Radical-mediated diamination of alkenes with phenylhydrazine and azodicarboxylates: Highly diastereoselective synthesis of trans-diamines from cycloalkenes

Article abstract of DOI:10.1002/chem.201203832

Metal-free synthesis: Diamination of alkenes by using phenylhydrazine and azodicarboxylates could be achieved in a one-pot manner under very mild conditions (see scheme; Boc=tert-butoxycarbonyl). This process works with the assistance of acetic acid by me

Full text of DOI:10.1002/chem.201203832

DOI: 10.1002/chem.201203832
Radical-Mediated Diamination of Alkenes with Phenylhydrazine and
Azodicarboxylates: Highly Diastereoselective Synthesis of
trans-Diamines from Cycloalkenes
Ming-Kui Zhu,[b] Yu-Chen Chen,[b] and Teck-Peng Loh*[a, b]
Vicinal diamines represent a very important class of com-
pounds in organic chemistry as they not only serve as lig-
Table 1. Optimization studies.[a]
ACHTUNGTRENNUNGands or catalysts in asymmetric reactions, but have also
been shown to exhibit a broad spectrum of biological activi-
ties.[1] Among the many methods, direct diamination of
simple unsaturated hydrocarbons offers one of the most
straightforward and practical approaches to this motif. Al-
though significant progress has been achieved in recent
years, many of these processes still required the use of toxic
chemicals or/and expensive transition metals.[2–5] Therefore,
the development of a new and efficient method for the
preparation of 1,2-diamines and their derivatives is still
highly desirable. Herein, we present a metal-free radical-
based diamination of alkenes, by using commercially availa-
ble phenylhydrazine and azodicarboxylates under very mild
conditions.
Entry Catalyst
Solvent T [8C]
t
Yield[%][b]
1
2
3
4
5
6
Pd
none
none
U
RT
8
8
8
8
8
3
38
trace
55
trace
45
75
PhCl
PhCl
PhCl
PhCl
PhCl
RT
40
RT
RT
40
Pd
HOAc (4 equiv)
HOAc (4 equiv)
[a] Unless noted otherwise, the reactions were carried out on
0.30 mmol scale of 1a and with 2.0 equiv of 2a (0.6 mmol) in solvent
(1.0 mL). [b] Isolated yield.
a
Recently, we have reported a palladium-catalyzed difunc-
tionalization of alkenes and palladium-catalyzed cross-cou-
pling of arylhydrazines with olefins.[6] On the basis of our
previous work, we hypothesized that it may be possible to
realize the palladium-catalyzed diamination of alkenes by
an intramolecular nucleopalladation and reductive elimina-
tion, while retarding b-hydride elimination. Due to the coor-
the absence of the palladium salt and/or acetic acid were
carried out. The results showed that both palladium catalyst
and acetic acid are not necessary for the reaction (entries 1–
4). However, the acetic acid helped improve the product
yield (entries 3 and 6). This transformation proceeded
smoothly at room temperature although a higher efficiency
was observed at 408C. Solvent also had much effect on the
reaction and we found that PhCl is the optimal choice of
solvent (for optimization conditions see the Supporting In-
formation). Eventually, we found that this alkene diamina-
tion process proceeded smoothly with four equivalents of
HOAc in PhCl as the solvent, without any additional re-
agents.
À
dinating ability and cleavage of the N N bond, and the ver-
satility of the resulting product,[7] initially, we chose (E)-hy-
drazone 1a containing a strategically positioned terminal
alkene, together with azodicarboxylates as the nitrogen
source for our model study.
Fortunately, when we reacted hydrazone 1a with two
equivalents of diisopropyl azodicarboxylate (DIAD) by
using our previously reported palladium-catalyzed system,
the desired diamination product 3a was isolated in 38%
yield (Table 1, entry 1). A series of control experiments in
With the optimal conditions in hand, we explored the gen-
erality of the reaction and the results are summarized in
Table 2. Other simple azodicarboxylates, such as diethyl azo-
dicarboxylate
(DEAD),
dibenzyl
azodicarboxylate
(DBAD), and di-tert-butyl azodicarboxylate (DTAD), were
also investigated and the diamination products could be ob-
tained in 73, 81, and 90% yield, respectively (see the Sup-
porting Information). Both electron-withdrawing and -do-
nating groups at the para-position of aromatic hydrazones
could be tolerated (3c–g). It is noteworthy that near quanti-
tative yields were observed even when para-halo-substituted
aromatic hydrazones were used in this diamination reaction
(3c–f). This feature provides an opportunity for further se-
lective functionalization at the halide group. meta-Substitut-
ed aromatic hydrazones were also tolerated, delivering the
[a] Prof. Dr. T.-P. Loh
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (P.R. China)
[b] Dr. M.-K. Zhu, Y.-C. Chen, Prof. Dr. T.-P. Loh
Division of Chemistry and Biological Chemistry School
of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371
Fax : (+65)6515-8229
E-mail: teckpeng@ntu.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203832.
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Chem. Eur. J. 2013, 19, 5250 – 5254

COMMUNICATION
Table 2. Diamination of alkenes with the azodicaboxylates.[a,b]
Table 3. Highly selective metal-free diamination of alkenes.[a,b,c]
[a] Unless noted otherwise, the reactions conditions were as follows: hy-
drazone (0.3 mmol), azodicarboxylates (0.36 mmol), HOAc (4.0 equiv),
PhCl (1.0 mL), 408C. [b] Isolated yield. [c] With DTAD (3.0 equiv) at
608C. Boc=tert-butoxycarbonyl.
[a] Unless noted otherwise, the reactions conditions were as follows: hy-
drazone (0.3 mmol), azodicarboxylates (0.36 mmol), HOAc (4.0 equiv),
PhCl (1.0 mL), 408C. [b] Isolated yield. [c] Diastereomeric ratios deter-
1
mined by crude H NMR spectroscopy. [d] At 608C. [e] By using the E/Z
desired products in moderate yields (3h and 3i). While the
reaction utilizing phenyl hydrazones was successful, reac-
tions with 4-methoxyphenyl hydrazones proceeded in a
much shorter reaction time (3j and 3k, 3n and 3o). A series
of terminal alkenes were tested and we found that the sub-
stituents on the terminal alkene moiety have no significant
influence on the efficiency of this reaction. Substrates disub-
stituted at the a-position of the alkenes were also suitable
for the reaction (3n–r). Both aromatic and aliphatic groups
were tolerated and afforded the target products in good
yields. Heterocyclic moieties on the imine carbon atom were
also tolerated, which is of importance for the preparation of
pharmaceuticals and agrochemicals (3q and 3r).
mixture at 508C.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ogy is also not limited to 5-exo cyclization, as the arylhydra-
zone of the chalcone substrate reacted to give a single dia-
stereomeric product in moderate yield (3d’). These results
indicate that the metal-free diamination of cycloalkenes pro-
vides a promising method to synthesize trans-diamines,
which is a useful complement to cis-selective metal-cata-
lyzed alkene diamination pathways.
This alkene diamination methodology is not limited to ter-
minal alkenes. trans-Diamination products were obtained
with high diastereoselectivities and in good to excellent
yields by using cycloalkene substrates. Difunctionalization
of differently substituted cyclopentenyl substrates proceeds
in a 5-exo fashion providing a [5,5]-cis-fused bicyclic product
as a single diastereomer in near quantitative yield (Table 3,
3s–u).[8] Cyclohexenes were also viable substrates for the
highly stereoselective diamination, affording [5,6]-cis-fused
bicyclic products in high yields and with high diastereoselec-
tivity (3v–x).[8] The substitution by aromatic and aliphatic
groups at the a-position of the terminal alkenes delivered
Considering that hydrazones are very readily formed from
the ketone and hydrazine, we examined the direct diamina-
tion of olefins with the phenylhydrazine and di-tert-butyl
azodicarboxylates in a one-pot manner. With the same opti-
mized conditions, the generality of the reaction is summa-
AHCTUNGTREGrNNUN ized in Table 4. Reactions involving terminal, 1,1-disubsti-
tuted, 1,2-disubstituted, and trisubstituted alkenes were
found to furnish the desired products in good yields and
with high stereoselectivities. The 6-exo cyclization is applica-
ble to the bicyclo
ACHTUNGTRENN[UNG 3,3,1]pyridazine 3h’ and the bicyclo-
AHCTUNGTREG[NNUN 6,5,0]pyridazine 3i’, affording the desired products in good
yields and with high stereoselectivities (Table 4, compounds
3h’and 3i’). It is important to note that there is no decrease
in selectivity when using this one-pot three-component pro-
tocol.
the products with high stereoACTHNUTRGNEUGNselectivity and in good yield
(3y–a’). A 1,2-disubstituted cis-alkene was converted into a
69:31 mixture of the two corresponding diastereomeric di-
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T.-P. Loh et al.
Table 4. One-pot diamination of alkenes with pheylhydrazine and di-tert-
butyl azodicarboxylate.[a]
Scheme 1. Reduction of difunctionalization product.
Alkenes
Products
Yield [%][b] (d.r.=anti/
syn)[c]
EPR studies revealed that formation of the hydrazonyl
radical is initiated by DTAD (see the Supporting Informa-
tion). We anticipated that the oxygen atom may help the
process from hydrazone to the hydrazonyl radical by a hy-
