Synthesis of cyclohexenylamines by ring closing metathesis

Article abstract of DOI:10.1055/s-1998-1789

Starting from 5-pentenaldehyde 1, the 1-allyl-4-pentenylamines 2a-d were prepared. The ring closing metathesis reaction of these dienes using the Grubbs catalyst 3 gave the corresponding cyclohexenylamines 4a,b and 4d in high yield. The secondary amine 2c

Full text of DOI:10.1055/s-1998-1789

August 1998
SYNLETT
891
Synthesis of Cyclohexenylamines by Ring Closing Metathesis
*,a
Martin E. Maier , Tzvetelina Lapeva
Martin-Luther-Universität Halle-Wittenberg, Fachbereich Chemie, Institut für Organische Chemie, Kurt-Mothes-Str. 2, 06120 Halle (Saale),
Germany,
a)
New address: Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany, FAX: (+49) 7071 29
5137, e-mail: martin.e.maier@uni-tuebingen.de
Received 6 June 1998
Abstract: Starting from 5-pentenaldehyde 1, the 1-allyl-4-
pentenylamines 2a-d were prepared. The ring closing metathesis
reaction of these dienes using the Grubbs catalyst 3 gave the
corresponding cyclohexenylamines 4a,b and 4d in high yield. The
secondary amine 2c was recovered unchanged. This route to compound
4d represents a formal total synthesis of the alkaloid epibatidine. In
addition, 4b was transformed by electrophilic transannular cyclization
to the bicyclic urethanes 5a and 5b.
of the benzyl amine 2c with trifluoroacetic anhydride in the presence of
triethylamine furnished the protected aminodiene 2d.
The ring-closing metathesis (rcm) is one of a few reactions that form a
double bond in the cyclization step. In contrast to the intramolecular
Wittig reaction or the McMurry cyclization, the starting materials,
acyclic nonconjugated dienes, are stable entities and usually easily
accessible. It is thus logical that the rcm reaction has found widespread
1
use since the discovery of carbene complexes that are able to mediate
this reaction efficiently. In addition, some of these complexes are easily
2
available. The rcm reaction allows the formation of cyclic olefins with
various ring sizes. However, as with other cyclization reactions, entropic
factors and ring strain make the formation of medium-sized cycloolefins
by this route difficult. Other well-known ways to some cyclic olefins
include cycloaddition reactions. While, for example, cyclohexenes can
be obtained by Diels-Alder reactions, not all substitution patterns are
suitable for this strategy. Examples include cyclohexenes with a hetero
atom at the homoallylic position. They require the use of special
Scheme 2
3
dienophiles, such as vinylboranes or rearrangement reactions on a
4
carboxylic substituent. Such cyclohexenes are of interest for the
The crucial ring closing reactions were performed by stirring a
dichloromethane solution of the dienes 2a-d in the presence of 3 mol%
of the Grubbs ruthenium carbene 3 catalyst at room temperature for 24
h. As can be seen, the 1,7-octadiene-4-amine derivatives 2a,b and 2d
cyclized in almost quantitative yield to the corresponding
synthesis of bicyclic heterocycles by transannular reactions (Scheme 1).
In this paper we show that for cyclohexenyl amines the rcm reaction
represents a useful alternative to the Diels-Alder strategy.
5
cyclohexenylamines 4a,b and 4d (Scheme 3). In contrast, the
unprotected amine 2c was recovered unchanged. This negative result
supports the observation of Fürstner et al. who found that a chelating
substituent in close proximity to one of the double bonds shuts down the
10
catalytic cycle.
