Zirconium-catalyzed intermolecular hydroamination of alkynes with primary amines

Article abstract of DOI:10.1002/ejoc.201101298

A simple catalyst system generated in situ by combination of 5 mol-% [Zr(NMe₂)₄] and 10 mol-% of a sulfonamide catalyzes the intermolecular hydroamination of alkynes with primary amines. At elevated temperatures, hydroamination is achieved with both internal and terminal alkynes as well as with sterically demanding and less demanding primary amines. In contrast, secondary amines do not react under identical conditions. Of the sulfonamide additives investigated, sterically demanding tosylamides such as N-(tert-butyl)-p-toluenesulfonamide give the best results. The regioselectivity of the addition of amine to unsymmetrically substituted internal as well as terminal alkynes is significantly influenced by the nature of the sulfonamide additive. In particular, the successful use of sterically less demanding primary amines such as n-hexyl-or benzylamine clearly indicates that the assumption that Zr catalysts generally form catalytically inactive bridging μ²-imido dimers or other unreactive intermediates in the presence of these amines is not correct. Intermolecular hydroamination reactions of alkynes with primary amines that are sterically less demanding than 2,6-dimethylaniline can be achieved with in situ generated zirconium catalysts. This finding is highly important for a better and more general understanding of the mechanism of group 4 metal-catalyzed hydroamination reactions. Copyright

Full text of DOI:10.1002/ejoc.201101298

FULL PAPER
DOI: 10.1002/ejoc.201101298
Zirconium-Catalyzed Intermolecular Hydroamination of Alkynes with Primary
Amines
Karolin Born[a] and Sven Doye*[a]
Keywords: Hydroamination / Amination / Amines / Alkynes / Zirconium
A simple catalyst system generated in situ by combination of
gioselectivity of the addition of amine to unsymmetrically
5 mol-% [Zr(NMe2)4] and 10 mol-% of a sulfonamide cata- substituted internal as well as terminal alkynes is signifi-
lyzes the intermolecular hydroamination of alkynes with pri-
mary amines. At elevated temperatures, hydroamination is
achieved with both internal and terminal alkynes as well as
with sterically demanding and less demanding primary
amines. In contrast, secondary amines do not react under
identical conditions. Of the sulfonamide additives investi-
gated, sterically demanding tosylamides such as N-(tert-
butyl)-p-toluenesulfonamide give the best results. The re-
cantly influenced by the nature of the sulfonamide additive.
In particular, the successful use of sterically less demanding
primary amines such as n-hexyl- or benzylamine clearly indi-
cates that the assumption that Zr catalysts generally form cat-
alytically inactive bridging μ2-imido dimers or other unreac-
tive intermediates in the presence of these amines is not cor-
rect.
with this zirconocene catalyst, [Cp2Zr(NH-2,6-Me2C6H3)2],
which is converted into a catalytically active zirconium-
imido complex under the reaction conditions, it was only
possible to use a single amine substrate, namely the steri-
cally demanding primary amine 2,6-dimethylaniline. This
severe disadvantage was overcome when our group found
in 1999 that closely related titanium catalysts such as
[Cp2TiMe2] catalyze the addition of a large number of pri-
mary aryl- and alkylamines to many alkynes.[3] Since then,
the Ti-catalyzed addition of primary amines to alkynes has
been investigated in detail by many groups around the
world[1c,4] and today it is regarded as a reliable and power-
ful tool in organic chemistry that is even mentioned in
undergraduate text books.[5] Although tetracoordinated ti-
tanium complexes are used as catalyst precursors in most
cases, it is generally accepted that titanium-imido com-
plexes possessing a Ti=N double bond are the catalytically
active species. These highly reactive metal complexes un-
Introduction
During the last two decades, the hydroamination of alk-
ynes has become a powerful synthetic tool in organic chem-
istry.[1] If primary amines are used as substrates, this ad-
dition reaction results in the direct formation of more or
less reactive enamines or imines. Although these initial
products can be used in a number of synthetically useful
transformations, in most cases they are simply reduced to
stable secondary amines (Scheme 1). As a result, the combi-
nation of an initial hydroamination of an alkyne and a sub-
sequent reduction in one pot has turned out to be a highly
efficient protocol for the synthesis of secondary amines
from alkynes and primary amines.
Scheme 1. Alkyne hydroamination/reduction sequence for the syn- dergo C–N bond-forming [2+2] cycloaddition reactions
thesis of secondary amines from alkynes and primary amines.
with the employed alkyne substrates yielding azatitanacy-
clobutenes. Subsequent protonation of the titanium–carbon
bond by excess amine and α-elimination of the hydroamin-
One of the most influential papers published in the field
of hydroamination chemistry appeared almost 20 years
ation products regenerate the catalytically active imido
ago.[2a] Therein, Walsh, Baranger, and Bergman reported
complexes.[6] Because the formation of titanium-imido com-
the first example of a zirconium complex that catalyzes the
plexes is essential for successful alkyne hydroamination the
intermolecular hydroamination of alkynes.[2] Unfortunately,
reaction is limited to primary amines. In addition, the pres-
ence of at least two labile ligands at the titanium center that
[a] Institut für Reine und Angewandte Chemie, Universität
can undergo protonolysis with the primary amine to form
Oldenburg,
the imido moiety is required. One major problem of the
hydroamination reactions mentioned above is the ability of
the catalytically active zirconium- or titanium-imido com-
plexes to undergo dimerization reactions that result in the
Carl-von-Ossietzky-Str. 9–11, 26111 Oldenburg, Germany
Fax: +49-441-798-3329
E-mail: doye@uni-oldenburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101298.
