Povarov Reaction of Cycloiminium Formed in Situ via Hydroamination Cycloisomerization of Homopropargylic Amines with Electron-Rich Olefins

Article abstract of DOI:10.1021/acs.joc.6b02496

A new, one-pot cascade reaction of homopropargylic amines with electron-rich olefins is developed in the presence of Cu(OTf)₂ and affords a series of octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline derivatives in yields of 38-80%. This reaction pro

Full text of DOI:10.1021/acs.joc.6b02496

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Article
The Povarov reaction of cycloiminium formed in situ via hydroamination
cycloisomerization of homopropargylic amines with electron-rich olefins
Qiangqiang Liu, Chan Wang, Qiang Li, Yajie Hou, Ye Wu, Lingyan Liu, Weixing Chang, and Jing Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02496 • Publication Date (Web): 21 Dec 2016
Downloaded from http://pubs.acs.org on December 23, 2016
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The Povarov reaction of cycloiminium formed in situ via
hydroamination cycloisomerization of homopropargylic
amines with electron-rich olefins
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Qiangqiang Liu1, Chan Wang1, Qiang Li1, Yajie Hou1, Ye Wu1, Lingyan Liu*1, Weixing
Chang1, Jing Li*1,2
1 the State Key Laboratory and Institute of Elemento-Organic Chemistry, the College of Chemistry, Nankai
University, Tianjin, 300071 (China)
2 Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Weijin Road 94#,
Nankai District, Tianjin 300071 (China)
E-mail: lijing@nankai.edu.cn; liulingyan@nankai.edu.cn
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ABSTRACT
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A new one pot cascade reaction of homopropargylic amines with electron-rich olefins is
developed in the presence of Cu(OTf)2, and affords a series of octahydrofuro[3,2-
c]pyrrolo[1,2-a]quinoline derivatives in yields of 38 to 80%. This reaction proceeds
through an intramolecular hydroamination cyclization of homopropargylic amine, to
generate a highly reactive cycloenamine intermediate in situ, which subsequently
isomerizes to cycloiminium cation, and followed by the Povarov-type reaction with
dihydrofuran, dihydropyran or dihydropyrrole. Notably, the Al2O3 additive plays a key role
for the effective inhibition of competitive self-dimerization of homoproargylic amines.
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INTRODUCTION
The Povarov reaction of N-arylimines with electron-rich olefins, an inverse electron-
demand aza-Diels-Alder (IEDDA), has been extensively explored.1 For the N-arylimines,
various strategies have been developed to access them, including cyclic amines. For
example, a typical condensation in situ or preparation in advance from aldehydes (or
ketones) and aromatic amines,2 or oxidation in situ of N-arylamines with active α-H,3 or
reduction of nitrobenzene derivatives.4 The former is the most classical and has been
widely used to comprise two-component methods or three-component approaches. As a
comparison, the latter two tactics were sparse. Especially, cycloiminium or oxidation of
cyclic amine enables the formation of polycyclic compounds.5 Therefore, it is highly
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desirable to develop novel N-arylimine equivalents or precursors as dienes in the Povarov
reaction for the construction of diverse tetrahydroquinoline derivatives, which are
ubiquitous scaffolds with a wide range of biological activities such as antifungal,
antimicrobial, anti-HIV, antibacterial, anti-inflammatory and anticancer.6 Our research
group has developed several cascade reactions of simple homopropargylic amines. It was
found that the homopropargylic amines could act as potential both 2C and 4C synthons.
Moreover, the dual roles of 4C and 2C synthons or a single role of 2C synthon has been
realized with the addition of other appropriate substrate molecules, respectively (Scheme
1).7 Based on these results, we envisioned that the single 4C synthon identity may be also
accessible. In fact, to achieve a single 4C synthon role of the homopropargylic amine, it is
full of great challenging and more difficult than the single 2C synthon role-play. It is
because that once cycloiminium cation is generated through isomerization of cycloenamine
formed in situ via an intramolecular hydroamination cyclization of homopropargylic amine,
it will inevitably react with its isomer cycloenamine to give a formal dimerized compound.
In spite of this, we believe that this competitive side reaction can be reduced as low as
possible through controlling the reaction conditions or introducing additional higher
reactivity substrates. Thus, the electron-rich cyclic alkenes were herein employed to react
with homopropargylic amines. To our delight, we could obtain the expected cycloaddition
product 4 in good yields through the great amount of experimental parameters screenings
(Scheme 1, this work).
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Scheme 1. The diverse reactions of homopropargylic amines
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RESULTS AND DISCUSSION
In our initial study, the dihydrofuran was selected as a model substrate to react with the
simple homopropargylic amine 1a under previously developed standard reaction
conditions. Consequently, the cross-cycloaddition products 4a and 4a’ were obtained in a
low yield (24%) but with the major self-dimerization compound 3a (Table 1, entry 1). In
order to inhibit the self-dimerization of homopropargylic amine 1a, we attempted to
introduce some additives (Table 1). Acid additives were firstly selected to accelerate the
isomerization of cycloenamine to cycloiminium cation. For example, the strong acid,
CF3COOH, and weak acid, CH3COOH and PhCOOH, could indeed increase the desired
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product’s yield (entries 2-4). The Lewis acid Sc(OTf)3 was also examined (entry 5).
However, no further improved results were obtained. Other microenvironment adjustment
was then considered through adding NaCl,8 silica gel9 and acidic Al2O310 into the reaction
system (entries 6-8). Surprisingly, this reaction gave obviously increased yield of cross-
cycloaddition product 4a and 4a’ with the addition of silica gel orAl2O3. More interestingly,
using the Al2O3 activated by water, a slightly higher yield of target compound was
generated (entry 9). It is noteworthy that the target compounds were obtained with
endo/exo-configuration in 63:37 diastereomeric ratio and the self-dimerization product 3a
was accompanied in more or less in all cases (Table 1).
