Catalytic Asymmetric Diamination of Styrenes

Article abstract of DOI:10.1021/jacs.7b01443

An enantioselective catalytic vicinal diamination of styrenes is reported, which proceeds under entirely intermolecular reaction control. It relies on a chirally modified aryliodine(I) catalyst and proceeds within an iodine(I/III) manifold with conventional 3-chloroperbenzoic acid as a terminal oxidant. An environmentally benign solvent combination not only adds to the attractiveness of the process but also slows down the rate of the undesired background reaction. A total of 30 examples are presented, which consistently provide high enantiomeric excesses in the range 91-98%.

Full text of DOI:10.1021/jacs.7b01443

Subscriber access provided by University of Newcastle, Australia
Communication
Catalytic Asymmetric Diamination of Styrenes
Kilian Muniz, Laura Barreiro, R. Martín Romero, and Claudio Martínez
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b01443 • Publication Date (Web): 09 Mar 2017
Downloaded from http://pubs.acs.org on March 9, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Catalytic Asymmetric Diamination of Styrenes
Kilian Muñiz,*1,2 Laura Barreiro,1† R. Martín Romero,1† and Claudio Martínez1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1 Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, 16 Avgda. Països
Catalans, 43007 Tarragona, Spain.
2 ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain
Supporting Information Placeholder
(Figure 1)15 have emerged as privileged structures. The
ABSTRACT: An enantioselective catalytic vicinal di-
preformed diacetoxy aryliodine(III) reagent of com-
pound 1a had been employed in an enantioselective
diamination of styrenes.16 We here report the first suc-
cessful iodine(I/III)-catalyzed enantioselective intermo-
lecular diamination.
amination of styrenes is reported, which proceeds under
entirely intermolecular reaction control. It relies on a
chirally modified aryliodine(I) catalyst and proceeds
within an iodine(I/III) manifold with conventional 3-
chloroperbenzoic acid as terminal oxidant. An environ-
mentally benign solvent combination not only adds to
the attractiveness of the process, but also slows down the
rate of the undesired background reaction. A total of 30
examples are presented, which consistently provide high
enantiomeric excesses in the range of 91-98%.
Vicinal diamines represent a family of compounds of
high importance in diverse fields of the biomedicinal
and pharmaceutical sciences.1 While the direct vicinal
diamination of alkenes has been recognized as a conven-
ient approach toward their synthesis,2 its challenge rests
with the native ability of diamines to function as effec-
tive bidentate ligands to conventional transition metal
promoters. As an illustrative example, while the Sharp-
less dihydroxylation3 and aminohydroxylation4 can be
conducted in a catalytic fashion, the related diamination
suffers from strong binding affinity of the diamine prod-
uct to the osmium atom, thus rendering the process non-
catalytic in metal.4 Catalytic diamination of alkenes has
thus remained largely limited to reactions involving
intramolecular amination steps,2c,6 and enantioselective
diamination with palladium,7 copper8 and titanium9 cata-
lysts currently requires at least one of the C-N bonds to
be formed in an intramolecular reaction.10 An alternative
approach11 uses homogeneous iodine based redox catal-
ysis,12 which represents an attractive concept.13 In this
area, enantioselective catalytic transformations that re-
place existing stoichiometric intermolecular reactions
have so far remained elusive.14 We considered chiral
catalysis within the aryliodine(I/III) manifold to broaden
the spectrum of catalytic enantioselective diamination
reactions to intermolecular reaction control. Redox-
active chiral aryl iodine derivatives of type 1 with modi-
fication of the chiral pool-derived lactic side chains
Figure 1. General Structure of Iodine(I) Catalysts 1, Reac-
tion Optimization of the Catalytic Asymmetric Diamination
a
b
and Reaction Kinetics. Ar = 2,6-(iPr)2C6H3. n.d. = not
determined.
