Synthesis of Chiral Propargylamines, Chiral 1,2-Dihydronaphtho[2,1-b]furans and Naphtho[2,1-b]furans with C-Alkynyl N,N′-di-(tert-butoxycarbonyl)-aminals and β-Naphthols

Article abstract of DOI:10.1002/chem.202102040

Chiral phosphoric acid-catalyzed couplings of C-alkynyl N,N′-di-(tert-butoxycarbonyl)-aminals with β-naphthols led to chiral propargylamines in moderate to high yields with high to excellent enantioselectivity, in which the reactions underwent sequential chiral phosphoric acid-catalyzed in situ formation of N-(tert-butoxycarbonyl)-imines (N-Boc-imines) from the aminals, and 1,2-addition of β-naphthols to the N-Boc-imines. Chiral 1,2-dihydronaphtho[2,1-b]furans and naphtho[2,1-b]furans were prepared with satisfactory results when 10 mol% AgOAc and 20 mol% 2,6-lutidine or 1.2 equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added to the resulting chiral propargylamines solution, respectively.

Full text of DOI:10.1002/chem.202102040

Accepted Article
Accepted Article
Title: Synthesis of Chiral Propargylamines, Chiral 1,2-
Dihydronaphtho[2,1-b]furans and Naphtho[2,1-b]furans with C-
Alkynyl N,N'-Di-(tert-Butoxycarbonyl)-Aminals and β-Naphthols
Authors: Ningning Man, Yuming Li, Jiyang Jie, Hongyun Li, Haijun
Yang, Yufen Zhao, and Hua Fu
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the VoR from the journal website shown below when it is published
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To be cited as: Chem. Eur. J. 10.1002/chem.202102040
Link to VoR: https://doi.org/10.1002/chem.202102040
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Synthesis
of
Chiral
Propargylamines,
Chiral
1,2-
Dihydronaphtho[2,1-b]furans and Naphtho[2,1-b]furans with C-
Alkynyl N,N'-Di-(tert-Butoxycarbonyl)-Aminals and β-Naphthols
Ningning Man, Yuming Li, Jiyang Jie, Hongyun Li, Haijun Yang, Yufen Zhao, and Hua Fu*
[*]
N. Man, Y. Li, J. Jie, H. Li, Dr. H. Yang, Prof. Dr. Y. Zhao, Prof. Dr. H. Fu
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education)
Department of Chemistry
Tsinghua University
Beijing 100084 (China)
E-mail: fuhua@mail.tsinghua.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: Chiral phosphoric acid-catalyzed couplings of C-alkynyl
N,N'-di-(tert-butoxycarbonyl)-aminals with β-naphthols led to chiral
propargylamines in moderate to high yields with high to excellent
enantioselectivity, in which the reactions underwent sequential chiral
phosphoric acid-catalyzed in situ formation of N-(tert-butoxycarbonyl)-
imines (N-Boc-imines) from the aminals, and 1,2-addition of β-
naphthols to the N-Boc-imines. Chiral 1,2-dihydronaphtho[2,1-
b]furans and naphtho[2,1-b]furans were prepared with the satisfactory
results when 10 mol% AgOAc and 20 mol% 2,6-lutidine or 1.2 equiv of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added to the
resulting chiral propargylamines solution, respectively.
