Synthesis of 4-substituted chlorophthalazines, dihydrobenzoazepinediones, 2-pyrazolylbenzoic acid, and 2-pyrazolylbenzohydrazide via 3-substituted 3-hydroxyisoindolin-1-ones

Article

pubs.acs.org/joc

Synthesis of 4-Substituted Chlorophthalazines,

Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid,

and 2-Pyrazolylbenzohydrazide via 3-Substituted

3-Hydroxyisoindolin-1-ones

Hanh Nho Nguyen,*^,†Victor J. Cee,^‡Holly L. Deak,^†Bingfan Du,^†Kathleen Panter Faber,^†,⊥

Hakan Gunaydin,^§Brian L. Hodous,^†,∥Steven L. Hollis,^§Paul H. Krolikowski,^§Philip R. Olivieri,^†

Vinod F. Patel,^†,#Karina Romero,^†Laurie B. Schenkel,^†and Stephanie D. Geuns-Meyer^†

†

§

Departments of Chemistry Research and Discovery and Molecular Structure, Amgen Inc., 360 Binney St., Cambridge,

Massachusetts 02142, United States

^‡Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States

S

* Supporting Information

ABSTRACT: Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the

key step, N,N-dimethylaminophthalimide (8a) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic

reagents to aﬀord 3-substituted 3-hydroxyisoindolinones 9b, 9i−9am. Many of these hydroxyisoindolinones are converted to

chlorophthalazines 1b−1v via reaction with hydrazine, followed by chlorination with POCl₃. We have also discovered two novel

transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to N,N-

dimethylaminophthalimide (8a) provided dihydrobenzoazepinediones 15a−15c via the proposed ring expansion of 3-vinyl-3-

hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to aﬀord

2-pyrazolyl benzoic acids 16a−16d and 2-pyrazolyl benzohydrazides 17a−17g rather than the expected alkynyl phthalazinones.

However, there are a limited number of suitable Friedel−

Crafts substrates 2a (e.g., electron-rich aromatic rings).

4-Substituted chlorophthalazines can also be prepared as shown

in Scheme 1.^2,5,20−22The key 2-keto benzoic acids 3a can be

prepared from phthalic anhydride (4a) via the Friedel−Crafts

reaction²²⁻²⁴or through a metalation route,²⁵⁻²⁹which expands

the scope to aryl, heteroaryl, and alkyl substrates. However, even

at low temperature (−70 to −78 °C), bisaddition of the

organolithium and Grignard reagents 5a to phthalic anhydride

(4a) can lead to isobenzofuranones 6a, often hampering the

puriﬁcation and the yield.^26,28,29The bisaddition byproduct 6a

may be minimized by adding 5a to excess 4a (inverse addition

order) at even lower temperature (−100 °C)^26,28or by employing

organocuprate reagents that must be generated from 5 equiv of

INTRODUCTION

■

Phthalazine is a common heterocycle present in a wide range of

potential therapeutics for the treatment of cancer,¹⁻⁷inﬂamma-

tion,^3,8−10epilepsy,¹¹diabetes,¹²cerebrovascular/circulation

disorders,¹³and chronic obstructive pulmonary disease.¹⁴We

desired a general method to synthesize 4-substituted heteroaryl

chlorophthalazines 1a for rapid preparation of aurora kinase

inhibitors.¹Several methods for the preparation of 4-aryl and

4-alkyl substituted chlorophthalazines have been reported

previously, but all suﬀer from signiﬁcant drawbacks. For example,

these substrates can be synthesized via Negishi¹⁵and Suzuki−

Miyaura^16,17monocoupling of 1,4-dichlorophthalazine. Unfortu-

nately, bis-coupling of organozinc/organoboron reagents with

1,4-dichlorophthalazine reduces the yield of the desired

monocoupling product and can require tedious chromatographic

puriﬁcation. 1,4-Dichlorophthalazine can also be transformed into

4-substituted chlorophthalazines by Friedel−Crafts reaction.^18,19

Received: February 9, 2012

Published: March 29, 2012

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Scheme 1. Reported Methods for the Synthesis of 4-Substituted Chlorophthalazines 1a from Phthalic Anhydride (4a)

Scheme 2. Proposed Three-Step Method to Prepare 4-Substituted Chlorophthalazines 1a from Phthalimide 8a

organomagnesium reagents.³⁰These limitations prompted us to

develop an alternative, eﬃcient, and general method to prepare

4-substituted aryl/heteroaryl/alkyl chlorophthalazines.

Table 1. Selective Monoaddition of Aryl Lithium 5b to

Phthalic Anhydride (4a) and Phthalimides 8a−8e

Enders, Deniau, and co-workers have shown that N,N-

dimethylaminophthalimide (8a) undergoes selective mono-

reduction with NaBH₄.³¹⁻³³They also showed the addition of

organometallic reagents to 8a.³⁴For example, 8a reacted with

phenylmagnesium bromide to provide 3-phenyl-3-hydroxy-

isoindolinones.³⁵We were also aware that 9a could be

transformed into phthalazinone 7a.^35,36From these observa-

tions, we envisioned a general three-step protocol for the

synthesis of 4-aryl/heteroaryl/alkyl chlorophthalazines 1a from

N,N-dimethylaminophthalimide (8a) (Scheme 2).³⁷

RESULTS AND DISCUSSION

■

The selective monoaddition of organometallic reagents to

phthalic anhydride (4a), phthalimides 8a−8e, tetrahydro-

phthalimide 8f, and maleimide 8g is illustrated in Tables 1

and 2. Compounds 8a−8g were prepared from reaction of the

corresponding cyclic anhydrides with the substituted hydra-

zines, O-methylhydroxylamine, or amines in reﬂuxing toluene

in the presence of a catalytic amount of p-TsOH with a Dean−

Stark apparatus for removing water azeotropically. In agree-

ment with previous reports,^26,28,29bisaddition of pyridinyl

lithium 5b to phthalic anhydride (4a) was observed, and

isobenzofuranone 6b was isolated in 12% yield along with the

desired monoaddition product 3-hydroxyisobenzofuranone

10a, which was isolated in only 25% yield (Table 1, entry 1).

In contrast, selective monoaddition of pyridinyl lithium 5b to

N,N-dimethylaminophthalimide (8a) was achieved, and 9b was

isolated in 67% yield (Table 1, entry 2).³⁴Variations to the

experimental procedure such as addition of 8a to anion 5b at

−78 °C or using diethyl ether as the solvent instead of THF

provided similar yields (60−70%). Screening of other phthalimides

8b−8e also revealed only monoaddition products 9c−9f (Table 1,

entries 3−6). In addition, tetrahydrophthalimide 8f and maleimide

8g were both suitable substrates (Table 2, entries 1 and 2). Besides

Table 2. Selective Monoaddition of Organometallic

Reagents to Tetrahydrophthalimide 8f and Maleimide 8g

(6-methylpyridin-2-yl)lithium (5b), benzylmagnesium bromide

(5c) and phenyl lithium (5d) were also suitable nucleophiles.

However, diethylzinc, a weaker nucleophile, did not react with

phthalimide 8a even at room temperature (data not shown).

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Scheme 3. Proposed Mechanism for the Addition of Aryl Lithium to 4a, 8a, and 8d

The signiﬁcant diﬀerences observed between phthalic

anhydride and phthalimides with regard to mono- and bis-

addition of organometallic reagents deserves further comment

(Scheme 3). Presumably, bisaddition arises from ring opening

of the initially formed alkoxy-isobenzofuranone 11a, leading to

diaryl ketone 11b, which reacts with the organometallic reagent

to give 6b. The lack of bisaddition products in reactions of the

analogous N,N-dimethylaminophthalimide 8a and N-methyl-

phthalimide 8d suggests that ring opening is substantially

reduced, although it is also possible that the ring-opened

intermediates 11d and 11f, if produced, are much less reactive

than 11a. Ab initio calculations (B3LYP/6-31+G(d)) of the

relative equilibrium free energies of 11a/b, 11c/d, and 11e/f

support the former hypothesis: ring-opened intermediate 11b is

favored over 11a by 7.4 kcal/mol, while ring-closed

intermediates 11c and 11e are favored over the corresponding

ring-opened intermediates 11d and 11f by 9.1 and 12.8 kcal/mol,

respectively.

Table 3. Preparation of 3-Substituted 3-Hydroxyisoindolin-

1-ones 9i−9am

a

Overall, the reaction of (6-methylpyridin-2-yl)lithium (5b)

to N,N-dimethylaminophthalimide (8a) provided selective

monoaddition product 9b in good yield. In addition, 8a is a

stable solid that can easily be made on large scale from

commercially available phthalic anhydride (4a). Therefore,

N,N-dimethylaminophthalimide (8a) was chosen as the

electrophile for further studies.

The scope of the organometallic reagent was explored next.

The organolithium reagents were generated using standard

conditions including lithium−halogen exchange or direct

lithiation of heterocycles and alkynes. Grignard reagents were

obtained from commercial sources. Table 3 shows moderate to

excellent yields of isoindolinones containing six- (9i−9m) and

ﬁve-membered (9n−9u) ring heterocycles, substituted ben-

zenes (9v−9z), alkyls (9aa and 9ab), cycloalkyls (9ac and

9ad), aromatic alkynes (9ae−9ag), silyl alkynes (9ah³⁸and

9ai), and alkyl alkynes (9aj−9am).

A limitation to the scope of the general reaction was

discovered when exploring vinylic organometallic reagents.

Reaction of vinyl magnesium bromide 12a and 8a aﬀorded a

1:3 mixture of vinyl hydroxyisoindolinones 13a and ring-

expanded dihydrobenzoazepinedione 15a in 16% yield.

Dihydrobenzoazepinediones 15b and 15c were isolated when

propenylmagnesium bromide 12b and phenylvinyl lithium 12c

were used. Attempts to improve the isolated yield of 15a−15c

by changing the temperature or addition order were not

successful. HMBC connectivities and ROESY cross-peaks

conﬁrmed the structure of 15a−15c. We postulate that the

ring-expansion products are more likely to be generated via a

[1,3]-shift of a chelated lithium vinylic hydroxyisoindolinone

(INT A) rather than through an intramolecular Michael

addition of an enone (INT B) to form the strained seven-

membered ring (INT C) (Scheme 4).

a

Anion sources. Lithium−halogen exchange: 9i−9 m, 9p, 9v−9z. Direct

lithiation with n-BuLi and TMEDA: 9n and 9o, 9q. Direct lithiation with

b

n-BuLi: 9r−9u, 9ae −9am. Grignard reagent: 9aa −9ad. Br−Li

exchange to form 9l was more eﬃcient in Et₂O than in THF.³⁹It was

possible that (5-chloropyridin-2-yl)lithium was insoluble and thus more

stable in Et₂O. For the synthesis of 9n and 9o, lithiation of

3-methylthiophene with n-BuLi alone gave a 3:1 mixture of C5:C2 lithio-

intermediates. The presence of TMEDA improved this ratio to 9:1, and

we were able to prepare up to 90% yield of 9n and 9o in a 9:1 ratio.^40,41

c

With a series of isoindolinones in hand, the chlorophthala-

zine syntheses were completed (Table 4). The transformation

of hydroxyisoindolinones 9b, 9i−9z, 9aa, and 9ad to

phthalazinones 7b−7v with hydrazine proceeded cleanly

(Step 1).³⁶Chlorination of phthalazinones 7b−7v with excess

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Scheme 4. Formation and Proposed Mechanism of Dihydrobenzoazepinediones 15a−15c

POCl₃aﬀorded chlorophthalazines 1b−1v in good yields

(Step 2). For the mixture of 1h and 1i, the major isomer 1h

could be cleanly separated by recrystallization with EtOAc. The

structures of both phthalazinone isomers 7h and 7i and

chlorophthalazine 1h were conﬁrmed by NMR analyses.

Overall, the three-step protocol to prepare aryl/heteroaryl/

alkyl chlorophthalazines 1b−1v from N,N-dimethylaminoph-

thalimide (8a) was straightforward.

For phenylethynyl hydroxyisoindolinone 9ae, reaction with

15 equiv of hydrazine in reﬂuxing ethanol yielded 58% of

2-pyrazolyl benzoic acid 16a instead of the anticipated alkynyl

phthalazinone (data not shown). Further optimization revealed

that a complete conversion of 9ae to 16a could also be achieved

with 3 equiv of anhydrous hydrazine in THF at room temper-

ature (Table 5, entry 1).⁴²The generality of the reaction was

demonstrated in the preparation of n-butyl, cyclopropyl, and

tert-butylpyrazole benzoic acids (entries 2−4).

Interestingly, for monoalkyl hydrazines, a similar reaction

with alkynyl hydroxyisoindolinone occurred but provided the

pyrazole benzohydrazides rather than the pyrazole carboxylic

acids. No reaction took place between methylhydrazine and 9ae

in THF at room temperature, but heating to 80 °C aﬀorded a

23:1 regioisomeric mixture of pyrazolyl benzohydrazides

17a:18a (Table 5, entry 5). The formation of the major

regioisomer 17a is consistent with literature reports for the

reaction of monoalkyl hydrazines and ynones.^18,43,44The same

conditions were also used to prepare a 13:1 mixture of 17b:18b

(entry 6). When methyl, n-butyl, and isobutyl hydrazines

reacted with either alkyl or aryl alkynyl isoindolinones under

similar conditions, only the major regioisomers 17a−17g were

isolated (entries 7−11). The structures of pyrazolyl benzohy-

drazides 17a, 17e, and 17g were conﬁrmed by 2D-NMR

analyses. In addition, structures of 17a, 17b, and 17g were

unambiguously determined by single crystal X-ray structure. All

structures showed R¹and R²were adjacent to one another,

conﬁrming the pyrazolyl structures of compounds 17a−17g.

Scheme 5 shows the proposed mechanism for the formation

and regioselectivity for the formation of 2-pyrazolyl benzohy-

drazides and 2-pyrazolyl benzoic acids. Since alkynyl

phthalazinone 19g was not obtained, Michael addition of

hydrazine to alkynyl hydroxyisoindolinone is likely the

predominant pathway. Hydrohydrazination of 19a is unlikely

as no Lewis acid was present.^45,46In Path A, which would lead

to major isomer 19d, the more nucleophilic hydrazine

nitrogen⁴⁷⁻⁴⁹undergoes conjugate addition to the activated

alkyne. We believe that alkynyl hydroxyisoindolinone contains a

“masked” ynone.⁵⁰The allene 19b can then rearrange to (Z)-β-

hydrazine enone 19c, which can undergo cyclodehydration to

aﬀord the major pyrazolyl benzohydrazide 19d. The

regioselectivity was similar to the reactions between hydrazines

and ynones.^43,44If hydrazine was used, benzohydrazides 19d

could be hydrolyzed by the liberated water from the previous

step to give the pyrazolyl benzoic acid 19f, possibly via a

tricyclic 19e that could be formed from the more nucleophilic

free NH-pyrazole.

CONCLUSIONS

■

Here we disclose a general three-step synthesis of 4-substituted

chlorophthalazines from N,N-dimethylaminophthalimide. N,N-

Dimethylaminophthalimide ensured clean monoaddition of

organometallic reagents. Intramolecular chelation and predom-

inant ring-closed hydroxyisoindolinone might have prevented

bisaddition of organometallic reagents. A wide variety of alkyl,

aryl, and heteroaryl chlorophthalazines were prepared in good

yields. This methodology did not provide a suitable route to

vinyl and alkynyl chlorophthalazines; instead, transformations

of vinyl and alkynyl hydroxyisoindolinones uncovered novel

routes to dihydrobenzoazepinediones and 2-pyrazolyl benzohy-

drazides/benzoic acids, respectively.

EXPERIMENTAL SECTION

■

Unless indicated otherwise, all materials were obtained from

commercial suppliers and used without further puriﬁcation. Dry

organic solvents (THF, dioxane, toluene, etc.) were commercially

available. Organometallic reagents such as alkyl lithiums and Grignard

reagents were purchased and were handled under an argon or a

nitrogen atmosphere. Anhydrous hydrazine and substituted hydrazines

and their vapors can be ﬂammable and explosive in the presence of

heat, ﬂame, sparks, contaminants, and oxidizers including air.

Quenching of POCl₃with aqueous base at low temperature can

cause a delayed exotherm. Monitoring the internal temperature during

the workup is advised. Chlorophthalazines hydrolyze over time at rt;

therefore, they should be used immediately. To minimize hydrolysis,

they should be stored under vacuum or in a desiccator.

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Table 4. Preparation of Chlorophthalazines 1b−1v

Table 5. Preparation of 2-Pyrazolyl Benzoic Acids 16a−16d

and 2-Pyrazolyl Benzohydrazides 17a−17g

a

b

c

d

THF, rt. THF, 80 °C. 23:1 mixture of regioisomers. 13:1 mixture

of regioisomers.

DCM or CHCl₃, and 1−2 drops of the solution was applied on a

2 mm × 2 mm square diamond, brazed into a tungsten carbide disk.

After DCM or CHCl₃had evaporated, the IR spectrum was acquired

and processed. ¹H NMR, ¹³C NMR, and ¹⁹F NMR spectra were

recorded on a NMR instrument at ambient temperature. For ¹H NMR

and ¹³C NMR spectra, chemical shifts are reported in ppm unit,

relative to residual deuterated solvent peaks. Data are reported as

follows: chemical shift (multiplicity, coupling constants, and number

of protons). The abbreviations for multiplicity are s = singlet, d =

doublet, t = triplet, q = quartet, quin = quintet, sex = sextet, sep =

septet, m = multiplet, br = broad. High-resolution mass spectra

(HRMS) were determined on a high-resonance electrospray time-

of-ﬂight mass spectrometer in positive electrospray ionization (ESI)

mode. Masses are reported in units of mass over charge (m/z) to four

decimal places. Melting points were obtained from a melt-temp

apparatus and were uncorrected. All yields reported refer to isolated

yields of compounds estimated to be greater than 95% purity as

1

determined by HPLC and H NMR. Compounds described in the

literature were characterized by comparison of their melting points and

¹H and/or ¹³C NMR spectra to the previously reported data. The

procedures in this section are representative, and thus the yields may

diﬀer from those reported in tables.

All calculations were computed in the gas phase by the HF/

6-31+G(d) method.⁵¹Thermal corrections were computed at room

temperature. All energies are reported in kcal/mol.

General Procedure To Prepare Phthalimide and Malei-

mide. 2-(Dimethylamino)isoindoline-1,3-dione (8a).⁵²⁻⁵⁴In a

round-bottom ﬂask were added isobenzofuran-1,3-dione (5.0 g,

34 mmol), N,N-dimethylhydrazine (2.9 mL, 37 mmol), and

toluene (75 mL). Then p-toluenesulfonic acid monohydrate

Reactions were monitored by thin layer chromatography or using

LC−MS with UV detection at 254 nm and a low-resonance

electrospray mode (ESI). Medium pressure liquid chromatography

(MPLC) was performed with normal phase silica gel (35−60 μm)

columns and UV detection at 254 nm. IR spectra were recorded and

are reported in wavenumbers (cm⁻¹). The sample was dissolved in

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Scheme 5. Proposed Mechanism for the Formation of 2-Pyrazolyl Benzohydrazide 19d and 2-Pyrazolyl Benzoic Acid 19f

(0.32 g, 1.7 mmol) was added. The Dean−Stark apparatus and

a condenser were attached. The mixture was reﬂuxed for 4 h.

After cooling to rt, toluene was removed under a reduced

pressure to aﬀord a residue. The crude product was dissolved in

DCM, washed with satd NaHCO₃, water, and brine. The

organic layer was dried over MgSO₄, ﬁltered, and concentrated

to aﬀord a light yellow solid, 2-(dimethylamino)isoindoline-1,3-

2-(Dimethylamino)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione

(8f). Following the general procedure to prepare 8a, 4,5,6,7-tetra-

hydroisobenzofuran-1,3-dione (2.3 g, 15 mmol) was allowed to react

with N,N-dimethylhydrazine (1.4 mL, 18 mmol) in toluene (33 mL)

in the presence of p-TsOH·H₂O (0.14 g, 0.74 mmol) for 4.5 h at

125 °C. Following similar workup procedure, the product was

1

obtained as a yellow solid (2.6 g, 90% yield). H NMR (400 MHz,

CDCl₃) δ 2.91 (s, 6H), 2.32−2.28 (m, 4H), 1.77−1.74 (m, 4H). ¹³C

NMR (101 MHz, CDCl₃) δ 169.6, 139.9, 44.9, 21.2, 19.8. FT-IR (thin

ﬁlm, cm⁻¹) 2943, 1712. MS calcd for C₁₀H₁₄N₂O₂[M]⁺= 194, found

[M + H]⁺= 195. HRMS calcd for C₁₀H₁₄N₂O₂[M + H]⁺= 195.1128,

[M + Na]⁺= 217.0948, found [M + H]⁺= 195.1132, [M + Na]⁺=

217.0955. Mp = 42−43 °C.

1

dione (6.1 g, 95% yield). H NMR (400 MHz, DMSO-d₆)

δ 7.84 (m, 4H), 2.89 (s, 6H). MS calcd for C₁₀H₁₀N₂O₂[M]⁺=

190, found [M + H]⁺= 191.

2-(Pyrrolidin-1-yl)isoindoline-1,3-dione (8b). Following the gen-

eral procedure to prepare 8a, isobenzofuran-1,3-dione (2.3 g,

15 mmol) was allowed to react with pyrrolidin-1-amine hydrochloride

(2.1 g, 17 mmol) in toluene (34 mL) in the presence of p-TsOH·H₂O

(0.15 g, 0.76 mmol) for 4.5 h at 125 °C. Similar workup provided a

crude product. This material was passed through a pad of silica gel

with the aid of 70:30 Hex/EtOAc to aﬀord 2-(pyrrolidin-1-

yl)isoindoline-1,3-dione as a beige solid (1.1 g, 34% yield). ¹H

NMR (400 MHz, CDCl₃) δ 7.85−7.81 (m, 2H), 7.74−7.70 (m, 2H),

3.39−3.36 (m, 4H), 2.05−1.99 (m, 4H). ¹³C NMR (101 MHz,

CDCl₃) δ 167.6, 136.3, 134.5, 123.5, 52.4, 24.3. FT-IR (thin ﬁlm,

cm⁻¹) 2986, 1702. MS calcd for C₁₂H₁₂N₂O₂[M]⁺= 216, found [M +

H]⁺= 217. HRMS calcd for C₁₂H₁₂N₂O₂[M + H]⁺= 217.0972, [M +

Na]⁺= 239.0791, found [M + H]⁺= 217.0985, [M + Na]⁺= 239.0798.

Mp = 146−148 °C.

1-(Dimethylamino)-3,4-dimethyl-1H-pyrrole-2,5-dione (8g). Fol-

lowing the general procedure to prepare 8a, 3,4-dimethylfuran-2,5-

dione (3.1 g, 25 mmol) was allowed to react with N,N-

dimethylhydrazine (2.1 mL, 28 mmol) in toluene (55 mL) in the

presence of p-TsOH·H₂O (0.24 g, 1.2 mmol) for 4.5 h at 125 °C.

Following similar workup procedure, a viscous yellow liquid was

1

obtained (3.7 g, 89% yield). H NMR (400 MHz, CDCl₃) δ 2.87 (s,

6H), 1.91. (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 170.4, 135.7, 44.8,

8.6. FT-IR (thin ﬁlm, cm⁻¹) 1705. MS calcd for C₈H₁₂N₂O₂[M]⁺=

168, found [M + H]⁺= 169. HRMS calcd for C₈H₁₂N₂O₂[M + H]⁺=

169.0972, [M + Na]⁺= 191.0791, found [M + H]⁺= 169.0992, [M +

Na]⁺= 191.0796.

