Regioselective, Asymmetric Formal Hydroamination of Unactivated Internal Alkenes

Article abstract of DOI:10.1002/anie.201509235

We report the regioselective and enantioselective formal hydroamination of unsymmetrical internal alkenes catalyzed by a copper catalyst ligated by DTBM-SEGPHOS. The regioselectivity of the reaction is controlled by the electronic effects of ether, ester, and sulfonamide groups in the homoallylic position. The observed selectivity underscores the influence of inductive effects of remote substituents on the selectivity of catalytic processes occurring at hydrocarbyl groups, and the method provides direct access to various 1,3-aminoalcohol derivatives with high enantioselectivity. A regio- and enantioselective formal hydroamination of unsymmetrical, unactivated internal alkenes occurs with a silane and hydroxylamine derivative. The regioselectivity is controlled by the electronic effects of ether, ester, and sulfonamide groups in the homoallylic position. This method provides direct access to 1,3-aminoalcohols with high enantioselectivity.

Full text of DOI:10.1002/anie.201509235

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International Edition: DOI: 10.1002/anie.201509235
German Edition: DOI: 10.1002/ange.201509235
Alkene Hydroamination
Regioselective, Asymmetric Formal Hydroamination of Unactivated
Internal Alkenes
Yumeng Xi, Trevor W. Butcher+, Jing Zhang+, and John F. Hartwig*
Abstract: We report the regioselective and enantioselective
formal hydroamination of unsymmetrical internal alkenes
catalyzed by a copper catalyst ligated by DTBM-SEGPHOS.
The regioselectivity of the reaction is controlled by the
electronic effects of ether, ester, and sulfonamide groups in
the homoallylic position. The observed selectivity underscores
the influence of inductive effects of remote substituents on the
selectivity of catalytic processes occurring at hydrocarbyl
groups, and the method provides direct access to various 1,3-
aminoalcohol derivatives with high enantioselectivity.
A
dditions to alkenes are a fundamental class of reaction,[1]
but the hydrofunctionalization of internal alkenes is challeng-
ing because of the low reactivity of internal alkenes and the
difficulty of controlling the regioselectivity and stereoselec-
[2]
À
tivity of addition of the H X bond. Directed hydrogena-
tions[3] have been developed in which binding of the catalyst
to the functional group controls the face of addition to which
the alkene occurs, and this concept has been extended to
directed hydrofunctionalizations, such as hydrosilyation,[4]
hydroboration,[5] and hydroacylation,[6] in which a polar
substituent controls the carbon to which the functional
group is bound in the product. Although basic functional
groups bind to the catalyst in some classes of directed addition
reactions, the electronic properties of the polar group could
control the regioselectivity of olefin functionalization in other
cases, particularly the palladium-catalyzed oxidative func-
tionalization of alkenes.[7]
Although the hydroamination of alkenes has been widely
studied,[8] hydroaminations with alkenes containing directing
groups are limited.[9] Our group has reported the hydro-
amination of internal a,b-unsaturated esters and nitriles,[10]
and b-substituted vinylarenes,[11] but the reactivity and
regioselectivity of the reactions of these substrates is domi-
nated by conjugation of the alkene to the carbonyl or arene
substituents. The transition-metal-catalyzed hydroamination
of unconjugated alkenes directed by a functional group is
limited to a single set of reactions of N-allyl imines.[9,12]
Scheme 1. Regioselective hydroamination of unactivated internal
alkenes.
The hydroamination of alkenes has been investigated with
many classes of catalyst and reagents. The intramolecular
À
addition of the N H bonds of amines to alkenes has been
reported with complexes of many transition metals, and
reactions catalyzed by those of the late transition metals occur
with high compatibility for functional groups.[13] Recently,
Miura[14] and Buchwald[15] showed independently that the
intermolecular reaction of a hydride from a silane and an
electrophilic amino (+NR2) group from a hydroxylamine
À
derivative, rather than the N H bond of an amine, gives rise
to the products from formal hydroamination[16] of vinylarenes
and later 1,1-disubstituted alkenes.[17] During the course of
our study on directed hydroamination of internal alkenes,
Buchwald also reported reactions of symmetrical internal
alkenes, as well as two unsymmetrical alkenes bearing
unfunctionalized alkyl groups.[18] However, three equivalents
of internal olefins were required to achieve high yields,
making the utility of this method for reactions of valuable
alkenes limited.
