Ring-rearrangement metathesis of substituted 2-aminonorbornenes

Article abstract of DOI:10.1055/s-2007-982573

In this report we describe the ring-rearrangement metathesis of 2-aminonorbornene derivatives. An efficient ruthenium-catalysed metathesis reaction occurs with a wide range of pendent alkenes and alkynes to generate bicyclic amines and amides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982573

LETTER
1663
Ring-Rearrangement Metathesis of Substituted 2-Aminonorbornenes
R
ing-Rearrangeme
d
nt Metathesi
a
s of Substit
m
ute
d
2-AminonorbornenesE. Nadany, John E. Mckendrick*
Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK
Fax +44(118)3786331; E-mail: j.e.mckendrick@reading.ac.uk
Received 3 April 2007
Abstract: In this report we describe the ring-rearrangement meta-
thesis of 2-aminonorbornene derivatives. An efficient ruthenium-
a
Cl
+
catalysed metathesis reaction occurs with a wide range of pendent
alkenes and alkynes to generate bicyclic amines and amides.
Cl
CN
1
CN
b
Key words: metathesis, Diels–Alder reaction, piperidine alkaloids
c
Olefin metathesis has now become an established synthet-
ic tool in organic synthesis. The introduction of Schrock’s
catalyst,1 and the widely used Grubbs and Hoveyda cata-
lysts,2,3 have resulted, not only in a number of alkene
formation processes including: ring-closing metathesis
(RCM),4 ring-opening metathesis (ROM), and cross-
metathesis (CM),5 but also the development of a number
of ‘domino’ processes utilising combinations of these
basic metathesis processes to prepare complex molecules.6
(82%)
2
O
3
NHBn
d
NBn
NBn
Domino metathesis or ring-rearrangement metathesis
(RRM) reactions result in products with rearranged cyclic
skeleton. These result from an intramolecular metathesis
reaction between an endocyclic olefin and a tethered exo-
cyclic C=C double bond, in such a way that one ring is
opened in a ROM process and subsequently a new ring is
formed in a RCM process.7 Ring-rearrangement meta-
thesis has the potential to lead to complex polycycles in a
stereocontrolled manner; any stereochemistry present in
the starting material is conserved during the reaction and
preserved in the reaction products.
n
O
O
n = 0
n = 1
n = 2
4a
4b
4c
(98%)
(51%)
4d
(87%)
(82%)
Scheme 1 Reagents and conditions: (a) toluene, 70 °C, then 45 °C,
18 h; (b) KOH, DMSO, H2O, 48 h r.t.; (c) benzylamine, AcOH, THF,
NaHB(OAc)3; (d) for 4a–c: H2C=CH(CH2)nCOCl, DMAP, CH2Cl2;
4d: HC≡CCO2H, DCC, DMAP, CH2Cl2.
enoyl chloride or pent-4-enoyl chloride in the presence of
DMAP gave amides 4a–c in good yield.
Ring-rearrangement metathesis has been previously used
to prepare molecules with carbocyclic and oxocyclic
frameworks,8–10 but there have been fewer reports on the
application of this reaction to systems containing other
heteroatoms such as nitrogen.11,12
Metathesis of the vinyl amide 4a with the Grubbs II cata-
lyst under an atmosphere of ethene resulted in an efficient
conversion (75%) to bicyclic amide 5a (Scheme 2).15 En-
couraged by this result, metathesis of the higher homo-
logues 4b and 4c using identical conditions resulted in
recovery of only starting norbornenes 4b and 4c. Presum-
ably, the reaction had been shut down through sequestra-
tion of the catalyst, chelation of the ruthenium to the
carbonyl oxygen of the amide would result in a five- or
six-membered ring. Precoordination of the aminonor-
bornenes 4b and 4c with a Lewis acid (TiOiPr4), following
the procedure developed by Fürstner, and subsequent
treatment with Grubbs I catalyst resulted in destruction of
the starting material in our hands.16 Acylation of 3 with
propiolic acid in the presence of DCC and DMAP gave
4d. Metathesis of 4d using the second generation Grubbs
catalyst resulted in the recovery of aproximately 90% of
the starting material, the mass balance of the reaction was
thought to be consumed into an unproductive ruthenium
complex of the type 5e.17
Reported herein are our initial results exploring the syn-
thetic potential of the 2-aminonorbornene system as a
suitable substrate core for RRM. Norbornene 1 was pre-
pared through a two-step, one-pot procedure that began
with the cycloaddition of cyclopentadiene and 2-chloro-
acrylonitrile.13 The Diels–Alder adduct was then treated
with potassium hydroxide in DMSO to convert the a-
chloronitrile into the desired ketone 2 (Scheme 1). Subse-
quent reductive amination of 2 using benzylamine in the
presence of sodium triacetoxyborohydride, resulted in N-
benzyl-2-aminonorbornene (3).14 Acylation of N-benzyl-
2-aminonorbornene (3) with acryloyl chloride, but-3-
SYNLETT 2007, No. 11, pp 1663–1666
0
3
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982573; Art ID: G12407ST
© Georg Thieme Verlag Stuttgart · New York

