One-Pot Reductive 1,3-Dipolar Cycloaddition of Secondary Amides: A Two-Step Transformation of Primary Amides

Article abstract of DOI:10.1021/acs.joc.6b01080

The one-pot reductive 1,3-dipolar cycloaddition of secondary aromatic N-(trimethylsilylmethyl)amides with reactive dipolarophiles is reported. The method relies on the in situ generation of nonstabilized NH azomethine ylide dipoles via amide activation with triflic anhydride, partial reduction with 1,1,3,3-tetramethyldisiloxane (TMDS), and desilylation with cesium fluoride (CsF). Running under mild conditions, the reaction tolerated several sensitive functional groups and provided cycloadducts in 71-93% yields. The use of less reactive dipolarophile methyl acrylate led to the cycloadduct in only 40% yield. A (Z) geometric intermediate of NH-azomethine 1,3-dipole was postulated to account for the observed higher yields and higher cis diastereoselectivity for the substrates bearing an electron-withdrawing group. This model features an unconventional cyclic transition state via carbanion-aryl ring interaction. Because the starting secondary amides can be prepared from common primary amides, the current method also constitutes a two-step transformation of primary amides.

Full text of DOI:10.1021/acs.joc.6b01080

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Article
One-pot Reductive 1,3-Dipolar Cycloaddition of Secondary
Amides: A Two-Step Transformation of Primary Amides
Pei-Qiang Huang, Qi-Wei Lang, and Xiu-Ning Hu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01080 • Publication Date (Web): 10 Jun 2016
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One-pot Reductive 1,3-Dipolar Cycloaddition of Secondary Amides: A Two-Step
Transformation of Primary Amides
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Pei-Qiang Huang,* Qi-Wei Lang, and Xiu-Ning Hu
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology,
iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), College
of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005,
P. R. China
ABSTRACT: The one-pot reductive 1,3-dipolar cycloaddition of secondary aromatic
N-(trimethylsilylmethyl)amides with reactive dipolarophiles is reported. The method
relies on the in situ generation of nonstabilized NH azomethine ylide dipoles via
amide activation with triflic anhydride (Tf2O), partial reduction with
1,1,3,3-tetramethyldisiloxane (TMDS), and desilylation with cesium fluoride (CsF).
Running under mild conditions, the reaction tolerated several sensitive functional
groups and provided cycloadducts in 71-93% yields. Use of less reactive
dipolarophile methyl acrylate led to the cycloadduct in only 40% yield. A (Z)-
geometric intermediate of NH-azomethine 1,3-dipole was postulated to account for
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the observed higher yields and higher cis-diastereoselectivity for the substrates
bearing an electron-withdrawing group. This model features an unconventional cyclic
transition state via carbanion - aryl ring interaction. Since the starting secondary
amides can be prepared from common primary amides, the current method also
constitutes a two-step transformation of primary amides.
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INTRODUCTION
The direct transformation of amides into other classes of compounds has attracted
considerable attention in recent years.1-4 However, in contrast to the many methods
developed for the transformation of common tertiary3 and secondary amides,4 the
direct transformation of primary amides involving C-C bond formation is rare.5 To the
best of our knowledge, only the reductive alkylation of primary amides has been
reported, which involves the one-pot dehydration of benzamides with organocerium
reagents to benzonitriles and subsequent nucleophilic addition to give tertiary
carbinamines.5
Azomethine-based 1,3-dipolar cycloaddition is a powerful methodology for the
synthesis of substituted pyrrolidines, pyrrolizidines and related alkaloids.6 Among the
many aspects of this chemistry, the generation and cycloaddition of nonstabilized
azomethines occupied a special position. Indeed, at the early phase of its development,
Vedejs and coworkers have demonstrated in 1980 that tertiary N-(silylmethyl)lactams
could serve as precursors of nonstabilized azomethine ylides, namely, imidate
methylides.7a The method consists of O-methylation of amide carbonyl followed by
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desilylation with CsF. Subsequent investigation showed that an improved yield could
be obtained by using thioamides to replace amides.7b,c Since this seminal work,
several research groups including those of Livinghouse,8 Padwa,9 and Snieckus10 have
contributed to the chemistry of tertiary amide-based 1,3-dipolar cycloaddition
reactions. Very recently, Chida/Sato have developed an elegant one-pot catalytic
reductive transformation of tertiary N-hydroxyamides to nitrones followed by
1,3-dipolar cycloaddition.11 However, the secondary amide-based reductive
1,3-dipolar cycloaddition reactions that involve the generation of the singular
nonstabilized N-protonated (NH) azomethine ylides A (Scheme 1) is elusive.12,13
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Scheme 1. The envisioned generation and cycloaddition of nonstabilized NH azomethine ylides A
from secondary amides
In this regard, the thermal 1,4-silatropic generation of azomethine ylides B-1 and B-2
from methyl N-(disilylmethyl)/ N-(phenylsilylmethyl)benzimidate 3a/b and
N-(phenylsilylmethyl)benzamide 4 developed by Komatsu and co-workers remains
the sole secondary amide-based 1,3-dipolar cycloaddition.12 After a workup procedure
the desilylated product 5a was isolated, which allowed viewing the azomethine ylide
B-1 as a synthetic equivalent of –non-substituted analog C and nitrile ylide D
(Scheme 2).12c However, this method requires a ylide-stabilizing group such as Ph or
Me3Si at the -carbon. To develop
a
stabilizing group-free method,
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N-(stannylmethyl)thioamide 6 was introduced for the one-pot thermal 1,4-stannatropy
and 1,3-dipolar cycloaddition.12d Nevertheless, while 7 could be obtained in 31-96%
yield, this method requires an additional step to prepare thioamide 6 from the
corresponding amide. Thus, direct generation and reaction of nonstabilized NH
azomethine ylides of type A from secondary amides remain challenging.12d
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Very recently, we have developed several methods for the direct transformation of
secondary amides, which include the reductive alkylation,14a reductive coupling with
ketones,14b reductive Ugi-type reaction,14c aza-Knoevenagel-type condensation,14d and
reductive cycloaddition with Danishefsky diene.14e In connection with those studies,
we report herein the Tf2O-mediated direct reductive 1,3-dipolar cycloaddition of
secondary N-(trimethylsilylmethyl)amides 1 (Scheme 1), readily available from acyl
chlorides and (trimethylsilyl)methylamine. We also disclosed that secondary amides 1
can be prepared by trimethylsilylmethylation of primary amides, which established a
two-step transformation of common primary amides.
Scheme 2. Komatsu’s 1,4-sila- and stannatropic strategies for the generation and cycloaddition of
1,3-dipoles
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RESULTS AND DISCUSSION
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Lately, we have reported the one-pot two-stage catalytic hydrosilylation of secondary
amides employing Tf2O – TMDS - B(C6F5)3 (cat.) combination,15 in which triflic
anhydride16 (Tf2O) was used to activate the amide group and
1,1,3,3-tetramethyldisiloxane (TMDS) served as a partial reducing agent to generate
the iminium salt F14,15 (stage 1, Scheme 3). The subsequent B(C6F5)3-catalyzed
reduction of F produced an amine (stage 2).15 It was envisaged that by employing
N-(trimethylsilylmethyl)amide 1 as a starting amide, after the amide activation-partial
reduction with Tf2O – TMDS, the presumed iminium ion intermediate F could be
used as a ready precursor of the nonstabilized NH azomethine ylide dipole A.
