Enantioselective Intermolecular Addition of Aliphatic Amines to Acyclic Dienes with a Pd-PHOX Catalyst

Article abstract of DOI:10.1021/jacs.7b03480

We report a method for the catalytic, enantioselective intermolecular addition of aliphatic amines to acyclic 1,3-dienes. In most cases, reactions proceed efficiently at or below room temperature in the presence of 5 mol % of a Pd catalyst bearing a PHOX ligand, generating allylic amines in up to 97:3 er. The presence of an electron-deficient phosphine within the ligand not only leads to a more active catalyst but also is critical for achieving high site selectivity in the transformation.

Full text of DOI:10.1021/jacs.7b03480

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Communication
Enantioselective Intermolecular Addition of Aliphatic
Amines to Acyclic Dienes with a Pd—PHOX Catalyst
Nathan J. Adamson, Ethan Hull, and Steven J. Malcolmson
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Apr 2017
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Enantioselective Intermolecular Addition of Aliphatic Amines to
Acyclic Dienes with a Pd—PHOX Catalyst
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Nathan J. Adamson, Ethan Hull, and Steven J. Malcolmson*
Department of Chemistry, Duke University, Durham, NC 27708, United States
Supporting Information Placeholder
Scheme 1. Catalytic Enantioselective Intermolecular
Diene Hydroamination Reactions.
ABSTRACT: We report a method for the catalytic, enanti-
oselective intermolecular addition of aliphatic amines to
acyclic 1,3-dienes. In most cases, reactions proceed efficient-
ly at or below room temperature in the presence of 5 mol %
of a Pd catalyst bearing a PHOX ligand, generating allylic
amines in up to 97:3 er. The presence of an electron-
deficient phosphine within the ligand not only leads to a
more active catalyst but is also critical for achieving high
site-selectivity in the transformation.
Aniline Additions to Cyclohexadiene (Hartwig, 2001)
2.5 mol % [Pd( 3-C3H5)Cl]2
NHPh
5 mol % (R,R)-Trost ligand
PhNH2
+
THF, 25 °C, 120 h
(4 equiv)
87% yield
94.5:5.5 er
Indoline Additions to Acyclic Dienes (Dong, 2017)
2 mol % [Rh(cod)OMe]2
4 mol % JoSPOphos ligand
N
N
Hydrofunctionalization reactions of unsaturated hydro-
carbons are highly atom economical means of generating
complex molecules from simple and readily accessible mate-
rials. Strategies to catalyze this broad class of transfor-
mations enantioselectively have been greatly sought after.
Among this cohort, hydroamination reactions1,2 are prized as
an expedient way to generate valuable chiral amines. De-
spite this, enantioselective intermolecular olefin hydroami-
nations are rare.
+
H
50 mol % triphenylacetic acid
DCE, 60 °C, 24 h
Ph
Me
Ph
(1.5 equiv)
81% yield
98:2 er
This Work: Aliphatic Amine Additions to Acyclic Dienes
2.5 mol % [Pd( 3-C3H5)Cl]2
5 mol % PHOX ligand
N
+
Ph
(2 equiv)
6 mol % AgBF4
N
H
Ph
Me
CH2Cl2, 22 °C, 20 h
84% yield
Until recently, successful enantioselective additions of
amines have been limited to aryl amines (Scheme 1). In 2001,
the Hartwig lab showed that anilines could be added to
symmetrical cyclic dienes in the presence of a chiral Pd cata-
lyst prepared from a Trost ligand.3–5 Although a Brønsted
acid additive permits a shorter reaction time, it also leads to
product racemization. Dong and coworkers demonstrated a
Rh-catalyzed 1,2-hydroamination of unsymmetrical acyclic
dienes utilizing indoline nucleophiles; in this case, an acid
additive positively impacts enantioselectivity.6 Recently, the
Hou lab disclosed the first highly enantioselective intermo-
lecular hydroaminations with aliphatic amines, where chiral
lanthanide half-sandwich catalysts allow for stereoselective
amine additions to cyclopropenes.7–10 In this work, we report
the enantioselective 1,2-addition of alkyl amines to unsym-
metrical acyclic dienes11–13 catalyzed by a cationic Pd—PHOX
complex.14 Transformations afford allylic amines15 in up to
91% yield in 3–24 hours without added Brønsted acid. An
electron deficient phosphine enhances both catalyst reactivi-
ty and site-selectivity for the 1,2-addition product.
