Formal anti-Markovnikov hydroamination of terminal olefins

Article abstract of DOI:10.1039/c3sc51897c

A new strategy to access linear amines from terminal olefin precursors is reported. This two-step, one-pot hydroamination methodology employs sequential oxidation and reduction catalytic cycles. The formal hydroamination transformation proceeds with excellent regioselectivity, and only the anti-Markovnikov product is observed. Up to 70% yield can be obtained from styrenes or aliphatic olefins and either primary or secondary aromatic amines. Additionally, the scope is broad with respect to the olefin and accommodates a variety of functionalities; we demonstrate that amines with removable aryl protecting groups may be utilized to allow access to a more diverse array of hydroamination adducts.

Full text of DOI:10.1039/c3sc51897c

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Formal anti-Markovnikov hydroamination of
terminal olefins†
Cite this: Chem. Sci., 2014, 5, 101
Sarah M. Bronner and Robert H. Grubbs*
A new strategy to access linear amines from terminal olefin precursors is reported. This two-step, one-pot
hydroamination methodology employs sequential oxidation and reduction catalytic cycles. The formal
hydroamination transformation proceeds with excellent regioselectivity, and only the anti-Markovnikov
product is observed. Up to 70% yield can be obtained from styrenes or aliphatic olefins and either
primary or secondary aromatic amines. Additionally, the scope is broad with respect to the olefin and
accommodates a variety of functionalities; we demonstrate that amines with removable aryl protecting
groups may be utilized to allow access to a more diverse array of hydroamination adducts.
Received 6th July 2013
Accepted 16th August 2013
DOI: 10.1039/c3sc51897c
www.rsc.org/chemicalscience
12
catalysis. More recently, some success in the metal-catalyzed
intermolecular anti-Markovnikov hydroamination of unactivated
Introduction
Due to the prevalence of amines in therapeutics, as well as in the olens has been reported. For example, the Hultzsch and Beller
production of dyes, solvents, agrochemicals, and commodity groups have both performed the base-catalyzed anti-Markovnikov
1
3
and ne chemicals, the formation of carbon–nitrogen bonds is hydroamination of styrenes using LiN(SiMe ) and TMEDA or
3 2
1
14
of tremendous importance. Hydroamination complements n-BuLi catalytic systems. Similarly, the Hartwig group has
existing methods for the fabrication of carbon–nitrogen bonds reported the rhodium-catalyzed anti-Markovnikov hydro-
and may also provide advantages – for example, catalytic amination of styrenes with secondary amines, while the Marks
15
hydroamination methodologies hold promise for being atom group has demonstrated that organolanthanide-catalysis is
2
efficient and environmentally friendly, not requiring harsh conducive to the anti-Markovnikov hydroamination of styrenes
16
conditions, and utilizing readily available and inexpensive and two additional substrates bearing directing groups.
amine and olen (1 and 2 respectively, Fig. 1) starting materials. Recently, Hill and coworkers disclosed the hydroamination of
The construction of linear amines from terminal olens repre- styrenes, dienes, and alkynes utilizing [Ca{N(SiMe or [Sr
precatalysts, and the Lalic group has developed a
selectivity is a consideration, as the amine may add at either of one-pot, two-step hydroboration/amination approach for the
) } ]
3 2 2 2
17
sents a particularly signicant and formidable transformation; {N(SiMe ) } ]
3 2 2 2
18
the two carbons of the alkene substrate (Fig. 1). Additions to give synthesis of tertiary alkyl amines from aliphatic olens.
linear amines are generally more challenging, as Markovnikov However, these metal-catalyzed hydroamination methodologies
addition is typically preferred. It should be noted that almost have various limitations such as harsh basic conditions, the
2
0 years ago, the addition of amines to olens in an anti- requirement of a directing group, and limited substrate scopes.
19 20
Markovnikov fashion was identied as one of the top ten chal- Two additional approaches from the Studer and Beauchemin
3
lenges to be addressed by catalysis.
groups accomplish this transformation through free radical and
Although substantial progress has been made, a general pericyclic additions, respectively, although selectivity is substrate-
21
catalytic method of anti-Markovnikov hydroamination of olens dependent in the latter case. Despite considerable advances in
4,5
remains to be developed. Previous approaches towards anti- the area of metal-catalyzed anti-Markovnikov hydroaminations of
4
c
Markovnikov hydroamination have traditionally involved acti- olens, a general method remains an elusive goal.
6–11
vated olens or intramolecular transformations.
However, in
Considering the importance of carbon–nitrogen bond
1
999 the Beller group disclosed the rst example of transition forming processes, we sought to develop
a
new, mild
metal-catalyzed anti-Markovnikov hydroamination of olens; this
seminal study accomplished a low-yielding hydroamination of
styrenes with secondary aliphatic amines using rhodium
Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry
and Chemical Engineering, California Institute of Technology, Pasadena, California,
9
†
1
1125, USA. E-mail: rhg@caltech.edu; Fax: +1 626-564-9297
Electronic supplementary information (ESI) available. See DOI:
0.1039/c3sc51897c
Fig. 1 Olefin hydroamination.
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hydroamination methodology. In this manuscript, we present a the reduction step to favor formation of the hydroamination
two-step, one-pot hydroamination protocol that tolerates a adduct (3) over the hydration product (7). We recently reported
22
variety of olen substrates, including aliphatic olens as well as the aldehyde-selective Wacker oxidation of styrenes, and it was
electronically biased systems such as styrenes. Both the olen expected that these optimized conditions, in which t-BuOH
23
and the amine substrate scope are explored, and this report enhances anti-Markovnikov selectivity, could be utilized in
demonstrates how the use of cleavable N-protecting groups can hydroamination to access the key aldehyde intermediate (Fig. 2).
give access to a diverse library of hydroamination adducts.
In order to execute the reductive amination, we expected that the
addition of an amine (2) would provide an imine/iminium
intermediate, which could subsequently be reduced in the pres-
ence of a transfer hydrogenation catalyst [M] and an appropriate
hydride source (6). It should be noted that the proposed one-pot
methodology is advantageous over a two-pot technique because
in addition to allowing for direct formation of the linear amine,
isolation of the unstable aldehyde is bypassed; in our previous
report of the aldehyde-selective oxidation of styrenes, the high
reactivity of the aldehyde product necessitated isolation as the
Results and discussion
It was envisioned that anti-Markovnikov hydroamination could
occur through a one-pot, two-step Wacker oxidation/transfer
hydrogenative reductive amination approach (1 / 3, Fig. 2) that
would proceed via an aldehyde intermediate (5). Key challenges
associated with this methodology include: (a) regioselectivity of
the initial oxidation (1 / 5), as Wacker chemistry typically favors
formation of the Markovnikov product, (b) catalyst compatibility
during the reductive amination step, and (c) chemoselectivity of
22
hydrazone derivative.
Previously, our group has demonstrated the compatibility of
24
Shvo’s catalyst (9, Table 1) with Wacker oxidation conditions;
thus Shvo’s catalyst, which is also well known to be effective in
25
the transfer hydrogenation of imines, was chosen for our
initial hydroamination studies. p-Methylstyrene (1a) and
N-methylaniline (2a) were selected as the initial substrates for
preliminary hydroamination studies. While p-methylstyrene
was chosen for methodology development because this
substrate yields exceptionally high anti-Markovnikov selectiv-
22
ities in Wacker oxidations when t-BuOH is used as a solvent,
N-methylaniline was selected because of the known compati-
26
bility of aryl amines with Pd(II)-catalyzed oxidations.
Using our one-pot, two-step hydroamination approach,
solution of p-methylstyrene (1a) in t-BuOH was treated with
27
Fig. 2 Challenges of the formal anti-Markovnikov hydroamination
methodology.
a
Table 1 Optimization of hydroamination methodology
a
Entry
[M]
Mol% [M]
[H]
Additives (step)
CuCl (ii)
Equiv. amine
Equiv. H
2
O
Yield
1
2
3
4
5
6
7
9
9
10%
10%
10%
10%
1%
Isopropyl alcohol
2,4-Dimethyl-3-pentanol
2
2.5
2.5
2.5
2.5
2.5
1.3
1.3
1
0
1
2
1
1
1
15%
25%
63%
59%
65%
66%
59%
Mol. sieves (i); CuCl (ii)
10
10
10
10
10
5 : 2 HCO
5 : 2 HCO
5 : 2 HCO
5 : 2 HCO
5 : 2 HCO
2
2
2
2
2
H/TEA
H/TEA
H/TEA
H/TEA
H/TEA
—
—
—
—
—
10%
1%
a
1
Yield determined from analysis of the H NMR spectrum using 1,4-dioxane as an external standard.
102 | Chem. Sci., 2014, 5, 101–106
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PdCl
2
(PhCN)
2
, the terminal oxidant benzoquinone, and H
2
O
Table 2 Hydroamination of styrenes with N-methylaniline
(
Table 1, entry 1). Aer allowing the oxidation to progress for 4
ꢀ
hours at 35 C, a solution of N-methylaniline (2a), Shvo’s cata-
lyst (9), and hydride source isopropanol was added to the
reaction vessel, which was subsequently heated at 85 C. In
ꢀ
addition to providing desired hydroamination adduct 3a in 15%
1
yield by H NMR spectroscopy, the hydration product (e.g., 7)
a
Entry
1
Substrate
Product
Yield
was also observed, suggesting unselective reduction. Addition-
ally, signicant quantities of 8 were observed, resulting from
reductive amination between the oxidized hydride donor and
amine 2a. In order to minimize these undesired byproducts, a
bulkier hydride source was used, and water was eliminated
from the reaction conditions and replaced with molecular
sieves (entry 2). Under these reaction conditions, hydro-
amination adduct 3a was obtained in 25% yield.
To address chemoselectivity issues in the reduction step, we
found it necessary to replace Shvo’s catalyst (9) with commercially
available Ir-complex 10, which was developed by the Xiao group
and has been demonstrated to be selective for transfer hydro-
genative reduction of imines in the presence of carbonyls. Also
necessary for this reduction, a 5 : 2 formic acid : triethylamine
b
3a
61% (66% )
2
3
4
5
6
3b
3c
3d
3e
3f
55%
c
55%
28
29
62%
65%
52%
29,30
azeotropic mixture
was utilized as the hydride source. Oper-
ationally, a solution of the hydride source, the Ir catalyst, and the
amine was added to the reaction mixture aer Pd-catalyzed
oxidation had completed. Under these new conditions, in which
formation of undesired hydration product 7 is signicantly dis-
favored because of the inherent chemoselectivity of Ir-catalyst 10
for imine reduction, linear amine 3a was obtained in 63% yield by
1
31
H NMR spectroscopy (entry 3). Importantly, no Markovnikov
c
7
8
9
3g
57%
32
hydroamination product was detected. Brief attempts to further
optimize the reaction conditions found no signicant improve-
ment in yield (e.g., entry 4), although it was found that either Ir
catalyst loading or amine equivalents could be reduced without
negatively impacting yields (entries 5 and 6, respectively).
However, reduction of both Ir-catalyst loading and amine equiv-
alents resulted in a slight decline in yield (entry 7).
c
3h
3i
43%
70%
The styrene substrate scope was examined using the opti-
mized conditions (Table 2). Hydroamination of aryl-substituted
styrenes 1a–j afforded desired linear amines 3a–j in good to
moderate yield and with excellent regioselectivity; in all cases,
no Markovnikov hydroamination product was isolated or
c
1
0
3j
50%
1
detected in H NMR spectra of the unpuried reaction
c
32
11
3k
24%
mixtures. The hydroamination methodology was found to
accommodate a variety of aryl-substitution patterns, including
ortho-substitution (entries 4 and 8). In addition to alkyl
a
b
Yields determined by isolation (0.6 mmol scale). Yield determined
1
substituents (entries 1, 3, and 4), several functional groups were from analysis of the H NMR spectrum using 1,4-dioxane as an
tolerated including ether (entry 5), aryl halide (entries 6–9), and
c
external standard. Yield obtained with 10 mol% 10.
alkyl halide (entry 10) groups. Yields substantially declined
when these hydroamination conditions were applied to
aliphatic olens, and in the case of 4-phenyl-1-butene (1k), was used as the nucleophile, N-(4-methylphenethyl)aniline (3m),
33
amine adduct 3k was isolated in 24% yield (entry 11).
resulting from tandem hydroamination and hydrogenolysis
Next, the amine substrate scope was investigated, and efforts reactions, was isolated in 46% yield (entry 4) – an improvement
initially focused on aryl amines (e.g., 2a–f), which are prevalent in from entry 3’s yield of 32% of the same adduct. Although primary
34
drug substances. Hydroamination of 1a with N-methylnaph- aryl amines oen do not participate in high yielding hydro-
thalene-2-amine (2b) gave a satisfactory 60% yield of desired amination transformations, this result demonstrates that
product 3l (Table 3, entry 2). Aniline (2c) was a more challenging one possible tactic for maximizing yields is to use benzyl-
substrate (entry 3), but interestingly, when N-benzylaniline (2d) protected derivatives. Furthermore, whereas a number of
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Table 3 Hydroamination of p-methylstyrene with amines
a new catalytic process for the aldehyde-selective Wacker
36
oxidation of aliphatic olens. To our delight, it was found that
the new Wacker oxidation conditions, which utilize AgNO2,
could be applied to our hydroamination methodology in order
to offer an entry into the anti-Markovnikov hydroamination of
aliphatic olens. As shown in Table 4, hydroamination of 4-
phenyl-1-butene (1k) with N-methylaniline (2a) furnished
adduct 3k in 64% yield (Table 4, entry 1), whereas our initial
approach delivered 3k in 24% yield (Table 2, entry 11). Anti-
Markovnikov hydroamination of 1-dodecene (1m), a trans-
formation that notably cannot be substrate-controlled, pro-
ceeded in 40% yield to provide 3p (entry 3). The more sterically
demanding allyl cyclohexane (1n) also proved to be a good
a
Entry
1
Amine
Product
Yield
b
66%
60%
c
2
b
d
d
3
4
5
32%
46%
60%
Fig. 3 Cleavage of removable aryl protecting group.
Table 4 Hydroamination of aliphatic olefins with N-methylaniline
d
6
61%
a
b
Yields determined by isolation (0.6 mmol scale). Yield obtained
c
d
with 1 mol% 10. Yield obtained with 5 mol% 10. Yield obtained
with 10 mol% 10.
a
Entry
1
Substrate
Product
Yield
previous anti-Markovnikov intermolecular hydroamination
17
strategies do not accommodate aryl amines, our approach is
best suited for this class of compounds; thus, our methodology
offers a complementary hydroamination approach.
3k
64%
Unfortunately, employing the optimized conditions gave only
decomposition mixtures when applied to hydroamination using
aliphatic amines. This shortcoming prompted us to examine
hydroamination with amines possessing removable aryl protect-
ing groups. Hydroamination of p-methylstyrene (1a) with
N-methylanisidine (2e) proceeded in 60% yield (entry 5). Simi-
larly, N-benzylanisidine (2f) proved to be a suitable substrate,
providing the hydroamination adduct 3o in 61% yield (entry 6).
