tert-Butyl 3-Diazo-2-oxopyrrolidine-1-carboxylate – A New Reagent for Introduction of the 2-Oxopyrrolidin-3-yl Motif via RhII-Catalyzed X–H Insertion Reactions

Article abstract of DOI:10.1002/ejoc.202000067

tert-Butyl 3-diazo-2-oxopyrrolidine-1-carboxylate synthesized on multigram scale has been employed to introduce a privileged NH-2-pyrrolidone moiety via oxygen, sulfur and nitrogen atom to partner molecules via Rh^II-catalyzed X–H insertion followed by Boc group removal. Further manipulation of pyrrolidine moiety has been exemplified.

Full text of DOI:10.1002/ejoc.202000067

A Journal of
Accepted Article
Title: tert -Butyl 3-diazo-2-oxopyrrolidine-1-carboxylate – a new reagent
for introduction of the privileged 2-oxopyrrolidin-3-yl motif via
RhII-catalyzed X-H insertion reactions
Authors: Daniil Zhukovsky, Dmitry Dar'in, and Mikhail Krasavin
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
tert-Butyl 3-diazo-2-oxopyrrolidine-1-carboxylate – a new reagent for
introduction of the privileged 2-oxopyrrolidin-3-yl motif via RhII-catalyzed X-
H insertion reactions
Daniil Zhukovsky,[a] Dr. Dmitry Dar’in,[a] and Prof. Dr. Mikhail Krasavin*[a],[b]
[a]Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation
[b]Immanuel Kant Baltic Federal University, Kaliningrad 236016 Russian Federation
E-mail: m.krasavin@spbu.ru
http://www.krasavin-group.org/
Supporting information and ORCID(s) from the author(s) for this article are available on the
WWW under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
ABSTRACT
tert-Butyl 3-diazo-2-oxopyrrolidine-1-carboxylate synthesized on multigram scale has been
employed to introduce a privileged NH-2-pyrrolidone moiety via oxygen, sulfur and nitrogen
atom to partner molecules via RhII-catalyzed X-H insertion followed by Boc group removal.
Further manipulation of pyrrolidine moiety has been exemplified.
Introduction
The simplest -lactam, 2-pyrrolidone is undoubtedly a privileged motif employed in drug design,
i. e. its incorporation in the structure of small molecules – as a core structure or as a periphery
element – endows the resulting compounds with diverse biological activities as the result of
affinity to respective protein targets[1]. Besides approved drugs based on 2-pyrrolidone as a
scaffold (e. g., natural metabolite of nicotine, antidepressant cotinine[2], respiratory stimulant
doxapram[3], nootropic and cognition-modulating drug piracetam[4] and anti-seizure
ethosuximide[5]), there is a wealth of bioactive molecules featured in the recent patent literature
which contains an N-unsubstituted (“NH-“) 2-pyrrolidone moiety as an element of molecular
periphery, linked via a bond between C-3 and a heteroatom (mostly nitrogen, less frequently
oxygen or sulfur). Relevant examples, include Bruton’s tyrosine kinase inhibitor 1[6], inhibitor of
respiratory syncytial virus (RSV) 2[7], Syngenta’s fungicide 3[8], immunomodulating inhibitor of
IL-17 4[9], hepatitis B virus capsid assembly modulator 5[10], adenosine receptor modulator 6[11]
,
ghrelin O-acyl transferase (GOAT) inhibitor 7 for treatment of diabetes and obesity[12], ubiquitin-
specific processing protease 7 (USP7) inhibitor 8 for cancer treatment[13] and cannabinoid
receptor hCB2 agonist 9[14] (Figure 1).
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
Figure 1. Approved drugs based on 2-pyrrolidone core and the bioactive compounds illustrating
the use of NH-2-pyrrolidone as a privileged periphery group.
From drug design prospective, the advantages of using NH-2-pyrrolidone are quite intuitive as
this polar (cLogP = -0.18[15]) motif contains a hydrogen bond donor/acceptor pair capable of
building cooperative interactions with protein backbone, would likely improve drug candidate’s
aqueous solubility and will not reflect negatively on the molecule’s degree of saturation (Fsp3), a
routinely observed parameter in modern drug discovery[16-17]
.
The primary means of introducing the NH-2-pyrrolidone moiety is via the use of either 3-amino-
2-pyrrolidone or 3-bromo-2-pyrrolidone. Recently, we have been investigating synthesis and
RhII-catalyzed X-H insertion reactions of a novel type of -diazocarbonyl compounds – -diazo-
-lactams 1[18-20]. The primary limitation of this chemistry was identified with respect to the
substituents on the lactam nitrogen atom: the diazo compounds were stable to isolation and use
in subsequent transformation only for N-aryl lactams, i. e. when the nitrogen lone pair is
delocalized thereby increasing the electron-withdrawing character of the aminocarbonyl moiety.
