A New Carbanionic One-Carbon Ring Enlargement-Alkylation of Lactams

Article abstract of DOI:10.1055/s-2003-42045

The lithium-bromine exchange of bicyclic bromo-substituted γ- and δ-lactams has been investigated finding that the lithium intermediates undergo a ring-enlargement reaction eventually leading to the isomeric six- and seven-membered lactams. Interception of the lithium species with electrophiles allows the synthesis of a series of functionalized quinolinones and benzoazepines.

Full text of DOI:10.1055/s-2003-42045

LETTER
2025
A New Carbanionic One-Carbon Ring Enlargement-Alkylation of Lactams
a
b
a
a
a
C
M
arbanionic
O
ne-Carb
i
on Rin
c
m
h
ent-Alkylatio
e
n
of Lactam
l
s
a Valacchi,* Walter Cabri,* Alessandro Mordini, Arnault De Philippis, Gianna Reginato
a
Istituto di Chimica dei Composti OrganoMetallici, Dipartimento di Chimica Organica ‘U. Schiff’, via della Lastruccia 13,
0019 Sesto Fiorentino, Firenze, Italy
5
Fax +39(055)4573580; E-mail: labormet@unifi.it
b
Antibioticos, Research & Development, strada Rivoltana km 6-7, 20090 Rodano, Milano, Italy
Fax +39(02)95321134; E-mail: WCabri@antibioticos.it
Received 3 September 2003
Abstract: The lithium-bromine exchange of bicyclic bromo-substi-
tuted g- and d-lactams has been investigated finding that the lithium
intermediates undergo a ring-enlargement reaction eventually lead-
ing to the isomeric six- and seven-membered lactams. Interception
of the lithium species with electrophiles allows the synthesis of a
series of functionalized quinolinones and benzoazepines.
N
N
O
O
.
5
6
M
Figure 1
Key words: lactams, rearrangement, carbanions, ring-expansion,
quinolines
In the first series of experiments, compound 1 was treated
During our investigations on the use of non-toxic nitrogen with two equivalents tert-butyllithium under various ex-
1
7
ligands in samarium(II)-mediated reactions, we have ob- perimental conditions as shown in Table 1 (Scheme 2).
served an unusual selectivity in the samarium mediated
cyclization of bicyclic bromolactam 1. In particular, we
found that the only 6-membered ring lactam detected in
the samarium(II) promoted ring expansion was 4, in
N
N
N
O
O
O
Li
contrast with the corresponding Bu SnH promoted radical
3
1
6
7
Br
Li
expansion in which a mixture of compounds 2 and 3 is
2
formed (Scheme 1).
This different behaviour can be attributed either to a dif-
ferent course in the rearrangement of radical 5 or to an an-
ionic pathway via the carbanionic species 6 (Figure 1).3
In order to have a clearer picture, we then decided to com-
pare the Sm(II) mediated process with the ring enlarge-
ment of the bromolactam 1, as well as other 5- and 6-
membered lactams, induced by treatment with tert-butyl-
lithium, thus hopefully moving towards an anionic path-
way. Anionic ring-enlargement processes are well
N
OLi
N
O
,4
Li
N
9
8
N
O
O
5
documented indeed even if, under such circumstances,
4
10
the formation of radical species cannot be completely
6
ruled out.
Scheme 2
N
O
N
O
N
N
SmI2
O
O
+
+
Br
1
2
3
4
Scheme 1
SYNLETT 2003, No. 13, pp 2025–2028
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42045; Art ID: G23003ST
Georg Thieme Verlag Stuttgart · New York
©

2
026
M. Valacchi et al.
LETTER
a
Table 1 Reaction of Bromolactam 1 with tert-Butyllithium Fol-
lowed by Quenching with Water
small amounts of the debrominated five-membered lac-
tam 2 together with compound 4, except THF in which no
traces of product 2 are found but some alkylated lactam 10
is isolated (entry 1, 2); its formation may be due either to
Entry T [°C]
Solvent
Conver- Product composition
sion [%]
8
reaction of lithium species 8 with isobutylene (generated
2
3
–
–
–
–
4
10
by the reaction of the excess tert-butyllithium with tert-
butyl bromide) or to single electron transfer from tertiary
benzylic anion 8 to tert-butyl bromide, followed by cou-
1
2
3
4
–45
–18
THF
THF
100
100
–
–
75 25
25
–
66
9
–
–
9
pling of the two radicals. Changing the temperature, the
time or the order of addition of the reagents affects the
results to a negligible extent.
