Fluorine-Labelled Spiro[3.3]heptane-Derived Building Blocks: Is Single Fluorine the Best?

European Journal of Organic Chemistry

Accepted Article

Title: Fluorine-labelled Spiro[3.3]heptane-Derived Building Blocks:

Is Single Fluorine the Best?

Authors: Andrii Malashchuk, Anton V. Chernykh, Alexey V. Dobrydnev,

and Oleksandr O Grygorenko

This manuscript has been accepted after peer review and appears as an

Accepted Article online prior to editing, proofing, and formal publication

of the final Version of Record (VoR). This work is currently citable by

using the Digital Object Identifier (DOI) given below. The VoR will be

published online in Early View as soon as possible and may be different

to this Accepted Article as a result of editing. Readers should obtain

the VoR from the journal website shown below when it is published

to ensure accuracy of information. The authors are responsible for the

content of this Accepted Article.

To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100804

Link to VoR: https://doi.org/10.1002/ejoc.202100804

01/2020

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Fluorine-labelled Spiro[3.3]heptane-Derived Building Blocks:

Is Single Fluorine the Best?

Andrii Malashchuk,^[a,b]Anton V. Chernykh,^[a,b]Alexey V. Dobrydnev,^[a,b]and

Oleksandr O. Grygorenko*^[a,b]

Dedicated to 130^thanniversary of Organic Chemistry Department, Chemical Faculty, Taras Shevchenko National University of Kyiv

[a]

[b]

A. Malashchuk, Dr. A. V. Chernykh, Dr. A. V. Dobrydnev, Prof. Dr. O. O. Grygorenko

Enamine Ltd. (www.enamine.net ),

Chervonotkatska Street 78, Kyiv 02094, Ukraine, Chervonotkatska Street 78, Kyiv 02094, Ukraine

A. Malashchuk, Dr. A. V. Chernykh, Dr. A. V. Dobrydnev, Prof. Dr. O. O. Grygorenko

Taras Shevchenko National University of Kyiv

Volodymyrska Street 60, Kyiv 01601, Ukraine

E-mail: gregor@univ.kiev.ua

Supporting information for this article is given via a link at the end of the document

Abstract: The reliable methodology for constructing 6-fluoro-

spiro[3.3]heptane scaffold is developed. A vast library of 2-mono-

and 2,2-difunctionallized 6-fluoro-spiro[3.3]heptane-derived building

blocks were obtained in a multigram scale (up to 302 g) though the

convergent synthetic strategy. This class of compounds was

designed for medicinal chemistry as fluorine-labelled con-

formationally restricted isosteres of cyclohexane framework. The

structure was confirmed by X-ray diffraction study and the physico-

chemical properties (acidity, lipophilicity and water solubility) were

characterized. Finally, the generation of virtual compound libraries

using the LLAMA software showed that the monofluorinated

spiro[3.3]heptane-derived building blocks demonstrated the highest

propensity to populate the lead-like chemical space as compared to

non- and difluorinated counterparts, as well as cyclohexane

derivatives, while retaining similar three-dimensionality features.

monofluorinated cycloalkane derivatives do not meet the above

requirements because of interconversion between isoenergetic

(or close in energy) conformers.^[18]Besides, their synthesis

requires specific approaches in order to control stereochemistry

as well as unique techniques for the separation of the

corresponding diastereomers. These obstacles could be

circumvented by exploiting the spirocyclic scaffolds^[19–22]that

have been proven to be 3D-shaped isosteres of cycloalkanes.

In this regard, spiro[3.3]heptane scaffold can be considered as a

close isostere and conformationally restricted surrogate of

cyclohexane motif (Figure 1, A).^[23]This is also true for the

heteroatom-substituted systems (Figure 1, B).^[24,25]Biological

evaluation of drug-like molecules bearing heteroatom-sub-

stituted azaspiro[3.3]heptane framework instead of piperidine,

piperazine, morpholine, or thiomorpholine units revealed

significantly improved pharmacological profile of the modified

compounds. Specifically, this allowed retaining biological activity

and increasing aqueous solubility, hydrophilicity, and metabolic

stability.^[24]

Introduction

Site-selective fluorine introduction has emerged as an important

tool not only in modern medicinal chemistry intended for

endowing the molecules with unique physiological properties

(e.g. altering the lipophilicity, protecting against oxidative

metabolism, functional group mimesis etc.)^[1–6]but also for the

preparation of fluorine-labelled building blocks widely used in

spectroscopic structural studies.^[7–9]For instance, incorporation

of ¹⁹F-labelled amino acids into membrane-active peptides

allows their deeper study under natural conditions in lipid

bilayers by solid-state ¹⁹F NMR spectroscopy technique.^[10–13]

An efficient ¹⁹F label must meet several criteria: (a) to be

conformationally constrained to place the ¹⁹F reporter in a well-

defined position; (b) to be compatible with the synthesis of the

target molecule; (c) not to change structure and function of the

target molecule.^[11]Meanwhile, introducing the fluorine atom

proximal to functional group into flexible building blocks can alter

the conformational preferences of the target system because of

the structural features contributing to a gauche effect between

these key moieties.^[14–17]This issue can be addressed with

conformationally rigid sp³-enriched building blocks bearing

fluorine atom (label) at the outward position. At the same time,

Figure 1. Spirocyclic isosteres of saturated carbo- and heterocyclic six-

membered rings

Taking into account all of the above, we propose 6-fluoro-

spiro[3.3]heptane scaffold as the conformationally rigid analogue

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of 4-fluorocyclohexane ring bearing definitely located fluorine

atom (label) at the outward position. An important feature of the

spirocyclic framework that also might be beneficial is attributed

to its (a)symmetry. While 1-substituted 4-fluorocyclohexanes are

often available as difficult-to-separate diastereomeric mix-

tures,^[26]2-(di)substituted 6-fluorospiro[3.3]heptanes exist as

enantiomeric pairs due to their axial chirality (Figure 1, C).

As an extension of our previous works on 5,5- and 6,6-

difluorinated spiro[3.3]heptane building blocks,^[27,28]herein we

report the results of our synthetic, physico-chemical, and

chemoinformatic studies on 2-substituted 6-fluorospiro[3.3]hep-

tanes, as well as the synthesis of a series of the corresponding

mono- and bifunctional building blocks derived from this scaffold.

To the best of our knowledge, this class of compounds have not

been presented in the literature. Therefore, we envisaged a

convergent synthetic strategy based on utilization of the key

intermediate – 1,1-bis(bromomethyl)-3-fluorocyclobutane (1).

The latter compound can be prepared in four steps from well-

documented diisopropyl 3-oxocyclobutane-1,1-dicarboxylate

(2).^[29–31]Following the convergent retrosynthetic strategy,

several 2,2-difunctionallized 6-fluorospiro[3.3]heptanes can be

prepared from 1, that in turn can be convenient common

precursors for a large series of 6-fluorospiro[3.3]heptane-derived

building blocks. (Scheme 1).

(76% yield), cyano ester 7 (72% yield), and ketone 8 (42% yield)

were obtained (Scheme 3). In turn, the latter compound was

subjected to NaBH₄-mediated reduction that afforded alcohol 9

in 94% yield.

Scheme 2. Synthesis of key intermediate 1

Scheme 3. Synthesis of 6-fluorospiro[3.3]heptane-derived common synthetic

precursors

Scheme 1. Retrosynthetic disconnection of 6-fluorospiro[3.3]heptane-derived

building blocks

With the set of these compounds in hands, we were able to

vastly expand the chemical space of available 2-(di)functionali-

zed 6-fluorospiro[3.3]heptane building blocks. At first, the exhau-

stive saponification of diester 6 gave corresponding dicarboxylic

acid 10 (95% yield), which was transformed into carboxylic acid

11 (94% yield) upon thermal decarboxylation in pyridine

(Scheme 4).

Results and Discussion

Following the above retrosynthetic plan, we subjected diisopro-

pyl 3-oxocyclobutane-1,1-dicarboxylate (2) to reduction with

NaBH₄and further deoxofluorination with Morph-DAST (Scheme

2). Thus obtained 3-fluorocyclobutane dicarboxylate 4 (60%

yield over two steps) was converted into the corresponding diol

5

(90% yield) upon the action of LiAlH₄. The next

deoxobromination under the modified Appel reaction conditions

afforded target dibromide 1 in 83% yield. Notably, nearly 500 g

of 1 could be obtained from a single run of the described

synthetic sequence.

Next, dibromo derivative 1 was used as 1,3-dielectrophile to

alkylate several functionalized active methylene compounds,

namely, diethyl malonate, ethyl cyanoacetate, and tosylmethyl

isocianide (TosMIC). Consequently, corresponding diester 6

Scheme 4. Synthesis of carboxylic acid 11

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Carboxylic acid 11 was an entry point to nearly all the

monofunctionalized building blocks described below. Thus,

following a modified Curtius protocol the corresponding N-Boc-

protected amine 12 was obtained in 77% yield (Scheme 5).

Further acid-promoted deprotection afforded amine hydro-

chloride 13 (83% yield) (Scheme 5). Alternatively, carboxylic

acid 11 was converted into amide 14 (89% yield); the following

LiAlH₄-promoted reduction gave adjacent homologous amine 15

that was also isolated as a hydrochloride in 73% yield.

into the corresponding trifluoroborates 21 (77% yield) and 22

(72% yield).

Scheme 7. Synthesis of trifluoroborate 21 and sulfonyl chloride 25

On the other hand, bromides 16 and 18 were susceptible to

nucleophilic substitution with KSAc to form the corresponding

thioacetates 23 (93% yield) and 24 (89% yield). The final-stage

oxidative chlorination under typical conditions (Cl₂, CH₂Cl₂, water,

0 C) provided homologous sulfonyl chlorides 25 (73% yield)

and 26 (74% yield) in a straightforward manner (Schemes 7 and

8).

Scheme 5. Synthesis of homologous amine hydrochlorides 13 and 15

In a similar way, carboxylic acid 11 was transformed into two

homologous bromides 16 and 18. The former one was obtained

in 71% yield adopting the Barton decarboxylative bromination

method. Meanwhile, the latter one was accessed via a modified

Appel deoxobromination of alcohol 17 in 83% yield, obtained

from 11 and LiAlH₄in 88% yield (Scheme 6).

Scheme 8. Synthesis of trifluoroborate 22 and sulfonyl chloride 26

Scheme 6. Synthesis of homologous bromides 16 and 18

The synthetic utility of alcohol 17 was also demonstrated by the

preparation of aldehyde 27 (85% yield) through the Swern

oxidation procedure and subsequent Seyferth–Gilbert homo-

logation with the Ohira–Bestmann reagent^[39,40]that gave alkyne

28, albeit in moderate yield (39%), partially due to the product

volatility (Scheme 9).

In their turn, bromides 16 and 18 pave the way to another

homologous series of supremely versatile organoboron and

organosulfur building blocks.^[32–38]In particular, pinacolborolane

functionality was installed through Cu(PPh₃)Br-catalyzed

reaction of above bromides with bis(pinacolato)diboron and

t-BuOLi (Schemes 7 and 8). Thus obtained pinacolates 19 and

20 (86% and 91% yields, respectively) were readily converted

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Scheme 9. The synthesis of aldehyde 27 and alkyne 28

Finally, synthesis of two homologous amino acids 29 and 30, as

well as a small set of their monoprotected derivatives was

succeeded. In this way, N-Boc-protected amino acid ester 32

(71% yield) resulted from Curtius rearrangement of monoester

31 (obtained from diester 6 in 77% yield, Scheme 10), whereas

its closest homologue 33 (84% yield) was provided by Raney Ni-

catalyzed hydrogenation of cyano ester 7 in the presence of

Boc₂O (Scheme 11). Further, they were both deprotected with

ethanolic HCl to give amino ester hydrochlorides 34 (88% yield,

Scheme 10) and 35 (92% yield, Scheme 11) as well as

saponified into the corresponding N-Boc-protected amino acids

36 (86% yield, Scheme 10) and 37 (87% yield, Scheme 11).

Ultimately, these Boc-protected amino acids 36 and 37 were

processed into target amino acids 29 (92% yield, Scheme 10)

and 30 (90% yield, Scheme 11) by simple refluxing in aqueous

media.

