Organic Process Research & Development
Communication
phosphonate 2c with various aldehydes commonly used to test
similar olefination reagents. These results are summarized in
Table 3. Compound 2c shows comparable Z-selectivity to the
Hz, 1H; Ar), 7.64 (app d, J = 8.1 Hz, 1H; Ar), 7.34−7.31 (app
m, 2H; Ar), 7.14−7.02 (m, 4H; Ar), 4.14 (dq, J = 10.7, 6.9 Hz,
1H; CH2CH3), 4.00 (dq, J = 10.7, 6.9 Hz, 1H; CH2CH3), 3.47
(dq, J = 24.0, 7.2 Hz, 1H; P(O)CHCH3), 1.68 (dd, J = 19.5,
t
7.2 Hz, 3H; P(O)CHCH3), 1.35 (s, 9H; Bu), 1.31 (s, 9H;
Table 3. HWE Reactions of 2c with Aromatic/Aliphatic
Aldehydes in THF
tBu), 1.08 (t, J = 6.9 Hz, 3H; CH2CH3); 13C NMR (100 MHz,
293 K, CDCl3): 168.4 (d, J = 4 Hz), 151.0 (d, J = 10 Hz),
150.6 (d, J = 9 Hz), 138.9 (d, J = 4 Hz), 138.8 (d, J = 4 Hz),
127.5, 127.5, 127.3, 127.3, 124.4, 124.3, 119.8 (d, J = 3 Hz),
119.6 (d, J = 3 Hz), 61.9, 41.7 (d, J = 138 Hz), 34.7, 30.2,
30.09, 13.8, 12.0 (d, J = 6 Hz) ppm; HRMS (ES+) calcd for
C25H35O5P [M + H]+. 447.22949, found 447.23151.
a
a
run
RCHO
time (h)
yield (%)
ratio (Z/E)
1
2
3
4
5
PhCHO
3
3
3
3
3
94
36
97:3
94:6
cC6H11CHO
ASSOCIATED CONTENT
■
nBuCH(Et)CHO
nC7H15CHO
iPrCHCHCHO
60(brsm)
100:0
86:14
70:30
S
* Supporting Information
84
69
The Supporting Information is available free of charge on the
a
1
Determined by the H NMR analyses of the crude mixtures.
1H and 13C NMR spectra for compound 2c (PDF)
nonalkylated 1c25 and related alkylated reagents27 with near-
perfect selectivity with aromatic (Table 3, run 1) and branched
(runs 2 and 3) aldehydes and lower selectivity with conjugated
and linear substrates (runs 4 and 5). The yields for the more
challenging substrates were lower than those from the
literature25,27 due to the shorter times.
In conclusion, we have developed a method to prepare
phosphonate 2c in high yield and chemoselectivity. The
procedure is devoid of column chromatography and does not
require expensive reagents. The preparation of phosphonate 2c
from PCl3 costs $0.49/mmol including all reagents and
solvents. The use of commercial THF without distillation
further simplifies the procedure. This reagent demonstrated
high Z-selectivity in the HWE reaction with several aldehydes.
AUTHOR INFORMATION
■
Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Damodaran Krishnan and Dr. Bhaskar Godugu
in our department for assisting with NMR and mass
spectroscopic (NIH Grant 1S10RR017977-01) analyses,
respectively. This work was in part supported by the U.S.
National Institutes of Health (R01 CA120792).
EXPERIMENTAL SECTION
■
Nondistilled THF (250 mL; water <0.008%) was added to a 1-
L round-bottom flask under a nitrogen atmosphere.
Phosphonate 1c (105.42 g, 243.76 mmol) was added to the
flask, and the resulting reaction mixture was cooled to 0 °C on
ice. The mixture was then treated with MeI (15.10 mL, 243.75
mmol) in one portion at 0 °C. The reaction mixture was kept
at 0 °C while KOtBu (27.35 g, 243.75 mmol) was added slowly
to the flask in small portions (Caution: exothermic). The
resulting mixture was allowed to stir for 1 h at 23 °C. The
reaction was cooled to 0 °C, and DBU (72.50 mL, 487.50
mmol) was added slowly, followed by MeI (15.10 mL, 243.75
mmol). The resulting slurry was allowed to stir for 1 h at 23
°C. The reaction was cooled to 0 °C and quenched using
saturated aqueous NH4Cl (200 mL), THF was removed under
reduced pressure, and the aqueous layer was extracted with
EtOAc (2 × 200 mL). The combined organic layers were
washed with brine (1 × 200 mL) and dried over Na2SO4. The
organic layers were then filtered through a cotton plug, and the
organic solvents were evaporated under reduce pressure to
yield a pale-yellow oil (108.45 g, quantitative yield, 78% purity
by 1H NMR analysis). The material was recrystallized from hot
REFERENCES
■
(1) Still, W. C.; Gennari, C. Direct Synthesis of Z-Unsaturated Esters
- a Useful Modification of the Horner-Emmons Olefination.
Tetrahedron Lett. 1983, 24, 4405.
(2) Ando, K. Practical Synthesis of Z-Unsaturated Esters by Using a
New Horner-Emmons Reagent, Ethyl Diphenylphosphonoacetate.
Tetrahedron Lett. 1995, 36, 4105.
(3) Bates, R. H.; Shotwell, J. B.; Roush, W. R. Stereoselective
Syntheses of the C(1)-C(9) Fragment of Amphidinolide C. Org. Lett.
2008, 10, 4343.
(4) Beaudry, C. M.; Trauner, D. Synthetic Studies toward Snf4435 C
and Snf4435 D. Org. Lett. 2002, 4, 2221.
(5) Bhatt, U.; Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse,
M. The First Total Synthesis of (+)-Ratjadone. J. Org. Chem. 2001,
66, 1885.
(6) Ceccarelli, S. M.; Piarulli, U.; Gennari, C. Synthetic Studies on
the Sarcodictyins: Synthesis of Fully Functionalized Cyclization
Precursors. Tetrahedron 2001, 57, 8531.
(7) Ceccarelli, S. M.; Piarulli, U.; Telser, J.; Gennari, C. A
Carbonylative Cross-Coupling Strategy to the Total Synthesis of
the Sarcodictyins: Preliminary Studies and Synthesis of a Cyclization
Precursor. Tetrahedron Lett. 2001, 42, 7421.
(8) Chen, Y.-T.; Tang, C.-L.; Ma, W.-P.; Gao, L.-X.; Wei, Y.; Zhang,
W.; Li, J.-Y.; Li, J.; Nan, F.-J. Design, Synthesis, and Biological
Evaluation of Novel 2-Ethyl-5-Phenylthiazole-4-Carboxamide Deriv-
atives as Protein Tyrosine Phosphatase 1B Inhibitors with Improved
Cellular Efficacy. Eur. J. Med. Chem. 2013, 69, 399.
1
hexanes to yield white crystals (72.7 g; 87% purity by H
NMR).
Rf = 0.34 (20% EtOAc in hexanes); mp = 70−72 °C; IR
(film): νmax = 3460, 3083, 2960, 2872, 1741 (CO), 1488,
1442, 1300 (PO), 1257, 1182, 1087, 1055, 945, 757 cm−1;
1H NMR (300 MHz, 293 K, CDCl3): δ 7.73 (app d, J = 8.1
C
Org. Process Res. Dev. XXXX, XXX, XXX−XXX