Dihydropyranone formation by ipso C-H activation in a glucal 3-carbamate-derived rhodium acyl nitrenoid

Article abstract of DOI:10.1021/jo101599q

By using (N-tosyloxy)-3-O-carbamoyl-d-glucal 10, which removes the need for a hypervalent iodine(III) oxidant, we provide evidence for rhodium nitrenoid-mediated ipso C-H activation as the origin of a C3-oxidized dihydropyranone product 3. This system may be especially susceptible to such a pathway because of the ease of forming a cation upon hydride transfer to the rhodium-complexed acyl nitrene.

Full text of DOI:10.1021/jo101599q

NOTE
pubs.acs.org/joc
Dihydropyranone Formation by Ipso C-H Activation in a Glucal
3-Carbamate-Derived Rhodium Acyl Nitrenoid
Brisa Hurlocker, Nadia C. Abascal, Lindsay M. Repka, Elsy Santizo-Deleon, Abigail L. Smenton,
Victoria Baranov, Ritu Gupta, Sarah E. Bernard, Shenjuti Chowdhury, and Christian M. Rojas*
Department of Chemistry, Barnard College, 3009 Broadway, New York, New York 10027, United States
S Supporting Information
b
ABSTRACT: By using (N-tosyloxy)-3-O-carbamoyl-D-glucal 10, which
removes the need for a hypervalent iodine(III) oxidant, we provide evidence
for rhodium nitrenoid-mediated ipso C-H activation as the origin of a C3-
oxidized dihydropyranone product 3. This system may be especially suscep-
tible to such a pathway because of the ease of forming a cation upon hydride
transfer to the rhodium-complexed acyl nitrene.
n the C-H insertion chemistry of metal carbenoids (usually
come from rhodium-complexed nitrene 5, and we discuss the
formation of 3 by analogy to Clark’s hypothesis (eq 1).
Our motivation to investigate the origin of 3 under our
reaction conditions was reinforced by Kirschning’s thorough
studies4a-c on dihydropyranone formation from glycals by
hydroxytosyloxyiodobenzene (Koser’s reagent6). This process,
which transforms a variety of 3O-protected glycals, including tri-
O-acetyl-D-glucal 6, entails initial addition of the iodine(III)
oxidant at the glycal alkene. While Koser’s reagent is considerably
more reactive than the iodosobenzene used in our reactions, a
Kirschning-type route to the 3 formed under our conditions,
perhaps with Lewis acid activation of PhIO by dirhodium-
(II)acetate, was a viable mechanistic option (Scheme 2).7 Fur-
thermore, it was possible that 2 could also form through initial
olefin activation by the iodine(III) oxidant, followed by cycliza-
tion of the carbamate nitrogen and glycosylation.
I
rhodium- but also copper- and ruthenium-stabilized), anom-
alous products can form when hydride transfer to the carbenoid
results in a particularly well-stabilized cation.1 For example, Clark
and co-workers found acetal byproducts in dirhodium(II)-cata-
lyzed reactions of certain R-diazoketones (eq 1).1c,i Mechanistic
investigations led to the conclusion that hydride transfer, prob-
ably to the rhodium center but possibly to the carbenoid carbon
(shown below), provided an oxocarbenium ion en route to the
acetal. In the area of metallanitrene chemistry, meanwhile, there
have been hints of related reactivity, but examples remain
limited.2 Herein, we report our investigations on a system that
is apparently well set up for intramolecular hydride transfer to a
rhodium acyl nitrenoid moiety.
