Rearrangement Reactions Leading to Optically Active α,α-Disubstituted Primary Allylamines

Article abstract of DOI:10.1002/ejoc.201601446

Synthetic routes to α,α-disubstituted allylamines have been examined. Racemic compounds were conveniently prepared by thermal Overman rearrangements of primary allylic alcohols with trisubstituted double bonds, but rearrangement of these substrates using

Full text of DOI:10.1002/ejoc.201601446

A Journal of
Accepted Article
Title: Rearrangement Reactions leading to Optically Active α,α-
Disubstituted Primary Allylamines
Authors: Martin Hennum, Hege Hortemo Odden, and Lise-Lotte
Gundersen
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10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
Rearrangement Reactions
leading to Optically Active α,α-
Disubstituted Primary
Allylamines
H
H
R'
RN
HN
R''
N
N
N
N
N
RCM
[red], deprotect.
N
N
N
Asmarine H
Martin Hennum,[a] Hege Hortemo Odden,[a] [‡] and
Lise-Lotte Gundersen*[a]
HN
X
R''
N
N
N
H
N
N
+
N
N
R'
Abstract: Synthetic routes to α,α-disubstituted allylamines have
been examined. Racemic compounds were conveniently prepared
by thermal Overman rearrangements of primary allyl alcohols with
trisubstituted double bonds, but rearrangement of these substrates
by the only commercially available compound known to catalyze
enantioselective Overman rearrangements, the cobalt oxazoline
palladacycle (R)-COP-Cl, failed. Instead optically active secondary
allyl alcohols with trisubstituted double bonds, obtained by CBS-
mediated reduction of the corresponding methyl ketones, were
synthesized and converted to α,α-disubstituted allylamines via a
thermal Overman rearrangement or an allyl cyanate to isocyanate
rearrangement. High chiral transfer (90-99%) was obtained with both
reaction sequences, but the chemical yields were greatly improved
when the allyl cyanate to isocyanate rearrangement were employed.
N
7,8,9,10-Tetrahydro-
[1,4]diazepino-
[1,2,3-gh]purine
H2N
R': H or alkyl
Figure 1. Structure of 7,8,9,10-tetrahydro-[1,4]diazepino-[1,2,3-gh]purine and
a retrosynthetic analysis of asmarine H.
There are relatively few examples of α,α-disubstituted primary
allylamines, except α-substituted vinyglycines or cyclic
compounds, the in the literature. These amines have been
synthesized as racemates from α,α-disubstituted propargyl
halides by reaction with ammonia followed by partial reduction of
the triple bond,[5] non-regioselective ring opening of 2-methyl-2-
vinyloxirane,[6] Pd-catalyzed formal [3,3] rearrangement of allylic
N-PMP trifluoroacetimidates,[7] addition of organosamarium
reagents to acrylonitrile,[8] addition of vinyl Grignard reagents to
sulfinylimines,[9] cycloaddition of bis(methoxycarbonyl)sulfur
Introduction
We have previously shown that 7,8,9,10-tetrahydro-
[1,4]diazepino-[1,2,3-gh]purine (Fig. 1), the heterocyclic part in
marine natural products called asmarines,[1,2] can be synthesized
diimide with alkenes followed by
a
[2,3] sigmatropic
rearrangement,[10] Pd-catalyzed hydroamination of 1,3-dienes
with hydrazines followed by reduction of the hydrazine product
or quite regioselective Pd-catalyzed allylic alylation of ammonia
synthons,[11] and last but not least the Overman rearrangement
of allylic alcohols,[12] and related rearrangements of allylic
cyanates.[13]
with a ring-closing metathesis (RCM) as a key-step.[3]
A
retrosynthetic analysis of asmarine H is shown in Fig. 1. 7-
Alkenyl-6-halopurines are easily available by base or ruthenium
mediated rearrangements of the corresponding 7-allylpurine,[3,4]
but synthesis of the α,α-disubstituted allylamine building block is
expected to be a major challenge.
Few of the methods listed above are applicable for the synthesis
of optically active α,α-disubstituted allylamines. Pd-catalyzed
regio- and enantioselective ring opening of isoprene monoxide
with primary amines has been achieved,[14] enantioselective Pd-
mediated aza-Claisen rearangements[15] and Pd-catalyzed
enantioselective decarboxylative cycloaddition of vinylene
carbonates with isocyanates or imines followed by hydrolysis of
the oxazilidinone formed[16] are reported. Vinyllithium addition to
a chiral 1,3 oxazolidine followed by reductive removal of the N-
substituent also gives optically active α,α-disubstituted primary
allylamines.[17] This last methodology is restricted to synthesis of
compounds where one of the α-substituents is CF3. We herein
report and compare several strategies for the synthesis of α,α-
disubstituted allylamines; useful building blocks in organic
synthesis and model substances for the amines required in
asmarine synthesis.
[a]
Department of Chemistry
University of Oslo
PO Box 1033, Blindern N-0315 Oslo, Norway
E-mail: l.l.gundersen@kjemi.uio.no
Present address: A/S Norske Shell
Tankveien 1, N-4098 Tananger, Norway
[‡]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
Our first approach to α,α-disubstituted allylamines was the
Overman rearrangement,[12] since also transition metal mediated
asymmetric versions of this reaction are known.[18] Scheme 1
presents synthesis of racemic amines with the thermal Overman
rearrangement as the key-step. Esters 3 were synthesized either
by a conjugated copper-mediated addition of Grignard reagents
to the alkynes 1[15a,19] or by a Horner-Wadsworth-Emmons
(HWE) olefination of ketones 2 (Scheme 1, Table 1). The total
yields of compounds 3 from the methods tried varied greatly with
the structure of the starting material. The HWE reaction on
ketone 2b in the presence of DBU and CsCO3 resulted only in a
low yield of the desired product 3b. Instead compound 4,[20]
where the double bond had migrated into conjugation with the
phenyl ring was formed as the major product. Changing the
base to NaH, however, allowed isolation of the desired α,β-
unsaturated ester 3b in 93% yield. The ketones needed for the
synthesis of esters 3d and 3e by the HWE reaction were not
commercially available and these esters were only prepared
from alkyne 1. In general addition of Grignard reagents to the
alkyne 1 in the presence of CuI, LiCl and TMSCl resulted in very
high E-selectivity compared with the other strategies. The α,β-
unsaturated esters 3 were conveniently reduced to the allylic
alcohols 5 by DIBAL-H. The E/Z ratio in the starting material was
conserved in the product and there were no indications that the
isomers of 3 reacted with a significantly different rate. Alcohols 5
were converted to the corresponding trichloroacetimidates 6,
employing a modified procedure of that previously used to
generate imidate 6c.[12e] The imidates 6 were, due to their low
stability, reacted directly to the amides 7 by a thermal Overman
rearrangement. Finally the amides 7 were hydrolyzed to the
racemic allylic amines 8. Best yields were in most cases
obtained when the amines were isolated as their HCl salts 9.
Table 1. Synthesis of compounds 3.
Entry
R
Yield [%] 3[a]
E/Z[b]
Starting
Reaction
conditions
material
1
1
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
PhCH2
A[c]
B[d]
C[e]
D[f]
A
90, 3a
72, 3a
60, 3a
95, 3a
62, 3b
56, 3b
12, 3b[g]
93, 3b
88, 3c
57, 3c
73, 3c
89, 3c
69, 3d
73, 3d
75, 3e
70, 3e
75:25
97:3
3:1
2
1
3
2a
2a
1
4
4:1
5
9:1
6
1
PhCH2
B
>99:1
2:1
7
2b
2b
1
PhCH2
C
8
PhCH2
D
6:1
9
Ph
A
62:38
>99:1
6:1
10
11
12
13
14
15
16
1
Ph
B
2c
2c
1
Ph
C
Ph
D
6:1
c-Hex(CH2)2
c-Hex(CH2)2
1-Naph(CH2)2
1-Naph(CH2)2
A
56:44
89:11
62:38
>99:1
1
B
1
A
1
B
[a] Isolated yield. [b] From 1H NMR. [c] RMgX, CuI, TMEDA, THF, -78 oC. [d]
RMgX, CuI, LiCl, TMSCl, THF, -78 oC. [e] (EtO)2POCH2CO2Et, DBU, CsCO. [f]
(EtO)2POCH2CO2Et, NaH, THF. [g] Compound 4 (E/Z: 9:8) was also observed.
The 1H NMR data of the E-isomer, were in good agreement with those
reported before.[20]
(a)
(b)
CO2Et
CO2Et
OH
R
R
1
3a-e
Yields see Table 1
5a R = PhCH2CH2, 88%
5b R = PhCH2, 86%
5c R = Ph, 85%
Next we examined the possibility for an enantioselective
Overman rearrangement of imidates 6. The only known
examples of aza-Claisen rearrangements in the presence of
chiral catalysts, leading to optically active α,α-disubstituted
5d R = c-HexCH2CH2, 92%
5e R = 1-NaphCH2CH2, 91%
(g)
CO2Et
Ph
(c)
O
R
2a R = PhCH2CH2
2b R = PhCH2
2c R = Ph
4
NH
allylamines,
include
reaction
of
N-substituted
O
CCl3
trifluoroacetimidates catalyzed by
a
ferrocenyl imidazoline
R
palladacycle,[15] or by a palladacycle combined with the chiral
TRIP anion.[21] However neither the ferrocenyl imidazoline
palladacycles nor the TRIP compound are commercially
available. Enantioselective Overman rearrangement of imidates
from disubstituted alkenes have been catalyzed by cobalt
oxazoline palladacycles (COP) including the commercially
available (R)-COP-Cl.[18] Unfortunately, no rearrangement took
place at all, when the in situ generated imidate 6a was reacted
with this catalyst following conditions previously employed for
rearrangement of imidates from disubstituted alkenes (Scheme
2).[18c] Raising the temperature to 55 oC did not improve the
reaction.
6a-e
8a R = PhCH2CH2, 52%
8b R = PhCH2, 62%
8c R = Ph, 37%
8d R = c-HexCH2CH2, 19%
8e R = 1-NaphCH2CH2, 44%
R
H2N
(d)
(e)
(e, f)
R
Cl3COCHN
9a R = PhCH2CH2, 72%
9b R = PhCH2, 50%
9c R = Ph, 66%
9d R = c-HexCH2CH2, 70%
9e R = 1-NaphCH2CH2, 35%
7a R = PhCH2CH2, 73%
7b R = PhCH2, 72%
7c R = Ph, 60%
7d R = c-HexCH2CH2, 59%
7e R = 1-NaphCH2CH2, 67%
Cl
R
H3N
Scheme 1. (a) Meth. A or B, see Table 1; (b) DIBAL-H, CH2Cl2 or toluene, -78
oC; (c) 1. NaH, 2. Cl3CCN, THF, 0 oC; (d) Na2CO3, xylenes, Δ; (e) NaOH(aq),
EtOH, 40 oC; (f) HCl (aq); (g) Meth. D or E, see Table 1.
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10.1002/ejoc.201601446
European Journal of Organic Chemistry
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O
O
NH
CCl3
(b)
(a)
(b)
(a)
CO2Et
O
n.r.
R
R
N
R
O
OH
Ph
Ph
6a
5a
3a R = PhCH2CH2, E/Z 4:1
3b R = PhCH2, E/Z 6:1
3c R = Ph, E/Z 6:1
3d R = c-HexCH2CH2, E/Z 3:1
3e R = 1-NaphCH2CH2, E/Z 3:1 10e 77%, E/Z 3:1
10a 99%, E/Z 4:1
10b 91%, E/Z 5:1
10c 88%, E/Z 9:1
10d 87%, E/Z 3:1
11a 98%, E/Z 4:1
11b 99%, E/Z 5:1
11c 98%, E/Z 10:1
11d 99%, E/Z 3:1
11e 99%, E/Z 3:1
O
N
Ph
H
(c)
Ph
Ph
Ph
Co
Ph
Ph
Co
Ph
Ph
O
Cl
Ph
Ph
OH
Pd
Pd
Cl
N
B
13
R
N
BH3
(R) 12a-e
O
(R)-COP-Cl
Scheme 3. (a) HNMeOMe•HCl, t-BuMgBr, THF, 0 °C; (b) MeMgBr THF, -
30 °C; (c) See Table 2.
Scheme 2. (a) 1. NaH, 2. Cl3CCN, THF, 0 oC; (b) (R)-COP-Cl (2.8 mol%),
CH2Cl2, 38 oC, 7 days.
There are many examples of thermal enantioselective Overman
rearrangements of imidates from optically active alcohols,[22] and
we turned to another route to optically active α,α-disubstituted
allylamines; enantioselective reduction of ketones to optically
active allylic alcohols followed by conversion to an imidate via a
Table 2. CBS-mediated reduction of compounds 11
Entry
ee [%] 12[c]
Starting
material
Reaction
conditions
Yield
[%]
12[a,b]
1
11a
11a
11b[g]
11b[i]
11c
11c
11d
11d
11e
11e
A[d]
B[f]
A
88[e]
87
91[e]
96
82
92
88
94
86
93
86
88
[3,3] rearrangement (Schemes 3-4). The esters
3 were
converted to ketones 11, via the corresponding Weinreb amide
10, according to a literature procedure for synthesis of ketones
11a and 11c (Scheme 3).[23] The ketones were first isolated as
E/Z mixtures as shown in Scheme 3 and we observed that E-
ketones 11 partly isomerized to the Z-isomer upon storage. In
the planned reaction sequence pure E-isomers of alcohols 12
were desired and the E and Z isomers of ketones 11 were
separated just before the next step was carried out.
Unfortunately, we were not able to isolate the ketone 11b as the
E-isomer only. Asymmetric reduction was first attempted
employing BINAL-H[24] generated from lithium aluminum hydride
and equimolar amounts of (R)-BINOL and EtOH. At its best, the
reaction gave the alcohol 12a in 78% chemical yield from ketone
11a, but the method was not reproducible with respect to %ee.
The literature also points out that generation of the reducing
agent can be difficult.[24] Instead we turned to CBS-mediated
reduction. However, we found, as also reported by others,[25] the
results not to be fully reproducible when commercially available
(R) 2-methyl-CBS-oxazaborolidine was used due to impurities
present and limited stability of the reagent. Instead we
synthesized the stable (S) oxazaborolidine-borane complex 13
(Scheme 3) by literature methods.[26] The ketones were reduced
both with a catalytic amount of borane 13 together with
BH3•SMe2 and with a stoichiometric amount of borane 13 only
(Table 2). Using 13 as a stoichiometric reagent gave higher
enantiomeric excess and generally better yield compared to
when complex 13 was used as a catalyst. The (R) configuration
and %ee of alcohols 12 were determined by Mosher ester
analysis using both 19F and 1H-NMR.[27]
2
3
87[h]
71[j]
94
4
B
5
A
6
B
98
7
A
84
8
B
89
9
A
87
10
B
89
[a] Isolated yield. [b] Isolated as pure E-isomer unless otherwise stated. [c]
Determined from the corresponding Mosher esters. [d] Comp. 13 (0.2
equivs.), BH3•SMe2 (0.5 equivs.), THF, -20 oC. [e] The ketone was added
over a period of 12 h. [f] Comp. 13 (1.5 equivs.), THF, -78 oC - r.t. [g] 24:1
mixture of the E- and Z-isomer. [h] Isolated as a 20:1 mixture of the E- and
Z-isomer. [i] 35:1 mixture of the E- and Z-isomer. [j] Isolated as a 33:1
mixture of the E- and Z-isomer.
Overman rearrangement of the imidate 14 from alcohol 12a is
shown in Scheme 4. The reaction occurred with reasonable
chiral transfer,[28] but the chemical yield was disappointingly low,
compared to what was achieved with the related primary allylic
alcohols 5 (Scheme 1).
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10.1002/ejoc.201601446
European Journal of Organic Chemistry
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NH
CCl3
O
OH
(a)
(b)
Table 3. Rearrangement of carbamates 17 to carbamates 20.
Ph
Ph
Ph
(R) 14
(R) 12a
Starting
material
Reaction
Reaction
Yield [%]
Chiral
transfer
[%]c]
Entry
20[a,b]
conditions for
generating
cyanate 18
conditions for
converting 19
to 20
O
HN
CCl3
NH2
(c)
A[d]
A
B[e]
C[f]
C
84
78
67
84
88
60
87
99.9
97.9
98.3
91.8
95.7
95.2
98.9
Ph
(S) 16a 89%, chiral transfer 90.1% from 12a
1
2
3
4
5
6
7
17a
17a
17a
17b
17c
17d
17e
(S) 15 21%
Scheme 4. (a) CCl3CN, DBU, CH2Cl2; (b) Na2CO3, xylenes, 120 oC; (c) NaOH
D[g]
A
(6M), EtOH 40 oC.