Herein, we disclose our results that the formal hydro-
amination of internal alkenes containing an oxygen or
nitrogen substituent in the homoallylic position occurs with
high regioselectivity and enantioselectivity, and without the
need for excess olefin (Scheme 1B). The observed regiose-
lectivity results from the electronic effect of the substituent on
the alkene, rather than direct coordination of the function-
ality to the metal. These results suggest that the inductive
effects of remote electronegative groups on regioselectivity
can be large enough to cause regioselectivity at an alkene to
be high,[7] much like they are large enough to influence the
[*] Y. Xi, T. W. Butcher,[+] Dr. J. Zhang,[+] Prof. J. F. Hartwig
Department of Chemistry, University of California
Berkeley, CA 94720 (USA)
E-mail: jhartwig@berkeley.edu
Y. Xi, Dr. J. Zhang,[+] Prof. J. F. Hartwig
Division of Chemical Sciences
Lawrence Berkeley National Laboratory
Berkeley, CA 94720 (USA)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509235.
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À
site-selectivity for C H bond functionalization on a saturated
hydrocarbyl substituent.[19] This chemistry provides a simple
route to highly enantioenriched 1,3-aminoalcohol derivatives,
which are prevalent in natural products and pharmaceuti-
cals[20] and are useful synthetic building blocks.[21]
Indeed, the reaction of an internal olefin bearing a 2,4,6-
trichlorobenzoyl group (1e) afforded the hydroamination
products in high yield, with high regioselectivity and without
formation of the competing reduction product. Moreover, this
reaction occurred with excellent enantioselectivity.
To probe the effect of functional groups on the regiose-
lectivity for the formal hydroamination of internal alkenes,
we first investigated the reaction of trans-3-hexenyl benzyl
ether (1a) with diethoxymethylsilane (DEMS) and N,N-
dibenzyl-O-benzoyl hydroxylamine (Table 1, entry 1). The
Reactions of alkenes containing other electron-deficient
groups, such as phenyl ethers (1 f, 1g) and a tosylate (1h) were
also studied. The reactions of the olefins bearing phenyl ether
groups formed the addition product in higher yield and
regioselectivity than those of reactions of olefins bearing alkyl
ether groups. The yield and regioselectivity of reactions of
alkenes bearing more electron-deficient phenyl ethers were
higher than those of reactions of alkenes bearing less
electron-deficient phenyl ethers (1 f vs. 1g). However, the
removal of the phenyl ether group requires harsh conditions,
rendering it impractical for controlling the regioselectivity of
the hydroamination. The alkene bearing a tosylate group
reacted to less than 5% conversion (1h).
Table 1: Evaluation of directing groups for regioselective hydroamina-
tion.[a]
The scope of the reactions of alkenes containing the 2,4,6-
trichlorobenzoyl group is summarized in the top section of
Table 2. Alkenes containing ethyl-, isopropyl-, tert-butyl-, and
cyclohexyl substituents (3a–3d) underwent hydroamination
in good isolated yields with consistently high regioselectivity
and excellent enantioselectivity. The alkenes with branching
a to the alkene formed a single constitutional isomer, but the
most hindered alkene bearing a tert-butyl group reacted in
slightly lower yield than those with secondary alkyl substitu-
ents at this position. Methyl-substituted alkene (3e) under-
went the reaction in low yield, but the lower yield was due to
the lack of conversion, rather than formation of side products.
A series of functional groups are tolerated. Reactions of
alkenes in substrates containing a silyl ether (3 f) occur at the
alkene, although lower regioselectivity (4.1:1) was observed,
perhaps because the functional groups counterbalance the
electronic influence of the homoallylic ester. Site-selective
hydroamination of a non-conjugated diene occurred at the
alkene proximal to the ester over the alkene distal to the ester
(3h). Internal alkenes containing a phenyl ether unit 3k–3o
(evaluated due to their facile synthesis) reacted in the
presence of halogens on the arene of the ether, as well as
ketals and heteroarenes.
This reaction was found to be very sensitive to the
substituents at nitrogen of the O-benzoylhydroxylamine. N,N-
dibenzyl- and N-benzyl-N-alkyl-O-benzoylhydroxylamines
underwent hydroamination in good yields (5j, 5k) and high
regioselectivity, but the reaction of an N,N-dialkyl-O-ben-
zoylhydroxylamine provided the product in low yield.[23]
Furthermore, to expand the scope of functionalized
alkenes that undergo this formal hydroamination, we found
that substrates (3p) that contain functionality connected at
the homoallylic position by heteroatoms other than oxygen,
also underwent hydroamination in high yield with good
regioselectivity and excellent enantioselectivity. This method
provides access to enantioenriched 1,3-diamine derivatives.
