Catalytic asymmetric addition of an amine N–H bond across internal alkenes

Article abstract of DOI:10.1038/s41586-020-2919-z

Hydroamination of alkenes, the addition of the N–H bond of an amine across an alkene, is a fundamental, yet challenging, organic transformation that creates an alkylamine from two abundant chemical feedstocks, alkenes and amines, with full atom economy^1–3. The reaction is particularly important because amines, especially chiral amines, are prevalent substructures in a wide range of natural products and drugs. Although extensive efforts have been dedicated to developing catalysts for hydroamination, the vast majority of alkenes that undergo intermolecular hydroamination have been limited to conjugated, strained, or terminal alkenes^2–4; only a few examples occur by the direct addition of the N–H bond of amines across unactivated internal alkenes^5–7, including photocatalytic hydroamination^8,9, and no asymmetric intermolecular additions to such alkenes are known. In fact, current examples of direct, enantioselective intermolecular hydroamination of any type of unactivated alkene lacking a directing group occur with only moderate enantioselectivity^10–13. Here we report a cationic iridium system that catalyses intermolecular hydroamination of a range of unactivated, internal alkenes, including those in both acyclic and cyclic alkenes, to afford chiral amines with high enantioselectivity. The catalyst contains a phosphine ligand bearing trimethylsilyl-substituted aryl groups and a triflimide counteranion, and the reaction design includes 2-amino-6-methylpyridine as the amine to enhance the rates of multiple steps within the catalytic cycle while serving as an ammonia surrogate. These design principles point the way to the addition of N–H bonds of other reagents, as well as O–H and C–H bonds, across unactivated internal alkenes to streamline the synthesis of functional molecules from basic feedstocks.

Full text of DOI:10.1038/s41586-020-2919-z

Article
Catalytic asymmetric addition of an amine
N–H bond across internal alkenes
Yumeng Xi1,2, Senjie Ma1,2 & John F. Hartwig1,2
ꢀ✉
https://doi.org/10.1038/s41586-020-2919-z
Received: 26 November 2019
Accepted: 27 October 2020
Published online: xx xx xxxx
Check for updates
Hydroamination of alkenes, the addition of the N–H bond of an amine across an
alkene, is a fundamental, yet challenging, organic transformation that creates an
alkylamine from two abundant chemical feedstocks, alkenes and amines, with full
atom economy1–3. The reaction is particularly important because amines, especially
chiral amines, are prevalent substructures in a wide range of natural products and
drugs. Although extensive eforts have been dedicated to developing catalysts for
hydroamination, the vast majority of alkenes that undergo intermolecular
hydroamination have been limited to conjugated, strained, or terminal alkenes2–4
;
only a few examples occur by the direct addition of the N–H bond of amines across
unactivated internal alkenes5–7, including photocatalytic hydroamination8,9, and no
asymmetric intermolecular additions to such alkenes are known. In fact, current
examples of direct, enantioselective intermolecular hydroamination of any type of
unactivated alkene lacking a directing group occur with only moderate
enantioselectivity10–13. Here we report a cationic iridium system that catalyses
intermolecular hydroamination of a range of unactivated, internal alkenes,
including those in both acyclic and cyclic alkenes, to aford chiral amines with
high enantioselectivity. The catalyst contains a phosphine ligand bearing
trimethylsilyl-substituted aryl groups and a trifimide counteranion, and the reaction
design includes 2-amino-6-methylpyridine as the amine to enhance the rates of
multiple steps within the catalytic cycle while serving as an ammonia surrogate.
These design principles point the way to the addition of N–H bonds of other
reagents, as well as O–H and C–H bonds, across unactivated internal alkenes to
streamline the synthesis of functional molecules from basic feedstocks.
Chiral amines are essential structural motifs in numerous active phar-
maceutical ingredients and in many agrochemicals and materials. They lytic hydroaminations of unactivated alkenes that bear more than one
also serve as chiral catalysts, resolving reagents and chiral auxiliaries14
substituent (Fig. 1a). Both experiments and theoretical studies have
There are considerable challenges facing the development of cata-
.
