Air oxidation of N-cyclopropylanilines

Article abstract of DOI:10.1080/00397911.2010.545166

Air oxidation of N-cyclopropylanilines was shown to occur under either ambient conditions or accelerated conditions (warming or shining light) in an open container. A subsequent fragmentation resulted in formation of the corresponding acetamide. While potential mechanisms have been previously proposed, simple aerobic oxidation to β-hydroxy-propionamides in the absence of a radical promoter has not been previously reported. Copyright Taylor & Francis Group, LLC.

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Air Oxidation of N-Cyclopropylanilines
Anthony Blackburn a , Daniel M. Bowles b , Timothy T. Curran a & Hui
Kim b
a Pfizer Global Research and Development, Michigan Laboratories,
Ann Arbor, Michigan, USA
b Pfizer Global Research and Development, Groton Laboratories,
Groton, Connecticut, USA
Accepted author version posted online: 07 Dec 2011.Version of
record first published: 27 Feb 2012.
To cite this article: Anthony Blackburn , Daniel M. Bowles , Timothy T. Curran & Hui Kim (2012): Air
Oxidation of N-Cyclopropylanilines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:12, 1855-1863
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Synthetic Communications1, 42: 1855–1863, 2012
Copyright # Pfizer Global Research and Development
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.545166
AIR OXIDATION OF N-CYCLOPROPYLANILINES
Anthony Blackburn,1 Daniel M. Bowles,2 Timothy T. Curran,1
and Hui Kim2
1Pfizer Global Research and Development, Michigan Laboratories,
Ann Arbor, Michigan, USA
2Pfizer Global Research and Development, Groton Laboratories, Groton,
Connecticut, USA
GRAPHICAL ABSTRACT
Abstract Air oxidation of N-cyclopropylanilines was shown to occur under either ambient
conditions or accelerated conditions (warming or shining light) in an open container. A
subsequent fragmentation resulted in formation of the corresponding acetamide. While
potential mechanisms have been previously proposed, simple aerobic oxidation to b-
hydroxy-propionamides in the absence of a radical promoter has not been previously
reported.
Keywords Air oxidation; cyclopropyl aniline; fragmentation; rearrangement
INTRODUCTION
The cyclopropylamine moiety is common in bioactive natural products as well
as in synthetic pharmaceutical candidates.[1] Oxidative ring opening has been repor-
ted for several enzymatic systems,[2] and recently synthetic utility has been demon-
strated in the reaction of tertiary amino-cyclopropylamines.[3] Interest remains
high for characterizing the behavior of the cyclopropyl group in biological systems
because of its unique properties in metabolism and in modification of basicity.[4]
RESULTS AND DISCUSSION
During the preparation of intermediates for a medicinal chemistry program, we
were asked to synthesize N-cyclopropyl-3,4-difluoro-2-methyl aniline 1.[5] An auth-
entic bulk sample was prepared for downstream chemistry and was set aside
as a neat oil in open air. Within about 1 week, it was noticed that the sample had
Received October 19, 2010.
Address correspondence to Timothy T. Curran, Vertex Pharmaceuticals Inc., 130 Waverly Street,
Cambridge, MA 02139, USA. E-mail: Timothy_Curran@vrtx.com
1855

1856
A. BLACKBURN ET AL.
solidified. Recrystallization from EtOAc=hexanes provided crystals suitable for
single-crystal x-ray analysis, which showed that the material was no longer cyclopro-
pyl aniline 1 but instead had formed an oxygenated adduct, N-(3,4-difluoro-2-
methyl-phenyl)-3-hydroxypropionamide 2a (Fig. 1).
While oxidation of N-cyclopropylamines and N-cyclopropylanilines has been
reported to occur when treated with mild oxidants such as LiOCl,[6] perbenzoic
acids, peroxides,[7] light with singlet O2 initiator,[8] Pb(OAc)4,[9] and CuCl2,[10] we
believe this to be the first report of open-air oxidation of N-cyclopropylanilines
into 3-hydroxypropionamides in the absence of additional accelerants. While prob-
ably not synthetically useful, this data may provide insight into some previously
reported low yield preparations of cyclopropylanilines[11–13] and may provide
guidance toward avoidance of these materials as storable intermediates in future
syntheses.
