Intermolecular ritter-type C-H amination of unactivated sp3 carbons

Article abstract of DOI:10.1021/ja212020b

Intermolecular Ritter-type C-H amination of unactivated sp³ carbons has been developed. This new reaction proceeds under mild conditions using readily available reagents and an inexpensive source of nitrogen (acetonitrile). A broad scope of substrates can be aminated with this method since many functional groups are tolerated. This reaction also allows for the direct, innate C-H amination of a variety of hydrocarbons such as cyclohexane without the need of prefunctionalization or installation of a directing group.

Full text of DOI:10.1021/ja212020b

Communication
pubs.acs.org/JACS
Intermolecular Ritter-Type C−H Amination of Unactivated sp3
Carbons
Quentin Michaudel,† Damien Thevenet,† and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: Intermolecular Ritter-type C−H amination
of unactivated sp3 carbons has been developed. This new
reaction proceeds under mild conditions using readily
available reagents and an inexpensive source of nitrogen
(acetonitrile). A broad scope of substrates can be aminated
with this method since many functional groups are
tolerated. This reaction also allows for the direct, innate
C−H amination of a variety of hydrocarbons such as
cyclohexane without the need of prefunctionalization or
installation of a directing group.
he pioneering studies of Barton,1 Breslow,2 and Corey3 on
Tthe functionalization of C−H bonds in terpenoid
skeletons have contributed to the recent resurgence of interest
in this area. The direct conversion of C−H bonds to C−N
bonds is of particular importance in the area of alkaloid and
heterocycle synthesis.4 Historically, the venerable Hofmann−
Loffler−Freytag (HLF) reaction (Figure 1A)5 has served as a
̈
practical and reliable method in intramolecular settings. With
the notable exception of some radical-based functionalizations,6
state-of-the-art developments are dominated by nitrene
chemistry. Free nitrenes had been mostly generated in situ by
thermolysis or photolysis of azides, and those rather harsh
conditions often resulted in both low selectivities and safety
concerns.7 Thus, metallonitrenes, also prepared in situ from
azides,8 haloamines,9 N-arenesulfonyloxycarbamates,10 or imi-
noiodanes,11 are preferred for intramolecular Csp −H amina-
3
tion. However, due to the instability of metallonitrene
intermediates, early intermolecular versions of these reactions
generally have not led to high yields and have mostly allowed
for the functionalization of benzylic or allylic positions. To
circumvent these problems, elegant methods that enhance the
3
Figure 1. (A) Overview of Csp −H amination methods. (B) Reported
synthesis of dihydrooxazinium salt 2 derived from (−)-menthol (1) by
Banks et al. and synthesis of hydroxymenthol 3 by Chen et al. (C)
Reaction optimization with 2,6-dimethylheptan-4-ol (4) (1.0 equiv,
0.13 mmol). aNumber of equivalents. Yields determined by 1H NMR
b
c
reactivity of the metal catalyst have been reported by Muller,12a
with an internal standard. 16% of recovered starting material 4.
̈
Che,12b Du Bois,12c Dauban,12d Lebel,12e Per
́
ez,12f He,12g and
achieve the direct oxidation of (−)-menthol (1) to hydrox-
ymenthol 3, as well as the synthesis of more complex natural
products of the eudesmane family.14 In a continuing effort to
Warren.12h Metal-free organonitrenoid reagents have recently
been discovered by Bettinger13a and Ochiai,13b enabling the
functionalization of alkanes when used as solvent. Herein, we
use such logic for the synthesis of terpenoid alkaloids,15 a Csp −
3
3
report the invention of a copper-catalyzed intermolecular Csp −
H amination was pursued, inspired by the unexpected finding
by Banks et al. of the formation of dihydrooxazinium salt 2
derived from 1 (Figure 1B).16 Those authors serendipitously
found that treatment of 1 with 2.0 equiv of F-TEDA-BF4
(Selectfluor® reagent, Air Products and Chemicals, Inc.) in
H amination of both unactivated (non-benzylic and allylic)
hydrocarbons and functionally rich molecules (see Figure 1A).
This reaction proceeds at room temperature or 50 °C, is
operationally simple, and is scalable. Moreover, the substrate
can be used as the limiting reagent, and the catalyst and
nitrogen source are readily available.
In the course of a research program geared toward the
synthesis of terpenes, a guided C−H oxidation was invented to
Received: December 23, 2011
Published: January 24, 2012
© 2012 American Chemical Society
2547
dx.doi.org/10.1021/ja212020b | J. Am. Chem.Soc. 2012, 134, 2547−2550

Journal of the American Chemical Society
Communication
3
refluxing acetonitrile gave heterocycle 2 instead of the expected
oxidation product (−)-menthone. Although the relatively harsh
reaction conditions and the very limited substrate scope (three
substrates reported) were obvious limitations, those findings
represented a useful starting point for optimization (see
selected examples shown in Figure 1C and Supporting
Information (SI) for more details). For instance, the conditions
of Banks et al. afforded 7% yield of dihydrooxazine 5 from
alcohol 4 after workup with 10% aq NaOH to neutralize the
dihydrooxazinium salt (entry 1). Since a radical-based
mechanism for the conversion of 1 to 2 was originally put
forth, it was reasoned that a metal such as Cu(I) or Cu(II)
could facilitate C−H abstraction, based on the pioneering
studies of Kochi.17 After extensive screening, a few commercial
Cu salts were found to dramatically affect the rate of the
reaction. In particular, the use of 25 mol% of CuBr2 with 2.2
equiv of F-TEDA-BF4 led to 37% yield of 5 in only 1 h at room
temperature (entry 2). As a control, the same reaction was
performed without either copper or F-TEDA-BF4 and in both
cases failed to generate product (entries 3 and 4). At least 2.0
equiv of F-TEDA-BF4 is needed to obtain full conversion
(entry 5). Fortunately, the addition of 50 mol% of a Lewis acid
such as Zn(OTf)2 allowed for a notable improvement in yield
(entry 6). Next, solubility issues of F-TEDA-BF4 at room
temperature were addressed by using a related fluorinating
agent, F-TEDA-PF6, which can be prepared in quantitative
yield from F-TEDA-BF4 by a simple anion exchange with
NH4PF6, according to Ritter’s procedure.18 Using this reagent,
the reaction became homogeneous, and the yield notably
improved (entry 7). Interestingly, no other fluorinating agents
or common oxidants that were tested enabled the reaction to
proceed. Hydrolysis of the dihydrooxazine moiety to the
hydroxyacetamide product was performed at 80 °C with 1.0
equiv of NaOH in a 1:1 mixture of acetonitrile and water.
Although a one-pot process is feasible, an intermediate workup
allowed for the use of only 1.0 equiv of NaOH in the
subsequent hydrolysis, resulting in a slightly higher yield.
With this simple procedure in hand, a range of saturated
Table 1. Scope of the Csp −H Amination for Alcohol and
Ketone Substrates
a
b
c
Isolated yields. Hydrolysis (step 2) was not necessary. 8.0 equiv of
9 was used, and yield was based on 2.0 equiv of F-TEDA-PF6 as the
limiting reagent. Hydrolysis conditions were modified: Ba(OH)2 (5.0
3
alcohols were employed as limiting reagents (Table 1). Csp −H
d
amination of alcohols 1, 4, and 6 proceeded with isolated yields
ranging from 53 to 91%. Although Banks et al. specifically
reported that 7 is unreactive under their reaction conditions,16
the reaction presented herein led to amination of 7 in 42%
isolated yield. Moreover, this demonstrates that phenyl groups
are tolerated, since fluorination of the arene was not observed.
Interestingly, hydroxyl groups are not necessary for the
reaction, since ketones 8 and 9 were transformed in 1 step
into β-amidoketones in good yields. In the case of 9, a mixture
of mono- (16) and bisamidation (17) products was observed
when only 1.0 equiv of 9 was used. When an excess of 9 (8.0
equiv) was used, monoadduct 16 was the exclusive product
(89% yield). Lastly, this process can be used to functionalize
fairly complex substrates in good yield, as exemplified by 6-epi-
dihydrojunenol (10), which could provide an important
functional handle for the synthesis of related natural products.19
equiv), 2:1 dioxane:H2O, 110 °C, 3 h.
that 2.0 equiv of F-TEDA-PF6 is required to transform 1.0
equiv of substrate, in accord with our initial observations (see
Figure 1C). When the temperature of the reaction was
increased to 50 °C, hydrocarbons 20−26 were amidated with
isolated yields ranging from 21 to 62%, whereas the use of 5.0
equiv of substrate gave yields of up to 90%. Interestingly, the
regioselectivity observed on trans-decalin (25) suggests that
sterics can favor the reaction of methylene over methine
positions. In the case of cis-decalin (26), formation of 34 is
probably due to the fact that the tertiary C−H bonds in this
molecule are more accessible. Moreover, isomerization of the
cis-junction to a trans-junction for 34 is consistent with a radical
or a carbocation involved in the reaction mechanism.20
Although many functional groups are tolerated, free amines
and olefins are currently not compatible with the reaction
conditions.
