Rapid Synthesis of Bicyclic N-Heterocyclic Cores from N-Terminal α,β-Unsaturated Diazoketones

Article abstract of DOI:10.1002/ejoc.201800239

A method for the synthesis of bicyclic N-heterocyclic cores from N-terminal α,β-unsaturated diazoketones has been developed. The transformation involves three sequential steps that include N-deprotection, an intramolecular aza-Michael, and a photochemical Wolff rearrangement as a one-pot protocol. By using this strategy, a series of substituted bicyclic N-heterocycles, particularly, indolizidines and pyrrolizidines, were synthesize in good yields.

Full text of DOI:10.1002/ejoc.201800239

A Journal of
Accepted Article
Title: Rapid synthesis of bicyclic N-heterocyclic cores from N-terminal
α,β-unsaturated diazoketones
Authors: João Victor Santiago and Antonio Carlos Bender Burtoloso
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800239
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10.1002/ejoc.201800239
European Journal of Organic Chemistry
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Rapid synthesis of bicyclic N-heterocyclic cores from N-terminal
α,β-unsaturated diazoketones
João Victor Santiago [a] and Antonio C. B. Burtoloso*[a]
Dedication ((optional))
Considering the importance of N-heterocycles, especially
for the pharmaceutical industry, the development of new synthetic
methodologies to access these cores in different ways and with
different substitution patterns is highly desired. Since 2010, our
research group has been involved with the chemistry of α,β-
unsaturated diazoketones, aiming the direct preparation of O- and
N-heterocycles.[13] For example, the synthesis of the popular
pyrrolidine alkaloid preussin could be accomplished in just three
steps from decanal, employing an unsaturated diazoketone as the
key intermediate.[14] Most of our focus has been directed to the
construction of monocyclic rings, being intermolecular Michael
additions and metal-catalyzed insertion reactions, the main
transformations involved (Scheme 1A).[13b,13c] Considering these
achievements so far, we wondered if by constructing new types
of α,β-unsaturated diazoketones, containing an appropriate N-
terminal chain, the sequential construction of two fused rings
would be feasible (after an intramolecular Michael addition,
followed by cyclization) (Scheme 1B). These N-terminal α,β-
unsaturated diazoketones could be synthesized from different
amino-alcohols by the appropriate protection of the amino group,
oxidation of hydroxyl group to the aldehyde and, finally, by an
Horner-Wadsworth-Emmons olefination in the presence of a
diazophosphonate.
Abstract: The synthesis of bicyclic N-heterocycles cores from N-
terminal α,β-unsaturated diazoketones is described. The
transformation consists in just three sequential steps and involves a
one-pot N-deprotection/intramolecular aza-Michael reaction, followed
by a photochemical Wolff rearrangement. By this strategy, a series of
substituted bicyclic N-heterocycles (especially indolizidines and
pyrrolizidines) were synthesize in good yields.
Introduction
The synthesis of N-heterocycles is a field in organic
synthesis that has been calling attention for many years. The
pursuit in the synthesis of these N-heterocyclic systems has
grown mainly due to the variety of compounds found in nature
containing these cores, as well as the broad biological activities
that they possess (Figure 1).[1-7] Therefore, many contributions for
the isolation and synthesis of different types of N-heterocycles
can be found in the literature, starting with the pioneering work of
Sertüner,[8] Pelletier-Caventou,[9] Parker-Wilkinson[10] and
Woodward[11]. Considering this perspective, the importance of
new methods to synthesize different kinds of N-heterocyclic
systems has been described over the years. Usually, these
methodologies are based on well-established reactions, such as
the Mannich reaction, aza-Michael addition, cycloadditions,
reductive amination and metal-catalyzed reactions.[12]
Figure 1. Examples of N-heterocycles with biological activity.
[a]
João Victor Santiago, Antonio C. B. Burtoloso
Instituto de Química de São Carlos
Universidade de São Paulo
Scheme 1. Synthetic strategy for the construction of bicyclic N-heterocycles.
CEP 13560-970, São Carlos, SP (Brazil)
E-mail: antonio@iqsc.usp.br;
http://burtolosogroup.wixsite.com/iqsc-usp
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201800239
European Journal of Organic Chemistry
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observed. Furthermore, bicyclic 6d (n= 4; seven-membered ring)
was formed only in 15% yield. This is in accordance with the
difficulty in the formation of four and seven membered-rings,
respectively. In the case of the indolizidine 6c (n= 3) and
pyrrolizidine 6b (n= 2), both could be prepared in 57% and 40%
yields, respectively (good overall yields for a reaction with three
transformations).
Results and Discussion
We started the synthesis of the desired α,β-unsaturated
diazoketones by first performing the N-protection and oxidation of
the commercially available amino alcohols 1a-d, containing 3 to 6
carbons in the chain, respectively (Scheme 2). We first decided to
protect the amino group as a trifluoroacetamide (TFA). This is due
to the need of a protecting group that could be easily removed in
basic conditions after the synthesis of the diazoketones
(deprotection in acid conditions would decompose the
diazoketones). Protection of the amino alcohols 1a-d with
trifluoroacetic anhydride (TFAA) proved to be efficient,[15]
furnishing the N-protected amino alcohols 2a-d in 94-96% yield.
Next, the classic Parik-Doering oxidation[16] afforded the N-
protected amino aldehydes 3a-d in 83-91% yield. Once the amino
aldehydes were prepared, we were able to investigate the Horner-
Wadsworth-Emmons olefination (HWE) in the presence of 5a and
NaH as the base, following our previously described protocol.[17]
Unfortunately, these conditions only led to low yields of the
desired N-terminal α,β-unsaturated diazoketones. This problem
was easily circumvented by using the classical condition for HWE
reactions, described by Masamune-Roush, which employs 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as base and Lithium
Chloride (LiCl) as additive.[18] Using these conditions, the N-
terminal α,β-unsaturated diazoketones 4a-d were prepared in 61-
79% yield with the exclusive formation of the E-isomer (Scheme
2).
Scheme 3. Synthesis of bicyclic N-heterocyclic cores from N-terminal α,β-
unsaturated diazoketones
As the best results were achieved for the indolizidine and
pyrrolizidine cores, we next decided to improve the substrate
scope of these heterocycles. First, several substituted N-terminal
α,β-unsaturated diazoketones (9a-h) were synthesized, aiming
the preparation of more complex indolizidines and pyrrolizidines
(Scheme 4).
The N-terminal amino alcohols 8a and 8b were prepared
from the reduction of 5-amino-3,3-dimethyl-5-oxopentanoic acid
7a[21]
and 5-amino-5-oxo-3-phenylpentanoic acid 7b[21]
,
respectively (Scheme 4, Chart A). The N-protected amino
alcohols 8a and 8b were prepared in 53% and 55% yield,
respectively, after the reaction with lithium aluminum hydride
(LiAlH4),[22] followed by amino group protection with trifluoroacetic
anhydride (TFAA), in a single step. N-terminal amino alcohols 8c
and 8d (Scheme 4, Chart C) were synthesized from the
commercially available amino alcohols 1e and 1f. The
Compounds 8c and 8d were obtained in 98% and 90% yield,
following the reduction/protection protocol previously described.
On the other hand, alcohols 8e and 8f were synthesized from the
ethyl 4-nitro-3-phenylbutanoate 10a[23] by the employment of a
divergent strategic synthesis approach (Scheme 4, Chart D). The
amino alcohol 8e was prepared in 35% yield from the reduction
reaction with LiAlH4 and the consecutive protection with TFAA of
the ethyl nitro ester 10a. For the synthesis of the amino alcohol 8f
(Scheme 4, Chart E), we performed an Arndt-Eistert
homologation reaction from the nitro acid 11 to furnish the methyl
5-nitro-4-phenylpentanoate 10b (diazomethane acylation and a
photochemical Wolff rearrangement).[17,20] Applying the same
reduction/protection protocol, we could afford the amino alcohol
8f in 51% yield.
