Photochemical and thermal ring-contraction of cyclic hydroxamic acid derivatives

Article abstract of DOI:10.1021/jo3023507

Cyclic hydroxamic acids can undergo a thermal ring contraction after an in situ triflation. High yields of ring-contraction products are obtained with DBU when the migrating carbon is a methylene, while best results are obtained with Et₃N for the migration of quaternary carbons. In some cases, the regiochemical outcome of the reaction can be controlled by changing the base. This novel thermal rearrangement complements a similar but photochemical rearrangement of N-mesyloxylactams.

Full text of DOI:10.1021/jo3023507

Article
pubs.acs.org/joc
Photochemical and Thermal Ring-Contraction of Cyclic Hydroxamic
Acid Derivatives
Simon Pichette, Samuel Aubert-Nicol, Jean Lessard,* and Claude Spino*
́ ́
Departement de Chimie, Universite de Sherbrooke, Sherbrooke, Quebec, Canada J1K 2R1
S
* Supporting Information
ABSTRACT: Cyclic hydroxamic acids can undergo a thermal ring
contraction after an in situ triflation. High yields of ring-
contraction products are obtained with DBU when the migrating
carbon is a methylene, while best results are obtained with Et3N for
the migration of quaternary carbons. In some cases, the
regiochemical outcome of the reaction can be controlled by
changing the base. This novel thermal rearrangement complements
a similar but photochemical rearrangement of N-mesyloxylactams.
Scheme 2. Rearrangements of N-Substituted Lactams
INTRODUCTION
■
Reactions in which a carbon migrates from a carbonyl to a
nitrogen atom, such as the Curtius, Hofmann, Schmidt and
Lossen rearrangement, are frequently used methods to make a
chiral carbon bearing a nitrogen atom (Scheme 1).1 There are
Scheme 1. Lossen-Type Rearrangements
rearrangements, divulging for the first time the thermal ring-
contraction and emphasizing the complementarity of the three
methods.
RESULTS AND DISCUSSION
■
A priori, there seems to be little difference between the three
methods shown in Scheme 2: all of them start with a N-
activated lactam 1−3 and lead to the regioisomeric products 4
or 5. In reality, the three methods are complementary and
display major differences in yields, regiochemistry, or methods
of preparation of the N-activated lactams.
several advantages to using these rearrangements to make a C−
N bond, not the least of which are their stereospecificity and
the comparative ease of preparation of carbonyl compounds
with an α-chiral carbon.2 In particular, quaternary chiral
carbons (Scheme 1; a, b, c = carbons) bearing nitrogen are
difficult to prepare by other means. However, such rearrange-
ments are only possible on primary amide derivatives:
secondary amide or lactam derivatives cannot be converted to
the corresponding carbamate.3 In the context of synthetic
strategies, this limits the “amine” component to ammonia or its
equivalent.
We have recently reported on the photochemical rearrange-
ment of N-chlorolactams4 and N-mesyloxylactams,5 currently
the only methods able to effect such migration on secondary
amides.6 Since these reports, we have developed a thermal
rearrangement of cyclic hydroxamic acids (Scheme 2), which
not only complements the current photochemical methods but
also gives an unprecedented level of control over the
regiochemical outcome of the ring-contraction event for certain
substrates. We wish to report here a full account of these
N-Chlorolactams, for example, are best prepared by direct N-
chloration of lactams in high yield (Scheme 3, 6 → 1a).4 So far,
we have not been able to develop a general and satisfactory
oxidation method to convert lactams to hydroxamic acids.7
Cyclic hydroxamic acid derivatives 3 can be prepared by
amidation (Scheme 3, 7 → 3i), cyclization (8 → 3b) or
Mitsunobu reactions (10 → 3c).5 Such methods are unsuitable
to make N-chlorolactams. O-Alkylation to produce cyclic
iminoethers 9 is a potential problem in the latter two reactions,
but one can distinguish the two products easily by 13C NMR
(the carbonyl signal is between 175 and 180 ppm for the
Received: October 24, 2012
Published: November 30, 2012
© 2012 American Chemical Society
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Scheme 3. Preparation of N-Chlorolactams and Cyclic Hydroxamic Acids
Scheme 4. Photochemical Ring-Contraction of N-Mesyloxylactams and N-Chlorolactams5
hydroxamic acids 3, while the iminoether signal is between 150
and 155 ppm in the O-alkylation products 9). Of course, these
methods of preparation are shown as useful suggestions and
should not be considered as a necessary part of the overall
sequence. We have used a number of other ways to prepare
these cyclic precursors to the rearrangement products,
including metathesis for example.
chlorolactams 1.5 Invariably, the former leads to higher yields
of products than the latter upon irradiation at 254 nm (Scheme
4). The main issue with N-chlorolactams was the formation of
the parent lactam and byproducts derived from side reactions of
the initially formed chlorine radical. Such byproducts were
never detected upon irradiation of N-mesyloxylactams. The
ring-contraction of N-mesyloxylactams is synthetically useful
starting from 6- to 8-membered rings, so long as the carbon α
to the amide carbonyl bears one or more substituents (Scheme
In earlier work, we have compared the photochemical
rearrangement of N-mesyloxylactams 2 with that of N-
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Scheme 5. Replacement of CO by N−CO2Me in a Cyclic Structure6
4, 2a,b,d−f). On the other hand, the direct chloration of lactam
allows one to obtain the N-chlorolactam in two steps from the
corresponding ketone via a Beckmann rearrangement (Scheme
5). The corresponding hydroxamic acid of 1g would be difficult
to obtain. The ring-contraction of rigid bicyclic N-chlorolactam
1g gave a synthetically useful 57% of product 4g (Scheme 5).4b
Conspicuously absent from Scheme 4 are examples of the
ring-contraction of 3-unsubstituted lactam derivatives. Un-
subtituted N-chlorovalerolactam 1h gave a low 5% yield of
rearranged product 4h upon irradiation, the remainder being
mostly the parent δ-valerolactam (Scheme 6).4 The N-
Scheme 7. Thermal Ring-Contraction of Cyclic Hydroxamic
Acid 3i and Photochemical Rearrangement of Its Analogue
N-Mesyloxylactam 2i
Scheme 6. Rearrangements of 3-Unsubstituted
Valerolactams
Table 1. Effect of the Base on the Rearrangement of
Hydroxamic Acid 3i or N-Mesyloxylactam 2i
C3
C5
starting
product
product
total
a
b
b
entry material conditions
base
(4i) (%) (5i) (%) (%)
1
13i
13i
3i
A
A
B
B
B
B
B
C
C
C
C
C
C
−
33
31
46
70
17
11
16
22
14
63
49
43
33
−
−
−
33
31
46
70
58
61
81
46
47
63
61
50
33
2
NaOMe
K2CO3
DBU
DMAP
Pyridine
Et3N
−
Et3N
DBU
−
3
4
3i
−
5
3i
41
50
65
24
33
−
mesyloxyvalerolactam 2o gave 32% of rearranged product 4o,
the remainder being decomposition material. The migrating
carbon in these compounds may not be sufficiently electron-
rich for the reaction to proceed at a competitive rate.
6
3i
7
3i
8
13i
13i
13i
2i
9
It was with this particular problem in mind that we decided
to explore other leaving groups in the hope of favoring
migration over other pathways. We should mention that
additives such as silver nitrate did not improve the situation
when used in conjunction with N-chlorolactams, nor did the
use of other Lewis acids increase the yields of products in the
case of N-chloro or N-mesyloxylactams. However, when we
performed the triflation of cyclic hydroxamic acid 3i, it became
apparent that it underwent partial rearrangement before we
could submit it to irradiation (Scheme 7). Heating it in
refluxing methanol without base gave 33% of pyrrolidine 4i
(Table 1, entry 1). This result was somewhat surprising since
N-chloro-, N-mesyloxy- or N-tosyloxylactams are inert below
190 °C.8 Above that temperature, they may undergo a thermal
rearrangement but usually in low yields.
We believed that the addition of a base during the
rearrangement, to remove triflic acid as it forms, could help
increase the yield of the rearrangement product. We therefore
tested a variety of bases, and the results are reported in Table 1.
The addition of NaOMe did not improve the yield of product
4i (entry 2), but K2CO3 did, albeit slightly (entry 3). A much
better result was obtained using DBU (70%, entry 4). This is
the first example of a 3-unsubstituted lactam derivative to
undergo the rearrangement in high yield. Such a high yield was
surprising, but even more surprising was the influence of the
10
11
12
13
12
c
2i
Et3N
7
2i
DBU
0
a
Conditions A: MeOH, base, reflux. Conditions B: (i) CH2Cl2, Tf2O;
(ii) evaporate, MeOH, base, reflux. Conditions C: MeOH, base, 250
b
c
nm, −78 °C. Isolated yield. Not isolated; ratio determined by NMR
of crude reaction mixture.
base on the regioselectivity of the reaction. Indeed, when
replacing DBU with other nitrogen-based bases such as DMAP,
pyridine or Et3N, we observed a reversal of the selectivity in
favor of the C5 rearrangement product 5i (Scheme 7 and Table
1, entries 5−7)!