The reaction was optimized exploring various iodine
catalysts 1a-e and oxidants.17 This extensive screening
identified compounds 1d and 1e as the only candidates
displaying reasonable activity, while mCPBA emerged
as the only suitable stoichiometric oxidant.17 Final opti-
mization with 1e was carried out with 4-fluorostyrene 2a
as substrate, which allowed for an accurate determina-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
tion of the relative ratio between the diamination product
case the asymmetric induction is independent of the
chiral information on the steroid backbone
3a and undesired epoxidation by 19F NMR analysis. The
initially high epoxidation percentage could be reduced
changing the solvent to tert-butyl methyl ether or tert-
butyl methyl ether/hexafluoro-2-propanol18 mixtures and
subsequent lowering of the reaction temperature (Figure
1). mCPBA is a common oxidant in intramolecular io-
dine(I/III) catalysis,12b,19 but had only recently14b,d been
employed in the corresponding intermolecular alkene
functionalization due to its innate high reactivity. Given
its particularly high reactivity in the epoxidation of sty-
rene, the use of mCPBA appeared challenging at first
sight. However, the subsequent exploration provided
two important insights. First, this oxidant can be com-
bined with non-chlorinated solvents, which renders the
process more benign and attractive. Second, the unde-
sired epoxidation background reaction was found to be
kinetically incompetent in the tBuOMe/HFIP solvent
combination. Figure 1 displays the initial kinetic profile
for the catalytic diamination of 4-fluorostyrene, which
demonstrates epoxidation (and derivatization to ami-
nooxygenation) to be comparably slow processes.20
Hence, 4-fluorostyrene derived diamine 3a was formed
in 68% isolated yield and with high 95% enantiomeric
excess, while the epoxidation pathway accounted for
less than 5% product. These reaction conditions provide
the desired entry into catalytic diamination of alkenes
under entirely intermolecular reaction control.
.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The final conditions are also noteworthy for including
a solvent combination outside the usual chlorinated de-
rivatives. The optimized catalyst system exercises gen-
erally high enantioselective control in favor of (S)-
configured diamines 3 as explored for 22 styrenes com-
prising different substitution patterns at the arene core,
which include 2-, 3-, 4- and higher-substituted deriva-
tives and common functional groups from organic chem-
istry (Scheme 1). The observed efficient face selection is
unprecedented in the intermolecular difunctionalization
with iodine(III) catalysts. The reactions are usually per-
formed best with 20 mol% catalyst and result in 40-87%
isolated yield and consistently high inductions of 91-
98% ee. To demonstrate the efficiency of the catalyst,
experiments with 10 mol% catalyst loading were ex-
plored, which for products 3d and 3p provided 70-71%
yield (equivalent to 7 TON) and 96% ee. In addition, the
catalysis with 15N labeled bismesylimide provided chiral
diamination product 3c’ in isotopically pure form. Pre-
vious approaches to mono-labeled diamines required
multistep syntheses.21 The enantiomeric catalyst ent-1e
was synthesized from non-natural lactic acid in order to
provide an entry into the enantiomeric series of (R)-
configured diamines as exemplified for product ent-3j.
Finally, a vinylated estrone derivative was employed to
demonstrate complete catalyst control under the chosen
reaction conditions. Depending on the catalyst configu-
ration, diamines 3w and 3x were obtained each with
high 10:1-diastereomeric ratio establishing that in this
Scheme 1. Enantioselective Vicinal Diamination of
a
b
Styrenes: Scope. With 15N-labeled bismesylimide.
With 10 mol% 1e. c With ent-1e as catalyst.
The obtained enantioselectivities from catalysis are
significantly higher than the ones from the previous
stoichiometric reactions with the preformed diacetoxy
reagent from 1a.16a The substrate scope can be enhanced
further to include traditionally challenging internal al-
kenes 4a-e (Scheme 2). For an efficient reaction out-
come, the conditions required slight modification17 for
the diaminations to proceed again with excellent enanti-
omeric excesses of 93-98% including substrate 4e with a
longer alkyl chain and provide diastereomerically pure
products with absolute (2S,3R)-stereochemistry. There-
fore, an identical face-selection is obviously involved in
the diamination of terminal and internal alkenes as
judged from the absolute configuration at the benzylic
stereocenter. This was further corroborated by the ex-
pected outcome with deuterated derivative 2b-d1, which
provided the selectively deuterated product 3b-d1 in
94% ee within a clean stereochemistry transfer of the
double bond geometry into the corresponding diastere-
omeric product composition demonstrating that the
overall process is comparable to the one from internal
alkenes.