Once the substituted N-protected amino alcohols 8a-f were
prepared, we performed the oxidation of these amino alcohols in
the presence of 2-Iodoxybenzoic acid (IBX) in reflux with ethyl
acetate.[24] Horner-Wadsworth-Emmons olefination using
diazophosphonate 5a and the substituted diazophosphonate 5b,
under the same conditions described in Scheme 2, was carried-
out directly on the clean crude aldehydes. Hence, a series of N-
terminal α,β-unsaturated diazoketones (9a-h) were synthesized
in 31-56% yield after two steps.
Scheme 2. Synthetic route for the synthesis of N-terminal α,β-unsaturated
diazoketones
After the secure synthesis of diazoketones 4a-d, we then
turned our attention to evaluate the key sequential transformation
that would led to the bicyclic N-heterocycles depicted in Scheme
1. For this study, the amino deprotection, the intramolecular aza-
Michael addition and the photochemical Wolff rearrangement
were carried out in a consecutive way, without any work-up or
purification (Scheme 3). For example, exposure of diazoketones
4a-d to an aqueous solution of potassium carbonate in methanol,
over reflux for approximately 45 minutes,[19] led to the one-pot
deprotection/Michael reaction. Then, concentration of the solvent,
addition of acetonitrile and irradiation in the presence of an Osram
150 Xenon lamp,[20] furnished the desired bicyclic N-heterocycles
in 0-57% yields after these three transformations. For the bicyclic
6a (n= 1; four-membered ring) none of the desired product was
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10.1002/ejoc.201800239
European Journal of Organic Chemistry
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Scheme 4. Synthesis of substituted N-terminal α,β-unsaturated diazoketones as key intermediates.
From the new synthesized N-terminal substituted α,β-
unsaturated diazoketones, we applied the same protocol
described for the construction of the simple bicyclic N-heterocyclic
cores, depicted in Scheme 3 above. Hence, a series of substituted
indolizidines and pyrrolizidines (13a-h) could be prepared in 30-
57% overall yield for the three key transformations (Scheme 5).
It is worth mentioning that the bicyclic N-heterocycle derived
from 9f was not achieved by the developed methodology. Despite
the other substrates, the reaction with 9f formed a complex
mixture and the desired indolizidine 13f was not observed. We
suppose that this complex mixture may has been formed by
competition reactions between the sulfur and nitrogen atoms in
the Wolff rearrangement and/or Michael addition.
Due to the presence of a chiral center or a prochiral carbon
on some of these N-terminal substituted α,β-unsaturated
diazoketones, cis or trans diastereoisomers could be formed. The
stereochemical outcome for the reaction with these diazoketones
were evaluated by proton NMR and GC as well as by comparison
with already described data.[25] For the N-heterocycles 13c, 13d
and 13g equal proportion of the cis and trans diastereoisomers
was observed, showing that the substituent in that specific
position did not have some influence in the aza-Michael
cyclization step. On the other hand, the indolizidines 13b and 13h
showed good diastereoselectivity for the formation of a specific
diastereoisomer. Indolizidine 13b has shown diastereoselectivity
in 3:1 ratio for the cis diastereoisomer. On the other hand, the
indolizidine 13h has shown the opposite diastereoselectivity,
favoring the trans diastereoisomer, in a 4:1 ratio. This shows that
by just changing the position of the substituent in the N-terminal
substituted α,β-unsaturated diazoketones is enough to invert the
diastereoselectivity in the aza-Michael cyclization step. The
stereochemical outcome for these two examples can be
explained considering a transition state which the two hindered
groups (phenyl and diazoketone portion) are in the equatorial
position as depict in the Scheme 6.
Scheme 5. Scope of substituted bicyclic N-heterocycles.
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10.1002/ejoc.201800239
European Journal of Organic Chemistry
FULL PAPER
quartets; qd, quartet of doublets; m, multiplet. Carbon nuclear magnetic
resonance (13C NMR) spectra were recorded using a NMR spectrometer
at 101 and 126 MHz. For 13C NMR spectra, chemical shifts (δ) are given
from CDCl3 (77.0 ppm) or CD3OD (49.0 ppm). Photochemical reactions
were carried out using UV light generated by an Osram 150 Xenon lamp
accommodated in an Oriel Model 8500 Universal arc lamp source with
focusing quartz lens, a water-filled infrared filter, and a thermostated cell
holder. Infrared spectra were obtained using FT-IR at 4.0 cm-1 resolution
and are reported in wavenumbers. Melting points were determined using
a digital melting point apparatus and were not corrected. High resolution
mass spectra (HRMS) were recorded using electron spray ionization (ESI)
(Hybrid linear ion trap-orbitrap FT-MS and QqTOF/MS-Microtof-QII
models).
GENERAL PROCEDURES
Protection of commercial amino alcohols as Trifluoroacetamide.[15]
2,2,2-trifluoro-N-(3-hydroxypropyl)acetamide 2a.
Colorless oil; 98% yield (4.45 g, 23.03 mmol); Rf = 0.40 (Hexanes/AcOEt
1:1 run twice); IR νmax = 3300, 3101, 2954, 2891, 1701, 1558, 1148, 1061
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.39 (bs, 1H), 3.80 (dd, J = 5.6, 5.5 Hz,
2H), 3.56-3.50 (m, 2H), 2.35 (bs, 1H), 1.87-1.79 (m, 2H) ppm; 13C NMR
(101 MHz, CDCl3) δ 157.6 (q, J= 36.7, 1C), 115.8 (q, J= 287.5, 1C), 61.1,
38.3, 30.4 ppm; HRMS (ESI-TOF) calcd for C5H8F3NNaO2 [M+Na]
194.0399 found 194.0403.
Scheme 6. Proposed transition states for the diastereoselective achievement
of the indolizidines 13b and 13h.
2,2,2-trifluoro-N-(4-hydroxybutyl)acetamide 2b.
Conclusions
Colorless oil; 95% yield (2.0 g, 10.80 mmol); Rf = 0.44 (Hexanes/AcOEt
1:1 run twice); IR νmax = 3299, 3096, 2944, 2881, 1702, 1561, 1448, 1376,
1149, 1055,cm-1; 1H NMR (500 MHz, CDCl3) δ 7.59 (bs, 1H), 3.71-3.69 (m,
2H), 3.39 (q, J = 6.4 Hz, 2H), 2.61-2.41 (m, 1H), 1.75-1.67 (m, 2H), 1.67-
1.59 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 157.5 (q, J= 36.8, 1C), 115.9
(q, J= 287.5, 1C), 62.1, 39.7, 29.4, 25.6 ppm. HRMS (ESI-Orbitrap) calcd
for C6H10F3NNaO2 [M+Na]+ 208.05558 found 208.05528.
In summary, we have described a new method for the
construction of bicyclic N-heterocycles cores in a single step from
N-terminal
α,β-unsaturated
diazoketones.
The
key
transformations involved a cascade deprotection and Michael
addition, followed by a photochemical Wolff rearrangement. Ten
structurally different bicyclic nitrogen heterocycles, the majority
being indolizidines and pyrrolizidines could be synthesized in a
direct fashion from these diazoketones in 15-57% overall yield.
2,2,2-trifluoro-N-(5-hydroxypentyl)acetamide 2c.
Colorless oil; 96% yield (3.68 g, 18.48 mmol), Rf = 0.41 (Hexanes/AcOEt
1:1 run twice); IR νmax = 3446, 3301, 3096, 2941, 2868, 1701, 1560, 1149,
1054 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.74 (bs, 1H), 3.67 (t, J = 6.3 Hz,
2H), 3.38 (q, J = 6.8 Hz, 2H), 2.33 (s, 1H), 1.71-1.51 (m, 4H), 1.51-1.35
(m, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 157.4 (q, J= 36.8, 1C ), 115.9
(q, J= 287.7 Hz, 1C), 62.4, 39.8, 31.8, 28.5, 22.9 ppm; HRMS (ESI-
Orbitrap) calcd for C7H12F3NNaO2 [M+Na]+ 222.07123 found 222.07103.
Experimental Section
GENERAL INFORMATION
All solvents were dried and distilled prior to use by standard procedures.
