Stereoselective synthesis of dienes from N-allylhydrazones

Article abstract of DOI:10.1021/ol802585r

(Chemical Equation Presented) A new method for the stereoselective synthesis of dienes from aldehydes and N-allylhydrazine derivatives has been developed. High levels of (E)-stereoselectivity are obtained for a variety of substrates. Addition of a dienoph

Full text of DOI:10.1021/ol802585r

ORGANIC
LETTERS
2009
Vol. 11, No. 2
465-468
Stereoselective Synthesis of Dienes
from N-Allylhydrazones
Devon A. Mundal, Kelly E. Lutz, and Regan J. Thomson*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston,
Illinois 60208
r-thomson@northwestern.edu
Received November 11, 2008
ABSTRACT
A new method for the stereoselective synthesis of dienes from aldehydes and N-allylhydrazine derivatives has been developed. High levels
of (E)-stereoselectivity are obtained for a variety of substrates. Addition of a dienophile to the reaction mixture allows a one-flask diene
synthesis-cycloaddition sequence.
The development of methods for the stereoselective synthesis
of dienes has been an area of long-standing importance to
chemists. This importance stems largely from the utility of
dienes as substrates for powerful transformations, such as
[4 + 2] cycloadditions1 and Ziegler-Natta polymerizations.2
Transition-metal-catalyzed sp2-sp2 cross-coupling reactions
are especially powerful for diene synthesis but typically
require that alkene geometry be set in the form of a vinyl
derivative prior to bond formation.3 Enyne cross-metathesis
does not require such prefunctionalization but often neces-
sitates that one reacting partner is used in excess.4 Con-
versely,dieneformationthroughWittig,Horner-Wadsworth-
Emmons, Julia, and Peterson olefinations can produce
mixtures of both (E)- and (Z)-isomers.5 Despite the utility
of these transformations, there remains significant room for
the development of additional complementary processes.
We recently reported a new copper(II) chloride promoted
rearrangement of N-allylhydrazones (Figure 1).6 This previ-
Figure 1. Diene synthesis from N-allylhydrazones.
ously unknown transformation provided a number of (E)-
alkenes from precursors lacking stereodefined alkene geom-
etries (i.e., 1 f 2).
During the course of investigating this chemistry we
wondered whether the chlorine atom, which is also incor-
porated during the reaction, might undergo stereoselective
elimination to afford a diene product in one pot (i.e., 1 f 2
(1) For a recent review of [4 + 2] cycloadditions with many relevant
dienes, see: Nicolaou, K. C.; Snyder, S. S.; Montagnon, T.; Vassilikogian-
nakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698.
(2) For two recent reviews, see: (a) Friebe, L.; Nuyken, O.; Obrecht,
W. AdV. Poylm. Sci. 2006, 204, 1–154. (b) Fischbach, A. A.; Anwander,
R. AdV. Polym. Sci. 2006, 204, 155–281.
(5) For reviews, see the following. Wittig reaction: (a) Vedejs, E.;
Peterson, M. J. In AdVances in Carbanion Chemistry; Snieckus, V., Ed.;
Jai Press Inc.: Greenwich, CT, 1996; Vol. 2. Horner-Wadsworth-Emmons
reaction: (b) Maryanoff, B. E.; Reitz, A. B Chem. ReV. 1989, 89, 863–927.
Modified Julia olefination: (c) Blakemore, P. R. J. Chem. Soc., Perkin Trans.
1 2002, 2563–2585. Peterson olefination: (d) Ager, D. J. Org. React. 1990,
38, 1–223.
(3) For a recent review of palladium-catalyzed cross-coupling reactions,
see: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4442–4489.
(4) For recent reviews of enyne metathesis, including sections on cross-
metathesis, see: (a) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104,
1317–1382. (b) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1–18.
(6) Mundal, D. A.; Lee, J. J.; Thomson, R. J. J. Am. Chem. Soc. 2008,
130, 1148–1149.
10.1021/ol802585r CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society

