Boron Trifluoride-Mediated Cycloaddition of 3-Bromotetrazine and Silyl Enol Ethers: Synthesis of 3-Bromo-pyridazines

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Boron Triﬂuoride-Mediated Cycloaddition of 3‑Bromotetrazine and

Silyl Enol Ethers: Synthesis of 3‑Bromo-pyridazines

Simon D. Schnell, Jorge A. Gonz á lez, Jan Sklyaruk, Anthony Linden, and Karl Gademann*

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ABSTRACT: Pyridazines are important scaﬀolds for medicinal

chemistry or crop protection agents, yet the selective preparation of 3-

bromo-pyridazines with high regiocontrol remains diﬃcult. We achieved

the Lewis acid-mediated inverse electron demand Diels−Alder reaction

between 3-monosubstituted s-tetrazine and silyl enol ethers and obtained

functionalized pyridazines. In the case of 1-monosubstituted silyl enol

ethers, exclusive regioselectivity was observed. Downstream functional-

ization of the resulting 3-bromo-pyridazines was demonstrated utilizing

several cross-coupling protocols to synthesize 3,4-disubstituted pyr-

idazines with excellent control over the substitution pattern.

air (Scheme 1B) and thus has to be synthesized in a glovebox.¹⁰

A one-pot procedure to obtain a pyridazine-coordinated air-

stable variant of the catalyst was also disclosed; however, here

too, strictly inert conditions and hazardous reagents have to

utilized to synthesis this compound.¹⁰In contrast to our recently

reported azaphilic addition of terminally substituted silyl enol

ethers (Scheme 1C),¹¹which delivers dearomatized dihydrote-

trazines and in some cases pyridazines as minor byproducts in

low yields, we envisioned using terminally unsubstituted silyl

enol ethers to selectively undergo iEDDA reactions (Scheme

1D).

Herein, we report in full detail the synthesis of polyfunction-

alized pyridazines using the Lewis acid-mediated iEDDA

reaction of 3-Br-Tet (1) with silyl enol ethers under very mild

reaction conditions. Additionally, the scale-up of the presented

method and downstream diversiﬁcation via various cross-

coupling reactions are demonstrated.

INTRODUCTION

■

Pyridazines have recently moved into the focus of research in the

context of biologically active N-heterocycles, such as crop

protection agents and pharmaceutically active compounds.¹

Since the pyridazine ring can be considered as a bioisostere to

both phenyl and pyridyl rings, the replacement of these aromatic

rings by a pyridazine ring gives rise to a number of diaza

analogues.²These heterocycles usually exhibit higher crystal-

linities and lower logP values and also have the possibility to

enhance the stability of the drug in the active pocket by

hydrogen bonding between the receptor protein and the active

compound.³In contrast to this great potential, the production of

functionalized pyridazines with high regiocontrol still remains a

challenge in organic synthesis.⁴The selective formation of

bromo-pyridazines would help to overcome this problem due to

facile downstream diversiﬁcation via a cross-coupling reaction or

nucleophilic aromatic substitution. The most common method

for installing a bromide substituent on the pyridazine moiety

relies on using a pyridazinone precursor and phosphoroxytri-

bromide at elevated temperatures (Scheme 1A).⁵This reagent

suﬀers from an incompatibility with an array of functional

groups and additionally produces toxic HBr on contact with

water. To overcome this issue, we envisioned the use of the

previously reported 3-bromotetratzine (3-Br-Tet) 1 as a suitable

precursor.⁶

RESULTS AND DISCUSSION

■

To establish suitable reaction conditions, the reaction of

tetrazine 1 and the silyl enol ether derived from cyclopentanone

was investigated (Table 1). Previous reports with unfunction-

alized tetrazine and (cyclopent-1-en-1-yloxy)trimethylsilane

required heating at 70 °C and prolonged reaction times (68

h) to aﬀord the product in a 51% yield.¹²Thus, we focused on

the development of a fast protocol, avoiding elevated temper-

In contrast to 3,6-dichlorotetrazine, which is commonly used

in inverse electron demand Diels−Alder (iEDDA) reactions to

generate 3,6-dichloropyridazines, the use of 3-halotetrazines in

the synthesis of 3-halopyridazines is under-exploited.^7,8Addi-

tionally, the employment of Lewis acids for the reaction of

tetrazines with dienophiles remains rare, and rather severe

thermal conditions have hitherto been required.^8,9The Wegner

group reported on a bisborane Lewis acid; however, it is diﬃcult

to obtain synthetically due to its instability towards moisture and

Received: June 11, 2021

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The Journal of Organic Chemistry

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Scheme 1. Approach to the Site-Selective Synthesis of 3,4-Disubstituted Bromopyridazines via iEDDA Reactions

Table 1. Optimization of the Reaction Conditions for Cyclic Silyl Enol Ethers

a

entry

R

equiv of silyl enol ether

equiv of BF₃·OEt₂

T (°C)

25

solvent

time (h)

yield 2a (%)

1

2

3

4

5

6

7

8

TMS

TBS

3

1

2

1

3

1

2

5

1.4

1

CH₂Cl₂

PhCF₃

1,4-dioxane

MeCN

CH₂Cl₂

PhCF₃

CH₂Cl₂

PhCF₃

2

20

traces

36

14

36

traces

29

19

0

35

49

44

25

18

1.05

−78 to 25

0−25

2.5

0.17

1.5

0.17

7

b

1.05

2.1

2

9

10

11

12

13

14

0−25

0

13

0

c

TMS

0−25

a

b

c

Isolated yield. BF₃·OEt₂and 3-Br-Tet (1) were premixed for 5 min at −78 °C. Tris(pentaﬂuorophenyl)borane was used instead of BF₃·OEt₂.

atures and long reaction times. Initially, the treatment of 3-Br-

Tet (1) with 3 equiv of (cyclopent-1-en-1-yloxy)trimethylsilane

aﬀorded only traces of the desired product (Table 1, entry 1).

Switching the solvent to triﬂuorotoluene (36% yield; Table 1,

entry 2) or dioxane (36% yield; Table 1, entry 4) and prolonging

the reaction time improved the formation of the desired bicycle

2a. Acetonitrile as a solvent led only to traces of product (Table

1, entry 5). To further improve the yield of the reaction, the use

of BF₃·OEt₂as a Lewis acid mediator was investigated. Using

1.05 equiv of BF₃·OEt₂in CH₂Cl₂aﬀorded a moderate yield of

29% (Table 1, entry 6).

As a coordination of the Lewis acid to the tetrazine core was

hypothesized as the ﬁrst step of the reaction,¹¹prestirring BF₃·

OEt₂with Br-Tet for 5 min prior to addition of the silyl enol

ether was tested. The yield of 2a, however, turned out to be

diminished (19%; Table 1, entry 7), probably due to

decomposition of tetrazine 1. Increasing the equivalents of

silyl enol ether also had a negative impact on the reaction (Table

1, entry 8). This entry emphasizes the necessity of the fast

kinetics achieved by employing a Lewis acid, since 3-BrTet (1)

does not seem to be stable toward the potentially nucleophilic

and basic silyl enol ether. However, raising the starting

temperature from −78 to 0 °C and increasing the amount of

the Lewis acid to 2.1 equiv improved the yield to 49% (Table 1,

entry 10), which is comparable to the yield published by Sauer

and coauthors.¹²This observation can be rationalized with the

higher Lewis basicity of the formed pyridazine over that of the

tetrazine so that a pyridazine−BF₃complex is formed, thereby

depleting the reaction mixture of BF₃.¹³In contrast, an increase

of the equivalents of silyl enol ether to 2 equiv decreased the

yield to 44% (Table 1, entry 11) and the us of 5 equiv only led to

decomposition (Table 1, entry 12). A change of the silyl enol

ether to the corresponding TBS-silyl enol ether or the solvent to

triﬂuoromethyltoluene was also shown to not be beneﬁcial

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Scheme 2. Substrate Scope for the Synthesis of Fused 3-Bromo-pyridazines

(Table 1, entries 13 and 14, respectively). Additionally, other

boron-based Lewis acids (e.g., B(C₆F₅)₃; Table 1, entry 14) led

to no conversion. With these optimized conditions in hand, we

investigated the substrate scope using cyclic silyl enol ethers of

diﬀerent ring sizes (Scheme 1). Gratifyingly, several ring sizes

from ﬁve- to eight-membered rings could be synthesized in

moderate to good yields (2a−2e; Scheme 2). Additionally,

substitution on the ring was also tolerated, as shown for

compound 2e. Interestingly, when submitting the correspond-

ing TBS-silyl enol ether to the standard reaction conditions,

product formation could also be observed, but with a

signiﬁcantly lower yield of 13%. Collectively, the data clearly

establish that bicyclic pyridazines with a variety of ring sizes can

be accessed by this method in moderate to good yields.

Acyclic silyl enol ethers were investigated next. A maximum

yield of 55% was observed for the phenyl-substituted pyridazine

3a with the TMS-silyl enol ether derived from acetophenone. A

short optimization of the reaction conditions using the

corresponding TBS-silyl enol ether 4 and 3-Br-Tet (1) quickly

revealed a slight excess of TBS-silyl enol ether to be beneﬁcial

(Table 2), aﬀording 3a in an 82% yield (Table 2, entry 4).

Intrigued by this strong eﬀect of the employed silyl enol ether,

we also tested the corresponding TES- and TIPS-silyl enol

ethers; however, the desired product was obtained in 67% and

49% yields, respectively (Table 2, entries 6 and 7, respectively),

demonstrating the optimal balance between stability and

reactivity for the TBS-silyl enol ether.

With the optimized conditions in hand, we investigated the

substrate scope for this transformation. The reaction was found

to be very robust, and a variety of diﬀerent 3-bromo-4-aryl

pyridazines could be synthesized in good to excellent yields with

exclusive regioselectivity (Scheme 3). The other possible isomer

(3-bromo-5-aryl pyridazine) was never observed in any of the

cases.

Electron-rich and electron-poor aromatic systems were

accepted under these conditions (3b and 3f, respectively).

Interestingly, alkenes and alkynes were inert under the reaction

conditions, and the [4 + 2] cycloaddition was observed to take

place solely at the TBS-silyl enol ether, delivering 3d and 3e in

78% and 85% yields, respectively. Bromide and chloride

substituents on the dienophile also aﬀorded the desired products

in excellent yields. Additionally, nitrile and TBS-protected

hydroxy groups were tolerated, albeit with a slightly reduced

yield (around 50%). para- or meta-substitution on the arene was

tolerated without greatly inﬂuencing the yield (3i or 3j,

respectively). To further increase the synthetic utility of the

presented method, heterocyclic derivatives 3m and 3n were

synthesized in good yields. Besides an aromatic substituent on

the TBS-silyl enol ether, we also investigated the compatibility of

an alkyl chain. Gratifyingly, several alkyl-substituted TBS-silyl

enol ethers could be reacted with 3-Br-Tet (1) to produce the

corresponding pyridazines in good to excellent yields. A

cyclohexyl derivative (3o; 88% yield) was isolated, as well as

the sterically hindered derivative 3p (45% yield). To complete

the substrate scope, we varied the distance of the aromatic ring

from the TBS-silyl enol ether and could isolate 3q in a 64% yield,

clearly demonstrating that this reaction is not limited to an aryl

group at the TBS-silyl enol ether and also that alkyl chains can be

installed at the 4-position of the pyridazine.

Table 2. Optimization of the Reaction Conditions for Acyclic

Silyl Enol Ethers

With these results in hand, we were intrigued to ascertain if

more electron-rich aryl and alkyl tetrazines could also be

activated eﬃciently with BF₃·OEt₂(Scheme 4). Thus, we

synthesized a variety of 3,4-aryl- and 3-alkyl-4-aryl-substituted

pyridazines in good to excellent yields using silyl enol ether 4

(5a−5f). In particular, the alkyl-substituted compounds might

be valuable, since these compounds would be diﬃcult to obtain

via the cross-coupling of bromopyridazine precursors. Electron-

withdrawing and electron-donating substituents on the aryl

tetrazine were compatible with the method. Additionally, alkyl

benzyl ethers and alkyl esters could be installed on the tetrazine

core and subsequently converted to the alkyl pyridazine in

equiv of silyl enol equiv of BF₃·

time

yield 4a

a

Entry

R

ether

OEt₂

(min)

(%)

1

2

3

4

5

6

7

8

TMS

TBS

TES

TIPS

TBS

1

2.1

0

60

90

10

55

47

72

82

93

1.2

1.4

b

c

67

49

0

10

120

a

b

c

Isolated yield. 25 mg scale (entry 4). 500 mg scale (entry 5).

C

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Scheme 3. Substrate Scope for the Synthesis of 3-Bromo-4-aryl-pyridazines and 3-Bromo-4-alkyl-pyridazines

Scheme 4. Pyridazines from Aryl and Alkyl Tetrazines

moderate to good yields (5e and 5f, respectively). Lastly,

disubstituted tetrazines were evaluated, and we found that these

could also be engaged in the reaction. Compounds 6 and 7 were

obtained in 60% and 41% yields, respectively, thereby also

validating the method for 3,6-disubsituted s-tetrazines.

To further demonstrate the utility of the selective synthesis of

3-bromo-4-aryl-pyridazines and 3-bromo-4-alkyl-pyridazines,

D

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Scheme 5. Demonstration of the Downstream Functionalization of 3a

Scheme 6. Mechanistic Proposal for the iEDDA Reaction and the Observation of an Intriguing Reactivity

E

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we investigated the downstream functionalization of the

obtained compounds (Scheme 3). In a ﬁrst step, a scale-up of

the presented method was run to ensure the smooth conversion

to the desired product 3a on a larger scale. Using the established

conditions, the yield could even be improved to 93% on a 500

mg scale (compared to 82% on a 25 mg scale), thereby opening

the door to producing gram quantities of 3a (Scheme 5). Next,

we evaluated the hypothesis that these compounds could easily

undergo cross-coupling reactions. Thus, we investigated the

functionalization of the pyridazine at the C−Br position.

Suzuki−Miyaura cross-coupling aﬀorded the diaryl pyridazine

8, and Sonogashira cross-coupling to compound 9 and

Buchwald−Hartwig cross-coupling reactions to compound 10

could easily be carried out.¹⁴Additionally, the method reported

gives entry to the selective synthesis of 3,4-functionalized

pyridazines with exclusive regiocontrol.¹⁵

We next undertook a mechanistic study to gain insight into

the role of BF₃·OEt₂in the reaction and to validate our

hypothesis that the deactivation of BF₃·OEt₂by the formed

pyridazine is a reason for needing to use 2.1 equiv. The reaction

of 1 (0.10 M, 1 equiv), 4 (0.35 M, 1.4 equiv), and BF₃·OEt₂

(1.05 M) provides a reaction mixture amenable to in situ analysis

by IR spectroscopy at −50 °C. Kinetic data were acquired every

15 s and focused on the signal at 1202 cm⁻¹, which allowed for

the straightforward determination of temporal concentrations of

tetrazine 1. The kinetic proﬁle of 1 (Scheme 6A) ﬁrst shows a

fast process up to approximately 50% conversion in the ﬁrst 2

min of the reaction, followed by an inhibition that slows the

consumption of 1. After 2 h, the reaction was quenched, and the

crude mixture was analyzed by NMR spectroscopy, conﬁrming

that the reaction reached 90% conversion. A kinetic model was

then built to account for the experimental results; a two-step

process model gave a very good correlation with the

experimental data. This simple model consists of a reversible

fast equilibration (k₁= 0.254 M⁻¹s⁻¹) and an irreversible slow

step (k₂= 6.53 x10⁻³M⁻¹s⁻¹). The ﬁrst step is a bimolecular

process where 1 reacts with BF₃to form the corresponding

adduct 1-BF₃. Then, in a bimolecular step, 1-BF₃is able to react

with 4 to deliver the product 3a-BF₃as an adduct with BF₃, with

the concomitant formation of nitrogen. The fact that BF₃is

preferentially sequestered by coordination with the product 3a

has a direct impact on the overall rate; the depletion of BF₃

prevents the system form working eﬃciently when only

substoichiometric amounts of BF₃are used. Collectively, the

data and the model provide a rationale for the requirement of 2.1

equiv of BF₃·OEt₂to reach almost-quantitative conversion in a

short period of time.

and adds to the most electron-deﬁcient nitrogen (N-4) in the

system.¹¹An azaphilic addition product is obtained after the

hydrolysis of the intermediate, as indicated by several single

crystal structures (Scheme 6).^11,17Interestingly, and in stark

contrast to reports by the Boger group,¹⁸neither the

intermediate oxonium ion nor the formed dihydrotetrazine

undergo a 6π ring-opening and a further reaction to form a

triazine.¹⁸Potentially, the strong Lewis acid BF₃bound to the

dihydrotetrazine renders this reaction pathway unfavorable.

CONCLUSION

■

A fast and straightforward protocol has been developed for the

preparation of 3,4-disubstituted pyridazines using 3-monosub-

stituted s-tetrazines and silyl enol ethers. Along these lines,

brominated pyridazines were obtained from 3-bromotetrazine

with exclusive selectivity in high yields. In contrast to terminally

substituted silyl enol ethers, no azaphilic attack was observed.

Thus, easy access to these brominated heterocycles is given with

this approach, avoiding strong thermal conditions or POBr₃. As

demonstrated, these products can then easily be derivatized

using cross-coupling reactions and can thus serve as versatile

precursors in modiﬁcation reactions involving pyridazines.

EXPERIMENTAL SECTION

■

General Experimental Details. All chemicals were purchased

from Sigma-Aldrich, Acros, Alfa Aesar, or Fluka and were used without

further puriﬁcation. All reactions were carried out in ﬂame-dried

glassware under a nitrogen atmosphere. Solvents applied for chemical

transformations were either puriss-quality or HPLC-grade solvents. For

workup and puriﬁcation, solvents were distilled from technical-grade.

All synthetic transformations were monitored by either thin layer

chromatography (TLC), ¹H NMR spectroscopy, or UHPLC/ESI. TLC

was performed on Merck silica gel 60 F₂₅₄plates (0.25 mm thickness)

precoated with a ﬂuorescent indicator. The developed plates were

examined under a UV light and stained with either ceric ammonium

molybdate or potassium permanganate, followed by heating. GC/EI-

MS measurements were performed on a Finnigan Trace GC ultra from

Thermo Electron Corporation with EI (electron ionization), a Zebron

ZB-5MS (30 m) column, and a Finnigan Trace DSQ. Concentration

under reduced pressure was performed by rotary evaporation at 40 °C.

Flash chromatography was performed using silica gel 60 (230−400

mesh) from Sigma-Aldrich with a forced ﬂow eluent at a 0.3−0.5 bar

pressure. All ¹H, ¹³C, and ¹⁹F NMR spectra were recorded using Bruker

400 (¹H), 376 (¹⁹F), and 101 MHz (¹³C) or Bruker 500 (¹H) and 126

MHz (¹³C) spectrometers at 25 °C. Chemical shifts (δ values) are

reported in parts per million (ppm). Spectra were calibrated relative to

the residual proton chemical shifts of the solvents (CHCl₃, δ 7.26;

methanol-d₄, δ 3.31; DMSO-d₅, δ 2.50) and their residual carbon

chemical shifts (CDCl_3,δ 77.16; methanol-d₄, δ 49.00; DMSO-d₆, δ

39.52). Multiplicity is reported as follows: s = singlet, d = doublet, t =

triplet, q = quartet, m = multiplet or unresolved, and the coupling

constant J (Hz). IR spectra were recorded on a Varian 800 FT-IR ATR

spectrophotometer. Intensities are reported as follows: very strong (vs),

strong (s), medium (m), weak (w), and very weak (vw). The

absorptions are reported in inverse centimeters (cm⁻¹). RP-HPLC was

conducted with a Prominence modular HPLC instrument (Shimadzu)

coupled to a SPD-20A UV−vis detector (Shimadzu) using a reversed-

phase column (Gemini-NX C18, 5 μm, 10 Å, 150 mm × 4.6 mm;

Phenomenex) for analytical HPLC. The LC was equipped with a CBM-

20A system controller, a LC-20AP solvent delivery unit, a DGU-20A

degassing unit, and a FRC-10A fraction collector (all Shimadzu). The

following solvents were used: H₂O + 0.1% HCOOH (A) and MeCN +

0.1% HCOOH (B). All high-resolution mass spectra (HRMS-ESI)

were recorded by the mass spectrometry service at the University of

Based on the experimental observations and our previous

work,¹¹we propose the following mechanism for the reaction.

BF₃·OEt₂prefers binding to N-1 over N-2 (Scheme 6) due to the

lower steric interaction with the Br-substituent, thereby

lowering the LUMO energy and leading to a stronger overlap

with the HOMO of the silyl enol ether.¹¹Activation of the

tetrazine core by BF₃·OEt₂at N-1 is followed by the selective

formation of intermediate C, which rapidly loses nitrogen.

Rearomatization via the loss of TBSOH then aﬀords the product

pyridazine.^11,16In contrast, the formation of intermediate C is

sterically unfavorable for terminally substituted silyl enol ethers,

leading to a completely diﬀerent reaction pathway. As was

demonstrated by the active strain model, the energy required to

transform the terminally substituted silyl enol ether into the

planar transition state renders the iEDDA reaction unfavor-

able.¹¹In this instance, the double bond acts as a nucleophile

Zurich on a Finnigan MAT95 mass spectrometer or (for EI) on a DFS

̈

double-focusing (BE geometry) magnetic sector mass spectrometer

(ThermoFisher Scientiﬁc, Bremen, Germany). Mass spectra were

F

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measured with electron ionization (EI) at 70 eV using a solid probe

inlet, a source temperature of 200 °C, an acceleration voltage of 5 kV,

and a resolution of 10 000. The instrument was scanned between m/z

300 and 350 at scan rate of 100−200 s/decade in the electric scan mode.

Perﬂuorokerosene (PFK, Fluorochem, Derbyshire, UK) served for

calibration or was analyzed with an Acquity UPLC (Waters, Milford,

USA) system connected to an Acquity eλ detector and a maXis QToF

high-resolution mass spectrometer (Bruker Daltonics, Bremen,

Germany). Separation was performed with an Acquity BEH C18

HPLC column (1.7 μm particle size, 2 × 100 mm, Waters) kept at 30

°C. The mobile phase consisted of H₂O + 0.1% HCOOH (A) and

CH₃CN + 0.1% HCOOH (B). A linear gradient was run from 5% to

98% B within 5 min, followed by ﬂushing with 98% B for 1 min at a 400

μL min⁻¹ﬂow rate. UV spectra were recorded between 200 and 600 nm

at a 1.2 nm resolution and 20 points/s. The mass spectrometer was

operated in the positive (negative) electrospray ionization mode at a

4000 V (−4000 V) capillary voltage and a −500 V (500 V) end plate

oﬀset, with a N₂nebulizer pressure of 1.6 bar and a dry gas ﬂow of 8l

min⁻¹at 200 °C. Spectra were acquired in the mass range from m/z 50

to 2000 at a 20 000 resolution (full-width at half-maximum) and a 1.5

Hz rate. The mass analyzer was calibrated prior to analysis between m/z

158 and 1450 using a 2 mM solution of sodium formate at a resolution

of 20 000 and a mass accuracy below 2 ppm. UV−vis spectra were

recorded on a Shimadzu UV-1800 spectrometer. In situ infrared spectra

were recorded with a Mettler Toledo ReactIR 15 system with a MCT

detector that was equipped with a DiComp probe and a silver halide

ﬁber (9.5 mm x 2 m). Melting points (mp) were determined using a

CH₂Cl₂) to aﬀord 3-benzyltetrazine (104 mg, 0.604 mmol, 30%) as a

red oil. ¹H NMR (CDCl₃, 400 MHz) δ 10.19 (s, 1H), 7.43 (d, J = 7.1

Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 4.67 (s, 2H).

The obtained analytical data are consistent with the values reported in

the literature.²¹

Synthesis of TMS-Silyl Enol Ethers (GP1). The respective ketone

(1.00 equiv) was dissolved in MeCN (0.2−0.3 M) and NaI (1.20 equiv)

and TMSCl (freshly distilled from CaH₂) (1.20 equiv) were added.

Triethylamine (1.20 equiv) was added and the mixture was stirred

overnight. Water and diethyl ether were added and the layers were

separated. The aqueous layer was extracted with diethyl ether or

pentane and the combined organic layers were dried over sodium

sulfate, ﬁltered and concentrated. The crude product was then puriﬁed

via ﬂash column chromatography on silica gel or distillation.

(Cyclopent-1-en-1-yloxy)trimethylsilane.²²(Cyclopent-1-en-1-

yloxy)trimethylsilane (763 mg, 4.88 mmol, 86%) was obtained from

cyclopentanone (0.50 mL, 5.65 mmol, 1.00 equiv) according to GP1

without puriﬁcation as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ

4.62−4.61 (m, 1H), 2.29−2.23 (m, 4H), 1.89−1.82 (m, 2H), 0.21 (s,

9H). The obtained analytical data are consistent with the values

reported in the literature.²²

(Cyclohex-1-en-1-yloxy)trimethylsilane.²³(Cyclohex-1-en-1-

yloxy)trimethylsilane (820 mg, 4.80 mmol, 85%) was obtained from

cyclohexanone (0.59 mL, 5.65 mmol, 1.00 equiv) according to GP1

without puriﬁcation as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ

4.87−4.85 (m, 1H), 2.03−1.96 (m, 4H), 1.68−1.62 (m, 2H), 1.54−

1.48 (m, 2H), 0.18 (s, 9H). The obtained analytical data are consistent

with the values reported in the literature.²³

Buchi B-545 apparatus in open capillaries and are reported uncorrected.

̈

X-ray diﬀraction data were recorded using a Rigaku Oxford Diﬀraction

SuperNova area-detector diﬀractometer.

(Cyclohept-1-en-1-yloxy)trimethylsilane.²⁴(Cyclohept-1-en-1-

yloxy)trimethylsilane (637 mg, 3.46 mmol, 41%) was obtained from

cycloheptanone (1.00 mL, 8.47 mmol, 1.00 equiv) according to GP1

after ﬂash column chromatography on silica gel (2% triethylamine in

pentane) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 5.02 (t, J =

6.6 Hz, 1H), 2.24−2.21 (m, 2H), 1.99 (q, J = 6.3 Hz, 2H), 1.70−1.66

(m, 2H), 1.59−1.50 (m, 4H), 0.17 (s, 9H). The obtained analytical data

are consistent with the values reported in the literature.²⁴

3-Bromotetrazine (1).⁶3-Hydrazinotetrazine^6,19(1.38 g, 12.3

mmol, 1.00 equiv) was added to MeCN (23 mL), and the mixture

was cooled to 0 °C. Dibromoisocyanuric acid (5.51 g, 18.5 mmol, 1.50

equiv) was added to the mixture in portions over 10 min. Then, the

bright orange suspension was allowed to warm to 25 °C and stirred for 1

h. The suspension was ﬁltered through a pad of Celite covered with

silica gel, and the ﬁlter cake was rinsed with CH₂Cl₂until the ﬁltrate

became colorless. The solvent was removed under a stream of nitrogen

(caution! product is volatile). The crude product was then puriﬁed via

ﬂash column chromatography on silica gel (CH₂Cl₂) to aﬀord 3-

bromotetrazine (1) (854 mg, 5.30 mmol, 43%) as a bright orange

(E)-(Cyclooct-1-en-1-yloxy)trimethylsilane.²⁴(E)-(Cyclooct-1-en-

1-yloxy)trimethylsilane (972 mg, 4.90 mmol, 52%) was obtained from

cyclooctanone (1.2 g, 9.51 mmol, 1.00 equiv) according to GP1 without

further puriﬁcation. ¹H NMR (CDCl₃, 400 MHz) δ 4.74 (t, J = 8.4 Hz,

1H), 2.19−2.16 (m, 2H), 2.03−1.98 (m, 2H), 1.60−1.45 (m, 8H), 0.19

(s, 9H). The obtained analytical data are consistent with the values

reported in the literature.^24,25

1

crystalline solid. H NMR (CDCl₃, 400 MHz) δ 10.34 (s, 1H); ¹³C

{¹H} NMR(CDCl₃, 101 MHz) δ 164.2, 158.0. The obtained analytical

data are consistent with the values reported in the literature.⁶

Trimethyl(([1,2,3,6-tetrahydro-1,1′-biphenyl]-4-yl)oxy)silane.²⁶

Trimethyl((1,2,3,6-tetrahydro-[1,1′-biphenyl-4-yl)oxy)silane (596 mg,

2.42 mmol, 42%) was obtained from 4-phenylcyclohexanone (1.00 g,

5.47 mmol, 1.00 equiv) according to GP1 after ﬂash column

chromatography on silica gel (10% diethyl ether/2% triethylamine in

pentane) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.35−7.18

(m, 5H), 4.96−4.94 (m, 1H), 2.80−2.76 (m, 1H), 2.32−2.19 (m, 3H),

2.10−2.07 (m, 1H), 1.99−1.96 (m, 1H), 1.93−1.85 (m, 1H), 0.22 (s,

9H). The obtained analytical data are consistent with the values

reported in the literature.²⁶

3-Phenyltetrazine.²⁰Ethyl benzimidate (1.00 g, 5.39 mmol, 1.00

equiv) was dissolved in hydrazine hydrate (5.24 mL, 108 mmol, 20.0

equiv), and formamidine acetate salt (2.24 g, 21.6 mmol, 4.00 equiv)

was added portionwise to the mixture. The mixture was stirred for 18 h,

then glacial acetic acid (10 mL) was added and the mixture was cooled

to 0 °C. NaNO₂(1.50 g, 21.6 mmol, 4.00 equiv), in H₂O (10 mL), was

added slowly, and the mixture was stirred for 1 h. Then, ice−water (50

mL) was added to the mixture, and the suspension was ﬁltered. The

residue was puriﬁed via ﬂash column chromatography on silica gel

(diethyl ether) to aﬀord tetrazine 3-phenyltetrazine (312 mg, 1.97

mmol, 37%) as a pink solid. ¹H NMR (CDCl₃, 400 MHz) δ 10.23 (s,

1H), 8.65−8.63 (m, 2H), 7.69−7.60 (m, 3H). The obtained analytical

data are consistent with the values reported in the literature.²⁰

Trimethyl((1-phenylvinyl)oxy)silane.²³Trimethyl((1-

phenylvinyl)oxy)silane (1.03 g, 5.36 mmol, 95%) was obtained from

acetophenone (0.66 mL, 5.65 mmol, 1.00 equiv) according to GP1 after

puriﬁcation via distillation under reduced pressure as a colorless oil. ¹H

NMR (CDCl₃, 400 MHz) δ 7.67−7.65 (m, 2H), 7.41−7.32 (m, 3H),

4.99 (d, J = 1.7 Hz, 1H), 4.50 (d, J = 1.7 Hz, 1H), 0.34 Hz (s, 9H). The

obtained analytical data are consistent with the values reported in the

literature.²³

Synthesis of TBS-silyl enol ethers (GP2). The respective ketone

(1.00 equiv) was dissolved in CH₂Cl₂. To the mixture was added

triethylamine, followed by TBSOTf at 0 °C. The reaction mixture was

allowed to warm to 25 °C and stirred until full completion was reached,

as judged by TLC (1−2 h). Then, a saturated aqueous ammonium

chloride solution (20 mL) was added to the mixture, and the layers were

separated. The organic layer was extracted with diethyl ether (2 × 50

mL), and the combined organic layers were dried over sodium sulfate,

3-Benzyltetrazine.²¹Benzyl cyanide (0.23 mL, 2.00 mmol, 1.00

equiv), sulfur (128 mg, 4.00 mmol, 2.00 equiv), and EtOH (1 mL) were

added to a microwave vial, and the vial was sealed. Through the septum

hydrazine hydrate (0.78 mL, 16.0 mmol, 8.00 equiv) was added, and the

mixture was heated to 50 °C in a microwave (Biotage Initiator+) for 24

h. The temperature was monitored by the internal thermometer of the

microwave. Then, CH₂Cl₂(6.0 mL) was added to the mixture, followed

by NaNO₂(1.39 g, 20 mmol, 10.0 equiv) in H₂O (20 mL) and glacial

acetic acid (20 mL). The layers were separated, and the aqueous layer

was extracted with CH₂Cl₂(2 × 20 mL) after the gas evolution had

ceased. The combined organic layers were dried over sodium sulfate,

ﬁltered, and concentrated. The crude product was puriﬁed via ﬂash

column chromatography on silica gel (33% CH₂Cl₂in pentane to 100%

G

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ﬁltered, and concentrated. The crude product was then puriﬁed via ﬂash

column chromatography.

7.70 mmol, 1.00 equiv), triethylamine (1.30 mL, 9.24 mmol, 1.20

equiv) and TBSOTf (1.95 mL, 8.47 mmol, 1.10 equiv) according to

GP2 after puriﬁcation via ﬂash column chromatography on silica gel

(1% triethylamine in pentane) as a colorless oil. ¹H NMR (CDCl₃, 400

MHz) δ 7.53 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 4.86 (d, J =

1.9 Hz, 1H), 4.43 (d, J = 1.9 Hz, 1H), 1.00 (s, 9H), 0.21 (s, 6H). The

obtained analytical data are consistent with the values reported in the

literature.²⁹

tert-Butyldimethyl((1-phenylvinyl)oxy)silane (4).²³tert-

Butyldimethyl((1-phenylvinyl)oxy)silane (4.00 g, 17.1 mmol, quant.)

was obtained from acetophenone (2.0 mL, 17.1 mmol, 1.00 equiv),

triethylamine (2.91 mL, 20.5 mmol, 1.20 equiv), and TBSOTf (4.32

mL, 18.8 mmol, 1.10 equiv) according to GP2 after puriﬁcation via ﬂash

column chromatography on silica gel (2.5% triethylamine in pentane)

as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.62−7.60 (m, 2H),

7.35−7.28 (m, 3H), 4.89 (d, J = 1.5 Hz, 1H), 4.42 (d, J = 1.5 Hz, 1H),

1.01 (s, 9H), 0.21 (s, 6H). The obtained analytical data are consistent

with the values reported in the literature.²³

((1-(4-Bromophenyl)vinyl)oxy)(tert-butyl)dimethylsilane.³⁰((1-

(4-Bromophenyl)vinyl)oxy)(tert-butyl)dimethylsilane (1.37 g, 4.37

mmol, 89%) was obtained from 4-bromoacetophenone (0.61 mL,

4.92 mmol, 1.00 equiv), triethylamine (0.83 mL, 5.90 mmol, 1.20

equiv), and TBSOTf (1.24 mL, 5.41 mmol, 1.10 equiv) according to

GP2 after puriﬁcation via ﬂash column chromatography on silica gel

(1% triethylamine in pentane) as a colorless oil. ¹H NMR (CDCl₃, 400

MHz) δ 7.48−7.43 (m, 4H), 4.87 (d, J = 1.9 Hz, 1H), 4.43 (d, J = 1.9

Hz, 1H), 0.99 (s, 9H), 0.21 (s, 6H). The obtained analytical data are

consistent with the values reported in the literature.³⁰

tert-Butyldimethyl((1-(4-(triﬂuoromethyl)phenyl)vinyl)oxy)-

silane.²³tert-Butyldimethyl((1-(4-(triﬂuoromethyl)phenyl)vinyl)-

oxy)silane (802 mg, 2.65 mmol, 94%) was obtained from p-

triﬂuoromethylacetophenone (529 mg, 2.81 mmol, 1.00 equiv),

triethylamine (0.47 mL, 3.37 mmol, 1.20 equiv), and TBSOTf (0.71

mL, 3.09 mmol, 1.10 equiv) according to GP2 after puriﬁcation via ﬂash

column chromatography on silica gel (1% triethylamine in pentane) as

a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.70 (d, J = 8.0 Hz, 2H),

7.58 (d, J = 8.3 Hz, 2H), 4.97 (d, J = 2.0 Hz, 1H), 4.52 (d, J = 2.0 Hz,

1H), 1.00 (s, 9H), 0.22 (s, 6H); ¹⁹F NMR (CDCl₃, 376 MHz) = −62.6.

The obtained analytical data are consistent with the values reported in

the literature.²³

tert-Butyldimethyl((1-(p-tolyl)vinyl)oxy)silane.²³tert-

Butyldimethyl((1-(p-tolyl)vinyl)oxy)silane (1.35 g, 5.45 mmol, 72%)

was obtained from 4-methylacetophenone (1.00 mL, 7.53 mmol, 1.00

equiv), triethylamine (1.27 mL, 9.04 mmol, 1.20 equiv), and TBSOTf

(1.90 mL, 8.28 mmol, 1.10 equiv) according to GP2 after puriﬁcation

via ﬂash column chromatography on silica gel (1% triethylamine in

pentane) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.51−7.54

(m, 2H), 7.14−7.17 (m, 2H), 4.87 (d, J = 1.6 Hz, 1H), 4.40 (d, J = 1.9

Hz, 1H), 2.37 (s, 3H), 1.01 (s, 9H), 0.21 (s, 6H). The obtained

analytical data are consistent with the values reported in the literature.²³

tert-Butyldimethyl((1-(m-tolyl)vinyl)oxy)silane. tert-

Butyldimethyl((1-(m-tolyl)vinyl)oxy)silane (1.08 g, 4.36 mmol, 73%)

was obtained from 3-methylacetophenone (0.80 mL, 6.02 mmol, 1.00

equiv), triethylamine (1.02 mL, 7.22 mmol, 1.20 equiv), and TBSOTf

(1.52 mL, 6.62 mmol, 1.10 equiv) according to GP2 after puriﬁcation

via ﬂash column chromatography on silica gel (1% triethylamine in

pentane) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.46−7.44

(m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.15−7.12 (m, 1H), 4.90 (d, J = 1.6

Hz, 1H), 4.42 (d, J = 1.6 Hz, 1H), 2.37 (s, 3H), 1.01 (s, 9H), 0.23 (s,

6H). The obtained analytical data are consistent with the values

reported in the literature.²³

tert-Butyl((1-(3,4-dimethoxyphenyl)vinyl)oxy)dimethylsilane.²³

tert-Butyl((1-(3,4-dimethoxyphenyl)vinyl)oxy)dimethylsilane (1.35 g,

4.58 mmol, 83%) was obtained from 3,4-dimethoxyacetophenone

(1.00 g, 5.55 mmol, 1.00 equiv), triethylamine (0.94 mL, 6.66 mmol,

1.20 equiv), and TBSOTf (1.40 mL, 6.11 mmol, 1.10 equiv) according

to GP2 after puriﬁcation via ﬂash column chromatography on silica gel

(15% diethyl ether/1% triethylamine in pentane) as a colorless oil. R_f

(15% diethyl ether in pentane) = 0.39 (UV, KMnO₄); ¹H NMR

(CDCl₃, 400 MHz) δ 7.21−7.16 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 4.79

(d, J = 1.7 Hz, 1H), 4.35 (d, J = 1.7 Hz, 1H), 3.89 (s, 6H), 1.01 (s, 9H),

0.21 (s, 6H); HRMS (ESI) m/z [M + H]⁺Calcd for C₁₆H₂₇O₃Si⁺

295.1724, found 295.1723.

tert-Butyl((3,3-dimethylbut-1-en-2-yl)oxy)dimethylsilane.²⁷tert-

Butyl((3,3-dimethylbut-1-en-2-yl)oxy)dimethylsilane (1.12 g, 5.22

mmol, 67%) was obtained from 3,3-dimethyl-2-butanone (1.00 mL,

7.84 mmol, 1.00 equiv), triethylamine (1.67 mL, 11.8 mmol, 1.50

equiv), and TBSOTf (2.16 mL, 9.41 mmol, 1.20 equiv) according to

GP2 after puriﬁcation via ﬂash column chromatography on silica gel

(2% triethylamine in pentane) as a colorless oil. ¹H NMR (CDCl₃, 400

MHz) δ 4.05 (d, J = 1.4 Hz, 1H), 3.90 (d, J = 1.4 Hz, 1H), 1.06 (s, 9H),

0.95 (s, 9H), 0.17 (s, 6H). The obtained analytical data are consistent

with the values reported in the literature.²⁷

4-(1-((tert-Butyldimethylsilyl)oxy)vinyl)benzonitrile. 4-(1-((tert-

Butyldimethylsilyl)oxy)vinyl)benzonitrile (1.20 g, 4.63 mmol, 67%)

was obtained from 4-acetylbenzonitrile (1.00 g, 6.89 mmol, 1.00 equiv),

triethylamine (1.16 mL, 8.27 mmol, 1.20 equiv), and TBSOTf (1.74

mL, 7.58 mmol, 1.10 equiv) according to GP2 after puriﬁcation via ﬂash

column chromatography on silica gel (33% diethyl ether/3%

1

triethylamine in pentane) as a colorless solid. H NMR (CDCl₃, 400

tert-Butyldimethyl((4-phenylbut-1-en-2-yl)oxy)silane.²⁸tert-

Butyldimethyl((4-phenylbut-1-en-2-yl)oxy)silane (1.50 g, 5.72 mmol,

86%) was obtained from benzylacetone (1.00 mL, 6.67 mmol, 1.00

equiv), triethylamine (2.27 mL, 16.0 mmol, 2.40 equiv), and TBSOTf

(1.84 mL, 8.00 mmol, 1.20 equiv) according to GP2 after puriﬁcation

via ﬂash column chromatography on silica gel (2% triethylamine in

pentane) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.12−7.10

(m, 1H), 7.07−6.90 (m, 4H), 4.00 (d, J = 0.9 Hz, 1H), 3.93 (d, J = 0.8

Hz, 1H), 2.69−2.65 (m, 2H), 2.22−2.18 (m, 2H), 0.84 (s, 9H), 0.00 (s,

6H).

MHz) δ 7.70−7.68 (m, 2H), 7.62−7.60 (m, 2H), 5.00 (d, J = 2.2 Hz,

1H), 4.57 (d, J = 2.2 Hz, 1H), 1.00 (s, 9H), 0.22 (s, 6H). The obtained

analytical data are consistent with the values reported in the literature.³¹

tert-Butyl((1-(4-((tert-butyldimethylsilyl)oxy)phenyl)vinyl)oxy)-

dimethylsilane.²³tert-Butyl((1-(4-((tert-butyldimethylsilyl)oxy)-

phenyl)vinyl)oxy)dimethylsilane (1.13 g, 3.10 mmol, 84%) was

obtained from 4-hydroxyacetophenone (0.50 g, 3.67 mmol, 1.00

equiv), triethylamine (1.24 mL, 8.81 mmol, 2.40 equiv), and TBSOTf

(1.86 mL, 8.07 mmol, 2.20 equiv) according to GP2 after puriﬁcation

via ﬂash column chromatography on silica gel (5% diethyl ether/1%

tert-Butyldimethyl((1-(thiophen-2-yl)vinyl)oxy)silane.²³tert-

Butyldimethyl((1-(thiophen-2-yl)vinyl)oxy)silane (1.61 g, 6.70

mmol, 89%) was obtained from 2-acetylthiophene (0.81 mL, 7.53

mmol, 1.00 equiv), triethylamine (1.27 mL, 9.04 mmol, 1.20 equiv),

and TBSOTf (1.90 mL, 8.28 mmol, 1.10 equiv) according to GP2 after

puriﬁcation via ﬂash column chromatography on silica gel (1%

1

triethylamine in pentane) as a colorless oil. H NMR (CDCl₃, 400

MHz) δ 7.49−7.46 (m, 2H), 6.79−6.77 (m, 2H), 4.76 (d, J = 1.7 Hz,

1H), 4.31 (d, J = 1.6 Hz, 1H), 1.00 (s, 9H), 0.98 (s, 9H), 0.20 (s, 6H),

+

0.20 (s, 6H); HRMS (ESI) m/z [M + H]⁺Calcd for C₂₀H₃₇O₂Si₂

365.2327, found 365.2328. The obtained analytical data are consistent

with the values reported in the literature.²³

1

triethylamine in pentane) as a colorless oil. H NMR (CDCl₃, 400

tert-Butyl((1-(3-((tert-butyldimethylsilyl)oxy)phenyl)vinyl)oxy)-

dimethylsilane. tert-Butyl((1-(3-((tert-butyldimethylsilyl)oxy)-

phenyl)vinyl)oxy)dimethylsilane (1.25 g, 3.43 mmol, 83%) was

obtained from 3-hydroxyacetophenone (560 mg, 4.11 mmol, 1.00

equiv), triethylamine (1.39 mL, 9.86 mmol, 2.40 equiv), and TBSOTf

(2.08 mL, 9.04 mmol, 2.20 equiv) according to GP2 after puriﬁcation

via ﬂash column chromatography on silica gel (5% diethyl ether/1%

triethylamine in pentane) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz)

MHz) δ 7.20−7.18 (m, 2H), 6.96 (dd, J = 5.0, 3.6 Hz, 1H), 4.79 (d, J =

2.0 Hz, 1H), 4.30 (d, J = 2.0 Hz, 1H), 1.01 (s, 9H), 0.23 (s, 6H). The

obtained analytical data are consistent with the values reported in the

literature.²³

tert-Butyl((1-(4-chlorophenyl)vinyl)oxy)dimethylsilane.²⁹tert-

Butyl((1-(4-chlorophenyl)vinyl)oxy)dimethylsilane (1.96 g, 7.30

mmol, 95%) was obtained from 4-chloroacetophenone (1.00 mL,

H

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δ 7.22−7.15 (m, 2H), 7.10 (dd, J = 2.5, 1.6 Hz, 1H), 6.77 (ddd, J = 7.6,

2.5, 1.4 Hz, 1H), 4.86 (d, J = 1.7 Hz, 1H), 4.40 (d, J = 1.7 Hz, 1H), 1.01

(s, 9H), 0.99 (s, 9H), 0.22 (s, 6H), 0.20 (s, 6H); HRMS (ESI) m/z [M

+ H]⁺Calcd for C₂₀H₃₇O₂Si₂⁺365.2327, found 365.2328.

and using 4-ﬂuorobenzoic acid. After column chromatography (20%

diethyl ether in pentane), ester (3-methyloxetan-3-yl)methyl 4-

ﬂuorobenzoate (1.05 g, 4.7 mmol, 94%) was obtained as a colorless

oil. R_f(20% diethyl ether in CH₂Cl₂) = 0.18 (UV, KMnO₄); ¹H NMR

(CDCl₃, 400 MHz) δ 8.10−8.05 (m, 2H), 7.16−7.10 (m, 2H), 4.63 (d,

J = 6.0 Hz, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.39 (s, 2H), 1.42 (s, 3H). The

obtained analytical data are consistent with the values reported in the

literature.¹¹

tert-Butyl((1-cyclohexylvinyl)oxy)dimethylsilane.³³tert-Butyl((1-

cyclohexylvinyl)oxy)dimethylsilane (1.60 g, 6.65 mmol, 92%) was

obtained from cyclohexyl methyl ketone (1.00 mL, 7.27 mmol, 1.00

equiv), triethylamine (1.23 mL, 8.72 mmol, 1.20 equiv), and TBSOTf

(1.84 mL, 8.00 mmol, 1.10 equiv) according to GP2 after puriﬁcation

via ﬂash column chromatography on silica gel (3% triethylamine in

pentane). The product was obtained as an impure mixture together

with the hydrolyzed product and was used directly in the next step

without further puriﬁcation.

Methyl ((3-Methyloxetan-3-yl)methyl) Terephthalate.³⁴Methyl

((3-methyloxetan-3-yl)methyl) terephthalate was synthesized by

following GP3 and using 4-(methoxycarbonyl)benzoic acid. After

column chromatography (20% diethyl ether in pentane), methyl ((3-

methyloxetan-3-yl)methyl) terephthalate (2.5 g, 9.5 mmol, 95%) was

obtained as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.12 (s, 4H),

4.64 (d, J = 6.0 Hz, 2H), 4.48 (d, J = 6.0 Hz, 2H), 4.43 (s, 2H), 3.96 (s,

3H), 1.44 (s, 3H). The obtained analytical data are consistent with the

values reported in the literature.³⁴

tert-Butyl((1-(furan-2-yl)vinyl)oxy)dimethylsilane.³²tert-Butyl((1-

(furan-2-yl)vinyl)oxy)dimethylsilane (2.07 g, 9.22 mmol, 92%) was

obtained from furyl methyl ketone (1.00 mL, 9.99 mmol, 1.00 equiv),

triethylamine (1.70 mL, 12.0 mmol, 1.20 equiv), and TBSOTf (2.53

mL, 11.0 mmol, 1.10 equiv) according to GP2 after puriﬁcation via ﬂash

column chromatography on silica gel (1% triethylamine in pentane) as

a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.34 (br s, 1H), 6.41−

6.37 (m, 2H), 4.87 (d, J = 11.7 Hz, 1H), 4.35 (d, J = 1.7 Hz, 1H), 0.99

(s, 9H), 0.21 (s, 6H).

(3-Methyloxetan-3-yl)methyl 2-(Benzyloxy)acetate.³⁴(3-Methyl-

oxetan-3-yl)methyl 2-(benzyloxy)acetate was synthesized by following

GP3 and using 2-(benzyloxy)acetic acid. After column chromatography

(20% diethyl ether in pentane), (3-methyloxetan-3-yl)methyl 2-

(benzyloxy)acetate (2.4 g, 9.6 mmol, 96%) was obtained as a colorless

oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.38−7.29 (m, 5H), 4.65 (s, 2H),

4.51 (d, J = 6.1 Hz, 2H), 4.38 (d, J = 6.1 Hz, 2H), 4.27 (s, 2H), 4.15 (s,

2H), 1.33 (s, 3H). The obtained analytical data are consistent with the

values reported in the literature.³⁴

Methyl 4-(1-((tert-Butyldimethylsilyl)oxy)vinyl)benzoate.³³Meth-

yl 4-(1-((tert-butyldimethylsilyl)oxy)vinyl)benzoate (1.36 g, 4.65

mmol, 83%) was obtained from methyl 4-acetylbenzoate (1.00 g,

5.61 mmol, 1.00 equiv), LHMDS (1 M in THF; 6.73 mL, 6.73 mmol,

1.20 equiv)), and TBSCl (1.02 g, 6.73 mmol, 1.20 equiv) according to

GP2 after puriﬁcation via ﬂash column chromatography on silica gel

(4% triethylamine in pentane) as a colorless oil. ¹H NMR (CDCl₃, 400

MHz) δ 8.00 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 4.99 (d, J =

1.8 Hz, 1H), 4.53 (d, J = 1.8 Hz, 1H), 3.91 (s, 3H), 1.00 (s, 9H), 0.21 (s,

6H). The obtained analytical data are consistent with the values

reported in the literature.³³

Methyl ((3-Methyloxetan-3-yl)methyl) Succinate.³⁴Methyl ((3-

methyloxetan-3-yl)methyl) succinate was synthesized by following

GP3 and using 4-methoxy-4-oxobutanoic acid. After column

chromatography (20% diethyl ether in pentane) methyl ((3-

methyloxetan-3-yl)methyl) succinate (1.8 g, 8.5 mmol, 85%) was

obtained as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 4.51 (d, J =

6.0 Hz, 2H), 4.38 (d, J = 6.0 Hz, 2H), 4.19 (s, 2H), 3.70 (s, 3H), 2.71−

2.63 (m, 4H), 1.33 (s, 3H). The obtained analytical data are consistent

with the values reported in the literature.³⁴

tert-Butyldimethyl((1-(4-vinylphenyl)vinyl)oxy)silane. tert-

Butyldimethyl((1-(4-vinylphenyl)vinyl)oxy)silane (1.16 g, 4.45

mmol, 98%) was obtained from 1-(4-vinylphenyl)ethan-1-one (664

mg, 4.52 mmol, 1.00 equiv), triethylamine (0.77 mL, 5.45 mmol, 1.20

equiv), and TBSOTf (1.15 mL, 4.99 mmol, 1.10 equiv) according to

GP2 after puriﬁcation via ﬂash column chromatography on silica gel

General Procedure for the Synthesis of Tetrazine Thioethers

(GP4).³⁴The ester (1.00 equiv) was dissolved in CH₂Cl₂(1 M), and the

mixture was cooled to 0 °C using an ice bath. Then, BF₃·OEt₂(0.50

equiv) was added via a syringe, and the reaction mixture was allowed to

warm to room temperature overnight. Then, the reaction was quenched

with pyridine (3.00 equiv), and to the mixture were added hydrazine-

urea (0.8 equiv) together with DMF (1 M). After the evaporation of the

residual CH₂Cl₂, the residue was stirred at 80 °C for 1 h. The reaction

mixture was cooled to 25 °C. To the mixture was added PIDA (0.80

equiv), and the reaction mixture was stirred for 1 h at 25 °C. After

quenching with a saturated aqueous NaHCO₃solution (50 mL), the

organic layer was extracted with CH₂Cl₂(3 × 50 mL). After washing

with water (50 mL) and brine (50 mL), the organic layer was dried over

sodium sulfate. The solvent was removed under reduced pressure, and

the crude product was puriﬁed via ﬂash column chromatography on

silica gel (20% diethyl ether in pentane) to aﬀord the desired tetrazine.

3-(4-Methoxyphenyl)-6-(methylthio)-1,2,4,5-tetrazine.³⁴3-(4-

Methoxyphenyl)-6-(methylthio)-1,2,4,5-tetrazine was synthesized ac-

cording to GP4 by using (3-methyloxetan-3-yl)methyl 4-methox-

ybenzoate. After work up, the crude material was puriﬁed by ﬂash

column chromatography on silica gel (20% diethyl ether in pentane) to

aﬀord 3-(4-methoxyphenyl)-6-(methylthio)-1,2,4,5-tetrazine (334 mg,

1.4 mmol, 45%) as a red solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.50−

8.46 (m, 2H), 7.09−7.06 (m, 2H), 3.91 (s, 3H), 2.78 (s, 3H). The

obtained analytical data are consistent with the values reported in the

literature.³⁴

1

(2% diethyl ether/2% triethylamine in pentane) as a colorless oil. H

NMR (CDCl₃, 400 MHz) δ 7.58 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz,

2H), 6.73 (dd, J = 17.6, 10.9 Hz, 1H), 5.77 (dd, J = 17.5, 1.0 Hz, 1H),

5.25 (dd, J = 10.9, 1.0 Hz, 1H), 4.90 (d, J = 1.8 Hz, 1H), 4.42 (d, J = 1.8

Hz, 1H), 1.01 (s, 9H), 0.21 (s, 6H); HRMS (ESI) m/z [M + H]⁺Calcd

for C₁₆H₂₅OSi⁺261.1669, found 261.1668.

tert-Butyl((1-(4-ethynylphenyl)vinyl)oxy)dimethylsilane. tert-

Butyl((1-(4-ethynylphenyl)vinyl)oxy)dimethylsilane (272 mg, 1.05

mmol, 25%) was obtained from 1-(4-ethynylphenyl)ethan-1-one

(600 mg, 4.16 mmol, 1.00 equiv), triethylamine (0.71 mL, 4.99

mmol, 1.20 equiv), and TBSOTf (1.05 mL, 4.58 mmol, 1.10 equiv)

according to GP2 after puriﬁcation via ﬂash column chromatography

on silica gel (2% triethylamine in pentane) as a colorless oil. ¹H NMR

(CDCl₃, 400 MHz) δ 7.56 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H),

4.91 (d, J = 1.9 Hz, 1H), 4.47 (d, J = 1.9 Hz, 1H), 3.11 (s, 1H), 1.00 (s,

9H), 0.21 (s, 6H).

General Procedure for the Synthesis of 3-Oxetane Esters (GP3).³⁴

3-Methyl-3-oxetanemethanol (1.10 equiv), DMAP (0.10 equiv), and

N-ethyl-N′-carbodiimide hydrochloride (1.20 equiv) were dissolved in

CH₂Cl₂(1 M), and the mixture was cooled to 0 °C with an ice bath.

Then, the carboxylic acid (1.00 equiv) was added to the mixture, and

the reaction mixture was stirred at 25 °C for 18 h. Then, a saturated

aqueous NaHCO₃solution (100 mL) was added to the mixture, and the

organic phase was extracted with CH₂Cl₂(3 × 100 mL). After washing

with water (100 mL) and brine (100 mL), the organic layer was dried

over sodium sulfate, and the solvent was removed under reduced

pressure. The crude product was puriﬁed via ﬂash column

chromatography on silica gel (20% diethyl ether in pentane) to aﬀord

the ester.

3-(4-Fluorophenyl)-6-(methylthio)-1,2,4,5-tetrazine.¹¹3-(4-Fluo-

rophenyl)-6-(methylthio)-1,2,4,5-tetrazine was synthesized according

to GP4 by using (3-methyloxetan-3-yl)methyl 4-ﬂuorobenzoate. After

work up, the crude material was puriﬁed by ﬂash column

chromatography on silica gel (20% diethyl ether in pentane) to aﬀord

3-(4-ﬂuorophenyl)-6-(methylthio)-1,2,4,5-tetrazine (258 mg, 1.2

mmol, 36%) as a red solid. R_f(20% diethyl ether in CH₂Cl₂) = 0.73

(3-Methyloxetan-3-yl)methyl 4-Fluorobenzoate.¹¹(3-Methylox-

etan-3-yl)methyl 4-ﬂuorobenzoate was synthesized by following GP3

1

(UV, KMnO₄); mp = 131−133 °C; H NMR (CDCl₃, 400 MHz) δ

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8.57−8.52 (m, 2H), 7.29−7.23 (m, 2H), 2.80 (s, 3H). The obtained

analytical data are consistent with the values reported in the literature.¹¹

Methyl 4-(6-(Methylthio)-1,2,4,5-tetrazin-3-yl)benzoate.³⁴Meth-

yl 4-(6-(methylthio)-1,2,4,5-tetrazin-3-yl)benzoate was synthesized

according to GP4 by using methyl ((3-methyloxetan-3-yl)methyl)

terephthalate. After work up, the crude material was puriﬁed by ﬂash

column chromatography on silica gel (20% diethyl ether in pentane) to

aﬀord methyl 4-(6-(methylthio)-1,2,4,5-tetrazin-3-yl)benzoate (700

(m, 2H), 3.99 (s, 3H). The obtained analytical data are consistent with

the values reported in the literature.³⁴

3-((Benzyloxy)methyl)-1,2,4,5-tetrazine.³⁴3-((Benzyloxy)-

methyl)-1,2,4,5-tetrazine was synthesized according to GP5 by using

3-(((4-(methylthio)benzyl)oxy)methyl)-1,2,4,5-tetrazine. After work

up, the crude product was puriﬁed via ﬂash column chromatography on

silica gel (20% diethyl ether in pentane) to aﬀord 3-((benzyloxy)-

1

methyl)-1,2,4,5-tetrazine (87 mg, 0.43 mmol, 53%) as a red oil. H

1

NMR (CDCl₃, 400 MHz) δ 10.28 (s, 1H), 7.43−7.30 (m, 5H), 5.16 (s,

2H), 4.83 (s, 2H). The obtained analytical data are consistent with the

values reported in the literature.³⁴

mg, 2.7 mmol, 67%) as a red solid. H NMR (CDCl₃, 400 MHz) δ

8.63−8.60 (m, 2H), 8.26−8.23 (m, 2H), 3.98 (s, 3H), 2.81 (s, 3H).

