Enantioselective CuH-catalyzed anti-markovnikov hydroamination of 1,1-disubstituted alkenes

Article abstract of DOI:10.1021/ja509786v

Enantioselective synthesis of β-chiral amines has been achieved via copper-catalyzed hydroamination of 1,1-disubstituted alkenes with hydroxylamine esters in the presence of a hydrosilane. This mild process affords a range of structurally diverse β-chiral amines, including β-deuterated amines, in excellent yields with high enantioselectivities. Furthermore, catalyst loading as low as 0.4 mol% could be employed to deliver product in undiminished yield and selectivity, demonstrating the practicality of this method for large-scale synthesis.

Full text of DOI:10.1021/ja509786v

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Communication
Enantioselective CuH-Catalyzed Anti-Markovnikov
Hydroamination of 1,1-Disubstituted Alkenes
Shaolin Zhu, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja509786v • Publication Date (Web): 22 Oct 2014
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Enantioselective CuH-Catalyzed Anti-Markovnikov
Hydroamination of 1,1-Disubstituted Alkenes
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Shaolin Zhu and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, Massachusetts 02139, United States
Supporting Information Placeholder
ABSTRACT: The enantioselective synthesis of
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The ability to access
β-chiral amines through catalytic hy-
β
-chiral
droamination would offer increased flexibility and generality
compared to existing approaches for their preparation. To
date, there are only a handful of reports describing the enan-
tioselective hydroamination of unactivated olefins,4 and alt-
hough several transition-metal mediated5 and metal-free6
approaches have recently been reported for anti-
Markovnikov hydroamination, an enantioselective process
remains elusive.
amines has been achieved using the copper-catalyzed hy-
droamination of 1,1-disubstituted alkenes with hydroxyla-
mine esters in the presence of a hydrosilane. This mild pro-
cess afforded a range of structurally diverse
β-chiral amines,
including -deuterated amines, in excellent yields with high
β
enantioselectivities. Furthermore, catalyst loading as low as
0.4 mol % could be employed to deliver product in undimin-
ished yield and selectivity, demonstrating the practicality of
this method for large-scale synthesis.
RS
R3SiOBz
L*CuH
RL
I
1
Asymmetric anti-Markovnikov
hydroamination
R3SiH
RS
As a privileged structural subclass,
found in a broad range of bioactive molecules, including a
number of widely employed medicinal agents (Figure 1, A).1
β-chiral amines are
ꢀ
Catalyst discrimination of
remote steric differences
CuL*
CuOBz
RL
III
II
ꢀ Broad functional group
compatibility
Although several strategies have been devised to access β-
R1 R2
N
RS R1
ꢀ Low catalyst loading
chiral amines in an enantioselective manner,2 catalytic hy-
droamination constitutes a potentially powerful yet unex-
plored direct approach for their construction.3 In particular,
we recognized that if asymmetric anti-Markovnikov hy-
3
R2
2
N
RL
OBz
Figure 2. Proposed Mechanism of CuH-Catalyzed An-
ti-Markovnikov Hydroamination
droamination could be achieved, enantioenriched
β-chiral
Recently, we reported a catalytic protocol for the hy-
droamination of styrene derivatives and monosubstituted
alkenes initiated by the hydrocupration of olefin double
bonds.7 Interception of the thus-generated alkylcopper spe-
cies by a hydroxylamine ester furnished the formal hydroam-
ination product.8 The copper hydride species was regenerat-
ed in situ by a stoichiometric amount of a hydrosilane to
achieve a net catalytic hydroamination reaction. We won-
dered whether this process could be extended to 1,1-
amines would be directly accessible from readily available 1,1-
disubstituted alkenes (Figure 1, B).
disubstituted alkene substrates to produce β-chiral amines in
an enantioselective manner (Figure 2). We anticipated that
hydroamination of 1,1-disubstituted olefins would proceed
with exclusive anti-Markovnikov regioselectivity, in analogy
to the regioselectivity previously observed for monosubsti-
tuted olefins.7a However, successful implementation of this
strategy would require a catalyst capable of efficient hydro-
cupration of these unactivated and sterically encumbered
substrates, as well as the effective discrimination of olefin
substituents well-removed from the copper center and its
chiral ligand. Indeed, the enantioselective functionalization
of 1,1-disubstituted olefins has been cited as a major chal-
lenge for asymmetric synthesis, 9 and only a few highly enan-
tioselective catalytic transformations of these substrates have
Figure 1. A) Representative β-Chiral Amines; B) Hy-
droamination Strategy for Their Preparation
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been reported.10 Herein we report the regio- and enantiose-
lective hydroamination of 1,1-disubstituted olefins as a prac-
tical and general method for the synthesis of -chiral amines.
