Allene functionalization via bicyclic methylene aziridines

Article abstract of DOI:10.1021/ol2002418

The oxidative functionalization of olefins is a common method for the formation of vicinal carbon-heteroatom bonds. However, oxidative methods to transform allenes into synthetic motifs containing three contiguous carbon-heteroatom bonds are much less dev

Full text of DOI:10.1021/ol2002418

ORGANIC
LETTERS
2011
Vol. 13, No. 8
1924–1927
Allene Functionalization via Bicyclic
Methylene Aziridines
Luke A. Boralsky, Dagmara Marston, R. David Grigg, John C. Hershberger, and
Jennifer M. Schomaker*
Department of Chemistry, University of Wisconsin;Madison, Madison Wisconsin
53706, United States
schomakerj@chem.wisc.edu
Received January 25, 2011
ABSTRACT
The oxidative functionalization of olefins is a common method for the formation of vicinal carbonꢀheteroatom bonds. However, oxidative
methods to transform allenes into synthetic motifs containing three contiguous carbonꢀheteroatom bonds are much less developed. This paper
describes the use of bicyclic methylene aziridines (MAs), prepared via intramolecular allene aziridination, as scaffolds for functionalization of all
three allene carbons.
Olefins are popular substrates for a host of oxidative
transformations designed to introduce new CꢀN bonds
intomolecules.1 However, considerably lessefforthasbeen
devoted to oxidations of allenes, despite the potential to
efficiently generate three new contiguous heteroatom-
bearing chiral centers.2,3 Herein, we describe our prelimin-
ary efforts to utilize intramolecular allene amination as a
key step for the stereoselective and flexible functionaliza-
tion of allenes.3
hydride source to reduce the resultant iminium could flexibly
generate motifs such as 4.3a,4
Scheme 1. Proposed Allene Functionalization
One proposed approach toward this goal is illustrated in
Scheme 1. Reaction of an intermediate bicyclic methylene
aziridine (MA) 2 with a nucleophile would generate en-
ecarbamate 3. Sequential addition of an electrophile and a
(1) For selected reviews on the aziridination of olefins, see:(a)
Pellissier, H. Tetrahedron 2010, 66, 1509. (b) Sweeney, J. B. Chem.
Soc. Rev. 2002, 31, 247. (c) Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2004. (d) Muller, P.; Fruit, C.
Chem. Rev. 2003, 103, 2905.
(2) For selected references on CꢀO bond-forming reactions with
allenes, see: (a) Katukojvala, S.; Barlett, K. N.; Lotesta, S. D.; Williams,
L. J. J. Am. Chem. Soc. 2004, 126, 15348. (b) Ghosh, P.; Lotesta, S. D.;
Williams, L. J. J. Am. Chem. Soc. 2007, 129, 2438. (c) Lotesta, S. D.;
Kiren, S.; Sauers, R. R.; Williams, L. J. Angew. Chem., Int. Ed. 2007, 46,
7108. (d) Ghosh, P.; Cusick, J. R.; Inghrim, J.; Williams, L. J. Org. Lett.
2009, 11, 4672.
(3) (a) Robertson, J.; Feast, G. C.; White, L. V.; Steadman, V. A.;
Claridge, T. D. W. Org. Biomol. Chem. 2010, 8, 3060. (b) Liu, R. Ph.D.
Dissertation, Brigham Young University, 2007. (c) Atkinson, R. S.;
Malpass, J. R. Tetrahedron Lett. 1975, 4305. (d) Bingham, E. M.; Gilbert,
J. C. J. Org. Chem. 1975, 40, 224.
Despite the great potential of bicyclic MAs to serve as
scaffolds for allene oxidation, a significantly more detailed
understanding of their preparation and reactivity is
needed.4 A recent report on allene aziridination utilizing
N-tosyloxycarbamates as nitrene precursors reported low
yields of MAs and limited substrate scope.3a Thus, our first
challenge was to examine factors including substrate,
(4) Shipman, M. Synlett. 2006, 3205.
r
10.1021/ol2002418
Published on Web 03/25/2011
2011 American Chemical Society