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
ecule, which engages in double hydrogen bonding
1
2
3
4
5
6
7
8
(Scheme 3). The resulting 11-membered ring is reminis-
cent of the chiral helicity induced in the iodine(III) de-
rivatives of 1c and of the same absolute configuration,
but with a significantly enlarged binding pocket for
bissulfonimide accommodation,17 while the structure of
1d does not reveal any related supramolecular bonding.
The intermolecular hydrogen bonding in 6d promoted
by a water molecule can provide a useful explanation for
the present high enantioselectivity. Since the terminal
oxidant mCPBA contains water, the latter is ubiquitously
present in the reaction medium throughout catalysis.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Scheme 2. Enantioselective Vicinal Diamination of
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Internal Styrenes: Scope. a With 5 equiv of HNMs2.
At this point, the exact mode of stereoinduction with
the new catalysts 1d and 1e remained to be examined.
While we had previously identified the formation of a
helical chiral environment around the central iodine(III)
through intramolecular hydrogen bonding as the decisive
motif in catalysts of type 1b and 1c,22 such a supramo-
lecular arrangement is not immediately available for the
secondary amides 1d and 1e. In addition, the crystal
structure analyses from compounds 1d and 1e, which
correspond to the iodine(I) catalyst states, do not suggest
any conformational pre-organization (Figure 1).
Figure 2. Mechanistic Context for the Enantioselective Cata-
lytic Diamination of Styrenes.
Interestingly, compound 6d also provides enantiose-
lective diacetoxylation of styrene under both stoichio-
metric and catalytic reaction control. Upon addition of
preformed 6d to a solution of styrene in the presence of
2.4 equivalents of bismesylimide, the reaction switches
selectively into the diamination pathway. Under standard
conditions, 1d provides diamination product with an
identical absolute (S)-configuration. These observations
suggest that the two vicinal difunctionalization reactions
proceed through identical enantiotopic differentiation of
the prochiral alkene of the styrene substrate. Based on
our previous mechanistic insight and on the reported
control experiments we suggest the following mecha-
nism for the catalytic cycle (Figure 2). It starts with an
oxidation that converts catalyst precursor 1e to the key
catalyst structure, which is in perfect agreement with an
earlier observation that bissulfonimides readily enter the
iodine(III) center.23 The helical chirality induced in io-
dine(III) compounds bearing the bislactamide motif
provides a scenario B for efficient differentiation of the
enantiotopic faces of the styrene substrate. It thereby
provides a diastereomerically highly enriched aminoio-
dinated catalyst state C. The high oxidation state nature
of iodine in C initiates the reductive displacement of this
Scheme 3. Synthesis, X-Ray Structure and Control Ex-
periments for Compound 6d.
The corresponding iodine(III) compound 6d could be
obtained from oxidation of 1d.17 Single crystal X-ray
structural analysis revealed the presence of a water mol-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
nucleophuge24 and thereby regenerates the iodine(I)
catalyst state 1e. In agreement with the overall stereo-
chemistry of the products 5, an intramolecular displace-
ment by the bissulfonimide is required.25 The second C-
N bond formation takes place through nucleophilic
opening of cyclic intermediate D16b to diamines 3 and 5,
respectively, which represents the hitherto unknown
Prevost mechanism26 in diamine formation. It generates
products with the opposite diastereomeric composition
as observed in the iodine(I/III)-catalyzed enantioselec-
tive diacetoxylation reactions,27 which proceed through
the dioxolonium intermediate of the Woodward mecha-
nism.28
(3)
(4)
(5)
(a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K.
B. Chem. Rev. 1994, 94, 2483. (b) Sharpless, K. B. An-
gew. Chem. Int. Ed. 2002, 41, 2024.
(a); Donohoe, T. J.; Callens, C. K. A.; Flores, A.; Lacy,
A. R.; Rathi, A. H. Chem. Eur. J. 2011, 17, 58. (b)
Muñiz, K. Chem. Soc. Rev. 2004, 33, 166.
(a) Muñiz, K.; Nieger, M.; Mansikkamäki, H. Angew.
Chem. Int. Ed. 2003, 425, 5958. (b) Muñiz, K. New. J.
Chem. 2005, 29, 1371.
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J.
Am. Chem. Soc. 2005, 127, 14586.
Ingalls, E. L.; Sibbald, P. A.; Kaminsky, W.; Michael, F.
E. J. Am. Chem. Soc. 2013, 135, 8854.
(a) Turnpenny, B. W.; Chemler, S. R. Chem. Sci. 2014,
5, 1786. (b) Sequeira, F. C.; Turnpenny, B. W.; Chem-
ler, S. R. Angew. Chem. Int. Ed 2010, 49, 6563. (c) Fu,
S.; Yang, H.; Li, G.; Deng, Y.; Jiang, H.; Zeng, W. Org.
Lett. 2015, 17, 1018.
Muñiz, K.; Nieger, M. Chem. Commun. 2005, 2729.
For 1,3-butadienes: (a) Zhu Y.; Cornwall R. G.; Du H.;
Zhao B.; Shi Y. Acc. Chem. Res. 2014, 47, 3665. (b) Du,
H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007,
129, 11688. (c) Xu, L.; Shi, Y. J. Org. Chem. 2008, 73,
749. (d) Cornwall, R. G.; Zhao, B.; Shi, Y. Org. Lett.
2013, 15, 796.
Mizar P.; Laverny A.; El-Sherbini M.; Farid U.; Brown
M.; Malmedy F.; Wirth T. Chem. Eur. J. 2014, 20, 9910.
(a) Uyanik M.; Ishihara K. Chem. Commun. 2009, 2086.
(b) Dohi T.; Kita Y. Chem. Commun., 2009, 2073. (c)
Finkbeiner, P.; Nachtsheim, B. Synthesis 2013, 45, 977.
Application in alkene difunctionalization: Romero, R.
M.; Wöste, T. H.; Muñiz, K. Chem. Asian J. 2014, 9,
972.
(a) Molnár, I. G.; Gilmour, R. J. Am. Chem. Soc. 2016,
138, 5004. (b) Banik, S. M.; Medley, J. W.; Jacobsen, E.
N. J. Am. Chem. Soc. 2016, 138, 5000. (c) Molnár, I. G.;
Thiehoff, C.; Holland, M. C.; Gilmour, R. ACS Catal.
2016, 6, 7167. (d) Banik, S. M.; Medley, J. W.; Jacob-
sen, E. N. Science 2016, 353, 6294.
1
2
3
4
5
6
7
8
(6)
(7)
(8)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, the development of an iodine(I/III)-
catalyzed enantioselective diamination of styrenes under
intermolecular reaction control has been accomplished
for the first time. This protocol acts as an asymmetric
gateway to the important class of vicinal diamines29 and
thus facilitates access to entities with particular im-
portance in pharmacophoric and medicinal research. It
can be foreseen that this approach of chiral aryliodine
catalyst will be an instrumental guide for the develop-
ment of related transformations.
(9)
(10)
(11)
(12)
ASSOCIATED CONTENT
(13)
(14)
Supporting Information. Experimental details, control
experiments and compound characterization (PDF), and
details on the X-ray analyses (CIF). The Supporting Infor-
mation is available free of charge on the ACS Publications
website.
AUTHOR INFORMATION
Corresponding Author
(15)
(16)
(a) Uyanik, M.; Ishihara, K. J. Synth. Org. Chem. Jpn.
2012, 70, 1116. (b) Uyanik, M.; Yasui, T.; Ishihara, K.
Angew. Chem. Int. Ed. 2010, 49, 2175.
(a) Röben, C.; Souto, J. A.; González, Y.; Lishchynskyi,
A.; Muñiz, K. Angew. Chem. Int. Ed. 2011, 50, 9478. (b)
Souto, J. A.; González. Y.; Iglesias, Á.; Zian, D.;
Lishchynskyi, A.; Muñiz, K. Chem. Asian J. 2012, 7,
1103.