To assess whether the chiral catalyst could control the
diastereoselectivity for the hydroamination of chiral alkenes,
we conducted the reaction of enantiopure internal alkene 6
bearing a stereogenic center at the site of the homoallylic
benzoate (Table 3). The reaction of 6 catalyzed by the copper
Entry R Group
Conversion[b]
(%)
Yield[b]
(%)
P:D[c] ee[d]
1
2
3
Bn (1a)
55
48
56
50
46
52
3.3:1[e]
3.2:1[e]
3.6:1[e]
–
–
–
PMB (1b)
4-CF3-C6H4CH2
(1c)
4
5
6
7
8
Bz (1d)
>95
90
90
84
<5
39
84
81
83
0
7.1:1 99
9.0:1 97
7.6:1 97
4.6:1 94
BzCl3[f] (1e)
C6F5 (1 f)
4-Br-C6H4 (1g)
Ts (1h)
–
–
[a] Reaction conditions: 1 (0.05 mmol), 2 (0.10 mmol, 2 equiv), Cu-
(PPh3)H (10 mol%) and (S)-DTBM-SEGPHOS (11 mol%) in THF
(0.14 mL), rt, 84 h; [b] Determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard; [c] Proximal:distal ratio was
determined by analysis of the 1H NMR spectra of the crude reaction
mixture; [d] Determined by SFC for the major isomer; [e] Determined by
GC; [f] BzCl3 =2,4,6-trichlorobenzoyl.
reaction of these reagents in the presence of 10 mol%
Cu(PPh3)H and 11 mol% (S)-DTBM-SEGPHOS[22] in THF
at room temperature for 84 h gave the hydroamination
products in moderate yield and regioselectivity (50% yield,
3.3:1 regioselectivity). Modification of the electronic proper-
ties of the aryl group on the benzyl ether from electron-rich p-
methoxy benzyl ether 1b to electron-poor p-trifluoromethyl
benzyl ether 1c did not alter the yield or regioselectivity
significantly. However, the regioselectivity was slightly higher
for the reaction of the more electron-poor 1c (entry 3).
Thus, this formal hydroamination was conducted on an
internal alkene bearing a more electron-withdrawing benzoyl
group (1d). The regioselectivity of the reaction of the
homoallylic benzoate was clearly higher than that for reaction
of the homoallylic ethers (1a–1c). However, the yield for
reaction of the benzoate was lower, owing to competing
reduction of the ester in both the starting material (1d) and
the corresponding hydroamination products.
To suppress the competing reduction, we studied reactions
of benzoates bearing substituents at the ortho positions.
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Table 2: Scope of regioselective hydroamination of unactivated internal
Table 3: Study of diastereoselectivity of hydroamination of a chiral
homoallylic ester.
alkenes.[a,b]
Entry Ligand
Product
Yield[a] d.r.[b]
1
2
3
(S)-DTBM-SEGPHOS
55% >20:1
(R)-DTBM-SEGPHOS
20%
11:1
4:1
rac-DTBM-SEGPHOS
(35%)
[a] Isolated yields. Yield in parenthesis refers to NMR yields using 1,3,5-
trimethoxybenzene as internal standard. [b] Determined by analysis of
1H NMR spectroscopy.
reaction to determine the inherent substrate bias on the
diastereoselectivity.
The 2,4,6-trichlorobenzoate groups of the hydroamination
products (5a and 5e) can be removed under saponification
conditions. The corresponding 1,3-aminoalcohols (8a and 8e)
were obtained as single isomers in high yield with high
enantiomeric excess [Eq. (1)].
To gain insight into the effects of the structure of the
substrate on the observed regioselectivity, we conducted
reactions of a series of substrates that vary in the geometry
and position of the alkene (Table 4). The cis-alkene (9a)
underwent hydroamination in low yield and with low
enantioselectivity, but did react with high regioselectivity.
The substrate 9b in which the alkene is positioned one carbon
further away from the directing group underwent hydro-
amination with poor regioselectivity (1.2:1) and low yield
(24%). Allylic benzoate 9c underwent SN2’ addition of
hydride and subsequent hydroamination to afford the termi-
nal amine (10c) in nearly quantitative yield.
