Inverted regioselectivity of C-H amination: Unexpected oxidation at β- Rather than γ-C-H

Article abstract of DOI:10.1039/c0ob00113a

A rare example of β- over γ-C-H selectivity during Rh-catalysed sulfamate ester cyclisation is presented; from derivatives of 1,6-anhydro-β-d-mannopyranose, five-membered sulfamidates were formed in preference to the typical six-membered oxathiazinane int

Full text of DOI:10.1039/c0ob00113a

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Inverted regioselectivity of C–H amination: Unexpected oxidation at b- rather
than c-C–H†
Filip J. Wyszynski, Amber L. Thompson and Benjamin G. Davis*
Received 12th May 2010, Accepted 5th July 2010
DOI: 10.1039/c0ob00113a
A rare example of b- over c-C–H selectivity during Rh-
catalysed sulfamate ester cyclisation is presented; from deriva-
tives of 1,6-anhydro-b-D-mannopyranose, five-membered sul-
famidates were formed in preference to the typical six-
membered oxathiazinane intramolecular insertion products.
A 3D structure of sulfamate 1 helps to rationalise this unusual
selectivity and analyses suggest that n→r*(CH) interactions
may be a key controlling factor.
Selective functionalisation of C–H bonds has commanded
widespread attention from organic chemists, offering an efficient
alternative to the activated handles often required for performing
complex synthetic transformations.1 Tremendous advances have
been made over the last decade,2 notably in the transition metal
catalysed amination of unactivated C–H bonds.3 Du Bois et al.
Scheme 1 Unexpected regioselectivity upon C–H amination of 1.
pioneered the use of carbamates and sulfamate esters for this
purpose, which upon exposure to RhII and an oxidant give
g-C–H would be brought into close proximity of the sulfamate ni-
trogen for subsequent RhII-catalysed oxidative cyclisation. Further
derivatisation of the resulting N,O-acetal would lead to selectively
protected galactosamine derivatives; starting material D-mannose
having undergone an overall process of configurational inversion
at both C-2 and C-4 and a selective amination.
To test out this approach, we synthesised acetonide sulfamate
1 through regioselective acetal formation followed by sulfamoy-
lation (Scheme 2) and exposed it to C–H amination conditions.
Unexpectedly, exclusive cyclisation to five-membered sulfamidate
3 was observed, foregoing any reaction at the seemingly more
favourable g-C2–H (to give 2) or indeed the equivalent b¢-C5–H.
access to 1,2- and 1,3-difunctionalised amine derivatives.4 Site
selectivity has been directed by exploiting the greater reactivity
of ethereal Ca–H bonds to metal-nitrene and -carbene species,
as well as the preference for tertiary rather than secondary C–
H bonds.4,5 Conformational control also steers selectivity, with
carbamates giving five-membered ring insertion products and
sulfamate esters forming six membered rings.4,6 This exclusive g-C–
H bond amination is accounted for by the elongated S–O and S–N
˚
bonds (1.58 A) and the obtuse angle of the N–S–O motif in the
sulfamate (103◦), which match the metric parameters of the six-
membered oxathiazinane product and thus make the formation
of a 5-membered ring less kinetically favourable.4 Although rare
cyclisation to a five-membered oxathiazolidine product has been
observed, this has only been in the absence of any possible g
insertion pathway4,7 or if the b-C–H bond has been selectively
activated over the g position with an a-electron donating group,8
with the single exception of a low-yielding cyclisation of an
unfunctionalised cyclopentyl sulfamate ester.9 Cyclisation to 7 and
8-membered sulfamidates has been reported, but again only when
driven by the presence of a heteroatom adjacent to the site of
insertion for specific C–H activation.10
In an attempt to create ready access to 2-amino-2-deoxy-
D-galactose derivatives11,12 and other aminosugars we explored
a novel synthetic route, utilising C–H amination methodology
(Scheme 1). By creating 1,6-anhydro-b-D-mannose derivatives
1
locked in an atypical C4 conformation, we postulated that the
Scheme 2 Synthesis of differentially protected 1,6-anhydro-D-mannose
sulfamate esters. Reagents and conditions: (a) see ref. 13; (b) ClSO2NH2,
Et3N, DMA, -10 ◦C, 80%; (c) anisaldehyde dimethylacetal, TsOH, DMF,
50 ◦C, 300 mbar; (d) ClSO2NH2, Et3N, DCM, -10 ◦C, 61% 5 (over 2 steps),
6 see discussion; (e) TFA/H2O 4 : 1, 100%; (f) TsOH, MeOH, 77%; (g)
TESCl, imidazole, 1,4-dioxane, 36%; (h) TBSCl, imidazole, DMA; (i)
TFA–THF–H2O 1 : 10 : 5, 0 ◦C, 51% (over 2 steps).
Department of Chemistry, University of Oxford, Chemistry Research
Laboratory, 12 Mansfield Road, Oxford, UK OX1 3TA. E-mail: ben.davis@
chem.ox.ac.uk; Fax: +44 (0)1865 285002; Tel: +44 (0)1865 275652
† Electronic supplementary information (ESI) available: Experimental
details. CCDC reference number 776943. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0ob00113a
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Table 1 C–H amination of 1,6-anhydro-D-mannose sulfamates
the exo sulfamate 6, allowing the exo product to be successfully
assigned (Entry 3). Lower yields were observed with the di-TES
derivative 8 resulting from losses during flash chromatography
caused by the lability of the O-TES ethers (Entry 4).
Crucially, careful analysis of the NMR spectra obtained from
all the sulfamidate products confirmed N-insertion had once again
taken place at C-3 rather than C-2 – clear 3J1-2 couplings of ~2 Hz
were observed alongside a lack of any 3J2-3 or 3J3-4 couplings. COSY
and HMBC analysis further confirmed these assignments. No
formation of six-membered oxathiazinanes was detected in any
of the examples. It appears that putative conformational changes
imposed by the different protecting groups had little or no effect
on the b-selectivity of C–H amination.
Entrya
R
Solvent
THFb
Product Conv. (%)
1
2
3d
4
5
6
–C(Me)2–
3
45c
92
49e
19
61
0
–CH(endo-p-MeOC6H4)– 1,4-Dioxane 10
–CH(exo-p-MeOC6H4)–
TES
TBS
H
1,4-dioxane 11
DCM
DCM
1,4-Dioxane
12
13
—
In the X-ray crystal structure‡ of acetonide sulfamate 1
(Fig. 1), structural analysis sheds further light on the unusual
regioselectivity observed. The C–H bonds at C-2, C-3 and C-5
are all accessible to the sulfamate nitrogen. Data from the crystal
structure would suggest insertion at C-2 – the S–O4 and S–N
a Reactions performed with 0.2M sulfamate, 5 mol% Rh2(OAc)2, 2.3 eq
MgO and 1.1 eq PhI(OAc)2. b 0.05M sulfamate used. c 54% starting
material recovered. d Reaction performed on exo-enriched 5 + 6 mixture
(2 : 1). e Determined from 1H NMR analysis of isolated product mixture.
˚
bond lengths are 1.5930(10) and 1.5921(12) A respectively and
This was especially surprising since all three possible insertion sites
are potentially activated as tertiary a-ethereal centres.
the O4–S–N angle is 101.75(6)◦, closely matching previous data
and thus favouring attack at the tertiary, a-ethereal g-C–H bond.4
Therefore, it is especially surprising that only b-C–H insertion
products are observed. In the case of acetal-protected sulfamates,
it is possible that cyclization onto C-2 would produce a highly
strained tetracyclic cage; the 5-membered cyclization product may
provide a lower energy pathway with the new ring formed both
minimising the strain imposed on the core pyranoside and avoiding
repulsion between sulfoxide and pyranose oxygen lone pairs. This
may also explain why the identity and/or stereochemistry of the
acetal protecting group – which was expected to impose small
conformational changes – had no bearing on the regioselectivity
of the insertion reaction. In particular, the silylated sulfamates 8
and 9 were expected to show greater flexibility. Again, however,
these sulfamates cyclized exclusively at C-3, showing no evidence
of any reaction at C-2 or C-5.
To probe this unusual selectivity we replaced the acetonide in 1
with a selection of different protecting groups to explore possible
increased conformational flexibility that might encourage rever-
sion to the expected g-C–H insertion pathway (Scheme 2). 1,6-
Anhydro-b-D-mannose13 was reacted with anisaldehyde dimethyl
acetal and TsOH under reduced pressure, giving a stereoisomeric
mixture of 2,3-O-acetals. Following purification, the endo isomer
was selectively crystallised in 31% yield, leaving an exo-enriched
mother liquor (endo/exo 1 : 2) in a 59% combined yield. These
acetals were next converted to sulfamate esters 5 and a mixture
of 5 + 6 in 76% and 46% yields respectively under standard
conditions. In order to access acyclic protection of the 2- and
3- hydroxyls, acetals 1 and 5 + 6 were cleaved with acid hydrolysis
in quantitative and 77% yields respectively. We next screened a
variety of conditions to selectively derivatise the resulting diol 7
in the presence of the sulfamate ester. Acetyl protection proved
unsuitable owing to equivalent reactivity of the hydroxyls and
sulfamate nitrogen, so silyl protection was instead chosen; Si–N
bonds are known to be significantly more labile than Si–O bonds.14
Di-TES 8 and di-TBS 9 derivatives were accessed in 36 and 46%
yields respectively, following selective deprotection of an N-TBS
derivative with TFA in wet THF.
With six differently protected sulfamates in hand, these 1,6-
anhydro-D-mannose derivatives were exposed to C–H amination
conditions (Table 1). All of the substrates successfully underwent
sulfamate insertion with the exception of diol 7; the free hydroxyls
presumably protonate the basic nitrene species (Entry 6).15 It was
found that a high concentration of sugar was required for efficient
conversion; fortunately the reaction was tolerant to a number
of aprotic solvents allowing the reaction solvent to be optimised
based on the solubility profile of individual substrates. With the
anisaldehyde acetal derivatives, the endo isomer was converted to
the insertion product 10 in 92% yield (Entry 2). The exo isomer was
reacted as an exo-enriched mixture of acetal isomers, and a single
spot by TLC was isolated in 49% yield. The NMR contained two
distinct products, in the same 2 : 1 ratio as the epimeric mixture of
starting materials. The minor compound corresponded exactly to
the endo product 10, suggesting that the other was derived from
Fig. 1 Thermal ellipsoid plot of acetonide sulfamate 1 drawn at 50%
probability.
There are several potential origins of this clear selectivity. The
rigid bi- or tricyclic scaffold might present the b-C3–H bond in a
much more favourable conformation for nitrene insertion than the
g-C2–H bond. The crystal structure does indeed show the pyranose
ring to be distorted away from a chair conformation, leaving the
axial bonds at C-2 and C-4 no longer parallel but pointing slightly
away from each other: the H–C2–C4–O torsion angle is 2.6◦ and
the angle between C2–H and C4–O vectors is 28.0◦. A potential
dominating effect consistent with the observed specificity of attack
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˚
at C-3 over C-5 can be considered through stereoelectronic effects.
Both C–H bonds are b to the sulfamate and both show similar
spatial orientation relative to C4–O. However, the C3–H bond
is selectively weakened by hyperconjugation from the adjacent
oxygen lone pair, which is held in a suitable conformation to
overlap well with the C3–H s* orbital (Fig. 2). In contrast, the lone
pair orbitals of the pyranose oxygen are more poorly aligned with
s*(C5–H), making this bond less activated for nitrene insertion.
Mo-Ka radiation (l = 0.71073 A). Cell parameters and intensity data
were processed using the DENZO-SMN package and reflection intensities
were corrected for absorption effects by the multi-scan method, based on
multiple scans of identical and Laue equivalent reflections.17 The structure
was solved by direct methods using SIR9218 and refined by full-matrix
least squares on F2 using the CRYSTALS suite.19 All non-hydrogen atoms
were refined with anisotropic displacement parameters and hydrogen
atoms were generally visible in the difference map, but were positioned
geometrically and refined separately with soft restraints before inclusion
in the final refinements using a riding model.20 The Flack x parameter21
refined to -0.02(4) and analysis of the Bijvoet pairs to gave a Hooft y
parameter of 0.00(2) giving a < 0.00001% probability that the structure is
the incorrect hand (assuming enantiopurity or racemic twinning).22 Crystal
data (clear yellow plate, 0.03 ¥ 0.10 ¥ 0.14 mm): C9H15NO7S Mr = 281.29;
˚
˚
˚
Triclinic, P1; a = 6.0756(2) A, b = 6.6423(2) ◦A, c = 7.3505(2) A, a =
◦
◦
3
˚
80.5318(12) , b = 84.2434(12) , g = 89.0269(12) , V = 291.120(15) A ; T =
150 K; Z = 2; m = 0.306 mm-1; Dc = 1.604 gcm-3; Drmin,max = -0.24,0.20 e A-3.
Reflections collected = 6964; independent reflections = 2545 (Rint = 0.034);
R indices [I > 3s(I), 2498 reflections]: R1 = 0.0232, wR2 = 0.0567. CCDC
776943.
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In conclusion, to the best of our knowledge this is the first
example of a high-yielding and regioselective sulfamate cyclisation
leading to the formation of a five membered ring in preference to
a six membered ring. Key factors appear to involve an effective
n→s* hyperconjugative interaction. This interesting and unique
observation on selectivity factors in C–H insertion will further
understanding of the influencing factors and mechanistic aspects
involved in C–H activation and nitrene insertion methodologies,
helping to direct the site of C–H oxidation based on both
stereoelectronic factors and also conformational control. We are
currently exploring the synthesis of 3-amino-sugars, especially
those that contain a quaternary centre such as vancosamine, for
which this reaction might see potential direct application.
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Acknowledgements
We gratefully acknowledge the EPSRC for financial support (FJW,
DTA studentship). BGD is a Royal Society–Wolfson Research
Merit Award recipient and is supported by an EPSRC LSI
Platform grant.
20 R. I. Cooper, A. L. Thompson, D. J. Watkin, J. Appl. Crystallogr., DOI:
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Notes and references
‡ The sample of 1 was mounted in perfluorinated polyether oil on a hair
and quench-cooled to 150 K using an Oxford Cryosystems Cryostream 600
series open-flow N2 cooling device.16 Data were collected using a Nonius
Kappa-CCD area detector diffractometer, with graphite-monochromated
4248 | Org. Biomol. Chem., 2010, 8, 4246–4248
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The Royal Society of Chemistry 2010
©