To test the generality of this reaction, several N-cyclopropylanilines were pre-
pared using standard literature conditions[12] via reduction of their corresponding
hemiaminals. Each N-cyclopropylaniline was purified via column chromatography,
characterized, immediately weighed into vials as neat oils, and then subjected to
one of three reaction conditions: (1) exposure to a 150-W (GE flood) lamp in open
air, (2) exposure to open air under normal laboratory lighting at ambient tempera-
ture, or (3) warmed in an oil bath in open air under normal laboratory lighting. The
oil bath was heated to 55 ꢀC to mimic the average temperature of samples held under
the lamp under condition A. The results are displayed in Table 1. Each of the sub-
strates examined reacted except for N,N-dicyclopropylaniline (11), which remained
unchanged for 6 weeks under condition set (1) and an additional 12 weeks under
condition set (2). The enhanced stability of this compound might be explained by
(a) electronic effects, (i.e., mitigation of the amine basicity, as oxidation of trisubsti-
tued cyclopropylamines containing two cyclopropyl groups would be expected to be
slow), (b) as a result of increased steric bulk, with two cyclopropyl groups forcing the
lone pair out of plane from the aromatic ring, diminishing the ability to support
radical formation, or (c) perhaps the rearrangement requires an N-H bond in the
Figure 1. X-ray crystal structure of 2a. (Figure is provided in color online.)

AIR OXIDATION OF N-CYCLOPROPYLANILINES
Table 1. Air oxidation of N-cyclopropylanilines
1857
Substrate
Product
Conditions (isolated yield)
Comment
X, 68 h (45%)
Y, 68 h (12%)a
Z, 14.5 d (20%)
15% 2b
17% 2b
60% 1
X, 40 h (54%)
Y, Not isolated
Z, 18 d (45%)
7% 4b
9% 4b
X, 66 h (40%)
Y, Not isolateda
Z, 10 d (39%)
48% 5; 4% 6b
6% 6b
X,8 d (24%)
Y, 72 h (5%)a
Z, 90 d (34%)
19% 8b
8b not isolated
50% 7; 23% 8b
X, 2 d (52%)
Y, 28 d (38%)a
Z, 28 d (52%)
30% 10b
9% 10b
6% 10b
No reaction
Not isolated
X, 22 d (35%)
Y, not isolatedb
Z, NR 21 d
7% 13b
Est. 20% 13a
by crude NMR
aYield affected by loss of materials to open atmosphere.
bClean product not obtainable from crude rxn. mixture.
cyclopropylaniline.[14] Configurationally, this species does not likely behave as a true
aniline, as the two cyclopropyl groups should force the electron pair out of conju-
gation with the aromatic ring.
Further support of a potential steric argument is the faster air oxidation of
substrate 3[15] in comparison to more highly substituted anilines 1 and 12. In most

1858
A. BLACKBURN ET AL.
cases, the decomposition mixtures also contained multiple minor impurities, most of
which were not individually isolated and identified. While the yield and spectrum of
by-products varied, the b-hydroxypropionamide was always the major product in
the crude reaction mixtures. Another major by-product observed in all cases in
which the rearrangement occurred was the corresponding acetamide, which presum-
ably is formed by fragmentation of the b-hydroxy anion (vide infra).
A proposed decomposition pathway is presented in Scheme 1. An oxidative
cascade is initiated by formation of radical cation 15 by reaction of cyclopropyl
aniline 14 with oxygen.[16] The radical undergoes ring opening[17] to 16, and a sub-
sequent reaction with additional oxygen generates the phenylamino-dioxolane
radical cation 17. It should be noted that these first few steps are analogous to the
pathway proposed by Wilmasalena and coworkers;[7] however, in this case oxygen
must be sufficient to initiate the pathway in the absence of external peroxide initia-
tors. Proton loss by intermediate 17 to unreacted cyclopropyl aniline or superox-
ide[18] followed by oxidation (by oxygen, superoxide, or N-cyclopropyl aniline)
results in fragmentation to form b-hydroxyamide anion 18. This intermediate could
undergo a retro-aldol fragmentation, liberating formaldehyde, to form N-phenyl
acetamide 19 or could accept a proton to afford b-hydroxypropionamide 20. One
might imagine several variations on the overall oxidation, for example, the reaction
of superoxide with intermediate 16 followed by cyclization to provide the neutral
dioxolane 17. This would then require subsequent oxidation of either neutral 18
with O2.
