Iron(II)-catalyzed asymmetric intramolecular olefin aminochlorination using chloride ion

Article abstract of DOI:10.1039/c5sc00221d

An iron-catalyzed enantioselective and diastereoselective intramolecular olefin aminochlorination reaction is reported (ee up to 92%, dr up to 15:1). In this reaction, a functionalized hydroxylamine and chloride ion are utilized as nitrogen and chlorine s

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EDGE ARTICLE
Iron(II)-Catalyzed Asymmetric Intramolecular Olefin
Aminochlorination with Chloride Ion
Cheng-Liang Zhu,‡a Jun-Shan Tian,‡a Zhen-Yuan Gu,a,b Guo-Wen Xing,b and Hao Xu*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An iron-catalyzed enantioselective and diastereoselective intramolecular olefin aminochlorination
reaction is reported (ee up to 92%, dr up to 15:1). In this reaction, a functionalized hydroxylamine and
chloride ion were utilized as the nitrogen and chlorine source. This new method tolerates a range of
synthetically valuable internal olefins that are all incompatible with the existing asymmetric olefin
10 aminochlorination methods.
diastereoselective and enantioselective intramolecular olefin
35 aminofluorination reactions.6 Our initial attempts to apply these
catalysts to olefin aminochlorination reactions led to either low
diastereoselectivity or low yield, presumably due to the reason
that chlorine and fluorine atom-transfer may proceed through
distinct mechanisms. Therefore, we explored a range of activating
40 groupligand combinations and discovered entirely new catalytic
conditions for asymmetric olefin aminochlorination. Herein, we
describe iron-catalyzed, enantioselective and diastereoselective
intramolecular aminochlorination for a range of internal, non-
chalconic olefins (ee up to 92%, dr up to 15:1). In these reactions,
45 a functionalized hydroxylamine and a chloride ion were utilized
as the nitrogen and chlorine source. This method tolerates a range
of synthetically valuable internal olefins that are all incompatible
with the existing asymmetric olefin aminochlorination
Introduction
Enantioselective olefin halo-functionalization reactions are a
range of synthetically valuable yet challenging transformations.1
Although
a variety of excellent asymmetric olefin halo-
15 oxygenation reactions have been discovered,2 there are much
fewer asymmetric olefin aminohalogenation methods available.3
In particular, there have been just a few reported catalytic
asymmetric olefin aminochlorination reactions.4 In one instance,
Feng discovered chiral Lewis-acid-catalyzed aminochlorination
20 of chalconic and other ,-unsaturated olefins.4a,c Also, Chemler
reported copper-catalyzed aminochlorination of terminal olefins
with chlorine radical donors in the presence of MnO2 (Scheme
1A).4b Despite these and other important discoveries, catalytic
asymmetric aminochlorination methods for internal, non-
25 chalconic olefins have yet to be developed. These methods would
be synthetically valuable because they readily provide vicinal
amino chloride, a class of important chiral building blocks.
Moreover, asymmetric olefin aminochlorination that proceeds
through an iron-nitrenoid intermediate has not been reported.5
approaches; it also provides
a
new approach that is
50 complementary to known methods for the asymmetric synthesis
of amino chloride with contiguous stereogenic centers.
Prior to this research, Bach reported an FeCl2-catalyzed racemic
intramolecular olefin aminochlorination method with an acyl
55 azide, TMSCl, and EtOH under ligand-free conditions.7 Excellent
syn-selectivity was observed with styrenyl olefins (dr up to
>20:1). However, poor diastereoselectivity was recorded with
non-styrenyl acyclic olefins (dr: 1:1). The new method presented
here has a few unique features which complement the existing
60 iron-catalyzed olefin aminochlorination method. First, excellent
anti-selectivity has been observed across a wide range of styrenyl
and non-styrenyl olefins. Next, good to excellent
enantioselectivity has been achieved with a variety of internal,
non-chalconic olefins (ee up to 92%). Finally, acyl azides are
65 non-reactive under the described reaction condition (vide infra),
which suggests that iron-nitrenoid generation may proceed
through different pathways compared with the known azide
activation pathway.
30
Scheme 1. Catalytic asymmetric olefin aminochlorination: summary of
this work and other existing asymmetric methods
Results and discussions
We previously discovered Fe(BF4)2-based catalysts for both
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A cinnamyl alcohol-derived acyloxyl carbamate 1 was selected as
compared with the known azide activation pathway.7
the model substrate for catalyst discovery (Table 1).8 In the
presence of tetra-n-butylammonium chloride (TBAC), we
observed that FeCl2 alone catalyzed a sluggish reaction under the
ligand-free condition (entry 1, 45% yield, dr: 2:1).9 However, the
FeCl2phenanthroline L1 complex catalyzed the anti-
aminochlorination with significantly improved yield and dr (entry
2, 80% yield, dr >20:1). We also noted that the Fe(NTf2)2L1
complex provided essentially the same reactivity and
10 diastereoselectivity (entry 3, 86% yield, dr >20:1). Interestingly,
the Fe(NTf2)2bisoxazoline L2 complex resulted in the loss of
diastereoselectivity (entry 4, 82% yield, dr: 0.83:1). Additionally,
the Fe(NTf2)2L3 complex promoted the syn-aminochlorination
with moderate yield and dr (entry 5, 34% yield, dr: 0.25:1). We
15 also observed that the Fe(NTf2)2L4 complex catalyzed the anti-
aminochlorination with a modest dr (entry 6, 75% yield, dr:
1.8:1). Notably, the ironL4 complex results in high dr and
reaction rate in the previously reported olefin aminofluorination
reaction.6 These observations suggest that ligands are involved in
20 the diastereoselectivity-determining step and they provide
excellent opportunities for diastereo-control.
5
45
aReaction condition: Fe(NTf2)2 (10 mol %), L1 (20 mol %), TBAC (2.5
equiv), CH2Cl2, 0 C, 2 h. bReaction condition: Fe(NTf2)2 (10 mol %), L4
(20 mol %), TBAC (2.5 equiv), CH2Cl2, 0 C, 2 h.
Scheme 2. Iron-catalyzed aminochlorination with a cis olefin and an acyl
50
azide
Table 2. Substrate scope of the iron-catalyzed diastereoselective olefin
aminochlorination reaction
2 2
o
2
2
Table 1. Catalyst discovery for the iron-catalyzed diastereoselective
olefin aminochlorination reaction
2
dr
dr
E
a
Z
dr
dr
dr
dr
dr
a
dr
dr
E
a
a
Z
dr
dr
dr
25
aUnless stated otherwise, the reactions were carried out under nitrogen
1
c
atmosphere. bConversion and dr were determined by H NMR. Isolated
b
dr
yield. TBAC: tetra-n-butylammonium chloride.
The observed ligand-enabled diastereo-control with trans-olefin 1
30 prompted us to evaluate cis-olefin 1′ (Scheme 2). To our surprise,
the Fe(NTf2)2L1 complex catalyzed syn-aminochlorination,
while
the
Fe(NTf2)2L4
complex
promoted
anti-
c
dr
dr
aminochlorination with essentially the same dr (Scheme 2). The
different reaction profiles for isomeric olefins 1 and 1′ suggest
35 that the aminochlorination reaction is neither stereospecific nor
fully stereo-convergent, which is significantly different from the
iron-catalyzed olefin aminofluorination reaction.6
c
55 aReaction condition: -15 C, 2 h. bReaction condition: 0 C, 5 h. Reaction
condition: 0 C, 12 h.