drogen-atom abstraction process.[9a] Hence we used 1j, with
an electron-donating substituent on the aromatic ring, under
1 atm. air in the presence of acetic acid, to examine the radi-
cal cyclization process. In accord with our expectations, oxy-
amination product 5 was obtained in 45% yield. We also at-
tempted the reaction with 2,2,6,6-tetramethylpiperidine-N-
oxide (TEMPO) to trap the radical intermediate under the
mode reaction conditions, in which the oxyamination prod-
uct 6 was generated instead of the diamination product 3s
in moderate yield. In contrast, when TEMPO (1.0 equiv)
was used in the absence of DTAD under the same condi-
tions, compound 6 was obtained in very low yield. Nonethe-
less, when two equivalents of TEMPO were used, the yield
increased dramatically. These results demonstrated clearly
that DTAD, TEMPO, and O2 could serve as aromatic hydra-
zonyl radical initiators as well as carbon radical trapping
agents in the reaction.[9a,10] Next we also examined the im-
portance of acetic acid. A control experiment in the absence
of acetic acid showed that it is not essential for the reaction,
serving only to improve the product yields (Scheme 2).
R=H, 52 (3e’)
R=Me, 83 (3y)
d.r.>20:1
R=Ph, 50 (3z)
d.r.>20:1
90 (3n)[d]
(87)[e]
73% (3p)[d]
(67)[e]
R=H, 70 (3b’)
d.r.=69:31
R=Me, 51 (3 f’)[d]
d.r.=55:45
41 (3g’)[d]
53 (3c’)
d.r.=80:20
R=Me, 97 (3s)[d]
d.r.>20:1
R=Allyl, 85 (3t)[d]
d.r.>20:1
A plausible mechanism is shown in Scheme 3. The diami-
nation reaction is initiated by formation of the hydrazonyl
radical II[9b] from the action of azodicarboxylate with assis-
R=Bn, 91 (3u)[d]
d.r.>20:1
72 (3h’)[d]
d.r.>20:1
35 (3i’)[d]
d.r.>20:1
R=H, 75 (3x)
d.r.>20:1
R=Me, 90 (3v)[d]
d.r.>20:1
[a] Unless noted otherwise, the reactions were carried out on a 0.3 mmol
scale of 2d (DTAD) with alkenes (0.45 mmol) and phenylhydrazine
(0.45 mmol) in PhCl (1.0 mL) at 408C. [b] Isolated yield. [c] Determined
by crude 1H NMR spectroscopy. [d] At 508C. [e]A gram scale of 3 mmol
hydrazone was used.
By following the diamination process, removal of the pro-
tecting group with trifluoroacetic acid and reductive cleav-
À
age the N N bond afforded the vicinal diamines and deriva-
tives in good yields (Scheme 1). However, our attempts to
Scheme 2. Oxygen, TEMPO, and DTAD-initiated hydrazonyl-radical cyc-
lization.
À
cleave the N N bond of hydrazone were not successful.
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Highly Diastereoselective Synthesis of trans-Diamines
COMMUNICATION
Acknowledgements
We gratefully acknowledge the Nanyang Technological University, Uni-
versity of Science and Technology of China, and Singapore Ministry of
Education, academic research fund (MOE2011-T2–1—013 and
MOE2010-T2–2—067) for the funding of this research. Prof. M. Lee
(Hope College in USA) is acknowledged for proof reading and valuable
discussions. We thank Dr. Y.-X. Li for X-ray analyses. We gratefully ac-
knowledge the Nanyang Technological University and the Singapore
Ministry of Education Academic Research Fund Tier 2 (MOE2011-T2—
1–013) for financial support.
Keywords: alkenes
·
cyclization
·
diamination
·
diastereoselectivity · radicals
Scheme 3. Possible mechanism.
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ACHTUNGTRENNUNG
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À
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Experimental Section
General method: Ketones (0.30 mmol), phenylhydrazine (0.45 mmol,
1.5 equiv), and HOAc (4 equiv, 1.2 mmol) in chlorobenzene (1 mL) were
added to a round-bottomed flask (5 mL) equipped with a magnetic stir-
ring bar under argon. The flask was stirred at 608C or reflux for 2—12 h
under argon. The mixture was cooled to room temperature and DTAD
was added under argon. The reaction was stirred for 5–12 h at 408C and
then the solvent was removed under reduced pressure and the residue
was purified by column chromatography on silica gel to give the desired
products.
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Received: October 26, 2012
Revised: February 1, 2013
Published online: March 7, 2013
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Chem. Eur. J. 2013, 19, 5250 – 5254