In contrast, N-alkyl derivatives (as well as o-substituted aromatic groups incapable of effective
conjugation for steric reasons) are unstable due to nitrogen-extrusive dimerization[18] and can
only be used in situ, as soon as they have been obtained[21]. We reasoned that if an
alkoxycarbonyl-type protecting group (e. g., Boc as in 2) was placed on the nitrogen atom of -
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
diazo--lactam core, this would increase the electron-withdrawing character of the lactam
carbonyl group and stabilize the resulting diazo compound (similarly to or even more than N-aryl
group). Furthermore, the use of such a reagent in RhII-catalyzed X-H insertion reactions with
subsequent removal of the protecting group would constitute a general approach of introducing
the privileged NH-2-pyrrolidone moiety at hydroxyl, sulfhydryl or amino groups thus expanding
the opportunities for studying the effects of this frequently employed modification on biological
profile of a lead molecule (Figure 2). Herein, we present the results of investigating this
approach.
Figure 2. Previously investigated reactions of -diazo--lactams and the approach to 3-
substituted NH-2-pyrrolidones investigated in this work.
Results and discussion
The synthesis of N-substituted -diazo--lactams 1 by diazo transfer required that the starting -
lactam be activated via -ethoxalylation[18]. Unfortunately, neither ethoxalylation nor
formylation of the enolate generated from known[22] (as well as commercially available) N-Boc
2-pyrrolidone (4) with respective esters did not produce the desired derivative, most likely, due
to the removal of the Boc group by the alkoxy group liberated in the course of the reaction (as
judged by the observed extensive gas evolution). So, it was decided to introduce a (N,N-
dimethylamino)methylene moiety as an equivalent to formylation. The conventional reagent
employed to this end, N,N-dimethylformamide dimethyl acetal (DMF DMA)[23] did not lead to
any appreciable conversion of 4 to the desired (N,N-dimethylamino)methylene derivative 5. A
viable solution was found in the use of more reactive tert-butoxy bis(dimethylamino)methane
(Brederick’s reagent, 6[24]) which furnished an excellent yield of the desired enamine 5, in line
with the previous reports from Young and co-workers[25]. It should be noted that previously, all
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
attempts to introduce the (N,N-dimethylamino)methylene moiety at N-aryl 2-pyrrolidones using
either DMF DMA or the Brederick’s reagent failed. Another advantage associated with
intermediate 5, contrasting it to -ethoxalylated N-aryl 2-pyrrolidones[18], was the applicability
to it of the recently developed ‘sulfonyl azide-free’ (SAFE) protocol for diazo transfer in
aqueous medium[26-27]. Treatment of 5 with the aqueous solution of sodium azide, m-
chlorosulfonyl benzoic acid and potassium carbonate furnished after extractive workup and flash
chromatography on alumina (to prevent the diazo compound from decomposing) an excellent
yield of desired compound 2 (Scheme 1). This procedure has been successfully performed on
multigram scale.
Scheme 1. Preparation of tert-butyl 3-diazo-2-oxopyrrolidine-1-carboxylate (2).
Capitalizing upon the previously conducted optimization studies for the RhII-catalyzed X-H
insertion reactions for N-aryl[18-20] and N-alkyl[21] -diazo--lactams 1, workable conditions for
similar reactions of tert-butyl 3-diazo-2-oxopyrrolidine-1-carboxylate (2) were promptly
identified. Using Rh2(OAc)4 (1 mol%) for alkohols and thiols and Rh2(esp)2 (0.5 mol%) for
aromatic amines was also found optimal in this case with longer (2 h) reaction times required in
the former case compared to the latter (15 min). After removal of the Boc protecting group in
situ using TFA, the respective O-, S-, and N-linked adducts 3a-l were isolated in moderate to
good yields over two steps (Scheme 2).
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
a RhII catalyst = Rh2(OAc)4 (1 mol%) for X = O and S; Rh2(esp)2 (0.5 mol%) for X = NR′
b 120 min for X = O and S, 15 min for X = NR′
c 5 equiv TFA in DCM, 30 min (for X = O and S); TFA (neat), 60 min (for X = NR′)
Scheme 2. Preparation of 3-substituted NH-2-pyrrolidones 3a-l.
Besides the aforementioned utility of the NH-2-pyrrolidone motif in medicinal chemistry,
compounds 3 can be viewed as starting materials for 3-substituted pyrrolidines, one of the most
commonly used amines in medicinal chemistry[28]. To illustrate this possibility, a small set of
NH-2-pyrrolidones 3 was reduced with LAH in refluxing THF to give pyrrolidines 7a-d in good
to excellent yields (Scheme 3).
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
Scheme 3. Preparation of pyrrolidines 7a-d.
Considering the availability of a highly nucleophilic pyrrolidine nitrogen atom in compounds 7,
these can be diversified further, for example, via reductive alkylation reaction. This possibility
exemplified by chemoselective introduction of an alkyl substituent at the aliphatic amino group
of compound 7d to give compounds 8a-b in good yields (Scheme 4).
