Unexpected rearrangement in the Heck cyclization of positional isomers of chiral 2,3-disubstituted perhydro-1,3-benzoxazines

Article abstract of DOI:10.1055/s-2002-19756

The intramolecular Heck cyclization on 2,3-disubstituted perhydro-1,3-benzoxazines, derived from (-)-8-amino menthol, easily proceeds at reflux of acetonitrile or DMF. The behavior of positional isomers was quite different. Reaction of 2-aryl-3-allyl perh

Full text of DOI:10.1055/s-2002-19756

LETTER
259
Unexpected Rearrangement in the Heck Cyclization of Positional Isomers of
Chiral 2,3-Disubstituted Perhydro-1,3-benzoxazines
Unexpected
Rear
a
rangement
f
inthe
H
e
a
ck
C
ycliza
e
tion l Pedrosa,* Celia Andrés,* Jesús M. Iglesias
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n. 47011-Valladolid, Spain
Fax +34(983)423013; E-mail: pedrosa@qo.uva.es
Received 6 December 2001
Abstract: The intramolecular Heck cyclization on 2,3-disubstitut-
OH
NH2
ed perhydro-1,3-benzoxazines, derived from (–)-8-amino menthol,
easily proceeds at reflux of acetonitrile or DMF. The behavior of
positional isomers was quite different. Reaction of 2-aryl-3-allyl pe-
rhydro-1,3-benzoxazines occurred as expected giving exclusively
6-exo cyclization products. On the contrary, regioisomeric 3-(iodo-
benzyl)-2-vinyl derivatives gave the normal cyclization compounds
and rearranged 1,2-dihydroisoquinoline nucleus.
CHO
X
CH2Cl2, r.t.
NaBH4
X
BF3 OEt2
THF
Key words: cyclizations, Heck reaction, palladium, rearrange-
ments
X
OH
N
H
O
N
H
R2
R1
Intramolecular diastereoselective Heck reaction has been
widely used in the construction of carbo- and heterocy-
cles,1 including isoquinoline derivatives.2 Two main strat-
egies have been used to control the stereochemistry of the
reaction: the use of chiral phosphines as ligands,3 or by us-
ing chiral auxiliaries such as ethers4 or amino ethers.5 In
this way, we have recently reported that chiral perhydro-
1,3-benzoxazines, derived from (–)-8-aminomenthol, are
excellent chiral auxiliaries for the synthesis of enan-
tiopure tetrahydro isoquinolines6 and related substances
by anionic cyclizations,7 and we envisaged a tetrahy-
droisoquinoline nucleus could be formed by intramolecu-
lar Heck reaction of conveniently substituted perhydro-
1,3-benzoxazines. However, we describe herein that the
reaction follows a different way on positional isomers 1
and 5. Whereas 2-aryl-3-allyl substituted perhydro-1,3-
benzoxazines 1a–e give a mixture of normal cyclization
compounds 2–4, the isomeric 2-allyl-3-aryl substituted
derivatives 5a–c led to the normal cyclization products,
and the enamine derivatives 9a–c, resulting from an un-
usual rearrangement process.
R2
R1
CHO
120 °C
Br
K2CO3
MeCN, ∆
sealed tube
R1 R2
X
X
O
R2
O
N
N
R1
5a-c
1a-e
1/5
a
H
H
I
b
c
d
e
R1
R2
X
H
Me
H
Me
Me
Me Me
Me
OTf
I
I
OTf
Scheme 1 Synthesis of starting compounds from (–)-8-amino-
menthol
The chiral perhydro-1,3-benzoxazines 1a–e for the Heck
reaction were synthesized in two steps, with excellent
yields, by condensation of (–)-8-aminomenthol with o-io-
dobenzaldehyde (for 1a–c) or salicylaldehyde triflate8 (for
1d–e), followed by N-alkylation with the corresponding
allyl bromide in the presence of potassium carbonate.9 In
turn, compounds 5a–c were prepared, in three steps, by re-
action of (–)-8-aminomenthol with o-iodobenzaldehyde
followed by reduction with diborane, and condensation of
the resulting N-(o-iodobenzyl)amino menthol with the
corresponding , -unsaturated aldehyde7 (Scheme 1).
The intramolecular Heck reaction was performed under
Jeffery conditions,10 and the first attempt was tested on
compound 1c by refluxing for 8 h a 0.2 M solution in
11
DMF with Pd(OAc)2 (5%), Ph3P (15%), TBAB (1
equiv) and KOAc (4 equiv). In these conditions, we ob-
tained a complex reaction mixture where it was possible
to isolate cyclization compounds 2c (48%), 3c (12%) and
8-(benzoylamino) menthol (14%) (entry 3 in Table). The
same reaction mixtures were obtained in reactions where
triphenylphosphine was changed by triphenylarsine, or
the palladium acetate was substituted by Pd2(dba)3. The
addition of silver acetate did not modify the chemical
yields nor the stereoselectivity of the reaction.
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0259,0262,ftx,en;D25301ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

