Far Away from Flatland. Synthesis and Molecular Structure of Dihetera[3.3. n]propellanes and Trihetera[3.3. n]propellanes: Advanced Analogues of Morpholine/Piperazine

Article abstract of DOI:10.1021/acs.joc.9b02067

An approach to di- and trihetera[3.3.n]propellanes (n = 2-4), advanced morpholine and piperazine analogues, is developed. The key step of the reaction sequence included a [3+2] cycloaddition reaction of unsaturated vicinal dicarboxylic acid derivatives and in situ generated azomethine ylide resulting in the formation of the pyrrolidine ring. One more heteroaliphatic ring (i.e., pyrrolidine or tetrahydrofuran) was annelated by nucleophilic cyclization of the appropriate 1,4-dielectrophilic intermediates. There were 11 examples of the title products obtained in 3-5 steps on a multigram scale with 10-72% overall yields. Additionally, molecular structures of homologous dihetera[3.3.n]propellanes, analogues of morpholine, were obtained from X-ray diffraction studies and analyzed using exit vector plots (EVPs). It was shown that the scaffolds obtained are somewhat larger as compared to the parent morpholine and bicyclic 3-oxa-7-azabicyclo[3.3.0]octane. Moreover, despite very similar chemical structures, they provide a very distinct spatial position of heteroatoms, which is clearly seen from the conformation adopted by a formal eight-membered ring including both N and O atoms (i.e., crown, boat-chair, twist chair-chair, and boat-boat for the oxaza[3.3.2]-, -[3.3.3]-, -[4.3.3]propellanes, and 3-oxa-7-azabicyclo[3.3.0]octane, respectively).

Full text of DOI:10.1021/acs.joc.9b02067

Subscriber access provided by Georgetown University | Lauinger and Blommer Libraries
Article
Far away from flatland. Synthesis and molecular structure of di- and tri-
hetera[3.3.n]propellanes – advanced analogues of morpholine/piperazine
Yevhenii M. Sokolenko, Yevhen Yu. Yurov, Bohdan V. Vashchenko, Oleksandr V. Hryshchuk, Yuliia
Filimonova, Eugeniy N. Ostapchuk, Artem Artemenko, Oleg V. Zaremba, and Oleksandr O. Grygorenko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02067 • Publication Date (Web): 11 Sep 2019
Downloaded from pubs.acs.org on September 12, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 40
The Journal of Organic Chemistry
1
2
3
Far away from flatland. Synthesis and molecular
4
5
6
7
8
structure of di- and tri-hetera[3.3.n]propellanes –
advanced analogues of morpholine/piperazine
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yevhenii M. Sokolenko,†,‡,§ Yevhen Yu. Yurov,†,‡ Bohdan V. Vashchenko,†,‡ Oleksandr V. Hryshchuk,†,‡
Yuliia Filimonova,† Eugeniy N. Ostapchuk,†,‡ Artem Artemenko,† Oleg V. Zaremba,†
Oleksandr O. Grygorenko†,‡,*
† Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
‡ Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
gregor@univ.kiev.ua
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract. An approach to di- and trihetera[3.3.n]propellanes (n = 2–4) – advanced morpholine and
piperazine analogues – is developed. The key step of the reaction sequence included [3+2] cycloaddition
reaction of unsaturated vicinal dicarboxylic acid derivatives and generated in situ azomethine ylide
resulting in the formation of the pyrrolidine ring. One more heteroaliphatic ring (i.e. pyrrolidine or
tetrahydrofuran) was annelated by nucleophilic cyclization of appropriate 1,4-dielectrophilic
intermediates. 11 examples of title products were obtained in 3–5 steps on a multigram scale with 10–
72% overall yield. In addition to that, molecular structures of homologous dihetera[3.3.n]propellanes –
analogues of morpholine – were obtained from X-Ray diffraction studies and analyzed using exit vector
plots (EVP). It was shown that the scaffolds obtained are somewhat larger as compared to the parent
morpholine and bicyclic 3-oxa-7-azabicyclo[3.3.0]octane. Moreover, despite very similar chemical
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 40
structure, they provide very distinct spatial position of the heteroatoms, which is clearly seen from the
conformation adopted by a formal eight membered ring including both N and O atoms (i.e. crown, boat-
chair, twist chair-chair and boat-boat for the oxaza[3.3.2]-, -[3.3.3]-, -[4.3.3]propellanes and 3-oxa-7-
azabicyclo[3.3.0]octane, respectively).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
2

Page 3 of 40
1
The Journal of Organic Chemistry
Introduction
2
3
4
5
6
7
8
Over the history of organic chemistry, molecules with unusual three-dimensional structures have
always attracted attention of chemists as possible synthetic targets.1–3 Among such structures,
propellanes (tricyclo[m.n.p.0x,y]alkanes) containing three rings fused by one C–C axis are one of the
most recognizable.4 The term “propellane” was coined by David Ginsburg in 1966; he had been the
main contributor into the tricycloalkane chemistry with more than hundred publications and a
monograph.5,6 Since then, the smallest representative (tricyclo[1.1.1.01,3]pentane) became the objects of
extensive study, while larger derivatives were scarcely reported.7 This is especially the case with
heterapropellanes, which are exotic in chemical and pharmaceutical practice to date, but extensively
abundant in nature. In particular, propellanes were found in a large group of alkaloids, i.e. hasubanans
1–8 with aza[4.4.3]propellane framework, aza[4.3.3]propellanes represented by (-)-acutumines 9–11,
and fendleridines 12 and 13 bearing oxaza[4.4.3]propellane scaffold (Figure 1). However, the simplest
representatives of oxa- / aza[3.3.n]propellanes (n = 2–4) were nor described in the literature, while being
promising conformationally restricted analogues of widespread heteroaliphatic amines, i.e. morpholine
and piperazine.8,9 It should be outlined that such three-dimensional sp3-enriched low-molecular weight
building blocks are of high demand in drug discovery as a tool for improving physico-chemical
properties, fine-tuning binding with biological targets, or reducing off-target activity.10–13
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Known synthetic approaches to oxapropellanes relied on the construction of tetrahydrofuran ring via
reduction of the corresponding bicyclic dicarboxylic acid derivatives, followed by intramolecular
cyclization of the resulting diol (Scheme 1, Method A).4,14,15 Meanwhile, amination of these starting
derivatives with subsequent imide reduction was applied for the preparation of azapropellanes.4,15–18
.
The required starting materials were generally obtained by double alkylation,19 the Weiss–Cook reaction
(i.e. double condensation of 1,2-dicarbonyl compounds and acetone dicarboxylates)20,21 or various
rearrangements.22,23 Alternative approaches included [2+2]24 or [4+2]25–28 cycloadditions (Method B),
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 40
R3
R1
1
2
3
4
5
6
1
2
3
R2
1
2
3
4
, ()-hasubanonine, R = R = OMe, R = H;
1
2
3
, ()-runanine, R = H, R = R = OMe;
, ()-delavayine, R = H, R + R = OCH2O;
, alkadinine, R = OH, R = OMe, R = H;
NMe
OMe
1
2
3
1
2
3
7
8
O
OMe
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeO
HO
4
6
5
7
5
6
7
8
, +)-longanine, E, R = R = Me, R = R = H;
NR4
OR5
OR6
4
7
5
6
, (+)-longanine, E, R = R = H, R = R = Me;
4
5
6
7
O
, (+)-N-methylstephuline, R = R = R = Me, R = H;
4
5
6
7
, stephalonine E, R = R = R = Me, R = cinnamate;
R7O
O
O
8
OMe
R8
9
, ()-acutumine, X = Cl, R = OH
, ()-dechloroacutumine, X = H, R = OH
, ()-acutuminine, X = Cl, R = H
MeO
8
10
X
8
11
MeO
Me
N
N
9
12
13
, fendieridine, R = H;
9
, 1-acetylaspidoalbidine, R = Ac
N
O
R9
H
Figure 1. Several important alkaloids bearing aza- or oxazapropellane core
X
Y
X
X
O
O
O
O
A
B
, (amination)
, [2+2] or
reduction
[4+2]
Y
Y
Z
Z
C
D
, ring-closing
metathesis
, esterification +
reduction
X = O, NMe,
NPh, NBn
Y or Z = O, NR,
S, (CH2)n etc.
X
O
O
X
O
O
AlkO2C
Y
O(H)
Previous works
Y
This work
O
O
R
N
MeO2C
MeO2C
CO2Me
[3+2]
[3+2]
O
X = NR,
Y = NR, O
X = (CH2)n
CO2Me
n
n = 02
X
Y
Scheme 1. Approaches to heterapropellane synthesis
ACS Paragon Plus Environment
4

Page 5 of 40
The Journal of Organic Chemistry
ring-closing metathesis (Method C),29–32 β-hydroxy-33 or β-formylester34 lactonization – reduction
(Method D), and recyclizations of polycyclic derivatives.35–40
1
2
3
4
5
6
7
8
9
In this work, we have aimed at the preparation and structural characterization of di- and
triheterapropellanes bearing pyrrolidine and tetrahydrofurane fragments via [3+2] cycloaddition of
alkene dicarboxylates with azomethine ylide. In particular, five structural motifs were studied:
oxaza[3.3.n]propellanes 14–16 and dioxaza[3.3.3]propellane 17 as morpholine analogues, oxadi-
aza[3.3.3]propellane 18 as dual morholine/piperazine mimetic, triaza[3.3.3]propellanes 19–21 and
diaza[n.3.3]propellanes 22–24 as piperazine analogues (Figure 2). To the best of our knowledge, the
only example of using the [3+2] cycloaddition reaction for the construction of heterapropellanes
included synthesis of the compound 14 which was described in our preliminary report.41 The
methodology itself was based on the work by Achiwa and co-workers, where it was used for the
construction of bicyclic systems.42 Some other representatives of the series were also reported in the
literature by Ginsburg and co-workers.15,16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
piperazine analogues
morpholine analogues
R1
Boc
Cl
Cl
2Cl
O
xCl
O
O
H2N
N
N
N R2
NH2
O
NH2
n
n
NH2
NH2
NH
, n = 2
, n = 1
, n = 0
1
2
22
23
24
14
15
16
17
18
, n = 2
, n = 1
, n = 0
19
20
21
, R = R = H, x = 3
1
2
, R = Boc, R = H, x = 0
1
2
, R = R = Bn, x = 1
oxaza[3.3.n]propellanes
diaza[3.3.n]propellanes
trihetera[3.3.3]propellanes
Figure 2. Propellanes 14–24 – target molecules of this study
Results and discussion
Synthesis. In our previous work cited above, preparation of the compound 14 relied on [3+2]
cycloaddition of cis-1,2-cyclohexnedicarboxylic anhydride (25) and azomethine ylide generated in situ
from the precursor 26, which provided the tricyclic derivative 27 (Scheme 2).41 Further steps of the
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 40
reaction sequence included reduction with LiAlH4, intramolecular cyclization of diol 28 to the
corresponding tetrahydrofurane 29, treatment of amines 30 with HCl in 1,4-dioxane – THF followed by
catalytic debenzylation leading to the target hydrochloride 14 in 34% overall yield. This method was
extended successfully to the five-membered analogue 30 for the preparation of 3,7-
oxaza[3.3.3]propellane 15, which was prepared in 48% yield (over four steps) on up to 80 g scale.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
O
O
OH
O
1. LiAlH4
THF, rt, 1 h
2. H2O, KOH
Ar, rt, 3 h
Bn N
O
O
O
n
n
N
n
N
Bn
Bn
27
31
25
30
TFA
CH2Cl2
, n = 2
, n = 1
, n = 2
, n = 1
28
32
, n = 2, 65% (for 2 steps)
, n = 1, 86% (for 2 steps)
Bn
N
1. t-BuOK, THF,
rt, 15 min
2. MsCl, t-BuOK
rt, 1 h, then
reflux, 2 h
MeO
TMS
26
O
Cl
1. HCl  dioxane
O
THF, rt
2. H2, Pd-C,
n
N
n
MeOH, rt, 12 h
Bn
NH2
14
, 90%
29
33
, n = 2, 59%
, n = 1, 80%
15
, 71%
Scheme 2. Synthesis of oxaza[n.3.3]propellanes 14 and15
In turn, reaction of anhydrides 27 and 31 (obtained from 25 and 30, respectively) with urea in
refluxing HOAc, followed by quenching with aq ammonia gave the corresponding imides 34 and 35
(79% and 82% yield for two steps, respectively) on up to 130 g scale (Scheme 3). Reduction of 34 and
35 with LiAlH4 in refluxing THF resulted in the formation of monobenzyl-protected bispyrrolidines 36
and 37 in 87% and 83% yield, respectively. The orthogonally protected diamines 38 and 39 were
obtained by the reaction of 36 and 37 with Boc2O in CH2Cl2. The derivartives 38 and 39 were obtained
in nearly quantitative yields and used in further debenzylation step (H2, Pd-C, MeOH, rt) without
additional purification, which gave the target mono-Boc-protected diaza[n.3.3]propellanes 22 and 23 in
92% and 89% yield, respectively.
ACS Paragon Plus Environment
6

Page 7 of 40
The Journal of Organic Chemistry
O
O
HN
1
2
3
4
5
6
7
8
HN
26
1. LiAlH4, THF,
reflux, 48 h
1. , TFA, Ar
O
CH2Cl2, rt, 3 h
O
O
2. H2O, KOH
n
2. urea, HOAc
reflux, 5 h
n
N
n
N
Bn
Bn
.
3. aq NH3 H2O
25
30
34
35
36
37
, n = 2
, n = 1
, n = 2, 79% (for two steps)
, n = 1, 82% (for two steps)
, n = 2, 87%
, n = 1, 83%
9
Boc2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CH2Cl2
rt, 1 h
Boc
Boc
N
N
H2, Pd-C
MeOH,
rt, 12 h
n
n
N
NH
Bn
22
23
38
39
, n = 2, 92% (for two steps)
, n = 1, 89% (for two steps)
, n = 2
, n = 1
Scheme 3. Synthesis of diaza[n.3.3]propellanes 22 and 23
A slightly different reaction was used for the preparation of a cyclobutane-derived analogue of 14 and
15, i.e. oxaza[3.3.2]propellane (16). In particular, cyclobutene dicarboxylate 40 was involved in the
[3+2] cycloaddition with azomethine ylide, which led to the corresponding vicinal diester 41 in 87%
yield on up to 150 g scale (Scheme 4). Reduction of 41 was performed with LiAlH4 in THF, which led
to the corresponding diol 42 in 93% yield. In contract to transformations of 28 and 32 into the
corresponding propellanes 29 and 33, cyclization of 42 into 43 was challenging. Thus, reaction of 42
with TsCl led to ca. 1:1 mixture of the target tetrahydrofuran 43 and the corresponding ditosylate.
Hence the cyclization was performed of 42 by treatment with 3-fold excess of methanesulfonic acid at
80 °C, which gave the corresponding N-benzyl oxaza[3.3.2]propellane 43 in 93% yield. The subsequent
benzyl group cleavage was performed in an autoclave under 30 bar of H2 in the presence of Pd-C, which
gave the corresponding pyrrolidine 16 (81% yield, 61% overall yield for four steps). In turn, catalytic
debenzylation of 42 gave the corresponding aminodiol 44 in 96% yield.
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 40
1. LiAlH4, THF,
20 °C, 45 min,
then rt, 5 h
HO
OH
1
2
3
4
5
6
7
8
1. MsOH,
80 °C, 48 h
EtO2C
CO2Et
O
2. H2O, NaOH
93%
2. H2O, NaOH,
10 °C
N
N
N
Bn
Bn
41
Bn
42
93%
43
Bn
1. HCl  MeOH
2. H2 (30 bar), Pd-C,
MeOH, rt, overnight
96%
1. HCl  MeOH
2. H2 (30 bar), Pd-C,
MeOH, rt, overnight
81%
MeO
N
TMS
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TFA, CH2Cl2, 40 °C
87%
HO
OH
Cl
EtO2C
CO2Et
O
NH2
N
H
40
44
16
Scheme 4. Synthesis of oxaza[3.3.2]propellane 16
To obtain the tricyclic piperazine analogue 24, the diester 41 reacted with p-methoxybenzyl amine at
190 °C to give imide 45 (42% yield) (Scheme 5). Debenzylation of 45 was performed with Pd(OH)2-C
in THF – i-PrOH (1:1, v/v), which led to derivative 46 in 91% yield. Subsequnet reduction of imide 46
to the corresponding monoprotected bispyrrolidine 47 was performed with LiAlH4 in refluxing THF.
Further formation of carbamate 48 via the reaction of 47 with Boc2O (92% yield), followed by catalytic
cleavage of the PMB group (H2, Pd(OH)2-C in MeOH, rt) provided the target N-Boc derivative 24 in
77% yield.
PMB
O
PMB
O
O
N
N
EtO2C
CO2Et
PMBNH2
H2, Pd(OH)2-C
O
THF  i-PrOH
(1:1, v/v)
rt, 12 h
190 °C, 12 h
42%
N
Bn
41
N
NH
Bn
45
46
91%
1. LiAlH4, THF, reflux, 8 h
2. H2O, NaOH, rt
76%
H2, Pd(OH)2C
Boc2O
NH
N PMB
Boc
N PMB
NH
N
MeOH, rt
77%
CH2Cl2
rt, 12 h
92%
Boc
N
24
48
47
Scheme 5. Preparation of monoprotected diaza[3.3.2]propellane 24
ACS Paragon Plus Environment
8

Page 9 of 40
The Journal of Organic Chemistry
Further synthetic efforts were aimed at the preparation of triheterapropellanes 17–21. The reaction
1
2
sequence for the synthesis of dioxaza[3.3.3]propellane 17 commenced with metallation of the
pyrrolidine diester 50 (prepared by the known [3+2] cycloaddition of dimethyl fumarate and azomethine
ylide42) with LDA in THF at −78 °C, followed by reaction with 3-fold excess of BOM-Cl, which gave
bis-(benzyloxy)methyl derivative 51 in 88% yield (Scheme 6). Subsequent reduction of 51 with LiAlH4
in THF provided bis-hydroxymethyl derivative 52 (93% yield). As in the case of 42, the TsCl-mediated
cyclization of 52 to the corresponding tetrahydrofurane 53 was unfruitful. Nevertheless, reaction of 52
with methanesulfonic acid gave the target compound 53 in 87% yield. Catalytic debenzylation of 53 (as
the hydrochloride) led to triheterapropellane 17 (76% yield, 54% overall yield for four steps). In turn,
catalytic debenzylation of 52 gave polyfucntional derivative 54 (81% yield), which can be considered as
an aminosugar mimetic.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HO
BnO
52
OBn
OH
OBn
MeO2C
CO2Me
1. LDA, THF, Ar
MeO2C
1. LiAlH4, THF,
rt, overnight
CO2Me
78 °C, 1.5 h
BnO
N
2. BOMCl, 78 °C,
1 h to rt, overnight
3. aq NH4Cl, rt
88%
2. H2O, NaOH, rt
93%
N
N
Bn
Bn
50
Bn
51
1. HCl  MeOH
2. H2 (30 bar), Pd-C
81%
OH
Cl
O
HO
HO
O
1. MsOH,
80 °C, 48 h
1. HCl  MeOH
OH
O
NH2
O
2. H2 (30 bar), Pd-C,
MeOH, rt, overnight
76%
2. H2O, NaOH, rt
87%
N
Cl
H2
N
Bn
17
53
54
Scheme 6. Synthesis of dioxaza[3.3.3]propellane 17
Preparation of oxadiaza[3.3.3]propellane 18 relied on the double [3+2] cycloaddition of dimethyl
acetylene dicarboxylate (55) with the azomethine ylide generated from 2.8-fold excess of precursor 26
(Scheme 7). In contrast to the preparation of other bi- and tricyclic pyrrolidine derivatives performed in
this work, in the case of 55, the reaction was performed in the presence of LiF in refluxing MeCN.
Althought the yield of the resulting bispyrrolidine diester 56 was moderate (35%), the product could be
obtained on up to 400 g scale in a single run. Reduction of 56 with LiAlH4 in THF gave the
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 40
corresponding diol 57 (84% yield). Cyclization of diol 57 into the target dibenzyl oxadi-
aza[3.3.3]propellane 58 was performed by heating of the neat starting material with DCC at 170 °C
(82% yield, up to 100 g scale). Cleavage of the benzyl group from the hydrochloride 58HCl led to the
title building block 18 (84% yield, up to 55 g scale).
1
2
3
4
5
6
7
8
9
Bn
N
Bn
N
26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bn
N
CO2Me
MeO
TMS
OH
LiAlH4
MeO2C
CO2Me
LiF, MeCN,
reflux, 12 h
35%
THF, rt,
overnight
84%
HO
CO2Me
N
N
Bn
56
Bn
57
55
DCC,
neat, 170 °C
82%
2Cl
Bn
H2N
N
1. HCl  MeOH
2. H2 (50 bar), Pd-C,
MeOH  H2O,
50 °C, overnight
84%
O
NH2
O
N
Bn
18
58
Scheme 7. Preparation of oxadiaza[3.3.3]propellane 18
Bn
Bn
O
N
N
BnNH2
O
MeO2C
CO2Me
neat, Ar, 180 °C
overnight
63%
N Bn
Bn
N
N
Bn
56
59
1. LiAlH4,
THF, reflux, 5 h
2. H2O, KOH, rt
3Cl
NH2
90%
H2N
Bn
1. HCl  MeOH
N
2. H2 (50 bar), Pd-C,
MeOH  H2O,
50 °C, overnight
80%
NH2
N Bn
N
19
Bn
60
Scheme 8. Synthesis of triaza[3.3.3]propellane 193HCl.
ACS Paragon Plus Environment
10

Page 11 of 40
The Journal of Organic Chemistry
Synthesis of triaza[3.3.3]propellane 19 started with amination of the aforementioned diester 56 with
1
2
3
4
5
6
7
8
9
benzylamine at 180 °C, which gave the corresponding tricyclic imide 59 in 63% yield on up to 100 g
scale (Scheme 8). Reduction of the imide moiety with LiAlH4 in refluxing THF resulted in the
formation of protected trispyrrolidine 60 (90% yield). Exhaustive debenzylation of 60 gave the target
C3-symmetric trihydrochloride 18 in 80% yield on up to 40 g scale.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Preparation of mono- and bis-protected derivatives of the triamine 19 (compound 20 and 21,
respectively) appeared to be the most challenging part of this study. Our preliminary experiments
commenced with amination of the diester 56 with urea, which was unfruitful in all applied conditions
(e.g. heating on up to 240 °C). Thus, condensation of 56 with p-methoxybenzylamine at 180 °C under
argon atmosphere was used for the preparation of tris-protected tricyclic derivative 61 in 68% yield
(Scheme 9). The subsequent PMB group cleavage was unsuccessful (either by refluxing with TFA or
TfOH in methoxybenzene or upon treatment with CAN in MeCN – H2O). Thus, removal of the benzyl
groups was performed (H2, Pd-C in MeOH); however, further cleavage of the PMB fragment in the
corresponding debenzylated derivative was also unfruitful in all attempts.
Bn
PMB
O
PMB
O
N
PMBNH2,
neat
1. LiAlH4,
THF, reflux, 6 h
N
N
MeO2C
CO2Me
Ar, 180 °C
overnight
68%
2. H2O, KOH, rt
79%
N Bn
Bn
N Bn
Bn
N
N
N
Bn
56
61
62
TFAA, Et3N,
rt, overnight
44%
Boc
Boc
HN
N
N
H2, Pd-C
Boc2O
N Bn
MeOH, rt,
overnight
44% (for 2 steps)
CH2Cl2,
rt, overnight
N Bn
NH
NH
N
N
Bn
Bn
20
63
21
Scheme 9. Synthesis of mono- and bis-protected triaza[3.3.3]propellanes 20 and 21
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 40
Finally, reduction of imide 61 with LiAlH4 in THF gave fully protected tris-pyrrolidine 62 (79%
yield). Selective removal of the p-methoxybenzyl group in 62 required tedious experimentations. In
particular, using CAN in MeCN – H2O, DDQ in CH2Cl2 – H2O (10:1, v/v), as well as 1-chloroethyl
chloroformate in THF at −78 °C and then – MeOH at 65 °C was unsuccessful. Fortunately, treatment of
62 with trifluoroacetic anhydride (TFAA) in Et3N led to the target derivative 21 in 44% yield. Further
N-Boc-protection of 21 followed by catalytic debenzylation gave the mono-N-Boc-
triaza[3.3.3]propellane (20) in 44% yield in two steps.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Molecular structure. X-Ray diffraction studies were performed with single crystals of the
morpholine analogues 14 – 16 (obtained by slow evaporation of their solutions in CH2Cl2 – hexanes or
CH2Cl2 – Et2O), 18H2O (from i-PrOH – H2O), and 3-oxa-7-azabicyclo[3.3.0]octane hydrochloride 64
(from MeOH). Crystals of 15, 16, 18H2O, and 64 contained single type of the conformations in the unit
cell, whereas for 14, two very similar conformers (A and B) were observed (Table 1).
To discuss their geometry, an exit vector plot (EVP)-based method was used,43,44 which had been
applied by our group for analysis of various cyclic systems previously.45–51 The basic idea behind this
methodology relies in simulating the functional groups mounted onto the ring system by so-called exit
vectors. In the case of morpholine or piperazine analogues, the corresponding heteroatoms X1 and X2
are used as the starting points of these vectors, whereas their direction is defined by bisectors of the C–
X1–C and C–X2–C angles (Figure 3a). Relative orientation of the exit vectors is described by four
geometric parameters r, 1, 2, and  defined in Figure 3b. Exit vector plots (EVP) are obtained by
depicting valu-
Figure 3. Definition of EVP parameters: (a) exit vectors; (b) r, 1, 2, and  (reproduced with
permission from ref. 48 Copyright (2019) American Chemical Society)
ACS Paragon Plus Environment
12

Page 13 of 40
The Journal of Organic Chemistry
es of these parameters in r – ,  – 1/2, and/or 1/2 plots.
1
2
3
4
5
6
7
8
EVP analysis of the compounds 14–16 shows that although these tricyclic scaffolds are very close
homologues, they provide distinct spatial arrangement of the corresponding heteroatoms (Table 1,
Figure 4). In the r –  plot, this difference is not clearly visible: all the compounds have r = 3.801–4.321
9
Å and  = 7.1–9.5. Therefore, they are expectedly larger than morpholine (r ~ 2.85 Å) and are found in
the “extended”  region of the r –  plot. This is not common for six-membered saturated heterocycles
with two heteroatoms which typically occupy the 1 region of the plots with large  values (that
corresponds to the chair conformation).44,48 Small  values are possible for the energetically unfavorable
boat conformation, which is not typically observed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Molecular geometry of the compounds 14–16, 18, and 64
1,a 2,a ||,
# Compound r, Å
ORTEP diagrams (two projections)c
deg
deg degb
1 14 (A)d
3.836 31.9 29
8.7
2 14 (B)d
3.854 30.2 28.1 7.1
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 40
1
2
3
4
5
6
7
8
9
3.801 57.2 8.4
4.321 11.6 5.6
3.802 60.3 9.0
9.5
3 15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9.0
4 16
5 18 (A)e
2.0
6 18 (B)e
3.910 1.1 53.0 10.6
3.136 72.4 69.2 4.8
7 64
a According to Figure 3, X1 = O, X2 = N. b Since the signs of  angle are opposite for different enantiomeric conformations,
c
d
only absolute values of  are considered. Thermal ellipsoids are shown at 30% probability level. Two slightly different
conformers in the crystal unit. e Two ways to define the exit vectors are possible due to the presence of two nitrogen atoms
ACS Paragon Plus Environment
14

