A highly efficient and selective route to isomeric cyclic diazadienes

Article abstract of DOI:10.1021/ja067304r

A highly selective Lewis acid-catalyzed ring expansion of methylenecyclopropyl hydrazones to isomeric cyclic diazadienes is reported. In general, good to excellent yields and selectivities were obtained for a broad range of hydrazone derivatives. Copyrigh

Full text of DOI:10.1021/ja067304r

Published on Web 01/18/2007
A Highly Efficient and Selective Route to Isomeric Cyclic Diazadienes
Mark E. Scott, Yann Bethuel, and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto, 80 St. George Street, Toronto,
Ontario, Canada M5S 3H6
Received October 11, 2006; E-mail: mlautens@chem.utoronto.ca
Table 1. Lewis Acid-Catalyzed Ring Expansion of MCP
While cyclic diazine and pyridazine derivatives represent an
important class of pharmaceutically interesting scaffolds,1,2 current
synthetic methods for their preparation are limited since only one
product can be prepared from a given starting material. To date,
no method exists for the preparation of diverse diazine scaffolds
from a common and easily prepared precursor.
As part of our research program in strained ring chemistry, we
have been interested in the synthetic utility of methylenecyclopro-
panes as a building block for a variety of different carbo- and
heterocyclic scaffolds.3 Recently, these highly reactive synthetic
precursors have attracted considerable attention due to their ease
of preparation4 and broad range of reactivity.5 Herein we report a
flexible and highly selective ring expansion of methylenecyclo-
propyl hydrazones as an expedient route to a class of unusual
isomeric cyclic diazadienes 2 and 3.
Initial optimization studies using 1a and MgI2 showed that
coordinating solvents were most effective (Table 1, entries 1-6),
affording the azadiene 3a as the major product in low to modest
selectivities and in moderate combined yield. In particular, DME
was ideal for this transformation, affording the ring-expanded
products after relatively short reaction times in an excellent yield,
albeit with modest selectivities (entries 6 and 7). We next focused
on modifying the selectivity of the reaction by changing the Lewis
acid,6 and while most failed to deliver any selectivity in the reaction
(entries 8-10), use of TMEDA as an additive reversed the inherent
selectivity for the azadiene to now cleanly and selectively afford
the dienamine product 2a (entry 11). Reaction yields could be
further improved while decreasing the reaction time by increasing
the reaction temperature as well as the amount of TMEDA used
(entries 12 and 13). Finally, replacing MgI2 with either MgCl2 or
MgBr2 in the presence of TMEDA afforded the desired diene
product in good yields without any erosion in selectivity.
Hydrazonesa
Lewis acid
(mol %)
temp
C)
time
(h)
yieldb
(%)
entry
solvent
(
°
2a:3a
1
2
3
4
5
MgI2 (50)
MgI2 (50)
MgI2 (50)
MgI2 (50)
MgI2 (50)
MgI2 (50)
MgI2 (10)
ZrI2 (10)
THF
50
90
90
90
90
90
90
90
90
90
90
24
1.5
1.5
48
1.5
1.5
1.5
1.5
1.5
1.5
24
58
76
43
70
65
90
92
48
40
48
65
65
78
83
85
1:3.5
CH3CN
toluene
dioxane
DCE
1:1.1
1:1.8
1:1
1:3.8
1:2.3
1:1.5
1:2.1
1:3
6
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
7c
8c
9c
FeI2 (10)
SrI2 (10)
10c
11c,d
12c,d
13c,e
14c,e
15c,e
3.8:1
MgI2 (10)
MgI2 (10)
MgI2 (10)
MgBr2 (10)
MgCl2 (10)
>20:1
>20:1
>20:1
>20:1
>20:1
120
120
120
120
2
2
3.75
3.5
a All reactions were performed using 1a (0.11 mmol) and the corre-
sponding Lewis acid and solvent (0.028 M unless otherwise noted).
b Combined isolated yield of 2a and 3a. c Run at 0.01 M. d Run using 20
mol % of TMEDA. e Run using 100 mol % of TMEDA.
Table 2. Dienamine Formation via Ring Expansion of Substituted
MCP Hydrazonesa
With suitable reaction conditions in hand, we next explored the
scope of the ring expansion using a variety of substituted N-tosyl
hydrazones (Table 2). The reaction tolerated a wide range of
functionalized and nonfunctionalized aliphatic substituents (entries
1-7) to afford 2 in good to excellent yields and selectivities. In
addition, our methodology also allows for the use of aromatic
substituted hydrazone derivatives (entries 8 and 9), affording the
ring-expanded products in good to excellent yields, though in
somewhat lower, yet synthetically useful, selectivities.
Our optimization studies using non-halide containing Lewis
acids6 suggest that the mechanism does not proceed via direct halide
addition in an analogous manner to our earlier work using MgI2.3a-e
We therefore sought to investigate the mechanism of this reaction
through the use of a deuterium-labeled MCP hydrazone (d2-1a)
(Scheme 1). Surprisingly, this study found exclusive deuterium
incorporation at the 3′-position of the dienamine product d2-2a.
Incorporating these findings, we propose that the reaction must
