Anti-Markovnikov Hydroamination of Homoallylic Amines

Article abstract of DOI:10.1021/jacs.5b08500

The development of an anti-Markovnikov-selective hydroamination of unactivated alkenes is a significant challenge in organometallic chemistry. Herein, we present the rhodium-catalyzed anti-Markovnikov-selective hydroamination of homoallylic amines. The proximal Lewis basic amine serves to promote reactivity and enforce regioselectivity through the formation of the favored metallacycle, thus over-riding the inherent reactivity of the alkene. The scope of both the amine nucleophiles and homoallylic amines that participate in the reaction is demonstrated.

Full text of DOI:10.1021/jacs.5b08500

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Communication
Anti-Markovnikov Hydroamination of Homoallylic Amines
Seth C. Ensign, Evan P. Vanable, Gregory D Kortman, Lee J. Weir, and Kami L. Hull
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08500 • Publication Date (Web): 12 Oct 2015
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Anti-Markovnikov Hydroamination of Homoallylic Amines
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Seth C. Ensign, Evan P. Vanable, Gregory D. Kortman, Lee J. Weir, and Kami L. Hull*
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Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61820.
Supporting Information Placeholder
Scheme 1. Directed hydroamination reactions.10
ABSTRACT: The development of an anti-Markovnikov se-
lective hydroamination of unactivated alkenes is a significant
challenge in organometallic chemistry. Herein, we present
the rhodium-catalyzed anti-Markovnikov selective hydroam-
ination of homoallylamines. The proximal Lewis basic amine
serves to promote reactivity and enforce regioselectivity
through the formation of the favored metallacycle thus over-
riding the inherent reactivity of the alkene. The scope of
both the amine nucleophiles and homoallylamines that par-
ticipate in the reaction is demonstrated.
Carbon–nitrogen bonds are prominent functionalities in
organic molecules – for example, 84% of small molecule
pharmaceuticals contain at least one.1 Hydroamination, the
addition of an amine across an alkene or alkyne, couples two
readily accessible functional groups to form new C–N and C–
H bonds with 100% atom economy.2 Hydroamination reac-
tions are hindered by high activation energies and entropic
and slows undesired β-hydride elimination through the for-
costs; as such, a number of transition metal catalysts have
motes the desired Markovnikov selective hydroamination
mation of a 5-membered metallacyclic intermediate. Next,
been developed to promote this highly desirable transfor-
we sought to identify a rhodium-catalyzed Lewis base di-
mation.2
rected anti-Markovnikov selective hydroamination reaction
The hydroamination of a terminal alkene can afford two
possible regioisomeric products, the Markovnikov and the
anti-Markovnikov, where the new C–N bond is formed at the
internal or terminal carbon, respectively.2-8 Anti-
Markovnikov hydroamination of unactivated alkenes is con-
sidered to be particularly challenging, as it requires the nu-
cleophilic amine to attack the less electrophilic primary car-
bon and generate the new [M]–C bond at the more sterically
encumbered carbon.2 Thus, unactivated alkenes typically
undergo Markovnikov selective functionalization.3 Known
metal-catalyzed approaches for anti-Markovnikov hydroami-
nation require activated alkenes, such as 1,3-dienes4, sty-
of unconjugated alkenes. It is known that coordinating
groups can promote anti-Markovnikov selective olefin inser-
tion reactions, where the C=C bond inserts into the metal–
nucleophile bond.11 However, cationic Rh(I)-catalyzed hy-
droamination with amine nucleophiles has been demonstrat-
ed to occur via coordination of the olefin followed by anti-
aminometallation;12 the ability of coordinating groups to
promote an anti-Markovnikov selective nucleophilic attack
onto a coordinated alkene is unknown. Five-membered
metallacycles are less strained than six-membered metallacy-
