Friedel-Crafts-type reactions with ureas and thioureas

Article abstract of DOI:10.1039/c2cc34062c

Despite the relatively low reactivities of urea and thiourea functional groups towards nucleophilic attack, we have found conditions in which they are useful substrates in Friedel-Crafts reactions. The Bronsted superacid, triflic acid, promotes these reactions and a mechanism is proposed involving dicationic, superelectrophilic intermediates.

Full text of DOI:10.1039/c2cc34062c

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Friedel-Crafts-type reactions with ureas and thioureas
Erum K. Raja,a Sten O. Nilsson Lill,b and Douglas A. Klumpp*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
effects of the aryl group. Our studies began with cyclizations of
50 phenethylamineꢀbased ureas (eq 1). The urea substrates (1-2)
were readily prepared by the reactions of phenethylamine and the
appropriate aryl isocyanate. When 1ꢀphenethylꢀ3ꢀphenylurea (1)
5
Despite the relatively low reactivities of urea and thiourea
functional groups towards nucleophilic attack, we have found
conditions in which they are useful substrates in Friedel-
Crafts reactions. The Brønsted superacid, triflic acid,
promotes these reactions and a mechanism is proposed
is reacted with CF
found in the product mixture. In contrast, the same reaction with
55 1ꢀ(2ꢀnitrophenyl)ꢀ3ꢀphenethylurea (2) provides nearly
3
SO
3
H at 50°C, only the starting material is
10 involving dicationic, superelectrophilic intermediates.
a
quantitative yield of 3,4ꢀdihydroisoquinolinꢀ1(2H)ꢀone (3). The
same product (3) is obtained in 85% yield with use of the 1ꢀ(4ꢀ
nitrophenyl)ꢀ3ꢀphenethylurea. Clearly, the nitro group can have a
profound effect on the reactivity of Nꢀphenylureas.
Following these conversions, a series of ureas (4-10) were
prepared for cyclization reactions (Table 1).8 Simple alkyl and
phenyl substituted derivatives (4-6) undergo cyclizations to give
the respective heterocyclic products (11-13). In an effort to
prepare other diverse structures, the branched derivatives (7-9)
Known since the 1870s, FriedelꢀCrafts reactions involve the
reactions of cationic electrophiles with arene nucleophiles.1 They
commonly involve reactive intermediates such as acyl cations,
carbocations, carboxonium ions, iminium ions, and other
15 species.2 These reactions are of great practical value, being used
to produce chemical feedstock, synthetic intermediates, and fine
chemicals. Recently, we reported several new methods of
accomplishing FriedelꢀCrafts acylation using amides.3 Amides
have not generally been considered viable substrates for Friedelꢀ
20 Crafts chemistry primarily because the strong amide bond
prevents cleavage to the acyl cation. Moreover, resonance
interactions are thought to raise the energy of the LUMO at the
carbonyl group ꢀ inhibiting direct nucleophilic attack. In our
acylations using amides, we utilized the high reactivities of
25 dicationic superelectrophiles. Amide activation involved chargeꢀ
charge repulsive effects and diminished amide resonance.3
Ureas or carbamides are another functional group known for
low reactivity towards nucleophiles. This stability is evident by
the remarkably slow hydrolysis rates of ureas.4 Indeed, the ureas
30 represent perhaps the weakest of all carbonylꢀcentered
electrophiles. Not surprisingly, there have been no previous
reports of ureas being using in FriedelꢀCrafts chemistry, as arenes
are also very weak nucleophiles. Recent work by Hutchby et al.
has shown that ureas may undergo activation by Nꢀprotonation
35 leading to cleavage and solvolysis reactions.5 The proposed
mechanism invokes cleavage of the urea to an isocyanate and
nucleophilic attack by the solvent (methanol) to provide
carbamate products. Since isocyanates are known to be useful in
FriedelꢀCraftsꢀtype reactions (giving amide products),6 we sought
40 to determine if ureas could provide aromatic amides through
analogous chemistry. In the following Communication, we
describe FriedelꢀCraftsꢀtype reactions with urea and thiourea
substrates.