Scheme 11. Synthesis of amino acid 30, its monoprotected derivatives, and

amino alcohol 38

To further demonstrate the feasibility of creating advanced

fluorine-labelled spiro[3.3]heptane-derived building blocks for the

needs of bioorganic and medicinal chemistry, we have put some

efforts to the preparation of enantiomerically pure derivatives. To

our delight, chiral-stationary-phase HPLC separation of racemic

N-Boc-protected amino ester 32 afforded the corresponding

single enantiomers (Scheme 12). To establish their absolute

configuration, one of these products was treated with 2 M HCl in

1,4-dioxane and then subjected to slow crystallization from

EtOAc. According to the results of X-Ray diffraction study, (R)

configuration could be assigned to corresponding derivative

34H₂O (Figure 2). These derivatives are rare examples of

enantiopure compounds where the axial chirality is defined

merely by the H/F difference.^[41]

Scheme 12. Separation of enantimeric N-Boc-amino esters 32 (chiral axis is

shown by blue dotted line)

Scheme 10. Synthesis of amino acid 29 and its monoprotected derivatives

Apart from that, cyano ester 7 was a suitable precursor of amino

alcohol 38 that was isolated as hydrochloride in 52% yield after

LiAlH₄-mediated reduction procedure (Scheme 11).

Figure 2. Molecular structure of (R)-34H₂O according to X-ray diffraction study

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Physicochemical properties. With an eye of more integrated

study of the discussed building blocks, we evaluated the impact

of the fluorinated carbon chain at the C-6 position of the 2-functi-

onalized spiro[3.3]heptane scaffold on their physico-chemical

properties, particularly, acidity/basicity, lipophilicity, and aqueous

solubility. We have limited this part of the work with the study of

carboxylic acids 11, 39, 40 and amine hydrochlorides 13, 41, 42

(Figure 3).

Figure 3. Model building blocks used to study the physico-chemical properties

It was found that within the studied series, the pK_avalues varied

in an expected manner. Thus, subsequent introducing the

fluorine atoms increased acidity by 0.20 (11) and 0.04 (40) pK_a

units for the carboxylic acids, and by 0.40 (13) and 0.23 (42) for

the amine hydrochlorides as compared to their non-fluorinated

counterparts (Figure 4). Notably, the observed correlation did

not follow a general rule of thumb established previously for

acyclic fluorinated amines (pK_a~ –0.1 per each -F).^[42]Speci-

fically, each fluorine atom introduced into the spiro[3.3]heptane

scaffold exerted a stronger basicity-lowering effect, as much as

it was expected. This correlates with the results obtained for the

-fluorinates acyclic aliphatic amines (pK_a~ –0.3) and can be

explained by more efficient inductive transmission of electronic

polarization from the fluorine atoms to the amino group through

the rigid spirocyclic scaffold.

Scheme 13. Synthesis and aqueous solubility (S_W, 23 ºC) of model derivatives

43–48

Interestingly, within the series of anilides 43–45 and benzamides

46–48 the measured LogP values varied in a non-monotonic

manner. Thus, monofluorinated anilide 44 and its isomer 47

were characterized by the smallest logP values (2.69 and 2.39,

respectively), while their nonfluorinated counterparts 43 and 46

had almost identical values of logP (3.27 and 3.26, respectively).

The measured lipophilicity of gem-difluorinated representatives

45 and 48 showed the intermediate logP values (2.93 and 2.53,

respectively) within the studied series (Figure 5). In general,

these results correlate with the trends reported in the literature

for the acyclic counterparts.^[42]

Figure 4. Measured pK_avalues (23 C) for carboxylic acids 11, 39, 40 and

amine hydrochlorides 13, 41, 42

Figure 5. Measured LogP values (23 C) for benzamides 43–45 and anilides

46–48

To evaluate the effect of the fluorinated methylene unit on the

aqueous solubility and lipophilicity of 2-functionallized

spiro[3.3]heptane derivatives, carboxylic acids 11, 39, 40 were

converted into anilides 43–45, while amines 13, 41, 42 were

transformed into the corresponding benzamides 46–48 (Scheme

13).

Finally, aqueous solubility (S_w) within both the anilide and

benzamide series correlated with their hydrophilicity: introducing

the fluorine atoms increased the solubility in all cases (Scheme

13).

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Exit vector plot (EVP) analysis^[43–45]of mono- and difluorinated

spiro[3.3]-heptane scaffolds (simulated from X-Ray data

obtained for (R)-34) showed that exit vectors representing the

polar functional groups attached to the bicyclic ring system are

further from the “colinear” orientation for the case of

monofluorinated derivative (Figure 6). This is apparent from the

values of ₂angle which is larger for this derivative. Such

orientation might be one of the factors responsible for somewhat

higher polarity of the monofluorinated spiro[3.3]heptanes.

se as more and more features of the lead-likeness definition by

Churcher and co-workers^[49]are violated.

It was found that the library generated from 6-fluorospiro[3.3]-

heptane-derived building blocks had the lowest mean lead-

likeness penalty (LLP) among all the compound series studied

(Table 1). 92% and 53% of this library members fit the lead-like

chemical space as defined by “rule-of-four” (MW < 400,

LogP < 4)^[50]and rigorous Churcher’s rules (MW = 200…350,

LogP = –1…3),^[49]respectively (Figure 7, A). The three-dimen-

sionality of all the four libraries was similar, as illustrated by the

average Fsp³and plane of best fit (PBF) values (Table 1), as

well as principal moment of inertia (PMI) plot describing the

overall molecular shape (Figure 76, B).

Figure 6. (A) Definition of exit vector plot (EVP) parameters r, , ₁, and ₂

(B) Exit vector analysis of mono- and gem-difluorinated spiro[3.3]heptanes

Virtual library generation. To further explore the potential of

the synthesized compounds for medicinal chemistry, we have

evaluated the building blocks shown in Figure 3 and compared

them to the parent cyclohexane derivatives (i.e. cyclohexane-

carboxylic acid and cyclohexanamine) using a LLAMA tool

developed by Nelson and co-workers.^[46]The key feature of their

method is the so-called lead-likeness penalty (LLP) that

assesses the compound compliance with the lead-likeness

criteria according to its physico-chemical properties (i.e. heavy

(non-hydrogen) atom count, AlogP, number of aromatic rings,

and an undesirable functional group filter).^[47,48]The LLP values

start with zero (for the ‘perfect’ lead-like compounds) and increa-

Table 1. LLAMA analysis of fluorinated spiro[3.3]heptane scaffolds and their

non-fluorinated analogues

Building blocks^[a]

Library

size

Lead-likeness

penalty

Fsp^3[b,c]Plane of best

fit (PBF),

[b,c]

(LLP)^[b]

Å

285

182

1.58

1.48

1.77

0.622

0.654

0.99

1.00

1.01

Figure 7. LLAMA-based virtual libraries generated from fluorinated

spiro[3.3]heptane scaffolds and their non-fluorinated analogues: (A) MW –

ALogP plot; (B) principal moment of inertia (PMI) plot. Data point colors refer

to derivatives of: green – parent spiro[3.3]heptane; red – 6-fluorospiro[3.3]hep-

tane; blue – 6,6-difluorospiro[3.3]heptane; grey – cyclohexane

285

1.70

0.599

1.04

Conclusion

[a] FG = CO₂H or NH₂[b] Mean values over the corresponding libraries are

given [c] Fraction of sp³-hybrid carbon atoms [d] Plane of best fit, the mean

atomic distance from a theoretical plane that passes through the molecule,

configured in such a way as to minimize the value

A convenient methodology to construct 6-fluoro-spiro[3.3]hep-

tane scaffold was developed. Following the convergent synthetic

strategy starting from the single key precursor – 1,1-bis(bromo-

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portionwise, maintaining the internal temperature below 5 C. Thus

obtained mixture was allowed to react with stirring at above temperature

for 1 h. After, saturated aq. NH₄Cl (4 L) was added, the obtained mixture

was extracted with EtOAc (3 L). The combined organic layer was washed

with brine, dried (Na₂SO₄), and evaporated at reduced pressure to give

the title compound 3 as colorless liquid. The product was pure enough to

be used without further purification. Yield 941 g, 93%; ¹H NMR (400 MHz,

CDCl₃): δ = 5.07 (sept, J = 6.2 Hz, 2H), 4.38 (p, J = 7.0 Hz, 1H), 2.91–

2.81 (m, 2H), 2.49–2.38 (m, 2H), 1.99 (br. s, 1H), 1.25 (d, J = 6.2 Hz,

12H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 170.6, 68.6, 61.9, 45.6,

39.6, 21.0 ppm; MS (EI): m/z = 185 [M – C₃H₇O]⁺; HRMS (ESI) m/z

[M + Na]⁺calcd for C₁₂H₂₀O₅Na: 267.1208, found: 267.1201.

methyl)-3-fluorocyclobutane (1) – a considerable variety of 2-

mono- and 2,2-difunctionalized 6-fluorospiro[3.3]heptane-deri-

ved building blocks was prepared in fewest possible steps at

multigram scale (33 representatives, up to 302 g). The described

procedures are readily scaled up and can be modified for

introducing other functional groups. Moreover, a possibility to

obtain the title compounds as pure enantiomers with rarely

occurring subtype of axial chirality (caused merely by the H/F

difference) was demonstrated.

The pK_avalues within the studied series of spiro[3.3]heptane-

derived carboxylic acids 11, 39, 40 and amines 13, 41, 42 varied

in an expected manner (i.e. decreased upon increasing the

degree of fluorination); however, the fluorine atom(s) had much

stronger impact on the acidity/basicity as compared to the

acyclic -fluorinated analogs. At the same time, the lipophilicity

followed a non-monotonic pattern: CH₂ CF₂> CHF, which is

consistent with the literature data for the acyclic counterparts.

Also, the fluorination increased aqueous solubility of the

corresponding spiro[3.3]heptane derivatives. These effects likely

arise from the relative spatial position of the functional group and

the fluorine atom(s), as well as concerted electronic polarization

within the rigid spiro[3.3]heptane scaffold.

Virtual library construction using the LLAMA tool showed that the

monofluorinated spiro[3.3]heptane-derived building blocks

demonstrated the highest propensity to populate the lead-like

chemical space as compared to non-^[27,51,52]and difluorinated^[28]

counterparts, as well as simple cyclohexane derivatives, while

retaining similar three-dimensionality features. Considering all

the above, the title compounds are indeed promising advanced

chemotypes for early drug discovery and ¹⁹F-labelling studies,

and they should find their application in these or related areas in

the nearest future.

Diisopropyl 3-fluorocyclobutane-1,1-dicarboxylate (4): Morph-DAST

(842 g, 4.81 mol) was added dropwise to the stirred ice-cold solution of

diisopropyl 3-hydroxycyclobutane-1,1-dicarboxylate (3) (941 g, 3.85 mol)

in CH₂Cl₂(5 L) maintaining the internal temperature below 5 C. Then it

was allowed to equilibrate to rt and left to react with stirring for 40 h. After,

the reaction mixture was slowly poured into stirred saturated aq. K₂CO₃

(5 L) (Caution: Gas evolution!). The organic layer was separated, dried

(Na₂SO₄), evaporated at reduced pressure, and distilled in vacuo to give

the title compound 4 as colorless liquid. Yield 604 g, 64%; b.p. 60–65 C

(1 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 5.21–4.98 (m, 3H), 2.94–2.83

(m, 2H), 2.80–2.65 (m, 2H), 1.26 (d, J = 2.8 Hz, 6H), 1.25 (d, J = 2.8 Hz,

6H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 170.3 (d, J = 133.4 Hz),

82.3 (d, J = 210.5 Hz), 69.3 (d, J = 33.1 Hz), 45.2 (d, J = 15.2 Hz), 38.1

(d, J = 23.6 Hz), 21.5 (d, J = 2.9 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz,

CDCl₃): δ = –166.9 ppm; MS (EI): m/z = 187 [M – C₃H₇O]⁺; HRMS (ESI)

m/z [M + H]⁺calcd for C₁₂H₂₀FO₄: 247.1345, found: 247.1334.

(3-Fluorocyclobutane-1,1-diyl)dimethanol

(5):

Diisopropyl

3-

fluorocyclobutane-1,1-dicarboxylate (4) (604 g, 2.45 mol) was added

dropwise to the stirred ice-cold suspension of LiAlH₄(112 g, 2.95 mol) in

THF (4.5 L). Then it was allowed to equilibrate to rt and left to react with

stirring for 16 h. After, the reaction mixture was quenched upon cooling

by sequential dropwise addition of water (112 mL), 50% aq. NaOH (112 g,

61 mL), and water (336 mL) again. Thus obtained mixture was allowed to

stir for 15 min, the precipitate formed was filtered off, washed with THF

(500 mL), and the filtrate was evaporated at reduced pressure. The

residue was dissolved in CH₂Cl₂(2 L), dried (Na₂SO₄), and evaporated at

reduced pressure to give the title compound 5 as yellowish crystals. Yield

296 g, 90%; m.p. 46–47 C; ¹H NMR (400 MHz, CDCl₃): δ = 5.08 (dquint,

J = 55.3, 6.3 Hz, 1H), 3.78 (s, 2H), 3.69 (s, 2H), 2.39–2.30 (m, 2H), 2.30

(br. s, 2H), 2.15–1.97 (m, 2H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ =

84.2 (d, J = 207.9 Hz), 68.8 (d, J = 234.5 Hz), 36.0 (d, J = 11.7 Hz), 34.7

(d, J = 21.0 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –167.8 ppm;

MS (EI): m/z = 85 [M – CH₂O – H₂O]⁺; HRMS (ESI) m/z [M + H]⁺calcd for

C₆H₁₂FO₂: 135.0821, found: 135.0816.

Experimental Section

The solvents were purified according to the standard procedures.^[53]All

the starting materials were obtained from Enamine Ltd. and UORSY.

Melting points were measured on MPA100 OptiMelt automated melting

point system. Analytical TLC was performed using Polychrom SI F254

plates. ¹H, ¹³C{¹H}, and ¹⁹F{¹H} NMR spectra were recorded on an

Agilent ProPulse 600 spectrometer (at 600 MHz for ¹H NMR and 151

MHz for ¹³C NMR), a Bruker 170 Avance 500 spectrometer (at 500 MHz

for ¹H, 126 MHz for ¹³C, and 470 MHz for ¹⁹F), or a Varian Unity Plus 400

spectrometer (at 400 MHz for ¹H, 101 MHz for ¹³C, and 376 MHz for ¹⁹F).

Chemical shifts are reported in ppm downfield from TMS as an internal

standard. Elemental analyses were performed on a CHNOS elementary

Vario MICRO Cube analyzer. Mass spectra were recorded on an Agilent

1100 LCMSD SL instrument (chemical ionization (APCI)) and Agilent

5890 Series II 5972 GCMS instrument (electron impact ionization (EI)).

HRMS analyses were conducted on an Agilent 1260 Infinity UHPLC

instrument coupled with an Agilent 6224 Accurate Mass TOF mass

spectrometer. Lipophilicity was measured as the logarithm of the

distribution coefficient between n-octanol and water using shake-flask

method; analytical HPLC was used to establish the concentrations in

both phases after the partitioning. CCDC deposition number for the

structure of (R)-34H₂O is 2093380. The data can be obtained free of

charge from The Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/getstructures .

1,1-Bis(bromomethyl)-3-fluorocyclobutane (1): Br₂(791 g, 255 mL,

4.94 mol) was added dropwise to the stirred ice-cold solution of Ph₃P (1.3

kg, 4.95 mol) in CH₂Cl₂(4 L) maintaining the internal temperature below

10 C. Thus obtained suspension was left to stir at 0 C for 45 min

followed by addition of Et₃N (502 g, 691 mL, 4.96 mol) and further stirring

at above temperature for 15 min. Next, the solution of (3-

fluorocyclobutane-1,1-diyl)dimethanol (5) (296.2 g, 2.21 mol) in CH₂Cl₂

(250 mL) was added dropwise at 0 C. Then it was allowed to warm to rt

and left to react with stirring for 16 h. After, the reaction mixture was

slowly diluted with water (4 L), the organic layer was separated, washed

with saturated aq. Na₂CO₃(2.5 L), dried (Na₂SO₄), and evaporated at

reduced pressure. The remainder was triturated with hexane (5 L) and

filtered, while precipitate was washed with hexane (2  500 mL). The

combined filtrate was evaporated at reduced pressure and the residue

was distilled in vacuo to give the title compound 1 as colorless liquid.

Yield 479 g, 83%; b.p. 56–57 C (1 mBar); ¹H NMR (400 MHz, CDCl₃): δ

= 5.16–4.94 (m, 1H), 3.71 (s, 2H), 3.60 (s, 2H), 2.56–2.42 (m, 2H), 2.32–

2.17 (m, 2H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 82.0 (d, J = 206.9

Hz), 40.4 (d, J = 144.9 Hz), 38.2 (d, J = 22.1 Hz), 37.1 (d, J = 11.2 Hz)

Diisopropyl 3-hydroxycyclobutane-1,1-dicarboxylate (3): Diisopropyl

3-oxocyclobutane-1,1-dicarboxylate (2) (1.0 kg, 4.13 mol) was dissolved

in THF (5.0 L) followed by addition of water (500 mL) and the resulting

mixture was cooled to 0 C. Then NaBH₄(94.2 g, 2.48 mol) was added

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ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –171.4 ppm; MS (EI): m/z =

214 [M – C₂H₃F]⁺; elemental analysis calcd. (%) for C₆H₉Br₂F: C 27.72, H

3.49; found: C 27.99, H 3.85.

pressure to give the title compound 9 as colorless liquid. Yield 15.2 g,

94%; ¹H NMR (400 MHz, CDCl₃): δ = 4.92 (dquint, J = 55.7, 6.8 Hz, 1H),

4.23 (quint, J = 7.4 Hz, 1H), 2.47–2.31 (m, 4H), 2.31–2.13 (m, 2H), 2.02

(dd, J = 12.0, 7.4 Hz, 1H), 1.94 (dd, J = 12.0, 7.4 Hz, 1H), 1.76 (s, 1H)

ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 83.5 (d, J = 212.3 Hz), 62.9,

44.8 (d, J = 30.5 Hz), 42.7 (d, J = 19.6 Hz), 42.4 (d, J = 19.6 Hz), 25.1 (d,

J = 17.2 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –168.6 ppm; MS

(EI): m/z = 84 [M – C₂H₃F]⁺; elemental analysis calcd. (%) for C₇H₁₁FO: C

64.59, H 8.52; found: C 64.45, H 8.33.

Diethyl 6-fluorospiro[3.3]heptane-2,2-dicarboxylate (6): Diethyl

malonate (517 g, 3.23 mol) was added dropwise to the stirred ice-cold

suspension of NaH (60% dispersion in mineral oil, 128 г, 3.2 mol) in DMF

(2 L) and the obtained mixture was left to stir for 1 h. Then it was

gradually heated to 60 C followed by addition of 1,1-bis(bromomethyl)-3-

fluorocyclobutane (1) (400 g, 1.54 mol). After, the reaction mixture was

slowly heated to 120 C and stirred at this temperature for 16 h. Then it

was allowed to warm to rt, diluted with water (3 L), and extracted with t-

BuOMe (3 L). The organic layer was washed with water (2  2 L), dried

(Na₂SO₄), evaporated at reduced pressure, and the residue was distilled

in vacuo to give the title compound 6 as colorless liquid. Yield 302 g,

76%; b.p. 81–82 C (1 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 4.90

(dquint, J = 55.7, 6.6 Hz, 1H), 4.21 (q, J = 7.1 Hz, 4H), 2.63 (s, 2H), 2.59

(s, 2H), 2.55–2.42 (m, 2H), 2.34–2.15 (m, 2H), 1.26 (t, J = 7.1 Hz, 6H)

ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 171.5, 83.3 (d, J = 211.7 Hz),

61.5, 49.1, 43.6 (d, J = 20.0 Hz), 40.7 (d, J = 30.7 Hz), 29.4 (d, J = 16.8

Hz), 14.0 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –169.9 ppm; MS

(EI): m/z = 258 [M]⁺; HRMS (ESI) m/z [M + H]⁺calcd for C₁₃H₂₀FO₄:

259.1346, found: 259.1336.

6-Fluorospiro[3.3]heptane-2,2-dicarboxylic acid (10): Diethyl 6-

fluorospiro[3.3]heptane-2,2-dicarboxylate (6) (300 g, 1.16 mol) was

added to the solution of NaOH (186 g, 4.65 mol) in water (2 L) and

MeOH (500 mL) and the resulting solution was stirred at rt for 16 h. Then

MeOH was evaporated at reduced pressure, the remaining aqueous

solution was acidified with 2 M aq. HCl to pH = 2, and extracted with

EtOAc (2  800 mL). The combined organic layer was dried (Na₂SO₄)

and evaporated at reduced pressure. The residue was triturated with

hexane (500 mL), filtered and washed with hexane (25 mL) to give the

title compound 10 as colorless crystals. Yield 224 g, 95%; m.p. 190–

192 C; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.69 (s, 2H), 4.91 (dquint, J

= 55.9, 6.5 Hz, 1H), 2.46 (s, 2H), 2.44 (s, 2H), 2.44–2.35 (m, 2H), 2.19–

2.04 (m, 2H) ppm; ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ = 173.1, 83.6 (d,

J = 209.8 Hz), 49.0, 43.6 (d, J = 19.5 Hz), 40.7 (d, J = 19.5 Hz), 29.1 (d, J

= 17.0 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ = – 167.8 ppm;

MS (EI): m/z = 112 [M – 2CO₂H]⁺; HRMS (ESI) m/z [M – H]^–calcd for

C₉H₁₀FO₄: 201.0563, found: 201.0568.

Ethyl 2-cyano-6-fluorospiro[3.3]heptane-2-carboxylate (7): 1,1-

Bis(bromomethyl)-3-fluorocyclobutane (1) (150 g, 577 mmol) and ethyl

cyanoacetate (67.9 g, 600 mmol) were dissolved in DMF (700 mL)

followed by addition of K₂CO₃(200 g, 1.45 mol). The resulting mixture

was gradually heated to 90 C and stirred at this temperature for 16 h.

Then it was allowed to warm to rt, diluted with water (1 L), and extracted

with EtOAc (1.2 L). The organic layer was washed with water (2  600

mL), dried (Na₂SO₄), evaporated at reduced pressure, and the residue

was distilled in vacuo to give the title compound 7 as colorless liquid.

Yield 87.3 g, 72%; b.p. 69–70 C (1 mBar); ¹H NMR (400 MHz, CDCl₃): δ

= 4.94 (dquint, J = 55.4, 6.4 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 2.87–2.61

(m, 5H), 2.61–2.49 (m, 1H), 2.49–2.22 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H)

ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 168.4, 120.0, 83.1 (d, J =

211.4 Hz), 63.0, 43.7 (d, J = 20.8 Hz), 43.2 (d, J = 20.8 Hz), 42.9, 35.9,

31.0 (d, J = 16.3 Hz), 13.9 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –

170.4 ppm; MS (EI): m/z = 165 [M – C₂H₃F]⁺; HRMS (ESI) m/z [M + H]⁺

calcd for C₁₁H₁₅FNO₂: 212.1087, found: 212.1078.

6-Fluorospiro[3.3]heptane-2-carboxylic

acid

(11):

6-

Fluorospiro[3.3]heptane-2,2-dicarboxylic acid (10) (220 g, 1.09 mol) was

dissolved in pyridine (2 L) and the resulting solution was refluxed with

stirring for 16 h. Then it was evaporated at reduced pressure, diluted with

water (1 L), acidified with 1M aq. HCl to pH 2, and extracted with EtOAc

(2  1 L). The combined organic layer was dried (Na₂SO₄) and

evaporated at reduced pressure to give the title compound 11 as

yellowish crystals. Yield 162 g, 94%; m.p. 65–67 C; ¹H NMR (400 MHz,

CDCl₃): δ = 11.36 (br. s, 1H), 4.92 (dquint, J = 55.6, 6.7 Hz, 1H), 3.10 (p,

J = 8.5 Hz, 1H), 2.53 (dq, J = 12.8, 6.7 Hz, 1H), 2.47–2.38 (m, 2H), 2.37–

2.10 (m, 5H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 181.5, 83.5 (d, J

= 212.1 Hz), 43.4 (d, J = 19.8 Hz), 43.1 (d, J = 19.8 Hz), 37.1 (d, J = 29.3

Hz), 33.5, 31.1 (d, J = 16.8 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ =

–169.8 ppm; MS (EI): m/z = 112 [M – CO – H₂O]⁺; HRMS (ESI) m/z [M –

H]^–calcd for C₈H₁₀FO₂: 157.0665, found: 157.0667.

