1,3,4,5-Tetrahydroazepin-2-ones by dearomatising anionic cyclisation of N-allyl-1-naphthamides

Article abstract of DOI:10.1055/s-1999-2977

On treatment with t-BuLi and DMPU, 1-naphthamides bearing N-allyl or N- prenyl substituents cyclise to give a mixture of products from which seven- membered lactams can be isolated in up to 73% yield - the first example of an organolithium-C=C cyclisation leading to a seven-membered ring.

Full text of DOI:10.1055/s-1999-2977

1
954
LETTER
1
,3,4,5-Tetrahydroazepin-2-ones by Dearomatising Anionic Cyclisation of
N-Allyl-1-Naphthamides
a
a
b
Anjum Ahmed, Jonathan Clayden,* Michael Rowley
aDepartment of Chemistry, University of Manchester, Oxford Rd., Manchester M13 9PL, U.K.
bMerck Sharp and Dohme Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, U.K.
E-mail: j.p.clayden@man.ac.uk
Received 22 September 1999
Abstract: On treatment with t-BuLi and DMPU, 1-naphthamides
bearing N-allyl or N-prenyl substituents cyclise to give a mixture of
products from which seven-membered lactams can be isolated in up
to 73% yield – the first example of an organolithium–C=C cyclisa-
tion leading to a seven-membered ring.
O
Cl
O
NH
O
N
R1
(i)
R2
(
ii) then
(iii), (iv)
or (v)
Key words: amide, cyclization, lithium, azepin, dearomatisation
1
2
3
4
5 (R , R = Me)
1
2
6
7
(R , R = H)
1
2
(R = Ph; R = H)
We recently described a cyclisation reaction of N-benzyl
1
2
Synthesis of the starting materials; (i) t-BuNH , NaOH, CH Cl
2 2 2
naphthamides 1 and N-benzyl benzamides which is trig-
gered by deprotonation with strong base (t-BuLi) in the
presence of an additive such as HMPA or DMPU, and
which leads to loss of aromaticity in one ring (Scheme 1).
The products of the cyclisation 2 contain a substituted
pyrrolidinone ring, formed with high stereoselectivity, but
invariably bearing a phenyl group in the 2-position. In an
attempt to broaden the scope of this new reaction, we sur-
veyed some other nitrogen substituents with moderate an-
(
(
98%); (ii) NaH, DMF; (iii) prenyl bromide (46%); (iv) allyl bromide
94%); (v) cinnamyl bromide (68%)
Scheme 2
O
N
R
O
N
R
3
(i)
(ii)
ion stabilising ability, and found that allylic N-
5 or 6
Li
R
R
substituents also allowed the cyclisation to take place.
(
iii) or
8
9
(iv)
O
N
Li
O
O
N
Ph
i), (ii), (iii)
N
R
R
H
Ph
(
10
H
LiO
R
N
N
LiO
1
2
R
R
R
A dearomatising anionic cyclisation; (i) t-BuLi, –78 °C, THF, 2 h; (ii)
H
H
DMPU or HMPA (6 equiv.), –78 °C, 16 h; (iii) NH Cl (82%)
4
12
Scheme 1
11
(v)
(v)
We made N-t-butyl-N-prenyl-1-naphthamide 5 by N-alky-
lation of N-t-butyl-1-naphthamide 4 (Scheme 2). The
amide was treated with t-BuLi at –78 °C for 2 h and the
resulting organolithium 8 quenched with MeI. Only the 2-
methyl product 9 was formed, suggesting that the organo-
lithium is principally an ortholithiated and not an a-lithi-
ated species. Prenyl must be a less powerful anion-
stabiliser than phenyl, since lithiated N-benzyl naphtha-
mides react with MeI to give only the a-methylated prod-
N
O
R
O
H
N
H
R
R
R
H
H
13a (R = Me) 22%
3b (R = H) 73%
14a (R = Me) 18%
14b (R = H) 17%
1
Cyclisation of N-allyl-1-naphthamides; (i) t-BuLi, THF, –78 °C, 2 h;
1
2
(
ii) MeI (91%, R = R = Me); (iii) DMPU (6 equiv.), –50 °C, 16 h;
1
,4
(iv) HMPA (6 equiv.), –78 °C, 16 h; (v) NH Cl
4
uct.
Scheme 3
Synlett 1999, No. 12, 1954–1956 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
7-Membered Rings by Dearomatising Anionic Cyclisation
1955
In the N-benzyl series, we had found that DMPU or
HMPA promotes the cyclisation by favouring an anion
4
N
O
translocation from the ortho to the a position. In the pres-
