Copper(II) carboxylate promoted intramolecular diamination of terminal alkenes: Improved reaction conditions and expanded substrate scope

Article abstract of DOI:10.1021/ol0706713

The copper(II) carboxylate promoted diamination reaction has been improved by the use of the organic soluble copper(II) neodecanoate [Cu(ND)₂]. Cu(ND)₂ allowed the less-polar solvent dichloroethane (DCE) to be used, and as a consequence, decomposition of less-reactive substrates could be avoided. High diastereoselectivity was observed in the synthesis of 2,5-disubstituted pyrrolidines. Ureas, bis(anllines), and α-amido pyrroles derived from 2-allylaniline could also participate in the diamination reaction.

Full text of DOI:10.1021/ol0706713

ORGANIC
LETTERS
2007
Vol. 9, No. 10
2035-2038
Copper(II) Carboxylate Promoted
Intramolecular Diamination of Terminal
Alkenes: Improved Reaction Conditions
and Expanded Substrate Scope
Thomas P. Zabawa and Sherry R. Chemler*
Department of Chemistry, The UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260
schemler@buffalo.edu
Received March 19, 2007
ABSTRACT
The copper(II) carboxylate promoted diamination reaction has been improved by the use of the organic soluble copper(II) neodecanoate
[Cu(ND)2]. Cu(ND)2 allowed the less-polar solvent dichloroethane (DCE) to be used, and as a consequence, decomposition of less-reactive
substrates could be avoided. High diastereoselectivity was observed in the synthesis of 2,5-disubstituted pyrrolidines. Ureas, bis(anilines),
and
r-amido pyrroles derived from 2-allylaniline could also participate in the diamination reaction.
Nitrogen heterocycles that contain vicinal amines are privi-
leged biologically active structures.1 Compounds containing
vicinal diamines have demonstrated a range of activity that
includes antiparasitic [e.g., (R)-Praziquantel, Oxamniquine],2
antidepressant (e.g., Mianserin),3 anticancer [(-)-quinocar-
cin],4 adenosine kinase,5 and protease inhibitory activity
(Figure 1).6 Cyclic sulfamides, which are especially acces-
sible via the technology described in this paper, appear
frequently as components of small molecule enzyme inhibi-
tors (Figure 1).7
The synthesis of vicinal diamines via olefin diamination is
an active area of research.1,8,9 The intramolecular diamination
of alkenes provides a direct entry into the cyclic vicinal
diamine motif.9b,c We recently reported a novel intramolecu-
lar alkene diamination protocol promoted by copper(II) ace-
(6) (a) Bachand, B.; Tarazi, M.; St-Denis, Y.; Edmunds, J. J.; Winocour,
P. D.; Leblond, L.; Siddiqui, M. A. Bioorg. Med. Chem. Lett. 2001, 11,
287. (b) St-Denis, Y.; Levesque, S.; Bachand, B.; Edmunds, J. J.; Leblond,
L.; Preville, P.; Tarazi, M.; Winocour, P. D.; Siddiqui, M. A. Bioorg. Med.
Chem. Lett. 2002, 12, 1181. (c) Bursavich, M. G.; Rich, D. H. J. Med.
Chem. 2002, 45, 541.
(7) Winum, J.-Y.; Scozzafava, A.; Montero, J.-L.; Supuran, C. T. Med.
Res. ReV. 2006, 26, 767.
(8) For reviews for olefin diamination: (a) Kemp, J. E. G. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 7, p 469. (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.
(1) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006,
67, 101.
(2) (a) Andrews, P.; Thomas, H.; Pohlke, R.; Seubert, J. Med. Res. ReV.
1983, 3, 147. (b) Reich, M. R.; Govindaraj, R. Health Policy 1998, 44, 1.
(c) Fenwick, A.; Keiser, J.; Utzinger, J. Drugs Future 2006, 31, 413.
(3) Brogden, R. N.; Heel, R. C.; Speight, T. M.; Avery, G. S. Drugs
1978, 16, 273.
(4) Scott, J. D.; Williams, R. M. Chem. ReV. 2002, 102, 1669.
(5) Bauser, M.; Delapierre, G.; Hauswald, M.; Flessner, T.; D’Urso, D.;
Hermann, A.; Beyreuther, B.; De Vry, J.; Spreyer, P.; Reissmuller, E.; Meier,
H. Bioorg. Med. Chem. Lett. 2004, 14, 1997.
10.1021/ol0706713 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/21/2007

