Complementary regioselectivity in the Cu(I)-catalyzed diamination of conjugated dienes to form cyclic sulfamides

Article abstract of DOI:10.1021/ol102767j

This paper describes the regioselective diamination of conjugated dienes using inexpensive Cu (I) as catalyst and N,N-di-tert-butylthiadiaziridine 1,1-dioxide as nitrogen source. The regioselectivity of diamination is likely due to dual mechanistic pathwa

Full text of DOI:10.1021/ol102767j

ORGANIC
LETTERS
2011
Vol. 13, No. 3
434-437
Complementary Regioselectivity in the
Cu(I)-Catalyzed Diamination of
Conjugated Dienes To Form Cyclic
Sulfamides
Richard G. Cornwall, Baoguo Zhao, and Yian Shi*
Department of Chemistry, Colorado State UniVersity, Fort Collins,
Colorado 80523, United States
yian@lamar.colostate.edu
Received November 15, 2010
ABSTRACT
This paper describes the regioselective diamination of conjugated dienes using inexpensive Cu(I) as catalyst and N,N-di-tert-butylthiadiaziridine
1,1-dioxide as nitrogen source. The regioselectivity of diamination is likely due to dual mechanistic pathways which are greatly influenced by
reaction conditions and the nature of the diene. A variety of useful internal and terminal cyclic sulfamides can be obtained in good yield.
Metal-catalyzed diamination of olefins presents an attractive
strategy for the synthesis of vicinal diamines which are
important functional moieties present in various biologically
active compounds and chiral ligands used in asymmetric
synthesis.1 Various metal-mediated and metal-catalyzed
processes to construct vicinal diamines from olefins have
been reported.1-8 We previously reported the diamination
of conjugated dienes using Pd(0)9 or Cu(I)10 as a catalyst
and di-tert-butyldiaziridinone (1)11 as a nitrogen source
(Figure 1). The Pd(0)-catalyzed reaction is proposed to
proceed through a concerted mechanism, affording diami-
nation of the internal double bond, whereas the Cu(I)-
catalyzed reaction is proposed to proceed through a stepwise
(4) For Rh(II)-, Cu(I)-, and Fe(III)-catalyzed diamination with TsNCl2
or TsNBr2, see: (a) Li, G.; Wei, H.-X.; Kim, S. H.; Carducci, M. D. Angew.
Chem., Int. Ed. 2001, 40, 4277. (b) Wei, H.-X.; Kim, S. H.; Li, G. J. Org.
Chem. 2002, 67, 4777. (c) Han, J.; Li, T.; Pan, Y.; Kattuboina, A.; Li, G.
Chem. Biol. Drug. Des. 2008, 71, 71.
(1) For leading reviews, see: (a) Michalson, E. T.; Szmuszkovicz, J. Prog.
Drug Res. 1989, 33, 135. (b) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 2580. (c) Mortensen, M. S.; O’Doherty, G. A.
Chemtracts: Org. Chem. 2005, 18, 555. (d) Kotti, S. R. S. S.; Timmons,
C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101. (e) Kizirian, J.-C. Chem.
ReV. 2008, 108, 140. (f) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W.
Acc. Chem. Res. 2008, 41, 831. (g) de Figueiredo, R. M. Angew. Chem.,
Int. Ed. 2009, 48, 1190. (h) Cardona, F.; Goti, A. Nat. Chem. 2009, 1, 269.
(2) For examples of metal-mediated diaminations, see: Tl: (a) Aranda,
V. G.; Barluenga, J.; Aznar, F. Synthesis 1974, 504. Os: (b) Chong, A. O.;
Oshima, K.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 3420. (c) Mun˜iz,
K. Eur. J. Org. Chem. 2004, 2243. Pd: (d) Ba¨ckvall, J.-E. Tetrahedron
Lett. 1978, 19, 163. Hg: (e) Barluenga, J.; Alonso-Cires, L.; Asensio, G.
Synthesis 1979, 962. Co: (f) Becker, P. N.; White, M. A.; Bergman, R. G.
J. Am. Chem. Soc. 1980, 102, 5676. Mn: (g) Fristad, W. E.; Brandvold,
(5) For a recent Au(I)-catalyzed intramolecular diamination of allenes via
dihydroamination, see: Li, H.; Widenhoefer, R. A. Org. Lett. 2009, 11, 2671.
(6) For a Pd(II)-catalyzed intermolecular diamination of conjugated
dienes, see: Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am.
Chem. Soc. 2005, 127, 7308.
(7) For Pd(II)-catalyzed intramolecular diamination of olefins, see: (a)
Streuff, J.; Ho¨velmann, C. H.; Nieger, M.; Mun˜iz, K. J. Am. Chem. Soc.
2005, 127, 14586. (b) Mun˜iz, K. J. Am. Chem. Soc. 2007, 129, 14542. (c)
Mun˜iz, K.; Ho¨velmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130,
763. (d) Ho¨velmann, C. H.; Streuff, J.; Brelot, L.; Mun˜iz, K. Chem.
Commun. 2008, 2334. (e) Mun˜iz, K.; Ho¨velmann, C. H.; Campos-Go´mez,
E.; Barluenga, J.; Gonza´lez, J. M.; Streuff, J.; Nieger, M. Chem.sAsian J.
2008, 3, 776. (f) Mun˜iz, K.; Streuff, J.; Cha´vez, P.; Ho¨velmann, C. H.
Chem.sAsian J. 2008, 3, 1248. (g) Sibbald, P. A.; Michael, F. E. Org.
Lett. 2009, 11, 1147. (h) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.;
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T. A.; Peterson, J. R.; Thompson, S. R. J. Org. Chem. 1985, 50, 3647
.
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D.; Chemler, S. R. J. Am. Chem. Soc. 2005, 127, 11250. (b) Zabawa, T. P.;
Chemler, S. R. Org. Lett. 2007, 9, 2035. (c) Sequeira, F. C.; Turnpenny,
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.
10.1021/ol102767j  2011 American Chemical Society
Published on Web 12/30/2010

Scheme 2
.
Pd(0)-Catalyzed Diamination of Terminal Olefins
with 1 or 2
Figure 1. Nitrogen sources.
radical mechanism, yielding predominantly the terminal
diamination product. Very recently, we found that the
regioselectivity of diamination of conjugated dienes can be
highly influenced by reaction conditions, choice of Cu(I)
catalyst, and substrates used (Scheme 1).12 It is proposed
functional moieties present in medicinal and biologically
active molecules, including antibacterial agents and protease
inhibitors.16 They have also been employed as chiral ligands
in asymmetric synthesis.17 All of these factors led us to
examine the behavior of compound 2 toward various dienes
under Cu(I) catalysis conditions. Herein we report our
preliminary studies on this topic.
Scheme 1. Cu(I)-Catalyzed Regioselective Diamination Using 1
Studies began with (E)-nona-1,3-diene (5a) as substrate
and by varying reaction conditions. As shown in Table 1,
Table 1. Effect of Reaction Conditions on Regioselectivity of
Cu(I)-Catalyzed Diamination of Dienesa
that the regioselectivity of this diamination is a result of dual
mechanistic pathways. Complementary to the previously
10a
entry
conditions
conv (%)
6a:7a
reported conditions using CuCl-Ln
yielding terminal
14:1d
14:1d
>25:1d
1:1e
diamination, it was shown that with 5-10 mol % CuBr as
catalyst, the internal double bond of conjugated dienes could
be efficiently diaminated with very high selectivity.12 While
the terminal diamination products are consistent with a
stepwise radical process, the internal diamination products
are consistent with a mechanism similar to that of the
proposed, concerted Pd(0)-catalyzed diamination of conju-
gated dienes.9a The mechanistic duality of the Cu(I)-catalyzed
reaction prompted us to investigate the use of alternate
nitrogen sources on the regioselectivity of diamination.
We have reported in our earlier studies that N,N-di-tert-
butylthiadiaziridine 1,1-dioxide13 (2) exhibits unique reactiv-
ity as an effective nitrogen source for diamination.14,15 For
example, terminal olefins were diaminated at the allylic and
homoallylic carbons using Pd(0) and 1, whereas the use of
2 resulted in dehydrogenation across the allylic and homoal-
lylic carbons with diamination occurring at the terminal
double bond (Scheme 2). In addition, cyclic sulfamides are
1
CuCl-P(Cy)3 (1:1)
CuCl-P(n-Bu)3 (1:1)
CuCl-P(n-Bu)3 (1:1)
CuCl-P(PPh)3 (1:1)
CuCl-dppe (1:1)
CuCl
CuBr
CuBr
CuBr-P(n-Bu)3 (1:1)
44
47
65
40
23
39
70
76
24
2
3b
4
5
6
2:1e
1:3e
7
1:10d
1:19d
1.7:1e
8c
9
a All reactions were carried out with olefin 5a (0.20 mmol), 2 (0.24
mmol), and Cu(I) catalyst (0.020 mmol) in CDCl3 (0.3 mL) under Ar at rt
for 14 h unless otherwise stated. b 0.1 mL of CDCl3 was used. c 0.6 mL of
CDCl3 was used. d When the selectivity is high, an accurate ratio of 6a to
7a was difficult to obtain by 1H NMR analysis of the crude reaction mixture
due to baseline noise interference. The ratio was then obtained by 1H NMR
analysis after flash chromatography (6a and 7a were nearly inseperable).
e
1
When the selectivity is low, the ratio of 6a to 7a was determined by H
NMR analysis of the crude reaction mixture.
both regioisomers can be formed and selectivity is dependent
upon the choice of catalyst as well as reaction concentration.
The terminal product was predominately obtained when
P(Cy)3 or P(n-Bu)3 was used with CuCl (Table 1, entries
1-2 vs 6) and further favored when a more concentrated
reaction mixture was used (Table 1, entry 2 vs 3). Alterna-
tively, internal diamination was favored when CuBr was used
without ligand (Table 1, entry 7). Addition of P(n-Bu)3 to
CuBr reaction conditions resulted in the reversal of selectivity
(Table 1, entry 7 vs 9). It was also observed that internal
diamination is further favored with a more dilute reaction
concentration (Table 1, entry 7 vs 8).
(9) (a) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762. (b)
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496.
(c) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129,
11688. (d) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 8590.
(e) Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
(10) (a) Yuan, W.; Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589.
(b) Du, H.; Zhao, B.; Yuan, W.; Shi, Y. Org. Lett. 2008, 10, 4231. (c)
Zhao, B.; Du, H.; Shi, Y. J. Org. Chem. 2009, 74, 8392.
(11) For a leading review on diaziridinones, see: Heine, H. W. The
Chemistry of Heterocyclic Compounds; John Wiley & Sons, Inc.: USA,
1983; p 547.
(12) Zhao, B.; Peng, X.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132,
11009.
(13) For preparation of N,N-di-tert-butylthiadiaziridine 1,1-dioxide (2),
see: (a) Timberlake, J. W.; Alender, J.; Garner, A. W.; Hodges, M. L.;
With optimal reaction conditions obtained, investigation
into the substrate scope for terminal as well as internal
diamination was pursued. As shown in Table 2, the terminal
¨
Ozmeral, C.; Szilagyi, S.; Jacobus, J. O. J. Org. Chem. 1981, 46, 2082. (b)
Ramirez, T. A.; Zhao, B.; Shi, Y. Tetrahedron Lett. 2010, 51, 1822.
Org. Lett., Vol. 13, No. 3, 2011
435

Table 2. CuCl-Catalyzed Regioselective Diaminationa
Table 3. CuBr-Catalyzed Regioselective Diaminationa
a All reactions were carried out with olefin 5 (0.40 mmol), CuCl/P(n-
Bu)3 (1:1) complex (0.020 mmol), and 2 (0.48 mmol) in CDCl3 (0.1 mL)
under Ar at rt unless otherwise stated. Reaction times: for entry 1, 24 h;
entry 2, 48 h; entry 3, 3.5 h; entry 4, 8 h; entry 5, 12 h; entry 6, 20 h; entry
7, 48 h; entry 8, 12 h; entry 9, 24 h; entry 10, 36 h; entry 11, 8 h. b Olefin
5a (0.20 mmol), CuCl/P(n-Bu)3 (1:1) complex (0.040 mmol), and 2 (0.24
mmol). c CuCl/P(n-Bu)3 (1:1) complex (0.080 mmol) and 2 (0.80 mmol).
d CuCl/P(n-Bu)3 (1:1) complex (0.080 mmol) and 2 (0.60 mmol).
e CuCl/P(n-Bu)3 (1:1) complex (0.040 mmol) and 2 (0.60 mmol). f 2 (0.6
mmol). g Isolated yield.
a All reactions were carried out with olefin 5 (0.20 mmol), CuBr (0.030
mmol), and 2 (0.24 mmol) in CDCl3 (0.6 mL) under Ar at rt for 24 h,
unless otherwise stated. For entry 1, 0.040 mmol of CuBr was used. For
entry 8, the reaction was carried out on double scale. b Diamination product
7q is acid sensitive and was obtained by crystallization from hexanes.
c Isolated yield. d The reaction was carried out with 8 mmol of olefin 5a.
e The ratio of 6a to 7a was determined by 1H NMR analysis after flash
chromatography.
diamination exhibited excellent substrate adaptability. Vari-
ous substituted dienes and trienes can be smoothly diami-
nated at room temperature. Both electron-deficient (Table
2, entries 5 and 7) and electron-rich (Table 2, entries 4 and
6) dienes can be diaminated under the reaction conditions.
Compared with alkyldienes (Table 2, entries 1-2), aryldienes
and trienes (Table 2, entries 3-6, 8, 10-11) exhibited higher
activity and could be diaminated with lower catalyst loading
(5 mol %). The reaction exhibited excellent regioselectivity,
and all the diaminations occurred at the terminal double bond.
The internal regioisomer, if there was any, was barely
diaminated at the internal double bond with high regiose-
lectivity. When Danishefsky’s diene (5p) was subjected to
the diamination conditions, internal diamination was ob-
served and desilylation occurred during purification on silica
gel yielding the ketone product 7p (Table 3, entry 7). The
diamination occurred highly regioselectively, and in most
cases only the internal regioisomer was formed as judged
1
by H NMR analysis. The diamination can be carried out
on gram scale (Table 3, entry 1). Removal of the tert-butyl
groups from internal diamination products is demon-
strated in Scheme 3. Treatment of 7a with a mixture of
CF3CO2H-hexanes (1:1) at rt resulted in deprotected product
8 in 83% yield.
Although further mechanistic studies are needed, it is
proposed that the mechanism of diamination proceeds Via dual
1
detectable by H NMR analysis.
Using CuBr as catalyst, the substrate investigation for
internal diamination is shown in Table 3. Various 1-mono-
substituted (Table 3, entries 1, 2), 1,2- (Table 3, entry 3)
and 1,3-disubstituted (Table 3, entries 4-7), and 1,2,3-
trisubstituted (Table 3, entry 8) dienes can be readily
436
Org. Lett., Vol. 13, No. 3, 2011

