Metal-free N-H insertions of donor/acceptor carbenes

Article abstract of DOI:10.1021/ol3020754

Synthetically useful transformations arise from the thermal decomposition of aryldiazoacetates in the presence of primary and secondary amines without the use of a metal catalyst. Thermally generated, free donor/acceptor carbenes directly undergo N-H insertion with amines through selective aza-ylide formation to afford a variety of α-amino esters in 53-96% yields.

Full text of DOI:10.1021/ol3020754

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4626–4629
Metal-Free NꢀH Insertions
of Donor/Acceptor Carbenes
Stephanie R. Hansen, Jillian E. Spangler, Jørn H. Hansen, and Huw M. L. Davies*
Emory University, Department of Chemistry, 1515 Dickey Drive, Atlanta,
Georgia 30322, United States
hmdavie@emory.edu
Received July 26, 2012
ABSTRACT
Synthetically useful transformations arise from the thermal decomposition of aryldiazoacetates in the presence of primary and secondary amines
without the use of a metal catalyst. Thermally generated, free donor/acceptor carbenes directly undergo NꢀH insertion with amines through
selective aza-ylide formation to afford a variety of R-amino esters in 53ꢀ96% yields.
Diazo compounds are versatile reagents in organic
synthesis1 and, in particular, are utilized as precursors for
the generation of metal carbenoid intermediates. These
reactive species can undergo a myriad of powerful syn-
thetic transformations such as CꢀH insertions,2 cyclo-
propanations,3 and ylide formations.4 We and others have
conducted extensive studies on the chemistry of metal-
bound carbenoids derived from aryldiazoacetates.5 How-
ever, we recently disclosed that these diazo compounds can
also be decomposed in a controlled manner under thermal
conditions without the use of a metal catalyst to provide
free carbenes and effect selective cycloaddition processes
with alkenes.6
pounds.4,7 A range of metals, most notably copper and
rhodium, have been studied as catalysts to effect the NꢀH
insertion process. However, the amino component of these
reactions is typically limited to amides, carbamates, and
anilines. The corresponding reactions of amines are much
less developed8 as the nucleophilic amines can bind to and,
consequently, poison the metal catalysts.8aꢀc
In 1996 Moody and co-workers described a thermal
NꢀH insertion into N,N-diethylamine with phenyldiazo-
acetate although the desired product was isolated in only
30ꢀ40% yield.8a Our recent observation of selective ther-
mal carbene cycloaddition reactions led us to hypothesize
that a general NꢀH insertion process could be feasible
under thermal conditions without the use of a metal
The metal-catalyzed NꢀH insertion of diazocarbonyls
has been developed as a rapid, general, and convergent
route to amino ketones, N-heterocycles, and amino esters.
These products are important precursors to amino acids as
well as other natural products and pharmaceutical com-
(7) (a) Huang, D.; Jiang, G. M.; Chen, H. X.; Gao, W. D. Synth.
Commun. 2009, 40, 229–234. (b) Salzmann, T. N.; Ratcliffe, R. W.;
Christensen, B. G.; Bouffard, F. A. J. Am. Chem. Soc. 1980, 102, 6163–
6165. (c) Deng, G.; Jiang, N.; Ma, Z.; Wang, J. Synlett 2002, 1913–1915.
(d) Dong, C.; Deng, G.; Wang, J. J. Org. Chem. 2006, 71, 5560–5564.
(e) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.; Zhou, Q.-L. J. Am. Chem.
Soc. 2007, 129, 5834–5835. (f) Lee, E. C.; Fu, G. C. J. Am. Chem. Soc.
2007, 129, 12066–12067. (g) Wang, Y. L.; Zhu, S. Z. Org. Lett. 2003, 5,
745–748. (h) Shi, B. L.; Blake, A. J.; Campbell, I. B.; Judkins, B. D.;
Moody, C. J. Chem. Commun. 2009, 3291–3293.
(8) (a) Aller, E.; Buck, R. T.; Drysdale, M. J.; Ferris, L.; Haigh, D.;
Moody, C. J.; Pearson, N. D.; Sanghera, J. B. J. Chem. Soc., Perkin
Trans. 1 1996, 2879–2884. (b) Yang, M.; Wang, X.; Li, H.; Livant, P.
J. Org. Chem. 2001, 66, 6729–6733. (c) Bachmann, S.; Fielenbach, D.;
Jørgensen, K. A. Org. Biomol. Chem. 2004, 2, 3044–3049. (d) Baumann,
L. K.; Mbuvi, H. M.; Du, G.; Woo, L. K. Organometallics 2007, 26,
3995–4002. (e) Morilla, M. E.; Diaz-Requejo, M. M.; Belderrain, T. R.;
(1) Doyle, M. P.; McKervey, M. A.; Te, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From Cyclopro-
panes to Ylides; John Wiley & Sons, Inc.: New York, NY, 1998.
(2) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103,
2861–2903. (b) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem.
Rev. 2010, 110, 704–724.
(3) (a) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57,
1–326. (b) Maas, G. Chem. Soc. Rev. 2004, 33, 183–190.
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T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091–1160.
(5) For a recent review, see: Zhang, Z.; Wang, J. Tetrahedron 2008,
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r
10.1021/ol3020754
Published on Web 08/24/2012
2012 American Chemical Society

catalyst. Herein, we disclose that free donor/acceptor
carbenes, derived from the thermal decomposition of
aryldiazoacetates, can readily undergo NꢀH insertion
reactions with a wide range of amines to directly generate
R-arylamino esters in good yield.
Scheme 2. Thermal NꢀH Insertions of Primary and Secondary
Amines
We initiated our evaluation of this reaction by inducing
the thermal decomposition of methyl phenyldiazoacetate
(1a) in the presence of 2,2-dimethoxyethylamine (Scheme 1,
entry 1). The reaction was conducted by slow addition of
a solution of the diazo compound to a refluxing solution of
the amine in trifluorotoluene.9 Under these conditions the
desired NꢀH insertion product, 2a, was isolated in 80%
yield. We next conducted a series of experiments to eval-
uate the scope of the diazo component in this transfor-
mation. As shown in Scheme 1, a wide array of aryl
diazoacetates, including those with electron-rich and -poor
substituents, can function as suitable carbene precursors to
provide the desired R-arylamino esters in good yield
(68ꢀ87% yield).
Scheme 1. Thermal NꢀH Insertions of Aryl Diazoacetates
As shown in Scheme 2, primary amines with quaternary,
secondary, and primary R-positions readily undergo NꢀH
insertion in moderate to good yields (3aꢀf, 61ꢀ84%
yield). In all cases selective monoinsertion at the amine
is observed. We attribute this selectivity to both steric
and electronic deactivation of the secondary amine prod-
ucts 3aꢀf, which would decrease the rate of a subsequent
NꢀH insertion. In addition, secondary amines are viable
substrates and afford the desired tertiary amine products
(3gꢀl, 54ꢀ78% yield). The mild reaction conditions of this
transformation are compatible with a variety of functional
groups including electron-rich aromatic rings, ethers, acet-
als, and alkynes (Scheme 2). Interestingly, the use of an
allylic amine provides only the NꢀH insertion product 3g;
the possible byproducts derived from cyclopropanation or
a (2,3)-ylide rearrangement are not formed. Furthermore,
in the presence of a free hydroxyl group, insertion is
observed exclusively at nitrogen, suggesting that this sys-
tem is highly selective for NꢀH insertion over OꢀH
insertion (Scheme 2, entry 3l).
a A dry round-bottom flask was charged with amine (2.0ꢀ5.0 equiv)
and dry trifluorotoluene. The reaction mixture was heated to reflux, and
the diazo compound (1.0 equiv) was added by syringe pump over a
period of 3 h and then stirred at reflux for an additional 9 h.
Aromatic and heteroaromatic amines are important
motifs in bioactive compounds. Consequently, the reactiv-
ity of aromatic and heteroaromatic amines in the NꢀH
insertion reaction was also evaluated. As highlighted in
Scheme 3, a range of anilines with both electron-rich and -
poor substituents readily undergo NꢀH insertion to pro-
vide the corresponding R-arylamino ester products in
moderate to good yields (4aꢀd, 54ꢀ75% yield). The reac-
tion also was found to be compatible with heteroarylamines
Having established effective conditions for the thermal
NꢀH insertion reaction we proceeded to explore the scope
of the amine substrate. Thus, the reactivity of aryldiazo-
acetate 1b with a variety of aliphatic amines was examined.
(9) Trifluorotoluene was utilized as the solvent because of its high
boiling point and inertness towards reactive carbene intermediates.
Org. Lett., Vol. 14, No. 17, 2012
4627

