b = 5.9, JCH,CH2a = 7.9, JCH,NH = 8.2 Hz, 1 H, –1.9, JCH2trans,CH = 17.1 Hz, 1 H, CH2-CH=CH2trans), 5.09 (ddd,
CHNH), 2.57 (ddddd, JCH2a,CH2cis = –1.1, JCH2a,CH2trans = –1.4, JCH,CH2a = 5.9, JCH,CH2b = 7.6, JCH,NH = 8.2 Hz, 1 H, CHNH),
1
H, CH2-CH=CH2), 5.25 (dddd, JCH2cisЈ,CH2bЈ
=
–1.0,
=
–1.1, JCH2cisЈ,CH2transЈ –1.6, JCH2cisЈ,CH=Ј
=
=
=
=
=
=
1
=
=
=
=
JCH2a,CH = 7.3, JCH2a,CH = 7.9, JCH2a,CH2b = –13.8 Hz, 1 H, CH2a-
CH=CH2), 2.56 (ddddd, JCH2b,CH2cis = –1.1, JCH2b,CH2trans = –1.4,
5.08 (dddd, JCH2cis,CH2b = –0.9, JCH2cis,CH2a = –1.2, JCH2cis,CH2trans
= –1.9, JCH2cisЈ,CH=Ј = 10.1 Hz, 1 H, CH2-CH=CH2cis), 3.03 (dddd,
JCH2aЈ,CH2cisЈ = –1.1, JCH2aЈ,CH2transЈ = –1.4, JCH2aЈ,CH=Ј = 7.1,
JCH2b,CH = 5.9, JCH2b,CH = 6.7, JCH2b,CH2a = –13.8 Hz, 1 H, CH2b
-
CH=CH2), 1.99 (s, 3 H, CH3) ppm. 13C NMR (CDCl3, 125.8 MHz, JCH2aЈ,CH2bЈ = –14.1 Hz, 1 H, CO-CH2aЈ-CHЈ=CH2Ј), 3.02 (dddd,
25 °C): δ = 169.3 (CO), 141.6 (arom. C), 134.0 (CH=CH2), 128.6 JCH2bЈ,CH2cisЈ = –1.0, JCH2bЈ,CH2transЈ = –1.4, JCH2bЈ,CH=Ј = 7.2,
(2 arom. C), 127.4 (arom. C), 126.5 (2 arom. C), 125.9 (Carom),
JCH2b,CH2aЈ = –14.1 Hz, 1 H, CO-CH2bЈ-CHЈ=CH2Ј), 2.56 (ddddd,
118.2 (CH=CH2), 52.5 (CHNH), 40.5 (CH2-CH=CH2), 23.4 JCH2a,CH2cis = –1.2, JCH2a,CH2trans = –1.4, JCH2a,CH = 5.9, JCH2a,CH
(COCH3) ppm. HRMS:: calcd. for C12H15NONa [M + Na]+ = 6.9, JCH2a,CH2b = –14.2 Hz, 1 H, CH2a-CH=CH2), 2.55 (ddddd,
212.1046; found 212.1039.
JCH2b,CH2cis = –0.9, JCH2b,CH2trans = –1.4, JCH2b,CH = 7.3, JCH2b,CH
= 7.6, JCH2b,CH2a = –14.2 Hz, 1 H, CH2b-CH=CH2) ppm. 13C
NMR (CDCl3, 125.8 MHz, 25 °C): δ = 169.6 (CO), 141.5 (arom.
C), 133.9 (CH=CH2), 131.3 (CЈH=CЈH2), 128.6 (2 arom. C), 127.4
(arom. C), 126.4 (2 arom. C), 120.0 (CЈH=CЈH2), 118.3
(CH=CH2), 52.2 (CHNH), 41.7 (CЈH2-CЈH=CЈH2), 40.5 (CH2-
CH=CH2) ppm. HRMS: calcd. for C14H17NONa [M + Na]+
238.1202; found 238.1187.
1-Phenylbut-3-en-1-amine (3a) with Ethyl Acrylate: rac-3a
(296 mg, 2.01 mmol) in 1:9 (v/v) mixture of ethyl acrylate in tolu-
ene was added on lipase PS-D (1.00 g, 50 mgmL–1) and molecular
sieves (4 Å, 1.00 g). After 5 d the reaction was stopped at 19%
conversion. The crude product was dissolved in H2O (5 mL) and
the solution was acidified with 2  HCl (5 mL) and extracted with
EtOAc (3ϫ10 mL). The organic phases were combined, dried
with Na2SO4, concentrated and purified by silica pad filtration 1-(4-Fluorophenyl)but-3-en-1-amine (3b) with Isopropyl Acetate: rac-
(EtOAc) to yield (R)-6 as a white solid [50 mg, 0.25 mmol, 65%,
ee = 95%, [α]D25 = +133 (c = 1.0, CHCl3), m.p. 83Ϯ1 °C]. 1H
NMR (CDCl3, 600.13 MHz, 25 °C): δ = 7.36–7.24 (m, 5 H, arom.
3b (429 mg, 2.60 mmol) was resolved as above. After 4 d the reac-
tion was stopped at 33% conversion. The work-up gave (S)-3b as
a pale yellow oil (216 mg, 1.31 mmol, 75%, ee = 48%). The enzy-
H), 6.28 (dd, JCH2transЈ,CH2cisЈ = –1.5, JCH2transЈ,CH=Ј = 17.0 Hz, 1 matic purification gave (S)-3b as a pale yellow oil [71 mg,
H, CO-CH=CH2trans), 6.11 (dd, JCH=Ј,CH2cisЈ = 10.4, JCH=Ј,CH2transЈ 0.43 mmol, 33%, ee = 95%, [α]2D5 = –35 (c = 1.0, CHCl3)]. (R)-5b
= 17.0 Hz, 1 H, CO-CH=CH2), 5.87 (d, JNH,CH = 8.1 Hz, 1 H, was a white solid [133 mg, 0.64 mmol, 75%, ee Ͼ 99%, [α]2D5
=
NH), 5.70 (dddd, JCH=,CH2b = 6.9, JCH=,CH2a = 7.1, JCH=,CH2cis
10.2, JCH=,CH2trans = 17.1 Hz, 1 H, CH2-CH=CH2), 5.64 (dd,
JCH2cisЈ,CH2transЈ –1.5, JCH2cisЈ,CH 10.4 Hz, H, CO- 7.04–6.99 (m, 2 H, arom. H), 5.75 (d, JNH,CH = 8.0 Hz, 1 H, NH),
CH=CH2cis), 5.17 (dd, JCH,CH2b = 6.4, JCH,CH2a = 7.3 Hz, 1 H, 5.66 (dddd, JCH=,CH2b = 6.8, JCH=,CH2a = 7.2, JCH=,CH2cis = 10.1,
CHNH), 5.12 (dddd, JCH2trans,CH2a = –1.4, JCH2trans,CH2b = –1.5, JCH=,CH2trans 17.2 Hz, H, CH2-CH=CH2), 5.11 (dddd,
JCH2trans,CH2cis –1.9, JCH2trans,CH 17.1 Hz, H, CH2- JCH2trans,CHa = –1.4, JCH2trans,CH2b = –1.5, JCH2trans,CH2cis = –1.9,
CH=CH2trans), 5.09 (dddd, JCH2cis,CH2a = –1.0, JCH2cis,CH2b = –1.2, JCH2trans,CH= = 17.2 Hz, 1 H, CH2-CH=CH2trans), 5.09 (dddd,
JCH2cis,CH2trans –1.9, JCH2cis,CH 10.2 Hz, H, CH2- JCH2cis,CHa = –1.1, JCH2cis,CH2b = –1.1, JCH2cis,CH2trans = –1.9,
CH=CH2cis), 2.62 (ddddd, JCH2a,CH2cis = –1.0, JCH2a,CH2trans JCH2cis,CH= = 10.1 Hz, 1 H, CH2-CH=CH2cis), 5.05 (ddd, JCH,CH2b
=
+109.0 (c = 1.0, CHCl3), m.p. 120Ϯ1 °C]. (R)-5b: 1H NMR
(CDCl3, 500.13 MHz, 25 °C): δ = 7.26–7.22 (m, 2 H, arom. H),
=
=
1
=
1
=
=
1
=
=
1
=
–1.4, JCH2a,CH = 7.1, JCH2a,CH = 7.3, JCH2a,CH2b = –13.7 Hz, 1 H, = 6.6, JCH,CH2a = 7.2, JCH,NH = 8.0 Hz, 1 H, CHNH), 2.54 (ddddd,
CH2a-CH=CH2), 2.61 (ddddd, JCH2b,CH2cis = –1.2, JCH2b,CH2trans JCH2a,CH2cis = –1.1, JCH2a,CH2trans = –1.4, JCH2a,CH = 7.2, JCH2a,CH
= –1.5, JCH2b,CH = 6.4, JCH2b,CH = 6.9, JCH2b,CH2a = –13.7 Hz, 1
H, CH2b-CH=CH2) ppm. 13C NMR (CDCl3, 150.9 MHz, 25 °C): JCH2b,CH2cis = –1.1, JCH2b,CH2trans = –1.5, JCH2b,CH = 6.6, JCH2b,CH
δ = 164.7 (CO), 141.4 (arom. C), 133.9 (CH=CH2), 130.7 (CO- = 6.8, JCH2b,CH2a = –13.9 Hz, 1 H, CH2b-CH=CH2), 1.99 (s, 3 H,
CH=CH2), 128.7 (2 arom. C), 127.4 (arom. C), 126.8 (CO- CH3) ppm. 13C NMR (CDCl3, 125.8 MHz, 25 °C): δ = 169.3 (CO),
= 7.2, JCH2a,CH2b = –13.9 Hz, 1 H, CH2a-CH=CH2), 2.54 (ddddd,
1
4
CH=CH2), 126.5 (2 arom. C), 118.3 (CH=CH2), 52.5 (CHNH),
162.0 (d, JC,F = 245.8 Hz, arom. C), 137.5 (d, JC,F = 2.8 Hz,
3
40.4 (CH2-CH=CH2) ppm. HRMS: calcd. for C13H15NONa [M arom. C), 133.7 (CH=CH2), 128.0 (d, JC,F = 8.3 Hz, 2 arom. C),
+ Na]+ 224.1046; found 224.1144.
118.5 (CH=CH2), 115.4 (d, JC,F = 21.1 Hz, 2 arom. C), 51.9
(CHNH), 40.5 (CH2-CH=CH2), 23.4 (COCH3) ppm. HRMS:
calcd. for C12H14FNONa [M + Na]+ 230.0952; found 230.0949.
2
1-Phenylbut-3-en-1-amine (3a) with Isopropyl 3-Butenoate: rac-3a
(693 mg, 4.71 mmol) in the 1:9 (v/v) mixture of isopropyl 3-buteno-
ate in toluene was added on lipase PS-D (2.36 g, 50 mgmL–1) and
molecular sieves (4 Å, 2.40 g). After 5 d the reaction was stopped
at 47% conversion. The crude product was dissolved in H2O
1-(4-Methoxyphenyl)but-3-en-1-amine (3c) with Isopropyl Acetate:
rac-3c (227 mg, 1.28 mmol) was resolved as above. After 4 d the
reaction was stopped at 49% conversion. The work-up gave (S)-3c
916
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 909–919

Synthesis of Enantiopure Benzyl Homoallylamines
as a colorless oil [0.108 mg, 0.61 mmol, 93%, ee = 94%, [α]2D5 = –34
(c = 1.0, CHCl3), [α]2D5 (lit.) = –42.3 (c = 0.81, CHCl3, ee =
97%)[7c]] and (R)-5c as a white solid [91 mg, 0.41 mmol, 65%, ee
Ͼ99%, [α]2D5 = +110 (c = 1.0, CHCl3), m.p. 122Ϯ1 °C]. (R)-5c: 1H
NMR (CDCl3, 500.13 MHz, 25 °C): δ = 7.22–7.18 (m, 2 H, arom.
H), 6.88–6.84 (m, 2 H, arom. H), 5.84 (d, JNH,CH = 8.1 Hz, 1 H,
tical to above except that the system was alkalized with 6  NaOH
and extracted with EtOAc (4ϫ20 mL). Purification yielded (R)-3a
(11 mg, 0.07 mmol, 21%, ee = 91%).
Synthesis of (1S)-1-Phenyl-N-(prop-2-en-1-yl)but-3-en-1-amine [(S)-
8]: In a Schlenk tube flushed with argon, (S)-3a (60 mg, 0.41 mmol,
ee 99%) was dissolved in anhydrous DMF (1.5 mL). KOH
(70.2 mg, 1.25 mmol, 3 equiv.) was added and the mixture was
stirred for 15 min. Allyl bromide (35 µL, 0.40 mmol, 1 equiv.) was
added and the mixture was stirred at room temperature for 3 h.