insertion of the nitrogen to the internal double bond of the diene.
Intermediate 14 then undergoes reductive elimination to give
the internal diamination product 7 and regenerate the Cu(I)
catalyst.
Scheme 3. Deprotection of Diamination Product 7a
As shown in the above studies, the regioselectivity is greatly
dependent upon diene substrate and reaction conditions. Con-
jugated dienes with radical stabilizing groups, such as arylb-
utadienes and trienes, are especially efficient for terminal
diamination (Table 2, entries 3-6, 8, and 10-11), due to their
ability to stabilize radical intermediate 11. Electron-rich dienes,
including polysubstituted dienes (Table 3, entries 3-8), have
shown high regioselectivity for internal diamination using CuBr
as a catalyst, analogous to Pd(0)-catalyzed diamination.9a The
substituents on the terminal olefins of entries 4-8 (Table 3)
could also play a role in sterically favoring the internal
diamination over the terminal diamination. Alkyl dienes present
a class of compounds which are efficient for both terminal and
internal diamination. The regioselectivity of the diamination can
be controlled by changing the reaction conditions. Addition of
a phosphine ligand favors terminal diamination. This is likely
due to the coordination of the ligand to the Cu center, favoring
the formation of radical species 9 while hindering the coordina-
tion of olefin 5 to Cu(III) species 10.12
mechanistic pathways analogous to that of the Cu(I)-catalyzed
diamination using 1 as a nitrogen source.12 As shown in Scheme
4, insertion of the Cu(I) catalyst into the N-N bond of 2 results
Scheme 4
.
Proposed Mechanistic Cycle for the Cu(I)-Catalyzed
Diamination of Conjugated Dienes Using 2
In summary, a variety of conjugated dienes have been
internally diaminated using CuBr and terminally diaminated
using CuCl-P(n-Bu)3, with N,N-di-tert-butylthiadiaziridine 1,1-
dioxide (2) as a nitrogen source, giving various cyclic sulfamides
in good yield. Cyclic sulfamides are useful functional motifs
in medicinal and biologically important molecules. The reaction
conditions, as well as the diene substrate, play a large role in
the regioselectivity of the diamination. A dual mechanistic
pathway involving Cu(II)/Cu(III) species is proposed for this
diamination. The terminal diamination likely proceeds Via a
radical mechanism involving a Cu(II) species while the internal
diamination likely undergoes a concerted pathway involving a
Cu(III) species. Further mechanistic investigation as well as the
development of an asymmetric process is ongoing.
in the formation of Cu(III) species 10 in equilibrium with Cu(II)
radical species 9. Terminal diamination is likely to proceed Via
a radical pathway.10a The addition of 9 into the terminal double
bond of diene 5 forms radical species 11 and/or Cu(III) species
12 which subsequently results in terminal diamination product
6 and regeneration of the Cu(I) catalyst. The alternate diami-
nation pathway involving Cu(III) species 10 likely results in
the formation of internal diamination product 7.18 Coordination
of diene 5 to Cu(III) species 10 forms the olefin complex 13
which is then converted to intermediate 14 Via migratory
Acknowledgment. We are thankful for the generous
financial support from the National Institute of General Medical
Sciences, National Institutes of Health (GM083944-03).
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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OL102767J
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