The Journal of Organic Chemistry
Article
we added aryl carbamate 1 (0.010 mmol) with stirring. For the most
rapid reactions, IR spectra were recorded every 15 s with monitoring
of the absorbance at 1730 cm− over the course of the reaction.
NMR Spectroscopic Analyses. NMR samples for reaction
monitoring and structure determination were routinely prepared
using stock solutions of NaDA in THF/hexane mixtures maintained
R. F.; Ma, Y.; Collum, D. B. Sodium Diisopropylamide in
Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Alkene
Isomerizations and Diene Metalations. J. Am. Chem. Soc. 2017, 139,
11544. (d) Algera, R. F.; Ma, Y.; Collum, D. B. Sodium
Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and
Mechanisms of Arene Metalations. J. Am. Chem. Soc. 2017, 139,
15197. (e) Zhang, Z.; Collum, D. B. Structures and Reactivities of
Sodiated Evans Enolates: Role of Solvation and Mixed Aggregation on
the Stereochemistry and Mechanism of Alkylations. J. Am. Chem. Soc.
2019, 141, 388. (f) Ma, Y.; Algera, R. F.; Woltornist, R. A.; Collum,
D. B. Sodium Diisopropylamide-Mediated Dehydrohalogenations:
Influence of Primary- and Secondary-Shell Solvation. J. Org. Chem.
1
1
at −80 °C and flame-sealed under partial vacuum. Standard H and
1
3
1
C{ H} NMR spectra were recorded on a 500 MHz spectrometer at
1
13
5
00 and 125.79 MHz, respectively. The H and C resonances were
referenced to the CH O resonance (3.58 ppm) and CH O resonance
2
2
(
67.57 ppm) of THF at −80 °C, respectively.
DFT Computations. DFT calculations were carried out at the
B3LYP/6-31G(d) level with single-point calculations at the M06-2X
2
(
019, submitted.
10,11
level of theory.
frequency.
Transition structures each had a single negative
2) (a) Mulvey, R. E.; Robertson, S. D. Synthetically Important
Alkali-Metal Utility Amides: Lithium, Sodium, and Potassium
Hexamethyldisilazides, Diisopropylamides, and Tetramethylpiperi-
dides. Angew. Chem., Int. Ed. 2013, 52, 11470. (b) Watson, B. T.;
Lebel, H. Sodium Hexamethyldisilazide. In e-EROS Encyclopedia of
Reagents for Organic Synthesis; John Wiley & Sons: New York, 2005;
pp 1−10. (c) Seyferth, D. Alkyl and Aryl Derivatives of the Alkali
Metals: Useful Synthetic Reagents as Strong Bases and Potent
Nucleophiles. 1. Conversion of Organic Halides to Organoalkali-
Metal Compounds. Organometallics 2006, 25, 2. (d) Seyferth, D. Alkyl
and Aryl Derivatives of the Alkali Metals: Strong Bases and Reactive
Nucleophiles. 2. Wilhelm Schlenk’s Organoalkali-Metal Chemistry.
The Metal Displacement and the Transmetalation Reactions.
Metalation of Weakly Acidic Hydrocarbons. Superbases. Organo-
metallics 2009, 28, 2. (e) Benkeser, R. A.; Foster, D. J.; Sauve, D. M.;
Nobis, J. F. Metalations With Organosodium Compounds. Chem. Rev.
2-Fluoro-6-hydroxy-N,N-diisopropylbenzamide (4e). 3-Fluoro-
phenyl diisopropylcarbamate (1c, 479 mg, 2.0 mmol) in 5.0 mL of
THF was added dropwise over 10 min to a solution of NaDA (2.2
mmol, 271.0 mg) in THF (10.0 mL) at −78 °C under N . The
2
resulting solution was warmed to 0 °C, stirred for 2 h, and quenched
with saturated aqueous ammonium chloride (8.0 mL). The THF was
removed under reduced pressure, and the aqueous residue was
extracted with dichloromethane (4 × 10 mL). The combined organic
extracts were dried (MgSO ), filtered, and concentrated under
4
reduced pressure to afford the crude product, which was purified
using flash column chromatography (8:1 CH Cl /EtOAc) to give 4e
2
2
1
(
7
79%) as white needles. H NMR (500 MHz, CDCl ). δ 8.28 (1H, s),
3
.15 (1H, dt, J = 8.3, 6.6 Hz), 6.75 (1H, dt, J = 8.3, 0.8 Hz), 6.58 (1H,
1
3
1
ddd, J = 9.3, 8.3, 1.0 Hz), 3.70 (1H, s, br), 1.35 (12H, s, br), C{ H}
NMR (125.8 MHz, CDCl ). δ 168.5, 158.5 (d, J = 246.4 Hz),
3
C−F
1
(
957, 57, 867.
