Hindered ureas as masked isocyanates: Facile carbamoylation of nucleophiles under neutral conditions

Article abstract of DOI:10.1002/anie.200904435

Bigger is better: Sterically hindered dialkyl ureas undergo nucleophilic substitution at dramatically faster rates than their less hindered counterparts (see scheme). Steric decompression upon the formation of an intermediate isocyanate can explain this c

Full text of DOI:10.1002/anie.200904435

Angewandte
Chemie
DOI: 10.1002/anie.200904435
Solvolysis
Hindered Ureas as Masked Isocyanates: Facile Carbamoylation of
Nucleophiles under Neutral Conditions**
Marc Hutchby, Chris E. Houlden, J. Gair Ford, Simon N. G. Tyler, Michel R. Gagnꢀ,
Guy C. Lloyd-Jones,* and Kevin I. Booker-Milburn*
Ureas are normally rather inert towards alcohols, amines, and
thiols: they require high temperatures, acidic or basic
conditions, or metal catalysis, to undergo nucleophilic sub-
stitution reactions.[1] Whilst this feature makes them robust
protecting groups for aromatic and aliphatic amines, it
somewhat limits their subsequent utility. Herein we demon-
strate that, in stark contrast to this general behavior, hindered
trisubstituted ureas undergo efficient substitution reactions
with a range of O, N, and S nucleophiles under neutral
conditions, and that in some cases reactions proceed to
completion in less than an hour at 208C.
by carrying out methanolysis on a range of simple urea
derivatives (Table 1).
As with hydrolysis, the aniline-based N,N-dimethyl (3a)
and N,N-diethyl ureas (3b) were unreactive, whereas after
Table 1: Solvolysis of ureas in neutral methanol. Bn=benzyl.
Entry
3
R
R’
R’’
T [8C] t [h]
Yield of 4 [%][a]
We have recently reported on the development of a PdII-
catalyzed ortho-carbonylation of alkyl aryl ureas, during
which we noted that N,N-diisopropyl urea 1 underwent slow
hydrolysis to aniline 2 at 1008C (Scheme 1), whereas the
1
2
3
4
5
6
7
8
3a
Ph
Me
Et
iPr
H
Me
Me
Et
Me
Et
iPr
tBu
tBu
tBu
tBu
tBu
70
70
70
70
70
50
50
20
50
20
18
18
18
18
<5 min
1
1
18
1
<1
<2
81
3b Ph
3c Ph
3d Ph
3e
3e
3 f
3 f
3g
3g
0
Ph
Ph
Ph
Ph
Ph
Ph
>99
>99
>99
>99
>99
>99
>99
33
85
26
85
>99
Et
9
nPr tBu
nPr tBu
10
11
12
13
14
15
16
18
1
3h Ph
iPr
iPr
iPr
iPr
iPr
tBu 20
Scheme 1. Neutral hydrolysis of aryl diisopropyl urea 1.
3i
3i
3j
3j
3k
Bn
Bn
tBu
tBu
tBu iPr
iPr
iPr
iPr
iPr
70
70
70
70
18
72
18
72
1
corresponding dimethyl and diethyl urea analogues failed to
react.[2] The key structural features responsible for this
remarkable difference in reactivity have now been elucidated
tBu 20
[a] Yield of isolated product.
[*] M. Hutchby, Dr. C. E. Houlden, Prof. Dr. G. C. Lloyd-Jones,
Prof. Dr. K. I. Booker-Milburn
18 hours at reflux the more hindered N,N-diisopropyl urea
(3c) gave the corresponding carbamate in 81% yield (Table 1,
entries 1–3). The requirement for N,N disubstitution at the
leaving group is evident from the extreme contrast in
reactivity of the tBu-N-H substrate 3d with the tBu-N-Me
substrate 3e (Table 1, entries 4 and 5), the latter underwent
methanolysis in minutes at 708C. As the Me group in 3e was
changed for the increasingly bulky Et (3 f), nPr (3g), and iPr
(3h) substituents (Table 1, entries 7–11), the reactivity
increased further; indeed the iPr derivative 3h underwent
quantitative methanolysis in less than an hour at 208C. This
phenomenon was not just limited to aryl ureas as the
benzylamine (3i) and tert-butylamine (3k) examples attest
(Table 1, entries 12–16). The latter derivative is of similar
reactivity to 3h, and underwent quantitative methanolysis in
under an hour at 208C.