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Why was the Al2O3 competent auxiliary in this reaction? With this question in our mind,
some explored experiments were further performed (Table 1, entries 10-14). The types and
levels activated by water of Al2O3 were subtly examined. As shown in table 1, it was found
that the I-activated level of acidic Al2O3 gave higher yield of cross-cycloaddition product
than neutral and basic Al2O3 (entries 10-13). These results demonstrated that the acidic
microenvironment was favor to the isomerization of cycloenamine to cycloiminium cation.
Additionally, a metal oxide, CuO, acting as a Lewis acid, was tested. As a result, this
reaction could also smoothly proceed and afford the corresponding product in moderate
yield (Table 1, entry 14). Obviously, the Al2O3 was superior to the CuO in this reaction. In
view of these results, we surmised that the unique reticular structure property and Lewis
acidity as well as weak protonic acidity of Al2O3 endow it special catalytic activity in this
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reaction, accelerating the isomerization of cycloenamine formed in situ to cycloiminium
cation, and thus impeding the occurrence of self-dimerization.
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Table 1. The screening of additives in the cascade reaction of homopropargylic amine 1a and
dihydrofurana
entry
Additive (equiv)
-
Total yield (4a + 4a’) (%)c Self-dimerized product yield (3a) (%)f
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CF3COOH (0.2)
CH3COOH (0.2)
PhCOOH (0.2)
Sc(OTf)3 (0.1)
NaCl (2.0)
Silica gel (2.0)
Al2O3 (2.0)
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9d
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Al2O3 (2.0)
Acidic Al2O3 (2.0)
Neutral Al2O3 (2.0)
Basic Al2O3 (2.0)
Acidic Al2O3 (2.0)
CuO (2.0)
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a
Reaction conditions: 1a (24 mg, 0.1 mmol, 1.2 equiv), dihydrofuran (21 mg, 0.3 mmol, 3.0 equiv), 5
mol % Cu(OTf)2 (0.005 mmol, 1.8 mg, 5 mol%), a certain amount of additive and DCE (1 mL) were
sequentially added into a tube. The reaction was carried out under the given reaction conditions and the
products were subsequently detected by TLC; b The diastereomeric ratios were determined based upon NMR
analysis of the crude products; c Isolated yield; d the 1mmol Al2O3 was activated by 25 ul H2O; e The Al2O3
was activated and named as II-activated level (1 mmol Al2O3 + 50 ul H2O), the above Al2O3 was activated
f
and named as I-activated level (1 mmol Al2O3 + 25 ul H2O) (acidic, neutral, basic); The side product is
(3a).
Then the other experimental parameters, such as solvents, reaction temperature and the
amount of catalyst and electron-rich olefins were investigated (Table 2). As a result, the
anisole displays advantage over other common used organic solvents (entries 1-8). And the
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60 C was the optimal (entries 9-10). In addition, whether increasing or reducing the
loading of Cu(OTf)2, the reaction gave decreased yield of target compound (Table 2, entries
11-15). In the case of 30 mol% Cu(OTf)2, most of the homopropargylic amine 1a suffered
decomposed (entry 14). Moreover, no obvious improved results were obtained in the case
of the increased amount of dihydrofuran (entries 16-17). Based on the above results, the
optimal reaction conditions were 5 mol% Cu(OTf)2, 2 equiv Al2O3, 3 equiv dihydrofuran
at 60 oC in the anisole.
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Table 2. The other experimental parameters screening in the reaction of homopropargylic amine 1a
and dihydrofurana
entry
Solv.
Temp.
(oC)
Cu(OTf)2
(mol%)
1H NMR
dr
Isolated
Yield (%)b
(endo:exo)c
Yield (%)
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DCE
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--
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MeOH
CH3CN
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trace/51d
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PhMe
PhOMe
THF
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85
r.t.
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DMF
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1,4-dioxane
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
PhOMe
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a Reaction conditions: 1a (24 mg, 0.1 mmol), dihydrofuran (21 mg, 0.3 mmol, 3.0 equiv), a certain amount
of Cu(OTf)2, Al2O3 (0.2 mmol, 20.4 mg, 2.0 equiv) and solvent (1 mL) were sequentially added into a tube.
The reaction was carried out under the given reaction conditions and the products were subsequently detected
by TLC (generally 3-4 h); b The NMR yield was calculated by adding a certain amount of DMF as an internal
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standard; c The diastereomeric ratios were determined based upon 1H NMR analysis of the crude products; d
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the yield of self-dimerized side product; the reaction time was 6 h; the amount of dihydrofuran was 0.4
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mmol (4.0 equiv); g the amount of dihydrofuran was 0.5 mmol (5.0 equiv).
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Having established the optimized reaction conditions, the scope of homopropargylic
amines was scrutinized by performing the reaction with dihydrofuran (Table 3). Generally,
all tested homopropargylic amines were able to tolerate this catalytic system to afford the
desired product 4a-o and 4a’-o’ in moderate to good yields (38%-80%). It should be noted
that all these reactions were traced by thin layer chromatography (TLC) with the small
amount of self-dimerization side products. And in the case of 4-CF3-substituted N-aryl
homopropargylic amine, only the self-dimerization competitive side product was obtained
in 78% yield. For the homopropargylic amine with R1 = 4-NO2-C6H4, the corresponding
products contained four diastereoisomers. In addition, all products were racemic. And the
endo or exo-configuration of the target compound was confirmed according to the x-ray
1
single crystal diffraction of exo-4q’ and theirs H NMR. And the endo or exo-
configurational product contains the extremely small amount of diastereoisomers,
respectively.
Table 3. The scope of homopropargylic amines and dihydrofurana
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a Reaction conditions: Homopropargylic amines 1 (0.1 mmol), dihydrofuran (21 mg, 0.3 mmol, 3.0 equiv),
Cu(OTf)2 (0.005 mmol, 1.8 mg, 5 mol%), Al2O3 (0.2 mmol, 20.4 mg, 2.0 equiv) and anisole (1 mL) were
o
sequentially added into a tube. The reaction was carried out at 60 C in the air and the products were
subsequently detected by TLC (generally 3-4 h); b The product was the self-dimerization compound (yield
78%); c The products contained four diastereoisomers (The diastereomeric ratios were determined based upon
NMR analysis of the crude products).
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Several other electron-rich olefins were further employed to test this methodology
application (Scheme 2). Under the above optimized reaction conditions, the reaction
resulted in the expected octahydro-2H-pyrano[3,2-c]pyrrolo[1,2-a]quinoline product in
low yield (27%) in the case of dihydropyran. Therefore, further additive screening
experiments were carried out as shown in Table 4. Interestingly, the Sc(OTf)3 exhibited the
best catalytic activity for the reaction of dihydropyran and homopropargylic amine 1a
(Table 4). And this reaction gave only one endo-configurational product 4p with excellent
diastereoselectivity (dr > 25:1) (Scheme 2, eq 1). Similarly, the N-Ts protected
dihydropyrrole rendered the corresponding products 4q and 4q’ in 80% yield with
Cu(OTf)2 and Sc(OTf)3 as cocatalysts. The exact configuration of exo-4q’ was
unambiguously determined by a single crystal X-ray diffraction (Figure 1).11 However, this
catalytic system was incompatible with vinyl n-butyl ether or vinyl t-butyl ether (4r-s).
Fortunately, using our developed methodology, a lung cancer inhibitor 4t could be facilely
synthesized in good yield (Scheme 2, eq 2)12.
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Table 4. The additive effect on the reaction of homopropargylic amine 1a and dihydropyrana
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Entry Additive (equiv) Isolated yield (%)b dr (endo:exo)c
6
7
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9
Al2O3 (2.0)
27
62
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30
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>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
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Sc(OTf)3 (0.1)
Y(OTf)3 (0.05)
Y(OTf)3 (0.1)
Yb(OTf)3 (0.1)
In(OTf)3 (0.1)
Zn(OTf)2 (0.1)
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SnCl2 (1.0)
SnCl2 (2.0)
41
36
48
>25:1
>25:1
>25:1
BF3·OEt (0.1)
10
a
Reaction conditions: 1a (24 mg, 0.1 mmol), dihydropyran (25.2 mg, 0.3 mmol, 3.0 equiv), 5 mol%
Cu(OTf)2 (1.8 mg), additive and anisole (1 mL) were sequentially added into a tube. The reaction was carried
out under the given reaction conditions and the products were subsequently detected by TLC; b Isolated yield;
c The diastereomeric ratios were determined based upon NMR analysis of the crude products.
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Figure 1. The ORTEP drawing (30% thermal ellipsoids) of exo-4q’
Scheme 2. The reactions of homopropargylic amine 1a and other electron-rich olefins.
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CONCLUSION
In summary, a novel Povarov reaction of cycloiminium with electron-rich olefins was
developed for the preparation of octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline derivatives.
The cycloiminium was formed in situ via a simple and efficient Cu-catalyzed
intramolecular hydroamination cycloisomerization reactions of homopropargylic amines.
Various homopropargylic amines were well tolerated in this methodology to give the
corresponding desired products in moderate to good yields. More importantly, the
inevitable competitive self-dimerization of homopropargylic amines could be effectively
reduced through introducing the Al2O3 additive or Sc(OTf)2 as a cocatalyst.
EXPERIMENTAL SECTION
1. General Information
The 1H NMR and 13C NMR spectra were recorded at 400 MHz or 600 MHz. 1H and 13C
NMR Chemical shifts were calibrated to tetramethylsilane as an internal reference.
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Chemical shifts are given in (ppm) and coupling constants (J) in Hz. The following
abbreviations are used to indicate the multiplicity: s, singlet; d, doublet: t, triplet; q, quartet;
m, multiplet; High resolution mass spectra (HRMS) were measured on a mass spectrometer
equipped with a TOF system and an electrospray ionization (ESI) ion source.
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2. Synthesis and Characterization of N-(4-nitrophenyl)benzene-1,4-diamine13
The 1-fluoro-4-nitrobenzene (5 mmol, 705 mg), Na2CO3 (5.0 mmol, 530 mg), 1,4-
phenylenediamine (10 mmol, 1.08 g) and 7 mL of water were sequentially added into a
flask and refluxed for 10 h. Then the reaction mixture was cold and 10 mL of toluene were
added and stirred vigorously for another 1 h. The precipitated product was collected by
filtration and washed thoroughly with water and toluene. The N-(4-nitrophenyl) benzene-
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1
1,4-diamine was obtained as an orange solid with 1.1 g, yield 78%, m.p. 210-211 C. H
NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.03-7.98 (m, 2H), 6.95-6.89 (m, 2H), 6.79-
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6.73 (m, 2H), 6.64-6.58 (m, 2H), 5.10 (s, 2H). C NMR (101 MHz, DMSO-d6) δ 153.2,
146.4, 136.4, 127.7, 126.4, 124.8, 114.6, 111.7. HRMS (ESI+) calculated for C12H12N3O2
(M+H+) 230.0930; found 230.0926.
3. Synthesis and Characterization of Homopropargylic Amines
The homopropargylic amines were prepared according to the known procedures7.
Because our research group has synthesized a series of homopropargylic amines, we herein
directly used or synthesized these substrates through using well-developed methods. And
these substrates are all known, the characterizations are consistent with that of our
synthesized compounds.
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General procedure for Homopropargylic Amines (1a-1o)
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An aluminum amalgam was prepared from aluminum powder (0.5 g, 18.0 mmol) and a
catalytic amount of mercuric chloride (10 mg) in 7.5 mL anhydrous THF by vigorously
stirring at room temperature for 1 h under a N2 atmosphere. A solution of propargylic
bromide (18.0 mmol) in 12.5 mL of anhydrous THF was then slowly added to the
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suspension at such a rate as to maintain the temperature between 30-40 C. After the
addition, the reaction mixture was continued to stir until a dark grey solution was formed.
The generated propargylic aluminum sesqui-bromide solution was added to a solution of
imine (6.0 mmol) in 20.0 mL of anhydrous THF at 0 oC under N2 atmosphere. The reaction
mixture was stirred at 0 oC for about 1 h, then warmed to room temperature and continued
to stir for additional 3-4 h (monitored by TLC). The mixture was quenched by adding
saturated NH4Cl aqueous solution, and extracted with EtOAc (3 × 20 mL). The combined
organic extracts were washed with brine and dried over MgSO4, and then filtered, the
filtration was concentrated in vacuo to give the residue. The residue was purified by flash
chromatography over silica gel (gradient elution of EtOAc /petroleum ether, PE : EA = 50 :
1).
N-(1-phenylbut-3-yn-1-yl)-4-(trifluoromethyl)aniline 1d
White solid, 1.44 g, yield 83%, m.p. 34.7-35.8 oC. 1H NMR (400 MHz, CDCl3) δ 7.32-
7.17 (m, 7H), 6.47 (d, J = 8.5 Hz, 2H), 4.66 (s, 1H), 4.49 (dd, J = 7.0, 5.2 Hz, 1H), 2.72
(ddd, J = 16.9, 5.3, 2.7 Hz, 1H), 2.58 (ddd, J = 16.9, 7.0, 2.7 Hz, 1H), 2.01 (t, J = 2.7 Hz,
13
1H). C NMR (101 MHz, CDCl3) δ 149.5, 141.3, 129.0, 128.0, 126.6 (d, J = 3.8 Hz),
126.4, 113.0, 79.9, 72.0, 56.1, 28.2. HRMS (ESI-) calculated for C17H13F3N (M-H+)
288.1000; found 288.1033.
N-(1-(4-nitrophenyl)but-3-yn-1-yl)aniline 1h
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Orange oil liquid, 1.06 g, yield 78%. 1H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J =
8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.03 (t, J = 7.7 Hz, 2H), 6.63 (t, J = 7.3 Hz, 1H),
6.41 (d, J = 8.0 Hz, 2H), 4.55 (t, J = 6.0 Hz, 1H), 4.41 (s, 1H), 2.73 (ddd, J = 16.9, 5.5, 2.7
Hz, 1H), 2.60 (ddd, J = 16.9, 6.5, 2.6 Hz, 1H), 2.03 (t, J = 2.7 Hz, 1H).13C NMR (101 MHz,
CDCl3) δ 149.8, 147.5, 146.3, 129.4, 127.5, 124.1, 118.6, 113.8, 79.1, 77.5, 77.2, 76.8,
72.5, 55.9, 27.9. HRMS (ESI-) calculated for C16H13N2O2 (M-H+) 265.0977; found
265.0981.
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4-bromo-N-(1-(p-tolyl)but-3-yn-1-yl)aniline 1i
Light yellow oil liquid, 1.41 g, yield 75%, m.p. 85.5-87.9 oC. 1H NMR (400 MHz, CDCl3)
δ 7.28 (dd, J = 7.2, 2.0 Hz, 2H), 7.19 (ddd, J = 10.2, 8.4, 2.0 Hz, 4H), 6.45 (dd, J = 8.7, 2.1
Hz, 2H), 4.59-4.39 (m, 1H), 2.87-2.57 (m, 2H), 2.36 (d, J = 1.9 Hz, 3H), 2.11 (q, J = 2.4
Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 146.1, 138.6, 137.5, 132.0, 129.6, 126.3, 115.4,
109.6, 80.3, 71.7, 56.3, 28.2, 21.3. HRMS (ESI+) calculated for C17H17BrN (M+H+)
314.0544; found 314.0543.
N-(1-(thiophen-2-yl)but-3-yn-1-yl)aniline 1m
1
Orange oil liquid, 845.6 mg, yield 62%. H NMR (400 MHz, CDCl3) δ 7.27-7.18 (m,
3H), 7.12 (d, J = 3.5 Hz, 1H), 7.02 (dd, J = 5.0, 3.6 Hz, 1H), 6.80 (t, J = 7.3 Hz, 1H), 6.72
(d, J = 8.0 Hz, 2H), 4.93 (t, J = 5.9 Hz, 1H), 4.41 (s, 1H), 2.96-2.79 (m, 2H), 2.15 (t, J =
2.7 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 146.9, 146.7, 127.0, 124.5, 124.2, 118.6, 114.1,
80.0, 71.9, 52.7, 28.1. HRMS (ESI+) calculated for C14H14NS (M+H+) 228.0847; found
228.0845.
2-phenyl-1-tosyl-2,3-dihydro-1H-pyrrole
The synthesis of 2-phenyl-1-tosyl-2,3-dihydro-1H-pyrrole was performed according to
the previously reported procedure14
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White solid, 61.5 mg, yield 70%, m.p. 103-105 oC, 1H NMR (400 MHz, Chloroform-d)
δ 7.65 (d, J = 7.9 Hz, 2H), 7.45-7.24 (m, 7H), 6.55 (d, J = 4.0 Hz, 1H), 5.14 (d, J = 4.0 Hz,
1H), 4.74 (dd, J = 11.0, 6.3 Hz, 1H), 2.94 (dd, J = 16.6, 11.2 Hz, 1H), 2.51 (d, J = 6.2 Hz,
1H), 2.47 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 143.8, 142.8, 134.0, 130.9, 129.7, 128.9,
128.6, 127.7, 127.6, 126.4, 110.3, 63.1, 40.8, 21.7. HRMS (ESI+) calculated for
C17H18NO2S (M+H+) 300.1058; found 300.1056.