Page 15 of 40
The Journal of Organic Chemistry
a
b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Figure 4. Geometric parameters of the compounds 14–16, 18, and 64 shown in (a) r –  plot (polar
coordinates); (b) 1 – 2 plot
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
On the contrary, compounds 14–16 are easily distinquished in the 1 – 2 plot. Whereas for 14 and
16, the molecules adopt pseudosymmetric conformations with small (5.6–11.6) and medium (ca. 30)
values of 1/2, respectively, in the case of 15, significant difference is observed betweem the 1 (57.2)
and 2 (8.4) values. This behaviour can be easily rationalized by a closer conformational analysis. In
particular, the cyclobutane ring of 16 adopts a non-common flattened conformation, whereas the
pyrrolidine and tetrahydrofuran are found in envelope conformations with exo orientation of both
heteroatoms with respect to the tricyclic system. For 15, all the three five-membered ring are found in
envelope conformations which are combined into a C3-pseudosymmetric propeller-like structure, with
opposite orientations of the heteroatoms redarding the scaffold. Finally, the chair conformation of the
cyclohexane ring in the molecule of 14 together with increased steric repulsion force both the
pyrrolidine and tetrahydrofuran rings to adopt the half-chair conformations. The difference is also
clearly seen if the formal eight-membered rings which contain both the heteroatoms are considered: it is
found in crown, boat-chair, and twisted conformations for 14, 15, and 16, respectively.
Conformation of the compound 18 bearing an additional nitrogen atom is very similar to that of 15
(although formally, two ways to discuss it using EVP should be taken into account since two nitrogen
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 40
atoms are present – thus two different data points in the plots). One might expect that due to signidicant
rigidity, conformational properties of other propellanes studied in this work should also resemple those
discussed for the parent structures 14–16.
1
2
3
4
5
6
7
8
9
Notably, the conformations of 14 – 16 and 18 are rather different from that of 64. In the latter case,
smaller r value (3.136 Å) is observed; it is nonetheless accompanied by  = 4.8, so that all the four
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
compounds are located in the same region of the r –  plot. Even so, much larger 1 and 2 (of ca. 70)
for 64 are indicative of considerably distinctive conformational behavior. In this case, the formal eight-
membered ring (formed by the two five-membered “envelopes” of pyrrolidine and tetrahydrofuran
rings) is found in non-typical boat-boat conformation. It should be noted that the conformation of 64
might be affected by packing of the ions in the crystal cell, which is stabilized by hydrogen bonds
involving both nitrogen and oxygen atoms. No such effect is observed for 14–16; in that case, only the
N–H…Cl hydrogen bonds occur in the crystals.
Conclusions
In this work, several methods for preparation of hetera[3.3.n]propellanes (n = 2–4) which relied on
[3+2] cycloaddition of unsaturated vicinal diesters or bicyclic anhydrides and in situ generated
azomethine ylide, were developed. The aforementioned key step resulted in construction of the
pyrrolidine ring of the target tricyclic system. In the case of oxaza[3.3.n]propellanes 14–16, annelation
of tetrahydrofuran ring was performed via reduction with LiAlH4 of the cycloadducts thus obtained and
cyclization of the resulting diols mediated by t-BuOK – MsCl. Diaza[3.3.n]propellanes 22–24 were
obtained from the same cycloadducts, which were subjected to amination and subsequent imide
reduction at the key steps (Scheme 10).
For the preparation of dioxaza[3.3.3]propellane 17, the initial [3+2] cycloadduct obtained from
dimethyl fumarate was bis-alkylated with BOMCl to introduce the two lacking carbon atoms of the
target tricyclic system. After reduction of the ester groups, construction of both tetrahydrofuran rings
was performed in one step by high-temperature MsOH-promoted cyclization.
ACS Paragon Plus Environment
16

Page 17 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
OBn
HO
BnO
OBn
OH
MeO2C
CO2Me
BnO
CO2Me
O
N
N
Bn
MeO2C
EtO2C
Bn
Y
OH
NH
EtO2C
CO2Et
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
OH
CO2Et
morpholine
analogues
N
Bn
N
LiAlH4
Bn
Y
NBn
Y = O, (CH2)n
(n = 02), NR2
R1/R2 = H, Bn,
PMB, Boc
O
O
O
[3+2]
O
diols
O
O
R1NH2
NBn
n = 1, 2
R1
R1
N
Bn
N
O
N
MeO2C
CO2Me
MeO2C
CO2Me
O
Y
Y
starting
dipolarophiles
N
NR2
NBn
Bn
[3+2] cycloadducts
imides
piperazine
analogues
Scheme 10. Approaches to hetera[3.3.n]propellane synthesis developed in this work
A common intermediate for the preparation of trihetera[3.3.3]propellanes 17-21 was obtained by
[3+2] cycloaddition of dimethyl acetylene dicarboxylate with two equivalents of the azomethine ylide.
To construct the tetrahydrofuran ring of the oxadiaza-derivative 18, cyclization with DCC was applied
after the reduction step. In turn, non-protected triazapropellane 19 was obtained via amination of the
same cycloadduct with BnNH2 and subsequent reduction of the intermediate imide. Finally, synthesis of
mono- and bis-protected triaza[3.3.3]propellanes 20 and 21, respectively, appeared to be the most
challenging. Although the reaction sequence resembled that for 19, it required carefully planned
manipulations with protective groups.
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The molecular structures of four representative heterapropellanes 14-16 and 18, as well as 3-oxa-7-
azabicyclo[3.3.0]octane derivative 64 were obtained from X-Ray diffraction studies and analyzed using
exit vector plots (EVP). The r and  parameters were similar for all the tricyclic compounds 14-16 and
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 40
18; they showed that these scaffolds can be considered as enlarged analogues of uncommon boat
conformers of morpholine/piperazine. Notably, despite very close chemical structure of the
aforementioned homologous heterapropellanes, they demonstrated very distinct conformational
behavior in terms of 1/2 angular parameters. It is particularly obvious from the conformation adopted
by a formal eight membered ring including both N and O atoms (i.e. crown, boat-chair, twist chair-chair
and boat-boat for the compounds 16, 15/18, 14, and 64, respectively).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Taking into account unusual conformational properties of di- and trihetera[3.3.n]propellanes obtained,
as well their easy accessibility on a multigram scale (up to 80 g, 3–5 steps from common precursors,
10–72% overall yield), the title morpholine/piperazine analogues can be considered as extremely
promising building blocks for drug discovery, as well as other areas such as supramolecular chemistry,
which are now readily available to chemical community.
Experimental part
The solvents were purified according to the standard procedures.52 The starting materials 25, 30, 40,
and 55 were purchased from commercial sources. The compound 50 was prepared according to the
literature method.42,53 Melting points were measured on an automated melting point system. Analytical
TLC was performed using silica gel plates. Column chromatography was performed using silica gel
1
(230–400 mesh) as the stationary phase. H and 13C NMR spectra were recorded on a NMR
spectrometer at 500 MHz for Protons and 126 MHz for Carbon-13 or at 400 MHz for protons and 101
MHz for Carbon-13. Chemical shifts are reported in ppm downfield from TMS as an internal standard.
Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry,
National Taras Shevchenko University of Kyiv. Mass spectra were recorded on an LCMS instrument
(chemical ionization (CI)) and GCMS instrument (electron impact ionization (EI)). Preparative flash
chromatography was performed on chromatograph using 40 g columns. CCDC 1943266 (18), CCDC
1943267 (16), CCDC 1943268 (15), CCDC 1943269 (14) and CCDC 1943270 (64) contain the
ACS Paragon Plus Environment
18