cles, therefore we hypothesized that substrates bearing a
homoallylic Lewis basic group may override the intrinsic
alkene reactivity and form anti-Markovnikov hydroamina-
tion products (Scheme 1).13 Additionally, coordination of the
Lewis basic group may promote the functionalization of the
alkene by increasing the relative concentration.10,11 Moreover,
it may slow the oxidative amination pathway, relative to the
preferred hydroamination pathway, by occupying a cis coor-
dination site and inhibiting β-hydride elimination.10
renes5 allenes6, or methylenecyclopropanes7, which form
,
stable π-allyl or π-benzyl intermediates upon aminometalla-
tion or where the nucleophile selectively attacks the sp2 hy-
bridized carbon. The direct addition of N–H bonds across
unactivated alkenes in an anti-Markovnikov fashion is an
unsolved challenge for organometallic chemists, therefore
several formal hydroamination reactions have been devel-
oped.9
Our initial investigations employed 1,1-diphenyl homoal-
lylamine derivatives, as they were hypothesized to promote
coordination of the alkene through the Thorpe-Ingold ef-
fect.14 When N-homoallylimines are subjected to the previ-
Recently, we demonstrated that N-allylimines undergo a
selective Rh-catalyzed hydroamination reaction to afford 1,2-
diamines.10 Coordination of the imine to the catalyst pro-
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Page 2 of 5
ously optimized conditions for the Markovnikov selective
examined (Table 1). In addition to morpholine, cyclic amine
Rh-catalyzed hydroamination of N-allyl imines10 no hy-
nucleophiles, including piperidine, N-ethylpiperazine, pyr-
rolidine, and azetidine all afforded the anti-Markovnikov
products 2a-2e in good to excellent yields (from 67-90%) and
excellent regioselectivities (>20:1). Further, an acyclic sec-
ondary amine nucleophile N,N-dimethyl amine undergoes
the hydroamination reaction to afford 2f in 80% yield and
>20:1 regioselectivity. Unfortunately, decreasing the nucleo-
philicity of the amine inhibits the hydroamination reaction,
i.e. N,N-diethylamine does not afford significant quantities of
the desired product (<5% yield).
1
2
3
4
5
6
7
8
droamination products were observed, rather a Lewis acid
15
catalyzed aza-Cope rearrangement occurred (Table S1).
Alternative nitrogen-based coordinating groups were investi-
gated, and while no reaction was observed with secondary
amines or carbamates, primary amines were identified as
effective directing groups. Excitingly, our hypothesis that
coordination of a Lewis basic group would promote an anti-
Markovnikov selective reaction proved correct; high selectiv-
ity was observed for the anti-Markovnikov (1,4-diamine) over
the Markovnikov (1,3-diamine) and no oxidative amination
product was detected (eq. 1). Further, the Lewis basic group
significantly increases the reactivity of the alkene, as 1-octene
was unreactive under the reaction conditions.
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Then, we further investigated reaction scope by subjecting
a variety of substituted-homoallylamines to reaction condi-
tions (Table 2). Substitution at the 2-position is well tolerat-
ed, as 1,1-diphenyl-2-methylbut-3-en-1-amine (3a) affords 4a
in excellent isolated yield (73%) and high regioselectivity
(>20:1), demonstrating that the metallacyclic intermediate is
tolerant of additional substitution. Reducing the size of the 1-
substituents significantly reduces the regioselectivity; 3b,
where one of the aryl rings is replaced with a methyl, affords
4b in 77% isolated yield as a 16:1 mixture of regioisomers.
Further, hydroamination of 1,1-dibutyl-homoallylamine (3c)
affords 4c in 74% isolated yield as a 5:1 mixture of regioiso-
mers. The loss in regioselectivity observed with sterically less
encumbering substituents suggests that 1-substituted-but-3-
en-1-amines may be significantly less regioselective. Indeed,
when 1-mesitylbut-3-en-1-amine (3d) is subjected to the hy-
droamination reaction conditions 4d is observed with 1.4:1 a-
M:M selectivity 42% yield.
NH2
5.0 mol %
[(DPEphos)Rh(COD)]BF4
O
N
Ph
NH2
H
O
Ph
+
1
+
NH2
Ph
N
(1)
Ph
MeCN (4.3 M), 100 °C, 24h
H
Ph
O
Ph
HN
5.0 equiv
66% yield
>20:1 a-M:M
2a
anti-Markovnikov (a-M) Markonvnikov (M)
Next, we sought to optimize the reaction conditions (Tables
S2-S4). Changing the solvent from acetonitrile (MeCN) to
dimethoxyethane (DME) improved the in situ yield from
66% to 92% (Table S2). The reaction was very sensitive to the
temperature; after 48 hours at 40 °C a 7% in situ yield was
observed while after 12 hours at 100 °C the reaction affords
92% in situ yield of 2a (Table S3). Variation of the bidentate
phosphine ligand significantly affected the reaction: DPEph-
os afforded the product in nearly quantitative yield (100% in
situ yield) and excellent selectivity for the anti-Markovnikov
product while other phosphine ligands afforded the desired
product in significantly reduced yields (Table S4). The opti-
mized reaction conditions are: 1.0 equiv. 1, 5.0 equiv. mor-
pholine, 5 mol % [Rh(COD)2]BF4, 5 mol % DPEphos in DME
(1.5 M) at 100 °C. All selectivities for 2a were >20:1 during the
course of optimization when DPEPhos was employed as a
ligand.
The observed trend of decreasing the steric bulk at the 1-
position suggested that the difference in strain associated
with the five and six membered metallacyclic intermediates
was minimized. We hypothesized that variation of the lig-
ands on the catalyst could restore the anti-Markovnikov se-
lectivity. Indeed, changing the the bidentate phosphine lig-
and (Table S5) and counter anion (Table S6) significantly
improved both the reactivity and regioselectivity: employing
5
mol
%
[1,3-bis(diphenylphosphino)propane)Rh]OTs
The scope of amine nucleophiles in the Rh-catalyzed anti-
Markovnikov selective hydroamination reaction with 1 was
Table 1. Scope of amines.a,b
([(dppp)Rh]OTs) as the catalyst afforded 4d in 68% in situ
yield and 14:1 a-M:M ratio as determined by GC analysis. In-
terestingly, the relative ratio of products formed correlates
Table 2. Substituents effect on regioselectivity. a.b
H2N
H2N
5 mol % [Rh(COD)2]BF4
5 mol % DPEphos
Ph
R1
5 mol % [Rh(COD)2]BF4
5 mol % DPEphos
R1 R2
N
Ph
+
R2
R3
R1 R2
N
H2N
Ph
H
R1
N
H2N
R1
H
R1
N
1
H2N
Ph
H2N
R1
+
+
3a-d
+
R2
H
R2
H
R1 R2
Ph
DME, 100 °C, 48 h
DME, 52-100 °C, 12-48 h
Ph
R1 R2
R2
N
H
R2
N
H
R3
R3
2a-h
2a-h
anti-Markovnikov
(a-M)
Markovnikov
(M)
anti-Markovnikov
(a-M)
Markovnikov
(M)
3.0-10.0 equiv
5.0-7.0 equiv
Et
H2N
Ph
H
O
H2N
n-Bu
H
O
H2N
Ph
H
O
H2N
Ph
H
H2N
H
N
N
N
N
N
N
Ph
Ph
n-Bu
4cc
74%, 5:1 a-M:M
Ph
Ph
Ph
2b
2cc
74%, >20:1 a-M:M
H2N
Ph
H2N
H
O
H2N
H
H
O
2a
4a
N
N
87%, >20:1 a-M:M
90%, >20:1 a-M:M
73%, >20:1 a-M:M
H2N
Ph
H
H2N
Ph
H
H
TMS
4b
77%, 16:1 a-M:M
4d
42%,c,d 1.4:1 a-M:M
N
N
N
Ph
Ph
Ph
2d
2e
2f
80%, >20:1 a-M:M
a
Amine (5.0-7.0 equiv), 3a-d (1.0 equiv), [Rh(COD)2]BF4 (5.0
mol %), DPEphos (5.0 mol %), DME (1.0 M), 100 °C, 48 h.
