Some new aspects of the boyer reaction

Article abstract of DOI:10.1021/ol051442o

(Chemical Equation Presented) The reaction outcome of 2-azidoethanol and aliphatic aldehyde is found to be dependent on the catalyst and the structure of the azido alcohol. Under the catalysis of Cu(II) triflate, the corresponding acetal is obtained. A si

Full text of DOI:10.1021/ol051442o

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4145-4148
Some New Aspects of the Boyer
Reaction
Rupak Chakraborty, Veronica Franz, Ghanashyam Bez, Dipali Vasadia,†
Chenchu Popuri,† and Cong-Gui Zhao*
Department of Chemistry, UniVersity of Texas at San Antonio, 6900 North Loop 1604
West, San Antonio, Texas 78249-0698
cong.zhao@utsa.edu
Received June 21, 2005
ABSTRACT
The reaction outcome of 2-azidoethanol and aliphatic aldehyde is found to be dependent on the catalyst and the structure of the azido alcohol.
Under the catalysis of Cu(II) triflate, the corresponding acetal is obtained. A similar reaction between 2-aryl-2-azidoethanol and aldehyde
catalyzed by BF3 yields a mixture of 3-oxazoline and 2-oxazoline. The latter reaction has been used for the preparation of 3-oxazolines in good
enantioselectivity.
The reaction of an azido compound with an aldehyde or
ketone catalyzed by a Brønsted acid or a Lewis acid, which
is generally known as the Schmidt reaction,1 may yield an
amide, a lactam, or a heterocyclic product, depending on
the structure of the azido compound and the carbonyl
compound. Through recent efforts in developing an asym-
metric version of this reaction, the Schmidt reaction has
become a new strategy for the synthesis of optically active
lactams and nitrogen-containing heterocyclic compounds.2
For example, Aube´ and co-workers have synthesized poten-
tial peptide â- and γ-turn mimics by using this method.3
Mechanistically akin to the Schmidt reaction, the Boyer
reaction refers to the reaction of 2-azidoethanol or 3-azi-
dopropanol and an aldehyde, where 2-oxazoline or dihy-
drooxazine form as the product (eq 1). This reaction was
originally studied by Boyer with H2SO4 as the catalyst, with
a very limited substrate scope;4 however, Aube´ and co-
workers demonstrated that this can be much improved by
using Lewis acids, such as BF3‚Et2O, as the catalyst.5
Recently, we accidentally found some new pathways of this
reaction when we studied the Lewis acid catalyzed ring-
† Undergraduate student.
(1) For reviews, see: (a) Wolff, H. Org. React. 1946, 3, 307-336. (b)
Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279-1300. (c) Krow, G.
R. Tetrahedron 1981, 37, 1283-1307.
(2) (a) Smith, B. T.; Gracias, V.; Aube´, J. J. Org. Chem. 2000, 65, 3771-
3774. (b) Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman, C.; Milligan,
G. L.; Aube´, J. J. Am. Chem. Soc. 2000, 122, 7226-7232. (c) Wrobleski,
A.; Aube´, J. J. Org. Chem. 2001, 66, 886-889. (d) Sahasrabudhe, K.;
Gracias, V.; Furness, K.; Smith, B. T.; Katz, C. E.; Reddy, D. S.; Aube´, J.
J. Am. Chem. Soc. 2003, 125, 7914-7922. (e) Katz, C. E.; Aube´, J. J. Am.
Chem. Soc. 2003, 125, 13948-13949.
(3) (a) Reddy, D. S.; Vander Velde, D.; Aube´, J. J. Org. Chem. 2004,
69, 1716-1719. (b) Ramanathan, S. K.; Keeler, J.; Lee, H.-L.; Reddy, D.
S.; Lushinton, G.; Aube´, J. Org. Lett. 2005, 7, 1059-1062.
(4) (a) Boyer, J. H.; Hamer, J. J. Am. Chem. Soc. 1955, 77, 951-954.
(b) Boyer, J. H.; Canter, F. C.; Hamer, J.; Putney, R. K. J. Am. Chem. Soc.
1956, 78, 325-327. (c) Boyer, J. H.; Morgan, L. R., Jr. J. Org. Chem.
1959, 24, 561-562.
(5) (a) Badiang, J. G.; Aube´, J. J. Org. Chem. 1996, 61, 2484-2487.
(b) Gracias, V.; Frank, K. E.; Milligan, G. L.; Aube´, J. Tetrahedron 1997,
53, 16241-16252.
10.1021/ol051442o CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/24/2005