We subsequently explored a range of olefins under optimized
conditions to evaluate the scope and limitations of this anti-
aminochlorination method (Table 2). We discovered that di-
60 substituted styrenyl olefins are generally good substrates; both
electron-donating and withdrawing substituents are compatible
with this method (entries 14). Importantly, ortho-substituents
and pyridyl groups are both tolerated (entries 56). Furthermore,
extended aromatics, including naphthyl olefins, are reasonable
65 substrates (entries 78). Moreover, both isomeric ene-ynes are
Furthermore, an acyl azide 3 was evaluated under the reaction
40 conditions as control experiments. Interestingly, the acyl azide 3
was fully recovered and no aminochlorination product was
detected. These results suggest that the activation of acyloxyl
carbamates (1 and 1′) may proceed through different pathways
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excellent substrates for the stereo-convergent and anti-selective 40 aminochlorination (entry 2, 68% yield, dr: 0.48:1). To our
method (entry 9). Additionally, we observed that both styrenyl
surprise, the anti-addition product 2a was obtained with moderate
ee (24% ee), while the syn-addition product 2b was isolated with
significant ee (79% ee). Furthermore, we evaluated chiral ligands
L7 and L8 and determined they are less effective for asymmetric
and
non-styrenyl
tri-substituted
olefins
underwent
aminochlorination smoothly with excellent dr (entries 1011).10
5
We also discovered that a cyclohexyl-substituted olefin was an
excellent substrate (entry 12, dr >20:1). Further exploration 45 induction (entries 34). Additionally, chiral ligand L9 induced a
revealed that both 1,1-disubstituted olefins and dienes are viable
substrates with excellent regio-selectivity (entries 1314). Most
fast yet non-selective aminochlorination with a high overall yield
(entry 5).15 With the ironL5 complex in hand, we subsequently
explored other reaction parameters. First, a decreased reaction
temperature benefits both dr and ee (entry 6, dr: 11:1 and 90% ee
notably,
a
cyclic olefin could also undergo highly
10 diastereoselective anti-aminochlorination (entry 15, dr >20:1), a
product which is difficult to obtain with known methods.11 Since 50 for 2a at -60 C). Next, replacing the 3,5-
the FeCl2L1 complex provides essentially the same dr and yield
in these diastereoselective reactions, FeCl2 can be a convenient
substitute for Fe(NTf2)2 in racemic reactions.
bis(trifluoromethyl)benzoyl activating group with a smaller acetyl
group further enhances the ee (entry 7, 97% ee for 2a); however,
much lower dr and yield were obtained (entry 7, dr: 1.1:1, 42%
yield). Finally, a chloroacetyl activating group induces an
55 effective balance between overall yield and stereoselectivity
(entry 8, 67% yield, dr: 9.6:1 and 89% ee for 2a). We also
observed that the FeCl2L5 complex induced a slightly less
selective reaction with lower yield (entry 9, 58% yield, dr: 9.0:1
and 83% ee for 2a).
15
Table 3. Catalyst discovery of the iron-catalyzed asymmetric olefin
aminochlorination reaction
Fe(NTf2)2 (15 mol %)
Cl
O
R
2-step
sequence
Cl
chiral ligand (15 mol %)
TBAC (2.5 equiv)
O
Ph
O
Ph
OH
NHBoc
O
O
Ph
O
N
H
HN
2a
no ee
erosionb
CHCl3, -40 °C, 6 h
60
4
Me
Me
Table 4. Substrate scope for the iron-catalyzed asymmetric olefin
aminochlorination reaction
O
O
N
O
O
Ph
Ph
N
N
N
N
L5
L6
Ph
Me
Ph
2 2
Me
N
a
a
O
O
O
o
N
O
O
3
N
Ph
Ph
N
N
N
N
L7
L8
L9
Ph
Ph
drc
eee
eee
entrya
R
ligand conversionc yieldd
(anti:syn)
(anti) (syn)
2
>95%
>95%
88%
3,5-(CF3)2-Ph
3,5-(CF3)2-Ph
3,5-(CF3)2-Ph
3,5-(CF3)2-Ph
3,5-(CF3)2-Ph
L5
L6
L7
L8
L9
53%
68%
61%
32%
82%
9.9:1
0.5:1
1.7:1
2.5:1
0.5:1
84%
24%
<5%
47%
8%
<5%
79%
<5%
30%
24%
1
2
3
4
5
dr
ee
dr
ee
dr
ee
>95%
>95%
6f 3,5-(CF3)2-Ph
51%
42%
67%
58%
90%
97%
89%
83%
<5%
<5%
<5%
<5%
L5
L5
L5
L5
>95%
>95%
>95%
>95%
11.0:1
1.1:1
9.6:1
9.0:1
7f
CH3
8f
9f,g
CH2Cl
CH2Cl
dr
dr
dr
ee
ee
ee
aUnless stated otherwise, the reactions were carried out under nitrogen
20 atmosphere with 4 Å molecular sieves. bReaction condition: Boc2O, Et3N,
DMAP; then Cs2CO3, MeOH, 85% over two steps; see Supporting
c
Information for details. Conversion and dr were determined by 1H NMR.