95:5 er
proposed catalytic cycle:
R1
Me
HNR2
N
P
N
Pd
Pd
H
P
R1
NR2
Me
R2HN
N
R1
Pd0
+
R1
acid source
Me
P
R1
by outer sphere amine attack.5 The resulting ammonium salt
may then oxidatively protonate Pd to regenerate the metal
hydride (Scheme 1).16 We therefore began by examining lig-
ands known for promoting enantioselective nucleophilic
additions to metal-π-allyl complexes for the hydroamination
of 1-phenylbutadiene (1a, Table 1) with tetrahydroisoquino-
line (THIQ). Unlike in previously reported aniline additions
to cyclohexadiene,3 Trost ligands, in combination with
[Pd(η3-C3H5)Cl]2, fail to promote hydroamination of 1a with
THIQ. Other classes of bis(phosphine) ligands lead to more
reactive catalysts; however, although they provide high selec-
tivity for the desired 1,2-hydroamination product 2a, poor
enantioselectivity is observed (<70:30 er).17
Previous work by the Hartwig group showed that Pd-
catalyzed hydroamination of dienes proceeds via Pd–H mi-
gratory insertion to generate a Pd-π-allyl complex, followed
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94.5:5.5 er, entry 7) relative to the diphenylphosphino ligand
Table 1. Reaction Optimization for Addition of Tet-
rahydroisoquinoline to 1-Phenylbutadiene.a
1
2
3
4
5
6
7
8
(2:1 2a:3a, 92:8 er, entry 6). Ligand L5 provides dramatically
increased reactivity as well, at room temperature (entry 8)
affording 79% yield of 2a in 0.5 h. Cooling to 0 ˚C further
enhances enantioselectivity: after 3 h, amine 2a is delivered
in 89% yield and 97:3 er. Indane-derived PHOX ligands L6–
L7 were also explored (entries 10–12) and lead to similar se-
lectivity trends albeit with overall reduced reactivity. Yield
could be improved if the reaction were run at 30 ˚C without
diminishing enantioselectivity (79% yield, 94:6 er, entry 12),
but a further increase negatively impacted enantioselectivity.
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Table 2. Addition of Tetrahydroisoquinoline to 1-
Substituted Butadienes.a–d
2.5 mol % [Pd( 3-C3H5)Cl]2
5 mol % L5
HN
6 mol % AgBF4
+
N
CH2Cl2, 0 °C, 3 h
R
R
Me
1b k
(2 equiv)
2b k
2b G = NMe2: 75% yield, 91.5:8.5 er, >20:1 2:3
NR1R2
Me
2c G = OMe:
2d G = Cl:
86% yield, 96:4 er, >20:1 2:3
82% yield, 96:4 er, 11:1 2:3
78% yield, 95.5:4.5 er, 6:1 2:3
2e G = CF3:
G
2fe G = NO2:
NR1R2
59% yield, 94.5:5.5 er, 3:1 2:3
NR1R2
Me
Me
Me
2hf
Me
2g
85% yield, 91:9 er
78% yield,g 91:9 er
>20:1 2:3
4:1 2:3
a
Reactions run with 0.2 mmol tetrahydroisoquinoline (0.8 M). See
NR1R2
NR1R2
Me
NR1R2
Me
b
the Supporting Information for experimental details. Determined
1
c
by 400 MHz H NMR spectroscopy of the unpurified mixture. Iso-
lated yield of a 2a/3a mixture unless otherwise noted. d Enantiomeric
ratio determined by HPLC analysis of purified products in compari-
son with authentic racemic standards. e Isolated yield of 2a only.
Ph
Me TBSO
2i
2j
2k
65% yield, 95:5 er
56% yield, 95:5 er
83% yield, 89:11 er
>20:1 2:3
>20:1 2:3
>20:1 2:3
We then turned our attention to phosphinooxazoline
(PHOX) ligands, which have enjoyed a great deal of success
in enantioselective allylic substitution,18 but to the best of
our knowledge have not been employed in hydrofunctionali-
a
b
See the Supporting Information for experimental details. Site-
1
isomer ratio determined by 400 MHz H NMR spectroscopy of the
unpurified mixture. c Isolated yield of 2 only unless otherwise noted.
d
zation reactions.14
We began by examining the Ph-
Enantiomeric ratio determined by HPLC analysis of purified prod-
ucts in comparison with authentic racemic standards. e Reaction for
substituted PHOX ligand L1 (Table 1, entry 1). After 20 h at
room temperature with 5 mol % catalyst, a mixture of desired
1,2-hydroamination
9 h. f Reaction at 22 ˚C. g Isolated yield of a mixture of 2 and 3.
A number of 1-substituted dienes take part in enantioselec-
tive addition of THIQ (Table 2).21 Electronic variation at the
arene’s para-position of aryl-substituted butadienes was in-
vestigated and proved to have a profound effect on site-
selectivity (allylic amines 2b–f). More electron-rich substitu-
ents lead to high selectivity for 1,2-addition product 2.13l For
example, dimethylamino-containing 2b and methoxy-
substituted 2c are formed as the exclusive product of the
reaction whereas nitroarene 1f leads to a 3:1 mixture of site-
isomers. In contrast, enantioselectivity is largely unchanged
(91.5:8.5 to 96:4 er). In cases where a mixture is obtained,
the two product isomers are separable. Methyl substitution
at the meta-position maintains high site-selectivity (>20:1)
for allylic amine 2g. In comparison, the ortho-tolyl 2h is
formed with only 80% selectivity13l although enantioselectivi-
product
2a
and
achiral
1,4-
hydroamination adduct 3a is generated (70% yield, 8.5:1
2a:3a). The desired allylic amine is formed in 81:19 er. The
addition of AgBF4 to the catalyst mixture improves the prod-
uct ratio and slightly increases the enantioselectivity as well
(12:1 2a:3a, 85:15 er, entry 2).19 Switching to a more electron-
poor phosphine (L2, entry 3) improves product yield20 and
increases the proportion of 2a13l (84% yield, 17:1 site-
selectivity) without significant change to enantioselectivity.
A bis[3,5-(CF3)2]-aryl phosphine (L3, entry 4) further increas-
es yield and site-selectivity and also offers enhanced enanti-
oselectivity (89:11 er). Similar trends in site- and enantiose-
lectivity are observed with the t-Bu-substituted oxazolines
(L4–L5, entries 5–7). Once more, the more electron-deficient
phosphine increases site- and enantioselectivity (19:1 2a:3a,
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Journal of the American Chemical Society
ty is the same in both cases (91:9 er); neither parameter in
(88.5:11.5–94.5:5.5 er). Sterically hindered dibenzylamine
affords 2q in 94:6 er with higher efficiency with indane-
derived ligand L7 at 30 ˚C.22 Primary alkyl amines undergo a
single hydroamination event: secondary amine 2t is generat-
ed in 48% yield (94:6 er). Aryl amines are also effective nu-
cleophiles, delivering allylic amines 2u–v in up to 96.5:3.5 er.
1
2
3
4
5
6
7
8
forming 2h is improved upon cooling to 0 ˚C. Alkyl-
substituted dienes efficiently undergo hydroamination to
deliver chiral amines 2i–k as the exclusive product in 89:11–
95:5 er. In all cases, olefin migration is not observed.
Table 3. Amine Variation in the Hydroamination of 1-
Phenylbutadiene.a–d
Scheme 2. Initial Mechanistic Investigations of Pd—
PHOX-Catalyzed Diene Hydroaminations.
2.5 mol % [Pd( 3-C3H5)Cl]2
5 mol % L5
R1 R2
N
H
(Z)-Phenylbutadiene
•
R1 R2
N
9
2.5 mol % [Pd( 3-C3H5)Cl]2
L5
O
N
6 mol % AgBF4
+
10
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5 mol %
Ph
Ph
Ph
Me
6 mol % AgBF4
CH2Cl2, temp, time
1a
(2 equiv)
2l v
Ph
Me
(Z)-1a
(2 equiv)
(ca. 88% Z)
O
2l
Boc
N
O
1:2 2l:3l (both >98% E)
79% combined yield
89.5:10.5 er
N
H
CH2Cl2, 0 °C, 3 h
N
N
N
•Isotopically-labeled tetrahydroisoquinoline
Ph
Me
Ph
Me
Ph
Me
2.5 mol % [Pd( 3-C3H5)Cl]2
2l
2m
2n
5 mol % L5
0 °C, 3 h, 91% yielde
95.5:4.5 er, 14:1 2:3
0 °C, 20 h, 68% yielde
22 °C, 20 h, 84% yielde
Ar
6 mol % AgBF4
+
96:4 er, 12:1 2:3
95:5 er, 17:1 2:3
1f
(2 equiv)
N
D
CH2Cl2, 22 °C, 20 h
Bn
Me
Me
Bn
Bn
Ar = 4-NO2C6H4
(90% D)
N
N
N
1
2
N
R R
Ph
Me
Ph
Ph
Me
D
55%
NR1R2
2qf
Ar
Ar
Ar
2o
2p
4
4
22 °C, 20 h, 59% yielde
0 °C, 3 h, 77% yield
94.5:5.5 er, >20:1 2:3
30 °C, 20 h, 60% yield
94:6 er, >20:1 2:3
25%
D
77% combined yield
d-2f 3f
91:9 er, 13:1 2:3
2:1
:
12%
1
2
D
1
N
D 95%
R R
91.5:8.5 er
Et
Et
Me
Me
PMB
Me
N
t-BuO2C
N
HN
NR1R2
Ar
Me
1
Ph
Me
Ph
Ph
d 2f
d 3f
2r
2s
2t
0 °C, 6 h, 45% yieldg
0 °C, 24 h, 68% yield
88.5:11.5 er, >20:1 2:3
22 °C, 13 h, 48% yield
94:6 er, >20:1 2:3
Initial mechanistic studies demonstrate that site-selectivity
in the reaction is strongly dependent upon diene stereo-
chemistry and isotope effects (Scheme 2). (Z)-Phenyl-
butadiene (Z)-1a (ca. 88% Z), when combined with morpho-
line and the Pd—L5 complex under the optimal conditions
for (E)-1a (Table 3), yields a dramatically higher proportion
of the 1,4-hydroamination product (1:2 2l:3l) compared to
reaction of the (E)-isomer, perhaps due to styrenyl olefin
insertion now being significantly kinetically preferred. Both
hydroamination products are formed exclusively as the (E)-
olefin isomer, signifying that olefin isomerization is faster
than amine attack in forming 2l. Excess diene 1a is recovered
with ca. 82% Z content. Furthermore, 2l is formed as the
same enantiomer from (Z)-1a as from the (E)-isomer.
92:8 er, >20:1 2:3
Ph
HN
N
Ph
Me
Ph
Me
2u
2v
60 °C, 20 h, 46% yielde
87:13 er, 12:1 2:3
0 °C, 20 h, 60% yielde
96.5:3.5 er, 8:1 2:3
See Table 2. e Isolated as a mixture of 2 and 3; see the Supporting
a–d
Information. f Ligand L7 used. g Lower yield due to product volatility.
Several aliphatic amines participate in hydroamination of
phenylbutadiene 1a with Pd—PHOX catalysts although the
optimal reaction conditions vary considerably depending on
the nature of the amine (Table 3). Like THIQ, cyclic amines
with inductively electron-withdrawing groups (e.g., morpho-
line and N-Boc-protected piperazine) are able to furnish al-
lylic amine products at 0 ˚C with the L5-derived catalyst: 2l
and 2m are obtained with ca. 92% site-selectivity and 96:4 er.
As the cyclic amines become more donating, higher tempera-
ture is required to promote reaction, presumably because of
increasing competition with the diene for coordination to
Pd.1 Piperidine forms allylic amine 2n in 84% yield at room
temperature (95:5 er). Pyrrolidine, a challenging amine for
many late transition metal catalysts, affords 2o in 91:9 er and
59% yield. Acyclic secondary amines are also competent
partners for the diene hydroamination, delivering amines
2p–s as a single site-isomer with good enantioselectivity
To determine the extent to which the diene/Pd–H inser-
tion might be reversible, reaction of N-deuterated THIQ with
diene 1f was examined. At room temperature, the reaction of
unlabeled THIQ with 1f generates an 8:1 mixture of 1,2- and
1,4-hydroamination products with L5.17 Unexpectedly, N-
deuterated THIQ significantly lowers the site-selectivity to
2:1 d-2f:d-3f (Scheme 2). The deuterium distribution in each
product, however, demonstrates that the site of migratory
insertion largely controls which product forms as indicated
by the relatively smaller amount of deuterium incorporation
into C1 in d-2f and C4 in d-3f. Whether this analysis extends
to unlabeled amines with L5 is ambiguous due to the isotope
effect in product distribution. Recovered diene 2f has ca.
12% D-incorporation into the C1 position but <2% at C4.
A Pd complex, bearing an electronically dissymmetric chi-
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(10) For other non-enantioselective intermolecular hydroamina-
ral PHOX ligand, is an efficient and highly enantioselective
catalyst for the intermolecular hydroamination of dienes
with aliphatic amines. Diene and ligand electronics have a
dramatic effect on product distribution, and a more electron
deficient phosphine ligand significantly increases catalyst
reactivity. Current studies are focused on further elucidating
the reaction mechanism and related methods development.
tions with alkyl amines, see: (a) Ickes, A. R.; Ensign, S. C.; Hull, K. L.
J. Am. Chem. Soc. 2014, 136, 11256. (b) Ensign, S. C.; Vanable, E. P.;
Kortman, G. D.; Weir, L. J.; Hull, K. L. J. Am. Chem. Soc. 2015, 137,
13748. (c) Musacchio, A. J.; Lainhart, B. C.; Zhang, X.; Naguib, S. G.;
Sherwood, T. C.; Knowles, R. R. Science 2017, 355, 727.
1
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(11) For non-enantioselective intermolecular hydroamination of this
class of dienes with anilines and alkyl amines, see: (a) Minami, T.;
Okamoto, H.; Ikeda, S.; Tanaka, R.; Ozawa, F.; Yoshifuji, M. Angew.
Chem., Int. Ed. 2001, 40, 4501. (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.
ASSOCIATED CONTENT
Supporting Information
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Experimental procedures and analytical data for new com-
pounds. This material is available free of charge via the In-
ternet at http://pubs.acs.org.
(12) For intramolecular enantioselective hydroamination of dienes,
see: (a) Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc.
2003, 125, 15878. (b) Deschamp, J.; Olier, C.; Schulz, E.; Guillot, R.;
Hannedouche, J.; Collin, J. Adv. Synth. Catal. 2010, 352, 2171. (c)
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D.
Nature 2011, 470, 245. (d) Kanno, O.; Kuriyama, W.; Wang, Z. J.;
Toste, F. D. Angew. Chem., Int. Ed. 2011, 50, 9919.
AUTHOR INFORMATION
Corresponding Author
(13) For select examples of other catalytic enantioselective intermo-
lecular reactions of acyclic 1,3-dienes, see: (a) Shirakura, M.;
Suginome, M. Angew. Chem., Int. Ed. 2010, 49, 3827. (b) Zbieg, J. R.;
Moran, J.; Krische, M. J. J. Am. Chem. Soc. 2011, 133, 10582. (c) Schus-
ter, C. H.; Li, B.; Morken, J. P. Angew. Chem., Int. Ed. 2011, 50, 7906.
(d) Watkins, A. L.; Landis, C. R. Org. Lett. 2011, 13, 164. (e) Zbieg, J.
R.; Yamaguchi, E.; McIntuff, E. L.; Krische, M. J. Science 2012, 336,
324. (f) Kliman, L. T.; Mlynarski, S. N.; Ferris, G. E.; Morken, J. P.
Angew. Chem., Int. Ed. 2012, 51, 521. (g) McIntuff, E. L.; Yamaguchi,
E.; Krische, M. J. J. Am. Chem. Soc. 2012, 134, 20628. (h) Ebe, Y.;
Nishimura, T. J. Am. Chem. Soc. 2014, 136, 9284. (i) Stokes, B. J.; Liao,
L.; de Andrade, A. M.; Wang, Q.; Sigman, M. S. Org. Lett. 2014, 16,
4666. (j) Timsina, Y. N.; Sharma, R. K.; RajanBabu, T. V. Chem. Sci.
