Urea activation of nitrimines: A mild, metal-free approach to sterically hindered enamines

Article abstract of DOI:10.1021/ol402310b

Nitrimines have been identified as impressive starting points for the syntheses of otherwise inaccessible, sterically encumbered enamines. The activation of nitrimines with urea catalysts for reaction with a variety of amines enables the formation of high

Full text of DOI:10.1021/ol402310b

ORGANIC
LETTERS
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Vol. XX, No. XX
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Urea Activation of Nitrimines: A Mild,
Metal-Free Approach to Sterically
Hindered Enamines
David M. Nickerson, Veronica V. Angeles, and Anita E. Mattson*
The Ohio State University, Department of Chemistry and Biochemistry,
100 West 18th Avenue, Columbus, Ohio 43210, United States
mattson@chemistry.ohio-state.edu
Received August 13, 2013
ABSTRACT
Nitrimines have been identified as impressive starting points for the syntheses of otherwise inaccessible, sterically encumbered enamines. The
activation of nitrimines with urea catalysts for reaction with a variety of amines enables the formation of highly substituted enamines in high yield.
The reactions benefit from mild, metal-free conditions, high functional group tolerance, and straightforward scale up.
Enamines have long been a staple in the organic che-
mist’s toolbox accomplishing a wide variety of synthetic
transformations.1 For example, through asymmetric hy-
drogenation, enamines provide access to highly substi-
tuted, enantioenriched amines, key components in a
number of active pharmaceutical ingredients.2 Many
simple enamines are accessible via traditional Lewis or
Brønsted acid promoted condensation reactions of amines
with carbonyl compounds; however, these methods often
suffer from harsh reaction conditions and fail with steri-
cally hindered carbonyls or electronically poor amines
(Scheme 1, eq 1).3
To address the limits of conventional methods, chemists
have recently developed organometallic processes as
alternatives for certain enamine preparations (Scheme 1,
eq 2).2b,4 Still, transition metal catalyzed enamine cross-
couplings are limited by low functional group tolerance
and failure in the presence of hindered substrates.4a Mild,
reliable, and general conditions to construct highly func-
tionalized, sterically encumbered enamines remain an un-
met demand.
(4) (a) Willis, M. C.; Brace, G. N. Tetrahedron Lett. 2002, 41, 9085.
(b) Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Chem.
Commun. 2002, 20, 2362.
(5) (a) Pihko, P. Hydrogen Bonding in Organic Synthesis; Wiley-VCH:
Weinheim, 2009. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713. (c) Akiyama, T. Chem. Rev. 2007, 107, 5744. (d) Berkessel, A.;
(1) (a) Enamines: Synthesis, Structure, and Reactions; Cook, G. A.,
Ed.; Marcel Dekker: New York, 1988. (b) Whitesell, J. K. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Oxford: Pergamon, 1991.
(c) The Chemistry of Enamines, Rappaport, Z., Ed.; Wiley: New York,
1994.
(2) For applications to pharmaceuticals, see: (a) Hansen, K. B.;
Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.; Krska, S.;
Rosner, T.; Simmons, B.; Balsells, J.; Ikemoto, N.; Sun, Y.; Spindler, F.;
Malan, C.; Grabowski, E. J.; Armstrong, J. D., III. J. Am. Chem. Soc.
2009, 131, 8798. (b) Wallace, D.; Campos, K.; Shultz, C. S.; Klapars, A.;
Zewge, D.; Crump, B.; Phenix, B.; McWilliams, J. C.; Krska, S.; Sun, K.;
Chen, C.; Spindler, F. Org. Process Res. Dev. 2009, 13, 84. (c) Kreis,
L. M.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3436. (d) For
examples of asymmetric catalytic reduction of enamines, see: (e) Lee,
N. E.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 5985. (f) Malkov,
A. V.; Vrankova, K.; Stoncius, S.; Kocovsky, P. J. Org. Chem. 2009, 74,
5839.
€
Groger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005.
(6) For recent reviews on (thio)urea catalysis, see: (a) Takemoto, Y.
Chem. Pharm. Bull. 2010, 58, 593–601. (b) Zhang, Z.; Schreiner, P.
Chem. Soc. Rev. 2009, 38, 1187–1198. (c) Connon, S.; Kavanagh, S.;
Piccinini, A. Org. Biomol. Chem. 2008, 6, 1339–1343. (d) Takemoto, Y.
Org. Biomol. Chem. 2005, 3, 4299. For recent examples, see: (e) Lin, S.;
Jacobsen, E. N. Nat. Chem. 2012, 4, 817. (f) Kimmel, K. L.; Weaver,
J. D.; Ellman, J. A. Chem. Sci. 2012, 3, 121. (g) So, S. S.; Auvil, T. J.;
Garza, V. J.; Mattson, A. E. Org. Lett. 2012, 14, 444. (h) So, S. S.;
Mattson, A. E. J. Am. Chem. Soc. 2012, 134, 8798. (i) Nickerson, D. M.;
Mattson, A. E. Chem.;Eur. J. 2012, 18, 8310. (j) Burns, N. Z.; Witten,
M. R.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 14578. (k) Li, X.; Xi,
Z.; Luo, S.; Cheng, J. Adv. Synth. Catal. 2010, 352, 1097. (l) Reisman,
S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198.
(m) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
(n) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999.
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(3) (a) Hickmott, P. W. Tetrahedron 1982, 38, 1975. (b) Carlson, R.;
Nilsson, A. Acta Chem. Scand. B 1984, 38, 49.
r
10.1021/ol402310b
XXXX American Chemical Society

