Organocatalytic Stereoselective Iodoamination of Alkenes

Article abstract of DOI:10.1002/chem.201404762

A new chiral thiohydantoin catalyst is used for the stereoselective iodoamination of alkenes. N-iodosuccinimide as the source of the electrophilic iodine is activated by catalytic amounts of different additives which also influence the regioselectivity of some cyclizations.

Full text of DOI:10.1002/chem.201404762

DOI: 10.1002/chem.201404762
Communication
&
Iodoamination
Organocatalytic Stereoselective Iodoamination of Alkenes
Pushpak Mizar,[a] Alessandra Burrelli,[a] Erika Gꢀnther,[a] Martin Sçftje,[a] Umar Farooq,[a, b] and
Thomas Wirth*[a]
Abstract: A new chiral thiohydantoin catalyst is used for
the stereoselective iodoamination of alkenes. N-iodosucci-
nimide as the source of the electrophilic iodine is activat-
ed by catalytic amounts of different additives which also
influence the regioselectivity of some cyclizations.
Scheme 1. Regioselectivity in thiourea-directed halocyclizations.
Haloaminations of alkenes are important organic transforma-
tions as they provide an effective approach to introduce two
heteroatoms onto non-activated CÀC double bonds.[1] Vicinal
amino halides serve as versatile synthetic intermediates which
have received considerable attention from chemists, and signif-
icant progress has been made in their application in drug dis-
covery and combinatorial chemistry.[2] Various methods for re-
agent-controlled enantioselective halogenations of alkenes
have been developed by using either chiral Lewis acids, chiral
amines, or chiral sulfides.[3] Enantioselective halogenations of
alkenes have received wide attention in recent years. Organo-
catalytic methods for enantioselective halolactonizations, bro-
moaminocylizations as well as transition metal-catalyzed ami-
nohalogenations of alkenes have been reported.[4] A few
metal-catalyzed stereoselective reactions of this type are
known,[5] but the enantioselectivites for organocatalyzed reac-
tion are fairly moderate and only a limited insight into the re-
gioselectivity of such reactions has been provided.
ic halogen-induced alkene heterodifunctionalization. The iodo-
nium intermediate can undergo 5-exo or 6-endo intramolecular
cyclization as shown in Scheme 1. According to Baldwin’s rules
of cyclization,[7] both the 5-exo and 6-endo products are feasi-
ble, however, the 5-exo product is the main product in most
haloaminations.
The iodoamination of N-protected 2,2-disubstituted-pent-4-
enylamines 1 using N-iodosuccinimide (NIS) as the electrophilic
iodine source was used as the model reaction to investigate
optimal reaction conditions. The efficient uncatalyzed reaction
was the first hurdle to overcome as the reaction takes place at
room temperature within 6 h to give a good yield of the prod-
uct. The rate of the reaction was much slower at À788C lead-
ing to 18% yield after 24 h (Table 1, entry 4), hence indicating
that the background reaction can be suppressed at low tem-
peratures. As studies have shown that additives can improve
the yield as well as the enantioselectivity of such reactions, ad-
ditives such as I2, KI, KBr (Table 1, entries 7–9) were used and
the yield of the reaction was determined. The background re-
action was found to be influenced dramatically and the reac-
We report here a catalytic method for the enantioselective
iodoamination of alkenes using a novel chiral organocatalyst.
Additional investigations have been performed to control the
regioselectivity of such iodoaminations. Earlier studies have
shown that N-bromosuccinimide-mediated bromoaminations
presumably proceed through a halogen bonding interaction
Table 1. Optimization of reaction conditions.
between the Lewis acidic catalyst and the bromine atom.[6]
A
thiourea-based catalyst should also be able to interact via halo-
gen bonding between the Lewis-basic sulfur center and the
electrophilic iodine atom. This might be pivotal for electrophil-
Entry Substrate
R
Solvent Additive Time Temperature 2: Yield
(2 mol%) [h]
[8C]
[%]
[a] Dr. P. Mizar, A. Burrelli, E. Gꢀnther, M. Sçftje, Prof. Dr. U. Farooq,
Prof. Dr. T. Wirth
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1c
1b
1b
1c
Ts
Ts
Ts
Ts
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
–
–
–
–
–
–
7
7
7
24
7
20
20
0
À78
20
34
87
56
18
0
School of Chemistry, Cardiff University
Park Place, Main Building, Cardiff CF10 3AT (UK)
Fax: (+44)29-2087-6968
E-mail: wirth@cf.ac.uk
Boc CH2Cl2
Cbz CH2Cl2
[b] Prof. Dr. U. Farooq
7
20
0
Current address: Department of Chemistry
COMSATS Institute of Information Technology
Abbottabad (Pakistan)
Boc CH2Cl2 I2
Boc CH2Cl2 KI
Cbz CH2Cl2 KBr
1
1
1
À78
À78
À78
53
83
67[a]
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404762.