260
R. Pedrosa et al.
LETTER
On the contrary, substantial increase in the chemical yield,
de and cleaner reaction mixtures were observed when the
reactions were carried out in acetonitrile as solvent. The
intramolecular Heck reaction for compounds 1a,b,d,e was
then performed under the above experimental conditions
by using acetonitrile as solvent, and the results are sum-
marized in Scheme 2 and Table (entries 1–6).
O
R2
R1
O
N
N
R2
R1
O
X
N
6a-c
7c
5a-c
R2
R1
N
R2
X
R1
R1
O
O
N
H
Pd(OAc) 2 (5%)
Ph3P (15%)
O
8b
9a-c
O
N
N
TBAB (1 equiv)
KOAc (4 equiv)
MeCN, reflux
Scheme 3 Heck cyclization of compounds 5a–c.
2b,c
1a-e
Table Intramolecular Heck Reaction of 1a–e and 5a–c
R1
R2
R1
Entry Com- X
pound
R1
R2
Solvent Time Products (%)
H
(h)
O
O
1
2
3
4
5
1a
1b
1c
1c
1d
I
H
H
H
MeCN
8
4a(85)a
N
N
I
Me MeCN
7
2b(12) 4b(72)a
2c(48) 3c(12)a,b
2c(64) 3c(16)a
3b,c
4a,b
I
Me Me DMF
Me Me MeCN
8
Scheme 2 Heck cyclization of compounds 1a–e.
I
8
OTf
H
Me MeCN
7
2b(29) 3b(29)
4b(29)a
It is noteworthy that the cyclizations occurred regiospecif-
ically in a 6-exo mode for all the compounds and as ex-
pected, unsubstituted perhydro-1,3-benzoxazine 1a led to
a single methylene derivative 4a. On the contrary, com-
pound 1b, with a methyl group at the external olefinic car-
bon, yielded a mixture (6:1) of the most stable ethylidene
derivative 4b and the unconjugated 4-substituted deriva-
tive 2b as a single diastereomer with configuration S at the
newly created stereocenter. The change of iodine in 1b to
a triflate group in 1d diminished both the stereoselection
and the regioselectivity in the final step of the catalytic cy-
cle. Cyclization of 1d gave an equimolar mixture of con-
jugated cyclization compound 4b and unconjugated
epimeric 2b and 3b. Interestingly, iodide 1c cyclized to a
mixture (4:1) of epimers 2c and 3c, but the triflate 1e led,
in lower yield, to a mixture (2:1) of the same compounds
and 8-(benzoylamino) menthol, resulting from the degra-
dation of the starting compound.
6
7
1e
OTf Me Me MeCN
7
2
8
1
1
2c(40) 3c(20)a,c
6a(50) 9a(50)
6a(10) 9a(90)
6a(22) 9a(78)
5a
5a
5ad
5b
I
I
I
I
H
H
H
H
H
H
H
MeCN
MeCN
MeCN
8
9
10
Me MeCN
Me DMF
Me MeCN
6b(69) 8b(8)
9b(23)
11
12
13
14
5b
I
I
I
I
H
H
1
1
1
1
6b(56) 8b(12)
9b(32)
5bd
5c
6b(26) 8b(10)
9b(64)
Me Me MeCN
Me Me MeCN
6c(70) 7c(14)
9c(16)
5cd
6c(57) 7c(9)
9c(34)
The behavior of positional isomers 5a–c was different
from that shown by 1a–e. As a general trend, the intramo-
lecular Heck reaction on 5a–c occurred much more quick-
ly than for 1a–e, and the reactions were completed after
heating in the same experimental conditions for only 1 h
(Scheme 3 and Table, entries 7–14). In addition, com-
pound 5b, derived from trans-crotonaldehyde, gave 6-
exo-cyclization compound 6b (69%), a small quantity of
7-endo-cyclization product 8b (8%) and, quite surprising-
ly, enamine 9b (23%) (entry 10). 5c lead to a mixture (5:1)
of 6-exo-cyclization isomers 6c and 7c, and the enamine
9c (16%) (entry 13), and 2-vinyl substituted perhydro-1,3-
benzoxazine 5a afforded an equimolar mixture of 6-exo-
cyclization compound 6a and rearranged enamine 9a after
heating for 2 h (entry 7).
a Yields in parenthesis refer to pure and isolated compounds.
b 14% of 8-(N-benzoylamino) menthol was isolated.
c 25% of 8-(N-benzoylamino) menthol was isolated.
d Ph3As, instead Ph3P, was used as ligand.
The remarkable formation of enamine derivatives 9 was
very interesting, and some more experiments were neces-
sary. In this way, we observed that the proportion of
enamine increased when the reaction temperature was
raised to reflux of DMF (compare entry 10 versus 11). In
addition, when triphenylphosphine was changed to triph-
enylarsine as ligand in the reactions of 5a–c, a high in-
crease of the enamine proportion in the final reaction
Synlett 2002, No. 2, 259–262 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Unexpected Rearrangement in the Heck Cyclization
261
mixtures was observed (compare entries 9, 12 and 14 ver-
sus 7, 11 and 13 respectively). Finally, the yield of enam-
ine 9a increased to 90% when the reaction of 5a was
refluxed in acetonitrile for 8 h12 (compare entries 7 and 8),