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Synthesis and Characterization of Homopropargylic Amines (1q)
N-(4-nitrophenyl)benzene-1,4-diamine (4 mmol, 916.9 mg) was added to the Ar-purged
flask in DMF (24 mL). K2CO3 (4.2 mmol, 580.3 mg) and 4-bromo-1-butyne (4.1 mmol,
545.3 mg) were added to the reaction system and the reaction mixture was stirred at 85 oC
for 12 h. The mixture was then quenched by saturated NH4Cl aqueous solution and
extracted with ethyl acetate for three times, the combined organic layers were washed with
brine and dried with anhydrous MgSO4. Then the extracts were filtered and the filtration
was concentrated to give a yellow liquid residue. The residue was purified by flash column
chromatography on silica gel (EtOAc /petroleum ether, PE : EA = 1 : 10) to afford the
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orange solid 1q, 382.6 mg, yield 34%, m.p. 55-57 C. 1H NMR (400 MHz, Chloroform-d)
δ 8.09-8.02 (m, 2H), 7.09-7.01 (m, 2H), 6.76-6.63 (m, 4H), 6.15 (s, 1H), 4.05 (s, 1H), 3.33
(t, J = 6.6 Hz, 2H), 2.53 (td, J = 6.5, 2.7 Hz, 2H), 2.07 (t, J = 2.6 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 152.5, 146.0, 138.8, 129.3, 126.5, 126.3, 114.0, 112.4, 81.7, 70.4, 42.7,
19.2. HRMS (ESI+) calculated for C16H16N3O2 (M+H+) 282.1243; found 282.1242.
4. The general procedure of this cascade reaction of homopropargylic amines with
olefins
Cu(OTf)2 (1.81 mg, 5 mol %) was added to a solution of homopropargylic amines (0.1
mmol), Al2O3 (0.2 mmol, 20.4 mg, 2.0 equiv) and 2,3-dihydrofuran (21 mg, 0.3 mmol) in
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1 mL anisole, and the mixture was stirred at 60 oC until the complete disappearance of the
starting material (monitored by TLC). The mixture was passed through a short kieselguhr
column by using CH2Cl2, the filtration was concentrated in vacuo and purified by column
chromatography with gradient elution (Silica gel, petroleum ether : EtOAc, gradient from
50 : 1 to 10 : 1) to give the final products 4. All the products are racemic. And the endo or
exo-configurational product contains the extremely small amount of diastereoisomers,
respectively.
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10-fluoro-6-phenyl-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline 4a (endo)
Orange oil liquid, 14.03 mg, yield 45%. 1H NMR (400 MHz, CDCl3) δ 7.20 (dt, J = 7.3,
4.6 Hz, 2H), 7.17-7.10 (m, 1H), 7.07 (d, J = 7.3 Hz, 2H), 6.99 (dt, J = 9.0, 2.9 Hz, 1H),
6.61 (m, 1H), 6.06 (m, 1H), 4.70 (m, 1H), 4.37 (t, J = 3.3 Hz, 1H), 4.06-3.87 (m, 1H), 3.80
(m, 1H), 3.32 (m, 1H), 2.45-2.29 (m, 1H), 2.19 (m, 2H), 1.79 (m, 3H), 1.71-1.60 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 154.6 (d, J = 235.3), 144.3, 139.9, 128.7, 126.8, 125.8,
117.4 (d, J = 21.6), 116.0 (d, J = 22.1), 113.7 (d, J = 7.1), 120.0 (d, J = 8.1 Hz), 76.8, 65.0,
64.7, 57.7, 39.8, 34.3, 29.7, 29.0. HRMS (ESI+) calculated for C20H20FNO (M+H+)
310.1607; found 310.1600.
10-fluoro-6-phenyl-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline
4a’ (exo)
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Orange oil liquid, 8.24 mg, yield 27%. H NMR (400 MHz, CDCl3) δ 7.22 (t, J = 7.2
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Hz, 2H), 7.15 (q, J = 7.6 Hz, 1H), 7.08 (d, J = 7.5 Hz, 2H), 6.98 (dd, J = 9.4, 3.0 Hz, 1H),
6.50 (td, J = 8.4, 2.8 Hz, 1H), 5.88 (dd, J = 4.4, 4.4 Hz, 1H), 5.10 (d, J = 7.2 Hz, 1H), 4.66
(dd, J = 7.8, 5.2 Hz, 1H), 4.19 (m, 1H), 3.85-3.69 (m, 3H), 2.67-2.57 (m, 1H), 2.53-2.41
(m, 1H), 2.08 (m, 1H), 1.92-1.58 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 155.1 (d, J =
253.3), 144.7, 138.8, 128.9, 126.8, 125.7, 115.2 (d, J = 23.0), 114.8 (d, J = 22.0), 112.3 (d,
J = 7.0), 122.5 (d, J = 6.1 Hz), 75.7, 66.6, 63.7, 56.7, 41.6, 35.9, 29.7, 24.8. HRMS (ESI+)
calculated for C20H21FNO (M+H+) 310.1607; found 310.1600.
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10-chloro-6-phenyl-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline
4b (endo)
Colorless liquid, 13.9 mg, yield 43%. 1H NMR (400 MHz, CDCl3) δ 7.28-7.11 (m, 4H),
7.10-7.02 (m, 2H), 6.84 (dd, J = 8.8, 2.6 Hz, 1H), 6.07 (d, J = 8.8 Hz, 1H), 4.74 (dd, J =
7.9, 3.8 Hz, 1H), 4.38 (d, J = 4.3 Hz, 1H), 3.98 (m, 1H), 3.84 (m, 1H), 3.34 (m, 1H), 2.42
(m, 1H), 2.22 (m, 2H), 1.81 (m, 3H), 1.67 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 143.9,
141.9, 131.1, 129.1, 128.8, 126.9, 125.8, 120.5, 114.1, 76.7, 65.0, 64.4, 57.7, 39.9, 34.5,
29.7, 29.3. HRMS (ESI+) calculated for C20H21ClNO (M+H+) 326.1312; found 326.1303.
10-chloro-6-phenyl-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline
4b’ (exo)
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Colorless liquid, 10.5 mg, yield 32%. 1H NMR (400 MHz, CDCl3) δ 7.37-7.28 (m, 5H),
7.28-7.21 (m, 1H), 7.17 (dd, J = 7.0, 1.7 Hz, 2H), 6.82 (dd, J = 8.8, 2.5 Hz, 1H), 5.99 (d, J
= 8.7 Hz, 1H), 5.20 (d, J = 7.1 Hz, 1H), 4.77 (dd, J = 7.8, 5.6 Hz, 1H), 4.29 (td, J = 8.8,
3.5 Hz, 1H), 3.97-3.81 (m, 2H), 2.74 (m, 1H), 2.59 (m, 1H), 2.25-2.13 (m, 1H), 2.01-1.68
(m, 4H). 13C NMR (101 MHz, CDCl3) δ 144.3, 140.9, 129.0, 128.7, 128.1, 126.9, 125.7,
122.9, 121.0, 112.9, 75.4, 66.6, 63.4, 56.7, 41.3, 36.0, 29.8, 24.8. HRMS (ESI+) calculated
for C20H21ClNO (M+H+) 326.1312; found 326.1303.