Scheme 4. Chemoselective reductive alkylation of compound 7d.
Additionally, the NH-lactam moiety in adducts 3 is, in principle, available for subsequent
modification at the nitrogen atom, which enable orthogonal manipulation of substituents in
positions 1 and 3 of the 2-pyrrolidone moiety. To illustrate this approach, compounds 3b and 3l
were decorated with propargyl and 2-cyanoethyl groups to give compounds 9 and 10,
respectively, in good isolated yields (Scheme 5).
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
Scheme 5. Alkylation of the NH-2-pyrrolidone moiety in 3b and 3l.
Conclusion
tert-Butyl 3-diazo-2-oxopyrrolidine-1-carboxylate is a new diazo reagent that can be prepared in
two steps from commercially available starting material on multigram scale. It can be employed
to introduce a privileged NH-2-pyrrolidone moiety via oxygen, sulfur and nitrogen atom to
partner molecules via RhII-catalyzed X-H insertion followed by Boc group removal. The
resulting 3-substituted 2-pyrroldones can be reduced to medicinally valuable 3-substituted
pyrroldines. The latter can be additionally modified via reductive alkylation. 3-Substituted NH-2-
pyrrolidones can also be modified at the lactam nitrogen atom by alkylation. The findings open
access to a wealth of heterocyclic building blocks using diazo chemistry.
Experimental section
General considerations. All reagents were purchased from the commercial sources.
Dichloromethane and tetrahydrofuran was distilled over drying agents. Mass spectra were
recorded with a Bruker Maxis HRMS-ESI-qTOF spectrometer (electrospray ionization mode).
NMR spectroscopic data were recorded with Bruker Avance 400 spectrometer (400.13 MHz for
13
1H and 100.61 MHz for C) in CDCl3 and were referenced to residual solvent proton peaks
(δH = 7.28) and solvent carbon peaks (δC = 77.0). Melting points were determined with a Stuart
SMP50 instrument in open capillary tubes.
Preparation
of
tert-butyl
(E)-3-((dimethylamino)methylene)-2-oxopyrrolidine-1-
carboxylate (5)
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
A mixture of 1-(tert-butoxycarbonyl)-2-pyrrolidinone 4 (2.96 g, 16 mmol) with Bredereck’s
reagent 6 (2.92 g, 16.8 mmol) in 20 ml of toluene was refluxed for 3 h and then volatiles were
removed under reduced pressure. The residue was triturated with 10 ml of n-hexane, the solid
1
was filtered and washed with n-hexane (2 x 5 ml). Yield 3.25 g, 85%. White semi-solid. H
NMR (400 MHz, CDCl3) δ 7.11 (s, 1H), 3.66 (dd, J = 8.5, 6.9 Hz, 2H), 3.03 (s, 6H), 2.98 – 2.82
(m, 2H), 1.53 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 170.4, 151.6, 145.8, 94.0, 81.5, 43.3, 41.9,
28.2, 21.4. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C12H20N2O3 241.1547; Found 241.1546.
Preparation of tert-butyl 3-diazo-2-oxopyrrolidine-1-carboxylate (2)
To a stirred solution of sodium azide (0.39 g, 6 mmol) and potassium carbonate (1.10 g, 8 mmol)
in water (10 mL) was added 3-(chlorosulfonyl)benzoic acid (1.17 g, 5.32 mmol) and the mixture
was stirred at ambient temperature for 10 min to give a clear solution. Then tert-butyl (E)-3-
((dimethylamino)methylene)-2-oxopyrrolidine-1-carboxylate 5 (0.96 g, 4 mmol) in 10 ml of
acetonitrile was added to the solution and the mixture was stirred for 1 h at room temperature.
The target diazo lactam was extracted with chloroform (2 × 15 mL), the combined organic
phases were dried over calcium chloride and evaporated to dryness. The residue was purified by
column chromatography on neutral Al2O3 using ethyl acetate-n-hexane 1:3 as eluent. Yield 670
1
mg, 79%. Orange amorphous solid. H NMR (400 MHz, CDCl3) δ 3.95 – 3.65 (m, 2H), 3.32 –
13
2.94 (m, 2H), 1.54 (s, 9H). C NMR (101 MHz, CDCl3) δ 166.3, 150.0, 82.8, 54.1, 42.8, 28.1,
17.4. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C9H13N3O3 234.0849; Found 234.0860.
Gram-scale reparation of tert-butyl 3-diazo-2-oxopyrrolidine-1-carboxylate (2)
A mixture of 1-(tert-butoxycarbonyl)-2-pyrrolidinone 4 (5.92 g, 32 mmol) with Bredereck’s
reagent 6 (5.84 g, 33.6 mmol) in 30 ml of toluene was refluxed for 3 h and then volatiles were
removed
under
reduced
pressure.