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Scheme 3.
We started our investigation by screening the solvent for the reaction. Given that
dichloromethane being the solvent of choice for the amide activation and subsequent
partial reduction,14,15 it was selected for the one-pot reductive cycloaddition. In the
event, secondary amide 1a was successively treated with Tf2O (1.1 equiv),
2-fluoropyridine17 (2-F-Pyr., 1.2 equiv), TMDS (0.7 equiv), CsF (3.0 equiv), and
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N-methylmaleimide (2.0 equiv), which gave the desired cycloadduct 2a in 15% yield
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(Table 1, entry 1). The observed low yield was attributed to the low efficiency of the
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desilylation reaction with CsF, because from the H NMR spectrum of the crude
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product, a signal of aldehyde resulted from the hydrolysis of the iminium ion
intermediate F was observed. It is possible that the excess of TMDS consumed some
CsF. To eliminate this possibility, after the stage 1, the reaction mixture was
concentrated under reduced pressure before addition of a solvent, CsF and a
dipolarophile. Indeed, even using the same CH2Cl2 as a solvent for the second stage,
the desired cycloaddition product 2a was obtained in 31% yield as a 55: 45
diastereomeric mixture (Table 1, entry 2). It was further envisioned that yield of the
1,3-dipolar cycloaddition could be improved by using a polar solvent. To our delight,
when polar solvents such as THF, dioxane, and DMF were used, the yield of 2a was
improved to 69%, 65% and 80%, respectively (entries 3-5). The best yield (85%) was
obtained with the use of acetonitrile as a convenient polar solvent (entry 6). Thus, the
conditions outlined in entry 6 were used in the subsequent investigation for the higher
yield. Alternatively, an operationally simpler protocol alleviating the change of
solvent was also established which employed CH2Cl2/ MeCN as a mixed solvent
system and afforded the cycloadduct 2a in 74% yield (entry 7). It is worth noting that
the order of efficiencies of solvents observed in this investigation is different from it
observed for a related trimethylsilyl triflate-catalyzed 1,3-dipolar cycloaddition, in
which the following order has been observed: DMF >> DME > THF >> acetonitrile >
dichloromethane.18
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Table 1. Effect of solvent on the reductive cycloaddition reactiona
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Entry
Solvent
DCMd
Yieldb (%) (trans: cis)c
15 (55: 45)
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DCMe
31 (55: 45)
THFe
69 (52: 48)
1,4-dioxanee
DMFe
65 (55: 45)
80 (49: 51)
MeCNe
85 (48: 52)
DCMc/ MeCNe
74 (48: 52)
a Conditions: Tf2O (1.1 equiv), 2-F-Pyr. (1.2 equiv), TMDS (0.7 equiv), CsF (3.0 equiv), and
N-methylmaleimide (2.0 equiv). Isolated yield. c Ratio determined by H NMR of the crude
b
1
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e
product. Without change of solvent. After the partial reduction, the reaction mixture was
concentrated and a new solvent was added.
Next, other reaction parameters including reaction time (Table 2, entries 1-3),
equivalents of dipolarophile (entries 4 and 5) and CsF (entries 6-8) were examined,
which allowed determining the optimized reaction conditions as those shown in entry
7 (Table 2).
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Table 2. Further optimization of the reaction conditions
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Time
(h)
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dipolarophile
CsF
Yielda (%)
Entry
(n equiv)
2.0
(n equiv) (trans: cis)b
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8
3.0
3.0
3.0
3.0
3.0
2.0
4.0
5.0
85 (48: 52)
62 (48: 52)
85 (48: 52)
76 (48: 52)
85 (48: 52)
63 (48: 52)
91 (48: 52)
88 (48: 52)
2.0
20
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2.0
1.5
2.5
2.0
2.0
2.0
a Isolated yield. b Determined by 1H NMR of the crude product.
Finally, several silanes including TMDS, PMHS, (EtO)3SiH, Et3SiH, i-Pr3SiH,
PhMe2SiH, and PhSiH3 were examined as the reducing reagents (Table 3), from which
TMDS (entry 1) turned out to be the best, which produced 2a in 91% yield.
Table 3. Screening of silanesa
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Silane
Yieldb (%)
Entry
(n equiv)
(trans: cis)c
91 (48: 52)
51 (47: 53)
18 (48: 52)
87 (48: 52)
84 (48: 52)
86 (48: 52)
74 (48: 52)
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TMDS (0.7)
PMHS (1.4 Si-H)
(EtO)3SiH (1.4)
Et3SiH (1.4)
i-Pr3SiH (1.4)
PhMe2SiH (1.4)
PhSiH3 (1.4)
a Conditions: Tf2O (1.1 equiv), 2-F-Pyr. (1.2 equiv), silane (1.4 equiv Si-H), CsF (4.0 equiv), and
N-methylmaleimide (2.0 equiv). b Isolated yield. c Determined by 1H NMR of the crude product.
After defining the optimal reaction conditions for the direct reductive 1,3-dipolar
cycloaddition of N-(trimethylsilylmethyl)amide 1a with N-methylmaleimide, we
turned our attention to explore the scope of the reaction. A series of secondary amides
1b-l were examined and the results are displayed in Table 4. Para, meta, and
ortho-methylbenzamides produced the corresponding adducts in 83% (2b), 81% (2c),
and 78% (2d) yield, respectively (entries 2-4). Introduction of an electron–donating
group (Me, OMe, entries 2 and 3) onto para-position of the benzene ring of
benzamide led to a decrease in yield (2b: 83%, 2e: 71% versus 91% for benzamide 2a,
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entry 1). Benzamide derivatives bearing electron-withdrawing groups such as CF3 and
Br afforded cycloadducts 2f and 2g in high yields (91% and 90%, entries 6 and 7). As
can be seen from entries 8-11, when performing the amide activation step at 78 C,
the reaction tolerates sensitive functional groups such as cyano (1h), ester [OAc (1i),
CO2Me (1j)], and nitro (1k) groups, and the reaction took place chemoselectively at
the secondary amide group. Note that when the amide activation was performed at rt,
the yield of 2k was only 61% (entry 11). N-Isopropyl-thiophene-2-carboxamide 1l, a
heteroaromatic amide, also reacted smoothly to give the desired adduct 2l in 85%
yield (entry 12). The trans/ cis stereochemistries were assigned on the basis of the
observed chemical shifts of H-2 in the cycloadducts (δtrans > δcis) and coupling
constants (Jtrans = 0-2.5 Hz, Jcis = 7.6-8.1 Hz).13a,b
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Table 4. Reductive 1,3-dipolar cycloaddition of N-(silylmethyl)amides 1a-l with
N-methylmaleimide
Entry
Substrate (Ar)
1a Ph
Yield (%)a (trans: cis)b
91c (48: 52)
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1b p-MeC6H4
1c m-MeC6H4
1d o-MeC6H4
83c (40: 60)
81c (41: 59)
78c (48: 52)
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1e p-MeOC6H4
1f p-CF3C6H4
1g p-BrC6H4
71c (45: 55)
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91c (38: 62)
90c (32: 68)
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1h p-NCC6H4
1i p-AcOC6H4
1j p-MeO2CC6H4
1k p-O2NC6H4
93d (31: 69)
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88d (46: 54)
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86d (37: 63)
61c/ 89d (15: 85)c,d
85c (47: 53)
1l 2-Thienyl
a
b
1
Isolated yield. Ratio determined by H NMR of the crude product, and the stereochemistry
determined by correlating with 2a. c The activation of the amide performed at 0 °C for 20 min, the
reduction with TMDS performed at 0 °C for 0.5 h, and at rt for 5 h. d The activation of the amide
performed at 78 °C for 20 min, then at 0 °C for 5 min, then reduction with TMDS performed at
0 °C for 3 h and at rt for 4 h.
To probe the nonstabilized NH azomethine ylide G (X = H, Figure 1), triethylamine
was introduced before the addition of a dipolarophile. When 1.5 equiv of
triethylamine were introduced, yield of the cycloadduct 2a dropped to 41%, while
with 3.0 equiv of triethylamine, less than 5% of 2a was observed. These results allow
assuming the intermediacy of the NH azomethine ylide G.
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Figure 1. Plausible substituent-dependent geometric isomers of the nonstabilized NH azomethine
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ylide dipoles G
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The cycloaddition reactions showed poor diastereoselectivities. This phenomenon is
generally observed12,13 for the 1,3-dipolar cycloaddition reactions of nonstabilized NH
azomethine ylides bearing no -chelating group.19 However the higher yields and
higher diastereoselectivities (ca. 2: 1 to 5: 1) observed for the benzamides bearing
electron-withdrawing groups on the benzene ring (Table 4, entries 6-11) as compared
with those bearing electron-donating groups (Table 4, entries 2-5) is unusual. This is
because the cycloaddition such as that displayed in Scheme 1 is believe to be
controlled by the HOMO (dipole) – LUMO (dipolarophile) interaction, which should
be accelerated by electron-donating substituents in the dipole.6c On the other hand,
(E)-NH-azomethine 1,3-dipole [(E)-G] has been assumed by Tsuge as the major
geometric isomer for the related 1,3-dipolar cycloaddition.13b To account for the
results obtained in this study we postulate (Z)-G as the predominant geometric isomer
of the NH-azomethine 1,3-dipole bearing an electron-withdrawing group. This model
features an unconventional cyclic transition state (Z)-G via carbanion - aryl ring
interaction.20 On the basis of this model, an electron-withdrawing group enhances the
carbanion - aryl ring interaction, and thus stabilizes the azomethine ylide (Z)-G. The
corresponding 1,3-dipolar cycloaddition reaction affords thus a higher yield.
Moreover, the carbanion - aryl ring interaction leads (Z)-G to adopt a non-planar
structure, which disfavors a secondary orbital interaction with an incoming
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dipolarophile. This can account for the observed slightly preferred exo-approach to
give cis-2 as the major diastereomer. On the other hand, an electron-donating group
on the benzene ring of a 1,3-dipole disfavors the carbanion - aryl ring interaction in
(Z)-G, and (E)-G might be the reactive intermediate, which produces the
corresponding cycloadduct in a lower yield and at almost stereo-random manner.
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We next examined the reductive 1,3-dipolar cycloaddition reactions of amide 1a with
different dipolarophiles (Table 5). The reductive cycloaddition with
N-phenylmaleimide produced 2m in 90% yield and in a 48: 52 dr, which is similar to
those obtained from the N-methyl analog (yield: 91%, dr = 48: 52). Dimethyl maleate,
dimethyl fumarate, and fumaronitrile are also suitable dipolarophiles for the reductive
cycloaddition, although moderate yields (2n: 71, 2o: 73%, 2p: 83%) were obtained.
The reaction of amide 1a with less reactive dipolarophile methyl acrylate produced
cycloadduct 2q in a moderate yield (40%).
Table 5. Reductive 1,3-dipolar cycloaddition of N-(silylmethyl)amide 1a with different
dipolarophilesa
Product (yieldb, trans: cisc)
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MeO2C
Ph
CO2Me
N
H
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2n (71%, 50: 50)
2a (91%, 48: 52)
2m (90%, 48: 52)
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MeO2C
Ph
CO2Me
N
H
2o (73%, 50: 50)
2p (83%, 50: 50) 2q (40%, 14: 86)
a Conditions: Tf2O (1.1 equiv), 2-F-Pyr. (1.2 equiv), TMDS (0.7 equiv), CsF (4.0 equiv), and
N-methylmaleimide (2.0 equiv). b Isolated yield. c Ratio determined by 1H NMR of crude product,
and the stereochemistry determined by correlating with the known compound.
To further extend the scope of the method, the preparation of secondary amides 1
from primary amides was investigated. Thus, successive treatment of benzamide 8
with NaH (2. 0 equiv) and iodomethyltrimethylsilane (2.0 equiv, rt to 60 C) produced
secondary amide 1a in 66% yield, along with the tertiary amide 10 in 15% yield and
16% of the recovered starting material (Scheme 4). Similarly, the
trimethylsilylmethylation of primary amide 9 afforded secondary amide 1e in 68%
yield, along with 16% of the recovered starting material.
Scheme 4.
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CONCLUSIONS
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In summary, we have developed the first direct reductive 1,3-dipolar cycloaddition
reaction of secondary amides 1 with reactive dipolarophiles. The reaction conditions
are mild which tolerate several sensitive functional groups including bromo, cyano,
acetoxy, ester and nitro groups. A controlled experiment allowed confirming the
intermediacy of a nonstabilized NH azomethine ylide dipole in the cycloaddition
reaction. To the best of our knowledge, the direct generation of a nonstabilized NH
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azomethine ylide from
a
secondary amide is unprecedented. Since
N-(trimethylsilylmethyl)amide substrates are available from primary amides in one
step, this method also constitutes a two-step transformation of primary amides
involving C-C bond formation that is rare in the chemistry of amides.
EXPERIMENTAL SECTION
For general experimental methods, see: ref. 14a. Note: 1H NMR and 13C NMR spectra
were recorded in CDCl3 on an instrument at 500 and 125 MHz, respectively.
General Procedure for preparation of N-(trimethylsilylmethyl)amides (General
Procedure A):
To a dry round-bottom flask equipped with a stirring bar and under argon were added
successively (trimethylsilyl)methylamine (1.1 equiv), triethylamine (1.1 equiv) and
dichloromethane [0.4 M]. The solution was cooled to 0 °C and an acyl chloride (1.0
equiv) was slowly added via a syringe (in case when an acyl chloride is solid, a
solution in dichloromethane was added). Then, the reaction was slowly warmed up to
rt and stirred overnight. The reaction was diluted with dichloromethane and washed
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successively with 1 M HCl, brine, a saturated aqueous NaHCO3 solution, and brine,
then dried over anhydrous sodium sulphate (Na2SO4). The organic layer was filtered
and evaporated to dryness to give the crude amide. The crude amide was purified by
recrystallization from a mixture of EtOAc/ Hexane to afford pure amide. (Note:
Following the general procedure A, N-(Trimethylsilylmethyl)amides 1b-l were
prepared in 5.0 mmol scale, excepted for amide 1a in 50.0 mmol scale.)
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General Procedure for preparation of N-(trimethylsilylmethyl)amides from
primary amides (General Procedure B):
The solution of primary amide (3.0 mmol) in DMF (5 mL) was added to a suspension
of sodium hydride (60% dispersion in mineral oil, 0.24 g, 6.0 mmol) in dry DMF (15
mL) at rt with efficient stirring under Ar atmosphere. After 2 h at rt,
(Iodomethyl)trimethylsilane (890 μL, 1.28 g, 6.0 mmol) was added neat. The resulting
mixture was allowed warming up to 60 °C and stirred at for 24 h. The reaction was
quenched with water (1 mL), and most of solvent was removed under reduced
pressure. Water (10 mL) was added and extracted with EtOAc (20 mL × 3). The
combined organic extracts were washed with sodium thiosulfate (Na2S2O3) and brine,
dried over anhydrous Na2SO4. The solvents were removed under reduced pressure and
the residue was purified by flash chromatography on silica gel (300-400 mesh) to give
the corresponding secondary amide.
General procedure for one-pot reductive 1,3-dipolar cycloadditon of secondary
amides (General Procedure C):
Into a dry 5-mL round-bottom flask equipped with a stirring bar were added
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successively a secondary amide 1 (0.5 mmol), 2 mL of anhydrous dichloromethane
and 2-fluoropyridine (52 μL, 0.6 mmol). After being cooled to –78 °C or 0 °C,
trifluoromethanesulfonic anhydride (Tf2O) (92 μL, 0.55 mmol) was added dropwise
via a syringe at 0 °C and the reaction mixture was stirred for 20 min. To the resulting
mixture, 1,1,3,3-tetramethyldisiloxane (TMDS) (62 μL, 0.35 mmol) was added
dropwise at 0 °C and the reaction was stirred for 10 min. The mixture was allowed to
warm up to rt and stirred for 6 h. The solvent was removed through a drying tube
charged with anhydrous CaCl2 under reduced pressure. Acetonitrile (2 mL) was added
to dissolve the residue, then a solution of a dipolarophile (1.0 mmol) in acetonitrile (1
mL) was added. The resulting mixture was added dropwise to the suspension of
cesium fluoride (304 mg, 2.0 mmol) in acetonitrile (2 mL) with vigorous stirring. The
reaction mixture was stirred for another 14 h at rt before addition of an appropriate
amount of silica gel (100-200 mesh). The solvents were removed under reduced
pressure and the residue was purified by flash chromatography on silica gel (300-400
mesh) to give the corresponding cycloadduct 2. (Note: the activation of the amides
1h-1k was performed at –78 °C for 20 min, then at 0 °C for 5 min, and the partial
reduction with TMDS was performed at 0 °C for 3 h and at rt for 4 h.)
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N-[(Trimethylsilyl)methyl]benzamide (1a)
Following general procedure A, amide 1a21 was obtained as white crystals (9.20 g,
yield: 89%). Or following general procedure B, the mono-trimethylsilylmethylation of
primary amide 8 (at a 3 mmol scale) gave, after flash column chromatography on
silica gel (eluent: EtOAc/ Hexane = 1/ 4), 1a as white solid (410 mg, yield: 66%). Mp:
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102-103 °C; (lit.21: mp: 99-100 °C). IR (film) max: 3351, 3067, 2958, 1626, 1546,
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1
1310, 1247, 890, 835, 695 cm-1; H NMR:  0.12 (s, 9H), 2.95 (d, J = 5.8 Hz, 2H),
9
13
6.12 (br s, 1H), 7.37-7.50 (m, 3H), 7.71-7.76 (m, 2H); C NMR:  2.6 (3C), 30.3,
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126.7 (2C), 128.5 (2C), 131.0, 135.1, 167.8 ppm. MS (ESI, m/z): 230 (M+Na+).
4-Methyl-N-[(trimethylsilyl)methyl]benzamide (1b)
Following general procedure A, amide 1b was obtained as white crystals (1.02 g,
yield: 93%). Mp: 123-124 °C; IR (film) max: 3345, 2956, 1623, 1549, 1306, 1118,
1
894, 840, 750 cm-1; H NMR:  0.12 (s, 9H), 2.38 (s, 3H), 2.94 (d, J = 5.8 Hz, 2H),
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6.03 (br s, 1H), 7.18-7.24 (m, 2H), 7.60-7.66 (m, 2H); C NMR:  2.6 (3C), 21.4,
30.2, 126.7 (2C), 129.1 (2C), 132.2, 141.4, 167.7 ppm. HRMS-ESI calcd for
[
C12H19NOSi+Na]+ (M+Na)+: 244.1128; found: 244.1134.
3-Methyl-N-[(trimethylsilyl)methyl]benzamide (1c)
Following general procedure A, amide 1c was obtained as white crystals (1.01 g, yield:
92%). Mp: 86-87 °C; IR (film) max: 3371, 2955, 1630, 1582, 1541, 1247, 845, 737
cm-1; 1H NMR:  0.13 (s, 9H), 2.39 (s, 3H), 2.95 (d, J = 5.8 Hz, 2H), 6.04 (br s, 1H),
7.26-7.32 (m, 2H), 7.46-7.52 (m, 1H), 7.54-7.58 (m, 1H); 13C NMR:  2.6 (3C), 21.3,
30.3, 123.5, 127.5, 128.3, 131.8, 135.1, 138.4, 167.9 ppm. HRMS-ESI calcd for
[
C12H19NOSi+Na]+ (M+Na)+: 244.1128; found: 244.1129.
2-Methyl-N-[(trimethylsilyl)methyl]benzamide (1d)
Following general procedure A, amide 1d was obtained as white crystals (1.06 g,
yield: 96%). Mp: 75-76 °C; IR (film) max: 3268, 2954, 1633, 1538, 1319, 1248, 898,
1
842, 729 cm-1; H NMR:  0.12 (s, 9H), 2.43 (s, 3H), 2.95 (d, J = 5.7 Hz, 2H), 5.63
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(br s, 1H), 7.15-7.23 (m, 2H), 7.25-7.34 (m, 2H); C NMR:  2.6 (3C), 19.7, 30.1,
6
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125.7, 126.6, 129.6, 130.9, 135.9, 137.0, 170.2 ppm. HRMS-ESI calcd for
8
9
[
C12H19NOSi+Na]+ (M+Na)+: 244.1128; found: 244.1133.
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4-Methoxy-N-[(trimethylsilyl)methyl]benzamide (1e)
Following general procedure A, amide 1e was obtained as white crystals (1.07 g, yield:
90%). Or following general procedure B, the mono-trimethylsilylmethylation of
primary amide 9 (in 3 mmol scale) gave, after flash column chromatography on silica
gel (eluent: EtOAc/ Hexane = 1/ 3), 1e as white solid (484 mg, yield: 68%). Mp:
91-92 °C; IR (film) max: 3330, 2954, 1621, 1553, 1505, 1250, 842 cm-1; H NMR: 
1
0.12 (s, 9H), 2.94 (d, J = 5.8 Hz, 2H), 3.83 (s, 3H), 6.25 (br s, 1H), 6.86-6.92 (m, 2H),
7.68-7.75 (m, 2H); 13C NMR:  2.6 (3C), 30.1, 55.2, 113.5 (2C), 127.3, 128.4 (2C),
161.7, 167.2 ppm. HRMS-ESI calcd for [C12H19NO2Si+Na]+ (M+Na)+: 260.1077;
found: 260.1080.
4-(Trifluoromethyl)-N-[(trimethylsilyl)methyl]benzamide (1f)
Following general procedure A, amide 1f was obtained as white crystals (1.21 g, yield:
88%). Mp: 62-63 °C; IR (film) max: 3285, 2957, 1637, 1552, 1327, 1169, 1131, 1069,
857 cm-1; 1H NMR:  0.13 (s, 9H), 2.97 (d, J = 5.7 Hz, 2H), 6.26 (br s, 1H), 7.62-7.69
(m, 2H), 7.80-7.86 (m, 2H); 13C NMR:  2.6 (3C), 30.6, 123.7 (q, JF-C = 272.0 Hz),
125.5 (2C), 127.2 (2C), 132.8 (q, JF-C = 32.5 Hz), 138.4, 166.5 ppm. HRMS-ESI calcd
for [C12H16F3NOSi+Na]+ (M+Na)+: 298.0846; found: 298.0847.
4-Bromo-N-[(trimethylsilyl)methyl]benzamide (1g)
Following general procedure A, amide 1g was obtained as white crystals (1.37 g, yield:
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96%). Mp: 96-97 °C; IR (film) max: 3319, 2954, 1623, 1548, 1484, 1249, 839 cm-1;
1H NMR:  0.12 (s, 9H), 2.94 (d, J = 5.8 Hz, 2H), 6.05 (br s, 1H), 7.53-7.64 (m, 4H);
13C NMR:  2.6 (3C), 30.4, 125.7, 128.3 (2C), 131.7 (2C), 133.9, 166.8 ppm.
HRMS-ESI calcd for [C11H16BrNOSi+Na]+ (M+Na)+: 308.0077 and 310.0056;
found: 308.0078 and 310.0058.
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4-Cyano-N-[(trimethylsilyl)methyl]benzamide (1h)
Following general procedure A, amide 1h was obtained as white crystals (1.03 g,
yield: 89%). Mp: 131-132 °C; IR (film) max: 3346, 2965, 2229, 1631, 1548, 1247,
836 cm-1; 1H NMR:  0.13 (s, 9H), 2.97 (d, J = 5.8 Hz, 2H), 6.18 (br s, 1H), 7.68-7.75
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(m, 2H), 7.80-7.86 (m, 2H); C NMR:  2.6 (3C), 30.7, 114.6, 118.0, 127.5 (2C),
132.3 (2C), 139.0, 165.9 ppm. HRMS-ESI calcd for [C12H16N2OSi+Na]+ (M+Na)+:
255.0924; found: 255.0928.
4-{[(Trimethylsilyl)methyl]carbamoyl}phenyl acetate (1i)
Following general procedure A, amide 1i was obtained as white crystals (1.25 g, yield:
94%). Mp: 94-95 °C; IR (film) max: 3307, 2954, 1759, 1633, 1544, 1500, 1199, 843
cm-1; 1H NMR:  0.12 (s, 9H), 2.32 (s, 3H), 2.94 (d, J = 5.8 Hz, 2H), 6.35 (br s, 1H),
7.12-7.17 (m, 2H), 7.72-7.78 (m, 2H); 13C NMR:  2.6 (3C), 21.0, 30.4, 121.6 (2C),
128.1 (2C), 132.7, 152.6, 166.9, 169.1 ppm. HRMS-ESI calcd for
[
C13H19NO3Si+Na]+ (M+Na)+: 288.1026; found: 288.1032.
Methyl 4-{[(trimethylsilyl)methyl]carbamoyl}benzoate (1j)
Following general procedure A, amide 1j was obtained as white crystals (1.21 g, yield:
88%). Mp: 100-101 °C; IR (film) max: 3292, 2953, 1727, 1635, 1545, 1281, 1108,
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843 cm-1; H NMR:  0.13 (s, 9H), 2.97 (d, J = 5.8 Hz, 2H), 3.93 (s, 3H), 6.35 (br s,
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1H), 7.75-7.80 (m, 2H), 8.03-8.07 (m, 2H); C NMR:  2.6 (3C), 30.6, 52.3, 126.8
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(2C), 129.7 (2C), 132.2, 139.0, 166.3, 166.8 ppm. HRMS-ESI calcd for
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[
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4-Nitro-N-[(trimethylsilyl)methyl]benzamide (1k)
Following general procedure A, amide 1k22 was obtained as white crystals (1.20 g,
yield: 95%). Mp: 124-125 °C (lit.22: mp: 123.5-124 °C); IR (film) max: 3360, 2964,
1632, 1593, 1519, 1347, 1300, 1246, 1109, 834 cm-1; 1H NMR:  0.14 (s, 9H), 2.99 (d,
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J = 5.8 Hz, 2H), 6.15 (br s, 1H), 7.87-7.91 (m, 2H), 8.25-8.30 (m, 2H); C NMR: 
2.6 (3C), 30.9, 123.7 (2C), 127.9 (2C), 140.7, 149.2, 165.7 ppm. HRMS-ESI calcd
for [C11H16N2O3Si+Na]+ (M+Na)+: 275.0822; found: 275.0831.
N-[(Trimethylsilyl)methyl]thiophene-2-carboxamide (1l)
Following general procedure A, amide 1l was obtained as white crystals (0.98 g, yield:
85%). Mp: 120-121 °C; IR (film) max: 3333, 2959, 1621, 1554, 1310, 1244, 873, 851,
716 cm-1; 1H NMR:  0.12 (s, 9H), 2.93 (d, J = 5.8 Hz, 2H), 5.98 (br s, 1H), 7.05 (t, J
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= 4.3 Hz, 1H), 7.43 (d, J = 4.9 Hz, 1H), 7.46-7.50 (d, J = 3.6 Hz, 1H); C NMR: 
2.6 (3C), 30.2, 127.5 (2C), 129.2, 139.2, 162.1 ppm. HRMS-ESI calcd for
[
C9H15NOSSi+Na]+ (M+Na)+: 236.0536; found: 236.0548.
(3aS*,4S*,6aR*)-2-Methyl-4-phenyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)
-dione (trans-2a) and
(3aS*,4R*,6aR*)-2-methyl-4-phenyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)
-dione (cis-2a)
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Following the general procedure C, the reductive 1,3-dipolar cycloaddition of the
secondary amide 1a (104 mg) with N-methylmaleimide gave, after flash column
chromatography on silica gel (eluent: EtOAc/ Hexane = 1/ 1), the known
cycloadducts trans/ cis-2a13a (105 mg, yield: 91%, trans: cis = 48: 52, determined by
1H NMR of the crude product). trans-2a: colorless oil; IR (film) max: 3327, 2917,
1774, 1697, 1435, 1384, 1282, 737, 701 cm-1; 1H NMR:  1.95 (br s, 1H), 3.03 (s, 3H),
3.33-3.40 (m, 3H), 3.42-3.47 (m, 1H), 4.67 (d, J = 2.5 Hz, 1H), 7.26-7.31 (m, 1H),
7.34-7.41 (m, 4H); 13C NMR:  25.2, 46.6, 48.8, 53.1, 64.8, 126.1 (2C), 127.4, 128.7
(2C), 141.3, 178.4, 178.9 ppm. cis-2a: white solid, mp: 98-99 °C; IR (film) max: 3334,
2926, 2849, 1774, 1699, 1435, 1384, 1284, 1094, 757, 703 cm-1; 1H NMR:  1.86 (br
s, 1H), 2.91 (s, 3H), 3.16 (dd, J = 9.7, 7.1 Hz, 1H), 3.28 (t, J = 7.1 Hz, 1H), 3.33 (t, J
= 8.1 Hz, 1H), 3.71 (d, J = 9.7 Hz, 1H), 4.39 (d, J = 8.1 Hz, 1H), 7.28-7.38 (m, 5H);
13C NMR:  24.9, 45.9, 49.0, 49.3, 65.6, 127.0 (2C), 128.0, 128.3 (2C), 137.7, 175.8,
179.3 ppm. MS (ESI, m/z): 253 (M+Na+).
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(3aS*,4S*,6aR*)-2-Methyl-4-(p-tolyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH
)-dione (trans-2b) and
(3aS*,4R*,6aR*)-2-methyl-4-(p-tolyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH
)-dione (cis-2b)
Following the general procedure C, the reductive 1,3-dipolar cycloaddition of the
secondary amide 1b (111 mg) with N-methylmaleimide gave, after flash column
chromatography on silica gel (eluent: EtOAc/ Hexane = 1/ 1), cycloadducts trans/
cis-2b (101 mg, yield: 83%, trans: cis = 40: 60, determined by 1H NMR of the crude
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product). trans-2b: colorless oil; IR (film) max: 3329, 2918, 1774, 1698, 1434, 1384,
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1281, 1127, 810 cm-1; H NMR:  1.82 (br s, 1H), 2.35 (s, 3H), 3.03 (s, 3H),
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3.34-3.38 (m, 3H), 3.40-3.44 (m, 1H), 4.64 (d, J = 1.9 Hz, 1H), 7.10-7.20 (m, 2H),
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7.24-7.28 (m, 2H); C NMR:  21.0, 25.2, 46.6, 48.8, 53.1, 64.7, 126.1 (2C), 129.4
(2C), 137.2, 138.2, 178.4, 179.0 ppm. cis-2b: white solid, mp: 148-149 °C; IR (film)
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
max: 3335, 2924, 1775, 1699, 1435, 1383, 1316, 1284, 1088, 810 cm-1; H NMR: 
1.79 (br s, 1H), 2.34 (s, 3H), 2.91 (s, 3H), 3.15 (dd, J = 9.7, 6.9 Hz, 1H), 3.27 (t, J =
6.9 Hz, 1H), 3.31 (t, J = 7.9 Hz, 1H), 3.69 (d, J = 9.7 Hz, 1H), 4.35 (d, J = 7.9 Hz,
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1H), 7.12-7.20 (m, 4H); C NMR:  21.2, 24.9, 46.0, 49.0, 49.3, 65.5, 126.9 (2C),
129.0 (2C), 134.5, 137.6, 175.9, 179.3 ppm. HRMS-ESI calcd for
[
C14H16N2O2+Na]+ (M+Na)+: 267.1104; found: 267.1103.
(3aS*,4S*,6aR*)-2-Methyl-4-(m-tolyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3a
H)-dione (trans-2c) and
(3aS*,4R*,6aR*)-2-methyl-4-(m-tolyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3a
H)-dione (cis-2c)
Following the general procedure C, the reductive 1,3-dipolar cycloaddition of the
secondary amide 1c (111 mg) with N-methylmaleimide gave, after flash column
chromatography on silica gel (eluent: EtOAc/ Hexane = 1/ 1), cycloadducts trans/
1
cis-2c (99 mg, yield: 81%, trans: cis = 41: 59, determined by H NMR of the crude
product). trans-2c: colorless oil; IR (film) max: 3329, 2917, 1775, 1699, 1435, 1383,
1281, 1128, 793 cm-1; H NMR:  1.90 (br s, 1H), 2.37 (s, 3H), 3.03 (s, 3H),
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3.35-3.40 (m, 3H), 3.43-3.48 (m, 1H), 4.65 (d, J = 2.0 Hz, 1H), 7.08-7.12 (m, 1H),
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7.15-7.21 (m, 2H), 7.24-7.28 (m, 1H); 13C NMR:  21.5, 25.2, 46.6, 48.9, 53.1, 64.8,
123.1, 126.9, 128.2, 128.7, 138.5, 141.2, 178.4, 178.9 ppm. cis-2c: white solid, mp:
130-131 °C; IR (film) max: 3334, 2923, 1775, 1701, 1434, 1383, 1284, 1084, 962,
783 cm-1; 1H NMR:  1.73 (br s, 1H), 2.34 (s, 3H), 2.91 (s, 3H), 3.15 (dd, J = 9.7, 7.0
Hz, 1H), 3.27 (t, J = 7.0 Hz, 1H), 3.32 (t, J = 8.1 Hz, 1H), 3.70 (d, J = 9.7 Hz, 1H),
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4.35 (d, J = 8.1 Hz, 1H), 7.07-7.12 (m, 3H), 7.20-7.24 (m, 1H); C NMR:  21.5,
24.9, 46.0, 49.0, 49.3, 65.6, 124.1, 127.8, 128.1, 128.8, 137.6, 137.8, 175.8, 179.3
ppm. HRMS-ESI calcd for [C14H16N2O2+Na]+ (M+Na)+: 267.1104; found: 267.1105.