Table 1. Development of Initial Bromination Step
Table 2. Synthesis of 1-Arylbutadienes
entry
Br
equiv Br
solvent
conversion (%)a
entry
Ar
yield of 10 from 8 (%)a
E:Zb
1
2
3
4
5
a
CuBr2
Br2
CBr4
DBH
NBS
2.0
2.0
1.1
1.1
1.1
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
95
0
1
2
3
4
5
6
7
8
9
2-naphthyl (8a)
1-naphthyl (8b)
Ph (8c)
78 (10a)
75 (10b)
47 (10c)
70 (10d)
65 (10e)
66 (10f)
70 (10g)
68 (10h)
69 (10i)
51 (10j)
58 (10k)
46 (10l)
1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
no reaction
>95
>95
4-Me-C6H4 (8d)
3-Me-C6H4 (8e)
2-Me-C6H4 (8f)
4-OMe-C6H4 (8g)
3-OMe-C6H4 (8h)
2-OMe-C6H4 (8i)
4-F-C6H4 (8j)
4-Cl-C6H4 (8k)
4-Br-C6H4 (8l)
b
1
Determined by H NMR spectroscopy.
f 3). Unfortunately, elimination of the chloride proved to
be prohibitively slow, and the resulting diene was formed
in low yield.7 We had hoped to circumvent this problem by
using copper(II) bromide, but this modification led to clean
generation of an oxazolidinone through cyclization of the
Boc-carbonyl group onto the pendant alkene. We now report
the successful implementation of this strategy for diene
synthesis, which requires only the sequential addition of
N-bromosuccinimide (NBS) and 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) to N-allylhydrazones (i.e., 4 f 5 f 3).
We initiated our research by preparing the N-allylhy-
drazone 6, which was synthesized in near quantitative
yield through the condensation of allylhydrazine8 with
2-naphthaldehyde. Exposure of hydrazone 6 to a modifi-
cation of our original conditions for chlorination, but using
copper(II) bromide in place of copper(II) chloride, did
provide the corresponding bromide 7, but with significant
formation of 2-naphthaldehyde (Table 1, entry 1). We
suspected that this bromination may be occurring by
activation of the hydrazone by an electrophilic bromonium
ion (Br in Table 1);9 we therefore treated hydrazone 6
with a variety of common brominating reagents. Bromine
failed to provide the desired product and instead gave what
appeared to be bromination of the alkene (Table 1, entry
2), whereas carbon tetrabromide induced no reaction
(Table 1, entry 3). 1,3-Dibromo-5,5-dimethylhydantoin
(DBH) did give the bromide 7 (Table 1, entry 4), but
ultimately we found N-bromosuccinimde (NBS) to be
superior in terms of product purity (Table 1, entry 5).
The addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
directly to the reaction mixture after treating hydrazone 9
(Ar ) 2-naphthyl) with NBS and allowing the mixture to
warm to room temperature smoothly converted the interme-
diate bromide to the desired diene 10a in 78% yield over
the two steps from 2-naphthaldehyde (8a, Table 2, entry 1).
Importantly, the disubstituted alkene was formed with high
(E)-selectivity (>20:1).10 In this procedure, the intermediate
10
11
12
a Isolated yield. Determined by H NMR spectroscopy.
hydrazone species 9 was not purified but was subjected
directly to the bromination-elimination conditions after
evaporation of the solvent. With reliable conditions in hand,
we examined the scope of this mild two-step procedure
(Table 2).
The condensation-bromination-elimination sequence is
tolerant of a wide variety of aromatic aldehydes. Generation
of the diene from benzaldehyde (i.e., 8c) proceeded in only
47% yield as a result of difficulties associated with product
volatility. Substituents are tolerated at ortho, meta, and para
positions (Table 2, entries 4-12). In all cases the diene
products were formed with excellent levels of stereoselec-
tivity (20:1 E:Z or greater). The successful conversion of
electron-rich substrates, in particular 4-methoxybenzaldehyde
(8g), was especially encouraging since these substrates had
performed poorly in the previous copper(II) chloride pro-
moted rearrangement.6 Unfortunately, aliphatic aldehydes
gave mixtures of products.
We next explored the use of a variety of hydrazine
fragments to expand the scope of this chemistry to more
highly substituted dienes (Table 3). Condensation of the
easily prepared N-allylhydrazine hydrochloride salts (i.e.,
12)11 with the desired aldehyde (11) in the presence of
potassium carbonate gave the desired hydrazones (i.e., 13).
Because of the sensitivity of these hydrazones to decomposi-
tion upon prolonged standing, the NBS-initiated diene
synthesis was conducted directly on the unpurified hydra-
(10) This procedure is stereocomplementary to the diene synthesis
developed by Yamamoto and co-workers; see: (a) Ukai, J.; Ikeda, Y.; Ikeda,
N.; Yamamoto, H. Tetrahedron Lett. 1983, 24, 4029–4032. (b) Ikeda, Y.;
Ukai, J.; Ikeda, N.; Yamamoto, H. Tetrahedron 1987, 43, 723–730. For an
additional recent method for the synthesis of (Z)-dienes, see: Steinhardt,
S. E.; Silverston, J. S.; Vanderwal, C. D. J. Am. Chem. Soc. 2008, 130,
7560–7561.
(7) It seems likely that the base was not compatible with the excess
copper(II) chloride used to promote the initial rearrangement.
(8) N-Allylhydrazine was purchased from Wako Chemicals.
(9) CuBr2 is a known source of electrophillic bromide ions; see: Hammer,
R. R.; Gregory, N. W. J. Phys. Chem. 1964, 68, 314–317.
(11) Prepared by a modification of the procedure reported by Brosse,
N.; Pinto, M. F.; Jamart-Gregoire, B. Tetrahedron Lett. 2000, 41, 205–
207.
466
Org. Lett., Vol. 11, No. 2, 2009

Table 3. Di- and Trisubstituted Dienes (Ar ) 2-naphthyl)
Figure 2. Triene synthesis.
14i) could be prepared from hydrazine 12 (R1, R2 ) Me, R3
) H). While the regiospecificity of the carbon-carbon bond-
forming step of the reaction is clearly seen by the regiospe-
cific synthesis of 14c and 14d from isomeric hydrazones,
we provided further evidence in the form the deuterium-
labeled diene 14l. In addition to diene formation, we also
showed that trans-cinnamaldehyde (15) may be converted
to the triene 16 in 54% yield using our two-step procedure
(Figure 2). This route to trienes may prove to be very useful,
and we are investigating the scope of this method.
In our prior work relating to the chlorination of N-Boc
hydrazones, we hypothesized that the initial carbon-carbon
bond-forming step proceeded by a radical-cation induced
sigmatropic rearrangement.6,12 In this case, copper(II) chlo-
ride was likely acting as a single-electron oxidant, with
chlorine incorporation possibly proceeding through a radical
mechanism akin to a Sandmeyer reaction.13 Although radical
reactions are commonplace for NBS, they typically require
light; our reaction proceeds in the dark. We therefore favor
an ionic mechanism that involves initial bromination of the
hydrazone I to afford II, followed by elimination of bromide
ion to generate the unusual diazoallene species III (Figure
1).14 Similar intermediates have been postulated by Barton
and co-workers in their pioneering work on the decomposi-
tion of hydrazones15 and may also be intermediates in the
Myers and Furrow diazoalkane synthesis from TBS-hydra-
zones.16 For our system, we hypothesize that a rapid [3,3]
sigmatropic rearrangement17 ensues to produce diazonium
ion IV, followed by nucleophilic attack of bromide ion to
form V. A chair-like transition state for such a rearrangement
would lead to the observed (E)-selectivity for terminally
substituted systems. Elimination of HBr by DBU through
an E2-mechanism then affords the diene VIII via the
conformation with the fewest eclipsing interactions (i.e., VI
vs VII).
b
a Isolated yield. Determined by H NMR spectroscopy; dr refers to
1
E:Z ratio or major isomer:sum of others.
zones following aqueous workup. In this way, a number of
diverse dienes were synthesized in a two-step procedure for
the corresponding aldehydes in good yield (Table 3).
Using the previously developed conditions for bromina-
tion/elimination, 3-methyldiene 14a was formed in 68% yield
as a 20:1 mixture of E:Z isomers over the two steps from
2-naphthaldehyde. Similarly, the 2-bromo derivative 14b
could be generated in 59% yield (20:1 E:Z). The use of a
terminally substituted hydrazine fragment 12 (R1, R2 ) H,
R3 ) Me) provided the 2-methyldiene 14c in 60% yield from
2-naphthaldehyde, in a 3:1 E:Z ratio. This ratio reflects the
initial diastereoselectivity obtained during the formation of
the intermediate bromide species: subsequent elimination of
HBr is a stereospecific process affording the mixture of
dienes. 1,4-Disubstituted dienes (i.e., 14d-14h) were gener-
ated with good levels of stereoselectivity for the shown (E,E)-
isomers. We also demonstrated that trisubstituted dienes (i.e.,
(12) Tantillo and Siebert have conducted DFT calculations on our
experimental work that support our original hypothesis; see: Siebert, M. R.;
Tantillo, D. J. Org. Lett. 2008, 10, 3219–3222
.
(13) Kochi, J. K. J. Am. Chem. Soc. 1957, 79, 2942–2948.
(14) A mechanism involving bromination at carbon, followed by loss
of HBr to generate putative intermediate III cannot be ruled out at this
time.
(15) (a) Barton, D. H. R.; O’Brien, R. E.; Sternhell, S. J. Chem. Soc.
1962, 470–476. (b) Barton, D. H. R.; Jaszberenyi, J. C.; Shinada, T.
Tetrahedron Lett. 1993, 34, 7191–7194.
(16) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 12222–
12223.
(17) A related sigmatropic rearrangement has been reported; see: Owens,
K. A.; Berson, J. A. J. Am. Chem. Soc. 1990, 112, 5973–5985. From orbital
considerations, such rearrangements may be considered as the microscopic
reverse of the well-known propargyl Claisen rearrangement.
Org. Lett., Vol. 11, No. 2, 2009
467