For example, megapodiol (A) is an antileukemic agent,[31]
neolignan callislignan A (B) exhibits
Introduction
Propargylamines are one kind of important synthetic
intermediates and versatile building blocks[1] for the synthesis of
diverse amine derivatives[2] as well as natural products[3] and
biologically active molecules.[4] Chiral propargylamines are key
precursors for the synthesis of pharmaceutical molecules.[5] The
reactions with propargylamines as the substrates can provide
miscellaneous heterocyclic compounds[6] such as pyrroles,[7]
pyrrolines,[8] pyrrolidine,[9] pyrazines,[10] pyrazoles,[11] pyridines,[12]
dihydropyridines,[13] isoxazoles,[14] oxazolidines,[15] thiazoles[16]
and thiazolidines.[17] The common methods for synthesis of chiral
propargylamines include the asymmetric alkynylation of
imines[18,19] and the catalytic asymmetric addition of nucleophiles
to previously prepared[20] or in situ generated[21,22] C-alkynyl
imines (Scheme 1a). In 2016, Shao and co-workers reported the
catalytic asymmetric arylations of C-alkynyl imines leading to
chiral propargylamines with C-alkynyl N-Boc-protected N,O-
acetals and phenols as the substrates.[23] Benzofurans and
naphthofurans are the important class of O-heterocyclic
compounds with various biological and pharmacological
activities.[24-26] The naphthofuran moiety is used as the privileged
structure[27] in the discovery of anticancer agents[24a] and
regulators of the nuclear receptors HNFa7.[28] Several methods
for the synthesis of naphthofurans have been developed because
of importance of naphthofurans in pharmaceutical chemistry.[29]
Dihydrobenzofurans that widely occur in the synthetic molecules
and natural products possess various biological activities.[30]
Scheme 1. a) Previous routes for synthesis of chiral propargylamines. b) The
representative examples of dihydrobenzofurans and dihydronaphtho[2,1-
b]furans with various biological activities. c) Our strategy for synthesis of chiral
propargylamines, chiral 1,2-dihydronaphtho[2,1-b]furans and naphtho[2,1-
b]furans.
antibacterial activity against Staphylococcus aureus,[32] (2R,3S)-
3,4′-di-O-methylcedrusin (C) is an antitumor neolignan,[33] and
annullatin A (D) isolated from Cordyceps annullata shows the
potent agonistic activity toward the cannabinoid receptors CB1
and CB2 (Scheme 1b).[34]
Particularly, 3-amino-2,3-
dihydrobenzofurans are of great importance in drug discovery.
For example, phalarine (E) isolated from Phalaris coerulescens
1
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using a Daicel Chiralpak OD-H column. [d] 50 oC. [e] 70 oC. [f] 1 mL of toluene.
[g] 3 mL of toluene. [h] 4 mL of toluene.
shows high structural diversity and a broad bioactivity profile,[35]
and compound F is an important cell motility inhibitor (Scheme
1b).[36] In the past decade years, several methods for
enantioselective synthesis of 3-amino-2,3-dihydrobenzofurans
have been developed.[37] 1,2-Dihydronaphtho[2,1-b]furans play a
key role in medicinal chemistry for their diverse pharmacological
activities such as antiinflammatory activity (G), melatonin receptor
ligands (H), α-chymotrypsin inhibitor (I), C17,20-lyase inhibitor (J)
and 5-lypoxygenase inhibitor (K).[38] However, enantioselective
synthesis of 1,2-dihydronaphtho[2,1-b]furans, especially 1-
amino-1,2-dihydronaphtho[2,1-b]furans is rare. Herein, we report
Initially, di-tert-butyl (3-phenylprop-2-yne-1,1-diyl)dicarbamate
(1a) and β-naphthalen-2-ol (2a) were used as the substrates to
optimize reaction conditions including chiral phosphoric acids,
additives, solvents, temperature and time. As shown in Table 1,
nine chiral phosphoric acids (5 mol% relative to 1a and 2a) were
o
first screened in 2 mL of toluene at 60 C for 10 h (entries 1-9),
and (R)-C9 gave the highest enantioselectivity (87% ee) and the
higher yield (76%). Three anhydrous additives, MgSO4, Na2SO4
and 3 Å MS, were attempted (entries 10-12), and Na2SO4
provided 90% ee value (entry 11). We investigated the affection
of reaction temperature and time (compare entries 9, 13-17), and
found that 60 oC and 12 h were suitable (entry 16). Other solvents
were attempted, and the results showed that toluene was optimal
(see Table S1). Different volume of toluene was surveyed (entries
18-20), and 3 mL of toluene was suitable (entry 19). It should be
pointed out that absolute configuration of 3a was determined by
comparing structure of (R)-3q (absolute configuration of 3q was
assigned to be (R)-form by X-ray diffraction analysis (see
Supporting Information for details)).
synthesis
of
chiral
propargylamines,
chiral
1,2-
dihydronaphtho[2,1-b]furans and naphtho[2,1-b]furans with C-
alkynyl N,N'-di-(tert-butoxycarbonyl)-aminals and β-naphthols
(Scheme 1c).