Thus, efficient methods to prepare chiral amines have been long sought. shown that the thermodynamic driving force is weak and the kinetic
Traditional approaches15 include chemical16,17 and enzymatic18 reduc- barrier to combining two nucleophiles is high1,31. Moreover, catalysts
tive amination, hydrogenation19, nucleophilic addition to imines20 and for hydroamination often catalyse undesirable, competing alkene
nucleophilic substitution21,22. However, these methods require starting isomerization, and isomerization is typically faster than addition of
materials containing reactive functionality that is often derived from the N–H bond during many metal-catalysed hydroaminations (Fig. 1b).
feedstock alkenes. Thus, hydroamination of alkenes is the most direct Such relative rates lead to a mixture of isomeric products32,33. Many cata-
method to construct chiral amines from a functional group that is present lysts for alkene hydroamination also promote formation of oxidative
in basic feedstocks and is typically unprotected. Asymmetric additions amination products by β-hydrogen elimination of β-aminoalkylmetal
to conjugated alkenes, such as dienes23–26 and vinylarenes27,28, have been intermediates34,35. These isomerization and oxidative side reactions
reported, but the scope of the direct addition of N–H bonds to more must be suppressed to achieve hydroamination of unactivated internal
common and less reactive unconjugated alkenes is severely limited, and alkenes. Finally, because hydroamination is usually almost ergoneutral,
the enantioselectivities of asymmetric processes are far lower than those isomerization and racemization of the products during the reaction
that would enable applications for the synthesis of chiral amines. Formal can erode regioselectivity and enantioselectivity36
.
hydroaminations provide an alternative approach to this problem, but
To address these challenges, we modified a neutral iridium complex
the use of silanes with electrophilic aminating reagents29 and even metal containing a bisphosphine ligand, which was previously shown to cata-
reductants30, instead of amines, undermines the atom economy of the lyse the formation of hydroamination and oxidative amination products
hydroamination reaction. Direct N–H additions of unactivated internal from the reaction of terminal alkenes with amides and indoles34,37–40
.
alkenes that occur with high enantioselectivity are unknown.
We have previously shown that these aminations occur by a mechanism
1
2
✉
Department of Chemistry, University of California, Berkeley, CA, USA. Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. e-mail: jhartwig@berkeley.edu
Nature | www.nature.com | 1

Article
a
Challenges
NH2
R1
NH2
H-NH2
R2
• Weak thermodynamic driving force
• Alkene isomerization and chain walking
• Competing oxidative amination
or
or
R1
R2
• Low reactivity of internal alkenes
cat.
Me
NHR
Me
b
Selectivity?
Me
Me
Me
Me
(Reacts much faster)
cat.
cat., RNH2
or
NHR
Me
Me
Me
Mixtures
Me
How to suppress
isomerization?
Me
Me
NHR
Me
Mixtures
Me
c
Removable
SiMe3
Enantioselective
regioselective
O
SiMe3
PyR removal
NH2
Ir+
+
2
R
R
N
NH
R′
O
O
P
R
N
NH2
–
R
R′
Ir
NTf2
R′
P
Ammonia
surrogate
R
Primary amines
SiMe3
O
Design elements: cationic iridium, bidendate amine with adjacent substituent
2
SiMe3
R′
Dissociates
readily
R
R′
Migratory
insertion
R′
R
R
H
LIr+
H
H
C–H RE
R
H
N
P
P
P
Ir
Ir
Ir
N–H OA
R
N
NH2
– PyRNH2
NH
*
*
*
R
N
NH
P
P
NH
P
NH NH2
N
R′
N
N
R
R
e–-deꢀcient Ir
R
R
e–-deꢀcient Ir
accelerates
alkene insertion
Rigid iridacyle
prevents
β-H elimination
accelerates
Weakens
coordination
Extra N-coordination
facilitates N–H OA
reductive elimination
III
II
I
Fig. 1 | Catalytic asymmetric hydroamination of unactivated internal
alkenes. a, Long-standing challenges and previous strategies for catalytic
hydroamination of unactivated internal alkenes. b, Alkene isomerization that
leads to a mixture of constitutional isomeric products. c, Design of a cationic
iridium catalyst and an ammonia surrogate based on 2-aminopyridine to
achieve asymmetric hydroamination of internal alkenes. OA, oxidative
addition. RE, reductive elimination.
