Catalytic enantioselective alkene aminohalogenation/cyclization involving atom transfer

Article abstract of DOI:10.1002/anie.201109044

Problem solved: The title reaction was used for the synthesis of chiral 2-bromo, chloro, and iodomethyl indolines and 2-iodomethyl pyrrolidines (see scheme). Stereocenter formation is believed to occur by enantioselective cis aminocupration and C-X bond formation is believed to occur by atom transfer. The ultility of the products as versatile synthetic intermediates was demonstrated, as was a radical cascade cyclization sequence. Copyright

Full text of DOI:10.1002/anie.201109044

Angewandte
Chemie
DOI: 10.1002/anie.201109044
Enantioselective Aminohalogenation
Catalytic Enantioselective Alkene Aminohalogenation/Cyclization
Involving Atom Transfer**
Michael T. Bovino and Sherry R. Chemler*
Dedicated to William R. Roush on the occasion of his 60th birthday
The intramolecular haloamination of alkenes is a direct
method for the synthesis of halogen-functionalized nitrogen
heterocycles.[1] Vicinal amino halides are highly versatile
synthetic intermediates that are especially useful in drug
discovery and combinatorial chemistry, and are also of
interest in their own right as chemotherapeutic agents.[2]
The synthesis of chiral nitrogen heterocycles using this
method has been dominated by substrate-controlled reactions
where the starting amine is already chiral.[3] Alternatively,
some chiral 2-halomethyl nitrogen heterocycles are also
available through multistep functional-group conversion
from a limited number of naturally occuring chiral nitrogen
heterocycles.[4] An alkene haloamination/cyclization in which
the enantioselectivity was contolled by a chiral catalyst would
be a powerful method for obtaining chiral products from
achiral substrates and would expand the diversity of the
product structure and the flexibility of the synthetic sequence.
Herein is reported the first metal-catalyzed enantioselective
alkene aminohalogenation/cyclization.
aminohalogenation/cyclization reactions catalyzed by Pd and
to a lesser extent Cu salts have been reported,[9] these
methods have not been extended to enantioselective versions.
The development of an enantioselective Pd- or Cu-catalyzed
aminohalogenation is a challenge because of: a) competing
background electrophilic halogenation that does not require
the agency of the chiral metal catalyst; b) different modes of
aminometallation, for example, cis aminometallation and
trans aminometallation, can be competitive, thus making
a specific enantiodetermining aminometallation transition-
state geometry difficult to achieve; and; c) the halide could
act as a ligand and coordinate to the metal, thus disrupting the
enantiodetermining step. Herein, we report a different strat-
egy for the catalytic enantioselective alkene aminohalogena-
tion/cyclization that relies on radical-based atom transfer to
install the carbon–halogen bond, thereby minimizing the
possibility for unselective electrophilic background amino-
halogenation and complications that derive from nucleophilic
or electrophilic halogen sources (Scheme 1).
The enantioselective halogenation of alkenes has been
a subject of vigorous investigations in recent years.[5–8]
Organocatalytic methods have been especially fruitful, thus
enabling the development of an enantioselective, electro-
phile-initiated, intramolecular alkene halolactonization,[5]
with the first enantioselective bromoaminocylization of
alkenes being accomplished by organocatalysis in 2011.[7]
The mechanistically distinct nucleophile-initiated organoca-
talytic intermolecular enantioselective aminohalogenation of
enones has also been reported.[8] These organocatalytic
methods are generally specialized for a specific halogen and
for a specific alkene substitution pattern. Transition-metal-
catalyzed asymmetric aminohalogenation methods have the
potential to extend the range of alkene substrates and scope
of halogen atoms, but athough a number of racemic alkene
Scheme 1. Aminohalogenation by atom transfer. Tf=trifluoromethyl-
sulfonyl.
In recent years, our group has developed a family of Cu-
catalyzed enantioselective alkene amination reactions, includ-
ing carboamination,[10] aminooxygenation,[11] and diamina-
tion.[12] These reactions occur through a cis aminocupration
II
ꢀ
followed by homolysis of the C Cu bond, thereby generating
a primary carbon radical.[10c] The fate of the carbon radical is
influenced by the substrate structure and reaction compo-
nents, and both determine which difunctionalized product is
formed.[13] We hypothesized that if we could identify a halogen
atom donor with a greater propensity for atom transfer than
for electrophilic halogenation under our Cu-catalyzed reac-
tion conditions, the enantioselective aminocupration step
would be favored over non-catalyzed (racemic) background
processes. An initial screen of several halogen sources (NBS,
CBr4, NIS, I2, and 2,4,4,6-tetrabromocyclohexa-2,5-dienone)
revealed that significant background aminohalogenation
occurred under the reaction conditions in the absence of the
[Cu(R,R)-Ph-box](OTf)2 catalyst. Fortunately, however, we
did find that 2-iodopropane[14] did not produce any amino-
iodination product (4a) under these reaction conditions in the
[*] M. T. Bovino, Prof. S. R. Chemler
Department of Chemistry
The State University of New York at Buffalo
Buffalo, NY 14260 (USA)
E-mail: schemler@buffalo.edu
[**] We are grateful to the National Institute of General Medical
Sciences, National Institutes of Health (grant no. GM078383) for
support of this research. We thank Prof. Nancy Totah for helpful
discussions and Tim Liwosz for preliminary aminochlorination
experiments. William W. Brennessel and the X-ray crystallographic
facility at the University of Rochester are gratefully acknowledged for
the X-ray structures of 4a and 8g.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201109044.
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Angewandte
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absence of catalyst (Table 1, entry 1). When the reaction was
carried out in the presence of the chiral catalyst (20 mol%)
under these reaction conditions 2-iodomethylindoline 4a was
obtained in 84% yield and with 70% enantiomeric excess
(Table 1, entry 2). As well as the desired aminoiodination
product two carboamination products 5 and 6 (< 10% each)
were obtained, where 5 is the product of intramolecular
addition onto the tosyl ring and 6 is the product of
intermolecular addition to the isopropyl radical. We believe
that most of the isopropyl radical is oxidized to propene under
these reaction conditions in analogy to similar secondary
radical intermediates under similar reaction conditions.[10c]
(not shown). Both the (R,R)-Ph-box ligand 2 and the (4R,5S)-
di-Ph-box ligand 3 performed well in the reaction (Table 1,
entries 4 and 7). A reduction of the amount of iPrI to
4 equivalents resulted in diminished yield (Table 1, entry 5),
as did reduction in temperature to 958C (Table 1, entry 6).
When the catalyst loading was decreased to 15 mol%
a decrease in yield and enantioselectivity was observed
(Table 1, entry 8). Both yield and enantioselectivity are
diminished in the presence of water and we hypothesize
that at low catalyst loading adventitious water becomes
a significant issue. When the reaction using the commercially
available (R,R)-Ph-box ligand
2 was scaled up from
a 0.174 mmol scale to a 0.870 mmol scale, with respect to
1a, the enantioselectivity was consistent although the yield
was reduced, but for the larger scale reaction an increase in
the amount of iPrI to 9 equivalents resulted in an increase in
the yield (Table 1, compare entries 4, 9, and 10). The more
soluble (4R,5S)-diphenylbis(oxazoline) ligand 3 provided
Table 1: Optimization of the enantioselective aminoiodination.[a]
better reproducibility than ligand
2 on a 1.74 mmol
Entry Ligand RI (equiv) t [h] T [8C] Yield[b] 4a [%] ee [%][c]
(500 mg) scale of 1a (Table 1, entry 12).[11] A further increase
in yield and selectivity was obtainedon this scale when the
amount of MnO2 was increased to 400 mol%, the iPrI was
increased to 12 equivalents, and the reaction time was
increased to 24 hours (Table 1, entry 13).[15] Recrystallization
provided 4a in > 98% ee.
1[d]
none
6
6
6
6
4
6
6
6
6
9
9
9
12
24
24
24
6
6
6
6
6
6
6
120
120
120
105
105
95
105
105
105
105
105
105
105
–
–
70
80
2
2
2
2
2
2
3
2
2
2
2
3
3
84
74
85
62
52
84
56
70
80
70
66
74
3[e]
4[e]
89
5[e]
n.d.[f]
6[e]
85
91
74
85
89
83
84
A variety of substituted 2-iodomethyl indolines 4 were
synthesized (Table 2) using the optimized reaction conditions
(Table 1, entry 4). Good yields and enantioselectivities were
observed with a range of para-substituted N-tosyl-2-allylani-
lines 1 (X = Me, CN, F, Cl, MeO; Table 2, entries 1–5). The
meta-methoxy substrate 1g also performed well (Table 2,
entry 6) but the ortho-methoxy substrate 1h reacted with
significant reduction in enantioselectivity (Table 2, entry 7).
7[e]
8[e,g]
9[e,h]
10[e,h]
11[e,i]
12[e,i]
13[e,i,j]
6
6
24
88 (>98)[k]
[a] Reactions run with 50.0 mg (0.174 mmol) of 1a at 0.1m concen-
tration with 300 mol% of MnO2 and RI=iPrI unless otherwise noted.
[b] Yield of product isolated by flash chromatography on SiO2. [c] Enan-
tioselectivity determined by HPLC on a chiral stationary phase.
[d] Reaction run without Cu(OTf)2. N-iPr-N-tosyl-2-allylaniline was the
major product. [e] Activated molecular sieves (4 ꢀ; 20 mgmLꢀ1) were
used. [f] Not determined. [g] Reaction run with 15 mol% of Cu(OTf)2
and 18 mol% of (R,R)-Ph-box. [h] Reaction run with 250 mg
(0.870 mmol) of 1a. [i] Reaction run with 500 mg (1.74 mmol) of 1a.
[j] 400 mol% of MnO2 was used. [k] After one recrystallization. Reactions
run 1–3 times each. Ts=p-toluenesulfonyl.
Table 2: Scope of indoline synthesis.[a]
Entry Substrate
Ligand Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
1b, X=4-Me, R=Ts
1c, X=4-CN, R=Ts
1d, X=4-F, R=Ts
1e, X=4-Cl, R=Ts
1 f, X=4-OMe, R=Ts
1g, X=3-OMe, R=Ts
1h, X=2-OMe, R=Ts
1i, X=H, R=Bs
1j, X=H, R=Ns
1k, X=H, R=Ms
1l, X=H, R=SES
1m, X=H, R=3,5-di-tBu-C6H3SO2
2
2
2
2
2
2
2
2
3
3
3
2
85
85
80
83
72
71
80
77
72
85
85
90
90
84
89
87
87
88
15
88
80
81
82
n.d.[e]
A variety of reaction conditions (temperature, time,
catalyst loading, ligand structure, amount of oxidant and 2-
iodopropane, iodoalkane structure, and the use of 4 ꢀ
molecular sieves) were examined to identify optimal con-
ditions for enantioselective aminoiodination. We found that
the use of activated molecular sieves (4 ꢀ) generally
increased the yield and selectivity and rendered the results
more reproducible (Table 1, entry 3). The temperature could
be lowered to 1058C and the reaction time could be reduced
to 6 hours without reducing the yield of 2a (Table 1, entry 4).
Changing from 2-iodopropane to 2-iodobutane and iodocy-
clohexane did not increase the yield of the desired product
9[d]
10
11
12
[a] Reaction conditions from Table 1, entry 4 were used. The indicated
ligand, 2 or 3, was used in each reaction. [b] Yield of product isolated by
flash chromatography on SiO2. [c] Enantioselectivity determined by
HPLC on a chiral stationary phase. [d] 40 mol% of Cu(OTf)2 and
50 mol% of 3 were used. [e] Not determined. The enantiomers could not
be separated by HPLC on a chiral stationary phase. Bs=benzenesul-
fonyl, Ms=methanesulfonyl, Ns=4-nitrophenylsulfonyl, SES=2-tri-
methylsilylethanesulfonyl.
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A variety of substituents on the nitrogen atom were also
examined. The benzenesulfonyl substrate 1i gave similar
yield and selectivity to the tosyl substrate 1a (Table 2, entry 8
and Table 1, entry 4), but the nosyl substrate 1j was less
reactive and required higher catalyst loading (40 mol% of
Cu(OTf)2 and 50 mol% of 3) for efficient conversion. The N-
mesyl and N-trimethylsilylethylsulfonyl substrates 1k and 1l
underwent aminoiodination with slightly diminished enantio-
selectivity and better results were achieved when ligand 3 was
used. The highest yielding reaction was that of N-3,5-di-tert-
butylbenzenesulfonyl substrate 1m to give the aminoiodina-
tion adduct 4m; the yield of the intramolecular carboamina-
tion side-product analogous to 5 was significantly diminished
for this reaction.
The less-reactive 4-pentenylsulfonamides 7 required the
use of the (4R,5S)-di-Ph-box ligand 3 and longer reaction
times (11 h) for optimal yield and enantioselectivity (Table 3).
Under these reaction conditions, up to 93% ee was observed.