[a] Additionally compound 3c (R=Cbz) is formed in 5% yield.
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tion proceeded even at À788C when 2 mol% of an additive
were used. A recent study by Sakakura and Ishihara et al. has
also highlighted that the combination of NIS and iodine gener-
ates a more reactive iodinating species.[8] While their study in-
dicates that stoichiometric amounts of NIS or the cheaper oxi-
dant N-chlorophthalimide are necessary, we observe a catalytic
activation of NIS with different additives. These results show
that a combination of NIS with an additive can generate highly
reactive species which are able to perform iodocyclizations at
very low reaction temperatures. This is shown by the high re-
action yields (53–83%) at À788C when either iodine, KBr, or KI
are used as an additive to stoichiometric amounts of NIS
(Table 1, entries 7–9). The nature of the protecting group in
the substrate 1 also has a large effect, it was observed that
with a tosyl (Ts) protecting group (1, R=Ts) the reaction took
place easily while this was not the case when the protecting
group was tert-butyloxycarbonyl (Boc) or carboxybenzoyl (Cbz)
(Table 1, entries 5 and 6). This also indicates that the nucleophi-
licity of the nitrogen atom has a major impact on the overall
reaction.
Table 2. Stereoseelctive iodoaminations using catalysts 4–6. Reaction
conditions: 1.2 equiv NIS, CH2Cl2, À788C.
Entry Substrate
R
Catalyst
Additive Time 2: Yield 2: ee
(10 mol%) (2 mol%) [h]
[%]
[%]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1c
1a
1a
1a
1a
1a
1b
1c
Ts
Ts
Ts
Ts
Ts
Ts
Cbz
Ts
Ts
Ts
Ts
Ts
Boc
Cbz
4
4
5
5
6
6
6
6
6
6
6
6
6
6
–
I2
–
I2
–
I2
I2
KI
KF
KCl
KBr
K2CO3
KBr
KBr
1
1
1
1
1
3
1
1
1
4
4
4
4
4
73
76
78
82
90
90
80
99
93
17
77[b]
–
6 (S)
10 (S)
11 (S)
20 (S)
17 (S)
81 (S)
79 (S)
78 (S)
63 (S)
n.d.[a]
n.d.[c]
–
9
10
11
12
13
14
–
–
–
–
Initially, the commercially available BOX ligand 4 (Figure 1)
was used in the reaction which led to very low selectivity in
[a] n.d.: Not determined. [b] Compound 3a is formed exclusively in 77%
yield. [c] n.d.: Not determined as 3a is unstable and undergoes elimina-
tion to a 1,4-dihydropyridine derivative.
the only catalyst and KBr. Similar behavior is found also at
higher temperatures up to 208C (see the Supporting Informa-
tion). The direct manifestation of this interaction is expressed
in the completely reversed regioselectivity of the iodoamina-
tion. The reaction with 2 mol% KBr as additive leads exclusive-
ly to the tetrahydropyridine compound 3a (Table 2, entry 11).
This compound is unstable under HPLC conditions and the
enantiomeric excess could not be determined. The reaction
with 2 mol% KI as additive produces only the five-membered
product 2a in 99% yield (Table 2, entry 8) as illustrated in
Scheme 2.
Figure 1. Chiral catalysts for iodoaminations.
product 2 (Table 2, entries 1 and 2). Similar low selectivities
were observed with catalyst 5, which was reported to be
highly efficient in Michael additions and aldol reactions
(Table 2, entries 3 and 4).[9] Based on the reasoning that one
should be able to control the stereoselectivity of the reaction
by halogen bonding interaction, we prepared a novel cyclic
thiourea catalyst 6 in 87% yield by reacting optically pure phe-
nylalanine ethyl ester hydrochloride with 5-isothiocyanato-1,3-
bis(trifluoromethyl) benzene. Recently, similar thiohydantoin
derivatives were reported to be efficient catalysts for asymmet-
ric Michael additions.[10]
Scheme 2. Change in regioselectivity with different additives.
Using the optimized reaction conditions, we explored the
substrate scope for the organocatalytic iodoamination. An alkyl
substitution in N-protected 2,2-disubstituted-pent-4-enylamine
had a large effect on the iodocyclization. Similar to our recent-
ly reported diamination reaction of alkenes,[11] no reaction was
observed here when N-protected 2,2-dimethyl-pent-4-enyla-
mine was used as a substrate with or without additives
(Table 3, entry 3). Good selectivities and yields were obtained
in the synthesis of tetrasubstituted chiral centers in the prod-
ucts 2d and 2e (Table 3, entries 1 and 2).
To understand the interaction of the additives with the cata-
lyst, variable temperature NMR experiments were carried out.