comprising oxidative addition of N–H bonds, migratory insertion of a series of heteroaromatic amines and one control arylamine that
alkenes and reductive elimination of C–H bonds34. We envisioned that possess varying structural properties. The hydroamination products
switching the iridium catalyst from neutral to cationic would lead to from these reactions consisted of three isomers (denoted A, B and
the formation of cationic iridium intermediates that would undergo C) that probably resulted from competing alkene isomerization and
migratory insertion of the alkene more rapidly41, a step that has been hydroamination. A larger amount of A reflects a faster rate for direct
shown to be rate-limiting in the reaction of terminal alkenes with the addition of the amine to the starting alkene than alkene isomerization
neutral catalyst34 (Fig. 1c). If binding and insertion of the alkene were before addition.
sufficiently enhanced, then the reaction scope might include internal
As shown in Fig. 2a, hydroamination of cis-4-octene in the presence of
alkenes. In addition, we envisioned that coordinating groups adja- [Ir(coe)2Cl]2, (S)-DTBM-SEGPHOS ((S)-(+)-5,5′-bis[di(3,5-di-tert-butyl-
cent to the amine (for example, 2-aminopyridine derivatives) could 4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole) and NaBARF
facilitate and make more thermodynamically favourable the initial (sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) occurred
N–H oxidative addition, and such enhancements of this step could be only when 6-substituted 2-aminopyridine derivatives were used as
important because the rate of oxidative addition of electron-deficient the amine source. The hydroamination of 2-amino-6-methylpyridine
metal complexes is generally slower than that of electron-rich ones42
.
formed amines A, B and C in a combined 73% yield, with A constitut-
If properly placed, the coordinating groups of the amine could also ing 28% of the amine products (defined as A/(A + B + C)). The reaction
form a rigid six-membered iridacycle upon insertion of the alkene; this of 2-amino-6-trifluoromethylpyridine afforded only 5% of isomer A.
geometry could suppress β-hydrogen elimination to form enamines. Other amines tested, including the parent 2-aminopyridine, did not
Such a combination of 2-aminopyridine and a cationic iridium cata- undergo this hydroamination. These results suggest that the substitu-
lyst was evaluated12 for the hydroamination of terminal vinylarenes, ent in the 6-position of the pyridine ring is essential to promote the
but only briefly for the hydroamination of unactivated α-alkenes. Low hydroamination.
enantioselectivities (≤11% enantiomeric excess, e.e.) were observed,
To suppress competing alkene isomerization and improve the
and the reactions of unstrained internal alkenes were not examined. reaction yield, we examined catalysts containing a series of bis-
We reasoned that a substituent near the binding group of the amine phosphine ligands and counteranions for hydroamination with
could modulate the strength of the coordination of the pyridine, lead- 2-amino-6-methylpyridine as the amine. Studies of the electronic
ing to potential enhancement of the activity of the iridium catalyst, and steric properties of ligands indicated that the ligands that are
due to weakened coordination (Fig. 1c). Finally, the pyridyl group of less electron-rich (Fig. 2b, entry 2) and more sterically encumbered
the product could be cleaved by known methods to reveal the cor- (Fig. 2b, entries 3–5) than (S)-DTBM-SEGPHOS form catalysts that
responding primary amine43
.
