One-pot synthesis of 3-arylaminomaleimides from terminal alkynes and isocyanates

Article abstract of DOI:10.1016/j.tetlet.2017.03.050

The reaction of aryl acetylide anions with phenyl isocyanate and subsequent addition of a protonating agent such as ethanol affords good yields of 3-aminomaleimides, formed by the cyclization of one molecule of alkyne with two isocyanates. When the reaction is quenched with water instead, cyclopentadienone imines are formed as the major products.

Full text of DOI:10.1016/j.tetlet.2017.03.050

Accepted Manuscript
One-pot synthesis of 3-arylaminomaleimides from terminal alkynes and iso-
cyanates
Harry Adams, Mark Baker, Hannah Hodson, Michael J. Morris
PII:
S0040-4039(17)30355-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.050
TETL 48751
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 January 2017
11 March 2017
17 March 2017
Please cite this article as: Adams, H., Baker, M., Hodson, H., Morris, M.J., One-pot synthesis of 3-
arylaminomaleimides from terminal alkynes and isocyanates, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.03.050
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Submitted to Tetrahedron Letters
One-pot synthesis of 3-arylaminomaleimides from terminal alkynes and isocyanates
Harry Adams, Mark Baker, Hannah Hodson and Michael J. Morris*
Department of Chemistry, University of Sheffield,
Sheffield S3 7HF, U.K.
M. J. Morris ORCID: 0000-0001-8802-9147

Graphical Abstract
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Abstract
The reaction of aryl acetylide anions with phenyl isocyanate and subsequent addition of a
protonating agent such as ethanol affords good yields of 3-aminomaleimides, formed by the
cyclization of one molecule of alkyne with two isocyanates. When the reaction is quenched with
water instead, cyclopentadienone imines are formed as the major products.
Keywords
Acetylide; Alkyne; Isocyanate; Hydantoin; Heterocycle; Maleimide
As part of a recent research effort targeted towards the synthesis of heterocycles from
acetylide anions and heterocumulenes, we have reported the efficient production of 1,2-dithiole-3-
thiones under very mild conditions from deprotonated terminal alkynes, CS2 and elemental sulfur.
Replacement of carbon disulfide by isothiocyanates gave access to the related 3-imino-1,2-
dithioles.1 More recently we have shown that the reaction of aryl acetylides with phenyl
isothiocyanate, followed by the addition of ethanol, leads to the formation of an unusual
thiazolidine heterocycle which is a dimer of the acetylenic thioamide PhC≡CC(=S)NHPh.2
We have now extended these investigations to isocyanates and herein report that cyclization
of aryl acetylides with phenyl isocyanate proceeds with the formation of 3-arylaminomaleimides.
Such compounds are of interest both as inhibitors of glycogen synthase kinase 2 (GSK-2)3 and also
as fluorophores and species that display the phenomenon of aggregate-induced emission.4
The reaction of phenylacetylene and its organometallic derivatives with phenyl isocyanate
is one with a long and surprisingly complicated history. Perhaps the seminal works in this area
were the initial investigations of Tyabji, later followed up by Bird, who studied the reaction of
sodium phenylacetylide with PhNCO in diethyl ether, hydrolysing the mixture with ethanol, water
and HCl.5, 6 Two products were isolated and identified spectroscopically as the 5-benzylidene
hydantoin 1 and the benzylidene benzodiazepinedione 2 (Fig. 1). Subsequently, the same hydantoin
was prepared by heating PhC≡CH with PhNCO in the presence of either [Fe(CO)5]7 or
[Mn(CO)5Br]8, by the reaction of PhC≡CBr with PhNCO and [Fe(CO)5],9 and by treating PhNCO
with phenylalkynyl derivatives of lead.10 More recently Mathur and co-workers have established
that heating PhC≡CH with PhNCO and [Fe(CO)5] under nitrogen produced the hydantoin 1,
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whereas in a CO atmosphere the maleimide derivative 3 was formed by cyclisation of one alkyne
molecule with one PhNCO and one CO derived from the metal carbonyl.11 Earlier papers claim that
the acetylenic Grignard PhC≡CMgBr reacts with PhNCO to give only the anilide
PhC≡CC(=O)NHPh,10, 12 and lithiation of ethyl propiolate and reaction with PhNCO at low
temperature was also shown to proceed only as far as the amide EtO2CC≡CCONHPh.13 More
recently the reaction of PhC≡CH with dibutyl magnesium and PhNCO was shown to give a
bis(imidazolidine-2,4-dione).14
Figure 1. Previously isolated products from the reaction of PhC≡CH with PhNCO.
The deprotonation of phenylacetylene with n-BuLi and addition of PhNCO (2 equiv.) at –
78 °C, followed by warming to room temperature, caused a rapid colour change to intense orange-
red. After quenching with ethanol or several other protonating agents (e.g. [NH Et ][Br] or acetic
2
2
acid), chromatographic work-up produced a bright orange compound which, according to its mass
spectrum (m/z 340), contained one phenylacetylene unit and two isocyanates. However its 1H NMR
spectrum did not correspond to that of hydantoin 1, and moreover its IR spectrum contained an
unmistakable N–H peak.15, 16 Single crystal X-ray structural determination (Fig. 2) established its
structure as the aminomaleimide derivative 4a (Scheme 1).
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Figure 2. Molecular structure of 4a in the crystal.
Scheme 1. Formation of the aminomaleimides.
The IR spectrum, melting point and UV-visible spectrum of 4a did however match those
reported for Bird’s minor product, originally identified as 2. We therefore attempted to repeat
Bird’s reaction, using sodium phenylacetylide in diethyl ether. In our hands, this gave a mixture of
hydantoin 1 and maleimide 4a that was to an extent separable by column chromatography. We
therefore suspect that the true identity of Bird’s minor product is 4a.
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Under our conditions the formation of hydantoin 1 is completely suppressed. If the
temperature of the reaction is maintained at –78°C after the addition of PhNCO and the reaction is
quenched without warming, 4a is still isolated but in lower yield and as a mixture with
PhC≡CC(=O)NHPh,17 and a small amount of hydantoin 1 is also formed. One possible mechanism
for the formation of 4 in the presence of excess PhNCO is shown below. Attempts to cause the
rearrangement of hydantoin 1 to 4a by stirring it in base (LiOEt), with or without additional
isocyanate, were however unsuccessful.
Scheme 2. Possible mechanism for the production of the aminomaleimides.
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In contrast to the aryl acetylenes, other terminal alkynes were more reluctant to react in an
analogous manner. Thus, ferrocenyl acetylene, while producing a compound of type 4 in low yield,
also gave a second compound which was identified as the acetylenic amide FcC≡CC(=O)NHPh.
When tBuC≡CH was lithiated and allowed to react with PhNCO, a white precipitate was deposited;
upon work-up the amide tBuC≡CC(=O)NHPh was isolated in virtually quantitative yield.18
Comments in Bird’s paper6 to the effect that the reaction only worked in conditions of high
humidity also led us to investigate the effect of quenching the reaction with water instead of
ethanol. Remarkably in this case the yield of 4 is drastically reduced and a new product 5 is
isolated as a red solid (Scheme 3).19 Compared to 4a and 4b, the mass spectra of 5a and 5b
unexpectedly showed increased molecular masses with molecular ions at m/z 515 and 543,
respectively. The latter compound was readily crystallized from CH2Cl2 and light petroleum as red
blocks, which were identified by single crystal X-ray analysis as the cyclopentadienone imine 5b
(Fig. 2). The mechanism for the formation of 5 is currently obscure, involving two alkyne
molecules, three isocyanates, and the apparent elimination of the elements of CO2 from the latter.
However the reaction provides a convenient route to these previously unknown dienes, and given
the fact that such bicyclic imines are accessed only with difficulty,20 and their similarity to the
ligands used in Shvo/Knölker-type hydrogenation/dehydrogenation catalysts, we are currently
exploring their coordination to iron and ruthenium carbonyl fragments.21
Scheme 3. Formation of cyclopentadienone imines.
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Figure 3. Molecular structure of 5b in the crystal.
In conclusion, we have demonstrated the efficient synthesis of aminomaleimide heterocycles
from terminal aryl alkynes and phenyl isocyanate, and by quenching the reaction with water instead
of ethanol that the major product can be changed to a previously unknown cyclopentadienone
imine. It is noticeable that in contrast to our earlier work with CS2 and PhNCS, the more reactive
isocyanate only gives rise to products containing multiple heterocumulene molecules.
Acknowledgements
We thank the University of Sheffield for support, and Prof. Joe Harrity for useful discussions.
This research did not receive any specific grant from funding agencies in the public, commercial or
not-for-profit sectors.
Supplementary data
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Crystallographic data for the structure determinations of 4a and 5b have been deposited with
the Cambridge Crystallographic Data Centre, reference numbers CCDC 1522806 and 1522805
respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplementary data associated with this article
can be found, in the online version, at...
References and notes
1.
(a) Adams, H.; Chung, L.-M.; Morris, M.J.; Wright, P.J. Tetrahedron Lett. 2004, 45, 7671;
(b) Adams, H.; Hughes, A.J.; Morris, M.J.; Quenby, S.I.A. Tetrahedron Lett. 2014, 55, 5283.
Adams, H.; Hodson, H.; Morris, M.J.; Venting, G.A. Tetrahedron Lett. 2016, 57, 1328.
(a) Smith, D.G.; Buffet, M.; Fenwick, A.E.; Haigh, D.; Ife, R.J.; Saunders, M.; Slingsby,
B.P.; Stacey, R.; Ward, R.W. Bioorg. Med. Chem. Lett. 2001, 11, 635; (b) Akhtar, M.;
Bharatam, P.V. Chem. Biol. Drug Des. 2012, 79, 560.
2.
3.
4.
(a) Mabire, A.B.; Robin, M.P.; Quan, W.-D.; Willcock, H.; Stavros, V.G.; O'Reilly, R.K.
Chem. Commun. 2015, 51, 9733; (b) Kato T.; Naka, K. Chem. Lett. 2012, 41, 1445; (c)
Boominathan, M.; Sathish, V.; Nagaraj, M.; Bhuvanesh, N.; Muthusubramanian, S.;
Rajagopal, S. RSC Adv. 2013, 3, 22246.
5.
6.
7.
8.
9.
Tyabji, A. J. Univ. Bombay, 1942, 10, 110.
Bird, C. W. J. Chem. Soc. 1965, 5762.
Ohshiro, Y.; Kinugasa, K.; Minami, T.; Agawa T. J. Org. Chem. 1970, 35, 2136.
Kuninobu, Y.; Kikuchi, K.; Takai, K. Chem. Lett. 2008, 37, 740.
Baba, A.; Ohshiro, Y.; Agawa, T. J. Organomet. Chem. 1975, 87, 247.
10. Davies, A.G.; Puddephatt, R.J. J. Chem. Soc. (C), 1968, 317. These authors originally
identified the product as a uracil derivative: Davies, A.G.; Puddephatt, R.J. Tetrahedron Lett.
1967, 8, 2265.
11. Mathur, P.; Joshi, R.K.; Rai, D.K.; Jha B.; Mobin, S.M. Dalton Trans. 2012, 41, 5045.
12. Johnson J.R.; McEwen, W.L. J. Am. Chem. Soc. 1926, 48, 469.
13. Katritzky, A.R.; Zhang, Y.; Singh, S.K.; Steel, P.J. Arkivoc, 2003, 15, 47.
14. Hill, M.S.; Liptrot, D.J. Mahon, M.F. Angew. Chem. Int. Ed. 2013, 52, 5364.
page 9

15. Typical experimental procedure for the synthesis of1,4-diphenyl-3-phenylaminomaleimide
(4a).
A solution of phenylacetylene (0.58 mL, 5.28 mmol) in THF (20 mL) was cooled to –78 °C
and treated with n-BuLi (3.3 mL of a 1.6 M solution in hexanes, 5.28 mmol), then warmed to
room temperature and stirred for 30 min. After again cooling to –78 °C, PhNCO (1.15 mL,
10.59 mmol) was added; on warming to room temperature and stirring for 1 h, the solution
gradually turned an intense orange-red colour. The solution was cooled to –78 °C for a third
time and after addition of EtOH (3 mL), was allowed to warm to room temperature and
stirred overnight. The solvent was removed in vacuo, the residue absorbed on a small amount
of silica and introduced to the top of a silica column made up in light petroleum. Elution with
light petroleum–CH2Cl2: (2:3, then 1:4) produced a large bright orange band of compound 4a
(840 mg, 47%). M.p. 201-203 °C. IR (CH2Cl2): 1769m, 1710vs, 1652s, 1597m cm–1. IR
1
(KBr): 3305s (NH). H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 4.3 Hz, 5 H), 7.40 (m, 1 H),
7.22-7.00 (m, 8 H), 6.72 (d, J = 7.5 Hz, 2 H). 13C NMR (100.6 MHz, CDCl3): δ 170.8, 167.5
(both CO), 136.2, 136.2, 131.9, 129.2 (3 Cipso + CNHPh), 129.8, 129.1, 128.3, 127.5, 127.3,
125.9, 124.7, 121.7 (m, Ph), 102.5 (CPh). MS (EI): m/z 340 (M+), 220, 193. UV-vis (EtOH,
λmax in nm, ε in M–1cm–1): 251 (ε 28450), 294sh (ε 7600), 408 (ε 6310). Analysis Found: C,
77.39; H, 4.74; N, 8.19. Calcd. for C22H16N2O2: C, 77.65; H, 4.71; N, 8.23%.
16. Characterisation data for 1 can be found in the Supplementary Information of reference 8. IR
(CH2Cl2): 1772ms, 1726vs, 1657m, 1597w cm–1. Notably the 1H NMR spectrum of 1 in
CDCl3 contains a doublet at δ 6.86 instead of the doublet at δ 6.72 observed for 4a.
17. The presence of PhC≡CC(=O)NHPh can be easily detected by its peak at δ 7.91 in the 1H
NMR spectrum.
18. IR (KBr): 2222 (C≡C), 1642 (CO). 1H NMR (400 MHz, d6-DMSO): δ 7.46 (t, 2 H, Ph), 7.15
(t, 2 H, Ph), 6.86 (t, 1 H, Ph), 1.21 (s, 9 H, tBu). MS (EI): m/z 201 (M+), 200, 186, 158. For
comparison, see Kawaguchi, H.; Tatsumi K. Organometallics 1995, 14, 4294.
19. Typical experimental procedure for 5b: A solution of 4-ethynyltoluene (0.63 mL, 4.94 mmol)
in THF (20 mL) at –78 °C was treated with n-BuLi (3.1 mL of a 1.6 M solution in hexanes,
4.96 mmol), allowed to warm to room temperature and stirred for 30 min. After again
cooling to –78 °C, PhNCO (1.08 mL, 9.94 mmol) was added; on warming to room
page 10