Reagents were purchased at the highest commercial quality and used
without further purification, unless otherwise stated. Reactions were
monitored by thin layer chromatography (TLC), carried out on 0.25 mm
silica gel plates using UV light as visualizing agent and potassium
permanganate in aqueous KOH for staining. Column chromatography was
performed using silica gel 60 (particle size 0.063-0.210 mm). Unless stated
otherwise, all the yields refer to isolated products after flash column
chromatography. The solvent mixtures employed in TLC analysis and in
flash column chromatography purifications are reported as volume by
volume and in ratios. Proton nuclear magnetic resonance (1H NMR)
2,2,2-trifluoro-N-(6-hydroxyhexyl)acetamide 2d.
White solid; 98% yield (1.68 g, 7.88 mmol); m.p. 54–56°C;Rf = 0.64
(Hexanes/AcOEt 1:1 run twice); IR νmax = 3446, 3298, 3095, 2937, 2863,
1702, 1562, 1150, 1055 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.53 (bs, 1H),
3.65 (t, J = 6.5 Hz, 2H), 3.37 (q, J = 6.8 Hz, 2H), 1.51-1.66 (m, 4H), 1.49-
1.27 (m, 4H) ppm, [OH absent]; 13C NMR (101 MHz, CDCl3) δ 157.3 (q, J
= 36.7 Hz, 1C), 116.0 (q, J = 287.14 Hz, 1C), 62.6, 39.8, 32.3, 28.8, 26.3,
25.2 ppm. HRMS (ESI-TOF) calcd for C8H14F3NNaO2 [M+Na]+ 236.0869
found 236.0880.
1
spectra were recorded using 400 and 500 MHz equipment. For H NMR
spectra, chemical shifts (δ) are referenced from TMS (0.00 ppm). Coupling
constants (J) are reported in Hz. For multiplicities the following
abbreviations were used: bs, broad singlet; s, singlet; d, doublet; t, triplet;
q, quartet; quint, quintet; dd, doublet of doublets; dt, doublet of triplets; dtd,
doublet of triplet of doublets; ddd, doublet of doublet of doublets; dddd,
doublet of doublet of doublet of doublets; td, triplet of doubles; dddt;
doublet of doublet of doublet of triplets; tt, triplet of triples; tq, triplet of
2,2,2-trifluoro-N-(2-(2-hydroxyethoxy)ethyl)acetamide 8c.
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10.1002/ejoc.201800239
European Journal of Organic Chemistry
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Colorless oil; 98% yield (1.90 g, 9.44 mmol); Rf = 0.47 (Hexanes/AcOEt
1:1 run twice); IR νmax = 3297, 3094, 2938, 2881, 1708, 1561, 1447, 1357,
1130, 1060 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.54 (bs, 1H), 3.79-3.74 (m,
2H), 3.66- 3.62 (m, 2H), 3.62- 3.59 (m, 2H), 3.57 (q, J = 5.1 Hz, 2H), 2.71
(s, 1H) ppm; 13C NMR (126 MHz, CDCl3) δ 157.5 (q, J = 37.1 Hz, 1C),
115.9 (q, J = 287.5 Hz, 1C), 72.2, 68.8, 61.6, 39.8 ppm.
7.26-7.21 (m, 1H), 7.20-7.15 (m, 2H), 6.44 (bs, 1H), 3.56 (ddd, J = 10.6,
6.2, 5.4 Hz, 1H), 3.48-3.41 (m, 1H), 3.37-3.26 (m, 1H), 3.22-3.09 (m, 1H),
2.80 (tt, J = 10.0, 5.1 Hz, 1H), 2.05-1.89 (m, 2H), 1.88-1.79 (m, 2H), 1.69
(bs, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ 157.1 (q, J = 36.6 Hz, 1C),
143.3, 128.9, 127.4, 126.9, 115.7 (q, J = 287.8 Hz, 1C), 60.4, 40.2, 39.1,
38.6, 35.4 ppm; HRMS (ESI-Orbitrap) calcd for C13H17F3NO2 [M+H]+
276.12059 found 276.11876.
2,2,2-trifluoro-N-(2-((2-hydroxyethyl)thio)ethyl)acetamide 8d.
Colorless oil; 90% yield (1.60 g, 7.37 mmol); Rf = 0.21 (Hexanes/AcOEt
1:1); IR νmax = 3304, 3095, 2927, 2884, 1703, 1557, 1148, 1044 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.34 (bs, 1H), 3.87-3.73 (m, 2H), 3.58 (q, J = 6.1
Hz, 2H), 2.84-2.68 (m, 4H), 2.44 (s, 1H) ppm; 13C NMR (101 MHz, CDCl3)
δ 157.5 (q, J = 37.2 Hz), 115.8 (q, J = 287.6 Hz), 61.3, 39.2, 34.9, 31.1
ppm. HRMS (ESI-Orbitrap) calcd for C6H10F3KNO2S [M+K]+ 256.00159
found 256.02212
Synthesis of N-terminal amino alcohols 8e and 8f from the nitro
esters 10a[23] and 10b.
The synthesis of the N-terminal amino alcohols 8e and 8f was conducted
according to the experimental procedure previously described for N-
protected amino alcohols 8a and 8b.
2,2,2-trifluoro-N-(4-hydroxy-2-phenylbutyl)acetamide 8e.
Colorless oil; 35% yield (500.0 mg, 1.91 mmol); Rf = 0.16 (Hexanes/AcOEt
1:1); IR νmax = 3304, 3068, 3029, 2937, 2883, 1708, 1454, 1375, 1156,
1002 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.30-7.24 (m,
1H), 7.21-7.15 (m, 2H), 6.89 (bs, 1H), 3.75-3.61 (m, 2H), 3.52 (ddd, J =
13.4, 8.1, 5.4 Hz, 1H), 3.45 (ddd, J = 13.5, 8.0, 5.5 Hz, 1H), 3.06-2.99 (m,
1H), 2.03 (bs, 1H), 2.00-1.85 (m, 2H) ppm; 13C NMR (126 MHz, CDCl3) δ
157.3 (q, J = 36.9 Hz, 1C), 141.2, 129.0, 127.5, 127.4, 115.8 (q, J = 287.7
Hz, 1C), 60.3, 45.2, 42.1, 36.1 ppm; HRMS (ESI-Orbitrap) calcd for
C12H14F3NNaO2 [M+Na]+ 284.08688 found 284.08610.
General procedure for the synthesis of N-terminal amino alcohols 8a
and 8b.[21]
In a previously flamed 125 mL two-neck round-bottom flask with a
connected condenser were added 1.43 g (37.69 mmol, 3.0 equiv.) of
LiAlH4 and 83.8 mL of anhydrous THF. The system was cooled to -10 ºC
with a NaCl/ice bath, then 2.0 g (12.56 mmol, 1.0 equiv.) of 5-amino-3,3-
dimethyl-5-oxopentanoic acid 7a was added in portions (CAUTION: Gas
extrusion). After the addition, the reaction was allowed to stir at room
temperature for 15 min, then allowed to reflux for 16 hours. After this period,
the reaction was cooled with an ice bath and quenched with cold water.
The solution was filtered and the aqueous phase was extracted with Ethyl
Ether (10 x 20.0 mL), followed by another extraction with AcOEt (5 x 20.0
mL). The organic phase was dried over Na2SO4, filtered and concentrated.
To a 50.0 mL round-bottom flask with the crude reaction mixture of the first
step was added 10.5 mL of anhydrous methanol and the system was
cooled to -10 °C with a NaCl/ice bath. Then 4.2 mL of Et3N (30.2 mmol,
2.4 equiv.) and 4.5 mL of TFAA (31.4 mmol, 2.5 equiv.) were added and
the reaction was allowed to stir at room temperature for 16 hours. After this
period the reaction was concentrated and the crude reaction mixture was
purified by flash column chromatography (Silica Gel, Hexanes/AcOEt
7:3→1:1) to afford the N-terminal amino alcohol 8a in 53% yield (1.52 g,
6.70 mmol) as a colorless oil.
2,2,2-trifluoro-N-(5-hydroxy-2-phenylpentyl)acetamide 8f.