Substitution on the carbon chain (R1 ¼ H) was beneficial to
the reactivity and enantioselectivity. Substrate 7e, which has
no carbon chain substituents (R1 = H), reacted with lower
enantioselectivity (Table 3, entry 5) but substrate 7 f, which
also has no carbon chain substituents but has a 3,5-di-tert-
butylbenzenesulfonyl substituent on the nitrogen atom,
reacted with increased yield and enantioselectivity (Table 3,
entry 6). An increase in the number of substituents on the
olefin led to formation of a tertiary amine-bearing stereo-
center but with significantly diminished enantioselectivity
(Table 3, entry 9). It is interesting to note that 1,1-disubstitu-
ted[7a] and internal[7b] alkenes perform best in organocatalytic
aminobrominations while monosubstituted terminal alkenes
are superior substrates in our reaction. A singular example of
a tetrahydroisoquinoline synthesis was examined (Table 3,
entry 10), but this reaction was also poorly selective. In
general, the enantioselectivity is higher with more-reactive
substrates and it is possible that with less-reactive substrates
a Cu-catalyzed background reaction can occur if the enantio-
selective cis-aminocupration step is relatively higher in
energy. The absolute configurations of indoline 4a and
pyrrolidine 8g were assigned by X-ray crystallography and
all other products were assigned by analogy.[16]
In an example of a radical cascade reaction, 4,4-diallyl-4-
pentenylsulfonamide 15 underwent a double cyclization that
terminated in atom transfer iodination. Bicyclic diastereomer
16 was formed exclusively in 70% yield and 91% ee [Eq. (1)].
Table 3: Scope of pyrrolidine synthesis.[a]
Entry Substrate
Product
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7a, R1 =Me, R2 =Ts
8a
8b
8c
8d
8e
8 f
81
78
80
85
77
85
88
43
60
93
73
88
7b, R1 =Me, R2 =Ms
7c, R1 =Me, R2 =Ns
7d, R1 =Ph, R2 =Ts
7e, R1 =H, R2 =Ts
7 f, R1 =H, R2 =3,5-di-
tBu-C6H3SO2
The utility of the new vicinal aminoiodides as chiral
synthetic intermediates is illustrated in Scheme 2. p-Fluoro-2-
iodomethylindoline 2d (obtained on a larger scale in 75%
yield and 92% ee using reaction conditions analogous to
Table 1, entry 12) underwent an SN2 reaction with NaN3 to
provide the chiral diamine 17 in 98% yield and an SN2
reaction with thiophenol to provide the chiral phenylthiosul-
fonamide 18 in 98% yield. This same indoline underwent Fe-
7
8
catalyzed[17a,b] C C bond formation with phenylmagnesium
ꢀ
bromide, thus generating adduct 19 in 80% yield. The optical
purity of the substrate was retained in all three reactions.
Extension of the atom transfer step to other halogen atom
donors was next explored (Scheme 3). Chlorine atom transfer
7g
8g
10
78
78
92
83
9
9
11
13
12
14
74
73
16
27
10[d]
[a] Reactions run as described in Table 1, entry 7 except reaction time
was extended to 11 h. [b] Yield of product isolated by flash chromatog-
raphy on SiO2. [c] Enantioselectivity determined by HPLC on a chiral
stationary phase. [d] Ligand 2 was used.
Scheme 2. Substitution reactions of the chiral alkyliodide. acac=ace-
toacetonate, DMF=N,N’-dimethylformamide, HMTA=hexamethylene-
tetramine, TMEDA=N,N,N’,N’-tetramethylethylenediamine.
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was explored using 1,1-dichloroethylene, tetrachloroethylene,
2-chloropropane, tert-butylchloride, and tetrachlorocyclopro-
pene as potential atom transfer reagents. Of these reagents,
only 1,1-dichloroethene and tert-butylchloride provided the
aminochloride 4n, and only 1,1-dichloroethylene (9 equiv)
provided a highly enantioselective reaction. Bromine atom
transfer was explored using 2-bromopropane, tert-butylbro-
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enantioselective alkene aminohalogenation reaction. Our
reaction provides a range of chiral 2-iodomethyl indolines
and pyrrolidines in good to excellent yield and enantioselec-
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efficient enantioselective alkene aminobromination and ami-
nochlorination. Such halogen generality in enantioselective
alkene halofunctionalization is unusual as most processes are
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products are highly crystalline and thus amenable to chiral
amplification by recrystallization (Table 1, entry 13). As
demonstrated in Scheme 2, this method can be coupled with
substitution reactions to provide a variety of functionalized
chiral heterocycles, an application which should be very useful
to organic synthesis and medicinal chemistry. Finally, this
aminohalogenation is the first example of an efficient atom
transfer process occurring in this class of Cu-catalyzed alkene
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Received: December 21, 2011
Published online: March 5, 2012
Keywords: aminohalogenation · copper · enantioselectivity ·
.
homogeneous catalysis · nitrogen heterocycles
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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