Adducts of Triallylborane with Ammonia and Aliphatic Amines as Stoichiometric Allylating Agents for Aminoallylation Reaction of Carbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.8b01317

Triallylborane-amines adducts are effective stoichiometric allylating agents in the aminoallylation reaction of carbonyl compounds in methanol. Moreover, copper-catalyzed diastereoselective allylation of Ellman's imine was achieved with triallylborane-methylamine adduct.

Full text of DOI:10.1021/acs.orglett.8b01317

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Adducts of Triallylborane with Ammonia and Aliphatic Amines as
Stoichiometric Allylating Agents for Aminoallylation Reaction of
Carbonyl Compounds
Nikolai Yu. Kuznetsov,* Rabdan M. Tikhov, Tatiana V. Strelkova, and Yuri N. Bubnov
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov 28, 119991 Moscow, Russian
Federation
S
* Supporting Information
ABSTRACT: Triallylborane−amines adducts are effective stoi-
chiometric allylating agents in the aminoallylation reaction of
carbonyl compounds in methanol. Moreover, copper-catalyzed
diastereoselective allylation of Ellman’s imine was achieved with
triallylborane−methylamine adduct.
ince the time of their discovery,1 allylboranes and
Scheme 1. Boranes for Allylation of Imines
Sallylboration reactions have become extremely important
synthetic tools.2 A survey of the amazing progress achieved in the
synthesis and application of allylboron species has been
published recently.2e Among the multiple allylborane-mediated
transformations, particular attention is paid to the synthesis of
homoallylamines via allylation of CN bonds of imines.3
Homoallylamines are versatile and useful synthetic intermediates
in the pharmaceutical chemistry and in the synthesis of natural
products and heterocyclic compounds.4 The most powerful
allylborating agents for synthesis of homoallylamines are tri- and
monoallylic organoboranes, which are capable of allylborating an
array of compounds with multiple C−N bonds.5−12 Allylic
organoboranes are highly reactive and react with imines at
compensated by the possibility of catalytic asymmetric trans-
formations, proceeding highly stereo- and enantioselectively.2e
Enhancement of the reactivity of allylboronates is achieved by
their conversion into more active borinate derivative, making
them closer to organoboranes.16 Similar improvement of
reactivity of allylboronic acids occurs upon dehydratation and
trimerization into boroxines.17 Despite the success achieved with
the use of allylboronates, the lack in the reactivity limits the
spectrum of the possible substrates and catalysts. On the other
hand, shortcomings inherent in allylic organoboranes hamper the
development of modern chemistry on their basis. Therefore, it
would be useful to have allylboranes with intermediate activity
possessing the advantages of both classes of compounds.
According to our results, amine adducts of allylic organoboranes
can be such promising reagents.
temperatures as low as −100 °C, providing excellent
enantioselectivity with chiral organoboranes.5b One of the
most important advantages of triallylic boranes along with their
activity is their atomic efficiency. The main disadvantages of the
allylic organoboranes is that they are sensitive to different factors:
oxygen of air, proton-donor compounds (water, alcohols ets.)
and poor compatibility with many FGs; in addition they cannot
be used in catalysis due to self-catalytic properties.13 As
alternatives to organoboranes for allylation of imines, low-active
allylboronic acids, their esters, and trifluoroborate salts, which are
generally free of the above disadvantages, are widely applied
(Scheme 1). Following the Petasis-type14 α-aminoallylation
procedure, even carbonyl compounds can be transformed in
“one-pot” to homoallylamines with allylboronic acids.15 The low
activity of allylboronic acid derivatives arising due to
neutralization of Lewis acidity of boron by the lone pairs of
oxygen atoms and their low atomic efficiency both are
Received: April 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01317
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Until this present work, no specific studies of adducts as
allylborating agents have been undertaken. We believe that such
inattention is objectively conditioned by the data obtained in
previous years, which unequivocally pointed to the lability of
adducts with ammonia and amines. Triallylborane (TAB), as
Lewis acid, forms sufficiently stable adducts with few tertiary
amines, which can be even distilled in vacuum without
decomposition. However, when treated with alcohols or water
these complexes are readily decomposed with propylene
evolution except for β- and γ-substituted pyridines.18 Pyridine
complexes of TAB and other triallylic boranes upon heating with
proton-donor compounds (water, alcohols, amines) undergo
intramolecular allylboration, yielding 2,6-diallylated tetrahydro-
pyridines.10 Interaction of TAB with NH3, primary, and
secondary amines produces aminoboranes, although the
formation of adducts is always assumed.19 Allylborane adducts
can follow two decomposition routes  through dissociation
(with tertiary amines) and proto-deallylation (for primary,
secondary amines) or both routes in the case of bulky amines
with an NH group (Scheme 2).
deallylation process was accelerated at 60 °C (31% for 1 h, 54%
for 4 h). Switching to the proton media demonstrates a surprising
effect of stabilization of 1a. The destruction of 1a in iPrOH for 1
h was 14%, in EtOH 19%, and MeOH 38%. However, this
stabilizing effect is limited, and more acidic alcohols, 2,2,2-
trifluoroethanol and HFIP, rapidly decompose 1a even at 25 °C.
