Full Paper
less mobile 6-membered isocyanides may not isomerize in the low temperature isocyanide-nitrile rearrangement-alkylation is
absence of TMEDA.[1]
highly unusual. Mechanistic experiments, supported by compu-
tational analyses, are consistent with formation of a carbene
intermediate formed by ejection of isocyanide in the form of
lithium cyanide. Reorientation and attack of cyanide on the
carbene generates a lithiated nitrile that effectively alkylates
electrophiles. Interrupting the cyanide ejection is readily
achieved through addition of external TMEDA or with a glycol
substituent. Effective lithium chelation allows efficient ex-
change-alkylations by preventing the isocyanide-to-nitrile
isomerization. Collectively, the computational and mechanistic
analyses provide insight into the isocyanide-nitrile rearrange-
ment and provide robust conditions to prepare an array of sub-
stituted nitriles or isocyanides.
Experimental Section
Full experimental details including the computational analyses are
provided in the supporting information.
Figure 3. Effect of ring distortion over non-TMEDA path in the sulfanyl-lithium
exchange.
The computational and mechanistic analyses are summa-
rized in Scheme 7. Addition of BuLi to the anisylsulfanyl iso-
cyanide 2 leads to chelation between lithium, the isocyanide π-
cloud, and the oxygen and sulfur moieties (31). The three-point
binding of BuLi facilitates nucleophilic attack on sulfur with
concomitant ejection of cyanide (31 → 32). Reorientation of
cyanide with attack on the carbene 32 generates the lithiated
nitrile 33 whose alkylation affords the quaternary nitrile 4. In
the presence of TMEDA, addition of BuLi to 2 or substrates with
an internal glycol-linker prevents complexation between lith-
ium and the isocyanide allowing sulfur-lithium exchange to af-
ford lithiated isocyanide 34. Alkylation of 34 affords the substi-
tuted isocyanide 3.
Acknowledgments
Financial support from Drexel University and initially from the
NIH (2R15AI051352–04) is gratefully acknowledged. JMC thanks
the LANCAD-UNAM-DGTIC-270 project for the use of computa-
tional resources, the DGAPA-UNAM for grant IN114418, and the
CONACYT for grant 282791. JALM thanks CONACYT (241445)
for support.
Keywords: Isocyanide · Rearrangement · Asmic ·
Carbenes · Alkylation
[1] E. Alwedi, J. A. Lujan-Montelongo, B. R. Pitta, A. Chao, R. Cortés-Mejía,
J. M. del Campo, F. F. Fleming, Org. Lett. 2018, 20, 5910–5913.
[2] H. Kang, A. N. Pae, Y. S. Cho, H. Y. Koh, B. Y. Chung, Chem. Commun.
1997, 821–822.
[3] a) C. Rüchardt, M. Meier, K. Haaf, J. Pakusch, E. K. A. Wolber, B. Müller,
Angew. Chem. Int. Ed. Engl. 1991, 30, 893–901; Angew. Chem. 1991, 103,
907; b) M. Meier, C. Rüchardt, Chem. Ber. 1987, 120, 1–4.
[4] a) A. S. Narula, K. Ramachandran e-EROS Encyclopedia of Reagents for
Organic Synthesis 2001, 1–3; b) F. Watjen, R. Baker, M. Engelstoff, R. Her-
bert, A. MacLeod, A. Knight, K. Merchant, J. Moseley, J. Saunders, C. J.
Swain, E. Wong, J. P. Springer, J. Med. Chem. 1989, 32, 2282–2291.
[5] a) Y. Huang, Y. Yu, Z. Zhu, C. Zhu, J. Cen, X. Li, W. Wu, H. Jiang, J. Org.
Chem. 2017, 82, 7621–7627; b) A. Bittermann, D. Baskakov, W. A. Herr-
mann, Organometallics 2009, 28, 5107–5111; c) L. Busetto, F. Marchetti,
S. Zacchini, V. Zanotti, Eur. J. Inorg. Chem. 2005, 3250–3260; d) J. P. Miller,
R. E. White, Biochemistry 1994, 33, 807–817; e) K. Saito, S. Kagabu, Y.
Horie, K. A. Takahashi, Org. Prep. Proced. Int. 1989, 21, 354–355; f) L.
Busetto, V. Zanotti, V. G. Albano, D. Braga, M. Monari, J. Chem. Soc., Dal-
ton Trans. 1988, 1067–1074; g) J. Jiricny, D. M. Orere, C. B. Reese, J. Chem.
Soc., Perkin Trans. 1 1980, 1487–1492.
Scheme 7. Bifurcating exchange isocyanide-nitrile rearrangement mecha-
nisms.
[6] X. Yang, F. F. Fleming, Acc. Chem. Res. 2017, 50, 2556–2568.
[7] a) V. H. Gessner, Chem. Commun. 2016, 52, 12011–12023; b) S. Molitor,
V. H. Gessner, Angew. Chem. Int. Ed. 2016, 55, 7712–7716; Angew. Chem.
2016, 128, 7843; c) V. Capriati, S. Floro, F. M. Perna, A. Salomone, A.
Abbotto, M. Amedjkouh, S. O Nilsson Lill, Chem. Eur. J. 2009, 15, 7958–
7979; d) P. Lohse, H. Loner, P. Acklin, F. Sternfeld, A. Pfaltz, Tetrahedron
Lett. 1991, 32, 615–618.
[8] The stannyl isocyanide 2d was unable to be separated from AnSBu,
which is generated in the exchange. Subsequent exchange experiments
were performed with the mixture.
Conclusions
Asmic provides a versatile route to substituted isocyanides
through a unique series of alkylations. The anisylsulfanyl group
is critical for the sulfanyl-lithium exchange, an unusual process
that affords a lithiated isocyanide or a lithiated nitrile depend-
ing on the presence or absence of TMEDA, respectively. The
Eur. J. Org. Chem. 0000, 0–0
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim