The intramolecular amination of allenes

Article abstract of DOI:10.1039/b926179f

Rhodium-bound nitrenoids are trapped by tethered allenes generating acyloxy-enamines, aminocyclopropanes, and methylene aziridines. The aminocyclopropanes undergo substitution of the acetoxy group by a variety of nucleophiles.

Full text of DOI:10.1039/b926179f

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The intramolecular amination of allenesw
George C. Feast,a Lee W. Pageb and Jeremy Robertson*a
Received (in Cambridge, UK) 11th December 2009, Accepted 1st February 2010
First published as an Advance Article on the web 26th February 2010
DOI: 10.1039/b926179f
Rhodium-bound nitrenoids are trapped by tethered allenes
generating acyloxy-enamines, aminocyclopropanes, and methylene
aziridines. The aminocyclopropanes undergo substitution of the
acetoxy group by a variety of nucleophiles.
Table 1 Rh(II)-catalysed aminations of penta-3,4-dienyl sulfamates
Products(s)a
Isolated yields
Entry
Sulfamate
Our group has applied intramolecular aminohydroxylation1 of
1,4- and 1,3-dienes in total synthesis efforts towards nagstatin2
and the sphingolipids.3 1,4-Dienes constituted a new substrate
class for this reaction and we now report preliminary results in
our study of the intramolecular amination of 1,2-dienyl
(allenyl) substrates.4 Reliable conditions for intramolecular
alkene aziridination5,6 of metal-bound nitrenoids, and their
equivalents, are now well established and we envisaged that
methylene aziridines should be produced from allenyl
substrates.7,8 Our initial intention was to combine this process
with subsequent ring-opening and cycloaddition of the
resulting 2-aminoallylic cations9 in a concise route to natural
product-like compound libraries.
Treatment of the unsubstituted parent penta-3,4-dienyl10
sulfamate 1 with rhodium(II) octanoate dimer, iodobenzene
diacetate, and magnesium oxide in dichloromethane for 18 hours
at 20 1C (Du Bois protocol)11 generated a-acetoxy ketone 2 as
the major product after chromatography (Scheme 1). The
participation of the sulfamate functionality in this process
was confirmed by the absence of any reaction when silyl ether
3 was exposed to the same conditions.12
1
2
3
4
5
6
Analogous reactions of the monoalkyl-substituted penta-
3,4-dienyl sulfamates shown in Table 1 gave three categories of
major products. The first, generated in substrates bearing
7
Scheme 1 Test reactions for intramolecular allene amination.
a Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: jeremy.robertson@chem.ox.ac.uk;
a
Reagents and conditions: Rh2(OAc)4 (0.05 equiv.), PhI(OAc)2
(1.3 equiv.), MgO (2.3 equiv.), CH2Cl2, 20 1C, 18 h.
Fax: +44 (0)1865 285002; Tel: +44 (0)1865 275660
b GlaxoSmithKline, New Frontiers Science Park, Third Avenue,
Harlow, Essex, UK CM19 5AW
w Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data, and copies of 1H and 13C NMR
spectra. CCDC 757478 (5), 757479 (12) and 763606 (17). For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b926179f
an iso-propyl substituent or an internal phenyl substituent
(entries 1, 2 and 5), contains cyclic enamines and their
imine tautomers corresponding to ketone 2 and its acetoxy
regioisomer. With 11-alkyl internal substituents, 1-acetoxy-1-
aminocyclopropanes were obtained in moderate yield
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There appears to be a fine balance between the rate of direct
acetate addition to 2-aminoallyl intermediate 23 and that of
C*–C* bond formation; the tert-butyl substituent in substrate
16 is sufficiently bulky to impede both of these processes with
the major product arising from bond formation between the
less encumbered nitrogen and terminal C* positions.
We speculate that the product profiles are under kinetic
control, particularly as heating either cyclopropane 10 or
aziridine 17 led17 to no productive change.18 However,
aziridine 17 was transformed in moderate yield into cyclo-
propyl hemiaminal 26 when treated with NaI in DMF
(Scheme 3). The yield (at fixed time) increased and the reaction
time (at comparable conversion) decreased with increasing
relative quantities of NaI. It is unlikely that this reaction is
induced by adventitious HI because a CD3CN solution of
aziridine 17 was unaffected by stirring with 10 mol% aqueous HI
(57% solution) over 24 hours. Iodide ion could act as a nucleo-
philic catalyst to effect rearrangement of aziridine 17 into imino-
cyclopropane 25, which would then be trapped with water giving
product 26.19 An equivalent iodide-mediated single electron
transfer mechanism could be considered as an alternative.
Fig. 1 Molecular structure of methylene aziridine 17 showing one of
the two molecules in the asymmetric unit. Displacement ellipsoids are
drawn at the 50% probability level.