generally proceeded with levels of enantioselectivity that
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correlated with the steric difference between the 1,1-
substituents. High levels of enantioselectivity were observed
when one of the alkene substituents was α-branched (3a, 3d-
f). Nevertheless, moderately enantioselective hydroamina-
tion could still be achieved for more challenging substrates
bearing methyl and primary alkyl substituents (3b, 3c).
The hydroamination of 1,1-disubstituted alkenes demon-
strated broad functional group compatibility (Table 2b). Un-
der these base-free and exceptionally mild reaction condi-
tions, a variety of functional groups were readily accommo-
dated, including an acetal (3j), a ketal (3k), a nitrile (3n), an
ester (3o), ethers (3g-i), and silanes (3l-n). 12 In particular,
vinylsilanes underwent hydroamination to afford highly en-
antioenriched amines containing stereogenic silicon substit-
β
We began our investigation by examining the enantiose-
lective hydroamination of 2,3-dimethyl-1-butene (1a), a 1,1-
disubstituted alkene substrate with moderately differentiated
substituents (Table 1). An evaluation of ligands revealed (R)-
DTBM-SEGPHOS to be superior to all others tested (entry 1
vs. entries 2–6). The use of (R)-DTBM-MeO-BIPHEP as lig-
and afforded product with good enantioselectivity, but in
moderate yield (entry 2). Copper catalysts based on other
ligands, including (R,R)-Ph-BPE, (R)-(S)-Josiphos, (S)-BINAP
and Xantphos, exhibited little or no activity (entries 3–6).
Although variation of solvent had minimal impact on enanti-
oselectivity, the use of THF was found to give the highest
reactivity (entry 1 vs. entries 7, 8). The enantiomeric excess
was essentially unchanged when the reaction was conducted
at room temperature instead of 40 °C. However, the reaction
did not proceed to full conversion after 36 h (entry 9). Like-
wise, reduction of catalyst loading to 0.4 mol % led to in-
complete conversion (entry 10). Hence the reaction condi-
tions shown in entry 1 were chosen for subsequent examina-
tion of the substrate scope of this transformation.11a
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uents (3l-n).
Moreover, silyl-protected allylic alcohols
proved to be excellent substrates for this transformation,
furnishing protected 1,3-amino alcohols in excellent yields
and enantioselectivities (3g-i). Surprisingly, subjection of α-
methylstyrene to hydroamination conditions provided a 7:1
mixture of anti-Markovnikov and Markovnikov products,
though enantioselectivity was only moderate (3p).
Table 2. Substrate Scope of 1,1-Disubstituted Alkenes
a,b,c
Table 1. Variation of Reaction Parameters
yield
entry
T/°C
solvent
L
(%)a
ee (%)b
1
2
40
40
40
40
40
40
40
40
r.t.
40
THF
THF
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
91
67
7
83
82
–12
—
—
—
82
82
84
81
3 c
4 c
5 c
6 c
7
THF
THF
0
THF
0
THF
0
toluene
cyclohexane
THF
60
74
64
35
8
9
10 d
THF
aYields were determined by GC using dodecane as the internal
b
standard. Enantioselectivities were determined by chiral HPLC
c
d
analysis. 10 mol % Cu(OAc)2 and 11 mol % L used. 0.4 mol %
Cu(OAc)2, 0.44 mol % (R)-DTBM-SEGPHOS used.
Under these optimized conditions, we first examined the
steric effect of substituents on the alkene on enantioselectivi-
ty. As illustrated in Table 2a, we found that hydroamination
aIsolated yields on 1 mmol scale (average of two runs). bAbsolute
configuration was assigned by chemical correlation or analogy.
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cEnantioselectivities were determined by chiral HPLC or chiral
formed to the product with high efficiency and outstanding
SFC analysis. dCu(OAc)2 (5 mol %), (R)-DTBM-SEGPHOS (5.5
1
2
3
4
diastereoselectivity (>50:1 dr, 3x). In contrast, the mis-
matched case furnished product with poor conversion and
low diastereoselectivity (3x’).
