10.1002/anie.201911896
Angewandte Chemie International Edition
RESEARCH ARTICLE
Toward this end, the use of TMZ for metal-catalyzed
cyclopropanations was explored. Employing 4-vinylanisole as a
model substrate, mild conditions were initially evaluated. Only
6% conversion of 4-vinylanisole to 4-cyclopropylanisole was
observed using 5 mol % Fe(TPP)Cl and the esterification
conditions (Table S1, Entry 2). Several other transition metals
N3 position, the site bearing the eventual alkylating moiety, can
yield precursors of other esters, but substitutions at the C8
position are also attainable and have been demonstrated to tune
the rate of hydrolysis.29 With several significant advantages over
other diazomethane precursors and its ready availability, TMZ
should find broad utility in chemical synthesis.
(palladium,
rhodium,
copper)
known
to
mediate
cyclopropanations with diazo compounds did not afford any
product. Proceeding with Fe(TPP)Cl, the dioxane/water solvent
system was exchanged for aqueous KOH, which led to a
significant increase in conversion (Table S1, Entries 6–7). It is
probable that a more basic solution is required to facilitate the
conversion of methyl diazonium to neutral diazomethane, which
can diffuse to the organic layer and act as the source for the
metallocarbene intermediate. Adding another equivalent of TMZ,
decreasing the temperature of the reaction to ambient
temperature, and increasing the concentration of the reaction
improved the conversion to 93% (Table S1, Entry 10). TMZ
effectively cyclopropanated several styrenyl (62–66) and natural
product-derived (67)36 substrates in 6 M KOH (Figure 5). More
electron-rich substrates furnished better yields akin to other
diazomethane-generating cyclopropanation methods.23 Beyond
electronics, solid substrates provided lower yields due to dilution
of the organic phase with toluene, necessary for compound
dissolution. The reactions were conducted open to air at room
temperature and products were quantitatively separated from 4-
amino-5-imidazolecarboxamide (AIC, Figure 1b) through an
extraction.
Acknowledgements
We thank David Sarlah, Marty Burke, and Scott Denmark
(Department of Chemistry, UIUC) for helpful comments on this
work. We thank Dr. Stephen Motika (UIUC) for verifying
experimental protocols for this transformation, specifically the
synthesis of 5 and 43. This work was supported by the
University of Illinois and the NIH (R01CA120439). R.L.S. is a
member of the NIH Chemistry-Biology Interface Training Grant
(T32-GM070421).
Keywords: Imidazotetrazine • Diazomethane • Alkylation •
Cyclopropanation • Diazo compounds
(1)
(2)
T. H. Black, Aldrichimica Acta 1983, 16, 3–10.
D. Dallinger, C. O. Kappe, Aldrichimica Acta 2016, 49,
57–66.
(3)
Diazomethane [MAK Value Documentation, 1999]. In
The MAK-Collection for Occupational Health and Safety
2012, 142–148.
(4)
(5)
R. Schoental, Nature 1960, 188, 420–421.
Diazomethane (November 29, 2018) Center for Disease
Control
and
Prevention.
Conclusion
March 21, 2019)
(6)
T. Bug, M. Hartnagel, C. Schlierf, H. Mayr, Chem. Eur. J.
2003, 9, 4068–4076.
TMZ’s unique mechanism of activation and water solubility
make it an exceptional generator of methyl diazonium under mild
conditions, with subsequent methyl ester formation particularly
efficient. TMS-diazomethane is frequently implemented as a less
explosive diazomethane surrogate for esterification, but it retains
lethal toxicity. Other methylating reagents such as methyl iodide,
dimethyl sulfate, or dimethyl carbonate are commonly used for
O-methylation, but are decisively less reactive often requiring
harsh conditions (e.g. strong base or temperatures >100°C)
and/or longer reaction times (12–24 hours).37 TMZ serves as a
complementary O-methylating reagent that has the advantages
of being a solid, affordable (~$3.70/mmol vs. ~$6.30/mmol for a
2 M solution of TMS-diazomethane in diethyl ether) precursor to
the methyl diazonium cation; in addition, the tolerability of this
compound is well known as it is administered to cancer patients
over months as a pharmaceutical. Since the tetrazinone motif
masks the alkyl diazonium equivalent, TMZ also exhibits
considerably more thermal stability than other diazomethane
precursors like Diazald, which bears an N-methyl N-nitroso
group; Diazald decomposes (explosively) at its melting point of
60°C,38 while TMZ is stable up to its melting point, 212°C. It
should be noted that, while more convenient than other
diazomethane precursors, proper caution is still warranted
(particularly on large scale) when employing TMZ in these
reactions. Finally, chemical derivatives of imidazotetrazines are
readily accessible; for example, we show that substitution at the
(7)
(8)
J. Podlech, J. Prakt. Chemie 1998, 340, 679–682.
N. G. Murphy, S. M. Varney, J. M. Tallon, J. R.
Thompson, P. D. Blanc, Clin. Toxicol. 2009, 47, 712.
G. Maas, Angew. Chem. Int. Ed. 2009, 48, 8186–8195.
A. F. McKay, J. Am. Chem. Soc. 1948, 70, 1974–1975.
V. K. Aggarwal, E. Alonso, G. Hynd, K. M. Lydon, M. J.
Palmer, M. Porcelloni, J. R. Studley, Angew. Chem. Int.
Ed. 2001, 40, 1430–1433.
T. Toma, J. Shimokawa, T. Fukuyama, Org. Lett. 2007,
9, 3195–3197.
B. Morandi, E. M. Carreira, Angew. Chem. Int. Ed. 2010,
49, 938–941.
M. Struempel, B. Ondruschka, R. Daute, A. Stark,
Green Chem. 2008, 10, 41–43.
E. Rossi, P. Woehl, M. Maggini, Org. Process Res. Dev.
2012, 16, 1146–1149.
R. A. Maurya, C. P. Park, J. H. Lee, D. P. Kim, Angew.
Chem. Int. Ed. 2011, 50, 5952–5955.
F. Mastronardi, B. Gutmann, C. O. Kappe, Org. Lett.
2013, 15, 5590–5593.
D. Dallinger, C. O. Kappe, Nat. Protoc. 2017, 12, 2138–
2147.
H. Lehmann, Green Chem. 2017, 19, 1449–1453.
E. Carlson, G. Duret, N. Blanchard, W. Tam, Synth.
Commun. 2016, 46, 55–62.
L. S. Barkawi, J. D. Cohen, Nat. Protoc. 2010, 5, 1619–
1626.
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
E. Carlson, W. Tam, Synthesis 2016, 48, 2449–2454.
This article is protected by copyright. All rights reserved.