A new synthesis of 2,3-Di- or 2,3,3-trisubstituted 2,3-Dihydro-4-pyridones by reaction of 3-ethoxycyclobutanones and N - P -Toluenesulfonyl imines using titanium(IV) chloride: Synthesis of (±)-bremazocine

Article abstract of DOI:10.1021/ol1012313

(Figure Presented) N-p-Toluenesulfonyl (Ts) aldimines reacted with 3-ethoxycyclobutanones by catalysis of titanium(IV) chloride to afford 2,3-di- or 2,3,3-trisubstituted N-Ts-2,3-dihydro-4-pyridones. Synthesis of (±)-bremazocine was efficiently accomplished by using this method.

Full text of DOI:10.1021/ol1012313

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3266-3268
A New Synthesis of 2,3-Di- or
2,3,3-Trisubstituted 2,3-Dihydro-4-
pyridones by Reaction of
3-Ethoxycyclobutanones and
N-p-Toluenesulfonyl Imines Using
Titanium(IV) Chloride: Synthesis of
(()-Bremazocine
Jun-ichi Matsuo,* Ryohei Okado, and Hiroyuki Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health
Sciences, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
jimatsuo@p.kanazawa-u.ac.jp
Received May 28, 2010
ABSTRACT
N-p-Toluenesulfonyl (Ts) aldimines reacted with 3-ethoxycyclobutanones by catalysis of titanium(IV) chloride to afford 2,3-di- or 2,3,3-trisubstituted
N-Ts-2,3-dihydro-4-pyridones. Synthesis of (()-bremazocine was efficiently accomplished by using this method.
2,3-Dihydro-4-pyridones are versatile synthetic intermediates
in organic synthesis.1 2-Monosubstituted dihydropyridones
are usually prepared by N-acylation or N-alkylation of
4-methoxypyridine followed by addition of a Grignard
reagent and subsequent hydrolysis.1 Another alternative
method to these systems, reported by Abramovitch,2 involves
the [4 + 2] cycloaddition between N-Ts-imine and Dan-
ishefsky’s diene.3 By these conventional methods, additional
mono- or dialkylation is required for preparation of 2,3-di-
or 2,3,3-trisubstituted dihydropyridones, which are often
employed in the synthesis of biologically active compounds.4
Therefore, a short synthesis of these multisubstituted dihy-
dropyridones would be valuable for the rapid synthesis of
various piperidine derivatives such as benzomorphans.4
We have recently reported that zwitterionic intermediate
2, which is formed by Lewis acid-catalyzed ring cleavage
of 3-alkoxycyclobutanones 1, reacts with aldehydes or
ketones to afford tri- or tetrasubstituted tetrahydropyrones
or dihydropyrones.5,6 It was thought that zwitterionic inter-
(3) Recently reported methods for synthesis of 2,3-dihydro-4-pyridones:
(a) Donohoe, T. J.; Connolly, M. J.; Walton, L. Org. Lett. 2009, 11, 5562–
5565. (b) Flick, A. C.; Padwa, A. ARKIVOC 2009, 4–14. (c) Harmata, M.;
Lee, D. R. ARKIVOC 2007, 91–103. (d) Svetlik, J.; Kettmann, V.; Zaleska,
B. Tetrahedron Lett. 2005, 46, 5511–5514. (e) Dong, D.; Bi, X.; Liu, Q.;
Comg, F. Chem. Commun. 2005, 3580–3582. (f) Kumar, A. S.; Haritha,
B.; Rao, B. V. Tetrahedron Lett. 2003, 44, 4261–4263.
(1) (a) Comins, D. L. J. Heterocycl. Chem. 1999, 36, 1491–1500. (b)
Joseph, S.; Comins, D. L. Curr. Opin. Drug DiscoVery DeV. 2002, 5, 870–
880. (c) Koulocheri, S. D.; Pitsinos, E. N.; Haroutounian, S. A. Curr. Org.
Chem. 2008, 12, 1454–1467.
(2) (a) Abramovitch, R. A.; Stowers, L. R. Heterocycles 1984, 22, 671–
673. (b) Pe´got, B.; Vo-Thanh, G. Synlett 2005, 1409–1412.
(4) Palmer, D. C.; Strauss, M. J. Chem. ReV. 1977, 77, 1–36.
10.1021/ol1012313  2010 American Chemical Society
Published on Web 06/22/2010