Colorless oil; 51% yield (205.0 mg, 0.74 mmol); Rf = 0.37 (Hexanes/AcOEt
1:1 run twice); IR νmax = 3310, 3087, 3031, 2940, 2884, 1707, 1554, 1454,
1209, 1156 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.39-7.32 (m, 2H), 7.30-
7.25 (m, 1H), 7.19-7.15 (m, 2H), 6.19 (bs, 1H), 3.83-3.73 (m, 1H), 3.60 (t,
J = 6.4 Hz, 2H), 3.34 (ddd, J = 13.9, 9.2, 5.1 Hz, 1H), 2.85 (tt, J = 9.3, 5.4
Hz, 1H), 1.85-1.77 (m, 1H), 1.76-1.66 (m, 1H), 1.56 -1.40 (m, 2H), 1.34 (bs,
1 H) ppm; 13C NMR (126 MHz, CDCl3) δ 157.1 (q, J = 36.9 Hz, 1C), 141.1,
129.1, 127.6, 127.4, 115.7 (q, J = 287.9 Hz, 1C), 62.5, 45.3, 45.0, 30.1,
29.5 ppm; HRMS (ESI-TOF) calcd for C13H16F3NNaO2 [M+Na]+ 298.1025
found 298.1026.
Synthesis of N-terminal amino aldehydes 3a-d by Parikh-Doering
oxidaditon. [16]
2,2,2-trifluoro-N-(5-hydroxy-3,3-dimethylpentyl)acetamide 8a.
Colorless oil; 53% yield (1.52 g, 6.70 mmol); Rf = 0.46 (Hexanes/AcOEt
1:1 run twice); IR νmax = 3447, 3301, 3099, 2960, 2876, 1702, 1560, 1149
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.33 (bs, 1H), 3.76 (t, J = 6.8 Hz, 2H),
3.48-3.28 (m, 2H), 2.36 (s, 1H), 1.62-1.52 (m, 4H), 0.96 (s, 6H) ppm; 13C
NMR (101 MHz, CDCl3) δ 157.3 (q, J= 36.8, 1C), 115.8 (q, J= 288.4, 1C),
59.4, 43.0, 39.8, 36.4, 31.9, 27.7 ppm; HRMS (ESI-Orbitrap) calcd for
C9H17F3NO2 [M+H]+ 228.12059 found 228.11937.
2,2,2-trifluoro-N-(3-oxopropyl)acetamide 3a.
White Solid; 30% yield (583.0 mg, 3.45 mmol); m.p. 82-86 °C; Rf = 0.46
(Silica gel, Hexanes/AcOEt 1:1); IR νmax = 2934, 2864, 1703, 1559, 1448,
1154 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.03 (bs, 1H), 3.65
(q, J = 5.9 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H) ppm; 13C NMR (126 MHz,
CDCl3) δ 200.6, 157.3 (q, J = 37.2 Hz), 115.7 (q, J = 287.5 Hz), 42.6, 33.3
ppm; HRMS (ESI-TOF) calcd for C5H7F3NO2 [M+H]+ 170.0423 found
170.0427.
2,2,2-trifluoro-N-(5-hydroxy-3-phenylpentyl)acetamide 8b.
Colorless oil; 55% yield (366.0 mg, 1.33 mmol); Rf = 0.45 (Hexanes/AcOEt
2,2,2-trifluoro-N-(4-oxobutyl)acetamide 3b.
1:1 run twice); IR νmax = 3333, 3083, 3060, 2927, 2866, 1568, 1493, 1432,
Colorless oil; 70% yield (1.40 g, 7.56 mmol); Rf = 0.43 (Silica gel,
Hexanes/AcOEt 1:1); IR νmax = 3106, 2954, 2897, 2844, 1705,1557, 1449,
1
1319, 1049, 1028 cm-1; H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 2H),
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10.1002/ejoc.201800239
European Journal of Organic Chemistry
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1139 cm-1;1H NMR (500 MHz, CDCl3) δ 9.80 (s, 1H), 7.20 (bs, 1H), 3.39
(q, 6.6 Hz, 2H), 2.60 (t, J = 6.8 Hz, 2H), 1.95-1.85 (m, 2H) ppm; 13C NMR
(126 MHz, CDCl3) δ 201.7, 157.5 (q, J= 36.7 Hz, 1C), 115.8 (q, J= 287.5
Hz, 1C), 41.2, 39.3, 21.0 ppm; HRMS (ESI-Orbitrap) calcd for
C6H8F3NNaO2 [M+Na]+ 206.03993 found 206.03979.
Yellow solid; 79% yield (21.0 mg, 0.08 mmol); m.p. 64-67 ºC; Rf = 0.31
(Silica gel, Hexanes/AcOEt 1:1); IR νmax = 3089, 2937, 2864, 2101, 1707,
1652, 1598, 1558, 1362, 1143 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.78 (dt,
J = 15.4, 7.0 Hz, 1H), 6.51 (bs, 1H), 6.00 (d, J = 15.5 Hz, 1H), 5.31 (s, 1H),
3.38 (q, J = 6.7 Hz, 2H), 2.25 (qd, J = 7.1, 1.6 Hz, 2H), 1.69-1.58 (m, 2H),
1.59-1.47 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ 184.5, 157.3 (q, J =
36.9 Hz), 143.8 , 127.8, 115.8 (q, J = 287.8 Hz), 55.4, 39.6, 31.5, 28.5,
25.2 ppm; HRMS (ESI-Orbitrap) calcd for C10H13F3N3O2 [M+H]+ 264.09544
found 264.09521.
2,2,2-trifluoro-N-(5-oxopentyl)acetamide 3c.
Colorless oil; 91 % yield (1.93 g, 9.13 mmol); Rf = 0.43 (Silica gel,
Hexanes/AcOEt 1:1); IR νmax = 3096, 2941, 2868, 1701, 1560, 1148, 1054
cm-1. 1H NMR (500 MHz, CDCl3) δ 9.79 (t, J = 1.2 Hz, 1H), 6.83 (bs, 1H),
3.38 (q, J = 6.4 Hz, 2H), 2.54 (td, J = 6.7, 1.1 Hz, 2H), 1.72-1.59 (m, 4H)
ppm; 13C NMR (126 MHz, CDCl3) δ 202.0, 157.4 (q, J = 37.0 Hz, 1C),
115.8 (q, J = 287.7 Hz, 1C), 43.1, 39.4, 28.2, 18.7 ppm; HRMS (ESI-
Orbitrap) calcd for C7H10F3NNaO2 [M+Na]+ 220.05558 found 220.05525.
(E)-N-(9-diazo-8-oxonon-6-en-1-yl)-trifluoroacetamide 4d.
Orange semisolid; 71% yield (92.51 mg, 0.33 mmol); Rf = 0.37 (Silica gel,
Hexanes/AcOEt 1:1); IR νmax = 3093, 2935, 2862, 2102, 1706, 1652, 1598,
1558, 1365, 1149 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.79 (dt, J = 15.4, 7.0
Hz, 1H), 6.54 (bs, 1H), 5.99 (d, J = 15.5 Hz, 1H), 5.31 (s, 1H), 3.36 (q, J =
6.8 Hz, 2H), 2.22 (qd, J = 7.2, 1.5 Hz, 2H), 1.60 (quint, J = 7.5 Hz, 2H),
1.51 (quint, J = 7.5 Hz, 2H), 1.42-1.32 (m, 2H) ppm; 13C NMR (126 MHz,
CDCl3) δ 184.7, 157.2 (q, J = 36.8 Hz, 1C), 144.5, 127.6, 115.8 (q, J =
287.8 Hz, 1C), 55.2, 39.8, 31.9, 28.7, 27.6, 26.1 ppm; HRMS (ESI-TOF)
calcd for C11H14F3N3NaO2 [M+Na]+ 300.0930 found 300.0944.
2,2,2-trifluoro-N-(6-oxohexyl)acetamide 3d.
