A mild synthesis of N-functionalised bromomaleimides, thiomaleimides and bromopyridazinediones

Article abstract of DOI:10.1016/j.tetlet.2013.04.088

Bromomaleimides are useful building blocks in synthesis and powerful reagents for the selective chemical modification of proteins. A mild new synthesis of these reagents is described, along with the convenient transferability of the approach to dithiomale

Full text of DOI:10.1016/j.tetlet.2013.04.088

Tetrahedron Letters 54 (2013) 3493–3495
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A mild synthesis of N-functionalised bromomaleimides, thiomaleimides and
bromopyridazinediones q
Lourdes Castañeda a, Zoë V. F. Wright a, Cristina Marculescu a, Trang M. Tran a, Vijay Chudasama a,
Antoine Maruani a, Elizabeth A. Hull a, João P. M. Nunes a, Richard J. Fitzmaurice a, Mark E. B. Smith a,
a,
Lyn H. Jones b, Stephen Caddick a, , James R. Baker
⇑
⇑
a Department of Chemistry, UCL, 20 Gordon St, London WC1H 0AJ, UK
b Chemical Biology Group, BioTherapeutics Chemistry, WorldWide Medicinal Chemistry, Pfizer, 200 Cambridge Park Drive, Cambridge, MA 02140, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 December 2012
Revised 5 April 2013
Accepted 19 April 2013
Available online 27 April 2013
Bromomaleimides are useful building blocks in synthesis and powerful reagents for the selective chem-
ical modification of proteins. A mild new synthesis of these reagents is described, along with the conve-
nient transferability of the approach to dithiomaleimides and bromopyridazinediones.
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Bromomaleimides
Thiomaleimides
Pyridazinediones
Reagent synthesis
Reagents for cysteine modification
Bromomaleimides 1 are useful building blocks for synthesis,
undergoing a diverse range of reactions including nucleophilic
addition and cross-coupling.1–4 For example, dibromomaleimides
have been used extensively as starting materials for the synthesis
of bisaryl maleimides, as inhibitors of protein kinase C.5,6 Bromo-
maleimides have also been demonstrated as powerful reagents
for the selective chemical modification of cysteine residues in pep-
tides and proteins.7–15 In this context, bromomaleimides represent
the parent members of a larger class of reagents for use in biocon-
jugation. Varying the leaving groups on the 3 and 4 positions of the
maleimide allows fine-tuning of the properties of the reagent.
Notably, exchanging the bromines with thiophenols affords re-
agents which can be employed in the in situ bridging of disulfide
bonds13 and are tolerant to incorporation into polymers.16 The
six-membered ring analogues, bromopyridazinediones 2, offer a
similar and yet distinct reactivity profile for cysteine conjugation.17
Bromomaleimides 1 and bromopyridazinediones 2 are com-
monly synthesised by treating a bromomaleic anhydride 3 with
an amine or hydrazine respectively and heating at reflux in AcOH
to carry out the dehydrative cyclisation (Scheme 1).8,17 These con-
ditions are extremely harsh, and are not suitable if the amine or
O
O
O
X
X
X
R-NH2
AcOH
reflux
RNHNHR
NR
NR
NR
O
AcOH
Br
Br
Br
reflux
O
O
O
X = Br or H
X = Br or H
X = Br or H
3
2
1
Scheme 1. The current synthesis of bromomaleimides 1 and bromopyridazined-
iones 2.
Table 1
Synthesis of N-methoxycarbonylmaleimides
O
O
Y
X
Y
X
O
ClCO2Me
NMM
N
NH
OMe
O
O
5
4
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
Entry
X
Y
Yield (%)
⇑
Corresponding authors. Tel.: +44 207 679 2653 (J.R.B.); tel.: +44 203 108 5071
(S.C.).
1
2
3
Br
Br
SPh
Br
H
SPh
97
100
97
E-mail addresses: s.caddick@ucl.ac.uk (S. Caddick), j.r.baker@ucl.ac.uk (J.R.
Baker).
0040-4039/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.088