are more reactive and selective for direct addition to form amine
Figure 2 summarizes our studies on the development of a cati- 1. The observed higher reactivity of catalysts generated from more
onic iridium catalyst and an ammonia surrogate for the asymmetric electron-poor ligands probably results from a greater rate of migratory
hydroamination of unactivated internal alkenes. These experiments insertion of the alkene (see below) into the Ir–N bond of complexes
revealed the effect of the reaction components of the system on the containing L2–L5 lacking the methoxy group than into the Ir–N bond
reaction yield, level of alkene isomerization and enantioselectivity. of the complex ligated by (S)-DTBM-SEGPHOS possessing the p-OMe
To identify a suitable ammonia surrogate for this reaction, we surveyed group44. The higher selectivity from the more hindered ligands could
2 | Nature | www.nature.com

2.5 mol% [Ir(coe)2Cl]2
6 mol%
(S)-DTBM-SEGPHOS
a
NHAr
NHAr
NHAr
Me
(10 equiv.)
+
+
Me
Me
Me
ArNH2
+
Me
Me
Me
Me
6 mol% NaBARF, 120 °C
3-amine (B)
4-amine (A)
2-amine (C)
Me
N
F3C
N
NH2
Me
N
NH2
N
NH2
N
NH2
Me
NH2
NH2
73%a (28%)c
51%a (5%)c
0%a,b
0%a,b
0%a,b
0%a,b
NHPyMe
Ligands used in this study
b
tBu OMe
Me
R
NHPyMe
Me
Me
4-amine (1)
O
O
tBu
R
R
5 mol% L*Ir+X–
Me
Me
2
2
2
2
+
3-amine (1′)
O
O
O
O
P
P
P
P
100 °C or
120 °C
NHPyMe
Me
N
NH2
(10 equiv.)
Me
Me
Me
tBu
tBu OMe
O
O
2-amine (1″)
PyMe
R
Yield
(1+1′+1″)
rac-DTB-SEGPHOS
(R = tBu) (L2)
rac-TMS-SEGPHOS
(R = SiMe3) (L3)
4-Selectivityd
Entry
L*
X
(S)-DTBM-SEGPHOS
(L1)
1e
2e
3e
4e
5e
16%
42%
34%
26%
22%
48%
50%
83%
83%
83%
28%
83%
67%
63%
n/a
BARF
BARF
BARF
BARF
BARF
BARF
OTf
(S)-DTBM-SEGPHOS (L1)
rac-DTB-SEGPHOS (L2)
rac-TMS-SEGPHOS (L3)
(R)-TMS-SYNPHOS (L4)
(R)-TMS-MeOBIPHEP (L5)
(S)-DTBM-SEGPHOS (L1)
(S)-DTBM-SEGPHOS (L1)
(S)-DTBM-SEGPHOS (L1)
(S)-DTBM-SEGPHOS (L1)
(S)-DTBM-SEGPHOS (L1)
(R)-TMS-SYNPHOS (L4)
SiMe3
SiMe3
O
SiMe3
SiMe3
SiMe3
SiMe3
2
2
2
2
O
O
P
P
MeO
MeO
P
P
6e
7f
8f
9f
73%
9%
O
9%
BF4
SiMe3
SiMe3
60% (–95% e.e.)
0%
NTf2
Cl
(R)-TMS-SYNPHOS (L4)
(R)-TMS-MeOBIPHEP
(L5)
10
11f,g
(new ligand)
89%
NTf2
78% (97% e.e.)
Fig. 2 | Development of asymmetric hydroamination of unactivated
internal alkenes with 2-amino-6-methylpyridine as an ammonia
surrogate. a, Identification of suitable ammonia surrogates to enable
hydroamination of unactivated internal alkenes. b, Identification of reaction
conditions to achieve asymmetric hydroamination and to suppress alkene
isomerization. aCombined yield. bNo reaction. cDefined as A/(A + B + C).
d4-Selectivity defined as 1/(1 + 1′ + 1″). eConditions: 2.5 mol% [Ir(coe)2Cl]2,
6 mol% ligand, 6 mol% NaBARF, toluene. fConditions: 5 mol% [L*Ir(COD)]X,
toluene. gIn 2-MeTHF.
result from a greater sensitivity of the rate of insertion of the alkene unsymmetrical internal alkenes bearing polar functional groups at the
into the metal–amido bond (Fig. 1c, structure II) to steric effects than homoallylic position occurred with synthetically useful regioselectiv-
the rate of insertion into the metal–hydride bond, which probably ity (2:1 to 10:1). These functional groups include phthalimidyl groups
leads to alkene isomerization45,46. Studies with various counterions (7, 8), sulfonamido groups (9), silyloxy groups (10), bis(ethoxycarbonyl)
revealed that reactions with triflimide as the counterion of the cata- methyl groups (11) and (hetero)aryloxy groups (12–14). These groups
lyst occurred with the highest selectivity at high conversion (Fig. 2b, presumably influence the regioselectivity by inductive effects that
entries 6–9). The origin of the effects of the counterions is difficult to are similar to those observed for other classes of functionalization of
ascertain, but an effect is clear. Control experiments showed that the unsymmetrical internal alkenes47–49
reaction catalysed by a neutral iridium complex under otherwise iden- The reactivity of the system for Z-alkenes enabled the hydroamina-
.
tical conditions (Fig. 2b, entry 10) resulted in the exclusive formation tion of cyclic alkenes, and these reactions also occurred with high enan-
of oxidative amination products. By combining the chiral ligand that tioselectivity. The combination of [Ir(coe)2Cl]2, (S)-DTBM-SEGPHOS
led to the highest selectivity with the triflimide anion in the form of and NaBARF was used as the catalyst because it was more reactive than
[((R)-TMS-SYNPHOS)Ir(COD)]NTf2, the model hydroamination reaction [((R)-TMS-SYNPHOS)Ir(COD)]NTf2 for the hydroamination of cyclic
formed the 4-aminooctane (1) in high yield; this reaction also occurred alkenes. The cyclic hydrocarbons cyclopentene, cyclohexene, cyclo-
with remarkably high enantioselectivity (Fig. 2b, entry 11). Thus, the heptene and cyclooctene all underwent hydroamination in high yields
substituent on the amine, the new phosphine ligand and the use of a (15–18). The hydroamination of a series of substituted cyclopentenes
triflimide counterion all led to the high activity, chemoselectivity and formed chiral amine products with high enantioselectivity (19–23,
enantioselectivity of the reaction.
90–92% e.e.). The reaction to form the 1,3-substituted cyclopentane 23
With this catalyst and reagent, we examined the scope of alkenes that from the 4-methoxycarbonyl-substituted cyclopentene occurred with
underwent hydroamination (Fig. 3). Both symmetrical internal alkenes high diastereoselectivity for the transproduct. In addition, cyclohex-
and unsymmetrical internal alkenes underwent hydroamination with ene derivatives with 3,3-substituents underwent hydroamination to
2-amino-6-methylpyridine. The reactions all proceeded in greater afford two products with regioselectivity of approximately 1:3 (24/24′,
than 90% e.e. Hydroamination of symmetrical alkenes afforded prod- 25/25′). Although the major isomer is achiral, the chiral minor isomer
ucts containing linear alkyl groups (1), aryl-substituted alkyl groups was formed with good to high enantioselectivity. We observed in some
(2), branched alkyl groups (3), silyloxy groups (4), alkoxy groups (5) cases that the hydroaminations of substituted cycloalkenes with rings
and alkoxycarbonyl groups (6) in good to high yields. Reactions of larger than that of cyclopentene occurred to high conversion, but were
Nature | www.nature.com | 3

Article
= PyMe
5 mol%
R
[(R)-TMS-SYNPHOSIr(COD)]NTf2
HN
N
Me
+
Me
N
NH2
R′
R
120 °C, 2-MeTHF
R′
NHPyMe
NHPyMe
NHPyMe
NHPyMe
a
Me
Me
Me
TBSO
Ph
Me
Me
OTBS
Ph
1a
52%, 97% e.e.
3
2a
4
Me
76%, 98% e.e.
