Cu-Catalyzed electrophilic amination of internal alkynes via hydroalumination

Article abstract of DOI:10.1039/c6ob02606k

A straightforward and efficient method for the synthesis of 1,2-diaryl-substituted enamines through the Cu-catalyzed electrophilic amination reaction of O-benzoyl hydroxylamines with vinylaluminum reagents generated in situ from the Ni-catalyzed hydroalumination of readily accessible internal aryl acetylenes is described. The amination is catalyzed by 1 mol% CuCl without any additive at ambient temperature to afford new versatile enamines in good yield (61-91%) with high selectivity (>98% E-enamine).

Full text of DOI:10.1039/c6ob02606k

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Cu-Catalyzed Electrophilic Amination of Internal Alkynes
via Hydroalumination
Hongju Yoon, Yuna Kim and Yunmi Lee*
Department of Chemistry, Kwangwoon University, Seoul 01897, Republic Korea
* To whom correspondence should be addressed.
Tel.: +82-2-940-8116; Fax: +82-2-942-0108; E-mail: ymlee@kw.ac.kr
ABSTRACT: A straightforward and efficient method for the synthesis of 1,2-diaryl-substituted
enamines through the Cu-catalyzed electrophilic amination reaction of O-benzoyl hydroxylamines with
vinylaluminum reagents generated in situ from the Ni-catalyzed hydroalumination of readily accessible
internal aryl acetylenes is described. The amination is catalyzed by 1 mol % CuCl without any additive
at ambient temperature to afford new versatile enamines in good yield (61-91%) with high selectivity
(>98% E-enamine).
INTRODUCTION
Copper-catalyzed electrophilic aminations of organometallic reagents with O-benzoyl
hydroxylamines (BzO−NR2) have emerged as attractive methods for the formation of carbon (sp2)-
nitrogen bonds due to the use of environmentally benign and low-cost copper salts, the easy availability

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of BzO−NR2 as an electrophilic amine source, and the mild reaction conditions.1 In addition, a diverse
2
3
range of aryl- and heteroarylmetals derived from organoaluminum,
organoboron,
organomagnesium,4 organosilicon,5 and organozinc6 have been utilized as carbon-based nucleophiles
in electrophilic amination reactions for the synthesis of aryl amines and heteroaryl amines. In spite of
the significant advances in Cu catalytic C(sp2)-N bond forming reactions of electrophilic amines
involving aryl- and heteroarylmetals, only a few examples of amination using vinylmetals to afford
enamines have been reported.7
Enamines are synthetically valuable intermediates in organic transformations, including
selective alkylations, acylations, cycloadditions, hydrogenations, and syntheses of N-heterocycles as
well as important building blocks for drug discovery.8 Due to the importance of their synthetic utility,
various approaches to form enamines have been developed. Commonly used methods involve
condensation of a secondary amine with carbonyl compounds in the presence of a water scavenger or a
Brønsted acid,9 Ti-mediated methylenation of amides,10 catalytic reductive dehydration of amides
with silanes,11 Pd- or Cu-catalyzed cross coupling of vinyl halides with amines,12 and transition metal-
catalyzed addition of primary or secondary amines to alkynes, known as the hydroamination reaction.13
Among these versatile synthetic strategies, the catalytic hydroamination of alkynes is one of the most
efficient methods to synthesize enamines because a N-H bond is directly added to a C-C triple bond
with 100% atom economy and readily accessible starting materials are used. However, compared to the
transition metal-catalyzed hydroamination of amines with terminal alkynes, efficient catalytic systems
with internal alkynes have been less examined.14 In addition, most of the previously reported
hydroaminations of internal alkynes exhibited several shortcomings related to the use of precious
metals such as palladium and gold and the need for high reaction temperatures. Therefore, the Cu-
catalyzed electrophilic amination reaction of vinylmetals derived from alkynes with O-benzoyl
hydroxylamines under mild conditions is a good alternative to prepare a broad range of 1,2-
disubstituted enamines. For example, Chen, Xi and coworkers demonstrated that vinylzirconocene

