Synthesis and reactivity of unique heterocyclic structures en route to substituted diamines

Article abstract of DOI:10.1021/ol2010769

Rhodium-catalyzed oxidative cyclization of allylic hydroxylamine-derived sulfamate esters furnishes a novel family of bicyclic aziridines that serve as functional precursors to substituted diamines. Investigations with the N4-Troc form of these heterocycles have led to manifold improvements in reaction performance and scope and have revealed unique differences in the stability and reactivity of such compounds dictated by the choice of N4-protecting group.

Full text of DOI:10.1021/ol2010769

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3336–3339
Synthesis and Reactivity of Unique
Heterocyclic Structures en Route to
Substituted Diamines
David E. Olson, Autumn Maruniak, Sushant Malhotra, Barry M. Trost,* and
J. Du Bois*
Department of Chemistry, Stanford University, Stanford, California 94305-5080,
United States
bmtrost@stanford.edu; jdubois@stanford.edu
Received April 24, 2011
ABSTRACT
Rhodium-catalyzed oxidative cyclization of allylic hydroxylamine-derived sulfamate esters furnishes a novel family of bicyclic aziridines that
serve as functional precursors to substituted diamines. Investigations with the N4-Troc form of these heterocycles have led to manifold
improvements in reaction performance and scope and have revealed unique differences in the stability and reactivity of such compounds dictated
by the choice of N4-protecting group.
The rapid assembly of aza-heterocycles from sulfamate
derivatives is made possible through selective CꢀH and
π-bond amination methods.1 Our laboratories have re-
cently reported that two catalytic processes, Pd π-allyl
coupling and Rh-catalyzed alkene aziridination, may be
used in sequence to generate a previously unknown class of
strained heterobicyclic products.2 While the potential to
synthesize differentially substituted 1,2- and 1,3-diamines3ꢀ6
from these unique oxathiadiazinane derivatives was evi-
dent, little was known about the factors that govern their
stability and reactivity. Herein, we detail new protocols to
prepare highly substituted forms of these heterocycles,
and highlight for the first time the unusual stability and
utility of Troc-protected oxathiadiazinanes for 1,2-dia-
mine synthesis (Figure 1).
(1) For general discussions on CꢀH and π-bond amination, see: (a)
Zalatan, D. N.; Du Bois, J. Top. Curr. Chem. 2010, 292, 347–378. (b) Li,
Z.; Capretto, D. A.; He, C. Silver in Organic Chemistry; John Wiley &
Sons: New York, 2010; pp 167ꢀ182. (c) Collet, F.; Dodd, R. H.; Dauban,
P. Chem. Commun. 2009, 5061–5074. (d) Davies, H. M. L.; Manning,
J. R. Nature 2008, 451, 417–424.
(2) Trost, B. M.; Malhotra, S.; Olson, D. E.; Maruniak, A.; Du Bois, J.
J. Am. Chem. Soc. 2009, 131, 4190–4191.
(3) For general applications of diamines, see: (a) Kizirian, J.-C. Chem.
Rev. 2008, 108, 140–205. (b) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem.
Biol. Drug Des. 2006, 67, 101–114. (c) de Parrodi, C. A.; Juaristi, E. Synlett
2006, 17, 2699–2715.
(4) For reviews on the synthesis of 1,2-diamines, see: (a) Cardona, F.;
Goti, A. Nature Chem. 2009, 1, 269–275. (d) de Figueiredo, R. M. Angew.
Chem., Int. Ed. 2009, 48, 1190–1193. (b) Mortensen, M. S.; O’Doherty,
G. A. Chemtracts: Org. Chem. 2005, 18, 555–561. (c) Lucet, D.; Le Gall, T.;
Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580–2627and references
therein.
(5) For examples of polyamine-derived natural products, see: Busscher,
G. F.; Rutjes, F. P. J. T.; van Delft, F. L. Chem. Rev. 2005, 105, 775–791.
(6) Differential diamine protection is possible using the diamination
method of Shi; see: Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007,
129, 762–763. For the synthesis of differentially protected 1,2-diamines
through Rh-catalyzed CꢀH amination, see: Olson, D. E.; Du Bois, J.
