Scope of the radical addition-cyclization-elimination reaction of oxime ether towards the synthesis of tricyclic lactam derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.07.114

The synthesis of tricyclic lactam building blocks by the radical addition-cyclization-elimination (RACE) reaction is presented. A range of oxime ethers carrying unsaturated ester part have been tested for the radical reaction. A variety of substituents were incorporated around the aromatic backbones and their effect on the RACE reaction has been examined. In addition, the power of RACE reaction is demonstrated by preparation of a key intermediate for the synthesis of constrained analogue of methoctramine.

Full text of DOI:10.1016/j.tetlet.2008.07.114

Tetrahedron Letters 49 (2008) 5789–5792
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Scope of the radical addition–cyclization–elimination reaction of oxime
ether towards the synthesis of tricyclic lactam derivatives
*
Habibur Rahaman, Atsushi Shirai, Okiko Miyata, Takeaki Naito
Kobe Pharmaceutical University, 4-19-1, Motoyamakita, Higashinada, Kobe 658-8558, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of tricyclic lactam building blocks by the radical addition–cyclization–elimination (RACE)
reaction is presented. A range of oxime ethers carrying unsaturated ester part have been tested for the
radical reaction. A variety of substituents were incorporated around the aromatic backbones and their
effect on the RACE reaction has been examined. In addition, the power of RACE reaction is demonstrated
by preparation of a key intermediate for the synthesis of constrained analogue of methoctramine.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 8 July 2008
Accepted 22 July 2008
Available online 25 July 2008
1. Introduction
stannyl radical mediated synthesis of chromeno [4,3-b] pyrrole
derivatives by radical addition–cyclization–elimination reaction.
Fused pyrrolidine rings are common structural motif of many
natural alkaloids.1 Compounds of the ring type 1 (Fig. 1: X = NH)
are found in naturally occurring martinelline or martinellic acid
alkaloids, and they possess antibacterial activity and act as a bra-
dykinin receptor antagonist.2 On the other hand, naturally occur-
ring chromene or chromane derivatives exhibit remarkable
physiological properties and some pyrrolidine annulated benzopy-
ran compounds are known as selective dopamine D3 receptor
antagonist.3 Over the past few years, most research laboratories
have utilized the [3+2] cycloaddition reactions of azomethine
ylides to construct the substituted pyrrolidine ring system 2.4 Re-
cently, the synthesis of chromeno [4,3-b] pyrroles by intramolecu-
lar 1,3-dipolar cycloaddition reaction under ultrasonic irradiation
has been performed.5 And we also published a few reports on the
pyrroloquinoline compounds 1 produced by utilizing the RACE
reaction.6 However, to the best of our knowledge, there is no report
on the synthesis of substituted pyrrolidine derivatives (like com-
pound 2) by RACE reaction. In this Letter, we wish to report the
Accordingly, we initiated a study on intramolecular radical
reaction of oxime ether carrying an unsaturated ester part. The
requisite substrate 5a for this reaction was prepared via straight-
forward alkylation of compound 4a with ethyl 4-bromocrotonate
in the presence of K2CO3 at room temperature. The product 5a
was isolated in 83% yield along with an isomerized product 6a in
12% yield (Scheme 1). In the literature, a similar kind of base-
catalyzed isomerization–cyclization reaction is reported.7
With a collection of substituted oxime ether 5a in hand, its rad-
ical reaction was next investigated. Thus, the reaction of the oxime
ether substrate 5a connected to the aromatic nucleus bearing an
ethoxycarbonyl group in oxygen tether with Bu3SnH and AIBN in
refluxing benzene furnished the tricylic lactams 7a and 8a along
with a cleaved product 4a (Scheme 2). The yields of the tricyclic
compounds 7a, 8a are higher and reaction time is shorter than
those of our previously reported nitrogen analogues.6b In our
earlier report on the nitrogen congeners, we have obtained the
bicyclic amino ester derivatives along with pyrroloquinoline
NOBn
Br
O
HN
CO2Et
BnONH3Cl, NaOAc
acetone, K2CO3
rt., 12 -14 h
NaOAc, MeOH
16 h, 82%
Fused pyrrolidine ring
OH
OH
4a
CO2Et
3a
X
CO2Et
BnON
NH, Martinelline or Martinellic acid building blocks
1. X =
BnON
2. X = O, Chromene or Chromane derivatives
+
Figure 1.
O
O
6a 12%
5a 83%
* Corresponding author. Tel.: +81 78 441 7554; fax: +81 78 441 7556.