The observed stability of 1a in iPrOH is superior, but we were
interested in MeOH, in which higher yields of homoallylamines
were observed.15c,d We found also the stability of 1a in
methanolic NH3 solution increases significantly: the half-life
time of 1a at 60 °C is 24 h and at 25 °C 36 days, and it can be
stored for months without any changes at −18 °C. Such an
excellent stability profile of the complex is totally fit to the
potential use of 1a as an allylborating reagent. Experimentally,
the three-component aminoallylation procedure consists of two
steps: first, an aldehyde is dissolved in methanolic NH3 (3−15
equiv) and held for 30−60 min, during which time almost all
amount of the aldehyde is converted to the so-called imine trimer
(hydrobenzamide),21 followed by the addition of 1a. The
reaction was conveniently monitored by 1H and 11B NMR, where
the boron chemical shift of 1a at −8.56 ppm (value can vary a
little) smoothly transforms to the signal of boric acid at 4.7 ppm.
There are signals of intermediates: mono- and diallylated boranes
are usually in a range of 0−10%.
Scheme 2. Decomposition of Allylborane−Amine Adducts
Aminoallylation of benzaldehyde 1b with 1a proceeds quickly
at the beginning of the reaction, giving rise to amine 1c (Scheme
4) and its Shiff base with 1b in a 1:1 ratio (see the SI for
mechanistic details). Further reaction is practically stopped at 25
°C; various additives (ZnCl2, Zn(OTf)2, MgCl2, In(OTf)3,
Sc(OTf)3, Y(OTf)3, CuCl2, NH4Cl) have no effect on the ratio of
the products. The reaction is markedly accelerated at 40 °C and
complete after 4 h. The most remarkable thing is that
unproductive protonolysis of 1a is completely absent under these
conditions, and consumption of all allyl groups takes place only via
allylation of the CN bond! The amine 1c was conveniently
isolated as hydrochloride salt (88%) after treatment with HCl
without chromatography (Scheme 4). On a series of substituted
benzaldehydes (2b−26b), it was shown that aldehydes enter the
aminoallylation reaction irrespective of the nature of the
substituent. The reaction involves aromatic aldehydes containing
a variety of FGs to nitro (22b, 23b) and cyano (24b) groups;
these are acetylene (25b), ester group (26b), azaheterocycles
(pyridine (27b), pyrazole (29b), indole (28c)), and furan (30c);
however, the adduct 1a (unlike pure triallylborane) selectively
allylates only the CN bond of imines, leaving virtually all FGs
unaffected. All homoallylamines were isolated as hydrochlorides
or oxalates in high yields, with the exception of 28c (84%), which
was isolated by chromatography. It is necessary to note the
peculiarity of the reaction of acetylene 32b with 1a where 32c
was obtained instead of the expected homoallylamine. Initially,
from the aldehyde 32b and NH3 isoquinoline 33b is formed,
which undergoes reductive allylboration upon addition of 1a in
the same way as with neat TAB.
Clearly, such properties did not stimulate additional studies of
amine adducts in allylation reactions. We proposed that careful
temperature control during the synthesis of adducts with NH-
group and the use of the amine in excess can prevent their
undesirable decomposition. A three-component aminoallylation
of carbonyl compounds in methanol was chosen as a model
reaction.15 Although this process works well with allylboronic
acid derivatives, the same reaction with TAB adducts might be
complicated by protonolysis of allyl−B bonds that is, in fact, a
textbook example. Indeed, very vigorous reaction occurs upon
addition of TAB to methanol solution of NH3 even at −60 °C,
leading to a mixture of di- and triallylborane−ammonia adducts
(1:1.2). To eliminate the protonolysis process, a flow of dry
ammonia was passed through the solution of TAB in pentane at
−20 °C (Scheme 3).
Scheme 3. Synthesis of Triallylborane−Amine Adducts
Under these conditions, ammonia complex (1a) is formed in
quantitative yield. Adduct 1a is a solid and can be handled
without argon, although it is slowly oxidized on air. Adducts 2a−
6a were synthesized similarly. It should be noted that
trialkylboranes form similar adducts with NH3 and some amines.
Adducts with higher boranes are less stable and readily dissociate
into the initial reagents that are successfully used in reactions of
radical polymerization.20
Apparently, 33b is the only azaheterocycle that is allylborated
under these conditions because neither indole, pyridine, nor
quinoline reacts with 1a (Scheme 5).
Along with ammonia adduct 1a, adducts 2−6a (Scheme 3)
were also tested in the aminoallylation reaction with different
carbonyl compounds (Table 1).
