The direct formation of α-carbamates from carbonyl compounds

Article abstract of DOI:10.1055/s-2007-967990

A simple one-pot method for the direct introduction of carbamates α to carbonyl groups that proceeds at room temperature in the presence of both moisture and air has been developed. Treatment of aldehydes and both cyclic and acyclic ketones with N-methyl-

Full text of DOI:10.1055/s-2007-967990

LETTER
293
The Direct Formation of a-Carbamates from Carbonyl Compounds
C
arbamate Synthe
d
sis rian Hall,b Edouard P. Huguet,a Kerri L. Jones,a Teyrnon C. Jones,a Niall M. Killeen,a Sze Chak Yau,a
Nicholas C. O. Tomkinson*a
a
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20874030; E-mail: tomkinsonnc@cardiff.ac.uk
b
Neurology & GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park,
Third Avenue, Harlow, Essex, CM19 5AW, UK
Received 6 October 2006
We have recently reported a series of novel reagents for
the a-oxybenzoylation of both aldehydes3 and ketones.4
Within these processes the hydroxylamine-based reagents
2 were reacted, generally at room temperature in the pres-
Abstract: A simple one-pot method for the direct introduction of
carbamates a to carbonyl groups that proceeds at room temperature
in the presence of both moisture and air has been developed. Treat-
ment of aldehydes and both cyclic and acyclic ketones with N-
methyl-O-carbamoyl hydroxylamine hydrochlorides provides the ence of both moisture and air, with a variety of carbonyl
a-functionalised products in 50–88% isolated yield. The trans-
formation is tolerant of a range of functional groups within the
substrate and is also effective for the introduction of a variety of
oxycarbamoyl groups.
compounds 1, providing the a-functionalised products 3
in good to excellent yield (Figure 1). We believe these
processes proceed via the enamine intermediate 4, which
undergo a concerted [3,3]-sigmatropic rearrangement,
followed by hydrolysis of the resulting imine to give the
product. We were interested to discover whether an anal-
ogous process could also be developed for the preparation
of carbamates, and reasoned that functionalised hydroxyl-
amines 5 might react in a direct fashion with carbonyl
compounds.
Key words: metal-free synthesis, hydroxylamine, carbamate, array
methods
The rapid introduction of molecular diversity during the
preparation of molecules of pharmaceutical interest is
pivotal to lead optimisation in drug discovery.1 In con-
junction with combinatorial methods this allows for the
synthesis of molecular arrays for biological testing.2
Therefore, novel, simple methods for the introduction of
scaffolds present in molecules of biological interest that
can be applied in a combinatorial manner are much sought
after. Within this letter we present a series of reagents that
provide the first method for the direct introduction of the
carbamate function a to carbonyl groups, providing a new
chemical tool for diversity-oriented synthesis.
O
O
Ph
O
N
NH
PhNCO
∆
no reaction
OH Hünig's base
O
N
KHMDS,
TMSCl
6
7
O
NaH, ∆
O
Ph
O
Ph
N–
N
H
NHPh
N
O–
O
N
O
O
R3
O
O
·HCl
O
R4
N
O
H
N
O
R3
R1
O
R2
O
R1
R4
12
9
8
O
1
2
3
R1 = Ph, Me, tBu, OMe, OBn
O
Ph
N
O
Ph
O–
NH
O
R6
– CO2,
R1
O
R2
R4
N
N
O
R5
N
H
O
+ PhNCO
N
N
NHPh
O
O
·HCl
R3
10
11
4
5
Scheme 1 Rearrangement of functionalised ene-hydroxylamines
Figure 1 a-Functionalisation of carbonyl compounds
It was not apparent from literature precedent that the
desired rearrangement would be observed with 5. Lobo
has shown that the ene-hydroxylamine 6, prepared in one
step from cyclohexanedione, can be reacted with phenyl-
isocyanate to give the adduct 7 (Scheme 1).5 Surprisingly,
in contrast to findings with alternative substrates, this
SYNLETT 2007, No. 2, pp 0293–0297
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-967990; Art ID: D29206ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
2.
2
0
0
7

