Enantioselective diamination with novel chiral hypervalent iodine catalysts

Article abstract of DOI:10.1002/chem.201403891

Vicinal diamines constitute one the most important functional motif in organic chemistry because of its wide occurrence in a variety of biological and pharmaceutical molecules. We report an efficient metal-free, highly stereoselective intramolecular diamination using a novel chiral hypervalent iodine reagent together with its application as an efficient catalyst for the synthesis of diamines.

Full text of DOI:10.1002/chem.201403891

DOI: 10.1002/chem.201403891
Communication
&
Diamination
Enantioselective Diamination with Novel Chiral Hypervalent
Iodine Catalysts
Pushpak Mizar, Aragorn Laverny, Mohammad El-Sherbini, Umar Farid, Michael Brown,
Florence Malmedy, and Thomas Wirth*[a]
Abstract: Vicinal diamines constitute one the most impor-
tant functional motif in organic chemistry because of its
wide occurrence in a variety of biological and pharma-
ceutical molecules. We report an efficient metal-free,
highly stereoselective intramolecular diamination using
a novel chiral hypervalent iodine reagent together with its
application as an efficient catalyst for the synthesis of dia-
Scheme 1. Intramolecular diamination with hypervalent iodine reagents.
mines.
chiometric amounts of hypervalent iodine reagents have been
used for diaminations to generate racemates[13] and also enan-
Hypervalent iodine reagents have found broad application in
tiomerically enriched products.[14] However, there are hardly
organic chemistry and are nowadays frequently used in syn-
thesis.[1,2] It is of great interest to investigate their ability as
any methods available to carry out the reaction stereoselec-
tively using chiral metal-free catalysts.[15]
highly selective oxidants,[3] electrophilic reagents,[4] to improve
known reactions like the a-functionalizations of ketones[5] and
to develop new reactions such as rearrangements[6] using
hypervalent iodine compounds. Oxidative transformations are
of particular interest and a great challenge for organocatalytic
processes. The requirement of developing new catalytic reac-
tions with metal-free reagents such as iodine is considerable as
efficient procedures of this type are still immature.[7]
Herein, we report the application of novel chiral iodine cata-
lysts for stereoselective intramolecular diamination reactions
using various homoallylic guanidine and diaminosulfone deriv-
atives. Initial investigations were carried out using substrate
5a. It was observed that (diacetoxyiodo)benzene and [bis(tri-
fluoroacetoxy)iodo]benzene led to a sluggish reaction at 08C
affording a very low yield of product 6a. As reported in other
reactions,[16] we tried to activate the reagents with a Lewis acid
and observed that, upon addition of BF3 · OEt2, TMSOTf, or
a 1:1 mixture of BF3 · OEt2 and TMSOTf (Table 1, entries 2–5),
the reaction proceeded faster with decent yields for the prod-
uct. The nature of the solvent and also the reaction tempera-
ture have a strong influence on the overall yield as summar-
ized in Table 1.
The addition of nitrogen nucleophiles to alkenes using
hypervalent iodine reagents is known and aziridinations of
alkenes,[8] aminohydroxylations[9] and aminofluorinations[10]
have already been carried out using stoichiometric amounts of
either achiral or chiral reagents. Bifunctional nucleophiles can
lead to interesting building blocks as shown in Scheme 1. After
the activation of the double bond in compound 1 with the
hypervalent iodine reagent, the first nucleophile attacks to
give intermediate 2. The hypervalent iodine moiety in 2 is at-
tached to a sp3-hybridized carbon atom and is therefore an ex-
cellent leaving group, several orders of magnitude more reac-
tive than triflates or tosylates.[11] Products of type 3 are formed
which can be transformed into 1,2-diamines 4. There are vari-
ous metal-catalyzed methods available to carry out vicinal di-
amination of alkenes,[12] but only a few reports in which stoi-
For homoallylic guanidine derivatives 7 (Table 2), the nature
of the N-protecting group had a dominant effect on the cycli-
Table 1. Optimization of reaction conditions.
Entry Reagent(s)
Solvent Temp 6a: Yield
[a] Dr. P. Mizar, A. Laverny, M. El-Sherbini, Dr. U. Farid, Dr. M. Brown,
F. Malmedy, Prof. Dr. T. Wirth
[8C]
[%]
1[a]
2
3
4
PhI(OCOCF3)2
MeCN
0
29
School of Chemistry
Cardiff University
Park Place, Main Building, Cardiff, CF10 3AT (UK)
Fax: (+44)29-2087-6968
E-mail: wirth@cf.ac.uk
PhI(OAc)2, TMSOTf
PhI(OAc)2, TMSOTf
PhI(OAc)2, BF3 · OEt2
CH2Cl2 ꢀ78 12
MeCN
MeCN
ꢀ48 87
ꢀ48 81
ꢀ48 85
5
PhI(OAc)2, BF3 · OEt2 and TMSOTf (1:1) MeCN
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403891.
[a] Reaction time 24 h.
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Table 2. Cyclization of homoallylic guanidine derivatives 7.
Table 3. Enantioselective reaction 5a
iodine reagents.
!
6a with chiral hypervalent
Entry
Alkene
Product
R1
R2
R3
8: Yield [%]
Entry
Reagent
6a: Yield
6a: ee
1
2
3
4
5
6
7a
7b
7c
7d
7e
7 f
Ph
Ph
Ph
Me
Me
Me
Boc
Cbz
H
Boc
Cbz
H
Boc
Cbz
Ts
Boc
Cbz
Ts
traces
82
84
traces
14
21
(1.1 equiv)
[%]
[%]
8a
8b
1
2
3
4
9a
9b
9c
10
11
11
11
11
11
11
21
24
20
45
52
21
43
traces
60
0
0
10
52
72
32
24
–
8c
8d
5
6[a]
7[b]
8[c]
9[d]
10[e]
82
92
zation. When tert-butyl oxycarbonate (Boc) was used as the
protecting group, only traces of the product 8 were observed
(Table 2, entries 1 and 4). However, with carboxybenzoyl (Cbz)
or tosylate (Ts) protecting groups, the products were obtained
in reasonable yields. Studies have shown that the final carbon–
nitrogen bond formation usually proceeds via an SN2-type tran-
sition state with inversion of configuration and, hence, the nu-
cleophilicity of the participating nitrogen moiety has a major
influence.[17] In addition, methyl substituents on the backbone
of the alkene 7 (R1 =Me) are less efficient in directing the cycli-
zation as with phenyl substituents in that place (R1 =Ph)
where the yields are much higher.
70
[a] BF3 · OEt2 used instead of TMSOTf. [b] Reaction temperature: 08C.
[c] Reaction temperature: 258C. [d] 3 equiv TMSOTf. [e] 1 equiv TMSOTf
and 1 equiv BF3 · OEt2.
(Table 3, entries 1–3). The relatively large conformational flexi-
bility in these reagents causes a weaker interaction of oxygen
or nitrogen heteroatoms of the lactate moieties with the
iodine which could also potentially be replaced by interactions
with nitrogen atoms of the substrate 5a. Reagent 10 has
much less conformational flexibility with a strong interaction
of the methoxy oxygen atom with the iodine established by X-
ray analysis.[21] With this simple chiral hypervalent iodine re-
agent 10, much better selectivities (52% ee) were observed in
the cyclization of 5a to 6a (Table 3, entry 4).
Based on this observation, we designed a novel hypervalent
reagent with a pyridine moiety attached to a chiral benzylic
center, which should allow an efficient coordination of the pyr-
idine nitrogen to the iodine atom. It is well known that pyri-
dines are good ligands for iodine(III), the close proximity to the
stereogenic center should allow high selectivities to be ob-
tained.[22] This was indeed observed when the reaction was car-
ried out using the novel hypervalent iodine reagent 11, which
led to the product 6 in 72% ee (Table 3, entry 5). NMR evi-
dence suggests that it is indeed the nitrogen that is coordinat-
ing to the iodine, but the instability of the reagent 11 prevents
further investigation and we cannot exclude that also the
oxygen atom of the methoxy moiety coordinates. Reagent 11
is prepared directly before use and has been investigated with
various Lewis acids for its activation, using different solvents
and reaction temperatures. It was observed that the highest
selectivity (92% ee) could be obtained with a 1:1 mixture of tri-
methylsilyl triflate (TMSOTf) and boron trifluoride etherate
(BF3 · OEt2) at ꢀ488C using acetonitrile as solvent (Table 3,
entry 10). Under these reaction conditions BF2OTf · OEt2 is
acting as the Lewis acid.[23]
To develop a stereoselective method for diamination reac-
tions, the reaction 5a ! 6a was performed using lactate-
based chiral hypervalent iodine reagents 9 (Figure 1) under the
optimized reaction conditions (Table 1, entry 3). Reagents 9
have been very successful in stereoselective reactions with al-
kenes[9,10,14,18] and also other substrates,[19,20] but here it was
observed that only minor stereoselectivities could be obtained
Figure 1. Chiral hypervalent iodine reagents.
Abstract in German: Durch die weite Verbreitung in einer
Vielzahl von biologischen und pharmazeutischen Molekꢁlen
stellen vicinale Diamine eine der wichtigsten Funktionalitꢂten
in der organischen Chemie dar. Wir berichten ꢁber eine effi-
ziente metallfreie, hochstereoselektive intramolekulare Diami-
nierung unter Verwendung eines neuartigen chiralen hyperva-
lenten Iod-Reagenz zusammen mit seinem Einsatz als effizient-
er Katalysator fꢁr die Synthese von Diaminen.
The synthesis of reagent 11 is straightforward and is shown
in Scheme 2. The aniline derivative 13, obtained by the addi-
tion of 2-lithiopyridine to 2-cyanoaniline 12, is iodinated to 14
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Communication
(R=H) (see the Supporting Information). By analogy it can
therefore be assumed that the products 6 and 8 (and 17) have
(R) absolute stereochemistry for R1 =H, Me and (S) for R1 =Ph
when using reagent 11. The new reagent 11 was also found to
show promising selectivities in other stereoselective reac-
tions.[26]
All reactions shown in Table 4 were performed with stoichio-
metric amounts of hypervalent iodine(III) reagent 11 and the
optical pure, reduced iodine(I) compound 16 was recovered
after the reaction.
Scheme 2. Synthesis of the novel chiral hypervalent iodine(III) reagent 11.
We then investigated the possibility of an in situ formation
of the hypervalent iodine species by using the iodine(I) catalyst
16 together with stoichiometric amounts of an oxidant. The re-
action occurred when 20 mol% of the iodine(I) catalyst 16 was
used together with 2.2 equivalents meta-chloroperbenzoic acid
(mCPBA) at ꢀ488C in acetonitrile. However, the yield was low
and the enantioselectivity only moderate. Upon changing the
oxidant to sodium perborate and after addition of three equiv-
alents of acetic acid at room temperature, much higher yields
and selectivities were obtained. There are reactions reported
for the oxidation of alkenes to oxiranes or vicinal acetoxy alco-
hols using sodium perborate, but these reactions usually take
about 24 h for completion and at higher temperatures under
highly acidic reaction conditions.[27] In the reaction described in
Table 5 almost no competing reactions are observed and the
and reduced by using a chiral ruthenium catalyst.[24] The alco-
hol 15, obtained in >99% ee, is methylated to 16 and oxidized
with sodium perborate to reagent 11 in 87% yield. The abso-
lute configuration of 15 was determined to be (R) by deiodina-
tion of 15 and comparison of the optical rotation with a litera-
ture reference (see the Supporting Information).[25]
The reagent 11 was then used in the diamination of various
substrates. It was again observed that diphenyl-substituted
substrates led to the cyclized products in good yields and with
high enantioselectivities. Independent of the linker between
the two nitrogen nucleophiles, the cyclization occurred with
selectivities at or above 90% ee using either sulfondiamides 5
(Table 4, entries 5 and 6) or guanidine derivatives 7 (Table 4,
entries 2 and 4), whereas dimethyl-substituted, dimethyl ester-
substituted or unsubstituted substrates showed almost no re-
action (Table 4, entries 1, 3, 7, 9–12). Also a substituent R1 on
the alkene moiety is tolerated leading to chiral products con-
taining a tetrasubstituted stereocenter with a nitrogen sub-
stituent. The absolute stereochemistry of the product 6a has
been determined to be (R) by independent synthesis of 17a
Table 5. Stereoselective catalytic cyclizations.
Table 4. Stereoselective cyclization to bicyclic products.
Entry
Alkene
Product
R
X
Yield
[%]
ee
[%]
Entry Alkene Product R1
R2
R3
X
Yield
[%]
ee
[%]
1
2
3
4
7b
5a
5b
5c
8a
6a
6b
6c
H
H
Ph
Me
C=NCbz
SO2
SO2
69
45
72
67
76
80
86
83
1
5d
7c
7 f
7b
5b
5c
5e
5a
5 f
7e
7g
7h
H
H
H
H
Me
Ph
Me
Ph
Cbz SO2
H
H
traces
75
traces
–
91
–
92
94
90
–
92
–
SO2
2
8b
C=NTs
C=NTs
3
4
5
6
8a
6b
6c
Cbz C=NCbz 71
Ph Ph
Me Ph
Cbz SO2
Cbz SO2
Cbz SO2
Cbz SO2
75
68
desired products 6 can be obtained in reasonable yields with
good selectivities. A removal of ‘X’ and the Cbz protecting
group is possible by reduction using lithium aluminum hy-
dride, and the free diamines 17 are easily obtained. The Cbz
protecting group has to be removed by hydrogenation (Pd/C)
prior to reduction.
7
8
9
10
11
12
H
H
H
H
H
H
H
Ph
n.r.[a]
70
6a
CO2Me Cbz SO2
Me
H
n.r.[a]
Cbz C=NCbz traces
Cbz C=NCbz n.r.[a]
H
–
–
–
H
C=NTs
n.r.[a]
In summary, we present a highly stereoselective intramolec-
ular diamination of alkenes using a novel, simple hypervalent
[a] n.r.: no reaction.
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Experimental Section
All synthetic methods including spectroscopic and analytical data
are included in the Supporting Information.
Acknowledgements
This project was supported by an EU Marie Curie fellowship to
P.M. (DIALMEC, No. 298642) and by support from ENCPB to
A. L. Support from the School of Chemistry, Cardiff University is
also gratefully acknowledged. We thank the EPSRC National
Mass Spectrometry Facility, Swansea, for mass spectrometric
data.
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Keywords: cyclization · diamination · hypervalent iodine ·
organocatalysis · stereoselective synthesis
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Received: June 10, 2014
Published online on July 17, 2014
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