The
obtained
crude
tert-butyl
(E)-3-
((dimethylamino)methylene)-2-oxopyrrolidine-1-carboxylate 5 (0.96 g, 4 mmol) dissolved in 15
ml of acetonitrile was added to the a pre-stirred for 30 min solution of sodium azide (0.78 g, 12
mmol), potassium carbonate (2.20 g, 16 mmol) and 3-(chlorosulfonyl)benzoic acid (2.34 g,
10.64 mmol) in water (15 mL). The resulting mixture was stirred for 1 h at room temperature and
the target diazo lactam was extracted with chloroform (2 × 20 mL), the combined organic phases
were dried over calcium chloride and evaporated to dryness. The residue was purified by column
chromatography on neutral Al2O3 using ethyl acetate-n-hexane 1:3 as eluent. Yield 4.19 g, 62%.
General procedure for S-H and O-H insertion reactions followed by Boc deprotection
(preparation of 3a-g)
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
Dirhodium tetraacetate (1.3 mg, 0.003 mmol) was added to a stirred solution of tert-butyl 3-
diazo-2-oxopyrrolidine-1-carboxylate 2 (63 mg, 0.3 mmol) and corresponding alcohol or thiol
(0.45 mmol) in 5 ml of dichloromethane. The mixture was stirred for 2 h at room temperature
and then trifluoroacetic acid (171 mg, 1.5 mmol) was added to the solution. The resulting
mixture was stirred for another 30 min at the same temperature, evaporated to dryness and the
residue was purified by column chromatography on silica gel using acetone-n-hexane 3:5 as
eluent.
3-Propoxypyrrolidin-2-one (3a)
1
Yield 28 mg, 66%. Green oil. H NMR (400 MHz, CDCl3) δ 7.61 – 7.37 (m, 1H), 4.00 (td, J =
7.5, 1.7 Hz, 1H), 3.90 – 3.71 (m, 1H), 3.60 – 3.45 (m, 1H), 3.41 (dddd, J = 11.4, 6.6, 3.2, 1.4 Hz,
1H), 3.32 – 3.19 (m, 1H), 2.39 (dtd, J = 13.1, 7.5, 3.5 Hz, 1H), 2.04 (dddd, J = 14.2, 8.7, 7.1, 3.5
13
Hz, 1H), 1.69 – 1.51 (m, 2H), 1.06 – 0.71 (m, 3H). C NMR (101 MHz, CDCl3) δ 176.7, 76.1,
72.2, 39.1, 28.6, 23.0, 10.4. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C7H13NO2 166.0838;
Found 166.0846.
3-(Cyclohexyloxy)pyrrolidin-2-one (3b)
Yield 41 mg, 75%. Green amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 4.13 (t, J
= 7.6 Hz, 1H), 3.86 – 3.54 (m, 1H), 3.46 – 3.34 (m, 1H), 3.26 (dt, J = 9.8, 7.3 Hz, 1H), 2.38 (dtd,
J = 13.0, 7.5, 3.4 Hz, 1H), 2.11 – 1.87 (m, 3H), 1.84 – 1.67 (m, 2H), 1.61 – 1.48 (m, 1H), 1.40 –
1.05 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 177.1, 77.5, 73.3, 39.0, 32.6, 32.4, 29.5, 25.7, 24.2,
24.2. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C10H17NO2 206.1151; Found 206.1156.
3-(Benzyloxy)pyrrolidin-2-one (3c)
1
Yield 32 mg, 55%. White amorphous solid. H NMR (400 MHz, CDCl3) δ 7.44 – 7.39 (m, 2H),
7.38 – 7.33 (m, 2H), 7.33 – 7.26 (m, 2H), 4.94 (d, J = 11.8 Hz, 1H), 4.75 (d, J = 11.9 Hz, 1H),
4.10 (t, J = 7.5 Hz, 1H), 3.56 – 3.37 (m, 1H), 3.27 (dt, J = 9.9, 7.2 Hz, 1H), 2.36 (dtd, J = 13.1,
13
7.6, 3.7 Hz, 1H), 2.10 (ddt, J = 13.3, 8.6, 7.1 Hz, 1H). C NMR (101 MHz, CDCl3) δ 176.7,
137.8, 128.4, 128.0, 127.8, 75.1, 72.1, 39.1, 28.7. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C11H13NO2 192.1019; Found 192.1026.
3-Phenethoxypyrrolidin-2-one (3d).
Yield 48 mg, 78%. Brown amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.27 (m, 2H),
7.27 – 7.18 (m, 3H), 6.93 (s, 1H), 4.09 (ddd, J = 9.3, 7.8, 6.5 Hz, 1H), 4.03 (t, J = 7.4 Hz, 1H),
3.78 (dt, J = 9.3, 7.5 Hz, 1H), 3.40 (ddd, J = 9.3, 6.9, 3.5 Hz, 1H), 3.28 (dt, J = 9.9, 7.2 Hz, 1H),
3.10 – 2.89 (m, 2H), 2.38 (dtd, J = 13.1, 7.5, 3.7 Hz, 1H), 2.03 (ddt, J = 13.4, 8.6, 7.0 Hz, 1H).
