Atom-economical synthesis of complex heterocycles with N-O moiety

Article abstract of DOI:10.1002/hlca.201500076

A concise and facile method for the synthesis of heterocyclic compounds with N-O tether was introduced. The two important steps of the synthesis are a Mitsunobu reaction and C-H activation. The Mitsunobu protocol allows to form the N-O moiety in the molec

Full text of DOI:10.1002/hlca.201500076

Helvetica Chimica Acta – Vol. 98 (2015)
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Atom-Economical Synthesis of Complex Heterocycles with NÀO Moiety
by GçkÅe Merey* and Gçkhan Sezen
Chemical Engineering Department, Faculty of Engineering, Hitit University, Kuzey Campus, TR-19030
Þorum (phone: þ 90-364-2274533; fax: þ 90-364-2274535; e-mail: gokcemerey@hitit.edu.tr)
A concise and facile method for the synthesis of heterocyclic compounds with NÀO tether was
introduced. The two important steps of the synthesis are a Mitsunobu reaction and CÀH activation. The
Mitsunobu protocol allows to form the NÀO moiety in the molecule, while subsequent CÀH activation
leads to heterocycles.
Introduction. – Construction of complex heterocycles [1 – 3] has been a particularly
fruitful area of investigation, and the diazo functionality seems to be a versatile tool to
synthesize those complex molecules. Recent advances have shown that the tether to the
diazo moiety can impact selectivity in reactions. For example, Du Bois and Novikov
showed that diazo sulfones/sulfates give unique six-membered rings, providing a useful
way to functionalize C-atoms in g-position to OH functionalities [4][5]. Cyclization of
a metallocarbenoid intermediate generated from the diazo precursor is one of the most
common methods. Recently, Sintimꢀs group reported a method which utilizes an NÀO
tether for the formation of cyclopropyl-fused pyrrolidines [6]. The NÀO tether is a very
practical tool to obtain aminoalcohols, as it can be easily cleaved under mild conditions
and the atoms that consitute the tether remain.
The OH function is easy to install in molecules enantioselectively. Consequently,
there have been numerous studies on the asymmetric synthesis of tertiary alcohols to
further functionalize molecules, e.g., Sharpless OH-directed epoxidation, Donohoe
OH-directed dihydroxylation, SimmonsÀSmith OH-directed cyclopropanation [7], and
asymmetric reduction of ketones [8]. However, catalytic asymmetric addition of C-
nucleophiles to ketones might be challenging due to the poor electrophilic character of
the ketone group (compared with aldehydes), and it is difficult to obtain enantiopure
tertiary alcohols by this method, because the smaller steric and electronic differences
between the two substituents of the ketone cause difficulty for the enantioface
differentiation [9]. Facile NÀO cleavage under mild conditions offers an easy method
for the enantioselective synthesis of tertiary alcohols (Scheme 1) [10]. For example,
treatment of enantiopure (À)-1 with Raney nickel yielded enantiopure (À)-2. This
method could be an alternative and better method to obtain enantiorich aldol products.
There are also pharmaceutically active molecules that contain the NÀO tether: the
alkaloid geneserine which is used for adjuvant treatment of dypepsia [11], the
dioxopiperazine antibiotic gliovirine and FA-2097 [12], and methylbenzoxazinones
which are nuclear hormone receptors for binding glucocorticoid [13] are examples of
NÀO tether-containing drugs.
ꢁ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 98 (2015)
Scheme 1
Since modern organic synthesis should be atom-economic with the goal of chemo-
and regioselectivitiy, transformation of inert CÀH bonds has attracted great interest,
because it allows the formation of CÀC bonds in an atom-economic and efficient way
[14 – 19]. In C,H insertion reactions, controlling regioselectivity against reactivity is
challenging, as high reactivity often results in poor regioselectivity. An efficient C,H
insertion requires the appropriate level of electrophilic character of the metallocarbe-
noid center. High electrophilicity of carbenoids causes poor regio- and stereocontrol,
while lack of electrophilicity means lack of reactivity to insert into the unactivated CÀH
bond. The electronic nature of the groups that are adjacent to the CÀH activation site is
also important. In most cases, electron-donating groups activate the adjacent CÀH
bond, while electron-withdrawing groups are deactivating [20][21]. Thus, electronic,
steric, and conformational factors, and catalysts affect the regioselectivity of C,H
insertion reactions, and extensive efforts have been made to design molecules with
suitable functional groups to give the desired products [22 – 25].
