1,4-diamination of cyclic dienes via a (4 + 3) cycloaddition of diaza-allyl cationic intermediates

Article abstract of DOI:10.1021/ol302771z

Diaza-(4 + 3) cycloadditions of putative diaza-oxyallyl cationic intermediates and cyclic dienes are reported as a method for the 1,4-diamination of cyclic dienes. This reaction was entirely selective for diamination and provided cycloadducts in good to excellent yield.

Full text of DOI:10.1021/ol302771z

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
1,4-Diamination of Cyclic Dienes via a
(4 þ 3) Cycloaddition of Diaza-allyl
Cationic Intermediates
Christopher S. Jeffrey,* Devendar Anumandla, and Christopher R. Carson
Department of Chemistry, University of Nevada;Reno, Reno, Nevada 89557,
United States
cjeffrey@unr.edu
Received October 9, 2012
ABSTRACT
Diaza-(4 þ 3) cycloadditions of putative diaza-oxyallyl cationic intermediates and cyclic dienes are reported as a method for the 1,4-diamination of
cyclic dienes. This reaction was entirely selective for diamination and provided cycloadducts in good to excellent yield.
1,n-Diamine (n = 2ꢀ5) motifs are found in numerous
pharmaceuticals and biologically active natural products,
including the anti-HIV molecules cobicistat1 and DMP-
4502 (Figure 1).3 Of the methods of diaminationof alkenes,
the vicinal 1,2-diamination of dienes and alkenes is the
most comprehensively investigated reaction type.4 Despite
the importance of 1,4-diamino motifs in biologically active
molecules, selective methods for the 1,4-diamination of
dienes have not been thoroughly explored.5 The hetero-
DielsꢀAlder reactions of diazocarboxylates and triazine
diones are the most widely used methods for the selective
diamination of dienes.6 Despite numerous applications of
this reaction, limitations due to a competitive ene-reaction
and the explosion hazard of the diazidocarboxylates have
limited their use.
The (4 þ 3) cycloaddition reaction of allylic cations and
dienes has developed into a powerful method for the
synthesis of seven-membered carbocycles.7 We have re-
cently reported the aza-(4 þ 3) cycloaddition of a putative
aza-oxyallylcation and a diene as a heteroatomic analog
of this reaction.8 It was envisioned that a related hetero-
(4 þ 3) type cycloaddition of a diaza-oxyallylcation could
deliver cyclic ureas and serve as a method for the chemo-
selective 1,4-diamination of dienes (Figure 1). This com-
munication describes our work on the aforementioned
reaction.
(1) Xu, L.; Liu, H.; Murray, B. P.; Callebaut, C.; Lee, M. S.; Hong,
A.; Strickley, R. G.; Tsai, L. K.; Stray, K. M.; Wang, Y. ACS Med.
Chem. Lett. 2010, 1, 209–213.
(2) Lam, P. Y.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.;
Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.
Science 1994, 263, 380.
(3) (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580–2627. (b) Saibabu Kotti, S. R.; Timmons, C.; Li, G.
Chem. Biol. Drug Des. 2006, 67, 101.
(4) (a) De Figueiredo, R. M. Angew. Chem., Int. Ed. 2009, 48, 1190.
(b) Cardona, F.; Goti, A. Nat. Chem. 2009, 1, 269. (c)
(5) For examples of methods of 1,4-diamination of conjugated
(6) For a general review of hetero-DielsꢀAlder reactions, see: (a) The
DielsꢀAlder Reaction: Selected Practical Methods; Fringuelli, F., Taticchi,
A., Eds.; John Wiley & Sons: New York, 2002. (b) Cycloaddition Reactions in
Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; WileyꢀVCH:
Weinheim, Germany, 2002; pp 151ꢀ209. (c) Comprehensive Asymmetric
Catalysis III; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; pp 1237ꢀ1254. (d) Gouverneur, V.; Reiter, M. Chem.;Eur. J. 2005,
11, 5806. (e) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558. (f)
Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1.
~
dienes, see: (a) Lishchynskyi, A.; Muniz, K. New J. Chem. 2012, 18,
€
€
2212. (b) Backvall, J. E. Acc. Chem. Res. 1983, 16, 335. (c) Backvall,
€
€
J.-E.; Nystrom, J.-E.; Nystrom, J.-E. J. Chem. Soc., Chem. Commun.
€
€
1981, 59. (d) Akermark, B.; Backvall, J.-E.; Lowenborg, A.; Zetterberg,
K. J. Organomet. Chem. 1979, 166, 33.
r
10.1021/ol302771z
XXXX American Chemical Society

Scheme 1. Preliminary Experimentsa
a R1 = Bn, Me, or Et; TFE = 2,2,2-trifluoroethanol.
With the N-chlorourea 2 in hand the cycloaddition reac-
tion with furan was evaluated. Treatment of the N-chloro-
€
urea 2 under Folisch conditions (CF3CH2OH, Et3N) with
furan provided the cycloadduct 3 along with significant
products 4 and 5.10 The nature of the substituents (R1 =
Bn, Et, Me) had little effect on the yield of the cycloadduct.11
The choice of base, however, had a significant effect on the
yield of the cycloadduct 3. Using the sodium alkoxide of
2,2,3,3-tetrafluoropropanol (TFP/TFP-Na) provided the
highest yield (74%) of the cycloadduct 3 with minimal
formation of the solvolysis product 5.12 The yield of the
desired product 3 was significantly improved when a
solution of N-chlorourea in CH3CN was added over 3 h
to the mixture of diene and base at 0 °C.13 Although it is
common that (4 þ 3) reactions are run in an excess of the
diene (>10 equiv),6 we found that the yield of the furan
adduct 3 was not very sensitive to the ratio of substrate to
diene, even when the reaction was conducted with 1.1 equiv
of diene (87% using 1.1 equiv vs 95% using 5ꢀ25 equiv)!
The scope of this reaction with respect to diene was ex-
plored. Cyclopentadiene and N-Boc pyrrole underwent the
reaction to provide the cycloadducts in similar yield to that
with furan (Table 1, entries 2ꢀ4). 2,5-Disubstituted (Table 1,
entry 5) and 3,4-disubstituted furans (Table 1, entry 6) pro-
vided the cycloadduct in good to excellent yields. However,
furans with electron-deficient substituents (2-carboethoxy)
and acyclic dienes (isoprene and 2,3-dimethyl-1,4-butadiene)
provided only solvolysis products and recovered starting
material after workup.14 6,6-Dimethyl fulvene (Table 1,
entry 8) and [2.2.2]-spiro-heptadiene (Table 1, entry 7) both
reacted in the desired manner providing the cycloadduct in
good to excellent yields. We found that 1,3-cyclohexadiene
also provided the cycloadduct in fair yield (entry 9).
Figure 1. Aza-(4 þ 3) cycloaddition of aza-oxyallyl cations with
dienes.
In our previous studies the proposed aza-allyl cationic
intermediate was generated via a dehydrohalogenation of
R-halohydroxamates. Likewise, N-chloroureas 2 could
dehydrohalogenate to the diazaallyl cationic intermediate,
which then could react with a diene to provide a seven-
membered urea 3 (Scheme 1). To study this hypothesis, we
prepared N,N0-dibenzyl, dialkyl, and diaryl ureas and
attempted their N-chlorination. Initial efforts to chlorinate
these urea derivatives provided complex mixtures of prod-
ucts. N-Alkoxy ureas 1 can be efficiently chlorinated at
the N-alkoxy position by tert-butyl hypochlorite.9 N-
Methoxy, N-ethoxy, and N-benzyloxy benzyl ureas rapidly
underwent chlorination to provide the solid N-chlorourea
products 2 that were isolable via silica gel column chro-
matography in good to excellent yield.
(7) (a) Lohse, A. G.; Hsung, R. P. Chem.;Eur. J. 2011, 17, 3812–
3822. (b) Harmata, M. Chem. Commun. 2010, 8904–8922. (c) Harmata,
M. Chem. Commun. 2010, 8886–8903. (d) Huan, J.; Hsung, R. P.
ChemTracts 2005, 18, 207–214. (e) Harmata, M. Adv. Synth. Catal.
2006, 2297–2306. (f) Harmata, M. Acc. Chem. Res. 2001, 34, 595–605. (g)
Cha, J. K.; Oh, J. Curr. Org. Chem. 1998, 2, 217–232. (h) Harmata, M. In
Advances in Cycloaddition; Lautens, M., Ed.; JAI: Grennwich, 1997; Vol. 4,
pp 41ꢀ86. (i) West, F. G. In Advances in Cycloaddition; Lautens, M., Ed.;
JAI: Grennwich, CT, 1997; Vol. 4, pp 1ꢀ40. (j) Harmata, M. Tetrahedron
1997, 53, 6235–6280. (k) Padwa, A.; Schoffstall, A. In Advances in
Cycloaddition; Curran, D. P., Ed.; JAI Press: Greenwich, CT, 1990; Vol. 2,
pp 1ꢀ89. (l) Harmata, M. Recent Res. Dev. Org. Chem. 1997, 1, 523–535.
(m) Rigby, J. H.; Pigge, F. C. Org. React. 1997, 51, 351–478. (n) Mann, J.
Tetrahedron 1986, 42, 4611–4659. (o) Hoffmann, H. M. R. Angew.
Chem., Int. Ed. 1984, 23, 1–19. (p) Hoffmann, H. M. R. Angew. Chem.,
Int. Ed. 1973, 12, 819–835.
€
(10) Fohlisch, B.; Gehrlach, E.; Herter, R. Angew. Chem., Int. Ed.
1982, 137.
(11) Although the yield was not significantly affected by the nature of
the R1, it was our finding that the ethyl and benzyl substituted substitute
hydroxy ureas were easier to handle due to their solubility and chroma-
tographic characteristics.
(12) 2,2,3,3-Tetrafluoropropanol is an inexpensive solvent. This
solvent base combination has been previously demonstrated to have
€
substantial benefits in the (4 þ 3) cycloaddition reaction; see: Fohlisch,
B.; Gehrlach, E.; Geywitz, B. Chem. Ber. 1987, 120, 1815.
