Synthesis of 2,3-syn-diarylpent-4-enamides via acyl-Claisen rearrangements of substituted cinnamyl morpholines: Application to the synthesis of magnosalicin

Article abstract of DOI:10.1016/j.tetlet.2012.06.088

The acyl-Claisen rearrangement of substituted phenylacetyl chlorides and cinnamyl morpholines gives 2,3-syn-diarylpent-4-enamides. Electron-rich cinnamyl morpholines containing alkoxy substituents only reacted with phenylacetyl chlorides; replacement of t

Full text of DOI:10.1016/j.tetlet.2012.06.088

Tetrahedron Letters 53 (2012) 4464–4468
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Tetrahedron Letters
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Synthesis of 2,3-syn-diarylpent-4-enamides via acyl-Claisen rearrangements
of substituted cinnamyl morpholines: application to the synthesis of
magnosalicin
⇑
Benjamin D. Dickson, Nora Dittrich, David Barker
School of Chemical Sciences, University of Auckland, 23 Symonds St., Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The acyl-Claisen rearrangement of substituted phenylacetyl chlorides and cinnamyl morpholines gives
2,3-syn-diarylpent-4-enamides. Electron-rich cinnamyl morpholines containing alkoxy substituents only
reacted with phenylacetyl chlorides; replacement of the phenylacetyl chlorides with alkyl acid chlorides
in these reactions gave no rearranged products. Use of the morpholine amides generated in the synthesis
of the natural tetrahydrofuran neolignan magnosalicin and tetraphenyl tetrahydrofuran is also reported.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 3 May 2012
Revised 1 June 2012
Accepted 14 June 2012
Available online 23 June 2012
Keywords:
Claisen rearrangement
Acyl-Claisen
Lignans
The acyl-Claisen rearrangement is a room temperature variant
of the Claisen rearrangement involving the rearrangement of N-al-
lyl ammonium enolates.1 These zwitterionic species, formed from
the reaction of an allylic amine with a ketene, generated in situ
from a carboxylic acid halide and base, rearrange at room temper-
ature or below. When (E)-allylic amines are employed, 2,3-syn-
disubstituted pentenamides are formed, often with much higher
levels of selectivity than their oxygen counterparts due to the well
defined (Z)-enolate geometry.2 We have recently shown3 that acyl-
Claisen derived amides can be used in the stereoselective synthe-
ses of a range of lignan natural products. There are no previous
examples of acyl-Claisen rearrangements where both the acid
chloride and allylic morpholine contained aromatic substituents,
whilst the yields of reactions involving alkyl acid chlorides with
cinnamyl morpholine 1a, are lower than the non-aromatic coun-
terparts.1a It should be noted that a silyl-modified Bellus–Claisen
rearrangement has been used to synthesise 2,3-diphenyl substi-
tuted pentenamides, however, this proceeded to give a mixture
of syn and anti isomers.4 We herein report the acyl-Claisen rear-
rangement of substituted cinnamyl morpholines 1, including elec-
tron-rich variants, and aromatic-containing acid chlorides 2, to
give aryl substituted morpholine pentenamides 3 with complete
stereocontrol. The synthetic utility of these substituted morpholine
pentenamides 3 in the synthesis of substituted tetrahydrofurans is
also reported.
We previously found3 that rearrangements involving non-aro-
matic components proceed, as reported,1a using 10 mol % of a Lewis
acid catalyst, preferably AlCl3 or TiCl4Á2THF. However, when these
conditions were used in the reaction between cinnamyl morpholine
1a and phenylacetyl chloride (2a) none of the desired amide 3a was
formed. Alternative Lewis acids, AlBr3, YbOTf3 and MgBr2ÁOEt2,
were investigated, but they also failed to give any of the desired
amide 3a. Increasing the catalyst loading to 50% and finally 100% re-
sulted in a significant improvement in yield, giving amide 3a in 94%
yield, exclusively as the syn diastereoisomer (Table 1, entry 1).5 Use
of stoichiometric Lewis acid in the reaction between morpholine 1a
and propionyl chloride (2b) gave amide 3b in an improved 86%
yield when compared to the catalytic conditions (Table 1, entry 2).