While the higher regioselectivity with substrates contain-
ing more electron-withdrawing and less basic substituents
than with less electron-withdrawing and more basic substitu-
ents suggest that the regioselectivity of hydroamination arises
from the electronic effects of the directing group, we sought
less equivocal data on the origin of the regioselectivity. To
distinguish between regioselectivity derived from the elec-
tronic effects of the proximal polar group and regioselectivity
derived from direct coordination to the catalyst, we con-
ducted the hydroamination of cyclopentene 11 (Scheme 2). If
[a] Reaction conditions: 3 (0.2 mmol), 4 (0.4 mmol), Cu(PPh3)H
(10 mol%) and (S)-DTBM-SEGPHOS (11 mol%) in THF (0.2 mL), rt,
84 h; [b] Regioselectivity and diastereoselectivity were determined by
analysis of the 1H NMR spectrum of the crude reaction mixture;
[c] Cu(PPh3)H (15 mol%) and (S)-DTBM-SEGPHOS (17 mol%) used.
complex ligated by either (S)-DTBM-SEGPHOS or (R)-
DTBM-SEGPHOS formed the addition products with excel-
lent diastereoselectivity (> 20:1 and 11:1, respectively) and
regioselectivity (> 20:1). The configuration at the carbon
bearing the amino group was controlled by the configuration
of the catalyst. When the reaction was conducted with rac-
DTBM-SEGPHOS as the ligand, a d.r. of 4:1 in favor of the
1,3-syn-aminoester was observed. This result indicates that
reaction of the (R)-substrate catalyzed by the (S)-DTBM-
SEGPHOS complex is faster than the reaction of this
substrate catalyzed by the (R)-DTBM-SEGPHOS complex.
We have not identified an achiral phosphine that catalyzes the
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Table 4: Effect of olefin position and geometry on the hydroamination.[a]
Finally, to test whether the 2,4,6-trichlorobenzoate simply
leads to selectivity or increases the reactivity of the substrate,
we conducted the reaction with a combination of trans-4-
octene and 1e. The reaction was conducted under the
standard conditions at partial conversion (68% of 1e, 18 h)
to gauge the relative reactivity (Scheme 3; see the Supporting
Information for details).[25] This experiment showed that
alkene 1e reacts significantly faster than trans-4-octene.
Entry
Substrate
Product
NMR yield
(conv.), ee
regioselectivity
84% (90%),
97% ee
regioselectivity
9.0:1
15% (16%),
67% ee
regioselectivity
9.0:1
1
2
Scheme 3. Relative reactivity of homoallylic benzoate 1e and trans-4-
octene.
24% (28%)
regioselectivity
1.2:1
3
4
In summary, we report the hydroamination of unsym-
metrical internal alkenes with excellent enantioselectivity and
regioselectivity controlled by synthetically valuable substitu-
ents that impart an electronic effect on the alkene. The 2,4,6-
trichlorobenzoate group controls the regioselectivity and
activates the alkene towards hydroamination, and it can be
removed easily to afford synthetically useful enantioenriched
1,3-aminoalcohols. Studies on the cyclic substrate 11 support
our hypothesis that the regioselectivity originates from the
electronic and steric effects on the alkene. Evaluation of
suitable directing groups for hydroamination reactions by the
97% (100%)
[a] Yield and conversion were determined by 1H NMR spectroscopy using
1,3,5-trimethoxybenzene as an internal standard.
À
addition of the N H bonds of the amines to alkenes are
currently underway in our laboratory.
Acknowledgements
This work was supported by the Director, Office of Science, of
the U.S. Department of Energy under contract no. DE-AC02-
05CH11231. Takasago is gratefully acknowledged for gifts of
(S)-DTBM-SEGPHOS. Y.X. thanks Dr. Bijie Li and Dr.
Qingwei Zhang for helpful discussions. Dr. York Schramm,
Rebecca Green, and Sophie Arlow are gratefully acknowl-
edged for their assistance in preparation of the manuscript.
T.W.B. thanks the UC Berkeley Amgen Scholars Program for
support.
Scheme 2. Probe of origin of regioselectivity.
the regioselectivity occurs by coordination of the benzoate to
the copper catalyst, insertion of the alkene would occur
predominantly on the same face of the alkene as the directing
group. This selectivity, followed by stereoretentive[15,24] elec-
trophilic amination, would provide the cis-aminoester. If the
regioselectivity occurs by an influence of the electronic
properties of the polar group without direct coordination of
the ester to the catalyst, the copper hydride would preferen-
tially approach the alkene on the face opposite the ester unit,
to avoid steric repulsions between the group and the catalyst.
In this scenario, subsequent stereoretentive electrophilic
amination would provide the trans-aminoester.
Keywords: electronic effects · enantioselectivity ·
hydroamination · regioselectivity · unactivated internal olefins
How to cite: Angew. Chem. Int. Ed. 2016, 55, 776–780
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Received: October 2, 2015
Published online: November 23, 2015
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