Convenient Approach to 2-Substituted (Thio)morpholin-3-ones from α-Diazoacetates via X-H Carbene Insertion – Lactamization Sequence

Article abstract of DOI:10.1002/ejoc.201901238

Stepwise coupling of N-Boc-protected β-aminoethanols or β-mercaptoethylamines with various α-diazoacetates provides a new, unified approach to constructing (thio)morpholin-3-ones. The process involves a Rh₂(esp)₂-catalyzed X-H insert

Full text of DOI:10.1002/ejoc.201901238

A Journal of
Accepted Article
Title: Convenient approach to 2-substituted (thio)morpholin-3-ones
from α-diazoacetates via X-H carbene insertion – lactamization
sequence
Authors: Igor Solovyov, Dmitry Dar'in, and Mikhail Krasavin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901238
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
Convenient approach to 2-substituted (thio)morpholin-3-ones from -
diazoacetates via X-H carbene insertion – lactamization sequence
Igor Solovyov, Dr. Dmitry Dar’in and Prof. Dr. Mikhail Krasavin*
Saint Petersburg State University, Saint Petersburg, 199034 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
Stepwise coupling of N-Boc-protected -aminoethanols or -mercaptoethylamines with various
-diazoacetates provides a new, unified approach to constructing (thio)morpholin-3-ones. The
process involves a Rh2(esp)2-catalyzed X-H insertion reaction, Boc group removal and ambient-
temperature lactamization and is conveniently conducted in one-pot format.
Introduction
Esters of -diazoacetic acids represent a common type of diazocarbonyl compounds (>190 000
hits in SciFinder, including diazomalonates[1]) and a densely functionalized template for ring-
forming transformations which might take advantage of both the diazo and the ester
functionalities. One common strategy (Figure 1A) involves attaching appropriately
functionalized side chains at the carboxy group (via an ester or amide linkage) followed by
intramolecular reactions (e. g., X-H insertion,[2] cycloaddition[3] or ylide formation[4]) with the
carbenoid generated from the diazo group by metal-catalyzed decomposition. Newly formed
heteroatom-containing six-membered rings represent the usual outcome of this approach. One
obvious drawback of the latter is the need to pre-functionalize the acyclic template prior to the
introduction of the diazo function instead of conveniently relying on an arsenal of common -
diazoacetate building blocks. An alternative approach (Figure 1B) would be to start from an
appropriately substituted -diazoacetate and couple it with a bifunctional building block
engaging diazo group chemistry first followed by cyclization onto the nearby ester group.
Surprisingly, such an apparently more convenient, modular approach can be only sporadically
encountered in the literature. The isolated examples include two-step preparation of piperazin-2-
one (1) from ethyl diazoacetate and ethylene diamine[5] and a similar ‘couple-deprotect-cyclize’
sequence realized with ethyl diazoacetate and protected -aminoethanols toward morpholine-3-
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
ones 2 required for the design of mGluR5 modulators,[6] BACE inhibitors[7] and DPPIV
inhibitors.[8]
Figure 1. Ring-forming approaches based on substituted -diazoacetates (red) and bifunctional
building blocks (blue).
We thought it worthwhile to investigate this potentially universal strategy of constructing
morpholin-3-ones beyond unsubstituted ethyl diazoacetate (so as to include reagents 3) and to
establish applicability of the same strategy not only to protected -aminoalcohols 4 but also to
protected -aminomercaptanes 5 which have not been employed in these reactions. Achieving
these aims will, on one hand, provide a far more streamlined entry into 2-substituted morpholin-
3-ones 6 compared to the currently available multistep routes.[9] On the other hand, expanding
the scope of this transformation to -aminomercaptanes will offer a new approach to 2-
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
substituted thiomorpholin-3-ones 7. The latter have a substantial track record as building blocks
for medicinal chemistry[10] and are encountered in the natural products realm.[11] Herein, we
present the results obtained in the course of working towards these goals.
Results and discussion
In order to test the viability of the proposed approach and to identify the optimal conditions for
the transformation, we screened the reaction between known[12] diazo compound 3a (prepared as
detailed below) and N-Boc-protected -aminoethanol (4a) and -mercaptoethylamine (5a) with
various catalysts capable of decomposing diazo compounds and generating the respective metal
carbene. The results are summarized in Table 1. The formation of the respective X-H insertion
product 8(9)a was very rapid with 0.3 mol. % Rh2(esp)2 and virtually independent of the
temperature. The highest yields (99% and 74% by 1H NMR analysis, respectively; Entries 6 and
13) were achieved when using 0.3 mol% Rh2(esp)2 at room temperature. Thus, these conditions
were subsequently employed throughout this study.
Table 1. Condition screening for the X-H insertion investigated in this work.
1H NMR
yield (%)
Entry
X
Temperature
Catalyst
Mol.% Time (min)
1
2
O
O
O
O
O
O
O
O
S
-
No reaction
<20
RT
RT
RT
RT
RT
RT
RT
0 °C
RT
RT
RT
RT
RT
RT
RT
0 °C
none
Rh2(OAc)4
Rh2(OPiv)4
Rh2(CF3CO2)4
Rh2(esp)2
Cu(acac)2
Rh2(esp)2
Rh2(esp)2
none
0
1.0
1.0
1.0
1.0
5.0
0.3
0.3
-
68
78
73
84
0
3
<20
4
<20
5
<20
6
No reaction
<20
7
89
88
0
8
<20
9
No reaction
<20
10
11
12
13
14
15
16
S
1.0
1.0
1.0
1.0
5.0
0.3
0.3
Rh2(OAc)4
Rh2(OPiv)4
Rh2(CF3CO2)4
Rh2(esp)2
Cu(acac)2
Rh2(esp)2
Rh2(esp)2
61
65
60
74
0
S
<20
S
<20
S
<20
S
No reaction
<20
S
74
76
S
<20
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
The 74% 1H NMR yield of compound 9a observed under the best conditions (Table 1, Entry 13)
translated into 49% isolated yield after chromatography. With isolated compound 9a at hand we
proceeded to identify the workable conditions to convert it to the desired thiomorpholin-3-one
7a. The Boc group was first removed with neat TFA (10 min at r. t.) followed by evaporation of
the volatiles to dryness. Notably, using TFA solution in DCM at various concentrations and time
and temperature regimens was not effective to achieve a complete Boc group removal. Attempts
to basify the free amine obtained at this point and cyclize it to 7a were ineffective with
triethylamine in various solvents (DCM, MeOH, and toluene) and at various temperatures (r. t. to
reflux). However, using potassium carbonate in aqueous methanol proved effective and
furnished 86% yield of the target compound 7a in 18 h at room temperature. Applying the same
conditions to crude 9a (i. e. in one-pot fashion, following the Rh2(esp)2-catalyzed S-H insertion
step) resulted in 54% yield of compound 7a, which constituted a noticeable improvement
compared to the combined yield (42%) over two steps intermitted with chromatographic
isolation of 9a (Scheme 1).
Scheme 1. Investigated syntheses of compound 7a.
Thus, the same one-pot protocol was applied to various combinations of diazo compounds 3a-g
with N-Boc-protected -aminoethanols (4a-b) and/or -mercaptoethylamines (5a-d) (Figure 2).
It should be noted that diazo compounds 3a-g were conveniently prepared using the recently
developed ‘sulfonyl-azide-free’ (SAFE) diazo transfer protocol[13] from the respective CH2-
acidic precursors (except for compound 3g which was prepared from commercially available -
acetyl--burtyrolactone[14]) directly (3d,f) or via in situ -formylation (3a-c, 3e).[15]
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
Figure 2. Selection of -diazoacetates and Boc-protected partners for the X-H insertion –
lactamization investigated herein.
As it follows from the results presented in Scheme 2, the general X-H insertion – lactamization
sequence was found applicable to the preparation of a range of (thio)morpholin-3-ones 6(7). The
moderate yields obtained in some cases can be attributed to the low yield in the first step while
the lactamization step was rather efficient, even for sterically hindered amines. For example, the
low yield of compound 7f is clearly due to the limitations of the S-H insertion step (which alone
gave a disappointing 17% isolated yield) and not the lactamization which gave 70% yield when
performed on the isolated S-H insertion product.
An interesting result was obtained with diazo compound 3f (R2 = 4-NO2C6H4) for which no
product 6e was observed. In this case, a by-product which we believe could be product 6eʹ based
on NMR, HRMS and IR analysis was formed, most likely in the course of O-H insertion
reaction.[16] The unwanted hydroxylation is probably facilitated by the nitro group in the phenyl
ring as the analogous coupling with diazo compound 3e (R2 = 4-ClC6H4) gave only the desired
product (6f). Interestingly, no unwanted hydroxylation was observed in the reaction of 3f and 5a;
in this case, only the desired thiomorpholinone 7e was obtained in low (17%) yield. p-Methoxy-
substituted 3c generally gave moderate yields of 6c and 7d, in contrast to 3a or 3b (R2 = 4-
CH3C6H4 and 2-ClC6H4, respectively) which gave good yields of both 6 and 7.
Scheme 2. Preparation of morpholin-3-ones 6a-f and thiomorpholin-3-ones 7a-j.
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
In order to further demonstrate the utility of the synthetic approach presented herein and of the
resulting (thio)morpholin-3-ones 6(7), we exemplified two rather straightforward possibilities for
the downstream processing of the latter. Reduction of the carbonyl group in 6a with LiAlH4
resulted in morpholine 10 which is related to the recently reported agonists of trace amine-
associated receptors.[17] Oxidation of the sulfur atom in 7a with oxone gave sulfone 11 which is
related to compounds endowed with sedative properties18 (Scheme 3).
Scheme 3. Examples of the downstream processing of (thio)morpholin-3-ones 6(7).
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
Conclusion
We developed
a
stepwise coupling of N-Boc-protected -aminoethanols or -
mercaptoethylamines with various -diazoacetates. The process involves a Rh2(esp)2-catalyzed
X-H insertion reaction, Boc group removal and ambient-temperature lactamization and is
conveniently conducted in one-pot format. While there are a handful of examples describing a
similar assembly of morpholin-3-ones from ethyl diazoacetate in the literature, the approach has
not been explored neither for substituted -diazoacetates nor for -aminoethanols. These results
represent a new, unified approach to constructing (thio)morpholin-3-ones which are medicinally
important on their own or as building blocks for bioactive compound design.
Experimental section
General considerations. N-Boc protected 2-aminoethanol[S1], 2-(methylamino)ethanol[S2], 2-
aminoethanethiol[S3], (S)-methyl 2-amino-3-mercaptopropanoate[S4], methyl 2-diazo-2-(4-
nitrophenyl)acetate and methyl 2-diazo-2-(phenylsulfonyl)acetate[S5], 3-diazodihydrofuran-
2(3H)-one[S6] were prepared according literature methods, other reagents were obtained from
commercial sources and used without additional purification. Tetrahydrofuran and
dichloromethane were distilled over suitable 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 1H and
13
100.61 MHz for C) and were referenced to residual solvent proton peaks and solvent carbon
peaks. Melting points were determined with a Stuart SMP50 instrument in open capillary tubes.
Preparation of tert-butyl (2-mercaptocyclohexyl)carbamate (5c)
2-Aminocyclohexanol (1.0 g, 8.7 mmol) in carbon tetrachloride (50 mL) was cooled in an ice
bath. Chlorosulfonic acid (1.0 g, 8.7 mmol) was slowly added to the solution under stirring. The
reaction mixture was stirred overnight and carbon tetrachloride was removed in vacuo to give 1.3
g of crude 2-aminocyclohexyl hydrogen sulfate. 2-Aminocyclohexyl hydrogen sulfate (1.3 g, 6.8
mmol) was dissolved in 50 mL of aqueous ethanol (50%) and cooled in an ice bath. To the
resulting solution CS2 (1.6 g, 20.6 mmol) and KOH (1.0 g, 17.2 mmol) in 10 mL of aqueous
ethanol (50%) were slowly added and the mixture was refluxed over 3 h and evaporated to
dryness. The resulting solid was refluxed in water for 1 h, cooled, collected by filtration and
dried in vacuo to give 650 mg of hexahydrobenzo[d]thiazole-2(3H)-thione.
Hexahydrobenzo[d]thiazole-2(3H)-thione (650 mg, 3.7 mmol) was refluxed for 3 days in 10 mL
of 48% aq. HBr under argon and evaporated to dryness. Residue was triturated with Et2O (10
mL) to give 480 mg of 2-aminocyclohexanethiol hydrobromide. The obtained crude
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
hydrobromide (480 mg, 2.2 mmol) was dissolved in 50 mL of dichloromethane and Et3N (250
mg, 2.5 mmol) at room temperature, di-t-butyl dicarbonate (494 mg, 2.2 mmol) was dissolved in
10 mL of dichloromethane and added gradually to the reaction mixture. The reaction was stirred
overnight and the resulting solution was washed with saturated solution of sodium bicarbonate (2
× 50 mL) and water (2 × 50 mL), dried over MgSO4 and evaporated. tert-Butyl (2-
mercaptocyclohexyl)carbamate was purified using column chromatography on silica gel. Eluent
1
ethyl acetate – n-hexane 1:10. Yield 392 mg, 20%. Colorless oil. H NMR (400 MHz,
Chloroform-d) δ 4.88 (s, 1H), 3.94 – 3.68 (m, 1H), 3.53 – 3.20 (m, 1H), 1.95 – 1.82 (m, 2H),
1.71 – 1.24 (m, 15H).
Preparation of tert-butyl (1-mercapto-2-methylpropan-2-yl)carbamate (5b)
Prepared according to the procedure described for tert-butyl (2-mercaptocyclohexyl)carbamate
1
from 2-amino-2-methylpropan-1-ol. Yield 375 mg, 21%. H NMR (400 MHz, Chloroform-d) δ
3.23 (s, 1H), 2.88 (s, 2H), 1.46 (s, 9H), 1.33 (s, 6H).
General procedure for the synthesis of diazocarbonyl compounds (3a-c,e)
Preparation of the ‘SAFE cocktail’. To a stirred solution of sodium azide (1.96 g, 30 mmol)
and potassium carbonate (5.52 g, 40.0 mmol) in water (80 mL) was added 3-
(chlorosulfonyl)benzoic acid (5.88 g, 26.8 mmol) and the mixture was stirred at ambient
temperature for 10 minutes to give clear solution. The resulting aqueous solution was used for
diazo transfer reactions.
Preparation of diazocarbonyl compounds. To a cooled with ice bath stirred solution of
phenylacetic acid ester (5.0 mmol) and methyl formate (1.20 g, 20.0 mmоl) in dry THF (10 mL)
was added t-BuOK (1.40 g, 12.5 mmоl) in one portion. The mixture was stirred for 1 h, then the
cooling bath was removed and stirring was continued for overnight at ambient temperature. The
resulting mixture was cooled with ice bath followed by addition of a 20 mL of the ‘SAFE
cocktail’ prepared as described above. After addition the ice bath was removed and the mixture
was stirred for 1 h at ambient temperature. Upon completion of diazo transfer reaction, the
product was extracted with chloroform (3×20 mL), organic phase was dried over calcium
chloride and evaporated to dryness.
1
Methyl 2-diazo-2-(p-tolyl)acetate (3a). Yield 668 mg, 70%. Red oil. H NMR (400 MHz,
Chloroform-d) δ 7.44 – 7.35 (m, 2H), 7.26 – 7.15 (m, 2H), 3.88 (s, 3H), 2.37 (s, 3H).