* kmuniz@iciq.es
† L. B. and R. M. R. contributed equally.
Notes
The authors declare no competing financial interest.
(17)
(18)
See Supporting Information for details.
Activation of iodine(III) derivatives with fluorinated al-
cohols: Colomer, I.; Batchelor-McAuley, C.; Odell, B.;
Donohoe, T. J.; Compton, R. G. J. Am. Chem. Soc. 2016,
138, 8855.
ACKNOWLEDGMENT
The authors thank Dr. S. Haubenreisser for initial experi-
ments. Financial support of this project was provided by
the Spanish Ministry for Economy and Competitiveness
and FEDER (CTQ2014-56474R grant to K. M., FPU doc-
toral grant to R. M. R. and Severo Ochoa Excellence Ac-
creditation 2014-2018 to ICIQ, SEV-2013-0319) and
CERCA program of the Government of Catalonia.
(19)
(20)
Quideau, S.; Lyvinec, G.; Marguerit, M.; Bathany, K.;
Ozanne-Beaudenon, A.; Buffeteau, T.; Cavagnat, D.;
Chénedé, A. Angew. Chem. Int. Ed. 2009, 48, 4605.
This kinetic preference for the enantioselective catalytic
pathway over the undesired stoichiometric one is of par-
ticular importance. From the investigation of a related
achiral iodine-catalysed aziridination reaction, it had
been called into question whether such an acceleration in
order to overcome the peracid-promoted background re-
action could be realised at all: Richardson, R. D.; De-
saize, M.; Wirth, T. Chem. Eur. J. 2007, 13, 6745.
Berger, G.; Gelbcke, M.; Cauët, E.; Luhmer, M.; Nève,
J.; Dufrasne, F. Tetrahedron Lett. 2013, 54, 545.
(a) Haubenreisser, S.; Wöste, T. H.; Martínez, C.; Ishi-
hara, K.; Muñiz, K. Angew. Chem. Int. Ed. 2016, 55,
413.
REFERENCES
(1)
(a) Lucet, D.; Le Gall, T; Mioskowski, C. Angew. Chem.
Int. Ed. 1998, 37, 2580. (b) Viso, A.; Fernández de la
Pradilla, R.; García, A.; Flores, A. Chem Rev. 2005, 105,
3167. (c) Viso, A.; Fernández de la Pradilla, R.; Tortosa,
M.; García, A.; Flores, A. Chem Rev. 2011, 111, PR1.
(a) De Jong, S.; Nosal, D. G.; Wardrop, D. J. Tetrahe-
dron 2012, 68, 4067. (b) Cardona, F.; Goti, A. Nature
Chem. 2009, 1, 269. (c) Martínez, C.; Muñiz, K. J. Org.
Chem. 2013, 78, 2168.
(21)
(22)
(2)
(23)
(a) Souto, J. A.; Martínez, C.; Velilla, I.; Muñiz, K. An-
gew. Chem. Int. Ed. 2013, 52, 1324. (b) Romero, R. M.;
Souto, J. A.; Muñiz, K. J. Org. Chem. 2016, 81, 6118.
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
(24)
(25)
Okuyama, T.; Takino, T.; Sueda, T.; Ochiai M. J. Am.
Chem. Soc. 1995, 117, 3360.
(26)
(27)
(28)
Prévost, C. Compt. Rend. 1933, 196, 1129.
Wöste, T. H.; Muñiz, K. Synthesis 2016, 48, 816.
Woodward, R. B.; Brutcher, F. V. Jr. J. Am. Chem. Soc.
1958, 80, 209.
Deprotection protocols to free diamines are available
and are given in the Supporting Information.
1
2
3
4
Although unprecedented, a direct stereoretentive reduc-
tive amination at stage C cannot be excluded. For a dis-
cussion on the related Csp2-N bond formation, see: Luc-
chetti, N.; M. Scalone, M.; Fantasia, S.; Muñiz, K. An-
gew. Chem. Int. Ed. 2016, 55, 13335.
(29)
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
ACS Paragon Plus Environment