Macrocyclic studies of EZ and ZZ 12-membered aza macrocycles; Novel molecular rearrangement observed

Article abstract of DOI:10.1055/s-1999-2772

EZ and ZZ hetero macrocyclic dienes 13a and 14b are generated respectively by an intramolecular displacement of α-chloroketones 11a and 11b using trifluoroacetamide as nucleophilic agent. Novel molecular rearrangements were observed.

Full text of DOI:10.1055/s-1999-2772

LETTER
1115
Macrocyclic Studies of EZ and ZZ 12-membered Aza Macrocycles;
Novel Molecular Rearrangement Observed
Élyse Bourque, Michel Grenon, Sébastien Laliberté, Pierre Deslongchamps*
Laboratoire de synthèse organique, Département de chimie, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001,
13e avenue nord, Sherbrooke (QC) Canada J1H 5N4
Fax +1 (819) 820-6823; E-mail: pierre.deslongchamps@courrier.chimie.usherb.ca
Received 13 April 1999
c
f
E
a, b
d, e
Abstract: EZ and ZZ hetero macrocyclic dienes 13a and 14b are
generated respectively by an intramolecular displacement of a-
chloroketones 11a and 11b using trifluoroacetamide as nucleophilic
agent. Novel molecular rearrangements were observed.
HO
THPO
THPO
1
3-butyn-1-ol
E
O
Key words: macrocyclization, chloroketone, trifluoroacetamide,
THPO
imide, lactam
3
2
TIPSO
R2O
i, j
We have recently reported the use of a-chloroketones for
the synthesis of macrocycles via the intramolecular dis-
placement with a carbon nucleophile.1 We have also ob-
served good yields of macrocyclization by the
displacement of an allylic chloride with a nitrogen derived
nucleophile.2 We wish now to report a study on the in-
tramolecular cyclization of EZ and ZZ a-chloroketone tri-
fluoroacetamide dienes 11a and 11b which led us to
observed unexpected molecular rearrangements during
the macrocyclization step.
E
Cl
R1O
Cl
E
6
4 R1=THP, R2=H
g, h
5 R1=H, R2=TIPS
Scheme 1 (a) DHP, TsOH, THF, r.t., 95% (b) n-BuLi, ClCO2Me,
THF, -78°C, 76% (c) MeLi, CuI, THF, -78°C, 95% (d) DIBAL-H,
CH2Cl2, -78°C, 88% (e) (COCl)2, DMSO, Et3N, CH2Cl2, 80% (f) Li,
BrCH2Cl, THF, -78°C, 98% (g) TIPSOTf, 2,6-lutidine, CH2Cl2, -
20°C, 98% (h) PPTS, i-PrOH, reflux, 94% (i) Ph3P, I2, imidazole,
Et2O/CH3CN (3:1), r.t., 90% (j) E2CH2, NaH, THF/DMF (1:1), 80°C,
88%. E = CO2Me.
The trisubstitued Z-olefin 6 (Scheme 1) was obtained
through a ten step sequence via the commercially avail-
able 3-butyn-1-ol which was protected as a tetrahydropy-
ranyl acetal.3 The corresponding lithium acetylide was
treated with methyl chloroformate to give the adduct 1 in
a combined yield of 72%. Carbocupration on the alkynic
ester provided specifically the corresponding Z olefin 2 in
a 95% yield.4 The ester 2 was reduced by DIBAL-H and
the resulting alcohol was oxidized to the aldehyde by the
Swern’s protocol.5 The chlorohydrin 4 was obtained in
98% yield as a mixture of diastereoisomers upon treat-
ment with chloromethyllithium.6 Protection of this mix-
ture as triisopropylsilylether followed by the removal of
the tetrahydropyranyl group in acidic medium gave race-
mic adduct 5 in a combined yield of 92%. Using Corey’s
procedure,7 the alcohol 5 was transformed to the iodide
which was alkylated with dimethyl malonate to give syn-
thon 6 in a global yield of 35%.8
precursors were submitted to the macrocyclization condi-
tions and the results are shown in the Table 1.