Initially, we engineered a series of control experiments to examine
these options. Neither 2 nor 3 formed from glucal 3-carbamate 1 in
the absence of rhodium.8 We also subjected noncarbamate glycals 6
and 7a,b9 (Figure 1) to our conditions but observed no dihy-
dropyranone formation, even though substrate 7a contained a
3O-silyl ether, making it particularly prone to Kirschning’s oxida-
tion.4a Furthermore, there was no sign of oxidative cyclization or
C3-H oxidation when we tested glucal- or allal-derived N-tosyl
or N-phenyl carbamates 7c-e.9
In an alkene activation mechanism, the Rh2(OAc)4 catalyst
would act as a Lewis acid to increase the electrophilicity of the
iodine(III) center.4d,e,10 Were this the case, other Lewis acids,
despite lacking the nitrene-stabilizing capacity of dirhodium(II),
should also promote formation of 2 and 3. To the contrary, a
number of Lewis acids [Zn(OTf)2, Sm(OTf)3, La(OTf)3] failed
to catalyze the reaction of 1.
During studies on the dirhodium(II)-catalyzed oxidative
cyclization of D-glucal 3-carbamates to oxazolidinone-protected
2-aminoglycosides (e.g., 1f2), we discovered concurrent for-
mation of C3-oxidized dihydropyranones such as 3.3 Our mech-
anistic hypothesis3b was that 2 and 3 both stemmed from a
common acyl nitrenoid intermediate (5), which could undergo
either alkene insertion or C3-H oxidation (Scheme 1). However,
the use of an iodine(III) oxidant4 in conjunction with the known
Lewis acidic properties of Rh(II) carboxylates5 left open the
possibility that 2, 3, or both might be forming via initial reaction
of the hypervalent iodine species at the enol ether π bond. In this
paper, we provide evidence, including examples where 2 and 3
arise from a pre-N-oxidized substrate in the absence of iodine-
(III), that both the amino sugar (2) and C3-oxidation (3) products
Since the control experiments indicated that 2 and 3 do not
arise through initial CdC activation by the iodine(III) species,
Received: September 15, 2010
Published: March 07, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 1. Amidoglycosylation and C3 Carbonyl Formation
from an Acyl Nitrenoid Intermediate
Scheme 3. Preparation of N-Tosyloxy Glucal 3-Carbamate
10 and 3-Azidoformate 11
chromatography on silica gel, but attempts to store it neat, even
at -20 °C, resulted in decomposition to a black tar, probably
indicating formation of O-p-toluenesulfonylhydroxylamine15 upon
decarboxylative loss of the C3 substituent. Nevertheless, 10 was
tractable when freshly prepared, purified by chromatography,
and used promptly in CH2Cl2 solution.
a Combined yield of both anomers after silica gel chromatography.
b Determined by 1H NMR analysis of the crude reaction mixture. Ratios
are the average of five experiments.
Upon treatment with dirhodium(II)acetate16 and K2CO3 in
CH2Cl2, N-tosyloxy glucal 3-carbamate 10 gave a complex
reaction mixture, from which we identified dihydropyranone 3
and primary carbamate 1 by comparison with authentic samples
(Table 1, entry 1). This shows that the C3 carbonyl of 3 can form
from an acyl nitrenoid precursor under conditions where the
Kirschning-type mechanism is impossible. The production of 1
under these conditions may occur via the nitrene by hydrogen
atom abstraction. Lebel has observed analogous products in
reactions of other N-arylsulfonyloxycarbamates.11c In the ab-
sence of dirhodium(II), decomposition of the starting material
10 occurred, but neither 1 nor 3 was detected by 1H NMR anal-
ysis of the reaction mixture.17
Scheme 2. Possible Route to Dihydropyranone 3 via Reaction
of the Glycal Alkene with the Iodine(III) Oxidant
Dirhodium(II)acetate-catalyzed reaction of 10 in the presence
of 4-penten-1-ol as a nucleophile provided R and β amidogly-
cosylation products 2, dihydropyranone 3, and primary carba-
mate 1 (Table 1, entry 2). The ratio of amidoglycosylation to
dihydropyranone formation (2:3) and the R:β ratio of 2 were
similar to the results using the primary carbamate 1 with iodo-
sobenzene oxidant (cf. Scheme 1).18 This is further evidence that
both the iodine(III)-mediated process with 1 and the reaction
starting from pre-N-oxidized substrate 10 proceed through the
same intermediate, the rhodium acyl nitrenoid 5, which parti-
tions between CdC insertion and C3-H activation. Control
experiments including 10 and 4-penten-1-ol, but omitting either
the Rh2(OAc)4 or the inorganic base, consumed the N-tosylox-
ycarbamate but did not lead to detectable formation of products
1, 2, or 3.17 Separately, we verified that a sample of dihydropyr-
anone 3, prepared by PDC oxidation of allylic alcohol 8, was
stable to the combination of Rh2(OAc)4 and K2CO3 in CD2Cl2,
either in the absence or presence of 4-penten-1-ol.
