N-O tethered carbenoid cyclopropanation facilitates the synthesis of a functionalized cyclopropyl-fused pyrrolidine

Article abstract of DOI:10.1021/jo400788a

We report a facile approach to a cyclopropyl-fused pyrrolidine, which contains four stereogenic centers, by employing the N-O tethered carbenoid methodology. The synthesis was facilitated by the development of a direct Mitsunobu reaction of alcohols with N-alkyl-N-hydroxyl amides to give diazo precursors, which upon intramolecular cyclopropanation yielded a library of N-O containing cyclopropyl-fused bicyclic intermediates. Elaboration of the N-O moiety of one member of this library resulted in the formation of the desired pyrrolidine ring demonstrating the potential of this methodology for making cyclopropyl-fused heterocycles.

Full text of DOI:10.1021/jo400788a

Article
pubs.acs.org/joc
N−O Tethered Carbenoid Cyclopropanation Facilitates the Synthesis
of a Functionalized Cyclopropyl-Fused Pyrrolidine
Dimpy Kalia,† Gokce Merey,†,‡ Min Guo,† and Herman O. Sintim*,†
̈
†Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
‡Chemical Engineering Department, Hitit University, Corum, Turkey
S
* Supporting Information
ABSTRACT: We report a facile approach to a cyclopropyl-fused pyrrolidine, which contains four stereogenic centers, by
employing the N−O tethered carbenoid methodology. The synthesis was facilitated by the development of a direct Mitsunobu
reaction of alcohols with N-alkyl-N-hydroxyl amides to give diazo precursors, which upon intramolecular cyclopropanation
yielded a library of N−O containing cyclopropyl-fused bicyclic intermediates. Elaboration of the N−O moiety of one member of
this library resulted in the formation of the desired pyrrolidine ring demonstrating the potential of this methodology for making
cyclopropyl-fused heterocycles.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Small molecules that contain polyfunctionalized pyrrolidine
structural units have interesting biological properties and have
found diverse applications in medicine.1−4 Cyclopropyl-fused
pyrrolidines are of particular interest as these structural motifs
have been shown to possess an extensive range of
pharmacological properties. For example, these compounds
have been shown to be inhibitors of dipeptidyl peptidase IV
and have the potential to be used as antidiabetic drugs.5
Another example of a biologically active cyclopropyl-fused
pyrrolidine is the antibiotic indolizomycin6 (more examples of
such compounds can be found in ref 7). Because of their useful
biological activities and promise for medicinal applications,
there has been interest in the development of general strategies
for the synthesis of polysubstituted pyrrolidines.
As a part of our research program that focuses on remote C−
H bond functionalization, we recently reported a method
utilizing N-alkoxy-N-alkyl amides as atom-economical tethers
for performing regioselective C−H insertion reactions8 that
employed diazo-containing substrates.8−22 Motivated by this
success, we reasoned that if we could extend this idea and
utilize N−O tethers for cyclopropanation and then elaborate
the N−O moiety to generate the pyrrolidine ring, we would
have a new approach for the synthesis of functionalized
pyrrolidines. To achieve this goal, we first developed three new
and improved approaches for making N-alkoxy-N-alkyl diazo
precursors and proceeded to perform N−O tether-directed
cyclopropanation to generate a library of cyclopropyl-fused
heterocycles. Cleavage of the N−O bond followed by
cyclization of the resulting amino alcohol gave the desired
cyclopropyl-fused substituted pyrrolidine (A in Scheme 1a).
For the synthesis of A, two traditional carbenoid cyclo-
propanation strategies23−30 could be envisaged using 2,5-
dihydro-1H-pyrrole 1 (strategy (a) in Scheme 1a) or
diazoamide 2 (strategy (b) in Scheme 1a) as substrates,
followed by further elaboration. However, we decided against
these two approaches because of potential drawbacks with each
of them. For strategy (a), the two faces of 1 are both sterically
encumbered with either an aryl or alkyl group, so achieving
diastereoselective cyclopropanation would be nontrivial.
Strategy (b) was also not deemed to be ideal because the C−
H insertion side-reactions of 2 to give 4-membered rings31 or
cyclopropanation of N-benzyl group to afford the Buchner ring-
expanded product32,33 (blue dotted arrow in Scheme 1a) could
compete with the desired cyclopropanation of the olefin (blue
dotted lines in Scheme 1a). In light of the limitations in these
two approaches, we designed a third approach to prepare A
(strategy (c), Scheme 1a), using the N−O tethered diazoamide
4. We hypothesized that this approach could yield the desired
cyclopropanation product 5 because the conformational
preference of the N-alkoxy amide places the alkene group
closer to the carbenoid than the N-alkyl group in 4 (see
Scheme 1b,c and refs 8, 34−38 for the basis of this hypothesis).
Rotation about the C−N bond in diazoamides (cis-to-trans
isomerization) is known to be slow; hence, we expected that
the conformational preference of the N−O tethered diazo-
amide would influence product distribution.8 A computational
Received: April 13, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. (a) Reterosynthetic Analysis of Cyclopropyl-Fused Pyrrolidine (A); (b) Carbenoid Reactivity in Amide Systems Is
Not Regioselective Because of Equal Populations of Conformers (I) and (II); (c) For N-Alkoxy-N-alkyl Diazoamides, However,
The Major Conformer Is (I), Which Is Predicted to Be about 5.0 kcal mol−1 More Stable than Conformer II in Some
a
Systems8,39
a
Dotted line denotes cyclopropanation, and dotted arrow denotes C−H insertion or aromatic cyclopropanation if R′ = phenyl.
Scheme 2. (a) Previously Used Strategy for the Synthesis of N−O Tethered Diazo Substrates;8 (b) New Routes Developed in
a
This Study for the Synthesis of N−O Tethered Diazo Substrates
a
Reaction conditions: (i) di-tert-butyl azodicarboxylate, PPh3, CH2Cl2; (ii) NH2NH2, CH2Cl2/EtOH, 40 °C; (iii) NaNO2, AcOH, H2O, CH2Cl2;
(iv) MsN3, DBU, CH2Cl2; (v) KOH, THF/H2O (1:1).
analysis of conformational preferences of N-alkoxy carbenoids
Our first challenge was to develop a facile route for the
can be found in ref 8.
synthesis of the requisite diazo precursors (compounds of
B
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. Substrates Made via Mitsunobu Reaction
a
Compound 25 was not purified but converted directly into diazo precursor S8 in 57% over 3 steps (see Supporting Information).
prototype 4 in Scheme 1a). In previous work, we had
developed a methodology for the synthesis of N−O tethered
diazo substrates that relied on a Mitsunobu reaction40−48
between N-hydroxy phthalimide and a precursor alcohol 6 to
give substrate 7 (Scheme 2a).8 Although successful in yielding
the desired products 8 in acceptable overall yields, this protocol
entailed a long 7-step synthesis, which involved several
chromatographic separations. Therefore, we decided to
investigate other more facile approaches for synthesizing our
diazo precursors.
We were successful in developing three new methods
(Scheme 2b) for the synthesis of various N−O tethered
diazo substrates via either a single flask operation (route (a)) or
two flasks operations (routes (b) and (c)). This is a remarkable
improvement over our previous method (Scheme 2a).8
Whereas our previous approach utilized N-hydroxy phthalimide
for the Mitsunobu reaction, our new methods employ N-alkyl-
N-hydroxy amides (compounds 10, 13, and 23).49,50 We were
initially apprehensive about using these amides for the
Mitsunobu reaction because of two reasons: (i) the lower
acidity of the OH group in N-alkyl-N-hydroxy amides (pKa ∼
8.8),51 compared to that of the commonly used Mitsunobu
substrate, N-hydroxy phthalimide (pKa ∼ 6.1),52 would render
them less reactive than N-hydroxy phthalimide, and (ii) the
possibility that the diazo moiety of 10 may undergo an
undesirable side reaction with the phosphine reagent to form
phosphonium ylides, after the extrusion of nitrogen.53−55 These
initial apprehensions were however found to be premature
because treatment of N-methyl-N-hydroxy diazoamide 10 with
olefinic alcohols under Mitsunobu reaction conditions afforded
products 11 and 12 (Scheme 3) in variable yields. Also, N-
hydroxy-N-phthalyl amides 13 reacted with alcohols to give
products 14−22, and N-hydroxy-N-methyl malonyl amide 23
gave products 24 and 25 in good to moderate yields (Scheme
3). The Mitsunobu reaction was sensitive to the nature of
phosphines, azodicarboxylates, and solvent. For example,
triphenylphosphine (TPP) was superior to a variety of
phosphines tested. Replacement of one of the phenyl groups
in TPP by a pyridyl group resulted in reduction of product
yield.
When 4-(dimethylamino)phenyldiphenylphosphine, 2-[2-
(diphenylphosphino)ethyl] pyridine or tributylphosphine
were used, no product was obtained. Di-tert-butylazodicarbox-
ylate was superior to a variety of azodicarboxylates and
azodiamides that were tested (diisopropyl azodicarboxylate,
1,1′- (azodicarbonyl)dipiperidine, di-tert-butyl azodicarboxylate,
diethyl azodicarboxylate solution (40 wt % in toluene), di-(4-
chlorobenzyl)azodicarboxylate). Solvent also played a key role
in the reaction. Dichloromethane (CH2Cl2) and benzene were
superior solvents to tetrahydrofuran (we preferred CH2Cl2 over
benzene because of safety considerations). The Mitsunobu
reaction of N-alkyl-N-hydroxy amides and alcohols is general
and works for primary and secondary alcohols and also for both
unsaturated and saturated alcohols (see Scheme 3 and
Supporting Information, Table S1).
The simple conversion of olefinic alcohols into N-alkoxy-N-
alkyl products (compounds 14−21, Scheme 3) was interesting
to us because we anticipated that we could convert these
products into diazo substrates, which would be amenable to
intramolecular cyclopropanation to afford cyclopropyl-fused
bicycles. The diazo substrates 26−33 were readily prepared in
one flask by deprotection of the phthalamide moiety in 14−21
with hydrazine followed by treating the resulting primary amine
with sodium nitrite and acetic acid (Table 1). Next, we
investigated N−O tethered intramolecular cyclopropanation of
26−33 with dirhodium tetraacetate. The reactivity of N-alkoxy-
C
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 1. Synthesis of N−O Tethered Cyclopropyl Amides 34−41
a
Yields were obtained after purification of products by chromatography on silica.