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
13C NMR (101 MHz, CDCl3) δ 176.4, 138.7, 129.0, 128.3, 126.2, 76.1, 71.3, 39.1, 36.4, 28.5.
HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C12H15NO2 228.0995; Found 228.0991.
3-(Сyclohexylthio)pyrrolidin-2-one (3e)
1
Yield 45 mg, 75%. Brown semi-solid. H NMR (400 MHz, CDCl3) δ 7.08 (s, 1H), 3.46 (td, J =
8.2, 5.7 Hz, 2H), 3.33 (td, J = 8.8, 4.5 Hz, 1H), 3.07 (tt, J = 10.4, 3.7 Hz, 1H), 2.54 (dtd, J =
13.3, 8.3, 6.3 Hz, 1H), 2.15 – 2.06 (m, 1H), 2.05 – 1.89 (m, 2H), 1.82 – 1.68 (m, 2H), 1.64 – 1.56
(m, 1H), 1.43 – 1.16 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 177.6, 43.1, 41.3, 40.5, 33.8, 33.3,
29.9, 26.0, 25.8, 25.8. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C10H17NOS 222.0923;
Found 222.0931.
3-(Phenylthio)pyrrolidin-2-one (3f)
Yield 31 mg, 54%. Beige semi-solid. 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.50 (m, 2H), 7.43 (s,
1H), 7.35 – 7.23 (m, 3H), 3.80 (dd, J = 8.8, 6.5 Hz, 1H), 3.43 – 3.16 (m, 2H), 2.55 (dtd, J = 13.5,
13
8.3, 5.2 Hz, 1H), 2.15 (ddt, J = 13.8, 8.1, 6.1 Hz, 1H). C NMR (101 MHz, CDCl3) δ 176.3,
133.3, 132.6, 129.0, 127.8, 47.4, 40.4, 29.1. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for
C10H11NOS 216.0454; Found 216.0464.
3-((4-Fluorophenyl)thio)pyrrolidin-2-one (3g)
Yield 31 mg, 49%. Brown amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.62 – 7.50 (m, 2H),
7.25 (s, 1H), 7.06 – 6.94 (m, 2H), 3.71 (dd, J = 8.9, 6.5 Hz, 1H), 3.30 (ddd, J = 9.9, 8.0, 5.6 Hz,
1H), 3.20 (ddd, J = 9.8, 8.2, 5.2 Hz, 1H), 2.55 (dtd, J = 13.6, 8.4, 5.2 Hz, 1H), 2.22 – 2.04 (m,
1H). 13C NMR (101 MHz, CDCl3) δ 176.3, 163.0 (d, J = 248.7 Hz), 135.9 (d, J = 8.2 Hz), 127.8
(d, J = 3.4 Hz), 116.2 (d, J = 21.7 Hz), 47.8, 40.4, 28.7. HRMS (ESI/Q-TOF) m/z: [M+Na]+
Calcd for C10H10FNOS 234.0359; Found 234.0360.
General procedure for N-H insertion reaction followed by Boc deprotection (preparation of
3h-k)
Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] (1.10 mg, 0.0015 mmol) was
added to a stirred solution of tert-butyl 3-diazo-2-oxopyrrolidine-1-carboxylate 2 (63 mg, 0.3
mmol) and corresponding arylamine (0.45 mmol) in 5 ml of dichloromethane. The mixture was
stirred at room temperature for 15 min, evaporated to dryness and then 3 ml of trifluoroacetic
acid was added. The resulting solution was stirred for another 60 min at the same temperature,
then evaporated to dryness and the residue was redissolved in 7 ml of dichloromethane, washed
with saturated NaHCO3 (2 x 5 ml). The organic phase was dried over Na2SO4, evaporated to
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
dryness and purified by column chromatography on silica gel using acetone-n-hexane 1:1 as
eluent.
3-(p-Tolylamino)pyrrolidin-2-one (3h)
Yield 31 mg, 55%. White amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 1H), 7.04 (d,
J = 8.1 Hz, 2H), 6.77 – 6.58 (m, 2H), 4.24 (s, 1H), 3.95 (dd, J = 10.0, 7.8 Hz, 1H), 3.64 – 3.32
(m, 2H), 2.85 – 2.63 (m, 1H), 2.28 (s, 3H), 2.16 – 1.93 (m, 1H). 13C NMR (101 MHz, CDCl3) δ
177.1, 145.2, 129.8, 127.6, 113.7, 54.7, 39.2, 31.4, 20.4. HRMS (ESI/Q-TOF) m/z: [M+Na]+
Calcd for C11H14N2O 213.0998; Found 213.1001.
3-((4-Fluorophenyl)amino)pyrrolidin-2-one (3i)
Yield 31 mg, 53%. Colorless crystals, mp 154.3-155.6 °C. 1H NMR (400 MHz, CDCl3) δ 6.93 (t,
J = 8.7 Hz, 2H), 6.75 – 6.57 (m, 3H), 4.36 (s, 1H), 3.91 (dd, J = 10.1, 7.8 Hz, 1H), 3.68 – 3.32
13
(m, 2H), 2.76 (dddd, J = 10.4, 7.9, 5.5, 2.4 Hz, 1H), 2.14 – 1.90 (m, 1H). C NMR (101 MHz,
CDCl3) δ 176.6, 156.4 (d, J = 236.1 Hz), 143.8 (d, J = 2.0 Hz), 115.7 (d, J = 22.4 Hz), 114.5 (d,
J = 7.4 Hz), 54.9, 39.1, 31.3. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C10H11FN2O
217.0748; Found 217.0748.
3-((4-Methoxyphenyl)amino)pyrrolidin-2-one (3j)
Yield 39 mg, 63%. Colorless crystals, mp 141.5-142.3 °C. 1H NMR (400 MHz, CDCl3) δ 6.86 –
6.79 (m, 2H), 6.71 (s, 1H), 6.70 – 6.63 (m, 2H), 4.23 (s, 1H), 3.90 (dd, J = 10.0, 7.8 Hz, 1H),
3.77 (s, 3H), 3.59 – 3.33 (m, 2H), 2.75 (dddd, J = 12.8, 8.0, 5.6, 2.5 Hz, 1H), 2.13 – 1.94 (m,
13
1H). C NMR (101 MHz, CDCl3) δ 176.9, 152.8, 141.6, 115.0, 114.9, 55.8, 55.1, 39.1, 31.5.
HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C11H14N2O2 229.0947; Found 229.0941.
3-(Benzo[d][1,3]dioxol-5-ylamino)pyrrolidin-2-one (3k)
1
Yield 17 mg, 26%. Brown amorphous solid. H NMR (400 MHz, CDCl3 + CD3OD) δ 6.48 (d, J
= 8.3 Hz, 1H), 6.17 (d, J = 2.3 Hz, 1H), 5.96 (dd, J = 8.3, 2.4 Hz, 1H), 5.68 (s, 2H), 4.09 (s, 2H),
3.85 – 3.65 (m, 1H), 3.34 – 3.14 (m, 2H), 2.51 (dddd, J = 12.5, 8.2, 5.8, 2.7 Hz, 1H), 1.89 – 1.68
13
(m, 1H). C NMR (101 MHz, CDCl3 + CD3OD) δ 177.0, 148.1, 142.7, 140.1, 108.2, 105.2,
100.4, 96.7, 55.2, 38.8, 30.4. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C11H12N2O3
221.0921; Found 221.0919.
3-(Indolin-1-yl)pyrrolidin-2-one (3l)
1
Yield 32 mg, 53%. Green semi-solid. H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.14 – 7.01
(m, 2H), 6.68 (t, J = 7.4 Hz, 1H), 6.50 (d, J = 7.8 Hz, 1H), 4.37 (t, J = 9.2 Hz, 1H), 3.77 – 3.43
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European Journal of Organic Chemistry
(m, 2H), 3.43 – 3.32 (m, 2H), 3.23 – 2.90 (m, 2H), 2.32 (dddd, J = 12.7, 8.9, 6.6, 2.7 Hz, 1H),
13
2.26 – 2.11 (m, 1H). C NMR (101 MHz, CDCl3) δ 176.0, 150.5, 130.2, 127.2, 124.6, 118.1,
107.4, 57.0, 49.1, 39.3, 28.4, 22.0. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C12H14N2O
225.0998; Found 225.0997.
General procedure for reductive amination (preparation of pyrrolidines 7)
The mixture of lithium aluminum hydride (48 mg, 1.25 mmol) with corresponding pyrrolidone 3
(0.25 mmol) in 5 ml of tetrahydrofuran was refluxed for 2 h, quenched with 5 ml of water and
extracted with ethyl acetate (2 x 5 ml). Combined organic fractions were evaporated to dryness
and the residue was purified by column chromatography on silica gel using chloroform-
methanol-triethylamine 100:8:3 as eluent.
3-(Benzyloxy)pyrrolidine (7a)
1
Yield 30 mg, 68%. Yellow oil. H NMR (400 MHz, CDCl3) δ 7.44 – 7.33 (m, 4H), 7.32 – 7.27
(m, 1H), 4.50 (d, J = 1.4 Hz, 2H), 4.13 (tt, J = 5.2, 2.4 Hz, 1H), 3.23 – 3.04 (m, 2H), 2.95 – 2.76
(m, 2H), 2.28 – 2.09 (m, 1H), 1.91 (ddt, J = 8.2, 6.3, 4.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ
138.5, 128.4, 127.6, 127.6, 80.0, 70.9, 53.2, 45.9, 32.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd
for C11H15NO 178.1226; Found 178.1225.