White solid; 83% yield (890.0 mg, 4.21 mmol); m.p. 99-104 ºC; Rf = 0.51
(Silica gel, Hexanes/AcOEt 1:1); IR νmax = 3115, 2923, 2861, 1697, 1563,
1348, 1177, 1150 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.77 (t, J = 1.5 Hz,
1H), 6.60 (bs, 1H), 3.38 (q, J = 6.8 Hz, 2H), 2.48 (td, J = 7.2, 1.5 Hz, 2H),
1.71-1.58 (m, 4H), 1.43-1.34 (m, 2H) ppm; 13C NMR (126 MHz, CDCl3) δ
202.3; 157.3 (q, J = 36.5 Hz, 1C); 115.8 (q, J = 288.5 Hz, 1C); 43.5; 39.6;
28.6; 26.0; 21.3 ppm; HRMS (ESI-TOF) calcd for C8H12F3NNaO2 [M+Na]+
234.0712 found 234.0724
General procedure for the synthesis of N-terminal α,β-unsaturated
diazoketones in 2 steps from N-terminal amino alcohols
In previously flamed 10 mL two-neck round-bottom flask with a connected
condenser were added 100.0 mg (0.44 mmol, 1.0 equiv.) of 2,2,2-trifluoro-
N-(5-hydroxy-3,3-dimethylpentyl)acetamide 8a and 4.5 mL of anhydrous
ethyl acetate. Then 370.0 mg of 2-Iodoxybenzoic acid (1.64 mmol, 3.0
equiv.) was added in portions and the reaction was allowed to stir over
reflux for 5 hours. After this period, the reaction solution was cooled to
room temperature, filtered with celite pad and concentrated. To a 25.0 mL
round-bottom flask with the crude reaction mixture of the first step was
added 6.40 mL of acetonitrile and 24.5 mg (0.58 mmol, 1.30 equiv.) of
dried LiCl. The reaction was cooled to 0 °C and the solution of
diazophosphonate 5a in acetonitrile (127.1 mg, 0.6 M, 1.3 equiv.) was
added dropwise. Then 54.1 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene
(0.36 mmol, 0.8 equiv.) was added and the reaction was allowed to stir for
2 hours. After this period the reaction was concentrated and the crude
reaction mixture was purified by flash column chromatography (Silica Gel,
Hexanes/AcOEt 7:3→1:1) to afford the N-terminal α,β-unsaturated
diazoketone 9a in 31% yield (40.0 mg, 0.14 mmol) as a viscous yellow oil.
General procedure for the Horner-Wadsworth-Emmons (H.W.E.)
olefination.
The Horner-Wadsworth-Emmnos Olefinations were conducted according
to the procedure described by Masamune-Roush.[18]
(E)-N-(6-diazo-5-oxohex-3-en-1-yl)-trifluoroacetamide 4a.
Yellow solid; 70% yield (97.0 mg, 0.41 mmol); m.p. 88-90 ºC; Rf = 0.29
(Silica gel, Hexanes/AcOEt 7:3); IR νmax = 3087, 2105, 1709, 1656, 1594,
1
1561, 1365, 1149 cm-1; H NMR (400 MHz, CDCl3) δ 6.87 (bs, 1H), 6.74
(dt, J = 15.4, 7.1 Hz, 1H), 6.06 (d, J = 15.5 Hz, 1H), 5.34 (s, 1H), 3.52 (q,
J = 6.5 Hz, 2H), 2.52 (qd, J = 6.8, 1.5 Hz, 2H) ppm; 13C NMR (126 MHz,
CDCl3) δ 184.3, 157.5 (q, J = 37.1 Hz, 1C), 139.8, 129.5, 115.7 (q, J =
287.4 Hz, 1C), 55.9, 38.4, 31.4 ppm; HRMS (ESI-TOF) calcd for
C8H8F3N3NaO2 [M+Na]+ 258.0461 found 258.0454.
(E)-N-(7-diazo-6-oxohept-4-en-1-yl)-trifluoroacetamide 4b.
Yellow solid; 61% yield (82.0 mg, 0.33 mmol); m.p. 61-63 ºC; Rf = 0.35
(Silica gel, Hexanes/AcOEt 1:1); IR νmax = 2940, 2852, 2101, 1706, 1653,
(E)-N-(8-diazo-3,3-dimethyl-7-oxooct-5-en-1-yl)-trifluoroacetamide 9a.
Viscous yellow oil; 31% yield (40.0 mg, 0.14 mmol); Rf = 0.39 (Silica gel,
Hexanes/AcOEt 1:1); IR νmax = 2959, 2917, 2873, 2851, 2103, 1708, 1652,
1601, 1557, 1155 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.82 (dt, J = 15.4, 7.7
Hz, 1H), 6.57 (bs, 1H), 6.02 (d, J = 15.3 Hz, 1H), 5.35 (s, 1H), 3.51-3.24
(m, 2H), 2.14 (dd, J = 7.8, 1.3 Hz, 2H), 1.55 -1.47 (m, 2H), 0.98 (s, 6H)
ppm; 13C NMR (101 MHz, CDCl3) δ 184.4 , 157.1 (q, J = 36.9 Hz, 1C),
141.0, 130.0, 115.7 (q, J = 287.5 Hz, 1C), 55.6, 44.6, 40.3, 36.1, 33.4, 27.0
ppm. HRMS (ESI-Orbitrap) calcd for C12H17F3N3O2 [M+H]+ 292.12674
found 292.12485.
1
1596, 1558, 1361, 1143 cm-1; H NMR (400 MHz, CDCl3) δ 6.78 (dt, J =
15.4, 6.9 Hz, 1H), 6.59 (bs, 1H), 6.03 (d, J = 15.4 Hz, 1H), 5.31 (s, 1H),
3.40 (q, J = 6.8 Hz, 2H), 2.31-2.23 (m, 2H), 1.78 (quint, J = 7.3 Hz, 2H)
ppm; 13C NMR (101 MHz, CDCl3) δ 184.6, 157.4 (q, J = 36.8 Hz), 143.0,
128.0, 115.8 (q, J = 287.8 Hz), 55.6, 39.3, 29.2, 27.4 ppm; HRMS (ESI-
Orbitrap) calcd for C9H10F3N3NaO2 [M+Na]+ 272.06173 found 272.06161.
(E)-N-(8-diazo-7-oxooct-5-en-1-yl)-trifluoroacetamide 4c.
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10.1002/ejoc.201800239
European Journal of Organic Chemistry
FULL PAPER
Hz, 1H), 6.19 (bs, 1H), 5.90 (d, J = 15.5 Hz, 1H), 5.26 (s, 1H), 3.83-3.71
(m, 1H), 3.34 (ddd, J = 13.8, 9.2, 5.0 Hz, 1H), 2.84 (tt, J = 9.5, 5.5 Hz, 1H),
2.25-2.06 (m, 2H), 1.92-1.71 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ
184.4, 157.1 (q, J = 37.1 Hz, 1C), 143.6, 140.3, 129.2, 128.9, 127.6, 127.6,
115.7 (q, J = 287.8 Hz, 1C), 55.3, 45.1, 44.7, 31.6, 29.7 ppm; HRMS (ESI-
TOF) calcd for C16H16F3N3NaO2 [M+Na]+ 362.1087 found 362.1085.
(E)-N-(8-diazo-7-oxo-3-phenyloct-5-en-1-yl)-trifluoroacetamide 9b.
Viscous yellow oil; 56% yield (62.0 mg, 0.18 mmol); Rf = 0.41 (Silica gel,
Hexanes/AcOEt 1:1); IR νmax = 3064, 2928, 2104, 1709, 1557, 1364, 1150
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m, 2H), 7.27-7.22 (m, 1H),
7.17-7.12 (m, 2H), 6.62 (dt, J = 15.4, 7.7 Hz, 1H), 6.30 (bs, 1H), 5.92 (d, J
= 15.4 Hz, 1H), 5.23 (s, 1H), 3.29 (dq, J = 13.8, 7.0 Hz, 1H), 3.21-3.09 (m,
1H), 2.80-2.71 (m, 1H), 2.55-2.41 (m, 2H), 2.06-1.96 (m, 1H), 1.93-1.81
(m, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ 184.3, 157.0 (q, J = 36.9 Hz),
142.4, 141.8, 129.0, 128.8, 127.2, 127.2, 115.7 (q, J = 287.4 Hz), 55.4,
43.4, 39.5, 38.5, 34.8 ppm; HRMS (ESI-Orbitrap) calcd for C16H17F3N3O2
[M+H]+ 340.12674 found 340.12453.
General procedure for Horner-Wadsworth-Emmons Olefination
(H.W.E.) with diethyl (4-diazo-3-oxobutan-2-yl) phosphonate 5b.
