A new mild radical route to 3-substituted maleimides using organoboroles

Article abstract of DOI:10.1016/j.tetlet.2011.12.012

A new, mild, radical route for the synthesis of 3-substituted maleimides has been developed. This new method incorporates alkene hydroboration, conjugate addition-aminoxylation and TEMPO-H elimination in a one-pot procedure, using cheap, readily available

Full text of DOI:10.1016/j.tetlet.2011.12.012

Tetrahedron Letters 53 (2012) 822–824
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Tetrahedron Letters
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A new mild radical route to 3-substituted maleimides using organoboroles
Peter Birch a, Andrew F. Parsons a, , Paul Cross b
⇑
a Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
b Cytec Engineered Materials, The Wilton Centre, Redcar TS10 4RF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, mild, radical route for the synthesis of 3-substituted maleimides has been developed. This new
method incorporates alkene hydroboration, conjugate addition-aminoxylation and TEMPO-H elimination
in a one-pot procedure, using cheap, readily available starting materials. A variety of 3-substituted malei-
mides have been prepared in good to excellent yield.
Received 4 November 2011
Revised 18 November 2011
Accepted 2 December 2011
Available online 8 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Radical
Maleimide
Organoborole
Addition
Elimination
Radical reactions are an important tool in organic synthesis, with
many applications in the synthesis of complex natural products.1–5
Despite the wide variety of efficient radical reactions, their wide-
spread industrial use in preparing small-molecules is thwarted be-
pling of a chlorinated maleimide, which itself can be obtained
through a chlorinated maleic anhydride precursor.16 However,
the harsh acidic conditions required for the maleic anhydride to
maleimide conversion limit the scope of this route. Alternatively,
in 1987, Barton and co-workers developed a radical approach to
the installation of an alkyl substituent directly onto a maleimide
C@C bond, which involves a variation of the Barton decarboxyl-
ation, however the experimental procedure can be quite time-con-
suming, with multiple purification steps required.17 Consequently,
there is a need to produce a new streamlined route for the synthe-
sis of 3-substituted maleimides, where a quick, flexible, clean and
efficient procedure would be highly desirable.
Initial studies towards the synthesis of substituted maleimides
involved the use of commercially available organoborole reagent
PBD (3), with respect to forming an alkoxyamine 4, which could
subsequently undergo elimination of the nitroxide to form the
substituted maleimide product in an efficient one-pot procedure.
We envisaged that the reaction of PBD (3) with the persistent
cause the traditional initiation–mediation pathway uses
a
combination of unstable and highly toxic reagents, typically azo
compounds and tributyltin hydride. Hence, the need for new and
cleaner methods of radical generation. Triethylborane,6–8 has
emerged as a non-toxic source of ethyl radicals, however the pyro-
phoricity and short shelf life of this reagent have limited its exten-
sive use. More recently, the commercially available organoborole,
2-propyl-1,3,2-benzadioxaborole PBD (3), has been shown to be a
more stable source of alkyl radicals than triethylborane, with appli-
cations in a number of synthetic procedures including dehalogen-
ation, ring cyclisation, and polymerisation.9 In related work,
Renaud and co-workers have shown that organoborole reagents
can be prepared, in situ, by the hydroboration of alkenes and subse-
quently used successfully as a source of alkyl radicals for a variety of
transformations.10
Maleimides are an important class of nitrogen heterocycle, find-
ing applications within polymer chemistry,11–13 and in the synthe-
sis of natural products and their analogues. For example, natural
products such as D-(+)-showdomycin (1), and farinomalein (2),
contain a maleimide ring substituted at the 3-position (Fig. 1). Both
1 and 2 have shown promising antibiotic behaviour.14,15
OH
OH
HO
O
O
O
O
N
Several methods are available for the synthesis of alkyl and dial-
kyl substituted maleimides, often involving an organometallic cou-
O
O
N
H
HO
1
2
⇑
Corresponding author. Tel.: +44 1904 322608; fax: +44 1904 322516.