(3aS*,4S*,6aR*)-2-Methyl-4-(o-tolyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH
)-dione (trans-2d) and
(3aS*,4R*,6aR*)-2-methyl-4-(o-tolyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH
)-dione (cis-2d)
Following the general procedure C, the reductive 1,3-dipolar cycloaddition of the
secondary amide 1d (111 mg) with N-methylmaleimide gave, after flash column
chromatography on silica gel (eluent: EtOAc/ Hexane = 1/ 1), cycloadducts trans/
1
cis-2d (95 mg, yield: 78%, trans: cis = 48: 52, determined by H NMR of the crude
product). trans-2d: colorless oil; IR (film) max: 3333, 2950, 1774, 1699, 1435, 1383,
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1282, 1128, 751 cm-1; H NMR:  1.64 (br s, 1H), 2.49 (s, 3H), 3.04 (s, 3H),
3.38-3.48 (m, 4H), 4.88 (s, 1H), 7.18-7.23 (m, 4H); 13C NMR:  19.6, 25.3, 46.7, 49.2,
52.2, 62.3, 124.5, 125.9, 127.5, 131.3, 135.9, 139.5, 178.7, 179.1 ppm. cis-2d:
colorless oil. IR (film) max: 3334, 2919, 2849, 1775, 1699, 1435, 1383, 1315, 1284,
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1084, 755 cm-1; H NMR:  1.65 (br s, 1H), 2.43 (s, 3H), 2.86 (s, 3H), 3.16 (dd, J =
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9.5, 7.1 Hz, 1H), 3.28 (t, J = 7.1 Hz, 1H), 3.43 (t, J = 8.1 Hz, 1H), 3.73 (d, J = 9.5 Hz,
1H), 4.50 (d, J = 8.1 Hz, 1H), 7.12-7.17 (m, 1H), 7.18-7.22 (m, 2H), 7.35-7.38 (m,
1H); 13C NMR:  19.4, 24.9, 46.0, 46.8, 48.7, 62.0, 125.3, 125.9, 127.5, 130.1, 135.5,
136.2, 175.5, 179.4 ppm. HRMS-ESI calcd for [C14H16N2O2+Na]+ (M+Na)+:
267.1104; found: 267.1108.
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(3aS*,4S*,6aR*)-2-Methyl-4-(4-methoxylphenyl)tetrahydropyrrolo[3,4-c]pyrrole
-1,3(2H,3aH)-dione (trans-2e) and
(3aS*,4R*,6aR*)-2-methyl-4-(4-methoxylphenyl)tetrahydropyrrolo[3,4-c]pyrrole
-1,3(2H,3aH)-dione (cis-2e)
Following the general procedure C, the reductive 1,3-dipolar cycloaddition of the
secondary amide 1e (119 mg) with N-methylmaleimide gave, after flash column
chromatography on silica gel (eluent: EtOAc/ Hexane = 1/ 1 to 2/ 1), cycloadducts
1
trans/ cis-2e (92 mg, yield: 71%, trans: cis = 45: 55, determined by H NMR of the
crude product). trans-2e: colorless oil; IR (film) max: 3332, 2918, 1775, 1699, 1512,
1435, 1383, 1282, 1249, 832 cm-1; 1H NMR:  1.82 (br s, 1H), 3.03 (s, 3H), 3.33-3.43
(m, 4H), 3.81 (s, 3H), 4.61 (d, J = 2.5 Hz, 1H), 6.88-6.92 (m, 2H), 7.28-7.32 (m, 2H);
13C NMR:  25.2, 46.6, 48.7, 53.1, 55.3, 64.4, 114.1 (2C), 127.3 (2C), 133.3, 158.9,
178.4, 178.9 ppm. cis-2e: white solid, mp: 132-133 °C; IR (film) max: 3335, 2927,
2837, 1774, 1698, 1513, 1434, 1383, 1247, 821 cm-1; 1H NMR:  1.79 (br s, 1H), 2.92
(s, 3H), 3.14 (dd, J = 9.6, 6.7 Hz, 1H), 3.24-3.31 (m, 2H), 3.68 (d, J = 9.6 Hz, 1H),
3.80 (s, 3H), 4.34 (d, J = 7.6 Hz, 1H), 6.85-6.89 (m, 2H), 7.19-7.23 (m, 2H); 13C
NMR:  24.9, 45.9, 48.9, 49.2, 55.1, 65.2, 113.6 (2C), 128.1 (2C), 129.5, 159.2, 175.9,
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179.3 ppm. HRMS-ESI calcd for [C14H16N2O3+Na]+ (M+Na)+: 283.1053; found:
283.1054.
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(3aS*,4S*,6aR*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)tetrahydropyrrolo[3,4-c]
pyrrole-1,3(2H,3aH)-dione (trans-2f) and
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(3aS*,4R*,6aR*)-2-methyl-4-(4-(trifluoromethyl)phenyl)tetrahydropyrrolo[3,4-c]
pyrrole-1,3(2H,3aH)-dione (cis-2f)
Following the general procedure C, the reductive 1,3-dipolar cycloaddition of the
secondary amide 1f (138 mg) with N-methylmaleimide gave, after flash column
chromatography on silica gel (eluent: EtOAc/ Hexane = 1/ 1 to 2/ 1), cycloadducts
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trans/ cis-2f (136 mg, yield: 91%, trans: cis = 38: 62, determined by H NMR of the
crude product). trans-2f: white solid, mp: 175-176 °C; IR (film) max: 3330, 2917,
1775, 1691, 1435, 1327, 1296, 1157, 1117, 811 cm-1; 1H NMR:  2.05 (br s, 1H), 3.04
(s, 3H), 3.32-3.45 (m, 4H), 4.70 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz,
2H); 13C NMR:  25.3, 46.8, 49.1, 53.6, 64.5, 124.0 (q, JC,F = 272.0 Hz), 125.7 (q, JC,F
= 3.7 Hz, 2C), 126.6 (2C), 129.8 (q, JC,F = 32.5 Hz), 145.3, 178.0, 178.5 ppm. cis-2f:
white solid, mp: 183-184 °C; IR (film) max: 3326, 2917, 2849, 1770, 1699, 1436,
1327, 1285, 1109, 817 cm-1; 1H NMR:  1.89 (br s, 1H), 2.91 (s, 3H), 3.18 (dd, J = 9.6,
7.3 Hz, 1H), 3.30 (t, J = 7.3 Hz, 1H), 3.37 (t, J = 8.0 Hz, 1H), 3.71 (d, J = 9.6 Hz, 1H),
4.43 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H); 13C NMR:
 25.0, 45.6, 49.0, 49.2, 65.0, 124.1 (d, JC,F = 272.4 Hz), 125.2 (q, JC,F = 3.7 Hz, 2C),
127.5 (2C), 130.1 (q, JC,F = 32.6 Hz), 141.9, 175.4, 179.0 ppm. HRMS-ESI calcd for
[
C14H13F3N2O2+Na]+ (M+Na)+: 321.0821; found: 321.0832.
