Regio- and stereoselective hydroamination of alkynes using an ammonia surrogate: Synthesis of N -Silylenamines as reactive synthons

Article abstract of DOI:10.1021/jacs.7b13783

An anti-Markovnikov selective hydroamination of alkynes with N-silylamines to afford N-silylenamines is reported. The reaction is catalyzed by a bis(amidate)bis(amido)Ti(IV) catalyst and is compatible with a variety of terminal and internal alkynes. Stoichiometric mechanistic studies were also performed. This method easily affords interesting N-silylenamine synthons in good to excellent yields and the easily removable silyl protecting group enables the catalytic synthesis of primary amines.

Full text of DOI:10.1021/jacs.7b13783

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Regio- and Stereoselective Hydroamination of Alkynes Using an
Ammonia Surrogate – Synthesis of N-Silylenamines as Reactive Synthons
Erica K. J. Lui, Jason W. Brandt, and Laurel L. Schafer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b13783 • Publication Date (Web): 12 Mar 2018
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Regio- and Stereoselective Hydroamination of Alkynes Using
an Ammonia Surrogate – Synthesis of N-Silylenamines as
Reactive Synthons
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Erica K. J. Lui, Jason W. Brandt and Laurel L. Schafer*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1
schafer@chem.ubc.ca
Supporting Information Placeholder
employed intramolecular transfer hydrogenation of vi-
nylaminosilane, to give N-silylenamine in 70% yield
(Scheme 1B).4m Over the past 25 years, no example of
N-silylenamine synthesis by hydroamination has been
reported, even though the reaction has been previously
attempted with catalysts that are known to catalyze the
hydroamination of alkynes with typical carbon substi-
tuted amines (Scheme 1C).7
ABSTRACT: An anti-Markovnikov selective hydroamina-
tion of alkynes with N-silylamines to afford N-
silylenamines is reported. The reaction is catalyzed by a
bis(amidate)bis(amido)Ti(IV) catalyst and is compatible
with a variety of terminal and internal alkynes. Stoichi-
ometric mechanistic studies were also performed. This
method easily affords interesting N-silylenamine
synthons in good to excellent yields and the easily re-
movable silyl protecting group enables the catalytic syn-
thesis of primary amines.
Scheme 1. Syntheses of N-Silylenamines
The intermolecular hydroamination of alkynes with
primary and secondary amines to generate imines and
enamines is a well-established catalytic methodology
utilizing catalysts from across the periodic table.1 How-
ever, the utilization of ammonia or ammonia surrogates
(i.e. RNH2 where R is a removable protecting group) in
alkyne hydroamination reactions is limited to Bertrand’s
Markovnikov selective example with ammonia,2 and
Doye’s report using diphenylmethanamine for selected
examples.3 The development of a broadly useful, regio-
and stereoselective alkyne hydroamination catalyst for
use with ammonia or ammonia surrogates would ena-
ble the in situ generation of primary or secondary
enamine intermediates. Such reactive synthons could
then undergo further reactivity, including catalytic re-
duction, to access primary amines.
N-alkyl substituted enamines are commonly used in
synthesis, yet the preparation4 and use4h, 4j, 4k, 4n, 4p, 4q, 5
of related N-silylenamines are limited, largely due to
their laborious syntheses. The preparation of N-
silylenamines is typically achieved by the stoichiometric
addition of highly active carbon nucleophiles to aro-
matic cyanide groups followed by trapping with either
silylchloride (Scheme 1A),4b, 4h, 4j, 4n, 4o, 4q, 4r or an intra-
molecular silyl-migration.4d-f, 4l, 4o, 6 A Rh-catalyzed route
Our group’s bis(amidate)bis(amido)-Ti(IV) catalyst (1)
has high activity and excellent anti-Markovnikov selec-
tivity for the hydroamination of alkynes with both aryl
and alkyl primary amines.8,9 Inspired by other transi-
tion-metal catalyzed reactions that utilize silylated
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amines as ammonia surrogates for the generation of
bis(trimethylsilylamine) (Scheme S1, Supporting Infor-
mation), a secondary amine, no product was observed
by H NMR spectroscopy. To further probe the role of
1
2
3
4
5
6
7
8
primary amines, such as (N-triphenylsilyl)amine in Pd-
catalyzed Buchwald-Hartwig cross-coupling,10 we envi-
sioned utilizing N-silylamines, H2NSiR3, as ammonia sur-
rogates for the hydroamination of alkynes. Herein we
disclose the regioselective hydroamination of a variety
of alkynes to give a broad range of (E)-N-silylenamines
(Scheme 1D). The use of these products as reactive
enamine intermediates to access primary amines upon
catalytic reduction is demonstrated and a mechanistic
proposal invoking catalytically active Ti-silylimido is pre-
sented.
