Modified Bucherer-Bergs reaction for the one-pot synthesis of 5,5′-disubstituted hydantoins from nitriles and organometallic reagents

Article abstract of DOI:10.1055/s-2006-949644

Diverse sets of 5,5′-disubstituted hydantoins can conveniently be made in moderate to good yields (40-92%) by a one-pot process involving treatment of aromatic, heteroaromatic or aliphatic nitriles with an organometallic reagent (RLi or RMgX) followed by

Full text of DOI:10.1055/s-2006-949644

LETTER
2203
Modified Bucherer–Bergs Reaction for the One-Pot Synthesis of 5,5¢-Disubsti-
tuted Hydantoins from Nitriles and Organometallic Reagents
One-PotSynthes
y
¢
-Dis
r
ubstitute
i
d
H
yda
l
ntoins Montagne, Michael Shipman*
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK
Fax +44(24)76524429; E-mail: m.shipman@warwick.ac.uk
Received 21 April 2006
the ketone 4 (or indeed the corresponding NH imine 6), in
Abstract: Diverse sets of 5,5¢-disubstituted hydantoins can conve-
niently be made in moderate to good yields (40–92%) by a one-pot
process involving treatment of aromatic, heteroaromatic or aliphatic
nitriles with an organometallic reagent (RLi or RMgX) followed by
KCN/(NH4)2CO3.
the same vessel as the Bucherer–Bergs reaction by a pro-
cess involving C–C bond formation. In this way, greater
structural diversity in the compounds produced could be
achieved. Of several possibilities, the reaction of a nitrile
7 with an organometallic reagent such as RMgX or RLi
seemed attractive (Scheme 1).9 Selection of this strategy
was based on the following: (1) a very large number of ni-
triles are commercially available or readily accessible; (2)
a variety of common organometallic reagents including
RMgX10 and RLi11 add to alkyl-, aryl- and heteroaryl-sub-
stituted nitriles in high yields; (3) protonation of the inter-
mediate metallated imine 8 directly leads to the NH imine,
an intermediate in the Bucherer–Bergs reaction.7 In this
communication, we report the successful development of
a practical, one-pot method for the synthesis of 5,5¢-disub-
stituted hydantoins 5 based upon this approach.
Key words: heterocycles, multicomponent reactions, combinatori-
al chemistry
The hydantoin nucleus displays many important pharma-
cological effects1 and is commonly used in drug discovery
programmes. Indeed, several clinically important medi-
cines including nilutamide (1)2 (anticancer) and phenytoin
(2)3 (antiepileptic) are based upon this heterocyclic scaf-
fold. Moreover, a number of hydantoin natural products
are known, e.g. (+)-hydantocidin (3, Figure 1).4 The hy-
dantoin nucleus also serves as a precursor to nonnatural
amino acids via chemical1 or enzymatic hydrolysis.5
Classical Bucherer–Bergs Reaction (4-CR, one point of diversity)
O
KCN,
(NH4)2CO3
O
O
NH
HN
O
O
CF3
NO2
HN
HO
HN
HN
NH
R1
O
R1
O
R
R1
R
NH
N
NH
Ph
Ph
R
4
6
5
O
O
O
HO
OH
Modified Bucherer–Bergs Reaction (4-CR, two points of diversity)
O
2, Phenytoin
3, (+)-Hydantocidin
1, Nilutamide
KCN,
(NH4)2CO3
NM
R1
HN
R1
M
NH
R1
R
N
Figure 1
O
R
R
7
8
5
where R, R1 ≠ H; M = Li, MgX, etc.