and provided a variety of substituted pyridines and iso-
xazole products in good yields (Scheme 3, entries 4eꢀi,
58ꢀ96% yield). More hindered substrates with ortho-
substitution can be utilized in this reaction, although the
isolated yields are slightly diminished (Scheme 3, entries
4cꢀe, 54ꢀ64% yield).
of nitrogen gas from 1a through TS-I, which was found to
have a free energy activation barrier of 30.3 kcal/mol.
Whensolvent effects from trifluorotoluene were included11
the barrier was lowered to 28.3 kcal/mol. Our previous
kinetic studies on thermal reactions with 1a showed a first-
order decomposition with k = 1.92 hꢀ1.6 Using Transition
State Theory, this corresponds to an experimental free
energy activation barrier of 27.7 kcal/mol, which is very
good agreement between theory and experiment (see Sup-
porting Information for details). Although the triplet
carbene I-T was more stable than the singlet I-S by
approximately 2.9 kcal/mol, a CurtinꢀHammett situation
can arise because addition of methylamine to the singlet
carbene is enthalpically barrierless.12 This addition gener-
ates the ylide II which is stable by ꢀ20.3 kcal/mol. Rapid
intramolecular proton transfer through a five-membered
transitionstate (TS-II) generates enolIII (ꢀ24.0kcal/mol),
which can rapidly tautomerize to the R-amino ester prod-
uct IV. The NꢀH insertion reaction is found to be highly
exergonic (ꢀ43.9 kcal/mol).13
Scheme 3. Thermal NꢀH Insertions with Aryl- and
Heteroarylamines
In contrast to other substrates, the reaction of the 1,1-
dimethylbenzylamine 5 with aryldiazoacetate 1b gave an
unanticipated result (Scheme 4a). While the desired NꢀH
insertion product 6 was obtained in 66% yield, a second
product, the highly congested R-quaternary amino ester 7,
was also obtained in 16% yield. This unexpected product
appears to arise via a formal [1,2]-alkyl shift of an aza-ylide
intermediate in a Stevens-type rearrangement process. We
anticipate that both products, 6 and 7, arise via formation
ofaninitial aza-ylide species. A subsequent proton transfer
would provide the NꢀH insertion product (Figure 1).
However, this zwitterionic intermediate can also fragment
to provide a radical pair with two stabilized carbon-
centered radicals. Rapid recombination would provide
the formal [1,2]-alkyl shift product. We reason that the
augmented stability of the tertiary benzylic radical facil-
itates this transformation and dictates the selectivity of the
[1,2]-alkyl shift.
The success of the thermal carbene reactions disclosed
herein and in previous work6 prompted us to conduct a
computational study to analyze the mechanistic details of
the transformation. These studies were performed at the
B3LYP/6-311þG(d,p) level of theory10 with the reaction
between 1a and methylamine as a model system. As shown
in Figure 1 the reaction initiates with the thermal extrusion
The use of carbenes to access ammonium ylides with
a subsequent [1,2]-alkyl shift was first observed by Stevens
in 1952 while heating 9-diazofluorene in the presence of
(10) (a) Frisch, M. J.; et al. Gaussian 09. See Supporting Information
for full reference. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789. (d) For
a computational study of these particular types of free carbenes, see:
Geise, C. M.; Wang, Y. H.; Mykhaylova, O.; Frink, B. T.; Toscano, J. P.;
Hadad, C. M. J. Org. Chem. 2002, 67, 3079–3088.
(11) Using the default IEFPCM model in Gaussian 09. See Support-
ing Information for details.
(12) The higher reactivity of singlet carbenes is well-known. See:
(a) Woodworth, R. C.; Skell, P. S. J. Am. Chem. Soc. 1959, 81, 3383–
3386. (b) Keating, A. E.; Merrigan, S. R.; Singleton, D. A.; Houk, K. N.
J. Am. Chem. Soc. 1999, 121, 3933–3938. For a discussion of Curtinꢀ
Hammett kinetics, see: (c) Seeman, J. I. Chem. Rev. 1983, 83, 83–134.
(13) The observed mechanism is consistent with other computational
studies on carbene XꢀH insertions: (a) Ramasami, K.; Ramalingam,
M.; Venuvanalingam, P. Int. J. Quantum Chem. 2010, 110, 1310–1316.
(b) Ramasami, K.; Ramalingam, M.; Venuvanalingam, P. J. Theor.
Comput. Chem. 2009, 8, 1143–1153.
(14) Stevens, T. S.; Bamford, W. R. J. Chem. Soc. 1952, 4675–4678.
(15) (a) For a review, see: Vanecko, J. A.; Wan, H.; West, F. G.
Tetrahedron 2006, 62, 1043–1062. (b) For an example of a Stevens
rearrangement of a tertiary amines, see: West, F. G.; Glaeske, B. N.;
Naidu, B. N. Synthesis 1993, 10, 977–980.
Figure 1. Gas-phase free-energy reaction coordinate diagram
for gas-phase reaction between 1a and methylamine at the
B3LYP/6-311þG(d,p) level of theory.
4628
Org. Lett., Vol. 14, No. 17, 2012

N,N-dimethylbenzylamine.14 Despite this early example,
only metal-bound (rhodium and copper) carbenes have
found synthetic utility in the Stevens rearrangement.15,16
Recently, Lacour and co-workers demonstrated the regio-
thermal Stevens rearrangement of free donor/acceptor
carbenes with tertiary amines. As anticipated, heating
diazo 1b in the presence of N,N-dimethyl benzylamine 8
provided the [1,2]-rearrangement product 9 in a 53%
isolated yield (Scheme 4b). We further found that we could
achieve ring expansion of an extremely complex alkaloid,
brucine (10), with diazo 1b under thermal conditions,
providing the [1,2]-rearrangement product in modest yield
(Scheme 4c). The regiochemistry of the ring expansion was
established by 2D-NMR analysis, and the stereochemistry
at the newly formed quaternary stereogenic center was
tentatively assigned by NOE correlations (see Supporting
Information).18 Thisreaction occursselectively atthe more
electron-rich amine in the presence of multiple reactive
functional groups including an alkene and electron-rich
aromatic ring. In accordance with our proposed mechan-
ism, both substrates 8 and 10 undergo a selective [1,2]-alkyl
shift at the substituent that is more capable of stabilizing a
radical intermediate.
€
selective ring expansion of Troger bases with donor/
acceptor carbenoids using Rh2(OAc)4 as a catalyst.17
Scheme 4. Thermal Stevens-like Rearrangement of Benzylic and
Allylic Amines
The studies presented herein demonstrate that the ther-
mal NꢀH insertion of aryldiazoacetates in the absence of a
metal catalyst can be a high-yielding process. A variety of
aliphatic, aromatic, and heteroaromatic amines are com-
patible with these reaction conditions and give rise to a
range of R-arylamino esters. Mechanistic DFT studies
were in very good agreement with experimental kinetics
and show that the reaction proceeds through ylide forma-
tion with the singlet carbene intermediate. Further studies
to utilize the highly selective aza-ylide formation of free
donor/acceptor carbenes are underway.
Acknowledgment. Financial support for this work by
the National Science Foundation is gratefully acknowl-
edged (CHE 1213246). We also wish to thank Prof. Jochen
Autschbach (University at Buffalo, State University of
New York) for providing computational resources and the
University at Buffalo’s Center for Computational Re-
search for technical support.
Formation of the Stevens rearrangement product 7 with
a primary amine substrate (5) prompted us to evaluate the
(16) The formation of aza-ylide intermediates via the photochemical
decomposition of diazo compounds in the presence of tertiary amines
has been previously described: Tomioka, H.; Suzuki, K. Tetrahedron
Lett. 1989, 30, 6353–6356.
ꢀ ꢀ
(17) Sharma, A.; Guenee, L.; Naubron, J.-V.; Lacour, J. Angew.
Supporting Information Available. Experimental pro-
cedures, characterization and spectral data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Chem., Int. Ed. 2011, 50, 3677–3680.
(18) Approximatly 10% of a mixture of two other regioisomeric or
stereoisomeric products was also isolated from this reaction. However,
we could not separate these compounds chromatographically and,
therefore, could not confidently assign their structure. Attempts to
obtain an X-ray quality crystal of 11 to support the structural assign-
ment were unsucesseful.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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