The direct introduction of carbonates α to carbonyl groups

Article abstract of DOI:10.1055/s-2006-956473

The first method for the direct formation of α-oxycarbonates from both aldehydes and ketones is described. N-Methyl-O-alkoxyformate hydroxylamine hydrochloride reagents can be prepared in two high-yielding steps from N-Boc-N-methyl hydroxylamine and were

Full text of DOI:10.1055/s-2006-956473

LETTER
3435
The Direct Introduction of Carbonates a to Carbonyl Groups
C
arbonate Synthes
d
is rian Hall,a Kerri L. Jones,b Teyrnon C. Jones,a Niall M. Killeen,a Robert Pörzig,a Paul H. Taylor,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 19 September 2006
We have recently reported a simple, versatile and general
method for the a-acyloxylation of both aldehydes5 and
ketones.6 These transformations proceed via a [3,3]-
sigmatropic rearrangement of an ene-hydroxylamine 4
Abstract: The first method for the direct formation of a-oxycar-
bonates from both aldehydes and ketones is described. N-Methyl-O-
alkoxyformate hydroxylamine hydrochloride reagents can be pre-
pared in two high-yielding steps from N-Boc-N-methyl hydroxyl-
amine and were found to be bench stable. These were reacted with (generated in situ by the treatment of a carbonyl com-
a variety of carbonyl compounds to give the corresponding a-func-
tionalised products in 48–98% isolated yield via a proposed [3,3]-
sigmatropic rearrangement.
pound 1 with an N-alkyl-O-acyl hydroxylamine hydro-
chloride 2) leading directly to the a-acyloxy carbonyl 3
(Scheme 1). We were intrigued to see whether the scope
of this novel one-step functionalisation could be extended
to allow the introduction of alternative functionalities.
Within this communication we report, to the best of our
Key words: metal-free synthesis, hydroxylamine, carbonate
The utility of the carbonyl group in organic synthesis is knowledge, the first method for the direct introduction of
unsurpassed. The ability to manipulate it in a chemo-, re- the oxycarbonate functionality into a variety of carbonyl
gio-, stereo- and enantioselective manner renders it pivot- compounds using the generic reagent 5.
al to the construction of complex synthetic targets.1 a-
The investigation began with the preparation of the
Functionalisation of the carbonyl group represents a cru-
reagents, which can be prepared in two steps from N-Boc-
cial synthetic transformation, and there are a plethora of
N-methyl hydroxylamine (6),7 by reaction with the ap-
methods for the formation of new C–C, C–O, C–S and C–
propriate chloroformate under basic reaction conditions
followed by removal of the tert-butoxycarbonyl protect-
N bonds at this position.2 In the context of C–O bond for-
mation, methods to introduce the hydroxyl functionality
ing group (Scheme 2). This was found to be a general and
generally rely on the preformation of a metal enolate or si-
reliable method with the methyl 7 (82%),8 ethyl 8 (73%),
benzyl 9 (69%), allyl 10 (79%) and phenyl 11 (73%)
lyl enol ether followed by introduction of an electrophilic
oxygenating source.3 In synthesis the free hydroxyl group
reagents being prepared in excellent yield as crystalline
is then generally protected as an ether, ester or carbonate
solids that were bench stable during the investigation.9
depending on synthetic strategy.4 Of particular use is the
carbonate functionality which is easily introduced, stable
to a variety of reaction conditions and can be hydrolytical-
ly or reductively removed.
1. R5OCOCl, Et3N,
O
OR5
OH
N
N
H·HCl
O
Boc
CH2Cl2, 0 °C to r.t.
2. HCl, dioxane,
r.t., 12 h.
6
7
8
9
R
5 = Me 82%
R5 = Et 73%
5 = Bn 69%
10 R5 = Allyl 79%
11 R5 = Ph 73%
O
R3
R
R4
O
O
H·HCl
R1
O
R3
N
R1
R2
R4
O
O
Scheme 2 Preparation of reagents
1
2
3
R1
O
R2
N
O
O
Having efficiently prepared the target reagents 7–11, we
went on to investigate their reactivity with a series of car-
bonyl compounds, hoping to discover characteristics anal-
ogous to the a-oxyacylation reagents described
previously.6 As a starting point, the methylchloroformate-
derived reagent 7 was reacted with cyclohexanone under
a variety of reaction conditions. The reaction worked well
in both polar and non-polar solvents at room temperature,
but consistently cleaner transformations were achieved
using either DMSO or THF as the reaction medium,
which led to their adoption in our standard protocol (see
typical procedure for experimental details). Reaction of
R5
N
H·HCl
O
R4
O
R3
4
5
Scheme 1 a-Functionalisation of carbonyl compounds
SYNLETT 2006, No. 20, pp 3435–3438
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956473; Art ID: D27506ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.1
2
.2
0
0
6

3436
A. Hall et al.
LETTER
cyclohexanone with one equivalent of 7 in DMSO at room yl 8 and allyl 10 reagents. Acid-sensitive functional
temperature for 16 hours gave the a-functionalised prod- groups such as esters (20, 88%) and acetals (17, 79% and
uct 12 in 82% yield after purification by chromatography 28, 79%) were tolerant of the reaction conditions along
(Scheme 3).10 We believe the reaction proceeds via con- with sulfides (25, 97%) and ethers (16, 72% and 24, 98%).
densation of the reagents to give an enamine which under-
goes a [3,3]-sigmatropic rearrangement to provide an a-
functionalised imine which is hydrolysed in situ to furnish
the observed product 12. Reaction of cyclohexanone with
the ethyl 8, benzyl 9 and allyl 10 reagents, also gave the
expected products 13–15 in good yields.
One limitation of the protocol was that we were unable to
functionalise primary centres with our reagents. Treat-
ment of acetone, acetophenone and 2-acetylthiophene
under a variety of reaction conditions showed no indica-
tion of the desired product.11 Although frustrating, this
enabled us to examine a series of non-symmetrical sub-
strates. For example, heptan-2-one gave 18 (74%) and 31
O
O
O
OR5
(75%) as the exclusive products on reaction with the
methyl 7 and allyl 10 reagents, respectively. Similarly, 5-
hexen-2-one gave the 3-functionalised products 19 (69%)
and 23 (57%) on reaction with the methyl and ethyl
carbonate reagents 7 and 8 and the allyl reagent 10 gave
30 (82%) upon reaction with 4-methyl-pentan-2-one. The
complete regiospecificity of these reactions greatly adds
to the practical utility of this procedure.
OR5
DMSO, r.t., 7 or 10
or THF, r.t., 8 or 9
12–24 h
O
N
+
H·HCl
O
O
12 R5 = Me 82%
13 R5 = Et 82%
14 R5 = Bn 63%
15 R5 = Allyl 76%
7–10
Scheme 3 Reactions with cyclohexanone
Finally, we examined the reaction of the phenyl chloro-
After completing these preliminary experiments we went formate derived reagent 11. In contrast with the other
on to establish the scope of the procedure with a variety of reagents prepared (7–10), the reaction of 11 with one
structurally diverse substrates (Figure 1). Pleasingly, the equivalent of cyclohexanone in both DMSO and THF
reaction worked well for aldehydes and both cyclic and gave the heterocycle 33 as the major product rather than
acyclic ketones. With isovaleraldehyde as the substrate, the expected a-functionalised compound 32 (Scheme 4).
the benzyl-derived reagent 9 gave product 26 in 70% yield We postulated this reaction was progressing though the
after 14 hours at room temperature. The reaction was effi- enamine intermediate 34, followed by a concerted [3,3]-
cient for seven-membered rings, with cycloheptanone sigmatropic rearrangement to give the a-functionalised
giving 21 (77%) and 29 (84%) upon reaction with the eth- imine 35; however, the increased leaving group ability of
a
O
O
O
O
O
H·HCl
O
OMe
O
OMe
( )
N
O
3
O
O
O
O
OMe
O
OMe
7
O
O
O
O
O
16 72%
17 79%
OEt
18 74%
19 69%
O
O
O
O
b
O
H·HCl
O
O
O
OEt
N
O
O
O
O
OEt
O
OEt
8
CO2Et
20 88%
O
O
23 57%
O
21 77%
22 48%
O
O
b
O
CHO
H·HCl
O
OBn
O
OBn
N
O
O
Ph
O
OBn
O
O
O
OBn
9
O
S
O
O
24 98%
25 97%
OAllyl
26 70%
27 61%
c
O
O
O
O
O
H·HCl
O
O
OAllyl
( )
3
N
O
O
O
O
O
O
OAllyl
OAllyl
10
O
O
O
O
28 79%
29 84%
30 82%
31 75%
a Reactions performed in DMSO with 1 equiv reagent
b Reactions performed in THF with 1 equiv reagent
c Reactions performed in DMSO with 1.5 equiv reagent
Figure 1 Scope of transformation
Synlett 2006, No. 20, 3435–3438 © Thieme Stuttgart · New York

LETTER
Carbonate Synthesis
3437
O
phenol when compared to an aliphatic alcohol led to an in-
tramolecular cyclisation to give the observed product 33.
It was rationalised that increasing the amount of water
present in the reaction medium may well lead to competi-
tive hydrolysis of the imine in 35 rather than an intramo-
lecular cyclisation, thus leading to the alternative product
32. Intrigued by the possibility of altering the observed re-
action product by the simple modification of the reaction
medium we sought to develop reaction conditions to di-
rectly access either 32 or 33 as the exclusive reaction
product.
OH
N
N
O
(MeO)2CO,
K2CO3,
190 °C, 7 h
48%
36
33
– MeOH
O
OMe
O
OMe
N
N
O
O
H
O
O
O
37
38
N
11
O
OPh
O
+
Scheme 5
DMSO or THF
O
32
33
O
O
11
11
O
O
N
DMSO, 4 Å MS
+ H2O
– MeNH2
THF–H2O (9:1)
– H2O
O
– PhOH
OCO2Ph
r.t., 24 h
50 °C, 24 h
59%
OPh
N
32
63%
33
N
[3,3]
O
OPh
O
O
O
N
O
11
O
DMSO, 4 Å MS
34
35
r.t., 24 h
Scheme 4
51%
O
39
O
O
It has been reported previously that 33 can be prepared in
48% isolated yield by heating cyclohexanone oxime 36 in
the presence of 20 equivalents of dimethyl carbonate un-
der basic reaction conditions in an autoclave at 190 °C for
7 hours (Scheme 5).12 It was proposed that this process
went via a mechanistic sequence analogous to that pro-
posed for our milder, more effective transformation.13
Thus, formation of the O-methyl carbonate, followed by
N-methylation gave the iminium species 37. Conversion
into the enamine, followed by a [3,3]-sigmatropic rear-
rangement gave the imine 38, which under the high tem-
peratures of the reaction underwent an intramolecular
cyclisation to give the product 33. The advantages of our
system are clear, with the reaction proceeding at room
temperature and atmospheric pressure greatly adding to
the practicality of the process.
O
N
11
O (9:1)
11
OCO2Ph THF–H2
DMSO, 4 Å MS
50 °C, 24 h
r.t., 24 h
CO2Et
CO2Et
CO2Et
41
40
47%
48%
Scheme 6
This class of heterocycle is well documented within the
literature. For example, it has been shown that catalytic
reduction of the alkene in 33 can lead directly to the cis-
substituted cyclohexane ring, providing a two-step proto-
col for the conversion of carbonyl compounds into pro-
tected 1,2-amino alcohols stereospecifically.14 The
heterocycle has also shown a variety of biological activity
associated with its derivatives, and is present in a number
of naturally occurring compounds.15
Reaction of one equivalent of 11 with cyclohexanone in
DMSO at room temperature for 24 hours in the presence
of 4 Å molecular sieves led to 33 as the exclusive reaction
product in a respectable 63% isolated yield (Scheme 6).
Changing the reaction medium to a mixture of THF and
water (9:1) and conducting the reaction at 50 °C allowed
for the isolation of the a-functionalised carbonyl 32 in
59% yield. This observation was general with alternative
substrates leading to the heterocyclic or a-functionalised
products being isolated from the reaction of both cyclo-
heptanone and ethyl 4-oxocyclohexanecarboxylate de-
pending on the reaction conditions adopted.
In summary, we have described the first method for the di-
rect formation of carbonates in the a-position of carbonyl
compounds. This method is advantageous as it avoids the
use of metals and sensitive intermediates, and also the ne-
cessity for separate a-hydroxylation and protection steps.
In addition the reaction proceeds under mild conditions in
the presence of both moisture and air and without the need
for purification of solvents. The reagents are easily pre-
pared in three high-yielding steps from commercially
available N-methyl hydroxylamine hydrochloride and are
bench stable. Significantly, the reaction is ineffective for
Synlett 2006, No. 20, 3435–3438 © Thieme Stuttgart · New York

3438
A. Hall et al.
LETTER
the functionalisation of primary centres and therefore al-
lows for complete regiospecificity in the reaction of non-
symmetrical substrates. Use of the phenyl carbonate re-
agent 11 allows rapid entry into the 4,5-disubstituted-4-
oxazolin-2-one framework or an a-functionalised carbon-
yl compound depending upon the reaction conditions
adopted, providing a useful extension to the chemistry ac-
cessible from these N,O-disubstituted hydroxylamine re-
agents. Work is currently underway to render this process
asymmetric and we will report on our findings shortly.
Acknowledgment
The authors thank the EPSRC for a research fellowship (N.C.O.T.),
the Leverhulme Trust (F/00 407/X) for financial support and the
Mass Spectrometry Service, Swansea for high-resolution spectra.
References and Notes
(1) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II;
Wiley-VCH: Weinheim, 2003.
(2) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry, 5th ed.; Wiley-Interscience: New York, 2001.
(3) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React.
2003, 62, 1.
Typical Experimental Procedure for the Preparation of Re-
agent
(4) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; Wiley: New York, 1991. (b) Kocieski,
P. J. Protecting Groups; Thieme: Stuttgart, 1994.
(5) Beshara, C. S.; Hall, A.; Jenkins, R. L.; Jones, T. C.; Parry,
R. T.; Thomas, S. P.; Tomkinson, N. C. O. Chem. Commun.
2005, 1478.
(6) Beshara, C. S.; Hall, A.; Jenkins, R. L.; Jones, K. L.; Jones,
T. C.; Killeen, N. M.; Taylor, P. H.; Thomas, S. P.;
Tomkinson, N. C. O. Org. Lett. 2005, 7, 5729.
(7) Carrasco, M. R.; Brown, R. T.; Serafimova, I. M.; Silva, O.
J. Org. Chem. 2003, 68, 195.
(8) Zinner, G.; Hitze, M. Arch. Pharm. Ber. 1969, 302, 916.
(9) All compounds prepared were characterised by mp, 1H
NMR, 13C NMR, IR, MS and HRMS.
(10) For an indirect method for the preparation of this compound
from preformed enol ethers, see: Schank, K.; Beck, H.;
Pistorius, S.; Rapold, T. Synthesis 1995, 964.
To a solution of N-methyl-N-Boc-hydroxylamine (3.0 g, 20.4
mmol) in CH2Cl2 (50 mL) at 0 °C, was added Et3N (3.4 mL, 24.5
mmol, 1.2 equiv) and ethyl chloroformate (2.4 mL, 24.5 mmol, 1.2
equiv). The resulting solution was allowed to warm to ambient tem-
perature and stirring was continued for a further 16 h before wash-
ing with 1.0 M HCl (2 × 60 mL). The CH2Cl2 layer was collected
and dried with anhydrous Na2SO4. The solvent was removed to
yield N-methyl-N-Boc-O-ethoxycarbonyl hydroxylamine as a
colourless oil (3.6 g, 74%). IR: 2981, 2937, 1786, 1727, 1478, 1413,
1393, 1243, 1150, 1012, 965, 844, 780 cm–1. 1H NMR (400 MHz,
CDCl3): d = 4.12 (q, J = 7.2 Hz, 2 H), 3.22 (s, 3 H), 1.49 (s, 9 H),
1.36 (t, J = 7.2 Hz, 3 H). 13 C NMR (100 MHz, CDCl3): d = 155.2,
154.2, 82.6, 65.6, 37.6, 28.0, 14.2. MS (EI): m/z = 220 [M + H]+.
HRMS: m/z calcd for C9H21N2O5: 237.144 [M + NH4]+; found:
237.1443.
(11) Heating of the reagents above 50 °C led to their
decomposition: White, E. H.; Reefer, J.; Erickson, R. H.;
Dzadzic, P. M. J. Org. Chem. 1984, 49, 4872.
(12) Marques, C. A.; Selva, M.; Tundo, P.; Montanari, F. J. Org.
Chem. 1993, 58, 5765.