N-alkyl diazoamides is influenced by the substituent that is
alpha to diazo moiety. Whereas a hydrogen substituent
permitted cyclopropanation (entries 2−9 in Table 1), an α-
carbonyl substituent suppressed cyclopropanation (entry 1 in
Table 1). For this compound (12), 2 mol % of three different
catalysts, Rh2(OAc)4, RuCl3, and Rh2(cap)4 (cap = caprolacta-
mate), were screened, but none catalyzed product formation.
Encouragingly, however, the intramolecular cyclopropanations
of compounds 26−33 were successful and afforded products
34−41 in 51−89% yields (Table 1). For entries 3, 5, and 7
(Table 1), only one diastereomer (shown in Table 1) was
obtained after column chromatography (assignment of each
D
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 4. (a) Synthesis of Cyclopropyl-Amino Alcohol 44 from N−O-Containing Bicycle 35; (b) Elaboration of 44a into
Cyclopropyl-Fused Pyrrolidine 45
Scheme 5. Plausible Mechanism to Account for the Formation of Compound 45b from the O-Mesylate of 44a
diastereomer was based on a NOESY experiment, see
Supporting Information).
at 10 and 23 °C. Cleavage of the N−O bond of 43 (43a:43b =
3.4:1), using zinc in acetic acid−water mixture, resulted in
diastereoselective reduction to give amino alcohol 44 (44a:44b
= 10:1). The enhancement of de from 3.4:1 in starting material
to 10:1 in product was unexpected, and a hypothesis to account
for this is provided in the Supporting Information. Next, we
sought to convert the hydroxyl group into a better leaving
group so that an intramolecular displacement of this leaving
group by nitrogen would afford a nitrogen-containing bi-
cycle.59,60 Because nitrogen is also nucleophilic and would also
react with the sulfonyl chlorides, this strategy is suitable for the
substrates in which the nitrogen is more sterically encumbered
than the hydroxyl group. Treating compound 44a with
N−O tether is a value-added56,57 moiety because it can be
converted into different functional groups found in biologically
active molecules. For example, it is possible to add nucleophiles
to N-alkoxy amides without overaddition, which is usually seen
with esters.58 Pleasingly, in line with our expectation, a phenyl
group was successfully added to substrate 35 to give 42.
Overaddition is presumably prevented by the formation of
stable chelate between the lithium and the two oxygens leading
to the formation of Int 1 (Scheme 4a). Compound 42 was then
reduced with NaCNBH3 to give compound 43 (dr of 43a:43b
= 3.4:1). A similar pattern of diastereoselectivity was observed
E
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 1. (a) NOE 1D experiments on compounds 45a and 45b. (b) Calculation of the conformation energy of 45a and 45b in CHCl3.
tosylchloride (TsCl) resulted in a compound whereby the
sulfonyl group reacted with the nitrogen and not the hydroxyl
group (compound S9 in Supporting Information). On the
other hand, using mesyl chloride (MsCl) resulted in oxygen but
not nitrogen mesylation. The active electrophile generated from
TsCl is probably a sulfonyl ammonium intermediate, which
may be less reactive than the sulfene intermediate, generated
from MsCl. In constrast to the less reactive sulfonyl
ammonium, which selects for the more nucleophilic amine
nucleophile, the sulfene intermediate may have a high enough
reactivity to react with either the 2° amine or alcohol, and so
steric differences between these two functionalities could
underpin the observed selectivity.61 Upon mesylation of the
hydroxyl group in 44a, a subsequent intramolecular displace-
ment of the mesylate by the amine resulted in the formation of
bicycle 45a (Scheme 4b). A minor compound, 45b was also
obtained presumably because of a double displacement (the
chloride anion from the mesyl chloride displaces the mesylate
in an intermolecular fashion before an intramolecular displace-
ment by the amine). An alternative hypothesis to account for
the formation of the minor product 45b from the O-mesylate of
44a, suggested by an anonymous reviewer (and which we like),
is shown in Scheme 5.
Attempts to suppress the presumed double displacement by
using mesylating agents with less nucleophilic leaving groups,
such as mesyl triflate or mesyl anhydride, did not work. In these
cases, a complex reaction mixture was obtained. Compounds
45a and 45b are however separable, using silica gel so the
production of the minor product 45b is not too much of a
detriment.
We determined the conformational preferences of 45a and
45b via NMR (NOE) and computational methods by
calculating the relative energies of the different conformers.
NOE data suggests that 45a exists as a boat conformer, whereas
45b exists as a chair conformer (Figure 1a). The assignment,
based on NOE, was corroborated by calculations (see
Supporting Information for computational details). The boat
conformer of 45a is 3.7 kcal/mol more stable than its chair
conformer. In contrast, the chair conformer of 45b is 1.9 kcal/
mol more stable than its boat conformer. These results are
consistent with a hypothesis, which posits that chair
conformation in 45a would have an unfavorable steric clash
between the methyl group and the cyclopropane hydrogens,
whereas a boat conformation in 45b would result in an
unfavorable diaxial interaction between the methyl and phenyl
groups (see Figure 1b).
In addition to enabling the synthesis of cyclopropyl-fused
pyrrolidine compound 45, N−O containing intermediates
(such as compounds 34−41) have several other potential
applications. For example, such intermediates can be utilized to
make other medically useful cyclopropyl-fused pyrrolidine
compounds such as indolizomycin (an antibiotic)6 and
DOV21947 (a potential antidepressant drug).62 Moreover, 7-
membered N−O containing cyclopropyl-fused heterocycles
(similar to compound 41) can be elaborated to generate
cyclopropyl-fused piperidines such as GSK1360707 (an
antidepressant drug).63
CONCLUSION
■
N−O-containing intermediates have a rich history of being
used for the synthesis of nitrogen-containing molecules. A
traditional way to make these intermediates involves the
cycloaddition of nitrones and π systems.64−67 In this paper, we
have demonstrated a complementary route for making N−O
containing heterocycles. We have demonstrated that N-alkoxy-
N-alkyl diazoamides are useful intermediates for the synthesis
of interesting and functionalized nitrogen-containing com-
pounds, including amino alcohols and nitrogen-containing
bicyclic compounds. Of note, we demonstrate that N-hydroxy-
N-alkyl amides are suitable substrates for Mitsunobu reaction.
Bicyclic compound 45 was synthesized in only six-flask
operations, staring from 3-buten-2-ol. The stereochemistries
in the final products are controlled by the stereochemistry of
the starting alcohol. Also, this strategy has allowed function-
alization of four contiguous centers on pyrrolidine ring. The use
of N−O tethered diazo substrates for the synthesis of
functionalized nitrogen-containing compounds adds to the
toolbox of complex molecule synthesis using diazo sub-
strates.9−22
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed using oven-dried
glassware (120 °C) under inert atmosphere of argon (Ar).
Dichloromethane (CH2Cl2) and triethylamine (Et3N) were distilled
over calcium hydride (CaH2) and toluene (PhMe) over sodium (Na)
prior to use, while other solvents and reagents were used as received
F
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
from the supplier. Reactions were monitored by thin-layer
chromatography (TLC). Visualization of TLC plates was accom-
plished by UV light or by staining with iodine (I2), potassium
permanganate (KMnO4), phosphomolybdic acid (PMA), and
ninhydrin solution. The purification of reaction mixtures were
performed using flash column chromatography on silica gel (230−
400 mesh). Low temperatures were obtained by ice bath or by mixing
dry ice with acetone, whereas thermostat controlled silicone oil baths
were employed to attain elevated temperatures. The chemical
structures of the isolated compounds were characterized by nuclear
magnetic resonance spectroscopy (1H and 13C) and high-resolution
mass spectra (HRMS) using a TOF instrument with ESI as the
before being concentrated in vacuo. The residue was purified by silica
gel chromatography (MeOH/CH2Cl2 1:20) to afford product 23 (268
1
mg, 92%) as maroon color oil: H NMR (CD3OD, 400 MHz) δ 3.73
(s, 3H), 3.53 (s, 2H), 3.24 (s, 3H); 13C NMR (CD3OD, 100 MHz) δ
168.4, 167.4, 51.4, 39.4, 34.9; HRMS (ESI-TOF) m/z calcd. for
C5H10NO4 [M + H]+ 148.0610, found 148.0607.
General Procedure for the Synthesis of Mitsunobu Adducts.
To a cooled (0 °C) solution of hydroxylamide (1.0 mmol), PPh3 (1.2
mmol) and alcohol (1.2 mmol) in CH2Cl2 (50 mL) was added a
solution of di-tert-butyl azodicarboxylate (1.2 mmol) in CH2Cl2 (10
mL) slowly via syringe pump over a period of 1 h. The reaction was
slowly warmed to room temperature and stirred for 16 h. The solvent
was concentrated in vacuo, and the residue was purified by flash
chromatography (EtOAc/hexanes) on silica gel to give the desired
Mitsunobu product.
Ethyl 2-diazo-3-[(hex-5-en-2-yloxy)(methyl)amino]-3-oxopropa-
noate (11). Following the procedure described above for the
Mitsunobu reaction, diazo amide 10 (78 mg, 0.42 mmol) and 5-
hexen-2-ol (60 μL, 0.50 mmol) afforded 11 (76 mg, 68%), as yellow
oil, after flash chromatography (EtOAc/hexanes 1:6) on silica gel
column: IR (neat) ν 3098, 2978, 2120, 1727, 1642, 1367, 1284 cm−1;
1H NMR (CDCl3, 400 MHz) δ 5.81−5.71 (m, 1H), 5.05−4.97 (m,
1
ionization method. H NMR chemical shifts are reported as (δ) in
ppm and are calibrated according to residual solvent peaks or indicated
external standards. 1H NMR coupling constants (J values) are reported
in hertz (Hz), and multiplicities are indicated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), p (pentaplet), dd (doublet of
doublets), td (triplet of doublets), dq (doublet of quartets), ddd
(doublet of doublet of doublets), tdd (triplet of doublet of doublets),
dddd (doublet of doublet of doublet of doublets), dt (doublet of
triplets), dq (doublet of quartets), m (multiplet), bs (broad singlet),
app (apparent). 13C NMR chemical shifts are reported as ppm relative
to residual solvent peak. Ethyl 2-diazomalonyl chloride was prepared
as reported in literature,68 and all the alcohols were purchased from
commercial supplier.
2H), 4.28 (q, J = 7.1 Hz, 2H), 4.07−4.01 (m, 1H), 3.23 (s, 3H), 2.15−
2.10 (m, 2H), 1.76−1.72 (m, 1H), 1.57−1.53 (m, 1H), 1.29 (t, J = 7.1
Hz, 3H), 1.22 (d, J = 6.2 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ
163.0, 161.1, 137.6, 115.5, 79.2, 61.8, 36.0, 33.6, 29.7, 18.1, 14.5;
HRMS (ESI-TOF) m/z calcd. for C12H20N3O4 [M + H]+ 270.1454,
found 270.1427.
General Procedure for the Synthesis of N-Hydroxy Amides.
Ethyl 2-diazo-3-(hydroxy(methyl)amino)-3-oxopropanoate (10). To
a cooled (0 °C) solution of N-methylhydroxylamine hydrochloride (79
mg, 0.95 mmol) and Et3N (0.3 mL, 2.26 mmol) in CH2Cl2 (25 mL)
under Ar was added dropwise a solution of ethyl 2-diazomalonyl
chloride68 (160 mg, 0.91 mmol) in CH2Cl2 (5 mL). The mixture was
slowly warmed to room temperature and stirred for 2 h. 1% HCl (15
mL) was then added to the reaction mixture, and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL),
and the combined organic layers were washed with brine (10 mL),
dried (MgSO4), filtered and concentrated in vacuo. The residue was
purified by flash chromatography (EtOAc/hexanes 1:9 to 2:3) on silica
Ethyl 3-[(allyloxy)(methyl)amino]-2-diazo-3-oxopropanoate (12).
Following the procedure described above for the Mitsunobu reaction,
diazo amide 10 (55 mg, 0.29 mmol) and allyl alcohol (24 μL, 0.35
mmol) afforded 12 (39 mg, 59%), as yellow oil, after flash
chromatography (EtOAc/hexanes 1:6) on silica gel column: IR
1
(neat) ν 3078, 2982, 2119, 1727, 1645, 1369, 1282 cm−1; H NMR
(CDCl3, 400 MHz) δ 5.96−5.90 (m, 1H), 5.42−5.37 (m, 2H), 4.36
(d, J = 6.4 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.26 (s, 3H), 1.30 (t, J =
7.1 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 162.7, 161.3, 130.8,
121.6, 75.3, 61.8, 35.0, 14.5; HRMS (ESI-TOF) m/z calcd. for
C9H14N3O4 [M + H]+ 228.0984, found 228.0977.
1
gel to give hydroxy amide 10 (102 mg, 60%) as a yellowish oil: H
NMR (CDCl3, 400 MHz) δ 8.96 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H),
3.27 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ
165.0, 162.1, 62.7, 36.9, 14.5; HRMS (ESI-TOF) m/z calcd. for
C6H10N3O4 [M + H]+ 188.0671, found 188.0662.
2-(1,3-Dioxoisoindolin-2-yl)-N-hydroxy-N-methylacetamide
(13a). Following the described general procedure above, phthalylglycyl
chloride (0.75 g, 3.35 mmol) and N-methylhydroxylamine hydro-
chloride (0.3 g, 3.52 mmol) afforded hydroxylamide 13a (0.7 g, 89%),
as a white solid, after flash chromatography (EtOAc/CH2Cl2 1:1) on
silica gel column: 1H NMR (CDCl3, 400 MHz) δ 7.91−7.88 (m, 2H),
7.7−7.75 (m, 2H), 4.71 (s, 2H), 3.26 (s, 3H), 1.69 (brs, 1H); 13C
NMR (CDCl3, 125 MHz) δ 168.6, 167.3, 134.5, 132.3, 132.2, 123.8,
39.2, 36.6; HRMS (ESI-TOF) m/z calcd. for C11H11N2O4 [M + H]+
235.0719, found 235.0723.
N-Benzyl-2-(1,3-dioxoisoindolin-2-yl)-N-hydroxyacetamide (13b).
Following the described general procedure above, phthalylglycyl
chloride (0.65 g, 2.90 mmol) and N-benzylhydroxylamine hydro-
chloride (0.44 g, 3.05g) afforded hydroxy amide 13b (0.83 g, 92%), as
an off-white solid, after flash chromatography (EtOAc/hexanes 1:4) on
silica gel column: 1H NMR (CDCl3, 400 MHz) δ 7.84−7.83 (m, 2H),
7.75−7.73 (m, 2H), 7.30−7.27 (m, 4H), 6.85−6.83 (m, 1H), 4.81 (s,
2H), 4.73 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 168.8, 168.6,
166.9, 135.4, 134.4, 132.3, 129.0, 128.9, 128.1, 123.8, 52.7, 39.3 ppm;
HRMS (ESI-TOF) m/z calcd. for C17H15N2O4 [M + H]+ 311.1032,
found 311.1029.
Methyl 3-(hydroxy(methyl)amino)-3-oxopropanoate (23). To a
suspension of N-methylhydroxylamine hydrochloride (334 mg, 4.00
mmol) in CH2Cl2 (30 mL) was added dry DBU (0.89 mL, 6.00
mmol) at room temperature. The mixture was cooled to −40 °C and a
solution of methyl malonyl chloride (0.2 mL, 2.00 mmol) in CH2Cl2
(5 mL) was added slowly via syringe pump over a period of 1 h. The
mixture was slowly warmed to room temperature and stirred for 18 h
N-(Allyloxy)-2-(1,3-dioxoisoindolin-2-yl)-N-methylacetamide
(14). Following the procedure described above for the Mitsunobu
reaction, amide 13a (87 mg, 0.37 mmol) and allyl alcohol (30 μL, 0.44
mmol) afforded 14 (69 mg, 68%), as a white solid, after flash
chromatography (EtOAc/hexanes 1:6 to 1:5) on silica gel column: 1H
NMR (CDCl3, 400 MHz) δ 7.86−7.84 (m, 2H), 7.72−7.70 (m, 2H),
6.07−5.98 (m, 1H), 5.48−5.39 (m, 2H), 4.62 (s, 1H), 4.48 (d, J = 6.5
Hz, 2H), 3.23 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 168.1, 167.7,
134.2, 132.4, 131.1, 123.6, 121.5, 75.4, 39.1, 33.9; HRMS (ESI-TOF)
m/z calcd. for C14H15N2O4 [M + H]+ 275.1032 found 275.1035.
N-(But-3-en-2-yloxy)-2-(1,3-dioxoisoindolin-2-yl)-N-methylaceta-
mide (15). Following the procedure described above for the
Mitsunobu reaction, amide 13a (100 mg, 0.43 mmol) and 3-buten-
2-ol (44 μL, 0.51 mmol) afforded 15 (106 mg, 86%), as a white solid,
after flash chromatography (EtOAc/hexanes 1:3) on silica gel column:
1H NMR (CDCl3, 400 MHz) δ 7.84−7.81 (m, 2H), 7.71−7.68 (m,
2H), 5.97−5.88 (m, 1H), 5.37−5.32 (m, 2H), 4.66−4.53 (m, 2H),
4.51−4.45 (m, 1H), 3.19 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 168.4, 168.1, 137.1, 134.1, 132.4, 123.5, 120.0,
81.8 39.4, 35.3, 19.3; HRMS (ESI-TOF) m/z calcd. for C15H17N2O4
[M + H]+ 289.1188, found 289.1178.
N-(Allyloxy)-N-benzyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (16).
Following the procedure described above for the Mitsunobu reaction,
amide 13b (350 mg, 1.12 mmol) and allyl alcohol (92 μL, 1.35 mmol)
afforded 16 (298 mg, 79%), as a white solid, after flash
chromatography (EtOAc/hexanes 1:6 to 1:5) on silica gel column:
1H NMR (CDCl3, 400 MHz) δ 7.91−7.88 (m, 2H), 7.76−7.72 (m,
2H), 7.38−7.30 (m, 5H), 5.99−5.91 (m, 1H), 5.38−5.34 (m, 2H),
4.84 (s, 2H), 4.68 (m, 2H), 4.39 (d, J = 6.4 Hz, 2H); 13C NMR
(CDCl3, 125 MHz) δ 176.8, 168.2, 135.9, 134.2, 132.5, 131.0, 128.9,
G
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
128.7, 128.1, 123.7, 121.4, 76.5, 51.1, 39.4; HRMS (ESI-TOF) m/z
calcd. for C20H19N2O4 [M + H]+ 351.1345, found 351.1336.
3H); 13C NMR (CDCl3, 100 MHz) δ 168.4, 168.3, 134.3, 132.9,
132.7, 130.3, 123.8, 81.5, 39.7, 35.3, 19.8, 18.2; HRMS (ESI-TOF) m/
z calcd. for C16H19N2O4 [M + H]+ 303.1345, found 303.1345.
Methyl 3-((but-3-en-2-yloxy)(methyl)amino)-3-oxopropanoate
(24). Following the procedure described above for the Mitsunobu
reaction, amide 23 (250 mg, 1.70 mmol) and 3-buten-2-ol (0.2 mL,
2.03 mmol) afforded 24 (189 mg, 55%), as clear oil, after flash
chromatography (EtOAc/hexanes 1:6) on silica gel column: 1H NMR
(CDCl3, 400 MHz) δ 5.89−5.80 (m, 1H), 5.32−5.27 (m, 2H), 4.41−
4.34 (m, 1H), 3.75 (s, 3H), 3.56−3.44 (m, 2H), 3.23 (s, 3H), 1.33 (d,
J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.9, 168.3, 137.4,
120.2, 82.2, 52.7, 41.0, 35.5, 19.5; HRMS (ESI-TOF) m/z calcd. for
C9H16NO4 [M + H]+ 202.1079, found 202.1080.
N-Benzyl-N-(but-3-en-2-yloxy)-2-(1,3-dioxoisoindolin-2-yl)-
acetamide (17). Following the procedure described above for the
Mitsunobu reaction, amide 13b (145 mg, 0.47 mmol) and 3-buten-2-
ol (49 μL, 0.56 mmol) afforded 17 (131 mg, 77%), as a white solid,
after flash chromatography (EtOAc/hexanes 1:6) on silica gel column:
1H NMR (CDCl3, 400 MHz) δ 7.88 (dd, J = 5.6, 3.2 Hz, 2H), 7.73
(dd, J = 5.6, 3.2 Hz, 2H), 7.37−7.30 (m, 5H), 5.98−5.89 (m, 1H),
5.37−5.26 (m, 2H), 4.92−4.79 (m, 2H), 4.73−4.62 (m, 2H), 4.84−
4.45 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
δ 168.8 168.2, 136.9, 136.0, 134.2, 132.5, 128.8, 128.6, 127.9, 123.7,
120.3, 82.0, 51.6, 39.7, 19.3 ppm; HRMS (ESI-TOF) m/z calcd. for
C21H21N2O4 [M + H]+ 365.1501, found 365.1498.
2-(1,3-Dioxoisoindolin-2-yl)-N-methyl-N-(3-methylbut-2-
enyloxy)acetamide (18). Following the procedure described above for
the Mitsunobu reaction, amide 13a (170 mg, 6.98 mmol) and 3-
methyl-2-buten-1-ol (85 μL, 8.38 mmol) afforded 18 (182 mg, 86%),
as a white solid, after flash chromatography (EtOAc/hexanes 1:4) on
silica gel column: 1H NMR (CDCl3, 400 MHz) δ 7.82 (dd, J = 5.4, 3.0
Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H), 5.44 (tdt, J = 7.6, 3.0, 1.5 Hz,
1H), 4.60 (s, 2H), 4.44 (d, J = 7.5 Hz, 2H), 3.21 (s, 3H), 1.82 (s, 3H),
1.75 (d, J = 1.3 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 167.7, 167.3,
142.0, 133.8, 132.2, 123.2, 117.1, 70.2, 38.9, 33.5, 25.7, 18.0; HRMS
(ESI-TOF) m/z calcd. for C16H19N2O4 [M + H]+ 303.1345, found
303.1320.
Ethyl 2-diazo-3-{methyl[(4-phenylbutan-2-yl)oxy]amino}-3-oxo-
propanoate (S1). Following the procedure described above for the
Mitsunobu reaction, diazo amide 10 (94 mg, 0.50 mmol) and 4-
phenyl-2-butanol (94 μL, 0.60 mmol) afforded S1 (115 mg, 72%), as
dark yellow oil, after flash chromatography (EtOAc/hexanes 1:6 to
1:3) on silica gel column: IR (neat) ν 2979, 2123, 1692, 1641, 1286
1
cm−1; H NMR (CDCl3, 400 MHz) δ 7.30 (t, J = 7.3 Hz Hz, 2H),
7.22−7.17 (m, 3H), 4.29 (q, J = 7.1 Hz, 2H), 4.09−4.01 (m, 1H), 3.22
(s, 3H), 2.74−2.68 (m, 2H), 2.01−1.97 (m, 1H), 1.83−1.79 (m. 1H),
1.31 (t, J = 7.1 Hz Hz, 3H), 1.27 (d, J = 6.3 Hz, 3H); 13C NMR
(CDCl3, 125 MHz,) δ 163.0, 161.2, 141.2, 128.7, 128.5, 126.3, 61.8,
36.2, 31.7, 28.4, 18.3, 14.6; HRMS (ESI-TOF) m/z calcd. for
C16H22N3O4 [M + H]+ 320.1610, found 320.1618.
(E)-N-(Cinnamyloxy)-2-(1,3-dioxoisoindolin-2-yl)-N-methylaceta-
mide (19). Following the procedure described above for the
Mitsunobu reaction, amide 13a (0.86 g, 3.53 mmol) and cinnamyl
alcohol (0.56 g, 4.24 mmol) afforded 19 (1.13 g, 92%), as a white
solid, after flash chromatography (EtOAc/hexanes 1:4) on silica gel
column: 1H NMR (CDCl3, 400 MHz) δ 7.86 (dd, J = 5.5, 3.0 Hz, 2H),
7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.47−7.42 (m, 2H), 7.41−7.36 (m,
2H), 7.35−7.30 (m, 1H), 6.77 (d, J = 15.9 Hz, 1H), 6.39 (dt, J = 15.9,
6.7 Hz, 1H), 4.69 (s, 2H), 4.65 (dd, J = 6.7, 1.3 Hz, 2H), 3.28 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 168.3, 168.0, 136.9, 136.1, 134.4,
Ethyl 2-[(2-diazo-3-ethoxy-N-methyl-3-oxopropanamido)oxy]-4-
phenylbutanoate (S2). Following the procedure described above for
the Mitsunobu reaction, diazo amide 10 (87 mg, 0.46 mmol) and ethyl
2-hydroxy-4-phenylbutanoate (0.1 mL, 0.55 mmol) afforded S2 (110
mg, 63%), as yellow oil, after flash chromatography (EtOAc/hexanes
1:6) on silica gel column: IR (neat) ν 2982, 2130, 1727, 1643, 1287
cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.30 (t, J = 7.4 Hz, 2 H), 7.23−
7.19 (m, 3H), 4.43 (t, J = 6.6 Hz, 1 H), 4.31−4.26 (m, 2H), 4.19 (q, J
= 7.1 Hz, 2H), 3.25 (s, 3H), 2.83−2.70 (m, 2H), 2.35−2.09 (m, 2H),
1.31 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 170.5, 162.6, 162.3, 140.3, 128.7, 128.5, 126.5, 81.4, 61.8,
61.7, 37.2, 32.7, 31.2, 28.3, 14.5, 14.2; HRMS (ESI-TOF) m/z calcd.
for C18H24N3O6 [M + H]+ 378.1665, found 378.1649.
132.6, 129.1, 128.9, 127.2, 123.8, 122.0, 75.6, 39.4, 34.4; HRMS (ESI-
TOF) m/z calcd. for C20H19N2O4 [M + H]+ 351.1345, found
351.1346.
2-(1,3-Dioxoisoindolin-2-yl)-N-methyl-N-(2-methylallyloxy)-
acetamide (20). Following the procedure described above for the
Mitsunobu reaction, amide 13a (150 mg, 0.61 mmol) and 2-methyl-2-
propen-1-ol (62 μL, 0.74 mmol) afforded 20 (150 mg, 85%), as a
white solid, after flash chromatography (EtOAc/hexanes 1:4) on silica
gel column: 1H NMR (CDCl3, 400 MHz) δ 7.82 (dd, J = 5.5, 3.1 Hz,
2H), 7.68 (dd, J = 5.5, 3.0 Hz, 2H), 5.09 (s, 1H), 5.03 (s, 1H), 4.60 (s,
2H), 4.36 (s, 2H), 3.21 (s, 3H), 1.83 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 168.3, 167.8, 139.3, 134.4, 132.6, 123.8, 116.3, 78.9, 39.2,
34.1, 20.3; HRMS (ESI-TOF) m/z calcd. for C15H17N2O4 [M + H]+
289.1188, found 289.1182.
N-(But-3-en-1-yloxy)-2-(1,3-dioxoisoindolin-2-yl)-N-methylaceta-
mide (21). Following the procedure described above for the
Mitsunobu reaction, amide 13a (135 mg, 0.57 mmol) and 3-buten-
1-ol (60 μL, 0.69 mmol) afforded 21 (125 mg, 75%), as a white solid,
after flash chromatography (EtOAc/hexanes 2:3) on silica gel column:
1H NMR (CDCl3, 400 MHz) δ 7.92−7.88 (m, 2H), 7.77−7.73 (m,
2H), 5.93−5.84 (m, 1H), 5.25−5.16 (m, 2H), 4.64 (s, 2H), 4.07 (t, J =
6.5 Hz, 2H), 3.25 (s, 3H), 2.49 (q, J = 6.5 Hz, 2H); 13C NMR (CDCl3,
100 MHz) δ 168.0, 167.4, 134.0, 133.5, 132.2, 123.4, 118.0, 73.4, 38.9,
33.4, 32.4; HRMS (ESI-TOF) m/z calcd. for C15H17N2O4 [M + H]+
289.1188, found 289.1154.
(E)-2-(1,3-Dioxoisoindolin-2-yl)-N-methyl-N-(pent-3-en-2-yloxy)-
acetamide (22). Following the procedure described above for the
Mitsunobu reaction, amide 13a (0.154 mg, 0.63 mmol) and 3-penten-
2-ol (77 μL, 0.75 mmol) afforded 22 (70 mg, 37%), as a white solid,
after flash chromatography (EtOAc/hexanes 1:4) on silica gel column:
1H NMR (CDCl3, 400 MHz) δ 7.85 (dd, J = 5.5, 3.1 Hz, 2H), 7.70
Ethyl 3-[(but-3-yn-1-yloxy)(methyl)amino]-2-diazo-3-oxopropa-
noate (S3). Following the procedure described above for the
Mitsunobu reaction, diazo amide 10 (64 mg, 0.34 mmol) and 3-
butyn-1-ol (31 μL, 0.41 mmol) afforded S3 (20 mg, 24%), as a
yellowish oil, after flash chromatography (EtOAc/hexanes 1:6) on
silica gel column: IR (neat) ν 3243, 2982, 2120, 1723, 1641, 1368,
1
1282 cm−1; H NMR (CDCl3, 400 MHz) δ 4.30 (q, J = 7.1 Hz, 2H),
4.01 (t, J = 6.6 Hz, 2H) 3.27 (s, 3H), 2.53 (td, J = 6.6, 2.6 Hz, 2H),
2.04 (t, J = 2.6 Hz, 1H), 1.32 (t, J = 7.1 Hz); 13C NMR (CDCl3, 125
MHz) δ 162.6, 161.6, 79.7, 72.0, 70.4, 61.8, 35.2, 18.4, 14.6; HRMS
(ESI-TOF) m/z calcd. for C10H14N3O4 [M + H]+ 240.0984, found
240.0974.
Ethyl 2-diazo-3-[methyl(prop-2-yn-1-yloxy)amino]-3-oxopropa-
noate (S4). Following the procedure described above for the
Mitsunobu reaction, diazo amide 10 (70 mg, 0.37 mmol) and
propargyl alcohol (30 μL, 0.45 mmol) afforded S4 (41 mg, 49%), as a
yellowish oil, after flash chromatography (EtOAc/hexanes 1:6) on
silica gel column: IR (neat) ν 3245, 2982, 2121, 1723, 1641, 1369,
1
1283 cm−1; H NMR (CDCl3, 400 MHz) δ 4.54 (d, J = 2.4 Hz, 2H),
4.29 (q, J = 7.1 Hz, 2H), 3.29 (s, 3H), 2.60 (t, J = 2.4 Hz, 1H), 1.30 (t,
J = 7.1 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz) δ 162.5, 162.0,
77.7, 76.7, 62.0, 61.8, 35.5, 28.3, 14.5 ppm; HRMS (ESI-TOF) m/z
calcd. for C9H12N3O4 [M + H]+ 226.0828, found 226.0842.
2-(1,3-Dioxoisoindolin-2-yl)-N-methyl-N-(prop-2-yn-1-yloxy)-
acetamide (S5). Following the procedure described above for the
Mitsunobu reaction, amide 13a (120 mg, 0.51 mmol) and propargyl
alcohol (36 μL, 0.61 mmol) afforded S5 (110 mg, 79%), as a white
solid, after flash chromatography (EtOAc/hexanes 1:6) on silica gel
1
column: H NMR (CDCl3, 400 MHz) δ 7.86−7.84 (m, 2H), 7.73−
(dd, J = 5.5, 3.0 Hz, 1H), 5.81 (dq, J = 15.3, 6.4 Hz, 1H), 5.55 (ddd, J
= 15.3, 8.5, 1.7 Hz, 1H), 4.64−4.51 (m, 2H), 4.43 (dq, J = 8.5, 6.4 Hz,
1H), 3.18 (s, 3H), 1.79 (dd, J = 6.5, 1.7 Hz, 3H), 1.35 (d, J = 6.4 Hz,
7.70 (m, 2H), 4.75 (s, 2H), 4.60 (s, 2H), 3.26 (s, 3H), 2.74 (s, 1H);
13C NMR (CDCl3, 125 MHz) δ 168.6, 168.1, 134.2, 132.5, 123.6,
H
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
78.24, 76.9, 39.6, 34.0; HRMS (ESI-TOF) m/z calcd. for calculated for
C14H13N2O4 [M + H]+ 273.0875, found 273.0869.
(CDCl3, 400 MHz) δ 7.44−7.32 (m, 5H), 6.71 (d, J = 15.9 Hz, 1H),
6.32 (dt, J = 15.8, 6.8 Hz, 1H), 5.41 (s, 1H), 4.49 (dd, J = 6.8, 1.2 Hz,
2H), 3.26 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 168.5, 135.5,
135.3, 128.2, 127.9, 126.2, 121.6, 74.5, 46.1, 34.3.
N-(But-3-yn-1-yloxy)-2-(1,3-dioxoisoindolin-2-yl)-N-methylaceta-
mide (S6). Following the procedure described above for the
Mitsunobu reaction, amide 13a (105 mg, 0.45 mmol) and 3-butyn-
1-ol (41 μL, 0.54 mmol) afforded S6 (63 mg, 49%), as a white solid,
after flash chromatography (EtOAc/hexanes 1:6) on silica gel column:
1H NMR (CDCl3, 400 MHz) δ 7.85−7.82 (m, 2H), 7.72−7.69 (m,
2-Diazo-N-methyl-N-(2-methylallyloxy)acetamide (32). Com-
pound 20 (0.7 g, 2.42 mmol) afforded 32 (0.28 g, 68%, 2 steps), as
yellow oil, after flash chromatography (EtOAc/hexanes 1:5) on silica
1
gel column: IR (neat) ν 2107, 1629, 1381 cm−1; H NMR (CDCl3,
2H), 4.68 (s, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.22 (s, 3H), 2.59 (m, 2H),
2.07 (t, J = 2.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 168.0, 134.1,
132.4, 123.6, 80.1, 72.2, 70.6, 39.1, 33.8, 18.5; HRMS (ESI-TOF) m/z
calcd. for C15H15N2O4 [M + H]+ 287.1032, found 287.1039.
400 MHz) δ 5.36 (s, 1H), 5.07−5.02 (m, 2H), 4.23 (s, 2H), 3.22 (s,
3H), 1.84−1.83 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.1,
139.7, 115.9, 78.9, 34.8, 28.5, 20.3.
N-(But-3-enyloxy)-2-diazo-N-methylacetamide (33). Compound
21 (0.4 g, 1.38 mmol) afforded 33 (163 mg, 70%, 2 steps), as yellow
oil, after flash chromatography (EtOAc/hexanes 1:6) on silica gel
General Procedure for the Synthesis of Diazo Compounds.
N-(But-3-en-2-yloxy)-2-diazo-N-methylacetamide (27). To a sol-
ution of 15 (540 mg, 1.87 mmol) in CH2Cl2/EtOH (15:0.3 mL) was
added hydrazine hydrate (65% aq solution (0.2 mL, 2.8 mmol)), and
the mixture was heated to 40 °C. After stirring for 1 h, white
suspension appeared in the reaction, and the mixture was stirred
vigorously at 40 °C for another 3 h before cooling down to room
temperature. The solvent was concentrated in vacuo, and the resultant
residue was suspended in CHCl3 (75 mL) and then filtered. The
filtrate was concentrated in vacuo to give primary amine product as
colorless oil, which was pure enough to proceed to the next stage of
the reaction. To a solution of crude amine in CH2Cl2 (15 mL) was
added acetic acid (0.5 mL, 9.36 mmol) followed by addition of
solution of NaNO2 (155 mg, 2.25 mmol) in water (3 mL). The
reaction was stirred vigorously for 0.5 h at room temperature and
neutralized with saturated aqueous NaHCO3 solution. The organic
layer was separated, and the aqueous layer was extracted with CH2Cl2
(50 mL × 2). The combined organic phase was dried (MgSO4),
filtered and concentrated in vacuo to afford crude product, which was
chromatographed on silica gel (EtOAc/hexanes 1:6) to give diazo
compound 27 (223 mg, 70%, 2 steps) as yellow oil: IR (neat) ν 2101,
1619 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.88−5.80 (m, 1H), 5.32−
5.24 (m, 3H), 4.35−4.31 (m, 1H), 3.19 (s, 3H), 1.32 (d, J = 6.4 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 169.7, 137.3, 118.9, 81.4, 46.9,
36.0, 19.1
1
column: IR (neat) ν 2106, 1630, 1381 cm−1; H NMR (CDCl3, 400
MHz) δ 5.84 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H), 5.37 (s, 1H), 5.24−5.11
(m, 2H), 3.89 (t, J = 6.5 Hz, 2H), 3.22 (s, 3H), 2.41 (qt, J = 6.6, 1.4
Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 169.6, 134.6, 118.4, 74.0,
47.1, 35.0, 33.1.
2-Diazo-N-methyl-N-(4-phenylbutan-2-yloxy)acetamide (S8).
Amide 23 (150 mg, 1.01 mmol) was reacted with 4-phenyl-2-butanol,
PPh3 and di-tert-butyl azodicarboxylate (Mitsunobu reaction con-
dition) as described above to afford crude 25 as pale yellow residue.
The residue was quickly passed through short silica gel column
(EtOAc/hexanes 1:6) to remove Ph3PO, and the crude product 25
(yield 50%) was used immediately for the next step. To a solution of
intermediate 25 in CH2Cl2 (15 mL) was added mesyl azide (148 mg,
1.22 mmol) followed by DBU (0.2 mL, 1.42 mmol) at room
temperature and stirred for 18 h. The solvent was concentrated in
vacuo to afford crude intermediate S7 as light yellow oil, which was
employed for the next step without further purification in the same
flask. For characterization purposes, small sample of reaction mixture
was purified by flash chromatography (EtOAc/hexanes 1:3) on silica
gel to afford pure S7 as yellowish oil: IR (neat) ν 2125, 1741, 1666,
1369 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.34−7.28 (m, 2H), 7.25−
7.19 (m, 3H), 4.09−4.04 (m, 1H), 3.86 (s, 3H), 3.25 (s, 3H), 2.78−
2.63 (m, 2H), 2.09−1.94 (m, 1H), 1.89−1.75 (m, 1H), 1.29 (d, J = 6.2
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 163.8, 161.2, 141.4, 128.9,
128.7, 126.6, 79.3, 53.0, 36.4, 36.0, 32.0, 18.5. Crude S7 was dissolved
in THF/water (5:5 mL), to which was added a concentrate solution of
KOH (571 mg, 10.2 mmol) in water (2 mL) and stirred for 3 h. The
reaction mixture was diluted with water (20 mL) and extracted with
EtOAc (2 × 30 mL). The combined organic layer was dried (MgSO4),
filtered and concentrated in vacuo to afford light yellow oil, which was
chromatographed on silica gel (EtOAc/hexanes 1:4) to give product
S8 as clear oil (144 mg, 57%, 3 steps). Detailed characterization of S8
is reported in ref 8.
N-(Allyloxy)-2-diazo-N-methylacetamide (26). Compound 14
(220 mg, 0.80 mmol) afforded 26 (69 mg, 55%, 2 steps), as a yellow
oil, after flash chromatography (EtOAc/hexanes 1:6) on silica gel
1
column: IR (neat) ν 2108, 1645, 1382 cm−1; H NMR (CDCl3, 400
MHz) δ 5.99−5.91 (m, 1H), 5.41−5.33 (m, 3H), 4.32 (d, J = 6.3 Hz,
2H), 3.21 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.4, 131.9,
121.1, 75.7, 47.0, 35.0.
N-(Allyloxy)-N-benzyl-2-diazoacetamide (28). Compound 16
(196 mg, 0.56 mmol) afforded 28 (68 mg, 53%, 2 steps) as yellow
oil, after flash chromatography (EtOAc/hexanes 1:5) on silica gel
column: IR (neat) ν 2106, 1639 cm−1; 1H NMR (CDCl3, 400 MHz) δ
7.38−7.28 (m, 5H), 5.92−5.83 (m, 1H), 5.39 (s, 1H), 5.31−5.27 (m,
2H), 4.81 (s, 2H), 4.23−4.20 (m, 2H); 13C NMR (CDCl3, 100 MHz)
δ 169.0, 136.4, 131.4, 128.7, 128.5, 127.7, 120.5, 76.2, 51.5, 47.0.
N-Benzyl-N-(but-3-en-2-yloxy)-2-diazoacetamide (29). Com-
pound 17 (318 mg, 0.87 mmol) afforded 29 (133 mg, 62%, 2
steps), as yellow oil, after flash chromatography (EtOAc/hexanes 1:6)
on silica gel column: IR (neat) ν 2102, 1616 cm−1; 1H NMR (CDCl3,
400 MHz) δ 7.34−7.28 (m, 5H), 5.87−5.78 (m, 1H), 5.36 (s, 1H),
5.24−5.17 (m, 2H), 4.89−4.72 (m, 2H), 4.31−4.27 (m, 1H), 1.27 (d, J
= 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.8, 137.2, 136.5,
128.7, 128.4, 127.6, 119.0, 81.6, 52.1, 47.4, 19.1.
General Procedure for the Synthesis of Cyclopropane-Fused
N−O Containing Bicyclics. ( )-2,4-Dimethyl-3-oxa-4-azabicyclo-
[4.1.0]heptan-5-one (35). A solution of 27 (164 mg, 0.97 mmol) in
dry CH2Cl2 (10 mL) was degassed by bubbling Ar for 30 min in one
flask (solution A). Likewise, a solution of catalyst Rh2(OAc)4 (8.6 mg,
2 mol %) in dry CH2Cl2 (30 mL) was degassed for 30 min in another
flask (solution B). After degassing, solution A was transferred to the
injector and was injected to solution B via syringe pump over a period
of 1 h under Ar atmosphere. The reaction mixture was stirred for 18 h
at room temperature and concentrated in vacuo. The resultant green
residue was purified by flash column chromatography (EtOAc/Hexane
1
1:6) on silica gel to give 35 (91 mg, 67%) as clear oil: H NMR
2-Diazo-N-methyl-N-(3-methylbut-2-enyloxy)acetamide (30).
Compound 18 (1.07 g, 3.53 mmol) afforded 30 (0.36 g, 56%, 2
steps), as yellow oil, after flash chromatography (EtOAc/hexanes 1:6)
on silica gel column: IR (neat) ν 2101, 1621 cm−1; 1H NMR (CDCl3,
400 MHz) δ 5.37−5.32 (m, 2H), 4.29 (d, J = 7.5 Hz, 2H), 3.19 (s,
3H), 1.78 (d, J = 1.4 Hz, 3H), 1.72 (d, J = 1.9 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 169.0, 141.7, 117.8, 70.8, 46.8, 34.7, 26.2, 18.5.
(E)-N-(Cinnamyloxy)-2-diazo-N-methylacetamide (31). Com-
pound 19 (498 mg, 1.42 mmol) afforded 31 (165 mg, 50%, 2
steps), as yellow oil, after flash chromatography (EtOAc/hexanes 1:4)
(CDCl3, 400 MHz) δ 4.31 (q, J = 6.4 Hz, 1H), 3.17 (s, 3H), 1.85−
1.80 (m, 1H), 1.60−1.58 (m, 1H), 1.49−1.46 (m, 1H), 1.34 (d, J = 6.4
Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 168.3, 71.7, 34.9, 22.1, 17.4,
15.6, 8.6; HRMS (ESI-TOF) m/z calcd. for C7H12NO2 [M + H]+
142.0868, found 142.0863.
4-Methyl-3-oxa-4-azabicyclo[4.1.0]heptan-5-one (34). Com-
pound 26 (87 mg, 0.56 mmol) afforded 34 (63 mg, 55%), as a clear
oil, after flash chromatography (EtOAc/hexanes 1:1) on silica gel
column, by employing the general procedure described above for
1
compound 35: H NMR (CDCl3, 400 MHz) δ 4.14−4.11 (m, 1H),
1
on silica gel column: IR (neat) ν 2106, 1626, 1381 cm−1; H NMR
3.98−3.96 (m, 1H), 3.17 (s, 3H), 1.87−1.82 (m, 1H), 1.77−1.72 (m,
I
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 1.55−1.51 (m, 1H), 1.08−1.03 (m, 1H); 13C NMR (CDCl3, 125
MHz) δ 169.1, 66.6, 33.8, 16.8, 16.2, 7.1; HRMS (ESI-TOF) m/z
calcd. for C6H10NO2 [M + H]+ 128.0712, found 128.0714.
solution was diluted with saturated aqueous NaHCO3 (50 mL), and
the aqueous layer was extracted with CHCl3 (2 × 30 mL). The
combined organic extracts were washed with brine (20 mL), dried
(MgSO4) and concentrated in vacuo to yield crude product 42 as a
mixture of two inseparable diastereomers that were used in the
subsequent transformation without separation. Small sample of crude
was purified for characterization of major isomer from the mixture of
diastereomers: clear oil, 1H NMR (CDCl3, 400 MHz) δ 7.97−7.94 (m,
2H), 7.47−7.43 (m, 1H), 7.40−7.35 (m, 2H), 3.42 (dq, J = 9.5, 6.2
Hz, 1H), 2.77−2.71 (m, 1H), 2.16 (s, 3H), 1.54−1.46 (m, 1H), 1.33−
1.29 (m, 1H), 1.22 (d, J = 6.2 Hz, 3H), 1.03 (ddd, J = 8.8, 7.3, 4.4 Hz,
1H); 13C NMR (CDCl3, 125 MHz) δ 139.1, 132.3, 128.3, 128.2,
128.1, 126.1, 74.8, 39.0, 29.5, 23.2, 19.4, 10.9; HRMS (ESI-TOF) m/z
calcd. for C13H18NO2 [M + H]+ 220.1338, found 220.1284.
4-Benzyl-3-oxa-4-azabicyclo[4.1.0]heptan-5-one (36). Com-
pound 28 (63 mg, 0.27 mmol) afforded 36 (49 mg, 89%) as clear
oil, after flash chromatography (EtOAc/hexanes 1:4) on silica gel
column, by employing the general procedure described above for
1
compound 35: H NMR (CDCl3, 400 MHz) δ 7.35−7.28 (m, 5H),
4.90−4.86 (m, 1H), 4.64−4.60 (m, 1H), 4.10−4.07 (m, 1H), 3.81−
3.78 (m, 1H), 1.94−1.89 (m, 1H), 1.76−1.73 (m, 1H), 1.58−1.54 (m,
1H), 1.10−1.04 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 168.7,
136.2, 128.5, 128.2, 127.6, 67.1, 50.1, 17.0, 16.3, 7.2; HRMS (ESI-
TOF) m/z calcd. for C12H14NO2 [M + H]+ 204.1025, found 204.1032.
( )-4-Benzyl-2-methyl-3-oxa-4-azabicyclo[4.1.0]heptan-5-one
(37). Compound 29 (93 mg, 0.38 mmol) afforded 37 (53 mg, 64%), as
a clear oil, after flash chromatography (EtOAc/hexanes 1:2) on silica
gel column, by employing the general procedure described above for
To a stirred solution of crude 42 in THF (5 mL) was added
NaCNBH3 (103 mg, 1.64 mmol) portionwise at −10 °C, followed by
trifluoroacetic acid (5−6 drops). The reaction mixture was stirred for
30 min and then concentrated in vacuo. To the residue was added
saturated aqueous NaHCO3 (20 mL), and the mixture was extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts were
washed with brine (25 mL), dried (MgSO4), and concentrated in
vacuo to yield crude 43 as a mixture of 2 inseparable diastereomers (dr
43a:43b = 3.4:1). Purification by flash column chromatography
(EtOAc/hexanes 5:95) on silica gel afforded 43a/43b (144 mg, 67%, 2
steps) as clear oil in a ratio of 4:1, respectively. Data for compound
1
compound 35: H NMR (CDCl3, 400 MHz) δ 7.34−7.28 (m, 5H),
4.71 (s, 2H), 4.23 (q, J = 6.4 Hz, 1H), 1.89−1.84 (m, 1H), 1.58−1.53
(m, 1H), 1.50−1.46 (m, 1H), 1.09−1.04 (m, 4H); 13C NMR (CDCl3,
100 MHz) δ 168.4, 136.5, 129.2, 128.8, 128.0, 72.0, 51.0, 22.7, 17.9,
16.0, 9.1; HRMS (ESI-TOF) m/z calcd. for C13H16NO2 [M + H]+
218.1181, found 218.1183.
( )-4,7,7-Trimethyl-3-oxa-4-azabicyclo[4.1.0]heptan-5-one (38).
Compound 30 (200 mg, 1.09 mmol) afforded 38 (120 mg, 71%), as a
clear oil, after flash chromatography (EtOAc/hexanes 1:2) on silica gel
column, by employing the general procedure described above for
compound 35: 1H NMR (CDCl3, 400 MHz) δ 4.16 (qd, J = 11.9, 3.5
Hz, 2H), 3.14 (s, 3H), 1.64 (d, J = 8.5 Hz, 1H), 1.48 (ddd, J = 8.6, 4.3,
2.8 Hz, 1H), 1.28 (s, 3H), 1.15 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 169.3, 66.6, 33.9, 28.6, 27.7, 27.2, 26.0, 16.6; HRMS (ESI-TOF) m/z
calcd. for C8H14NO2 [M + H]+ 156.1025, found 156.1052.
1
43a (major): H NMR (CDCl3, 400 MHz) δ 7.35 −7.32 (m, 2H),
7.30−7.23 (m, 2H), 7.23−7.18 (m, 1H), 4.08 (qd, J = 6.5, 1.5 Hz,
1H), 3.53 (bs, 1H), 2.15 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.16−1.10
(m, 1H), 0.94−0.88 (m, 1H), 0.71−0.64 (m, 2H); 13C NMR (CDCl3,
125 MHz) δ 142.6, 129.1, 128.2, 127.5, 75.6, 68.3, 43.2, 21.3, 17.4,
1
15.3, 10.9. Data for compound 43b (minor): H NMR (CDCl3, 400
MHz) δ 7.18−7.29 (m, 5H), 4.05−3.99 (m, 1H), 3.65 (d, J = 3.6 Hz,
1H), 2.29 (s, 3H),1.27 (d, J = 6.5 Hz, 3H), 1.22−1.20 (m, 1H), 1.02−
0.96 (m, 2H), 0.60−0.54 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ
142.0, 128.5, 127.9, 127.5, 73.4, 44.0, 21.3, 19.7, 18.5, 10.2; HRMS
(ESI-TOF) m/z calcd. for C13H18NO [M + H]+ 204.1388, found
204.1391.
( )-4-Methyl-7-phenyl-3-oxa-4-azabicyclo[4.1.0]heptan-5-one
(39). Compound 31 (75 mg, 0.32 mmol) afforded 39 (50 mg, 77%), as
a clear oil, after flash chromatography (EtOAc/hexanes 2:3) on silica
gel column, by employing the general procedure described above for
1
compound 35: H NMR (CDCl3, 400 MHz) δ 7.32−7.25 (m, 2H),
7.25−7.21 (m, 1H), 7.21−7.11 (m, 1H), 4.27 (dt, J = 11.2, 0.8 Hz,
1H), 4.04 (dt, J = 11.1, 1.0 Hz, 1H), 3.23 (s, 3H), 3.03 (t, J = 4.6 Hz,
1H), 2.21−2.18 (m, 1H), 2.08 (ddt, J = 8.3, 4.9, 1.2 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 167.8, 139.0, 129.0, 127.1, 126.6, 66.6,
34.3, 27.2, 26.1, 24.5; HRMS (ESI-TOF) m/z calcd. for C12H14NO2
[M + H]+ 204.1025, found 204.1055.
( )-1,4-Dimethyl-3-oxa-4-azabicyclo[4.1.0]heptan-5-one (40).
Compound 32 (192 mg, 1.13 mmol) afforded 40 (82 mg, 51%), as
a clear oil, after flash chromatography (EtOAc/hexanes 2:3) on silica
gel column, by employing the general procedure described above for
compound 35: 1H NMR (CDCl3, 400 MHz) δ 3.94 (dd, J = 10.8, 0.9
Hz, 1H), 3.75 (d, J = 10.9 Hz, 1H), 3.13 (s, 3H), 1.66 (t, J = 4.7 Hz,
1H), 1.61−1.58 (m, 1H), 1.19 (s, 3H), 0.91−0.87 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ 169.4, 71.0, 34.1, 24.5, 23.9, 18.0, 15.2; HRMS
(ESI-TOF) m/z calcd. for C7H12NO2 [M + H]+ 142.0868, found
142.0862.
Amino alcohol ( )-44. A solution of mixture 43a/43b (3.4:1, 140
mg, 0.67 mmol) in AcOH/H2O (10:2 mL) was degassed for 10 min
by bubbling Ar. After degassing, Zn dust (0.9 g, 13.8 mmol) was added
to the mixture, which was heated at 70 °C with vigorous stirring for 4
h. The reaction was quenched to pH 9 by the addition of aqueous
Na2CO3 solution (1 M). The resultant precipitate was filtered, and the
aqueous layer was extracted with CHCl3 (3 × 30 mL). The combined
organic extracts were dried (MgSO4), filtered and concentrated in
vacuo to yield 44 (dr 44a/44b 10:1). Purification by flash
chromatography (CH2Cl2/MeOH/NH4OH 1:9:0.1) afforded 44a
1
(102 mg, 72%) as off-white semisolid: H NMR (CDCl3, 400 MHz)
δ 7.33−7.28 (m, 2H), 7.24−7.15 (m, 3H), 4.15 (bs, 1H), 3.53−3.43
(m, 1H), 3.09−3.04 (m, 1H), 2.10 (s, 3H), 1.28 (d, J = 6.2 Hz, 3H),
1.13−1.03 (m, 2H), 0.65 (td, J = 8.3, 5.1 Hz, 1H), 0.23 (q, J = 5.3 Hz,
1H); 13C NMR (CDCl3, 125 MHz) δ 142.2, 128.8, 127.4, 126.6, 69.8,
65.1, 32.8, 25.7, 23.4, 22.5, 10.3; HRMS (ESI-TOF) m/z calcd. for
C13H20NO [M + H]+ 206.1545, found 206.1568.
( )-3-Methyl-4-oxa-3-azabicyclo[5.1.0]octan-2-one (41). Com-
pound 33 (110 mg, 0.65 mmol) afforded 41 (60 mg, 66%), as a
clear oil, after flash chromatography (EtOAc/hexanes 1:1) on silica gel
column, by employing the general procedure described above for
( )-2,3-Dimethyl-4-phenyl-3-azabicyclo[3.1.0]hexane (45). To a
cooled (0 °C) solution of amino alcohol 44a (43 mg, 0.21 mmol) and
Et3N (87 μL, 0.63 mg) in anhydrous CH2Cl2 (3 mL) was added mesyl
chloride (25 μL, 0.25 mmol) under argon atmosphere, and the mixture
was stirred for 1 h. The mixture was slowly warmed to room
temperature for 16 h before being concentrated in vacuo. To the
residue was added 1 M HCl (1 mL) and EtOAc (5 mL). The aqueous
layer was separated, basified with 1 M NaOH (pH 8−9) and extracted
with CHCl3 (2 × 10 mL). The organic layers were combined, washed
with brine (10 mL), dried (MgSO4), and concentrated in vacuo to
yield crude 45 as a mixture of 2 diastereomers (dr 45a:45b = 7:1) and
unreacted 44a. Purification by flash column chromatography (3:7
EtOAc/hexanes) afforded 45a (25 mg, 63%) as clear oil. 45a (5 mg)
was converted to its hydrochloride salt. Data for compound 45a
1
compound 35: H NMR (CDCl3, 400 MHz) δ 4.07 (ddd, J = 11.3,
6.6, 1.3 Hz, 1H), 3.83 (td, J = 11.4, 5.1 Hz, 1H), 3.15 (s, 3H), 2.33−
2.27 (m, 1H), 1.79 (td, J = 9.0, 5.4 Hz, 1H), 1.23−1.10 (m, 1H),
1.09−0.98 (m, 2H), 0.58 (q, J = 5.2 Hz, 1H); 13C NMR (CDCl3, 125
MHz) δ 173.0, 69.4, 33.6, 29.0, 18.5, 11.0, 10.1; HRMS (ESI-TOF)
m/z calcd. for C7H12NO2 [M + H]+ 142.0868, found 142.1064.
( )-2,4-Dimethyl-5-phenyl-3-oxa-4-azabicyclo[4.1.0]heptane
(43). To a cooled (−78 °C) solution of 35 (155 mg, 1.10 mmol) in
anhydrous toluene (9 mL) was added PhLi (1.8 M solution in dibutyl
ether (1.3 mL, 2.30 mmol)) dropwise under argon atmosphere and
stirred for 2 h. The red/orange reaction was slowly warmed to −10 °C,
during which time the color changed to pale yellow. The reaction was
quenched by the addition of 1 M HCl (5 mL). The resultant colorless
1
(major): H NMR (CDCl3, 400 MHz) δ 7.35−7.30 (m, 2H), 7.28−
7.22 (m, 3H), 4.03 (s, 1H), 2.94 (qd, J = 5.8, 3.6 Hz, 1H), 1.88 (s,
J
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3H), 1.67 (ddd, J = 10.4, 7.7, 3.7 Hz, 1H), 1.48−1.43 (m, 1H), 1.08
(d, J = 5.9 Hz, 3H), 0.83−0.79 (m, 1H), 0.48 (td, J = 7.8, 4.4 Hz, 1H);
13C NMR (CDCl3, 125 MHz) δ 141.8, 128.8, 128.1, 127.1, 69.5, 57.3,
(7) de Carne-
́
Carnavalet, B.; Archambeau, A.; Meyer, C.; Cossy, J.;
Follea
16716−16727.
́
s, B.; Brayer, J.-L.; Demoute, J.-P. Chem.Eur. J. 2012, 18,
34.6, 23.4, 20.4, 16.5, 6.0. Data for compound 45b (minor): 1H NMR
(CDCl3, 400 MHz) δ 7.46−7.43 (m, 2H), 7.35−7.31 (m, 2H), 7.28−
7.22 (m, 1H), 3.30 (d, J = 1.8 Hz, 1H), 2.51 (qd, J = 6.3, 1.8 Hz, 1H),
2.12 (s, 3H), 1.48−1.43 (m, 1H), 1.37 (tdd, J = 7.7, 4.0, 1.8 Hz, 1H),
1.30 (d, J = 6.3 Hz, 1H), 0.92 (td, J = 8.0, 4.6 Hz, 1H), 0.37−0.34 (m,
1H); 13C NMR (CDCl3, 125 MHz) δ 144.9, 128.3, 127.6, 126.9, 75.9,
66.7, 38.5, 27.0, 26.2, 20.9, 19.3.
(8) Wang, J.; Stefane, B.; Jaber, D.; Smith, J. A.; Vickery, C.; Diop,
M.; Sintim, H. O. Angew. Chem., Int. Ed. Engl. 2010, 49, 3964−3968.
(9) England, D. B.; Padwa, A. J. Org. Chem. 2008, 73, 2792−2802.
(10) Jung, Y. C.; Yoon, C. H.; Turos, E.; Yoo, K. S.; Jung, K. W. J.
Org. Chem. 2007, 72, 10114−10122.
(11) Hodgson, D. M.; Man, S. Chem.Eur. J. 2011, 17, 9731−9737.
(12) Taber, D. F.; Tian, W. J. Org. Chem. 2007, 72, 3207−3210.
(13) Flynn, C. J.; Elcoate, C. J.; Lawrence, S. E.; Maguire, A. R. J. Am.
Chem. Soc. 2010, 132, 1184−1185.
(14) John, J. P.; Novikov, A. V. Org. Lett. 2007, 9, 61−63.
(15) Bequette, J. P.; Jungong, C. S.; Novikov, A. V. Tetrahedron Lett.
2009, 50, 6963−6964.
(16) Wolckenhauer, S. A.; Devlin, A. S.; Bois, J. D. Org. Lett. 2007, 9,
4363−4366.
(17) Zhang, B.; Wee, A. G. Org. Lett. 2010, 12, 5386−5389.
(18) Hansen, J. H.; Parr, B. T.; Pelphrey, P.; Jin, Q.; Autschbach, J.;
Davies, H. M. Angew. Chem., Int. Ed. Engl. 2011, 50, 2544−2548.
(19) Price Mortimer, A. J.; Plet, J. R.; Obasanjo, O. A.; Kaltsoyannis,
N.; Porter, M. J. Org. Biomol. Chem. 2012, 10, 8616−8627.
(20) Moody, C. J.; Slawin, A. M.; Willows, D. Org. Biomol. Chem.
2003, 1, 2716−2722.
(21) Shimada, N.; Oohara, T.; Krishnamurthi, J.; Nambu, H.;
Hashimoto, S. Org. Lett. 2011, 13, 6284−6287.
(22) Dong, C.; Deng, G.; Wang, J. J. Org. Chem. 2006, 71, 5560−
5564.
(23) Xu, X.; Lu, H.; Ruppel, J. V.; Cui, X.; Lopez de Mesa, S.; Wojtas,
L.; Zhang, X. P. J. Am. Chem. Soc. 2011, 133, 15292−15295.
(24) McDowell, P. A.; Foley, D. A.; O’Leary, P.; Ford, A.; Maguire, A.
R. J. Org. Chem. 2012, 77, 2035−2040.
(25) DeAngelis, A.; Dmitrenko, O.; Fox, J. M. J. Am. Chem. Soc. 2012,
134, 11035−11043.
(26) Zhang, B.; Wee, A. G. Org. Biomol. Chem. 2012, 10, 4597−4608.
(27) Tarwade, V.; Liu, X.; Yan, N.; Fox, J. M. J. Am. Chem. Soc. 2009,
131, 5382−5383.
Data for ( )-45a (Hydrochloride salt): Clear gum, 1H NMR
(CD3OD, 400 MHz) δ 7.44 (d, J = 1.0 Hz, 5H), 4.65 (s, 1H), 3.73
(qd, J = 6.4, 3.7 Hz, 1H), 2.21−2.15 (m, 4H), 1.85 (td, J = 7.0, 4.8 Hz,
1H), 1.39 (d, J = 6.4 Hz, 3H), 0.92−0.86 (m, 2H); 13C NMR
(CD3OD, 125 MHz) δ 133.7, 131.6, 131.2, 130.6, 72.4, 64.1, 35.6,
23.5, 20.4, 13.7, 5.6; HRMS (ESI-TOF) m/z calcd. for C13H18N [M +
H]+ 188.1439, found 188.1434.
( )-N-((2-(1-Hydroxyethyl)cyclopropyl)(phenyl)methyl)-N,4-di-
methylbenzenesulfonamide (S9). Following the procedure described
for 45, amino alcohol 44a (13 mg, 0.063 mmol) and tosyl chloride (14
mg, 0.075 mmol) afforded compound S9 (14 mg, 62%), as a clear oil,
after flash column chromatography (EtOAc/CH2Cl2 7:93) on silica
1
gel: H NMR (CDCl3, 400 MHz) δ 7.47−7.45 (m, 2H), 7.16−7.14
(m, 3H), 7.13−7.09 (m, 4H), 4.78 (d, J = 10.5 Hz, 1H), 3.74−3.66
(m, 1H), 3.42 (d, J = 2.8 Hz, 1H), 2.73 (s, 3H), 2.30 (s, 3H), 1.48
(ddt, J = 10.5, 8.3, 4.1 Hz, 1H), 1.30 (d, J = 6.2 Hz, 3H), 1.26−1.18
(m, 1H), 0.86 (td, J = 8.7, 5.1 Hz, 1H), 0.05 (q, J = 5.7 Hz, 1H); 13C
NMR (CDCl3, 125 MHz) δ 143.5, 139.2, 135.9, 129.5, 128.4, 128.1,
127.8, 67.4, 60.8, 30.2, 27.0, 23.0, 21.6, 19.9, 9.9; HRMS (ESI-TOF)
m/z calcd. for C20H26NO3S [M + H]+ 360.1633, found 360.1625.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR spectra, 13C NMR spectra, NOESY spectra,
computational data, and an explanation for the conversion of
compound 43 (dr 3.4:1) into 44 (dr 10:1). This material is
available free of charge via the Internet at http://pubs.acs.org.
(28) Briones, J. F.; Davies, H. M. Org. Lett. 2011, 13, 3984−3987.
(29) Qian, Y.; Xu, X.; Wang, X.; Zavalij, P. J.; Hu, W.; Doyle, M. P.
Angew. Chem., Int. Ed. Engl. 2012, 51, 5900−5903.
(30) Sambasivan, R.; Ball, Z. T. Angew. Chem., Int. Ed. Engl. 2012, 51,
8568−8572.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hsintim@umd.edu.
(31) Choi, M. K.; Yu, W., Y.; Che, C. M. Org. Lett. 2005, 7, 1081−
1084.
Notes
(32) Anciaux, A. J.; Demonceau, A.; Noels, A. F.; Hubert, A. J.;
Warin, R.; Teyssie, P. J. Org. Chem. 1981, 46, 873−876.
(33) Reisman, S. E.; Nani, R. R.; Levin, S. Synlett 2011, 17, 2437−
2442.
(34) Sippl, S. P.; Schenck, H. L. Magn. Reson. Chem. 2013, 51, 72−75.
(35) Ishikawa, T.; Senzaki, M.; Kadoya, R.; Morimoto, T.; Miyake,
N.; Izawa, M.; Saito, S. J. Am. Chem. Soc. 2001, 123, 4607−4608.
(36) Shireman, B. T.; Miller, M. J.; Jonas, M.; Wiest, O. J. Org. Chem.
2001, 66, 6046−6056.
(37) Crapster, J. A.; Stringer, J. R.; Guzei, I. A.; Blackwell, H. E.
Biopolymers 2011, 96, 604−616.
(38) Olivato, P., R.; da Silva Gomes, R.; Rodrigues, A.; Reis, A. K. C.
A.; Domingues, N. L. C.; Rittner, R.; Colle, M. D. J. Mol. Struct. 2010,
977, 106−116.
(39) Ishikawa, T.; Senzaki, M.; Kadoya, R.; Morimoto, T.; Miyake,
N.; Izawa, M.; Saito, S.; Kobayashi, H. J. Am. Chem. Soc. 2001, 123,
4607−4608.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Maryland for funding this project.
We also thank Istanbul Technical University for funding G.M.
during her stay at UMD. We thank an anonymous reviewer for
suggesting an explanation for the preference of O-mesylation
over N-tosylation and also for providing an alternative
explanation for the formation of 45b, via cyclopropyl cation.
REFERENCES
■
(1) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
8748−8758.
(2) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 19, 3693−
3712.
(40) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
1967, 40, 935−939.
(41) Ahn, C.; Correia, R.; DeShong, P. J. Org. Chem. 2002, 67, 1751−
1753.
(3) Donohoe, T. J.; Bataille, C. J. R.; Churchill, G. W. Annu. Rep.
Prog. Chem., Sect. B: Org. Chem. 2006, 102, 98−122.
(4) Li, X.; Li, J. Mini-Rev. Med. Chem. 2010, 10, 794−805.
(5) Robl, J. A.; Sulsky, R. B.; Augeri, D. J.; Magnin, D. R.; Hamann, L.
G.; Betebenner, D. A. Cyclopropyl-fused pyrrolidine-based inhibitors
of dipeptidyl peptidase IV. U.S. Patent 6,395,767, May 28, 2002.
(6) Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J.
Am. Chem. Soc. 1993, 115, 30−39.
(42) Toma, T.; Kita, Y.; Fukuyama, T. J. Am. Chem. Soc. 2010, 132,
10233−10235.
(43) Vintonyak, V. V.; Kunze, B.; Sasse, F.; Maier, M. E. Chemistry
2008, 14, 11132−11140.
K
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(44) Quader, S.; Boyd, S. E.; Jenkins, I. D.; Houston, T. A. J. Org.
Chem. 2007, 72, 1962−1979.
(45) Shen, R.; Lin, C. T.; Porco, J. A. J. Am. Chem. Soc. 2002, 124,
5650−5651.
(46) Liao, X.; Wu, Y.; De Brabander, J. K. Angew. Chem., Int. Ed. Engl.
2003, 42, 1648−1652.
(47) Poullennec, K. G.; Romo, D. J. Am. Chem. Soc. 2003, 125,
6344−6345.
(48) Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449−455.
(49) Miyata, O.; Namba, M.; Ueda, M.; Naito, T. Org. Biomol. Chem.
2004, 2, 1274−1276.
(50) Shi, G.-Q. Tetrahedron Lett. 2000, 41, 2295−2298.
(51) Codd, R. Coord. Chem. Rev. 2008, 252, 1387−1408.
(52) Dekamin, M. G.; Moghaddam, F. M.; Saeidian, H.; Mallakpour,
S. Monatsh. Chem. 2006, 137, 1591−1595.
(53) Hendrick, J. B.; Wolf, W. A. J. Org. Chem. 1968, 33, 3601−3618.
(54) Alder, M. J.; Flower, K. R.; Pritchard, R. G. Tetrahedron Lett.
1998, 39, 3571−3574.
(55) Hartzler, H. D. J. Am. Chem. Soc. 1964, 86, 2174−2177.
(56) Trost, B. M.; Lumb, J. P.; Azzarelli, J. M. J. Am. Chem. Soc. 2011,
133, 740−743.
(57) Trost, B. M.; Yang, H.; Wuitschik, G. Org. Lett. 2005, 7, 4761−
4764.
(58) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815−
3818.
(59) Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem.
2005, 70, 7297−7304.
(60) Donohoe, T. J.; Sintim, H. O. Org. Lett. 2004, 6, 2003−1006.
(61) This hypothesis was suggested by an anonymous reviewer.
(62) Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.; Lippa, A. S. Eur. J.
Pharmacol. 2003, 461, 99−104.
(63) Micheli, F.; Cavanni, P.; Andreotti, D.; Arban, R.; Benedetti, R.;
Bertani, B.; Bettati, M.; Bettelini, L.; Bonanomi, G.; Braggio, S.;
Carletta, R.; Checchia, A.; Corsi, M.; Fazzolari, E.; Fontana, S.;
Marchioro, C.; Merlo-Pich, E.; Negri, M.; Oliosi, B.; Ratti, E.; Read, K.
D.; Roscic, M.; Sartori, I.; Spada, S.; Tedesco, G.; Tarsi, L.; Terreni, S.;
Visentini, F.; Zocchi, A.; Zonzini, L.; Di Fabio, R. J. Med. Chem. 2010,
53, 4989−501.
(64) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1997, 62, 1675−
1686.
(65) Denmark, S. E.; Hurd, A. R. Org. Lett. 1999, 1, 1311−1314.
(66) Young, I. S.; Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953−
955.
(67) Davis, F. A.; Gaddiraju, N. V.; Theddu, N.; Hummel, J. R.;
Kondaveeti, S. K.; Zdilla, M. J. J. Org. Chem. 2012, 77, 2345−2359.
(68) Brown, D. S.; Elliott, M. C.; Moody, C. J.; Mowlem, T. J.;
Marino, J. P.; Padwa, A. J. Org. Chem. 1994, 59, 2447−2455.
L
dx.doi.org/10.1021/jo400788a | J. Org. Chem. XXXX, XXX, XXX−XXX