B
A
B
Instead, we transformed the alcohols 12 to carbamates 17 and
examined the allyl cyanate to isocyanate rearrangement
(Scheme 5, Table 3).[13] The carbamates 17 were converted to
cyanates 18, which spontaneously rearranged to the
isocyanates 19, by treatment with TFAA and base.[29] The
isocyanates 19 were reacted further to carbamates 20 by a
MoO2Cl2(DMF)2 catalyzed reaction with t-BuOH.[30] The use of t-
BuOLi[31] instead of the Mo-catalyst in the second step of the
synthesis of carbamate 20a and / or PPh3, CBr4 and Et3N[31,32]
for the generation of the cyanate 18a resulted in almost the
same chiral transfer but somewhat reduced chemical yields. The
carbamates 19 were hydrolyzed under basic conditions[33] to
give the free amines in excellent yields and with very good chiral
A
B
A
B
[a] Isolated yield. [b] Only the E-isomer was formed. [c] Calculated from the
ratios of the starting alcohol 12 and the final free amine 16, both determined
from the corresponding Mosher esters. [d] TFAA, Et3N, CH2Cl2, -78 oC - r.t. [e]
cat. MoO2Cl2(DMF)2, t-BuOH, CH2Cl2. [f] t-BuOLi, t-BuOH, THF, -15 oC. [g]
PPh3, CBr4, Et3N, CH2Cl2, -28 oC.
Allyl cyanates are believed to rearrange to isocyanates via a
concerted cyclic transition state as shown in Figure 2 and
transfer of chirality generally occurs with very high selectivity.[13b]
The E-isomer of the cyanate 18 was expected to rearrange via
transition state A and not transition state B where the two methyl
groups are occupying pseudo-axial positions. Unfortunately, is
was not possible to prepare carbamate 17b as pure E-isomer
and minor amounts of the (E,R) isocyanate 19b could be
formed by rearrangement of the (Z,R) cyanate 18b via the
favored transition state A'. This might explain why the synthesis
of amine 16b occurred with slightly lower chiral transfer
compared to the other examples (Table 3). Likewise, if some E
to Z isomerization of the carbamates 17 or cyanates 18 took
place in solution before the rearrangement, this would also result
in reduced chiral transfer.
transfer. Carbamate cleavage with aqueous HCl or TFA in
[34]
CH2Cl2, or by treatment with TMSI in CH2Cl2
was
unsuccessful due to the formation of elimination products.
Isocyanate 19a, generated from carbamate 17a by treatment
with PPh3, CBr4 and Et3N, could also be converted to carbamate
21 when reacted with Bu3SnOMe.[32] The overall yield of the
target allylamine 16a from carbamate 17a and chiral transfer
(92.3%) were comparable of what was achieved with the
conditions described above and in Table 3 using less toxic
reagents.
O
N
C
O
NH2
O
OH
(b)
(a)
R
R
R
18
(R) 12a R = PhCH2CH2
(R) 12b R = PhCH2
(R) 12c R = Ph
(R) 12d R = c-HexCH2CH2
(R) 12e R = 1-NaphCH2CH2
(R) 17a 90%, E/Z >99:1
(R) 17b 93%, E/Z 20:1
(R) 17c 86%, E/Z >99:1
(R) 17d 88%, E/Z >99:1
(R) 17e 88%, E/Z >99:1
O
C
N
19
O
(c)
R
OBut
HN
(e)
R = PhCH2CH2
NH2
(d)
R
R
20
O
(S) 16a 99%
(S) 16b 82%
(R) 16c 91%
(S) 16d 98%
(S) 16e 89%
HN
OMe
(d)
(R) 16a 99%
chiral transfer 92.3%
Ph
(S) 21 88%
Scheme 5. 1. Cl3CCONCO, CH2Cl2, 0 oC, 2. K2CO3(aq), MeOH; (b) See Table
3; (c) See Table 3; (d) t-BuOK, KOH, THF, 55 oC; (e) Bu3SnOMe, MeOH.
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10.1002/ejoc.201601446
European Journal of Organic Chemistry
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N
C
N
above. Various reaction conditions for the generation of the
cyanate and conversion of the rearrangement product to a
stable carbamate were compared. Best results were obtained
when the cyanate was generated by treatment of the
corresponding carbamate with TFAA and Et3N and the
isocyanate was trapped with t-BuOH in the presence of a
catalytic amount of MoO2Cl2(DMF)2. We envisage that the
methodology described here in can be applied in syntheses of a
wide variety of optically active α,α-disubstituted allylamines
including building blocks for the synthesis of asmarines and
analogs (cf. Fig. 1).
C
Me
O
R
O
R
Me
Me
Me
(E,R)-18
(Z,R)-18
N
N
Me
R
C
C
Me
Me
R
Me
N C
N
C
O
Me
O
Me
Me
O
O
R
Me
R
H
H
H
H
TS A
TS B
TS A'
TS B'
O
O
O
O
C
N
C
C
C
N
N
N
Me
Me
Me
R
R
Me
R
Me
Me
R
Me
Me
Experimental Section
(Z,R)-19
not observed
(E,S)-19
major isomer
(Z,S)-19
not observed
(E,R)-19
minor isomer
General remarks: 1H NMR spectra were recorded at 600 MHz with a
Bruker AV 600 instrument, at 400 MHz with a Bruker AVII 400 instrument
or at 300 MHz with a Bruker DPX instrument. The decoupled 13C NMR
spectra were recorded at 150, 100 or 75 MHz. using instruments
mentioned above. Mass spectra under electron impact conditions were
recorded on a VG Prospec instrument at 70 eV ionizing voltage. Mass
spectra under electron-spray condition were recorded on a Bruker Maxis
II ETD or a Micromass Q-Tof-2 instrument. All mass spectra are
presented as m/z (% rel. int.). HRMS-EI and HRMS-ESI were performed
with the instruments mentioned above. Melting points were determined
with a Büchi Melting Point B-545 apparatus and are uncorrected. Flash
chromatography was performed on silica gel (Merck no. 09385). Optical
rotations were measured on a Perkin-Elmer 341 polarimeter. %ee for
compounds 12, 16 and 17 were determined by Mosher ester analysis[27]
and the %ee for compounds 19 were assumed to be the same as for the
corresponding compounds 16. CuI and LiCl were dried at high vacuum at
120 oC for 24 h. Et3N, TMSCl, toluene and xylenes were distilled from
CaH2. Dry CH2Cl2 and THF were obtained from solvent purification
Figure 2. Rearrangement of the E- and Z isomers of cyanate 18 via the
favored transition states A / A' and the more strained transition states B /
B'.[13b]
The expected absolute configuration (S) was confirmed for the
amine 16a the following way: Compound 16a was converted to
the corresponding Fmoc ester 22, which was subjected to
ozonylysis and oxidation (Scheme 6). The carboxylic acid 23
thus formed showed (+) rotation, whereas the (R) enatiomer of
compound 23 previously is reported to be the (-) form.[15a]
Fmoc
NH
Fmoc
NH
NH2
(a)
(b)
Ph
Ph
Ph
CO2H
system, MB SPS-800 from MBraun. Compounds available by literature
16a
22 93%
23 72%
[35]
methods: MoO2Cl2(DMF)2
and (S)-1-methyl-3,3-diphenyltetrahydro-
1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole BH3 adduct 13.[26]
Scheme 6. (a) FmocCl, NaHCO3(aq), CH2Cl2; (b) 1. O3, CH2Cl2, -78 oC, 2.
DMS, CH2Cl2, -78 oC, 3. NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O.
Synthesis of compounds 3 from alkyne 1, alternative 1: A mixture of
CuI (583 mg, 3.06 mmol) and LiCl (133 mg, 3.14 mmol) in dry THF (20
mL) was stirred under N2-atm. at ambient temperatures until the salts
were dissolved; ca. 30 min. The solution was cooled to -78 °C and the
alkyne 1 (3.00 mmol) followed by TMSCl (0.50 mL, 4.0 mmol) and
Grignard reagent in THF (7.2 mmol) were added. After 1 h the reaction
was quenched by addition of sat. aq NH4Cl (20 mL). The solution was
heated to ambient temperature and extracted with EtOAc (3× 25 mL) and
washed with water (25 mL) and brine (25 mL). The organic layer was
dried (MgSO4) and evaporated. The product was purified by flash
chromatography.
Conclusions
Racemic α,α-disubstituted allylamines where conveniently
prepared by thermal Overman rearrangements of primary allylic
alcohols with trisubstituted double bonds, but enantioselective
rearrangement of these substrates catalyzed by the
commercially available chiral cobalt oxazoline palladacycle, (R)-
COP-Cl, failed. Optically active secondary allylic alcohols with
trisubstituted double bonds, obtained by CBS-mediated
reduction of the corresponding methyl ketones, were converted
to the corresponding α,α-disubstituted allylamines via a thermal
Overman rearrangement or an allyl cyanate to isocyanate
rearrangement. The Overman reaction utilizes less expensive
reagents and constitutes of one step less than the
rearrangement of allyl cyanate, but the chemical yield in the
Overman rearrangement was low. The allyl cyanate to
isocyanate rearrangement gave target products with high
chemical yields and a very good chiral transfer ranging from 92
to 99%. When the sequence was carried out with carbamates
available as pure E-isomers, the chiral transfer was 95% or
Synthesis of compounds 3 from alkyne 1, alternative 2: CuI (664 mg,
3.49 mmol) was dissolved in THF (9 mL) and cooled to -40 °C under Ar-
atm. before addition of TMEDA (1.26 mL, 8.45 mmol). The Grignard
reagent in THF (3.0 mmol) was added and the mixture was stirred at -
40 °C for 10 min. The reaction mixture was cooled to -78 °C, the alkyne 1
(2.70 mmol) was added and the reaction was stirred at -78 °C for 2 h.
The reaction was quenched with addition of methanol (10 mL) followed
by sat. aq (NH4)2SO4 (10 mL). The mixture was heated to ambient
temperature and extracted with EtOAc (3× 25 mL) and washed with
water (25 mL) and brine (25 mL). The organic layer was dried (MgSO4)
and evaporated. The crude product was purified by flash chromatography.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
Synthesis of compounds 3 from ketones 2, alternative 1: To a
mixture of triethyl phosphonoacetate (2.24 g, 10.0 mmol), 1,8-
diazabicycloundec-7-ene (152 mg, 1.00 mmol) and CsCO3 (1.95 g, 10.1
mmol) was added ketone 2 (5.00 mmol) and the resulting mixture was
stirred at ambient temperature under N2 atm. for 18 h. The reaction was
quenched with water (25 mL) and extracted with a 1:2 mixture of EtOAc-
hexane (3× 20 mL). The combined organic extracts were dried (MgSO4),
and evaporated. The crude product was purified by flash chromatography.
(CO) ppm. 13C NMR (75 MHz, CDCl3, Z-isomer): δ = 13.9 (CH3), 27.1
(CH3), 59.7 (CH2), 117.8 (=CH), 126.3 (2× CH in Ph), 127.7 (CH in Ph),
128.5 (2× CH in Ph), 140.9 (CH3C=), 155.3 (C in Ph), 165.9 (CO) ppm.
MS (EI): m/z (%) = 190 (92) [M]+, 161 (33), 145 (100), 115 (43), 91 (16).
HRMS (EI) calcd. for C12H14O2 [M]+ 190.0994; found 190.0989. The NMR
data of were in good agreement with those reported before.[36]
Ethyl 5-cyclohexyl-3-methylpent-2-enoate (3d): EtOAc-hexane (1:49)
was used as eluent for flash chromatography; yield and E/Z ratio, see
Table 1, pale yellow liquid. 1H NMR (600 MHz, CDCl3, E-isomer): δ =
0.85–0.88 (m, 2 H, c-hex), 1.13–1.35 (m, 10 H, c-hex and CH3 in Et),
1.63–1.69 (m, 5 H, c-hex), 2.09–2.13 (m, 5 H, CH2 and CH3), 4.12 (q, J =
7.2 Hz, 2 H, OCH2), 5.63 (s, 1 H, CH=) ppm. 13C NMR (100 MHz, CDCl3,
E-isomer): δ = 14.3 (CH3), 18.8 (CH3), 26.3 (CH2 in c-hex), 26.6 (CH2 in
c-hex), 33.2 (CH2 in c-hex), 35.1 (CH2), 37.3 (CH in c-hex), 38.4 (CH2),
59.4 (OCH2), 115.2 (CH=), 160.9 (C=), 167.0 (CO) ppm. MS (EI): m/z (%)
= 224 (14) [M]+, 179 (58), 128 (100). HRMS (EI) calcd. for C14H24O2 [M]+
224.1776; found 224.1784.
Synthesis of compounds 3 from ketones 2, alternative 2: Triethyl
phosphonoacetate (5.95 mL, 30.0 mmol) was added dropwise to a
suspension of ca. 60 % NaH (1.12 g, ca. 28.0 mmol) in THF (15 mL) at
0 °C under Ar-atm. The mixture was warmed to ambient temperatures
and stirred for 30 min. Acetophenone (2.33 mL, 20.0 mmol) was added
and the solution was stirred for 20 h and subsequently quenched with sat.
aq. NH4Cl (20 mL). The mixture was extracted with ethyl acetate (3× 20
mL) and the combined organic extracts were dried (MgSO4), and
evaporated. The crude products were purified by flash chromatography.
Ethyl-3-methyl-5-phenylpent-2-enoate (3a): EtOAc-hexane (1:19) was
used as eluent for flash chromatography; yield and E/Z ratio, see Table 1,
pale yellow liquid. 1H NMR (600 MHz, CDCl3, E-isomer): δ = 1.26 (t, J =
7.2 Hz, 3 H, CH3), 2.19 (d, J = 0.6 Hz, 3 H, CH3), 2.42 (t, J = 7.8 Hz, 2 H,
CH2), 2.77 (t, J = 7.8 Hz, 2 H, PhCH2), 4.13 (q, J = 7.2 Hz, 2 H, OCH2),
5.67 (q, J = 0.6 Hz, 1 H, =CH), 7.12–7.28 (m, 5 H, Ph) ppm. 13C NMR
(150 MHz, CDCl3, E-isomer): δ = 14.3 (CH3), 18.9 (CH3), 33.9 (PhCH2),
42.7 (CH2), 59.5 (OCH2), 116.0 (=CH), 126.1 (CH in Ph), 128.3 (2× CH in
Ph), 128.5 (2× CH in Ph), 141.1 (C in Ph), 158.9 (CH3C=), 166.7 (CO)
ppm. MS (EI): m/z (%) = 218 (5) [M]+, 173 (14), 144 (24), 91 (100).