Diastereomer ratios in 36c and 40c (entries 3 and 7) are close
to the previously obtained values.15a,22 Generally, compounds
with a branching site adjacent the carbonyl group (entries 2−4
and 7) react more slowly, demonstrating the great importance of
The stability of 1a was tested by heating its solution in
benzene. Gradual transformation of 1a into the amino(diallyl)-
borane at 40 °C (Scheme 2) was detected by NMR, while the
B
DOI: 10.1021/acs.orglett.8b01317
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Organic Letters
Letter
Scheme 4. Aminoallylation of Aromatic Aldehydes
Table 1. Aminoallylation of Carbonyl Compounds with
Triallylborane−Amine Adducts 1−3a
product, time (h)/temp
yield
(%)
entry
R1−, R2−
adduct
R3−
(°C)
1
2
3
4
5
6
7
Pr−, H−, 34b
1a
1a
1a
1a
1a
1a
1a
34c, H−
35c, H−
36c, H−
37c, H−
38c, H−
39c, H−
40c, H−
6/40
16/40
16/40
16/40
0.5/40
0.5/40
2/40
77
74
95
96
94
96
90
iPr−, H−, 35b
αPhEt−, H−, 36b
Ph−, Me−, 37b
−(CH2)4−, 38b
−(CH2)5−, 39b
2-Ph[CH(CH2)4]−,
40b
8
9
Ph−, H−, 1b
Ph−, H−, 1b
2a
3a
1d, Me−
2d, All−
54/55
16/55
94
96
Product isolated in the form of free base. Syn/anti = 2:1. Anti/syn =
27:1. 2-Phenylcyclohexanone (see the SI).
glycine ester 1e (Scheme 6). Since many FGs are not compatible
with TAB, 6a can be an excellent replacement to avoid of the
Scheme 6. Aminoallylation via Exchange Reaction
preparation of the TAB adduct with amines containing reactive
FGs. Homoallylamine 3d (94%) is formed cleanly in such
exchange reactions.
TAB is not the only organoborane that forms reactive amine
adducts suitable for the aminoallylation. The reaction of 1b with
NH3 in the presence of chiral (−)-AllB(Ipc)2 also results in 1c
with ee 64%.
Scheme 5. Isoquinoline Allylboration
The ee indicates that aminoallylation occurs at temperature
close to 25 °C, similar to the ee value obtained by Itsuno.5a It can
be assumed that the Soderquist’s borane can provide a higher
enantioselectivity in this process because it less susceptible to the
temperature effect.23
the steric environment. Steric interaction also weakens the
strength of adducts 4a and 5a, making them unsuitable for the
aminoallylation of aromatic and aliphatic carbonyl compounds in
methanol. The 1-adamantylamine adduct 5a decomposes
immediately with the release of propylene upon dissolution in
methanol. In the case of isopropylamine adduct 4a, only 1-
phenyl-3-buten-1-ol (65%) was obtained with 1b, indicating that
intermediate imine is less reactive toward 4a then 1b.
Methylamine adduct 2a is much stronger than 1a and reacts
slower (see entry 8) even at the elevated temperature, producing
N-Me-amine 1d (94%). The adduct of allylamine 3a is more
reactive (see entry 9) and gives rise to the corresponding N-
allylamine 2d (96%). Dimethylamine adduct 6a stays aside
because the secondary amine (Me2NH) does not form or
incorporate into the homoallylamines. It serves solely as a carrier
for TAB, whose molecule recombines when mixed with primary
amine. The addition of 6a to the NH3 solution of 1b produces
amine 1c (Scheme 4). An application of 6a became even more
convenient with functionalized amines, for example, the salt of
The obtained results clearly show that adducts of TAB with
NH3 and amines are prospective atom-economical allylborating
agents possessing the same advantages as allylboronates.
However, to stimulate further development of the adduct
chemistry, their use in catalysis has to be tested. For
allylboronates, a number of allylation catalysts are known to
date.2e,3g The most accessible and effective catalysts can be
considered copper(I) derivatives.3g,24 The choice of the adduct
for testing of the catalytic process fell on the methylamine
complex 2a as the most stable and the least active (see Table 1,
entry 8). Addition of solely Cu(OTf)2 (5 mol %) to the solution
of 2a in MeOH does not change 2a, but if PPh3 is added to the
mixture, 2a begins deteriorate rapidly, which indicates the
protonation of the intermediate allylcopper(I) species. Allylation
of the Ellman’s imine 1f, which is very sensitive to steric and
chelate effects, was used as a model reaction (Scheme 7).
It was previously shown that allylboronates slowly allylate
imines in the presence of CuCl, methanol, and t-BuONa with
different diastereoselectivity depending on the addition of
C
DOI: 10.1021/acs.orglett.8b01317
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01317.
■
S
Full experimental procedures, study of the mechanism and
spectroscopic data for 1−6a, 1−32c, 34−40c, 1−3d, 2f,
and chiral HPLC analysis data of N-Boc-derivatives 1c
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nkuznff@ineos.ac.ru.
ORCID
Nikolai Yu. Kuznetsov: 0000-0003-2702-5366
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to Dr. Lubimov (INEOS RAS) for
carrying out the enantiomeric analysis. The contribution of the
Center of Molecular Composition Studies of INEOS RAS is
gratefully acknowledged. The authors are grateful to the Russian
Science Foundation (Grant No. 15-13-00109) for funding the
study.
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