Bicyclic Pyrrolidines for Medicinal Chemistry via [3 + 2]-Cycloaddition

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Bicyclic Pyrrolidines for Medicinal Chemistry via [3 + 2]-

Cycloaddition

Vladimir I. Savych,^†Vladimir L. Mykhalchuk,^†Pavlo V. Melnychuk,^†Andrii O. Isakov, Taras Savchuk,

Vadim M. Timoshenko, Sergiy A. Siry, Sergiy O. Pavlenko, Dmytro V. Kovalenko,

Oleksandr V. Hryshchuk, Vitalii A. Reznik, Bohdan A. Chalyk, Vladimir S. Yarmolchuk,

Eduard B. Rusanov, and Pavel K. Mykhailiuk *

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ABSTRACT: A general approach to bicyclic fused pyrrolidines via

[3 + 2]-cycloaddition between nonstabilized azomethyne ylide and

endocyclic electron-deﬁcient alkenes was elaborated. “Push−pull”

alkenes and CF₃-alkenes did not react with the azomethyne ylide

under the previously reported conditions, and we developed a

superior protocol (LiF, 140 °C, no solvent). Among obtained

products were medchem-relevant bicyclic sulfones, monoﬂuoro-,

diﬂuoro-, and triﬂuoromethyl-substituted pyrrolidines. This

approach not only allowed preparation of novel molecules but

also signiﬁcantly simpliﬁed synthesis of the existing ones (e.g.,

soﬁnicline).

endocyclic alkenes (Figure 2). In the literature, there were

indeed many examples on constructing tricyclic, polycyclic,¹¹

and benzoannulated compounds¹²using that approach (Figure

2). Precedents on bicyclic pyrrolidines also existed,¹³but those

studies were not systematic and led to polysubstituted

products with additional alkyl or aryl groups. In addition,

reactions of cyclic “push−pull” alkenes and cyclic CF₃-alkenes

with reagent 1 were unknown.

In this work, we developed a general approach to medchem-

relevant fused bicyclic pyrrolidines via [3 + 2]-cycloaddition.

Our strategy leads to derivatives with one or two functional

groups and only strategic additional substituents (ﬂuorine,

gem-diﬂuoro, triﬂuoromethyl, and sulfone) important for

medicinal chemistry. To the best of our knowledge, this is

the ﬁrst systematic study on that topic to date.

INTRODUCTION

■

Pyrrolidine is one of the most frequently used secondary

amines in organic synthesis and medicinal chemistry.¹⁻³The

structure of more than 50 drugs comprises the fragment of

pyrrolidine.⁴At the beginning of this century, a concept called

“conformational restriction” appeared that changed the way

medicinal chemists think.^5,6This is because conformationally

restricted compounds are often more active and selective

ligands for various targets due to preorganization of a molecule

in a bioactive conformation.⁷Bicyclic pyrrolidines are

intrinsically conformationally restricted and, hence, of high

interest to medicinal chemists (Figure 1).

Three types of bicyclic pyrrolidines exist: bridged,

spirocyclic, and fused (Figure 1). In recent years, we developed

practical methods to bridged,⁸spirocyclic,⁹and some fused

pyrrolidines.¹⁰The latter class was assembled via [2 + 2]-

photocycloaddition. In this work, we report a general approach

to medicinal chemistry related fused pyrrolidines via [3 + 2]-

cycloaddition (Figures 1 and 2).

Received: June 7, 2021

Previously, we synthesized spirocyclic derivatives by [3 + 2]-

cycloaddition between azomethyne ylide precursor 1 and

exocyclic electron-deﬁcient alkenes (Figure 2).⁹In this work,

we envisioned that fused pyrrolidines could also be assembled

following a similar logic starting from electron-deﬁcient

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A

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Figure 2. State of the art and objectives of this work.

identical conditions, ﬁve-membered alkene 6 also reacted with

compound 1 to provide the needed product 6a in a lower yield

of 51%. For that substrate, we somewhat optimized the

conditions. We found that slow addition of compound 1 to the

reaction mixture during 12 h using a syringe pump improved

the yield to 77% without changing the reaction stoichiometry.

In the future, we used these conditions (protocol B) for

problematic substrates. Performing the reaction with LiF in

acetonitrile under reﬂux also allowed product 6a to be

obtained in 71% yield (protocol C). Five-membered

tetrasubstituted ﬂuorine-containing alkene 7 and alkene 8

were less active than substrate 6. However, we could obtain the

needed products 7a and 8a in good yields by heating the

reaction mixture with LiF in acetonitrile (protocol C).

Unexpectedly, alkene 9 did not react under any of the

previously applied conditions (Table 1). Catalysis with TFA at

room temperature (protocol A) gave no product, but only the

starting alkene. Slow addition of reagent 1 during 12 h

(protocol B) did not give any improvement either. Performing

the reaction with LiF in acetonitrile (protocol C) also did not

provide any product. Presumably, the reason why alkene 9

remained inactive in [3 + 2]-cycloaddition was its “push−pull”

resonance form A (Table 1). In this structure, the C(2)−C(3)

bond is single and, therefore, cannot participate in the

cycloaddition. Optimization of this transformation took us

several years, until by accident we did not ﬁnd that the reaction

proceeded under heating at 140 °C without any solvent

(protocol D). Luckily, the formed ylide did not polymerize at

this temperature, as we originally were afraid of, but reacted

with alkene 9 ﬁrst. The corresponding bicyclic amine 9a was

ﬁnally isolated in 85% yield (Table 1). Moreover, the

procedure was scalable, as we could synthesize ca. 20 g of

the product in a single run.

Figure 1. Bicyclic pyrrolidines in drug discovery.

RESULTS AND DISCUSSION

■

Optimization and Scope. Previously, during the synthesis

of spirocyclic pyrrolidines,⁹we used two diﬀerent conditions to

generate azomethyne ylide from reagent 1: (a) catalysis with

triﬂuoroacetic acid (TFA) at room temperature (protocol A)¹⁴

and catalysis with lithium ﬂuoride (LiF) under heating in

acetonitrile (protocol C).¹⁵For the synthesis of fused

pyrrolidines, we started optimization with the same conditions.

At the beginning, we easily synthesized bicyclic amines 2a−5a

(Scheme 1) in 87−98% yield from the corresponding active

four-membered alkenes and reagent 1 using TFA catalysis at

room temperature (protocol A). Products 3a−5a contained

the medicinal chemistry relevant sulfone moiety.¹⁶The

structure of sulfone 3a was proven by X-ray analysis. Under

Having the optimized conditions in handthe previously

known protocols A, C ande protocols B, D developed her for

problematic substrateswe next studied the scope of the

reaction. Five-membered oxygen-containing alkenes 10−13,

nitrogen-containing 14−17 and 19, sulfone-containing 20, 21,

B

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Scheme 1. Bicyclic Pyrrolidines via [3 + 2]-Cycloaddition*

*

Reaction conditions: protocol A, alkene (1.0 equiv), 1 (1.2 equiv), TFA (0.1 equiv), CH₂Cl₂, 20 °C, 12 h; protocol B, alkene (1.0 equiv), slow

addition of 1 (1.1 equiv) during 12 h, TFA (0.1 equiv), CH₂Cl₂, 20 °C; protocol C, alkene (1.0 equiv), 1 (1.2 equiv), LiF (3.0 equiv), CH₃CN, 80

a

°C, 12 h; protocol D, alkene (1.0 equiv), 1 (2.0 equiv), dry LiF (3.0 equiv), 140 °C, 12 h and 110 °C, 12 h. An additional portion of 1 (0.3 equiv)

b

c

was added after 12 h. Two additional portions of 1 were added after 12 h (0.3 equiv) and 24 h (0.3 equiv). Alkyne (CF₃−CC−CF₃, 1.0 equiv), 1

(2.0 equiv), TFA (0.2 equiv), CH₂Cl₂, −40 to +20 °C, 12 h.

C

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incomplete even with protocol D (LiF, 140 °C, 12 h), and an

additional portion of reagent 1 was required. Other protocols

A−C did not work for 26 at all. Isomeric alkene 31 and six-

membered triﬂuoromethyl-substituted alkenes 34 and 37 also

showed reduced activity.

Table 1. Optimization of the [3 + 2]-Cycloaddition of

Inactive Push−Pull Alkene 9 with Azomethine Ylide

Precursor 1

In terms of medicinal chemistry perspective, the obtained

substrates 2a−41a have large potential. Among them were

interesting sulfones (3a, 4a, 5a, 20a, 21a) and monoﬂuoro-

(7a, 30a, 35a), diﬂuoro- (25a), and triﬂuoromethyl-substituted

molecules (17a, 18a, 34a, 35a). Fluorine-substituted building

blocks play in important role in drug discovery and

agrochemistry.¹⁷During elaboration of the reaction scope,

we also tried isomeric and homologous molecules. For

example, oxygen-containing ﬁve-membered isomers 9a and

12a, oxygen-containing six-membered isomers 28a, 29a, and

31a, sulfones 20a and 21a, and sulfones 38a and 40a were

synthesized. Indeed, for medicinal chemistry projects during

structure−activity relationship (SAR) studies, it is important to

use stepwise modiﬁcations of an active compound, for

example, by using homologous and/or isomeric building

blocks, following a minimum modiﬁcation principle.¹⁸

a,b

yield

entry

conditions

(%)

protocol A

1

2

3

1 (1.2 equiv), TFA (0.1 equiv), CH₂Cl₂, rt, 12 h

0

<5

1 (2 equiv)

1 (3 equiv)

protocol B

4

1 (1.2 equiv), slow addition, TFA (0.1 equiv), CH₂Cl₂,

<5

rt

5

6

1 (2 equiv)

1 (3 equiv)

protocol C

<5

<10

Mechanism. A general mechanism for the formation of the

nonstabilized azomethyne ylide from reagent 1 was reported

before.^14,15However, to provide readers with the correspond-

ing background, a brief summary is given below. Compound 1

under acidic conditions (TFA, CH₂Cl₂) forms protonated

intermediate I-1 that eliminates MeOTMS and gives the

azomethyne ylide (Scheme 2).¹⁴The latter reacts electron-

7

8

9

1 (1.2 equiv), LiF (3 equiv), CH₃CN, 80 °C, 12 h

1 (2 equiv)

1 (3 equiv)

protocol D

0

<5

<10

10

11

1 (1.2 equiv), LiF(3eq ), no solvent, 140 °C, 12 h

63

85

c

1 (2 equiv), LiF (3 equiv), no solvent, 140 °C, 12 h

a

b

10 mmol. Yield determined by ¹H NMR with CH₂Br₂as an internal

standard. Isolated yield.

c

Scheme 2. Reaction Mechanism

and 23, and sulfur-containing one 22 all gave the needed

bicyclic pyrrolidines 10a−23a in good to excellent yields.

Product 18a was obtained directly from bis-triﬂuoromethyl

acetylene (18) with an excess of reagent 1. For every substrate,

we initially tried the known protocols A (TFA, rt, CH₂Cl₂) and

C (LiF, reﬂux, CH₃CN). Active alkenes, like 20 and 21,

reacted smoothly with 1 even under the conditions of protocol

A. When the reaction was incomplete, we optimized it by

adding more agent 1, trying the superior protocol B (TFA,

slow addition of 1) or using the most eﬀective protocol D (LiF,

140 °C, 12 h). The latter worked eﬀectively on a gram scale,

but on a smaller scale it was technically somewhat challenging

(reaction without a solvent). Therefore, we always used this

protocol last when other conditions did not work.

Six-membered alkene 24 was less active than the

corresponding ﬁve-membered substrate 6. Standard TFA-

catalyzed reaction with 1 at room temperature (protocol A)

led to a low conversion. We could obtain the desired product

24a with optimized protocols B and C by adding an additional

portion of 1. In general, six-membered alkenes were less active

than the corresponding ﬁve-membered ones, and protocol A

did not work well for them. We used mostly protocols B and C

with an additional amount of reagent 1 or even protocol D.

Only active alkenes 38 and 40 bearing two electron-

withdrawing substituents (triﬂuoromethyl and sulfone) gave

the desired bicyclic pyrrolidines 38a and 40a in 81−98% yield

under the standard TFA catalysis. Seven-membered alkene 41

also gave the desired product 41a in 49% yield under LiF-

optimized conditions.

deﬁcient endocyclic alkenes via [3 + 2]-cycloaddition to aﬀord

the needed bicyclic pyrrolidines. Reaction of reagent 1 with

LiF is believed to proceed via a concerted mechanism:

polarized ﬂuorine atom (δ⁻) attacks silicon, while polarized

lithium atom (δ⁺) coordinates with methoxy group as a Lewis

acid (Scheme 2).¹⁵Elimination of TMSF and LiOMe gives the

azomethyne ylide that participates next in [3 + 2]-cyclo-

addition with electron-deﬁcient alkenes.

Activity of Substrates. Some aspects of the activity of

alkenes were brieﬂy mentioned above. Here, we summarize

some trends that we observed:

(a) Activity of alkenes decreased with the increase of the

ring size (Figure 3). Four-membered alkenes were the most

active, and protocol A (TFA, rt) could be used. Five-

membered alkenes were less active, and protocol B (TFA, rt,

slow addition of 1) and C (LiF, CH₃CN, reﬂux) were required.

It is worth noting that among all tested alkenes, six-

membered compound 26 (push−pull resonance form

possible) was the least active (Scheme 1). The reaction was

D

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Figure 5. Inﬂuence of the EWG group on the activity of alkenes in [3

+ 2]-cycloaddition with azomethine ylide precursor 1.

Figure 3. Inﬂuence of ring size on the activity of alkenes in [3 + 2]-

cycloaddition with azomethine ylide precursor 1.

In summary, among all tested cyclic alkenes (Scheme 1), the

least active ones were (a) “push−pull” alkenes 9, 26, and 31

and (b) six-membered CF₃-alkenes 34 and 37. Attempted

cycloaddition of these alkenes with reagent 1 under the

reported conditions failed. Only protocol D (LiF, 140 °C, 12

h) developed in this work provided the needed bicyclic

products.

Modiﬁcations. The substrates depicted in Scheme 1

cannot be directly used in medicinal chemistry projects

because they have N- and C-protecting groups. Therefore,

we performed some representative transformations to convert

them into the desired building blocks. For example, [Pd]-

catalyzed hydrogenation of the N-benzyl bond in pyrrolidine

25a, N-Boc protection, and alkali hydrolysis of the ester group

gave an interesting ﬂuorinated bicyclic β-proline 25b (Scheme

3).²⁰The synthesis was performed on 20 g scale. Using this

three-step strategy, we easily synthesized several interesting

bicyclic β-prolines depicted on Scheme 3. Among them were

ﬂuorine-containing amino acids 7b, 25b, and 30b,²¹sulfone-

substituted amino acids 23b and 39b, and numerous isomeric/

homologue oxygen- and nitrogen-containing bicyclic β-pro-

lines.

Six and seven-membered substrates were the least active. In

many cases, only protocol D (LiF, 140 °C, 12 h) worked.

For example, while CF₃-substituted ﬁve-membered alkene

17 reacted with 1 already under conditions of protocol A

(TFA, rt), the homologous six-membered alkenes 34 and 37

did not react under these conditions. In both cases, protocol D

(LiF, 140 °C, 12 h) was required (Scheme 1).

(b) Activity of alkenes decreased upon conjugation of the

double bond with oxygen atom. For example, among three

substrates 9, 10, and 12, alkene 10 was the most active. Distal

oxygen atom was not included in the conjugation with the C

C double bond, and it even additionally activated it by and

(−I)-inductive eﬀect. Alkene 12 was less active than 10.

Compound 12 could be represented by an inactive resonance

form (Figure 4), where oxygen atom is conjugated with a C

Cleavage of the N-benzyl group in compound 19a with

[Pd]-catalyzed hydrogenation gave bicyclic α-proline analogue

19c in 77% yield (Scheme 4). A similar tactic was used to

obtain other bicyclic NH-free pyrrolidines as shown in Scheme

4. Among them were bicyclic sulfones 3c−5c, 20c, 21c, 38c,

and 40c, ﬂuorine-containing pyrrolidine 35c, and unique bis-

triﬂuoromethyl-substituted diamine 18c.

Alkali hydrolysis of the ester group in 29a, Curtius reaction

with tert-butyl alcohol, and hydrogenative cleavage of the N-

benzyl group gave bicyclic diamine 29d in 37% combined yield

(Scheme 5). Following that three-step tactic, other diamines

2d, 6d, 7d, 23d−25d, and 28d were easily synthesized. All

syntheses were performed on a gram scale. Among the

products were ﬂuorine-containing diamine 7d, diﬂuoro-

substituted diamine 25d, and sulfone-containing diamine 23d.

Reduction of the ester group in compound 7a with LiAlH₄

and the standard cleavage of the N-benzyl moiety gave the

ﬂuorine-substituted amino alcohol 7e in 73% combined yield

(Scheme 6). Analogously, three bicyclic amino alcohols 2e, 6e,

and 24e, two nitrogen-containing amino alcohols 14e and 32e,

and ﬁve oxygen-containing alcohols 10e, 12e, and 26e were

rapidly prepared.

Several other representative modiﬁcations were performed

as well. Reduction of nitrile 15a with LiAlH₄, N-Boc

protection, and cleavage of the N-benzyl bond gave diamine

15f in 64% yield (Scheme 6). An analogous sequence of steps

was performed with nitrile 27a to produce diamine 27f in 68%

combined yield (Scheme 7). Amino alcohol 9e was N-Boc

protected, O-alkylated with methyl iodide, and N-deprotected

to aﬀord bicyclic amine 9g in 71% combined yield (Scheme 7).

From amino alcohol 12, analogous derivative 12g was also

Figure 4. Inﬂuence of the position of O-atom in the ring on the

activity of alkenes in [3 + 2]-cycloaddition with azomethine ylide

precursor 1.

C bond. Alkene 9 possessed the lowest activity because its

structure could be shown by push−pull resonance form where

the oxygen atom, CC bond, and ester group are all involved

in the conjugation (Figure 4, Table 1). The same trend was

observed in six-membered substrates 26, 28, 29, and 31.

(c) The activity of alkenes increased with higher electron-

withdrawing ability (EWG) of the substituent. For example,

within alkenes 15−17, compound 16 showed the highest

activity (Figure 5). Alkene 15 with a nitrile group was slightly

less active. The triﬂuoromethyl substituent has lower electron-

withdrawing ability than both nitrile and ester groups.¹⁹

Therefore, alkene 17 was the least active. The same trend was

observed in six-membered substrates. For example, while

alkenes 32 and 33 with a CO₂Me group reacted with 1 using

protocol C (LiF, CH₃CN, reﬂux), the CF₃analogue 34 gave

no product under these conditions. Only with protocol D (LiF,

140 °C, 12 h) was the corresponding ﬂuorinated bicycle 34a

obtained (Scheme 1).

E

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a

Scheme 3. Synthesis of Bicyclic Amino Acid−β-Prolines

Scheme 4. Synthesis of Bicyclic Pyrrolidine-Containing

Amines and Amino Acids

a

1 M HCl in dioxane was added after the reaction.

In addition, the [3 + 2]-cycloaddition of reagent 1

proceeded with alkenes that already contained the electron-

withdrawing moiety in the cycle (Scheme 9). For example,

cyclic sulfones 45 and 46 smoothly reacted with 1 under TFA

catalysis (45, protocol A) or under LiF catalysis (46, protocol

C).²⁴Six-membered substrate 47 was less active, and only ca.

50% conversion was observed with standard protocol C.

Therefore, an additional portion of reagent 1 was added after

48 h to ﬁnish the transformation. The corresponding bicyclic

products 45a−47a were obtained in 70−84% yield. Cleavage

of the N-Bn group with [Pd]-catalyzed hydrogenation

provided bicyclic sulfone-containing pyrrolidines 45c−47c in

90−95% yield.

a

Synthesis was performed from nitrile 41a: (a) NaOH; (b) H₂/Pd,

MeOH; (c) Boc₂O.

Applications. A practical [3 + 2]-cycloaddition approach

to fused pyrrolidines developed in this work allowed not only

preparation of novel compounds but also dramatically

simpliﬁed synthesis of the existing ones. For example,

compound 48 (DS21412020) was discovered in 2018 by

Daiichi Sankyo scientists as a promising antibacterial agent.²⁵

The authors synthesized key diamine intermediate 29d in 13

steps from acid 49 (Scheme 10). Our approach allowed for the

rapid preparation of diamine 29d on a 10 g scale in only four

steps from alkene 29 (Schemes 5 and 10).

obtained. Representative heterocyclization of the carboxylic

group in 10b compound gave oxadiazole 10h (Scheme 7).

Finally, it is important to add that in some cases an external

electron-withdrawing group (EWG) was not needed for the [3

+ 2]-cycloaddition. First, we were also surprised to see that

four-membered alkene 42 having no EWG reacted with

compound 1 in the presence of LiF in acetonitrile to aﬀord the

needed bicyclic azetidine 42a in 12% yield.²²Presumably, the

driving force of that reaction was the strained structure of the

starting four-membered alkene.²³Under analogous conditions,

ﬁve-membered alkene 43 and six-membered alkene 44 did not

react, however (Scheme 8).

In 2007, Abbott chemists reported on the discovery of novel

agent against dementia, soﬁnicline.²⁶Synthesis of the key

diamine 50 was undertaken from amine 51 in 12 steps

F

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Scheme 5. Synthesis of Bicyclic Pyrrolidine-Containing

Diamines

Scheme 7. Synthesis of Diamines 15f and 27f, OMe-

pyrrolidines 9g and 12g, and Oxadiazole 10h

a

1 M HCl in EtOAc was added.

Scheme 8. Attempted [3 + 2]-Cycloaddition of Enamides

42-44

a

1 M HCl in EtOAc was added after the reaction.

Scheme 6. Synthesis of Bicyclic Pyrrolidine-Containing

a,b

Amino Alcohols

Scheme 9. [3 + 2]-Cycloaddition of Sulfones 45−47 with

a,b

1

a

b

Additional portion of 1 was added after 48 h. 1 M HCl in dioxane

was added after the reaction.

commercially available N-Boc azetidinol (52) in only four

steps.

In 2016, chemists from ARIAD Pharmaceuticals reported on

the discovery of brigatinib, a potent, orally active inhibitor of

anaplastic lymphoma kinase (Scheme 10).²⁷In 2017, it was

approved by the FDA as an anticancer drug. Since that time,

a

b

1 M HCl in dioxane was added after the reaction. Reduction was

performed with NaBH₄/LiCl in THF/EtOH.

(Scheme 10). Our [3 + 2]-cycloaddition strategy allowed

preparation of diamine 50 in milligram quantities from the

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Scheme 10. Synthesis of Bicyclic Pyrrolidines 29d and 50 (Literature Approach vs This Work) and Bicyclic POMe₂-

Substituted Piperidine 53a

P(O)Me₂-substituted building blocks immediately became

popular in medicinal chemistry.²⁸In this context, we

performed the [3 + 2]-cycloaddition of alkene 53 with reagent

1. Under the conditions of protocol D (LiF, 140 °C, 12 h), the

needed bicyclic P(O)Me₂-containing pyrrolidine was isolated

in 80% yield. Systematic study on the preparation of various

P(O)Me₂-pyrrolidines via [3 + 2]-cycloaddition is ongoing and

will be reported later.

Basicity of Amines. As it was mentioned before, during

elaboration of scope of [3 + 2]-cycloaddition (Scheme 1), we

tried to prepare isomeric/homologous molecules. The latter

are especially interesting for medicinal chemistry applications.

For example, compounds with basic aliphatic nitrogen atom

often cause toxicity due to aﬃnity to HERG-channel.²⁹

Therefore, medicinal chemists usually try to ﬁne-tune nitrogen

basicity by introducing various electron-deﬁcient substituents

at diﬀerent positions of a molecule.³⁰

Figure 6. Experimental pK_avalues of conjugated acids of amines 6c,

7c, 9c, 10c, 12c, and 23c.

7.8; pK_a(10c·HCl) = 8.2; pK_a(12c·HCl) = 7.6. Indeed, this

eﬀect was less pronounced in pyrrolidine 10c because oxygen

and nitrogen atoms are separated by four single bonds. In

pyrrolidines 9c and 12c, however, oxygen and nitrogen atoms

are separated by three single bonds only.

We also wanted to show how diverse substituents at bicyclic

pyrrolidines aﬀected basicity of the nitrogen atom. Indeed,

incorporation of ﬂuorine atom into 6c and pyrrolidine 7c

reduced the basicity by more than one order magnitude: pK_a

(6c·HCl) = 9.2, pK_a(7c·HCl) = 7.6 (Figure 6). Pyrrolidine

23c with a sulfone group was more than three magnitudes of

order less basic than 6c: pK_a(23c·HCl) = 6.1. Incorporation of

oxygen atom into pyrrolidine 6c also reduced basicity in

diﬀerent extent depending on the position: pK_a(9c·HCl) =

CONCLUSION

■

Pyrrolidine is one of the most frequently used secondary

amines in drug discovery. The structures of more than 50

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3.73 (s, 3H), 2.99 (d, J = 8.7 Hz, 2H), 2.87 (d, J = 9.2 Hz, 1H), 2.56−

2.43 (m, 1H), 2.40 (d, J = 9.2 Hz, 1H), 2.30 (dd, J = 8.7, 6.0 Hz, 2H),

2.23−2.04 (m, 2H), 1.88−1.74 (m, 1H) ppm. ¹³C{¹H} NMR (126

MHz, CDCl₃): δ 176.2, 139.6, 128.7, 128.3, 127.0, 62.3, 60.3, 59.6,

51.9, 51.8, 41.9, 27.6, 21.9 ppm. LCMS (M + H)⁺: 246. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₅H₂₀NO₂246.1494; found

246.1480.

drugs contain the pyrrolidine motif. In this work, we developed

a general protocol to medchem-relevant fused pyrrolidines via

[3 + 2]-cycloaddition between reagent 1 and electron-deﬁcient

endocyclic alkenes. Known conditions for generation of the

azomethyne ylide from compound 1protocol A (TFA, rt)

and protocol C (LiF, acetonitrile, reﬂux)worked well for [3

+ 2]-cycloaddition of activated four- and ﬁve-membered

alkenes (Scheme 1). For less active substrates, more eﬀective

protocol B (TFA, rt, slow addition of 1) was elaborated.

Unexpectedly, push−pull alkenes 9, 26, and 31 and six-

membered CF₃-substituted 34 and 37 failed to react with 1

under all previously reported conditions (Scheme 1, Table 1).

Therefore, in this work we developed superior protocol D

(LiF, 140 °C, 12 h) and could also convert these substrates

into the corresponding bicyclic pyrrolidines 9a, 26a, 31a, 34a,

and 37a. The synthesis of most products was performed on a

5−30 g scale. From the [3 + 2]-cycloaddition adducts 2a−41a,

unique building blocks for medicinal chemistryamino acids,

diamines, amino alcohols, amines, and β-prolineswere easily

synthesized (Schemes 2−8). Among the obtained compounds

were medchem-relevant sulfones, monoﬂuoro-, diﬂuoro-, and

triﬂuoromethyl-substituted derivatives. Importantly, the devel-

oped approach not only led to the practical preparation of

novel compounds but also signiﬁcantly simpliﬁed the synthesis

of existing ones (Scheme 10). Also, after discovery of the

anticancer drug brigatinib (Scheme 10), P(O)Me₂-substituted

compounds have been gaining popularity in medicinal

chemistry. Therefore, here we also synthesized the ﬁrst

representative P(O)Me₂-substituted bicyclic pyrrolidine 53a

via [3 + 2]-cycloaddition (Scheme 10).

Protocol B (6a as an Example). Methyl 2-Benzylhexahydro-

cyclopenta[c]pyrrole-3a(1H)-carboxylate (6a). To a stirred solution

of 6 (12.50 g, 0.1 mol, 1.0 equiv) and 1 (4.75 g, 0.02 mol, 0.2 equiv)

in CH₂Cl₂(500 mL) was added CF₃COOH (1.14 g, 0.01 mol, 0.1

equiv) dropwise. The temperature was maintained in the range of

20−30 °C by the occasional cooling of the reaction ﬂask in an ice−

water bath. Then a second portion of 1 (23.70 g, 0.1 mol, 1.0 equiv)

was slowly added dropwise (over 2 h) to the mixture. The mixture

was stirred overnight at room temeperature. The mixture was

neutralized with a saturated solution of NaHCO₃. The organic layer

was washed with brine (1 × 200 mL), dried over Na₂SO₄, and

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography (hexane/EtOAc = 8:2). Yield: 19.94 g, 0.077

mol, 77%, yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.38−7.20 (m,

5H), 3.70 (s, 3H), 3.58 (q, J = 13.2 Hz, 2H), 2.95 (d, J = 9.3 Hz, 1H),

2.93−2.84 (m, 1H), 2.70 (t, J = 8.2 Hz, 1H), 2.47 (d, J = 9.3 Hz, 1H),

2.34 (dd, J = 8.8, 4.1 Hz, 1H), 2.04 (dd, J = 11.8, 6.6 Hz, 1H), 1.95−

1.61 (m, 4H), 1.59−1.46 (m, 1H) ppm. ¹³C{¹H} NMR (126 MHz,

CDCl₃): δ 177.9, 139.3, 128.6, 128.3, 126.9, 63.8, 61.3, 59.7, 59.7,

52.1, 47.8, 38.4, 33.6, 26.9 ppm. LCMS (M + H)⁺: 260. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₆H₂₂NO₂260.1651; found

260.1644.

Protocol C (14a as an Example). Methyl 2,5-Dibenzylhexa-

hydropyrrolo[3,4-c]pyrrole-3a(1H)-carboxylate (14a). Compound 1

(28.44 g, 0.12 mol, 1.2 equiv) and LiF (9.36 g, 0.36 mol, 3.0 equiv)

were added to a solution of 14 (21.70 g, 0.1 mol, 1.0 equiv) in

CH₃CN (500 mL), and the mixture was stirred at reﬂux in an oil bath

with a thermocouple during 12 h. When ¹H NMR spectroscopy

indicated that the reaction was complete, the solvent was evaporated

under reduced pressure, and the residue was dissolved in EtOAc (500

mL). The mixture was washed with a 10% cold solution of K₂CO₃(2

× 100 mL), a saturated aqueous solution of CuSO₄(3 × 100 mL) and

brine (1 × 100 mL). The organic phase was separated and dried over

Na₂SO₄, and the solvent was evaporated. The crude product was

puriﬁed by ﬂash chromatography in a mixture of hexanes/EtOAc =

We believe that with the results described here scientists will

soon use diverse bicyclic pyrrolidines routinely in medicinal

chemistry.

EXPERIMENTAL SECTION

■

General Considerations. All chemicals were provided by

Enamine, Ltd. (www.enamine.net). All solvents were treated

according to standard methods. All reactions were monitored by

thin-layer chromatography (TLC) and were visualized using UV light.

Product puriﬁcation was performed using silica gel column

chromatography. TLC characterization was performed with precoated

silica gel GF254 (0.2 mm), while column chromatography character-

ization was performed with silica gel (100−200 mesh). ¹H NMR

spectra were recorded at 400, 500, or 600 MHz (Varian); ¹⁹F NMR

spectra were recorded at 376 MHz (Varian), and ¹³C NMR spectra

were recorded at 100, 126, or 151 MHz (Varian). ¹H NMR chemical

shifts are calibrated using residual undeuterated solvents CHCl₃(δ =

7.26 ppm) or DMSO (δ = 2.50 ppm). ¹³C NMR chemical shifts for

¹³C NMR are reported relative to the central CHCl₃(δ = 77.16 ppm)

1

8:2. Yield: 16.45 g, 0.047 mol, 47%, brown oil. H NMR (400 MHz,

CDCl₃): δ 7.39−7.24 (m, 10H), 3.71 (s, 3H), 3.64 (q, J = 13.2 Hz,

4H), 3.13−3.03 (m, 1H), 2.94 (d, J = 9.1 Hz, 2H), 2.79 (t, J = 8.1 Hz,

2H), 2.58 (d, J = 9.2 Hz, 2H), 2.46 (dd, J = 8.7, 4.5 Hz, 2H) ppm.

¹³C{¹H} NMR (126 MHz, CDCl₃): δ 176.2, 139.1, 128.6, 128.3,

127.0, 62.6, 59.7, 59.4, 59.3, 52.3, 46.7 ppm. LCMS (M + H)⁺: 351.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₂₂H₂₇N₂O₂351.2073;

found 351.2065.

Protocol D (9a as an Example). Methyl 5-Benzylhexahydro-

3aH-furo[2,3-c]pyrrole-3a-carboxylate (9a). Compound 9 (12.80 g,

0.1 mol, 1.0 equiv) and 1 (47.40 g, 0.2 mol, 2.0 equiv) were mixed

with LiF (7.80 g, 0.3 mol, 3.0 equiv) in a three-necked round-bottom

ﬂask equipped with a magnetic stir bar, thermometer, and condenser.

The mixture was heated to 140−150 °C for 12 h and then 12 h at

100−110 °C in an oil bath with a thermocouple. The conversion was

checked by NMR. After full conversion, the mixture was cooled to

room temperature, and acetone (200 mL) was added to the mixture.

The mixture was ﬁltered and concentrated under reduced pressure.

The residue was puriﬁed by column chromatography (gradient,

CHCl₃/CH₃CN, 9:1 to 7:3) and distillation. Yield: 22.19 g, 0.085

or DMSO (δ = 39.52 ppm). Coupling constants are given in hertz.

High-resolution mass spectra (HRMS) were recorded on an Agilent

LC/MSD TOF mass spectrometer by electrospray ionization time-of-

ﬂight reﬂectron experiments.

Protocol A (2a as an Example). Methyl 3-Benzyl-3-azabicyclo-

[3.2.0]heptane-1-carboxylate (2a). To a stirred solution of 2 (11.20

g, 0.1 mol, 1.0 equiv) and CF₃COOH (1.14 g, 0.01 mol, 0.1 equiv) in

CH₂Cl₂(500 mL) was added 1 (28.44 g, 0.12 mol, 1.2 equiv)

dropwise. The temperature was maintained in the range of 20−35 °C

by the occasional cooling of the reaction ﬂask in an ice−water bath.

The mixture was stirred for 12 h at rt. The mixture was neutralized

with a saturated solution of NaHCO₃. The organic layer was washed

with brine (1 × 200 mL), dried over Na₂SO₄, and concentrated under

reduced pressure. The residue was puriﬁed by column chromatog-

raphy (hexane/EtOAc = 9:1). Yield: 23.52 g, 0.096 mol, 96%,

1

mol, 85%, yellow oil. H NMR (400 MHz, DMSO-d₆): δ 7.34−7.11

(m, 5H), 4.55 (d, J = 5.0 Hz, 1H), 3.95 (dd, J = 14.5, 6.7 Hz, 1H),

3.74 (dd, J = 14.3, 6.5 Hz, 1H), 3.65 (s, 3H), 3.52 (s, 2H), 2.77 (d, J =

9.3 Hz, 1H), 2.73 (d, J = 10.3 Hz, 1H), 2.61 (d, J = 9.3 Hz, 1H), 2.35

(dd, J = 10.2, 5.3 Hz, 1H), 2.29−2.19 (m, 1H), 1.94 (dt, J = 12.3, 6.2

Hz, 1H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 174.5, 138.5,

128.3, 128.2, 126.9, 85.3, 68.6, 61.8, 60.4, 59.0, 58.5, 52.2, 39.5 ppm.

1

colorless oil. H NMR (400 MHz, CDCl₃): δ 7.43 (d, J = 7.5 Hz,

2H), 7.35 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 5.7 Hz, 1H), 3.74 (s, 2H),

I

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Article

LCMS (M + H)⁺: 262. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₅H₂₀NO₃262.1443; found 262.1437.

1H), 2.71 (d, J = 9.3 Hz, 1H), 2.47 (dd, J = 9.4, 3.2 Hz, 1H), 2.40

(dd, J = 13.1, 9.9 Hz, 1H), 2.26−2.16 (m, 2H), 1.93−1.82 (m, 1H)

ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 173.9, 138.2, 128.6,

127.4, 124.4, 65.1, 60.9, 59.0, 52.1, 49.6, 44.7, 44.6, 41.9, 36.8. LCMS

(M + H)⁺: 285. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₇H₂₁N₂O₂285.1603; found 285.1627.

3-Benzyl-1-(triﬂuoromethyl)-6-thia-3-azabicyclo[3.2.0]heptane

6,6-Dioxide (3a). Protocol A was used. Yield: 29.89 g, 0.098 mol,

98%, colorless solid, mp = 105−106 °C. ¹H NMR (400 MHz,

CDCl₃): δ 7.42−7.26 (m, 5H), 4.66 (d, J = 4.5 Hz, 1H), 4.41 (dd, J =

13.8, 2.6 Hz, 1H), 4.16 (d, J = 13.7 Hz, 1H), 3.85 (d, J = 13.3 Hz,

1H), 3.72 (d, J = 13.6 Hz, 1H), 3.69 (d, J = 12.1 Hz, 1H), 3.07 (d, J =

9.4 Hz, 1H), 2.61 (dd, J = 11.4, 6.8 Hz, 1H), 2.57 (d, J = 9.4 Hz, 1H)

ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 137.2, 128.7, 128.4,

127.7, 125.5 (q, J = 277.9 Hz), 81.6, 70.7, 57.9, 57.5, 54.3, 41.7 (q, J =

31.0 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −73.1 (s) ppm.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₃H₁₅F₃NO₂S

306.0776; found 306.0764.

3-Benzyl-1-phenyl-6-thia-3-azabicyclo[3.2.0]heptane 6,6-Diox-

ide (4a). Protocol A was used. The residue was puriﬁed by column

chromatography (hexane/EtOAc = 9:1). Yield: 27.23 g, 0.087 mol,

87%, brown solid, mp = 110−112 °C. ¹H NMR (400 MHz, CDCl₃):

δ 7.45−7.25 (m, 10H), 4.73 (dd, J = 6.5, 2.6 Hz, 1H), 4.46 (d, J =

13.0 Hz, 1H), 4.28 (dd, J = 12.9, 2.8 Hz, 1H), 3.88 (d, J = 13.3 Hz,

1H), 3.76 (d, J = 11.2 Hz, 1H), 3.72 (d, J = 13.3 Hz, 1H), 3.30 (d, J =

9.2 Hz, 1H), 2.66 (dd, J = 11.1, 6.9 Hz, 1H), 2.49 (d, J = 9.2 Hz, 1H)

ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 140.7, 138.0, 129.2,

128.6, 128.6, 127.8, 127.5, 126.1, 84.6, 76.7, 64.9, 58.3, 54.9, 41.8

ppm. LCMS (M + H)⁺: 314. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₁₈H₂₀NO₂S 314.1215; found 314.1210.

tert-Butyl 5-Benzyltetrahydro-1H-furo[3,4-c]pyrrole-3a(3H)-car-

boxylate (10a). Protocol A was used. The oil residue was left in

the refrigerator for a few hours to crystallize. The precipitate was then

triturated, cooled to the melting point of Et₂O, and ﬁltered. The left

residue was concentrated and puriﬁed by column chromatography

(gradient, hexane/EtOAc, 9:1 to 7:3). Yield: 24.85 g, 0.082 mol, 82%,

1

yellow solid. H NMR (400 MHz, CDCl₃): δ 7.36−7.22 (m, 5H),

4.12 (d, J = 8.8 Hz, 1H), 4.03 (t, J = 8.0 Hz, 1H), 3.66 (d, J = 8.9 Hz,

1H), 3.63−3.53 (m, 3H), 3.11−3.01 (m, 1H), 2.76 (d, J = 9.3 Hz,

1H), 2.66 (d, J = 7.9 Hz, 1H), 2.64 (d, J = 9.0 Hz, 1H), 2.52 (dd, J =

9.1, 3.2 Hz, 1H), 1.44 (s, 9H) ppm ¹³C{¹H} NMR (126 MHz,

CDCl₃): δ 173.9, 139.1, 128.5, 128.4, 127.1, 81.1, 77.0, 74.6, 62.3,

61.6, 59.1, 58.8, 48.4, 28.1 ppm. LCMS (M + H)⁺: 304. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₈H₂₆NO₃304.1913; found

304.1931.

Methyl 5-Benzyl-3,3-dimethyltetrahydro-1H-furo[3,4-c]pyrrole-

3a(3H)-carboxylate (11a). Protocol C was used. Two additional

portions of 1 were added after 12 h (7.11 g, 0.03 mol, 0.3 equiv) and

24 h (7.11 g, 0.03 mol, 0.3 equiv). The residue was puriﬁed by

column chromatography (hexane/EtOAc = 7:3). Yield: 20.81 g, 0.072

mol, 72%, yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.35−7.22 (m,

5H), 4.03 (t, J = 8.5 Hz, 1H), 3.72 (s, 2H), 3.62 (dd, J = 9.2, 2.9 Hz,

1H), 3.58 (s, 2H), 3.51−3.40 (m, 1H), 3.10 (t, J = 8.5 Hz, 1H), 3.00

(d, J = 9.4 Hz, 1H), 2.58 (d, J = 9.4 Hz, 1H), 2.26 (dd, J = 8.9, 5.1 Hz,

1H), 1.37 (s, 3H), 1.11 (s, 3H) ppm. ¹³C{¹H} NMR (151 MHz,

CDCl₃): δ 174.2, 138.9, 128.5, 128.3, 127.1, 82.3, 71.2, 68.0, 61.6,

59.9, 59.6, 52.3, 46.1, 23.6, 23.3 ppm. LCMS (M + H)⁺: 290. HRMS

(ESI-TOF) m/z: [M + H]+ calcd for C₁₇H₂₄NO₃290.1756; found

290.1762.

Methyl 5-benzylhexahydro-6aH-furo[2,3-c]pyrrole-6a-carboxy-

late (12a). Protocol D was used. The residue was puriﬁed by column

chromatography (hexane/EtOAc = 7:3). Yield: 23.75 g, 0.091 mol,

91%, yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.37−7.21 (m, 5H),

4.20−4.09 (m, 1H), 3.90 (dd, J = 14.9, 7.5 Hz, 1H), 3.77 (s, 3H),

3.72 (d, J = 13.1 Hz, 1H), 3.54 (d, J = 13.1 Hz, 1H), 3.07 (d, J = 10.3

Hz, 1H), 3.00−2.92 (m, 1H), 2.75 (d, J = 10.0 Hz, 1H), 2.73 (d, J =

7.9 Hz, 1H), 2.53 (dd, J = 9.1, 7.0 Hz, 1H), 2.19−2.08 (m, 1H),

1.89−1.79 (m, 1H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃): δ

174.1, 138.7, 128.7, 128.4, 127.1, 92.1, 70.5, 63.8, 59.9, 59.4, 52.6,

48.6, 33.5 ppm. LCMS (M + H)⁺: 262. HRMS (ESI-TOF) m/z: [M

+ H]⁺calcd for C₁₅H₂₀NO₃262.1443; found 262.1448.

3-Benzyl-1-(4-ﬂuorophenyl)-6-thia-3-azabicyclo[3.2.0]heptane

6,6-dioxide (5a). Protocol A was used. The residue was puriﬁed by

column chromatography (hexane/EtOAc = 7:3). Yield: 29.46 g, 0.089

1

mol, 89%. H NMR (400 MHz, DMSO-d₆): δ 7.53−7.46 (m, 2H),

7.41−7.31 (m, 4H), 7.30−7.18 (m, 3H), 4.95 (d, J = 4.6 Hz, 1H),

4.45−4.31 (m, 2H), 3.75 (q, J = 13.7 Hz, 2H), 3.47 (d, J = 11.2 Hz,

1H), 3.35−3.32 (m, 1H), 2.64 (dd, J = 11.1, 7.1 Hz, 1H), 2.28 (d, J =

9.1 Hz, 1H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 161.3 (d,

J = 244.0 Hz), 138.1, 137.0, 128.6, 128.6, 128.2, 128.2, 126.9, 115.4

(d, J = 21.3 Hz), 83.7, 75.5, 65.3, 57.1, 54.1, 41.0 ppm. LCMS (M +

H)⁺: 332. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₈H₁₉FNO₂S

332.1121; found 332.1104.

Ethyl 2-benzyl-6a-ﬂuorohexahydrocyclopenta[c]pyrrole-3a(1H)-

carboxylate (7a). Modiﬁed protocol C was used. Compound 1

(28.44 g, 0.12 mol, 1.2 equiv) and LiF (7.80 g, 0.3 mol, 3.0 equiv)

were added to a solution of 7 (14.40 g, 0.1 mol, 1.0 equiv) in CH₃CN

(500 mL), and the mixture was stirred at reﬂux in an oil bath with a

thermocouple during 12 h, and an additional portion of 1 (7.11 g,

0.03 mol, 0.3 equiv) was added. When ¹H NMR spectroscopy

indicated that the reaction was complete, the solvent was evaporated

under reduced pressure, and the residue was dissolved in EtOAc (500

mL). The mixture was washed with a 10% cold solution of K₂CO₃(2

× 100 mL), a saturated aq solution of CuSO₄(3 × 100 mL), and

brine (1 × 100 mL). The organic phase was separated and dried over

Na₂SO₄, and the solvent was evaporated. The crude product was

puriﬁed by ﬂash chromatography in a mixture of hexanes/EtOAc/

Et₃N = 5:1:0.1. R_f= 0.53. Yield: 19.79 g, 0.068 mol, 68%, yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 7.56−7.21 (m, 5H), 4.27−4.10 (m,

2H), 3.64 (q, J = 13.1 Hz, 2H), 3.32 (d, J = 9.3 Hz, 1H), 2.96−2.73

(m, 2H), 2.63−2.45 (m, 2H), 2.27−2.05 (m, 1H), 2.04−1.89 (m,

2H), 1.84−1.71 (m, 1H), 1.68−1.54 (m, 1H), 1.29 (t, J = 7.1 Hz,

3H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 171.8 (d, J = 6.3

Hz), 138.5, 128.3, 128.1, 126.9, 111.2 (d, J = 199.5 Hz), 63.8 (d, J =

28.8 Hz), 62.6, 60.9 (d, J = 17.6 Hz), 60.7, 59.2, 38.3 (d, J = 24.9 Hz),

36.9 (d, J = 0.8 Hz), 24.8 (d, J = 4.3 Hz), 14.0 ppm. ¹⁹F{¹H} NMR

(470 MHz, CDCl₃): δ −178.3 (s) ppm. HRMS (ESI-TOF) m/z: [M

+ H]⁺calcd for: C₁₇H₂₃FNO₂292.1713; found 292.1720.

5-Benzylhexahydro-6aH-furo[2,3-c]pyrrole-6a-carbonitrile

(13a). Protocol C. The residue was puriﬁed by column chromatog-

raphy (CHCl₃/CH₃CN = 9:1). Yield: 16.64 g, 0.073 mol, 73%, yellow

1

oil. H NMR (400 MHz, CDCl₃): δ 7.39−7.24 (m, 5H), 4.22−4.10

(m, 1H), 3.90 (td, J = 8.5, 6.3 Hz, 1H), 3.69 (d, J = 13.1 Hz, 1H),

3.56 (d, J = 13.1 Hz, 1H), 3.22 (d, J = 10.6 Hz, 1H), 3.19−3.07 (m,

1H), 2.71 (d, J = 8.4 Hz, 1H), 2.64 (d, J = 10.6 Hz, 1H), 2.54 (dd, J =

9.5, 7.0 Hz, 1H), 2.35−2.19 (m, 1H), 1.93−1.79 (m, 1H) ppm.

¹³C{¹H} NMR (151 MHz, CDCl₃): δ 137.9, 128.7, 128.5, 127.4,

120.4, 82.3, 71.0, 64.4, 59.0, 58.7, 50.6, 33.4 ppm. LCMS (M + H)⁺:

229. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₄H₁₇N₂O

229.1341; found 229.1324.

tert-Butyl 5-benzyl-3a-cyanohexahydropyrrolo[3,4-c]pyrrole-

2(1H)-carboxylate (15a). Protocol C was used. The crude product

was puriﬁed by chromatography (gradient, hexane/methyl tert-butyl

ether, 9:1 to 7:3). Yield: 14.39 g, 0.044 mol, 44%, white solid, mp =

100−101 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.37−7.21 (m, 5H),

3.73−3.53 (m, 5H), 3.21 (d, J = 11.3 Hz, 1H), 3.07 (br s, 1H), 2.84

(d, J = 9.6 Hz, 1H), 2.79 (t, J = 8.5 Hz, 1H), 2.67 (d, J = 9.6 Hz, 1H),

2.40−2.29 (m, 1H), 1.40 (s, 9H) ppm. ¹³C{¹H} NMR (151 MHz,

DMSO-d₆): δ 153.0, 138.1, 128.3, 128.2, 127.0, 123.1, 79.2, 62.2,

58.8, 57.4, 54.2, 50.8, 48.4 (br s), 44.5 (br s), 28.0 ppm. LCMS (M +

Methyl 2-Benzyl-3a-cyanooctahydrocyclopenta[c]pyrrole-5-car-

boxylate (8a). Modiﬁed protocol C was used. An additional portion

of 1 (7.11 g, 0.03 mol, 0.3 equiv) was added after 12 h. The residue

was puriﬁed by column chromatography (hexane/EtOAc = 7:3).

1

Yield: 14.48 g, 0.051 mol, 51%, yellow oil, d.r. = 1:1. H NMR (400

MHz, CDCl₃): δ 7.36−7.25 (m, 5H), 3.72 (s, 3H), 3.57 (s, 2H),

3.23−3.05 (m, 2H), 2.84 (d, J = 9.5 Hz, 1H), 2.75 (d, J = 9.1 Hz,

J

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Article

H)⁺: 328. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₉H₂₆N₃O₂

328.2025; found 328.2020.

5-Benzyl-6a-(triﬂuoromethyl)hexahydro-2H-thieno[2,3-c]pyrrole

1,1-Dioxide (21a). Protocol A was used. Crystallization from EtOAc−

n-hexane gave pure compound 21a. Yield: 30.62 g, 0.096 mol, 96%,

colorless crystals, mp = 116−117 °C. ¹H NMR (400 MHz, CDCl₃): δ

7.46−7.09 (m, 5H), 3.79−3.68 (m, 2H), 3.59 (d, J = 13.1 Hz, 1H),

3.38−3.25 (m, 1H), 3.23−3.06 (m, 2H), 2.77 (d, J = 9.3 Hz, 1H),

2.70 (d, J = 10.8 Hz, 1H), 2.59 (t, J = 7.9 Hz, 1H), 2.43−2.26 (m,

1H), 2.10−1.93 (m, 1H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ

137.7, 128.6, 128.4, 127.5, 124.4 (q, J = 280.0 Hz), 71.8 (q, J = 26.7

Hz), 59.5, 58.6, 56.0, 51.7, 43.6, 25.6 ppm. ¹⁹F{¹H} NMR (376 MHz,

CDCl₃): δ −67.9 (s), −162.2 (s) ppm. GCMS (M): 319. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₁₄H₁₇F₃NO₂S 320.0932; found

320.0945.

2-tert-Butyl 3a-Ethyl-5-benzyltetrahydropyrrolo[3,4-c]pyrrole-

2,3a(1H,3H)-dicarboxylate (16a). Protocol C was used. The residue

was puriﬁed by column chromatography (hexane/EtOAc = 9:1).

Yield: 17.20 g, 0.046 mol, 46%, yellow oil. ¹H NMR (400 MHz,

DMSO-d₆): δ 7.34−7.20 (m, 5H), 4.09 (q, J = 7.0 Hz, 2H), 3.74 (d, J

= 11.4 Hz, 1H), 3.62−3.49 (m, 3H), 3.34 (d, J = 11.4 Hz, 1H), 3.18

(dd, J = 11.0, 3.5 Hz, 1H), 2.95 (br s, 1H), 2.73 (d, J = 9.2 Hz, 1H),

2.69−2.54 (m, 2H), 2.47 (br s, 1H), 1.39 (s, 9H), 1.17 (t, J = 7.1 Hz,

3H) ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ 173.8, 153.1,

138.6, 128.18, 128.16, 126.8, 78.6, 61.7, 60.7, 59.3, 58.1, 54.6, 51.8 (br

s), 45.4 (br s), 28.1, 13.9 ppm. LCMS (M + H)⁺: 375. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₂₁H₃₁N₂O₄375.2284; found

375.2277.

tert-Butyl 5-Benzyl-3a-(triﬂuoromethyl)hexahydropyrrolo[3,4-c]-

pyrrole-2(1H)-carboxylate (17a). Protocol D was used. The residue

was puriﬁed by column chromatography (hexane/EtOAc = 9:1).

Yield: 27.75 g, 0.075 mol, 75%, yellow oil. ¹H NMR (500 MHz,

CDCl₃): δ 7.33−7.24 (m, 5H), 3.94−3.86 (m, 1H), 3.83−3.68 (m,

1H), 3.61 (s, 2H), 3.43−3.30 (m, 1H), 3.26 (dd, J = 11.0, 4.3 Hz,

1H), 2.87 (br s, 1H), 2.72−2.55 (m, 4H), 1.47 (s, 9H) ppm. ¹³C{¹H}

NMR (126 MHz, CDCl₃): δ 154.0, 138.5, 128.52, 128.49, 127.3, 80.0,

59.7 (br s), 59.4, 59.0, 53.0 (br s), 51.6 (br s), 44.5 (br s), 43.6 (br s),

28.6 ppm. ¹⁹F{¹H} NMR (470 MHz, CDCl₃): δ −74.2 ppm. LCMS

(M + H)⁺: 371. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₉H₂₆F₃N₂O₂371.1946; found 371.1928.

Methyl 5-Benzyltetrahydro-1H-thieno[3,4-c]pyrrole-3a(3H)-car-

boxylate (22a). Protocol C was used. The residue was puriﬁed by

column chromatography (hexane/EtOAc = 9:1). Yield: 11.91 g, 0.043

1

mol, 43%. H NMR (400 MHz, CDCl₃): δ 7.33−7.20 (m, 5H), 3.72

(s, 3H), 3.59 (q, J = 13.1 Hz, 2H), 3.40−3.29 (m, 1H), 3.22 (d, J =

12.0 Hz, 1H), 3.15 (d, J = 9.3 Hz, 1H), 3.06 (dd, J = 11.7, 7.1 Hz,

1H), 2.91 (t, J = 8.2 Hz, 1H), 2.76 (d, J = 12.0 Hz, 1H), 2.62 (dd, J =

11.8, 3.8 Hz, 1H), 2.47 (d, J = 9.3 Hz, 1H), 2.36 (dd, J = 8.8, 6.1 Hz,

1H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 175.5, 138.6, 128.4,

128.2, 127.1, 126.9, 64.3, 62.8, 59.8, 59.1, 52.4, 51.7, 41.8, 38.4 ppm.

LCMS (M + H)⁺: 278. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₅H₂₀NO₂S 278.1215; found 278.1208.

Ethyl 5-Benzyltetrahydro-1H-thieno[3,4-c]pyrrole-3a(3H)-car-

boxylate 2,2-Dioxide (23a). Protocol A was used. The residue was

puriﬁed by column chromatography (hexane/EtOAc = 9:1). Yield:

26.16 g, 0.081 mol, 81%, yellow oil. ¹H NMR (400 MHz, DMSO-d₆):

δ 7.44−7.10 (m, 5H), 4.14 (q, J = 7.0 Hz, 2H), 3.67−3.63 (d, J = 14.0

Hz, 1H), 3.64 (d, J = 13.3 Hz, 1H), 3.56 (d, J = 13.3 Hz, 1H), 3.49−

3.38 (m, 1H), 3.35−3.26 (m, 1H), 3.22 (d, J = 14.0 Hz, 1H), 2.97

(dd, J = 13.4, 7.6 Hz, 1H), 2.78 (d, J = 9.5 Hz, 1H), 2.71 (d, J = 9.0

Hz, 1H), 2.68 (d, J = 9.3 Hz, 1H), 2.59 (dd, J = 9.2, 3.6 Hz, 1H), 1.19

(t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ

172.5, 138.3, 128.2, 127.0, 62.8, 61.4, 58.4, 57.4, 55.4, 53.6, 53.5, 40.4,

13.9 ppm. LCMS (M + H)⁺: 324. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₁₆H₂₂NO₄S 324.1270; found 324.1291.

Methyl 2-Benzyloctahydro-3aH-isoindole-3a-carboxylate (24a).

Protocol C was used. Two additional portions of 1 were added after

12 h (7.11 g, 0.03 mol, 0.3 equiv) and 24 h (7.11 g, 0.03 mol, 0.3

equiv). The residue was puriﬁed by column chromatography

(hexane/EtOAc = 9:1). Yield: 22.66 g, 0.083 mol, 83%, yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 7.39−7.20 (m, 5H), 3.80−3.73 (m,

2,5-Dibenzyl-3a,6a-bis(triﬂuoromethyl)octahydropyrrolo[3,4-c]-

pyrrole (18a). To a stirred solution of 1 (47.40 g, 0.20 mol, 2.0 equiv)

in CH₂Cl₂(500 mL) was added 18 (16.20 g, 0.10 mol, 1.0 equiv) in

portions at −40 °C under Ar. Then a solution of CF₃COOH (2.20 g,

0.02 mol, 0.2 equiv) in CH₂Cl₂(300 mL) was added dropwise at −35

°C. The mixture was stirred at −30 °C for 5 and 7 h at rt. The mixture

was neutralized with a saturated solution of NaHCO₃. The mixture

was stirred for 30 min at rt. The organic layer was separated and

washed with brine (4 × 200 mL), dried over Na₂SO₄, and

concentrated under reduced pressure. The crude product was puriﬁed

by column chromatography (hexane/EtOAc/2,2,2-triﬂuoroethanol =

75:15:10) to give the desired product as colorless oil. Yield: 29.96 g,

1

0.07 mol, 70%. R_f= 0.3. H NMR (400 MHz, CDCl₃): δ 7.34−7.22

(m, 10H), 3.63 (s, 4H), 2.96 (d, J = 9.4 Hz, 4H), 2.68 (d, J = 9.1 Hz,

4H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 138.1, 128.6, 128.4,

127.4, 60.9, 60.0 (br s), 58.5 ppm. ¹⁹F{¹H} NMR (376 MHz,

CDCl₃): δ −68.1 (s) ppm. GCMS (M): 428. HRMS (ESI-TOF) m/

z: [M + H]⁺calcd for C₂₂H₂₃F₆N₂429.1765; found 429.1759.

1-tert-Butyl 6a-Methyl-5-benzylhexahydropyrrolo[3,4-b]pyrrole-

1,6a-dicarboxylate (19a). Protocol A was used. The residue was

puriﬁed by column chromatography (hexane/EtOAc = 9:1). Yield:

19.80 g, 0.055 mol, 55%, yellow oil. ¹H NMR (400 MHz, DMSO-d₆):

δ 7.44−7.11 (m, 5H), 3.65, 3.60 (2 × s, 3H), 3.54−3.39 (m, 4H),

3.21, 3.09 (2 × d, J = 10.2 Hz, 1H), 2.86−2.67 (m, 2H), 2.49−2.37

(m, 2H), 1.81−1.63 (m, 1H), 1.81−1.63 (m, 1H), 1.37, 1.26 (2 × s,

9H) ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ 173.0, 152.1,

138.7, 128.2, 128.1, 126.8, 79.1, 78.9, 73.3, 73.0, 62.5, 61.4, 58.3, 58.1,

52.2, 52.1, 49.9, 48.8, 47.5, 47.1, 28.1, 28.0, 27.8 ppm. LCMS (M +

H)⁺: 361. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₂₀H₂₉N₂O₄

361.2127; found 361.2122.

2H), 3.70 (s, 3H), 2.96 (d, J = 9.4 Hz, 1H), 2.84−2.67 (m, 3H),

2.04−1.90 (m, 1H), 1.82−1.66 (m, 2H), 1.61−1.22 (m, 5H) ppm.

¹³C{¹H} NMR (126 MHz, CDCl₃): δ 176.9, 139.5, 128.7, 128.3,

127.0, 62.4, 60.6, 57.0, 52.0, 51.3, 39.0, 30.6, 25.4, 22.4, 21.4 ppm.

LCMS (M + H)⁺: 274. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₇H₂₄NO₂274.1807; found 274.1822.

Methyl 2-Benzyl-6,6-diﬂuorooctahydro-3aH-isoindole-3a-car-

boxylate (25a). Protocol B was used. An additional portion of 1

(7.11 g, 0.03 mol, 0.3 equiv) was added after 12 h. The residue was

puriﬁed by column chromatography (hexane/EtOAc = 9:1). Yield:

1

23.48 g, 0.076 mol, 76%, yellow oil. H NMR (400 MHz, CDCl₃): δ

7.34−7.23 (m, 5H), 3.73 (s, 3H), 3.71−3.66 (m, 2H), 2.99 (d, J = 9.7

Hz, 1H), 2.96−2.89 (m, 1H), 2.85−2.75 (m, 2H), 2.74 (d, J = 9.7 Hz,

1H), 2.22−2.10 (m, 2H), 2.09−1.96 (m, 3H), 1.95−1.79 (m, 1H)

ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 175.9, 139.2, 128.6,

128.4, 127.1, 123.7 (t, J = 241.0 Hz), 62.0, 60.1, 57.5, 52.4, 50.4, 38.5

(t, J = 4.4 Hz), 33.5 (t, J = 24.1 Hz), 30.9 (t, J = 24.8 Hz), 28.1 ppm.

¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ −90.4 − −92.6 (m) ppm.

5-Benzyl-3a-(triﬂuoromethyl)hexahydro-2H-thieno[2,3-c]pyrrole

1,1-dioxide (20a). Protocol A was used. The crude product was

crystallized from CCl₄. Yield: 26.80 g, 0.084 mol, 84%, colorless

crystals, mp = 80−82 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.35−7.22

(m, 5H), 3.77 (d, J = 13.1 Hz, 1H), 3.64 (d, J = 10.6 Hz, 1H), 3.50

(d, J = 13.1 Hz, 1H), 3.36 (d, J = 6.3 Hz, 1H), 3.34−3.17 (m, 2H),

2.90 (d, J = 9.6 Hz, 1H), 2.68 (d, J = 9.7 Hz, 1H), 2.63 (dd, J = 10.6,

6.5 Hz, 1H), 2.60−2.49 (m, 1H), 2.29−2.16 (m, 1H) ppm. ¹³C{¹H}

NMR (126 MHz, CDCl₃): δ 137.4, 128.7, 128.4, 127.6, 126.8 (q, J =

279.4 Hz), 62.6, 60.9, 58.6, 56.0, 55.3 (q, J = 27.3 Hz), 50.4, 28.1

ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ −74.8 (s) ppm. GCMS

(M): 319. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₄H₁₇F₃NO₂S 320.0932; found 320.0948.

LCMS (M + H)⁺: 310. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₇H₂₂F₂NO₂310.1619; found 310.1611.

Methyl 6-Benzylhexahydropyrano[2,3-c]pyrrole-4a(2H)-carboxy-

late (26a). Protocol D was used. An additional portion of 1 (7.11 g,

0.03 mol, 0.3 equiv) was added after 12 h. The residue was puriﬁed by

column chromatography (hexane/EtOAc = 8:2). Yield: 17.33 g, 0.063

mol, 63%, yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.34−7.21 (m,

5H), 4.37 (d, J = 5.1 Hz, 1H), 3.95−3.85 (m, 1H), 3.73 (s, 3H), 3.72

K

https://doi.org/10.1021/acs.joc.1c01327

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(s, 2H), 3.43 (td, J = 11.1, 3.6 Hz, 1H), 3.17 (dd, J = 10.8, 5.4 Hz,

1H), 3.01 (d, J = 8.9 Hz, 1H), 2.83 (d, J = 8.9 Hz, 1H), 2.61 (d, J =

10.9 Hz, 1H), 2.03−1.93 (m, 1H), 1.91−1.71 (m, 2H), 1.57−1.45

(m, 1H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 176.1, 139.4,

128.5, 128.3, 126.9, 78.8, 65.1, 60.1, 59.7, 57.8, 52.2, 51.9, 26.2, 21.4

ppm. LCMS (M + H)⁺: 276. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₁₆H₂₂NO₃276.1600; found 276.1615.

2-Benzylhexahydropyrano[3,4-c]pyrrole-7a(1H)-carbonitrile

(27a). Protocol C was used. Two additional portions of 1 were added

after 12 h (7.11 g, 0.03 mol, 0.3 equiv) and 24 h (7.11 g, 0.03 mol, 0.3

equiv). The residue was puriﬁed by column chromatography

(hexane/EtOAc = 7:3). Yield: 19.60 g, 0.081 mol, 81%, yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 7.42−7.18 (m, 5H), 3.89 (dt, J =

11.9, 3.9 Hz, 1H), 3.84−3.70 (m, 4H), 3.63 (td, J = 11.6, 2.7 Hz, 1H),

3.05 (d, J = 9.3 Hz, 1H), 3.02−2.92 (m, 1H), 2.96 (d, J = 9.3 Hz,

1H), 2.84 (t, J = 9.3 Hz, 1H), 2.52 (dd, J = 10.2, 6.5 Hz, 1H), 2.29−

2.15 (m, 1H), 1.90 (d, J = 14.2 Hz, 1H) ppm. ¹³C{¹H} NMR (151

MHz, CDCl₃): δ 138.7, 128.5, 128.5, 127.3, 122.8, 65.4, 64.3, 62.3,

59.7, 53.4, 41.6, 37.2, 30.6 ppm. LCMS (M + H)⁺: 243. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₅H₁₉N₂O 243.1497; found

243.1484.

Methyl 2-Benzylhexahydropyrano[3,4-c]pyrrole-7a(1H)-carboxy-

late (28a). Protocol C was used. Two additional portions of 1 were

added after 12 h (7.11 g, 0.03 mol, 0.3 equiv) and 24 h (7.11 g, 0.03

mol, 0.3 equiv). The residue was puriﬁed by column chromatography

(hexane/EtOAc = 8:2). Yield: 23.38 g, 0.085 mol, 85%, yellow oil. ¹H

NMR (400 MHz, CDCl₃): δ 7.35−7.24 (m, 5H), 3.89−3.62 (m, 8H),

3.51 (td, J = 11.4, 2.8 Hz, 1H), 2.95 (d, J = 9.2 Hz, 1H), 2.91 (d, J =

7.9 Hz, 1H), 2.83 (d, J = 9.0 Hz, 1H), 2.79 (d, J = 9.0 Hz, 1H), 2.71−

2.61 (m, 1H), 2.17−2.05 (m, 1H), 2.03−1.94 (m, 1H) ppm. ¹³C{¹H}

NMR (126 MHz, CDCl₃): δ 175.9, 139.4, 128.6, 128.4, 127.0, 66.4,

64.9, 62.4, 60.3, 54.9, 52.2, 48.6, 39.4, 30.3 ppm. LCMS (M + H)⁺:

276. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₆H₂₂NO₃

276.1600; found 276.1612.

128.4, 127.1, 83.7, 65.8, 65.1, 60.9, 55.7, 52.4, 39.3, 20.9, 20.7 ppm.

LCMS (M + H)⁺: 276. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₆H₂₂NO₃276.1600; found 276.1625.

Methyl-2-benzyl-5-methyloctahydro-7aH-pyrrolo[3,4-c]pyridine-

7a-carboxylate (32a). Protocol C was used. An additional portion of

1 was added after 12 h (7.11 g, 0.03 mol, 0.3 equiv). The residue was

puriﬁed by column chromatography (hexane/EtOAc = 9:1). Yield:

22.75 g, 0.079 mol, 79%, yellow oil. ¹H NMR (400 MHz, DMSO-d₆):

δ 7.31−7.19 (m, 5H), 3.69 (d, J = 13.3 Hz, 1H), 3.62 (d, J = 13.2 Hz,

1H), 3.62 (s, 3H), 2.81 (d, J = 9.1 Hz, 1H), 2.78−2.56 (m, 4H),

2.44−2.31 (m, 2H), 2.17 (dd, J = 11.8, 4.4 Hz, 1H), 2.09 (s, 3H),

2.01−1.84 (m, 3H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ

175.2, 139.4, 128.2, 128.1, 126.7, 61.2, 59.5, 55.3, 55.0, 52.2, 51.8,

48.1, 46.1, 30.0 ppm. LCMS (M + H)⁺: 289. HRMS (ESI-TOF) m/z:

[M + H]⁺calcd for C₁₇H₂₅N₂O₂289.1916; found 289.1934.

Methyl-2-benzyl-5-tosyloctahydro-7aH-pyrrolo[3,4-c]pyridine-

7a-carboxylate (33a). Protocol C was used. An additional portion of

1 was added after 12 h (7.11 g, 0.03 mol, 0.3 equiv). The residue was

puriﬁed by column chromatography (hexane/EtOAc = 9:1). Yield:

1

38.95 g, 0.091 mol, 91%, white solid. mp = 146−148 °C. H NMR

(600 MHz, DMSO-d₆): δ 7.71 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.7

Hz, 2H), 7.49−7.25 (m, 2 5H), 3.71 (s, 2H), 3.64 (s, 3H), 3.46−3.44

(m, 1H), 3.29 (dd, J = 12.8, 3.8 Hz, 1H), 2.85 (d, J = 9.5 Hz, 1H),

2.83−2.71 (m, 2H), 2.68 (d, J = 9.5 Hz, 1H), 2.50 (s, 3H), 2.12−2.00

(m, 2H) ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ 174.5, 143.4,

139.0, 133.1, 129.9, 128.2, 128.2, 127.3, 126.8, 61.5, 59.0, 54.7, 52.1,

48.0, 44.6, 42.7, 38.6, 29.1, 21.0 ppm. HRMS (ESI-TOF) m/z: [M +

H]⁺calcd for C₂₃H₂₉N₂O₄S 429.1848; found 429.1845.

Tert-butyl (2-benzyl-7a-(triﬂuoromethyl)octahydro-5H-pyrrolo-

[3,4-c]pyridine-5-carboxylate (34a). Protocol D was used. The

residue was puriﬁed by column chromatography (hexane/EtOAc =

9:1). Yield: 24.19 g, 0.063 mol, 63%, yellow oil. Mixture of

1

diastereomers (∼3:2). H NMR (400 MHz, CDCl₃): δ 7.34−7.27

(m, 5H), 3.67−3.31 (m, 6H), 2.89−2.68 (m, 2H), 2.62−2.45 (m,

3H), 2.12−2.02 (m, 1H), 1.90−1.76 (m, 1H), 1.50, 1.47 (2 × s, 9H)

ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 155.8, 155.5, 138.8, 129.0

(q, J = 280.6 Hz), 128.5, 127.2, 59.6, 57.9, 57.4, 47.0, 41.7, 40.7, 39.4,

38.7, 38.3, 28.6, 26.1, 26.0 ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ

−76.3, −76.4 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₂₀H₂₈F₃N₂O₂385.2103; found 385.2118.

Methyl 2-Benzylhexahydropyrano[3,4-c]pyrrole-3a(4H)-carboxy-

late (29a). Protocol C was used. Two additional portions of 1 were

added after 12 h (7.11 g, 0.03 mol, 0.3 equiv) and 24 h (7.11 g, 0.03

mol, 0.3 equiv). The residue was puriﬁed by column chromatography

(hexane/EtOAc = 7:3). Yield: 22.83 g, 0.083 mol, 83%, yellow oil. ¹H

NMR (400 MHz, CDCl₃): δ 7.34−7.20 (m, 5H), 4.08 (d, J = 11.7

Hz, 1H), 3.77−3.74 (m, 1H), 3.73 (s, 3H), 3.72−3.60 (m, 4H),

2.98−2.83 (m, 3H), 2.79 (d, J = 7.1 Hz, 1H), 2.66 (d, J = 9.7 Hz,

1H), 2.02−1.90 (m, 1H), 1.59−1.49 (m, 1H) ppm. ¹³C{¹H} NMR

(126 MHz, CDCl₃): δ 175.2, 139.3, 128.6, 128.4, 127.1, 69.7, 64.7,

60.3, 59.2, 56.5, 52.4, 50.9, 36.3, 24.9 ppm. LCMS (M + H)⁺: 276.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₆H₂₂NO₃276.1600;

found 276.1608.

5-(Tert-butyl) 7a-methyl-2-benzyl-3a-ﬂuorohexahydro-1H-

pyrrolo[3,4-c]pyridine-5,7a-dicarboxylate (35a). Protocol C was

used. Two additional portions of 1 were added after 12 h (7.11 g, 0.03

mol, 0.3 equiv) and 24 h (7.11 g, 0.03 mol, 0.3 equiv). The crude

product was puriﬁed by column chromatography (hexane/EtOAc,

8:1). R_f= 0.26. Yield: 20.78 g, 0.053 mol, 53%, yellow oil. Mixture of

1

diastereomers (∼3:2). H NMR (500 MHz, CDCl₃): δ 7.43−7.23

(m, 5H), 4.31−3.95 (m, 2H), 3.94−3.75 (m, 2H), 3.73, 3.71 (2 × s,

3H), 3.69−3.62 (m, 1H), 3.47−3.12 (m, 4H), 2.89−2.68 (m, 2H),

2.19 (br s, 1H), 1.92−1.81 (m, 2H), 1.47, 1.42 (2 × s, 9H) ppm.

¹³C{¹H} NMR (126 MHz, CDCl₃): δ 171.8, 171.8, 155.0, 154.6,

138.9, 128.4, 127.1, 100.2, 98.7, 80.2, 61.0, 60.8, 59.7, 59.7, 53.6, 53.4,

52.1, 45.6, 45.3, 44.5, 44.2, 40.5, 39.4, 31.8, 31.5, 28.5 ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃): δ −146.1 (s), −146.4 (s) ppm. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₂₁H₃₀FN₂O₄393.2190; found

393.2173.

5-tert-Butyl 3a-Ethyl-2-benzylhexahydro-5H-pyrrolo[3,4-c]-

pyridine-3a,5(4H)-dicarboxylate (36a). Protocol D was used. The

residue was puriﬁed by column chromatography (hexane/EtOAc =

8:2). Yield: 36.46 g, 0.093 mol, 93%, yellow oil. ¹H NMR (500 MHz,

DMSO-d₆): δ 7.34−7.19 (m, 5H), 4.11−3.72 (m, 2H), 3.63−3.40

(m, 2H), 3.33−3.05 (m, 4H), 2.72−2.63 (m, 3H), 2.46−2.27 (m,

2H), 1.83−1.75 (m, 1H), 1.63−1.55 (m, 1H), 1.37 (s, 9H), 1.16 (br

s, 3H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 174.3, 154.5,

153.8, 138.8, 128.2, 128.2, 126.8, 78.4, 60.5, 60.3, 58.7, 58.4, 58.2,

52.0, 45.2, 43.9, 40.9, 40.3, 36.7, 28.0, 24.5, 24.2, 13.9 ppm. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₂₂H₃₃N₂O₄389.2440; found

389.2426.

Methyl 2-Benzyl-7a-ﬂuorohexahydropyrano[3,4-c]pyrrole-3a-

(4H)-carboxylate (30a). Protocol C was used. Two additional

portions of 1 were added after 12 h (7.11 g, 0.03 mol, 0.3 equiv)

and 24 h (7.11 g, 0.03 mol, 0.3 equiv). The crude product was

puriﬁed by column chromatography (gradient, hexane/EtOAc = 3:1

to 5:1). Yield: 19.92 g, 0.068 mol, 68%, yellow oil. R_f= 0.15. ¹H NMR

(400 MHz, D₂O): δ 7.69−7.47 (m, 5H), 4.65−4.48 (m, 2H), 4.40−

4.22 (m, 2H), 4.16 (br s, 1H), 4.12−3.88 (m, 2H), 3.82 (s, 3H),

3.65−3.39 (m, 3H), 2.58−2.40 (m, 1H), 2.16 (d, J = 13.7 Hz, 1H)

ppm. ¹³C{¹H} NMR (151 MHz, D₂O): δ 169.6 (d, J = 4.3 Hz), 130.7,

130.4, 129.4, 129.0, 98.8 (d, J = 186.9 Hz), 70.0 (br s), 64.7 (d, J =

10.4 Hz), 60.1 (br s), 58.2 (d, J = 25.1 Hz), 56.1, 53.9 (d, J = 18.7

Hz), 53.4, 27.1 (d, J = 21.0 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz,

D₂O): δ −141.6 (s) ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₁₆H₂₁FNO₃294.1505; found 294.1521.

Methyl-6-benzylhexahydropyrano[2,3-c]pyrrole-7a(2H)-carbox-

ylate (31a). Protocol D. The residue was puriﬁed by column

chromatography (hexane/EtOAc = 7:3). Yield: 19.25 g, 0.07 mol,

70%, yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.36−7.23 (m, 5H),

3.91 (d, J = 11.4 Hz, 1H), 3.78 (s, 3H), 3.77−3.69 (m, 2H), 3.54 (td,

J = 11.5, 2.2 Hz, 1H), 3.23 (d, J = 11.1 Hz, 1H), 2.95−2.79 (m, 3H),

2.76 (d, J = 11.1 Hz, 1H), 1.91−1.64 (m, 3H), 1.37 (d, J = 12.2 Hz,

1H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 173.4, 139.2, 128.9,

tert-Butyl (2-Benzyl-3a-(triﬂuoromethyl)octahydro-5H-pyrrolo-

[3,4-c]pyridine-5-carboxylate (37a). Protocol D was used. The

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residue was puriﬁed by column chromatography (hexane/EtOAc =

was added to the mixture. Then Boc₂O (21.80 g, 0.1 mol, 1.0 equiv)

in CH₂Cl₂(25 mL) was added dropwise at rt (the mixture can be

cooled in a water bath). The solution was stirred overnight at rt. The

mixture was washed with 0.5 M HCl (1 × 20 mL), water (1 × 20

mL), and brine (1 × 20 mL), dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure. The crude product was

dissolved in MeOH (200 mL), and NaOH (8.00 g, 0.2 mol, 2.0

equiv) was added to the mixture. The solution was stirred at rt

overnight. The solution was concentrated under reduced pressure.

The residue was washed with methyl tert-butyl ether (2 × 50 mL) and

then acidiﬁed with 1 M HCl to pH ∼ 4. The solution was extracted

with EtOAc (3 × 100 mL). The combined fractions were washed with

brine (1 × 100 mL), dried over Na₂SO₄, ﬁltered, and concentrated

under reduced pressure. Yield: 19.00 g, 0.079 mol, 79%, white solid,

mp = 104−105 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 12.54 (s, 1H),

3.59 (d, J = 11.2 Hz, 1H), 3.44 (d, J = 11.3 Hz, 2H), 3.27−3.16 (m,

1H), 3.02−2.94 (m, 1H), 2.47−2.36 (m, 1H), 2.17−2.06 (m, 1H),

1.90−1.79 (m, 1H), 1.64−1.53 (m, 1H), 1.42 (s, 9H) ppm. ¹³C{¹H}

NMR (126 MHz, DMSO-d₆): δ 175.4, 154.1, 78.7, 54.4, 52.3, 42.1,

41.0, 28.1, 26.7, 21.3 ppm. LCMS (M − H)⁻: 240. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₂H₂₀NO₄242.1392; found

242.1381.

2-(tert-Butoxycarbonyl)hexahydrocyclopenta[c]pyrrole-3a(1H)-

carboxylic Acid (6b). General procedure E. Yield: 19.60 g, 0.077 mol,

77%, white solid, mp = 95−97 °C. ¹H NMR (400 MHz, DMSO-d₆):

δ 12.46 (s, 1H), 3.76 (d, J = 11.4 Hz, 1H), 3.48 (dd, J = 11.0, 8.2 Hz,

1H), 3.16 (d, J = 11.4 Hz, 1H), 3.07 (dd, J = 11.1, 4.1 Hz, 1H), 2.78

(br s, 1H), 2.10−1.99 (m, 1H), 1.94−1.78 (m, 1H), 1.76−1.59 (m,

3H), 1.49−1.42 (m, 1H), 1.39 (s, 9H) ppm. ¹³C{¹H} NMR (151

MHz, DMSO-d₆): δ 177.0, 153.3, 78.4, 59.3, 58.4, 54.3, 51.5, 47.7,

46.8, 35.8, 32.1, 28.1, 25.0 ppm. LCMS (M − H)⁻: 254. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₃H₂₂NO₄256.1549; found

256.1542.

8:2). Yield: 24.96 g, 0.065 mol, 65%, yellow oil. Mixture of

1

diastereomers (∼3:2). H NMR (600 MHz, CDCl₃): δ 7.35−7.21

(m, 5H), 3.96, 3.87 (2 × d, J = 14.4 Hz, 1H), 3.65−3.07 (m, 4H),

2.70−2.44 (m, 3H), 2.44−2.32 (m, 1H), 1.95−1.68 (m, 2H), 1.58−

1.33 (m, 11H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 155.8,

155.0, 138.9, 128.5, 128.5, 128.3 (d, J = 280.7 Hz), 127.2, 79.9, 79.7,

59.5, 58.9, 58.6, 42.8, 41.2, 40.8, 40.3, 36.0, 35.9, 28.6, 28.5, 24.9, 24.7

ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₂₀H₂₈F₃N₂O₂

385.2103; found 385.2129.

6-Benzyl-4a-(triﬂuoromethyl)octahydrothiopyrano[2,3-c]pyrrole

1,1-Dioxide (38a). Protocol A was used. Crude product was

crystallized from a mixture of CHCl₃:hexane. Yield: 32.63 g, 0.098

mol, 98%, colorless crystals, mp = 102−104 °C. ¹H NMR (400 MHz,

CDCl₃): δ 7.39−7.19 (m, 5H), 3.74 (d, J = 12.8 Hz, 1H), 3.54 (d, J =

12.2 Hz, 2H), 3.52−3.42 (m, 1H), 3.36−3.24 (m, 1H), 3.12−2.98

(m, 1H), 2.87 (d, J = 8.9 Hz, 1H), 2.82 (d, J = 10.1 Hz, 1H), 2.65 (d,

J = 9.7 Hz, 1H), 2.46−2.33 (m, 1H), 2.31−2.11 (m, 2H), 1.95−1.85

(m, 1H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 137.6, 128.7,

128.4 (d, J = 23.2 Hz), 127.7, 127.1 (q, J = 281.7 Hz), 61.2, 60.0,

58.9, 55.4, 52.5 (q, J = 26.0 Hz), 46.0, 23.5, 17.6 ppm. ¹⁹F{¹H} NMR

(376 MHz, CDCl₃): δ −75.62 (s), −75.65 (s), −162.20 (s), −162.23

(s) ppm. GCMS (M): 333. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₁₅H₁₉F₃NO₂S 334.1089; found 334.1082.

Methyl 2-Benzylhexahydrothiopyrano[3,4-c]pyrrole-7a(1H)-car-

boxylate 5,5-Dioxide (39a). Protocol B was used. The residue was

puriﬁed by column chromatography (hexane/EtOAc = 8:2). Yield:

1

26.49 g, 0.082 mol, 82%, brown oil. H NMR (400 MHz, CDCl₃): δ

7.37−7.26 (m, 5H), 3.77 (s, 3H), 3.68 (s, 2H), 3.28−2.98 (m, 6H),

2.89 (d, J = 9.7 Hz, 1H), 2.86−2.80 (m, 1H), 2.77 (d, J = 9.7 Hz,

1H), 2.54 (dd, J = 7.4, 5.1 Hz, 2H) ppm. ¹³C{¹H} NMR (126 MHz,

CDCl₃): δ 174.6, 138.6, 128.5, 127.3, 62.5, 59.5, 56.8, 52.9, 50.4, 49.8,

49.2, 39.7, 29.5 ppm. LCMS (M + H)⁺: 324. HRMS (ESI-TOF) m/z:

[M + H]⁺calcd for C₁₆H₂₂NO₄S 324.1270; found 324.1262.

6-Benzyl-7a-(triﬂuoromethyl)octahydrothiopyrano[2,3-c]pyrrole

1,1-Dioxide (40a). Protocol A was used. Crude product was

crystallized from CCl₄. Yield: 26.97 g, 0.081 mol, 81%, colorless

crystals, mp = 68−69 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.38−7.25

(m, 5H), 3.79 (s, 2H), 3.45 (d, J = 12.6 Hz, 1H), 3.34 (d, J = 12.5 Hz,

1H), 3.30−3.17 (m, 3H), 3.11−2.99 (m, 1H), 2.99−2.89 (m, 1H),

2.33 (br s, 1H), 2.11−1.95 (m, 1H), 1.95−1.79 (m, 2H) ppm.

¹³C{¹H} NMR (126 MHz, CDCl₃): δ 138.7, 128.6, 128.5, 127.3,

124.6 (q, J = 281.6 Hz), 71.8 (q, J = 25.8 Hz), 59.1, 55.7, 52.8, 50.7,

41.5, 21.0, 20.2 ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ −67.6 (s)

ppm. GCMS (M): 333. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₅H₁₉F₃NO₂S 334.1089; found 334.1082.

2-Benzyloctahydrocyclohepta[c]pyrrole-3a(1H)-carbonitrile

(41a). Protocol C was used. Two additional portions of 1 were added

after 12 h (7.11 g, 0.03 mol, 0.3 equiv) and 24 h (7.11 g, 0.03 mol, 0.3

equiv). The residue was puriﬁed by column chromatography

(hexane/EtOAc = 7:3). Yield: 12.45 g, 0.049 mol, 49%, yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 7.39−7.24 (m, 5H), 3.62 (d, J = 13.1

Hz, 1H), 3.53 (d, J = 13.1 Hz, 1H), 3.26 (d, J = 9.5 Hz, 1H), 3.18 (t, J

= 8.4 Hz, 1H), 2.76−2.61 (m, 1H), 2.16 (d, J = 9.5 Hz, 1H), 1.99−

1.82 (m, 5H), 1.78−1.56 (m, 3H), 1.46−1.13 (m, 3H) ppm. ¹³C{¹H}

NMR (151 MHz, CDCl₃): δ 138.4, 128.6, 128.4, 127.2, 126.7, 66.2,

61.6, 59.2, 49.2, 45.7, 33.5, 31.2, 30.7, 28.6, 26.3 ppm. LCMS (M +

H)⁺: 255. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₇H₂₃N₂

255.1861; found 255.1852.

General Procedure E for Synthesis of 2b, 6b, 7b, 9b−12b,

24b−26b, 28b−32b, 39b, and 41b. See 2b as an example. Scale:

0.1 mol for all derivatives.

3-(tert-Butoxycarbonyl)-3-azabicyclo[3.2.0]heptane-1-carboxylic

Acid (2b). A solution of 2a (24.50 g, 0.1 mol, 1.0 equiv) in MeOH

(500 mL) was hydrogenated in the presence of 10% Pd/C (5.00 g) at

a pressure of 50 atm for 15 h at rt. Then the catalyst was ﬁltered oﬀ,

and the residue was washed with MeOH. The ﬁltrate was

concentrated to a half of original volume, ﬁltered through a thin

pad of silica gel, and concentrated to dryness. The residue was

dissolved in CH₂Cl₂(250 mL) and Et₃N (10.10 g, 0.1 mol, 1.0 equiv)

2-(tert-Butoxycarbonyl)-6a-ﬂuorohexahydrocyclopenta[c]-

pyrrole-3a(1H)-carboxylic Acid (7b). General procedure E. Yield:

1

23.80 g, 0.087 mol, 87%, white solid, mp = 126−127 °C. H NMR

(400 MHz, CDCl₃): δ 4.07 (d, J = 11.5 Hz, 1H), 3.90−3.65 (m, 2H),

3.41 (d, J = 11.2 Hz, 1H), 2.59−2.46 (m, 1H), 2.40−2.25 (m, 1H),

2.10−1.93 (m, 2H), 1.90−1.68 (m, 2H), 1.46 (s, 9H) ppm. ¹³C{¹H}

NMR (126 MHz, CDCl₃): δ 177.0 (d, J = 3.6 Hz), 154.5, 110.3 (d, J

= 203.2 Hz), 109.7 (d, J = 200.7 Hz), 80.5, 61.0, 60.3, 55.4 (d, J =

30.7 Hz), 53.7, 36.1 (d, J = 22.1 Hz), 35.6 (d, J = 24.7 Hz), 34.2, 28.6,

22.7, 22.5 ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ −154.9 (s),

−155.4 (s) ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₃H₂₁FNO₄274.1455; found 274.1451.

5-(tert-Butoxycarbonyl)hexahydro-3aH-furo[2,3-c]pyrrole-3a-

carboxylic Acid (9b). General procedure E. Cleavage of N-Bn bond

was performed under modiﬁed conditions: 10 atm (H₂), 10% Pd/C,

50 °C, MeOH, 15h. Yield: 20.56 g, 0.08 mol, 80%, white solid, mp =

109−110 °C. ¹H NMR (400 MHz, CDCl₃): δ 11.22 (br s, 1H), 4.61

(d, J = 4.5 Hz, 1H), 4.07 (dd, J = 15.2, 7.0 Hz, 1H), 4.00−3.90 (m,

2H), 3.66 (d, J = 12.3 Hz, 1H), 3.59−3.34 (m, 2H), 2.61−2.47 (m,

1H), 2.16−1.99 (m, 1H), 1.44 (s, 9H) ppm. ¹³C{¹H} NMR (126

MHz, CDCl₃): δ 178.0, 154.6, 86.6, 86.0, 80.4, 68.9, 59.8, 58.9, 53.9,

52.4, 51.8, 36.5, 28.5 ppm. LCMS (M − H)⁻: 256. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₂H₂₀NO₅258.1341; found

258.1348.

5-(tert-Butoxycarbonyl)tetrahydro-1H-furo[3,4-c]pyrrole-3a(3H)-

carboxylic Acid (10b). General procedure E. Yield: 17.48 g, 0.068

mol, 68%, white solid, mp = 98−99 °C. ¹H NMR (400 MHz,

CDCl₃): δ 10.82 (br s, 1H), 4.22 (d, J = 9.2 Hz, 1H), 4.09 (t, J = 7.9

Hz, 1H), 3.91 (d, J = 11.6 Hz, 1H), 3.79 (d, J = 9.2 Hz, 1H), 3.72−

3.60 (m, 2H), 3.54 (br s, 1H), 3.38 (br s, 1H), 3.24−3.06 (m, 1H),

1.45 (s, 9H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 178.1, 154.5,

80.5, 76.0, 74.3, 60.0 (br s), 53.1, 50.5 (br s), 48.1 (br s), 28.6 ppm.

LCMS (M − H)⁻: 256. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₂H₂₀NO₅258.1341; found 258.1329.

5-(tert-Butoxycarbonyl)-3,3-dimethyltetrahydro-1H-furo[3,4-c]-

pyrrole-3a(3H)-carboxylic Acid (11b). General procedure E. Yield:

1

22.23 g, 0.078 mol, 78%, white solid, mp = 138−140 °C. H NMR

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(400 MHz, CDCl₃): δ 10.99 (br s, 1H), 4.18 (t, J = 9.2 Hz, 1H), 3.85

(br s, 1H), 3.67−3.55 (m, 3H), 3.49−3.41 (m, 1H), 3.41 (br s, 1H),

1.45 (s, 9H), 1.39 (s, 3H), 1.24 (s, 3H) ppm. ¹³C{¹H} NMR (126

MHz, CDCl₃): δ 177.1, 154.6, 83.1, 80.3, 70.7, 66.4 (br s), 65.4 (br

s), 50.8, 45.3 (br s), 44.6 (br s), 28.6, 24.5, 23.1 ppm. LCMS (M −

H)⁻: 284. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₄H₂₄NO₅

286.1654; found 286.1645.

47.05, 46.8, 39.0, 38.1, 28.9, 28.8, 28.6 ppm. LCMS (M + H)⁺: 272.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₃H₂₂NO₅272.1498;

found 272.1491.

2-(tert-Butoxycarbonyl)hexahydropyrano[3,4-c]pyrrole-3a(4H)-

carboxylic Acid (29b). General procedure E. Yield: 19.24 g, 0.071

1

mol, 71%, white solid, mp = 127−128 °C. H NMR (400 MHz,

DMSO-d₆): δ 12.86 (s, 1H), 3.80, 3.77 (2 × d, J = 5.9 Hz, 1H), 3.70−

3.61 (m, 1H), 3.53−3.33 (m, 4H), 3.26−3.17 (m, 2H), 2.71−2.57

(m, 1H), 1.83−1.71 (m, 1H), 1.39 (s, 9H), 1.38−1.27 (m, 1H) ppm.

¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 174.4, 153.8, 153.7, 78.6,

5-(tert-Butoxycarbonyl)hexahydro-6aH-furo[2,3-c]pyrrole-6a-

carboxylic Acid (12b). General procedure E. Yield: 21.59 g, 0.084

1

mol, 84%, white solid, mp = 108−109 °C. H NMR (400 MHz,

DMSO-d₆): δ 12.99 (br s, 1H), 3.98 (dd, J = 14.8, 7.2 Hz, 1H), 3.93−

3.82 (m, 1H), 3.64 (d, J = 11.8 Hz, 1H), 3.60−3.52 (m, 1H), 3.49 (d,

J = 12.1 Hz, 1H), 3.17 (dd, J = 11.1, 5.6 Hz, 1H), 2.99 (br s, 1H),

2.16−2.01 (m, 1H), 1.82−1.70 (m, 1H), 1.39 (s, 9H) ppm. ¹³C{¹H}

NMR (126 MHz, DMSO-d₆): δ 173.2, 153.3, 78.7, 68.7, 54.5, 50.9,

47.5, 46.5, 31.1, 28.1 ppm. LCMS (M − H)⁻: 256. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₂H₂₀NO₅258.1341; found

258.1328.

67.39, 67.35, 64.3, 64.2, 50.0, 49.6, 49.5, 49.03, 48.98, 48.7, 35.9, 35.2,

28.1, 24.54, 24.48 ppm. LCMS (M − H)⁻: 270. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₁₃H₂₂NO₅272.1498; found 272.1484.

2-(tert-Butoxycarbonyl)-7a-ﬂuorohexahydropyrano[3,4-c]-

pyrrole-3a(4H)-carboxylic Acid (30b). General procedure E. Yield:

1

21.10 g, 0.073 mol, 73%, white solid, mp = 167−169 °C. H NMR

(400 MHz, DMSO-d₆): δ 12.93 (s, 1H), 4.02−3.91 (m, 2H), 3.88,

3.79 (2 × d, J = 13.4 Hz, 1H), 3.69−3.43 (m, 3H), 3.27−3.16 (m,

2H), 2.45−2.29 (m, 1H), 1.95−1.83 (m, 1H), 1.41 (s, 9H) ppm.

¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 170.88, 170.86, 153.5, 99.2

5-(tert-Butoxycarbonyl)tetrahydro-1H-thieno[3,4-c]pyrrole-3a-

(3H)-carboxylic Acid 2,2-Dioxide (23b). General procedure E. Yield:

1

21.66 g, 0.071 mol, 71%, white solid, mp = 162−163 °C. H NMR

(d, J = 186.3 Hz), 98.4 (d, J = 185.6 Hz), 79.1, 70.2 (d, J = 4.7 Hz),

64.9 (d, J = 9.8 Hz), 53.4, 53.3, 53.2, 53.1, 52.9, 52.6, 52.5, 49.3, 49.1,

28.4, 28.2, 28.1 ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ

−142.76 (s) ppm. LCMS (M − H)⁻: 288. HRMS (ESI-TOF) m/z:

[M + H]⁺calcd for C₁₃H₂₁FNO₅290.1404; found 290.1384.

6-(tert-Butoxycarbonyl)hexahydropyrano[2,3-c]pyrrole-7a(2H)-

carboxylic Acid (31b). General procedure E. Cleavage of the N-Bn

bond was performed under modiﬁed conditions: 10 atm (H₂), 10%

Pd/C, 50 °C, MeOH, 15h. Yield: 20.33 g, 0.075 mol, 75%, white

solid, mp = 157−158 °C. Mixture of diastereomers (∼1:1). ¹H NMR

(400 MHz, DMSO-d₆): δ 13.16 (br s, 1H), 3.79−3.70 (m, 1H),

3.55−3.24 (m, 5H), 2.79−2.63 (m, 1H), 1.65 (br s, 3H), 1.40, 1.38

(2 × s, 9H), 1.33−1.25 (m, 1H) ppm. ¹³C{¹H} NMR (151 MHz,

DMSO-d₆): δ 172.0, 171.9, 153.5, 153.3, 82.0, 81.3, 78.62, 78.56,

64.1, 64.0, 57.1, 56.9, 46.7, 46.5, 37.7, 36.8, 28.13, 28.09, 19.52, 19.49,

19.0 ppm. LCMS (M − H)⁻: 270. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₁₃H₂₂NO₅272.1498; found 272.1486.

(400 MHz, DMSO-d₆): δ 13.37 (br s, 1H), 3.87 (d, J = 11.8 Hz, 1H),

3.72 (dd, J = 12.7, 9.3 Hz, 1H), 3.59 (d, J = 14.2 Hz, 1H), 3.46 (d, J =

11.9 Hz, 1H), 3.45−3.40 (m, 2H), 3.39 (d, J = 14.3 Hz, 1H), 3.27 (br

s, 2H), 3.23−3.16 (m, 1H), 1.39 (s, 9H) ppm. ¹³C{¹H} NMR (126

MHz, DMSO-d₆): δ 173.5, 153.1, 79.0, 55.6, 53.8, 53.6, 49.6, 41.7,

40.8, 28.1 ppm. LCMS (M − H)⁻: 304. HRMS (ESI-TOF) m/z: [M

+ H]⁺calcd for C₁₂H₂₀NO₆S 306.1011; found 306.1002.

2-(tert-Butoxycarbonyl)octahydro-3aH-isoindole-3a-carboxylic

Acid (24b). General procedure E. Yield: 19.10 g, 0.071 mol, 71%,

1

white solid, mp = 133−134 °C. H NMR (400 MHz, DMSO-d₆): δ

12.60 (s, 1H), 3.41 (dd, J = 14.5, 10.7 Hz, 1H), 3.35−3.23 (m, 1H),

3.21 (d, J = 10.8 Hz, 1H), 3.16−3.03 (m, 1H), 1.85−1.76 (m, 1H),

1.69−1.57 (m, 1H), 1.53−1.41 (m, 3H), 1.39 (s, 9H), 1.36−1.29 (m,

4H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 176.0, 153.8,

78.4, 53.0, 52.8, 50.1, 49.3, 48.8, 48.5, 38.3, 37.5, 28.6, 28.5, 28.1,

24.3, 21.9, 21.3 ppm. LCMS (M − H)⁻: 268. HRMS (ESI-TOF) m/

z: [M + H]⁺calcd for C₁₄H₂₄NO₄270.1705; found 270.1717.

2-(tert-Butoxycarbonyl)-6,6-diﬂuorooctahydro-3aH-isoindole-

3a-carboxylic Acid (25b). General procedure E. Yield: 22.57 g, 0.074

mol, 74%, white solid, mp = 157−158 °C. Mixture of diastereomers

(∼1:1). ¹H NMR (400 MHz, DMSO-d₆): δ 12.97 (br s, 1H), 3.55 (t,

J = 11.5 Hz, 1H), 3.40−3.30 (m, 2H), 3.17−3.08 (m, 1H), 2.82−2.68

(m, 1H), 2.17−1.94 (m, 3H), 1.92−1.74 (m, 3H), 1.39, 1.39 (2 × s,

9H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 175.3, 153.7,

153.6, 123.6 (t, J = 239.7 Hz), 78.59, 78.57, 51.0, 50.9, 49.4, 49.2,

48.9, 48.5, 38.1, 37.3, 32.3 (t, J = 23.7 Hz), 29.3 (t, J = 24.3 Hz), 28.1,

25.54, 25.49 ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −90.4

(s), −91.0 (s) ppm. LCMS (M − H)⁻: 304. HRMS (ESI-TOF) m/z:

[M + H]⁺calcd for C₁₄H₂₂F₂NO₄306.1517; found 306.1510.

6-(tert-Butoxycarbonyl)hexahydropyrano[2,3-c]pyrrole-4a(2H)-

carboxylic Acid (26b). General procedure E. Cleavage of N-Bn bond

was performed under modiﬁed conditions: 10 atm (H₂), 10% Pd/C,

50 °C, MeOH, 15h. Yield: 18.16 g, 0.067 mol, 67%, beige solid, mp =

2-(tert-Butoxycarbonyl)-5-methyloctahydro-7aH-pyrrolo[3,4-c]-

pyridine-7a-carboxylic Acid (32b). General procedure E. Yield: 17.89

g, 0.063 mol, 63%, white solid, mp = 224−225 °C. Mixture of

1

diastereomers (∼1:1). H NMR (400 MHz, D₂O): δ 3.98−3.61 (m,

1H), 3.51−3.26 (m, 5H), 3.15−2.92 (m, 2H), 2.85 (s, 3H), 2.29 (d, J

= 15.5 Hz, 1H), 2.18−2.02 (m, 1H), 1.82 (t, J = 13.4 Hz, 1H), 1.43

(s, 9H) ppm. ¹³C{¹H} NMR (151 MHz, D₂O): δ 180.5, 178.6, 156.3,

81.8, 55.2, 54.6, 53.4, 51.8, 51.2, 50.3, 48.4, 47.9, 46.3, 45.8, 43.2,

37.7, 37.3, 27.6, 26.6, 26.1 ppm. LCMS (M − H)⁻: 283. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₄H₂₅N₂O₄285.1814; found

285.1810.

2-(tert-Butoxycarbonyl)hexahydrothiopyrano[3,4-c]pyrrole-7a-

(1H)-carboxylic Acid 5,5-Dioxide (39b). General procedure E. Yield:

24.88 g, 0.078 mol, 78%, white solid, mp = 78−79 °C. ¹H NMR (400

MHz, DMSO-d₆): δ 13.21 (br s, 1H), 3.63−3.51 (m, 1H), 3.50−3.36

(m, 3H), 3.31−3.01 (m, 5H), 2.40−2.28 (m, 1H), 2.25−2.09 (m,

1H), 1.40 (s, 9H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ

174.61, 174.55, 153.6, 153.5, 78.7, 51.0, 50.9, 48.7, 48.2, 48.1, 48.0,

47.9, 47.8, 46.2, 46.1, 28.1, 27.3 ppm. LCMS (M − H)⁻: 318. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₁₃H₂₂NO₆S 320.1168; found

320.1175.

2-(tert-Butoxycarbonyl)octahydrocyclohepta[c]pyrrole-3a(1H)-

carboxylic Acid (41b). Compound 41a (25.40 g, 0.1 mol, 1.0 equiv)

was dissolved in MeOH (200 mL), and NaOH (8.00 g, 0.2 mol, 2.0

equiv) was added to the mixture. The solution was stirred at reﬂux in

an oil bath with a thermocouple overnight. The solution was

concentrated under reduced pressure. The residue was washed with

methyl tert-butyl ether (2 × 50 mL) and then acidiﬁed with 1 M HCl

to pH ∼ 4. The solution was extracted with EtOAc (3 × 100 mL).

The combined fractions were washed with brine (1 × 100 mL), dried

over Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The

crude product was dissolved in MeOH (500 mL) and hydrogenated

in the presence of 10% Pd/C (3.00 g) at pressure 50 atm for 15 h at

1

142−143 °C. H NMR (400 MHz, DMSO-d₆): δ 12.81 (br s, 1H),

4.15−4.03 (m, 1H), 3.83, 3.80 (2 × d, J = 2.5 Hz, 1H), 3.66 (t, J =

10.2 Hz, 1H), 3.42−3.24 (m, 3H), 3.20, 3.17 (2 × d, J = 5.2 Hz, 1H),

1.90−1.80 (m, 2H), 1.73−1.59 (m, 1H), 1.51−1.43 (m, 1H), 1.39,

1.38 (2 × s, 9H) ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ

175.6, 153.7, 153.9, 78.5, 78.48, 77.7, 76.9, 65.5, 52.1, 51.8, 50.9, 50.0,

48.1, 47.9, 28.2, 28.1, 25.3, 20.4 ppm. LCMS (M + H)⁺: 272. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₁₃H₂₂NO₅272.1498; found

272.1477.

2-(tert-Butoxycarbonyl)hexahydropyrano[3,4-c]pyrrole-7a(1H)-

carboxylic Acid (28b). General procedure E. Yield: 18.70 g, 0.069

1

mol, 69%, white solid, mp = 148−149 °C. H NMR (400 MHz,

DMSO-d₆): δ 12.86 (s, 1H), 3.70−3.58 (m, 2H), 3.54−3.26 (m, 6H),

3.25−3.13 (m, 1H), 1.91−1.82 (m, 1H), 1.64−1.51 (m, 1H), 1.39 (s,

9H) ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ 175.6, 154.3,

154.2, 79.02, 78.97, 65.0, 64.9, 64.32, 64.27, 54.0, 53.9, 48.0, 47.1,

N

https://doi.org/10.1021/acs.joc.1c01327

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

rt. Then the catalyst was ﬁltered oﬀ, and the residue was washed with

MeOH. The ﬁltrate was concentrated to a half of original volume,

ﬁltered through a thin pad of silica gel, and concentrated to dryness.

The residue was dissolved in CH₂Cl₂(250 mL), and Et₃N (10.10 g,

0.1 mol, 1.0 equiv) was added to the mixture. Then Boc₂O (21.80 g,

0.1 mol, 1.0 equiv) in CH₂Cl₂(25 mL) was added dropwise at rt (the

mixture can be cooled in a water bath). The solution was stirred

overnight at rt. The mixture was washed with 0.5 M HCl (1 × 20

mL), water (1 × 20 mL), and brine (1 × 20 mL), dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure. Yield: 17.26 g,

51.0 (br s), 49.6 (br s), 28.6, 14.3 ppm. HRMS (ESI-TOF) m/z: [M

+ H]⁺calcd for C₁₄H₂₅N₂O₄285.1814; found 285.1802.

tert-Butyl 3a-(Triﬂuoromethyl)hexahydropyrrolo[3,4-c]pyrrole-

2(1H)-carboxylate Hydrochloride (17c). General procedure F.

Cleavage of N-Bn bond was performed under modiﬁed conditions:

10 atm (H₂), 10% Pd/C, 50 °C, MeOH, 15h. Yield: 26.90 g, 0.085

1

mol, 85%, white solid, mp = 115−116 °C. H NMR (400 MHz,

DMSO-d₆): δ 10.22 (br s, 2H), 3.80−3.53 (m,, 4H), 3.49−3.36 (m,

3H), 3.27−3.12 (m, 2H), 1.40 (s, 9H) ppm. ¹³C{¹H} NMR (126

MHz, DMSO d₆): δ 152.9, 127.0 (q, J = 280 Hz), 79.4, 57.5 (br s),

50.2, 49.0, 48.6, 43.5, 28.0 ppm. ¹⁹F{¹H} NMR (470 MHz, DMSO-

d₆): δ −73.3 (s) ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₂H₂₀F₃N₂O₂281.1477; found 281.1459.

1

0.061 mol, 61%, white solid, mp = 97−98 °C. H NMR (400 MHz,

DMSO-d₆): δ 12.55 (s, 1H), 3.79 (d, J = 11.1 Hz, 1H), 3.50 (br s,

1H), 3.03 (d, J = 10.9 Hz, 1H), 2.94 (dd, J = 11.1, 3.6 Hz, 1H), 2.69

(br s, 1H), 2.03 (br s, 1H), 1.77 (d, J = 11.8 Hz, 1H), 1.71 (d, J = 12.1

Hz, 1H), 1.67−1.42 (m, 4H), 1.37 (s, 9H), 1.31−1.16 (m, 3H) ppm.

¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ 177.4, 153.1, 78.3, 56.0,

3a,6a-Bis(triﬂuoromethyl)octahydropyrrolo[3,4-c]pyrrole (18c).

General procedure F. Yield: 16.84 g, 0.068 mol, 68%, white solid,

mp = 160−161 °C. ¹H NMR (400 MHz, CDCl₃): δ 3.45 (d, J = 12.1

Hz, 4H), 2.99 (d, J = 12.0 Hz, 4H), 2.27 (br s, 2H) ppm. ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ 126.9 (q, J = 282.1 Hz), 64.0 (q, J = 23.4

Hz), 56.7 ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ −67.5 (s) ppm.

GCMS (M): 248. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₈H₁₁F₆N₂249.0826; found 249.0835.

55.2 (br s), 53.1 (br s), 43.6, 42.8, 33.3, 30.8, 30.2, 28.5, 28.1, 24.2

ppm. LCMS (M − H)⁻: 282. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₁₅H₂₆NO₄284.1862; found 284.1845.

General Procedure F for synthesis of 3c−5c, 16c−21c, 34c,

35c, 38c, and 40c. See compound 3c as an example. Scale: 0.10 mol

for all derivatives. Note: Amines 4c, 5c, 17c, 35c, and 40c were

treated with 1 M HCl in dioxane, and the precipitate was ﬁltered oﬀ

to obtain amines hydrochlorides.

1-tert-Butyl 6a-Methyl Hexahydropyrrolo[3,4-b]pyrrole-1,6a-di-

carboxylate (19c). General procedure F. Yield: 20.79 g, 0.077 mol,

1

77%, yellow oil. Mixture of diastereomers (∼1:2). H NMR (400

MHz, CDCl₃): δ 3.71, 3.71 (2 × s, 3H), 3.70−3.51 (m, 3H), 3.28−

3.01 (m, 2H), 2.86−2.66 (m, 2H), 2.56 (br s, 1H), 2.18−1.97 (m,

1H), 1.75−1.58 (m, 1H), 1.43, 1.38 (2 × s, 9H) ppm. ¹³C{¹H} NMR

(126 MHz, CDCl₃): δ 174.5, 174.1, 154.4, 153.5, 80.3, 80.1, 76.7,

76.4, 58.2, 57.1, 54.1, 53.6, 52.7, 52.4, 48.5, 48.2, 29.2, 28.5, 28.4, 28.2

ppm. LCMS (M + H)⁺: 271. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₁₃H₂₃N₂O₄271.1658; found 271.1666.

1-(Triﬂuoromethyl)-6-thia-3-azabicyclo[3.2.0]heptane 6,6-Diox-

ide (3c). A solution of 3a (30.50 g, 0.10 mol, 1.0 equiv) in MeOH

(300 mL) was hydrogenated in the presence of 10% Pd/C (3.00 g) at

pressure 50 atm for 15 h at rt. Then the catalyst was ﬁltered oﬀ, and

the residue was washed with MeOH. The ﬁltrate was concentrated to

half the original volume, ﬁltered through a thin pad of silica gel, and

concentrated to dryness. The ﬁnal product was crystallized from

dioxane. Yield: 18.92 g, 0.088 mol, 88%, white solid, mp = 113−114

3a-(Triﬂuoromethyl)hexahydro-2H-thieno[2,3-c]pyrrole 1,1-Di-

oxide (20c). General procedure F. The ﬁnal product was crystallized

from a mixture of i-PrOH/benzene. Yield: 21.53 g, 0.094 mol, 94%,

1

°C. H NMR (400 MHz, CDCl₃): δ 4.77 (d, J = 5.5 Hz, 1H), 4.51

(dd, J = 14.3, 2.3 Hz, 1H), 3.93 (d, J = 14.3 Hz, 1H), 3.83 (d, J = 13.5

Hz, 1H), 3.31 (d, J = 12.1 Hz, 1H), 3.18 (d, J = 12.6 Hz, 1H), 3.13

(dd, J = 13.8, 6.8 Hz, 1H), 2.45 (br s, 1H) ppm. ¹³C{¹H} NMR (126

MHz, CDCl₃): δ 125.9 (q, J = 278.3 Hz), 84.2, 70.1, 54.1, 50.1, 43.7

(q, J = 30.1 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −71.0

(s) ppm. LCMS (M + H)⁺: 216. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₆H₉F₃NO₂S 216.0306; found 216.0300.

1

white solid, mp = 126−127 °C. H NMR (400 MHz, DMSO-d₆): δ

3.58 (dd, J = 7.2, 2.6 Hz, 1H), 3.40−3.25 (m, 3H), 3.14−3.05 (m,

3H), 2.82 (br s, 1H), 2.37−2.18 (m, 2H) ppm. ¹³C{¹H} NMR (126

MHz, DMSO-d₆): δ 127.6 (q, J = 280.2 Hz), 64.1, 57.3 (q, J = 25.3

Hz), 55.2, 50.4, 49.2, 26.0 ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-

d₆): δ −73.2 (s) ppm. LCMS (M + H)⁺: 230. HRMS (ESI-TOF) m/

z: [M + H]⁺calcd for C₇H₁₁F₃NO₂S 230.0463; found 230.0451.

6a-(Triﬂuoromethyl)hexahydro-2H-thieno[2,3-c]pyrrole 1,1-Di-

oxide (21c). General procedure F. Crystallization from a mixture of

benzene/hexane gave the pure product. Yield: 17.86 g, 0.078 mol,

1-Phenyl-6-thia-3-azabicyclo[3.2.0]heptane 6,6-dioxide Hydro-

chloride (4c). General procedure F. Yield: 23.61 g, 0.091 mol, 91%,

1

beige solid, mp = 154−155 °C. H NMR (400 MHz, DMSO-d₆): δ

10.52 (br s, 2H), 7.55 (d, J = 7.3 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H),

7.37 (t, J = 7.3 Hz, 1H), 5.31 (d, J = 8.5 Hz, 1H), 4.99 (d, J = 14.7 Hz,

1H), 4.61 (dd, J = 14.7, 3.5 Hz, 1H), 4.08−3.97 (m, 2H), 3.91 (dd, J

= 13.8, 8.6 Hz, 1H), 3.23 (d, J = 12.0 Hz, 1H) ppm. ¹³C{¹H} NMR

(151 MHz, DMSO-d₆): δ 138.9, 128.9, 127.9, 126.6, 82.3, 73.3, 55.8,

46.6, 42.4 ppm. LCMS (M + H)⁺: 224. HRMS (ESI-TOF) m/z: [M

+ H]⁺calcd for C₁₁H₁₄NO₂S 224.0745; found 224.0722.

1

78%, white solid, mp = 150−151 °C. H NMR (400 MHz, DMSO-

d₆): δ 3.57 (d, J = 13.3 Hz, 1H), 3.54−3.43 (m, 1H), 3.26−3.08 (m,

2H), 3.03 (d, J = 13.3 Hz, 1H), 2.90−2.78 (m, 3H), 2.32−2.19 (m,

1H), 1.81−1.68 (m, 1H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-

d₆): δ 125.0 (q, J = 280.0 Hz), 73.7 (q, J = 24.8 Hz), 53.3, 51.2, 50.5,

47.3, 23.2 ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −67.1 (s)

ppm. GCMS (M): 229. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₇H₁₁F₃NO₂S 230.0463; found 230.0448.

1-(4-Fluorophenyl)-6-thia-3-azabicyclo[3.2.0]heptane 6,6-diox-

ide Hydrochloride (5c). General procedure F. Yield: 23.03 g, 0.083

1

mol, 83%, white solid, mp = 207−209 °C. H NMR (400 MHz,

tert-Butyl 7a-(Triﬂuoromethyl)octahydro-5H-pyrrolo[3,4-c]-

pyridine-5-carboxylate (34c). General procedure F. Cleavage of N-

Bn bond was performed under modiﬁed conditions: 10 atm (H₂),

10% Pd/C, 50 °C, MeOH, 15h. Yield: 23.52 g, 0.080 mol, 80%,

yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 3.66 (br s, 1H), 3.42 (br s,

2H), 3.36−3.15 (m, 3H), 2.79 (d, J = 12.6 Hz, 1H), 2.65 (br s, 1H),

2.43 (br s, 1H), 2.08−2.00 (m, 2H), 1.70 (br s, 1H), 1.44 (s, 9H)

ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 155.6, 129.4 (q, J = 281

Hz), 80.0, 53.6, 51.2, 48.5, 40.9, 40.5, 39.5, 39.0, 38.5, 28.6, 28.5 (m),

25.1 ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ −76.4 (s), −76.7 (s)

ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₃H₂₂F₃N₂O₂

295.1633; found 295.1615.

DMSO-d₆): δ 10.33 (br s, 2H), 7.61 (dd, J = 8.2, 5.4 Hz, 2H), 7.29 (t,

J = 8.6 Hz, 2H), 5.30 (d, J = 8.5 Hz, 1H), 4.91 (d, J = 14.8 Hz, 1H),

4.61 (dd, J = 14.7, 3.3 Hz, 1H), 4.07−3.95 (m, 2H), 3.90 (dd, J =

13.7, 8.7 Hz, 1H), 3.24 (d, J = 11.9 Hz, 1H) ppm. ¹³C{¹H} NMR

(151 MHz, DMSO-d₆): δ 161.6 (d, J = 245.1 Hz), 135.1 (d, J = 2.9

Hz), 129.0 (d, J = 8.4 Hz), 115.6 (d, J = 21.5 Hz), 82.4, 73.4, 55.7,

46.6, 42.0 ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −115.0 (s)

ppm. LCMS (M + H)⁺: 242. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₁₁H₁₃FNO₂S 242.0651; found 242.0634.

2-tert-Butyl 3a-Ethyl Tetrahydropyrrolo[3,4-c]pyrrole-2,3a-

(1H,3H)-dicarboxylate (16c). General procedure F. Yield: 21.02 g,

0.074 mol, 74%, yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.16 (dd,

J = 14.1, 7.1 Hz, 2H), 3.79 (d, J = 11.7 Hz, 1H), 3.60−3.43 (m, 2H),

3.41 (d, J = 12.0 Hz, 1H), 3.30 (dd, J = 11.6, 7.6 Hz, 2H), 3.01−2.91

(m, 1H), 2.85 (d, J = 11.9 Hz, 1H), 2.70 (dd, J = 11.5, 5.1 Hz, 1H),

2.35 (br s, 1H), 1.44 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H}

NMR (126 MHz, CDCl₃): δ 174.9, 154.5, 79.9, 61.4, 58.4, 54.9, 53.4,

5-tert-Butyl 7a-methyl-3a-ﬂuorohexahydro-1H-pyrrolo[3,4-c]-

pyridine-5,7a-dicarboxylate Hydrochloride (35c). General proce-

dure F. Yield: 27.42 g, 0.081 mol, 81%, white solid, mp = 177−178

1

°C. H NMR (400 MHz, DMSO-d₆): δ 10.35 (br s, 2H), 4.28−4.10

(m, 1H), 3.96−3.79 (m, 1H), 3.73 (s, 3H), 3.72−3.68 (m, 1H),

3.48−3.30 (m, 3H), 3.13 (br s, 1H), 2.08−1.88 (m, 2H), 1.42 (s, 9H)

O

https://doi.org/10.1021/acs.joc.1c01327

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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Article

ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 169.0 (d, J = 3.8 Hz),

153.8, 98.5 (d, J = 186.8 Hz), 80.0, 52.7 (d, J = 18.9 Hz), 52.7, 50.4,

49.9 (d, J = 25.5 Hz), 42.2 (br s), 30.2, 27.9 ppm. LCMS (M + H)⁺:

303. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₄H₂₄FN₂O₄

303.1720; found 303.1727.

tert-Butyl (6a-Fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-

carbamate Hydrochloride (7d). General procedure G. The residue

was dissolved in EtOAc (50 mL), and 1 M HCl in EtOAc (50 mL)

was added dropwise. The mixture was stirred for 0.5 h and ﬁltered.

Yield: 4.49 g, 0.016 mol, 32%, white solid, mp = 60−62 °C. ¹H NMR

(400 MHz, DMSO-d₆): δ 9.75 (br s, 2H), 7.15 (br s, 1H), 3.76−3.57

(m, 2H), 3.38 (d, J = 13.4 Hz, 1H), 3.32 (d, J = 13.3 Hz, 1H), 3.16

(d, J = 12.6 Hz, 1H), 2.23−2.08 (m, 1H), 2.05−1.82 (m, 3H), 1.80−

1.65 (m, 1H), 1.62−1.48 (m, 1H), 1.40 (s, 9H) ppm. ¹³C{¹H} NMR

(151 MHz, DMSO-d₆): δ 155.6, 106.2 (d, J = 203.9 Hz), 78.9, 67.5

(d, J = 15.7 Hz), 53.6, 53.3, 35.8, 34.9 (d, J = 23.6 Hz), 28.1, 20.3 (d,

J = 6.3 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −151.8 (s)

ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₂H₂₂FN₂O₂

245.1665; found 245.1649.

4a-(Triﬂuoromethyl)octahydrothiopyrano[2,3-c]pyrrole 1,1-Di-

oxide (38c). General procedure F. The ﬁnal product was crystallized

from benzene. Yield: 21.14 g, 0.087 mol, 87%, white solid, mp = 133−

1

134 °C. H NMR (400 MHz, CDCl₃): δ 3.71 (dd, J = 13.0, 3.4 Hz,

1H), 3.47 (dd, J = 7.6, 3.6 Hz, 1H), 3.36 (dd, J = 13.1, 7.7 Hz, 1H),

3.27 (d, J = 12.4 Hz, 1H), 3.18−3.08 (m, 1H), 3.05−2.95 (m, 2H),

2.39−2.07 (m, 4H), 2.04−1.86 (m, 1H) ppm. ¹³C{¹H} NMR (151

MHz, CDCl₃): δ 127.8 (q, J = 282.6 Hz), 61.9, 55.8, 55.0 (q, J = 24.2

Hz), 48.6, 46.4, 23.4, 18.6 ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ

−74.1 (s) ppm. LCMS (M + H)⁺: 244. HRMS (ESI-TOF) m/z: [M

+ H]⁺calcd for C₈H₁₃F₃NO₂S 244.0619; found 244.0605.

tert-Butyl (2,2-Dioxidotetrahydro-1H-thieno[3,4-c]pyrrol-3a(3H)-

yl)carbamate (23d). General procedure G. Yield: 6.76 g, 0.0245 mol,

1

49%, white solid, mp = 195−196 °C. H NMR (400 MHz, DMSO-

7a-(Triﬂuoromethyl)octahydrothiopyrano[2,3-c]pyrrole 1,1-di-

oxide Hydrochloride (40c). General procedure F. The ﬁnal product

was crystallized from i-PrOH. Yield: 23.48 g, 0.084 mol, 84%, white

d₆): δ 7.46 (s, 1H), 3.46−3.36 (m, 2H), 3.22 (d, J = 14.2 Hz, 1H),

3.10 (dd, J = 11.2, 8.0 Hz, 1H), 3.01−2.90 (m, 3H), 2.82−2.73 (m,

1H), 2.72 (br s, 1H), 2.58 (dd, J = 11.5, 5.0 Hz, 1H), 1.39 (s, 9H)

ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 155.0, 78.4, 65.2, 60.3,

57.1, 53.6, 52.4, 46.0, 28.2 ppm. LCMS (M + H)⁺: 277. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₁H₂₁N₂O₄S 277.1222; found

277.1241.

1

solid, mp = 160−162 °C. H NMR (400 MHz, DMSO-d₆): δ 10.41

(br s, 2H), 3.95 (d, J = 14.3 Hz, 1H), 3.71 (br s, 1H), 3.65 (d, J = 14.4

Hz, 1H), 3.55−3.30 (m, 4H), 3.30−3.19 (m, 1H), 2.20−1.99 (m,

2H), 1.97−1.84 (m, 1H), 1.86−1.70 (m, 1H) ppm. ¹³C{¹H} NMR

(151 MHz, DMSO-d₆): δ 123.4 (q, J = 282.6 Hz), 70.0 (q, J = 26.2

Hz), 50.5, 46.7, 44.2, 40.7, 19.0 ppm. ¹⁹F{¹H} NMR (376 MHz,

DMSO-d₆): δ −65.9 (s) ppm. LCMS (M + H)⁺: 244. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₈H₁₃F₃NO₂S 244.0619; found

244.0610.

tert-Butyl (Octahydro-3aH-isoindol-3a-yl)carbamate (24d). Gen-

eral procedure G. Yield: 6.36 g, 0.0265 mol, 53%, white solid, mp =

91−92 °C. ¹H NMR (400 MHz, CDCl₃): δ 4.70 (s, 1H), 3.15 (d, J =

11.4 Hz, 1H), 3.09 (dd, J = 10.6, 7.6 Hz, 1H), 2.99 (d, J = 11.3 Hz,

1H), 2.78 (dd, J = 10.6, 6.6 Hz, 1H), 2.42 (br s, 1H), 2.14 (br s, 1H),

1.98 (br s, 1H), 1.78−1.41 (m, 7H), 1.40 (s, 9H) ppm. ¹³C{¹H}

NMR (126 MHz, CDCl₃): δ 154.8, 79.1, 60.5, 55.8, 49.7, 43.1, 29.6,

28.5, 25.7, 22.2, 22.1 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₁₃H₂₅N₂O₂241.1916; found 241.1902.

General procedure G for synthesis of 2d, 6d, 7d, 23d−25d,

28d, and 29d. See 2d as an example. Scale: 0.05 mol.

tert-Butyl (3-Azabicyclo[3.2.0]heptan-1-yl)carbamate (2d). To a

solution of 2a (12.25 g, 0.05 mol, 1.0 equiv) in MeOH (100 mL) was

added NaOH (4.00 g, 0.1 mol, 2.0 equiv). The solution was stirred at

rt overnight. The solution was concentrated under reduced pressure.

The residue was washed with methyl tert-butyl ether (2 × 50 mL) and

then acidiﬁed with 1 M HCl to pH ∼ 4. The solution was extracted

with EtOAc (3 × 100 mL). The combined fractions were washed with

brine (1 × 100 mL), dried over Na₂SO₄, ﬁltered, and concentrated

under reduced pressure.The crude product was dissolved in t-BuOH

(150 mL), and Et₃N (7.6 mL, 0.055 mol, 1.1 equiv) was added. The

solution was heated to boiling, and (PhO)₂PON₃(13.80 g, 0.05 mol,

1.0 equiv) was added dropwise. The solution was heated at reﬂux in

an oil bath with a thermocouple for 5 h. After heating was stopped,

the mixture was concentrated under reduced pressure, and the residue

was dissolved in methyl tert-butyl ether (200 mL). The solution was

washed with saturated solution of NaHCO₃(1 × 100 mL). The

aqueous layer was additionally extracted with methyl tert-butyl ether

(1 × 100 mL). The combined organic layers were dried over Na₂SO₄,

ﬁltered and concentrated under reduced pressure. The residue was

dissolved in MeOH (100 mL) and Pd/C (10%), (1.00 g) was added

to the solution. The mixture was hydrogenated under a rubber ball

ﬁlled with H₂at rt for 1 d. Pd/C was ﬁltered, and the reaction mixture

was concentrated under reduced pressure to give the desired product

tert-Butyl (6,6-Diﬂuorooctahydro-3aH-isoindol-3a-yl)carbamate

(25d). General procedure G. Yield: 7.31 g, 0.0265 mol, 53%, yellow

oil. ¹H NMR (400 MHz, DMSO-d₆): δ 6.92 (s, 1H), 3.31 (br s, 1H),

3.02 (d, J = 11.3 Hz, 1H), 2.96−2.86 (m, 1H), 2.80 (d, J = 11.3 Hz,

1H), 2.65−2.56 (m, 1H), 2.41−2.29 (m, 1H), 2.19−2.05 (m, 2H),

1.90−1.70 (m, 4H), 1.38 (s, 9H) ppm. ¹³C{¹H} NMR (151 MHz,

DMSO-d₆): δ 154.6, 124.2 (t, J = 240.2 Hz), 77.6, 58.8, 55.2, 49.1,

41.1, 31.9 (t, J = 22.7 Hz), 29.5 (t, J = 23.9 Hz), 28.2, 25.6 ppm.

¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ −89.60 − −92.26 (m, 2F)

ppm. LCMS (M + H)⁺: 277. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₁₃H₂₃F₂N₂O₂277.1728; found 277.1720.

tert-Butyl (Hexahydropyrano[3,4-c]pyrrol-7a(1H)-yl)carbamate

(28d). General procedure G. Yield: 6.41 g, 0.0265 mol, 53%, white

solid, mp = 100−101 °C. ¹H NMR (400 MHz, CDCl₃): δ 4.77 (br s,

1H), 3.70−3.51 (m, 4H), 3.24−3.05 (m, 3H), 2.93 (dd, J = 10.8, 7.6

Hz, 1H), 2.19 (br s, 1H), 2.13−1.99 (m, 2H), 1.98−1.83 (m, 1H),

1.41 (s, 9H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 154.8, 79.7,

65.3, 64.4, 57.7, 56.3, 47.1, 43.6, 30.2, 28.5 ppm. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₁₂H₂₃N₂O₃243.1709; found 243.1726.

tert-Butyl (Hexahydropyrano[3,4-c]pyrrol-3a(4H)-yl)carbamate

(29d). General procedure G. Yield: 4.48 g, 0.0185 mol, 37%, white

solid, mp = 133−134 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 6.82 (s,

1H), 3.70 (d, J = 11.6 Hz, 1H), 3.61−3.48 (m, 2H), 3.47−3.32 (m,

1H), 3.23 (br s, 1H), 3.03−2.94 (m, 2H), 2.85 (d, J = 11.4 Hz, 1H),

2.65 (dd, J = 10.3, 5.3 Hz, 1H), 2.24 (br s, 1H), 1.81−1.69 (m, 1H),

1.37 (s, 9H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 154.7,

77.6, 67.4, 64.3, 58.4, 52.7, 49.1, 28.2, 25.1 ppm. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₁₂H₂₃N₂O₃243.1709; found 243.1702.

General Procedure H for Synthesis of 2e, 6e, 7e, 9e, 10e,

12e, 14e, 24e, 26e, 31e, and 32e. See 2e as an example. Scale:

0.05 mol. Note: Amines 7e, 12e, 26e, and 32e were treated with 1 M

HCl in dioxane, and the precipitate was ﬁltered oﬀ to obtain amines

hydrochlorides.

1

as a white solid, mp = 112−113 °C. Yield: 4.3 g, 0.02 mol, 41%. H

NMR (400 MHz, CDCl₃): δ 4.94 (br s, 1H), 3.06 (d, J = 11.2 Hz,

1H), 2.99 (dd, J = 11.1, 5.5 Hz, 1H), 2.80−2.72 (m, 2H), 2.37 (br s,

1H), 2.25−2.08 (m, 2H), 2.05−1.91 (m, 1H), 1.42 (s, 9H), 1.36−

1.26 (m, 1H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 154.8, 79.4,

62.6, 59.6, 53.8, 43.8, 30.6, 28.5, 19.4 ppm. HRMS (ESI-TOF) m/z:

[M + H]⁺calcd for C₁₁H₂₁N₂O₂213.1603; found 213.1579.

tert-Butyl (Hexahydrocyclopenta[c]pyrrol-3a(1H)-yl)carbamate

(6d). General procedure G. Yield: 4.97 g, 0.022 mol, 44%, white oil.

¹H NMR (400 MHz, CDCl₃): δ 4.87 (br s, 1H), 3.36−3.10 (m, 2H),

2.76 (d, J = 11.8 Hz, 1H), 2.52−2.39 (m, 1H), 2.35 (br s, 1H), 2.20

(br s, 1H), 1.97−1.74 (m, 3H), 1.72−1.51 (m, 2H), 1.41 (s, 9H),

1.36−1.28 (m, 1H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ

155.2, 79.2, 72.3, 69.4, 60.6, 54.8, 52.4, 39.4, 31.8, 28.6, 25.8 ppm.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₂H₂₃N₂O₂227.1760;

found 227.1751.

3-Azabicyclo[3.2.0]heptan-1-yl)methanol (2e). A solution of 2a

(12.25 g, 0.05 mol, 1.0 equiv) in Et₂O (50 mL) was added dropwise

to a suspension of LiAlH₄(1.20 g, 0.03 mol, 0.6 equiv) in (100 mL) at

0−10 °C. Then the reaction mixture was warmed to rt and allowed to

P

https://doi.org/10.1021/acs.joc.1c01327

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

stir overnight. The mixture was quenched with water (1.1 mL, 0.06

mol, 1.2 equiv) and an aq solution of NaOH (4.80 g, 0.12 mol, 2.4

equiv). The mixture was ﬁltered through a thick pad of Na₂SO₄. The

solid residue was washed with hot THF (100 mL). The ﬁltrated was

concentrated. The crude product was dissolved in MeOH (100 mL),

and Pd/C (10%), (1.00 g) was added to the solution. The mixture

was hydrogenated under a rubber ball ﬁlled with H₂overnight at rt.

Pd/C was ﬁltered, and the reaction mixture was concentrated under

reduced pressure to give the desired product as a white gum. Yield:

4.51 g, 0.036 mol, 71%. ¹H NMR (400 MHz, CDCl₃): δ 3.66 (d, J =

10.9 Hz, 1H), 3.58 (d, J = 10.8 Hz, 1H), 3.16 (br s, 2H), 2.89−2.71

(m, 3H), 2.60 (d, J = 11.3 Hz, 1H), 2.52−2.42 (m, 1H), 2.18−1.88

(m, 2H), 1.73−1.54 (m, 1H), 1.48−1.33 (m, 1H) ppm. ¹³C{¹H}

NMR (101 MHz, CDCl₃): δ 66.8, 56.8, 54.5, 51.4, 40.2, 25.9, 20.8

ppm. LCMS (M + H)⁺: 128. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₇H₁₄NO 128.1075; found 128.1061.

27.2, 25.3, 22.2, 21.5 ppm. LCMS (M + H)⁺: 156. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₉H₁₈NO 156.1388; found 156.1380.

Hexahydropyrano[2,3-c]pyrrol-4a(2H)-yl)methanol Hydrochlor-

ide (26e). To a mixture of 26a (5.22 g, 19.0 mmol) in THF (100 mL)

and ethanol (25 mL) was added NaBH₄(2.17 g, 57.4 mmol, 3 equiv)

followed by addition of LiCl (2.43 g, 58.6 mmol, 3 equiv) at 0 °C.

The mixture was stirred at room temperature for 12 h and quenched

with saturated aq NH₄Cl (50 mL), and the pH value of the reaction

mixture was adjusted to 9 by adding 1 M aq NaOH. The reaction

mixture was extracted with CH₂Cl₂(3 × 150 mL). The combined

organic phase was dried over Na₂SO₄and concentrated under

reduced pressure. The crude product was dissolved in MeOH (50

mL) and 10% Pd/C (500 mg) was added to the solution. The mixture

was hydrogenated in an autoclave at 10 atm (H₂), 50 °C during 15 h.

The catalyst was ﬁltered oﬀ, and the reaction mixture was

concentrated under reduced pressure. The residue was dissolved in

dioxane (50 mL), and an excess of 1 M HCl in dioxane was added.

The reaction mixture was evaporated under vacuum to provide

product 26e as a yellow gum. Yield: 2.61 g, 13.5 mmol, 71%. ¹H NMR

(400 MHz, D₂O): δ 4.04 (d, J = 3.5 Hz, 1H), 3.95−3.87 (m, 1H),

3.61 (dd, J = 13.0, 3.3 Hz, 1H), 3.44 (s, 2H), 3.44−3.18 (m, 4H),

1.87−1.38 (m, 4H) ppm. ¹³C{¹H} NMR (126 MHz, D₂O): δ 78.2,

65.9, 65.7, 51.3, 46.9, 45.5, 23.0, 19.7 ppm. LCMS (M + H)⁺: 158.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₈H₁₆NO₂158.1181;

found 158.1177.

Hexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methanol (6e). General

1

procedure H. Yield: 5.36 g, 0.038 mol, 76%, yellow gum. H NMR

(400 MHz, DMSO-d₆): δ 3.27 (d, J = 10.3 Hz, 1H), 3.23 (d, J = 10.3

Hz, 1H), 2.88 (dd, J = 10.7, 7.9 Hz, 1H), 2.73 (d, J = 10.9 Hz, 1H),

2.32 (d, J = 11.2 Hz, 1H), 2.30−2.24 (m, 1H), 2.02−1.91 (m, 1H),

1.67−1.38 (m, 4H), 1.35−1.19 (m, 2H) ppm. ¹³C{¹H} NMR (151

MHz, DMSO-d₆): δ 67.3, 57.4, 57.3, 54.5, 35.2, 32.1, 25.5 ppm.

GCMS (M): 141. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₈H₁₆NO 142.1232; found 142.1238.

5-Methyloctahydro-7aH-pyrrolo[3,4-c]pyridin-7a-yl)methanol

6a-Fluorohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)methanol

Dihydrochloride (32e). General procedure H. Yield: 5.26 g, 0.026

Hydrochloride (7e). General procedure H. Yield: 7.13 g, 0.037 mol,

1

mol, 51%, white solid, mp = 192−193 °C. H NMR (400 MHz,

73%, white solid, mp = 105−106 °C. H NMR (400 MHz, DMSO-

D₂O): δ 3.83−3.11 (m, 10H), 2.94, 2.92 (2 × s, 3H), 2.89−2.71 (m,

2H), 2.16−1.85 (m, 2H) ppm. ¹³C{¹H} NMR (151 MHz, D₂O): δ

66.0, 61.4, 52.9, 52.5, 49.8, 49.0, 48.0, 46.9, 45.8, 43.3, 43.1, 43.0,

41.5, 36.8, 35.7, 24.1, 23.7 ppm. LCMS (M + H)⁺: 171. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₉H₁₉N₂O 171.1497; found

171.1476.

d₆): δ 9.96 (br s, 1H), 9.65 (br s, 1H), 4.56 (br s, 1H), 3.57−3.26 (m,

5H), 3.02−2.87 (m, 1H), 2.22−2.05 (m, 1H), 1.99−1.83 (m, 1H),

1.80−1.66 (m, 2H), 1.66−1.58 (m, 2H) ppm. ¹³C{¹H} NMR (126

MHz, DMSO-d₆): δ 109.6 (d, J = 196.4 Hz), 61.9 (d, J = 14.3 Hz),

55.8 (d, J = 17.3 Hz), 53.8 (d, J = 32.5 Hz), 52.5, 35.7 (d, J = 24.3

Hz), 33.0, 21.6 (d, J = 5.7 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz,

DMSO-d₆): δ −159.8 (s) ppm. LCMS (M + H)⁺: 160. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₈H₁₅FNO 160.1138; found

160.1145.

tert-Butyl (Hexahydro-6aH-furo[2,3-c]pyrrol-6a-yl)methyl)-

carbamate Hydrochloride (15f). A solution 15a (11.40 g, 0.05

mol, 1.0 equiv) in 200 mL of MeOH−NH₃(17%) was reduced in

autoclave with Raney nickel at 50 atm, 8 h. The mixture was ﬁltered

and concentrated under reduced pressure. The resulting amine was

dissolved in EtOAc (150 mL) and triturated with 5 M HCl in

dioxane. The solid residue was dissolved in CH₂Cl₂(200 mL), and

Et₃N (10.10 g, 0.1 mol, 2.0 equiv) was added to the mixture. Then

Boc₂O (10.90 g, 0.05 mol, 1.0 equiv) in CH₂Cl₂(20 mL) was added

dropwise at rt (the mixture can be cooled in a water bath). The

solution was stirred overnight at rt. The mixture was washed with 0.5

M HCl (1 time), water (1 time), and brine and dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure. The oily product

was dissolved in MeOH (100 mL), and Pd/C (10%), (1.00 g) was

added to the solution. The mixture was hydrogenated under a rubber

ball ﬁlled with H₂overnight at rt. Pd/C was ﬁltered, and the reaction

mixture was concentrated under reduced pressure. The residue was

dissolved in EtOAc (100 mL), and 1 M HCl in EtOAc (100 mL) was

added dropwise. The mixture was stirred for 0.5 h and ﬁltered. Yield:

(Tetrahydro-1H-furo[3,4-c]pyrrol-3a(3H)-yl)methanol (10e).

General procedure H. Yield: 4.58 g, 0.032 mol, 64%, white solid,

1

mp = 89−90 °C. H NMR (400 MHz, CDCl₃): δ 3.87 (dd, J = 8.8,

7.5 Hz, 1H), 3.67 (t, J = 8.8 Hz, 1H), 3.64−3.51 (m, 4H), 3.11 (dd, J

= 11.0, 7.5 Hz, 1H), 2.98 (d, J = 11.1 Hz, 1H), 2.90 (br s, 2H), 2.80

(d, J = 11.1 Hz, 1H), 2.70 (dd, J = 11.1, 4.5 Hz, 1H), 2.46−2.36 (m,

1H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 76.2, 74.3, 66.6,

59.4, 56.2, 53.6, 48.8 ppm. LCMS (M + H)⁺: 144. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₇H₁₄NO₂144.1025; found 144.1031.

Hexahydro-6aH-furo[2,3-c]pyrrol-6a-yl)methanol Hydrochloride

(12e). General procedure H. Yield: 5.96 g, 0.031 mol, 61%, orange

1

gum. H NMR (400 MHz, D₂O): δ 4.05 (dd, J = 14.9, 7.6 Hz, 1H),

3.93 (dd, J = 15.5, 7.2 Hz, 1H), 3.72 (d, J = 12.1 Hz, 1H), 3.67 (d, J =

12.1 Hz, 1H), 3.61−3.49 (m, 1H), 3.45 (d, J = 12.8 Hz, 1H), 3.37 (d,

J = 12.8 Hz, 1H), 3.31 (dd, J = 12.3, 4.3 Hz, 1H), 3.05−2.87 (m, 1H),

2.41−2.22 (m, 1H), 1.96−1.82 (m, 1H) ppm. ¹³C{¹H} NMR (151

MHz, D₂O): δ 92.5, 68.1, 62.6 52.6, 51.0, 43.0, 31.5 ppm. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₇H₁₄NO₂144.1025; found

144.1016.

1

8.91 g, 0.032 mol, 64%, white solid, mp = 182−183 °C. H NMR

(400 MHz, DMSO-d₆): δ 9.81 (br s, 1H), 9.46 (br s, 1H), 3.98−3.88

(m, 1H), 3.80−3.70 (m, 1H), 3.35 (s, 1H), 3.32−3.24 (m, 1H),

3.20−3.08 (m, 4H), 3.03 (dd, J = 12.0, 4.4 Hz, 1H), 2.83−2.71 (m,

1H), 2.14−2.01 (m, 1H), 1.91−1.80 (m, 1H), 1.38 (s, 9H) ppm.

¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 156.1, 92.1, 78.0, 67.3, 52.1,

Hexahydropyrrolo[3,4-c]pyrrol-3a(1H)-yl)methanol (14e). Gen-

eral procedure H. Yield: 5.75 g, 0.041 mol, 81%, white solid, mp =

1

63−64 °C. H NMR (400 MHz, CDCl₃): δ 3.57−3.42 (m, 2H),

49.9, 43.3, 43.0, 31.3, 28.2 ppm. LCMS (M + H)⁺: 243. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₂H₂₃N₂O₃243.1709; found

243.1718.