opening reaction of epoxides.6 Herein, we wish to report our
preliminary results.
acetal with hexanal under the catalysis of Cu(OTf)2 (data
not shown).
Although most Lewis acids catalyze the reaction 2-azi-
doethanols and aliphatic aldehydes to give the reported
2-oxazoline products, we found that Cu(II) triflate behaves
totally differently. Instead of the normal 2-oxazoline, this
reaction gives an acetal as the product (eq 2).7 The results
are summarized in Table 1 (Caution: Although we did not
To demonstrate the usefulness of this new reaction, acetal
1a was reduced to diamine 2 (Scheme 1). Reaction of 2 with
Scheme 1. Synthesis of Ligand 3
Table 1. Formation of Acetals between Aliphatic Aldehydes
and Azido Alcoholsa
entry
R1
R2
yieldb (%)
1
2
3
4
5
6
7
8
9
n-C5H11
n-C6H13
n-C8H17
PhCH2CH2
cyclohexyl
Me3C
n-C5H11
n-C6H13
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
68
64
75
87
66
42
81
65
66
65
pyridine-2,6-dicarbaldehyde produced a macrocyclic com-
pound 3, which may be used as a ligand in the Cu(OTf)-
catalyzed addition of phenylacetylene to N-benzylidene-
aniline to yield the propargylamine in 75% yield (eq 3, no
yield without 3).8 Moreover, since the azido group is a
masked amino group, the present acetal formation reaction
may be viewed as a selective protection method for the
hydroxyl group of an amino alcohol, which is usually
difficult to achieve.
PhCH2CH2
cyclohexyl
10
a Carried out with the aldehyde (1.0 mmol), the azido alcohol (1.0 mmol),
and 5 mol % of Cu(OTf)2 in dry CH2Cl2 (5 mL) under reflux overnight.
b Yield of isolated product after chromatography.
encounter any problem with these products, diazides are
potential explosives and should be handled with care and
all necessary protective measures should be taken during the
reaction). Aldehydes with straight alkyl chain, such as
hexanal (entry 1), heptanal (entry 2), nonanal (entry 3), and
hydrocinnamaldehyde (entry 4), all gave good yields of the
acetal products when 2-azido-2-phenylethanol was used.
Aldehydes with branching at the R position also participate
in this reaction. For example, cyclohexanecarbaldehyde gave
66% yield of the desired acetal (entry 5). A sterically
hindered 2,2-dimethylpropionaldehyde also gave a 42% yield
of the expected acetal (entry 6). When 2-azidoethanol was
used as the substrate, similar results were obtained (Table
1, entries 7-10). However, when aromatic aldehydes or
ketones were used, no acetal could be obtained (data not
shown).
When BF3‚Et2O was used as the catalyst, the reaction of
aldehydes with 2-aryl-2-azido alcohol was found to be more
complicated than expected: Besides the expected 2-oxazo-
lines (5), 3-oxazoline (4) and a third product, which we
tentatively assigned the structure 6, were also isolated (eq
4). The results are summarized in Table 2.
As shown in Table 2, 3-oxazoline (4) is always formed
except for 4-nitro-substituted azido alcohol, while the forma-
tion of the other two products is dependent on the substrates.
Again, different types of aliphatic aldehydes (entries 1-6)
can be used as substrates for this reaction. As in the
aforementioned acetal formation reaction, aromatic aldehydes
do not react (data not shown). Since multiple products are
formed in this reaction, the yield of each of the individual
products is low. The best yields of the 3-oxazoline product
were achieved with aldehydes with two phenyl substituents
at the R position (entries 4 and 6). Similarly, azido alcohols
Formation of an acetal from aldehyde and azido alcohol
under acid catalysis is unprecedented in the literature. Even
though the acid-catalyzed formation of acetal from aldehyde
and alcohol is well-known, the present reaction is apparently
different from such a reaction, since ethanol does not form
(8) For recent examples of transition-metal-catalyzed addition of acety-
lene to imines, see: (a) Li, C.-J.; Wei, C. Chem. Commun. 2002, 268-
269. (b) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319-4321. (c)
Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638-5639.
(6) Bez, G.; Zhao, C.-G. Org. Lett. 2003, 5, 4991-4993.
(7) A mixture of d,l and meso compounds was obtained when a racemic
azido alcohol was used.
4146
Org. Lett., Vol. 7, No. 19, 2005