Results and Discussion
Optimization of conditions for the synthesis of chiral
propargylamines
Table 1. Optimization of conditions for synthesis of (R)-3a.[a]
Substrate scope for the synthesis of chiral propargylamines
Table 2. Synthesis of chiral propargylamines ((R)-3).[a]
(R)-3 (yield, ee)
Entry
1
CPA
additive
t (h)
10
yield (%)[b]
ee (%)[c]
59
(R)-C1
(R)-C2
(R)-C3
(R)-C4
(R)-C5
(R)-C6
(R)-C7
(R)-C8
(R)-C9
(R)-C9
(R)-C9
(R)-C9
(R)-C9
(R)-C9
(R)-C9
(R)-C9
(R)-C9
(R)-C9
(R)-C9
(R)-C9
78
74
80
2
10
74
3
10
38
4
10
79
19
5
10
10
81
64
18
52
6
7
10
10
10
10
10
10
10
10
8
80
77
76
83
78
41
62
82
66
77
77
67
77
75
3
8
16
87
70
90
80
90
87
91
92
92
80
93
91
9
10
11
12
13
14
15
16
17
18
19
20
Mg2SO4
Na2SO4
3 Å MS
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
12
14
12
12
12
[a] Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0 equiv), CPA
((R)-C1~(R)-C9) (5 µmol, 5 mol%), toluene (2.0 mL), temperature (60 oC), time
(8-14 h) in a sealed Schlenk tube without extrusion of air. [b] Isolated yield. [c]
The ee values were determined by HPLC analysis on a chiral stationary phase
2
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0.12 mmol, 0.2-1.2 equiv), time (20 min-2 h) for the second step. [b] Isolated
yield. [c] The ee values were determined by HPLC analysis on a chiral stationary
phase using a Daicel Chiralpak ID column. TEA = triethylamine. Py = pyridine.
[a] Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0 equiv), (R)-
C9 (5 µmol, 5 mol%), toluene (3.0 mL), temperature (60 oC), time (12 h) in a
sealed Schlenk tube without extrusion of air. Isolated yield. The ee values were
DMAP
=
4-dimethylaminopyridine. Lut
=
2,6-lutidine. DBU
=
1,8-
determined by HPLC analysis on
a chiral stationary phase. Absolute
diazabicyclo[5.4.0]undec-7-ene.
configuration of 3q was assigned to be (R)-form by X-ray diffraction analysis
(see Supporting Information for details), and absolute configurations of products
3a ~ 3p and 3r were determined by comparing structure of (R)-3q.
Subsequently, we investigated one-pot two-step reactions of di-
tert-butyl (3-phenylprop-2-yne-1,1-diyl)dicarbamate (1a) and β-
naphthalen-2-ol (2a) including (R)-C9-catalyzed coupling of 1a
and 2a to 3a, and cyclization of 3a under different conditions. The
first-step reaction was performed under the optimal conditions of
Table 2. Here, we surveyed the second-step reaction conditions
including bases, catalysts, temperature and time (see Table S2-
S4 for more details). As shown in Table 3, six bases (1.2 euiv)
were added to the first-step resulting solution, respectively, and
the reaction was conducted at 60 oC for 2 h. Surprisingly, only 4a
(entry 5) or 5a (entry 6) was obsrved in the presence of 2,6-
lutidine or DBU, respectively. The yields of (S)-4a obviously
increased when two silver salts were added the reaction solution,
respectively (entries 7 and 8). We attempted variation of
temperature and time, and found that 30 oC and 30 min were
suitable for the formation of (S)-4a (entry 9). In addition, we also
found that 70 oC was favorable for the synthesis of 5a (entry 10).