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10-bromo-6-phenyl-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline
4c (endo)
Colorless liquid, 17.6 mg, yield 48%. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 5.0 Hz,
1H), 7.19 (m, 3H), 7.11-7.03 (d, J = 7.2 Hz, 2H), 6.96 (dd, J = 8.8, 2.4 Hz, 1H), 6.02 (d, J
= 8.8 Hz, 1H), 4.73 (dd, J = 7.9, 3.9 Hz, 1H), 4.38 (d, J = 4.0 Hz, 1H), 3.98 (m, 1H), 3.84
(m, 1H), 3.38-3.29 (m, 1H), 2.42 (m, 1H), 2.22 (m, 2H), 1.88-1.76 (m, 3H), 1.73-1.62 (m,
1H). 13C NMR (101 MHz, CDCl3) δ 143.8, 142.3, 134.0, 131.9, 128.8, 126.9, 125.8, 121.1,
114.6, 107.5, 76.7, 65.0, 64.4, 57.7, 39.9, 34.5, 29.8, 29.3. HRMS (ESI+) calculated for
C20H21BrNO (M+H+) 370.0807; found 370.0794.
10-bromo-6-phenyl-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline
4c’ (exo)
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Colorless liquid, 8.7 mg, yield 23%. 1H NMR (400 MHz, CDCl3) δ 7.35-7.33 (d, J = 2.0
Hz, 1H), 7.28-7.12 (m, 4H), 7.10-7.03 (m, 2H), 6.85 (dd, J = 8.8, 2.5 Hz, 1H), 5.84 (d, J =
8.8 Hz, 1H), 5.10 (d, J = 7.1 Hz, 1H), 4.66 (dd, J = 7.8, 5.6 Hz, 1H), 4.18 (td, J = 7.6, 3.2
Hz, 1H), 3.87-3.71 (m, 2H), 2.64 (m, 1H), 2.49 (m, 1H), 2.14-2.04 (m, 1H), 1.93-1.57 (m,
4H). 13C NMR (101 MHz, CDCl3) δ 144.2, 141.2, 131.5, 130.9, 129.0, 126.9, 125.7, 123.4,
113.4, 108.1, 75.4, 66.6, 63.4, 56.7, 41.3, 36.0, 29.8, 24.8. HRMS (ESI+) calculated for
C20H21BrNO (M+H+) 370.0807; found 370.0793.
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6-phenyl-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline 4e and 4e’
Colorless liquid, 18.6 mg, yield 64%, dr (endo:exo) = 63:37. 1H NMR (400 MHz, CDCl3)
δ 7.31-7.18 (m, 6H), 7.18-7.07 (m, 5H), 6.95-6.88 (m, 1H), 6.83-6.77 (m, 0.51H), 6.54 (m,
1.48H), 6.17 (d, J = 8.2 Hz, 1H), 5.99 (d, J = 8.2 Hz, 0.53H), 5.17 (d, J = 7.3 Hz, 0.55H),
4.78 (dd, J = 8.0, 3.5 Hz, 1H), 4.72 (dd, J = 7.9, 5.1 Hz, 0.59H), 4.45 (d, J = 4.3 Hz, 1H),
4.22 (td, J = 7.1, 3.5 Hz, 0.56H), 3.99 (m, 1H), 3.89-3.71 (m, 2H), 3.38 (m, 1H), 2.69-2.59
(m, 0.42H), 2.53 -2.34 (m, 1.56H), 2.30-2.13 (m, 1.81H), 2.08 (m, 0.46H), 1.90-1.74 (m,
4H), 1.74-1.62 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 144.7, 144.4, 143.4, 142.4, 131.6,
129.3, 129.0, 128.8, 128.7, 128.2, 126.7, 125.9, 125.8, 121.3, 119.1, 116.2, 115.8, 113.0,
111.8, 75.8, 66.5, 65.0, 64.4, 63.4, 57.6, 56.6, 41.8, 39.8, 35.8, 34.4, 29.9, 29.6, 29.2, 24.9.
HRMS (ESI+) calculated for C20H22NO (M+H+) 292.1701; found 292.1698.
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6-(4-chlorophenyl)-10-fluoro-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-
a]quinoline 4f (endo)
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Light green oil liquid, 13.9 mg, yield 40%. 1H NMR (400 MHz, CDCl3) δ 7.33 -7.23 (m,
2H), 7.15-7.08 (m, 3H), 6.76 (td, J = 8.6, 3.0 Hz, 1H), 6.13 (dd, J = 9.0, 4.6 Hz, 1H), 4.79
(dd, J = 7.9, 3.1 Hz, 1H), 4.49 (d, J = 4.4 Hz, 1H), 4.08 (m, 1H), 3.94 (m, 1H), 3.42 (m,
1H), 2.51 (m, 1H), 2.41-2.20 (m, 2H), 1.99-1.74 (m, 4H). 13C NMR (101 MHz, CDCl3) δ
154.8 (d, J = 253.3), 142.9, 139.7, 132.5, 128.9, 127.3, 117.6 (d, J = 21.2), 116.1 (d, J =
22.2), 113.7 (d, J = 7.1), 120.2 (d, J = 6.1 Hz), 76.8, 65.1, 64.2, 57.7, 39.8, 34.3, 29.8, 29.0.
HRMS (ESI+) calculated for C20H20ClFNO (M+H+) 344.1217; found 344.1217.