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reagents prepared from the Zr-mediated carbozirconation of internal alkynes effectively underwent
electrophilic amination in the presence of 10 mol % CuCl at ambient temperature to provide highly
substituted enamines.7c Hirano, Miura and coworkers also showed that alkenylborons, which were
synthesized from the Zr-catalyzed hydroboration of terminal alkynes with pinacolborane, can be used
in Cu-catalyzed electrophilic amination reactions.7b Aryl-substituted enamines were obtained with high
site selectivity; however, the amination suffered from limited substrate scope to only terminal alkynes,
the use of relatively high catalyst loadings (10 mol % Cu(OAc)2•H2O and 20 mol % phosphine ligand)
and the use of excess LiOt-Bu. Recently, the Cu-catalyzed amination of internal alkynes with O-
benzoyl hydroxylamines and diethoxymethylsilane (HSiMe(OEt)2) as a hydride source was described
by Buchwald and coworkers.7a The addition of Cu hydride species obtained from the reaction of Cu salt
and silanes to aryl-substituted internal alkynes generated a vinyl copper intermediate, which was
aminated with electrophilic amines to prepare enamines. Although the reaction was effectively
catalyzed by 2 mol % Cu(OAc)2 in good yields with high stereo- and site selectivity, there are some
challenges to be overcome to obtain a more efficient and practical method, namely, the need for
additional phosphine ligand, the use of excess silanes, long reaction times, and elevated temperatures.
In recent discoveries by the Zhou group and our laboratory, aryl- and heteroarylaluminum
reagents exhibited high reactivity towards O-benzoyl hydroxylamines to construct (hetero)aromatic
C(sp2)-N bonds in the copper catalytic process.2 Therefore, we envisioned that vinylaluminum reagents
prepared from the hydroalumination of diisobutylaluminum hydride (DIBAL-H) with alkynes15 could
be employed in Cu-catalyzed electrophilic amination reactions as a new approach to the synthesis of a
wide range of enamines. Herein, we have discovered that the electrophilic amination reaction of
internal aryl acetylenes with O-benzoyl hydroxylamines proceeds efficiently and selectively in the
presence of only 1 mol % CuCl without any additive such as phosphine ligands. Hydroalumination of
readily accessible internal alkynes with commercially available and relatively inexpensive DIBAL-H is
promoted much more efficiently by using 1 mol % Ni catalyst16 at room temperature to form

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vinylaluminum reagents with high stereoselectivity (>98% E-vinylAl), which are directly used without
further filtration or purification for amination in a single vessel. A variety of new 1,2-diaryl-substituted
enamines as well as tertiary amines after the reduction of the corresponding enamines, were obtained in
good yields.
RESULTS AND DISCUSSION
We began by exploring the activity of vinylaluminum reagent 2a towards the electrophilic
amination of O-benzoyl hydroxylamine 3a catalyzed by a Cu catalyst. As shown in Scheme 1,
diphenylvinylaluminum 2a was prepared from direct hydroalumination of diphenylacetylene (1a) using
the readily available and inexpensive DIBAL-H in hexanes at 60 °C for 12 h and was then used in the
amination reaction. When electrophilic amine 3a was treated with 2a in the presence of 1 mol % CuCl
at ambient temperature, the reaction was completed within 1 h to give the desired enamine 4aa in 53%
yield. In contrast, without the use of CuCl, the amination did not proceed (<2% 4aa). These results
indicate that the in situ-generated vinylcopper intermediate plays an essential role by reacting with O-
benzoyl hydroxylamine to form the C-N bond. Although the initial copper catalytic reaction proceeded
to full conversion, the desired enamine 4aa was obtained in moderate yield (53%) because O-benzoyl
hydroxylamine 3a may be rapidly decomposed by unreacted DIBAL-H from the inefficient
hydroalumination reaction (75% conversion).17 Therefore, we decided to investigate an efficient
method for the preparation of 1,2-disubstituted vinylaluminum reagent 2a via the hydroalumination of
DIBAL-H under mild conditions. As summarized in Table 1, the ability of various nickel catalysts,
which were used in hydroalumination of terminal alkynes by Hoveyda and coworkers,16 to promote the
addition of DIBAL-H to internal alkyne 1a was examined. While the direct hydroalumination of 1a
with DIBAL-H was sluggish and required high reaction temperatures and long reaction times (Scheme
1), catalytic hydroalumination in the presence of 3 mol % Ni(PPh3)2Cl2 could be performed under mild
conditions at room temperature for 3 h, generating vinylaluminum 2a in 96% conversion with >98% E-