3494
L. Castañeda et al. / Tetrahedron Letters 54 (2013) 3493–3495
Table 2
leimides 7 in good yields (Table 2, entries 1–15). This represents
A mild synthesis of dibromomaleimides
an extremely mild synthesis, and is effective for alkyl and aryl
amines. It should be noted that aniline itself led to a lower yield (en-
try 11), due to an undetermined competing degradation pathway,
but this could be precluded by substitution in the para position of
the aniline (entries 12 and 13). Notable examples include: dibromo-
maleimide–alkyne12 (entry 3) and dibromomaleimide–azide (entry
6), useful as heterobifunctional cross-linkers, bis-dibromomalei-
mide (entry 4) as a homobifunctional cross-linker, and dibromoma-
leimide–aryl fluorides for prospective PET imaging applications
(entries 10, 14 and 15). In an analogous fashion N-methoxycarbon-
ylbromomaleimide (8) underwent effective reaction with a number
of amines to form monobromomaleimides 9 in moderate yields (en-
tries 16–20). It should be noted that the products in all these reac-
tions are reactive conjugate acceptors, and thus no more than a
stoichiometric equivalent of amine should be employed otherwise
bis-addition products are observed.
The dithiophenolmaleimide variants proved more challenging,
and required subtle tuning of the reaction conditions. Addition of
amines to activated maleimide 10 led to initial attack to form the
acyclic ring-opened intermediates (i.e., cyclisation with release of
methyl carbamate was not observed). Upon column chromatogra-
phy of these intermediates, some cyclisation was observed,
implying that the mildly acidic conditions provided by the silica
could facilitate the cyclisation. Thus silica was added as a second
step in the reaction, and this served to afford the desired dithio-
phenolmaleimides 11 (Table 3). For simple alkyl amines and ben-
zylamine the yields in this reaction were still disappointing
(entries 5–7). In these examples, it was found that the addition
of Et3N (1 equiv) at the start of the reaction improved the yield
O
O
X
X
O
RNH2
CH2Cl2, RT
N
NR
OMe
Br
Br
O
O
6 X = Br
7 X = Br
8
9
X = H
X = H
Entry
X
R
Yield (%)
1
2
Br
Br
79
79
OH
3
4
5
6
Br
Br
Br
Br
82
70a
69
O
O
O
O
O
O
OH
N3
O
O
80
7
8
Br
Br
60
78
9
Br
Br
86
72
F
10
11
12
Br
Br
19
78
OH
F
13
14
Br
Br
99
64
Table 3
A mild synthesis of dithiophenolmaleimides
O
O
F
i) RNH2, CH2Cl2
ii) silica, CH2Cl2
PhS
PhS
PhS
PhS
O
15
Br
46
NR
N
OMe
O
O
11
10
Amine
16
17
H
H
74
62
Entry
Yield (%)
98
1
2
O
18
19
H
H
58
44
O
O
83
O
3
4
86
45
20
H
63
O
O
a
0.4 equiv of diamine used.
O
OH
5
42 (66)a
6
7
30 (75)a
15 (59)a
hydrazine contains sensitive functionality. Furthermore, to access
the dithiophenolmaleimides a subsequent step is required involv-
ing the treatment of the dibromomaleimide with thiophenol and a
base.13
a
Yields in parenthesis indicate the outcome of the reaction when 1 equiv of Et3N
was added at the start of the reaction.
The reaction of amines with N-methoxycarbonylmaleimide (5, X
and Y = H) has been reported as a mild approach to synthesise
maleimides.18,19 We report herein on our efforts towards transfer-
ring this chemistry to provide a mild and general synthesis of
bromomaleimides, dithiophenolmaleimides and bromo-pyridazin-
ediones. Treatment of dibromo-, monobromo- and dithiophenol-
maleimides with methyl chloroformate and N-methylmorpholine
(NMM) afforded the corresponding N-methoxycarbonyl activated
species 5 in excellent yields (Table 1).
O
O
O
X
X
O
EtHN NHEt
CH2Cl2
NEt
NEt
N
OMe
Br
12
Br
O
6
, X = Br
, X = Br, 57%
13 X = H, 64%
8, X = H
Stirring N-methoxycarbonyldibromomaleimide (6) with a range
of amines at room temperature successfully afforded dibromoma-
Scheme 2. A mild synthesis of bromopyridazinediones.