In an effort to provide further evidence of a radical mechanism, we performed
a crossover study in which N-cyclopropylaniline 7 and b-hydroxypropionamide 4a
were mixed and subjected to a 150-W lamp in open air (Scheme 2). High-
performance liquid chromatography (HPLC) analysis indicated conversion of 7 to
Scheme 1. Oxygen-mediated degradation of cyclopropylanilines.

AIR OXIDATION OF N-CYCLOPROPYLANILINES
1859
Scheme 2. Crossover radical study.
chlorohydroxypropionamide 8a and chloroacetamide 8b along with unreacted 4a, as
there was no indication of formation of difluoroacetamide 4b. These data suggest
that the acetamide is likely derived from the b-oxyradical or anion and not by a frag-
mentation pathway from the hydroxypropionamide.
EXPERIMENTAL
Representative Preparation of N-Cyclopropylaniline Substrates
Based on Standard Literature Conditions:[12] Cyclopropyl-
(3,4-difluoro-2-methyl-phenyl)-amine (1)
Step A. To a solution of 3,4-difluoro-2-methylaniline (24.4 g, 170.5 mmol) in
methanol (170 mL) and acetic acid (40 mL) was charged [(1-ethoxycyclopropyl)oxy]-
trimethylsilane (41 mL, 203.1 mmol), and the resulting mixture was heated to reflux
for 6 h. The mixture was cooled and concentrated in vacuo to afford 37.7 g of a
yellow oil that was carried into step B without further purification.
Step B. A slurry of sodium borohydride (8.0 g; 223.4 mmol, 1.35 eq) in tetra-
hydrofuran (250 mL) was cooled to ꢁ10 ꢀC and treated portionwise with aluminum
trichloride (14.0 g, 105.0 mmol, 0.64 eq) over 30 min, maintaining the reaction tem-
perature below 0 ꢀC. After stirring for 1 h at ꢁ10 ꢀC, a solution of N-(1-ethoxycyclo-
propyl)-3,4-difluoro-2-methylaniline (step A product, 37.7 g, 165.9 mmol, 1 eq) in
THF (100 mL) was added dropwise over 40 min, while maintaining the pot tempera-
ture below 0 ꢀC. The resulting mixture was warmed to 50 ꢀC over 1 h and held for 2 h.
The reaction mixture was concentrated under vacuum to remove ca. 300 mL solvent,
and the resulting slurry was quenched by pouring onto ice (800 g). The mixture was
extracted with EtOAc (600 mL), washed with water (100 mL), and concentrated to
afford a crude residue that was purified by silica-gel chromatography with 5%
methyl-text-butyl ether (MTBE) in hexanes to afford 15.4. g (50%, two steps) of

1860
A. BLACKBURN ET AL.
the title compound as a pale yellow oil that was stored in the refrigerator under Ar
until ready for use. dH (400 MHz, CH3OD): 0.43 (2H, dd, J ¼ 3.66, 2.20 Hz, CH2),
0.67 (2H, dd, J ¼ 6.50, 2.11 Hz, CH2), 1.95 (3H, d, J ¼ 2.01 Hz, CH3), 6.62–6.65
(1H, m, Ar), 6.79–6.84 (1H, m, Ar). HRMS (m=z): [M þ H]: found: 184.0951; calc.
for C10H12F2N: 184.0938.