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(3aS*,4S*,6aR*)-4-(4-Bromophenyl)-2-methyltetrahydropyrrolo[3,4-c]pyrrole-1,
3(2H,3aH)-dione (trans-2g) and
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3(2H,3aH)-dione (cis-2g)
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Following the general procedure C, the reductive 1,3-dipolar cycloaddition of the
secondary amide 1g (143 mg) with N-methylmaleimide gave, after flash column
chromatography on silica gel (eluent: EtOAc/ Hexane = 1/ 1 to 2/ 1), cycloadducts
trans/ cis-2g (139 mg, yield: 90%, trans: cis = 32: 68, determined by 1H NMR of the
crude product). trans-2g: white solid, mp: 107-108 °C; IR (film) max: 3330, 2945,
1776, 1699, 1487, 1436, 1384, 1281, 1129, 810 cm-1; 1H NMR:  1.78 (br s, 1H), 3.03
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(s, 3H), 3.32-3.42 (m, 4H), 4.60 (s, 1H), 7.28-7.32 (m, 2H), 7.47-7.51 (m, 2H); C
NMR:  25.2, 46.7, 48.9, 53.3, 64.4, 121.3, 127.9 (2C), 131.8 (2C), 140.3, 178.1,
178.6 ppm. cis-2g: white solid, mp: 165-166 °C; IR (film) max: 3337, 2917, 2849,
1
1776, 1699, 1435, 1384, 1315, 1284, 1087, 1010, 813 cm-1; H NMR:  1.82 (br s,
1H), 2.91 (s, 3H), 3.15 (dd, J = 9.6, 7.0 Hz, 1H), 3.27 (t, J = 7.0 Hz, 1H), 3.32 (t, J =
8.0 Hz, 1H), 3.69 (d, J = 9.6 Hz, 1H), 4.33 (d, J = 8.0 Hz, 1H), 7.16-7.21 (m, 2H),
7.43-7.47 (m, 2H); 13C NMR:  25.0, 45.7, 48.9, 49.1, 64.9, 121.8, 128.8 (2C), 131.4
(2C), 136.8, 175.5, 179.1 ppm. HRMS-ESI calcd for [C13H13BrN2O2+Na]+ (M+Na)+:
331.0053 and 333.0032; found: 331.0061 and 333.0039.
(3aS*,4S*,6aR*)-2-Methyl-4-(4-cyanophenyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3
(2H,3aH)-dione (trans-2h) and
(3aS*,4R*,6aR*)-2-methyl-4-(4-cyanophenyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3
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(2H,3aH)-dione (cis-2h)
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Following the general procedure C (the amide activation performed at –78 °C for 20
min, the at 0 °C for 5 min), the reductive 1,3-dipolar cycloaddition of the secondary
amide 1h (116 mg) with N-methylmaleimide gave, after flash column
chromatography on silica gel (eluent: EtOAc/ Hexane = 2/ 1 to 3/ 1), cycloadducts
trans/ cis-2h (119 mg, yield: 93%, trans: cis = 31: 69, determined by 1H NMR of the
crude product). trans-2h: white solid, mp: 176-178 °C; IR (film) max: 3329, 2917,
2849, 2228, 1775, 1699, 1436, 1384, 1282, 842 cm-1; 1H NMR:  1.83 (br s, 1H), 3.04
(s, 3H), 3.30-3.39 (m, 3H), 3.41-3.46 (m, 1H), 4.68 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H),
7.67 (d, J = 8.3 Hz, 2H); 13C NMR:  25.3, 46.8, 49.2, 53.7, 64.6, 111.4, 118.6, 127.0
(2C), 132.6 (2C), 146.8, 177.8, 178.3 ppm. cis-2h: white solid, mp: 192-194 °C; IR
(film) max: 3334, 2929, 2850, 2226, 1775, 1699, 1434, 1384, 1317, 1285, 823 cm-1;
1H NMR:  1.96 (br s, 1H), 2.90 (s, 3H), 3.19 (dd, J =9.7, 7.5 Hz, 1H), 3.31 (t, J = 7.5
Hz, 1H), 3.38 (t, J = 8.1 Hz, 1H), 3.71 (d, J = 9.7 Hz, 1H), 4.43 (d, J = 8.1 Hz, 1H),
7.43-7.47 (m, 2H), 7.60-7.64 (m, 2H); 13C NMR:  25.0, 45.5, 49.0, 49.2, 64.8, 111.7,
118.7, 127.9 (2C), 132.1 (2C), 143.4, 175.3, 178.8 ppm. HRMS-ESI calcd for
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[
C14H13N3O2+Na]+ (M+Na)+: 278.0900; found: 278.0906.
(3aS*,4S*,6aR*)-2-Methyl-4-(4-acetoxylphenyl)tetrahydropyrrolo[3,4-c]pyrrole-
1,3(2H,3aH)-dione (trans-2i) and
(3aS*,4R*,6aR*)-2-methyl-4-(4-acetoxylphenyl)tetrahydropyrrolo[3,4-c]pyrrole-
1,3(2H,3aH)-dione (cis-2i)
Following the general procedure C (the amide activation performed at –78 °C for 20
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min, the at 0 °C for 5 min), the reductive 1,3-dipolar cycloaddition of the secondary
amide 1i (133 mg) with N-methylmaleimide gave, after flash column chromatography
on silica gel (eluent: EtOAc/ Hexane = 2/ 1 to 3/ 1), cycloadducts trans/ cis-2i (127
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mg, yield: 88%, trans: cis = 46: 54, determined by H NMR of the crude product).
trans-2i: colorless oil; IR (film) max: 3332, 2918, 1753, 1697, 1507, 1435, 1383,
1282, 1198, 848 cm-1; H NMR:  1.81 (br s, 1H), 2.30 (s, 3H), 3.03 (s, 3H),
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3.33-3.44 (m, 4H), 4.66 (d, J = 2.3 Hz, 1H), 7.06-7.11 (m, 2H), 7.39-7.44 (m, 2H);
13C NMR:  21.1, 25.2, 46.7, 48.9, 53.4, 64.4, 121.8 (2C), 127.3 (2C), 138.8, 149.9,
169.5, 178.2, 178.8 ppm. cis-2i: white solid, mp: 160-161 °C; IR (film) max: 3334,
2917, 2849, 1755, 1699, 1507, 1436, 1384, 1316, 1285, 1194, 834 cm-1; H NMR: 
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1.82 (br s, 1H), 2.28 (s, 3H), 2.91 (s, 3H), 3.15 (dd, J = 9.5, 7.2 Hz, 1H), 3.27 (t, J =
7.2 Hz, 1H), 3.32 (t, J = 7.9 Hz, 1H), 3.68 (d, J = 9.5 Hz, 1H), 4.37 (d, J = 7.9 Hz,
1H), 7.06 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H); 13C NMR:  21.1, 24.9, 45.8,
49.0, 49.2, 65.0, 121.4 (2C), 128.1 (2C), 135.3, 150.2, 169.4, 175.6, 179.2 ppm.
HRMS-ESI calcd for [C15H16N2O4+Na]+ (M+Na)+: 311.1002; found: 311.1005.
(3aS*,4S*,6aR*)-2-Methyl-4-(4-methoxycarbonylphenyl)tetrahydropyrrolo[3,4-c
]pyrrole-1,3(2H,3aH)-dione (trans-2j) and
(3aS*,4R*,6aR*)-2-methyl-4-(4-methoxycarbonylphenyl)tetrahydropyrrolo[3,4-c
]pyrrole-1,3(2H,3aH)-dione (cis-2j)
Following the general procedure C (the amide activation performed at –78 °C for 20
min, the at 0 °C for 5 min), the reductive 1,3-dipolar cycloaddition of the secondary
amide 1j (133 mg) with N-methylmaleimide gave, after flash column chromatography
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