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Hydroamination of Alkynes with Primary Amines
formation of catalytically inactive bridging μ2-imido dimers. amido complexes are the catalytically active species, which
Although the dimerization seems to be reversible with tita- can undergo alkene insertion into the metal–nitrogen bond
nium-imido complexes,[6] zirconium-imido complexes with in the C–N bond-forming reaction. This suggestion was re-
nitrogen substituents that are sterically less demanding than cently supported by the finding of Schafer and co-workers
the 2,6-dimethylphenyl group are expected to dimerize irre- that bis(ureate)-zirconium complexes also catalyze the inter-
versibly.[7] This difference in reactivity, which is mainly molecular hydroamination of alkynes with secondary
caused by the different sizes of the titanium and zirconium amines.[12b] The insertion mechanism would also explain
atoms, has been used as one simple explanation[1c] for the why primary aminoalkenes with sterically less demanding
superior performance of titanium catalysts in intermo- NH2 groups are suitable substrates for Zr-catalyzed intra-
lecular alkyne hydroamination reactions. It also explains molecular hydroamination because it does not rely on the
why successful intermolecular Zr-catalyzed addition reac- formation of imido intermediates, which are supposed to
tions involving alkynes and primary amines that are steri- undergo irreversible dimerization. In respect of the various
cally less demanding than 2,6-dimethylaniline are still ex- experimental results and the ongoing discussion of the
tremely rare.[2,8] To the best of our knowledge, only one mechanism, we thought it would be helpful to find out
report exists that describes the very slow addition reactions whether zirconium catalysts can also be used for efficient
of aniline and ethylamine to (trimethylsilyl)acetylene (reac- intermolecular addition of sterically less demanding pri-
tion times: 9 and 20 d at 110 °C). Interestingly, these reac- mary amines to alkynes or not. To answer this question we
tions were achieved with 10 mol-% of a Zr catalyst that pos- herein report the use of [Zr(NMe2)4] in conjunction with
sesses three ancillary ligands and only one labile amido sulfonamides as a successful catalyst system in the intermo-
group. For this reason, this catalyst is expected not to gen- lecular alkyne hydroamination with a number of primary
erate an imido species under the reaction conditions.[8] amines including aryl- and alkylamines as well as sterically
However, another possible explanation for the poor cata- less demanding amines. Of the sulfonamides investigated,
lytic performance of zirconium catalysts in intermolecular sterically demanding tosylamides gave the best results.
alkyne hydroamination is that azametallacycle formation
between sterically less demanding zirconium-imido com-
Results and Discussion
plexes and alkyne substrates results in very stable intermedi-
Initially, to support the expectation that simple zirco-
ates that are either sluggish or unreactive in terms of cata-
nium catalysts are not able to catalyze the intermolecular
lytic turnover.
addition of sterically less demanding primary amines to al-
A significant improvement in the field of group 4 metal-
kynes we performed hydroamination experiments with 1-
catalyzed hydroamination chemistry was the finding that Ti
phenylpropyne (1) and p-toluidine (2) at 105 and 130 °C in
toluene in the presence of 5 mol-% of commercially avail-
complexes are also able to catalyze the intramolecular hy-
droamination of alkenes.[9] Although a large number of
able [Zr(NMe2)4] (Table 1, entries 1 and 2). As expected,
suitable Ti catalysts could be identified for the cyclization
of aminoalkenes,[10] it turned out that in this case, Zr cata-
Table 1. Hydroamination/reduction sequence performed with 1-
phenylpropyne (1) and p-toluidine (2).
lysts are catalytically far more active,[11] a finding that is in
sharp contrast to the behavior in alkyne hydroamination.
Particularly interesting is the fact that the cyclization of pri-
mary aminoalkenes performed with zirconium catalysts
does not require the presence of a sterically crowded amino
group. Clearly, in this case irreversible dimerization of in
situ generated zirconium-imido complexes or the formation
of stable intermediates does not represent a problem at all.
Entry
Sulfon-
amide
T [°C]
Yield [%][a,b]
3a/3b[c]
Although the majority of Ti and Zr catalysts only allow the
cyclization of aminoalkene substrates possessing primary
amino groups, there are a few examples of catalysts that
also allow cyclization reactions of secondary amino-
alkenes.[12,13] This finding led to an ongoing extensive dis-
cussion about the mechanism of the group 4 metal-cata-
lyzed intramolecular hydroamination of alkenes because
metal-imido complexes cannot be formed from titanium or
zirconium catalyst precursors and secondary amines. As a
consequence, metal-imido complexes cannot be the catalyti-
cally active species in hydroamination reactions performed
with secondary amines. Consequently, an alternative
mechanism for the Zr-catalyzed intramolecular hydroamin-
ation of alkenes has recently been proposed by Stubbert
and Marks.[13] In analogy to rare-earth-metal-catalyzed hy-
1
2
3
4
5
6
7
8
–
–
4
4
5
5
6
6
7
8
9
105
130
105
130
105
130
105
130
130
130
130
Ͻ1
Ͻ1
Ͻ1
Ͻ1
7
74
13
72
84
46
Ͻ1
–
–
–
–
87:13
86:14
95:5
88:12
90:10
92:8
–
9
10
11
[a] Reaction conditions: 1) Alkyne
1 (2.0 mmol), amine 2
(2.2 mmol), [Zr(NMe2)4] (0.1 mmol, 5 mol-%), sulfonamide
(0.2 mmol, 10 mol-%), toluene (2 mL), 105 or 130 °C, 96 h;
2) NaBH3CN (4.0 mmol), ZnCl2 (2.0 mmol), MeOH (10 mL),
25 °C, 20 h. [b] Yields refer to isolated compounds. [c] Determined
droamination reactions,[14] it is suggested that zirconium- by GC prior to chromatography.
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K. Born, S. Doye
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even after a long reaction time of 96 h and a subsequent solution of [Zr(NMe2)4] at room temperature led to the
reduction step (NaBH3CN, ZnCl2, MeOH, 25 °C, 20 h) it slow disappearance (within 2 h) of the NMe2 signal (singlet
was not possible to detect either of the potential products at δ = 2.98 ppm) of [Zr(NMe2)4]. During the reaction a new
3a or 3b in the crude reaction mixtures. Thus, in subsequent doublet at δ = 2.17 ppm, which can be assigned to dimeth-
hydroamination experiments we generated a number of zir- ylamine, and a new NMe2 signal (singlet) shifted downfield
conium catalysts in situ by combining 5 mol-% [Zr- to 3.13 ppm appeared. In addition, the signal of the tert-
(NMe2)4] and 10 mol-% of a sulfonamide (4–9, Figure 1) in butyl group of 5 (singlet at δ = 1.03 ppm) disappeared and
toluene and stirring the mixture at room temperature for a new singlet appeared at δ = 1.27 ppm. Integration of the
2 h prior to the addition of substrates 1 and 2. After heating new NMe2 and tBu signals at δ = 3.13 and 1.27 ppm sug-
the resulting reaction mixtures (105 or 130 °C) for 96 h and gested that one tBu group and three NMe2 groups are pres-
subsequent reduction the products 3a and 3b were formed ent in the newly formed species. This finding is in agreement
in a number of cases. Of the sulfonamides tested, the steri- with the formation of the mono-sulfonamide zirconium
cally more demanding derivatives 5–8 gave the best results species [(tBuNpTs)Zr(NMe2)3] from a 1:1 mixture of
(Table 1, entries 5–10) whereas the sterically less demanding [Zr(NMe2)4] and 5. Importantly, this species could only be
sulfonamides 4 and 9 turned out to be poor additives detected as a minor compound in the experiment with a 1:2
(Table 1, entries 3, 4, and 11). Overall, a maximum yield of mixture of [Zr(NMe2)4] and 5. In this case, a new NMe2
84% of the desired mixture of products 3a and 3b was ob- signal (broad singlet) appeared at δ = 3.35 ppm together
tained with N-(cyclohexyl)-p-toluenesulfonamide (7) at a re- with the signal of dimethylamine (in this experiment, a
action temperature of 130 °C for the hydroamination step. broad singlet at δ = 2.21 ppm). Integration of these two
In addition, good yields of 74 and 72% were obtained un- signals supported the expectation that 2 equiv. of dimeth-
der identical conditions with tert-butyl- and p-meth- ylamine are formed with two NMe2 groups remaining
oxyphenyl-substituted p-toluenesulfonamides
5 and 6, bonded to the Zr center. Integration of the new NMe2 sig-
respectively. As expected for a group 4 metal-catalyzed hy- nal at δ = 3.35 ppm relative to the new signal for the tBu
droamination of a 1-aryl-2-alkylalkyne the anti-Markovni- group at δ = 1.31 ppm is in agreement with the presence of
kov product 3a was always the major product of the reac- two tBu groups and two NMe2 groups. Although these data
tion.[1b,1c] However, note that the regioselectivity of the ad- strongly suggest the formation of a bis-sulfonamido zirco-
dition reaction, which is usually around 90:10, is signifi- nium species [(tBuNpTs)2Zr(NMe2)2], we believe that the
cantly influenced by the structure of the added sulfonamide. broadened signals do not allow the unequivocal confirm-
ation of this structure. Because the broad signals may be
caused by ligand-exchange processes it cannot be excluded
that other species are present in the mixture.
With these promising results in hand, we turned our at-
tention towards the corresponding reactions of 1-phenyl-
propyne (1) with cyclopentylamine (10) and n-hexylamine
(11; Table 2). These hydroamination reactions were also
successful in toluene at 130 °C in the presence of catalyst
systems generated in situ from mixtures of 5 mol-%
[Zr(NMe2)4] and 10 mol-% of one of the sulfonamides 5–9.
After a reaction time of 96 h and subsequent reduction, the
Figure 1. Sulfonamides used as additives in the Zr-catalyzed inter-
desired products were obtained as mixtures of regioisomers
molecular hydroamination of alkynes.
in moderate yields. With regard to the overall yield, the best
results were obtained with the sterically demanding N-(tert-
Interestingly, additional reaction sequences performed butyl)-p-toluenesulfonamide (5). Unfortunately, with this
with a 1:1 or 1:3 ratio of [Zr(NMe2)4] and the sulfonamide additive the regioselectivities of the hydroamination step
5 as the catalyst system did not lead to improved results. were poor, ranging between 50:50 and 53:47. Although bet-
For example, a mixture of 5 mol-% [Zr(NMe2)4] and 5 mol- ter regioselectivities of up to 87:13 were observed with other
% of 5 delivered the products 3a and 3b in a yield of only sulfonamide additives it should be noted that the corre-
53%, which is significantly lower than the yield of 74% ob- sponding Ti-catalyzed processes generally gave much better
tained with the 1:2 mixture (Table 1, entry 6). Neither was regioselectivities.[15]
the yield improved with a 1:3 mixture (69% isolated yield);
Once we had established that hydroamination reactions
in this case unreacted sulfonamide 5 was detected in the of 1-phenylpropyne (1) could be achieved with various pri-
crude product by GC analysis, which was not the case when mary amines using in situ generated mixtures of [Zr-
a 1:2 mixture was used. To acquire some preliminary infor- (NMe2)4] and sulfonamides, we examined the reactions of
mation about the structures of the species formed in the the sterically more demanding alkyne diphenylacetylene
reactions between sulfonamides and [Zr(NMe2)4], in situ (14). In this study we recognized that good results could
NMR studies were performed with mixtures of sulfonamide not be obtained when the hydroamination reactions were
5 and [Zr(NMe2)4] in C6D6 with ferrocene (δ = 4.00 ppm) performed at 130 °C. However, an increase in temperature
as an internal standard. The addition of 1 equiv. of 5 to a to 160 °C led to much better results (Table 3). After a reac-
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Hydroamination of Alkynes with Primary Amines
Table 2. Hydroamination/reduction sequences performed with 1-
phenylpropyne (1) and amines 10 and 11.
Table 3. Hydroamination/reduction sequence performed with di-
phenylacetylene (14) and various amines.
[a] Reaction conditions: 1) Alkyne 1 (2.0 mmol), amine (2.2 mmol),
[Zr(NMe2)4] (0.1 mmol, 5 mol-%), sulfonamide (0.2 mmol, 10 mol-
%), toluene (2 mL), 130 °C, 96 h; 2) NaBH3CN (4.0 mmol), ZnCl2
(2.0 mmol), MeOH (10 mL), 25 °C, 20 h. [b] Yields refer to isolated
compounds. [c] Determined by GC prior to chromatography.
tion time of 96 h it was possible to achieve successful ad-
dition reactions of p-toluidine (2), cyclopentylamine (10),
n-hexylamine (11), and benzylamine (15) with 14. Al-
though, the desired secondary amines 16–18 were obtained
in modest-to-very-good yields with most of the sulfon-
amides employed (5–9), the best results were observed with
the sterically demanding N-(tert-butyl)-p-toluenesulfon-
amide (5). Most impressively, with this additive, the hydro-
amination/reduction sequence performed with the sterically
less demanding n-hexylamine (11) gave the product 18 in
[a] Reaction conditions: 1) Alkyne 14 (2.0 mmol), amine
(2.2 mmol), [Zr(NMe2)4] (0.1 mmol, 5 mol-%), sulfonamide
(0.2 mmol, 10 mol-%), toluene (2 mL), 160 °C, 96 h; 2) NaBH3CN
(4.0 mmol), ZnCl2 (2.0 mmol), MeOH (10 mL), 25 °C, 20 h. [b]
Yields refer to isolated pure compounds.
93% yield. The superior suitability of the N-(tert-butyl)sul- obtained with these last three sulfonamides clearly indicates
fonamide 5 as an additive for the Zr-catalyzed hydroamin- that these additives do not differ significantly in their cata-
ation step is additionally supported by the fact that a suc- lytic performance. Thus, one can conclude that the elec-
cessful reaction between diphenylacetylene (14) and ben- tronic properties of the sulfonamide are less important for
zylamine (15) could only be achieved with 5 (Table 3, en- the catalytic performance than its size.
try 20). Particularly surprising is the fact that one of the
We next turned our attention towards the reactions of
hydroamination reactions, namely the addition of p-tolu- terminal alkynes 1-octyne (23) and phenylacetylene (25).
idine (2) to 14, could also be achieved in the absence of The hydroamination reactions were performed with p-tolu-
sulfonamide (Table 3, entry 1). However, the yield of the re- idine (2) and 5 mol-% [Zr(NMe2)4] either in the presence
action sequence was only moderate.
or absence of 10 mol-% sulfonamide 5 (Scheme 2). Because
In addition to the p-toluenesulfonamide derivatives 4–9, terminal alkynes are known to undergo hydroamination re-
we also studied a number of other N-(tert-butyl)sulfon- actions under much milder conditions than internal al-
amides. For this purpose, the methylsulfonyl (20), p-tri- kynes,[15] the hydroamination step was always performed at
fluoromethylphenylsulfonyl (21), and p-methoxyphenylsulf- 105 °C. After a relatively short reaction time of 24 h and
onyl (22) derivatives were used as alternative additives in subsequent reduction it was possible in all cases to isolate
the hydroamination/reduction sequence of diphenylacetyl- the desired secondary amines in modest yields. Particularly
ene (14) and p-toluidine (2) under the already established interesting is the fact that addition of a sulfonamide to the
conditions (Table 4). In this study the sterically less de- reaction mixture is not necessary for successful hydroamin-
manding methanesulfonamide 20 gave
a poor yield ation reactions. Note, however, that the sulfonamide addi-
(Table 4, entry 2), whereas the three bulkier aromatic sul- tive significantly influences the regioselectivity of the hy-
fonamides 5, 21, and 22 led to the isolation of the product droamination. For example, the Markovnikov regioisomer
16 in high yields (82–90%). A comparison of the results 24b was obtained almost exclusively (24a/24b = 4:96) from
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767

K. Born, S. Doye
FULL PAPER
Table 4. Hydroamination/reduction sequence performed in the effect was found for the addition of p-toluidine (2) to phen-
presence of various N-(t-butyl)sulfonamides.
ylacetylene (25). Although use of the catalyst [Zr(NMe2)4]
led to the preferred formation of the Markovnikov re-
gioisomer 26b (26a/26b = 25:75), the selectivity was re-
versed when a mixture of 5 mol-% [Zr(NMe2)4] and 10 mol-
% sulfonamide 5 was used as the catalytic system.
Finally, we attempted additional reaction sequences with
the secondary amines morpholine and N-methylbenzyl-
amine. However, by using a mixture of 5 mol-% [Zr-
(NMe2)4] and 10 mol-% sulfonamide 5 as the catalyst sys-
tem, no reaction was observed with the alkynes 1-phenyl-
propyne (1) and phenylacetylene (25) when the hydroamin-
ation step was performed at 105 or 130 °C for 96 h.
Conclusions
We have shown that zirconium-based catalyst systems
can be used successfully for intermolecular hydroamination
reactions of alkynes with primary amines that are sterically
less demanding than 2,6-dimethylaniline. The catalysts can
be simply generated in situ by using a combination of
5 mol-% [Zr(NMe2)4] and 10 mol-% of a sulfonamide in tol-
uene and stirring the mixture at room temperature for 2 h
prior to the addition of the substrates. At elevated tempera-
[a] Reaction conditions: 1) Alkyne 14 (2.0 mmol), amine
2
tures, hydroamination can be achieved with internal and
terminal alkynes as well as with sterically demanding and
less demanding primary amines. In contrast, secondary
amines do not react under identical conditions. Of the
sulfonamide additives investigated in our study, sterically
demanding tosylamides such as N-(tert-butyl)-p-toluene-
sulfonamide (5) gave the best results. Interestingly, the re-
gioselectivity of the addition of amines to unsymmetrically
substituted internal as well as terminal alkynes is signifi-
cantly influenced by the nature of the sulfonamide additive.