e
dIsolated yield. Enantiomeric excess (ee) was measured by HPLC with
chiral columns; the absolute stereochemistry was determined by X-ray
25 crystallographic analysis of an analog of 2a. fThe reaction was carried out
at -60 C for 12 h. gThe FeCl2L5 complex was applied.
dr
ee
dr
ee
dr
ee
In order to fill the gap in catalytic asymmetric olefin
aminochlorination, we further explored asymmetric induction for
internal, non-chalconic olefins with a variety of ironchiral ligand
30 complexes (Table 3).12 First, we discovered that the ironL5
complex induced a diastereoselective and enantioselective anti-
aminochlorination, albeit with a low yield, mostly due to the
competing aminohydroxylation reaction (entry 1, 53% yield, dr:
9.9:1). Interestingly, the anti-addition product 2a was obtained
35 with excellent ee (84% ee), while the syn-addition product 2b
was obtained essentially as racemate (<5% ee).13 Additionally, a
two-step procedure can convert 2a to a chlorinated amino alcohol
triad 4 without ee erosion.14 Next, we observed that the ironL6
dr
ee
dr
ee
dr
eeb
dr
eeb
dr
eeb,c
dr
eeb,d
dr
ee
aUnless stated otherwise, mono-chloroacetyl group was selected as the
65 activing group in asymmetric catalysis; the ee for all syn-
aminochlorination product is less than 5%. Bis(trifluoromethyl)-benzoyl
complex induced
a
moderately diastereoselective syn-
b
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group was selected as the activating group. cThe ee for syn-addition
product is 12%. dL6 is used as the ligand for asymmetric induction; the ee
for the syn-addition product is 50%.
15 1011, dr: 4.512:1, ee: 7779%). Interestingly, both  and -
naphthyl olefins are excellent substrates (entries 1213, dr:
4.510:1, ee: 8992%). To our pleasure, a 3-pyridyl olefin with a
basic nitrogen atom is a reasonable substrate for the asymmetric
aminochlorination (entry 14, dr: 1.8:1, ee: 70% for the anti-
20 diastereomer). Moreover, we observed that the ironL5 complex
can induce significant ee in the aminochlorination with non-
styrenyl olefins (entry 15, dr: 2:1, ee: 52% for the anti-
diastereomer). To our surprise, the ironL6 complex proves
uniquely effective for the asymmetric induction with tri-
25 substituted olefins while the ironL5 complex becomes less
effective (entry 16, dr: 2.3:1, ee: 84% for the anti-
diastereomer).16
In order to evaluate the scope of this asymmetric method, we
explored the asymmetric induction of a range of internal olefins
(Table 4). The chiral catalyst provides excellent asymmetric
induction with styrenyl olefins. A range of para-substituted
styrenyl olefins with different electronic properties were
converted to the corresponding aminochlorination products with
10 high dr and ee (entries 16, dr: 9.615:1, ee: 8691%).
Additionally, meta-substituted styrenyl olefins are also good
substrates but with slightly decreased ee (entries 79, dr:
1015:1, ee: 8087%). However, we discovered that ortho-
substitution on styrenes has a deleterious effect on ee (entries
5
30 aReaction condition: Fe(NTf2)2 (15 mol %), L1 (15 mol %), TBAC (2.5 equiv), CHCl3, -60 C, 12 h. bReaction condition: Fe(NTf2)2 (15 mol %), L1 (15
mol %), CHCl3, -60 C, 12 h.
Scheme 3. Control experiments to probe for a plausible mechanism
During the exploration of substrate scope, it is surprising to
observe completely different ee for the anti- and syn-
35 diastereomers (e.g. 2a and 2b). In contrast, exactly the same ee
for both diastereomeric products was observed in the iron-
selectivity (both dr and ee) was observed in an Fe(NTf2)2-
catalyzed reaction with cis-olefin 1′ (Scheme 3A, 85% ee for 2a
and 31% ee for 2b, dr: 6:1; 93% ee for 5a and 83% ee for 5b, dr:
7:1). In both cases, 5a and 5b cannot be converted to 2a under the
catalyzed aminofluorination of 1.6 In order to obtain more 50 reaction condition.