mediate 2 would also react with imines 3 to afford tetrahy-
dropyridones 4 or dihydropyridones 5 (Scheme 1). In this
were perfomed, and the corresponding dihydropyridones
were obtained in 28%, 41%, and 7% yields, respectively.
Next, the scope and limitations of the titanium(IV)
chloride-catalyzed cyclization of cyclobutanone 6 were
investigated using various N-Ts-imines 9 (Table 2). N-Ts-
Scheme 1
.
Synthesis of Dihydropyridones 5 by Reaction of
Cyclobutanone 1 with Imine 3
Table 2. Synthesis of Dihydropyridones 10a-m by the
Reaction between Cyclobutanone 6 and Various N-Ts-imines
9a-ma
entry
R (imine 9)
conditions
10
yieldb (%)
1
2
3
4
5
6
7
8
4-MeOC6H4 (9a) 0 °C, 30 min
10a
10b
10c
10d
10e
10f
10g
10h
10i
40
71
78
77
76
32
31
62
84
64
62
67
trace
4-MeC6H4 (9b)
4-BrC6H4 (9c)
4-ClC6H4 (9d)
4-FC6H4 (9e)
4-NO2C6H4 (9f)
1-Naph (9g)
2-Naph (9h)
PhCHdCH (9i)
PhC’C (9j)
0 °C, 30 min
-45 °C, 1 h
-45 °C, 1 h
-45 °C, 1 h
0 °C, 30 min
0 °C, 30 min
-45 °C, 1 h
-20 °C, 1 h
regard, we now report here a direct method for the synthesis
of multisubstituted dihydropyridones 5 by the reaction of
3-ethoxycyclobutanone 1 with N-Ts imines, and we also
describe herein a synthesis of (()-bremazocine, whose (-)-
enantiomer is a benzomorphan-based κ-opioid agonist.7 For
the latter, this was achieved using a newly developed
synthetic method for dihydropyridones.
9
10
11
12
13
-20 °C, 30 min 10j
First, we explored a suitable Lewis acid for the reaction
of cyclobutanone 6 and N-Ts-benzylideneimine 7 (Table 1).
n-Pr (9k)
c-Hex (9l)
t-Bu (9m)
-20 °C, 1 h
-20 °C, 1 h
-20 °C, 1 h
10k
10l
10m
a For conditions, see Table 1. b Isolated yield.
Table 1. Effects of Lewis Acidsa
imines 9a-h, which were prepared from aromatic aldehydes,
gave the corresponding dihydropyridones 10a-h in good
yields (62-78% yields) except 9a, 9f, and 9g (entries 1-8).
Reaction with conjugated N-Ts-imines such as alkenylimine
9i and alkynylimine 9j also proceeded smoothly to afford
the corresponding cyclization adducts 10i and 10j in 84%
and 64% yields, respectively (entries 9 and 10). Aliphatic
aldimines such as 9k and 9l readily reacted with cyclobu-
tanone 6 following activation with titanium(IV) chloride
(entries 11 and 12). The fact that 1-naphthylimine 9g and
tert-butylimine 9m gave the desired adducts 10g,m in low
yields suggests that the present reaction was strongly
influenced by steric effects (entries 7 and 13). The reaction
between 6 and N-Ts-ketimine derived from acetophenone
gave the desired product only in a trace amount. Therefore,
it was difficult to synthesize 2,2,3,3-tetrasubstituted 2,3-
dihydro-4-pyridones by the present method.
entry
Lewis acid
conditions
yieldb (%)
1
2
3
4
5
6
7
TiCl4
-45 °C, 1 h
-45 °C, 1 h
-45 °C to rt, 1 h
-45 °C to rt, 3.5 h
-45 °C to rt, 4 h
-45 to 0 °C, 2 h
-45 °C, 1 h
80
56
74
41
34
10
41
TiBr4
SnCl4
SnBr4
BF3-OEt2
EtAlCl2
Me3SiOTf
a Imine 7 (1 equiv), cyclobutanone 6 (1.6 equiv), and Lewis acid (1.3
equiv) were employed. b Isolated yield.
It was found that titanium(IV) chloride catalyzed the desired
cyclization most efficiently, with dihydropyridone 8 being
isolated in 80% yield (Table 1, entry 1). Tetrahydropyridone
4 was not obtained under these conditions probably due to
the participation of nitrogen in the elimination of ethanol
from 4 (see Scheme 1). Tin(IV) chloride also gave the desired
cycloadduct 8 in a comparable yield (entry 3). With
ethylaluminum dichloride, ethylation of imine 7 (33%) was
also observed (entry 6).
Reactions between various 3-ethoxycyclobutanones 11a-e
and N-Ts-imine 7 were performed (Table 3). 2,2-Diethyl-
cyclobutanone 11a and spirocyclobutanone 11b bearing a
quaternary carbon center at their 2-position reacted smoothly
at -20 °C to afford the corresponding adducts 12a and 12b
in 74% and 75% yields, respectively (entries 1 and 2).
2-Monoalkyl-substituted cyclobutanones 11c-e also reacted
at -45 °C to afford the corresponding dihydropyridones
12c-e in about 60% yield (entries 3-5).
Titanium(IV) chloride-mediated reactions of cyclobu-
tanone 6 with N-Cbz-, N-Boc-, and N-Bn-benzylideneamines
Org. Lett., Vol. 12, No. 14, 2010
3267

effectively to afford dihydropyridone 14 in 72% yield.
Catalytic hydrogenation of 14 with palladium on carbon gave
ketone 15 in 84% yield. Addition of ethylmagnesium chloride
to ketone 15 gave the desired ethylated product 16b in 23%
yield9 along with reduction products (17a (25%) and 17b
(19%)) and recovered ketone 15 (9%). Ishihara’s method of
using the zinc(II) ate complex (EtMgCl, ZnCl2, and LiCl)10
greatly improved the yield of 16 to 89% (16a (1%) and 16b
(88%)). These products were formed alongside a small
amount of reduction products (17a (3%) and 17b (2%)).11
Deprotection of the N-Ts group of 16b with sodium
naphthalenide afforded 18b in 96% yield. Intramolecular
Grewe-type carbocation cyclization12 of 18b and deprotection
of the methyl ether moiety took place under carefully
optimized reaction conditions using 85% phosphoric acid at
135 °C for 78 h to give benzomorphan 19 in 68% isolated
yield.13 Selective acylation of the secondary amino group
in 19 with carboxylic acid chloride 20 gave the corresponding
amide 21 in 86% yield, and reduction of 21 with aluminum
hydride, which was prepared from lithium aluminum hydride
and sulfuric acid, gave (()-bremazocine (22) in 86% yield.
In summary, we have developed a new method for the
synthesis of dihydropyridones that involves a reaction
between 3-ethoxycyclobutanones and N-Ts-imines under
catalysis by titanium(IV) chloride. This method provides
rapid access to 2,3-di- or 2,3,3-trisubstituted dihydropyri-
dones and is useful for the synthesis of benzomorphans.
Table 3. Reaction of Various 3-Ethoxycylobutanones 11a-e
with N-Ts-imine 7a
entry cyclobutanone (11) R, R′ conditions
12
yield (%)b
1
2
3
4
5
Et, Et (11a)
-20 °C, 1 h 12a 74
-(CH2)5- (11b)
-20 °C, 1 h 12b 75
Me, H (11c) (26:74)c
Et, H (11d) (30:70)c
i-Pr, H (11e) (40:60)c
-45 °C, 1 h 12c 61 (59:41)c
-45 °C, 1 h 12d 57 (63:37)c
-45 °C, 1 h 12e 60 (60:40)c
a For reaction conditions, see Table 1. b Isolated yield. c Cis/trans ratio.
The stereochemistry was determined by 1H NMR spectra (see the Supporting
Information).
The present new method for preparation of dihydropyri-
dones was applied to a synthesis of (()-bremazocine (22)
Scheme 2. Synthesis of (()-Bremazocine (22)
Acknowledgment. This work was supported by SUNBOR
grant and a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan.
Supporting Information Available: Detailed experimen-
tal procedures and full spectroscopic characterization data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL1012313
(5) Matsuo, J.; Sasaki, S.; Tanaka, H.; Ishibashi, H. J. Am. Chem. Soc.
2008, 130, 11600–11601.
(6) Other reactions: (a) Matsuo, J. I.; Sasaki, S.; Hoshikawa, T.; Ishibashi,
H. Org. Lett. 2009, 11, 3822–3825. (b) Matsuo, J.; Negishi, S.; Ishibashi,
H. Tetrahedron Lett. 2009, 50, 5831–5833. (c) Matsuo, J.; Sasaki, S.;
Hoshikawa, T.; Ishibashi, H. Chem. Commun. 2010, 46, 934–936.
(7) Roemer, D.; Buescher, H.; Hill, R. C.; Maurer, R.; Petcher, T. J.;
Welle, H. B. A.; Bakel, H. C. C. K.; Akkerman, A. M. Life Sci. 1980, 27,
971–978.
(8) (a) Greiner, E.; Folk, J. E.; Jacobson, A. E.; Rice, K. C. Bioorg.
Med. Chem. 2004, 12, 233–238. (b) Thomas, J. B.; Brieaddy, L. E.; Boldt,
K. G.; Perretta, C.; Carroll, F. I. Synthesis 2007, 1481–1484.
(9) Compound 16a was not obtained. For details, see the Supporting
Information.
(10) (a) Hatano, M.; Suzuki, S.; Ishihara, K. Synlett 2010, 321–324. (b)
Hatano, M.; Ito, O.; Suzuki, S.; Ishihara, K. Chem. Commun. 2010, 46,
2674–2676.
(11) 1,2-Addition of lithium trimethylsilylacetylide to ketone 15 gave a
1,2-adduct in 84% yield. Deprotection of trimethylsilyl group with potassium
carbonate in methanol followed by hydrogenation of the terminal alkynyl
group with palladium on carbon gave 16 in 84% yield for two steps. For
details, see the Supporting Information.
(12) (a) Grewe, R.; Mondon, A. Chem. Ber. 1948, 81, 279–286. (b)
Takeda, M.; Jacobson, A. E.; Kanematsu, K.; May, E. L. J. Org. Chem.
1969, 34, 4154–4157. (c) Comins, D. L.; Zhang, Y.-m.; Joseph, S. P. Org.
Lett. 1999, 1, 657–659.
(Scheme 2).8 The titanium(IV) chloride-promoted reaction
between cyclobutanone 6 and N-Ts-imine 13 proceeded
(13) The use of hydrobromic acid instead of phosphoric acid gave 18
in lower yields.
3268
Org. Lett., Vol. 12, No. 14, 2010