We next prepared alkoxy substituted, electron-rich, cinnamyl
morpholines 1b–d and phenylacetyl chlorides 2c–e to test them
in the acyl-Claisen rearrangement. Morpholines 1b and 1c were
prepared from benzaldehydes 4a and 4b, firstly by Horner-
Wadsworth-Emmons reactions to give acrylates 5a and 5b, both
in quantitative yields (Scheme 1). Reduction of 5a and 5b using
diisobutylaluminium hydride in CH2Cl2 gave alcohols 6a and 6b
in 95% and 72% yields, respectively. Bromination of 6a followed
by substitution of the resultant bromide gave allylic morpholine
1b in 49% yield over two steps. Bromination of 6b proved problem-
atic, therefore an alternative route via oxidation of 6b with manga-
nese dioxide followed by reductive amination using NaCNBH3 gave
allylic morpholine 1c in an 87% yield over the two steps. Morpho-
line 1d was prepared by selective demethylation6 of 4b to give
diphenol 4c in 75% yield; sequential alkylation of the two phenols
⇑
Corresponding author. Tel.: +64 9 373 7599; fax: +64 64 373 7422.
E-mail address: d.barker@auckland.ac.nz (D. Barker).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.088

B. D. Dickson et al. / Tetrahedron Letters 53 (2012) 4464–4468
4465
Table 1
i
Reagents and conditions: (i) 1 (1 equiv), 2 (1.2 equiv), Lewis acid (1 equiv), Pr2NEt (1.5 equiv), CH2Cl2, rt, 18 h
R1
O
O
O
i
R2
R1
N
N
Cl
O
R2
1a-e
2a-f
3a-x
Entry
1
Allylic morpholine 1
R1 = Ph, 1a
Acid chloride 2
Amide 3
Yield of 3 (%)
O
O
O
O
O
N
Ph
Ph
Ph
94a
2a
Cl
Cl
3a
3b
Ph
O
N
2
3
1a
1b
86a
40b
2b
Me
MeO
O
OMe
3c
2a
O
N
Ph
OMe
MeO
O
O
2c
OMe
O
OMe
N
O
Cl
4
1b
63a
3d
MeO
OMe
MeO
OMe
2d
O
OMe
Cl
O
N
5
6
7
1b
1b
1c
83b
3e
MeO
—
b
2b
0a,
OiPr
O
2f
Cl
OMe
52a
MeO
O
OMe
OMe
8
9
1c
1c
2a
2b
3g
40a
O
O
N
Ph
O
OMe
OMe
0
N
8
OMe
MeO
OiPr
O
O
N
10
11
1d
2f
79a
OMe
MeO
3h
Me
iPrO
O
O
N
R1 = Me, 1e
2a
86b
3i
Ph
(continued on next page)

4466
B. D. Dickson et al. / Tetrahedron Letters 53 (2012) 4464–4468
Table 1 (continued)
Entry
Allylic morpholine 1
Acid chloride 2
OMe
Amide 3
Yield of 3 (%)
O
O
N
Me
OMe
3j
O
12
1e
77b
Cl
2e
MeO
OMe
OMe
MeO
O
O
N
Me
3k
13
1e
2d
73b
MeO
a
TiCl4Á2THF was used.
b
AlCl3 was used.
O
N
CH2OH
R4
iii-iv
or
CHO
R1
R2
R1
R2
v-vi
R1
R2
i, ii
R4
R4
R3
R3
R3
1
3
2
4
6a R1,R3=H, R2,R4=OMe
6b R1,R3,R4=OMe, R2=H
1b R1,R3=H, R2,R4=OMe
4a
4b
R ,R =H, R ,R =OMe
1
3
4
2
R ,R ,R =OMe, R =H
1c R1,R3,R4=OMe, R2=H
i
1d R1,R4=OMe, R3=O Pr, R2=H
xi-xii
HO
vii
CHO
HO
CHO
MeO
viii-ix
MeO
x
OMe
OH
OMe
OMe
i
i
OPr
OPr
4c
4d
7
Scheme 1. Reagents and conditions: (i) (EtO)2POCH2CO2Et, K2CO3, THF, reflux, 20 h, 5a,5b quant.; (ii) DIBAL-H, CH2Cl2, À78 °C, 3 h, 6a (95%), 6b (72%); (iii) PBr3, CH2Cl2, 0 °C
to rt, 18 h; (iv) morpholine, NEt3, CH2Cl2, 0 °C to rt, 18 h, 1b (49%) from 6a; (v) MnO2, EtOAc, rt, 3 h; (vi) morpholine, NaCNBH3, AcOH, MeCN, rt, 16 h, 1c (87%) from 6b; (vii)
i
4b, AlCl3, CH2Cl2, 72 h, 75%; (viii) PrI, NaHCO3, TBAI, DMF, 80 °C, 72 h, 58%; (ix) MeI, K2CO3, DMF, rt, 2 h, 86%; (x) vinylmagnesium bromide, THF, rt, 23 h, 88%; (xi) Ac2O,
pyridine, DMAP, THF, 0 °C to rt, 40 h; (xii) morpholine, Pd(PPh3)4, THF, 48 h, 34% from 7.