HCl gas (generated from the dropwise addition of concentrated
H2SO4 (ca. 40 mL) to NH4Cl (ca. 50 g) was bubbled through a so-
lution of N-Boc-O-ethoxycarbonylhydroxylamine (2.0 g, 9.1
mmol) in 1,4-dioxane (20 mL) for 1.5 h at ambient temperature. The
solvent was removed from the resulting pale yellow solution to give
a viscous oil that solidified upon refrigeration (1.3 g, 99%). IR (thin
(13) For alternative methods for the preparation of this class of
heterocycles, see: (a) Filler, R. Adv. Heterocycl. Chem.
1965, 4, 75. (b) Hakimelahi, G. H.; Boyce, C. B.; Kasmai,
H. S. Helv. Chim. Acta 1977, 60, 342. (c) Gompper, R.
Chem. Ber. 1956, 89, 1748. (d) Dziomko, V. M.;
Ivashchenko, A. V. Zh. Org. Khim. 1973, 9, 2191.
(e) Lemmens, J. M.; Blommerde, W. W. J. M.; Thijs, L.;
Zwanenburg, B. J. Org. Chem. 1984, 49, 2231. (f) Krieg,
B.; Konieczny, P. Liebigs Ann. Chem. 1976, 1862.
(g) Filler, R.; Shyamsunder Rao, Y. J. Heterocycl. Chem.
1964, 1, 292. (h) Sheehan, J. C.; Guziec, F. S. Jr. J. Am.
Chem. Soc. 1972, 94, 6561. (i) Shono, T.; Matsumura, Y.;
Kanazawa, T. Tetrahedron Lett. 1983, 24, 4577. (j) Sasaki,
Y.; Dixneuf, P. H. J. Org. Chem. 1987, 52, 4389.
(k) Okonya, J. F.; Hoffman, R. V.; Johnson, M. C. J. Org.
Chem. 2002, 67, 1102.
1
film): 3411, 1799, 1636, 1258, 1011 cm–1. H NMR (400 MHz,
CDCl3): d = 10.85 (br s, 2 H), 4.41 (q, J = 7.0 Hz, 2 H), 3.15 (s, 3
H), 1.38 (t, J = 7.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d =
151.7, 67.9, 35.9, 13.9. MS (APCI): m/z = 120 [M + H]+.
Typical Experimental Procedure for the Direct a-Carbamoyla-
tion of Carbonyl Groups
O-Ethoxycarbonyl-2-hydroxycyclohexanone (13)
Cyclohexanone (32 mg, 0.33 mmol) was added in one portion to a
solution of N-methyl-O-ethoxycarbonylhydroxylamine hydrochlo-
ride (8, 50 mg, 0.32 mmol) in THF (3 mL) and the resulting solution
was stirred at 25 °C for 24 h during which time a white precipitate
formed. The solvent was removed under reduced pressure and the
crude product was purified directly on silica eluting with EtOAc–
light PE (3:7) to give the title compound 13 as a colourless oil (49
mg, 82%). IR (neat): 2945, 1754, 1453, 1736, 1303, 1264, 1116,
(14) Sheehan, J. C.; Guzuec, F. S. Jr. J. Org. Chem. 1973, 38,
3034.
1
1028, 871, 787 cm–1. H NMR (400 MHz, CDCl3): d = 4.97 (dd,
(15) (a) Belen’kii, L. I.; Kruchkovskaya, N. D. Adv. Heterocycl.
Chem. 1998, 71, 291. (b) Shyamsunder Rao, Y.; Filler, R.
Chemistry of Heterocyclic Compounds: Oxazoles, Vol. 45;
Turchi, I. J., Ed.; Wiley-Interscience: Chichester, UK, 1986,
361–729.
J = 6.5, 11.3 Hz, 1 H), 4.22–4.14 (m, 2 H), 2.52–2.46 (m, 1 H),
2.40–2.30 (m, 2 H), 2.08–2.02 (m, 1 H), 1.97–1.92 (m, 1 H), 1.76–
1.72 (m, 2 H), 1.64–1.52 (m, 1 H), 1.29 (t, J = 6.5 Hz, 3 H). 13C
NMR (100 MHz, CDCl3): d = 204.4, 154.3, 79.2, 64.4, 40.5, 33.0,
27.0, 23.6, 14.2. MS (APCI): m/z 187 [M + H]+. HRMS: m/z calcd
for C9H14O4: 187.0965 [M + H]+; found: 187.0965.
Synlett 2006, No. 20, 3435–3438 © Thieme Stuttgart · New York