A control experiment was performed by irradiating the
triflate derivative 13i (derived from 3i and isolated) at 254 nm
in methanol. In the absence of base, 22% of 4i and 24% of 5i
were obtained (Table 1, entry 8). In the presence of Et3N, the
C5-rearrangement product was again favored, with isolated
yields of 14% 4i and 33% 5i (entry 9). As we suspected, in the
presence of DBU only the C3-rearrangement product 5i was
obtained in 63% isolated yield (entry 10). We photolyzed the
N-mesyloxy derivative 2i in the absence of base (entry 11) or
the presence of Et3N (entry 12) or DBU (entry 13), for
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Figure 1. Possible competing transition states in the thermal rearrangement of N-trifloxylactams.
comparison, and found that the C3 product 4i is predominant,
regardless of the nature of the base used.
DBU and Et3N can be attributed to the development of ring-
strain in the corresponding products, especially in the case of
5m.
In cyclic hydroxamic acid derivatives, two C−C bonds are
well aligned with the σ* orbital of the N−O bond, thus
enabling the formation of two rearrangement products: the C3
and the C5 migration products (Figure 1). This nearly locked-
in alignment of the migrating bond with the departing group is
crucial for the efficiency of the rearrangement, perhaps
explaining why acyclic N-activated amides do not usually
undergo this reaction efficiently.5a The carbonyl lone pair
should assist the migration of the C3 carbon, much like the
intramolecular Schmidt reaction of azidohydrin intermediates
where the lone pair of the hydroxyl group dictates the
regiochemistry of the rearrangement (Figure 1, bottom).9
Indeed, the normal preference we observe is for migration of
the C3 carbon (via transition state C3-A in Figure 1). The same
preference for C3 migration is also observed upon irradiation of
N-mesyloxylactams or N-chlorolactams.5 However, in sub-
strates such as 3i−l, this preference is much less pronounced,
contrary to the Schmidt reaction just mentioned that never
gives the product equivalent to a C5-migration (via transition
state C5-D in Figure 1). Moreover, the dependence of the
regiochemistry on the nature of the base, in the case of
substrates 3i−l, has no precedent that we are aware of. A more
in-depth mechanistic study is required to elucidate the role of
the base in the regioselectivity.
We investigated other substrates to test the generality of this
new thermal ring-contraction and to determine more fully its
regiochemical particularities. The prospect of exercising a
control over the regiochemical outcome was indeed appealing.
We soon established that in most cases, it is possible and
desirable to perform the whole operation in one-pot by simply
evaporating the dichloromethane after triflation, adding
methanol and the base, and heating.
Several trends can be discerned from the results shown in
Table 2. First, the use of DBU gives good yields of the C3-
rearrangement product 4 and better yields than the use of Et3N
when the C3-position is unsubstituted (entries 1−3, 5, 6);
second, the use of Et3N gives similar or higher yields of product
4 than DBU when the substrate possesses at least one
substituent at C3 (entries 7−16); third, and most importantly,
while the use of DBU leads exclusively to the C3-rearrange-
ment product 4 in most cases, no matter the substitution (all
entries except entries 2 and 4), the use of Et3N allows for the
regioselective formation of the C5-rearrangement product 5 in
some substrates (Table 1, entry 7 and Table 2, entries 1−4).
The formation of large amounts of the C5-rearrangement
products 5k and 5m from 3k and 3m, respectively, with both
The C5 rearrangement product 5 was obtained only with
substrates bearing both an alkyl group at position 6 and at
position 5 (Table 1, entry 7, and Table 2, entries 1−4). None of
the corresponding product 5 was obtained from the rearrange-
ment of substrate 3n bearing two methyl groups at position 5
but no substituent at position 6 (entry 5) or of substrate 3o
bearing only a methyl at position 6 (entry 6). Substitution at
position 6 is necessary to stabilize the developing positive
charge in the product 5 (Figure 1). This stabilization competes
with the stabilization provided by the carbonyl’s lone pair of
electrons during migration of the C3 carbon. The fact that the
migration of electron-rich carbons is faster explains the need for
substituents at position 5.
The thermal rearrangement of N-trifloxylactams under these
reaction conditions is tolerant of spectator functional groups.
The results shown in entries 14−16 demonstrate that esters,
silyl ethers, acetals and epoxides are all compatible with the
reaction conditions. By contrast, an acetonide group was
hydrolyzed to the corresponding diol in the photochemical
rearrangement of a N-mesyloxy lactam.5a In addition, the
rearrangement can be performed in alcohols other than
methanol. For example, the N-benzylcarbamate (Cbz) 33,
analogue of 4i (c.f. Scheme 7, MeO = BnO), was obtained in
60% yield by heating the triflate 13i at 70 °C in benzyl alcohol
in the presence of DBU.
In cases where the C5 rearrangement can compete with the
C3 rearrangement, we now have the possibility to control the
regioselectivity of the rearrangement simply by choosing the
appropriate base. For example, substrates 3j, 3k, 3l and 3i led
exclusively or mostly to the corresponding C3-rearrangement
product 4 when DBU was used but gave predominantly or
exclusively the corresponding C5-rearrangement product 5
when Et3N was utilized (Table 1, entry 7 and Table 2 entries
1−3).
The underlying reasons for the regioselectivity brought about
by a simple change in base with substrates 3j, 3k, 3l and 3i is
not well understood at the moment. We speculate that DBU
may favor the addition of methanol to the carbonyl of the
amide derivative thereby promoting the C3-rearrangement.
Possibly, the weaker bases like Et3N or pyridine do not favor
this pathway and instead may let the regiochemical outcome of
the reaction be decided by the relative migrating abilities of C3
vs. C5 as well as by the degree of substitution at C6. However,
the reason why the thermal rearrangement of N-trifloxylactams
with Et3N leads to a different regioisomer as compared to the
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Table 2. Thermal Rearrangements of Cyclic Hydroxamic Acids 3a,c,d,j−u in the Presence of DBU or Et3N and Photochemical
Rearrangements of the Corresponding N-Mesyloxy 2a,c,d,j−u
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Table 2. continued
a
b
Isolated yields. Isolated as a mixture of the usual C5 product 5 and the corresponding enamide 14 (derived from 3j,k) and enamide 15 (derived
c
from 3l,m) (Figure.2). Represents the highest yield obtained with 3o (15−68%). We believe the instability of the triflate intermediate may be at the
origin of this nonreproducibility. Combined yield of carbamate 4p (8%), isocyanate 16 (15%) and acyclic carbamate 17 (40%), all of which are C3-
d
e
migration products (Figure 2). Compound 18 (Figure 2) was also isolated (21% using DBU and 15% using Et3N); see the Supporting Information.
f
Rearrangement performed using the same procedure, but the triflate derivatives 13s (entry14) and 13u (entry 16) were isolated and purified
between steps i and ii (c.f. Scheme 7).
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To a solution of this oxime (20) (7.00 g, 28.1 mmol) in acetic acid
(95 mL) was added portionwise sodium cyanoborohydride (3.64 g,
56.2 mmol). The reaction mixture was stirred at rt for 2.25 h and at 80
°C for 30 min before it was added dropwise into a 5 N aqueous NaOH
solution (400 mL) at 0 °C. The aqueous layer was extracted with
dichloromethane (3 × 100 mL), and the organic extracts were
combined, dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. 1-Benzyloxy-6-methylpiperidin-
2-one (21) (5.79 g, 94%) was obtained as colorless oil: 1H NMR (300
MHz, CDCl3) δ (ppm) 7.49−7.42 (m, 2H), 7.41−7.31 (m, 3H), 5.04
(d, 1H, J = 10.0 Hz), 4.90 (d, 1H, J = 10.0 Hz), 3.61 (sext, 1H, J = 6.3
Hz), 2.46 (t, 2H, J = 6.1 Hz), 2.00−1.74 (m, 2H), 1.72−1.54 (m, 2H),
1.29 (d, 3H, J = 6.3 Hz); 13C NMR (75.5 MHz, CDCl3) δ (ppm)
167.7 (s), 135.5 (s), 129.3 (d), 128.5 (d), 128.4 (d), 76.1 (t), 56.5 (d),
33.5 (t), 31.4 (t), 19.3 (q), 18.5 (t); IR (CHCl3) ν (cm−1) 3065, 3037,
2978, 2950, 2884, 1657, 1450, 1406, 1381, 1325, 1294, 1159, 1078;
LRMS (m/z, relative intensity) 242 (MNa+, 100), 220 (MH+, 7);
HRMS calculated for C13H17NO2Na 242.1152, found 242.1154.
1-Benzyloxy-6-methylpiperidin-2-one (21) (5.79 g, 26.4 mmol) was
dissolved in anhydrous ethanol (275 mL) at rt. Then, 5% Pd/C (500
mg) was added, and the solution was degassed by bubbling argon
through for 10 min. Argon was replaced by hydrogen, and the latter
was bubbled into the solution for several seconds. The solution was
stirred under hydrogen for 1 h, and argon was bubbled through the
solution for another 10 min. The reaction mixture was filtered over
Celite, and the filter cake was washed with anhydrous ethanol. The
solvent was removed under reduced pressure to give product 3o as
Figure 2. Compounds 14−18.
photochemical rearrangement of the corresponding N-
mesyloxylactam is puzzling.
