Selective mono-N-alkylation of 3-amino alcohols via chelation to 9-BBN

Article abstract of DOI:10.1021/ol048554k

(Chemical Equation Presented) A method for selective mono-N-alkylation of amino alcohols is introduced. This method relies on formation of a stable chelate with 9-BBN, which serves in the dual roles of protecting and activating the amine group. Three prot

Full text of DOI:10.1021/ol048554k

ORGANIC
LETTERS
2
004
Vol. 6, No. 20
549-3551
Selective Mono-N-alkylation of 3-Amino
Alcohols via Chelation to 9-BBN
3
Galia Bar-Haim and Moshe Kol*
The School of Chemistry, Raymond and BeVerly Sackler Faculty of Exact Sciences,
Tel AViV UniVersity, Ramat AViV, Tel AViV 69978, Israel
moshekol@post.tau.ac.il
Received July 26, 2004
ABSTRACT
A method for selective mono-N-alkylation of amino alcohols is introduced. This method relies on formation of a stable chelate with 9-BBN,
which serves in the dual roles of protecting and activating the amine group. Three prototypical amino alcohols featuring various three-carbon
bridging units led selectively to the monoalkylated derivatives in very high yields. The straightforward synthesis of the N-CD
3
derivatives
demonstrates the effectiveness of this approach.
alcohols.5 Several representative 1,3-amino alcohols were
-7
The selective mono-N-alkylation of primary amines by direct
nucleophilic substitution on alkyl halides is a familiar
challenge in organic synthesis. Since the produced secondary
amines are usually at least as reactive as the starting primary
amines, they react further, yielding mixtures of alkylation
chosen for this preliminary feasibility study, and all proved
to undergo exclusive mono-N-alkylation in high yields
(Figure 1).
1
products. The common solutions are either the use of an
excess of the primary amine followed by distillation or
utilizing an alternative route such as reductive amination.
However, if the amine is expensive, or when other functional
groups in the molecule are sensitive to reduction, these
schemes may become unsatisfactory. Recently, we introduced
a method for selective mono-N-alkylations of certain di-
amines with alkyl halides relying on formation of a chelate
with 9-BBN that enabled the efficient N-alkylation and N,N′-
dialkylation of 1,8-diaminonaphthalene2 and the regiose-
Figure 1. Amino alcohols studied in this work.
,3
4
lective mono-N-alkylation of 2-aminobenzylamine. In this
paper we report that the “chelation to 9-BBN” approach is
applicable for selective mono-N-alkylation of various amino
The essential requirement for successful mono-N-alkyla-
tion by this approach would be the formation of a stable
chelate between the amino alcohol and 9-BBN. This chelate
(
1) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, 4th ed.;
Kluwer Academic: New York, 2001; Part B, Chapter 3.2.5.
2) Bar Haim, G.; Kol, M. J. Org. Chem. 1997, 62, 6682. See also: Bar
Haim, G.; Shach, R.; Kol, M. Chem. Commun. 1997, 229.
3) For application of this approach in the synthesis of chiral “proton
(
(5) For the selective monoacylation of symmetrical diamines via prior
complexation with 9-BBN, see: Zhang, Z. X.; Yin, Z. W.; Meanwell, N.
A.; Kadow, J. F.; Wang, T. Org. Lett. 2003, 5, 3399.
(
sponges”, see: (a) Charmant, J. P. H.; Lloyd-Jones, G. C.; Peakman, T.
M.; Woodward, R. L. Tetrahedron Lett. 1998, 39, 4733. (b) Charmant, J.
P. H.; Lloyd-Jones, G. C.; Peakman, T. M.; Woodward, R. L. Eur. J. Org.
Chem. 1999, 2501. (c) Lloyd-Jones, G. C. Synlett 2001, 161.
(6) For selective N-alkylation employing cesium bases, see: Salvatore,
R. N.; Nagle, A. S.; Jung, K. W. J. Org. Chem. 2002, 67, 674.
(7) For selective monomethylation of substituted anilines by dimethyl
carbonate in the presence of a zeolite catalyst, see: Selva, M.; Tundo, P.;
Perosa, A. J. Org. Chem. 2003, 68, 7374.
(4) Bar Haim, G.; Kol, M. Tetrahedron Lett. 1998, 39, 2643.
1
0.1021/ol048554k CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/10/2004