60
65 were also reacted in superacid. Although the methylꢀsubstituted
urea (7) reacted smoothly to provide compound 14 in good yield,
the (S)ꢀprolinolꢀderived urea
8
did not give
a
3,4ꢀ
dihydroisoquinolinꢀ1(2H)ꢀone but rather cyclized to the
benzylsubstituted oxazolidinone (15). Since the hydroxyl group is
70 a stronger nucleophile than a phenyl group, cyclization occurs at
the hydroxymethyl and product 15 is formed. The desired 3,4ꢀ
dihydroisoquinolinꢀ1(2H)ꢀone ring may be formed however, if
the hydroxyl group is blocked the nicotinoyl group. Thus,
compound 9 undergoes cyclization to provide heterocycle 16 in
75 good yield. Under the acidic reaction conditions, the pyridyl ring
is completely protonated and the ester exhibits little or no
nucleophilic reactivity, allowing for cyclization at the phenyl
group. Finally, urea 10 also provides the cyclization product,
isoindolinꢀ1ꢀone 17, although the yield is somewhat lower than
80 the reactions giving 3,4ꢀdihydroisoquinolinꢀ1(2H)ꢀones. In
addition to the reactions of ureas, several thiourea substrates were
examined and also found to provide the cyclization products (eq
2). The phenethylamineꢀderived thiourea 18 gives the 3,4ꢀ
dihydroisoquinolineꢀ1(2H)ꢀthione (21) in fair yield, while the
85 tolyl and chlorophenyl derivatives (19-20) provide the respective
heterocycles (22-23) in good yields.
Both urea and thiourea substrates were also found to undergo
intermolecular reactions in reactions with benzene. For example,
Nꢀphenylbenzamide (28) is produced in 68% yield from the urea
90 24 (Table 2). The piperidinyl urea 25 also gives products from
carboxamidation of benzene (29) and toluene (30), though the
yields are somewhat low. Surprisingly, the urea from
Previously, Shudo and coꢀworkers had demonstrated the high
45 reactivities of species bearing nitroꢀsubstituted aryl groups when
the reactions are done in superacidic media.7 We reasoned that
nitrophenylꢀsubstituted ureas might exhibit an enhanced level of
electrophilic reactivity by virtue of the electron withdrawing
benzylamine (26) provides nearly
a quantitative yield of
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triphenylmethanol (31) from reaction with benzene in triflic acid.
birthday.
The thiourea 27 also provides a FriedelꢀCraftsꢀtype product with
benzene, as the thioamide 32 is isolated in 53% yield. Finally,
1,3ꢀbisꢀ(4ꢀnitrophenyl)urea (33) reacts with benzene in triflic acid
to give benzophenone (34) in good yield (eq 3). This conversion
likely involves formation of the amide 35 ꢀ a compound which is
known to provide benzophenone in high yield under the reaction
conditions.3c
1
2
C. Friedel, J. M. Crafts Compt. Rend. 1877, 84,1450.
65
70
75
80
85
P. H. Gore in Friedel-Crafts and Related Reactions; G. A.
Olah, Ed.; John Wiley & Sons Inc.: London, 1964, Vol. III,
Part I, p. 1.
(a) D. A. Klumpp, R. Rendy, Y. Zhang, A. Gomez, A.
McElrea, Org. Lett. 2004, 6, 1789. (b) “FriedelꢀCrafts
Acylation with Amides” Raja, E. K.; DeSchepper, D. J.;
Klumpp, D. A. Abstracts of Papers, 243th ACS National
Meeting, San Diego, CA, United States, March 25ꢀ29, 2012,
ORGNꢀ463. (c) Manuscript submitted.
R. L. Blakeley; A. Treston; R. K. Andrews; B. Zerner J. Am.
Chem. Soc. 1982, 104, 612.
M. Hutchby, C. E. Houlden, J. G. Ford, S. N. G. Tyler, M. R.
Gagné, G. C. LloydꢀJones, K. I. BookerꢀMilburn Angew.
Chem. Int. Ed. 2009, 48, 8721.
5
3
For the reactions of the urea substrates, a mechanism is
10 proposed involving protonation of the nitro group and urea
nitrogen, cleavage to the protonated isocyanate, followed by
reaction with the arene nucleophile (Scheme 1). To examine this
mechanism, theoretical calculations were done to study the
reaction of urea 24 with acid.9 Urea substrates are relatively
15 strong bases. The pKa values for protonated ureas range from
about +2 to ꢀ2.10 As one of the strongest Brønsted acids,10 triflic
acid should completely protonate the urea substrates and
4
5
6
7
D. Gauvreau, S. J. Dolman, G. Hughes, P. D. O’Shea, I. W.
Davies J. Org. Chem. 2010, 75, 4078.
(a) T. Ohta, K. Shudo, T. Okamoto Tetrahedron Lett.1984, 25,
325. (b) T. Ohta, R. Machida, K. Takeda, Y. Endo, K. Shudo,
T. Okamoto J. Am. Chem. Soc. 1980, 102, 6386.
Triflic acid may be quantitatively recovered and recycled, see:
Booth, B. L.; ElꢀFekky, T. A. J. Chem. Soc. Perkin Trans. I
1979, 2441.
equilibria
would
be
established
with
deprotonated
8
9
superelectrophilic species. Thus, urea 24 would form the
20 monocation 36 by protonation of the carbonyl oxygen. A second
protonation at the nitro group leads to dication 37 – the most
stable dicationic species. Hutchby’s recent work demonstrated
that protonation of the urea nitrogen may lead to cleavage
reactions.5 Equilibration with the O,Nꢀdiprotonated species 38 is
25 estimated to require +11.3 kcal/mol of energy and the transition
state leading to carbonꢀnitrogen bond cleavage (39) is about
+17.3 kcal/mol above dication 37. At the reaction temperature of
60°C, this should be a readily surmountable barrier. Previous
studies have shown that dicationic superelectrophiles tend to
30 favor reaction steps that separate or jettison charge from the
multiply charged ions.12 Cleavage to the monocations (protonated
o-nitroaniline 40 and isocyanate 41) serves this purpose. Product
28 is then formed by a FriedelꢀCraftsꢀtype reaction of the 41 and
the arene nucleophile. Presumably, a similar mechanism operates
35 for the intramolecular reactions and the conversions involving
thioureas. It is not presently clear how triphenylmethanol 31
arises from urea 26, but a possible route involves some type of
cleavage reaction to liberate the benzyl cation.
Full description of the computations is found in the Supporting
Information section.
10 E. M. Arnett Prog. Phys. Org. Chem. 1963, 1, 223.
11 G. A. Olah, G. K. S. Prakash, A. Molnar, J. M. Sommer
Superacids, 2nd Ed.; John Wiley & Sons Inc.: New York, 2009.
12 (a) D. A. Klumpp Chem. Eur. J. 2008, 14, 2004. (b) R. R.
Naredla; C. Zheng; S. O. Nilsson Lill; D. A. Klumpp J. Am.
Chem. Soc. 2011, 133, 13169.
90
95
40 We have found that urea and thiourea substrates will participate
in superacid catalysed FriedelꢀCraftsꢀtype reactions. Both intra
and intermolecular reactions have been demonstrated, although
the intramolecular conversions were generally more efficient.
This is
45 dihydroisoquinolinꢀ1(2H)ꢀones and related thiones. A mechanism
is proposed involving formation of diprotonated,
a
particularly good synthetic route to 3,4ꢀ
superelectrophilic intermediates and cleavage to isocyanateꢀtype
electrophiles.
50 Notes and references
Department of Chemistry and Biochemistry, Northern Illinois University,
DeKalb, Illinois 60115, United States. Fax: 815-753-4802; Tel: 815-753-
1959; E-mail: dklumpp@niu.edu
b Department of Chemistry and Molecular Biology, University of
55 Gothenburg, SE-412 96 Gothenburg, Sweden. Fax: +46-31-772 3840;
Tel: +46-31-772 3840; E-mail: stenil@chem.gu.se
† Electronic Supplementary Information (ESI) available: experimental
procedures, NMR spctra of new compounds, and details of computational
studies.
60
‡
Dedicated to Professor George A. Olah on the occasion of his 85th
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Table 1. Products and yields from reactions of ureas (4-10) with
CF3SO3H.
5
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Table 2. Products and yields from reactions of substrates (24-27)
with CF3SO3H and benzene or toluene.
5
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O
OH
NHPh
N
CF3SO3H
C6H6
NHPh
N
H
H
NO2
24
NO2
36
OH
O
HO2N HN
HO2N
N
H
NHPh
NHPh
H
37
38
Relative
Energy:
0.0
+11.3
O
C
O
δ
NHPh
δ
HO2N
N
O2N
N H
N
H
H
H
Ph
H
H
39
+17.3
40
41
-11.9
C6H6
28
OH
OH
NHPh
H
+ C6H6
HO2N HN
HO2N HN
PhHN
37
42
Relative
Energy:
+48.2
0.0
5
Scheme 1. Proposed mechasnim with calculated relative free
energies (kcal/mol) in solution for M06/6ꢀ31G(d) optimized
structures of intermediates and transition state (39) for urea 24
cleavage. Alternative reaction path with tetrahedral intermediate
42.
10
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Graphical abstract:
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