6-Fluorospiro[3.3]heptan-2-one (8): NaH (60% dispersion in mineral oil,

86 g, 2.15 mol) was added to the solution of 1,1-bis(bromomethyl)-3-

fluorocyclobutane (1) (160 g, 615 mmol) in a mixture of DMSO (960 mL)

and Et₂O (600 mL) followed by dropwise addition of the solution of

TosMIC (324 g, 1.66 mol) in a mixture of DMSO (640 mL) and Et₂O (200

mL) maintaining the temperature below 20 C. Thus obtained mixture

was left to react with stirring for 2 h; then it was diluted with water (2 L)

and extracted with EtOAc (2 L). The organic layer was washed with water

(2  1.5 L), dried (Na₂SO₄), and evaporated at reduced pressure.

Obtained brown viscous residue was distilled in vacuo to give the title

compound 8 as colorless liquid. Yield 33.0 g, 42%; b.p. 30–31 C (1

mBar); ¹H NMR (400 MHz, CDCl₃): δ = 5.06 (dquint, J = 55.5, 6.7 Hz, 1H),

3.18 (d, J = 3.8 Hz, 2H), 3.10 (d, J = 3.8 Hz, 2H), 2.70–2.42 (m, 4H) ppm;

¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 206.1, 83.0 (d, J = 212.5 Hz), 58.7

(d, J = 32.5 Hz), 42.5 (d, J = 20.6 Hz), 24.3 (d, J = 17.7 Hz) ppm; ¹⁹F{¹H}

NMR (376 MHz, CDCl₃): δ = –169.8 ppm; MS (EI): m/z = 100 [M – CO]⁺

(100), 128 [M]⁺(5); elemental analysis calcd. (%) for C₇H₉FO: C 65.61, H

7.08; found: C 65.33, H 7.37.

tert-Butyl

(6-fluorospiro[3.3]heptan-2-yl)carbamate

(12):

6-

Fluorospiro[3.3]heptane-2-carboxylic acid (11) (45 g, 285 mmol) was

dissolved in a mixture of CH₂Cl₂(400 mL) and DMF (1 mL) followed by

dropwise addition of (COCl)₂(45.2 g, 30.5 mL, 356 mmol). The resulting

solution was stirred at rt for 2 h and evaporated at reduced pressure.

Thus obtained crude acid chloride was dissolved in EtOAc (200 mL) and

cooled to 0 C followed by dropwise addition of a solution of NaN₃(55.5 g,

854 mmol) in water (350 mL) maintaining the above temperature. The

reaction mixture was stirred at 0 C for an additional 1 h and extracted

with EtOAc (2  200 mL). The combined organic layer was dried

(Na₂SO₄) and evaporated to a half of initial volume at reduced pressure

and external temperature below 30 C. This solution was added dropwise

to hot (90 C) mixture of t-BuOH (220 mL) and PhMe (400 mL) and thus

obtained reaction mixture was stirred at above temperature for an

additional 40 h. Then it was evaporated at reduced pressure to give the

title compound 12 as colorless powder. Yield 50.3 g, 77%; m.p. 102–105

C; mixtures of Boc-rotamers were observed by NMR spectroscopy; ¹H

NMR (400 MHz, CDCl₃): δ = 4.87 (dquint, J = 55.7, 6.6 Hz, 1H), 2.51–

2.40 (m, 1H), 4.60 (br. s, 1H), 2.40–2.23 (m, 3H), 2.23–2.07 (m, 2H),

1.89 (t, J = 10.1 Hz, 1H), 1.81 (t, J = 10.1 Hz, 1H), 1.40 (s, 9H) ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 154.9, 83.8 (d, J = 212.5 Hz), 79.4,

43.1 (d, J = 3.6 Hz), 43.0 (d, J = 20.0 Hz), 42.6 (d, J = 20.0 Hz), 41.8,

28.4, 27.8 (d, J = 17.5 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –

6-Fluorospiro[3.3]heptan-2-ol (9): 6-Fluorospiro[3.3]heptan-2-one (8)

(16 g, 125 mmol) was dissolved in THF (100 mL) followed by addition of

water (10 mL) and the resulting mixture was cooled to 0 C. Then NaBH₄

(2.85 g, 75 mmol) was added portionwise and the resulting mixture was

stirred at above temperature for 1 h. After, saturated aq. NH₄Cl (150 mL)

was added, the obtained mixture was extracted with EtOAc (100 mL).

The organic layer was dried (Na₂SO₄) and evaporated at reduced

8

10.1002/ejoc.202100804

European Journal of Organic Chemistry

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169.0 ppm; HRMS (ESI) m/z [M + Na]⁺calcd for C₁₂H₂₀FNNaO₂:

252.1375, found: 252.1369.

filtered off and washed with CH₂Cl₂(150 mL). The combined filtrate was

evaporated at reduced pressure to the half of initial volume (ca. 400 mL).

After, CBrCl₃(264 g, 1.33 mol) was added and the obtained mixture was

irradiated with daylight lamp upon stirring and reflux for 2 h. Finally, it

was evaporated at reduced pressure and the residue was distilled in

vacuo to give the title compound 16 as colorless liquid. Yield 60.9 g,

71%; b.p. 30–32 C (1 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 4.92

(dquint, J = 55.5, 6.8 Hz, 1H), 4.38 (p, J = 7.8 Hz, 1H), 2.78–2.62 (m, 2H),

2.62–2.42 (m, 4H), 2.41–2.14 (m, 2H) ppm; ¹³C{¹H} NMR (126 MHz,

CDCl₃): δ = 83.2 (d, J = 212.4 Hz), 46.7 (d, J = 6.0 Hz), 42.9 (d, J = 20.1

Hz), 42.3 (d, J = 20.1 Hz), 37.1, 31.5 (d, J = 16.6 Hz) ppm; ¹⁹F{¹H} NMR

(376 MHz, CDCl₃): δ = –169.4 ppm; MS (EI): m/z = 145/147 [M –

C₂H₃F]⁺; elemental analysis calcd. (%) for C₇H₁₀BrF: C 43.55, H 5.22;

found: C 43.66, H 5.37.

6-Fluorospiro[3.3]heptan-2-amine hydrochloride (13): tert-Butyl (6-

fluorospiro[3.3]heptan-2-yl)carbamate (12) (40 g, 174 mmol) was added

portionwise to the stirred 2M HCl in MeOH (400 mL) and thus obtained

mixture was additionally stirred for 2 h. Then it was evaporated at

reduced pressure, triturated with EtOAc (200 mL), and filtered to give the

title compound 13 as colorless powder. Yield 23.8 g, 83%; m.p. 232–

235 C; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.37 (s, 3H), 4.93 (dquint, J =

55.8, 6.7 Hz, 1H), 2.49–2.43 (m, 1H), 2.38–2.30 (m, 1H), 2.29–2.20 (m,

4H), 2.20–2.13 (m, 2H), 2.12–2.06 (m, 1H) ppm; ¹³C{¹H} NMR (126 MHz,

DMSO-d₆): δ = 83.4 (d, J = 210.2 Hz), 42.4 (d, J = 19.7 Hz), 42.2 (d, J =

19.7 Hz), 40.6, 38.7 (d, J = 8.0 Hz), 28.1 (d, J = 17.6 Hz) ppm; ¹⁹F{¹H}

NMR (376 MHz, DMSO-d₆): δ = –167.4 ppm; MS (APCI): m/z = 130

[M + H]⁺; HRMS (ESI) m/z [M + H] calcd for C₇H₁₃FN: 130.1032, found:

130.1025.

(6-Fluorospiro[3.3]heptan-2-yl)methanol (17): 6-Fluorospiro[3.3]hep-

tane-2-carboxylic acid (11) (150 g, 948 mmol) was added dropwise to the

stirred ice-cold suspension of LiAlH₄(36.1 g, 950 mmol) in THF (1.4 L).

Then it was allowed to warm to rt and left to react with stirring for 16 h.

After, the reaction mixture was quenched upon cooling by sequential

dropwise addition of water (36 mL), 50% aq. NaOH (36 g, 20 mL), and

water (110 mL) again. Thus obtained mixture was allowed to stir for 15

min, the precipitate formed was filtered off, washed with THF (2  150

mL), and the filtrate was evaporated at reduced pressure. The residue

was dissolved in CH₂Cl₂(1 L), dried (Na₂SO₄), and evaporated at

reduced pressure to give the title compound 17 as colorless liquid. Yield

121 g, 88%; ¹H NMR (400 MHz, CDCl₃): δ = 4.90 (dquint, J = 55.8, 6.7

Hz, 1H), 3.58 (dd, J = 6.7, 2.3 Hz, 2H), 2.55–2.30 (m, 2H), 2.29–2.04 (m,

4H), 1.89–1.75 (m, 2H), 1.42 (s, 1H) ppm; ¹³C{¹H} NMR (126 MHz,

CDCl₃): δ = 83.8 (d, J = 212.3 Hz), 67.0, 44.0 (d, J = 19.2 Hz), 43.7 (d, J

= 19.2 Hz), 36.7 (d, J = 30.8 Hz), 32.4, 30.7 (d, J = 16.7 Hz) ppm; ¹⁹F{¹H}

NMR (376 MHz, CDCl₃): δ = –169.3 ppm; MS (EI): m/z = 106 [M – H₂O –

HF]⁺; elemental analysis calcd. (%) for C₈H₁₃FO: C 66.64, H 9.09; found:

C 66.31, H 9.11.

6-Fluorospiro[3.3]heptane-2-carboxamide (14): 6-Fluorospiro[3.3]hep-

tane-2-carboxylic acid (11) (25 g, 158 mmol) was dissolved in a mixture

of CH₂Cl₂(250 mL) and DMF (0.5 mL) followed by dropwise addition of

(COCl)₂(24.1 g, 16.3 mL, 190 mmol). The resulting solution was stirred

at rt for 2 h and evaporated at reduced pressure. Thus obtained crude

acid chloride was dissolved in THF (250 mL) and cooled to 0 C followed

by bubbling gaseous NH₃through the reaction mixture for 30 min

maintaining the above temperature. Then it was left to stir for 2 h and

allowed to equilibrate to rt. The precipitate formed was filtered off,

washed with THF (50 mL) and the filtrate was evaporated at reduced

pressure to give the title compound 14 as beige powder. Yield 22.1 g,

89%; m.p. 158–159 C; ¹H NMR (400 MHz, CDCl₃): δ = 5.59 (br. s, 1H),

5.35 (br. s, 1H), 4.92 (dquint, J = 55.6, 6.7 Hz, 1H), 2.97 (p, J = 8.5 Hz,

1H), 2.61–2.47 (m, 1H), 2.46–2.29 (m, 3H), 2.32–2.11 (m, 4H) ppm;

¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 177.0, 83.6 (d, J = 212.0 Hz), 43.5

(d, J = 19.7 Hz), 42.9 (d, J = 19.7 Hz), 37.3 (d, J = 9.2 Hz), 34.6, 30.7 (d,

J = 16.9 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –169.7 ppm; MS

(EI): m/z = 111 [M – C₂H₃F]⁺(100), 157 [M]⁺(9); HRMS (ESI) m/z

[M + H]⁺calcd for C₈H₁₃FNO: 158.0981, found: 158.0969.

2-(Bromomethyl)-6-fluorospiro[3.3]heptane (18): Br₂(86.2 g, 27.8 mL,

539 mmol) was added dropwise to the stirred ice-cold solution of Ph₃P

(142 g, 541 mmol) in CH₂Cl₂(700 mL) maintaining the internal

temperature below 10 C. Thus obtained suspension was stirred at 0 C

for 45 min, Et₃N (55.2 g, 76 mL, 545 mmol) was added, and the mixture

was stirred at above temperature for 15 min. Next, the solution of (6-

fluorospiro[3.3]heptan-2-yl)methanol (17) (65 g, 451 mmol) in CH₂Cl₂

(100 mL) was added dropwise at 0 C. Then the mixture was allowed to

warm to rt and stirred for 16 h. After, the reaction mixture was slowly

diluted with water (1 L), the organic layer was separated, washed with

saturated aq. Na₂CO₃(500 mL), dried (Na₂SO₄), and evaporated at

reduced pressure. The remainder was triturated with hexane (500 mL)

and filtered, while precipitate was washed with hexane (2  50 mL). The

combined filtrate was evaporated at reduced pressure and the residue

was distilled in vacuo to give the title compound 18 as colorless liquid.

