A practical variant of the Claisen-Eschenmoser rearrangement: Synthesis of unsaturated morpholine amides

Article abstract of DOI:10.1055/s-2002-20453

A Claisen-Eschenmoser type rearrangement giving rise to unsaturated morpholine-, piperidine- and pyrrolidine amides is described.

Full text of DOI:10.1055/s-2002-20453

LETTER
411
A Practical Variant of the Claisen–Eschenmoser Rearrangement: Synthesis of
Unsaturated Morpholine Amides
A
P
ractica
l
V
a
t
riant of
e
the Claise
f
n–Esche
a
nmoser
R
ea
n
rrangement N. Gradl, Joshua J. Kennedy-Smith, James Kim, Dirk Trauner*
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, CA 94720-1460, USA
Fax +1(510)6439480; E-mail: trauner@cchem.berkeley.edu
Received 10 December 2001
R2 = -(CH2)2O(CH2)2-] as the reagent. Morpholine amides
Abstract: A Claisen–Eschenmoser type rearrangement giving rise
have recently emerged as viable alternatives to Weinreb
to unsaturated morpholine-, piperidine- and pyrrolidine amides is
described.
amides in the synthesis of ketones.3 Although 1b is a
known compound,4 no procedure for its preparation has
been reported in the literature. Unfortunately, all attempts
to prepare 1b from N-acetyl morpholine by O-alkylation
Key words: Claisen–Eschenmoser rearrangement, morpholine
amides, ketene N,N-acetal, guanacastepene, ring closing metathesis
and subsequent addition of NaOMe were met with limited
success.
The Claisen–Eschenmoser rearrangement is arguably the
We now report that simple condensation of DMADMA
(1a) with morpholine gives access to 1b and related re-
agents. This uncatalyzed exchange is driven by the vola-
tility of dimethyl amine and methanol.5 Heating of 1a with
excess morpholine under a stream of nitrogen initially re-
sults in a complex mixture consisting predominantly of 1b
and the known ketene N,N-acetal 5 (Scheme 2).6 Upon
further heating, this mixture converts fully into 5. Dilution
with a solvent (benzene or xylenes), followed by addition
of allyl alcohol (2a) and further heating afforded the rear-
ranged product 4a in 89% yield. Conveniently, the prepa-
ration of the reagent 5 and the subsequent rearrangement
can be performed as a one-pot procedure.
most powerful method for the synthesis of , -unsaturated
carbonyl compounds (Scheme 1).1 It involves the reaction
of an amide acetal, typically N,N-dimethylacetamide dim-
ethyl acetal (DMADMA, 1a, R1 = R2 = Me), with an ally-
lic alcohol 2 to produce a mixed ketene acetal 3. This
intermediate then undergoes [3,3]-sigmatropic rearrange-
ment at relatively low temperatures to afford the amide 4.
To date, the reaction has remained confined mostly to the
preparation of N,N-dimethylamides. Relatively little at-
tention has been given to other substituents at the nitro-
gen, primarily due to the somewhat tedious preparation of
the corresponding amide acetals 1 (R1, R2 = Me). Typi-
cally, these reagents are made by treatment of an aceta-
mide with an alkylating agent, followed by addition of an
alkoxide.2
Scheme 2
Scheme 1
The application of these conditions to other allylic alco-
hols 2b–m is summarized in the Table.7 The reactions
usually required high temperatures or sealed tube condi-
tions. Molecules featuring quarternary centers could be
prepared in good yields (entries 7 an 8). Dienols (entries 5
and 6) and secondary alcohols (entries 9 and 10) also per-
formed well. Rearrangement of 2j and 2k resulted in the
exclusive formation of the E-isomers 4j and 4k, respec-
tively. Cycloalkenols, however, gave poor yields (entries
11 and 12).
In the context of a natural product total synthesis (vide in-
fra), we sought to prepare , -unsaturated morpholine
amides directly from allylic alcohols through a Claisen–
Eschenmoser rearrangement using amide acetal 1b [R1,
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0411,0414,ftx,en;S08601ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