L. Castañeda et al. / Tetrahedron Letters 54 (2013) 3493–3495
3495
2. Choi, D. S.; Huang, S. L.; Huang, M. S.; Barnard, T. S.; Adams, R. D.; Seminario, J.
M.; Tour, J. M. J. Org. Chem. 1998, 63, 2646–2655.
3. Marminon, C.; Pierre, A.; Pfeiffer, B.; Perez, V.; Leonce, S.; Joubert, A.; Bailly, C.;
Renard, P.; Hickman, J.; Prudhomme, M. J. Med. Chem. 2003, 46, 609–622.
4. Souffrin, A.; Croix, C.; Viaud-Massuard, M.-C. Eur. J. Org. Chem. 2012, 2499–
2502.
5. Davis, P. D.; Hill, C. H.; Lawton, G.; Nixon, J. S.; Wilkinson, S. E.; Hurst, S. A.;
Keech, E.; Turner, S. E. J. Med. Chem. 1992, 35, 177–184.
6. Wang, J. J.; Soundarajan, N.; Liu, N.; Zimmermann, K.; Naidu, B. N. Tetrahedron
Lett. 2005, 46, 907–910.
7. Tedaldi, L. M.; Smith, M. E. B.; Nathani, R.; Baker, J. R. Chem. Commun. 2009,
6583–6585.
8. Smith, M. E. B.; Schumacher, F. F.; Ryan, C. P.; Tedaldi, L. M.; Papaioannou, D.;
Waksman, G.; Caddick, S.; Baker, J. R. J. Am. Chem. Soc. 2010, 132, 1960–1965.
9. Moody, P.; Smith, M. E. B.; Ryan, C. P.; Chudasama, V.; Baker, J. R.; Molloy, J.;
Caddick, S. ChemBioChem 2012, 13, 39–41.
10. Ryan, C. P.; Smith, M. E. B.; Schumacher, F. F.; Grohmann, D.; Papaioannou, D.;
Waksman, G.; Werner, F.; Baker, J. R.; Caddick, S. Chem. Commun. 2011, 5452–
5454.
significantly. It could be postulated that the triethylamine was
important to prevent protonation, and thus deactivation, of these
more basic alkyl amines during the reaction.
Finally, we attempted to transfer this approach to the synthesis
of bromopyridazinediones. Thus treatment of activated dibromo-
and monobromomaleimides 6 and 8 with N,N0-diethylhydrazine
was carried out. Simply stirring the reagents in CH2Cl2 at room
temperature led to the desired dibromopyridazinedione 12 and
monobromopyridazinedione 13 in moderate yields (Scheme 2).
In conclusion, we have shown that bromomaleimides, dithio-
phenolmaleimides and bromopyridazinediones can all be accessed
by the addition of amines to the appropriate N-methoxycarbonyl
activated maleimides. The employed methods are extremely mild
and provide a general route to this important class of reagents.
11. Tedaldi, L. M.; Aliev, A. E.; Baker, J. R. Chem. Commun. 2012, 4725–4727.
12. Jones, M. W.; Strickland, R. A.; Schumacher, F. F.; Caddick, S.; Baker, J. R.;
Gibson, M. I.; Haddleton, D. M. J. Am. Chem. Soc. 2012, 134, 1847–1852.
13. Schumacher, F. F.; Nobles, M.; Ryan, C. P.; Smith, M. E. B.; Tinker, A.; Caddick, S.;
Baker, J. R. Bioconjugate Chem. 2011, 22, 132–136.
14. Nathani, R. I.; Chudasama, V.; Ryan, C. P.; Moody, P. R.; Morgan, R. E.;
Fitzmaurice, R. J.; Smith, M. E. B.; Baker, J. R.; Caddick, S. Org. Biomol. Chem.
2013, 11, 2408–2411.
Acknowledgments
We gratefully acknowledge Fundación Alfonso Martín Escudero,
RCUK, BBSRC, UCL, Pfizer, and the Wellcome Trust for support of
our programme.
15. Schumacher, F. F.; Sanchania, V. A.; Tolner, B.; Wright, Z. V. F.; Ryan, C. P.;
Smith, M. E. B.; Ward, J. M.; Caddick, S.; Kay, C. W. M.; Aeppli, G.; Chester, K. A.;
Baker, J. R. Sci. Rep. 2013, 3, 1525.
Supplementary data
16. Jones, M. W.; Strickland, R. A.; Schumacher, F. F.; Caddick, S.; Baker, J. R.;
Gibson, M. I.; Haddleton, D. M. Chem. Commun. 2012, 4064–4066.
17. Chudasama, V.; Smith, M. E. B.; Schumacher, F. F.; Papaioannou, D.; Waksman,
G.; Baker, J. R.; Caddick, S. Chem. Commun. 2011, 8781–8783.
18. Wang, L. X.; Ni, J. H.; Singh, S. Bioorg. Med. Chem. 2003, 11, 159–166.
19. Heredia, K. L.; Bontempo, D.; Ly, T.; Byers, J. T.; Halstenberg, S.; Maynard, H. D.
J. Am. Chem. Soc. 2005, 127, 16955–16960.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.
088.
References and notes
1. Awuah, E.; Capretta, A. J. Org. Chem. 2011, 76, 3122–3130.