The reaction was quenched by adding H2O (5 mL) and extracted
with Et2O (3ϫ5 mL). The combined organic layers were dried with
anhydrous Na2SO4, filtered and concentrated to yield the crude
product that was purified by flash chromatography (eluent hexane/
EtOAc, 1:1 + 1% Et3N; silica enriched with ca. 0.1% Ca) yielding
of (1S)-1-phenyl-N-(prop-2-en-1-yl)but-3-en-1-amine (51.5 mg,
0.27 mmol, 67%) as a colorless oil. [α]2D0 = –27 (c = 0.01, CHCl3).
Rf = 0.65 (hexane/EtOAc, 1:1). 1H NMR (600.13 MHz, CDCl3,
25 °C): δ = 7.35–7.29 (m, 4 H, arom. H), 7.26–7.22 (m, 1 H, arom.
NH), 5.68 (dddd, JCH=,CH2b = 6.9, JCH=,CH2a = 7.1, JCH=,CH2cis
=
10.2, JCH=,CH2trans = 17.2 Hz, 1 H, CH2-CH=CH2), 5.09 (dddd,
JCH2trans,CHa = –1.4, JCH2trans,CH2b = –1.5, JCH2trans,CH2cis = –1.9,
JCH2trans,CH = 17.2 Hz, 1 H, CH2-CH=CH2trans), 5.06 (dddd,
JCH2cis,CHa = –1.1, JCH2cis,CH2b = –1.1, JCH2cis,CH2trans = –1.9,
JCH2cis,CH = 10.2 Hz, 1 H, CH2-CH=CH2cis), 5.03 (ddd, JCH,CH2b
= 6.7, JCH,CH2a = 7.3, JCH,NH = 8.1 Hz, 1 H, CHNH), 2.56 (ddddd,
JCH2a,CH2cis = –1.1, JCH2a,CH2trans = –1.4, JCH2a,CH = 7.1, JCH2a,CH
= 7.3, JCH2a,CH2b = –14.2 Hz, 1 H, CH2a-CH=CH2), 2.53 (ddddd,
JCH2b,CH2cis = –1.1, JCH2b,CH2trans = –1.5, JCH2b,CH = 6.7, JCH2b,CH
= 6.9, JCH2b,CH2a = –14.2 Hz, 1 H, CH2b-CH=CH2), 1.97 (s, 3 H,
CH3) ppm. 13C NMR (CDCl3, 125.8 MHz, 25 °C): δ = 169.2 (CO),
158.8 (arom. C), 134.2 (CH=CH2), 133.7 (arom. C), 127.7 (2 arom.
C), 118.0 (CH=CH2), 114.0 (2 arom. C), 55.3 (OCH3), 52.0
(CHNH), 40.4 (CH2-CH=CH2), 23.4 (COCH3) ppm. HRMS:
calcd. for C13H17NO2Na [M + Na]+ 242,1152; found 242,1257.
H), 5.86 (dddd, JCH=Ј,CH2aЈ = 5.4, JCH=Ј,CH2bЈ = 6.7, JCH=Ј,CH2cisЈ
=
10.2, JCH=Ј,CH2transЈ = 17.2 Hz, 1 H, CH2Ј-CHЈ=CH2Ј), 5.72 (dddd,
JCH=,CH2a = 5.9, JCH=,CH2b = 8.3, JCH=,CH2cis = 10.1, JCH=,CH2trans
= 17.1 Hz, 1 H, CH2-CH=CH2), 5.10 (dddd, JCH2transЈ,CH2bЈ = –1.4,
3-Methyl-1-phenylbut-3-en-1-amine (3d) with Ethyl Methoxyacetate:
rac-3d (380 mg, 2.36 mmol) was resolved as above except that 17.2 Hz, 1 H, CH2Ј-CHЈ=CH2transЈ), 5.09 (dddd, JCH2trans,CH2b
JCH2transЈ,CH2aЈ = –1.7, JCH2transЈ,CH2cisЈ = –1.9, JCH2transЈ,CH=Ј
=
=
=
CAL-B (Novozym 435, 1.22 g, 50 mgmL–1) was used in the place
of lipase PS-D. After 7 d the reaction was stopped at 31% conver-
sion. The crude product was dissolved in H2O (10 mL) and the
solution was acidified with 4  HCl (4 mL) and extracted with
EtOAc (3ϫ20 mL). The aqueous phase was alkalized with 4 
NaOH (4 mL) and extracted with EtOAc (3ϫ20 mL). The organic
phases were combined, dried with Na2SO4 and concentrated to
yield (S)-3d as a colorless oil (93 mg, 0.57 mmol, 35%, ee = 44%).
The enantiomerically enriched (S)-3d was purified under kinetic
resolution conditions, yielding (S)-3d as a colorless oil [20 mg,
0.12 mmol, 21%, ee = 72%, [α]2D5 = –31 (c = 1.0, CHCl3)]. The
combined organic phases containing (R)-4d was treated in the same
way and purified by silica pad filtration (EtOAc) to yield (R)-4d as
–1.2, JCH2trans,CH2a = –1.7, JCH2trans,CH2cis = –2.0, JCH2trans,CH
17.1 Hz, 1 H, CH2-CH=CH2trans), 5.06 (dddd, JCH2cisЈ,CH2bЈ = –1.2,
JCH2cisЈ,CH2aЈ –1.4, JCH2cisЈ,CH2transЈ –1.9, JCH2cisЈ,CH=Ј
=
=
=
10.2 Hz, 1 H, CH2Ј-CHЈ=CH2cisЈ), 5.05 (dddd, JCH2cis,CH2b = –0.9,
JCH2cis,CH2a = –1.3, JCH2cis,CH2trans = –2.0, JCH2cis,CH= = 10.1 Hz, 1
H, CH2-CH=CH2cis), 3.70 (dd, JCH,CH2a = 5.8, JCH,CH2b = 7.9 Hz,
1 H, CHNH), 3.11 (dddd, JCH2aЈ,CH2cisЈ = –1.4, JCH2aЈ,CH2transЈ
–1.7, JCH2aЈ,CH=Ј = 5.4, JCH2aЈ,CH2bЈ = –14.2 Hz, 1 H, CH2aЈ-
CHЈ=CH2Ј), 3.02 (dddd, JCH2bЈ,CH2cisЈ = –1.2, JCH2bЈ,CH2transЈ
–1.4, JCH2bЈ,CH=Ј = 6.7, JCH2bЈ,CH2aЈ = –14.2 Hz, 1 H, CH2bЈ-
CHЈ=CH2Ј), 2.43 (ddddd, JCH2a,CH2cis = –1.3, JCH2a,CH2trans = –1.7,
JCH2a,CH = 5.8, JCH2a,CH = 5.9, JCH2a,CH2b = –13.9 Hz, 1 H, CH2a-
CH=CH2), 2.40 (ddddd, JCH2b,CH2cis = –0.9, JCH2b,CH2trans = –1.2,
JCH2b,CH = 7.9, JCH2a,CH= = 8.3, JCH2a,CH2b = –13.9 Hz, 1 H, CH2a-
=
=
a white solid [184 mg, 0.79 mmol, quant. yield, ee Ͼ 99%, [α]2D5
=
1
+45 (c = 1.0, CHCl3), m.p. 53Ϯ1 °C]. (R)-4d: H NMR (CDCl3, CH=CH2) ppm. 13C NMR (150.9 MHz, CDCl3, 25 °C): δ = 143.7
500.13 MHz, 25 °C): δ = 7.35–7.23 (m, 5 H, arom. H), 6.78 (d, (arom. C), 136.9 (CЈH=CЈH2) 135.4 (CH=CH2), 128.3 (2 arom.
JNH,CH = 8.4 Hz, 1 H, NH), 5.20 (ddd, JCH,CH2a = 5.8, JCH,NH
8.4, JCH,CH2b = 9.4 Hz, 1 H, CHNH), 4.82 (ddq, JCH2trans,CHa
=
=
C) 127.2 (2 arom. C.), 127.0 (arom. C), 117.5 (CH=CH2), 115.7
(CHЈ=CH2Ј), 61.7 (CHNH), 50.0 (CЈH2-CЈH=CЈH2), 43.0 (CH2-
–0.6, JCH2trans,CH3 = 1.4, JCH2trans,CH2cis = –2.0 Hz, 1 H, CH2- CH=CH2) ppm. HRMS: calcd. for C13H17N [M]+ 187.1361; found
CH=CH2trans), 4.74 (dddq, JCH2cis,CH3 = 0.9, JCH2cis,CH2b = –1.0,
JCH2cis,CHa –1.3, JCH2cis,CH2trans –2.0 Hz, H, CH2-
CH=CH2cis), 3.88 (s, 2 H, CH2OCH3), 3.40 (s, 3 H, CH2OCH3),
2.54 (dddd, JCH2a,CH2trans = –0.6, JCH2a,CH2cis = –1.3, JCH2a,CH
5.8, JCH2a,CH2b = –14.2 Hz, 1 H, CH2a-CH=CH2), 2.50 (ddd,
JCH2b,CH2cis = –1.0, JCH2b,CH = 9.4, JCH2b,CH2a = –14.1 Hz, 1 H,
CH2b-CH=CH2), 1.74 (s, 3 H, CH3) ppm. 13C NMR (CDCl3,
125.8 MHz, 25 °C): δ = 168.8 (CO), 142.1 (arom. C), 141.8
[C(CH3)=CH2], 128.6 (2 arom. C), 127.3 (arom. C), 126.3 (2 arom.
C), 113.8 [C(CH3)=CH2], 72.0 (CH2OCH3), 59.3 (CH2OCH3), 50.5
(CHNH), 45.1 [CH2-C(CH3)=CH2], 22.1 (CH3) ppm. HRMS:
calcd. for C14H19NO2Na [M + Na]+ 256.1308; found 256.1396.
187.1350.
=
=
1
Synthesis of (2S)-2-Phenyl-1,2,3,6-tetrahydropyridine [(S)-9]: In a
Schlenk tube flushed with argon, (1S)-1-phenyl-N-(prop-2-en-1-yl)
but-3-en-1-amine (S)-8 (22.0 mg, 0.12 mmol) was dissolved in an-
hydrous CH2Cl2 (1.2 mL). p-toluenesulfonic acid monohydrate
(23.4 mg, 0.12 mmol) of was added and the mixture was stirred for
10 min. Grubbs’ second-generation catalyst (NHC)(PCy3)-
Cl2Ru=CHR (10.2 mg, 0.012 mmol, 10 mol-%) was added and the
resulting mixture was stirred at room temperature for 17 h. The
solvent was evaporated and the residue dissolved in EtOAc
(15 mL). The organic layer was extracted with 1  HCl (4ϫ5 mL).
The combined aqueous layers were alkalized (pH = 14) by adding
=
Procedure for the Hydrolysis of (R)-5a and (R)-4a: (R)-5a (169 mg, NaOH (s). The basic solution was extracted with EtOAc
0.89 mmol, ee = 97%) was refluxed in 4  HCl for 19 h, and there-
after the solution was cooled to room temperature, alkalized with
4  NaOH and extracted with EtOAc (3ϫ25 mL). The combined
organic layer was concentrated in vacuo and the residue purified
through column chromatography (EtOAc) to yield (R)-3a (24 mg,
0.16 mmol, 18%, ee = 97%.). (R)-4a (74 mg, 0.34 mmol, ee = 94%)
was refluxed in 6  HCl for one hour, and thereafter handled iden-
(3ϫ10 mL). The organic layers were combined, dried with anhy-
drous Na2SO4, filtered and concentrated to yield the crude product
that was purified by flash chromatography (eluent hexane/EtOAc,
1:1 + 1% Et3N; silica enriched with ca. 0.1% Ca) yielding of (2S)-
2-phenyl-1,2,3,6-tetrahydropyridine (13.4 mg, 0.084 mmol, 70%) as
yellowish oil. [α]2D0 = –88 (c = 0.01, CHCl3). Rf = 0.15 (hexane/
EtOAc, 1:1). 1H NMR (600.13 MHz, CDCl3, 25 °C): δ = 7.40–7.37
Eur. J. Org. Chem. 2010, 909–919
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
917

R. Leino, L. T. Kanerva et al.
FULL PAPER
(m, 2 H arom. H), 7.36–7.32 (m, 2 H, arom. H), 7.28–7.25 (m, 1
H, arom. H), 5.87 (ddddd, JCH=,CH2aЈ = –1.8, JCH=,CH2a = 1.8,
= –1.0, JCH2aЈ,CH=Ј = 2.4, JCH2aЈ,CH = 2.9, JCH2aЈ,CH2a = –4.3,
JCH2aЈ,CH = 12.1, JCH2aЈ,CH2bЈ = –18.2 Hz, 1 H, CH-CH2aЈ), 2.48
JCH=,CH2b = 2.5, JCH=,CH2bЈ = –5.3, JCH=,CH=Ј = 10.1 Hz, 1 H, (ddddddd, JCH2bЈ,CH=Ј = 1.8, JCH2bЈ,CH2b = –1.9, JCH2bЈ,NH = –2.3,
CHЈ=CHЈ), 5.79 (ddddd, JCH=Ј,CH2bЈ = 1.5, JCH=Ј,CH2b = –1.9,
JCH=Ј,CH2aЈ = 2.7, JCH=Ј,CH2a = –4.4, JCH=Ј,CH= = 10.1 Hz, 1 H,
CHЈ=CHЈ), 3.85 (dd, JCH,CH2bЈ = 3.8, JCH,CH2aЈ = 10.3 Hz, 1 H,
JCH2bЈ,CH = 2.4, JCH2bЈ,CH2a = –3.6, JCH2bЈ,CH = 5.1, JCH2bЈ,CH2aЈ =
–18.2 Hz) ppm. 13C NMR (150.9 MHz, CDCl3, 25 °C): δ = 174.2
(CO), 140.4 (arom. C), 129.2 (2 arom. C), 128.7 (CH=CHЈ), 128.4
CH), 3.62 (ddddd, JCH2a,CH = 1.8, JCH2a,CH2aЈ = –2.5, JCH2a,CH2bЈ (arom. C), 126.3 (2 arom. C), 120.3 (CH=CHЈ), 55.0 (CH), 37.1
= –3.4, JCH2a,CH=Ј = –4.4, JCH2a,CH2b = –16.9 Hz, 1 H, CH2a-
CH=CHЈ), 3.50 (ddddd, JCH2b,CH2bЈ = –0.9, JCH2b,CH=Ј = –1.9,
JCH2b,CH = 2.5, JCH2b,CH2aЈ = –4.7, JCH2b,CH2a = –16.9 Hz, 1 H,
(CH2Ј), 35.4 (CH2) ppm. HRMS: calcd. for C12H13NO [M]+
187.0997; found 187.0993.
Supporting Information (see also the footnote on the first page of
this article): Gas chromatograms of the resolved compounds and
1H and 13C NMR spectra of the prepared compounds.
CH2b-CH=CHЈ), 2.29 (dddddd, JCH2aЈ,CH = –1.8, JCH2aЈ,CH2a
=
–2.5, JCH2aЈ,CH=Ј = 2.7, JCH2aЈ,CH2b = –4.7, JCH2aЈ,CH = 10.3,
JCH2aЈ,CH2bЈ = –17.3 Hz, 1 H, CH2aЈ-CHЈ=CHЈ), 2.25 (dddddd,
JCH2bЈ,CH2b = –0.9, JCH2bЈ,CH=Ј = 1.5, JCH2bЈ,CH2a = –3.4, JCH2bЈ,CH
= 3.8, JCH2bЈ,CH = –5.3, JCH2bЈ,CH2aЈ = –17.3 Hz, 1 H, CH2bЈ-
CHЈ=CHЈ) ppm. 13C NMR (150.9 MHz, CDCl3, 25 °C): δ = 144.4
(arom. C), 128.6 (2 arom. C), 127.2 (arom. C), 126.6 (2 arom. C)
125.9 (CH=CHЈ), 125.6 (CH=CHЈ), 57.7 (CH), 46.1 (CH2), 34.1
(CH2Ј) ppm. HRMS: calcd. for C11H13N [M]+ 159.1048; found
159.1046.
Acknowledgments
The authors thank the Academy of Finland for financial support
[research grants to L. K. (#121983) and R. L. (#121334); project:
Fusing Biocatalytic and Chemocatalyzed Reaction Technologies].
Stipendiary support from the Swedish Academy of Engineering
Sciences in Finland (to T. S.), the Waldemar von Frenckell Founda-
tion and the Rector of Åbo Akademi University (to S. R.) is also
gratefully acknowledged. Markku Reunanen is thanked for HRMS
analysis.