–45 to 0 Pentane
–
–45
Pentane:
MTBE (9:1)
70
–
100
b
Reaction with electrophiles other than water may lead to
two products 11 and 12 deriving from the lithium enolate
5
6
7
8
9
0
–45
–45
–45c
–18
MTBEb
100
95
14
14
27
20
15
11
–
86
86
73
80
85
89
–
9
and the benzyl lithium species 8 (Scheme 3), respective-
ly. In order to check this regioselectivity profile, we sub-
mitted bromolactam 1 to sequential treatment with tert-
butyllithium and an electrophilic reagent. Despite the
nature of the electrophile, compound 11 is always isolated
Et O
2
Et O
100
95
–
–
–
–
–
–
–
–
2
Et O
2
10
as the only product in acceptable yields.
–45
Bu O
80
2
The tert-butyllithium promoted ring-enlargement of bro-
momethyl substituted lactams has strict structural require-
ments. The isomerization to the benzyllithium
intermediate 8 postulated above, implies the presence of a
benzofused aromatic ring and the bromomethyl substitu-
ent bound to the benzylic position in the starting lactams.
Indeed, when we treated bromolactams 13 and 14 with
tert-butyllithium no ring-enlarged product 15 and 16 were
detected and only the reduced lactams 17 and 18 were
recovered almost quantitatively (Scheme 4).
–45c
Ethylald
1
100
a
b
c
d
All experiments have been carried out in two hours unless specified.
MTBE = methyl tert-butyl ether.
Reaction time: 4 h.
Ethylal = formaldehyde diethylacetal.
The composition of the final reaction mixture is quite sim-
ilar to that observed in the samarium(II) promoted rear-
rangement, the only rearranged product being the six- On the other hand we were very pleased to find that the
membered ring 4, although some reduction to 2 also oc- bromolactam 19 {readily obtained from N-[(2-chlorophe-
curs. As shown in Table 1, the reaction is reasonably se- nyl)-methyl-N-methylpropanamide via lithiation with
lective affording the bicyclic lactam 4 as the only LDA and quenching with dibromethane}11 gave a very
rearranged product in ethereal solvents (entry 4–10), clean one-carbon ring expansion to the 7-membered ring
while in pentane (entry 3) only starting material is recov- lactam 20 after treatment with tert-butyllithium and
ered. All ethereal solvents behave similarly, affording quenching with water (Scheme 5).12
N
O
N
O
El-X
El-X
8
Li
N
El
tert-BuLi
O
Br
1
2a–d
THF, –45 °C
N
OLi
N
O
1
El
9
11a–d
a: El-X = D O (58%); b: El-X = CH I (70%);
2
3
c: El-X = CH =CH-CH Br (67%);
2
2
d: El-X = PhCHO (60%)
Scheme 3
Synlett 2003, No. 13, 2025–2028 © Thieme Stuttgart · New York

LETTER
Carbanionic One-Carbon Ring Enlargement-Alkylation of Lactams
2027
O
N
O
N
N
15
N
O
O
16
N
Br
Br
N
O
O
14
13
17
18
Scheme 4
a higher stability of the benzyllithium species 21 com-
pared to the analogue 8.
1
. tert-BuLi
N
N
THF, –45 °C
O
O
In conclusion, this simple and general approach can be re-
garded as a new entry into the synthesis of both the quin-
olinonic and azepinonic structures which are widely
found in many compounds endowed with biologically
2
. H O
2
2
0
1
9
Br
6
0%
Scheme 5
14
relevant properties (some examples: cilostazol, car-
teolol,15 carbostyril, galanthamine, lycoramine, and
16
17
18
1
9
A comparison between lactams 1 and 19 reveals a differ- haemanthidine ).
ent behaviour concerning the ring-enlargement/function-
alization process. Lactam 1 gives only products deriving
from reaction of the lithium enolate when the reaction is
Acknowledgment
Financial support by the Consiglio Nazionale delle Ricerche, Roma,
is much appreciated.
conducted at 0 °C. Interestingly, it has been found howev-
er that when allylbromide is added at –78 °C, only allyl
derivative 12c is formed, though in moderate yield, thus
indicating that the benzyllithium species 8 enolizes to 9 as
the temperature is raised to 0 °C. On the other hand the 6-
membered ring lactam 19 affords exclusively 7-mem-
bered ring lactams 23a–c (Scheme 6) in the investigated
temperature range (–78 °C to r.t.) without any contamina-
tion from the enolate-derived lactam 24, although a de-
crease of the chemical yield is observed at higher
temperatures. This regioselectivity profile may be due to
References
(
1) Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi,
A. Tetrahedron Lett. 1995, 36, 949.
1
3
(
2) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem.