Organocatalytic methods offer mild, metal-free plat-
forms to accomplish synthetic transformations.5 We are
particularly attracted to the potential of urea catalysis6 and
hypothesized that the urea-nitro group interaction7 may
offer a solution for direct and mild access to sterically hin-
dered enamines (Scheme 1, eq 3). Specifically, we envi-
sioned that urea activation of N-nitroenamines would
enable the direct formation of sterically encumbered en-
amines that are inaccessible with conventional methods.
reactive nitrimine 1a.9 Nitrimines are known to react with
highly active secondary aliphatic amines such as pyrroli-
dine, piperidine, and morpholine;10 however, to the best of
our knowledge, no reports of their coupling with less
reactive nucleophiles such as aromatic amines or sterically
hindered amines have been reported. We were pleased to
find that the coupling of pinacolone derived nitrimine 1a
with indoline in the presence of a urea catalyst was almost
identical to that of the nitroenamine.
Scheme 1. Approaches toward the Synthesis of Enamines
Scheme 2. Urea-Catalyzed Enamine Synthesis
We were delighted to find initial testing supported our
hypothesis: the activation of pinacoline-derived N-nitroe-
namine for reaction with indoline under the influence of
10 mol % of urea 3a gave rise to the desired enamine pro-
duct in excellent yield (95%) (Scheme 2, eq 4). Our new
method was found to be superior to known BuchwaldÀ
Hartwig conditions4a for construction of the sameenamine
(14%) (Scheme 2, eq 5). While the mechanism of action
remains uncertain, we propose initial urea coordination to
the N-nitroenamine yields an activated species capable of
undergoing facile reaction with the nucleophile present.
The absence of nitramide in the crude product along with
the observed formation of gas suggests release of N2O and
H2O during the reaction.
To benchmark the utility and significance of urea cata-
lysis on N-nitrimine to enamine conversion, we performed
a rate study comparing urea 3a and thiourea 3b catalysts
and found that the urea catalyst promoted the reaction
three times faster than the thiourea (Scheme 2, eq 6). Im-
portantly, the reaction did not proceed without a hydrogen
bond donor catalyst.
After demonstrating the feasibility of mild, urea-cata-
lyzed cross-coupling approaches to sterically hindered
enamine formation, our attention turned to comparing
our methodology to the more conventional Lewis acid,
Brønsted acid, and organometallic approaches to synthe-
size enamines (Scheme 3). More specifically, we set out to
determine if urea catalyst 3a would enable enamine for-
mation from less reactive aminesthatwere notamenableto
Since N-nitroenamines are known to equilibrate slowly
to their more stable nitrimine tautomer,8 we were curious
to try our urea catalyzed coupling conditions with the less
(7) For pioneering work on ureas in molecular recognition, see: (a)
Etter, M. C.; Urbanczyk-Lipkowska, Z.; Zia-Ebrahimi, M.; Panunto,
T. W. J. Am. Chem. Soc. 1990, 112, 8415. For reactions plausibly
proceeding through urea-nitro group interactions, see: (b) Robak,
M, T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129,
15110. (c) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett.
2005, 7, 1967. (d) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X. N.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (e) Herrera, R. P.;
Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44,
6576. (f) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed.
2005, 44, 4032.
(9) For a review on N-nitrimines, see: (a) Li, J. J. Sci. Synth. 2004, 27,
825. For examples of reactions of N-nitrimines, see: (b) Wuest, H.;
Buchi, G. J. Org. Chem. 1979, 23, 4116. (c) Russo, J. M.; Guziec, F. S.
Synthesis 1984, 6, 479. (d) Trost, B. M.; Marrs, C. M. J. Am. Chem. Soc.
1993, 115, 6636. (e) Ranise, A.; Bondavelli, F.; Schenone, P.; Mugnoli,
A.; Pani, M. J. Chem. Soc., Perkin Trans. 1 1990, 11, 3053. (f) Lalk, M.;
Peseke, K.; Reinke, H. J. Prakt. Chem. 1999, 341, 552.
(8) Hantzsch, A.; Dollfuss, F. E. Ber. Dtsch. Chem. Ges. 1902, 35,
226.
(10) Bondavalli, F.; Schenone, P.; Ranise, A. Synthesis 1979, 10, 830.
B
Org. Lett., Vol. XX, No. XX, XXXX