temperature and stirring for 1 h, the solution gradually turned an intense orange-red colour.
After cooling the solution to –78 °C, water (1 mL) was added and the mixture allowed to
warm to room temperature and stir overnight; it remained a red colour. Column
chromatography as above gave a red band of 5b, eluted in light petroleum–CH2Cl2: (2:3). The
latter part of the band also contains a small amount of 4b, which is easily removed by
crystallization (diffusion of light petroleum into a CH2Cl2 solution). Yield 236.7 mg, 17%.
M.p. 260-262 °C. IR (CH2Cl2): 1754 cm–1. 1H NM• •R••(•4•00••M• •H•z•,1C9 DCHl,3):•δ••••••••••••••••19 H,
Ph + tol), 6.,361,556. .532( C(=bOo)t,h1b4r9.s4,(2CH, Ph), 2.28, 2.06 (both s, 3H, Me). 13C NMR (100.6 M( HC=z,N)
CDC6l3):6δ1•166.6 (C=N), 155.5 (C=O), 149.4 (Cipso of NPh), 136.3, 136.1, 133.8, 133.2, 130.9,
129.5, 128.6, 128.4, 127.6, 127.5, 127.4, 127.1, 126.7, 126.5, 126.2, 125.9, 125.3, 123.3,
120.6 (m, Ph + tol), 21.3, 21.0 (Me). MS: m/z 544 (M+H)+. Analysis Found: C, 83.58; H,
5.45; N, 7.63. Calcd. for C38H29N3O: C, 83.98; H, 5.34; N, 7.73%.
20. (a) Tamao, K.; Kobayashi, K.; Ito, Y. J. Org. Chem. 1989, 54, 3517. (b) Hu, Q.; Lu, J.;
Wang, C.; Wang, C.; Xi, Z. Tetrahedron 2007, 63, 6614. (c) Shibata, T.; Tamashita, K.;
Katayama, E.; Takagi, K. Tetrahedron 2002, 58, 8661.
21. (a) Quintard, A.; Rodriguez, J. Angew. Chem. Int. Ed. 2014, 53, 4044. (b) Knölker, H.-J.;
Baum, E.; Goesmann, H.; Klauss, R. Angew. Chem. Int. Ed. 1999, 38, 2064.
page 11

Captions for Figures and Schemes
Figure 1 Previously isolated products from the reaction of PhC≡CH with PhNCO.
Figure 2 Molecular structure of 4a in the crystal.
Figure 3 Molecular structure of 5b in the crystal.
Scheme 1 Formation of the aminomaleimides.
Scheme 2 Possible mechanism for the production of the aminomaleimides.
Scheme 3 Formation of cyclopentadienone imines.
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•
•
•
A simple route to 3-arylaminomaleimides is reported
By changing the conditions, unusual bicyclic cyclopentadienone imines can be accessed
Single crystal X-ray structures of both types of compound are reported
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