Scheme 1
The corresponding substrates, 1-allyl-4-pentenylamines should be
available by addition of an allyl anion equivalent to a suitable 4-
pentenylimine. According to this strategy, the 1,7-octadien-4-amine
5
derivatives 2a-d were prepared. The urethanes 2a,b were synthesized
6
in analogy to a published procedure. Thus, addition of boron trifluoride
7
etherate to
a
mixture of 4-pentenal, benzyl carbamate and
allyl(trimethyl)silane followed by stirring of the reaction mixture over
night gave the urethane 2a in 60% yield. In a similar manner the
urethane 2b was prepared by using tert-butyl carbamate instead. No
product was obtained with trifluoroacetamide (Scheme 2).
It was also of interest to study the influence of substituents at the amino
function upon the rcm reaction. Therefore, the secondary amine 2c was
synthesized in a simple two-step operation by first converting the
aldehyde 1 with benzylamine to the corresponding imine followed by
Scheme 3
Since compound 4d had been used in a total synthesis of the alkaloid
epibatidine, the present work also constitutes a formal total synthesis
8,9
11
addition of allyl(tributyl)stannane and trifluoroacetic acid. Treatment

892
LETTERS
SYNLETT
12
of racemic epibatidine. This natural product contains a 7-aza-
Then the mixture was poured into satd. aqueous NaHCO and
diluted with toluene (30 ml). The organic phase was washed with
3
13
bicyclo[2.2.1]heptane ring plus a 5-(2-chloropyridyl) substituent.
brine, dried (Na SO ), filtered and evaporated in vacuo. The crude
product was purified by flash column chromatography on silica
gel.
The cyclohexenylamine derivative 4b was also subjected to cyclization
reactions involving electrophilic halogen atoms. Thus, treatment of 4b
with N-bromosuccinimide (NBS) in dichloromethane provided the
2
4
14
bicyclic urethane 5a in good yield. Similarly, reaction of 4b with iodine
in diethyl ether gave the corresponding iodo compound 5b.
N1-(1-allyl-4-pentenyl)-benzylcarbamate
chromatography (heptane/ethyl acetate; 7:1) provided 2a as a
(2a):
Flash
15
5
o
white solid (1.87 g, 60%), m.p. 26-28 C. TLC (heptane/ethyl
1
acetate, 7:1): R = 0.41. H NMR (400 MHz, CDCl ): δ = 1.44-
f
3
1.61 (m, 2 H, CH ), 2.06-2.17 (m, 2 H, CH ), 2.19-2.30 (m, 2 H,
2
2
CH ), 3.73 (d, br., J = 5.7 Hz, 1 H, CH), 4.57 (d, br., J = 7.4 Hz, 1
2
H, NH), 4.93-5.04 (m, 4 H, olefinic H), 5.07 (s, 2 H, benzylic H),
13
5.70-5.83 (m, 2 H, olefinic H), 7.29-7.36 (m, 5 H, aryl H).
C
NMR (50 MHz, CDCl ): δ = 30.1, 33.8, 39.4 (3 CH ), 50.3 (CH),
3
2
66.5 (benzyl C), 115.0, 117.9 (2 olefinic CH ), 128.0, 128.5 (aryl
2
CH), 134.0 (olefinic CH), 136.6 (aryl C), 137.8 (olefinic CH),
155.9 (CO). MS (EI), m/z (%): 218 (15) [M - allyl], 174 (20), 91
Scheme 4
+
(100). C
found C 73.96, H 7.82, N 5.42.
H NO (259.35): calcd. C 74.10, H 8.10, N 5.40;
16 21 2
In summary, we have described
a straightforward synthesis of
cyclohexenylamines by rcm reaction of 1,7-octadiene-4-amine
derivatives. This route provides a valuable alternative to the Diels-Alder
strategy to cyclohexenes with an electron donating substituent in the
homoallylic position. The combination of the rcm reaction with
transannular cyclization should provide access to interesting natural
products. Studies along these lines are currently in progress in our
laboratory.