nitrene precursor, catalyst and oxidant identity to improve
the efficiency of allene aziridination to synthetically useful
levels and reasonable stereoselectivities.
Attempts to utilize N-tosyloxycarbamates as nitrene
precursors were met with limited success for the synthesis
of 7 (Table 1, entries 1ꢀ4), similar to previously reported
results.3a The competitive formation of CꢀH amination
product 8 was a recurring issue, as well as unproductive
For the purposes of isolating the target MAs, we found
that carbamates provided the best balance between the
reactivity of the nitrene precursor and the subsequent
stability and reactivity of the product.6 A series of allenic
carbamates were subjected to various reaction conditions
as illustrated in Table 2. We found that the Rh2(OAc)4 and
Rh2(oct)4 (oct = O2CC7H15) catalysts previously used in
thistypeofchemistry didnotperformwellinourhands.3a,b
Rh2esp2 (esp = R,R,R0,R0-tetramethyl-1,3-benzenedipro-
pionate) and Rh2(TPA)4 (TPA = triphenyl acetate) pro-
ved to be more effective catalysts, giving complete conver-
sion of the carbamate in most cases. The choice of oxidant
was also crucial, as the leaving group released from the
PhI(OAc)2 or PhI(OPiv)2 oxidants can ring-open sensitive
MAs to yield the corresponding enecarbamates. For ex-
ample (Table 2, entry 1), the Z isomer of MA 12a was
susceptible to ring-opening by pivalate to give 12b in
addition to the desired 12a. Placing a methyl group at
the carbon R to the allene (entry 2) suppressed ring-open-
ing to give an 87% yield of MA 13a as a 2.4:1 mixture of
E/Z isomers at the olefin, with the methyl group and the
aziridine proton maintaining a trans relationship in both
alkene stereoisomers as observed by 1H NMR. The use of
Table 1. N-Tosyloxycarbamate and Sulfamate Precursors
˚
PhIO in the presence of 4 A molecular sieves minimized the
MA ring-opening and was the oxidant of choice for most
of the reactions in Table 2.
Competing CꢀH amination can occur when the tether
between the allene and the carbamate is two or more
carbons. As illustrated in entry 3, the nature of the catalyst
and oxidant influenced the aziridination vs CꢀH amina-
tion ratio and the overall yield of the reaction. A Rh2esp2
catalyst with PhI(OAc)2 (condition A) gave good conver-
sion to a mixture of 14a and 14b, but with no selectivity for
azirdination over CꢀH amination. Changing the oxidant
to PhI(OPiv)2 (condition B) improved the E/Z ratio of the
MA product from 1.5:1 to 4.1:1 but did not increase the
ratio of 14a:14b. Switching the oxidant to PhIO (condition
C) increased the ratio of 14a:14b to 4:1, with a 66% yield of
the MA. Finally, changing the catalyst to Rh2(TPA)4
resulted in a 5.3:1 ratio of 14a:14b, with an 80% yield of
the desired MA 14a (condition D). Changing the side chain
on the allene in combination with the use of Rh2(TPA)4 as
the catalyst gave only the isolated E isomer (entries 4 and
6), but CꢀH amination was competitive. Placement of
alkyl groups at positions R or β to the allene resulted in
increased amounts of CꢀH amination products (entries
7ꢀ9), although the use of Rh2(TPA)4 did improve the
aziridination/CꢀH amination ratio to some extent. Final-
ly, shutting down the possibility of CꢀH amination (entry
10) gave an excellent 94% yield of the desired MA 21a.
The E/Z ratios of the MAs in Table 2 also deserve
comment. NOESY 1D studies suggest that the E olefin
geometry is present in the major product (see the Support-
ing Information for further details). Indirect evidence that
interactions between the nitrenoid intermediate and the
alkyl chain play a role in determining the E/Z ratio is sug-
gestedbyentry 3 inTable2. Themorestericallydemanding
Rh2(TPA)4 complex increased the E/Z ratio from 1.5:1 to
around 4:1. Further studies are underway to increase the
a K2CO3, 0.1 M in acetone. b Substrate was added over 2 h, and the
acetone was dried over 4 A MS. c 2.0 equiv of PhIO, 4 A MS, CH2Cl2, rt.
d Products of hydrolysis of 10 were also observed. e 2.0 equiv of PhI-
(OAc)2, MgO, CH2Cl2, 40 °C.
tosylation of 5 with another molecule of itself to yield 9.5
The use of sulfamate 6 was successful and gave no compet-
ing CꢀH amination, but ring-opening of the labile MA to
10 (entry 5) was problematic. Increasing the tether length
between the allene and the sulfamate to three carbons (11,
entry 6) completely suppressed ring-opening of the desired
11a but also gave significant amounts of the CꢀH amina-
tion product 11b.
(5) Hayes, C. J.; Beavis, P. W.; Humphries, L. A. Chem. Commun.
2006, 4501.
(6) (a) Padwa, A.; Flick, A. C.; Leverett, C. A.; Stengel, T. J. Org.
Chem. 2004, 69, 6377. (b) Lebel, H.; Huard, K.; Lectard, S J. Am. Chem.
Soc. 2005, 127, 14198. (c) Espino, C. G.; Du Bois, J. Angew. Chem., Int.
Ed. 2001, 40, 598. (d) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem.
Soc. 2005, 127, 14198. (e) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois,
J. J. Am. Chem. Soc. 2001, 123, 6935.
Org. Lett., Vol. 13, No. 8, 2011
1925

the necessary enecarbamate (Scheme 1, 3) intermediate via
aziridine ring-opening. We expected the additional ring
strain present in 14a might allow for milder conditions
thanwould typically beexpected for aziridine ring-opening
(Scheme 2).7 Indeed, carboxylic acid nucleophiles gave the
Table 2. Carbamate Precursors for Allene Aziridination
Scheme 2. Nucleophilic Ring-Opening of Bicyclic MAs
enecarbamates 22 and 26 in excellent yields, while the use
ofTMSClat rt gave 24in good yield. We hypothesized that
since MA ring-opening using carboxylic acids as nucleo-
philes was so facile, Lewis acids might also activate the
aziridine toward ring-opening with neutral nucleophiles.
Indeed, the use of Sc(OTf)3 as a mild Lewis acid in the
presence of methanol and thiophenol promoted the ring-
opening of 14a to give 27 and 28 in modest yields. No
reaction occurred in the absence of the Lewis acid. Reac-
tion with a cyanide nucleophile was also improved in the
presence of a Lewis acid, although the double bond
migrated to give an isomeric enecarbamate 25. Finally,
treatment of 14a with NaN3/TMSCl generated 23 in 82%
yield, likely via initial ring-opening of the MA, followed by
a [3,3]-sigmatropic rearrangement.8
Based on the results in Scheme 2, we felt that carboxylic
acids were the most promising nucleophiles to pursue for
further studies. As illustrated in entry 1 of Scheme 3,
eliminating the ring-opening step and simply treating the
MA 14a with NBS in a mixture of THF/H2O gave 29 with
an initial dr of 5.5:1. Not surprisingly, the R-bromo ketone
epimerized slowly over time to give a 1.1:1 mixture of
bulk of the Rh ligands to improve the stereoselectivity of
the aziridination.
The reactions in Table 2 represent the first reliable
methods to access bicyclic MAs bearing electron-with-
drawing groups on the aziridine nitrogen. The next step
was to determine what types of nucleophiles would yield
(7) Hu, X. E. Tetrahedron 2004, 60, 2701.
(8) (a) Feldman, A. K.; Colasson, B.; Sharpless, K. B.; Fokin, V. V.
J. Am. Chem. Soc. 2005, 127, 13444. (b) VanderWerf, C. A.; Heasley,
V. L. J. Org. Chem. 1966, 31, 3534.
1926
Org. Lett., Vol. 13, No. 8, 2011