1
6
57.0 (d, JC−F = 6.4 Hz), 132.6 (d, JC−F = 10.6 Hz), 112.0 (d, JC−F
=
3) (a) Raynolds, S.; Levine, R. The Synthesis of Nitrogen-
.4 Hz), 106.8 (d, JC−F = 22.5 Hz), 20.7. (The isopropyl methinyl
1
9
containing Ketones. VIII. The Acylation of 3-Picoline, 4-Picoline and
Certain of their Derivatives. J. Am. Chem. Soc. 1960, 82, 472. (b) For
a bibliography of NaDA-mediated reactions see reference 1b.
carbon is missing owing to a conformational coalescence.) F NMR
+
(
470.33 MHz, CDCl ) δ −113.8. HRMS (ESI-TOF) m/z [M + H]
3
calcd for C H FNO 240.1399; found 240.1390.
12
18
2
(4) For leading references to trialkylamine-solvated lithium amides,
see: Godenschwager, P. F.; Collum, D. B. Lithium Hexamethyldisi-
lazide-Mediated Enolizations: Influence of Triethylamine on E/Z
Selectivities and Enolate Reactivities. J. Am. Chem. Soc. 2008, 130,
8726.
(5) The preparation of NaDA in reference 1a is a modified
procedure reported previously: Barr, D.; Dawson, A. J.; Wakefield, B.
J. A Simple, High-Yielding Preparation of Sodium Diisopropylamide
and Other Sodium Dialkylamides. J. Chem. Soc., Chem. Commun.
ASSOCIATED CONTENT
Supporting Information
■
*
S
1H, 13C{ H}, and 19F NMR spectra; IR spectrum of the
metalation rearrangement; plot of absorbance versus
time depicting the rearrangement of 2b from an
equilibrium mixture of 1b and 2b generated with
corrected M06-2X energies (PDF)
1
1
992, 2, 204.
(6) Jalil Miah, M. A.; Sibi, M. P.; Chattopadhyay, S.; Familoni, O. B.;
Snieckus, V. Directed ortho-Metalation of O-Aryl N,N-Dialkylcarba-
mates: Methodology, Anionic ortho-Fries Rearrangement, and Lateral
Metalation. Eur. J. Org. Chem. 2018, 2018, 440.
(
7) (a) Singh, K. J.; Collum, D. B. Lithium Diisopropylamide-
AUTHOR INFORMATION
ORCID
Notes
The authors declare no competing financial interest.
■
Mediated Ortholithiation and Anionic Fries Rearrangement of Aryl
Carbamates: Role of Aggregates and Mixed Aggregates. J. Am. Chem.
Soc. 2006, 128, 13753. (b) Riggs, J. C.; Singh, K. J.; Ma, Y.; Collum,
D. B. Anionic Snieckus-Fries Rearrangement: Solvent Effects and Role
of Mixed Aggregates. J. Am. Chem. Soc. 2008, 130, 13709.
*
(8) (a) Roy, T.; Biju, A. T. Recent Advances in Molecular
Rearrangements Involving Aryne Intermediates. Chem. Commun.
2018, 54, 2580. (b) Yoshida, S.; Hosoya, T. The Renaissance and
Bright Future of Synthetic Aryne Chemistry. Chem. Lett. 2015, 44,
1450.
ACKNOWLEDGMENTS
The authors thank the National Institutes of Health
GM131713) for support.
■
(
(9) Andrews, P. C.; Barnett, N. D. R.; Mulvey, R. E.; Clegg, W.;
O’Neil, P. A.; Barr, D.; Cowton, L.; Dawson, A. J.; Wakefield, B. J. X-
ray Crystallographic Studies and Comparative Reactivity Studies of a
Sodium Diisopropylamide (NDA) Complex and Related Hindered
Amides. J. Organomet. Chem. 1996, 518, 85.
(10) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
REFERENCES
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(
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Ma, Y.; Collum, D. B. Sodium Diisopropylamide: Aggregation,
Solvation, and Stability. J. Am. Chem. Soc. 2017, 139, 7921. (c) Algera,
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