1664
A. E. Nadany, J. E. Mckendrick
LETTER
a
a
72%
O
NBn
O
N
NH
b
Bn
5a
6
2
75%
O
O
4a
a
X
n
c
NBn
N
Bn
n
O
4b n = 1
4c n = 2
NR
5b n = 1
5c n = 2
N
R
R = Boc (90%)
R = Cbz (90%)
R = Ts (99%)
R = Boc (90%)
R = Cbz (99%)
R = Ts (70%)
8a
8b
8c
7a
7b
7c
a
X
+
O
N
NBn
O
N
Bn
Scheme 3 Reagents and conditions: (a) allylamine, AcOH, THF,
NaBH(OAc)3; (b) (Boc)2O, Et3N, CH2Cl2 or BzCl, K2CO3, acetone–
H2O or TsCl, Et3N, CH2Cl2; (c) Grubbs I (10 mol%), ethene, CH2Cl2.
[Ru]
Ph
O
4d
5d
5e
Scheme 2 Reagents and conditions: (a) Grubbs II (10 mol%),
ethene, CH2Cl2.
ed 5,6- and 5,7-fused bicycles 13c and 13d, resulting from
an efficient ene–yne metathesis reaction (Scheme 5). Dis-
appointingly, RRM of aminonorbornene 12e resulted in
In order to circumvent the problems of catalyst coordina- only the ring-opened structure 13e, no evidence of any
tion to an amide carbonyl we chose to undertake further ring-closed ene–yne reaction was evident from the NMR
study of the RRM reaction with analogous amine sub- spectrum. That the yields were lower, but acceptable, is a
strates. Therefore, reductive amination of 2 using allyl- reflection of the increase in ring size formed upon ring-
amine and sodium triacetoxyborohydride, resulted in N- closing metathesis.
allyl-2-aminonorbornene (6, Scheme 3).14 Protection of
the amine prior to the RRM reaction was undertaken and
the facile introduction of protecting groups, Boc, Cbz and
a
Ts, gave three substrates on which to test the metathesis
reaction. Treatment of the protected N-allyl-2-aminonor-
bornenes 7a–c, with the first generation Grubbs catalyst,
under an atmosphere of ethene, resulted in efficient con-
version into the desired bicyclic amines 8a–c.18 All of the
protecting groups were facile to install, however, the Ts
group provided the opportunity to exploit the enhanced
acidity of the NH proton in other synthetic routes and for
this reason it was chosen as the standard amine protecting
group.
(58%)
CO2H
Cl
NH3
9
10
b
(76%)
c
R
OTs
+
n
R
NTs
NHTs
n
CH CH2
CH CH2
n = 2, R =
n = 3, R =
n = 1, R =
11
12a n = 2, R =
12b n = 3, R =
(65%)
2 (60%)
(70%)
As the preparation of the 5,6-fused bicycle had proven to
be straightforward, attention turned to the possibility of
preparing other bicyclic amines with larger heterocyclic
rings. Problems arising from the instability of longer-
chain unsaturated aldehydes prevented synthesis via the
reductive amination route. Consequently, Curtius rear-
rangement of norbornene 9, derived from Diels–Alder re-
action of cyclopentadiene and acryloyl chloride, gave 2-
aminonorbornene hydrochloride 10 (Scheme 4).11h,19 Pro-
tection and activation of the amine as its p-toluene-
sulfonate resulted in 11; alkylation of the anion of 11,
formed by deprotonation using sodium hydride, with alk-
enol toluenesulfonates gave five metathesis substrates
12a–e.
CH CH2
C
CH
CH CH
12c n = 1, R =C CH
12d n = 2, R =C CH
12e n = 3, R =C CH
(28%)
(29%)
Scheme 4 Reagents and conditions: (a) i) EtOCOCl, Et3N, acetone,
ii) NaN3, H2O, iii) 2 M HCl, D; (b) TsCl, Et3N, CH2Cl2; (c) ROTs,
K2CO3, MeCN, D.
In summary it is clear that the RRM reaction on suitably
functionalised 2-aminonorbornene derivatives can be a
powerful reaction for the synthesis of more complex fused
bicycles. Substrates with unsaturation attached through an
amide bond were found to be sensitive to the number of
Rearrangement of aminonorbornenes 12a–d with Grubbs methylene units in the attached side chain, with success
I catalyst (ethene atmosphere) resulted in clean conver- only when there was no possibility for chelation of the
sion in good yields to the corresponding 5,7- and 5,8- ruthenium. On all other substrates ring-rearrangement
fused bicyclic amines 13a and 13b and the vinyl-substitut- metathesis has proven to be efficient with the reaction
Synlett 2007, No. 11, 1663–1666 © Thieme Stuttgart · New York

LETTER
Ring-Rearrangement Metathesis of Substituted 2-Aminonorbornenes
1665
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a
n
N
NTs
Ts
n
13a n = 2 (80%)
12a n = 2
12b n = 3
(80%)
13b n = 3
a
n
N
NTs
n
Ts
(80%)
(34%)
12c n = 1
12d n = 2
12e n = 3
13c n = 1
13d n = 2
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Ts
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(84%)
13e
Scheme 5 Reagents and conditions: (a) Grubbs I (10 mol%),
ethene, CH2Cl2.
only beginning to show reduced yields when the tether
length increased. We are currently exploring the possibil-
ity of developing this methodology towards a synthesis of
piperidine alkaloids such as the streptazolins.20
Acknowledgment
This work was supported by the EPSRC (AEN).
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References and Notes
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(15) Spectroscopic Data for 5a
(1) (a) Bazan, G. C.; Oskam, J. H.; Cho, H. N.; Park, L. Y.;
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18.
1H NMR (400 MHz, CDCl3, 70 °C): d = 1.35–1.38 (m, 1 H,
CH2CHN), 1.35–1.38 (m, 1 H, CH2CHCHN), 2.12–2.33 (m,
1 H, CH2CHN), 2.12–2.33 (m, 1 H, CH2CHCHN), 2.12–
2.33 (m, 1 H, CHCH2CHN), 2.90–2.94 (m, 1 H, CHCHN),
3.69 (dt, 1 H, CHN, J = 10.5, 6.5 Hz), 4.06 (d, 1 H, CH2Ph,
J = 15.0 Hz), 4.90–5.03 (m, 2 H, CH=CH2), 5.29 (d, 1 H,
CH2Ph, J = 15.0 Hz), 5.71 (ddd, 1 H, CH=CH2, J = 17.0,
13.0, 7.0 Hz), 5.87 (dd, 1 H, HC=CH, J = 10.0, 2.5 Hz), 6.24
(dd, 1 H, HC=CH, J = 10.0, 3.0 Hz), 7.25–7.33 (m, 5 H,
5 × ArH). 13C NMR (100 MHz, CDCl3, 70 °C): d = 36.6
(CHCHN), 38.6 (CH2CHCHN), 39.0 (CH2CHN), 40.1
(CHCH2CHN), 48.5 (CH2Ph), 58.7 (CHN), 114.5
(CH=CH2), 122.0 (HC=CH), 127.8 (1 × ArH), 128.4
(2 × ArH), 129.0 (2 × ArH), 138.0 (1 × Ar), 141.2
(CH=CH2), 143.4 (HC=CH), 162.7 (C=O). IR (thin film):
1610 (C=C), 1667 (C=O), 2955 (sat. C–H) cm–1. MS: m/z
calcd: 254.1546 [MH+]; found: 254.1546.
(5) Blechert, S.; Connon, S. J. Angew. Chem. Int. Ed. 2003, 42,
1900.
Synlett 2007, No. 11, 1663–1666 © Thieme Stuttgart · New York

