Sulfonylation-induced N-to O -Acetyl migration in 2-acetamidoethanol derivatives

Article abstract of DOI:10.1021/jo100456z

The first example of sulfonylation-induced N- to O-acetyl migration of 2-acetamidoethanol derivatives is described. This type of reaction could happen with any 2-acetamidoethanol derivatives under typical sulfonylation conditions (TsCl or MsCl, pyridine) and might be a common side reaction of significance. Furthermore, the results reveal that 2-acetamidoethanol derivatives with a sterically encumbered hydroxyl group result in the migration products in high yields. The mechanism of the migration reaction is discussed.

Full text of DOI:10.1021/jo100456z

pubs.acs.org/joc
SCHEME 1. Tosylation of N-Acetylglucosamine Derivative 1a
Sulfonylation-Induced N- to O-Acetyl Migration
in 2-Acetamidoethanol Derivatives
Takao Yamaguchi, Dusan Hesek, Mijoon Lee,
Allen G. Oliver, and Shahriar Mobashery*
pyridine for a longer duration, two compounds were obtained,
as outlined in Scheme 1, with the major component identified as
the product of acetyl migration 3a. The products 2a and 3a
Department of Chemistry and Biochemistry, University of
Notre Dame, Notre Dame, Indiana 46556
1
showed similar H and 13C NMR spectra, and had the same
mobashery@nd.edu
mass. Thus, the differentiation of each compound was difficult.
Received March 11, 2010
The first example of sulfonylation-induced N- to O-acetyl
migration of 2-acetamidoethanol derivatives is described.
This type of reaction could happen with any 2-acetamido-
ethanol derivatives under typical sulfonylation conditions
(TsCl or MsCl, pyridine) and might be a common side
reaction of significance. Furthermore, the results reveal that
2-acetamidoethanol derivatives with a sterically encumbered
hydroxyl group result in the migration products in high
yields. The mechanism of the migration reaction is discussed.
FIGURE 1. 1H NMR spectra of compounds (A) 1a in DMSO-d6,
(B) 2a in CDCl3, and (C) 3a in CDCl3. Compound 1a was not
soluble in CDCl3.
In the 1H NMR spectra (Figure 1), the H-2 resonance of 3a
(δ 3.53 ppm) appeared at higher field than that of 2a (δ4.46 ppm).
The H-3 resonance of 3a appeared at δ 5.24 ppm, and the axial
orientation for the hydrogen was confirmed by the coupling
constants (J2,3 =J3,4 = 10 Hz). Confirmatory evidence for the
structure of 3a was the ester carbonyl stretch at 1734 cm-1 in the
IR spectrum. The IR resonances of the amide carbonyl groups of
1a and 2a were seen at 1651 and 1656 cm-1, respectively.
A similar observation for acetyl migration in compound 1a
was reported by Calvo-Mateo et al. (Scheme 2).2 They obtained
the product 6 by heating of the unstable triflate 4 in a mixture of
pyridine, water, and DMF (Scheme 2a). It is interesting that an
inversion at the C-3 position was observed in their reaction, in
contrast to our result. They proposed the transient formation of
the oxazoline intermediate 5, with the attendant inversion of
configuration at C-3, which then underwent hydrolysis to give 6.
The authors indicated that a rearrangement product 9 also
formed as a byproduct in small yield after the treatment of 8
with NaN3 (Scheme 2b). To our knowledge, this is the only
example that approaches the reaction that we report here.3
Sulfonylation of alcohols is a common transformation in
numerous synthetic processes. This derivatization is generally
performed by utilizing sulfonyl chlorides in the presence of a
base (typically, pyridine, triethylamine, DABCO, and the like),
and gives the desired products in high yield. However, during
the course of our efforts to synthesize 3-O-tosyl glucosamine
derivative 2a, we identified a significant byproduct (Scheme 1).
The byproduct was found to have the same mass as 2a, and the
resonances of both the acetyl and tosyl groups were seen in the
1H NMR spectrum. After full characterization, the byproduct
was assigned the structure 3a, which disclosed an unusual N- to
O-acetyl migration. Our follow-up on this reaction revealed
that this type of acetyl migration could happen with facility
with any number of 2-acetamidoethanol derivatives under
typical sulfonylation conditions.
For tosylation of 1a,1 we initially used a mild condition (TsCl,
pyridine, CH2Cl2, room temperature). However, the starting
material was fully recovered. When heated under reflux in
(2) Calvo-Mateo, A.; Fiandor, J.; De Las Heras, F. G. An. Quim. 1987,
83, 77–80.
(3) The same type of acyl migration to Scheme 2a is known: (a) D’hooghe,
M.; Vervisch, K.; Van Nieuwenhove, A.; De Kimpe, N. Tetrahedron Lett. 2007,
48, 1771–1774. (b) Feng, Z.; Mohapatra, S.; Klimko, P. G.; Hellberg, M. R.;
May, J. A.; Kelly, C.; Williams, G.; McLaughlin, M. A.; Sharif, N. A. Bioorg.
Med. Chem. Lett. 2007, 17, 2998–3002. (c) Gornostaev, L. M.; Sokolova, M. S.
Russ. J. Org. Chem. 2006, 42, 1473–1476. (d) Avenoza, A.; Busto, J. H.; Canal,
N.; Peregrina, J. M. J. Org. Chem. 2005, 70, 330–333.
(1) Compound 1a was prepared from D-glucosamine in 3 steps with an
overall yield of 77%, by a small variation of a known procedures: (a) Berger,
I.; Nazarov, A. A.; Hartinger, C. G.; Groessl, M.; Valiahdi, S.-M.; Jakupec,
M. A.; Keppler, B. K. ChemMedChem 2007, 2, 505–514. (b) Babic, A.; Pecar,
S. Tetrahedron: Asymmetry 2008, 19, 2265–2271.
DOI: 10.1021/jo100456z
r
Published on Web 04/05/2010
J. Org. Chem. 2010, 75, 3515–3517 3515
2010 American Chemical Society

Yamaguchi et al.
JOCNote
SCHEME 2. The Acetyl Migration Reactions of
SCHEME 4. Tosylation of Compound 14
2-Acetamidoethanol Derivatives2
TABLE 1. Tosylation of Various 2-Acetamidoethanol Derivativesa
SCHEME 3. Mechanistic Possibilities of N- to
O-Acetyl Migration of 1a
aThe tosylation was performed under condition A or B. Condition A:
TsCl (1.05 equiv) and pyridine (3 equiv) were added to a solution of
substrate in CH2Cl2 at 0 °C, and the mixture was stirred at room tem-
perature for 24 h. Condition B: TsCl (2 equiv) was added to a solution of
substrate in pyridine at room temperature, and the mixture was heated
under reflux for 30 h. bRecovery of starting substrate. c4-(Acetamido)-
cyclohexanol was used as a substrate in this case.
We carried out a series of additional reactions to gain
insight into the mechanism of this acetyl migration reaction.
Initially, we wondered whether the acetyl group could mig-
rate to the hydroxyl group before the N-tosylation event
(Scheme 3, route A). To examine this possibility, compound
1a was heated under reflux in pyridine for 48 h. However, in
the absence of TsCl, no transformation took place and the
starting compound 1a was recovered as the only compound.
It is also conceivable that the migration product 3a might be
generated from 2a (route D). To confirm this, compound 2a
was heated under reflux in pyridine with and without TsCl
for 48 h. Again, under these conditions starting 2a was fully
recovered. These results, thus, ruled out routes A and D.
Two additional possibilities, routes B and C, can be
envisioned. That is to say that product 3a could be formed
via an intermediate ortho amide, 12, which would be gene-
rated from tosylation of 10 (route B) or through N-tosylation
of the acetamido group of 1a (route C). However, N-tosyla-
tion of an amide moiety (as in route C) generally requires a
strong base such as n-BuLi or LiHMDS.4 Tosylation of a
simple acetamido group in a compound such as 14 under the
same condition as Scheme 1 resulted only in the recovery of
the starting material (Scheme 4). For this reason, route C
might be ruled out. The most probable mechanism would
then be through route B.
To explore the scope of this transformation, we investigated
tosylations of several additional examples (Table 1). Substrates
1b, 1d, and 1g were prepared from the corresponding commer-
cially available amines (see the Supporting Information). To-
sylation of 1b, with the flexible cyclohexane skeleton, also
afforded the acetyl migration compound 3b as the major
product, and O-tosyl product 2b was present in smaller yield
at 9% (entry 1). Unexpectedly, N-tosyl cyclohexanol 15b and
N,O-diacetyl product 16b were present in 25% and 19%,
respectively. We believe that the activated acetyl group of 18
probably migrated via an intermolecular reaction to afford
compounds 15b and 16b (Scheme 5). The structures of products
3b, 15b, and 16b were confirmed by comparison to the reported
data.5 In contrast to this result, tosylation of 1g gave O-tosyl
compound 2g as the major product, and the migration pro-
duct 3g was not seen, as to be expected (entry 6). This result
supports that the migration products 3a and 3b are produced
by intramolecular acetyl migration. The case of the simple
(4) For n-BuLi see: (a) Harling, J. D.; Steel, P. G.; Woods, T. M.; Yufit,
D. S. Org. Biomol. Chem. 2007, 5, 3472–3476. For LiHMDS see: (b) Hong,
S.; Yang, J.; Weinreb, S. M. J. Org. Chem. 2006, 71, 2078–2089.
3516 J. Org. Chem. Vol. 75, No. 10, 2010

Yamaguchi et al.
JOCNote
SCHEME 5. The Proposed Mechanistic Outcome for
Transformations of 1b
the 2-acetamidoethanol motif is common in both natural
products and synthetic samples, this type of acetyl migration
might be generally useful. Also significantly, the type of acetyl
(acyl) migration could be happening as a side product of
consequence in reactions of this type.
Experimental Section
General Procedures for the Tosylation of 2-Acetamidoethanol
Derivatives. Condition A: p-Toluenesulfonyl chloride (1.05 equiv)
and pyridine (3.0 equiv) were added to a solution of substrate
in CH2Cl2 at 0 °C, and the mixture was stirred at room tempera-
ture for 24 h. The solvent was removed under reduced pressure,
and the crude product was purified by silica gel column chro-
matography. Condition B: p-Toluenesulfonyl chloride (2.0 equiv)
was added to a solution of substrate in pyridine, and the mixture
was heated under reflux for 30 h. The mixture was cooled to
room temperature, and the solvent was removed under reduced
pressure. The crude product was purified by silica gel column
chromatography.
SCHEME 6. Mesylation of Compound 1d
2-acetamidoethanol (1c) is of interest (entry 2), as this too gave
the migration product 3c, in the highest yield among the three
products, whereas O-tosyl product 2c was not obtained. We
conclude that acetyl migration can happen with any kind of
2-acetamidoethanol derivatives under typical tosylation condi-
tion. Compound 1d, with a hindered hydroxyl group, afforded
the migration product 3d in 52% yield (entry 3, condition A).
Moreover, under condition B, 3d was obtained in 96% yield.
It is possible that the tertiary alcohol in this example might
have played an entropic role as the intramolecular nucleophile.
1-Deoxy-N-acetylglucosamine 1e, prepared from an oxazoline
derivative,6 wasalsoallowedtoreactwithTsCl(entry 4). In this
case, the migration product 3e was produced in 94%. Com-
pared to compound 1a having the R-benzyloxy group at C-1,
the less-hindered 1e gave the migration product in higher yield.
Meanwhile, tosylation of 2-acetamidophenol (1f) gave O-tosyl
product 2f exclusively in 98% yield (entry 5, conditions A or B).
This result might be due to different reactivity of phenol 1f
compared to alcohols. The structure of 2f was confirmed by
X-ray structure analysis (see the Supporting Information).
We also tested the scope of this type of acetyl migration in
a mesylation reaction. As shown in Scheme 6, mesylation of
compound 1d efficiently afforded migration product 19.
Therefore, the mesylation reaction also can afford the N- to
O-acetyl migration.
Sample Procedure and Data for 2a and 3a. Condition B was
used for compound 1a (100 mg, 0.25 mmol), and the crude pro-
duct was purified by silica gel column chromatography (AcOEt/
hexane, 1:3) to afford 2a (46 mg, 33%) and 3a (74 mg, 53%) as
1
white solids. 2a: H NMR (500 HMz, CDCl3) δ 2.02 (s, 3H,
CH3CO), 2.28 (s, 3H, CH3Ph), 3.68 (dd, J = 9.6, 9.6 Hz, 1H,
H-4), 3.72 (dd, J=10.7, 10.7 Hz, 1H, H-6a), 3.88 (ddd, J=4.8,
9.8, 9.8 Hz, 1H, H-5), 4.21 (dd, J=5.0, 10.4 Hz, 1H, H-6b), 4.46
(ddd, J=3.6, 9.2, 10.4 Hz, 1H, H-2), 4.53 and 4.73 (AB, J=11.9
Hz, 2H, OCH2Ph), 4.92 (dd, J=10.0, 10.0 Hz, 1H, H-3), 5.02 (d,
J = 3.8 Hz, 1H, H-1), 5.37 (s, 1H, CHPh), 6.00 (d, J = 9.0 Hz,
1H, NH), 6.97 (d, J=8.0 Hz, 2H, Ts), 7.19-7.44 (m, 10H), 7.67
(d, J = 8.4 Hz, 2H, Ts); 13C NMR (126 MHz, CDCl3) δ 21.9
(CH3Ph), 23.4 (CH3CO), 52.5 (C-2), 63.6 (C-5), 68.9 (C-6), 70.6
(OCH2Ph), 78.4 (C-3), 79.2 (C-4), 98.0 (C-1), 101.8 (CHPh),
126.4, 128.1, 128.3, 128.4, 128.6, 128.9, 129.2, 129.5, 133.9,
136.7, 136.8, 144.6, 170.6 (CdO); IR 3324, 1656, 1547, 1362,
1182, 1123, 1097 cm-1; HRMS (FAB) calcd for C29H32NO8S
(M þ Hþ), 554.1849, found 554.1848. 3a: 1H NMR (500 HMz,
CDCl3) δ 1.72 (s, 3H, CH3CO), 2.37 (s, 3H, CH3Ph), 3.53 (ddd,
J =3.8, 10.2, 10.2 Hz, 1H, H-2), 3.56 (dd, J =9.7, 9.7 Hz, 1H,
H-4), 3.67 (dd, J=10.3, 10.3 Hz, 1H, H-6a), 3.83 (ddd, J=4.8,
9.8, 9.8 Hz, 1H, H-5), 4.15 (dd, J=4.8, 10.4 Hz, 1H, H-6b), 4.37
and 4.62 (AB, J=11.6 Hz, 2H, OCH2Ph), 4.71 (d, J=3.8 Hz,
1H, H-1), 5.00 (d, J=10.2 Hz, 1H, NH), 5.24 (dd, J=10.1, 10.1
Hz, 1H, H-3), 5.42 (s, 1H, CHPh), 7.21 (d, J=8.4 Hz, 2H, Ts),
7.26-7.39 (m, 10H), 7.62 (d, J=8.4 Hz, 2H, Ts); 13C NMR (126
MHz, CDCl3) δ 20.8 (CH3CO), 21.7 (CH3Ph), 56.8 (C-2), 63.1
(C-5), 68.9 (C-6), 69.4 (C-3), 70.5 (OCH2Ph), 79.4 (C-4), 98.0
(C-1), 101.7 (CHPh), 126.3, 127.1, 128.4, 128.6, 128.6, 128.9,
129.3, 129.9, 136.4, 137.0, 138.4, 143.7, 170.8 (CdO); IR 3356,
1734, 1498, 1337, 1234, 1163, 1090 cm-1; HRMS (ESI) calcd for
C29H31NNaO8S (M þ Naþ), 576.1659, found 576.1662.
In summary, we have demonstrated sulfonylation-induced
N- to O-acetyl migration of 2-acetamidoethanol derivatives.
The acetyl migration proceeds even in a simple compound
such as 2-acetamidoethanol (1c), although the sterically
hindered hydroxyl group is found to be an excellent substrate
for acetyl migration. Furthermore, it is also noteworthy that
the unusual “N- to O-acetyl migration” proceeds under
typical sulfonylation conditions in 2-acetamidoethanol. Since
Acknowledgment. This work was supported by a grant
from the National Institutes of Health.
(5) For compound 3b see: (a) Liu, Y.-K.; Li, R.; Yue, L.; Li, B.-J.; Dhen,
Y.-C.; Wu, Y.; Ding, L.-S. Org. Lett. 2006, 8, 1521–1524. For compound 15b
see: (b) Wang, Z.; Cui, Y.-T.; Xu, Z.-B.; Qu, J. J. Org. Chem. 2008, 73, 2270–
2274. (c) Fan, R.-H.; Hou, X.-L. Org. Biomol. Chem. 2003, 1, 1565–1567.
For compound 16b see: (d) Miller, S. J.; Copeland, G. T.; Papaioannou, N.;
Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629–1630.
(e) Tabanella, T.; Valancogne, I.; Jackson, R. F. W. Org. Biomol. Chem.
2003, 1, 4254–4261.
Supporting Information Available: General experimental
procedures, characterization data for all new compounds, inclu-
ding copies of 1D NMR spectra (1H, 13C NMR, and DEPT) and
2D NMR spectra (H-H COSY and C-H HETCOR), and
crystallographic information file (CIF) for compound 2f. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(6) Hesek, D.; Lee, M.; Yamaguchi, T.; Noll, B. C.; Mobashery, S. J. Org.
Chem. 2008, 73, 7349–7352.
J. Org. Chem. Vol. 75, No. 10, 2010 3517