Yield 77.5 g, 83%; b.p. 45–46 C (1 mBar); ¹H NMR (400 MHz, CDCl₃): δ

= 4.91 (dquint, J = 55.7, 6.8 Hz, 1H), 3.39 (d, J = 7.6 Hz, 2H), 2.62 (hept,

J = 7.6 Hz, 1H), 2.56–2.45 (m, 1H), 2.42–2.30 (m, 1H), 2.30–2.10 (m,

4H), 1.91–1.73 (m, 2H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 83.2 (d,

J = 212.5 Hz), 43.3 (d, J = 19.5 Hz), 42.9 (d, J = 19.5 Hz), 39.0 (d, J =

31.9 Hz), 38.4, 32.4, 29.0 (d, J = 16.8 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz,

CDCl₃): δ = –169.4 ppm; MS (EI): m/z = 159/161 [M – C₂H₃F]⁺; elemental

analysis calcd. (%) for C₈H₁₂BrF: C 46.40, H 5.84; found: C 46.16, H 5.87.

(6-Fluorospiro[3.3]heptan-2-yl)methanamine hydrochloride (15): A

solution of 6-fluorospiro[3.3]heptane-2-carboxamide (14) (22.1 g, 141

mmol) in THF (100 mL) was added dropwise to a stirred boiling

suspension of LiAlH₄(10.6 g, 280 mmol) in THF (400 mL) and the

resulting mixture was refluxed with stirring for 2 h. Then it was allowed to

warm to rt and stirred for an additional 16 h. After, the reaction mixture

was quenched upon cooling by sequential dropwise addition of water (10

mL), 50% aq. NaOH (10 g), and water (30 mL) again. Thus obtained

mixture was allowed to stir for 15 min, the precipitate formed was filtered

off, washed with THF (2  50 mL), and the filtrate was evaporated at

reduced pressure. The residue was dissolved in CH₂Cl₂(250 mL), dried

(Na₂SO₄), and evaporated at reduced pressure. Thus obtained residue

was dissolved in Et₂O (150 mL) followed by addition of 4 M HCl in Et₂O

(20 mL). The precipitate formed was filtered and washed with a minimal

amount of Et₂O to give the title compound 15 as beige powder. Yield

18.6 g, 73%; m.p. 190–193 C; ¹H NMR (400 MHz, DMSO-d₆): δ = 7.93

(br. s, 3H), 4.92 (dquint, J = 55.8, 6.8 Hz, 1H), 2.77 (p, J = 6.0 Hz, 2H),

2.49–2.36 (m, 2H), 2.36–2.27 (m, 1H), 2.19–1.99 (m, 4H), 1.89–1.75 (m,

2H) ppm; ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ = 83.5 (d, J = 210.6 Hz),

43.6, 43.2 (d, J = 19.2 Hz), 42.9 (d, J = 19.1 Hz), 37.4 (d, J = 6.8 Hz),

30.1 (d, J = 16.4 Hz), 28.0 ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ =

–167.3 ppm; MS (APCI): m/z = 144 [M + H]⁺; HRMS (ESI) m/z [M + H]⁺

calcd for C₈H₁₅FN: 144.1189, found: 144.1184.

General procedure for the preparation of pinacol boronates 19 and

20: The corresponding bromide 16, 18 (155 mmol) was dissolved in DMF

(300 mL) followed by sequential addition of t-BuOLi (24.9 g, 311 mmol),

(BPin)₂(47.4 g, 187 mmol), Ph₃P (5.3 g, 20.2 mmol), and CuBr (2.26 g,

15.8 mmol) under Ar atmosphere maintaining internal temperature below

30 C (Caution: Exothermic reaction!). Thus obtained mixture was stirred

for 16 h; then it was diluted with EtOAc (300 mL) and filtered through

silica gel. The filtrate was washed with water (1 × 500 mL and 2 × 150

mL), dried (Na₂SO₄), and evaporated at reduced pressure. The residue

2-Bromo-6-fluorospiro[3.3]heptane (16): 1-Hydroxypyridine-2(1H)-

thione (61.9 g, 487 mmol) was added to the stirred solution of 6-

fluorospiro[3.3]heptane-2-carboxylic acid (11) (70 г, 443 mmol) in CH₂Cl₂

(700 mL) and the resulting solution was cooled to 0 C. Next, DCC (100 g,

487 mmol) was added dropwise and obtained reaction mixture was

allowed to stir in the dark at rt for 16 h. The formed precipitate was

9

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was subjected to silica gel column chromatography (EtOAc – hexane

1:15) affording the title compound 19, 20 as colorless liquid.

S-(6-Fluorospiro[3.3]heptan-2-yl) ethanethioate (23): from 2-bromo-6-

fluorospiro[3.3]heptane (16) (25 g, 129 mmol). Yield 22.6 g, 93%; ¹H

NMR (400 MHz, CDCl₃): δ = 4.90 (dquint, J = 55.6, 6.7 Hz, 1H), 3.98 (p,

J = 8.3 Hz, 1H), 2.63–2.45 (m, 3H), 2.46–2.29 (m, 2H), 2.28 (s, 3H),

2.25–2.04 (m, 3H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 195.8, 83.6

(d, J = 212.5 Hz), 43.2 (d, J = 19.8 Hz), 43.1 (d, J = 19.8 Hz), 42.1 (d, J =

33.1 Hz), 32.2, 31.8 (d, J = 16.8 Hz), 30.4 ppm; ¹⁹F{¹H} NMR (376 MHz,

CDCl₃): δ = –169.5 ppm; MS (EI): m/z = 145 [M – CH₃CO]⁺; HRMS (ESI)

m/z [M + H]⁺calcd for C₉H₁₄FOS: 189.0749, found: 189.0741.

2-(6-Fluorospiro[3.3]heptan-2-yl)-4,4,5,5-tetramethyl-1,3,2-

dioxaborolane (19): from 2-bromo-6-fluorospiro[3.3]heptane (16) (30 g,

155 mmol), t-BuOLi (24.9 g, 311 mmol), (BPin)₂(47.4 g, 187 mmol),

Ph₃P (5.3 г, 20.2 mmol), and CuBr (2.26 g, 15.8 mmol). Yield 32.1 g,

86%, R_f0.45; ¹H NMR (400 MHz, CDCl₃): δ = 4.87 (dquint, J = 55.8, 6.8

Hz, 1H), 2.55–2.34 (m, 2H), 2.26–1.95 (m, 6H), 1.80 (p, J = 8.1 Hz, 1H),

1.26 (s, 12H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 83.9 (d, J =

212.2 Hz), 83.1, 43.6 (d, J = 19.2 Hz), 43.5 (d, J = 19.2 Hz), 35.9 (d, J =

24.7 Hz), 34.0 (d, J = 16.4 Hz), 24.7, 12.6 (br. s) ppm; ¹⁹F{¹H} NMR (376

MHz, CDCl₃): δ = –169.6 ppm; MS (EI): m/z = 220 [M – HF]⁺; HRMS

(ESI) m/z [M + H]⁺calcd for C₁₃H₂₃BFO₂: 241.1775, found: 241.1768.

S-((6-Fluorospiro[3.3]heptan-2-yl)methyl) ethanethioate (24): from 2-

(bromomethyl)-6-fluorospiro[3.3]heptane (18) (25 g, 121 mmol). Yield

21.7 g, 89%; ¹H NMR (400 MHz, CDCl₃): δ = 4.89 (dquint, J = 55.7, 6.8

Hz, 1H), 2.93 (d, J = 7.5 Hz, 2H), 2.54–2.35 (m, 3H), 2.34 (s, 3H), 2.26–

2.06 (m, 4H), 1.83–1.67 (m, 2H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ

= 195.3, 83.4 (d, J = 212.5 Hz), 43.2 (d, J = 19.4 Hz), 42.9 (d, J = 19.4

Hz), 39.2 (d, J = 16.7 Hz), 34.5, 30.2, 29.8, 29.6 (d, J = 16.7 Hz) ppm;

¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –169.2 ppm; MS (EI): m/z = 159

[M – CH₃CO]⁺; HRMS (ESI) m/z [M + H]⁺calcd for C₁₀H₁₆FOS: 203.0906,

found: 203.0907.

2-((6-Fluorospiro[3.3]heptan-2-yl)methyl)-4,4,5,5-tetramethyl-1,3,2-

dioxaborolane (20): from 2-(bromomethyl)-6-fluorospiro[3.3]heptane

(18) (35 g, 169 mmol), t-BuOLi (27 g, 337 mmol), (BPin)₂(51 g, 201

mmol), Ph₃P (5.76 g, 22 mmol), and CuBr (2.45 g, 17 mmol). Yield 37.8 g,

91%, R_f0.42; ¹H NMR (400 MHz, CDCl₃): δ = 4.87 (dquint, J = 56.0, 6.9

Hz, 1H), 2.54–2.44 (m, 1H), 2.38 (hept, J = 8.9 Hz, 1H), 2.33–2.23 (m,

1H), 2.23–2.04 (m, 4H), 1.78–1.54 (m, 2H), 1.24 (s, 12H), 0.92 (d, J = 7.9

Hz, 2H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 84.2 (d, J = 212.4 Hz),

82.9, 43.8 (d, J = 19.1 Hz), 43.3 (d, J = 19.1 Hz), 42.8 (d, J = 14.1 Hz),

30.2 (d, J = 16.8 Hz), 27.0, 24.8, 19.2 (br. s) ppm; ¹⁹F{¹H} NMR (376

MHz, CDCl₃): δ = –168.9 ppm; MS (EI): m/z = 170 [M – C₆H₁₂]⁺; HRMS

(ESI) m/z [M + NH₄]⁺calcd for C₁₄H₂₈BFNO₂: 272.2197, found: 272.2194.

General Procedure for the Preparation of Sulfonyl Chlorides 25 and

26: The corresponding ethanethioate 23, 24 (117 mmol) was added to a

stirred mixture of CH₂Cl₂(200 mL) and water (200 mL) and the resulting

emulsion was cooled to 0 C. Then Cl₂was bubbled through the stirred

reaction mixture maintaining the above temperature until it became

yellow green (ca. 30 min). After, the reaction mixture was allowed to

warm to 10 C, the organic layer was separated, washed with water (2 

150 mL), dried (Na₂SO₄), and evaporated at reduced pressure to give the

title compound 24, 26 as yellow liquid.

General procedure for the preparation of potassium trifluoroborates

21 and 22: The corresponding pinacol boronate 19, 20 (117 mmol) was

dissolved in MeOH (200 mL) followed by addition of a solution of KHF₂

(45.5 g, 583 mmol) in water (100 mL). Thus obtained mixture was stirred

at rt for 16 h and evaporated at reduced pressure. The residue was

triturated with EtOAc (200 mL), filtered, and washed with EtOAc (3  100

mL). The combined filtrate was evaporated at reduced pressure to give

the title compound 21, 22 as colorless powder.

6-Fluorospiro[3.3]heptane-2-sulfonyl chloride (25): from S-(6-

fluorospiro[3.3]heptan-2-yl) ethanethioate (23) (22.- g, 117 mmol). Yield

18.1 g, 73%; ¹H NMR (400 MHz, CDCl₃): δ = 4.97 (dquint, J = 55.3, 6.5

Hz, 1H), 4.34 (p, J = 8.1 Hz, 1H), 2.85–2.72 (m, 2H), 2.64–2.51 (m, 4H),

2.41–2.30 (m, 2H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 82.5 (d, J =

212.0 Hz), 62.8, 42.72 (d, J = 20.6 Hz), 42.68 (d, J = 20.6 Hz), 36.6 (d, J

= 26.7 Hz), 29.6 (d, J = 16.4 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ

= –170.4 ppm; MS (APCI): m/z = 193 [M – H]^–(for the corresponding

sulfonic acid); elemental analysis calcd. (%) for C₇H₁₀ClFO₂S: C 39.54, H

4.74, S 15.08; found: C 39.15, H 4.91, S 15.31.