2015, 6, 3994. (k) Wu, X.; Lin, H-C.; Li, M-L.; Li, L-L.; Han, Z-Y.;
Gong, L-Z. J. Am. Chem. Soc. 2015, 137, 13476. (l) Liu, Y.; Xie, Y.;
Wang, H.; Huang, H. J. Am. Chem. Soc. 2016, 138, 4314.
*steven.malcolmson@duke.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful to Duke University for sponsoring this re-
search. N. J. A. was supported by NIGMS (T32GM007105–42).
We thank Katherine Wilbur for experimental assistance.
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ination of unsaturated hydrocarbons, see: (a) Hirano, K.; Miura, M.
Pure Appl. Chem. 2014, 86, 291. (b) Pirnot, M. T.; Wang, Y-M.; Buch-
wald, S. L. Angew. Chem., Int. Ed. 2016, 55, 48.
(15) For intermolecular enantioselective hydroamination of alkynes
to generate allylic amines, see: (a) Chen, Q-A.; Chen, Z.; Dong, V. M.
J. Am. Chem. Soc. 2015, 137, 8392. For intermolecular enantioselective
hydroamination of allenes to generate allylic amines, see: (b) Butler,
K. L.; Tragni, M.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2012, 51,
5175. (c) Kim, H.; Lim, W.; Im, D.; Kim, D-g.; Rhee, Y. H. Angew.
Chem., Int. Ed. 2012, 51, 12055. For a review concerning other exam-
ples, see: (d) Koschker, P; Breit, B. Acc. Chem. Res. 2016, 49, 1524.
(3) Löber, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001,
123, 4366.
(4) For enantioselective Pd-catalyzed aniline additions to styrenes,
see: (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122,
9546. (b) Hu, A.; Ogasawara, M.; Sakamoto, T.; Okada, A.; Nakajima,
K.; Takahashi, T.; Lin, W. Adv. Synth. Catal. 2006, 348, 2051.
(16) Amine attack upon the original η3-allyl Pd salt generates an
ammonium salt that oxidatively protonates Pd, initiating catalysis.
(5) For mechanistic studies of Pd-catalyzed styrene and diene hy-
droamination with anilines, see: (a) Nettekoven, U.; Hartwig, J. F. J.
Am. Chem. Soc. 2002, 124, 1166. (b) Johns, A. M.; Utsunomiya, M.;
Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 1828. For a
study with a Ni catalyst and alkyl amines, see: (c) Pawlas, J.; Nakao,
Y.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 3669.
(17) See the Supporting Information for details.
(18) For reviews, see: (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res.
2000, 33, 336. (b) Bausch, C. C.; Pfaltz, A.; PHOX Ligands. In Privi-
leged Chiral Ligands and Catalysts; Zhou, Q-L., Ed.; Wiley-VCH:
Weinheim, Germany, 2011; Chapter 6. (c) Liu, Y.; Han, S-J.; Liu, W-B.,
Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740.
(6) Yang, X-H.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, 1774.
(19) Other Ag salts afford greater quantities of achiral 3a although
the er of 2a is largely invariant. Additionally, polar solvents lead to
greater product yields with CH2Cl2 proving optimal.
(7) Teng, H-L.; Luo, Y.; Wang, B.; Zhang, L.; Nishiura, M.; Hou, Z.
Angew. Chem., Int. Ed. 2016, 55, 15406.
(8) For other intermolecular enantioselective hydroaminations with
alkyl amines, see: (a) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 14286. (b) Reznichenko, A. L.; Nguyen, H. N.;
Hultzsch, K. C. Angew. Chem., Int. Ed. 2010, 49, 8984.
(20) Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. Org.
Lett. 2007, 9, 2529.
(21) 1,4-disubstituted dienes fail to generate hydroamination prod-
uct. Other substitution patterns deliver 1,4-hydroamination or a
complex mixture. See the Supporting Information.
(9) For intermolecular enantioselective hydroaminations with N-
nucleophiles other than amines, see: (a) Zhang, Z.; Du Lee, S.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 5372. (b) Sevov, C. S.;
Zhou, J. (S.); Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 11960.
(22) Product 2q is obtained in 53% yield, 12:1 2q:3q, and 93:7 er after
17 h at 0 ˚C with L5.
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