A number of methods exist for the synthesis of hydanto-
ins.1,6 Of these, the classical Bucherer–Bergs provides the
one of the most direct methods.7 It involves reaction of a
ketone 4 (or aldehyde) with cyanide, ammonia and carbon
dioxide (conveniently generated from ammonium carbon-
ate) and directly produces the hydantoin 5 via the NH
imine 6 (Scheme 1). It is highly practical and new appli-
cations of this reaction continue to be developed.8 Despite
the enormous scope and potential of this four-component
reaction (4-CR), only changes in the structure of one
component, namely 4, leads to variation in the structure of
the final hydantoin 5. Thus, for every 5,5¢-disubstituted
hydantoin to be synthesized, the corresponding ketone
with the correct R and R1 groups has to be made or pur-
chased. To increase the utility of this chemistry in drug
discovery programmes, it would be desirable to generate
Scheme 1
Initial studies were undertaken to ascertain whether
Bucherer–Bergs reactions can be performed in solvent
mixtures containing THF, an ideal solvent for organome-
tallic additions to nitriles.10,11 These experiments were
performed on n-butyl phenyl ketone (1 mmol scale) under
a standard set of reaction conditions [KCN (3 equiv),
CO3(NH4)2 (6 equiv), 75 °C, 24 h].12 The reaction solvent
was varied (total volume constant at 9 mL) and the extent
of conversion to the corresponding hydantoin (5a, R = Ph,
1
R1 = Bu) monitored by H NMR spectroscopy. In THF–
H2O (1:1), no appreciable conversion (<15%) to 5a was
observed. Similar results were obtained using the ternary
solvent system, THF–H2O–EtOH (2:1:1). However, re-
ducing the amount of THF [THF–H2O–EtOH, 1:4:4) did
improve the conversion to 47%. Complete conversion
(>95%) was achieved using these latter conditions when a
SYNLETT 2006, No. 14, pp 2203–2206
0
1
.0
9
.2
0
0
6
Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-949644; Art ID: D11506ST
© Georg Thieme Verlag Stuttgart · New York

2204
C. Montagne, M. Shipman
LETTER
low concentrations, the planned one-pot sequence was at-
tempted. Gratifyingly, treatment of benzonitrile with n-
BuLi at 0 °C in THF for 30 min smoothly generated the
lithiated imine. Direct addition of EtOH (to quench the ex-
cess organolithium) then KCN, CO3(NH4)2 and H2O, and
subsequent heating at 75 °C produced crystalline 5a in
70% yield via this one-pot process (Table 1, entry 1).13,14
The scope of this new 4-CR has been explored using a
range of commercially available nitriles and easily acces-
sible organolithiums (Table 1). Considerable variation in
the nature of the nitrile (Table 1, entries 1, 2, 4, and 6–11)
and the organolithium reagent (Table 1, entries 1–3, 5 and
12) can be achieved. The reaction shows good functional-
group tolerance (Table 1, entries 5 and 7–11) and offers a
simple, practical route to 5,5¢-disubstituted hydantoins.
Table 1 Selection of Hydantoins Made Using Organolithium
Reagents
O
1. R1Li, THF, 0 °C, 30 min
HN
R
N
NH
R1
2. KCN, CO3(NH4)2, EtOH–H2O (1:1),
75 °C, sealed tube, 24 h
O
R
7
5a–l
Entry RCN
R1Li
Hydantoin Yield (%)a
1
2
3
4
PhCN
BuLi
MeLi
PhLi
MeLi
5a
70
64
61
75
Me(CH2)4CN
Me(CH2)4CN
5b
5c
5d
CN
Grignard reagents can also be used in this modified
Bucherer–Bergs process. In this instance, the organome-
tallic addition to the nitrile is more sluggish and requires
prolonged heating in the presence of catalytic amounts of
copper(I) iodide10 to facilitate complete conversion to the
metallated imine 8 (M = MgX). However, under these
conditions, good yields of a range of functionalised hy-
dantoins can be produced (Table 2).14,15 The results indi-
cate that appreciable variation in the structure of the nitrile
and Grignard reagent is possible.
5
5e
50b
CN
Li
N
6
7
t-BuCN
MeLi
5f
75
MeLi
5g
45c
CN
N
H
8
9
BuLi
PhLi
5h
5i
84
92
CN
F
Table 2 Selection of Hydantoins Made Using Grignard Reagents
O
1. R1MgX, cat. CuI, THF, 70 °C, 24 h
HN
CN
R
N
NH
R1
2. KCN, CO3(NH4)2, EtOH–H2O (1:1),
75 °C, sealed tube, 24 h
O
R
7
5a, 5m–s
OMe
CN
10
11
12
PhLi
PhLi
Li
5j
5k
5l
54
Entry RCN
1
R1MgX
Hydantoin Yield (%)a
5m
58
CN
MgBr
S
NMe2
CN
2
3
4
5
6
t-BuCN
PhCH2MgCl
BuMgCl
5n
5o
5a
5p
5q
74
58
57
77
40
88
t-BuCN
PhCN
PhCN
CN
BuMgCl
O
O
PhCH2MgCl
t-BuMgCl
53d
CN
F
OMe
OMe
OMe
7
8
5r
5s
65
61
CN
MgCl
a Isolated yield of product. All reactions performed using the proce-
dure described in ref. 13.