indicating that the formation of enamines 9 occurs from
the normal cyclization products 6. It is also interesting to
note that enamines 9 were formed as single diastereomers
as shown by NOE experiments.
R1
R2
O
I
O
H
N
N
7c
5a-c
-"HPdI"
The formation of cyclization compounds 2–4 from 2-aryl-
3-allyl substituted perhydrobenzoxazines 1 can be inter-
preted in agreement with the general way for the Heck re-
action: oxidative addition of the aryl group,
intramolecular carbopalladation of the double bond and
syn reductive elimination.13 The formation of regioiso-
mers 2, 3 or 4 depends upon the substitution pattern at the
double bond and the sense of the final dehydropalladation
step.1 On the other hand, the stereoselective formation of
2c versus 3c in the reactions of 1c or 1e is a consequence
of the predominance of the eclipsed coplanar conforma-
tion over the twisted one of the Pd-C and the double bonds
in the transition state.14 This is also valid for the formation
of compounds 6a–c from 5a–c or 7c from 5c, while the
small amount of the 7-membered derivative 8b formed in
the reactions of 5b is a consequence of the competitive 7-
endo cyclization process.1d
R1
R2
H
O
PdI
O
N
N
R1
CH2-H
A
PdI
Pd-5a-c
1. Rotation
2. -"HPdI"
+"HPdI"
O
N
R2
R1
PdI
R2
O
N
R1
B
6a-c
R1
O-
R2
R2
R1
The formation of enamines is more interesting from a
mechanistic point of view, and we propose a simplified
transformation summarized in Scheme 4 on the basis of
the following experimental facts: i) The increase of the re-
action time favors the formation of 9 by decreasing the
yield of the former cyclization compound 6. ii) The sub-
stitution of Ph3P to the poorer coordinating ligand Ph3As
also increases the proportion of enamines 9a–c, probably
due to the encouragement of the reversible -hydride
eliminations and additions.15 The different behavior of the
positional isomers 1 and 5 is not a consequence of their
different structures but due to the special nature of the cy-
clization products 6 resulting from 5, which are allylic
N,O-acetals.
N
O
N
H
Pd
H
IPd
C
D
Pd
R2
R2
R1
N
R1
O
OH
N
+
I-
H
9a-c
Scheme 4 Proposed pathway for the formation of Heck cyclization
products 6, 7, and 9 from 5.
The cyclization process of 5a–c starts with the formation
of -palladium intermediates Pd-5a–c by oxidative addi-
tion of the aryl iodides to the Pd(0) complex followed by
intramolecular carbopalladation to the palladium deriva-
tive A. Dehydropalladation with a hydrogen at the methyl
group, only when R1 = R2 = Me, led to the final product
7c, whereas syn-elimination with the hydrogen attached to
the tertiary carbon yielded the allylic N,O-acetals 6a–c.
Readdition of a palladium hydride species to 6a–c would
lead to the intermediate B, which evolved to C after syn-
dealkoxypalladation16 because the better ability of the ox-
ygen substituent as leaving group than that of the nitrogen
substituent.17 Evolution of C to the palladium-nitrogen18
intermediate D, followed by syn-dehydropalladation
would lead to the iminium intermediate19 which cyclizes
to the final enamines 9a–c.
In summary, we have shown that positional isomers of
2,3-disubstituted perhydro-1,3-benzoxazines, bearing an
aryl group and a double bond as substituents, react in a
different way under similar intramolecular Heck condi-
tions. Cyclization compounds resulting from 2-vinyl-3-
aryl substituted substrates suffer additional readdition of
palladium hydride species, and syn-dealkoxypalladation
with concomitant ring opening-ring closing to the rear-
ranged enamines 9.
Acknowledgement
Financial support for this work by the Ministerio de Educación y
Cultura (DGESIC, project PB98-0361) and Junta de Castilla y León
(project VA40/01) is gratefully acknowledged. J. M. I. thanks the
Ministerio de Educación y Cultura for a predoctoral fellowship.
Synlett 2002, No. 2, 259–262 ISSN 0936-5214 © Thieme Stuttgart · New York

262
R. Pedrosa et al.
LETTER
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(11) Prepared from PdCl2 as described in: Stephenson, T. A.;
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Synlett 2002, No. 2, 259–262 ISSN 0936-5214 © Thieme Stuttgart · New York