It can be stated that, in general, five-membered rings are preferable, as long as the
molecule is sterically available [15]. Three-, four-, six-, and rarely higher-membered
rings [26][27] can only be obtained by intramolecular C,H insertion, if the system is
specially constrained [28], contains special moieties [4][5], or if the CÀH bond is
activated (Scheme 2) [27][29][30].
Starting with diazo compounds 3, the five-membered ring 4 would be obtained via
the entropically most favored transition state, whereas the formation of the six-
membered ring 5 would also be possible. On the other hand, it has been shown that
NÀO-tethered diazo acetamides can insert at g-positions to give rare seven-membered
rings. It has been rationalized that electronic and/or conformational factors account for
the regioselectivity observed in NÀO-tethered reactions [10].
When the alkyl chains attached to the N- and O-atoms are long enough, the
question arises which alkyl group will be preferred for the insertion. Conformer 7a with
alkoxy and C¼O groups s-trans to each other is entropically more favored than
conformer 7b with s-cis alkoxy and C¼O groups [10][31]. As shown in Scheme 3, lone
pairÀlone pair repulsion and dipol moments of conformer 7b might result in lower
stability and hinder the formation of 8. Thus, these factors might affect C,H insertion to
take place at the a-position to the O-atom in conformer 7a to yield 9.
Results and Discussion. – In this study, we aimed to investigate RhII-catalyzed C,H
insertions on new substrates of type 3 having an NÀO and ester moiety in order to
obtain new heterocycles with useful functional groups which can be modified according
to necessary targets. These substrates are easy to obtain with high yields via Mitsunobu

Helvetica Chimica Acta – Vol. 98 (2015)
1317
Scheme 2
Scheme 3
reaction under optimum conditions [6]. The Mitsunobu protocol is a classic reaction
[32] that allows for the direct displacement of the OH group of alcohols by several
nucleophiles, and several classic total syntheses of complex molecules have utilized the
Mitsunobu protocol [33 – 37].
Eight different substrates, 13a – 13h, were prepared in high yields via the Mitsunobu
protocol according to the procedure described in [6] (Scheme 4). The yields are given
in Table 1.
In the RhII-catalyzed reactions of 13a – 13d, the C,H insertion forms five-membered
rings only (Scheme 5). No other carbenoid product could be observed from these
Scheme 4

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Helvetica Chimica Acta – Vol. 98 (2015)
Table 1. Yields of the Mitsunobu Reactions
Entry
10
R1
Diazo compound
R2
Product
Yield [%]
1
2
3
4
5
6
7
8
MeOCH(Me)CH2À
PhÀ(CH2)2À
H
11
11
11
11
11
11
12
12
13a
13b
13c
13d
13e
13f
13g
13h
89
76
68
61 [6]
53
49
72
87
Me
Me
H
H
H
CH2¼CHÀ(CH2)2À
CH2¼CHÀ
CHꢀCÀ(CH2)2À
CHꢀCÀ
PhÀ(CH2)2À
Me
COOEt
PhÀ(CH2)2À
Scheme 5
reactions. This result agrees with the usual findings of several research groups [30][38 –
41], because five-membered ring formation is more favorable compared to other ring
sizes. Also, electron-donating groups such as alkoxy substituents or O- and N-atoms
facilitate the insertions on the adjacent CÀH bond. The formation of the five-
membered rings 14a – 14d took place via insertion at the a-position to the O-atom of
the alkoxy group. No cyclopropane formation was observed in the reactions of 13c and
13d, which bear a tether with a C¼C bond. The (AcO)4Rh2-catalyzed reaction of 13d
was tried before, but no reaction was observed at low temperature (408) in CH2Cl2,
although other substrates without the ester function adjacent to the diazo group yielded
cyclopropane derivatives [6]. Stabilization of the carbene by the electron-withdrawing
ester group lowers the reactivity of the diazo function for C,H insertions. Increasing the
reaction temperature to 808 might help to activate the diazo function.
In the reactions of 13e and 13f, there were no starting materials left, but the
products could not be isolated. GC/MS of the crude mixtures showed peaks for
products with very high molecular weight. As known, sp-hybridized C-atoms are more
electronegative than sp2-hybridized C-atoms, which are in turn more electronegative
than sp3-hybridized C-atoms [42]. Due to the electrophilic nature of carbene/
carbenoid, the higher reactivity of sp-hybridized C-atoms of 13e and 13f might result
in several additions to yield compounds with high molecular weight. When a Bn group
was attached to the N-atom (in 13g and 13h), the reactions took place at the Bn group.
The b-lactam ring 15g was solely obtained from the reaction of 13g via insertion on

Helvetica Chimica Acta – Vol. 98 (2015)
1319
benzylic CÀH. b-Lactam ring formation via benzylic C,H insertion is favorable, when a
bulky group is attached to the N-atom [43]. From the reaction of 13h, the main product
was again a b-lactam ring, 15h. Besides, product 16h formed via cycloaddition to the
benzene ring of the Bn group was also observed in a minor amount. Aromatic
cycloaddition generally requires the deformation of the aromatic ring and if the final
product will be a five-membered ring, the reaction might be prefered [44 – 46].
Aromatic cycloaddition was observed only in the reaction of 13h, but not 13g. This
result may be explained because of the electron-withdrawing effect of the ester group
(R2 in 13h), which reduces the chance of insertion on the related CH group to form the
b-lactam ring.
The yields of the RhII-catalyzed reactions are given in Table 2.
Table 2. Yields of RhII-Catalyzed Reactions of 13a – 13h
Entry
13
R1
R2
R3
14 [%]
15 [%]
16 [%]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
MeOCH(Me)CH2À
PhÀ(CH2)2À
H
Me
Me
Me
Me
Me
Me
Bn
75a)
51
63
–
–
–
–
–
–
–
–
Me
Me
H
H
H
CH2¼CHÀ(CH2)2À
CH2¼CHÀ
71
b
b
b
CHꢀCÀCH2À
CHꢀCÀ
)
)
)
)
)
)
b
b
b
g
h
PhÀ(CH2)2À
Me
COOEt
–
–
64a)
51
–
11
PhÀ(CH2)2À
Bn
a) Total yields of two isomers are given. b) Products with very high molecular weight.
Conclusions. – In conclusion, we have demonstrated an atom-economical way to
synthesize complex heterocycles containing NÀO and ester moieties. It may allow to
apply known ester modifications, such as hydrolysis, substitution, and reduction [47 –
49], and easy NÀO cleavage to synthesize targeted useful molecules [10][31].
Although a carbenoid with insufficient electrophilicity caused by an ester function
lowers the reactivity for the C,H insertion [16][50 – 58], it was observed that this was
not the only parameter. Besides carbenoid electrophilicity, the nature of the metal-
locarbenoid, temperature, and the substituents adjacent to the CH group, where the
activation reaction takes place, affect the reaction mechanism as well. Also, the effect
of an alkene function was investigated during this study, but attaching an alkene moiety
to the molecule did not alter the reaction mechanism. No possible cyclopropanation
was observed, and CÀH activation took place under the effect of adjacent electro-
negative atoms. Only an aromatic ring attached to a C,H insertion center could alter the
product types. With a Bn group linked to the N-atom, reactions took place via the N-
substituted branch to yield four-membered lactams, and cycloaddition on the aromatic
ring was also observed in minor amounts.
This study was funded by Hitit University (Research Project MUH01.13.009) and The Scientific and
Technological Research Council of Turkey (Research Fund 113Z911).

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Experimental Part
General. All reagents were obtained commercially, unless otherwise noted. Reactions were
performed using oven-dried glassware under Ar atmosphere. Air- and moisture-sensitive liquids and
solns. were transferred via syringe or stainless steel cannula. Anh. CH2Cl2 was distilled over CaH2 prior to
use, benzene was dried (Na wire). Thin layer chromatography (TLC): Merck Kieselgel 60 F254 plates
(SiO2); visualized by UV light. Flash column chromatography (FC): silica gel (SiO2; 230 – 400 mesh).
Compounds purified by FC were typically applied to the absorbent bed using the indicated solvents with
a minimum amount of added CH2Cl2 as needed for solubility. Solvents were removed from the mixture or
combined org. extracts by concentration under reduced pressure using an evaporator with bath at 35 –
558. Elevated temps. were obtained using thermostat-controlled silicone oil baths. Low temps. were
1
obtained by ice bath. IR Spectra: PerkinElmer Spectrum One instrument; n˜ in cmÀ1. H- and 13C-NMR
spectra: Bruker AV-400 (400 and 100 MHz, resp.) or Agilent VNMRS 500 (500 and 125 MHz, resp.); d in
ppm rel. to residual solvent peaks or indicated external standards for 1H-NMR and rel. to residual solvent
peak for 13C-NMR, J in Hz. HR-ESI-MS: Bruker Customer micrOTOF-Q 125 high-resolution mass
spectrometer; in m/z.