ence of DMPU at –50 °C for 16 h, the ortholithiated N-
prenyl amide 8 must also undergo anion translocation to
O
N
O
E
N
E
(
i), (ii),
then
H
H
1
0, because protonation returned a moderate yield of dear-
(
iii), (iv),
omatised cyclised products 13a and 14a, presumably via
the enolates 11 and 12. Remarkably, the major product 13
is a tetrahydroazepinone formed by attack at the g position
6
(v) or (vi)
15a (E = Me)
15b (E = Et)
16a (E = Me)
16b (E = Et)
16c (E = Bn)
15c (E = Bn)
15d (E = PhCHOH) 16d (E = PhCHOH)
5
,6
of the lithiated prenyl group. Seven-membered rings are
typically slow to form by cyclisation reactions, and to our
knowledge had never been made previously by an organo- Cyclisation–alkylation of 6; (i) t-BuLi, THF, –78 °C, 2 h; (ii) DMPU
7
(6 equiv.), –50 °C, 16 h; (iii) MeI; (iv) EtI; (v) BnBr; (vi) PhCHO
lithium cyclisation onto a C=C double bond. In this case,
6
the probable Z-geometry of the intermediate 10 will Scheme 4
favour 7-ring formation.
8
In view of the structural similarity between these rare cy-
clic N-acyl enamines and the pharmaceutically important
9
,10
benzazepin-2-ones,
we aimed to optimise the forma-
tion of the seven- over the five-membered ring product.
Removing the geminal methyl groups of the prenyl sub-
stituent improved the yield of the reaction and increased
the selectivity for seven-membered ring formation. Ally-
lation of N-t-butyl-1-naphthamide gave the starting mate-
rial 6, which was lithiated with t-BuLi and cyclised in the
presence of DMPU or HMPA at –50 °C or at –78 °C. Pro-
tonation gave the seven-membered ring product 13b in
The C=C double bonds of 13b could be reacted selective-
ly under hydrogenation or hydrolysis conditions. Hydro-
gen over palladium on carbon reduced the styrene double
bond of 13b to give a quantitative yield of 17. Hydrolysis
of 13b’s N-acyl enamine group with aqueous HCl in THF
gave the aldehyde 18 in 76% yield (Scheme 5), in which
the trans stereochemistry presumably arises by epimerisa-
7
3% isolated yield,11 along with only 17% of the five-
membered ring product 14b. The structure and stere-
ochemistry of the product was confirmed by an X-ray
crystal structure, shown in the Figure.
1
2
tion of a first-formed cis isomer. The cyclisation/hydrol-
ysis sequence represents in this case a formal addition of
13
the homoenolate of propionaldehyde to the naphthalene
ring.
In a final attempt to increase still further the selectivity of
the reaction for seven-membered ring formation we tried
cyclising the N-cinnamyl compound 7. This time, after
treatment with t-BuLi and DMPU (–50 °C, 16 h) no cycli-
sation product was observed: instead, we obtained a quan-
titative yield of the unstable imine 19, which hydrolysed
during purification to give the aldehyde 20 in 46% yield.
14
The imine is formed by an NÆC acyl transfer: the orga-
nolithium attacks the amide carbonyl group instead of the
aromatic ring.
X-ray crystal structure of 13b
Figure
N
O
NH
O
H
(i)
(ii)
13a
CHO
The initial products of the cyclisation, lactam enolates 11
and 12, could be alkylated to give more highly substituted
seven-membered ring products, as shown in Scheme 4
and the Table. Five-membered rings were still among the
by-products of the reaction, but single diastereoisomers
were formed in each case, even with benzaldehyde, which
gave a single aldol product 15d of unknown stereochem-
istry at the hydroxyl-bearing centre.
H
17
18
Transformations of the seven-membered lactam;(i) H (1 atm.), Pd/C,
6 h (quant.); (ii) HCl, H O, THF (76%)
2
1
2
Scheme 5
Synlett 1999, No. 12, 1954–1956 ISSN 0936-5214 © Thieme Stuttgart · New York

