Catalytic Enantioselective 1,4-Iodofunctionalizations of Conjugated Dienes

Article abstract of DOI:10.1021/acs.orglett.5b02026

The first catalytic enantioselective 1,4-iodofunctionalizations of conjugated dienes have been developed. Starting from β,γ,δ,ε-unsaturated oximes and 4-Ns hydrazones, these N-iodosuccinimide-mediated reactions are catalyzed by newly modified tertiary aminothiourea derivatives and furnish Δ²-isoxazoline and Δ²-pyrazoline derivatives, respectively, containing an (E)-allyl iodide group at the quaternary stereogenic center generally in high yield and with excellent enantioselectivity (up to 98.5:1.5 er).

Full text of DOI:10.1021/acs.orglett.5b02026

Letter
pubs.acs.org/OrgLett
Catalytic Enantioselective 1,4-Iodofunctionalizations of Conjugated
Dienes
Chandra Bhushan Tripathi and Santanu Mukherjee*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
S
* Supporting Information
ABSTRACT: The first catalytic enantioselective 1,4-iodofunctionalizations of conjugated dienes have been developed. Starting
from β,γ,δ,ε-unsaturated oximes and 4-Ns hydrazones, these N-iodosuccinimide-mediated reactions are catalyzed by newly
modified tertiary aminothiourea derivatives and furnish Δ2-isoxazoline and Δ2-pyrazoline derivatives, respectively, containing an
(E)-allyl iodide group at the quaternary stereogenic center generally in high yield and with excellent enantioselectivity (up to
98.5:1.5 er).
egioselective 1,4-difunctionalization of 1,3-dienes is a highly
desirable class of synthetic transformations since the
Scheme 1. Halofunctionalization of Conjugated Dienes
R
resulting alkene-containing compounds are versatile building
blocks in organic synthesis. Electrophilic halogen-induced
nucleophilic addition1 to 1,3-dienes offers a potential approach
toward 1,4-heterodifunctionalization. Catalytic asymmetric
halofunctionalization of unactivated olefins has received
considerable attention during the past few years.2 Emergence
of new modes of activation and catalysis concepts have led to the
rapid expansion of the reaction scope within a short period.3−5
However, while tremendous advancement in this direction took
place for the reactions of various nucleophiles with isolated6,7
and, to some extent, cumulated π-systems,8 the enantioselective
halofunctionalization reactions involving conjugated π-systems
remained far less developed. This is particularly surprising since
bromolactonization of conjugated (Z)-enynes, reported by Tang
et al., was among the first highly enantioselective catalytic
halofunctionalizations to be developed.4 The reason behind this
paucity possibly lies in the challenging regiochemical require-
ment (1,2- vs 1,4-halofunctionalization) associated with such
systems. While the regioselectivity issue, in the case of enynes, is
resolved due to the affinity of more electron-rich alkynes to
electrophilic halogens,4 the same issue becomes prominent for
conjugated dienes due to the presence of two nearly equally
reactive olefins (Scheme 1A).9 In 2013, Toste and co-workers
addressed this regioselectivity problem through the use of
anionic phase-transfer catalysis and developed an enantioselec-
tive 1,4-fluoroaminocyclization of 1,3-dienes.10 This report, as of
today, remained the lone example of catalytic enantioselective
1,4-halofunctionalization of 1,3-dienes.11
describe the first catalytic enantioselective 1,4-iodofunctionaliza-
tion of conjugated dienes.
1,1-Disubstituted 1,3-dienes (R2 ≠ H; Scheme 1B) were
selected as the diene component to facilitate the regiochemical
discrimination between the two otherwise similar π-systems. The
desired 1,4-halofunctionalization was hypothesized to occur
through the reaction of the relatively less hindered haliranium ion
B (Scheme 1A, path b).
In line with our previous observations,12 we once again chose
tertiary amino(thio)urea derivatives13 as possible catalyst
candidates. We surmised that a combination of Brønsted base
Encouraged by our recent studies on the highly enantiose-
lective catalytic iodocyclizations of β,γ-unsaturated oximes and
hydrazones,12 we decided to pursue the halocyclization of
conjugated dienes using the same nucleophiles. In this report, we
Received: July 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02026
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and chiral anion-binding catalysis should be able to discriminate
between the two enantiomeric iodiranium cations besides
activating the nucleophile (Scheme 1B).3b,6d,h
Table 2. Catalytic Enantioselective 1,4-Iodoetherification:
Substrate Scope
a
Indeed, the exposure of β,γ,δ,ε-unsaturated oxime 1a to N-
iodosuccinimide (NIS) 2 in the presence of 10 mol % of the
dihydroquinine-derived thiourea I in a 1:1 mixture of toluene and
dichloromethane at −80 °C led to 1,4-iodoetherification
exclusively. We were delighted to find that the desired Δ2-
isoxazoline 3a was obtained with substantial er (Table 1, entry 1).
b
c
entry
R1
R2
3
yield (%)
er
1
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
87
95.5:4.5
93:7
2
4-FC6H4
4-MeC6H4
Ph
88
Table 1. Catalytic Enantioselective 1,4-Iodoetherification:
3
99
89:11
a
Reaction Optimization
4
4-FC6H4
3-FC6H4
4-ClC6H4
4-OMeC6H4
4-MeC6H4
2-naphthyl
2-furyl
86
97:3
5
Ph
86
94.5:5.5
96.5:3.5
95.5:4.5
95:5
6
Ph
82
7
Ph
3g
3h
3i
76
8
Ph
84
9
Ph
96
88:12
10
11
Ph
3j
77
95.5:4.5
96.5:3.5
65:35
Ph
Me
3k
3l
92
d
12
e
Me
Ph
24 (73)
81 (99)
93
13
c-Hex
Ph
3m
3n
80:20
14
c-Hex
Me
76.5:23.5
a
Reactions were carried out on a 0.1 mmol scale. Unless stated
b
otherwise, 1 with E/Z ratio >20:1 was used. Yields correspond to the
b
c
entry
catalyst
conv (%)
er
isolated yield. The values in parentheses are yields based on the
c
1
2
3
4
I
>95
>95
>95
>95
86:14
reactive geometrical isomer of the substrate. Enantiomeric ratio (er)
d
II
87:13
was determined by HPLC analysis using a chiral stationary phase. E/
e
III
IV
95.5:4.5
5.5:94.5
Z ratio for 1l 2:1. E/Z ratio for 1m 4.2:1.
a
Reactions were carried out using 1.0 equiv of 1a and 1.2 equiv of 2.
lectivity varied considerably depending on the electronic nature
of the aryl group (entries 1−3). Oximes bearing aryl or heteroaryl
substituents were found to be suitable substrates, and regardless
of their steric or electronic nature, the Δ2-isoxazolines were
usually obtained in high yield with good to excellent er (entries
4−10). While aliphatic substituent on the diene prevailed with
high er (entry 11), a noticeable drop in enantioselectivity was
observed for oximes containing an aliphatic substituent (entries
12 and 13).
The requirement of an aryl or heteroaryl substituent on the
oxime for attaining a useful level of er constitutes a current
limitation of this protocol. Even though Δ2-isoxazolines are
valuable in their own right,17 the synthetic utility of our 1,4-
iodoetherification adducts was demonstrated through a series of
transformations involving 3a and 3k (see the Supporting
Information).
Having successfully accomplished the catalytic enantioselec-
tive 1,4-iodoetherification of β,γ,δ,ε-unsaturated oximes, we
turned our attention to the 1,4-iodoaminocyclization of related
hydrazone derivatives. To begin with this investigation,
analogous β,γ,δ,ε-unsaturated 4-nitrobenzenesulfonyl (4-Ns)
hydrazone 4a was chosen as the model substrate (Table 3).
The bifunctional catalyst V derived from trans-1,2-diaminocy-
clohexane, which was used in our previously reported
enantioselective 1,2-iodoaminocyclization reaction,12a turned
out to be a potent catalyst and generated the 1,4-iodoaminocy-
lization adduct Δ2-pyrazoline derivative 5a exclusively, without
any trace of 1,2-addition products (entry 1). However, the
product was obtained with only moderate enantioselectivity.
Dihydroquinine-derived thiourea I, on the other hand, provided
5a with a superior er of 81:19 (entry 3). A change in the reaction
medium proved crucial, and improved er was observed in a 3:1
mixture of toluene and CH2Cl2 (entries 4 and 5). Although the
exchange of the ethyl substituent on the quinuclidine of I with a
b
1
Conversion of 1a as determined by H NMR of the crude reaction
c
mixture. Enantiomeric ratio (er) was determined by HPLC analysis
using a chiral stationary phase.
No 5-exo or 6-endo cyclization products resulting from 1,2-
addition could be detected. The exclusive (E)-selectivity of the
product alkene is hardly surprising given the concerted nature of
the reaction (nucleophilic addition and haliranium opening) and
the preference for s-trans conformation of the allylic haliranium
intermediate B (Scheme 1A). Moreover, failure of a thiourea
derivative lacking Brønsted basic functionality to induce
sufficient enantioselectivity further corroborated our catalytic
hypothesis.14 The dihydrocinchonidine-derived thiourea II
slightly improved the enantioselectivity (entry 2). Replacing
ethyl group on the quinuclidine ring with a bulkier homobenzyl
group led to catalyst III, which to the best of our knowledge has
never been reported in the literature.15 In the presence of III at
−80 °C, 3a was obtained with markedly improved enantiose-
lectivity (95.5:4.5 er; entry 3). All further attempts to boost the
enantioselectivity by tweaking other reaction parameters proved
futile.14 The reaction with dihydrocinchonine-derived thiourea
IV under the same conditions furnished the other product
antipode ent-3a (entry 4), the absolute configuration of which
was established as (S) through single-crystal X-ray diffraction
analysis.16
The optimized catalyst and the reaction conditions (Table 1,
entry 3) were then extended to other substrates in order to probe
the generality of our intramolecular 1,4-iodoetherification
protocol. These reaction conditions were found to be fairly
general to an array of β,γ,δ,ε-unsaturated oximes 1. As shown in
Table 2, both electron-deficient and electron-rich aryl sub-
stituents on the diene are tolerated and furnished the products
3a−c in good to excellent yields, even though the enantiose-
B
DOI: 10.1021/acs.orglett.5b02026
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Catalytic Enantioselective 1,4-Iodoaminocyclization:
Reaction Optimization
Table 4. Catalytic Enantioselective 1,4-Iodoaminocyclization:
Substrate Scope
a
a
b
c
entry
R1
R2
5
yield (%)
er
d
1
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
54 (87)
32 (71)
31 (77)
61
98.5:1.5
96.5:3.5
91:9
e
2
4-FC6H4
f
3
4-MeC6H4
Ph
4
4-FC6H4
2,5-F2C6H3
4-ClC6H4
4-OMeC6H4
4-MeC6H4
2-naphthyl
c-Hex
91:9
g
5
Ph
52 (80)
34 (79)
33 (69)
37 (75)
74
93:7
b
c
h
entry
catalyst
solvent
conv (%)
er
6
Ph
95:5
i
7
Ph
5g
5h
5i
93:7
1
2
3
4
5
6
7
8
V
toluene/CH2Cl2 (1:1)
toluene/CH2Cl2 (1:1)
toluene/CH2Cl2 (1:1)
toluene/CH2Cl2 (2:1)
toluene/CH2Cl2 (3:1)
toluene/CH2Cl2 (3:1)
toluene/CHCl3 (3:1)
toluene/CHCl3 (3:1)
>95
>95
>95
>95
>95
>95
>95
>95
75:25
71.5:28.5
81:19
89:11
92:8
j
8
Ph
96.5:3.5
97:3
II
I
9
Ph
10
Ph
5j
66
95:5
I
k
11
Ph
Me
Me
5k
5l
61
96.5:3.5
89:11
I
k,l
12
c-Hex
43 (99)
VI
VI
VII
93:7
a
98.5:1.5
9:91
Reactions were carried out on a 0.1 mmol scale. Unless stated
b
otherwise, 4 with E/Z ratio >20:1 was used. Yields correspond to the
a
isolated yield. The values in parentheses are yields based on the
reactive geometrical isomer (E) of the substrate. Enantiomeric ratio
Reactions were carried out using 1.0 equiv of 4a and 1.2 equiv of 2.
Conversion of the reactive geometrical isomer (E)-4a as determined
c
b
c
1
(er) was determined by HPLC analysis using a chiral stationary phase.
by H NMR of the crude reaction mixture. Enantiomeric ratio (er)
was determined by HPLC analysis using a chiral stationary phase.
d
e
f
E/Z ratio for 4a 1.7:1. E/Z ratio for 4b 1:1.2. E/Z ratio for 4c 1:1.5.
g
h
i
E/Z ratio for 4e 1.7:1. E/Z ratio for 4f 1:1.3. E/Z ratio for 4g 1:1.1.
j
k
l
E:Z ratio for 4h 1:1. Reaction was conducted at −60 °C. E/Z ratio
for 4l 1:1.3.
homobenzyl group (in VI) marginally improved the er, a
combination of this catalyst (VI) and a more polar medium (3:1
toluene/CHCl3) provided 5a with excellent enantioselectivity
(entries 6 and 7). The enantiomeric product ent-5a could be
accessed under the same conditions, albeit with lower er, using
dihydroquinidine-derived thiourea VII (entry 8).
products were formed as a single diastereomer with respect to the
olefin geometry in the allylic unit.
Having verified the scope of the enantioselective 1,4-
iodoaminocyclization reaction, the product Δ2-pyrazoline
derivative (5a) was applied in a number of transformations
(see the Supporting Information). In particular, protecting group
exchange of the azide derivative 6 in a one-pot manner followed
by hydrogenation furnished an N-acetyl 3,5-diaryl Δ2-pyrazoline
8 having a structure similar to that of a potent kinesin spindle
protein (KSP) inhibitor (Scheme 2).19 No trace of racemization
was observed during any of these transformations.18
With the optimum catalyst and the reaction conditions (Table
3, entry 7) in hand, we examined the scope of this catalytic
enantioselective 1,4-iodoaminocyclization reaction. The insepa-
rable E/Z mixtures (with respect to CN) obtained during the
preparation of hydrazone in most cases18 initially appeared as
potentially problematic. However, only the (E)-isomer was
found to undergo the desired iodoaminocyclization, and the
unreactive (Z)-hydrazone could be recovered in most cases.18 As
depicted in Table 4, the optimized reaction conditions were
found to be suitable for β,γ,δ,ε-unsaturated 4-nitrobezenesul-
fonyl (4-Ns) hydrazone containing both aromatic and aliphatic
substituents. Electronically diverse aryl substituents on either
hydrazone or diene furnished the Δ2-pyrazoline derivatives in
good to excellent enantioselectivities. Moreover, this 1,4-
iodoaminocyclization reaction stands in sharp contrast to the
1,4-iodoetherification, discussed above, in that the high level of
enantioselectivities was preserved for substrates containing alkyl
groups on either positions (R1 and R2) (Table 4, entries 10 and
11). The compatibility of a more challenging substrate (R1 = Me,
R2 = Ph) could not be tested as the hydrazone was formed
exclusively as the undesired (E)-isomer (see the Supporting
Information). However, the dialkylated hydrazone (4l) afforded
the desired product (5l) with reasonably high er (entry 12). The
absolute configuration of the products was assigned by
comparison with that of 5a, obtained by single-crystal X-ray
diffraction analysis.16
Scheme 2. Conversion of 5a to a KSP Inhibitor Analogue (8)
In summary, we have achieved the first catalytic enantiose-
lective 1,4-iodocyclizations of conjugated dienes with the help of
newly modified bifunctional tertiary aminothiourea catalysts.
Under the mild reaction conditions with NIS as the electrophilic
iodine source, β,γ,δ,ε-unsaturated oximes and 4-Ns-hydrazones
underwent cyclization exclusively in a 1,4-fashion to furnish Δ2-
isoxazoline and Δ2-pyrazoline derivatives, respectively, contain-
ing a quaternary stereogenic center generally in high yield with
good to excellent enantioselectivity and impeccable diaster-
eoselectivity.
In addition to being completely regioselective, a common
feature of both the iodoetherification and iodoaminocyclization
is that, irrespective of the nature of the substituents, all the
C
DOI: 10.1021/acs.orglett.5b02026
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Akakura, M.; Sakakura, A.; Ishihara, K. Chirality 2014, 26, 356. (e) Xie,
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02026.
■
S
Experimental details, characterization data, and crystallo-
graphic data (PDF)
NMR spectra of obtained compounds (PDF)
X-ray data for compound ent-3a (CIF)
X-ray data for compound 5a (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sm@orgchem.iisc.ernet.in.
Notes
(7) Halofunctionalization of alkynes: Wilking, M.; Muck-Lichtenfeld,
̈
The authors declare no competing financial interest.
C.; Daniliuc, C. G.; Hennecke, U. J. Am. Chem. Soc. 2013, 135, 8133.
(8) Halofunctionalization of allenes: (a) Murai, K.; Shimizu, N.;
Fujioka, H. Chem. Commun. 2014, 50, 12530. (b) Wilking, M.; Daniliuc,
C. G.; Hennecke, U. Synlett 2014, 25, 1701. (c) Miles, D. H.; Veguillas,
M.; Toste, F. D. Chem. Sci. 2013, 4, 3427.
(9) For a catalytic enantioselective 1,2-bromoaminocyclization of 1,3-
dienes, see: Huang, H.; Pan, H.; Cai, Y.; Liu, M.; Tian, H.; Shi, Y. Org.
Biomol. Chem. 2015, 13, 3566.
ACKNOWLEDGMENTS
■
This work is funded by SERB, New Delhi (Grant No. SB/S1/
OC-63/2013). C.B.T. thanks CSIR, New Delhi, for a doctoral
fellowship. We thank Mr. Amar A. Hosamani (SSCU, IISc,
Bangalore) for his help with the X-ray structure analysis.
(10) Shunatona, H. P.; Fruh, N.; Wang, Y.-M.; Rauniyar, V.; Toste, F.
D. Angew. Chem., Int. Ed. 2013, 52, 7724.
(11) For nonenantioselective 1,4-halofunctionalizations of 1,3-dienes,
see: (a) Hong, S.-P.; McIntosh, M. C.; Barclay, T.; Cordes, W.
̈
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(b) Qian, H.; Yu, X.; Zhang, J.; Sun, J. J. Am. Chem. Soc. 2013, 135,
18020.
(16) CCDC 1060900 and CCDC 1060901 contain the crystallo-
graphic data for ent-3a and 5a, respectively. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(17) (a) Castellano, S.; Kuck, D.; Viviano, M.; Yoo, J.; Lop
F.; Conti, P.; Tamborini, L.; Pinto, A.; Medina-Franco, J. L.; Sbardella,
G. J. Med. Chem. 2011, 54, 7663. (b) Poutiainen, P. K.; Venalainen, T. A.;
́
ez-Vallejo,
̈
̈
Perakyla, M.; Matilainen, J. M.; Vaisanen, S.; Honkakoski, P.;
̈
̈
̈
̈
Laatikainen, R.; Pulkkinen, J. T. Bioorg. Med. Chem. 2010, 18, 3437.
(c) Namboothiri, I. N. N.; Rastogi, N. In Topics in Heterocyclic Chemistry,
Vol. 12; Hassner, A., Ed.; Springer: Berlin, 2008; p 1. (d) Kozikowski, A.
P. Acc. Chem. Res. 1984, 17, 410.
(18) See the Supporting Information for details.
(19) (a) Coleman, P. J.; Cox, C. D. Mitotic Kinesin Inhibitors. U.S.
Patent 20090042966 A1, Feb 12, 2009. (b) Coleman, P. J.; Schreier, J.
D.; Cox, C. D.; Fraley, M. E.; Garbaccio, R. M.; Buser, C. A.; Walsh, E. S.;
Hamilton, K.; Lobell, R. B.; Rickert, K.; Tao, W.; Diehl, R. E.; South, V.
J.; Davide, J. P.; Kohl, N. E.; Yan, Y.; Kuo, L.; Prueksaritanont, T.; Li, C.;
Mahan, E. A.; Fernandez-Metzler, C.; Salata, J. J.; Hartman, G. D. Bioorg.
Med. Chem. Lett. 2007, 17, 5390.
(6) Selected examples with olefins: (a) Toda, Y.; Pink, M.; Johnston, J.
N. J. Am. Chem. Soc. 2014, 136, 14734. (b) Nakatsuji, H.; Sawamura, Y.;
Sakakura, A.; Ishihara, K. Angew. Chem., Int. Ed. 2014, 53, 6974. (c) Yin,
Q.; You, S.-L. Org. Lett. 2014, 16, 2426. (d) Sawamura, Y.; Nakatsuji, H.;
D
DOI: 10.1021/acs.orglett.5b02026
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