Potassium trifluoro(6-fluorospiro[3.3]heptan-2-yl)borate (21): from 2-

(6-fluorospiro[3.3]heptan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(19) (28.0 g, 117 mmol). Yield 19.8 g, 77%; m.p.  250 C; ¹H NMR (400

MHz, DMSO-d₆): δ = 4.80 (dquint, J = 56.0, 7.0 Hz, 1H), 2.44–2.30 (m,

1H), 2.28–2.14 (m, 1H), 2.03–1.76 (m, 2H), 1.79–1.56 (m, 4H), 1.13–0.93

(m, 1H) ppm; ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ = 84.4 (d, J = 211.2

Hz), 44.8 (d, J = 18.0 Hz), 43.9 (d, J = 18.0 Hz), 36.6 (d, J = 5.8 Hz), 32.6

(d, J = 15.4 Hz), 20.5 (br. s) ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ =

–144.2, –166.5 ppm; MS (APCI): m/z = 203 [M –K–3F+2OH+HCO₂]^–;

HRMS (ESI) m/z [M]^–calcd for C₇H₁₀BF₄: 181.0812, found: 181.0814.

(6-Fluorospiro[3.3]heptan-2-yl)methanesulfonyl chloride (26): from

S-((6-fluorospiro[3.3]heptan-2-yl)methyl) ethanethioate (24) (21 g, 104

mmol). Yield 17.3 g, 74%.; ¹H NMR (400 MHz, CDCl₃): δ = 4.93 (dquint,

J = 55.6, 6.8 Hz, 1H), 3.76 (d, J = 7.2 Hz, 2H), 2.97 (hept, J = 8.1 Hz, 1H),

2.67–2.52 (m, 1H), 2.44–2.30 (m, 3H), 2.30–2.14 (m, 2H), 2.11–1.92 (m,

2H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 83.0 (d, J = 212.4 Hz),

70.1, 42.8 (d, J = 20.0 Hz), 42.4 (d, J = 20.0 Hz), 39.4 (d, J = 21.6 Hz),

31.1 (d, J = 16.8 Hz), 25.7 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –

169.7 ppm; MS (APCI): m/z = 207 [M – H]^–(for the corresponding

sulfonic acid); elemental analysis calcd. (%) for C₈H₁₂ClFO₂S: C 42.39, H

5.34, S 14.14; found: C 42.22, H 5.52, S 14.30.

Potassium

trifluoro((6-fluorospiro[3.3]heptan-2-yl)methyl)borate

(22): from 2-((6-fluorospiro[3.3]heptan-2-yl)methyl)-4,4,5,5-tetramethyl-

1,3,2-dioxaborolane (20) (32.0 g, 126 mmol). Yield 21.1 g, 72%; m.p. 

230 C; ¹H NMR (400 MHz, DMSO-d₆): δ = 4.85 (dquint, J = 56.0, 6.7 Hz,

1H), 2.39 (dq, J = 12.5, 6.7 Hz, 1H), 2.19 (dq, J = 12.5, 6.7 Hz, 1H),

2.14–2.02 (m, 1H), 2.00–1.89 (m, 4H), 1.60–1.41 (m, 2H), 0.09 (p, J =

6.6 Hz, 2H) ppm; ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ = 84.3 (d, J =

211.4 Hz), 44.13 (d, J = 28.3 Hz), 44.07 (d, J = 18.1 Hz), 43.50 (d, J =

18.1 Hz), 30.3 (d, J = 16.1 Hz), 29.4, 29.0 (br. s) ppm; ¹⁹F{¹H} NMR (376

MHz, DMSO-d₆): δ = –136.0, –166.3 ppm; MS (APCI): m/z = 217 [M –K–

3F+2OH+HCO₂]^–; HRMS (ESI) m/z [M]^–calcd for C₈H₁₂BF₄: 195.0968,

found: 195.0971.

6-Fluorospiro[3.3]heptane-2-carbaldehyde (27): (COCl)₂(47.6 g, 32.2

mL, 375 mmol) was added dropwise to cold ( –78 C) solution of DMSO

(58.5 g, 53.2 mL, 749 mmol) in CH₂Cl₂(900 mL) maintaining the

temperature below –70 C, and the resulting mixture was stirred at above

temperature for 15 min. Then the solution of (6-fluorospiro[3.3]heptan-2-

yl)methanol (17) (45 g, 312 mmol) in CH₂Cl₂(100 mL) was added

dropwise at –78 C and thus obtained mixture was stirred at above

temperature for 30 min. Next, Et₃N (126 g, 174 mL, 1.25 mol) was added,

and the reaction mixture was warmed to 0 C. Finally, water (500 mL)

was added, the organic layer was separated, washed with saturated aq.

Na₂CO₃(200 mL) and brine (200 mL), dried (Na₂SO₄), and evaporated at

reduced pressure. The residue was distilled in vacuo to give the title

compound 27 as colorless liquid. Yield 37.7 g, 85%; b.p. 45–46 C (1

General Procedure for the Preparation of Ethanethioates 23 and 24:

The corresponding bromide 16, 18 (129 mmol) was dissolved in DMF

(125 mL), KSAc (29.5 g, 258 mmol) was added, and the resulting mixture

was stirred at 50 C for 16 h. Then it was cooled to rt, diluted with water

(250 mL), and extracted with t-BuOMe (250 mL). The organic layer was

washed with water (2  150 mL), dried (Na₂SO₄) and evaporated at

reduced pressure to give the title compound 23, 24 as yellow liquid.

1

mBar); H NMR (400 MHz, CDCl₃): δ = 9.71 (s, 1H), 4.92 (dquint, J =

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55.6, 6.7 Hz, 1H), 3.13 (p, J = 9.0 Hz, 1H), 2.60–2.46 (m, 1H), 2.45–2.09

(m, 7H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 201.4, 82.9 (d, J =

212.3 Hz), 43.2 (d, J = 19.8 Hz), 42.8 (d, J = 19.8 Hz), 40.6, 33.8 (d, J =

17.0 Hz), 30.9 (d, J = 16.9 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ =

–169.9 ppm; MS (EI): m/z = 96 [M – C₂H₃F]⁺; HRMS (ESI) m/z

[M + NH₄]⁺calcd for C₈H₁₅NFO: 160.1137, found: 160.1114.

NMR (151 MHz, CDCl₃): δ = 173.6, 154.8, 83.7 (d, J = 211.1 Hz), 79.8,

61.4, 54.8, 44.3 (d, J = 20.0 Hz), 43.8 (d, J = 20.0 Hz), 43.4 (br. s), 28.30

(d, J = 17.5 Hz), 28.27, 14.1 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –

169.7 ppm; MS (APCI): m/z = 202 [M – CO₂– C₄H₈+ H]⁺; HRMS (ESI)

m/z [M + Na]⁺calcd for C₁₅H₂₄FNNaO₄: 324.1587, found: 324.1578.

A sample of 32 (200 mg) was subjected to chiral stationary phase HPLC

separation (Chiralpak AS-H 2504.6 mm, 5 m column, gradient elution

with hexane – i-PrOH (90 to 10 v/v), 0.6 mL/min). (S)-32: 85 mg, 42%;

2-Ethynyl-6-fluorospiro[3.3]heptane (28): K₂CO₃(73 g, 528 mmol) was

dispersed in MeOH (200 mL) followed by addition of 6-

fluorospiro[3.3]heptane-2-carbaldehyde (27) (25 g, 176 mmol). Thus

obtained mixture was cooled to 0 C, and the Ohira-Bestmann reagent

(39.2 г, 204 mmol) was slowly added. The reaction mixture was allowed

to warm to rt and stirred for 1 h. Then it was diluted with water (500 mL)

and extracted with hexane (400 mL). The organic layer was washed with

water (300 mL), dried (Na₂SO₄), and evaporated at reduced pressure.

Thus obtained residue was distilled in vacuo to give the title compound

28 as colorless oil. Yield 9.6 g, 39%; b.p. 60–61 C (28 mBar); ¹H NMR

(400 MHz, CDCl₃): δ = 4.90 (dquint, J = 55.7, 6.7 Hz, 1H), 2.94 (pd, J =

8.3, 2.5 Hz, 1H), 2.56–2.39 (m, 2H), 2.40–2.28 (m, 2H), 2.28–2.08 (m,

5H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 87.3, 83.1 (d, J = 212.4

Hz), 68.5, 42.8 (d, J = 19.7 Hz), 42.7 (d, J = 19.7 Hz), 40.9 (d, J = 16.0

Hz), 31.3 (d, J = 16.9 Hz), 19.7 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ =

–169.6 ppm; MS (EI): m/z = 92 [M – C₂H₃F]⁺; elemental analysis calcd.

(%) for C₉H₁₁F: C 78.23, H 8.02; found: C 78.22, H 7.71.

20

colorless oil; t_R= 13.7 min; [α]_D= +7.12 (c = 1.0 in MeOH). (R)-32: 85

20

mg, 42%; colorless oil; t_R= 17.2 min; [α]_D= –7.08 (c = 1.0 in MeOH).

Spectral data for the enantiomers were in accordance with those for the

racemic mixture.

Ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-6-fluorospiro[3.3]hep-

tane-2-carboxylate (33): Ethyl 2-cyano-6-fluorospiro[3.3]heptane-2-

carboxylate (7) (75 g, 355 mmol) and Boc₂O (107 g, 492 mmol) were

dissolved in EtOH (500 mL) followed by addition of freshly prepared

Raney-Ni (15 g). The reaction mixture was loaded in an autoclave and

hydrogenated at 50 Bar for 64 h. Then it was filtered and evaporated at

reduced pressure to give the crude product, which was subjected to silica

gel column chromatography (hexane – EtOAc 6:1, R_f0.54) affording the

title compound 33 as colorless oil. Yield 94.4 g, 84%; mixtures of Boc-

rotamers were observed by NMR spectroscopy; ¹H NMR (400 MHz,

CDCl₃): δ = 4.92 (br. s, 1H), 4.91 (dquint, J = 55.7, 6.7 Hz, 1H), 4.18 (q, J

= 7.2 Hz, 2H), 3.53–3.35 (m, 2H), 2.68–2.56 (m, 1H), 2.56–2.39 (m, 3H),

2.39–2.16 (m, 2H), 2.13–2.00 (m, 2H), 1.45 (s, 9H), 1.30 (t, J = 7.2 Hz,

3H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 175.2, 155.8, 83.1 (d, J =

211.6 Hz), 78.8, 60.4, 45.4, 44.0 (d, J = 19.8 Hz), 43.7 (d, J = 19.8 Hz),

43.3, 39.8 and 39.7, 28.4 (d, J = 16.7 Hz), 27.9, 13.7 ppm; ¹⁹F{¹H} NMR

(376 MHz, CDCl₃): δ = –169.5 ppm; MS (APCI): m/z = 216 [M – CO₂–

C₄H₈+ H]⁺; HRMS (ESI) m/z [M + Na]⁺calcd for C₁₆H₂₆FNNaO₄:

338.1744, found: 338.1735.

2-(Ethoxycarbonyl)-6-fluorospiro[3.3]heptane-2-carboxylic acid (31):

A solution of diethyl 6-fluorospiro[3.3]heptane-2,2-dicarboxylate (6) (125

g, 484 mmol) in a mixture of EtOH (600 mL) and water (300 mL) was

brought to boil followed by dropwise addition of a solution of NaOH (18.4

g, 460 mmol) in water (300 mL) at reflux within 1 h. Then it was allowed

to equilibrate to rt and left to stir for 16 h. EtOH was evaporated at

reduced pressure, the remaining aqueous solution was diluted with water

(500 mL) and extracted with t-BuOMe (500 mL). The aqueous layer was

separated, acidified with 2M aq. HCl to pH 3, and extracted with EtOAc

(2  300 mL). The organic layer was dried (Na₂SO₄) and evaporated at

reduced pressure to give the title compound 31 as yellowish oil. Yield 86

General procedure for the Preparation of Amino Acid Ester

Hydrochlorides 34 and 35: The corresponding Boc-protected ester 32,

33 (8.5 mmol) was added to 2M ethanolic HCl (25 mL) and the resulting

mixture was stirred for 2 h. Then it was evaporated at reduced pressure,

the residue was triturated with Et₂O (20 mL) and filtered to give the title

compound 34, 35 as colorless powder.