3-Phenethoxypyrrolidine (7b)
1
Yield 28 mg, 59%. Yellow oil. H NMR (400 MHz, CDCl3) δ 7.29 (t, J = 7.5 Hz, 2H), 7.23 –
7.16 (m, 3H), 3.99 (td, J = 5.7, 5.1, 2.6 Hz, 1H), 3.60 (td, J = 7.5, 3.7 Hz, 2H), 3.10 – 2.93 (m,
13
2H), 2.90 – 2.73 (m, 4H), 2.62 (s, 1H), 1.91 – 1.68 (m, 2H). C NMR (101 MHz, CDCl3) δ
139.1, 128.9, 128.3, 126.2, 80.3, 69.8, 53.0, 45.6, 36.6, 32.7. HRMS (ESI/Q-TOF) m/z: [M+H]+
Calcd for C12H17NO 192.1383; Found 192.1390.
N-(p-Tolyl)pyrrolidin-3-amine (7c)
1
Yield 39 mg, 88%. Brown semi-solid. H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 8.0 Hz, 2H),
6.64 – 6.28 (m, 2H), 4.11 – 3.90 (m, 1H), 3.40 – 3.07 (m, 2H), 2.96 (ddd, J = 11.0, 8.4, 6.0 Hz,
1H), 2.88 (dd, J = 11.3, 3.4 Hz, 1H), 2.78 (broad s, 1H), 2.26 (s, 3H), 2.18 (ddt, J = 13.4, 8.2, 6.7
13
Hz, 1H), 1.79 – 1.60 (m, 1H). C NMR (101 MHz, CDCl3) δ 145.2, 129.8, 126.8, 113.5, 54.2,
53.8, 45.8, 33.7, 20.4. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C11H16N2 177.1386; Found
177.1381.
N-(4-Methoxyphenyl)pyrrolidin-3-amine (7d)
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European Journal of Organic Chemistry
Yield 39 mg, 82%. Brown semi-solid. 1H NMR (400 MHz, CDCl3) δ 6.93 – 6.72 (m, 2H), 6.69 –
6.46 (m, 2H), 3.86 (ddd, J = 7.6, 6.0, 3.6 Hz, 1H), 3.74 (s, 3H), 3.25 – 3.00 (m, 2H), 2.99 – 2.85
(m, 1H), 2.81 (dd, J = 11.3, 3.5 Hz, 1H), 2.13 (dtd, J = 13.4, 8.1, 6.4 Hz, 1H), 1.61 (dddd, J =
13.5, 8.0, 5.9, 3.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 152.2, 141.8, 114.9, 114.7, 55.8, 54.8,
54.0, 45.9, 33.8. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C11H16N2O 193.1335; Found
193.1344.
General procedure for reductive alkylation (preparation of pyrrolidines 8)
The mixture of pyrrolidine 7d (38 mg, 0.2 mmol) with sodium triacetoxyborohydride (85 mg,
0.4 mmol) and aldehyde or ketone (0.25 mmol) in 5 ml of dichloromethane was stirred 18 h at
room temperature. The resulting solution was washed with saturated NaHCO3 (5 ml) and water
(5 ml). The dichloromethane fraction was dried over Na2SO4, evaporated to dryness and the
residue was purified by column chromatography on silica gel using acetone-hexane-triethylamine
66:33:1 as eluent.
N-(4-Methoxyphenyl)-1-(4-methylbenzyl)pyrrolidin-3-amine (8a)
Yield 30 mg, 50%. Brown oil. 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 7.8 Hz, 2H), 7.16 (d, J
= 7.7 Hz, 2H), 6.88 – 6.74 (m, 2H), 6.61 – 6.55 (m, 2H), 5.38 (s, 1H), 4.01 (ddt, J = 7.9, 6.6, 3.9
Hz, 1H), 3.76 (s, 3H), 3.74 – 3.62 (m, 2H), 3.07 – 2.80 (m, 2H), 2.65 (dd, J = 9.9, 3.7 Hz, 1H),
2.61 – 2.49 (m, 1H), 2.37 (s, 3H), 2.35 – 2.21 (m, 1H), 1.73 (dddd, J = 12.5, 8.0, 6.7, 4.1 Hz,
1H). 13C NMR (101 MHz, CDCl3) δ 152.2, 141.7, 137.0, 134.4, 129.1, 129.1, 114.9, 114.9, 60.3,
59.6, 55.8, 53.2, 52.5, 32.3, 21.1. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C19H24N2O
297.1961; Found 297.1967.
1-Cyclohexyl-N-(4-methoxyphenyl)pyrrolidin-3-amine (8b)
Yield 32 mg, 59%. Brown semi-solid. 1H NMR (400 MHz, CDCl3) δ 6.97 – 6.69 (m, 2H), 6.67 –
6.45 (m, 2H), 3.95 (s, 1H), 3.76 (s, 3H), 3.62 (s, 1H), 3.04 – 2.76 (m, 2H), 2.61 (dd, J = 9.6, 3.9
Hz, 1H), 2.59 – 2.47 (m, 1H), 2.30 (dtd, J = 13.2, 8.1, 5.0 Hz, 1H), 2.10 – 1.98 (m, 1H), 1.98 –
13
1.88 (m, 2H), 1.83 – 1.72 (m, 2H), 1.70 – 1.55 (m, 2H), 1.42 – 1.12 (m, 5H). C NMR (101
MHz, CDCl3) δ 152.2, 141.8, 114.9, 114.8, 63.5, 58.7, 55.8, 52.9, 50.4, 32.3, 31.8, 26.1, 25.1,
25.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C17H26N2O 275.2118; Found 275.2109.
