First synthesis of medium-sized ring allenyl lactams

Article abstract of DOI:10.1002/ejoc.201100830

Medium-sized lactams bearing an axially chiral allene unit have been synthesized by using an aza-ketene Claisen rearrangement. Starting from 2-alkynylpiperidines or 2-alkynylazepines, ring enlargement enabled the highly diastereoselective formation of 10-

Full text of DOI:10.1002/ejoc.201100830

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100830
First Synthesis of Medium-Sized Ring Allenyl Lactams
Moritz Perscheid,[a] Dieter Schollmeyer,[a] and Udo Nubbemeyer*[a]
Dedicated to Prof. Dr. Horst Kunz on the occasion of his 70th birthday
Keywords: Allenes / Rearrangement / Heterocycles / Lactams / Ring expansion
Medium-sized lactams bearing an axially chiral allene unit
with a 4,5-allene subunit. X-ray analysis of the allenylacezi-
have been synthesized by using an aza-ketene Claisen re- none showed the presence of a strained cumulated olefin sys-
arrangement. Starting from 2-alkynylpiperidines or 2-alk-
ynylazepines, ring enlargement enabled the highly dia-
stereoselective formation of 10- or 11-membered lactams
tem with a defined arrangement of the functional groups.
The cyclic allenes were found to be stable upon heating up
to 50 °C.
Introduction
Medium-sized unsaturated heterocycles with a defined
configuration are useful key intermediates in the syntheses
of natural and biologically active products. Earlier investi-
gations from our laboratory indicated that zwitterionic aza-
Claisen rearrangement enables the reaction of 2-vinylpyr-
rolidines 1 (Scheme 1) and Lewis acid activated ketenes to
generate unsaturated azoninones 2. A complete 1,3-chirality
transfer gave rise to the formation of nine-membered ring
lactams with defined stereogenic centers and E double
bonds with defined planar chiral arrangements. Dia-
stereospecific and regioselective transannular ring contrac-
tions delivered indolizidinones 3 and 4 with high selectivity
and yields, which serve as key intermediates in natural
product syntheses.[1]
The efficient generation and transformation of planar
chiral cyclic olefins suggested that axially chiral cyclic all-
enes might be synthesized and transformed in a similar
manner. We wondered whether we could rearrange a phen-
ylethynyl-substituted pyrrolidine, piperidine, and azepane
to build up 9-, 10-, and 11-membered ring model systems,
respectively, bearing axially chiral allene units. In analogy
to the planar chiral olefins of the azoninones, one face of
each allene double bond should be shielded by the ring that
could potentially undergo highly selective proceeding con-
versions. Focusing for example on 10-membered allenyl
lactams, regio- and diastereoselective ring contractions
should allow the formation of substituted 1-azabicyclo-
Scheme 1. Aza-Claisen rearrangement and regio- and diastereo-
selective ring contraction for the synthesis of indolizidinones with
a defined configuration.[1]
[5.3.0]decanes and quinolizidines, respectively, which should
serve as versatile key intermediates in the total syntheses of
the alkaloids homoerythrina and lycopodium.[2]
Upon planning the syntheses of medium-sized ring all-
enyl lactams, the minimal ring size had to be explored. The
smallest isolable cyclic allene is 1,2-cyclononadiene 7 (Fig-
ure 1), which is stable at room temperature and which di-
merizes only upon heating.[3] As expected, smaller congener
1,2-cyclooctadiene 9 is too strained and undergoes rapid
dimerization at room temperature.[4] In contrast, 1,2,5-cy-
clononatriene 8 and 1,2,5-cyclodecatriene 6 have been iso-
lated and show thermal stability.[5] 1,2-Cyclodecadiene 5 is
known to behave like a noncyclic 1,3-dialkylallene.[6] Re-
[a] Institut für Organische Chemie, Johannes Gutenberg-
Universität,
Duesbergweg 10-14, 55128 Mainz, Germany
Fax: +49-6131-3924533
E-mail: nubbemey@uni-mainz.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100830.
Figure 1. Eight- to 10-membered carbocyclic allenes.
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First Synthesis of Medium-Sized Ring Allenyl Lactams
garding heterocyclic medium-sized rings, Tsuchiya reported idine, or -azepine was formed as the major side product,
the synthesis of an aza-nonadiene in moderate yield by indicating incomplete or reversible alkyne addition.
using a Wittig-type 2,3-sigmatropic rearrangement of a 2-
First ring expansion reactions of these propargylamines
alkynylpiperidine.[7] The so-formed allene was reported to were carried out by using the in situ formed Lewis acid
be unstable, suffering from rapid decomposition upon col- activated chloroketene. Treatment of 2-alkynylpiperidine
umn chromatography. Until now, azadecadienes and unde- 11b and -azepane 11c with chloroacetyl fluoride[14,15] and
cadienes incorporating allenes are unknown.
trimethylaluminum[16] in the presence of solid potassium
The Claisen rearrangement of propargyl vinyl ethers are carbonate smoothly delivered allenyl lactams 12b and 12c
well-known reactions that allow the synthesis of allenes in 77 and 70% yield, respectively (Scheme 3). The NMR
even in highly complex substrates.[8] Rearrangements of spectra of the products always displayed at least a double
propargyl esters often involve in situ generated ester enol- set of peaks because of the slow interconversion of the
ates. In most cases, an additional driving force is required to amide mesomers.[17] Because HPLC analyses always gave
induce the reaction; thus, steric repulsions force the reaction predominating peaks, the formation of one diastereomer
towards the allene product.[9] To the best of our knowledge, with high selectivity seemed reasonable. In contrast, the
allenes obtained from Claisen rearrangements are linear, ring expansion of 2-alkynylpyrrolidine 11a failed, and no
unstrained systems. Upon synthesizing ring systems with corresponding nine-membered ring lactam was found to
constrained allene subunits, the zwitterionic aza-ketene form despite the complete consumption of the starting ma-
Claisen reaction potentially offers enough driving force terial. Ring strain of the product might have caused a low
(charge neutralization) to form the allenyl lactam products stability of the lactam, inducing rapid decomposition.
in acceptable yield.
Results and Discussion
Initial investigations required simple and efficient access
to cyclic 2-(2-arylpropargyl)amines.[10] Focusing on N-
methyl heterocycles, most literature procedures used thiol-
actams as starting materials.[11] Initially, the thioamide
function had to be activated in situ by S-methylation or
-acylation. Then, a sequence of alkynyl anion addition and
subsequent LiAlH4 reduction allowed the generation of the
N-methyl-2-alkynyl heterocycles in 67–80% yield. Without
thioamide activation, the results had been reported to be
Scheme 3. Synthesis of allenyl lactams by zwitterionic aza-Claisen
rearrangement.
poor.
In 1983, M. Yamaguchi and I. Hirao published a com-
munication using lactams as starting materials to avoid the
use of thiolactam congeners.[12] One-pot reactions of simple
The 10- and 11-membered allenyl lactams 12b and 12c
magnesium and lithium acetylide additions and subsequent
LiAlH4 reductions failed. In contrast, the use of preformed
BF3·OEt2-mediated alkynyl anions enabled the synthesis of
the propargylamine products after a final aluminum hy-
dride reduction. Careful optimization of the reaction condi-
tions gave satisfactory results. Starting from pyrrolidone
10a (n = 0), piperidone 10b (n = 1), or azepinone 10c (n =
2), phenylethynyllithium addition in the presence of
BF3·OEt2 delivered the intermediate iminium salt, which
was immediately reduced with LiAlH4 to give propar-
gylamine product 11a, 11b, or 11c in 52–72% yield overall
(Scheme 2).[13] In several runs, N-methylpyrrolidine, -piper-
were found to be stable at room temperature, and up to
50 °C no dimerization was observed. The major dia-
stereomer (rac-3R,aR) of 10-membered allenyl lactam 12b
crystallized (Figure 2). X-ray data showed a slightly de-
formed allene (angle of 173.4°), which is in good accord-
Figure 2. Crystal structure of rac-(3R,aR)-1-methyl-3-chloro-1-aza-
deca-4,5-diene-2-one 12b.
Scheme 2. Synthesis of propargylamines.
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M. Perscheid, D. Schollmeyer, U. Nubbemeyer
SHORT COMMUNICATION
washed with water (2ϫ50 mL) and dried (MgSO4). Evaporation
of the solvent gave propargylamines 11 (52–70%) pure enough for
ring expansion studies. For spectroscopic data see ref.[10–12] and the
Supporting Information
ance with the ring strain expected. The planes of the double
bond π systems are almost rectangular (89.3°), whereas C3
suffered from a 4.5° distortion out of the C1–C2–C10 plane.
