Tosylhydrazide-Promoted Diastereoselective Intramolecular 1,3-Dipolar Cycloadditions: Synthesis of Tetrahydropyrrolo[3,4-c]pyrazoles

Article abstract of DOI:10.1002/ejoc.201301587

A very straightforward diastereoselective synthesis of tetrahydropyrrolo[3,4-c]pyrazoles by intramolecular 1,3-dipolar cycloaddition is described. The starting materials for the synthetic route are N-Boc-protected α-amino acids, which are first transformed into N-allyl-α-amino ketones through conventional methodologies. Then, a one-pot sequence that involves formation of a tosylhydrazone from the ketone, base-induced decomposition of the hydrazone, and intramolecular 1,3-dipolar cycloaddition of the diazo compound generated, gives rise to the bicyclic systems with total diastereoselectivity and high preservation of the enantiomeric purity. However, the analogous process employing α-amino aldehydes lacks stereoselectivity. DFT computational modeling has been carried out to account for the different behavior of the two types of systems.

Full text of DOI:10.1002/ejoc.201301587

FULL PAPER
DOI: 10.1002/ejoc.201301587
Tosylhydrazide-Promoted Diastereoselective Intramolecular 1,3-Dipolar
Cycloadditions: Synthesis of Tetrahydropyrrolo[3,4-c]pyrazoles
Raquel Barroso,[a] Maria Escribano,[a] Maria-Paz Cabal,*[a] and Carlos Valdés*[a]
Keywords: Cycloaddition / Diazo compounds / Nitrogen heterocycles / α-Amino acids / Diastereoselectivity
A very straightforward diastereoselective synthesis of tetra-
hydropyrrolo[3,4-c]pyrazoles by intramolecular 1,3-dipolar
cycloaddition is described. The starting materials for the syn-
thetic route are N-Boc-protected α-amino acids, which are
1,3-dipolar cycloaddition of the diazo compound generated,
gives rise to the bicyclic systems with total diastereoselec-
tivity and high preservation of the enantiomeric purity. How-
ever, the analogous process employing α-amino aldehydes
first transformed into N-allyl-α-amino ketones through con- lacks stereoselectivity. DFT computational modeling has
ventional methodologies. Then, a one-pot sequence that in-
volves formation of a tosylhydrazone from the ketone, base-
induced decomposition of the hydrazone, and intramolecular
been carried out to account for the different behavior of the
two types of systems.
recently reported a new and general procedure for the syn-
thesis of cyclopropanes by in situ base-promoted decompo-
sition of tosylhydrazones in the presence of alkenes
(Scheme 1, a).[7] This intermolecular process is postulated
to proceed through diastereoselective construction of a pyr-
azoline ring by 1,3-dipolar cycloaddition followed by a
spontaneous extrusion of nitrogen with retention of config-
uration of the pyrazoline stereocenters.[8]
Introduction
The desire for practical and synthetically efficient organic
transformations has led to the discovery of many innovative
strategies, concepts and methodologies. In this context,
tosylhydrazones are versatile synthetic intermediates that
have been used for the unconventional transformation of
carbonyl compounds through different types of transition
metal-catalyzed as well as metal-free processes.[1] Over the
last few years, we and others have demonstrated that, in the
presence of a metal catalyst, mainly Pd and Cu, tosyl-
hydrazones can be used as a general source of diazo com-
pounds without any limitation in the structure of the carb-
onyl precursor. Indeed, several important transformations
such as cross-couplings,[2] oxidative cross-coupling[3] and
cascade reactions[4] have been devised. The same strategy
has been applied in the absence of a metal catalyst to pro-
vide for new metal-free carbon–carbon and carbon–hetero-
atom bond forming reactions.[5] Thus, tosylhydrazones can
be seen as a vehicle to accomplish a variety of unconven-
tional modifications of carbonyl compounds. Importantly,
we have also demonstrated that this strategy is very useful
for the elaboration of α-chiral carbonyl compounds, even if
they are configurationally unstable, without erosion of the
enantiomeric purity.[6]
On the other hand, and in continuing with our interest
in metal-free processes employing tosylhydrazones, we have
Scheme 1. (a) Synthesis of cyclopropanes from tosylhydrazones by
1,3-dipolar cycloaddition/nitrogen extrusion sequence. (b) Synthe-
sis of bicyclic diazenes by intramolecular 1,3-dipolar cycloaddition.
[a] Instituto Universitario de Química Organometálica “Enrique
Moles”, Unidad asociada al CSIC, Universidad de Oviedo,
c/ Julián Clavería 8, 33006 Oviedo, Spain
The intramolecular version of this type of 1,3-dipolar
cycloaddition was reported for the first time by Padwa in
1980 by heating ω-alkenyltosylhydrazones in the presence
of NaH to give 1-pyrazolines.[9] Over the last few years, this
E-mail: pcabal@uniovi.es;
acvg@uniovi.es
Homepage: http://emoles.uniovi.es/investigacion/moscat
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301587.
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Diastereoselective Intramolecular 1,3-Dipolar Cycloadditions
methodology has been very useful for the construction of
bicyclic and/or tricyclic diazenes (Scheme 1, b).[10] Recently,
Taber modified this procedure to generate the tosylhydraz-
one species in situ to deliver carbobicyclopropanes after ir-
radiation of the corresponding bicyclic diazene deriva-
tives.[11,12]
The construction of heterobicyclic systems is of great im-
portance in the preparation of structurally complex and
biologically important natural products.[13] With this in
mind, and continuing with our interest in metal-free pro-
cesses employing tosylhydrazones, we envisioned the pos-
sibility of an asymmetric one-pot synthesis of tetra-
hydropyrrolo[3,4-c]pyrazoles IV by an intramolecular 1,3-
dipolar cycloaddition reaction, starting with α-amino acids
derivatives I and following the retrosynthetic pathway
shown in Scheme 2.
Scheme 3. Synthetic protocol for the preparation of the α-all-
ylamino ketones 5.
We started with the α-allylamino ketone 5a to study the
intramolecular 1,3-dipolar cycloaddition leading to triaza-
bicyclo adduct 6a. In this case, the putative tosylhydrazone
intermediate was not isolated under the reaction conditions.
Therefore we decided to develop a one-pot cycloaddition
procedure following the reaction conditions previously re-
ported by us for the intermolecular cycloaddition of diazo-
alkanes generated from the corresponding tosylhydraz-
ones.[7]
Thus, 5a was heated in 1,4-dioxane at 70 °C with tosyl-
hydrazide for 2 h to generate tosylhydrazone, and sub-
sequently, the base (K2CO3, 6 equiv.) was added, and the
mixture was heated for an additional 12 h. Desired bicyclic
compound 6a was formed as the minor product whereas
major adduct 7a resulted from elimination of the starting
tosylhydrazone (Bamford–Stevens reaction)[17] (Table 1, En-
Scheme 2. Retrosynthetic analysis for the synthesis of hetero-
bicyclic compounds.
As usual for intramolecular 1,3-dipolar cycloadditions,
the present protocol would allow for the formation of a
fused-ring bicyclic core. Furthermore, two novel stereocen-
ters were envisioned to arise from enantiopure and readily
accessible starting materials. Carbonyl compounds II would
be obtained by conventional transformations from corre-
sponding Boc-protected α-amino acids I. Pyrrolo[3,4-c]pyr-
azoles are important core structures found in a variety of
molecules with a wide range of biological activities, such as
antiinflamatory and antitumor drugs as well as protein kin-
ase inhibitors.[14] Herein we present our results, which have
led to the development of a new methodology for diastereo-
selective synthesis of tetrahydropyrrolo[3,4-c]pyrazoles
from enantiomerically pure α-amino acids.
Table 1. Influence of the reaction conditions in the formation of 6a
by intramolecular 1,3-dipolar cycloaddition.[a]
Entry
T1/T2 [°C]
t1/t2 [h]
K2CO3 [equiv.]
6a/7a[b]
1
2
70/70
70/70
85/110
85/110
85/110
85
2/12
5/12
12/12
2/12
2/12
12
6
6
6
6
10
6
1: 4.6
1: 4.6
1.7:1
1.9:1
1.8:1
–
Results and Discussion
3
4[c]
5
α-Allylamino ketones 5 were prepared following the pro-
tocol shown in Scheme 3. Thus, commercially available N-
Boc-l-amino acids 2 were converted to corresponding
Weinreb amide[15] 3 under standard conditions. Allylation
using NaH as a base afforded derivatives of type 4 in mod-
erate yields.[16] Subsequent reaction with several Grignard
reagents yielded α-allylamino ketones 5, as precursors of
bicyclic compounds 6.
6
7
8
110
12
1
6
6
–
–
150 (MW)[d]
[a] Reaction conditions: α-allylamino ketone 5a (0.3 mmol), N-
tosylhydrazide (0.33 mmol), 1,4-dioxane (3.5 mL). [b] Calculated
by H NMR on the reaction crude mixture. [c] Optimized reaction
conditions. [d] Reaction carried out in the presence of water
1
(10 μL).
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try 1). Longer reaction time (t1) for the formation of the N-
These results prompted us to investigate the scope of this
tosylhydrazone did not furnish better results (Entry 2).
reaction under the optimized conditions, using α-amino
On the other hand, increasing temperature in both steps ketone derivatives from l-Boc-alanine 5a–d and 5i–k
(T1 and T2) gave encouraging results, changing the ratio to (Table 2, Entries 1–4 and 9–11), l-Boc-valine 5e (Table 2,
2:1 in favor of the desired bicycle 6a (Table 1, Entries 3–5). Entry 5), l-Boc-leucine 5f and 5l (Table 2, Entries 6 and 12)
No product was obtained under multicomponent condi- and l-Boc-phenylalanine 5g, 5h and 5m (Table 2, Entries 7,
tions (simultaneous addition of the ketone, tosylhydrazide 8 and 13); and a set of different Grignard reagents bearing
and base), either under heating (Table 1, Entries 6, 7), or Me (Table 2, Entries 1, 5–7, 9, 11 and 13), Et (Table 2, En-
at higher temperature under microwave irradiation (Table 1, tries 2 and 8), Ph (Table 2, Entry 3), and Bn (Table 2, En-
Entry 8). Therefore, we deemed it necessary to form the tries 4 and 10). We observed that the transformation pro-
tosylhydrazone in situ prior to generation of the 1,3-dipole, ceeds efficiently when using the methylketone of l-Boc-
with the optimal conditions being 85 °C and 2 h for the alanine (Table 2, Entry 1), whereas bulkier substituents
tosylhydrazone formation followed by 110 °C, 12 h in the (Table 2, Entries 2–4) provided moderate yields, due proba-
presence of 6 equiv. of K2CO3 for the intramolecular 1,3- bly to increased steric hindrance in the transition state of
dipolar cycloaddition (Table 1, Entry 4).
the dipolar cycloaddition. Similarly, when the reaction was
Table 2. General synthesis of tetrahydropyrrolo[3,4-c]pyrazoles 6a–m by intramolecular 1,3-dipolar cycloaddition.[a]
[a] Reaction conditions: α-allyl amino ketone 5 (0.3 mmol), N-tosylhydrazide (0.33 mmol), 1,4-dioxane (3.5 mL). [b] Isolated yield of 6 as
a pure diastereoisomer after flash chromatography.
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Diastereoselective Intramolecular 1,3-Dipolar Cycloadditions
carried out using the methylketone of l-Boc-valine (Table 2, afford the tetrahydropyrrolo[3,4-c]pyrazole as a mixture of
Entry 5), the reaction proceeded in moderate yields (50% two diastereoisomers 10a and 10b, together with the Bam-
vs. 81%) (Table 2, Entry 5 vs. 1) probably as a consequence ford–Stevens side product 11 in a 31:14:55 ratio. As seen in
of the larger steric requirements of the iPr versus the Me previous cycloaddition trials, the reaction could be per-
group. From these results we suggest that the TS (transition formed applying the one-pot protocol from compound 8
state) of the reaction is highly dependent on steric hin- with the same result. Unfortunately, for this system, tetra-
drance, since variations in R1 and/or R2 can significantly hydropyrrolopyrazole 10 was obtained as a mixture of dia-
affect the yield of the cycloaddition product.
stereoisomers 10a and 10b in about a 2:1 ratio, and the
Moreover, the reaction tolerates substitution on the ole- major isomer could be isolated in only 25% yield. In this
finic double bond with only a slight reduction in yield. case, neither the yield or diastereoselectivity could be im-
Thus, when R3 = R4 = Me, (Table 2, Entries 9 and 10), proved upon by altering reaction conditions. Beyond this
adducts 6i–j were obtained, albeit with lower yields than point, we deemed that the reaction warranted no further
adducts obtained with the monosubstituted olefin. Surpris- evaluation.
ingly, the cycloaddition was found to takes place also with
sterically encumbered N-2-methylallyl derivatives 5k–m (R5
= Me) affording the trisubstituted tetrahydropyrrolopyra-
zoles 6k–m, featuring two vicinal quaternary centers, with
moderate yields.
It is important to point out that desired tetrahydropyr-
rolo[3,4-c]pyrazoles 6a–m were obtained as single diastereo-
isomers, whose structures were confirmed by NOESY ex-
periments on compounds 6b and 6l (see Supporting Infor-
mation for details) (Figure 1). A strong nuclear Overhauser
enhancement (NOE) was observed between the two protons
Ha and Hb, with the two diastereotopic protons Hc and HcЈ
on the ethyl group, suggesting that the R1 and R2 groups
(from the α-amino acid and the Grignard reagent, respec-
tively) are in a trans arrangement and that R2 is cis with
protons Ha and Hb.
Scheme 4. Synthesis of tetrahydropyrrolo[3,4-c]pyrazole 10 as a
mixture of diastereoisomers.
To explain the formation of heterobicyclics 6 and 10 we
propose the following mechanism as is supported by the
literature (Scheme 5). First, condensation of the carbonyl
compound with the N-tosylhydrazide generates N-tosyl-
Figure 1. Relevant NOEs observed in compound 6b. Some hydro-
hydrazone A in situ, which undergoes base-promoted de-
gens have been omitted for clarity.
composition to furnish diazo compound B. Intermediate B
Moreover, it has been previously demonstrated that is envisioned to have two possible reaction paths available
tosylhydrazones can be employed to carry out transforma- to it. These include: (a) intramolecular 1,3-dipolar cycload-
tions on α-chiral ketones without erosion of enantiomeric dition with the terminal olefin to afford desired bicyclic
purity, and in particular, in tosylhydrazones derived from product C; and (b) Bamford–Stevens degradation to give
N-Boc-α-amino acids.[18,6] To investigate whether this fea- undesired diene D concomitant with generation of N2.
ture is retained in the present transformation, racemic de-
The intramolecular 1,3-dipolar cycloaddition to form
rivatives were prepared for derivatives 6f and 6g and the tetrahydropyrrolo[3,4-c]pyrazoles 6 proceeds with complete
enantiomeric excesses determined by HPLC. The values ob- diasteroselectivity, whereas the formation of compounds 10
tained, (ee Ͼ 99% for 6f, and ee Ͼ 95% for 6g) indicate takes place with very poor diastereoselectivity. To under-
that, again, enantiomeric purity is preserved during these stand the different behaviors of diazo compounds generated
transformations. Therefore, this method allows for the prep- from ketones 5 and aldehyde 8 respectively, DFT based
aration of enantiomerically enriched tetrahydropyrrolo[3,4- computations of the possible transition states (TS) for the
c]pyrazoles featuring three stereocenters, inclusive of one or dipolar cycloadditions were performed on model structures
two quaternary stereogenic centers.
I and II at the B3LYP/6-311++G** level (Scheme 6).[20]
We started our studies with diazo compound I (R = Me)
Consequently, the reaction was extended to α-allylamino
aldehyde 8[19] affording bicycloadduct 10 (Scheme 4). In this (Scheme 6) which derives from methyl ketone 5a. Four com-
case, tosylhydrazone 9 was successfully isolated from the peting transition states (TSA-I – TSD-I) lead to corre-
reaction, and then subjected to the intramolecular 1,3-di- sponding diastereomeric tetrahydropyrrolopyrazoles (12A–
polar cycloaddition in the presence of K2CO3 as a base, to D, Scheme 6). The transition states corresponding to the
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R. Barroso, M. Escribano, M.-P. Cabal, C. Valdés
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TSC-I). The results of the computations indicated that
TSB-I, leading to bicyclic 12B, is more stable by 2.10 kcal/
mol than TSD-I, which leads to diastereoisomer 12D. In
TSD-I, the methyl substituents at C1 and C2 are in a syn-
periplanar disposition, and therefore, significant steric in-
teractions are present. Conversely, in TSB-I, the methyl
substituents are in a nearly anti-periplanar arrangement
(Figure 2). Consequently, we envision that the minimized
steric interactions in TSB-I are largely responsible for cyclo-
addition diastereoselectivity.
Scheme 5. Possible mechanistic pathways for the 1,3-dipolar cyclo-
addition from tosylhydrazone derivatives of α-amino ketones and/
or α-amino aldehydes.
Figure 2. Molecular models obtained for TSB-I and TSD-I (b3lyp/
6-311++G**).
Lastly, we studied the cycloaddition with diazo com-
pound II derived from aldehyde 8 (R = H) (Scheme 6). Tak-
ing into consideration the results presented above, we con-
sidered only the transition states TSB-II and TSD-II, lead-
ing to cis-fused bicyclics 13B and 13D respectively
(Scheme 6). In this case, both TSs featured very similar en-
ergy values, ΔGact = 18.7 and 19.0 kcal/mol for TSB-II and
TSD-II respectively, which is in agreement with the lack of
stereoselectivity observed in the reaction. This small energy
difference between TSB-II and TSD-II (0.3 kcal/mol) could
be explained considering that now, since R = H, there is no
significant steric interaction between substituents at C1 and
C2 in TSD-II, and therefore, the energy of both transition
states is very close.
Conclusions
In summary, we have developed a new metal-free pro-
cedure for the diastereoselective synthesis of tetrahydropyr-
rolo[3,4-c]pyrazoles by base-promoted intramolecular 1,3-
dipolar cycloaddition of tosylhydrazones of α-allylamino
ketones. Notably, the starting materials are readily available
from α-amino acids. Interestingly, the stereogenic center in
the α-amino acid is not affected during the synthetic se-
quence. The stereochemistry of the final products was as-
Scheme 6. Energy calculations of the transition states from the
model diazo compounds I and II at the B3LYP/6-311++G** level
of theory.
bicyclic systems with a cis-fusion (TSB-I and TSD-I) are signed by two-dimensional NMR studies and also by com-
clearly favored, whereas those that would furnish trans- putational analysis of the competing transition states. From
fused bicyclic 12A and 12C, feature very distorted transition these results we conclude that the TS of the reaction, and
states and are energetically very disfavoured (TSA-I and thus the yield of product, is highly sensitive to the steric
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Diastereoselective Intramolecular 1,3-Dipolar Cycloadditions
1
EtOAc, 1:1); H NMR (300 MHz, CDCl3): δ = 0.87 (m, 6 H, iPr),
hindrance. The major advantage of this procedure is the
operational simplicity, in that it is not essential to use an
inert atmosphere or ultra-dry solvents. Moreover, the reac-
tion can be conducted in a one-pot manner directly from
the carbonyl-containing starting material; the tosyl-
hydrazone intermediate does not have to be isolated. Fi-
nally, this approach allows the construction of more than
one heterocyclic ring at a time with control of new
stereogenic centers. For these reasons, we believe that this
short, metal-free protocol may become a useful tool for the
construction of biologically important scaffolds in both or-
ganic synthesis and medicinal chemistry.
1.36 (s, 9 H, Boc), 1.92 (m, 1 H, CH iPr), 3.15 (s, 3 H, CH3), 3.71
(s, 3 H, CH3O), 4.50 (m, 1 H, CH), 5.14 (m, 1 H, NH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 17.4 (CH3-iPr), 19.2 (CH3-iPr), 28.1
(Boc), 31.1 (CH), 31.6 (CH), 54.8 (CH3), 61.3 (OCH3), 79.0 (C-
Boc), 155.6 (C), 172.7 (C) ppm. EI HRMS: calcd. for
C12H24N2O4: 260.1809, found 260.1804. [α]2D5 = +6.47 (c = 1.70,
CH2Cl2). CAS: 87694–52–8.
tert-Butyl {(S)-1-[Methoxy(methyl)amino]-4-methyl-1-oxopentan-2-
yl}carbamate (3c): White solid, 96% yield; m.p. 105–107 °C; Rf =
0.43 (hexane/EtOAc, 3:1); H NMR (300 MHz, CDCl3): δ = 0.88
(m, 6 H, iso-Bu), 1.35 (s, 11 H, Boc and CH2), 1.63 (m, 1 H, CH),
3.12 (s, 3 H, CH3), 3.71 (s, 3 H, CH3O), 4.65 (m, 1 H, CH), 5.08
(m, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3) δ = 21.5 (CH3),
23.3 (CH), 24.6 (CH3), 28.3 (Boc), 32.0 (CH), 41.9 (CH2), 48.9
(CH3), 61.5 (OCH3), 79.2 (C-Boc), 155.5 (C), 173.8 (C) ppm. [α]2D1
= –5.00 (c = 0.46, CH2Cl2). CAS: 87694–50–6.
1
Experimental Section
General Methods: Dioxane, dichloromethane, diethyl ether and di-
methylformamide were dried accoding to literature procedures.[25]
All amino acids, allyl halides and Grignard reagents are commer-
cially available. NMR spectra were recorded in CDCl3 or C6D6 at
600, 400 or 300 MHz for 1H and 150 or 75 MHz for 13C, with
tert-Butyl {(S)-1-[Methoxy(methyl)amino]-1-oxo-3-phenylpropan-2-
yl}carbamate (3d): White solid, 90% yield; m.p. 135–136 °C; Rf =
0.18 (hexane/EtOAc, 3:1); H NMR (300 MHz, CDCl3): δ = 1.37
1
1
(s, 9 H, Boc), 2.85 (dd, J = 6.0, 13.1 Hz, 1 H, CH2), 3.03 (dd, J =
6.1, 13.5 Hz, 1 H, CH2), 3.14 (s, 3 H, CH3), 3.63 (s, 3 H, CH3O),
4.92 (m, 1 H, CH), 5.20 (m, 1 H, NH), 7.21 (5 H, Ph) ppm. 13C
NMR (75 MHz, CDCl3): δ = 28.3 (Boc), 32.1 (CH), 38.8 (CH2),
51.5 (CH3), 61.5 (OCH3), 79.5 (C-Boc), 126.7 (CH), 128.3
(2ϫCH), 129.4 (2ϫCH), 136.6 (C-Ph), 155.2 (C), 172.3 (C) ppm.
FAB HRMS: calcd. for C16H25N2O4: 309.1814 [M + H]+, found
309. 1811. [α]1D7 = +20.37 (c = 0.27, CH2Cl2). CAS: 87694–53–9.
tetramethylsilane as internal standard for H and the residual sol-
vent signals as standard for 13C. The data is being reported as s =
singlet, br. s = broad singlet, d = doublet, t = triplet, q = quaduplet
and m = multiplet or unresolved, chemical shifts in ppm and cou-
pling constant(s) in Hz. The 2D experimental NOESY using the
pulse program NOESYGPPH from Bruker instruments with a mix-
ing time of 0.5 s. was used. MS and HRMS were measured in EI,
ESI or FAB mode, and the mass analyzer of the HRMS was TOF.
Melting points are uncorrected. The microwave-assisted reactions
were conducted using a focused microwave unit (Biotage Initia-
torTM 2.0). The temperature was monitored with an infrared tem-
perature sensor. In all experiments the microwave temperature was
held constant. Reactions were performed in 0.5–2 mLglass vessels,
which were sealed with a cap with septum. Enantiomeric ratios
were determined by chiral HPLC analyses (with a V-UV 2996 or
996 photodiode Array detector) in comparison with the authentic
racemic products, which were synthesized employing the same
route from the racemic starting materials. Specific rotations were
generated using an automatic polarimeter with a sodium lamp and
MeOH or CH2Cl2 as solvent (c, g/100 mL).
General Procedure for the Synthesis of α-Allylamides 4 Derived from
Boc-Amino Acid Amides: To a solution of amide 3 (3 mmol,
1 equiv.) in dry DMF was added NaH (60%, 2 equiv.) at 0 °C. The
resulting mixture was stirred at 0 °C for 30 min. Then, allyl brom-
ide (1 equiv.) was added and the mixture was stirred at room tem-
perature for 24 h. The reaction mixture was quenched with KOH
3m (3 mL) and H2O (10 mL). The residual mixture was extracted
three times with EtOAc and DCM. The organic layers were washed
three times with sat Na2S2O3, dried with anhydrous Na2SO4, fil-
tered and concentrated. The pure product was isolated by flash
chromatography on silica gel using a mixture of hexane/ethyl acet-
ate as eluent.
General Procedure for the Synthesis of Amides 3 Derived from Boc-
Amino Acids:[6a,16,21] To a solution of a commercially available Boc-
amino acid (5 mmol, 1 equiv.) in dry DCM was added HN(OMe)-
Me·HCl (1 equiv.) and DIPEA (99%, 1 equiv.) at –5 °C. After stir-
ring several minutes, a solution of EDCI, 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (1 equiv.), in dry DCM
was added dropwise under nitrogen atmosphere and the resulting
mixture was stirred at –5 °C for 2 h. When the reaction was com-
pleted, the crude was washed two times with 1 n HCl. Then the
organic layers were dried with anhydrous Na2SO4, filtered, and
concentrated in vacuo. The amide was obtained pure enough to be
used in the next reaction step.
tert-Butyl N-Allyl-N-{(S)-1-[methoxy(methyl)amino]-1-oxopropan-
2-yl}carbamate (4a): Colorless oil, 61% yield; Rf = 0.42 (hexane/
EtOAc, 3:1); 1H NMR (300 MHz, CDCl3): δ = 1.40 (d, J = 7.2 Hz,
3 H, CH3), 1.46 (s, 9 H, Boc), 3.18 (s, 3 H, CH3), 3.78 (s, 3 H,
CH3O), 4.65 (m, 1 H, CH), 5.26 (dd, J = 1.2, 10.4 Hz, 1 H, CH2),
5.35 (dd, J = 1.5, 17.2 Hz, 1 H, CH2), 5.93 (m, 1 H, CH) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 15.1 (CH3), 28.12 (Boc), 31.7 (CH3),
46.0 (CH2), 49.8 (CH), 61.2 (CH3O), 79.5 (C-Boc), 114.9 (CH2),
115.4 (CH2), 135.8 (CH), 135.3 (CH), 155.2 (C), 172.9 (C) [some
signals are duplicated due to presence of rotamers] ppm. EI
HRMS: calcd. for C10H15N2O4: 216.1110 [-tBu + H]+, found
216.1116. [α]1D8 = –30.97 (c = 1.40, CH2Cl2).
tert-Butyl {(S)-1-[Methoxy(methyl)amino]-1-oxopropan-2-yl}carb-
amate (3a): White solid, 87% yield; m.p. 145–146 °C. Rf = 0.64
(hexane/EtOAc, 1:1); H NMR (300 MHz, CDCl3): δ = 1.32 (d, J
= 6.9 Hz, 3 H, CH3), 1.44 (s, 9 H, Boc), 3.22 (s, 3 H, CH3), 3.78
(s, 3 H, CH3O), 4.69 (m, 1 H, CH), 5.30 (m, 1 H, NH) ppm. 13C
NMR (75 MHz, CDCl3) δ = 18.6 (CH3), 28.3 (Boc), 32.1 (CH),
46.5 (CH3), 61.6 (CH3O), 79.5 (C-Boc), 155.2 (C), 173.6 (C) ppm.
[α]2D2 = +1.31 (c = 1.15, CH2Cl2). CAS: 87694–49–3.
tert-Butyl
N-Allyl-N-{(S)-1-[methoxy(methyl)amino]-3-methyl-1-
oxobutan-2-yl}carbamate (4b): Colorless oil, 94% yield. Rf = 0.20
(hexane/EtOAc, 1:1). Following the previous procedure, in this ex-
ample 3 equiv. of NaH (99%) were used; 1H NMR (300 MHz,
CDCl3): δ = 0.85 (d, J = 6.5 Hz, 6 H, CH3-iPr), 1.40 (br. s, 9 H,
Boc), 2.20 (m, 1 H, CH-iPr), 3.09 (s, 3 H, CH3), 3.66 (s, 3 H,
CH3O), 3.85 (m, 2 H, CH2), 4.87 (m, 1 H, CH), 4.95 (m, 2 H,
CH2), 5.72 (m, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ =
18.1 (CH3-iPr), 19.3 (CH3-iPr), 27.1 (CH-iPr), 28.0 (Boc), 31.8
1
tert-Butyl {(S)-1-[Methoxy(methyl)amino]-3-methyl-1-oxobutan-2-
yl}carbamate (3b): Colorless oil, 94% yield; Rf = 0.20 (hexane/ (CH), 44.9 (CH3), 45.4 (CH3), 58.0 (CH2), 59.5 (CH3O), 61.6
Eur. J. Org. Chem. 2014, 1672–1683
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1677

R. Barroso, M. Escribano, M.-P. Cabal, C. Valdés
FULL PAPER
(CH3O), 79.4 (C-Boc), 115.3 (CH2), 134.2 (CH), 135.0 (CH), 154.8
(C), 155.5 (C), 171.6 (C) ppm [some signals are duplicated due to
the presence of rotamers]. EI HRMS: calcd. for C15H28N2O4:
300.2049, found 300.2051. [α]2D5 = +6.47 (c = 1.70, CH2Cl2).
vious procedure, in this example 1.5 equiv. of NaH (99%) were
used and 3-bromo-2-methylpropene was used instead of allyl brom-
ide. Colorless oil, 79% yield; Rf = 0.46 (hexane/EtOAc, 3:1); 1H
NMR (300 MHz, CDCl3): δ = 0.85 (m, 6 H, iso-Bu), 1.34 (s, 9 H,
Boc), 1.41 (m, 1 H, CH iso-Bu), 1.59 (s, 3 H, CH3), 1.64 (m, 2 H,
CH2 iso-Bu), 3.12 (s, 3 H, CH3), 3.66 (m, 2 H, CH2), 3.71 (m, 3 H,
CH3O), 4.63 (m, 2 H, CH2), 5.07 (m, 1 H, CH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.4 (CH3), 21.4 (CH3), 22.5 (CH), 22.6
(CH), 23.2 (CH3), 24.6 (CH3), 28.2 (Boc), 32.0 (CH3), 38.3 (CH2),
41.9 (CH2), 48.9 (CH3), 51.8 (CH), 61.4 (CH3O), 79.3 (C-Boc),
109.0 (CH2), 141.8 (CH), 142.5 (CH), 155.6 (C), 173.8 (C) ppm
[some signals are duplicated due to the presence of rotamers]. EI
tert-Butyl N-Allyl-N-{(S)-1-[methoxy(methyl)amino]-4-methyl-1-oxo-
pentan-2-yl}carbamate (4c): Colorless oil, 72% yield; Rf = 0.46 (hex-
ane/EtOAc, 3:1); 1H NMR (300 MHz, CDCl3): δ = 0.87 (m, 6 H,
iso-Bu), 1.37 (s, 9 H, Boc), 1.47 (m, 1 H, CH iso-Bu), 1.51 (CH2 iso-
Bu), 3.07 (s, 3 H, CH3), 3.66 (s, 3 H, CH3O), 3.75 (CH2), 4.94 (m, 1
H, CH), 5.04 (CH2), 5.23 (m, 1 H, CH), 5.74 (m, 1 H, NH) ppm.
13C NMR (75 MHz, CDCl3): δ = 20.8 (CH3), 21.5 (CH3), 24.0 (CH),
27.7 (Boc), 30.4 (DMF), 35.5 (DMF), 37.8 (CH2), 45.5 (CH2), 51.1
(CH3), 52.3 (CH), 60.9 (CH3O), 79.0 (C-Boc), 114.8 (CH2), 134.8
(CH), 135.4 (CH), 154.1 (C), 154.8 (C), 161.6 (DMF), 171.1 (C),
172.0 (C) ppm [some signals are duplicated due to the existence of
rotamers]. EI HRMS: calcd. for C16H30N2O4: 314.2206, found
314.2198. [α]2D1 = –67.93 (c = 0.27, CH2Cl2).
HRMS: calcd. for C17H32N2O4: 328.2362, found 328.2369. [α]2D1
- 64.22 (c = 0.55, CH2Cl2).
=
tert-Butyl N-{(S)-1-[Methoxy(methyl)amino]-1-oxo-3-phenylpropan-
2-yl}-N-(2-methylprop-2-en-1-yl)carbamate (4h): Following the pre-
vious procedure, in this example 1.5 equiv. of NaH (99%) were
used and 3-bromo-2-methylpropene was used instead of allyl brom-
ide. Colorless oil, 65% yield; Rf = 0.47 (hexane/EtOAc, 3:1); 1H
NMR (300 MHz, CDCl3): δ = 1.35 (s, 9 H, Boc), 1.68 (s, 3 H,
CH3), 2.91 (m, 1 H, CH2), 3.05 (s and m, 4 H, CH3 and 1 H, CH2),
3.56 (s, 3 H, CH3O), 3.76 (m, 2 H, CH2), 4.70 (s, 1 H, CH2), 4.74
(s, 1 H, CH2) 5.19 (m, 1 H, CH), 7.21 (m, 5 H, Ph) ppm. 13C NMR
(75 MHz, CDCl3): δ = 28.2 (CH3), 28.3 (Boc), 32.0 (CH2), 38.8
(CH), 43.2 (CH2), 51.5 (CH3), 61.5 (CH3O), 79.5 (C-Boc), 109.8
(CH2), 126.7 (CH), 128.3 (2ϫCH), 129.4 (2ϫCH), 136.6 (C-Ph),
143.9 (C), 155.2 (C), 172.3 (C) ppm. EI HRMS: calcd. for
C20H30N2O4: 362.2206, found 362.2213. [α]1D8 = +13.76 (c = 2.58,
CH2Cl2).
tert-Butyl N-Allyl-N-{(S)-1-[methoxy(methyl)amino]-1-oxo-3-phen-
ylpropan-2-yl}carbamate (4d): Pale yellow oil, 67% yield; Rf = 0.32
(hexane/EtOAc, 2:1); Following the previous procedure, in this ex-
ample 1.5 equiv. of NaH (99%) were used; 1H NMR (300 MHz,
CDCl3): δ = 1.35 (s, 9 H, Boc), 2.92 (m, 1 H, CH2), 3.08 (br. s, 4
H, CH3 and 1 H, CH2), 3.57 (s, 3 H, CH3O), 3.82 (m, 2 H, CH2),
5.14 (m, 2 H, CH2), 5.51 (m, 1 H, CH), 5.76 (m, 1 H, CH), 7.20
(m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.2 (Boc),
35.8 (CH2), 45.8 (CH2), 54.5 (CH), 56.5 (CH3), 61.4 (CH3O), 79.8
(C-Boc), 115.6 (CH2), 116.0 (CH2), 126.3 (CH), 128.2 (2ϫCH),
129.5 (2ϫCH), 134.5 (CH), 135.3 (CH), 137.4 (C-Ph), 138.0 (C-
Ph), 154.4 (C), 155.2 (C), 171.4 (C) ppm [some signals are dupli-
cated due to the existence of rotamers]. EI HRMS: calcd. for
C19H28N2O4: 348.2049, found 348.2042. [α]2D2 = –17.54 (c = 3.61,
CH2Cl2).