Page 19 of 40
The Journal of Organic Chemistry
supplementary crystallographic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1
2
3
4
5
6
7
8
9
cis-(2-Benzyloctahydrocyclopenta[c]pyrrole-3a,6a-diyl)dimethanol (32). The compound 26 (244
g, 1.03 mol) was added to a solution of alkene 30 (141 g, 1.02 mol) in CH2Cl2 (700 mL). Then, a
solution of TFA (7.79 mL, 11.6 g, 0.102 mol) in CH2Cl2 (20 mL) was added dropwise at 25 °C under an
argon atmosphere. The mixture was stirred for 3 h, washed with H2O (400 mL) and brine (400 mL),
dried over Na2SO4 and evaporated in vacuo. The resulting yellowish oil 31 (246 g, ca. 89% yield) was
used in the next step without purification. A suspension of LiAlH4 (38.7 g, 1.02 mol) in THF (1200 mL)
was added dropwise to the stirred solution of 31 (ca. 136 g, 0.503 mol) in THF (300 mL) at 25 °C. The
resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with H2O (100 mL)
carefully added in portions, 10% aq KOH (200 mL) and additionally with H2O (100 mL). The
precipitate was filtered, washed with THF, and the combined filtrates were evaporated in vacuo. The
compound was purified by HPLC (0.5–6.5 min; MeOH; flow rate: 30 mL / min). Yield 113 g (86%);
colorless oil. 1H NMR (500 MHz, DMSO-d6) δ 7.31 – 7.28 (m, 4H), 7.25 – 7.18 (m, 1H), 4.73 (s, 2H),
3.45 (s, 2H), 3.43 (d, J = 10.6 Hz, 2H), 3.39 (d, J = 10.6 Hz, 2H), 2.37 (dd, J = 14.6, 8.8 Hz, 4H), 1.73 –
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1.63 (m, 3H), 1.54 – 1.47 (m, 3H). C{1H} NMR (126 MHz, DMSO-d6) δ 140.0, 128.6, 128.6, 127.1,
65.8, 64.9, 60.0, 55.7, 38.1, 24.3. LC/MS (CI): m/z = 262 [M+H]+. Anal. Calcd. for C16H23NO2: C
73.53; H 8.87; N 5.36. Found: C 73.67; H 8.87; N 5.26.
cis-2-Benzylhexahydro-3a,6a-(methanooxymethano)cyclopenta[c]pyrrole (33). The diol 32 (107
g, 0.410 mol) was dissolved in THF (1000 mL), and t-BuOK (92.0 g, 0.820 mol) was added in portions.
The mixture was stirred for 15 min; MsCl (47.0 g, 0.410 mol) was added dropwise, and then additional
t-BuOK (46.0 g, 0.410 mol) was added at rt. The mixture was stirred at rt for 1 h, then refluxed for 2 h
and cooled to rt. The solvent was evaporated in vacuo, the residue was diluted with H2O (500 mL) and
extracted with t-BuOMe (3×300 mL). The combined organic extracts were washed with H2O and
evaporated in vacuo. The product was purified by distillation in vacuo. Yield 79.8 g (80%); colorless
1
liquid; bp 115–117 °C / 0.2 Torr. H NMR (500 MHz, CDCl3) δ 7.35 – 7.29 (m, 4H), 7.26 – 7.22 (m,
1H), 3.66 (d, J = 8.7 Hz, 2H), 3.58 (d, J = 8.7 Hz, 2H), 3.58 (s, 2H), 2.54 (d, J = 9.2 Hz, 2H), 2.38 (d, J
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 40
= 9.2 Hz, 2H), 1.71 – 1.65 (m, 4H), 1.60 – 1.54 (m, 2H). C{1H} NMR (126 MHz, CDCl3) δ 139.5,
128.4, 128.2, 126.8, 79.0, 64.4, 63.6, 59.1, 37.0, 26.5. LC/MS (CI): m/z = 244 [M+H]+. Anal. Calcd. for
C16H21NO: C 78.97; H 8.70; N 5.76. Found: C 78.77; H 8.91; N 5.77.
13
1
2
3
4
5
6
7
8
9
cis-Hexahydro-3a,6a-(methanooxymethano)cyclopenta[c]pyrrol-2-ium chloride (15). Compound
33 (61.2 g, 0.252 mol) was dissolved in THF (200 mL), and 10% HCl in dioxane (280 mL) was added.
The mixture was evaporated in vacuo, and 33·HCl thus obtained was dissolved in MeOH (500 mL).
Then, 10% Pd-C (20.0 g) was added to this solution, and the resulting mixture was stirred under H2
atmosphere at rt for 12 h. The catalyst was filtered off, and the filtrate was evaporated in vacuo to give
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
the target compound 15·HCl. Yield 33.9 g (71%); yellowish solid; mp 181–184 °C. H NMR (500
MHz, DMSO-d6) δ 9.80 (br s, 2H), 3.81 (d, J = 9.2 Hz, 2H), 3.35 (d, J = 9.2 Hz, 2H), 3.16 (d, J = 12.0
Hz, 2H), 2.97 (d, J = 12.0 Hz, 2H), 1.79 – 1.72 (m, 2H), 1.66 – 1.59 (m, 4H). 13C{1H} NMR (126 MHz,
DMSO-d6) δ 77.4, 63.8, 54.7, 36.0, 26.2. LC/MS (CI): m/z = 154 [M–HCl+H]+. Anal. Calcd. for
C9H16ClNO: C 56.99; H 8.50; N 7.38; Cl 18.69. Found: C 56.69; H 8.90; N 7.27; Cl 18.37.
General procedure for the preparation of 34 and 35. The compound 26 (244 g, 1.03 mol) was
added to the solution of alkene 25 or 30 (1.02 mol) in CH2Cl2 (700 mL). Then, the solution of TFA
(11.6 g, 0.102 mol) in CH2Cl2 (20 mL) was added dropwise at 25 °C under an argon atmosphere. The
mixture was stirred for 3 h, washed with H2O (400 mL) and brine (400 mL), dried over Na2SO4 and
evaporated in vacuo. The resulting yellowish oil 27 or 31 was used in the next step without purification.
The corresponding anhydride 27 or 31 (0.500 mol) and urea (60.1 g, 1.00 mol) were dissolved in glacial
HOAc (500 mL) at rt. The reaction mixture was refluxed for 5 h; then, most of acetic acid was
evaporated in vacuo and the residue was poured into conc. aq NH3·H2O (1000 mL). The resulting
solution was extracted with CH2Cl2 (300 mL), the organic phase was separated, dried over Na2SO4 and
evaporated in vacuo.
cis-9-Benzyltetrahydro-1H-3a,7a-(methanoiminomethano)isoindole-1,3(2H)-dione
(34).
An
analytical sample was obtained by HPLC (0.5–6.5 min; MeCN; flow rate: 30 mL / min). Yield 112 g
(79% for two steps); yellowish oil. 1H NMR (500 MHz, DMSO-d6) δ 11.33 (br s, 1H), 7.31 – 7.27 (m,
2H), 7.24 – 7.20 (m, 3H), 3.50 (s, 2H), 3.12 (d, J = 9.4 Hz, 2H), 2.14 (d, J = 9.4 Hz, 2H), 1.83 – 1.77
ACS Paragon Plus Environment
20

Page 21 of 40
The Journal of Organic Chemistry
(m, 2H), 1.54 – 1.44 (m, 4H), 1.26 – 1.16 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 183.4, 138.6,
128.7, 128.7, 127.4, 62.9, 58.1, 53.7, 25.4, 17.4. LC/MS (CI): m/z = 285 [M+H]+. Anal. Calcd. for
C17H20N2O2: C 71.81; H 7.09; N 9.85. Found: C 72.09; H 7.08; N 9.84.
1
2
3
4
5
6
7
8
9
cis-8-Benzyldihydro-3a,6a-(methanoiminomethano)cyclopenta[c]pyrrole-1,3(2H,4H)-dione (35).
An analytical sample was obtained by HPLC (0.5–6.5 min; MeOH; flow rate: 30 mL / min). Yield 111 g
(82% for two steps); yellowish oil. 1H NMR (500 MHz, DMSO-d6) δ 11.08 (br s, 1H), 7.32 – 7.28 (m,
2H), 7.26 – 7.21 (m, 3H), 3.53 (s, 2H), 3.15 (d, J = 9.6 Hz, 2H), 2.19 (d, J = 9.6 Hz, 2H), 1.81 – 1.66
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(m, 6H). C{1H} NMR (126 MHz, DMSO-d6) δ 182.3, 138.6, 128.8, 128.7, 127.5, 63.8, 62.0, 58.1,
33.3, 28.0. LC/MS (CI): m/z = 271 [M+H]+. Anal. Calcd. for C16H18N2O2: C 71.09; H 6.71; N 10.36.
Found: C 71.32; H 6.59; N 10.35.
General procedure for the preparation of 36 and 37. A solution of the corresponding imide 34 or
35 (0.440 mol) in THF (500 mL) was added dropwise to the stirred suspension of LiAlH4 (66.8 g, 1.76
mol) in THF (1000 mL) at 25 °C and the resulting mixture was refluxed for 48 h. The reaction mixture
was quenched with H2O (100 mL) added carefully in portions, 10% aq KOH (2200 mL), and
additionally with H2O (100 mL). The precipitate was filtered, washed with THF, and the combined
filtrates were evaporated in vacuo.
cis-2-benzylhexahydro-1H-3a,7a-(methanoiminomethano)isoindole dihydrochloride (36). The
compound (as a base) was purified by distillation in vacuo. Yield 98.1 g (87%); colorless liquid; bp
132–134 °C / 0.1 mmHg. The analytical sample was obtained as dihydrochloride 36·2HCl: 2 M HCl
solution in Et2O (7.5 mL) was added to the diamine 36 (1.00 g, 3.90 mmol) at rt. The resulting mixture
1
was stirred for 1 h, then filtered, and dried in vacuo. H NMR (500 MHz, D2O) δ 7.50 – 7.44 (m, 5H),
4.45 (s, 2H), 3.66 – 3.47 (m, 4H), 3.42 – 3.39 (m, 4H), 1.66 – 1.53 (m, 4H), 1.47 – 1.39 (m, 4H).
13C{1H} NMR (126 MHz, D2O) δ 130.9, 130.4, 129.4, 129.2, 60.4, 59.8, 52.5, 49.8, 27.5, 19.3. LC/MS
(CI): m/z = 257 [M–2HCl+H]+. Anal. Calcd. for C17H26Cl2N2: C 62.00; H 7.96; N 8.51; Cl 21.53.
Found: C 62.18; H 8.12; N 8.31; Cl 21.55.
cis-2-Benzylhexahydro-3a,6a-(methanoiminomethano)cyclopenta[c]pyrrole (37). The compound
was purified by distillation in vacuo; bp 121–123 °C / 0.1 mmHg. Yield 88.5 g (83%); colorless liquid.
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 40
1H NMR (500 MHz, CDCl3) δ 7.31 – 7.26 (m, 4H), 7.22 – 7.17 (m, 1H), 3.52 (s, 2H), 2.81 (d, J = 10.7
Hz, 2H), 2.65 (d, J = 10.7 Hz, 2H), 2.42 (d, J = 8.8 Hz, 2H), 2.35 (d, J = 8.8 Hz, 2H), 2.07 (s, 1H), 1.65
1
2
3
4
5
13
– 1.58 (m, 4H), 1.47 – 1.40 (m, 2H). C{1H} NMR (126 MHz, CDCl3) δ 139.6, 128.4, 128.1, 126.7,
6
7
8
9
65.6, 63.2, 59.5, 59.3, 37.5, 26.2. LC/MS (CI): m/z = 243 [M+H]+. Anal. Calcd. for C16H22N2: C 79.29;
H 9.15; N 11.56. Found: C 79.36; H 9.32; N 11.29.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the preparation of monoprotected diamines 22 and 23. The corresponding
N-benzyl amine 36 or 37 (0.382 mol) was dissolved in CH2Cl2 (300 mL) and Boc2O (87.8 mL, 83.4 g,
0.382 mol) was added dropwise ar rt. The resulting mixture was stirred for additional 1 h and
evaporated in vacuo. The resulting colorless liquids 38 or 39 were obtained in nearly quantitative yield
and used in the next step without additional purification. Next, 10% Pd-C (20.0 g) was added to a
solution of 38 or 39 (ca. 0.382 mol) in MeOH (500 mL), and the resulting mixture was stirred under H2
atmosphere at rt for 12 h. The catalyst was filtered off, and the filtrate was evaporated in vacuo.
tert-Butyl tetrahydro-1H-3a,7a-(methanoiminomethano)isoindole-2(3H)-carboxylate (22). The
compound existed as a mixture of ca. 1:1 of rotamers. Yellowish oil; yield: 93.6 g (92%). 1H NMR (400
MHz, DMSO-d6) δ 3.18 (s, 4H), 2.77 (d, J = 10.6 Hz, 2H), 2.71 (d, J = 10.6 Hz, 2H), 1.55 – 1.42 (m,
2H), 1.38 (s, 4.5H), 1.38 – 1.34 (m, 9.5H), 1.11 – 1.08 (m, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ
154.5, 78.6, 56.0 and 55.8, 55.4 and 54.9, 49.9 and 49.0, 29.4, 28.7, 22.1. GC/MS (EI): m/z = 193 [M–
Ot-Bu]+, 210 [M–H2C=C(CH3)2]+. Anal. Calcd. for C15H26N2O2: C 67.63; H 9.84; N 10.52. Found: C
67.77; H 9.84; N 10.14.
tert-Butyl
tetrahydro-3a,6a-(methanoiminomethano)cyclopenta[c]pyrrole-2(1H)-carboxylate
1
(23). Yield 85.8 g (89%); colorless oil. H NMR (400 MHz, DMSO-d6) δ 3.33 (d, J = 11.3 Hz, 2H),
13
3.18 (d, J = 11.3 Hz, 2H), 2.79 (d, J = 2.3 Hz, 4H), 1.69 – 1.47 (m, 7H), 1.37 (s, 9H). C{1H} NMR
(101 MHz, DMSO-d6) δ 154.2, 79.0, 62.6, 57.4, 57.0, 37.8, 28.6, 26.1. GC/MS (EI): m/z = 179 [M–Ot-
Bu]+, 196 [M–H2C=C(CH3)2]+, 237 [M–CH3]+, 252 [M]+. Anal. Calcd. for C14H24N2O2: C 66.63; H
9.59; N 11.10. Found: C 66.95; H 9.47; N 11.01.
Diethyl 3-benzyl-3-azabicyclo[3.2.0]heptane-1,5-dicarboxylate (41). The diester 40 (100 g, 0.504
mol) was dissolved in CH2Cl2 (2000 mL), and TFA (5.75 g, 3.74 mL, 50.4 mmol) was added to the
ACS Paragon Plus Environment
22