Synthesis of (6R)-6-Phenyl-5,6-dihydropyridin-2(1H)-one [(R)-10]:
In a Schlenk tube flushed with argon, (R)-N-(1-phenylbut-3-enyl)
acrylamide (R)-6 (20.2 mg, 0.10 mmol, ee 95%) was dissolved in
anhydrous CH2Cl2 (1.5 mL). Grubbs’ second-generation catalyst
(NHC)(PCy3)Cl2Ru=CHR (3.6 mg, 0.0042 mmol) dissolved in an-
hydrous CH2Cl2 (0.5 mL) was added and the resulting mixture was
stirred at room temperature for 30 min and then refluxed (+40 °C)
for 4 h after which Grubbs’ second-generation catalyst (3.9 mg,
0.0046 mmol) dissolved in anhydrous CH2Cl2 (0.5 mL) was added
and stirring at reflux was continued for 18.5 h. The crude product
was purified by flash chromatography (eluent hexane/EtOAc, 1:1 +
1% Et3N; silica enriched with ca. 0.1% Ca) yielding (6R)-6-phenyl-
5,6-dihydropyridin-2(1H)-one (14.4 mg, 0.083 mmol, 83%) as a off-
white solid. [α]2D0 = +210 (c = 0.01, CHCl3). Rf = 0.09 (hexane/
EtOAc, 1:1). 1H NMR (600.13 MHz, CDCl3, 25 °C): δ = 7.41–7.33
(m, 5 H, arom. H), 6.65 (ddd, JCH=,CH2b = –2.8, JCH=,CH2a = –5.5,
[1] J. Birks, J. Grimley Evans, V. Iakovidou, M. Tsolaki, F. E. Holt,
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JCH=,CH=Ј = 10.0 Hz, 1 H, CO-CH=CH), 6.03 (dddd, JCH=Ј,CH
=
–1.1, JCH=Ј,CH2a = 1.4, JCH=Ј,CH2b = 2.6, JCH=Ј,CH = 10.0 Hz, 1 H,
CO-CH=CH), 5.58 (br. s., 1 H, NH), 4.75 (dd, JCH,CH2a = 5.5,
JCH,CH2b = 11.8 Hz, 1 H, CH), 2.59 (dddd, JCH2a,CH=Ј = 1.4,
JCH2a,CH = 5.5, JCH2a,CH = –5.5, JCH2a,CH2b = –17.8 Hz, 1 H,
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CH2a), 2.52 (dddd, JCH2b,CH=Ј = 2.6, JCH2b,CH = –2.8, JCH2b,CH
=
11.8, JCH2b,CH2b = –17.8 Hz,
1
H, CH2b) ppm. 13C NMR
(150.9 MHz, CDCl3, 25 °C): δ = 166.5 (CO), 141.0 (arom. C), 140.3
(CO-CH=CHЈ), 129.0 (2 arom. C), 128.4 (arom. C), 126.4 (2 arom.
C), 124.5 (CO-CH=CHЈ), 56.0 (CH), 33.1 (CH2) ppm. HRMS:
calcd. for C11H11NONa [M + Na]+ 196.0738; found 196.0750.
Synthesis (7R)-7-Phenyl-1,3,6,7-tetrahydro-2H-azepin-2-one [(R)-
11]: Procedure as above starting from (R)-7 (16.6 mg, 0.08 mmol, ee
Ͼ 99%). Yield (3.2 mg, 0.017 mmol, 22%). The amount of purified
material was not sufficient for reliable measurement of the optical
rotation. Rf = 0.15 (hexane/EtOAc, 1:1), 1H NMR (600.13 MHz,
CDCl3, 25 °C): δ = 7.42–7.38 (m, 2 H, arom. H), 7.37–7.33 (m, 3
H, arom. H), 5.76 (dd, JNH=,CH2bЈ = –2.3, JNH=,CH = 5.8 Hz, 1 H,
NH), 5.74 (dddd, JCH=,CH2aЈ = 2.9, JCH=,CH2a = 3.1, JCH=,CH2bЈ
=
5.1, JCH=,CH=Ј = 11.6 Hz, 1 H, COCH2CH=CHЈ), 5.66 (ddddd,
JCH=Ј,CH2bЈ = 1.8, JCH=Ј,CH2aЈ = 2.4, JCH=Ј,CH2a = 2.8, JCH=Ј,CH2b
= 8.6, JCH=Ј,CH = 11.6 Hz, 1 H, COCH2CH=CHЈ), 4.95 (ddd,
JCH,CH2bЈ = 2.4, JCH,NH = 5.8, JCH,CH2aЈ = 12.1 Hz, 1 H, CH),
3.66 (ddddd, JCH2a,CH=Ј = 2.8, JCH2a,CH = 3.1, JCH2a,CH2bЈ = –3.6,
JCH2a,CH2aЈ = –4.3, JCH2a,CH2b = –16.7 Hz, 1 H, CO-CH2a), 2.92
(dddd, JCH2b,CH2aЈ = –1.0, JCH2b,CH2bЈ = –1.9, JCH2b,CH=Ј = 8.6,
JCH2b,CH2a = –16.7 Hz, 1 H, CO-CH2b), 2.71 (dddddd, JCH2aЈ,CH2b
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Received: October 26, 2009
Published Online: December 22, 2009
Eur. J. Org. Chem. 2010, 909–919
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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