294
A. Hall et al.
LETTER
hydroxylamine derivative was thermally stable and did Having prepared the desired hydroxylamines, we then
not rearrange to give an a-functionalised carbamate. In- went on to investigate their reactivity with carbonyl com-
stead, treatment of 7 with sodium hydride followed by pounds. Each reagent was treated with cyclohexanone
thermolysis in refluxing THF gave the amine 11 in 49% (21) as a test substrate and we were delighted to discover
isolated yield. Compound 11 was believed to have arisen in each case that the reaction proceeded to give the expect-
by a concerted [3,3]-sigmatropic rearrangement of the de- ed a-oxycarbamoylation products 22–25 in good to excel-
rived anion 9, addition of a second equivalent of phenyl- lent yield (Scheme 3).8 With aromatic substituted reagents
isocyanate and loss of a molecule of CO2. It was also 18 and 16 we found DMSO to be the most effective sol-
reported that a C–O bond forming process could be vent, whereas when the reagents contained aliphatic sub-
brought about by treatment of the adduct 7 with an excess stituents on the carbamoyl nitrogen, higher conversions
of KHMDS and TMSCl followed by thermolysis and and better product recovery was observed using THF as
acidic aqueous work-up to give the carbamate 12 in 54% the reaction medium.
isolated yield. Although these examples suggested that we
Ph
N
O
Ph
N
may not be able to introduce the expected carbamate
functionality through the regents 5 we sought to develop
methods for their preparation and to determine their
associated reactivity.
21, DMSO,
O
O
N
Ph
Ph
H
r.t., 16 h
O
O
·HCl
18
22 79%
The investigation began with the preparation of the
carbamoylation reagents, which were made by one of two
methods, both of which were amenable to scale-up and
allowed access to good quantities of material. Commer-
cial availability of a range of carbamoyl chlorides allowed
for carbamoylation of the tert-butoxycarbonyl-protected
N-methyl hydroxylamine 156 under basic conditions. Re-
moval of the protecting group with freshly prepared HCl
in dioxane led to the desired reagents 16–18 in good yield,
which crystallised directly from the reaction mixture
(Scheme 2). An equally effective route started from the
appropriate amine and treatment with carbonyldiimida-
zole followed by N-methylation to give the activated
imidazolium salt 19 as reported by Batey.7 Treatment of
the salt 19 with N-Boc-N-methyl hydroxylamine (15) un-
der basic reaction conditions, followed by deprotection in
an analogous manner to that described above led to the
O
S
21, DMSO,
S
O
N
O
N
N
N
r.t., 24 h
N
H
O
O
16
·HCl
23 74%
O
O
21, THF,
O
N
N
O
N
H
r.t., 18 h
O
O
·HCl
17
24 60%
21, THF,
O
O
N
H
Ph
Ph
r.t., 24 h
O
O
·HCl
20
25 59%
alternative carbamoylation reagent 20. These two com- Scheme 3 Reaction with cyclohexanone
plimentary routes provided rapid access to oxycarbamoy-
lation reagents with varying amine functionality.
In line with previous observations3,4 we believe these
reactions proceed via condensation of reagent 18 with
cyclohexanone (21), to give iminium ion 26 followed by
conversion to enamine 27. Concerted [3,3]-sigmatropic
rearrangement then provides imine 28 which is hydroly-
sed under the aqueous acidic reaction conditions to give
the observed a-functionalised product 22 (Scheme 4).
S
O
O
Ph
N
N
Cl
N
Cl
Ph
O
Cl
12
13
14
O
O
R1
1. 12, 13, or 14, Et3N,
CH2Cl2, 0 °C, r.t.
O
NPh2
DMSO, r.t.
16 h
OH
N
O
NPh2
+
O
N
N
H
N
R1
O
·HCl
2. HCl, dioxane,
r.t., 12 h
H
Boc
O
O
·HCl
21
18
22
15
16 from 12 48%
17 from 13 91%
18 from 14 83%
– H2O
+ H2O
O
I–
1. 15, Et3N, CH2Cl2
O
N
N
O
NPh2
O
NPh2
N+
N
N
N
N
N
Ph
2. HCl, dioxane,
r.t., 12 h
H
Ph
O
NPh2
O
·HCl
O
O
19
20 69%
O
Scheme 2 Preparation of reagents
26
27
28
Scheme 4 Proposed mechanism of a-oxycarbamoylation
Synlett 2007, No. 2, 293–297 © Thieme Stuttgart · New York