We obtained similar results (Table 1, entry 3), including for-
mation of dihydropyranone 3, with the copper catalyst used in
Fleming’s study,12a suggesting that the analogy between carbe-
noid and nitrenoid chemistry extends both to rhodium and copper
catalysis. Indeed, copper carbenoid reactions corresponding to
the process in eq 1 are known.1k-m
Finally, we prepared glucal 3-azidoformate 11 (Scheme 3) via
the acyl imidazole under aqueous conditions19 and investigated it
as a nitrene source. Photolysis without or with Rh2(OAc)4 (Table 1,
entries 4 and 5) gave the amidoglycosylation product 2, but no
trace of 3.20 The thermal reactions led only to very limited
amounts of products 1-3.21 The catalyst-free thermal reaction
Figure 1. Control compounds that gave neither dihydropyranone
formation nor oxidative cyclization under the amidoglycosylation con-
ditions [PhIO (1.8 equiv), Rh2(OAc)4 (0.1 equiv), 4-penten-1-ol
(5 equiv), 4 Å MS, CH2Cl2].
we next sought to probe whether 2 and 3 form when a rhodium-
complexed nitrene 5 is generated in the absence of any iodine-
(III) oxidant. The means to conduct such a test came from Lebel
and co-workers who have used N-tosyloxycarbamates as a pre-
oxidized nitrogen atom source for dirhodium(II)-catalyzed C-H
and CdC insertions.11 Both the Fleming and Lebel groups have
demonstrated copper-catalyzed variants,12 and Donohoe has
applied a similar strategy, using N-acyloxycarbamates in os-
mium-catalyzed tethered aminohydroxylations.13
We prepared what turned out to be a sensitive N-tosyloxy glucal
3-carbamate 10 from silylene-protected alcohol 89a (Scheme 3).
The intermediate N-hydroxycarbamate 9 was a stable solid.
However, attempted tosylation under Lebel’s and Fleming’s
conditions (TsCl, Et3N, Et2O) provided a complex mixture,
from which we isolated primary carbamate 1 as the principal
component. Evidently, as the desired N-tosyloxycarbamate 10
formed, it underwent base-induced, metal-free nitrene formation
and subsequent hydrogen atom abstraction.11c,14 Using an alter-
native procedure (TsCl, pyr, CH2Cl2), however, provided clean
conversion to the desired 10. This material could be purified by
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NOTE
Table 1. Results Using 10 and 11 as Metal Nitrenoid or
Nitrene Precursors
Scheme 4. Proposed Formation of 3 by Hydride Transfer or
C-H Insertion from the Rhodium Acyl Nitrene
inductive and conformational factors when the 4O and 6O
protecting groups are electron-withdrawing.3b
In conclusion, this study presents evidence that rhodium
acyloxy nitrenoids can undergo ipso carbonyl formation. Certain
glycal 3-carbamate substrates are particularly prone to this path-
way because of the electron-rich character of the C3-H bond
and the stability of the resulting vinylogous oxocarbenium ion. A
better understanding of mechanism will aid efforts to improve
the chemoselectivity of nitrenoid CdC and C-H insertion
processes.