gave benzaldehyde 4d in 50% over two steps. Addition of vinyl-
magnesium bromide to aldehyde 4d gave allylic alcohol 7 in 88%
yield. Acetylation, followed by Pd(PPh3)4-mediated displacement
of the resultant acetate7 gave allylic morpholine 1d. The known
acid chlorides 2c8, 2d9 and 2e10 were prepared using literature
conditions, whilst 2f was prepared from commercially available
homovanillic acid.11
The reaction of the allylic morpholine 1b with phenylacetyl
chloride 2a gave amide 3c in 40% yield (entry 3) and when acid
chloride 2c was used, amide 3d was obtained in 63% yield (entry
4). Similarly when aromatic allylic morpholines 1b–d were reacted
with aryl substituted acid chlorides 2a,c–f, 2,3-syn-diaryl amides
3e–h were generated in 40–83% yields (entries 5–10). Notably, re-
moval of the methyl or isopropyl ethers was not observed with any
Lewis acid used. Reaction of propionyl chloride 2b, or acetyl chlo-
ride, with allylic morpholines 1b-d failed to give any of the rear-
ranged amide products. In most cases starting materials were
returned except in the case of 1c where reaction with propionyl
chloride 2b gave only amide 8 formed via von Braun degradation.12
Reaction of acid chlorides 2a,b,e with crotyl morpholine 1e pro-
ceeded as expected giving 2-aryl-3-methyl amides 3i–k in 73–
86% yields (entries 11–13). These results indicate that whilst 2a–
f react with both aryl and alkyl allylic morpholines 1a–e, elec-
tron-rich substituted cinnamyl morpholines 1a-d preferentially re-
act with aryl substituted acid chlorides 2a,c–f.
Polyoxygenated, electron-rich aromatic rings are found in a
wide array of natural products including lignans,13 the lamellarin
family of pyrrole alkaloids14 and resveratrol oligomers,15 to name
just a few. Magnosalicin (9) is a racemic tetrasubstituted tetrahy-
drofuran neolignan found in the buds of Magnolia salicifolia Max-
im,16 and has an unusual cis, trans, trans-2,4-diaryl substitution,
rather than the more commonly found 2,5-diaryl substitution. Pre-
viously reported syntheses17 of magnolsalicin (9) or analogues
have predominately given the trans,trans,trans epimer of the natu-
ral product. Our synthesis of magnosalicin (9) began with the addi-
tion of methyllithium, at 0 °C in THF, to amide 3j and gave ketone
10 in 52% yield. Reduction of ketone 10 with NaBH4 at À78 °C gave
alcohols 11a and 11b in a 9:1 ratio favouring the desired isomer
11a. Protection of the alcohol 11a as the MOM ether, followed by
dihydroxylation and oxidative cleavage gave aldehyde 12 in 42%

B. D. Dickson et al. / Tetrahedron Letters 53 (2012) 4464–4468
4467
R2
O
Ph
O
O
Ph
CHO
O
R1
i
i
ii-iii
ii
Ph
N
3a
3j
Ph
16
Ph
O
O
Ar
Ar
17
1
2
10
11a
11b
, R =OH, R =H
, R =H, R =OH
1
2
Ar = 2,4,5-tri(MeO)Ph
iv
iii-v
Ph
Ph
Ph
Ph
Ph
N
MOMO
MOMO
vi
O
Ph
OH
Ar
Ar OH
13
O
CHO
19
Ar
12
18
v
vii
MeO
Ph
HO
Ph
Ph
Ph
Ph
Ph
Ph
vi
OMe
MeO
Ph
O
O
OMe
20
21
O
OMe
magnosalicin 9
MeO
Scheme 3. Reagents and conditions: (i) PhLi or PhMgCl, THF or Et2O, no reaction;
(ii) 1 mol % OsO4, NMO, tBuOH/H2O, rt, 24 h; (iii) NaIO4, MeOH/H2O, rt, 5 h, 87% over
2 steps; (iv) PhBr, t-BuLi, THF, À78 °C to rt, 2 h, 69%; (v) PhBr, t-BuLi, THF, À78 °C to
rt, 2 h, 77%; (vi) BF3.OEt2, Et3SiH, CH2Cl2, À78 °C for 1 h then À10 °C 3 h, quant.