In summary, we have presented the first thermal Lossen-type
rearrangement of secondary amide derivatives. In addition to
improved yields of rearrangement products, this method is
complementary to our previously reported photochemical
rearrangements of N-chloro- and N-mesyloxylactams.4,5 Efforts
to uncover the exact reaction mechanism and to explain the
base-dependent regiochemistry are currently under way.
1
orange oil (3.28 g, 96%): H NMR (300 MHz, CDCl3) δ (ppm)
EXPERIMENTAL SECTION
3.91−3.79 (m, 1H), 2.45 (t, 2H, J = 6.2 Hz), 2.13−1.98 (m, 1H),
1.95−1.81 (m, 1H), 1.79−1.60 (m, 2H), 1.36 (d, 3H, J = 6.2 Hz); 13C
NMR (75.5 MHz, CDCl3) δ (ppm) 165.4 (s), 55.6 (d), 31.4 (t), 30.7
(t), 19.1 (q), 18.0 (t); IR (CHCl3) ν (cm−1) 3519−3025 (br), 2959,
2871, 1604, 1450, 1391, 1331, 1300, 1162, 1093; LRMS (m/z, relative
intensity) 152 (MNa+, 100), 130 (MH+, 11); HRMS calculated for
C6H11NO2Na 152.0682, found 152.0679.
1-Hydroxy-3,3-dipropylazepan-2-one (3r). To a solution of
AlMe3 (2 M in hexanes, 59.4 mL, 119 mmol) in THF (235 mL) at
−10 °C was added O-benzylhydroxylamine hydrochloride (19.0 g, 119
mmol) portionwise. The reaction mixture was stirred at −10 °C for 30
min and at rt for 30 min. The solution was cooled back to −10 °C
before a solution of 3,3-diallyloxepan-2-one 22 (7.69 g, 39.6 mmol) in
THF (20 mL) was added dropwise. The reaction mixture was stirred
15 min at −10 °C and 2 h at rt before a 1 N aqueous HCl solution was
added carefully. When all of the AlMe3 was quenched, the solution was
allowed to warm to rt. The aqueous layer was extracted with
dichloromethane (3 × 200 mL), and the organic extracts were
combined, dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The crude product was purified
by flash chromatography on silica gel using ethyl acetate and hexanes
(60:40) as eluent to give the product as a sticky gum (12.5 g, 99%)
that was used in the next reaction without purification.
Diisopropylazodicarboxylate (12.2 mL, 58.9 mmol) was added to a
solution of triphenylphosphine (15.5 g, 58.9 mmol) in dichloro-
methane (355 mL). The solution was stirred at rt for 30 min before
the addition of the product of the previous step dissolved in
dichloromethane (10 mL). The reaction mixture was stirred at rt for
18 h, and the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography on silica gel using ethyl
acetate and hexanes (10:90) as eluent to give 3,3-diallyl-1-(benzyloxy)-
azepan-2-one (23) as colorless oil (5.34 g, 45%): 1H NMR (300 MHz,
CDCl3) δ (ppm) 7.45−7.40 (m, 2H), 7.39−7.31 (m, 3H), 5.80 (dddd,
2H, J = 20.7, 9.3, 7.3, 7.3 Hz), 5.14−5.03 (m, 4H), 4.88 (s, 2H), 3.65−
3.61 (m, 2H), 2.48 (dd, 2H, J = 13.8, 7.3 Hz), 2.30 (dd, 2H, J = 13.8,
7.3 Hz), 1.68−1.47 (m, 6H); 13C NMR (75.5 MHz, CDCl3) δ (ppm)
174.1 (s), 135.8 (s), 134.1 (d), 129.5 (d), 128.4 (d), 128.2 (d), 118.0
(t), 75.8 (t), 52.8 (t), 47.0 (s), 41.5 (t), 31.6 (t), 26.6 (t), 22.4 (t); IR
(CHCl3) ν (cm−1) 3003, 2981, 2943, 2878, 1641, 1450, 1391, 1359,
1309, 1262, 996, 915; LRMS (m/z, relative intensity) 322 (MNa+,
100), 300 (MH+, 15); HRMS calculated for C19H25NO2Na 322.1778,
found 322.1775.
■
All reactions were performed under an inert atmosphere of argon in
glassware that had been flame-dried. Solvents were distilled from
potassium/benzophenone ketyl (THF), from calcium hydride
(CH2Cl2, toluene) and from 4 Å molecular sieves (MeOH) prior to
use. Triflic anhydride and DBU were distilled prior to use. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded on a
300 or 400 MHz spectrometer. NMR samples were dissolved in
chloroform-d (unless specified otherwise), and chemical shifts are
reported in ppm relative to the residual undeuterated solvent. Carbon
nuclear magnetic resonance (13C NMR) spectra were recorded on a
75.5 or 100.7 MHz spectrometer. NMR samples were dissolved in
chloroform-d (unless specified otherwise), and chemical shifts are
reported in ppm relative to the solvent. LRMS analyses were
performed on a GC system spectrometer (30 m length, 25 μ OD,
DB-5 ms column) coupled with a mass spectrometer. High-resolution
spectrometry was performed by electrospray time-of-flight. Reactions
were monitored by thin-layer chromatography (TLC) on 0.25 mm
silica gel coated glass plate UV 254. Silica gel (particle size: 230−400
mesh) was used for flash chromatography. Melting points are
uncorrected
1-Hydroxy-6-methylpiperidin-2-one (3o). Methyl 5-oxohexa-
noate 19 (4.84 g, 33.6 mmol) was dissolved at rt in a 2:1 mixture of
H2O (63 mL) and methanol (32 mL). Sodium acetate (13.8 g, 168
mmol) and O-benzylhydroxylamine hydrochloride (6.43 g, 40.3
mmol) were successively added. The reaction was stirred for 3.5 h
at reflux temperature, after which time the methanol was removed
under reduced pressure. The residue was diluted with water (200 mL)
and extracted with dichloromethane (3 × 100 mL). The organic
extracts were combined, dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel using a mixture of
ethyl acetate and hexanes (10:90) as eluent to give methyl 5-
1
(benzyloxyimino)hexanoate (20) as colorless oil (7.00 g, 84%): H
NMR (300 MHz, CDCl3) δ (ppm) 7.37−7.27 (m, 5H), 5.07 (s, 2H),
3.67 (s, 3H), 2.31 (t, 2H, J = 7.3 Hz), 2.21 (t, 2H, J = 7.3 Hz), 1.87 (s,
3H), 1.84 (quint, 2H, J = 7.3 Hz); 13C NMR (75.5 MHz, CDCl3) δ
(ppm) 173.6 (s), 157.0 (s), 138.3 (s), 128.2 (d), 127.9 (d), 127.5 (d),
75.3 (t), 51.4 (q), 35.1 (t), 33.1 (t), 21.5 (t), 14.2 (q); IR (CHCl3) ν
(cm−1) 3065, 3037, 2953, 2874, 1725, 1453, 1367, 1262, 1159, 1043;
LRMS (m/z, relative intensity) 272 (MNa+, 100), 250 (MH+, 12);
HRMS calculated for C14H19NO3Na 272.1257, found 272.1260.
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3,3-Diallyl-1-(benzyloxy)azepan-2-one (23) (5.34 g, 17.8 mmol)
was dissolved in anhydrous ethanol (180 mL) at rt. Then, 10%
palladium hydroxide on activated carbon (500 mg) was added, and the
solution was degassed by bubbling argon for 10 min. Argon was
replaced by hydrogen, and the latter was bubbled in the solution for
several minutes. The solution was stirred under hydrogen for 2 h, and
argon was bubbled through the solution again for another 10 min. The
reaction mixture was filtered over Celite, and the filter cake was
washed with anhydrous ethanol. The solvent was removed under
reduced pressure to give product 3r as colorless oil (3.45 g, 91%): 1H
NMR (300 MHz, CDCl3) δ (ppm) 3.80−3.72 (m, 2H), 1.86−1.67
(m, 4H), 1.64−1.45 (m, 6H), 1.35−1.17 (m, 4H), 0.90 (t, 6H, J = 7.2
Hz); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 172.9 (s), 50.5 (t), 46.0
(s), 38.7 (t), 32.0 (t), 26.8 (t), 22.6 (t), 16.9 (t), 14.5 (q); IR (CHCl3)
ν (cm−1) 3435−3022, 2950, 2874, 1588, 1444, 1378, 1334, 1272,
1162, 993; LRMS (m/z, relative intensity) 236 (MNa+, 100), 214
(MH+, 10); HRMS calculated for C12H23NO2Na 236.1621, found
236.1620.