With the optimized conditions for synthesis of (R)-3 in hand, the
substrate scope was surveyed for reactions of C-alkynyl N,N'-di-
(tert-butoxycarbonyl)-aminals (1) and β-naphthols (2) under
catalysis of (R)-C9 (Table 2). First, we investigated variation of R1
subsituents in 1, and found that neutral ((R)-3a and (R)-3i, 77%
and 67% yields with 93% and 96% ee, respectively), electron-
donating ((R)-3b-3d, 64-80% yields with 90-96% ee), poor
electron-withdrawing ((R)-3e-3g, 71-84% yields with 92% ee),
strong electron-withdrawing ((R)-3h, 67% yield with 90% ee)
groups were feasible. Subsequently, affection of R2 subsituents in
2 was surveyed. β-naphthols (2) containing 6-Me ((R)-3j), 6-Br
((R)-3k), 7-p-tolyl ((R)-3l), 6-p-tolyl ((R)-3m), 6-naphthalen-1-yl
((R)-3n), 6-anthracen-9-yl ((R)-3o) and 6-phenanthren-9-y ((R)-
3p) provided moderate to high yields (54-83%) with high to
excellent ee values (86-94% ee). Finanlly, we attempted
simultaneous variation of subsituents R1 and R2 in 1 and 2, and
the couplings also afforded the satisfactory results ((R)-3q and
(R)-3r, 60% and 53% yields with 94% and 91% ee, respectively).
Substrate scope for the synthesis of chiral 1,2-
dihydronaphtho[2,1-b]furans and naphtho[2,1-b]furans
Table 4. One-pot two-step synthesis of chiral 1,2-dihydronaphtho[2,1-b]furans
((S)-4).[a]
Optimization of conditions for one-pot two-step synthesis of
chiral 1,2-dihydronaphtho[2,1-b]furans and naphtho[2,1-
b]furans
Table 3. Optimization of conditions for one-pot two-step synthesis of (S)-4a and
5a.[a]
(S)-4 (yield, ee)
yield, ee of
Entry
condition
yield of 5a[c]
4a[b]
1.2 equiv K2CO3, 60 oC, 2
h
1
2
24%, 90% ee
21%
25%
36%
29%
0
1.2 equiv TEA, 60 oC, 2 h
26%, 91% ee
42%, 90% ee
24%, 92% ee
30%, 92% ee
0
3
1.2 equiv Py, 60 oC, 2 h
1.2 equiv DMAP, 60 oC, 2
h
4
5
1.2 equiv Lut, 60 oC, 2 h
6
1.2 equiv DBU, 60 oC, 2 h
75%
0
0.1 equiv Ag2CO3, 1.2
equiv Lut, 60 oC, 2 h
0.1 equiv AgOAc, 1.2
equiv Lut, 60 oC, 2 h
0.1 equiv AgOAc, 0.2
equiv Lut, 30 oC, 20 min
7
77%, 91% ee
80%, 93% ee
80%, 93% ee
0
8
0
9
0
1.2 equiv DBU, 70 oC, 2 h
88%
[a] Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0 equiv), (R)-
C9 (5 µmol, 5 mol%), toluene (3.0 mL), temperature (60 oC), time (12 h) for the
first step; AgOAc (0.01 mmol, 0.1 equiv), 2,6-lutidine (0.02 mmol, 0.2 equiv),
temperature (30 oC), time (20 min) for the second step. Isolated yield. The ee
values were determined by HPLC analysis on a chiral stationary phase.