N1-(1-allyl-4-pentenyl)-tert-butylcarbamate
chromatography (petroleum ether/ethyl acetate; 5:1) provided 2b
as a colorless oil (1.3 g, 48%). TLC (petroleum ether/ethyl acetate,
(2b):
Flash
1
5:1): R = 0.51. H NMR (400 MHz, CDCl ): δ = 1.43 (s, 9 H,
f
3
tert-butyl), 1.46-1.58 (m, 2 H, CH ), 2.03-2.40 (m, 4 H, CH ),
3.64 (s, br., 1 H, CH), 4.33 (s, br., 1 H, NH), 4.94-5.09 (m, 4 H,
olefinic H), 5.71-5.85 (m, 2 H, olefinic H). C NMR (100 MHz,
2
2
13
CDCl ): δ = 29.4 (C(CH ) ), 31.2, 34.9, 40.5 (3 CH ), 50.7 (CH),
3
3 3
2
Acknowledgment.
Forschungsgemeinschaft
Reaktionsverhalten
Metallkomplexen) and the Fonds der Chemischen Industrie is gratefully
Financial
support
by
the
Synthese
Deutsche
und
64.8 (C(CH ) ), 115.9, 118.7 (2 olefinic CH ), 135.5, 139.2 (2
3 3
2
(Graduiertenkolleg
olefinic CH), 156.8 (CO). MS (ESI), m/z (%): 248 (100) [M +
von
Organometallverbindungen
und
+
Na] . C
H NO (225.33): calcd. C 69.30, H 10.29, N 6.22;
13 23 2
found C 69.01, H 9.94, N 6.38.
acknowledged.
N4-benzyl-1,7-octadien-4-amine (2c): TLC (Al O , petroleum
2
3
1
ether/ethyl acetate, 5:1): R = 0.79. H NMR (400 MHz, CDCl ):
f
3
References and Notes
δ = 1.50-1.58 (m, 2 H, CH ), 2.09-2.29 (m, 4 H, CH ), 2.62-2.67
2
2
(1) Reviews: (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem.
Res. 1995, 28, 446-452. (b) Schmalz, H.-G. Angew. Chem. 1995,
107, 1981-1984; Angew. Chem. Int. Ed. Engl. 1995, 34, 1833-
1836. (c) Schuster, M.; Blechert, S. Angew. Chem. 1997, 109,
2124-2145; Angew. Chem. Int. Ed. Engl. 1997, 36, 2036-2055.
(d) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-
388. (e) Grubbs, R. H.; Chang, S. Tetrahedron 1988, 54, 4413-
4450. (f) Fürstner, A. Top. Catal. 1997, 4, 285-299.
(m, 1 H, CH), 3.76 (s, br., 2 H, benzylic CH ), 4.92-5.09 (m, 4 H,
2
olefinic H), 5.73-5.84 (m, 2 H, olefinic H), 7.20-7.35 (m, 5 H, aryl
13
H). C NMR (125 MHz, CDCl ): δ = 30.0, 33.2, 38.3 (3 CH ),
3
2
51.1 (benzylic C), 55.8 (CH), 114.4, 117.2 (olefinic CH ), 126.8,
2
128.1, 128.3 (aryl CH), 135.6, 138.8 (olefinic CH), 140.8 (aryl C).
+
MS (ESI), m/z (%): 216 (100) [M + H] .
N1-(1-allyl-4-pentenyl)-N1-benzyl-2,2,2-trifluoracetamide (2d):
1
TLC (petroleum ether/ethyl acetate, 5:1): R = 0.68. H NMR (400
f
(2) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem. 1995, 107, 2179-2181; Angew. Chem. Int. Ed. Engl. 1995,
34, 2039-2041. (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1996, 118, 100-110. (c) Dias, E. L.; Nguyen, S. T.;
Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887-3897.