1
intermediate imido complexes, we synthesized and
characterized silylimido species from 1. The generation
of imido complex 2a was obtained by reacting one
equivalent of (N-tert-butyldimethylsilyl)amine with one
equivalent of Ti complex 1 (Figure 1). Recrystallization
afforded the desired silylimido species in 55% yield. At-
tempts to remove the neutral dimethyl amine donor
under vacuum proved unsuccessful. However, the addi-
tion of excess pyridine resulted in ligand exchange to
give complex 2b in 44% recrystallized yield from com-
plex 1.
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Our studies toward the catalytic hydroamination of
alkynes with N-silylamines began by using commercially
available (N-triphenylsilyl)amine, ethynylbenzene, and
the commercialized Ti catalyst 1. In an NMR tube scale
reaction the N-silylenamine product was observed ex-
clusively after 18 hours at 70 °C using 2.5 mol% of 1.
The anti-Markovnikov product was assigned as the E-
isomer on the basis of the observed 13.7 Hz coupling
between the vicinal olefinic hydrogens (δ 6.99, 5.61
ppm). With this successful reaction in hand we sought
to use a more common trialkylsilylamine. Thus, (N-tert-
butyldimethylsilyl)amine was prepared in 82% yield
from ammonia and tert-butyldimethylchlorosilane. Sub-
sequent hydroamination of ethynylbenzene with the
synthesized N-silylamine gave the anti-Markovnikov (E)-
N-silylenamine product using only 1 mol% catalyst load-
ing at 70 °C over 6 hours.
Tetrakis(dimethylamido)titanium is known to catalyze
the hydroamination of alkynes.11 However, when this
complex was tested as a potential catalyst, no N-
silylenamine formation could be observed (Scheme 2).
By adding the amide proligand (L) to the unreacted re-
action mixture, catalyst 1 was formed in situ and full
conversion to the desired product was achieved. This
experiment demonstrates the importance of the
bis(amidate) ligand environment to promote hydroami-
nation with silylamine substrates.
Figure 1. Synthesis of complexes 2a and 2b (top). Single
crystal molecular structures of 2a (bottom-left) and 2b
(bottom-right). Thermal ellipsoids are shown at 50% prob-
ability. Phenyl and 2,6-diisopropylphenyl groups of the
ligand, and hydrogen atoms are omitted for clarity.