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isomer (entry 1). Other Ni salts such as Ni(PPh3)4 and Ni(acac)2 also exhibited good activities (88%
and 83% conversion, entries 2-3); however, reactions catalyzed by Ni(dppe)Cl2 or Ni(dppp)Cl2 were
not effective (8-64% conversion, entries 4-5). In the absence of Ni catalyst, there was no reaction in
THF (entry 7). Thus, Ni(PPh3)2Cl2 was selected as the optimal catalyst for the mild and efficient
synthesis of vinylaluminum 2a. The result in entry 6 illustrated that a 1 mol % catalyst loading was
effective for the addition of DIBAL-H to 1a.
Scheme 1. Cu-catalyzed electrophilic amination of vinylaluminum 2a via hydroalumination of
diphenylacetylene 1a
Table 1. Optimization of Ni-catalyzed hydroalumination of 1a with DIBAL-H.a
entry
Ni catalyst
Ni(PPh3)2Cl2
Ni(PPh3)4
Ni(acac)2
Ni(dppe)Cl2
Ni(dppp)Cl2
Ni(PPh3)2Cl2
0
mol %
conv (%)b
1
2
3
4
5
6
7
3
3
3
3
3
1
0
96
88
83
8
64
93
<2
a Reaction conditions: diphenylacetylene (1a, 0.50 mmol), DIBAL-H (0.50 mmol), and THF (1.0 M) under N2. b
Determined by 1H NMR spectrum analysis of unpurified mixtures after quench with H2O. In all cases, >98% E-
vinylaluminum was produced.

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The vinylaluminum 2a generated from the Ni-catalyzed hydroalumination was directly used in
the amination reaction, and its reactivity towards O-benzoyl hydroxylamine 3a was examined using
various Cu salts (Table 2). The data in entries 1-2 in Table 2 illustrated that the Ni catalyst did not
influence the amination reaction. The desired enamine 4aa was observed in 97% yield in the presence
of 1 mol % CuCl; however, no reaction occurred without the addition of Cu catalyst (<2% 4aa). As the
results of the Cu screening demonstrated in Table 2, when 1.0 mol % CuCl was used, the electrophilic
amination reaction of 3a rapidly proceeded to complete conversion at ambient temperature within 0.5 h
to afford the enamine product 4aa in 98% yield (entry 8).
Table 2. Optimization of the Cu-Catalyzed Electrophilic Amination of Internal Alkyne 1aa
Al(i-Bu)2
1 mol % Ni(PPh3)2Cl2
N(Bn)2
Ph
1 mol % Cu salts
3a
Ph
Ph
Ph
Ph
BzO-N(Bn)2
THF, 22 C, 0.5-1 h
H Al(i-Bu)2
Ph
THF, 22 C, 3 h
1a
4aa (>98% E)
2a (>98% E)
entry
Cu salts
CuCl
time (h)
conv (%)b
>98
<2
yield (%)c
97
1
2
3
4
5
6
7
8
1
1
0
<2
76
73
83
94
93
98
CuBr
1
>98
>98
94
CuI
1
CuOAc
Cu(OAc)2
Cu(OTf)2
CuCl
1
1
>98
>98
>98
1
0.5
aReactions were performed on a 0.15 mmol scale of 3a in THF (0.2 M) under N2. Conditions: 1.5 equiv. of 1a,
b
1.5 equiv. of DIBAL-H, 1.0 equiv. of BzON(Bn)2 3a and 1 mol % Cu salts. Determined by 1H NMR spectrum
c
1
analysis of unpurified mixtures. Determined by H NMR spectrum analysis using 1,3,5-trimethoxybenzene as
an internal standard after the reductive amination reaction of 4aa, which was carried out with 4.0 equiv. of
NaBH(OAc)3 and 4.0 equiv. of AcOH in CH2Cl2 (0.1 M) for 12 h at room temperature.