mechanistic insights, we carried out ee analysis for all isolable
products in several control experiments (Scheme 3). First, in an
40 Fe(NTf2)2-catalyzed reaction with trans-olefin 1, two
aminochlorination products were obtained (Scheme 3A, 90% ee
These observations provide several important mechanistic
insights. First, the non-stereospecificity observed in the iron-
catalyzed olefin aminochlorination suggests that the formation of
for 2a, <5% ee for 2b, dr: 11:1).17 Simultaneously, 55 CN and CCl bonds occurs in a stepwise fashion.18 Next, the
diastereomeric 5a and 5b were also isolated with the same ee as
two competing olefin aminohydroxylation products (Scheme 3A,
45 88% ee for 5a and 5b, dr: 4:1). However, completely different
lack of complete stereo-convergence between reaction profiles of
isomeric olefins (1 and 1′) suggests that CN bond formation
may be the rate- and ee-determining step.18 Furthermore, since
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essentially the same ee was observed for 2a, 5a, and 5b from the
reaction with trans-olefin 1, it is likely that these products are
derived from the same intermediate after the ee-determining step.
Additionally, the fact that the syn-aminochlorination product 2b
Notably, 2a was isolated with essentially the same ee compared
with the one obtained under the standard condition (88% ee for
2a and <5% ee for 2b). This result suggests that the catalytically
relevant species may also be generated from the FeCl2L5
5
was isolated as racemate suggests that 2b may be derived from 25 complex.
non-stereoselective pathways which are distinct from the one
leading to the formation of 2a, 5a, and 5b.
To probe for more mechanistic details, we subsequently carried
out the FeCl2-promoted olefin aminochlorination in the absence
The product divergence (2a vs 5a/b) after the ee-determining step
of TBAC (100 mol % FeCl2, 100 mol % L5 in Scheme 3C).
10 is mechanistically interesting. Therefore, we studied the effect of 30 Under this condition, FeCl2 is the only available chlorine source.
external chloride ion. To our surprise, in the absence of TBAC,
the Fe(NTf2)2L5 complex alone was ineffective for the nitrogen
atom-transfer at -60 C; 1 and 1′ were both fully recovered
(Scheme 3B). However, the aminochlorination occurred as soon
Surprisingly, we discovered that 2a was obtained with essentially
the same ee compared with two previous control experiments
(88% ee for 2a). Furthermore, a syn-aminohydroxylation product
5a was isolated with excellent dr and ee (dr >20:1, 88% ee).
15 as a stoichiometric amount of TBAC was introduced. This 35 These observations suggest that FeCl bond cleavage may be
observation suggests that the Fe(NTf2)2L5 complex may serve
as a pre-catalyst and it may be activated by chloride ion in situ.
relevant for the chlorine atom-transfer step during the
enantioselective anti-aminochlorination.19 In addition, we also
identified a small amount of aziridine 6 (15% yield, 82% ee) and
further discovered that it could not be converted to either 2a or 5a
In order to test this hypothesis, we further carried out the FeCl2-
20 catalyzed reaction in the presence of TBAC (Scheme 3C). 40 under the reaction condition.
Scheme 4. Proposed mechanistic working hypothesis for the iron-catalyzed asymmetric aminochlorination of trans-olefin 1.
With the accumulated mechanistic evidence, we propose a 70 atom-transfer. Our current effort focuses on the mechanistic
45 plausible mechanistic working hypothesis for the iron-catalyzed
asymmetric aminochlorination of trans-olefin 1 (Scheme 4).
First, the iron catalyst could reversibly cleave the NO bond in
acyloxyl carbamate 1, generating iron-nitrenoid A with chloride
as a counter ion. From there, A may participate in the
50 enantioselective and diastereoselective aminohydroxylation and
aminochlorination to afford 2a and 5a respectively. Since the
aminochlorinationaminohydroxylation competition occurs after
the ee-determining step, 2a is obtained with essentially the same
ee compared with 5a. At the same time, 1 may also be converted
55 to 2b through a non-stereoselective pathway which is distinct
from the one leading to the formation of 2a and 5a. Further
mechanistic studies are required to elucidate details.
investigation of this new reaction and method development for
the enantioselective intermolecular olefin aminochlorination.