proceed via initial activation of the hydrazone moiety by the Lewis
acid followed by cyclization of nitrogen at the exo-methylene carbon
a All reactions were performed using 1, MgCl2 (10 mol %), and TMEDA
(1 equiv) in DME (0.01 M) at 120 °C. b Combined isolated yield of 2 and
3. c 0.028 M in DME.
(Scheme 2). Although this nitrogen is not highly nucleophilic,
cyclization may occur through sufficient development of partial
9
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J. AM. CHEM. SOC. 2007, 129, 1482-1483
10.1021/ja067304r CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. MgCl2-Mediated Rearrangement of Oximes
Scheme 1. Deuterium Labeling Studies
Scheme 2. Proposed Reaction Mechanism
In summary, we have reported a novel and selective Lewis acid-
mediated ring expansion of methylenecyclopropyl hydrazones to
cyclic dienamines and azadienes in good to excellent yields and in
excellent selectivities. Additional studies have found that the choice
of Lewis acid and ligand was key in selectively obtaining either
the azadiene or dienamine products. Further exploration of the
reaction scope and mechanistic studies to determine the origin of
this highly unusual and reversal in selectivity are ongoing.
Acknowledgment. The authors would like to thank Merck-
Frosst Canada, the National Sciences and Engineering Research
Council (NSERC) of Canada, and the University of Toronto for
supporting this research.
Scheme 3. Selective Azadiene Formation
Supporting Information Available: Experimental procedures for
the preparation of new compounds and characterization data. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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positive charge at the 3-position of the cyclopropane ring (5). In
fact, previous studies by Dieter found that the regioselectivity for
halide-mediated ring opening of substituted cyclopropanes using
weak nucleophiles could best be explained by proposing a similar
intermediate.7 The development of a positive charge in this case is
crucial for cyclization to occur since a concerted process would be
unlikely given the inability of the π-orbitals to align with the σ*-
orbitals of the cyclopropane ring. Alternatively, the reaction may
proceed via a two-electron disrotatory ring opening to afford the
zwitterionic intermediate 6. While zwitterionic ring openings of
activated MCPs of this type are rare, an analogous intermediate
has been proposed by Monti and co-workers for the TiCl4-mediated
addition of allylic silanes to activated MCP ketones.8 We note that
although the formation of a ring-opened intermediate would be
expected to result in significant deuterium scrambling at carbons 1
and 3′, a significant memory effect (i.e., cyclization of 6 occurs
prior to bond rotation) could account for the observed deuterium
labeling in d2-2a.
Since the addition of ligand played an important role in the
outcome of the reaction, we were interested in whether the catalyst
system could be modified to selectively afford the azadiene product.
In fact, use of MgI2 in the presence of N-benzylidene toluene-
sulfonamide was found to reverse the selectivity of the reaction to
favor the azadiene product in good yields and in excellent
selectivities (Scheme 3). While studies to determine the reason for
this drastic reversal in selectivity are ongoing, product intercon-
version studies using the less stable dienamine 2a9 under these
reaction conditions failed to afford the observed azadiene 3a,
suggesting that the product is produced directly from the reaction
and not via dienamine isomerization.
(4) For a recent review on the preparation of methylenecyclopropanes, see:
Brandi, A.; Goti, A. Chem. ReV. 1998, 98, 589.
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compounds, see: (a) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.
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(6) BF3‚OEt2 and Sn(OTf)2 (1 equiv) in toluene at 25 °C were also found to
catalyze the ring expansion of the MCP hydrazone 1a in <20% yields.
(7) (a) Dieter, R. K.; Pounds, S. J. Org. Chem. 1982, 47, 3174. For related
studies see: (b) Miller, R. D.; McKean, D. R. J. Org. Chem. 1981, 46,
2412. (c) Miller, R. D.; McKean, D. R. Tetrahedron Lett. 1979, 25, 2305.
(8) Monti, H.; Rizzotto, D.; Le´andri, G. Tetrahedron 1998, 54, 6725.
(9) Single-point calculations using Spartan at the RB3LYP level show an
energy difference of 19.8 kcal/mol between the more stable azadiene and
dienamine.
Finally, we report our preliminary studies on the extension of
the dienamine-selective conditions (MgCl2/TMEDA) to MCP
oximes. Reaction of oxime 9 selectively afforded the desired
oxazene 10 in modest selectivity and good yield (Scheme 4).
JA067304R
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