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Under the optimal reaction conditions, Cu-catalyzed electrophilic aminations of 3a with
various vinylaluminum reagents prepared in situ from readily accessible internal aryl acetylenes were
carried out in the presence of 1 mol % CuCl as shown in Table 3. All hydroalumination reactions of
internal aryl acetylenes with DIBAL-H were catalyzed by 1 mol % Ni(PPh3)2Cl2 to proceed with more
than 90% conversion to the vinylaluminums in group 2 with >98% stereoselectivity. Most of the Cu
catalytic electrophilic aminations were completed within 2 h at room temperature to obtain a variety of
new 1,2-diaryl-substituted enamines in moderate to high yields. A diverse set of phenylacetylene
derivatives, including trifluoromethyl-, methoxy-, fluoro-, chloro-, or methyl-substituents in the meta-
or para-positions, were tolerated in the catalytic system, affording the desired enamine products in 71-
91% yields (entries 1-7 in Table 3). It should be noted that all catalytic aminations provided >98% E-
enamines; however, the enamines (4ba-4ea) are slightly unstable in alumina column chromatography
and slowly isomerized during purification, where <8% inseparable Z-enamine isomers were observed
(entries 1-4). In addition, enamines derived from the internal alkynes 1f, 1g, and 1h were unsuitable for
common column chromatography and were reduced using NaBH(OAc)3 to isolate the tertiary amine
products in 87-95% yields (entries 5-7). When ortho-substituted aryl acetylenes 1i and 1j were used,
the Cu catalytic aminations of vinylaluminum reagents were less efficient; 30-62% yields of the desired
enamines were obtained with the use of higher catalyst loading (5 mol % vs. 1 mol %) for the reaction
with 1j (entries 8-9). The low yields are presumably because the sluggish amination of sterically
demanding vinyl groups on aluminum reagents is competitive with the amination of isobutyl groups on
aluminum reagents, which results in ~20% of the undesired isobutyl-aminated product, and
decomposition of the electrophilic amine 3a. Amination with heteroaryl-substituted acetylene 1k,
containing thiophenyl substituents, also proceeded to full conversion, although the reaction was less
reactive; 5 mol % CuCl and longer reaction times (12 h vs. 0.5-2 h) were required to give the desired
enamine 4ka in 76% yield (entry 10). Additionally, the alkyl-substituted alkyne 1l was converted to the
resulting amine in 72% yield (entry 11).

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Table 3. Substrate Scope of the Cu-Catalyzed Electrophilic Aminationa
entry
1
alkyne
time (h)
0.5
yield (%)b
86c
1b
1c
2
3
0.5
1
71c
91c
1d
4
5
6
7
1e
1f
0.5
0.5
0.5
1.5
85c
95d
87d
93d
1g
1h
8
9
1i
1
2
62
30
1je
10
11
1ke
1l
12
2
76
72d
aReactions run on 0.3 mmol scale of 3a. Conditions: 1.5 equiv. of internal alkyne 1, 1.5 equiv. of DIBAL-H,
b
CuCl (1 mol %), 1.0 equiv. of 3a and THF (0.2 M) under N2; all conversions were >98%. Yields of the isolated
c
d
enamine products. <8% of the Z-enamine product was observed after column chromatography. Yields of the
isolated products after the reductive amination reaction. Conditions: 4.0 equiv. of NaBH(OAc)3 and 4.0 equiv. of
AcOH in CH2Cl2 (0.1 M) for 12 h at room temperature. e5 mol % CuCl was used.
A range of O-benzoyl hydroxylamines can be utilized (Table 4). With 1 mol % CuCl, all

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electrophilic aminations of the vinylaluminum reagent 2a derived from diphenylacetylene proceeded to
complete conversion within 30 min. The resulting enamines were subsequently transformed to the
corresponding amines using NaBH(OAc)3 and AcOH owing to the instability of the enamine products.
Substrates bearing acyclic N-alkyl substituents such as N,N-dibenzyl, N,N-diisopropyl, N,N-diallyl, and
N-benzyl-N-methyl groups were reacted with 2a to result in moderate to good yields of the products
(61-90%, 4aa-4ad). These catalytic conditions were tolerant to O-benzoyl hydroxylamines synthesized
from six- or seven-membered cyclic amines, including piperidine, thiomorpholine, morpholine, N-Boc-
protected piperazine, and N-Boc-protected homopiperazine, to efficiently afford the desired amine
products 4ae-4ai in 69-85% yields. The synthesis of the secondary amine product 4aj, however, was
not efficient due to the fast decomposition of O-benzoyl-N-(tert-butyl)hydroxylamine(3j) by the
aluminum reagent (36% yield of 4aj).
Table 4. Cu-Catalyzed Electrophilic Amination Reactions with Various O-Benzoyl Hydroxylaminesa