(entries 3 and 4). A similar product was generated in entry 5
but partial hydrolysis13 led to its isolation as the hemiaminal
(14). When faced with a sterically demanding tert-butyl
substituent (entry 6), the reaction took a different course
leading to the unprecedented bicyclic methylene aziridines 17
and 18 in high yield. The reaction tolerates dialkyl substitution
on the allene (entry 7), generating cyclopropane 20 as a single
diastereomer14 in roughly equal proportion to acetoxy-enamine
21. The structures of representative members of each product
class (5, 12 and 17) were confirmed by single crystal X-ray
crystallography.z Further discussion of the structure of 17 is
available elsewhere15 but the distortion at C3 is noteworthy,
with +(C5–C3–C4) = 157.5(1)1 (Fig. 1).
The reported yields for most of the entries in Table 1
represent at least two runs repeated under the same conditions,
without optimisation. Substrate 9 was used to examine any
scope for improvement and the use of Rh2esp2 (0.01 equiv.)16
in toluene proved advantageous, with cyclopropane 10 being
generated reproducibly in ca. 60% yield.
Scheme 3 Iodide ion-mediated ring-transforming reaction of methylene
aziridine 17.
Although, as stated above, products 10 and 17 have not yet
been shown to undergo useful reactions under purely thermal
conditions, we have briefly explored the possibility of
elaborating the cyclopropyl products by substitution of the
acetate in 10. Scheme 4 summarises our results to date. The
formation of most of the products can be rationalised on the
basis of elimination of AcOH to generate a strained imino-
cyclopropane (cf. 25, Scheme 3) that is rapidly and efficiently
trapped by nucleophiles.20 Uniquely in this series, the LiAlH4
reaction apparently initiates with acetate reduction to liberate
the methyl analogue of hemiaminals 14 and 26.
A reaction pathway consistent with the production of acetoxy
ketone 2 and the products illustrated in Table 1 initiates with
rhodium nitrenoid formation (-22, Scheme 2) and activation of
the tethered allene to form a 2-aminoallyl intermediate of the
form 23. Acetate trapping of this intermediate would then lead
to the enamine-type products. In this scheme, the cyclopropyl
products and methylene aziridines would arise by ring-closure of
the formal azatrimethylenemethane 23 either between the
starred carbons, or between the nitrogen and one of the starred
carbons. The relative timing of the C*–C* ring closure and
addition of acetate is open to question; acetate trapping of a
first-formed iminocyclopropane seems intuitively obvious but
the possibility that acetate addition occurs in concert with ring
closure cannot yet be discounted.
These rhodium(II)-mediated allene aminations present
opportunities for compelling new synthetic methodology when
combined with substitution by functionalised nucleophiles,
Scheme 2 Rhodium-stabilised 2-aminoallyl species 23 as a proposed
common intermediate in intramolecular allene aminations.
Scheme 4 Reactivity of cyclopropane 10.
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and we are actively engaged in exploring the broader applica-
tions of these preliminary results. Future work will establish
the scope for harnessing the ‘high chemical potential’ of
aminoallyls of general structure 23 with a focus on cyclo-
addition chemistry and intramolecular nucleophilic capture.
These results also raise a number of mechanistic questions that
warrant deeper consideration for their wider implications.
The authors gratefully acknowledge GSK and the EPSRC
for funding, the Oxford Chemical Crystallography Service for
the use of the instruments, and Drs T. D. W. Claridge and B.
Odell for help with NMR experiments.
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7 Methylene aziridines are only rarely prepared by allene aziridina-
tion: (a) E. M. Bingham and J. C. Gilbert, J. Org. Chem., 1975, 40,
224; (b) Y. V. Zeifman, E. M. Rokhlin, U. Utebaev and
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Notes and references
z Crystal data for compound 5: (clear colourless, 0.14 ꢁ 0.30 ꢁ 0.34 mm):
C10H17NO5S Mr = 263.31; monoclinic, P21/n; a = 6.5055(2) A, b =
22.4224(6) A, c = 8.9905(3) A, b = 108.6921(10)1, V = 1019.55(6) A3;
Z = 4; m = 0.270 mmꢂ1; Dcalc = 1.408 g cmꢂ3; reflections collected =
12 353; independent reflections = 2829 (Rint = 0.035); R values
8 Blakey’s group has studied analogous reactions of alkynyl sulfa-
mates and has very recently extended those studies to encompass
allenyl substrates to generate 1-alkyl-1-aminocyclopropanes:
(a) A. R. Thornton and S. B. Blakey, J. Am. Chem. Soc., 2008,
130, 5020; (b) A. R. Thornton, V. I. Martin and S. B. Blakey,
J. Am. Chem. Soc., 2009, 131, 2434; (c) A. H. Stoll and
S. B. Blakey, J. Am. Chem. Soc., 2010, 132, 2108.
[I 4 2s(I), 2141 reflections]: R1 = 0.0391, wR2 = 0.0864; rmin/max
=
ꢂ0.47/0.41 e Aꢂ3; CCDC 757478. Crystal data for compound 12:
(clear colourless, 0.34 ꢁ 0.62 ꢁ 0.64 mm): C10H17NO5S Mr = 263.31;
ꢀ
triclinic, P1; a = 7.6562(2) A, b = 8.7683(2) A, c = 10.0293(2) A, a =
77.2922(12)1, b = 78.9430(12)1, g = 69.3572(10)1, V = 609.79(2) A3;
Z = 2; m = 0.275 mmꢂ1; Dcalc = 1.434 g cmꢂ3; reflections collected =
8663; independent reflections = 2766 (Rint = 0.021); R values
9 cf. G. Prie, N. Prevost, H. Twin, S. A. Fernandes, J. F. Hayes and
M. Shipman, Angew. Chem., Int. Ed., 2004, 43, 6517.
[I 4 2s(I), 2569 reflections]: R1 = 0.0330, wR2 = 0.0837; rmin/max
=
ꢂ0.40/0.34 e Aꢂ3; CCDC 757479. Crystal data for compound 17 were
published by Feast et al.15 but are included in the CIF for complete-
ness (CCDC 763606).w
10 Initial attempts to prepare buta-2,3-dienyl sulfamates failed due to
the reactivity of the products towards nucleophilic substitution
under the reaction conditions. Indeed, even the grouping
CQC–CH2–OSO2NH2 does not seem to be represented in the
literature.
11 (a) C. G. Espino and J. Du Bois, Angew. Chem., Int. Ed., 2001, 40,
598; (b) C. G. Espino, P. M. Wehn, J. Chow and J. Du Bois, J. Am.
Chem. Soc., 2001, 123, 6935.
12 Inclusion of one mole equivalent of propyl sulfamate in the
reaction mixture with substrate 3 did not result in intermolecular
amination, the allene being returned unchanged after work-up.
13 It is possible that the intermediate iminocyclopropane in this case
survives the reaction conditions, by virtue of the presence of the
iso-propyl group, and is hydrated during product isolation.
14 Assuming the reaction to follow the pathway suggested in
Scheme 2, rotation of the terminal methyl-bearing carbon away
from the N-bound dirhodium ligand, upon amination, would
generate a U-shaped methyl,ethyl-substituted allyl cation that
would be expected to close in a disrotatory fashion, giving rise to
the observed (NOESY) stereochemistry.
15 G. C. Feast, J. Haestier, L. W. Page, J. Robertson, A. L. Thompson
and D. J. Watkin, Acta Crystallogr., Sect. C, 2009, 65, o635.
16 C. G. Espino, K. W. Fiori, M. Kim and J. Du Bois, J. Am. Chem.
Soc., 2004, 126, 15378.
17 A CD3CN solution of each substrate was subjected to microwave
heating first at 100 1C and then at 120 1C for 10–20 minutesat each
temperature.
18 Quast first demonstrated the thermal interconversion of methylene
aziridines and iminocyclopropanes, and showed that the latter
cycloreverted rapidly to alkene and isocyanide at 190 1C:
(a) H. Quast and W. Risler, Angew. Chem., Int. Ed., 1973, 12,
414. Reetz commented later that ‘‘electrocyclic ring opening [of
cyclopropanone N,N-dialkylhydrazones] is a high energy process
which cannot be realized in a synthetically meaningful way.’’;
(b) M. T. Reetz and J. Rheinheimer, J. Org. Chem., 1986, 51, 5465.
19 The transformation 24 - 26 is analogous to the well-known
reactions of chloroenamines with nucleophiles resulting in amino-
cyclopropane derivatives; for leading early work see:
J. Szmuszkovicz, E. Cerda, M. F. Grostic and J. F. Zieserl, Jr.,
Tetrahedron Lett., 1967, 8, 3969.
1 T. J. Donohoe, P. D. Johnson, A. Cowley and M. Keenan, J. Am.
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3 S. L. Kostiuk, Chemistry Part II Thesis, University of Oxford, 2006.
4 This account focuses on the reactions of sulfamate substrates;
details of analogous reactions with carbamate substrates, that
behave quite differently, will be published separately:
(a) J. Robertson, G. C. Feast, L. V. White and V. A. Steadman,
manuscript in preparation; (b) see also L. V. White, Chemistry
Part II Thesis, University of Oxford, 2007.
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6 Carbamate substrates: (a) M. Egli and A. S. Dreiding, Helv. Chim.
Acta, 1986, 69, 1442; (b) S. Rhouati and A. Bernou, J. Chem. Soc.,
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20 Related reactions are described for example in ref. 19 and
subsequent papers; however, apart from the examples in ref. 8c,
we are aware of just a single paper describing the a-substitutions of
1-(N-sulfonylamino)-1-oxycyclopropane substrates: D. Matthies and
U. Buchling, Arch. Pharm. (Weinheim, Germany), 1983, 316, 598.
¨
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