1′-Hydroxy-6-oxaspiro[bicyclo[3.1.0]hexane-3,3′-piperidin]-
2′-one (3s). To a solution of 3,3-diallyl-1-(benzyloxy)piperidin-2-one
24 (10.6 g, 37.2 mmol) in toluene (745 mL) was added Grubbs first
gen catalyst (922 mg, 1.12 mmol) and titanium(IV) isopropoxide (3.3
mL, 11 mmol). The mixture was stirred for 18 h at rt, after which time
the solvent was removed under reduced pressure. The crude product
was purified by flash chromatography on silica gel using ethyl acetate
and hexanes (20:80 to 30:70) as eluent to give a 7-(benzyloxy)-7-
azaspiro[4.5]dec-2-en-6-one (25) as waxy solid (8.89 g, 93%): 1H
NMR (300 MHz, CDCl3) δ (ppm) 7.46−7.43 (m, 2H), 7.40−7.35
(m, 3H), 5.61 (s, 2H), 4.96 (s, 2H), 3.39 (t, 2H, J = 6.1 Hz), 3.02 (d,
2H, J = 14.2 Hz), 2.24 (d, 2H, J = 14.2), 1.83−1.75 (m, 2H), 1.70−
1.66 (m, 2H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 173.5 (s),
135.5 (s), 129.7 (d), 128.6 (d), 128.3 (d), 128.0 (d), 75.4 (t), 51.1 (t),
49.2 (s), 45.5 (t), 34.7 (t), 20.4 (t); IR (CHCl3) ν (cm−1) 3059, 2978,
1657; LRMS (m/z, relative intensity) 280 (MNa+, 45), 257 (MH+, 7);
HRMS calculated for C16H19NO2Na+ 280.1308, found 280.1301; mp
40−43 °C.
7-(Benzyloxy)-7-azaspiro[4.5]dec-2-en-6-one (25) (100 mg, 0.390
mmol), methyltrioxorhenium (Re 71−76%, 0.3 mg, 0.0008 mmol) and
pyrazole (2.7 mg, 0.039 mmol) were dissolved in CH2Cl2 (0.2 mL) at
rt. A 30% aqueous H2O2 solution (0.09 mL, 0.8 mmol) was then
added, and the biphasic mixture was stirred vigorously for 4 h. EtOAc
(10 mL) was added, and the organic layer was washed sequentially
with a 10% aqueous Na2S2O3 solution (2 × 5 mL), saturated aqueous
NH4Cl (5 mL) and saturated aqueous NaHCO3 (5 mL). The organic
layer was then dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel using ethyl acetate and hexanes (40:60 to
100:0) as eluent to give 1′-(benzyloxy)-6-oxaspiro[bicyclo[3.1.0]-
hexane-3,3′-piperidin]-2′-one (26) as colorless oil (83 mg, 78%). The
stereochemistry of the product was determined by NOESY (see
Supporting Information): 1H NMR (400 MHz, CDCl3) δ (ppm)
7.43−7.34 (m, 5H), 4.93 (s, 2H), 3.59 (s, 2H) 3.35−3.30 (m, 2H),
2.45 (d, 2H, J = 14.5 Hz), 1.94 (d, 2H, J = 14.5 Hz), 1.73−1.71 (m,
4H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 172.0 (s), 135.1 (s),
129.6 (d), 128.7 (d), 128.4 (d), 75.3 (t), 58.5 (d), 50.7 (t), 48.2 (s),
39.0 (t), 36.3 (t), 19.7 (t); IR (CHCl3) ν (cm−1) 3047, 2978, 1641,
1253; LRMS (m/z, relative intensity) 296 (MNa+, 100), 274 (MH+,
10); HRMS calculated for C16H19NO3Na+ 296.1257, found 296.1258.
1′-(Benzyloxy)-6-oxaspiro[bicyclo[3.1.0]hexane-3,3′-piperidin]-2′-
one (26) (925 mg, 3.39 mmol) was dissolved in anhydrous EtOH (35
mL). A catalytic amount of 5% palladium hydroxide on activated
carbon was added, and the solution was degassed by bubbling argon
for 10 min. Argon was replaced by hydrogen, and the latter was
bubbled through the solution for several seconds. After being stirred
for 3.5 h under hydrogen, argon was bubbled through the solution for
another 10 min. The reaction mixture was then filtered on Celite,
which was washed with anhydrous EtOH. The solvent was removed
under reduced pressure to yield hydroxamic acid 3s (606 mg, 98%) as
a gum: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.60 (t, 2H, J = 5.8 Hz),
3.60 (s, 2H), 2.42 (d, 2H, J = 14.5 Hz), 1.98 (d, 2H, J = 14.5 Hz),
1.93−1,82 (m, 4H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 169.3
(s), 58.4 (d), 49.7 (t), 46.6 (s), 38.7 (t), 36.1 (t), 19.1 (t); IR (CHCl3)
ν (cm−1) 3294, 2978, 1607, 1266; LRMS (m/z, relative intensity) 206
(MNa+, 100); HRMS calculated for C9H13NO3Na+ 206.0788, found
206.0788.
1′-Hydroxy-2,2-dimethyltetrahydrospiro[cyclopenta[d][1,3]-
dioxole-5,3′-piperidin]-2′-one (3t). To a solution of AD-mix β
(10.9 g) in a 1:1 mixture of t-BuOH (40 mL) and water (40 mL)
cooled to 0 °C was added 7-(benzyloxy)-7-azaspiro[4.5]dec-2-en-6-
one (25) (2.00 g, 7.77 mmol). The mixture was left to warm up to rt
and stirred for 48 h. Sodium sulfite (11.7 g) was then added, and the
mixture was stirred for 1 h. Water (100 mL) was then added, and the
mixture was extracted with EtOAc (3 × 100 mL). The organic extracts
were combined, washed with brine (2 × 100 mL), dried over
anhydrous MgSO4, filtered and concentrated under reduced pressure
to yield 7-(benzyloxy)-2,3-dihydroxy-7-azaspiro[4.5]decan-6-one (27)
(2.26 g, 100%) as viscous colorless oil. The stereochemistry of the
product was determined by NOESY (see Supporting Information): 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.42−7.38 (m, 2H), 7.38−7.33
(m, 3H), 4.90 (s, 2H), 4.33−4.29 (m, 2H), 3.34 (t, 2H, J = 6.1 Hz),
2.86 (s 2H), 2.34 (dd, 2H, J = 13.6, 6.5 Hz), 1.84−1.81 (m, 2H), 1.78-
1.72 (m, 2H), 1.65 (dd, 2H, J = 13.6, 5.2 Hz); 13C NMR (75.5 MHz,
CDCl3) δ (ppm) 174.0 (s), 135.1(s), 129.6 (d), 128.8 (d), 128.4 (d),
75.4 (t), 73.8 (d), 50.9 (t), 47.5 (s), 42.8 (t), 36.4 (t), 20.6 (t); IR
(CHCl3) ν (cm−1) 3438 (br), 3059, 2978, 1641, 1043; LRMS (m/z,
relative intensity) 314 (MNa+, 100); HRMS calculated for
C16H21NO4Na+ 314.1363, found 314.1366.
To a solution of 7-(benzyloxy)-2,3-dihydroxy-7-azaspiro[4.5]decan-
6-one (27) (1.00 g, 3.43 mmol) and 2,2-dimethoxypropane (9.25 mL,
75.5 mmol) in acetone (35 mL) was added a catalytic amount of p-
TsOH. The reaction mixture was stirred at rt for 2.5 h, and then were
added saturated aqueous NaHCO3 (25 mL) and water (50 mL). The
mixture was extracted with EtOAc (3 × 75 mL). The organic extracts
were combined, dried over anhydrous MgSO4, filtered and then
evaporated under reduced pressure. The crude product was purified by
flash chromatography on silica gel using ethyl acetate and hexanes
(50:50) as eluent to give 1′-(benzyloxy)-2,2-dimethyltetrahydrospiro-
[cyclopenta[d][1,3]dioxole-5,3′-piperidin]-2′-one (28) as a colorless
1
solid (830 mg, 73%): H NMR (300 MHz, CDCl3) δ (ppm) 7.43−
7.33 (m, 5H), 4.93 (s, 2H), 4.84−4.78 (m, 2H), 3.33 (t, 2H, J = 6.1
Hz), 2.40 (ddd, 2H, J = 14.5, 4.7, 1.6 Hz), 1.94−1.90 (m, 2H), 1.86 (d,
2H, J = 14.5 Hz), 1.80−1.72 (m, 2H), 1.47 (s, 3H), 1,30 (s, 3H); 13C
NMR (75.5 MHz, CDCl3) δ (ppm) 171.6 (s), 135.1 (s), 129.5 (d),
128.5 (d), 128.2 (d), 81.2 (d), 77.6 (s), 75.0 (t), 52.0 (s), 50.6 (t),
42.5 (t), 32.9 (t), 26.3 (q), 23.5 (q), 20.4 (t); IR (CHCl3) ν (cm−1)
3047, 2981, 1641, 1050; LRMS (m/z, relative intensity) 354 (MNa+,
100); HRMS calculated for C19H25NO4Na+ 354.1676, found
354.1679; mp 88−90 °C.
1′-(Benzyloxy)-2,2-dimethyltetrahydrospiro[cyclopenta[d][1,3]-
dioxole-5,3′-piperidin]-2′-one (28) (830 mg, 2.50 mmol) was
dissolved in anhydrous EtOH (25 mL). A catalytic amount of 5%
palladium on activated carbon was added, and the solution was
degassed with argon for 10 min. Argon was replaced by hydrogen, and
the latter was bubbled through the solution for several seconds. After
being stirred for 4.5 h under hydrogen, argon was bubbled through the
solution for another 10 min. The reaction mixture was then filtered on
Celite while being washed with anhydrous EtOH. The solvent was
removed under reduced pressure to yield hydroxamic acid 3t (576 mg,
95%) as a solid: 1H NMR (300 MHz, CDCl3) δ (ppm) 4.82−4.78 (m,
2H), 3,63 (t, 2H, J = 6.1 Hz), 2.36 (dd, 2H, J = 14.7, 6.1 Hz), 2.09−
2.05 (m, 2H), 2.00−1.91 (m, 2H), 1.94 (d, 2H, J = 14.7 Hz), 1.49 (s,
3H), 1,30 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 168.4 (s),
81.4 (d), 50.0 (s), 48.6 (t), 42.2 (t), 32.8 (t), 26.2 (q), 24.0 (s), 23.5
(q), 19.7 (t); IR (CHCl3) ν (cm−1) 3275 (br), 2978, 2940, 1610,
1128; LRMS (m/z, relative intensity) 264 (MNa+, 100); HRMS
calculated for C12H19NO4Na+ 264.1206, found 264.1211; mp 146−
149 °C.