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aReactions were performed on a 0.3 mmol scale of 3. Conditions: 1.5 equiv. of diphenylacetylene (1a), 1.5
equiv. of DIBAL-H, CuCl (1 mol %), 1.0 equiv. BzONR2 3 and THF (0.2 M) under N2. Reductive amination
conditions: 4.0 equiv. of NaBH(OAc)3 and 4.0 equiv. of AcOH in CH2Cl2 (0.1 M) for 12 h at room temperature.
Yields of the isolated products; all conversions were >98%. bAmination for 1 h.
Next, we turned our attention to Cu-catalyzed electrophilic amination reactions with
unsymmetrical internal aryl acetylenes. As illustrated in Table 5, the Ni-catalyzed hydroamination of
DIBAL-H with diaryl-substituted acetylenes in group 5, which have a methoxy substituent at the ortho-
position of one of the aryl groups, was highly efficient and selective in generating the major
regioisomer 6 of the vinylaluminum reagents in >95% conversion with >98% E-stereoselectivity and
>90% site selectivity. The methoxy group on the substrate may play a critical role as a directing group
to achieve high site selectivity.18 Various diaryl-substituted enamine products 8aa-8da, which have not
been well-studied, were synthesized selectively from the corresponding unsymmetrical internal alkynes
bearing methoxy-, trifluoromethyl-, fluoro-, and chloro-substituted aryl groups with high efficiency in
80-89% yields (Table 5).19 It is worth noting that all the single regioisomeric enamines can be isolated
using alumina column chromatography without isomerization.
Table 5. Cu-Catalyzed Electrophilic Amination Reactions with Unsymmetrical Internal Aryl
Acetylenesa

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aReactions were performed on a 0.3 mmol scale of 3a. Conditions: 1.5 equiv. of internal alkyne 5, 1.5 equiv. of
DIBAL-H, CuCl (1 mol %), 1.0 equiv. BzON(Bn)2 3a and THF (0.2 M) under N2. Yields of the isolated
products for a major regioisomer; >98% conversion and >98% E-enamine in all cases.
CONCLUSIONS
In summary, we have demonstrated a new and facile method for the synthesis of a wide range of diaryl-
substituted enamines from readily available and synthetically versatile internal aryl acetylenes and O-
benzoyl hydroxylamines. The amination can proceed in a single vessel via the Ni-catalyzed
hydroalumination of internal alkynes with inexpensive DIBAL-H to form vinylaluminum reagents,
which are subsequently reacted with electrophilic amines in the presence of 1 mol % CuCl. The
catalytic process enables the preparation of new diaryl-, diheteroaryl-, and dialkyl-substituted enamines
in good yield with high site and stereoselectivity. Further investigations will focus on expanding the
substrate scope to other types of alkynes.
ACKNOWLEDGMENTS. This research was supported by the Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT &
Future Planning (NRF-2014R1A1A1003650 and NRF-2015M3A9E6029594) and partially supported
by the Research Grant of Kwangwoon University in 2015. The authors thank the Korea Basic Science
Institute for technical assistance in MS spectrometry.