Representative Degradation of N-Cyclopropylaniline Substrates
A sample of freshly purified N-cyclopropylaniline (1, 3, 5, 7, 9, 11, or 12) was
weighed into a 20 mL clear scintillation vial and exposed to one of three different
reaction conditions: (1) exposure to a 150-W (GE flood) lamp in open air, (2)
exposure to open air under normal laboratory lighting at ambient temperature, or
(3) warmed in an oil bath in open air under normal laboratory lighting for the time
1
described in the table. Periodic in-process samples were analyzed by H NMR to
evaluate percentage of conversion. The resulting crude mixture was purified by col-
umn chromatography on SiO2 using the SP4 Biotage system and eluted with an
appropriate mixture of EtOAc=heptane. After collection of common fractions and
evaporation of solvent, the resulting products were isolated according to the yields
indicated in Table 1.
N-(3,4-Difluoro-2-methylphenyl)-3-hydroxypropanamide
(2a). dH
(300 MHz, CD3OD): 2.19 (3H, s, ArMe), 2.60 (2H, t, COCH2), 3.31 (1H, bs, OH),
3.91 (2H, t, OCH2), 7.06 (1H, q, Ar), 7.01–7.25 (1H, m, Ar). HRMS (m=z):
[M þ H] found: 216.0829; calc for C10H12F2NO2: 216.0836. Anal. found: C, 55.9;
H, 5.0; N, 6.4; calc. for C10H11F2NO2: C, 55.8; H, 5.15; N 6.5.
N-(3,4-Difluoro-2-methyl-phenyl)-acetamide
(2b)[19]. dH
(400 MHz,
CD3OD): 2.15 (3H, s, ArMe), 2.17 (3H, d, J ¼ 2.49 Hz, COCH3), 7.07–7.10 (2H,
m, Ar). HRMS (m=z): [M þ H] found: 186.0736; calc. for C9H10F2NO: 186.0730.
N-(3,4-Difluoro-phenyl)-3-hydroxy-propionamide (4a). dH (400 MHz,
CD3OD): 2.45 (2H, t, J ¼ 6.22 Hz, COCH2), 3.70 (2H, m, OCH2), 4.72 (1H, m,
OH), 7.25–7.40 (2H, m, Ar), 7.78–7.84 (1H, m, Ar). HRMS (m=z): [M þ H] found:
202.0671; calc. for C9H10F2NO2: 202.0680. Anal. found: C, 53.9; H, 4.3; N, 6.9; calc.
for C9H10F2NO2: C, 53.7, H, 4.5; N, 7.0.
N-(3,4-Difluoro-phenyl)-acetamide (4b)[20]. dH (400 MHz, CD3OD): 2.16
(3H, s, COCH3), 4.98 (1H, bs, NH), 7.18 (2H, m, Ar), 7.68 (1H, d, J ¼ 4.56 Hz,
Ar). HRMS (m=z): [M þ H] found: 172.0560; calc. for C8H8F2NO: 172.0574.
N-(4-Fluorophenyl)-3-hydroxypropanamide
(6a)[21]. dH
(400 MHz,
CDCl3): 2.61 (2H, t, COCH2), 3.98 (2H, t, OCH2), 6.99–7.03(2H, m, Ar),
7.46–7.48 (2H, m, Ar), 7.72 (bs, 1H, NH). HRMS (m=z): [M þ H] found:
184.0764; calc. for C9H11FNO2: 184.0774. Anal. found: C, 59.0; H, 5.5; N, 7.65; calc.
for C9H10FNO2: C, 59.0; H, 5.4; N, 7.5.
N-Acetyl-(4-fluoro)aniline (6b). Consistent with previously reported spectral
data.[22]

AIR OXIDATION OF N-CYCLOPROPYLANILINES
1861
N-(2-Chloro-phenyl)-3-hydroxy-propionamide
(8a). dH
(400 MHz,
CDCl3): 2.69 (2H, t, J ¼ 10.9 Hz, COCH2), 4.01 (2H, t, J ¼ 10.8 Hz, OCH2),
7.02–7.06 (1H, m, Ar), 7.25–7.27 (1H, m, Ar), 7.35–7.38 (1H, m, Ar), 8.20 (1H,
bs, NH), 8.35 (1H, d, J ¼ 8.2 Hz, Ar). HRMS (m=z): [M þ H] found: 200.0489; calc.
for C9H11ClNO2: 200.0478. Anal. found: C, 54.1; H, 5.2; N, 6.9; calc. for
C9H10ClNO2: C, 54.15; H, 5.05; N, 7.0.