Ratio of 1,4-diamine to 1,3-diamine after hydroamination was
67%, >20:1 a-M:M
82%, >20:1 a-M:M
b
a
Amine (3.0-10.0 equiv), 1 (1.0 equiv), [Rh(COD)2]BF4 (5.0
mol %), DPEphos (5.0 mol %), DME (1.5 M), 52-100 °C, 12-48
c
determined by gas chromatography.
The reaction was
b
stirred at 120 °C for 72 h. d In situ yield determined by gas
h. Ratio of 1,4-diamine to 1,3-diamine after hydroamination
was determined by gas chromatography, c The reaction was
run for 72 h.
chromatography and comparison to an internal standard.
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Table 3. Scope of homoallylic amines. a,b
1. 2.5 mol % [(COD)RhCl]2
5 mol % dppp
O
1
2
3
4
5
6
7
8
H2N
2.5 mol % [(COD)RhCl]2
5 mol % dppp
Boc
H2N
5 mol % AgBF4
NH H
O
(2)
+
N
H
R1
R1
N
R1
H2N
R2
DME, 80 °C, 48 h
then Boc2O
5 mol % AgOTs
H2N
R1
H
R1
N
N
5
+
3d-m
R2
+
6
H
DME, 60-100 °C, 48 h
R1
R2
5.0 equiv
83%, > 20:1 aM:M
N
H
4d-o
anti-Markovnikov
(a-M)
Markovnikov
(M)
The proposed mechanism for the transformation is shown
in Scheme 2; Catalytic Cycle A forms the anti-Markovnikov
(1,4-diamine) product while Catalytic Cycle B affords the
Markovnikov (1,3-diamine) product.12 First, coordination of
both the amine and alkene to the catalyst generates interme-
diate I. Next, the regioselectivity determining step occurs:
nucleophilic attack by the secondary amine onto the alkene
affords metallacyclic intermediates II or II´. Under the opti-
mized conditions, selectivity is determined by the formation
of the favored metallayclic intermediate II. Direct protolytic
cleavage of the Rh–C bond or proton transfer/reductive elim-
ination generates the C–H bond, and coordination of the
amine to the catalyst generates III and III´. Finally, ligand
exchange of the product for the olefinic substrate continues
the catalytic cycle.
1.0-7.0 equiv
H2N
H
O
NH2 H
O
O
O
H2N
Ph
H
O
N
N
N
p-MeO-Ph
Mes
4d
4e
4f
79%, 18:1 a-M:M
9
66%, 12:1 a-M:M
90%, 15:1 a-M:M
10
11
12
13
14
15
16
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H2N
p-tol
H
H2N
p-Br-Ph
H
O
O
H2N
p-CF3-Ph
H
O
N
N
N
4g
4h
90%, 18:1 a-M:M
4i
89%, 16:1 a-M:M
88%, 18:1 a-M:M
H2N
H
H2N
Cy
4l
54%, 9:1 a-M:M
H
O
H2N
H
Me
N
N
N
6
Ph
4j
73%, 10:1 a-M:M
4k
74%, >20:1 a-M:M
H2N
H
O
H2N
p-tol
H
H2N
p-tol
H
N
N
N
8
4m
4n
78%, >20:1 a-M:M
4o
74%, 18:1 a-M:M
Scheme 2. Proposed Catalytic Cycle
81%, 12:1 a-M:M
NH2 H Me
N
NH2 H Me
N
Ph
Mes
Ph
Ph
4p
4q
78%, 16:1 a-M:M
83%, 18:1 a-M:M
a Amine (1.0-7.0 equiv), 3d-m (1.0 equiv), [Rh(COD)2]Cl (2.5 mol
%), DPPP (5.0 mol %), AgOTs (5.0 mol %), DME (1.0-1.5 M), 52-
b
100 °C, 12-48 h. Ratio of 1,4-diamine to 1,3-diamine after hy-
droamination was determined by gas chromatography.
with the bite angle and flexibility of the phosphine ligand
(Table S4). The re-optimized reaction conditions are as fol-
lows: 2.5 mol % [(COD)RhCl]2, 5 mol % AgOTs, 5 mol %
dppp in DME (1.5 M) for two days. Importantly, while a large
excess of amine is often employed to maximize the yield of
the hydroamination reaction, changing from 7.0 to 2.0
equiv. of morpholine leads to moderately reduced yields of
4d, 92 and 67%, respectively (Table S7).
Deuterium incorporation experiments were conducted as a
mechanistic probe. Subjection of 7 to the hydroamination
reaction with N-deutero-N-methyl benzylamine allows for
insight into the selectivity of the C–H bond formation. As
with the hydroamination of N-allyl imines,10 no H/D ex-
change is observed into the nucleophile nor the C–H bond
adjacent to the amine directing group. Interestingly, as seen
in eq. 3, both 1,2- and 1,1-addition of the N–D bond to the
alkene is observed, in a 74:26 ratio. This indicates that once
the metallacyclic intermediate II is formed, β-hydride elimi-
nation/reinsertion occurs to exchange the exocyclic C–H
bond.17
Next, the scope of 1-substituted-homoallylic amines was
explored, as seen in Table 3. Reducing the size of the 1-aryl
substituent, from mesityl to phenyl, slightly improved the
yield and regioselectivity, to afford 4e in 90% isolated yield
and 15:1 selectivity. Further, aryl rings bearing an electron
donating (OMe and Me), aryl bromide, or electron withdraw-
ing groups (CF3), were well tolerated, affording 4f, 4g, 4h,
and 4i in 79, 88, 90, and 89% yield all with ≥16:1 selectivity.
Aliphatic substitution at the 1-position was varied; n-heptyl
(3j), phenethyl (3k), and cyclohexyl (3l) groups had little
effect on the regioselectivity of the reaction, affording the
diamines in 73, 74, and 54% isolated yield with selectivities
≥9:1. Olefins distal from the amino group were unaffected
under the reaction conditions, as 4m is afforded in 81% iso-
lated yield and 12:1 regioselectivity.16 Finally, reactions with 1-
substituted-homoallylamines are not limited to morpholine
as the nucleophile, as piperidine, pyrrolidine, N-methyl-N-(2-
phenyl)ethylamine, and benzylmethylamine undergoes the
hydroamination reaction to afford 4n-4q in very good yields
74-83%.
2.5 mol % [(COD)RhCl]2
74% D
5 mol % dppp
Ph
NH2 D
D2N
5 mol % AgOTs
N
Ph
(3)
+
N
D
Ph
Ph
DME, 80 °C, 48 h
D
26% D
7
5.0 equiv
8
61%, 19:1 aM:M
To further support our proposed catalytic cycle attempts
were made to isolate a amino–olefin bound complex.
[DPEphosRh(1)]BF4 (9) was synthesized by heating 1,
[(COD)RhCl]2, AgBF4, and DPEphos in THF. X-ray quality
crystals were grown by crystallization from hot THF (Figure
1). The rhodium is in a distorted square planer geometry,
with the two phosphorous and the amine ligands coplanar.
The two Rh–C bonds are of similar length, Rh–C4 is
2.2369(14) Å and Rh–C3 is 2.2662(14) Å. The C3–C4 bond is
Excitingly, when homoallylamine (5), which lacks any sub-
stitution, is subjected to slightly modified reaction condi-
tions, B6 is obtained in 83% yield and a >20:1 regioselectivity
favoring the desired anti-Markovnikov product (eq. 2).
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(3) For examples of late transition metal catalyzed Markoni-
1.375(2) Å, consistent with a Rh–olefin complex rather than a
metallacyclopropane.
1
2
3
4
5
6
7
8
kov selective hydroamination see: (b) Kawatsura, M.; Hartwig, J.
F. J. Am. Chem. Soc. 2000, 122, 9546; (a) Bender, C. F.; Widen-
hoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070; (c) Liu, Z.; Hart-
wig, J. F. J. Am. Chem. Soc. 2008, 130, 1570; (d) Cochran, B. M.;
Michael, F. E. J. Am. Chem. Soc. 2008, 130, 2786; (e) Hesp, K. D.;
Stradiotto, M. Org. Lett. 2009, 11, 1449; (f) Ohmiya, H.; Moriya,
T.; Sawamura, M. Org. Lett. 2009, 11, 2145; (g) Shen, X.; Buch-
wald, S. L. Angew. Chem. Int. Ed. Engl. 2010, 49, 564.
(4) (a) Baker, R.; Halliday, D. E. Tetrahedron Lett. 1972, 2773;
(b) Goldfogel, M. J.; Roberts, C. C.; Meek, S. J. J. Am. Chem. Soc.
2014, 136, 6227; (c) Banerjee, D.; Junge, K.; Beller, M. Org. Chem.
Front. 2014, 1, 368.
Ph
Ph
H
N
2 Ph
Ph
P
P2
N1
O
Rh
P
–
BF4
Rh1
Ph Ph
C3
P1
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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C4
(5) (a) Beller, M.; Trauthwein, H.; Eichberger, M.; Breindl, C.;
Herwig, J.; Muller, 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) Takemiya, A.; Hartwig, J. F. J. Am.
Chem. Soc. 2006, 128, 6042; (d) Sevov, C. S.; Zhou, J.; Hartwig, J.
F. J. Am. Chem. Soc. 2012, 134, 11960; (e) Sevov, C. S.; Zhou, J. S.;
Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 3200.
(6) (a) Tafazolian, H.; Samblanet, D. C.; Schmidt, J. a. R.
Organometallics 2015, 34, 1809; (b) Chen, Q.-A.; Chen, Z.; Gong, V.
M. J. Am. Chem. Soc. 2015, 137, 8392.
(7) Timmerman, J. C.; Robertson, B. D.; Widenhoefer, R. A.
Angew. Chem. Int. Ed. 2015, 54, 2251.
(8) For an example of radical-catalyzed anti-Markovnikov hy-
droamination see: Guin, J.; Mück-Lichtenfeld, C.; Grimme, S.;
Struder, A. J. Am. Chem. Soc. 2007, 129, 4498.
(9) (a) Rucker, R. P.; Whittaker, A. M.; Dang, H.; Lalic, G. J. Am.
Chem. Soc. 2012, 134, 6571; (b) Strom, A. E.; Hartwig, J. F. J. Org.
Chem. 2013, 78, 8909; (c) Zhu, S.; Niljianskul, N.; Buchwald, S. L. J.
Am. Chem. Soc. 2013, 135, 15746; (d) Bronner, S. M.; Grubbs, R. H.
Chem. Sci. 2014, 5, 101 (e) Nakamura, Y.; Ohta, T.; Oe, Y. Chem.
Commun. 2015, 51, 7459.
(10) (a) Ickes, A. R.; Ensign, S. C.; Gupta, A. K.; Hull, K. L. J. Am.
Chem. Soc. 2014, 136 , 11256; (b) Gupta, A.; Hull, K. Synlett 2015, 1779–
1784.