E-mail address: andy.parsons@york.ac.uk (A.F. Parsons).
Figure 1. D-(+)-Showdomycin (1) and farinomalein (2).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.012

P. Birch et al. / Tetrahedron Letters 53 (2012) 822–824
823
N-Phenyl-
maleimide (5 eq.),
DMPU (1 eq.),
O N
O
O
TEMPO (2.2 eq.)
B
O N
O
O
N
CH2Cl2, r.t.,
N2, 16 h
Ph
3
4, 0%
5, 24%
Scheme 1. Initial studies using commercially available PBD (3).
Table 1
Preparation of 3-substituted maleimides 8a–i using the route outlined in Scheme 2
Alkene 6a–g
Maleimide (N-R1)
Conditions (Final Step)
Yield 8a–i (%)
Yield 9a–g (%)
Cyclohexene, (a)
Cyclohexene, (a)
Cyclohexene, (a)
Cyclopentene, (b)
Cyclooctene, (c)
4-Methyl-cyclohexene, (d)
1-Methyl-cyclohexene, (e)
1-Octene, (f)
N-phenyl
N-phenyl
N-phenyl
N-phenyl
N-phenyl
N-phenyl
N-phenyl
N-phenyl
N-phenyl
N-ethyl
PhMe, reflux, 2 h
PhMe, reflux, 2 ha
CHCl3, 60 °C, 48 hb
PhMe, reflux, 2 h
PhMe, reflux, 2 h
PhMe, reflux, 2 h
PhMe, reflux, 2 h
PhMe, reflux, 2 h
PhMe, reflux, 2 h
PhMe, reflux, 2 h
PhMe, reflux, 2 h
91
52
85
63
63
62c
68d
35
32e
72
87
2
—
—
22
—
—
—
26
35
—
—
Allylbenzene, (g)
Cyclohexene, (a)
Cyclopentene, (b)
N-ethyl
a
b
c
Toluene, 40 °C, 3 h (for hydroboration).
CHCl3, 60 °C, 3 h (for hydroboration).
2 (d.r. 1:1) mixture of regioisomers.
d.r. 5:1.
d
e
9:1 mixture of regioisomers.
nitroxide radical 2,2,6,6-tetramethylpiperidine (TEMPO) would re-
lease an alkyl radical able to undergo conjugate addition onto the
maleimide C@C, where subsequent trapping by a second TEMPO
radical would form the desired alkoxyamine 4 (Scheme 1).
However, the expected conjugate addition product 4 was not
observed. The recovery of a small quantity of alkoxyamine 5 sug-
gests that the alkyl radical released through reaction of the organ-
oborole with TEMPO has been directly trapped by a further TEMPO
molecule, without undergoing conjugate addition to the maleimide
C@C bond. Also, the low yield of 5 suggests that PBD (3) has low
reactivity towards TEMPO under these conditions. In order to im-
prove the reactivity of the organoborole component, it was thought
that an alternative, more reactive organoborole species, with a
weaker C–B bond, could be formed in situ, immediately prior to
the radical cascade sequence.
mild reaction conditions and non-toxic reagents. The method starts
with the hydroboration of an alkene 6a–g under Fu’s conditions,18
to form an alkylated organoborole intermediate (Table 1, Scheme
2). Addition of TEMPO to the organoborole results in the release
of an alkyl radical,19 which can undergo conjugate addition to
the maleimide C@C bond. Alkoxyamines 7a–i are formed when an-
other equivalent of TEMPO traps the resulting radical at the 4-po-
sition of the maleimide. Subsequent heating of the reaction
mixture results in the elimination of TEMPO-H to reform the
maleimide C@C bond. The alkylated maleimide products 8a–i can
be isolated, after
chromatography.
a simple aqueous work-up, using flash
Using cheap, readily available alkenes and maleimide sub-
strates, a number of alkylated maleimides have been prepared in
good to excellent yield as shown in Table 1.20
Our new protocol for the synthesis of 3-alkyl-substituted malei-
mides involves a three-step, one-pot procedure combining both
The formation of alkylated maleimides using N-phenylmaleim-
ide or N-ethylmaleimide is efficient when cyclic alkenes are used
1. EtOH (1.2 eq.),
2. N-R1 maleimide (5 eq.),
R = alkyl
DMPU (1 eq.),
DMA (10 mol%),
Catecholborane (2 eq.)