Page 23 of 40
The Journal of Organic Chemistry
stirred solution, then warmed up to 50 °C. A solution of compound 26 (240 g, 1.01 mol) in CH2Cl2
(2000 mL) was added dropwise, and the resulting mixture was stirred at 50 °C overnight. Then, the
solution was washed with saturated aq NaHCO3 (1000 mL), H2O (21000 mL), organic layer was
separated, dried over Na2SO4, and evaporated in vacuo. The compound was purified by column
1
2
3
4
5
6
7
8
9
1
chromatography using gradient CHCl3 – MeCN as eluent. Yield 145 g (87%); yellowish oil. H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(400 MHz, CDCl3) δ 7.37 (d, J = 7.4 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.24 – 7.17 (m, 1H), 4.09 (q, J =
7.1 Hz, 4H), 3.71 (s, 2H), 2.96 (d, J = 9.3 Hz, 2H), 2.59 (d, J = 9.3 Hz, 2H), 2.50 (dt, J = 6.2, 5.7 Hz,
2H), 2.01 (dt, J = 6.2, 5.7 Hz, 2H), 1.21 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 173.2,
139.2, 128.5, 128.3, 127.0, 62.3, 60.6, 59.3, 55.6, 25.4, 14.1. LC/MS (CI): m/z = 332 [M+H]+. Anal.
Calcd. for C19H25NO4: C 68.86; H 7.6; N 4.23. Found: C 68.81; H 7.39; N 4.10.
(3-Benzyl-3-azabicyclo[3.2.0]heptane-1,5-diyl)dimethanol (42). THF (1500 mL) was cooled to
–20 °C, and LiAlH4 (34.4 g, 0.906 mol) was added in portions under argon over 15 min. Then, a
solution of diester 41 (100 g, 0.302 mol) in THF (500 mL) was added dropwise at –20 °C for 45 min.
The resulting mixture was warmed up to rt and stirred for 5 h. The reaction completion was monitored
by TLC using CHCl3 – i-PrOH (19:1, v/v) as eluent. Then, the reaction mixture was cooled to –10 °C,
and H2O (35.0 mL), 15% aq NaOH (35.0 mL), and then H2O (105 mL) were slowly added dropwise at
–10 °C. The resulting mixture was warmed up to rt and stirred overnight, the precipitate was filtered off,
washed with THF (2100 mL). The combined filtrates were evaporated in vacuo, the residue was
dissolved in CH2Cl2 (500 mL). The solution was dried over Na2SO4 and evaporated in vacuo. The
compound was purified by HPLC (0.5–6.5 min; H2O - MeCN; flow rate: 30 mL / min). Yield 69.5 g
(93%); beige powder; mp 104-105 °C 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 7.4 Hz, 2H), 7.33 (t, J
= 7.4 Hz, 2H), 7.27 – 7.23 (m, 1H), 3.77 (br s, 2H), 3.74 (d, J = 11.7 Hz, 2H), 3.69 (s, 2H), 3.52 (d, J =
11.7 Hz, 2H), 2.68 (d, J = 9.0 Hz, 2H), 2.46 (d, J = 9.0 Hz, 2H), 1.89 – 1.81 (m, 2H), 1.76 – 1.69 (m,
2H). 13C{1H} NMR (126 MHz, CDCl3) δ 139.5, 128.6, 128.2, 126.8, 63.6, 62.5, 60.1, 50.2, 24.2.
LC/MS (CI): m/z = 248 [M+H]+. Anal. Calcd. for C15H21NO2: C 72.84; H 8.56; N 5.66. Found: C 72.5;
H 8.68; N 5.55.
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 40
5-Benzyltetrahydro-1H-3a,6a-ethanofuro[3,4-c]pyrrole (43). MsOH (35.0 g, 0.384 mol) was added
to diol 42 (30.0 g, 0.121 mol), and the resulting mixture was stirred at 80 °C for 48 h. The resulting
mixture was evaporated in vacuo, diluted with H2O (100 mL), and 10% aq NaOH (16.0 g, 0.400 mol)
was added in portions. The aqueous solution was extracted with CH2Cl2 (2100 mL), combined organic
layer was dried over Na2SO4, and evaporated in vacuo. The compound was purified by column
chromatography using gradient t-BuOMe – MeOH as eluent. Yield 25.8 g (93%); yellowish powder, mp
47-49 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.35 – 7.29 (m, 4H), 7.26 – 7.20 (m, 1H), 3.72 (d, J = 8.9
Hz, 2H), 3.65 (s, 2H), 3.37 (d, J = 8.9 Hz, 2H), 2.72 (d, J = 9.2 Hz, 2H), 2.24 (d, J = 9.2 Hz, 2H), 1.94 –
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1.87 (m, 2H), 1.87 – 1.80 (m, 2H). C{1H} NMR (126 MHz, DMSO-d6) δ 139.7, 128.7, 128.6, 127.2,
77.4, 63.0, 58.9, 56.0, 26.5. LC/MS (CI): m/z = 230 [M+H]+. Anal. Calcd. for C15H19NO: C 78.56; H
8.35; N 6.11. Found: C 78.23; H 8.18; N 5.88.
Tetrahydro-1H-3a,6a-ethanofuro[3,4-c]pyrrol-5-ium chloride (16). The N-benzyl amine 43 (25.0
g, 0.109 mol) was dissolved in 2 M HСl in MeOH (250 mL), the resulting solution was evaporated in
vacuo. The crystalline 43·HCl was dissolved in МеОН (600 mL), and 10% Pd-C (5.63 g) was added.
The resulting mixture was hydrogenated with H2 (30 bar) in autoclave at rt overnight, the catalyst was
filtered off, and washed with MeOH (2100 mL). Combined filtrates were evaporated in vacuo, the
residue was dried in vacuo (1 mmHg). Yield 15.5 g (81%); colorless powder; mp 214-217 °C. 1H NMR
(400 MHz, DMSO-d6) δ 10.22 (br d, J = 77.6 Hz, 2H), 3.76 (d, J = 9.2 Hz, 2H), 3.56 (d, J = 9.2 Hz,
2H), 3.34 (d, J = 11.8 Hz, 2H), 3.09 – 3.02 (m, 2H), 2.11 (dt, J = 6.4, 5.8 Hz, 2H), 1.88 (dt, J = 6.4, 5.8
13
Hz, 2H). C{1H} NMR (126 MHz, DMSO-d6) δ 76.9, 56.7, 53.1, 25.0. LC/MS (CI): m/z = 140 [M–
HCl+H]+. Anal. Calcd. for C8H14ClNO: C 54.70; H 8.03; N 7.97; Cl 20.18. Found: C 54.69; H 7.95; N
8.19; Cl 19.89.
3-Azabicyclo[3.2.0]heptane-1,5-diyldimethanol (44). The N-benzyl amine 42 (18.0 g, 72.8 mmol)
was dissolved in МеОН (500 mL), and 10% Pd-C (4.03 g) was added. The resulting mixture was
hydrogenated with H2 (30 bar) in autoclave at rt overnight, the catalyst was filtered off, and washed with
MeOH (2100 mL). Combined filtrates were evaporated in vacuo, and the residue was dried in vacuo
ACS Paragon Plus Environment
24