Importantly, 1 mol% of 2a catalyzes the hydroamina-
tion
of
ethynylbenzene
with
(N-tert-
butyldimethylsilyl)amine to give the same enamine
product in 6 h at 70 °C. This suggests that catalysis with
silylamines and 1 proceeds via a [2+2] cycloaddition to
reactive Ti–imido species. These results contrast with
previous reactivity investigations of primary N-
silylamines with group 4 organometallic complexes.7a, 7b,
Scheme 2. Testing importance of amidate ligands
13
For example, Bergman and coworkers showed that
bis(cyclopentadienyl)zirconaazametallacyclobutenes
could be used as catalysts for the generation of
enamines with anilines.7a However, when the analogous
isolated zircona(N-silyl)azametallacyclobutene was re-
acted with excess silylamine, no enamine formation was
observed and only the products resulting from cy-
cloreversion, free diphenylacetylene and Cp2Zr
bis(silyl)amide, were recovered (Scheme S3A, Support-
The accepted mechanism for Ti-catalyzed hydroami-
nation invokes the formation of an imido reactive in-
termediate, thereby limiting reactivity to primary amine
substrates.12 Consistent with this mechanistic proposal,
when
the
reaction
was
attempted
with
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ing Information).7a More recently, Odom and co-workers
prepared a (N-triphenylsilyl)imido Ti complex supported
by pyrrole ligands (Scheme S3B, Supporting Infor-
mation).7b However, this complex was also not useful as
Pleasingly most substrates resulted in the formation
of the (E)-isomer as the sole product. However, a mix-
ture of (E)- and (Z)-isomers were observed in some cas-
es (3j, 3m, 3u-y), presumably resulting from isomeriza-
tion via a minor amount of intermediate imine tauto-
mer.
1
2
3
4
5
6
a
hydroamination catalyst when using (N-
triphenylsilyl)amine as a substrate.7b
The excellent regioselectivity and substrate scope of-
fered by complex 1 has been attributed to the hemi-
lability of the 1,3-N,O-donor amidate ligands.8g Interest-
ingly, Ti-imido complexes 2a and 2b display variable κ1
and κ2 coordination modes, simply due to the change in
the neutral donor ligand. Complex 2a is a 5-coordinate
pseudo-square based pyramidal complex with an axial
N-silylimido ligand and one κ2 – and one κ1 – amidate
ligand. However, substitution of the dimethylamino lig-
and with pyridine furnishes the 6-coordinate, distorted
octahedral complex 2b, with two κ2 – amidate ligands.
We attribute this difference in binding mode to the
slight steric differences in the dimethylamine and pyri-
dine neutral ligands (Figures S2 and S3, Supporting In-
formation). We propose that the coordinative flexibility
of N,O-chelating amidate ligands can relieve steric con-
gestion about the reactive metal center to accommo-
date sterically demanding substrates such as (N-tert-
butyldimethylsilyl)amine.
The observation of the preferential formation of
enamine products when using silylamines is in contrast
to reactivity trends observed with primary alkyl amine
substrates which yield imine products.8g To further un-
derstand the preference of N-silylenamines over the N-
silylimine tautomer, DFT calculations were performed
(B3LYP/6-311g(d,p)) (See Supporting Information). Cal-
culated tautomer ratios correlated well with experimen-
tally determined equilibria (Scheme S4). For example,
the calculated and observed tautomeric ratios for the
hydroamination reaction using ethynylcyclohexane
showed that when N is alkylated, the observed
imine:enamine ratio is 100:0 (DFT calc. 99.7:0.3), yet
when N is silylated the observed imine:enamine ratio is
reversed at 12:88 (DFT calc. 8:92). NBO calculations
show a change in bond polarity between the N-alkyl and
N-silyl cases, such that the electropositive Si affords a
more electron rich N. This results in significant delocali-
zation of the N lone pair by donation into the π* of the
enamine double bond. Although this interaction exists
in both N-alkyl and N-silyl enamines, NBO analysis esti-
mates this stabilization to be ~9 kcal/mol greater in the
N-SiMe2tBu case. These insights highlight the different
electronic features accessible of N-silylenamines.
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The scope of this hydroamination reaction was stud-
ied with a variety of terminal and internal alkynes
(Scheme 3). Due to the moisture sensitivity of the N-
1
silylenamine products, H NMR spectroscopy was used
to determine reaction yields. In all cases, full consump-
tion of starting materials was observed and only the
anti-Markvnikov product was formed. The yields ob-
tained for the hydroamination of a range of ethynylben-
zene derivatives (3a-i) were excellent, independent of
the arene substitution pattern. Even substrates with
sterically demanding and potentially chelating ortho-
methoxy substituents (3i) could be accommodated.
Good yields were also obtained using alkynes with ni-
trogen and sulfur containing heterocycles (3j-p). In all
cases where conjugated products result, only the
enamine tautomer could be observed. Interestingly,
when using alkyl substituted alkynes such as 1-hexyne
(3q) or 1-ethynylcyclohexane (3r) a minor amount of
imine tautomer can be observed. Notably, the conju-
gated 1-ethynylcyclohex-1-ene delivered the enamine
product exclusively (3s). Other functional groups, such
as silylether (3t) and amide (3u) were also compatible
with catalyst 1. Internal alkynes were employed suc-
cessfully (3v-y) to give products regioselectively and in
high yield. Notably these reactions can be scaled up to
5 mmol scale in non-deuterated solvents furnish silyle-
namine products that can be isolated by distillation.
Scheme 3. Scope of Alkyne Hydroaminationa
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1H NMR yields obtained quantitatively by using 1,3,5-
Page 4 of 6
a
useful class of organic synthons. To test the [2+2] cy-
b
1
2
3
4
5
6
7
8
trimethoxybenzene as internal standard, Reactions were
performed at 5 mmol scale using non-deuterated toluene
and products were purified by vacuum-distillation under
heat
cloaddition mechanistic hypothesis, catalytically active
silylimido species were isolated. Characterization by X-
ray crystallography provided insights regarding the
hemilabile nature of the 1,3-N,O-chelating amidate lig-
ands that support this new transformation by hydroam-
ination. As a demonstration of the use of N-silylamine
as a viable ammonia surrogate, a tandem sequential
catalytic route was used to prepare primary amines
from alkynes in good yields. On-going work focuses on
the application of selectively prepared (E)-N-
silylenamines as reactive intermediates in the prepara-
tion of N-heterocycles.
Recently, we reported on the facile synthesis and iso-
lation of secondary amines using commercially available
titanium catalyst 1 followed by catalytic hydrogenation
with Pd/C.8i As an illustration of the use of N-
silylenamines as in situ generated reactive intermedi-
ates and a demonstration of the use of N-silylamines as
ammonia surrogates for hydroamination, primary amine
products were prepared using this sequential catalytic
approach. First, the hydroamination reaction was per-
formed as described above and the reactive N-
silylenamine intermediate was then exposed to catalytic
Pd/C and H2. The salt of the crude amine product could
be isolated by filtration following treatment with 1M
hydrochloric acid (Scheme 4). In some cases, unwanted
secondary amine byproducts were formed during the
hydrogenation reaction (See Supporting Information).
Gratifyingly, the salt of the primary amine product can
be isolated by sublimation. Various terminal alkynes and
an internal alkyne could be used in this tandem sequen-
tial approach.
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ASSOCIATED CONTENT
Experimental procedures, characterization data and NMR
spectra for all new compounds. The Supporting Infor-
mation is available free of charge on the ACS Publications
website.
Full experimental procedures and spectroscopic data (PDF)
X-ray data for compounds 2a-c (CIF)
AUTHOR INFORMATION
Corresponding Author
Scheme 4. Sequential Catalysis for the Synthesis of
Primary Amines from Terminal Alkynes and N-
Silylaminea
* E-mail: schafer@chem.ubc.ca
Funding Sources
No competing financial interests have been declared.
Any funds used to support the research of the manuscript
should be placed here (per journal style).
ACKNOWLEDGMENT
The authors thank NSERC for financial support of this
work.
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TOC Graphic:
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R2
Ph
Ar
Ar
H
N
N
Ti
N
R1
NH2•HCl
1-10 mol% 1
Hydrogenation
R1
R1
NMe2
NMe2
O
SiR3
R2
Hydroamination
R2
then
Deprotection
O
SiR3
H2N
Ph
25 examples
54-99%
9 examples
59-84%
R1 = Alkyl, aryl
R2 = H, alkyl, aryl
SiR3 = SitBuMe2, SiPh3
Ar = 2,6-diisopropylphenyl
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