1

g, 77%; H NMR (400 MHz, CDCl₃): δ = 4.91 (dquint, J = 55.6, 6.5 Hz,

1H), 4.25 (q, J = 7.1 Hz, 2H), 2.72–2.67 (m, 2H), 2.67–2.62 (m, 2H),

2.57–2.46 (m, 2H), 2.35–2.20 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H) ppm;

¹³C{¹H} NMR (154 MHz, CDCl₃): δ = 177.1, 171.2, 83.2 (d, J = 211.5 Hz),

61.9, 48.9, 43.7 (d, J = 8.9 Hz), 43.6 (d, J = 8.9 Hz), 40.9 (d, J = 29.0 Hz),

29.5 (d, J = 16.6 Hz), 13.96 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = –

170.1 ppm; MS (EI): m/z = 166 [M – CO₂– HF]⁺; HRMS (ESI) m/z

[M + H]⁺calcd for C₁₁H₁₆FO₄: 231.1033, found: 231.1023.

Ethyl

2-amino-6-fluorospiro[3.3]heptane-2-carboxylate

hydro-

chloride (34): from ethyl 2-((tert-butoxycarbonyl)amino)-6-fluoro-

spiro[3.3]heptane-2-carboxylate (32) (2.5 g, 8.3 mmol). Yield 1.74 g,

88%; m.p. 127–129 C; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.82 (s, 3H),

4.94 (dquint, J = 56.8, 5.9 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 2.70–2.51 (m,

6H), 2.32–2.11 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H) ppm; ¹³C{¹H} NMR (126

MHz, DMSO-d₆): δ = 171.2, 83.7 (d, J = 208.6 Hz), 62.3, 53.3, 43.8 (d, J

= 19.7 Hz), 43.6 (d, J = 19.7 Hz), 41.6 (d, J = 18.6 Hz), 27.8 (d, J = 17.5

Hz), 14.2 ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ = –168.2 ppm; MS

(APCI): m/z = 202 [M + H]⁺; HRMS (ESI) m/z [M + H]⁺calcd for

C₁₀H₁₇FNO₂: 202.1243, found: 202.1237.

Ethyl

carboxylate

2-((tert-butoxycarbonyl)amino)-6-fluorospiro[3.3]heptane-2-

(32): 2-(Ethoxycarbonyl)-6-fluorospiro[3.3]heptane-2-

carboxylic acid (31) (75 g, 326 mmol) was dissolved in a mixture of

CH₂Cl₂(800 mL) and DMF (1 mL) followed by dropwise addition of

(COCl)₂(50 g, 33.8 mL, 394 mmol). The resulting solution was stirred at

rt for 2 h and evaporated at reduced pressure. Thus obtained crude acid

chloride was dissolved in EtOAc (260 mL) and cooled to 0 C followed by

dropwise addition of a solution of NaN₃(63.6 g, 978 mmol) in water (400

mL) maintaining the above temperature. The reaction mixture was

allowed to stir at 0 C for an additional 1 h and extracted with EtOAc (2 

250 mL). The combined organic layer was dried (Na₂SO₄) and

evaporated to a half of initial volume at reduced pressure and external

temperature below 30 C. This solution was added dropwise to hot

(90 C) mixture of t-BuOH (250 mL) and PhMe (500 mL) and thus

obtained reaction mixture was stirred at above temperature for an

additional 40 h. Then it was evaporated at reduced pressure to give the

crude product which was subjected to silica gel column chromatography

(hexane – EtOAc 6:1, R_f0.46) affording the title compound 32 as

colorless crystals. Yield 70.1 g, 71%; m.p. 53–55 C; mixtures of Boc-

rotamers were observed by NMR spectroscopy; ¹H NMR (400 MHz,

CDCl₃): δ = 5.12 (br. s, 1H), 4.92 (dquint, J = 55.7, 6.7 Hz, 1H), 4.21 (q, J

= 7.1 Hz, 2H), 2.73–2.64 (m, 4H), 2.64–2.49 (m, 2H), 2.51–2.35 (m, 2H),

2.37–2.24 (m, 2H), 1.44 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H) ppm; ¹³C{¹H}

Ethyl 2-(aminomethyl)-6-fluorospiro[3.3]heptane-2-carboxylate hyd-

rochloride (35): from ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-6-

fluorospiro[3.3]heptane-2-carboxylate (33) (25 g, 79.3 mmol). Yield 18.3

g, 92%; b.p. 98–101 C; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.18 (s, 3H),

4.93 (dquint, J = 55.8, 6.4 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.08 (s, 2H),

2.62–2.51 (m, 2H), 2.42–2.33 (m, 2H), 2.31–2.07 (m, 4H), 1.22 (t, J = 7.1

Hz, 3H) ppm; ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ = 174.0, 83.8 (d, J =

209.6 Hz), 61.4, 44.03 (d, J = 20.0 Hz), 43.85 (d, J = 20.0 Hz), 43.88,

41.8, 40.0, 28.8 (d, J = 16.4 Hz), 14.3 ppm; ¹⁹F{¹H} NMR (376 MHz,

DMSO-d₆): δ = –167.6 ppm; MS (APCI): m/z = 216 [M + H]⁺; HRMS (ESI)

m/z [M + H]⁺calcd for C₁₁H₁₉FNO₂: 216.1400, found: 216.1391.

General procedure for the preparation of Boc-protected amino acids

36 and 37: The corresponding Boc-protected ester 32, 33 (99.5 mmol)

was added to the solution of NaOH (12 g, 300 mmol) in a mixture of

water (150 mL) and MeOH (150 mL) and the resulting mixture was

11

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European Journal of Organic Chemistry

FULL PAPER

allowed to stir at rt for 16 h. Then MeOH was evaporated at reduced

pressure, the remaining aqueous solution was acidified with 1M aq. HCl

to pH 3, and extracted with EtOAc (2  200 mL). The combined organic

layer was dried (Na₂SO₄) and evaporated at reduced pressure. The

residue was triturated with hexane (100 mL), filtered and washed with

hexane (7 mL) to give the title compound 36, 37 as colorless powder.

stirring for 16 h. After, the reaction mixture was quenched upon cooling

by sequential dropwise addition of water (1.8 mL), 50% aq. NaOH (1.8 g,

1 mL), and water (5.4 mL) again. The resulting mixture was allowed to

stir for 15 min, the precipitate formed was filtered off, washed with THF (2

 15 mL), and the filtrate was evaporated at reduced pressure. The

residue was dissolved in CH₂Cl₂(100 mL), dried (Na₂SO₄), and

evaporated at reduced pressure. The residue was dissolved in Et₂O (100

mL) followed by addition of 4M HCl in Et₂O (15 mL). The precipitate

formed was filtered and washed with a minimal amount of Et₂O to give

the title compound 38 as colorless powder. Yield 5.18 g, 52%; m.p. 138–

140 C; ¹H NMR (400 MHz, DMSO-d₆): δ = 7.91 (s, 3H), 5.07 (t, J = 5.4

Hz, 1H), 4.91 (dquint, J = 56.0, 6.8 Hz, 1H), 3.39 (s, 2H), 2.82 (s, 2H),

2.42 (p, J = 6.8 Hz, 2H), 2.20–2.04 (m, 2H), 2.01–1.90 (m, 2H), 1.90–

1.78 (m, 2H) ppm; ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ = 83.9 (d, J =

210.3 Hz), 65.5, 44.69, 44.72 (d, J = 19.0 Hz), 44.37 (d, J = 19.0 Hz),

39.2 (d, J = 17.2 Hz), 37.8, 28.0 (d, J = 16.2 Hz) ppm; ¹⁹F{¹H} NMR (376

MHz, DMSO-d₆): δ = –166.9 ppm; MS (APCI): m/z = 174 [M + H]⁺; HRMS

(ESI) m/z [M + H]⁺calcd for C₉H₁₇FNO: 174.1294, found: 174.1286.

2-((tert-Butoxycarbonyl)amino)-6-fluorospiro[3.3]heptane-2-

carboxylic acid (36): from ethyl 2-((tert-butoxycarbonyl)amino)-6-

fluorospiro[3.3]heptane-2-carboxylate (32) (30 g, 99.5 mmol). Yield 23.4

g, 86%; m.p. 159–160 C; mixtures of Boc-rotamers were observed by

NMR spectroscopy; ¹H NMR (400 MHz, CDCl₃): δ = 5.14 (br. s, 1H), 4.93

(dquint, J = 55.6, 6.7 Hz, 1H), 2.84–2.71 (m, 2H), 2.66–2.47 (m, 2H),

2.42–2.16 (m, 4H), 1.45 (s, 9H) ppm; ¹³C{¹H} NMR (151 MHz, DMSO-d₆):

δ = 175.9 and 175.4, 155.1 and 154.7, 83.8 (d, J = 209.8 Hz), 78.5 and

78.3, 54.6 and 54.3, 44.2 (d, J = 19.2 Hz), 43.7 (d, J = 19.2 Hz), 43.0 (d,

J = 12.1 Hz), 28.7, 28.4 (d, J = 14.7 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz,

CDCl₃): δ = –169.8 ppm; MS (APCI): m/z = 174 [M – CO₂– C₄H₈+ H]⁺;

HRMS (ESI) m/z [M + Na]⁺calcd for C₁₃H₂₀FNNaO₄: 296.1274, found:

296.1264.

General procedure for the preparation of N-phenyl carboxamides

43–45: The corresponding carboxylic acid 11, 39, 40 (6.32 mmol) was

dissolved in CH₂Cl₂(20 mL) followed by addition of DMF (0.02 mL) and

(COCl)₂(970 mg, 0.66 mL, 7.64 mmol). The resulting mixture was stirred

at rt for 3 h and evaporated at reduced pressure. Thus obtained crude

acyl chloride was dissolved in CH₂Cl₂(5 mL) and added dropwise to cold

(0 C) solution of PhNH₂(620 mg, 0.62 mL, 6.66 mmol) and Et₃N (958

mg, 1.32 mL, 9.47 mmol) in CH₂Cl₂(20 mL), maintaining the above

temperature. Then it was allowed to warm to rt and left to react with

stirring for 16 h. After, the reaction mixture was successively washed with

water (25 mL) and saturated aq. Na₂CO₃(20 mL), dried (Na₂SO₄), and

evaporated at reduced pressure. The residue was triturated with hexane

(10 mL) and filtered to give the title compound 43–45 as colorless

powder.

2-(((tert-Butoxycarbonyl)amino)methyl)-6-fluorospiro[3.3]heptane-2-

carboxylic acid (37): from ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-

6-fluorospiro[3.3]heptane-2-carboxylate (33) (35 g, 111 mmol). Yield 27.7

g, 87%; m.p. 121–123 C; mixtures of Boc-rotamers were observed by

NMR spectroscopy; ¹H NMR (400 MHz, CDCl₃): δ = 4.99 (br. s, 1H), 4.93

(dquint, J = 56.5, 6.4 Hz, 1H), 3.57–3.36 (m, 2H), 2.77–2.43 (m, 4H),

2.42–2.19 (m, 2H), 2.18–1.98 (m, 2H), 1.49 (s, 9H) ppm; ¹³C{¹H} NMR

(151 MHz, CDCl₃): δ = 181.7 and 179.7, 157.8 and 156.4, 83.5 (d, J =

211.9 Hz), 81.3 and 79.5, 46.9 and 45.4, 44.5 (d, J = 19.4 Hz), 44.1 (d, J

= 19.4 Hz), 43.7, 40.1 and 40.0, 28.9 (d, J = 16.8 Hz), 28.4 ppm; ¹⁹F{¹H}

NMR (376 MHz, CDCl₃): δ = –169.5 ppm; MS (APCI): m/z = 286 [M – H]^–

; HRMS (ESI) m/z [M + Na]⁺calcd for C₁₄H₂₂FNNaO₄: 310.1430, found:

310.1420.

N-Phenylspiro[3.3]heptane-2-carboxamide

(43):

from

spiro[3.3]heptane-2-carboxylic acid (39) (886 mg, 6.32 mmol). Yield 1.14

g, 84%; m.p. 125–126 C; H NMR (400 MHz, DMSO-d₆): δ = 9.71 (s,

General procedure for the preparation of amino acids 29 and 30:

The corresponding Boc-protected amino acid 36, 37 (36.5 mmol) was

dispersed in water (100 mL) and the resulting mixture was stirred at

reflux for 40 h. Then it was evaporated at reduced pressure, the residue

was triturated with MeCN (50 mL), filtered, and washed with MeCN (2 

25 mL) to give the title compound 29, 30 as colorless powder.