The N-terminal diazoketones 9c and 9d were prepared following the
methodology previously described for the synthesis of N-terminal
diazoketones in 2 steps from N-terminal amino alcohols, with the
diazophosphonate 5b.
(E)-N-(2-((5-diazo-4-oxopent-2-en-1-yl)oxy)ethyl)-trifluoroacetamide
9e.
Viscous yellow oil; 45% yield (50.0 mg, 0.22 mmol); Rf = 0.37 (Silica gel,
Hexanes/AcOEt 1:1); IR νmax = 2942, 2876, 2107, 1714, 1658, 1602, 1558,
1363, 1178, 1151 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.80 (dt, J = 15.6, 4.4
Hz, 1H + bs, 1H, N-H), 6.19 (d, J = 15.6 Hz, 1H), 5.35 (s, 1H), 4.19 (dd, J
(E)-N-(7-diazo-5-methyl-6-oxohept-4-en-1-yl)-trifluoroacetamide 9c.
Yellow solid; 40% yield (87.0 mg, 0.33 mmol ); m.p. 66-69 ºC; Rf = 0.32
(Silica gel, Hexanes/AcOEt 7:3); IR νmax = 2933, 2103, 1709, 1647, 1594,
1
1556, 1344, 1147 cm-1; H NMR (500 MHz, CDCl3) δ 6.57 (bs, 1H), 6.27
3
= 4.4, 2.0 Hz, 2H), 3.68-3.54 (m, 4H) ppm; C NMR (101 MHz, CDCl3) δ
(tq, J = 7.3, 1.4 Hz, 1H), 5.56 (s, 1H), 3.40 (q, J = 6.8 Hz, 2H), 2.29-2.22
(m, 2H), 1.84-1.82 (m, 3H), 1.76 (quint, J = 7.4 Hz, 2H) ppm; 13C NMR
(126 MHz, CDCl3) δ 188.3, 157.3 (q, J = 37.1 Hz), 136.3, 135.7, 115.8 (q,
J = 287.9 Hz), 53.3, 39.5, 28.0, 25.6, 12.2 ppm; HRMS (ESI-TOF) calcd
for C10H12F3N3NaO2 [M+Na]+ 286.0774 found 286.0779.
183.9, 157.3 (q, J = 37.1 Hz), 139.1, 126.9, 115.8 (q, J = 287.7 Hz), 69.8,
68.4, 56.0, 39.6 ppm; HRMS (ESI-TOF) calcd for C9H10F3N3NaO3 [M+Na]+
288.0567 found 288.0577.
(E)-N-(2-((5-diazo-4-oxopent-2-en-1-yl)thio)ethyl) trifluoroacetamide
9f.
(E)-N-(8-diazo-6-methyl-7-oxooct-5-en-1-yl)-trifluoroacetamide 9d.
Yellow solid; 35% yield (50.0 mg, 0.18 mmol); m.p. 47-50 ºC; Rf = 0.27
(Silica gel, Hexanes/AcOEt 7:3); IR νmax = 2953, 2852, 2104, 1709, 1596,
1557, 1368, 1342, 1152 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.44 (bs, 1H),
6.26 (tq, J = 7.3, 1.4 Hz, 1H), 5.55 (s, 1H), 3.39 (q, J = 6.8 Hz, 2H), 2.28-
2.20 (m, 2H), 1.83 (d, J = 1.2 Hz, 3H), 1.68-1.58 (m, 2H), 1.56-1.44 (m,
2H) ppm; 13C NMR (101 MHz, CDCl3) δ 188.5, 157.3 (q, J = 36.8 Hz),
136.9, 135.9, 115.8 (q, J = 288.0 Hz), 53.1, 39.7, 28.7, 28.0, 25.7, 12.2
ppm. HRMS (ESI-TOF) calcd for C11H14F3N3NaO2 [M+Na]+ 300.0930
found 300.0943.
Yellow solid; 30% yield (150.0 mg, 0.53 mmol); m.p. 56-59 ºC; Rf = 0.35
(Silica gel, Hexanes/AcOEt 1:1); IR νmax = 2955, 2924, 2854, 2105, 1706,
1555, 1365, 1149 cm-1;.1H NMR (400 MHz, CDCl3) δ 6.87 (bs, 1H), 6.72
(dt, J = 15.1, 7.4 Hz, 1H), 6.08 (d, J = 15.3 Hz, 1H), 5.39 (s, 1H), 3.53 (q,
J = 6.5 Hz, 2H), 3.27 (d, J = 7.3 Hz, 2H), 2.66 (t, J = 6.7 Hz, 2H) ppm; 13
C
NMR (101 MHz, CDCl3) δ 183.8, 157.3 (q, J = 37.2 Hz), 138.3, 129.2,
115.7 (q, J = 287.7 Hz), 56.0, 38.6, 32.4, 29.7 ppm. HRMS (ESI-Orbitrap)
calcd for C9H10F3N3NaO2S [M+Na] 304.03380 found 304.03292.
(E)-N-(7-diazo-6-oxo-2-phenylhept-4-en-1-yl)-trifluoroacetamide 9g.
Yellow solid; 52% yield (64.0 mg, 0.20 mmol); m.p. 75-78 ºC; Rf = 0.32
(Silica gel, Hexanes/AcOEt 1:1); IR νmax = 3089, 3031, 2954, 2923, 2850,
2102, 1709, 1653, 1362, 1144 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.40-
7.32 (m, 2H), 7.33-7.25 (m, 1H), 7.19-7.13 (m, 2H), 6.64 (dt, J = 15.5, 7.2
Hz, 1H), 6.26 (bs, 1H), 5.98 (d, J = 15.4 Hz, 1H), 5.24 (s, 1H), 3.83-3.73
(m, 1H), 3.39 (ddd, J = 13.7, 8.9, 5.2 Hz, 1H), 3.08-2.99 (m, 1H), 2.60-2.54
(m, 2H) ppm; 13C NMR (126 MHz, CDCl3) δ 184.1, 157.2 (q, J = 37.2 Hz),
140.8, 139.8, 129.4, 129.2, 127.7, 127.4, 115.7 (q, J = 288.5 Hz), 55.5,
44.7, 44.3, 36.0 ppm; HRMS (ESI-TOF) calcd for C15H14F3N3NaO2
[M+Na]+ 348.0930 found 348.0944.
General procedure for the syntheses of N-heterocycles cores.[20]
To a 10 mL round-bottom flask equipped with a magnetic stir-bar flask
were added 20.0 mg of N-terminal α,β-unsaturated diazoketone 4c (0.075
mmol, 1.0 equiv.) and 1.5 mL of methanol. Then 0.32 mL of K2CO3 5%
aqueous solution (0.11 mmol, 1.5 equiv.) was added and the reaction was
allowed to stir over reflux for 45 minutes. After this period, the reaction
solution was cooled to room temperature and concentrated. In a quartz cell
of 1 cm light path, containing a magnetic stirrer and fitted with a rubber
septum, were added the crude reaction mixture of the first step and
anhydrous acetonitrile (2.5 mL, 0.025 M) under argon atmosphere. The
reaction mixture was irradiated with an Osram 150 xenon arc lamp and
allowed to stir at room temperature for 4 hours. The solvent was then
removed under reduced pressure in a rotatory evaporator and the crude
product was purified by flash chromatography with a short pad of silica
(CHCl3 as the eluent) to furnish the hexahydroindolizin-3(2H)-one 6c in
57% yield as a yellowish oil.
(E)-N-(8-diazo-7-oxo-2-phenyloct-5-en-1-yl)-trifluoroacetamide 9h.