2-Methoxyisoindoline-1,3-dione (8c). Following the general

procedure to prepare 8a, isobenzofuran-1,3-dione (2.3 g, 15 mmol)

was allowed to react with methoxyamine hydrochloride (1.9 g,

23 mmol) in toluene (34 mL) in the presence of p-TsOH·H₂O

(0.14 g, 0.76 mmol) for 4.5 h at 125 °C. Following similar workup

3-Hydroxy-3-(6-methylpyridin-2-yl)isobenzofuran-1(3H)-one

(10a) and 3,3-Bis(6-methylpyridin-2-yl)isobenzofuran-1(3H)-one

(6b). In a dry round-bottom ﬂask were added 2-bromo-6-methyl-

pyridine (0.44 mL, 3.8 mmol) and THF (6.4 mL). The reaction was

purged with argon and cooled to −78 °C. n-BuLi (1.6 mL, 4.0 mmol;

2.5 M solution in THF) was added via a syringe. After 30 min, the

anion was cannulated into a solution of isobenzofuran-1,3-dione (0.68 g,

4.6 mmol) in 5 mL of THF at −30 °C over a period of 45 min. After

15 min, the temperature was warmed to rt. After another 30 min, LC−

MS showed the desired product at 1.564 min as [M + H]⁺= 242,

bisaddition lactone at 2.244 min as [M + H]⁺= 317, and bisaddition

benzoic acid at 1.257 min as [M + H]⁺= 335. The ratio of monoaddtion

product:bisaddition lactone:bisaddition benzoic acid was 1:8.4:3.2. The

reaction was quenched with 2 mL of MeOH and concentrated to give a

yellow oil. The residue was puriﬁed further by using 70:30 Hex/EtOAc

and 90:10 DCM to provide two products. The ﬁrst series of fractions gave

1

procedure, a white solid was obtained (2.0 g, 75% yield). H NMR

(400 MHz, CDCl₃) δ 7.83−7.80 (m, 2H), 7.76−7.73 (m, 2H), 4.05 (s,

3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.2, 134.4, 128.8, 123.5, 65.8.

FT-IR (thin ﬁlm, cm⁻¹) 1799, 1732. MS calcd for C₉H₇NO₃[M]⁺=

177, found [M + H]⁺= 178. HRMS calcd for C₉H₇NO₃[M + H]⁺=

178.0499, [M + Na]⁺= 200.0318, found [M + H]⁺= 178.0517, [M +

Na]⁺= 200.0337. Mp =139−140 °C (lit.⁵⁵mp =142−143 °C).

2-Methylisoindoline-1,3-dione (8d). This compound was commer-

cially available.

2-Isopropylisoindoline-1,3-dione (8e). Following the general

procedure to prepare 8a, isobenzofuran-1,3-dione (1.3 g, 8.4 mmol)

was allowed to react with propan-2-amine (0.79 mL, 9.3 mmol) in

toluene (19 mL) in the presence of p-TsOH·H₂O (0.080 g, 0.42 mmol)

for 5 h at 125 °C. Following similar workup procedure, a white

solid was obtained (1.5 g, 94% yield). ¹H NMR (400 MHz, CDCl₃) δ

7.81−7.78 (m, 2H), 7.69−7.67 (m, 2H), 4.52 (sep, J = 7.1 Hz, 1H),

1.48 (d, J = 6.8 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 168.4, 133.8,

132.1, 123.0, 43.0, 20.2. FT-IR (thin ﬁlm, cm⁻¹) 2979, 1699. MS calcd

for C₁₁H₁₁NO₂[M]⁺= 189, found [M + H]⁺= 190. HRMS calcd

for C₁₁H₁₁NO₂[M + H]⁺= 190.0863, [M + Na]⁺= 212.0682, found

[M + H]⁺= 190.0869, [M + Na]⁺= 212.0687. Mp = 81−82 °C.

1

an oﬀ-white solid that corresponded to the monoaddition product. H

NMR and ¹³C NMR of the oﬀ-white solid in DMSO were complicated

possibly because the carboxylic acid (ring open) was in equilibrium with

the lactone (ring closed). FT-IR (thin ﬁlm) of the oﬀ-white solid was also

complicated, but the IR spectrum showed the OH-carboxylic acid and

carbonyl stretching frequencies. A second series of fractions gave an oﬀ-

white solid. ¹H NMR and LC−MS showed the bis-addition product. On

the FT-IR spectrum, there was no evidence for OH-carboxylic acid or the

alcohol stretching frequencies. Therefore, the bis-addition product existed

in the lactone form.

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Article

3-Hydroxy-3-(6-methylpyridin-2-yl)isobenzofuran-1(3H)-one

132.2, 130.8, 129.1, 122.7, 122.4, 122.2, 117.2, 88.7, 51.5, 23.8, 23.5. FT-

IR (thin ﬁlm, cm⁻¹) 3324 (br), 1986, 2874, 1703. MS calcd for C₁₈H₁₉-

N₃O₂[M]⁺= 309, found [M + H]⁺= 310. HRMS calcd for C₁₈H₁₉N₃O₂

[M + H]⁺= 310.1550, [M + Na]⁺= 332.1370, found [M + H]⁺=

310.1563, [M + Na]⁺= 332.1374. Mp = 146−147 °C.

(10a) and 2-(2-Methylpicolinoyl)benzoic Acid. A mixture of the

1

lactone and the carboxylic acid were obtained (0.23 g, 25% yield). H

NMR (400 MHz, DMSO-d₆) δ 7.85−7.83 (m, 1H), 7.78 (t, J =

7.8 Hz, 1H), 7.71−7.69 (m, 1H), 7.48−7.29 (m, 4H), 7.21−7.19 (m, 1H),

3.70 (m, 1H), 2.23 (s, 3H). ¹³C NMR was complicated. FT-IR (thin

ﬁlm, cm⁻¹) 3500−2500 (br), 1720, 1670, 1592, 1564. MS calcd for

C₁₄H₁₁NO₃[M]⁺= 241, found [M + H]⁺= 242. HRMS calcd for

C₁₄H₁₁NO₃[M + H]⁺= 242.0812, [M + Na]⁺= 264.0631, found

[M + H]⁺= 242.0833, [M + Na]⁺= 264.0664. Mp > 250 °C.

3,3-Bis(6-methylpyridin-2-yl)isobenzofuran-1(3H)-one (6b). The

bisaddition product was obtained as an oﬀ-white solid (0.15 g, 12%

3-Hydroxy-2-methoxy-3-(6-methylpyridin-2-yl)isoindolin-1-one

(9d). In a dry round-bottom ﬂask were added 2-bromo-6-

methylpyridine (0.20 mL, 1.7 mmol) and THF (2.9 mL). The

reaction ﬂask was purged with argon and cooled to −78 °C. n-BuLi

(0.73 mL, 1.8 mmol; 2.5 M solution in THF) was added via a syringe.

After 30 min, the anion was cannulated into a solution of 2-

methoxyisoindoline-1,3-dione (0.37 g, 2.1 mmol) in 5.0 mL of THF at

−30 °C over a period of 45 min. After 15 min at −30 °C, the

temperature was warmed to rt. After 30 min, LC−MS showed the

product at 1.571 min as [M + H]⁺= 271. The reaction was quenched

slowly with saturated aqueous NH₄Cl. The product was extracted with

DCM. The organic layer was washed with brine, dried over MgSO₄,

ﬁltered, and concentrated to give a yellow oil. The residue was puriﬁed

by performing a column chromatography on silica gel eluting with

70:30 Hex/EtOAc to aﬀord a white solid, 3-hydroxy-2-methoxy-3-(6-

methylpyridin-2-yl)isoindolin-1-one (0.26 g, 55% yield). ¹H NMR

(400 MHz, CDCl₃) δ 7.86−7.84 (m, 1H), 7.53−7.40 (m, 4H), 7.23−

7.21 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 3.94

(s, 3H), 2.64 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 164.2, 156.7,

153.9, 144.9, 138.1, 133.1, 129.7, 128.9, 123.5, 123.4, 122.4, 117.4,

89.3, 65.7, 24.0. FT-IR (thin ﬁlm, cm⁻¹) 3309 (br), 1721. MS calcd for

C₁₅H₁₄N₂O₃[M]⁺= 270, found [M + H]⁺= 271. HRMS calcd

for C₁₅H₁₄N₂O₃[M + H]⁺= 271.1077, [M + Na]⁺= 293.0897, found

[M + H]⁺= 271.1081, [M + Na]⁺= 293.0897. Mp = 112−114 °C.

3-Hydroxy-2-methyl-3-(6-methylpyridin-2-yl)isoindolin-1-one

(9e). In a dry round-bottom ﬂask were added 2-bromo-6-

methylpyridine (0.20 mL, 1.7 mmol) and THF (5.8 mL) under an

argon atmosphere. The reaction was purged with argon and cooled to

−78 °C. Then n-butyllithium (0.73 mL, 1.8 mmol; 2.5 M solution in

THF) was added via a syringe. After 30 min, the anion was cannulated

into a solution of 2-methylisoindoline-1,3-dione (0.30 g, 1.8 mmol) in

5.0 mL of THF. After 15 min, the temperature was warmed to rt. LC−

MS showed product as [M − OH]⁺= 237 and [2M + Na]⁺= 531. The

reaction was quenched slowly with saturated aqueous NH₄Cl. The

product was extracted with Et₂O. The organic layer was washed with

brine, dried over MgSO₄, ﬁltered, and concentrated to give a colorless

oil. After hexanes was added to the oily residue, a beige solid

precipitated out. The solid was ﬁltered oﬀ with the aid of cold hexanes

and dried under vacuum to aﬀord a beige solid, 3-hydroxy-2-methyl-3-

1

yield). H NMR (400 MHz, CDCl₃) δ 8.26 (d, J = 7.8 Hz, 1H), 7.89

(d, J = 7.5 Hz, 1H), 7.69 (td, J = 7.4, 1.0 Hz, 1H), 7.56−7.51 (m, 3H),

7.37 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.5 Hz, 2H), 2.48 (6H). ¹³C

NMR (101 MHz, CDCl₃) δ 170.2, 158.1, 158.0, 151.3, 136.7, 133.5,

129.0, 126.8, 125.5, 124.8, 122.4, 118.1, 24.5 (one carbon was not

accounted for). ¹³C NMR (151 MHz, CDCl₃) δ 170.2, 158.1, 158.0,

151.3, 136.7, 133.5, 129.0, 126.8, 125.5, 124.8, 122.4, 118.1, 90.8, 24.5.

FT-IR (thin ﬁlm, cm⁻¹) 1773. MS calcd for C₂₀H₁₆N₂O₂[M]⁺= 316,

found [M + H]⁺= 317. HRMS calcd for C₂₀H₁₆N₂O₂[M + H]⁺=

317.1285, [M + Na]⁺= 339.1104, found [M + H]⁺= 317.1317, [M +

Na]⁺= 339.1125. Mp = 169−170 °C.

General Procedure To Prepare Heteroaryl Hydroxyisoindo-

linone. 2-(Dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)-

isoindolin-1-one (9b). In a dry round-bottom ﬂask were added

2-bromo-6-methylpyridine (66 μL, 0.58 mmol) and THF (1.2 mL).

The reaction was purged with argon and cooled to −78 °C.

n-BuLi (0.24 mL, 0.61 mmol; 2.5 M solution in THF) was

added via a syringe. After 30 min, the anion was cannulated into

a solution of 2-(dimethylamino)isoindoline-1,3-dione (0.17 g,

0.87 mmol) in 2 mL of THF that was previously submerged in

a cold bath at −78 °C for 2 min. After 15 min at −78 °C, the

temperature was warmed to −30 °C. After 1 h, LC−MS showed

the product at 1.535 min. The reaction was warmed to rt and

quenched slowly with saturated aqueous NH₄Cl. The product was

extracted with DCM. The organic layer was washed with brine,

dried over MgSO₄, ﬁltered, and concentrated to give a yellow oil.

The product was puriﬁed by performing a column chromatog-

raphy on silica gel eluting with 85:15 DCM/(90:10:1 DCM/

MeOH/NH₄OH) to aﬀord 2-(dimethylamino)-3-hydroxy-3-

(6-methylpyridin-2-yl)isoindolin-1-one as a yellow solid (0.11 g,

1

67% yield). H NMR (400 MHz, DMSO-d₆) δ 7.78−7.64 (m,

3H), 7.54−7.45 (m, 2H), 7.17−7.13 (m, 2H), 3.33 (s, 1H), 2.76

(s, 6H), 2.31 (s, 3H). C NMR (101 MHz, DMSO-d₆) δ 165.9,

13

1

(6-methylpyridin-2-yl)isoindolin-1-one (0.33 g, 74% yield). H NMR

157.6, 156.6, 147.3, 137.2, 132.3, 130.8, 129.0, 122.46, 122.49,

122.0, 118.9, 91.0, 44.4, 23.9. FT-IR (thin ﬁlm, cm⁻¹) 3324 (br),

2954, 2884, 1704, 1460, 1344. MS calcd for C₁₆H₁₇N₃O₂[M]⁺=

283, found [M + H]⁺= 284. HRMS calcd for C₁₆H₁₇N₃O₂[M +

H]⁺= 284.1394, [M + Na]⁺= 306.1213, found [M + H]⁺=

284.1395, [M + Na]⁺= 306.1205. Mp = 142−143 °C.

(400 MHz, CDCl₃) δ 7.85 (s, 1H), 7.56−7.47 (m, 3H), 7.27−7.17 (m,

3H), 6.70 (d, J = 7.5 Hz, 1H), 2.75 (s, 3H), 2.66 (s, 3H). ¹³C NMR

(101 MHz, CDCl₃) δ 167.7, 156.8, 155.2, 147.6, 138.4, 132.3, 131.5,

129.5, 123.4, 123.2, 122.3, 117.3, 89.0, 24.1, 23.5. FT-IR (thin ﬁlm,

cm⁻¹) 3297 (br), 1700. MS calcd for C₁₅H₁₄N₂O₂[M]⁺= 254, found

[M − OH]⁺= 237 and [2M + Na]⁺= 531. HRMS calcd for C₁₅H₁₄-

N₂O₂[M + H]⁺= 255.1128, [M + Na]⁺= 277.0948, found [M + H]⁺=

255.1129, [M + Na]⁺= 277.0945. Mp = 133−134 °C.

3-Hydroxy-2-isopropyl-3-(6-methylpyridin-2-yl)isoindolin-1-one

(9f). 2-Bromo-6-methylpyridine (0.13 mL, 1.2 mmol) and THF (3.9 mL)

were added into a dry round-bottom ﬂask under an argon atmos-

phere. The reaction was purged with argon and cooled to −78 °C.

Then n-butyllithium (0.49 mL, 1.2 mmol; 2.5 M solution in THF) was

added via a syringe. After 30 min, the anion was cannulated into

a solution of 2-isopropylisoindoline-1,3-dione (0.23 g, 1.2 mmol) in

5.0 mL of THF. After 15 min, the temperature was warmed to rt. LC−

MS showed the product at 1.740 min as [M − OH]⁺= 265 and [2M +

Na]⁺= 587. The reaction was quenched slowly with saturated aqueous

NH₄Cl. The product was extracted with Et₂O. The organic layer was

washed with brine, dried over MgSO₄, ﬁltered, and concentrated to

give a colorless oil. The product was puriﬁed by performing a column

chromatography on silica gel eluting with 75:25 Hex/EtOAc to aﬀord

a viscous colorless oil, 3-hydroxy-2-isopropyl-3-(6-methylpyridin-2-

yl)isoindolin-1-one (0.19 g, 58% yield). ¹H NMR (400 MHz, CDCl₃)

δ 7.83−7.81 (m, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.49−7.43 (m, 2H),

3-Hydroxy-3-(6-methylpyridin-2-yl)-2-(pyrrolidin-1-yl)isoindolin-

1-one (9c). In a dry round-bottom ﬂask were added 2-bromo-6-

methylpyridine (0.20 mL, 1.7 mmol) and THF (2.9 mL). The reaction

was purged with argon and cooled to −78 °C. n-BuLi (0.73 mL,

1.8 mmol; 2.5 M solution in THF) was added via a syringe. After 30 min,

the anion was cannulated into a solution of 2-(pyrrolidin-1-yl)iso-

indoline-1,3-dione (0.45 g, 2.1 mmol) in 5.0 mL of THF. After 15 min,

the temperature was warmed to rt. After 30 min, LC−MS showed the

product at 1.654 min as [M + H]⁺= 310. The reaction was quenched

slowly with saturated aqueous NH₄Cl. The product was extracted with

DCM. The organic layer was washed with brine, dried over MgSO₄,

ﬁltered, and concentrated to give a yellow oil. The product was

puriﬁed by performing a column chromatography on silica gel eluting

with 70:30 DCM/(90:10:1 DCM/MeOH/NH₄OH) to aﬀord 3-hydroxy-

3-(6-methylpyridin-2-yl)-2-(pyrrolidin-1-yl)isoindolin-1-one as a yellow

foam (0.30 g, 56% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.87−7.86 (m,

1H), 7.60−7.50 (m, 3H), 7.22−7.21 (m, 2H), 6.87 (d, J = 7.8 Hz, 1H),

3.49−3.44 (m, 2H), 3.11−3.05 (m, 2H), 2.72 (s, 3H), 1.91−1.79 (m,

4H). ¹³C NMR (101 MHz, CDCl₃) δ 165.8, 156.1, 155.4, 145.8, 137.2,

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The Journal of Organic Chemistry

Article

7.30 (s, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.13−7.11 (m, 1H), 6.80 (d, J =

7.8 Hz, 1H), 3.51 (quin, J = 7.1 Hz, 1H), 2.67 (s, 3H), 1.41 (d, J =

6.8 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ

167.8, 156.3, 156.0, 147.7, 138.0, 132.5, 132.1, 129.4, 123.3, 122.9,

122.1, 118.0, 89.7, 44.5, 24.1, 20.7, 20.1. FT-IR (thin ﬁlm, cm⁻¹) 3311

(br), 2976, 1694. MS calcd for C₁₇H₁₈N₂O₂[M]⁺= 282, found [M −

OH]⁺= 265 and [2M + Na]⁺= 587. HRMS calcd for C₁₇H₁₈N₂O₂

[M + H]⁺= 283.1441, [M + Na]⁺= 305.1261, found [M + H]⁺=

283.1445, [M + Na]⁺= 305.1270.

[M + Na]⁺= 306.1213, found [M + H]⁺= 284.1403, [M + Na]⁺=

306.1201. Mp = 73−74 °C.

2-(Dimethylamino)-3-hydroxy-3-(4-methylpyridin-2-yl)-

isoindolin-1-one (9j). Following the general procedure to prepare

2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-

one (9b), this compound was prepared using 2-bromo-4-methylpyridine

(6.5 mL, 58 mmol) and THF (97 mL), n-BuLi (24 mL, 61 mmol),

2-(dimethylamino)isoindoline-1,3-dione (13 g, 70 mmol) in 70 mL of

THF. The crude product was triturated in hexanes until the solid

precipitated out of the solution. The solid was ﬁltered oﬀ with the aid of

hexanes and dried under vacuum to aﬀord 2-(dimethylamino)-3-hydroxy-

3-(4-methylpyridin-2-yl)isoindolin-1-one (12 g, 70% yield).

3-Benzyl-2-(dimethylamino)-3-hydroxy-2,3,4,5,6,7-hexahydroi-

soindol-1-one (9g). In a dry round-bottom ﬂask were added

2-(dimethylamino)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.31 g,

1.6 mmol) and THF (7.7 mL). The reaction was purged with argon

and cooled to −78 °C. Benzylmagnesium bromide (1.2 mL, 1.5 mmol)

in 5.0 THF was added via a syringe. After 15 min, the temperature was

warmed to rt. LC−MS showed the product at 1.96 min as [M + H]⁺=

285. The reaction was quenched slowly with saturated aqueous

NH₄Cl. The product was extracted with Et₂O. The organic layer was

washed with brine, dried over MgSO₄, ﬁltered, and concentrated to

give a colorless oil. Hexanes were added followed by a small amount of

Et₂O. White solid precipitated out of the solution. The solid was

ﬁltered oﬀ with the aid of cold hexanes and dried under vacuum to

provide a sticky oﬀ-white solid, 3-benzyl-2-(dimethylamino)-3-

The second batch was obtained from the ﬁltrate. After

concentration of the ﬁltrate, the residue was puriﬁed by column

chromatography eluting with 80:20 DCM/(90:10:1 DCM/MeOH/

NH₄OH) to aﬀord a yellow solid (1.0 g, 6% yield). The overall yield

was 76%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J = 4.8 Hz, 1H),

7.77 (s, 1H), 7.65−7.63 (m, 1H), 7.52−7.46 (m, 2H), 7.16−7.10 (m,

3H), 2.70 (s, 6H), 2.40 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ

165.8, 158.3, 148.2, 147.59, 147.57, 132.3, 130.9, 128.9, 123.8, 122.52,

122.49, 121.9, 90.7, 44.3, 20.8. FT-IR (thin ﬁlm, cm⁻¹) 3436 (br),

1655, 1024. MS calcd for C₁₆H₁₇N₃O₂[M]⁺= 283, found [M + H]⁺=

284; [2M + Na]⁺= 589. HRMS calcd for C₁₆H₁₇N₃O₂[M + H]⁺=

284.1394, [M + Na]⁺= 306.1213, found [M + H]⁺= 284.1413; [M +

Na]⁺= 306.1248. Mp = 150−152 °C.

1

hydroxy-2,3,4,5,6,7-hexahydroisoindol-1-one (0.30 g, 68% yield). H

NMR (400 MHz, CDCl₃) δ 7.28−7.20 (m, 5H), 3.30 (d, J = 14.1 Hz,

1H), 3.11 (d, J = 14.1 Hz, 1H), 2.95 (s, 7H), 2.11−2.06 (m, 3H),

1.91−1.80 (m, 1H), 1.69−1.50 (m, 4H). ¹³C NMR (101 MHz,

CDCl₃) δ 169.2, 152.9, 135.5, 132.8, 129.8, 128.2, 126.9, 90.8, 45.7,

41.8, 22.1, 21.9, 21.6, 19.5. FT-IR (thin ﬁlm, cm⁻¹) 3330, 2940, 1678.

MS calcd for C₁₇H₂₂N₂O₂[M]⁺= 286, found [M + H]⁺= 287. HRMS

calcd for C₁₇H₂₂N₂O₂[M + H]⁺= 287.1754, [M + Na]⁺= 309.1574,

found [M + H]⁺= 287.1771, [M + Na]⁺= 309.1594.

1-(Dimethylamino)-5-hydroxy-3,4-dimethyl-5-phenyl-1H-pyrrol-

2(5H)-one (9h). 1-(Dimethylamino)-3,4-dimethyl-1H-pyrrole-2,5-

dione (0.40 g, 2.4 mmol) and THF (7.5 mL) were added into a dry

round-bottom ﬂask under an argon atmosphere. The reaction was

purged with argon and cooled to −78 °C. Then phenyl lithium

(1.3 mL, 2.3 mmol; 1.8 M in di-n-butylether) at 0 °C was added via a

syringe. After 15 min, the temperature was warmed to rt. LC−MS

showed the product at 1.792 min as [M + H]⁺= 247. The reaction was

quenched slowly with saturated aqueous NH₄Cl. The product was

extracted with Et₂O. The organic layer was washed with brine, dried

over MgSO₄, ﬁltered, and concentrated to give a colorless oil. The

product was puriﬁed by performing a column chromatography on

silica gel eluting with 60:40 Hex/EtOAc to aﬀord a white solid,

1-(dimethylamino)-5-hydroxy-3,4-dimethyl-5-phenyl-1H-pyrrol-

2(5H)-one (0.39 g, 70% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.43−

7.28 (m, 5H), 3.43, (s, 1H), 2.79 (s, 6H), 1.84 (s, 3H), 1.65 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 170.2, 150.7, 138.0, 128.34, 128.29,

2-(Dimethylamino)-3-hydroxy-3-(6-methylpyridin-3-yl)isoindolin-1-

one (9k). Following the general procedure to prepare 2-(dimethyla-

mino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one (9b), this

compound was prepared using 5-bromo-2-methylpyridine (0.4 g,

2.3 mmol) and THF (7.8 mL), n-BuLi (9.8 mL, 2.4 mmol; 2.5 M in

THF), 2-(dimethylamino)isoindoline-1,3-dione (0.66 g, 3.5 mmol) in

15 mL of THF. The product was triturated with hexanes to aﬀord a

yellow solid, 2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-3-yl)-

1

isoindolin-1-one (0.50 g, 76%). H NMR (400 MHz, DMSO-d₆) δ

8.46−8.45 (d, 1H), 7.72−7.70 (m, 1H), 7.61−7.51 (m, 3H), 7.22−

7.18 (m, 2H), 7.11 (s, 1H), 2.73 (s, 6H), 2.44 (s, 3H). ¹³C NMR (101

MHz, DMSO-d₆) δ 164.9, 156.9, 146.8, 146.7, 134.0, 132.4, 132.0,

129.6, 129.0, 122.6, 121.8, 88.6, 44.2, 23.2. FT-IR (thin ﬁlm, cm⁻¹)

3100 (br), 2956, 2885, 1702, 1467, 1343. MS calcd for C₁₆H₁₇N₃O₂

[M]⁺= 283, found [M + H]⁺= 284. HRMS calcd for C₁₆H₁₇N₃O₂

[M + H]⁺= 284.1394, [M + Na]⁺= 306.1213, found [M + H]⁺=

284.1419, [M + Na]⁺= 306.1247. Mp = 164−165 °C.