Table 1. 9-BBN Chelates, 11B NMR Chemical Shifts, and
Yields of Final N-Alkylated Products
Scheme 1. General Alkylation Scheme of Amino Alcohols via
Chelation to 9-BBN
9
-BBN
11B NMR
isolated
product
total
yield
chelate
(ppm, vs BF3‚OEt2)
1
1
1
1
1
2
2
2
2
2
3
3
3
3
3
-BBN
-0.6
0.8
100%
95%
-BBN-Me
-BBN-Et
-BBN-Pr
-BBN-Bn
-BBN
1-Me
1-Et
1-P r
1-Bn
1.3
95%
1.4
95%
1.8
95%
3.0
100%
100%
100%
100%
100%
100%
90%
-BBN-Me
-BBN-Et
-BBN-Pr
-BBN-Bn
-BBN
4.3
2-Me‚HCl
2-Et‚HCl
2-P r ‚HCl
2-Bn ‚HCl
5.0
5.2
5.6
13.5
9.2
-BBN-Me
-BBN-Et
-BBN-Pr
-BBN-Bn
3-Me
3-Et
3-P r
3-Bn
23.1
31.6
41.0
90%
90%
90%
white, air-sensitive crystalline compound. The spectral
properties of 1-BBN support its proposed structure (see
Supporting Information for full spectroscopic characterization
of 1-BBN). In particular, the formation of an O-B-N
should consist of an oxygen-boron covalent bond and a
strong nitrogen-boron coordinative bond. In this neutral
form, the amine functionality is, at the same time, protected
from alkylation as well as being more acidic since the
nitrogen lone pair is coordinating to the Lewis acidic boron
center. Facile removal of a single proton by a relatively mild
base should lead to formation of an anionic nucleophile that
can react with a single equivalent of an alkyl halide giving
the mono-N-alkyl product that is protected from further
alkylation by coordination to the boron. Finally, a mild acidic
hydrolysis of 9-BBN should release the mono-N-alkylated
amine (Scheme 1).
11
chelate is supported by the B NMR chemical shift, which
is consistent with a tetracoordinate boron atom (Table 1).
As expected, 1-BBN did not react with electrophiles such
as methyl iodide at room temperature. However, on addition
of potassium tert-butoxide at room temperature to 1-BBN
dissolved in THF followed by a primary alkyl halide R-X
namely, iodomethane, iodoethane, 1-bromopropane, or ben-
zyl chloride, an immediate reaction took place, as was evident
from the precipitation of a white solid (potassium halide).
Filtration and removal of the solvent gave the mono-N-alkyl
1
derivatives 1-BBN-R quantitatively. H NMR spectra of
the crude products indicated that alkylation took place only
on the nitrogen atom and that polyalkylation did not occur.
In analogy to 1-BBN, the mono-N-alkyl derivatives 1-BBN-R
Therefore, the first substrate we chose was 2-hydroxy-
8
benzylamine (1), which is expected to bind to 9-BBN by a
strong oxygen-boron covalent bond and a strong nitrogen-
boron coordinative bond, thus completing a six-membered
chelate ring. N-Alkyl derivatives of 2-hydroxybenzylamine,
which are intermediates in the synthesis of several biologi-
cally active compounds, have previously been prepared by
amine condensation with salicylaldehyde followed by reduc-
11
are also chelating according to B NMR (Table 1). An acidic
hydrolysis of the 9-BBN group at room temperature followed
by a basic workup gave the four mono-N-substituted 2-hy-
droxybenzylamines 1-R (R ) Me, Et, Pr, Bn) in very high
yields (Table 1).
The second prototypical amino alcohol we investigated
was the aliphatic 3-aminopropanol (2), whose tendency to
form a six-membered chelate with 9-BBN may be somewhat
diminished due to loss of entropic conformational freedom.
A previous synthesis of N-substituted 3-amino alcohol relied
on a Michael addition between a primary amine and ethyl
9
tion, since a direct reaction of 2-hydroxybenzylamine with
alkyl halides is expected to yield a mixture of alkylation
products. Adding 1.0 equiv of 9-BBN-H to 2-hydroxyben-
zylamine in ether resulted in evolution of hydrogen gas and
formation of the chelate 1-BBN, which was isolated by
removal of the solvent in quantitative yield. Alternatively,
1
0
acrylate followed by reduction. In addition, the N-benzyl
derivative was synthesized by a nucleophilic substitution
employing a large excess of the amine to avoid over-
1-BBN can be synthesized from methoxy-9-BBN and 2-hy-
droxybenzylamine with formation of methanol. 1-BBN is a
(
8) Holly, F. W.; Cope, A. C. J. Am. Chem. Soc. 1944, 66, 1875. (b)
Zaugg, H. E.; Schaefer, A. D. J. Org. Chem. 1963, 28, 2925.
9) (a) Neuvonen, K.; Pihlaja, K. J. Chem. Soc., Perkin Trans. 2 1988,
4
1
(10) (a) Le Lann, M.; Saba, S.; Shoja, M. J. Heterocycl. Chem. 1991,
28, 1789. (b) Jones, R. A. Y.; Katritzky, A. R.; Trepanier, D. L. J. Chem.
Soc. B 1971, 1300. (c) Israeli, H. Z.; Derel, J. M.; Cunningham, R. F.;
Dayton, P. G.; Y u¨ , T. F.; Gutman, A. B.; Long, K. R.; Long, R. C.;
Goldstein, J. H. J. Med. Chem. 1972, 15, 709.
(
61. (b) Yoshikawa, H.; Fuchigami, K.; Shono, T. J. Pesticide Sci. 1986,
1, 631. (c) Neuvonen, K.; Pihlaja, K. Magn. Reson. Chem. 1990, 28, 239.
d) Clark, J. S.; Middleton, M. D. Org. Lett. 2002, 4, 765.
(
3550
Org. Lett., Vol. 6, No. 20, 2004