Viscous yellow oil; 32% yield (47.0 mg, 0.14 mmol); Rf = 0.43 (Silica gel,
Hexanes/AcOEt 1:1); IR νmax = 3089, 3065, 3031, 2951, 2856, 2104, 1713,
1653, 1365, 1266, 1207, 1152 cm-1;1H NMR (400 MHz, CDCl3) δ 7.41-
7.32 (m, 2H), 7.32-7.27 (m, 1H), 7.19-7.12 (m, 2H), 6.72 (dt, J = 15.4, 6.9
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10.1002/ejoc.201800239
European Journal of Organic Chemistry
FULL PAPER
[diastereoisomer mixture] δ 3.97 (dt, J = 9.7, 6.4 Hz, 1H), 3.59-3.46 (m,
3H), 3.11 -3.00 (m, 2H), 2.90 (ddt, J = 16.4, 8.0, 1.2 Hz, 1H), 2.62-2.48 (m,
2H), 2.40 (ddt, J = 16.1, 11.2, 1.3 Hz, 1H), 2.19-1.98 (m, 6H), 1.76-1.65
(m, 2H), 1.60-1.50 (m, 1H), 1.42-1.36 (m, 1H), 1.16 (d, J = 6.6 Hz, 3H),
0.98 (d, J = 7.1 Hz, 3H) ppm; 13C NMR (126 MHz, CDCl3) [diastereoisomer
mixture] δ 174.3, 174.3, 69.0, 65.1, 43.9, 43.1, 41.4, 41.2, 38.0, 30.8, 29.6,
27.0, 26.9, 25.1, 18.0, 16.0 ppm.
Tetrahydro-1H-pyrrolizin-3(2H)-one 6b.
Yellowish oil; 40% yield (4.0 mg, 0.032 mmol); Rf = 0.33 (Silica gel,
AcOEt/Methanol 9:1); IR νmax = 2962, 2925, 2881, 1664, 1421, 1308, 1204
cm-1; 1H NMR (400 MHz, CDCl3) δ 3.95-3.83 (m, 1H), 3.61-3.50 (m, 1H),
3.10- 3.01 (m, 1H), 2.74 (dddt, J = 16.6, 11.4, 9.1, 1.3 Hz, 1H), 2.44 (ddd,
J = 16.6, 9.5, 2.0 Hz, 1H), 2.30 (dddd, J = 12.7, 8.9, 6.8, 2.0 Hz, 1H), 2.17-
1.95 (m, 3H), 1.73 (dddd, J = 12.7, 11.1, 9.4, 7.7 Hz, 1H), 1.41-1.24 (m,
1H) ppm; 13C NMR (101 MHz, CDCl3) δ 174.8, 62.1, 41.0, 35.4, 32.2, 27.2,
27.0 ppm.
1-methylhexahydroindolizin-3(2H)-one 13d.
Yellowish oil; 56% yield (6.0 mg, 0.039 mmol) [diastereoisomers mixture
cis:trans (1:1)]; Rf = 0.45 (Silica gel, AcOEt/Methanol 9:1); IR νmax = 2924,
2853, 1670, 1454, 1377, 1200, 1126 cm-1; 1H NMR (500 MHz, CDCl3)
[diastereoisomer mixture] δ 4.15-4.06 (m, 2H), 3.44-3.37 (m, 1H), 2.90
(ddd, J = 10.9, 7.0, 3.5 Hz, 1H), 2.68-2.44 (m, 5H), 2.06-1.85 (m, 6H), 1.74-
1.57 (m, 3H), 1.47-1.19 (m, 6H), 1.12 (d, J = 6.5 Hz, 3H), 1.01 (d, J = 6.9
Hz, 3H) ppm; 13C NMR (126 MHz, CDCl3) [diastereoisomer mixture] δ
173.5, 173.3, 64.2, 60.7, 40.6, 40.1, 39.1, 38.7, 34.6, 31.8, 28.9, 26.6, 24.6,
24.3, 23.9, 23.6, 18.2, 15.1 ppm.
Hexahydroindolizin-3(2H)-one 6c.
Yellowish oil; 57% yield (6.0 mg, 0.043 mmol); Rf = 0.35 (Silica gel,
AcOEt/Methanol 9:1); IR νmax = 2925, 2854, 1657, 1445, 1423, 1370, 1260,
1057 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.17-4.06 (m, 1H), 3.40 (dtd, J =
10.8, 7.2, 3.4 Hz, 1H), 2.68-2.55 (m, 1H), 2.41-2.31 (m, 2H), 2.26-2.13 (m,
1H), 1.93-1.81 (m, 2H), 1.74-1.64 (m, 1H), 1.66-1.53 (m, 1H), 1.46-1.28
(m, 2H), 1.23-1.08 (m, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ 173.7, 57.3,
40.2, 33.6, 30.3, 25.3, 24.4, 23.7 ppm.
Tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6(7H)-one 13e.
Hexahydro-1H-pyrrolo[1,2-a]azepin-3(2H)-one 6d.
Yellowish oil; 47% yield (5.0 mg, 0.035 mmol); Rf = 0.41 (Silica gel,
Light brown oil; 15% yield (4.1 mg, 0.027 mmol); Rf = 0.45 (Silica gel,
AcOEt/Methanol 9:1); IR νmax = 2925, 2854, 1651, 1458, 1436, 1171, 1126,
1093 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.80-3.65 (m, 2H), 3.22-3.01 (m,
1H), 2.42-2.30 (m, 2H), 2.15-2.00 (m, 1H), 1.85-1.74 (m, 1H), 1.68-1.52
(m, 8H) ppm; 13C NMR (101 MHz, CDCl3) δ 172.5, 59.3, 42.5, 35.2, 31.1,
29.8, 27.8, 26.4, 25.0 ppm.
AcOEt/Methanol 9:1); IR νmax = 2933, 2857, 1664, 1450, 1364, 1267, 1196,
1
1059 cm-1; H NMR (500 MHz, CDCl3) δ 4.00 (dd, J = 11.1, 3.9 Hz, 1H),
3.96-3.89 (m, 2H), 3.72-3.65 (m, 1H), 3.34 (ddd, J = 11.8, 11.7, 3.2 Hz,
1H), 3.08 (t, J = 11.0 Hz, 1H), 3.04-2.92 (m, 1H), 2.47-2.34 (m, 2H), 2.18-
2.09 (m, 1H), 1.59-1.49 (m, 1H) ppm; 13C NMR (126 MHz, CDCl3) δ 173.3,
72.8, 66.0, 54.9, 40.2, 29.9, 20.7 ppm.
7,7-dimethylhexahydroindolizin-3(2H)-one 13a.
6-phenyltetrahydro-1H-pyrrolizin-3(2H)-one 13g.
Yellowish oil; 37% yield (4.3 mg, 0.026 mmol); Rf = 0.39 (Silica gel,
AcOEt/Methanol 9:1); IR νmax = 2950, 2923, 2869, 1669, 1457, 1295, 1128
cm-1. 1H NMR (400 MHz, CDCl3) δ 3.98 (ddd, J = 13.5, 5.3, 2.0 Hz, 1H),
3.67-3.55 (m, 1H), 2.85-2.74 (m, 1H), 2.41-2.31 (m, 2H), 2.24-2.11 (m, 1H),
1.61-1.49 (m, 2H), 1.40-1.33 (m, 1H), 1.33-1.25 (m, 2H), 1.01 (s, 3H), 0.97
(s, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 173.5, 53.2, 46.4, 37.1, 36.3,
32.6, 30.5, 30.0, 25.5, 23.0 ppm; HRMS (ESI-TOF) calcd for C10H18NO
[M+H]+ 168.1383 found 168.1387.
Yellow oil; 35% yield (4.3 mg, 0.021 mmol) [diastereoisomers mixture
cis:trans (1:1)]; Rf = 0.36 (Silica gel, AcOEt/Methanol 9:1); IR νmax = 2924,
2854, 1683, 1454, 1376, 1286, 1203, 1178, 1047 cm-1; 1H NMR (500 MHz,
CDCl3) [diastereoisomers mixture] δ 7.37-7.29 (m, 4H), 7.28-7.19 (m, 6H),
4.22-4.05 (m, 3H), 3.73-3.63 (m, 1H), 3.61-3.49 (m, 2H), 3.47 (q, J = 7.4
Hz, 1H), 3.07 (ddd, J = 11.9, 7.0, 1.4 Hz, 1H), 2.85-2.67 (m, 2H), 2.56-2.30
(m, 5H), 2.19-2.10 (m, 1H), 1.97 (ddd, J = 12.9, 8.6, 6.6 Hz, 1H), 1.86
(dddd, J = 12.7, 11.2, 9.5, 7.7 Hz, 1H), 1.75 (tt, J = 12.1, 8.8 Hz, 1H), 1.60-
1.49 (m, 1H) ppm; 13C NMR (126 MHz, CDCl3) [diastereoisomers mixture]
δ 175.9, 174.6, 142.5, 141.3, 128.7, 128.7, 127.1, 127.0, 127.0, 126.8,
62.5, 60.3, 48.9, 47.9, 47.3, 45.2, 41.5, 39.9, 35.1, 34.7, 28.9, 27.0 ppm.
