Chemo- and Stereoselective Transition-Metal-Free Amination of Amides with Azides

Article abstract of DOI:10.1021/jacs.6b04061

The synthesis of α-amino carbonyl/carboxyl compounds is a contemporary challenge in organic synthesis. Herein, we present a stereoselective α-amination of amides employing simple azides that proceeds under mild conditions with release of nitrogen gas. The

Full text of DOI:10.1021/jacs.6b04061

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Chemo- and Stereoselective Transition-Metal-Free Amination of
Amides with Azides
Veronica Tona,† Aurelien de la Torre,†,§ Mohan Padmanaban, Stefan Ruider, Leticia Gonzalez,‡
,§
†
†,‡
́
́
,
†
and Nuno Maulide*
†
Faculty of Chemistry, Institute of Organic Chemistry, University of Vienna, Wah
̈
ringer Strasse 38, 1090 Vienna, Austria
Faculty of Chemistry, Institute of Theoretical Chemistry, University of Vienna, Wahringer Strasse 17, 1090 Vienna, Austria
S Supporting Information
‡
̈
*
Scheme 1. Strategies for the α-Amination of Carbonyl
Compounds
ABSTRACT: The synthesis of α-amino carbonyl/carbox-
yl compounds is a contemporary challenge in organic
synthesis. Herein, we present a stereoselective α-amination
of amides employing simple azides that proceeds under
mild conditions with release of nitrogen gas. The amide is
used as the limiting reagent, and through simple variation
of the azide pattern, various differently substituted
aminated products can be obtained. The reaction is fully
chemoselective for amides even in the presence of esters or
ketones and lends itself to preparation of optically
enriched products.
s one of nature’s key building blocks, α-amino acids form a
recurrent motif in bioactive natural products. In particular,
A
α-amino acids and peptides are becoming an increasing subset
1
of commercialized drugs. In this context, non-natural α-amino
acids are especially interesting as their incorporation in peptides
2
can modify properties to a large extent, and thus the synthesis
of α-amino carbonyl/carboxyl compounds has attracted
3
considerable attention from synthetic chemists.
Direct α-amination is perhaps the most logical and flexible
strategy to access α-amino carbonyl derivatives. Classical
approaches are summarized in Scheme 1, and electrophilic
4
,5
amination features prominently among them. Due to the
need for an electrophilic source of nitrogen, most of these
methods actually lead to α-hydrazinyl or α-oxy-amino products
that need to be further modified to get to the biologically
relevant α-amino compounds. For instance, Ohshima et al.
recently presented an elegant copper-catalyzed amination of
carboxylic acid derivatives with a preformed iminoiodinane
which requires drybox manipulation and delivers tosyl-
conditions led to the smooth formation of 3aa in 52% isolated
yield. Importantly, single-crystal X-ray analysis confirmed the
anticipated connectivity of 3aa (Scheme 2).
With this encouraging preliminary result, we screened
different reaction conditions (employing substrate 1b), and
key observations are compiled in Table 1. The use of 2-
fluoropyridine was found to give a slightly increased yield
11
6
protected amines that are not simple to deprotect. Another
(
Table 1, entry 2), while simple pyridine did not afford the
approach allows to simply couple an amine with a carbonyl
under oxidative conditions, though only disubstituted amines
7
Scheme 2. Preliminary Study
can be employed (Scheme 1b).
Our group has recently exploited metal-free amide activation
as a powerful chemoselective strategy for the functionalization
8
,9
of amides. Herein we report a chemo- and stereoselective α-
amination of amides employing simple azides, known as good
1
0
nucleophiles, that proceeds under mild conditions (Scheme
1
c) with release of nitrogen gas.
At the outset, we decided to study the reaction of the amide
a with the azide 2a using amide activation conditions
1
Received: April 20, 2016
8
b
previously developed by our group. Pleasingly, these
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b04061
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
,
a b
Table 1. Optimization of the Reaction Conditions
Scheme 3. Substrate Scope of the Amination of Amides with
Azides
equiv
of 2a
equiv
of 4
equiv
yield
(%)
entry
of Tf O
X
quench
2
1
2
3
4
5
6
7
2.0
2.0
1.0
2.0
2.0
2.0
2.0
2.0
3.0
3.0
3.0
3.0
3.0
2.0
2.0
2.0
2.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
I
56
61
0
F
NaOH-NaCl
H
OMe
30
74
80
79
85
F
F
F
F
NaHCO3
NaHCO3
c
8
(1 h)
a
Reaction conditions: A mixture of amide 1b (0.3 mmol, 1 equiv) and
base in DCM (1 mL) was treated with Tf O at 0 °C. The mixture was
2
stirred at 0 °C for 15 min, then the azide 2a was added, and the
reaction was allowed to warm to room temperature for 1 h prior to
b
quenching. Yield determined by NMR analysis with mesitylene as the
c
internal standard. Reaction time of 30 min prior to quenching.
desired product (entry 3). Significantly, the quenching method
had a noteworthy impact on the process. Quenching the
reaction mixture with a saturated solution of NaHCO3
significantly improved the yield (entries 5−7), while reducing
the reaction time to 30 min finally gave the best results (entry
1
1
8).
With these optimized conditions, we decided to evaluate the
scope of the reaction with particular emphasis on functional
group tolerance. As shown in Scheme 3, various aliphatic
substituents were allowed on the amide component, giving
moderate to excellent yields of products (Scheme 3, 3ba−3ga).
Unsaturations were also tolerated (3ha) as well as aromatic
rings on both partners (3ia−3ja). Remarkably, this metal-free
reaction was chemoselective for the amide moiety in the
presence of an ester group (3ma), an alkyl nitrile (3la), or even
a naked methyl ketone (3ka). Similarly, the presence of halides
(
3bd−3be), esters (3bg), or cyano groups (3bf) on the azide
did not significantly affect the yield. Of added interest is also
the formation of benzyl-protected amines using benzyl azide
(
3bb).
to preparation of both classes of compounds depicted in
Scheme 5.
We then turned our attention to the scope on differently
substituted, N-functionalized amides (Scheme 4). To our
delight, both cyclic and acyclic amides gave good results, even
when the nitrogen center carried hindered isopropyl- or benzyl
moieties (3pa−3qa). This showcases the general applicability
of this chemistry to various amide backbones, a synthetically
useful trait. Interestingly, Weinreb amides proved to be
unreactive under the reaction conditions, as well as lactams,
offering opportunities for chemoselectivity even among differ-
ent amide moieties.
Importantly, the method can be tuned to generate tertiary
amine products in at least two different manners (Scheme 5).
For instance, use of an amide substrate 1w carrying a remote
bromine substituent triggers a domino amination/cyclization to
form a six-membered ring (Scheme 5). Alternatively, the use of
a halogenated azide 2h delivers α-pyrrolidine 3oh in very good
yield. The flexibility of these two approaches is yet another
feature of this simple amination procedure. Indeed, few
amination procedures available in the literature lend themselves
At this stage, we wished to interrogate the system with regard
to stereoselectivity. Submitting racemic compound 1x, bearing
a stereocenter β- to the amide carbonyl, to amination with azide
2a smoothly led to the desired product 3xa in 71% yield with
6:1 diastereoselectivity (anti:syn) (Scheme 6a).
On the other hand (Scheme 6b), the use of a chiral amide 1y
led to an excellent 15:1 diastereoselectivity upon amination
with azide 2a. The experiments in Scheme 6 delineate a highly
stereoselective amination procedure.
During our study of the functional group tolerance, one
specific experiment led to an unexpected result with
mechanistic implications. In the event, subjecting mixed adipic
acid ester/amide 4 to amination with azide 2a led to the
complex bicyclic product 5 (Scheme 7a), as elucidated by X-ray
11
analysis. Our interest piqued, we decided to quench the
reaction with NaBH instead of the usual aqueous workup
4
(Scheme 7b). This afforded the diamine 7, suggesting that the
12
intermediate prior to quench might be an azirinium species 6.
B
DOI: 10.1021/jacs.6b04061
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 4. Direct Amination of Different Amide Backbones
Scheme 7. Mechanistically Relevant Observations
Scheme 8. Computed Pathway for the Formation of Final
a
Hydrolysis Precursor, Amidinium D (ref 13)
Scheme 5. Tertiary Amine Formation
Scheme 6. Studies on Diastereoselectivity and Asymmetric
Induction
a
o
o
Free energies ΔG
and enthalpies ΔH
are given with respect
DCM
DCM
to A′.
forming N,N-ketene aminal C′. While the formation of C′ is
o
−1
endergonic (A′ ⇌ B ⇌ C′: ΔG
= +5.4 kcal mol ), the
DCM
reaction is ultimately driven by the subsequent highly exergonic
extrusion of dinitrogen (TS , C′ → D: ΔG
mol ). The extrusion of N is supported by a pivotal
o
= −63.2 kcal
C′‑D
DCM
−1
14
2
15
π−σ*N−N2 orbital overlap, and the formation of amidinium D
is a direct consequence of the stereoelectronic implications
thereof. Iminium D also represents the final, resting
intermediate prior to aqueous workup. The latter is a facile
Intrigued by these observations, we undertook density
functional theory (DFT) calculations to investigate the
11
two-step hydrolytic opening (D → E). These computational
results neatly rationalize the observations of Scheme 7.
In summary, we developed a metal-free, direct α-amination
of amides with simple azides that proceeds under mild
conditions through electrophilic amide activation. This trans-
formation is highly chemoselective for amides even in the
presence of other carbonyl derivatives. Furthermore, it displays
high stereoselectivity in multiple contexts, including asymmetric
induction. Key mechanistic experiments and DFT analysis
pinpoint the intermediacy of a pivotal azirinium/amidinium
intermediate with remarkable synthetic versatility.
1
3
mechanism (Scheme 8). In agreement with our prior
8
b
studies, we commenced our DFT analysis with N,N-ketene
aminal A (Scheme 8), formation of which experimentally
precedes addition of azide 2b.
As reflected by the experiments above (in particular Scheme
b), the reaction pathway involves two distinct parts:
7
generation of amidinium D and hydrolytic liberation of
1
1
aminated amide E (Scheme 8). In particular, DFT
computations evidence the involvement of a discrete
keteniminium species B in the process (Scheme 8) which
undergoes nucleophilic addition from the azide component,
C
DOI: 10.1021/jacs.6b04061
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
D.; Dai, Y.-C.; Zhang, H.; Yan, L.-Q.; Sheng, E.-H.; Wei, Y.; Mu, X.-L.;
Huang, K.-W. Org. Biomol. Chem. 2014, 12, 5509.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b04061.
■
*
S
(
8) (a) Peng, B.; Geerdink, D.; Fares
Soc. 2013, 135, 14968. (b) Peng, B.; Geerdink, D.; Fares
N. Angew. Chem., Int. Ed. 2014, 53, 5462.
̀
, C.; Maulide, N. J. Am. Chem.
̀
, C.; Maulide,
Crystallographic data (CIF)
Crystallographic data (CIF)
Experimental details and data; complete ref 13 (PDF)
(9) For elegant examples of metal-free amide activation, see: (a) Sisti,
N. J.; Fowler, F. W.; Grierson, D. S. Synlett 1991, 1991, 816.
(
b) Thomas, E. W. Synthesis 1993, 1993, 767. (c) Sisti, N. J.; Zeller, E.;
Grierson, D. S.; Fowler, F. W. J. Org. Chem. 1997, 62, 2093.
d) Charette, A. B.; Grenon, M. Tetrahedron Lett. 2000, 41, 1677.
(e) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 14254.
f) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007,
29, 10096. (g) Movassaghi, M.; Hill, M. D. Org. Lett. 2008, 10, 3485.
(
AUTHOR INFORMATION
Corresponding Author
nuno.maulide@univie.ac.at
Author Contributions
■
(
1
*
(
(
h) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18.
i) Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc. 2010,
§
These authors contributed equally.
1
32, 12817. (j) Bechara, W. S.; Pelletier, G.; Charette, A. B. Nat. Chem.
2012, 4, 228.
10) Kyba, E. P. In Azide and Nitrenes, Reactivity and Utility; Scriven,
E. F. V., Ed.; Academic Press Inc.: Orlando, FL, 1984, 2−34.
11) See SI for full crystallographic data, optimization of the reaction
Notes
(
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
conditions, a mechanistic proposal for the formation of 5 and 8 and
the DFT computations for the hydrolysis of amidinium D into 3bb.
(12) Rens, M.; Ghosez, L. Tetrahedron Lett. 1970, 43, 3765.
(13) All DFT computations were carried out at the SMD(DCM)
M06-2X/def2-QZVP//M06-2X/6-31+G* level of theory using the
Gaussian 09 software package. Frisch, M. J., et al. Gaussian 09,
Revision D.01; Gaussian, Inc.: Wallingford, CT, 2013. For the full
citation as well as the full computational details, see the SI.
Generous support of this research by the University of Vienna,
the ERC (StG 278872) and the FWF (P27194) is acknowl-
edged. Invaluable assistance by Ing. A. Roller (U. Vienna) with
crystallographic analysis and Dr. H. Kahlig (U. Vienna) with
̈
NMR analysis is acknowledged.
REFERENCES
■
(
14) The rather long incipient N−N bond (1.67 Å) and rather short
(
1) (a) Albericio, F.; Kruger, H. G. Future Med. Chem. 2012, 4, 1527.
b) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2016, 79, 629.
incipient C−N bond (1.39 Å) are indicative of a late transition state.
(
orbital interaction adds 15.1 kcal mol of stabilizing energy to TS
Notably, the very same orbital interaction already adds 4.1 kcal mol
(
15) As judged by NBO analysis, the pivotal π(CC)→σ*(N−N)
(
2) For general reviews, see: (a) Liu, C. C.; Schultz, P. G. Annu. Rev.
Biochem. 2010, 79, 413. (b) Young, T. S.; Schultz, P. G. J. Biol. Chem.
010, 285, 11039. (c) Maza, J. C.; Jacobs, T. H.; Uthappa, D. M.;
Young, D. D. Synlett 2016, 27, e6.
3) For general reviews, see: (a) Vogt, H.; Bras
Chem. 2007, 5, 406. (b) Perdih, A.; Sollner Dolenc, M. Curr. Org.
Chem. 2007, 11, 801. (c) Stevenazzi, A.; Marchini, M.; Sandrone, G.;
Vergani, B.; Lattanzio, M. Bioorg. Med. Chem. Lett. 2014, 24, 5349.
−1
.
C′‑D
−1
2
worth of stabilizing energy in preceding C′. The existence of a distinct
orbital in the HOMO of TS
provides further evidence for this crucial interaction. See the SI for the
illustration of the respective MO.
connecting all three atoms (CC-N)
C′‑D
(
̈
e, S. Org. Biomol.
(
́
4) For general reviews, see: (a) Guillena, G.; Ramon, D. J.
Tetrahedron: Asymmetry 2006, 17, 1465. (b) Marigo, M.; Jørgensen, K.
A. Chem. Commun. 2006, 2001. (c) Vilaivan, T.; Bhanthumnavin, W.
Molecules 2010, 15, 917. (d) Smith, A. M. R.; Hii, K. K. Chem. Rev.
2011, 111, 1637. (e) Zhou, F.; Lia, F.-M.; Yu, J.-S.; Zhou, J. Synthesis
2014, 46, 2983. (f) Maji, B.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2015,
88, 753.
(
5) For selected examples, see: (a) Regitz, M. Angew. Chem., Int. Ed.
Engl. 1967, 6, 733. (b) Weininger, S. J.; Kohen, S.; Mataka, S.; Koga,
G.; Anselme, J. P. J. Org. Chem. 1974, 39, 1591. (c) Miura, T.;
Morimoto, M.; Murakami, M. Org. Lett. 2012, 14, 5214. (d) Scarpino
Schietroma, D. M.; Monaco, M. R.; Bucalossi, V.; Walter, P. E.;
Gentili, P.; Bella, M. Org. Biomol. Chem. 2012, 10, 4692. (e) Fu, J.-Y.;
Wang, Q.-L.; Peng, L.; Gui, Y.-Y.; Wang, F.; Tian, F.; Xu, X.-Y.; Wang,
L.-X. Eur. J. Org. Chem. 2013, 2013, 2864. (f) Vita, M. V.; Waser, J.
Org. Lett. 2013, 15, 3246. (g) Shevchenko, G. A.; Pupo, G.; List, B.
Synlett 2015, 26, 1413. (h) Sandoval, D.; Samoshin, A. V.; Read de
̈
Alaniz, J. Org. Lett. 2015, 17, 4514. (i) Otvo
̈
́
s, S. B.; Szloszar, A.;
Mandity, I. M.; Fulop, F. Adv. Synth. Catal. 2015, 357, 3671. (j) Yang,
X.; Toste, F. D. J. Am. Chem. Soc. 2015, 137, 3205. (k) Miles, D. H.;
Guasch, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137, 7632.
́
̈
̈
(
5
l) Ramakrishna, I.; Sahoo, H.; Baidya, M. Chem. Commun. 2016,
2, 3215.
6) Tokumasu, K.; Yazaki, R.; Ohshima, T. J. Am. Chem. Soc. 2016,
38, 2664.
7) For selected recent examples, see: (a) Tian, J.-S.; Ng, K. W. J.;
Wong, J. R.; Loh, T.-P. Angew. Chem., Int. Ed. 2012, 51, 9105.
(
1
(
(
(
b) Lamani, M.; Prabhu, K. R. Chem. - Eur. J. 2012, 18, 14638.
c) Evans, R. W.; Zbieg, J. R.; Zhu, S.; Li, W.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2013, 135, 16074. (d) Jiang, Q.; Xu, B.; Zhao, A.; Jia,
J.; Liu, T.; Guo, C. J. Org. Chem. 2014, 79, 8750. (e) Jia, W.-G.; Li, D.-
D
DOI: 10.1021/jacs.6b04061
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