Super fast cobalt carbonyl-mediated synthesis of ureas

Article abstract of DOI:10.1016/j.tetlet.2005.03.076

Fast cobalt carbonyl-mediated generation of ureas from primary amines was performed using high-density microwave irradiation. This enhanced method permitted the preparation of symmetrical ureas in good yields and unsymmetrical ureas in moderate yields. Th

Full text of DOI:10.1016/j.tetlet.2005.03.076

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3335–3339
Super fast cobalt carbonyl-mediated synthesis of ureas
Per-Anders Enquist, Peter Nilsson, Johan Edin and Mats Larhed*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box-574, SE-75123 Uppsala, Sweden
Received 9 February 2005; revised 8 March 2005; accepted 15 March 2005
Available online 2 April 2005
Abstract—Fast cobalt carbonyl-mediated generation of ureas from primary amines was performed using high-density microwave
irradiation. This enhanced method permitted the preparation of symmetrical ureas in good yields and unsymmetrical ureas in
moderate yields. The reaction times varied between 10s and 40min. The proposed mechanism for the reaction includes in situ genera-
tion of an intermediate isocyanate that subsequently traps the free amine, producing the urea product.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
O
Co2(CO)8
H
R
R
R
N
H
N
H
N
H
NEt3, MeCN
10 s - 40 min
Ureas are of fundamental importance in both pharma-
ceutical and agricultural applications but demand sensi-
tive and aggressive reagents when manufactured. The
classical synthetic methods are based on the use of phos-
gene,1 isocyanates,2 or carbonyldiimidazole.3 Alterna-
tively, protocols for the generation of urea structures
by metal-catalyzed oxidative carbonylation under high-
pressure CO-gas have been identified.4,5 Examples of
urea syntheses in domestic microwave oven were also
recently reported.6,7
1a - j
2a - j
Scheme 1.
selective transformations and new functional group
interconversions after only 10–15 s of single-mode
microwave heating.13,14 In this short communication,
we wish to present the successful enhancement of a
hitherto little developed dicobalt octacarbonyl-mediated
The development of high-speed synthesis continues to be
a key objective within the explorative pharmaceutical
industry.8 In laboratories of today, the increasing use
of automation, together with the invention of dedicated
equipment for high-throughput purification have greatly
accelerated compound production.9 Controlled micro-
wave irradiation has proved to be an additional power-
ful technique both for enhancing preparative chemistry
and for speeding up the Ôhypothesis-iterationÕ process
in the optimization of novel chemistry.10,11 The syn-
thetic expedience of this heating method is of special
importance for reactions requiring a high temperature
and harsh conditions. We have applied this form of
super heating previously in our attempts to discover
not only fast reactions, but super fast organic reac-
tions.12 Thus, our group recently reported highly stereo-
Keywords: Microwave; Carbonylation; Cobalt carbonyl; Urea;
Isocyanate.
Figure 1. Temperature, power, and pressure profiles from 10s of
microwave heating (Table 1, entry 1). Note that the microwave power
is divided into two separate pulses separated by 2 s.13
*
Corresponding author. Tel.: +46 18 471 4667; fax: +46 18 471
4474; e-mail: mats@orgfarm.uu.se
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.076

3336
P.-A. Enquist et al. / Tetrahedron Letters 46 (2005) 3335–3339
protocol for direct and CO-free15 high-speed prepara-
tion of ureas from various amines.
metal-coordinating ability were evaluated. The results
obtained during these studies provided the selected
reaction conditions. The choice of acetonitrile as solvent
was not self-evident, especially compared to the prepara-
tive results with non-polar toluene.