b Organolithium made by deprotonation of (2-methyl)pyridine using
n-BuLi. This example was conducted in Et2O.
OMe
c Conducted using MeLi (2.4 equiv).
CN
d Organolithium prepared in situ by lithium–iodine exchange.
MgBr
S
sealed tube was used to prevent release of the ammonia
and carbon dioxide generated. In this way, hydantoin 5a
was isolated in 77% yield. Once it was established that
THF is tolerated in Bucherer–Bergs reactions, albeit at
Cl
Cl
a Isolated yield of product. All reactions performed using the proce-
dure described in ref. 15.
Synlett 2006, No. 14, 2203–2206 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of 5,5¢-Disubstituted Hydantoins
2205
mixture is stirred for 30 min at 0 °C then carefully quenched
with EtOH (4 mL). Then, (NH4)2CO3 (576 mg, 6 mmol),
KCN (197 mg, 3 mmol; CAUTION) and H2O (4 mL) are
successively added and the tube is sealed. The hetero-
geneous solution is heated at 75 °C (preheated bath) for 24 h
then allowed to cool to r.t. The mixture is poured into H2O
(50 mL) and extracted with EtOAc (2 × 25 mL). The
combined organic extract is washed with brine (25 mL),
dried over MgSO4 and evaporated to dryness. The resulting
solid is washed with n-pentane (2 × 10 mL) and dried under
high vacuum to yield the hydantoin in a high state of purity
as judged by NMR analysis and microanalytical data.
To conclude, this chemistry offers a simple, practical
method for the synthesis of 5,5¢-disubstituted hydantoins
exploiting two points of diversity. Since all the hetero-
cycles produced in these modified Bucherer–Bergs reac-
tions are isolated in high purity without recourse to
chromatography,13,15 this chemistry seems well suited for
the rapid generation of hydantoin chemical libraries.16
Work in this direction continues in our laboratories.
Acknowledgment
(14) Selected Data.
The Engineering and Physical Sciences Research Council (GR/
R82586/02) is gratefully acknowledged for financial support.
Compound 5f: mp 228–229 °C. IR (neat): 3169, 2961, 1750,
1717, 1430, 1370, 1108, 764 cm–1. 1H NMR (400 MHz,
DMSO-d6): d = 0.92 (s, 9 H), 1.24 (s, 3 H), 7.95 (s, 1 H),
10.50 (s, 1 H). 13C NMR (100 MHz, DMSO-d6): d = 18.8,
24.5, 36.1, 66.8, 156.7, 178.2. MS (ES): m/z = 169 [M –
H]–. HRMS (EI): m/z calcd for C8H12N2O2: 171.1134; found:
171.1128. Anal. Calcd for C8H14N2O2 (%): C, 56.45; H,
8.29; N, 16.46. Found: C, 56.52; H, 8.35; N, 16.35.
Compound 5h: mp 181–182 °C. IR (neat): 3180, 3052,
2927, 1774, 1709, 1432, 1232, 813, 756 cm–1. 1H NMR (400
MHz, DMSO-d6): d = 0.89 (t, J = 7.0 Hz, 3 H), 1.09–1.20
(m, 1 H), 1.24–1.41 (m, 3 H), 2.00–2.09 (m, 2 H), 7.21 (dt,
J = 1.0, 7.0 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 1 H), 7.38–7.45 (m,
1 H), 7.53 (dt, J = 1.5, 8.2 Hz, 1 H), 8.31 (s, 1 H), 10.87 (s,
1 H). 13C NMR (100 MHz, DMSO-d6): d = 13.9, 22.0, 24.8,
34.7, 64.9, 116.3 (d, J = 22 Hz), 124.4 (d, J = 3 Hz), 126.3
(d, J = 11 Hz), 128.1 (d, J = 3 Hz), 130.4 (d, J = 9 Hz),
156.7, 160.4 (d, J = 247 Hz), 176.1. MS (ES): m/z = 249
[M – H]–. HRMS (EI): m/z calcd for C13H15FN2O2:
250.1118; found: 250.1114. Anal. Calcd for C13H15FN2O2
(%): C, 62.39; H, 6.04; N, 11.19. Found: C, 62.50; H, 6.11;
N, 11.01.