77%, 97% e.e.
82%, 92% e.e.
O
NHPyMe
NHPyMe
NHPyMe
Me Me
O
MeO
N
MeO
OMe
OTBS
OMe
Me Me
O
7
O
5b
55%, 97% e.e.
6
63%, 95% e.e.
regioselectivity 2.9:1
85%, 98% e.e.
NHPyMe
NHPyMe
NHPyMe
O
Me
NHPyMe
Tf
N
TBSO
Me
Me
Me
Me
EtO2C
N
Me
EtO2C
9
10
37%, 97% e.e.
regioselectivity 2.5:1
11
62%, 90% e.e.
8
O
62%, >99% e.e.
64%, 94% e.e.
regioselectivity 10:1
regioselectivity 2.2:1
regioselectivity 2.9:1
NHPyMe
NHPyMe
NHPyMe
O
F3C
O
Me
F3C
N
O
Me
H
H
14
12
13c
60%, >20:1 d.r.
regioselectivity 2.8:1
H
56%, >99% e.e.
regioselectivity 8:1
60% (13+13′), 99% e.e.
regioselectivity 4:1
CF3
O
O
bd
NHPyMe
NHPyMe
NHPyMe
NHPyMe
NHPyMe
NHPyMe
O
O
MeO2C
MeO2C
Me
Me
19
20
58%, 90% e.e.
15
84%
16
81%
17
90%
18
82%
60%, 92% e.e.
trans
NHPyMe
R
R
NHPyMe
NHPyMe
NHPyMe
TBSO
TBSO
NHPyMe
AcO
AcO
MeO2C
+
R
R
R = CO2Et
R = Me
24, 24%, 92% e.e.
25, 69% e.e.
52% (25+25′), regioselectivity 1:3.5
24′, 48%
25′
21
22
23
64%, 90% e.e.
53%, 90% e.e.
55%, 91% e.e.
10:1 d.r.
ce,f
O
Me
HN
NH2
NH2
27
Me Me
Me
Tf
N
MeO
Me
Me
Me
26
28
79% yield
O
71% yield, >96% e.e.
85% GC yield, >93% e.e.
(35% yield isolated as Boc amide)
Fig. 3 | Scope of internal alkenes that undergo hydroamination. a, Scope of
asymmetric hydroamination of acyclic internal alkenes. b, Scope of
hydroamination of simple cycloalkenes and of asymmetric hydroamination of
substituted cyclic alkenes. c, Products from the removal of the 2-(6-methyl)
pyridyl group. a2.5 mol% catalyst. b7.5 mol% catalyst. c20 mol% catalyst.
dConditions: 2.5 mol% [Ir(coe)2Cl]2, 7.5 mol% (S)-DTBM-SEGPHOS, 6 mol%
NaBARF, 1,4-dioxane, 120ꢀ°C. eConditions: PtO2, HCl, H2 (1 atm); NaBH4,
THF/EtOH. fEnantioselectivities were determined after conversion to the
original hydroamination product by palladium-catalysed cross-coupling of the
primary amine with 2-bromo-6-methylpyridine.
complicated by competing alkene isomerization, which led to mixtures
of isomers that were difficult to separate.
To understand how the combination of a cationic iridium catalyst
and 2-amino-6-methylpyridine enabled the hydroamination of unac-
The pyridyl group of the hydroamination products (1, 9) was cleaved tivated internal alkenes, we investigated the reaction mechanism.
by a short sequence that consisted of protonation, hydrogenation The reaction of a substituted cyclopentene with N,N-dideuterio-
and borohydride reduction. The corresponding primary amines 2-amino-6-methylpyridine showed that the addition occurred in
(26, 27) formed in 71–85% yield with little or no erosion in enantio- a syn fashion. This stereochemistry is consistent with a mecha-
meric excess (see Supplementary Information sections VI and X). By nism that involves migratory insertion of an alkene, rather than
the same sequence, hydroamination product 6 was converted to the nucleophilic attack on a metal-bound alkene complex (Fig. 4a).
corresponding δ-lactam (28) in 79% yield.