O
O
TEMPO (2.2 eq.)
Alkene
R
B
6a-g
CH2Cl2, 40 °C, N2 , 3 h
CH2Cl2, r.t., N2, 16 h
R1 = Ph, Et
R
R
O N
O
toluene or CHCl3
heat
R O N
O
O
N
O
N
R1
R1
9a-g
8a-i
7a-i
Scheme 2. A new procedure for the synthesis of 3-substituted maleimides.

824
P. Birch et al. / Tetrahedron Letters 53 (2012) 822–824
DMA (10 mol%),
Catecholborane (2 eq.)
References and notes
O
B
1. Barrero, A. F.; Quílez del Moral, J. F.; Sánchez, E. M.; Arteaga, J. F. Eur. J. Org.
Chem. 2006, 1627–1641.
CH2Cl2, 40 °C, N2 , 3 h
O
2. Justicia, J.; Alvarez de Cienfuegos, L.; Campana, A. G.; Miguel, D.; Jakoby, V.;
Gansauer, A.; Cuerva, J. M. Chem. Soc. Rev. 2011, 40, 3525–3537.
3. Sibi, M. P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-x. J. Org. Chem. 2002, 67, 1738–1745.
4. Bogliotti, N.; Dalko, P. I.; Cossy, J. J. Org. Chem. 2006, 71, 9528–9531.
5. Palframan, M. J.; Parsons, A. F.; Johnson, P. Tetrahedron Lett. 2011, 52, 1154–
1156.
6. Barton, D. H. R.; Doo, O. J.; Jaszberenyi, J. C. Tetrahedron Lett. 1990, 31, 4681–
4684.
7. Deprele, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66, 6745–6755.
8. Yamada, K.-i.; Nakano, M.; Maekawa, M.; Akindele, T.; Tomioka, K. Org. Lett.
2008, 10, 3805–3808.
10
1. EtOH (1.2 eq.),
2. TEMPO (2.2 eq.),
DMPU (1 eq.)
O N
CH2Cl2, r.t., N2, 16 h
11, 59%
Scheme 3. Direct trapping of a primary alkyl radical by TEMPO.
9. Montgomery, I.; Parsons, A. F.; Ghelfi, F.; Roncaglia, F. Tetrahedron Lett. 2008,
49, 628–630.
10. Renaud, P.; Schaffner, A. P. Eur. J. Org. Chem. 2004, 2291–2298.
11. Liu, X. Y.; Zhan, G. Z.; Han, Z. W.; Li, S. J.; Yu, Y. F. J. Appl. Polym. Sci. 2007, 106,
77–83.
12. Jin, L.; Agag, T.; Ishida, H. Eur. Polym. J. 2010, 46, 354–363.
13. Zhang, X.; Chen, G.-C.; Collins, A.; Jacobson, S.; Morganelli, P.; Dar, Y. L.; Musa,
O. M. J. Polym. Sci., Part A: Polym. Chem. 2009, 47, 1073–1084.
14. Nakagawa, Y.; Kano, H.; Tsukuda, Y.; Koyama, H. Tetrahedron Lett. 1967, 8,
4105–4109.
15. Putri, S. P.; Kinoshita, H.; Ihara, F.; Igarashi, Y.; Nihira, T. J. Nat. Prod. 2009, 72,
1544–1546.
16. Stewart, S. G.; Polomska, M. E.; Lim, R. W. Tetrahedron Lett. 2007, 48, 2241–
2244.
O N
O
OH
Zn, 50% aq. AcOH
100 °C, 1 h
O
O
O
N
N
Ph
Ph
7a
12, 94%
17. Barton, D. H. R.; Hervé, Y.; Potier, P.; Thierry, J. Tetrahedron 1987, 43, 4297–
4308.