LETTER
Carbamate Synthesis
Table 1 Scope of Transformation (continued)
295
Table 1 Scope of Transformation
Entry
1a
Reaction
Product
Yield (%)
88
Entry
10a
Reaction
Product
Yield (%)
16 + 29
18 + 34
84
79
78
73
O
CHO
O
NPh2
Ar2N
O
O
tBu
O
40
49
2b
20 + 29
59
11a
12a
13a
18 + 35
18 + 36
16 + 37
O
CHO
PhMeN
O
O
NPh2
HO
O
O
41
50
3a
18 + 30
16 + 31
72
80
NPh2
O
O
O
O
O
NPh2
Br
42
O
4a
51
O
O
NAr2
O
O
O
O
NAr2
43
O
5b
6b
7a
17 + 31
20 + 32
16 + 33
55
82
57
O
52
O
O
O
NMe2
NMePh
NAr2
14b
15b
16b
20 + 37
17 + 38
17 + 39
60
64
50
O
O
O
O
O
44
O
NMePh
O
O
53
S
O
45
O
Me2N
O
O
54
O
O
O
45
8b
17 + 33
59
76
Me2N
O
O
O
NMe2
O
55
O
O
O
a Reactions performed in DMSO as solvent.
b Reactions performed in THF as solvent
47
9b
20 + 34
O
After completing these preliminary experiments we went
on to investigate the generality of the procedure for a
series of carbonyl compounds (Table 1). Pleasingly, the
reaction worked well for a wide variety of substrates pro-
viding direct access to the a-carbamoyl products of alde-
hydes (entries 1 and 2), cyclic ketones (entries 3–10) and
acyclic ketones (entries 11–16) in 50–88% isolated yield.
O
NMePh
O
tBu
48
Synlett 2007, No. 2, 293–297 © Thieme Stuttgart · New York

296
A. Hall et al.
LETTER
O
O
O
O
O
O
O
O
O
O
CHO
O
O
O
S
HO
Br
tBu
34
29
30
31
32
33
35
36
37
38
39
Figure 2 Carbonyl substrates used in this study
ride (860 mg, 3.7 mmol) in CH2Cl2 (2 mL) was then added dropwise
to the reaction over a period of 5 min. After warming to r.t. and stir-
ring for 16 h, the reaction was concentrated to dryness and triturated
with PE to precipitate triethylamine hydrochloride, which was sub-
sequently removed by filtration. After concentration in vacuo the
resultant crude reaction mixture was purified by flash chromatogra-
phy (20% Et2O–PE) to furnish N-Boc-N-methyl-O-diphenylcar-
bamoyl hydroxylamine as white needles (1.12g, 92%); mp (Et2O–
PE) 112–114 °C. IR (CH2Cl2): 2976, 1754, 1721, 1592, 1492, 1339,
1149 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.32–7.09 (m, 10 H),
3.19 (s, 3 H), 1.43 (s, 9 H). 13C NMR (100 MHz, CDCl3): d = 155.2
(s), 153.3 (s), 141.8 (s), 129.2 (d, 2 C), 126.8 (d), 82.2 (s), 37.9 (q),
28.3 (q). MS (APCI): m/z = 343 [M + H]+. HRMS: m/z calcd for
C19H23N2O4 [M + H]+: 343.1652; found: 343.1655.
The reaction with aldehyde substrates was complete in
less than four hours at room temperature providing the
products 40 and 41 (entry 1: 88%; entry 2: 59%). The
reaction also proceeded at room temperature for both 6-
(entries 4–10) and 7-membered (entry 3) rings and was
tolerant of a variety of functional groups including ethers,
sulfides and ketals. With the substituted cyclohexanone
34 the thermodynamic cis-isomers 49 and 50 were pre-
pared in an excellent 76% and 84% yield, respectively
(entries 9 and 10). With acyclic substrates it was neces-
sary to warm the reaction mixture up to 50 °C in order to
achieve reasonable reaction times of less than 24 hours
(entries 11–16). For example, 4-hydroxypropiophenone
(35) underwent reaction with the carbamoylation reagent
18 in 79%. This highlights that the reactions proceed not
only in the presence of moisture and air, but also in the
presence of unprotected phenol groups, thereby adding to
the applicability of this process. The reagents were in-
effective in the a-functionalisation of primary centres un-
der a variety of reaction conditions which allowed for the
regiospecific functionalisation of the non-symmetrical
substrates 38 and 39 (Figure 2). 4-Methylpentan-2-one
(entry 15) and hexan-2-one (entry 16) gave the products
54 (64%) and 55 (50%) with the dimethyl reagent 17,
where reaction had taken place exclusively at the second-
ary centre.
N-Boc-N-methyl-O-diphenylcarbamoyl hydroxylamine (500 mg,
1.46 mmol) was dissolved in 4 M HCl–dioxane solution (1.83 mL,
7.3 mmol) and stirred at r.t. for 6 h. The resultant precipitate was
collected by filtration, and washed with 25 mL ice-cold Et2O before
drying in vacuo to yield N-methyl-O-diphenylcarbamoyl hydroxyl-
amine hydrochloride (18) as green microcrystals (402 mg, 99%);
mp (Et2O–PE) 124–126 °C. IR (nujol): 2974, 1760, 1545, 1152
1
cm–1. H NMR (400 MHz, DMSO-d6): d = 11.8 (br s, 2 H), 7.34–
7.28 (m, 4 H), 7.23–7.18 (m, 6 H), 2.75 (s, 3 H). 13C NMR (100
MHz, DMSO-d6): d = 152.8 (s), 141.7 (s), 129.8 (d), 127.7 (d),
127.5 (d), 37.5 (q). MS (APCI): m/z = 243 [M + H]+. HRMS:
m/z calcd for C14H16N2O2Cl [M + H – HCl]+: 243.1128; found:
243.1126.
Typical Experimental Procedure for the Direct a-Carbamoyla-
tion of Carbonyl Compounds
In summary, we have developed the first method for the
direct a-oxycarbamoylation of carbonyl compounds. The
reagents are easily prepared in three high-yielding steps
from N-methyl hydroxylamine hydrochloride and are
bench-stable solids that can be stored for prolonged peri-
ods. The reaction proceeds readily at either room temper-
ature for aldehydes and cyclic ketones or at 50 °C in the
case of acyclic ketones. The transformations are opera-
tionally simple, without any specialised reaction tech-
niques, proceed in the presence of both moisture and air
and are tolerant of a variety of functional groups. We are
currently investigating alternative reagents for the forma-
tion of C–N and C–S bonds to add to this structural class
and will report on our findings shortly.
Cyclohexanone (56 mL, 0.54 mmol) and N-methyl-O-diphenylcar-
bamoyl hydroxylamine hydrochloride (18, 150 mg, 0.54 mmol)
were dissolved together in DMSO (1 mL) and stirred at r.t. for 16 h.
After this period, the reaction broth was diluted with EtOAc (50
mL) and washed sequentially with brine (50 mL) and H2O (2 × 50
mL). The organic layer was then dried (MgSO4) and concentrated
in vacuo to yield the crude product as a yellow oil. This residue was
subjected to flash chromatography (5% Et2O–CH2Cl2) to furnish 2-
oxocyclohexyl diphenylcarbamate (22) as salmon-pink microcrys-
tals (121 mg, 79%); mp (Et2O–PE) 146–148 °C. IR (CH2Cl2): 2084,
1
1750, 1718, 1570, 1093 cm–1. H NMR (400 MHz, CDCl3): d =
7.29–7.05 (m, 10 H), 5.15–5.06 (m, 1 H), 2.43–2.27 (m, 2 H), 2.21–
2.11 (m, 1 H), 2.01–1.89 (m, 1 H), 1.84–1.76 (m, 1 H), 1.70–1.41
(m, 3 H). 13C NMR (125 MHz, CDCl3): d = 205.1 (s), 153.9 (s),
142.6 (s), 128.8 (d), 127.1 (d), 126.1 (d), 78.0 (d), 40.6 (t), 32.9 (t),
27.0 (t), 23.7 (t). MS (APCI): m/z = 310 [M + H]+. HRMS: m/z calcd
for C19H20NO3 [M + H]+: 310.1438; found: 310.1439.
Typical Experimental Procedure for the Preparation of
Reagent
N-Boc-N-methyl-hydroxylamine (15, 500 mg, 3.7 mmol), Et3N
(512 mL, 3.7 mmol) and a catalytic amount of dimethylaminopyri-
dine (45 mg, 10 mol%) were dissolved in CH2Cl2 (8 mL) and cooled
to 0 °C in an ice-water bath. A solution of diphenylcarbamoyl chlo-
Acknowledgment
The authors thank the EPSRC, GlaxoSmithKline and the Lever-
hulme Trust (F/00 407/X) for financial support and the Mass
Spectrometry Service, Swansea for high-resolution spectra.
Synlett 2007, No. 2, 293–297 © Thieme Stuttgart · New York

LETTER
Carbamate Synthesis
297
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(8) All compounds prepared were characterised by mp, IR, 1H
NMR, 13C NMR, MS and HRMS.
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