Kinetic experiments showed that the reaction is first-order in
4 | Nature | www.nature.com

R′
2.5 mol% [Ir(coe)2Cl]2
6 mol% (S)-DTBM-SEGPHOS
6 mol% NaBARF
NHPyMe
CO2Me
5 equiv.
D
Ir
a
b
R
P
P
MeO2C
+
*
Probably via
Me
N
ND2
ND
Dioxane, 120 °C, 36 h
D
N
44% isolated yield
40% D
23-D
90% D
Me
NHPyMe
[(R)-TMS-SYNPHOSIr(COD)]NTf2
Me
+
Me
Me
Me
2-MeTHF, 120 °C
Me
N
NH2
1
1.7
1.5
1.3
1.1
0.9
0.7
0.5
0.3
25
4.5
4.0
3.5
3.0
2.5
2.0
y = 2.6 × 103x – 4.5
2 = 0.99
y = 2.5x + 0.14
2 = 0.99
y = 5.7x + 1.4
2 = 0.99
20
15
10
5
R
R
R
0
0.05 0.15
0.25
0.35
0.45
0.55
0.65
0
0.002 0.004 0.006 0.008 0.010 0.012
[lr] (M)
0.1
0.2
0.3
0.4
0.5
1/[Alkene] (M–1
)
[Amine] (M)
5 mol%
c
Me
[(R)-TMS-SYNPHOSIr(COD)]NTf2
+
+
No reaction
Me
2-MeTHF, 120 °C, 48 h
Me
N
NH2
N
NH2
1 equiv.
1 equiv.
10 equiv.
d
H
H
Ir
Ir
C
C
Npy
C
Nam
C
Nam
Npy
H
Ir
NH
P
P
H
TS-1a
TS-2a
*
P
P
Ir
Me
*
Me
N
Ir-Npy (Å)
Ir-Nam (Å)
2.14
2.32
2.42
2.14
Side view
N
HN
TS-2a
G‡ = 4.1 kcal mol–1
TS-1a
ΔΔG‡ = 0 kcal mol–1
ΔΔ
Fig. 4 | Mechanistic study of the hydroamination. a, Deuterium-labelling
experiments. b, Experiments to reveal kinetic orders of each reaction
component. c, Competition experiments using 2-amino-6-methylpyridine and
2-aminopyridine. d, Transition-state structures of alkene migratory insertion
computed by DFT. Single-point energies were computed at the M06/6-
311+G(d,p)/SDD/SMD(1,4-dioxane) level of theory with structures optimized at
the B3LYP/6-31G(d)/SDD level. The ligand used for the calculations is
(S)-TMS-SEGPHOS. The hydride is located trans to the amido ligand in the
lowest-energy transition state (TS-1a) that leads to the (R)-enantiomer but is
located trans to the pyridyl group in the lowest-energy transition state (TS-2a)
that leads to the (S)-enantiomer. Error bars in b correspond to those in the
initial rates that result from errors in the integration of peaks in the gas
chromatogram.
[iridium catalyst], positive-order in [cis-4-octene] and inverse-order reaction, we conducted hydroamination of cis-4-octene with equi-
in [2-amino-6-methylpyridine] (Fig. 4b). These data suggest that a molar amounts of 2-amino-6-methylpyridine and 2-aminopyridine.
molecule of 2-amino-6-methylpyridine dissociates reversibly from Whereas the reaction of 2-amino-6-methylpyridine alone afforded
iridium in the catalyst resting state before rate-limiting insertion of the hydroamination product in high yield, the reaction that contained
the alkene, presumably into the metal–amido bond41. To elucidate both 2-amino-6-methylpyridine and 2-aminopyridine provided neither
why the methyl group of 2-amino-6-methylpyridine is essential in this hydroamination product (Fig. 4c). This result implies that stronger
Nature | www.nature.com | 5

Article
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hydroamination, we conducted calculations on the alkene migratory
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enantiomer of the products with cis-2-butene as the model alkene.