Scheme 1. Merged Diene Synthesis and Diels-Alder Reaction
We wished to apply this method in conjunction with a
subsequent Diels-Alder reaction to rapidly generate more
complex molecules from relatively simple precursors
(Scheme 1).
Figure 3. Potential mechanism for diene synthesis.
such as a Diels-Alder cycloaddition. It will be interesting
to see whether other electrophiles may be used to initiate
this type of hydrazone rearrangement and thus allow for the
incorporation of diverse functional groups.
When using N-phenylmaleimide (17) as the dienophile,
cycloadduct 18 was obtained in an overall yield of 56% from
aldehyde 8a (Ar ) 2-naphthyl). In this case, 1,2-dichloro-
ethanewasusedasthesolventforthebromination-elimination
sequence to effect smooth cycloaddition at 80 °C. The more
reactive aza-dienophile 19 underwent cycloaddition at room
temperature to afford the diaminated adduct 20 in 77% yield
from aldehyde 8a (Ar ) 2-naphthyl).
In summary, by investigating the chemistry of N-allylhy-
drazones we have developed a stereoselective synthesis of
dienes from aldehydes that requires only simple precursors
and reagents. This process may potentially be utilized for
the synthesis of complex molecules, especially if the diene
is employed in a subsequent bond-forming transformation,
Acknowledgment. This work was supported by the ACS
Petroleum Research Fund (46778-G1), Northwestern Uni-
versity (NU), and the NU Integrated Molecular Structure and
Education Research Center (DMR0114235 and
CHE9871268).
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL802585R
468
Org. Lett., Vol. 11, No. 2, 2009