412
S. N. Gradl et al.
LETTER
higher temperatures than the original Claisen–Eschen-
moser procedure due to the slower elimination of morpho-
line instead of methanol. Interestingly, although ketene
N,O-acetals are known to participate in Claisen–Eschen-
moser rearrangements,8 ketene N,N-acetals like the com-
Table Synthesis of Morpholine Amides.
Entry Allylic alcohol
Product
Method/yielda
(A, 89%)
1
2a
mercially available compound
5 have not been
investigated in this context.
4a
4b
The crystal structure of 5 is shown in Figure 1.9 It is one
of two known X-ray crystal structures of 1,1-diamino sub-
stituted ethylenes.10 The molecule adopts a C2-symmetric
conformation in the solid state with the C2-axis along the
double bond. To avoid steric conflicts, the morpholine
rings are twisted about 60° with respect to the alkene axis.
2
(B, 76%)
(A, 77%)
2b
3
2c
4c
4
(B, 96%)
(B, 75%)
2d
4d
5
2e
4e
6
(B, 74%)
2f
Figure 1 Crystal structure of ketene N,N-acetal 5.
4f
7
(A, 73%)
(B, 81%)
In an attempt to make our procedure more economical, we
also investigated the reaction of orthoesters with amines
as a route to the ketene aminal 5 and similar compounds,
e.g. 7 (Scheme 3). The preparation of dimorpholino
ketene N,N-acetals from triethyl orthoacetate or triethyl
orthopropionate (6) and morpholine has been previously
described.6b,c Reagent 7, which was also prepared in situ
and used without purification, allowed us to investigate
relative diastereoselectivities. Heating of 7 with crotyl al-
cohol (mixture of diastereomers; E:Z = 18:1) resulted in a
5.1:1-mixture of diastereomeric amides 9a and 9b. The
preference for the anti-diastereomer 9a can be explained
in terms of a chair-shaped transition state. Mixed ketene
N,O-acetals are known to be formed mostly as Z-isomers
under Claisen–Eschenmoser conditions. In combination
with a E-allylic alcohol, this affords predominantly anti
diastereomers, provided the reaction proceeds through
transition state 8.11 The stereochemical outcome of this re-
action contrasts recent results by MacMillan who ob-
served very high syn-diastereoselectivities for E-isomers
in the course of ketene-Claisen rearrangements of N-allyl
morpholines.12
2g
4g
8
2h
4h
4j
9
(B, 84%)
(A, 90%)
(A, 36%)
2j
10
2k
4k
11
2l
4l
12
(A, 16%)
The extension of our method to other amines is shown in
Scheme 4. Pyrrolidine and piperidine reacted cleanly to
yield the corresponding amides 10 and 11. It can be pre-
sumed that intermediates analogous to 5 and 7 are in-
volved in these reactions. Chiral amines such as 12 were
also explored. Heating of enantiomerically pure 12 with
trimethyl orthopropionate and catalytic amounts of tolu-
ene sulfonyl chloride, followed by further heating with al-
2m
4m
a Method A: 5, PhH, sealed tube, 160 °C; Method B: 5, xylenes, reflux
Mechanistically, the reaction proceeds presumably via
rapid addition of the allylic alcohol to 5, followed by ther-
mal elimination of morpholine. It requires significantly
Synlett 2002, No. 3, 411–414 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Practical Variant of the Claisen–Eschenmoser Rearrangement
413
yield of furyl ketone 15,16 which underwent intramolecu-
lar Heck-cyclization to furano cyclohexanone 16. Con-
versely, coupling of 4f with vinyl magnesium bromide
proceeded smoothly to furnish vinyl ketone 17 in good
yield. Exposure of this substrate to Grubbs’ N-heterocy-
clic carbene catalyst 1917 resulted in clean ring closing
metathesis to afford the volatile cyclopentenone 18.
Scheme 3 Reagents and conditions: (a) Morpholine, cat. TsCl, 160
°C. (b) Crotyl alcohol (E:Z = 18:1), PhH, sealed tube, 160 °C (84%;
9a:9b = 5.1:1).
lyl alcohol (2a) or crotyl alcohol (2b) afforded amides 13
and 14, respectively, as mixtures of diastereomers. In ac-
cordance with similar reports in the literature, however,
the diastereoselectivities observed were rather low.13
Morpholine amides 4f and 4k were used in a program di-
rected towards the total synthesis of (+)-guanacastepene,
a novel diterpene with potent antibiotic properties.14 Re-
action of 4k with 3-iodo-4-lithiofuran15 afforded a low
Scheme 5 Reagents and conditions: (a) 3-Iodo-4-lithiofuran, Et2O
37%). (b) Pd2dba3, (o-tol)3P, Cs2CO3, MeCN, H2O (74%). (c) Vinyl-
MgBr (82%). (b) 19 (2.5%), CH2Cl2 (50%).
Together, 16 and 18 represent the skeletal carbons of (+)-
guanacastepene. Our retrosynthetic analysis is outlined in
Scheme 6. Efforts to render the intramolecular Heck reac-
tion and the ring closing metathesis asymmetric and join
the two fragments are well underway in our laboratories
and will be reported in due course.18
Scheme 6
In summary, we have developed a practical variant of the
Claisen–Eschenmoser rearrangement that gives access to
a variety of functionalized amides in high yields. Our sim-
ple one-pot procedure can be applied to a range of rela-
tively unhindered allylic alcohols. Importantly, the
reaction obviates the preparation of costly starting materi-
als or the isolation of sensitive amide acetals and avoids
toxic alkylating agents such as Meerwein-salts or dime-
Scheme 4 Reagents and conditions: (a) 1a,
Z-2-hexenol,
.
(82%). (b) 1a,
Z-2-hexenol, . (86%). (c) 6, cat. TsCl, allyl
alcohol, (82%; 1.8:1 mixt. of diastereomers). (d) 6, cat. TsCl,
(E:Z = 18:1), (75%; 7:4:1:1 mixture of diastereomers).
Synlett 2002, No. 3, 411–414 ISSN 0936-5214 © Thieme Stuttgart · New York