Scheme 2. Reagents and conditions: (i) MeLi, THF, À78 °C to rt, 2 h, 52%; (ii) NaBH4,
MeOH, À78 °C to rt, 3 h, 11a (83%), 11b (9%); (iii) MOMCl, DIPEA, CH2Cl2, rt, 18 h,
68%; (iv) 10 mol % OsO4, NMO, tBuOH/H2O, rt, 24 h; (v) NaIO4, MeOH/H2O, rt, 4 h,
62% over 2 steps; (vi) 2,4,5-trimethoxybromobenzene, BuLi, Et2O, 0 °C, then add 12,
3 h, 76%; (vii) MsCl, Et3N, CH2Cl2, rt, 2 h, 62%.
In summary, the acyl-Claisen rearrangement of electron-rich,
substituted cinnamyl morpholines 1 and substituted phenylacetyl
chlorides 2 to give aryl substituted 2,3-syn-substituted pentena-
mides 3 can be achieved using stoichiometric Lewis acids. Amide
3j was converted into the lignan magnolsalicin (9) in seven steps
whilst amide 3a was converted into tetraphenyl tetrahydrofuran
21 in five steps. Tetrahydrofuran 21 is a deoxygenated analogue
of resveratrol dimers and this methodology should allow the syn-
thesis of these natural compounds and their analogues.
HO OH
HO OH
HO
OH
HO
OH
O
tricuspidatol A
O
OH
OH
HO
HO
Acknowledgements
14
15
restrytisol A
Figure 1. Resveratrol dimers tricuspidatol A 14 and restryisol A 15.
We acknowledge the Royal Society of New Zealand Marsden
Fund for funding this research and
a doctoral scholarship
(B.D.D.). We thank the University of Auckland for additional fund-
ing and a doctoral scholarship (ND).
yield over three steps. Addition of 2,4,5-trimethoxyphenyllithium
(from the bromo compound) to aldehyde 12, gave alcohol 13 in
76% yield. Finally, activation of alcohol 13 using mesyl chloride
and Et3N gave magnosalicin 9 in 62% yield (Scheme 2). The spectro-
scopic data of the isolated product matched reported literature
data.16
Tricuspidatol A (14) and restrytisol A (15) are tetraaryl tetra-
hydrofurans, isolated from Parthenocissus tricuspidata (Fig. 1).18,19
These compounds are antioxidants and are formed in a non-stereo-
specific manner from oxidative dimerisation of resveratrol.20 We
envisaged that 2,3-syn-diaryl amides could be used to form ana-
logues of these natural products, using similar methodology to that
used in the synthesis of magnosalicin 9.
To test this proposal 2,3-diphenylpentenamide 3a was reacted
with phenyllithium in an attempt to form the ketone 16. However
under all the conditions tested21 substitution of the morpholine
group was not observed. In the belief that the neighbouring 2-phe-
nyl group was sterically hindering the amide we attempted to cir-
cumvent this by conversion of the alkene in 3a into aldehyde 17,
which it was hoped would be more susceptible to nucleophilic at-
tack. Dihydroxylation of 3a, followed by oxidative cleavage gave
aldehyde 17 in 87% yield over two steps. Addition of phenyllithium
to aldehyde 17 resulted in the formation of alcohol 18 which cyc-
lised in situ to give lactone 19 in 69% yield, as a single diastereoiso-
mer. Addition of phenyllithium to lactone 19 gave hemiketal 20 in
77% yield, which was then dehydroxylated using BF3ÁOEt2 and Et3-
SiH in CH2Cl2 at low temperature to give trans,trans,trans-2,3,4,5-
tetraphenyltetrahydrofuran 21 in quantitative yield (Scheme 3).