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
Fax: (+44)117-929-8611
E-mail: guy.lloyd-jones@bris.ac.uk
k.booker-milburn@bristol.ac.uk
Prof. Dr. M. R. Gagnꢀ
Department of Chemistry, Caudill and Kenan Laboratories
UNC-Chapel Hill, NC 27599-3290 (USA)
Dr. J. G. Ford
AstraZeneca PR&D
Silk Road, Macclesfield, Cheshire, SK10 2NA (UK)
Dr. S. N. G. Tyler
AstraZeneca, Global Process R&D
Severn Road, Hallen, Bristol, BS10 7ZE (UK)
[**] We thank Dr. M. Haddow for X-ray crystallography, the EPSRC (GR/
R02382 and E061575) and AstraZeneca for support, the joint
EPSRC/AstraZeneca/GlaxoSmithKline/Pfizer Organic Studentship
Initiative, and the NIH (GM-60578). G.C.L.-J. is a Royal Society
Wolfson Research Merit awardee.
An explanation for this reactivity was initially sought by
comparison of the physical data of 3a and 3c. The IR
13
=
stretching frequencies and C NMR signals of the C O
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904435.
groups showed no significant differences (nmax = 1641 vs.
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1635 cmÀ1 and d = 155.8 vs. 154.5 ppm, respectively). Their
single-crystal X-ray structures[13] showed no significant differ-
À
ences in C N bond lengths, and DFT calculations on the urea
compounds as well as their tetrahedral methanol adducts
showed few differentiating structural features.[3]
A more extensive mechanistic investigation was then
undertaken by choosing a pair of reasonably reactive
substrates (3c and 3 f) and exploring the kinetics of their
methanolysis. A Hammett analysis (see the Supporting
Information) of the pseudo-first-order rates of solvolysis
(MeOH, 708C) of 3c and its Ph-substituted analogues (p/m
MeO, Br, and NO2) revealed a weak activating effect of the
electron-withdrawing substitutents (1 = 0.7 Æ 0.1, R2 = 0.92;
Figure 1). Irreversible methanolysis of 3 f in toluene at 358C,
under pseudo-first-order conditions, indicated a fractional
dependence on MeOH concentration (Àd[3 f]/dt = 3.2 ꢀ 10À5
[3 f][MeOH]0.32), and no dependence on the concentration of
tBuN(H)Et, with a predicted half-life of 2 hours for 3 f in pure
MeOH.
Scheme 2. N-phenyl isocyanate 5 liberation from 3 f through a proton
switch by MeOH (A), and by amine transfer (B) to p-bromophenyl
isocyanate 7.
hydrolysis conditions (A-2, B-2 mechanisms), without any
involvement of an isocyanate. Recently, Clayden and Hen-
necke[9] reported on the butanolysis of N,N’-dimethyl-N’-alkyl
ureas at 1188C and suggested the intermediacy of alkyl
isocyanates.
The finding of increased rates of methanolysis of N-
phenyl ureas 3a–3h as the steric hindrance of the N’,N’ sub-
stituents increases weighs against an analogous addition/
elimination mechanism. Certainly, nucleophilic attack would
be more hindered and the greater nucleofugacity of an
anilinium over N,N-dialkylammonium moiety would give a
carbamate of the form R2NCO2Me, rather than 4.[10] The data
is, however, consistent with the increased basicity of the
dialkylamino group for participation in the proton switch, a
substantial steric decompression[14] upon liberation of R2NH
and N-phenyl isocyanate 5, and a positive Hammett 1-value
(+ 0.7) arising from a proton transfer from PhNH. The
isocyanate 5 may be liberated directly, or through the much
postulated zwitterionic precursor 6, the latter being driven by
relief of allylic strain in 6. Monomeric methanol can facilitate
the proton switch (A; Scheme 2) in an identical manner to
that proposed for water;[4] the fractional order in MeOH/
toluene reflects the tendency for alcohols to aggregate by
hydrogen bonding in hydrocarbon media, nominally as a
cyclic trimer.[11] Importantly, the lack of any rate suppression
upon methanolysis of 3 f by added tBuN(H)Et suggests that
the generation of the isocyanate or zwitterion is rate limiting.
The facile liberation of isocyanate from urea 3 f under
neutral conditions in toluene (0.2m) was confirmed by the
addition of 0.2m of N-p-bromophenyl isocyanate (7,
Scheme 2), which generated an equilibrium mixture with
isocyanate 5 and urea 8 (K = 1.0). However, the rate of this
equilibration (ꢀ 1 min at 208C; 3:2 ratio of 8/3 f) is faster than
would be predicted based on the kinetics of methanolysis at
358C and suggests a direct reaction (B; Scheme 2) between
isocyanate (5/7) and urea (3 f/8).[12]
Figure 1. Methanolysis of 3 f (0.11m) in toluene at 358C. Open circles:
reaction in the presence of added tBuN(H)Et (0.28 to 0.83m).
The mechanism of hydrolysis of N-aryl ureas has been the
subject of a number of detailed studies,[4,5,6] with a general
consensus that N-aryl isocyanates are generated as transient
intermediates through the expulsion of R2NH from a
À
+
À =
À
zwitterion of the form Ar N C(O ) NR2H . Pioneering
work by OꢁConnor and co-workers,[4] led to the suggestion
that water mediates a “proton switch”[7,8] (see A; Scheme 2)
to generate the zwitterion from the urea at neutral pH, or to
generate the R2N-protonated urea under acidic conditions
(pH ꢀ 6.5). In the most recent study, Capasso and co-work-
ers[6] presented a unified mechanism to account for reactions
at low, neutral, and high pH: all of which proceed through the
zwitterion, with buffer species (carboxylic acids, hydrogen
phosphates etc.) mediating the proton switch. Nonetheless,
there are alternative interpretations of the data, for example
Laudien and Mitzner[5] have suggested that a simple addition/
elimination mechanism occurs under both acidic and basic
A more specific result supporting the intermediacy of
isocyanate 5 during methanolysis came from the reaction of
3 f (0.1m) with a mixture of MeOH (1m), EtOH (1m), and
PrOH (1m) in toluene at 358C, to give the corresponding
carbamates 4Me/4Et/4Pr (Scheme 3). Control experiments con-
firmed that there is no equilibration under these conditions
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Scheme 2), or directly, an isocyanate (5, Scheme 2), which is
then captured in a subsequent reaction with the nucleophile.
The remarkable reactivity of hindered trisubstituted ureas
will be of interest to synthetic chemists in the preparation of
amine derivatives. For example, a single urea is efficiently
converted under neutral conditions into N-protected aniline
derivatives incorporating three commonly employed amine
protecting groups: Cbz, Boc, and Fmoc (Table 2, entries 3–5;
Boc = tert-butoxycarbonyl,
Cbz = benzyloxycarbonyl,
Fmoc = 9-fluorenylmethyloxycarbonyl). Finally, the crystal-
line nature of these hindered ureas make them highly
convenient as reagents for in situ liberation of isocyanates,
simply requiring release through a proton switch.
Scheme 3. Partitioning of N-phenyl isocyanate 5, which was generated
in situ, with a 1:1:1 mixture of MeOH/EtOH/PrOH (3m).
Received: August 7, 2009
Published online: October 8, 2009
and the partitioning between the three carbamates is identi-
cal, within experimental error, to that generated by the
reaction of a reference sample of N-phenyl isocyanate 5 under
the same conditions.
Keywords: carbamoylation · isocyanates · reaction mechanisms ·
.
proton switch · urea solvolysis
À
Alcohols, and indeed any species containing an X H unit
in which the X group bears an available lone pair of electrons,
can in principle act to effect a proton switch in trisubstituted
urea 3 f and a range of such species were found to react
readily to give the corresponding carbamates in excellent
yields (Table 2). The substantial reactivity of the N-phenyl
[1] For selected examples of the generally forcing conditions needed
for the cleavage of urea, see: a) J. Akester, J. Cui, G. Fraenkel, J.
Org. Chem. 1997, 62, 431; b) N. V. Kaminskaia, N. M. Kostic,
Inorg. Chem. 1997, 36, 5917; c) R. L. Blakeley, A. Treston, R. K.
Andrews, B. Zerner, J. Am. Chem. Soc. 1982, 104, 612; d) N. V.
´
´
Kaminskaia, N. M. Kostic, Inorg. Chem. 1998, 37, 4302; e) J.
Table 2: Synthetic potential of trisubstituted ureas as masked isocya-
nates.
Clayden, J. Dufour, D. M. Grainger, M. Helliwell, J. Am. Chem.
Soc. 2007, 129, 7488; f) H. M. I. Osborn, N. A. O. Williams, Org.
Lett. 2004, 6, 3111; g) A. Hassner, D. Yagudayev, T. K. Pradhan,
A. Nudelman, B. Amit, Synlett 2007, 2405; h) J. Wang, Q. Li, W.
Dong, M. Kang, S. Peng, Appl. Catal. A 2004, 261, 191; i) A. B.
Shivarkar, S. P. Gupte, R. V. Chaudhari, J. Mol. Catal. A 2004,
223, 85.
Entry
NuH (equiv)
t [h]
Product
Yield [%][a]
[2] C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G.
Tyler, M. R. Gagnꢂ, G. C. Lloyd-Jones, K. I. Booker-Milburn,
Angew. Chem. 2009, 121, 1862; Angew. Chem. Int. Ed. 2009, 48,
1830.
[3] The 10 lowest energy conformers (from AM1 calculations) of 3a
and 3c were fully optimized using DFT methods (B3LYP-6-
31G*) on MacSpartan 2008 to generate the lowest energy
structure; uncorrected energies were utilized. While the meth-
1
2
3
4
5
6
7
8
H2O[b]
1
6
8
8
5
18
18
5
9a[c]
9b
9c
9d
9e
9 f
>99
>99
70
94
78
72
62
>99
MeOH (1.1)
tBuOH[b,d]
PhCH2OH (1.1)
9-fluorenylmethanol (2)
PhOH (2)
PhSH (2)
tBuNH2 (1.1)
9g
9h
anolysis of 3c was more favorable than that of 3a by 3 kcalmolÀ1
,
its tetrahedral intermediate was also 2.5 kcalmolÀ1 higher in
energy, thereby predicting a slower methanolysis of 3c than 3a
by the addition/elimination pathway, which is in contrast to our
observation.
[a] Yield of isolated product. [b] Used as a solvent. [c] The aniline
generated through decarboxylation is trapped in situ to yield 1,3-
diphenylurea. [d] Reaction was performed at 908C. Nu=nucleophile.
[4] a) C. J. OꢁConnor, J. W. Barnett, J. Chem. Soc. Perkin Trans. 2
1973, 1457; b) C. J. Giffney, C. J. OꢁConnor, J. Chem. Soc. Perkin
Trans. 2 1976, 362; c) K. J. Mollett, C. J. OꢁConnor, J. Chem. Soc.
Perkin Trans. 2 1976, 369.
[5] a) R. Laudien, R. Mitzner, J. Chem. Soc. Perkin Trans. 2 2001,
2226; b) R. Laudien, R. Mitzner, J. Chem. Soc. Perkin Trans. 2
2001, 2230.
[6] S. Salvestrini, P. Di Cerbo, S. Capasso, J. Chem. Soc. Perkin
Trans. 2 2002, 1889.
[7] A. Williams, W. P. Jencks, J. Chem. Soc. Perkin Trans. 2 1974,
1753.
isocyanate intermediate means that even weak nucleophiles
such as phenol (pKa = 9.9) and thiophenol (pKa = 6.6) effi-
ciently give the corresponding carbamates. Entries 3–5 of
Table 2 show the synthetic potential of these bulky urea
compounds as precursors with reactivity reminiscent of acyl
halides, for the conversion of a single amine into derivatives
of three of the most common nitrogen protecting groups
under neutral conditions.
[8] a) A. N. Alexandrova, W. L. Jorgensen, J. Phys. Chem. B 2007,
111, 720; b) B. P. Callahan, Y. Yuan, R. Wolfenden, J. Am. Chem.
Soc. 2005, 127, 10828.
[9] J. Clayden, U. Hennecke, Org. Lett. 2008, 10, 3567.
[10] Amides, carbamates, and tetrasubstituted ureas fail to react
under methanolysis conditions (see the Supporting Informai-
tion).
In conclusion, we have demonstrated the unique ability of
hindered trisubstituted ureas to undergo rapid and high-
yielding acyl substitution with simple nucleophiles (amines,
alcohols, thiols) under neutral conditions. The mechanism of
the reaction appears to involve a nucleophile-mediated
proton-switch to generate either a zwitterionic precursor (6,
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Communications
[11] a) M. Mandado, A. M. Graꢃa, R. A. Mosquera, Chem. Phys.
is a known compound: R. J. Lewis, P. Camilleri, A. J. Kirby, C. A.
Marby, A. A. Slawin, D. J. Williams, J. Chem. Soc. Perkin Trans.
2, 1991, 1625.
Lett. 2003, 381, 22, and references therein; b) D. P. N. Satchell,
R. S. Satchell, Chem. Soc. Rev. 1975, 4, 231.
[12] S. Ozaki, Chem. Rev. 1972, 72, 457.
[14] N’,N’-dialkyl ureas of 2,6-xylidine undergo slow dissociation in
anisole (40–1408C) to generate equilibrium mixtures of N-(2,6-
dimethylphenyl)isocyanate and the corresponding dialkylamine:
J. C. Stowell, S. J. Padegimas, J. Org. Chem. 1974, 39, 2448.
[13] CCDC 749529 (for compound 3c) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. Compound 3a
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