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6-(4-chlorophenyl)-10-fluoro-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-
a]quinoline 4f’ (exo)
Light green oil liquid, 8.1 mg, yield 24%. 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 2H),
7.06-6.95 (m, 3H), 6.52 (td, J = 8.6, 3.1 Hz, 1H), 5.83 (dd, J = 8.9, 4.5 Hz, 1H), 5.09 (d, J
= 7.2 Hz, 1H), 4.63 (dd, J = 8.1, 4.9 Hz, 1H), 4.17 (td, J = 7.0, 3.5 Hz, 1H), 3.81 (q, J =
8.1 Hz, 1H), 3.73 (td, J = 9.0, 3.5 Hz, 1H), 2.63 (m, 1H), 2.48 (m, 1H), 2.13-2.03 (m, 1H),
1.86 (m 1H), 1.78-1.59 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 155.3 (d, J = 253.3), 143.2,
138.6, 132.5, 129.1, 127.2, 115.4 (d, J = 22.2), 114.8 (d, J = 22.2), 112.2 (d, J = 7.1), 122.7
(d, J = 6.1 Hz), 75.6, 66.6, 63.2, 56.7, 41.5, 35.9, 29.7, 24.8. HRMS (ESI+) calculated for
C20H20ClFNO (M+H+) 344.1217; found 344.1220.
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6-(3-bromophenyl)-10-fluoro-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-
a]quinoline 4g (endo)
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Yellowish-green liquid, 14.8 mg, yield 38%. 1H NMR (400 MHz, CDCl3) δ 7.31 -7.25
(m, 2H), 7.09 (t, J = 7.6 Hz, 1H), 7.01 (m, 2H), 6.67 (td, J = 8.6, 3.1 Hz, 1H), 6.05 (dd, J
= 8.9, 4.6 Hz, 1H), 4.67 (dd, J = 7.9, 3.1 Hz, 1H), 4.39 (d, J = 4.4 Hz, 1H), 3.98 (td, J =
8.6, 6.3 Hz, 1H), 3.83 (td, J = 9.5, 5.7 Hz, 1H), 3.33 (m, 1H), 2.46-2.33 (m, 1H), 2.30-2.12
(m, 2H), 1.86-1.64 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 154.5 (d, J = 236.3 Hz), 147.0,
140.0, 130.4, 130.1, 128.9, 124.4, 123.0, 120.2 (d, J = 6.1 Hz), 117.6 (d, J = 22.2 Hz),
116.2 (d, J = 22.2 Hz), 113.8 (d, J = 7.1 Hz), 76.7, 65.1, 64.6, 57.7, 39.6, 34.2, 29.7, 28.8.
HRMS (ESI+) calculated for C20H20BrFNO (M+H+) 388.0712; found 388.0712.
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6-(3-bromophenyl)-10-fluoro-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-
a]quinoline 4g’ (exo)
Yellowish-green liquid, 7.4 mg, yield 19%. 1H NMR (400 MHz, CDCl3) δ 7.32-7.22 (m,
2H), 7.10 (t, J = 7.8 Hz, 1H), 7.00 (m, 2H), 6.53 (td, J = 8.6, 3.1 Hz, 1H), 5.85 (dd, J = 8.9,
4.5 Hz, 1H), 5.11 (d, J = 7.1 Hz, 1H), 4.61 (dd, J = 7.8, 5.0 Hz, 1H), 4.19 (td, J = 6.9, 3.5
Hz, 1H), 3.82 (q, J = 8.1 Hz, 1H), 3.74 (td, J = 9.0, 3.4 Hz, 1H), 2.63 (m, 1H), 2.54-2.43
(m, 1H), 2.09 (m, 1H), 1.86 (m, 1H), 1.80-1.51 (m, 3H). 13C NMR (101 MHz, CDCl3) δ
155.4 (d, J = 235.3 Hz), 147.4, 138.5, 130.6, 130.1, 130.0, 128.8, 124.3, 123.1, 122.7 (d, J
= 6.1 Hz), 115.3 (d, J = 22.2 Hz), 114.9 (d, J = 22.2 Hz), 112.1 (d, J = 7.1 Hz), 75.6, 66.6,
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63.5, 56.7, 41.5, 35.8, 29.7, 24.8. HRMS (ESI+) calculated for C20H20BrFNO (M+H+)
388.0712; found 388.0696.
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6-(4-nitrophenyl)-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline 4h
and 4h’
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Orange liquid, 26.9 mg, dr (endo:exo) = 69:31, yield 80%. 1H NMR (400 MHz, CDCl3)
δ 9.69 (t, J = 1.8 Hz, 0.52H), 8.10 (m, 6H), 7.39-7.24 (m, 8H), 7.10-6.99 (m, 2H), 6.96-
6.88 (m, 1.41H), 6.83-6.77 (m, 0.56H), 6.64-6.50 (m, 3H), 6.36 (t, J = 7.2, 0.49H), 6.14 (d,
J = 8.1 Hz, 0.39H), 6.03 (d, J = 8.2 Hz, 1H), 5.91-5.86 (m, 0.51H), 5.64 (d, J = 6.1 Hz,
0.55H), 5.19 (d, J = 5.4 Hz, 0.43H), 5.09 (dd, J = 8.5, 3.4 Hz, 0.50H), 5.01 (dd, J = 4.4,
1.5 Hz, 0.55H), 4.92-4.83 (m, 1.67H), 4.76 (q, J = 7.4 Hz, 1H), 4.46 (d, J = 4.2 Hz, 1H),
4.39-4.30 (m, 0.58H), 4.00 (td, J = 8.6, 6.3 Hz, 1H), 3.87 (m, 1H), 3.79 (dd, J = 7.5, 5.9
Hz, 1.29H), 3.65-3.53 (m, 0.93H), 3.44-3.29 (m, 1.73H), 2.79 (m, 0.47H), 2.65 (m, 0.80H),
2.57-2.46 (m, 1H), 2.43 (td, J = 7.1, 1.8 Hz, 1H), 2.36-2.14 (m, 2.48H), 2.12-1.92 (m,
0.77H), 1.92-1.64 (m, 7H). 13C NMR (101 MHz, CDCl3) δ 152.7, 152.4, 152.2, 147.4,
147.1, 147.0, 146.1, 142.7, 141.5, 131.9, 129.8, 129.5, 129.4, 129.1, 128.7, 128.35, 128.3,
127.4, 127.2, 126.7, 126.5, 126.4, 124.5, 124.4, 124.2, 124.1, 121.8, 121.5, 119.4, 117.7,
117.5, 116.7, 116.6, 115.8, 115.7, 114.7, 114.1, 112.8, 111.6, 111.5, 103.9, 77.4, 77.0, 67.1,
66.2, 66.1, 65.1, 64.0, 63.7, 61.0, 60.3, 58.7, 57.7, 57.2, 57.1, 41.2, 39.9, 39.7, 36.9, 35.8,
35.1, 34.6, 34.3, 33.2, 32.4, 29.8, 29.8, 29.4, 23.6, 22.8. HRMS (ESI+) calculated for
C20H21N2O3 (M+H+) 337.1552; found 337.1553.