J. Am. Chem. Soc. 2008, 130, 11248–11249.
Figure 1. Novel heterocyclic substrates as precursors to substi-
tuted diamines.
r
10.1021/ol2010769
Published on Web 05/27/2011
2011 American Chemical Society

Our initial studies described the synthesis and reactivity
of aziridine-fused N-Mbs-[1,2,3,6]oxathiadiazinane-2,
2-dioxide heterocycles, which were found, in select cases,
to undergo nucleophilic ring-opening with modest effi-
ciency (Figure 2a).7ꢀ9 Studies to further optimize these
addition reactions and to determine the origin of material
lossledus toconcludethataziridine displacementoccurred
with little regiocontrol. The intermediate generated from
nucleophilic attack at C7 was, however, unstable to the
reaction conditions and decomposed to liberate MbsNH2.
A series of control experiments using oxathiadiazinane 210
demonstrated that base additives (e.g., KN(SiMe3)2, pyr-
idine, or NaH) would promote rapid ring fragmentation
(Figure 2b). The unusual and unprecedented reactivity of
the N-Mbs oxathiadiazinane heterocycle has no obvious
explanation. We speculated that replacing the N4-Mbs
group with an acyl substituent might mitigate the decom-
position of these heterocycles by influencing the ring
conformation. Such an alteration would present new
challenges for substrate synthesis and would likely affect
the oxidative cyclization reaction; however, the ease of
removing the N4-acyl group as compared to the Mbs-
would be advantageous for the overall utility of the
method. Accordingly, N-Boc and N-Troc substrates were
targeted with these considerations in mind.
These sulfamate derivatives engage in either Mitsunobu or
asymmetric π-allyl Pd-coupling reactions with alcohol or
carbonate starting materials, respectively. The Troc-re-
agent 3, in particular, operates with superior performance
in both types of displacement reactions when compared to
either 4 or the Mbs-variant. As shown in Figure 3, Pd-
catalyzed π-allylation of 3 using carbonate 7 gives the R,
R-disubstituted sulfamate in high yield and with excellent
regiocontrol (>20:1 branched/linear product). The analo-
gous reaction utilizing 4 proceeds in modest yield
while the same reaction, when performed with MbsNHO-
SO2NH2, fails to give any allylated product. In light of
these findings, most of our subsequent investigations have
been conducted with the N-Troc sulfamate reagent 4. The
identification of this sulfamate derivative should markedly
facilitate access to a range of substituted oxathiadiazinane
heterocycles and thus 1,2- and 1,3-diamine products.
Figure 3. N-Carbamoyl sulfamate reagents perform optimally in
allylation reactions.
Intramolecular aziridination reactions with both Boc-
and Troc-derived sulfamates are highlighted in Table 1. In
general, cyclizations performed optimally using a dinuc-
lear tetracarboxylate rhodium catalyst (2 mol %), PhI-
(OAc)2, and MgO.11 Oxidations occur smoothly in
isopropyl acetate, which proves more effective as a solvent
than others typically employed for Rh-catalyzed amina-
tion (e.g., CH2Cl2, benzene).12 Olefinic substitution does
not have a large influence on the reaction as terminal
(entries 1 and 2), disubstituted (entries 3 and 4), and
trisubstituted (entry 5) alkenes are all converted in
high yields to the corresponding bicyclic aziridines.
While product yields of N-Boc substrates were slightly
depressed, those of N-Troc substrates were excellent
and comparable to the performance of analogous N-Mbs
substrates.2,6
Figure 2. Unusual base-promoted decomposition of Mbs-sub-
stituted oxathiadiazinanes. Mbs = p-methoxybenzenesulfonyl.
Synthesis of TrocNHOSO2NH2 3 and BocNHO-
SO2NH2 4 is easily accomplished in two steps from hydrox-
ylamine. Both reagents are crystalline and can be pre-
paredon >10 g scalewithoutrecourse to chromatography.
(7) We refer to these heterocycles as oxathiadiazinanes for simplicity.
(8) Prior to our work, we are only aware of one report of these
heterocycles; see: Arfaei, A.; Smith, S. J. Chem. Soc., Perkin Trans. 1
1984, 1791–1794.
(9) For the synthesis and reactivity of related aziridine-fused oxathia-
zinanes, see: (a) Wehn, P. M.; Du Bois, J. Angew. Chem. 2009, 121, 3860–
3863. (b) Guthikonda, K.; Wehn, P. M.; Caliando, B. J.; Du Bois, J.
Tetrahedron 2006, 62, 11331–11342. (c) Wehn, P. M.; Lee, J.; Du Bois, J.
Org. Lett. 2003, 5, 4823–4826. (d) Duran, F.; Leman, L.; Ghini, A.;
Burton, G.; Dauban, P.; Dodd, R. H. Org. Lett. 2002, 4, 2481–2483.
(10) Compound 2 was prepared using Rh-catalyzed CꢀH amination;
see ref 6.
(11) Rh2(esp)2 is sold by Aldrich Chemical Co. as Rh2(R,R,R0,
R0-tetramethyl-1,3-benzenedipropionate)2. For the initial report of this
catalyst, see: Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am.
Chem. Soc. 2004, 126, 15378–15379.
(12) The use of i-PrOAc was prompted by a previous report describ-
ing aldehyde CꢀH sulfamidation; see: Chan, J.; Baucom, K. D.; Murry,
J. A. J. Am. Chem. Soc. 2007, 129, 14106–14107.
Org. Lett., Vol. 13, No. 13, 2011
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Table 1. Rh-Catalyzed Intramolecular Aziridination
Figure 4. Diastereoselectivity in aziridination reactions influ-
enced by nitrogen protecting group (R = Troc, Boc, or Mbs;
R0 = CH2CCl3 or tBu).
our earlier observation, tricyclic structures like the one
depicted in entry 7 (Table 1) react to form bridged 7-mem-
bered ring products. One of these derivatives, 11, has been
crystallographically characterized (Figure 5).14 Interest-
ingly, the cyclohexane unit in 11 adopts an almost perfect
chair-likeconfiguration despite having all three substituent
groups positioned axially. The preferential formation of 11
over the corresponding fused-bicyclic [4.4.0] isomer is
likely the result of stereoelectronic factors, which favor a
trans-diaxial transition structure for ring-opening. The
predilection for the aziridine derived from 10 and related
tricyclic aziridines to ring open in this manner appears to
be invariant of the choice of N-substituent group (i.e., acyl
or sulfonyl).
a Reactions conducted in iPrOAc using 2 mol % of Rh2(esp)2,
2.3 equiv of MgO, and 1.1 equiv of PhI(OAc)2. b Substrates were pre-
pared using either Mitsunobu or π-allyl Pd chemistry in yields ranging
from 60ꢀ99%. See the Supporting Information for details. c Isolated
yield of this aziridine was reduced due to difficulties associated with its
purification. See the Supporting Information for details. d Product
diastereomeric ratios determined by 1H NMR integration.
As noted in Table 1, modest to high levels of product
diastereocontrol are observed for acyclic and cyclic alkene
starting materials, respectively (entries 4, 6, and 7). For
acyclic structures (entry 4), stereoselectivity is clearly
influenced by the choice of the N4-substituent group.
The sense of induction in these products may be rationa-
lized through a chairlike transition state model (Figure 4).
Introduction of a destabilizing A1,3-type interaction in
both the N-Boc and N-Troc sulfamate derivatives could
account for the reduced degree of product stereocontrol in
comparison to the N-sulfonyl compound.13 With cyclic
olefins, cis-fused tricyclic structures are formed exclusively
regardless of the N-blocking group.2
Figure 5. Regioselective aziridine ring-opening favors seven-
membered ring projects.
We have found that bicyclic aziridines, like their tricyclic
counterparts, share a similar tendency for nucleophilic
ring-opening to afford 7-membered ring heterocycles;
however, optimal selectivity is only achieved when steric
factors reinforce this preference (Figure 5).15 Furthermore,
judicious placement of substitutent groups can in select
cases bias attack toward C7. As shown in Figure 6,
Oxathiadiazinane-derivedaziridinesundergofacilering-
opening with a range of nucleophiles. In agreement with
(13) A similar rationale was put forth to explain diastereoselectivity
in analogous reactions involving sulfamides; see: Kurokawa, T.; Kim,
M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 2777–2779.
(14) Crystallographic data has been deposited at the Cambridge
Crystallographic Data Centre (CCDC 809399).
3338
Org. Lett., Vol. 13, No. 13, 2011

nucleophilic displacement reactions with 15 afford the
corresponding six-membered oxathiadiazinanes as the ex-
clusive products. These N-Troc-substituted oxathiadiazi-
nanes are stable to chromatography and are isolable,
a finding that stands in stark contrast to the marked
instability of analogous N-Mbs oxathiadiazinane deriva-
tives (see Figure 2). As shown in eq 1, the N-Troc hetero-
cycles serve as precursors to highly functionalized,
differentially protected 1,2-diamines. While the assembly
of structures of this type using traditional methods for
amine synthesis would generally require multiple transfor-
mations, such products are now easily prepared from
commercial allylic alcohols using the protocols outlined
in this report.
surrogates. These findings have motivated us to examine the
use of saturated N-Troc hydroxylamine sulfamate esters as
substrates for CꢀH amination.16
Rhodium-catalyzed alkene aziridination has given rise
to a collection of unprecedented heterocyclic structures
that serve as useful precursors to functionalized diamine
products. In the course of developing these chemistries, we
have identified an unexpected and heretofore unknown
fragmentation reaction of N-sulfonyl oxathiadiazinanes.
This reaction is entirely suppressed by changing the nature
of the N-protecting group, a modification that enables for
the first time isolation and subsequent reactions of struc-
tures such as 16. Importantly, the necessary N-Troc sulfa-
mate starting materials can be synthesized in high yield
through two different protocols and perform exceptionally
well in intramolecular Rh-catalyzed olefin aziridination.
All told, our discoveries should facilitate the use of and
greatly expand the application potential of this unique
family of oxathiadiazinane heterocycles.
Figure 6. Isolable oxathiadiazinane derivatives through regio-
selective aziridine displacement.
Acknowledgment. This work has been supported by the
National Institutes of Health and the National Science Foun-
dation. Partial funding for this work was also provided to
J.D.B. by the National Science Foundation Center for Stereo-
selective CꢀH Functionalization (CSCHF). D.E.O. and S.M.
gratefully acknowledge Eli Lilly and Stanford University,
respectively, for fellowship support. Palladium salts were
generously supplied by Johnson-Matthey. X-ray crystallo-
graphic analysis was performed by Dr. Allen Oliver; diffrac-
tion data were recorded on an instrument supported by the
National Science Foundation, Major Research Instrumenta-
tion (MRI) Program under Grant No. CHE-0521569.
We speculate that subtle conformational differences be-
tween the N-Troc 16 (see Figure 6) and N-Mbs 2 (see
Figure 2) six-membered heterocycles are responsible for
the striking difference in stability between these two structu-
rally related species. Although the mechanism by which
oxathiadiazinanes such as 2 undergo fragmentation to lib-
erate MbsNH2 is still opaque, the switch from Mbs to a
carbamoyl blocking group has resulted in manifold improve-
ments in the overall aziridination process and, perhaps more
importantly, has made available a potentially important
class of six-membered heterocyclic structures as 1,2-diamine
(15) Ring opening reactions of bicyclic aziridines such as those
featured in Figure 5 are currently limited to azide, cyanide, and thiolate
nucleophiles. Reactions performed with oxygen-based nucleophiles
(e.g., carboxylates, alkoxides, peroxide) fail to give the desired 7-membered
ring product.
Supporting Information Available.
Experimental
procedures, characterization data, and X-ray crystallo-
graphic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Olson, D. E.; Roberts, D. A.; Du Bois, J. Manuscript in
preparation.
Org. Lett., Vol. 13, No. 13, 2011
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