1

1H), 7.59 (d, J = 7.7 Hz, 2H), 7.26 (t, J = 7.7 Hz, 2H), 7.00 (t, J = 7.7 Hz,

1H), 3.05 (p, J = 7.4 Hz, 1H), 2.23–2.08 (m, 4H), 2.03 (t, J = 7.4 Hz, 2H),

1.88 (t, J = 7.4 Hz, 2H), 1.77 (p, J = 7.4 Hz, 2H) ppm; ¹³C{¹H} NMR (126

MHz, DMSO-d₆): δ = 172.7, 139.4, 128.6, 122.8, 119.0, 37.3, 34.8, 34.4,

33.9, 15.9 ppm; MS (APCI): m/z = 216 [M + H]⁺; HRMS (ESI) m/z

[M + H]⁺calcd for C₁₄H₁₈NO: 216.1388, found: 216.1379.

2-Amino-6-fluorospiro[3.3]heptane-2-carboxylic acid (29): from 2-

((tert-butoxycarbonyl)amino)-6-fluorospiro[3.3]heptane-2-carboxylic acid

(36) (10 g, 36.5 mmol). Yield 5.83 g, 92%; m.p. 242–245 C; ¹H NMR

(400 MHz, D₂O): δ = 4.86 (dquint, J = 56.4, 6.8 Hz, 1H), 2.59–2.46 (m,

3H), 2.44–2.33 (m, 1H), 2.28 (t, J = 13.8 Hz, 2H), 2.24–2.09 (m, 2H)

ppm; ¹³C{¹H} NMR (126 MHz, D₂O): δ = 176.2, 84.3 (d, J = 205.7 Hz),

54.6, 42.8 (d, J = 20.5 Hz), 42.6 (d, J = 20.5 Hz), 41.1 (d, J = 50.1 Hz),

26.6 (d, J = 18.3 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, D₂O): δ = –168.9

ppm; MS (APCI): m/z = 174 [M + H]⁺; HRMS (ESI) m/z [M + H]⁺calcd for

C₈H₁₃FNO₂: 174.0930, found: 174.0921.

6-Fluoro-N-phenylspiro[3.3]heptane-2-carboxamide (44): from 6-

fluorospiro[3.3]heptane-2-carboxylic acid (11) (1 g, 6.32 mmol). Yield

1.17 g, 79%; m.p. 106–108 C; ¹H NMR (400 MHz, DMSO-d₆): δ = 9.74

(s, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.27 (t, J = 7.6 Hz, 2H), 7.01 (t, J = 7.6

Hz, 1H), 4.95 (dquint, J = 55.9, 6.6 Hz, 1H), 3.11 (p, J = 8.3 Hz, 1H),

2.43–1.97 (m, 8H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 172.0,

137.4, 128.5, 123.7, 119.2, 83.2 (d, J = 212.1 Hz), 43.1 (d, J = 20.0 Hz),

42.49 (d, J = 20.0 Hz), 36.8 (d, J = 5.8 Hz), 35.8, 30.3 (d, J = 16.5 Hz)

ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ = –167.5 ppm; MS (APCI):

m/z = 234 [M + H]⁺; MS (APCI): m/z = 234 [M + H]⁺; HRMS (ESI) m/z

[M + H]⁺calcd for C₁₄H₁₇FNO: 234.1294, found: 234.1284.

2-(Aminomethyl)-6-fluorospiro[3.3]heptane-2-carboxylic acid (30):

from 2-(((tert-butoxycarbonyl)amino)methyl)-6-fluorospiro[3.3]heptane-2-

carboxylic acid (37) (10 g, 34.8 mmol). Yield 5.87 g, 90%; m.p. 225–

227 C; ¹H NMR (400 MHz, D₂O): δ = 4.87 (dquint, J = 56.5, 6.8 Hz, 1H),

3.08 (s, 2H), 2.49–2.27 (m, 4H), 2.23–2.02 (m, 2H), 2.02–1.85 (m, 2H)

ppm; ¹³C{¹H} NMR (126 MHz, D₂O): δ = 181.6, 84.5 (d, J = 206.5 Hz),

45.1, 43.1 (d, J = 19.0 Hz), 42.8 (d, J = 19.0 Hz), 41.7, 39.7 (d, J = 11.3

Hz), 27.4 (d, J = 18.0 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, D₂O): δ = –167.8

ppm; MS (APCI): m/z = 188 [M + H]⁺; HRMS (ESI) m/z [M + H]⁺calcd for

C₉H₁₅FNO₂: 188.1087, found: 188.1079.

6,6-Difluoro-N-phenylspiro[3.3]heptane-2-carboxamide (45): from

6,6-difluorospiro[3.3]heptane-2-carboxylic acid (40) (1.11 g, 6.32 mmol).

Yield 1.19 g, 75%; m.p. 117–118 C; ¹H NMR (400 MHz, DMSO-d₆): δ =

9.78 (s, 1H), 7.59 (d, J = 7.7 Hz, 2H), 7.28 (t, J = 7.7 Hz, 2H), 7.01 (t, J =

7.7 Hz, 1H), 3.15 (p, J = 9.2 Hz, 1H), 2.67 (t, J = 12.5 Hz, 2H), 2.54 (t, J =

12.5 Hz, 2H), 2.35 (t, J = 9.2 Hz, 2H), 2.26 (t, J = 9.2 Hz, 2H) ppm;

¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ = 172.7, 139.7, 129.1, 123.4,

120.7 (t, J = 279.3 Hz), 119.5, 47.3 (t, J = 21.2 Hz), 46.6 (t, J = 21.2 Hz),

36.5, 34.9, 28.8 (t, J = 9.2 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆):

δ = –89.5 ppm; MS (APCI): m/z = 252 [M + H]⁺; HRMS (ESI) m/z

[M + H]⁺calcd for C₁₄H₁₆F₂NO: 252.1199, found: 252.1190.

(2-(Aminomethyl)-6-fluorospiro[3.3]heptan-2-yl)methanol (38): Ethyl

2-cyano-6-fluorospiro[3.3]heptane-2-carboxylate (7) (10 g, 47.1 mmol)

was added to the stirred suspension of LiAlH₄(1.8 g, 47.3 mmol) in THF

(70 mL) at 0 C. Then it was allowed to warm to rt and left to react with

12

10.1002/ejoc.202100804

European Journal of Organic Chemistry

FULL PAPER

General Procedure for the Preparation of Benzamides 46–48: The

corresponding amine hydrochloride 13, 41, 42 (6.04 mmol) was dissolved

in CH₂Cl₂(20 mL) followed by addition of Et₃N (1.52 g, 2.09 mL, 15

mmol) and the resulting mixture was cooled to 0 C. Then PhCOCl (0.89

g, 0.74 mL, 6.33 mmol) was added dropwise and thus obtained reaction

mixture was stirred at rt for 16h. Then it was successively washed with

water (25 mL) and saturated aq. Na₂CO₃(20 mL), dried (Na₂SO₄), and

evaporated at reduced pressure. The residue was triturated with hexane

(10 mL) and filtered to give the title compound 46–48 as colorless

powder.

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N-(Spiro[3.3]heptan-2-yl)benzamide (46): from spiro[3.3]heptan-2-

amine hydrochloride (41) (890 mg, 6.04 mmol). Yield 1.08 g, 83%; m.p.

1

167–169 C; H NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 7.5 Hz, 2H),

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[9]

A. S. Ulrich, Prog. Nucl. Magn. Reson. Spectrosc. 2005, 46, 1–21.

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7.48 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 6.31 (br. s, 1H), 4.45 (h,

J = 8.1 Hz, 1H), 2.52 (td, J = 8.1, 3.2 Hz, 2H), 2.08 (t, J = 7.3 Hz, 2H),

2.00–1.78 (m, 6H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 166.2,

134.2, 130.8, 128.0, 126.4, 43.0, 40.4, 37.1, 34.3, 33.8, 16.3 ppm; MS

(APCI): m/z = 216 [M + H]⁺; HRMS (ESI) m/z [M + H]⁺calcd for

C₁₄H₁₈NO: 216.1388, found: 216.1385.

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D. Bandak, O. Babii, R. Vasiuta, I. V. Komarov, P. K. Mykhailiuk,

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Pharmaceuticals, Medicinal Diagnostics, and Agrochemicals,

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N-(6-Fluorospiro[3.3]heptan-2-yl)benzamide

(47):

from

6-

fluorospiro[3.3]heptan-2-amine hydrochloride (13) (1 g, 6.04 mmol). Yield

1.2 g, 85%; m.p. 137–138 C; ¹H NMR (400 MHz, CDCl₃): δ = 7.72 (d, J

= 7.5 Hz, 2H), 7.45 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 6.50 (br. s,

1H), 4.88 (dquint, J = 55.5, 7.0 Hz, 1H), 4.46 (h, J = 8.1 Hz, 1H), 2.56–

2.35 (m, 3H), 2.35–2.10 (m, 3H), 2.04 (t, J = 10.2 Hz, 1H), 1.95 (t, J =

10.2 Hz, 1H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 166.8, 134.4,

131.4, 128.5, 126.9, 83.8 (d, J = 212.4 Hz), 43.0 (d, J = 19.8 Hz), 42.8,

42.6 (d, J = 19.8 Hz), 41.2, 28.3 (d, J = 16.9 Hz) ppm; ¹⁹F{¹H} NMR (376

MHz, CDCl₃): δ = –166.8 ppm; MS (APCI): m/z = 234 [M + H]⁺; HRMS

(ESI) m/z [M + H]⁺calcd for C₁₄H₁₇FNO: 234.1294, found: 234.1284.

[12]

[13]

S. O. Kokhan, A. V Tymtsunik, S. L. Grage, S. Afonin, O. Babii, M.

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66, 2196–2202.

N-(6,6-Difluorospiro[3.3]heptan-2-yl)benzamide (48): from 6,6-

difluorospiro[3.3]heptan-2-amine hydrochloride (42) (1.11 g, 6.04 mmol).

Yield 1.34 g, 88%; m.p. 134–135 C; ¹H NMR (400 MHz, DMSO-d₆): δ =

8.60 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 7.4 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H),

7.45 (t, J = 7.4 Hz, 2H), 4.37 (h, J = 8.2 Hz, 1H), 2.69 (t, J = 13.3 Hz, 2H),

2.57 (t, J = 13.3 Hz, 2H), 2.41 (td, J = 8.2, 3.0 Hz, 2H), 2.25 (td, J = 8.2,

3.0 Hz, 2H) ppm; ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ = 165.9, 134.8,

131.5, 128.6, 127.7, 120.8 (t, J = 279.3 Hz), 47.0 (t, J = 21.2 Hz), 46.2 (t,

J = 21.2 Hz), 41.6, 26.2 (t, J = 9.5 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz,

DMSO-d₆): δ = –89.5 ppm; MS (APCI): m/z = 252 [M + H]⁺; HRMS (ESI)

m/z [M + H]⁺calcd for C₁₄H₁₆F₂NO: 252.1199, found: 252.1189.

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Acknowledgements

A. Chernykh, D. Radchenko, O. Grygorenko, C. Daniliuc, D.

Volochnyuk, I. Komarov, J. Org. Chem. 2015, 80, 3974–3981.

J. A. Burkhard, B. Wagner, H. Fischer, F. Schuler, K. Müller, E. M.

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The work was funded by Enamine Ldt. Additional funding from

Ministry of Education and Science of Ukraine, Grants No.

19BF037-03 (A.V.D. and O.O.G.) and 21BF037-01M (A.V.C.

and O.O.G) is also acknowledged. The authors thank Dr.

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Fluorinated spirocycles

The convergent synthesis of a series of mono- and bifunctional 6-fluoro-spiro[3.3]heptanes – advanced fluorine-labelled

conformationally rigid building blocks for medicinal chemistry – is developed. The target products were obtained on a multigram scale

(up to 302 g), characterized (pKa, LogP, and S_w), and assessed with the lead-likeness criteria.

Institute and/or researcher Twitter usernames: @DrGregor2 @KyivUniversity @EnamineLtd

15

Article Doi

Fluorine-Labelled Spiro[3.3]heptane-Derived Building Blocks: Is Single Fluorine the Best?

DOI: 10.1002/ejoc.202100804

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