It was observed that the additive KBr influences the interaction
between the catalyst 6 and the substrate 1a. This is evident as
the chemical shifts values move downfield when KBr is added
to a mixture of 1a and the catalyst 6 at À508C. No such inter-
action is observed with only the substrate and KBr or between
The protocol of the stereoselective iodoamination was fur-
ther extended to 2-allylaniline derivatives of type 7. With these
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Communication
observed dihydroindol products 8a and 8c (up to 89% ee). In-
terestingly, the absolute configuration for 8a is opposite to
that of 8b and 8c for unknown reasons. The enantioselectivi-
ties for the endo-products 9a and 9c (Table 4, entries 5 and 7)
could not be determined as the molecule underwent de-iodi-
nation when dissolved in 2-propanol or even CDCl3 in certain
cases, to obtain 1-tosyl-1,4-dihydroquinoline products and
hence lost its chirality. Their optical rotation, however, shows
that the compounds 9a and 9c are not racemic.
Table 3. Cyclization of homoallylic tosylamine derivatives.
Entry
Substrate
Additive
Product
Yield
[%]
ee
[%]
1
I2 or KBr
87
90
In conclusion, we have developed a highly stereoselective
organocatalytic method for iodoaminations of substituted pen-
tenylamines and 2-allylanilines. A control of the regioselectivity
is possible with the help of additives.
2
3
I2 or KBr
89
85
Experimental Section
–
0[a]
–
Procedure for cyclization: N-Iodosuccinimide (18 mg, 0.08 mmol)
was dissolved in dry CH2Cl2 (2 mL) under argon and cooled to
À788C. After 15 min, a solution of the catalyst 6 (2.8 mg, 6.6 mmol)
in dry CH2Cl2 (2 mL) was added. The mixture was stirred for anoth-
er 15 min before the additive (1.3 mmol) [KI: 2.2 mg; KBr: 1.6 mg;
I2: 3.3 mg], dissolved in dry CH2Cl2 (2 mL), was added. After 15 min
at À788C a solution of the substrate (66.5 mmol) in CH2Cl2 (2 mL)
was added. The reaction was monitored by TLC. Upon completion,
the reaction was quenched by adding saturated aqueous Na2S2O3
solution (3 mL) at À788C. The aqueous layer was extracted with
CH2Cl2 (3ꢂ5 mL) and the combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica
gel using ethyl acetate/hexane (1:9).
[a] Also no reaction with iodine as additive.
Table 4. Cyclization of 2-allyl aniline derivatives 6.
Entry
Substrate
R
Additive
(2 mol%)
8: Yield
[%]
8: ee
[%]
9: Yield
[%]
All synthetic methods including spectroscopic and analytical data
are included in the Supporting Information.
1
2
3
4
5
6
7
7a
7a
7b
7c
7a
7b
7c
H
H
OMe
Cl
H
–
I2
–
–
KBr
KBr
KBr
57
89
23
86
58
33
14
87 (S)
80 (S)
83[a] (R)
88 (R)
87 (S)
19[a] (R)
89 (R)
0
0
0
0
14
0
10
Acknowledgements
OMe
Cl
This project was supported by an EU Marie Curie fellowship to
P.M. (DIALMEC, No. 298642) and by support from the Erasmus
program to A.B. and E.G. We thank the Commonwealth Schol-
arship Commission in the United Kingdom for support to U. F.
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.
We thank Dr. M. Brown, Cardiff University, for HPLC measure-
ments.
[a] This enantiomeric excess was determined by optical rotation as the
enantiomers were not separable with the available HPLC columns.
substrates it was also observed that KBr as additive can influ-
ence the regiochemistry of the cyclization. But also the elec-
tronic properties of the aromatic ring have a major effect on
the regioselectivity. In the presence of electron-donating sub-
stituents such as a methoxy group in compound 7b (Table 4,
entries 3 and 6), the exo-cyclization compound 8b was the
only product obtained, albeit in much lower yields. However,
in the presence of an electron-withdrawing group such as
chlorine, both the exo- and the endo-product were obtained
and this observation is similar to the reaction in the absence of
a substitution on the aromatic ring (7a, R=H) (Table 4,
entry 5), thereby confirming the hypothesis that the additive
influences the halogen bonding interaction between the thio-
urea catalyst, the substrate, and the electrophilic iodine spe-
cies. Since the electron density of the substrate plays a pivotal
role, any change would influence the regioselectivity. Sub-
strates 7a and 7c also lead to good enantioselectivities in the
Keywords: cyclization · diamination · hypervalent iodine ·
organocatalysis · stereoselective synthesis
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Received: August 7, 2014
Published online on && &&, 0000
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Communication
COMMUNICATION
&
Iodoamination
P. Mizar, A. Burrelli, E. Gꢀnther, M. Sçftje,
U. Farooq, T. Wirth*
&& – &&
An unexplored class of chiral thiohy-
dantoins can be used as efficient cata-
lysts for iodoaminations while additives
effect the regiochemistry. Also quaterna-
ry stereocenters can be easily generated
with this metal-free, organocatalytic
protocol.
Organocatalytic Stereoselective
Iodoamination of Alkenes
Chem. Eur. J. 2014, 20, 1 – 5
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