C O MMU N I C A T I O N S
Scheme 2. Potential Mechanism for Olefin Formationa
resulting in stabilization of the alkoxy-substituted ylide. Presumably,
the origin of this stability is through improved overlap of the
negative charge on carbon with the lower-lying P-O antibonding
(
σ*) orbitals.12 The increased E selectivity observed with ylide 2b
a
31P NMR chemical shifts are listed in italics.
can perhaps be rationalized based on these observations of relative
ylide stability. This ylide is perhaps best regarded not as a semi-
stabilized ylide, which traditionally gives low selectivity, but as a
stabilized ylide which, according to the Vedejs model, is known
to give high E selectivity. The low selectivity with ester-stabilized
ylides is more difficult to rationalize and is currently being analyzed
computationally.
Table 2. Olefinations Using EDA with a Range of Aldehydes
1
3
entry
R
yield (%)a
E:Zb
1
2
3
4
5
6
7
8
Ph
4-(MeO)C
2,6-(Me)
(E)-PhCHdCH
4-(CH CO)C
4-(Cl)C
PhCH
c-C
86
59
45
90
75
90
92
82
96:4
98:2
94:6
89:11
95:5
96:4
Finally, the efficiency of this new process is demonstrated in
6
H
4
1
4
2
C
6
H
3
the synthesis of the recently reported anticancer compound 10.
The Wittig reaction leading to stilbene derivatives usually gives
3
6 4
H
low selectivity, and therefore alternative routes or an additional E
6
H
4
2
90:10
94:6
f Z equilibration step is required. The use of our new protocol
15
6
H
11
gave the desired substituted stilbene with 97:3 E/Z selectivity (eq
4), providing a clean and efficient route to this compound.
a
Isolated yield. b Determined by GC-MS.
Interestingly, addition of LiBr to our tosylhydrazone system did
not result in an increase of the E/Z selectivity.
These reactions are presumed to proceed via iron-catalyzed car-
bene transfer to the phosphite to form a phosphorus ylide. However,
two different pathways could be envisioned for olefin formation
(Scheme 2): (i) Wittig reaction (path A) leading to trimethyl phos-
phate 4 or (ii) Horner-Wadswoth-Emmons (HWE) reaction (path
B) via phosphonate anion 3 which would generate phosphate anion
bypro-
Acknowledgment. We gratefully thank GlaxoSmithKline and
AstraZeneca for CASE Awards to C.G.S. and J.d.V.
duct 5. Phosphonate anion 3 could be formed in an Arbuzov reaction
from ylide 2.
To determine which pathway was operative, reactions were
followed by 31P NMR (Scheme 2). In the absence of halide ions,
both diazo compounds 1a/b led to new intermediates which, upon
Supporting Information Available: The use of alternative phos-
phites, experimental procedures, compound characterization data, and
mechanistic 31P NMR data. This material is available free of charge
via the Internet at http://pubs.acs.org.
treatment with H
treatment with PhCHO, led to the olefins and trimethyl phosphate
and none of the phosphonate anion 5. These observations are
2
O, gave the known phosphonates 6a/b and, upon
References
(
1) (a) Hoffmann, R. W. Angew. Chem., Int. Ed. 2001, 40, 1411. (b) Lawrence,
N. J. In Preparation of Alkenes: a Practical Approach; Williams, J. M.
J., Ed.; Oxford University Press: Oxford, 1995. (c) Kolodiazhnyi, O. I.
Phosphorus Ylides: Chemistry and Applications in Organic Chemistry;
Wiley-VCH: New York, 1999.
4
consistent with ylide 2a/b as the new intermediate and reactions
occurring through a Wittig process. Interestingly, olefination
reactions that used hydrazone salts as the diazo precursor gave
exclusively trimethyl phosphate 4 as the phosphorus-containing
byproduct, indicating that these are also Wittig-type reactions.
In contrast, in reactions involving EDA and LiBr, the phosphorus
byproduct formed was found to be 5 and the known anion 3a was
observed as a transient intermediate. Thus, in the presence of LiBr,
an Arbuzov-type reaction has indeed intervened, leading to a new
base-free method for conducting a HWE reaction. This could clearly
find application with especially base sensitive substrates. It is well-
known that lithium ions can influence selectivity in Wittig reac-
tions11 but in our case it is the bromide ion which is responsible
(2) (a) Wang, Z.; Zhang, G.; Guzei, I.; Verkade, J, G. J. Org. Chem. 2001,
6
6, 3521. (b) Vedejs, E.; Marth, C. F.; Ruggeri J. Am. Chem. Soc. 1988,
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1
(3) For a review of the Arbuzov reaction, see: Bhattacharya, A. K.;
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(
4) High E selectivity for semistabilized ylides has been achieved with ylide
PhCHdP(MeNCH CH ) N. See ref 2a and references therein for alterna-
2
2 3
tive methods.
(
5) Reduction of Fe(III)-porphyrin complexes with EDA is discussed in the
following: Wolf, J. R.; Hamaker, C. G.; Djukic, J.-P.; Kodadek, T.; Woo,
L. K. J. Am. Chem. Soc. 1995, 117, 9194.
(
(
(
6) Mirafzal, G. A.; Cheng, G.; Woo, L. K. J. Am. Chem. Soc. 2002, 124,
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7) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.;
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4
returned a
(9) Aggarwal, V. K.; de Vicente, J.; Pelotier, B.; Holmes, I. P.; Bonnert, R.
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similar ratio of olefins as under salt-free conditions (63:38, E:Z).
Ylide 2a is substantially less hindered than ylide 7 and, on the
basis of steric effects, would be expected to be the more reactive.
To test the differences in reactivity, we conducted a competition
experiment between the stabilized ylides 2a and 7 (eq 3). This
experiment only gave olefin 8, indicating that the more hindered
ylide 7 is substantially more reactiVe than the alkoxy-substituted
ylide 2a. In other words, there is a Very significant electronic effect
(
10) For a recent review of the HWE reaction, see: Martyn, D. C.; Hoult, D.
A.; Abell, A. D. Aust. J. Chem. 2001, 54, 391.
(
11) Ward, W. J.; McEwen, W, E. J. Org. Chem. 1990, 55, 493.
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(
(
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(
(
15) Yu, J.; Gaunt, M. J.; Spencer, J. B.J. Org. Chem. 2002, 67, 4627.
JA029573X
J. AM. CHEM. SOC.
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VOL. 125, NO. 20, 2003 6035