The obtained analytical data are consistent with the values reported in

the literature.³⁴

Methyl 3-(1,2,4,5-tetrazin-3-yl)propanoate.³⁴Methyl 3-(1,2,4,5-

tetrazin-3-yl)propanoate was synthesized according to GP5 by using

methyl 3-(6-(methylthio)-1,2,4,5-tetrazin-3-yl)propanoate. After work

up, the crude product was puriﬁed via ﬂash column chromatography on

silica gel (20% diethyl ether in pentane) to aﬀord methyl 3-(1,2,4,5-

3-((Benzyloxy)methyl)-6-(methylthio)-1,2,4,5-tetrazine.³⁴3-

((Benzyloxy)methyl)-6-(methylthio)-1,2,4,5-tetrazine was synthesized

according to GP4 by using (3-methyloxetan-3-yl)methyl 2-

(benzyloxy)acetate. After work up, the crude material was puriﬁed by

ﬂash column chromatography on silica gel (20% diethyl ether in

pentane) to aﬀord 3-((benzyloxy)methyl)-6-(methylthio)-1,2,4,5-

1

tetrazin-3-yl)propanoate (93 mg, 0.55 mmol, 68%) as a red solid. H

NMR (CDCl₃, 400 MHz) δ 10.21 (s, 1H), 3.72−3.08 (m, 5H), 3.10 (t,

J = 7.1 Hz, 2H). The obtained analytical data are consistent with the

values reported in the literature.³⁴

1

tetrazine (284 mg, 1.1 mmol, 72%) as a red oil. H NMR (CDCl₃,

400 MHz) δ 7.40−7.28 (m, 5H), 5.05 (s, 2H), 4.78 (s, 2H), 2.75 (s,

3H). The obtained analytical data are consistent with the values

reported in the literature.³⁴

General Procedure for the Synthesis of Bicyclic 3-Bromopyr-

idazines from TMS-Silyl Enol Ethers (GP6; Scheme 2). 3-

Bromotetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) was dissolved

in CH₂Cl₂(0.75 mL), and to the mixture was added the respective

TMS-silyl enol ether (0.155 mmol, 1.00 equiv). Then, BF₃·OEt₂(2 M

in CH₂Cl₂; 0.163 mL, 0.326 mmol, 2.1 equiv) was added to the mixture

dropwise at 0 °C. The mixture was allowed to warm to 25 °C and stirred

until the starting material was consumed. The reaction was quenched

by the addition of saturated aqueous sodium bicarbonate, and the

mixture was stirred until the gas evolution had ceased. Then, the layers

were separated, and the aqueous layer was extracted with CH₂Cl₂(2 ×

10 mL). The combined organic layers were dried over sodium sulfate,

ﬁltered, and concentrated under reduced pressure.

Methyl 3-(6-(Methylthio)-1,2,4,5-tetrazin-3-yl)propanoate.³⁴

Methyl 3-(6-(methylthio)-1,2,4,5-tetrazin-3-yl)propanoate was synthe-

sized according to GP4 by using methyl ((3-methyloxetan-3-

yl)methyl) succinate. After work up, the crude material was puriﬁed

by ﬂash column chromatography on silica gel (20% diethyl ether in

pentane) to aﬀord methyl 3-(6-(methylthio)-1,2,4,5-tetrazin-3-yl)-

propanoate (203 mg, 1 mmol, 59%) as a red solid. ¹H NMR (CDCl₃,

400 MHz) δ 3.70 (s, 3H), 3.59 (t, J = 7.2 Hz, 2H), 3.03 (t, J = 7.2 Hz,

2H), 2.73 (s, 3H). The obtained analytical data are consistent with the

values reported in the literature.³⁴

General Procedure for the Desulfurization of Tetrazine-Thioether

(GP5).³⁴The tetrazine thioether (1.00 equiv) and PdCl₂(0.10 equiv)

were dissolved in THF (0.5 M), then Et₃SiH (6 equiv) was added to the

mixture. The reaction mixture was stirred at reﬂux for 48 h. After

cooling to 25 °C, PIDA (1.20 equiv) was added to the mixture, and the

reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was

quenched with a saturated aqueous NaHCO₃solution (50 mL). Then,

the organic layer was extracted with CH₂Cl₂(100 mL). After washing

with water (50 mL) and brine (50 mL), the organic layer was dried over

sodium sulfate, and the solvent was removed under reduced pressure.

The crude product was puriﬁed via ﬂash column chromatography on

silica gel (20% diethyl ether in pentane) to give the product as a red

solid or oil.

Pyridazine 2a. Pyridazine 2a was synthesized according to GP6 by

using (cyclopent-1-en-1-yloxy)trimethylsilane (24.2 mg, 0.155 mmol,

1.00 equiv). After 2 h the reaction was complete, and after work up the

crude product was puriﬁed via ﬂash column chromatography on silica

gel (60% ethyl acetate in pentane) to aﬀord 2a (14.1 mg, 0.071 mmol,

46%) as a colorless crystalline solid. R_f(60% EtOAc in pentane) = 0.27

(UV, KMnO₄); mp = 110−113 °C (decomp.); ¹H NMR (CDCl₃, 400

MHz) δ 9.02 (s, 1H), 3.09 (t, J = 8.0 Hz, 2H), 3.01 (t, J = 7.8 Hz, 2H),

2.18 (p, J = 7.6 Hz, 2H); ¹³C {¹H} NMR (CDCl₃, 126 MHz) δ 148.7,

147.3, 147.0, 146.3, 33.3, 31.9, 22.6; IR (neat) v 2923 (m), 1557 (m),

̃

1535 (vs), 1422 (s), 1295 (m), 1267 (m), 1147 (vs), 908 (m) cm⁻¹;

HRMS (EI) m/z Calcd for C₇H₇BrN₂⁺197.9793, found 197.9785.

Pyridazine 2b. Pyridazine 2b was synthesized according to GP6 by

using (cyclohex-1-en-1-yloxy)trimethylsilane (26.4 mg, 0.155 mmol,

1.00 equiv). After 2 h the reaction was complete, and after work up the

crude material was puriﬁed via ﬂash column chromatography on silica

gel (20% Et₂O in CH₂Cl₂) to aﬀord 2b (24.3 mg, 0.114 mmol, 74%) as

a colorless crystalline solid. R_f(60% EtOAc in pentane) = 0.35 (UV,

KMnO₄); mp = 120−125 °C (decomp.); ¹H NMR (CDCl₃, 400 MHz)

δ 8.74 (s, 1H), 2.71 (dt, J = 12.9, 6.4 Hz, 4H), 1.92−1.79 (m, 4H); ¹³C

{¹H} NMR (CDCl₃, 101 MHz) δ 152.3, 152.1, 139.9, 139.3, 28.3, 26.3,

3-(4-Methoxyphenyl)-1,2,4,5-tetrazine.³⁴3-(4-Methoxyphenyl)-

1,2,4,5-tetrazine was synthesized according to GP5 by using 3-(4-

methoxyphenyl)-6-(methylthio)-1,2,4,5-tetrazine. After work up, the

crude product was puriﬁed via ﬂash column chromatography on silica

gel (20% diethyl ether in pentane) to aﬀord 3-(4-methoxyphenyl)-

1

1,2,4,5-tetrazine (92 mg, 0.49 mmol, 49%) as a red solid. H NMR

(CDCl₃, 400 MHz) δ 10.13 (s, 1H), 8.61−8.57 (m, 2H), 7.12−7.08

(m, 2H), 3.93 (s, 3H). The obtained analytical data are consistent with

the values reported in the literature.³⁴

22.0, 21.2; IR (neat) ṽ 2941 (vs), 2882 (m), 1550 (s), 1540 (s), 1462

3-(4-Fluorophenyl)-1,2,4,5-tetrazine.¹¹3-(4-Fluorophenyl)-

1,2,4,5-tetrazine was synthesized according to GP5. After work up,

the crude product was puriﬁed via ﬂash column chromatography on

silica gel (20% diethyl ether in pentane) to aﬀord 3-(4-ﬂuorophenyl)-

(m), 1415 (vs), 1351 (m), 1196 (vs), 825 (m) cm⁻¹; HRMS (EI) m/z

Calcd for C₈H₉BrN₂⁺211.9949, found 211.9943.

Pyridazine 2c. Pyridazine 2c was synthesized according to GP6 by

using (cyclohept-1-en-1-yloxy)trimethylsilane (28.6 mg, 0.155 mmol,

1.00 equiv). After 10 min the reaction was complete, and after work up

the crude material was puriﬁed via ﬂash column chromatography on

silica gel (80% Et₂O in pentane) to aﬀord 2c (18.5 mg, 0.082 mmol,

53%) as a colorless crystalline solid. R_f(Et₂O) = 0.36 (UV, KMnO₄);

mp = 96−98 °C (decomp.); ¹H NMR (CDCl₃, 400 MHz) δ 8.77 (s,

1H), 3.07−3.04 (m, 2H), 2.83−2.80 (m, 2H), 1.94−1.88 (m, 2H),

1.70−1.66 (m, 4H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 151.7, 151.4,

1

1,2,4,5-tetrazine (114 mg, 0.65 mmol, 65%) as a red solid. H NMR

(CDCl₃, 400 MHz) δ 10.22 (s, 1H), 8.67−8.62 (m, 2H), 7.32−7.26

(m, 2H). The obtained analytical data are consistent with the values

reported in the literature.¹¹

Methyl 4-(1,2,4,5-Tetrazin-3-yl)benzoate.³⁴Methyl 4-(1,2,4,5-

tetrazin-3-yl)benzoate was synthesized according to GP5 by using 3-

(4-ﬂuorophenyl)-6-(methylthio)-1,2,4,5-tetrazine. After work up, the

crude product was puriﬁed via ﬂash column chromatography on silica

gel (20% diethyl ether in pentane) to aﬀord methyl 4-(1,2,4,5-tetrazin-

144.6, 144.2, 33.4, 33.1, 32.0, 26.4, 25.4; IR (neat) ṽ 2930 (vs), 2854

(s), 1536 (vs), 1439 (m), 1299 (vs), 1261 (s), 1126 (vs), 972 (vs), 877

1

+

(s) cm⁻¹; HRMS (EI) m/z Calcd for C₉H₁₁BrN₂226.0106, found

3-yl)benzoate (119 mg, 0.55 mmol, 63%) as a red solid. H NMR

(CDCl₃, 400 MHz) δ 10.28 (s, 1H), 8.74−8.71 (m, 2H), 8.29−8.26

226.0100.

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Pyridazine 2d. Pyridazine 2d was synthesized according to GP6 by

using (cyclohept-1-en-1-yloxy)trimethylsilane (30.7 mg, 0.155 mmol,

1.00 equiv). After 10 min, the reaction was complete, and after work up

the crude material was puriﬁed via ﬂash column chromatography on

silica gel (80% Et₂O in pentane) to aﬀord 3d (21.0 mg, 0.087 mmol,

56%) as a colorless crystalline solid. R_f(20% pentane in Et₂O) = 0.40

tert-butyl((1-(3,4-dimethoxyphenyl)vinyl)oxy)dimethylsilane (63.9

mg, 0.217 mmol, 1.40 equiv). After 10 min, the reaction was complete,

and after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (10% Et₂O in CH₂Cl₂) to aﬀord 3b (38.0

mg, 0.129 mmol, 83%) as a colorless crystalline solid. R_f(10% Et₂O in

1

CH₂Cl₂) = 0.41 (UV, CAM); mp = 128 °C; H NMR (CDCl₃, 400

1

(UV, KMnO₄); mp = 86−88 °C (decomp.); H NMR (CDCl₃, 400

MHz) δ 9.12 (d, J = 5.0 Hz, 1H), 7.40 (d, J = 5.0 Hz, 1H), 7.05−6.96

(m, 3H), 3.94 (s, 3H), 3.92 (s, 3H); ¹³C{¹H} NMR (CDCl₃, 101 MHz)

δ 150.7, 150.4, 149.0, 142.8, 128.2, 127.9, 122.0, 112.1, 111.2, 56.2,

MHz) δ 8.77 (s, 1H), 2.95−2.92 (m, 2H), 2.80−2.77 (m, 2H), 1.85−

1.72 (m, 4H), 1.48−1.43 (m, 2H), 1.35−1.30 (m, 2H); ¹³C{¹H} NMR

(CDCl₃, 101 MHz) δ 152.0, 151.5, 143.3, 141.9, 31.4, 30.4, 29.6, 28.1,

56.1; IR (neat) ṽ 2936 (w), 1585 (w), 15513 (vs), 1463 (m), 1305 (s),

1254 (vs), 1224 (s), 1144 (m), 1023 (s) cm⁻¹; HRMS (EI) for

C₁₂H₁₁O₂BrN₂⁺calculated: 294.0003, found 294.0000.

26.0, 25.5; IR (neat) ṽ 2927 (vs), 2916 (s), 2859 (m), 1540 (m), 1473

(m), 1301 (vs), 1154 (vs), 1075 (s), 1011 (m) cm⁻¹; HRMS (EI) m/z

Calcd for C₁₀H₁₃BrN₂⁺240.0262, found 240.0256.

Pyridazine 3c. Pyridazine 3c was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

((1-(4-bromophenyl)vinyl)oxy)(tert-butyl)dimethylsilane (68.0 mg,

0.217 mmol, 1.40 equiv). After 10 min, the reaction was complete,

and after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (80−90% Et₂O in pentane) to aﬀord 3c

(44.0 mg, 0.140 mmol, 90%) as a colorless solid. R_f(90% Et₂O in

Pyridazine 2e. Pyridazine 2e was synthesized according to GP6 by

using trimethyl((1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yl)oxy)silane

(38.2 mg, 0.155 mmol, 1.00 equiv). After 10 min, the reaction was

complete, and after work up the crude material was puriﬁed via ﬂash

column chromatography on silica gel (CH₂Cl₂− 10% Et₂O in CH₂Cl₂)

to aﬀord 2e (19.0 mg, 0.066 mmol, 42%) as a colorless crystalline solid.