Table 1 Results for the macrocyclization step
Coupling of the latter with the commercially available
dichlorides 7a and 7b (Scheme 2) afforded the corre-
sponding dienes 8a and 8b. Displacement of the allylic
chloride with sodium azide provided adducts 9a and 9b
which were converted into the corresponding amines fol-
lowing the Staudinger’s protocol.9 Acetylation led to trif-
luoroacetamides 10a and 10b. The triisopropylsilylether
was removed with tetrabutylammonium fluoride to gener-
ate the alcohols which were oxidized by Dess-Martin
periodinane10 to give chloroketones 11a and 11b. These
(a) Macrocyclization was carried out at 2.0 X 10-3 M in CH3CN using
Cs2CO3 as a base. (b) Time of the substrate addition via a syringe
pump. (c) Yield of isolated product. (d) Degradation products were ob-
served. (e) DMF was used as solvent.
Results and discussion
Temperature was shown to influence the relative forma-
tion of the expected macrocycle 12a and the unexpected
Synlett 1999, No. 07, 1115–1117 ISSN 0936-5214 © Thieme Stuttgart · New York

1116
É. Bourque et al.
LETTER
resulting cyclopropanoxide on the allylic side providing
the macrocyclic trifluoroketoimide 17. This compound
would then be hydrolysed in the reaction medium to give
macrocyclic lactam 14b. Single crystal X-ray diffraction
analysis of compounds 13a and 14b confirmed unambig-
uously their structures (Figures 1-2).15 Both series have
demonstrated that the direct macrocyclization pathway is
disfavored over the unexpected rearrangements.
Cl
TIPSO
Cl
Cl
Cl
7a
a
+
6
or
E
Cl
Cl
E
8a (EZ) 83%
8b (ZZ) 44%
7b
TIPSO
TIPSO
Cl
Cl
c, d
b
O
Cl
O
E
E
O
N3
B-
NHCOCF3
E
E
10a (EZ) 46%, 3 steps
10b (ZZ) 60%, 2 steps
9a (EZ)
-
CF3
N
E
H
O
9b (ZZ) 84%
E
E
N
-
CF3
O
E
15
Cl
from 11a
e, f
E
E
NHCOCF3
-
-
O
O
11a (EZ) 69%
11b (ZZ) 89%
CF3
CF3
O
O
N
N
E
E
E
E
O
O
O
O
O
O
N
CF3
NH
N
O
N
O
O
N
E
E
E
E
E
E
E
E
E
13a
E
13a
12a (EZ)
12b (ZZ)
13a (E)
13b (Z)
14a (EZ)
14b (ZZ)
Scheme 3 E = CO2Me, B = Cs2CO3.
Scheme 2 (a) NaH, THF/DMF (1:1), r.t., then 7a or 7b, 75°C (b)
NaN3, DMSO, r.t., 18 h (c) Ph3P, H2O, THF, r.t., 18 h (d) TFAA, py-
ridine, CH2Cl2, 0°C (e) TBAF, THF, -20°C (f) Dess-Martin periodi-
nane, CH2Cl2, r.t., 10 min. E = CO2Me.
The above procedure using an a-chloroketone nucleo-
philic displacement by an heteroatom shows that it is pos-
sible to generate 12-membered macrocycles. Moreover, it
bicyclic macrocycle 13a as indicated in entries 1-3.11,12 also allowed us to observe a new molecular rearrangement
When macrocyclization was carried out at 60°C, macro- leading to unusual bicyclic imides and macrocyclic lac-
cycle 12a was not formed but degradation products ap- tams.
peared. As shown in Scheme 3, we explained the
formation of the bridged macrocycle 13a by the competi-
Acknowledgement
tive formation of a cyclopropanone intermediate which is
usually occurring in the Favorskii's rearrangement.13
Financial support from Merck Laboratories (Montreal) and NSERC
(Canada) through a University-Industry research grant is greatly ap-
preciated. We also thank FCAR for a fellowship support (E.B.). We
are also greatly indebted to Marc Drouin, Université de Sherbrooke,
Thus, chloroketone 11a would first be converted to cyclo-
propanone 15, trifluoroacetamide anion would then add to
the carbonyl and the resulting intermediate would break
down by attacking the fluoroacetamide carbonyl (two
routes are possible) to finally eject trifluoromethane car-
banion and produce the rearranged bicyclic macrocycle
13a. The unexpected formation of the non-conjugated
macrocyclic lactam 14b (Scheme 4)14 would start by the
formation of cyclopropanone intermediate 16 by remov-
ing an allylic proton on the alkyl chain. This would be fol-
lowed by a N-nucleophilic attack and cleavage of the
for the X-ray structural determinations.
References and Notes
(1) Couturier, M.; Deslongchamps, P. Synlett 1996, 1140;
Barriault, L.; Ouellet, S.G.; Deslongchamps, P. Tetrahedron
1997, 53, 14937; Barriault, L.; Deslongchamps, P. Bull. Soc.
Chim. Fr. 1997, 134, 969.
(2) Fortin, D. Unpublished results.
Synlett 1999, No. 07, 1115–1117 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Macrocyclic Studies of EZ and ZZ 12-membered Aza Macrocycles
1117
(7) Corey, E.J.; Pyne, S.G.; Su, W. Tetrahedron Lett. 1983, 24,
4883.
O
O
-
Cl
B
H
(8) Adduct 6: colorless oil; 1H NMR (300 MHz, CDCl3) d 5.18 (d,
J = 8.5 Hz, 1H, RC(CH3)=CHR), 4.60-4.52 (m, 1H,
CHOTIPS), 3.75 (s, 6H, 2 X COOCH3), 3.48 (dd, J = 10.7, 6.4
Hz, 1H, CH2Cl), 3.35 (dd, J = 10.7, 6.4 Hz, 1H, CH2Cl), 3.34
(m, 1H, RCH(COOCH3)2), 2.20-1.85 (m, 4H, CH2CH2), 1.73
(s, 3H, RC(CH3)=CHR ), 1.03 (s, 21H, OTIPS); 13C NMR (75
MHz, CDCl3) d 169.5, 136.7, 128.0, 69.5, 52.5, 51.3, 49.2,
30.2, 27.0, 22.8, 17.9, 17.7, 12.3; IR (neat, cm-1) 2945, 2866,
1739, 1462, 1436, 1155, 883, 681; HRMS: calc. for
C18H32O5Si1C11 (M - C3H9): 391.1707, found: 391.1714.
(9) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
(10) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(11) Macrocycle 12a: amorphous solid; 1H NMR (300 MHz,
CDCl3) d 5.95 (s, 1H, RC(CH3)=CHCOR), 5.60-5.36 (m, 2H,
RCH=CHR), 4.30-3.80 (m, 2H, CH2NR2), 3.75 (s, 6H, 2 X
COOCH3), 2.74 (d, J = 6 Hz, 2H, CH=CHCH2C(COOCH3)2),
2.35-1.75 (m, 2H, CH2CH2), 1.84 (s, 3H, RC(CH3)=CHCOR),
1.36-1.14 (m, 2H, CH2CH2); 13C NMR (75 MHz, CDCl3) d
197.9, 197.0, 150.4, 148.8, 129.6, 129.2, 129.0, 124.8, 123.8,
56.2, 55.1, 52.9, 52.3, 52.2, 51.1, 34.6, 34.3, 32.7, 29.7, 26.0;
IR (neat, cm-1) 2928, 1727, 1692, 1448, 1255, 1207, 1154,
912; HRMS: calc. for C18H22O6N1F3: 405.1399, found:
405.1393.
O
O
-
N
CF3
E
N
-
CF3
E
E
E
16
from 11b
-
O
O
B-H
N
CF3
E
E
O
O
N
O
NH
CF3
E
14b
(12) Bicyclic imide 13a: colorless flakes, mp 164°C; 1H NMR (300
MHz, CDCl3) d 6.07-5.85 (m, 2H, RCH=CHR), 5.15 (s, 1H,
CH2=CR2), 5.03 (s, 1H, CH2=CR2), 4.38 (dd, J = 13.2, 6.0 Hz,
1H, CH2N), 3.83 (dd, J = 13.2, 7.0 Hz, 1H, CH2N), 3.72 (s, 3H,
COOCH3), 3.70 (s, 3H, COOCH3), 3.47 (dd, J = 8.6, 1.2 Hz,
1H, CHCH2COR), 2.96 (dd, J = 18.4, 8.7 Hz, 1H,
E
E
17
E
Scheme 4 E = CO2Me, B = Cs2CO3.
CHCH2COR), 2.86 (dd, J = 13.6, 8.2 Hz, 1H,
O
CHCH2C(COOCH3)2), 2.41 (dd, J = 18.4, 1.6 Hz, 1H,
CHCH2COR), 2.34-2.20 (m, 2H, CHCH2C(COOCH3)2,
CH2CH2), 1.95-1.40 (m, 2H, CH2CH2), 1.30-1.19 (m, 1H,
CH2CH2); 13C NMR (75 MHz, CDCl3) d 178.4, 176.1, 172.1,
171.0, 144.7, 131.5, 130.3, 118.5, 55.9, 52.9, 52.5, 48.8, 38.9,
35.1, 33.4, 29.7, 24.7; IR (neat, cm-1) 2955, 2257, 1732, 1703,
1602, 1436, 1388, 1322, 1244, 1168.
O
N
E
E
13a
(13) For a review, see March, J. Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 4th ed; Wiley: New
York, 1992, pp. 1080-1083.
Figure 1 Stereoview of the ORTEP drawing of 13a.
(14) Lactam 14b: colorless flakes, mp 135-137 °C; 1H NMR (300
MHz, CDCl3) d 6.02 (dd, J = 18.3, 7.5 Hz, 1H,
O
NH
RCH=CHCH2N), 5.75 (s, 1H, NH), 5.14 (dd, J = 18.7, 8 Hz,
1H, RCH=CHCH2N), 4.89 (t, J = 6.5 Hz, 1H,
RCH=C(CH3)R), 3.77 (s, 6H, 2 X COOCH3), 3.65 (dd, J = 7.3,
5.8 Hz, 2H, CH2NH), 2.66-2.61 (m, 4H, CH2CH=CH,
CH2CH=C(CH3)CH2), 2.42-2.23 (m, 4H, CH2CONH,
CH2CH=C(CH3)CH2), 1.77 (s, 3H, CH2CH=C(CH3)CH2); IR
(neat, cm-1) 2978, 1733, 1663, 1442, 1216, 1110; HRMS: calc.
for C16H23O5N1: 309.1576, found: 309.1579.
E
14b
E
Figure 2 Stereoview of the ORTEP drawing of 14b.
(15) Crystallographic data of compounds 13a (CCDC 114598) and
14b (CCDC 114599) have been deposited with the Cambridge
Crystallographic Data Center, University Chemical
Laboratory, 12 Union Road, Cambridge CB2 1EZ, England.
(3) Bernady, K.F.; Floyd, M.B.; Poletto, J.F.; Weiss, M.J. J. Org.
Chem. 1979, 44, 1438.
(4) Corey, E.J.; Katzenellenbogen, J.A. J. Am. Chem. Soc. 1969,
91, 1851; Hall, D.G.; Chapdelaine, D.; Préville, P.;
Deslongchamps, P. Synlett 1994, 660.
(5) Mancuso, A.J.; Swern, D. Synthesis 1981, 165.
(6) Beaulieu, P.L.; Wernic, D. J. Org. Chem. 1996, 61, 3635;
Einhorn, C.; Allavena, C.; Luche, J.L. J. Chem. Soc., Chem.
Commun. 1988, 333.
Article Identifier:
1437-2096,E;1999,0,07,1115,1117,ftx,en;S01699ST.pdf
Synlett 1999, No. 07, 1115–1117 ISSN 0936-5214 © Thieme Stuttgart · New York