3
Encouraged by these results, we attempted this Csp −H
amination reaction on hydrocarbon substrates bearing no
directing functional groups (Table 2). Gratifyingly, the
transformation of adamantane (19) proceeded at room
temperature in 90% yield with only 1.0 equiv of 19. The
reaction with 5.0 equiv of 19 and 1.0 equiv of F-TEDA-PF6
afforded only 0.44 equiv of acetamide 27 along with 4.2 equiv
of unreacted 19 (see Table 2), which supports the postulation
Removal of the protecting group on the amine (e.g.,
sulfonimidoyl, alkoxysulfonamide, or trifluoromethanesulfona-
mide) introduced at the C−H amination step in other methods
is often not trivial.12−14 In comparison, an acetamide can be
cleaved in many ways,21 and acid hydrolysis has shown to
2548
dx.doi.org/10.1021/ja212020b | J. Am. Chem.Soc. 2012, 134, 2547−2550

Journal of the American Chemical Society
Communication
3
37 required 3 steps for an overall yield of 34% from
(+)-pulegone, a starting material that is considerably more
expensive than (−)-menthol.22
A postulated mechanistic scenario that is consistent with
experimental data and literature precedent is summarized in
Figure 2A, with cyclohexane as a model. The role of the Lewis
Table 2. Scope of the Csp −H Amination for Hydrocarbon
Substrates
Figure 2. (A) Postulated mechanism for the reaction. (B) Kinetic
isotope effect with cyclohexane and cyclohexane-d12.
acid was neglected here, since it is not necessary for the
reaction to proceed; F-TEDA+ is shown without a counter-
anion, since the counterion is not believed to affect the
mechanism of the reaction. Copper(II) is likely to be oxidized
to copper(III) using F-TEDA+ through a single-electron
transfer (SET) mechanism, since it is known that N−F
fluorinating agents such as F-TEDA+ can react through a SET
pathway23 as a bystanding oxidant.24 In the present reaction,
the addition of 1.0 equiv of 2,2,6,6-tetramethylpiperidine N-
oxide (TEMPO) decreased the yield; 5.0 equiv inhibited the
C−H amination completely, which is consistent with a radical-
based mechanism.25 A premixed solution of CuBr2 and F-
TEDA-BF4 remains active but affords lower yields if the
substrate is added 1 h later (see SI). This suggests the
formation of a rather unstable copper(III) species, which has
been previously reported for the reaction of copper(II) with F-
TEDA-BF4.6c,26 The structure of a complex obtained by mixing
copper(II) trifluoroacetylacetonate and F-TEDA-BF4 has been
previously characterized by X-ray crystallography,27 but all
attempts to identify a similar structure starting with CuBr2
failed. However, crystalline H-TEDA-BF4 was isolated after
mixing F-TEDA-BF4 and CuBr2 in MeCN, and the resulting
salt was characterized by X-ray crystallography (see SI for
details), suggesting that hydrogen abstraction occurred on the
solvent. A similar abstraction is proposed to occur when an
electron-rich hydrocarbon substrate is present, with the
resulting carbocation trapped by a molecule of acetonitrile to
form a Ritter nitrilium intermediate. In the case of the alcohol
substrates (1, 4, 6, 7, or 10), this nitrilium is then trapped by
the hydroxyl moiety, leading to dihydrooxazine derivatives.
Other examples of Ritter-type reactions that occur via two
SETs have been reported.6b A significant isotope effect was
observed (kH/kD = 3.5, Figure 2B), consistent with the fact that
C−H bond cleavage takes place during the rate-limiting step of
the reaction.
a
b
Isolated yields (%) starting from 1.0 equiv of substrate. Isolated
yields (%) starting from 5.0 equiv of substrate and based on 2.0 equiv
c
of F-TEDA-PF6 as the limiting reagent. Reaction performed at rt.
d
e
Reaction performed at 95 °C. Inseparable mixture of three
f
unassigned regio- and stereoisomers at C1 and C2. Inseparable
mixture of two unassigned regio- and/or stereoisomers.