E-mail address: taknaito@kobepharma-u.ac.jp (T. Naito).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.114

5790
H. Rahaman et al. / Tetrahedron Letters 49 (2008) 5789–5792
O
O
NOBn
NOBn
Bu3SnH
AIBN
BnON
HN
O
HN
O
CO2Et
Bu3SnH, AIBN
TrH
12
C6H6
reflux
+
TrO
HO
Sn
NOBn
°
C6H6, reflux (80 C)
11
10
O
27%
5-6 h
7a
8a
30%
32%
33%
5a
NOBn
Sn
H
Tr = triphenylmethyl
Sn = Bu3Sn
BnOH
22%
+
OH
Tr
O
4a
12%
Scheme 2.
10
Scheme 4.
compounds, but interestingly, in our present study no bicyclic
amino ester derivative was found.
Compounds 7a and 8a were characterized from their spectral
analyses8 and the absence of benzyloxy group in the 1H NMR spec-
tra suggests that this group on oxime ether moiety was eliminated
during the transformation process.
According to the proposed mechanism given for RACE reaction
of nitrogen derivatives,6b a plausible reaction pathway for the oxy-
gen heterocycle is depicted in Scheme 3. Tributyl stannyl radical
generated from Bu3SnH and AIBN would add mainly to oxime part
of 5a to give the intermediate radical RA, which upon cyclization
will produce the amino stannane 9 (route a). The more nucleo-
philic amino stannane 9 undergoes intramolecular cyclization to
the ester, transfer of the stannyl group on nitrogen to oxygen
and cleavage of the benzyloxy group to form tricyclic NH–lactams
7a and 8a. We propose two possible pathways for the formation of
phenol 4a: one is via the radical intermediate RA, which upon bond
cleavage between oxygen and carbon will produce compound 4a
and ethyl crotonate. Another possibility is that the stannyl radical
would attack the ester part to generate the unstable intermediate
radical RB which would be readily subjected to bond cleavage
between carbon and oxygen to afford the phenol 4a (route b).
A possible attack of the stannyl radical on the oxime ether
group was firmly established by the reaction of simple oxime ether
10 with Bu3SnH and AIBN, which yielded the compounds 11 and 12
in 33% and 27% yields, respectively. The formation of these com-
pounds explains that the tributyl stannyl radical first attacked
the oxime part of the compound 10 to generate the more stable tri-
phenylmethyl radical, which subsequently produced the triphenyl-
methane 12 and the phenolic compound 11 in moderate yields
(Scheme 4). This reaction could also be an indirect evidence for
the formation of 4a from the intermediate radical RA (in Scheme
3). More detail mechanistic investigation of the RACE reaction on
the oxygen heterocycle is in progress in our laboratory.
In order to investigate the effects of tether atom on the intramo-
lecular RACE reaction, we also attempted the RACE reaction of sul-
fur derivatives 13 and 14,9 which, however, gave only unidentified
products (Fig. 2). Therefore, both oxygen and nitrogen atoms are
found to be better tether than sulfur in our RACE reaction.
Sn
Sn
b
a
Sn
H Sn
O
Sn
BnO N
OEt
BnO
N
BnON
CO2Et
CO2Et
cyclization
addition
route a
O
N
O
RA
O
9
5a
addition
H
Sn
route b
Sn
cyclization
Sn
Sn
O
H
OEt
O
O
BnON
Bn
NOBn
OH
O
O
4a
elimination
Sn
H
RB
BnOH
O
Sn = SnBu3
HN
O
7a and 8a
Scheme 3.

H. Rahaman et al. / Tetrahedron Letters 49 (2008) 5789–5792
5791
reaction. The RACE precursors 5b–g were prepared in good to
excellent yields (see Table 1 for the isolated yields of 5b–g starting
from the compounds 4b–g) according to the procedure described
in Scheme 1. In the RACE reaction, introduction of methyl, tert-bu-
tyl and methoxy group at para position to the aromatic ether pro-
vided almost similar stereoselectivity and comparable yield (Table
1, entries 1, 3 and 5). High yield was obtained with the substrate
bearing an electron-donating group at the four position of the aro-
matic ring (Table 1, entry 2). We were pleased to isolate the chloro-
substituted derivatives 7g and 8g in moderate yields (Table 1,
entry 6).11
BnON
S
CO2Et
BnON
S
CO2Et
O O
14
13
Figure 2.
2. Substituent effect of the aromatic ring of the oxime ether
The examples given in Table 1 demonstrate the power of RACE
reaction in constructing the polycyclic lactam backbones, which
are useful building blocks of many natural and unnatural products.
One of the important applications of our strategy would be the
construction of constrained analogue of methoctramine derivative
16.12
In our previous work, we observed that the substituent of
aromatic ring of the oxime ether plays an important role on the
intermolecular radical addition reaction.10 We then decided to
introduce electron-donating and electron-withdrawing substitu-
ents around the aromatic backbone of the oxime ether to under-
stand their effects on reactivity and selectivity of the RACE
Table 1
Preparation and intramolecular radical addition–cyclization–elimination reaction of 5b–g
O
O
HN
O
HN
O
BnON
NOBn
Br
CO2Et
Bu3SnH, AIBN
CO2Et
+
acetone, K2CO3
rt., 12 - 14 h
C6H6, reflux (80 °C)
O
5b-g
R
R
R
OH
4b-g
R
5-6 h
8b-g
7b-g
Entry
1
5b–g; yield in (%)
7b–g; yield in (%)
8b–g; yield in (%)
O
O
BnON
Me
CO2Et
HN
HN
Me
Me
5b
[81]
8b [25]
7b [28]
O
O
O
O
O
BnON
CO2Et
HN
HN
2
3
8c
[30]
5c
[78]
7c [34]
O
MeO
O
O
MeO
MeO
O
O
BnON
CO2Et
HN
HN
5d
[86]
[29]
7d
8d [26]
O
O
O
O
O
BnON
CO2Et
HN
HN
O
4
5
6
5e
[98]
8e
7e [30]
[28]
O
O
OMe
OMe
OMe
O
O
BnON
O
CO2Et
HN
O
HN
O
MeO
MeO
MeO
5f
[97]
[28]
7f
8f [26]
O
O
BnON
O
CO2Et
HN
HN
5g
[82]
7g
]26]
[24]
8g
Cl
Cl
O
Cl
O

5792
H. Rahaman et al. / Tetrahedron Letters 49 (2008) 5789–5792
H
X
O
Known
synthetic
route
HN
O
H
N
H
H
(CH2)6NH(CH2)8HN(CH2)6
H
N
7a. X = O
BH3-THF
0 °C-reflux
1.5 h
16
O
H
15. X = H2
Scheme 5.
Dubuffet, T.; Muller, O.; Simonef, S. S.; Descomhes, J.-J.; Laubie, M.; Verheuren,
T. J.; Lavielle, G. Bioorg. Med. Chem. Lett. 1996, 6, 349–352.
4. (a) Vedejs, E. In Advances in Cycloaddition; Curran, D. P., Ed.; JAI Press:
Greenwich, CT, 1988; Vol. 1, p 33; (b) Martin, S. F.; Cheavens, T. H. Tetrahedron
Lett. 1989, 30, 7017–7020; (c) Snider, B. B.; O’Hare, S. M. Tetrahedron Lett. 2001,
42, 2455–2458.
5. Ramesh, E.; Raghunathan, R. Tetrahedron Lett. 2008, 49, 1125–1128.
6. (a) Shirai, A.; Miyata, O.; Tohnai, N.; Miyata, M.; Procter, D. J.; Sucunza, D.;
Naito, T. J. Org. Chem. 2008, 73, 4464–4475; (b) Miyata, O.; Shirai, A.; Yoshino,
S.; Nakabayashi, T.; Takeda, Y.; Kiguchi, T.; Fukumoto, D.; Ueda, M.; Naito, T.
Tetrahedron 2007, 63, 10092–10117; (c) Miyata, O.; Shirai, A.; Yoshino, S.;
Takeda, Y.; Sugiura, M.; Naito, T. Synlett 2006, 893–896; (d) Takeda, Y.;
Nakabayashi, T.; Shirai, A.; Fukumoto, D.; Kiguchi, T.; Naito, T. Tetrahedron Lett.
2004, 45, 3481–3483.
Methoctramine is the prototype polyethylene tetraamine for
antagonism of muscarinic acetylcholine receptor (mAChR).13 Com-
pound 16 is a weaker antagonist than its free analogue at both
nAChR and M2 mAChR, but similarly potent at M3 mAChR. Borane
reduction of the lactam 7a produced the viable synthetic interme-
diate 15 in 70% yield.
One can easily prepare the constrained analogue of methoctr-
amine derivative 16 from the compound 15 by known synthetic
way (Scheme 5).12
In conclusion, the scope of the radical addition–cyclization–
elimination has been described. The reaction proceeds with a vari-
ety of substrates including the electron-donating and electron-
withdrawing groups. Keeping moderate yield in mind, this meth-
odology will allow the preparation of highly substituted aromatic
and heteroaromatic subunits that could be well set during the nat-
ural product synthesis. Currently, we are elaborating the reaction
sequences not only for the construction of tricyclic lactams, but
also towards the total synthesis of pyrrolidine fused natural
alkaloids.
7. For similar type of base-catalyzed cyclization reaction see: Ciganek, E. Synthesis
1995, 1311–1314.
8. Typical procedure for the RACE reaction of oxime ether 5a: To a boiling solution of
5a (270 mg, 0.79 mmol) in benzene (20 ml) was added a solution of Bu3SnH
(0.4 ml, 1.5 mmol) and AIBN (30 mg, 0.18 mmol) in benzene (10 ml) by syringe
pump under a N2 atmosphere. After being stirred at reflux for 5 h, the reaction
mixture was extracted with hexane/MeCN. The MeCN phase was concentrated
at reduced pressure and the residue was purified by flash chromatography
(hexane/AcOEt) to afford 7a (32%), 8a (30%), 4a (12%) and benzyl alcohol (22%).
Compound 7a: 1H NMR (CDCl3, 500 MHz) d: 2.19 (1H, dd, J = 17, 3.5 Hz). 2.66
(1H, dd, J = 17, 8.5 Hz), 2.92 (1H, m), 3.86 (1H, dd, J = 11.5, 9 Hz), 4.12 (1H, dd,
J = 11.5, 4.5 Hz), 4.76 (1H, d, J = 6.5 Hz), 6.54 (1H, br s), 6.90 (1H, dd, J = 8.5,
1.5 Hz), 6.97 (1H, td, J = 7.5, 1.5 Hz), 7.20 (2H, m). 13C NMR (CDCl3, 125 MHz) d:
32.8, 33.0, 50.7, 65.7, 117.7, 121.4, 121.8, 129.4, 129.6, 154.8, 176.1; HRMS
(ESI+): m/z calcd for C11H11NO2: 189.0790; found: 189.0789.
Acknowledgements
Compound 8a: 1H NMR (CDCl3, 500 MHz) d: 2.29 (1H, m), 2.54 (2H, m), 4.29
(1H, dd, J = 12, 10 Hz), 4.42 (1H, d, J = 10 Hz), 4.53 (1H, dd, J = 10, 4.5 Hz), 6.85
(1H, d, J = 9 Hz), 6.91 (1H, td, J = 7.5, 1 Hz), 7.01 (1H, br d, J = 7.5 Hz), 7.18 (2H,
m). 13C NMR (CDCl3, 125 MHz) d: 34.5, 40.1, 56.0, 69.1, 116.7, 120.3, 122.9,
123.8, 128.8, 152.5, 178.2; HRMS (ESI+): m/z calcd for C11H11NO2: 189.0790;
found: 189.0780.
We acknowledge the research Grants-in-Aid for Scientific Re-
search (B) (to T.N.) and C (to O.M.) from the Japan Society for the
Promotion of Science (JSPS) and Scientific Research on Priority
Areas (A) (to T.N.) from the Ministry of Education, Culture, Sports
and Technology. H.R. thanks the JSPS for a Research Grant and
Financial Assistance.
9. The sulfur containing compound 13 was prepared from 2-mercapto-
benzaldoxime ether according to the procedure described in Scheme 1. The
two-step yield of the compound 13 was 77% and the m-CPBA oxidation of 13
provided the compound 14 in 68% yield.
10. Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro, C.; Naito, T. Tetrahedron 1998, 54,
11431–11444.
11. 4-Chlorosalicylaldehyde 3g was prepared according to the published
procedure, see; Leonard, K.; Marugan, J. J.; Roboisson, P.; Calvo, R.; Gushue, J.
M.; Koblish, H. K.; Lattanze, J.; Zhao, S.; Cummings, M. D.; Player, M. R.;
Maroney, A. C.; Lu, T. Bioorg. Med. Chem. Lett. 2006, 16, 3463–3468.
12. Rosini, M.; Budriesi, R.; Bixel, M. G.; Bolognesi, M. L.; Chiarini, A.; Hucho, F.;
Krogsgaard-Larsen, P.; Mellor, I. R.; Minarini, A.; Tumiatti, V.; Usherwood, P. N.
R.; Melchiorre, C. J. Med. Chem. 1999, 42, 5212–5223.
References and notes
1. (a) Confalone, P. N.; Huie, E. M. J. Am. Chem. Soc. 1984, 106, 7175–7178; Smith,
L. T.; Livingouse, T. J. Org. Chem. 1983, 48, 1554–1555; Smith, L. T.; Livingouse,
T. Tetrahedron 1985, 41, 3559–3568; (c) Pearson, W. H. In Studies in Natural
Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1988; Vol. 1, p
317.
2. Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard, A. M.; Salvatore, M. J.;
Lumma, W. C.; Anderson, P. S.; Pitzenberger, S. M.; Varga, S. L. J. Am. Chem. Soc.
1995, 117, 6682–6685.
13. Melchiorre, C.; Cassinelli, A.; Quaglia, W. J. Med. Chem. 1987, 30, 201–204.
3. (a) Dubuffet, T.; Newman-Tancerdi, A.; Cussac, D.; Audinot, V.; Loutz, A.;
Millan, M. J.; Lavielle, G. Bioorg. Med. Chem. Lett. 1999, 9, 2059–2064; (b)