The structures of the lowest-energy transition states that lead to
the major and minor enantiomers are illustrated in Fig. 4d. The
two transition states of many metal-catalysed enantioselective
hydrofunctionalization reactions of alkenes to form two enantiomers
differ principally by the face of the alkene to which the metal is bound.
In the current system, the orientation of ancillary ligands around the
metal, in addition to the face of the alkene, differs greatly in the two
transition states. The geometry of TS-1a, the transition state leading
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pyridine and amido ligands with the hydride transto the amido group.
By contrast, these three ligands in TS-2a, which is the lowest-energy
transition state leading to the minor enantiomer, are arranged with
the hydride transto the pyridine donor. A geometry analogous to TS-
1a that would form the opposite enantiomer by orienting the methyl
groups away from the pyridine ligand (TS-2c and TS-2d; Supplemen-
tary Information Scheme S4) is higher in energy than is TS-2a. TS-1a
is probably the lowest-energy transition state for several reasons.
First, the Ir–Nam bond to the amido group, which is transto a hydride in
TS-1a, is elongated (2.32 Å), thereby leading to higher reactivity
towards insertion. Second, the alkene is perpendicular to the P–Ir–P
plane in TS-1a, whereas the alkene is almost co-planar with the P–Ir–P
plane in TS-2a. These orientations place the substituents on the alkene
in TS-1a farther from the phosphine ligand than those on the alkene
in TS-2a, leading to less steric hindrance in TS-1a than in TS-2a. This
analysis suggests that electronic and steric effects together impart
high enantioselectivity to the hydroamination.
Our work demonstrates that the direct N–H addition of amines
to unactivated internal alkenes can occur with high enantioselec-
tivity under thermal conditions, without the need for strategies
involving formal hydroamination. Despite the typically high barri-
ers and weak thermodynamic driving force for hydroamination,
the use of cationic bisphosphine-ligated iridium as the catalyst and
2-amino-6-methylpyridine as the amine led to enhancements of the
rates of multiple steps within the catalytic cycle and to suppression of
alkene isomerization and oxidative amination, enabling the hydroami-
nation of unactivated internal alkenes in high yield and with high enan-
tioselectivity. The hydroamination products can be converted to the
corresponding primary amines readily with preservation of the high
enantiomeric excess of the hydroamination products. These design
principles should provide a starting point to address the long-standing
challenge of applying hydroamination of unactivated internal alkenes
to the synthesis of chiral amines and inspire advances in other asym-
metric hydrofunctionalizations of internal alkenes.
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Article
Author contributions Y.X. and J.F.H. conceived the project. Y.X. discovered the reaction and
performed experiments and DFT calculations. S.M. performed experiments for revision. Y.X.
and J.F.H. wrote the manuscript.
Data availability
The data that support the findings of this study are available within the
article and its Supplementary Information.
Competing interests The authors declare no competing interests.
Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/s41586-020-
2919-z.
Correspondence and requests for materials should be addressed to J.F.H.
Peer review information Nature thanks the anonymous reviewer(s) for their contribution to the
peer review of this work.
Acknowledgements The enantioselective aspects of the work were supported by the National
Institutes of Health under grant R35GM130387 and the catalyst development was supported
by the Director, Office of Science, of the US Department of Energy under contract number
DE-AC02-05CH11231. Calculations were performed at the Molecular Graphics and
Computation Facility at UC Berkeley funded by the NIH (S10OD023532). We gratefully
acknowledge Takasago for gifts of (S)-DTBM-SEGPHOS, and H. Celik for assistance with
nuclear magnetic resonance (NMR) experiments. Instruments in the College of Chemistry
NMR facility are supported in part by NIH S10OD024998. We thank R. G. Bergman, B. Su and
T. Butcher for discussions. Y.X. thanks Bristol-Myers Squibb for a graduate fellowship,
S. Pedram for supply of NaBARF and D. Small for assistance with DFT calculations.
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