Supplementary data
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.06.088.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
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B. D. Dickson et al. / Tetrahedron Letters 53 (2012) 4464–4468
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IR m
max/cmÀ1 2960, 2838, 1637, 1456, 1150, 726; HRMS (ESI+): found (MH+):
422.2223 C25H32NO6 requires 422.2224. Data for 3h: dH (400 MHz; CDCl3;
Me4Si) 1.25–1.28 (12H, m, 2 Â CH(CH3)2), 3.16–3.21 and 3.45–3.56 (8H, m,
N(CH2CH2)2O), 3.60 (3H, s, OCH3), 3.70 (6H, s, 2 Â OCH3), 4.16 (1H, d,
J = 10.8 Hz, 2-H), 4.34–4.41 (2H, m, 2 Â CH(CH3)2), 4.47 (1H, dd, J = 7.2,
10.4 Hz, 3-H), 5.06–5.12 (2H, m, 5-CH2), 6.18 (1H, ddd, J = 7.2, 10.4, 17.2 Hz,
4-H), 5.30 (1H, s, Ar-H), 6.39–6.58 (3H, m, Ar-H), 6.68–6.69 (1H, d, J = 2.0 Hz,
Ar-H); dC (100 MHz; CDCl3) 22.1 (2 Â CH(CH3)2), 42.5 and 46.2 (N(CH2CH2)2O),
47.8 (C-3), 51.0 (C-2), 55.9, 56.0 and 57.0 (3 Â OCH3), 66.5 and 66.9
(N(CH2CH2)2O), 71.2 and 72.0 (2 Â CH(CH3)2), 102.5 (Ar-CH), 112.1 (Ar-CH),
115.1 (C-5), 115.2 (Ar-CH), 115.4 (Ar-CH), 120.9 (Ar-CH), 122.2 (Ar-C),130.6
(Ar-C), 139.7 (C-4), 144.4 (Ar-C), 145.8 (Ar-C), 146.2 (Ar-C), 149.9 (Ar-C), 151.5
(Ar-C), 171.1 (C-1); IR m
max/cmÀ1 2974, 2933, 1639, 1507, 1206, 1111; HRMS
(ESI+): found (MH+): 528.2957 C30H42NO7 requires 528.2956. Data for 3j: dH
(400 MHz, CDCl3) 0.77 (3H, d, J = 7.0 Hz, 3-CH3), 2.93–3.03 (1H, m, 3-H), 3.12–
3.20 and 3.41–3.74 (8H, m, N(CH2CH2)2O), 3.82 (3H, s, OCH3), 3.83 (3H, s,
OCH3), 3.89 (3H, s, OCH3), 4.06 (1H, d, J = 10.4 Hz, 2-H), 5.00 and 5.10 (2 Â 1H,
dt, J = 1.0, 10.5 Hz, 5-CH2), 5.91 (1H, ddd, J = 7.0, 10.5, 17.3 Hz, 4-CH), 6.50 (1H,
s, Ar-H), 6.98 (1H, s, Ar-H); dC (100 MHz, CDCl3) 16.8 (3-CH3), 40.2 (C-3), 42.5
and 45.9 (N(CH2CH2)2O), 44.4 (C-2), 56.1 (OCH3), 56.4 (OCH3), 56.5 (OCH3), 66.7
and 66.9 (N(CH2CH2)2O), 96.9 (Ar-CH), 111.4 (Ar-CH), 113.8 (C-5), 117.9 (Ar-C),
18. Lins, A. P.; Felicio, J. D.; Braggio, M. M.; Roque, L. C. Phytochemistry 1991, 30,
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19. Cichewicz, R. H.; Kouzi, S. A.; Hamann, M. T. J. Nat. Prod. 2000, 63, 29–33.
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142.9 (C-4), 144.0 (Ar-C), 148.6 (Ar-C), 149.9 (Ar-C), 171.9 (C-1); IR m
max/cmÀ1
3080, 2965, 2851, 1634, 1513, 1203, 1110, 870; HRMS (ESI+): found (MH+):
350.1934 C19H28NO5 requires 350.1962.
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21. We have attempted the substitution of the morpholine group in a number of 2-
aryl morpholine amides with a variety of aromatic organometallic species and
yields of the aryl ketone are generally <10%.