An efficient synthesis of N-unsubstituted imines as organoborane adducts stable at room temperature: New promising intermediates for synthesis [3]

Full text of DOI:10.1021/ja993965v

J. Am. Chem. Soc. 2000, 122, 4217-4218
4217
liberation of the NH aldimine intermediate from the N-trimeth-
ylsilylaldimine derivative upon the addition of water or methanol,
followed by a fast reaction of the NH aldimine with 2. Although
a preliminary low-temperature NMR experiment did not detect
this intermediate, presumably because the allylboration of the
intermediate with 2 proceeded too rapidly, we applied this
methodology successfully for the synthesis of several aromatic
homoallylamines in high yield and ee.13
Recently, we utilized a variable-temperature NMR technique
for a thorough study of this reaction. To our surprise, we found
that 1 does not undergo methanolysis or hydrolysis at -78 °C in
deuterated THF. Even at room temperature, methanolysis of 1 in
CDCl3 took nearly 12 h to complete without detectable NH
aldimine formation, probably due to its rapid polymerization on
formation. However, in the presence of organoboranes, such as
B-ethyldiisopinocampheylborane (3), the methanolysis was com-
plete instantly and the NH benzaldimine was successfully iden-
tified at -78 °C. The 1H NMR spectrum of the reaction mixture
showed two doublets at 9.4 and 8.0 ppm, respectively, corre-
sponding to the two imino-hydrogens. This observation indicated
that the methanolysis or hydrolysis of N-trimethylsilylaldimine
can be effectively initiated at -78 °C in the presence of organo-
boranes. Possibly, the N-Si bond is weakened by coordination
of boron to the imino nitrogen, thereby becoming more susceptible
to the proton-donating agents, methanol or water (eq 1).
An Efficient Synthesis of N-Unsubstituted Imines as
Organoborane Adducts Stable at Room
Temperature: New Promising Intermediates for
Synthesis
Guang-Ming Chen and Herbert C. Brown*
H. C. Brown and R. B. Wetherill Laboratories of Chemistry
Purdue UniVersity, West Lafayette, Indiana 47907-1393
ReceiVed NoVember 10, 1999
Imine chemistry has achieved a dramatic development in the
past decades. Due to their importance in organic synthesis, many
N-substituted imines have been developed and applied for the
syntheses of amino acids, â-lactams, heterocycles, alkaloids, aziri-
dines, and amines.1 These include applications of N-sulfonyl-,2
N-sulfinyl-,3 N-trialkylsilyl-,4 and other N-metalloimines.5 How-
ever, these imines are most successful in the form of non-enol-
izable aldimines. There is still lacking a reliable, general method
for generating enolizable aldimines and ketimines. Very recently,
Ellman and co-workers reported a general synthesis of both non-
enolizable and enolizable N-tert-butanesulfinyl imines via the con-
densation of tert-butanesulfinamide and aldehydes or ketones in
the presence of excess Lewis acidic dehydrating agents. Unfortu-
nately, these reactions can also provide a mixture of E- and Z-ket-
imine isomers.6 Furthermore, difficulties in the preparation and
isolation of N-unsubstituted imines have been well documented.7
The access to NH aldimines has been limited to vacuum line
techniques8 and low-temperature detection.9,10 Indeed, to the best
of our knowledge, only two NH aldimines, acrylaldimine and
2-methylacrylaldimine, have ever been isolated at low temper-
ature,9,10 while a few more have been identified without isolation.10
None of them could survive long enough to permit further inves-
tigation even at low temperatures. Similarly, very few NH ket-
imines have been isolated as single isomeric compounds.11,12 This
has greatly restricted the scope of application of imine chemistry.
We herein report a general, efficient preparation of NH imines as
organoborane adducts, which are single E isomers, stable at room
temperature. This new chemistry should greatly benefit synthetic
chemists, interested in utilizing imines as synthetic intermediates.
Not long ago, we reported that the allylboration of N-
trimethylsilylbenzaldimine (1) with B-allyldiisopinocampheylbo-
rane (2) proceeded only in the presence of 1 molar equiv of water
to give the corresponding homoallylamine in 92% ee and 90%
yield.13 Further investigation revealed that methanol can replace
water in this allylboration, providing the same products. We
rationalized that the reaction might have proceeded by a rapid
We then examined other boron species with different Lewis
acidity, including trimethyl borate (5), B-allyl-1,3,2-dioxaborinane
(6), and B-methoxydiisopinocampheylborane (7), for the initiation
of the methanolysis of 1 in CD2Cl2 at -78 °C. In all cases, 1
methanolized instantly with methanol and an immediate formation
1
of the NH benzaldimine was observed by H NMR analysis.
Interestingly, we also noticed that the chemical shifts of the two
1
imino-protons in the H NMR spectra varied significantly with
different boron compounds in the reaction. Using 5 as initiator,
we observed two doublets at 9.9 and 8.7 ppm (J ) 16.1 Hz,
corresponding to a cis geometry of the imino-hydrogens), in
contrast to 9.4 and 8.0 ppm (J ) 21.0 Hz, corresponding to a
trans geometry of the imino-hydrogens) using 3. On the other
hand, using 7 as the initiator, two sets of two doublets were
detected in the 1H NMR analysis, 9.9, 8.7 (J ) 16.1 Hz) and 9.6,
8.3 ppm (J ) 21.0 Hz), respectively, in a 3:2 ratio. We believe
that this phenomenon probably corresponds to the presence of
an equilibrium mixture of free and complexed benzaldimine (with
the borane derivative) in the solution, in which the free benzaldi-
mine’s imino-proton signals showed downfield shifts at 9.9 and
8.7 ppm, while the complexed benzaldimine’s imino-proton
signals shifted upfield to 9.6 and 8.3 ppm. In fact, by applying a
0.5 molar equiv of 3 for the methanolysis of 1, we detected two
sets of two doublets at 9.9, 8.7 (J ) 16.1 Hz) and 9.4, 8.0 ppm
(J ) 21.0 Hz) in a 1:1 ratio in the 1H NMR analysis, in contrast
to only one set of two doublets of 9.4 and 8.0 ppm (J ) 21.0 Hz)
observed using a 1.0 molar equiv of 3 for the same reaction. In
(1) (a) Adams, J. P. Contemp. Org. Synth. 1997, 4, 517. (b) Bloch, R. Chem.
ReV. 1998, 98, 1407. (c) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry
1997, 8, 1895. (d) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(2) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131 and references therein.
(3) Davis, F. A.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13 and references
therein.
(4) Panunzio, M.; Zarantonello, P. Org. Process Res. DeV. 1998, 2, 49
and references therein.
(5) Cainelli, G.; Panunzio, M.; Andreoli, P.; Martelli, G.; Spunta, G.; Giaco-
mini, D.; Bandini, E. Pure Appl. Chem. 1990, 62, 605 and references therein.
(6) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278.
(7) (a) Nielsen, A. T.; Atkins, R. L.; Moore, D. W. J. Org. Chem. 1973,
38, 3288. (b) Nielsen, A. T.; Atkins, R. L.; DiPol, J.; Moore, D. W. J. Org.
Chem. 1974, 39, 1349.
(8) Guillemin, J.-C.; Denis, J.-M. Angew. Chem., Int. Ed. 1982, 21, 690.
(9) Bogdamovic, B.; Velic, M. Angew. Chem., Int. Ed. 1967, 6, 803.
(10) Boyd, D. R.; Hamilton, R.; Thompson, N. T.; Stubbs, M. E.
Tetrahedron Lett. 1979, 20, 3201.
(11) Boyd, D. R.; McCombe, K. M.; Sharma, N. D. Tetrahedron Lett. 1982,
23, 2907.
(12) Pickard, P. L.; Tolbert, T. L. J. Org. Chem. 1961, 26, 4886.
(13) Chen, G.-M.; Ramachandran, P. V.; Brown, H. C. Angew. Chem., Int.
Ed. 1999, 38, 825.
10.1021/ja993965v CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/13/2000

4218 J. Am. Chem. Soc., Vol. 122, No. 17, 2000
Communications to the Editor
Table 1. Preparation of N-Unsubstituted Imine-Borane Adductsa
that case, all the benzaldimine formed was completely complexed
with 3.14 From the above observation, it clearly appeared to us
that all the boron species initiate the methanolysis of 1, but the
more alkylated boron species tend to favor complex formation
with the aldimine, because of the stronger Lewis acidity of these
borane derivatives as compared to the alkoxy derivatives. We
also observed that such complexation stabilizes NH benzaldimine.
For example, benzaldimine generated using 3 as initiator was
stable for at least 2 days at -78 °C, much longer than the earlier
report,10 while it vanished completely within 2 h when 5 was
used as the initiator.
Consequently, we envisioned the preparation of imine-borane
adducts stable at room temperature by implementing this new
chemistry using trialkylboranes. Attempts to isolate the NH
benzaldimine-3 adduct failed. Though the aldimine was stable
at -78 °C in THF, it vanished in less than 0.5 h at room
temperature. The imino group was reduced by 3, as the temper-
ature was raised, eliminating 1 mol of R-pinene and providing
benzylamine, after workup.
entry
R1
Ph
Ph
Ph
2-Furyl
t-Bu
CH3
CH3
n-Bu
Ph
R2
R3
borane
adductb yield (%)
1
2
3
4
5
6
7
8
9
H
SiMe3 B-Me-9-BBN
SiMe3 Et3B
SiMe3 n-Bu3B
SiMe3 Et3B
9
10
11
12
13
15
16
17
20
21
26
85
72
69
75
70
84
71
83
89
78
73
H
H
H
H
H
H
H
SiMe3 Et3B
AliBu2 B-Me-9-BBN
AliBu2 Et3B
AliBu2 B-Me-9-BBN
CH3 SiMe3 Et3B
CH3 SiMe3 B-Me-9-BBN
CH3 SiMe3 B-Me-9-BBN
10
11
t-Bu
n-Bu
a The reactions were carried out in THF or pentane at 1 M
1
concentration. b All the adducts were isolated and confirmed by H,
11B, and 13C NMR and elementary analysis. Only the (E)-isomer was
We were gratified, however, that employment of equimolar
amounts of B-methyl-9-BBN (8) and methanol at -78 °C for
the methanolysis of 1 provided the benzaldimine-B-methyl-9-
BBN adduct (9) in 85% isolated yield as a yellow crystalline
material. This adduct was stable at room temperature in a nitrogen
atmosphere without observable alteration. To the best of our
knowledge, this is the first NH aldimine-borane adduct ever
isolated. Encouraged by this success, we subsequently synthesized
several non-enolizable aldimine-borane adducts, such as benz-
aldimine-triethylborane (10), benzaldimine-tri-n-butylborane
(11), 2-furfurylcarboxaldimine-triethylborane (12), and trimethyl-
acetaldimine-triethylborane (13) adducts from the corresponding
N-trimethylsilylaldimine derivatives, and isolated them in good
yields via crystallization from pentane at low temperatures
1
detected by 300 or 600 MHz H NMR.
In addition, treatment of valeronitrile with methyllithium in
ethyl ether at 0 °C, followed by silylation with trimethylsilyl
chloride provided a mixture of N-trimethylsilyl-2-hexanimine (22),
N-trimethylsilyl-1-hexen-2-amine (23), (Z)-N-trimethylsilyl-2-
hexen-2-amine (24), and (E)-N-trimethylsilyl-2-hexen-2-amine
(25) in a ratio of 4:2:1:1. However, methanolysis of this
complicated mixture in the presence of B-methyl-9-BBN provided
(E)-2-hexenimine-B-methyl-9-BBN adduct (26) solely in 73%
isolated yield.16 All the enamine isomers were converted to the
more stable ketimine form (eq 2).
1
(Scheme S1, Supporting Information). H NMR analysis of all
the adducts revealed that only the E isomer formed.14 Under an
inert atmosphere, all the aldimine-borane adducts are stable at
room temperature without significant decomposition for several
days.
We next explored the synthesis of enolizable aldimine-borane
adducts. Partial reduction of acetonitrile with diisobutylaluminum
hydride (DIBAL-H) provided N-diisobutylaluminoacetaldimine
(14). Treatment of this alumino-aldimine with an equimolar
amount of MeOH and B-methyl-9-BBN furnished the desired
acetaldimine-B-methyl-9-BBN adduct (15), which was formed
exclusively in the (E)-imine form in 84% isolated yield (Scheme
S2, Supporting Information). Similarly, the (E)-acetaldimine-
triethylborane adduct (16) and the (E)-pentanaldimine-B-methyl-
9-BBN adduct (17) were prepared in 71% and 83% isolated yield,
respectively.
In summary, we have demonstrated that in the presence of
trialkylboranes, N-trimethylsilylimines or N-diisobutylalumi-
noimines can be readily methanolyzed to afford N-unsubstituted
imine-borane adducts as the (E)-isomer exclusively. The adducts
can be isolated and are stable at room temperature. Using this
methodology, aliphatic as well as aromatic, non-enolizable as well
as enolizable, aldimine- as well as ketimine-borane adducts can
be conveniently prepared.
We believe that this new class of compounds can be important
intermediates for synthetic operations. In fact, our preliminary
investigations revealed that the imine-organoborane adducts can
be used as intermediates for the synthesis of chiral homoallyl-
amines and â-lactams in very high yields.17 These results will be
reported subsequently.
To establish a procedure for the synthesis of ketimine-borane
adducts, we synthesized various N-trimethylsilylketimines by
adopting the procedure developed by Ahlbrecht et al.15 Thus,
treatment of benzonitrile with methyllithium at -78 °C, followed
by the reaction with trimethylsilyl chloride at room temperature
provided N-trimethylsilylacetophenimine (18) and N-trimethyl-
silylphenylethylenamine (19) in a ratio of 3:7. To our satisfaction,
methanolysis of this mixture with methanol in the presence of
triethylborane afforded the (E)-acetophenimine-triethylborane
adduct (20) exclusively in 89% isolated yield. We could not detect
Supporting Information Available: Schemes S1 and S2 showing
the synthesis of 9-13 and 15, experimental details for all procedures,
the 1H, 11B, and 13C NMR spectra of all the new imine-borane adducts,
and X-ray structural information on 26 (PDF), and an X-ray crystal-
lographic file (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
1
any enamine isomer, by H NMR analysis, even in the crude
product. Obviously, the coordination of boron to the imino-
nitrogen significantly lowered the energy of the imine form,
favoring its formation. Similarly, the (E)-3,3-dimethyl-2-butan-
imine-B-methyl-9-BBN adduct (21) was prepared in 78%
isolated yield.
JA993965V
(16) The geometry of 26 was determined by X-ray crystallography as E.
The variable-temperature NMR technique reveals only one isomer. The
geometry of other ketimines was then determined based on the analogy.
(17) For example, asymmetric allylboration of 10 with B-allyldiisopi-
nocampheylborane provides the product 1-phenyl-3-buteneamine, in 90% ee
and 79% isolated yield. Further, the reaction of 10 with methyl trimethylsilyl
dimethylketene acetal, in the presence of ZnI2, followed by the addition of
Grignard reagent, provides the product 3,3-dimethyl-4-phenylazetidin-2-one
in 94% isolated yield.
(14) In fact, 1 can be methanolyzed instantly and completely in the presence
of only 5 mol % of 3 at -78 °C. The free aldimine produced, as reported
previously (ref 10), is not stable even for a short period. For characterization
of the E- and Z-isomer of aldimines, see ref 8.
(15) Ahlbrecht, H.; Du¨ber, E.-O. Synthesis 1982, 4, 273.