Page 25 of 40
The Journal of Organic Chemistry
(1 mmHg). Yield 11.0 g (96%); colorless powder; mp = 214-217 °C. 1H NMR (400 MHz, DMSO-d6) δ
4.71 (s, 2H), 3.49 (d, J = 10.8 Hz, 2H), 3.44 (d, J = 10.8 Hz, 2H), 3.17 (s, 1H), 2.62 (d, J = 11.3 Hz,
2H), 2.58 (d, J = 11.3 Hz, 2H), 1.75 – 1.65 (m, 2H), 1.53 – 1.43 (m, 2H). 1H NMR (400 MHz, CDCl3) δ
3.79 (d, J = 11.8 Hz, 2H), 3.55 (d, J = 11.8 Hz, 2H), 2.99 (d, J = 11.2 Hz, 2H), 2.89 – 2.64 (m, 5H), 1.78
– 1.70 (m, 2H), 1.62 – 1.50 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ 62.8, 55.9, 51.6, 23.5. LC/MS
(CI): m/z = 158 [M+H]+. Anal. Calcd. for C8H15NO2: C 61.12; H 9.62; N 8.91. Found: C 61.07; H 9.58;
N 9.20.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-Benzyl-2-(4-methoxybenzyl)dihydro-3a,6a-ethanopyrrolo[3,4-c]pyrrole-1,3(2H,4H)-dione (45).
p-Methoxybenzylamine (34.7 mL, 36.4 g, 0.266 mol) was added to the diester 41 (20.0 g, 53.1 mmol),
and the resulting mixture was heated at 180 °С for 12 h. The product was separated by column
chromatography on silica gel using gradient hexanes – t-BuOMe as eluent. Analytical sample was
obtained by HPLC (0.5–6.5 min; H2O – MeCN; flow rate: 30 mL / min). Yield 8.40 g (42%); yellow
oil. 1H NMR (500 MHz, DMSO-d6) δ 7.30 (t, J = 7.3 Hz, 2H), 7.26 – 7.20 (m, 3H), 7.14 (d, J = 8.2 Hz,
2H), 6.89 (d, J = 8.2 Hz, 2H), 4.51 (s, 2H), 3.73 (s, 3H), 3.64 (s, 2H), 2.78 (d, J = 9.7 Hz, 2H), 2.71 (d, J
= 9.7 Hz, 2H), 2.35 – 2.26 (m, 2H), 2.26 – 2.17 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 179.3,
159.0, 138.7, 128.9, 128.7, 128.7, 128.6, 127.5, 114.4, 59.5, 57.6, 55.5, 51.4, 41.6, 24.6. LC/MS (CI):
m/z = 377 [M+H]+. Anal. Calcd. for C23H24N2O3: C 73.38; H 6.43; N 7.44. Found: C 73.38; H 6.54; N
7.43.
2-(4-Methoxybenzyl)dihydro-3a,6a-ethanopyrrolo[3,4-c]pyrrole-1,3(2H,4H)-dione hydrocloride
(46). Pd(OH)2-C (2.07 g) was added to the solution of N-benzyl amine 45 (7.95 g, 21.1 mmol) in THF –
i-PrOH (120 mL, 1:1, v/v), the resulting mixture was degased, refilled with H2, and stirred at rt for 12 h.
The catalyst was filtered off, washed with THF (230 mL), and combined filtrates were evaporated in
vacuo. The analytical sample was obtained as hydrochloride 46·HCl: 2 M HCl in Et2O (3.5 mL) was
added to the diamine 36 (1.00 g, 3.49 mmol) at rt. The resulting mixture was stirred for 1 h, then
filtered, and dried in vacuo. Yield 5.50 g (91% as a base); colorless powder; mp 244–247 °С. 1H NMR
(400 MHz, DMSO-d6) δ 10.42 (br s, 2H), 7.21 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 4.49 (s,
2H), 3.73 (s, 3H), 3.62 (d, J = 12.1 Hz, 2H), 3.45 (d, J = 12.1 Hz, 2H), 2.58 (dd, J = 6.9, 5.9 Hz, 2H),
ACS Paragon Plus Environment
25

The Journal of Organic Chemistry
Page 26 of 40
2.22 (dd, J = 6.9, 5.9 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 176.8, 159.1, 129.3, 128.3,
114.5, 55.5, 51.9, 49.8, 42.1, 24.4. LC/MS (CI): m/z = 287 [M+H]+. Anal. Calcd. for C16H19ClN2O3: C
59.54; H 5.93; N 8.68; Cl 10.98. Found: C 59.68; H 5.89; N 8.53; Cl 11.38.
1
2
3
4
5
6
7
8
9
2-(4-Methoxybenzyl)hexahydro-3a,6a-ethanopyrrolo[3,4-c]pyrrole (47). To a suspension of
LiAlH4 (1.46 g, 38.4 mmol) in THF (100 mL), the imide 46 (5.50 g, 19.2 mmol) was added in portions
at rt. The resulting mixture was refluxed for 8 h, then H2O (1.20 mL), 20% aq NaOH (1.20 mL), and
H2O (3.60 mL) were added. The precipitate was filtered off, washed with THF (220 mL), combined
filtrates were evaporated in vacuo. The residue was diluted with toluene – CCl4 (50 mL, 1:1, v/v) and
evaporated in vacuo. The compound was purified by HPLC (0.5-6.5 min; MeOH – NH3; flow rate: 30
mL / min). Yield 3.77 g (76%); colorless powder; mp 80–81 °С. 1H NMR (500 MHz, CDCl3) δ 7.28 (d,
J = 8.3 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 3.81 (s, 3H), 3.62 (s, 2H), 2.89 (d, J = 11.2 Hz, 2H), 2.80 (d, J
= 9.2 Hz, 2H), 2.68 (d, J = 11.2 Hz, 2H), 2.65 (s, 1H), 2.16 (d, J = 9.2 Hz, 2H), 2.00 (dd, J = 6.5, 5.7
Hz, 2H), 1.76 (dd, J = 6.5, 5.7 Hz, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ 158.4, 131.7, 129.6, 113.5,
64.1, 58.7, 57.9, 55.9, 55.2, 26.9. LC/MS (CI): m/z = 259 [M+H]+. Anal. Calcd. for C16H22N2O: C
74.38; H 8.58; N 10.84. Found: C 74.59; H 8.37; N 10.65.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tert-Butyl 5-(4-methoxybenzyl)tetrahydro-3a,6a-ethanopyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
(48). Boc2O (3.27 mL, 3.10 g, 14.2 mmol) was added dropwise to a solution of amine 47 (3.50 g, 13.5
mmol) in CH2Cl2 (50 mL) at rt. The resulting mixture was stirred at rt for 12 h, and evaporated in vacuo.
The compound was purified by column chromatography using gradient hexanes – t-BuOMe as eluent.
Yield 4.45 g (92%); yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J = 8.5 Hz, 2H), 6.87 (d, J =
8.5 Hz, 2H), 3.73 (s, 3H), 3.57 (s, 2H), 3.49 (d, J = 11.3 Hz, 2H), 3.12 – 3.05 (m, 2H), 2.77 (d, J = 9.2
Hz, 2H), 2.11 (d, J = 9.2 Hz, 2H), 1.97 – 1.88 (m, 2H), 1.88 – 1.79 (m, 2H), 1.40 (s, 9H). 13C{1H} NMR
(126 MHz, DMSO-d6) δ 158.6, 154.2, 131.4, 129.9, 114.0, 79.7, 78.9, 64.2, 58.2, 56.9, 55.4, 28.6, 27.5.
LC/MS (CI): m/z = 359 [M+H]+. Anal. Calcd. for C21H30N2O3: C 70.36; H 8.44; N 7.81. Found: C
70.33; H 8.60; N 7.81.
tert-Butyl tetrahydro-3a,6a-ethanopyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (24). Pd(OH)2-C
(1.20 g) was added to the solution of p-methoxybenzylamine 48 (4.30 g, 12.0 mmol) in MeOH (100
ACS Paragon Plus Environment
26

