Zirconocene-Initiated Intramolecular Hydride Transfer in N -Isoalkyl-Substituted Propargylamines

Article abstract of DOI:10.1055/s-0037-1609336

The unusual transformation of N -isoalkyl-substituted propargylamines into alkenylamines under the action of Cp ₂ ZrCl ₂ and organoaluminum compounds (Me ₃ Al, EtAlCl ₂) has been observed. The proposed mechanism, involving the N -isoalkyl-substituted propargylamine undergoing zirconocene-initiated intramolecular hydride transfer was supported by B3LYP/6-31G(d)/LanL2DZ calculations.

Full text of DOI:10.1055/s-0037-1609336

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
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A
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I. R. Ramazanov et al.
Letter
Synlett
Zirconocene-Initiated Intramolecular Hydride Transfer in N-Iso-
alkyl-Substituted Propargylamines
Ilfir R. Ramazanov*
Rita N. Kadikova
R3
N
H
N
1. Cp2ZrCl2 (0.2–1 equiv)
Me3Al or EtAlCl2 (2 equiv)
CH2Cl2, 40 °C, 3 h
R4
H
R2
R2
Zukhra R. Saitova
Usein M. Dzhemilev
R1
R1
H
2. H2O
69–89%
11 examples
R1 = Alk, Ph
R2 = i-Pr, ArCH2, c-Hex
R3R4CH = i-Pr, c-Hex, Ph(Me)CH
Institute of Petrochemistry and Catalysis of Russian Academy of
Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Russian Federation
ilfir.ramazanov@gmail.com
H2O
R2
Cp2ZrX
R3
4 R3
R2
R
R4
N
N
X = Me, Cl
H
H
R1
hydride transfer
Zr(X)Cp2
R1
Zr(X)Cp2
Received: 23.01.2018
Accepted after revision: 10.02.2018
Published online: 08.03.2018
substituted propargylamine (N-benzylpent-2-yn-1-amine);
however, the yield of iodoalkene after iodinolysis was only
26%.7 We were curious to find out why the substituted
propargylamines we tested were inactive towards the
Cp2ZrCl2-Me3Al reagent. Then we turned to studies dealing
with polymerization of nitrogen-containing monomers in
the presence of titanium complexes,8–10 according to which
polymerization is possible only in the case where the nitro-
gen atom is shielded by bulky branched alkyl groups. More-
over, monomers containing a dimethyl- or diethylamino
group almost completely deactivate the catalyst that is
quite reasonable. It is known that Ti-catalyzed polymeriza-
tion of olefins involves positively charged titanium com-
plexes,11 which can be easily bound to the substrate nitro-
gen atoms. The presence of bulky substituents at nitrogen
prevents the complex formation and facilitates the reaction
at the unsaturated bond. A similar situation may occur in
the case of Zr-catalyzed methylalumination of substituted
propargylamines. The mechanism of alkyne methylalumi-
nation under the action of Cp2ZrCl2 has been interpreted in
different ways ranging from Zr-assisted direct methyl-
alumination12 to methylzirconation.13 Possibly, the reaction
of acetylenic compounds with Cp2ZrCl2-Me3Al can proceed
either as Al-assisted carbozirconation or as Zr-assisted car-
boalumination, depending on the unsaturated substrate.14
In the general case, it can be stated that the reaction in-
volves Al/Zr cationic species. We assumed that the presence
of bulky substituents at the nitrogen atom in a substituted
propargylamine molecule would be favorable for Zr-cata-
lyzed methylalumination.
DOI: 10.1055/s-0037-1609336; Art ID: st-2018-d0788-l
Abstract The unusual transformation of N-isoalkyl-substituted prop-
argylamines into alkenylamines under the action of Cp2ZrCl2 and orga-
noaluminum compounds (Me3Al, EtAlCl2) has been observed. The pro-
posed mechanism, involving the N-isoalkyl-substituted propargylamine
undergoing zirconocene-initiated intramolecular hydride transfer was
supported by B3LYP/6-31G(d)/LanL2DZ calculations.
Key words alkenylamine, hydride transfer, negative hyperconjugation,
propargylamine, zirconocene cation
Zirconium-catalyzed carbo-1 and cycloalumination2 of
alkynes are among the preferred methods for the synthesis
of trisubstituted alkenes. These methods are well suited for
alkyl- and aryl-substituted alkynes and, therefore, they are
widely used to synthesize natural products and their ana-
logues.3 However, the presence of a heterofunctional group
in the alkyne substrate may promote side reactions. While
studying Zr-catalyzed cycloalumination of acetylenic alco-
hols and substituted propargylamines, we ran across some
limitations of the method as regards substituted propargyl
alcohols, but the cycloalumination of alkyl-substituted
propargylamines occurred regioselectively with high yield.
All our subsequent attempts to perform the reaction of alk-
2-ynyl-substituted N,N-dimethylamine and piperidine
(N,N-dimethylhept-2-yn-1-amine, N,N-dimethylnon-2-yn-
1-amine, 1-(non-2-yn-1-yl)piperidine) with Cp2ZrCl2-Me3Al
reagent were unsuccessful. This was surprising, because
N,N-dimethylhept-2-yn-1-amine was only twofold less re-
active towards cycloalumination than 5-decyne.4 Despite
the fact that methylalumination has been accomplished for
heterosubstituted arylethynes containing O, S, and Cl5 and
even for propargyl alcohols,6 by the beginning of our stud-
ies, there was a single example of methylalumination of
We found that N,N-diisopropyl-substituted propargyl-
amines (N,N-diisopropyloct-2-yn-1-amine, N,N-diisopro-
pylundec-2-yn-1-amine, and N,N-diisopropyl-3-phenyl-
prop-2-yn-1-amine) proved to react with 2 equivalents of
Me3Al and 1 equivalent of Cp2ZrCl2 in dichloromethane at
40 °C to give after deuterolysis or hydrolysis E-alkenyl-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
I. R. Ramazanov et al.
Letter
Synlett
amines 1a–d within 3 hours with high regio- and stereo-
selectivity and in high yield (77–88%, Scheme 1).15 N,N,N,N-
Tetraisopropyldeca-2,8-diyne-1,10-diamine containing two
acetylenic bonds was easily converted, under the reaction
conditions, into diamine 2 in 89% yield. The stereochemical
configuration of the resulting allylamines was reliably es-
tablished by single-crystal X-ray diffraction study of (E)-N-
isopropyloct-1-en-1-aminium chloride and (E)-N-isopro-
pyl-3-phenylprop-2-en-1-aminium chloride, obtained from
the compounds 1c,d, and by the NOESY spectra of the com-
pounds 1c,d, which showed coupling between the methy-
lene group at nitrogen and the hydrogen atom at the double
bond. The structure of obtained E-alkenylamines 1 and 2
did not correspond to the expected methylalumination
products. First, the compounds 1 and 2 are formally the
products of alkyne hydrometalation, which is unusual for
Me3Al. Second, one isopropyl group at the nitrogen atom is
eliminated during the reaction.
atoms of functional groups such as CH2OH, NH2, NH, and
COOH are well-known to easily exchange with deuterium
(hence, deuterium atoms can be replaced by hydrogens) on
any adsorbents.16
Further investigation of this reaction demonstrated that
N,N-diisopropyl-substituted propargylamines are fully con-
verted into E-alkenylamines 1 and 2 also under the action
of 0.2 equivalents of Cp2ZrCl2 and 2 equivalents of Me3Al,
and also with EtAlCl2 used instead of Me3Al with catalytic
or stoichiometric amounts of Cp2ZrCl2. However, the re-
placement of Cp2ZrCl2 by Cp2TiCl2 results in complete inhi-
bition of the reaction. The reaction also does not occur if
only Me3Al or EtAlCl2 is used without the zirconium salt.
So, our assumption that the presence of bulky substitu-
ents at nitrogen prevents the complex formation and facili-
tates the reaction at the unsaturated bond was true. There-
fore, the unreactivity of N-butyl-N-isopropyloct-2-yn-1-
amine was not a surprise to us. Unfortunately, our attempts
to extend the reaction to N,N-dibenzyl- and N,N-dicyclo-
hexyl(1-alkynyl)amines were unsuccessful. These com-
pounds were unreactive under the reaction conditions. This
result was unexpected, because both benzyl and cyclohexyl
groups are bulky substituents. Considering a special role of
the N-isopropyl group, we prepared N-isopropylpropargyl-
amines containing naphthalen-1-ylmethyl, 4-methoxy-
benzyl, and cyclohexyl substituents at the nitrogen atom. In
the first two cases (Table 1, entries 1 and 2), the reaction
with Me3Al and Cp2ZrCl2 was accompanied by isopropyl
group elimination and gave, after hydrolysis, E-alkenyl-
amines 3a,b in high yield (83–86%). In the case of propar-
gylamines with N-cyclohexyl substituent (Table 1, entries
3–5), the yield of E-alkenylamines 3c–e was lower, being
only 48–58%, which was caused by the formation of cycloal-
kyl group elimination products 4c–e in 11–18% yield, in-
stead of the isopropyl elimination products. Note the high
reactivity of N-isopropyl-N-(non-2-yn-1-yl)cyclohexana-
mine as compared with N-cyclohexyl-N-(non-2-yn-1-yl)-
cyclohexanamine, which is unreactive under these condi-
tions. In view of this fact we assumed that configuration of
the substituent at the nitrogen atom or volatility of some
derivative of the leaving group are the key factors deter-
mining the course of the reaction. However, N-(non-2-yn-
1-yl)-N-(1-phenylethyl)cyclohexanamine we synthesized
was selectively converted under the reaction conditions
into (E)-N-(non-2-en-1-yl)cyclohexanamine 3d in 85% yield
(Table 1, entry 6). Thus, the 1-phenylethyl group is elimi-
nated more readily than the isopropyl group; this discards
the hypothesis about the necessary formation of a volatile
compound.