3-(tert-Butyldimethylsilyloxy)-7-hydroxy-6-oxo-7-azaspiro-
[4.5]decan-2-yl acetate (3u). A solution of 7-(benzyloxy)-2,3-
dihydroxy-7-azaspiro[4.5]decan-6-one (27) (1.11 g, 3.81 mmol) in
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Article
THF (20 mL) was cooled down to 0 °C. Sodium hydride (60%
dispersion in mineral oil, 160 mg, 4.00 mmol) was added, and the
solution was stirred for 15 min at 0 °C and then 15 min at rt. Then, t-
butyldimethylsilyl chloride (633 mg, 4.20 mmol) was added, and the
reaction mixture was stirred at rt for 18 h. Saturated aqueous
ammonium chloride (20 mL) and water (20 mL) were then added.
The aqueous phase was extracted with CH2Cl2 (3 × 50 mL); the
organic extracts were combined, dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel using ethyl acetate and
hexanes (30:70) as eluent to give 7-(benzyloxy)-2-(tert-butyldime-
thylsilyloxy)-3-hydroxy-7-azaspiro[4.5]decan-6-one (29) as colorless
2,3,3-Trimethyl-6-oxopiperidin-1-yl trifluoromethanesulfo-
nate (13i). To a solution of hydroxamic acid 3i (0.200 g, 1.27
mmol) in dichloromethane (6 mL) at 0 °C was added triethylamine
(0.26 mL, 1.9 mmol) and triflic anhydride (0.26 mL, 1.52 mmol).
After being stirred 5 min at 0 °C, the solvent was removed under
reduced pressure, and the residue was purified by flash chromatog-
raphy on silica gel using ethyl acetate and hexanes (15:85) as eluent to
give 13i as colorless oil (0.258 g, 70%): 1H NMR (300 MHz, CDCl3)
δ (ppm) 3.72 (q, 1H, J = 6.4 Hz), 2.66 (ddd, 1H, J = 17.4, 11.0, 7.0
Hz), 2.56 (ddd, 1H, J = 17.4, 6.7, 3.8 Hz), 1.84 (ddd, 1H, J = 14.1,
11.0, 6.7 Hz), 1.57−1.49 (m, 1H), 1.30 (d, 3H, J = 6.4 Hz), 1.27 (s,
3H), 1.06 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 169.4 (s),
118.4 (q, J = 322 Hz), 70.8 (d), 36.1 (s), 30.5 (t), 30.1 (t), 25.7 (q),
13.6 (q); IR (CHCl3) ν (cm−1) 2978, 1641, 1463, 1291, 1168, 1029.
LRMS and HRMS could not be obtained because of the thermal
instability of the molecule.
2,3,3-Trimethyl-6-oxopiperidin-1-yl 4-methylbenzenesulfo-
nate (32). To a solution of hydroxamic acid 3i (0.151 g, 0.960 mmol)
in dichloromethane (7 mL) was added triethylamine (0.16 mL, 1.2
mmol), DMAP (35 mg, 0.29 mmol) and tosyl chloride (0.202 g, 1.06
mmol). After being stirred 15 min at rt, water (25 mL) and a 1 M
aqueous HCl solution (25 mL) were added. The aqueous phase was
extracted with dichloromethane (3 × 50 mL); the organic extracts
were combined, dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The crude product was purified
by flash chromatography on silica gel using ethyl acetate and hexanes
(25:75) as eluent to give 2,3,3-trimethyl-6-oxopiperidin-1-yl 4-
methylbenzenesulfonate (32) as colorless oil (0.156 g, 52%): 1H
NMR (300 MHz, CDCl3) δ (ppm) 7.88 (d, 2H, J = 8.3 Hz), 7.32 (d,
2H, J = 8.3 Hz), 3.79 (q, 1H, J = 6.4 Hz), 2.44 (s, 3H), 2.29−2.24 (m,
2H), 1.77 (ddd, 1H, J = 13.8, 9.1, 9.1 Hz), 1.38 (dt, 1H, J = 13.8, 4.8
Hz), 1.25 (d, 3H, J = 6.4 Hz), 1.25 (s, 3H), 1.00 (s, 3H); 13C NMR
(75.5 MHz, CDCl3) δ (ppm) 168.4 (s), 145.9 (s), 131.4 (s), 129.5
(d), 129.3 (d), 69.3 (d), 35.2 (s), 30.2 (t), 29.7 (t), 26.1 (q), 25.9 (q),
21.8 (q), 13.9 (q); IR (CHCl3) ν (cm−1) 3047, 2978, 2943, 2874,
1710, 1600, 1463, 1372, 1175, 1090; LRMS (m/z, relative intensity)
334 (MNa+, 100); HRMS calculated for C15H21NO4SNa 334.1084,
found 334.1088.
1
oil (1.30 g, 84%): H NMR (300 MHz, CDCl3) δ (ppm) 7.44−7.40
(m, 2H), 7.38−7.35 (m, 3H), 4.96−4.89 (AB quartet, 2H), 4.40 (ddd,
1H, J = 7.5, 7.5, 4.2 Hz), 4.13−4.09 (m, 1H), 3.42−3.29 (m, 2H), 2.54
(br s, 1H), 2.32 (ddd, 2H, J = 13.8, 7.5, 5.4 Hz), 1.85−1.71 (m, 4H),
1.67 (dd, 1H, J = 13.8, 3.3 Hz), 1.56 (dd, 1H, J = 13.8, 7.6 Hz), 0.91
(s, 9H,) 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ
(ppm) 173.7 (s), 135.3 (s), 129.6 (d), 128.7 (d), 128.4 (d), 75.3 (t),
75.0 (d), 73.9 (d), 50.9 (t), 47.7 (s), 43.6 (t), 42.4 (t), 36.6 (t), 25.8
(q), 20.6 (t), 18.0 (s), −4.6 (q), −5.0 (q); IR (CHCl3) ν (cm−1) 3050,
2956, 1641, 1256, 1100; LRMS (m/z, relative intensity) 406 (MH+,
100), 428 (MNa+, 50); HRMS calculated for C22H35NO4SiH+
406.2408, found 406.2413.
7-(Benzyloxy)-2-(tert-butyldimethylsilyloxy)-3-hydroxy-7-azaspiro-
[4.5]decan-6-one (29) (1.30 g, 3.21 mmol) was dissolved in CH2Cl2
(16 mL) and cooled down to 0 °C. Triethylamine (1.12 mL, 8.01
mmol), acetic anhydride (0.61 mL, 6.4 mmol), and a catalytic amount
of DMAP were then successively added, and the reaction mixture was
stirred for 2 h while being left to slowly warm up to rt. Aqueous
saturated NH4Cl (15 mL) and water (15 mL) were then added, and
the mixture was extracted with CH2Cl2 (3 × 50 mL). The organic
extracts were combined, washed with aqueous saturated K2CO3 (50
mL), dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure to yield 7-(benzyloxy)-3-(tert-butyldimethylsilyloxy)-
6-oxo-7-azaspiro[4.5]decan-2-yl acetate (30) (1.44 g, 100%) as
1
colorless oil: H NMR (300 MHz, CDCl3) δ (ppm) 7.44−7.40 (m,
2H), 7.38−7.35 (m, 3H), 5.18 (ddd, 1H, J = 6.0, 6.0, 4.1 Hz), 4.93 (s,
2H), 4.45 (ddd, 1H, J = 6.0, 6.0, 4.1 Hz), 3.42−3.30 (m, 2H), 2.46
(dd, 1H, J = 13.6, 6.0 Hz), 2.36 (dd, 1H, J = 13.3, 6.0 Hz), 2.05 (s,
3H), 1.85−1.74 (m, 4H), 1.70 (dd, 1H, J = 13.6, 6.0 Hz), 1.59 (dd,
1H, J = 13.3, 6.0 Hz), 0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C
NMR (75.5 MHz, CDCl3) δ (ppm) 173.2 (s), 170.1 (s), 135.2 (s),
129.5 (d), 128.6 (d), 128.3 (d), 76.1 (d), 75.2 (t), 73.0 (d), 50.8 (t),
46.7 (s), 43.7 (t), 40.0 (t), 36.4 (t), 25.7 (q), 21.1 (q), 20.5 (t), 18.0
(s), −5.0 (q), −5.1 (q); IR (CHCl3) ν (cm−1) 3040, 2953, 1726, 1657,
1262, 1125; LRMS (m/z, relative intensity) 448 (MH+, 100), 470
(MNa+, 85); HRMS calculated for C24H37NO5SiH+ 448.2514, found
448.2518.
