Tandem carbon-carbon and carbon-chlorine bond formation by Cu(II) chloride-promoted [3,3] sigmatropic rearrangement of N-allylhydrazones

Article abstract of DOI:10.1021/ja7101967

A new copper(II) chloride-promoted rearrangement of N-allylhydrazones has been developed. Treatment of a number of aromatic N-allylhydrazones with copper(II) chloride provides the formation of both a new carbon-carbon bond and a carbon-chlorine bond in the same reaction. Substrate studies revealed that the carbon-carbon bond-forming step proceeds by way of a concerted [3,3] sigmatropic rearrangement and selectively generates trans-substituted alkenes. Copyright

Full text of DOI:10.1021/ja7101967

Published on Web 01/09/2008
Tandem Carbon-Carbon and Carbon-Chlorine Bond Formation by Cu(II)
Chloride-Promoted [3,3] Sigmatropic Rearrangement of N-Allylhydrazones
Devon A. Mundal, Jennifer J. Lee, and Regan J. Thomson*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208
Received November 9, 2007; E-mail: r-thomson@northwestern.edu
Table 1. Optimization of CuCl2-Promoted Rearrangement
The Wolff-Kishner reduction, in which a carbonyl function is
converted to the corresponding methylene upon exposure to
hydrazine and strong base, is arguably the most well-known
hydrazone-based transformation.1 This reaction involves the forma-
tion of carbon-hydrogen bonds, while other hydrazone transforma-
tions, such as hydrazone-based alkylations2 afford carbon-carbon
bond formation. N-Sulfonylhydrazones have been utilized for both
carbon-hydrogen3 and carbon-carbon4 bond formation. A less
familiar reaction is the thermal [3,3] sigmatropic rearrangement of
N-allylhydrazones, which was reported by Stevens in 1973 (eq 1).5
As part of a research program aimed at exploiting the synthetic
potential of N-allylhydrazones, we prepared a number of Boc-
protected hydrazones (i.e., 3) and now report a new Cu(II) chloride-
promoted tandem carbon-carbon and carbon-chlorine bond
forming reaction (eq 2).
entry
solvent
temp (
°
C)
CuCl2 (equiv)
time (h)
conversion (%)b
1
2
3
4
5
toluene
toluene
THF
MeOH
DCM
MeCN
MeCN
MeCN
110
23
23
23
23
23
23
82
0
24
24
24
24
24
24
16
0.3
0
0
0
1.0
1.0
1.0
1.0
1.0
4.0
4.0
0
25
28
100
100
6
7
8c
a With 0.5 mmol 5. b Determined by 1H NMR spectroscopy. c Conducted
in the presence of 1.0 equiv of diisopropylethylamine.
Table 2. Substrate Scope of CuCl2-Promoted Rearrangementa
entry
R
yield 6 (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
2-naphthyl (5a)
1-naphthyl (5b)
4-F-Ph (5c)
4-Cl-Ph (5d)
4-Br-Ph (5e)
3-Cl-Ph (5f)
2-Cl-Ph (5g)
3,4-diCl-Ph (5h)
Ph (5i)
4-Me-Ph (5j)
3-Me-Ph (5k)
2-Me-Ph (5l)
3-OMe-Ph (5m)
73 (6a)
55 (6b)
72 (6c)
58 (6d)
62 (6e)
50 (6f)
26 (6g)
44 (6h)
56 (6i)
48 (6j)
45 (6k)
44 (6l)
47 (6m)
Our initial goal was to determine the effect that placing an
electron-withdrawing substituent on the allyl-bearing nitrogen atom
would have on the barrier to the thermal rearrangement of these
hydrazones. Therefore, we prepared hydrazone 5 by simple
condensation between 2-napthaldehyde and the corresponding
hydrazide, prepared according to the procedure described by Jamart-
Gre´goire and workers.6 Heating of 5 in toluene at reflux afforded
no reaction (Table 1, entry 1), and while elevating the temperature
may have resulted in some rearrangement we elected to explore
the use of Lewis acids. In particular, we reasoned that azaphilic
copper salts would be effective. However, under the assumed Lewis
acidic conditions we did not expect loss of the Boc group or nitrogen
extrusion to occur, and therefore treated 5 with one equivalent of
CuCl2 to ensure that turnover would not be an issue (Table 1, entries
2-6).7 To our surprise, the reactions conducted in dichloromethane
and acetonitrile afforded the unexpected product 6 at approximately
25% conversion after 24 h at room temperature.8 Both a carbon-
carbon bond and a carbon-chlorine bond are formed in this
previously unknown rearrangement.9 The use of four equivalents
of CuCl2 in acetonitrile provided 6 with complete consumption of
all starting material after 16 h (Table 1, entry 7).
a With 1 mmol 5. b Isolated yield after chromatography.
Heating the mixture to reflux decreased the reaction time to 20
min, but gave more complex mixtures. Because loss of the Boc-
group presumably forms isobutene and an equivalent of acid, we
surveyed a number of amine additives, and found the addition of
one equivalent of diisopropylethylamine was effective at suppress-
ing undesired byproducts (Table 1, entry 8). With optimized
conditions developed (4 equiv of CuCl2, 1 equiv of i-Pr2EtN in
acetonitrile at reflux for 20 min), we next examined the scope of
this new transformation (Table 2).
Chloride 6a could be reliably obtained from 5a in an isolated
yield of 73% (Table 2, entry 1). We found that electron-deficient
aryl hydrazones provided higher yields of the desired chloride than
electron-rich compounds. Halogen substitution at the 4-position
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J. AM. CHEM. SOC. 2008, 130, 1148-1149
10.1021/ja7101967 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
We began to speculate that this new reaction might proceed by
initial oxidation of the hydrazone to a radical-cation.12 To test this
notion we treated hydrazone 5a with one equivalent of (4-BrPh)3N‚
SbCl6, a stable aminium salt known to promote radical-cation
mediated reactions (eq 4).13 Although this transformation was not
efficient, chloride 6a was clearly observable in the 1H NMR
spectrum of the reaction mixture, providing initial evidence that
these reactions may proceed via radical-cation intermediates.
In summary, we have discovered a new CuCl2-promoted [3,3]
sigmatropic rearrangement of N-allylhydrazones that forms both a
carbon-carbon and carbon-chlorine bond. Continuing research is
focused on determining the mechanism of this new transformation,
especially the activation and chlorination steps.
Figure 1. Variation of the hydrazide fragment, isolated yields. E:Z ratios
determined by H NMR spectroscopy.
1
afforded the corresponding benzyl chlorides in good yield (Table
2, entries 3-5), while 3-chloro and 2-chloro derivatives were
slightly less effective (Table 2, entries 6 and 7). Phenyl hydrazone
5i provided a 56% yield of 6i (Table 2, entry 9). Methyl-substituted
derivatives gave modest yields (Table 2, entries 10-12), while only
3-methoxy derivative 5m provided the desired product when
methoxy-substituted hydrazones were explored. The lower yields
for these electron-rich systems is most likely a consequence of
product instability. Aliphatic hydrazones gave complex reaction
mixtures, and no chloride could be isolated.
Acknowledgment. This work was supported by the American
Chemical Society Petroleum Research Fund (Type G), Northwestern
University (NU), and the NU Analytical Services Laboratory (NSF
Grants DMR0114235 and CHE9871268). J.L. acknowledges the
award of a NU undergraduate research grant. We thank Michael
Ambrogio (NU) for assistance in substrate preparation.
Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
Several different hydrazine derivatives were prepared using the
Jamart-Gre´goire conditions6 and condensed with 2-napthaldehyde
to afford the corresponding hydrazones (i.e, 7) in excellent yield.
Exposure of these substrates to the optimized reaction conditions
gave rise to the corresponding napthyl chlorides (Figure 1). The
simple allyl derivative 7a gave chloride 8a in 67% yield. Terminal
substitution was tolerated, with crotyl-derived hydrazone 7c provid-
ing the rearranged product 8c as a single regioisomer (2:1 dr). This
result provided initial evidence that the key carbon-carbon bond
was generated through a [3,3] sigmatropic rearrangement. Further
support for this hypothesis was gained when hydrazone 7d produced
only regioisomer 8d in a 9:1 ratio of E:Z isomers. This regio- and
stereoselectivity proved to be general for a number of additional
substrates, providing a unique method for preparing stereodefined
disubstituted olefins. Small quantites (∼5%) of the corresponding
diene products were also observed, but no attempt was made to
optimize for these products.
Further evidence in favor of a concerted mechanism over a
possible ionization-recombination mechanism was obtained when
exposure of 910 to our standard conditions for chlorination provided
regioisomer 10, with no detectable traces of isotopic scrambling
(eq 3). This result, in conjunction with the previously discussed
syntheses of 8c-h, is consistent with the hypothesis that the
carbon-carbon bond is formed through a concerted intramolecular
rearrangement.11
References
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with 9% scrambling of the deuterium label, see ref. 5.
(12) CuCl2 is known to be a good single electron oxidant of enolates to promote
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We also investigated the ability of other metal salts to promote
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TiCl4 did not provide any of the corresponding chlorinated product.
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