Table 4. Scope of Hydroxylamine Electrophilesa,b,c
e
mol %) used. Isolated as a 7:1 mixture of anti-Markovnikov and
Markovnikov regioisomers, respectively. Enantioselectivity re-
f
fers to that of the anti-Markovnikov regioisomer. Cu(OAc)2 (4
mol %), (R)-DTBM-SEGPHOS (4.4 mol %) used.
5
6
7
8
The observed regioselectivity for this substrate is presumably
due to preferential formation of the less crowded alkylcopper
species during the hydrocupration step, which overcomes the
preference for benzylic cupration that we previously ob-
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served for α
-unsubstituted styrenes.7
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In some cases, a judicious choice of protecting group al-
lowed good enantioselectivity to be achieved in substrates
with remote or otherwise ineffective steric differentiation
(Table 2c). For β-methallyl alcohol, we found that installa-
tion of a trityl protecting group allowed good enantioselec-
tivity to be achieved (3q), while the use of bulky silyl protect-
ing groups was ineffective (3r, 3s). This strategy could be
extended to the corresponding amine to generate the dia-
mine product in comparable enantioselectivity (3t). The
presence of an unprotected N—H group in this case did not
adversely affect reactivity or selectivity of the hydroamina-
tion. The catalyst system was also able to effectively differen-
tiate between two remote alcohol protecting groups installed
onto 2-methylene-1,3-propanediol: hydroamination proceed-
ed with high efficiency and good enantioselectivity to afford
the orthogonally-protected aminodiol products (3u, 3v). Fi-
nally, an additional benefit of employing the trityl protecting
group in some cases is the high crystallinity of the resulting
hydroamination products. Thus, the enantiopurity of 3q and
3t could each be upgraded to >90% ee upon a single recrys-
tallization (see the Supporting Information).
b
aIsolated yields on 1 mmol scale (average of two runs). Enanti-
c
oselectivities were determined by chiral HPLC analysis. Abso-
lute configuration was assigned by chemical correlation or anal-
ogy.
A survey of hydroxylamine esters revealed that a range
of amino groups could be installed under these hydroamina-
tion conditions (Table 4). The use of dimethyl O-
11b
benzoylhydroxylamine was successful (4b),
allowing for
the enantioselective synthesis of dimethylamine derivatives,
which are prevalent in pharmaceutical agents. Furthermore,
4-(pyrimidin-2-yl)piperazin-1-yl benzoate (4c) as well as the
sterically hindered reagent derived from tetramethylpiperi-
dine (4d), were well tolerated by our system. Finally, a stere-
ocenter adjacent to the nitrogen atom of the electrophilic
aminating reagent could be accommodated, with the hy-
droamination reaction proceeding in a completely catalyst-
controlled manner (4e, 4e’).
The anti-Markovnikov hydroamination could be extend-
ed to the synthesis of amines with stereogenic deuterium
substituents, which may find utility in chemical or biological
labeling studies.13 An enantioenriched deuterated alkene with
an adjacent stereocenter was prepared to permit determina-
tion of stereoselectivity by NMR spectroscopy. Deuterated
alkene 5 was readily prepared by deuteroalumination of the
corresponding enantioenriched alkyne. Subjection of 5 to
hydroamination conditions selectively afforded either dia-
stereomer of the expected β−deuterated amine product de-
pending on the antipode of ligand employed (Scheme 1). The
observation of catalyst-controlled selectivity in this example
suggests that the catalyst can achieve effective facial discrim-
ination for monosubstituted aliphatic alkenes as well as for
1,1-disubstituted alkenes and styrenes.
Table 3. Hydroamination of Chiral 1,1-Disubstituted Al-
kenesa, b, c
aIsolated yields on 1 mmol scale (average of two runs). bAbsolute
configuration was assigned by chemical correlation or analogy.
Scheme 1. Practical Synthesis of
Aminesa,b,c
β-Chiral Deuterated
1
cDiastereoselectivities were determined by H NMR analysis of
the crude reaction mixture.
We next explored the ability of the catalyst to control dia-
stereoselectivity in reactions of enantiopure chiral olefins. As
shown in Table 3, the hydroamination of (R)-limonene pro-
ceeded with excellent catalyst control (3w, 3w’). However, in
the case of conformationally rigid estrone-derived substrate
1x, a substrate-catalyst matching and mismatching effect was
observed. In the matched case, the substrate was trans-
aIsolated yields on 1 mmol scale (average of two runs). bAbsolute
configuration assigned by chemical correlation or analogy.
cDiastereoselectivities determined by 1H NMR analysis.