1. Me3Al (2 equiv)
Cp2ZrCl2 (1 equiv)
CH2Cl2, 40 °C, 3 h
H
NH
N
R
2. 2H2O or 1H2O
R
R
E
1
E
Yield (%)
2H
2H
1H
1H
a
b
c
d
Am
Oct
Am
Ph
82
69
88
77
H
N
N
1. Me3Al (4 equiv)
Cp2ZrCl2 (2 equiv)
CH2Cl2, 40 °C, 3 h
H
2H
(CH2)4
2H
2 (89%)
(CH2)4
2. 2H2O
H
NH
N
Scheme 1 The reaction of N,N-diisopropyl-substituted propargyl-
amines with Cp2ZrCl2-Me3Al reagent
We assumed that the deuterolysis product should have
deuterium atoms attached to nitrogen. However, we did not
detect a molecular ion corresponding to N-deuterium-sub-
stituted amine in the mass spectra of compounds 1a,b and
3. It is known that secondary amines often do not produce
molecular ions because hydrogen at the nitrogen atom is
readily eliminated. Also, the absence of deuterium at the ni-
trogen atom can be a consequence of column chromatogra-
phy on silica gel used to isolate the products. The hydrogen
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
I. R. Ramazanov et al.
Letter
Synlett
Table 1 Cp2ZrCl2-Catalyzed Reaction of Substituted Propargylamines
with Me3Al
Using B3LYP/6-31G(d)/LanL2DZ calculations, the transi-
tion state was located, corresponding to the hydrogen
transfer from the tertiary carbon atom of the isopropyl
group to the electrophilic sp-hybridized carbon atom. The
activation barrier of the process is only 4.7 kcal/mol and the
change of free energy of the reaction is –15.9 kcal/mol. As
result the rearrangement of intermediate A (Scheme 2)
gives iminium salt B. Deuterolysis of the latter affords E-
alkenylamine С. It is known that the α-hydrogen atom in
tertiary amines is prone to hydride abstraction.17 However
the carbon–carbon double bond to be reduced usually
needs to be strongly activated by adjacent electron-with-
drawing substituents such as CF3, CN, COOR, NO2.18 The evi-
dence in favor of this mechanism is the finding that the ad-
dition of sixfold excess of LiAlH4 to the reaction mixture led
to the formation of (E)-N,N-diisopropylnon-2-en-1-amine
(5) in good yield (80%) when R = n-Hex (Scheme 2).
1. Me3Al (2 equiv)
Cp2ZrCl2 ( 0.2 equiv)
CH2Cl2, 40 °C, 3 h
R2
H
NHR2
H
NHR3
N
R3
+
R1
R1
E
R1
E
2. 1H2O or 2H2O
3
4
Entry R1
R2
R3
E
Yield of Yield of
3 (%) 4 (%)
1
2
3
4
5
6
n-Hex
n-Am
n-Am
n-Hex
n-Bu
1-naphthylmethyl i-Pr
1H
1H
1H
1H
2H
3a 86
4a nda
4-methoxybenzyl
c-Hex
i-Pr
i-Pr
i-Pr
i-Pr
3b 83
3c 54
3d 48
3e 58
3d 85
4b nd
4c 15
4d 18
4e 11
4f nd
c-Hex
c-Hex
n-Hex
c-Hex
1-phenyl- 1H
ethyl
a nd: not detected.