1.1. Symmetrical ureas
Initial experiments were carried out using Co2(CO)8 and
several primary amines 1 to assess appropriate condi-
tions for the microwave-assisted amine to urea 2 trans-
formation depicted in Scheme 1. Importantly, the
reactions were carried out in sealed microwave-transpar-
ent vessels under air without an external CO-source.15
Several bases,16 additives,17 and solvents of different
Acetonitrile is a frequently used solvent for reactions
performed under microwave irradiation because of its
relatively high ability to absorb microwave energy.10
In contrast, toluene has a lower dissipation factor and
therefore a slower heating profile (Fig. 1). To compare
Table 1. Rapid microwave-heated generation of symmetrical ureas from primary aminesa
Entry
Amine
Time (s)
10Variable
Temp (°C)
Product
Yieldb (%)
84
c
H
N
H
N
NH2
10Variable
10Variable
10Variable
5 h
62
61
84
1
d
e
O
1a
2a
Rt
Rt
75
O
C6H
C6H11
11 N
H
N
H
NH2
2
3
4
10Variable
5 h
83
81
1b
2b
O
NH2
N
H
N
H
13
600
Variable
130g
74
75f
1c
2c
O
NH2
N
N
H
10Variable
10Variable
66
68
O
H
1d
O
O
2d
O
NH2
N
H
N
5
F3C
H
1e
F3C
CF3
2e
O
6
7
10Variable
10Variable
O
N
N
H
O
86
61e
O
NH2
1f
H
Variable
2f
O
NH2
N
H
N
H
10
61
38
46f
1g
2g
O
NH2
120g
120g
150g
N
H
N
H
8
1200
1200
2400
1h
2h
O
9
N
H
N
H
NH2
1i
2i
H
N
H
N
NH2
10
O
O
2j
O
O
1j
a Employing 1.0equiv amine, 0.66 equiv Co 2(CO)8, and 2.0equiv triethylamine in 2.5 mL acetonitrile.
b Isolated yield based on 1 (>95% purity of 2 by GC–MS). Variable temp (Tmax = 120 °C, see Fig. 1).
c DMSO as solvent. Variable temp (Tmax = 10 5°C).
d THF as solvent. Variable temp (Tmax = 10 5°C).
e Toluene as solvent. Variable temp (Tmax = 60 °C, see Fig. 1).
f 1.0equiv of propylene carbonate added.
g Constant temp.

P.-A. Enquist et al. / Tetrahedron Letters 46 (2005) 3335–3339
3337
the two solvents, a set of test reactions was performed
O
Co2(CO)8
O
1
using amines 1a and f (Table 1). It is interesting to note
the identical yield after a 10s reaction time (entry 1)
with the outcome in entry 6. Thus, to identify a general
protocol, acetonitrile was chosen as the standard sol-
vent. All entries in Table 1 were optimized toward reac-
tion rate and reaction yield. The 10–13 s reactions
utilized maximum microwave power (300 W) while the
slower transformations were performed at constant tem-
perature (entry 3 at 130 °C, entries 8 and 9 at 120 °C, en-
try 10at 150 °C). The limited tolerance of functional
groups present in the substrates was probably a conse-
quence of interfering coordination to the cobalt metal.
Alkyl fluorides (entry 5) and ethers (entries 4, 6, and
10) are non-coordinating, or only weakly coordinating
to cobalt, and their presence did not reduce the yield.
However the presence of alkene (entry 7), ester and alco-
hol functionalities instead decreased the yield drasti-
cally. The reactions of the aliphatic amines 1a and b
with cobalt carbonyl could also be conducted without
irradiation at room temperature, but at the expense of
increased reaction times and somewhat lower yields.
Sterically hindered 1h,i, and sluggish 1j demanded pro-
longed heating to afford workable yields. Unsubstituted
aniline furnished less than 5% yield according to
GC–MS after 20min at 120 °C with the standard reac-
tion protocol. For anilines to function, an electron-
donating p-methoxy group was needed to increase the
nucleophilicity, 1j. In entry 10, propylene carbonate
was also added to stabilize the cobalt carbonyl at higher
temperatures and to improve the conversion of 1j.18 The
work-up procedure of the cold product mixture was
convenient, involving simple dilution with CH2Cl2 and
washing with hydrochloric acid (0.1 M) until it became
colorless.19 After separation, drying, and evaporation
of the organic phase, pure product 2 was isolated.
R
R
R
C
R
NH2
N
H
N
N
H
1
3
2
Scheme 2.
3, and 10( Table 1). These observations gave rise to our
mechanistic proposal with an isocyanate 3 as the key
intermediate, capturing the free primary amine 1, or
alternatively, undergoing self-condensation20 to form
the urea 2 (Scheme 2). In support of the proposed isocy-
anate route, amine 1b reacts immediately with pre-
formed isocyanate 3b in acetonitrile to afford a 93%
isolated yield of urea 2b. However, Hong and Chang
have recently published an alternative mechanism based
on density functional calculations and not involving free
isocyanate as an intermediate.21
1.2. Unsymmetrical ureas
A method for direct preparation of unsymmetrical ureas
without using isolated isocyanates,22 solid-supported
reactants23,24 or sensitive phosgene equivalents would
be of great synthetic value. However, when two different
primary amines were used in our standard Co2(CO)8-
protocol, a mixture of products was consistently formed.
In order to bypass this problem, we used a primary
amine 1 in combination with an excess of a secondary
amine (Scheme 3).
R'2NH 4
(excess)
O
O
Co2(CO)8
R
R'
R
R
C
NH2
N
H
N
N
R'
1
3
5
While monitoring the preparative outcome by GC–MS,
small amounts of isocyanate 3 were detected in entries 1,
Scheme 3.
Table 2. Rapid microwave-heated generation of unsymmetrical ureas from primary and secondary aminesa
Entry
Amines
Time (s)
Product
Yieldb (%)
n-Pr
H
44
25c
N
N
1
1a + HN(n-Pr)2
4a
10
n-Pr
O
5a
H
N
N
2
3
1a + HN
10
10
35
55
4b
O
5b
n-Pr
H
N
N
1b + 4a
1f + 4a
n-Pr
O
5c
5d
n-Pr
H
N
O
N
4
10
41
n-Pr
O
a Employing 1.0equiv primary amine, 5.0equiv secondary amine, 0.66 equiv Co 2(CO)8, and 2.0equiv triethylamine in 2.5 mL acetonitrile. Variable
temp (Tmax = 110 °C).
b Isolated yield based on 1 (>95% purity of 5 by GC–MS).
c 20min of microwave irradiation at 130 °C.

3338
P.-A. Enquist et al. / Tetrahedron Letters 46 (2005) 3335–3339
In this way, 1 generates the corresponding isocyanate
via an initial reaction with Co2(CO)8, before the nucleo-
philic attack by the secondary amine 4 delivers the
unsymmetrical urea 5. The preparative results are
presented in Table 2, employing 10s of heating and
5 equiv of 4. This one-pot, two-step reaction furnished
unsymmetrical ureas in workable yields (35–55%), utiliz-
ing the same quick purification protocol as described
above. Notably, some of the yields of 5 were modest de-
spite full conversion after 10s of heating, probably as a
consequence of side reactions in which the urea product
competes with the secondary amine to attack the isocy-
anate. Possibly, the isocyanates may also react with each
other upon heating, forming trimers.25 Increasing the
reaction time did not improve the outcome of these reac-
tions but instead resulted in reduced yields (see Table 2,
entry 1).
1.6. N,N0-Di-tert-butylurea 2i28,29
13C NMR (100 MHz, CDCl3) d 156.9, 50.2, 29.6.
Characterization data for novel 2e is listed below.
1.7. N,N0-Bis-(4-trifluoromethylbenzyl)urea 2e
1H NMR (400 MHz, CDCl3) d 7.58 (AA0 part of
0
AA0XX0, 4H) 7.40(XX part of AA0XX0, 4H), 4.70
(br t, J = 6.1 Hz, 2H), 4.47 (d, J = 6.1 Hz, 4H). 13C
NMR (100 MHz, CDCl3:DMSO-d6, 80:20) d 157.7,
143.9, 128.4 (q, J = 31.5 Hz), 126.6, 124.2 (q,
J = 3.8 Hz), 123.3 (q, J = 272.0Hz), 42.5. HRMS, ESI,
(M+H+): 377.1080, C17H15N2OF6 requires 377.1089.
1.8. General method for synthesis of unsymmetrical ureas
from a primary amine and a secondary amine
In summary, a novel and very fast gas-free carbonyla-
tion method for the preparation of ureas has been pre-
sented. By combining the power of high-density
microwave heating with in situ generation of intermedi-
ate isocyanates from Co2(CO)8, amines were converted
to the corresponding ureas in reaction times as short
as 10s.
Primary amine (0.50 mmol), secondary amine
(2.5 mmol), Co2(CO)8 (113 mg, 0.33 mmol), NEt3
(101 mg, 1.0 mmol), and 2.5 mL of acetonitrile were
mixed in a vial which was immediately capped with a
5 mL Teflon septum under air. The Smith microwave
synthesizer was set to 250 °C, and the irradiation time
to 10s. After 10s the temperature was ca. 110–115 °C.
The reaction mixture was filtered and the precipitate
extracted with 40mL of warm CH 2Cl2. The organic
extract was washed with 0.1 M HCl until it became
colorless, then dried (K2CO3) and evaporated. Com-
pounds 5a30 and b31 are known compounds but are
1.3. General method for synthesis of symmetrical ureas
from primary amines
Primary amine, (0.60 mmol), Co2(CO)8 (0.40 mmol,
137 mg), NEt3 (121 mg, 1.2 mmol) and 2.5 mL of aceto-
nitrile were mixed in a 5 mL vial which was immediately
capped with a Teflon septum under air. The Smith
microwave synthesizer was set to 250 °C, and the irradia-
tion time to 10or 13 s. Alternatively, the target temper-
ature was programmed as described in Table 1. After
cooling, the reaction mixture was filtered and trans-
ferred to a separating funnel. The vial was washed with
40mL of warm CH 2Cl2 and the organic extract was
added to the separating funnel. The combined organic
layer was washed with 0.1 M HCl until it became
colorless. The organic layer was thereafter separated,
dried (K2CO3) and evaporated. Products 2a,c,g, and j
are commercially available, while compounds
2b,26d,4,26f,26h,27 and i28,29 are known compounds. Spec-
tral data were in agreement with the proposed
structures. Known compounds lacking literature spectro-
scopic data are listed below.
1
lacking earlier published H and 13C NMR spectra.
1.9. N-Cyclohexyl-N0-di-n-propylurea 5a30
1H NMR (400 MHz, CDCl3) d 4.10(br d, J = 6.8 Hz,
1H), 3.68–3.59 (m, 1H), 3.15–3.10(m, 4H), 1.96–1.90
(m, 2H), 1.71–1.64 (m, 2H), 1.61–1.49 (m, 5H), 1.41–
1.30 (m, 2H), 1.19–1.02 (m, 3H), 0.88 (t, J = 7.6 Hz,
6H). 13C NMR (100 MHz, CDCl3) d 157.0, 49.2, 34.1,
25.7, 25.1, 21.8, 11.5.
1.10. N-Cyclohexyl-N0-pyrrolidinourea 5b31
1H NMR (400 MHz, CDCl3) d 3.99 (br d, J = 6.7 Hz,
1H), 3.69–3.60(m, 1H), 3.32–3.29 (m, 4H), 1.98–1.92
(m, 2H), 1.90–1.87 (m, 4H), 1.72–1.65 (m, 2H), 1.64–
1.56 (m, 1H), 1.42–1.31 (m, 2H), 1.19–1.04 (m, 3H).
13C NMR (100 MHz, CDCl3) d 156.2, 49.0, 45.4, 34.3,
25.7, 25.6, 25.1.
1.4. N,N0-Di-n-hexylurea 2b26
1H NMR (400 MHz, CDCl3) d 4.37 (br s, 2H), 3.14 (dd,
J = 7.0, 5.9 Hz, 4H), 1.51–1.44 (m, 4H), 1.34–1.23 (m,
12H), 0.89–0.85 (m, 6H). 13C NMR (100 MHz, CDCl3)
d 158.3, 40.7, 31.6, 30.3, 26.7, 22.7, 14.1.
Characterization data for novel compounds 5c and 5d
are listed below.
1.11. N-Hexyl-N0,N0-dipropylurea 5c
1.5. N,N0-Bis-(3-isopropoxypropyl)urea 2f 26
1H NMR (400 MHz, CDCl3) d 4.26 (br s, 1H), 3.22–3.17
(m, 2H), 3.14–3.10(m, 4H), 1.59–1.44 (m, 6H), 1.31–
1.27 (m, 6H), 0.90–0.85 (m, 9H). 13C NMR (100
MHz, CDCl3) d 157.7, 49.0, 40.8, 31.5, 30.4, 26.6,
22.5, 21.8, 14.0, 11.4. HRMS, ESI, (M+H+): 229.2282,
C13H29N2O requires 229.2280.
1H NMR (400 MHz, CDCl3) d 4.89 (br s, 2H), 3.53
(hep, J = 6.1 Hz, 2H), 3.48 (m, 4H), 3.23 (dt, J = 6.3,
5.8 Hz, 4H), 1.72 (m, 4H), 1.12 (d, J = 6.1 Hz, 12H).
13C NMR (100 MHz, CDCl3) d 158.5, 71.6, 66.6, 39.0,
30.9, 30.1.

P.-A. Enquist et al. / Tetrahedron Letters 46 (2005) 3335–3339
3339
1.12. N-(3-Isopropoxypropyl)-N0-dipropylurea 5d
12. Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res.
2002, 35, 717–727.
13. Enquist, P. A.; Nilsson, P.; Larhed, M. Org. Lett. 2003, 5,
4875–4878.
14. Kaiser, N. F. K.; Bremberg, U.; Larhed, M.; Moberg, C.;
Hallberg, A. J. Organomet. Chem. 2000, 603, 2–5.
15. Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004,
43, 5580–5588.
16. Triethylamine, 1,2,2,6,6-pentamethylpiperidine (PMP)
and NaOAc were investigated, but provided reduced
yields.