2-Methyl-6-oxopiperidin-1-yl methanesulfonate (2o). Trie-
thylamine (0.49 mL, 3.5 mmol) and 4-dimethylaminopyridine (86 mg,
0.70 mmol) were added to a solution of hydroxamic acid 3o (300 mg,
2.32 mmol) in dichloromethane (12 mL). Mesyl chloride (0.22 mL,
2.8 mmol) was added, and the reaction mixture was stirred at rt for 15
min. The solvent was removed under reduced pressure, and the crude
product was purified by flash chromatography on silica gel using a
mixture of ethyl acetate and hexanes (50:50) as eluent to give
1
compound 2o as colorless oil (376 mg, 78%): H NMR (300 MHz,
CDCl3) δ (ppm) 4.17−4.04 (m, 1H), 3.29 (s, 3H), 2.56 (t, 2H, J = 6.6
Hz), 2.24−2.09 (m, 1H), 1.99−1.87 (m, 1H), 1.86−1.72 (m, 2H),
1.38 (d, 3H, J = 6.4 Hz); 13C NMR (75.5 MHz, CDCl3) δ (ppm)
169.0 (s), 60.2 (d), 39.1 (q), 33.7 (t), 31.2 (t), 18.4 (q), 18.0 (t); IR
(CHCl3) ν (cm−1) 2984, 2959, 2884, 1688, 1450, 1366, 1325, 1291,
1172, 968; LRMS (m/z, relative intensity) 230 (MNa+, 100), 208
(MH+, 1); HRMS calculated for C7H13NO4SNa 230.0458, found
230.0474; mp 52−54 °C.
7-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-6-oxo-7-azaspiro[4.5]-
decan-2-yl acetate (30) (956 mg, 2.13 mmol) was dissolved in ethanol
(21 mL). A catalytic amount of 5% palladium on activated carbon was
added, and the solution was degassed by bubbling argon for 10 min.
Argon was replaced by hydrogen, and the latter was bubbled through
the solution for several seconds. After being stirred for 1 h under
hydrogen, argon was bubbled through the solution for another 10 min.
The reaction mixture was then filtered on Celite while being washed
with EtOH. The solvent was removed under reduced pressure to yield
2-Oxo-3,3-dipropylazepan-1-yl methanesulfonate (2r). Trie-
thylamine (0.30 mL, 2.1 mmol) and 4-dimethylaminopyridine (51 mg,
0.42 mmol) were added to a solution of hydroxamic acid 3r (300 mg,
1.41 mmol) in dichloromethane (9 mL). Mesyl chloride (0.13 mL, 1.7
mmol) was added, and the reaction mixture was stirred at rt for 5 min.
The solvent was removed under reduced pressure, and the crude
product was purified by flash chromatography on silica gel using a
mixture of ethyl acetate and hexanes (10:90) as eluent to give
1
hydroxamic acid 3u as an oil (713 mg, 93%): H NMR (300 MHz,
CDCl3) δ (ppm) 5.17 (ddd, 1H, J = 6.3, 6.3, 4.0 Hz), 4.43 (ddd, 1H, J
= 5.6, 5.6, 4.0 Hz), 3.65−3.58 (m, 2H), 2.43 (dd, 1H, J = 13.6, 6.3
Hz), 2.33 (dd, 1H, J = 13.4, 5.6 Hz), 2.05 (s, 3H), 1.97−1.91 (m, 4H),
1.76 (dd, 1H, J = 13.6, 6.3 Hz), 1.64 (dd, 1H, J = 13.4, 5.6 Hz), 0.87
(s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ
(ppm) 170.9 (s), 170.2 (s), 76.1 (d), 72.9 (d), 49.8 (t), 45.2 (s), 43.5
(t), 39.9 (t), 36.3 (t), 25.7 (q), 21.1 (q), 19.9 (t), 18.0 (s), −5.1 (q),
−5.1 (q); IR (CHCl3) ν (cm−1) 3281 (br), 2978, 1729, 1610, 1256,
1046; LRMS (m/z, relative intensity) 380 (MNa+, 100); HRMS
calculated for C17H31NO5SiNa+ 380.1864, found 380.1866.
1
compound 2r as colorless oil (391 mg, 95%): H NMR (300 MHz,
CDCl3) δ (ppm) 3.95−3.91 (m, 2H), 3.13 (s, 3H), 1.93−1.80 (m,
2H), 1.78−1.45 (m, 8H), 1.27 (sext, 4H, J = 7.2 Hz), 0.92 (t, 6H, J =
7.2 Hz); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 177.1 (s), 56.0 (t),
47.7 (s), 39.3 (t), 37.7 (q), 32.1 (t), 26.6 (t), 22.3 (t), 17.0 (t), 14.6
(q); IR (neat) ν (cm−1) 2965, 2934, 2878, 1691, 1466, 1366, 1322,
1175, 1046, 962, 880; LRMS (m/z, relative intensity) 314 (MNa+,
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100); HRMS calculated for C13H25NO4SNa 314.1397, found
314.1400.
LRMS (m/z, relative intensity) 250 (MNa+, 100), 228 (MH+, 3);
HRMS calculated for C13H25NO2Na 250.1778, found 250.1782.
Methyl 6-oxaspiro[bicyclo[3.1.0]hexane-3,2′-pyrrolidine]-1′-
carboxylate (4s). Triethylamine (0.09 mL, 0.6 mmol) was added to a
solution of 2′-oxo-6-oxaspiro[bicyclo[3.1.0]hexane-3,3′-piperidine]-1′-
yl trifluoromethanesulfonate (35) (100 mg, 0.317 mmol) in MeOH (3
mL). The solution was stirred at reflux temperature for 30 min and
was then allowed to cool to rt before the solvent was removed under
reduced pressure. The crude product 4s was purified by flash
chromatography on silica gel using ethyl acetate and hexanes (15:85)
as eluent to give product 4s a colorless solid in 66% yield (58% when
2′-Oxo-6-oxaspiro[bicyclo[3.1.0]hexane-3,3′-piperidine]-1′-
yl trifluoromethanesulfonate (13s). Hydroxamic acid 3s (300 mg,
1.10 mmol) was dissolved in dichloromethane (9 mL) at 0 °C. Et3N
(0.23 mL, 1.7 mmol) was added followed by the addition of freshly
distilled triflic anhydride (0.22 mL, 1.3 mmol). The solution was
stirred 2 min at 0 °C before the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography on
silica gel using ethyl acetate and hexanes (10:90) as eluent to give 2′-
oxo-6-oxaspiro[bicyclo[3.1.0]hexane-3,3′-piperidine]-1′-yl trifluoro-
1
1
using DBU instead of triethylamine): H NMR (300 MHz, CDCl3) δ
methanesulfonate (13s) as colorless oil (346 mg, 100%): H NMR
(ppm) Rotamer A 3.64 (s, 3H), 3.52 (s, 2H), 3.32 (t, 2H, J = 6.8 Hz),
2.68 (d, 2H, J = 14.1 Hz), 1.91−1.67 (m, 6H); Rotamer B 3.71 (s,
3H), 3.52 (s, 2H), 3.40 (t, 2H, J = 6.5 Hz), 2.43 (d, 2H, J = 14.3 Hz),
1.91−1.67 (m, 6H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) Rotamer
A 154.3 (s), 66.8 (s), 56.6 (d), 51.7 (q), 47.1 (t), 44.7 (t), 37.8 (t),
22.6 (t); Rotamer B 154.3 (s), 66.8 (s), 56.6 (d), 52.1 (q), 48.1 (t),
46.0 (t), 39.4 (t), 22.2 (t); IR (CHCl3) ν (cm−1) 2978, 1691, 1247;
LRMS (m/z, relative intensity) 220 (MNa+, 80), 198 (MH+, 100);
HRMS calculated forC10H16NO3+ 198.1125, found 198.1119; mp 36−
40 °C.
Methyl 2,2-dimethyltetrahydrospiro[cyclopenta[d][1,3]-
dioxole-5,2′-pyrrolidine]-1′-carboxylate (4t). Carbamate 4t was
synthesized according to the general procedure starting from 3t. The
reaction was made on a 0.414 mmol scale, the eluent for the flash
chromatography was a mixture of ethyl acetate and hexanes (10:90),
and the product 4t was obtained as a colorless solid in 77% yield when
using Et3N as base and 33% when using DBU instead of triethylamine:
1H NMR (300 MHz, CDCl3) δ (ppm) 4.72 (d, 2H, J = 4.8 Hz), 3.63
(300 MHz, CDCl3) δ (ppm) 3.80 (t, 2H, J = 6.0 Hz), 3.60 (s, 2H),
2.44 (d, 2H, J = 14.8 Hz), 2.09−2.04 (m, 2H), 2.07 (d, 2H, J = 14.8
Hz), 1.90−1.86 (m, 2H); 13C NMR (75.5 MHz, CDCl3) δ (ppm)
175.2 (s), 118.3 (q, J = 322 Hz), 57.9 (d), 55.9 (t), 50.3 (s), 37.9 (t),
36.2 (t), 20.7 (t); IR (CHCl3) ν (cm−1) 2975, 1604, 1253, 1046. A
mass spectrum could not be obtained because of the thermal instability
of the compound.