Scheme 4. Formation of a hydroxy-succinimide.
18. Garrett, C. E.; Fu, G. C. J. Org. Chem. 1996, 61, 3224–3225.
19. Renaud, P.; Cadot, C.; Dalko, P. I.; Cossy, J.; Ollivier, C.; Chuard, R. J. Org. Chem.
2002, 67, 7193–7202.
20. Preparation of 3-cyclohexyl-N-phenyl-1H-pyrrole-2,5-dione (8a). To a solution
of cyclohexene (0.30 mL, 3.0 mmol, 1 equiv) and N,N-dimethylacetamide
(0.028 mL, 0.3 mmol, 0.1 equiv) in CH2Cl2 (2.0 mL) at 0 °C under N2, was
added catecholborane (0.64 mL, 6.0 mmol, 2 equiv) dropwise. The reaction
mixture was heated at reflux for 3 h before EtOH (0.21 mL, 3.6 mmol,
1.2 equiv) was added at 0 °C and the solution stirred for 0.25 h at rt N-
Phenylmaleimide (2.6 g, 15.0 mmol, 5 equiv) in CH2Cl2 (13 mL) and DMPU
(0.36 mL, 3.0 mmol, 1 equiv) were successively added followed by TEMPO
(1.0 g, 6.6 mmol, 2.2 equiv) in CH2Cl2 (6 mL) via syringe-pump over 2 h at room
temperature. The mixture was stirred overnight at room temperature. The
solvent was removed under reduced pressure, before the crude mixture was
re-dissolved in toluene (20 mL) and refluxed for 2 h. The solution was treated
with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (100 mL).
The organic layer was dried (MgSO4), filtered, and concentrated. The crude
product was purified by flash chromatography (9:1 petrol/EtOAc) to afford 8a
(0.699 g, 91%) as a white crystalline solid. Mp 100–102 °C. Rf 0.33 (9:1 petrol/
EtOAc). mmax (CHCl3) 2933 (m, C–H), 2856 (w), 1713 (C@O, strong), 1502 (m),
1390 (m). 1H NMR (400 MHz, CDCl3) dH 1.20–2.05 (m, 10H, cyclohexyl), 2.55–
2.65 (m, 1H, cyclohexyl), 6.35 (d, 1H, J = 1.5 Hz, C@CH), 7.32–7.36 (m, 3H, Ph),
7.42–7.48 (m, 2H, Ph). 13C NMR (100 MHz, CDCl3) dC 25.7 (CH2), 25.75 (CH2),
25.77 (CH2), 31.30 (CH2), 31.31 (CH2), 34.9 (CH), 124.8 (CH, Ph), 125.81 (CH,
Ph), 125.82 (CH, Ph), 127.5 (C@CH), 128.90 (CH, Ph), 128.91 (CH, Ph), 131.5 (N–
C, Ph) 154.6 (C@CH), 169.8 (C@O), 169.9 (C@O). m/z (ESI) 256 (100%) [MH+],
278 (31) [MNa+]. ESI-MS m/z 256.1339 [MH+] (C16H17NO2 requires 255.1259).
21. Preparation of N-(4-methylpentyloxy)-2,2,6,6-tetramethylpiperidine (11). To a
solution of 4-methylpent-1-ene (0.38 mL, 3.0 mmol, 1 equiv) and N,N-
dimethylacetamide (0.028 mL, 0.3 mmol, 0.1 equiv) in CH2Cl2 (2.0 mL) at 0 °C
under N2, was added catecholborane (0.64 mL, 6.0 mmol, 2 equiv) dropwise.