Scheme 2. Synthesis of N-Deuteriomethyl Derivatives of
Amino Alcohols 1-3
Figure 2. Possible equilibrium between chelate and open-form
isomers in 3-BBN-R.
the N-substituents increases (Figure 2). Again, a facile acidic
hydrolysis gave the four alkylated products 3-R in very high
yields (Table 1).
alkylation,11 as well as by copper-catalyzed coupling of
iodobenzyl alcohol with benzylamine. Adding 1.0 equiv
of 9-BBN-H to 2 resulted in evolution of hydrogen gas and
quantitative formation of the desired six-membered chelate
12
Preliminary experiments indicated that the chelation to
9-BBN approach is not successful for 1,2-amino alcohols.
Thus, even though the reaction of norephedrine with
1
4
2
-BBN, as supported by spectroscopic data and especially
B NMR. Following the same deprotonation and alkylation
9-BBN-H led to a five membered chelate, the following
deprotonation and alkylation sequence led to a mixture of
alkylation products. It is possible that the monoalkylated
chelate is too strained and reacts further with an alkyl halide
via its neutral open-form isomer. It is possible that given an
appropriate Lewis acid-chelating center, the selective alkyl-
ation of these important substrates may be achieved.
The advantage of the chelation to 9-BBN method over
the common reductive amination procedure may be appreci-
ated by the selective and essentially quantitative formation
3
1
1
as above led to the mono-N-alkylated products 2-BBN-R
in quantitative yields whose 11B NMR indicated that they,
too, were chelating. Finally, a mild acidic hydrolysis
procedure led to the four mono-N-alkyl 3-hydroxypropyl-
amines 2-R (R ) Me, Et, Pr, Bn) isolated as the hydrochlo-
ride salts in quantitative yields.
We found that this alkylation method is successful even
for six-membered chelates featuring a weak donor, namely,
2-aminobenzyl alcohol (3). Previous syntheses of alkyl
of the CD -derivatives of all these prototypical amino
derivatives of this amino alcohol relied on various combina-
tions of condensation followed by reduction.1 Reacting 3
with 9-BBN-H led to the air-sensitive chelate 3-BBN in
quantitative yield. Even though this chelate is expected to
be less stable due to formation of a weak aromatic nitrogen-
boron coordinative bond, the sequence of deprotonation-
alkylation led selectively to the formation of the respective
alkylated chelates 3-BBN-R, quantitatively. Interestingly,
alcohols by employing CD I as the alkylating agent (Scheme
2). Obviously, a classical approach to these compounds
would have required a less economical use of deuterated
agents.
3
3
In conclusion, we have shown that the “chelation to
9-BBN” is a straightforward, mild, and efficient method for
selective mono-N-alkylation of several prototypical 3-amino
15
alcohols. This approach can clearly be extended to various
substrates featuring a 1,3-relationship between an amine and
an alcohol group.
1
1
the B NMR chemical shifts of the alkylated chelates
featured a substantial downfield shift as a function of the
bulk of the N-alkyl groups (a similar but much less apparent
trend may be observed for the former series). This trend may
result from equilibrium between a chelate (having a typical
Acknowledgment. We thank the Israel Science Founda-
tion for financial support.
11
B NMR chemical shift of ca. 0 ppm) and its relatively stable
open-form isomer in which the nitrogen lone pair is donated
Supporting Information Available: Synthetic procedures
and analytical data of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
11
to the aromatic ring (having a typical B NMR chemical
shift of ca. 50 ppm)2 that favors the latter as the bulk of
,14
OL048554K
(
11) (a) Ravina, E.; Ramos, R. G.; Masaguer, C. F.; Garcia Mera, G.
Synth. Commun. 1994, 24, 321. (b) Ali, Sk. A.; Hashmi, S. M. A.; Siddiqui,
M. N.; Wazeer, M. I. M. Tetrahedron 1996, 52, 14917.
(14) Parent compound, 2-aminoethanol, is known to form a five-
membered chelate with 9-BBN: (a) Krishnamurthy, S.; Brown, H. C. J.
Org. Chem. 1977, 42, 1197. (b) Brown, H. C.; Prasad, J. V. N. V. J. Org.
Chem. 1986, 51, 4526.
(15) Attempted extension of this methodology to secondary alkyl halides
(e.g., isopropyl bromide) failed, apparently due to a competing elimination
reaction.
(
12) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
81.
13) (a) Yamakawa, T.; Matsukura, H.; Nomura, Y.; Yoshioka, M.;
5
(
Masaki, M.; Igata, H.; Okabe, S. Chem. Pharm. Bull. 1991, 39, 1746. (b)
Coppola, G. M. J. Heterocycl. Chem. 1986, 23, 223.
Org. Lett., Vol. 6, No. 20, 2004
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