These two transformations furnished the linear amine product
bearing a PMP (p-methoxyphenyl) protecting group, which can be
2
3
3p
3q
65%
40%
4
3r
56%
5
6
3s
3t
60%
39%
35
readily cleaved by the action of dilute acid (e.g. 3n / 11, Fig. 3);
thus, the use of amines with removable aryl protecting groups
allows access to a diverse array of hydroamination products.
The hydroamination approach described thus far is not best
suited for aliphatic olens (e.g., Table 2, entry 11). Our group’s
olen hydration research previously demonstrated that the
initial oxidation proceeds in moderate to poor yield and with
7
3u
46%
24
regioselectivity favoring the Markovnikov (ketone) product.
However, during the course of our studies, coworkers developed
a
Yield determined by isolation (0.6 mmol scale).
104 | Chem. Sci., 2014, 5, 101–106
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substrate (entry 4), delivering 3r in 56% yield. Examination of
the substrate scope revealed that this transformation could
accommodate a variety of functional groups, including nitro
6 S. Zhang, Y. Wei, S. Yin and C.-t. Au, Catal. Commun., 2011,
12, 712–716.
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28, 326–330.
(
(
entry 2), ester (entry 5), alkyl halide (entry 6), and aryl halide
entry 7) groups. To the best of our knowledge, this method-
ology represents the rst metal-catalyzed approach to the
intermolecular anti-Markovnikov hydroamination of an unbi-
ased olen with an aryl amine. Furthermore, it should be noted
that this catalytic system allows access to elusive linear amine
adducts through a one-pot technique, thus avoiding isolation of
less stable aldehyde intermediates.
8 (a) C. Munro-Leighton, S. A. Delp, E. D. Blue and
T. B. Gunnoe, Organometallics, 2007, 26, 1483–1493; (b)
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Conclusions
1
1 (a) D. C. Leitch, P. R. Payne, C. R. Dunbar and
L. L. Schafer, J. Am. Chem. Soc., 2009, 131, 18246–18247;
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2006, 128, 6042–6043.
In summary, a one-pot methodology for the intermolecular
anti-Markovnikov hydroamination of olens with aryl amines
has been developed. The scope of the methodology is broad
with respect to the olen, and although the amine substrate 12 M. Beller, H. Trauthwein, M. Eichberger, C. Breindl,
scope is more limited, the use of amines with removable aryl
protecting group expands the suite of accessible linear
J. Herwig, T. E. M u¨ ller and O. R. Thiel, Chem.–Eur. J., 1999,
5, 1306–1309.
amines. This mild methodology complements existing litera- 13 P. Horrillo-Mart ´ı nez, K. C. Hultzsch, A. Gil and
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intermolecular hydroamination of aliphatic olens, as well as
the use of aryl amines.
M. Arlt, T. Heinrich, H. B ¨o ttcher and M. Beller, Chem.–Eur.
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1
5 (a) M. Utsunomiya, R. Kuwano, M. Kawatsura and
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Acknowledgements
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under Award Number F32GM102984. NMR 16 J.-S. Ryu, G. Y. Li and T. J. Marks, J. Am. Chem. Soc., 2003, 125,
spectra were obtained by instruments supported by the NIH 12584–12605.
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(
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aldehyde were observed to peak between 2–4 hours of
reaction time, and then declined thereaer. Minimal
starting material was observed in the H NMR spectra of
the unpuried reaction mixtures.
32 Although the Markovnikov hydroamination product was not
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7 Initial attempts to design a one-pot, one-step hydroamination
2
methodologywere unsuccessful. Reactions utilizing Shvo’s 34 J. Njardarson, Top 200 Brand Name Drugs by US Retail
catalyst gave decomposition mixtures, while reactions
involving iridicycle$OMe 10 resulted in the reduction of Pd(II)
to Pd(0).
8 Iridicycle catalyst 10 is commercially available from Strem.
Catalogue number: 77-0418; CAS number 1258964-48-5.
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2
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