HRMS (EI) calcd. for C14H18O2 [M]+ 218.1307; found 218.1208. The NMR
data were in good agreement with those reported before.[36]
Ethyl 3-methyl-5-(naphtalene-1-yl)pent-2-enoate (3e): EtOAc-hexane
(1:49) was used as eluent for flash chromatography; yield and E/Z ratio,
see Table 1, pale yellow liquid. 1H NMR (400 MHz, CDCl3, E-isomer): δ =
1.28 (t, J = 7.2 Hz, 3 H, CH3), 2.73 (s, 3H, CH3), 2.54–2.58 (m, 2 H, CH2),
3.21–3.25 (m, 2 H, CH2), 4.16 (q, J = 7.2 Hz, 2 H, OCH2), 5.76 (s, 1 H,
CH=), 7.29–7.53 (m, 4 H in Ar), 7.71 (d, J = 8.4 Hz, 1 H, Ar), 7.85 (d, J =
7.6 Hz, 1 H, Ar), 7.99 (d, J = 8.4 Hz, 1 H, Ar) ppm. 13C NMR (100 MHz,
CDCl3, E-isomer): δ = 14.3 (CH3), 19.0 (CH3), 31.2 (CH2), 42.0 (CH2),
59.6 (OCH2), 115.9 (CH=), 123.4 (CH in Ar), 125.6 (CH in Ar), 125.6 (CH
in Ar), 125.9 (CH in Ar), 126 (CH in Ar), 126.9 (CH in Ar), 128.9 (CH in
Ar), 131.6 (C in Ar), 133.9 (C in Ar), 137.2 (C in Ar), 159.1 (C=), 167.5
(CO) ppm. MS (EI): m/z (%) = 268 (22) [M]+, 141 (100), 115 (11). HRMS
1
(EI) calcd. for C18H20O2 [M]+ 268.1463; found 268.1464. H NMR data of
the E-isomer, are in good agreement with those reported before.[37]
Ethyl 3-methyl-4-phenylbut-2-enoate (3b): EtOAc-hexane (1:9) was
used as eluent for flash chromatography; yield and E/Z ratio, see Table 1,
pale yellow liquid. 1H NMR (300 MHz, CDCl3, E-isomer): δ = 1.27 (m, 3 H,
CH3, overlap with signal from Z-isomer), 2.11 (d, J = 1.2 Hz, 3 H, CH3),
3.41 (s, 2 H, CH2), 4.09–4.19 (m, 2 H in OCH2, overlap with signal from
Z-isomer), 5.67 (br s, 1 H, =CH), 7.14–7.31 (m, 5 H, Ph, overlap with
signal from Z-isomer) ppm. 1H NMR (300 MHz, CDCl3, Z-isomer): δ =
1.27 (m, 3 H, CH3, overlap with signal from E-isomer), 1.77 (d, J = 1.2 Hz,
3 H, CH3), 4.01 (s, 2 H, CH2), 4.09–4.19 (m, 2 H in OCH2, overlap with
signal from E-isomer), 5.67 (br s, 1 H, =CH), 7.14–7.31 (m, 5 H, Ph,
overlap with signal from Z-isomer) ppm. 13C NMR (75 MHz, CDCl3, E-
isomer): δ = 14.3 (CH3), 18.6 (CH3), 47.0 (CH2), 59.6 (OCH2), 117.2
(=CH), 126.7 (CH in Ph), 128.5 (2× CH in Ph), 129.1 (2× CH in Ph),
137.8 (C in Ph), 158.2 (CH3C=), 166.7 (CO) ppm. 13C NMR (75 MHz,
CDCl3, Z-isomer): δ = 14.3 (CH3), 24.5 (CH3), 38.8 (CH2), 59.7 (OCH2),
117.1 (=CH), 126.2 (CH in Ph), 128.4 (2× CH in Ph), 128.9 (2× CH in Ph),
138.9 (C in Ph), 157.5 (CH3C=), 166.5 (CO) ppm. MS (EI): m/z (%) = 204
(100) [M]+, 159 (89), 158 (94), 131 (99), 91 (62). HRMS (EI) calcd. for
C13H16O2 [M]+ 204.1150; found 204.1153. The NMR data were in good
agreement with those reported before.[37]
Synthesis of allyl alcohols 5 by DIBAL-H reduction of esters 3,
alternative 1: Ester 3a, 3d or 3e (6.33 mmol) was dissolved in dry
CH2Cl2 (17 mL) and cooled to -78 °C under N2-atm. DIBAL-H (16.8 mL, 1
M in hexanes, 16.8 mmol) was added to the solution. The reaction
mixture was stirred at -78 °C for 1 h and quenched by dropwise addition
of 1M HCl. The mixture was extracted with CH2Cl2 (2× 25 mL), the
combined organic extract were washed with water (20 mL), dried
(MgSO4) and evaporated. The crude products were considered pure as
judged by NMR and used without further purification in the next step.
3-Methyl-5-phenylpent-2-en-1-ol (5a): Colorless liquid (982 mg, 88%).
The starting material and product were pure E-isomers. 1H NMR (300
MHz, CDCl3): δ = 1.08 (br s, 1 H, OH), 1.56 (s, 3H, CH3), 2.31 (m, 2 H,
PhCH2), 2.73 (m, 2 H, CH2), 4.12 (m, 2 H, OCH2), 5.39–5.41 (m, 1 H,
=CH), 7.15–7.27 (m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.4
(CH3), 34.4 (CH2), 41.3 (CH2), 59.3 (OCH2), 123.9 (=CH), 125.8 (CH in
Ph), 128.3 (2× CH in Ph), 128.3 (2× CH in Ph), 139.1 (CH3C=), 141.9 (C
in Ph) ppm. MS (ESI): m/z (%) = 183 (100) [M + Li]+. HRMS (ESI) calcd.
for C12H16LiO [M + Li]+ 183.1361; found 183.1370. The NMR data were in
good agreement with those reported before.[38]
Ethyl 3-phenylbut-2-enoate (3c): EtOAc-hexane (1:9) was used as
eluent for flash chromatography; yield and E/Z ratio, see Table 1, pale
yellow liquid. 1H NMR (300 MHz, CDCl3, E-isomer): δ = 1.30 (t, J = 7.2
Hz, 3 H, CH3), 2.56 (d, J = 1.5 Hz, 3 H, CH3), 4.20 (q, J = 7.2 Hz, 2 H,
CH2), 6.12 (q, J = 1.5 Hz, 1 H, =CH), 7.17–7.58 (m, 5 H Ph) ppm. 1H
NMR (300 MHz, CDCl3, Z-isomer): δ = 1.06 (t, J = 7.2 Hz, 3 H, CH3),
2.16 (d, J = 1.5 Hz, 3 H, CH3), 3.98 (q, J = 7.2 Hz, 2 H, CH2), 5.89 (q, J =
1.5 Hz, 1 H, =CH), 7.17–7.58 (m, 5 H, Ph, overlapping with Ph signals
from the E-isomer) ppm. 13C NMR (75 MHz, CDCl3, E-isomer): δ = 14.3
(CH3), 17.9 (CH3), 59.8 (CH2), 117.2 (=CH), 126.8 (2× CH in Ph), 127.9
(2× CH in Ph), 128.9 (CH in Ph), 142.2 (CH3C=), 155.5 (C in Ph), 166.8
5-Cyclohexyl-3-methylpent-2-en-1-ol (5d): Colorless liquid (1.06 g,
92%). The starting material and product were pure E-isomers. 1H NMR
(300 MHz, CDCl3): δ = 0.84–0.91 (m, 2 H, c-hex), 1.10–1.31 (m, 7 H, c-
hex and CH2), 1.61–2.02 (m, 7 H, c-hex and CH3), 4.10–4.14 (m, 2 H,
OCH2), 5.35–5.40 (m, 1 H, CH=) ppm. 13C NMR (100 MHz, CDCl3): δ =
16.3 (CH3), 26.3 (CH2 in c-hex), 26.7 (CH2 in c-hex), 33.3 (CH2 in c-hex),
35.5 (CH2), 36.9 (CH2), 37.4 (CH in c-hex), 59.4 (OCH2), 122.8 (CH=),
140.7 (C-3) ppm. MS (EI): m/z (%) = 182 (9) [M]+, 164 (6), 96 (100), 71
(70). HRMS (EI) calcd. for C12H22O [M]+ 182.1671; found 182.1675.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
3-Methyl-5-(naphtalene-1-yl)pent-2-en-1-ol (5e): Colorless liquid (1.30
g, 91%). The starting material and product were pure E-isomers. 1H NMR
(600 MHz, CDCl3): δ = 1.12 (s, 1 H, OH), 1.79 (s, 3 H, CH3), 2.44 (m, 2 H,
CH2), 3.19 (m, 2 H, CH2), 4.16 (m, 2 H, CH2), 5.45 (m, 1 H, CH=), 7.30–
7.50 (m, 4 H, Ar), 7.70 (d, J = 7.8 Hz, 1 H, Ar), 7.84 (d, J = 7.8 Hz, 1 H,
Ar), 8.02 (d, J = 8.0 Hz, 1 H, Ar) ppm. 13C NMR (150 MHz, CDCl3,): δ =
16.5 (CH3), 31.6 (CH2), 40.6 (CH2), 59.4 (OCH2), 123.6 (CH=), 123.8 (CH
in Ar), 125.4 (CH in Ar), 125.5 (CH in Ar), 125.8 (CH in Ar), 125.9 (CH in
Ar), 126.7 (CH in Ar), 128.8 (CH in Ar), 131.8 (C in Ar), 133.9 (C in Ar),
138.1 (C in Ar), 139.4 (C=) ppm. MS (EI): m/z (%) = 226 (18) [M]+, 208
(23), 141 (100). HRMS (EI) calcd. for C16H18O [M]+ 226.1358; found
226.1361. 1H NMR data of the E-isomer, are in good agreement with
those reported before.[39]
silica gel pad and evaporated. The intermediate 6 was dissolved in
xylenes (35 mL) and after addition of Na2CO3 (90 mg, 0.86 mmol), the
mixture was stirred at reflux for 24 h. The reaction was cooled to ambient
temperature, evaporated and the residue purified by flash
chromatography.
2,2,2-Trichloro-N-(3-methyl-5-phenylpent-1-en-3-yl)acetamide (7a):
EtOAc-hexane (1:3) was used as eluent for flash chromatography to give
7a (548 mg, 73%) as a yellow wax. 1H NMR (400 MHz, CDCl3): δ = 1.55
(s, 3 H, CH3), 2.10–2.14 (m, 1 H, HA in CH2), 2.19–2.24 (m, 1 H, HB in
CH2), 2.58–2.60 (m, 2 H, CH2), 5.20 (d, J = 17.4 Hz, 1 H, HA in =CH2),
5.24 (d, J = 10.8 Hz, 1 H, HB in =CH2), 5.97 (dd, J = 17.4, 10.8 Hz, 1 H,
CH=), 6.61 (s, 1 H, NH), 7.16–7.28 (m, 5 H, Ph) ppm. 13C NMR (150 MHz,
CDCl3): δ = 24.1 (CH3), 30.3 (CH2), 40.5 (CH2), 58.7 (CN), 93.2 (CCl3),
113.8 (CH2=), 126.1 (2× CH in Ph), 128.4 (2× CH in Ph), 128.6 (CH in
Ph), 141.2 (CH=), 141.3 (C in Ph), 160.0 (CO) ppm. MS (ESI): m/z (%) =
268 (100) [M + Li]+. HRMS (ESI) calcd. for C14H16Cl3NO [M + Li]+
326.0458; found 326.0465.
Synthesis of allyl alcohols 5 by DIBAL-H reduction of esters 3,
alternative 2: Ester 3b or 3c (6.53 mmol) were dissolved in dry toluene
(35 mL) under N2-atm. and cooled to -78 °C. DIBAL-H (20 mL, 1 M sol. in
hexanes, 20 mmol) was added dropwise and the solution was stirred for
2 h. before the reaction was quenched by pouring it into sat. aq.
potassium sodium tartrate (60 mL). The water phase was extracted with
ethyl acetate (3× 30 mL) and the combined organic phases were washed
with water (30 mL) and brine (30 mL), dried (MgSO4) and evaporated.
The crude product was purified by flash chromatography.
2,2,2-Trichloro-N-(2-methyl-1-phenylbut-3-en-2-yl)acetamide
(7b):
EtOAc-hexane (1:3) was used as eluent for flash chromatography to give
7b (517 mg, 72%) as a yellow wax. 1H NMR (400 MHz, CDCl3): δ = 1.50
(s, 3 H, CH3), 3.04 (d, J = 13.0 Hz, 1 H, HA in CH2), 3.19 (d, J = 13.0 Hz,
1 H, HB in CH2), 5.09 (d, J = 17.2 Hz, 1 H, HA in =CH2), 5.19 (d, J = 10.8
Hz, 1 H, HB in =CH2), 6.00 (dd, J = 17.2, 10.8 Hz, 1 H, CH=), 6.53 (s, 1 H,
NH), 7.13–7.29 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.4
(CH3), 44.5 (CH2), 58.7 (CN), 113.9 (CH2=), 127.1 (CH in Ph), 128.3 (2×
CH in Ph), 130.7 (2× CH in Ph), 135.7 (C in Ph), 141.0 (CH=), 160.3 (C=)
ppm, CCl3 signal was hidden. MS (ESI): m/z (%) = 312/310/308/306
(3/34/94/100) [M + H]+. HRMS (ESI) calcd. for C13H14Cl3NO [M + Li]+
312.0301; found 312.0288.
3-Methyl-4-phenylbut-2-en-1-ol (5b): EtOAc-hexane (1:3) was used as
eluent for flash chromatography to give 5b (910 mg, 86%) as a pale
yellow liquid. E/Z ratio in starting material and product was 86:14. 1H
NMR (600 MHz, CDCl3, E-isomer): δ = 1.22 (br s, 1 H, OH), 1.61 (s, 3 H,
CH3), 3.31 (s, 2 H, CH2), 4.17 (d, J = 6.0 Hz, 2 H, OCH2), 5.46–5.49 (m, 1
H, CH=), 7.13–7.30 (m, 5 H, Ph) ppm. 1H NMR (600 MHz, CDCl3, Z-
isomer): δ = 1.22 (br s, 1 H, OH), 1.67 (s, 3 H, CH3), 3.41 (s, 2 H, CH2),
4.26 (d, J = 6.0 Hz, 2 H, OCH2), 5.57–5.59 (m, 1 H, CH=), 7.13–7.30 (m,
5 H, Ph) ppm. 13C NMR (150 MHz, CDCl3, E-isomer): δ = 16.1 (CH3),
46.0 (CH2), 59.4 (OCH2), 125.3 (CH=), 126.2 (2× CH in Ph), 128.4 (CH in
Ph), 128.9 (2× CH in Ph), 138.9 (C=), 139.4 (C in Ph) ppm. 13C NMR
(150 MHz, CDCl3, Z-isomer): δ = 23.4 (CH3), 38.0 (CH2), 59.3 (OCH2),
125.2 (CH=), 126.1 (CH in Ph), 128.3 (2× CH in Ph), 128.5 (2× CH in Ph)
ppm, two signals were hidden. MS (ESI): m/z (%) = 169 (100) [M + Li]+.
HRMS (ESI) calcd. for C11H14O [M + Li]+ 169.12005; found 169.1219.
The NMR data were in good agreement with those reported before.[40]
2,2,2-Trichloro-N-(2-phenylbut-3-en-2-yl)acetamide
(7c):
EtOAc-
hexane (1:9) was used as eluent for flash chromatography to give 7c
(411 mg, 60%) as a pale yellow wax. 1H NMR (400 MHz, CDCl3): δ =
1.87 (s, 3 H, CH3), 5.22 (d, J = 17.2 Hz, 1 H, HA in =CH2), 5.31 (d, J =
10.8 Hz, 1 H, HB in =CH2), 6.26 (dd, J = 17.2, 10.8 Hz, 1 H, CH=), 6.97 (s,
1 H, NH), 7.24–7.36 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ =
25.9 (CH3), 61.6 (CN), 93.6 (CCl3), 115.2 (CH2=), 125.8 (2× CH in Ph),
128.1 (CH in Ph), 129.2 (2× CH in Ph), 140.9 (CH=), 143.5 (C in Ph),
160.3 (CO) ppm. MS (ESI): m/z (%) = 304/302/300/298 (3/30/92/100) [M
+ Li]+. HRMS (ESI) calcd. for C12H12Cl3NO [M + Li]+ 298.0145; found
298.0132. NMR data were in good agreement with those reported
before.[12e]
3-Phenylbut-2-en-1-ol (5c): EtOAc-hexane (1:3) was used as eluent for
flash chromatography to give 5c (823 mg, 85%) as a pale yellow liquid.
E/Z ratio in starting material and product was 88:12. 1H NMR (300 MHz,
CDCl3, E-isomer): δ = 1.78 (br s, 1 H, OH), 2.06 (br s, 3 H, CH3), 4.34 (m,
2 H, CH2), 5.92–5.99 (m, 1 H, CH=), 7.17–7.41 (m, 5 H, Ph) ppm. 1H
NMR (300 MHz, CDCl3, Z-isomer): δ = (br s, 1 H, OH), 2.06 (br s, 3 H,
CH3), 4.05 (m, 2 H, CH2), 5.66–5.72 (m, 1 H, CH=), 7.17–7.41 (m, 5 H,
Ph) ppm. 13C NMR (75 MHz, CDCl3, E-isomer): δ = 16.4 (CH3), 60.3
(CH2), 126.2 (2× CH in Ph), 126.9 (CH=), 128.6 (CH in Ph), 128.7 (2× CH
in Ph), 138.2 (C=), 143.3 (C in Ph) ppm. 13C NMR (75 MHz, CDCl3, Z-
isomer): δ = 25.7 (CH3), 60.7 (CH2), 126.5 (CH=), 127.6 (2× CH in Ph),
127.7 (CH in Ph), 128.2 (2× CH in Ph) ppm, two signals were hidden. MS
(EI): m/z (%) = 148 (32) [M]+, 133 (100), 105 (74), 91 (59), 77 (37).
HRMS (EI) calcd. for C10H12O [M]+ 148.0888; found 148.0892. The 1H
NMR data of both isomers were in good agreement with those reported
before.[41]
2,2,2-Trichloro-N-(5-cyclohexyl-3-methylpent-1-en-3-yl)acetamide
(7d): EtOAc-hexane (1:3) was used as eluent for flash chromatography
to give 7d (451 mg, 59%) as a yellow wax. 1H NMR (300 MHz, CDCl3): δ
= 0.87–0.89 (m, 2 H, c-hex), 1.11–1.24 (m, 7 H, c-hex and CH2), 1.46 (s,
3 H, CH3), 1.61–1.69 (m, 4 H, c-hex), 1.76–1.86 (m, 2 H, CH2), 5.12 (d, J
= 17.4 Hz, 1 H, HA in =CH2), 5.16 (d, J = 10.8 Hz, 1 H, HB in =CH2), 5.89
(dd, J = 17.4, 10.8 Hz, 1 H, CH=), 6.55 (s, 1 H, NH) ppm. 13C NMR (75
MHz, CDCl3): δ = 23.8 (CH3), 26.3 (2× CH2 in c-hex), 26.6 (CH2 in c-hex),
31.2 (CH2), 33.3 (2× CH2 in c-hex), 36.3 (CH2), 37.8 (CH in c-hex) 58.7
(CN), 93.3 (CCl3), 113.4 (CH2=), 141.4 (CH=), 160.1 (CO) ppm. MS (EI):
m/z (%) = 332/330/328/326 (4/40/98/100) [M + H]+, 256 (53), 214 (52),
165 (74). HRMS (EI) calcd. for C14H22Cl3NO [M]+ 325.0767; found
325.0773.
General procedure for the synthesis of amides 7: To a mixture of
NaH (231 mg, ca. 60% dispersion in mineral oil, ca. 5.77 mmol) in dry
THF (12 mL) under N2-atm. was added the allylic alcohol 5 (2.34 mmol)
in THF (2 mL). The mixture was cooled to 0 oC before trichloroacetonitrile
(0.28 mL, 2.8 mmol) was added and the reaction was stirred for 2 h at 0
oC. The mixture was warmed to ambient temperature, filtered through a
2,2,2-Trichloro-N-[3-methyl-5-(naphthalen-1-yl)pent-1-en-3-
yl]acetamide (7e): EtOAc-hexane (1:3) was used as eluent for flash
chromatography to give 7e (512 mg, 59%) as a pale yellow wax. 1H NMR
(400 MHz, CDCl3): δ = 1.62 (s, 3 H, CH3), 2.21–2.37 (m, 1 H, HA in CH2),
2.32–2.38 (m, 1 H, HB in CH2), 3.05–3.07 (m, 2 H, CH2), 5.27 (d, J = 17.3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
Hz, 1 H, HA in =CH2), 5.31 (d, J = 10.8 Hz, 1 H, HB in =CH2), 6.05 (dd, J =
17.3, 10.8 Hz, 1 H, CH=), 6.71 (s, 1 H, NH, 1H), 7.31–7.53 (m, 2 H, Ar),
7.70 (d, J = 8.0 Hz, 1 H, Ar), 7.83 (d, J = 8.0 Hz, 1 H, Ar), 7.96 (d, J = 8.0
Hz, 1 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.2 (CH3), 27.5
(CH2), 39.9 (CH2), 58.9 (CN), 114.0 (CH2=), 123.5 (CH in Ar), 125.6 (CH
in Ar), 125.7 (CH in Ar), 126.1 (CH in Ar), 126.2 (CH in Ar), 126.9 (CH in
Ar), 128.9 (CH in Ar), 131.7 (C in Ar), 133.9 (C in Ar), 137.4 (C in Ar),
141.2 (CH=), 160.3 (CO) ppm, CCl3 signal was hidden. MS (EI): m/z (%)
= 375/373/371/369 (1/7/21/22) [M]+, 208 (38), 141(100). HRMS (EI) calcd.
for C18H18Cl3NO [M]+ 369.0454; found 369.0447.
3-Methyl-5-(naphthalene-1-yl)pent-1-en-3-amine (8e): EtOH-EtOAc
(1:3) was used as eluent for flash chromatography to give 8e (79 mg,
44%) as a yellow wax. 1H NMR (400 MHz, CDCl3): δ = 1.30 (s, 3 H, CH3),
1.69 (s, 2 H, NH2), 1.83–1.84 (m, 1 H, HA in CH2), 1.86–1.87 (m, 1 H HB
in CH2), 3.05 (t, J = 8.0 Hz, 2 H, CH2), 5.12 (d, J = 10.4 Hz, 1 H, HA in
=CH2), 5.22 (d, J = 17.2 Hz, 1 H, HB in =CH2), 6.03 (dd, J = 17.2, 10.4 Hz,
1H, =CH), 7.30 (d, J = 6.8 Hz, 1 H, CH in Ar), 7.31–7.37 (m, 1 H, CH in
Ar), 7.44–7.49 (m, 2 H, 2 × CH in Ar), 7.68 (d, J = 8.0 Hz, 1 H, CH in Ar),
7.83 (d, J = 7.6 Hz, 1 H, CH in Ar), 8.00 (d, J = 8.0 Hz, 1 H, CH in Ar)
ppm. 13C NMR (100 MHz, CDCl3): δ = 27.8 (CH2), 28.4 (CH3), 44.2 (CH2),
54.1 (CN), 111.4 (=CH2), 123.7 (CH in Ar), 125.6 (CH in Ar), 125.6 (CH in
Ar), 125.7 (CH in Ar), 125.8 (CH in Ar), 126.5 (CH in Ar), 128.8 (CH in Ar),
131.8 (C in Ar), 133.9 (C in Ar), 138.7 (C in Ar), 146.7 (=CH) ppm. MS
(EI): m/z (%) = 225 (8) [M]+, 208 (46), 141 (41), 70 (100). HRMS (EI)
calcd. for C16H19N [M]+ 225.1517; found 225.1520.
General procedure for the hydrolysis of amides 7, and isolation of
products as free amines 8: A mixture of amide 7 (0.794 mmol), NaOH
(3.8 mL, 6 M, 23 mmol) and EtOH (4 mL) was stirred at 40 °C for 24 h.
The reaction mixture was extracted with diethyl ether (2× 10 mL). The
combined organic layers were washed with water (10 mL), dried (MgSO4)
and evaporated. The crude product was purified by flash chromatography.
General procedure for the hydrolysis of amides 7, and isolation of
products as ammonium chlorides 9: The hydrolysis was carried out as
described for the synthesis of free amines 8 above. The reaction mixture
was extracted with CH2Cl2 (2× 10 mL), acidified with aq. HCl (0.95 mL, 1
M, 1.1 eq.), dried (MgSO4) and evaporated. The product was isolated by
crystallization / precipitation from acetone-hexane.
3-Methyl-5-phenylpent-1-en-3-amine (8a): EtOAc was used as eluent
for flash chromatography to give 8a (72 mg, 52%) as a yellow wax. 1H
NMR (300 MHz, CDCl3): δ = 1.22 (s, 3 H, CH3), 1.37 (s, 2 H, NH2), 1.67–
1.76 (m, 2 H, CH2), 2.55–2.61 (m, 2 H, CH2), 5.04 (dd, J = 10.6, 1.1 Hz,
1H, HA in =CH2), 5.13 (dd, J = 17.4, 1.1 Hz, 1 H, HB in =CH2), 5.95 (dd, J
= 17.4, 10.6 Hz, 1 H, CH=), 7.15–7.28 (m, 5 H, Ph) ppm. 13C NMR (100
MHz, CDCl3): δ = 28.5 (CH3), 30.7 (CH2), 45.1 (CH2), 53.7 (CN), 111.0
(CH2=), 125.7 (CH in Ph), 128.3 (2× CH in Ph), 128.3 (2× CH in Ph),
142.6 (C in Ph), 147.1 (CH=) ppm. MS (ESI): m/z (%) = 176 (100) [M +
H]+. HRMS (ESI) calcd. for C12H17N [M + H]+ 176.1439; found 176.1443.
3-Methyl-5-phenylpent-1-en-3-aminium chloride (9a): Yellow waxy
solid (121 mg, 72%). 1H NMR (600 MHz, CDCl3): δ = 1.54 (s, 3 H, CH3),
2.03–2.05 (m, 1 H, HA in CH2), 2.14–2.18 (m, 1 H, HB in CH2), 2.63–2.68
(m, 1 H, HA in PhCH2), 2.71–2.76 (m, 1 H, HB in PhCH2), 5.25 (d, J =
10.8 Hz, 1 H, HA in =CH2), 5.46 (d, J = 17.4 Hz, 1 H, HB in =CH2), 5.89
(dd, J = 17.4, 10.8, Hz, 1 H, =CH), 7.13–7.20 (m, 5 H, Ph), 8.79 (s, 3 H,
NH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 24.2 (CH3), 30.1 (PhCH2),
41.4 (CH2), 58.3 (CN), 116.9 (=CH2), 126.1 (CH in Ph), 128.3 (2× CH in
Ph), 128.4 (2× CH in Ph), 137.9 (=CH), 140.6 (C in Ph) ppm. MS (ESI):
m/z (%) = 176 (100) [M]+. HRMS (ESI) calcd. for C12H18N [M]+ 176.1434;
found 176.1443. NMR data were in good agreement with those reported
for the (R)-enantiomer before.[15b]
2-Methyl-1-phenylbut-3-en-2-amine (8b): EtOH-EtOAc (1:3) was used
as eluent for flash chromatography to give 8b (79 mg, 62%) as a yellow
wax. 1H NMR (400 MHz, CDCl3): δ = 1.18 (s, 3 H, CH3), 2.74 (d, J = 13.0
Hz, 1 H, HA in CH2), 2.69 (d, J = 13.0 Hz, 1 H, HB in CH2), 4.97 (dd, J =
10.6, 1.0 Hz, 1 H, HA in =CH2), 5.00 (dd, J = 17.4, 1.0 Hz, 1 H, HB in
=CH2), 5.96 (dd, J = 17.4, 10.6 Hz, 1 H, CH=), 7.14–7.28 (m, 5 H, Ph)
ppm. 13C NMR (100 MHz, CDCl3): δ = 28.3 (CH3), 49.6 (CH2), 54.1 (CN),
110.9 (CH2=), 126.3 (CH in Ph), 127.9 (2× CH in Ph), 130.6 (2× CH in
Ph), 137.5 (C in Ph), 146.9 (CH=) ppm. MS (ESI): m/z (%) = 162 (100)
[M + H]+. HRMS (ESI) calcd. for C11H15N [M + H]+ 162.1283; found
162.2435.
2-Methyl-1-phenylbut-3-en-2-aminium chloride (9b): Beige needles
(78 mg, 50%), m.p. 158–160 oC. 1H NMR (400 MHz, CDCl3): δ = 1.53 (s,
3 H, CH3), 3.16 (br s, 2 H, CH2), 5.30 (d, J = 10.4 Hz, 1 H, HA in =CH2),
5.32 (d, J = 16.4 Hz, 1 H, HB in =CH2), 5.94 (m, 1 H, =CH), 7.19–7.26 (m,
5 H, Ph), 8.71 (s, 3 H, NH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.9
(CH3), 45.7 (CH2), 58.7 (CN), 117.1 (=CH2), 127.3 (CH in Ph), 128.3 (2×
CH in Ph), 130.8 (2× CH in Ph), 134.0 (C in Ph), 137.5 (=CH) ppm. MS
(ESI): m/z (%) = 162 (100) [M]+. HRMS (ESI) calcd. for C11H16N [M]+
162.1283; found 162.1288.
2-Phenylbut-3-en-2-amine (8c): EtOH-EtOAc (1:3) was used as eluent
for flash chromatography to give 8c (51 mg, 44%) as a yellow wax. 1H
NMR (300 MHz, CDCl3): δ = 1.88 (s, 3 H, CH3), 5.22 (d, J = 17.4 Hz, 1 H,
HA in =CH2), 5.31 (d, J = 10.8 Hz, 1 H, HB in =CH2), 6.26 (dd, J = 17.4,
10.8 Hz, 1 H, CH=), 7.25–7.86 (m, 5 H, Ph) ppm. 13C NMR (75 MHz,
CDCl3): δ = 25.4 (CH3), 61.2 (CN), 114.8 (CH2=), 125.4 (2× CH in Ph),
127.7 (CH in Ph), 128.8 (2× CH in Ph), 140.5 (CH=), 143.1 (C in Ph) ppm.
MS (EI): m/z (%) = 147 (83) [M]+, 133 (100), 115 (66), 91 (59), 77 (37).
HRMS (EI) calcd. for C10H13N [M]+ 147.1048; found 147.1054. NMR data
were in good agreement with those reported before.[12e]
2-Phenylbut-3-en-2-aminium chloride (9c): Beige waxy solid (96 mg,
66%). 1H NMR (300 MHz, CDCl3): δ = 1.84 (s, 3 H, CH3), 5.31 (d, J =
10.8 Hz, 1 H, HA in =CH2), 5.38 (d, J = 17.4 Hz, 1 H, HB in =CH2), 6.05
(dd, J = 17.4, 10.8 Hz, 1 H, =CH), 7.24–7.53 (m, 5 H, Ph), 9.12 (s, 3 H,
NH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.2 (CH3), 60.4 (CN), 116.6
(=CH2), 126.1 (2× CH in Ph), 128.3 (CH in Ph), 128.7 (2× CH in Ph),
138.6 (=CH), 139.2 (C in Ph) ppm. MS (ESI): m/z (%) = 148 (1) [M]+, 147
(11), 132 (100), 120 (44). HRMS (EI) calcd. for C10H14N [M - H]+
147.1048; found 147.1054.
5-Cyclohexyl-3-methylpent-1-en-3-amine (8d): EtOH-EtOAc (1:1) was
used as eluent for flash chromatography to give 8d (27 mg, 19%) as a
yellow wax. 1H NMR (400 MHz, CDCl3): δ = 0.83–0.88 (m, 2 H, c-hex),
1.06–1.28 (m, 10 H, CH3, c-hex and NH2), 1.38–1.42 (m, 2 H, CH2),
1.60–1.68 (m, 6 H, c-hex), 4.95 (d, J = 10.8, 1 H, HA in =CH2), 5.04 (d, J
5-Cyclohexyl-3-methylpent-1-en-3-aminium chloride (9d): Yellow
waxy solid (121 mg, 70%). 1H NMR (400 MHz, CDCl3): δ = 0.82–0.87 (m,
2 H, CH2 in c-hex), 1.14–1.24 (m, 11 H, NH3, CH3, 3 H in c-hex, CH2),
1.45–1.49 (m, 2 H, CH2), 1.59–1.70 (m, 4 H, 2× CH2 in c-hex), 5.01 (d, J
= 10.8 Hz, 1 H, HA in =CH2), 5.09 (d, J = 17.2 Hz, 1 H, HB in =CH2), 5.84
(dd, J = 17.2, 10.8 Hz, 1 H, =CH) ppm. 13C NMR (100 MHz, CDCl3): δ =
26.4 (2× CH2 in c-hex), 26.7 (CH2 in c-hex), 27.1 (CH3), 31.5 (CH2), 33.4
(2× CH2 in c-hex), 38.1 (CH in c-hex), 39.8 (CH2), 54.4 (CN), 117.7
= 17.1, 1 H, HB in =CH2), 5.85 (dd, J = 17.1, 10.8 Hz, 1 H, CH=) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 26.4 (2× CH2 in c-hex), 26.7 (CH2 in c-hex),
28.3 (CH3), 31.7 (CH2), 33.4 (2× CH2 in c-hex), 38.1 (CH in c-hex), 40.5
(CH2), 53.6 (CN), 110.4 (CH2=), 147.6 (CH=) ppm. MS (ESI): m/z (%) =
182 (100) [M + H]+. HRMS (ESI) calcd. for C12H23N [M + H]+ 182.1916;
found 182.1914.
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10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
(=CH2), 145.7 (=CH) ppm. MS (ESI): m/z (%) = 182 (100) [M]+. HRMS
(EI) calcd. for C12H24N [M]+ 182.1909; found 182.1914. NMR data were in
good agreement with those reported for the (R)-enantiomer before.[15a]
(%) = 190 (82) [M - CH3]+, 161 (32), 145 (100), 144 (40), 117 (33), 115
(48), 91 (22). HRMS (EI) calcd. C12H15NO2 [M - CH3]+ 190.0868; found
190.0998. NMR data were in good agreement with those reported
before.[23]
3-Methyl-5-(naphthalen-1-yl)pent-1-en-3-aminium
chloride
(9e):
Yellow waxy solid (73 mg, 35%). 1H NMR (400 MHz, CDCl3): δ = 1.29 (s,
3 H, CH3), 1.79–1.86 (m, 2 H, CH2), 3.02–3.06 (m, 2 H, CH2), 5.12 (d, J =
10.8 Hz, 1 H, HA in =CH2), 5.21 (d, J = 17.6 Hz, 1 H, HB in =CH2), 6.03
(dd, J = 17.6, 10.8 Hz, 1 H, =CH), 7.30 (d, J = 6.4 Hz, 1 H, CH in Ar),
7.34–7.38 (m, 1 H, CH in Ar), 7.43–7.50 (m, 2 H, 2× CH in Ar), 7.68 (d, J
= 8.0 Hz, 1 H, CH in Ar), 7.83 (d, J = 7.6 Hz, 1 H, CH in Ar), 7.99 (d, J =
8.4 Hz, 1 H, CH in Ar) ppm. 13C NMR (100 MHz, CDCl3,): δ = 27.9 (CH2),
28.6 (CH3), 44.4 (CH2), 53.9 (CN), 111.3 (=CH2), 123.7 (CH in Ar), 125.4
(CH in Ar), 125.6 (CH in Ar), 125.7 (CH in Ar), 125.8 (CH in Ar), 126.5
(CH in Ar), 128.8 (CH in Ar), 131.8 (C in Ar), 133.9 (C in Ar), 138.8 (C in
Ar), 147.1 (=CH) ppm. MS (EI): m/z (%) = 225 (4) [M - H]+, 208 (45), 141
(67), 70 (100); HRMS (EI) calcd. for C16H20N [M - H]+ 225.1517; found
225.1520.
5-Cyclohexyl-N-methoxy-N,3-dimethylpent-2-enamide (10d): The title
compound was synthesized in 5.89 mmol scale otherwise as described
for 10a above. EtOAc-hexane (0-50% EtOAc) was used as eluent for
flash chromatography to give 10d (1.22 g, 87%) as a colorless oil, E/Z
ratio 3:1. The NMR data for the major isomer are given. 1H NMR (400
MHz, CDCl3): δ = 0.82–0.92 (m, 2 H, c-hex), 1.09–1.25 (m, 4 H, c-hex),
1.29–1.36 (m, 2 H, c-hex-CH2), 1.56–1.74 (m, 5 H, c-hex), 2.09 (d, J =
1.3 Hz, 3 H, CCH3), 2.11–2.13 (m, 2 H, c-hex-CH2CH2), 3.17 (s, 3 H,
NCH3), 3.65 (s, 3 H, OCH3), 6.07 (s, 1 H, =CH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.7 (CH3C=), 26.3 (c-hex), 26.6 (c-hex), 32.3 (NCH3), 33.3
(c-hex), 35.3 (c-hex-CH2), 37.3 (c-hex), 38.5 (c-hex-CH2CH2), 61.4
(OCH3), 113.6 (=CH), 157.3 (C=), 168.2 (CO). MS (EI): m/z (%) = 224
(23) [M - CH3]+, 179 (52), 178 (9), 151 (100), 88 (13) ppm. HRMS (EI)
calcd. for C14H25NO2 [M - CH3]+ 224.1651; found 224.1612.
N-Methoxy-N,3-dimethyl-5-phenylpent-2-enamide
(10a):
N,O-
dimethylhydroxylamine hydrochloride (3.26 g, 33.5 mmol) was added to a
solution of ester 3a (4.05 g, 18.6 mmol) in dry THF (50 mL) under Ar-atm.
The suspension was cooled to 0 °C and t-BuMgCl (34.2 mL, 65.1 mmol,
1.9 M in ether) was added. The solution was stirred for 30 min at ambient
temperature and subsequently quenched with sat. aq. NH4Cl (20 mL).
The mixture was extracted with EtOAc (3× 20 mL) and the combined
organic phases were dried (MgSO4) and concentrated under reduced
pressure. The crude product was purified by flash chromatography
eluting with EtOAc-hexane (0-50% EtOAc) to give 10a (4.30 g, 99%) as a
colorless oil, E/Z ratio 4:1. The NMR data for the major isomer are given.
1H NMR (400 MHz, CDCl3): δ = 2.16 (d, J = 1.4 Hz, 3 H, CH3C=), 2.40–
2.50 (m, 2 H, CH2), 2.74–2.83 (m, 2 H, CH2Ph), 3.15 (s, 3 H, CH3N), 3.52
(s, 3 H, CH3O), 6.05 (s, 1 H, CH=), 7.10–7.20 (m, 3 H, Ph), 7.22–7.30 (m,
2 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.7 (CH3C=), 32.2
(CH3N), 33.9 (CH2Ph), 42.7 (CH2), 61.3 (CH3O), 114.5 (CH=), 126.0 (CH
in Ph), 128.3 (2× CH in Ph), 128.4 (2× CH in Ph), 141.2 (C in Ph), 155.0
(C=), 167.9 (CO) ppm. MS (EI): m/z (%) = 218 (8) [M - CH3]+, 173 (15),
172 (7), 145 (11), 144 (24), 129 (7), 91 (100). HRMS (EI) calcd. for
C14H19NO2 [M - CH3]+ 218.1181; found 218.1307.
N-Methoxy-N,3-dimethyl-5-(naphthalen-1-yl)pent-2-enamide
(10e):
The title compound was synthesized in 18.1 mmol scale otherwise as
described for 10a above. EtOAc-hexane (0-40% EtOAc) was used as
eluent for flash chromatography to give 10e (1.70 g, 77%) as a colorless
oil, E/Z ratio 3:1. The NMR data for the major isomer are given. 1H NMR
(400 MHz, CDCl3): δ = 2.24 (d, J = 0.8 Hz, 3 H, CH3C=), 2.57–2.61 (m, 2
H, CH2C=), 3.17 (s, 3 H, NCH3), 3.24–3.28 (m, 2 H, ArCH2), 3.50 (s, 3 H,
OCH3), 6.09 (s, 1 H, =CH), 7.30 (d, J = 6.7 Hz, 1 H, Ar), 7.36–7.39 (m, 1
H, Ar), 7.45–7.54 (m, 2 H, Ar), 7.70 (d, J = 8.0 Hz, 1 H, Ar), 7.84 (d, J =
8.1 Hz, 1 H, Ar), 8.01 (d, J = 8.2 Hz, 1 H, Ar) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.8 (CH3C=), 31.2 (ArCH2), 32.3 (NCH3), 42.0 (CH2C=),
61.3 (OCH3), 114.5 (=CH), 123.4 (CH in Ar), 125.5 (CH in Ar), 125.5 (CH
in Ar), 125.9 (CH in Ar), 126.0 (CH in Ar), 126.8 (CH in Ar), 128.8 (CH in
Ar), 131.6 (C in Ar), 133.9 (C in Ar), 137.3 (C in Ar), 155.5 (C=), 167.3
(CO) ppm. MS (EI): m/z (%) = 268 (7) [M - CH3]+, 223 (21), 195 (9), 129
(7) 141 (100). HRMS (EI) calcd. for C18H21NO2 [M - CH3]+ 268.1338;
found 268.1375.
4-Methyl-6-phenylhex-3-en-2-one (11a): The Weinreb amide 10a (6.41
g, 27.5 mmol) in dry THF (25 mL) was cooled to -30 °C under Ar-atm.
MeMgBr (12.5 mL, 27.6 mmol, 2.2 M in ether) was added and the
solution was stirred for 1 h. Sat. aq. NH4Cl (20 mL) was added and the
mixture was extracted with EtOAc (3× 20 mL). The combined organic
phases were dried (MgSO4) and concentrated under reduced pressure.
The crude product was purified by flash chromatography eluting with
EtOAc-hexane (0-5% EtOAc) to give 10a (5.09 g, 98%) as a colorless oil,
E/Z ratio 4:1. The pure E-isomer was isolated by flash chromatography
just before use in the synthesis of compound 12a. The NMR data for the
major isomer are given. 1H NMR (400 MHz, CDCl3): δ = 2.17 (s, 3 H,
CH3CO), 2.20 (d, J = 1.3 Hz, 3 H, CH3C=), 2.40–2.48 (m, 2 H, CH2),
2.78–2.85 (m, 2 H, CH2Ph), 6.06 (q, J = 1.3 Hz, 1 H, CH=), 7.16–7.27 (m,
3 H, Ph), 7.27–7.35 (m, 2 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ =
25.7 (CH3C=), 31.7 (CH3CO), 34.4 (CH2Ph), 35.9 (CH2), 124.4 (CH=),
125.9 (CH in Ph), 128.3 (2× CH in Ph), 128.5 (2× CH in Ph), 141.7 (C in
Ph), 158.2 (C=), 198.1 (CO) ppm. MS (EI): m/z (%) = 188 (18) [M]+, 173
N-Methoxy-N,3-dimethyl-4-phenylbut-2-enamide (10b): The title
compound was synthesized in 18.3 mmol scale otherwise as described
for 10a above. EtOAc-hexane (0-50% EtOAc) was used as eluent for
flash chromatography to give 10b (3.70 g, 91%) as a colorless oil, E/Z
ratio 5:1. The NMR data for the major isomer are given. 1H NMR (400
MHz, CDCl3): δ = 2.10 (s, 3 H, CH3C=), 3.21 (s, 3 H, CH3N), 3.47 (s, 2 H,
CH2), 3.64 (s, 3 H, CH3O), 6.13 (s, 1 H, CH=), 6.94–7.44 (m, 5 H, Ph)
ppm. 13C NMR (100 MHz, CDCl3): δ = 18.6 (CH3C=), 32.2 (CH3N), 47.2
(CH2), 61.4 (CH3O), 115.8 (CH=), 126.5 (CH in Ph), 128.4 (2× CH in Ph),
129.1 (2× CH in Ph), 138.3 (C in Ph), 154.7 (C=), 168.0 (CO) ppm. MS
(EI): m/z (%) = 204 (89) [M - CH3]+, 159 (81), 158 (82), 131 (100), 130
(72), 129 (52), 115 (33) 91 (70). HRMS (EI) calcd. for C14H20NO2 [M -
CH3]+ 204.1025; found 204.1144.
N-Methoxy-N-methyl-3-phenylbut-2-enamide
(10c):
The
title
(16), 145 (22), 130 (9), 91 (100), 65 (9). HRMS (EI) calcd. for C13H16
O
compound was synthesized in 17.6 mmol scale otherwise as described
for 10a above. EtOAc-hexane (0-50% EtOAc) was used as eluent for
flash chromatography to give 10c (3.16 g, 88%) as a colorless oil, E/Z
ratio 9:1. The NMR data for the major isomer are given. 1H NMR (400
MHz, CDCl3): δ = 2.51 (s, 3 H, CH3C=), 3.25 (s, 3 H, CH3N), 3.69 (s, 3 H,
CH3O), 6.55 (s, 1 H, CH=), 7.27–7.42 (m, 3 H, Ph), 7.42–7.52 (m, 2 H,
Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.0 (CH3C=), 32.4 (CH3N),
61.6 (CH3O), 116.0 (CH=), 126.3 (CH in Ph), 128.5 (2× CH in Ph), 128.9
(2× CH in Ph), 143.0 (C in Ph), 152.3 (C=), 168.0 (CO) ppm. MS (EI): m/z
[M]+ 188.1201; found 188.1200. NMR data were in good agreement with
those reported before.[23]
4-Methyl-5-phenylpent-3-en-2-one (11b): The title compound was
synthesized in 16.8 mmol scale otherwise as described for 11a above.
EtOAc-hexane (0-5% EtOAc) was used as eluent for flash
chromatography to give 11b (2.89 g, 99%), colorless oil, E/Z ratio 5:1.
The NMR data for the major isomer are given. 1H NMR (400 MHz,
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10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
CDCl3): δ = 2.07 (d, J = 1.2 Hz, 3 H, CH3C=), 2.16 (s, 3 H, CH3CO), 3.40
(s, 2 H, CH2), 6.05 (q, J = 1.2 Hz, 1 H, CH=), 7.10–7.17 (m, 2 H, Ph),
7.17–7.35 (m, 3 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.7
(CH3C=), 31.9 (CH3CO), 38.9 (CH2), 124.9 (CH=), 126.2 (CH in Ph),
128.4 (2× CH in Ph), 129.0 (2× CH in Ph), 138.9 (C in Ph), 156.0 (C=),
198.3 (CO) ppm. MS (EI): m/z (%) = 174 (100) [M]+, 159 (45), 144 (15),
141 (14), 131 (94), 115 (18), 91 (57). HRMS (EI) calcd. for C12H14O [M]+
174.1045; found 174.1045. NMR data were in good agreement with
those reported before.[42]
was warmed to ambient temperatures and stirred for an additional 20 min.
The reaction mixture was concentrated under reduced pressure and
MeOH (10 mL) was added. The reaction mixture was again concentrated
under reduced pressure and the crude product was purified by flash
chromatography eluting with EtOAc-hexane (0-20% EtOAc) to give 12a
(96 mg, 87%) as a colorless oil. [α]20 = +20.5 (c = 1.1, CHCl3, 96% ee)
D
[lit. for (S,E) 12a[43] [α]20 = -11.0 (c = 2.05, CHCl3, 98% ee)]. 1H NMR
D
(400 MHz, CDCl3): δ = 1.19 (d, J = 6.2 Hz, 3 H, CH3), 1.30 (br s, 1 H,
OH), 1.72 (s, 3 H, CH3C=), 2.18–2.34 (m, 2 H, CH2Ph), 4.47–4.62 (m, 1
H, CHO), 5.17–5.20 (m, 1 H, CH=), 7.15–7.19 (m, 3 H, Ph), 7.25–7.29 (m,
2 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.7 (CH3C=), 23.7 (CH3),
34.4 (CH2Ph), 41.4 (CH2), 64.8 (OCH), 126.0 (CH in Ph), 128.4 (2× CH in
Ph), 128.5 (2× CH in Ph), 129.8 (CH=), 137.0 (C=), 142.1 (C in Ph) ppm.
MS (EI): m/z (%) = 190 (2) [M]+, 172 (25), 157 (18), 132 (35), 129 (11),
91 (100), 85 (49), 65 (13). HRMS (EI) C13H18O requires 190.1358, found
190.1362. HRMS (EI) calcd. for C13H18O [M]+ 190.1358; found 190.1362.
NMR data were in good agreement with those reported for (S,E) 12a.[43]
4-Phenylpent-3-en-2-one (11c): The title compound was synthesized in
15.2 mmol scale otherwise as described for 11a above. EtOAc-hexane
(0-5% EtOAc) was used as eluent for flash chromatography to give 11c
(2.37 g, 98%) as a colorless oil, E/Z ratio 10:1. The NMR data for the
major isomer are given. 1H NMR (400 MHz, CDCl3): δ = 2.27 (s, 3 H,
CH3CO), 2.52 (d, J = 1.3 Hz, 3 H, CH3C=), 6.49 (q, J = 1.3 Hz, 1 H, CH=),
7.32–7.40 (m, 3 H, Ph), 7.44–7.50 (m, 2 H, Ph) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.3 (CH3C=), 32.2 (CH3CO), 124.5 (CH=), 126.4 (2× CH in
Ph), 128.5 (2× CH in Ph), 129.0 (CH in Ph), 142.5 (C=), 153.8 (C in Ph),
198.8 (CO) ppm. MS (EI): m/z (%) = 160 (75) [M]+, 159 (100), 145 (92),
117 (60), 115 (60), 91 (24). HRMS (EI) calcd. for C11H12O [M]+ 160.0888;
found 160.0886. NMR data were in good agreement with those reported
before.[23]
(R,E)-4-Methyl-5-phenylpent-3-en-2-ol (12b): The title compound was
synthesized in 1.21 mmol scale otherwise as described for 12a above.
EtOAc-hexane (0-20% EtOAc) was used as eluent for flash
chromatography to give 12b (152 mg, 71%) as a colorless oil, E/Z ratio
33:1. [α]20 = +21.0 (c = 0.10, CHCl3, 92% ee). 1H NMR (400 MHz,
D
CDCl3): δ = 1.25 (d, J = 6.3 Hz, 3 H, CHCH3), 1.60 (d, J = 1.3 Hz, 3 H,
CH3C=), 3.27 (s, 2 H, PhCH2), 4.52–4.64 (m, 1 H, CHOH), 5.31 (dd, J =
8.5, 1.3 Hz, 1 H, =CH), 7.06–7.36 (m, 5 H, Ph) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.2 (CHCH3), 23.6 (CH3C=), 46.0 (PhCH2), 64.8 (CHOH),
126.1 (=CH), 128.3 (CH in Ph), 128.9 (2× CH in Ph), 131.0 (2× CH in Ph),
136.8 (C=), 139.5 (C in Ph) ppm. MS (EI): m/z (%) = 161 (4) [M - CH3]+,
158 (18), 143 (63), 118 (72), 91 (66), 85 (100). HRMS (ESI) calcd. for
C12H16O [M + Na]+ 199.1099; found 199.1102. NMR data were in good
agreement with those reported for rac. (E)-12b.[44]
6-Cyclohexyl-4-methylhex-3-en-2-one (11d): The title compound was
synthesized in 5.10 mmol scale otherwise as described for 11a above. c-
Hexane-TBME (0-5% TBME) was used as eluent for flash
chromatography to give 11d (981 mg, 99%) as a colorless oil, E/Z ratio
3:1. The NMR data for the major isomer are given. 1H NMR (400 MHz,
CDCl3): δ = 0.83–0.92 (m, 2 H, c-hex), 1.10–1.21 (m, 4 H, c-hex), 1.30–
1.35 (m, 2 H, c-hex-CH2), 1.65–1.70 (m, 5 H, c-hex), 2.09 (t, J = 8.0 Hz, 2
H, c-hex-CH2CH2), 2.09 (d, J = 1.3 Hz, 3 H, CH3C=), 2.14 (s, 3 H,
COCH3), 6.04 (q, J = 1.3 Hz, 1 H, =CH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.3 (CH3C=), 26.3 (c-hex), 26.6 (c-hex), 31.7 (COCH3), 33.3
(c-hex), 35.3 (c-hex-CH2), 37.4 (c-hex), 38.7 (c-hex-CH2CH2), 123.3
(=CH), 159.4 (C=), 198.8 (CO) ppm. MS (EI): m/z (%) = 194 (67) [M]+,
179 (32), 151 (100). HRMS (EI) calcd. for C13H22O [M]+ 194.1671; found
194.1667.
(R,E)-4-Phenylpent-3-en-2-ol (12c): The title compound was
synthesized in 4.47 mmol scale otherwise as described for 12a above.
EtOAc-hexane (0-25% EtOAc) was used as eluent for flash
chromatography to give 12c (729 mg, 98%) as a colorless oil. [α]20
=
D
+28.5 (c = 1.0, CHCl3, 94% ee) [lit.[45] [α]D = +30.6 (c = 1.9, EtOH, 98%
ee); lit.[46] [α]23 = +26.9 (c = 1.9, EtOH, 98% ee)]. 1H NMR (600 MHz,
D
CDCl3): δ = 1.33 (d, J = 6.3 Hz, 3 H, CHCH3), 1.52 (s, 1 H, OH), 2.09 (d,
J = 1.3 Hz, 3 H, CH3C=), 4.70–4.79 (m, 1 H, CHOH), 5.79 (dq, J = 8.3,
1.3, Hz, 1 H, =CH), 7.22–7.33 (m, 3 H, Ph), 7.37–7.40 (m, 2 H, Ph) ppm.
13C NMR (150 MHz, CDCl3): δ = 16.1 (CH3C=), 23.5 (CHCH3), 65.2
(CHOH), 125.8 (2× CH in Ph), 127.2 (CH in Ph), 128.2 (2× CH in Ph),
131.9 (=CH), 136.2 (C=), 142.9 (C in Ph) ppm. MS (EI): m/z (%) = 162
(14) [M]+, 147 (100), 129 (65). HRMS (EI) calcd. for C11H14O [M]+
162.1045; found 162.1044. NMR data were in good agreement with
those reported before.[45,46]
4-Methyl-6-(naphthalen-1-yl)hex-3-en-2-one (11e): The title compound
was synthesized in 10.0 mmol scale otherwise as described for 11a
above. EtOAc-hexane (0-5% EtOAc) was used as eluent for flash
chromatography to give 11e (2.36 g, 99%) as a colorless oil, E/Z ratio 3:1.
The NMR data for the major isomer are given. 1H NMR (400 MHz,
CDCl3): δ = 2.15 (s, 3 H, COCH3), 2.25 (d, J = 1.3 Hz, 3 H, CH3C=),
2.52–2.56 (m, 2 H, CH2C=), 3.21 (m, 2 H, ArCH2), 6.07 (q, J = 1.3 Hz, 1
H, =CH), 7.29 (d, J = 7.2 Hz, 1 H, Ar), 7.40 (dd, J = 8.2, 7.0 Hz, 1 H, Ar),
7.47–7.56 (m, 2 H, Ar), 7.73 (d, J = 8.1 Hz, 1 H, Ar), 7.87 (d, J = 8.0 Hz,
1 H, Ar), 8.01 (d, J = 8.2 Hz, 1 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ
= 19.4 (CH3C=), 31.1 (COCH3), 31.7 (ArCH2), 42.1 (CH2C=), 123.3 (CH
in Ar), 123.9 (=CH), 125.5 (CH in Ar), 125.5 (CH in Ar), 125.9 (CH in Ar),
125.9 (CH in Ar), 126.9 (CH in Ar), 128.9 (CH in Ar), 131.5 (C in Ar),
133.8 (C in Ar), 137.0 (C in Ar), 157.2 (C=), 198.7 (CO) ppm. MS (EI):
m/z (%) = 238 (22) [M]+, 223 (9), 195 (18), 141 (100), 83 (7). HRMS (EI)
calcd. for C17H18O [M]+ 238.1358; found 238.1361.
(R,E)-6-Cyclohexyl-4-methylhex-3-en-2-ol (12d): The title compound
was synthesized in 0.263 mmol scale otherwise as described for 12a
above. EtOAc-hexane (0-20% EtOAc) was used as eluent for flash
chromatography to give 12d (45.8 mg, 89%) as a colorless oil. [α]20
=
D
+11.8 (c = 0.1, CHCl3, 93% ee). 1H NMR (400 MHz, CDCl3): δ = 0.86–
0.95 (m, 2 H, c-hex), 1.14–1.33 (m, 6 H, c-hex, c-hex-CH2), 1.25 (d, J =
6.2 Hz, 3 H, CHCH3), 1.62–1.77 (m, 5 H, c-hex), 1.69 (d, J = 1.3 Hz, 3 H,
CH3C=), 2.00 (t, J = 8.0 Hz, 2 H, CH2C=), 4.56–4.63 (m, 1 H, CHOH),
5.22 (dq, J = 8.5, 1.3 Hz, 1 H, =CH) ppm. 13C NMR (100 MHz, CDCl3): δ
= 16.4 (CH3C=), 23.7 (CHCH3), 26.38 (c-hex), 26.39 (c-hex), 26.7 (c-hex),
33.3 (c-hex), 33.4 (c-hex), 35.5 (c-hex-CH2), 36.8 (CH2C=), 37.5 (c-hex),
64.8 (CHOH), 128.6 (=CH), 138.5 (C=) ppm. MS (ESI): m/z (%) = 219
(100) [M + Na]+. HRMS (ESI) calcd. for C13H24O [M + Na]+ 219.1725;
found 219.1728.
(R,E)-4-Methyl-6-phenylhex-3-en-2-ol (12a): Oxazaborolidine-borane
complex 13 (253 mg, 0.870 mmol) was added to dry THF (5 mL) under
Ar-atm. The solution was cooled to -78 °C and ketone 11a (109 mg,
0.580 mmol), freshly isolates as pure E-isomer, was added. After addition
of the ketone, the solution was immediately placed in
a water /
ethyleneglycol bath at -20 ºC and stirred for 1h. The reaction mixture was
quenched with careful addition of MeOH (2 mL) at -20 ºC. When
evolution of H2-gas no longer could be observed, the reaction mixture
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10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
(R,E)-4-Methyl-6-(naphthalen-1-yl)hex-3-en-2-ol (12e): The title
compound was synthesized in 0.764 mmol scale otherwise as described
for 12a above. EtOAc-hexane (0-15% EtOAc) was used as eluent for
aqueous phase was extracted with methyl tert-butyl ether (3× 5 mL). The
combined organic extracts were dried (MgSO4) and concentrated under
reduced pressure to give 16a (148 mg, 95%) as a colorless oil. [α]20
=
D
flash chromatography to give 12e (163 mg, 89%) as a colorless oil. [α]20
+15.6 (c = 1.0, CHCl3, 88% ee). 1H NMR (400 MHz, CDCl3): δ = 1.22 (s,
3 H, CH3), 1.47 (s, 2 H, NH2), 1.58–1.89 (m, 5 H, CH3C= and CH2), 2.48–
2.72 (m, 2 H, CH2Ph), 5.43–5.68 (m, 2 H, 2× CH=), 7.06–7.40 (m, 5 H,
Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.8 (CH3CH=), 28.9 (CH2Ph),
30.9 (CH3), 45.6 (CH2), 53.0 (CNH2), 121.6 (CH=CH3) 125.6 (CH in Ph),
128.3 (4× CH in Ph), 139.9 C-CH=), 142.7 (C in Ph) ppm. MS (EI) m/z
(rel. int.) 147 (17), 131 (13), 129 (11), 122 (14), 105 (69), 91 (100), 77
(35). MS (ESI): m/z (%) = 190 (100) [M + H]+. HRMS (ESI) calcd. for
C13H19N [M + Na]+ 212.1415; found 212.1417.
D
= +13.1 (c = 1.0, CHCl3, 88% ee). 1H NMR (400 MHz, CDCl3): δ = 1.19 (d,
J = 6.3 Hz, 3 H, CHCH3), 1.78 (d, J = 1.3 Hz, 3 H, CH3C=), 2.40 (t, J =
8.2 Hz, 2 H, CH2C=), 3.17 (t, J = 8.2 Hz, 2 H, ArCH2), 4.47–4.66 (m, 1 H,
CHOH), 5.21 (dq, J = 8.6, 1.3 Hz, 1 H, =CH), 7.29 (dd, J = 7.2, 1.2 Hz, 1
H, Ar), 7.37 (t, J = 7.8 Hz, 1 H, Ar), 7.42–7.54 (m, 2 H, Ar), 7.70 (d, J =
8.2 Hz, 1 H, Ar), 7.84 (dd, J = 7.8, 1.5 Hz, 1 H, Ar), 8.01 (dd, J = 8.2, 1.5
Hz, 1 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.7 (CH3C=), 23.6
(CHCH3), 31.5 (ArCH2), 40.5 (CH2C=), 64.8 (CHOH), 123.6 (CH in Ar),
125.4 (CH in Ar), 125.5 (CH in Ar), 125.8 (CH in Ar), 125.9 (CH in Ar),
126.7 (CH in Ar), 128.8 (CH in Ar), 129.6 (=CH), 131.8 (C in Ar), 133.9 (C
in Ar), 137.1 (C=), 138.1 (C in Ar) ppm. MS (ESI): m/z (%) = 263 (100) [M
+ Na]+. HRMS (ESI) calcd. for C17H20O [M + Na]+ 263.1412; found
263.1420.
(S,E)-2-Methyl-1-phenylpent-3-en-2-amine (16b): The title compound
was synthesized in 0.247 mmol scale otherwise as described for 16a
above to give 16b (35.4 mg, 82%) as a colorless oil. [α]20 = +16.5 (c =
D
1.0, CHCl3, 67% ee). 1H NMR (400 MHz, CDCl3): δ = 1.14 (s, 3 H, CCH3),
1.16 (s, 2 H, NH2), 1.66 (dd, J = 6.3, 1.5 Hz, 3 H, =CHCH3), 2.67 (s, 2 H,
PhCH2), 5.33–5.46 (m, 1 H, =CHCH3), 5.55 (dq, J = 15.5, 1.5 Hz, 1 H,
CH=CHCH3), 7.11–7.17 (m, 2 H, Ph), 7.18–7.28 (m, 3 H, Ph) ppm. 13C
NMR (100 MHz, CDCl3): δ = 17.8 (CH3CH=), 28.9 (CH2Ph), 30.9 (CH3),
45.6 (CH2), 53.0 (CNH2), 121.6 (CH=CH3) 125.6 (CH in Ph), 128.3 (4×
CH in Ph), 139.9 C-CH=), 142.7 (C in Ph) ppm. MS (EI) m/z (rel. int.) 147
(17), 131 (13), 129 (11), 122 (14), 105 (69), 91 (100), 77 (35). MS (ESI):
m/z (%) = 198 (100) [M + Na]+. HRMS (ESI) calcd. for C12H17N [M + Na]+
198.1259; found 198.1259.
General procedure for the reduction of ketones 11 with catalytic
amounts of oxazaborolidine-borane complex 13:
Oxazaborolidine-borane complex 13 (385 mg, 1.32 mmol) was dissolved
in dry THF (3 mL) under Ar-atm. and cooled to -20 ºC. Ketone 11, freshly
isolates as pure E-isomer, (6.62 mmol, in 4 mL THF) and BH3•SMe2
(0.314 mL, 3.31 mmol in 4 mL THF) were simultaneously added over a
period of 2 h using a syringe pump. After the addition was completed, the
mixture was stirred for 1 h and quenched with careful addition of MeOH
(10 mL) at -20 ºC. When evolution of H2-gas no longer could be observed,
the reaction mixture was warmed to ambient temperatures and stirred for
an additional 20 min. The reaction mixture was concentrated under
reduced pressure and MeOH (10 mL) was added. The reaction mixture
was again concentrated under reduced pressure and the crude product
was purified by flash chromatography. The yields and % ee are given in
Table 2.
(R,E)-2-Phenylpent-3-en-2-amine (16c): The title compound was
synthesized in 0.609 mmol scale otherwise as described for 16a above to
give 16c (89.4 mg, 91%) as a colorless oil. [α]20D = +29.7 (c = 1.0, CHCl3,
80% ee). 1H NMR (400 MHz, CDCl3): δ = 1.51 (s, 3 H, CCH3), 1.59 (s, 2
H, NH2), 1.70 (dd, J = 6.3, 1.5 Hz, 3 H, =CHCH3), 5.57 (dq, J = 15.5, 6.3
Hz, 1 H, =CHCH3), 5.72 (dq, J = 15.5, 1.5 Hz, 1 H, CH=CHCH3), 7.17–
7.22 (m, 1 H, Ph), 7.27–7.34 (m, 2 H, Ph), 7.43–7.47 (m, 2 H, Ph) ppm.
13C NMR (100 MHz, CDCl3): δ = 17.7 (=CHCH3), 30.5 (CCH3), 56.1
(CNH2), 121.7 (=CHCH3), 125.5 (2× CH in Ph), 126.3 (CH in Ph), 128.1
(2× CH in Ph), 140.4 (CH=CHCH3), 148.6 (C in Ph) ppm. MS (ESI): m/z
(%) = 184 (100) [M + Na]+. HRMS (ESI) calcd. for C11H15N [M + Na]+
184.1102; found 184.1101.
(S,E)-2,2,2-trichloro-N-(3-methyl-1-phenylhex-4-en-3-yl)acetamide
(15): 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.0280 mL, 0.187 mmol) was
added to a solution of compound 12a (176 mg, 0.926 mmol) in CH2Cl2 (5
mL) under Ar-atm. The mixture was cooled to
0
ºC and
trichloroacetonitrile (0.140 mL, 1.40 mmol) was added over a period of 5
min. After stirring for 1 h, the mixture was concentrated under reduced
pressure and the crude trichloroacetimidate was filtered through a short
plug (4 cm) of silica, eluting with 2% EtOAc in hexanes (40 mL). Solvents
were evaporated under reduced pressure and the residue was dissolved
in xylenes (20 mL). Na2CO3 (19.6 mg, 0.185 mmol) was added and the
mixture was stirred for 20 h under Ar-atm. at 130 oC. The mixture was
concentrated under reduced pressure and the crude product was purified
by flash chromatography eluting with EtOAc-hexanes (0-15% EtOAc) to
give 15 (65.8 mg, 21%) as a pale yellow wax. 1H NMR (400 MHz,
CDCl3): δ = 1.53 (s, 1 H, CH3), 1.75 (d, J = 5.1 Hz, 3 H, CH3), 2.05–2.25
(m, 2 H, CH2), 2.55–2.59 (m, 2 H, CH2Ph), 5.62–5.66 (m, 2 H, CH=CH),
7.14–7.17 (m, 3 H, Ph), 7.24–7.28 (m, 2 H, Ph) ppm. 13C NMR (100 MHz,
CDCl3): δ = 17.9 (CH3CH=), 24.5 (CH2Ph), 30.5 (CH3), 40.8 (CH2), 58.3
(CN), 93.3 (CCl3), 124.9 (CH3CH=), 126.0 (CH in Ph), 128.4 (2× CH in
Ph), 128.5 (2× CH in Ph), 134.3 (CH=), 141.5 (C in Ph), 160.1 (CO) ppm.
MS (ESI): m/z (%) = 356 (100) [M + Na]+. HRMS (ESI) calcd. for
C15H18Cl3NO [M + Na]+ 356.0352, found 356.0349.
(S,E)-1-Cyclohexyl-3-methylhex-4-en-3-amine
compound was synthesized in 0.102 mmol scale otherwise as described
for 16a above to give 16d (19.5 mg, 98%) as a colorless oil. [α]20
(16d):
The
title
=
D
+12.4 (c = 0.9, CHCl3, 77% ee). 1H NMR (400 MHz, CDCl3): δ = 0.79–
0.90 (m, 2 H, c-hex), 1.08–1.24 (m, 6 H, c-hex, c-hex-CH2), 1.10 (s, 3 H,
=CHCH3), 1.31–1.40 (m, 2 H, c-hex -CH2CH2), 1.58–1.73 (m, 5 H, c-hex),
1.66 (d, J = 4.7 Hz, 3 H, CCH3), 5.43–5.46 (m, 4 H, 2× CH= and NH2)
ppm. 13C NMR (100 MHz, CDCl3): δ = 17.5 (=CHCH3), 26.1 (c-hex), 26.4
(c-hex), 28.4 (CCH3), 31.5 (c-hex-CH2), 33.1 (c-hex), 38.0 (c-hex), 40.0
(c-hex-CH2CH2), 52.5 (CNH2), 120.6 (=CHCH3), 140.2 (CCH=) ppm. MS
(ESI): m/z (%) = 218 (100) [M + Na]+. HRMS (ESI) calcd. for C13H25N [M
+ Na]+ 218.1885; found 218.1884.
(S,E)-3-Methyl-1-(naphthalen-2-yl)hex-4-en-3-amine (16e): The title
compound was synthesized in 0.252 mmol scale otherwise as described
for 16a above to give 16e (39.9 mg, 89%) as a colorless oil. [α]20
=
D
+13.5 (c = 1.0, CHCl3, 84% ee). 1H NMR (400 MHz, CDCl3): δ = 1.26 (s,
3 H, CCH3), 1.47 (s, 2 H, NH2), 1.73–1.77 (m, 3 H, =CHCH3), 1.77–1.85
(m, 2 H, ArCH2CH2), 2.99–3.07 (m, 2 H, ArCH2), 5.56–5.67 (m, 2 H, 2×
CH=), 7.27–7.40 (m, 2 H, Ar), 7.41–7.52 (m, 2 H, Ar), 7.68 (d, J = 8.2 Hz,
1 H, Ar), 7.82 (d, J = 7.6 Hz, 1 H, Ar), 7.99 (d, J = 8.2 Hz, 1 H, Ar) ppm.
13C NMR (100 MHz, CDCl3): δ = 17.8 (=CHCH3), 28.0 (ArCH2), 28.9
(CCH3), 44.9 (ArCH2CH2), 53.3 (CNH2), 121.9 (=CHCH3), 123.7 (CH in
Ar), 125.4 (CH in Ar), 125.6 (CH in Ar), 125.7 (CH in Ar), 125.8 (CH in Ar),
(S,E)-3-Methyl-1-phenylhex-4-en-3-amine (16a): Potassium tert-
butoxide (371 mg, 3.31 mmol) and finely grounded KOH (92.8 mg, 1.65
mmol) was added to a solution of compound 20a (239 mg, 0.827 mmol)
in THF (5 mL) under Ar-atm. The mixture was heated to 55 ºC and stirred
for 18 h. The reaction mixture was concentrated under reduced pressure.
Methyl tert-butyl ether (5 mL) and water (5 mL) was added and the
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10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
126.5 (CH in Ar), 128.8 (CH in Ar), 131.8 (C in Ar), 133.9 (C in Ar), 138.9
(C in Ar), 139.9 (CH=CHCH3) ppm. MS (ESI): m/z (%) = 262 (100) [M +
Na]+. HRMS (ESI) calcd. for C17H21N [M + Na]+ 262.1572; found
262.1569.
(100), 91 (22), 84 (42). HRMS (ESI) calcd. for C12H15NO2 [M + Na]+
228.1000; found 228.0994.
(R,E)-6-Cyclohexyl-4-methylhex-3-en-2-yl carbamate (17d): The title
compound was synthesized in 1.62 mmol scale otherwise as described
for 17a above. EtOAc-hexane (0-40% EtOAc) was used as eluent for
flash chromatography to give 17d (341 mg, 88%) as colorless crystals,
Synthesis of compound 16a, alternative 2: A mixture of amide 15
(65.9 mg, 0.197 mmol), NaOH (2 mL, 6M, 12 mmol) and EtOH (3 mL)
was stirred at 40 °C for 24 h. The reaction mixture was extracted with
diethyl ether (2× 10 mL). The combined organic layers were washed with
water (10 mL), dried (MgSO4) and evaporated. The crude product was
purified by flash chromatography eluting with EtOH-EtOAc (1:3) to give
16a (33.1 mg, 89%) as a colorless oil.
m.p. 51–54 °C. [α]20 = +15.2 (c = 1.0, CHCl3, 93% ee). 1H NMR (400
D
MHz, CDCl3): δ = 0.79–0.91 (m, 2 H, c-hex), 1.09–1.29 (m, 6 H, c-hex, c-
hex-CH2), 1.25 (d, J = 6.2 Hz, 3 H, CHCH3), 1.59–1.72 (m, 5 H, c-hex),
1.68 (d, J = 1.3 Hz, 3 H, CH3C=), 1.97 (t, J = 8.0 Hz, 2 H, CH2C=), 4.48
(br s, 2 H, NH2), 5.12 (dd, J = 8.8, 1.3 Hz, 1 H, =CH), 5.47 (m, 1 H, OCH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 16.7 (CH3C=), 21.1 (CHCH3), 26.4
(c-hex), 26.4 (c-hex), 26.7 (c-hex), 33.3 (c-hex), 33.4 (c-hex), 35.4 (c-
hex-CH2), 36.8 (CH2C=), 37.4 (c-hex), 69.0 (OCH), 124.3 (=CH), 140.4
(C=), 156.4 (CO) ppm. MS (ESI): m/z (%) = 262 (100) [M + Na]+. HRMS
(ESI) calcd. for C18H21NO2 [M + Na]+ 306.1470; found 306.1481.
(R,E)-4-Methyl-6-phenylhex-3-en-2-yl carbamate (17a): Trichloroacetyl
isocyanate (0.885 mL, 7.48 mmol) was added over a period of 1 min to a
stirred solution of compound 12a (712 mg, 3.75 mmol) in dry CH2Cl2 (20
mL) at 0 °C under Ar-atm. After stirring for 10 min, the mixture was
concentrated under reduced pressure. MeOH (10 mL) and aqueous
K2CO3 (2.0 M, 15 mL) were added and the mixture was stirred 18 h at
ambient temperatures. MeOH was removed under reduced pressure and
the remaining aqueous residue was extracted with CH2Cl2 (3× 30 mL).
The combined organic extracts were dried (MgSO4) and concentrated
under reduced pressure and the crude product was purified by flash
chromatography eluting with EtOAc-hexane (0-40% EtOAc) to give 17a
(R,E)-4-Methyl-6-(naphthalen-1-yl)hex-3-en-2-yl carbamate (17e): The
title compound was synthesized in 0.443 mmol scale otherwise as
described for 17a above. EtOAc-hexane (0-30% EtOAc) was used as
eluent for flash chromatography to give 17e (111 mg, 88%) as colorless
crystals, m.p. 66–70 °C. [α]20 = +11.3 (c = 0.55, CHCl3, 88% ee). 1H
D
NMR (400 MHz, CDCl3): δ = 1.23 (d, J = 6.4 Hz, 3 H, CHCH3), 1.82 (d, J
= 1.3 Hz, 3 H, CH3C=), 2.41 (t, J = 8.0 Hz, 2 H, CH2C=), 3.04–3.29 (m, 2
H, ArCH2), 4.49 (br s, 2 H, NH2), 5.17 (d, J = 8.5 Hz, 1 H, =CH), 5.43–
5.59 (m, 1 H, OCH), 7.28 (d, J = 6.8 Hz, 1 H, Ar), 7.36 (t, J = 8.2 Hz, 1 H,
Ar), 7.41–7.56 (m, 2 H, Ar), 7.69 (d, J = 8.2 Hz, 1 H, Ar), 7.83 (d, J = 7.8
Hz, 1 H, Ar), 8.01 (d, J = 8.2 Hz, 1 H, Ar) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.9 (CH3C=), 21.0 (CHCH3), 31.5 (ArCH2), 40.5 (CH2C=),
68.9 (CHO), 123.7 (CH in Ar), 125.3 (CH in Ar), 125.4 (CH in Ar), 125.5
(CH in Ar), 125.8 (CH in Ar), 126.0 (=CH), 126.6 (CH in Ar), 128.8 (CH in
Ar), 131.8 (C in Ar), 133.9 (C in Ar), 138.0 (C=), 139.0 (C in Ar), 156.4
(CO) ppm. MS (ESI): m/z (%) = 306 (100) [M + Na]+. HRMS (ESI) calcd.
for C18H21NO2 [M + Na]+ 306.1470; found 306.1481.
(787 mg, 90%) as colorless crystals, m.p. 54–56 oC. [α]20 = +13.9 (c =
D
1.0, CHCl3, 96% ee). 1H NMR (400 MHz, CDCl3): δ = 1.22 (d, J = 6.4 Hz,
3 H, CHCH3), 1.75 (s, 3 H, CH3C=), 2.28 (t, J = 8.0 Hz, 2 H, CH2), 2.64–
2.77 (m, 2 H, CH2Ph), 4.69 (s, 2 H, NH2), 5.13 (d, J = 8.7 Hz, 1 H, CH=),
5.48 (dq, J = 8.7, 6.4 Hz, 1 H, OCH), 7.12–7.20 (m, 3 H, Ph), 7.22–7.29
(m, 2 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.8 (CH3C=), 21.0
(CHCH3), 34.2 (CH2Ph), 41.2 (CH2), 68.8 (OCH), 125.3 (CH=), 125.7 (CH
in Ph), 128.2 (2× CH in Ph), 128.4 (2× CH in Ph), 138.7 (C in Ph), 156.6
(CO) ppm. MS (EI): m/z (%) 173 (23) [M - NH2CO2]+, 172 (74), 157 (58),
143 (31), 129 (16), 91 (100), 81 (13). MS (ESI): m/z (%) = 256 (100) [M +
Na]+. HRMS (ESI) calcd. for C14H19NO2 [M + Na]+ 256.1313; found
256.1318.
(S,E)-tert-Butyl (3-methyl-1-phenylhex-4-en-3-yl)carbamate (20a):
Triethylamine (0.547 mL, 3.93 mmol) was added to a solution of
carbamate 17a (229 mg, 0.983 mmol) in dry CH2Cl2 (10 mL) under Ar-
atm. The mixture was cooled to -78 ºC and trifluoroacetic anhydride
(0.208 mL, 1.47 mmol) was added over a period of 2 min. The reaction
mixture was stirred 1 h at -78 ºC and warmed to ambient temperatures.
After stirring for 20 min, the reaction mixture was concentrated under
reduced pressure. The residue was redissolved in a minimal amount of
dry CH2Cl2 and filtered through a short silica pad (2 cm), eluting with
CH2Cl2 (10 mL). tert-BuOH (0.937 mL, 9.83 mmol) and MoCl2O2(DMF)2
(6.76 mg, 0.0197 mmol) was added under Ar-atm. and the mixture was
stirred for 18 h at ambient temperatures. The reaction mixture was
concentrated under reduced pressure and the crude product was purified
by flash chromatography eluting with EtOAc-hexane (0-10% EtOAc) to
give 20a (239 mg, 84%) as a colorless oil. [α]20D = +14.3 (c = 1.1, CHCl3,
(R)-4-Methyl-5-phenylpent-3-en-2-yl carbamate (17b): The title
compound was synthesized in 0.811 mmol scale otherwise as described
for 17a above. EtOAc-hexane (0-40% EtOAc) was used as eluent for
flash chromatography to give 17b (165 mg, 93%) as colorless crystals,
E/Z ratio 20:1, m.p. 62–64 °C. [α]20 = +26.5 (c = 0.98, CHCl3, 92% ee),
D
The NMR data for the major isomer are given. 1H NMR (400 MHz,
CDCl3): δ = 1.28 (d, J = 6.4 Hz, 3 H, CHCH3), 1.64 (d, J = 1.3 Hz, 3 H,
CH3C=), 3.28 (s, 2 H, PhCH2), 4.53 (br s, 2 H, NH2), 5.24 (dd, J = 8.6, 1.3
Hz, 1 H, =CH), 5.49 (dq, J = 8.6, 6.3 Hz, 1 H, OCH), 7.11–7.30 (m, 5 H,
Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.5 (CHCH3), 21.1 (CH3C=),
45.9 (PhCH2), 68.9 (CHO), 126.1 (=CH), 126.8 (CH in Ph), 128.3 (2× CH
in Ph), 128.9 (2× CH in Ph), 138.5 (C=), 139.3 (C in Ph), 156.4 (CO) ppm.
MS (ESI): m/z (%) = 242 (100) [M + Na]+. HRMS (ESI) calcd. for
C13H17NO2 [M + Na]+ 242.1157; found 242.1155.
1
88% ee). H NMR (400 MHz, CDCl3): δ = 1.38 (s, 3 H, CH3CN), 1.43 (s, 9
H, t-Bu), 1.70 (d, J = 4.7 Hz, 3 H, CH3C=), 1.94–2.08 (m, 2 H, CH2), 2.53
(t, J = 8.5 Hz, 2 H, CH2Ph), 4.53 (s, 1 H, NH), 5.53–5.55 (m, 2 H, 2×
CH=), 7.15–7.20 (m, 3 H, Ph), 7.21–7.28 (m, 2 H, Ph) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.6 (CH3C=), 25.3 (CH3CN), 28.3 (3× CH3 in t-
Bu), 30.4 (CH2Ph), 41.5 (CH2), 55.5 (CN), 78.6 (C in t-Bu), 122.7
(CH3C=), 125.5 (CH in Ph), 128.1 (2× CH in Ph), 128.2 (2× CH in Ph),
136.4 (NCCH=), 142.2 (C in Ph), 154.1 (CO) ppm. MS (EI): m/z (%) =
289 (0.2) [M]+, 233 (12), 184 (16), 173 (11), 172 (18), 157 (10), 128 (100),
91 (22), 84 (42). HRMS (ESI) calcd. for C18H17NO2 [M + Na]+ 289.2042;
found 289.2041.
(R,E)-4-Phenylpent-3-en-2-yl carbamate (17c): The title compound was
synthesized in 5.67 mmol scale otherwise as described for 17a above.
EtOAc-hexane (0-40% EtOAc) was used as eluent for flash
chromatography to give 17c (834 mg, 86%) as colorless crystals, m.p.
85–88 °C. [α]20 = +33.6 (c = 1.0, CHCl3, 94% ee). 1H NMR (600 MHz,
D
CDCl3): δ = 1.36 (d, J = 6.3 Hz, 3 H, CHCH3), 2.12 (d, J = 1.3 Hz, 3 H,
CH3C=), 4.59 (s, 2 H, NH2), 5.61–5.69 (m, 1 H, CHO), 5.71 (dq, J = 8.7,
1.3, Hz, 1 H, =CH), 7.22–7.32 (m, 3 H, Ph), 7.35–7.40 (m, 2 H, Ph) ppm.
13C NMR (150 MHz, CDCl3): δ = 16.4 (CH3C=), 21.0 (CHCH3), 69.1
(CHO), 125.9 (2× CH in Ph), 127.3 (CH in Ph), 127.6 (=CH), 128.2 (2×
CH in Ph), 137.9 (C=), 142.7 (C in Ph), 156.4 (CO) ppm. MS (EI): m/z
(%) = 289 (0.2) [M]+, 233 (12), 184 (16), 173 (11), 172 (18), 157 (10), 128
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
(S,E)-tert-Butyl 2-methyl-1-phenylpent-3-en-2-ylcarbamate (20b): The
title compound was synthesized in 0.525 mmol scale otherwise as
described for 20a above. EtOAc-hexane (0-10% EtOAc) was used as
eluent for flash chromatography to give 20b (121 mg, 84%) as a
Synthesis of compound 20a, alternative 2: Triethylamine (0.451 mL,
3.24 mmol) was added to a solution of carbamate 17a (0.189 g, 0.809
mmol) in dry CH2Cl2 (5 mL) under Ar-atm. The mixture was cooled to -78
ºC and trifluoroacetic anhydride (0.171 mL, 1.21 mmol) was added over a
period of 2 min. The reaction mixture was stirred 1 h at -78 ºC and
warmed to ambient temperatures. After stirring for 20 min, the reaction
mixture was concentrated under reduced pressure. The residue was
dissolved in a minimal amount of dry CH2Cl2 and filtered through a short
silica pad (2 cm), eluting with CH2Cl2 (10 mL). The mixture was
concentrated under reduced pressure and the crude isocyanate was
dissolved THF (5 mL) and cooled to -15 ºC. tert-BuOH (3.60 mL, 37.7
mmol) and lithium tert-butoxide (0.890 mL, 1M in THF) was added and
the mixture was stirred for 2 h. Sat. aq. NH4Cl (20 mL) was added and
the mixture was extracted with EtOAc (3× 20 mL). The combined organic
phases were dried (MgSO4) and concentrated under reduced pressure.
The crude product was purified by flash chromatography eluting with
EtOAc-hexane (0-10% EtOAc) to give 20a (199 mg, 85%) as a colorless
oil.
1
colorless oil. [α]20D = +15.4 (c = 0.30, CHCl3, 67% ee). H NMR (400 MHz,
CDCl3): δ = 1.33 (s, 3 H, CH3CN), 1.48 (s, 9 H, t-Bu), 1.72 (dd, J = 6.3,
1.6 Hz, 3 H, =CHCH3), 2.96 (d, J = 13.2 Hz, 1 H, PhCH2), 3.16 (d, J =
13.2 Hz, 1 H, PhCH2), 4.40 (br s, 1 H, NH), 5.42–5.53 (m, 1 H, =CHCH3),
5.66 (dd, J = 15.2, 1.6 Hz, 1 H, CH=CHCH3), 7.14–7.19 (m, 2 H, Ph),
7.21–7.32 (m, 3 H, Ph) ppm. 13C NMR (C100 MHz, CDCl3): δ = 17.8
(=CHCH3), 25.6 (CH3CN), 28.5 (3× CH3 in t-Bu), 44.8 (PhCH2), 55.9 (CN),
78.8 (C in t-Bu), 123.0 (=CHCH3), 126.2 (CH in Ph), 127.8 (2× CH in Ph),
130.8 (2× CH in Ph), 136.4 (CH=CHCH3), 137.5 (C in Ph), 154.5 (CO)
ppm. MS (ESI): m/z (%) = 298 (100) [M + Na]+. HRMS (ESI) calcd. for
C17H25NO2 [M + Na]+ 298.1783; found 298.1787.
(R,E)-tert-Butyl 2-phenylpent-3-en-2-ylcarbamate (20c): The title
compound was synthesized in 3.77 mmol scale otherwise as described
for 20a above. EtOAc-hexane (0-15% EtOAc) was used as eluent for
flash chromatography to give 20c (868 mg, 88%) as a colorless oil. [α]20
Synthesis of compound 20a, alternative 3: Carbamate 17a (784 mg,
3.36 mmol), triphenylphosphine (1.32 g, 5.04 mmol) and triethylamine
(938 mg, 6.72 mmol) was subsequently added to dry CH2Cl2 (18 mL)
under Ar-atm. and the solution was cooled to -28 °C. Carbon
tetrabromide (1.67 g, 5.04 mmol) dissolved in CH2Cl2 (2 mL) was added
dropwise over a period of 1 min and the solution was stirred at -28 °C for
1 h. Heptane (50 mL) was added and the suspension was warmed to
ambient temperature. Aq. KHSO4 (1 M, 20 mL) was added and the
mixture was vigorously stirred for 20 min. The phases were separated
and the aqueous phase was extracted with heptane (2× 10 mL). The
combined organic phases were dried (MgSO4), concentrated under
reduced pressure to ca. 2/3 of its original volume and filtered through a
plug of cotton. The solution was further concentrated to give the
intermediate isocyanate as a pale yellow oil. THF (15 mL) and tert-BuOH
(5 mL) was added and the solution was cooled to -15 ºC. Lithium tert-
butoxide (3.36 mL, 1 M in THF) was added and the solution was stirred
for 1 h. Sat. aq. NH4Cl (20 mL) and water (10 mL) were added and the
mixture was extracted with Et2O (30 mL) and CH2Cl2 (3× 20 mL). The
combined organic phases were dried (MgSO4) and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography eluting with EtOAc-hexane (0-30 % EtOAc) to give 20a
(651 mg, 67%) as a colorless oil.
D
= +26.1 (c = 1.0, CHCl3, 80% ee). 1H NMR (400 MHz, CDCl3): δ = 1.35 (s,
9 H, t-Bu), 1.69 (s, 3 H, CH3CN), 1.71 (dd, J = 6.5, 1.7 Hz, 3 H, =CHCH3),
4.93 (s, 1 H, NH), 5.50 (dq, J = 15.6, 6.5 Hz, 1 H, =CHCH3), 5.84 (dd, J =
15.6, 1.7 Hz, 1 H, CH=CHCH3), 7.16–7.22 (m, 1 H, Ph), 7.26–7.32 (m, 1
H, Ph), 7.33-7.37 (m, 2 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ =
17.8 (=CHCH3), 27.1 (CH3CN), 28.3 (3× CH3 in t-Bu), 58.8 (CN), 79.1 (C
in t-Bu), 124.2 (=CHCH3), 125.6 (2× CH in Ph), 126.5 (CH in Ph), 128.1
(2× CH in Ph), 136.3 (CH=CHCH3), 146.1 (C in Ph) 154.8 (CO) ppm. MS
(ESI): m/z (%) = 284 (100) [M + Na]+. HRMS (ESI) calcd. for C16H23NO2
[M + Na]+ 284.1626; found 284.1624.
(S,E)-tert-Butyl 1-cyclohexyl-3-methylhex-4-en-3-ylcarbamate (20d):
The title compound was synthesized in 0.829 mmol scale otherwise as
described for 20a above. EtOAc-hexane (0-10% EtOAc) was used as
eluent for flash chromatography to give 20d (163 mg, 67%) as a
colorless oil. [α]20D = +10.5 (c = 0.9, CHCl3, 77% ee). 1H NMR (400 MHz,
CDCl3): δ = 0.79–0.89 (m, 2 H, c-hex), 1.05–1.21 (m, 6 H, c-hex, c-hex-
CH2), 1.29 (s, 3 H, CH3CN), 1.40 (s, 9 H, t-Bu), 1.52–1.70 (m, 10 H, c-
hex, c-hex-CH2CH2, =CHCH3), 4.43 (br s, 1 H, NH), 5.44–5.47 (m, 2 H,
2× CH=) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.9 (=CHCH3), 25.2
(CH3CN), 26.4 (c-hex), 26.7 (c-hex), 28.5 (3× CH3 in t-Bu), 31.4 (c-hex-
CH2), 33.5 (c-hex), 37.5 (c-hex), 38.0 (c-hex-CH2CH2), 55.7 (CN), 78.7
(C in t-Bu), 122.5 (=CHCH3), 136.9 (CCH=), 154.5 (CO) ppm. MS (ESI):
m/z (%) = 318 (100) [M + Na]+. HRMS (ESI) calcd. for C18H33NO2 [M +
Na]+ 318.2409; found 318.2406.
(S,E)-Methyl
(3-methyl-1-phenylhex-4-en-3-yl)carbamate
(21):
Carbamate 17a (224 mg, 0.961 mmol) and triphenylphosphine (755 mg,
2.88 mmol) were dissolved in toluene (10 mL) and concentrated under
reduced pressure. The resulting solid was dissolved in dry CH2Cl2 (15
mL), and triethylamine (582 mg, 5.76 mmol) was added. The solution
was cool to 0 °C under Ar-atm. and carbon tetrabromide (956 mg, 2.88
mmol) in CH2Cl2 (10 mL) was added. The solution was stirred at 0 °C for
20 min. Tributyltin methoxide (302 µL, 1.06 mmol) in MeOH (9 mL) was
added and the solution was stirred for 12 h at ambient temperature. The
reaction mixture was diluted with Et2O (50 mL) and washed with aq.
KHSO4 (1 M, 2× 20 mL), sat. aq. NaHCO3 (20 mL) and brine (20 mL).
The solution was concentrated under reduced pressure and the resulting
residue was dissolved in a solution of KF in acetonitrile (1 M, 15 mL).
After stirring for 1 h, the suspension was diluted with Et2O (50 mL) and
filtered. The filtrate was washed with water (2× 10 mL) and brine (10 mL),
dried (Na2SO4) and concentrated under reduced pressure. The crude
product was purified by flash column chromatography eluting with EtOAc-
(S,E)-tert-Butyl 3-methyl-1-(naphthalen-1-yl)hex-4-en-3-ylcarbamate
(20e): The title compound was synthesized in 0.435 mmol scale
otherwise as described for 20a above. EtOAc-hexane (0-10% EtOAc)
was used as eluent for flash chromatography to give 20e (128 mg, 87%)
1
as a colorless oil. [α]20D = +11.2 (c = 1.37, CHCl3, 84% ee). H NMR (400
MHz, CDCl3): δ = 1.46 (s, 3 H, CH3CN), 1.47 (s, 9 H, t-Bu), 1.75 (d, J =
5.0 Hz, 3 H, =CHCH3), 2.06–2.20 (m, 2 H, ArCH2CH2), 3.00 (t, J = 8.6 Hz,
2 H, ArCH2), 4.63 (br s, 1 H, NH), 5.59–5.67 (m, 2 H, 2× CH=), 7.30 (d, J
= 7.0 Hz, 1 H, Ar), 7.36 (t, J = 7.6 Hz, 1 H, Ar), 7.41–7.52 (m, 2 H, Ar),
7.68 (d, J = 8.3 Hz, 1 H, Ar), 7.82 (d, J = 7.9 Hz, 1 H, Ar), 8.03 (d, J = 8.3
Hz, 1 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.9 (=CHCH3), 25.6
(CH3CN), 27.8 (ArCH2), 28.5 (3× CH3 in t-Bu), 40.9 (ArCH2CH2), 55.9
(CN), 79.0 (C in t-Bu), 123.2 (=CHCH3), 123.9 (CH in Ar), 125.4 (CH in
Ar), 125.6 (CH in Ar), 125.8 (CH in Ar), 126.0 (CH in Ar), 126.5 (CH in Ar),
128.7 (CH in Ar), 131.9 (C in Ar), 133.9 (C in Ar), 136.6 (CH=CHCH3),
138.6 (C in Ar), 154.4 (CO) ppm. MS (ESI): m/z (%) = 362 (100) [M +
Na]+. HRMS (ESI) calcd. for C22H29NO2 [M + Na]+ 362.2096; found
362.2094.
hexane (0-30% EtOAc) to give 21 (651 mg, 67%) as a colorless oil. [α]20
D
= +12.1 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.42 (s, 3 H,
CH3CN), 1.72 (d, J = 4.1 Hz, 3 H, CH3C=), 1.95–2.10 (m, 2 H, CH2), 2.55
(t, J = 8.6 Hz, 2 H, CH2Ph), 3.61 (s, 3 H, CH3O), 4.68 (s, 1 H, NH), 5.54-
5.59 (m, 2 H, 2× CH=), 7.13–7.18 (m, 3 H, Ph), 7.21–7.29 (m, 2 H, Ph)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601446
European Journal of Organic Chemistry
FULL PAPER
ppm. 13C NMR (100 MHz, CDCl3): δ = 17.9 (CH3C=), 25.1 (CH3CN), 30.5
(CH2Ph), 41.6 (CH2), 51.6 (CH3O), 55.9 (CN), 123.6 (CH3C=), 125.7 (CH
in Ph), 128.3 (2× CH in Ph), 128.4 (2× CH in Ph), 136.0 (NCCH=), 142.2
(C in Ph), 155.2 (CO) ppm. MS (EI): m/z (%) = 247 (1) [M]+, 172 (17), 157
(15), 142 (100), 129 (6), 110 (10), 99 (5), 91 (30). HRMS (EI) calcd. for
C15H21NO2 [M]+ 247.1572; found 247.1572.
spectroscopic data where in good agreement with those reported for the
(R) enantiomer before.[15a]
Acknowledgements
The Research Council of Norway (RCN, Grant No. 209330) and
Alf Bjerckes legat are gratefully acknowledged for grants to MH.
RCN is also acknowledged for partial financing of the Bruker
Avance instruments used in this study.
(R,E)-3-Methyl-1-phenylhex-4-en-3-ylcarbamic acid 9H-fluoren-9-
ylmethyl ester (22): Compound 16a (68.0 mg, 0.359 mmol) was added
to a mixture of CH2Cl2 (10 mL) and sat. aq. NaHCO3 (10 mL). 9-
Fluorenylmethylchloroformate (111 mg, 0.431 mmol) was added and the
reaction mixture was stirred at ambient temperature for 18 h. The phases
were separated and the aqueous phase was extracted with CH2Cl2 (2×
10 mL). The combined organic extracts were dried (MgSO4),
concentrated under reduced pressure and the crude product was purified
by flash column chromatography eluting with EtOAc-hexane (0-30%
Keywords: Allylic compounds • Amines • Enantioselectivity •
Sigmatropic rearrangements
EtOAc) to give 22 (138 mg, 93%) as a colorless oil. [α]20 = +8.2 (c =
D
[1]
[2]
For recent reviews, see for instance: (a) L.-L. Gundersen, Phytochem.
Rev. 2013, 12, 467–486; (b) K. K. Wan, R. A. Shenvi, Synlett 2016,
1145–1164.
0.99, CHCl3, 72% ee). 1H NMR (400 MHz, CDCl3): δ = 1.41 (s, 3 H,
CCH3), 1.70 (s, 3 H, =CHCH3), 1.92–2.10 (m, 2 H, PhCH2CH2), 2.44–
2.61 (m, 2 H, PhCH2), 4.19 (t, J = 6.6 Hz, 1 H, OCH2CH in Fmoc), 4.38 (d,
J = 6.6 Hz, 2 H, CH2 in Fmoc), 4.72 (s, 1 H, NH), 5.45–5.61 (m, 2 H, 2×
CH=), 7.09–7.19 (m, 3 H, Ph), 7.20–7.33 (m, 4 H, Ph and Fmoc), 7.37 (t,
J = 7.3 Hz, 2 H, Fmoc), 7.58 (d, J = 7.3 Hz, 2 H, Fmoc), 7.74 (d, J = 7.5
Hz, 2 H, Fmoc) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.9 (=CHCH3),
25.1 (CCH3), 30.5 (PhCH2), 41.6 (PhCH2CH2), 47.4 (OCH2CH in Fmoc),
56.0 (CNH), 65.9 (OCH2CH in Fmoc), 119.9 (2× CH in Fmoc), 123.7
(=CHCH3), 125.0 (2× CH in Fmoc), 125.8 (CH in Ph), 127.0 (2× CH in
Fmoc), 127.6 (2× CH in Fmoc), 128.3 (CH in Ph), 128.4 (CH in Ph),
135.9 (CH=CHCH3), 141.3 (C in Fmoc), 142.1 (C in Ph), 144.1 (C in
Fmoc), 154.5 (CO) ppm. MS (EI): m/z (%) = 196 (24), 178 (24), 166 (74),
165 (100), 139 (11), 115 (10). HRMS (ESI) calcd. for C28H29NO2 [M +
Na]+ 434.2096; found 434.2095.
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Entry for the Table of Contents (Please choose one layout)
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Asymmetric synthesis
Martin Hennum, Hege Hortemo Odden,
Lise-Lotte Gundersen*
Page No. – Page No.
Rearrangement Reactions leading to
Optically Active α,α-Disubstituted
Primary Allylamines
Optically active α,α-disubstituted primary allylamines from allylic alcohols prepared
by CBS-reduction, employing either an Overman- or an allyl cyanate to isocyanate
rearrangement as a key-step. The target amines were formed in high %ee in both
cases, but the chemical yield was substantially higher in the allyl cyanate to
isocyanate rearrangement
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