efficiently remove the acetamide moiety. For instance,
enantiopure aminomenthol 37 can be synthesized from
inexpensive (−)-menthol (1) in 3 steps and 87% yield (or in
2 steps and 73% yield) with only one chromatographic
separation (Scheme 1). The only other reported synthesis of
Scheme 1. Hydrolysis of Acetamide Products: Synthesis of
Aminomenthol 37
In summary, C−H amination of unactivated sp3 centers
(non-benzylic and allylic) using readily available reagents and
an inexpensive source of nitrogen has been disclosed. This
reaction proceeds under mild conditions for a broad scope of
2549
dx.doi.org/10.1021/ja212020b | J. Am. Chem.Soc. 2012, 134, 2547−2550

Journal of the American Chemical Society
Communication
(10) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127,
14198−14199.
substrates used in limiting amounts. It displays a high functional
group tolerance, is operationally trivial to execute, is scalable,
and can be used to directly functionalize natural product
derivatives such as 6-epi-dihydrojunenol. The mechanism of
this intriguing transformation and the nature of the interaction
between copper salts and TEDA-based reagents are clear areas
for further study. We expect this new protocol to complement
existing amination methods and serve as a potential lead for the
design of future C−H functionalization methods.28
(11) (a) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975,
361−362. (b) Breslow, R.; Gellman, S. H. J. Am. Chem. Soc. 1983, 105,
6728−6729. (c) Mansuy, D.; Mahy, J.-P.; Dureault, A.; Bedi, G.;
Battioni, P. J. Chem. Soc., Chem. Commun. 1984, 1161−1163.
(12) (a) Nageli, I.; Baud, C.; Bernardinelli, G.; Jacquier, Y.; Moran,
̈
M.; Muller, P. Helv. Chim. Acta 1997, 80, 1087−1105. (b) Yu, X.-Q.;
̈
Huang, J.-S.; Zhou, X.-G.; Che, C.-M. Org. Lett. 2000, 2, 2233−2236.
(c) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc.
2004, 126, 15378−15379. (d) Liang, C.; Robert-Peillard, F.; Fruit, C.;
Muller, P.; Dodd, R. H.; Dauban, P. Angew. Chem., Int. Ed. 2006, 45,
4641−4644. (e) Lebel, H.; Huard, K. Org. Lett. 2007, 9, 639−642.
(f) Fructos, M. R.; Trofimenko, S.; Mar Díaz-Requejo, M.; Perez, P. J.
́
̈
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data for all
J. Am. Chem. Soc. 2006, 128, 11784−11791. (g) Li, Z.; Capretto, D. A.;
Rahaman, R.; He, C. Angew. Chem., Int. Ed. 2007, 46, 5184−5186.
(h) Badiei, Y. M.; Dinescu, A.; Dai, X.; Palomino, R. M.; Heinemann,
F. W.; Cundari, T. R.; Warren, T. H. Angew. Chem., Int. Ed. 2008, 47,
9961−9964.
reaction and products, including H and 13C NMR spectra
1
and CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) (a) Bettinger, H. F.; Filthaus, M.; Bornemann, H.; Oppel, I. M.
Angew. Chem., Int. Ed. 2008, 47, 4744−4747. (b) Ochiai, M.;
Miyamoto, K.; Kaneaki, T.; Hayashi, S.; Nakanishi, W. Science 2011,
332, 448−451.
AUTHOR INFORMATION
■
Corresponding Author
pbaran@scripps.edu
(14) (a) Bruckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem.
̈
Author Contributions
Res. 2012, No. DOI: 10.1021/ar200194b. (b) Chen, K.; Richter, J. M.;
Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247−7249. (c) Chen, K.;
Baran, P. S. Nature 2009, 459, 824−828.
†These authors contributed equally to this paper.
Notes
(15) Cherney, E. C.; Baran, P. S. Isr. J. Chem. 2011, 51, 391−405.
(16) Banks, R. E.; Lawrence, N. J.; Besheesh, M. K.; Popplewell, A.
L.; Pritchard, R. G. Chem. Commun. 1996, 1629−1630.
(17) Kochi, J. K. Science 1967, 155, 415−424.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. A. Rheingold and Dr. Curtis E. Moore for X-ray
crystallographic analysis. Financial support for this work was
provided by the NIH/NIGMS (GM-097444) and the Swiss
National Science Foundation (postdoctoral fellowship to D.T.).
(18) Furuya, T.; Strom, A. E.; Ritter, T. J. Am. Chem. Soc. 2009, 131,
1662−1663.
(19) Ciminiello, P.; Fattorusso, E.; Magno, S.; Mayol, L. Can. J.
Chem. 1987, 65, 518−522.
(20) Hill, R. K.; Conley, R. T.; Chortyk, O. T. J. Am. Chem. Soc.
1965, 87, 5646−5651.
REFERENCES
■
(21) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons, Inc.: New York, 1999; p 779.
(22) (a) He, X.-C.; Eliel, E. L. Tetrahedron 1987, 43, 4979−4987.
(b) (−)-Menthol (99% purity) costs $0.39/g, and (+)-pulegone
(97%) costs $2.95/g (Sigma-Aldrich, 2011).
(1) Barton, D. H. R., Ed. Reason and Imagination: Reflections on
Research in Organic Chemistry: Selected Papers of Derek H. R. Barton;
World Scientific: River Edge, NJ, 1996.
(2) Breslow, R.; Baldwin, S. W. J. Am. Chem. Soc. 1970, 92, 732−734.
(3) Corey, E. J.; Hertler, W. R. J. Am. Chem. Soc. 1958, 80, 2903−
2904.
(4) For selected recent reviews, see: (a) Collet, F.; Lescot, C.;
Dauban, P. Chem. Soc. Rev. 2011, 40, 1926−1936. (b) Zalatan, D. N.;
Du Bois, J. Top. Curr. Chem. 2010, 292, 347−378. (c) Collet, F.;
Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061−5074. (d) Díaz-
́
Requejo, M. M.; Perez, P. J. Chem. Rev. 2008, 108, 3379−3394.
(5) (a) Hofmann, A. W. Ber. 1883, 16, 558−560. (b) Hofmann, A.
W. Ber. 1885, 18, 5−23.
(6) (a) Zhdankin, V. V.; Krasutsky, A. P.; Kuehl, C. J.; Simonsen, A.
J.; Woodward, J. K.; Mismash, B.; Bolz, J. T. J. Am. Chem. Soc. 1996,
118, 5192−5197. (b) Sakagushi, S.; Hirabayashi, T.; Ishii, Y. Chem.
Commun. 2002, 516−517. (c) Xiong, T.; Li, Y.; Bi, X.; Lv, Y.; Zhang,
Q. Angew. Chem., Int. Ed. 2011, 50, 7140−7143. (d) Ni, Z.; Zhang, Q.;
Xiong, T.; Zheng, Y.; Li, Y.; Zhang, H.; Zhang, J.; Liu, Q. Angew.
Chem., Int. Ed. 2011, 51, 1244−1247.
(7) (a) Moody, C. J. In Comprehensive Organic Synthesis: Selectivity,
Strategy & Efficiency in Modern Organic Chemistry; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, p 21.
(b) Breslow, D. S.; Edwards, E. I.; Linsay, E. C.; Omura, H. J. Am.
Chem. Soc. 1976, 98, 4268−4275.
́
(23) (a) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.;
Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192−212. (b) Stavber,
S.; Zupan, M. Acta Chim. Slov. 2005, 52, 13−26. (c) Stavber, S.; Jereb,
M.; Zupan, M. J. Phys. Org. Chem. 2002, 15, 56−61.
(24) Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2011, 50, 1478−1491.
(25) Vincent, S. P.; Burkart, M. D.; Tsai, C.; Zhang, Z.; Wong, C.-H.
J. Org. Chem. 1999, 64, 5264−5279.
(26) Jin, Z.; Xu, B.; Hammond, G. B. Tetrahedron Lett. 2011, 52,
1956−1959.
(27) Twamley, B.; Gupta, O. D.; Shreeve, J. M. Acta Crystallogr.
2002, E58, 663−665.
(28) While this manuscript was in preparation, two elegant Pd-
3
catalyzed intramolecular Csp −N bond formations were reported:
(a) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc.
2012, 134, 3−6. (b) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc.
2012, 134, 7−10. For related studies, see: (c) Wasa, M.; Yu, J.-Q. J.
Am. Chem. Soc. 2008, 130, 14058−14059. (d) Pan, J.; Su, M.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 8647−8651.
(8) (a) Ragaini, F.; Penoni, A.; Gallo, E.; Tollari, S.; Li Gotti, C.;
Lapadula, M.; Mangioni, E.; Cenini, S. Chem. Eur. J. 2003, 9, 249−259.
(b) Omura, K.; Murakami, M.; Uchida, T.; Irie, R.; Katsuki, T. Chem.
Lett. 2003, 32, 354−355. (c) Lu, H.; Subbarayan, V.; Tao, J.; Zhang, X.
P. Organometallics 2010, 29, 389−393.
(9) Chanda, B. M.; Vyas, R.; Bedekar, A. V. J. Org. Chem. 2001, 66,
30−34.
2550
dx.doi.org/10.1021/ja212020b | J. Am. Chem.Soc. 2012, 134, 2547−2550