General Procedure for the Synthesis of α-Allylamino Ketones (5): To
a solution of the α-allylamide 4 (1 mmol, 1 equiv.) in dry Et2O
(30 mL) was added the magnesium halide (1.4 equiv.) at 0 °C. The
mixture was stirred at 0 °C for 1 h. The reaction mixture was
quenched with saturated aqueous solution NH4Cl (25 mL) and
then extracted three times with Et2O. The organic layers were
washed three times with H2O, dried with anhydrous Na2SO4, fil-
tered, and concentrated in vacuo. The crude product was chro-
matographed on silica gel (mixtures of hexane/EtOAc).
tert-Butyl N-{(S)-1-[Methoxy(methyl)amino]-1-oxopropan-2-yl}-N-
(3-methylbut-2-en-1-yl)carbamate (4e): Colorless oil, 61% yield; Rf
= 0.35 (hexane/EtOAc, 2:1); Following the previous procedure, in
this example 1-bromo-3-methyl-but-2-ene was used instead of allyl
1
bromide; H NMR (300 MHz, CDCl3): δ = 1.30 (d, J = 6.5 Hz, 3
H, CH3), 1.46 (s, 9 H, Boc), 1.64 (s, 3 H, CH3), 1.70 (s, 3 H, CH3),
3.17 (s, 3 H, CH3), 3.73 (s, 3 H, CH3O), 3.85 (m, 2 H, CH2), 5.14
(m, 2 H, 2ϫCH) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.3
(CH3), 17.9 (CH3), 25.7 (CH3), 28.4 (Boc), 42.0 (CH2), 46.7 (CH),
50.1 (CH3), 61.4 (CH3O), 79.6 (C-Boc), 123.1 (CH), 132.1 (C),
155.6 (C), 173.4 (C) ppm. EI HRMS: calcd. for
C15H28N2O4: 300.2049, found 300.2054. [α]2D2 = –7.83 (c = 1.09,
CH2Cl2).
tert-Butyl (S)-N-Allyl-N-(3-oxobutan-2-yl)carbamate (5a): Colorless
oil, 89% yield; Rf = 0.71 (hexane/EtOAc, 1:1); 1H NMR (300 MHz,
CDCl3): δ = 1.30 (d, J = 6.8 Hz, 3 H, CH3), 1.44 (br. s, 9 H, Boc),
2.13 (s, 3 H, CH3), 3.65 (dd, J = 6.5, 14.7 Hz, 1 H, CH2), 3.75 (dd,
J = 6.5, 14.7 Hz, 1 H, CH2), 4.64 (m, 1 H, CH), 5.24 (dd, J = 1.2,
10.4 Hz 1 H, CH2), 5.30 (dd, J = 1.4, 17.2 Hz, 1 H, CH2), 5.90 (m,
1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.4 (CH3), 13.7
(CH3), 26.1 (CH3), 26.4 (CH3), 28.1 (Boc), 48.7 (CH2), 50.2 (CH2),
60.8 (CH), 61.7 (CH), 80.4 (C-Boc), 81.0 (C-Boc), 116.8 (CH2),
118.2 (CH2), 134.1 (CH), 134.6 (CH), 154.3 (C), 155.1 (C), 206.1
(C), 206.8 (C) ppm [some signals are duplicated due to the presence
of rotamers]. EI HRMS: calcd. for C10H18NO2: 184.1338 [-C(O)-
CH3]+, 184.1333. [α]2D6 = –10.90 (c = 1.96, CH2Cl2).
tert-Butyl N-{(S)-1-[Methoxy(methyl)amino]-1-oxopropan-2-yl}-N-
(2-methylprop-2-en-1-yl)carbamate (4f): Colorless oil, 79% yield. Rf
= 0.32 (hexane/EtOAc, 3:1). Following the previous procedure, in
this example 3-bromo-2-methylpropene was used instead of allyl
1
bromide; H NMR (300 MHz, CDCl3): δ = 1.25 (d, J = 6.5 Hz, 3
H, CH3), 1.38 (s, 9 H, Boc), 1.65 (s, 3 H, CH3), 3.11 (s, 3 H, CH3),
3.72 (m, 4 H, CH2 and CH3O), 3.83 (m, 1 H, CH2), 4.69 (s, 1 H,
CH2), 4.73 (s, 1 H, CH2), 5.17 (m, 1 H, CH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.9 (CH3), 15.2 (CH3), 20.2 (CH3), 28.2
(Boc), 32.1 (CH), 49.2 (CH2), 49.8 (CH2), 50.2 (CH3), 52.0 (CH3),
61.4 (CH3O), 79.6 (C-Boc), 80.0 (C-Boc), 109.1 (CH2), 109.8
(CH2), 142.7 (C), 143.1 (C), 155.7 (C), 173.3 (C) ppm [some signals
are duplicated due to the presence of rotamers]. EI HRMS: calcd.
for C14H26N2O4: 286.1893, found 286.1885. [α]2D2 = +18.49 (c =
1.65, CH2Cl2).
tert-Butyl (S)-N-Allyl-N-(3-oxopentan-2-yl)carbamate (5b): Color-
less oil, 77% yield; Rf = 0.33 (hexane/EtOAc, 3:1); 1H NMR
(300 MHz, CDCl3): δ = 1.01 (m, 3 H, CH3-Et), 1.27 (d, J = 6.4 Hz,
3 H, CH3), 1.42 (m, 9 H, Boc), 2.48 (m, 2 H, CH2-Et), 3.72 (m, 2
H, CH2), 4.32 (m, 1 H, CH), 5.13 (m, 2 H, CH2), 5.84 (m, 1 H,
CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9 (CH3-Et), 22.6
(CH3), 28.2 (Boc), 31.3 (CH2-Et), 31.9 (CH2-Et), 48.4 (CH2), 50.2
(CH2), 59.8 (CH), 60.9 (CH), 80.3 (C-Boc), 80.9 (C-Boc), 116.6
tert-Butyl N-{(S)-1-[Methoxy(methyl)amino]-4-methyl-1-oxopentan- (CH2), 118.1 (CH2), 134.3 (CH), 134.9 (CH), 154.4 (C), 155.2 (C),
2-yl}-N-(2-methylprop-2-en-1-yl)carbamate (4 g): Following the pre- 208.7 (C), 209.6 (C) ppm [some signals are duplicated due to the
1678
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1672–1683

Diastereoselective Intramolecular 1,3-Dipolar Cycloadditions
presence of rotamers]. FAB MS: calcd. for C8H15NO: 141.11 [-Boc
138.6 (C-Ph), 154.3 (C), 155.0 (C), 205.3 (C), 205.8 (C) ppm [some
signals are duplicated due to the presence of rotamers]. EI HRMS:
calcd. for C15H20NO3: 262.1443 [-CH2=CH-CH2)]+, found
262.1440. [α]2D1 = –160.23 (c = 3.90, CH2Cl2).
+ H]+, found 141.15. [α]1D9 = –54.32 (c = 1.85, CH2Cl2).
tert-Butyl
(S)-N-Allyl-N-(1-oxo-1-phenylpropan-2-yl)carbamate
(5c): Colorless oil, 48% yield; Rf = 0.35 (hexane/EtOAc, 6:1); 1H
NMR (400 MHz, CDCl3): δ = 1.34 (d, J = 7.4 Hz, 3 H, CH3), 1.39
(s, 9 H, Boc), 3.55 (d, J = 16.0 Hz, 1 H, CH2), 3.68 (d, J = 16.0 Hz,
tert-Butyl
(S)-N-Allyl-N-(3-oxo-1-phenylpentan-2-yl)carbamate
1
(5h): Colorless oil, 57% yield; Rf = 0.73 (hexane/EtOAc, 2:1); H
1 H, CH2), 4.95 (m, 2 H, CH2), 5.10 (m, 1 H, CH), 5.63 (m, 1 H, NMR (300 MHz, CDCl3): δ = 1.06 (t, J = 7.3 Hz, 3 H, CH3), 1.45
CH), 7.44 (m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.5
(s, 9 H, Boc), 1.59 (m, 2 H, CH2), 2.61 (m, 2 H, CH2), 3.91 (m, 2
(CH3), 15.0 (CH3), 28.2 (Boc), 46.7 (CH2), 48.6 (CH2), 54.8 (CH), H, CH2), 4.70 (m, 1 H, CH), 5.20 (m, 2 H, CH2), 5.86 (m, 1 H,
57.3 (CH), 80.3 (C-Boc), 116.0 (CH2), 116.9 (CH2), 128.4 (CH), CH), 7.29 (m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 7.7
133.0 (CH), 135.2 (CH), 135.7 (C-Ph), 155.2 (C), 199.6 (C) ppm (CH3), 28.3 (Boc), 31.9 (CH2), 32.8 (CH2), 34.9 (CH2), 35.8 (CH2),
[some signals are duplicated due to the presence of rotamers]. EI
50.0 (CH2), 51.1 (CH2), 65.8 (CH), 68.9 (CH), 79.9 (C-Boc), 81.2
(C-Boc), 117.5 (CH2), 118.9 (CH2), 126.3 (CH), 126.4 (2ϫCH),
129.5 (2ϫCH), 133.7 (CH), 134.2 (CH), 138.7 (C-Ph), 154.3 (C),
155.1 (C), 207.9 (C) ppm [some signals are duplicated due to the
presence of rotamers]. EI HRMS: calcd. for C10H18NO2: 184.1338
[-C(O)CH3]+, found 184.1333. [α]1D7 = +32.40 (c = 0.25, CH2Cl2).
HRMS: calcd. for C17H23NO3: 289.1678, found 289.1679. [α]1D8
–73.87 (c = 0.38, CH2Cl2).
=
tert-Butyl (S)-N-allyl-N-(3-oxo-4-phenylbutan-2-yl)carbamate (5d):
1
Colorless oil, 56% yield; Rf = 0.32 (hexane/EtOAc, 6:1); H NMR
(300 MHz, CDCl3): δ = 1.27 (br. s, 3 H, CH3), 1.44 (br. s, 9 H,
Boc), 3.61 (m, 1 H, CH2-Bn), 3.71 (m, 1 H, CH2-Bn), 3.85 (m, 2
tert-Butyl (S)-N-(3-Methylbut-2-en-1-yl)-N-(2-oxobutan-2-yl)carb-
H, CH2), 4.40 (m, 1 H, CH), 5.15 (m, 2 H, CH2), 5.85 (m, 1 H, amate (5i): Colorless oil, 76% yield; Rf = 0.87 (hexane/EtOAc, 3:1);
CH), 7.29 (m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.6 1H NMR (300 MHz, CDCl3): δ = 1.29 (d, J = 6.5 Hz, 3 H, CH3),
(CH3), 14.1 (CH3), 28.3 (Boc), 45.4 (CH2-Bn), 46.0 (CH2-Bn), 48.7 1.44 (br. s, 9 H, Boc), 1.69 (s, 3 H, CH3), 1.75 (s, 3 H, CH3), 2.13
(CH2), 50.5 (CH2), 59.6 (CH3O), 60.7 (CH3O), 80.6 (C-Boc), 81.4 (s, 3 H, CH3), 3.58 (m, 2 H, CH2), 4.13 (m, 1 H, CH), 5.27 (m, 1
(C-Boc), 117.0 (CH2), 118.4 (CH2), 127.0 (CH), 128.6 (2ϫCH), H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.2 (CH3), 13.6
129.5 (2ϫCH), 134.2 (CH), 134.8 (C-Ph), 154.5 (C), 206.4 (C) ppm
(CH3), 17.7 (CH3), 25.7 (CH3), 26.1 (CH3), 28.3 (Boc), 29.6 (CH3),
43.9 (CH2), 44.7 (CH2), 60.8 (CH), 61.6 (CH), 80.2 (C-Boc), 80.9
(C-Boc), 120.2 (CH), 121.2 (CH), 134.6 (C), 136.6 (C), 155.2 (C),
206.6 (C) ppm [some signals are duplicated due to the presence of
rotamers]. EI HRMS: calcd. for C14H25NO3: 255.1834, 255.1834.
[α]1D7 = +12.86 (c = 0.07, CH2Cl2).
[some signals are duplicated due to the presence of rotamers]. EI
HRMS: calcd. for C18H25NO3: 303.1810, found 303.1821. [α]2D5
–46.65 (c = 1.51, CH2Cl2).
=
tert-Butyl
(S)-N-Allyl-N-(2-methyl-4-oxopentan-3-yl)carbamate
(5e): Colorless oil, 80% yield; Rf = 0.66 (hexane/EtOAc, 1:1); 1H
NMR (300 MHz, CDCl3): δ = 0.83 (m, 6 H, CH3-iPr), 1.34 (m, 1 tert-Butyl (S)-N-(3-Methylbut-2-en-1-yl)-N-(3-oxo-4-phenylbutan-2-
H, CH-iPr), 1.39 (s, 9 H, Boc), 2.06 (br. s, 3 H, CH3), 3.58 (m, 2 yl)carbamate (5j): Colorless oil, 76% yield. Rf = 0.61 (hexane/
H, CH2), 4.23 (m, 1 H, CH), 5.05 (m, 2 H, CH2), 5.67 (m, 1 H, EtOAc, 2:1). 1H NMR (300 MHz, CDCl3): δ = 1.17 (d, J = 6.7 Hz,
CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.5 (CH3-iPr), 19.0
3 H, CH3), 1.47 (br. s, 9 H, Boc), 1.62 (s, 3 H, CH3), 1.73 (s, 3 H,
(CH3-iPr), 20.0 (CH3-iPr), 21.1 (CH3-iPr), 25.6 (CH-iPr), 26.7 CH3), 2.95 (dd, J = 4.4, 12.1 Hz, 1 H, CH2-Bn), 3.28 (m, 1 H, CH2-
(CH-iPr), 28.3 (Boc), 29.2 (CH3), 47.3 (CH2), 49.7 (CH2), 68.1 Bn), 3.48 (m, 2 H, CH2), 4.12 (q, J = 6.8 Hz, 1 H, CH), 5.18 (m,
(CH), 70.4 (CH), 80.3 (C-Boc), 80.8 (C-Boc), 117.0 (CH2), 118.0 1 H, CH), 7.25 (m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ
(CH2), 133.7 (CH), 134.0 (CH), 154.7 (C), 155.9 (C), 204.8 (C),
205.8 (C) ppm [some signals are duplicated due to the presence of
rotamers]. EI MS: calcd. for C12H22NO2: 212.17 [-C(O)CH3]+,
found 212.17. [α]2D5 = +161.91 (c = 0.47, CH2Cl2).
= 15.2 (CH3), 17.7 (CH3), 25.6 (CH3), 28.3 (Boc), 32.3 (CH2-Bn),
41.8 (CH2), 63.5 (CH), 79.4 (C-Boc), 123.0 (CH), 127.0 (CH), 128.7
(2ϫCH), 129.5 (2ϫCH), 131.9 (C), 134.5 (C), 155.4 (C), 207.8
(C) ppm. EI HRMS: calcd. for C20H29NO3: 331.2147, found
331.2151. [α]2D2 = –8.74 (c = 2.50, CH2Cl2).
tert-Butyl (S)-N-Allyl-N-(5-methyl-2-oxohexan-3-yl)carbamate (5f):
1
Colorless oil, 92% yield; Rf = 0.59 (hexane/EtOAc, 2:1); H NMR
tert-Butyl (S)-N-(2-Methylallyl)(3-oxobutan-2-yl)carbamate (5k):
1
(300 MHz, CDCl3): δ = 0.84 (m, 6 H, iso-Bu), 1.37 (m, 9 H, Boc),
Colorless oil, 69% yield; Rf = 0.61 (hexane/EtOAc, 2:1); H NMR
1.44 (m, 1 H, CH iso-Bu), 1.68 (m, 2 H, CH2 iso-Bu), 2.05 (s, 3 H, (300 MHz, CDCl3): δ = 1.29 (d, J = 6.4 Hz, 3 H, CH3), 1.42 (br.
CH3), 3.43 (m, 1 H, CH), 3.85 (m, 2 H, CH2), 5.07 (m, 2 H, CH2), s, 9 H, Boc), 1.77 (s, 3 H, CH3), 2.12 (s, 3 H, CH3), 3.57 (m, 2 H,
5.80 (m, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.8 CH2), 4.03 (m, 1 H, CH), 4.57 (m, 2 H, CH2) ppm. 13C NMR
(CH), 21.9 (CH3), 23.0 (CH3), 27.0 (CH3), 27.3 (CH3), 28.2 (Boc), (75 MHz, CDCl3): δ = 13.2 (CH3), 13.7 (CH3), 20.1 (CH3), 26.1
36.3 (CH2), 37.3 (CH2), 48.0 (CH2), 49.5 (CH2), 62.6 (CH), 63.9 (CH3), 26.4 (CH3), 28.2 (Boc), 52.4 (CH2), 53.7 (CH2), 61.3 (CH),
(CH), 80.3 (C-Boc), 80.8 (C-Boc), 116.8 (CH2), 117.9 (CH2), 134.2 62.0 (CH), 80.4 (C-Boc), 81.2 (C-Boc), 112.2 (CH2), 113.9 (CH2),
(CH), 134.7 (CH), 154.7 (C), 155.6 (C), 206.4 (C), 207.1 (C) ppm 141.8 (C), 154.8 (C), 155.3 (C), 206.2 (C) ppm [some signals are
[some signals are duplicated due to the presence of rotamers]. EI
duplicated due to the presence of rotamers]. EI HRMS: calcd. for
C13H23NO3: 241.1678, found 241.1679. [α]2D2 = +65.41 (c = 0.91,
CH2Cl2).
HRMS: calcd. for C15H27NO3: 269.1991, found 269.2002. [α]2D1
–137.38 (c = 0.65, CH2Cl2).
=
tert-Butyl (S)-N-Allyl-N-(3-oxo-1-phenylbutan-2-yl)carbamate (5 g): tert-Butyl (S)-N-(2-Methylallyl)-N-(5-methyl-2-oxohexan-3-yl)carb-
1
Colorless oil, 78% yield; Rf = 0.76 (hexane/EtOAc, 1:1); H NMR
amate (5l): Colorless oil, 68% yield. Rf = 0.69 (hexane/EtOAc, 2:1);
(300 MHz, CDCl3): δ = 1.45 (s, 9 H, Boc), 2.15 (br. s, 3 H, CH3), 1H NMR (300 MHz, CDCl3): δ = 0.92 (m, 6 H, iso-Bu), 1.45 (s, 9
2.94 (m, 2 H, CH2), 3.32 (m, 2 H, CH2), 4.07 (m, 1 H, CH), 5.05 H, Boc), 1.60 (m, 1 H, CH2 iso-Bu), 1.76 (m, 4 H, CH iso-Bu and
(m, 2 H, CH2), 5.65 (m, 1 H, CH), 7.18 (m, 5 H, Ph) ppm. 13C CH3), 1.87 (m, 1 H, CH2 iso-Bu), 2.13 (s, 3 H, CH3), 3.49 (m, 1 H,
NMR (75 MHz, CDCl3): δ = 26.7 (CH3), 27.2 (CH3), 28.3 (Boc),
CH2), 3.84 (m, 1 H, CH2), 4.12 (m, 1 H, CH), 4.85 (m, 2 H,
34.8 (CH2), 35.8 (CH2), 50.8 (CH2), 51.3 (CH2), 67.1 (CH), 67.7 CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.4 (CH), 22.8
(CH), 79.9 (C-Boc), 80.6 (C-Boc), 117.8 (CH2), 119.1 (CH2), 126.3
(CH), 128.2 (2ϫCH), 128.5 (2ϫCH), 129.5 (CH), 133.5 (CH),
(CH3), 22.9 (CH3), 27.0 (CH3), 27.5 (CH3), 28.2 (Boc), 36.7 (CH2),
37.9 (CH2), 51.6 (CH2), 53.0 (CH2), 63.1 (CH), 64.3 (CH), 80.4 (C-
Eur. J. Org. Chem. 2014, 1672–1683
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1679

R. Barroso, M. Escribano, M.-P. Cabal, C. Valdés
Boc), 81.0 (C-Boc), 112.3 (CH2), 113.8 (CH2), 141.8 (C), 155.8 (C), 1 H, CH2), 4.47 (q, J = 6.7 Hz, 1 H, CH), 4.70 (dd, J = 1.9,
FULL PAPER
206.2 (C) ppm. EI HRMS: calcd. for C12H20NO3: 226.1443 [-iPr-
17.9 Hz; 1 H, CH2), 7.32 (m, 5 H, Ph) ppm. 13C NMR (150 MHz,
CDCl3): δ = 15.9 (CH3-Ala), 28.5 (CH3-Boc), 41.3 (CH), 50.9
(CH2), 64.5 (CH), 80.0 (C-Boc), 81.2 (CH2), 105.8 (C), 125.1
(2ϫCH), 127.8 (CH), 128.4 (C-Ph), 128.8 (2ϫCH), 140.6 (C),
153.5 (C) ppm. EI HRMS: calcd. for C17H23N3O2: 301.1790, found
301.1790. [α]2D7 = –250.00 (c = 0.01, CH2Cl2).
CH2]+, found 226.1440. [α]2D1 = –103.55 (c = 2.91, CH2Cl2).
tert-Butyl (S)-N-(2-Methylallyl)-N-(3-oxo-1-phenylbutan-2-yl)carb-
amate (5m): Colorless oil, 72% yield; Rf = 0.80 (hexane/EtOAc,
1:1); 1H NMR (300 MHz, CDCl3): δ = 1.48 (s, 9 H, Boc), 1.67 (br.
s, 3 H, CH3), 2.13 (s, 3 H, CH3), 2.92 (m, 1 H, CH2), 3.07 (m, 1
H, CH2), 3.40 (m, 1 H, CH2), 3.76 (m, 1 H, CH2), 4.02 (m, 1 H,
CH), 4.81 (s, 1 H, CH2), 4.85 (s, 1 H, CH2), 7.24 (m, 5 H, Ph) ppm.
13C NMR (75 MHz, CDCl3): δ = 20.4 (CH3), 26.8 (CH3), 27.3
(CH3), 28.3 (Boc), 34.1 (CH2), 35.1 (CH2), 54.1 (CH2), 54.5 (CH2),
tert-Butyl
(6S,6aS)-6a-Benzyl-6-methyl-3a,4,6,6a-tetrahydropyr-
rolo[3,4-c]pyrazole-5(3H)-carboxylate (6d): Colorless oil, 65% yield;
1
Rf = 0.38 (hexane/EtOAc, 1:2); H NMR (400 MHz, CDCl3): δ =
1.41 (d, J = 6.7 Hz, 3 H, CH3), 1.48 (s, 9 H, Boc), 2.39 (ddd, J =
67.1 (CH), 67.8 (CH), 80.6 (C-Boc), 81.4 (C-Boc), 114.0 (CH2), 2.0, 7.4, 17.1 Hz, 1 H, CH), 2.62 (dd, J = 8.0, 11.6 Hz, 1 H, CH2),
115.1 (CH2), 126.5 (CH), 128.4 (2ϫCH), 129.4 (2ϫCH), 138.7
(C), 141.4 (C), 154.7 (C), 205.1 (C), 205.6 (C) ppm [some signals
are duplicated due to the presence of rotamers]. EI HRMS: calcd.
for C19H27NO3: 317.1991, found 317.2002. [α]2D1 = –183.14 (c =
0.26, CH2Cl2).
2.93 (d, J = 13.8 Hz, 1 H, CH2-Bn), 3.32 (dd, J = 7.5, 17.8 Hz; 1
H, CH2), 3.45 (d, J = 13.8 Hz, 1 H, CH2-Bn), 3.84 (dd, J = 9.4,
11.6 Hz; 1 H, CH2), 4.30 (m, 2 H, CH and CH2), 7.24 (m, 5 H,
Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.0 (CH3), 28.5 (Boc),
37.2 (CH), 41.9 (CH2-Bn), 50.6 (CH2), 61.2 (CH), 79.8 (C-Boc),
81.5 (CH2), 106.6 (C), 127.0 (CH), 128.3 (2ϫCH), 130.0 (2ϫCH),
135.4 (C), 153.4 (C) ppm. EI MS: calcd. for C18H26N3O2: 316.20
[M + 1]+, found 316.21. [α]2D0 = –10.00 (c = 0.03, CH2Cl2).
General Procedure for the Synthesis of N-Boc-tetrahydropyrrolo[3,4-
c]pyrazoles (6): A carousel reaction tube was charged with the cor-
responding α-allylamino ketone 5 (0.3 mmol, 1 equiv.), N-tosyl-
hydrazide (1.1 equiv.) and dioxane (3 mL). The system was heated
tert-Butyl (6S,6aS)-6-Isopropyl-6a-methyl-3a,4,6,6a-tetrahydropyr-
at 85 °C with stirring for 2 h. Then, K2CO3 (6 equiv.) was added rolo[3,4-c]pyrazole-5(3H)-carboxylate (6e): Colorless oil, 50% yield;
1
and the reaction mixture was allowed to refluxed for 24 h. After
cooling to room temperature, the 1,4-dioxane was removed under
reduced pressure. The reaction crude was treated with a 1:1 mixture
of EtOAc and H2O and extracted three times with EtOAc. The
organic layers were washed three times with H2O, dried with an-
hydrous Na2SO4, filtered and concentrated. The crude product was
isolated by flash chromatography on silica gel (mixtures of hexane/
EtOAc).
Rf = 0.29 (hexane/EtOAc, 3:1); H NMR (300 MHz, CDCl3): δ =
1.00 (d, J = 6.9 Hz, 3 H, CH3), 1.20 (d, J = 6.6 Hz, 3 H, CH3),
1.37 (s, 3 H, CH3), 1.47 (s, 9 H, Boc), 2.04 (m, 1 H, CH), 2.19 (m,
1 H, CH), 2.38 (m, 1 H, CH2), 4.01 (m, 1 H, CH2), 4.06 (m, 1 H,
CH), 4.17 (dd, J = 7.2, 18.0 Hz, 1 H, CH2), 4.49 (dd, J = 1.5,
18.0 Hz; 1 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.1
(CH), 20.5 (CH3), 24.1 (CH3), 28.4 (Boc), 30.0 (CH3), 41.9 (CH),
50.5 (CH2), 71.2 (CH), 77.9 (CH2), 79.8 (C-Boc), 103.1 (C), 154.2
(C) ppm. EI HRMS: calcd. for C14H26N3O2: 268.2025 [M + H]+,
found 268.2017. [α]1D0 = –27.50 (c = 1.80, CH2Cl2).
tert-Butyl (6S,6aS)-6,6a-Dimethyl-3a,4,6,6a-tetrahydropyrrolo[3,4-
c]pyrazole-5(3H)-carboxylate (6a): Colorless oil, 64% yield; Rf = =
1
0.62 (hexane/EtOAc, 1:1); H NMR (300 MHz, CDCl3): δ = 1.34 tert-Butyl (6S,6aS)-6-isobutyl-6a-methyl-3a,4,6,6a-tetrahydropyr-
(s, 3 H, CH3), 1.45 (s, 3 H, CH3), 1.47 (s, 9 H, Boc), 2.24 (dd, J = rolo[3,4-c]pyrazole-5(3H)-carboxylate (6f): Colorless oil, 52% yield;
1
2.0, 9.0 Hz, 1 H, CH), 2.66 (dd, J = 9.0, 11.8 Hz, 1 H, CH2), 3.84 Rf = 0.32 (hexane/EtOAc, 3:1); H NMR (300 MHz, CDCl3): δ =
(dd, J = 9.3, 11.7 Hz, 1 H, CH2), 4.08 (q, J = 6.7 Hz, 1 H, CH),
0.98 (d, J = 6.5 Hz, 3 H, CH3), 1.03 (d, J = 6.6 Hz, 3 H, CH3),
4.33 (dd, J = 7.2, 17.8 Hz, 1 H, CH2), 4.60 (dd, J = 1.9, 17.8 Hz, 1.39 (s, 3 H, CH3), 1.43 (m, 1 H, CH), 1.47 (s, 9 H, Boc), 2.13 (m,
1 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.8 (CH3), 21.3 2 H, CH2), 2.23 (dd, J = 2.3, 7.6 Hz, 1 H, CH), 2.49 (dd, J = 9.2,
(CH3), 28.4 (Boc), 31.0 (acetone), 39.8 (CH), 50.7 (CH2), 62.1
(CH), 79.7 (C-Boc), 80.4 (CH2), 101.4 (C), 153.6 (C) ppm. EI
11.9 Hz, 1 H, CH2), 3.99 (dd, J = 9.1, 11.8 Hz, 1 H, CH2), 4.21 (t,
J = 8.5 Hz, 1 H, CH), 4.25 (dd, J = 7.5, 17.9 Hz, 1 H, CH2), 4.50
HRMS: calcd. for C12H22N3O2: 240.1712 [M
+
H]+, found (dd, J = 2.3, 18.0 Hz, 1 H, CH2) ppm. 13C NMR (75 MHz, CDCl3):
δ = 22.1 (CH3), 23.5 (CH), 24.8 (CH3), 28.3 (CH3), 28.5 (Boc), 40.0
(CH2), 41.5 (CH), 49.9 (CH2), 63.7 (CH), 79.1 (CH2), 79.8 (C-Boc),
240.1721. [α]1D9 = –20.00 (c = 0.03, CH2Cl2).
tert-Butyl
(6S,6aS)-6a-Ethyl-6-methyl-3a,4,6,6a-tetrahydropyr-
102.3 (C), 153.5 (C) ppm. EI HRMS: calcd. for
C11H18N3O2: 224.1399 [-iPr-CH2]+, found 224.1392. [α]1D4 = –4.14
(c = 0.58, CH2Cl2).
rolo[3,4-c]pyrazole-5(3H)-carboxylate (6b): Colorless oil, 32% yield;
1
Rf = 0.25 (hexane/EtOAc, 2:1); H NMR (400 MHz, CDCl3): δ =
0.83 (t, J = 7.5 Hz, 3 H, CH3-Et), 1.33 (d, J = 6.7 Hz, 3 H, CH3),
1.47 (s, 9 H, Boc), 1.77 (q, J = 7.4 Hz, 1 H, CH2-Et), 1.97 (q, J =
7.4 Hz, 1 H, CH2-Et), 2.31 (ddd, J = 2.7, 7.8, 12.2 Hz, 1 H, CH),
tert-Butyl
(6S,6aS)-6-Benzyl-6a-methyl-3a,4,6,6a-tetrahydropyr-
rolo[3,4-c]pyrazole-5(3H)-carboxylate (6 g): Colorless oil, 35%
2.70 (dd, J = 7.8, 11.8 Hz, 1 H, CH2), 3.88 (dd, J = 9.4, 11.7 Hz, yield; Rf = 0.32 (hexane/EtOAc, 2:1); 1H NMR (300 MHz, CDCl3):
1 H, CH2), 4.19 (q, J = 6.7 Hz, 1 H, CH), 4.33 (dd, J = 7.9,
18.0 Hz, 1 H, CH2), 4.50 (dd, J = 2.7, 18.0 Hz, 1 H, CH2) ppm.
δ = 1.00 (s, 3 H, CH3), 1.44 (s, 9 H, Boc), 2.24 (ddd, J = 1.5, 9.2,
17.6 Hz, 1 H, CH), 2.53 (dd, J = 2.5, 8.9 Hz, 1 H, CH2), 3.07 (m,
13C NMR (150 MHz, CDCl3): δ = 8.4 (CH3-Et), 16.0 (CH3), 28.4 2 H, CH2-Bn), 4.00 (m, 1 H, CH2), 4.20 (dd, J = 6.9, 17.8 Hz, 1
(CH3-Boc), 29.4 (CH2), 30.9 (acetone), 37.4 (CH), 50.9 (CH2), 60.4 H, CH2), 4.36 (t, J = 7.6 Hz, 1 H, CH), 4.60 (dd, J = 1.5, 17.8 Hz,
(CH), 79.8 (C-Boc), 81.8 (CH2), 105.7 (C), 153.5 (C) ppm. EI
1 H, CH2), 7.32 (m, 5 H, CH-Ph) ppm. 13C NMR (75 MHz,
CDCl3): δ = 22.5 (CH3), 28.4 (Boc), 36.4 (CH2-Bn), 41.2 (CH),
50.2 (CH2), 67.8 (CH), 78.9 (CH2), 80.0 (C-Boc), 101.7 (C), 126.2
(CH), 128.2 (2ϫCH), 130.0 (2ϫCH), 138.7 (C), 153.5 (C) ppm.
EI HRMS: calcd. for C18H26N3O2: 316.2027 [M + H]+, found
316.2030. [α]1D4 = –14.74 (c = 0.19, CH2Cl2).
HRMS: calcd. for C13H23N3O2: 253.1790, found 253.1798. [α]1D8
10.77 (c = 0.07, CH2Cl2).
=
tert-Butyl
(6S,6aR)-6-Methyl-6a-phenyl-3a,4,6,6a-tetrahydropyr-
rolo[3,4-c]pyrazole-5(3H)-carboxylate (6c): Colorless oil, 36% yield;
1
Rf = 0.76 (hexane/EtOAc, 2:1); H NMR (300 MHz, CDCl3): δ =
1.48 (s, 9 H, Boc), 1.51 (d, J = 6.7 Hz, 3 H, CH3), 2.79 (ddd, J =
2.1, 7.6, 14.8 Hz, 1 H, CH), 2.83 (dd, J = 7.6, 17.1 Hz; 1 H, CH2),
4.05 (dd, J = 7.9, 10.5 Hz; 1 H, CH2), 4.27 (dd, J = 7.0, 17.7 Hz, Rf = 0.24 (hexane/EtOAc, 2:1); H NMR (300 MHz, CDCl3): δ =
tert-Butyl
(6S,6aS)-6-Benzyl-6a-ethyl-3a,4,6,6a-tetrahydropyr-
rolo[3,4-c]pyrazole-5(3H)-carboxylate (6h): Colorless oil, 63% yield.
1
1680
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1672–1683

Diastereoselective Intramolecular 1,3-Dipolar Cycloadditions
0.67 (t, J = 7.4 Hz, 3 H, CH3), 1.33 (s, 9 H, Boc), 1.66 (q, J =
7.1 Hz, 2 H, CH2), 2.33 (dd, J = 8.9, 17.0 Hz, 1 H, CH), 2.60 (dd,
J = 2.1, 11.9 Hz, 2 H, CH2), 2.96 (dd, J = 7.5, 13.3 Hz, 1 H, CH2),
4.09 (m, 1 H, CH2), 4.25 (dd, J = 7.9, 18.1 Hz, 1 H, CH2), 4.44 (t,
tert-Butyl
(3aR,6S,6aS)-6-Benzyl-3a,6a-dimethyl-3a,4,6,6a-tetra-
hydropyrrolo[3,4-c]pyrazole-5(3H)-carboxylate (6m): Colorless oil,
78% yield; Rf = 0.58 (hexane/EtOAc, 2:1); 1H NMR (300 MHz,
C6D6): δ = 0.55 (s, 3 H, CH3), 0.58 (s, 3 H, CH3), 1.57 (s, 9 H,
J = 7.1 Hz, 1 H, CH), 4.50 (dd, J = 2.4, 18.0 Hz, 1 H, CH2), 7.34 Boc), 2.49 (d, J = 10.9 Hz, 1 H, CH2), 3.18 (d, J = 17.2 Hz, 1 H,
(m, 5 H, CH-Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 8.2 (CH3), CH2), 3.46 (m,1 H, CH2-Bn), 3.53 (d, J = 10.2 Hz, 1 H, CH2), 3.65
28.2 (Boc), 30.0 (CH2), 36.3 (CH2), 38.2 (CH), 50.4 (CH2), 65.7 (m, 1 H, CH), 4.20 (d, J = 16.9 Hz, 1 H, CH2), 4.39 (m, 1 H, CH2),
(CH), 79.9 (CH2), 79.9 (C-Boc), 101.8 (C), 126.1 (CH), 128.1
(2ϫCH), 129.9 (2ϫCH), 138.7 (C), 153.3 (C) ppm. EI MS: calcd.
for C19H28N3O2: 330.22 [M + 1]+, found 330.96. [α]1D4 = –37.71 (c
= 0.18, CH2Cl2).
7.36 (m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.9
(CH3), 17.4 (CH3), 28.2 (Boc), 37.0 (CH2-Bn), 44.4 (C) 56.3 (CH2),
68.1 (CH), 79.1 (C-Boc), 84.0 (CH2), 107.4 (C), 126.3 (CH), 127.5
(2ϫCH), 128.1 (2ϫCH), 139.6 (C), 153.7 (C) ppm. EI HRMS:
calcd. for C19H27N3O2: 329.2102, found 329.2396. [α]2D4 = –12.03 (c
= 0.62, CH2Cl2).
tert-Butyl (6S,6aS)-3,3,6,6a-Tetramethyl-3a,4,6,6a-tetrahydropyr-
rolo[3,4-c]pyrazole-5(3H)-carboxylate (6i): Colorless oil, 61% yield.
1
Rf = 0.30 (hexane/EtOAc, 3:1); H NMR (300 MHz, CDCl3): δ =
(S)-N-Allyl-N-[1-(2-tosylhydrazono)propan-2-yl]-4-nitrobenzenesulf-
onamide (9): Aldehyde 8 (0.2 mmol, 1 equiv.) was added to a stirred
slurry of N-tosylhydrazide (1.1 equiv.) in methanol (3 mL). After
2–3 d, the tosylhydrazone precipitated from solution. It was iso-
lated by suction filtration, washed with cold methanol and dried in
vacuo. Orange oil, 79% yield; Rf = = 0.26 (hexane/EtOAc, 2:1); 1H
NMR (300 MHz, CDCl3): δ = 1.24 (d, J = 7.0 Hz, 3 H, CH3), 1.64
(s, 1 H, NH), 2.45 (s, 3 H, CH3), 3.69 (m, 2 H, CH2), 4.64 (m, 1
H, CH), 5.02 (m, 2 H, CH2), 5.56 (m, 1 H, CH), 7.03 (d, J =
3.5 Hz, 1 H, HCN), 7.35–7.79 (m, 4 H, Ts), 7.97–8.31 (m, 4 H,
Ns) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.7 (CH3), 21.6 (CH3),
47.1 (CH2), 56.6 (CH), 119.0 (CH2), 124.4 (2 ϫ CH), 127.9
(2ϫCH), 128.3 (2ϫCH), 129.7 (2ϫCH), 134.0 (CH), 135.0 (C),
136.1 (C), 142.6 (C), 144.9 (C), 148.1 (C) ppm. FAB MS: calcd. for
C13H17N3O2S: 279.10 [M – Ns], found 279.01. [α]2D1 = –20.00 (c =
0.04, MeOH).
1.31 (d, J = 6.7 Hz, 3 H, CH3), 1.36 (s, 3 H, CH3), 1.44 (s, 3 H,
CH3), 1.46 (s, 9 H, Boc), 1.52 (s, 3 H, CH3), 1.90 (dd, J = 6.3,
10.1 Hz, 1 H, CH), 3.17 (dd, J = 6.3, 12.1 Hz, 1 H, CH2), 3.56 (dd,
J = 10.1, 12.1 Hz, 1 H, CH2), 3.92 (q, J = 6.7 Hz, 1 H, CH) ppm.
13C NMR (75 MHz, CDCl3): δ = 15.4 (CH3), 21.7 (CH3), 25.1
(CH3), 28.4 (CH3), 28.4 (Boc), 46.5 (CH2), 49.4 (CH), 62.9 (CH),
79.8 (C-Boc), 90.2 (C), 102.4 (C), 154.1 (C) ppm. EI HRMS: calcd.
for C14H26N3O2: 268.2027 [M + H]+, found 268.2014. [α]2D0
+11.39 (c = 0.36, CH2Cl2).
=
tert-Butyl
(6S,6aS)-6a-Benzyl-3,3,6-trimethyl-3a,4,6,6a-tetra-
hydropyrrolo[3,4-c]pyrazole-5(3H)-carboxylate (6j): Colorless oil,
36% yield; Rf = 0.49 (hexane/EtOAc, 2:1); 1H NMR (300 MHz,
CDCl3): δ = 1.18 (d, J = 6.7 Hz, 3 H, CH3), 1.29 (s, 3 H, CH3),
1.47 (s, 9 H, Boc), 1.61 (s, 3 H, CH3), 1.93 (dd, J = 4.5, 9.2 Hz, 1
H, CH), 2.95 (d, J = 13.8 Hz, 1 H, CH2-Bn), 3.28 (dd, J = 4.5,
12.2 Hz, 1 H, CH2), 3.50 (dd, J = 9.4, 12.2 Hz, 1 H, CH2), 3.67 (d,
J = 13.4 Hz, 1 H, CH2-Bn), 4.11 (q, J = 6.7 Hz, 1 H, CH), 7.23
(m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.8 (CH3),
21.7 (CH3), 27.0 (CH3), 28.4 (Boc), 43.7 (CH2), 45.0 (CH), 46.6
(CH2), 61.5 (CH), 79.9 (C-Boc), 91.0 (C), 106.9 (C), 127.0 (CH),
128.3 (2ϫCH), 130.6 (2ϫCH), 135.9 (C), 154.3 (C) ppm. EI
(3aS,6S,6aS)-6-Methyl-5-[(4-nitrophenyl)sulfonyl]-3,3a,4,5,6,6a-hexa-
hydropyrrolo[3,4-c]pyrazole (10a). Method A: One-Pot Procedure
Starting from Aldehyde 8:[19] A carousel reaction tube was charged
with the corresponding aldehyde (0.3 mmol, 1 equiv.), N-tosylhyd-
razide (1.1 equiv.) and dioxane (3 mL). The system was heated at
70 °C for 2 h. Then, K2CO3 (6 equiv.) was added and the reaction
mixture was allowed to stirring at 70 °C for 24 h. After cooling
to room temperature, the 1,4-dioxane was removed under reduced
pressure. The reaction crude was dissolved in a mixture of EtOAc
and H2O 1:1 and extracted three times with EtOAc and with H2O.
The organic phases were dried with anhydrous Na2SO4, filtered
and concentrated. The crude product was isolated by flash
chromatography on silica gel (a mixture of hexane/EtOAc, 1:2).
HRMS: calcd. for C20H30N3O2: 344.2340 [M
+
H]+, found
344.2338. [α]1D1 = –21.43 (c = 0.14, CH2Cl2).
tert-Butyl (3aR,6S,6aS)-3a,6,6a-Trimethyl-3a,4,6,6a-tetrahydropyr-
rolo[3,4-c]pyrazole-5(3H)-carboxylate (6k): Colorless oil, 65% yield.
1
Rf = 0.27 (hexane/EtOAc, 2:1); H NMR (300 MHz, CDCl3): δ =
1.10 (s, 3 H, CH3), 1.13 (s, 3 H, CH3), 1.47 (s, 9 H, Boc), 1.59 (d,
J = 6.7 Hz, 3 H, CH3), 2.80 (d, J = 11.5 Hz, 1 H, CH2), 3.45 (d, J
= 11.5 Hz, 1 H, CH2), 3.92 (d, J = 17.4 Hz, 1 H, CH2), 4.00 (q, J
= 6.6 Hz, 1 H, CH), 4.70 (d, J = 17.4 Hz, 1 H, CH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 16.6 (CH3), 17.4 (CH3), 28.2 (CH3),
28.4 (Boc), 43.5 (C), 56.9 (CH2), 62.0 (CH), 79.8 (C-Boc), 85.2
(CH2), 99.5 (C), 154.0 (C) ppm. EI MS: calcd. for
C13H22N3O2: 252.17, found 252.19. [α]2D1 = +2.69 (c = 0.78,
CH2Cl2).
Method B: Starting from Tosylhydrazone 9: A carousel reaction
tube was charged with the corresponding N-tosylhydrazone
(0.3 mmol), K2CO3 (6 equiv.) and dioxane (3.5 mL). The system
was heated at 70 °C for 7 h. After cooling to room temperature,
the 1,4-dioxane was removed under reduced pressure. The reaction
crude was dissolved in a mixture of EtOAc and H2O 1:1 and ex-
tracted three times with EtOAc and with H2O. The organic phases
were dried with anhydrous Na2SO4, filtered and concentrated. The
crude product was isolated by flash chromatography on silica gel
(a mixture of hexane/EtOAc, 1:2); yellow oil, 25% yield. Rf = =
tert-Butyl (3aR,6S,6aS)-6-Isobutyl-3a,6a-dimethyl-3a,4,6,6a-tetra-
hydropyrrolo[3,4-c]pyrazole-5(3H)-carboxylate (6l): Colorless oil,
31% yield. Rf = 0.47 (hexane/EtOAc, 2:1); 1H NMR (600 MHz,
CDCl3): δ = 0.64 (s, 3 H, CH3), 0.75 (br. s, 1 H, CH), 0.89 (s, 3 H,
CH3), 1.21 (m, 6 H, 2ϫCH3), 1.56 (s, 9 H, Boc), 1.84 (m, 1 H,
1
0.67 (hexane/EtOAc, 1:1); H NMR (300 MHz, CDCl3): δ = 1.68
CH2), 2.06 (m, 1 H, CH2), 2.49 (s, 1 H, CH2), 2.51 (s, 1 H, CH2), (d, J = 6.7 Hz, 3 H, CH3), 2.45 (m, 1 H, CH), 3.14 (dd, J = 4.4,
3.35 (d, J = 17.4 Hz, 1 H, CH2), 4.18 (d, J = 17.4 Hz, 1 H, CH2), 10.8 Hz, 1 H, CH2), 3.30 (dd, J = 8.1, 10.9 Hz, 1 H, CH2), 3.80 (q,
4.34 (m, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.1 J = 6.8 Hz, 1 H, CH), 4.58 (m, 2 H, CH2), 4.96 (m, 1 H, CH),
(CH) 18.6 (CH3), 22.0 (CH3), 23.6 (CH3), 24.8 (CH3), 28.5 (Boc),
40.6 (CH2), 44.9 (C), 55.8 (CH2), 63.8 (CH), 79.8 (C-Boc), 83.9
8.01–8.42 (m, 4 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.9
(CH3), 31.9 (CH), 54.4 (CH2), 59.5 (CH), 83.5 (CH2), 95.3 (CH),
(CH2), 100.0 (C), 154.1 (C) ppm. EI HRMS: calcd. for 124.5 (2ϫCH), 128.4 (2ϫCH), 142.6 (C), 150.3 (C) ppm. EI
C16H30N3O2: 296.2340 [M + H]+, found 296.2339. [α]2D1 = –3.98 (c
= 1.16, CH2Cl2).
HRMS: calcd. for C12H14N4O4S: 310.0736, found 310.0731. [α]2D8
+12.61 (c = 0.03, CH2Cl2).
=
Eur. J. Org. Chem. 2014, 1672–1683
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1681

R. Barroso, M. Escribano, M.-P. Cabal, C. Valdés
FULL PAPER
Chem. Int. Ed. 2010, 49, 4993–4996; c) H. Li, L. Wang, Y.
Zhang, J. Wang, Angew. Chem. 2012, 124, 2997; Angew. Chem.
Int. Ed. 2012, 51, 2943–2946; d) J. Barluenga, M. Tomás-Gam-
asa, C. Valdés, Angew. Chem. 2012, 124, 6052; Angew. Chem.
Int. Ed. 2012, 51, 5950–5952; e) M. C. Pérez-Aguilar, C. Valdés,
Angew. Chem. 2012, 124, 6055; Angew. Chem. Int. Ed. 2012,
51, 5953–5957.
a) J. Barluenga, M. Escribano, F. Aznar, C. Valdés, Angew.
Chem. 2010, 122, 7008; Angew. Chem. Int. Ed. 2010, 49, 6856–
6859; b) J. Barluenga, N. Quiñones, M.-P. Cabal, F. Aznar, C.
Valdés, Angew. Chem. 2011, 123, 2398; Angew. Chem. Int. Ed.
2011, 50, 2350–2353.
DFT Molecular Modelling Studies: All calculations were performed
with the Gaussian09, Revision B.01 package of programs.[22] Full
geometry optimizations were carried out with the b3lyp density
functional method.[23] Geometry optimizations were performed
employing the standard 6-311++G** basis set for H, C and N.
Harmonic force constants were computed at the optimized geome-
tries employing the same basis set to characterize the stationary
points as minima or saddle points. Zero-point vibrational correc-
tions were determined from the harmonic vibrational frequencies
to convert the total energies Eel to ground-state energies E0 and
Gibbs free energies G. The relative energy values indicated refer to
Gibbs free energies and are denoted in hartee. Computational data,
three-dimensional models and cartesian coordinates for all the sta-
tionary points found are included below. The three-dimensional
models have been obtained with Jmol13.0.12.[24] Energy values,
three dimensional models and Cartesian coordinates are available
in the Supporting Information.
[6]
[7]
[8]
J. Barluenga, N. Quiñones, M. Tomás-Gamasa, M.-P. Cabal,
Eur. J. Org. Chem. 2012, 2312–2317.
a) A. Padwa, 1,3-Dipolar Cycloaddition Chemistry, Wiley, New
York, 1984, vol. 1; b) Y. Nakano, M. Hamaguchi, T. Nagai, J.
Org. Chem. 1989, 54, 1135–114; c) G. Maas, Synthetic Applica-
tions of 1,3-Dipolar Cycloaddition Chemistry toward Heterocy-
cles and Natural Products, Wiley, New York, 2002, p. 539–622.
A. Padwa, H. Ku, J. Org. Chem. 1980, 45, 3756–3766.
a) U. H. Brinker, T. Schrievers, L. Xu, J. Am. Chem. Soc. 1990,
112, 8609–8611; b) P. C. Miller, P. P. Gaspar, J. Org. Chem.
1991, 56, 5101–5107; c) E. C. Ashby, B. Park, G. S. Patil, K.
Gadru, R. Gurumurthy, J. Org. Chem. 1993, 58, 424–437; d)
M. E. Jung, A. Huang, Org. Lett. 2000, 2, 2659–2661.
a) D. F. Taber, P. Guo, J. Org. Chem. 2008, 73, 9479–9481; b)
D. F. Taber, P. Guo, N. Guo, J. Am. Chem. Soc. 2010, 132,
11179–11182.
[9]
[10]
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all the compounds
described. Two-dimensional NOESY experiments for compounds
6b and 6l. HPLC chromatograms for 6f and 6g. Experimental pro-
cedure for the synthesis of aldehyde 8. Computational details, en-
ergy values, three dimensional models and cartesian coordinates.
[11]
[12]
For the synthesis of pyrazoles by 1,3-dipolar cycloadditions of
alkynes and diazo compounds generated from tosylhydrazones,
see: a) V. K. Aggarwal, J. de Vicente, R. V. Bonnert, J. Org.
Chem. 2003, 68, 5381–5383; b) M. C. Pérez-Aguilar, C. Valdés,
Angew. Chem. Int. Ed. 2013, 52, 7219–7223.
Acknowledgments
The authors gratefully acknowledge the Spanish Dirección General
de Investigación (DGI) (grant number CTQ-2010-16790) for finan-
cial support.
[13]
[14]
For a review of dipolar cycloadditions in targeted synthesis see:
V. Nair, T. D. Suja, Tetrahedron 2007, 63, 12247–12275.
a) V. J. Bauer, S. R. Safir, J. Med. Chem. 1971, 14, 1129–1130;
b) G. Broggini, G. Molteni, T. Pilati, G. Zecchi, Synth. Com-
mun. 2001, 31, 3799–3806; c) C. Moustapha, N. A. Abdel-
Riheem, A. O. Abdelhamid, Synth. Commun. 2005, 35, 249–
261; d) J. Shi, G. Xu, W. Zhu, H. Ye, S. Yang, Y. Luo, J. Han,
J. Yang, R. Li, Y. Wei, L. Chen, Bioorg. Med. Chem. Lett. 2010,
20, 4273–4278; e) A. Dos Santos, L. El Kaïm, L. Grimaud, C.
Ronsseray, Eur. J. Org. Chem. 2011, 3117–3121; f) C. Guo, L.
Dong, J. Marakovits, S. Kephart, Tetrahedron Lett. 2011, 52,
1692–1696; g) H. Li, Y. Hong, S. Nukui, J. Lou, S. Johnson, S.
Scales, I. Botrous, E. Tompkins, C. Yin, R. Zhou, M. He, J.
Jensen, D. Bouzida, G. Alton, J. Lafontaine, S. Grant, Bioorg.
Med. Chem. Lett. 2011, 21, 584–587.
[1] For some reviews see: a) J. R. Fulton, V. K. Aggarwal, J.
de Vicente, Eur. J. Org. Chem. 2005, 1479–1492; b) J. Bar-
luenga, C. Valdés, Angew. Chem. 2011, 123, 7626; Angew.
Chem. Int. Ed. 2011, 50, 7486–7500; c) Z. H. Shao, H. B.
Zhang, Chem. Soc. Rev. 2012, 41, 560; d) Q. Xiao, Y. Zhang,
J. Wang, Acc. Chem. Res. 2013, 46, 236.
[2] a) J. Barluenga, P. Moriel, C. Valdés, F. Aznar, Angew. Chem.
2007, 119, 5683; Angew. Chem. Int. Ed. 2007, 46, 5587; b) J.
Barluenga, M. Tomás-Gamasa, P. Moriel, F. Aznar, C. Valdés,
Chem. Eur. J. 2008, 14, 4792–4795; c) J. Barluenga, M. Escrib-
ano, P. Moriel, F. Aznar, C. Valdés, Chem. Eur. J. 2009, 15,
13291–13294; d) Q. Xiao, J. Ma, Y. Yang, Y. Zhang, J. Wang,
Org. Lett. 2009, 11, 4732–4735; e) J. Barluenga, M. Tomás-
Gamasa, F. Aznar, C. Valdés, Adv. Synth. Catal. 2010, 352,
3235–3240; f) J. Barluenga, M. Tomás-Gamasa, F. Aznar, C.
Valdés, Chem. Eur. J. 2010, 16, 12801–1280; g) E. Brachet, A.
Hamze, J.-F. Peyrat, J.-D. Brion, M. Alami, Org. Lett. 2010,
12, 4042–4045; h) J. Barluenga, L. Florentino, F. Aznar, C.
Valdés, Org. Lett. 2011, 13, 510–513; i) X. Zhao, G. Wu, Y.
Zhang, J. Wang, J. Am. Chem. Soc. 2011, 133, 3296–3299; j) L.
Zhou, Y. Shi, Q. Xiao, Y. Liu, F. Ye, Y. Zhang, J. Wang, Org.
Lett. 2011, 13, 968–971; k) F. Ye, X. Ma, Q. Xiao, H. Li, Y.
Zhang, J. Wang, J. Am. Chem. Soc. 2012, 134, 5742–5745.
[3] a) X. Zhao, J. Jing, K. Lu, Y. Zhang, J. Wang, Chem. Commun.
2010, 46, 1724–1726; b) H. Chen, L. Huang, W. Fu, X. Liu,
H. Jiang, Chem. Eur. J. 2012, 18, 10497–10500.
[4] a) L. Zhou, F. Ye, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2010,
132, 13590–13591; b) A. Khanna, C. Maung, K. R. Johnson,
T. T. Luong, D. L. Van Vranken, Org. Lett. 2012, 14, 3233–
3235; c) P.-X. Zhou, J.-Y. Luo, L.-B. Zhao, Y.-Y. Ye, Y.-M.
Liang, Chem. Commun. 2013, 49, 3254–3256.
[5] a) J. Barluenga, M. Tomás-Gamasa, F. Aznar, C. Valdés, Na-
ture Chem. 2009, 1, 494–499; b) J. Barluenga, M. Tomás-Gam-
asa, F. Aznar, C. Valdés, Angew. Chem. 2010, 122, 5113; Angew.
[15]
[16]
S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815–
3818.
L. Moisan, P. Thuéry, M. Nicolas, E. Doris, B. Rousseau, An-
gew. Chem. 2006, 118, 5460; Angew. Chem. Int. Ed. 2006, 45,
5334–5336.
W. R. Bamford, T. S. Stevens, J. Chem. Soc. 1952, 4733–4740.
A. G. Myers, M. Movassaghi, J. Am. Chem. Soc. 1998, 120,
8891–8892.
See Supporting Information for the synthesis of aldehyde 8.
See Supporting Information for computational details.
J.-M. Fehrentz, B. Castro, Synthesis 1983, 676.
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-
erov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari,
A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N.
Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V.
[17]
[18]
[19]
[20]
[21]
[22]
1682
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1672–1683

Diastereoselective Intramolecular 1,3-Dipolar Cycloadditions
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Strat-
mann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski,
G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D.
Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski,
D. J. Fox, Gaussian 09, revision B.01, Gaussian, Inc., Wall-
ingford, CT, 2010.
[23] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) A. D.
Becke, Phys. Rev. A 1988, 38, 3098–3100; c) C. Lee, W. Yang,
R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
[24] http://www.Jmol.org.
[25] D. Perrin, Purification of Laboratory Chemicals, 2nd ed., Perga-
mon Press Ltd., New York, 1980.
Received: October 22, 2013
Published Online: January 10, 2014
Eur. J. Org. Chem. 2014, 1672–1683
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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