Table 1. Temperature, Solvent, and Ligand Effectsa
entry
CuXn
Cu(OAc)2 DMF
Cu(OAc)2 DMF/DMSO 90 °C, 48 h
solvent
temp, time
yield (%)b
1
2
3
4
5
6
7
8
9
90 °C, 48 h
78
92
94
90
38
94
73
40
38
Cu(ND)2 DMF
Cu(ND)2 DMF
Cu(OAc)2 CH3CN
Cu(ND)2 CH3CN
Cu(ND)2 DCE
Cu(ND)2 toluene
90 °C, 24 h
120 °C (µW), 20 min
90 °C, 48 h
90 °C, 24 h
90 °C, 24 h
90 °C, 24 h
Cu(OAc)2 tert-amylOH 90 °C, 48 h
Figure 1. Biologically active cyclic vicinal diamines.
a All reactions were run in sealed tubes at 0.1 M w/r to 1. Cu(ND)2 )
b
copper(II) neodecanoate. Yield refers to amount of product isolated after
purification by flash chromatography on silica gel.
tate.9b This protocol provided efficient synthesis of fused
cyclic sulfamide pyrrolidines and piperidines (eq 1). This reac-
2, Table 1).9b We subsequently found that the use of more
organic soluble copper(II) carboxylates, e.g., copper(II)
neodecanoate [Cu(ND)2], allowed shorter reaction times (90
°C, 24 h) than the use of less-polar solvents (dichloroethane,
toluene). The reaction time could be further reduced by
the use of microwave heating (120 °C for 20 min, entry 4,
Table 1). All of these reactions are carried out in pressure
tubes.
tion is a member of a growing class of copper(II)-promoted
oxidative cyclizations that also includes the intramolecular
copper(II)-promoted alkene carboamination reaction.10
We report herein an expansion of the diamination substrate
scope to include substrates with other linked (RNHXnNHR)
bis(amino) units. In addition, the diastereoselectivity in the
oxidative cyclization of alkyl-substituted pent-4-enyl sulfa-
mides and a deuterated alkene substrate was examined. The
substrate expansion was enabled by the use of an organic
soluble copper(II) salt, copper(II) neodecanoate [Cu(ND)2],
and the less-polar solvent dichloroethane (DCE). The level
and direction of observed diastereoselectivity, and compari-
son to the mechanistically similar copper(II)-promoted car-
boamination reaction, provided insight into a plausible
reaction mechanism (vide infra).
Under the new reaction conditions [Cu(ND)2, (CH2Cl)2],
the reactions of substrates 3, 5, and 7 were significantly
improved (Table 2). At 120 °C or above, these less-reactive,
Table 2. Diamination of Challenging Substrates
The effect of solvent, copper(II) ligand, and heating
method (oil bath vs microwave) was systematically examined
as shown in Table 1. We quickly found that the solubility
of the copper(II) carboxylate in the organic solvent was
important to the efficiency of the reaction. In initial experi-
ments, we used Cu(OAc)2 with polar solvents (DMF) and
an additive (4 equiv of DMSO, 90 °C, 48 h) (entries 1 and
a Reaction conditions A: 3 equiv of Cu(OAc)2, 2 equiv of K2CO3, DMF
(0.1 M), DMSO (10 equiv), 120 °C, 48 h, sealed tube. Conditions B: 3
equiv of Cu(ND)2, 2 equiv of K2CO3, DCE (0.1 M), 120 °C, 48 h, sealed
tube. Conditions C: Same as B except Cu(OAc)2 was used instead of
Cu(ND)2. Conditions D: Same as B except DMF was used instead of DCE.
bYield refers to amount of product isolated after purification by flash
chromatography on silica gel.
(9) Recent metal-facilitated olefin diaminations: (a) Bar, G. L. J.; Lloyd-
Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2005, 127, 7308.
(b) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc. 2005, 127,
11250. (c) Streuff, J.; Hovelmann, C. H.; Nieger, M.; Muniz, K. J. Am.
Chem. Soc. 2005, 127, 14586. (d) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem.
Soc. 2007, 129, 762. (e) Wei, H.-X.; Kim, S. H.; Li, G. J. Org. Chem.
2002, 67, 4777.
(10) (a) Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O. Org.
Lett. 2004, 6, 1573. (b) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler,
S. R. J. Org. Chem, 2007, ASAP. (c) Chemler, S. R.; Fuller, P. H. Chem.
Soc. ReV. 2007, DOI: 10.1039/B607819M.
more entropically challenging substrates tended to undergo
decomposition (removal of the sulfamide) using the Cu-
2036
Org. Lett., Vol. 9, No. 10, 2007

(OAc)2, DMSO, and DMF reaction conditions. It is possible
that DMF or its decomposition product (Me2NH) could
promote sulfamide decomposition. Under the new conditions,
the isoindoline adduct 4 was obtained in 81% yield. The
unsubstituted, aliphatic sulfamide 5 cyclized efficiently to
provide pyrrolidine 6 in 86% yield. The N-2-γ-butenyl-3-
methylphenyl-N′-benzylsulfamide (7) cyclized to form the
tetrahydroquinoline adduct 8 in 81% yield.
The use of Cu(ND)2 and dichloroethane as solvent was
especially important in the case of monosubstituted N-pent-
4-enyl-N′-benzyl sulfamides 9, 11, and 13 (Table 3).
N-2-allylphenyl-N′-benzyl sulfamide 1 reacted at the lowest
temperature of all the substrates examined (90 °C, Table 1),
the reaction could be extended at higher temperature (120
°C) to analogous substrates with different diamine units such
as ureas, bis(anilines), and R-amidopyrroles. Diamination
with the urea substrates 15a-c produced bicyclic ureas 16a-
c, whereas cyclization of the R-amidopyrrole 17 and the bis-
(aniline) 19 produced 1,4-diazines 18 and 20. Cyclic ureas
and 1,4-diazines are common components in biologically
active compounds. The N-tosyl urea 15d and aliphatic
γ-pentenylureas were unreactive under the reaction condi-
tions.
Table 3. Diastereoselectivity in Cyclizations of Pent-4-enyl
Sulfamidesa
Upon the basis of the high diastereoselectivity of the
diamination reactions with R substituents, wherein the cis-
pyrrolidines are highly favored, we propose that the first
C-N bond is formed via a syn-aminocupration (e.g.,
transition state 21), in analogy to the mechanistically similar
copper(II)-promoted intramolecular carboamination reaction
Table 4. Formation of Cyclic Ureas and 1,4-Diazines
a Reaction conditions: 3 equiv of Cu(ND)2, 2 equiv of K2CO3, DCE
(0.1 M), 120 °C, 48 h, sealed tube. bYield refers to amount of product
isolated upon purification by flash chromatography on silica gel. cSelectivity
1
determined by analysis of the crude H NMR spectrum.
Good to excellent levels of diastereoselectivity were
observed with these substrates (Table 3). Reactions of sub-
strates 9 with substitution R to the sulfamide unit were highly
diastereoselective, generating the cis-pyrrolidine core 10 with
>20:1 selectivity (entries 1-3, Table 3). The high degree
of cis-pyrrolidine selectivity is similar to that observed in
the copper(II) carboxylate promoted carboamination reaction.10b
Pent-4-enyl sulfonamide 11 containing an allylic stereocenter
also provided a diastereoselective reaction (dr ) 3:1) favoring
the trans diastereomer (entry 4, Table 3). The 2-substituted
pent-4-enyl sulfamide 13 afforded pyrrolidines cis-14 and
trans-14 in a 1:1 ratio of diastereomers (entry 5, Table 3).
Discussion of the reaction diastereoselectivity is provided
in eq 2 (vide infra) and in the Supporting Information. We
have previously demonstrated that sulfur dioxide can be
reductively removed to reveal the diamine if desired.9b
The generality of the intramolecular diamination protocol
was further examined as illustrated in Table 4. Although the
a Reaction conditions A: 3 equiv of Cu(ND)2, 2 equiv of K2CO3, DCE
(0.1 M), 120 °C, 48 h, sealed tube. Conditions B: same as A except DMF
was used as solvent instead of DCE. bYield refers to amount of product
isolated after purification by flash chromatography on silica gel. 11% of
the carboamination product was also formed (see Supporting Information).
c
Org. Lett., Vol. 9, No. 10, 2007
2037