Finally, as previously observed by Lipshutz and coworkers
in related CuH-based systems,14 it was found that the addi-
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Soc. 2007, 129, 8976. (d) Czekelius, C.; Carreira, E. M. Angew.
tion of triphenylphosphine as a secondary ligand improved
catalyst turnover numbers without significantly impacting
the reaction rate or enantioselectivity of hydroamination,
thereby allowing a reduced loading of copper precatalyst and
chiral ligand to be used. Thus, we developed a slightly modi-
fied protocol for practical hydroamination reactions con-
ducted on large scale. A catalyst loading of 0.4 mol % proved
sufficient for reactions performed on 10 mmol scale using
commercially available (R)-limonene as the substrate
(Scheme 2).
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Chem. Int. Ed. 2003, 42, 4793; (e) Mampreian, D. M.; Hoveyda, A.
H. Org. Lett. 2004, 6, 2829. (f) Côté, A.; Lindsay, V. N. G.; Cha-
rette, A. B. Org. Lett. 2007, 9, 85.
(3)
For reviews on hydroamination, see: (a) Müller, T. E.;
Hultzch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008,
108, 3795. (b) Nobis, M.; Drießen-Hölscher, B. Angew. Chem. Int.
Ed. 2001, 40, 3983.
(4)
For the asymmetric hydroamination of terminal alkyl
alkenes to form the respect branched amines, see: (a) Zhang, Z.
B.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131,
5372; (b) Reznichenko, A. L.; Nguyen, H. N.; Hultzsch, K. A. An-
gew. Chem. Int. Ed. 2010, 49, 8984.
9
Scheme 2. Large-scale Hydroamination with Lower Cata-
lyst Loading
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(5)
For transition metal-catalyzed intermolecular anti-
Markovnikov hydroamination reactions, see: (a) Beller, M.;
Trauthwein, H.; Eichberger, M.; Breindl, C.; Herwig, J.; Müller, T.
E.; Thiel, O. R. Chem. Eur. J. 1999, 5, 1306. (b) Utsunomiya, M.;
Kuwano, R.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003,
125, 5608. (c) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc.
2003, 125, 12584. (d) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2004, 126, 2702. (e) Takaya, J.; Hartwig, J. F. J. Am. Chem.
Soc. 2005, 127, 5756. (f) Munro-Leighton, C.; Delp, S. A.; Alsop,
N. M.; Blue, E. D.; Gunnoe, T. B. Chem. Commun. 2008, 111. (g)
Barrett, A. G. M.; Brinkmann, C.; Crimmin, M. R.; Hill, M. S.;
Hunt, P.; Procopiou, P. A. J. Am. Chem. Soc. 2009, 131, 12906. (h)
Brinkmann, C.; Barrett, A. G. M.; Hill, M. S.; Procopiou, P. A. J.
Am. Chem. Soc. 2012, 134, 2193. For one-pot two-step procedures,
see: (i) Rucker, R. P.; Whittaker, A. M.; Dang, H.; Lalic, G. J. Am.
Chem. Soc. 2012, 134, 6571. (j) Bronner, S. M.; Grubbs, R. H.;
Chem. Sci. 2014, 5, 101.
In conclusion, we have described a mild catalytic process
for the synthesis of
β-chiral amines by asymmetric anti-
Markovnikov hydroamination of 1,1-disubstituted alkenes.
This versatile method tolerated a wide range of functional
groups on the alkene component and was compatible with
heterocycle-containing and sterically hindered aminating
reagents. This approach was further applied to the stereose-
lective synthesis of
β-deuterated amines. The amount of
catalyst required could be reduced by the addition of tri-
phenylphosphine as an inexpensive secondary ligand, further
enhancing the practicality of this system for large-scale syn-
thesis. The application of this protocol towards the synthesis
of pharmaceutical agents and natural products is currently
underway and will be reported in due course.