414
S. N. Gradl et al.
LETTER
ethylacetate, v/v). The solvent was partially removed using
a rotary evaporator. The residue was purified by column
chromatography (hexanes ethyl acetate:hexanes = 1:1) to
afford the pure product as a colorless oil (1.95 g, 8.74 mmol,
74.3%). 1H NMR (500 MHz, CDCl3) 4.84 (s, 2 H), 4.73 (s,
2 H), 3.63 (m, 6 H), 3.47 (m, 2 H), 3.21 (t, J = 9 Hz, 1 H),
2.54 (d, J = 9 Hz, 2 H), 1.66 (s, 6 H). 13C NMR (125MHz,
CDCl3) 170.3, 145.5, 111.2, 66.9, 66.7, 49.9, 46.1, 42.0,
34.6, 20.8. IR(neat) 3077, 2966, 2855, 1650, 1643, 1432,
1271, 1234, 1115, 1034 cm–1. MS (EI) m/z 223(23), 129(42),
114(42), 109(17), 95(100). HRMS (EI) m/z calcd for
C13H21NO2: 223.1572, found: 223.1570.
thyl sulfate. Future work will be directed at the synthesis
of Weinreb amides using the corresponding N,N-ketene
acetals and at the improvement of the stereoselectivites
obtained to date.
Acknowledgement
We thank Dr. Frederick J. Hollander and Dr. Allen G. Oliver for the
crystal structure determination of 5. Financial support by Bristol-
Meyers-Squibb (CNDOS) and Merck & Co is gratefully acknow-
ledged.
(8) Bolton, I. J.; Harrison, R. G.; Lythgoe, B. J. Chem. Soc. C
1971, 2950.
(9) Details of the crystal structure determination (deposition
number CCDC 165896) may be obtained from: The
Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1 EZ, UK.
(10) Arduengo, J. A. I.; Davidson, F.; Dias, H. V. R.; Goerlich, J.
R.; Khasnis, D.; Marshall, W. J.; Prakasha, T. K. J. Am.
Chem. Soc. 1997, 119, 12742.
(11) An analogous reaction involving Z-2-hexenol(4b) gave a
13:1 mixture of diastereomers. Their relative configurations,
however, were not assigned.
(12) Yoon, T. P.; Dong, Y. M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 1999, 121, 9726.
(13) Welch, J. T.; Eswarakrishnan, S. J. Am. Chem. Soc. 1987,
109, 6716.
(14) Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. J. Am.
Chem. Soc. 2000, 122, 2116.
(15) Zaluski, M.-C.; Robba, M.; Bonhomme, M. Bull. Soc. Chim.
Fr. 1970, 1838.
(16) Yields were much higher (70%) when the corresponding
Weinreb amide was used.
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(18) For a review of asymmetric intramolecular Heck-reactions,
see: (a)Donde, Y.; Overman, L. E. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000,
675–697. For a review of asymmetric RCM reactions, see:
(b)Hoveyda, A. H.; Schrock, R. R. Chem.–Eur. J. 2001, 7,
945.
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(7) Representative Procedure, Morpholine Amide 4f: A round-
bottomed flask was charged with 8 mL morpholine (80
mmol) and dimethylacetamide dimethyl acetal (3.8 mL, 30
mmol) and the mixture was slowly heated to 190 °C over 5
hours under a steady stream of N2. After cooling to room
temperature, xylenes (10 mL) and 2,4-dimethyl-penta-2,4-
dien-1-ol (1.32 g, 11.7 mmol) were added and the reaction
mixture was refluxed until the allylic alcohol was consumed
(14 hours) as determined by TLC (30% hexanes in
Synlett 2002, No. 3, 411–414 ISSN 0936-5214 © Thieme Stuttgart · New York