Absolute configuration of 4a was assigned to be (S)-form by X-ray diffraction
10
[a] Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0 equiv), (R)-
C9 (5 µmol, 5 mol%), toluene (3.0 mL), temperature (60 oC), time (12 h) for the
first step; temperature (30-70 oC), AgOAc (0.01 mmol, 0.1 equiv), base (0.02-
3
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analysis (see Supporting Information for details), and absolute configurations of
products 4b ~ 4r were determined by comparing structure of (S)-4a.
Reaction mechanism
When (S)-4a was conducted at 70 oC for 2 h in the presence of
1.2 equiv of DBU, 5a was obtained in 94% yield (Scheme 2a),
which showed that the reactions underwent an intermediate 4
process during the formation of 5. A possible mechanism for
synthesis of (R)-3, (S)-4 and 5 is proposed in Scheme 2b based
on our experimental results and previous references.[22] First,
transformation of chiral phosphoric acid ((R)-C9)-catalyzed C-
alkynyl N,N'-di-(Boc)-aminal (1) provides C-alkynyl N-Boc-imine
(1'),[22a] and then treatment of (R)-C9 with in situ generated 1' and
2 through hydrogen bonds leads to coupling of 1' and 2 giving (R)-
3. Silver-catalyzed intramolecular cyclization of (R)-3 provides
(S)-4 in the presence of 2,6-lutidine. Meanwhile, treatment of (R)-
3 in the presence of DBU undergoes a sequential two-step
process including intramolecular cyclization of (R)-3 to 4, and
isomerization of 4 to 5.
After getting the optimized conditions for the one-pot two-step
reactions, we first surveyed substrate scope for synthesis of (S)-
4. As shown in Table 4, the aminals (1) containing different
substituents R1 on the aryl rings were amenable to this one-pot
two-step reactions, and the formation of (S)-4 was not obviously
affected by the substituents R1 including neutral ((S)-4a and (S)-
4i, 80% yields with 93% and 98% ee, respectively), electron-
donating ((S)-4b-4d, 67-75% yields with 91-93% ee), poor
electron-withdrawing ((S)-4e-4g, 67-77% yields with 87-91% ee),
strong electron-withdrawing ((S)-4h, 71% yield with 90% ee)
groups. Next, various substituents R2 in 2 including 6-Me ((S)-4j),
6-Br ((S)-4k), 7-p-tolyl ((S)-4l), 6-p-tolyl ((S)-4m), 6-naphthalen-1-
yl ((S)-4n), 6-anthracen-9-yl ((S)-4o) and 6-phenanthren-9-y ((S)-
4p) were attempted, and the corresponding β-naphthols (2)
afforded moderate to high yields (58-75%) with high to excellent
ee values (80-98% ee). We simultaneously changed subsituents
R1 and R2 in 1 and 2, and the target products ((S)-4q and (S)-4r)
were obtained in 56% and 57% yields with 87% and 85% ee,
respectively. Subsequently, one-pot two-step synthesis of
naphtho[2,1-b]furans (5) was investigated (Table 5). Similarly to
Table 2 and Table 4, we tried respective and simultaneous
variation of R1 and R2 in 1 and 2, and the target products (5a-5r)
were successfully got in 59-88% yields.
Table 5. One-pot two-step synthesis of naphtho[2,1-b]furans (5).[a]
5 (yield)
Scheme 2. a) Transformation of (S)-4a to 5a in the presence of
DBU. b) Possible mechanism for synthesis of (R)-3, (S)-4 and 5.
Scale synthesis and application of products
[a] Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0 equiv), (R)-
C9 (5 µmol, 5 mol%), toluene (3.0 mL), temperature (60 oC), time (12 h) for the
first step; DBU (0.12 mmol, 1.2 equiv), temperature (70 oC), time (2 h) for the
second step. Isolated yield. Sructure of 5a was determined by X-ray diffraction
analysis (see Supporting Information for details).
Scheme 3. a) Scale synthesis of (S)-4a. b) Scale synthesis of 5a. c)
Application of 5a.