R_f(10% Et₂O in CH₂Cl₂) = 0.45 (UV, KMnO₄); mp = 136 °C

1

pentane) = 0.37 (UV); mp = 176−178 °C; H NMR (CDCl₃, 500

1

(decomp.); H NMR (CDCl₃, 400 MHz) δ 8.81 (s, 1H), 7.39−7.38

MHz) δ 9.17 (d, J = 4.9 Hz, 1H), 7.66−7.64 (m, 2H), 7.39 (d, J = 4.9

Hz, 1H), 7.36−7.33 (m, 2H); ¹³C{¹H} NMR (CDCl₃, 126 MHz) δ

(m, 2H), 7.31−7.24 (m, 3H), 3.05−2.76 (m, 5H), 2.32−2.27 (m, 1H),

2.04−1.93 (m, 1H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 152.0, 151.9,

144.0, 139.4, 138.8, 129.0, 127.1, 126.8, 38.8, 34.0, 29.2, 29.0; IR (neat)

150.9, 149.0, 142.0, 134.7, 132.2, 130.6, 127.8, 124.5; IR (neat) v 1591

̃

(m), 1488 (w), 1324 (vs), 1300 (m), 1111 (m), 1012 (m), 815 (vs)

+

cm⁻¹; HRMS (EI) m/z Calcd for C₁₀H₆Br₂N₂311.8898, found

v 3024 (w), 1603 (w), 1493 (m), 1420 (m), 1179 (m), 1189 (m), 942

̃

(m) cm⁻¹; HRMS (EI) m/z Calcd for C₁₄H₁₃BrN₂⁺288.0262, found

288.0256.

311.8887.

Pyridazine 3d. Pyridazine 3d was synthesized according to by GP7

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyldimethyl((1-(4-vinylphenyl)vinyl)oxy)silane (56.5 mg, 0.217

mmol, 1.40 equiv). After 10 min, the reaction was complete, and after

work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (5% Et₂O in CH₂Cl₂) to aﬀord 3d

(32.0 mg, 0.123 mmol, 78%) as a colorless solid. R_f(5% Et₂O in

CH₂Cl₂) = 0.27 (UV, KMnO₄); mp = 113−116 °C; ¹H NMR (CDCl₃,

400 MHz) δ 9.16 (d, J = 4.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.46 (d, J

= 7.3 Hz, 2H), 7.40 (d, J = 4.9 Hz, 1H), 6.78 (dd, J = 17.6, 10.9 Hz, 1H),

5.88 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 10.9 Hz, 1H); ¹³C{¹H} NMR

(CDCl₃, 101 MHz) δ 150.8, 149.2, 142.7, 139.1, 135.9, 135.0, 129.3,

General Procedure for the Synthesis of Pyridazines from TBS-Silyl

Enol Ethers (GP7; Schemes 3 and 4). The s-tetrazine was dissolved in

CH₂Cl₂(0.2 M), and to the solution was added the respective TBS-silyl

enol ether (1.40 equiv) in CH₂Cl₂(0.2 M). Then, to the mixture was

added BF₃·OEt₂(2 M in CH₂Cl₂; 2.1 equiv) dropwise at 0 °C. The

mixture was allowed to warm to 25 °C and stirred until the starting

material was consumed (5−10 min). The reaction was quenched by the

addition of saturated aqueous sodium bicarbonate, and the mixture was

stirred until the gas evolution had ceased. Then, the layers were

separated, and the aqueous layer was extracted with CH₂Cl₂(2 × 10

mL). The combined organic layers were dried over sodium sulfate,

ﬁltered, and concentrated under reduced pressure. The crude product

was puriﬁed via ﬂash column chromatography on silica gel.

Pyridazine 3a. Pyridazine 3a was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyldimethyl((1-phenylvinyl)oxy)silane (50.9 mg, 0.217 mmol,

1.40 equiv). After 10 min the reaction was complete, and after work up

the crude material was puriﬁed via ﬂash column chromatography on

silica gel (15% Et₂O in CH₂Cl₂) to aﬀord 3a (30.0 mg, 0.128 mmol,

82%) as a colorless crystalline solid. R_f(5% Et₂O in CH₂Cl₂) = 0.30

(UV, KMnO₄); mp = 112 °C; ¹H NMR (CDCl₃, 400 MHz) δ 9.17 (d, J

= 4.9 Hz, 1H), 7.52−7.45 (m, 5H), 7.41 (d, J = 4.9 Hz, 1H); ¹³C{¹H}

NMR (CDCl₃, 101 MHz) δ 150.8, 149.4, 143.1, 135.9, 129.8, 128.9,

127.9, 126.5, 116.0; IR (neat) v 3043 (m), 1630 (m), 1559 (m), 1509

̃

(m), 1328 (vs), 1318 (vs), 1292 (s), 1110 (s), 992 (vs), 904 (vs), 837

+

(vs) cm⁻¹; HRMS (ESI) m/z [M + H]⁺Calcd for C₁₂H₁₀BrN₂

261.0022, found 261.0022.

Pyridazine 3e. Pyridazine 3e was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyl((1-(4-ethynylphenyl)vinyl)oxy)dimethylsilane (56.1 mg,

0.217 mmol, 1.40 equiv). After 10 min, the reaction was complete,

and after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (10% Et₂O in CH₂Cl₂) to aﬀord 3d (34.0

mg, 0.131 mmol, 85%) as a colorless solid. R_f(10% Et₂O in CH₂Cl₂) =

0.48 (UV, KMnO₄); mp = 195 °C; ¹H NMR (CDCl₃, 400 MHz) δ 9.18

(d, J = 4.9 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H),

7.39 (d, J = 4.9 Hz, 1H), 3.20 (s, 1H); ¹³C{¹H} NMR (CDCl₃, 101

MHz) δ 150.8, 149.0, 142.3, 136.1, 132.5, 129.0, 127.8, 124.0, 82.7,

128.8, 128.0; IR (neat) ṽ 3057 (w), 3032 (w), 1562 (m), 1493 (m),

1446 (w), 1399 (m), 1326 (s), 1311 (s), 1108 (vs), 1043 (m), 991 (m)

+

cm⁻¹; HRMS (EI) m/z Calcd for C₁₀H₇BrN₂233.9793, found

233.9789.

79.4; IR (neat) v 3237 (vs), 1559 (m), 1325 (vs), 1301 (s), 1116 (m),

̃

Large-Scale Reaction. 3-Bromotetrazine (1) (501 mg, 3.11 mmol,

1.00 equiv) was dissolved in CH₂Cl₂(30 mL), and the mixture was

cooled to 0 °C. To the mixture was added tert-butyldimethyl((1-

phenylvinyl)oxy)silane (1.02 g, 4.35 mmol, 1.40 equiv) in CH₂Cl₂(5

mL), followed by the dropwise addition of BF₃·OEt₂(2 M in CH₂Cl₂;

3.27 mL, 6.53 mmol, 2.10 equiv) (caution! strong gas evolution). The

mixture was allowed to warm to 25 °C, and after 10 min the reaction

was quenched by the careful addition of a saturated aqueous sodium

bicarbonate solution (50 mL). The layers were separated, and the

aqueous layer was extracted with CH₂Cl₂(2 × 30 mL). The combined

organic layers were dried over sodium sulfate, ﬁltered, and

concentrated. The crude product was puriﬁed via ﬂasch column

chromatography (15% diethyl ether in CH₂Cl₂) to produce pyridazine

3a (683 mg, 2.91 mmol, 93%) as a colorless solid.

837 (vs), 828 (vs) cm⁻¹; HRMS (ESI) m/z [M + H]⁺Calcd for

C₁₂H₈BrN₂⁺258.9865, found 258.9866.

Pyridazine 3f. Pyridazine 3f was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyldimethyl((1-(4-(triﬂuoromethyl)phenyl)vinyl)oxy)silane

(65.6 mg, 0.217 mmol, 1.40 equiv). After 10 min, the reaction was

complete, and after work up the crude material was puriﬁed via ﬂash

column chromatography on silica gel (80% Et₂O in pentane) to aﬀord

3f (32.0 mg, 0.106 mmol, 68%) as a colorless solid. R_f(80% Et₂O in

pentane) = 0.29 (UV, KMnO₄); mp = 98−100 °C; ¹H NMR (CDCl₃,

400 MHz) δ 9.22 (d, J = 4.9 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.60 (d, J

= 8.1 Hz, 2H), 7.42 (d, J = 4.9 Hz, 1H); ¹³C{¹H} NMR (CDCl₃, 101

MHz) δ = 150.6, 148.8, 141.7, 139.4, 132.1 (q, J = 32.8 Hz), 129.5,

127.9, 125.8 (q, J = 3.8 Hz), 122.5 (q, J = 272.5 Hz); ¹⁹F{¹H}NMR

Pyridazine 3b. Pyridazine 3b was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

(CDCl₃, 376 MHz) δ −62.88; IR (neat) v 3048 (w), 1328 (vs), 1167

̃

K

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(m), 1106 (vs), 1072 (m), 836 (m) cm⁻¹; HRMS (EI) m/z Calcd for

C₁₁H₆F₃BrN₂⁺301.9666, found 301.9662.

2H), 2.43 (s, 3H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 150.8, 149.4,

143.3, 138.7, 135.9, 130.5, 129.5, 128.7, 128.0, 126.0, 21.6; IR (neat) v

̃

Pyridazine 3g. Pyridazine 3g was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyl((1-(4-chlorophenyl)vinyl)oxy)dimethylsilane (58.3 mg,

0.217 mmol, 1.40 equiv). After 10 min, the reaction was complete,

and after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (10% Et₂O in CH₂Cl₂) to aﬀord 3g (34.1

mg, 0.126 mmol, 82%) as a colorless solid. R_f(10% Et₂O in CH₂Cl₂) =

3047 (m), 2916 (w), 1560 (m), 1322 (vs), 1294 (m), 1109 (m), 864

+

(m), 785 (s) cm⁻¹; HRMS (EI) m/z Calcd for C₁₁H₉BrN₂: 247.9949,

found 247.9942.

Pyridazine 3l. Pyridazine 3l was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

methyl 4-(1-((tert-butyldimethylsilyl)oxy)vinyl)benzoate (63.5 mg,

0.217 mmol, 1.40 equiv). After 10 min, the reaction was complete,

and after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (5% Et₂O in CH₂Cl₂) to aﬀord 3l (41.0

mg, 0.112 mmol, 90%) as a colorless crystalline solid. R_f(5% Et₂O in

CH₂Cl₂) = 0.23 (UV); mp = 181 °C; ¹H NMR (CDCl₃, 400 MHz) δ

9.21 (d, J = 5.0 Hz, 1H), 8.18 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz,

2H), 7.42 (d, J = 5.0, 1H), 3.96 (s, 3H); ¹³C{¹H} NMR (CDCl₃, 101

MHz) δ 166.2, 150.7, 148.7, 142.0, 140.0, 131.3, 129.9, 129.0, 127.7,

1

0.6 (UV, CAM); mp = 155 °C (decomp.); H NMR (CDCl₃, 400

MHz) δ 9.18 (d, J = 5.0 Hz, 1H), 7.50−7.48 (m, 2H), 7.42−7.40 (m,

2H), 7.39 (d, J = 4.9 Hz, 1H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ

150.9, 149.1, 142.0, 136.3, 134.3, 130.4, 129.2, 127.9; IR (neat) ṽ 1596

(w), 1492 (s), 1324 (vs), 1302 (m), 1108 (m), 1092 (s), 833 (vs), 817

+

(vs) cm⁻¹; HRMS (EI) m/z Calcd for C₁₂H₁₁BrClN₂267.9403;

267.9400.

52.5; IR (neat) v 3055 (w), 1730 (vs), 1434 (m), 1325 (s), 1274 (vs),

̃

Pyridazine 3h. Pyridazine 3h was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and 4-

(1-((tert-butyldimethylsilyl)oxy)vinyl)benzonitrile (56.3 mg, 0.217

mmol, 1.40 equiv). After 10 min, the reaction was complete, and

after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (5% Et₂O in CH₂Cl₂) to aﬀord 3h (20.0

mg, 0.077 mmol, 50%) as a colorless crystalline solid. R_f(5% Et₂O in

CH₂Cl₂) = 0.47 (UV); mp = 105 °C (decomp.); ¹H NMR (CDCl₃, 400

MHz) δ 9.23 (d, J = 4.9 Hz, 1H), 7.83−7.80 (m, 2H), 7.61−7.58 (m,

2H), 7.41 (d, J = 5.0 Hz, 1H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ

1187 (m), 1109 (s), 1096 (vs), 854 (m) cm⁻¹; HRMS (ESI) m/z [M +

H]⁺Calcd for C₁₂H₁₀BrN₂O₂⁺292.9920, found 292.9921.

Pyridazine 3m. Pyridazine 3m was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyldimethyl((1-(thiophen-2-yl)vinyl)oxy)silane (52.2 mg, 0.217

mmol, 1.40 equiv). After 10 min, the reaction was complete, and after

work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (80% Et₂O in pentane) to aﬀord 3m

(20.3 mg, 0.084 mmol, 54%) as a colorless oil. R_f(80% Et₂O in

pentane) = 0.41 (UV, KMnO₄); ¹H NMR (CDCl₃, 400 MHz) δ 9.10

(d, J = 5.1 Hz, 1H), 7.72 (dd, J = 3.8, 1.2 Hz, 1H), 7.61 (dd, J = 5.1, 1.2

Hz, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.21 (dd, J = 5.1, 3.8 Hz, 1H);

¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 150.5, 147.5, 136.1, 136.0, 130.6,

150.8, 148.3, 141.1, 140.1, 132.5, 129.7, 127.5, 117.9, 113.8; IR (neat) v

̃

3073 (w), 2228 (s), 1561 (w), 1329 (vs), 1308 (s), 1116 (m), 850 (m)

+

cm⁻¹; HRMS (EI) m/z Calcd for C₁₁H₆BrN₃258.9745, found

258.9738.