a single pot was further demonstrated by a tandem
aziridination/ring-opening of the allene 13 to 32 (entry
4). The substrate was treated under condition B (Table 2)
to form the intermediate MA. N-aminophthalimide and
additional oxidant were then addedtothe same pottoyield
the unusual spiroaminal 32 in 46% yield, where four new
carbonꢀheteroatom bonds have been formed in a single
pot. The stereochemistry between the Me and OAc groups
at a and b was exclusively trans by 1H NMR (see Support-
ing Information for further details). The 2.4:1 E/Z ratio of
the MA olefin isomers (see 13a, Table 2, entry 2) appears to
havebeentranslatedfromtheintermediateMAintoa 2.4:1
dr in the final product 32. This result suggests that better
control of the E/Z stereochemistry in the MA formation
will translate into excellent dr in the spiroaminal products.
In conclusion, we have described a synthetically viable
approach toward bicyclic MAs activated by electron-with-
drawing groups. The potential of these MAs as scaffolds for
the construction of motifs bearing three contiguous het-
eroatom-bearing carbons has been demonstrated. Future
work is directed toward expansion of the substrate scope,
particularly in the use of different nitrene precursors to mini-
mize competing CꢀH amination. The asymmetric syntheses
of MAs from enantioenriched allenes9 and their subsequent
reactivity will be further explored. The scope of nucleophiles
and electrophiles for efficient and flexible multicomponent
reactions that install multiple carbonꢀheteroatom bonds
into a simple allene precursor will be expanded.
Table 3. Formation of Three Contiguous CarbonꢀHeteroatom
Bonds from Allenes via Bicyclic Methyleneaziridines
a Compound epimerized to a 1.1:1 mixture upon standing.
diastereomers. Loss of stereochemical integrity was also
noted when 26 was subjected to similar conditions, giving
the tetrasubstituted bromoalkene 30 as a 2.3:1 mixture of
E/Z isomers (entry 2). We postulated that isomerization of
an intermediate imine was leading to the brominated
olefin. This prompted us to add NaCNBH3 as a reductant
to the reaction mixture, whereupon 31 was obtained in
73% yield with a dr of 10:1 (see the Supporting Informa-
tion for details and a proposed stereochemical model). It is
possible that anchimeric assistance from the acetate group
of the enecarbamate is playing a role in controlling the
stereochemical outcome of the reaction. This result,
coupled with the ease of ring-opening MAs with acids, is
an exciting step toward flexible, stereoselective methods
for allene functionalization. The power of allene aziridina-
tion to generate multiple carbon-heteroatom bonds in
Acknowledgment. Funding was provided by the Uni-
versity of Wisconsin, Madison. Alan Meis and Cale
Weatherly (UW;Madison) are thanked for help in the
preparation of allene substrates. Dr. Charles Fry (UW;
Madison) is thanked for assistance with NMR spectro-
scopy, and Professors Hans Reich and Steven Burke
(UW;Madison) for insightful comments. D.M. was sup-
ported by the NIH (ChemistryꢀBiology Interface Train-
ing Grant, GM08505). The NMR facilities at UW;
Madison are funded by the NSF (CHE-9208463, CHE-
9629688) and NIH (RR08389-01).
Supporting Information Available. Experimental pro-
cedures and full characterizations or all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) (a) Ogasawara, M. Tetrahedron: Asymmetry 2009, 20, 259. (b)
Kim, H.; Williams, L. J. Curr. Opin. Drug Disc. 2006, 11, 870.
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