N
H
N
A
Cp2ZrX
R
R
We were unable to find examples of similar transforma-
tions in the literature; therefore, we performed quantum
chemical modeling for the N,N-diisopropylbut-2-yn-1-
amine complex with the methylzirconocene cation
Cp2Zr(+)Me, which is formed in the reaction of Cp2ZrCl2 and
Me3Al. Since it has been assumed that bulky substituents
prevent the interaction of cationic species with the nitro-
gen atom, we considered only those reactant configurations
in which the zirconium atom interacts with the triple car-
bon–carbon bond. Using B3LYP/631G(d)/LanL2DZ calcula-
tions, several stationary points were located on the poten-
tial energy surface, corresponding to the complex in which
the methylzirconocene cation is coordinated to a larger ex-
tent to the sp-hybridized carbon atom bearing the amino-
methyl group. According to calculations, this coordination
is favorable for pronounced polarization of the triple bond.
In one conformation of the aminomethyl substituent,
hydrogen attached to the tertiary carbon atom is proximate
to the arising electrophilic site of the molecule. Notably, in
this conformation, a pronounced HOMO electron density is
concentrated on this hydrogen atom and the length of the
CH bond is increased to 1.13 Å, compared to 1.09 Å for the
length of the CH bond in adjacent isopropyl group. Obvi-
ously, this is a consequence of negative hyperconjugation of
lone pair of nitrogen atom and antibonding orbitals σ*CH
(Figure 1).
Zr(X)Cp2
2H
N
N
LiAlH4 H2O
N
H
H
H
R
H
R
+
2H
2H2O
O
R
Zr(X)Cp2
C
B
5 (R = n-Hex)
Scheme 2 Plausible mechanism of the conversion of substituted prop-
argylamines into E-alkenylamines under the action of cationic zircono-
cene complexes
The reaction of N,N-diisopropyloct-2-yn-1-amine with
2 equivalents of Me3Al and 1 equivalent of Cp2ZrCl2 at 40 °C
does not proceed in hexane. There are two possible expla-
nations for this result: (a) nonpolar solvent does not con-
tribute to the stabilization of the intermediate A; (b) cation-
ic zirconocene complexes in nonpolar solvent are electro-
philic enough to be easily bound to the substrate nitrogen
atoms.
So, as regards the nature of the cationic species, we are
inclined to the opinion that they are either Cp2Zr(+)Me or
Cp2Zr(+)Cl, depending on the organoaluminum compound
used (Me3Al or EtAlCl2). This conclusion is supported by the
fact that the reactions do not proceed in the presence of
Cp2TiCl2, which is similar to Cp2ZrCl2 in many aspects. That
is, the nature of the metal has a crucial role for the reaction,
which implies direct involvement of the metal ion in the re-
action site.
Me
i-Pr
N
H
Me
R
MeCp2Zr
It follows from Table 1 that the capability of elimination
decreases in the following series of N-substituents: N-1-
phenylethyl > N-isopropyl > N-c-Hex. According to Scheme
Figure 1 Hypothesized negative hyperconjugation in the complexes of
N,N-diisopropyl-substituted propargylamines
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
I. R. Ramazanov et al.
Letter
Synlett
2, the ease of hydrogen transfer from the tertiary carbon
atom should be determined by (а) stability of the iminium
salt thus formed; (b) lower steric hindrance in the transi-
tion state leading to intermediate B. According to B3LYP/6-
31G(d,p) calculations, the relative free energy of the formation
of the iminium salt from amine increases in the series
of amines: N,N-dimethyl-1-phenylethan-1-amine (–3.91
References and Notes
(1) Negishi, E.-i. ARKIVOC 2011, (viii), 34.
(2) Dzhemilev, U. M.; D’yakonov, V. A. Modern Organoaluminum
Reagents, in Topics in Organometallic Chemistry, Vol. 41;
Woodward, S.; Dagorne, S., Eds.; Springer: Berlin, Heidelberg,
2013, 215.
(3) Negishi, E. Bull. Chem. Soc. Jpn. 2007, 80, 233.
(4) Ramazanov, I. R.; Kadikova, R. N.; Dzhemilev, U. M. Russ. Chem.
Bull. 2011, 60, 99.
kcal/mol)
<
N,N-dimethylcyclohexanamine
(–1.85
kcal/mol) < N,N-dimethylpropan-2-amine (0 kcal/mol). The
higher capability of the isopropyl group for hydrogen atom
transfer compared with the cyclohexyl group can be due to
steric factors. A more intricate issue is the lack of reactivity
of N-cyclohexyl-N-(non-2-yn-1-yl)cyclohexanamine under
the reaction conditions as compared with the reactive N-
isopropyl-N-(non-2-yn-1-yl)cyclohexanamine. According
B3LYP/6-31G(d)/LanL2DZ calculations, the activation barri-
er of the hydride transfer step in the case of N-cyclohexyl-
N-(non-2-yn-1-yl)cyclohexanamine is 5.8 kcal/mol. This
represents a slight difference from the value calculated for
the diisopropyl derivative (4.7 kcal/mol), but it may be
somewhat underestimated because insufficient account
was taken of the steric interactions of the two bulk cyclo-
hexyl groups.