Notes and references
aDepartment of Chemistry, Georgia State University. 100 Piedmont
75 Avenue SE, Atlanta Georgia, 30303, United States Fax: +1-404-413-
5505; Tel: +1-404-413-5553; E-mail: hxu@gsu.edu
bDepartment of Chemistry, Beijing Normal University. Beijing, 100875,
China
This work was supported by the National Institutes of Health
80 (GM110382) and Georgia State University. Z.-Y. G. was supported by
NSFC (21272027) and a fellowship from China Scholarship Council.
† Electronic Supplementary Information (ESI) available: Experimental
procedure, characterization data for all new compounds, selected NMR
85 spectra and HPLC traces. See DOI: 10.1039/b000000x/
‡ These authors contributed equally.
Conclusions
1
For selected reviews of asymmetric olefin halofunctionalization, see:
(a) S. E. Denmark, W. E. Kuester and M. T. Burk, Angew. Chem. Int.
Ed., 2012, 51, 10938; (b) S. R. Chemler and M. T. Bovino, ACS
Catal., 2013, 3, 1076; (c) S. A. Snyder, D. S. Treitler and A. P.
Brucks, Aldrichimica Acta, 2011, 44, 27.
60 In conclusion, we have described an iron-catalyzed
enantioselective and diastereoselective aminochlorination method
for internal, non-chalconic olefins. This method tolerates a range
of synthetically valuable olefins that are all incompatible with the
existing asymmetric olefin aminochlorination methods. It also
65 provides a complementary approach for the asymmetric synthesis
of amino chloride with contiguous stereogenic centers. Our
preliminary mechanistic studies revealed that an FeCl2-derived
nitrenoid may be a feasible reactive intermediate and that FeCl
bond cleavage may be relevant for the stereoselective chlorine
90
95
2
For selected references of catalytic asymmetric olefin halo-
oxygenation, see: (a) S. H. Kang, S. B. Lee and C. M. Park, J. Am.
Chem. Soc., 2003, 125, 15748; (b) G. E. Veitch and E. N. Jacobsen,
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Yeung, J. Am. Chem. Soc., 2010, 132, 15474; (e) K. Murai, T.
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75
80
85
5
10
15
20
25
30
13 The absolute stereochemistry of 2a was determined by X-ray
crystallographic analysis of a structural analog of 2a. See Supporting
Information for details.
14 For detailed procedure and HPLC traces of 4, see Supporting
Information.
15 For the synthesis of L9, see ref. 6.
16 The ironL5 complex catalyzed the reaction favoring the syn-
addition product: dr(anti/syn): 0.47:1; ee for the anti-addition product
is 60% and ee for the syn-addition product is <5%. The relative
stereochemistry was assigned based on the 1H NMR and X-ray
crystallographic analysis of a structural analog described in ref. 6; see
Supporting Information for details.
17 When chloroacetyl group is used as the activating group, different
result was obtained. For details, see entry 8 of Table 3.
3
90 18 For a selected example of stepwise atom transfer reactions with
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N. H. Lee and E. N. Jacobsen, Tetrahedron Lett., 1991, 32, 6533.
19 For the oxidation of a radical species by a high-valent metal through
ligand transfer or electron transfer, see: (a) M. S. Kharasch and G.
95
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5
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6
7
8
9
For substrate synthesis, see Supporting Information for details.
Acyloxyl carbamates are reactive, while tosyloxyl and alkoxyl
carbmates are nonreactive and fully recovered under the reaction
condition.
The relative stereochemistry of 2a was determined by comparison of
the experimental NMR data with the ones reported in ref. 7. It was
further corroborated by 1H NMR and X-ray crystallographic analysis
of a structural analog of 2a. See Supporting Information for details.
10 The relative stereochemistry was assigned based on the 1H NMR and
X-ray crystallographic analysis of a structural analog described in ref.
6; see Supporting Information for details.
11 Complementary stereochemistry was achieved (in entry 15 of Table
2), compared with the known method reported in ref. 7, where the
syn-aminochlorination product was isolated. This substrate did not
undergo kinetic resolution with chiral catalyst, the Fe(NTf2)2L5
complex. Both the starting material and product were isolated as
racemate.
70 12 For leading references of chiral BOX and relevant ligands, see: (a) D.
A. Evans, K. A. Woerpel, M. M. Hinman and M. M. Faul, J. Am.
6
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