of the azido group to the oxonium ion forms the intermediate
7,5a The hydrides at 4- or 2-position of this intermediate
migrate followed by N2 loss to form two new cationic
intermediates 8 and 9, stabilized by phenyl and oxygen
groups, respectively. The relative energy of these two cationic
intermediates would affect the rate of hydride migration. Our
results and those of Aube´5 and Boyer4 indicate that, without
a phenyl group at 4-position, the formation of intermediate
8 is unfavorable and the normal 2-oxazoline product is
observed,4,5 while the formation of 8 becomes important
when such a phenyl group is present, since its energy is now
lowered through conjugation. This mechanism explains better
why arene with a strong electron-withdrawing para substi-
tutent (NO2) totally inhibits the formation of 3-oxazoline.
3-Oxazolines are very useful compounds. Their derivatives
have been isolated and characterized as volatile flavor com-
pounds in food.9 Some of these compounds have shown im-
portant organoleptic properties.10 Reported synthetic methods
of 3-oxazolines include photochemically induced11 or base-
catalyzed12 ring opening of substituted 2H-azirines and oxida-
tive elimination of 1,3-oxazolidines with t-BuOCl/KO213 or
with NaOCl/KOH.14 However, none of these methods may
be used to synthesize 3-oxazoline enantioselectiVely.
Table 2. Boyer Reaction of Aliphatic Aldehyde with
2-Aryl-2-azidoethanola
yieldb (%)
entry
R
X
4
5
6
1
2
3
4
5
6
7
8
9
n-C6H13
n-C8H17
n-C9H19
Ph2CH
PhMeCH
Ph2MeC
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
H
H
H
H
H
H
Me
MeO
Cl
24c
20
18
47d,e
17d,f
40
23
24
15
17
14
38
41
21
28
trace
26
29
20
11
38
During the formation of 3-oxazoline in our reaction, a new
chiral center at the 2-position is created (Scheme 2). Although
the yield of this reaction is not satisfactory, it is possible to
control the stereo outcome of the 2-position based on the
proposed mechanism. Thus, we tried the asymmetric induc-
tion in this reaction, and the preliminary results are sum-
marized in Table 3. When enantiomerically pure (S)-2-azido-
10
11
F
NO2
a Carried out with the aldehyde (0.3 mmol) and 2-aryl-2-azidoethanol
(0.3 mmol) in dry CH2Cl2 with BF3‚Et2O (2 equiv) as the catalyst at room
temperature (25 °C) for 3 h, unless otherwise indicated. b Yields of isolated
products after column chromatography. c With 1.0 equiv of BF3‚Et2O and
overnight reaction. d At 40 °C. e With 2.5 equiv of BF3‚Et2O for 6 h. f With
1.66 equiv of BF3‚Et2O for 5 h.
Table 3. Asymmetric Induction in Reaction of Nonanal with
(S)-2-Aryl-2-azidoethanola
with different aryl substituents also participate in the reaction
to give these products (entries 2, 7-11). The data indicate
that the electronic effects of the substituent on the para
position of the phenyl ring have some influence on the
product distribution: An electron-withdrawing group favors
the formation of product 6 (entries 9-11), while the strong
electron-withdrawing nitro group totally inhibits the forma-
tion of the 3-oxazoline product (entry 11).
entry
Ar
Ph
Ph
Ph
t (h)
T (°C)
yieldb (%)
eec (%)
1
2
3
4
3
9
9
9
25
0-5
-23
-23
16
15
15
14
45d
65d
74d
67e
The formation of 3-oxazoline product may be rationalized
by a modified reaction mechanism proposed originally by
Aube´ and co-workers.5a As shown in Scheme 2, the addition
4-Cl-Ph
a Carried out with a mixture of nonanal (0.3 mmol), (S)-2-aryl-2-
azidoethanol (0.3 mmol), and BF3‚Et2O (2 equiv) in dry CH2Cl2 at the
specified temperature. b Yield of isolated product after column chromatog-
raphy. c Absolute configuration of the major enantiomer not determined.
d Determined by HPLC analysis using a Chiralcel OD-H column. e Deter-
mined by HPLC analysis using a Chiralcel AS column.
Scheme 2. Mechanism for the Formation of 3-Oxazoline
2-phenylethanol2d was used, the product of nonanal gives
an ee value of 45% at room temperature (entry 1). When
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Org. Lett., Vol. 7, No. 19, 2005
4147

the temperature was lowered to ca. 0 °C, the ee value was
improved to 65% (entry 2). The enantioselectivity of this
reaction may be further improved to 74% ee by carrying
out the reaction at -23 °C (entry 3). A similar result was
also obtained with (S)-2-azido-2-(4-chlorophenyl)ethanol15
(entry 4).
alcohol. When Cu(OTf)2 is used as the catalyst, an acetal is
formed, while when 2-aryl-2-azidoethanol is used with BF3
as the catalyst, formation of 3-oxazoline is observed. The
latter reaction has been used for the enantioselective synthesis
of 3-oxazolines in good ee values for the first time.
Optically active 3-oxazolines, although unexplored previ-
ously, have the potential to be used as chiral ligands for
asymmetric catalysis, since their structural isomers, 2-ox-
azolines, have been widely utilized for this purpose.16
In summary, we have found some new pathways in the
Lewis acid catalyzed reaction of aldehyde and 2-azido
Acknowledgment. The financial support of the Welch
Foundation (Grant No. AX-1593) for this research is
gratefully appreciated. We also appreciate the reviewer’s
insights into the reaction mechanism.
Supporting Information Available: Experimental de-
tails, NMR characterization data for all new compounds, and
HPLC data for compounds listed in Table 3. This material
is available free of charge via the Internet at http://pubs.acs.org.
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OL051442O
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(15) Synthesized in a similar way as (S)-2-azido-2-phenylethanol.
4148
Org. Lett., Vol. 7, No. 19, 2005