3-(tert-Butyldimethylsilyloxy)-6-oxo-7-(trifluoromethylsulfo-
nyloxy)-7-azaspiro[4.5]decan-2-yl acetate (13u). Hydroxamic
acid 3u (200 mg, 0.559 mmol) was dissolved in dichloromethane (6
mL) at 0 °C. Et3N (0.12 mL, 0.84 mmol) was added followed by the
addition of freshly distilled triflic anhydride (0.11 mL, 0.67 mmol).
The solution was stirred 2 min at 0 °C before the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography on silica gel using ethyl acetate and hexanes (10:90)
as eluent to give 3-(tert-butyldimethylsilyloxy)-6-oxo-7-(trifluorome-
thylsulfonyloxy)-7-azaspiro[4.5]decan-2-yl acetate (13u) as oil (234
1
mg, 85%): H NMR (300 MHz, CDCl3) δ (ppm) 5.09 (ddd, 1H, J =
(s, 3H), 3.34 (t, 2H, J = 6.7 Hz), 2.82 (dd, 2H, J = 14.2, 4.8 Hz), 2.14
(t, 2H, J = 6.7 Hz), 1.75 (quint, 2H, J = 6.7 Hz), 1.69 (d, 2H, J = 14.2
Hz), 1.49 (s, 3H), 1.29 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ
(ppm) 154.1 (s), 108.8 (s), 79.7 (d), 69.7 (s), 51.5 (q), 47.0 (t), 40.7
(t), 40.3 (t), 25.9 (q), 23.4 (q), 22.8 (t); IR (CHCl3) ν (cm−1) 2981,
1691, 1378, 1115; LRMS (m/z, relative intensity) 278 (MNa+, 100),
256 (MH+, 30); HRMS calculated for C13H21NO4Na+ 278.1363,
found 278.1366; mp 66−69 °C.
6.4, 6.4, 4.0 Hz), 4.33 (ddd, 1H, J = 5.6, 5.6, 4.0 Hz), 3,84 (t, 2H, J =
6.0 Hz), 2.56 (dd, 1H, J = 13.8, 6.4 Hz), 2.38 (dd, 1H, J = 13.6, 5.6
Hz), 2.15−2.07 (m, 2H), 2.05 (s, 3H), 1.99−1.94 (m, 2H), 1.79 (dd,
1H, J = 13.8, 6.4 Hz), 1.71 (dd, 1H, J = 13.6, 5.6 Hz), 0.87 (s, 9H),
0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ (ppm)
176.3 (s), 170.1 (s), 118.3 (q, J = 322 Hz), 75.2 (d), 72.4 (d), 56.0 (t),
48.7 (s), 43.1 (t), 39.1 (t), 36.5 (t), 25.6 (q), 21.4 (t), 21.0 (q), 17.9
(s), −5.2 (q), −5.2 (q); IR (CHCl3) ν (cm−1) 2978, 1710, 1600, 1250,
1046. A mass spectrum could not be obtained because of the thermal
instability of the compound.
General Procedure for the Thermal Rearrangement. The
cyclic hydroxamic acid (1 equiv) was dissolved in dichloromethane
(0.15 M) and cooled to 0 °C. Base (1.5 equiv) was added followed by
the addition of freshly distilled triflic anhydride (1.2 equiv). After 5
min (reaction monitored by TLC) the solvent was removed under
reduced pressure. Methanol (0.15 M) and base (2.0 equiv) were
successively added, and the solution was stirred at reflux temperature
for 30 min. The reaction mixture was then allowed to cool to rt before
the solvent was removed under reduced pressure. The crude product
was purified by flash chromatography on silica gel.
Methyl 2-methylpyrrolidine-1-carboxylate (4o). Carbamate
4o was synthesized according to the general procedure starting from
3o. The reaction was made on a 0.774 mmol scale, the base used was
DBU, the eluent for the flash chromatography was a mixture of ethyl
acetate and hexanes (10:90), and the product 4o was obtained in 68%
yield as colorless oil: 1H NMR (300 MHz, CDCl3) δ (ppm) 4.01−3.80
(m, 1H), 3.69 (s, 3H), 3.46−3.28 (m, 2H), 2.05−1.73 (m, 3H), 1.65−
1.48 (m, 1H), 1.23−1.08 (m, 3H).
Methyl 2,2-dipropylpiperidine-1-carboxylate (4r). Carbamate
4r was synthesized according to the general procedure starting from
3r. The reaction was made on a 0.47 mmol scale, the base used was
triethylamine, the eluent for the flash chromatography was a mixture of
ethyl acetate and hexanes (5:95), and the product 4r was obtained in
74% yield as colorless oil: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.63
(s, 3H), 3.47−3.43 (m, 2H), 1.96 (ddd, 2H, J = 16.8, 12.0, 4.9 Hz),
1.63−1.53 (m, 8H), 1.35−1.11 (m, 4H), 0.89 (t, 6H, J = 7.2 Hz); 13C
NMR (75.5 MHz, CDCl3) δ (ppm) 156.7 (s), 60.1 (s), 51.7 (q), 41.9
(t), 39.7 (t), 30.5 (t), 23.5 (t), 17.9 (t), 17.1 (t), 14.7 (q); IR (CHCl3)
ν (cm−1) 2962, 2874, 1691, 1444, 1381, 1353, 1266, 1153, 1090;
Methyl 7-acetoxy-8-(tert-butyldimethylsilyloxy)-1-azaspiro-
[4.4]nonane-1-carboxylate (4u). Triethylamine (0.09 mL, 0.6
mmol) was added to a solution of 3-(tert-butyldimethylsilyloxy)-6-
oxo-7-(trifluoromethylsulfonyloxy)-7-azaspiro[4.5]decan-2-yl acetate
(3u) (100 mg, 0.317 mmol) in MeOH (3 mL). The solution was
stirred at reflux temperature for 30 min and was then allowed to cool
to rt before the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography on silica gel using
ethyl acetate and hexanes (15:85) as eluent to give product 4u as
colorless oil in 67% yield (same yield with DBU instead of
1
triethylamine): H NMR (300 MHz, CDCl3) δ (ppm) Rotamer A
5.35 (ddd, 1H, J = 6.4, 6.4, 4.5 Hz), 4.56 (ddd, 1H, J = 4.5, 4.5, 4.5
Hz), 3.64 (s, 3H), 3.34 (t, 2H, J = 6.7 Hz), 2.49−1.60 (m, 8H), 2.03
(s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); Rotamer B 5.22−
5.16 (m, 1H), 4.42−4.38 (m, 1H), 3.71 (s, 3H), 3.48−3.39 (m, 2H),
2.49−1.60 (m, 8H), 2.03 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.02 (s,
3H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) Rotamer A 170.3 (s),
154.3 (s), 76.8 (d), 73.2 (d), 66.5 (s), 51.7 (q), 47.2 (t), 43.9 (t), 43.5
(t), 39.9 (t), 25.7 (q), 22.9 (t), 21.1 (q), 18.0 (s), −5.0 (q), −5.1 (q);
Rotamer B 170.3 (s), 154.3 (s), 76.2 (d), 73.2 (d), 66.0 (s), 52.1 (q),
48.2 (t), 45.1 (t), 44.5 (t), 40.8 (t), 25.7 (q), 22.4 (t), 21.1 (q), 18.0
(s), −5.0 (q), −5.1 (q); IR (CHCl3) ν (cm−1) 2956, 1726, 1691, 1269,
1078; LRMS (m/z, relative intensity) 372 (MH+, 50), 394 (MNa+,
100); HRMS calculated for C18H33NO5SiNa+ 394.2020, found
394.2024.
9-Methyl-7,8,9,9a-tetrahydro-1H-pyrrolo[1,2-a]azepin-
3(2H)-one (14). Enamide 14 was synthesized according to the general
procedure starting from 3j or 3k. The reaction was made on a 1.09
mmol scale, the base used was DBU, the eluent for the flash
chromatography was a mixture of ethyl acetate and hexanes (25:75),
1
and the product 14 was obtained in 28% yield as colorless oil: H
NMR (300 MHz, CDCl3) δ (ppm) 6.40 (dd, 1H, J = 9.0, 3.1 Hz), 5.18
11225
dx.doi.org/10.1021/jo3023507 | J. Org. Chem. 2012, 77, 11216−11226

The Journal of Organic Chemistry
Article
(ddd, 1H, J = 11.3, 9.0, 3.2 Hz), 2.59−2.43 (m, 2H), 2.41−2.25 (m,
1H), 2.13−2.01 (m, 1H), 1.99−1.77 (m, 3H), 1.69−1.52 (m, 3H),
1.19 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 174.1 (s), 123.1
(d), 115.6 (d), 63.2 (s), 42.7 (t), 34.3 (t), 29.5 (t), 28.7 (t), 21.5 (q),
20.1 (t); IR (CHCl3) ν (cm−1) 3014, 2946, 2874, 1678, 1445, 1402,
1359, 957, 906; LRMS (m/z, relative intensity) 353 (2MNa+, 59), 188
(MNa+, 100); HRMS calculated for C10H15NONa 188.1046, found
188.1049.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC), the Fonds de Reherche
■
Queb
Universite
́
ec
́
ois Nature et Technologies (FRQ-NT) and the
de Sherbrooke for financial support.
́
8a-Methyl-1,2,8,8a-tetrahydroindolizin-3(7H)-one (15). En-
amide 15 was synthesized according to the general procedure starting
from 3l or 3m. The reaction was made on a 0.591 mmol scale, the base
used was DBU, the eluent for the flash chromatography was a mixture
of ethyl acetate and hexanes (50:50), and the product 15 was obtained
REFERENCES
■
(1) For lead references and reviews, see: (a) Lang, S.; Murphy, J. A.
Chem. Soc. Rev. 2005, 35, 146−156. (b) Kurti, L.; Czako, B. In Strategic
́
̈
1
in 64% yield as colorless oil: H NMR (300 MHz, CDCl3) δ (ppm)
Applications of Named Reactions in Organic Synthesis; Elsevier Academic
Press: Burlington, MA, 2005; pp 116−117, pp 210−211, pp 266−267,
and pp 396−397. (c) Kyba, P. E. In Azides and Nitrenes: Reactivity and
Utility; Scriven, E. F. V., Ed.; Academic Press: Orlando, FL, 1984; p 2.
(d) Abramovich, R. A.; Kyba, E. P. In The Chemistry of the Azido
Group; Patai, S. J., Ed.; Wiley & Sons: London, 1971; p 221.
(2) For reviews on chiral enolates, see: (a) Arya, P.; Qin, H.
Tetrahedron 2000, 56, 917−947 and references cited therein.
(b) Davies, S. G.; Garner, A. C.; Roberts, P. M.; Smith, A. D.;
Sweet, M. J.; Thomson, J. E. Org. Biomol. Chem. 2006, 4, 2753−2768.
(c) Palomo, C.; Oiarbide, M.; García, J. M. Chem. Soc. Rev. 2004, 33,
65−75. (d) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5128−5175. (e) For a review on chiral enolate equivalents, see: Spino,
C. Org. Prep. Proced. Int. 2003, 35, 1−140.
(3) The Hofmann rearrangement of cyclic imides is possible: Jiang,
X.; Wang, J.; Hu, J.; Ge, Z.; Hu, Y.; Hu, H.; Covey, D. F. Steroids 2001,
66, 655−662. However, it likely proceeds via a base-promoted ring-
opening followed by a normal Lossen-like rearrangement.
(4) (a) Drouin, A.; Lessard, J. Tetrahedron Lett. 2006, 47, 4285−
4288. (b) Winter, D. K.; Drouin, A.; Lessard, J.; Spino, C. J. Org. Chem.
2010, 75, 2610−2618.
(5) (a) Drouin, A.; Winter, D. K.; Pichette, S.; Aubert-Nicol, S.;
Lessard, J.; Spino, C. J. Org. Chem. 2011, 76, 164−169. (b) Pichette,
S.; Aubert-Nicol, S.; Lessard, J.; Spino, C. Eur. J. Org. Chem. 2012,
1328−1335.
(6) Edwards and co-workers have reported that the photolysis of N-
mesyloxy-4-aza-cholestan-3-one in methanol at rt gave the undesired
ring-contracted carbamate in 35% yield, besides several other products.
To the best of our knowledge, no further study of this reaction has
been reported since. See: Edwards, O. E.; Grue-Sørensen, G.;
Blackwell, B. A. Can. J. Chem. 1997, 75, 857−872.
6.74 (dt, 1H, J = 8.2, 2.0 Hz), 5.10−5.05 (m, 1H), 2.60 (ddd, 1H, J =
18.8, 12.0, 7.6 Hz), 2.36 (dd, 1H, J = 18.8, 9.2 Hz), 2.28−2.07 (m,
2H), 2.01 (dd, 1H, J = 11.8, 8.0 Hz), 1.89 (dd, 1H, J = 11.8, 4.6 Hz),
1.78 (ddd, 1H, J = 12.0, 9.2 Hz), 1.53 (ddd, 1H, J = 12.0, 7.6 Hz), 1.16
(s, 3H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 170.8 (s), 120.3 (d),
108.2 (d), 58.3 (s), 34.2 (t), 34.1 (t), 29.6 (t), 21.2 (q), 20.2 (t); IR
(CHCl3) ν (cm−1) 2975, 2943, 1691, 1460, 1406, 1325, 1299, 1153,
1050; LRMS (m/z, relative intensity) 174 (MNa+, 100), 152 (MH+,
20); HRMS calculated for C9H13NONa 174.0889, found 174.0891.
(E)-5-(4-Methoxyphenyl)-2,2-dimethylpent-4-enenitrile (18).
Nitrile 18 was obtained as a side product starting from 3q following
general procedure. The reaction was made on a 0.20 mmol scale, the
base used was triethylamine, the eluent for the flash chromatography
was a mixture of ethyl acetate and hexanes (10:90), and the product 18
was obtained in 15% yield as colorless oil: 1H NMR (300 MHz,
CDCl3) δ (ppm) 7.32 (d, 2H, J = 8.7 Hz), 6.86 (d, 2H, J = 8.7 Hz),
6.44 (d, 1H, J = 15.4 Hz), 6.11 (dt, 1H, J = 15.4, 7.3 Hz), 3.81 (s, 3H),
2.41 (dd, 2H, J = 7.3, 0.7 Hz), 1.37 (s, 6H); 13C NMR (75.5 MHz,
CDCl3) δ (ppm) 159.2 (s), 134.1 (d), 129.5 (s), 127.5 (d), 124.9 (s),
121.2 (d), 114.0 (d), 55.3 (q), 44.3 (t), 32.6 (s), 26.3 (q); IR (CHCl3)
ν (cm−1) 3024, 2982, 2932, 2200, 1609, 1510, 1468, 1305, 1252, 1178,
1036, 969; LRMS (m/z, relative intensity) 238 (MNa+, 100), 216
(MH+, 15), 207 (100), 173 (75); HRMS calculated for C14H17NONa+
238.1202, found 238.1203.
Benzyl 2,3,3-trimethylpyrrolidine-1-carboxylate (31). DBU
(0.10 mL, 0.70 mmol) was added to a solution of triflate 13i (100 mg,
0.346 mmol) in BnOH (3 mL). The solution was stirred at 70 °C for
30 min and was then allowed to cool to rt. The crude product was
directly purified by flash chromatography on silica gel using ethyl
acetate and hexanes (5:95) as eluent to give benzyl 2,3,3-
trimethylpyrrolidine-1-carboxylate (31) as colorless oil (52 mg,
(7) We are aware of only one method to oxidize N-silylatedlactams to
cyclic hydroxamic acids, but this method proved unsatisfactory in our
hands: (a) Matlin, S. A.; Sammes, P. G. J. Chem. Soc., Chem. Commun.
1972, 1222−1223. (b) Matlin, S. A.; Sammes, P. G.; Upton, R. M. J.
Chem. Soc., Perkin Trans 1 1979, 2481−2487. For other oxidative
methods to obtain cyclic hydroxamic acids, see: (c) Nesset, S. M.;
Benneche, T.; Undheim, K. Acta Chem. Scand. 1993, 47, 1141−1143.
(d) Yamada, K.; Tanaka, S.; Naruchi, K.; Yamamoto, M. J. Org. Chem.
1982, 47, 5283−5289. (e) Banerjee, R.; King, S. B. Org. Lett. 2009, 11,
4580−4583.
1
60%): H NMR (400 MHz, CDCl3) δ (ppm) 7.37−7.30 (m, 5H),
5.21−5.08 (m, 2H), 3.57−3.48 (m, 1H), 3.44 (dd, 1H, J = 9.2, 5.2
Hz), 1.76 (ddd, 1H, J = 12.4, 9.2, 9.2 Hz), 1.54 (dt, 1H, J = 12.4, 5.2
Hz), 1.08 (s(br), 3H), 1.01 (s, 3H), 0.98 (s, 3H); 13C NMR (100.7
MHz, CDCl3) δ (ppm) Rotamer A 155.5 (s), 137.4 (s), 128.6 (d),
128.0 (d), 127.9 (d), 66.8 (t), 62.8 (d), 44.7 (t), 41.0 (s), 36.9 (t), 27.7
(q), 23.2 (q), 17.0; Rotamer B 155.2 (s), 137.4 (s), 128.6 (d), 128.0
(d), 127.9 (d), 66.6 (t), 62.4 (d), 44.4 (t), 40.2 (s), 35.9 (t), 27.6 (q),
23.0 (q), 16.0 (q); IR (CHCl3) ν (cm−1) 3009, 2966, 2893, 1684,
1412, 1358, 1105, 1047; LRMS (m/z, relative intensity) 270 (MNa+,
100), 248 (MH+, 20); HRMS calculated forC15H21NO2Na+ 270.1465,
found 270.1467.
(8) Edwards and co-workers had previously reported two examples of
bicyclic N-mesyloxylactams undergoing rearrangement when heated in
MeOH at 190 °C in a sealed tube (see ref 6).
(9) For a leading reference and a more mechanistic discussion on the
ASSOCIATED CONTENT
́
Schmidt rearrangement, see: Guttierez, O.; Aube, J.; Tantillo, D. J. J.
■
Org. Chem. 2012, 77, 640−647.
S
* Supporting Information
Characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Claude.Spino@USherbrooke.ca; Jean.Lessard@
USherbrooke.ca.
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dx.doi.org/10.1021/jo3023507 | J. Org. Chem. 2012, 77, 11216−11226