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European Journal of Organic Chemistry
Methyl 2-(2-chlorophenyl)-2-diazoacetate (3b). Yield 754 mg, 72%. Yellow solid, mp 37.0-
1
38.0 ºC. H NMR (400 MHz, Chloroform-d) δ 7.57 (dd, J = 7.6, 1.9 Hz, 1H), 7.45 (dd, J = 7.8,
1.7 Hz, 1H), 7.38 – 7.30 (m, 2H), 3.87 (s, 3H).
Methyl 2-diazo-2-(4-methoxyphenyl)acetate (3c). Yield 380 mg, 37%. Orange solid, mp 45-
45.8 ºC. 1H NMR (400 MHz, Chloroform-d) δ 7.45 – 7.37 (m, 2H), 7.00 – 6.94 (m, 2H), 3.88 (s,
3H), 3.84 (s, 3H).
Methyl 2-(4-chlorophenyl)-2-diazoacetate (3e). Yield 705 mg, 67%. Orange solid, mp 57.0-
58.3 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.48 – 7.42 (m, 2H), 7.41 – 7.34 (m, 2H), 3.89 (s,
3H).
General procedure for morpholinone (6a-f)/thiomorpholinone (7a-j) synthesis
To a vigorously stirred solution of corresponding N-Boc aminoalcohol (N-Boc aminothiol)
(0.6 mmol) and diazo compound (0.65 mmol) in dichloromethane (5 mL) was added Rh2(esp)2
(1.6 mg, 0.002 mmol, 0.3 mol %). After completion of nitrogen evolution (30 minutes) the
reaction mixture was evaporated to dryness. To the resulting oil TFA (2 mL) was added. After
10 minutes the resulting mixture was evaporated to dryness, dissolved in methanol (5 mL), then
K2CO3 (3 mmol) and water (1 mL) were added. The resulting suspension was stirred at room
temperature overnight. On the next day water (4 mL) was added and the solution was extracted
with EtOAc (3×5 mL). Extracts were combined, washed with water, dried (MgSO4), evaporated
and purified using column chromatography on silica gel if needed.
2-(p-Tolyl)morpholin-3-one (6a). Eluent ethyl acetate – n-hexane 1:2. Yield 89 mg, 77%.
White solid, mp 119.0-120.8 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.36 (d, J =
8.2 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 5.14 (s, 1H), 4.00 (dt, J = 11.8, 4.2 Hz, 1H), 3.88 – 3.78
(m, 1H), 3.63 – 3.50 (m, 1H), 3.44 – 3.34 (m, 1H), 2.37 (s, 3H). 13C NMR (101 MHz,
Chloroform-d) δ 170.5, 138.3, 134.1, 129.2, 128.0, 79.5, 61.7, 42.0, 21.2. HRMS (ESI/Q-TOF)
m/z: [M+Na]+ Calcd for C11H13NO2 214.0838; Found 214.0844.
1
2-(2-Chlorophenyl)morpholin-3-one (6b). Yield 81 mg, 64%. Colorless oil. H NMR (400
MHz, Chloroform-d) δ 7.91 (s, 1H), 7.59 – 7.39 (m, 2H), 7.35 – 7.28 (m, 2H), 5.49 (s, 1H), 4.03
13
(dt, J = 11.9, 3.8 Hz, 1H), 3.95 – 3.82 (m, 1H), 3.75 – 3.55 (m, 1H), 3.41 – 3.25 (m, 1H). C
NMR (101 MHz, Chloroform-d) δ 169.8, 134.9, 134.6, 130.7, 130.1, 126.9, 77.6, 62.5, 41.9.
HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C10H10ClNO2 234.0292; Found 234.0295.
2-(4-Methoxyphenyl)morpholin-3-one (6c). Eluent ethyl acetate–n-hexane 1:3. Yield 38 mg,
30%. White solid, mp 140.5-141.9 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.39 (d, J = 8.8 Hz,
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
2H), 6.93 (d, J = 8.8 Hz, 2H), 5.14 (s, 1H), 4.11 – 3.98 (m, 1H), 3.82 (s, 4H), 3.67 – 3.59 (m,
13
1H), 3.49 – 3.38 (m, 1H). C NMR (101 MHz, Chloroform-d) δ 170.2, 159.8, 129.4, 129.2,
114.0, 79.4, 61.6, 55.3, 42.2, 1.01. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C11H13NO3
230.0788; Found 230.0797.
2-(Phenylsulfonyl)morpholin-3-one (6d). Eluent ethyl acetate. Yield 60 mg, 41%. White solid,
1
mp 136.0-138.2 °C. H NMR (400 MHz, Acetone-d6) δ 8.00 – 7.83 (m, 2H), 7.80 – 7.74 (m,
1H), 7.70 – 7.63 (m, 2H), 7.62 (s, 1H), 5.26 (s, 1H), 4.51 – 4.35 (m, 1H), 4.04 – 3.87 (m, 1H),
13
3.62 – 3.51 (m, 1H), 3.48 – 3.33 (m, 1H). C NMR (101 MHz, Acetone-d6) δ 159.9, 138.8,
133.9, 129.3, 128.9, 90.2, 61.8, 40.6. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C10H11NO4S
264.0301; Found 264.0289.
2-Hydroxy-4-methyl-2-(4-nitrophenyl)morpholin-3-one (6e′).
Eluent ethyl acetate.