1
a Yields and anomeric ratios determined by H NMR analysis of the
crude reaction mixture with mesitylene as an internal standard. b The
reported value is the average of three experiments. c 254 nm, Vycor filter.
d Not detected, but regions in H NMR spectra of the crude reaction
1
’ EXPERIMENTAL SECTION
mixture that would have contained resonances for 1 were obscured by
other signals. e The R anomer was also detected by 1H NMR analysis, but
the R/β ratio could not be reliably determined due to overlapping
signals.
4,6-O-Di-tert-butylsilylene-3-O-(N-hydroxycarbamoyl)-D-
glucal (9). To a solution of alcohol 89a (0.501 g, 1.75 mmol) in
CH2Cl2 (20 mL) was added 1,10-carbonyldiimidazole (0.425 g, 2.62
mmol). After 2 h at room temperature, the mixture was diluted with
CH2Cl2 (80 mL) and washed with satd aq NH4Cl (3 ꢀ 80 mL). The
organic layer was dried (MgSO4), filtered, and concentrated, providing
the carbonyl imidazole intermediate as a light yellow foam. Without
further purification, this material (assumed 1.75 mmol) was dissolved
in pyridine (4.0 mL), and hydroxylamine hydrochloride (0.365 g,
5.25 mmol) was added. After being stirred for 60 h at room tempera-
ture, the reaction mixture was diluted with CH2Cl2 (80 mL) and
washed with water (2 ꢀ 80 mL) and brine (80 mL). The organic layer
was dried (MgSO4), filtered, and concentrated. The crude product was
chromatographed (30% EtOAc/hexanes, 100 mL SiO2), yielding N-
hydroxycarbamate 9 as a white solid (0.470 g, 78%): mp 110.0 °C; Rf =
0.21 (30% EtOAc/hexanes); IR (thin film) 3315, 1731, 1649 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 6.92 (very br s, 1H), 6.33
(dd, J = 6.0, 1.5 Hz, 1H), 5.34 (dt, J = 7.5, 1.8 Hz, 1H), 4.80 (dd, J = 6.1,
2.1 Hz, 1H), 4.25-4.10 (m, 2H), 4.04-3.85 (m, 2H), 1.05 (s, 9H),
0.99 (s, 9H); 13C NMR22 (75 MHz, CDCl3) δ 160.0 (s), 145.2 (o),
100.3 (o), 74.4 (o), 73.6 (o), 72.8 (o), 65.6 (t), 27.4 (o), 26.8 (o), 22.7
(s), 19.8 (s); HRMS (FAB) m/z calcd for C15H28NO6Si (M þ H)þ
346.1686, found 346.1688.
4,6-O-Di-tert-butylsilylene-3-O-(N-tosyloxycarbamoyl)-D-
glucal (10). N-Hydroxycarbamate 9 (105 mg, 0.304 mmol) was
dissolved in CH2Cl2 (1.5 mL), and pyridine (74 μL, 0.92 mmol) was
added, followed by p-toluenesulfonyl chloride (89 mg, 0.47 mmol). The
solution was stirred at 25 °C during 4.5 h, diluted with CH2Cl2 (25 mL),
and washed with water (2 ꢀ 20 mL) and brine (1 ꢀ 20 mL). The
organic layer was dried (MgSO4), filtered, and concentrated. The crude
material was chromatographed immediately (20f25f30% EtOAc/
hexanes, 50 mL of SiO2). Because 10 was prone to decomposition when
kept neat for extended periods of time, the yield was determined by
weight after concentration on the rotovap, followed by 5 min on the
(entry 6) gave none of the dihydropyranone 3, while a detectable
level of this material did form when Rh2(OAc)4 was included
(entry 7). From our experiments with 11, we conclude that the
metal-free nitrene undergoes the amidoglycosylation process to 214a
but does not provide C3-oxidized 3. Also, the rhodium-complexed
nitrene is not constituted photochemically but does arise to a small
extent thermally, as suggested by formation of 3 in the reac-
tion of entry 7.
The significance of the findings outlined in this paper lies in
clarifying the origin of the ipso-oxidized 3 rather than from the
synthetic utility of the process. In fact, the use of either N-tosyloxy
glucal 3-carbamate 10 or azidoformate 11 is considerably less
effective for the desired alkene insertion process than using pri-
mary carbamate 1 with iodosobenzene and Rh2(OAc)4 as
depicted in Scheme 1.
While our results do not provide detailed information about
the nitrene-mediated C3-H oxidation process, possibilities
include C-H insertion followed by fragmentation of the result-
ing four-membered-ring carbamate 12 (Scheme 4), as suggested
in the work of Du Bois.2a,b Alternatively, particularly in 5 where the
C3-H bond is vinylogously anomeric and favorably aligned with
the enol etherπ system, the oxidation may involve hydride transfer
(5f13), leading to the resonance-stabilized cationic portion of
zwitterion 13. Given the analogous processes previously identified
for dirhodium(II) carbenoids,1 hydride transfer to the acyl carbo-
nyl, to the rhodium center, or directly to nitrogen (as shown in
Scheme 4) are all viable alternatives. Consistent with hydride
migration from C3 to the metallanitrene, we have recen-
tly reported that dihydropyranone formation is suppressed by
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NOTE
vacuum line. The resulting product 10, a colorless foam (∼120 mg, 80%),
consequently contained traces of solvent, and the reported yield is
therefore approximate. After weighing, 10 was dissolved in CH2Cl2
(1.0 mL) and used immediately: Rf = 0.52 (30% EtOAc/hexanes); IR
(thin film) 3281, 1775, 1736, 1647, 1597 cm-1; 1H NMR (300 MHz,
CD2Cl2) δ 8.20 (s, 1H), 7.86 (apparent d, J = 8.4 Hz, 2H), 7.37
(apparent d, J = 8.0 Hz, 2H), 6.31 (dd, J = 6.0, 1.4 Hz, 1H), 5.21 (dt, J =
7.4, 1.8 Hz, 1H), 4.53 (dd, J = 6.1, 2.0 Hz, 1H), 4.16 (dd, J = 9.6, 4.4 Hz,
1H), 4.03 (dd, J = 10.2, 7.4 Hz, 1H), 3.95 (t, J = 9.9 Hz, 1H), 3.87 (td, J =
10.1, 4.5 Hz, 1H), 2.45 (s, 3H), 1.05 (s, 9H), 0.96 (s, 9H); 13C NMR22
(75 MHz, CD2Cl2) δ 155.9 (s), 147.0 (s), 146.1 (o), 131.0 (s), 130.4
(o), 130.0 (o), 100.0 (o), 75.7 (o), 73.9 (o), 73.4 (o), 66.2 (t), 27.7 (o),
27.2 (o), 23.1 (s), 22.1 (o), 20.2 (s); HRMS (FAB) m/z calcd for
C22H34NO8SiS (M þ H)þ 500.1774, found 500.1760.
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Reaction of 10 Including 4-Penten-1-ol. Potassium carbonate
(96 mg, 0.69 mmol) and Rh2(OAc)4 (11 mg, 0.025 mmol) were
combined in a 10 mL round-bottom flask, and 4-penten-1-ol (125 μL,
1.23 mmol) was added, followed immediately by a solution of freshly
prepared N-tosyloxycarbamate 10 (∼114 mg, 0.228 mmol) in CH2Cl2
(1.0 mL). The carbamate-containing pear-shaped flask was rinsed with
CH2Cl2 (2 ꢀ 1.0 mL) with the rinsings being added to the reaction
mixture. The well-stirred mixture turned from a blue-green-gray to a
purple color within 20-30 min. Stirring was continued for 16 h, and the
purple mixture was filtered through a tightly packed pad of Celite, rinsing
with EtOAc (80 mL). The filtrate was concentrated and the crude
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1
material analyzed by H NMR (separately in CDCl3 and acetone-d6),
with comparison to authentic samples of 1-3. The 2:3 and 2-r:2-β
ratios were best measured in acetone-d6 from the resonances for H3 of 2-
r (δ 4.56), H1 of 2-β (δ 4.86), and H2 of 3 (δ 5.33). The yields were
determined by 1H NMR analysis of the crude in CDCl3 using the H1
signals for 2-r and 2-β (δ 4.81 and δ 4.69, respectively), the H2 signal
for 3 (δ 5.41), and the H3 signal for 1 (δ 5.27) versus mesitylene added
as an internal standard. The reported ratios and yields are the averages
from three separate runs.23
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’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental details,
b
including preparation and characterization of compounds 7a-e,
procedures for control experiments, and copies of H and 13C
1
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: crojas@barnard.edu.
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’ ACKNOWLEDGMENT
We thank the National Institutes of Health (R15 GM081889-
03) and the National Science Foundation (CHE-0957181) for
generous support. The Howard Hughes Medical Institute Science
Pipeline Project and the Barnard College Bernice Segal Fund
provided undergraduate student summer research fellowships.
We are grateful to Ms. Kimberly Sogi for early studies with glucal
3-azidoformates and to Dr. Yasuhiro Itagaki (Columbia Uni-
versity) for mass spectrometric analyses.
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(1) Rhodium: (a) Doyle, M. P.; Dyatkin, A. B.; Autry, C. L. J. Chem.
Soc., Perkin Trans. 1 1995, 619–621. (b) Lee, E.; Choi, I.; Song, S. Y.
J. Chem. Soc., Chem. Commun. 1995, 321–322. (c) Clark, J. S.; Dossetter,
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The Journal of Organic Chemistry
NOTE
and Utility; Scriven, E. F. V., Ed.; Academic Press: New York, 1984;
pp 205-246.
(15) Begtrup, M. In e-EROS Encyclopedia of Reagents for Organic
Synthesis; John Wiley & Sons: New York, 2004.
(16) With substrate 10, Rh2(OAc)4 gave better results than
dirhodium(II)triphenylacetate [Rh2(tpa)4]. The latter catalyst was
preferred in Lebel’s studies (see ref 11c).
(17) The crude reaction mixtures were analyzed by 1H NMR
(CDCl3 and/or acetone-d6) and TLC with comparison to authentic
samples of 1-3. See the Supporting Information for details.
(18) Differences in the mean values for the 2-r:2-β and the 2:3
ratios for the reactions in Scheme 1 and Table 1, entry 2, are quite small
but nevertheless statistically significant according to a Student’s t test
analysis (see the Supporting Information for details). We attribute this
to the effect of the different reaction conditions (especially the presence
of K2CO3 in reactions of 10) on trapping of the intermediate glycosyl
donor formed by CdC insertion of the acyl nitrenoid.
(19) Yoshimitsu, T.; Ino, T.; Futamura, N.; Kamon, T.; Tanaka, T.
Org. Lett. 2009, 11, 3402–3405.
(20) Control experiments showed that 3 degrades by about 60% in 1
h under the photolysis conditions. Because we used limited photolysis
times and examined the reaction mixtures at partial conversion, we
expect that 3 would have been detected had it formed during photolysis
of 11. See the Supporting Information for complete experimental details.
(21) The main product was allylic substitution by 4-penten-1-ol at
C1 upon loss of the -OC(O)N3 group from C3.
(22) 13C NMR peak multiplicities were inferred via DEPT 135
measurements. The label “o” (for odd number of attached hydrogens)
denotes a CH or CH3, “s” denotes a carbon with no attached hydrogens,
and “t” denotes a CH2.
(23) See the Supporting Information for standard deviations.
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