(6)
For intermolecular anti-Markovnikov hydroamination
reactions using group 1 and 2 alkylmetal bases, see: (a) Kumar,
K.; Michalik, D.; Castro, I. G.; Tillack, A.; Zapf, A.; Arlt, M.; Hein-
rich, T.; Böttcher, H.; Beller, M. Chem. Eur. J. 2004, 10, 746. (b)
Horrillo-Martínez, P.; Hultzsch, K. C.; Gil, A.; Branchadell, V.;
Eur. J. Org. Chem. 2007, 331. (c) Zhang, X.; Emge, T. J.; Hultzsch,
K. C. Angew. Chem. Int. Ed. 2012, 51, 394. For intermolecular anti-
Markovnikov hydroamination reactions based on radical pro-
cesses, see: (d) Guin, J.; Mück-Lichtenfeld, C.; Grimme, S.; Stu-
der, A. J. Am. Chem. Soc. 2007, 129, 4498. (e) Nguyen, T. M.;
Manohar, N.; Nicewicz, D. A. Angew. Chem. Int. Ed. 2014, 53,
6198.
ASSOCIATED CONTENT
Experimental procedures, characterization data for all com-
pounds, and crystallographic data of 3x (CIF). This material
is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(7)
(a) Zhu, S.; Niljianskul, N.; Buchwald, S. L. J. Am.
Chem. Soc. 2013, 135, 15746. For a related system for the asym-
metric hydroamination of styrene derivatives, see: (b) Miki, Y.;
Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2013, 52,
10830. See also: (c) Hesp, K. D. Angew. Chem. Int. Ed. 2014, 53,
2034.
sbuchwal@mit.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(8)
For leading references on various electrophilic amine
Research reported in this publication was supported by the
National Institutes of Health under award number GM58160.
The content of this publication is solely the responsibility of
the authors and does not necessarily represent the official
views of the National Institutes of Health. We would like to
thank Christina Kraml (Lotus Separations, LLC) for deter-
mining the enantiopurity of 3f by chiral SFC and Dr. Yi-Ming
Wang and Phillip J. Milner for their advice on the prepara-
tion of this manuscript.
sources and their applications, see: (a) Berman, A. M.; Johnson, J.
S. J. Am. Chem. Soc. 2004, 126, 5680; (b) Erdik, E.; Ay M. Chem.
Rev. 1989, 89, 1947; (c) Barker, T. J.; Jarvo, E. R. Synthesis 2011,
3958.
(9)
Thomas, S. P.; Aggarwal, V. K. Angew. Chem. Int. Ed.
2009, 48, 1896.
(10)
For asymmetric hydrogenation, see: (a) McIntyre, S.;
Hörmann, E.; Menges, F.; Smidt, S. P.; Pfaltz, A. Adv. Synth.
Catal. 2005, 347, 282. (b) Roseblade, S. J.; Pfaltz, A. Acc. Chem.
Res. 2007, 40, 1402. For asymmetric epoxidation, see: (c) Xia, Q.-
H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem. Rev. 2005,
105, 1603. (d) Wang, B.; Wong, O. A.; Zhao, M. -X.; Shi, Y. J. Org.
Chem. 2008, 73, 9539. For asymmetric hydroboration, see: (e)
Gonzalez, A. Z.; Román, J. G.; Gonzalez, E.; Martinez, J.; Medina,
J. R.; Matos, K.; Soderquist, J. A. J. Am. Chem. Soc. 2008, 130,
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Chem. Int. Ed. 2011, 50, 7079.
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The crude R2NOBz can be used directly in the hy-
1
2
3
4
5
6
7
8
droamination reaction after simple aqueous workup, although
the yield was somewhat lower. (a) Using crude Bn2NOBz, 3a was
obtained in 87% isolated yield, 83% ee; (b) Using crude
Me2NOBz, 4b was obtained in 70% isolated yield, 95% ee.
(12)
(a) Only poor to moderate conversion to the hydroam-
ination products was observed for unactivated 1,2-disubstituted
alkenes. No hydroamination products were observed for either
unactivated trisubstituted alkenes or α-substituted acrylates. (b)
Free alcohols will undergo silylation while aldehydes and ke-
tones are hydrosilylated under the current reaction conditions.
9
(13)
(14)
Gant, T. G. J. Med. Chem. 2014, 57, 3595.
For leading references employing Stryker’s reagent
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13
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15
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([Cu(PPh3)H]6) as a copper source in combination with a chiral
ligand in copper hydride chemistry, see: (a) Lipshutz, B. H.;
Servesko, J. M. Angew. Chem. Int. Ed. 2003, 42, 4789. (b) Lip-
shutz, B. H.; Servesko, J. M.; Taft, B.R. J. Am. Chem. Soc. 2004,
126, 8352. (c) Lipshutz, B. H.; Frieman, B. A. Angew. Chem. Int.
Ed. 2005, 44, 6345.
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