N-(2-Chloro-phenyl)-acetamide (8b). dH (400 MHz, CDCl3): 2.23 (3H, s,
COCH3), 7.04 (1H, t, J ¼ 7.42 Hz, Ar), 7.27 (1H, t, J ¼ 7.33 Hz, Ar), 7.37 (1H, d,
J ¼ 8.06 Hz, Ar), 7.64 (1H, br. s, NH), 8.36 (1H, d, J ¼ 8.24 Hz, Ar). HPLC > 99 area
%. Data consistent with commercially available sample from TCI America.
3-Hydroxy-N-phenylpropanamide (10a). dH (400 MHz, CDCl3): 2.59–2.64
(2H, m, COCH2), 3.97–3.99 (2H, m, OCH2), 7.07–7.21 (1H, m, Ar), 7.25–7.31
(2H, m, Ar), 7.49–7.51 (2H, m, Ar). IR: 3353, 3247, 2920, 2884, 1675, 1662, 1595,
1548, 1310. Anal. found: C, 65.3; H, 6.8; N, 8.3; calc. for C9H11NO2: C, 65.4; H,
6.7; N, 8.5.[7]
N-Phenyl-acetamide (10b). dH (400 MHz, CDCl3): 2.17 (3H, s, COCH3),
7.08–7.10 (1H, m, Ar), 7.28 (2H, t, J ¼ 8.10 Hz, Ar), 7.60 (2H, d, J ¼ 7.63 Hz, Ar).
HPLC > 99 area %. Data consistent with commercially available sample purchased
from Sigma Aldrich.
N-(2,4-Dibromophenyl)-3-hydroxypropanamide (13a). dH (400 MHz,
CDCl3): 2.69 (2H, t, J ¼ 10.9 Hz, COCH2), 4.01 (2H, t, J ¼ 10.9 Hz, OCH2), 7.44
(1H, d, J ¼ 8.8 Hz, Ar), 7.68 (1H, s, Ar), 8.23 (1H, bs, NH), 8.24–8.26 (1H, m,
Ar). HRMS (m=z): [M þ H]; found: 321.9088; calc. for C9H10Br2NO2: 321.9078.
Anal. found: C, 33.8; H, 2.8; N, 4.25; calc. for C9H9Br2NO2: C, 33.5; H, 2.8; N, 4.3.
N-(2,4-Dibromophenyl)acetamide (13b). dH NMR (400 MHz, CDCl3):
2.23 (3H, s, COCH3), 7.42–7.46 (1H, m, Ar), 7.55 (1H, bs, NH), 7.67 (1H, s, Ar),
8.24–8.26 (1H, m, Ar). HRMS (m=z): [M þ H] found: 291.8955; calc. for
C8H8Br2NO: 291.8973.
CONCLUSION
We have demonstrated that a variety of N-cyclopropylanilines are susceptible
to decomposition, providing their corresponding b-hydroxypropionamides and acet-
amides. We have isolated and characterized the major corresponding products from
crude reaction mixtures and have proposed a mechanism by which this transform-
ation could occur in open air without the need for additional promoters. This work
provides a rationale as to why some cyclopropylanilines should not be considered
viable candidates for storable intermediates.
ACKNOWLEDGMENTS
We thank Jared Van Haitsma and Ronald Morris for analytical support and
Brian Samas for help in providing the CIF files from x-ray analysis. We thank
Jim Davidson, Dan Belmont, Russ Linderman, and Hayden Thomas for support

1862
A. BLACKBURN ET AL.
of these experimental efforts and Peter Wuts for helpful scientific discussions during
the course of this work.
REFERENCES
1. Kulinkovich, O.G.; de Meijere, A. n-Dicarbanionic titanium intermediates from monocar-
banionic organometallics and their application in organic synthesis. Chem. Rev. 2000, 100,
2789–2834.
2. (a) Hanzlik, R.P.; Harriman, S. P.; Shaffer, C. L.; Koen, Y. M.; Totah, R. A.; Cerny, M.
A. Synthesis and Applications of Isotopically Labelled Compounds; D. C. Dean, C. N. Filer,
K. E. McCarthy, (Eds.); John Wiley & Sons: New York, 2004; vol. 8; pp. 111–114; (b)
Shaffer, C. L.; Morton, M. D.; Hanzlik, R. P. Enzymatic N-dealkylation of an N-cyclo-
propylamine: An unusual fate for the cyclopropyl group. J. Am. Chem. Soc. 2001, 123,
349–350; (c) Dinnocenzo, J. P.; Karki, S. B.; Jones, J. P. On isotope effects for the cyto-
chrom P-450 oxidation of substituted N,N-dimethylanilines. J. Am. Chem. Soc. 1993, 115,
7111–7116; (d) Karki, S. B.; Dinnocenzo, J. P.; Jones, J. P.; Korzekwa, K. R. Mechanism
of oxidative amine dealkylation of substituted N,N-dimethylanilines by cytochrome P-
450: Application of isotope effect profiles. J. Am. Chem. Soc. 1995, 117, 3657–3664.
3. (a) Lee, J.; Sun, U. J.; Blackstock, S. C.; Cha, J. K. Facile ring opening of tertiary ami-
nocyclopropanes by photooxidation. J. Am. Chem. Soc. 1997, 119, 10241–10242; (b)
Ha, J. D.; Lee, J.; Blackstock, S. C.; Cha, J. K. Intramolecular [3 þ 2] annulation of ole-
fin-tethered cyclopropylamines. J. Org. Chem. 1998, 63, 8510–8514.
4. Gillaspy, M. L.; Lefker, B. A.; Hada, W. A.; Hoover, D. J. A simple method for the for-
mation of cyclopropylamines: The first synthesis of tricyclopropylamine. Tetrahedron
Lett. 1995, 36, 7399–7402
5. Yoshida, Y.; Umezu, K.; Hamada, Y.; Atsumi, N.; Tabuchi, F. Practical synthesis of
N-cyclopropylanilines via direct condensation of anilines with [(1-ethoxycyclopropyl)oxy]-
trimethylsilane. Synlett 2003, 14, 2139–2142.
6. Vaidyanathan, G.; Wilson, J. W. Reaction of cyclopropanamines with hypochlorite.
J. Org. Chem. 1989, 54, 1815–1820.
7. Wimalasena, K.; Wickman, H. B.; Mahindaratne, M. P. D. Autocatalytic radical ring
opening of N-cycloproopyl-N-phenylamines under aerobic conditions—exclusive forma-
tion of the unknown oxygen adducts, N-(1,2-dioxolan-3-yl)-N-phenylamines. Eur. J.
Org. Chem. 2001, 3811–3817.
8. Rynbrandt, R. H.; Dutton, F. E. Cleavage of a cyclopropane ring by singlet oxygen.
J. Org. Chem. 1975, 40, 3079–3081.
9. Hiyama, T.; Koide, H.; Nozaki, H. Oxidation of cyclopropylamines and 2-phenylaziridine
with lead tetraacetate. Tetrahedron Lett. 1973, 24, 2143–2144.
10. Itoh, T.; Kaneda, K.; Teranishi, S. Novel oxygenolysis of cyclopropylamines to epoxy
ketones. Tetrahedron Lett. 1975, 32, 2801–2804.
11. Cui, W.; Loeppky, R. N. The synthesis of N-arylcyclopropylamines via palladium-
catalyzed C-N bond formation. Tetrahedron 2001, 57, 2953–2956.
12. Based on literature conditions. See Ref. [5].
13. Joullie and Faler reported the facile fragmentation of hydroxyphenyl-N-N-dimethylcyclo-
propylamine and suggested that the fragmentation was likely due to oxygen and water
during purification. See Faler, C. A.; Joullie, M. M. The Kulinkovich reaction in the
synthesis of constrained N,N-dialkyl neurotransmitter analogues. Org. Lett. 2007, 9,
1987–1990.

AIR OXIDATION OF N-CYCLOPROPYLANILINES
1863
14. A large variety of N-alkyl-cyclopropylanilines are commercially available. For selected
additional examples of stable N-alkyl-cyclopropylanilines in the literature, see (a) Satoh,
T.; Miura, M.; Sakai, K.; Yokoyama, Y. Reaction of magnesium cyclopropylidene with
N-lithio arylamines: A method for generation of a-amino-substituted cyclopropylmagne-
siums and a study for their reactivity with electrophiles. Tetrahedron 2006, 62, 4253–4261;
(b) Kang, J.; Kim, K. S. N-Cyclopropylation of aromatic amines. J. Chem. Soc. Chem.
Commun. 1987, 12, 897–898; (c) Benard, S.; Neuville, L.; Zhu, J. Copper-promoted
´
N-cyclopropylation of anilines and amines by cyclopropylboronic acid. Chem. Commun.
2010, 46, 3393–3395.
15. See Ref. [5].
16. While mild conditions as observed here to produce 15 have not been reported elsewhere,
the O2 oxidation of tertiary amines under more rigorous conditions has been reported:
Riley, D. P.; Correa, P. E. An unprecedented selective autoxidation of tertiary amines
to amine oxides. J. Org. Chem. 1985, 50, 1563–1564.
17. The ‘‘very fast’’ opening of the cyclopropane ring system has been reported. (a) Maeda,
Y.; Ingold, K. U. Kinetic applications of electron paramagnetic resonance spectroscopy.
35. The search for a dialkylaminyl rearrangement: Ring opening of N-cyclobutyl-N-n-pro-
pylaminyl. J. Am. Chem. Soc. 1980, 102, 328–331; (b) Musa, O. M.; Horner, J. H.; Shahin,
H.; Newcomb, M. A kinetic scale for dialkylaminyl radical reactions. J. Am. Chem. Soc.
1996, 118, 3862–3868.
18. (a) Schreiber, S. L. Hydrogen transfer from tertiary amines to trifluoroacetic anhydride.
Tetrahedron Lett. 1980, 21, 1027–1030; (b) Dinnocenzo, J. P.; Banach, T. E. Deprotona-
tion of tertiary amine cation radicals: A direct experimental approach. J. Am. Chem. Soc.
1989, 111, 8646; (c) Zhang, X.; Yeh, S. R.; Hong, S.; Freccero, M.; Albini, A.; Falvey,
Mariano P. S. Dynamics of a-CH deprotonation and a-desilylation reactions of tertiary
amine cation radicals. J. Am. Chem. Soc. 1994, 116, 4211–4220; (d) Loeppky, R. N.;
Singh, S. P.; Elomari, S.; Hastings, R.; Theiss, T. E. Evidence for radical cations in linked
mechanisms of N,N-dialkyl aromatic amine nitration and nitrosative dealkylation. J. Am.
Chem. Soc. 1998, 120, 5193–5202.
19. Antibacterial Quinolones and Their Preparations. Otsuka Pharmaceutical Co., Ltd.: Japan.
NL 8700471, September 16, 1987.
20. Fifolt, M. J.; Sojka, S. A.; Wolfe, R. A.; Hojnicki, D. S.; Bieron, J. F.; Dinan, F. J. A
chemical shift additivity method for the prediction of fluorine-19 chemical shifts in fluor-
oaromatic compounds. JOC 1989, 54(13), 3019–3023.
21. Bradley, G.; Clark, J.; Kernick, W. 2,3-Dihydroquinolin-4(1H)-ones. Part I. Halogen-sub-
stituted 2,3-dihydroquinolin-4(1H)-ones and their 1-(2-acylethyl) derivatives. J. Chem.
Soc., Perkin Trans. 1 1972, 16, 2019–2023.
22. Kajihara, K.; Arisaua, M.; Shuto, S. A method for cleaving an allyl protecting group at
the amid nitrogen of peptides by one-pot olefin isomerization-oxidation. JOC 2008,
73(23), 9494–9496.