(eqs 2 and 3).10b By comparing the direction and degree of
diastereoselectivity in the carboamination reaction to the
preferences found in analogous reactions, we argued that a
syn-aminocupration mechanism (analogous to transition
state 21) best accounted for the observed diastereoselec-
tivity.
To probe the mechanism of the second C-N bond-forming
step, we submitted the trans-deuteroalkene 25 to the diami-
nation conditions (eq 4). Partial conversion to diamination
adduct 26 allowed for the recovery and examination of the
remaining starting material 25. We found that adduct 26 is
formed in a 1:1 ratio of diastereomers. This is in contrast to
the analogous study by Muniz and co-workers, who found
that this bond is formed stereospecifically in their palladium-
catalyzed diamination reaction (eq 5).9c
cis-pyrrolidine. The unstable organocopper(II) intermediate
28 would undergo C-Cu bond homolysis, generating
primary radical 29. Organocopper(II) species are known to
be unstable due to the paramagnetic nature of copper(II).12,13
The primary radical does not revert back to the starting
material, as indicated by the fact that the recovered deuterated
alkene 25 can be isolated without olefin isomerization (vide
supra, eq 4). Because another electron must be lost from the
substrate in this net two-electron oxidation process, it seems
necessary that copper be involved in the second C-N bond-
forming process. One likely scenario would involve com-
bination of the primary radical with Cu(ND)2. The affinity
of carbon radicals for Cu(II) has previously been stud-
ied.13 The resulting Cu(III) intermediate 30 could then
undergo ligand exchange and reductive elimination or SN2
to provide the observed product. Prior coordination of Cu-
(ND)2 to the second sulfamide nitrogen and intramolecular
delivery to the carbon radical may also be operative. Because
copper carboxylate salts can easily disproportionate, an
adequate amount of Cu(II) can be provided for the entire
process.
An alternative mechanism would involve ligand exchange
and reductive elimination or SN2 of organocopper(II) inter-
mediate 28, but the stereorandom formation of the second
C-N bond would still have to be accounted for. Although
a mechanism involving a primary carbocation intermediate
could also account for the stereorandom second C-N bond
formation, such a species seems unlikely as no rearrangement
or elimination products are observed. Also, Kochi has
previously observed that copper(II) salts do not promote
carbocation formation unless a stable carbocation can be
formed.13b
The proposed reaction mechanism for the copper(II)
carboxylate promoted intramolecular alkene diamination is
illustrated in Scheme 1. The stereorandom formation of
In summary, we have identified milder reaction conditions
that allow an expanded substrate scope in the copper(II)
carboxylate promoted intramolecular diamination of terminal
alkenes. Stereochemical probes have been used to identify
a probable reaction mechanism. The copper(II) carboxylate
promoted protocol has demonstrated the highest levels of
diastereoselectivity among intramolecular alkene diamina-
tions to date.
Scheme 1. Proposed Diamination Mechanism
Acknowledgment. We thank Mr. Joseph King (from the
University of West Alabama, NSF REU Fellowship at
SUNY, Buffalo, CHE-0453206) for his contributions toward
the synthesis of 25. This work was supported by the National
Institutes of Health (NIGMS RO1-GM07838301.)
Supporting Information Available: Procedures and
characterization data and NMR spectra for all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
deuterated diamination adducts 26 (eq 4) indicates the
presence of an intermediate with an sp2 hybridized deuterium-
substituted carbon, possibly a primary radical (e.g., 29,
Scheme 1).11 Thus, ligand exchange in the reaction of 9a
with Cu(ND)2 would provide for N-Cu bond formation (cf.
9a f 27, Scheme 1). Syn aminocupration would occur in
stereoselective fashion via transition state 21, forming the
OL0706713
(12) Chmielewski, P. J.; Latos-Grazynski, L.; Schmidt, I. Inorg. Chem.
2000, 39, 5475.
(13) (a) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351. (b) Kochi, J. K.;
Bacha, J. D. J. Org. Chem. 1968, 33, 2746. (c) Mansano-Weiss, C.; Epstein,
D. M.; Cohen, H.; Masarwa, A.; Meyerstein, D. Inorg. Chim. Acta 2002,
339, 283. (d) Navon, N.; Golub, G.; Cohen, H.; Meyerstein, D. Organo-
metallics 1995, 14, 5670. (e) Goldstein, S.; Czapski, G.; Cohen, H.;
Meyerstein, D. Inorg. Chem. 1992, 31, 2439.
(11) Attempts to trap the radical intermediate with TEMPO have been
frustrated by starting material decomposition. Reactions performed in the
presence of O2 gave only diamination.
2038
Org. Lett., Vol. 9, No. 10, 2007