(13) The order and rate of addition were found to dramatically affect
the yield of the cycloaddition of electron-rich dienes. For example, the
yield of the cycloadduct of 2,5-dimethyl furan improved from 35% to
65% yield when the N-chlorourea was added over 3 h.
(8) Jeffrey, C. S.; Barnes, K. L.; Eickhoff, J. A.; Carson, C. R. J. Am.
Chem. Soc. 2011, 133, 7688–7691.
(9) Shtamburg, V. G.; Shishkin, O. V.; Zubatyuk, R. I.; Kravchenko,
S. V.; Tsygankov, A. V.; Mazepa, A. V.; Klots, E. A.; Kostyanovsky,
R. G. Mendeleev Commun. 2006, 16, 323–325.
(14) Generally electron-deficient and acyclic dienes do not react
efficiently with oxyallylic cations; see refs 6b and 6c.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Scope of the Diaza-(4 þ 3) Cycloaddition of 2 with
Table 2. Scope of the Diaza-(4 þ 3) Cycloaddition of 2 with
Cyclic Dienesa
Monosubstituted Cyclic Dienesa
a Conditions: N-Chlorourea in CH3CN was added to a solution of
the diene [5 equiv (condition A) or 1.1 equiv (condition B)] and TFP-Na
(2.0 equiv) in TFP (0.25 M). b Isolated yield of both regioisomers of the
cycloadducts 7 and 8.
remained high with a variety of substituents, including a free
alcohol (Table 2, entry 2) and a halide (Table 2, entry 3).
1,4-Diamino moieties are widely represented in a variety
of biologically active molecules (Figure 1).3 The substrates
derived from our cycloaddition can serve as useful building
blocks for the synthesis of these targets. As an example of
this versatility, we treated the [3.2.2] diaza-bicyclononene 9
under a variety of conditions (Scheme 2). Products of these
Scheme 2. Examples of Selective Transformations of the [3.2.2]-
Diazabicyclononene 9
a Conditions: N-Chlorourea 2 in CH3CN was added to a solution of
the diene [5 equiv (condition A) or 1.1 equiv (condition B)] and TFP-Na
(2.0 equiv) in TFP (0.25 M). b Isolated yield of the cycloadduct 13.
Reactions using monosubstituted dienes provided a mix-
ture of regioisomeric cycloadducts (Table 2). This ratio of
regioisomers was close to 1:1 in all cases and remained
largely unaffected by the hyrdoxamate substituent.15
Although using a symmetric dibenzyloxy or methoxy urea
would avoid this issue, problems associated with monochlori-
nation of the urea thwarted this approach. Nonetheless, the
combined yield of the mixture of regioisomeric products
(15) The regioisomeric ratio was determined by crude 1H NMR
analysis. The structures of the regioisomers were assigned from NOSEY
correlations of the isolated products.
Org. Lett., Vol. XX, No. XX, XXXX
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reactions provide useful scaffolds for the synthesis of
cyclohexane diamines, such as those found in the fortimi-
cin type antibiotics. Hydrogenation of the alkene could be
completed to provide 10 without cleavage of either of the
benzyl groups or the NꢀO bond. Under more strenuous
hydrogenation conditions, the O-benzyl and N-benzyl
group were cleaved to provide the hydroxamic acid 11 in
good yield. The NꢀO bond could be chemoselectively
reduced using Mo(CO)6 in the presence of the N-Bn and
alkene to provide 12 in good yield. Oxidation of the alkene
to the diol 13 or the epoxide 14 was found to be diaste-
reoselective for the convex-face of the diaza-[3.2.2] bicycload-
duct. Reductive ring opening of the urea 9 using LiAlH4
provided the N-methyl diamine 15 in good yield
(ca. 3:1 r.r. based upon crude 1H NMR analysis). Diaza-
allylic cations, generated by the heterolysis of N-chloro
ureas, reacted with cyclic dienes to provide cyclic urea
products in good toexcellent yields in a single step. Current
efforts are directed toward understanding the mechanism
of this transformation, developing new reactions of diaza-
allylic cations, and applying this reaction toward the
synthesis of various target molecules.
Acknowledgment. This work was supported through an
ACS-PRF grant (51442-DNI1) and through startup fund-
ing from the University of Nevada, Reno. We thank Prof.
Benjamin King (University of Nevada, Reno) for helpful
discussions and Dr. Stephen M. Spain (University of
Nevada, Reno) for assistance with mass spectrometry.
Supporting Information Available. Experimental pro-
cedures, tabulated characterization data, and copies of
1H and 13C NMR spectra for all new compounds are pro-
vided in the Supporting Information. This material is avail-
able free of charge via the Internet at http://pubs.acs.org
The authors declare no competing financial interest.
D
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