1H NMR (400 MHz, CDCl3) d 5.06 (br s, 1H), 3.53
(hep, J = 6.1 Hz, 1H), 3.52–3.49 (m, 2H), 3.35–3.31
(m, 2H), 3.12–3.08 (m, 4H), 1.76–1.70 (m, 2H), 1.58–
1.48 (m, 4H), 1.13 (d, J = 6.1 Hz, 6H), 0.86 (t,
J = 7.4 Hz, 6H). 13C NMR (100 MHz, CDCl3) d 157.8,
71.7, 68.0, 48.9, 40.1, 30.0, 22.1, 21.7, 11.3. HRMS,
ESI, (M+H+): 245.2227, C13H29N2O2 requires 245.2229.
17. Propylene carbonate and water were added separately to
investigate their impact on the reaction.
Acknowledgements
18. Personal communication from Professor M. Beller.
19. The acidic solution will cause the urea–cobalt complex to
dissociate according to the equation below. B can either be
a base or, as in our case, a urea compound. With benzylic
compounds 2d and e, the use of more concentrated HCl
(aq) results in debenzylation. 4[[BCo(CO)4]+[Co(CO)4]À] +
8HCl ! 2H2(g) + 8CO(g) + 3[Co(CO)4]2 + 2CoCl2 +
4BHCl. See: Wender, I.; Sternberg, H. W.; Orchin, M.
J. Am. Chem. Soc. 1952, 74, 1216–1219.
We acknowledge the Swedish Research Council and
Knut and Alice WallenbergÕs Foundation. We thank
Jonas Lindh for assistance, Shane Peterson for linguistic
advice and Biotage AB for providing the Smith Synthe-
sizer microwave reactor.
References and notes
20. Blanco, J. L. J.; Barria, C. S.; Benito, J. M.; Mellet, C. O.;
Fuentes, J.; Santoyo-Gonzalez, F.; Fernandez, J. M. G.
Synthesis 1999, 1907–1914.
21. Hong, F. E.; Chang, Y. C. Organometallics 2004, 23, 718–
729.
22. Patil, B. S.; Vasanthakumar, G. R.; Babu, V. V. S. J. Org.
Chem. 2003, 68, 7274–7280.
23. Estep, K. G.; Neipp, C. E.; Stramiello, L. M. S.; Adam,
M. D.; Allen, M. P.; Robinson, S.; Roskamp, E. J. J. Org.
Chem. 1998, 63, 5300–5301.
1. Smith, M. B.; March, J. March’s Advanced Organic
Chemistry. Reactions, Mechanisms, and Structure, 5th ed.;
Wiley Interscience: New York, Chichester, Brisbane,
Toronto, Singapore, 2001.
2. Nowick, J. S.; Holmes, D. L.; Noronha, G.; Smith, E. M.;
Nguyen, T. M.; Huang, S. L. J. Org. Chem. 1996, 61,
3929–3934.
3. Batey, R. A.; Santhakumar, V.; Yoshina-Ishii, C.; Taylor,
S. D. Tetrahedron Lett. 1998, 39, 6267–6270.
4. McCusker, J. E.; Main, A. D.; Johnson, K. S.; Grasso, C.
A.; McElwee-White, L. J. Org. Chem. 2000, 65, 5216–
5222.
24. Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994,
35, 4055–4058.
25. Duong, H. A.; Cross, M. J.; Louie, J. Org. Lett. 2004, 6,
4679–4681.
26. Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F.
J. Org. Chem. 1961, 26, 3306–3308.
5. Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. J. Mol.
Catal. 1990, 60, 41–48.
6. Kim, Y. J.; Varma, R. S. Tetrahedron Lett. 2004, 45, 7205–
7208.
27. Leung, M. K.; Lai, J. L.; Lau, K. H.; Yu, H. H.; Hsiao,
H. J. J. Org. Chem. 1996, 61, 4175–4179.
28. Stevens, T. E. J. Org. Chem. 1966, 31, 2025–2026.
29. Mashima, K.; Yamanaka, Y.; Gohro, Y.; Nakamura, A.
J. Organomet. Chem. 1993, 459, 131–138.
30. Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F.;
Breed, L. W. J. Am. Chem. Soc. 1962, 27, 4341–4346.
31. Gross, H.; Zinner, G. Chem. Ber. 1973, 106, 2315–
2323.
7. Mojtahedi, M. M.; Saidi, M. R.; Bolourtchian, M. J.
Chem. Res. (S) 1999, 710–711.
8. Hunter, D. J. Cell. Biochem. 2001, 22–27.
9. Dolle, R. E. J. Comb. Chem. 2004, 6, 623–679.
10. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
11. Larhed, M.; Hallberg, A. Drug Discov. Today 2001, 6,
406–416.