MHz, CDCl ): mixture of rotamers (ratio 58:42): δ = 0.82-0.88,
3
1.56-1.89 (m, 4 H, CH ), 2.28-2.33, 2.41-2.48 (m, 2 H, CH ),
2
2
3.58-3.63, 3.96-4.03 (2 m, 1 H, CH), 4.43, 4.70 (2 d, J = 15.2, 1.2
H, benzylic CH ), 4.44-4.58 (m, 0.8 H, benzylic CH ), 4.83-5.08
2
2
(m, 4 H, olefinic H), 5.52-5.64 (m, 2 H, olefinic H), 7.26-7.37 (m,
13
5 H, aryl H). C NMR (100 MHz, CDCl ): δ = 31.1, 31.6, 31.7,
(3) (a) Singleton, D. A.; Martinez, J. P. J. Am. Chem. Soc. 1990, 112,
7423-7424. (b) Noiret, N.; Youssofi, A.; Carboni, B.; Vaultier, M.
J. Chem. Soc. Chem. Commun. 1992, 1105-1107. (c) Singleton, D.
A.; Redman, A. M. Tetrahedron Lett. 1994, 35, 509-512.
(d) Jehanno, E.; Vaultier, M. Tetrahedron Lett. 1995, 36, 4439-
4442.
3
33.0, 37.1, 39.3, 46.7, 52.5, 58.9, 60.6, 116.3, 116.5, 118.9, 119.7,
128.6, 129.4, 129.7, 129.8, 134.3, 135.7, 136.5, 137.8, 138.1,
+
+
138.5, 159.3, 159.6. MS (EI), m/z: 311 [M ], 270 [M - allyl].
F NO (311.20): calcd. C 65.61, H 6.43, N 4.50; found C
C
H
17 20
3
65.98, H 6.28, N 4.50.
General procedure for preparation of cyclohexenylamines (4a-d)
using rcm: To a solution of diene 2a-d (0.3 – 0.9 µmol, 0.006 M)
in dry and degassed dichloromethane was added ruthenium
carbene 3 (3 mol%). After stirring the reaction mixture for 24 h at
room temp., the solvent was removed in vacuo and the residue
was purified by flash chromatography on silica gel.
(4) Pfister, J. R.; Wymann, W. E. Synthesis 1983, 38-40.
(5) Procedure for the preparation of N1-(allyl-4-pentenyl)-
carbamates (2a,b): To a stirred solution of aldehyde 1 (1.00 g,
12.0 mmol), allyltrimethylsilane (1.37 g, 12.0 mmol) and
carbamate (12.0 mmol) in dry dichloromethane (20 ml), cooled to
0-5°C was added boron trifluoride etherate (1.48 ml, 12.0 mmol)
in one portion. After 30 min of stirring the reaction mixture was
allowed to warm to room temperature and further stirred for 12 h.
N1-(3-cyclohexenyl)benzylcarbamate (4a): Cyclization of 2a (250
mg, 964 µmol) in 160 ml of dichloromethane in the presence of 3

August 1998
SYNLETT
893
(24 mg, 28 µmol) gave after flash chromatography (heptane/ethyl
NMR (100 MHz, CDCl ): δ = 24.0, 24.7, 26.9 (3 CH ), 45.2
3 2
acetate, 7:1) 4a as white crystals (212 mg, 95%). TLC (heptane/
(CNH), 48.1 (CBr), 75.4 (C-O), 154.0 (C=O). MS (ESI), m/z (%):
244 (40) [M + Na] , 221 (98) [M + H] .
1
+
+
ethyl acetate, 7:1): R = 0.26. m.p.: 61-63°C. H NMR (400 MHz,
f
CDCl ): δ = 1.49-1.59 (m, 1 H, CH ), 1.86-1.98 (m, 2 H, CH ),
3
2
2
(6) Veenstra, S. J.; Schmid, P. Tetrahedron Lett. 1997, 38, 997-1000.
2.12-2.13 (m, 2 H, CH ), 2.38 (d, br., J = 15.6 Hz, 1 H, CH ), 3.84
2
2
(7) Rossiter, J. T.; James, D. C. J. Chem. Soc., Perkin Trans. 1 1990,
(s, br., 1 H, CH), 4.75 (s, br., 1 H, NH), 5.08 (s, 2 H, benzylic
1909-1913.
CH ), 5.58-5.67 (m, 2 H, olefinic H), 7.29-7.35 (m, 5 H, aryl H).
2
13
(8) Wuts, P. G. M.; Jung, J.-W. J. Org. Chem. 1991, 56, 365-372.
(9) Grieco, P. A.; Bahsas, A. J. Org. Chem. 1987, 52, 1378-1380.
(10) Fürstner, A.; Langemann, K. Synthesis 1997, 792-803.
C NMR (100 MHz, CDCl ): δ = 23.3, 28.1, 31.9 (3 CH ), 46.1
3
2
(CH), 66.5 (benzylic C), 124.3, 127.1 (2 olefinic CH), 128.16,
128.21, 128.6 (aryl CH), 136.7 (aryl C), 158.8 (CO). IR (KBr): =
-1
+
3322 cm , 1687, 1542. MS (ESI), m/z (%): 254 (100) [M + Na] .
NO (231.16): calcd. C 72.70, H 7.41, N 6.06; found C
(11) Fletcher, S. R.; Baker, R.; Chambers, M. S.; Herbert, R. H.;
Hobbs, S. C.; Thomas, S. R.; Verrier, H. M.; Watt, A. P.; Ball, R.
G. J. Org. Chem. 1994, 59, 1771-1778.
C
H
14 17
2
72.93, H 7.54, N 6.13.
8-Bromo-2-oxa-4-azabicyclo[3.3.1]nonan-3-one (5a): To a cooled
(-78°C) solution of cyclohexenylamine 4b (20 mg, 0.10 mmol) in
dichloromethane (2 ml) was added at once N-bromosuccinimide
(22 mg, 0.12 mmol). After being stirred for 18 h at this temp., the
reaction mixture was allowed to warm up to room temp. Stirring
was continued for 3 d (TLC monitoring), and then the reaction
was quenched by addition of satd. aqueous Na SO . The mixture
(12) Recent syntheses: (a) Kosugi, H.; Abe, M.; Hatsuda, R.; Uda, H.;
Kato, M. J. Chem. Soc., Chem. Commun. 1997, 1857-1858.
(b) Ikeda, M.; Kugo, Y.; Kondo, Y.; Yamazaki, T.; Sato, T. J.
Chem. Soc., Perkin Trans. 1 1997, 3339-3344. (c) Pandey, G.;
Bagul, T. D.; Sahoo, A. J. Org. Chem. 1998, 63, 760-768. (d)
Sirisoma, N.; Johnson, C. R. Tetrahedron Lett. 1998, 39, 2059-
2062.
2
3
was diluted with ether and the organic layer washed with brine,
satd. aqueous NaHCO , dried (Na SO ), filtered and concentrated
3
2
4
(13) Review: Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179-
to give
a pale yellow oil which solidified on standing.
1193.
Recrystallization from pentane/ether provided 5a as white crystals
(14) Tamaru, Y.; Kawamura, S.; Bando, T.; Tanaka, K.; Hojo, M.;
1
(13 mg, 60%). m.p.: 157°C. H NMR (400 MHz, CDCl ): δ =
3
Yoshida, Z.-i. J. Org. Chem. 1988, 53, 5491-5501.
1.69 (d, J = 13.6 Hz, 1 H), 1.92-2.01 (m, 3 H, CH ), 2.28-2.38 (m,
2
1 H), 2.53 (dd, J = 2.0, 13.8 Hz, 1 H), 3.64 (s, br., 1 H, CHN), 4.46
(15) Friesen, R. W.; Kolaczewska, A. E. J. Org. Chem. 1991, 56, 4888-
13
(s, 1 H, CHBr), 4.64 (s, 1 H, CH-O), 6.04 (s, br., 1 H, NH).
C
4895.