Organic Process Research & Development
Communication
mL) and dried over anhyd. MgSO4. Solvent was evaporated
under vacuum, and the crude product (isomer ratio 5:7 equal
to 75:25) was recrystallized from ethanol using the following
procedure: The crude product was dissolved in hot ethanol
(300 mL) and allowed to slowly cool down to room
temperature (yellow crystals of the desired product 5
precipitated). The precipitate was filtrated, washed with hexane
(3 × 25 mL), and dried on vacuum (83.43 g, 50%). Yellow,
low-melting crystalline solid.10 1H NMR (300 MHz, CDCl3) δH
= 1.47 (d, 6H, J = 6.0 Hz), 4.83 (q, 1H, J = 6.0 Hz), 7.10 (d,
1H, J = 9.3 Hz), 8.40 (dd, 1H, J = 2.9, 9.2 Hz), 8.69 (d, 1H, J =
3.0 Hz), 10.41 (s, 1H). 13C NMR (75 MHz, CDCl3) δC = 21.9,
72.7, 113.4, 124.8, 125.0, 130.5, 141.0, 164.5, 188.0. IR (KBr):
3115, 2991, 2942, 1679, 1609, 1526, 1348, 1284, 1111, 950,
832, 748, 667 cm−1. HRMS (EI) calcd for M + (C10H11O4N):
209.0688. found 209.0689.
ASSOCIATED CONTENT
* Supporting Information
Description of the nitration process with the use of 2-
hydroxybenzaldehyde (2) as substrate and detailed procedure
for the fabrication of the microreactor used in this work. This
material is available free of charge via the Internet at http://
■
S
AUTHOR INFORMATION
Corresponding Author
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Apeiron Synthesis acknowledges the Operation Programme
Innovative Economy (PO IG) for financial support within PO
IG 1.4-4.1. Programme. P.K. acknowledges the Poznan
■
Protocol for the Nitration of 2-Isopropoxybenzalde-
hyde (4) with Red Fuming HNO3 - 1 kg Scale. A 10 L
́
ski
Buchi minipilot reactor (series RWDE 20) equipped with
̈
Akademicki Inkubator Przedsiebiorczosci (PAIP) for the
́
̨
PTFE anchor stirrer paddle was charged with fuming HNO3
(1210 mL, 28.43 mol) and cooled to −10 °C (Huber Unistat
510 cooling/heating apparatus). A solution of 2-isopropox-
ybenzaldehyde (4) (1000 g, 6.08 mol) in CH2Cl2 (3000 mL)
was added slowly over 4 h, maintaining the temperature of the
reaction mixture at −10 °C (stirring 120 rpm). After the
addition was complete, the reaction mixture was allowed to
slowly warm to 10 °C over 10 h. After that time, ice (∼1000 g)
and then H2O (500 mL) were added to the reaction mixture.
The product was extracted with CH2Cl2 (4 × 500 mL). The
combined organic layers were washed with 5% aqueous NaOH
(2 × 400 mL), H2O (2 × 400 mL), and brine (2 × 500 mL)
and dried over anhyd. MgSO4. Solvent was evaporated under
vacuum, and the crude product (isomer ratio 5:7 equal to
60:40) was recrystallized from ethanol using the following
procedure: The crude product was dissolved in hot ethanol
(2000 mL) and allowed to slowly cool down to room
temperature (yellow crystals of the desired product 5
contaminated with unwanted isomer 7 precipitated). The
precipitate was filtrated and washed with warm hexane (several
times to remove the isomer 7 that is better soluble in hexane
than is 5). If necessary the recrystallization from hot ethanol
can be repeated. The yield of the pure 5 was 30% (382 g) as a
yellow, low-melting, amorphous solid.
scholarship Kluczowy Stazysta which is co-funded by the EU
̇
under the European Social Fund.
REFERENCES
■
(1) For recent comprehensive reviews on metathesis, see:
(a) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110,
1746. (b) Samojlowicz, C.; Bieniek, M.; Grela, K. Chem. Rev. 2009,
109, 3708.
(2) For reviews on synthetic applications of olefin metathesis, see:
(a) Clavier, H.; Grela, K.; Kirschning, A.; Mauduit, M.; Nolan, S. P.
Angew. Chem., Int. Ed. 2007, 46, 6786. (b) Kotha, S.; Lahiri, K. Synlett
2007, 2767. (c) Compain, P. Adv. Synth. Catal. 2007, 349, 1829.
(3) For selected spectacular examples of application of olefin
metathesis, see: (a) Endo, K.; Grubbs, R. H. J. Am. Chem. Soc. 2011,
133, 8525. (b) Xia, Y.; Boydston, A. J.; Grubbs, R. H. Angew. Chem.,
Int. Ed. 2011, 50, 5882. (c) Xia, Y.; Boydston, A. J.; Yao, Y.; Kornfield,
J. A.; Gorodetskaya, I. A.; Spiess, H. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2009, 131, 2670.
(4) For the Nobel Prize Lectures see: (a) Chauvin, Y. Angew. Chem.,
Int. Ed. 2006, 45, 3740. (b) Schrock, R. R. Angew. Chem., Int. Ed. 2006,
45, 3748. (c) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760.
(5) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168. (b) Kingsbury, J. S.; Harrity, J. P. A.;
Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791.
(6) (a) Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127,
4510. (b) Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.;
Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org.
Biomol. Chem. 2004, 2, 8. (c) Van Veldhuizen, J. J.; Garber, S. B.;
Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954.
(7) For chiral version of H2, see: Chiral Grubbs and Hoveyda
catalysts: (a) Costabile, C.; Mariconda, A.; Cavallo, L.; Longo, P.;
Bertolasi, V.; Ragone, F.; Grisi, F. Chem.Eur. J. 2011, 17, 8618.
(b) Gillingham, D. G.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46,
3860. (c) Fournier, P.-A.; Collins, S. K. Organometallics 2007, 26,
2945. (d) van Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.;
Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502.
(e) van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H.
J. Am. Chem. Soc. 2002, 124, 4954. (f) Seiders, T. J.; Ward, D. W.;
Grubbs, R. H. Org. Lett. 2001, 3, 3225.
Protocol for the Nitration of 2-Isopropoxybenzalde-
hyde (4) with Red Fuming HNO3 in Continuous Flow
Using Microreactor Described in This Work. The reagent
stock bottles were filled with 2-isopropoxybenzaldehyde (4) in
CH2Cl2 (2.5 M) and neat fuming nitric acid, respectively. The
equipment (Ascor AP23 syringe pump) was set to flow with 4/
fuming HNO3 ratio of 1:6.47. Syringe 1 delivered 28 mL/h of
2-isopropoxybenzaldehyde (4) solution and syringe 2 delivered
19.6 mL/h of fuming nitric acid to give a residency time of 5.4 s
at 10 °C and a final outlet flow rate of 47.6 mL/h. The outlet
stream was collected for 120 min and poured directly into ice
water (1 L). When collection stopped, the aqueous layer was
extracted with ethyl acetate (3 × 100 mL). The combined
organic layers were washed with aqueous 5% NaOH (3 × 50
mL) and brine (1 × 50 mL) and dried over anhydrous MgSO4.
After filtration of drying agent and evaporation of solvent, the
crude 2-isopropoxy-5-nitrobenzaldehyde (5) was isolated as a
yellow solid. Washing with warm hexane afforded pure 5 (26 g)
as pale-yellow crystals (65% yield). Rate of production = 13 g/
h.
(8) (a) Grela, K. EP 1554294B1, 2006. (b) Michrowska, A.; Bujok,
R.; Harutyunyan, S.; Sashuk, V.; Dolgonos, G.; Grela, K. J. Am. Chem.
Soc. 2004, 126, 9318. (c) Grela, K.; Harutyunyan, S.; Michrowska, M.
Angew. Chem., Int. Ed. 2002, 41, 4038.
(9) (a) Michrowska, A.; List, B. Nature Chem. 2009, 1, 225.
(b) Weychardt, H.; Plenio, H. Organometallics 2008, 27, 1479.
(c) Goldup, S. M.; Pilkington, C. J.; White, A. J. P.; Burton, A.; Barrett,
M. J. Org. Chem. 2006, 71, 6185. (d) Krause, J. O.; Nuyken, O.;
1434
dx.doi.org/10.1021/op300116j | Org. Process Res. Dev. 2012, 16, 1430−1435