We attempted the scale synthesis of (S)-4a and 5a under the
standard conditions (Scheme 3a, 3b), and the two products were
prepared with the satisfactory results (81% yield and 90% ee for
4
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[4]
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V. A. Peshkov, O. P. Pereshivko, A. A. Nechaev, A. A.
Peshkov, E. V. Van der Eycken, Chem. Soc. Rev. 2018, 47,
3861-3898.
M. Wünsch, D. Schröder, T. Fröhr, L. Teichmann, S. Hedwig,
N. Janson, C. Belu, J. Simon, S. Heidemeyer, P. Holtkamp, J.
Rudlof, L. Klemme, A. Hinzmann, B. Neumann, H.-G.
Stammler, N. Sewald, Beilstein J. Org. Chem. 2017, 13,
2428-2441.
(S)-4a; 78% yield for 5a), which indicated that the present
methods were very effective and practical for synthesis of chiral
1,2-dihydronaphtho[2,1-b]furans
and
naphtho[2,1-b]furans.
Subsequently, we investigated application of 5a. Oxidation of 5a
with SeO2 in dioxane afforded 6 in 77% yield, and reduction of 6
with H2 under catalysis of Pd/C gave 7 in 85% yield (Scheme 3c).
[6]
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40, 1301-1304.
Conclusion
In summary, we have developed
propargylamines, chiral 1,2-dihydronaphtho[2,1-b]furans and
naphtho[2,1-b]furans using C-alkynyl N,N'-di-(tert-
synthesis of chiral
[8]
[9]
butoxycarbonyl)-aminals and β-naphthols as the substrates. For
synthesis of chiral propargylamines, the reactions underwent
sequential chiral phosphoric acid-catalyzed in situ formation of N-
Boc-imines from the aminals, and 1,2-addition of β-naphthols to
N-Boc-imines. The chiral propargylamines effectively and
selectively transferred into chiral 1,2-dihydronaphtho[2,1-b]furans
and naphtho[2,1-b]furans with the satisfactory results when 10
mol% AgOAc and 20 mol% 2,6-lutidine or 1.2 equiv of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) were added to the
resulting solution, respectively. Therefore, the present methods
provide a new strategy for synthesis of diverse molecules.
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Experimental Section
Detailed experimental procedures, analytical data, NMR spectra,
and HPLC traces are provided in the Supporting Information.
[16] a) P. K. Sasmal, S. Sridhar, J. Iqbal, Tetrahedron Lett. 2006,
47, 8661-8665; b) V. Yarovenko, A. Polushina, I. Zavarzin, M.
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E. V. Van der Eycken, Eur. J. Org. Chem. 2017, 2017, 1063-
1069.
Crystallographic data: Deposition number 2045931 ((R)-3q),
2058506 ((S)-4a) and 2058504 (5a) contains the supplementary
crystallographic data for this paper. These data are provided free
of charge by the joint Cambridge Crystallographic Data Centre.
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Acknowledgements
The authors thank the National Natural Science Foundation of
China (Grant Nos. 21772108 and 22077074) for financial support.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric synthesis • chiral phosphoric acid • chiral
propargylamines
•
chiral dihydronaphtho[2,1-b]furans
•
naphtho[2,1-b]furans
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
Synthesis of chiral propargylamines, chiral 1,2-dihydronaphtho[2,1-b]furans and naphtho[2,1-b]furans has been developed using C-
alkynyl N,N'-di-(tert-butoxycarbonyl)-aminals and β-naphthols as the substrates. 1,2-Addition of β-naphthols to chiral phosphoric acid-
catalyzed in situ generated N-Boc-imines provided chiral propargylamines in moderate to high yields with high to excellent
enantioselectivity. Addition of 10 mol% AgOAc and 20 mol% 2,6-lutidine or 1.2 equiv of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
the resulting chiral propargylamine solution provided chiral 1,2-dihydronaphtho[2,1-b]furans in good yields with high to excellent
enantioselectivity and naphtho[2,1-b]furans in moderate to high yields, respectively.
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