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Page 28 of 38
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10-bromo-6-(p-tolyl)-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-
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Yellowish-green liquid, 10.2 mg, yield 27%. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J =
2.4 Hz, 1H), 7.03 (d, J = 7.9 Hz, 2H), 6.98-6.93 (m, 3H), 6.04 (d, J = 8.7 Hz, 1H), 4.70 (dd,
J = 7.9, 3.8 Hz, 1H), 4.37 (d, J = 4.3 Hz, 1H), 3.97 (m, 1H), 3.88-3.77 (m, 1H), 3.31 (ddd,
J = 11.2, 7.4, 5.7 Hz, 1H), 2.46-2.31 (m, 1H), 2.25 (s, 3H), 2.19 (ddd, J = 12.5, 8.4, 4.3 Hz,
1H), 1.84-1.73 (m, 3H), 1.66 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 142.4, 140.8, 136.5,
133.9, 131.9, 129.5, 125.7, 121.1, 114.5, 107.4, 76.7, 65.0, 64.1, 57.6, 39.9, 34.6, 29.8,
29.3, 21.2. HRMS (ESI+) calculated for C21H23BrNO (M+H+) 384.0963; found 384.0960.
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10-bromo-6-(p-tolyl)-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo[1,2-
a]quinoline 4i’ (exo)
Yellowish-green liquid, 4.4 mg, yield 11%. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J =
2.4, 1H), 7.04 (d, J = 7.8 Hz, 2H), 6.95 (d, J = 7.8 Hz, 2H), 6.85 (dd, J = 8.7, 2.5 Hz, 1H),
5.86 (d, J = 8.7 Hz, 1H), 5.09 (d, J = 7.1 Hz, 1H), 4.63 (dd, J = 7.7, 5.6 Hz, 1H), 4.16 (td,
J = 6.8, 2.4 Hz, 1H), 3.86-3.71 (m, 3H), 2.68-2.57 (m, 1H), 2.53-2.42 (m, 1H), 2.25 (s, 3H),
2.14-2.02 (m, 1H), 1.91-1.59 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 141.3, 141.1, 136.5,
131.5, 130.9, 129.6, 125.6, 123.4, 113.4, 108.0, 75.4, 66.6, 63.1, 56.6, 41.3, 36.0, 29.8,
24.7, 21.2. HRMS (ESI+) calculated for C21H23BrNO (M+H+) 384.0963; found 384.0950.
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Light green liquid, 23.6 mg, yield 74%, dr (endo:exo) = 64:36. H NMR (400 MHz,
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CDCl3) δ 7.11-7.06 (m, 1.59H), 7.05-6.95 (m, 5.62H), 6.73 (dd, J = 8.4, 1H), 6.62 (dd, J =
8.0, 0.46H), 6.10 (d, J = 8.4 Hz, 1H), 5.92 (d, J = 8.0 Hz, 0.44H), 5.14 (d, J = 7.2 Hz,
0.45H), 4.70 (m, 1.47H), 4.41 (d, J = 4.4 Hz, 1H), 4.18 (td, J = 7.0, 3.3 Hz, 0.48H), 3.97
(m, 1H), 3.80 (m, 2H), 3.33 (m, 1H), 2.61 (m, 0.21H), 2.49-2.30 (m, 1H), 2.24 (m, 5H),
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2.11 (s, 3H), 1.78 (m, 3H). C NMR (101 MHz, CDCl3) δ 141.9, 141.6, 141.2, 140.3,
136.2, 136.2, 131.9, 129.9, 129.5, 129.4, 129.3, 128.8, 125.8, 125.8, 125.0, 124.8, 121.3,
119.0, 113.0, 111.9, 77.2, 76.0, 66.6, 65.0, 64.2, 63.1, 57.6, 56.6, 42.1, 39.9, 35.8, 34.4,
29.9, 29.5, 29.0, 25.0, 21.2, 20.5, 20.3. HRMS (ESI+) calculated for C22H26NO (M+H+)
320.2014; found 320.2008.
6-(4-methoxyphenyl)-10-methyl-2,3,3a,3b,4,5,6,11b-octahydrofuro[3,2-c]pyrrolo
[1,2-a]quinoline 4k and 4k’
White solid, 22.1 mg, yield 66%, m.p. 169.8-172.4 oC, dr (endo:exo) = 67:33. 1H NMR
(400 MHz, CDCl3) δ 7.08 (m, 1.78H), 7.01 (m, 3H), 6.77-6.70 (m, 4H), 6.62 (d, J = 8.0,
0.55H), 6.11 (d, J = 8.3 Hz, 1H), 5.93 (d, J = 8.2 Hz, 0.54H), 5.13 (d, J = 7.3 Hz, 0.54H),
4.68 (m, 1.66H), 4.41 (d, J = 4.4 Hz, 1H), 3.97 (td, J = 8.4, 6.3 Hz, 1H), 3.81 (m, 1H), 3.70
(s, 5H), 3.32 (m, 1H), 2.61 (m, 0.58H), 2.49-2.39 (m, 0.51H), 2.34 (m, 0.91H), 2.21 (m,
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