The nearly ideal coplanar arrangement of the vinyl C–H
bond, the π orbital of the C4–C5 double bond, and the
C–Cl bond caused some sensitivity towards bases. Upon
washing the 11-membered lactam with an aqueous solution
of KOH, 1,4-HCl elimination gave enyne lactam 13 in high
yield.
Preparation of Lactams 12b and 12c by Aza-Claisen Rearrangement:
Under an atmosphere of argon, amine 11 (2 mmol) was dissolved in
a suspension of K2CO3 (0.3 g, 2.2 mmol, 1.1 equiv.) in dry CH2Cl2
(20 mL). After cooling to 0 °C, freshly prepared chloroacetyl fluo-
ride (0.42 mL, 6 mmol, 3 equiv.) was added, and the mixture was
stirred at 0 °C. Then, trimethylaluminum (2 m in toluene, 3 mL,
6 mmol, 3 equiv.) was injected, and the mixture was stirred for 16 h,
allowing the temperature to reach 20 °C (TLC monitoring). The
reaction was stopped by quenching with water (0.5 mL). After di-
lution with additional CH2Cl2, drying was achieved by addition of
MgSO4. Then, the solvent was evaporated, and the crude lactams
were purified by column chromatography on silica gel to give the
products in 70–77% yield as mixtures of diastereomers (Ͼ6:1).
Conclusions
In summary, treatment of 2-alkynylpiperidines and 2-alk-
ynylazepines with chloroacetyl fluoride resulted in ring ex-
pansion to form 10- and 11-membered 3-chloro-4,5-allenyl
lactams in Ͼ70% yield. Further investigations into the syn-
thesis of optically active propargylamine derivatives, the ap-
plication of the zwitterionic aza-Claisen rearrangement to
generate enantiomerically pure allenyl lactams (via 1,3-chi-
rality transfer), and the exploration of the scope and limita-
tions concerning the substitution pattern of the compounds
involved are in progress.[18]
1-Methyl-3-chloro-1-aza-deca-4,5-diene-2-one (12b): Green crystals
(light petroleum ether/EtOAc); m.p. 130–132 °C (decomp.). Double
signal set due to cis/trans amide isomers (1:0.7) 1H NMR
(400 MHz, CDCl3): δ = 7.56–7.46 (m, 3.4 H), 7.41–7.32 (m, 3.4 H),
3
7.28–7.22 (m, 2 H), 5.96–5.76 (m, 2.5 H), 5.72–5.68 (dd, JHH
=
3
6.8 Hz, JHH = 10.5 Hz, 0.8 H), 4.39–4.29 (0.6 H), 3.41–3.13 (1.5
H), 2.95 (s, 2 H), 2.92 (s, 3 H), 2.65–2.59 (m, 0.7 H), 2.54–2.41 (m,
1 H), 2.33–2.25 (m, 0.7 H), 2.21–2.09 (m, 0.7 H), 2.09–2.01 (m, 0.7
H) 1.99–1.90 (m, 1 H), 1.87–1.67 (m, 2.7 H), 1.67–1.52 (m, 2.4 H),
1.48–1.34 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 204.9
(C-sp), 167.2 (CO), 133.3 (C), 128.8 (CH), 128.6 (CH), 127.6 (CH),
126.4 (CH), 126.0 (CH), 107.2 (C), 104.9 (C), 99.4 (CH), 98.9 (CH),
60.4 (CH), 59.6 (CH), 50.7 (CH2), 49.7 (CH2), 37.1 (CH3), 33.1
(CH3), 28.5 (CH2), 28.2 (CH2), 27.8 (CH2), 25.6 (CH2), 25.3 (CH2)
ppm. HRMS (ESI): calcd. for C16H18NONaCl [M]+ 298.0975;
Experimental Section
General Remarks: Reaction solvents were dried by standard pro-
cedures prior to use when necessary. All reactions containing
moisture- or air-sensitive reagents were carried out under an argon
atmosphere. 1H NMR, 13C NMR, and 2D (COSY, HSQC) spectra
were recorded at room temperature with a Bruker ARX400 or
AV400 spectrometer in CDCl3 using the signal of residual CHCl3
as an internal standard. IR spectra were recorded with a FTIR-
400 plus spectrometer. High-resolution mass spectra (HRMS) were
recorded with a Waters Q TOF Ultima 3 Micromasses spectrome-
ter. Optical rotation were recorded with a Perkin–Elmer P 241 po-
larimeter using dichloromethane (Uvasol) as solvent. Column
chromatography was performed on MN silica gel 60M from Mach-
erey–Nagel (grain size: 0.040–0.063 mm). Progress of the reaction
was monitored by thin-layer chromatography (TLC) performed on
aluminum sheets precoated with 60F254 silica gel from Merck.