traditional conditions. Focusing on the syntheses of steri-
cally encumbered enamines 2b, 2c, and 2d, we were pleased
to find camphor-derived nitrimine 1b coupled in excellent
yield with indoline under the influence of 10 mol % of 3a to
yield 95% of 2b. Less electron-rich indolines also coupled
well in the process: the incorporation of 5-bromo indoline
afforded product 2c in high yield (75%) while 6-nitroindo-
line gave rise to 2d in 52% yield. Importantly, all of our
attempts to isolate the same sterically encumbered enam-
ines 2bÀ2d were unsuccessful under traditional Lewis
or Brønsted acid catalyzed conditions. Only product 2b,
albiet in low yield (15%), could be prepared under con-
ventional, previously optimized BuchwaldÀHartwig type
reaction conditions.4a No products were observed under
identical palladium-catalyzed conditions with the 5-bromo
or 6-nitro indoline derivatives.
Scheme 4. Substrate Scope for the Formation of Hindered
Enamines Using Organocatalytic Couplinga
Scheme 3. Urea-Catalyzed Sterically Hindered Enamine
Formation Compared to Conventional Approaches
To further probe the limits of the reaction, a variety of
hindered nitrimines and amines were explored (Scheme 4).
Asexpected, the reactionwas rapidand nearly quantitative
with unhindered aliphatic secondary amines 2e and 2f
(98% and 94% yield respectively). Impressively, even di-
benzylamine was successful with our method and afforded
a 93% yield of 2g; this excellent yield is in stark contrast to
the reported <5% yield using an optimized BuchwaldÀ
Hartwig approach with a similarly substituted substrate.4a
Next, the tolerance of the reaction with respect to steric
hindrance was explored with a series of substituted tetra-
lone nitrimines and indolines. 6-Methoxy-2-methyltetra-
lone-derived nitrimine easily reacted with indoline to
afford 2h in excellent yield. The reaction was also easily
able to accommodate substituents on the indoline as
2-methylindoline gave rise to 2i in quantitative yield. Even
the nitrimine derived from 6-methoxy-2-methyltetralone
coupled with 2-methylindoline to afford 2j in moderate
yield (51%) as a mixture of two atropisomers. This em-
phasizes the point that this methodology can be used to
a See Supporting Information for detailed experimental information
and also for additional enamines not shown. b Yield determined by 1H
NMR spectroscopy based on an internal standard. Isolated yield.
Pyridine (1 equiv) added to promote solubility. Yield based on
NaBH(OAc)3 reduction and subsequent isolation of the amine. f Mixture
of two atropisomers. g Only the thermodynamic enamine was observed.
c
d
e
form extremely hindered enamines, even to the point of
restricted NÀC bond rotation.
Bromo-substituted substrates, which are incompatible
with palladium cross-coupling technologies, were also well
tolerated in the reaction. For example, 5-bromoindoline
readily coupled with the nitrimines derived from 1,1-
diphenylacetone and pinacolone to afford the correspond-
ing enamines 2o and 2p in 97% and 85% isolated yields,
respectively.
Org. Lett., Vol. XX, No. XX, XXXX
C

N-Methyl anilines also proved to be valuable substrates in
the organocatalytic cross-coupling reaction. For example
4-methoxy-N-methylaniline gave rise to 2q and 2s in high
yields. An 84% yield of 2r was isolated with the coupling of
N-methyl aniline and 6-methoxytetralone-derived nitrimine.
the coupling of nitrimine 1c and 1 equiv of piperidine gave
rise to enamine 2t in 98% yield in solvent-free conditions
requiring only a filtration to access the pure enamine
product. Subsequent reduction gave the amine 4 in ex-
cellent yield. The efficiency of the organocatalytic metho-
dologyisincontrast to the traditional Brønstedacid, Lewis
acid, and cross-coupling enamine procedures which typi-
cally require excess amine thereby necessitating further
purification steps.
Scheme 5. Scale-up and Reduction
In summary, sterically encumbered enamines are readily
accessible via the coupling of a wide array of amines and
nitrimines under the influence of urea catalysis. This mild,
metal-freeapproach toenamines is tolerant of a wide range
of functional groups and easy to scale up. Ongoing efforts
in our laboratory are dedicated toward uncovering the
potential of nitrimines as handles for organocatalytic
cross-coupling reactions.
Acknowledgment. Support for this research has been
provided by the OSU Department of Chemistry and
Biochemistry. V.V.A. is supported by an NSF graduate
research fellowship. Dr. Judith Gallucci (OSU) is thanked
for expert crsytallographic analysis.
As demonstrated in the formation of enamines 2e, 2f,
and 2g, the urea-catalyzed cross-coupling of aliphatic
amines and nitrimines is highly efficient, producing high
yields with few byproducts in solvent-free conditions. We
found the reaction to be suitable for the preparation of
enamines on a large scale without the need for significant
purification (Scheme 5). For example, on a gram scale,
Supporting Information Available. Experimental pro-
cedures and spectral data (PDF) and crystallographic
data (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX