A convergent strategy towards febrifugine and related compounds

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ISSN 1477-0520

COMMUNICATION

Takeharu Haino et al.

Solvent-induced emission of organogels based on tris(phenylisoxazolyl)

benzene

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A Convergent Strategy to Febrifugine and Related Compounds

T. M. M. Maiden,^aN. Mbelesi, ^aP. A. Procopiou,^bS. Swanson,^band J. P. A. Harrity ^*a

Received 00th January 20xx,

Accepted 00th January 20xx

DOI: 10.1039/x0xx00000x

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restinosis, autoimmune disorders and fibrotic diseases.⁶

Halofuginone hydrobromide (tempostatin^TM) has been tested

We report a modular five step synthetic route to the febrifugines

that employs 2-(chloromethyl)allyl-trimethylsilane as a conjuctive

reagent for the coupling of the piperidine and quinazolinone in Phase 1 clinical studies to assess dose-limiting toxicities, the

maximum tolerated dose and human pharmacokinetics.⁷

groups. We also demonstrate the application of a recent Rh-

catalyzed quinazolinone synthesis for the facile generation of

febrifugine analogs.

Observed side-effects included nausea, vomiting and fatigue,

and the recommended maximum dose for further studies was

determined to be 0.5 mg/day. Other analogues of febrfugine

and halofuginone, devoid of toxicity and side-effects are

therefore required for further exploitation and development

of new medicines.

Introduction

Quinazolinones are an important class of heterocycles in

organic chemistry, and they are found in many natural

products and biologically active compounds.¹Most methods of

generating these compounds rely on the availability of

anthranilic acids and related systems.²Recently however, we

have reported a directed amidation strategy for the synthesis

of quinazolinones, which allows a broad range of these

compounds to become available from simple (and often

commercial) carboxylic acids.³

O

H

N

R₁

R₂

N

O

N

X

Y

R₁/R₂=H, X=H, Y=OH: Febrifugine

R₁/R₂=H, X=OH, Y=H: Isofebrifugine

R₁=Cl, R₂=Br, X=H, Y=OH: Halofuginone

Figure 1. Febrifugine and related analogs.

Amongst the many important quinazolinone-containing

compounds found in nature and medicinal chemistry, the

febrifugine family of alkaloids together with their synthetic

Despite the attractive biological applications which the

febrifugine family offer, only limited SAR has been

analog halofuginone, have attracted considerable interest investigated.⁸We sought to develop a modular route to the

(Figure 1).⁴Febrifugine, isolated from the roots of Dichroa

febrifugine family and synthesize biologically relevant analogs

by utilizing our C-H amidation cyclocondensation sequence.

With respect to febrifugine, Ogasawara prepared this

compound through the synthesis of a 2-allyl piperidin-3-ol

derivative that allows the final compound to be delivered after

alkene epoxidation, quinazolinone addition, oxidation level

adjustment and protecting group manipulation.⁹This route has

the advantage of introducing the quinazolinone at a late-stage

thereby providing a means for acquiring SAR at this position.

On the other hand, several steps are required before the key

piperidine intermediate is made available.

febrifuga plant and Hydrangea, has powerful antimalarial

properties against Plasmodium falciparum, however, because

of side-effects, such as severe vomiting and hepatotoxicity, is

not used clinically. The synthetic analog halofuginone lactate is

used as an antiparasitic agent in veterinary medicine for the

treatment of neonatal dairy calves preventing infection with

cryptosporidium and in poultry against coccidiosis.⁵

Furthermore, halofuginone inhibits the development of human

Th17 cells and collagen type 1 gene expression and has the

potential to be used for the treatment of scleroderma, cancer,

In an effort to devise a convergent route to this class of

compounds and explore SAR, we were attracted to the

approaches of Burgess and Rutjes. Burgess had employed a

tetrahydropyridine oxide that allowed the quinazolinone

containing ketone fragment to be introduced in one step.¹⁰

Rutjes however had devised an elegant allylsilane conjunctive

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reagent

stage lactam analog of febrifugine.¹¹We envisaged that stereoselectivity of the allylation reaction using conjunctive

combining these strategies could offer a rapid and convergent reagent , and our results are summarized in Table 1.

2 that offered a highly convergent approach to a late- Aminals 1a-c provided a platform to explore the efficiency and

2

method for the synthesis of febrifugine and its analogs that Carbonate 1a provided piperidine 3a in modest yield and with

included the option of exploiting our C-H amidation a marginal preference for the trans-diastereomer. Diester 1b

methodology for the late-stage introduction of a range of and epoxide 1c performed similarly and provided compounds

bespoke quinazolinones. Our strategy is summarized in 3a,b with low cis/trans-selectivity. As low selectivities were

Scheme 1.

observed in every case, we decided to use the route that

employed 1c as this encompassed only a two-step sequence.

Moreover, as cis/trans-3a were separable by chromatography

this procedure allowed gram quantities of each intermediate

to be prepared for subsequent transformation to the target

compounds.

Results and Discussion

Our first task was to develop a scalable method for the

coupling of Rutjes’ conjunctive reagent

2 to the piperidine ring

of the target compound series. We therefore investigated the

synthesis of functionalized piperidines 1a-c, all of which

represented potential precursors to the first key intermediate

Table 1 Coupling reaction of allylsilane 2 with piperidines 1a-d

Entry^a

Piperidine

R

Yield (trans:cis)^b

40% (1.2:1)

63% (1:1.3)

66% (1:1.1)

1

2^c

3

1a

1b

1c

H; 3a

Ac; 3b

H; 3a

^aReaction conditions: 1a-d, 2 (1.2 equiv), BF₃.OEt₂(2 equiv) in CH₂Cl₂stirred

at -78 ^oC under N₂for 1 h and warmed to rt overnight. ^bIsolated yields of

purified compounds. ^c1 Equiv BF₃.OEt₂used in this case.

We next turned our attention to the introduction of the

quinazolinones, with a view to using our recently developed

Rh-catalyzed

ortho-amidation

cyclocondensation

sequence.^3(a),(b)Employing this methodology, we were able to

readily prepare a range of functionalized quinazolinones.

Scheme 1. Convergent route to febrifugine analogs.

Halofuginone quinazolinone 4a, its corresponding isomer 4b

,

3

(Scheme 2). Accordingly, commercial Cbz-protected

aza-quinazolinone 4c and the quinazolinone of the tyrosine

kinase inhibitor, 4d. The required quinazolinones for the

febrifugine analog 4f and the mono-Br 4e were acquired from

a commercial source (Scheme 3).

tetrahydropyridine was subjected to dihydroxylation followed

by functionalization of the diol moiety as a carbonate and

diester¹²1a,b in synthetically useful overall yields. In addition,

we prepared epoxide 1c

. Our preliminary method for

With quinazolinones 4a-f in hand, we next explored the

coupling of these heterocycles with the trans-piperidine 3a. In

the event, the couplings took place smoothly in all cases to

deliver a family of fully coupled febrifugine analogs (Scheme

4). Having successfully coupled the key fragments, our final

objective was to confirm that intermediates 5a-f could be

taken forward to the corresponding febrifugine derivatives.

epoxidation employed freshly prepared DMDO (method A) but

the in situ generation of this reagent (method B) proved to be

more practical and allowed gram quantities of substrate to be

accessed more conveniently.

Scheme 2. Synthesis of functionalized piperidines.

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good yield under these conditions as the HBr salts. Moreover,

isolation of the free base of trans-5f followed by

recrystallization from CH₂Cl₂/petroleum ether allowed us to

record the first reported X-ray crystal structure of febrifugine,

thereby unambiguously confirming the trans-stereochemistry

of the piperidine ring.¹³

Scheme 5. Investigation towards the synthesis of the iso-

febrifugines.

Scheme 3. Synthesis of quinazolinones by directed CH-

amidation.

We next turned our attention to the synthesis of the

corresponding cis-analogs of the febrifugines, but found these

transformations to be less straightforward (Scheme 5).

Specifically, while cis-6 (iso-halofuginone) could be prepared

and isolated as the free base, albeit in low yield, the

corresponding derivatives derived from other quinazolinones

could not be isolated cleanly by this process. Indeed, evidence

for the instability of these products under acid was uncovered

during the attempted syntheses of cis-

6. Specifically, we were

able to isolate imine 7 as major by-products in this case, and

the compound structure was assigned by NMR spectroscopy

and mass spectrometry, and by comparison to literature data

of a similar compound.¹⁴We believe that this side reaction is

initiated by an acid catalyzed β-amino elimination, as this

pathway has been invoked as a mechanism for cis/trans

isomerization in the febrifugines. Furthermore, and as shown

in Scheme 5, enolization of the ring-opened product can

provide a 1,4-diketone that undergoes condensation to the

observed imine

7.

As we had developed

a

convergent strategy for the

preparation of biologically relevant trans-febrifugine analogs,

especially those that contained halogenated quinazolinone

fragments, we wanted to demonstrate that this chemistry

could offer the opportunity for directed analog synthesis.

Specifically, we were intrigued by a recent report by Zhou who

employed crystallography to show how halofuginone binds

and inhibits ATP-dependent, human prolyl tRNA synthetase

(ProRS).¹⁵We were especially drawn to the presence of the

glutamic acid 1100 residue which was in close proximity to the

bound quinazolinone, and were interested in the introduction

of a basic moiety such as an aminomethyl group to increase

the binding affinity of these compounds. We envisaged that

Scheme 4. Synthesis of febrifugine and analogs.

We employed an oxidative cleavage and deprotection

protocol, using a modification of the method described by

Rutjes.¹¹We were pleased to find that halofuginone trans-5a

,

febrifugine trans-5f and analogs trans-5b-e were all isolated in

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quinazolinone 4a would offer convenient access to these

compounds.

Accordingly, we designed a route to a selection of amino-

methyl functionalized febrifugine analogs. Our strategy for

introduction of the aminomethyl motif was underpinned by

cross-coupling of Molander’s potassium amino-methyl

trifluoroborate salts.¹⁶In the event, coupling aminomethyl-

borate salts to quinazolinone 4a proceeded in low yield, and

we attributed this to low solubility of the coupling partners.

Gratifyingly, we found that employing the quinazolinone

precursors derived from our C-H amidation chemistry

satisfactorily

addressed

this

problem.

Specifically,

aminoquinazoline

8

offered improved conversion and isolated

yields of cross-coupled products. Subsequent hydrolysis

allowed access to a range of amino-methyl functionalized

quinazolinones 9a-c (Scheme 6).

Scheme 7. Synthesis of amino-methyl febrifugine analogs.

With the required quinazolinones in hand, the aminomethyl

functionalized analogs were smoothly progressed through to

the final compounds trans-10a-c as HBr salts (Scheme 7).

Biological evaluation of the amino-methyl and halogenated

analogs is ongoing and will be reported in due course.

Experimental

Compounds

1b,¹⁰

4a,^3(a)

4c,^3(a)

4d,^3(b)

Et-

and

morpholineaminomethyl potassium trifluoroborates¹⁶were

synthesized according to literature procedures.

Conclusions

Benzyl 2,3-dihydroxypiperidine-1-carboxylate.¹⁰To a solution

of N-Boc-3,4-dihydro-2H-pyridine (1.0 g, 5.4 mmol) in acetone

(50 mL) and water (5 mL) were added a few crystals of osmium

tetroxide. The reaction was stirred at room temperature and

monitored by TLC analysis. After completion, the mixture was

cooled and quenched with an aqueous saturated solution

of sodium metabisulfite (10 mL). Water (10 mL) was added and

the product was extracted with ethyl acetate (3 x 10 mL).

The combined organic layers were washed with brine and

dried over MgSO₄. The mixture was filtered and concentrated

under reduced pressure to give the crude product. The crude

residue was purified via flash column chromatography eluting

with petroleum ether : EtOAc (6 : 4) to give the title compound

We have developed a modular route to the febrifugines that

delivers these compounds in a 5 step sequence. This synthesis

route offers significant scope for analog preparation, as

demonstrated by the synthesis of amino-methyl derivatives,

and in this regard, we highlight the potential of a recent

catalytic quinazolinone synthesis for the diversification of

these compounds.

1

(922 mg, 68%); H NMR (400 MHz, CDCl₃): δ 7.38 - 7.34 (5H,

m), 5.75 (1H, d, J = 3.5 Hz), 5.13 (2H, s), 3.90 - 3.82 (1H, m),

3.64 - 3.56 (1H, m), 3.10 (1H, dt, J = 12.0, 2.0 Hz), 1.86 - 1.78

(1H, m), 1.74 - 1.66 (2H, m), 1.56 - 1.46 (1H, m); ¹³C NMR (101

MHz, CDCl₃): δ 156.0, 136.1, 128.5, 128.2, 127.9, 76.5, 69.0,

67.5, 36.1, 26.6, 23.5.

Scheme 6. Synthesis of amino-methyl functionalized

quinazolinones.

Benzyl 2-oxotetrahydro-[1,3]dioxolo[4,5-b]pyridine-4(3aH)-

carboxylate (1a). To

a

solution of benzyl 2,3-

dihydroxypiperidine-1-carboxylate (200 mg, 0.79 mmol) and

pyridine (251 mg, 3.18 mmol) in dichloromethane (6 mL) at 0

°C was added triphosgene (259 mg, 0.87 mmol). The reaction

was stirred at ice/water bath temperature for 6 h. After

completion, diethyl ether (10 mL) was added and the crude

mixture was washed with saturated aqueous CuSO₄. The

organic extract was washed with brine, dried over MgSO₄and

the solvent removed under reduced pressure to afford 1a as a

clear oil (141 mg, 64%); ¹H NMR (400 MHz, DMSO-d⁶): δ 7.53 -

7.19 (5H, m), 6.64 (1H, d, J = 8.0 Hz), 5.19 (2H, s), 5.11 – 5.05

(1H, m), 3.66 – 3.55 (2H, m), 1.83 – 1.71 (3H, m), 1.68 – 1.57

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(1H, m); ¹³C NMR (101 MHz, DMSO-d⁶): δ 154.8, 153.7, 136.4, d⁶): δ 155.2, 155.1, 142.9, 142.8, 137.6, 137.1, 128.9, 128.5,

128.9, 128.6, 128.2, 128.0, 82.5, 73.3, 67.8, 23.9, 16.0; FTIR: 128.1, 127.7, 117.5, 117.1, 68.2, 67.8, 66.8, 66.4, 55.4, 54.4,

ν_max2956 (w), 1794 (s), 1704 (s), 695 (s); HRMS calculated for 53.6, 48.2, 48.0, 37.8, 37.4, 27.7, 26.8, 24.6, 24.2; FTIR: ν_max

C₁₄H₁₅NO₅(ES⁺)(+Na⁺): 300.0842. Found: 300.0846.

3444 (w), 2938 (w), 1670 (s), 1424 (s); HRMS calculated for

C₁₇H₂₃NO₃³⁵Cl₂(ES⁺)(+H⁺): 324.1366. Found: 324.1367.

Benzyl 7-oxa-2-azabicyclo[4.1.0] heptane-2-carboxylate (1c).

Oxone monopersulfate (45.0 g, 147.0 mmol) was added Synthesis of 4-chloro-3-bromo-N-(2-hydroxyethyl)benzamide.

portion wise to a solution of sodium bicarbonate (60.0 g, 720.0 To a stirred solution of 4-chloro-3-bromo benzoic acid (5.0 g,

mmol) in water (300 mL), and the mixture was allowed to stir 21 mmol) in MeCN (35 mL) was added CDI (3.79 g, 23.4 mmol).

for 10 mins. To this solution was added acetone (240 mL) and The reaction mixture was allowed to stir for a period of 2

benzyl 3,4-dihydropyridine-1(2H)-carboxylate (4.0 g, 18.0 hours at room temperature before ethanol (2.45 g, 53.1 mmol)

mmol). The mixture was allowed to stir for 16 h at room was added via syringe. The reaction was then stirred overnight

temperature. After completion, water (100 mL) was added and at room temperature, before diluting with dichloromethane

the organic layer extracted with ethyl acetate (2 x 50 mL). The and transferring to a separating funnel. The organic phase was

combined organic layers were dried over MgSO₄and the then subsequently washed with a saturated solution of

solvent removed under reduced pressure to afford the crude NaHCO₃(aq.) and deionised water. The organic layer was dried

product, which was purified by flash column chromatography over anhydrous MgSO₄, filtered and the solvent was removed

eluting with cyclohexane : EtOAc (2 : 8) to afford 1c as a clear in vacuo to afford the crude ester product. To a dried round

oil (3.5 g, 83%) and as a 1 : 1 mixture of rotamers. ¹H NMR (400 bottomed flask was added the crude ester product (5.00 g,

MHz, CDCl₃): δ 7.37 (5H, s), 5.75 (0.5H, s), 5.60 (0.5H, s), 5.15 18.8 mmol) and heated to 55 °C with stirring. Upon reaching

(2H, s), 4.17 - 4.11 (0.5H, m), 3.95 - 3.85 (2H, m), 3.65 - 3.55 the desired temperature ethanolamine (1.72 g, 28.2 mmol)

(0.5H, m), 3.24 - 3.16 (1H, m), 3.12 - 3.04 (1H, m), 1.57 - 1.40 was added slowly via syringe and the reaction was stirred for 3

(2H, m); ¹³C NMR (101 MHz, CDCl₃): δ 171.4, 156.9, 136.2, h before cooling to room temperature, and stirring for a

128.5, 128.2, 128.1, 128.0, 127.96, 127.90, 78.2, 69.0, 67.5, further 18 hours. The crude reaction mixture was then purified

67.0, 60.3, 38.5, 26.7, 25.0, 23.5, 21.0, 18.4, 14.2; FTIR: ν_maxby flash column chromatography on silica gel eluting with

3375 (w), 2947 (w), 1673 (s), 1255 (s), 987 (s); HRMS dichloromethane and methanol (1% MeOH to 20% MeOH) to

calculated for C₁₃H₁₅NO₃(ES⁺)(+H⁺): 234.2613. Found: afford the amide product as a colourless solid (3.37 g, 64%).

234.2614.

M.p.: 166 – 167 °C; ¹H NMR (400 MHz, DMSO-d⁶); δ 8.63 (1H, t,

J = 5.5 Hz), 8.23 (1H, d, J = 2.0 Hz), 7.86 (1H, dd, J = 8.5, 2.0 Hz),

Benzyl

2-(2-chloromethyl)allyl)-3-methylpiperidine-1- 7.73 (1H, d, J = 8.5 Hz), 4.74 (1H, t, J = 5.5 Hz), 3.55 – 3.47 (2H,

carboxylate (trans- and cis-3a). To a solution of benzyl 7-oxa- m), 3.35 – 3.29 (2H, m – peak overlapped with residual H₂O);

2-azabicyclo[4.1.0]heptane-2-carboxylate (3.5 g, 149.0 mmol) ¹³C NMR (100.6 MHz, DMSO-d⁶); δ 163.9, 135.9, 134.9, 132.4,

and chlorotrimethylsilane (2.9 g, 179.0 mmol) in 130.5, 128.1, 121.5, 59.5, 42.3 FTIR: v_max(neat) 3289 (m), 1641

dichloromethane (40 mL) at -78 °C, BF₃.OEt₂(2.1 g, 149.0 (m), 1550 (m), 1466 (m), 1328 (m), 1248 (m), 1057 (s), 1023

mmol) was added. The reaction was allowed to stir overnight. (m), 751 (m); HRMS calculated for C₉H₁₀⁸¹Br³⁵ClNO₂(ES⁺)(+H⁺):

Aqueous NaHCO₃(20 mL) was added and the reaction mixture 279.9516. Found: 279.9554.

was extracted with EtOAc (2 x 20 mL). The combined organic

layers were dried over MgSO₄and the solvent was removed Synthesis of 2-(4-chloro-3-bromophenyl)-4,5-dihydrooxazole.

under reduced pressure to afford the crude oil which was To a dried round bottomed flask was added 4-chloro-3-bromo-

purified by chromatography eluting with petroleum ether : N-(2-hydroxyethyl)benzamide (3.00 g, 10.8 mmol) and dry

EtOAc (4 : 6) to afford trans-3a as a clear oil (1.5 g, 31%), and dichloromethane (18 mL). With stirring NEt₃(2.07 g, 20.5

cis-3a as a clear oil (1.7 g, 35 %). trans-3a (1 : 1 mixture of mmol) was then added, followed by DMAP (263 mg, 2.15

rotamers): ¹H NMR (400 MHz, DMSO-d⁶): δ 7.42 - 7.30 (5H, m), mmol) and p-TsCl (3.49 g, 18.3 mmol). The reaction mixture

5.16 - 5.14 (1H, m), 5.08 - 4.98 (2H, m), 4.80 - 4.78 (1H, m), was allowed to stir at room temperature overnight, before

4.35 - 3.95 (3H, m), 3.90 - 3.85 (1H, m), 3.65 - 3.55 (1H, m), being diluted with dichloromethane and water. The mixture

2.97 - 2.82 (1H, m), 2.35 - 2.25 (2H, m), 1.80 - 1.70 (2H, m), was then transferred to a separating funnel and the layers

1.60 - 1.55 (2H, m), 1.35 - 1.25 (1H, m); ¹³C NMR (101 MHz, partitioned. The aqueous layer was further extracted with

DMSO-d⁶): δ 155.9, 155.8, 142.4, 142.2, 137.7, 137.4, 128.8, dichloromethane. The combined organic layers were dried

128.2, 128.0, 127.6, 117.6, 117.3, 66.6, 66.3, 65.9, 65.4, 55.7, over anhydrous MgSO₄, filtered and the solvent was removed

55.4, 53.2, 48.2, 47.9, 38.9, 38.6, 32.5, 26.0, 24.4, 24.1; FTIR: in vacuo. The crude residue was dissolved in MeOH (22 mL)

ν

_max3444 (w), 2938 (w), 1670 (s), 1424 (s); HRMS calculated for and NaOH pellets (1.29 g, 32.3 mmol) were added in one

C₁₇H₂₃NO₃³⁵Cl₂(ES⁺)(+H⁺): 324.1366. Found: 324.1374. cis-3a (1 portion. The reaction mixture was stirred at room temperature

: 1 mixture of rotamers): ¹H NMR (400 MHz, DMSO-d⁶): δ 7.40 - for 2 h before removing the solvent in vacuo. The residue was

7.29 (5H, m), 5.12 - 4.99 (4H, m), 4.45 - 4.40 (2H, m), 4.30 - dissolved in dichloromethane and water, and transferred to a

4.25 (1H, m), 4.20 - 4.15 (2H, m), 4.05 - 3.95 (1H, m), 3.85 - separating funnel. The layers were partitioned and the

3.75 (1H, m), 3.65 - 3.55 (1H, m), 2.86 - 2.74 (2H, m), 1.66 - aqueous layer was further extracted with dichloromethane

1.62 (2H, m), 1.42 - 1.30 (1H, m); ¹³C NMR (101 MHz, DMSO- and ethyl acetate. The combined organic layers were dried

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over anhydrous MgSO₄, filtered and the solvent was removed chromatography on silica gel eluting with dichloromethane

in vacuo. The residue was purified by flash column and methanol (0 to 15% methanol) to afford the quinazoline

chromatography on silica gel eluting with petroleum ether product as a colourless solid (1.32 g, 73%). M.p.: 220 – 221 °C;

(40/60) and ethyl acetate (0% ethyl acetate to 100% ethyl ¹H NMR (400 MHz, DMSO-d⁶); δ 8.79 (1H, s), 8.54 (1H, app. d, J

acetate) to afford the oxazoline product as a colourless solid = 5.0 Hz), 8.47 (1H, s), 7.90 (1H, s), 4.82 (1H, t, J = 5.0 Hz), 3.65

1

(2.26 g, 81%). M.p.: 75 – 76 °C; H NMR (400 MHz, CDCl₃); δ – 3.53 (4H, m); ¹³C NMR (100.6 MHz, DMSO-d⁶); δ 158.5, 156.5,

8.12 (1H, d, J = 2.0 Hz), 7.73 (1H, dd, J = 8.5, 2.0 Hz), 7.41 (1H, 149.0, 137.0, 128.4, 128.3, 117.8, 115.0, 58.9, 43.5; FTIR: v_max

d, J = 8.5 Hz), 4.37 (2H, t, J = 9.5 Hz), 3.99 (2H, t, J = 9.5 Hz); ¹³C (neat) 3285 (w), 2986 (w), 1684 (m), 1587 (s), 1543 (m), 1442

NMR (100.6 MHz, CDCl₃); δ 162.9, 137.8, 133.6, 130.6, 128.3, (m), 1412 (m), 1059 (s); HRMS calculated for C₁₀H₁₀⁸¹Br³⁵ClN₃O

128.1, 122.8, 68.3, 55.4; FTIR: v_max(neat) 2973 (w), 1650 (m), (ES⁺)(+H⁺): 303.9668. Found: 303.9666.

1466 (m), 1372 (m), 1261 (m), 1238 (m), 1067 (s), 1016 (m);

HRMS calculated for C₉H₈⁸¹Br³⁵ClNO (ES⁺)(+H⁺): 261.9450. Synthesis of 6-bromo-7-chloroquinazolin-4(3H)-one (4b). 2-

Found: 261.9451.

((6-bromo-7-chloroquinazolin-4-yl)amino)ethanol (258 mg,

0.852 mmol) was suspended in 6 M HCl aq. (6.5 mL) in a round

Synthesis of N-(4-bromo-5-chloro-2-(4,5-dihydrooxazol-2- bottomed flask equipped with reflux condenser, and heated to

yl)phenyl)-2,2,2-trifluoroacetamide. To dried round 100 – 105 °C for a period of 2 hours. The reaction was then

bottomed flask equipped with stirrer bar and reflux allowed to cool to room temperature, and further cooled to 0

a

condenser was added 2-(4-chloro-3-bromophenyl)-4,5- °C with an ice/water bath. The reaction mixture was basified to

dihydrooxazole (3.50 g, 13.4 mmol), [RhCp*Cl₂]₂(69 mg, 0.13 pH 11 with aqueous NaOH solution (10% w/v) and allowed to

mmol, 1 mol %), AgSbF₆(154 mg, 0.520 mmol, 4 mol %), stir for 15 minutes. The colourless precipitate was collected by

PhI(OAc)₂(5.41 g, 16.8 mmol) and trifluoroacetamide (1.27 g, vacuum filtration, washing with a little ice cold water. The

11.2 mmol). The system was evacuated and refilled with precipitate was then dried further to afford the quinazolinone

nitrogen (3 times), followed by the addition of dry product as a colourless solid (202 mg, 91%). M.p.: > 250 °C; ¹H

dichloromethane via syringe (110 mL). The reaction mixture NMR (400 MHz, DMSO-d⁶); δ 8.35 (1H, s), 8.20 (1H, s), 7.94

was stirred at reflux (40 – 45 °C) for 24 h. After cooling to room (1H, s); ¹³C NMR (100.6 MHz, DMSO-d⁶); δ 159.1, 148.5, 147.4,

temperature the solvent was removed in vacuo and the 138.9, 130.6, 128.5, 122.8, 119.4; FTIR: v_max/ cm^-1(neat) 3043

residue was purified by flash column chromatography on silica (w), 3006 (w), 1721 (m), 1660 (s), 1610 (s), 1442 (s), 1254 (s),

gel eluting with petroleum ether (40/60) followed by 899 (s); HRMS calculated for C₈H₅⁸¹Br³⁵ClN₂O (ES⁺)(+H⁺):

dichloromethane to afford the aminated product as

a

260.9246. Found: 260.9252.

colourless solid (2.29 g, 46%). M.p.: 109 – 110 °C; ¹H NMR (400

MHz, CDCl₃); δ 13.63 (1H, s), 8.86 (1H, s), 8.11 (1H, s), 4.46 (2H, General Procedure for the Synthesis of febrifugine analogs.

t, J = 9.5 Hz), 4.18 (2H, t, J = 9.5 Hz); ¹³C NMR (100.6 MHz, Potassium carbonate (1.5 eq.) was added to a suspension of

CDCl₃); δ 155.9 (q, J = 38.5 Hz), 163.2, 139.0, 137.2, 133.9, quinazolinone (1.0 eq.) in MeCN (0.1 M) and the mixture was

121.9, 117.5, 115.8 (q, J = 288.5 Hz), 114.3, 67.1, 54.6; ¹⁹F NMR heated at reflux. A solution of benzyl 2-(2-(chloromethyl)allyl)-

(376.5 MHz, CDCl₃): δ – 76.0; FTIR: v_max/ cm^-1(neat) 2990 (w), 3-hydroxypyrrolidine-1-carboxylate (1.0 eq.) in MeCN (0.3 M)

1711 (m), 1607 (m), 1523 (m), 1261 (s), 1147 (s), 1073 (s); was added dropwise to the reaction mixture and the reaction

HRMS calculated for C₁₁H₈⁸¹Br³⁵ClF₃N₂O₂(ES⁺)(+H⁺): 372.9382. was left to stir for 16 h. After completion, aqueous NH₄Cl was

Found: 372.9385.

added and the product was extracted with ethyl acetate. The

organic layers were dried over MgSO₄and the solvent was

Synthesis

of

2-((6-bromo-7-chloroquinazolin-4- removed under reduced pressure to afford the crude product.

yl)amino)ethanol. N-(4-Bromo-5-chloro-2-(4,5-dihydrooxazol- The crude residue was purified via flash column

2-yl)phenyl)-2,2,2-trifluoroacetamide (2.29 g, 6.16 mmol) was chromatography eluting with CH₂Cl₂: MeOH (8 : 2) to afford

dissolved in ethanol (62 mL), NaOH pellets (4.93 g, 123 mmol) the corresponding alkene intermediates, which were subjected

were added and the reaction mixture was allowed to stir at to the subsequent step following ¹H NMR analysis (see SI).

room temperature. The reaction was monitored by TLC OsO₄(few crystals) was added to a suspension of the alkene

analysis until complete conversion of the starting material was substrate (1.0 eq.) and NaIO₄(2.0 eq.) in THF (0.1 M) and

observed; upon completion the solvent was removed in vacuo. water (0.2 M), and the solution was left to stir for 16 h. After

The residue was dissolved in water and ethyl acetate, and completion, a saturated aqueous solution of Na₂S₂O₅was

transferred to a separating funnel. The layers were partitioned, added, transferred to a separating funnel and extracted with

followed by further extraction of the aqueous layer with ethyl ethyl acetate. The combined organic layers were dried over

acetate. The combined organics were then washed with brine, anhydrous MgSO₄and the solvent was removed under

followed by drying over anhydrous MgSO₄, filtered and the reduced pressure to afford the crude product. The crude

solvent removed in vacuo. The residue was then dissolved in residue was purified via flash column chromatography eluting

ethanol (60 mL) and formamidine acetate (1.88 g, 18.1 mmol) with CH₂Cl₂: MeOH (8 : 2) to afford the corresponding ketone.

was added, and the mixture heated at reflux for 1 hour. After Trans substrates: To the ketone substrate (1.0 eq.) in a round

cooling to room temperature, the reaction mixture was dry bottom flask was added methanol (0.2 M) and HBr (33 wt% in

loaded onto silica gel and purified by flash column AcOH) (100 eq.) at 0 °C. The mixture was stirred for 30 mins

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and after completion the solvent was removed in vacuo, trans-6-Chloro-3-(3-(3-hydroxypiperidin-2-yl)-2-

purification by recrystallization from ethanol afford the oxopropyl)pyrido[3,4-d]pyrimidin-4(3H)-one dihydrobromide

corresponding products.

(trans-5c). 6-Chloropyrido[3,4-d]pyrimidin-4(3H)-one (4c) (100

Cis substrates: To the ketone substrate (1.0 eq.) in a round mg, 0.550 mmol), K₂CO₃(114 mg, 0.826 mmol) and trans-3a

bottom flask was added dichloromethane (0.2 M) and HBr (33 (178 mg, 0.55 mmol) were subjected to the general conditions

wt% in AcOH) (100 eq.) at 0 °C. The mixture was stirred for 30 for 16 h to afford the trans-alkene intermediate as a colourless

mins and after completion, aqueous NaOH was added, oil (144 mg, 56%). trans-Alkene intermediate (140 mg, 0.298

transferred to a separating funnel and extracted with ethyl mmol) was subjected to the general conditions to afford trans-

acetate (2 x 20 mL). The combined organic layers were dried ketone intermediate as a colorless oil (43 mg, 31%). trans-

over anhydrous MgSO₄and the solvent removed under Ketone intermediate (40 mg, 0.085 mmol) was subjected to

reduced pressure to afford a crude residue, which was purified the general conditions to afford trans-5c as a colorless

by flash column chromatography eluting CH₂Cl₂: MeOH (8 : 2) amorphous solid (15 mg, 36%). ¹H NMR (400 MHz, DMSO-d⁶): δ

to afford the corresponding products.

9.00 (1H, s), 8.35 (1H, s), 8.04 (1H, s), 5.57 (1H, d, J = 5.5 Hz),

5.15 (1H, d, J = 18.0 Hz), 5.09 (1H, d, J = 18.0 Hz), 3.55 – 3.42

(1H, m), 3.30 – 3.11 (2H, m), 2.97 – 2.81 (2H, m), 1.98 – 1.86

trans-7-Bromo-6-chloro-3-(3-(3-hydroxypiperidine-2-yl)-2-

oxopropyl)quinazolin-4(3H)-one hydrobromide (trans-5a). 7- (1H, m), 1.89 – 1.75 (1H, m), 1.69 – 1.54 (1H, m), 1.52 – 1.37

Bromo-6-chloroquinazolin-4(3H)-one (4a) (50 mg, 0.19 mmol), (1H, m); ¹³C NMR (100.6 MHz, DMSO-d⁶): δ 200.6, 158.2, 151.3,

K₂CO₃(40 mg, 0.28 mmol) and trans-3a (62 mg, 0.92 mmol) 150.1, 146.9, 141.9, 129.1, 118.6, 66.8, 56.1, 54.6, 43.0, 30.5,

were subjected to the general conditions for 16 h to afford the 20.2 – one peak not resolved due to overlap with DMSO-d⁶;

trans-alkene intermediate as a yellow oil (98 mg, 93%). trans- FTIR: v_max(neat) 2936 (w), 1738 (m), 1694 (s), 1600 (s), 1436

Alkene intermediate (88 mg, 0.16 mmol) was subjected to the (s), 1372 (s), 1288 (m), 1073 (s); HRMS calculated for

general conditions to afford trans-5a as a colorless solid (55 C₁₅H₁₈³⁵ClN₄O₃(ES⁺)(+H⁺): 337.1062. Found: 337.1063.

mg, 70%). M.p.: > 250 °C; ¹H NMR (400 MHz, MeOD-d⁴): δ 8.32

(1H, s), 8.22 (1H, s), 8.12 (1H, s), 5.11 (1H, d, J = 17.5 Hz), 5.02 trans-3-(3-(3-Hydroxypiperidin-2-yl)-2-oxopropyl)-6,7-bis(2-

(1H, d, J = 17.5 Hz), 3.70 - 3.60 (1H, m), 3.55 - 3.45 (2H, m), methoxyethoxy)quinazolin-4(3H)-one hydrobromide (trans-

3.40 (1H, d, J = 5.0 Hz), 3.05 (1H, dd, J = 15.0, 4.0 Hz), 3.00 (1H, 5d). 6,7-Bis(2-methoxyethoxy) quinazolin-4(3H)-one (4d) (20

dd, J = 15.0, 4.0 Hz), 2.15 - 2.00 (2H, m), 1.85 - 1.75 (1H, m), mg, 0.06 mmol), K₂CO₃(14 mg, 0.10 mmol) and trans-3a (22

1.65 - 1.55 (1H, m); ¹³C NMR (101 MHz, MeOD-d⁴) δ 202.2, mg, 0.06 mmol) were subjected to the general conditions for

161.0, 150.5, 148.4, 134.6, 133.5, 129.5, 128.4, 123.2, 68.2, 16 h to afford the trans-alkene intermediate as a colourless oil

58.1, 55.8, 44.9, 39.9, 31.5, 21.4; FTIR: ν_max3290 (w), 2943 (w), (28 mg, 71%). trans-Alkene intermediate (28 mg, 0.04 mmol)

1715 (m), 1677 (s), 1598 (s), 1080 (s); HRMS calculated for was subjected to the general conditions to afford trans-5d as a

C₁₆H₁₇⁷⁹Br³⁵ClN₃O₃(ES⁺)(+H⁺): 416.0193. Found: 416.0193.

colorless solid (20 mg, 80%). M.p.: > 250 °C; ¹H NMR (400 MHz,

MeOD-d⁴): δ 9.20 (1H, s), 7.70 (1H, s), 7.27 (1H, s), 5.33 (1H, d,

J = 18.0 Hz), 5.26 (1H, d, J = 18.0 Hz), 4.40 - 4.30 (4H, m), 3.90 -

trans-6-Bromo-7-chloro-3-(3-(3-hydroxypiperidine-2-yl)-2-

oxopropyl)quinazolin-4(3H)-one hydrobromide (trans-5b). 6- 3.80 (4H, m), 3.70 - 3.60 (1H, m), 3.52 - 3.45 (2H, m), 3.43 (6H,

Bromo-7-chloroquinazolin-4(3H)-one (4b) (77 mg, 0.30 mmol), s), 3.41 (1H, d, J = 5.0 Hz), 3.08 (1H, dd, J = 15.0, 4.0 Hz), 3.00

K₂CO₃(62 mg, 0.45 mmol) and trans-3a (96 mg, 0.30 mmol) (1H, dd, J = 15.0, 4.0 Hz), 2.15 - 2.00 (2H, m), 1.85 - 1.75 (1H,

were subjected to the general conditions for 16 h to afford the m), 1.67 - 1.57 (1H, m); ¹³C NMR (101 MHz, MeOD-d⁴): δ 201.0,

trans-alkene intermediate as a yellow oil (145 mg, 89%). trans- 157.5, 156.3, 150.6, 149.1, 134.9, 113.5, 107.5, 102.5, 70.5,

Alkene intermediate (102 mg, 0.186 mmol) was subjected to 70.3, 69.5, 69.0, 67.0, 58.1, 58.0, 56.6, 55.2, 43.4, 39.0, 30.0,

the general conditions to afford trans-ketone intermediate as 20.0; FTIR: ν_max3346 (w), 2926 (w), 1659 (s), 1705 (s), 1604 (s),

a colorless oil (64 mg, 64%). trans-Ketone intermediate (60 mg, 1382 (s), 987 (s); HRMS calculated for C₂₂H₃₁N₃O₇(ES⁺)(+H⁺):

0.11 mmol) was subjected to the general conditions to afford 450.2235. Found: 450.2237.

trans-5b as a colorless solid (27 mg, 50%). M.p.: 240 °C

1

(decomp.); H NMR (400 MHz, DMSO-d⁶): δ 8.38 (1H, s), 8.29 trans-6-Bromo-3-(3-(3-hydroxypiperidin-2-yl)-2-

(1H, s), 8.03 (1H, s), 5.57 (1H, d, J = 5.5 Hz), 5.12 (1H, d, J = 18.0 oxopropyl)quinazolin-4(3H)-one hydrobromide (trans-5e). 6-

Hz), 5.06 (1H, d, J = 18.0 Hz), 3.56 – 3.42 (1H, m), 3.27 – 3.11 Bromoquinazolin-4(3H)-one (4e) (139 mg, 0.618 mmol), K₂CO₃

(3H, m), 2.90 (2H, dd, J = 17.5, 6.0 Hz), 1.98 – 1.88 (1H, m), (128 mg, 0.928 mmol) and trans-3a (200 mg, 0.618 mmol)

1.86 – 1.76 (1H, m), 1.70 – 1.54 (1H, m), 1.52 – 1.40 (1H, m); were subjected to the general conditions for 16 h to afford the

¹³C NMR (100.6 MHz, DMSO-d⁶): δ 200.8, 158.5, 149.8, 147.9, trans-alkene intermediate as a colourless oil (229 mg, 72%).

139.4, 130.8, 128.8, 121.5, 120.1, 66.8, 56.1, 54.4, 43.0, 30.5, trans-Alkene intermediate (229 mg, 0.447 mmol) was

20.2 – one peak not resolved due to overlap with DMSO-d⁶; subjected to the general conditions to afford trans-ketone

FTIR: v_max/ cm^-1(neat) 2924 (w), 1724 (w), 1673 (s), 1606 (s), intermediate as a colorless oil (140 mg, 61%). trans-Ketone

1442 (s), 1358 (s), 1090 (s), 1070 (s); HRMS calculated for intermediate (100 mg, 0.085 mmol) was subjected to the

C₁₆H₁₈⁸¹Br³⁵ClN₃O₃(ES⁺)(+H⁺): 416.0193. Found: 416.0200.

general conditions to afford trans-5e as a colorless solid (30

1

mg, 33%). M.p.: 221 - 222 °C; H NMR (400 MHz, DMSO-d⁶): δ

8.69 (2H, s), 8.28 (1H, s), 8.23 (1H, d, J = 2.5 Hz), 8.03 (1H, dd, J

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= 8.5, 2.5 Hz), 7.73 – 7.66 (1H, m), 5.13 (1H, d, J = 18.0 Hz), calculated for C₁₆H₁₆⁷⁹Br³⁷ClN₃O₂(ES⁺)(+H⁺): 398.0087. Found:

5.08 (1H, d, J = 18.0 Hz), 3.56 – 3.47 (1H, m), 3.39 – 3.29 (1H, 398.0085.

m), 3.24 (1H, dd, J = 17.5, 5.5 Hz), 3.17 (1H, d, J = 12.5 Hz), 2.92

(2H, dd, J = 17.5, 6.0 Hz), 1.98 – 1.90 (1H, m), 1.87 – 1.77 (1H, Potassium

N,N-dimethyltrifluoroboratomethylamine.

m), 1.70 – 1.58 (1H, m), 1.53 – 1.40 (1H, m); ¹³C NMR (101 Potassium bromomethyltrifluoroborate (1.00 g, 4.98 mmol)

MHz, DMSO-d⁶): δ 200.9, 158.9, 148.5, 146.9, 137.5, 129.8, was added to neat dimethylamine in THF (20 mL) at RT, heated

128.1, 122.9, 119.8, 66.7, 56.1, 54.4, 43.0, 39.4, 30.5, 20.1; at 80 °C for 30 minutes and then concentrated in vacuo. The

FTIR: ν_max3088 (w), 2671 (w), 1713 (m), 1631 (w), 1522 (m), product was dissolved in a solution of acetone (150 mL) and

1099 (m); HRMS calculated for C₁₆H₁₉⁷⁹BrN₃O₃(ES+)(+H+): K₂CO₃(689 mg, 4.98 mmol) and stirred for 30 minutes. The

380.0604. Found: 380.0613.

insoluble salts were filtered off, and the filtrate was

concentrated in vacuo. The crude solid was dissolved in a

minimal amount of hot acetone, and diethyl ether was added

3-(3-(3-Hydroxypiperidin-2-yl)-2-oxopropyl)quinazolin-4(3H)-

one hydrobromide (trans-5f). Quinazolin-4(3H)-one (4f) (50 dropwise leading to precipitation of the product. The product

mg, 0.03 mmol), K₂CO₃(70 mg, 0.05 mmol) and trans-3a (110 was then filtered and collected and dried under vacuum. The

mg, 0.03 mmol) were subjected to the general conditions for product was afforded as a colourless solid (320 mg, 39%).

1

16 h to afford the trans-alkene intermediate as a yellow oil M.p.: 65 – 66 °C; H NMR (400 MHz, DMSO-d⁶): δ 2.63 (6H, s),

(113 mg, 77%). trans-Alkene intermediate (113 mg, 0.26 mmol) 1.98 – 1.88 (2H, m); ¹³C NMR (100.6 MHz, DMSO-d⁶): δ 52.0

was subjected to the general conditions to afford trans-5f as a (br), 45.2; ¹⁹F NMR (376.5 MHz, DMSO-d⁶): δ – 138.5; ¹¹B

colorless solid (88 mg, 89%). M.p.: > 250 °C; ¹H NMR (400 MHz, (128.4 MHz, DMSO-d⁶): δ 2.5; FTIR: v_max(neat) 3215 (w), 1483

MeOD-d⁴): δ 8.90 (1H, s), 8.40 - 8.30 (1H, m), 8.10 - 7.95 (1H, (w), 1463 (w), 1256 (m), 1023 (s), 952 (s); HRMS calculated for

m), 7.85 - 7.70 (2H, m), 5.30 (1H, d, J = 17.5 Hz), 5.22 (1H, d, J = C₃H₈¹¹BF₃N (M^-): 126.0707. Found: 126.0713.

17.5 Hz), 3.75 - 3.65 (1H, m), 3.55 - 3.50 (2H, m), 3.45 (1H, d, J

= 4.5 Hz), 3.05 (1H, dd, J = 15.0, 4.0 Hz), 3.01 (1H, dd, J = 15.0, General procedure for synthesis of amino methyl

4.0 Hz), 2.16 - 2.04 (2H, m), 1.88 - 1.76 (1H, m), 1.68 - 1.60 (1H, quinazolinones (9a – c). Step 1: To a round bottomed flask

m); ¹³C NMR (101 MHz, MeOD-d⁴): δ 201.1, 158.0, 151.0, equipped with a reflux condenser was added quinazoline (1.0

147.4, 138.4, 136.8, 129.5, 127.5, 120.7, 66.9, 56.6, 55.2, 43.5, eq.), aminomethyl-BF₃K (1.1 eq.), Cs₂CO₃(3.0 eq.) and

39.0, 30.1, 19.9; FTIR: ν_max3329 (w), 2924 (w), 1704 (s), 1660 PdXPhosG2 (10 mol %). The reaction vessel was evacuated and

(s), 1507 (s), 1028 (s); HRMS calculated for C₁₆H₁₉N₃O₃refilled with N₂(3 cycles). The degassed solvent mixture

(ES⁺)(+H⁺): 302.3404. Found: 302.3403.

THF/H₂O (10:1) was then added via syringe, and the reaction

was heated at reflux for 16 hours. The reaction was then

cooled to room temperature, and transferred to a larger round

cis-7-Bromo-6-chloro-3-((6-hydroxyoctahydro-1H-

cyclopenta[b]pyridine-6-yl)methyl)quinazolin-4(3H)-one (cis- bottomed flask, rinsing with dichloromethane and methanol.

6) and 7-bromo-6-chloro-3-(4-(3,4-dihydro-2H-pyrrol-5-yl)-2- The solvent was then removed in vacuo to afford the crude

oxobutyl)quinazolin-4(3H)-one

(7).

7-Bromo-6- residue. The crude reaction mixture was purified by flash

chloroquinazolin-4(3H)-one (4a) (50 mg, 0.19 mmol), K₂CO₃(40 column chromatography on silica gel eluting with

mg, 0.28 mmol) and cis-3a (62 mg, 0.92 mmol) were subjected dichloromethane and methanol (0 to 20% methanol) to afford

to the general conditions for 16 h to afford the cis-alkene the corresponding products. Step 2: The purified Suzuki

intermediate as a colourless oil (88 mg, 85%). cis-Alkene product was then suspended in 6 M HCl aq. (100 eq.) in a

intermediate (88 mg, 0.16 mmol) was subjected to the general round bottomed flask equipped with reflux condenser, and

conditions to afford cis-

6

as a colorless solid (10 mg, 16%) and heated to 100 – 105 °C for a period of 2 hours. The reaction

¹H NMR (400 MHz, was then allowed to cool to room temperature, and further

7

as a colorless oil (25 mg, 40%). cis-6:

CDCl₃): δ 8.37 (1H, s), 8.30 (1H, s), 8.03 (1H, s), 4.39 (1H, d, J = cooled to 0 °C with an ice/water bath. The reaction mixture

14.0 Hz), 4.19 (1H, d, J = 14.0 Hz), 3.94 - 3.91 (1H, m), 3.34 - was basified to pH 11 with aqueous NaOH solution (10% w/v)

3.32 (1H, m), 3.04 - 3.05 (2H, m), 2.56 - 2.53 (1H, m), 2.20 - and allowed to stir for 15 minutes. The reaction mixture was

2.05 (1H, m), 1.90 - 1.80 (2H, m), 1.65 - 1.55 (2H, m), 1.50 - then concentrated to remove H₂O. The reaction mixture was

1.45 (2H, m); ¹³C NMR (101 MHz, CDCl₃): δ 160.2, 149.5, 147.2, then dry loaded onto silica and purified by flash column

133.4, 132.8, 129.5, 128.0, 122.1, 105.3, 78.0, 55.8, 50.3, 44.6, chromatography, eluting with dichloromethane and 10%

43.6, 26.9, 20.2; FTIR: ν_max3294 (w), 2944 (w), 1672 (s), 1609 methanol to afford the quinazolinone product.

(s), 1473 (s); HRMS calculated for C₁₆H₁₇⁷⁹Br³⁵ClN₃O₃(ES⁺)(+H⁺):

416.1504. Found: 416.1495. 7:

¹H NMR (400 MHz, CDCl₃): δ 6-Chloro-7-((diethylamino)methyl)quinazoline-4(3H)-one

8.32 (1H, s), 8.02 (1H, s), 7.87 (1H, s), 4.97 (2H, s), 3.87 – 3.69 (9a). Step 1: Following the general procedure, using 2-((7-

(2H, m), 2.88 (2H, t, J = 6.5 Hz), 2.67 (2H, t, J = 6.5 Hz), 2.46 bromo-6-chloroquinazolin-4-yl)amino)ethanol (300 mg, 0.992

(2H, t, J = 8.0 Hz), 2.01 – 1.80 (2H, m); ¹³C NMR (101 MHz, mmol), potassium N,N-diethyltrifluoroboratomethylamine

CDCl₃): δ 202.3, 176.7, 159.7, 148.0, 147.3, 133.7, 132.8, 129.6, (210 mg, 1.09 mmol), Cs₂CO₃(970 mg, 2.97 mmol), PdXPhosG2

127.8, 122.1, 60.6, 54.7, 38.0, 35.8, 27.9, 22.9; FTIR: ν_max2918 (78 mg, 10 mol %, 0.099 mmol) and THF/H₂O (10:1, 4 mL) the

(w), 1722 (w), 1676 (s), 1608 (s), 1447 (s), 1354 (s); HRMS product was afforded as a cream solid (166 mg, 54%). M.p.: 62

– 63 °C; ¹H NMR (400 MHz, DMSO-d⁶): δ 8.44 (1H, s), 8.43 (1H,

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s), 8.39 – 8.26 (1H, m), 7.80 (1H, s), 4.88 – 4.76 (1H, m), 3.71 (s), 1117 (s), 1060 (s), 862 (s); HRMS calculated for

(2H, s), 3.65 – 3.52 (4H, m), 2.56 (4H, q, J = 7.0 Hz), 1.01 (6H, t, C₁₅H₂₀³⁵ClN₄O₂(ES⁺)(+H⁺): 323.1269. Found: 323.1276. Step 2:

J = 7.0 Hz); ¹³C NMR (100.6 MHz, DMSO-d⁶): δ 158.7, 155.5, Following the general procedure, using 2-((6-chloro-7-

147.9, 142.3, 130.0, 128.6, 123.0, 114.6, 59.1, 54.5, 46.8, 43.4, (morpholinomethyl)quinazoline-4-yl)amino)ethanol (128 mg,

11.8; FTIR: v_max(neat) 3302 (m), 2973 (w), 1587 (m), 1547 (m), 0.397 mmol) and 6 M HCl aq. (3.0 mL) the product was

1416 (m), 1278 (m), 1067 (m), 748 (s); HRMS calculated for afforded as a colourless solid (63 mg, 57%).M.p.: 187 – 188 °C;

C₁₅H₂₂³⁵ClN₄O (ES⁺)(+H⁺): 309.1477. Found: 309.1484. Step 2: ¹H NMR (400 MHz, DMSO-d⁶): δ 12.37 (1H, s), 8.11 (1H, s), 8.05

Following the general procedure, using 2-((6-chloro-7- (1H, s), 7.78 (1H, s), 3.67 (2H, s), 3.64 – 3.58 (4H, m), 2.49 –

((diethylamino)methyl)quinazoline-4-yl)amino)ethanol

(100 2.46 (4H, m); ¹³C NMR (100.6 MHz, DMSO-d⁶): δ 159.6, 147.4,

mg, 0.323 mmol) and 6 M HCl aq. (2.5 mL) the product was 146.0, 142.1, 131.4, 128.9, 125.8, 122.5, 66.2, 59.0, 53.3; FTIR:

1

afforded as a beige solid (60 mg, 70%). M.p.: 139 – 140 °C; H v_max(neat) 3020 (m), 2963 (m), 1698 (s), 1674 (s), 1607 (s),

NMR (400 MHz, MeOD-d⁴): δ 8.10 (1H, s), 8.08 (1H, s), 7.91 1426 (m), 1258 (m), 1114 (s), 865 (m); HRMS calculated for

(1H, s), 3.80 (2H, s), 2.65 (4H, q, J = 7.0 Hz), 1.10 (6H, t, J = 7.0 C₁₃H₁₅³⁵ClN₃O₂(ES⁺)(+H⁺): 280.0847. Found: 280.0851.

Hz); ¹³C NMR (100.6 MHz, MeOD-d⁴): δ 162.1, 148.4, 146.9,

146.1, 133.8, 129.7, 127.3, 123.5, 56.0, 48.6, 12.1; FTIR: v_maxGeneral Procedure for the Synthesis of aminomethyl

(neat) 2970 (w), 1698 (s), 1613 (s) 1432 (m), 1379 (m), 1258 halofuginone analogs (10a-c). Potassium carbonate (1.5 eq.)

(s), 922 (s), 751 (s); HRMS calculated for C₁₃H₁₇³⁵ClN₃O was added to a suspension of quinazolinone (1.0 eq.) in MeCN

(ES⁺)(+H⁺): 266.1055. Found: 266.1055.

(0.1 M) and the mixture was heated at reflux. A solution of

benzyl 2-(2-(chloromethyl)allyl)-3-hydroxypyrrolidine-1-

carboxylate (1.0 eq.) in MeCN (0.3 M) was added dropwise to

6-Chloro-7-((dimethylamino)methyl)quinazoline-4(3H)-one

(9b). Step 1: Following the general procedure, using 2-((7- the reaction mixture and the reaction was left to stir for 16 h.

bromo-6-chloroquinazolin-4-yl)amino)ethanol (200 mg, 0.661 After completion, aqueous NH₄Cl was added and the product

mmol), potassium N,N-dimethyltrifluoroboratomethylamine was extracted with ethyl acetate. The organic layers were

(120 mg, 0.727 mmol), Cs₂CO₃(645 mg, 1.98 mmol), dried over MgSO₄and the solvent was removed under reduced

PdXPhosG2 (52 mg, 10 mol %, 0.066 mmol) and THF/H₂O pressure to afford the crude product. The crude residue was

(10:1, 2.6 mL) the product was afforded as

a

yellow purified via flash column chromatography eluting with CH₂Cl₂:

2) to afford the corresponding alkene

amorphous solid (126 mg, 68%). ¹H NMR (400 MHz, MeOD-d⁴): MeOH (8

:

δ 8.44 (1H, s), 8.27 (1H, s), 7.79 (1H, s), 3.82 (2H, t, J = 5.5 Hz), intermediates, which were subjected to the subsequent step

1

3.79 – 3.68 (4H, m), 2.37 (6H, s); ¹³C NMR (100.6 MHz, MeOD- following H NMR analysis (see SI). Alkene substrate (1.0 eq.)

d⁴): δ 160.8, 156.6, 148.3, 142.3, 133.3, 130.1, 124.3, 116.5, and TFA (1.1 eq.) in THF (0.1 M) and water (0.2 M) were stirred

61.5, 61.2, 45.6, 44.8; FTIR: v_max(neat) 3436 (w), 2986 (w), for 30 minutes prior to the addition of OsO₄(few crystals) and

1590 (w), 1274 (m), 1261 (m); HRMS calculated for NaIO₄(2.0 eq.). The solution was left to stir at RT for 16 h.

C₁₃H₁₈³⁵ClN₄O (ES⁺)(+H⁺): 281.1164. Found: 281.1162. Step 2: After completion, a saturated aqueous solution of Na₂S₂O₅was

Following the general procedure, using 2-((6-chloro-7- added, transferred to a separating funnel and extracted with

((dimethylamino)methyl)quinazoline-4-yl)amino)ethanol (121 ethyl acetate. The combined organic layers were dried over

mg, 0.431 mmol) and 6 M HCl aq. (3.4 mL) the product was anhydrous MgSO₄and the solvent was removed under

afforded as a colourless solid (53 mg, 52%). M.p.: 161 – 162 °C; reduced pressure to afford the crude product. The crude

¹H NMR (400 MHz, MeOD-d⁴): δ 8.15 (1H, s), 8.08 (1H, s), 7.80 residue was purified via flash column chromatography eluting

(1H, s), 3.70 (2H, s), 2.34 (6H, s); ¹³C NMR (100.6 MHz, MeOD- with CH₂Cl₂: MeOH (8 : 2) to afford the corresponding ketone.

d⁴): δ 162.1, 148.5, 147.0, 144.3, 134.3, 130.4, 127.5, 123.9, To the ketone substrate (1.0 eq.) in a round bottom flask was

61.4, 45.7; FTIR: v_max(neat) 2973 (w), 1691 (m), 1614 (m), 1258 added methanol (0.2 M) and HBr (33 wt% in AcOH) (100 eq.) at

(m), 902 (m), 764 (s); HRMS calculated for C₁₁H₁₃³⁵ClN₃O 0 °C. The mixture was stirred for 30 mins and after completion

(ES⁺)(+H⁺): 238.0742. Found: 238.0750.

the solvent was removed in vacuo, purification by

recrystallization from ethanol afford the corresponding

products.

6-Chloro-7-((morpholinomethyl)methyl)quinazoline-4(3H)-

one (9c). Step 1: Following the general procedure, using 2-((7-

bromo-6-chloroquinazolin-4-yl)amino)ethanol (200 mg, 0.661 trans-6-Chloro-7-((diethylamino)methyl)-3-(3-(3-

mmol), potassium 4-trifluoroboratomethyl-morpholine (140 hydroxypiperidin-2-yl)-2-oxopropyl)quinazoline-4(3H)-one

mg, 0.727 mmol), Cs₂CO₃(645 mg, 1.98 mmol), PdXPhosG2 (52 dihydrobromide

(trans-10a).

6-Chloro-7-

mg, 10 mol %, 0.066 mmol) and THF/H₂O (10:1, 2.6 mL) the ((diethylamino)methyl)quinazoline-4(3H)-one (9a) (55 mg, 0.21

product was afforded as a colourless solid (161 mg, 76%). mmol), K₂CO₃(43 mg, 0.31 mmol) and trans-3a (69 mg, 0.21

1

M.p.: 76 – 77 °C; H NMR (400 MHz, MeOD-d⁴): δ 8.41 (1H, s), mmol) were subjected to the general conditions for 16 h to

8.20 (1H, s), 7.83 (1H, s), 3.82 (2H, t, J = 5.5 Hz), 3.77 – 3.69 afford the trans-alkene intermediate as a colorless oil (97 mg,

(8H, m), 2.62 – 2.54 (4H, m); ¹³C NMR (100.6 MHz, MeOD-d⁴): δ 84%). trans-Alkene intermediate (111 mg, 0.200 mmol) was

160.8, 156.4, 148.3, 142.5, 133.1, 129.2, 124.1, 116.2, 68.0, subjected to the general conditions to afford trans-ketone

61.2, 60.7, 54.8, 44.8; FTIR: v_max(neat) 3319 (m), 3120 (m), intermediate as a colorless oil (65 mg, 58%). trans-Ketone

2926 (m), 2832 (m), 1587 (s), 1543 (s), 1429 (s), 1409 (s), 1332 intermediate (49 mg, 0.088 mmol) was subjected to the

J. Name., 2013, 00, 1-3 | 9

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general conditions to afford trans-10a as a colorless solid (18 with residual H₂O), 3.27 – 3.09 (3H, m), 2.90 (2H, dd, J = 17.5,

1

mg, 35%). M.p.: 178 – 179 °C; H NMR (400 MHz, DMSO-d⁶): δ 6.0 Hz), 1.98 – 1.88 (1H, m), 1.88 – 1.76 (1H, m), 1.70 – 1.53

8.32 (1H, s), 8.22 (1H, s), 8.19 (1H, s), 5.16 (1H, d, J = 18.0 Hz), (1H, m), 1.54 – 1.37 (1H, m); ¹³C NMR (100.6 MHz, DMSO-d⁶): δ

5.11 (1H, d, J = 18.0 Hz), 4.62 (2H, d, J = 5.5 Hz), 3.56 – 3.31 200.6, 158.7, 149.2, 146.5, 133.8, 133.2, 132.8, 126.6, 123.3,

(peak not fully resolved due to overlap with residual H₂O), 3.29 66.9, 63.2, 56.2, 55.9, 54.5, 51.5, 43.0, 30.6, 20.2 – one peak

– 3.13 (6H, m), 2.92 (2H, dd, J = 17.5 Hz, 6.0 Hz), 1.97 – 1.88 not resolved due to overlap with DMSO-d⁶; FTIR: v_max(neat)

(1H, m), 1.87 – 1.78 (1H, m), 1.70 – 1.56 (1H, m), 1.50 – 1.39 3011 (w), 2984 (w), 1677 (m), 1610 (m), 1278 (s), 1258 (s);

(1H, m), 1.29 (6H, t, J = 7.0 Hz); ¹³C NMR (100.6 MHz, DMSO- HRMS calculated for C₂₁H₂₈³⁵ClN₄O₄(ES⁺)(+H⁺): 435.1794.

d⁶): δ 201.1, 159.1, 149.7, 147.0, 135.3, 133.2, 133.0, 127.2, Found: 435.1807.

123.7, 67.4, 56.6, 55.0, 52.6, 47.5, 43.4, 31.0, 20.6, 9.0 – one

peak not resolved due to overlap with DMSO-d⁶; FTIR: v_max

Conflicts of interest

(neat) 3387 (s), 2943 (m), 1733 (s), 1677 (s), 1605 (s), 1472 (s),

1397 (s), 1363 (s), 1080 (m); HRMS calculated for

C₂₁H₃₀³⁵ClN₄O₃(ES⁺)(+H⁺): 421.2001. Found: 421.2009.

There are no conflicts to declare.

trans-6-Chloro-7-((dimethylamino)methyl)-3-(3-(3-

Acknowledgements

hydroxypiperidin-2-yl)-2-oxopropyl)quinazoline-4(3H)-one

We gratefully acknowledge GlaxoSmithKline and the EPSRC

for financial support.

dihydrobromide

(trans-10b).

6-Chloro-7-

((dimethylamino)methyl)quinazoline-4(3H)-one (9b) (51 mg,

0.21 mmol), K₂CO₃(43 mg, 0.31 mmol) and trans-3a (69 mg,

0.21 mmol) were subjected to the general conditions for 16 h

to afford the trans-alkene intermediate as a colorless oil (83

mg, 74%). trans-Alkene intermediate (81 mg, 0.15 mmol) was

subjected to the general conditions to afford trans-ketone

intermediate as a colorless oil (59 mg, 73%). trans-Ketone

intermediate (54 mg, 0.10 mmol) was subjected to the general

conditions to afford trans-10b as a pale orange solid (24 mg,

Notes and references

1

For important quinazolinone based motifs see: (a) M. S.

Butler, Nat. Prod. Rep., 2005, 22, 162; (b) S. Eguchi, T. Suzuki,

T. Okawa, Y. Matsushita, E. Yashima and Y. Okamoto, J. Org.

Chem., 1996, 61, 7316; (c) J. Wu, S. Bai, M. Yue, L.-J. Luo, Q.-

C. Shi, J. Ma, X.-L. Du, S.-H. Kang, D. Hu and S. Yang, Chem.

Pap., 2014, 68, 969; (d) M. Sharma, K. Chauhan, R. Shivahare,

P. Vishwakarma, M. K. Suthar, A. Sharma, S. Gupta, J. K.

Saxena, J. Lal, P. Chandra, B. Kumar and P. M. S. Chauhan, J.

Med. Chem., 2013, 56, 4374; (e) B. B. Snider and H. Zeng,

1

43%). M.p.: 221 °C (decomp.); H NMR (400 MHz, DMSO-d⁶): δ

8.33 (1H, s), 8.21 (1H, s), 8.18 (1H, s), 5.16 (1H, d, J = 18.5 Hz),

5.11 (1H, d, J = 18.5 Hz), 4.64 (2H, app s), 3.58 – 3.49 (1H, m),

3.25 (1H, d, J = 6.0 Hz), 3.47 – 3.31 (peak not fully resolved due

to overlap with residual H₂O), 3.22 – 3.13 (2H, m), 2.98 – 2.84

(8H, m), 1.97 – 1.90 (1H, m), 1.87 – 1.78 (1H, m), 1.71 – 1.59

(1H, m), 1.52 – 1.40 (1H, m); ¹³C NMR (100.6 MHz, DMSO-d⁶): δ

200.6, 158.7, 149.2, 146.6, 134.8, 132.6, 132.4, 126.7, 123.2,

66.9, 56.3, 56.2, 54.5, 43.0, 42.6, 30.5, 20.2 – one peak not

resolved due to overlap with DMSO-d⁶; FTIR: v_max(neat) 3299

(w), 3011 (w), 2924 (w), 1720 (m), 1678 (s), 1610 (m), 1472

(m), 1325 (m), 1278 (m), 1093 (m); HRMS calculated for

C₁₉H₂₆³⁵ClN₄O₃(ES⁺)(+H⁺): 393.1688. Found: 393.1699.

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For representative examples see: (a) D. J. Connolly and P. J.

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(a) T. M. M. Maiden, S. Swanson, P. A. Procopiou and J. P. A.

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(d) For a recent cobalt catalyzed approach see: R. Mei, J.

trans-6-Chloro-3-(3-(3-hydroxypiperidin-2-yl)-2-oxopropyl)-7-

(morpholinomethyl)quinazoline-4-(3H)-one dihydrobromide

(trans-10c).

6-Chloro-7-

((morpholinomethyl)methyl)quinazoline-4(3H)-one (9c) (50

mg, 0.18 mmol), K₂CO₃(25 mg, 0.27 mmol) and trans-3a (58

mg, 0.18 mmol) were subjected to the general conditions for

16 h to afford the trans-alkene intermediate as a colorless oil

(70 mg, 69%). trans-Alkene intermediate (76 mg, 0.13 mmol)

was subjected to the general conditions to afford trans-ketone

intermediate as a colorless oil (52 mg, 68%). trans-Ketone

intermediate (47 mg, 0.082 mmol) was subjected to the

general conditions to afford trans-10c as a pale orange solid (5

Loup and L. Ackermann, ACS Catal., 2016, 6, 793.

For isolation and preliminary structural reports on

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1

mg, 10%). M.p.: 58 °C (decomp.); H NMR (400 MHz, DMSO-

d⁶): δ 8.30 (1H, s), 8.20 (2H, br), 5.14 (1H, d, J = 18.0 Hz), 5.09

(1H, d, J = 18.0 Hz), 4.68 (2H, app s), 3.96 (2H, app s), 3.72 (2H,

app s), 3.56 – 3.26 (peaks not fully resolved due to overlap

10 | J. Name., 2012, 00, 1-3

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13 The supplementary crystallographic data for our synthetic

sample of febrifugine has been deposited with the

Cambridge Crystallographic Data centre as supplementary

publication number CCDC 1450620. These data can be

obtained free of charge from the Cambridge Crystallographic

Data centre

http://www.ccdc.cam.ac.uk/data_request/cif.

via

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A convergent strategy towards febrifugine and related compounds

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