1
956
A. Ahmed et al.
LETTER
(
9) Ishibashi, H.; Harada, S.; Okada, M.; Somekawa, M.; Kido,
Ph
Ph
M.; Ikeda, M. Chem. Pharm. Bull. 1989, 37, 939.
O
O
CHO
N
(10) Kasparek, S. in Adv. Heterocyclic Chem.; Katritzky, A. R.;
Boulton, A. J. Eds.; Academic Press: New York, 1974; Vol.
17; p. 45.
(i), (ii), (iii)
(iv)
7
(
11) t-BuLi (2.60ml of a 1.5M solution in pentane, 1.3 equiv.) was
added dropwise to a stirred solution of 6 (0.802 g, 3.0 mmol)
in THF (50 ml) under nitrogen at –78°C. After 2hrs DMPU
(2.18mL, 6 equiv.) was added and the reaction mixture was
warmed to -50°C and stirred at this temperature overnight.
Saturated ammonium chloride solution was then added and
the mixture was allowed to warm to room temperature. Water
19
20
Attempted cyclisation of N-cinnamyl-1-naphthamide 7; (i) t-BuLi,
THF, –78 °C, 2 h; (ii) DMPU (6 equiv.), –50 °C, 16 h; (iii) NH Cl
4
(
quant.); (iv) SiO chromatography (46%)
2
Scheme 6
(
100ml) was added and the organic phase was extracted with
ether (3 x 100ml), washed with water (3 x 100ml) and brine
2 x 100ml), dried (MgSO ) and concentrated under reduced
(
4
Acknowledgement
pressure. Flash chromatography [7:1 petrolum ether (b.p. 40-
6
0 °C)–ethyl acetate] gave the 1,3,4,5-tetrahydroazepin-2-one
We are grateful to the EPSRC for a CASE award (to AA).
13b (0.582g, 73%) as a white solid, m.p. 131-132 °C;
–
1
νmax (CH Cl )/cm 3054, 3019, 2973, 2855, 1662 and 1399;
2
2
References and Notes
δ
H
(300 MHz; CDCl
and 2.5), 6.16 (1H, dd, J=7.5 and 1.5), 5.77 (1H, q, J=7.5),
.54 (1H, dd, J=9.5 and 2.5), 3.92 (1H, d, J=9.5), 3.26 (1H,
q×m, J=9.5), 2.18 (2H, m, CH ) and 1.33 (9H, s, t-Bu); δC
3
) 7.16-6.82 (4H, m), 6.36 (1H, dd, J=9.5
(
(
(
1) Ahmed, A.; Clayden, J.; Rowley, M. J. Chem. Soc., Chem.
Commun. 1998, 297.
2) Ahmed, A.; Clayden, J.; Yasin, S. A. J. Chem. Soc., Chem.
5
2
(
CDCl ) 173.9, 134.6, 133.5, 130.8, 129.6, 128.2, 127.6,
3
Commun. 1999, 231.
1
27.5, 127.4, 126.3, 121.2, 58.2, 48.1, 45.0, 28.4 and 28.3
3) The N-substituent needs to stabilise the a-lithiated species
sufficiently for it to form, but not so much that it is too stable
to react.
+
(
CH ); m/z CI 268 (100%, M+H ) EI 267 (20%, M), 128
2
+
(
75%) and 57 (100%, t-Bu). (Found M 267.1623. C H NO
18
21
requires M 267.1623).
(
4) Ahmed, A.; Clayden, J.; Rowley, M. Tetrahedron Lett. 1998,
(
12) The trans stereochemistry of 18 was confirmed by a strong
39, 6103.
NOE between CHCONHt-Bu and CH CHO. We assume that
1
13) Hoppe, D. Angew. Chem. Int. Ed. Engl. 1984, 23, 932;
Stowell, J. C. Chem. Rev. 1984, 84, 409.
14) For a recent stereoselective example of this type of reaction,
see Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998, 39,
2
(
(
(
5) Biellman, J.; Ducep, J. Org. Reac. 1982, 27, 1.
6) Beak, P.; Lee, B. J. Org. Chem. 1989, 54, 458.
5a-d have a cis ring junction by analogy with 13b.
(
7) However, see Parham, W. E.; Jones, L. D.; Sayed, Y. A. J.
Org. Chem. 1976, 41, 1184; Durst, T.; van der Elzen, R.;
LeBelle, M. J. J. Am. Chem. Soc. 1972, 94, 9261; Crandall, J.
K.; Ayers, T. A. J. Org. Chem. 1992, 57, 2993 and Arany, A.;
Groundwater, P. W.; Nyerges, M. Tetrahedron Lett. 1998, 39,
(
5
537.
3
267.
8) For a previous synthesis of a similar 1,3,4,5-tetrahydroazepin-
-one, see ref. 9
(
Article Identifier:
437-2096,E;1999,0,12,1954,1956,ftx,en;L14499ST.pdf
2
1
Synlett 1999, No. 12, 1954–1956 ISSN 0936-5214 © Thieme Stuttgart · New York