Synthesis of Ethyl 2-Diazomalonyl Chloride [56]. To a dried two-necked flask equipped with
thermometer were added 8.4 g (28.3 mmol) of triphosgene and 50 ml of anh. benzene. The soln. was
cooled to 08, 0.25 ml (3 mmol) of anh. pyridine were added, and a white precipitate was observed. To this
mixture, 8.05 g (70 mmol, 8.5 ml from 15% CH2Cl2-containing soln.) of N2CHCOOEt were added
dropwise. The internal temp. was kept below 108. Then, the mixture was warmed to r.t. and stirred for 6 h
under N2 atmosphere. The red soln. was filtered and concentrated under reduced pressure. Afterwards,
cold pentane was added in order to precipitate unreacted triphosgene. The mixture was filtered again and
concentrated. The residue was subjected to vacuum distillation which provided 4.9 g of ethyl 2-
diazomalonyl chloride as light yellow liquid in 39% yield. IR (neat): 2120, 1750, 1690. 1H-NMR
(400 MHz, CDCl3): 4.30 (q, J ¼ 5.0, 2 H); 1.29 (t, J ¼ 5.0, 3 H). 13C-NMR (100 MHz, CDCl3): 167.4; 158.6;
64.2; 62.8; 14.3.
Synthesis of Diazo Hydroxyamides 11 and 12. To an oven-dried round-bottom flask were added
6 mmol of N-hydroxymethanamine hydrochloride (for 11) or N-hydroxy-1-phenylmethanamine hydro-
chloride (for 12) and 35 ml of anh. CH2Cl2. The soln. was cooled to 08 and 1.7 ml (12 mmol) of anh. Et3N
were added. After stirring for 10 min at 08, 1.06 g (6 mmol) of ethyl 2-diazomalonyl chloride soln. in 25 ml
anh. CH2Cl2 were added dropwise. The mixture was then warmed to r.t. After stirring for 1 h under N2
atmosphere, the mixture was washed with 1% HCl and brine. The org. layer was dried (Na2SO4), and the
solvent was removed under reduced pressure. The residue was subjected to FC to give the desired
products.
Ethyl 2-Diazo-3-[hydroxy(methyl)amino]-3-oxopropanoate (11) [6]. Yield: 0.61 g (54%). Yellow oil.
Ethyl 3-[Benzyl(hydroxy)amino]-2-diazo-3-oxopropanoate (12). Yield: 1.25 g (79%). Dark yellow
oil. IR (neat): 3150, 2982, 2127, 1712, 1601, 1292. 1H-NMR (400 MHz, CDCl3): 8.85 (s, 1 H); 7.38 – 7.27 (m,
5 H); 4.82 (s, 2 H); 4.30 (q, J ¼ 7.1, 2 H); 1.32 (t, J ¼ 7.1, 3 H). 13C-NMR (125 MHz, CDCl3): 164.7; 161.7;
135.8; 128.7 (2 C); 128.5 (2 C); 127.8; 69.2; 62.6; 52.7; 14.4. HR-ESI-MS: 264.0990 ([M þ H]þ,
C12H14N3Oþ4 ; calc. 264.0979).
General Procedure for the Mitsunobu Reactions. To a soln. of 1.0 mmol of 11 or 12 in 15 ml of anh.
CH2Cl2 were added 144 mg (1.1 mmol) of Ph3P in 5 ml of CH2Cl2 and 1.1 mmol of the corresponding
alcohol 10. Then, 253 mg (1.1 mmol) of di-tert-butyl azodicarboxylate soln. in 10 ml CH2Cl2 were added
within 1 h. After stirring for 24 h at r.t., the solvent was removed under reduced pressure, and the crude
mixture was subjected to FC to give the products.
Ethyl 2-Diazo-3-[(3-methoxybutoxy)(methyl)amino]-3-oxopropanoate (13a). Yield: 235 mg (86%).
1
Yellow oil. IR (neat): 2973, 2120, 1729, 1650, 1372. H-NMR (400 MHz, CDCl3): 4.29 (q, J ¼ 7.1, 2 H);
4.03 – 3.91 (m, 2 H); 3.46 – 3.38 (m, 1 H); 3.31 (s, 3 H); 3.24 (s, 3 H); 1.78 – 1.72 (m, 2 H); 1.23 (t, J ¼ 7.1,
3 H); 1.15 (d, J ¼ 6.1, 3 H). 13C-NMR (125 MHz, CDCl3): 162.6; 160.8; 73.3; 70.9; 62.3; 61.6; 56.0; 34.7;
34.2; 19.0; 14.3. HR-ESI-MS: 274.1419 ([M þ H]þ, C11H20N3O5þ ; calc. 274.1397).