3-(5-Chloropyridin-2-yl)-2-(dimethylamino)-3-hydroxyisoindolin-

1-one (9l). Following the general procedure to prepare 2-(dimethylamino)-

3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one (9b), this com-

pound was prepared using 2-bromo-5-chloropyridine (3.5 g, 18 mmol)

and Et₂O (73 mL), n-BuLi (7.7 mL, 19 mmol; 2.5 M in THF),

2-(dimethylamino)isoindoline-1,3-dione (4.2 g, 22 mmol) in 20 mL of

THF. The product was puriﬁed by performing a column chromatography

eluting with 80:20 Hex/EtOAc to aﬀord a brown solid, 3-(5-chloropyridin-

2-yl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (2.0 g, 36% yield). ¹H

NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.01 (s, 2H), 7.67 (d, J = 6.6

Hz, 1H), 7.52 (quin, J = 7.0 Hz, 2H), 7.27 (s, 1H), 7.18 (d, J = 6.6 Hz,

1H), 2.72 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 165.7, 157.4, 147.0,

136.6, 132.4, 130.8, 130.2, 129.1, 123.5, 122.6, 122.0, 90.4, 44.4. FT-IR

(thin ﬁlm, cm⁻¹) 3332 (br), 3053, 2954, 2884, 1686. MS calcd for

C₁₅H₁₄ClN₃O₂[M]⁺= 303, found [M + H]⁺= 304. HRMS calcd

for C₁₅H₁₄ClN₃O₂[M + H]⁺= 304.0847, [M + Na]⁺= 326.0667, found

[M + H]⁺= 304.0856, [M + Na]⁺= 326.0673. Mp = 137−139 °C.

2-(Dimethylamino)-3-hydroxy-3-(6-methoxypyridin-2-yl)isoindolin-

1-one (9m). Following the general procedure to prepare 2-(dimethyl-

amino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one (9b), this

compound was prepared using 2-bromo-6-methoxypyridine (2.0 mL,

16 mmol) and THF (27 mL), n-BuLi (6.7 mL, 17 mmol; 2.5 M in

THF), 2-(dimethylamino)isoindoline-1,3-dione (3.6 g, 19 mmol). The

crude product was triturated in hexanes to provide an oﬀ-white solid,

2-(dimethylamino)-3-hydroxy-3-(6-methoxypyridin-2-yl)isoindolin-1-

128.13, 126.1, 91.3, 45.3, 10.1, 8.1. FT-IR (thin ﬁlm, cm⁻¹) 3351 (br),

2951, 2882, 1686. MS calcd for C₁₄H₁₈N₂O₂[M]⁺= 246, found [M +

H]⁺= 247. HRMS calcd for C₁₄H₁₈N₂O₂[M + H]⁺= 247.1441, [M +

Na]⁺= 269.1261, found [M + H]⁺= 247.1465, [M + Na]⁺= 269.1272.

Mp = 198−199 °C.

2-(Dimethylamino)-3-hydroxy-3-(5-methylpyridin-2-yl)-

isoindolin-1-one (9i). Following the general procedure to prepare

2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-

one (9b), this compound was prepared using 2-bromo-5-methylpyr-

idine (1.0 g, 5.8 mmol) and THF (9.7 mL), n-BuLi (2.4 mL,

6.1 mmol; 2.5 M solution in THF), 2-(dimethylamino)isoindoline-1,3-

dione (1.3 g, 7.0 mmol) in 10 mL of THF. The product was puriﬁed

by performing a column chromatography eluting with 85:15 DCM/

(90:10:1 DCM/MeOH/NH₄OH) to aﬀord a viscous yellow oil (1.4 g,

1

86% yield). H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.50−7.47

(m, 1H), 7.19−7.12 (m, 3H), 6.82−6.80 (m, 1H), 6.70 (br s, 1H),

6.54 (d, J = 8.1 Hz, 1H), 2.50 (s, 6H), 2.05 (s, 3H). ¹³C NMR

(101 MHz, CDCl₃) δ 166.6, 153.4, 147.5, 146.0, 138.0, 133.5, 132.6,

131.2, 129.6, 122.8, 122.6, 120.1, 88.8, 45.0, 18.1. FT-IR (thin ﬁlm,

cm⁻¹) 3337 (br), 1700. MS calcd for C₁₆H₁₇N₃O₂[M]⁺= 283, found

[M + H]⁺= 284. HRMS calcd for C₁₆H₁₇N₃O₂[M + H]⁺= 284.1394,

1

one (4.2 g, 88% yield). H NMR (400 MHz, DMSO-d₆) δ 7.80 (m,

1H), 7.65 (dd, J = 7.0, 1.0 Hz, 1H), 7.58−7.45 (m, 3H), 7.15 (dd,

J = 7.0, 1.0 Hz, 1H), 7.11 (s, 1H), 6.72 (dd, J = 7.0, 1.0 Hz, 1H), 3.52

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(s, 3H), 2.77 (s, 6H). ¹³C NMR (101 MHz, DMSO-d₆) δ 165.8, 162.4,

156.3, 147.3, 139.8, 133.2, 130.8, 128.9, 122.4, 121.8, 114.8, 109.6,

90.7, 52.5, 44.4. MS calcd for C₁₆H₁₇N₃O₃[M]⁺= 299, found [M + H]⁺=

300; [2M + Na]⁺= 621. HRMS calcd for C₁₆H₁₇N₃O₃[M + H]⁺=

300.1343, found [M + H]⁺= 300.1337. Mp = 142 °C.

for C₁₅H₁₆N₂O₂S [M + H]⁺= 289.1005, [M + Na]⁺= 311.0825, found

[M + H]⁺= 289.1022, [M + Na]⁺= 311.0838. Mp = 138−140 °C.

2-(Dimethylamino)-3-(5-ethylthiophen-2-yl)-3-hydroxyisoindo-

lin-1-one (9q). n-BuLi (5.9 mL, 15 mmol) was added slowly into a

solution of THF (18 mL) in TMEDA (2.2 mL, 15 mmol) at 0 °C.

After 30 min at 0 °C, 2-ethylthiophene (1.5 g, 13 mmol) was added

slowly. The whole was warmed to rt and heated to 50 °C for 30 min.

After cooling down to 0 °C, the solution was cannulated slowly into

a cold mixture of 2-(dimethylamino)isoindoline-1,3-dione (2.5 g,

13 mmol) in 30 mL of ether at 0 °C. After warming to rt for 15 min,

the reaction was quenched slowly with saturated aqueous NH₄Cl and

brine. The product was extracted with DCM. The organic layer was

washed with brine, dried over MgSO₄, ﬁltered, and concentrated to

give a brown oil. The product was puriﬁed by performing column

chromatography on silica gel eluting with 70:30 Hex/EtOAc to aﬀord

2-(dimethylamino)-3-(5-ethylthiophen-2-yl)-3-hydroxyisoindolin-1-

2-(Dimethylamino)-3-hydroxy-3-(4-methylthiophen-2-yl)isoindolin-

1-one and 2-(Dimethylamino)-3-hydroxy-3-(3-methylthiophen-2-yl)-

isoindolin-1-one (9n and 9o).^40,41,56,57Under a nitrogen atmosphere,

n-BuLi (1.3 mL, 3.4 mmol) was added into a solution of TMEDA

(0.55 mL, 3.7 mmol) in Et₂O (3.1 mL) at rt. Then 3-methylthiophene

(0.29, 3.1 mmol) was added via a syringe. The mixture was heated to

reﬂux under a nitrogen atmosphere for 5 min. The reaction was cooled

to rt, and the whole was cannulated into a mixture of 2-(dimethyl-

amino)isoindoline-1,3-dione (0.70 g, 3.7 mmol) in ether (10 mL). The

solution became milky. After 15 min, LC−MS showed product at

1.913 min as [M + H]⁺= 289. The ratio of regioisomers could not be

determined from LC−MS at this point. TLC showed one intense spot.

The reaction was quenched slowly with brine. The product was

extracted with DCM. The organic layer was washed with brine, dried

over MgSO₄, ﬁltered, and concentrated to give a yellow oil. The

residue was puriﬁed by performing a column chromatography eluting

with 80:20 DCM/(90:10:1 DCM/MeOH/NH₄OH) to aﬀord a light

yellow solid (0.96 g, 90% yield). HPLC showed a 9:1 mixture of two

isomers. Minor isomer 9o, 2-(dimethylamino)-3-hydroxy-3-(3-meth-

ylthiophen-2-yl)isoindolin-1-one, was at 6.156 min. Major isomer 9n,

2-(dimethylamino)-3-hydroxy-3-(4-methylthiophen-2-yl)isoindolin-1-

one, was at 6.335 min. MS calcd for C₁₅H₁₆N₂O₂S [M]⁺= 288, found

[M + H]⁺= 289. A small amount of the mixture was puriﬁed by HPLC

for characterization of both isomers. This mixture was carried on to

the next step.

1

one (3.2 g, 79% yield). H NMR (400 MHz, CDCl₃) δ 7.68 (d, J =

7.3 Hz, 1H), 7.63−7.51 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.09 (s, 1H),

6.70 (d, J = 3.8 Hz, 1H), 6.66 (d, J = 3.5 Hz, 1H), 2.81 (s, 6H), 2.76

(q, J = 7.3 Hz, 2H), 1.20 (t, J = 7.3 Hz, 3H). ¹³C NMR (101 MHz,

CDCl₃) δ 165.0, 147.3, 146.8, 141.2, 132.7, 129.5, 129.4, 124.8, 123.1,

122.8, 122.1, 88.4, 44.6, 22.8, 15.8. FT-IR (thin ﬁlm, cm⁻¹) 3265 (br),

2963, 2879, 1679. MS calcd for C₁₆H₁₈N₂O₂S [M]⁺= 302, found [M +

H]⁺= 303. HRMS calcd for C₁₆H₁₈N₂O₂S [M + H]⁺= 303.1162,

[M + Na]⁺= 325.0981, found [M + H]⁺= 303.1177, [M + Na]⁺=

325.0988. Mp = 104−105 °C.

3-(Benzo[b]thiophen-2-yl)-2-(dimethylamino)-3-hydroxyisoindo-

lin-1-one (9r). To a solution of benzo[b]thiophene (0.75 g, 5.6 mmol)

in 19 mL of THF at −78 °C was added n-BuLi (2.4 mL, 5.9 mmol;

2.5 M in hexanes). The reaction was allowed to stir for 15 min at −78 °C

and was warmed to 0 °C for 30 min. The reaction was cooled back to

−78 °C, and a solution of 2-(dimethylamino)isoindoline-1,3-dione (1.1 g,

5.9 mmol) in 5 mL of THF was added via a cannula over 5 min. The

resulting yellow solution was allowed to stir for 15 min and was warmed

to rt. A precipitate was formed. After 30 min, the reaction was quenched

with saturated aqueous NH₄Cl and diluted with Et₂O. The organic layer

was washed with brine (1x), dried over sodium sulfate, ﬁltered, and

concentrated in vacuum to give an oil. Puriﬁcation by silica gel

chromatography (MPLC, 80 g, 0−50% EtOAc in hexanes) provided

1.7 g of a white foam. Recrystallization from a 2:1 mixture of hot H₂O/

ACN provided 3-(benzo[b]thiophen-2-yl)-2-(dimethylamino)-3-hydrox-

yisoindolin-1-one (1.2 g, 64% yield) as white crystals. ¹H NMR

(400 MHz, DMSO-d₆) δ ppm 7.86 - 7.93 (m, 1 H), 7.77 - 7.82 (m, 1 H),

7.72 (d, J = 7.0 Hz, 1 H), 7.64 (t, J = 7.5 Hz, 1 H), 7.58 (t, J = 7.3 Hz, 1 H),

7.43 (d, J = 7.5 Hz, 1 H), 7.37 (s, 1 H), 7.29 - 7.36 (m, 3 H), 2.83 (s, 6 H).

¹³C NMR (101 MHz, DMSO-d₆) δ ppm 165.0, 146.9, 145.4, 139.2,

138.9, 132.9, 129.7, 129.5, 124.4, 124.2, 123.8, 123.1, 122.3, 122.3,

122.0, 88.5, 44.7. FT-IR (thin ﬁlm, cm⁻¹) 3277, 1682. HRMS calcd

for C₁₈H₁₇N₂O₂S [M + H]⁺= 325.1011, found [M + H]⁺= 325.1005.

Mp = 168.8−169.5 °C.

2-(Dimethylamino)-3-hydroxy-3-(4-methylthiophen-2-yl)isoindolin-

1-one (9n). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 7.3 Hz, 1H),

7.56−7.46 (m, 2H), 7.42−7.40 (m, 1H), 6.86 (m, 2H), 4.04 (br s,

1H), 2.95 (s, 6H), 2.21 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ

166.0, 145.4, 143.1, 137.1, 132.4, 129.5, 127.6, 122.8, 122.6, 121.1,

88.7, 45.2, 15.4. ¹³C NMR (151 MHz, CDCl₃) δ 166.3, 145.8, 143.4,

139.4, 137.4, 132.7, 129.8, 128.0, 123.1, 122.9, 121.4, 89.0, 45.5, 15.7.

FT-IR (thin ﬁlm, cm⁻¹) 3315 (br), 1689. MS calcd for C₁₅H₁₆N₂O₂S

[M]⁺= 288, found [M + H]⁺= 289. HRMS calcd for C₁₅H₁₆N₂O₂S

[M + Na]⁺= 311.0825, found [M + Na]⁺= 311.0835. Mp = 157−159 °C.

2-(Dimethylamino)-3-hydroxy-3-(3-methylthiophen-2-yl)isoindolin-

1-one (9o). ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 7.3 Hz, 1H),

7.56−7.46 (m, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 3.0 Hz, 1H),

6.78 (d, J = 3.0 Hz, 1H), 3.80 (br s, 1H), 2.80 (s, 6H), 2.51 (s, 3H).

FT-IR (thin ﬁlm, cm⁻¹) 3282, 1686. MS calcd for C₁₅H₁₆N₂O₂S

[M]⁺= 288, found [M + H]⁺= 289. HRMS calcd for C₁₅H₁₆N₂O₂S

[M + Na]⁺= 311.0825, found [M + Na]⁺= 311.0800. Mp = 163−165 °C.

2-(Dimethylamino)-3-hydroxy-3-(5-methylthiophen-2-yl)isoindolin-

1-one (9p). A solution of 2-bromo-5-methylthiophene (0.60 mL,

5.3 mmol) in THF (11 mL) was purged with nitrogen and cooled to

−78 °C. n-Butyllithium (2.2 mL, 5.5 mmol; 2.5 M in THF) was added,

and the mixture was stirred under nitrogen for 30 min. The resulting

solution was cannulated into a ﬂask containing a solution of 2-(dimethyl-

amino)isoindoline-1,3-dione (1.5 g, 7.9 mmol) in THF (16 mL) at

−78 °C under a nitrogen atmosphere. The reaction was allowed to warm

to −30 °C over 1 h, at which point LC−MS showed complete conversion

of 2-bromo-5-methylthiophene to product. The reaction was quenched by

careful addition of saturated aqueous NH₄Cl. The whole was diluted with

dichloromethane and water, and the layers were separated. The aqueous

portion was extracted with dichloromethane, and the combined organics

were dried over MgSO₄, ﬁltered, concentrated, and puriﬁed by silica gel

chromatography eluting with 0−2% MeOH in dichloromethane to

provide a light yellow solid, 2-(dimethylamino)-3-hydroxy-3-(5-methyl-

2-(Dimethylamino)-3-hydroxy-3-(5-methylthiazol-2-yl)isoindolin-1-

one (9s). Following the procedure to prepare 2-(dimethylamino)-3-

hydroxy-3-(4-methylthiazol-2-yl)isoindolin-1-one (9t), this compound

was prepared using 5-methylthiazole (0.66 g, 6.6 mmol) and THF

(13 mL), n-BuLi (2.8 mL, 6.9 mmol), 2-(dimethylamino)isoindoline-

1,3-dione (1.9 g, 9.9 mmol) in 15 mL of THF. The product was puri-

ﬁed by trituration with hexanes to aﬀord an orange solid, 2-(dimethyl-

amino)-3-hydroxy-3-(5-methylthiazol-2-yl)isoindolin-1-one (1.4 g,

1

73% yield). H NMR (400 MHz, DMSO-d₆) δ 7.75−7.73 (m, 1H),

7.67−7.57 (m, 2H), 7.63 (s, 1H), 7.43 (d, 1H), 7.37−7.36 (m, 1H),

2.86 (s, 6H), 2.50 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 168.1,

165.3, 145.9, 140.3, 135.0, 132.7, 130.0, 129.6, 122.83, 122.2, 89.1,

44.5, 11.5. FT-IR (thin ﬁlm, cm⁻¹) 3100 (br), 2954, 2885, 1710,

1464, 1442, 1341. MS calcd for C₁₄H₁₅N₃O₂S [M]⁺= 289, found [M +

H]⁺= 290. HRMS calcd for C₁₄H₁₅N₃O₂S [M + H]⁺= 290.0958,

[M + Na]⁺= 312.0777, found [M + H]⁺= 290.0988, [M + Na]⁺=

312.0780. Mp = 160−161 °C.

1

thiophen-2-yl)isoindolin-1-one (1.2 g, 80% yield). H NMR (400 MHz,

DMSO-d₆) δ 7.68−7.65 (m, 1H), 7.63−7.59 (m, 1H), 7.57−7.51 (m,

1H), 7.37 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.69−6.66 (m, 1H), 6.65−

6.62 (m, 1H), 2.81 (s, 6H), 2.40 (s, 3H). ¹³C NMR (101 MHz, DMSO-

d₆) δ 165.0, 147.3, 141.6, 139.3, 132.7, 129.49, 129.46, 125.0, 124.7, 123.0,

122.1, 88.4, 44.7, 14.9. FT-IR (thin ﬁlm, cm⁻¹) 3347, 3215, 1673. MS

calcd for C₁₅H₁₆N₂O₂S [M]⁺= 288, found [M + H]⁺= 289. HRMS calcd

General Procedure To Prepare Thiazole Hydroxyisoindoli-

nones. 2-(Dimethylamino)-3-hydroxy-3-(4-methylthiazol-2-yl)-

isoindolin-1-one (9t). In a dry round-bottom ﬂask, a solution of

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4-methylthiazole (1.5 g, 15 mmol) in THF (25 mL) was

purged with argon. The whole was cooled to −78 °C. n-BuLi

(6.4 mL, 16 mmol) was added via a syringe. After 30 min at

−78 °C, the reaction was allowed to warm to 0 °C. After

30 min, the whole was cooled back to −78 °C. Then, the anion

was cannulated into a solution of 2-(dimethylamino)-

isoindoline-1,3-dione (3.2 g, 17 mmol) in 20 mL of THF at

−30 °C. After 15 min, the temperature was warmed to rt,

quenched slowly with saturated aqueous NH₄Cl, and extracted

with DCM. The organic layer was washed with brine, dried

over MgSO₄, ﬁltered, and concentrated to give a yellow oil.

Trituration with hexanes aﬀorded a beige solid, 2-(dimethyla-

mino)-3-hydroxy-3-(4-methylthiazol-2-yl)isoindolin-1-one (3.4 g,

77% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 6.7 Hz,

1H), 7.61−7.52 (m, 3H), 7.30 (d, J = 7.3 Hz, 1H), 7.26 (d, J =

23 mmol) in THF (20 mL), n-butyllithium (25 mL; 1.04 M solution in

hexanes), 2-(dimethylamino)isoindoline-1,3-dione (5.4 g, 28 mmol)

and THF (15 mL). The product was puriﬁed by MPLC silica gel

chromatography using 0−100% (90:10 MeOH/CH₂Cl₂) in DCM to

yield 3-(4-tert-butylphenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-

1

one (4.2 g, 55% yield) as a light yellow solid. H NMR (400 MHz,

DMSO-d₆) δ 7.68−7.66 (m, 1H), 7.56−7.48 (m, 2H), 7.35−7.33 (m,

2H), 7.29−7.26 (m, 2H), 7.17−7.15 (m, 1H), 6.90 (s, 1H), 2.73 (s,

6H), 1.25 (s, 9H). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 165.3,

149.9, 147.9, 136.7, 132.4, 129.8, 128.8, 125.8, 124.4, 122.7, 121.8,

89.8, 44.3, 34.0, 30.9. FT-IR (thin ﬁlm, cm⁻¹) 3310 (br), 2954, 2867,

1681, 1466, 1360. MS calcd for C₂₀H₂₄N₂O₂[M]⁺= 324.4, found [M +

H]⁺= 325.1. HRMS calcd for C₂₀H₂₄N₂O₂[M + H]⁺= 325.1911, [M +

Na]⁺= 347.1730, found [M + H]⁺= 325.1924, [M + Na]⁺= 347.1746.

Mp = 68−69 °C.

13

2-(Dimethylamino)-3-hydroxy-3-m-tolylisoindolin-1-one (9x).

Following the general procedure to prepare 3-(4-chlorophenyl)-2-

(dimethylamino)-3-hydroxyisoindolin-1-one (9v), this compound was

prepared using 1-bromo-3-methylbenzene (1.1 mL, 8.8 mmol) and

THF (15 mL), n-BuLi (3.7 mL, 9.2 mmol), 2-(dimethylamino)-

isoindoline-1,3-dione (1.9 g, 9.9 mmol) in 15 mL of THF. The

product was puriﬁed by trituration with hexanes to aﬀord 2-

(dimethylamino)-3-hydroxy-3-m-tolylisoindolin-1-one (1.8 g, 73%) as

1.0 Hz, 1H), 2.80 (s, 6H), 2.23 (s, 3H). C NMR (101 MHz,

CDCl₃) δ 169.3, 165.2, 151.9, 145.8, 132.7, 130.0, 129.6, 122.8,

122.2, 115.7, 89.0, 44.4, 16.8. FT-IR (thin ﬁlm, cm⁻¹) 3300

(br), 2956, 2887, 1690. MS calcd for C₁₄H₁₅N₃O₂S

[M]⁺= 289, found [M + H]⁺= 290. HRMS calcd for C₁₄H₁₅N₃-

O₂S [M + H]⁺= 290.0958, [M + Na]⁺= 312.0777, found [M +

H]⁺= 290.0968, [M + Na]⁺= 312.0775. Mp = 137−139 °C.

2-(Dimethylamino)-3-(4,5-dimethylthiazol-2-yl)-3-hydroxyisoindo-

lin-1-one (9u). Following the general procedure to prepare 2-(dimethyl-

amino)-3-hydroxy-3-(4-methylthiazol-2-yl)isoindolin-1-one (9t), this

compound was prepared using 4,5-dimethylthiazole (2.0 g, 18 mmol)

and THF (29 mL), n-BuLi (7.4 mL, 19 mmol), 2-(dimethylamino)-

isoindoline-1,3-dione (3.7 g, 19 mmol) in 20 mL of THF. The product

was puriﬁed by trituration with hexanes to aﬀord a yellow solid,

2-(dimethylamino)-3-(4,5-dimethylthiazol-2-yl)-3-hydroxyisoindolin-1-

1

a white solid. H NMR (400 MHz, CDCl₃) δ 7.76−7.74 (m, 1H),

7.47−7.44 (m, 2H), 7.30 (s, 1H), 7.23−7.19 (m, 3H), 7.13−7.12 (m,

1H), 4.03 (s, 1H), 2.85 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ

167.1, 147.0, 139.3, 138.3, 133.0, 130.5, 129.7, 129.4, 128.5, 127.1,

123.6, 123.4, 123.2, 100.0, 45.5, 21.8. FT-IR (thin ﬁlm, cm⁻¹) 3317,

2954, 1686, 1611, 1468, 1447, 1360. MS calcd for C₁₇H₁₈N₂O₂[M]⁺=

282, found [M + H]⁺= 283. HRMS calcd for C₁₇H₁₈N₂O₂[M + H]⁺

= 283.1441, [M + Na]⁺= 305.1261, found [M + H]⁺= 283.1467,

[M + Na]⁺= 305.1292. Mp = 160−161 °C.

1

one (3.7 g, 70% yield). H NMR (400 MHz, CDCl₃) δ 7.79−7.77 (m,

1H), 7.55−7.48 (m, 2H), 7.35−7.33 (m, 1H), 5.39 (s, 1H), 2.95 (s, 6H),

2.34 (s, 3H), 2.31 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.4, 163.7,

147.5, 144.9, 132.8, 130.1, 129.3, 123.2, 122.8, 88.6, 45.4, 14.7, 11.5. FT-

IR (thin ﬁlm, cm⁻¹) 3305 (br), 1690. MS calcd for C₁₅H₁₇N₃O₂S [M]⁺=

303, found [M + H]⁺= 304. HRMS calcd for C₁₅H₁₇N₃O₂S [M + H]⁺=

304.1114, [M + Na]⁺= 326.0934, found [M + H]⁺= 304.1130, [M +

Na]⁺= 326.0964. Mp = 183−185 °C.

2-(Dimethylamino)-3-hydroxy-3-(3-(triﬂuoromethyl)phenyl)-

isoindolin-1-one (9y). Following the general procedure to prepare 3-

(4-chlorophenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9v),

this compound was prepared using 1-bromo-3-(triﬂuoromethyl)-

benzene (0.61 mL, 4.4 mmol) and THF (7.4 mL), n-BuLi (1.9 mL,

4.7 mmol), 2-(dimethylamino)isoindoline-1,3-dione (1.7 g, 8.9 mmol)

in 15 mL of THF. The product was puriﬁed by trituration with

hexanes to aﬀord 2-(dimethylamino)-3-hydroxy-3-(3-

(triﬂuoromethyl)phenyl)isoindolin-1-one (1.1 g, 74% yield) as a

General Procedure To Prepare Substituted Phenyl Hydroxy-

isoindolinones. 3-(4-Chlorophenyl)-2-(dimethylamino)-3-hy-

droxyisoindolin-1-one (9v). In a dry round-bottom ﬂask, a

solution of 1-bromo-4-chlorobenzene (9.2 g, 48 mmol) and

THF (80 mL) was cooled to −78 °C. n-BuLi (20 mL, 50 mmol)

was added via a syringe. After 30 min, the anion was cannulated

into a solution of 2-(dimethylamino)isoindoline-1,3-dione

(10 g, 53 mmol) in 100 mL of THF (the SM precipitated

out of the solution at low temp) over a period of 45 min. After

15 min at −78 °C, the temperature was warmed to rt. After 1 h,

the reaction was quenched slowly with saturated aqueous

NH₄Cl (10 mL). After concentration, the residue was dissolved

with DCM (50 mL), and brine (20 mL) was added. The

organic layer was separated. The aqueous layer was extracted

with DCM (2 × 50 mL). The combined organic layer was dried

over MgSO₄, ﬁltered, and concentrated to give a viscous

colorless oil. Trituration with hexanes aﬀorded the ﬁrst batch as

white solid (9.9 g, 68% yield). The second batch (0.51 g, 3.5%

1

white solid. H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.76−7.74

(m, 1H), 7.55−7.61 (m, 2H), 7.50−7.44 (m, 3H), 7.19−7.21 (d, 1H),

4.23 (s, 1H), 2.82 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 167.0,

146.4, 140.8, 133.4, 131.3, 130.4, 130.2, 130.1, 129.1, 125.7, 125.6,

123.7, 123.6, 123.2, 90.5, 45.6. FT-IR (thin ﬁlm, cm⁻¹) 3318, 1687,

1468, 1446, 1328, 1167, 1126. MS calcd for C₁₇H₁₅F₃N₂O₂[M]⁺=

336, found [M + H]⁺= 337. HRMS calcd for C₁₇H₁₅F₃N₂O₂[M +

H]⁺= 337.1158, [M + Na]⁺= 359.0978, found [M + H]⁺= 337.1161,

[M + Na]⁺= 359.0988. Mp = 113−114 °C.

3-(4-Chloro-3-methoxyphenyl)-2-(dimethylamino)-3-hydroxy-

isoindolin-1-one (9z). Following the general procedure to prepare

3-(4-chlorophenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one

(9v), this compound was prepared using 4-bromo-1-chloro-2-

methoxybenzene (1.2 g, 5.4 mmol) and THF (9.0 mL), n-BuLi

(23 mL, 5.7 mmol), 2-(dimethylamino)isoindoline-1,3-dione (1.1 g,

6.0 mmol) in 10 mL of THF. The product was puriﬁed by

recrystallization with a mixture of DCM/hexanes to aﬀord the ﬁrst

batch as white crystals, 3-(4-chloro-3-methoxyphenyl)-2-(dimethyla-

mino)-3-hydroxyisoindolin-1-one (0.62 g, 34% yield). A second batch

was obtained from the mother liquor by column chromatography

eluting with 60:40 Hex/EtOAc to aﬀord an oﬀ-white solid (0.14 g, 8%

1

yield) was obtained from the ﬁltrate. H NMR (400 MHz,

CDCl₃) δ 7.76−7.74 (m, 1H), 7.52−7.45 (m, 2H), 7.41−7.37

(m, 2H), 7.33−7.30 (m, 2H), 7.20−7.17 (m, 1H), 3.87 (s, 1H),

2.84 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 166.6, 146.3,

137.8, 134.4, 133.0, 130.2, 129.8, 128.5, 127.9, 123.3, 122.9,

90.2, 45.3. FT-IR (thin ﬁlm, cm⁻¹) 3303 (br), 1678. MS calcd

for C₁₆H₁₅ClN₂O₂[M]⁺= 302, found [M + H]⁺= 303. HRMS

calcd for C₁₆H₁₅ClN₂O₂[M + H]⁺= 303.0895, [M + Na]⁺=

325.0714, found [M + H]⁺= 303.0900, [M + Na]⁺= 325.0735.

Mp = 133−134 °C.

3-(4-tert-Butylphenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-

one (9w). Following the general procedure to prepare 3-(4-chloro-

phenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9v), this com-

pound was prepared using 1-bromo-4-tert-butylbenzene (4.1 mL,

1

yield). The overall yield was 42%. H NMR (400 MHz, CDCl₃) δ

7.82−7.80 (m, 1H), 7.56−7.49 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H),

7.24−7.23 (m, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 8.1, 2.1 Hz,

1H), 3.91 (s, 3H), 3.74 (s, 1H), 2.93 (s, 6H). ¹³C NMR (101 MHz,

CDCl₃) δ 166.6, 155.0, 146.2, 139.4, 133.0, 130.03, 129.95, 129.8,

123.3, 122.78, 122.7, 119.2, 110.3, 90.4, 56.2, 45.4. FT-IR (thin ﬁlm,

cm⁻¹) 3332 (br), 2958, 2885, 1687. MS calcd for C₁₇H₁₇ClN₂O₃

[M]⁺= 332, found [M + H]⁺= 333. HRMS calcd for C₁₇H₁₇ClN₂O₃

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1

[M + H]⁺= 333.1001, [M + Na]⁺= 355.0820, found [M + H]⁺=

333.1024, [M + Na]⁺= 355.0833. Mp = 178−179 °C.

yield). H NMR (400 MHz, DMSO-d₆) δ 7.60−7.57 (m, 2H), 7.50−

7.48 (m, 2H), 6.29 (s, 1H), 5.77 (s, 1H), 2.90 (s, 6H), 2.13−2.05 (m,

2H), 1.80−1.77 (m, 1H), 1.61−1.50 (m, 2H), 1.33−0.94 (m, 5H). ¹³C

NMR (151 MHz, DMSO-d₆) δ 165.2, 145.2, 131.8, 130.9, 128.8, 122.8,

121.9, 92.2, 44.5, 42.3, 27.7, 26.8, 26.2, 26.0, 25.6. FT-IR (thin ﬁlm,

cm⁻¹) 3365 (br), 2930, 2833, 1688. MS calcd for C₁₆H₂₂N₂O₂[M]⁺=

274, found [M + H]⁺= 275. HRMS calcd for C₁₆H₂₂N₂O₂

[M + H]⁺= 275.1754, [M + Na]⁺= 297.1573, found [M + H]⁺=

275.1771, [M + Na]⁺= 297.1582. Mp = 139−140 °C.

General Procedure To Prepare Alkyl/Cycloalkyl Hydroxyi-

soindolinones. 2-(Dimethylamino)-3-hydroxy-3-isopropylisoin-

dolin-1-one (9aa). In a dry round-bottom ﬂask were added

2-(dimethylamino)isoindoline-1,3-dione (2.8 mg, 15 mmol)

and THF (16 mL). After cooling to −78 °C, isopropylmagne-

sium chloride (4.9 mL, 9.7 mmol; 2 M solution in diethyl

ether) was added via a syringe over 10 min. After 30 min at

−78 °C, the reaction was warmed to rt. After 30 min, the

reaction was quenched slowly with saturated aqueous NH₄Cl.

The product was extracted with DCM. The organic layer was

washed with brine, dried over MgSO₄, ﬁltered, and concen-

trated to give a yellow solid. The product was puriﬁed by

column chromatography eluting with 85:15 DCM/(90:10:1

DCM/MeOH/NH₄OH) to aﬀord a white solid, 2-(dimethy-

lamino)-3-hydroxy-3-isopropylisoindolin-1-one (2.1 g, 90%

yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.61 (d, J =

7.1 Hz, 2H), 7.53−7.49 (m, 2H), 6.31 (s, 1H), 2.91 (s, 6H),

2.49 (sep, J = 6.8 Hz, 1H), 1.15 (d, J = 7.1 Hz, 3H), 0.53 (d, J =

7.1 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 165.3, 144.8,

131.3, 131.1, 128.9, 122.81, 121.9, 92.6, 44.5, 32.2, 17.4, 17.0.

FT-IR (thin ﬁlm, cm⁻¹) 3362 (br), 2960, 2876, 1682. MS calcd

for C₁₃H₁₈N₂O₂[M]⁺= 234, found [M + H]⁺= 235. HRMS

calcd for C₁₃H₁₈N₂O₂[M + H]⁺= 235.1441, [M + Na]⁺=

257.1269, found [M + H]⁺= 235.1454, [M + Na]⁺= 257.1269.

The solid melted at 69−70 °C to form a glass, which was then

recrystallized. It eventually melted again at 166−167 °C.

3-Benzyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9ab).

Following the general procedure to prepare 2-(dimethylamino)-3-

hydroxy-3-isopropylisoindolin-1-one (9aa), this compound was prepared

using 2-(dimethylamino)isoindoline-1,3-dione (0.76 g, 4.0 mmol) and

THF (5.5 mL), benzylmagnesium chloride (2.5 mL, 3.3 mmol; 1.3 M

solution in THF). The product was puriﬁed using 60:40 Hex/EtOAc to

aﬀord a light yellow foam, 3-benzyl-2-(dimethylamino)-3-hydroxyisoindo-

lin-1-one (0.49 g, 52% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J =

2.7 Hz, 1H), 7.43 (td, J = 7.3, 1.0 Hz, 1H), 7.37 (td, J = 7.6, 1.3 Hz, 1H),

7.29−7.26 (m, 3H), 7.19−7.15 (m, 2H), 6.75 (d, J = 7.3 Hz, 1H), 3.81 (d,

J = 13.9 Hz, 1H), 3.28 (s, 1H), 3.06 (s, 6H), 2.91 (d, J = 13.9 Hz, 1H).

¹³C NMR (101 MHz, CDCl₃) δ 165.8, 143.9, 135.3, 131.7, 130.8, 129.4,

General Procedure To Prepare Alkynyl Hydroxyisoindoli-

nones. 2-(Dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydrox-

yisoindolin-1-one (9al). In a dry round-bottom ﬂask were added

3,3-dimethylbut-1-yne (0.40 g, 4.9 mmol) and THF (8.1 mL).

After purging with argon and cooling to −78 °C, n-BuLi

(2.0 mL, 5.1 mmol) was added via a syringe. After 30 min at −78 °C,

a solution of 2-(dimethylamino)isoindoline-1,3-dione (0.93 g,

4.9 mmol) in 10 mL of THF at rt was added into the anion over a

period of 15 min. After another 15 min, the temperature was

warmed to rt. After 1 h at rt, the reaction was quenched slowly with

saturated aqueous NH₄Cl (15 mL). The product was extracted with

Et₂O (3 × 30 mL). The organic layer was washed with brine, dried

over MgSO₄, ﬁltered, and concentrated to give an oil. Trituration

with hexanes aﬀorded a white solid, 2-(dimethylamino)-

3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (1.1 g,

1

83% yield). H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 7.3 Hz,

1H), 7.62−7.56 (m, 2H), 7.48 (td, J = 6.8, 1.5 Hz, 1H), 4.12 (s, 1H),

3.05 (s, 6H), 1.21 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 165.3,

144.0, 132.7, 129.8, 122.9, 122.6, 93.0, 82.1, 75.4, 45.2, 30.5, 27.3. FT-

IR (thin ﬁlm, cm⁻¹) 3315 (br), 2970, 1690. MS calcd for C₁₆H₂₀N₂O₂

[M]⁺= 272, found [M + H]⁺= 273. HRMS calcd for C₁₆H₂₀N₂O₂

[M + H]⁺= 273.1598, [M + Na]⁺= 295.1417, found [M + H]⁺=

273.1620, [M + Na]⁺= 295.1447. Mp = 179−181 °C.

2-(Dimethylamino)-3-hydroxy-3-(phenylethynyl)isoindolin-1-one

(9ae). Following the general procedure to prepare 2-(dimethylamino)-

3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (9al), this com-

pound was prepared using 1-ethynylbenzene (0.54 mL, 4.9 mmol) and

THF (8.2 mL), n-BuLi (2.1 mL, 5.1 mmol), 2-(dimethylamino)-

isoindoline-1,3-dione (1.0 g, 5.4 mmol) in 20 mL of THF. The

product was puriﬁed by performing a column chromatography on

silica gel eluting with 75:25 Hex/EtOAc to aﬀord an oﬀ-white solid,

2-(dimethylamino)-3-hydroxy-3-(2-phenylethynyl)isoindolin-1-one

(1.2 g, 82% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 7.6 Hz, 1H),

7.70 (d, J = 7.6 Hz, 1H), 7.62 (td, J = 7.5, 1.2 Hz, 1H), 7.51 (td, J =

8.6, 1.0 Hz, 1H), 7.45−7.42 (m, 2H), 7.35−7.29 (m, 3H), 4.58 (s,

1H), 3.12 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 165.3, 143.5,

132.9, 131.8, 130.1, 130.0, 129.1, 128.3, 123.1, 122.8, 121.4, 85.4, 84.0,

82.4, 45.4. FT-IR (thin ﬁlm, cm⁻¹) 3315 (br), 1690. MS calcd for

C₁₈H₁₆N₂O₂[M]⁺= 292, found [M + H]⁺= 293. HRMS calcd for

C₁₈H₁₆N₂O₂[M + H]⁺= 293.1285, [M + Na]⁺= 315.1104, found

[M + H]⁺= 293.1306, [M + Na]⁺= 315.1121. Mp = 145−146 °C.

2-(Dimethylamino)-3-hydroxy-3-(pyridin-2-ylethynyl)isoindolin-

1-one (9af). Following the general procedure to prepare 2-(dimethyl-

amino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (9al),

this compound was prepared using 2-ethynylpyridine (0.66 g, 6.4

mmol) and THF (11 mL), n-BuLi (2.7 mL, 6.7 mmol), 2-(dimethyl-

amino)isoindoline-1,3-dione (1.3 g, 7.0 mmol) in 15 mL of THF. The

product was puriﬁed by performing a column chromatography eluting

with 30:70 Hex/EtOAc to aﬀord an orange solid, 2-(dimethylamino)-

3-hydroxy-3-(2-(pyridin-2-yl)ethynyl)isoindolin-1-one (0.94 g, 50%

yield). This analogue must be stored cold to prevent decomposition.

¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 4.1 Hz, 1H), 7.78 (d, J =

128.0, 127.0, 123.6, 122.9, 90.1, 45.7, 43.5. FT-IR (thin ﬁlm, cm⁻¹) 3351

(br), 2953, 2885, 1683. MS calcd for C₁₇H₁₈N₂O₂[M]⁺= 282, found

[M + H]⁺= 283. HRMS calcd for C₁₇H₁₈N₂O₂[M + H]⁺= 283.1441,

[M + Na]⁺= 305.1261, found [M + H]⁺= 283.1453, [M + Na]⁺=

305.1284. Mp = 133−134 °C.

3-Cyclopropyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one

(9ac). Following the general procedure to prepare 2-(dimethylamino)-

3-hydroxy-3-isopropylisoindolin-1-one (9aa), this compound was

prepared using 2-(dimethylamino)isoindoline-1,3-dione (1.0 g,

5.3 mmol) and THF (8.0 mL), cyclopropylmagnesium bromide (9.6 mL,

4.8 mmol; 0.5 M in THF). The product was puriﬁed by performing a

column chromatography on silica gel eluting with 70:30 Hex/EtOAc

to aﬀord a white solid, 3-cyclopropyl-2-(dimethylamino)-3-hydroxy-

1

isoindolin-1-one (0.75 g, 67% yield). H NMR (400 MHz, CDCl₃) δ

7.60 (d, J = 7.6 Hz, 1H), 7.52−7.41 (m, 3H), 3.49 (s, 1H), 2.99 (s,

6H), 1.31−1.21 (m, 1H), 0.86 (sex, J = 5.3 Hz, 1H), 0.68−0.61 (m,

1H), 0.47−0.40 (m, 1H), 0.36−0.29 (m, 1H). ¹³C NMR (101 MHz,

CDCl₃) δ 165.6, 144.5, 132.0, 130.8, 129.4, 122.9, 122,4, 88.6, 45.3,

17.6, 1.42, 0.41. FT-IR (thin ﬁlm, cm⁻¹) 3332, 2952, 1675. MS calcd

for C₁₃H₁₆N₂O₂[M]⁺= 232, found [M + H]⁺= 233. HRMS calcd for

C₁₃H₁₆N₂O₂[M + H]⁺= 233.1285, [M + Na]⁺= 255.1104, found

[M + H]⁺= 233.1302, [M + Na]⁺= 255.1115. Mp = 169−170 °C.

3-Cyclohexyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one

(9ad). Following the general procedure to prepare 2-(dimethylamino)-

3-hydroxy-3-isopropylisoindolin-1-one (9aa), this compound was

prepared using 2-(dimethylamino)isoindoline-1,3-dione (1.2 g,

6.4 mmol) and THF (8.9 mL), cyclohexylmagnesium bromide (6.4 mL,

5.3 mmol; 18% in THF). The product was puriﬁed using 85:15 DCM/

(90:10:1 DCM/MeOH/NH₄OH) to aﬀord a light yellow foam, 3-

cyclohexyl-2-(dimethylamino)-3-hydroxyisoindolin-1-one (1.3 g, 87%

8.6 Hz, 2H), 7.67 (td, J = 7.6, 1.7 Hz, 1H), 7.61 (td, J = 8.6, 1.2 Hz,

1H), 7.52 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.30−7.26 (m,

1H), 5.48 (br s, 1H), 3.14 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ

165.1, 149.6, 142.9, 141.5, 136.0, 132.6, 129.6, 129.84, 129.76, 127.1,

123.2, 122.8, 85.4, 82.4, 81.9, 45.1. FT-IR (thin ﬁlm, cm⁻¹) 3059 (br),

1703. MS calcd for C₁₇H₁₅N₃O₂[M]⁺= 293, found [M + H]⁺= 294.

HRMS calcd for C₁₇H₁₅N₃O₂[M + H]⁺= 294.1237, [M + Na]⁺=

316.1057, found [M + H]⁺= 294.1249, [M + Na]⁺= 316.1056. Mp:

crystallized at 73−78 °C and melted at 109−110 °C.

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2-(Dimethylamino)-3-hydroxy-3-((3-hydroxyphenyl)ethynyl)-

isoindolin-1-one (9ag). Following the general procedure to prepare

2-(dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-

one (9al), this compound was prepared using 3-ethynylphenol (0.50 g,

4.2 mmol) and THF (15 mL), n-BuLi (3.4 mL, 8.6 mmol),

2-(dimethylamino)isoindoline-1,3-dione (0.84 g, 4.4 mmol) in 10 mL

of THF. The product was puriﬁed by performing a column chromato-

graphy eluting with 60:40 Hex/EtOAc to aﬀord an oﬀ-white solid,

2-(dimethylamino)-3-hydroxy-3-(2-(3-hydroxyphenyl)ethynyl)-

δ 7.6 (d, J = 7.6 Hz, 1H), 7.64−7.58 (m, 2H), 7.49 (td, J = 7.3, 1.5 Hz,

1H), 4.19 (s, 1H), 3.07 (s, 6H), 1.09−0.99 (m, 21H). ¹³C NMR (101

MHz, CDCl₃) δ 165.5, 143.6, 132.9, 130.0, 130.1, 123.1, 122.7, 103.2,

86.4, 81.9, 45.4, 18.5, 11.1. FT-IR (thin ﬁlm, cm⁻¹) 3317, 2944, 2866,

1693. MS calcd for C₂₁H₃₂N₂O₂Si [M]⁺= 372, found [M + H]⁺= 373.

HRMS calcd for C₂₁H₃₂N₂O₂Si [M + H]⁺= 373.2306, [M + Na]⁺=

395.2125, found [M + H]⁺= 373.2332, [M + Na]⁺= 395.2152. Mp =

134−135 °C.

2-(Dimethylamino)-3-(hex-1-ynyl)-3-hydroxyisoindolin-1-one

(9aj). Following the general procedure to prepare 2-(dimethylamino)-

3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (9al), this com-

pound was prepared using hex-1-yne (0.68 mL, 6.1 mmol) and THF

(10 mL), n-BuLi (2.6 mL, 6.4 mmol), 2-(dimethylamino)isoindoline-

1,3-dione (1.3 g, 6.7 mmol) in 15 mL of THF. The product was

recrystallized in hexanes to yield light yellow crystals, 2-(dimethyla-

mino)-3-(hex-1-ynyl)-3-hydroxyisoindolin-1-one (1.6 g, 95% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 7.4 Hz, 1H), 7.63−7.57

1

isoindolin-1-one (0.75 g, 58% yield). H NMR (400 MHz, CDCl₃) δ

7.74 (d, J = 7.4 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz,

1H), 7.49 (t, J = 7.6 Hz, 1H), 7.29 (br s, 1H), 7.14 (t, J = 8.1 Hz, 1H),

6.95−6.88 (m, 3H), 4.80 (br s, 1H), 3.09 (s, 6H). ¹³C NMR (101

MHz, CDCl₃) δ 165.8, 156.0, 143.4, 133.2, 130.2, 129.7, 129.6, 124.0,

123.2, 122.1, 122.9, 118.6, 117.1, 84.7, 84.1, 82.6, 45.3. FT-IR (thin

ﬁlm, cm⁻¹) 3314 (br), 1688. MS calcd for C₁₈H₁₆N₂O₃[M]⁺= 308,

found [M + H]⁺= 309. HRMS calcd for C₁₈H₁₆N₂O₃[M + H]⁺=

309.1334, [M + Na]⁺= 331.1053, found [M + H]⁺= 309.1300, [M +

Na]⁺= 331.1055. Mp = 134−135 °C.

(m, 2H), 7.48 (td, J = 7.1, 1.5 Hz, 1H), 4.06 (s, 1H), 3.07 (s, 6H), 2.23

(t, J = 7.1 Hz, 2H), 1.49 (quin, J = 7.3 Hz, 2H), 1.39 (sex, J = 8.1 Hz,

2H), 0.88 (t, J = 7.3 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 165.3,

143.9, 132.8, 129.8, 123.0, 122.6, 85.6, 82.1, 76.7, 45.3, 30.2, 21.9, 18.3,

13.5. FT-IR (thin ﬁlm, cm⁻¹) 3319, 2955, 2932, 2872, 2239, 1687. MS

calcd for C₁₆H₂₀N₂O₂[M]⁺= 272, found [M + H]⁺= 273. HRMS

calcd for C₁₆H₂₀N₂O₂[M + H]⁺= 273.1598, [M + Na]⁺= 295.1417,

found [M + H]⁺= 273.1610, [M + Na]⁺= 295.1422. Mp = 87−88 °C.

2-(Dimethylamino)-3-hydroxy-3-(4-hydroxybut-1-ynyl)-

isoindolin-1-one (9ak). Following the general procedure to prepare

2-(dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-

one (9al), this compound was prepared using but-3-yn-1-ol (0.16 mL,

2.1 mmol) and THF (3.6 mL), n-BuLi (1.8 mL, 4.4 mmol), 2-(dimethyl-

amino)isoindoline-1,3-dione (0.43 g, 2.2 mmol) in 10 mL of THF. The

product was puriﬁed by performing a column chromatography eluting

with 60:40 Hex/EtOAc to aﬀord a sticky oﬀ-white solid, 2-(dimethyl-

amino)-3-hydroxy-3-(4-hydroxybut-1-ynyl)isoindolin-1-one (0.43 mg,

2-(Dimethylamino)-3-hydroxy-3-((trimethylsilyl)ethynyl)-

isoindolin-1-one (9ah). Following the general procedure to prepare 2-

(dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-

one (9al), this compound was prepared using ethynyltrimethylsilane

(0.86 mL, 6.1 mmol) and THF (10 mL), n-BuLi (2.6 mL, 6.4 mmol),

2-(dimethylamino)isoindoline-1,3-dione (1.3 g, 6.7 mmol) in 15 mL

of THF. Because the anion formed was so thick, normal addition was

used. Trituration with hexanes aﬀorded a white solid, 2-(dimethyla-

mino)-3-hydroxy-3-(2-(trimethylsilyl)ethynyl)isoindolin-1-one (0.89 g,

51% yield). A second batch was obtained from the mother liquor

1

as a white solid (0.82 g, 47% yield). The overall yield was 98%. H

NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 7.4 Hz, 1H), 7.65−7.58 (m,

2H), 7.50 (td, J = 7.1, 1.5 Hz, 1H), 4.12 (s, 1H), 3.07 (s, 6H), 0.17 (s,

9H). ¹³C NMR in CDCl₃showed a complex mixture of product

probably due to C−O silyl migration. FT-IR (thin ﬁlm, cm⁻¹) 3301

(br) 2960, 1693. MS calcd for C₁₅H₂₀N₂O₂Si [M]⁺=288, found [M +

H]⁺=289. HRMS calcd for C₁₅H₂₀N₂O₂Si [M + H]⁺= 289.1367,

[M + Na]⁺= 311.1186, found [M + H]⁺= 289.1374, [M + Na]⁺=

311.1183. Mp = 194−195 °C.

1

77% yield). H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 7.6 Hz, 1H),

7.65−7.60 (m, 2H), 7.51 (t, J = 4.3 Hz, 1H), 4.60 (s, 1H), 3.76

(distorted t, J = 5.6 Hz, 2H), 3.08 (s, 6H), 2.75 (br s, 1H), 2.52

(distorted t, J = 4.8 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 165.6,

144.1, 133.3, 130.3, 130.0, 123.3, 122.9, 83.0, 82.2, 78.8, 60.9, 45.6, 23.3.

FT-IR (thin ﬁlm, cm⁻¹) 3304 (br), 2956, 2885, 2245, 1688. MS calcd for

C₁₄H₁₆N₂O₃[M]⁺= 260, found [M + H]⁺= 261. HRMS calcd for

C₁₄H₁₆N₂O₃[M + H]⁺= 261.1234, [M + Na]⁺= 283.1053, found [M +

H]⁺= 261.1257, [M + Na]⁺= 283.1067.

3-(Cyclopropylethynyl)-2-(dimethylamino)-3-hydroxyisoindolin-

1-one (9am). Following the general procedure to prepare 2-(dimethyl-

amino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (9al),

this compound was prepared using ethynylcyclopropane (0.57 g,

6.1 mmol; 70% by wt. in toluene) and THF (10 mL), n-BuLi (2.5 mL,

6.4 mmol), 2-(dimethylamino)isoindoline-1,3-dione (1.2 g, 6.3 mmol)

in 10 mL of THF. Trituration with hexanes aﬀorded a yellow solid, 3-

(2-cyclopropylethynyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one

(1.2 g, 77% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 7.6 Hz,

1H), 7.61−7.55 (m, 2H), 7.47 (td, J = 7.4, 1.8 Hz, 1H), 4.38 (br s,

1H), 3.04 (s, 6H), 1.30−1.23 (m, 1H), 0.81−0.67 (m, 4H). ¹³C NMR

(101 MHz, CDCl₃) δ 165.3, 143.9, 132.7, 129.83, 129.79, 122.9, 122.6,

88.3, 82.1, 71.8, 45.2, 8.23, −0.10. FT-IR (thin ﬁlm, cm⁻¹) 3316 (br),

2245, 1689. MS calcd for C₁₅H₁₆N₂O₂[M]⁺= 256, found [M + H]⁺=

257. HRMS calcd for C₁₅H₁₆N₂O₂[M + H]⁺= 257.1285, [M + Na]⁺=

279.1104, found [M + H]⁺= 257.1313, [M + Na]⁺= 279.1118. Mp =

133−134 °C.

2-(Dimethylamino)-3-ethynyl-3-hydroxyisoindolin-1-one (9ah′).

To shed light on the complex ¹³C NMR, desilylation with TBAF

was performed. Tetrabutylammonium ﬂuoride (0.27 mL, 1.0 mmol;

1.0 M in THF) was added into a cold solution of 2-(dimethylamino)-

3-hydroxy-3-(2-(trimethylsilyl)ethynyl)isoindolin-1-one (0.20 g,

0.69 mmol) in THF (1.4 mL) at 0 °C. After 15 min, the reaction

was warmed to rt and quenched with saturated aqueous NH₄Cl. The

product was extracted with Et₂O. The organic layer was separated,

dried over MgSO₄, ﬁltered, and concentrated. The product was

puriﬁed further by performing a column chromatography eluting with

1

60:40 Hex/EtOAc to aﬀord a white solid. H NMR showed product

cleanly. However, ¹³C NMR in CDCl₃again was complex. ¹³C NMR

in DMSO-d₆conﬁrmed product, 2-(dimethylamino)-3-ethynyl-3-

1

hydroxyisoindolin-1-one (0.12 g, 80% yield). H NMR (400 MHz,

DMSO-d₆) δ 7.76 (td, J = 7.6, 1.3 Hz, 1H), 7.64−7.60 (m, 2H), 7.56

(td, J = 7.3, 1.2 Hz, 1H), 4.07 (s, 1H), 3.09 (s, 6H), 2.63 (s, 1H). ¹³C

NMR (101 MHz, DMSO-d₆) δ 164.4, 144.9, 133.1, 129.9, 129.1,

122.8, 122.2, 81.5, 81.3, 74.2, 44.5. FT-IR (thin ﬁlm, cm⁻¹) 3291 (br),

1691. MS calcd for C₁₂H₁₂N₂O₂[M]⁺= 216, found [M + H]⁺= 217.

HRMS calcd for C₁₂H₁₂N₂O₂[M + H]⁺= 217.0972, [M + Na]⁺=

239.0791, found [M + H]⁺= 217.0983, [M + Na]⁺= 239.0796. Mp =

165−166 °C, decomposed.

2-(Dimethylamino)-3-hydroxy-3-((triisopropylsilyl)ethynyl)-

isoindolin-1-one (9ai). Following the general procedure to prepare

2-(dimethylamino)-3-(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-

one (9al), this compound was prepared using ethynyltriisopropylsilane

(0.46 g, 2.5 mmol) and THF (4.2 mL), n-BuLi (1.1 mL, 2.6 mmol),

2-(dimethylamino)isoindoline-1,3-dione (0.53 g, 2.8 mmol) in 5 mL

of THF. The product was puriﬁed by performing a column

chromatography eluting with 80:20 Hex/EtOAc to aﬀord a white

solid, 2-(dimethylamino)-3-hydroxy-3-(2-(triisopropylsilyl)ethynyl)-

General Procedure To Prepare Phthalazinones. 4-(6-Methyl-

pyridin-2-yl)phthalazin-1(2H)-one (7b). 2-(Dimethylamino)-3-hy-

droxy-3-(6-methylpyridin-2-yl)isoindolin-1-one (3.2 g, 11 mmol),

EtOH (11 mL), and hydrazine (5.3 mL, 168 mmol) were added

into a round-bottom ﬂask. A nitrogen balloon was attached on top

of the condenser. After reﬂuxing overnight, the reaction was

cooled to rt. An oﬀ-white solid precipitated out of the solution.

After cooling to 0 °C, water was added slowly. The solid

was ﬁltered oﬀ with the aid of water and dried under vacuum to

aﬀord a white solid, 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one

1

isoindolin-1-one (0.67 g, 71% yield). H NMR (400 MHz, CDCl₃)

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(2.6 g, 98% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.80 (br s,

1H), 8.46−8.41 (m, 2H), 8.02−7.95 (m, 3H), 7.72 (d, J = 7.5 Hz,

1H), 7.50 (d, J = 7.6 Hz, 1H), 2.67 (s, 3H). ¹³C NMR (101 MHz,

DMSO-d₆) δ 159.4, 157.1, 153.7, 144.1, 137.7, 133.4, 131.6, 128.7,

128.0, 127.5, 125.8, 123.2, 121.2, 24.1. FT-IR (thin ﬁlm, cm⁻¹)

2918, 2850, 1674. MS calcd for C₁₄H₁₁N₃O [M]⁺= 237, found

[M + H]⁺= 238. HRMS calcd for C₁₄H₁₁N₃O [M + H]⁺=

238.0975, found [M + H]⁺= 238.0970. Mp = 242−243 °C.

4-(5-Methylpyridin-2-yl)phthalazin-1(2H)-one (7c). Following the

general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-

1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)-

3-hydroxy-3-(5-methylpyridin-2-yl)isoindolin-1-one (0.45 g, 1.6 mmol),

ethanol (1.6 mL), and hydrazine (0.75 mL, 24 mmol). Similar

workup provided a white solid, 4-(5-methylpyridin-2-yl)phthalazin-

ethanol (18 mL), and hydrazine (7 mL, 0.21 mol). Similar workup

provided 4-(6-methoxypyridin-2-yl)phthalazin-1(2H)-one (2.4 g, 66%

yield). ¹H NMR (400 MHz, CDCl₃) δ 12.91 (s, 1H), 8.64 (d, J = 7.3 Hz,

1H), 8.33 (dd, J = 7.4, 1.1 Hz, 1H), 7.95−7.86 (m, 3H), 7.44 (d, J =

7.4 Hz, 1H), 6.98 (d, J = 7. Eight Hz, 1H), 3.91 (s, 3H). ¹³C NMR (101

MHz, DMSO-d₆) δ 162.6, 159.4, 151.9, 143.6, 140.2, 133.4, 131.5, 128.6,

127.9, 127.2, 125.9, 117.0, 110.7, 53.3. MS calcd for C₁₄H₁₁N₃O₂[M]⁺=

253, found [M + H]⁺= 254; [2M + Na]⁺= 529. HRMS calcd for

C₁₄H₁₁N₃O₂[M + H]⁺= 254.09240, found [M + H]⁺= 254.09267.

Mp = 249 °C.

4-(4-Methylthiophen-2-yl)phthalazin-1(2H)-one (7h) and 4-(3-

Methylthiophen-2-yl)phthalazin-1(2H)-one (7i). Following the gen-

eral procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-

one (7b), these compounds was prepared using a mixture of 2-

(dimethylamino)-3-hydroxy-3-(4-methylthiophen-2-yl)isoindolin-1-

one and 2-(dimethylamino)-3-hydroxy-3-(3-methylthiophen-2-yl)-

isoindolin-1-one (7.7 g, 27 mmol) from the previous step, EtOH

(27 mL), and hydrazine (13 mL, 0.40 mol). Following similar workup

procedure provided a mixture of phthalazinones that were separated

by prep-HPLC.

1

1(2H)-one (0.35 g, 93% yield). H NMR (400 MHz, DMSO-d₆) δ

12.95 (s, 1H), 8.62 (s, 1H), 8.44 (d, J = 6.8 Hz, 1H), 8.35 (d, J =

6.8 Hz, 1H), 7.95−7.77 (m, 4H), 2.44 (s, 3H). ¹³C NMR (101 MHz,

DMSO-d₆) δ 160.3, 151.7, 149.2, 145.7, 137.7, 133.6, 133.5, 131.5,

129.3, 128.4, 127.8, 126.6, 123.8, 18.4. FT-IR (thin ﬁlm, cm⁻¹) 1672.

MS calcd for C₁₄H₁₁N₃O [M]⁺= 237, found [M + H]⁺= 238. HRMS

calcd for C₁₄H₁₁N₃O [M + H]⁺= 238.0975, [M + Na]⁺= 260.0794,

found [M + H]⁺= 238.0984, [M + Na]⁺= 260.0795. Mp = 247−

248 °C.

4-(4-Methylthiophen-2-yl)phthalazin-1(2H)-one (7h). Major iso-

mer was obtained as a brown solid (2.9 g, 45% yield). ¹H NMR

showed the desired isomer. Two singlets for thiophene were evident at

1

7.2 and 7.1 ppm. H NMR (600 MHz, DMSO-d₆) δ 12.89 (s, 1H),

4-(4-Methylpyridin-2-yl)phthalazin-1(2H)-one (7d). Following the

general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-

one (7b), this compound was prepared using 2-(dimethylamino)-3-

hydroxy-3-(4-methylpyridin-2-yl)isoindolin-1-one (0.50 g, 1.8 mmol),

hydrazine (1.1 g, 35 mmol) and ethanol (8.8 mL). Similar workup

provided 1-chloro-4-(4-methylpyridin-2-yl)phthalazine as a light

8.34 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.99 (t, J = 7.2 Hz,

1H), 7.92 (t, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.33 (s, 1H), 2.31 (s, 3H).

¹³C NMR (151 MHz, DMSO-d₆) δ 158.9, 140.4, 137.9, 136.7, 134.0,

131.9, 130.8, 128.3, 127.8, 126.30, 126.27, 122.9, 15.6. FT-IR (thin

ﬁlm, cm⁻¹) 2928, 1655. HRMS calcd for C₁₃H₁₀N₂OS [M]⁺

=

yellow solid (0.39 g, 93% yield). H NMR (400 MHz, DMSO-d₆) δ

242.0514, found [M + H]⁺= 243.0537. Mp = 238−239 °C.

1

12.91 (s, 1H), 8.59−8.58 (d, 1H), 8.36−8.31 (m, 2H), 7.91−7.84 (m,

2H), 7.66 (s, 1H), 7.36−7.35 (M, 1H), 2.41 (s, 3H). ¹³C NMR (101

MHz, DMSO-d₆) δ 159.2. 154.0, 148.1, 148.0, 143.8, 133.0, 131.3,

128.4, 127.7, 127.2, 125.5, 124.4, 124.4, 20.4. FT-IR (thin ﬁlm, cm⁻¹)

3180, 3045, 1660, 1604, 1557, 1471, 1336. MS calcd for C₁₄H₁₁N₃O₂

[M]⁺= 237, found [M + H]⁺= 238. HRMS calcd for C₁₄H₁₁N₃O₂

[M + H]⁺= 238.0975, [M + Na]⁺= 260.0794, found [M + H]⁺=

238.1007, [M + Na]⁺= 260.0823. Mp = 238−239 °C.

4-(3-Methylthiophen-2-yl)phthalazin-1(2H)-one (7i). Minor iso-

1

mer was obtained as a brown solid (0.93 g, 14% yield). H NMR

(600 MHz, DMSO-d₆) δ 12.96 (s, 1H), 8.33 (dd, J = 7.2, 0.6 Hz, 1H),

7.94−7.88 (m, 2H), 7.69 (d, J = 4.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H),

7.10 (d, J = 4.8 Hz, 1H), 2.09 (s, 3H). ¹³C NMR (151 MHz, DMSO-

d₆) δ 159.6, 140.8, 137.6, 134.3, 132.3, 130.6, 130.0, 129.8, 127.9,

126.90, 126.87, 126.4, 15.0. COSY (600 MHz, DMSO-d₆) showed two

doublets at 7.54 and 7.10 ppm that were correlated with one another.

FT-IR (thin ﬁlm, cm⁻¹) 1659. HRMS calcd for C₁₃H₁₀N₂OS [M +

H]⁺= 243.0514, found [M + H]⁺= 243.0536. mp =208−209 °C.

4-(5-Methylthiophen-2-yl)phthalazin-1(2H)-one (7j). Following

the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-

1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)-

3-hydroxy-3-(5-methylthiophen-2-yl)isoindolin-1-one (1.1 g, 0.40 mmol),

hydrazine (0.19 mL, 59 mmol) and 4.0 mL of EtOH. Similar workup

provided a white solid, 4-(5-methylthiophen-2-yl)phthalazin-1(2H)-

one (0.82 g, 85% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.57 (s, 1H),

8.50−8.39 (m, 1H), 8.14−8.04 (m, 1H), 7.83−7.69 (m, 2H),

7.20−7.17 (m, 1H), 6.82−6.71 (m, 1H), 2.47 (s, 3H). ¹³C NMR

(101 MHz, CDCl₃) δ 159.9, 142.5, 141.1, 134.3, 133.7, 131.7, 129.4,

128.8, 128.3, 127.1, 126.6, 125.8, 15.4. FT-IR (thin ﬁlm, cm⁻¹) 2891,

1660, 1334. MS calcd for C₁₃H₁₀N₂OS [M]⁺= 242, found [M + H]⁺=

243. HRMS calcd for C₁₃H₁₀N₂OS [M + H]⁺= 243.0587, found

[M + H]⁺= 243.0581. Mp = 191−194 °C.

4-(5-Ethylthiophen-2-yl)phthalazin-1(2H)-one (7k). Following the

general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-

1(2H)-one (7b), this compound was prepared using 2-(dimethyl-

amino)-3-(5-ethylthiophen-2-yl)-3-hydroxyisoindolin-1-one (3.2 g,

11 mmol), EtOH (21 mL), and hydrazine (5.0 mL, 0.16 mol).

Similar workup provided a light yellow solid, 4-(5-ethylthiophen-2-

yl)phthalazin-1(2H)-one (2.3 g, 86% yield). ¹H NMR (400 MHz,

CDCl₃) δ 12.8, (s, 1H), 8.34 (d, J = 6.8 Hz, 1H), 8.18 (d, J = 7.8 Hz,

1H), 7.98−7.88 (m, 2H), 7.41 (d, J = 3.6 Hz, 1H), 6.97 (d, J = 3.8 Hz,

1H), 2.88 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H). ¹³C NMR (101

MHz, CDCl₃) δ 158.4, 148.6, 140.4, 134.2, 133.9, 131.8, 123.4, 128.3,

127.8, 126.2, 126.1, 124.4, 22.7, 15.8. FT-IR (thin ﬁlm, cm⁻¹) 1662.

MS calcd for C₁₄H₁₂N₂OS [M]⁺= 256, found [M + H]⁺= 257. HRMS

calcd for C₁₄H₁₂N₂OS [M + H]⁺= 257.0743, [M + Na]⁺= 279.0563,

found [M + H]⁺= 257.0752, [M + Na]⁺= 279.0568. Mp = 198−

200 °C.

4-(6-Methylpyridin-3-yl)phthalazin-1(2H)-one (7e). Following the

general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-

one (7b), this compound was prepared using 2-(dimethylamino)-3-

hydroxy-3-(6-methylpyridin-3-yl)isoindolin-1-one (0.50 g, 1.8 mmol),

hydrazine (1.1 mL, 35 mmol), and ethanol (8.8 mL). Similar workup

provided a yellow solid, 4-(6-methylpyridin-3-yl)phthalazin-1(2H)-one

1

(0.40 g, 96% yield). H NMR (400 MHz, DMSO-d₆) δ 12.93 (s, 1H),

8.65 (s, 1H), 8.35 (m, 1H), 7.92 (m, 3H), 7.67 (m, 1H), 7.45−7.43 (m,

1H), 2.58 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 158.8, 158.1,

148.5, 143.6, 136.7, 133.3, 131.4, 128.5, 127.7, 127.4, 125.9, 125.7, 122.3,

23.5. FT-IR (thin ﬁlm, cm⁻¹) 2917, 2849, 2357, 1652, 1558, 1539, 1455.

MS calcd for C₁₄H₁₁N₃O [M]⁺= 237, found [M + H]⁺= 238. HRMS

calcd for C₁₄H₁₁N₃O [M + H]⁺= 238.0975, [M + Na]⁺= 260.0794,

found [M + H]⁺= 238.1000, [M + Na]⁺= 260.0816. Mp > 250 °C.

4-(5-Chloropyridin-2-yl)phthalazin-1(2H)-one (7f). Following the

general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-

one (7b), this compound was prepared using 3-(5-chloropyridin-2-yl)-2-

(dimethylamino)-3-hydroxyisoindolin-1-one (2.0 g, 6.6 mmol), ethanol

(6.6 mL), and hydrazine (3.1 mL, 99 mmol). Similar workup provided an

oﬀ-white solid, 4-(5-chloropyridin-2-yl)phthalazin-1(2H)-one (1.0 g, 94%

1

yield). H NMR (400 MHz, CDCl₃) δ 8.79 (d, J = 2.5 Hz, 1H), 8.39−

8.32 (m, 2H), 8.12 (dd, J = 6.1, 2.5 Hz, 1H), 7.93−7.86 (m, 3H). ¹³C

NMR (101 MHz, CDCl₃) δ 159.3, 152.9, 147.1, 142.8, 137.4, 133.4,

131.7, 131.3, 128.3, 127.9, 127.3, 125.9, 125.4. FT-IR (thin ﬁlm, cm⁻¹)

1688, 1668. MS calcd for C₁₃H₈ClN₃O [M]⁺= 257, found [M + H]⁺=

258. HRMS calcd for C₁₃H₈ClN₃O [M + H]⁺= 258.0429, [M + Na]⁺=

280.0248, found [M + H]⁺= 258.0414, [M + Na]⁺= 280.0249. Mp >

250 °C.

4-(6-Methoxypyridin-2-yl)phthalazin-1(2H)-one (7g). Following

the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-

1(2H)-one (7b), this compound was prepared using 2-(dimethylamino)-

3-hydroxy-3-(6-methoxypyridin-2-yl)isoindolin-1-one (4.2 g, 14 mmol),

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4-(Benzo[b]thiophen-2-yl)phthalazin-1(2H)-one (7l). Following

the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-

1(2H)-one (7b), this compound was prepared using 3-(benzo[b]-

thiophen-2-yl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (0.70 g,

2.3 mmol), and hydrazine (1.1 mL, 35 mmol) in 2.3 mL EtOH.

Similar workup provided 4-(benzo[b]thiophen-2-yl)phthalazin-1(2H)-

[M + Na]⁺= 279.0296, found [M + H]⁺= 257.0480, [M + Na]⁺=

279.0301. Mp > 250 °C.

4-(4-tert-Butylphenyl)phthalazin-1(2H)-one (7q). Following the

general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-

1(2H)-one (7b), this compound was prepared using 3-(4-tert-

butylphenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (3.5 g,

11 mmol), ethanol (11 mL), and anhydrous hydrazine (5.2 mL,

0.16 mol). Similar workup provided 4-(4-tert-butylphenyl)phthalazin-

1

one as a gray solid (0.61 g, 95% yield). H NMR (400 MHz, DMSO-

d₆) δ ppm 13.02 (s, 1H), 8.26−8.51 (m, 2H), 7.82−8.16 (m, 5H),

7.30−7.59 (m, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 158.9,

140.1, 139.7, 138.9, 137.5, 134.1, 132.0, 128.1, 127.7, 126.3, 126.0,

125.4, 125.3, 124.7, 124.5, 122.2. FT-IR (thin ﬁlm, cm⁻¹) 3155, 1656.

HRMS calcd for C₁₆H₁₁N₂OS [M + H]⁺= 279.0592, found [M + H]⁺=

279.0588. Mp = 246−247 °C.

4-(5-Methylthiazol-2-yl)phthalazin-1(2H)-one (7m). Following

the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-

1(2H)-one (7b), this compound was prepared using 2-(dimethylami-

no)-3-hydroxy-3-(5-methylthiazol-2-yl)isoindolin-1-one (0.92 g,

0.32 mmol), hydrazine (0.20 mL, 64 mmol), and ethanol (16 mL). Similar

workup provided 4-(5-methylthiazol-2-yl)phthalazin-1(2H)-one as a

light yellow solid (0.70 g, 90% yield). ¹H NMR (400 MHz, DMSO-d₆)

δ 13.04 (s, 1H), 9.35−9.33 (m, 1H), 8.31−8.29 (m, 1H), 8.01−7.97

(m, 1H), 7.92−7.87 (m, 1H), 7.72−7.71 (m, 1H), 2.50 (s, 3H). ¹³C

NMR (101 MHz, DMSO-d₆) δ 163.5, 159.2, 141.5, 137.7, 135.7,

133.9, 131.9, 127.6, 127.3, 127.0, 126.0, 11.5. FT-IR (thin ﬁlm, cm⁻¹)

3028, 2896, 1665, 1607, 1577, 1450, 1336. MS calcd for C₁₂H₉N₃OS

[M]⁺= 243, found [M + H]⁺= 244. HRMS calcd for C₁₂H₉N₃OS

[M + H]⁺= 244.0539, [M + Na]⁺= 266.0359, found [M + H]⁺=

244.0560, [M + Na]⁺= 266.0380. Mp = 230 °C.

1

1(2H)-one as an oﬀ-white solid (2.6 g, 87% yield). H NMR (400

MHz, DMSO-d₆) δ 12.82 (s, 1H), 8.35−8.32 (m, 1H), 7.92−7.86 (m,

2H), 7.72−7.70 (m, 1H), 7.58−7.51 (m, 4H), 1.35 (s, 9H). ¹³C NMR

(101 MHz, DMSO-d₆) δ ppm 159.2, 151.4, 146.3, 133.5, 132.2, 131.5,

129.0, 127.9, 126.6, 126.0, 125.3, 34.5, 31.1. FT-IR (thin ﬁlm, cm⁻¹)

2950, 2865, 1659, 1605, 1492, 1455, 1341. MS calcd for C₁₈H₁₈N₂O

[M]⁺= 278.3, found [M + H]⁺= 279.1. HRMS calcd for C₁₈H₁₈N₂O

[M + H]⁺= 279.1492, [M + Na]⁺= 301.1311, found [M + H]⁺=

279.1504, [M + Na]⁺= 301.1319. Mp > 250 °C.

4-m-Tolylphthalazin-1(2H)-one (7r). Following the general

procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one

(7b), this compound was prepared using 2-(dimethylamino)-3-

hydroxy-3-m-tolylisoindolin-1-one (1.00 g, 0.35 mmol), hydrazine

(2.2 mL, 71 mmol), and EtOH (18 mL). Similar workup provided 4-

m-tolylphthalazin-1(2H)-one as a light yellow solid (0.73 g, 87%

1

yield). H NMR (400 MHz, DMSO-d₆) δ 12.75 (s, 1H), 8.34−8.32

(m, 1H), 7.89−7.87 (m, 2H), 7.68−7.66 (m, 1H), 7.45−7.43 (m, 4H),

2.39 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 159.6, 146.9, 138.3,

135.2, 134.0, 132.0, 130.2, 130.0, 129.4, 128.8, 128.3, 127.0, 126.8,

126.5, 21.4. FT-IR (thin ﬁlm, cm⁻¹) 2900, 1669, 1341. MS calcd for

C₁₅H₁₂N₂O [M]⁺= 236, found [M + H]⁺= 237. HRMS calcd for

C₁₅H₁₂N₂O [M + H]⁺= 237.1022, found [M + H]⁺= 237.1033. Mp =

210−211 °C.

4-(4-Methylthiazol-2-yl)phthalazin-1(2H)-one (7n). Following the

general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-

one (7b), this compound was prepared using 2-(dimethylamino)-3-

hydroxy-3-(4-methylthiazol-2-yl)isoindolin-1-one (3.4 g, 12 mmol),

ethanol (23 mL), and hydrazine (5.5 mL, 0.17 mol). Similar workup

provided 4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one as a light yellow

4-(3-(Triﬂuoromethyl)phenyl)phthalazin-1(2H)-one (7s). Follow-

ing the general procedure to prepare 4-(6-methylpyridin-2-yl)-

phthalazin-1(2H)-one (7b), this compound was prepared using 2-

(dimethylamino)-3-hydroxy-3-(3-(triﬂuoromethyl)phenyl)isoindolin-

1-one (0.80 g, 2.4 mmol), hydrazine (1.5 mL, 48 mmol), and ethanol

(12 mL). Similar workup provided 4-(3-(triﬂuoromethyl)phenyl)-

1

solid (2.4 g, 85% yield). H NMR (400 MHz, CDCl₃) δ 13.0 (s, 1H),

9.41 (d, J = 8.1 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.06−8.02 (m, 1H),

7.93 (t, J = 7.3 Hz, 1H), 7.44 (s, 1H), 2.52 (s, 3H). ¹³C NMR (101 MHz,

CDCl₃) δ 164.3, 159.2, 153.0, 137.7, 134.0, 131.9, 127.6, 127.3, 127.0,

126.0, 116.2, 17.1. FT-IR (thin ﬁlm, cm⁻¹) 1656. MS calcd for

C₁₂H₉N₃OS [M]⁺= 243, found [M + H]⁺= 244. HRMS calcd for

C₁₂H₉N₃OS [M + H]⁺= 244.0539, [M + Na]⁺= 266.0359, found [M +

H]⁺= 244.0561, [M + Na]⁺= 266.0373. Mp > 250 °C.

1

phthalazin-1(2H)-one as a light yellow solid (0.61 g, 88% yield). H

NMR (400 MHz, DMSO-d₆) δ 12.85 (s, 1H), 8.36−8.34 (m, 1H),

7.93−7.87 (m, 5H), 7.82−7.78 (m, 1H), 7.61−7.65 (m, 1H). ¹³C

NMR (101 MHz, DMSO-d₆) δ 160.0, 145.5, 136.6, 134.2, 134.0,

132.2, 130.1, 130.0, 129.7, 129.2, 128.3, 126.6, 126.3, 126.0, 125.8. FT-

IR (thin ﬁlm, cm⁻¹) 3178, 3032, 2359, 2337, 1695, 1652, 1558, 1324.

MS calcd for C₁₅H₉F₃N₂O [M]⁺= 290, found [M + H]⁺= 291.

HRMS calcd for C₁₅H₉F₃N₂O [M + H]⁺= 291.0740, [M + Na]⁺=

313.0559, found [M + H]⁺= 291.0762, [M + Na]⁺= 313.0577. Mp =

259−260 °C.

4-(4,5-Dimethylthiazol-2-yl)phthalazin-1(2H)-one (7o). Following

the general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-

1(2H)-one (7b), this compound was prepared using 2-(dimethylami-

no)-3-(4,5-dimethylthiazol-2-yl)-3-hydroxyisoindolin-1-one (3.7 g,

12 mmol), ethanol (25 mL), and hydrazine (5.8 mL, 0.19 mol).

Similar workup provided 4-(4,5-dimethylthiazol-2-yl)phthalazin-1(2H)-

4-(4-Chloro-3-methoxyphenyl)phthalazin-1(2H)-one (7t). Follow-

ing the general procedure to prepare 4-(6-methylpyridin-2-yl)-

phthalazin-1(2H)-one (7b), this compound was prepared using 3-(4-

chloro-3-methoxyphenyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-

one (0.76 g, 2.3 mmol), ethanol (4.6 mL), and hydrazine (1.1 mL, 34

mmol). Similar workup provided 4-(4-chloro-3-methoxyphenyl)-

1

one as a light yellow solid (3.1 g, 98% yield). H NMR (400 MHz,

DMSO-d₆) δ 13.0 (s, 1H), 9.38 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 7.3 Hz,

1H), 8.02−7.99 (m, 1H), 7.90 (t, J = 7.4 Hz, 1H), 2.38 (s, 3H), 2.39 (s,

3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 160.3, 159.1, 148.9, 137.6,

133.9, 131.8, 128.8, 127.6, 127.3, 127.1, 125.9, 14.8, 10.9. FT-IR (thin

ﬁlm, cm⁻¹) 1663. MS calcd for C₁₃H₁₁N₃OS [M]⁺= 257, found [M +

H]⁺= 258. HRMS calcd for C₁₃H₁₁N₃OS [M + H]⁺= 258.0696, [M +

Na]⁺= 280.0515, found [M + H]⁺= 258.0724, [M + Na]⁺= 280.0528.

Mp > 250 °C.

1

phthalazin-1(2H)-one as a light yellow solid (0.53 g, 81% yield). H

NMR (400 MHz, DMSO-d₆) δ 12.9 (br s, 1H), 8.34 (m, 1H), 7.91

(m, 2H), 7.75 (m, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 7.16 (d,

J = 7.9 Hz, 1H), 3.90 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ

159.2, 154.5, 145.5, 135.3, 133.7, 131.7, 129.8, 128.9, 127.8, 126.6,

126.0, 122.3, 121.8, 113.8, 56.3. FT-IR (thin ﬁlm, cm⁻¹) 1695. MS

calcd for C₁₅H₁₁ClN₂O₂[M]⁺= 286, found [M + H]⁺= 287. HRMS

calcd for C₁₅H₁₁ClN₂O₂[M + H]⁺= 287.0582, [M + Na]⁺= 309.0401,

found [M + H]⁺= 287.0604, [M + Na]⁺= 309.0416. Mp >250 °C.

4-Isopropylphthalazin-1(2H)-one (7u). Following the general

procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one

(7b), this compound was prepared using 2-(dimethylamino)-3-hydroxy-

3-isopropylisoindolin-1-one (2.1 g, 8.8 mmol), ethanol (8.8 mL), and

hydrazine (4.1 mL, 0.13 mol). An additional 3 mL of anhydrous

hydrazine was added to ensure complete consumption of starting material.

Similar workup provided a white solid, 4-isopropylphthalazin-1(2H)-one

(1.5 g, 92% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (s, 1H), 8.29

4-(4-Chlorophenyl)phthalazin-1(2H)-one (7p). Following the

general procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-

1(2H)-one (7b), this compound was prepared using 3-(4-chlorophen-

yl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (9.9 g, 33 mmol),

ethanol (65 mL), and hydrazine (15 mL, 0.49 mol). An additional

5 mL of hydrazine was added to ensure complete consumption of

starting material. Similar workup provided a light yellow solid, 4-(4-chloro-

1

phenyl)phthalazin-1(2H)-one (7.9 g, 94% yield). H NMR (400 MHz,

DMSO-d₆) δ 12.9 (br s, 1H), 8.35−8.33 (m, 1H), 7.92−7.87 (m, 2H),

7.68−7.60 (m, 4H). ¹³C NMR (101 MHz, DMSO-d₆) δ 159.2, 145.3,

133.9, 133.8, 133.6, 131.7, 131.2, 128.8, 128.6, 127.8, 126.3, 126.1. FT-IR

(thin ﬁlm, cm⁻¹) 1670. MS calcd for C₁₄H₉ClN₂O [M]⁺= 256, found

[M + H]⁺= 257. HRMS calcd for C₁₄H₉ClN₂O [M + H]⁺= 257.0476,

3900

dx.doi.org/10.1021/jo3000628 | J. Org. Chem. 2012, 77, 3887−3906

The Journal of Organic Chemistry

Article

(d, J = 7.5 Hz, 1H), 8.06 (s, J = 8.3 Hz, 1H), 7.95 (t, J = 7.3 Hz, 1H), 7.85

(t, J = 7.0 Hz, 1H), 3.58 (sep, J = 6.3 Hz, 1H), 1.29 (d, J = 6.5 Hz, 6H).

¹³C NMR (101 MHz, DMSO-d₆) 159.2, 150.0, 133.5, 131.2, 128.7, 127.8,

126.1, 124.7, 39.5, 21.4. FT-IR (thin ﬁlm, cm⁻¹) 3178, 3052, 2968, 2929,

1656, 1594, 1468, 1350, 1158, 1017, 781, 752, 686. MS calcd for

C₁₁H₁₂N₂O [M]⁺= 188, found [M + H]⁺= 189; [2M + H]⁺= 399.1.

(d, J = 8.1 Hz, 1H), 8.21 (t, J = 7.1 Hz, 1H), 8.15 (t, J = 7.1 Hz, 1H),

7.98 (s, 1H), 7.55 (d, J = 4.6 Hz, 1H), the methyl group was

overlapped with the DMSO peaks. MS calcd for C₁₄H₁₀ClN₃[M]⁺=

255 Found [M + H]⁺= 256. HRMS calcd for C₁₄H₁₀ClN₃[M + H]⁺=

256.0636, found [M + H]⁺= 256.0622.

1-Chloro-4-(6-methylpyridin-3-yl)phthalazine (1e). Following the

general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(6-methylpyr-

idin-3-yl)phthalazin-1(2H)-one (0.15 g, 0.63 mmol) and POCl₃(0.71 mL,

7.6 mmol). Similar workup provided 1-chloro-4-(6-methylpyridin-3-

yl)phthalazine (0.12 g, 74% yield). ¹H NMR (400 MHz, DMSO-d₆) δ

8.77 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.21−8.01 (m, 4H), 7.51 (d,

J = 7.7 Hz, 1H), 2.61 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ

160.0, 158.5, 154.6, 150.0, 138.3, 135.2, 135.0, 128.8, 127.3, 127.2,

125.9, 125.6, 123.5, 24.6. FT-IR (thin ﬁlm, cm⁻¹) 1599, 1389, 1353,

1291. MS calcd for C₁₄H₁₀ClN₃[M]⁺= 255, found [M + H]⁺= 256.

HRMS calcd for C₁₄H₁₀ClN₃[M + H]⁺= 256.0636, [M + Na]⁺=

278.0456, found [M + H]⁺= 256.0627, [M + Na]⁺= 278.0441. Mp =

186−187 °C.

1-Chloro-4-(5-chloropyridin-2-yl)phthalazine (1f). Following the

general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(5-chloropyr-

idin-2-yl)phthalazin-1(2H)-one (1.6 g, 6.2 mmol) and phosphoryl

trichloride (9.8 mL, 0.11 mol). Similar workup provided a brown solid,

1-chloro-4-(5-chloropyridin-2-yl)phthalazine (1.4 g, 82% yield). ¹H

NMR (400 MHz, CDCl₃) δ 8.89 (d, J = 7.3 Hz, 1H), 8.78 (d, J = 2.3

Hz, 1H), 8.41 (d, J = 7.4 Hz, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.05−7.93

(m, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 155.9, 155.6, 153.2, 147.6,

137.2, 133.6, 133.3, 133.2, 127.6, 126.8, 126.6, 126.5, 125.3. FT-IR

(thin ﬁlm, cm⁻¹) 1574, 1557, 1295. MS calcd for C₁₃H₇Cl₂N₃[M]⁺=

275, found [M + H]⁺= 276, [2M + Na]⁺= 575. HRMS calcd for

C₁₃H₇Cl₂N₃[M + H]⁺= 276.0090, [M + Na]⁺= 297.9909, found

[M + H]⁺= 276.0089, [M + Na]⁺= 297.9910. Mp = 180−182 °C.

1-Chloro-4-(6-methoxypyridin-2-yl)phthalazine (1g). Following

the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(6-methoxy-

pyridin-2-yl)phthalazin-1(2H)-one (2.8 g, 11 mmol) and POCl₃

(12 mL, 0.13 mol). Similar workup provided a tan solid, 1-chloro-4-

(6-methoxypyridin-2-yl)phthalazine (3.0 g, 99% yield). ¹H NMR

(400 MHz, CDCl₃) δ 8.92 (d, J = 8.0 Hz, 1H), 8.44 (d, J = 8.1 Hz, 1H),

8.07−8.00 (m, 2H), 7.88−7.81 (m, 2H), 6.99 (d, J = 7.9 Hz, 1H), 4.01

(s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.9, 156.9, 154.6, 151.7,

140.4, 134.3, 127.4, 126.4, 125.6, 124.9, 118.4, 111.7, 80.7, 53.5. MS

calcd for C₁₄H₁₀ClN₃O [M]⁺= 271, found [M + H]⁺= 272; [2M +

Na]⁺= 565. HRMS calcd for C₁₄H₁₀ClN₃O [M + H]⁺= 272.0585,

[M + Na]⁺= 294.0421, found [M + H]⁺= 272.0600; [M + Na]⁺=

294.0421. Mp > 250 °C.

HRMS calcd for C₁₁H₁₂N₂O [M + H]⁺= 189.1022, [M + Na]⁺

=

211.0842, found [M + H]⁺= 189.1070; [M + H]⁺= 211.0888. Mp =

164−165 °C.

4-Cyclohexylphthalazin-1(2H)-one (7v). Following the general

procedure to prepare 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one

(7b), this compound was prepared using 3-cyclohexyl-2-(dimethyla-

mino)-3-hydroxyisoindolin-1-one (1.3 g, 4.7 mmol), ethanol (4.7 mL),

and hydrazine (4.4 mL, 0.14 mol). Similar workup procedure provided

an oﬀ-white solid, 4-cyclohexylphthalazin-1(2H)-one (0.96 g, 90%

1

yield). H NMR (400 MHz, CDCl₃) δ 10.35 (s, 1H), 8.51 (d, J = 7.8

Hz, 1H), 7.90−7.75 (m, 3H), 3.12 (distorted t, J = 11.3 Hz, 1H),

2.00−1.31 (m, 10H). ¹³C NMR (101 MHz, DMSO-d₆) 159.2, 149.6,

13.4, 131.2, 128.7, 127.8, 126.1, 124.6, 40.2, 38.5, 31.6, 25.9. MS calcd

for C₁₄H₁₆N₂O [M]⁺= 228, found [M + H]⁺= 229; [2M + H]⁺=

479. HRMS calcd for C₁₄H₁₆N₂O [M + H]⁺= 229.1335, [M + Na]⁺=

251.1155, found [M + H]⁺= 229.1368; [M + Na]⁺= 251.1189. FT-IR

(thin ﬁlm, cm⁻¹) 3178, 3049, 2928, 2853, 1657, 1449, 1346, 783, 768,

684. Mp = 201−202 °C.

General Procedure To Prepare Chlorophthalazines. 1-Chloro-

4-(6-methylpyridin-2-yl)phthalazine (1b). A dry round-bottom

ﬂask equipped with a stirring bar and a reﬂux condenser was

charged with 4-(6-methylpyridin-2-yl)phthalazin-1(2H)-one

(0.78 g, 3.3 mmol) and POCl₃(11 mL, 0.12 mol). After

reﬂuxing for 18 h, excess POCl₃was removed under vacuum

with the aid of toluene. The residue was cooled to 0 °C and

basiciﬁed with cold 6 N NaOH until pH = 9. Occasionally, ice

was added to keep the mixture cold. It is very critical to keep

the reaction mixture cold during the work up at all times to

avoid the hydrolysis of the product back to phthalazinone.

Stirring, agitation, and sonication would eventually provide a

solid. This solid was ﬁltered and washed quickly with ample

amount of water. The solid was quickly transferred into a ﬂask

and dried under vacuum to aﬀord a white solid (0.67 g, 80%

yield). ¹H NMR (400 MHz, CDCl₃) δ 8.74 (dd, J = 9.3, 1.5 Hz,

1H), 8.40 (dd, J = 9.6 Hz, 7.8 Hz, 1H), 7.92−8.07 (m, 3H),

7.87 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 2.73 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 157.8, 137.9, 133.4, 133.2,

127.9, 127.2, 125.2, 124.0, 122.8, 77.4, 77.2, 77.0, 76.7, 24.4.

FT-IR (thin ﬁlm, cm⁻¹) 3070, 1597, 1532, 1458, 1393, 1285,

832, 775. MS calcd for C₁₄H₁₀ClN₃[M]⁺= 255, found [M +

H]⁺= 256. HRMS calcd for C₁₄H₁₀ClN₃[M + H]⁺= 256.0636,

found [M + H]⁺= 256.0630. Mp = 138−140 °C.

1-Chloro-4-(4-methylthiophen-2-yl)phthalazine (1h). Following

the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(4-methyl-

thiophen-2-yl)phthalazin-1(2H)-one (2.8 g, 12 mmol) and POCl₃(19

mL, 0.20 mol). Similar workup provided a tan solid, 1-chloro-4-(4-

methylthiophen-2-yl)phthalazine (2.8 g, 93% yield). Note: If a mixture

of phthalazinones 7h and 7i was carried on to this chlorination step,

the major isomer 1-chloro-4-(3-methylthiophen-2-yl)phthalazine 1h

could be separated cleanly from the minor isomer 1i by

1-Chloro-4-(5-methylpyridin-2-yl)phthalazine (1c). Following the

general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(5-methylpyr-

idin-2-yl)phthalazin-1(2H)-one (0.35 g, 1.5 mmol) and POCl₃

(1.7 mL, 18 mmol). Similar workup provided a grayish green solid,

1

1-chloro-4-(5-methylpyridin-2-yl)phthalazine (0.17 g, 45% yield). H

NMR (600 MHz, DMSO-d₆) δ 8.72 (d, J = 7.8 Hz, 1H), 8.0 (s, 1H),

8.31 (d, J = 3.6 Hz, 1H), 8.06−8.04 (m, 1H), 8.03−7.98 (m, 2H), 7.80

(dd, J = 7.8, 1.2 Hz, 1H), 2.44 (s, 3H). ¹³C NMR (151 MHz, DMSO-

d₆) δ 156.6, 154.4, 151.4, 148.7, 137.6, 133.9, 133.4, 133.3, 127.5,

126.4, 125.7, 124.55, 124.51, 17.9. FT-IR (thin ﬁlm, cm⁻¹) 1570, 1352,

1292. MS calcd for C₁₄H₁₀ClN₃[M]⁺= 255, found [M + H]⁺= 256.

HRMS calcd for C₁₄H₁₀ClN₃[M + H]⁺= 256.0636, [M + Na]⁺=

278.0456, found [M + H]⁺= 256.0659, [M + Na]⁺= 278.04602. Mp =

182 °C.

1-Chloro-4-(4-methylpyridin-2-yl)phthalazine (1d). Following the

general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using with 4-(4-

methylpyridin-2-yl)phthalazin-1(2H)-one (0.39 g, 1.6 mmol) and

POCl₃(31 mL, 0.33 mol). Similar workup provided 1-chloro-4-(4-

methylpyridin-2-yl)phthalazine (0.30 g, 71% yield). ¹H NMR (400 MHz,

DMSO-d₆) δ 8.71 (d, J = 5.1 Hz, 1H), 8.62 (d, J = 8.2 Hz, 1H), 8.41

1

recrystallization with EtOAc. H NMR (400 MHz, CDCl₃) δ 8.58−

8.55 (m, 1H), 8.42−8.39 (m, 1H), 8.08−8.01 (m, 2H), 7.57 (d, J = 1

Hz, 1H), 7.25 (distorted t, 1H), 2.41 (s, 3H). ¹³C NMR (151 MHz,

CDCl₃) δ 153.98, 153.93, 138.7, 136.3, 133.7, 133.5, 132.9, 126.6,

126.5, 126.4, 125.8, 125.6, 15.8. The structure was conﬁrmed by 2D

NMR. FT-IR (thin ﬁlm, cm⁻¹) 1609, 1290. HRMS calcd for C₁₃H₉-

ClN₂S [M]+H⁺= 261.0175, found [M + H]⁺= 261.0248. Mp = 155−

156 °C.

1-Chloro-4-(3-methylthiophen-2-yl)phthalazine (1i). Following

the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(3-methyl-

thiophen-2-yl)phthalazin-1(2H)-one (3.1 g, 13 mmol) and phosphoryl

trichloride (20 mL, 0.22 mol). Similar workup provided a yellow solid,

1-chloro-4-(3-methylthiophen-2-yl)phthalazine (3.2 g, 94% yield).

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¹H NMR (400 MHz, CDCl₃) δ 8.40−8.38 (m, 1H), 8.05−7.95 (m,

3H), 7.52 (d, J = 5.1 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 2.20 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 155.5, 154.7, 138.9, 133.52, 133.50,

130.5, 129.8, 128.2, 127.23, 127.22, 126.1, 125.5, 15.2. FT-IR (thin

ﬁlm, cm⁻¹) 1548, 1520, 1435, 1289, 732. MS calcd for C₁₃H₉ClN₂S

[M]⁺= 260, found [M + H]⁺= 261. HRMS calcd for C₁₃H₉ClN₂S

[M + H]⁺= 261.0247, [M + Na]⁺= 283.0067, found [M + H]⁺=

261.0267, [M + Na]⁺= 283.0076. Mp = 152−153 °C.

1-Chloro-4-(5-methylthiophen-2-yl)phthalazine (1j). Following

the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(5-methyl-

thiophen-2-yl)phthalazin-1(2H)-one (0.79 g, 3.3 mmol) and POCl₃

(11 mL, 114 mmol). Similar workup provided 1-chloro-4-(5-

methylthiophen-2-yl)phthalazine (0.81 g, 94% yield). ¹H NMR

(400 MHz, CDCl₃) δ 8.45−8.38 (m, 1H), 8.29−8.23 (m, 1H),

7.95−7.86 (m, 2H), 7.41 (d, J = 4.0, 1H), 6.86−6.81 (m, 1H), 2.52 (s,

3H). ¹³C NMR (101 MHz, CDCl₃) δ 154.1, 153.5, 144.8, 135.3, 133.5,

133.2, 130.5, 126.4, 126.4, 126.3, 125.6, 125.4, 15.6. FT-IR (thin ﬁlm,

cm⁻¹) 3073, 2917. MS calcd for C₁₃H₉ClN₂S [M]⁺= 260, found

[M + H]⁺= 261. HRMS calcd for C₁₃H₉ClN₂S [M + H]⁺= 261.0248,

[M + Na]⁺= 283.0057, found [M + H]⁺= 261.0244, [M + Na]⁺=

283.0057. Mp = 103−107 °C.

¹H NMR (400 MHz, CDCl₃) δ 9.84 (d, J = 8.0 Hz, 1H), 8.38 (d,

J = 7.9 Hz, 1H), 8.10−8.01 (m, 2H), 7.15 (s, 1H), 2.64 (s, 3H). ¹³C

NMR (101 MHz, CDCl₃) δ 164.9, 155.2, 154.6, 150.5, 134.1, 133.4,

127.7, 126.2, 125.4, 125.0, 117.7, 17.4. FT-IR (thin ﬁlm, cm⁻¹) 3090,

1520, 1461, 1289. MS calcd for C₁₂H₈ClN₃S [M]⁺= 261, found [M +

H]⁺= 262. HRMS calcd for C₁₂H₈ClN₃S [M + H]⁺= 262.0200, [M +

Na]⁺= 284.0020, found [M + H]⁺= 262.0203, [M + Na]⁺= 284.0016.

Mp = 152−153 °C.

1-Chloro-4-(4,5-dimethylthiazol-2-yl)phthalazine (1o). Following

the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(5-methyl-

thiazol-2-yl)phthalazin-1(2H)-one (3.1 g, 13 mmol) and phosphoryl

trichloride (18 mL, 0.19 mol). Similar workup provided a pink solid,

1-chloro-4-(4,5-dimethylthiazol-2-yl)phthalazine (2.9 g, 82% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.6 (d, J = 7.6 Hz, 1H), 7.1 (d, J = 7.1

Hz, 1H), 8.00 (t, J = 7.6 Hz, 2H), 2.49 (s, 3H), 2.47 (s, 3H). ¹³C NMR

(101 MHz, CDCl₃) δ 160.8, 154.9, 150.71, 150.67, 134.1, 133.3, 131.4,

128.0, 126.4, 125.6, 125.1, 15.1, 11.6. FT-IR (thin ﬁlm, cm⁻¹) 1521,

1463, 1289. MS calcd for C₁₃H₁₀ClN₃S [M]⁺= 275, found [M +

H]⁺= 276. HRMS calcd for C₁₃H₁₀ClN₃S [M + H]⁺= 276.0357, [M +

Na]⁺= 298.0176, found [M + H]⁺= 276.0327, [M + Na]⁺= 298.0177.

Mp = 148−150 °C.

1-Chloro-4-(5-ethylthiophen-2-yl)phthalazine (1k). Following the

general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(5-ethyl-

thiophen-2-yl)phthalazin-1(2H)-one (3.2 g, 13 mmol) and phosphoryl

trichloride (17 mL, 0.19 mol). Similar workup provided a light yellow

solid, 1-chloro-4-(5-ethylthiophen-2-yl)phthalazine (2.7 g, 79% yield).

¹H NMR (400 MHz, CDCl₃) δ 8.55−8.52 (m, 1H), 8.38−8.36 (m,

1H), 8.04−7.99 (m, 2H), 7.54 (d, J = 3.5 Hz, 1H), 6.97 (d, J = 3.8 Hz,

1H), 2.98 (q, J = 7.6 Hz, 2H), 1.41 (t, J = 7.6 Hz, 3H). ¹³C NMR

(101 MHz, CDCl₃) δ 153.9, 153.3, 152.3, 134.5, 133.4, 133.1, 130.3,

126.2, 126.1, 125.4, 124.4, 23.5, 15.7. FT-IR (thin ﬁlm, cm⁻¹) 2967,

1470. MS calcd for C₁₄H₁₁ClN₂S [M]⁺= 274, found [M + H]⁺= 275.

HRMS calcd for C₁₄H₁₁ClN₂S [M + H]⁺= 275.0404, [M + Na]⁺=

297.0223, found [M + H]⁺= 275.0407, [M + Na]⁺= 297.0218. Mp =

104−105 °C.

1-Chloro-4-(4-chlorophenyl)phthalazine (1p). Following the

general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(4-

chlorophenyl)phthalazin-1(2H)-one (7.9 g, 31 mmol) and phosphoryl

trichloride (43 mL, 0.46 mol). Similar workup provided light a yellow

1

solid, 1-chloro-4-(4-chlorophenyl)phthalazine (8.4 g, 99% yield). H

NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 8.1 Hz, 1H), 8.06−7.94 (m,

3H), 7.70 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H). ¹³C NMR (101

MHz, CDCl₃) δ 159.2, 154.7, 136.1, 133.7, 133.5, 133.4, 131.4, 129.0,

127.0, 126.6, 126.3, 125.6. FT-IR (thin ﬁlm, cm⁻¹) 1597, 1402, 1351,

1291, 1093. MS calcd for C₁₄H₈Cl₂N₂[M]⁺= 274, found [M + H]⁺=

275. HRMS calcd for C₁₄H₈Cl₂N₂[M + H]⁺= 275.0137, [M + Na]⁺=

296.9957, found [M + H]⁺= 275.0155, [M + Na]⁺= 296.9974. Mp =

199−200 °C.

1-(4-tert-Butylphenyl)-4-chlorophthalazine (1q). Following the

general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(4-tert-

butylphenyl)phthalazin-1(2H)-one (2.6 g, 9.3 mmol), phosphorus

oxychloride (8.7 mL, 93 mmol). Similar workup provided light yellow

precipitate that was further puriﬁed by trituration with ethyl acetate to

yield 1-(4-tert-butylphenyl)-4-chlorophthalazine (1.6 g, 58% yield) as

1-(Benzo[b]thiophen-2-yl)-4-chlorophthalazine (1l). Following

the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(benzo[b]-

thiophen-2-yl)phthalazin-1(2H)-one (0.50 g, 1.8 mmol) in phosphorus

oxychloride (2.9 mL, 31 mmol). This product was puriﬁed by silica gel

chromatography (MPLC, 40-g cartridge, 30−100% EtOAc in hexanes) to

aﬀord 1-(benzo[b]thiophen-2-yl)-4-chlorophthalazine (0.31 g, 58% yield)

1

an oﬀ-white solid. H NMR (400 MHz, DMSO-d₆) δ 8.39−8.37 (m,

1

1H), 8.21−8.17 (m, 1H), 8.14−8.10 (m, 1H), 8.08−8.06 (m, 1H),

7.69−7.64 (m, 4H), 1.38 (s, 9H). ¹³C NMR (101 MHz, DMSO-d₆) δ

ppm 159.99, 152.33, 140.61, 134.40, 134.21, 132.15, 129.76, 126.94,

126.56, 125.46, 125.36, 124.92, 78.72, 54.87, 34.61, 31.06. MS calcd

for C₁₈H₁₇ClN₂[M]⁺= 296.8, found [M + H]⁺= 297.1. HRMS calcd

for C₁₈H₁₇ClN₂[M + H]⁺= 297.1153, [M + Na]⁺= 319.0973, found

[M + H]⁺= 297.1155, [M + Na]⁺= 319.0968. Mp = 138−139 °C.

1-Chloro-4-m-tolylphthalazine (1r). Following the general proce-

dure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine (1b),

this compound was prepared using 4-m-tolylphthalazin-1(2H)-one

(0.50 g, 2.1 mmol) and POCl₃(65 g, 0.42 mol). Similar workup

as an orange solid. H NMR (400 MHz, DMSO-d₆) δ ppm 8.68 - 8.76

(m, 1H), 8.37 - 8.46 (m, 1H), 8.31 (s, 1H), 8.21 - 8.27 (m, 2H), 8.07 -

8.14 (m, 1H), 8.01 - 8.07 (m, 1H), 7.44 - 7.56 (m, 2H). ¹³C NMR (101

MHz, DMSO-d₆) δ ppm 153.7, 153.7, 140.0, 139.8, 137.5, 135.0, 134.5,

128.1, 126.2, 126.1, 125.7, 125.4, 125.3, 125.0, 124.9, 122.4. FT-IR (thin

ﬁlm, cm⁻¹) 1520, 1289, 1280, 984. HRMS calcd for C₁₆H₉ClN₂S [M +

H]⁺= 297.0250, found [M + H]⁺= 297.0249. Mp = 165−167 °C

2-(4-Chlorophthalazin-1-yl)-5-methylthiazole (1m). Following the

general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(4-methyl-

thiazol-2-yl)phthalazin-1(2H)-one (0.20 g, 0.82 mmol) and POCl₃

(0.92 mL, 9.9 mmol). Similar workup provided 1-chloro-4-

(4-methylthiazol-2-yl)phthalazine (0.19 g, 88% yield). ¹H NMR

(400 MHz, CDCl₃) δ 9.65−9.63 (m, 1H), 8.27−8.25 (m, 1H), 8.00−

7.92 (m, 2H), 7.68 (s, 1H), 2.52 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ

163.5, 154.8, 150.2, 142.0, 138.2, 134.1, 133.3, 127.4, 126.0, 125.2, 124.9,

11.8. FT-IR (thin ﬁlm, cm⁻¹) 1519, 1442, 1341, 1289, 1112. MS calcd for

C₁₂H₈ClN₃S [M]⁺= 261, found [M + H]⁺= 262. HRMS calcd for

C₁₂H₈ClN₃S [M + H]⁺= 262.0200, [M + Na]⁺= 284.0020, found [M +

H]⁺= 262.0213, [M + Na]⁺= 284.0013. Mp = 151−152 °C.

1

provided 1-chloro-4-m-tolylphthalazine (0.45 g, 84% yield). H NMR

(400 MHz, CDCl₃) δ 8.38−8.36 (d, 1H), 8.09−8.07 (d, 1H), 8.02,

7.98 (m, 1H), 7.94−7.90 (m, 1H), 7.54 (s, 1H), 7.50−7.43 (m, 2H),

7.38−7.36 (m, 1H), 2.47 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ

160.1, 154.0, 138.1, 134.8, 132.8, 132.8, 130.3, 130.0, 128.1, 126.9,

126.8, 126.7, 125.9, 125.0, 21.1. FT-IR (thin ﬁlm, cm⁻¹) 1525, 1423,

1379, 1352, 1290. MS calcd for C₁₅H₁₁ClN₂[M]⁺= 254, found [M +

H]⁺= 255. HRMS calcd for C₁₅H₁₁ClN₂[M + H]⁺= 255.0684, [M +

Na]⁺= 277.0544, found [M + H]⁺= 255.0700, [M + Na]⁺= 277.0544.

Mp = 118−119 °C.

1-Chloro-4-(3-(triﬂuoromethyl)phenyl)phthalazine (1s). Follow-

ing the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-

yl)phthalazine (1b), this compound was prepared using 4-(3-

(triﬂuoromethyl)phenyl)phthalazin-1(2H)-one (0.50 g, 1.7 mmol)

and phosphoryl oxychloride (53 g, 0.35 mol). Similar workup provided

1-Chloro-4-(4-methylthiazol-2-yl)phthalazine (1n). Following the

general procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)-

phthalazine (1b), this compound was prepared using 4-(4-methyl-

thiazol-2-yl)phthalazin-1(2H)-one (2.4 g, 9.9 mmol) and phosphoryl

trichloride (14 mL, 0.15 mol). Similar workup provided a brown solid,

1-chloro-4-(4-methylthiazol-2-yl)phthalazine (2.4 g, 94% yield).

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1

1-chloro-4-(3-(triﬂuoromethyl)phenyl)phthalazine (0.40 g, 75%

yield). H NMR (400 MHz, CDCl₃) δ 8.43−8.41 (d, 1H), 8.08−

room temperature over time. H NMR (400 MHz, CDCl₃) of

the dihydrobenzoazepinedione 15a δ 7.85 (dt, J = 8.4, 1.0 Hz,

1H), 7.59−7.50 (m, 3H), 3.74−3.71 (m, 2H), 2.96−2.93

(m,2H), 2.81 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 202.2,

167.1, 135.6, 133.9, 132.3, 131.4, 129.8, 127.7, 45.1, 44.8, 44.0.

FT-IR (thin ﬁlm, cm⁻¹) 2950, 2887, 1765, 1688, 1650. MS calcd

for C₁₂H₁₄N₂O₂[M]⁺= 218, found [M + H]⁺= 219. HRMS calcd

for C₁₂H₁₄N₂O₂[M + H]⁺= 219.1128, [M + Na]⁺= 241.0948 ,

found [M + H]⁺= 219.1152, [M + Na]⁺= 241.0955.

1

8.04 (m, 1H), 8.01−7.98 (m, 3H), 7.94−7.92 (m, 1H), 7.85−7.83 (m,

1H), 7.71−7.75 (m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 159.2,

155.2, 136.5, 134.0, 133.8, 133.6, 129.6, 127.2, 126.8, 126.6, 126.0,

125.5, 122.8. FT-IR (thin ﬁlm, cm⁻¹) 1380, 1362, 1325, 1309, 1290.

MS calcd for C₁₅H₈ClF₃N₂[M]⁺= 308, found [M + H]⁺= 309.

HRMS calcd for C₁₅H₈ClF₃N₂[M + H]⁺= 309.0401, [M + Na]⁺=

331.0220, found [M + H]⁺= 309.0431, [M + Na]⁺= 331.0248. Mp =

160 °C.

2-(Dimethylamino)-4-methyl-3,4-dihydro-2H-benzo[c]azepine-

1,5-dione (15b). In a dry round-bottom ﬂask were added 2-(dimethyl-

amino)isoindoline-1,3-dione (0.43 g, 2.3 mmol) and THF (3.4 mL).

After purging with argon and cooling to −30 °C, prop-1-en-2-

ylmagnesium bromide (4.1 mL, 2.1 mmol; 0.50 M in THF) was

added. After 15 min, the whole was warmed to rt. After 30 min, the

reaction was quenched slowly with saturated aqueous NH₄Cl. The

product was extracted with DCM. The organic layer was washed with

brine, dried over MgSO₄, ﬁltered, and concentrated to give a yellow

oil. The product was puriﬁed by column chromatography on silica gel

eluting with 50:50 Hex/EtOAc to aﬀord a white solid (80 mg, 17%

1-Chloro-4-(4-chloro-3-methoxyphenyl)phthalazine (1t). Follow-

ing the general procedure to prepare 1-chloro-4-(6-methylpyridin-2-

yl)phthalazine (1b), this compound was prepared using 4-(4-chloro-

3-methoxyphenyl)phthalazin-1(2H)-one (0.53 g, 1.8 mmol) and

phosphoryl trichloride (2.6 mL, 28 mmol). Similar workup provided

a gray solid, 1-chloro-4-(4-chloro-3-methoxyphenyl)phthalazine (0.52

g, 92% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.40 (d, J = 8.1 Hz, 1H),

8.11−7.95 (m, 3H), 7.56 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.23 (d, J =

7.8 Hz, 1H), 3.98 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 159.0,

155.1, 154.4, 134.4, 133.20, 132.18, 129.8, 126.7, 126.4, 126.1, 125.3,

124.4, 122.5, 113.5, 56.0. FT-IR (thin ﬁlm, cm⁻¹) 1577. MS calcd for

C₁₅H₁₀Cl₂N₂O [M]⁺= 304, found [M + H]⁺= 305. HRMS calcd for

C₁₅H₁₀Cl₂N₂O [M + H]⁺= 305.0243, [M + Na]⁺= 327.0062, found

[M + H]⁺= 305.026, [M + Na]⁺= 327.009. Mp = 237−238 °C.

1-Chloro-4-isopropylphthalazine (1u). Following the general

procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine

(1b), this compound was prepared using 4-isopropylphthalazin-

1(2H)-one (0.60 g, 3.2 mmol) and POCl₃(3.6 mL, 38 mmol).

Similar workup provided a light yellow solid, 1-chloro-4-isopropylph-

thalazine (0.57 g, 87% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.13

(d, J = 2.8, 1H), 8.06 (d, J = 2.8, 1H), 7.96−7.92 (m, 1H), 7.86−7.82

(m, 1H), 3.58−3.55 (m, 1H), 1.26 (d, J = 5.8, 6H). ¹³C NMR (101

MHz, DMSO-d₆) δ 153.5, 145.0, 134.1, 133.3, 126.2, 125.1, 124.7,

38.9. 21.9, 21.4. FT-IR (thin ﬁlm, cm⁻¹) 2970, 2931, 2872, 1292. MS

calcd for C₁₁H₁₁ClN₂[M]⁺= 206, found [M + H]⁺= 207. HRMS

calcd for C₁₁H₁₁ClN₂[M + H]⁺= 207.0684, [M + Na]⁺= 229.0503,

found [M + H]⁺= 207.0689, [M + Na]⁺= 229.0487. Mp = 73−74 °C

1-Chloro-4-cyclohexylphthalazine (1v). Following the general

procedure to prepare 1-chloro-4-(6-methylpyridin-2-yl)phthalazine

(1b), this compound was prepared using 4-cyclohexylphthalazin-

1(2H)-one (0.85 g, 3.7 mmol) and POCl₃(10 mL, 0.11 mol). Similar

workup provided a light yellow solid (1.7 g, 96% yield). ¹H NMR (400

MHz, DMSO-d₆) δ 8.49−8.45 (m, 1H), 8.33−8.26 (m, 1H), 8.18−

8.14 (m, 2H), 3.68−3.62 (m, 2H), 2.72−2.68 (m, 1H), 1.96−1.71 (m,

4H), 1.61−1.47 (m, 2H), 1.36−1.29 (m, 2H). ¹³C NMR (101 MHz,

DMSO-d₆) δ 159.2, 149.6, 133.4, 131.2, 128.7, 127.8, 126.1, 124.7,

39.9, 39.1, 38.5, 25.8. FT-IR (neat, cm⁻¹) 2924, 2853, 1600, 997. MS

calcd for C₁₄H₁₅ClN₂[M]⁺= 246, found [M + H]⁺= 247. HRMS

calcd for C₁₄H₁₅ClN₂[M + H]⁺= 247.0997, [M + Na]⁺= 269.0816,

found [M + H]⁺= 247.0996; [M + Na]⁺= 269.0801. Mp = 150−152 °C.

Synthesis of Dihydrobenzoazepinediones. 2-(Dimethylami-

no)-3,4-dihydro-1H-benzo[c]azepine-1,5(2H)-dione (15a) and 2-(Dime-

thylamino)-3-hydroxy-3-vinylisoindolin-1-one (13a). In a dry round-

bottom ﬂask were added 2-(dimethylamino)isoindoline-1,3-

dione (0.48 mg, 2.5 mmol) and THF (11 mL). After purging

with argon and cooling to −78 °C, vinylmagnesium bromide

(2.3 mL, 2.3 mmol; 0.5 M in THF) at 0 °C was added via

a syringe. After 15 min, the whole was warmed to rt. After

30 min, the reaction was quenched slowly with saturated

aqueous NH₄Cl. The product was extracted with DCM. The

organic layer was washed with brine, dried over MgSO₄,

ﬁltered, and concentrated to give a yellow oil. The product was

puriﬁed by column chromatography on silica gel eluting with

70:30 DCM/(90:10:1 DCM/MeOH/NH₄OH) to aﬀord a

white solid. The product was puriﬁed further with RPLC.

Fractions containing the product were combined and washed

with saturated aqueous NaHCO₃. The organic layer was

washed with brine, dried over MgSO₄, ﬁltered, and concen-

trated to aﬀord a light yellow solid. ¹H NMR showed a 3:1 ratio

of 15a:13a (80 mg, 16% yield). This mixture decomposed at

1

yield). H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 7.3 Hz, 1H), 7.59

(t, J = 7.3 Hz, 1H), 7.53 (t, J = 7.3 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H),

3.60 (d, J = 6.8 Hz, 2H), 3.09 (m, 1H), 2.86 (s, 6H), 1.21 (d, J = 7.3

Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 206.5, 167.4, 135.9, 133.4,

132.0, 131.5, 129.5, 127.8, 52.4, 49.7, 43.8, 15.4. 2D-NMR conﬁrmed

the dihydrobenzoazepinedione structure. FT-IR (thin ﬁlm, cm⁻¹)

2948, 2887, 1688, 1653. MS calcd for C₁₃H₁₆N₂O₂[M]⁺= 232, found

[M + H]⁺= 233. HRMS calcd for C₁₃H₁₆N₂O₂[M + H]⁺= 233.1285,

[M + Na]⁺= 255.1104, found [M + H]⁺= 233.1300, [M + Na]⁺=

255.1123. Mp = 59−60 °C.

2-(Dimethylamino)-4-phenyl-3,4-dihydro-1H-benzo[c]azepine-

1,5(2H)-dione (15c). In a dry round-bottom ﬂask were added 1-(1-

bromovinyl)benzene (0.28 mL, 2.2 mmol) and THF (7.3 mL). After

purging with argon and cooling to −78 °C, n-butyllithium (0.92 mL,

2.3 mmol) was added. After 30 min, the anion was cannulated into a

solution of 2-(dimethylamino)isoindoline-1,3-dione (0.46 g, 2.4

mmol) in 10 mL of THF at −30 °C. After 15 min, the whole was

warmed to rt. After 30 min, the reaction was quenched slowly with

saturated aqueous NH₄Cl. The product was extracted with DCM. The

organic layer was washed with brine, dried over MgSO₄, ﬁltered, and

concentrated to give a yellow oil. The product was puriﬁed by column

chromatography on silica gel eluting with 60:40 Hex/EtOAc to aﬀord

a sticky white solid that was puriﬁed further by RPLC to aﬀord a light

yellow sticky solid (240 mg, 37% yield). ¹H NMR (400 MHz, CDCl₃)

δ 7.98 (d, J = 7.6 Hz, 1H), 7.68 (td, J = 7.5, 1.2 Hz, 1H), 7.60 (td, J =

7.3, 1.0 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.34−7.29 (m, 3H), 7.14−

7.12 (m, 2H), 4.31 (dd, J = 12.3, 3,8 Hz, 1H), 4.18 (t, J = 14.7 Hz,

1H), 3.76 (dd, J = 14.7, 3.8 Hz, 1H), 2.91 (s, 6H). ¹³C NMR (101

MHz, CDCl₃) δ 204.0, 167.1, 136.5, 136.3, 133.1, 131.9, 131.7, 129.4,

128.8, 127.8, 127.7, 127.4, 60.5, 52.1, 43.8. 2D-NMR conﬁrmed the

dihydrobenzoazepinedione structure. FT-IR (thin ﬁlm, cm⁻¹) 2951,

2889, 1690, 1653. MS calcd for C₁₈H₁₈N₂O₂[M]⁺= 294, found [M +

H]⁺= 295. HRMS calcd for C₁₈H₁₈N₂O₂[M + H]⁺= 295.1441, [M +

Na]⁺= 317.1261 , found [M + H]⁺= 295.1474, [M + Na]⁺

317.1275.

=

Preparation of Pyrazoles. 2-(5-Phenyl-1H-pyrazol-3-yl)-

benzoic Acid (16a). Conditions A. 2-(Dimethylamino)-3-

hydroxy-3-(2-phenylethynyl)isoindolin-1-one (0.12 g, 4.0 mmol),

ethanol (8.1 mL), and hydrazine (1.9 mL, 61 mmol) were added

into a round-bottom ﬂask equipped with a condenser. The whole

was reﬂuxed under argon. After 5 h, the reaction was cooled to rt

and concentrated under reduced pressure to aﬀord a solid. The

solid was triturated with hexanes and a small amount of ether.

Sonication for 1 h provided an oﬀ-white solid that was ﬁltered oﬀ

with the aid of cold hexanes. The product, 2-(5-phenyl-1H-

pyrazol-3-yl)benzoic acid was obtained as a light yellow solid (0.62 g,

1

58%). H NMR (400 MHz, DMSO-d₆) δ 7.86 (dd, J = 8.3,

1.2 Hz, 2H), 7.72 (dd, J = 7.8, 1.3 Hz, 1H), 7.60 (dd, J = 7.6, 1.5 Hz,

1H), 7.41 (t, J = 7.6 Hz, 2H), 7.36−7.25 (m, 3H), 7.08 (s, 1H).

¹³C NMR (101 MHz, DMSO-d₆) δ 173.7, 149.4, 144.9, 140.2,

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133.6, 129.6, 128.6, 127.8, 127.7, 127.2, 127.1, 126.0, 125.1,

100.9. 2D-NMR conﬁrmed the pyrazole structure. FT-IR (thin

ﬁlm, cm⁻¹) 3361−2962 (br), 1540. MS calcd for C₁₆H₁₂N₂O₂

[M]⁺= 264, found [M + H]⁺= 265. HRMS calcd for C₁₆H₁₂N₂O₂

[M + H]⁺= 265.1972, [M + Na]⁺= 287.0791, found [M + H]⁺=

265.1996, [M + Na]⁺= 287.0807. Mp > 250 °C.

C₁₄H₁₆N₂O₂[M + H]⁺= 245.1285, found [M + H]⁺= 245.1283.

Mp > 250 °C.

N′,N′-Dimethyl-2-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-

benzohydrazide (17a). Conditions C. 2-(Dimethylamino)-3-hydroxy-

3-(phenylethynyl)isoindolin-1-one (80 mg, 0.27 mmol), THF

(0.27 mL), and methylhydrazine (73 μL, 1.4 mmol) were added

into a sealed tube. The tube was sealed and heated to 80 °C. After 16

h, LC−MS showed the hydrazide product. The whole was

concentrated. The product was puriﬁed by performing column

chromatography eluting with 70:30 DCM/(90:10:1 DCM/MeOH/

NH₄OH). The product was puriﬁed further by RPLC. Fractions

containing the product were combined and concentrated. The water

residue was passed through a 5-g SCX column with the aid of MeOH.

The product was eluted with a solution of 2 M NH₃in methanol. The

ﬁltrate was concentrated to aﬀord N′,N′-dimethyl-2-(1-methyl-5-

phenyl-1H-pyrazol-3-yl)benzohydrazide as an oﬀ-white solid (55 mg,

63% yield). LC−MS conﬁrmed product. HPLC showed 96% pure,

23:1 ratio of major:minor isomer. 1H NMR in CDCl₃conﬁrmed the

2-(5-Phenyl-1H-pyrazol-3-yl)benzoic Acid Hydrochloride

(16a·HCl). Conditions B. 2-(Dimethylamino)-3-hydroxy-3-(2-

phenylethynyl)isoindolin-1-one (40 mg, 0.14 mmol), THF

(0.27 mL), and hydrazine (14 μL, 0.41 mmol) were added into a

sealed tube. After stirring at rt for 16 h, LC−MS showed a complete

conversion to the pyrazole carboxylic acid. The whole was diluted with

1 mL of water and acidiﬁed dropwise with 2 N aqueous HCl to pH =

1. White solid precipitated out of the solution and collected by

ﬁltration with the aid of water to aﬀord 2-(5-phenyl-1H-pyrazol-3-yl)-

1

benzoic acid hydrochloride (27 mg, 66% yield). H NMR (400 MHz,

DMSO-d₆) δ 13.0 (br s, 2H), 7.78 (distorted d, J = 7.3 Hz, 2H),

7.70−7.50 (m, 3H), 7.45 (distorted t, J = 7.8 Hz, 3H), 7.34 (distorted

t, J = 7.2 Hz, 1H), 6.85 (br s, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ

169.8, 130.9, 130.4, 129.4, 128.9, 128.6, 127.8, 125.0, 124.8, 101.7.

All 14 carbons were not accounted for because peaks appeared broad.

FT-IR (thin ﬁlm, cm⁻¹) 3500−2500 (br), 1548. MS calcd for C₁₆H₁₂-

N₂O₂[M]⁺= 264, found [M + H]⁺= 265. HRMS calcd for C₁₆H₁₂N₂-

O₂[M + H]⁺= 265.0972, found [M + H]⁺= 265.1004. Mp > 250 °C.

In order to conﬁrm both the products from the original and

modiﬁed conditions were the same, both samples were subjected to

LC−NMR using D₂O/CAN buﬀer as an eluent. Both spectra were the

same; therefore, both samples were in diﬀerent forms. The conditions

B utilized aqueous HCl in the workup, and two hydrogens were

detected in the carboxylic region (12−14 ppm). Therefore, conditions

B yielded the product as the HCl salt.

1

product. H NMR (400 MHz, CDCl₃) δ 7.67−7.62 (m, 2H), 7.50−

7.38 (m, 8H), 6.55 (s, 1H), 3.95 (s, 3H), 2.59 (s, 6H). ¹³C NMR (101

MHz, CDCl₃) δ 167.7, 149.2, 144.8, 131.2, 130.14, 130.05, 129.3,

128.8, 128.74, 128.72, 128.67, 128.63, 127.9, 106.4, 47.2, 37.6. 2D

NMRs conﬁrmed the pyrazole structure. FT-IR (thin ﬁlm, cm⁻¹) 3201

(br), 2951, 1658. MS calcd for C₁₉H₂₀N₄O [M]⁺= 320, found [M +

H]⁺= 321. HRMS calcd for C₁₉H₂₀N₄O [M + H]⁺= 321.1710, found

[M + H]⁺= 321.1707. Mp = 44−45 °C.

2-(5-(3-Hydroxyphenyl)-1-methyl-1H-pyrazol-3-yl)-N′,N′-dime-

thylbenzohydrazide (17b). Following conditions C using 2-

(dimethylamino)-3-hydroxy-3-((3-hydroxyphenyl)ethynyl)isoindolin-

1-one (80 mg, 0.26 mmol), THF (0.26 mL), and methylhydrazine

(69 μL, 1.3 mmol), 2-(5-(3-hydroxyphenyl)-1-methyl-1H-pyrazol-3-yl)-

N′,N′-dimethylbenzohydrazide was obtained as an oﬀ-white solid (44

mg, 50% yield). HPLC showed a 13:1 ratio of major:minor isomer. ¹H

NMR (400 MHz, CDCl₃) δ 7.67−7.57 (m, 2H), 7.45 (td, J = 7.7, 1.5 Hz,

1H), 7.37 (td, J = 7.5, 1.3 Hz, 1H), 7.25−7.23 (m, 1H), 6.91−6.80

(m, 4H), 6.41 (s, 1H), 3.83 (s, 3H), 2.54 (s, 6H). ¹³C NMR

(101 MHz, CDCl₃) δ 168.5, 157.0, 148.8, 144.9, 133.8, 131.2, 131.0,

130.2, 129.8, 129.2, 128.6, 127.9, 119.9, 116.2, 115.8, 106.0, 47.1, 37.5. FT-

IR (thin ﬁlm, cm⁻¹) 300−2700 (br), 1643, 1584. MS calcd for C₁₉H₂₀-

N₄O₂[M]⁺= 336, found [M + H]⁺= 337. HRMS calcd for C₁₉H₂₀N₄-

O₂[M + H]⁺= 337.1659, found [M + H]⁺= 337.1657. Mp = 89−90 °C.

2-(5-Butyl-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydra-

zide (17c). Following conditions C using 2-(dimethylamino)-3-(hex-1-

ynyl)-3-hydroxyisoindolin-1-one (80 mg, 0.29 mmol), THF

(0.29 mL), and methylhydrazine (78 μL, 1.5 mmol), 2-(5-butyl-1-

methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide was obtained

as an oﬀ-white solid (50 mg, 57% yield). ¹H NMR (400 MHz, CDCl₃)

δ 7.59 (td, J = 7.7, 0.9 Hz, 2H), 7.43 (td, J = 7.6, 1.4 Hz, 1H), 7.36 (td,

J = 7.5, 1.4 Hz, 1H), 6.74 (br s, 1H), 6.24 (s, 1H), 3.83 (s, 3H), 2.61

(distorted t, J = 7.5 Hz, 1H), 2.54 (s, 6H), 1.66 (m, 3H), 1.44 (sex, J =

7.5 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ

167.7, 148.7, 144.3, 134.2, 131.6, 129.9, 129.2, 128.7, 127.7, 104.8,

47.2, 36.2, 30.6, 25.3, 22.4, 13.8. 2D-NMR conﬁrmed the pyrazole

structure. FT-IR (thin ﬁlm, cm⁻¹) 3209 (br), 2955, 2869, 1664, 1546.

MS calcd for C₁₇H₂₄N₄O [M]⁺= 300, found [M + H]⁺= 301. Calcd

for C₁₇H₂₄N₄O [M + H]⁺= 301.2023, found [M + H]⁺= 301.2021.

Mp = 130−131 °C.

2-(5-Butyl-1H-pyrazol-3-yl)benzoic Acid Hydrochloride (16b).

Following conditions B using 2-(dimethylamino)-3-(hex-1-ynyl)-3-

hydroxyisoindolin-1-one (60 mg, 0.22 mmol), anhydrous hydrazine

(21 μL, 0.66 mmol), and THF (0.44 mL), 2-(5-butyl-1H-pyrazol-3-

yl)benzoic acid hydrochloride was isolated as a yellow solid (42 mg,

1

68% yield). H NMR (400 MHz, DMSO-d₆) δ 12.68 (br s, 2H), 7.60

(d, J = 7.7 Hz, 1H), 7.52−7.46 (m, 2H), 7.37 (td, J = 7.4, 1.2 Hz, 1H),

6.21 (s, 1H), 2.60 (t, J = 7.5 Hz, 2H), 1.59 (quin, J = 7.7 Hz, 2H), 1.35

(sex, J = 7.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). ¹³C NMR (101 MHz,

DMSO-d₆) δ 170.4, 147.8, 145.2, 132.7, 131.5, 129.9, 128.7, 128.0,

127.0, 102.2, 30.9, 25.0, 21.7, 12.6. FT-IR (thin ﬁlm, cm⁻¹) 3500−

2500 (br), 3056, 2930, 1695. MS calcd for C₁₄H₁₆N₂O₂[M]⁺= 244,

found [M + H]⁺= 245. HRMS calcd for C₁₄H₁₆N₂O₂[M + H]⁺=

245.1285, [M + Na]⁺= 267.1104 , found [M + H]⁺= 245.1300, [M +

Na]⁺= 267.1123.

2-(5-Butyl-1H-pyrazol-3-yl)benzoic Acid Hydrochloride (16c).

Following conditions B using 3-(2-cyclopropylethynyl)-2-(dimethyla-

mino)-3-hydroxyisoindolin-1-one (60 mg, 0.23 mmol), anhydrous

hydrazine (22 μL, 0.70 mmol), and THF (0.47 mL), 2-(5-cyclopropyl-

1H-pyrazol-3-yl)benzoic acid hydrochloride was isolated as a yellow

solid (40 mg, 65% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (br

s, 2H), 7.58−7.46 (m, 3H), 7.37 (td, J = 7.4, 1.2 Hz, 1H), 6.11 (s, 1H),

1.93−1.89 (m, 1H), 0.94−0.90 (m, 2H), 0.71−0.67 (m, 2H). ¹³C

NMR (101 MHz, DMSO-d₆) δ 168.4, 149.8, 146.6, 132.0, 131.1,

130.2, 129.4, 129.1, 128.8, 102.0, 8.78, 6.94. FT-IR (thin ﬁlm, cm⁻¹)

3500−2500 (br), 1696. MS calcd for C₁₃H₁₂N₂O₂[M]⁺= 228, found

[M + H]⁺= 229. HRMS calcd for C₁₃H₁₂N₂O₂[M + H]⁺= 229.0972,

found [M + H]⁺= 229.0973. Mp > 250 °C.

2-(5-Cyclopropyl-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylben-

zohydrazide (17d). Following conditions C using 3-(cyclopropyle-

thynyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (80 mg,

0.31 mmol), THF (0.31 mL), and methylhydrazine (83 μL, 1.6 mmol),

2-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohy-

2-(5-tert-Butyl-1H-pyrazol-3-yl)benzoic Acid Hydrochloride (16d).

Following conditions B using 2-(dimethylamino)-3-(3,3-dimethylbut-

1-ynyl)-3-hydroxyisoindolin-1-one (60 mg, 0.22 mmol), anhydrous

hydrazine (28 μL, 0.66 mmol), and THF (0.44 mL), 2-(5-tert-butyl-

1H-pyrazol-3-yl)benzoic acid hydrochloride was obtained as a light

1

drazide was obtained as a light yellow solid (34 mg, 38%). H NMR

(400 MHz, CDCl₃) δ 7.62 (dd, J = 7.7, 1.2 Hz, 1H), 7.56 (dd, J = 7.7,

0.9 Hz, 1H), 7.43 (td, J = 7.7, 1.5 Hz, 1H), 7.36 (td, J = 7.4 1.2 Hz,

1H), 6.05 (s, 1H), 3.96 (s, 3H), 2.58 (s, 6H), 1.76−1.72 (m, 1H),

1.02−0.99 (m, 2H), 0.72−0.69 (m, 2H). ¹³C NMR (101 MHz,

CDCl₃) δ 167.7, 148.6, 146.3, 134.0, 131.5, 130.0, 129.3, 128.8, 127.8,

103.1, 47.0, 36.4, 6.8, 6.1. FT-IR (thin ﬁlm, cm⁻¹) 3208 (br), 2952, 1659,

1555. MS calcd for C₁₆H₂₀N₄O [M]⁺= 284, found [M + H]⁺= 285.

1

yellow solid (41 mg, 66% yield). H NMR (400 MHz, DMSO-d₆) δ

12.71 (br s, 2H), 7.52−7.46 (m, 2H), 7.36 (td, J = 7.6, 1.1 Hz, 1H),

6.24 (s, 1H), 1.29 (s, 9H). ¹³C NMR (101 MHz, DMSO-d₆) δ 170.4,

154.3, 147.3, 132.7, 131.5, 129.8, 128.6, 127.9, 127.0, 99.9, 30.7, 30.1.

FT-IR (thin ﬁlm, cm⁻¹) 3500−2500 (br), 2962, 1695. MS calcd for

C₁₄H₁₆N₂O₂[M]⁺= 244, found [M + H]⁺= 245. HRMS calcd for

3904

dx.doi.org/10.1021/jo3000628 | J. Org. Chem. 2012, 77, 3887−3906

The Journal of Organic Chemistry

Article

HRMS calcd for C₁₆H₂₀N₄O [M + H]⁺= 285.1710, found [M + H]⁺=

285.1710. Mp = 132−133 °C.

AUTHOR INFORMATION

■

Corresponding Author

*Corresponding author. Tel.: +1 617 444 5254; fax: +1 617

577 9822; e-mail: hanhn@amgen.com.

2-(5-tert-Butyl-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzo-

hydrazide (17e). Following conditions C using 2-(dimethylamino)-3-

(3,3-dimethylbut-1-ynyl)-3-hydroxyisoindolin-1-one (80 mg,

0.29 mmol), THF (0.29 mL), and methylhydrazine (78 μL, 1.5 mmol),

2-(5-tert-butyl-1-methyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydra-

Present Addresses

^∥Blueprint Medicines, 215 First Street, Cambridge, MA 02142.

^⊥University of California, San Francisco, CA 94143.

^#Sanoﬁ-Aventis, Cambridge, MA 02139.

1

zide was obtained as an oﬀ-white solid (14 mg, 16% yield). H NMR

(400 MHz, CDCl₃) δ 7.60 (dd, J = 5.6, 1.1 Hz, 1H), 7.54 (dd, J = 6.8,

1.5 Hz, 1H), 7.42 (td, J = 7.6, 1.5 Hz, 1H), 7.35 (td, J = 7.5, 1.3 Hz,

1H), 6.71 (br s, 1H), 6.21 (s, 1H), 4.01 (s, 3H), 2.51 (s, 6H), 1.39 (s,

9H). ¹³C NMR (101 MHz, CDCl₃) δ 167.6, 152.1, 148.0, 134,2, 131.5,

129.9, 129.3, 128.8, 127.7, 104.3, 47.2, 39.4, 31.2, 29.6. 2D-NMR

conﬁrmed the pyrazole structure. FT-IR (thin ﬁlm, cm⁻¹) 3180 (br),

2959, 2215, 1652, 1600. MS calcd for C₁₇H₂₄N₄O [M]⁺= 300, found

[M + H]⁺= 301. HRMS calcd for C₁₇H₂₄N₄O [M + H]⁺= 301.2023,

found [M + H]⁺= 301.2015. Mp = 156−157 °C.

2-(1-Butyl-5-phenyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydra-

zide (17f). Following conditions C using 2-(dimethylamino)-3-hydroxy-

3-(phenylethynyl)isoindolin-1-one (80 mg, 0.27 mmol), THF (0.27 mL),

and butylhydrazine (0.12 g, 1.4 mmol), 2-(1-butyl-5-phenyl-1H-pyrazol-3-

yl)-N′,N′-dimethylbenzohydrazide was obtained as a viscous colorless oil

(76 mg, 77% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.68−7.63 (m, 2H),

7.49−7.38 (m, 8H), 6.50 (s, 1H), 4.18 (t, J = 7.5 Hz, 2H), 2.60 (s, 6H),

1.84 (quin, J = 7.7 Hz, 2H), 1.27 (sex, J = 7.6 Hz, 2H), 0.86 (t, J = 7.4 Hz,

3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.7, 149.2, 144.7, 131.5, 130.5,

130.1, 129.4, 128.9, 128.79, 128.77, 128.69, 128.6, 127.9, 106.5, 49.5, 47.2,

32.7, 19.8, 13.6. FT-IR (thin ﬁlm, cm⁻¹) 3197 (br), 3038, 2955, 2871,

1652, 1600. MS calcd for C₂₂H₂₆N₄O [M]⁺= 362, found [M + H]⁺=

363. HRMS calcd for C₂₂H₂₆N₄O [M + H]⁺= 363.2179, found [M +

H]⁺= 363.2180.

2-(5-Cyclopropyl-1-isobutyl-1H-pyrazol-3-yl)-N′,N′-dimethylben-

zohydrazide (17g). Following conditions A using 3-(2-cyclopropyle-

thynyl)-2-(dimethylamino)-3-hydroxyisoindolin-1-one (0.30 g,

1.2 mmol), EtOH (2.34 mL), and 1-isobutylhydrazine (0.52 g,

5.9 mmol), 2-(5-cyclopropyl-1-isobutyl-1H-pyrazol-3-yl)-N′,N′-dimethyl-

benzohydrazide was obtained as a white solid (0.24 g, 63% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.57−7.55 (m, 2H), 7.41 (td, J = 7.4,

1.4 Hz, 1H), 7.33 (td, J = 7.7, 1.2 Hz, 1H), 6.56 (br s, 1H), 6.00 (s,

1H), 4.01 (d, J = 7.5 Hz, 2H), 2.49 (s, 6H), 2.39−2.31 (sep, 1H),

1.75−1.68 (m, 1H), 0.99−0.94 (m, 8H), 0.69−0.65 (m, 2H). ¹³C

NMR (101 MHz, CDCl₃) δ 167.7, 148.6, 146.3, 134.2, 131.8, 129.9,

129.4, 128.7, 127.8, 102.6, 56.5, 47.2, 29.7, 20.2, 7.41, 6.35. FT-IR

(thin ﬁlm, cm⁻¹) 3205, 2958, 2871, 1660, 1550. MS calcd for

C₁₉H₂₆N₄O [M]⁺=326, found [M + H]⁺= 327. HRMS calcd

for C₁₉H₂₆N₄O [M + H]⁺= 327.2179, [M + Na]⁺= 349.1999, found

[M + H]⁺= 327.2209, [M + Na]⁺= 349.2004. Mp = 126−127 °C.

Following conditions C using 3-(cyclopropylethynyl)-2-(dimethy-

lamino)-3-hydroxyisoindolin-1-one (80 mg, 0.31 mmol), THF (0.31 mL),

and isobutylhydrazine (0.14 mg, 1.6 mmol), 2-(5-cyclopropyl-1-

isobutyl-1H-pyrazol-3-yl)-N′,N′-dimethylbenzohydrazide was obtained

as a white solid (102 mg, 100% yield). ¹H NMR (400 MHz, CDCl₃) δ

7.58 (m, 2H), 7.43 (td, J = 7.5, 1.4 Hz, 1H), 7.37 (td, J = 7.5, 1.3 Hz,

1H), 6.02 (s, 1H), 4.02 (d, J = 7.6 Hz, 2H), 2.53 (s, 6H), 2.37 (sep,

1H), 1.77−1.70 (m, 1H), 1.01−0.97 (m, 8H), 0.71−0.69 (m, 2H). ¹³C

NMR (101 MHz, CDCl₃) δ 167.7, 148.6, 146.3, 134.1, 131.7, 130.0,

129.4, 128.7, 127.7, 102.6, 56.4, 47.1, 29.6, 20.1, 7.4, 6.3. 2D-NMR

conﬁrmed the pyrazole structure. FT-IR (thin ﬁlm, cm⁻¹) 3208, 2957,

2871, 1657, 1600. MS calcd for C₁₉H₂₆N₄O [M]⁺= 326, found [M +

H]⁺= 327. HRMS calcd for C₁₉H₂₆N₄O [M + H]⁺= 327.2179, found

[M + H]⁺= 327.2177. Mp = 122−123 °C.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We would like to thank Cary Fridrich, Kritti Modi, and Dr. Jay

Larrow for the synthesis of 2-(dimethylamino)isoindoline-1,3-

dione; Matt Potter and Larry Miller for the puriﬁcation; Dr.

Richard J. Staples for the crystallography; and Dr. Margaret Y.

Chu-Moyer for proofreading this manuscript.

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Article Doi

Synthesis of 4-substituted chlorophthalazines, dihydrobenzoazepinediones, 2-pyrazolylbenzoic acid, and 2-pyrazolylbenzohydrazide via 3-substituted 3-hydroxyisoindolin-1-ones

DOI: 10.1021/jo3000628

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