A diastereoselective carbocyclisation of allene-hydrazones through the intramolecular allylic transfer reaction

Article abstract of DOI:10.1039/b712856h

A diastereoselective synthesis of cyclic hydrazines was achieved from a carbocyclisation of allene-hydrazones by the Pd-catalyzed distannylation of an allene moiety, followed by the transmetallation of allylic stannane intermediates with TiCl₄. The Royal Society of Chemistry.

Full text of DOI:10.1039/b712856h

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A diastereoselective carbocyclisation of allene-hydrazones through the
intramolecular allylic transfer reaction{
Sang-Hoon Kim, Seung-Ju Oh, Yurim Kim and Chan-Mo Yu*
Received (in Cambridge, UK) 21st August 2007, Accepted 18th September 2007
First published as an Advance Article on the web 3rd October 2007
DOI: 10.1039/b712856h
would expand the scope and utility of this reaction. As a
consequence, we became interested in the practical and convenient
synthesis of 4 by the three-component assembly of allene-imine 3
with a stannyl group through an intramolecular allylic transfer
reaction, as illustrated in Scheme 1. There have been a variety of
reports regarding nucleophilic addition reactions to imines to
produce amines in the literature.7 However, the lack of data
concerning cyclisations between imines and unsaturated bonds
involving the use of transition metal catalysts or reagents surprised
us,8 in view of the expected similarity of such systems to the well-
defined cycloisomerisation reactions with aldehydes.9 Recently,
Grigg and co-workers reported an intramolecular allylic transfer
reaction of allene-sulfinimines with aryl iodides involving the use of
Pd/In.10 We wish to report our discovery of a remarkable substrate
effect by the introduction of the hydrazone functionality for the
conversion of 3 to 4, which allows the reaction process to complete
in good yield and with excellent diastereoselectivity.
A diastereoselective synthesis of cyclic hydrazines was achieved
from a carbocyclisation of allene-hydrazones by the Pd-
catalyzed distannylation of an allene moiety, followed by the
transmetallation of allylic stannane intermediates with TiCl4.
Among the variety of synthetic methods for the construction of
cyclic compounds, reactions involving the use of transition metals
offer some of the most attractive methodologies, since reactions
can directly construct complicated molecules from relatively simple
starting materials.1 As a consequence, many advances in cyclisa-
tions mediated by transition metals have been made through a
variety of synthetic strategies.2 In this regard, allenes have proved
to be useful substrates for a variety of transition metal catalytic
reactions, particularly for cyclisations in the construction of carbo-
and heterocycles.3 For example, the transition metal-catalysed
cyclisation of an allene-aldehyde has emerged as a highly
convergent method for the stereoselective synthesis of cyclic
alkenols. Many advances relating to this methodology have been
reported.4
With this issue in mind, several allene-imine, -oxime and
-hydrazones were prepared, as shown in eqn. (1). Initial attempts
to cyclize 3 with Me3SnSnMe3 in the presence of (p-allyl)2Pd2Cl2
(3 mol%) at 240 uC for 3 h in CH2Cl2 (similar conditions to those
mainly employed for the carbocyclisation of allene-aldehydes5a)
indicated that the conversion to the corresponding lactam 4 could
not be realized, mainly due to a lack of reactivity for the
cyclisation. Reactions always produced the distannylated 5 with
good conversions in all cases.11
Recently, we disclosed our discoveries of cyclisation methods for
the synthesis of 2 from allene-carbonyl functionalities 1 by using
transition metals, as shown in Scheme 1,5 as part of an allylic
transfer strategy using allenes as substrates or intermediates.6 The
characteristic features of this protocol, in terms of the chemical
efficiency of the three component coupling process and the
structural features of the products, have encouraged us to carry
out further investigations to introduce other functionalities, which
ð1Þ
We subsequently speculated that the utilization of an additional
Lewis acid might be needed to enhance reactivity. However, the
introduction of various Lewis acids to the allene-imine and -oxime
turned out to be unpromising. Fortunately, we found that allene-
hydrazones could be converted to 4 under Lewis acidic conditions.
