Preparation of an N-sec-alkyl 2,6-disubstituted aniline: a key intermediate in the divergent synthesis of S-Metolachlor metabolites

Article abstract of DOI:10.1016/j.tetlet.2016.10.077

A simple method to prepare a 2,6-disubstituted aniline containing a N-sec-alkyl group and a carbonyl on one ortho substituent is reported. This method was used to accomplish the first synthesis of side chain oxidized ethylsulfonic acid (ESA) and oxanilic acid (OXA) metabolites of S-Metolachlor (S-Moc) herbicide. The 2,6-disubstituted aniline functionality was installed by a Sugasawa reaction of readily available ortho-toluidine. The N-sec alkyl group was introduced by a Mitsunobu alkylation of the nosyl-activated 2-acetyl-6-methyl-substituted aniline. This crucial step enabled access to the key 2,6-disubstituted aniline intermediate which was used in the divergent synthesis of S-Moc metabolites. A bioinspired synthesis of the keto-ESA metabolite was achieved in one step from the hydroxyl-ESA metabolite using a ruthenium-catalyzed oxidation.[Figure presented]

Full text of DOI:10.1016/j.tetlet.2016.10.077

Tetrahedron Letters 57 (2016) 5363–5367
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Preparation of an N-sec-alkyl 2,6-disubstituted aniline: a key
intermediate in the divergent synthesis of S-Metolachlor metabolites
a
a
a
a
Sameer Tyagi a, , Moses G. Gichinga , Christopher D. Cook , Jeffrey A. Key , Bruce P. McKillican ,
⇑
William J. Eberle a, Timothy J. Carlin a, David A. Hunt a, Alan J. Dowling b
a Product Metabolism Analytical Sciences, Syngenta Crop Protection, 410 Swing Road, Greensboro, NC 27409, USA
b Isotope and Metabolite Synthesis, Syngenta Crop Protection, Jealott’s Hill International Research Center, Bracknell, Berkshire RG 42 6EY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple method to prepare a 2,6-disubstituted aniline containing a N-sec-alkyl group and a carbonyl on
one ortho substituent is reported. This method was used to accomplish the first synthesis of side chain
oxidized ethylsulfonic acid (ESA) and oxanilic acid (OXA) metabolites of S-Metolachlor (S-Moc) herbicide.
The 2,6-disubstituted aniline functionality was installed by a Sugasawa reaction of readily available
ortho-toluidine. The N-sec alkyl group was introduced by a Mitsunobu alkylation of the nosyl-activated
2-acetyl-6-methyl-substituted aniline. This crucial step enabled access to the key 2,6-disubstituted
aniline intermediate which was used in the divergent synthesis of S-Moc metabolites. A bioinspired syn-
thesis of the keto-ESA metabolite was achieved in one step from the hydroxyl-ESA metabolite using a
ruthenium-catalyzed oxidation.
Received 24 September 2016
Revised 13 October 2016
Accepted 20 October 2016
Available online 21 October 2016
Keywords:
Metabolite synthesis
S-Metolachlor metabolites
Divergent synthesis
Sugasawa ortho-acetylation
Mitsunobu N-alkylation
-
+Na O3S
CH3
CH3
R
Mitsunobu
-alkylation
Sugasawa
o-acetylation
CH3
N
O
O
O
O
N
O
N
HN
NH2
HO
O
O
R=CH2SO3 Na+
R=CO2-Na+
bioinspired
synthesis
-
Ó 2016 Elsevier Ltd. All rights reserved.
Introduction
it was later established that the majority of the herbicidal activity
of the racemic Metolachlor was due to the 10S enantiomer ( R,10S
and
S,10S atropisomers).5 It is noteworthy that both R,10S and
S,10S atropisomers display identical herbicidal activity. Hence,
a
Effective weed control is an essential factor in high yield agri-
culture needed to feed the world’s rising population. Metolachlor
(1), an important member of the chloroacetamide class of herbi-
cides, is used as a selective, pre-emergence herbicide to control a
broad spectrum of grass weeds and small-seeded broadleaves
(Fig. 1).1,2 The molecule contains a stereocenter and a chiral axis
due to hindered rotation around the phenyl-N bond axis (atropiso-
merism) thus leading to four stereoisomers (Fig. 1).3,4 Metolachlor
was initially launched as a mixture of all the four stereoisomers but
a
a
a
an enantioenriched form of Metolachlor containing a mixture of
80–100% of 10S and 0–20% of 10R isomers was subsequently
introduced in the market. This blend is currently named as
S-Metolachlor (S-Moc) and is commercially available as Dual
MagnumÒ herbicide. S-Moc is mainly taken up through the roots
and shoots of the germinating plants and seedlings, leading to
the eradication of the weeds before emergence.6,7 Mechanistically,
S-Moc is believed to reduce the formation of very-long-chain fatty
acids (VLCFA) in the plasma membrane and epicuticular waxes of
weeds by inhibition of fatty acid elongases.8,9
⇑
Corresponding author. Tel.: +1 336 632 6733; fax: +1 336 632 7581.
E-mail address: Sameer.tyagi@syngenta.com (S. Tyagi).
http://dx.doi.org/10.1016/j.tetlet.2016.10.077
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

5364
S. Tyagi et al. / Tetrahedron Letters 57 (2016) 5363–5367
N-sec alkyl group
Highly polar groups
Cl
O
Cl
O
Cl
O
O
Cl
O
O
O
O
R = CH2SO3-Na+
R = CO2-Na+
2'
1'
H
H
H
Cl
O
H
O
R
CH3
N
O
N
N
N
O
N
N
Hindered
X
tertiary amine
&
Oxidized side-chain
X = OH, (O)
Atropisomerism
αR,1'S
αS,1'S
Metolachlor (1)
αR,1'R
αS,1'R
Figure 1. Structures of Metolachlor (1) and the individual stereoisomers.
Figure 3. Structural features of metabolites 2–4.
The metabolism of Metolachlor/S-Moc has been studied exten-
sively and is the subject of several publications.10a–e During the
course of product re-registration, we identified side chain
CH3
ortho-carbonylation
O
HN
CH3
R
CH3
H
oxidized ethylsulfonic acid (ESA) metabolites
2 and 3 and
O
O
p
e
t
O
N
HN
s
-
e
oxanilic acid (OXA) metabolite 4 of S-Moc (Fig. 2). Since these
metabolites had not been observed previously, we needed to
prepare standards to support additional product registration
requirements. The only available methods to obtain side chain
oxidized ESA and OXA metabolites of S-Moc have hitherto been
on analytical scale (with low yields) using microbial
transformations.10d,e In this report, we describe our efforts to
develop a synthesis that would generate all the stereoisomers of
metabolites 2–4 since the technical S-Moc contains 80–100% of
the S and 0–20% of the R isomers.
n
o
red. alkylation,
6
X
O
N-arylation
R
Y
2. R=CH2SO3-Na+; X=OH
3. R=CH2SO3-Na+; X=(O)
4. R=CO2-Na+; X=OH
5
Y = NH2 or Br,
R = CH3, OCH3,
or OH
O
7
Figure 4. Retrosynthetic approach to metabolites 2–4.
Synthesis of intermediate 5
Results and discussion
We initially attempted to synthesize 5 via a one-step, Sugasawa
ortho-acetylation of 6 (Scheme 1a) but isolated a mixture consist-
ing of ortho-toluidine, N-(1-chloropropan-2-yl)-2-methyl aniline,
and 2,7-dimethylindoline side products. Although the Sugasawa
reaction has been demonstrated only on a limited number of meta-
and para-substituted primary11e and secondary13 anilines, the Lewis
acids (BCl3 and GaCl3) in this reaction are incompatible with the N-
sec-alkyl functionality in 6. We next tested a variety of reductive
alkylation3,14 and Pd- and Cu-catalyzed N-arylation15 conditions
to install the N-sec-alkyl group on substrates 7 (Scheme 1b). How-
ever, our efforts resulted in a recovery of either starting material,
debromination, isolation of trace amounts of product, and/or a
complex mixture.16 We also attempted to synthesize 5 via isatoic
anhydride 8 since N-alkylated isatoic anhydrides serve as attrac-
tive latent precursors to N-alkylated anthranilates and anthranilic
acids (Scheme 1c).17 This approach also proved unsuccessful due
Important structural features of 2–4 include the presence of an
ortho-disubstitution arrangement, an oxidized ethyl side chain, an
N-sec alkyl group, and highly polar functionalities (Fig. 3). The
presence of two stereocenters coupled with a restricted rotation
around the phenyl-N bond axis (atropisomerism) results in the for-
mation of eight stereoisomers of metabolites 2 and 4. Literature
reports describing the synthesis of such densely functionalized ani-
lines consisting of contiguous substituents are rare. We found only
a limited number of reports describing preparation of 2-carbonyl-
substituted anilines functionalized with primary N-alkyl11 or sec-
ondary N-alkyl (isopropyl, methylpiperidine, and diethy-
laminoethyl)11e,12,13 groups on the aniline nitrogen. To the best of
our knowledge, there are no known methods for the synthesis of
2-carbonyl-6-alkyl-substituted anilines functionalized with
secondary N-alkyl groups.
We envisioned that the most efficient method to synthesize the
biosynthetically similar metabolites 2–4 would be from the 2-
acetyl-6-methyl-substituted aniline 5, using a divergent approach
(Fig. 4). Aniline 5 contains the N-sec-alkyl group and a functional
oxidation state of the ethyl side chain. With these key functional-
ities in place, we reasoned that the synthesis of metabolites 2–4
could be completed in 2–3 steps. Intermediate 5 could be synthe-
sized either (i) in one step by installation of the ortho-carbonyl on
to the N-sec-alkyl-substituted aniline 6 or (ii) via the introduction
of the N-sec-alkyl group on to 2-carbonyl-6-methyl-substituted
substrates 7 (Fig. 4).
(a) Sugasawa ortho-acetylation
6
5
(b) Reductive alkylation and N-arylation
CH3
O
HN
Y
R
R
7
Y = NH2, Br
R = CH3C(O), CO2H,
CH3CH(OH), Br
+Na-O3S
O
+Na-O
O
O
N
+Na-O3S
(c) Isatoic anhydride approach
CH3
CH3
CH3
O
H
O
O
O
O
N
O
O
N
O
O
N
O
N
HO
HO
O
O
base-mediatedand
Mitsunobu alkylation
2
3
4
8
Figure 2. ESA and OXA metabolites 2–4 of S-Moc.
Scheme 1. Attempted approaches to synthesis of 5.

S. Tyagi et al. / Tetrahedron Letters 57 (2016) 5363–5367
5365
Ns
to our inability to N-alkylate the isatoic anhydride 8 by either a
NH2 1. GaCl3, BCl3, CH3CN,
1,2-DCE, -10°C-rt-90°C
2. H2O, 75°C
NH
NH2
Mitsunobu reaction (using 1-methoxy-2-propanol) or via alkyla-
tion methods (using 2-methoxy-1-methyl-ethyl-triflate) under
basic conditions.15d,18,19 While the efforts described above are
o-NsCl, Pyr.,
rt, overnight
O
O
82%
88%
12
11
10
effective
methodologies
for
introducing primary alkyl
DIAD, PPh3,
THF:CH2Cl2,
rt, 18 h
OH
O
substituents in substrates 7 and 8, such methods were rendered
ineffective for secondary alkyl substituents.
90%
After several unsuccessful attempts to introduce the N-sec alkyl
group, we finally pursued a strategy that involved alkylation of an
activated aniline 9 (Fig. 5). To test our synthesis plan via 9, we first
performed an ortho-acetylation of ortho-toluidine (10) using a
modified Sugasawa reaction20 (by replacement of AlCl3 with GaCl3)
to obtain 1121 in 88% yield (Scheme 2). Our next step was to deter-
mine a suitable activating group to facilitate an alkylation reaction.
After a few trials,22 a nosyl group activation of the aniline 11 was
carried out using 2-nitrobenzensulfonyl chloride to obtain the
ortho-nosyl-protected intermediate 12.23 We were delighted to
achieve a Mitsunobu reaction of 12 with 1-methoxy-2-propanol24
using PPh3 and DIAD to afford the desired N-alkylated derivative
13 in 90% purified yield (Scheme 2).23 Finally, deprotection of the
nosyl group was accomplished using thiophenol and K2CO3 to form
the desired key intermediate 5.23
O
O
Ns
HN
N
PhSH, K2CO3,
DMF, rt, 2 h
O
O
93%
5
13
Scheme 2. Synthesis of intermediate
5
by
a
Mitsunobu alkylation of nosyl-
activated aniline.
Cl
O
O
N
O
NH
NaBH4, EtOH,
80°C, 1h
OH
OH
5
quant
14
15
Synthesis of metabolites 2–4
ClC(O)CH2Cl,
K2CO3, THF,
rt,3 h
85%
O
O
Having secured intermediate 5, we set our sights on completing
the synthesis of metabolites 2–4. Reduction of the carbonyl group
in 5 was achieved using NaBH4 to afford the desired secondary
alcohol 14 as an approximately 1:1 mixture of diastereomers
(Scheme 3).25 Our momentum was however impeded in the next
step due to the inability to selectively N-acylate intermediate 14
to form 15.26 We attempted to circumvent this issue by preparing
intermediate 16 followed by a reduction of the carbonyl group in
intermediate 16 using sodium borohydride. However, our efforts
resulted in the formation of cyclized side product 17 instead of
the desired product 15 (Scheme 3). After some experimentation,
we settled on pursuing a strategy of diacylating intermediate 14
followed by a selective cleavage of the O-acyl linkage (Scheme 4).
Thus, diacylation of 14 using 5 equiv of chloroacetyl chloride
yielded the diacylated intermediate 18 as atropisomers of both
the diastereomers. Selective cleavage of the O-acyl linkage in 18
was achieved by Ti(OiPr)4 to form the desired N-acylated interme-
diate 15 as mostly a single atropisomer of both the diastereomers.
Finally, the sulfonic acid functionality was introduced by the reac-
tion of 15 with sodium sulfite and catalytic KI to form the sodium
salt of the metabolite 2. Our initial attempts to purify the metabo-
lite 2 in the free sulfonic acid form using either preparative reverse
phase (RP) or conventional normal phase flash purification meth-
ods (diol silica) were unsuccessful and resulted in partial decom-
position of the product. However, we were able to purify 2 as a
sodium salt by flash chromatography on a RP polar end-capped
C18 stationary phase to afford the purified product in 72% yield
as a diastereomeric mixture with both having atropisomers.
The synthesis of metabolite 4 was pursued by diacylation of 14
using 5 equiv of ethyloxalyl chloride to afford intermediate 19 in
79% purified yield as a mixture of four diastereomers (Scheme 5).
Cl
O
N
reduction
N
O
O
O
17
undesired
side product
16
Scheme 3. Attempted synthesis of metabolite 2.
A one-pot, in situ cleavage of the O-acyl linkage and hydrolysis of
the ester in 19 afforded the desired sodium salt of metabolite 4
in 75% yield as a mixture of four diastereomers. Due to inherent
instability and foreseeable challenges in purification of the free
acid form, we purified metabolite 4 also as a sodium salt using a
RP polar end-capped C18 stationary phase.
Having completed the synthesis of metabolites 2 and 4, we then
pursued the synthesis of metabolite 3. Nucleophilic displacement
of the chloride in 16 by Na2SO3 surprisingly afforded a complex
mixture, containing only approximately 20% product (Scheme 6).
Multiple attempts to purify this mixture to isolate the pure product
(in >95% purity) were unsuccessful. We next considered a one-step
bioinspired oxidation of metabolite 2 to 3 under aqueous condi-
tions. Considering our limitations for oxidizing 2 in its salt form
(due to the instability of the free acid form), we needed to employ
aqueous non-acidic reaction conditions. We were specifically
drawn to a report by DuBois and co-workers, describing the use
of catalytic RuCl3 and KBrO3 to oxidize tertiary C–H bonds under
aqueous neutral conditions.27,28 Due to the low redox potential of
2° alcohols, we surmised that such mild reaction conditions could
also be used in the oxidation of metabolite 2 to 3 with high
chemoselectivity. Thus, we tested the oxidation of
2 using
10 mol % RuCl3, 10 mol % pyridine, and KBrO3 as stoichiometric
oxidant in water:CH3CN (1:1) as the solvent (Scheme 6). We were
pleased to achieve a full conversion of metabolite 2 to the desired
product 3 with high level of chemoselectivity. The purified product
was isolated in 57% yield as an approximately 1:1 mixture of
diastereomers. We observed approximately 5% of the over oxidized
side product resulting from the oxidation of the benzylic methyl at
the 6-position to form the corresponding aldehyde.
alkylation
H
AG
N
R
5
O
9
R = CH3 or OCH3
AG = activating group
Figure 5. N-alkylation of an activated aniline.

5366
S. Tyagi et al. / Tetrahedron Letters 57 (2016) 5363–5367
SO3-Na+
O
Cl
ClC(O)CH2Cl,
K2CO3, THF,
rt,18 h
Na2SO3, KI (cat.),
H2O:EtOH (9:1),
45°C, 48 h
O
O
N
N
O
Ti(OiPr)4, THF,
rt, 48h
15
14
OH
O
97%
72%
72%
O
2
18
Cl
Scheme 4. Completion of the synthesis of metabolite 2.
2. Bader, R.; Flatt, P.; Radimerski, P. EP Patent 605363, July 6, 1994; Chem. Abstr.
1992, 121, 133721z.
3. Blaser, H. U. Adv. Synth. Catal. 2002, 344, 17–31.
EtO
O
O
+Na-O
O
O
N
O
O
ClC(O)C(O)OCH2CH3,
K2CO3, THF,
rt,18 h
N
4. Blaser, H. U.; Spindler, F. Chimia 1997, 51, 297–299.
NaOH, THF,
5. Moser, H.; Rihs, G.; Sauter, H. P. Z. Naturforsch. B 1982, 37b, 451–462.
6. Herbicide Handbook; Senseman, S. A., Ed., 9th ed.; Weed Science Society of
America, 2007; pp 275–278.
7. Fuerst, E. P. Weed Technol. 1987, 1, 270–277.
8. Eckermann, C.; Matthes, B.; Nimtz, M.; Reiser, V.; Lederer, B.; Boger, P.;
Schroder, J. Phytochemistry 2003, 64, 1045–1054.
MeOH, rt, 1 h
14
O
HO
79%
O
75%
O
19
4
OEt
Scheme 5. Completion of the synthesis of metabolite 4.
9. Boger, P.; Gotz, T. Z. Naturforsch. 2004, 59c, 549–553.
10. For select publications describing metabolism of S-Moc, see (a) Aga, D. S.;
Thurman, E. M.; Yockel, M. E.; Zimmerman, L. R.; Williams, T. D. Environ. Sci.
Technol. 1996, 30, 592–597; (b) Liu, S. Y.; Freyer, A. J.; Bollag, J. M. J. Agric. Food
Chem. 1991, 39, 631–636; (c) Loch, A. R.; Lippa, K. A.; Carlson, D. L.; Chin, Y. P.;
Traina, S. J.; Roberts, A. L. Environ. Sci. Technol. 2002, 36, 4065–4073; (d)
Pothuluri, J. V.; Evans, F. E.; Doerge, D. R.; Churchwell, M. I.; Cerniglia, C. E. Arch.
Environ. Contam. Toxicol. 1997, 32, 117–125; (e) Krause, A.; Hancock, W. G.;
Minard, R. D.; Freyer, A. J.; Honeycutt, R. C.; LeBaron, H. M.; Paulson, D. L.; Liu,
S. Y.; Bollag, J. M. J. Agric. Food Chem. 1985, 33, 584–589.
SO3-Na+
O
Na2SO3, KI (cat.),
H2O:EtOH (9:1),
45°C, 48 h
RuCl3.xH2O, KBrO3,
pyr., CH3CN:H2O (1:1),
60°C, 3 h
N
O
O
2
16
trace levels
of product
57%
11. (a) Kobzina, J. W. US Patent 4456471, June 26, 1984.; (b) Koichi, A.; Yoshitaka,
S.; Shirakura, S.; Keiji, E.; Nakamura, S.; Seiji, U.; Chieko, U. WO Patent 2009/
024251, February 26, 2009.; (c) Chiron, S.; Abian, J.; Ferrer, M.; Sanchez-Baeza,
F.; Messeguer, A.; Barcelo, D. Environ. Toxicol. Chem. 1995, 14, 1287–1298; (d)
Beaulieu, P. L.; Forgione, P.; Gagnon, A.; Godbout, C.; Joly, M. A.; Llinas-Brunet,
M.; Naud; J.; Poirier, M.; Rancourt, J. WO Patent 2009/076747, June 25, 2009.;
(e) Sugasawa, T.; Toyoda, T.; Adachi, M.; Sasakura, K. J. Am. Chem. Soc. 1978,
100, 4842–4852.
3
Scheme 6. Bioinspired synthesis of metabolite 3.
Conclusions
In summary, the first high yielding synthesis of polar and ster-
ically hindered ESA and OXA metabolites of S-Moc has been
achieved. Furthermore, a simple method for the synthesis of an
N-sec-alkyl 2-acetyl-6-methyl-substituted aniline is also reported.
The synthesis of such class of anilines had hitherto been elusive.
Pivotal to the success of our synthesis was the incorporation of
the sec alkyl group via a Mitsunobu reaction of the nosyl-activated
ortho-carbonylated aniline. This method offers a convenient means
to introduce a sec alkyl group on to 2-carbonyl-6-alkyl-substituted
anilines. A one-step, bioinspired synthesis of the keto-ESA metabo-
lite was accomplished from the hydroxyl-ESA metabolite using a
Ru-catalyzed oxidation. Our synthetic approach was dictated by
the need to prepare test substances containing all the stereoiso-
mers that could form metabolically from the technical S-Moc.
However, a stereoselective synthesis of individual isomers could
also be achieved using the synthetic route reported in this work.
12. Coombs, R. V.; Danna, R. P.; Denzer, M.; Hardtmann, G. E.; Huegi, B.; Koletar, G.;
Koletar, J. J. Med. Chem. 1973, 16, 1237–1245.
13. Sugasawa, T.; Sasakura, K. EP Patent 0131921, January 23, 1985.
14. (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, E. D. J.
Org. Chem. 1996, 61, 3849–3862; (b) da Silva, R. A.; Bieber, L. W. Tetrahedron
Lett. 2010, 51, 689–691; (c) Bhattacharyya, S.; Rehr, E. W.; Gonzalez, A. M.
Synthesis 2003, 2206–2210.
15. (a) Altman, R. A.; Fors, B. P.; Buchwald, S. L. Nat. Protoc. 2007, 2, 2881–2887; (b)
Zeng, L.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2009, 351, 1671–
1676; (c) Tedesco, R.; Shaw, A. N.; Bambal, R.; Chai, D.; Concha, N. O.; Darcy, M.
G.; Dhanak, D.; Fitch, D. M.; Gates, A.; Gerhardt, W. G.; Halegoua, D. L.; Han, C.;
Hofmann, G. A.; Johnston, V. K.; Kaura, A. C.; Liu, N.; Keenan, R. M.; Goerke, J. L.;
Sarisky, R. T.; Wiggall, K. J.; Zimmerman, M. N.; Duffy, K. J. J. Med. Chem. 2006,
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16. Further efforts to introduce the N-sec-alkyl group via an ipso substitution on
methyl
2-fluoro-3-methylbenzoate
and
2-fluoro-3-methylbenzonitrile
resulted in low yields (15–20%) and recovery of starting material respectively.
17. Staiger, R. P.; Miller, E. B. J. Org. Chem. 1959, 24, 1214–1219.
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565–572.
Acknowledgements
19. Subsequent to completion of this work, we found a report by Guan and co-
workers on a Pd(II)-catalyzed synthesis of N-alkyl isatoic anhydrides. However,
all examples reported consisted of primary alkyl groups; see Guan, Z. H.; Chen,
M.; Ren, Z. H. J. Am. Chem. Soc. 2012, 134, 17490–17493.
20. Atechian, S.; Nock, N.; Norcross, R. D.; Ratni, H.; Thomas, A. W.; Verron, J.;
Masciadri, R. Tetrahedron 2007, 63, 2811–2823.
We are grateful to Dr. Gordon Vail, Eric Thomas (Syngenta), and
Prof. Mitchell Croatt (University of North Carolina, Greensboro) for
valuable discussions during the preparation of the manuscript. We
thank Pike Mitchener (Syngenta) for helping with DSC
measurements.
21. Compound 11 is available commercially via
a custom synthesis order.
Synthesis of 11 has also been reported by Satoh and co-workers in 40% yield
using conditions originally reported by Sugasawa; see Tabuchi, S.; Ito, H.;
Sogabe, H.; Kuno, M.; Kinoshita, T.; Katumi, I.; Yamamoto, N.; Mitsui, H.; Satoh,
Y. Chem. Pharm. Bull. 2000, 48, 1–15.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.10.
077.
22. Efforts to perform N-alkylation (under basic or Mitsunobu conditions) of the
aniline using amide activating groups were unsuccessful.
23. Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373–6374.
24. (S)-(+)- and (R)-(ꢀ)-1-Methoxy-2-propanol are commercially available and
may be used in a chiral synthesis.
References and notes
25. The diastereomeric ratio for all the isolated compounds, including 14 were
quantified by the integration values of the resolved resonances (of a particular
proton environment) in the 1H NMR spectrum.
1. Vogel, C.; Aebi, R. DE Patent 2328340, December 20, 1973; Chem. Abstr. 1972,
80, 82440g.

S. Tyagi et al. / Tetrahedron Letters 57 (2016) 5363–5367
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26. Subsequent to completion of this work, we found that Kwon and co-workers
had also reported a similar observation; see Andrews, I. P.; Kwon, O. Chem. Sci.
2012, 3, 2510–2514.
28. For select examples of ruthenium-catalyzed oxidation of alcohols, see (a)
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27. McNeill, E.; Du Bois, J. J. Am. Chem. Soc. 2010, 132, 10202–10204.