Pyridazine 3i. Pyridazine 3i was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyl((1-(4-((tert-butyldimethylsilyl)oxy)phenyl)vinyl)oxy)-

dimethylsilane (79.1 mg, 0.217 mmol, 1.40 equiv). After 10 min, the

reaction was complete, and after work up the crude material was

puriﬁed via ﬂash column chromatography on silica gel (60% Et₂O in

pentane) to aﬀord 3i (33.0 mg, 0.09 mmol, 58%) as a colorless

crystalline solid. R_f(60% Et₂O in pentane) = 0.36 (UV, CAM); mp =

138 °C; ¹H NMR (CDCl₃, 400 MHz) δ 9.12 (d, J = 5.0 Hz, 1H), 7.39−

7.36 (m, 3H), 6.96−6.93 (m, 2H), 1.01 (s, 9H), 0.25 (s, 6H); ¹³C{¹H}

NMR (CDCl₃, 101 MHz) δ 157.2, 150.6, 149.4, 142.7, 130.4, 128.4,

130.0, 128.2, 126.9; IR (neat) ṽ 3087 (m), 1553 (vs), 1424 (vs), 1314

(vs), 1110 (m), 1020 (m) cm⁻¹; HRMS (EI) m/z Calcd for

C₁₁H₆BrN₂S⁺239.9357, found 239.9352.

Pyridazine 3n. Pyridazine 3n was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyldimethyl((1-(furan-2-yl)vinyl)oxy)silane (48.7 mg, 0.217

mmol, 1.40 equiv). After 10 min, the reaction was complete, and

after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (2−10% Et₂O in CH₂Cl₂) to aﬀord 3n

(18.0 mg, 0.08 mmol, 52%) as a colorless oil. R_f(10% Et₂O in CH₂Cl₂)

= 0.38 (UV, KMnO₄); mp = 99 °C (decomp.); ¹H NMR (CDCl₃, 400

MHz) δ 9.11 (d, J = 5.3 Hz, 1H), 7.83 (d, J = 5.3 Hz, 1H), 7.72 (dd, J =

3.6, 0.6 Hz, 1H), 7.67 (dd, J = 1.8, 0.6 Hz, 1H), 6.64 (dd, J = 3.6, 1.8 Hz,

1H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 150.5, 146.4, 145.8, 143.9,

127.7, 120.2, 25.6, 18.2, −4.3; IR (neat) ṽ 2953 (m), 2928 (m), 1608

(m), 1504 (s), 1323 (m), 1258 (vs), 1170 (m), 1109 (s), 906 (vs), 847

(s) cm⁻¹; HRMS (EI) m/z Calcd for C₁₆H₂₁BrN₂OSi⁺364.0607, found

364.0600.

131.2, 123.1, 116.3, 112.9; IR (neat) ṽ 3101 (s), 1579 (s), 1551 (s),

Pyridazine 3j. Pyridazine 3j was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyl((1-(3-((tert-butyldimethylsilyl)oxy)phenyl)vinyl)oxy)-

dimethylsilane (79.1 mg, 0.217 mmol, 1.40 equiv). After 10 min, the

reaction was complete, and after work up the crude material was

puriﬁed via ﬂash column chromatography on silica gel (60% Et₂O in

pentane) to aﬀord 3j (33.0 mg, 0.08 mmol, 52%) as a colorless oil. R_f

1514 (s), 1474 (s), 1419 (m), 1314 (vs), 1164 (w), 1023 (vs), 866 (m)

cm⁻¹; HRMS (EI) m/z Calcd for C₈H₅BrN₂O⁺223.9585, found

223.9583.

Pyridazine 3o. Pyridazine 3o was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyl((1-cyclohexylvinyl)oxy)dimethylsilane (52.2 mg, 0.217

mmol, 1.40 equiv). After 10 min, the reaction was complete, and

after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (5% MeOH in CH₂Cl₂) to aﬀord 3o (32.8

mg, 0.136 mmol, 88%) as a yellow oil. R_f(5% MeOH in CH₂Cl₂) = 0.43

1

(60% Et₂O in pentane) = 0.35 (UV, CAM); H NMR (CDCl₃, 400

MHz) δ 9.15 (d, J = 5.0 Hz, 1H), 7.39 (d, J = 4.9 Hz, 1H), 7.35 (d, J =

8.1 Hz, 1H), 7.02−6.99 (m, 1H), 6.98−6.95 (m, 1H), 6.93 (ddd, J =

2.3, 1.7, 0.5 Hz, 1H), 0.99 (s, 9H), 0.23 (s, 6H); ¹³C{¹H} NMR

(CDCl₃, 101 MHz) δ 155.9, 150.8, 149.3, 142.9, 137.2, 130.0, 128.0,

1

(UV, KMnO₄); H NMR (CDCl₃, 400 MHz) δ 9.00 (d, J = 5.1 Hz,

1H), 7.27 (d, J = 5.1 Hz, 1H), 2.86 (tt, J = 11.9, 3.1 Hz, 1H), 1.97−1.87

(m, 4H), 1.84−1.79 (m, 1H), 1.44 (tt, J = 12.8, 3.2 Hz, 2H), 1.36−1.22

(m, 3H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 152.0, 150.9, 148.1,

121.8, 121.6, 120.6, 25.8, 18.3, − 4.2; IR (neat) ṽ 2955 (w), 2930 (w),

2858 (w), 1581 (s), 1483 (s), 1302 (s), 1224 (s), 1109 (m), 939 (vs),

831 (vs) cm⁻¹; HRMS (EI) m/z Calcd for C₁₆H₂₁BrN₂OSi⁺364.0607,

found 364.0603.

125.1, 42.1, 32.0, 26.3, 25.8; IR (neat) ṽ 2927 (vs), 2853 (s), 1564 (m),

1449 (s), 1332 (vs), 1305 (m), 1230 (m), 1108 (s), 852 (m) cm⁻¹;

HRMS (ESI) m/z [M + H]⁺Calcd for C₁₀H₁₄BrN₂⁺241.0335, found

241.0338.

Pyridazine 3k. Pyridazine 3k was synthesized according to GP7 by

using 3-bromotetetrazine (1) (25.0 mg, 0.155 mmol, 1.00 equiv) and

tert-butyldimethyl((1-(m-tolyl)vinyl)oxy)silane (53.9 mg, 0.217 mmol,

1.40 equiv). After 10 min, the reaction was complete, and after work up

the crude material was puriﬁed via ﬂash column chromatography on

silica gel (70% Et₂O in pentane) to aﬀord 3k (28.0 mg, 0.112 mmol,

73%) as a colorless crystalline solid. R_f(70% Et₂O in pentane) = 0.43

(UV); mp = 90−92 °C; ¹H NMR (CDCl₃, 400 MHz) δ 9.15 (d, J = 4.9

Hz, 1H), 7.41−7.37 (m, 2H), 7.32 (d, J = 7.7 Hz, 1H), 7.27−7.25 (m,

Pyridazine 3p. Pyridazine 3p was synthesized according to GP7 by

using 3-bromotetetrazine (25.0 mg, 0.155 mmol, 1.00 equiv) and tert-

butyl((3,3-dimethylbut-1-en-2-yl)oxy)dimethylsilane (46.5 mg, 0.217

mmol, 1.40 equiv). After 30 min, the reaction was complete, and after

work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (80% Et₂O in pentane) to aﬀord 3p

(15.0 mg, 0.07 mmol, 45%) as a colorless solid. R_f(80% Et₂O in

L

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pentane) = 0.39 (UV, KMnO₄); mp = 39−40 °C; ¹H NMR (CDCl₃,

400 MHz) δ 9.00 (d, J = 5.3 Hz, 1H), 7.44 (d, J = 5.3 Hz, 1H), 1.52 (s,

9H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 150.8, 150.3, 149.8, 125.8,

gel (15% diethyl ether in CH₂Cl₂) to aﬀord 5d (25.0 mg, 0.102 mmol,

66%) as a colorless oil. R_f(15% Et₂O in CH₂Cl₂) = 0.27 (UV, KMnO₄);

¹H NMR (CDCl₃, 400 MHz) δ 9.13 (d, J = 5.1 Hz, 1H), 7.46−7.39 (m,

3H), 7.28 (d, J = 5.1 Hz, 1H), 7.15−7.10 (m, 5H), 6.97 (dd, J = 7.4, 2.0

Hz, 2H), 4.27 (s, 2H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 160.6,

149.8, 140.7, 138.5, 136.4, 128.8, 128.8, 128.6, 128.5, 128.3, 126.9,

35.9, 28.6; IR (neat) ṽ 2966 (w), 1367 (m), 1321 (vs), 1138 (m), 1067

+

(vs), 1008 (m) cm⁻¹; HRMS (EI) m/z Calcd for C₈H₁₁BrN₂

214.0106, found 214.0098.

Pyridazine 3q. Pyridazine 3q was synthesized according to GP7 by

using 3-bromotetetrazine (25.0 mg, 0.155 mmol, 1.00 equiv) and tert-

butyldimethyl((4-phenylbut-1-en-2-yl)oxy)silane (57.0 mg, 0.217

mmol, 1.40 equiv). After 10 min, the reaction was complete, and

after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (ﬁrst with 5% Et₂O in CH₂Cl₂, then with

40% ethyl acetate in pentane) to aﬀord 3q (26.0 mg, 0.99 mmol, 64%)

as a colorless oil. R_f(5% Et₂O in CH₂Cl₂) = 0.41 (UV, KMnO₄); ¹H

NMR (CDCl₃, 400 MHz) δ 8.94 (d, J = 4.9 Hz, 1H), 7.32−7.21 (m,

3H), 7.16−7.13 (m, 2H), 7.10 (d, J = 4.9 Hz, 1H), 3.07−3.03 (m, 2H),

3.00−2.96 (m, 2H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 151.9, 150.7,

126.3, 40.0; IR (neat) ṽ 3058 (w), 3029 (w), 1569 (m), 1494 (s), 1357

(m), 1013 (w), 759 (s), 897 (vs) cm⁻¹; HRMS (ESI) m/z [M + H]⁺

Calcd for C₁₇H₁₅N₂⁺247.1230, found 247.1231.

Pyridazine 5e. Pyridazine 5e was synthesized according to GP7 by

using 3-((benzyloxy)methyl)-s-tetrazine (29.3 mg, 0.145 mmol, 1.00

equiv) and tert-butyldimethyl((1-phenylvinyl)oxy)silane (47.6 mg,

0.203 mmol, 1.40 equiv). After 10 min, the reaction was complete, and

after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (10−20% diethyl ether in CH₂Cl₂) to

aﬀord 5e (15.0 mg, 0.054 mmol, 37%) as a colorless oil. R_f(10% Et₂O in

CH₂Cl₂) = 0.36 (UV, CAM); ¹H NMR (CDCl₃, 400 MHz) δ 9.20 (d, J

= 5.2 Hz, 1H), 7.53−7.46 (m, 5H), 7.42 (d, J = 5.2 HZ, 1H), 7.34−7.26

(m, 5H), 4.81 (s, 2H), 4.62 (s, 2H); ¹³C{¹H} NMR (CDCl₃, 101 MHz)

δ 157.2, 151.0, 141.5, 137.8, 135.9, 129.3, 128.9, 128.9, 128.5, 128.1,

142.9, 139.5, 128.8, 128.6, 127.9, 126.8, 36.7, 34.2; IR (neat) v 3027

̃

(w), 2925 (m), 2855 (w), 1565 (m), 1496 (m), 1454 (s), 1411 (w),

1338 (vs), 1103 (vs), 1084 (vs), 849 (m) cm⁻¹; HRMS (ESI) m/z [M +

H]⁺Calcd for C₁₂H₁₂BrN₂⁺263.0178, found 263.0180.

127.9, 127.1, 73.1, 70.5; IR (neat) v 3059 (w), 3031 (w), 2865 (w),

̃

Pyridazine 5a. Pyridazine 5a was synthesized according to GP7 by

using tert-butyldimethyl((1-phenylvinyl)oxy)silane (64.1 mg, 0.217

mmol, 1.40 equiv). After 10 min, the reaction was complete, and after

work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (20% diethyl ether in CH₂Cl₂) to aﬀord

5a (36.0 mg, 0.144 mmol, 93%) as a colorless oil. R_f(20% diethyl ether

in CH₂Cl₂) = 0.45 (UV, KMnO₄); ¹H NMR (CDCl₃, 400 MHz) δ 9.21

(d, J = 5.2 Hz, 1H), 7.48 (d, J = 5.2 Hz, 1H), 7.45−7.41 (m, 2H), 7.38−

7.32 (m, 3H), 7.20−7.18 (m, 2H), 7.02−6.97 (m, 2H); ¹³C{¹H} NMR

(CDCl₃, 101 MHz) δ 164.6 (d, J = 249 Hz), 150.2, 139.2, 136.7, 133.1

(d, J = 3.4 Hz), 132.1 (d, J = 8.3 Hz), 129.1, 129.0, 129.0, 127.5, 115.6

(d, J = 21.7 Hz); ¹⁹F{¹H} NMR (CDCl₃, 376 MHz) δ −112.4; IR

1569 (m), 1495 (m), 1453 (m), 1349 (m), 1075 (s), 1059 (s), 861 (w),

760 (s), 698 (vs) cm⁻¹; HRMS (ESI) m/z [M + H]⁺Calcd for

C₁₈H₁₇N₂O⁺277.1335, found 277.1335.

Pyridazine 5f. Pyridazine 5f was synthesized according to GP7 by

using methyl 3-(1,2,4,5-tetrazin-3-yl)propanoate (26.1 mg, 0.155

mmol, 1.00 equiv) and tert-butyldimethyl((1-phenylvinyl)oxy)silane

(50.9 mg, 0.217 mmol, 1.40 equiv). After 10 min, the reaction was

complete, and after work up the crude material was puriﬁed via ﬂash

column chromatography on silica gel (20% diethyl ether in CH₂Cl₂) to

aﬀord 5f (29.6 mg, 0.122 mmol, 79%) as a colorless oil. R_f(20% Et₂O in

CH₂Cl₂) = 0.27 (UV); ¹H NMR (CDCl₃, 400 MHz) δ 9.10 (d, J = 5.1

Hz, 1H), 7.52−7.45 (m, 3H), 7.37−7.35 (m, 2H), 7.28 (d, J = 5.1 Hz,

1H), 3.63 (m, 3H), 3.26 (t, J = 7.3 Hz, 2H), 2.95 (t, J = 7.3 Hz, 2H);

¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 173.4, 159.4, 149.7, 140.3, 136.2,

(neat) ṽ 1604 (s), 1511 (vs), 1426 (s), 1350 (s), 1224 (vs), 1159 (s),

841 (vs), 797 (s), 760 (s), 559 (vs) cm⁻¹; HRMS (EI) m/z Calcd for

C₁₅H₁₂N₂F⁺251.0979, found 251.0977.