3-(Cyclohexyloxy)-1-(prop-2-yn-1-yl)pyrrolidin-2-one (9)
NaH (10 mg, 0.25 mmol, 60% wt in mineral oil) was added to a solution of pyrrolidone 3b (32
mg, 0.175 mmol) in 5 ml of THF and the mixture was stirred 15 min at room temperature. Then
propargyl bromide (50 mg, 0.35 mmol, 80% wt in toluene) was added and the mixture was
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10.1002/ejoc.202000067
European Journal of Organic Chemistry
stirred for 24h. The solution was diluted with 5 ml of water and extracted with 10 ml of
dichloromethane. The organic phase was dried over Na2SO4 and evaporated to dryness. The
residue was purified by column chromatography on silica gel using ethyl acetate-n-hexane 1:2 as
eluent. Yield 23 mg, 62%. Colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.25 – 4.13 (m, 2H), 4.05
(dd, J = 17.5, 2.6 Hz, 1H), 3.83 – 3.66 (m, 1H), 3.50 (ddd, J = 9.6, 8.7, 3.6 Hz, 1H), 3.37 (dt, J =
9.6, 7.3 Hz, 1H), 2.37 (dtd, J = 13.0, 7.8, 3.6 Hz, 1H), 2.23 (t, J = 2.6 Hz, 1H), 2.09 – 1.89 (m,
13
3H), 1.86 – 1.63 (m, 2H), 1.61 – 1.49 (m, 1H), 1.44 – 1.10 (m, 5H). C NMR (101 MHz,
CDCl3) δ 172.6, 77.5, 77.2, 73.7, 72.4, 42.9, 32.8, 32.2, 32.2, 27.1, 25.7, 24.2, 24.2. HRMS
(ESI/Q-TOF) m/z: [M+Na]+ Calcd for C13H19NO2 244.1308; Found 244.1306.
3-(3-(Indolin-1-yl)-2-oxopyrrolidin-1-yl)propanenitrile (10)
A mixture of pyrrolidone 3l (54 mg, 0.27 mmol) with acrylonitrile (21 mg, 0.4 mmol) and small
pellet of NaOH were stirred 4 h at room temperature in 5 ml of THF. The solution was diluted
with 5 ml of water and extracted with 10 ml of dichloromethane. The organic phase was dried
1
over Na2SO4 and evaporated to dryness. Yield 50 mg, 74%. Colorless oil. H NMR (400 MHz,
CDCl3) δ 7.16 – 6.89 (m, 2H), 6.83 – 6.59 (m, 1H), 6.46 (d, J = 7.9 Hz, 1H), 4.44 (t, J = 9.1 Hz,
1H), 3.68 – 3.62 (m, 1H), 3.61 – 3.52 (m, 3H), 3.43 (ddd, J = 8.9, 7.7, 3.4 Hz, 2H), 3.18 – 2.94
(m, 2H), 2.79 – 2.58 (m, 2H), 2.34 (dddd, J = 13.1, 8.8, 6.6, 3.3 Hz, 1H), 2.15 (dq, J = 13.0, 9.0
13
Hz, 1H). C NMR (101 MHz, CDCl3) δ 172.5, 150.4, 130.2, 127.2, 124.7, 118.3, 118.0, 107.4,
57.4, 48.9, 45.1, 39.6, 28.4, 20.4, 16.4. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C15H17N3O
278.1264; Found 278.1256.
ASSOCIATED CONTENT
Supporting Information
Copies of the 1H and 13C NMR spectra.
AUTHOR INFORMATION
Corresponding Author
* E-mail: m.krasavin@spbu.ru
ORCID
Dmitry Dar’in: 0000-0002-0413-7413.
Mikhail Krasavin: 0000-0002-0200-4772.
Notes
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10.1002/ejoc.202000067
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The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was supported by the Russian Science Foundation (project grant 19-75-30008). We
thank the Research Centre for Magnetic Resonance, the Center for Chemical Analysis and
Materials Research, and the Centre for X-ray Diffraction Methods of Saint Petersburg State
University Research Park for obtaining the analytical data.
KEYWORDS: privileged structures; 2-pyrrolidone; diazo transfer; RhII-catalyzed X-H
insertion; lactam reduction
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European Journal of Organic Chemistry
Graphical abstract
TOC text
A new diazo reagent for introduction of a privileged NH-2-pyrrolidone moiety via oxygen, sulfur
and nitrogen atom is presented.
Key topic
Diazo compounds
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