Page 27 of 40
The Journal of Organic Chemistry
mL), the resulting mixture was degased, refilled with H2, and stirred at rt for 12 h. The catalyst was
filtered off, washed with MeOH (225 mL), and combined filtrates were evaporated in vacuo. The
compound was purified by column chromatography using gradient t-BuOMe – MeOH as eluent. Yield
1
2
3
4
5
6
7
8
1
2.20 g (77%); white powder; mp 204–207 °С. H NMR (400 MHz, DMSO-d6) δ 3.58 (d, J = 11.4 Hz,
9
2H), 3.30 (d, J = 11.9 Hz, 2H), 3.22 (d, J = 11.4 Hz, 2H), 3.03 (d, J = 11.9 Hz, 2H), 2.50 – 2.48 (m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1H), 2.13 (dd, J = 6.9, 5.8 Hz, 2H), 1.86 (dd, J = 6.9, 5.8 Hz, 2H), 1.40 (s, 9H). C{1H} NMR (126
MHz, DMSO-d6) δ 154.2, 79.2, 56.5, 54.3, 53.7, 28.6, 26.1. LC/MS (CI): m/z = 165 [M–Ot-Bu]+, 183
[M-H2C=C(CH3)2+H]+. Anal. Calcd. for C13H22N2O2: C 65.52; H 9.30; N 11.75. Found: C 65.62; H
9.01; N 12.12.
Dimethyl 1-benzyl-3,4-bis((benzyloxy)methyl)pyrrolidine-3,4-dicarboxylate (51). Diisopropyl-
amine (63.2 mL, 45.3 g, 0.448 mol) was dissolved in THF (750 mL) under argon atmosphere, and the
resulting solution was cooled to –40 °C. n-BuLi (180 mL, 2.5 M in hexanes, 0.448 mol) was added
dropwise at –40 °C. The resulting mixture was cooled to –78 °C, and a solution of diester 50 (50.0 g,
0.180 mol) in THF (250 mL) was slowly added dropwise for 30 min. After 1 h, a solution of BOMCl
(84.7 g, 0.540 mol) in THF (250 mL) was added dropwise at –78 °C, and the reaction mixture was
stirred at –78 °C for 1 h, then warmed up to rt overnight. Then, saturated aq NH4Cl (1000 mL) was
added in portions at rt. Organic layer was separated, evaporated in vacuo, the residue was dissolved in
CH2Cl2 (500 mL), dried over Na2SO4, and evaporated in vacuo. The compound was purified by column
1
chromatography using gradient CHCl3 – MeCN as eluent. Yield 82.0 g (88%); yellowish oil. H NMR
(400 MHz, DMSO-d6) δ 7.35 – 7.26 (m, 11H), 7.21 – 7.17 (m, 4H), 4.40 (s, 4H), 3.59 (s, 6H), 3.59 –
3.56 (m, 4H), 3.50 (d, J = 8.1 Hz, 2H), 3.08 (d, J = 9.4 Hz, 2H), 2.70 (d, J = 9.4 Hz, 2H). 13C{1H} NMR
(126 MHz, DMSO-d6) δ 171.7, 139.2, 138.3, 128.7, 128.6, 128.0, 127.9, 127.3, 73.0, 72.0, 59.0, 58.9,
57.1, 52.3. LC/MS (CI): m/z = 518 [M+H]+. Anal. Calcd. for C31H35NO6: C 71.93; H 6.82; N 2.71.
Found: C 71.85; H 6.54; N 3.10.
(1-Benzyl-3,4-bis((benzyloxy)methyl)pyrrolidine-3,4-diyl)dimethanol (52). THF (1500 mL) was
cooled to –20 °C, and LiAlH4 (22.2 g, 0.585 mol) was added in portions for 15 min under argon. Then, a
solution of diester 51 (101 g, 0.195 mol) in THF (500 mL) was added dropwise at –20 °C for 45 min.
ACS Paragon Plus Environment
27

The Journal of Organic Chemistry
Page 28 of 40
The resulting mixture was warmed up to rt and stirred for 5 h. The reaction completion was monitored
by TLC using CHCl3 – i-PrOH (19:1, v/v) as eluent. The reaction mixture was cooled to –10 °C, and
H2O (23.0 mL), 15% aq NaOH (23.0 mL), and H2O (69.0 mL) were added slowly dropwise. The
resulting mixture was warmed up to rt and stirred overnight, the precipitate was filtered off, washed
with (2300 mL), and combined filtrated were evaporated in vacuo. The residue was dissolved in
CH2Cl2 (500 mL), dried over Na2SO4, and evaporated in vacuo. The compound was purified by column
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
chromatography using gradient CHCl3 – MeCN as eluent. Yield 83.7 g (93%); yellowish oil. H NMR
(400 MHz, DMSO-d6) δ 7.35 – 7.23 (m, 15H), 4.89 (s, 2H), 4.50 (d, J = 12.3 Hz, 2H), 4.45 (d, J = 12.3
Hz, 2H), 3.65 – 3.52 (m, 6H), 3.49 (d, J = 10.6 Hz, 2H), 3.40 (d, J = 10.6 Hz, 2H), 2.66 (d, J = 9.4 Hz,
2H), 2.48 (d, J = 9.4 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 139.9, 139.2, 128.7, 128.6, 128.6,
127.7, 127.7, 127.1, 73.0, 70.5, 60.9, 60.0, 59.2, 51.4. LC/MS (CI): m/z = 462 [M+H]+. Anal. Calcd. for
C29H35NO4: C 75.46; H 7.64; N 3.03. Found: C 75.64; H 7.73; N 3.19.
5-Benzyltetrahydro-1H-3a,6a-(methanooxymethano)furo[3,4-c]pyrrole (53). A mixture of the bis-
benzyloxydiol 52 (80.0 g, 0.173 mol) and MsOH (66.6 g, 0.693 mol) was heated at 80 °C for 48 h. The
mixture was evaporated in vacuo, the residue was diluted with H2O (200 mL), and 10% aq NaOH
(27.7 g, 0.693 mol) was added in portions at rt. The reaction mixture was extracted with CH2Cl2 (2200
mL), dried over Na2SO4, and evaporated in vacuo. The compound was purified by column
chromatography on silica gel using gradient CHCl3 - MeCN as eluent. The analytical sample was
obtained by HPLC (0.5–6.5 min; H2O – MeCN; flow rate: 30 mL / min). Yield 36.9 g (87%); yellow
1
oil. H NMR (500 MHz, DMSO-d6) δ 7.34 – 7.28 (m, 4H), 7.25 – 7.20 (m, 1H), 3.60 – 3.55 (m, 6H),
3.51 (d, J = 8.8 Hz, 4H), 2.45 (s, 4H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 139.3, 128.7, 128.7,
127.3, 76.4, 66.3, 62.1, 58.3. LC/MS (CI): m/z = 246 [M+H]+. Anal. Calcd. for C15H19NO2: C 73.44; H
7.81; N 5.71. Found: C 73.23; H 7.56; N 5.97.
Tetrahydro-1H-3a,6a-(methanooxymethano)furo[3,4-c]pyrrol-5-ium chloride (17). The N-benzyl
amine 53 (20.0 g, 81.5 mmol) was dissolved in 2 M HСl in MeOH (200 mL), the resulting solution was
evaporated in vacuo. The crystalline 53·HCl was dissolved in МеОН (600 mL), and 10% Pd-C (4.00 g)
ACS Paragon Plus Environment
28

Page 29 of 40
The Journal of Organic Chemistry
was added. The resulting mixture was hydrogenated with H2 (30 bar) in autoclave at rt overnight, the
catalyst was filtered off, and washed with MeOH (2100 mL). Combined filtrates were evaporated in
vacuo, the residue was dried in vacuo (1 mmHg). Yield 11.9 g (76%); yellowish crystals; mp 234–236
1
2
3
4
5
6
7
8
1
°C. H NMR (400 MHz, DMSO-d6) δ 10.02 (br s, 2H), 3.84 (d, J = 9.3 Hz, 4H), 3.55 (d, J = 9.3 Hz,
9
4H), 3.17 (s, 4H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 75.9, 66.7, 52.5. LC/MS (CI): m/z = 156 [M–
HCl+H]+. Anal. Calcd. for C8H14ClNO2: C 50.13; H 7.36; N 7.31; Cl 18.50. Found: C 49.91; H 7.32; N
6.94; Cl 18.42.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pyrrolidine-3,3,4,4-tetrayltetramethanol hydrochloride (54). Amine 52 (27.5 g, 59.6 mmol) was
dissolved in 2 M HСl in MeOH (300 mL), the resulting solution was evaporated in vacuo. The
crystalline 52·HCl was dissolved in МеОН (700 mL), and 10% Pd-C (5.44 g) was added. The resulting
mixture was hydrogenated with H2 (30 bar) in autoclave at rt overnight, the catalyst was filtered off, and
washed with MeOH (2150 mL). Combined filtrates were evaporated in vacuo, the residue was dried in
vacuo (1 mmHg). Yield 11.0 g (81%); yellow crystals; mp 203–206 °С. 1H NMR (400 MHz, DMSO-d6)
13
δ 9.03 (br s, 2H), 5.00 (br s, 4H), 3.50 (s, 8H), 3.14 (t, J = 6.1 Hz, 4H). C{1H} NMR (126 MHz,
DMSO-d6) δ 60.8, 52.3, 50.5. GC/MS (EI): m/z = 227 [M]+. Anal. Calcd. for C8H18ClNO4: C 42.20; H
7.97; N 6.15; Cl 15.57. Found: C 42.47; H 8.23; N 5.97; Cl 15.31.
Dimethyl 2,5-dibenzyloctahydropyrrolo[3,4-c]pyrrole-3a,6a-dicarboxylate (56). Dimethyl
acetylenedicarboxylate (55, 100 g, 0.704 mol) and the compound 26 (468 g, 1.97 mol) were dissolved in
MeCN (2500 mL), and LiF (91.3 g, 3.52 mol) was added. The resulting suspension was refluxed for 12
h, then evaporated in vacuo. The residue was diluted with H2O (1000 mL), and extracted with EtOAc
(21000 mL). Combined organic layers were dried over Na2SO4, and evaporated in vacuo. The
analytical sample was obtained by HPLC (0.5–6.5 min; H2O – MeCN; flow rate: 30 mL / min). Yield
1
101 g (35%); yellowish oil. H NMR (500 MHz, CDCl3) δ 7.37 – 7.30 (m, 8H), 7.28 – 7.24 (m, 2H),
13
3.70 – 3.65 (m, 10H), 3.10 (d, J = 9.1 Hz, 4H), 2.73 (d, J = 9.1 Hz, 4H). C{1H} NMR (126 MHz,
CDCl3) δ 173.9, 138.7, 128.4, 128.2, 126.9, 62.9, 62.8, 58.7, 52.1. LC/MS (CI): m/z = 409 [M+H]+.
Anal. Calcd. for C24H28N2O4: C 70.57; H 6.91; N 6.86. Found: C 70.92; H 7.04; N 6.56.
ACS Paragon Plus Environment
29