Yield 30 mg, 21%. Yellow solid, mp 161.8-162.6 °C. 1H NMR (400 MHz, Acetone-d6) δ 8.35 –
8.15 (m, 2H), 8.07 – 7.89 (m, 2H), 6.36 (s, 1H), 4.51 (td, J = 11.6, 3.4 Hz, 1H), 4.08 – 3.81 (m,
2H), 3.51 – 3.30 (m, 1H), 2.93 (s, 3H). 13C NMR (101 MHz, Acetone-d6) δ 165.7, 149.1, 147.9,
128.4, 122.3, 96.2, 57.9, 48.8, 33.8. IR (KBr)  3303 (O-H), 1660, 1514, 1354, 1076, 845 cm-1.
HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C11H12N2O5 275.0644; Found 275.0623.
2-(2-Chlorophenyl)-4-methylmorpholin-3-one (6f). Yield 85 mg, 63%. Colorless oil. 1H NMR
(400 MHz, Chloroform-d) δ 7.44 – 7.39 (m, 1H), 7.37 – 7.33 (m, 1H), 7.31 – 7.20 (m, 2H), 5.46
(s, 1H), 4.11 – 4.03 (m, 1H), 3.99 – 3.88 (m, 1H), 3.79 – 3.62 (m, 1H), 3.33 (dt, J = 12.2, 3.6 Hz,
1H), 3.06 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 167.19, 135.37, 134.46, 130.66, 130.08,
129.90, 126.77, 77.85, 62.35, 48.83, 34.48. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for
C11H12ClNO2 226.0629; Found 226.0633.
Methyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)thio)-2-(p-tolyl)acetate (9a). Purified using
column chromatography on silica gel. Eluent ethyl acetate – n-hexane 1:5. Yield 80 mg, 49%.
Colorless oil. 1H NMR (400 MHz, Chloroform-d) δ 7.34 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 7.9 Hz,
2H), 4.98 (s, 1H), 4.62 (s, 1H), 3.72 (s, 3H), 3.38 – 3.14 (m, 2H), 2.75 – 2.55 (m, 2H), 2.33 (s,
3H), 1.44 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 171.38, 155.74, 138.12, 132.84, 129.45,
128.33, 79.34, 52.71, 51.56, 32.19, 28.37, 21.10. [M+Na]+ Calcd for C17H25NO4S 362.1402;
Found 362.1385.
2-(p-Tolyl)thiomorpholin-3-one (7a). Eluent ethyl acetate – n-hexane 1:1. Yield 63 mg, 54%.
White solid, mp 168.0-170.0 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.43 – 7.30 (m, 2H), 7.23
– 7.10 (m, 2H), 6.96 (s, 1H), 4.64 (s, 1H), 3.74 – 3.59 (m, 2H), 3.04 – 2.80 (m, 2H), 2.36 (s, 3H).
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
13C NMR (101 MHz, Chloroform-d) δ 169.7, 137.6, 134.1, 129.3, 128.5, 46.3, 44.2, 25.4, 21.1.
HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C11H13NOS 230.0610; Found 230.0601.
2-(4-Chlorophenyl)thiomorpholin-3-one (7b). Eluent ethyl acetate–n-hexane 1:3. Yield 75 mg,
55%. White solid, mp 134.9-137.0 C. 1H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.37 (m, 2H),
7.37 – 7.32 (m, 2H), 6.63 (s, 1H), 4.64 (s, 1H), 3.77 – 3.62 (m, 2H), 2.99 – 2.81 (m, 2H). 13C
NMR (101 MHz, Chloroform-d) δ 169.4, 135.6, 133.8, 130.1, 128.8, 45.8, 44.1, 25.6. HRMS
(ESI/Q-TOF) m/z: [M+Na]+ Calcd for C10H10ClNOS 250.0064; Found 250.0066.
2-(2-Chlorophenyl)thiomorpholin-3-one (7c). Eluent ethyl acetate – n-hexane 1:3. Yield 64
mg, 47%. White solid, mp 162.2-163.6 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.46 – 7.42 (m,
1H), 7.42 – 7.37 (m, 1H), 7.31 – 7.23 (m, 3H), 6.89 (s, 1H), 5.11 (s, 1H), 3.93 – 3.68 (m, 2H),
13
2.97 – 2.84 (m, 2H). C NMR (101 MHz, Chloroform-d) δ 168.7, 135.5, 134.3, 130.1, 129.8,
129.1, 126.9, 44.9, 43.3, 24.6. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C10H10ClNOS
250.0064; Found 250.0067.
2-(4-Methoxyphenyl)thiomorpholin-3-one (7d). Eluent ethyl acetate – n-hexane 1:3. Yield 25
mg, 19%. White solid, mp 162.2-163.8 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.32 (m,
2H), 7.04 (s, 1H), 6.95 – 6.86 (m, 2H), 4.64 (s, 1H), 3.82 (s, 3H), 3.73 – 3.60 (m, 2H), 2.99 –
13
2.82 (m, 2H). C NMR (101 MHz, Chloroform-d) δ 169.9, 159.2, 129.8, 128.9, 114.0, 55.3,
45.9, 44.2, 25.6. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C11H13NO2S 246.0559; Found
246.0548.
2-(4-Nitrophenyl)thiomorpholin-3-one (7e). Eluent ethyl acetate. Yield 24 mg, 17%. White
solid, mp 167.8-170.1 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.29 – 8.17 (m, 2H), 7.68 – 7.60
13
(m, 2H), 6.19 (s, 1H), 4.76 (s, 1H), 3.79 – 3.70 (m, 2H), 3.03 – 2.86 (m, 2H). C NMR (101
MHz, Acetone-d6) δ 167.3, 147.3, 145.8, 130.3, 123.2, 44.9, 43.4, 26.1. HRMS (ESI/Q-TOF)
m/z: [M+Na]+ Calcd for C10H10N2O3S 261.0304; Found 261.0307.
2-(4-Chlorophenyl)-5,5-dimethylthiomorpholin-3-one (7f). Eluent ethyl acetate – n-hexane
1
1:3. Yield 28 mg, 18%. White solid, mp 160.0-161.7 °C. H NMR (400 MHz, Chloroform-d) δ
13
7.34 (s, 4H), 5.93 (s, 1H), 4.51 (s, 1H), 2.93 – 2.34 (m, 2H), 1.46 (s, 6H). C NMR (101 MHz,
Chloroform-d) δ 167.7, 136.2, 133.6, 129.8, 128.7, 56.1, 46.0, 35.7, 30.1, 29.7. HRMS (ESI/Q-
TOF) m/z: [M+Na]+ Calcd for C12H14ClNOS 278.0377; Found 278.0367.
2-(Phenylsulfonyl)thiomorpholin-3-one (7g). Eluent ethyl acetate. Yield 56 mg, 35%. White
solid, mp 175.0-177.0 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.16 – 7.90 (m, 2H), 7.75 – 7.68
(m, 1H), 7.63 – 7.56 (m, 1H), 6.24 (s, 1H), 4.64 (s, 1H), 4.00 – 3.89 (m, 1H), 3.78 – 3.66 (m,
13
1H), 3.56 – 3.38 (m, 1H), 2.88 – 2.64 (m, 1H). C NMR (101 MHz, Chloroform-d) δ 207.2,
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159.9, 137.6, 134.4, 129.4, 129.0, 66.3, 44.1, 24.2. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for
C10H11NO3S2 280.0073; Found 280.0085.
(±) (2S,4aS,8aR)-2-(p-Tolyl)hexahydro-2H-benzo[b][1,4]thiazin-3(4H)-one (7h) and
(±) (2R,4aS,8aR)-2-(p-Tolyl)hexahydro-2H-benzo[b][1,4]thiazin-3(4H)-one (7h’)
Prior to chromatography the mixture of diastereomers was obtained. Individual diastereomers
were isolated by column chromatography, eluent ethyl acetate–n-hexane 1:10.
1
(7h) Yield 16 mg, 11%. White solid, mp 197.0-198.2 °C. H NMR (400 MHz, Chloroform-d) δ
7.29 (d, J = 6.3 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.10 (s, 1H), 4.71 (s, 1H), 3.88 – 3.77 (m, 1H),
3.52 – 3.44 (m, 1H), 2.36 (s, 3H), 2.22 – 2.07 (m, 1H), 1.99 – 1.87 (m, 1H), 1.86 – 1.74 (m, 2H),
1.71 – 1.59 (m, 2H), 1.54 – 1.47 (m, 1H), 1.46 – 1.36 (m, 1H). 13C NMR (101 MHz, Chloroform-
d) δ 170.2, 137.9, 132.3, 129.6, 129.2, 53.2, 46.3, 43.6, 30.6, 30.2, 23.3, 21.6, 21.2. HRMS
(ESI/Q-TOF) m/z: [M+Na]+ Calcd for C15H19NOS 284.1080; Found 284.1083.
(7h’) Yield 40 mg, 25%. White solid, mp 163.4-164.4 °C. 1H NMR (400 MHz, Chloroform-d) δ
7.38 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.05 – 6.84 (m, 1H), 4.64 (s, 1H), 3.87 – 3.62
(m, 1H), 3.25 – 3.06 (m, 1H), 2.35 (s, 3H), 2.05 – 1.76 (m, 1H), 1.73 – 1.55 (m, 2H), 1.49 – 1.34
13
(m, 2H). C NMR (101 MHz, Chloroform-d) δ 169.3, 137.2, 135.4, 129.3, 128.0, 54.1, 45.7,
39.0, 30.8, 29.4, 23.6, 21.3, 21.1. HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C15H19NOS
284.1080; Found 284.1086.
5-Oxo-6-(p-tolyl)thiomorpholine-3-carboxylic acid (7i) Last step reaction conditions lead to
hydrolysis of ester group to give mixture of cis/trans 1:1 product. Water (20 mL) was added to
the resulting suspension and washed with EtOAc (2x10). The resulting aqueous layer was
acidified with HCl and extracted with EtOAc (3x10). Combined organic layers were washed
with brine (2x5), dried (MgSO4) end evaporated to give pure product. Yield 42 mg, 28%. Yellow
solid. 1H NMR (400 MHz, Chloroform-d) δ 14.28 (s, 2H), 9.44 (s, 1H), 9.32 (s, 1H), 7.37 (d, J =
7.8 Hz, 2H), 7.31 – 7.24 (m, 3H), 7.22 – 7.16 (m, 3H), 4.70 (s, 1H), 4.60 (s, 1H), 4.56 – 4.43 (m,
1H), 4.33 – 4.23 (m, 1H), 3.39 – 3.23 (m, 2H), 3.14 – 2.81 (m, 2H), 2.36 (s, 6H). 13C NMR (101
MHz, DMSO-d6) δ 172.42, 172.28, 167.43, 167.03, 137.05, 136.87, 136.81, 135.79, 129.45,
129.28, 129.17, 128.59, 56.97, 56.76, 46.01, 45.27, 27.76, 25.39, 21.16, 21.11. HRMS (ESI/Q-
TOF) m/z: [M+Na]+ Calcd for C12H13NO3S 274.0508; Found 274.0512.
2-(2-Hydroxyethyl)thiomorpholin-3-one (7j)
On the first step tert-butyl (2-((2-oxotetrahydrofuran-3-yl)thio)ethyl)carbamate was purified by
column chromatography to give 113 mg. Eluent ethyl acetate – n-hexane 1:3. To the resulting oil
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2 mL of TFA were added. After 10 minutes the resulting mixture was evaporated to dryness,
dissolved in methanol (5 mL) and K2CO3 (3 mmol) was added. The resulting suspension was
stirred at room temperature overnight, evaporated and 10 ml of EtOAc were added. The resulting
suspension was filtered and filtrate was evaporated to give pure product. Yield 29 mg, 30%.
Colorless oil. 1H NMR (400 MHz, Deuterium Oxide) δ 3.80 – 3.73 (m, 1H), 3.71 – 3.61 (m, 1H),
13
3.58 – 3.48 (m, 1H), 2.97 – 2.89 (m, 1H), 2.31 – 2.17 (m, 1H), 1.96 – 1.82 (m, 1H). C NMR
(101 MHz, Deuterium Oxide) δ 174.3, 59.1, 42.7, 37.5, 33.0, 24.8. HRMS (ESI/Q-TOF) m/z:
[M+Na]+ Calcd for C6H11NO2S 184.0403; Found 184.0410.
2-(p-Tolyl)morpholine (10)
LAH (68 mg, 1.8 mmol) in THF (5 mL) was cooled to 0 °C in an ice bath under argon. A
solution of 2-(p-tolyl)morpholine (115 mg, 0.6 mmol) in THF (4 mL) was added dropwise, and
the resulting solution was stirred at RT for 16 hrs. The reaction mixture was cooled to 0 °C and
carefully quenched with water (0.5 mL), 2 N NaOH (0.5 mL) and water (1 mL). The resulting
slurry was stirred at RT for 1 h and filtered through Celite. The filter cake was washed with ethyl
acetate and discarded. The filtrate was dried (Na2SO4), separated, concentrated and purified
using column chromatography on silica gel. Eluent ethyl acetate – methanol 10:1. Yield 45 mg,
1
42%. Yellow oil. H NMR (400 MHz, Chloroform-d) δ 7.28 – 7.24 (m, 2H), 7.19 – 7.14 (m,
2H), 4.51 (dd, J = 10.5, 2.5 Hz, 1H), 4.10 – 4.01 (m, 1H), 3.83 (td, J = 11.4, 3.0 Hz, 1H), 3.47 (s,
2H), 3.14 – 3.07 (m, 1H), 3.07 – 2.93 (m, 2H), 2.83 (dd, J = 12.5, 10.4 Hz, 1H), 2.35 (s, 3H). 13C
NMR (101 MHz, Chloroform-d) δ 137.6, 137.1, 129.1, 126.0, 78.7, 67.8, 52.5, 45.2, 21.1.
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C11H15N1O 178.1226; Found 178.1227.
2-(p-Tolyl)thiomorpholin-3-one 1,1-dioxide (11)
Oxone (62 mg, 0.3 mmol) was added to the solution of 2-(p-tolyl)thiomorpholin-3-one (7a)
(369 mg, 0.6 mmol) in 10 mL of dioxane/water 5:1. The resulting suspension was stirred at room
temperature overnight. The resulting suspension was filtered and EtOAc (20 mL), water (20 mL)
were added to the filtrate. Organic layer was separated and aqueous layer was washed with
EtOAc (2x10 mL). Combined organic layers were washed with brine (2x10 mL), dried (MgSO4)
1
and evaporated to give pure product. Yield 44 mg, 61%. White solid, mp 201.8-202.5 °C H
NMR (400 MHz, DMSO-d6) δ 8.55 – 8.18 (m, 1H), 7.20 (s, 4H), 5.57 (s, 1H), 3.72 – 3.57 (m,
4H). 13C NMR (101 MHz, DMSO-d6) δ 165.6, 138.6, 132.1, 129.1, 124.8, 70.3, 47.7, 36.8, 21.2.
HRMS (ESI/Q-TOF) m/z: [M+Na]+ Calcd for C11H13N1O3S 262.0508; Found 262.0502.
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10.1002/ejoc.201901238
European Journal of Organic Chemistry
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, analytical data and 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
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was supported by the Russian Science Foundation (project grant 19-75-30008). We
thank Research Centre for Magnetic Resonance and the Center for Chemical Analysis and
Materials Research of Saint Petersburg State University Research Park for obtaining the
analytical data.
KEYWORDS: -diazoacetates; diazo transfer; Rh(esp)2 catalysis; metal carbene insertion;
lactamization.
REFERENCES
[1] Search performed on August 19th, 2019.
[2] (a) U. Trstenjak, J. Ilas, D. Kikelj, Helv. Chem. Acta 2013, 96, 2160-2172; (b) M. P. Moyer,
P. L. Feldman, H. Rapoport, J. Org. Chem. 1985, 50, 5223-5230.
[3] D. B. England, A. Padwa, J. Org. Chem. 2008, 73, 2792-2802.
[4] F. G. West, B. N. Naidu, J. Org. Chem. 1994, 59, 6051-6056.
[5] H. M. Mbuvi, E. R. Klobukowski, G. M. Roberts, L. K. Woo, J. Porphyrins Phthalocyanines
2010, 14, 284-292.
[6] L. Green, W. Guba, G. Jaeschke, S. Jolidon, L. Lindemann, A. Ricci, D. Rueher, D. H.
Stadler, E. Vieira, US Pat. Appl. 20110251169; Chem. Abstr. 2011, 135, 536165.
[7] (a) H. Rueeger, US Patent 8,338,413; Chem. Abstr. 2012, 158, 105157; (b) S. Badiger, M.
Chebrolu, M. Frederiksen, P. Holzer, K. Hurth, L. Li, H. Liu, R. M. Lueoend, R. Machauer, H.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901238
European Journal of Organic Chemistry
Moebitz, U. Neumann, R. Ramos, H. Rueeger, M. Schaefer, M. Tintelnot-Blomley, S. J.
Veenstra, M. Voegtle, X. Xiong, PCT Int. Appl. 2012006953; Chem. Abstr. 2012, 156, 203282;
(c) K. Hurth, R. M. Lueoend, R. Machauer, U. Neumann, H. Rueeger, M. Schaefer, M.
Tintelnot-Blomley, S. J. Veenstra, M. Voegtle, PCT Int. Appl. 2012095463; Chem. Abstr. 2012,
157, 229666.
[8] C.-S. Lee, J. S. Koh, K. D. Koo, G. T. Kim, K.-H. Kim, S. Y. Hong, S. Kim, M.-J. Kim, H. J.
Yim, D. Lim, H. J. Kim, H. O. Han, S. C. Bu, O. H. Kwon, S. H. Kim, G.-C. Hur, J. Y. Kim, Z.-
H. Yeom, D.-J. Yeo, PCT Int. Appl. WO2006104356; Chem. Abstr. 2006, 145, 397795.
[9] J. Keldenich, A. Denicourt-Nowicki, C. Michon, F. Agbossou-Niedercorn, Tetrahedron
2013, 69, 6424-6430.
[10] (a) M. Biava, G. C. Porretta, G. Poce, C. Battilocchio, S. Alfonso, A. D. Logu, N. Serra, F.
Manetti, M. Botta, Bioorg. Med. Chem. 2010, 18, 8076–8084; (b) D. L. Gray, W. Xu, B. M.
Campbell, A. B. Dounay, N. Barta, S. Boroski, L. Denny, L. Evans, N. Stratman, A. Probert,
Bioorg. Med. Chem. Lett. 2009, 19, 6604–6607; (c) A. M. Velázquez, L. Martínez, V. Abrego,
M. A. Balboa, L. A. Torres, B. Camacho, S. Díaz-Barriga, A. Romero, R. López-Castañares, E.
Angeles, Eur. J. Med. Chem. 2008, 43, 486–500.
[11] G. Carr, D. E. Williams, A. R. Díaz-Marrero, B. O. Patrick, H. Bottriell, A. D. Balgi, E.
Donohue, M. Roberge, R. J. Andersen, J. Nat. Prod. 2010, 73, 422–427.
[12] H. Keipour, T. Ollevier, Org. Lett. 2017, 19, 5736-5739.
[13] D. Dar'in, G. Kantin, M. Krasavin, Chem. Commun. 2019, 55, 5239-5242.
[14] I. Shershnev, D. Dar’in, S. Chuprun, G. Kantin, O. Bakulina, M. Krasavin, Tetrahedron
Lett. 2019, 60. 1800-1802.
[15] D. Dar'in, G. Kantin, M. Krasavin, Synthesis 2019, in press.
[16] P. Truong, X. Xu, M. P. Doyle, Tetrahedron Lett. 2011, 52, 2093-2096.
[17] G. Galley, M. Hoener, R. Norcross, P. Pflieger, PCT Int. Appl. WO 2017157873; Chem.
Abstr. 2017, 167, 420415.
[18] H. Lehr, S. Karlan, M. W. Gtdberg, J. Med. Chem. 1963, 6, 136-141.
[S1] M. Mansueto, W. Frey, S. Laschat, Chem. - Eur. J. 19 (2013) 16058–16065.
[S2] J.M. Chalker, L. Lercher, N.R. Rose, C.J. Schofield, B.G. Davis, Angew. Chem. Int. Ed. 51
(2012) 1835–1839.
[S3] B.E.-D.M. El‐Gendy, E.H.G. Zadeh, A.C. Sotuyo, G.G. Pillai, A.R. Katritzky, Chem. Biol.
Drug Des. 81 (2013) 577–582.
[S4] K.H. Pardon, S.D. Graney, D.L. Capone, J.H. Swiegers, M.A. Sefton, G.M. Elsey, J. Agric.
Food Chem. 56 (2008) 3758–3763.
[S5] D. Dar’in, G. Kantin, M. Krasavin, Chem. Commun. 55 (2019) 5239–5242.
[S6] Shershnev, I.; Dar'in, D.; Chuprun, S.; Kantin, G.; Bakulina, O.; Krasavin, M. Tetrahedron
Lett. 2019, 60. 1800-1802
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Graphical abstract
TOC text
Substituted -diazo acetates are coupled with N-Boc-protected -aminoethanols or -
mercaptoethylamines to give medicinally important (thio)morpholin-3-ones.
Key topic
Diazo compounds
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