(7R,8aR)-7-phenylhexahydroindolizin-3(2H)-one 13b.
Yellowish oil; 49% yield (4.0 mg, 0.019 mmol) [diastereoisomers mixture:
cis:trans (3:1)]; Rf = 0.52 (Silica gel, AcOEt/Methanol 9:1); IR νmax = 3084,
3060, 2927, 2856, 1673, 1452, 1421, 1282, 1269, 1122 cm-1; 1H NMR (400
MHz, CDCl3) [major diastereoisomer] δ 7.36-7.29 (m, 2H), 7.25-7.17 (m,
3H), 4.26 (ddd, J = 13.3, 4.9, 1.7 Hz, 1H), 3.71-3.54 (m, 1H), 2.86-2.68 (m,
2H), 2.46-2.38 (m, 2H), 2.31-2.14 (m, 2H), 2.11-2.03 (m, 1H), 1.95-1.84
(m, 1H), 1.73-1.61 (m, 1H), 1.39 (q, J = 12.5 Hz, 1H) ppm; 13C NMR (126
MHz, CDCl3) [major diastereoisomer] δ 173.6, 145.0, 128.6, 126.6, 126.5,
57.2, 41.9, 41.0, 39.9, 32.0, 30.4, 25.1 ppm.
(6R,8aR)-6-phenylhexahydroindolizin-3(2H)-one 13h.
Yellowish oil; 51% yield (4.1 mg, 0.019 mmol) [diastereoisomers mixture
cis:trans (1:4)]; Rf = 0.44 (Silica gel, AcOEt/Methanol 9:1); IR νmax = 3084,
3060, 2927, 2854, 1666, 1446, 1310, 1031 cm-1; 1H NMR (400 MHz,
CD3OD) [major diastereoisomer] δ 7.57-7.06 (m, 5H), 4.10 (ddd, J = 12.9,
4.5, 1.8 Hz, 1H), 3.67-3.59 (m, 1H), 2.77 (dd, J = 12.4, 12.4 Hz, 1H), 2.66-
2.57 (m, 1H), 2.52-2.33 (m, 2H), 2.37-2.21 (m, 1H), 2.14-1.94 (m, 2H),
1.88-1.75 (m, 1H), 1.75-1.61 (m, 1H), 1.49-1.34 (m, 1H) ppm; 13C NMR
(101 MHz, CD3OD) [major diastereoisomer] δ 176.1, 144.1 129.7, 128.1,
127.9, 58.6, 47.6, 43.4, 34.4, 32.1, 31.5, 25.7 ppm .
1-methyltetrahydro-1H-pyrrolizin-3(2H)-one 13c.
Yellowish oil; 30% yield (3.1 mg, 0.022 mmol) [diastereoisomers mixture
cis:trans (1:1)]; Rf = 0.39 (Silica gel, AcOEt/Methanol 9:1); IR νmax = 2956,
2924, 2873, 1666, 1456, 1377, 1234 cm-1; 1H NMR (500 MHz, CDCl3)
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10.1002/ejoc.201800239
European Journal of Organic Chemistry
FULL PAPER
Synthesis of the intermediate 12 via diazomethane acylation
methodology from the activated nitro acid 11.
The 1-diazo-5-nitro-4-phenylpentan-2-one 12 were prepared following the
methodology previously described [20]
Keywords: α,β-unsaturated diazoketones • aza-Michael addition
•
Wolff rearrangement
•
heterocycles
•
indolizidines
•
pyrrolizidines
[1]
[2]
[3]
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1-diazo-5-nitro-4-phenylpentan-2-one 12.
Viscous yellow oil; 65% yield (136.0 mg, 0.58 mmol); Rf = 0.33 (Silica gel,
Hexanes/AcOEt 7:3); IR νmax = 3106, 3032, 2920, 2104, 1788, 1729, 1633,
1
1547, 1376, 1139 cm-1; H NMR (500 MHz, CDCl3) δ 7.38-7.31 (m, 2H),
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7.33-7.25 (m, 1H), 7.26-7.20 (m, 2H), 5.20 (s, 1H), 4.77 (dd, J = 12.5, 6.6
Hz, 1H), 4.66 (dd, J = 12.6, 8.0 Hz, 1H), 4.04 (quint, J = 7.2 Hz, 1H), 2.85-
2.67 (m, 2H) ppm; 13C NMR (126 MHz, CDCl3) δ 191.1, 138.5, 129.1,
128.0, 127.3, 79.4, 55.6, 43.3, 40.1 ppm; HRMS (ESI-TOF) calcd for
C11H11N3NaO3 [M+Na]+ 256.0693 found 256.0681.
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Methyl 5-nitro-4-phenylpentanoate 10b.
Colorless oil; 61% yield (75.0 mg, 0.32 mmol); Rf = 0.58 (Silica gel,
Hexanes/AcOEt 7:3); IR νmax = 3062, 3031, 2953, 2923, 2869, 2852, 1732,
1551, 1378, 1265, 1162 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39-7.31 (m,
2H), 7.31-7.24 (m, 1H), 7.21-7.16 (m, 2H), 4.65-4.51 (m, 2H), 3.62 (s, 3H),
3.56-3.43 (m, 1H), 2.24-2.15 (m, 2H), 2.16-2.04 (m, 1H), 2.03-1.92 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 173.0, 138.1, 129.1, 128.0, 127.6, 80.5,
51.7, 43.6, 31.3, 28.0 ppm. HRMS (ESI-TOF) calcd for C12H15NNaO4
[M+Na]+ 260.0893 found 260.0901.
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Procedure for the synthesis of the Diethyl (4-diazo-3-oxobutan-2-yl)
phosphonate 5b.
The diazophosphote 5b was prepared in 2 steps via the Arbuzov reaction
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Yellow oil; 30% yield (153.0 mg, 0.65 mmol); Rf = 0.33 (Silica gel,
Et2O/MeOH 95:5); IR νmax = 2984, 2941, 2909, 2101, 1733, 1634, 1352,
1244, 1013 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.66 (s, 1H), 4.23-4.03 (m,
4H), 3.10-2.87 (m, 1H), 1.41 (dd, J = 17.9, 7.2 Hz, 3H), 1.34 (td, J = 7.0,
2.6 Hz, 6H) ppm; 13C NMR (126 MHz, CDCl3) δ 189.4, 62.8 (d, J = 6.8 Hz),
62.6 (d, J = 6.9 Hz), 55.8, 44.6 (d, J = 129.8 Hz), 16.3 (d, J = 6.1 Hz), 11.2
(d, J = 6.1 Hz) ppm; HRMS (ESI-TOF) calcd for C8H15N2NaO4P [M+Na]+
257.0662 found 257.0657.
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Acknowledgements ((optional))
We would thank FAPESP (Research Supporting
Foundation of the State of Sao Paulo) for financial support
(2013/18009-4) and CAPES for fellowship for J.V.S. (PROEX-
1480644). We also thank IQSC-USP for the facilities and
FAPESP (2004/09498-2) for HRMS multiuser equipment.
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10.1002/ejoc.201800239
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Synthesis of N-heterocycles*
João Victor Santiago, Antonio C. B.
Burtoloso*
((Insert TOC Graphic here; max. width: 11.5 cm; max. height: 2.5 cm; NOTE: the
final letter height should not be less than 2 mm.))
Page No. – Page No.
Rapid synthesis of bicyclic N-
heterocyclic cores from N-terminal
α,β-unsaturated diazoketones
The synthesis of bicyclic N-heterocycles cores from N-terminal α,β-unsaturated
diazoketones is described. The transformation consists in just three sequential steps
and involves a one-pot N-deprotection/intramolecular aza-Michael reaction, followed
by a photochemical Wolff rearrangement.
*one or two words that highlight the emphasis of the paper or the field of the study
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