In particular, the successful use of sterically less demanding
primary amines such as n-hexyl- or benzylamine clearly in-
dicates that the simple assumption that Zr catalysts irrevers-
ibly form catalytically inactive bridging μ2-imido dimers or
other unreactive intermediates in the presence of these
amines[1c] is not correct. This finding is very important for
a better and more general understanding of the mechanism
of group 4 metal-catalyzed hydroamination reactions.
(2.2 mmol), [Zr(NMe2)4] (0.1 mmol, 5 mol-%), sulfonamide
(0.2 mmol, 10 mol-%), toluene (2 mL), 160 °C, 96 h; 2) NaBH3CN
(4.0 mmol), ZnCl2 (2.0 mmol), MeOH (10 mL), 25 °C, 20 h. [b]
Yields refer to isolated pure compounds.
1-octyne (23) and p-toluidine (2) with the catalyst precursor
[Zr(NMe2)4] whereas the regioselectivity was only 41:59
when the reaction was performed in the presence of 10 mol-
% of the additive 5. In this context it must be noted that the
observed preference for the formation of the Markovnikov
regioisomer 24b is in good agreement with the correspond-
ing results reported for the Ti-catalyzed addition of aryl-
amines to terminal alkylalkynes.[1b,1c,15,16] An even stronger
Experimental Section
General: All reactions were performed under an inert atmosphere
of nitrogen in oven-dried Schlenk tubes (Duran glassware, 100 mL,
Ø 30 mm) equipped with Teflon® stopcocks and magnetic stirring
bars (15ϫ4.5 mm). [Zr(NMe2)4], N-methyl-p-toluenesulfonamide
(4), and toluene (extra dry toluene with molecular sieves) were pur-
chased from Acros Organics. Prior to use, volatile alkynes and
amines were purified and dried by distillation (20 cm Vigreux col-
umn) from CaH2 on molecular sieves at ambient pressure under an
inert atmosphere. Diphenylacetylene (14) was purified by kugelrohr
distillation. The synthesis and purification of the sulfonamides 5–
9 and 20–22 are described in the Supporting Information. All other
reagents were purchased from commercial sources and were used
without further purification. All alkynes, amines, sulfonamides, and
Scheme 2. Hydroamination/reduction sequences with terminal
alkynes using sulfonamide 5 as an additive.
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Hydroamination of Alkynes with Primary Amines
[Zr(NMe2)4] were stored in a nitrogen-filled glove-box (M. Braun,
Unilab). Unless otherwise noted, yields refer to isolated yields of
pure compounds as gauged by thin-layer chromatography (TLC)
[Zr(NMe2)4] and 10 mol-% tBuNHpTs (5). The regioisomeric ratio
12a/12b was determined to be 53:47. After purification by flash
chromatography (PE/EtOAc, 40:1), a mixture of 12a and 12b
(267 mg, 1.30 mmol, 65%) was obtained as a colorless oil. 1H
NMR (500 MHz, CDCl3, important signals of the mixture of 12a
1
and H and 13C NMR spectroscopy. The ratio of regioisomers was
determined by gas chromatography prior to purification by flash
chromatography. For TLC, Polygram® SIL G/UV254 plates from and 12b): δ = 0.71 (t, J = 7.4 Hz, 3 H), 0.98 (d, J = 6.2 Hz, 3 H),
Macherey–Nagel were used. The substances were detected with UV
light and/or iodine. For flash chromatography, silica gel from Fluka
(particle size 0.040–0.063 mm) was used. Prior to use in flash
chromatography, light petroleum ether (PE, boiling range 40–
60 °C) and EtOAc were distilled. All products were identified by
comparison of their 1H and 13C NMR spectroscopic data with
those reported in the literature.[15,17] NMR spectra were recorded
with Bruker Avance DRX 500 and Bruker Avance III 500 MHz
spectrometers. All NMR spectra are reported in δ (ppm) relative to
the signal of TMS at δ = 0.00 ppm (1H NMR) and to the central
line of the triplet of CDCl3 at δ = 77.0 ppm (13C NMR). GC analy-
ses were performed with a Shimadzu GC-2010 gas chromatograph
equipped with a flame ionization detector.
2.51 (dd, J = 6.2 Hz, 3 H), 2.67 (dd, J = 6.2 Hz, 3 H), 2.78 (quint.,
J = 7.1 Hz, 1 H), 2.89 (sext, J = 6.4 Hz, 1 H), 3.11 (quint., J =
7.1 Hz, 1 H), 3.45 (dd, J = 5.9, 8.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, DEPT, CDCl3, important signals of the mixture of 12a
and 12b): δ = 10.9 (CH3), 20.5 (CH3), 52.9 (CH), 56.9 (CH), 57.1
(CH), 63.5 (CH), 139.6 (C), 144.5 (C) ppm.
Amines 13a and 13b:[17] The general procedure was used to synthe-
size a mixture of 13a and 13b from 1-phenylpropyne (1; 232 mg,
2.0 mmol) and n-hexylamine (11; 206 mg, 2.2 mmol). The hydro-
amination was performed at 130 °C for 96 h with 5 mol-%
[Zr(NMe2)4] and 10 mol-% tBuNHpTs (5). The regioisomeric ratio
13a/13b was determined to be 50:50. After purification by flash
chromatography (PE/EtOAc, 40:1), a mixture of 13a and 13b
(202 mg, 0.92 mmol, 46%) was obtained as a colorless oil. 1H
NMR (500 MHz, CDCl3, important signals of the mixture of 13a
and 13b): δ = 0.70 (t, J = 7.5 Hz, 3 H), 0.96 (d, J = 6.3 Hz, 3 H),
2.79 (sext, J = 6.4 Hz, 1 H), 3.37 (dd, J = 5.8, 8.0 Hz, 1 H) ppm.