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ASSOCIATED CONTENT
Supplementary data. Experimental procedures and spectral and analytical data for all products.
AUTHOR INFORMATION
Corresponding Author
*Tel.: +82-2-940-8116. E-mail: ymlee@kw.ac.kr
Notes
The authors declare no competing financial interest.
REFERENCES
1. (a) X. Dong, Q. Liu, Y. Dong, H. Liu, Chem.—Eur. J. 2016, 22, early view. (b) X. Yan, X. Yang, C. Xi, Catal.
Sci. Technol. 2014, 4, 4169. (c) T. J. Barker, E. R. Jarvo, Synthesis 2011, 3954. (d) P. Dembech, G. Seconi, A.
Ricci, Chem.—Eur. J. 2000, 6, 1281. (e) E. Erdik, M. Ay, Chem. Rev. 1989, 89, 1947.
2. (a) H. Yoon, Y. Lee, J. Org. Chem. 2015, 80, 10244. (b) S. Zhou, Z. Yang, X. Chen, Y. Li, L. Zhang, H. Fang,
W. Wang, X. Zhu, S. Wang, J. Org. Chem. 2015, 80, 6323.
3. (a) Y. Fukami, T. Wada, T. Meguro, N. Chida, T. Sato, Org. Biomol. Chem. 2016, 14, 5486. (b) R. P. Rucker,
A. M. Whittaker, H. Dang, G. Lalic, Angew. Chem., Int. Ed. 2012, 51, 3953. (c) N. Matsuda, K. Hirano, T. Satoh,
M. Miura, Angew. Chem., Int. Ed. 2012, 51, 3642. (d) Q. Xiao, L. Tian, R. Tan, Y. Xia, D. Qiu, Y. Zhang, J.
Wang, Org. Lett. 2012, 14, 4230. (e) C. He, C. Chen, J. Cheng, C. Liu, W. Liu, Q. Li, A. Lei, Angew. Chem. Int.
Ed. 2008, 47, 6414. (f) Z. Zhang, Y. Yu, L. S. Liebeskind, Org. Lett. 2008, 10, 3005. (g) S. Liu, Y. Yu, L. S.
Liebeskind, Org. Lett. 2007, 9, 1947.
4. (a) T. Hatakeyama, Y. Yoshimoto, S. K. Ghorai, M. Nakamura, Org. Lett. 2010, 12, 1516. (b) M. J. Campbell,
J. S. Johnson, Org. Lett. 2007, 9, 1521. (c) H. Tsutsui, Y. Hayashi, K. Narasaka, Chem. Lett. 1997, 26, 317.

Page 13 of 15
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C6OB02606K
5. (a) Y. Miki, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2013, 15, 172. (b) M. H. Nguyen, A. B. Smith III, Org.
Lett. 2013, 15, 4872. (c) N. Matsuda, K. Hirano, T. Satoh, M. Miura, Angew. Chem., Int. Ed. 2012, 51, 11827.
6. (a) S. L. McDonald, C. E. Hendrick, Q. Wang, Angew. Chem., Int. Ed. 2014, 53, 4667. (b) T. J. Barker, E. R.
Jarvo, J. Am. Chem. Soc. 2009, 131, 15598. (c) A. M. Berman, J. S. Johnson, J. Org. Chem. 2006, 71, 219. (d) A.
M. Berman, J. S. Johnson, J. Org. Chem. 2005, 70, 364. (e) A. M. Berman, A. S. Johnson, Synlett 2005, 1799. (f)
A. M. Berman, J. S. Johnson, J. Am. Chem. Soc. 2004, 126, 5680.
7. (a) S.-L. Shi, S. L. Buchwald, Nat. Chem. 2015, 7, 38. (b) R. Sakae, K. Hirano, T. Satoh, M. Miura, Chem.
Lett. 2013, 42, 1128. (a) X. Yan, C. Chen, Y. Zhou, C. Xi, Org. Lett. 2012, 14, 4750.
8. For representative reviews, see: (a) S. Mukherjee, L. W. Yang, S. Hoffman, B. List, Chem. Rev. 2007, 107,
5471. (b) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069. (c) Z. Rappaport, The Chemistry of Enamines,
Wiley, New York, 1994. (d) A. G. Cook, Enamines: Their Synthesis, Structure, and Reactions, Dekker, New
York, 1988.
9. (a) G. Bélanger, M. Doré, F. Mѐnard, V. Darsigny, J. Org. Chem. 2006, 71, 7481. (b) P. W. Hickmott,
Tetrahedron 1982, 38, 1975.
10. N. A. Petasis, S.-P. Lu, Tetrahedron Lett. 1995, 36, 2393.
11. A. Volkov, F. Tinnis, H. Adolfsson, Org. Lett. 2014, 16, 680.
12. (a) K. Isa, M. Minakawa, M. Kawatsura, Chem. Commun. 2015, 51, 6761. (b) Y. Wang, Q. Liao, C. Xi, Org.
Lett. 2010, 12, 2951. (c) J. R. Dehli, J. Legros, C. Bolm, Chem. Commun. 2005, 973. (d) C. R. V. Reddy, S.
Urgaonkar, J. G. Verkade, Org. Lett. 2005, 7, 4427. (e) J. Barluenga, M. A. Fernández, F. Aznar, C. Valdés,
Chem. —Eur. J. 2004, 10, 494. (f) J. Barluenga, M. A. Fernández, F. Aznar, C. Valdés, Chem. Commun. 2004,
1400. (g) J. Barluenga, M. A. Fernández, F. Aznar, C. Valdés, Chem. Commun. 2002, 2362. (h) M. C. Willis, G.
N. Brace, Tetrahedron Lett. 2002, 43, 9085.
13. For representative recent reviews for transition-metal catalyzed hydroaminations, see: (a) J. C.-H. Yim, L. L.
Schafer, Eur. J. Org. Chem. 2014, 6825. (b) X. Zeng, Chem. Rev. 2013, 113, 6864. (c) K. D. Hesp, M. Stradiotto,

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DOI: 10.1039/C6OB02606K
ChemCatChem 2010, 2, 1192. (d) T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev. 2008,
108, 3795. (e) R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36, 1407.
14. For representative recent examples of transition-metal catalyzed hydroamination of internal alkynes, see: (a)
R. S. Manan, P. Kilaru, P. Zhao, J. Am. Chem. Soc. 2015, 137, 6136. (b) D. C. Leitch, C. S. Turner, L. L.
Schafer, Angew. Chem. Int. Ed. 2010, 49, 6382. (c) K. D. Hesp, M. Stradiotto, J. Am. Chem. Soc. 2010, 132,
18026. (d) X. Zeng, G. D. Frey, R. Kinjo, B. Donnadieu, G. Bertrand, J. Am. Chem. Soc. 2009, 131, 8690. (e) X.
Zeng, G. D. Frey, S. Kousar, G. Bertrand, Chem. —Eur. J. 2009, 15, 3056.
15. (a) T. L. May, J. A. Dabrowski, A. H. Hoveyda, J. Am. Chem. Soc. 2011, 133, 736. (b) F. Gao, K. P.
McGrath, Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 14315. (c) K. Akiyama, F. Gao, A. H. Hoveyda,
Angew. Chem., Int. Ed. 2010, 49, 419. (d) Y. Lee, K. Akiyama, D. G. Gillingham, M. K. Brown, A. H. Hoveyda,
J. Am. Chem. Soc. 2008, 130, 446.
16. (a) K. P. McGrath, A. H. Hoveyda, Angew. Chem., Int. Et. 2014, 53, 1910. (b) F. Gao, A. H. Hoveyda, J. Am.
Chem. Soc. 2010, 132, 10961.
17. When 3a was treated with DIBAL-H, 54% of the electrophilic amine 3a was disappeared within 1 h,
generating unidentified products.
18. The Ni-catalyzed hydroalumination of 1-methoxy-4-(phenylethynyl)benzene (9) with DIBAL-H provided
the vinylaluminum reagents in a 73:27 ratio of 10a:10b regioisomers by electronic effect.
19. Cu-catalyzed aminations with 1-phenyl-1-propyne and phenylacetylene as different types of unsymmetrical
internal alkynes were also examined. The hydroalumination with 1-phenyl-1-propyne was not site selective to
provide a 45:55 mixture of regioisomers of vinylaluminums. The subsequence amination was proceeded to >98%
conversion to obtain two regioisomeric enamines in a combined yield of 75%. When 1 mol % of Ni(dppp)Cl2
was used for hydroalumination of phenylacetylene, >98% of site selectivity was achieved to afford the

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corresponding internal vinylaluminum reagent (ref. 16 (b)). It was directly aminated to form the desired enamine
with less efficiency (55% yield), compared to reactions with diaryl-substituted internal alkynes. See
Supplementary Information for experimental details.