The reaction mixture was heated at reflux for 3 h before EtOH (0.21 mL,
3.6 mmol, 1.2 equiv) was added at 0 °C and the solution stirred for 0.25 h at rt
TEMPO (1.0 g, 6.6 mmol, 2.2 equiv) in CH2Cl2 (4 mL) and DMPU (0.36 mL,
3.0 mmol, 1 equiv) were successively added and the mixture stirred overnight
at room temperature. The solution was treated with saturated aqueous
NaHCO3 (20 mL) and extracted with EtOAc (100 mL). The organic layer was
dried (MgSO4), filtered, and concentrated. The crude product was purified by
as precursors to the organoborole radical initiator. However, when
terminal alkenes are used as precursors the yield of alkylated
maleimide product is significantly lower. This can be explained
by the terminal alkenes producing a more reactive primary radical
species, which can be trapped directly with TEMPO, rather than
undergoing conjugate addition to the maleimide, to give 9a–g.
The direct reaction of a primary alkyl radical with TEMPO is
emphasised by the reaction shown in Scheme 3, whereby exclusion
of the maleimide from the reaction mixture, allows the primary al-
kyl radical to be trapped by the nitroxide to give alkoxyamine 11 in
a good yield.21
Mechanistically, the final step in the formation of the 3-substi-
tuted maleimide (Scheme 2) is believed to involve a syn-periplanar
elimination, whereby TEMPO and the adjacent H-atom (on the
same face of the ring) undergo intramolecular elimination under
heating, to reform the maleimide C@C. Indeed, efforts to promote
the elimination at ambient temperature using basic additives
(e.g., Et3N, DBU) showed no improvement in yield or rate of reac-
tion of 7 to give 8. The optimum conditions for a quantitative yield
of 8 (in the final step) were using toluene at 110 °C for 2 h.
To summarise, we have developed a new synthetic route for the
synthesis of 3-alkyl maleimides using mild conditions and non-
toxic reagents. This one-pot procedure combines alkene hydrobo-
ration, radical addition-aminoxylation and nitroxide elimination
to afford alkylated maleimides in good to excellent yield. It is
envisaged that this method could be employed to prepare biologi-
cally important targets, such as some carbocyclic analogues of
showdomycin,22,23 and it is our intention to explore this area fur-
ther. This methodology also offers a new route towards hydroxyl-
ated succinimides, as illustrated by the efficient reduction of
alkoxyamine 7a, using Zn in AcOH,24 to give 12 (Scheme 4).
flash chromatography (9:1 petrol/EtOAc) to give 11 (0.425 g, 59%) as
a
colourless oil. Rf 0.71 (9:1 petrol/EtOAc). mmax (CHCl3) 2934 (s, C–H), 2871
(m), 1468 (m, N–O), 1375 (m, N–O), 1360 (m, C–O), 1132 (m), 1049 (m), 908
(s). 1H NMR (400 MHz, CDCl3) dH 0.87–0.89 (d, 6H, J = 6.6 Hz, 2 Â CH3), 1.08 (s,
6H, 2 Â CH3), 1.14 (s, 6H, 2 Â CH3), 1.20–1.26 (m, 11H, alkyl, piperidinyl), 3.70
(t, 2H, J = 6.8 Hz, –OCH2). 13C NMR (100 MHz, CDCl3) dC 17.2 (CH2), 20.1 (CH3),
22.6 (4 Â CH3), 26.6 (CH2), 28.0 (CH3), 33.1 (CH), 35.5 (CH2), 39.6 (2 Â CH2),
59.59 (C(CH3)2), 59.61 (C(CH3)2), 77.2 (–OCH2-). m/z (ESI) 242 (100%) [MH+].
ESI-MS m/z 242.2484 [MH+] (C15H31NO requires 241.2406).
Acknowledgments
22. Saksena, A. K.; Ganguly, A. K. Tetrahedron Lett. 1981, 22, 5227–5230.
23. Renner, J.; Kruszelnicki, I.; Adamiak, B.; Willis, A. C.; Hammond, E.; Su, S.;
Burns, C.; Trybala, E.; Ferro, V.; Banwell, M. G. Aust. J. Chem. 2005, 58, 86–93.
24. Howell, A. R.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1990, 2715–2720.
We would like to thank the EPSRC and Cytec Engineered Mate-
rials for funding.