As a starting point, allene-hydrazones 6a and 9a (Table 1) were
selected as model substrates. Attempted cyclisation reactions of 6a
and 9a indicated that their conversion to the corresponding 7a and
10a could not be satisfied with many Lewis acids, including
Sn(OTf)2, AlMe3, Al(NTf2)3 and Me3SiOTf, under various
reaction conditions. We could not observe any notable effect of
Lewis acids on the promotion of the cyclization process.
Fortunately, we found that BF3?OEt2 could be an effective
Lewis acid for this purpose. Initial experiments on the distannyla-
tion of 6a under the same conditions as those described in eqn. (1),
followed by intramolecular allylic transfer with BF3?OEt2
Scheme 1 Our general synthetic route.
BK-21 School of Chemical Materials Science and Department of
Chemistry, Sungkyunkwan University, Suwon 440-746, Korea.
E-mail: cmyu@chem.skku.ac.kr; Fax: +82 31 290 7075;
Tel: +82 31 290 7067
{ Electronic supplementary information (ESI) available: Experimental
procedures, characterization data and NMR spectra for all products. See
DOI: 10.1039/b712856h
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Table 1 Selected preliminary investigations
Table 2 Intramolecular allylic transfer reactions of 6
Entry Allene-hydrazone (6)
Product (7)
Yield (%)a
83
1
2
3
4
5
6
61
68
63
75
77
Entry 6/9 Lewis acida t/h cis : transb Ratiob,c Yield (%)d
1
2
3
4
5
6
7
8
9
10
a
6a BF3?OEt2
9a BF3?OEt2
6a SnCl4
9a SnCl4
6a TiCl4
9a TiCl4
12
12
10
10
2
78 : 22
71 : 29
7 only
10 only
7 only
.95 : 5
.95 : 5
80 : 20 54
34 : 66 24
33
23
.98 : 2
83
37 : 63 27
71 : 29 41
35 : 65 22
2
.95 : 5
6a Ti(OiPr)2Cl2 10
9a Ti(OiPr)2Cl2 10
7 only
10 only
7 only
6a TiBr4
9a TiBr4
b
5
5
92 : 8 67
29 : 71 23
10 only
1.1 equivalents. cis : trans ratios (7 : 10) were determined by 1H
c
NMR spectroscopy of the crude products. Ratios of 7 : 8 or
d
10 : 11. Isolated yields of 7 or 10 after chromatography.
(1.1 equiv.) at 278 uC for 12 h in CH2Cl2, afforded encouraging
but marginal results. Although 7a and 10a were produced during
the reactions, moderate diastereoselectivities (7a, dr = 78 : 22; 10a,
dr = 71 : 29) and low chemical yields (7a, 33%; 10a, 23%) remained
problems to be solved. After surveying numerous conditions with a
variety of Lewis acids, we were delighted to find that TiCl4 was a
suitable Lewis acid in terms of diastereoselectivity and chemical
conversion, as shown in Table 1.
During the orienting experiments, several key findings emerged
as follows: (1) the use of TiCl4 proved to be most effective Lewis
acid for the intramolecular allylic transfer; (2) 1.1 equivalents of
TiCl4 were required for the optimal conditions in terms of chemical
yields and reaction rates; (3) reactions performed at 278 uC in
CH2Cl2 resulted in the best chemical yields in comparison with
other solvents, such as toluene and CH3CH2CN; (4) the
phthaloylhydrazone 6a proved to be a more suitable substrate
than the benzoylhydrazone 9a for this transformation; (5) the
reaction also produced destannylated products 8a or 11a, along
with unidentified base line impurities, especially for 9a. Under
optimal conditions, the reaction was conducted by the dropwise
addition of a mixture of 6a (1 equiv.) and Me3SnSnMe3 (1.1 equiv.)
in CH2Cl2 for 20 min to a solution of (p-allyl)2Pd2Cl2 (3 mol%) at
240 uC in CH2Cl2. After 3 h at 240 uC, the reaction mixture was
cooled to 278 uC. To this solution, pre-cooled TiCl4 (1.1 equiv.) at
278 uC in CH2Cl2 was added in one portion using a cannula.
After 2 h at 278 uC, the reaction was quenched by the addition of
saturated aqueous NaHCO3, and then worked up and chromato-
7
67
a
In reference to the isolated product.
relationships for 7a and 7g were proved by NOE experiments,
and also by the X-ray crystallographic analysis of 7f (the ORTEP
drawing of ent-7f with 50% probability thermal ellipsoids is shown
in Scheme 2{). We also observed that the internal chirality transfer
of substituted 1d and 1e turned out to be excellent. It is worthy of
note that the reaction produced none or only trace amounts of the
destannylated products (less than 2%), except for 6b (9% isolated;
1
graphed on silica gel to afford 7a in 83% yield in
a
Table 2, entry 2), according to the H NMR spectra of the crude
diastereomerically pure form.
products. Unfortunately, the extension of this method to the
synthesis of 6-membered rings turned out to be unpromising.
Although the exact mechanistic aspects of this transformation
have not been rigorously elucidated, Scheme 2 could illustrate a
possible stereochemical route for the remote stereocontrol
and diastereoselectivity of the products. From a mechanistic
perspective, the two major functions that determine the
With the notion that this approach might lead to a general and
efficient method for the synthesis of 7, we set out to determine the
scope for producing various structurally related products. Indeed,
the method was successful with 6b–f, yielding the cyclic products
7b–f, respectively, as single diastereomers in moderate to high
yields, as can be seen in Table 2. Relative stereomerical
5026 | Chem. Commun., 2007, 5025–5027
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and the Korea Research Foundation (KRF-2006-312-C00234) is
gratefully acknowledged.
Notes and references
{ Crystal data for 7f: C32H37N3O4SSn, M = 678.40, orthorhombic, space
group Pbca, a = 21.858(5), b = 12.108(3), c = 24.590(4) s, V = 6508(2) s3,
Z = 8, Dcalc = 1.385 Mg m23, mMo-Ka = 0.888 mm21, T = 293(2) K. 5734
reflections were collected and used in the refinement. wR2/R1 = 0.1749/
0.0916 (I . 2s) and 0.2509/0.2761 (all data). CCDC 656121. For
crystallographic data in CIF or other electronic format see DOI:
10.1039/b712856h
1 For general discussions, see: Transition Metals for Organic Synthesis, ed.
M. Beller and C. Bolm, Wiley-VCH, Weinheim, vol. 1 and 2, 2004.
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Scheme 2 A plausible stereochemical route, and the ORTEP structure of
7f.
stereoselectivity are immediately discernable in the reaction
process: transmetallation and chelation effects. After the distanny-
lation of an allene functionality, the allylic stannane moiety must
be transmetallated by TiCl4 to the allylic titanium reagent,12 and
then subsequently undergo an intramolecular addition of the latter
to the hydrazone. We reasoned that if model A, assembled from
the allylic titanium species, was an intermediate on the reaction
pathway, then it might be possible to describe the remote
stereocontrol by the existing R-group, as well as the cis-selectivity
during the cyclisation. The products obtained can be accounted-for
by the intervention of the pseudopericyclic stereochemical model
A, with minimal steric interactions and optimal orbital interactions
that lead to the major reaction pathway illustrated in Scheme 2.
The enhanced reactivity offered by the phthaloylhydrazone
functionality, compared to the others, could be explained by
assuming that the tight chelation to the allylic titanium by the
phthaloylhydrazone group in a hexacoordinate array could result
in the extent of LUMO energy decreasing as well as HOMO
energy increasing, similar to the Lewis base-catalyzed carbonyl
addition.13
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In summary, this Communication describes a carbocyclisation
of allene-hydrazones 6 to 7 through the intramolecular allylic
transfer reaction, which promises to become synthetically useful.
This transformation involves the distannylation of an allene by a
palladium catalyst, the transmetallation of the allylstannyl moiety
to a titanium species and subsequently the intramolecular allylic
transfer reaction with the hydrazone. Further studies, including
synthetic applications and the extension of this method to
enantiomeric pathways, are in progress.
Generous financial support from the Korea Science
&
Engineering Foundation (CMDS and R01-2005-000-10381-0)
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Chem. Commun., 2007, 5025–5027 | 5027