1666
A. E. Nadany, J. E. Mckendrick
LETTER
(16) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
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(17) Kinoshita, A.; Sakakibara, N.; Mori, M. J. Am. Chem. Soc.
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5.61 (m, 2 H, HC=CH), 5.64 (ddd, 1 H, HC=CH2, J = 17.5,
10.0, 7.5 Hz), 7.30 (app. d, 2 H, ArH, J = 8.5 Hz), 7.70 (app.
d, 2 H, ArH, J = 7.5 Hz). 13C NMR (100 MHz, CDCl3): d =
21.5 (CH3), 32.0 (H2CHCHC=CH), 35.4 (HCHC=CH2),
35.8 (CH2CHN), 39.4 (CH2N), 39.7 (HCHC=CH), 55.6
(CHN), 113.1 (HC=CH2), 120.0 (HC=CH), 127.2
(2 × ArCH), 129.6 (2 × ArCH), 130.8 (HC=CH), 136.8
(1 × ArC), 142.4 (HC=CH2), 143.2 (1 × Ar). IR (thin film):
1162, 1384 (SO2), 2975 (sat. C–H) cm–1. MS: m/z calcd for
303.1290 [M+]; found: 303.1293.
(18) General Procedure for Olefin Metathesis, Synthesis of 8c
A flask was charged with toluenesulfonyl amine 7c (91 mg,
0.3 mmol) and CH2Cl2 (90 mL). Ethene gas was bubbled
through the solution for 20 s. Then, Grubbs I catalyst (25 mg,
0.03 mmol) was added to the reaction. A balloon filled with
ethene gas was placed over the flask and the reaction was
allowed to stir at r.t. overnight. The reaction mixture was
then concentrated and subjected to column chromatography
eluting PE–Et2O (19:1 to 4:1) to furnish 8c as a colourless oil
(89 mg), 99% yield. 1H NMR (400 MHz, CDCl3): d = 1.11
(ddd, 1 H, CH2CHN, J = 13.5, 8.0, 4.0 Hz), 1.33 (dd, 1 H,
H2CHCHC=CH, J = 14.5, 7.5 Hz), 1.66 (dt, 1 H,
(19) Parham, W. E.; Hunter, W. T.; Hanson, R. J. Am. Chem. Soc.
1951, 73, 5068.
(20) (a) Fangzheng, L.; Warshakoon, N. C.; Miller, M. J. J. Org.
Chem. 2004, 69, 8836. (b) Kozikowski, A. P.; Park, P. J.
Am. Chem. Soc. 1985, 107, 1736. (c) Kozikowski, A. P.;
Park, P. J. Org. Chem. 1990, 55, 4668. (d) Flann, C. J.;
Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6115.
(e) Yamada, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc.
1996, 118, 1054. (f) Huang, S.; Comins, D. L. Chem.
Commun. 2000, 569.
H2CHCHC=CH, J = 12.0, 6.5 Hz), 2.13 (td, 1 H, CH2CHN,
J = 16.0, 13.5 Hz), 2.41 (s, 3 H, CH3), 2.41–2.43 (m, 1 H,
HCHC=CH), 2.60–2.65 (br m, 1 H, HCHC=CH2), 3.45–3.50
(m, 1 H, CH2N), 4.06–4.10 (m, 1 H, CH2N), 4.37 (dt, CHN,
1 H, J = 12.0, 7.0 Hz), 4.83–4.94 (m, 2 H, HC=CH2), 5.51–
Synlett 2007, No. 11, 1663–1666 © Thieme Stuttgart · New York

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