found 298.0977. IR: ν = 3056, 2924, 2855, 1948 (w), 1660 (s, br.),
˜
1596, 1577, 1495 (m), 1440 (m), 1399 (m), 800 (m), 773 (m), 693
(m), 611 (m) cm–1.
CCDC-743967 (for 12b) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1-Methyl-3-chloro-1-aza-undeca-4,5-dien-2-one (12c): Containing
approximately 5–10% of the minor diastereomer/conformer. 1H
NMR (400 MHz, CDCl3): δ = 7.45–7.38 (m, 2 H), 7.40–7.33 (m, 2
3
H), 7.32–7.25 (m, 1 H), 5.91–5.85 (m, 1 H), 5.79–5.75 (d, JHH
=
Synthesis of 2-(2-Phenylethynyl)pyrrolidine, -piperidine, and
-azepane 11a–c: Under an atmosphere of argon, phenylethyne
(5.76 g, 56.4 mmol, 1.2 equiv.) and dry THF (50 mL) were placed
in a 500-mL, three-necked flask equipped with a mechanical stirrer.
At –78 °C, nBuLi (1.6 m in toluene, 35.3 mL, 56.4 mmol) was added
by syringe. The solution was kept at this temperature for 3 h until a
white milky solution was obtained. BF3·OEt2 (7.15 mL, 56.4 mmol,
1.2 equiv.) was injected, and after another 10 min lactam 10
(1 equiv.) was added. After raising the temperature to 0 °C, LiAlH4
(4.1 g, 108 mmol, 2.3 equiv.) was added portionwise. The reaction
mixture was diluted with diethyl ether to maintain an easily stirred
suspension. After about 3 h, the reaction was found to be complete
(careful TLC monitoring). Then, water (20 mL) was added drop-
wise to precipitate the aluminum salts. The mixture was extracted
with diethyl ether (8ϫ100 mL). The combined organics were ex-
tracted with aq. HCl (5ϫ100 mL, 1 m). Then, the combined aque-
ous solutions were re-extracted with diethyl ether. With cooling,
the remaining aqueous solution was neutralized by adding NaOH
3.2 Hz, 1 H), 4.16–4.00 (m, 1 H), 3.33–3.14 (m, 1 H), 2.93 (s, 3 H),
2.60–2.44 (m, 1 H) 2.01–1.87 (m, 1 H), 1.81–1.64 (m, 4 H), 1.64–
1.51 (m, 1 H), 1.49–1.30 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 203.6 (C-sp), 167.5 (CO), 134.2 (C), 128.5 (CH), 127.6
(CH), 126.7 (CH), 105.4 (C), 98.1 (CH), 60.0 (CH), 47.5 (CH2),
32.4 (CH3), 26.4 (CH2), 25.2 (CH2), 23.8 (CH2), 23.2 (CH2) ppm.
HRMS (ESI): calcd. for C17H21ClNO 290.1312; found 290.1323.
IR: ν = 3056, 2930, 2862, 2242 (w), 1945 (w), 1715, 1636 (s, br.),
˜
1493, 1444, 1400, 909 (m), 727 (s), 692 (s), 607 (s) cm–1.
Supporting Information (see footnote on the first page of this arti-
cle): Spectral data for known compounds and copies of the 1H and
13C NMR spectra.
Acknowledgments
We are grateful to the Deutsche Forschungsgemeinschaft (DFG)
(s) until pH Ͼ8. After extraction with diethyl ether (150 mL, and the Fonds der Chemischen Industrie (FCI) for financial sup-
2ϫ50 mL, vigorous stirring) the combined organic phases were port.
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First Synthesis of Medium-Sized Ring Allenyl Lactams
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Published Online: August 17, 2011
Eur. J. Org. Chem. 2011, 5250–5253
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