Compound 5j: mp 244–245 °C. IR (neat): 3304, 3191, 1775,
1759, 1728, 1710, 1411, 1023, 747, 693 cm–1. 1H NMR (400
MHz, DMSO-d6): d = 2.88 (s, 6 H), 6.70 (d, J = 8.8 Hz, 2 H),
7.11 (d, J = 8.8 Hz, 2 H), 7.29–7.40 (m, 5 H), 9.12 (s, 1 H),
10.9 (s, 1 H). 13C NMR (100 MHz, DMSO-d6): d = 40.0,
69.8, 111.9, 126.6, 127.1, 127.2, 127.7, 128.3, 140.4, 149.8,
156.0, 175.4. MS (ES): m/z = 294 [M – H]–. HRMS (EI):
m/z calcd for C17H17N3O2: 295.1321; found: 295.1317. Anal.
Calcd for C17H17N3O2 (%): C, 69.14; H, 5.80; N, 14.23.
Found: C, 68.80; H, 5.88; N, 13.96.
References and Notes
(1) (a) Ware, E. Chem. Rev. 1950, 46, 403. (b) López, C. A.;
Trigo, G. G. Adv. Heterocycl. Chem. 1985, 38, 177.
(c) Meusel, M.; Gütschow, M. Org. Prep. Proced. Int. 2004,
36, 391.
(2) Nakabayashi, M.; Regan, M. M.; Lifsey, D.; Kantoff, P. W.;
Taplin, M.-E.; Sartor, O.; Oh, W. K. Br. J. Urol. Int. 2005,
96, 783.
(3) Bazil, C. W. Curr. Treat. Options Neurol. 2004, 6, 339.
(4) Nakajima, M.; Itoi, K.; Takamatsu, Y.; Kinoshita, T.;
Okazaki, T.; Kawakubo, K.; Shindo, M.; Honma, T.;
Tohjigamori, M.; Haneishi, T. J. Antibiot. 1991, 44, 293.
(5) Burton, S. G.; Dorrington, R. A. Tetrahedron: Asymmetry
2004, 15, 2737.
(6) For recent illustrative examples, see: (a) Zhang, D.; Xing,
X. C.; Cuny, G. D. J. Org. Chem. 2006, 71, 1750.
(b) Ignacio, J. M.; Macho, S.; Marcaccini, S.; Pepino, R.;
Torroba, T. Synlett 2005, 3051. (c) Patel, V. M.; Desai, K.
R. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
2005, 44, 1084. (d) Manku, S.; Curran, D. P. J. Org. Chem.
2005, 70, 4470. (e) Alsina, J.; Scott, W. L.; O’Donnell, M. J.
Tetrahedron Lett. 2005, 46, 3131. (f) Volonterio, A.; de
Arellano, C. R.; Zanda, M. J. Org. Chem. 2005, 70, 2161.
(7) (a) Bergs, H. DRP 566094, 1929. (b) Bucherer, H. T.;
Brandt, W. J. Prakt. Chem. 1934, 140, 129. (c) Bucherer,
H. T.; Steiner, W. J. Prakt. Chem. 1934, 140, 291.
(d) Bucherer, H. T.; Lieb, V. A. J. Prakt. Chem. 1934, 141,
5; see also ref. 1a.