Soc., Chem. Commun. 1980, 482.
(3) Curran, D. P.; Fevig, T. L.; Jasperse, C. P.; Totleben, M. J.
Synlett 1992, 943.
(4) (a) Molander, G. A. Chem. Rev. 1992, 92, 29.
(b) Molander, G. A.; Harris, C. H. Chem. Rev. 1996, 96, 307.
N
O
N
O
El-X
Li
El
N
21
tert-BuLi
23a–c
THF, –45 °C
O
Br
N
N
O
19
El-X
OLi
El
22
24a–c
a: El-X = CH I (74%)
3
b: El-X = CH2=CH-CH2Br (50%)
c: El-X = PhCHO (64%)
Scheme 6
Synlett 2003, No. 13, 2025–2028 © Thieme Stuttgart · New York

2
028
M. Valacchi et al.
LETTER
(
5) (a) Greatrex, B. W.; Taylor, D. K.; Tiekink, E. R. T. Org.
Lett. 2002, 4, 221. (b) Lavoisier-Gallo, T.; Charonnet, E.;
Rodriguez, J. J. Org. Chem. 1998, 63, 900. (c) For reviews
see: Hesse, M. Ring Enlargement in Organic Chemistry;
VCH: Weinheim, 1991. (d) See also: Wovkulich, P. M.
Comprehensive Organic Synthesis, Vol. 1; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, Chap. 3.3.
6) Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352,
CDCl ): d = 170.4, 141.9, 138.3, 128.9, 128.6, 128.5, 128.3,
3
128.0, 127.7, 126.6, 123.6, 115.0, 73.3, 56.6, 33.4, 29.7,
21.2. MS: m/z (%) = 281 (1.5), 175 (5), 160 (100), 146 (4),
132 (6), 117 (6), 91 (7), 77 (17).
(11) (a) Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi,
M. C.; Wolfe, J. F. J. Am. Chem. Soc. 1985, 107, 435.
(b) Kessar, S. V.; Singh, P.; Chawla, R.; Kumar, P. J. Chem.
Soc., Chem. Commun. 1981, 1074.
(12) 2,5-Dimethyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one
(20): The crude mixture was purified by flash
(
(
1.
7) Typical Rearrangement Procedure: Bromolactam 1 (66.0
mg, 0.25 mmol) was dissolved in the solvent (1 mL) under
chromatography (EtOAc–petroleum ether, 10:1) affording
1
N and the solution cooled to –45 °C. t-BuLi (0.29 mL of a
72 mg (60%) of compound 20. H NMR (200 MHz, CDCl ):
2
3
1
.7 M solution in pentane, 0.5 mmol) was then added drop
d = 7.38–7.05 (m, 4 H), 4.47 (AB system, 2 H), 3.39–3.25
wise and the resulting clear orange solution stirred at the
above temperature for 2 h. After this period, the electrophile
was added and the reaction allowed warming to r.t. (about 30
min). The organic layer was washed twice with NaCl sat.
(m, 1 H), 3.11 (m, 1 H), 3.05 (s, 3H), 2.72 (m, 1 H), 1.37 (d,
1
3
3 H, J = 7 Hz). C NMR (50.3 MHz, CDCl ): d = 172.4,
3
142.8, 133.6, 130.3, 130.2, 128.6, 128.1, 125.8, 54.6, 41.0,
33.5, 29.7, 24.5. MS: m/z (%) = 243 (2.5), 189 (100), 174
(87), 159 (74), 129 (100).
solution, the water phase extracted with Et O and the
2
combined organic layers dried over Na SO .
(13) 2,5,5-Trimethyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-
one (23a): The crude mixture was purified by flash column
chromatography (CH Cl –MeOH, 98:2) affording 72 mg
2
4
2
0
1,4-Dimethyl-3,4-dihydro-2-quinolinone (4): The crude
mixture was purified by flash chromatography (EtOAc–
2
2
1
petroleum ether, 1:1) affording 104 mg (62%) of a colourless
(74%) of compound 23a. H NMR (200 MHz, CDCl ): d =
3
1
oil. H NMR (200 MHz, CDCl ): d = 7.26–6.97 (m, 4 H),
7.45–7.41 (m, 1 H), 7.33–7.24 (m, 1 H), 7.15–6.99 (m, 2 H),
3
1
3
3
.37 (s, 3 H), 3.05 (m, 1 H), 2.73 (dd, 1 H, J = 15.8, 5.6 Hz),
4.47 (s, 2 H), 3.03 (s, 3 H), 2.87 (s, 2 H), 1.40 (s, 6 H). C
1
3
2.44 (dd, 1 H, J = 15.8, 7.6 Hz), 1.27 (d, 3 H, J = 7.0 Hz). C
NMR (50.3 MHz, CDCl ): d = 172.5, 146.6, 133.3, 129.6,
3
NMR (50.3 MHz, CDCl ): d = 169.8, 139.8, 131.0, 127.3,
129.5, 128.6, 126.1, 55.9, 48.4, 34.8, 33.3, 28.5, 28.4. MS:
m/z (%) = 203 (44), 188 (14), 174 (8), 145 (87).
3
126.15, 123.0, 114.7, 39.1, 30.3, 29.4, 19.2. MS: m/z (%) =
1
75 (63), 160 (80), 132 (100), 117 (35), 91 (20), 77 (18).
2,5-Dimethyl-5(prop-3-enyl)-1,2,4,5-tetrahydro-
benzo[c]azepin-3-one (23b): The crude mixture was
purified by flash chromatography (CH Cl –MeOH, 98:2)
(
(
8) Krief, A.; Barbeaux, P. Synlett 1990, 511.
9) Kulkarni, V.; Cohen, T. Tetrahedron 1997, 53, 12089.
10) 1,4-Dimethyl-3-d-3,4-dihydro-2-quinolinone (11a): The
2
2
1
(
affording 54 mg (50%) of compound 23b. H NMR (200
crude mixture was purified by flash chromatography
MHz, CDCl ): d = 7.44–7.30 (m, 2 H), 7.16–7.00 (m, 2 H),
3
(
Et O:petroleum ether, 2:3) affording 28 mg (58%) of
5.62–5.44 (m, 1 H), 5.02 (bd, 1 H, J = 17.2 Hz), 5.00 (bd, 1
H, J = 10.6 Hz), 4.86 (d, 1 H, J = 16.2 Hz), 3.98 (d, 1 H,
J = 16.2 Hz), 3.34 (d, 1 H, J = 13.6 Hz), 3.01 (s, 3 H), 2.68
(ddt, 1 H, J = 14.0, 5.8, 1.4 Hz), 2.37 (d, 1 H, J = 13.6 Hz),
2
1
compound 11a. H NMR (200 MHz, CDCl ): d = 7.30–6.99
(
3
m, 4 H), 3.37 (s, 3 H), 3.09–3.00 (m, 1 H), 2.43 (dq, 1 H,
J = 7.2, 3.9 Hz), 1.19 (d, 3 H, J = 7.2 Hz). MS: m/z (%) =
1
3
1
76 (60), 161 (85), 133 (100), 91 (25), 77 (20).
2.26 (dd, 1 H, J = 14.0, 8.8 Hz), 1.40 (s, 3 H). C NMR (50.3
2
1
1,3,4-Trimethyl-3,4-dihydro-2-quinolinone (11b):
MHz, CDCl ): d = 172.6, 144.9, 138.1, 134.4, 134.3, 129.5,
3
The crude mixture was purified by flash chromatography
EtOAc–petroleum ether, 1:3) affording 46 mg (70%) of
128.7, 126.1, 118.6, 55.8, 50.2, 45.2, 40.0, 34.6, 31.5. MS:
m/z (%) = 229 (1), 201 (3), 188 (7), 146 (100).
(
1
compound 11b. H NMR (200 MHz, CDCl ): d = 7.28–6.82
(
(
3
1
2
2,5-Dimethyl-5(hydroxyphenylmethyl)-1,2,4,5-
tetrahydro-benzo[c]azepin-3-one (23c): The crude
mixture was purified by flash chromatography (CH Cl –
3
m, 4 H), 3.36 (s, 3 H), 2.71 (dq, 1 H, J = 7.4, 4.0 Hz), 2.54
dq, 1 H, J = 7.2, 4.0 Hz), 1.22 (d, 3 H, J = 7.0 Hz), 1.11 (d,
H, J = 7.0 Hz). C NMR (50.3 MHz, CDCl ): d = 172.9,
38.7, 129.8, 127.8, 127.3, 123.1, 114.5, 42.8, 37.8, 29.5,
2
2
1
3
1
MeOH, 98:2) affording 88 mg (64%) of compound 23c. H
3
NMR (200 MHz, CDCl ): d = 7.47 (dd, 1 H, J = 8.0, 1.2 Hz),
3
0.0, 16.0. MS: m/z (%) = 189 (59), 174 (77), 160 (80), 146
7.36–7.24 (m, 6 H), 7.21–7.05 (m, 2 H), 4.91 (d, 1 H,
J = 16.2 Hz), 4.90 (bs, 1 H), 3.96 (d, 1 H, J = 16.2 Hz), 3.59
(d, 1 H, J = 13.6 Hz), 2.98 (s, 3 H), 2.37 (bs, 1 H), 2.22 (d, 1
(100), 130 (60), 117 (48), 91 (36), 77 (50).
1,4-Dimethyl-3(1-propen-2yl)-3,4-dihydro-2-
1
3
quinolinone (11c): The crude mixture was purified by flash
H, J = 13.6 Hz), 1.34 (d, 3 H, J = 7 Hz). C NMR (50.3
chromatography (Et O–petroleum ether, 2:3) affording 36
MHz, CDCl ): d = 172.8, 143.2, 139.7, 135.9, 130.0, 129.9,
2
3
1
mg (67%) of compound 11c. H NMR (200 MHz, CDCl ):
129.7, 128.8, 128.5, 128.1, 128.0, 126.7, 126.6 83.0, 56.0,
45.8, 40.9, 34.5, 27.8. MS: m/z (%) = 189 (80), 174 (100),
160 (17), 146 (48), 115 (41).
3
d = 7.28–6.99 (m, 4 H), 5.80–5.64 (m, 1 H), 5.00 (bd, 1 H,
J = 10.2 Hz), 4.92 (bd, 1 H, J = 16.8 Hz), 3.37 (s, 3 H), 2.91–
2
1
.81 (m, 1 H), 2.60–2.53 (m, 1 H), 2.30–2.18 (m, 1 H), 2.09–
(14) Desos, P.; Schlewer, G.; Lugnier, C.; Beretz, A.; Maffrand,
J. P.; Bernat, A.; Wermuth, C. G. Eur. J. Med. Chem. 1991,
26, 189.
(15) Olesen, H.; Cowan, D.; Bruunshuus, I.; Klempel, K.; Hill, G.
Pure Appl. Chem. 1997, 69, 1081.
(16) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218.
(17) Chaplin, D. A.; Johnson, N. B.; Paul, J. M.; Potter, G. A.
Tetrahedron Lett. 1998, 39, 6777.
.96 (m, 1 H), 1.18 (d, 3 H, J = 7.4 Hz). 13C NMR (50.3
MHz, CDCl ): d = 171.6, 138.6, 135.1, 129.2, 128.0, 127.6,
3
123.2, 117.3, 114.6, 48.1, 34.9, 34.5, 29.4, 20.6. MS: m/z
(
(
%) = 215 (65), 200 (68), 173 (82), 159 (53), 130 (73), 117
37), 91 (41), 77 (50), 41 (100).
1,4-Dimethyl-(1-phenylmethanol)-3,4-dihydro-2-
quinolinone (11d): The crude mixture was purified by flash
chromatography (EtOAc–petroleum ether, 1:1) affording 54
(18) Lee, T. B. K.; Goehring, K. E.; Ma, Z. J. Org. Chem. 1998,
63, 4535.
1
mg (60%) of compound 11d. H NMR (200 MHz, CDCl ):
3
d = 7.40–7.18 (m, 5 H), 7.16–7.03 (m, 4 H), 4.38 (dd, 1 H,
J = 10.2 Hz, J = 2.6 Hz), 3.46 (s, 3 H), 2.95 (d, 1 H, J = 2.6
Hz), 2.77 (dd, 1 H, J = 10.2 Hz, J = 1.4 Hz), 2.46–2.42 (m,
(19) Nishimata, T.; Mori, M. J. Org. Chem. 1998, 63, 7586.
(20) Sato, T.; Ishida, S.; Ishibashi, H.; Ikeda, M. J. Chem. Soc.,
Perkin Trans. 1 1991, 353.
1
3
1
H), 1.08 (d, 3 H, J = 7.0 Hz). C NMR (50.3 MHz,
(21) Clark, A. J.; Jones, K. Tetrahedron 1992, 33, 6875.
Synlett 2003, No. 13, 2025–2028 © Thieme Stuttgart · New York