(11) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307; for recent examples of directed olefin insertion see: (b)
Delcamp, J. H.; Brucks, A. P.; White, M. C. J. Am. Chem. Soc. 2008,
130, 11270; (c) Grünanger, C. U.; Breit, B. Angew. Chem. Int. Ed. 2008,
47, 7346; (d) Weiner, B.; Baeza, A.; Jerphagnon, T.; Feringa, B. L. J.
Am. Chem. Soc. 2009, 131, 9473; (e) Choi, P. J.; Sperry, J.; Brimble, M.
A. J. Org. Chem. 2010, 75, 7388.
Figure 1. X-Ray crystal structure of 9•THF. Hydrogens at-
oms, BF4 , and THF are omitted for clarity. Ellipsoids are
drawn at the 50% probability level.
–
In conclusion, we have demonstrated the ability of
homoallylic primary amines to reverse the inherent regiose-
lectivity of the Rh-catalyzed hydroamination reaction and
afford selectively the anti-Markovnikov product. The product
distribution is primarily dependent upon the substitution
pattern on the homoallylic amine and the ligand employed.
Current efforts on the development of directed hydroamina-
tion reactions are focusing on mechanism determination and
expansion the scope of both the amine nucleophile and co-
ordinating groups which promote the anti-Markovnikov hy-
droamination reaction.
ASSOCIATED CONTENT
Experimental procedures and characterization data is availa-
ble free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
kamihull@illinois.edu
(12) (a) Julian, L. D.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
13813; (b) Hesp, K. D.; Tobisch, S.; Stradiotto, M. J. Am. Chem.
Soc. 2010, 132, 413; (c) Liu, Z.; Yamamichi, H. Y.; Madrahimov, S.
T.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2772-27812.
(13) (a) DeHayes, L. J.; Busch, D. H. Inorg. Chem. 1973, 12 , 1505;
(b) Boutadla, Y.; Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Jones, R. C.;
Singh, K. Dalt. Trans. 2010, 39, 10447; (c) Desai, L. V.; Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542.
(14) Beesley, R. M.; Ingold, C. K.; F., T. J. J. Chem. Soc., Trans. 1
1915, 107, 1080.
(15) Hiersemann, M.; Nubbemeyer, U. Aza-Claisen Rearrangement.
Wiley-VCH: Weinheim, 2007.
Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
The authors would like to thank the University of Illinois,
Urbana-Champaign for their generous support.
REFERENCES
(16) Competition experiments with proximal alkenes, homoal-
lylic vs. allylic or bishomoallylic, gave mixture of hydroamination
products.17
(1) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem.
2014, 57 , 10257.
2. For recent review articles on metal-catalyzed hydroamina-
tion see: (a) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.;
Tada, M. Chem. Rev. 2008, 108, 3795. (b) Reznichenko, A. L.;
Hultzsch, K. C. Top. Organomet. Chem. 2013, 43, 51. (c) Nishina, N.;
Yamamoto, Y. Top. Organomet. Chem. 2013, 43, 115. (d) Huang, L.;
Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Chem. Rev. 2015, 115,
2596.
(17) See Supporting Information for more details.
(18) (a) Schreiner, B.; Wagner-Schuh,B.; Beck, W. Z.
Naturforsch. 2010, 65b, 679; (b) Zhao, P.; Incarvito, C. D.; Hart-
wig, J. F. J. Am. Chem. Soc. 2006, 128, 9642; (c) Tau, K. D.; Meek,
D. W.; Sorrell, T.; Ibers, J. A. J. Inorg. Chem. 1978, 17, 3454.
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H2N
R1
NH2
R2
H
Catalytic [Rh]+
N
+
R1
N
H
1
R2
R3
R3
2
3
54-90% isolated yield
up to 10:1 to >20:1 anti-Markovnikov Selectivity
4
5
6
7
Ph
P
Rh
P
Ph
O
H
N
2 Ph
Ph
–
BF4
Ph Ph
8
Metallacyclic Intermediate
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