Ethyl 2-Diazo-3-{methyl[(4-phenylbutan-2-yl)oxy]amino}-3-oxopropanoate (13b). Yield: 242 mg
(76%). Dark yellow oil. IR (neat): 2979, 2123, 1692, 1641, 1286. 1H-NMR (400 MHz, CDCl3): 7.30 (t, J ¼

Helvetica Chimica Acta – Vol. 98 (2015)
1321
7.3, 2 H); 7.22 – 7.17 (m, 3 H); 4.29 (q, J ¼ 7.1, 2 H); 4.09 – 4.01 (m, 1 H); 3.23 (s, 3 H); 2.74 – 2.68 (m, 2 H);
2.04 – 1.95 (m, 1 H); 1.85 – 1.76 (m, 1 H); 1.31 (t, J ¼ 7.1, 3 H); 1.28 (d, J ¼ 6.3, 3 H). 13C-NMR (125 MHz,
CDCl3): 162.8; 160.9; 141.0; 128.5 (2 C); 128.3 (2 C); 126.1; 61.8; 35.9; 31.5; 28.1; 18.0; 14.3. HR-ESI-MS:
320.1618 ([M þ H]þ, C16H22N3Oþ4 ; calc. 320.1605).
Ethyl 2-Diazo-3-[(hex-5-en-2-yloxy)(methyl)amino]-3-oxopropanoate (13c). Yield: 198 mg (73%).
1
Yellow oil. IR (neat): 2978, 2120, 1727, 1642, 1367, 1284. H-NMR (400 MHz, CDCl3): 5.82 – 5.74 (m,
1 H); 5.07 – 4.98 (m, 2 H); 4.30 (q, J ¼ 7.1, 2 H); 4.09 – 4.02 (m, 1 H); 3.25 (s, 3 H); 2.16 – 2.12 (m, 2 H);
1.80 – 1.73 (m, 1 H); 1.59 – 1.52 (m, 1 H); 1.31 (t, J ¼ 7.1, 3 H); 1.25 (d, J ¼ 6.2, 2 H). 13C-NMR (125 MHz,
CDCl3): 162.7; 161.0; 137.3; 115.3; 79.0; 63.3; 61.5; 35.8; 33.4; 29.4; 17.9; 14.3. HR-ESI-MS: 270.1427
([M þ H]þ, C12H20N3Oþ4 ; calc. 270.1448).
Ethyl 2-Diazo-3-[methyl(prop-2-en-1-yloxy)amino]-3-oxopropanoate (13d) [6]. Yield: 120 mg
(53%). Yellow oil.
Ethyl 3-[(But-3-yn-1-yloxy)(methyl)amino]-2-diazo-3-oxopropanoate (13e). Yield: 86 mg (38%).
Yellow oil. 1H-NMR (400 MHz, CDCl3): 4.31 (q, J ¼ 7.1, 2 H); 4.03 (t, J ¼ 6.6, 2 H); 3.29 (s, 3 H); 2.55 (td,
J ¼ 6.6, 2.6, 2 H); 2.05 (t, J ¼ 2.6, 1 H); 1.33 (t, J ¼ 7.1, 3 H). 13C-NMR (125 MHz, CDCl3): 162.3; 161.4;
79.5; 71.8; 70.1; 61.6; 34.9; 18.1; 14.3. HR-ESI-MS: 240.0974 ([M þ H]þ, C10H14N3O4þ ; calc. 240.0979).
Ethyl 2-Diazo-3-[methyl(prop-2-yn-1-yloxy)amino]-3-oxopropanoate (13f). Yield: 118 mg (49%).
1
Yellow oil. IR (neat): 2982, 2121, 1723, 1641, 1369. H-NMR (400 MHz, CDCl3): 4.54 (d, J ¼ 2.4, 2 H);
4.30 (q, J ¼ 7.1, 2 H), 3.31 (s, 3 H); 2.61 (t, J ¼ 2.4, 1 H); 1.32 (t, J ¼ 7.1, 3 H). 13C-NMR (125 MHz,
CDCl3): 162.3; 161.8; 77.5; 76.5; 61.8; 61.6; 35.3; 14.3. HR-ESI-MS: 226.0835 ([M þ H]þ , C9H12N3O4þ ;
calc. 226.0822).
Ethyl 3-{Benzyl[(4-phenylbutan-2-yl)oxy]amino}-2-diazo-3-oxopropanoate (13g). Yield: 284 mg
(72%). Yellow oil. IR (neat): 2977, 2932, 2122, 1657, 1642, 1367. 1H-NMR (400 MHz, CDCl3): 7.34 – 7.27
(m, 7 H); 7.22 (d, J ¼ 7.4, 1 H); 7.11 (d, J ¼ 6.9, 2 H); 4.89 (d, J ¼ 15.5, 1 H); 4.72 (d, J ¼ 15.5, 1 H); 4.32
(qd, J ¼ 7.1, 1.7, 2 H); 4.02 – 3.94 (m, 1 H); 2.61 – 2.56 (m, 2 H); 2.00 – 1.91 (m, 1 H); 1.82 – 1.71 (m, 1 H);
1.33 (t, J ¼ 7.1, 3 H); 1.25 (d, J ¼ 6.2, 3 H). 13C-NMR (125 MHz, CDCl3): 161.5; 155.7; 141.0; 136.1; 128.5
(2 C); 128.4 (2 C); 128.3 (2 C); 128.2 (2 C); 127.7; 126.0; 79.3; 61.6; 51.9; 35.8; 28.1; 17.9; 14.3. HR-ESI-
MS: 396.1941 ([M þ H]þ, C22H26N3O4þ ; calc. 396.1918).
Ethyl 2-{[Benzyl(2-diazo-3-ethoxy-3-oxopropanoyl)amino]oxy}-4-phenylbutanoate (13h). Yield:
1
394 mg (87%). Yellow oil. IR (neat): 2980, 2928, 2129, 1650, 1370. H-NMR (400 MHz, CDCl3): 7.38 –
7.23 (m, 8 H); 7.12 (d, J ¼ 7.2, 2 H); 4.93 (d, J ¼ 15.8, 1 H); 4.77 (d, J ¼ 15.8, 1 H); 4.39 (t, J ¼ 6.5, 1 H);
4.33 (q, J ¼ 7.1, 2 H); 4.17 (q, J ¼ 7.2, 2 H); 2.70 – 2.57 (m, 2 H); 2.08 – 2.01 (m, 2 H); 1.33 (t, J ¼ 7.1, 3 H);
1.27 (t, J ¼ 7.1, 3 H). 13C-NMR (125 MHz, CDCl3): 176.6; 170.0; 162.4; 140.0; 135.9; 128.6 (2 C); 128.5
(2 C); 128.3 (2 C); 128.2 (2 C); 127.8; 126.3; 81.6; 61.6; 61.5; 52.8; 32.3; 31.0; 14.3; 14.0. HR-ESI-MS:
454.1971 ([M þ H]þ, C24H28N3Oþ6 ; calc. 454.1973).
General Procedure for CÀH Activation Reactions. Diazo compounds 13a – 13h (0.50 mmol),
throughly dried to minimize H2O content, were dissolved in benzene (10 ml) and degassed for 20 min.
(AcO)4Rh2 (4.6 mg) and 25 ml of benzene were added to a dried three-necked flask equipped with
condenser and degassed for 20 min. Then, the soln. of the diazo compound was added via a syringe pump
over 1 h. The mixture was stirred under reflux (808) for 4 h. The solvent was then evaporated and the
product was purified by FC (hexane/AcOEt).
Ethyl 5-(2-Methoxypropyl)-2-methyl-3-oxo-1,2-oxazolidine-4-carboxylate (14a). Yield: 97 mg (75%,
mixture (ratio 1:1.8) of two isomers, 14a_i and 14a_ii). 1H-NMR (400 MHz, CDCl3) for 14a_i: 4.95 – 4.91
(m, 1 H); 4.35 – 4.24 (m, 2 H); 3.58 (d, J ¼ 10.1, 1 H); 3.37 – 3.32 (m, 1 H); 3.25 (s, 3 H); 3.19 (s, 3 H);
1
1.87 – 1.80 (m, 4 H); 1.35 (t, J ¼ 7.1, 3 H); 1.19 (d, J ¼ 6.1, 3 H). H-NMR (400 MHz, CDCl3) for 14a_ii:
4.97 – 4.92 (m, 1 H); 4.35 – 4.24 (m, 2 H); 3.63 (d, J ¼ 10.0, 1 H); 3.37 – 3.32 (m, 1 H); 3.28 (s, 3 H); 3.20 (s,
3 H); 2.05 – 1.99 (m, 4 H); 1.34 (t, J ¼ 7.1, 3 H); 1.22 (d, J ¼ 6.2, 3 H). 13C-NMR (125 MHz, CDCl3) for
14a_i: 167.2; 164.9; 78.9; 73.1; 61.9; 56.2; 55.7; 39.0; 31.8 (2 C); 19.0; 14.1. 13C-NMR (125 MHz, CDCl3)
for 14a_ii: 167.2; 164.9; 78.2; 72.9; 62.0; 56.2; 55.8; 39.0; 31.8 (2 C); 18.7; 14.1. HR-ESI-MS: 246.1352
([M þ H]þ, C11H20NOþ5 ; calc. 246.1336).
Ethyl 2,5-Dimethyl-3-oxo-5-(2-phenylethyl)-1,2-oxazolidine-4-carboxylate (14b). Yield: 74 mg
(51%). IR (neat): 3021, 2928, 1742, 1682, 1370. 1H-NMR (400 MHz, CDCl3): 7.40 – 7.28 (m, 3 H);

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7.25 – 7.19 (m, 2 H); 4.22 (q, J ¼ 7.1, 2 H); 3.37 (s, 1 H); 3.22 (s, 3 H); 2.47 (t, J ¼ 7.3, 2 H); 1.61 – 1.55 (m,
2 H); 1.32 (t, J ¼ 7.0, 3 H); 1.28 (s, 3 H). 13C-NMR (125 MHz, CDCl3): 168.1; 166.1; 139.9; 128.5 (2 C);
128.2; 127.9; 126.3; 72.9; 64.5; 61.2; 39.7; 33.2; 30.6; 25.1; 14.2. HR-ESI-MS: 292.1554 ([M þ H]þ,
C16H22NOþ4 ; calc. 292.1543).
Ethyl 5-(But-3-en-1-yl)-2,5-dimethyl-3-oxo-1,2-oxazolidine-4-carboxylate (14c). Yield: 76 mg (63%).
1
Yellow oil. IR (neat): 2981, 1725, 1632, 1364. H-NMR (400 MHz, CDCl3): 5.89 – 5.77 (m, 1 H); 5.11 –
4.99 (m, 2 H); 4.43 (q, J ¼ 7.1, 2 H); 3.85 (s, 3 H); 3.21 (s, 1 H); 2.25 – 2.16 (m, 2 H); 1.44 (t, J ¼ 6.4,
2 H); 1.38 (s, 3 H); 1.32 (t, J ¼ 7.1, 3 H). 13C-NMR (125 MHz, CDCl3): 167.4; 165.9; 134.3; 120.2; 80.3;
63.5; 62.2; 39.0; 31.9; 25.3; 21.8; 14.1. HR-ESI-MS: 242.1399 ([M þ H]þ, C12H20NO4þ ; calc. 242.1387).
Ethyl 5-Ethenyl-2-methyl-3-oxo-1,2-oxazolidine-4-carboxylate (14d). Yield: 71 mg (71%). Dark
yellow oil. IR (neat): 3000, 1717, 1666, 1369. 1H-NMR (400 MHz, CDCl3): 5.95 – 5.88 (m, 1 H); 5.51 (dt,
J ¼ 17.2, 1.0, 1 H); 5.42 (dt, J ¼ 10.4, 0.9, 1 H); 5.21 (ddt, J ¼ 10.0, 6.9, 0.9, 1 H); 4.30 (q, J ¼ 7.1, 2 H); 3.63
(d, J ¼ 10.0, 1 H); 3.22 (s, 3 H); 1.34 (t, J ¼ 7.1, 3 H). 13C-NMR (125 MHz, CDCl3): 167.7; 166.5; 132.1;
121.1; 81.2; 62.2; 55.2; 31.9; 14.1. HR-ESI-MS: 200.0927 ([M þ H]þ, C9H14NO4þ ; calc. 200.0917).
Ethyl 2-Oxo-4-phenyl-1-[(4-phenylbutan-2-yl)oxy]azetidine-3-carboxylate (15g). Yield: 117 mg
(64%, mixture (ratio 1:1.6) of two isomers, 15g_i and 15g_ii). IR (neat, for the mixture): 3064, 2980,
1
2935, 1752, 1730, 1442, 1316. H-NMR (400 MHz, CDCl3) for 15g_i: 7.45 – 7.38 (m, 5 H); 7.26 – 7.17 (m,
3 H); 7.10 (d, J ¼ 6.8, 2 H); 5.10 (d, J ¼ 2.3, 1 H); 4.29 (q, J ¼ 7.1, 2 H); 4.09 – 3.98 (m, 1 H); 3.70 (d, J ¼
2.4, 1 H); 2.68 – 2.57 (m, 2 H); 2.06 – 1.88 (m, 1 H); 1.83 – 1.70 (m, 1 H); 1.33 (t, J ¼ 7.1, 3 H); 1.32 (d, J ¼
6.2, 3 H). 1H-NMR (400 MHz, CDCl3) for 15g_ii: 7.45 – 7.38 (m, 5 H); 7.26 – 7.17 (m, 3 H); 7.03 (d, J ¼ 6.8,
2 H); 5.08 (d, J ¼ 2.1, 1 H); 4.28 (qd, J ¼ 7.1, 0.9, 2 H); 4.09 – 3.98 (m, 1 H); 3.69 (d, J ¼ 2.2, 1 H); 2.68 –
2.57 (m, 2 H); 2.06 – 1.88 (m, 1 H); 1.83 – 1.70 (m, 1 H); 1.33 (t, J ¼ 7.1, 3 H); 1.32 (d, J ¼ 6.2, 3 H).
13C-NMR (125 MHz, CDCl3) for 15g_i: 169.8; 164.5; 142.8; 141.7; 128.7 (3 C); 128.5; 128.4 (3 C); 126.9
(2 C); 126.2; 78.1; 63.3; 61.0; 47.9; 37.5; 31.3; 21.2; 14.1. 13C-NMR (125 MHz, CDCl3) for 15g_ii: 169.8;
164.2; 142.8; 141.9; 128.7 (3 C); 128.5; 128.4 (3 C); 126.9 (2 C); 126.1; 78.0; 63.3; 59.6; 47.3; 37.5; 31.3;
21.2; 14.1. HR-ESI-MS: 368.1877 ([M þ H]þ, C22H26NO4þ ; calc. 368.1856).
Ethyl 1-[(1-Ethoxy-1-oxo-4-phenylbutan-2-yl)oxy]-2-oxo-4-phenylazetidine-3-carboxylate (15h).
Yield: 108 mg (51%). Yellow oil. IR (neat): 2980, 1761, 1727, 1645, 1496, 1371. 1H-NMR (400 MHz,
CDCl3): 7.44 – 7.40 (m, 2 H); 7.33 – 7.28 (m, 4 H); 7.25 – 7.22 (m, 4 H); 5.38 (d, J ¼ 4.8, 1 H); 4.30 – 4.16 (m,
4 H); 4.24 (q, J ¼ 7.1, 2 H); 2.37 (t, J ¼ 7.5, 2 H); 2.32 – 2.28 (m, 2 H); 1.31 (t, J ¼ 7.1, 6 H). 13C-NMR
(125 MHz, CDCl3): 169.9 (2 C); 165.2; 143.0; 141.7; 128.9 (2 C); 128.4 (2 C); 127.8; 127.7; 126.9 (2 C);
126.4; 125.9; 85.5; 62.1; 61.7; 60.0; 47.4; 33.4; 31.8; 14.1; 14.0. HR-ESI-MS: 426.1928 ([M þ H]þ,
C24H28NOþ6 ; calc. 426.1911).
Ethyl 2-[(1-Ethoxy-1-oxo-4-phenylbutan-2-yl)oxy]-3-oxo-2,3-dihydrocyclohepta[c]pyrrole-3a(1H)-
carboxylate (16h). Yield: 23 mg (11%). Dark yellow oil. IR (neat): 2981, 2925, 1761, 1734, 1725, 1645,
1
1466, 1363. H-NMR (400 MHz, CDCl3): 7.43 – 7.40 (m, 1 H); 7.33 – 7.13 (m, 4 H); 6.51 – 6.44 (m, 2 H);
6.35 – 6.31 (m, 1 H); 5.62 (d, J ¼ 9.5, 1 H); 5.57 (d, J ¼ 9.3, 1 H); 4.27 (q, J ¼ 7.0, 2 H); 4.13 (t, J ¼ 7.0, 1 H);
4.10 (q, J ¼ 7.1, 2 H); 3.93 – 3.89 (m, 2 H); 2.92 (t, J ¼ 7.2, 2 H); 2.23 – 2.16 (m, 2 H); 1.32 (t, J ¼ 7.1, 3 H);
1.28 (t, J ¼ 7.1, 3 H). 13C-NMR (125 MHz, CDCl3): 169.9; 166.2; 165.8; 143.5; 143.0; 138.1; 134.7; 129.5;
128.5 (2 C); 127.6; 127.3; 126.0; 125.5; 124.9; 87.2; 62.8; 61.6; 59.5; 47.0; 32.9; 31.9; 14.2; 14.1. HR-ESI-MS:
426.1931 ([M þ H]þ, C24H28NOþ6 ; calc. 426.1911).
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Received March 24, 2015