13C NMR (125 MHz, DEPT, CDCl3, important signals of the mix-
ture of 13a and 13b): δ = 10.6 (CH3), 13.8 (CH3), 14.0 (CH3), 20.0
(CH3), 21.2 (CH3), 43.4 (CH2), 47.2 (CH2), 47.6 (CH2), 54.5 (CH),
65.0 (CH), 139.3 (C), 144.1 (C) ppm.
General Procedure for the Hydroamination of Alkynes: A Schlenk
tube equipped with a Teflon® stopcock and a magnetic stirring bar
was transferred into a nitrogen-filled glove-box and charged with
[Zr(NMe2)4] (0.1 mmol, 5 mol-%), toluene (0.3 mL), a sulfonamide
(0.2 mmol, 10 mol-%) and toluene (0.7 mL). The resulting mixture
was stirred for 2 h at room temperature. Then the alkyne
(2.0 mmol), the amine (2.2 mmol), and toluene (1.0 mL) were
added to the Schlenk tube. The tube was sealed and the resulting
mixture was heated at 105–160 °C for 24–96 h. After the mixture
had cooled to room temperature, NaBH3CN (302 mg, 4.80 mmol,
2.0 equiv.), ZnCl2 (328 mg, 2.40 mmol, 1.0 equiv.), and MeOH
(10 mL) were added. After stirring this mixture at 25 °C for 20 h,
CH2Cl2 (50 mL) and saturated aqueous Na2CO3 solution (20 mL)
were added. The resulting mixture was filtered and the solid residue
was washed with CH2Cl2 (50 mL). After extraction, the organic
layer was separated. The aqueous layer was extracted with CH2Cl2
(6ϫ50 mL) and the combined organic layers were dried with
MgSO4. After concentration under vacuum, the regioisomeric ratio
was determined by GC (if applicable), and the crude product was
purified by flash chromatography (SiO2).
Amine 16:[15] The general procedure was used to synthesize 16 from
diphenylacetylene (14; 356 mg, 2.0 mmol) and p-toluidine (2;
235 mg, 2.2 mmol). The hydroamination was performed at 160 °C
for 96 h with 5 mol-% [Zr(NMe2)4] and 10 mol-% tBuNHpTs (5).
After purification by flash chromatography (PE/EtOAc, 40:1),
product 16 (499 mg, 1.74 mmol, 87%) was obtained as a beige so-
1
lid. H NMR (500 MHz, CDCl3): δ = 2.07 (s, 3 H), 2.91 (dd, J =
8.2, 14.0 Hz, 1 H), 3.03 (dd, J = 5.7, 14.0 Hz, 1 H), 3.89 (br. s, 1
H), 4.47 (dd, J = 5.7, 8.2 Hz, 1 H), 6.29 (d, J = 8.5 Hz, 2 H), 6.77
(d, J = 8.1 Hz, 2 H), 7.09–7.29 (m, 10 H) ppm. 13C NMR
(125 MHz, DEPT, CDCl3): δ = 20.3 (CH3), 45.1 (CH2), 59.4 (CH),
113.8 (CH), 126.5 (CH), 126.5 (C), 126.6 (CH), 128.5 (CH), 128.5
(CH), 129.2 (CH), 129.5 (CH), 131.6 (CH), 137.8 (C), 143.6 (C),
145.0 (C) ppm.
Amines 3a and 3b:[15] The general procedure was used to synthesize
a mixture of 3a and 3b from 1-phenylpropyne (1; 232 mg,
2.0 mmol) and p-toluidine (2; 235 mg, 2.2 mmol). The hydroamin-
ation was performed at 130 °C for 96 h with 5 mol-% [Zr(NMe2)4]
and 10 mol-% tBuNHpTs (5). The regioisomeric ratio 3a/3b was
determined to be 86:14. After purification by flash chromatography
(PE/EtOAc, 20:1), a mixture of 3a and 3b (335 mg, 1.49 mmol,
74%) was obtained as a colorless oil. 1H NMR (500 MHz, CDCl3,
mixture of 3a and 3b): δ = 1.18 (t, J = 7.4 Hz, 3 H), 1.36 (d, J =
6.5 Hz, 3 H), 1.95–2.20 (m, 2 H), 2.43 (s, 3 H), 2.51 (s, 3 H), 2.90
(dd, J = 7.4, 13.4 Hz, 1 H), 3.16 (dd, J = 4.7, 13.4 Hz, 1 H), 3.60
(br. s, 1 H), 3.90–4.05 (m, 1 H), 4.43 (t, J = 6.7 Hz, 1 H), 6.68 (d,
J = 8.4 Hz, 2 H), 6.80 (d, J = 8.3 Hz, 2 H), 7.14 (d, J = 8.3 Hz, 1
H), 7.26 (d, J = 8.4 Hz, 2 H), 7.30–7.65 (m, 2ϫ 5 H) ppm. 13C
NMR (125 MHz, DEPT, CDCl3, mixture of 3a and 3b): δ = 10.7
(CH3), 20.0 (CH3), 20.2 (CH3), 20.3 (CH3), 31.5 (CH2), 42.1 (CH2),
49.5 (CH), 59.8 (CH), 113.2 (CH), 113.5 (CH), 126.1 (CH), 126.2
(CH), 128.2 (CH), 129.4 (CH), 129.5 (CH), 129.8 (CH), 138.5 (C),
144.0 (C), 144.8 (C), 145.1 (C) ppm.
Amine 17:[15] The general procedure was used to synthesize 17 from
diphenylacetylene (14; 356 mg, 2.0 mmol) and cyclopentylamine
(10; 173 mg, 2.2 mmol). The hydroamination was performed at
160 °C for 96 h with 5 mol-% [Zr(NMe2)4] and 10 mol-%
tBuNHpTs (5). After purification by flash chromatography (PE/
EtOAc, 40:1), product 17 (368 mg, 1.39 mmol, 70%) was obtained
as a beige solid. 1H NMR (500 MHz, CDCl3): δ = 0.95–1.08 (m, 2
H), 1.18–1.28 (m, 2 H), 1.30–1.44 (m, 2 H), 1.51–1.64 (m, 2 H),
2.69–2.85 (m, 3 H), 3.80 (dd, J = 6.1, 8.1 Hz, 1 H), 6.94–7.24 (m,
10 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3): δ = 23.3 (CH2),
23.3 (CH2), 32.1 (CH2), 33.5 (CH2), 45.2 (CH2), 57.1 (CH), 63.0
(CH), 126.0 (CH), 126.7 (CH), 127.1 (CH), 128.0 (CH), 128.1
(CH), 129.0 (CH), 138.8 (C), 144.0 (C) ppm.
Amine 18:[15] The general procedure was used to synthesize 18 from
diphenylacetylene (14; 356 mg, 2.0 mmol) and n-hexylamine (11;
206 mg, 2.2 mmol). The hydroamination was performed at 160 °C
for 96 h with 5 mol-% [Zr(NMe2)4] and 10 mol-% tBuNHpTs (5).
After purification by flash chromatography (PE/EtOAc, 40:1),
product 18 (523 mg, 1.86 mmol, 93%) was obtained as a white so-
lid. 1H NMR (500 MHz, CDCl3): δ = 0.93 (t, J = 7.2 Hz, 3 H),
Amines 12a and 12b:[15] The general procedure was used to synthe-
size a mixture of 12a and 12b from 1-phenylpropyne (1; 232 mg,
2.0 mmol) and cyclopentylamine (10; 173 mg, 2.2 mmol). The hy-
droamination was performed at 130 °C for 96 h with 5 mol-% 1.22–1.36 (m, 6 H), 1.38–1.50 (m, 2 H), 1.54 (br. s, 1 H), 2.41–2.55
Eur. J. Org. Chem. 2012, 764–771
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
769

K. Born, S. Doye
FULL PAPER
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(m, 2 H), 2.98 (dd, J = 8.3, 13.4 Hz, 1 H), 3.04 (dd, J = 5.9,
13.4 Hz, 1 H), 3.94 (dd, J = 5.9, 8.2 Hz, 1 H), 7.20–7.45 (m, 10
H) ppm. 13C NMR (125 MHz, DEPT, CDCl3): δ = 13.7 (CH3),
22.3 (CH2), 26.5 (CH2), 29.6 (CH2), 31.4 (CH2), 45.1 (CH2), 47.4
(CH2), 64.6 (CH), 126.0 (CH), 126.6 (CH), 127.0 (CH), 127.9 (CH),
128.0 (CH), 128.9 (CH), 138.7 (C), 143.8 (C) ppm.
Amine 19:[15] The general procedure was used to synthesize 19 from
diphenylacetylene (14; 356 mg, 2.0 mmol) and benzylamine (15;
235 mg, 2.2 mmol). The hydroamination was performed at 160 °C
for 96 h with 5 mol-% [Zr(NMe2)4] and 10 mol-% tBuNHpTs (5).
After purification by flash chromatography (PE/EtOAc, 20:1),
product 19 (391 mg, 1.36 mmol, 68%) was obtained as a colorless
[2]
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For selected examples of Ti-catalyzed hydroamination of al-
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5013; e) L. Ackermann, R. G. Bergman, Org. Lett. 2002, 4,
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Org. Lett. 2003, 5, 4767–4770; j) L. Ackermann, R. G.
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4736; l) V. Khedkar, A. Tillack, M. Michalik, M. Beller, Tetra-
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Garcia Castro, C. G. Hartung, M. Beller, Chem. Eur. J. 2004,
10, 2409–2420; n) A. Tillack, V. Khedkar, M. Beller, Tetrahe-
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Jiao, M. Beller, Eur. J. Org. Chem. 2005, 5001–5002; p) A.
Heutling, F. Pohlki, I. Bytschkov, S. Doye, Angew. Chem. 2005,
117, 3011–3013; Angew. Chem. Int. Ed. 2005, 44, 2951–2954;
q) D. Mujahidin, S. Doye, Eur. J. Org. Chem. 2005, 2689–2693;
r) K. Marcseková, B. Wegener, S. Doye, Eur. J. Org. Chem.
2005, 4843–4851; s) M. A. Esteruelas, A. M. López, A. C. Ma-
teo, E. Oñate, Organometallics 2005, 24, 5084–5094; t) M. A.
Esteruelas, A. M. López, A. C. Mateo, E. Oñate, Organometal-
lics 2006, 25, 1448–1460; u) D. L. Swartz II, A. L. Odom, Orga-
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teruelas, A. M. López, A. C. Mateo, Organometallics 2006, 25,
4079–4089; w) A. V. Lee, L. L. Schafer, Synlett 2006, 2973–
2976; x) M. L. Buil, M. A. Esteruelas, A. M. López, A. C. Ma-
teo, E. Oñate, Organometallics 2007, 26, 554–565; y) Z. Zhang,
D. C. Leitch, M. Lu, B. O. Patrick, L. L. Schafer, Chem. Eur.
J. 2007, 13, 2012–2022; z) R. Severin, D. Mujahidin, J. Reimer,
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C. Elschenbroich, Organometallchemie, 4th ed., Teubner, Stutt-
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Chem. Int. Ed. 2001, 40, 2305–2308.
P. J. Walsh, F. J. Hollander, R. G. Bergman, J. Am. Chem. Soc.
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2005, 7, 1959–1962.
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1
oil. H NMR (500 MHz, CDCl3): δ = 1.82 (br. s, 1 H), 2.92–3.11
(m, 2 H), 3.55 (d, J = 13.6 Hz, 1 H), 3.75 (d, J = 13.6 Hz, 1 H),
3.98 (dd, J = 5.5, 8.5 Hz, 1 H), 7.15–7.22 (m, 4 H), 7.25–7.50 (m,
11 H) ppm. 13C NMR (125 MHz, DEPT, CDCl3): δ = 45.3 (CH2),
51.3 (CH2), 63.6 (CH), 126.3 (CH), 126.7 (CH), 127.1 (CH), 127.4
(CH), 127.9 (CH), 128.2 (CH), 128.3 (CH), 129.2 (CH), 138.8 (C),
140.4 (C), 143.7 (C) ppm.
Amine 24b:[15] The general procedure was used to synthesize 24b
from 1-octyne (23; 220 mg, 2.0 mmol) and p-toluidine (2; 235 mg,
2.2 mmol). The hydroamination was performed at 105 °C for 24 h
with 5 mol-% [Zr(NMe2)4]. The regioisomeric ratio 24a/24b was de-
termined to be 4:96. After purification by flash chromatography
(PE/EtOAc, 20:1), 24b (197 mg, 0.90 mmol, 45%) was obtained as
1
a yellow oil. H NMR (500 MHz, CDCl3): δ = 0.82 (t, J = 6.4 Hz,
3 H), 1.06 (d, J = 6.4 Hz, 3 H), 1.15–1.42 (m, 9 H), 1.44–1.52 (m,
1 H), 2.14 (s, 3 H), 3.29–3.33 (m, 2 H), 6.44 (d, J = 8.2 Hz, 2 H),
6.88 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (125 MHz, DEPT,
CDCl3): δ = 14.0 (CH3), 20.3 (CH3), 20.7 (CH3), 22.6 (CH2), 26.1
(CH2), 29.3 (CH2), 31.8 (CH2), 37.1 (CH2), 48.9 (CH), 113.4 (CH),
126.0 (C), 129.7 (CH), 145.2 (C) ppm.
Amines 26a and 26b:[15] The general procedure was used to synthe-
size a mixture of 26a and 26b from phenylacetylene (25; 204 mg,
2.0 mmol) and p-toluidine (2; 235 mg, 2.2 mmol). The hydroamin-
ation was performed at 105 °C for 24 h with 5 mol-% [Zr(NMe2)4]
and 10 mol-% tBuNHpTs (5). The regioisomeric ratio 26a/26b was
determined to be 75:25. After purification by flash chromatography
(PE/EtOAc, 20:1), a mixture of 26a and 26b (115 mg, 0.56 mmol,
28%) was obtained as a yellow oil. 1H NMR (500 MHz, CDCl3,
mixture of 26a and 26b): δ = 1.42 (d, J = 6.7 Hz, 3 H), 2.11 (s, 3
H), 2.16 (s, 3 H), 2.83 (t, J = 7.0 Hz, 2 H), 3.30 (t, J = 7.0 Hz, 3
H), 3.66 (br. s, 1 H), 4.37 (q, J = 6.7 Hz, 1 H), 6.35 (d, J = 8.2 Hz,
2 H), 6.47 (d, J = 8.2 Hz, 2 H), 6.82 (d, J = 8.2 Hz, 2 H), 6.92 (d,
J = 8.1 Hz, 2 H), 7.14–7.28 (m, 2ϫ 5 H) ppm. 13C NMR
(125 MHz, DEPT, CDCl3, mixture of a and b): δ = 20.3 (CH3),
20.4 (CH3), 25.0 (CH3), 35.5 (CH2), 45.4 (CH2), 53.6 (CH), 113.2
(CH), 113.4 (CH), 125.8 (CH), 126.4 (CH), 126.7 (C), 126.8 (CH),
128.6 (CH), 128.8 (CH), 129.6 (CH), 129.8 (CH), 139.4 (C), 145.0
(C), 145.4 (C), 145.7 (C) ppm.
[5]
[6]
[7]
[8]
[9]
[10]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for the synthesis of sulfonamides and
characterization data.
Acknowledgments
We thank the Deutsche Forschungsgemeinschaft (DFG) for finan-
cial support of our research. We also thank Daniel Jaspers for the
preparation of sulfonamides 5, 6, and 7.
[1] For selected reviews on the hydroamination of alkynes, see: a)
F. Pohlki, S. Doye, Chem. Soc. Rev. 2003, 32, 104–114; b) I.
770
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 764–771

Hydroamination of Alkynes with Primary Amines
[11] For selected examples of the Zr-catalyzed intramolecular hy-
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[12]
For examples of group 4 metal-catalyzed intramolecular hy-
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A. L. Odom, Organometallics 2008, 27, 1174–1177; b) D. C. Le-
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B. D. Stubbert, T. J. Marks, J. Am. Chem. Soc. 2007, 129, 6149–
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For reviews on rare-earth-metal-catalyzed hydroamination, see:
a) S. Hong, T. J. Marks, Acc. Chem. Res. 2004, 37, 673–686; b)
K. C. Hultzsch, Adv. Synth. Catal. 2005, 347, 367–391; c) K. C.
Hultzsch, Org. Biomol. Chem. 2005, 3, 1819–1824; d) K. C.
Hultzsch, D. V. Gribkov, F. Hampel, J. Organomet. Chem.
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[13]
[14]
[15] A. Heutling, F. Pohlki, S. Doye, Chem. Eur. J. 2004, 10, 3059–
3071.
[16] I. Bytschkov, S. Doye, Eur. J. Org. Chem. 2001, 4411–4418.
[17] A. Heutling, S. Doye, J. Org. Chem. 2002, 67, 1961–1964.
Received: September 6, 2011
Published Online: December 12, 2011
Eur. J. Org. Chem. 2012, 764–771
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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