(5) Wang, G.; Zhu, G.; Negishi, E.-i. J. Organomet. Chem. 2007, 692,
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Part C 1968, 22, 157.
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In summary, the unusual transformation of N-isoalkyl-
substituted propargylamines into alkenylamines under the
action of Cp2ZrCl2and organoaluminum compounds (Me3Al,
EtAlCl2) was first observed. According to proposed plausible
mechanism of the conversion, N-isoalkyl-substituted prop-
argylamines undergo zirconocene-initiated intramolecular
hydride transfer that was confirmed by B3LYP/6-
31G(d)/LanL2DZ calculations. Obviously, one of the most
important factors of the transformation is the presence of
negative hyperconjugation of lone pair of nitrogen atom
and antibonding orbitals σ*CH located at the isoalkyl group.
(15) (E)-2-d-N-Isopropyloct-2-en-1-amine (1a)To a 25 mL, argon-
swept flask, equipped with a magnetic stirrer and rubber
septum, was added Cp2ZrCl2 (585 mg, 2 mmol) suspended in
CH2Cl2 (5 mL) and Me3Al (0.38 mL, 4 mmol; caution: organoalu-
minums are pyrophoric and can ignite on contact with air,
water or any oxidizer!) at room temperature. To the solution
was added N,N-diisopropyloct-2-yn-1-amine (418 mg, 2 mmol)
at room temperature and stirred for 3 h at 40 °C. Then, the reac-
tion mixture was diluted with with hexane (5 mL), and D2O (3
mL) was added dropwise while cooling the reactor flask in an
ice bath. The precipitate was filtered on a filter paper. The
aqueous layer was extracted with diethyl ether (3 × 5 mL). The
combined organic layers were washed with brine (10 mL), dried
over anhydrous CaCl2. Evaporation of solvent and purification of
the residue by column chromatography (hexane/ethyl acetate,
5:1) gave a colourless oil; yield 279 mg (82%); Rf = 0.8 (hex-
ane/ethyl acetate, 5:1). 1H NMR (400 MHz, CDCl3): δ = 0.85 (t,
J = 6.9 Hz, 3 Н, С(11)Н3), 1.02 (d, J = 6.3 Hz, 6 Н, С(5,6)Н3), 1.17–
1.30 (m, 4 Н, С(9,10)Н2), 1.30–1.37 (m, 2 Н, С(8)Н2), 1.98 (q, J =
7.1 Hz, 2 Н, С(7)Н2), 2.74–2.83 (m, 1 Н, С(4)Н1), 3.14 (s, 2 Н,
С(1)Н2), 5.45–5.60 (m, 1 Н, С(3)Н1). 13C NMR (100 MHz, CDCl3):
δ = 13.97 (C(11)), 22.47 and 31.35 (C(9) and C(10)), 22.88 (2 C,
С(5,6)), 28.93 (C(8)), 32.25 (С(7)), 47.99 (С(4)), 49.30 (C(1)),
Funding Information
This work was supported by the Russian Foundation for Basic Re-
search (Grant No. 18-03-00817 and 16-33-60167) and by Grant of the
RF President (Sci. Sh.–6651.2016.3).
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F
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1
7
R)
u
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Acknowledgment
The authors are indebted to Prof. Tamotsu Takahashi (Catalysis Re-
search Center, Hokkaido University) for useful discussions especially
concerning the mechanism of the unusual transformation. We ac-
knowledge the Center of collective use of the unique equipment
‘Agidel’ at the Institute of Petrochemistry and Catalysis of the Russian
Academy of Sciences.
1
128.08 (t, JCD =18.5 Hz, C(2)), 132.34 (С(3)). MS (EI): m/z (%) =
170 (4) [М]+, 155 (22), 141 (<1), 127 (2), 111 (8), 99 (12), 82 (7),
69 (31), 44 (100), 41 (21). Anal. Calcd (%) for C11H22DN: C, 77.57;
N, 8.22. Found: C, 77.7; N, 8.3.
(16) Papirer, E. In Surfactant Science Series;
9
0Vo.
l
Marcel Dekker: New
York, 2000, 690.
(17) Meerwein, H.; Allendörfer, H.; Beekmann, P.; Kunert, F.;
Morschel, H.; Pawellek, F.; Wunderlich, K. Angew. Chem. 1958,
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Supporting Information
(18) Kaitmazova, G. S.; Gambaryan, N. P.; Rokhlin, E. M. Russ. Chem.
Rev. 1989, 58, 1145.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609336.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D