128.9, 128.9, 128.5, 126.3, 51.7, 31.8, 28.5; IR (neat) ṽ 2951 (w), 1734

Pyidazine 5b. Pyridazine 5b was synthesized according to GP7 by

using tert-butyldimethyl((1-phenylvinyl)oxy)silane (64.1 mg, 0.217

mmol, 1.40 equiv). After 10 min, the reaction was complete, and after

work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (20% diethyl ether in CH₂Cl₂) to aﬀord

5b (36.0 mg, 0.137 mmol, 89%) as a colorless solid. R_f(20% diethyl

ether in CH₂Cl₂) = 0.36 (UV, KMnO₄); mp = 121−123 °C; ¹H NMR

(CDCl₃, 400 MHz) δ 9.16 (d, J = 5.1 Hz, 1H), 7.44 (d, J = 5.2 Hz, 1H),

7.41−7.37 (m, 5H), 7.23−7.21 (m, 2H), 6.84−6.81 (m, 2H), 3.81 (s,

3H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 160.3, 159.7, 149.8, 138.9,

(vs), 1571 (w), 1495 (w), 1436 (m), 1360 (m), 1197 (m), 1175 (m),

+

703 (m) cm⁻¹; HRMS (ESI) m/z [M + H]⁺Calcd for C₁₄H₁₅N₂O₂

243.1128, found 243.1129.

Pyridazine 6. Pyridazine 6 was synthesized according to GP7 by

using dimethyl s-tetrazine-3,6-dicarboxylate (30.7 mg, 0.155 mmol,

1.00 equiv) and tert-butyldimethyl((1-phenylvinyl)oxy)silane (50.9

mg, 0.217 mmol, 1.40 equiv). After 2 h, the reaction was complete, and

after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (2% MeOH in CH₂Cl₂) to aﬀord 6 (25.5

mg, 0.094 mmol, 60%) as a pale yellow oil. R_f(5% MeOH in CH₂Cl₂) =

1

137.2, 131.6, 129.4, 129.1, 128.9, 128.8, 127.4, 113.8, 55.4; IR (neat) v

̃

0.43 (UV, KMnO₄); H NMR (CDCl₃, 400 MHz) δ 8.27 (s, 1H),

1608 (s), 1513 (s), 1411 (m), 1352 (m), 1298 (m), 1250 (vs), 1177 (s),

7.52−7.51 (m, 3H), 7.47−7.43 (m, 2H), 4.11 (s, 3H), 3.88 (s, 3H).

The obtained analytical data are consistent with the values reported in

the literature.³⁵

+

1032 (m), 838 (s) cm⁻¹; HRMS (EI) m/z Calcd for C₁₇H₁₅ON₂

263.1179, found 263.1184.

Pyridazine 5c. Pyridazine 5c was synthesized according to GP7 by

using methyl 4-(1,2,4,5-tetrazin-3-yl)benzoate (24.0 mg, 0.111 mmol,

1.00 equiv) and tert-butyldimethyl((1-phenylvinyl)oxy)silane (36.4

mg, 0.155 mmol, 1.40 equiv). After 10 min, the reaction was complete,

and after work up the crude material was puriﬁed via ﬂash column

chromatography on silica gel (20% diethyl ether in CH₂Cl₂) to aﬀord

5c (25.3 mg, 0.087 mmol, 79%) as a colorless crystalline solid. R_f(20%

Et₂O in CH₂Cl₂) = 0.33 (UV, CAM); mp = 151 °C; ¹H NMR (CDCl₃,

400 MHz) δ 9.24 (d, J = 5.2 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.53−

7.51 (m, 3H), 7.38−7.30 (m, 3H), 7.18−7.15 (m, 2H), 3.91 (s, 3H);

¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 166.8, 159.2, 150.4, 141.5, 139.4,

Pyridazine 7. Pyridazine 7 was synthesized according to GP7 using

3,6-dimethyl-s-tetrazine (47.9 mg, 0.435 mmol, 1.00 equiv) and tert-

butyldimethyl((1-phenylvinyl)oxy)silane (143 mg, 0.609 mmol, 1.40

equiv). After 1 h, the reaction was complete, and after work up the crude

material was puriﬁed via ﬂash column chromatography on silica gel

(CH₂Cl₂to 2% MeOH in CH₂Cl₂) to aﬀord 7 (33.0 mg, 0.179 mmol,

1

41%) as a colorless oil. R_f(5% MeOH in CH₂Cl₂) = 0.43 (UV); H

NMR (CDCl₃, 400 MHz) δ 7.50−7.42 (m, 3H), 7.34−7.32 (m, 2H),

7.13 (s, 1H), 2.71 (s, 3H), 2.64 (s, 3H); ¹³C{¹H} NMR (CDCl₃, 126

MHz) δ 158.2, 156.0, 140.2, 137.1, 128.9, 128.8, 128.6, 126.7, 22.0,

21.0; IR (neat) ṽ 3057(w), 2925 (w), 1698 (w), 1588 (s), 1495 (m),

136.3, 130.4, 130.2, 129.5, 129.1, 129.0, 127.4, 52.3; IR (neat) v

̃

2951

1446 (s), 1407 (vs), 1222 (w), 1076 (w), 887 (w), 778 (s), 702 (vs)

+

(w), 1721 (vs), 1611 (w), 1558 (w), 1495 (w), 1435 (w), 1277 (vs),

1113 (s), 1018 (m), 861 (m), 769 (s), 702 (s) cm⁻¹; HRMS (ESI) m/z

[M + H]⁺for C₁₈H₁₅N₂O₂⁺291.1128, found 291.1124.

cm⁻¹; HRMS (ESI) m/z [M + H]⁺Calcd for C₁₂H₁₃N₂185.1073,

found 185.1074.

Pyridazine 8. Pyridazine 3a (100 mg, 0.425 mmol, 1.00 equiv) was

dissolved in dioxane/water (4:1, v/v; 5 mL), and to the mixture were

added potassium carbonate (235 mg, 1.70 mmol, 4.00 equiv),

phenylboronic acid (64.1 mg, 0.51 mmol, 1.20 equiv), and Pd(PPh₃)₄

(98.2 mg, 85.0 μmol, 20 mol %) sequentially. The mixture was heated

to 100 °C for 16 h in an oil bath. Then, water (20 mL) and ethyl acetate

Pyridazine 5d. Pyridazine 5d was synthesized according to GP7 by

using 3-benzyl-s-tetrazine (26.7 mg, 0.155 mmol, 1.00 equiv) and tert-

butyldimethyl((1-phenylvinyl)oxy)silane (50.9 mg, 0.217 mmol, 1.40

equiv). After 10 min, the reaction was complete, and after work up the

crude material was puriﬁed via ﬂash column chromatography on silica

M

https://doi.org/10.1021/acs.joc.1c01384

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(20 mL) were added to the mixture, and the layers were separated. The

aqueous layer was extracted with ethyl acetate (2 × 20 mL), and the

combined organic layers were washed with brine (20 mL), dried over

sodium sulfate, ﬁltered, and concentrated under reduced pressure. The

crude product was puriﬁed via ﬂash column chromatography on silica

gel (15% diethyl ether in CH₂Cl₂) to aﬀord pyridazine 8 (78.0 mg, 0.34

mmol, 79%) as a colorless oil. R_f(10% Et₂O in CH₂Cl₂) = 0.17 (UV,

KMnO₄); ¹H NMR (CDCl₃, 400 MHz) δ 9.22 (d, J = 5.1 Hz, 1H), 7.49

(d, J = 5.1 Hz, 1H), 7.45 (d, J = 7.3 Hz, 2H), 7.36−7.29 (m, 6H), 7.21

(d, J = 7.7 Hz, 2H); ¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 160.1, 150.1,

139.2, 137.0, 136.9, 130.1, 129.2, 128.9, 128.9, 128.8, 128.3 127.4; IR

then quenched with NaHCO₃(aq), and the total conversion was

determined by ¹H NMR.

Data were analyzed using the iC IR 7.1.84 program, and the

absorbance data were converted to normalize the absorbance (%) and

then to concentration (M). The trace at 1202 cm⁻¹was selected to

follow the kinetics. Dynochem was used to carry out the ﬁtting and

simulation of reaction kinetics.

ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01384.

(neat) v 3058 (w), 2924 (w), 1495 (w), 1446 (m), 1416 (m), 1352

̃

(m), 1285 (m), 1255 (m), 1089 (m), 755 (s), 763 (vs), 697 (vs) cm⁻¹;

+

HRMS (ESI) m/z [M + H]⁺Calcd for C₁₆H₁₃N₂233.1073, found

¹H and ¹³C{¹H} NMR spectra, crystallographic data, and

detailed experimental data for kinetic experiments (PDF)

233.1072.

Pyridazine 9. Pyridazine 3a (10.0 mg, 42.5 μmol, 1.00 equiv) was

dissolved in degassed THF (1 mL) in a pressure tube. To the solution

were added Pd(PPh₃)₄(9.82 mg, 8.5 μmol, 20 mol %), CuI (4.05 mg,

21.3 μmol, 50 mol %), TMS acetylene (30.2 μL, 0.213 mmol, 5.00

equiv), and triethylamine (23.9 μL, 0.17 mmol, 4.00 equiv)

sequentially, and the mixture was heated to 70 °C for 2 h in an oil

bath. Then, the solvent was removed under reduced pressure, and the

crude product was puriﬁed via ﬂash column chromatography on silica

gel (10% diethyl ether in CH₂Cl₂) to aﬀord pyridazine 9 (10.7 mg, 42.0

μmol, quant.) as a yellow oil. R_f(10% Et₂O in CH₂Cl₂) = 0.43 (UV,

Accession Codes

CCDC 2087882−2087885 contain the supplementary crystallo-

graphic data for this paper. The data can be obtained free of

charge from The Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/structures.

AUTHOR INFORMATION

■

1

Corresponding Author

KMnO₄); H NMR (CDCl₃, 400 MHz) δ 9.16 (d, J = 5.3 Hz, 1H),

7.68−7.66 (m, 2H), 7.50−7.45 (m, 4H), 0.19 (s, 9H); ¹³C{¹H} NMR

(CDCl₃, 101 MHz) δ 149.6, 146.3, 142.1, 135.1, 129.9, 129.1, 128.6,

Karl Gademann − Department of Chemistry, University of

Zurich, 8057 Zurich, Switzerland; orcid.org/0000-0003-

3053-0689; Email: karl.gademann@uzh.ch

125.2, 103.4, 100.4, − 0.6; IR (neat) ṽ 3058 (w), 1558 (w), 1419 (w),

1251 (m), 869 (vs), 841 (vs) cm⁻¹; HRMS (ESI) m/z [M + H]⁺Calcd

for C₁₅H₁₇N₂Si⁺253.1156, found 253.1156.

Authors

Pyridazine 10. Pyridazine 3a (30.1 mg, 0.128 mmol, 1.00 equiv),

sodium tert-butoxide (36.9 mg, 0.384 mmol, 3.00 equiv), and

Pd(dppf)Cl₂(18.7 mg, 25.6 μmol, 20 mol %) were added to a pressure

ﬂask, and the ﬂask was purged with N₂. Degassed dioxane (2 mL) was

added, followed by 4-ﬂuoroaniline (17 μL, 0.179 mmol, 1.40 equiv).

The mixture was heated to 100 °C for 3 h in an oil bath. Then, the

mixture was ﬁltered through a pad of Celite, and the ﬁlter cake was

rinsed with CH₂Cl₂(20 mL). The solvent was removed under reduced

pressure, and the crude product was puriﬁed via ﬂash column

chromatography (2% MeOH in CH₂Cl₂) followed by column

chromatography on silica gel (40−60% ethyl acetate in pentane) to

aﬀord pyridazine 10 (14.4 mg, 54.0 μmol, 42%) as a yellow oil. R_f(2%

Simon D. Schnell − Department of Chemistry, University of

Zurich, 8057 Zurich, Switzerland; orcid.org/0000-0002-

0734-9462

Jorge A. González − Department of Chemistry, University of

Zurich, 8057 Zurich, Switzerland

Jan Sklyaruk − Department of Chemistry, University of Zurich,

8057 Zurich, Switzerland

Anthony Linden − Department of Chemistry, University of

Zurich, 8057 Zurich, Switzerland; orcid.org/0000-0002-

9343-9180

1

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01384

MeOH in CH₂Cl₂) = 0.27 (UV, KMnO₄); H NMR (CDCl₃, 400

MHz) δ 8.79 (d, J = 4.6 Hz, 1H), 7.60−7.47 (m, 7H), 7.15 (d, J = 4.6

Hz, 1H), 7.00 (t,, J = 8.7 Hz, 2H), 6.45 (s, 1H); ¹³C{¹H} NMR (CDCl₃,

101 MHz) δ 160.0 (d, J = 242 Hz), 154.8, 145.6, 135.6 (d, 2.7 Hz),

134.3, 130.0, 129.8, 128.5, 128.5, 127.0, 122.0 (d, J = 7.7 Hz), 115.7 (d,

Notes

The authors declare no competing ﬁnancial interest.

22.5 Hz); ¹⁹F{¹H} NMR (CDCl₃, 376 MHz): − 120.1; IR (neat) v

̃

3418 (w), 1058 8w), 1561 (m), 1506 (vs), 1404 (s), 1211 (m), 998

(w), 829 (m) cm⁻¹; HRMS (ESI) m/z [M + H]⁺Calcd for

ACKNOWLEDGMENTS

■

+

C₁₆H₁₃FN₂: 266.1088, found 266.1087.

We would like to express our gratitude to Joana Hauser

(University of Zurich) for laboratory assistance.

Kinetics Measurement and Modeling. The reaction was performed

in an oven-dried 50 mL two-neck round-bottom ﬂask charged with a

Teﬂon-coated magnetic stirring bar. The ﬂask was ﬁtted to the React IR

probe with a Teﬂon adapter, and the system was closed with a rubber

septum. The background spectrum was recorded from 650 to 2500

cm⁻¹. Then, the system was purged with nitrogen and connected to a

balloon ﬁlled with nitrogen before being placed into a cooling bath (dry

ice/acetone) for 10 min.

IR spectra were recorded approximately every 15 s with a spectral

width from 650 to 2500 cm⁻¹. The internal temperature was tracked

simultaneously with the React IR probe. Stock solutions of 1 and 4 were

made up and added sequentially to the reaction vessel as follows:

dichloromethane (2.5 mL), 1 (10 mL, 0.25 M), and 4 (10 mL, 0.35 M).

Upon thermal equilibration (−50 1.5 °C) and with vigorous stirring,

no changes were observed in the IR spectra of the reaction mixture. At

this point, BF₃·Et₂O (2.5 mL, 1.05 M) was added via syringe to the

mixture within approximately 5 s (t = 0). The reaction was followed

until no changes in the IR traces were observed. The reaction crude was

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Boron Trifluoride-Mediated Cycloaddition of 3-Bromotetrazine and Silyl Enol Ethers: Synthesis of 3-Bromo-pyridazines

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