Compound 5m: mp 199 °C (decomp.). IR (neat): 3227,
2958, 1767, 1736, 1713, 1396, 1232, 1006, 763, 710 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.14–1.32 (m, 2 H),
1.44–1.66 (m, 6 H), 2.63–2.73 (m, 1 H), 7.02 (dd, J = 3.8,
5.0 Hz, 1 H), 7.09 (dd, J = 1.3, 3.8 Hz, 1 H), 7.48 (dd,
J = 1.3, 5.0 Hz, 1 H), 8.83 (s, 1 H), 10.83 (s, 1 H). 13C NMR
(100 MHz, DMSO-d6): d = 25.0, 25.4, 26.2, 26.8, 46.6, 68.5,
124.5, 125.8, 127.0, 143.1, 156.9, 175.1. MS (ES): m/z = 249
[M – H]–. HRMS (EI): m/z calcd for C12H14N2O2S:
250.0776; found: 250.0767. Anal. Calcd for C12H14N2O2S
(%): C, 57.58; H, 5.64; N, 11.19. Found: C, 57.91; H, 5.80;
N, 11.04.
Compound 5q: mp 244–245 °C. IR (neat): 3250, 3042,
1760, 1712, 1598, 1450, 1255, 758 cm–1. 1H NMR (400
MHz, DMSO-d6): d = 0.92 (s, 9 H), 3.74 (s, 3 H), 6.88–6.92
(m, 1 H), 7.22–7.30 (m, 3 H), 8.91 (s, 1 H), 10.80 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 24.8, 37.8, 55.1, 71.9,
112.5, 113.8, 119.6, 128.3, 137.6, 156.3, 158.4, 175.3. MS
(ES): m/z = 261 [M – H]–. HRMS (EI): m/z calcd for
C14H19N2O3: 263.1396; found: 263.1384. Anal. Calcd for
C14H18N2O3 (%): C, 64.10; H, 6.92; N, 10.68. Found: C,
64.00; H, 6.95; N, 10.59.
(8) For recent applications, see: (a) Wermuth, U. D.; Jenkins, I.
D.; Bott, R. C.; Byriel, K. A.; Smith, G. Aust. J. Chem. 2004,
57, 461. (b) Micová, J.; Steiner, B.; Koós, M.; Langer, V.;
Gyepesová, D. Carbohydr. Res. 2003, 338, 1917.
(c) Micová, J.; Steiner, B.; Koós, M.; Langer, V.;
Gyepesová, D. Synlett 2002, 1715.
(9) A similar approach has been used to improve and extend
other multicomponent reactions, see: (a) Simoneau, C. A.;
Ganem, B. Tetrahedron 2005, 61, 11374. (b) Simoneau, C.
A.; George, E. A.; Ganem, B. Tetrahedron Lett. 2006, 47,
1205.
(10) Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1987, 52, 3901; and
references cited therein.
(11) Wakefield, B. J. The Chemistry of Organolithium
Compounds; Pergamon: Oxford, 1974.
(12) Lower conversion was observed when the quantities of KCN
and (NH4)2CO3 were reduced.
(13) Experimental Method (Using RLi).
In a flame dried ACE thick-walled pressure tube under
nitrogen, are successively added THF (1 mL) and the
organolithium reagent (1.2 mmol). The solution is cooled to
0 °C whereupon the nitrile (1.0 mmol) is added. The reaction
Synlett 2006, No. 14, 2203–2206 © Thieme Stuttgart · New York

2206
C. Montagne, M. Shipman
LETTER
(15) Experimental Method (Using RMgX).
quenched with EtOH (4 mL). Then, (NH4)2CO3 (576 mg,
6 mmol), KCN (197 mg, 3 mmol; CAUTION) and H2O
(4 mL) are successively added and the tube is sealed. The
heterogeneous solution is heated at 75 °C (preheated bath)
for 24 h then allowed to cool to r.t. The hydantoin is isolated
using the same work-up and crystallisation protocol
described in ref. 12.
In a flame-dried ACE pressure tube under nitrogen, are
successively added copper iodide (9.5 mg, 0.05 mmol), THF
(1 mL) and the organomagnesium reagent (1.2 mmol)
immediately followed by the nitrile [1 mmol; either as liquid
or in THF (1 mL) if solid]. The vessel is quickly heated to
70 °C (preheated bath) and maintained at this temperature
for 24 h. Upon cooling to r.t., the reaction is carefully
(16) Shipman, M.; Montagne, C. GB 0603239.5, 2006.
Synlett 2006, No. 14, 2203–2206 © Thieme Stuttgart · New York