3.09−3.02 (m, 2H), 2.98 (br s, 2H), 2.89−2.85 (m, 2H), 2.72−2.63

(m, 2H), 2.64−2.52 (m, 2H), 2.36−2.21 (m, 1H) ppm. ¹³C{¹H}

NMR (151 MHz, CDCl₃): δ 67.7, 67.6, 58.8, 58.7, 56.4, 56.4, 53.7,

48.7, 48.6 ppm. LCMS (M + H)⁺: 143. HRMS (ESI-TOF) m/z: [M

+ H]⁺calcd for C₇H₁₅N₂O 143.1184; found 143.1169.

tert-Butyl (Hexahydropyrano[3,4-c]pyrrol-7a(1H)-yl)methyl)-

carbamate (27f). The same procedure as for 15f was applied. The

product was obtained as a free base. HCl in EtOAc was not added at

the end. Yield: 8.70 g, 0.034 mol, 68%, white solid, mp = 82−83 °C.

¹H NMR (400 MHz, DMSO-d₆): δ 3.60−3.41 (m, 4H), 3.28−3.13

(m, 2H), 3.01 (dd, J = 13.8, 6.0 Hz, 2H), 2.85 (br s, 2H), 1.86 (br s,

1H), 1.77 (br s, 2H), 1.61−1.49 (m, 1H), 1.37 (s, 9H) ppm. ¹³C{¹H}

NMR (101 MHz, DMSO-d₆): δ 156.5, 78.1, 63.3, 52.8, 45.3, 42.9,

Octahydro-3aH-isoindol-3a-yl)methanol (24e). General proce-

1

dure H. Yield: 6.43 g, 0.042 mol, 83%, white gum. H NMR (400

MHz, DMSO-d₆): δ 3.36 (d, J = 10.6 Hz, 1H), 3.13 (d, J = 10.6 Hz,

1H), 2.86 (dd, J = 10.1, 7.6 Hz, 1H), 2.63 (dd, J = 10.1, 6.6 Hz, 1H),

2.54 (br s, 2H), 1.76−1.69 (m, 1H), 1.54−1.17 (m, 9H) ppm.

¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 65.7, 54.5, 50.2, 45.2, 38.8,

Q

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28.3, 27.1 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₁₃H₂₅N₂O₃257.1865; found 257.1860.

chromatography (hexane/EtOAc/Et₃N = 1:1:0.2). Yield: 19.90 g,

0.084 mol, 84%, white solid. mp = 76−77 °C. H NMR (500 MHz,

1

3a-(Methoxymethyl)hexahydro-2H-furo[2,3-c]pyrrole Hydro-

chloride (9g). Compound 9e (2.20 g, 0.014 mol, 1.0 equiv; 9e was

obtained from 9a following the same protocol that was used in the

transformation 26a → 26e) was dissolved in CH₂Cl₂(50 mL) and

Et₃N (1.56 g, 0.015 mol, 1.1 equiv) was added to the mixture. Then

Boc₂O (3.36 g, 0.15 mol, 1.1 equiv) in CH₂Cl₂(10 mL) was added

dropwise at rt. The solution was stirred overnight at rt. The mixture

was washed with 0.5 M HCl (1 × 10 mL), water (1 × 10 mL), brine

(1 × 20 mL) and dried over Na₂SO₄, ﬁltered and concentrated under

reduced pressure. The crude product was dissolved in THF (100 mL)

and NaH (60% in oil, 1.12 g, 0.028 mol, 2 equiv) was added. Then

MeI (5.96 g, 0.42 mol, 3.0 equiv) was added dropwise at 0 °C. The

mixture was stirred overnight and quenched with water (10 mL),

diluted with EtOAc and water. The organic layer was separated and

the aqueous was extracted with EtOAc (2 × 50 mL). The combined

organic layers were washed with brine (2 × 50 mL), dried over

Na₂SO₄, ﬁltered and concentrated under reduced pressure. The

residue was dissolved in EtOAc (50 mL), and 1 M HCl in EtOAc (20

mL) was added dropwise. The mixture was stirred for 0.5 h and

ﬁltered. Yield: 1.92 g, 0.01 mol, 71%, yellow solid, mp = 72−73 °C.

¹H NMR (400 MHz, DMSO-d₆): δ 9.80 (br s, 1H), 9.43 (br s, 1H),

DMSO-d₆): δ 7.43−7.29 (m, 4H), 7.25 (t, J = 6.8 Hz, 1H), 4.65 (t, J

= 6.9 Hz, 1H), 4.31−4.19 (m, 1H), 3.87 (dd, J = 13.4, 5.8 Hz, 1H),

3.76 (d, J = 13.7 Hz, 1H), 3.65 (d, J = 13.7 Hz, 1H), 3.36−3.32 (m,

1H), 3.04−2.94 (m, 1H), 2.89 (d, J = 9.3 Hz, 1H), 2.36−2.21 (m,

2H) ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ 138.4, 128.2,

128.1, 126.9, 80.5, 70.2, 57.4, 57.2, 53.3, 24.2 ppm. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₂H₁₆NO₂S 238.0902; found

238.0928.

5-Benzylhexahydro-2H-thieno[2,3-c]pyrrole 1,1-Dioxide (46a).

Modiﬁed protocol C was used, 70 °C, 3 days. The residue was

puriﬁed by column chromatography (hexane/EtOAc/Et₃N = 1:1:0.2).

Yield: 18.07 g, 0.072 mol, 72%, yellow oil. ¹H NMR (500 MHz,

CDCl₃): δ 7.42−7.24 (m, 5H), 3.71 (d, J = 13.1 Hz, 1H), 3.57−3.44

(m, 2H), 3.34 (t, J = 7.7 Hz, 1H), 3.22−3.08 (m, 2H), 3.08−2.97 (m,

1H), 2.71 (d, J = 9.1 Hz, 1H), 2.57−2.45 (m, 2H), 2.41−2.27 (m,

1H), 2.07−1.93 (m, 1H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ

138.2, 128.5, 128.5, 127.3, 61.6, 60.9, 59.0, 56.0, 50.0, 39.5, 27.4 ppm.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₃H₁₈NO₂S 252.1058;

found 252.1065.

6-Benzyloctahydrothiopyrano[2,3-c]pyrrole 1,1-Dioxide (47a).

Modiﬁed protocol C was used. The mixture was heated at 70 °C

for 48 h. Ca. 50% conversion was observed according to ¹H NMR. An

additional portion of 1 (35.55 g, 0.15 mol, 1.5 equiv) was added. The

mixture was heated for 48 h. The residue was puriﬁed by column

chromatography (hexane/EtOAc/Et₃N = 1:1:0.2). Yield: 18.55 g,

0.07 mol, 70%, yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 7.36−7.25

(m, 5H), 3.75 (d, J = 2.2 Hz, 2H), 3.59−3.47 (m, 1H), 3.23 (dd, J =

11.2, 6.6 Hz, 1H), 3.15−2.99 (m, 2H), 2.99−2.89 (m, 1H), 2.84−

2.68 (m, 3H), 2.22−2.00 (m, 2H), 1.89−1.71 (m, 2H) ppm. ¹³C{¹H}

NMR (126 MHz, CDCl₃): δ 138.8, 128.7, 128.5, 127.3, 61.7, 59.9,

58.2, 51.3, 48.9, 39.7, 24.9, 21.7 ppm. HRMS (ESI-TOF) m/z: [M +

H]⁺calcd for C₁₄H₂₀NO₂S 266.1215; found 266.1202.

4.21 (d, J = 4.4 Hz, 1H), 3.94 (dd, J = 14.8, 6.3 Hz, 1H), 3.66 (dd, J =

15.8, 7.2 Hz, 1H), 3.43 (s, 2H), 3.34 (s, 1H), 3.30 (s, 3H), 3.29−3.23

(m, 1H), 3.16−3.10 (m, 2H), 1.97−1.88 (m, 2H) ppm. ¹³C{¹H}

NMR (126 MHz, DMSO-d₆): δ 83.9, 74.4, 67.5, 58.7, 54.6, 51.9, 50.5,

35.5 ppm. LCMS (M + H)⁺: 158. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₈H₁₆NO₂158.1181; found 158.1175.

6a-(Methoxymethyl)hexahydro-2H-furo[2,3-c]pyrrole Hydro-

chloride (12g). The same procedure as for 9g was used. Yield: 1.20

1

g, 0.006 mol, 44%, yellow solid, mp = 139−140 °C. H NMR (400

MHz, DMSO-d₆): δ 9.77 (br s, 1H), 9.42 (br s, 1H), 3.92 (dd, J =

13.7, 6.8 Hz, 1H), 3.75 (dd, J = 13.5, 6.7 Hz, 1H), 3.42 (s, 2H), 3.34

(s, 1H), 3.30 (s, 3H), 3.15 (s, 2H), 3.11−3.02 (m, 1H), 2.81−2.68

(m, 1H), 2.15−2.00 (m, 1H), 1.87−1.77 (m, 1H) ppm. ¹³C{¹H}

NMR (126 MHz, DMSO-d₆): δ 91.3, 73.5, 67.6, 58.9, 51.8, 49.8, 43.5,

31.4 ppm. LCMS (M + H)⁺: 158. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₈H₁₆NO₂158.1181; found 158.1175.

6-Thia-3-azabicyclo[3.2.0]heptane 6,6-Dioxide (45c). General

procedure F. Yield: 14.06 g, 0.095 mol, 95%, white solid. mp =

1

85−86 °C. H NMR (400 MHz, DMSO-d₆): δ 4.61 (t, J = 7.4 Hz,

1H), 4.27−4.15 (m, 1H), 3.80 (dd, J = 13.6, 6.0 Hz, 1H), 3.42 (d, J =

13.1 Hz, 1H), 3.00−2.92 (m, 2H), 2.79 (dd, J = 13.1, 7.2 Hz, 2H),

2.61 (dd, J = 11.4, 5.3 Hz, 1H) ppm. ¹³C{¹H} NMR (126 MHz,

DMSO-d₆): δ 82.4, 68.7, 52.1, 48.5, 26.0 ppm. LCMS (M + H)⁺: 148.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₅H₁₀NO₂S 148.0432;

found 148.0426.

5-(Tetrahydro-1H-furo[3,4-c]pyrrol-3a(3H)-yl)-1,3,4-oxadiazol-2-

amine Hydrochloride (10h). Semicarbazide hydrochloride (4.46 g,

0.04 mol, 2.0 equiv) was slowly added to a solution of 10b (5.14 g,

0.02 mol, 1.0 equiv) in phosphorus oxychloride (30 mL). The mixture

was stirred at room temperature overnight and then poured into

crushed ice (100 g). A viscous solid was decanted from the aqueous

layer, and then the aqueous layer was adjusted to pH 4 to 5 with

sodium hydroxide (50% aqueous solution). The resulting precipitate

was ﬁltered. The residue was dissolved in 5 M HCl in dioxane, and

the precipitate was ﬁltered and dried. Yield: 4.10 g, 0.0176 mol, 88%,

Hexahydro-2H-thieno[2,3-c]pyrrole 1,1-Dioxide Hydrochloride

(46c). General procedure F. 1 M HCl in dioxane (50 mL) was

added to the product, and the formed hydrochloride was ﬁltered oﬀ.

1

Yield: 17.78 g, 0.09 mol, 90%, white solid, mp = 226−227 °C. H

NMR (400 MHz, DMSO-d₆): δ 9.88 (s, 2H), 3.84−3.74 (m, 1H),

3.65−3.48 (m, 2H), 3.43−3.29 (m, 3H), 3.28−3.18 (m, 1H), 3.11 (q,

J = 9.2 Hz, 1H), 2.29−2.13 (m, 1H), 2.03−1.89 (m, 1H) ppm.

¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 60.1, 49.4, 49.1, 44.9, 40.2,

1

white solid, mp = 219−221 °C. H NMR (400 MHz, DMSO-d₆): δ

10.17 (br s, 1H), 8.55 (br s, 1H), 6.73 (br s, 2H), 4.06 (d, J = 9.5 Hz,

1H), 3.99 (d, J = 9.5 Hz, 1H), 3.93 (dd, J = 9.1, 7.2 Hz, 1H), 3.84

(dd, J = 9.3, 4.4 Hz, 1H), 3.69 (dd, J = 12.0, 6.0 Hz, 1H), 3.53−3.45

(m, 1H), 3.45−3.33 (m, 2H), 3.19 (dd, J = 10.1, 3.9 Hz, 1H) ppm.

¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 161.9, 158.9, 75.1, 72.5,

23.4 ppm. LCMS (M + H)⁺: 162. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₆H₁₂NO₂S 162.0589; found 162.0572.

Octahydrothiopyrano[2,3-c]pyrrole 1,1-Dioxide Hydrochloride

(47c). General procedure F. 1 M HCl in dioxane (50 mL) was

added to the product, and the formed hydrochloride was ﬁltered oﬀ.

53.1, 51.2, 49.1, 48.5 ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₈H₁₃N₄O₂197.1039; found 197.1016.

1

Yield: 19.46 g, 0.092 mol, 92%, white solid, mp = 228−229 °C. H

tert-Butyl 3-benzyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxy-

late (42a). Protocol C was applied. Scale: 0.01 mol. Yield: 350 mg,

1.2 mmol, 12%, pale yellow oil. Puriﬁed by column chromatography

twice (hexane/ methyl tert-butyl ether = 7:3), CHCl₃:CH₃CN

NMR (400 MHz, DMSO-d₆): δ 9.87 (br s, 2H), 3.99−3.85 (m, 1H),

3.61 (dd, J = 13.0, 5.2 Hz, 1H), 3.50 (dd, J = 12.9, 8.0 Hz, 1H), 3.29−

3.11 (m, 4H), 2.86−2.74 (m, 1H), 2.09−1.85 (m, 2H), 1.85−1.60

(m, 2H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 59.6, 48.5,

47.2, 42.0, 39.0, 21.4, 20.5 ppm. LCMS (M + H)⁺: 176. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd C₇H₁₄NO₂S 176.0745; found 176.0732.

tert-Butyl 3,6-Diazabicyclo[3.2.0]heptane-6-carboxylate Hydro-

chloride (50). Compound 42a (200 mg, 1 mmol) was dissolved in

MeOH (50 mL), and Pd/C (10%) (10 mg) was added to the

solution. The mixture was hydrogenated under a rubber ball ﬁlled

with H₂overnight at rt. Pd/C was ﬁltered, and the reaction mixture

was concentrated under reduced pressure. The residue was dissolved

in EtOAc (1 mL), 1 M HCl EtOAc (1 mL) was added dropwise, and

1

(85:15). H NMR (400 MHz, DMSO-d₆): δ 7.54−6.97 (m, 5H),

4.53 (m, 1H), 3.91 (m, 1H), 3.56 (m, 3H), 3.19 (m, 1H), 2.87 (m,

2H), 2.07 (m, 1H), 1.96 (m, 1H), 1.33 (2 × s, 9H). ¹³C{¹H} NMR of

both Boc-rotamers (126 MHz, CDCl₃): δ 155.2, 139.1, 128.7, 128.3,

127.0, 79.2, 65.9, 65.0, 59.0, 57.9, 57.5, 57.3, 57.0, 54.0, 52.6, 33.18,

33.1, 28.6 ppm LCMS (M + H)⁺: 289. Anal. Calcd for C₁₇H₂₄N₂O₂:

C, 70.80; H, 8.39; N, 9.71. Found: C, 71.13; H, 8.66; N, 9.44.

3-Benzyl-6-thia-3-azabicyclo[3.2.0]heptane 6,6-Dioxide (45a).

Protocol A was used. The residue was puriﬁed by column

R

https://doi.org/10.1021/acs.joc.1c01327

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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Article

the precipitate was ﬁltered and dried. Yield: 222 mg, 0.95 mmol, 95%,

Vitalii A. Reznik − Enamine Ltd., 02094 Kyiv, Ukraine,

www.enamine.net

Bohdan A. Chalyk − Enamine Ltd., 02094 Kyiv, Ukraine,

www.enamine.net; Institute of Organic Chemistry,

National Academy of Sciences of Ukraine, 02094 Kyiv,

Ukraine

Vladimir S. Yarmolchuk − Enamine Ltd., 02094 Kyiv,

Ukraine, www.enamine.net

Eduard B. Rusanov − Institute of Organic Chemistry,

National Academy of Sciences of Ukraine, 02094 Kyiv,

Ukraine

1

white solid, mp = 158−160 °C. H NMR (500 MHz, DMSO-d₆): δ

8.74 (br s, 2H), 4.98−4.52 (m, 1H), 3.98−3.76 (m, 1H), 3.61 (m,

1H), 3.49−3.25 (m, 2H), 3.25−2.76 (m, 3H), 1.32 (s, 9H) ppm.

¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ 154.9, 154.4, 79.5, 65.2,

64.3, 52.8, 51.5, 49.7, 49.4, 49.1, 32.9, 28.6 ppm. LCMS (M-Cl)⁻:

199. Anal. Calcd for C₁₀H₁₉ClN₂O₂: C, 51.17; H, 8.16; N, 11.93.

Found: C, 50.86; H, 8.41; N, 11.64.

tert-Butyl (3aS,7aS)-2-Benzyl-7a-(dimethylphosphoryl)-

octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (53a).³¹Proto-

1

col D was used. Yield: 314 mg, 0.8 mmol, 80%, yellow oil. H NMR

(400 MHz, CDCl₃): δ 7.34−7.19 (m, 5H), 3.87−3.39 (m, 5H), 3.18

(dd, J = 21.6, 14.0 Hz, 1H), 3.02−2.76 (m, 2H), 2.70−2.52 (m, 1H),

2.43−2.13 (m, 3H), 1.65 (d, J = 14.5 Hz, 1H), 1.54−1.35 (m, 15H)

ppm. ¹³C{¹H} NMR both Boc-rotamers (151 MHz, CDCl₃): δ 156.0,

155.7, 138.8, 138.7, 128.6, 128.50, 128.47, 127.3, 79.8, 79.7, 59.8,

58.2, 58.2, 57.8, 57.5, 41.3, 40.8, 39.6, 38.9, 38.8, 38.4, 38.3, 38.2,

38.1, 28.6, 28.6, 24.2, 24.0, 12.5 (m) ppm. ³¹P{¹H} NMR (162 MHz,

CDCl₃): δ 52.6, 52.5 ppm. LCMS (M + H)⁺: 393. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd C₂₁H₃₄N₂O₃P 393.2307; found 393.2301.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01327

Author Contributions

^†V.I.S., V.L.M., and P.V.M. contributed equally.

Notes

The authors declare no competing ﬁnancial interest.

ASSOCIATED CONTENT

■

ACKNOWLEDGMENTS

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01327.

We are grateful to Prof. A. Tolmachov and Enamine, Ltd. for

ﬁnancial support, Mr. Y. Yurov for help with synthesis, Dr. A.

Konovets for help with pK_ameasurements, and Mrs. I. Sadkova

for help with the preparation of the manuscript.

Copies of NMR spectra, pK_adetermination, and X-ray

crystallographic data (PDF)

REFERENCES

Accession Codes

■

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CCDC 2077600−2077602 contain the supplementary crys-

tallographic data for this paper. These data can be obtained

free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by

emailing data_request@ccdc.cam.ac.uk, or by contacting The

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION

■

Corresponding Author

Pavel K. Mykhailiuk − Enamine Ltd., 02094 Kyiv, Ukraine,

www.enamine.net; orcid.org/0000-0003-1821-9011;

Email: pavel.mykhailiuk@gmail.com

Authors

Vladimir I. Savych − Enamine Ltd., 02094 Kyiv, Ukraine,

www.enamine.net

Vladimir L. Mykhalchuk − Enamine Ltd., 02094 Kyiv,

Ukraine, www.enamine.net

Pavlo V. Melnychuk − Enamine Ltd., 02094 Kyiv, Ukraine,

www.enamine.net

Andrii O. Isakov − Enamine Ltd., 02094 Kyiv, Ukraine,

www.enamine.net

Taras Savchuk − Enamine Ltd., 02094 Kyiv, Ukraine,

www.enamine.net

Vadim M. Timoshenko − Institute of Organic Chemistry,

National Academy of Sciences of Ukraine, 02094 Kyiv,

Ukraine

Sergiy A. Siry − Institute of Organic Chemistry, National

Academy of Sciences of Ukraine, 02094 Kyiv, Ukraine

Sergiy O. Pavlenko − Enamine Ltd., 02094 Kyiv, Ukraine,

www.enamine.net

Dmytro V. Kovalenko − Enamine Ltd., 02094 Kyiv, Ukraine,

www.enamine.net

Oleksandr V. Hryshchuk − Enamine Ltd., 02094 Kyiv,

Ukraine, www.enamine.net

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U

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Bicyclic Pyrrolidines for Medicinal Chemistry via [3 + 2]-Cycloaddition

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